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The management of T-lymphoblastic lymphoma (T-LBL) in adults poses uncertainties, including optimal chemotherapy regimen, need for radiotherapy, and the benefit of stem cell transplant. This retrospective case series investigated the efficacy of the pediatric BFM-90 regimen in adult patients and evaluated the role of early response assessment by positron emission tomography with computed tomography (PET-CT) in predicting outcomes.Patients aged 15 years or older with T-LBL diagnosed at Tata Memorial Hospital, Mumbai, India were given chemotherapy according to the European BFM-90 protocol (n = 38). The patients were evaluated for early response by interim PET-CT, post-induction and monitored for toxicity and long-term outcomes.Thirty-eight consecutive patients (median age 23.5 years) were analyzed. After a median follow-up of 33.5 (1-77) months, following induction, 35 out of 38 patients (92.1%) had achieved complete response (CR) on PET-CT. Thirty (78.9%) patients treated according to BFM-90 were alive in first remission. Three-year event-free survival for those with CR on PET-CT was 78%, against no survivors for those who remained PET-positive.This study demonstrates the feasibility and efficacy of BFM-90 approach in adults with T-LBL. We found an early PET response to be highly predictive of outcome.

INTRODUCTION: Primary Mediastinal B cell lymphoma (PMBCL) is a biologically and clinically distinct subset of diffuse large B cell lymphoma. We analysed the outcomes of our cohort of PMBCL patients treated with Dose adjusted (DA)-R-EPOCH regimen. PATIENTS AND METHODS: This is a retrospective analysis of consecutive PMBCL patients who received chemotherapy consisting of DA-R-EPOCH with filgrastim support. Survival analysis was done using Kaplan–Meier method. All calculations were performed using SPSS version 20 for windows. RESULTS: A total of 43 consecutive suspected PMBCL patients were reviewed for this study, 6 patients were excluded as diagnosis of PMBCL could not be established. All patients except one (97.3%) received 6 cycles of R-DA-EPOCH regimen. Median age of the patients was 27 years (range 15–58). Bulky disease (> 7 cm) was present in 97% patients and 54% patients had extranodal disease. With a median follow up of 40 months, 3-year overall survival was 80.6% (95% CI: 74.0–87.2). The 3-year event free survival was 78.4% (95% CI: 71.6–85.2). There were 6 (16.2%) relapses, 1 (2.7%) primary progression and 7 (23%) deaths. Mediastinal radiotherapy was administered to 17 (45.9%) patients. All the deaths were due to disease progression. Grade III/IV toxicities were seen in 28 (75.7%) patients, febrile neutropenia being the most common one. CONCLUSIONS: DA-R-EPOCH regimen is an effective and tolerable regimen in PMBCL patients even with adverse features.

Previously we have shown, using a primary glioblastoma (GBM) cell model, that a subpopulation of innately radiation resistant (RR) GBM cells survive radiotherapy and form multinucleated and giant cells (MNGCs) by homotypic fusions. We also showed that MNGCs may cause relapse. Here, we set out to explore whether molecular characteristics of RR cells captured from patient-derived primary GBM cultures bear clinical relevance. Primary cultures were derived from 19 naive GBM tumor samples. RR cells generated from these cultures were characterized using various cell biological assays. We also collected clinicopathological data of the 19 patients and assessed associations with RR variables using Spearman’s correlation test and with patient survival using Kaplan-Meier analysis. Significance was determined using a log-rank test. We found that SF2 (surviving fraction 2) values (p = 0.029), days of RR cell formation (p = 0.019) and percentage of giant cells (p = 0.034) in the RR population independently correlated with a poor patient survival. We also found that low ATM (Ataxia-telangiectasia mutated) expression levels in RR cells showed a significant (p = 0.002) negative correlation with SF2 values. A low ATM expression level in RR cells along with a high tumor volume was also found to negatively correlate with patient survival (p = 0.011). Finally, we found that the ATM expression levels in RR cells independently correlated with a poor patient survival (p = 0.014). Our data indicate that molecular features of innately radiation resistant GBM cells independently correlate with clinical outcome. Our study also highlights the relevance of using patient-derived primary GBM cultures for the characterization of RR cells that are otherwise inaccessible for analysis.

Medulloblastoma is a WHO grade IV neoplasm that is usually restricted to the central nervous system, with metastasis occurring along the neuraxis through the ventricular system and cerebrospinal fluid. Extraneural metastasis is rare, usually occurs in bones/lymph nodes, and carries poor prognosis. We report multimodal imaging in a 14-year-old boy with desmoplastic medulloblastoma having multiple extraneural nodal and skeletal metastases, which was misdiagnosed as lymphoma. This case highlights the importance of understanding tumor biology with active clinical and radiological surveillance that is useful in early detection of extraneural metastasis of this aggressive tumor that helps in advocating appropriate and timely treatment.

Introduction: Systemic anaplastic large cell lymphoma (ALCL) accounts for 5%–10% of adult non Hodgkin's lymphoma (NHL) and 10%–30% of childhood NHL. Owing to significant differences in survival and gene expression profile, current WHO classifies ALCL into two distinct entities as anaplastic lymphoma receptor tyrosine kinase (ALK) positive and ALK negative ALCL with ALK expression by tumour as a good prognostic indicator. However, in our institute which is a cancer referral institute, our preliminary experience was that even ALK positive tumours did not fare well as compared to ALK- negative ALCL. So, the current study aims at exploring more clinical and pathological factors impacting survival in ALCL patients. Objective: To study clinical and pathological prognostic factors in cases of ALCL. Methods: 102 cases of ALCL were retrieved from pathology database. Pathological features and clinical features of these cases were recorded and factors found to impact overall survival (OAS) and disease-free survival (DFS) curves were identified based on univariate and multivariate analysis. Results: ALK 1 expression was seen in 71/102 (69.6%) cases and was not found to impact OAS or DFS. The 2 year OAS rate for ALK positive patients was 63.5% and DFS rate was 54.4%, while for ALK negative patients, the OAS was 60.5% and DFS was 43.5%. The Ann Arbor stage, performance status, international prognostic index, histological subtype, and the degree of the background inflammatory infiltrate were found to impact the OAS significantly. Increased reactive inflammatory component also negatively impacted DFS. In the multivariate analysis, only the histologic type emerged as significant for OAS. Conclusion: Though ALK plays a role in prognostication of systemic ALCL, advanced stage disease and an inflammatory milieu may modulate the final outcome. We report a study of clinical and pathologic prognostic features in 102 cases of anaplastic large cell lymphoma (ALCL) from a cancer referral institute in India. Anaplastic lymphoma receptor tyrosine kinase (ALK-1) expression was seen in 71/102 (69.6%) cases and was not found to impact overall survival (OAS) or disease-free survival (DFS). The 2-year OAS rate for ALK-positive patients was 63.5% and DFS rate was 54.4%, while for ALK-negative patients, the OAS was 60.5% and DFS was 43.5%. The Ann Arbor stage, performance status, international prognostic index, histological subtype, and the degree of the background inflammatory infiltrate were found to impact the OAS significantly. Increased reactive inflammatory component also negatively impacted DFS. In the multivariate analysis, only the histologic type emerged as significant for OAS. Thus, though ALK plays a role in prognostication of systemic ALCL, advanced stage disease and an inflammatory milieu may modulate the final outcome.

Primary tuberculosis (TB) of tonsil is a rare form of extra-pulmonary tuberculosis. Most tonsillar TB cases present with coexistent pulmonary tuberculosis. It can simulate tonsillar malignancy and poses a diagnostic challenge. Histopathological examination is often needed for confirmation. Herein, we report a case of primary tonsillar tuberculosis in a 55-year-old gentleman mimicking carcinoma of the tonsil.

Heterogeneity within GBMs and variability of visualized fluorescence combine to confer practical limitations to the technique of optical imaging. A biometric analysis was planned to objectively ascertain and analyse this phenomenon METHODS: 25 adult glioblastoma subjects undergoing resection were prospectively accrued. Biopsies were taken from various parts of the tumor and safe peritumoral zones. White light (WL) and visualized fluorescence was subjectively recorded. Corresponding histopathology [coalescent (C) or infiltrating (I) tumor] and protoporphyrin-IX (PPIX) levels were assayed.WL was very sensitive for detecting tumor. SF was more specific and had high positive predictive value for detecting tumor. WF on the other hand had a poor discriminatory efficacy. Mean PPIX levels were 3.0, 2.01 and 0.16 for SF, WF, and NF respectively. WF had a wide variable range of PPIX levels. Within the coalescent tumor areas, there was a variable distribution of fluorescence (both subjective as well as objective PPIX levels) with only 54% samples showing SF and high PPIX. In seven cases this discordance was noted within the same tumor (biological heterogeneity).Fluorescence may miss important tumor areas even if objective assessment is used. Histologically similar tumor areas may exhibit contrasting fluorescence properties, a phenomenon which needs further investigation and elucidation of underlying mechanisms which could potentially be manipulated to optimize the utility of fluorescence guidance.

Immune dysfunction is critical in pathogenesis of cutaneous T-cell lymphoma (CTCL). Few studies have reported abnormal cytokine profile and dysregulated T-cell functions during the onset and progression of certain types of lymphoma. However, the presence of IL9-producing Th9 cells and their role in tumor cell metabolism and survival remain unexplored. With this clinical study, we performed multidimensional blood endotyping of CTCL patients before and after standard photo/chemotherapy and revealed distinct immune hallmarks of the disease. Importantly, there was a higher frequency of “skin homing” Th9 cells in CTCL patients with early (T1 and T2) and advanced-stage disease (T3 and T4). However, advanced-stage CTCL patients had severely impaired frequency of skin-homing Th1 and Th17 cells, indicating attenuated immunity. Treatment of CTCL patients with standard photo/chemotherapy decreased the skin-homing Th9 cells and increased the Th1 and Th17 cells. Interestingly, T cells of CTCL patients express IL9 receptor (IL9R), and there was negligible IL9R expression on T cells of healthy donors. Mechanistically, IL9/IL9R interaction on CD3+ T cells of CTCL patients and Jurkat cells reduced oxidative stress, lactic acidosis, and apoptosis and ultimately increased their survival. In conclusion, coexpression of IL9 and IL9R on T cells in CTCL patients indicates the autocrine-positive feedback loop of Th9 axis in promoting the survival of malignant T cells by reducing the oxidative stress. Implications: The critical role of Th9 axis in CTCL pathogenesis indicates that strategies targeting Th9 cells might harbor significant potential in developing robust CTCL therapy.

BACKGROUND Incidence of intracranial germ cell tumors (ICGCT) in Western literature is low (0.3–0.6 %) as compared to East Asia (3–4 %), & their clinicopathological features are well documented. However, there are scant studies on ICGCT from India. MATERIAL AND METHODS Retrospective observational study of all ICGCT histologically diagnosed in our hospital from 2007–2018. Metastasis were excluded. Clinicopathological features were retrieved from hospital’s electronic medical records. RESULTS We diagnosed 82 primary ICGCT, forming approx. 0.54 % of all primary brain tumors, & 3.5% of pediatric brain tumors. Age range: 2 months-32 yrs (Median age 14 yrs). M:F ratio: 1.82:1 (53M,29F). Nearly 80% patients were pediatric (3 yrs. Females were associated mainly with G (21/29, 72%). NGGCT were predominantly seen in males (M:F=2.9:1). Also, pure IT (9) were seen only in males. Posterior fossa tumors were all IT (4/4). Spinal tumors were NGGCT (1 mature teratoma, 1 YST). Majority of suprasellar tumors (25/31, 80.6%), other midline locations like corpus callosal, midbrain, & all thalamic tumors were G. However, pineal tumors showed equal distribution of G (15/31) & NGGCT (16/31). Spine screening was positive in 8 patients (6 G, 2 IT)- 7 on MRI and 1 only on CSF cytology. Serum tumor markers were raised in 13/54 cases- 6/34G(17.6%), vs 7/20 NGGCT (35%). CSF tumor markers were raised in 14/34-10/23 G (43.4%), vs 4/11 NGGCT (36.3%). Follow up was available for 37 patients (Duration 3 months-10 yrs, median 2 yrs). On f/u 6/15 (40%) NGGCT showed progression/death, while only 2/32 G relapsed (6.5%). Four deaths in G group were not directly attributable to the tumor. CONCLUSION Frequency of ICGCT in our hospital similar to western data rather than Asian, albeit with less striking male preponderance. ICGCT were tumors of 2nd decade & majority occurred in pineal/suprasellar areas. About 2/3rd were pure G on histology, and showed good prognosis. NGGCT were common in infants, males and in posterior fossa. IT were seen exclusively in males and pure YST mainly in males. Although majority of ICGCT are in midline, rarely non midline involvement also occurs, and it’s essential to exclude metastasis before considering primary ICGCT. Expectedly, NGGCT showed poorer prognosis, compared to pure germinomas.

Genome-wide expression profiling studies have identified four core molecular subgroups of medulloblastoma: WNT, SHH, Group 3 and Group 4. Molecular markers are necessary for accurate risk stratification in the non-WNT subgroups due to the underlying heterogeneity in genetic alterations and overall survival. MiR-204 expression was evaluated in molecularly classified 260 medulloblastomas from an Indian cohort and in 763 medulloblastomas from the MAGIC cohort, SickKids, Canada. Low expression of miR-204 in the Group 3 / Group 4 tumors identify a highly aggressive subset of tumors having poor overall survival, in the two independent cohorts of medulloblastomas. Downregulation of miR-204 expression correlates with poor survival within the Group 4 as well indicating it as a valuable risk-stratification marker in the subgroup. Restoration of miR-204 expression in multiple medulloblastoma cell lines was found to inhibit their anchorage-independent growth, invasion potential and tumorigenicity. IGF2R was identified as a novel target of miR-204. MiR-204 expression resulted in downregulation of both M6PR and IGF2R that transport lysosomal proteases from the Golgi apparatus to the lysosomes. Consistent with this finding, miR-204 expression resulted in reduction in the levels of the lysosomal proteases in medulloblastoma cells. MiR-204 expression also resulted in inhibition of autophagy that is known to be dependent on the lysosomal degradation pathway and LC3B, a known miR-204 target. Treatment with HDAC inhibitors resulted in upregulation of miR-204 expression in medulloblastoma cells, suggesting therapeutic role for these inhibitors in the treatment of medulloblastomas. In summary, miR-204 is not only a valuable risk stratification marker in the combined cohort of Group 3 / Group 4 medulloblastomas as well as in the Group 4 itself, that has paucity of good prognostication markers, but also has therapeutic potential as indicated by its tumor suppressive effect on medulloblastoma cells. Electronic supplementary material The online version of this article (10.1186/s40478-019-0697-3) contains supplementary material, which is available to authorized users.

Figure S2. Kaplan Meier Survival Analysis of Group 3 medulloblastomas from the Indian cohort comparing overall survival of ‘miR-204 high’ subset with that of ‘miR-204 low’ subset. (PPTX 69 kb)

Table S1. The nucleotide sequences of the primers used in the study. All sequences are given in 5â ˛ to 3â ˛ direction. (DOCX 15 kb)

Figure S3. Methylation analysis of the CpG island from the promoter region of TRPM3/MIR204. A 203â bp region of the CpG island from the promoter region of the TRPM3 gene was PCR amplified from bisulfite converted genomic DNA of the medulloblastoma cell lines. Representative nucleotide sequence of this PCR product from the indicated medulloblastoma cell line is shown. Arrows indicate the CpG residues in the DNA sequence and their sequence in the bisulfite converted (BSP) DNA from the medulloblastoma cells. (PPTX 121 kb)

Figure S1. MiR-204 expression levels in the 8 subtypes of Group 3 / Group 4 medulloblastomas from Northcott et al. [34] data. (PPTX 39 kb)

Gliomas are the most prevalent primary brain tumors with immense clinical heterogeneity, poor prognosis and survival. Gliomas arise from glial cells and are heavily infiltrated with innate immune cells. In India high-grade gliomas or Glioblastomas (GBM) account for 59.5% of CNS tumours. A key challenge for clinical management of GBM is its highly heterogeneous nature-between patients and within a single tumour-making current therapies ineffective. The nucleotide-binding domain, and leucine-rich repeat containing receptors (NLRs) and absent-in-melanoma 2 (AIM2) are innate immune receptors crucial for initiation and progression of several cancers. There is a dearth of reports investigating NLRs and AIM2 in glioma pathology. We are interested in studying the cellular and molecular contribution of NLRs and AIM2 in malignant gliomas in the Indian subcontinent. We previously reported a data-driven approach to identify NLRs, AIM2 and NLR-associated gene expression in gliomas using The Cancer Genome Atlas (TCGA) patient datasets. However, TCGA data is obtained from diverse populations and cellular diversity within individual tumor tissues remains unexplored. In this study we carried out tumour primary cell culture, human brain immunohistochemistry and proteomic analysis and same patient serum controls (n=100). Our results characterize novel cell specific differential expression and signalling profile of several NLR genes (including NLRP3, NLRP12 and ASC) in microglia, astrocytes, endothelial cells and the tumour cell populations in GBM patient tissue. We provide critical insights into innate immune signalling within the GBM microenvironment and identify key markers for future therapeutic interventions.