Hypo-fractionated accelerated radiotherapy with concurrent and maintenance temozolomide in newly diagnosed glioblastoma: updated results from phase II HART-GBM trial.

BACKGROUND: Glioblastoma (GBM) patients have poor survival outcomes despite treatment advances and most recurrences occur within the radiation field. Survival outcomes after dose escalation through hypofractionated accelerated RT(HART) were evaluated in this study. We previously reported the study's initial results showing similar survival outcomes with acceptable toxicities. Updated results after 5 years are being analysed to determine long-term survival trends. PATIENTS AND METHODS: 89 patients of newly diagnosed GBM after surgery were randomized to conventional radiotherapy (CRT) or HART. CRT arm received adjuvant RT 60 Gy in 30 fractions over 6 weeks and the HART arm received 60 Gy in 20 fractions over 4 weeks, both with concurrent and adjuvant temozolomide. RESULTS: 83 patients were eligible for analysis. After a median follow-up of 18.9 months, the median OS was 26.5 months and 22.4 months in the HART and CRT arms respectively. 5 year OS was 18.4% in the HART arm versus 3.8% in the CRT arm. This numerical difference in overall survival between the two arms was not statistically significant. The median PFS was not significantly different. CONCLUSION: The long-term results of the trial support HART as a promising treatment option with comparable survival outcomes to the current standard of care. Phase III trials are required for further validation of this regimen which has the potential to become the new standard of care in GBM.

Hypofractionated accelerated radiotherapy (HART) with concurrent and adjuvant temozolomide in newly diagnosed glioblastoma: a phase II randomized trial (HART-GBM trial).

INTRODUCTION: Maximal safe surgical resection followed by adjuvant chemoradiation has been standard for newly diagnosed glioblastoma multiforme (GBM). Hypofractionated accelerated radiotherapy (HART) has the potential to improve outcome as it reduces the overall treatment time and increases the biological effective dose. METHODS: Between October 2011 and July 2017, a total of 89 newly diagnosed GBM patients were randomized to conventional fractionated radiotherapy (CRT) or HART. Radiotherapy was delivered in all patients with a three-dimensional conformal radiotherapy technique in CRT arm (60 Gy in 30 fractions over 6 weeks @ 2 Gy/per fraction) or simultaneous integrated boost intensity modulated radiotherapy in HART arm (60 Gy in 20 fractions over 4 weeks @ 3 Gy/per fraction to high-risk planning target volume (PTV) and 50 Gy in 20 fractions over 4 weeks @ 2.5 Gy/per fraction to low-risk PTV). The primary endpoint of the trial was overall survival (OS). RESULTS: After a median follow-up of 11.4 months (Range: 2.9-42.5 months), 26 patients died and 39 patients had progression of the disease. Median OS for the entire cohort was 23.4 months. Median OS in the CRT and HART arms were 18.07 months (95% CI 14.52-NR) and 25.18 months (95% CI 12.89-NR) respectively, p = 0.3. Median progression free survival (PFS) for the entire cohort was 13.5 months (Range: 11.7-15.7 months). In multivariate analysis patients younger than 40 years of age, patients with a gross total resection of tumor and a mutated IDH-1 had significantly better OS. PFS was significantly better for patients with a gross total resection of tumor and a mutated IDH-1. All patients included in the trial completed the planned course of radiation. Only two patients required hospital admission for features of raised intracranial tension. One patient in the HART arm required treatment interruption. CONCLUSION: HART is comparable to CRT in terms of survival outcome. HART arm had no excess treatment interruption and minimal toxicity. Dose escalation, reduction in overall treatment time, is the advantages with use of HART.

Genome-wide ChIP-seq analysis of EZH2-mediated H3K27me3 target gene profile highlights differences between low- and high-grade astrocytic tumors.

Enhancer of zeste homolog-2(EZH2) is a key epigenetic regulator that functions as oncogene and also known for inducing altered trimethylation of histone at lysine-27 (H3K27me3) mark in various tumors. However, H3K27me3 targets and their precise relationship with gene expression are largely unknown in astrocytic tumors. In this study, we checked EZH2 messenger RNA and protein expression in 90 astrocytic tumors of different grades using quantitative PCR and immunohistochemistry, respectively. Further, genome-wide ChIP-seq analysis for H3K27me3 modification was also performed on 11 glioblastomas (GBMs) and 2 diffuse astrocytoma (DA) samples. Our results showed EZH2 to be highly overexpressed in astrocytic tumors with a significant positive correlation with grade. Interestingly, ChIP-seq mapping revealed distinct differences in genes and pathways targeted by these H3K27me3 modifications between GBM versus DA. Neuroactive ligand receptor pathway was found most enriched in GBM (P = 9.4 × 10-25), whereas DA were found to be enriched in metabolic pathways. Also, GBM showed a higher enrichment of H3K27me3 targets reported in embryonic stem cells and glioma stem cells as compared with DAs. Our results show majority of these H3K27me3 target genes were downregulated, not only due to H3K27me3 modification but also due to concomitant DNA methylation. Further, H3K27me3 modification-associated gene silencing was not restricted to promoter but also present in gene body and transcription start site regions. To the best of our knowledge, this is the first high-resolution genome-wide mapping of H3K27me3 modification in adult astrocytic primary tissue samples of human, highlighting the differences between grades. Interestingly, we identified SLC25A23 as important target of H3K27me3 modification, which was downregulated in GBM and its low expression was associated with poor prognosis in GBMs.

Surviving Triple Trouble: Synchronous Breast and Cervical Cancer, HIV Infection and Myocardial Infarction.

Breast and cervical cancer are the two most common cancers in female. However, owing to the contrasting risk factors, synchronous breast and cervical cancer has very rarely been reported. However, noncommunicable disease like cardiovascular disease and different infections has tended to make situations complicated because of complex interaction. In recent years, such cases are being seen frequently and their management is challenging. We report such a case of synchronous breast and cervical cancer complicated by HIV infection and myocardial infarction. This highlights the importance of a wide spectrum of clinical knowledge and skill and interdisciplinary coordination.

Extent of surgical resection and adjuvant temozolomide improves survival in pediatric GBM: a single center experience.

BACKGROUND: Pediatric glioblastoma (pGBM) is an uncommon entity. The importance of concurrent and adjuvant temozolomide is not known in this subset of patients. METHODS: We retrospectively analyzed our database between 2000 and 2015. All patients were treated with maximally safe surgical resection. This was followed by a uniform treatment schedule of post-operative radiation with concurrent daily temozolomide at 75 mg/m2. Radiation dose was 60 Gy in 30 fractions planned by 3-dimensional conformal radiotherapy. Concurrent and adjuvant temozolomide was used in all patients treated after 2007. Four weeks later, adjuvant temozolomide was started at 150 mg/m2, day 1 to 5 every 28 days and escalated to 200 mg/m2 from the second cycle onwards if well tolerated. Log-rank test was used to compare survival distribution. The data was analyzed using SPSS (version 16). RESULTS: Fifty-one patients were analyzed. Median age was 14 years (range: 5 to 21 years). Thirty-five males and 16 females were noted. Median symptom duration was 4 months. Twenty-eight patients underwent a gross total resection (GTR) while 17 underwent a subtotal resection; six patients underwent decompression. Thirty-three patients received concurrent chemotherapy while 27 received adjuvant chemotherapy. Median progression-free survival (PFS) was 15.1 months. One- and 3-year PFS was 54.4% and 3-year PFS was 24.6.7%. The median overall survival was 17.4 months. In univariate analysis survival was better for gross total resection (17.4 months vs. 11.5 months; p = 0.037), and significance maintained after multivariate analysis p = 0.026, HR 3.069, 95% CI 1.14-8.23. In univariate analysis, survival was better for patients receiving temozolomide but did not achieve significance. However, in multivariate analysis, use of temozolomide was associated with significantly improved survival p = 0.036, HR 3.315, 95% CI 1.07-10.19. CONCLUSIONS: GTR improves survival significantly in pGBM. Adjuvant temozolomide may improve survival in pGBM.

Treatment Outcome in Patients with Primary Central Nervous System Germ Cell Tumour: Clinical Experience from a Regional Cancer Centre in North India.

BACKGROUND: Primary intracranial germ cell tumour is a rare entity and constitutes 2-3% of all paediatric brain tumours in Western countries. We herein intend to report the clinical features and treatment outcome of patients with primary central nervous system germ cell tumour treated at our institute. METHODS: Clinical data were collected by retrospective chart review from 2006 to 2012. Histopathology slides were reviewed and relevant immunohistochemistry stains were done. Overall survival (OS) and progression-free survival (PFS) were analysed by the Kaplan-Meier product-limit method. RESULTS: Twenty patients met the study criterion (male:female = 7:3). Median age at presentation was 13 years. Tumour location was pineal in 10 patients, suprasellar in 6, thalamic in 2, basal ganglion in 1, and spinal in 1. Leptomeningeal spread was noted in 1 patient at presentation. Surgical resection was gross-total in 7 patients (35%), near-total in 2 (10%), subtotal in 4 (20%), and limited to biopsy in 6 (30%). The tumours were germinomatous, non-germinomatous, and of mixed germ cell subtype in 17 patients (85%), 2 patients (10%), and 1 patient (5%), respectively. Systemic chemotherapy (median of 4 cycles) was given to 19 patients (95%). The common regimens used were a combination of bleomycin, etoposide and cisplatin (BEP) in 14 patients (70%) and etoposide and cisplatin (EP) in 5 patients (25%). Radiation therapy (40-50 Gy in conventional fractionation; median of 42 Gy) was delivered to 17 patients (85%): local radiation in 6 and whole ventricular, whole brain, and craniospinal irradiation followed by a boost in 5, 3, and 3 patients, respectively. After a median follow-up of 44.52 months, 17 patients (85%) were in complete response and 3 (15%) had progressive disease. Death and disease recurrence were noted in 6 patients (30%) and 1 patient, respectively. Median OS and PFS were not reached. The actuarial rates of OS at 3 and 5 years were 75.8 and 68.9%, respectively. The actuarial rates of PFS at both 3 and 5 years were 81.6%. CONCLUSION: Multimodality treatment consisting of limited resection followed by platinum-based systemic chemotherapy and radiotherapy (40-50 Gy) is a reasonable treatment strategy in patients of primary central nervous system germ cell tumour in a developing nation.

Expression of DNA methyltransferases 1 and 3B correlates with EZH2 and this 3-marker epigenetic signature predicts outcome in glioblastomas.

This study aims to analyze expression of EZH2 and DNA-methyltransferases (DNMT1, 3A and 3B) in astrocytic tumors and investigate their link as well as their correlation with survival, especially in GBMs. Expression of EZH2 and DNMTs (DNMT1, DNMT3A and DNMT3B) in different grades of astrocytomas (n=93) was assessed by qRT-PCR and immunohistochemistry. GBM-U87MG cell line was used for functional studies. Strong immunopositivity (LI≥25%) for EZH2, DNMT1 and DNMT3B was detected in 52%, 56% and 64% cases of GBMs respectively, which was significantly higher as compared to Grade II/III cases. Similarly, their median fold change of mRNA expression was also significantly higher in GBMs. There was also a significant positive correlation between DNMT1/DNMT3B and EZH2 mRNA and protein expression, which was in concordance with TCGA data set. Inhibition of DNMTs in cell line by Azacytidine resulted in down-regulation of EZH2, while knock-down of EZH2 by siRNA was not associated with any significant alteration of DNMTs, indicating that EZH2 expression in GBMs is possibly regulated by DNMTs, but not the reverse. Strong immunopositivity for EZH2, DNMT1 and DNMT3B were individually associated with significantly shorter survival and showed no correlation with IDH1 mutation status. In addition, the combination of these 3 markers represented an independent prognostic signature with cases having weak/negative expression of all 3 markers being associated with best prognosis. For the first time, the present study describes an epigenetic prognostic signature in GBMs based on immunohistochemical expression of EZH2, DNMT1 and 3B which can be used easily in routine neuropathology practice.

Treatment outcome and patterns of failure in patients of pinealoblastoma: review of literature and clinical experience from a regional cancer centre in north India.

PURPOSE: Pinealoblastoma is a highly malignant embryonal tumour of the pineal region affecting children and young adults. We herein intend to report the clinical features and treatment outcome of patients of pinealoblastoma treated at our institute. METHODS: Clinical data was collected by retrospective chart review from 2003-2012. Histopathology slides were reviewed, and relevant immunohistochemistry stains were done. Overall survival (OS) and recurrence-free survival (RFS) were analysed by Kaplan-Meier product-limit method. Univariate and multivariate analyses of prognostic factors were done by log rank test and Cox proportional hazard regression model, respectively. RESULTS: Seventeen patients met the study criterion (male:female = 11:6). Median age at presentation was 14 years (range 4-47 years). Surgical resection was gross total in 6 (35.29%), near-total in 2 (11.76%), sub-total in 2 (11.76%), and limited to biopsy in 7 (41.18 %) patients. At presentation, 4 patients had leptomeningeal dissemination. Radiation therapy was delivered in all patients-craniospinal irradiation in 15 (88.24%), whole brain irradiation in 1 (5.88%), and whole ventricular irradiation followed by boost in 1 (5.88%) patient. Systemic chemotherapy (median 6 cycles) was given in 14 (82.35%) patients. The most common regimen was a combination of carboplatin and etoposide, used in 10 (58.82%) patients. After a median follow-up of 30.3 months (mean 32.01 months), death and disease recurrences were noted in 3 (17.65%) and 7 (41.18%) patients. Amongst the patients with recurrent disease, 4 had spinal drop metastases and 3 had local recurrence along with spinal drop metastases. Median OS was not reached, and estimated median RFS was noted to be 5.49 years. The actuarial rates of OS and RFS at 2 years were 85.6 and 73.1%, respectively. On univariate analysis, age more than 8 years (P = 0.0071) and M0 stage (P = 0.0483) were significant predictors of improved RFS. Age retained significance on multivariate analysis of RFS (P = 0.02932). CONCLUSION: Maximal safe resection followed by craniospinal irradiation and systemic chemotherapy with 6 cycles of carboplatin-etoposide regimen is a reasonable treatment strategy in patients of pinealoblastoma more than 8 years of age in a developing nation. However, the same strategy is less effective in younger children and innovative study designs of intensification of post-operative treatment must be explored in this age group.

Pediatric gliosarcoma treated with adjuvant radiotherapy and temozolomide.

PURPOSE: Primary pediatric gliosarcoma (pPGS) is an extremely rare entity with only 25 cases reported in the English literature. The value of concurrent and adjuvant temozolomide is not known in this group of patient. METHODS: Five patients of pPGS treated from 2006 to 2011 were included in this retrospective analysis. All patients underwent maximal safe surgical resection. Adjuvant therapy included conformal radiation 60 Gy in 30 fractions (2 Gy daily for 5 days in a week) with concurrent temozolomide 75 mg/m(2) daily followed by six cycles of maintenance temozolomide 150-200 mg/m(2) (day 1 to day 5) every 4 weeks. We combined the survival data of 25 patients (already published) and five of our patients and analyzed them in terms of progression free survival (PFS) and overall survival (OS) using Kaplan-Meier method. RESULTS: Male to female ratio was 1:4 and median age was 12 years (range, 7-19 years). All but one patient underwent gross total resection and four patients completed adjuvant radiotherapy as well as concurrent and adjuvant temozolomide. At a median follow up of 22.6 months (range, 0 to 45.3 months), two patients were dead and two were alive without disease while one was lost to follow up. For the pooled data, estimated median PFS and OS of all 30 patients reported in literature were 12 and 43 months, respectively. Two years PFS and OS rate for all patients was 44.2 and 62.9%, respectively. CONCLUSION: Adjuvant radiotherapy and temozolomide is well tolerated and show an encouraging survival in pPGS.

Intracranial atypical teratoid rhabdoid tumor: current management and a single institute experience of 15 patients from north India.

OBJECTIVE: We intended to assess the clinicopathological features and treatment outcome in patients of intracranial atypical teratoid rhabdoid tumor (AT/RT), a rare malignant tumor of the brain. METHODS: Medical records were reviewed and clinical data collected on AT/RT in a 6-year period (2006-2012). Overall survival was analyzed by Kaplan-Meier method. Univariate analysis of factors predictive of overall survival was done by log-rank test. RESULTS: Fifteen patients met the study criterion (male:female = 4:1). Median age at presentation was 5 years (range, 0.8-8 years). Presenting complaints included vomiting (73.33 %), headache (46.67 %), orbital symptoms (33.33 %), motor impairment (26.67 %), gait abnormality (20 %), and seizure (20 %). Median duration of symptoms was noted to be 2 months (range, 0.5-6 months). On contrast-enhanced MRI of brain, tumor location was supratentorial in 60 % patients and infratentorial in 40 % of patients. Cystic component and hydrocephalus were noted in 73.33 % patients each, whereas contrast enhancement and calcification were discerned in 53.33 and 40 % of the patients, respectively. All patients underwent tumor resection-gross total (26.67 %), near-total (13.33 %) and subtotal (60 %). Histopathology was confirmative of AT/RT with MIB-1 labeling index varying from 11 to 85 % (median 45 %). There was a lack of immunostaining for INI-1 protein, suggesting INI-1gene mutation or deletion. Adjuvant radiation (36 Gray/20 fractions/4 weeks to entire neuraxis followed by local boost 20 Gray/10 fractions/2 weeks) was started in six patients (40 %) and completed in five patients. Young age at presentation and poor performance status precluded the use of radiation in the remainder. Systemic chemotherapy was administered in ten (66.67 %) patients. Median number of cycles given was three (range, 1-12) with ICE (ifosfamide, carboplatin, etoposide) and VAC (vincristine, dactinomycin, cyclophosphamide) being the common regimens (26.67 and 20 %, respectively). After a median follow-up of 8.33 months (mean, 12.27 months), median overall survival was noted to be 10 months. At last follow-up, two patients are in complete response, one patient is on treatment, three patients are alive with evidence of disease, and nine patients expired due to disease progression. The 1- and 2-year actuarial rate of overall survival was noted to be 48.1 and 24.1 %, respectively. On univariate analysis, extent of surgery (p = 0.0149), use of craniospinal radiation (p = 0.0087), and MIB1 labeling index (p = 0.0034) were significant predictors of overall survival while age (≥5 years versus <5 years) was of borderline significance (p = 0.08). CONCLUSIONS: Median survival of 10 months reflects the aggressive biology of this rare neoplasm. Maximal safe resection followed by craniospinal irradiation and systemic chemotherapy with ICE or VAC regimen is a reasonable treatment strategy in this uncommon malignancy.

Treatment outcome and patterns of failure in patients of non-pineal supratentorial primitive neuroectodermal tumor: review of literature and clinical experience form a regional cancer center in north India.

BACKGROUND: Supra-tentorial primitive neuroectodermal tumors (SPNET) are high-grade, hemispheric tumors, which account for around 2-3 % of pediatric brain tumors. We herein intend to report the clinical features and treatment outcome of patients with nonpineal SPNET treated at our institute. METHODS: Clinical data were collected by retrospective chart review from 2006 to 2012. Histopathology slides were reviewed, and relevant immunohistochemistry stains were done. Overall survival (OS), recurrence-free survival (RFS) and event-free survival (EFS) were analyzed by the Kaplan-Meier product-limit method. RESULTS: Fifteen patients met the study criterion (male: female = 2:1). Median age at presentation was 11 years (range 3-49 years). Surgical resection was gross total in 6 (40%) and subtotal in 8 (53.33%) patients. At presentation, two patients had leptomeningeal dissemination. Radiation therapy was delivered in 11 (73.33%) patients: craniospinal irradiation in 8 (36 Gy/20 fractions/4 weeks to the craniospinal axis followed by a local boost of 20 Gy/10 fractions/2 weeks) and focal RT in 3 patients. Systemic chemotherapy (median 6 cycles; range 1-16 cycles), given in 13 (86.67%) patients, included the VAC regimen (vincristine, adriamycin, cyclophosphamide) alternating with IE (ifosfamide,etoposide). After a median follow-up of 22.6 months (mean, 24.47 months), complete response and progressive disease were noted in 8 (53.33%) and 7 (46.67%) patients, respectively. Median OS was not reached, and estimated median EFS was noted to be 4.12 years (actuarial rate of EFS at 2 years, 55.2%). CONCLUSION: Maximal safe resection followed by craniospinal irradiation and systemic chemotherapy with 6-12 cycles of an alternating regimen of VAC and IE is a reasonable treatment strategy in patients with nonpineal SPNET.

Diagnostic accuracy of ¹8F-FDG PET/CT for detection of suspected recurrence in patients with oesophageal carcinoma.

PURPOSE: To evaluate the role of (18)F-FDG PET/CT in the detection of recurrence in patients with oesophageal carcinoma, suspected clinically or following conventional investigations. METHODS: This was a retrospective study. Data from 180 patients (age 56.3 ± 10.4 years; 126 men, 54 women) with histopathologically proven oesophageal carcinoma (squamous cell 115, adenocarcinoma 59, neuroendocrine carcinoma 4, small cell 1, poorly differentiated 1) who had undergone 227 (18)F-FDG PET/CT studies for suspected recurrence were analysed. Recurrence was suspected clinically or following conventional investigations. PET/CT images were revaluated by two nuclear medicine physicians in consensus. Findings were grouped into local, nodal and distant recurrence. Results were compared to those from contrast-enhanced (CE) CT when available (109 patients). Clinical/imaging follow-up (minimum 6 months) with histopathology (when available) was taken as the reference standard. RESULTS: Of the 227 (18)F-FDG PET/CT studies,166 were positive and 61 were negative for recurrent disease. PET/CT showed local recurrence in 134, nodal recurrence in 115 and distant recurrence in 47, with more than one site of recurrence in 34. The PET/CT findings were true-positive in 153 studies, true-negative in 54, false-positive in 13 and false-negative in 7. The sensitivity of (18)F-FDG PET/CT was 96%, the specificity was 81%, the positive and negative predictive values were 92% and 89%, respectively, and the accuracy was 91%. PET/CT showed similar accuracy in patients with squamous cell carcinoma and in those with adenocarcinoma (P = 0.181).(18)F-FDG PET/CT was more specific than CECT (67% vs. 21%; P < 0.0001). PET/CT was superior to CECT for the detection of nodal recurrence (P < 0.0001), but not local recurrence (P = 0.093) or distant metastases (P = 0.441). CONCLUSION: (18)F-FDG PET/CT shows high accuracy in the detection of suspected recurrence in patients with oesophageal carcinoma. It is more specific than and is superior to CECT in the detection of nodal recurrence.

Perfusion-metabolism coupling in recurrent gliomas: a prospective validation study with 13N-ammonia and 18F-fluorodeoxyglucose PET/CT.

INTRODUCTION: We assessed the validity of "perfusion-metabolism coupling" hypothesis in recurrent glioma with 13N-ammonia (13N-NH3) PET/CT and 18F-fluorodeoxyglucose (18F-FDG) PET/CT. METHODS: Fifty-six consecutive patients (age, 38.8 ± 12.1 years; 62.5% males) with histologically proven and previously treated glioma presenting with clinical suspicion of recurrence were prospectively enrolled and evaluated with 13N-NH3 PET/CT and 18F-FDG PET/CT. PET/CT images were evaluated both qualitatively and semiquantitatively. Tumor to white matter uptake ratio (T/W) and tumor to gray matter uptake ratio (T/G) were calculated and analyzed for both the modalities. A combination of clinico-radiological follow-up, repeated imaging, and biopsy (when available) were considered as the reference standard. RESULTS: Based on the reference standard, 27/56 patients had recurrence. 13N-NH3 PET/CT and 18F-FDG PET/CT were concordant in 55/56 patients. Overall sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of 13N-NH3PET/CT were 77.8, 86.2, 84.0, 80.7, and 82.1%, respectively, and for 18F-FDG PET/CT were 77.8, 89.7, 87.5, 81.2, and 83.9%, respectively. There was excellent agreement between results of 13N-NH3 PET/CT and 18F-FDG PET/CT (ĸ = 0.964; P < 0.001). The performances of 13N-NH3 PET/CT and 18F-FDG PET/CT were not significantly different between high-grade and low-grade glioma (P = 1.000). A strong positive correlation was noted between the uptake ratios derived on the two modalities (ρ = 0.866, P < 0.001 for T/W; ρ = 0.918, P < 0.001 for T/G). CONCLUSION: A combination of 13N-NH3 PET/CT and 18F-FDG PET/CT demonstrates that perfusion and metabolism are coupled in recurrent gliomas. These tracers target two different but interrelated aspects of the same pathologic process and can be used as surrogates for each other.

Meningeal hemangiopericytomas: a clinicopathological study with emphasis on MGMT (O(6) -methylguanine-DNA methyltransferase) promoter methylation status.

Meningeal hemangiopericytomas (HPCs) are aggressive dural-based tumors, for which no prognostic or predictive marker has been identified. Gross total resection is treatment of choice, but not easily achieved; hence, alkylating agents like temozolomide (TMZ) are now being tried. O(6) -methylguanine-DNA methyltransferase (MGMT) promoter methylation has proven prognostic and predictive value in glioblastomas. This study evaluates MGMT promoter methylation in meningeal HPCs to determine its role in HPC oncogenesis and its association with patient outcome. Meningeal HPCs diagnosed between 2002 and 2011 were retrieved and clinicopathological features reviewed. MGMT promoter methylation status was assessed by methylation-specific polymerase chain reaction (MSP) and immunohistochemistry (IHC) for MGMT protein. HPCs accounted for 1.1% of all CNS tumors. Forty cases were analyzed; the majority were adults (mean age = 41.4 years). Seventy percent were primary and 30% were recurrent tumors; 60% were grade II and 40% were grade III. MGMT promoter methylation was identified in 45% of cases, including Grade II (54.2%) and Grade III (31.3%) (P = 0.203). Promoter methylation was significantly (P = 0.035) more frequent in primary (57.1%) than in recurrent (16.7%) tumors. No correlation was noted between MGMT promoter methylation by MSP and MGMT protein expression by IHC, or with progression-free survival. Thus, a significant proportion of HPCs demonstrate MGMT promoter methylation, suggesting possible susceptibility to TMZ. As promoter methylation is more frequent in primary tumors, TMZ may serve as a therapeutic option in residual primary tumors. Epigenetic inactivation of MGMT in HPCs necessitates the assessment of prognostic and predictive value of MGMT promoter methylation in HPCs in larger clinical trials.

Role of gefitinib in patients with recurrent or metastatic cervical carcinoma ineligible or refractory to systemic chemotherapy: first study from Asia.

OBJECTIVES: There are limited options for patients with recurrent or metastatic cervical carcinoma who are either refractory to or ineligible for systemic chemotherapy. We conducted a clinical study to evaluate the role of gefitinib, an epidermal growth factor receptor tyrosine kinase inhibitor, in such patients. METHODS: Eligible patients were enrolled into the study and were treated with gefitinib at a dose of 250 mg/day orally until disease progression, development of intolerable adverse effects, or withdrawal of consent. The primary end point of the study was progression-free survival. The secondary end points were stable disease, overall survival, and toxicity. RESULTS: From January 2008 to June 2011, a total of 20 patients were enrolled. Median age was 52 years and median disease-free interval was 15 months. Twelve patients presented with locoregional recurrence, 2 patients presented with distant metastases, and 6 patients presented with both locoregional recurrence and distant metastasis. Median duration of gefitinib therapy was 4 months. One patient had complete response, 1 patient had partial response, 4 patients had stable disease, and 14 patients had progressive disease. The median progression-free survival and overall survival were 4 months and 5 months, respectively. Only 1 patient had severe drug-related toxicity. CONCLUSIONS: Gefitinib is safe and seems to be effective in recurrent or metastatic cervical carcinoma. Further studies are warranted to identify the subgroup of patients, based on epidermal growth factor receptor mutations, who are more likely to benefit.

Long-Term 5-Year Response to Pembrolizumab, Bevacizumab, and Capecitabine Regimen in a Metastatic Colon Cancer Patient with MSI-High and KRAS Mutation: Case Report.

With an estimated 1.88 million new cases and 0.92 million deaths in 2020, colorectal cancer accounts for nearly one-tenth of all new cancer and cancer-related deaths worldwide. Nearly half of the patients of colorectal cancer are diagnosed with metastatic or inoperable disease with a very dismal 5-year survival rate. Chemotherapy, targeted therapy, and immunotherapy have been used to treat metastatic disease, either alone or in combination. We present a case of recurrent metastatic colon carcinoma with KRAS exon 2 mutation and high microsatellite instability that was treated with a combination regimen of bevacizumab, capecitabine oral chemotherapy, and pembrolizumab immunotherapy. At nearly 5 years of treatment, the patient is alive with good performance status and improved quality of life owing to a favorable response to the molecular profiling-based treatment approach.

A study of clinico-pathological parameters and O6-methylguanine DNA methyltransferase (MGMT) promoter methylation status in the prognostication of gliosarcoma.

Gliosarcoma is a rare variant of glioblastoma multiforme (GBM) with similar clinical presentation and prognosis but a distinct genetic profile. The clinicopathological features of 22 cases of gliosarcoma were analyzed with respect to age, sex, KPS score, operative diagnosis, extent of resection and histopathological subtype (predominantly sarcomatous [PS], predominantly gliomatous [PG] or mixed). Twelve cases were PS, six were PG and four were mixed. The histological subtype did not correlate with the operative diagnosis; however, it did significantly correlate with the extent of resection (P=0.014). In 14 cases with available survival data it was found that none of the clinicopathological parameters significantly correlated with survival (P>0.05). Methyl guanine DNA methyl transferase promoter methylation studies were performed using methylation-specific PCR in 16 cases which showed a methylation rate of 31.25% (5/16). The promoter methylation status did not correlate with the histological subtype and did not significantly affect survival (P>0.05). Although gliosarcomas continue to be treated in the same way as GBM, the role of chemotherapy with temozolomide is not clear. This cohort is the largest to date to uniformly receive the Stupp's protocol which is currently "standard of care" for GBM. A median overall survival of 18.5 months is substantially higher than previous studies, suggesting that temozolomide should be included in gliosarcoma therapy.

Indeterminate lesions on planar bone scintigraphy in lung cancer patients: SPECT, CT or SPECT-CT?

OBJECTIVE: The objective of the present study was to compare the role of single photon emission computed tomography (SPECT), computed tomography (CT) and SPECT-CT of selected volume in lung cancer patients with indeterminate lesions on planar bone scintigraphy (BS). METHODS: The data of 50 lung cancer patients (53 ± 10.3 years; range 30-75; male/female 38/12) with 65 indeterminate lesions on planar BS (January 2010 to November 2010) were retrospectively evaluated. All of them underwent SPECT-CT of a selected volume. SPECT, CT and SPECT-CT images were independently evaluated by two experienced readers (experience in musculoskeletal imaging, including CT: 5 and 7 years) in separate sessions. A scoring scale of 1 to 5 was used, in which 1 is definitely metastatic, 2 is probably metastatic, 3 is indeterminate, 4 is probably benign and 5 is definitely benign. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were calculated for each modality, taking a score ≤2 as metastatic. With receiver operating characteristic (ROC) curve analysis, areas under the curve (AUC) were calculated for each modality and compared. Clinical and imaging follow-up and/or histopathology were taken as reference standard. RESULTS: For both readers SPECT was inferior to CT (P = 0.004, P = 0.022) and SPECT-CT (P = 0.003, P = 0.037). However, no significant difference was found between CT and SPECT-CT for reader 1 (P = 0.847) and reader 2 (P = 0.592). The findings were similar for lytic as well as sclerotic lesions. Moderate inter-observer agreement was seen for SPECT images (к = 0.426), while almost perfect agreement was seen for CT (к = 0.834) and SPECT-CT (к = 0.971). CONCLUSION: CT alone and SPECT-CT are better than SPECT for accurate characterisation of indeterminate lesions on planar BS in lung cancer patients. CT alone is not inferior to SPECT-CT for this purpose and might be preferred because of shorter acquisition time and wider availability.

F-18 FDG PET-CT for predicting survival in patients with recurrent glioma: a prospective study.

INTRODUCTION: Recurrent gliomas are usually histologically high grade; either due to recurrence of a de novo high-grade primary or anaplastic transformation in case of low-grade tumors. Survival in these patients is variable. The objective of the present study is to evaluate the role of FDG PET-CT for predicting survival in a large group of patients with suspected recurrent glioma. METHODS: A total of 81 previously treated histopathologically proven glioma patients; with clinical and conventional imaging findings suspicious of recurrence were included in this study. All patients underwent FDG PET-CT study. Based on tumor to white matter (T/W) and tumor to grey matter (T/G) ratios, all lesions were scored on PET-CT (PET scores 0, 1 and 2). Patients were followed up clinically and by repeated imaging. Data was censored, if the patient died of disease or at the end of the study. Survival analysis was done for each variable employing univariate analysis followed by multivariate analysis, using variables found significant on univariate analysis. RESULTS: PET score was found to be the most significant predictor of survival in univariate and multivariate analysis (p 0.003). Patients having PET score 2 had poorer survival compared to both PET score 0 (p 0.001) and PET score 1 (p 0.004). Other covariates found to have significant correlation with survival were primary treatment modality and clinical symptoms at the time of recurrence. CONCLUSION: FDG uptake on PET-CT is a strong predictor of survival in patients with suspected recurrent glioma.

Spinal myxopapillary ependymoma with Down syndrome: exploring an unusual association.

SUMMARY: In patients with Down syndrome, cancers like leukemia and testicular tumors are frequent, but association with central nervous system tumors is rare. Only 1 case of ependymoma has been observed as an incidental autopsy finding in a 19-week-old female fetus. We herein report the second case of ependymoma and the fifth case of spinal tumor occurring in association with Down syndrome. We have also attempted to elucidate the various mechanisms of tumorigenesis implicated in this multiple malformation syndrome. A 13-year-old girl with Down syndrome presented with progressively increasing paraparesis and neurogenic bladder. Magnetic resonance imaging of dorsolumbar spine revealed an intramedullary mass (L1 to L5 level). The patient underwent near total excision of tumor with postoperative histopathology showing myxopapillary ependymoma. Karyotyping showed classic Down syndrome with trisomy 21. Postoperative irradiation (45 Gy in 25 fractions over 5 wk followed by boost up to 55 Gy) was subsequently delivered. One year after the completion of the tumor-directed therapy, the patient is in radiologic complete remission, with improved power in both lower limbs. Association of ependymoma with Down syndrome is a rarity, which at best, can be explained as a chance phenomenon.