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.

No Doppler Single Position-Lateral Intercostal Artery Perforator Flap (NDSP-LICAP): a Safe and Versatile Flap for Breast Oncoplasty in Resource-Limited Setting.

INTRODUCTION: The lateral intercostal artery perforator flap (LICAP) has emerged as one of the safest and less morbid flaps for lateral and central breast defects. We hereby describe a reproducible no Doppler single position (NDSP) technique to harvest it in single position without handheld Doppler, making it a versatile flap for lateral breast defects in resource-limited setting also. MATERIALS AND METHODS: With this technique, we performed a total of 22 LICAP turnover flaps over a period of 18 months from January 2020 to June 2021. In all 22 cases, the indication of flap was to fill the post-breast conservation surgery (BCS) defects in outer quadrant of breast. All LICAP flaps were harvested by surface marking of anatomical landmarks and without handheld Doppler. RESULTS: Out of 22 LICAP turnover flaps, thirteen were harvested for left breast and nine for right breast. The median width and length of the flap were 12.2 cm and 19.6 cm, respectively. The additional mean operative time was 41 min. All LICAP flaps survived well, and grade 1 Clavien-Dindo morbidity was documented in four cases. Mean hospital stay was 2.6 days. All patients received radiotherapy on their stipulated schedule. Early cosmetic outcome was good, and long-term outcomes are awaited. CONCLUSION: NDSP-LICAP flap is a workhorse for lateral breast defects. Precise knowledge of perforators and anatomical landmarks can be used for harvesting these flaps, thus avoiding ultrasound Doppler and dedicated training for perforator localization. This technique has short learning curve without the need for any plastic surgery training. The early cosmetic outcomes are good.

A systematic review and meta-analysis of the impact of radiation-related lymphopenia on outcomes in pancreatic cancer.

Background: Pancreatic cancer is a devastating disease with a 5-year survival rate of 5-10%. Radiation is commonly used in neoadjuvant and adjuvant settings to improve local control. Studies have shown that circulating lymphocyte count depletion after radiation has been associated with poor tumor control and inferior overall survival (OS) outcomes. Method: To better understand the impact of radiation-associated lymphopenia in pancreatic cancer, the authors undertook this systematic review and meta-analysis of clinical studies that have reported radiation-related lymphopenia in pancreatic cancer. Results: A systematic methodology search of PubMed, Embase and the Cochrane Library resulted in 2969 abstracts. Nine studies fulfilled the inclusion criteria. Six studies reported on outcomes in patients undergoing definitive chemoradiation and three studies comparing outcomes in stereotactic body radiotherapy versus definitive chemoradiation. The patients with severe lymphopenia were at increased risk of death with a pooled hazard ratio of 2.33 (95% CI: 1.79, 3.03; I2: 36%; p < 0.001) compared with patients with no severe lymphopenia. The odds of developing severe lymphopenia were 1.12 (95% CI: 0.45, 2.79; I2: 95%; p < 0.81). The pooled mean difference for OS was -6.80 months (95% CI: -10.35, -3.24; I2: 99%; p < 0.002), suggesting that patients who develop grade 3 or 4 lymphopenia have inferior median OS outcomes. Limiting the mean splenic dose to less than 9 Gy as well as various spleen dosimetric parameters such as visit (V)10 <32%, V15 <23% and V20 <15.4% can reduce the incidence of severe lymphopenia. Conclusion: Radiation-related lymphopenia is associated with an increased hazard of death and inferior median OS. Spleen dosimetric parameters correlate with the incidence of severe lymphopenia and with sub-optimal survival outcomes. There is a need to validate these findings in prospective studies.

A Systematic Review of Radiation-Related Lymphopenia in Genito-urinary Malignancies.

BACKGROUND: The impact of radiation-related lymphopenia on clinical outcomes has been reported in various solid malignancies such as high grade gliomas, head and neck cancers, thoracic malignancies and gastro-intestinal malignancies but its impact is not clearly known in the context of common genito-urinary (GU) malignancies. METHODOLOGY: To better understand the effect of radiation-associated lymphopenia in prostate and bladder cancer, we undertook this systematic review of clinical studies that have studied radiation-related lymphopenia in GU malignancies. A systematic methodology search of PubMed, Embase, and Cochrane library resulted in 2125 abstracts. Ten studies fulfilled the inclusion criteria which included any prospective, retrospective study or cohort study of prostate, urinary bladder, kidney, ureter, urethra, penile cancer in humans, and radiation should be part of treatment and intent has to be in definitive or adjuvant settings. Finally the study should have data on radiation-related lymphopenia. RESULTS: Four studies reported on the cancer-specific outcomes related to the lymphopenia. The incidence of low lymphocyte counts were documented in all the studies. Three studies analyzed the factors associated with the Lymphocyte depletion. Pooled incidence of severe lymphopenia was 29.25% and mild to moderate lymphopenia was 60.75%. Bone marrow volume receiving 40 Gy was associated with the incidence of lymphopenia. CONCLUSION: One-third of the patients suffer from severe lymphopenia after radiation in prostate and bladder cancer. There are no clear data to support the correlation between severe lymphopenia and disease outcomes. Bone marrow dosimetry can affect the incidence and severity of lymphopenia. There is need of prospective datasets to identify the impact of radiation-related lymphopenia in GU malignancies focusing on long-term side effects, recurrence rates, and overall survival.

A phase III randomised trial of trans-abdominal ultrasound in improving application quality and dosimetry of intra-cavitary brachytherapy in locally advanced cervical cancer.

INTRODUCTION: Intra-cavitary brachytherapy (ICB) remains an integral part of radiotherapy treatment in cervical cancer. Two-dimensional X ray point-based planning remains common and blind insertion leads to uterine perforations and higher toxicity. We conducted a randomised controlled trial of using trans-abdominal ultrasound in performing ICB to reduce perforation and organ at risk doses. PATIENT AND METHODS: The present study is a phase III open label randomised controlled trial of ultrasound guided ICB conducted on invasive cervical cancer patients. Patients were randomised by a simple computer-generated randomization chart into Arm A (No Ultrasound guidance) and Arm B (ICB with ultrasound guidance). The uterine perforation rates, tandem length change rates, bladder doses, rectal dose and procedure times were compared. Fischer exact test was used to compare the arms and p value <0.05 considered significant. RESULTS: A total of 160 patients were randomised. With US assistance, the uterine perforation rate was 1.25% (n = 1). In the non-US assistance arm the perforation rate was 12.5% (n = 10) (p = 0.005). Mean time to complete the entire procedure was significantly shortened from 26 min to 19 min favouring the US arm (p = 0.001). Dosimetric assessment between the two groups showed significant decrease in dose received by the various organs at risk with US assistance. CONCLUSION: The present study confirms significant improvement in application quality as well as dosimetry with reduction in procedure time. Trans-Abdominal US should be routinely used for ICB procedures, particularly in resource limited settings.

Moderate hypofractionation for early laryngeal cancer improves local control: a systematic review and meta-analysis.

INTRODUCTION: Radiation therapy is considered the standard treatment for early glottic cancers; and recent trials have evaluated the role of hypofractionation with mixed results. We conducted this systematic review and meta-analysis to assess the impact of hypofractionation in early glottic cancers. METHODS: We performed a comprehensive search of the PubMed, Embase and Google scholar to look for studies which have evaluated the role of hypofractionation in early glottic cancers. Only prospective trials were included in the present analysis. RevMan software (Cochrane Collaboration's Information Management System) was used for the meta-analysis. RESULTS: The analysis included a total of five studies and 1153 patients. Hypofractionation was found to significantly improve local control rates with an Odds ratio of 0.55 [95% CI 0.13-0.85]. The voice preservation rates with hypofractionation ranged from 86 to 94%. No significant improvement in overall survival was noted with the used of hypofractionation [hazard ratio 1.09, 95% CI 0.69-1.71]. There was an increased incidence of grade 2 or higher acute mucositis toxicity with use of hypofractionation [Odds ratio 1.54, 95% CI 1.12-2.11]. The incidence of acute skin toxicity was not increased with use of hypofractionation. Late toxicity was very low and not increased with use of hypofractionation. CONCLUSION: Moderate hypofractionation as compared to conventional fractionation, in laryngeal cancer, is associated with significantly improved local control without impact on overall survival. The use of hypofractionation is associated with an increased incidence of acute mucositis though incidence of long-term toxicity was not significantly increased. Hence, moderate-dose hypo-fractionation should be considered as the new standard of care in early laryngeal cancer.

Adjuvant radiation therapy for malignant tumours of the eyelid: Experience from a tertiary cancer centre in India.

Background: . Tumours of the eyelid are a rare subgroup of neoplasms with varied histology and inherent differences in clinical behaviour. Surgery is the standard of care, and adjuvant radiation therapy (RT) is given in the presence of features suggesting a high risk of local recurrence. The treatment of lymph nodes in the neck is debatable. We reviewed the utility of RT for lymph nodes in the neck in patients with malignant tumours of the eyelid. Methods: . We reviewed medical records of all patients with tumours of the eyelid treated at our centre from July 2006 to December 2014 for their demographic, clinical profile, treatment details and outcome. Results: . The records of 37 patients were included for analysis, of these 34 underwent surgery and 21 received adjuvant RT. Their median age was 60 (range 30-85) years. Sebaceous cell carcinoma was the most common (50.4%). The median disease-free survival (DFS) was 35 months (95% CI 17.9-52.0). The 1- and 3-year DFS were 82.7% and 45%, respectively. Univariate analysis showed a superior outcome with early stage (T1) tumours (p=0.01), RT dose of ≥60 Gy and those underwent lymph node dissection (p=0.03). The presence of high-risk factors including close or positive margin had an inferior outcome with a trend towards statistical significance (p=0.06). Conclusion: . We found a favourable outcome with early T stage, RT dose of ≥60 Gy and lymph node dissection. High-risk histopathological features including close margins and positive lymph nodes merit adjuvant RT including regional lymph nodes.

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.

Impact of surgery, adjuvant treatment, and other prognostic factors in the management of anaplastic ganglioglioma.

BACKGROUND/PURPOSE: Anaplastic ganglioglioma (AGG) is a rare tumor with both glial and neuronal component accounting for less than 1% of all CNS tumors with limited information about the optimum treatment and outcome of these tumors. METHOD AND MATERIALS: We did a thorough search of the PubMed with the following MesH terms: "Ganglioglioma; Anaplastic ganglioglioma; Ganglioglioma AND treatment; and Anaplastic ganglioglioma AND survival" to find all possible publications related to AGG to perform an individual patient data analysis and derive the survival outcome and optimum treatment of these tumors. RESULTS: A total of 56 articles were retrieved pertaining to AGG with 88 patients. However, a total of 40 publications found eligible with 69 patients for individual patient data analysis. Median age for the entire cohort was 16 years (range 0.2-77 years). Surgical details were available for 64 patients. A gross total or near total resection was reported in 21 cases (32.8%), subtotal resection or debulking was reported in 25 cases (39.1%). Surgical details were available for 64 patients. A gross total or near total resection was reported in 21 cases (32.8%), and subtotal resection or debulking was reported in 25 cases (39.1%). Median overall survival (OS) was 29 months [95% CI 15.8-42.2 months] with 2- and 5-year OS 61 and 39.4% respectively. CONCLUSION: AGG is associated with a dismal. Pediatric age and a gross total resection of tumor confer a better progression-free survival and OS. Hence, surgery should remain the cornerstone of therapy. However, because of modest survival, there is enough opportunity to improve survival with addition of adjuvant radiation and chemotherapy. A whole genome sequencing and molecular characterization would help to derive the best treatment option.

Patterns of care and impact of prognostic factors in the outcome of NUT midline carcinoma: a systematic review and individual patient data analysis of 119 cases.

INTRODUCTION: NUT midline carcinoma is a rare tumour occurring in young adults which is frequently misdiagnosed as poorly differentiated squamous cell carcinoma or germ cell tumour. Though considered highly aggressive, there is limited information about the clinical behaviour of such patients. We intended to perform this review of published literature to assess the demographic profile, pattern of care and assess survival outcomes. METHODS: Two authors independently searched PubMed and Google search for eligible studies from 1950 till July 1 2017 published in English language using MESH terms NUT midline carcinoma; NUT midline carcinoma and radiotherapy and translocation 15:19 tumour. RESULTS: Data of 119 patients were retrieved from 64 publications for statistical analysis. Median age of the entire cohort was 23 years (range 0-68 years). The analysis revealed equal incidence in males and females (60:58). The present analysis revealed that the most common location is the lung (n = 42) followed by head and neck (n = 40). Median OS for the entire cohort was only 5 months with 1 and 5 year OS for the entire cohort was 24.99 and 7.09% respectively. Radiotherapy and chemotherapy inclusion in primary treatment had a significant impact on overall survival on univariate analysis while surgery did not affect survival significantly. No impact on overall survival was found based on type of molecular translocation, i.e., NUT-BRD4, NUT-BRD3 or other variants. Inadequate data were available for identify impact of BET inhibitors and HiDAc on PFS and OS. CONCLUSION: NUT midline carcinoma has dismal prognosis. Radiotherapy and chemotherapy improves survival, but do not provide long term control except in anecdotal cases. Further research is needed to improve outcomes in future.

Pattern of care and impact of prognostic factors on the outcome of head and neck extramedullary plasmacytoma: a systematic review and individual patient data analysis of 315 cases.

INTRODUCTION: Head and neck extramedullary plasmacytoma is a rare localized plasma cell neoplasm. We intended to perform this review of the published literature to assess the demographic profile, pattern of care and survival outcomes. METHODS: Two authors independently searched PubMed, Google search and Cochrane library for eligible studies from 1950 till July 1, 2016, published in English language. RESULTS: Median age of the cohort was 57 years (range 11-85). Site-wise distributions were paranasal sinuses 22.3% (70), nasal cavity 17.5% (55), nasopharynx 10.8% (34). Median size of SEMP was 3 cm (range 0.3-12 cm). Treatment distribution was radiotherapy (RT) in 52% (164), surgery (S) 19% (60), chemotherapy (C) 5% (16), S + RT 23.49% (74),CRT 1.9% (6), S + C 0.6% (2), S + RT + C 0.95% (3).Radiation was used as a modality in 78.4%(247), surgery in 44.1%(139), chemotherapy in 4.8%(15). Median radiation dose used was 45 Gy with range 20-61 Gy. Median overall survival (OS) was 40 months (range 0.5-298). Median local progression-free survival was 36 months (range 0-298). Median myeloma relapse-free survival was 36 months (range 0.5-298). Five- and 10-year OS was 78.33 and 68.61%. Five-year cause-specific survival (CSS) and 10-year CSS was 90.15 and 83.31%. Five-year LPFS was 94.78%, and 10-year LPFS was 88.43%. Five-year myeloma progression-free survival was 84.46%, and 10-year myeloma PFS was 80.44%. The factors associated with risk of local relapse were site of disease (sinonasal), secretory EMP, type of treatment received (surgery + RT > RT alone > surgery on univariate analysis). Risk factors for myeloma relapse were coexisting diseases, site of disease (sinonasal), bony erosion, size of lesion > 5 cm and type of treatment received on univariate analysis. CONCLUSION: Our study shows that combined modality S + RT is superior compared to uni-modality in preventing local recurrence. Radiation dose of 45 Gy is optimal. Nodal irradiation has no impact on local recurrence.

Patterns of care and survival outcomes in patients with an extraventricular neurocytoma: An individual patient data analysis of 201 cases.

INTRODUCTION:: Extraventricular neurocytoma is a rare neuronal tumor arising outside the ventricles. However, because of its rarity, its optimum treatment remains undefined. MATERIALS AND METHODS: We intended to perform an individual patient data analysis to examine the patterns of care and prognostic factors involved in the treatment of extraventricular neurocytomas. PubMed, SCOPUS, and Google Scholar were searched with the following MeSH terms: "Neurocytoma, Extra ventricular neurocytoma, Spinal neurocytoma AND treatment, Survival" to find all possible publications pertaining to EVN. RESULTS: From 108 publications, we retrieved 201 patients of extraventricular neurocytoma. Their median age was 30 years (range: 0.6-78 years). Sixty seven patients were in the pediatric (age ≤20 years) age group. There was a bimodal age distribution. Surgical details were available for 132 cases, and 51.5% underwent a gross total resection whereas 41.7% underwent a subtotal resection. Adjuvant radiation was used in 40% cases. For the entire cohort, the median progression free survival was 77 months (53.3-100.7). However, we could not find an impact of any of the prognostic factors on survival. CONCLUSION: An extraventricular neurocytoma is a very rare disease with varied presentations and different sites of origin. Gross total resection remains the standard of care. Adjuvant radiation may be used for salvage. However, radiation therapy after subtotal resection of an atypical neurocytoma may be administered.

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.

Patterns of care and survival outcomes in patients with astroblastoma: an individual patient data analysis of 152 cases.

BACKGROUND: Astroblastoma (AB) is a rare tumor with significant dilemma regarding diagnostic criteria, behavior, and optimum treatment. MATERIALS AND METHODS: We searched PubMed, Google Search, and Cochrane Library for eligible studies with the following search words: astroblastoma, high-grade astroblastoma, and anaplastic astroblastoma till July 1, 2016, published in English language and collected data regarding age, sex, site of disease, pathological grade, treatment received, and survival. RESULTS: Data of 152 patients were retrieved from 63 publications. Median age was 16 years (range 0-71). Females were affected twice more frequently than male (70.3 vs. 29.7%). Tumors were most commonly located in the frontal (39%) followed by parietal lobe (26.7%). Fifty-two and 25% of the patients had headache and seizure at presentation, 76.3% of the patients underwent a gross total resection, 41 out of 89 had a high-grade tumor, and 56 patients received adjuvant radiation with a median dose of 54 Gy (range 20-72). Adjuvant chemotherapy was used in 23 patients. Temozolomide was the most common drug used in 30% of the patients. A combination of cisplatin, etoposide with vincristine, or ifosfamide was used in 17%. Median follow-up duration was 37 months (range 1-238). Median progression-free survival and OS were 36 and 184 months, respectively. Patients with a higher-grade tumor had significantly worse OS with HR 5.260 and p = 0.001. Forty patients experienced local progression. Sixty-five percent patients underwent surgery while 50% underwent radiation as salvage. CONCLUSION: AB has two distinct grades with higher-grade tumors having significantly poor survival. Maximal safe surgery followed by adjuvant radiation and temozolomide should be advocated for these tumors.

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.

Pattern of care and impact of prognostic factors in the outcome of ameloblastic carcinoma: a systematic review and individual patient data analysis of 199 cases.

Ameloblastic carcinoma is a rare locally aggressive odontogenic neoplasm. These tumors are most commonly found to arise from mandible. Because of rarity, there is limited information about the clinical behaviour of such patients. We intended to perform this review of published literature to assess the demographic profile, pattern of care and assess survival outcomes. Two authors independently searched PubMed, Google search, and Cochrane library for eligible studies from 1950 until July 1 2016 published in English language. Data of 199 patients were retrieved from 94 publications for statistical analysis. Median age of the entire cohort was 49 years (range 7-91 years). The analysis revealed that a clear twofold higher incidence in male with male-to-female ratio was 2.4:1 (140:57). Mandible was found to be the commonest tumor location in 66.7% (n = 132) cases followed by maxilla (31.8%) (n = 64). The present analysis revealed that median PFS of 57 months (95% CI 39-120 months) with 5- and 10-year PFS was found to be 47.88 and 29.48%, respectively. Median OS for the entire cohort which was 122 months (95% CI 96-153 months) with 2- and 5-year OS for the entire cohort was 87.16 and 69.08%, respectively. In univariate analysis, patients with an R0 resection were found to have a favourable survival. In addition, patients with localized disease and younger age were found to have a better survival. Adjuvant radiation did not confer any survival advantage. The present analysis revealed excellent outcome for patients treated with an R0 resection. Older patients with high-risk factor may benefit from adjuvant radiation. Role of chemotherapy needs to be evaluated.

ATRX loss in glioneuronal tumors with neuropil-like islands indicates similarity to diffuse astrocytic tumors.

Glioneuronal tumor with neuropil-like islands (GTNI) is a rare, recently described neoplasm, whose pathogenesis has not been studied extensively. The role of ATRX mutations, a class-defining alteration in diffuse astrocytic neoplasms, has not been assessed in GTNIs previously. We therefore aimed to assess the status of ATRX, along with IDH1, 1p/19q and p53, in cases of GTNI in order to evaluate the molecular profile of these tumors. All cases of GTNI diagnosed at our Institute were retrieved and clinicopathological features were reviewed. Immunohistochemistry for ATRX, IDH1 and p53 was performed. We identified four cases of GTNI, majority of which occurred in young adults. Loss of ATRX immunoexpression, a surrogate marker for ATRX mutation, was seen in all four cases. All cases were immunopositive for p53, while IDH1 positivity was seen in all three cases assessed. 1p/19q codeletion was absent in the three cases analyzed. These results indicate that the molecular pathogenesis of GTNIs similar to that of diffuse astrocytic tumors. Further, the loss of ATRX expression is seen in both the glial as well as neuronal components, indicating that both arise from the same tumor stem/progenitor cell and that the latter may be a metaplastic change. Thus, loss of ATRX immunoexpression, shown for the first time in these tumors, along with immunopositivity for p53 and IDH1, indicates that these tumors are molecular astrocytomas, and their clinical behaviour is likely to recapitulate that of ATRX-mutant and IDH-mutant diffuse astrocytomas of the same grade.

Clinicopathological characteristics, molecular subgrouping, and expression of miR-379/miR-656 cluster (C14MC) in adult medulloblastomas.

Medulloblastoma (MB) is a childhood tumor comprising four molecular subgroups: WNT, SHH, group 3 and group 4, with diagnostic and prognostic connotations. Very few studies are available on molecular subgrouping of adult MBs due to their rarity. Recently, loss of chromosome14q has been reported in SHH MBs, with downregulation of miR-379/miR-656 cluster (C14MC) in pediatric SHH MBs. Hence, the present study on adult MBs was undertaken to enumerate clinicopathological characteristics and molecular subgroups, and to analyze expression of C14MC and its transcriptional regulators, MEF2, JUN and ESRRG. Immunohistochemistry for ß-catenin, GAB1 and YAP1 was performed to identify molecular subgroups. MYC amplification was evaluated by FISH. Expression profiling of 47 miRNAs from C14MC was performed using customized Taqman low-density array. Expression of transcriptional regulators was examined using RT-PCR. Seventy-one adult MBs were analyzed. They had male predominance and majority were located laterally (52 %). A significant proportion of cases were of Desmoplastic/nodular histology (32 %); MBEN was not seen. WNT tumors constituted 4.2 %, SHH 62 %, and non-WNT/non-SHH 33.8 %. MYC amplification was identified in 11.1 % cases. Patient outcome was worse in adults. Significant downregulation of C14MC was observed in all MB subgroups, and MEF-2 expression was downregulated. Adult MBs are distinct from childhood MBs in terms of location, histopathological subtypes, molecular subgroups, as well as prognosis. Silencing of C14MC in all MB subgroups suggests its role as a tumor suppressor locus in tumorigenesis. Deregulation of C14MC can possibly be attributed to repression of MEF2.

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.