Background: Re-irradiation (ReRT) is an effective treatment modality in appropriately selected pa... more Background: Re-irradiation (ReRT) is an effective treatment modality in appropriately selected patients with recurrent/progressive high-grade glioma (HGG). The literature is limited regarding recurrence patterns following ReRT, which was investigated in the current study. Methods: Patients with available radiation (RT) contours, dosimetry, and imaging-based evidence of recurrence were included in the retrospective study. All patients were treated with fractionated focal conformal RT. Recurrence was detected on imaging with magnetic resonance imaging (MRI) and/ or amino-acid positron emission tomography (PET), which was co-registered with the RT planning dataset. Failure patterns were classified as central, marginal, and distant if >80%, 20–80%, or <20% of the recurrence volumes were within 95% isodose lines, respectively. Results: Thirty-seven patients were included in the current analysis. A total of 92% of patients had undergone surgery before ReRT, and 84% received chemothe...
Nearly 10% of patients with adult diffuse glioma develop clinically significant myelotoxicity whi... more Nearly 10% of patients with adult diffuse glioma develop clinically significant myelotoxicity while on temozolomide (TMZ) leading to treatment interruptions. This study aimed to assess single nucleotide polymorphisms (SNPs) in the O6-methylguanine-DNA methyltransferase (MGMT) gene in adults with biopsy-proven diffuse glioma who develop TMZ-induced myelotoxicity and correlate their presence with severity and duration of such toxicity. This study assessed 33 adults treated with TMZ for diffuse glioma who developed ≥ grade 2 thrombocytopenia and/or ≥ grade 3 neutropenia. Genomic DNA was extracted from peripheral blood cells for MGMT SNP analysis after written informed consent. TMZ-induced severe myelotoxicity (≥ grade 3) was correlated with three specified SNPs commonly seen in the MGMT gene (L84F, I143V/K178R) using chi-square test or Fischer’s exact test as appropriate. Of the 33 adults, 24 (72.7%) experienced ≥ grade 3 thrombocytopenia and/or neutropenia, while 9 (27.3%) developed grade 2 thrombocytopenia only. The variant T allele of L84F was expressed in 28.7% (19/66) of analyzed alleles, which was substantially higher than previously reported for South Asian ancestry. The variant G allele of I143V/K178R was expressed in 9.3% (6/64) of analyzed alleles. Of which 3 patients showed statistically significant association with prolonged myelosuppression for > 2 months (p = 0.03). No significant correlation was established between the mentioned SNPs and severe myelotoxicity. There is substantially higher frequency of variant T allele (L84F) in Indian patients than previously reported for South Asians. The presence of specific SNPs in the MGMT gene correlates with prolonged duration but not severity of TMZ-induced myelotoxicity.
We read with great interest the systematic review and metaanalysis by Crocetta et al. [1] compari... more We read with great interest the systematic review and metaanalysis by Crocetta et al. [1] comparing sentinel lymphnode biopsy (SLNB) versus elective neck dissection (END) in early stage oral cancer. Two large prospective randomized-controlled trials (RCTs) and a pooled meta-analysis [2, 3] established the survival benefit of END over watchful waiting making it the contemporary standard of care in clinically node-negative (cN0) early stage oral cancer. SLNB was proposed over 2 decades ago as a strategy for management of early stage oral cancer through selective excision of the ‘sentinel’ node with meticulous histopathological examination (step-serial sectioning) thought to reflect the true nodal status of the remaining neck. Involvement of sentinel node by cancer cells requires completion neck dissection, whereas uninvolved sentinel node obviates the need for any further surgery, reducing morbidity and potentially impacting upon neck-dissection-related quality of life (QOL). The diagnostic accuracy of SLNB in early stage oral cancer has consistently been high. In the largest pooled analysis involving 5917 oral cancer patients enrolled in 98 studies [4], the pooled SLNB identification rate was 98%. SLNB was associated with an overall sensitivity of 82.7% and specificity of 98.1% with area under curve of summary receiver-operating characteristics (SROC) being 0.98 implying excellent diagnostic accuracy. To synthesize evidence, Crocetta et al. [1] pooled data from 5 non-randomized observational studies comparing SLNB with END to report on comparative effectiveness using neck recurrence rate (NRR), disease-free survival (DFS), and overall survival (OS) as efficacy endpoints. Data regarding morbidity from 4 studies were also included in a narrative summary. The NRRs between SLNB (n = 353) and END (n = 207) were not significantly different (10.5% vs 11.6%, respectively) with pooled risk ratio (RR) and 95% confidence interval (CI) of 1.09 (95% CI 0.67–1.76, p = 0.72). In terms of absolute numbers, the use of SLNB strategy led to 10 more recurrences per 1000 patients (ranging between 38 fewer and 88 more recurrences). However, this has to be weighed against the fact that SLNB spares unnecessary neck dissection in over 60% of patients. Reassuringly, none of the studies reported statistically significant differences in either DFS or OS between SLNB and END. As expected, SLNB was associated with lower rates of postoperative complication and shoulder dysfunction compared to END. No significant differences in QOL were recorded for the two approaches. However, quality of included studies was poor leading to very low certainty of evidence which precluded recommending SLNB as an evidence-based strategy in the management of cN0 neck in early stage oral cancer. Surprisingly, despite the low false-negative rates and high negative predictive values, SLNB was not compared directly with END in an RCT previously. Very recently, Garrel et al. [5] have demonstrated the oncologic equivalence of SLNB and END in clinically node-negative early stage oral/oropharyngeal cancer through an appropriately designed and adequately powered phase III RCT (level 1 evidence). Data from 279 patients were analyzed in a modified intention-totreat analysis with no significant difference (p = 0.91) in the 2 year neck node recurrence-free survival (RFS) between END (89.6%, 95% CI 83–84%) versus SLNB (90.7%, 95% CI 84–95%). Similarly, there was no significant difference in loco-regional RFS, disease-specific survival, and OS This comment refers to the article available online at https ://doi. org/10.1007/s0040 5-020-06090 -9.
Endolymphatic sac tumour (ELST) is a rare low-grade locally aggressive neoplasm arising from the ... more Endolymphatic sac tumour (ELST) is a rare low-grade locally aggressive neoplasm arising from the endolymphatic duct or sac. It presents mostly with vestibulo-cochlear symptoms either sporadically or as part of von Hippel–Lindau (VHL) syndrome. Micro-neurosurgical excision remains the cornerstone of therapy with the role of radiotherapy (RT) being controversial. This is a clinico-pathological analysis of consecutive ELST patients presenting to a single-institution in India. Neuropathology database of a tertiary-care comprehensive cancer centre was searched electronically to identify consecutive patients with histopathological diagnosis of ELST registered at the institute over last one decade. Data regarding demographic profile, clinical presentation, histopathological features, treatment details and outcomes were retrieved from electronic medical records for this retrospective analysis. Electronic search identified seven unique patients with biopsy-proven ELST registered at the institute between 2009 and 2020. Median age of the study cohort was 39 years (range 24–65 years) with strong male predilection (5:2 ratio) and left-sided preponderance (71%). Most common presenting symptoms were hearing loss (86%) and earache (71%) on affected side followed by headache (43%). All patients underwent maximal safe resection at initial diagnosis and were followed-up closely with periodic surveillance imaging. Two patients underwent salvage RT using high-precision conformal techniques at recurrence/progression. ELST is a rare low-grade locally aggressive neoplasm that arises generally as part of VHL syndrome or sometimes sporadically. Gross total resection provides the best chance of cure with RT being reserved for unresectable disease, large residue, medical inoperability, or as salvage therapy for recurrent/progressive tumor.
Aim: To assess systemic inflammatory biomarkers in non invasive differential diagnosis of primary... more Aim: To assess systemic inflammatory biomarkers in non invasive differential diagnosis of primary central nervous system lymphoma (PCNSL) from high-grade glioma (HGG). Materials & methods: Patients with similar morphology (PCNSL or HGG) on conventional neuro-imaging were included. Systemic inflammatory indices were calculated from pretreatment complete blood counts and liver function tests and compared against histopathology as reference standard. Results: Mean values of absolute lymphocyte count and prognostic nutritional index were significantly different between PCNSL (n = 42) versus HGG (n = 16). Area under receiver operating characteristics curve for absolute lymphocyte count and prognostic nutritional index in the diagnosis of PCNSL was 0.70 and 0.72 respectively suggesting fair and acceptable diagnostic accuracy. Conclusion: Systemic inflammatory biomarkers complement established clinico-radiological features and aid in the differential diagnosis of PCNSL from HGG.
Background The purpose of this study was to report long-term neurocognitive and clinical outcomes... more Background The purpose of this study was to report long-term neurocognitive and clinical outcomes in children treated for average-risk medulloblastoma with hyperfractionated radiation therapy (HFRT) alone. Methods Between 2006 and 2010, 20 children with rigorously staged average-risk medulloblastoma were treated on a prospective study with HFRT without upfront adjuvant systemic chemotherapy after written informed consent. HFRT was delivered as twice-daily fractions (1 Gy/fraction, 6–8 hours apart, 5 days/week) to craniospinal axis (36 Gy/36 fractions) plus conformal tumor-bed boost (32 Gy/32 fractions). Neurocognitive function was assessed at baseline and periodically on follow-up using age-appropriate intelligence quotient (IQ) scales. Results Median age was 8 years (range 5–14 years) with 70% being males. Mean and standard deviation (SD) scores at baseline were 90.5 (SD = 17.08), 88 (SD = 16.82) and 88 (SD = 17.24) for Verbal Quotient (VQ), Performance Quotient (PQ), and Full-Scal...
Imaging features are known to reflect inherent disease biology in various cancers including brain... more Imaging features are known to reflect inherent disease biology in various cancers including brain tumors. We report on the prognostic impact of magnetic resonance imaging (MRI) features on survival in patients with medulloblastoma treated between 2007 and 2018 at our institute. Sixteen semantic imaging features (with predefined categories) were extracted from pre- and postcontrast T1-weighted and T2-weighted MRI by consensus. Univariate analysis and multivariate Cox regression analysis were performed to assess the correlation of semantic features with relapse-free survival (RFS) and overall survival (OS). The study cohort comprised 171 medulloblastoma patients (median age 9 years) treated with maximal safe resection followed by risk-stratified adjuvant radio(chemo)therapy. A total of 55 patients experienced recurrent/progressive disease (commonly neuraxial metastases) resulting in 44 deaths, including one treatment-related death. At a median follow-up of 45 months (interquartile range 19–65 months), 5‑year Kaplan–Meier estimates of RFS and OS were 64% and 71%, respectively. Semantic MRI features such as non-central tumor location on vertical axis, absence of brainstem involvement, ≤ 80% solid tumor area with contrast uptake, heterogenous pattern of contrast enhancement, necrosis, calcification, and T2-weighted heterogeneity were associated with significantly worse RFS and/or OS in univariate analysis. Cox regression analysis identified tumor location on the vertical axis, brainstem involvement, and calcification as independent prognostic factors impacting outcomes. Distinctive MRI features correlated with survival even within individual molecular subgroups of medulloblastoma. Distinctive semantic MRI features correlate significantly with survival outcomes in medulloblastoma, also within individual molecular subgroups, reflecting their prognostic impact.
Journal of Adolescent and Young Adult Oncology, 2021
Purpose: Medulloblastomas, comprising 20%-25% of all primary brain tumors in children are much ra... more Purpose: Medulloblastomas, comprising 20%-25% of all primary brain tumors in children are much rarer in adulthood. Disease biology varies substantially across different age groups; however, owing to rarity, adults with medulloblastoma are traditionally treated using pediatric protocols. This is a retrospective audit of adolescent and adult medulloblastoma from a comprehensive cancer center. Methods: Data regarding demography, clinical presentation, imaging characteristics, histopathological features, molecular profiling, risk stratification, treatment details, and outcomes were retrieved from medical records. All time-to-event outcomes were analyzed using Kaplan-Meier method and compared with the log-rank test. Univariate and multivariate analysis of relevant prognostic factors was done with p value <0.05 being considered statistically significant. Results: A total of 162 patients q15 years of age with medulloblastoma were included. The median age was 25 years (range: 15-59 years) with leptomeningeal metastases seen in 31 (19%) patients at initial diagnosis. Following surgery, patients were treated with appropriate risk-stratified adjuvant therapy comprising of craniospinal irradiation plus boost with or without systemic chemotherapy. At a median follow-up of 50 months, 5-year Kaplan-Meier estimates of progression-free survival and overall survival were 53.5% and 59.5%, respectively. The addition of adjuvant systemic chemotherapy did not impact upon survival in standard-risk medulloblastoma. High-risk (HR) disease and anaplastic histology emerged as significant and independent predictors of poor survival on multivariate analysis. Conclusion: Medulloblastoma is a rare tumor in adolescents and adults with key differences in disease biology and resultant outcomes compared with the pediatric population. Contemporary management comprising maximal safe resection followed by appropriate risk-stratified adjuvant therapy provides acceptable survival outcomes.
The aim of this study was to correlate endogenous tissue biomarkers of hypoxia with quantitative ... more The aim of this study was to correlate endogenous tissue biomarkers of hypoxia with quantitative imaging parameters derived from 18F-fluoro-misonidazole (F-MISO) and 18F-fluoro-deoxy-glucose (FDG) positron emission tomography/computed tomography (PET/CT) and clinical outcomes in locoregionally advanced head and neck squamous cell carcinoma (HNSCC). Tumor-tissue blocks of HNSCC patients with pretreatment F-MISO-PET/CT and FDG-PET/CT were de-archived for expression of hypoxia-inducible factor-1 alpha (HIF-1α) subunit, carbonic anhydrase-IX (CA-IX), and glucose transporter subunit-1 (GLUT-1) using immunohistochemistry (IHC). The intensity of staining was graded and correlated with quantitative imaging parameters and with disease-related outcomes. Tissue blocks were analyzed for 14 of 20 patients. On IHC, median H-scores for HIF-1α, CA-IX, and GLUT-1 were 130, 0, and 95, respectively. No significant correlation of tissue biomarkers of hypoxia with quantitative imaging parameters was fou...
Background Imaging features are known to reflect inherent disease biology in various cancers incl... more Background Imaging features are known to reflect inherent disease biology in various cancers including brain tumors. We report prognostic impact of magnetic resonance imaging (MRI) features on survival in patients with medulloblastoma treated between 2007 and 2018 at our institute. Methods Sixteen semantic imaging features (with pre-defined categories) were extracted from pre- and post-contrast T1-weighted and T2-weighted MRI by consensus. Univariate analysis and multivariate Cox regression analysis were performed to assess correlation of semantic features with relapse-free survival (RFS) and overall survival (OS). Results The study cohort comprised of 171 medulloblastoma patients (median age 9 years) treated with maximal safe resection followed by risk-stratified adjuvant radio(chemo)therapy. A total of 55 patients experienced recurrent/progressive disease (commonly neuraxial metastases) resulting in 44 deaths including one treatment-related death. At a median follow-up of 45 month...
BACKGROUND Survivors of pediatric brain tumors are at high risk of developing endocrine disorders... more BACKGROUND Survivors of pediatric brain tumors are at high risk of developing endocrine disorders, potentially impacting growth,development and quality of life. METHODS etrospective audit of 2-year survivors of PEBT(3-18years at diagnosis)viz. medulloblastoma(MB),Central nervous system Primitive neuro-ectodermal tumors(CNS-PNET) and atypical teratoid/rhabdoid tumor(ATRT) treated January 2006-December 2017 at Tata Memorial Centre,Mumbai, with surgery, cranio-spinal irradiation(CSI; 35Gy in high-risk MB,CNS-PNET,ATRT and 23.4Gy in average-risk MB with tumor boost 19.8Gy)and six cycles of adjuvant chemotherapy(cyclophosphamide,cisplatin and vincristine).Patients were followed up by a paediatric endocrinology team specialized in management of PEBT. RESULTS Of 249 PEBT treated during this period,88 are alive in remission >2 years (69-MB, 15-CNS PNET,4-ATRT),median age at diagnosis 6 years. At a median follow-up of 5.6 years (range 3- 12.5years),63 patients(72%) had at least one endocr...
BACKGROUND Ependymomas are heterogenous group of tumours with variable clinical course and divers... more BACKGROUND Ependymomas are heterogenous group of tumours with variable clinical course and diverse molecular features. RELA fusion status has been reported to have prognostic impact in ST-EPEN. Our retrospective study analysed the prevalence and clinical impact of RELA fusion in childhood ST-EPEN at our centre. STUDY METHODS FFPE tissues of all childhood ST-EPEN diagnosed during 2011–2017 were evaluated for RELA fusion 1/2 by RT-PCR. Children were treated as per guidelines by the Neuro-oncology multidisciplinary team. Outcomes were correlated with RELA fusion, histological features and immunohistochemical parameters(L1CAM expression and Mib-1 index). Only patients with therapy details were included. RESULTS A total of 37 patients(0–50 years) with ST-EPEN were included(median age-10.2 years; boy:girl ratio-1.4:1)for analysis. Histological grade II, II/III and III was seen in 4(11%),2(5%) and 31(84%) patients respectively. Mib-1 index was assessable in 33 patients of which, 9 patients...
To report survival outcomes and identify prognostic factors of salvage re-irradiation (re-RT) in ... more To report survival outcomes and identify prognostic factors of salvage re-irradiation (re-RT) in recurrent/progressive glioma. Medical records of patients treated with high-dose re-RT as part of multi-modality salvage therapy for recurrence/progression of adult diffuse glioma from 2010 to 2019 were analyzed retrospectively. A total of 111 patients developing recurrent/progressive high-grade glioma after adequate upfront treatment at initial diagnosis were included. The first course of radiotherapy (RT) had been delivered to a median dose of 59.4 Gy with an inter-quartile range (IQR) of 54-60 Gy. Median time to recurrence/progression was 4.3 years (IQR = 2.3–7.4 years) while the median time to re-RT was 4.8 years (IQR = 3.6–7.9 years). Re-RT was delivered with intensity-modulated radiation therapy (IMRT) using 1.8 Gy/fraction to a median dose of 54 Gy (IQR = 50.4–55.8 Gy) for a cumulative median equivalent dose in 2-Gy fractions (EQD2) of 104.3 Gy (IQR = 102.6–109.4 Gy). At a median follow-up of 14 months after re-RT, the 1-year Kaplan–Meier estimates of post-re-RT progression-free survival (PFS) and overall survival (OS) were 42.8 and 61.8%, respectively. Univariate analysis identified histological grade at recurrence/progression; histological subtype; disease-free interval (DFI) and time interval between both courses of RT; performance status at re-RT; dose at re-RT and cumulative EQD2; isocitrate dehydrogenase (IDH) mutation; and O6-methyl-guanine DNA methyl transferase (MGMT) gene promoter methylation as significant prognostic factors. Preserved performance status, longer DFI, prolonged time interval between both courses of RT, and presence of IDH mutation were associated with significantly improved PFS on multi-variate analysis. However, only performance status retained independent prognostic significance for OS on multi-variate analysis. Post-treatment changes were seen in 33 (30%) patients on follow-up imaging, with higher cumulative dose (EQD2 ≥ 104.3 Gy) being associated with increased risk of post-re-RT pseudo-progression. This clinical audit reports encouraging survival outcomes and identifies key prognostic factors associated with high-dose salvage re-RT in recurrent/progressive glioma.
2063 Background: To present SHH pathway driven medulloblastoma (MB) diversities in pediatric and ... more 2063 Background: To present SHH pathway driven medulloblastoma (MB) diversities in pediatric and adult patient populations. Methods: 60 patients with SHH-MB seen at our institute during 2009-2015. We assigned 22 predefined radiological features for all MB subgroups including SHH. Outcome data was retrieved from a prospectively maintained database. Results: Median age of entire cohort was 14 years (1-48 years). 29 were adults (a-SHH) and 31 were pediatric SHH (p-SHH). Radiological data available for 39 patients showed a-SHH having lateralised location in 72% cases. Distinct MRI features to predict SHH include mild/moderate contrast enhancement (90%), cystic changes (82%), edema (92%); identical in two age groups. We could predict SHH accurately 95% times. p-SHH were seen to have higher frequency of p53 mutations (70% vs 45%). At median follow-up of 37 months, 25 patients failed [isolated tumor bed (TB) in 10, TB and supratentorially in 2, cranium outside TB in 1, craniospinal in 5 (a...
Lung cancer is the commonest source of brain metastases, which has been traditionally treated wit... more Lung cancer is the commonest source of brain metastases, which has been traditionally treated with Whole Brain Radiation Therapy (WBRT) with or without focal boost. We herein report our preliminary experience of the planning and delivery of WBRT with Simultaneous Integrated Boost (SIB) to brain metastases along with synchronous limited-field thoracic radiotherapy using Helical TomoTherapy in four patients with lung cancer. All plans were iteratively optimized for maximal target volume coverage and organ-at-risk (OAR) sparing. Standardized dose metrics were used for plan evaluation. All treated regions were imaged with a megavoltage computed tomography (CT) prior to treatment and co-registered with planning CT for image-guidance. Helical TomoTherapy was able to achieve highly conformal and homogeneous dose distributions with excellent OAR sparing both in the brain and the chest. The mean (standard deviation) Dose Homogeneity Index (DHI) and Conformity Index (CI) was 0.06 (0.01) & 0.7...
ObjectiveThe objective of the study was to report mature outcomes in patients treated on a prospe... more ObjectiveThe objective of the study was to report mature outcomes in patients treated on a prospective feasibility study of helical tomotherapy-based craniospinal irradiation.MethodsPatients needing craniospinal irradiation were accrued, treated, and followed up longitudinally for survival and toxicity on an institutional review board-approved study.ResultsTwenty patients (median age of 15 years) constituted the study cohort. Tomotherapy-based craniospinal irradiation was well tolerated with self-limiting and reversible acute toxicity. Four (20 %) patients needed growth factor or platelet support during craniospinal irradiation. Significant late neuro-toxicity was seen in only one (5 %) patient. None of the patients developed symptomatic radiation pneumonitis or second new malignancy. At a median follow-up of 62 months (inter-quartile range 24–71 months), the 5-year progression-free survival and overall survival for the entire cohort was 50 and 55 %, respectively. Outcomes within the cohort varied significantly; patients with favorable biology disease had good outcomes while patients with high-risk, metastatic, or recurrent disease fared poorly reflecting inherently aggressive biology.ConclusionsHelical tomotherapy is an ideal platform for planning, verification, and delivery of supine craniospinal irradiation in clinical practice resulting in moderate, self-limiting, reversible acute toxicity and modest delayed toxicity. Patterns of failure and survival outcomes are largely dependent upon disease biology and are not any different compared to conventional techniques.
International Journal of Head and Neck Surgery, 2010
BackgroundPrimary mucosal melanoma of the head and neck (MMHN) is a rare, aggressive tumor of neu... more BackgroundPrimary mucosal melanoma of the head and neck (MMHN) is a rare, aggressive tumor of neural-crest origin. Despite universal progress in cancer care, the prognosis of MMHN continues to remain dismal.AimsTo analyze and report the outcomes of primary head and neck mucosal melanomas treated at Tata Memorial Hospital.MethodsRetrospective chart review of all patients with a diagnosis of nonocular MMHN presenting to the institute between 1995 to 2003. Locoregional control and disease-free survival were used as outcome measures.Results42 patients presenting within the study period with nonocular MMHN (oral-55%, sinonasal-40%, and pharyngeal-5%) at a median age of 53 years constituted the demographic cohort. 11 (26%) patients not amenable to any active anticancer treatment were treated with best supportive care alone and excluded from outcome analysis. 26 patients underwent surgery with complete resection of tumor. Seven (27%) also received adjuvant radiotherapy due to the adverse h...
To the Editor: Ang et al. (July 1 issue)1 developed a risk model for death from oropharyngeal squ... more To the Editor: Ang et al. (July 1 issue)1 developed a risk model for death from oropharyngeal squamous-cell carcinoma on the basis of human papillomavirus (HPV) status, pack-years of tobacco smoking, tumor stage, and nodal stage. Their results showed that the risk of death significantly increased with each additional pack-year of tobacco smoking. It would be interesting to include in the statistical Cox regression analysis the pattern of alcohol consumption. Recent studies2 have indicated that alcohol consumption has a role in the genesis of head and neck cancer in HPV-positive patients, showing consistency with the observation and hypothesis (reinforced by the study by Ang et al.) that HPV infection is not a sufficient cause of cancer and that it requires the accumulation of additional cellular changes.
Background: Re-irradiation (ReRT) is an effective treatment modality in appropriately selected pa... more Background: Re-irradiation (ReRT) is an effective treatment modality in appropriately selected patients with recurrent/progressive high-grade glioma (HGG). The literature is limited regarding recurrence patterns following ReRT, which was investigated in the current study. Methods: Patients with available radiation (RT) contours, dosimetry, and imaging-based evidence of recurrence were included in the retrospective study. All patients were treated with fractionated focal conformal RT. Recurrence was detected on imaging with magnetic resonance imaging (MRI) and/ or amino-acid positron emission tomography (PET), which was co-registered with the RT planning dataset. Failure patterns were classified as central, marginal, and distant if >80%, 20–80%, or <20% of the recurrence volumes were within 95% isodose lines, respectively. Results: Thirty-seven patients were included in the current analysis. A total of 92% of patients had undergone surgery before ReRT, and 84% received chemothe...
Nearly 10% of patients with adult diffuse glioma develop clinically significant myelotoxicity whi... more Nearly 10% of patients with adult diffuse glioma develop clinically significant myelotoxicity while on temozolomide (TMZ) leading to treatment interruptions. This study aimed to assess single nucleotide polymorphisms (SNPs) in the O6-methylguanine-DNA methyltransferase (MGMT) gene in adults with biopsy-proven diffuse glioma who develop TMZ-induced myelotoxicity and correlate their presence with severity and duration of such toxicity. This study assessed 33 adults treated with TMZ for diffuse glioma who developed ≥ grade 2 thrombocytopenia and/or ≥ grade 3 neutropenia. Genomic DNA was extracted from peripheral blood cells for MGMT SNP analysis after written informed consent. TMZ-induced severe myelotoxicity (≥ grade 3) was correlated with three specified SNPs commonly seen in the MGMT gene (L84F, I143V/K178R) using chi-square test or Fischer’s exact test as appropriate. Of the 33 adults, 24 (72.7%) experienced ≥ grade 3 thrombocytopenia and/or neutropenia, while 9 (27.3%) developed grade 2 thrombocytopenia only. The variant T allele of L84F was expressed in 28.7% (19/66) of analyzed alleles, which was substantially higher than previously reported for South Asian ancestry. The variant G allele of I143V/K178R was expressed in 9.3% (6/64) of analyzed alleles. Of which 3 patients showed statistically significant association with prolonged myelosuppression for > 2 months (p = 0.03). No significant correlation was established between the mentioned SNPs and severe myelotoxicity. There is substantially higher frequency of variant T allele (L84F) in Indian patients than previously reported for South Asians. The presence of specific SNPs in the MGMT gene correlates with prolonged duration but not severity of TMZ-induced myelotoxicity.
We read with great interest the systematic review and metaanalysis by Crocetta et al. [1] compari... more We read with great interest the systematic review and metaanalysis by Crocetta et al. [1] comparing sentinel lymphnode biopsy (SLNB) versus elective neck dissection (END) in early stage oral cancer. Two large prospective randomized-controlled trials (RCTs) and a pooled meta-analysis [2, 3] established the survival benefit of END over watchful waiting making it the contemporary standard of care in clinically node-negative (cN0) early stage oral cancer. SLNB was proposed over 2 decades ago as a strategy for management of early stage oral cancer through selective excision of the ‘sentinel’ node with meticulous histopathological examination (step-serial sectioning) thought to reflect the true nodal status of the remaining neck. Involvement of sentinel node by cancer cells requires completion neck dissection, whereas uninvolved sentinel node obviates the need for any further surgery, reducing morbidity and potentially impacting upon neck-dissection-related quality of life (QOL). The diagnostic accuracy of SLNB in early stage oral cancer has consistently been high. In the largest pooled analysis involving 5917 oral cancer patients enrolled in 98 studies [4], the pooled SLNB identification rate was 98%. SLNB was associated with an overall sensitivity of 82.7% and specificity of 98.1% with area under curve of summary receiver-operating characteristics (SROC) being 0.98 implying excellent diagnostic accuracy. To synthesize evidence, Crocetta et al. [1] pooled data from 5 non-randomized observational studies comparing SLNB with END to report on comparative effectiveness using neck recurrence rate (NRR), disease-free survival (DFS), and overall survival (OS) as efficacy endpoints. Data regarding morbidity from 4 studies were also included in a narrative summary. The NRRs between SLNB (n = 353) and END (n = 207) were not significantly different (10.5% vs 11.6%, respectively) with pooled risk ratio (RR) and 95% confidence interval (CI) of 1.09 (95% CI 0.67–1.76, p = 0.72). In terms of absolute numbers, the use of SLNB strategy led to 10 more recurrences per 1000 patients (ranging between 38 fewer and 88 more recurrences). However, this has to be weighed against the fact that SLNB spares unnecessary neck dissection in over 60% of patients. Reassuringly, none of the studies reported statistically significant differences in either DFS or OS between SLNB and END. As expected, SLNB was associated with lower rates of postoperative complication and shoulder dysfunction compared to END. No significant differences in QOL were recorded for the two approaches. However, quality of included studies was poor leading to very low certainty of evidence which precluded recommending SLNB as an evidence-based strategy in the management of cN0 neck in early stage oral cancer. Surprisingly, despite the low false-negative rates and high negative predictive values, SLNB was not compared directly with END in an RCT previously. Very recently, Garrel et al. [5] have demonstrated the oncologic equivalence of SLNB and END in clinically node-negative early stage oral/oropharyngeal cancer through an appropriately designed and adequately powered phase III RCT (level 1 evidence). Data from 279 patients were analyzed in a modified intention-totreat analysis with no significant difference (p = 0.91) in the 2 year neck node recurrence-free survival (RFS) between END (89.6%, 95% CI 83–84%) versus SLNB (90.7%, 95% CI 84–95%). Similarly, there was no significant difference in loco-regional RFS, disease-specific survival, and OS This comment refers to the article available online at https ://doi. org/10.1007/s0040 5-020-06090 -9.
Endolymphatic sac tumour (ELST) is a rare low-grade locally aggressive neoplasm arising from the ... more Endolymphatic sac tumour (ELST) is a rare low-grade locally aggressive neoplasm arising from the endolymphatic duct or sac. It presents mostly with vestibulo-cochlear symptoms either sporadically or as part of von Hippel–Lindau (VHL) syndrome. Micro-neurosurgical excision remains the cornerstone of therapy with the role of radiotherapy (RT) being controversial. This is a clinico-pathological analysis of consecutive ELST patients presenting to a single-institution in India. Neuropathology database of a tertiary-care comprehensive cancer centre was searched electronically to identify consecutive patients with histopathological diagnosis of ELST registered at the institute over last one decade. Data regarding demographic profile, clinical presentation, histopathological features, treatment details and outcomes were retrieved from electronic medical records for this retrospective analysis. Electronic search identified seven unique patients with biopsy-proven ELST registered at the institute between 2009 and 2020. Median age of the study cohort was 39 years (range 24–65 years) with strong male predilection (5:2 ratio) and left-sided preponderance (71%). Most common presenting symptoms were hearing loss (86%) and earache (71%) on affected side followed by headache (43%). All patients underwent maximal safe resection at initial diagnosis and were followed-up closely with periodic surveillance imaging. Two patients underwent salvage RT using high-precision conformal techniques at recurrence/progression. ELST is a rare low-grade locally aggressive neoplasm that arises generally as part of VHL syndrome or sometimes sporadically. Gross total resection provides the best chance of cure with RT being reserved for unresectable disease, large residue, medical inoperability, or as salvage therapy for recurrent/progressive tumor.
Aim: To assess systemic inflammatory biomarkers in non invasive differential diagnosis of primary... more Aim: To assess systemic inflammatory biomarkers in non invasive differential diagnosis of primary central nervous system lymphoma (PCNSL) from high-grade glioma (HGG). Materials & methods: Patients with similar morphology (PCNSL or HGG) on conventional neuro-imaging were included. Systemic inflammatory indices were calculated from pretreatment complete blood counts and liver function tests and compared against histopathology as reference standard. Results: Mean values of absolute lymphocyte count and prognostic nutritional index were significantly different between PCNSL (n = 42) versus HGG (n = 16). Area under receiver operating characteristics curve for absolute lymphocyte count and prognostic nutritional index in the diagnosis of PCNSL was 0.70 and 0.72 respectively suggesting fair and acceptable diagnostic accuracy. Conclusion: Systemic inflammatory biomarkers complement established clinico-radiological features and aid in the differential diagnosis of PCNSL from HGG.
Background The purpose of this study was to report long-term neurocognitive and clinical outcomes... more Background The purpose of this study was to report long-term neurocognitive and clinical outcomes in children treated for average-risk medulloblastoma with hyperfractionated radiation therapy (HFRT) alone. Methods Between 2006 and 2010, 20 children with rigorously staged average-risk medulloblastoma were treated on a prospective study with HFRT without upfront adjuvant systemic chemotherapy after written informed consent. HFRT was delivered as twice-daily fractions (1 Gy/fraction, 6–8 hours apart, 5 days/week) to craniospinal axis (36 Gy/36 fractions) plus conformal tumor-bed boost (32 Gy/32 fractions). Neurocognitive function was assessed at baseline and periodically on follow-up using age-appropriate intelligence quotient (IQ) scales. Results Median age was 8 years (range 5–14 years) with 70% being males. Mean and standard deviation (SD) scores at baseline were 90.5 (SD = 17.08), 88 (SD = 16.82) and 88 (SD = 17.24) for Verbal Quotient (VQ), Performance Quotient (PQ), and Full-Scal...
Imaging features are known to reflect inherent disease biology in various cancers including brain... more Imaging features are known to reflect inherent disease biology in various cancers including brain tumors. We report on the prognostic impact of magnetic resonance imaging (MRI) features on survival in patients with medulloblastoma treated between 2007 and 2018 at our institute. Sixteen semantic imaging features (with predefined categories) were extracted from pre- and postcontrast T1-weighted and T2-weighted MRI by consensus. Univariate analysis and multivariate Cox regression analysis were performed to assess the correlation of semantic features with relapse-free survival (RFS) and overall survival (OS). The study cohort comprised 171 medulloblastoma patients (median age 9 years) treated with maximal safe resection followed by risk-stratified adjuvant radio(chemo)therapy. A total of 55 patients experienced recurrent/progressive disease (commonly neuraxial metastases) resulting in 44 deaths, including one treatment-related death. At a median follow-up of 45 months (interquartile range 19–65 months), 5‑year Kaplan–Meier estimates of RFS and OS were 64% and 71%, respectively. Semantic MRI features such as non-central tumor location on vertical axis, absence of brainstem involvement, ≤ 80% solid tumor area with contrast uptake, heterogenous pattern of contrast enhancement, necrosis, calcification, and T2-weighted heterogeneity were associated with significantly worse RFS and/or OS in univariate analysis. Cox regression analysis identified tumor location on the vertical axis, brainstem involvement, and calcification as independent prognostic factors impacting outcomes. Distinctive MRI features correlated with survival even within individual molecular subgroups of medulloblastoma. Distinctive semantic MRI features correlate significantly with survival outcomes in medulloblastoma, also within individual molecular subgroups, reflecting their prognostic impact.
Journal of Adolescent and Young Adult Oncology, 2021
Purpose: Medulloblastomas, comprising 20%-25% of all primary brain tumors in children are much ra... more Purpose: Medulloblastomas, comprising 20%-25% of all primary brain tumors in children are much rarer in adulthood. Disease biology varies substantially across different age groups; however, owing to rarity, adults with medulloblastoma are traditionally treated using pediatric protocols. This is a retrospective audit of adolescent and adult medulloblastoma from a comprehensive cancer center. Methods: Data regarding demography, clinical presentation, imaging characteristics, histopathological features, molecular profiling, risk stratification, treatment details, and outcomes were retrieved from medical records. All time-to-event outcomes were analyzed using Kaplan-Meier method and compared with the log-rank test. Univariate and multivariate analysis of relevant prognostic factors was done with p value <0.05 being considered statistically significant. Results: A total of 162 patients q15 years of age with medulloblastoma were included. The median age was 25 years (range: 15-59 years) with leptomeningeal metastases seen in 31 (19%) patients at initial diagnosis. Following surgery, patients were treated with appropriate risk-stratified adjuvant therapy comprising of craniospinal irradiation plus boost with or without systemic chemotherapy. At a median follow-up of 50 months, 5-year Kaplan-Meier estimates of progression-free survival and overall survival were 53.5% and 59.5%, respectively. The addition of adjuvant systemic chemotherapy did not impact upon survival in standard-risk medulloblastoma. High-risk (HR) disease and anaplastic histology emerged as significant and independent predictors of poor survival on multivariate analysis. Conclusion: Medulloblastoma is a rare tumor in adolescents and adults with key differences in disease biology and resultant outcomes compared with the pediatric population. Contemporary management comprising maximal safe resection followed by appropriate risk-stratified adjuvant therapy provides acceptable survival outcomes.
The aim of this study was to correlate endogenous tissue biomarkers of hypoxia with quantitative ... more The aim of this study was to correlate endogenous tissue biomarkers of hypoxia with quantitative imaging parameters derived from 18F-fluoro-misonidazole (F-MISO) and 18F-fluoro-deoxy-glucose (FDG) positron emission tomography/computed tomography (PET/CT) and clinical outcomes in locoregionally advanced head and neck squamous cell carcinoma (HNSCC). Tumor-tissue blocks of HNSCC patients with pretreatment F-MISO-PET/CT and FDG-PET/CT were de-archived for expression of hypoxia-inducible factor-1 alpha (HIF-1α) subunit, carbonic anhydrase-IX (CA-IX), and glucose transporter subunit-1 (GLUT-1) using immunohistochemistry (IHC). The intensity of staining was graded and correlated with quantitative imaging parameters and with disease-related outcomes. Tissue blocks were analyzed for 14 of 20 patients. On IHC, median H-scores for HIF-1α, CA-IX, and GLUT-1 were 130, 0, and 95, respectively. No significant correlation of tissue biomarkers of hypoxia with quantitative imaging parameters was fou...
Background Imaging features are known to reflect inherent disease biology in various cancers incl... more Background Imaging features are known to reflect inherent disease biology in various cancers including brain tumors. We report prognostic impact of magnetic resonance imaging (MRI) features on survival in patients with medulloblastoma treated between 2007 and 2018 at our institute. Methods Sixteen semantic imaging features (with pre-defined categories) were extracted from pre- and post-contrast T1-weighted and T2-weighted MRI by consensus. Univariate analysis and multivariate Cox regression analysis were performed to assess correlation of semantic features with relapse-free survival (RFS) and overall survival (OS). Results The study cohort comprised of 171 medulloblastoma patients (median age 9 years) treated with maximal safe resection followed by risk-stratified adjuvant radio(chemo)therapy. A total of 55 patients experienced recurrent/progressive disease (commonly neuraxial metastases) resulting in 44 deaths including one treatment-related death. At a median follow-up of 45 month...
BACKGROUND Survivors of pediatric brain tumors are at high risk of developing endocrine disorders... more BACKGROUND Survivors of pediatric brain tumors are at high risk of developing endocrine disorders, potentially impacting growth,development and quality of life. METHODS etrospective audit of 2-year survivors of PEBT(3-18years at diagnosis)viz. medulloblastoma(MB),Central nervous system Primitive neuro-ectodermal tumors(CNS-PNET) and atypical teratoid/rhabdoid tumor(ATRT) treated January 2006-December 2017 at Tata Memorial Centre,Mumbai, with surgery, cranio-spinal irradiation(CSI; 35Gy in high-risk MB,CNS-PNET,ATRT and 23.4Gy in average-risk MB with tumor boost 19.8Gy)and six cycles of adjuvant chemotherapy(cyclophosphamide,cisplatin and vincristine).Patients were followed up by a paediatric endocrinology team specialized in management of PEBT. RESULTS Of 249 PEBT treated during this period,88 are alive in remission >2 years (69-MB, 15-CNS PNET,4-ATRT),median age at diagnosis 6 years. At a median follow-up of 5.6 years (range 3- 12.5years),63 patients(72%) had at least one endocr...
BACKGROUND Ependymomas are heterogenous group of tumours with variable clinical course and divers... more BACKGROUND Ependymomas are heterogenous group of tumours with variable clinical course and diverse molecular features. RELA fusion status has been reported to have prognostic impact in ST-EPEN. Our retrospective study analysed the prevalence and clinical impact of RELA fusion in childhood ST-EPEN at our centre. STUDY METHODS FFPE tissues of all childhood ST-EPEN diagnosed during 2011–2017 were evaluated for RELA fusion 1/2 by RT-PCR. Children were treated as per guidelines by the Neuro-oncology multidisciplinary team. Outcomes were correlated with RELA fusion, histological features and immunohistochemical parameters(L1CAM expression and Mib-1 index). Only patients with therapy details were included. RESULTS A total of 37 patients(0–50 years) with ST-EPEN were included(median age-10.2 years; boy:girl ratio-1.4:1)for analysis. Histological grade II, II/III and III was seen in 4(11%),2(5%) and 31(84%) patients respectively. Mib-1 index was assessable in 33 patients of which, 9 patients...
To report survival outcomes and identify prognostic factors of salvage re-irradiation (re-RT) in ... more To report survival outcomes and identify prognostic factors of salvage re-irradiation (re-RT) in recurrent/progressive glioma. Medical records of patients treated with high-dose re-RT as part of multi-modality salvage therapy for recurrence/progression of adult diffuse glioma from 2010 to 2019 were analyzed retrospectively. A total of 111 patients developing recurrent/progressive high-grade glioma after adequate upfront treatment at initial diagnosis were included. The first course of radiotherapy (RT) had been delivered to a median dose of 59.4 Gy with an inter-quartile range (IQR) of 54-60 Gy. Median time to recurrence/progression was 4.3 years (IQR = 2.3–7.4 years) while the median time to re-RT was 4.8 years (IQR = 3.6–7.9 years). Re-RT was delivered with intensity-modulated radiation therapy (IMRT) using 1.8 Gy/fraction to a median dose of 54 Gy (IQR = 50.4–55.8 Gy) for a cumulative median equivalent dose in 2-Gy fractions (EQD2) of 104.3 Gy (IQR = 102.6–109.4 Gy). At a median follow-up of 14 months after re-RT, the 1-year Kaplan–Meier estimates of post-re-RT progression-free survival (PFS) and overall survival (OS) were 42.8 and 61.8%, respectively. Univariate analysis identified histological grade at recurrence/progression; histological subtype; disease-free interval (DFI) and time interval between both courses of RT; performance status at re-RT; dose at re-RT and cumulative EQD2; isocitrate dehydrogenase (IDH) mutation; and O6-methyl-guanine DNA methyl transferase (MGMT) gene promoter methylation as significant prognostic factors. Preserved performance status, longer DFI, prolonged time interval between both courses of RT, and presence of IDH mutation were associated with significantly improved PFS on multi-variate analysis. However, only performance status retained independent prognostic significance for OS on multi-variate analysis. Post-treatment changes were seen in 33 (30%) patients on follow-up imaging, with higher cumulative dose (EQD2 ≥ 104.3 Gy) being associated with increased risk of post-re-RT pseudo-progression. This clinical audit reports encouraging survival outcomes and identifies key prognostic factors associated with high-dose salvage re-RT in recurrent/progressive glioma.
2063 Background: To present SHH pathway driven medulloblastoma (MB) diversities in pediatric and ... more 2063 Background: To present SHH pathway driven medulloblastoma (MB) diversities in pediatric and adult patient populations. Methods: 60 patients with SHH-MB seen at our institute during 2009-2015. We assigned 22 predefined radiological features for all MB subgroups including SHH. Outcome data was retrieved from a prospectively maintained database. Results: Median age of entire cohort was 14 years (1-48 years). 29 were adults (a-SHH) and 31 were pediatric SHH (p-SHH). Radiological data available for 39 patients showed a-SHH having lateralised location in 72% cases. Distinct MRI features to predict SHH include mild/moderate contrast enhancement (90%), cystic changes (82%), edema (92%); identical in two age groups. We could predict SHH accurately 95% times. p-SHH were seen to have higher frequency of p53 mutations (70% vs 45%). At median follow-up of 37 months, 25 patients failed [isolated tumor bed (TB) in 10, TB and supratentorially in 2, cranium outside TB in 1, craniospinal in 5 (a...
Lung cancer is the commonest source of brain metastases, which has been traditionally treated wit... more Lung cancer is the commonest source of brain metastases, which has been traditionally treated with Whole Brain Radiation Therapy (WBRT) with or without focal boost. We herein report our preliminary experience of the planning and delivery of WBRT with Simultaneous Integrated Boost (SIB) to brain metastases along with synchronous limited-field thoracic radiotherapy using Helical TomoTherapy in four patients with lung cancer. All plans were iteratively optimized for maximal target volume coverage and organ-at-risk (OAR) sparing. Standardized dose metrics were used for plan evaluation. All treated regions were imaged with a megavoltage computed tomography (CT) prior to treatment and co-registered with planning CT for image-guidance. Helical TomoTherapy was able to achieve highly conformal and homogeneous dose distributions with excellent OAR sparing both in the brain and the chest. The mean (standard deviation) Dose Homogeneity Index (DHI) and Conformity Index (CI) was 0.06 (0.01) & 0.7...
ObjectiveThe objective of the study was to report mature outcomes in patients treated on a prospe... more ObjectiveThe objective of the study was to report mature outcomes in patients treated on a prospective feasibility study of helical tomotherapy-based craniospinal irradiation.MethodsPatients needing craniospinal irradiation were accrued, treated, and followed up longitudinally for survival and toxicity on an institutional review board-approved study.ResultsTwenty patients (median age of 15 years) constituted the study cohort. Tomotherapy-based craniospinal irradiation was well tolerated with self-limiting and reversible acute toxicity. Four (20 %) patients needed growth factor or platelet support during craniospinal irradiation. Significant late neuro-toxicity was seen in only one (5 %) patient. None of the patients developed symptomatic radiation pneumonitis or second new malignancy. At a median follow-up of 62 months (inter-quartile range 24–71 months), the 5-year progression-free survival and overall survival for the entire cohort was 50 and 55 %, respectively. Outcomes within the cohort varied significantly; patients with favorable biology disease had good outcomes while patients with high-risk, metastatic, or recurrent disease fared poorly reflecting inherently aggressive biology.ConclusionsHelical tomotherapy is an ideal platform for planning, verification, and delivery of supine craniospinal irradiation in clinical practice resulting in moderate, self-limiting, reversible acute toxicity and modest delayed toxicity. Patterns of failure and survival outcomes are largely dependent upon disease biology and are not any different compared to conventional techniques.
International Journal of Head and Neck Surgery, 2010
BackgroundPrimary mucosal melanoma of the head and neck (MMHN) is a rare, aggressive tumor of neu... more BackgroundPrimary mucosal melanoma of the head and neck (MMHN) is a rare, aggressive tumor of neural-crest origin. Despite universal progress in cancer care, the prognosis of MMHN continues to remain dismal.AimsTo analyze and report the outcomes of primary head and neck mucosal melanomas treated at Tata Memorial Hospital.MethodsRetrospective chart review of all patients with a diagnosis of nonocular MMHN presenting to the institute between 1995 to 2003. Locoregional control and disease-free survival were used as outcome measures.Results42 patients presenting within the study period with nonocular MMHN (oral-55%, sinonasal-40%, and pharyngeal-5%) at a median age of 53 years constituted the demographic cohort. 11 (26%) patients not amenable to any active anticancer treatment were treated with best supportive care alone and excluded from outcome analysis. 26 patients underwent surgery with complete resection of tumor. Seven (27%) also received adjuvant radiotherapy due to the adverse h...
To the Editor: Ang et al. (July 1 issue)1 developed a risk model for death from oropharyngeal squ... more To the Editor: Ang et al. (July 1 issue)1 developed a risk model for death from oropharyngeal squamous-cell carcinoma on the basis of human papillomavirus (HPV) status, pack-years of tobacco smoking, tumor stage, and nodal stage. Their results showed that the risk of death significantly increased with each additional pack-year of tobacco smoking. It would be interesting to include in the statistical Cox regression analysis the pattern of alcohol consumption. Recent studies2 have indicated that alcohol consumption has a role in the genesis of head and neck cancer in HPV-positive patients, showing consistency with the observation and hypothesis (reinforced by the study by Ang et al.) that HPV infection is not a sufficient cause of cancer and that it requires the accumulation of additional cellular changes.
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Papers by Tejpal Gupta