|Year : 2022 | Volume
| Issue : 2 | Page : 19-36
|Date of Web Publication||8-Apr-2023|
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
. Abstract. Int J Neurooncol 2022;5:19-36
Lymphopenia during image-guided, pencil-beam scanning proton beam therapy for consecutive glioma patients: An initial experience from India
Anindita Das, Jacinthlyn Sylvia, S. Preethi, Sanjib Gayen, Pankaj K. Panda, Roopesh Kumar, R. Adhithyan, Sushama Patil, Dayananda Sharma, Rakesh Jalali; Apollo Proton Cancer Centre, Chennai, Tamil Nadu, India
Aim: To assess the toxicities including cytopenia and tolerance in consecutive patients of central nervous system (CNS) WHO Gr-2/3/4 gliomas treated with image-guided pencil beam scanning proton beam therapy (PBS-PBT) in South Asia and India’s first PBT facility.
Patients and Methods: We report here the data of consecutive patients with newly diagnosed and recurrent glioma (CNS WHO Gr-2/3/4) treated between January 2019 and December 2021 with image-guided, PBS PBT at our center. Patients with Gr-1 tumors, i.e., pilocytic astrocytoma were excluded from this report. All PBS-PBT plans were generated with Monte Carlo-based dose optimization and calculation. Acute toxicities were assessed based on NCI CTCAE v5.0.
Results: Seventy-two consecutive glioma patients (CNS WHO Gr-2/3/4) (65 adults, 7 pediatric), received partial brain irradiation using PBS-PBT between January 2019 and December 2021. Twenty-one of these patients received re-irradiation, whereas 51 were newly diagnosed. Prior to radiotherapy, 28 (38.9%), 39 (54.2%), 4 (5.6%), and 1 (1.3%) patient(s), respectively, had undergone gross total resection, subtotal resection, biopsy alone for histopathological confirmation, or no surgical procedure. Thirteen (18.1%), 15 (20.8%), and 44 (61.1%) patients, respectively, had Gr-2, Gr-3, and Gr-4 (glioblastoma, Gr-4 astrocytoma, or H3K27M-altered diffuse midline glioma) tumors. In all but two patients, standard dose-fractionation (1.8GyE/fraction) was used. 93.1% patients received concurrent temozolomide (TMZ) in doses ranging from 100 to 160 mg (75 mg/m2). Among acute toxicities, no patient had Gr-3 dermatitis, Gr-2 dermatitis was seen in 4 (5.6%) patients, while 68 (94.4%) patients had Gr-1 dermatitis only. Thirty-seven (51.4%) patients maintained normal lymphocyte counts throughout radiation therapy, whereas Gr-1, Gr-2, and Gr-3 lymphopenia were seen in 13 (18.1%), 16 (22.2%), and 6 (8.3%) patients, respectively. No patient developed Gr-4 lymphopenia. Fifty-three (73.6%) patients subsequently received sequential adjuvant TMZ and 6 (8.3%) received CCNU-based next line systemic therapy.
Conclusion: Our initial experience with PBS-PBT is encouraging and PBT is well tolerated in patients with gliomas in both newly diagnosed and re-irradiation scenarios. Early results are promising, including lower incidence of Grade-3 and above lymphopenia which has been correlated with better outcomes in the literature.
Encouraging early experience of intensitymodulated proton beam therapy (IMPT) in cranio-spinal irradiation; emphasizing crucial considerations for pediatric proton cranio-spinal irradiation
Utpal Gaikwad, Anindita Das, V. R. Roopeshkumar1, Ramya Uppuluri2, Jacynthlin Sylvia, Srinivas Chilukuri, Dayananda Sharma3, M. P. Naufal3, Rakesh Jalali; Departments of Radiation Oncology, 1Surgical oncology, 2Paediatric oncology and 3Medical physics, Apollo Proton Cancer Centre, Chennai, Tamil Nadu, India
Introduction: To report the early outcomes of cranio-spinal irradiation (CSI) patients treated with IMPT at South East Asia’s first proton center and to discuss the unique challenges faced during planning, plan implementation, and special considerations for pediatric patients.
Patients and Methods: First forty patients, received CSI using IMPT technique included in this analysis. The median age was 8 years for this cohort, in which 20 were medulloblastoma, 7 recurrent ependymoma, 3 pineoblastoma, 3 were germ cell tumors, and remaining 7 constituted other diagnoses. Forty percent patients received concurrent chemotherapy. Average planning target volume (PTV) length was 68 cm and PTV volume 2509 cc. Contouring and planning were done using Raystation system Citrix version 9. IMPT plan generated using, 4 or 5 fields, SFO technique and eight cm junctions with dose gradient technique. All patients underwent baseline neuropsychological and quality of life (QOL) assessment and then planned for subsequent assessment on follow-up. Special consideration with modification in standard contouring used at our institute helped in limiting acute toxicities in pediatric CSI patients.
Results: Median CSI dose was 23.4 Gy (Gray; range 21.6–35 Gy). Mean Conformity index is 1.1 and mean homogeneity index is 1.02. No patient had grade 2/> weight loss during the treatment. Forty-five percent (18) developed Grade 1 hematological toxicities and 20% (8) developed grade 2 or 3 toxicities; none had Grade 4 toxicities. At median follow-up of 12 months, 90% patients are alive of whom 88.9% are having local control.
Conclusion: With IMPT, it is practically feasible to achieve good homogenous conformal coverage and reduce radiation doses to organs at risk (OARs) significantly, limiting acute and late effects, improving QOL and therapeutic ratio. At the same time, it is important to adapt newer contouring guidelines for pediatric CSI and to plan dose gradient while radiating whole vertebrae, further limiting OAR doses.
Keywords: Cranio-spinal irradiation, gradient technique, IMPT, monte carlo, PBS
Cervical cord glioblastoma multiforme: A case report and review of literature
Karishma Agarwal, Ayush Garg, Piyush Kumar; SRMS IMS, Bareilly, Uttar Pradesh, India
Introduction: Primary spinal cord glioblastoma multiforme (GBM) is a rare clinical entity with an aggressive course and an invariably dismal prognosis. There are around 200 reported cases of spinal cord GBM in total and approximately 70 cases in the cervical region. Median survival for this disorder is only 12 months. We report the case of a 36-year-old female patient with primary spinal cord GBM.
Case Summary: A 36-year-old female patient presented with complaints of pain in the neck and progressive left limb paresis. Magnetic resonance imaging (MRI) cervical spine was suggestive of an infiltrating intramedullary lesion. She underwent C2-D1 laminectomy and tumor decompression. Histopathology was suggestive of spinal cord glioblastoma. Postoperative MRI was suggestive of a possibility of leptomeningeal tumor seeding. The patient was planned for cranio-spinal radiotherapy by IMRT technique along with concurrent chemotherapy with Tab. Temozolomide. Tab. Temozolomide was discontinued after the 1st week due to severe bone marrow suppression. Adjuvant temozolomide was started after 4 weeks of completion of radiotherapy. However, after first cycle, she developed febrile neutropenia, and thereafter, further chemotherapy was withheld as patient attendant refused further treatment. The patient was given supportive therapy and she defaulted treatment thereafter. The patient expired after 13 months from the date of diagnosis.
Conclusion: Primary spinal GBM is a clinically rare entity that progresses rapidly with a dismal prognosis and a short survival time despite aggressive management.
A dorsal spine intramedullary dermoid cyst masquerading atypical clinically and radiologically: An extremely extraordinary site
Prachi, Hema Malini Aiyer, Gaurav Sharma, Ashish Kumar Shrivastava; Dharamshila Narayana Superspeciality Hospital, New Delhi, India
Dermoid cysts presumably arises in the head and neck region in the pediatric age group. Intramedullary dorsal spine dermoid cysts are extremely rare, accounting to 0.1% of all adult tumour. The predilection ranges from lumbar to thoracic to dorsal spine. Dermoid cyst can be congenital or acquired. Majority of the times, it is detected incidentally, as the patient remains asymptomatic till 3rd to 4th decade of their life. We present this rare case in a 30 year old female, who was asymptomatic till 3rd decade. Now she presented with paraplegia and ataxia, in her third trimester of pregnancy. She developed right limb weakness in the first trimester, which has improved eventually but recurred again. On examination, increased tone in bilateral lower limbs with decreased power. She is not aware of her bowel and bladder symptoms. On contrast-enhanced magnetic resonance imaging, an intramedullary mass was seen, which was suggestive of neoplastic etiology. Neurosurgical intervention was done. Frozen was sent and was signed out as cyst wall lined by stratified lining. Further the complete histopathological examination was done, and microscopic findings showed derivatives of all the three embroyological layers, neuroparenchyma, bone formation, microcalcification, mucinous lined glands, and skin with adnexal structures were seen. Findings were consistent with dermoid cyst. the differentials that can be entertained in this case was epidermoid cyst, but both differ from each other histologically. Hence, histopathology always remains the gold standard for definitive diagnosis. Postoperative phase was uneventful. we document this case, to create awareness amongst the neuro-oncologist, pathologist and radiologist. This report showed presentation of a commoner at rarest site. very few cases have been reported in literature till date.
Comparison of hippocampal sparing intensitymodulated radiotherapy plans in patients of brain tumors treated by three-dimensional conformal radiotherapy
Diksha Chaturvedi, Piyush Kumar, Arvind Kumar, Pavan Kumar, Jitendra Nigam, N. Silambarasan, Navitha; Department of Radiation Oncology, Shri Ram Murti Smarak Institute of Medical Sciences, Bareilly, Uttar Pradesh, India
Introduction: Radiotherapy plays an important role in brain tumors after surgery. However, concerns regarding neurocognitive toxicity after radiotherapy are being raised. Newer radiotherapy techniques can deliver radiotherapy with better precision planning and delivery. Effective hippocampal sparing is possible with intensity modulated radiotherapy (IMRT) which governs the neurocognitive functions. The present study is done to compare whether hippocampal sparing is possible in brain tumors by three-dimensional conformal radiotherapy (3D-CRT) and IMRT and their effects on neurocognitive functions.
Materials and Methods: Twenty-two patients with brain cancer were recruited from November 2019 to April 2021. Patients were treated with 3D-CRT technique and alternate IMRT plans were generated. Dosimetric parameters of planning target volume (PTV), organs at risk (OARs) along with hippocampus were evaluated and compared for 3DCRT and IMRT plans. Neurocognitive functions were evaluated using Mini Mental Status Examination score.
Results: In study group, there were 16 males and 6 females with median age 45 years. Brain tumors were commonly located in frontal lobe (36%) followed by parieto-occipital lobe (18%) and fronto-temporo-parietal lobe (13.63%). PTV parameters were better for IMRT and statistically significant. The OARs did not show significant difference except in both lens though they are within tolerance limits. There is no significant difference in the dosimetric parameters of hippocampus in 3D-CRT and IMRT plans. The P-value for Dmax is 0.79, Dmean is 0.26, Dmin is 0.18 between hippocampal sparing radiotherapy plans.
Conclusion: Anatomic location of tumor plays an important role in deciding hippocampal sparing. Patients who’s NCFs showed improvement on subsequent visits, highlights the fact that primary tumor control is an important factor in deciding decline or improvement in NCFs. It should be be beneficial for low-grade glioma that have better survival and prognosis as compared to high-grade gliomas cases.
Keywords: Hippocampal sparing three-dimensional conformal radiotherapy, intensity-modulated radiotherapy, neurocognitive function
Diffuse intrinsic pontine gliomas: Reappraisal for biopsy
Nishanth Sadashiva, Udai Krishna, Subhas Konar, Dhaval Shukla, Venkatesh Madhugiri, Manish Beniwal, Jithender Saini, Vani Santosh; National Institute of Mental Health and Neurosciences, Bengaluru, Karnataka, India
Introduction: Children with diffuse intrinsic pontine gliomas (DIPGs) have a median survival of 9 months. They represent a therapeutic challenge in neuro-oncology. The characteristic location as well as the presence of infiltration means that resection is not possible. Limited treatment options and dismal prognosis with diagnosis of DIPG have historically led to a sense of nihilism. The only way forward is to biopsy patients with DIPG and to do molecular profiling for identifying targets for treatment. In this study, we present our experience of doing biopsy in cases of DIPG.
Methodology: We did a prospective study following patients who underwent biopsy for DIPG in children as well as in adults. The complications as well as the biopsy success rate were reported.
Results: From April 2018 to April 2022, about 109 cases of DIPG were encountered in the tertiary referral institute. All patients were explained about the pros and cons of biopsy and its prognostic significance. Fifty-five patients underwent frameless biopsy in the study period. There were 33 pediatric and 22 adult patients in the study. The mean age of pediatric group was 9.3 years and that of adult group was 31.9 years. 54.5% of pediatric and 50% adult patients comprised males. There was one negative biopsy (success rate 98.2%) in the overall study. Twenty-eight (85%) of pediatric biopsies and 9 (41%) of adult biopsied showed H3K27 immunohistochemistry positive status. One adult and one child had transient post operative neurological deficit which improved in weeks. There was no procedural mortality.
Conclusion: Brainstem biopsy of DIPG was feasible and yielded sufficient material for histopathological studies. Relevant molecular targets can be identified impacting clinical management in further studies. The results of the molecular profiling can help identifying markers as well as targets in future.
Radiotherapy planning in hemangiopericytoma of posterior fossa brain � A rare case report with review of literature
Brijesh Bhagwan Maheshwari, Pavan Kumar, Piyush Kumar; SRMS Medical College, Bareilly, Uttar Pradesh, India
Introduction: Intracranial hemangiopericytoma is rare entities accounting for 2% to 4 % of intracranial tumors and those occurring in posterior fossa are extremely rare. Surgery is the mainstay of treatment. Although postoperative adjuvant radiotherapy is often used, there is no standard guidelines due to its uncommon incidence. Here, we report an unusual case of hemangiopericytoma of posterior fossa to analyze the impact of postoperative radiotherapy.
Case Summary: A 42-year-old male patient underwent prior tumor excision in 2014, postoperative histopathology was suggestive of meningioma Grade II. No adjuvant treatment was taken thereafter. About 7 years later, patient presented with severe headache on and off with diminision of vision for 10–12 months. Contrast -enhanced magnetic resonance imaging (MRI) was done which was suggestive of a large lobulated, extra-axial lesion in the right occipital region based on dura. There were multiple internal flow voids. The lesion was causing mass effect resulting in buckling of cortex, mid line shift and rotation of brain stem suggestive of hemangiopericytoma/meningioma. Patient underwent right external carotid artery ligation after neck exploration along with re-exploration of posterior cranial fossa and decompression of mass. Histopathology report was suggestive of hemangiopericytoma, WHO grade II. Postsurgery patient was planned for adjuvant radiotherapy. After 1 month of surgery, MRI brain was done on was suggestive of residual in parieto-occipital region. Patient was planned for postoperative radiotherapy, with 59.4 GY in 33 fractions; 1.8GY per fraction. The patient is now on monthly follow-up. There is no sign and symptom of disease clinically or radiologically. The patient came on last follow-up in July 2022.
Conclusion: Hemangiopericytoma of the central nervous system is rare neoplasm with unpredictable behavior. There is no standard treatment due to the scarcity of data. In reference to what is currently available surgical treatment associated with radiotherapy is valued to achieve better therapeutic efficacy.
Endoscopic biopsy of pineal region tumors: Experience of a single neurosurgical unit
Krishna B. Shroff, Chandrashekhar Deopujari, Suhas Malineni,Vikram Karmarkar, Chandan Mohanty; Bombay Hospital Institute of Medical Sciences, Mumbai, Maharashtra, India
Introduction: Pineal region tumors represent a wide variety of histologically heterogeneous lesions. They include tumors of the pineal gland, tumors in the posterior third ventricle, and aqueductal/periaqueductal tumors. The practice of a radiation test dose is now obsolete and biochemical/histological diagnosis is recommended before further therapy. Most patients present with hydrocephalus. Advances in neuroendoscopy have allowed safe and effective management of this obstructive hydrocephalus with an opportunity to sample cerebrospinal fluid (CSF) and obtain tissue for histopathology and definitive surgery is generally required in less than a third of these patients.
Aim and Objectives: To study the diagnostic rate, diagnostic accuracy, and safety of neuroendoscopic biopsy in patients with tumors of the pineal region, and the success rate of concurrent endoscopic third ventriculostomy (ETV).
Materials and Methods: This is a retrospective study of neuroendoscopic biopsy procedures in patients with pineal region tumours from 2002 to 2021 at a single neurosurgical unit in a tertiary care hospital. All patients initially underwent MRI with contrast and evaluation of serum germ cell tumor markers. If negative, endoscopic biopsy and ETV were performed, and CSF was collected for tumor markers and malignant cytology. Demographic data, clinical presentation, operative notes, complications, histopathology, and follow-up data were all retrospectively reviewed and descriptively analyzed.
Results: There were 42 patients who underwent endoscopic biopsy procedures for tumors in the pineal region. The male:female ratio was 2:1. The median age at presentation was 17 years. Raised ICP (85.7%) was the most common mode of presentation. The endoscopic tumor biopsy diagnosis rate was 95.23% and the accuracy rate (in patients who underwent a subsequent open/microsurgical resection) was 88.9%. ETV was performed in all these patients except one who underwent a septostomy. The ETV success rate was 87.8%. Major intraoperative hemorrhage during endoscopic biopsy requiring conversion to open surgery was seen in one patient. Three others had transient deficits of extraocular movements. No patient died due to endoscopic biopsy.
Conclusion: Neuroendoscopy has revolutionized the management of pineal region tumors. It is a safe and effective procedure in this cohort of patients with a good diagnostic yield and allows successful concurrent CSF diversion, thereby avoiding major surgeries and shunt implantation.
Outcomes of hippocampal avoidance - Whole brain radiotherapy with simultaneous integrated boost with memantine in brain metastasis
Joyce Christina, Tanvir pasha, Uday Krishna; Kidwai Memorial Institute of Oncology, Bengaluru, Karnataka, India
Objectives: To assess long-term neurocognitive outcomes, local control, quality of life (QOL), and survival after hippocampal avoidance -whole brain radiotherapy (HA-WBRT) with simultaneous integrated boost (SIB) and memantine among brain metastasis.
Methods: This prospective study was performed after obtaining clearance from institute scientific and ethical committees to assess long-term neuro-cognition, QOL, local control, and survival among patients with brain metastasis following HA-WBRT with SIB and memantine. Between September 2019 and March 2022, 36 patients (aged >18 years, male:female: 17:19) referred for WBRT in RPA class I/II, oligo metastasis and no prior radiation therapy (RT) to brain were enrolled into the study. Baseline clinical/neurological evaluation, magnetic resonance imaging (including thin cuts of axial post GADO for RT planning), QOL assessment by EORTC QLQ30, neuro-cognitive battery by Hopkins Verbal Learning Test (HVLT), MiniMental Status Examination (MMSE), and TMT A/B were performed. After written consent, they underwent HA-WBRT with SIB to a dose of 30 Gy (40Gy SIB) in 10 fractions with Hippocampal OAR constraint as per RTOG CC001 protocol. Patients received oral memantine 10 mg twice daily started on the day of RT and continued up to 12 weeks after the completion of RT. Post-RT evaluation with all parameters was done at 4 weeks, 3 months, 6 months, and until the last follow-up. RANO criteria were used for radiological response. All results were tabulated on SPSS and survival assessed done by Kaplan−Meier analysis.
Results: Mean baseline values – qol - 32.6, hvlt 1 - 6.42, 2–6.72, mmse −22.03, tmt a/b 2.22/4.75. Six weeks qol - 28.03, hvlt 1 - 7.44, 2 - 7.81, mmse −23.67, tmt a/b 1.89/4.04, 3 months qol-25.50, hvlt 1-1.69, 2 - 8.0, mmse −23.72, tmt a/b 1.80/3.84, 6 months qol - 24.36, hvlt 1 - 8.08, 2 - 8.32, mmse −23.36, tmt a/b 2.19/3.72. The P-values from post hoc tests showed significant increase in cognitive and QOL values from baseline to 6 weeks ( <0.001). Furthermore, the difference was significant between baseline 3 months and baseline 6 months, which shows significant increase in cognition and QOL. However, there was no decrease in scores between 6 weeks and 3 months and 3 months–6 months, which shows the cognition was preserved and no long-term detoriation. Median follow-up was 8 months, OS of the cohort was 9.4 months. Local control assessed with MR at 3 months and 6 months with RANO criteria results were as follows CR-26%, PR-56%, SD-17%, PD-4% (no patients developed local failure in the HAZ) . Memantine was well tolerated in all the patients with no serious adverse effects reported.
Conclusion: (HA-WBRT) with SIB with memantine improves preserves cognitive function and QOL with significant intracranial local control and should be considered a standard of care for patients with good performance status and oligo metastasis.
Comparison of set up margins between three frameless stereotactic head immobilization devices treated with linear accelerator based stereotactic radiosurgery
Riddhijyoti Talukdar, Archya Dasgupta1, Abhishek Chatterjee1, Ajay Mishra1, Oindrila Roy Chowdhury2, Kishore Joshi1, Avdhoot Sutar3, Jayant Sastri Goda1, Revathy Krishnamurthy1, Tabassum Wadasadawala1, Priyamvada Maitre1, Vedang Murthy1, Ankita Gupta1, Supriya Chopra1, Vikas Singh4, Prakash Shetty4, Aliasgar Moiyadi3, Rajesh Kinhikar2, Rajiv Sarin1, Jaiprakash Agarwal1, Tejpal Gupta1; Departments of 1Radiation Oncology, 2Biostatistics, 3Medical Physics and 4Neurosurgery, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, Maharashtra, India
Aims: The introduction of frameless stereotactic immobilization device has improved patient compliance and enabled the delivery of fractionated stereotactic radiosurgery (SRS). With several variants of immobilization devices available for clinical use, the practice is often variable, using different planning target volume (PTV) margins. The current study evaluated setup accuracy for linear accelerator (LINAC) based SRS.
Methods: Patients treated with frameless SRS were included in the retrospective study. The three immobilization devices were: CIVCO’s trUpoint ARCH™ SRS/SRT system, BrainLAB mask fixation system, and POCL cradle mask. All the patients were treated with single isocenter LINAC SRS equipped with cone-beam computed tomography (CBCT). The workflow included an initial CBCT to assess translational errors in three dimensions and matching. A subsequent CBCT was undertaken to evaluate residual errors before treatment delivery.
Results: One hundred and forty-three fractions from 36 patients treated between January 2021 and June 2022 were included in the analysis. Sixty-five and seventy-eight fractions were delivered for benign tumors and brain metastases, respectively. Single, 3, and 5 fractions were done in 17%, 17%, and 64%, respectively. BrainLAB, CIVCO, and POCL were used for 71, 47, and 25 fractions, respectively. The mean shifts obtained from index CBCT were 1.05 mm (antero-posterior, [AP]), 1.74 mm (supero-inferior, [SI]) and 1.15 mm (medio-lateral, [ML]). Following the application of shifts with repeat CBCT, the shifts were 0.19 mm, 0.24 mm, and 0.19 mm. Residual shift data were available for 83 fractions. Using the Van Herk and Stroom formula, the recommended PTV margins are 1.15, 1.15, 0.62 mm (AP, SI, ML) and 1.41, 1.39, 0.76 mm (AP, SI, ML), respectively, for the overall cohort. It was least for CIVCO 0.38 mm (Van Herk) and 0.47 mm (Stroom) (maximum in any direction). The mean vectors initially were 2.3, 2.7, and 3.1 mm for CIVCO, BrainLAB, and POCL mask, respectively. The corresponding values for residual shifts were 0.13, 0.73, and 1.87 mm, respectively, for CIVCO, BrainLAB, and POCL. In terms of mean residual vector, CIVCO and BrainLAB were significantly better than POCL (P = 0.00 and P = 0.049, respectively). CIVCO was significantly better than BrainLAB (P = 0.01). The mean 3D residual vector was 0.56 mm for the first fraction versus 0.71 mm for subsequent fractions (P = 0.66).
Conclusion: CIVCO provided the best immobilization, followed by BrainLAB. With the use of CBCT and online corrections, a PTV margin of 1 mm can be used in appropriate cases for CIVCO and BrainLAB, while 2mm should be used for POCL.
Comprehensive management of pediatric, adolescent, and young adult patients with malignant primary central nervous system tumors in a new set-up: Challenges and initial experience
Soujanya Ferdinand, Rohit Vadgaonkar, Anupurva Dutta, Swetha Venkata Reddy, Pradeep Ventrapati, Raviteja Miriyala, Spandana Pilli, Aarathi Ardha Reddy, Umesh Mahantshetty; Homi Bhabha Cancer Hospital and Research Centre, Visakhapatnam, Andhra Pradesh, India
Objective: The study aims to address the challenges in the management of malignant primary central nervous system (PCNS) tumors in pediatric and Adolescent and Young adult (AYA) population in a new cancer setup and audit of initial experience.
Methodology: A retrospective audit of prospectively maintained database of all PCNS tumors in our institute between November 2019 and July 2022 was performed. Demographic profile, histopathological, molecular information, treatment summary, and follow-up status of pediatric (age: 0–14 years) and AYA (age: 15–39 years) group were extracted.
Results: Important challenge in a new setup was to establish a comprehensive multi-disciplinary tumor board for the adequate management of PCNS tumors, particularly when in-house neurosurgical facilities are not available; tele-consultations with operating surgeons is an alternative approach to ensure multi-disciplinary management. A predesigned integrated radiotherapy suite consisting OT, recovery room and teletherapy facility was effective in handling anesthesia requirements of patients aged ≤5 years. A simpler, cost-effective method of designing and coloring of thermoplastic molds, similar to the masks worn by the superheroes or cartoon characters for children between 5 and 10 years was effective in ensuring their cooperation and compliance. Of 78 patients who were registered with a diagnosis of PCNS malignancy, 45 (pediatric: 11, 24.4% and AYA: 34, 75.6%) were included. The median age was 26 years (2–39 years) and 29 (64.4%) were males. The most common diagnosis was astrocytoma in 28 (low grade in 4, grade 3 in 13, and grade 4 in 11), oligodendroglioma (ODG) in 6 (grade 3 in 5), followed by ependymoma (n = 3), medulloblastoma (n = 2), and others (n = 6). Molecular profile demonstrated IDH1 mutations in 53% of astrocytomas (80% in grade 3, 12.5% in grade 4), 80% in ODG. P53 was mutated in 88.5% astrocytomas (84.6% in grade 3, 90% in grade 4) and 80% in ODG. MGMT was unmethylated in 85.7% of astrocytomas and 1p19q was co-deleted in all ODGs. Forty-four underwent surgery consisting gross total resection in 8 (18.2%) and near total to subtotal resection in 28 (63.6%). Radiotherapy was delivered to a dose of 59.4Gy/33# in 23 (51.1%), 54–55.8Gy/30-31# in 9 (20%) and 30 (66.7%) patients received by VMAT technique. Two patients with medulloblastoma received CSI followed by posterior fossa boost. All high-grade glial patients received concurrent temozolomide (TMZ) and 87% received adjuvant TMZ. At median follow-up of 13 months, 88% patients are alive (89% astrocytoma, 83% ODG).
Conclusion: The study highlights the unique challenges, distinct histopathological, and molecular profile of pediatric and AYA population.
Radiotherapy planning in a rare case of clear cell ependymoma of frontal lobe: A case report
Pallavi Gour, Piyush Kumar, Arvind Kumar, Jitendra Nigam, S. Navitha; Shri Ram Murthi Smarak Institute of Medical Sciences,Bareilly, Uttar Pradesh, India
Introduction: Clear cell ependymomas (CCEs) are the rare variants of ependymomas. Tumors show anaplastic histological features and behave as an aggressive manner. These tumors should be radiologically and pathologically differentiated from oligodendrogliomas. On microscopic examination, CCEs are composed of sheets of cells and resemble oligodendroglioma. However, upon closer examination, the nature of CCEs can be detected earlier, resulting in prompt treatment of the tumor. In our case report, we highlight the aggressive clinical behavior, the histological mimics, the diagnostic dilemmas, the need for an early evaluation of the craniospinal axis, and the possible adjuvant radiotherapy that needs to be administered to the entire axis.
Case Summary: Patient Ram Kishore 28 years presented to the opd on as a postoperative case of anaplastic CCE WHO grade III, preoperatively, patient had complaints of single episode of seizure. Magnetic resonance imaging (MRI) brain was suggestive of large well-defined cystic lesion with thin irregular peripheral wall involving the left cortical and subcortical white matter of left frontal - likely low-grade glioma oligodendroglioma. The patient underwent surgery left frontal craniotomy with gross tumor resection of primary tumor with duraplasty was done. Histopathology was suggestive of anaplatic CCE WHO Grade III. Immunohistochemistry s/o - GFAP+ve, Vimentin+ve, EMA+ve, KI 67%-8%, referred for postoperative radiotherapy, Postoperative MRI brain was done for knowing the disease status and planning purpose s/o 2.7 cm × 2.4 cm in left frontal lobe with surrounding odema. Lesion is of heterogeneous intensity on TW images TR hyperintense on images ? postoperative collection. Postoperative computed tomography (s/o hypodense lesion 2.6 cm × 2.1 cm × 2.5 cm noted in left frontal lobe cortical subcortical region. Patient was planned for radiotherapy 59.4 gy in 33 fractions, 6.5 weeks, 1.8 gy/fraction along with concurrent 100 mg patient is now on adjuvant chemotherapy with Tab. Temozolamide and has completed four cycles without any complication. Patient is on follow-up and with no sign and symptoms of disease clinically.
Conclusion: CCE is a rare entity with features of aggressive tumor behavior. Diagnosis is difficult due its distinction from other tumors. A large study is needed to determine therapeutic responsiveness and prognosis of this rare cancer.
Intensity-modulated radiotherapy planning spares hippocampus in craniopharyngioma retrospective evaluation of a case treated with conventional planning (long-term neurocognitive deficit function)
Abhishek Bhadri, Piyush Kumar, Pavan Kumar, Navitha Selvi; SRMS IMS, Bareilly, Uttar Pradesh, India
Introduction: Craniopharyngiomas arise from epithelial remnants of the Rathke pouch and are typically found in the suprasellar region in children or adolescents. They account for <5% of all central nervous system neoplasms in adults. Radiotherapy remains the mainstay of treatment for achieving long-term disease control in patients with residual or recurrent tumors where complete surgical is considered inappropriate due to unacceptable morbidity. This is a retrospective study done to evaluate the sparing of the hippocampus dose with intensity-modulated radiotherapy (IMRT) planning done in treated cases with conventional planning.
Case Summary: Patient Hemender Kumar 21-year-old male presentedto the outpatient department as a postoperative case of adamantinomatous craniopharyngioma. Preoperatively, patient had complaints of headache, vomiting, and fever for 2 years. Preoperative computed tomography (CT) scan was suggestive of calcified lesion of size 39 mm × 33 mm × 42 mm is seen at sella, suprasellar region extending further to adjacent left frontal and temporal region associated with surrounding hypodensity at the frontal region of size approximately 50 mm × 30 mm. Patient underwent left pterygonal craniotomy with tumor decompression. Postoperative CT SCAN was suggestive of craniotomy defect. Sellar widening with a heterogeneous and calcified lesion measuring approximately 3.3 cm × 3.2 cm × 2.7 cm (TR × CC × AP) seen in the sellar region with superasellar and mild parasellar extension suggestive of residual craniopharyngioma. Histopathology suggestive of adamantinomatous craniopharyngioma. MRI brain was suggestive of 3.7 cm × 3.4 cm × 3.6 cm heterogeneous enhancing combined intrasellar and suprasellar space-occupying lesion suggestive of residual lesion. Noncontrast computed tomography was done suggestive of sellar widening with a heterogeneous rim calcified lesion measuring approximately 3.7 cm CC ×3.2 cm AP × 3.2 cm TR seen in the sellar region with suprasellar and mild parasellar extension, suggestive of residual craniopharyngeal craniopharyngioma. Left frontoparietal temporal craniotomy flap noted in situ. Patient underwent radiotherapy by conventional technique 50.4 Gy/28 fractions. Hippocampus dosimetry was evaluated in conventional and IMRT plans. The dose was reduced and was within constraint in the IMRT plan (Dmax 16 Gray, Dmean 8.5 Gray). Now patient came for follow-up on 07/07/2022 and there were no signs of disease progression clinically.
Conclusion: The standard treatment of craniopharyngioma is surgery followed by postoperative radiotherapy. Hippocampus is a critical structure located in the temporal lobe responsible for neurocognitive function. Hence, it is important to save this structure to provide a better quality of life to patients.
Spectrum of medulloblastoma in children: A single-center experience over 10 years
Payal Malhotra, Anjali kakaria, Jain Sandeep, Kapoor Gauri; Rajiv Gandhi Cancer Institute and Research Centre, New Delhi, India
Aims and Objective: To summarize our experience of spectrum of medulloblastoma in terms of incidence, clinical presentation, radiological features, risk stratification, treatment strategies, and outcome.
Materials and Methods: This was a retrospective analysis of all newly diagnosed medulloblastoma patients registered in our department between January 1998 and December 2021. Demographic, disease, treatment details, and follow-up status/outcome of these patients was abstracted from the e-medical records. All these patients underwent surgery followed by cranio-spinal radiation (CSRT) for children aged >3 years. This was followed by adjuvant chemotherapy as per POG 9031 protocol.
Results: A total of 80 children with brain tumors were registered and treated at our institute during the study period. Of these 34/80 (42.5%) were medulloblastoma. 28/34 (82%) were >3 years of age and 3/34 (9%) were infants. Median age of presentation was 6 years (1 year–25 year) with 70% males. Majority of patients presented with vomiting 34% (27/34), focal neurological deficits -unsteady gait/diplopia/cranial nerve palsy 44% (15/34), headache 41% (14/34), others irritability, feeding issues, loss of weight, and fever 82% (28/34). Median duration of symptoms was 2 months (1 week–1 year). Most patients (85%) revealed a mid-line tumor growing into the fourth ventricle on magnetic resonance imaging. Leptomeningeal spread and spine seeding was reported in 20% and 19% patients, respectively. Staging workup revealed 35 % (12/34) as metastatic, with 15% (5/34) being cerebrospinal fluid positive. Forty-five percent (15/34) was high risk as per modified chang’s staging. Surgery was performed for all patients and 88% (30/34) underwent gross total or near total resection. Eighty-two ( 28/34) received CSRT, with median dose of 36 gy and posterior fossa boost of 54gy. All patients received chemotherapy with tolerable toxicity. Over a median follow-up duration of 15 months (1–148 months), 18% ( 4/34) relapsed, 6% ( 2/34) had progressive disease, and 12% (4/34) expired (2 relapse and 2 progressive disease).
Conclusion: In the present study, medulloblastoma was the most common brain tumor, with vomiting and focal neurological signs as most reported symptoms. Treatment strategy included multi-modal treatment with omission of CSRT in children <3 years. At follow-up, 76% children were alive and disease free.
*No grants were provided in the current study.
1p Deletion in meningiomas: A simple easy-toimplementable prognostic stratifier in meningiomas
Jayesh Saha, Neeti Goyal, Mandar Ankolkar, Omshree Shetty, Ayushi Sahay, Abhishek Chatterjee, Archya Dasgupta, Tejpal Gupta, Vikash Singh, Prakash Shetty, Aliasgar Moiyadi, Sridhar Epari; Tata Memorial Hospital, Mumbai, Maharashtra, India
Introduction: Loss/deletion of chromosome 1p has now been shown to be a robust independent prognostic marker in sporadic NF1-mutant meningiomas, resulting in histomolecular integrated algorithms for better risk stratification in meningiomas, especially among Grade 1 and 2 meningiomas. This study outlines our experience about the same.
Methods: Twenty-four meningiomas that were evaluated for 1p deletion by fluorescence in situ hybridization (FISH) using Zytolight SPEC 1p36/1q25 Dual Color Probe set formed the study cohort. 1p deletion was considered if >50% nuclei contained 1 signal of 1p probe with ≥2 signals of 1q probe and 1p/1q ratio ≤0.8 ratio. DNA extracted from the samples was amplified via polymerase chain reaction using primers specific for TERT promoter hotspot regions. The amplified product was purified using EXOSAP-IT (USB) followed by cycle sequencing using Big Dye X-Terminator Kit (ABI) and was subsequently sequenced on 3500 Genetic Analyzer (ABI). The electropherograms were analyzed manually using Chromas Lite v2.1.
Results: Age ranged from 28 to 63 years (median age: 48 years) with 13 male and 11 female patients. Most common sites affected were frontoparietal regions (n = 10) and sphenoid region (n = 5) followed by basifrontal region (n = 3), posterior fossa (n = 3), parieto-occipital region (n = 2), and involving olfactory groove(n = 1). 8(33.3%) were histologically grade 1, 15(62.5%) were grade 2 and 1(4.1%) was grade 3. 46.6% (n = 7) Grade 2 and one Grade 3 meningiomas showed 1p deletion; while all grade 1 and 6 (40%) grade 2 meningiomas did not show copy number variation of chromosome 1. Other 2 cases of grade 2 could not be categorized due to discordance between the ratio and percentage of 1p deleted cells. Twenty-two cases (grade 1: 7 cases and grade 2: 14 cases) evaluated for TERT-promoter hotspot (C228 and C250) mutations were negative. Recurrence of the tumor was seen in seven cases (grade 1: 2 cases; grade 2: 5 cases), 3 of which (grade 2: 3) showed 1p deletion.
Conclusions: 1p deletion is noted grade 2 and grade 3 meningiomas. Detection of 1p deletion by FISH with appropriate cut-off criteria can be implemented in routine practice, especially in cases where the histological features are debatable for better adjuvant clinical decision.
Wingless-pathway medulloblastoma in adolescent and young adult: Is it any different from childhood medulloblastoma?
Shakthivel Mani, Abhishek Chatterjee, Sridhar Epari, Ayushi Sahay, Neelam Shirsat, Aliasgar Moiyadi, Prakash Shetty, Girish Chinnaswamy, Archya Dasgupta, Rahul Krishnatry, Jayant Goda, Nazia Bano, Farnaz Shaikh, Tejpal Gupta; Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, Maharashtra, India
Background: Medulloblastoma (MB) is considered a molecularly heterogeneous disease comprising mainly of 4 molecular subgroups - wingless (WNT), sonic hedgehog, Group 3, and Group 4 tumors. Children (<15-years) with WNT-MB have the best outcomes (5-year survival >90%) that has prompted the testing of various de-escalation strategies to reduce long-term treatment-related toxicity. Adolescents and young adults (AYA) with WNT-MB seemingly have worse survival compared to children and are largely excluded from de-escalation studies. The objective of this analysis was to compare clinico-pathological features and survival outcomes between childhood and AYA WNT-MB.
Methods: Patients with molecularly confirmed WNT-MB treated with maximal safe resection followed by post-operative standard-of-care risk-stratified adjuvant radio(chemo)therapy were identified retrospectively. Data regarding clinico-radiological presentation, histo-pathological features, treatment details, patterns of failure, and survival outcomes was extracted from electronic medical records. Patient and treatment characteristics were compared between the two groups using Chi-square test or Fishers’ exact test as appropriate. Time-to-event outcomes were analyzed using the Kaplan-Meier method and compared with the log-rank test.
Results: Seventy four patients with WNT-MB were identified retrospectively from an institutional cohort of 504 MB cases who underwent molecular profiling at a comprehensive cancer centre between 2004 and 2020. Seven patients treated on a prospective clinical trial of therapy de-intensification were excluded leaving 67 patients that constitute the present study cohort. There were 44 (66%) children and 23 (34%) AYA patients with male preponderance in both groups. Five children with WNT-MB had leptomeningeal metastases (M+) at presentation; in contrast none of the AYA WNT-MB presented with M+ disease (12% vs. 0%; P = 0.16). Children with WNT-MB were more likely to have received adjuvant systemic chemotherapy compared to AYA WNT-MB (81% vs. 50%; P = 0.04). There was no significant difference in the pattern of failure between the two subgroups (neuraxial dissemination with or without local recurrence) with only one adult developing isolated extraneuraxial relapse on follow-up. Survival analysis was restricted to 61 patients (excluding 1 post-operative mortality and 5 without adequate details of treatment and/or outcomes). At a median follow up of 72 months, 5-year Kaplan-Meier estimates of progression free survival (86.2% vs. 81.8%; P = 0.88) and overall survival (91.1% vs. 91.7%; P = 0.30) were similar for childhood versus AYA WNT-MB cohort.
Conclusion: There are modest differences in clinical presentation and adjuvant treatment between childhood and AYA WNT-MB. However, despite such differences, survival remains excellent across all age-groups suggesting that AYA patients with WNT-MB be included in future de-escalation studies.
Acknowledgements Brain tumor foundation (BTF) of India.
Influence of radiation doses to hippocampal subvolumes on memory outcomes in pituitary tumors: Does entire hippocampus need to be spared?
Ajay Thomas Alex, Archya Dasgupta, Arpita Sahu, Ujjwal Agarwal, Abhishek Chatterjee, Oindrila Roy Chowdhury,Savita Goswami, Utpal Gaikwad, Vikas Singh, Prakash Shetty, Aliasgar Moiyadi, Ayushi Sahay, Epari Sridhar, Rakesh Jalali, Tejpal Gupta, Jayant Sastri Goda; Tata Memorial Hospital, Mumbai, Maharashtra, India
Introduction: Hippocampus plays an integral role in memory formation. Several studies have demonstrated that radiation therapy (RT) doses to the hippocampus strongly influence neurocognitive outcomes. However, the role of hippocampal subvolumes (head, body, tail) in memory functioning has not been reported, which prompted the current study.
Methods: Adults with pituitary tumors treated with conformal fractionated RT (45 Gy/25 fractions/5 weeks) were accrued in the prospective study. Hippocampus was delineated on T1-weighted 3D-FSPGR sequences with 1 mm slice thickness. Although no specific dose constraints were applied to the hippocampus, as low as reasonably achievable principle was used without compromising target coverage. The head, body, and tail of hippocampus were drawn retrospectively for the current study based on the consensus of two neuroradiologists. The anatomical landmarks were: head (basilar artery to interpeduncular cistern), body (interpeduncular cistern to superior colliculus), and tail (beyond superior colliculus). Memory assessment was done pre-RT and 18 months post-RT by dedicated neuropsychologist using Weschler Memory Scale. The dose-volume parameters (maximum, mean, D10-D100 increments of 10) were extracted from bilateral hippocampi and individual subvolumes, which were correlated with the memory outcomes. Binary endpoints of >5% drop of global memory quotient (MQ) or not at 18 months were analyzed using an independent t-test or Mann–Whitney test as appropriate.
Results: In the prospective study, 52 patients were accrued, of whom 25 had follow-up memory assessment at 18 months post-RT (impacted by COVID-19 pandemic). Of 25 patients included in the current analysis, 11 had drop of MQ >5% at 18 months. Dose parameters to the entire volumes of the left (D10, D20, D30) and right (D10) hippocampus influenced memory outcomes. For the subvolumes, only the dose to the left head had a significant impact on MQ. The mean values of D10 (35 Gy vs. 28 Gy, P = 0.02), D20 (32 Gy vs. 26 Gy, P = 0.01), D30 (30 Gy vs. 24 Gy, P = 0.01), D40 (28 Gy vs. 22 Gy, P = 0.01), D50 (26 Gy vs. 21 Gy, P = 0.01), D60 (24 Gy vs. 20 Gy, P = 0.02), and D70 (23 Gy vs. 19 Gy, P = 0.03) was showing patients with >5% MQ drop received higher doses to left hippocampus head.
Conclusion: Doses to bilateral hippocampi were shown to impact memory functioning. Of the subvolumes, only the left head appeared significant from the current pilot study, opening a window for exploring tighter dose constraints towards hippocampal head for primary or metastatic brain tumors.
Prognostic factors associated with long-term survival in patients with glioblastoma multiforme at Fortis Memorial Research Institute, Gurugram
Anita Priyadarshini, Sakshi Rana, Shaleen Agrawal, Ashu Abhishek, Amal Roy Chaudhary, Rakesh Kumar Gupta, Rana Patir; Fortis Memorial Research Institute, Gurugram, Haryana, India
Background: Glioblastoma is one of the most aggressive and most common primary central nervous system tumours. Due to its intratumoral heterogeneity, behaviour of this malignancy remains unpredictable. Inspite of advances in neurosurgery, chemotherapy and radiation, median survival still remains 12–15 months. It is seen that subset of glioblastoma multiforme (GBM) who survive longer than 2 years are termed as long-term survival (LTS) constitute around 27% of the GBM patient after standard treatment. There are many factors such as performance status,young age, MGMT methylation status, extent of surgery which has found to be associated with better survival but still it is unknown and needs to be studied extensively. Hence, we did this retrospective study to analyze the factors associated with LTS of GBM patients.
Aims: To analyze the factors associated with LTS GBM patients.
Materials and Methods: It is a retrospective analysis of all the biopsy-proven GBM cases diagnosed and treated at our center. Demographic, treatment, and follow-up data of all the GBM patients registered in our centers from 2015 to March 2020 were reviewed. Patients surviving more than 2 years were termed as long-term survivors. The clinical, radiological, and molecular features between those having better survival >2 years were compared with those surviving <2 years.
Result: A total of 112 patients were included in the study. Out of 112 patients, 53 patients were termed as LTSs. Younger age, good performance status, gross total resection, tumour volume <40 cc, low tumor perfusion, and unifocal tumor were associated with long-term survivor but the association was not statistically significant. Only the good performance status was statistically significant with P = 0.003. Recurrence pattern, timely diagnosis intervention, and aggressive multimodality treatment were also seen to be associated with long-term survivors.
Conclusion: Survival in GBM patients is heterogenous and multiple factorial. Younger age, good performance status, tumor volume <40 cc, and unifocality are some of the factors associated with long-term survivors.
Diagnostic accuracy of intraoperative consultation for the diagnosis of central nervous system lesions: A 2-year study from a tertiary care centre
Garima Durga, Prachi Gupta, Kaushik Majumdar1, Ankur kumar, Raghav Kapoor, Anila Sharma, Meenakshi Kamboj, Sunil Pasricha, Gurudutt Gupta, Anurag Mehta; Department of Pathology, Rajiv Gandhi Cancer Institute and Research Centre, New Delhi, India, 1Department of Pathology, Al Sabah Hospital, Kuwait
Aims and Objectives: Intraoperative evaluation of the central nervous system(CNS) lesions is an important tool which helps the neurosurgeon to determine the endpoint of surgery and overall appropriate therapeutic decision-making in the management of the patient. In this study, we determine the diagnostic accuracy of using frozen section (FS) of CNS lesions.
Materials and Methods: In this retrospective study, we included cases of CNS lesions for which intraoperative consultation was sought during the year July 2019–July 2020 and June 2021–June 2022. A total of 77 cases were analyzed and diagnosis on FS was compared with the final paraffin slides to assess the concordance and discordance rates between both using Statistical Package for the Social Sciences (SPSS) software v20.
Results: The reports of FS and paraffin sections were studied with respect to benign or malignant and histological subtype and grade, if malignant. The paraffin section diagnosis was taken as the gold standard.
In our study, out of 77, 62 (80.5%) cases had complete concordance between FS and final diagnosis, 8 (10.4%) cases had a partial concordance, and 7 (9.1%) cases were discordant.
Conclusion: Our results were in resonance with similar studies conducted by several authors. Main causes for discrepant reports in our study included pathologist’s misinterpretation, small non representative biopsy material, technical errors, incomplete clinicoradiological information about the lesion. Overall, intraoperative consultation forms an important instrument in the management of patients with CNS lesions, provided its pitfalls are understood properly.
Grant Acknowledgments No grant was sought for this study as it was an observational work.
Intercepting the crosstalk between neural stem cells and glioblastoma mutiforme
M. Jwala, Rahul Lal Chowdhary, Muhammed Ismail Sharief, Kundan S. Chufal, Swarupa Mitra, Munish Gairola; Rajiv Gandhi Cancer Institute and Research Centre, New Delhi, India
Aims and Objectives: Despite several advancements in glioblastoma multiforme (GBM) treatment, long term survival remains elusive. Recent evidence suggests that a minority of cancer stem cells in the tumour mass account for most of the proliferation, growth and resistance to radiation therapy and subventricular zone (SVZ) around lateral ventricles could be a potential reservoir of these stem cells. Studies extant in literature exploring the impact of radiation dosimetric profile of the SVZ and GBM survival have been ambiguous. We performed a retrospective analysis on GBM patients treated at our hospital facility in a zest to find a correlation between radiation doses received by the SVZ and its impact on overall survival in GBM patients.
Material and Methods: Electronic medical records of 45 GBM patients, treated with surgery and adjuvant chemoradiotherapy, between 1st January 2016 and 31st December 2019 were retrieved for the study. SVZ was contoured bilaterally on the simulation Computed tomography scans and dosimetric parameters were evaluated from the radiation plans. Based on MRI findings, tumours were also categorized into 4 subgroups based on their contact with the SVZ and cortex with category 1, having a contact with both the SVZ and cortex, category 2 having contact with only SVZ, category 3 touching the cortex and category 4 having no contact with either SVZ or cortex. Overall survival (OS) was taken from the time of diagnosis to death.
Clinical, pathological and treatment related variables were taken up for multivariate analysis (MVA), by cox regression, in a bid to identify prognostic factors influencing OS.
Results: The median age in the study cohort was 51 years (range, 25–75 years) and 49% of the patients were females. Percentage of patients presenting with a KPS score of >70%, 60%–70% and <60% was 35.6%, 55.6% and 8.8% respectively. In the entire cohort, 19/45 (42.3%), 7/45 (15.5%) and 12/45 (26.7%) of the patients underwent gross total resection (GTR), near total resection and subtotal resection respectively. Age, KPS score, type of resection, tumour categories, and dosimetric parameters of SVZ were taken into MVA. Type of resection, with those undergoing GTR, tumour category, with category 1 performing the worst, and SVZ dosimetric parameter of D95%, Dmin were seen to have significant impact (P < 0.05) on OS.
Conclusions: SVZ could prove to be a potential target in radiation planning in our quest for long term survival in GBM patients. Acknowledging the small sample size and inherent bias associated with retrospective nature of our study, a larger sample sized prospective study could provide us with more meaningful answers.
A prospective assessment of neurocognitive function and quality of life in patients undergoing conformal radiotherapy for brain metastases
Kratika Bhatia, Kundan Singh Chufal, Irfan Ahmad, Rahul Lal Chowdhary, Muhammad Ismail Sharief, Munish Gairola; Department of Radiation Oncology, Rajiv Gandhi Cancer Institute and Research Centre, New Delhi, India
Aims and Objectives: Excellent control of macroscopic and microscopic disease made Whole Brain radiotherapy (WBRT) an automatic choice in patients with brain metastases (BM). With increasing survival, a decline in neurocognitive function (NCF) and health-related quality of life (HR-QoL) with WBRT led to the development of novel techniques like hippocampus avoiding-WBRT (HA-WBRT) and stereotactic radiosurgery (SRS), to preserve neurocognition. To analyze the impact of these techniques on NCF and HR-QoL, we performed a prospective observational analysis of patients with an indication for Cranial RT (HA-WBRT and SRS).
Materials and Methods: Between 2020 and 2021, a total of 70 patients diagnosed with BM, with KPS ≥70 and expected median survival ≥6 months (by ds-GPA), treated with HA-WBRT or SRS, were prospectively enrolled. NCF and HR-QoL were assessed at baseline, before starting cranial radiation therapy (RT), and at three and 6 months post-RT completion. HR-QoL was assessed using the EORTC BN20 questionnaire. For assessment of NCF, Hopkins Verbal Learning Test-Revised (HVLT-R) and Mini Mental Status Examination (MMSE) was used. Repeated measures ANOVA was used to compare the mean scores at baseline, 3 months and 6 months. Statistical analyses were performed using SPSS® Version 26.0 software.
Results: MMSE scores showed no statistically significant decline when baseline scores were compared to scores at 3 months (absolute difference = 0.49, P = 0.53) or 6 months (absolute difference 0.07, P = 0.45). HVLT-IR and HVLT-DR scores were found to be significantly better at 3 months when compared to baseline (absolute difference = 0.85, P <0.01 and 0.46, P < 0.01, respectively) and remained stable over the next 3 months (P = NS). HR-QOL assessment using the EORTC QLQ- BN20 questionnaire revealed a statistically significant improvement in future uncertainty (absolute difference = 5.89, P < 0.01), domains of motor dysfunction (absolute difference = 3.53, P = 0.02 and absolute difference = 2.98, P = 0.03) and communication deficit (absolute difference = 2.71, P =0.05 and absolute difference = 1.62, P = 0.06) when compared at 3 months and 6 months respectively. Similarly, on single item symptom scale, significant improvement was observed over the study duration in headache (P < 0.01 for both) and weakness (P = 0.07 and 0.03) at 3 and 6 months follow up, respectively.
Conclusion: HA-WBRT and SRS in the treatment of BM significantly preserves NCF and QOL, with no deleterious effect on immediate or long-term memory and other functional domains.
Delyaed rare metastatic presentation of pinealoblastoma
Arya Bhanu, Jaskaran Singh Sethi, Anjali Pahuja, Varghese Anthony; Rajiv Gandhi Cancer Institute and Research Centre, New Delhi, India
Aim: To present a case of rare metastatic presentation of Pinealoblastoma after a decade of treatment.
Materials and Methods: Young female with no family history or any comorbidities presented at our institute in February 2012 as a diagnosed case of pinealoblastoma WHO grade IV. She was evaluated elsewhere for clinical symptoms of headache and vomiting of 10 days, diplopia, forgetfulness and unsteadiness of gait for 7 days duration. Magnetic resonance imaging brain revealed posterior third ventricular tumor with hydrocephalus. She underwent midline sub-occipital craniotomy, supracerebellar infratentorial approach and microsurgical decompression of the tumor in January 2012. Postoperative computed tomography (CT) brain showed post op collection with bulky residual heterogeneously enhancing irregular mass involving thalamus, cerebrum and cerebellum. Cerebrospinal fluid analysis was negative for malignant cells. In view of residual disease, she received external beam radiation therapy by image-guided radiation therapy to a dose of 53.82Gy/30# brain and 35.09Gy/20# to craniospinal axis. Patient was on regular follow up thereafter on outpatient department basis with interval scans since 2013. On March 2022, patient came with complaints of progressive, painless right chest wall swelling. Biopsy from RIB lesion showed metastasis from pinealoblastoma. Contrast-enhanced computed tomography thorax and abdomen showed solid cystic swelling arising from right 11th rib with associated soft tissue component. After multidisciplinary team discussion, patient was planned for neoadjuvant chemotherapy followed by local therapy. She received 3 cycles Etoposide and Cisplatin, last on June 2022. Follow up positron emission tomography CT (July 2022) showed partial response to neoadjuvant chemotherapy. Patient at present planned for local therapy.
Discussion: Pineoblastoma is a rare, primitive, and malignant tumor arising from the parenchyma of the pineal gland. Pineal tumors comprise 0.5%–1% of all intracranial tumors and 15%–32% of pineal tumors arise from pineal parenchyma. Pineoblastoma represents 25%–50% of pineal parenchymal tumors. It typically metastasizes along the cerebral neural axis, with rare extra-neural metastasis and even more rare intraosseous extra-neural metastasis. Earlier case reports had documented metastatic cases which had either occurred within months after the treatment or with multiple site involvement with delayed presentation.
Conclusion: Our case demonstrates an extremely rare delayed metastatic presentation of pinealoblastoma wherein the patient presented with a Solitary extracranial osseous metastasis after a decade.
Multi-disciplinary team discussion is imperative with treatment approach involving Chemotherapy, Radiotherapy and Surgery to individualize the treatment according to presentation. Robust reporting of such rare clinical presentations should be encouraged to formulate a scientific guideline for management.
To present feasibility of stereotactic radiosurgery in a 3-year-old child with solitary cranial metastasis in a known case of pleuropulmonary blastoma
Arya Bhanu, Jaskaran Singh Sethi, Anjali Pahuja, Varghese Anthony; Rajiv Gandhi Cancer Institute and Research Centre, New Delhi, India
Aim: To present feasibility of stereotactic radiosurgery (SRS) in a 3-year-old child with solitary cranial metastasis in a known case of pleuropulmonary blastoma (PPB).
Materials and Methods: A 3-year-old boy evaluated for left sided chest pain was found to have ipsilateral pleural effusion and a mixed density lesion with mediastinal shift towards right side on imaging. After placing an ICD tube, computed tomography (CT) guided tumor biopsy was performed which was suggestive of Germ cell tumor and immunohistochemistry (IHC) revealed mature teratoma. The solid-cystic friable mass was removed piecemeal by Left Anterolateral Thoracotomy. Histopathology with IHC suggested Pleuropulmonary blastoma, Type positron emission tomography(PET) CT and magnetic resonance imaging (MRI) brain did not show any active disease. He was started on IVADo based chemotherapy. After 12 cycles of chemotherapy, follow up PET and MRI brain showed an enhancing lesion of size 0.5 cm × 0.3 cm in right frontal region and a low volume recurrence in the mediastinum. After multispeciality board discussion, SRS was planned to the solitary brain metastasis along with radiotherapy to the mediastinal disease. After standard simulation under general anaesthesia (GA), images were registered with diagnostic MRI brain and contoured in Eclipse software. Plans were generated on eclipse at dose prescription of 24Gy in single fraction, with organs at risk (OAR) constraints specially recommended in literature for paediatric population. Plan was evaluated with adequate parameters of conformity, heterogeneity and control of low dose spill. OAR constraints were achieved well within limits. Treatment was implemented on SRS enabled LINAC under GA. He tolerated the treatment well without any acute adverse effects. The child also received 45Gy/25fractions to the mediastinal disease. He was continued on 2nd line rescue chemotherapy. However, the child died of progressive disease in mediastinum after 9 months of SRS, while maintaining complete remission in brain.
Discussion: PPB is an uncommon aggressive disease, representing only 0.25%–0.5% of all lung malignancies. Around 200 cases have been reported since 1945, only 20 cases had brain metastasis. Type II PPB present with brain metastasis in 11% of cases, with a reported survival of below 6 months. SRS can be offered as an alternative to neurosurgical intervention for asymptomatic brain metastasis from PPB with gratifying results.
Conclusion: SRS in paediatric cases is challenging as it requires prolonged sedation, perfect immobilization, meticulous target delineation, and plan evaluation to minimize long-term radiation-related neurotoxicity. It should be practiced at high volume centers with expertise and good multidisciplinary coordination.
Biologically aggressive pituitary adenomas - A tertiary hospital-based study
Kuldeep Singh Khangarot, Surabhi Tyagi, Amrit Raj Kalla, B. S. Sharma; Mahatma Gandhi Medical College, Jaipur, Rajasthan, India
Aims and Objectives: To assess the hormonal profile of pituitary adenomas and study the clinically silent and biologically aggressive pituitary adenomas.
Materials and Methods: This is a tertiary hospital-based study of forty cases of pituitary adenomas. All specimens were fixed in 10 percent formalin and entire biopsy tissue was processed as per standard guidelines. Immunohistochemistry (IHC) markers were done after H and E microscopy. IHC was done using primary antibody against the these antigens adrenocorticotropic hormone, growth hormone, luteinizing hormone, follicle-stimulating hormone, prolactin, thyroid-stimulating hormone and MIB1.
Results/Discussion: Out of forty cases, 22 were aggressive pituitary adenomas (55%) of which there were two clinically silent corticotrophs, one clinically functioning corticotroph with high MIB1, four plurihormonal of which one was clinically silent, four lactotrophs in males, three somatotrophs and one mammosomatotroph with high MIB1, seven gonadotrophs of which four were recurrent adenomas with high MIB1 and other three were non recurrent but with high MIB1. Hence, majority of the cases were gonadotrophs comprising 31.81% of all aggressive adenomas in our study. As certain pituitary adenomas are considered as biologically aggressive adenomas irrespective of MIB-1 LI on basis of gender, hormonal activity, histological, and immunohistochemical findings such as lactotrophs in males, Sparsely granulated somatotroph, silent corticotroph, Pit-1 positive plurihormonal adenomas, and recurrent adenomas, hence, we studied and subtyped the cases for aggressive adenomas using immunohistochemistry according to 2017 WHO classification.
Conclusion: Silent and aggressive pituitary adenomas represent a challenging group of tumors.
MIB-1 LI is used as a gold standard for assessing the biological aggressiveness and the MIB-1 LI of >2 % is of prognostic significance. However, clinically silent adenomas are also found to be aggressive and can be detected on IHC. Thus, correlation of immunohistochemistry and proliferative index with clinical and biochemical history is an important tool for proper evaluation and may be helpful in further adjuvant therapies which may be needed.
Factors predicting remission and recurrence after surgical treatment of Cushing�s disease
Nidhisha Sadhwani, Ashish Suri, Santanu Kumar Bora, Meher Chand Sharma, Rajesh Khadgawat, Ajay Garg, Deepa S, Ravi Sharma, Varidh Katiyar; AIIMS, New Delhi, India
Objectives: This study aims to determine various clinical, biochemical, radiological, molecular, and histological factors that correlate with persistence and recurrence in patients with Cushing’s disease (CD).
Methods: From January 2009 to December 2021, the clinical, radiological, biochemical, molecular, and histopathological data of 160 patients who underwent surgical treatment for CD were retrospectively analyzed.
Results: 69.3 % of the tumors were seen among females with an average age of 31 years (range 13–56). 78% patients presented with a primary tumor. Thirty pediatric patients were included. 73.4% of the patients experienced remission after primary surgery. Postoperative day 1 plasma cortisol level was seen to be a strong independent predictor of remission with a cutoff of <11.2 µgm/dl predicting remission (P < 0.001). Remission rates after endoscopic TSS were higher than those after microscopic TSS, both in patients undergoing primary surgery as well as repeat surgery (P = 0.018). The presence of adenoma on histopathological examination was a good predictor of disease remission (odds ratio 4.47 [1.68–11.86], P = 0.0027). Intraoperative cerebrospinal fluid leak did not predict postoperative leak.
Conclusion: Postoperative day 1 serum cortisol is a reliable predictor of remission. However, it does not reliably predict recurrence of disease and thus these patients need to undergo life-long follow-up. Somatostatin receptor expression was enriched in the densely granulated adenomas and thus could be used as a novel marker for targeted therapy.
Epigenetic profiling of meningioma identifies clinically distinct molecular subgroups
Jyotsna Singh, Ravi Sharma, Nidhi Shukla, Amit Katiyar, Swati Mahajan, Saumya Sahu, Ajay Garg, Mehar C. Sharma, Ashish Suri, Chitra Sarkar, Vaishali Suri; All India Institute of Medical Sciences, New Delhi, India
Aim and Objective: DNA methylation is beyond doubt the most prominent epigenetic mark in the human genome and has been recognized as a crucial tool in integrated diagnosis for enhancing diagnostic accuracy, tumor sub-classification, and prediction of therapeutic response. Due to the paucity of data on the molecular profiling of meningiomas and their clinical implications, no effective therapies and new treatments have been implemented. In this study, we performed methylation profiling of meningiomas and corelated it with clinical, radiological, histopathological, and molecular data. Further, we have used DKFZ classifier and explored the prospects and challenges associated with it.
Materials and Methods: DNA methylation profiling, copy number analysis, targeted Sequencing, and H3K27me3 expression were performed on 35 histopathologically proven meningiomas and 5 controls. Unsupervised clustering (UHC) of the samples was done to segregate the meningioma based on DNA methylation and profiles were also reviewed with DKFZ classifier.
Results/Discussion: UHC analysis revealed four distinct molecular subgroups: Malignant; Intermediate; Benign A and Benign B. Molecular heterogeneity was observed within the same grade as the Intermediate, Benign A and Benign B subgroup were composed of WHO Grade 1 as well as Grade 2 cases. There was association of mutations with distinct methylation subgroups (NF2, AKT1, SMO, TRAF7, and pTERT). Loss of chromosome 22q was observed across all subgroups. 1p/14q co-deletion was seen in 50% of malignant and intermediate while CDKN2A loss was predominantly observed in malignant subgroup (50%). Majority of malignant (75%) and a small proportion of other subgroups (Intermediate: 25%, Benign A: 38.5% and Benign B: 20%) harbored H3K27me3 loss. 38,734 genes were dysregulated amongst the four subgroups. DKFZ classified 71% cases with acceptable score. On survival analysis, methylation profiling had significant impact on progression-free-survival in WHO grade 1 and 2 meningiomas (P = 0.0051).
Conclusions: Genome-wide DNA methylation profiling highlights clinically distinct molecular subgroups and heterogeneity within the same grade of meningiomas. The role of methylation profiling is especially useful in WHO grade 1 or grade 2 meningioma to identify cases which need more stringent follow-up and might have poorer prognosis. Correlation with clinical, histopathological, molecular, and radiological data revealed its dominance in risk stratification and prognosis.
Acknowledgement This work was supported by a research grant from the Department of Science and Technology, Government of India.
Factors determining the extent of tumor resection in eloquent area glioma surgery
Sushant Kumar Sahoo; PGIMER, Chandigarh, India
Background: Excision of eloquent area glioma is difficult owing to the adjacent functional neural structures. However maximal surgical excision is considered the most favourable prognostic factor. Here we highlight the use of neuronavigation, awake mapping for achieving maximal tumor excision in patients with eloquent area glioma surgery.
Methods: Patients operated for eloquent area glioma between January 2018 and March 2022 was included in this analysis. Preoperatively, all patients were evaluated clinically and radiologically. Neuropsychological assessment was done by a separate team and the brief assessment score was also used intraoperatively. In addition to standard computed tomography/magnetic resonance imaging, diffusion tensor imaging (DTI) sequences were obtained in all patients. Awake mapping was performed in all cases. Intraoperatively, DTI images were used with navigation and direct cortical or subcortical mapping was done close to the white fiber tracts. Intraoperative/postoperative clinical deficit were then correlated with postoperative radiology. Same neuropsychological assessment was performed in the immediate postoperative period and at 3 months’ follow-up. The tumor resection was then correlated with peritumoral white fibre tracts, intraoperative direct electrical stimulation, and new onset deficit in the postoperative period.
Results: A total of 102 patients of eloquent area glioma (52 insular, 29 motor area, and 21 temporo-parietal) were evaluated. Majority of the white fiber tracts were normal (cortico spinal tract, [CST] – 31.3%, inferior fronto occipital fasciculuc, [IFOF] – 39.2%, superior longitudinal fasciculus/arcuate fasciculus, [SLF/AF]- 40.19%) or displaced (CST – 59.8%, IFOF – 47.05%, AF/SLF – 44.11%) and few were disrupted (CST – 8.8%, IFOF – 13.7%, SLF/AF – 15.7%). The extent of tumor resection was 82.8%, 86.5%, 94% for insular glioma, motor area glioma, and temporo-parietal glioma, respectively. Eighteen patients developed speech and language disturbances and all except three improved. Fourteen patients developed motor deficit and all except four improved gradually. Presence of preoperative deficit, infiltration of white fiber tracts by tumor where DES was negative, development of language deficit in the early intraoperative period were associated with subtotal resection in 12 cases (extent of resection was 68.8%). Use of integrated navigation with cortical and subcortical mapping improved the extent of resection over 85%.
Conclusion: The extent of resection in eloquent area glioma depends on the identification of functional areas close to the tumor before and during surgery. Continuous navigation of white fiber tracts along with awake mapping allows maximal tumor resection with minimal added deficit.
High-grade astrocytoma with piloid features: Experience with a new cns tumor type
A. V. Hema, Shilpa Rao, Harsha Sugur, Vani Santosh; National Institute of Mental Health and Neuroscience, Bengaluru, Karnataka, India
Aim and Objective: High-grade astrocytoma with piloid features (HGAP) is a newly recognized tumor type under circumscribed astrocytic tumors in 2021 WHO classification of tumors of the central nervous system (CNS) and a definite CNS WHO grade is not assigned. This tumor is defined by a specific DNA methylation profile. However, the tumor can be reasonably diagnosed using immunohistochemistry and molecular markers.
Materials and Methods: The study included adult astrocytomas with histopathological features suggestive of HGAP, diagnosed between June 2021 and May 2022. The cases were analyzed with immunohistochemistry and molecular fluorescence in situ hybridization (FISH) testing.
Results and Discussion: During the study period, four cases were histologically suspected to be HGAP. These tumors were localized in cerebellum (n = 3) and midbrain (n =1). The lesions were T2 hyperintense with heterogenous contrast enhancement on magnetic resonance imaging. On histology, all cases showed significant nuclear pleomorphism, increased mitosis with large areas of confluent necrosis and microvascular proliferation. Rosenthal fibers, eosinophilic granular bodies were present in 3 of 4 cases. On immunohistochemical examination, OLIG2 was positive, IDH1 p.R132H, H3 p.K28M (K27M) and BRAF p.V600E were negative. All the tumors showed loss of ATRX nuclear expression and increased Ki-67 labelling. By FISH, KIAA1549::BRAF fusion was evident in all the cases. One patient presented with recurrence after 4 months.
Conclusion: HGAP is a newly recognized tumor type, and DNA methylation profiling is an essential criteria for the diagnosis. However, high-grade histological features with or without Rosenthal fibers and eosinophilic granular bodies, loss of ATRX expression, and KIAA1549::BRAF fusion would help provide the diagnosis of HGAP, not otherwise specified. This tumor type needs special attention as it is associated with an aggressive behavior.
Baseline quality of life burden in the central nervous system tumors treated with pencil beam proton therapy at India�s first proton therapy center
Pankaj Kumar Panda, Anindita Das, Preethi Subramanian, Jacinthlyn Sylvia, R. Adhityan, Sushama Patil, Srinivas Chilukuri, Roopesh Kumar, Sapna Nangia, Rakesh Jalali; Apollo Proton Cancer Centre, Chennai, Tamil Nadu, India
Background and Aim: The aim of this study is to evaluate and assess the impact of baseline quality of life (QOL) in adult patients with central nervous system tumors treated with pencil beam proton therapy (PT) seen consecutively at India’s first PT centre.
Materials and Methods: Data sets of 126 consecutive adult patients with histologically proven brain neoplasms (both primary and recurrent) who were planned for PT at our center were during one full calendar year were considered for this study. The study included detailed neurological assessment, evaluation of QOL using EORTC questionnaire (QLQ-C30) and specific Brain Cancer module (BN20). In the present analysis, QOL scores before starting adjuvant treatment were measured and impact of patient and tumor-related factors were analyzed.
Results: Baseline global QOL data of all patients (available in 126) was 55.6 which is relatively low including in all histological tumor types. Physical function, role function, emotion function, and cognitive and social function scores were 76.4, 81.3, 78.2, 79.6, and 69.4 (higher values better), respectively. Domains of visual disorder, motor deficit, communication deficit, headache, seizures, and drowsiness scores were 20.4, 21.2, 32.4, 31.2, 22.4, 32.6, and 13.5 (lower values better), respectively. Elderly patients (> 50 years) had poorer global score (P < 0.05). Patients with lower performance status (KPS < 70) had a lower global QOL (KPS > or = 80 vs. < or = 70; 44 vs. 75; P < 0.05) including in all histological types of high-grade gliomas (HGG) (HGG vs. low-grade glioma; 64 vs. 59; P < 0.05). Patients undergoing re-irradiation had poorer global score as compared to ones who had not received any radiation previously (P < 0.05).
Conclusion: Patients with malignant, recurrent tumours, poor performance status, and patients who had previously been irradiated had significantly lower QOL scores even before starting adjuvant treatment.
FAT1: A new player in immunosuppressive tumor microenvironment
Khushboo Irshad, Chitrangda Srivastava, Nargis Malik, Manvi Arora, Yakhlesh Gupta, Sanjeev Goswami, Chitra Sarkar1, Vaishali Suri1, Swati Mahajan1, Deepak Kumar Gupta2, Ashish Suri2, Parthaprasad Chattopadhyay, Subrata Sinha, Kunzang Chosdol; Departments of Biochemistry, 1Pathology and 2Neurosurgery, All India Institute of Medical Sciences, New Delhi, India
Introduction: Solid tumors, especially glioblastoma (GBM), harbor an immunosuppressive microenvironment which is sustained by key players such as transforming growth factor (TGF)-β1/2 cytokines; and mediators of PD-1/PD-L1/2 pathway. Previously, our lab had shown the role of a new gene, FAT1, in promoting gliomagenesis by promoting the production of pro-inflammatory cytokines (interleukin [IL]-1β, IL-6, etc.) in glioma cells. Here, we show a potent role of FAT1 gene in the regulation of anti-inflammatory genes in human glioma tumors, cell lines, and primary cultures. Our findings indicate an additional way in which FAT1 might contribute to gliomagenesis.
Methodology: Quantitative-polymerase chain reaction was used to analyze transcript levels of FAT1 and genes of the TGF-β1/2 and PD-L1/2 pathways in fresh-frozen GBM samples relative to normal brain RNA. Gene expression correlation was analyzed using Spearman’s test and semi-supervised clustering. TCGA expression data were extracted to analyze the correlation of FAT1 with anti-inflammatory genes. Primary tumor cultures and cell lines were transfected with FAT1-specific siRNA to check the effect on expression of anti-inflammatory cytokines, as well as effect on migratory properties of monocytes towards FAT1-knockdown tumor cells (supernatants).
Results: Significant positive correlation was found between upregulation of FAT1 and that of anti-inflammatory genes in fresh-frozen GBM samples as well as TCGA datasets. Upon siRNA-mediated knockdown of FAT1 in in vitro glioma cell cultures, we observed decreased anti-inflammatory genes’ expression. We also found increased transmigration of monocytes towards the supernatants from siFAT1-transfected cells.
Conclusion: FAT1 favors the immunosuppressive milieu in glioblastoma by supporting expression of anti-inflammatory genes. This emerging role of the new oncogene FAT1 is crucial to our understanding of its contributions to hallmarks of cancer.
AKT1 E17K mutation in meningioma survival responses
Swati Singh, Kirti Lathoria1, Jyotsna Singh, Vaishali Suri, Ellora Sen1; Neuropathology, Neurosciences Centre, All India Institute of Medical Sciences, New Delhi, 1National Brain Research Centre, Manesar, Haryana, India
Background: The AKT1-E17K is a hotspot mutation frequently detected in meningiomas and other cancers. In meningioma, this mutation is associated with earlier tumour recurrence and increased proliferative potential. While involvement of AKT1-E17K in activating the PI3K/mTOR signaling pathway leading to increased AKT phosphorylation is known, its role on metabolic genes remains largely unknown. Fatty acid synthase (FASN) which plays a crucial role in de novo synthesis of fatty acids is overexpressed in meningiomas and other cancers. Despite being reported in meningiomas, the role of FASN in the context of AKT1 E17K is not known. This study for the first time reports the effect of this mutation in differentially regulating levels of FASN. Further, the study highlights the effect of this metabolic reprogramming in facilitating tumour proliferation and survival responses in meningioma.
Methodology: IOMM-Lee cells were culture in Dulbecco’s Modified Eagle Medium. Cells were transiently transfected with AKT1-WT or AKT1-E17K and cell lysates were subjected to western blot analysis to determine AKT, p-AKT and FASN levels. Similarly, qRT-PCR was performed to study the mRNA levels of these genes. Pharmacological manipulations were done using AKT and FASN inhibitors to demonstrate the survival responses in AKT1-E17K cells.
Results: Overexpression of meningioma cells (IOMM-Lee) with AKT1-E17K increased the levels of FASN, both at protein and mRNA levels when compared to cells transfected with AKT1-WT. Treatment of cells with AKT inhibitor resulted in a decreased expression of FASN. This indicates the positive role of active form of AKT (p-AKT) in regulating FASN.
Conclusion and Future Objective: As upregulation of FASN in cells harbouring AKT1-E17K mutation could contribute to increased proliferation and survival when compared to wild-type AKT1, further studies on patient meningiomas and pharmacological inhibition experiments will be performed to provide mechanistic insights into the role of this mutation.
Acknowledgement This work was supported by a research grant from the Department of Science and Technology (Government of India).
Awake surgery for resections of tumors in or near eloquent areas of the brain without invasive monitoring for maximal safe resection: An institutional experience
Nitin Garg, Sumit Awasarmol, Rahul Jain, Deepa Navkar, Laxmikant Banakbode; Bansal Hospital, Bhopal, Bhopal, Madhya Pradesh, India
Background: Surgery of the brain tumors in or near eloquent areas of the brain always carries the risk of either disabling neurological deficit or inadequate resection. Awake craniotomy is widely used for surgery in eloquent brain in order to facilitate maximal safe resection of brain tumours. This work aims to evaluate safety, feasibility, and outcome of operating on patients with lesions in or near eloquent areas under scalp block with continuous neurological monitoring by neuroanaesthetist and psychologist during the procedure, through retrospective study of 46 cases of tumors related to language or sensorimotor cortex, operated between 2017 and 2022.
Results: 46 patients were operated with a mean age of 42.0 ± 14 years. The frontal lobe was the most common location (n = 24, 55.8%). WHO grade IV were the most common tumors(n = 18). The median length of stay was 7 days. Mean operating time was 247 minutes. Gross or near total resection was achieved in 29 cases, 16 cases had subtotal resection and biopsy was done in one patient. The cause for subtotal resection was onset of neurological deficits during the procedure in majority and hidden anatomical region in few patients. Three patients had complications with neurological deficits however only one patient had permanent neurological deficits. Three patients had intraoperative seizures which were controlled with ice-cold saline irrigation and antiepileptics.
Conclusion: We found that together with the neurosurgeon, neuroanesthetist, psychologist and operating room nurse team, awake surgeries can be performed with continuous neurological examination and without the need for invasive neuromonitoring in developing countries like India. The technique was found to be effective in early detection and prevention of permanent neurological deficits.
Transcriptome profiling identifies MYBL2 as a novel aggressive biomarker in astrocytoma, IDH mutant, central nervous system WHO grade 3 tumors
Harsha S. Sugur, B. Padmanaban, D. Prashant, G. Gejo; National Institute of Mental Health and Neuro Sciences, Bengaluru, Karnataka, India
Aims and Objectives: Astrocytoma, IDH-mutant, central nervous system WHO grade 3 (A3, IDH-mt), has a heterogenous clinical outcome and existing molecular biomarkers cannot fully explain the differences in clinical behaviour. Hence, a comprehensive molecular characterization is essential. We aimed to study the transcriptome profiling data of A3, IDH-mt and validate the shortlisted genes in our cohort for clinical significance and elucidated the functional role of most robust gene.
Methods: TCGA mRNA sequencing data of Anaplastic Astrocytoma, IDH-mutant (AA, IDH-mt, n = 100, TCGA terminology not changed) and normals (n = 5) was analysed to derive differentially expressed genes (DEGs) using Deseq2 R-package. Various methods such as, pathway (Enrichr), connectivity (STRING) and survival analysis (TCGA cohort), were performed to short-list robust genes. The mRNA expression of short-listed genes were validated using Nanostring nCounter platform (n = 80) on uniformly treated and molecularly characterized cohort of A3, IDH-mt patients (n = 100) and correlated with survival. We studied the protein expression (n = 100) of the most robust gene, MYBL2, on the same cohort using immunohistochemistry (IHC) and compared its expression in paired samples, in different grades of astrocytoma, IDH-mt and in glioblastoma, IDH-wildtype (GBM, IDH-wt). The functional role of MYBL2 in two different malignant astrocytoma cell-lines was demonstrated using siRNA knock-down approach.
Results: TCGA analysis identified 96 DEGs in AA, IDH-mt when compared to normals. Fifty-seven genes were short-listed through various analyses and further narrowed down to 14 genes based on literature review. The mRNA studies showed, 12/14 genes validated in our cohort. Univariate survival analysis revealed significant association of mRNA count of MYBL2 (P < 0.05, HR: 1.003) with the progression free survival (PFS) and overall survival (OS) of patients. MYBL2 was selected for IHC and nuclear expression was considered for labelling index (LI), and the median LI was 15% (0%–50%). On survival analysis, we found higher MYBL2-LI was associated with shorter PFS and OS (P < 0.05). In paired sample study, MYBL2 expression was not significantly different in primary and recurrent tumors. In grade-wise expression studies, MYBL2 was lower in A2, IDH-mt and GBM, IDH-wt but MBL2 expression was relatively the same in A3 and A4, IDH-mt cases. After knocking down of MYBL2 gene in two cell-lines SW1088 and SW1783, we noticed decrease in the proliferation rate when compared to scramble of the respective cell-lines.
Conclusions: A comprehensive study on A3, IDH-mt tumors we identified MYBL2 as a novel aggressive biomarker, associated with poor prognosis in patients, thus highlighting its potential utility in clinical practice.
Acknowledge Indian Council of Medical Research for the award of senior research fellow and for funding the work.
Role of novel bromodomain inhibitor in U87MG glioma cells
D. N. Nandakumar, B. Padmanaban, D. Prashant, G. Gejo; National Institute of Mental Health and Neuro Sciences, Bengaluru, Karnataka, India
Background: Glioblastoma is the most aggressive and deadliest primary brain tumor. They are prone to develop resistance to the current repertoire of drugs, including the first-line chemotherapeutic agents with frequent recurrence, limiting therapeutic success. The prognosis is very poor with the overall survival rate of <18 months, despite multimodal approaches.
Aims and Objectives: Aim of the study was to explore the potential role of novel compound NS5, a pyrano 1,3 oxazine derivative as an inhibitor of BRD2 in glioblastoma.
Materials and Methods: Proliferation, MMP-2 activation, migration and mRNA expression were determined by MTT assay, gelatin zymography, Matrigel trans well migration assay and reverse transcription-quantitative polymerase chain reaction (RTqPCR) in U87MG glioma cells.
Results: The cell-based assays in the U87MG glioma cells, revealed that the novel compound NS5 significantly attenuated proliferation, MMP-2 activity and migration of glioma cells compared to control. The binding assay indicate that the NS5 binds to BRD2.
Conclusion: We conclude that NS5 has antiproliferative effect on glioma cells in a dose dependent manner. NS5 attenuated glioma cell migration possibly mediated through down regulating the MMP-2 activity. Further, the RT-qPCR study established specific inhibition of BRD2 mRNA level upon treatment of NS5.
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