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Table of Contents
Year : 2019  |  Volume : 2  |  Issue : 1  |  Page : 30-74

Papers Abstracts

Date of Web Publication3-Jun-2019

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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/2590-2652.259561

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How to cite this article:
. Papers Abstracts. Int J Neurooncol 2019;2:30-74

How to cite this URL:
. Papers Abstracts. Int J Neurooncol [serial online] 2019 [cited 2019 Jun 20];2:30-74. Available from: http://www.Internationaljneurooncology.com/text.asp?2019/2/1/30/259561

  Papers Abstracts Top

“What happens after therapy? Quality of life and neurocognitive functions of children with malignant posterior fossa tumors after adjuvant therapy”

Ujjwal Yeole; NIMHANS, Bengaluru, Karnataka, India

Introduction: Health-related quality of life (HRQoL) is an important endpoint in modern clinical practice with improved survival of pediatric posterior fossa malignant brain tumors. We attempt to see the effect of environmental and psychosocial milieu on QoL and cognitive functioning (CF) of Indian children in terms of QoL, getting back to school, and daily social activities following treatment completion.

Materials and Methods: In a cross-sectional study, 47 children <18 years of age with medulloblastoma or anaplastic ependymoma were evaluated ≥6 months after completion of adjuvant therapy. All clinical and treatment details, educational status of child and family members, socioeconomic status, and environmental factors affecting QoL were documented. Children underwent HRQoL and CF evaluation using pediatric quality of life inventory (PedsQL) questionnaire.

Results: The median age of cohort at presentation was 7 years (1–18) and median duration of evaluation after adjuvant therapy was 16 months (±26.64). In 47 families, 72.34% had monthly income <20,000 INR and 76.60% of mothers took formal education. As per the PedsQL, QoL scores were above median values. Twenty-seven children had below average IQ. Young age at presentation (P = 0.020), maternal education (P = 0.032), high socioeconomic status (P = 0.001) influenced IQ score.

Conclusion: Overall cognitive functioning scores of these children are good, but they are not representative of actual neurocognitive task-based performance or IQ scores. Children should remain under regular follow-up with neurocognitive assessment and psychological counseling at regular intervals. Longitudinal evaluation with larger sample sizes will help modify existing treatment and formulate newer interventions for rehabilitation.

Spectrum of clinical features and management strategies of intracranial germ cell tumors: Experience from a tertiary center

Borde Tushar Deepak; Dr. DY Patil Medical College Hospital and Research Centre, Pimpri, Pune, Maharashtra, India

Introduction: Central nervous system (CNS) germ cell tumors (GCTs) represent about 3% of primary pediatric brain tumors in the West and 8%–15% in Asia. Clinical presentation varies with site of occurrence. Treatment and prognosis differ greatly between histopathological groups. The clinicopathological data regarding the CNS GCTs and their proportion among all brain tumors in the Indian population are inadequate. Our study reviews the clinicopathological spectrum and management strategies of these tumors in an Indian cohort.

Aims and Objectives:

  1. To analyze the hospital-based incidence of CNS GCTs
  2. To identify the spectrum of pathologies encountered and to correlate them with clinicoradiological features
  3. To study the various management strategies and prognosis.

Materials and Methods: This retrospective study included patients with proven diagnosis of intracranial GCTs managed at NIMHANS from January 1998 to December 2013. The histopathology slides were reviewed by a neuropathologist and the diagnosis was confirmed. The demography, pre- and post-operative hormonal status, clinical presentation, ophthalmological examination, radiology, and treatment modalities were analyzed.

Results: A total of 48 patients (36 males and 12 females) with CNS GCTs were managed during the study period with a proportion of 0.29%. The mean age was 16.5 years (2–35 years). Maximum GCTs (43.7%) were observed in the second decade. Germinomas accounted for 56.3% of all tumors. Mixed GCT was the most common histology among non-GCT (NGCT). Tumors occurred predominantly in the pediatric age group (58%). Posterior third ventricle was the most common location (58.3%). Metastasis was infrequent (10.5%) with testes being the most common primary site. Raised intracranial pressure (ICP) was the most common presentation followed by visual disturbances. Endocrine disturbances were encountered less frequently (6.3%). Both germinomas and NGCTs were well defined on imaging with intense contrast enhancement. Calcifications were frequent in NGCTS (57.1%). Hydrocephalus was a common finding in both groups (80%–85%). Intratumoral bleed was more common in germinomas. Serum AFP levels were elevated in 95% of germinomas. Cerebrospinal fluid (CSF) diversion was performed in 72% of patients (ventriculoperitoneal shunt more common than endoscopic third ventriculostomy). Definitive surgery was the predominant mode of tissue biopsy. Poppen’s approach was the most common procedure for posterior third ventricular tumors (72.2%). Suprasellar tumors were resected using transylvian and subfrontal approaches. Most tumors underwent subtotal resection (85.7% germinoma and 77.7% NGCT). Follow-up was available in 75% of patients with a period ranging from 1 month to 11 years. 64% and 33% of patients received adjuvant radiotherapy (45 Gy tumor bed and 30 Gy craniospinal irradiation) and chemotherapy, respectively. All recurrences were seen in NGCTS. The mean overall survival of the cohort was 110 months. (pediatric 107.4 months and adults 75.5 months). Overall survival in germinomas and NGCTs was 60 and 70 months, respectively. Survival was better in males and those receiving adjuvant radiotherapy.

Conclusion: The incidence of GCTs in our study was 0.29% (much less compared to the oriental population). Tumors were common at a younger age, and posterior third ventricle was the most common site. Germinomas were frequent and majority of patients presented with hydrocephalus needing CSF diversion. Surgical approach was guided by location, and adjuvant therapy was offered according to histology. Gender and adjuvant radiotherapy significantly affected survival whereas the association between survival and age and tumor location. Although the mean overall survival was low in germinomas as compared to NGCTs, this value was not statistically significant. A multidisciplinary approach with a treatment protocol tailored according to clinicopathological characteristics of CNS GCTs needs to be developed for the Indian population.

Keywords: Central nervous system germ cell tumors, cerebrospinal fluid diversion, Poppen’s approach germinoma, nongerm cell tumors, posterior third ventricle

Contralateral approach to diaphragma sellae meningiomas: Does it result in better visual outcome?

Nupur Pruthi; NIMHANS, Bengaluru, Karnataka, India

Aims and Objectives: Diaphragma sellae meningiomas are the second most common tumors in the suprasellar region. The removal of these tumors is usually performed through ipsilateral transcranial approaches. We provide our experience with the contralateral approach. We believe that it results in a better visual outcome.

Materials and Methods: This is a retrospective review of six patients with diaphragma sellae meningiomas. All of them had asymmetrical visual loss. Transcranial surgery was done from the side of better vision. Follow-up duration ranged from 6 months to 3 years.

Results/Discussion: All the patients demonstrated stabilization or improvement of vision, even in the more involved eye. No deterioration of vision in the lesser involved eye was observed. Gross total removal was achieved in four cases. This approach allowed a better view of the undersurface of the more involved optic nerve, which is usually a blind area in ipsilateral approaches. There was minimal handling of the more compromised nerve as compared with the ipsilateral approach.

Conclusion: The contralateral approach is safe and allows less invasive decompression of the optic nerves, especially the one which is more compromised.

Keywords: Contralateral approach, diaphragma sella meningiomas, ipsilateral approach, visual outcome

Risk stratification in low-grade glioma (Rule of Five)

Vikrant Keshri; Krishna Institute of Medical Sciences, KIMS Hospitals, Secunderabad, Telangana, India

Objectives: There is ethnic and genetic variation in cancer risk. Hence, we studied risk factors to prognosticate long-term outcome in low-grade glioma (LGG) in our population to validate or differ from preexisting risk criteria developed by EORTC and UCSF.

Methods: We observed 130 supratentorial LGG patients undergoing surgery, classified based on the WHO 2016 Classification with the integration of molecular markers. Prognostic factors were assessed for their effect on the outcome.

Results: The mean age of the patients studied was 37.67 years and 70% were males. Twenty-four patients were in the age group >50 years. Sixty-four patients had tumor size of more than 5 cm. 72.3% of patients underwent GTR, 23.3% of patients underwent STR, and 3.8% of patients underwent biopsy only. 40.8% of patients had oligodendroglioma, 38.8% astrocytoma, 19.2% oligoastrocytoma, and 2.3% gemistocytic astrocytoma based on morphology. 27% of patients had higher MIB1 index (>5%). The mean progression-free survival and overall survival (PFS and OS) were 4.7 and 4.9 years, respectively. Recurrence occurred in nine patients and death in six patients. Five-year PFS and OS rates were 81.3% and 92.3%, respectively. Mean survival of patients with Karnofsky’s performance scale (KPS) score <50 and >50 was 1.5 and 4.9 years, respectively.

Conclusion: Based on multivariate analysis of various prognostic factors, we further propose to use following five factors as “Rule of 5” to describe the prognosis and tumor recurrence in Indian population: (1) Age >50 years, (2) tumor size >5 cm, (3) MIB index >5%, (4) KPS score <70, and (5) gemistocytic pathology. Molecular markers were not included in risk criteria as long long-term follow-up is not available currently.

Keywords: Karnofsky’s performance scale score, low-grade glioma, MIB index, risk scoring, survival

Real-time neuronavigation using the anesthetic SonoSite™ probe: Our experience

Sudha Ram; Sri Ramachandra Institute of Higher Education and Research, Chennai, Tamil Nadu, India

Introduction: Intraoperative three-dimensional (3-D) ultrasound with neuronavigation in cranial tumor surgeries has been recognized as the closest solution to brain shift that occurs following craniotomy and provided updated more accurate information regarding the location and extent of tumor resection. For centers yet to acquire such costly 3-D ultrasound/neuronavigation system, we report our experience with the readily available, anesthetist’s SonoSite™ probe for cranial and spinal surgeries.

Materials and Methods: S-ICU ultrasound system (SonoSite™, Inc., Fujifilm) machine in B scan mode with curvilinear probe of bandwidth 6 MHz is being used at our center as real-time adjuncts for cranial and spinal tumor resection. We describe the clinical presentation, intraoperative findings, and outcomes in patients undergoing cranial and spinal surgery for tumor resection using the SonoSite™ probe between 2017 and 2018.

Results/Discussion: Intraoperative ultrasound (IOUS) with SonoSite™ probe helped us in lesion localization, reduce need for large corticectomy, so that eloquent areas are not breached, and reduce the extent of durotomy and localizing the poles of spinal lesions. Gross total excision was achieved in eight of nine cases.

Conclusion: IOUS is an effective way to localize and to assist with the real monitoring of the surgical field for the improvement of resectability and reduction of the risk of parenchymal injury. SonoSite probe is readily available in almost all centers, requires little training, and is cheaper compared to bespoke systems.

Keywords: Intraoperative ultrasound, neuronavigation, SonoSite™

Acknowledgment/Disclosure: We thank the Department of Anesthesia for availing us with their SonoSite™ probe ultrasound for our surgical procedures. The article is being considered for publication.

The artery of Bernasconi and Cassinari: A morphometric study for superselective catheterization facilitating embolization of complex brain tumors

Anirban Deep Banerjee; Institute of Neurosciences, Medanta-The Medicity, Gurgaon, Haryana, India

Aims and Objectives: The artery of Bernasconi and Cassinari is an important infraclinoid branch of the internal cerebral artery. It is of neuroendovascular relevance in view of its supply to complex brain tumors such as meningiomas in the tentorial and Falco-tentorial regions. The present microanatomic study attempts a morphometric elucidation of this slender but important branch of the meningohypophyseal trunk so as to enhance the efficacy of presurgical embolization of these lesions.

Materials and Methods: The origin, course, dimensions, and related variations of the tentorial artery were studied in 10 formalin-fixed human cadaveric sides.

Results: The tentorial artery originated from the meningohypophyseal trunk in all but one specimen, in which it arose directly from the intracavernous internal carotid artery. In 80% of specimens, it took origin as a single branch; as a bifurcation and trifurcation in one each. It was usually the terminal branch of the meningohypophyseal trunk (in 90%). In all, five distinct microvascular patterns were noted. The mean diameter of this artery was 0.7 mm (range, 0.3–0.8 mm; standard deviation [SD] ±0.1 mm). The mean length was 15.4 mm (range, 9–23 mm; SD ±4.4 mm). Its mean distance from the origin of the meningohypophyseal trunk was 1.7 mm (range, 1.3–2.3 mm; SD ±0.4 mm). The mean distance from the free edge of the tentorium was 3.7 mm (range, 3–5 mm; SD ±0.7 mm).

Conclusions: The artery of Bernasconi and Cassinari is an important vascular conduit to myriad neoplasms in the vicinity of the tentorium cerebelli. In this era of advanced microneurosurgical techniques and superselective endovascular interventions, morphometric knowledge of this artery is important for precise and safe embolization and subsequent further management of these lesions.

Keywords: Artery of Bernasconi and Cassinari, complex brain tumors embolization, superselective

Comparison of outcome of adult versus pediatric patients following surgery for craniopharyngioma

P Arun Prasad

Objective: To study and compare the visual, endocrinological, neurological, neuropsychological, and functional outcome following surgery for craniopharyngioma among children (5–16 years) and adults (>16 years).

Study Design: This is an institutional-based prospective and retrospective cohort study.

Study Area: The study was conducted at Narayana Institute of Neurosciences.

Study Population: Patients operated for craniopharyngioma from 2010 to 2017 (14 children and 11 adults) were included in the study.

Tools Preprocedure Evaluation: Clinical evaluation hormonal evaluation (TSH, FSH, LH, GH, 8 am Serum Cortisol) Imaging– MRI brain Plain and contrast, CT Brain plain Visual acuity using Snellen’s chart and visual field using perimetry Neuropsychological evaluation-NIMHANS Battery. Both prospective and retrospective patients were followed periodically with same as above. Functional outcome using SF 36 questionnaire for adults, Modified Blooms index and Kid screen 10 questionnaires for children.

Results and Discussion: There was bimodal age distribution with male preponderance in the adult population. Headache and visual disturbances were the most common presenting symptoms in both pediatric and adult group. We found that vomiting and endocrinological disturbances were more commonly found in children as compared to adults. Polyuria was an uncommon symptom, and those presenting with the same had normal serum sodium value due to intact thirst mechanism. Growth hormone deficiency is common in craniopharyngioma, especially children. Hypothyroidism was more common in our study population as compared to other studies. Calcification is more common in craniopharyngioma in pediatric population. Craniopharyngiomas are predominantly mixed cystic-solid lesion as compared to being cystic. Adamantinomas are more common in children while papillary occurs more commonly in adults. For pediatric patients, a preoperative grading system has been proposed according to the degree of hypothalamic involvement. Similar studies in adults are lacking.

Nevertheless, it appears reasonable to follow these recommendations established in pediatric patients. The recognition of hypothalamic involvement as the main factor associated with morbidity led many groups to develop treatment strategies to avoid hypothalamic injury. Craniopharyngioma not involving the hypothalamus (type 0 preoperative), total resection is suitable; when the tumor compresses the hypothalamus (type 1 preoperative), total resection may still be the best solution. Tumor involving the hypothalamus (type 2 preoperative), subtotal resection with respect to the involved hypothalamus combined with local irradiation currently appears to be the better option. Majority of the patients underwent transcranial surgery with three cases preceded by endoscopic cyst fenestration. Sole endoscopic approach decompression was done only in few adult patients. All pediatric grade 1 lesions underwent complete excision, but only in 33% of adult grade 1 lesion total excision was possible due to proximity and adherence to important neurovascular structures. The risk of progression following incomplete resection alone is 71%–90% whereas it is estimated to be in the order of 15%–20% when followed by radiotherapy. Grade 2 lesion underwent subtotal excision followed by radiotherapy. In children, 34% of grade 2 patients with subtotal excision had disease progression despite receiving radiotherapy and subsequently had to undergo repeat surgery. Patients operated transnasal endoscopically had subtotal excision and 50% of them required subsequent transcranial surgery despite receiving radiotherapy. There was disease progression in the one patient who underwent transcranial and endoscopic cyst fenestration approach in single setting but not leading to re-exploration. In our study, transcranial total excision has the best outcome with no disease progression at 3-year follow-up. Fifteen patients with subtotal excision underwent radiation out of which disease progression was observed only in six. Our data on the effect of radiotherapy are not significant but are similar to previous studies supporting the role of radiotherapy after subtotal excision. We found that visual outcome (visual acuity, visual field) either improved or remained the same post-surgery in both adults and children with no significant statistical difference among them Hormone deficits after total removal of craniopharyngioma appear to be the common complication of surgery. Hypothyroidism and diabetes insipidus are more frequent after surgery. Thyroxin and glucocorticoids should be administered routinely after total removal of craniopharyngioma. We noted in our study with all adults and children needing hormonal supplementation and minirin for a long period. We found no significant difference between adults and children with respect to the neuropsychological factors. Similar number of adults and children had poor outcome on the basis of Blooms index (children) and LESS (children and adults) with no statistically significance difference among adults and children. Mortality was present only in children due to delayed vasospasm and endocrinological disturbances.

Only preoperative presence of GH deficiency was found to be a factor favoring the outcome in children but this does not seem to have any clinical relevance. Overall, there was no statistical significance among the variables determining outcome. Even hypothalamic involvement did not influence outcome because it was used in most patients as a guide to less aggressive surgery and hence, did not contribute to deterioration in outcome.

Conclusion: Craniopharyngiomas are benign tumors with bimodal age distribution with male preponderance in adults. Headache is the most common presentation. Endocrinological disturbances and vomiting were more common in children at the time of presentation. Visual disturbance is as common in adults as in children. Initial hormonal evaluation will show hypopituitarism in the majority of adults and children. Childhood lesions are predominantly calcified adamantinomas, while papillary type is seen only in adults. Surgery is the first-line approach to the treatment of craniopharyngiomas. Extent of hypothalamic involvement based on the Sainte-Rose classification is an important factor guiding the approach to surgical excision. Once the patient undergoes complete excision, there is no progression of the disease; however, in cases of subtotal excision, irrespective of receiving radiotherapy, chances of progression are there. Visual outcome (improvement of visual acuity and visual field), and Hormonal outcome (continuous hormonal supplementation) are the same in children and adults. Diabetes Insipidus is the most common complication following surgery leading to prolonged intake of minirin in both groups. Quality of life and cognitive functioning are normal for both children and adults following surgery. A multidisciplinary approach to management of craniopharyngiomas will result in a good outcome in the majority of patients.

Keywords: Craniopharyngioma, hormonal therapy outcomes, radiation therapy, surgery

Embryonal brain tumor of an unusual site in a child: A case report

Pulla Reddy Seelam; Sri Ramachandra Medical College and Research Institute, Chennai, Tamil Nadu, India

Aims and Objectives: Embryonal cell tumor is a rare malignant brain tumor and accounts for 5% of all intracranial germ cell tumors. They are most commonly seen in the posterior third ventricle and pineal region. Here we report a rare case of embryonal cell tumor presenting as a sellar and suprasellar lesion with a skip lesion in the fourth ventricle.

Materials and Methods: A 9-year-old female child presented with bifrontal headache for 3 months associated with polydipsia and polyuria for 2 months. MRI brain revealed 3 cm × 2.8 cm × 2.8 cm lobulated lesions hyperintense on T2-weighted image (T2WI) and hypointense on T1WI in sellar and suprasellar region encasing optic chiasm and causing mild pressure effect over hypothalamic–pituitary axis and midbrain extending into 3rd ventricle superiorly and interpeduncular cistern inferiorly. In contrast, administration lesion showed heterogeneous enhancement. A similar enhancing lesion measuring 1.6 cm × 0.9 cm noted within the fourth ventricle on the left side – no evidence of hydrocephalus.

Results and Discussion: Endoscopic assisted transnasal transsphenoidal excision of the lesion was done. Tumor was pinkish white and mildly vascular. Postoperatively child continued to have features of diabetes insipidus and was managed with vasopressin supplementation. Histopathology report revealed cellular lesion composed of atypical cells arranged in sheets with focal myxoid areas with cells having scanty cytoplasm and pleomorphic nuclei, increased mitosis, and apoptosis. Immunohistochemistry revealed tumor cells are positive for CD56, synaptophysin. Ki-67 labeling index was 80% indicating highly malignant lesion with rapid mitosis-embryonal tumor NOS. She was planned to be treated as a high-risk medulloblastoma protocol with craniospinal radiation with concurrent chemotherapy. However, she deteriorated and succumbed to the disease. Embryonal brain tumors are a heterogeneous group of neoplasms that primarily occur in infants and young children. They are highly cellular tumors with brisk mitotic activity, and they share a propensity for dissemination throughout the neuroaxis. Surgical excision followed by radiotherapy and adjuvant chemotherapy may increase the survival rate. The reported 5-year survival rate remains low about 25%.

Conclusion: We report this case for the neurosurgeons and pediatric oncologist to be aware of this rare tumor in this unusual site.

Keywords: Embryonal cell tumor, intracranial, sellar, suprasellar

School re-entry after treatment for pediatric brain tumors at Tata Medical Center, Kolkata

Anirban Das, Parag Das, Rimpa Basu Achari, Soumitra Sankar Datta, K S Reghu, Arpita Bhattacharyya; Tata Medical Center, Kolkata, West Bengal, India

Aims and Objectives: Childhood survivors of brain tumors are at significant risk of physical, psychosocial, and neurocognitive morbidities, which may affect their school attendance and performance. Our aim was to audit re-entry and initial performance at school after the end of treatment so that appropriate measures could be instituted to aid early re-integration.

Materials and Methods: A cross-sectional study was conducted among children diagnosed and treated for brain tumors at Tata Medical Center, Kolkata, between 2012 and 2018. Families were contacted telephonically, and the parents were requested to respond to a preformatted standardized questionnaire regarding rejoining school, performance, and perceived barriers. Demographic and medical data were extracted from the electronic hospital records. Data were analyzed using SPSSv20.

Results: Fifty children were assessed. Median age at diagnosis was 81.2 months (range: 6–228) and at assessment was 132 months (range: 44–249). Male:female was 0.9:1. Location of the tumor was supratentorial in 18 (36%) and infratentorial in 32 (64%). Underlying diagnoses included medulloblastoma (18, 36%); low-grade glioma (13, 26%); ependymoma (11, 22%); craniopharyngioma (3, 6%); germ cell tumor (2, 4%); pinealoblastoma (1, 2%); high-grade glioma (1, 2%); and intracranial sarcoma, DICER1-related (1, 2%). Majority (46, 92%) had neurosurgical intervention, 39 (78%) received radiotherapy, and 30 (60%) received chemotherapy.

At a median time of 25 months (range: 4–137) after completing treatment, 35 (70%) children had joined back to school; 7 (14%) were waiting for a new session to begin; 8 (16%) were not going to school. Thirty (60%) had lost an academic year due to their cancer treatment. Academic performance was rated by parents as average in 20 (40%), below average in 9 (18%), and above average in 21 (42%). However, additional tutoring at home was required in majority (32; 64%). Visual problems were reported in 8 (16%) and hearing difficulty in 11 (22%), although audiometry demonstrated impairment in 38 (76%). Number of parents reporting difficulty faced by the children in comprehension, reading, and writing were 4 (8%), 7 (14%), and 9 (18%), respectively. Majority of parents reported change in behavior in the form of increased restlessness and irritability (36, 72%). However, peer interaction was impaired in 8 (16%). Reasons reported by the eight families for not sending the child to school were incapacitating motor problems (5, 62%); significant intellectual disability (4, 50%); and bullying at school (1, 12.5%). However, majority (40, 83.3%) of the parents who had re-admitted or had planned to re-admit their children in school reported getting adequate support from the schools to plan and aid re-integration. Limitations of the study include a one-time assessment for re-entry without follow-up for absenteeism, and dependence on parental assessment without a second, objective corroboration.

Conclusion: Although a significant proportion (84%) of children treated for brain tumors had planned to (14%), or actually joined back in school (70%), the audit helped identify disabilities reported by parents requiring specific evaluation, intervention, and support. Parental assessment may be biased by modified expectations following recovery from a life-threatening experience like cancer and may overestimate the child’s functional capacities, as in the case of hearing and school performance. Objective assessment, including neuropsychological testing, followed by dedicated mechanisms and targeted support to aid re-integration in school is needed.

Keywords: Childhood brain tumors, neurocognition, school attendance

Developing dedicated pediatric neuro-oncology services in Eastern India over the past 2 years: Early experience from Tata Medical Center, Kolkata

Anirban Das, Rimpa Basu Achari, Lateef Zameer, Saugata Sen, K S Reghu, Soumitra Sankar Datta, Neeraj Arora, Mayur Parihar, Gopal Achari, Bikramjit Pal, Parag Das, Pritha Banerjee, Sarbani Chowdhury, Arpita Bhattacharyya; Tata Medical Center, Kolkata, West Bengal, India

Aims and Objectives: Management of childhood brain tumors is challenging and needs coordinated efforts from a multidisciplinary team of experts. Lack of dedicated neuro-oncology services is an impediment to optimal outcomes for children with brain tumors in developing countries. Limited number of centers has the capacity to offer such services in India. Our aim was to audit our experience of developing a dedicated, multi-disciplinary neuro-oncology team at Tata Medical Center, Kolkata (TMCK).

Materials and Methods: A multidisciplinary neuro-oncology group was conceptualized in January 2017. A series of meetings were coordinated between stakeholders between January and March 2017. Dedicated, monthly tumor board meetings were initiated from March 2017. Data of patients managed by the service between January 2017 and December 2018 were retrospectively extracted from the hospital’s electronic medical records. The analysis was performed using SPSSv20 (IBM).

Results: Seventy-one children, aged 18 years, with neoplasms of the central nervous system, were diagnosed over 24 months. Male:female was 1.3:1. Median age at diagnosis was 97 months (range: 5–228); 11 (15.5%) were 36 months. Median symptom interval was 8 weeks (range: 1–106). Children were referred from neurosurgical centers within (32, 45%) and outside the city (39, 55%). The families were from Kolkata (11, 15%); South Bengal (39, 55%); North Bengal (7, 10%); neighboring states (7, 10%); and neighboring countries (7, 10%) and traveled a median of 64.3 km (range: 14–1340) for consultation.

Diagnoses included medulloblastoma (20, 28%); low-grade glioma (20, 28%; including 6 patients with opto-chiasmatic glioma), ependymoma (12, 17%); high-grade glioma (10, 14.3%; including three patients with diffuse intrinsic pontine glioma); craniopharyngioma (3, 4%); germ cell tumor (2, 3%); pinealoblastoma (1, 1.5%); cerebellar melanoma (1, 1.5%); chordoma (1, 1.5%); and DICER1-related intracranial sarcoma (1, 1.5%). Metastatic workup was indicated in 30 (50%) children; 13/30 (43%) had spinal involvement.

Thirty-seven (52.2%) children completed treated at TMCK, 30 (42.2%) had visited for second consults, and 4 (5.6%) refused/abandoned treatment. Families belonging from Kolkata were more likely to take treatment at our center (P = 0.04). Thirty-nine (55%) cases were discussed in the monthly tumor boards, including all 37 who were treated at our center. Treatment provided at TMCK (n = 37) included both radiation and chemotherapy (19, 51.3%); radiotherapy alone (10, 27%); and chemotherapy alone (8, 21.7%). Nutritional rehabilitation was required in 30/37 (81%). Formal neuro-psychology evaluation was performed in 25/37 (67.5%). Audiometry was performed in 29/37 (78%), of whom 25 (86%) had some degree of hearing impairment. Support was provided in the form of counseling and guidance for accessing assistance (21/37, 57%); free drugs (19/37, 51.3%); funding (19/37, 51.3%); and free accommodation (6/37, 16%). One child on palliative care expired; there were no deaths related to treatment-related toxicity.

Conclusions: Following the introduction of dedicated service, the proportion of central nervous system tumors among all pediatric malignancies diagnosed at the hospital had almost doubled in 2018 (n = 47/404, 11.6%), as compared to previous years (2011–2017: n = 112/2010, 5.5%). Management decisions for all children treated at our center were reviewed jointly by the dedicated neuro-oncology multidisciplinary tumor board. More than half of the families received logistic assistance. There was no treatment-related mortality. The current challenges for the team include building upon the early momentum, developing cost-effective methods for molecular diagnosis, follow-up of the current cohort for outcome, and coordinating rehabilitation and re-integration services for survivors.

Keywords: Childhood brain tumors, low-middle income country, multidisciplinary team

A subset of phenotypic anaplastic astroblastomas conform to central nervous system high-grade neuroepithelial tumor-MN1 altered entity

Radhika Mhatre, NIMHANS, Bengaluru, Karnataka, India

Introduction: Astroblastomas are unique tumors with unresolved issues in terms of their origin, histomorphology, molecular biology, clinical behavior, and response to treatment.

Aims and Objectives: To study the histological and molecular profile of astroblastoma with emphasis on MN1 rearrangement.

Materials and Methods: All the cases diagnosed as astroblastoma in our institute over a period of 8 years (2011–2018) were reviewed and reevaluated with immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) for the newly emerged MN1 rearrangement which was recently reported in central nervous system high-grade neuroepithelial tumors (CNS-HGNETs). A total of 13 cases were included, of which five were excluded with revised diagnosis as ependymoma after extended IHC panel. Thus, the remaining eight cases were further analyzed.

Results: The mean age at diagnosis was 18.6 years with all cases seen in females and with supratentorial localization. The tumors showed the typical circumscription and bubbly appearance on imaging. All the cases in this cohort constituted anaplastic astroblastomas based on histologic and IHC profile. They displayed the characteristic astroblastic pseudorosettes with hyalinized vascular core and variable immunopositivity for glial fibrillary acidic protein, pan-cytokeratin, and epithelial membrane antigen. MIB-1 labeling index was significantly elevated in all the cases. MN1 break-apart by FISH was found in 62.5% of our cases. Tumor recurrence was noted in three cases.

Conclusion: We account for one of the largest series to study the MN1 rearrangement in astroblastomas. We conclude that MN1 alteration is seen in a subset of anaplastic astroblastomas and that there is a potential role for other genetic alterations in the etiopathogenesis of this tumor.

Keywords: Astroblastoma, central nervous system high-grade neuroepithelial tumor, immunohistochemistry, fluorescence in situ hybridization MN1

Eosinophilic granuloma of pituitary stalk and sphenoid bone: A rare case

Prem Kumar; Department of Radiotherapy, Omega Institute of Oncology, Hyderabad Telangana, India

Aims and Objective: The objective of this study was to evaluate the role of radiotherapy in pediatric eosinophilic granuloma of pituitary stalk and sphenoid bone.

Materials and Methods: A 4-year-old male presented with polyuria, nocturia, and polydipsia of 1-year duration with increase in body weight. He had recurrent fevers and occasional headaches of 6-month duration. He was under treatment by a local pediatrician for 1 year. Magnetic resonance imaging brain revealed intensely enhancing soft-tissue mass lesion measuring 16 mm × 18 mm × 13 mm involving hypothalamus, infundibulum of pituitary gland with moderate perilesional edema, destructive lesion involving greater wing of sphenoid extending into the pterygoid fossa on right side, enhancing lesion involving greater wing of sphenoid, enhancing lesion involving left aditus and mastoid antrum – likely Langerhans cell histiocytosis/lymphoma. Computed tomography (CT)-guided fine-needle aspiration from sphenoid lesion suggestive of eosinophilic granuloma. Positron emission tomography-CT showed metabolically active enhancing lesion in suprasellar region measuring 15 mm × 16 mm × 14 mm with maximum standard uptake value (SUVmax) of 8.75 and metabolically active ill-defined lytic lesion with adjacent soft tissue component involving greater wing of sphenoid on the right side showing SUVmax of 7. The patient was treated with low-dose radiotherapy (15 Gy in 10 fractions) and vasopressin as nasal spray. He completed radiotherapy on October 28, 2018, and came for follow-up in January 2019.

Results: The boy’s symptoms of polyuria and polydipsia have subsided. The body weight has become stationary, and there is no increase in body weight.

Conclusion: A rare case of intracranial pituitary eosinophilic granuloma with destruction of the right wing of sphenoid bone was treated with low-dose external beam radiotherapy with very good outcome. This case is presented because of its rarity. Details of the case will be presented in the conference.

Keywords: Effectivity, eosinophilic granuloma, radiotherapy, rare case

Analysis of BRAF V600E mutation in central nervous system tumors in a tertiary cancer center in India

Sahil Bambroo; Amrita Institute of Medical Sciences, Kochi, Kerala, India

Introduction: Majority of central nervous system (CNS) tumors are generally plagued by limited options of treatment. In the era of personalized medicine, the scenario is changing. Many mutations including EGFR and BRAF V600E are being studied. It is well known that there are geographical variations to their occurrences as exemplified by studies on EGFR in lung cancer. In other studies, BRAF V600E has been frequently seen in low-grade gliomas including pleomorphic xanthoastrocytomas and extra-cerebellar pilocytic astrocytomas, but survival trends have shown varying results. Determining the frequency and distribution of BRAF V600E mutations across various types of NS tumors in our population would help to identify those tumor entities that might potentially benefit from BRAF V600E targeted therapy.

Aim: To ascertain the frequency and assess the prognostic significance of BRAF V600E mutation in CNS tumors.

Materials and Methods: This nonrandomized, retrospective analytical study was conducted in the Departments of Medical Oncology and Molecular Diagnostics at Amrita Institute of Medical Sciences, Kochi, including patients from September 2017 to August 2018. After institutional ethical committee clearance, 132 samples were subjected to testing for BRAF V600E mutation. DNA extraction was done from archival formalin-fixed paraffin-embedded tissues.

Real-time PCR was used to detect BRAF V600E mutation. For high-resolution melting analysis of V600E status, we used a single probe-based assay specifically designed to detect both BRAF V600E and V600K (LightMix® Kit BRAF V600E/K, 2015 version, including a control reaction; TIB MOLBIOL, Berlin, Germany) according to the manufacturer’s instructions. All reactions were performed using the Roche Diagnostics Light Cycler FastStart DNA Master Hybridization Probe reaction mix and run on a Light Cycler 480 instrument (Roche, Basel, Switzerland). Genotype calling based on melting curves was performed using the LightCycler 480 software release 1.5.1 (Roche). The patient demographics, treatment records, and follow-up details were obtained from hospital electronic medical records.

Results and Discussion: 9.8% (13/132) samples tested positive for BRAF V600E mutation in this study. Among patients <18 years, the BRAF mutation was found to be positive in 21.2% (7/33) patients as opposed to 6.1% (6/99) adult patients and this difference was statistically significant (P = 0.028). The median overall survival for the BRAF V600E mutation-positive glioblastoma multiforme (GBM) patients was 11.3 months as compared to 21.76 months among the mutation-negative GBM patients (P = 0.033). This was in contrast to other studies, where BRAF V600E mutation was encountered in rarer, more favorable subtypes of GBM and which were more amenable to complete resection, translating in better outcomes. The mean progression-free survival (PFS) for pilocytic astrocytoma (PA) patients with a positive BRAF V600E mutation was 43.9 months, which was significantly lower as compared to 105.4 months for patients with PA with a negative mutation (P = 0.047). This is in concordance with few studies that report a poorer PFS in BRAF V600E-mutant CNS tumors.

Conclusion: The frequency of BRAF V600E mutation among Indian patients is more or less similar to the rest of the world, and there is probably no geographic variation. Low-grade gliomas are more likely to be BRAF V600E mutant and the frequency decreases with increasing grade of tumor. Unlike some of the reports, the BRAF V600E mutation is a negative prognostic factor in Indian patients. BRAF V600E mutation has the potential to become a prime target of cancer therapy in the coming years. Very few case reports and studies on this topic have been reported from the Indian subcontinent. Further studies need to be done considering confounding factors such as age, tumor grade, and the status of other genetic events.

Keywords: 2016 CNS WHO classification, anaplastic astrocytoma, BRAFV600E mutation, central nervous system tumors, glial tumors, glioblastoma, pilocytic astrocytoma

To determine the role of diffusion tensor imaging tractography of corticospinal tract in the management of brainstem lesions

Mallappa, Manas Panigrahi, Y B V K Chandrasekhar, Ananthram; Krishna Institute of Medical Sciences, Secunderabad, Telangana, India

Aims and Objectives: To understand the role of diffusion tensor imaging tractography of the corticospinal tract in the evaluation and surgical planning of patients with brainstem lesions.

Materials and Methods: It is a retrospective study of 44 patients who underwent surgical treatment for brainstem lesions from January 2010 to till date. Immediate postoperative focal neurological deficit was assessed in all patients undergoing treatment. We divided the patients into two groups. Group A included 37 patients from 2010 to 2017 with brainstem lesions who did not undergo diffusion tensor imaging preoperatively. Group B included seven patients with brainstem lesions from 2017 to December 2019 who underwent diffusion tensor imaging tractography of corticospinal tract preoperatively.

Discussion and Results: Diffusion tensor imaging noninvasively allowed for visualization of the anatomical relationship between corticospinal tract and brainstem lesion. Diffusion tensor imaging also helped in determining the type of surgical approach and entry point decision making. Patients with diffuse brainstem gliomas were referred for primary radiotherapy. Patients with focal brainstem lesions were treated either with stereotactic biopsy or surgical resection. In Group A, 4 out of 37 patients (10 %) had fresh postoperative focal neurological deficit(hemiparesis/hemiplegia). In Group B, 4 out of 7 patients had hemiparesis preoperatively which did not worsen postoperatively; other three patients did not develop any new-onset focal neurological deficit postoperatively. In Group B, three patients with infiltration of corticospinal tract on diffusion tensor imaging underwent stereotactic biopsy, whereas four patients in whom corticospinal tract was displaced underwent primary resection of the tumor.

Conclusion: We observed that patients who underwent preoperative assessment with diffusion tensor imaging in brainstem lesion had better outcome as diffusion tensor imaging helped in complex neurosurgical planning during resection of brainstem lesion, and it is a promising technique to overcome the iatrogenic injury to corticospinal tract during surgical resection, which reduces the morbidity and overall outcome in the patient.

Keywords: Brainstem gliomas, corticospinal tract, diffusion tensor imaging

Involving parents in neuropsychological assessments and evaluating adaptive functioning: Experience from a tertiary cancer center in Eastern India

Rocheta Mahanta; Tata Medical Center, Kolkata, West Bengal, India

Aims and Objectives: Children and adolescents with brain tumor are treated best by a multidisciplinary team, and with improved survival, target of treatment has moved much beyond the tumor alone. Neuropsychological tests that are dependent on paper-and-pencil tests are complemented by evaluation of executive functioning and adaptive functioning based on parent reports. The current paper discusses the advantages of this method, the tests that are used, and the profile of findings of the test done on a group of children with brain tumor. The data and interpretation of the Vineland Adaptive Behavior Scale, Second Edition (VABS II) and Behavior Rating Inventory of Executive Function (BRIEF 2) are presented.

Materials and Methods: Children with brain tumor presenting to Tata Medical Center, Kolkata, were routinely referred for neuropsychological assessment to the Department of Psycho-Oncology at the onset of treatment and also during follow-up following treatment completion. The adaptive and executive functions were quantified using VABS II and BRIEF 2, respectively. The VABS II quantifies the constructs of communication, daily living skills, socialization, and motor skills and an optional domain of maladaptive behavior. The BRIEF 2 quantifies the executive functioning, and there are individual scores for set-shifting, behavioral inhibition, emotional control, initiation, and working memory among other subscales. Global executive composite can also be calculated.

Results and Discussion: The findings for the results of the neuropsychological test for children (n = 11) are presented. Four of the children had been diagnosed to medulloblastoma, three had ependymoma, three had astrocytoma, and one had craniopharyngioma. Five of the children opted to be tested at the start of the treatment and six of the families brought the children after treatment completion. The test was chosen based on the problems reported by the parents. The decision of treatment assessment was left to the parent team and the choice of the family. The median score for the various VABS II subscales was as follows: communication (88, interquartile range [IQR] 45–100); daily living skills (90, IQR 70–97); socialization (78, IQR 65–96); motor skills (61). On BRIEF 2, the children scored as follows: behavior regulation index (43, IQR 39–50); emotional regulation index (49, IQR 40–71), cognitive regulation index (42, IQR 40–71); and global cognitive index (45, IQR 40–53). The median age of the sample was 9 (IQR 4–11).

Conclusion: The multidisciplinary involvement of neuropsychologists in the treating team of pediatric oncologists treating solid brain tumors complements the medical care of children. Assessing adaptive functions and executive functions based on parent rating is particularly useful when the child is not co-operative for formal testing or is very young. Several children in addition to neuropsychological deficits had primary psychiatric diagnoses which were addressed in clinical consultations. The timing of neuropsychological testing needs to be optimized so that it is beneficial to the child and posttest neuro-psychological tests inform rehabilitation and optimal school placements and support needed in daily living of the child.

Keywords: Adaptive functioning, brain tumors, neuropsychological assessment, psychiatric diagnosis

Endoscopic transcortical transventricular approach for cystic craniopharyngioma

Tejesh Mishra; NIMHANS, Bengaluru, Karnataka, India

Aims and Objectives: To study the outcome of transcortical transventricular endoscopic approach and Ommaya Reservoir placement in cases of cystic craniopharyngioma.

Introduction: The treatment of craniopharyngioma is varied. It ranges from radical excision to direct radiotherapy. As the morbidity of excision is high, more conservative approaches are used. Placement of a catheter and reservoir is one such option for cystic craniopharyngiomas. The positioning of catheters has been performed by various means including endoscopic approach for reservoir catheter placement.

Materials and Methods: The study was conducted as a prospective longitudinal interventional study in the Department of Neurosurgery, NIMHANS, from 2014 to 2018. Twenty patients with ages ranging from 1.5 to 50 years with diagnosed cystic craniopharyngioma were included in the study. Patients presented with clinical features suggestive of raised intracranial pressure. Out of twenty, ten had visual impairment at presentation. Imaging showed a predominantly cystic craniopharyngioma extending into suprasellar cistern causing endocrinological dysfunction and visual deterioration. All underwent precoronal burr hole, transcortical transventricular endoscopic biopsy of craniopharyngioma, and Ommaya reservoir placement. Follow-up was done from 2 months postoperative to 46 months.

Discussion and Results: Of twenty patients, 14 had good functional outcome after the surgery. Eight of the ten patients had improvement in vision. Radiologically, more than 50% had complete collapse of the cyst. All patients did well after surgery and there were no major complications in any of the patients. However, two patients required cyst reaspiration through the reservoir, two patients required ventriculoperitoneal shunting, and two patients developed multicystic recurrence without any significant hydrocephalus. One patient required surgical decompression of the lesion.

Conclusion: Endoscopic placement of Ommaya reservoir by transcortical transventricular approach in cases of cystic craniopharyngioma is a safe and effective treatment modality with good functional outcome.

Keywords: Cystic craniopharyngioma, endoscopic catheter placement

Medulloblastoma across the oceans treated with ISNO Guidelines

Runu Sharma; Department of Medical Oncology, Sri Aurobindo Medical College and PG Institute, Indore, Madhya Pradesh, India

Introduction: Medulloblastoma is a collection of clinically and molecularly distinct tumor subgroups that arise either in cerebellum or brainstem. It is a relatively rare disease in adults accounting for less than 1% of all intracranial malignancies. Molecularly, it is divided into four major subgroups: wingless-type, sonic Hedgehog (SHH), Group 3, Group 4. These subgroups differ in their biological behavior, genetic profiles, as well as prognosis. The 2016 updated WHO classification incorporates genetic classification along with histo-morphology. Thus, molecular profiling plays an important role in therapeutic decision-making and is strongly recommended nowadays.

Case Discussion: We report a case of a 30-year-old charted accountant from Fiji who presented to us with a history of giddiness, headache, and “double vision” since mid-January 2018. He was detected to have cerebellar signs and papilledema. Magnetic resonance imaging (MRI) showed peripherally enhancing left-sided lesion in the cerebellar cortex. An occipital craniotomy was done on February 20, 2018, and the mass was resected “near–total.” The histopathology was intermediate-grade medulloblastoma. He was referred to our center, nearly 12,000 km away, for adjuvant radiochemotherapy. On arrival on April 21, 2018, he was conscious, was ambulant, and had no focal lateralizing pyramidal or cerebellar deficits. The postoperative MRI was normal and cerebrospinal fluid study was within normal limits. He received radiation to the lesion with 6MEV photons 50.4 Gy, 25 fractions over 34 days along with concurrent vincristine. The gene expression profile on the tumor block showed medulloblastoma with SHH mutation and wild-type p53 gene indicating an intermediate prognosis. He later received chemotherapy as per the ISNO Guidelines on medulloblastoma (2016) that consisted of vincristine, cyclophosphamide, and cisplatin (with dose modifications in cyclophosphamide: reduced by 30%–35% in each cycle). He remained well with one episode of febrile neutropenia (grade 4) and venous thrombosis of the left subclavian vein related to peripherally inserted venous catheter, managed with rivaroxaban. He completed six cycles of VCR-CDDP-Cytoxan on December 3, 2018, and returned home to Fiji on Christmas Eve 2018. He has been advised 3 monthly clinical follow-up locally with MRI scans, and chart-of-survivorship investigations have been explained to his primary care physicians.

Conclusion: Every case of medulloblastoma should have molecular risk stratification and efforts should be taken to device treatment plan accordingly. The ISNO Guidelines help to provide easy-to-deliver yet high-quantity management, including presurgical workup, surgical principles, neuropathology reporting, and molecular testing, appropriate adjuvant therapy, and follow-up. The Guidelines should be adopted by health care providers in the country to ensure uniform standard of care. SHH activated medulloblastoma is a heterogeneous subgroup with regard to clinical outcome and TP53 has a prognostic role in SHH activated subgroup. TP53 mutant-type SHH activated is usually of anaplastic morphology and associated with poor prognosis while TP53 wild type is more commonly of desmoplastic variety and favorable prognosis. Thus, TP53 mutation should be tested once SHH subtype of medulloblastoma is detected. Although this experience may not be common, the case emphasizes the evidence-based and risk-stratified care of an individual patient from across a vast distance, an example of global or “planetary” medicine.

An exploratory study on cognitive profile of children diagnosed with medulloblastoma and ependymoma

Devi Nandakumar1, Soumitra Shankar Datta1,4, Procheta Mahanta1, A Rimpa2, Anirban Das3, Tania Saha1, Aparupa Ojha1, K S Reghu3, Arnab Mukherjee1; Departments of 1Palliative Care and Psycho-Oncology, 2Radiation Oncology and 3Paediatric Haemato-Oncology, Tata Medical Center, Kolkata, West Bengal, India, 4Institute for Women’s Health, University College London, London, UK

Aim and Objective: Ependymoma and medulloblastoma are common brain tumors in children. In this paper, we explore the feasibility of conducting routine neuropsychological assessments in children diagnosed with medulloblastoma and ependymoma.

Materials and Methods: Children with ependymoma and medulloblastoma were routinely referred for neuropsychological assessment before and after treatment completion. The psychological assessment included a child psychiatric history-taking, clinical interview, and appropriate neuropsychological testing. In this paper, we present the data for tests administered to children – namely Wechsler Preschool and Primary Scale of Intelligence™-Fourth Edition (WPPSI™-IV) and Wechsler Intelligence Scale for Children (WISC) – 4th Edition India. WPPSI is used for children aged 2 years 6 months to 7 years 7 months and generates FSIQ, primary index scores, and ancillary index scores. WISC is used for children aged 6–16 years of age and generates FSIQ, index scores, and subtest scaled scores.

Results and Discussion: The data presented in this paper are for a total of nine patients with medulloblastoma (n =6) and ependymoma (n = 3). In real-life clinical scenario, most of the families chose to have the neuro-psychological assessment post-treatment as opposed to pretreatment. The trend was toward a lesser overall full-scale IQ score in the posttreatment time point (median 75, interquartile range [IQR] 52–89) as compared to the scores of children who were tested pretreatment test scores (median 110, IQR 90–115) although this is not a paired data. For those children who underwent WISC-IV, the median (IQR) index and subscale scores were as follows: verbal comprehension index 94 (63–104), perceptual reasoning index 86 (65–109), working memory index 88 (65–109), processing speed index 83 (54–89). For the current data, the median age in years is 11 (IQR 8.5–13.5). One child with ependymoma and one child with medulloblastoma qualified for a psychiatric diagnosis. The families were suggested advice on the following domains: optimal educational placement, cognitive retraining where appropriate, behavioral management, and family support and follow-up plans for further neuropsychological testing.

Conclusion: The posttreatment neuropsychological testing picks up deficits in neurocognitive functioning and is likely to be more acceptable to family members than pretreatment neuropsychological testing. The neuropsychological assessment is best embedded in the context of a comprehensive psychological assessment. Structured neuropsychological batteries may be able to pick up neuropsychological deficits, and this may contribute to the neuropsychological rehabilitation of children.

Keywords: Ependymoma, medulloblastoma, neuropsychological rehabilitation, neuropsychological tests, Wechsler Intelligence Scale for Children, Wechsler Preschool and Primary Scale of Intelligence-Fourth Edition

Suprasellar pilocytic astrocytoma variants in pediatric population: An aggressive disease?

Rakesh Kumar Mishra; National Institute of Mental Health and Neurosciences, Bengaluru, Karnataka, India

Objectives: Pilomyxoid astrocytoma (PMA) (WHO Grade II) and pilocytic astrocytoma (PA) with anaplastic features (WHO Grade III) are the two potentially aggressive variants of PA. PMA occurs in infants and young children, most commonly in the suprasellar region. However, the clinical behavior of the tumor can be unpredictable with a benign course in at least some of them. Preoperative identification of aggressive variants of PA may help in planning the treatment and prognostication. The aim of this study is to compare the clinicoradiological features of aggressive variants of PA with classical PA.

Methods: All histopathologically confirmed cases of pediatric suprasellar Pas and its variants operated in this institute were followed up. The clinical and radiological features of these cases were reviewed and compared. Aggressive behavior in terms of cerebrospinal fluid (CSF) dissemination and tumor progression was studied.

Results: A total of 15 cases of PA and nine of PMA and one case of PA with anaplastic features (>5 mitoses/10 HPF) were studied. CSF dissemination was found in two cases of PMA at the time of diagnosis.

Discussion: PA variants have a shorter duration of symptoms when compared to classical PA. Radiological evidence of tumor dissemination in CSF was identified in two patients of PMA and confirmed by cytological study of LP-CSF in one. On follow-up, the majority of the cases of PMA, i.e., 5/7 cases (71%), did not show tumor progression similar to 11/12 cases (92%) of PA. There was one case of PA with anaplastic features (WHO Grade III) who is tumor-free after adjuvant radiotherapy. Literature review suggests adjuvant chemotherapy (cisplatin or carboplatin) additional to radiotherapy for these patients.

Conclusions: Clinical features of PA variants are in stark contrast with classical PA. The absence of early involvement of visual axis and predominant third ventricular location of the tumor may suggest a hypothalamic origin of PMA. There is an aggressive subset of PMA with CSF dissemination and early age of presentation. MIB-1 labeling index may not be a marker to identify these aggressive subsets. PA with anaplastic features is a rare variant requiring adjuvant therapy. Molecular markers have to be elucidated in the future to differentiate these variants from classical PA and to predict their clinical behavior and response to adjuvant therapy.

Endocrine manifestations of craniopharyngioma

Nishant Kumar Shukla; SCB Medical College, Cuttack, Odisha, India

Craniopharyngiomas are relatively uncommon tumors and have a bi-peaked incidence. These are relatively common tumors of childhood, presenting in predominantly children and middle age. Because of the location of these tumors, they tend to produce a variety of endocrine manifestations. In the present study, clinical and endocrine profile of patients presenting for with craniopharyngioma to our center over 1 year were analyzed for endocrine manifestations and results were presented. Such patients need tailor-made perioperative care for the special needs based on the endocrine profile; prolonged follow-up as endocrine manifestations may develop remote to surgery.

An analysis of medulloblastoma

Nafees Ahmad Siddiqui; Nabeel Health Care Centre, Lucknow, Uttar Pradesh, India

Aims and Objectives: Medulloblastoma is an embryonal tumor with aggressive behavior and is more commonly seen in children than adults. The aim of this study was to determine the epidemiological patterns of medulloblastoma.

Introduction: Medulloblastoma is one of the most common brain tumors in the pediatric age group. The incidence in children varies between 12% and 25% and less than 1% in adults. According to a recent pediatric multi-institutional study in India, its incidence was 22.4% of all the central nervous system tumors. This tumor is known to respond very well to radiation and chemotherapy following surgery. Being of common occurrence, the epidemiology should be well understood to help in the management of this potentially curable disease. Although there are data about various management profiles, molecular biology, and risk stratification, there are few articles in the literature discussing the epidemiological pattern, prognosis, treatment, and outcome of this particular tumor, from developing countries. Medulloblastoma has been found to be second only after glioma in incidence in the pediatric age group. There is no study from India discussing medulloblastoma from a sociodemographic aspect in the literature. The main objective of this study was to analyze the sociodemographic data with emphasis on the pattern of the disease, prognostic factors, and outcome.

Materials and Methods: It is a retrospective study, in which the records of all the clinically diagnosed medulloblastoma cases in the last 5 years (2013–2018) were analyzed. The records of patients diagnosed with medulloblastoma at our institute in the last 5 years (2013–2018) were retrieved and thoroughly studied. Various aspects were explored such as epidemiology, disease pattern, presentation, treatment and its outcome, and survival and disease status at follow-up visits.

Results: A total of 23 cases were found, with the mean age at diagnosis being 5 years. There was a slight predilection for male sex (58.62%). The first presenting symptom was mostly related to raise intracranial pressure and the mean duration of symptoms was 200 days. Nearly, 89.6% of patients were in Stage 0 and had a central tumor location. Multimodality treatment included surgery followed by craniospinal irradiation up to 36 Gy followed by posterior fossa boost up to 54 Gy. Median radiation therapy duration was 6.5 weeks, and concurrent single agent vincristine was the most common chemotherapy used. Most of the patients showed only a partial response to treatment, mainly because of large tumors at presentation, which could be attributed to the lack of awareness, delayed medical attention, and poor follow-up. Maximum number of cases belonged to the age group of 3–20 years (76%). The mean age at diagnosis was 10 years. Almost 90% showed a classical type of histopathology and 5% each of desmoplastic and large cell anaplastic variants. Homer Wright rosettes were observed in 82% of cases. Medulloblastoma is known to be associated with syndromes such as Gorlin’s or Turcot, but no association with any syndrome was found in any patient in our study.

Diagnosis was mainly established by symptomatology at presentation, imaging, and histopathological examination. Due to paucity of resources and financial constraints, immunohistochemistry was available only for two patients. The first symptom in the maximum number of cases was a raised intracranial pressure (93.10%) manifesting as headache, vomiting, and hydrocephalus on the magnetic resonance imaging (MRI). Ataxia and progressive weakness were the other early manifesting signs. Raised intracranial pressure developed in 98.2% cases eventually. Cranial nerve deficit developed in 15.5% of patients, with the sixth nerve being the most affected. Ataxia was not seen in 46.5%, but those who developed ataxia had truncal type (41.37%) more than the lateral ataxia. Long tract signs were observed in 17.2% of patients. MRI and cerebrospinal fluid (CSF) analysis, which is a standard investigation for medulloblastoma, was not available for many of patients, especially for cases in the earlier part of the decade under study. This highlights the limitations and lack of resources at the hospital level. However, CSF was found to be positive for atypical cells in approximately 4%, negative in around 14% of the total number. About 40% cases showed T1 hypointense to isointense mass lesion on MRI, typical of medulloblastoma. Most patients had a computed tomography brain, which is a cheaper investigation, and it showed typical features in 71% cases. According to the modified Chang staging, 89.6% were Stage 0, 1.7% Stage 1, and 3.4% Stage 2 and 4 each. 82.7% had a centrally located tumor, involving the fourth ventricle in 55.1%. Upfront ventriculoperitoneal shunting was needed in 90% cases while 10% did not require it at any stage. Subtotal excision was performed for 43% tumors; almost an equal percentage could be biopsied only and around 7% were completely excised. Incomplete consequently increasing the percentage of high-risk cases to 94%. Correlation between various prognostic factors such as age, histology, type of surgery, and the outcome was not found to be statistically significant in our study for the simple reason of a small study population.

Discussion: Medulloblastoma was first described by Bailey and Harvey Cushing in 1929. Back then, surgery was the main or only modality of management, but there has been continuous development in its management over the years. Multimodality approach (surgery, radiation, chemotherapy) is the cornerstone for the treatment of medulloblastoma. This tumor accounts for about 20% of childhood brain tumors globally and almost the same incidence has been found in India. The incidence of medulloblastoma in various studies was initially found to increase with passing years; however, after the segregation of medulloblastoma from primitive neuroectodermal tumor, the recent studies have found that the incidence of medulloblastoma has not increased with time. At our center, 23 cases of medulloblastoma were diagnosed in the 5 years studied. The mean age at diagnosis was 10 years, with most cases between the age of 3 and 20 years. Even though tumors were bulky in size, majority were Stage 0 lesions with only around 3.4% presenting with metastasis. The most common site of metastasis was bone, more often vertebrae. Due to the relatively bigger sized lesions and high vascularity, a gross total resection was possible in very few. Subtotal or partial excision was commonly carried out, and sometimes, biopsy only was feasible due to very poor performance status of the children. This is in contrast to other studies, which have quoted up to 90% total excision of the tumor. Partial excision resulted in larger residual tumors, which made most cases being categorized as high risk and hence relatively carrying a worse prognosis. All patients were treated with postoperative radiotherapy. The standard protocol of 1.8 Gy per fraction, 5 fractions per week to a total dose of 36 Gy to the craniospinal axis was followed, with an additional boost to the posterior fossa up to 54 Gy. In about 6% of cases, major treatment violations were observed, which were dose to craniospinal axis less than 28 Gy and posterior fossa dose less than 43 Gy. This resulted due to poor performance status and inability to continue further treatment. The poor follow-up and late reporting to the hospital can be attributed to the fact that most population had a rural background with lack of awareness, financial constraints, and lack of easy hospital access. As noticed toward the latter part of the decade, with subsidizing the treatment and more easy accessibility, an improvement in patient reporting and further management was seen. However, there is still a long way to go, and active measures are in line for the same.

Our study has shown the general presentation and management of the disease and pointed out the areas of improvement. All institutes should have a protocol-based approach so that the loopholes in management are not missed. The treating physicians should work as part of a multidisciplinary team to improve the survival, quality-of-life, neurocognitive outcomes, and standards of care for children with medulloblastoma.

Conclusion: Early diagnosis and treatment is the key to management of medulloblastoma, which still needs to be achieved. Bulky tumors have a poor outcome; efforts should be aimed at complete surgery and giving risk stratification-based treatment. Resources need to be allocated to make more conformal methods of radiotherapy available, which will decrease the growth abnormalities and cognitive impairment.

Keywords: Epidemiology, medulloblastoma, prognosis, radiotherapy, surgery

Antiemetic prophylaxis with temozolomide: An audit from a tertiary care center

Vijay M Patil

Background: In our previous experience, a significant proportion of patients who received 5HT3 antagonist monotherapy with adjuvant temozolomide (150–200 mg/m2) had chemotherapy-induced nausea and vomiting (CINV). This is an audit comparing the multiple antiemetic therapies in the prevention of temozolomide-associated CINV.

Methods and Results: This was a retrospective audit. Adult glioma patients treated with temozolomide in a dose of 150–200 mg/m2 between October 2017 and June 2018 were selected for this analysis. Three antiemetic prophylaxis was used in this period; ondansetron (October 2017 to November 2017), ondansetron + domperidone (December 2017 to February 2018), and ondansetron + olanzapine (March 2018 to June 2018). The rate of CINV, nausea, and vomiting was compared between the three cohorts using Chi-square test with Bonferroni correction. A P < 0.016 was considered statistically significant.

Results: Three hundred and sixty patients were selected for this analysis. There were 91 patients in the ondansetron prophylaxis group (25.3%), 113 (31.4%) in ondansetron plus domperidone group, and 156 (43.3%) in ondansetron plus olanzapine group. The overall incidence of CINV, nausea, and vomiting was 25.0% (n = 90); 25.0% (n = 90); and 7.2% (n = 26). Overall, the rate of CINV (P = 0.052), nausea (P = 0.052), and vomiting (P = 0.481) were similar in all three cohorts. However, the rate of Grade 2 and above nausea (P = 0.012) and vomiting (P = 0.015) was significantly lower in the olanzapine group.

Conclusion: The combination of ondansetron with olanzapine leads to statistically significant decrease in the rate of moderate-to-severe emesis and nausea and needs to be explored in a prospective study.

Keywords: Antiemetic, emesis, nausea, olanzapine, temozolomide

Histological diagnosis and grading of pilomyxoid astrocytomas: An enigma revisited

Hanni V Gulwani, Sukhpreet Kaur; Bhopal Memorial Hospital and Research Centre, Bhopal, Madhya Pradesh, India

Objectives: Pilomyxoid astrocytoma (PMA) was first officially described as a new separate entity in 2007. However, recent reports suggest close relationship between pilocytic astrocytoma (PA) and PMA with the latter maturing into classic PA overtime. Studies have suggested that usually, PMAs are more aggressive than PA with considerable variation in their clinical behavior. Our aims were to analyze the clinical presentation, radiologic findings, and postoperative follow-up in the PMA and PA subgroups, to critically observe and correlate the varied histomorphologic spectrum with clinical behavior, and to identify the relationship among the two entities.

Methods: Between 2003 and 2018, 17 patients with PA and PMA underwent treatment at BMHRC, Bhopal. Patient’s demographic features, radiological findings, and neuropathological spectrum were studied in both the groups. The mean follow-up period was 44.64 months (range 1–180 months).

Results: A total of 10 cases of PA and 5 cases of PMA and 2 cases of intermediate pilomyxoid tumor (IPMT) were included in the study. Median age of PA was 12 years while PMA was 13 years. Majority of patients in both the subgroups PA (80%) and PMA (60%) were in the first and second decades of life. Clinical presentation in majority of patients was headache and vomiting. The average size of tumor in PA was 4.5 cm whereas in PMA subgroup was 3.7 cm. Most common site of involvement in both the PMA and PA subgroups was cerebellum. Radiologically, more than 50% of cases demonstrated solid cystic tumor in both PA and PMA. Marked variation was observed in histological features among PA and PMA subgroups. Two cases that were earlier reported as PA were reclassified as IPMT due to significant overlapping of histologic features of both PMA and PA. In addition, focal myxoid change was noted in 25% cases of PA. Mean of MIB-1 labeling index in PA and PMA subgroups was 1.3% and 13.6%, respectively. Synaptophysin and vimentin expression was observed in majority of PA and PMA tumors. Tumor recurrence was noted in three cases of PA and one case of PMA.

Conclusion: PMA is a histological variant of PA; not all cases of PMA show aggressive behavior. Existence of intermediate cases with biphasic morphology suggests an intricate relationship among the two entities.

Curcumin potentiates the anticancer effect of 2-deoxy-D-glucose by inhibiting proliferation and migration in glioma

Kavita Peter, Ragini Gothalwal, Puneet Gandhi; BMHRC, Bhopal, Madhya Pradesh, India

Objective: Resistance to drugs remains an on-going challenge in malignant glioma chemotherapy. A rational combination of drugs which act synergistically targeting multiple mechanisms would thus be more potent in abrogating chemoresistance. In this study, we aimed to investigate the anticancer effects of a natural polyphenol curcumin (CUR) in combination with 2-deoxy-D-glucose (2-DG), a glycolytic inhibitor in human glioblastoma cells. CUR has been reported to have anticancer, antioxidant, and anti-inflammatory properties apart from being cancer cell-specific. 2-DG, a glycolytic inhibitor, has been found to be relatively ineffective as a single agent and is not regularly used for glioma therapy. However, the combination is novel as both the agents have the capacity to cross the blood–brain barrier, have presented an exceptional safety profile in clinical trials, and are being tested for the first time in combination.

Methods: The U-87 glioma cancer cells were chosen as the assay system as they simulate the heterogeneous GB in vitro and possess gliomasphere-forming capacity. The cells were treated with CUR, 2-DG, or CUR + 2-DG 0/0 h for 24 and 48 h. We evaluated cell survival by MTT assay, clone-forming ability by clonogenic assay, and cell migration by the wound-healing assay. To assess the combined action of the drugs, the combination index (CI) was analyzed. CIs >1, <1, and =1 indicate antagonism, synergism, and addictiveness, respectively.

Results: The antitumor effect of the drug combination was more than that seen for a single agent, at clinically relevant concentrations. CUR enhanced the antiproliferative effect of 2-DG in glial cancer cells. It also improved 2-DG induced inhibition of colony formation and cell migration. The combination of CUR and 2-DG showed a synergistic effect in reducing cell viability with a combination index of <0.9.

Conclusion: These data suggest that the combination therapy of CUR and 2-DG augments the anti-cancerous effect of 2-DG. Further studies are being undertaken to establish the potential of this novel combination to inhibit glioma stem cells which contribute to tumor recurrence and drug resistance.

Keywords: 2-Deoxyglucose combination therapy, curcumin, glioblastoma, synergism

Best adjuvant treatment in elderly glioblastoma: Results from a systematic review and network meta-analysis

Babusha Kalra, Sadhana Kannan, Tejpal Gupta; Department of Radiation Oncology and Clinical Research, Tata Memorial Centre, ACTREC, Navi Mumbai, Maharashtra, India

Introduction: Glioblastoma (GBM) is the most frequent malignant primary brain tumor accounting for 40% of primary central nervous system tumors in adults with a universally dismal prognosis. Recent data from the Central Brain Tumor Registry of the United States report 64 years as the median age at diagnosis for GBM and an increasing incidence with aging. The 1-year and 2-year relative survival rates of 40.7% and 14.2% for patients aged 55–64 years fall sharply to 9.2% and 2.6% for patients aged 75 years or older. Adjuvant therapy in the management of newly-diagnosed elderly GBM poses unique challenges due to limited life-expectancy (median survival ~6 months), existing comorbidities, and increased risk of treatment-related toxicity on the aging brain. Although several adjuvant therapy regimens have been tested in randomized controlled trials (RCTs) across the world, most elderly patients with newly-diagnosed GBM continue to be treated on personal and physician biases and preferences with significant cost and resource implications.

Aims and Objectives: The aim of this study was to identify the best adjuvant therapy regimen in elderly patients with newly-diagnosed GBM through a systematic review and network meta-analysis (NMA) of previously reported RCTs.

Materials and Methods: The study was designed and conducted in accordance with the Preferred Reporting in Systematic Reviews and Meta-analysis statement. Eligibility criteria were defined in terms of population, interventions, comparisons, outcomes, and study design criteria. Prospective RCTs that randomly assigned elderly patients with newly diagnosed GBM postoperatively to any adjuvant therapy regimen were included, provided there was a comparator arm. The definition of the elderly was arbitrary and variable in the included studies with the age cut-off ranging from 60 years and above to ≥70 years. Two investigators independently reviewed the full manuscripts of eligible studies and extracted information into an electronic database, including patient characteristics, inclusion and exclusion criteria, treatment regimen, and outcomes. The primary outcome measure was overall survival. Numbers of events, patients at-risk, and censored patients for survival and time-to-progression were estimated from Kaplan–Meier survival curves in 0–12 months, using the appropriate methodology. The total person-time at risk and the mortality or progression ×100 person-months was properly estimated.

The network was also checked for inconsistency to assess when the direct comparison of one treatment versus another one, derived from one or more studies included in the NMA, conflicts with evidence drawn via the indirect comparison estimated through the NMA. The restricted maximum likelihood method was used to estimate heterogeneity, assuming a common variance estimate across different comparisons for each single outcome considered. A frequentist approach of NMA was used to compare available treatment strategies within a single analytical framework. NMA was performed with Stata 14.0 (StataCorp, College Station, TX, USA) using the “network” command and routines developed by Chaimani and White. The relative ranking probability of each treatment was estimated, and rankograms were used to estimate the hierarchy of each intervention in terms of patient survival. The mean rank values and the surface under the cumulative ranking (SUCRA) curves were also calculated.

Results: A systematic literature search of the indexed medical literature identified 1278 abstracts, which were screened to retrieve the full-text of potentially eligible articles for detailed assessment. Eight publications corresponding to seven primary RCTs were included in the network. Data from 1569 patients from the seven index RCTs randomized to one of the following adjuvant therapy regimens was extracted and analyzed: normofractionated radiotherapy (RT) delivered over 5–6 weeks; moderately hypofractionated RT (2–3 weeks) either alone or in combination with temozolomide or bevacizumab; extreme hypofractionation (1 week); temozolomide alone; and best supportive care alone. In terms of overall survival, moderately hypofractionated RT (3 weeks) with concurrent plus adjuvant temozolomide emerged as the best and second-best adjuvant therapy option with 81% probability and 99.1% probability, respectively. Using SUCRA, the surface area for moderately hypofractionated RT (3 weeks) with concurrent plus adjuvant temozolomide reached almost 100%, confirming it to be the best intervention. As expected, the best supportive care alone was ranked as the worst treatment strategy in terms of overall survival.

Conclusion: This is the first attempt to compare RCTs in a network to rank various adjuvant therapy regimens in the management of elderly patients with newly diagnosed GBM. Moderately hypofractionated RT (3 weeks) with concurrent plus adjuvant temozolomide is associated with best overall survival and should be the preferred therapeutic regimen in elderly GBM.

Keywords: Adjuvant, elderly, glioblastoma, radiotherapy, temozolomide

Functional radiosurgery with CyberKnife: An effective noninvasive strategy for trigeminal neuralgia

Kushal Narang; Medanta-The Medicity, Gurugram, Haryana, India

Aims and Objectives: Stereotactic radiosurgery (SRS) is an effective nonsurgical option for patients of trigeminal neuralgia not controlled with medications. However, its application necessitates accurate knowledge of the trigeminal nerve anatomy, its precise localization and delineation on appropriate magnetic resonance imaging sequences, meticulous radiosurgical planning, and treatment delivery. We analyzed the pain response outcome for 12 cases of trigeminal neuralgia treated at our institute over the past 6 years.

Materials and Methods: Prospectively collected data from electronic medical records and CyberKnife treatment planning system were analyzed. Efficacy of response in the form of initial (within 3 months) and sustained pain relief was noted as per visual analog scale (VAS) and Barrow Neurological Institute (BNI) pain intensity score. The trends of pain response over time were assessed.

Results: The mean age was 61 years with male:female ratio of 1:3 and right:left laterality as 1:1. Pain along single division of the trigeminal nerve was observed in three, along two divisions in five, and along all three divisions in four cases. In 7/12 patients, a definite vascular loop compressing the trigeminal nerve was evident, 2/12 cases had associated trigeminal schwannomas, and no definite cause of pain was evident in 3/12 cases. All patients were medicine refractory cases and received CyberKnife SRS, with the target defined as the trigeminal nerve segment at 3–8 mm from the Root Entry Zone. The average SRS dose was 60.0 Gy, prescribed at a marginal isodose of 74%. Average Dmax was 80.0 Gy, and average Dmean was 70.1 Gy. Average brainstem maximum dose was 15.4 Gy. Fixed collimator-based planning using 5 mm and 7.5 mm collimators was employed in most cases. The two patients with associated trigeminal schwannomas additionally received 18 Gy in 3 fractions for schwannoma. Median available follow-up was 7 months (range 0–47 months). At 3 months post-SRS, 4/8 (50%) patients attained good pain relief on VAS (score between 0 and 3) and 2/8 (25%) had moderate pain relief (score between 4 and 6), resulting in an overall pain response in 6/8 (75%) patients. No or minimal pain relief (score > 7) occurred in the remaining 2/8 (25%) patients. BNI Score III was seen in 6/8 patients (75%) at 3 months, of which three patients attained BNI Score I at 6 months. Pain response was sustained beyond 1 year for all these patients. 2/8 (25%) patients had BNI Score IV or V, of which one patient had to undergo microvascular decompression at 3 months post-SRS. Recurrent pain occurred in two patients, at 15 and 18 months post-SRS, which was managed with medication. Of 12 patients, 4 (33%) patients reported one or more side effects including hypoesthesia, numbness, or dizziness on follow-up.

Conclusion: CyberKnife SRS gave an effective, immediate, and sustained pain relief in 75% of patients with trigeminal neuralgia that was refractory to medication.

Keywords: CyberKnife, radiosurgery, trigeminal neuralgia

A study to assess whether surgical resection of recurrent glioma improves survival and outcome among the patients

Sourabh Dixit; Bhopal Memorial Hospital and Research Centre, Bhopal, Madhya Pradesh, India

Aims and Objectives: (1) To assess whether surgical resection helps to improve survival and functional outcome in a patient of recurrent gliomas. (2) To compare the survival of operative group with a conservative group.

Materials and Methods: This is a prospective observational study. In the current study, a total of nine patients were included. Five patients underwent surgical resection and four patients refused the surgery. The patients were followed up for more than 6 months and pertinent characteristics were followed and data were collected. Statistical analysis was done and t-test was applied.

Results: Only two patents in operative had clear survival advantage as compared to conservative group.

Conclusion: In this study, we concluded that aggressive surgical resection failed to improve survival and functional outcome among patients.

Mitochondrial DNA copy number in new-onset and recurrent glioblastoma and its clinical significance

Palavalasa Sravya; Department of Clinical Neurosciences, NIMHANS, Bengaluru, Karnataka, India

Background: The biology behind therapeutic resistance of glioblastoma has been the topic of research for several years now. Although considerable insights into the glioblastoma nuclear gene milieu have been attained following the technology growth spurt, mitochondrial genome has remained in the shadows. Mitochondria orchestrate cellular metabolism which is known to be abnormal in malignancy. Evidence of altered mitochondrial DNA (mtDNA) content in several malignancies has surfaced in recent years. However, in glioblastoma, this aspect remains to be evaluated. Hence, the focus of our study is to delineate the role of mtDNA content in glioblastoma pathogenesis.

Aims and Objectives: To elucidate the mtDNA content in glioblastoma tumor tissue at first presentation and at recurrence and its prognostic significance and understand its role in radiation resistance.

Materials and Methods: Formalin-fixed paraffin-embedded tissues of newly diagnosed glioblastoma (n = 134), recurrent glioblastoma (n = 32), and nonneoplastic brain (n = 30) archived in the Department of Neuropathology, NIMHANS, were utilized for the study. U87 and LN229 cell lines were studied for the difference in mtDNA content following radiation exposure (2 and 4 Gy). Clinical details of the patients were obtained from their files. IDH, ATRX and TERT promoter mutations, MGMT promoter methylation, and EGFR amplification were assessed using immunohistochemistry (IHC), Sanger’s sequencing, methylation-specific PCR, and fluorescent in situ hybridization. The expression of nuclear genes known to regulate mtDNA replication, namely, PGC1 alpha, TFAM, and RRM2B, was assessed using IHC. mtDNA copy number was analyzed using quantitative real-time PCR (relative quantification). The mtDNA content was calculated as percentage of normal using the formula 2−ΔΔCT × 100.

Results: mtDNA content was lower than nonneoplastic brain tissue (mean mtDNA copy number 19.8) in all cases studied. Among the cases, the mtDNA content was significantly lower in older patients (P = 0.04). Among the molecular markers, IDH wild-type, MGMT-unmethylated, and EGFR-amplified tumors had a lower mean mtDNA copy number when compared to their counterparts, though not statistically significant. Survival analysis using Cox regression showed that lower mtDNA copy number is associated with higher risk and hence poorer prognosis (P = 0.047). Paired tumor analysis was performed in 32 patients with recurrence. Nineteen of these patients had received radiation therapy (RT) while the others had defaulted RT. The mtDNA content had increased at recurrence when compared to the primary tumor in all 19 cases who received RT (mean at diagnosis 20.32; mean at recurrence 48.02, P = 0.02). In the remaining 13 cases who did not receive RT, the mtDNA content had decreased significantly in 6 (46.1%) and was variable in the remaining. To understand this difference in copy number at recurrence, U87 and LN229 cell lines were subjected to radiation (2 and 4 Gy) and the difference in mtDNA copy number before and after radiation exposure was studied. Both the cell lines showed an increase of 15% in mtDNA content after 4 Gy radiation exposure. Among the nuclear genes known to regulate mtDNA replication, TFAM and RRM2B immunoreactivity was noted variably within glioblastoma tumor tissues while PGC1 alpha specifically stained the neurons in the peritumoral brain zone.

Conclusion: Our study, for the first time, elucidates mtDNA copy number in glioblastoma tumor tissue at diagnosis and at recurrence. We show that lower mtDNA copy number is associated with poorer survival in glioblastoma, further supported by the fact that tumors harboring markers associated with aggressiveness had lower mtDNA content. Our study also throws light on the expression of mtDNA regulatory nuclear genes in glioblastoma. The novel finding of this study is that RT increases the mtDNA content in both patient samples and malignant glioma cell lines. Hence, we establish the potentially significant role of mtDNA alterations in the pathogenesis and treatment resistance of glioblastoma.

Keywords: Clinical significance, glioblastoma, mitochondrial DNA, radiation resistance recurrence

Service evaluation of medulloblastoma at a tertiary care center treated over the past 8 years

Mohd Suhaib, Shalini Singh, Lily Pal1, K J Maria Das, Sushma Agrawal, A K Shrivastava2, Lokesh Sharma3, V L Bhatia3, Shaleen Kumar4; Departments of Radiotherapy, 1Pathology, 2Neuosurgery and 3Endocrinology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, 4Super Speciality Cancer Institute and Hospital, Lucknow, Uttar Pradesh, India

Aims and Objectives: Service evaluation of medulloblastoma at a tertiary care center treated over the past 8 years was carried out to assess management approach, toxicity, pattern of failure, and outcome.

Materials and Methods: Between 2011 and 2018, a total of 1771 patients of brain tumors were registered in the Department of Radiotherapy (RT), of which the medical records of histopathologically confirmed medulloblastoma were retrieved to abstract the demography, related treatment parameters, and outcome. Acute and late toxicity was documented as per CTCAE v 5.0. Overall survival was calculated from the time of surgery and computed by the Kaplan–Meier method. Death due to any cause and lost to follow-up was considered as an event for survival analysis, i.e., assuming the worst case scenario.

Results/Discussion: Sixty-two patients of medulloblastoma were registered in this period with a median age of presentation 11 years (range 1–63) with male predominance. Most of the patients presented with complaints of headache, nausea, and vomiting at median of 3 months (range 1–16). Magnetic resonance imaging at presentation was done in all patients with 79%, 8%, and 13% of the tumor located in midline, cerebellar hemisphere, and CP angle, respectively, with two-third showing patchy contrast enhancement. Nearly two-third patients had near-total excision as gleaned from neurosurgery discharge summaries. 83% were histologically classical type followed by 10% of desmoplastic variant, 5% of MBEN, and only 2% of large cell/anaplastic type. Molecular subtyping was available only in few patients (n = 4). A total of 44 patients took adjuvant RT at our institute of which 15 (34%) were high risk and 29 (66%) were categorized as low risk. All patients received CSI up to 36 Gy in 20 fractions followed by a boost of 18 Gy in 10 fractions to primary tumor area. Any spinal deposit was boosted up to 45 Gy (n = 5). No concurrent chemotherapy was used. Patients with high-risk group went on to receive adjuvant chemotherapy. Median duration of RT was 43 days (range 39–64). Generally, patients tolerated the RT with Grade 3 or more hematological toxicity reported in less than 4% and Grade 3 skin toxicity nearly 9%. All patients had pre- and post-RT endocrinological evaluation and replenishment of hormone when needed. At a median follow-up of 23 months (range 3–89), the median overall survival (OS) of all the patients was 66 months with 2-year and 5-year OS being 82% and 58%, respectively. On risk-based categorization, the median OS was 66 months versus NR (P = 0.97) with 2- and 5-year OS 80%, 65% and 83%, 51% for low and high-risk group, respectively.

Conclusion: Medulloblastoma is a disease of childhood. Multimodality approach based on risk categorization should be considered in the management of these patients to achieve optimal results. High-risk patients have poor outcomes

Keywords: Craniospinal radiotherapy, medulloblastoma, outcome

Prognostic role of preoperative FDG PET-CT in patients with IDH1-negative WHO Grade IV glioma

Indraja Devidas Dev; Resident, Tata Memorial Hospital, Parel, Mumbai

Aim: To assess role of metabolic parameters on FDG PET-CT in the prediction of outcome in patients with IDH-1-negative high-grade glioma.

Methods: This is a retrospective observational study. We included 33 patients who underwent 18F-FDG PET-CT preoperatively, with the intent of ruling out metastases. All patients underwent surgical resection, and postoperative histopathological diagnosis was Grade IV glioblastoma multiforme. Primary tumor SUVmax, MTV, TLG, and T/W ratio were calculated using tumor tracking software in PHILIPS EBW workstation. Overall survival was calculated from the date of FDG PET-CT done on the date of last clinical follow-up/death. Median of metabolic parameters was used to stratify into two groups. Survival graphs were drawn using Kaplan–Meier method and were compared using log-rank test. P < 0.05 was considered statistically significant.

Results: Median survival was 7 months (range of 1–40 months). Median values for SUVmax, T/W ratio, MTV, and TLG were 11.7, 1.8, 50, and 407, respectively. Higher T/W ratio, MTV, and TLG are statistically significant for prognostication in Grade IV glioma. Overall survival curve did not differ significantly for higher SUVmax groups. Average overall survival for T/W ratio >1.8 was 9 months while <1.8 was 21 months (P = 0.019). Average overall survival for MTV <50 was 6 months while <50 was 24 months. (P = 0.001). Average overall survival for TLG >403 was 5.8 months while for <403 was 24 months (P = 0.01).

Conclusion: FDG PET-CT-derived metabolic parameters have shown a significant role in prognosticating patients with IDH-negative Grade IV glioma.

Intracranial germ cell tumors: Insights from 15 consecutive cases

Kuntal Kanti Das: Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India

Aims and Objectives: Intracranial germ cell tumors (ICGCTs) are relatively rare and predominantly affect children and adolescents. These can be germinomas with very good survival or a group of nongerminomatous tumors with poorer prognosis. They are best managed by surgical debulking followed by radiochemotherapy. We operated 15 patients with a variety of GCTs over 5 years. We intend to share our experience with their management.

Materials and Methods: Between 2013 and 2018, we operated 15 patients with ICGCTs (male:female = 7:8). All were supratentorial and all except one affected the midline. Our surgical approach and intent depended on the tumor location and size.

Results and Discussion: The mean age was 17.47 ± 17.14 years (range 6–75 years). All but one patient was <20 years of age. Everyone had unifocal disease. Eight patients had suprasellar tumor, six had posterior third ventricular tumor, while one patient had basal ganglionic germinoma. The most common symptom was headache with vision loss (seen in 13 patients each). While germinomas were found in all the locations, nongerminomatous tumors (n = 3) tended to affect the suprasellar area only. We performed near-total tumor excision in four patients and subtotal excision in four patients, while the seven remaining patients underwent tumor biopsy with or without cerebrospinal fluid diversion. Of 11 patients available for follow-up (mean 17.4 months), five patients had tumor recurrence and three of them underwent re-surgery. Hemorrhagic complications such as operative site hematoma (2) and extradural hematoma (1) were seen in three patients.

Conclusion: The clinical presentation coupled with their size often call for expansive neurosurgical procedures. Histological sampling with minimally invasive biopsy procedures may fail to decipher the exact histoarchitecture of these tumors which may result in treatment failures.

Keywords: Biopsy, brain, germinoma, non-germinomatous tumor, radiotherapy surgery

Diagnostic and prognostic potential of a non-invasive panel of candidate molecular markers in glioma: Are we ready for the clinic?

Richa Shrivastava, Puneet Gandhi, Nitin Garg, Sandeep K Sorte, Jharna Mishra, Sukhpreet Kaur; Bhopal Memorial Hospital and Research Centre, Bhopal, Madhya Pradesh, India

Aims and Objectives: Glioma is the most prevalent intracranial malignancy, with content for latent progression; leading to unpredictable tumor behavior. It has a dismal prognosis, partly due to lack of molecular workup during routine radiological monitoring of the disease. Consequently, a number of molecular prognostic indicators are being characterized in line with current World Health Organization guidelines 2016 on central nervous system tumors. Quite a few tissue-based prognostic biomarkers with cited thresholds values are documented in the literature, but their clinical use becomes limited because of the attached invasiveness of repeat sampling required for detecting progression. Therefore, minimally invasive markers from blood to aid early diagnosis and prognosis of glioma are the need of the hour.

Material and Methods: Selection criteria of the study were adult subjects, with symptomatic indications such as headache, vomiting, seizures, and neurological deficit. No patient had undergone any intervention at the time of enrolment. Herein, candidate biomarkers Kynurenine (KYN), neutrophil-lymphocyte ratio (NLR), human telomerase reverse transcriptase (hTERT), human-chitinase-3-like-one protein (YKL-40), and tissue inhibitor of metalloproteinases-1 (TIMP-1) reflecting tumor-related inflammation, proliferation, angiogenesis, and ECM degradation were considered. The cohort comprising 79 glioma patients was stratified into two groups based on IDH-mutant (n = 49) and IDH-wild type (n = 30) status, with median age 35 and 51.5 years, respectively. Forty-five healthy subjects, without recent clinical history of inflammation, autoimmune or neurological disease, were taken as controls. Six milliliters of blood sample was collected before surgery as per institutional ethics approval and processed according to the standardized laboratory protocol. Quantitative comparisons were performed on the serum/plasma samples using enzyme-linked immune-sorbent assay technique. All the markers except NLR were validated in corresponding tissue samples (n = 30) by immunofluorescence-based histochemistry.

Statistical Analysis: Nonparametric statistical analysis was carried out on estimated data. Mann–Whitney test was used to differentiate between patients and controls; Spearman’s coefficient correlation was applied to check the association of markers with histological grade and overall survival (OS). OS defined as the time from randomization to death from any cause was considered as a direct measure of clinical benefit to the patient. Patients alive or lost to follow-up were treated as censored, for constructing Kaplan–Meier curves. Analysis of area under the curve for receiver operating characteristic (AUROC) was performed to define the cut-off values and sensitivity of the markers which attained ≥95% specificity. To establish the prognostication potential, we chose the multivariate Cox proportional regression model.

The diagnostic accuracy and the predictive probability of the candidate marker panel were verified using CombiROC software. The P value of all statistical tests was two-sided (P < 0.05).

Results: The systemic concentrations (median values) of markers in the identified groups were as follows; KYN – 73.109 ng/ml, 237.318 ng/ml; NLR – 3.41, 5.85; hTERT – 1.364 ng/l, 2.1865 ng/l; YKL-40 – 57.97 pg/ml, 101.15 pg/ml; and TIMP-1 81.715 ng/ml, 107.09 ng/ml, respectively. These were significantly different from controls; P < 0.0001, P < 0.0001, P = 0.028, P < 0.0001, and P = 0.0174, respectively. The expression of biomarkers was found to correlate with histopathological grade (r = 0.5685; P < 0.0001) and OS (r = −0.6137; P < 0.0001). Based on AUROCs, an optimal cutoff value to differentiate between IDH-mutant and IDH wild-type glioma patients was ascertained for KYN >22.89 with sensitivity = 87.34, specificity = 96.67; NLR >2.33 with sensitivity = 83.33, specificity = 93.33; hTERT >1.22 with sensitivity = 70.89, specificity = 73.33; YKL-40 >42.55 with sensitivity = 77.22, specificity = 83.33, and for TIMP-1 >70.9 with sensitivity = 73.42, specificity = 93.1. Using log-rank analysis, comparison of survival curves between wild-type and mutant samples provided optimal cutoff with significant hazard ratios for KYN = 3.176 (OS 22 vs. undefined months), NLR = 2.436 (20 vs. 48 months), and hTERT = 2.15 (18 vs. 48 months) respectively. Cox-regression analysis revealed that higher levels of these circulating markers were indicators of poor clinical outcome. The sensitivity of the panel increased to 98.7% in combination, thereby improving the accuracy of diagnosis. The panel could differentiate between IDH-wild-type and mutants with 100% sensitivity and specificity for the former group. Using multivariate analysis, all the markers were found to be independent of confounding factors namely age, site and extent of resection (P > 0.05).

Conclusion: The current findings suggest that increased levels of these molecular markers in blood correlate with a worse OS in glioma patients indicating that the panel can serve as potential prognosticator for glioma. Among these five markers, KYN and hTERT were evaluated for the first time in the plasma of glioma patients. Evaluating disease outcome noninvasively can pave way for designing targeted intervention to control inflammation, proliferation, angiogenesis, and in turn tumor progression. This study presented a novel panel of specific candidate molecular markers of glial tumor microenvironment for tailoring IDH signature-based therapeutic strategies.

Keywords: Combination panel, glioma, inflammation, noninvasive, overall survival, proliferation, tumor progression

Acknowledgment: Financial assistance from M.P Biotech Council Project no. 249 was acknowledged.

Comparison of different arc techniques for suprasellar and sellar tumors

K C Patro, C R Kundu, P S Bhattacharyya, V K Reddy, Madhuri Palla, Prashant Patel, A C Prabu, Subhra Das, Srinu Aketi, Anil Kumar; Mahatma Cancer Hospital and Research Institute, Visakhapatnam, Andhra Pradesh, 1Dhiraj Hospital, Waghodiya, Vadodara, Gujarat, India

Aim: The purpose of this study is to examine the plan quality, treatment planning time, monitor unit (MU) used, and estimated treatment delivery time for different volumetric arc modulation therapy (VMAT) plans for radiotherapy in suprasellar and sellar tumors.

Background: VMAT is a novel technique that has recently been made available for clinical use. Planning study was done for the evaluation of different VMAT.

Materials and Methods: A single patient of suprasellar meningioma was taken for different VMAT plans. For this, four VMAT plan Alexender, Helmet, Butterfly, and Carousel were created. Plans were evaluated based on ability to meet dose-volume constraints, dose homogeneity index, conformity index, planning time, and estimated delivery time. We had used multiple (1–3) arcs with different angel to angel, to meet our criteria. We had used three half arcs in Alexendar plan with noncoplanner beam too; it is more complex plan. We had used two half arcs in Butterfly and Helmet plans and single full arc in Carousel plan, which was not complex and simple plan. All plans had met the criteria for organ at-risk dose constraints with dose homogeneity and conformity.

Results: Carousel plan (full arc plan) with single arc had shorter planning time, shorted estimated treatment time, higher conformity index, and lower integral dose.

Conclusion: Carousel plan (full arc plan) had lesser MU and lesser delivery time with superior dose-volume constraints, and dose homogeneity.

Impact of interval imaging during focused radiation therapy for residual cystic craniopharyngiomas

Ranjith K Moorthy

Aims and Objectives: To study the changes in cyst volume detected on interval computed tomography (CT) in patients undergoing radiation therapy (RT) for residual cystic craniopharyngiomas after surgery.

Materials and Methods: A retrospective analysis of CT scans done during RT for residual cystic craniopharyngiomas between January 2005 and January 2018 was done. The volume of the tumor in CT/magnetic resonance imaging (MRI) done preoperatively, pre–RT, and during RT (after completion of 15 fractions) was determined. Interventions in those patients with increase in cyst volume were documented. The fate of the tumor at follow-up in those cases with increase in cyst volume was studied.

Results: Thirty-three patients who underwent surgical excision or aspiration of cystic craniopharyngiomas during the study period fulfilled the inclusion criteria. There were 23 males and 10 females; their median age at time of RT was 15 years (interquartile range [IQR], 8–21 years). Twenty-five patients underwent stereotactic RT and eight patients underwent conformal RT. The median preoperative tumor volume was 22.2cc (IQR, 13.9–36.2 cc). The median tumor volume following surgical excision or cyst aspiration was 7.1 cc (IQR, 2.9–13cc). The extent of resection/reduction in tumor volume following cyst aspiration was 66.5% ± 17.9% (range, 20.6%–88.9%). The median interval between tumor excision and the MRI/CT done for planning RT was 2 weeks (IQR, 1.5–5 weeks). The median tumor volume in the MRI/CT done for planning RT was 8.4 cc (IQR, 4.5–13.1 cc). 6 (18.2%) of the 33 patients had a median increase in cyst volume of 11.1 cc (IQR, 9.1–12.1cc; range, 6.3–40 cc) that necessitated additional intervention. The median time between the imaging done for planning and the interval CT was 30 days (IQR, 27–30 days). Four of these six patients underwent cyst aspiration to reduce the tumor volume followed by repeat planning of RT while the other two patients underwent repeat contouring of tumor and an increase in tumor volume being targeted. In five of these six patients, the increase in cyst volume was not associated with clinical symptoms. In the other 27 patients, the volume of the tumor remained stable and RT was continued with the initial planning target volume. The mean age of the patients who had significant cyst recurrence in the surveillance CT was 10.8 ± 3.6 years while that of the patients who did not have cyst recurrence was 20 ± 14.2 years (P = 0.002). 15 (55%) of the 27 patients with no cyst recurrence underwent gross total/near-total excision of cyst wall at initial surgery while only 1 (16.7%) of the 6 patients with cyst recurrence underwent near-total excision of cyst wall at surgery (P = 0.08). At median follow-up of 69 months, there was stable residue in three of the four patients who had cyst enlargement during RT and the other patient had a cystic recurrence distant from site of conformal RT at 132 months.

Conclusions: Cyst recurrence occurs in nearly one-fifth of patients with cystic craniopharyngiomas during RT. As nearly all these recurrences are asymptomatic and the recurrent cyst needs to be decompressed followed by recontouring of residue for conformal RT, interval CT scans midway through RT are essential to avoid missing part of the tumor.

Keywords: Conformal radiation therapy, craniopharyngiomas, multicompartmental, radiation therapy, stereotactic radiation therapy

Postoperative health-related quality of life outcome in supratentorial gliomas: A highly under-utilized surgical outcome measure

Deepak Khatri; Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India

Introduction: With improvements in overall and progression-free survivals (OS and PFS) in gliomas with the current standard of treatment, there is a paradigm shift observed in treatment objectives from “survival” to “functional outcome and quality of life (QOL).” Clinicians have started to focus on the “actual benefit” of surgery, rather than radiological extent of tumor removed. Patient’s outcome status is usually over-assessed by a clinician and a discrepancy exists in the actual outcome. Health and functional status of a patient is most accurately perceived by the patient himself/herself. Therefore, patient-reported outcomes are considered better than objective tools (OS, PFS, Karnofsky’s Performance Scale [KPS]) for QOL studies. However, such questionnaires are often time-consuming, often limiting their frequent use in neurosurgical practice. Most QOL studies conducted till date are either cross-sectional or retrospective. Large prospective studies assessing clinico-radiological and surgery-related factors responsible for QOL are still lacking. In addition, current health-related QOL (HRQOL) data in gliomas represent the scenario in western countries and similar studies are still deficient in our country. Here, we present a prospective analysis of postoperative QOL in glioma patients operated at our center.

Methods: HRQOL was evaluated prospectively in 103 patients between May 2016 and November 2017 at Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow. All included patients underwent maximum possible safe surgical excision, followed by histopathological examination, and received adjuvant therapy accordingly. Young (<18 years) patients and those with biopsy other than glioma were excluded. The level of performance impairment was evaluated using KPS in preoperative period and at follow-up. A licensed version of Short form-36 health survey questionnaire (Optum™ SF-36v2®) in English and Hindi language was used for evaluation of HRQOL objectively. It helps evaluate functional health and well-being of a patient using norm-based scoring across eight health domains – physical health, physical role (RP), bodily pain (BP), general health (GH), vitality, social functioning, emotional role, and mental health. The combined scores thus obtained give an overall objective assessment of patient’s functional status. All patients were asked to fill the survey forms at time of admission and postoperatively at 1 month, 3 months, 6 months, and 1 year of follow-up. The percentage of patients with highest (ceiling) and lowest (floor) possible scores at baseline was also recorded. Patient with floor score may not be able to appreciate any health deterioration (floor effect) or those with ceiling scores may not report any further improvement (ceiling effect). These effects are considered significant if >15% of patients achieved such scores. Changes in SF-36 scores were evaluated in terms of the smallest difference that a patient perceives clinically beneficial, termed as the minimum clinically important difference (MCID). Based upon previous QOL studies, we chose 0.5 standard deviation (SD) on a paired sample t-test as surrogate for MCID. Assessment of responsiveness of a scale establishes its validity for evaluation. A QOL scale should be able to detect the change whether improvement or deterioration in health over time.

In the present study, we utilized effect size (ES), relative efficiency (RE), and MCID for assessment of responsiveness. Effect size is defined as the mean change score divided by SD of baseline score. Cohen’s benchmarks were used to categorize the magnitude of ES as 0.20–0.49 is considered as small, 0.50–0.79 as moderate, and ≥0.80 as large. RE was measured as square of the absolute t-value for each health domain relative to the domain with the highest t-value. Thus, it helps to determine the likelihood of a particular domain to change after surgery. Cronbach’s alpha coefficient was used to assess the reliability of scale used in our study.

Results: Seizures were the most common (n = 57, 55.3%) presenting symptom followed closely by features of raised intracranial pressure (ICP, n = 50, 48.5%). Frontal lobe was most frequently (n = 36, 35%) involved, followed closely by insular (n = 24, 23.3%) gliomas. Fifty-nine patients (57.3%) had a good (80) KPS score, while there were 44 patients (42.7%) with poor KPS. Preoperatively, SF-36 score ranged from 0 to 100 in all domains except physical role (0–93.75) and general health (0–92). 17 patients (16.5%) scored 0 (floor score) in role limitation due to emotional problems, whereas no domain had a significant ceiling score. Mean preoperative score was lowest in physical role (36.73–29.25). Preoperative scores were significantly lower in patients who presented with features of raised ICP, neurological deficits, poor KPS, and large tumors (>4 cm), tumors in eloquent location, and deep-seated tumors. There was significant improvement in mean postoperative scores across all domains except physical role (P = 0.20). Calculated mean change ranged from 4.04 (RP domain) to 15.06 (BP domain). Mean score difference at first follow-up was found significant across all domains except physical role (P = 0.20). Among all factors studied, only a low baseline SF-36 score was significantly associated (P = 0.00) with change in QOL after surgery. Largest number of patients (n = 54, 55.7%) achieved their target MCID in GH domain. Overall, GH domain was most responsive to change with largest t-value (6.56). Social functioning domain showed the least improvement with only 30% of patients reaching target MCID value. At first follow-up, ES in various domains ranged from lowest 0.14 (RP domain) to highest 0.73 (GH domain). All domains showed improvement in effect size at serial follow-up. One month postoperatively, GH domain was found most responsive. However, improvements in bodily pain and mental health were most likely at successive follow-ups. The overall internal consistency of SF-36 scores as measured by Cronbach’s alpha coefficient ranged from 0.85 to 0.87 (excellent) in our study.

Conclusion: Most parameters of HRQOL improved following surgery. Only small-to-moderate improvements occur in the early follow-up period. However, large improving trends in perceived QOL are noted on long-term irrespective of the histopathological grade. Similar improvements are also noted in patients who undergo re-surgery, despite development of postoperative complications or new deficits. A low baseline QOL score heralds poor outcome in terms of survival. Therefore, HRQOL evaluation in glioma patients has considerable importance to guide treatment decisions, counseling their family, postoperative care, and further management plan.

Keywords: Glioma, life, postoperative, quality

Complications of endoscopic endonasal transsphenoidal surgery for sellar–suprasellar tumors and their avoidance: our experience

Pawan Goyal

Aims and Objectives: The present study assesses experience of endoscopic endonasal transsphenoidal surgery using neuronavigation for sellar suprasellar tumors at our center.

Materials and Methods: Data were analyzed from 50 consecutive patients with sellar suprasellar who underwent endoscopic endonasal transsphenoidal surgery using neuronavigation between June 2016 and December 2018. Follow-up was done up to 6 months.

Results: Gross total excision rate for pituitary adenomas was found to be inversely proportional to Knosp grading. Gross total excision was achieved in 100% cases in Grade 0 while it was 33.3% in Grade 3. Gross total excision was achieved in 65% cases. Cerebrospinal fluid (CSF) leak was noted in seven cases. Five cases were managed with lumbar drainage while two patients had to be reexplored for CSF leak repair. One patient developed subarachnoid hemorrhage. No mortality was observed. There were two cases of recurrent tumors in whom navigation was found to be extremely helpful.

Conclusion: The exclusive endoscopic approach is a safe, efficacious, and minimally invasive technique for treatment of sellar suprasellar tumors. There is a learning curve while shifting from microscopic to endoscopic approach. Hence, initial cases are associated with difficulties and complications which can be gradually overcome with patience and persistence.

Case selection for single sitting sequential trans-sphenoidal and cranial surgery for giant pituitary adenomas

Manish Baldia; Department of Neurosurgery, Christian Medical College, Vellore, Tamil Nadu, India

Objective: To define magnetic resonance (MR) based criteria for single sitting sequentially combined surgery (endoscopic trans-sphenoidal surgery [ETSS] followed by transcranial [TC] surgery) for giant pituitary adenomas (GPA).

Methods: Data on all patients with GPA operated between 2006 and 2017 were reviewed. We identified patients who underwent ETSS alone and those who underwent combined surgery and compared the MR characteristics of the tumors in these two groups to define criteria for selecting cases for the combined surgery. Shape (smooth, dumb-bell, and lobulated), number of lobulations (0 versus ≥1), extensions (anterior, lateral, and posterior), and encasement of vessels in the circle of Willis (present or absent) were noted. The total tumor volume (TTV), tumor extension volume (TEV), and suprasellar extension of tumor (SET) were calculated based on the lines drawn on MR images. Statistical analysis was done by calculating the mean, sensitivity, specificity, and receiver operating characteristic (ROC) curve for TTV, TEV, and SET.

Results: Of 80 patients with GPA, eight underwent combined approach surgery in the same sitting. Of 72 patients who underwent ETSS alone, 21 (29.1%) had lobulations, 26 (36.2%) had anterior/lateral extensions, and 12 (16.7%) had encasement of the circle of Willis. All eight patients who underwent a combined approach had multilobulated tumors, with anterior, posterior, or lateral extensions and encasement of the vessels of the circle of Willis (except one). The mean TTV, TEV, and SET for the combined surgery were significantly higher than those in the ETSS group (55.3 cc vs. 22.4cc, 10.8 cc vs. 2.26 cc, and 3.57 cm vs. 2.57 cm, respectively). The ROC curve, area under the curve, and P for TTV, TEV, and SET were 0.863, 0.967, 0.760 and 0.001, 0.001, 0.02, respectively.

Conclusion: GPA requiring combined surgery can be predicted preoperatively with specific MR characteristics and TEV volumes. The combined surgery should be considered when the TTV and TEV values are more than 40 cc and 2.2 cc, respectively. Encasement of vessels in the circle of Willis is also a significant factor.

Keywords: Combined surgery, craniotomy, endoscopy, giant pituitary adenoma, magnetic resonance imaging

Intracranial germ cell tumors: Clinicopathological spectrum, a tertiary cancer center experience

Ayushi Sahay; Tata Memorial Center, Mumbai, Maharashtra, India

Introduction: Intracranial germ cell tumors (ICGCTs) are rare and classified by the World Health Organization (WHO) as germinomatous and nongerminomatous germ cell tumors (NGGCT).

Aim: To assess the clinicopathological features of ICGCT diagnosed at our tertiary care cancer institute

Material and Methods: This was a retrospective observational study of all ICGCT diagnosed in the Department of Pathology, at our Institute from January 2007 to December 2018. Electronic medical records were reviewed for information regarding age, gender, presenting features, location, histopathological findings, tumor markers, treatment instituted, and follow-up, where available.

Results: A total of 70 patients were diagnosed as ICGCT, of which one patient (62-year-old male with parietal region mixed GCT) was found to have a concomitant testicular mass and was excluded from further evaluation. ICGCT formed approximately 0.46% of all primary brain tumors, and 3.5% of pediatric brain tumors histologically diagnosed at our hospital during this period. The age range was 6 months to 32 years (median age 14 years). There were five patients aged <3 years, 50 patients aged between 4 and 18 years, 13 patients between 19 and 30 years, and only one patient older than 30 years; hence, approximately 75% of patients were pediatric age. There were 44 males and 25 females (male:female = 1.76:1). All the infantile group patients (<3 years) were males. Duration of symptoms varied from 10 days to 4 years (average 8 months). Location was most commonly sellar/suprasellar (27/69, 39.1%), as well as pineal/posterior third ventricular (27/69, 39.1%), and one case with both suprasellar and pineal involvement. Other rarer sites included posterior fossa (3 cases), midbrain (1 case), corpus callosum (1 case), and 9 cases of nonmidline parenchymal location (3 thalamic, 2 left frontal, 2 right frontal, 1 left cerebellar, and 1 right cerebellopontine angle). Five of these nonmidline location tumors (thalamic, CP angle, and frontal) were proven nonmetastatic clinically, while others were referral cases, and their clinical details were not available.

Predominant histology was germinoma (44/69, 63.7%), followed by NGGCT (15/69, 21.7%) and mixed germinomatous GCT and NGGCT (10/69, 14.4%). Among the NGGCT, nine were pure teratomatous tumors (8 immature, 1 mature), while the rest had variable proportions of other components including yolk sac, choriocarcinoma, or embryonal carcinoma. Eleven germinoma cases showed associated epithelioid granulomatous reaction. In one case of germinoma in an 8-year-old female with a CP angle tumor, syncytiotrophoblastic giant cells were noted on histology, although no other GCT components were seen. Interestingly, all the infantile age group patients (<3 years), showed NGGCT histology (4/5 immature teratoma and one NGGCT with predominantly yolk sac tumor component). The pediatric age group patients (4–18 years) showed a predominance of germinomatous morphology (35/50, 70%), and similarly, adults (>18 yrs) also showed a preponderance of germinomas (9/14, 64.2%) as compared to NGGCT (2/14, 14.2%) and mixed histology (3/14, 21.4%). In a 26-year-old male patient with NGGCT in non midline location, high-grade sarcomatous transformation was seen. Germinomas were almost equally distributed between males and females (56% in males vs. 44% in females); however, nonpure germinomatous morphology was predominantly seen in males (19/25, 76% vs. 6/25 in females, 24%). Furthermore, among the NGGCT, immature teratomas were seen only in males (8/8).

Radiologically, tumor size varied from 1.7 to 7 cm (average 3.9 cm). Germinomatous morphology tumors were slightly smaller on average than nongerminomatous morphology (3.76 cm vs. 4.3 cm).

On assessing the histology vis-a-vis the location of tumor, all the posterior fossa tumors were nongerminomatous immature teratoma (3/3). Majority of the sellar/suprasellar tumors (22/27, 81.5%) and other midline locations such as corpus callosal, midbrain, and all nonmidline thalamic tumors were germinomas. However, pineal/third ventricular location showed almost equal distribution between germinomatous and nongerminomatous histology (12/27 and 15/27, respectively).

On magnetic resonance imaging (MRI) spine screening, spinal dissemination was identified in six patients (out of 32 with available data), out of which three also showed concomitant positive cerebrospinal fluid (CSF) cytology. In one case, CSF cytology was positive but MRI spine screening was negative.

Follow-up was available for 37 patients. Duration of follow-up ranged from 4 months to 10 years (median follow-up duration 2 years). Three patients of NSGCT (1 posterior fossa and 1 suprasellar immature teratoma, and 1 third ventricular mixed yolk sac and teratoma) and one of mixed GCT progressed on treatment while one patient of pineal immature teratoma died due to progressive disease (total 4 out of 11 nonpure germinomatous morphology with follow-up). In contrast, out of 26 pure germinoma patients with follow-up, only one of the cases showed relapse 2 years after radiotherapy, although two patients died due to metabolic complications of associated central diabetes insipidus and one due to complications associated with chemotherapy.

Conclusions: ICGCT were tumors of the second decade with male preponderance and majority occurred in the pineal/sellar location. About two-third were pure germinomas on histology and were associated with good prognosis. NGGCTs were more common in infants and males and in posterior fossa location. Immature teratomas were seen exclusively in males. Although majority of the ICGCT are in midline location, rarely nonmidline involvement can also be seen, and it is essential to exclude a metastatic lesion before considering a primary brain ICGCT. Expectedly, mixed and nonpure germinomatous tumors were associated with poorer prognosis, as compared to pure germinomas.

Radiological characteristics of RELA fusion-associated marker-L1CAM-positive supratentorial ependymomas

Vishal Malavade, Uday Krishna, S D Madhu, T Naveen, Lokesh Vishwanath; Departments of Radiation Oncology and 1Radiodiagnosis, Kidwai Memorial Institute of Oncology, Bengaluru, Karnataka, India

Introduction: Presence of RELA fusion in supratentorial ependymomas carries poor prognosis compared to those with negative tumors, and L1CAM is a marker associated with this fusion gene. We intend to describe radiological characteristics of RELA fusion-associated marker-L1CAM-positive supratentorial ependymomas.

Materials and Methods: Preoperative scans (contrast enhanced computed tomography [CECT] and gadolinium-magnetic resonance imaging [Gado-MRI]) of patients diagnosed with RELA fusion-associated marker-L1CAM-positive supratentorial ependymoma were reviewed independently by a radiologist and a radiation oncologist. The findings on T1W, T2W FLAIR, and postcontrast Gado and CECT scans for both the cohort of patients was compared.

Results: The median age group of the cohort of patients with ST-EPEN (5: L1CAM+ vs. 1: L1CAM−) was 16 years. All patients had presented with features of raised ICT due to hydrocephalus, 80% patients had undergone total excision followed by adjuvant radiotherapy. MRI of patients with L1CAM+ tumors showed a large, enhancing cystic lesion with a peripheral small enhancing mural nodule toward the ventricle. CECT scan showed a solid cystic lesion with large cystic component and peripherally situated enhancing cyst wall. Comparison of radiological findings between the two cohorts showed that L1CAM − patient had larger peripherally situated solid component with mass effect and smaller cystic component and heterogeneous enhancement of the entire solid component. Two patients previously diagnosed as Grade 2 ependymoma at recurrence as anaplastic these patients had the classic RELA fusion MRI picture, concordant MRI findings even at initial diagnosis. Two patients with recurrent anaplastic ependymoma had discordant MRI findings at recurrence-attaining the RELA fusion picture at recurrence. Overall survival of patients with L1CAM-positive tumors at a median follow-up of 1 year was inferior compared to those with L1CAM negative.

Conclusions: L1CAM (which is an associated marker of RELA fusion)-positive supratentorial ependymomas, predominantly found in younger children and being aggressive tumors, have unique radiological characteristics to differentiate from their counterparts. It aids in identifying the molecular subtype preoperatively to guide extent of surgical excision and optimize further adjuvant therapy for patients at initial diagnosis or at recurrence.

Adjuvant radiotherapy for atypical meningiomas

V Hemalatha, A S Uday Krishna, C Varatharaj, P Siddanna, P Tanvir, T Naveen, V Lokesh, Departments of Radiation Oncology and 1Radiation Physics, Kidwai Memorial Institute of Oncology, Bengaluru, Karnataka, India

Introduction: To assess the prognostic significance of various patient-related, tumor-related, and therapy-related factors on outcomes of atypical meningiomas treated at our institute with adjuvant radiotherapy.

Materials and Methods: Prospective database of 30 patients with atypical meningioma (14: skull base vs. 16: convexity) who had previously undergone surgical excision (Simpsons – Grade 1 only in 8; more than Grade 2 in 22) and were referred for adjuvant radiotherapy was reviewed for long-term local control. Patients were treated either by 3DCRT/IMRT/VMAT (coplanar beam arrangement: 15 vs. noncoplanar beam arrangement: 15) to a dose of 54–60 Gy in 25–30 fractions. Long-term local control was defined as complete radiological regression of the lesion. Impact of various factors (such as age of the patients [stratified into 3 groups as <40, 41–60, and >61 years], gender, duration and type of the presenting complaint, location of the lesion, extent of surgery, type of radiotherapy plan and total dose of radiation [and dose/fraction]) on time to complete response was analyzed.

Results: The median age of the cohort was 45 years (13:male17:female). The most common presenting complaint was weakness (long tract signs/CN palsy) in 45% of them and combination of weakness and seizure in the remaining with symptoms lasting for a median duration of 6 months in 60% of the patients before diagnosis. 75% of the patients with convexity meningiomas had Simpsons >2 surgery. At a median follow-up of 18 months, 64% had achieved local control, 70% in convexity versus 57% in skull base meningiomas (P = nonsignificant [NS]). Woman with convexity meningiomas had superior long-term local control compared to men (P = NS), while in skull base meningiomas, gender of the patient did not have any impact. Patients aged <40 years with skull base meningiomas and aged 41–60 years with convexity meningiomas had higher local control rates, while in patients aged <61 years, there was no difference. Extent of surgery in skull base lesions did not have any impact while in convexity meningiomas a Simpsons Grade 2 or higher was better (P = 0.08). Patients who received noncoplanar beam arrangement of radiotherapy had superior long-term local control compared to those with coplanar beam arrangement (P = 0.04). Total dose of radiotherapy of >54 Gy and dose per fraction of 2 Gy had significant impact on long-term local control (P = 0.04).

Conclusion: Women with atypical meningiomas have longer local control compared to men. Extent of surgery is an important factor for convexity meningioma. Type of radiotherapy plan and total dose of radiation has significant impact on local control, irrespective of location of an atypical meningioma.

Optimal radiotherapy for midline benign/intermediate tumors at various locations

Anup Hegde, Uday Krishna, H B Dhoke, C Varatharaj, T Naveen, V Lokesh; Department of Radiation Oncology and Radiation Physics, Kidwai Memorial Institute of Oncology, Bengaluru, Karnataka, India

Purpose: To define dosimetrically optimal radiotherapy plans for anterior, middle, and posterior midline benign/intermediate-grade tumors.

Materials and Methods: Computed tomographic data sets of six patients with midline benign/intermediate-grade tumors (2, anterior [craniopharyngioma]; 2, middle [pineal parenchymal tumors of intermediate grade]; and 2, posterior [vermian/brainstem recurrent pilocytic astrocytoma]) was utilized to generate three sets of radiotherapy plans on Monaco platform of Elekta system (step and shoot IMRT [7 beam arrangement with/without noncoplanar beams], coplanar [full arc for middle tumors], noncoplanar arc [anterior or posterior partial arc + noncoplanar partial arc]). All the plans were optimized to deliver 100% dose to 100% PTV with prescription dose of 54 Gy in 30 fractions. Between the three plans, we compared doses to organs at risk (D30% of normal brain, V40 B/L temporal lobes, dose to 1% of optic apparatus, and 1 cc brainstem) based on the location of PTV. Set of three plans for each site was later compared to plans made on similar historical patients planned and treated on the Varian system with Eclipse platform.

Results: With neck in flexion, noncoplanar step and shoot IMRT plan has higher sparing of the brain, temporal lobe, and optic apparatus for the anterior midline tumors. Full coplanar arc in middle midline tumors was superior in normal brain sparing, and for the posterior midline tumors, noncoplanar partial arcs gave superior dosimetry compared to IMRT/coplanar arc plans. Arc-based IMRT planning process was faster with lesser delivery monitor units compared to the step and shoot IMRT.

Conclusion: It is essential to optimize radiotherapy plans for midline tumors at various locations in the brain, for each has varied pathogenesis and aggressiveness to deliver therapeutic radiation with acceptable toxicity. We describe optimal radiotherapy techniques for each of the location.

Glioblastoma diagnosed during treatment for colonic carcinoma identifies a child with the constitutional mismatch repair deficiency: A case report

Anirban Das, Lateef Zameer, Rimpa Basu Achari, K S Reghu, Bivas Biswas, Gopal Achari, Saugata Sen, Sheetal Kulkarni Modi, Arpita Bhattacharyya; Tata Medical Center, Kolkata, West Bengal, India

Objective: Pediatric high-grade gliomas are tumors with poor prognosis. A subset may be associated with inherited cancer predisposition syndrome, having therapeutic and genetic implications. We report a diagnosis of the constitutional mismatch repair deficiency (CMMRD) in a child who developed glioblastoma, while on treatment for colonic carcinoma.

Methods: Immunohistochemistry (IHC) was performed using monoclonal antibodies (Dako, Agilent Technologies, USA) for the mismatch repair proteins, MSH2, MSH6, PMS2, and MLH1.

Case Report: A 9-year-old boy presented with a history of pain abdomen and constipation for 2 months. Clinical examination was unremarkable. There was neither history of consanguinity nor any family history of malignancy. Ultrasonography revealed mild concentric mural thickening in the splenic flexure of the colon. Computed tomography revealed circumferential wall thickening of sigmoid colon with pericolic fat stranding and increased vascularity, with enlarged mesenteric lymph nodes and mild ascites. Colonoscopy revealed a polypoid structuring lesion in the mid-sigmoid colon, obliterating the lumen. Exploratory laparotomy with resection of the sigmoid colon with lymph nodal sampling and a colostomy were performed. The pathology was reported as moderately differentiated adenocarcinoma of the colon (pT3 N0 M0). Postoperative imaging showed no evidence of residual disease. A decision was taken to treat with eight cycles of single-agent capecitabine.

Following Cycle 5 of capecitabine, the child presented to the emergency with headache and vomiting. Computed tomography of the brain revealed a 6 cm × 4 cm × 3 cm, well-defined solid-cystic lesion with postcontrast enhancement of solid areas and peripheral rim in the right frontal lobe involving the gray–white matter interface and subcortical white matter, causing subfalcine herniation. Craniotomy was performed and the tumor was surgically removed. The pathology was reported as glioblastoma.

Both the colonic and the brain tumor specimens were tested by IHC for expression of MSH2, MSH6, MLH1, and PMS2 proteins. In view of the loss of nuclear expression of PMS2 in both the tumor cells, as well as the native normal tissue, germline biallelic mutation of PMS2 was suspected, suggestive of CMMRD. Germline genetic testing has been performed and results are awaited.

The child received radiotherapy of 59.4 Gy over 33 fractions to the residual tumor in the right frontoparietal region with adequate margins. Fluorodeoxyglucose-positron emission tomography revealed no metabolically active lesions elsewhere. Posttreatment complications included a pseudomeningocele requiring repeated lumbar punctures and dexamethasone. Magnetic resonance imaging (MRI) performed 6 weeks after the end of radiotherapy revealed a residual mass which was excised. Repeat imaging showed no significant residual disease.

Conclusion: The metachronous presentation of a high-grade glioma and colonic carcinoma in a young child led to the suspicion of an inherited cancer predisposition syndrome, even in the absence of consanguinity, family history, and characteristic clinical findings. IHC demonstrated absence of expression of PMS2 protein in both tumor and normal tissue, suggesting a diagnosis of CMMRD. This is of significance, as in addition to surveillance for future malignancy and screening family members; these hypermutated tumors with poor prognosis do not benefit from temozolomide but are now known to respond to immunotherapy.

Keywords: Adenocarcinoma colon, GBM, inherited cancer predisposition

Acknowledgment: We gratefully acknowledge the guidance and advice of Dr. Uri Tabori, Hospital for Sick Children, Toronto, in managing this patient.

Germline DICER-1-mutant intracranial spindle cell sarcoma with rhabdomyosarcoma-like features and pulmonary metastases in an adolescent girl: A case report

Anirban Das, Sheetal Kulkarni Modi, Paromita Roy, Rimpa Basu Achari, Saugata Sen, Arpita Bhattacharyya; Tata Medical Center, Kolkata, West Bengal, India

Objective: Pediatric intracranial mesenchymal tumors are rare and pose a diagnostic challenge. Recently, a group of pediatric intracranial sarcomas have been described, which are histologically heterogeneous, but homogeneous at the molecular level, with a characteristic methylation profile. We describe an adolescent girl with this novel entity, associated with germline DICER-1 mutation, the first such report from India.

Methods: Histopathology was reported at Tata Medical Center, Kolkata, and reviewed at the All India Institute of Medical Science, New Delhi. Molecular analysis was performed in the framework of Pediatric Targeted Therapy 2.0 at the German Cancer Research Center (DKFZ), Heidelberg using Illumina Human Methylation 850 (850k) Array. Mutational analysis on tumor DNA was performed via next-generation sequencing (NGS) on Illumina NextSeq platform for 130 brain tumor-related genes applying the panel NPHD2015A, enriched with Agilent Sure-Select method.

Case Report: A 12-year-old girl presented with headache, left-sided hemiparesis, and seizures. Magnetic resonance imaging (MRI) was suggestive of a 7 cm × 5.7 cm, heterogeneous space-occupying lesion in the right frontoparietal per-falcine region, with post-contrast enhancement and midline shift. Following partial resection, the child was referred with a diagnosis of an embryonal tumor with metaplastic changes. On examination, she had spastic hemiplegia with intact higher motor and cranial nerve function. MRI demonstrated residual tumor, with imaging of the spine, and the cerebrospinal fluid examination was normal. Histopathology demonstrated sheets of malignant oval-to-spindle cells with prominent mitosis and apoptosis, with multiple abrupt island of cartilage and spindled tumor cell nuclei streaming out of the chondroid foci. IHC with desmin, myogenin, and myo-D1 showed patchy but strong staining in the spindle cell component, while GFAP, NSE, and synaptophysin were negative. INI-1 was retained and CD99 demonstrated a weak membranous pattern of staining in the spindle cell component, which was absent in the cartilaginous area. A diagnosis of mesenchymal chondrosarcoma with rhabdomyosarcomatous component was favored. Alfa-fetoprotein and beta-HCG were normal. Chest X-ray was unremarkable.

The child presented 12 days later with raised intracranial pressure, and the MRI revealed increase in size of the lesion as compared with the postoperative scan. Re-surgery with gross total resection was performed. In view of the aggressive nature of the malignancy, this was followed immediately by radiotherapy of 59.4 Gy in 33 fractions to the tumor cavity, with adequate margins. After multidisciplinary discussion, the child was started on chemotherapy with vincristine, doxorubicin, and cyclophosphamide (VDC), alternating with ifosfamide, cisplatin, and etoposide (ICE).

Meanwhile, it was reported that the DNA methylation profile had not matched any of the established methylation classes for central nervous system (CNS) tumors. However, it did demonstrate the highest concordance with the methylation class “CNS/embryonal rhabdomyosarcoma,” though this did not reach the diagnostic reference range. Copy number profile revealed gain of chromosome 1q and a gain of chromosome 8. Mutational analysis on tumor DNA by NGS revealed a non-sense mutation c.C1870T, p.R624X in exon 11 of the DICER1 gene, resulting in a premature stop codon and protein truncation. Sanger sequencing of the respective gene on the blood DNA confirmed the same mutation in the DICER1 gene already detected with NGS. In addition, a second, somatic mis-sense mutation was detected in the tumor in exon 25 of the DICER1 gene (c.A5438C, p.E1813A). Co-occurrence of two mutations in DICER1 has been previously been described in tumors arising in patients with the DICER1 syndrome.

After the above results, a computed tomography (CT) of the chest was performed, and this revealed bilateral pulmonary nodules of maximum size 1.3 cm × 1 cm. Ultrasound of abdomen, pelvis, and thyroid and ophthalmological evaluation were unremarkable. Following five alternating cycles each of VDC and ICE, the child was treated with vincristine, actinomycin-D, and cyclophosphamide for a total duration of 45 weeks. At end of treatment, the MRI brain revealed no active disease in the brain, while the FDG-PET images revealed multiple tiny, calcified, nonavid lesions in the lung. As the latter were not amenable to surgery, the child continues to remain on close follow-up and is well 4 months after completion of therapy.

Conclusion: We report the first case of the recently proposed “spindle cell sarcoma with rhabdomyosarcoma-like features, DICER1-mutant” intracranial tumor from India. The clinical behavior of this newly classified entity is not known but is seemingly aggressive from available reports. She was treated based on principles derived from previous reports of successful treatment of intracranial rhabdomyosarcoma. The child also had germline mutation of DICER1 suggestive of DICER1 syndrome, without any prior features to suggest this inherited cancer predisposition syndrome. Although long-term outcome is awaited, she is currently well and being followed up as per the recently published surveillance strategy for the DICER1 syndrome.

Keywords: Central nervous system sarcoma, DICER1 syndrome, multimodal treatment

Acknowledgment: We gratefully acknowledge the guidance and advice of Prof. Stefan Rutkowski, Dr. Chitra Sarkar, Dr. Jonas Ecker, Dr. Kris Ann Schultz, Dr. Ibrahim Quaddomi, Dr. Ashley Hill, and Dr. Junne Kamihara in diagnosing and managing this patient, and the Pediatric Targeted Therapy 2.0 program at the German Cancer Research Center (DKFZ), Heidelberg, for the comprehensive molecular testing.

Case selection for single sitting sequential trans-sphenoidal and cranial surgery for giant pituitary adenomas

Manish Baldia; Department of Neurosurgery, Christian Medical College, Vellore, Tamil Nadu, India

Objective: To define magnetic resonance (MR) based criteria for single sitting sequentially combined surgery (endoscopic trans-sphenoidal surgery [ETSS] followed by transcranial [TC] surgery) for giant pituitary adenomas (GPA).

Methods: Data on all patients with GPA operated between 2006 and 2017 were reviewed. We identified patients who underwent ETSS alone and those who underwent combined surgery and compared the MR characteristics of the tumors in these two groups to define criteria for selecting cases for the combined surgery. Shape (smooth, dumb-bell, and lobulated), number of lobulations (0 versus ≥1), extensions (anterior, lateral, and posterior), and encasement of vessels in the circle of Willis (present or absent) were noted. The total tumor volume (TTV), tumor extension volume (TEV), and suprasellar extension of tumor (SET) were calculated based on the lines drawn on MR images. Statistical analysis was done by calculating the mean, sensitivity, specificity, and receiver operating characteristic (ROC) curve for TTV, TEV, and SET.

Results: Of 80 patients with GPA, eight underwent combined approach surgery in the same sitting. Of 72 patients who underwent ETSS alone, 21 (29.1%) had lobulations, 26 (36.2%) had anterior/lateral extensions, and 12 (16.7%) had encasement of the circle of Willis. All eight patients who underwent a combined approach had multilobulated tumors, with anterior, posterior, or lateral extensions and encasement of the vessels of the circle of Willis (except one). The mean TTV, TEV, and SET for the combined surgery were significantly higher than those in the ETSS group (55.3 cc vs. 22.4cc, 10.8 cc vs. 2.26 cc, and 3.57 cm vs. 2.57 cm, respectively). The ROC curve, area under the curve, and P for TTV, TEV, and SET were 0.863, 0.967, 0.760 and 0.001, 0.001, 0.02, respectively.

Conclusion: GPA requiring combined surgery can be predicted preoperatively with specific MR characteristics and TEV volumes. The combined surgery should be considered when the TTV and TEV values are more than 40 cc and 2.2 cc,respectively. Encasement of vessels in the circle of Willis is also a significant factor.

Keywords: Combined surgery, craniotomy, endoscopy, giant pituitary adenoma, magnetic resonance imaging

Infant brain tumors: A tale of two cities

Satya Shiva Munjal; PGIMER and RMC Hospital, New Delhi, India

Introduction: Infantile brain tumors (age <1 year) are increasingly being diagnosed due to advances in prenatal and perinatal diagnostic imaging. We present here our retrospective study of 64 infant brain tumors that brings to the fore the epidemiology, clinical presentation, pathology, and outcome of this unique subset of pediatric brain tumors presenting to two tertiary referral centers at Kolkata in India and Lille in France between 1999 and 2014.

Methods: Data were retrospectively collected from Kolkata (n = 30) and Lille (n = 34) for patients presenting with infant brain tumors and analyzed for factors such as age at presentation, clinical features, gender, location of tumor, pathology, management, and outcome. Follow-up was available for all patients.

Results: The mean age at presentation was 6.8 months at Kolkata and 6.3 months at Lille. More than two-thirds of tumors in both the groups were supratentorial and presented with signs of raised intracranial pressure. There were also a similar proportion of tumors presenting as congenital tumors. At Kolkata, germ cell tumors (n = 7) were the most common while low-grade gliomas (n = 11) formed the largest group at Lille. Kolkata had a higher incidence of high-grade gliomas (n = 5) and PNETs (n = 4) while ATRT (n = 3) and choroid plexus carcinoma (n = 4) were more common at Lille. Surgery was the mainstay of treatment at both centers.

Conclusion: Brain tumors in infants presenting to tertiary centers in Europe and India are challenging to manage and usually have dismal prognosis. These tumors differ markedly in the pathology and, therefore, overall outcome. Surgery forms mainstay of treatment. Radiotherapy is best avoided in this age group.

Keywords: Congenital brain tumors, infant brain tumors

SERPINA3: A novel biomarker with invasive properties is associated with poor patient prognosis and tumor recurrence in glioblastoma

Vidya Prasad Nimbalkar; National Institute of Mental Health and Neurosciences, Bengaluru, Karnataka, India

Introduction: Glioblastoma (GBM) patients have a dismal prognosis despite aggressive treatment and the tumors invariably recur. In our previous microarray-based study, we identified SERPINA3 as a highly expressed gene in the tumor core and peritumoral brain zone (PBZ) of GBM. SERPINA3, a member of serine protease inhibitors superfamily, is a secreted, acute-phase protein, with antichymotrypsin activity and is associated with inflammatory processes. SERPINA3 expression and functions have been studied in various malignancies although infrequently in GBM. Hence, the purpose of this study was to understand the role of SERPINA3 in the pathobiology of GBM.

Aims and Objectives: In this study, we aimed to assess the expression pattern of SERPINA3 at the mRNA and protein levels in the tumor core and PBZ of GBM, to evaluate its association with patient prognosis and tumor recurrence, and to study its in vitro functional characteristics.

Materials and Methods: SERPINA3 expression was assessed at the mRNA level by quantitative real-time polymerase chain reaction (qRT PCR) and at the protein level by immunohistochemistry (IHC) on GBM tumor core and PBZ samples (n = 37) and control brain tissues (n = 20). IHC was also performed on GBM tumors from a larger retrospective cohort of patients with available treatment and follow-up data (n = 113). To study the expression of SERPINA3 at recurrence, IHC was carried out on paired GBM samples (newly diagnosed and recurrent, n = 20 pairs). The labeling index (LI) was calculated as the percentage of cells expressing cytoplasmic and membrane positivity in each tumor. The expression of SERPINA3 was assessed in two publicly available datasets, The Cancer Genome  Atlas More Details (TCGA) and Rembrandt datasets, using the betastasis online tool. Clinically relevant GBM biomarkers, i.e., IDH, ATRX, TERT promoter mutations, and MGMT promoter methylation were assessed using IHC, Sanger’s sequencing, and methylation-specific PCR, respectively, and SERPINA3 expression was correlated with these markers. Appropriate statistical analysis was carried out using SPSS (version 20). SERPINA3 correlation with patient prognosis was analyzed using Kaplan–Meier survival curve analysis. Functional characterization was carried out in vitro using shRNA knockdown approach in malignant glioma cell lines. Role of SERPINA3 in invasion, migration, and proliferation was studied using Boyden chamber, Scratch, and MTT assays, respectively.

Results: The mRNA and protein expression of SERPINA3 in tumor core and PBZ were significantly higher compared to control samples (P < 0.0001), validating our previous microarray data as well as TCGA and Rembrandt datasets. We observed that despite the PBZ having fewer tumor cells when compared to the tumor core, the mRNA expression of SERPINA3 was almost similar in PBZ compared to tumor core (median log 2fold change of core vs. PBZ = 4.07 vs. 4.03) and the IHC expression was higher in PBZ compared to tumor core (median LI of core vs. PBZ = 37.5 vs. 40).

The immunoreactivity pattern of SERPINA3 in GBM was variable with predominant cytoplasmic and membrane staining of tumor cells which was considered for calculating the LI. Occasional nuclear staining and focal stromal staining of variable intensity were noted in several tumors. SERPINA3 levels were associated with poor overall survival in GBM patients. Based on median LI of SERPINA3, survival cohort was divided into high and low expression group. The median survival of patients with high SERPINA3 expression in the tumor was 15 months versus 8 months in cases with low expression (P < 0.0001). Recurrent GBM samples showed significantly increased SERPINA3 expression as compared to newly diagnosed GBM samples (median LI 35 vs. 27.5, P < 0.05). Correlation with other GBM markers showed that the expression of SERPINA3 was higher in IDH1-R13H-negative cases compared to IDH1-R132H-positive cases (median LI 30 vs. 12.5). There was no correlation of SERPINA3 expression with TERT promoter mutation or MGMT promoter methylated cases. In vitro studies in glioma cell lines demonstrated a significant decrease in invasion, migration, and proliferation in SERPINA3 shRNA knockdown clones as compared to control.

Conclusion: Our study shows that SERPINA3 is a novel prognostic GBM-specific biomarker. Higher expression of SERPINA3 in the PBZ as compared to tumor core of GBM and in recurrent tumors as well as its in vitro functional characteristics suggests its role in tumor cell invasion, migration, and proliferation, thereby contributing to the aggressiveness of GBM tumors.

Keywords: Glioblastoma, invasion peritumoral brain zone, recurrence, SERPINA3

Acknowledgments: This work was carried out as a part of the project under the umbrella of Centre of Excellence in Neuro-Oncology funded by Department of Biotechnology, Government of India. ICMR is acknowledged for fellowship.

Classification of pituitary adenomas in the WHO 2017 perspective: Data from a tertiary neurological center

Paramita Paul, Department of Neuropathology, NIMHANS, Bengaluru, Karnataka, India

Introduction: The WHO 2017 classification of pituitary adenomas (PAs) incorporates lineage-specific transcription factors and hormones produced and excludes the entity of atypical adenoma. There is a paucity of studies that describe the spectrum of PA based on this classification.

Aims and Objectives: To delineate the spectrum of PA based on the WHO 2017 classification.

Materials and Methods: Data of intracranial tumors were collected from the neuropathology department registers for 5 years (2014–2018). PA diagnosed in 2018 (n = 88) were taken up for the study. Patient demographics and clinical details were obtained from the biopsy request forms. Tissue microarrays were built for 60 cases, and for the remaining, conventional sections were used. Routine hematoxylin and eosin and hormonal immunohistochemistry (IHC) for GH, PRL, ACTH, TSH, FSH, LH, CK, and MIB-1 were performed and the cases were analyzed.

Results: PA accounted for 7% (n = 430/5924) of all brain tumors in the 5-year period, of which 88 cases diagnosed in the year 2018 were studied. Male:female ratio was 2:1. The age of the patients ranged from 7 to 75 years with major representation in the age group of 40–60 years constituting 57% of the cases. Clinically, 22 cases (25%) were functional and 66 (75%) were nonfunctional adenomas. Among the clinically functional adenomas, GH secreting adenomas were the most common (n = 15, 68%) followed by ACTH (n = 4, 14%) secreting adenomas. PRL, TSH, and FSH secreting adenomas accounted for one case each. Of 88 cases, five cases were described to be clinically invasive. Following IHC for hormonal expression, we noted that of the 15 clinically GH secreting adenomas, 12 were somatotroph adenomas (sparsely granulated-5, densely granulated-3, mamosomatotrophic-3, mixed somatotroph/lactotroph-1) and 3 cases were plurihormonal adenomas. The clinically ACTH secreting adenomas included densely granulated corticotroph adenoma (n = 3) and Crooke cell adenoma (n = 1). One case each of clinically PRL and TSH secreting adenoma were plurihormonal adenomas on IHC. There was only one gonadotroph adenoma in this group. Of 66 clinically nonfunctional adenomas, 55 (83%) were positive for one or more pituitary hormone/s, with gonadotroph adenomas being the most common (40/55, 72.7%), followed by corticotroph (7/55, 12.7%), plurihormonal (4/55, 7.2%), somatotroph (2/55, 3.6%), and lactotroph (2/55, 3.6%) adenomas. Eleven cases (12.5 %) were both clinically and hormonally silent. The MIB-1 labeling ranged from 1% to 8% though no predilection was found for a particular adenoma subtype. The aggressive adenomas identified by IHC included sparsely granulated somatotroph adenoma, Crooke cell adenoma, silent corticotroph adenoma, densely granulated lactotroph adenoma in men constituted 17% (n = 15/88) of the total number of cases.

Conclusion: This is one of the few studies delineating the clinical and hormonal status of pituitary adenoma based on WHO 2017 classification.

In this series, only a quarter of cases were clinically functional and in this group, most cases correlated with the subtypes of the corresponding trophic adenoma on IHC, although 23% of these cases were plurihormonal adenomas. Among the clinically nonfunctional adenomas, the large majority expressed one or more pituitary hormone/s, with gonadotroph adenoma being the most common. Clinically and hormonally silent adenomas constituted 12.5% cases in this series. Addition of transcription factors would help identify the subset of null cell adenomas in this group. Furthermore, although several aggressive adenomas can be identified by hormonal IHC itself, transcription factors would strengthen recognition of these tumors, thereby assisting in patient management.

Keywords: Immunohistochemistry, pituitary adenoma

Efficacy of addition of clonidine to 0.25% bupivacaine in scalp block for awake craniotomy: A prospective study

Deepa Navakar, Bansal Hospital, Bhopal, Madhya Pradesh, India

Introduction: Conventional long-acting local anesthetics provide a sensory blockade for 3–4 h. Addition of clonidine in local anesthetics prolongs the duration of sensory blockade. We conducted this study to investigate the benefits of clonidine in term of duration of analgesia, sedation, and hemodynamic changes.

Methods: This was a prospective study. Data were collected from the patients who underwent awake craniotomy for tumor resection in eloquent cortex. 0.5% bupivacaine + 2 mcg/kg clonidine was used for scalp block. Hemodynamic parameters (heart rate [HR] and mean arterial pressure [MAP]) were recorded during head clamp fixation, skin incision, craniotomy, dura opening and closure, bone flap reposition, and skin closure and in postoperative period hourly till weaning of block. Total dose of fentanyl and propofol required was noted. Duration of surgery, duration of scalp block, postoperative pain by numeric pain scale (NPS), and perioperative complications were noted.

Result: A total of 20 patients were included in this study. The mean surgical duration was 247 minutes while anesthesia duration was 388 min. HR and MAP decreased progressively but no hemodynamic instability occurred. Total dose of fentanyl and propofol required in our study was 152 ± 53 mcg and 53 ± 22 mg, respectively. In our study, 1 h after surgery, NPS was 2 ± 1 while 2 h after surgery, NPS was 3 ± 1. Two patients developed seizures while one patient developed bradyarrhythmia. Postoperatively, two patients developed transient hemiparesis which was recovered in few days.

Conclusion: Addition of clonidine helps to achieve early onset of scalp block with better perioperative hemodynamic stability. It produces prolong anesthesia and reduces use of intraoperative opioid.

Expression of immune checkpoint markers in paired samples of primary and recurrent glioblastoma

Nandaki Nag Kanuri; NIMHANS, Bengaluru, Karnataka, India

Introduction: Despite aggressive treatment with radio and chemo-therapy, glioblastoma (GBM) patients have dismal prognosis with recurrence seen in most of the patients. One of the novel therapeutic approaches for GBM treatment is immunotherapy that is targeting immune checkpoints in the tumors. There are few studies that have described the expression of immune checkpoint markers in newly diagnosed and recurrent GBM samples. The best known immune checkpoint markers are programmed cell death protein 1 (PD-1/PD-1 ligand [PD-L 1]), cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), and indoleamine 2,3-dioxygenase (IDO). Signal transducer and activator of transcription 3 (STAT-3) is known to be involved in the up-regulation of genes responsible for immune suppression. The CTLA4-TYK2-STAT3 signaling pathway has been shown to be associated with oncogenic events in several tumors including GBM. However, the expression of these markers in paired GBM samples of individual patients, which includes primary and matched recurrent tumors, are reported in only few studies.

Aim: In the present study, we describe the expression pattern of PDL-1, CTLA-4, IDO, and STAT-3 in the paired tumor samples of 12 GBM patients (newly diagnosed and recurrent tumors). In addition, the expression of PDL-1 and CTLA-4 was studied in 55 retrospective cases of newly diagnosed GBM with available survival data.

Materials and Methods: The patient population consisted of two retrospective cohorts of GBM. The first included 55 newly diagnosed cases operated from 2015 to 2016, with available clinical data and follow-up details. A second retrospective cohort consisted of 12 GBM patients with availability of tissue samples from both primary and recurrent tumor in each case. Immunohistochemistry (IHC) was performed on the formalin-fixed paraffin-embedded (FFPE) tissue for PDL-1 and CTLA-4. RNA was extracted from the FFPE blocks and reverse transcribed to cDNA, and mRNA expression of IDO and STAT-3 was assessed in 12 paired GBM samples using quantitative polymerase chain reaction. Wilcoxon signed-rank test was performed for comparing expression of the above markers in paired samples. Kaplan–Meier survival analysis was performed in newly diagnosed GBM cohort.

Results: PDL-1 and CTLA-4 showed membrane and/or cytoplasmic staining of GBM tumor cells. This staining was variable and patchy in tumors. The labeling index of each of these markers was assessed by a visual semi-quantitative method. PDL-1 expression was noted in 55% tumors and CTLA-4 in 40% tumors. There is no association of these markers with overall survival. Paired sample analysis showed increased median fold change (FC) of STAT-3 mRNA expression in recurrent tumors (FC = 0.77) when compared to primary (FC = 0.41) which was statistically significant (P = 0.034); this was not seen with IDO expression. By IHC, the median LI of CTLA-4 was higher in recurrent GBM when compared to the primary tumor (P = 0.041). PDL-1 expression was not significantly altered in recurrent when compared to primary GBM.

Conclusion: The present study highlights the comparison of immune checkpoint markers in paired samples of GBM. We observed an increased mRNA expression of STAT-3 in recurrent GBM when compared to the primary tumor. Although PDL-1 and CTLA were not associated with overall survival in newly diagnosed GBM patients, increased expression of CTLA4 was evident in the recurrent GBM samples. Taken together, our study suggests an activated CTLA4-STAT3 signaling pathway in recurrent GBM. Understanding this signaling pathway may throw open avenues for novel immunotherapy modalities in GBM.

Keywords: Cytotoxic T-lymphocyte-associated antigen 4, immune checkpoint markers, indoleamine 2,3-dioxygenase, programmed cell death protein 1 ligand, recurrent glioblastoma, STAT-3

Perioperative and long-term outcomes in pediatric ependymomas: A retrospective Analysis of 47 patients

Vikas Singh; Department of Neurosurgery, Tata Memorial Centre, Mumbai, Maharashtra, India

Aim: To analyze clinicodemographic profiles and outcome following surgery and adjuvant therapy in pediatric intracranial ependymoma.

Materials and Methods: Pediatric (<18 years) patients diagnosed with intracranial ependymoma from January 2008 to December 2015 were retrospectively analyzed. All charts, files, and electronic medical records of these patients were studied. The patients were divided into two subgroups, Group A and B. Group A consisted of patients who underwent primary surgery and the second look surgery at our center, while Group B consisted of patients who underwent surgery at progression or at recurrence. The demographic, surgical, pathological, and follow-up data (at least 2 years postsurgical resection) of these patients were collected and analyzed using SPSS version 21 software. Univariate and multivariate analysis were performed on prognostic factors using Kaplan–Meier and Log–Rank analysis.

Results: During the study period, 47 pediatric patients were diagnosed with intracranial ependymoma. Mean age at diagnosis was 7.7 years. Raised intracranial tension was the most common presentation seen in 55.31% (n = 26). 65.96% (n = 31) had received some form of prior treatment (surgery/radiotherapy/chemotherapy). Supratentorial location was seen in 51% (n = 24). Gross total resection was achieved in 72.34% (n = 34). Anaplastic ependymoma was the most common histologic subtype seen in 76.6% (n = 36). 40.43% (n = 19) patients were alive without disease while 38.30% (n = 18) succumbed to the disease. Median overall survival (OS) at 5 years in Group A and B was 68.9% and 66.7%, respectively. Median progression-free survival (PFS) for Group A and B was 69.2% and 38.1%, respectively. There was no statistical difference in OS and PFS between the two groups. Subset analysis of know prognostic factors on OS and PFS showed significant results with extent of resection in Group A (P = 0.047) and age in Group B (P = 0.001).

Conclusion: Extent of surgical resection significantly affects OS and PFS in pediatric intracranial ependymomas. Young age may negatively affect survival.

Keywords: Ependymomas, intracranial, pediatric

Spectral estimate to determine 1p/19q co-deletion status in Grade-III glioma

Debanjali Bhattacharya; International Institute of Information Technology, Bengaluru, Karnataka, India

Aims and Objectives: Glioma is a type of brain tumor that leaves the subject with very low survival rate. There are many characteristics that influence treatment response and prognosis in patients with low-grade giloma (LGG). One such characteristic is the co-deletion of chromosome arms 1p/19q in LGG which showed good response to therapy in LGG and is associated with longer survival rate. Therefore, predicting 1p/19q status is useful for effective treatment planning of LGG and predicting outcome. There are several studies related to predicting deletion of chromosomal arms 1p/19q using multimodal medical images. Our study aims to determine the 1p/19q mutational status noninvasively by volumetric spectral analysis for patients having grade-III glioma from magnetic resonance imaging (MRI) that provides outstanding soft-tissue contrast for brain tumor diagnosis.

Materials and Methods: The dataset is collected from The Cancer Imaging Archive (TCIA) public access. T2-weighted MR images of a total of 55 patients with grade-III glioma, who had biopsy-proven 1p/19q status consisting neither deletion nor co-deletion, were used in our study. The data included 19 nondeleted and 36 co-deleted grade-II glioma subjects. The histological subtypes of LGG were oligoastrocytoma and astrocytomas where a total of 165 slices (3 slices per LGG subject that include the one with the largest tumor diameter and ones below and above) were included in this study. Glioma portion from whole MRI was segmented using ground truth provided by TCIA where the ground truth was used as a mask to segment the whole tumor. Each image was normalized by standard Z-scores. The difference in spectral signature using Lomb-Scargle power spectral density (PSD) estimate obtained from variance of cross-correlation (VoCC) across slices was investigated. The inner product of PSD estimates provides the spectral signature of two classes. Energy and cutoff frequency values of the spectral signature were utilized as the features for differentiating tumors with and without 1p/19q co-deletion. Due to unbalanced dataset (mutation:wild-type = 36:19), we performed RUSBoost classification to classify mutation and wild type.

Results and Discussion: The experiment showed consistency in the pattern of VoCC curve between the consecutive slices in case of mutant subjects, whereas random pattern was observed in wild-type cases. The difference in pattern of VoCC depicts the presence of heterogeneity across slices for nonco-deleted whereas the similarity in VoCC pattern for co-deleted tumor subjects showed the homogeneity across slices. Quantification of the variability in observed pattern was performed by means of spectral analysis where energy and cutoff values of Lomb-Scargle PSD estimate were used as features for classification. RUSBoost classification showed 91% accuracy in classifying tumors with and without 1p/19q co-deletion. Our result outperforms the results reported in the literature that utilized multiscale convolutional neural network approach investigating the same problem with 75.6% accuracy.

Although the surgical biopsy followed by fluorescence in situ hybridization (FISH) test is the gold standard currently to identify mutational status for diagnosis and treatment planning, there are several imaging studies that have performed to predict this mutational status from different medical images such as DWI, PWI, and MR spectroscopy and FET-PET imaging.[1],[2],[3],[4] However, the results of these studies could not show promising results to predict the status of 1p/19q in individual patients. One of the previous studies has shown promising results with more than 90% accuracy in discriminating tumors with and without 1p/19q co-deletion preoperatively with accuracy of >90% using textural measurements.[5] Contrary to the studies reported in literature, we presented a different approach that assessed the tumor volume heterogeneity by means of cross-correlation spectral analysis to determine 1p/19 co-deletion status from conventional MR images.

Conclusions: In this study, we present a noninvasive method to estimate the 1p/19q chromosomal arm deletion from T2-weighted MR images using spectral analysis of VoCC across selected glioma slices. The proposed method provides promising results in classifying mutant and wild-type gliomas.

Keywords: 1p/19q co-deletion, cross-correlation, Lomb-Scargle periodogram, low-grade gliomas

Acknowledgment: We gratefully acknowledge the support from Visvesvaraya PhD scheme for Electronics and IT, Ministry of Electronics and Information Technology, Government of India, for providing with the necessary fellowship to pursue research at IIIT, Bangalore.


  1. Latysheva A, Emblem KE, Brandal P, Vik-Mo EO, Pahnke J, Røysland K, et al. Dynamic susceptibility contrast and diffusion MR imaging identify oligodendroglioma as defined by the 2016 WHO classification for brain tumors: Histogram analysis approach. Neuroradiology 2019.
  2. Kebir S, Weber M, Lazaridis L, Deuschl C, Schmidt T, Mönninghoff C, et al. Hybrid 11C-MET PET/MRI combined with ‘machine learning” in glioma diagnosis according to the revised glioma WHO classification 2016. Clin Nucl Med 2019;44:214-20.
  3. Fellah S, Caudal D, De Paula AM, Dory-Lautrec P, Figarella-Branger D, Chinot O, et al. Multimodal MR imaging (diffusion, perfusion, and spectroscopy): Is it possible to distinguish oligodendroglial tumor grade and 1p/19q codeletion in the pretherapeutic diagnosis? AJNR Am J Neuroradiol 2013;34:1326-33.
  4. Jansen NL, Schwartz C, Graute V, Eigenbrod S, Lutz J, Egensperger R, et al. Prediction of oligodendroglial histology and LOH 1p/19q using dynamic [(18)F]FET-PET imaging in intracranial WHO grade II and III gliomas. Neuro Oncol 2012;14:1473-80.
  5. Brown R, Zlatescu M, Sijben A, Roldan G, Easaw J, Forsyth P, et al. The use of magnetic resonance imaging to noninvasively detect genetic signatures in oligodendroglioma. Clin Cancer Res 2008;14:2357-62.

Immune and molecular profile of pediatric and adult midline gliomas

Prerana Jha, Niveditha Manjunath, Jyotsna Singh, Ajay Garg, Kavneet Kaur, Mehar C Sharma, Ashish Suri, Chitra Sarkar, Vaishali Suri

Background: Diffuse midline gliomas are rare and devastating tumors with limited therapeutic options. Programmed death-ligand 1 (PDL1) expression represents a potential predictive biomarker of immune checkpoint blockade response. PDL1 expression and T-cell infiltration in different genetic cohorts of pediatric and adult midline gliomas (MGs) were analyzed and correlated with genetic markers of diagnostic and prognostic relevance.

Methods: One hundred and twenty-six MGs were assessed for immune (PDL1, CD3, CD8) and genetic profile (H3K27M, ATRX, IDH1, p53, MIB-LI) by immunohistochemistry. Sanger sequencing was done for IDH1 mutation.

Results: There were 89 adult and 37 pediatric cases. Thalamus was the most common site, and majority were Grade IV (85.7%). H3K27M mutation was more frequent in children (P = 0.0001). PDL1 expression was observed across all age, with higher frequency in elderly (>50 years), compared to adults (19–50 years) and pediatric cases (18 years) (P = 0.002). PDL1 expression increased with tumor grade. On univariate analysis, there was no direct correlation of PDL1 with any genetic alteration. However, PDL1 expression was highest in H3K27M nonmutant IDH1 wild-type and mutant adult GBMs. Frequency of CD3 infiltration was similar in both age while CD8 expression was more in adults (P < 0.05). Positive PDL1 expression was strongly associated with high tumor infiltrating lymphocytes count and poor median overall survival.

Conclusions: This is the first comprehensive analysis highlighting heterogeneous molecular profile and immune microenvironment of MGs across various age groups. These results provide a strong basis for an integrated approach employing clinical, radiological, molecular, and immune features for stratifying MGs to develop effective immunotherapies.

Keywords: GBM, midline glioma, programmed death-ligand 1, pediatric T-cell

Funding: We are thankful for financial support for funds and support received from J C Bose Fellowship of Prof. Chitra Sarkar, Department of Pathology and Neuro Science Center, AIIMS, India.

Optimizing the planning target volume margins and IGRT schedule for supine craniospinal irradiation

Shivakumar Gudi; Tata Memorial Hospital, Mumbai, Maharashtra, India

Aims and Objectives: The setup errors for patients treated with supine craniospinal irradiation (CSI) using dual immobilization (head-neck and pelvic thermoplast) with universal baseplate were reviewed to identify optimal image guidance (IG) schedule with least planning target volume (PTV) margins and compared with conventional PTV margins of 5, 8 mm (cranial [C], spinal [S]) used currently.

Materials and Methods: A total of 398 on-board daily volumetric computed tomographic (CT) images of brain (C) and lumbosacral spine (S) for 13 consecutive patients treated with CSI using dual immobilization were reviewed for setup errors. Systematic (∑) and random error (σ) were calculated in three axes (mediolateral, x; craniocaudal, y; anteroposterior, z). Three no-action-level offline protocols were tested: (1) setup errors of the first three (PF3), (2) five fractions (PF5) averaged and implemented for the remaining fractions, (3) post-PF5 daily errors implemented for C alone (PF5B). The PTV margins were determined using the Van Herk (H) and Stroom’s (St) formula. Optimal IG is suggested based on least margins with minimum IG utilization, and hence, generated PTV volume is compared with PTV generated using conventional margins.

Results: With no IG correction, H/St PTV margins (x, y, z; mm) for C and S were estimated to be 3.2/2.8, 5.8/4.9, 3.2/2.8 and 7.6/6.3, 6.8/5.7, 6.9/5.9, respectively. The C and S margins were minimum for PF5 (3/2.5, 4/3.4, 3.2/2.9 and 4.8/4.7, 5.3/4.4, 6.2/5.3) followed by PF3 (4.5/3.7, 4.6/4, 4.9/4.1 and 6.2/5.3, 5.3/4.4, 4.8/4.7). The respective S margins for 5PFB were 6.9/5.9, 5.8/4.9, 7.9/6.8. The PF5 with minimum PTV margins of 3 and 5mm for C and S, respectively, turned out to be most optimal and resulted in significant reduction in 8% and 32% PTV volume as compared to conventional PTV for C and S, respectively.

Conclusion: Dual immobilization with IG-PF5 is the most optimal IG method and least PTV margins with a significant reduction in PTV volume, which may have considerable dosimetric implications in long-term survivors.

Keywords: Craniospinal irradiation, image guidance setup errors, margins

Clinicopathologic spectrum, treatment characteristics, and outcome analyses of intracranial germ cell tumors treated at a single institution: A retrospective audit

Sulagna Mohanty; Tata Memorial Hospital, Mumbai, Maharashtra, India

Background: Intracranial germ cell tumors (IC-GCTs) accounting for 2%–11% of children and young adults with primary GCTs are a heterogeneous group of tumors with diverse presentation, varied histology, unique ethno-geographic distribution, and variable clinical outcomes.

Aims and Objectives: To study the clinicopathologic spectrum, treatment characteristics, and outcomes in a cohort of IC-GCTs treated within an academic neuro-oncology unit at a tertiary care cancer center.

Materials and Methods: An audit of patients with the diagnosis of IC-GCT registered and treated between 2006 and 2017 at our institution was conducted. Patient, disease, and treatment characteristics were retrieved retrospectively from electronic medical case records or case files as appropriate. Patients were contacted telephonically to update the disease status.

Results: The present cohort consists of 61 patients (41 males and 20 females) with a median age of 15 years at index diagnosis. Pineal region was the most common location (56%) followed by suprasellar region (37%) and thalamus accounting for 7% of IC-GCTs. Pineal GCTs were found to be predominant among males (83%). The most common histology was germinoma (74%) followed by nongerminomatous germ cell tumors (NGGCT)/mixed GCT (26%). Details regarding therapy and outcome were not available for 15 out of 61 patients, who were excluded from survival analysis. Germinoma patients were treated with radiotherapy alone in the form of craniospinal irradiation (CSI) plus tumor bed boost (TBB) or with combined modality treatment with preirradiation chemotherapy followed by whole ventricular irradiation plus TBB. Patients with NGGCT/mixed GCT were treated with combined modality treatment (preirradiation chemotherapy followed by CSI plus TBB). Of the 31 patients with germinoma, 7 (23%) had syncytiotrophoblastic differentiation. Seven percent of germinoma patients had metastatic disease at presentation. Patients with NGGCT/mixed GCT were classified as localized (89%) or metastatic (11%) disease. Forty-four patients (96%) underwent biopsy including four patients who had debulking surgery. The remaining two (4%) patients underwent endoscopic third ventriculostomy without biopsy and were treated as IC-GCT in view of raised tumor markers in cerebrospinal fluid (CSF). Thirty-three (72%) patients received cisplatin-based systemic chemotherapy, which had to be modified/omitted in 6 (18%) patients in view of significant hematologic and neurologic toxicity. Forty-three (94%) patients received definitive radiotherapy according to the histology and extent of disease. Three (6%) patients did not receive radiotherapy, one of whom had defaulted and is presently on salvage therapy following progression, while the second patient with mature teratoma was kept on observation following gross total resection. Eight (17%) patients had recurrence/progression with a median time to recurrence of 18 months. All patients received salvage therapy at recurrence/progression; however, three patients succumbed to further disease progression. At a median follow up of 37 months (interquartile range 24–68 months), the 3-year overall survival (OS) was 89% and 93% and 3-year event-free survival (EFS) was 74% and 69% for germinoma and NGGCT/mixed GCT, respectively. On subset analyses, the 3-year OS was 94% and 71% and 3-year EFS was 76% and 71% for pure germinoma and germinoma with syncytiotrophoblastic differentiation (nonsignificant).

Conclusion: IC-GCTs are unique group of tumors with varied histologic spectrum, diverse clinical presentation, and excellent survival outcomes with combined modality treatment.

Keywords: Germ cell tumor, intracranial, outcome, survival

Probability of neurocognitive, endocrine, and hearing impairment for pediatric medulloblastoma treated with rotational IMRT-based tumor bed boost versus conventional posterior fossa boost

Sulagna Mohanty; Tata Memorial Hospital, Mumbai, Maharashtra, India

Background: We hereby predict the rates of decline in neurocognitive, endocrine, and hearing function in pediatric medulloblastoma patients treated with conventional craniospinal irradiation (CSI) followed by rotational IMRT-based tumor bed boost (I-TBB) versus conventional posterior fossa boost (CBP).

Materials and Methods: Treatment plans for 30 consecutive pediatric medulloblastoma treated with CSI (17:23.4, 12:35, and 1:40 Gy) followed by I-TBB (total: 54 Gy) were reviewed to capture the mean doses (Dmean) to organs at risk (OARs) (H, C, and P). We contoured the conventional posterior fossa volume (PTV-PFB-vol) and CBP were planned to record the OARs Dmean doses. Probability of long-term toxicities was estimated as per Dmean OARs for both I-TBB and CBP. The neurocognitive decline (defined as impaired task efficiency [TE], organization [O], and memory [M]) using H_Dmean over logistic-dose-response model (Brodin et al.), Growth hormone deficiency (GHD) cumulative risk at 5 years posttreatment by applying P_Dmean and age to dose/age plots (Vatner et al.) and hearing loss (HD) by estimating number of ears and patients (bilateral) with C_Dmean doses >36 and 42 Gy thresholds (Paulino et al.) risk were estimated and compared for I-TBB versus CBP using paired t-tests, Chi-square test as applicable (Chi-square mentioned, where used).

Results: The mean ± standard deviation (SD) H_doses for I-TBB versus CBP were 41 ± 7.65 versus 54 ± 0.55 Gy, respectively (P < 0.000). The corresponding estimated risk of impairment in TE, O, and M decline in task efficiency, organization, and memory were 95% versus 99% (P < 0.000), 77% versus 91% (P < 0.000), and 60% versus 71% (P < 0.000), respectively. The mean ± SD P doses for I-TBB versus CBP were 38 ± 7.28 versus 51 ± 3.99 Gy, respectively (P < 0.000), with number of patients with >80 percentile probability of GHD in 3 versus 18, respectively (Chi square, P = 0.001). The mean ± SD right, left C_Dmean for I-TBB versus CBP were 40.3 ± 8.65, 40.56 ± 8.09 versus 54.6 ± 0 both sides, respectively (P < 0.001). There were 40, 23 ears and 15, 7 patients with >36 and 42 Gy, respectively, with I-TBB.

Conclusion: Favorable dosimetry for OARs with I-TBB over CBP predicts significantly decreased rates of long-term morbidity. Prospective clinical outcomes need to be investigated.

Keywords: Boost, impairment, medulloblastoma, neurocognitive, probability

Calvarial tumors: A tertiary center experience

Ved Prakash Maurya; SGPGIMS, Lucknow, Uttar Pradesh, India

Aims and Objectives: To study the clinicoradiological aspects, surgical nuances, and histopathological characteristics of calvarial tumors undergoing management at a tertiary care center.

Materials and Methods: We analyzed 33 patients who underwent surgical excision at our center between February 2004 and December 2018. Informed written consent was taken for all these cases. The clinical and radiological profile, histopathological diagnosis, and operative details were obtained from the hospital record system.

The radiological examination involved computerized tomography (CT) of head with contrast to detect the extent of bone invasion and assess the nature of lesion whether osteoblastic or osteolytic. The magnetic resonance imaging (MRI) head with contrast revealed the enhancing pattern, vascularity, intracranial venous sinus invasion, and compression over vital areas of cerebral hemispheres. The detailed preoperative evaluation also involved metastatic workup to find out the primary source, if any. In cases of highly vascular tumors, preoperative embolization was done. During surgical excision, the most symptomatic lesion was addressed first in case of multiple calvarial lesion. In majority of the cases (21 cases, 63.6%), complete excision was done and partial excision was done due to multiplicity of the lesions and diffuse nature of the tumor. Histopathological diagnosis was established and 27 cases (81.8%) were found to have primary calvarial pathology and remaining 6 cases (18.2%) had metastatic calvarial involvement. Patients were subjected to radiotherapy as well as adjuvant chemotherapy depending on the nature of tumor.

Results and Discussion: The age distribution in our study ranges from 2 to 62 years. Of 33 patients, 18 were male (54.5%) and 15 were female (45.5%). Swelling over the head was the most common presenting complaint (23 cases, 69.7%). Features of raised intracranial pressure such as headache and vomiting were present in 19 cases (57.6%) while features of parenchymal invasion manifested as seizures in 5 cases (15.2%). Clinical examination revealed decreased visual acuity 6 cases (18.2%), otological complaints 3 cases (9.1%), anosmia 2 cases (6.1%), and altered sensorium 1 case (6.1%) in addition to localized swelling over the head. Radiological examination revealed frontal bone to be the most common site (13 cases, 39.4%), as compared to the occipital (4 cases, 12.1%), temporal (4 cases, 12.1%), and parietal (2 cases, 6.1%) bone. Orbital wall invasion was notice in 4 cases (12.1%) and skull base involvement was noticed in 3 cases (9.1%).

Surgical strategy in treating such cases with varied etiology involves quick and precise resection to avoid massive blood loss. The underlying dura was always considered to be pathological in view of long standing disease. Of 21 patients who underwent complete excision, six patients were considered for reconstruction using titanium mesh graft. All patients improved significantly in the postoperative period though 7 (21.1%) of them had prolonged hospital stay due to wound-related complications.

Conclusion: Calvarial tumors are one of the least explored tumors in the neuro-oncological arena. Complete multisystemic evaluation and timely intervention form the basis of improvement for these cases. A teamwork attitude involving radiation oncologist, neuroradiologist, and neurosurgeons is always a prerequisite to give the best outcome in these less explored zones of neuro-oncology.

Keywords: Calvarial, magnetic resonance imaging, surgery

Cerebellar glioblastoma multiforme mimicking metastasis in an operated case of ovarian malignancy: A rare entity!

More Nilesh Bhaskar; LTMMC and LTM General Hospital, Sion, Mumbai, Maharashtra, India

Glioblastoma multiforme is the most malignant primary intracranial tumor and commonly occupies supratentorial compartment. On the contrary, infratentorial glioblastoma multiforme also called as cerebellar glioblastoma multiforme is very rare. In this report, we describe a case of cerebellar glioblastoma multiforme in a 45-year-old female. The patient was a known case of carcinoma of the ovary and underwent oophorectomy followed by chemotherapy as part of her treatment regimen. Eventually, she presented signs and symptoms of raised intracranial pressure. Magnetic resonance imaging revealed a contrast-enhancing mass lesion in the posterior fossa which was homogenous hypointense on T1-weighted images and homogenous hyperintense on T2-weighted images. Clinicoradiological findings indicated the presence of a metastatic lesion which was surgically excised. Histopathological examination of the excised lesion revealed cerebellar glioblastoma multiforme. We report a case of cerebellar glioblastoma multiforme mimicking metastatic lesion in a previously operated case of carcinoma of the ovary.

Molecular characterization of cerebral hemispheric glioblastoma in pediatric and young adult patients with emphasis on histone H3 mutations

Harsha Sugur; National Institute of Mental Health and NeuroScience, Bengaluru, Karnataka, India

Introduction: Glioblastoma (GBM) tumors manifest at all ages but most often affect adults with a peak incidence between 45 and 75 years. They are uncommon in the pediatric age group, accounting for about 3% of childhood brain tumors. Their frequency in adolescent and young adult group (AYA, 15–39 years) is about 15%–18% of all the brain tumors. Recently, it has been shown that recurrent somatic mutations of two histone coding genes, H3F3A (encoding H3.3 protein) and HIST1H3B (encoding H3.1 protein) occurs in a subset of pediatric high-grade gliomas and young adult group, resulting in amino acid substitution of two histone H3 proteins, at either H3K27M or H3G34R/V residues. The H3K27M-mutant midline tumors are now designated as diffuse midline glioma, H3K27M mutant (DMG). The H3G34R mutation occurs exclusively in the cerebral hemisphere. It is predominantly seen in AYA patients and shows a significant overlap with mutations in ATRX/DAXX and p53 in nearly 100% of cases. H3G34 mutant tumors have a high frequency of MGMT promoter methylation, thus explaining the better clinical course when compared to other GBM molecular subtypes. However, the exact incidence of H3G34- and H3K27-mutant tumors in different cohorts is not established. With this background, the focus of the present study was to establish the incidence of H3.3 mutations in our cohort of pediatric and young adult patients with cerebral hemispheric GBM and to correlate the same with other molecular markers.

Aim: (1) To study the molecular profile of pediatric and young adult cerebral hemispheric GBM tumors. (2) To evaluate the incidence of mutation in H3F3A gene coding for H3.3 protein at G34R/V and K27M residues, using Sanger sequencing method. (3) To correlate the H3.3 mutational status with ATRX, P53 mutations.

Materials and Methods: This retrospective study was performed on cerebral hemispheric GBM tumors occurring in pediatric and young adult patients operated during the period 2014–2018. The archived formalin-fixed paraffin-embedded tissue blocks were retrieved. Clinical and demographic details were noted. Immunohistochemistry (IHC) was performed for biomarkers such as IDH1 (R132H), ATRX, P53, and BRAF (V600E). Sanger sequencing was carried out for H3.3 G34R/G34V (codon GGG) and K27M (codon AAG) mutations on H3F3A gene. Mutation status was correlated with other biomarkers such as ATRX and P53.

Results: A total of 115 GBM cases were included in the study. The median age of patients was 19.5 years (1–39 years). The cohort had 34% IDH1 (R132H)-mutant GBM, 6% epithelioid GBM (E.GBM), and 60% IDH1 (R132H) negative by IHC GBM tumors. The median age of IDH1-mutant GBM patients was 29.5 years (range 8–38years) and of E.GBM patients was 25 years (range 14–33 years). Of IDH1 (R132H)-negative cases, 29% showed ATRX loss of expression and 61% were positive for P53 out of which only 25% cases showed both p53 immunopositivity and ATRX loss of expression. In the IDH1 (R132H)-negative cases, H3.3 G34R mutations were noted in 6.5% and K27M mutations in 4.7% cases.

There were no cases with G34V mutations. The median age of patients with G34R mutations was 22.5 years (range 20–36 years), and for K27M mutations, it was 18 years (range 14-35 –years). The H3.3-mutated cases were located predominantly in the corpus callosum. ATRX loss of expression with P53 immunopositivity was noted in all cases of G34R mutations, but not in K27M-mutant tumors.

Conclusion: Our study on cerebral hemispheric GBM in pediatric and young adult group shows that IDH-mutant GBM accounts for one-third of cases, E.GBM accounts for 6% cases, and a large number (about 60%) are negative for IDH1 (R132H) mutation. Among these, we show that H3.3 G34R-mutant tumors account for only a small percentage of cases, and these tumors show a characteristic association with ATRX and P53 mutations. We also noted few H3K27M-mutant hemispheric GBM tumors which do not come under the umbrella of DMG and needs further characterization. Identifying cases with H3G34R mutations in the pediatric and young adult age group is essential since they are associated with a better prognosis when compared to other molecular GBM subgroups in this age.

Keywords: Cerebral hemispheric glioblastoma, H3.3 G34R/V and K27M point mutations, pediatric and young adult patients, Sanger sequencing

Radiomic-based discrimination of high-grade gliomas – Grade 3 and Grade 4

Jitender Saini

Aim and Objective: Grade 3 and Grade 4 gliomas differ significantly regarding clinical behavior, genetic features, and clinical management. Accurate distinction of glioma grades is useful and may be helpful in the assessment of prognosis as well as in deciding appropriate therapy. The aim of the current study is to investigate the ability of radiomic features to discriminate Grade 3 and Grade 4 gliomas using routine magnetic resonance imaging (MRI) sequences.

Materials and Methods: Clinical image data, i.e., MRI scans of 35 patients with Grade 3 and 26 patients with Grade 4 glioma, were used for this study. These patients were scanned at National Institute of Mental Health and Neurosciences, Bengaluru. Each patient was scanned for four different contrasts – T1ce, FLAIR, T1 and T2, i.e., a total of 140 Grade 3 and 104 Grade 4 image volumes. T1ce scans were obtained as 3D isotropic scans whereas the other contrasts were axial scans. We used affine registration to co-register each subject’s scans to their T1ce MRI scan, which had a higher spatial resolution – usually 1 mm × 1 mm × 1 mm. Manual annotation of tumor regions of interest was performed on FLAIR volumes to include edema; the segmentations were cross-checked on T2 and T1ce images. Preprocessing involved N4 Bias Field correction. Radiomic feature extraction was performed using PyRadiomics library. Radiomic features include shape-based features, statistical features, and gray-level co-occurrence matrix. Various filters such as wavelet filter and Laplacian of Gaussian filter were applied to extract more features from the images. These features were normalized and fed to a Random Forest Classifier and an XGBoost Classifier. In both cases, 26 Grade 3 and 19 Grade 4 glioma patients were used for training and the remaining were used for testing. A 5-fold cross-validation was performed to evaluate the models.

Results: Figure 1a shows the comparison of the two classifiers over 5-fold of cross-validation. The XGBoost Classifier proved to be superior with an accuracy of 81% ± 4% and mean AUC-ROC of 86%. However, the Random Forest Classifier provided a mean accuracy of 75.5% ± 6% and mean AUC-ROC of 71.4%.

Discussion: In Figure 2a, all of the top ten important features are obtained from T1ce contrast, and in Figure 2b, eight out of ten features are extracted from T1ce contrast. Indicating that, of the total four contrasts used for the study, T1ce is most important for classification. In both classifiers, a statistical feature – first-order kurtosis makes up around three of the top five features. An interesting trend is observed in XGBoost, where all of the top three features are kurtosis extracted from various filtered images. Kurtosis indicates the distribution of pixels intensities from mean values. However, robust-mean-absolute-deviation (RobustMeanAD) is the mean distance of all intensity values from mean intensity value. The class difference between of kurtosis and RobustMeanAD is shown in Figure 3. Based on that, Grade 3 tumors have a higher kurtosis – the intensity values are concentrated away from toward the tails of intensity distribution. However, Grade IV tumors have a higher value of RobustMeanAD – indicating that the mean distance of all intensity values from the center of intensity distribution is higher in them. These statistical features can be used for delineation of these high-grade gliomas. These methods can be used to generate an automated classifier for classification of different tumors, trained on a larger dataset.


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Interclinician variation in radiation oncologists at the same institution while contouring organs at risk for brain

Kanika Bansal; Manipal Hopsitals, Dwarka, Delhi, India

Aims and Objectives: Contouring is one the most critical and error prone steps in radiotherapy planning, including brain radiotherapy. We aimed to quantify the interclinician variation among radiation oncologists in delineation of organs at risk (OAR) while contouring brain.

Materials and Methods: Twenty-one data sets of magnetic resonance imaging (MRI) brain of 21 patients who had been already treated were selected for delineation of the following OARs – right optic nerve, left optic nerve, optic chiasm, left hippocampus, and right hippocampus. Each of the defined OAR was contoured independently on the same data set by three radiation oncologists of the same radiation oncology center, blinded to each other. Interclinician variation in delineation was quantified as (1) variation in total organ volume (mean and standard deviation were acquired for all of the five OARs) and (2) volumetric quantifications as measured by Dice-Jaccard (DJ) coefficient.

Results/Discussion: A total number of 21 patients were evaluable for each OAR – optic chiasm, left optic nerve , right optic nerve, left hippocampus, and right hippocampus. Deviation in the mean OAR volume ranged from −25.39% to +21.09% for optic chiasm, −44.36% to +36.52% for left optic nerve, −37.57% to +29.33% for right optic nerve, −3.92% to +5.5% for left hippocampus, and −0.97% to +6.95% for right hippocampus. The values of DJ coefficient were between 0.13 and 0.29 for optic chiasm, 0.12 and 0.26 for left optic nerve, 0.23 and 0.35 for right optic nerve, 0.54 and 0.65 for left hippocampus, and 0.51 and 0.67 for right hippocampus. Left optic nerve had the lowest DJ coefficient of 0.12, whereas right hippocampus had the highest DJ coefficient of 0.67.

Conclusion: The interclinician variation in contouring of OAR in the brain can be significant. Oncology centers need to be aware of this difference and should aim to do periodic assessments within the team to keep this variation to the least possible limit.

Keywords: Brain contouring, delineation, interobserver variation, organ at risk

Stereotactic biopsy of intracranial lesions: Validity of histologic diagnosis

Sukhpreet Kaur, V Hanni1, Sandeep Sorte1, Nitin Garg2; Memorial Hospital, 1Bhopal Memorial Hospital and Research Centre, Bansal Hospital, Bhopal, Madhya Pradesh, India

Aims and Objectives: The purpose of this study was to determine the yield of stereotactic biopsies of intracranial lesions (neoplastic and nonneoplastic) and the validity of histologic diagnosis and to find out the pitfalls and problems in the histopathologic evaluation.

Materials and Methods: This is a retrospective observational study of the stereotactic biopsies (STBs) of intracranial lesions received in the Department of Pathology, Bhopal Memorial Hospital and Research Centre. For neoplastic lesions, the diagnosis and grading were done by correlating histological and immunohistochemical findings.

Results/Discussion: During a study period of 10 years, 120 patients with brain lesions underwent stereotactic brain biopsy procedures. The average age was 46 years (range 11–85 years). There were 75 male and 45 female patients. Specimens were taken from various brain regions, particularly from the deep aspect of the cerebral hemispheres and midline structures. 52% were supratentorial and 48% were infratentorial lesions. In 9 cases, we had repeat stereotactic biopsies, and in 13 cases, open biopsy was done later. Average number of tissue cores that we received was two and the size varies from 0.1 cm × 0.8 cm to 0.1 cm × 2 cm. Definitive positive diagnoses were obtained in 87.5%. In case of glial tumors, the diagnostic yield is 98.6% while definitive diagnosis (with proper WHO grading) was provided in 71.2% cases. In nine cases, repeat STB was done and the yield was 100%. The mean hospital stay was 3 days. No major complication was experienced post-STB procedure except in two patients with minor bleeding episode. The permanent morbidity rate was nil. The pathologic entities included 73 gliomas (28 glioblastomas, 10 high-grade gliomas [WHO grade III/IV], 7 gliomas [WHO grade II/III], 23 astrocytomas, 1 pilomyxoid astrocytoma, 2 oligoastrocytoma, and 2 oligodendrogliomas), 15 non-Hodgkin’s lymphomas, 3 PNET, 2 metastatic carcinomas, 1 case each of germinoma and meningioma, 7 nonneoplastic lesions (9 inflammatory, 3 granulomatous, 1 case each of neurocysticercosis and epidermoid cyst). In 11 patients, the biopsies were negative for any lesion and revealed normal brain tissue. In 13 cases, a correlation was also found between the biopsy specimens and corresponding material obtained during open surgery, of these, 8 cases (61.5%) had concordant results. Four cases that were negative in STB were subsequently diagnosed as inflammatory lesions (3) and metastasis (1). Misdiagnosis (0.8%) was seen in only one case that is the oligodendroglioma was reported astrocytoma on STB. With the help of modern computer-assisted imaging techniques, direct evidence of intracerebral lesions can be provided earlier and in more detail. The choice of treatment chiefly depends on the histological nature of the lesion. STB is a valuable and safe diagnostic tool for classifying intracranial lesions. In some cases like in glial tumors, due to their regional heterogeneity, it is difficult to obtain abnormal material and also to assign an actual grade. In these cases, proper correlation with clinicoradiological findings and taking several tissue cores from different target points help the pathologist to arrive at a proper diagnosis. The pathologic interpretation is limited by the small size of the specimen; however, diagnostic accuracy of the STB is purely dependent on the experience of both neurosurgeon and pathologist.

Conclusion: We conclude that stereotactic brain biopsy can be performed relatively safely has a high diagnostic yield and facilitates planning of treatment if done by the experienced neurosurgeon and pathologist. Correlation with the radiological findings, morphological features, and immunohistochemical markers should be done for the proper diagnosis.

Keywords: Biopsy, intracranial, stereotactic

Financially effective test algorithm to identify molecular subgroups of medulloblastoma in routine clinical practice especially in resource-constrained centers

Kavneet Kaur, Prerana Jha, Pankaj Pathak, Vaishali Suri, Mehar Chand Sharma, Ajay Garg1, Ashish Suri2, Chitra Sarkar; Departments of Pathology, 1Neuroradiology and 2Neurosurgery, All India Institute of Medical Sciences, New Delhi, India

Introduction: The last decade has seen tremendous progress in research at the molecular level in medulloblastoma (MB). MB is now considered a heterogeneous disease encompassing the following molecular-subgroups: (i) wingless (WNT), (ii) sonic-Hedgehog (SHH), and (iii) non-WNT/non-SHH and further divided into Group 3 and Group 4. Molecular classification is prognostically and therapeutically relevant and helps in better risk stratification. Many clinical trials are already under-way, whereby patients are stratified according to molecular groups, histopathological subtypes, and clinical details. Thus, the information on molecular subgrouping has become an integral component for prospective clinical trials. Translation of this subgrouping to routine practice still remains a challenge. Recommended gold standard methods including DNA methylation 850k array are not suitable for routine diagnostics, pertaining to problems related to availability, cost, technical expertise, and turnaround times. The most pathologist-accessible techniques for molecular subgrouping include immunohistochemistry (IHC), fluorescent in situ hybridization (FISH), and nanostring. Comparative evaluation of these techniques with each other and the gold standard is the need of the hour to develop guidelines for their use in different centers depending on resource availability.

Objectives: (1) To establish cost-effective, relatively robust, and easy method for molecular subgrouping in the Indian context by molecular subgrouping of MBs by three-panel IHC and FISH, and nanostring assay. (2) To compare their efficacy against the gold standard EPIC 850K methylation array. (3) To compare the cost of applicability in resource-constrained centers. (4) To correlate with follow-up (wherever available).

Methods: Ninety-five cases of MB with adequate tissue were included. Molecular subgrouping was performed by IHC for β-catenin, GAB1, and YAP1 and FISH for MYC amplification. Further, total RNA was isolated from formalin-fixed, paraffin-embedded (FFPE) tumor sections using Invitrogen-RecoverAllTM total nucleic-acid isolation following the manufacturer’s protocol for molecular subgrouping by nanostring assay using 22-gene panel on the same set of MBs. DNA was isolated from FFPE sections using Invitrogen-RecoverAllTM from a subset of cases, for CTNNB1 sequencing. Further, total DNA was extracted using Maxwell Promega DNA purification kit and EPIC 850k DNA methylation array was performed.

Results: Comparison of IHC supplemented by FISH and nanostring Assay IHC+FISH classified MBs into 15.8% WNT, 16.8% SHH, and 67.4% non-WNT/non-SHH subgroups; with MYC amplification identified in 20.3% cases of non-WNT/non-SHH. Nanostring assay successfully classified 91.5% MBs into 25.3% WNT, 17.2% SHH, 23% Group 3, and 34.5% Group 4. However, nanostring assay failure was seen in eight cases, all of which were >8-year-old formalin-fixed paraffin-embedded tissue blocks. Concordant subgroup assignment was noted in 88.5% cases, while subgroup switching was seen in 11.5% cases. Confirmation of discrepant WNT subgroup cases by Sanger sequencing DNA was isolated from all seven discrepant cases; however, sequencing for CTNNB1 was possible only in five cases. Among the five discrepant cases, which switched to WNT subgroup by Nanostring, only two were found to have CTNNB1 mutation EPIC DNA methylation array. The discordant cases as well as cases which could not be classified by nanostring assay were subjected to 850k DNA methylation array. Among the four cases, which were WNT by nansostring and other subgroups by IHC: one turned out to be WNT by methylation (the index case did not show CTNNB1 mutation), other three turned out to be concordant with IHC resulting in 75% concordance. Two cases which were SHH by nanostring and non-WNT/non-SHH by IHC (one case had MYC amplification) turned out to be SHH by methylation, hence 100% concordance with nanostring. Two cases of non-WNT/non-SHH by IHC and Group 3 and 4 by nanostring turned out to be Group 3 and 4, respectively by methylation, hence concordant with both IHC and nanostring. Among the unclassified cases by nanostring, the result by methylation profiling was consonant with the molecular subgrouping by IHC (n = 4, 100% concordance). Correlation with Kaplan–Meier analysis of survival of MB subgroups by IHC plus FISH revealed IHC-WNT subgroup to have the best prognosis, non-WNT/non-SHH MYC amplified to have the worst prognosis, and non-MYC amplified non-WNT/non-SHH and SHH had an intermediate survival. MB subgroups by nanostring also revealed significant difference in prognostication. However, the nanostring-WNT subgroup did not maintain the excellent prognosis of IHC-WNT and showed an intermediate prognosis comparable to nanostring-SHH subgroup. This difference was seen because five out of seven WNT cases which switched on nanostirng developed either progression of disease or died due to disease. This is difficult to explain as WNT subgroup patients generally are expected to have the best outcome. Nanostring derived Group 3 subgroup showed a significantly worse prognosis as compared to Group 4. Proposed algorithm for molecular subgrouping in routine practice. On the basis of these findings, we suggest an algorithmic approach using histopathology and IHC as the first steps, followed by nanostring or FISH or CTNNB1 sequencing. The cost of IHC plus nanostring will almost be the same as IHC plus FISH. For identifying WNT subgroup >10% beta-catenin nuclear positivity with classic histology- <10% nuclear positivity, any histological subtype, confirm by CTNNB1 sequencing For SHH subgroup:- Strong and diffuse positivity of both GAB1 and YAP1, any histological subtype- Focal or weak positivity for both GAB1 and YAP1, but desmoplastic/nodular (D/N) histology- Focal or weak positivity for GAB1 and YAP1, histological subtype other than D/N, confirm by Nanostring assay- Isolated GAB1 or YAP1 positivity, any histological subtype, confirm by Nanostring assay For Non-WNT/non-SHH group: Negative for all three IHC markers (beta-catenin, GAB1 and YAP1), any histological subtype- Perform MYC amplification by FISH to identify the cases with the worst prognosis OR- If nanostring is available, perform Nanostring assay to divide non-WNT/non-SHH into Group 3 and Group 4, with Group 3 having the worst prognosis.

Conclusions: Both IHC supplemented by FISH and nanostring are robust methods for molecular subgrouping, albeit with their own advantages and few disadvantages. IHC cannot differentiate between Groups 3 and 4, while nanostring cannot classify older-archived tumors, and is not available at most centers. Thus, both the methods complement each other and can be used in concert for high confidence allotment of molecular subgroups in clinical practice. This will be the best use of resources in economically challenged centers.

A rare synchronous diagnosis of non-Hodgkin’s lymphoma and glioblastoma with primitive neuroectodermal-like components in a 14-year-old male

Mohammed Basalathullah

Introduction: Glioblastoma (GBM) with primitive neuroectodermal (PNET)-like components is a rare malignancy in children and young adults. Synchronous diagnoses of hematological and solid malignancies are extremely rare. Here, we report a case of a 14-year-old male who was synchronously diagnosed with GBM with PNET-like features and B-cell non-Hodgkin’s lymphoma (NHL). To the best of our knowledge, there has never been a case report of the simultaneous occurrence of GBM-PNET and NHL.

Case Description: A 14-year-old male had initially presented with a 6-month history of headache, generalized weakness, low back pain, and intermittent fever. He was found to have pallor, cervical lymphadenopathy, and spine tenderness. Magnetic resonance imaging showed multiple lesions in the spine and an incidentally detected space occupying lesion in the right parieto-occipital lobe. Bone marrow biopsy was done and was suggestive of marrow involvement by leukemia, and after immunohistochemical (IHC) panel, a diagnosis of B-cell NHL, Stage IV was made. He underwent excision of the brain lesion which was reported as GBM with PNET-like areas, confirmed by IHC panel. After a multidisciplinary team discussion, he received six cycles of VAC chemotherapy. He was subsequently treated with craniospinal irradiation of 36 Gy in 20 fractions followed by a boost to the tumor bed in the brain of 24 Gy, along with concurrent chemotherapy with five cycles of carboplatin (area under the curve of 1). On follow-up, he was doing well and an additional three cycles of adjuvant temozolomide was given. He expired at home around 14 months after the initial diagnosis and exact cause of death could not be ascertained.

Discussion: Synchronous reports of GBM with other solid or hematological malignancies have been reported in a few case reports. In a series of 1547 patients reported by Hamza et al., with synchronous or metachronous non-central nervous system primary with GBM, only nine cases of hematological malignancies were reported, none of which were synchronous. Survival outcomes in such patients were reported to be similar to those of malignant glioma. Craniospinal irradiation and concurrent carboplatin is usually the recommended regimen in various case series of GBM-PNET cases. Concurrent chemotherapy with temozolomide was used to address the GBM component.

Conclusion: This extremely rare case report is to raise awareness about unrelated dual pathologies and synchronous cancers. It is necessary to treat them with an integrated approach by a multidisciplinary team.

A rare synchronous diagnosis of non-Hodgkin’s lymphoma and glioblastoma with primitive neuroectodermal-like components in a 14-year-old male

Kavneet Kaur; All India Institute of Medical Sciences, New Delhi, India

Introduction: Glioblastoma (GBM) with primitive neuroectodermal (PNET)-like components is a rare malignancy in children and young adults. Synchronous diagnoses of hematological and solid malignancies are extremely rare. Here, we report a case of a 14-year-old male who was synchronously diagnosed with GBM with PNET-like features and B-cell non-Hodgkin’s lymphoma (NHL). To the best of our knowledge, there has never been a case report of the simultaneous occurrence of GBM-PNET and NHL.

Case Description: A 14-year-old male had initially presented with a 6-month history of headache, generalized weakness, low back pain, and intermittent fever. He was found to have pallor, cervical lymphadenopathy, and spine tenderness. Magnetic resonance imaging showed multiple lesions in the spine and an incidentally detected space occupying lesion in the right parieto-occipital lobe. Bone marrow biopsy was done and was suggestive of marrow involvement by leukemia, and after immunohistochemical (IHC) panel, a diagnosis of B-cell NHL, Stage IV was made. He underwent excision of the brain lesion which was reported as GBM with PNET-like areas, confirmed by IHC panel. After a multidisciplinary team discussion, he received six cycles of VAC chemotherapy. He was subsequently treated with craniospinal irradiation of 36 Gy in 20 fractions followed by a boost to the tumor bed in the brain of 24 Gy, along with concurrent chemotherapy with five cycles of carboplatin (area under the curve of 1). On follow-up, he was doing well and an additional three cycles of adjuvant temozolomide was given. He expired at home around 14 months after the initial diagnosis and exact cause of death could not be ascertained.

Discussion: Synchronous reports of GBM with other solid or hematological malignancies have been reported in a few case reports. In a series of 1547 patients reported by Hamza et al., with synchronous or metachronous non-central nervous system primary with GBM, only nine cases of hematological malignancies were reported, none of which were synchronous. Survival outcomes in such patients were reported to be similar to those of malignant glioma. Craniospinal irradiation and concurrent carboplatin is usually the recommended regimen in various case series of GBM-PNET cases. Concurrent chemotherapy with temozolomide was used to address the GBM component.

Conclusion: This extremely rare case report is to raise awareness about unrelated dual pathologies and synchronous cancers. It is necessary to treat them with an integrated approach by a multidisciplinary team.

Detection of cytogenetic aberrations using fluorescence in situ hybridization and TP53 mutation using Sanger sequencing in pediatric medulloblastoma: Experience from an exploratory cohort at Tata Medical Center, Kolkata

Avijeet Kumar Mishra; Tata Medical Center, Kolkata, West Bengal, India

Background: Copy number aberrations (MYC, MYC-N, chromosome 17) and TP53 mutations have been variably associated with prognosis in medulloblastoma and have been used for risk-stratification in conjunction with molecular subgrouping. Our aim was to explore their distribution in children treated at our hospital.

Methods: Children (<18 years) treated between February 2016 and August 2018 were included. FFPE tissue was processed for beta-catenin (DAKO Mouse Mab) and YAP1 (YAP63.7 SC-101199S) immunostaining, fluorescence in situ hybridization (FISH) using MYC-C, MYC-N (Zytolight SPEC MYC/2q11 Dual Color Probe), and 17p-deletion probes (Zytovision, Germany), and Sanger sequencing to detect TP53 mutation. Age <3 years, residual tumor >1.5 cm2, metastasis, and large-cell/anaplastic (LCA) histology were classified as “high-risk” (HR). TP53 mutation in the absence of beta-catenin nucleopositivity, MYCN-amplification and MYC-amplification were included as “molecular high-risk features (M-HRF).”

Results: Median age was 8.9 years (n = 15); 2 (13.3%) were <3 years. Male to female ratio was 1.1:1. Clinical features were headache/vomiting (12, 80%); ataxia (7, 46.7%); and cranial nerve palsies (4, 26.7%). Residual tumor was >1.5 cm2 in 4 (26.7%). Five cases (33.3%) were metastatic (spinal deposits: 3, 20%; malignant cells in cerebrospinal fluid: 1, 6.2%; both: 1, 6.2%). Histology was classical (5, 33.3%); desmoplastic/nodular (3, 20%); LCA (4, 26.7%); or unspecified (4, 26.7%). Of 15 (60%), nine were HR. None had beta-catenin nucleopositivity or MYC-C amplification. MYC-N amplification was demonstrated in 3 (20%). 17p-deletion was detected in 6 (40%). TP53 mutations were detected in 5 (33.3%), including 2 children with MYC-N amplification and LCA-morphology. Overall, nine (60%) children had at least one cytogenetic or molecular aberration. Six (6/15; 40%) specimens had M-HRF; 2 (33%) of these children were standard risk (SR). Six/9 (70%) HR had M-HRF. Presence of M-HRF was independent of age <3 years, residual >1.5 cm2, metastasis, and LCA histology (P > 0.5).

Discussion: M-HRF was distributed independently of conventional risk factors in this small cohort of children with medulloblastoma. This strategy helps identify additional HR children who otherwise were conventionally SR. Studies using risk stratification incorporating clinical, radiological, pathological, molecular, and cytogenetic prognostic indicators, on a larger cohort of children treated prospectively on a uniform protocol are needed.

Malignant meningiomas: Risk factors and determinants of good clinical outcome

Jaskaran Singh Gosal; Department of Neurosurgery, SGPGI, Lucknow, Uttar Pradesh

Aims and Objectives: Meningiomas account for 15%–20% of all intracranial tumors. Grade II and Grade III meningiomas are termed high-grade or malignant meningiomas according to the 2007 WHO classification. Most of the meningiomas are Grade 1, around 5%–10% are Grade II and Grade III are rarer lesions. High-grade meningiomas have higher rates of recurrence and worse outcome than Grade I/II meningiomas. The objective of this study is to study and analyze the clinical profile of the Grade II and Grade III meningiomas so as to predict the risk factors and the determinants of good clinical outcome, as there is less published data on the high-grade meningiomas.

Materials and Methods: A retrospective analysis of meningioma database from 2012 to 2018 spanning 6 years of our center was done and patients with a histopathological diagnosis of Grade II and Grade III meningiomas were included in the study. Clinico-radiological profile of the patients was studied.

Results: There were 33 patients of high-grade Grade II (25) and Grade III (8) meningiomas. Mean age was 46.48 years (range 21–72). Sixteen patients were males and 17 females. Twelve patients (36.36%) had convexity meningioma, nine patients (27.27%)had the tumor in parasagittal/falcine location, 2 at the anterior skull base, 6 (18.18%) at the middle skull base, 2 (6.06%) in cerebellopontine angle, and 2 ventricular. Simpson Grade I excision was done in 10 patients, Grade II excision done in 12, Grade III in 8, and Grade IV in 3 patients. Four patients of Grade II and 3 patients of Grade III developed recurrence. Twenty-two patients (66.67%) had good clinical outcome at discharge.

Conclusion: High-grade meningiomas tend to occur at a slightly younger age than the more common low-grade meningiomas. There is no sex predilection for high-grade meningiomas as demonstrated in few other studies. High-grade meningiomas have a propensity to occur at non skull base locations rather than at skull base. Aggressive surgical resection (Grade I and Grade II Simpson excision), which is usually possible at nonskull base location, coupled with adjuvant chemo-radiotherapy helps in preventing recurrence and in progression-free survival in high-grade meningiomas.

Keywords: High-grade meningioma, location, malignant meningioma, risk factor

Novel approach using three-dimensional deep convolutional neural networks for predicting survival in gliomas: Deep learning radiomics algorithm for glioma model

Abhishek Mahajan, Ujjwal R Baid, Nilesh Sable, Sanjay Talbar, Swapnil Rane, Aliasgar Moyadi, Jayashree Kalpathy-Cramer, Pushpa Tandon, Sudeep Gupta, Meenakshi H Thakur, Rajendra A Badwe; Tata Memorial Centre, Mumbai, 1Shri Guru Gobind Singh Ji Institute of Engineering and Technology, Nanded, Maharashtra, India

The project was under the grant from Quantitative Imaging Network (QIN) National Cancer Institute, Bethesda, MD, USA. The proposed algorithm was third-best performer at the international BRATS challenge for the year 2018. https://www.med.upenn.edu/sbia/brats2018/rankings.html

Aim: Segmentation of brain tumors from multimodal magnetic resonance (MR) imaging remains a challenge, and deep learning has a potential role in diagnosis, prognosis, and survival prediction. The project aimed at findings potential radiomic features which can be effectively used for the overall survival (OS) prediction in glioma.

Materials and Methods: The study was approved by IEC and proposed method was trained and validated on BRATS 2018 dataset. We developed patch-based three-dimensional (3D)-Unet model for tumor segmentation and evaluated efficiency of radiomic features for overall survival prediction. Radiomic features are extracted from all four MR modalities for OS prediction. The training dataset included 210 high-grade glioma cases and 75 cases with low-grade glioma while validation set consisted of 66 cases. The trained model is validated on 83 patient’s data from our hospital.

Methods: The steps in our proposed method for brain tumor segmentation include pre-processing of the images, patch extraction, training using a 3D U-Net structure, usage of the model for full volume prediction, postprocessing to refine label maps, as described below.

Preprocessing: Brain volume is extracted with skull stripping algorithm using brain extraction tool and slices are co registered to 1 mm × 1 mm × 1 mm isotropic resolution. Bias correction algorithm based on N4ITK is first applied to the T1 and T1c images. Intensity normalization step is applied to each volume of all subjects by subtracting the mean and dividing by the standard deviation so that each MR volume will have a zero mean and unit variance. Patch extraction: 64 × 64 × 64 size 3D patches are extracted from brain volumes for training the model. To increase the predicting accuracy of the model, the extracted patches should cover all possible cases including all background, mostly background, mostly foreground and equally distributed.

Proposed Model: A 3D U-Net based structure containing three encoding and three decoding layers is used in our model as shown in Figure 1. Intensity normalized images with all MR protocols are concatenated as the four-channel input for the model. The corresponding segmentation map of the input patch is given as the ground truth labels. The output of the model is 64 × 64 × 64 × 4 matrix containing the probability of each input voxel belonging to each category (3 foreground classes and the background). From 285 patients, 3D patches are extracted for training 6 epochs are used on all extracted patches, which takes about 48 h to train on a NVIDIA P5000 GPU.

Prediction: To make a prediction for the full volume, a sliding window approach is used with stride size 16. Therefore, each voxel will be predicted by four models and the mean output is used as the final probability. For the given image size, it takes 5 min to generate the output for the entire volume on the same GPU. False positives are reduced using the connected component analysis.

Results: All 285-training dataset are used in the model training process. Segmentation output of few cases is given in Figure 2. The results are based on all 46 validations dataset. The final mean dice indexes of the enhanced tumor (ET), whole tumor (WT) and tumor core (TC) are 0.75, 0.89 and 0.81 which shows out approach outperforms other submissions of the BRATS17 challenge.

Discussion: The method achieved good performance with dice scores as 0.88, 0.83, and 0.75 for whole tumor, tumor core, and enhancing tumor, respectively. For the prediction of survival categories (<300 and ≥300 days), the neural network demonstrated an accuracy of 70.2% in the training subset and 62.5% and 63.6% in the validation and testing subsets, respectively. The accuracy was 73% for the entire training dataset. The area under the curve was 0.799. For the validation data set from our hospital, the set were subjected to a supervised principal component (SPC) analysis to predict OS and progression-free survival (PFS). SPC this allowed stratification based on 13 features of patients in the discovery set into a low-or high-risk group for PFS (hazard ratio [HR], 2.43; P = 0.003) and OS (HR, 4.08; P < 0.001), and the results were validated successfully in the validation set for PFS (HR, 2.38; P = 0.032) and OS (HR, 3.25; P = 0.002).

Conclusion: Comparison of experimental results of our proposed method with other state of the art brain tumor segmentation methods demonstrated that proposed method outperforms existing segmentation techniques. We identified 13-feature radiomic signatures that allow prediction of survival and stratification of patients with newly diagnosed gliomas. The major finding of this study was that radiomic-based classification allows noninvasive prediction of survival and stratification of patients with gliomas with better accuracy than that with established clinical or radiologic risk models. Deep learning radiomics algorithm has potential radiomic features that can be extracted from the segmented area which can be used for overall survival prediction.

Differentiating dural metastases from meningioma in cancer patients: Role of 68Ga DOTANOC PET/CT

Ameya Puranik

Aim: To assess the diagnostic utility of 68Ga DOTA-NOC PET/CT in differentiating meningioma from dural metastases.

Methods: Cancer patients with a dural-based lesion seen on MRI/CT/FDG PET-CT considered equivocal for metastases or meningioma by a multidisciplinary team, who were referred for 68Ga DOTA-NOC PET/CT, were included in the study. 68Ga DOTA-NOC was synthesized in the hospital radio pharmacy using a 68Ge/68Ga generator. 68Ga PET/CT was performed 45–60 min after intravenous injection of 74–100 MBq of the radiotracer. Scan interpretation-visual score (VS) was defined as stated below and assigned to each lesion, VS-1: intensity of uptake < liver, VS-2: > liver < spleen, VS-3: > spleen. SUVmax of the lesions was also noted. Final diagnosis was decided by histopathological confirmation whenever available. Stability of the lesion on imaging follow-up (1 year) was considered diagnostic of meningioma when histopathology was unavailable.

Results: Thirty-five patients (male:female 21:14) with a median age of 51.5 years (range 35–71 years) were included. Lung and breast were the two most common sites of primary malignancy. Meningioma was considered as the final diagnosis in 26 patients (7 histopathological confirmation, 19 stability on radiological follow-up), metastases in 6 patients (4 histopathological correlation). There was one patient each of pseudotumor, abscess, and hemangioblastoma. Meningioma showed intense tracer uptake in 25 patients (VS-3, > spleen). One patient of atypical meningioma showed lesser uptake, VS-2 (>liver < spleen). None of the metastatic lesions showed intense uptake (VS-1 and 2). Hemangioblastoma was the only nonmeningiomatous lesion showing intense (VS-3) tracer uptake. Meningioma showed a significantly higher median SUVmax value compared to metastases (21.1 vs. 4.9).

Conclusion: Meningioma shows high SSTR expression (VS>3) compared to metastases (majority VS-1). For dural-based lesions in cancer patients, strong 68Ga DOTA PET/CT positivity (VS-3) suggests the diagnosis of meningioma. These patients can be observed (without biopsy) with greater assurance if asymptomatic.

Molecular analysis of oligodendroglioma

V P Singh, Ishani Mohapatra, Karanjit S Narang, Sudhir Dubey; Department of Pathology and Lab Medicine, Institute of Neurosciences, Medanta-the-Medicity, Gurgaon, Haryana, India

Introduction: According to the WHO 2016 update on Classification of central nervous system (CNS) Tumors, 1p19q co-deletion is mandatory to classify a tumor as an oligodendroglioma. However, it is observed that about 30%–40% of cases do not fulfill these criteria and exhibit either 1p or 19q co-deletion. This category has now been classified as not elsewhere classified (NEC) according to the consortium to inform molecular and practical approaches to CNS tumor taxonomy-Not on WHO (C IMPACT NOW).

Materials and Methods: The study was done at the Institute of Neurosciences and Department of Pathology, Medanta-The Medicity, Gurgaon, Delhi NCR. Paraffin-embedded tissue sections of surgically resected specimens were studied for their histomorphological and immunohistochemical features. The paraffin blocks were used for FISH for 1p19q co-deletion using probes by Vysis. We have 20 cases of oligodendroglioma from January 2018 to December 2018 which were evaluated for 1p19q co-deletion. These patients were kept under clinical and radiological follow-up to diagnose an early recurrence.

Results: Of the 20 cases of oligodendroglioma, 14 cases revealed deletion of both 1p and 19q, 4 cases showed only 19q deletion, and 2 showed only 1p deletion. Two cases had early recurrence and both of them were found to have an isolated 1p deletion. The first case was of a 53-year-old female patient with a parieto-frontal tumor which was diagnosed as anaplastic oligodendroglioma in May 2017. She presented with a recurrence in D7-D8 spine in October 2018. The second case was a 64-year-old male with frontal tumor operated in November 2017 – he presented with a recurrence at the local site in October 2018. These tumors possibly belong to the NEC as discussed in C IMPACT NOW Update-1.

Conclusion: The significance of molecular subgroups of oligodendrogliomas now designated as NEC is not known. The preliminary findings of our small series suggest that isolated 1p deletion may be a marker of a more aggressive variant prone to an early recurrence. However, the numbers and follow-up are too small to opine conclusively and there is need for a more detailed study.

Keywords: 1p19q co-deleted, oligodendroglioma, Vysis


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