Clinicopathologic Profile and Treatment Outcomes of Children With Diffuse Large B-cell Lymphomas: Experience From a Tertiary Cancer Center in India.

Clinicopathologic profile and outcome of 15 children (15 years or above) with diffuse large B-cell lymphoma treated with MCP-842 protocol are reported. Eleven of 15 presented with advanced (stage-III/IV) disease. Post-2 cycles of chemotherapy, complete metabolic and morphologic response was documented in 10 (66%) and rest 5 (33%) with partial response achieved complete metabolic remission by end of treatment. At a median follow-up of 44 months (range: 16 to 79 mo), the 3-year event-free survival and overall-survival were 77.1%±11.7% and 85.7%±9.4%, respectively. Though majority of our patients had advanced disease, outcome on MCP-842 protocol was satisfactory.

Assessment of tumor Epstein-Barr Virus status and its impact on outcomes in intermediate and high-risk childhood classic Hodgkin Lymphoma treated at a tertiary cancer center in India.

Indian studies on EBV in childhood classic Hodgkin Lymphoma (cHL) have mainly analyzed the epidemiology of EBV-positive [EBV(+)HL] or negative HL [EBV(-)HL], with limited data on outcomes. We studied a large cohort of children with intermediate and high-Risk cHL for tumor EBV status and its impact on outcomes retrospectively. Of evaluable 189 patients, 84.7% had EBV(+)HL. Positive status was significantly associated with age ≤ 10 years (p < .001), males (p = .015), non-Nodular Sclerosis (NS) histology (p = .004) and inversely with bulky-mediastinal disease (p < .001). At a median follow-up of 29-months (range1-75), 3-year Event-Free Survival (EFS) for EBV(+)HL and EBV(-)HL was 93.6%(95%CI:89.8%-97.5%), 81.1%(95%CI:67.2%-97.9%), (p = .048) and Overall Survival (OS) was 94.9%(95%CI:91.6%-98.4%), 84.6%(95%CI:71.5%-100%), (p = .075) respectively. Three-year EFS was better in males (HR-0.267,95%CI:0.078-0.916, p = .036) in EBV(+)HL and in patients with serum-albumin > 3g/dL (HR-0.117,95%CI:0.019-0.705, p = .019) in EBV(-)HL. EBV is associated with most of intermediate and high-risk childhood cHL, occurs in younger male patients with non-NS histology, with reduced incidence of bulky-mediastinal disease and favorable survival in childhood cHL.

Differentiating dural metastases from meningioma: role of 68Ga DOTA-NOC PET/CT.

OBJECTIVE: To assess the ability of Ga DOTA-NOC PET/computed tomography (CT) to differentiate dural metastases from meningioma. PATIENTS AND METHODS: Patients who underwent a Ga DOTA-NOC PET/CT for differentiating meningiomas from dural metastases were included in the study. A visual score was assigned to the dural lesions (visual score - 1 to 3) in relation to the uptake in liver and spleen and variation in the visual score was evaluated. SUVmax of the dural lesions was also noted and difference in the values of the two pathologies were compared for statistical significance using nonparametric statistical tests. Final diagnosis was decided by histopathological confirmation whenever available. RESULTS: Imaging, histopathology or follow-up data of 42 patients was available for analysis. Meningioma was the final diagnosis in 31 (73.8%) patients, whereas dural metastases were diagnosed in 9 (21.4%) patients. In two patients, histopathology revealed inflammatory pseudotumor and hemangioblastoma. Meningiomas showed intense tracer uptake in 30/31 patients (visual score 3). All metastatic lesions showed some degree of tracer uptake though the intensity was lesser compared to meningioma (visual score 1, 2). Meningiomas showed a significantly higher median SUV max value compared to metastases (12.7 vs. 6.0, P = 0.001). CONCLUSION: Meningiomas can be differentiated from dural metastases by virtue of their higher uptake of Ga-labeled DOTA peptides reflecting higher SSTR expression. An asymptomatic meningeal based lesion with a high visual score (Visual score 3) has a very high probability to be a meningioma rather than dural metastasis.

Clinical profile and outcome of classical Hodgkin lymphoma treated with a risk-adapted approach in a tertiary cancer center in India.

BACKGROUND: Classical Hodgkin lymphoma (cHL) has excellent survival rates, but late effects are an issue and dictate modern approaches. We analyzed the clinical profile and outcome of cHL treated on a risk-adapted approach aimed at reducing late effects while improving historical outcomes at our center. PROCEDURE: Children (≤15 years) consecutively treated for cHL from January 2013 through December 2016 were retrospectively analyzed. 18 FDG-PET-CT-based staging and response assessment was done after two cycles for early response (ERA) and end of chemotherapy (late-response assessment [LRA]) if not in complete response (CR; Deauville < 4) at ERA. Stages IA/IB/IIA were low risk (LR) and received two cycles of ABVD (adriamycin/bleomycin/vinblastine/dacarbazine). Stages IAX/IBX/IIAX/IIB/IIIA were intermediate risk (IR), and stages IIBE/IIBX/IIIAE/IIIAX/IIIB/IVA/IVB were high risk (HR). Both received two cycles of OEPA (oncocristine/etoposide/prednisolone/adriamycin). Those in ERA-CR received two cycles of ABVD if LR, and two and four cycles of COPDac (cyclophosphamide/oncocristine/prednisolone/dacarbazine), respectively, for IR and HR. Involved-field radiotherapy (IFRT) was given to bulky sites and ERA < CR. Those at LRA < CR (Deauville < 3) or progression at any stage received salvage regimens. RESULTS: In the study period, 126 patients were identified who received the above protocol. There were 12 LR, and 114 advanced staged Hodgkin lymphoma (AHL) (18, IR; 96, HR) of which 91 (79.8%) had bulky sites. Eight (66.6%) LR and 93 (83%) AHL patients achieved ERA-CRs. IFRT was given to 4 (33.3%) LR patients with ERA < CR, and 92 (80.7%) of AHL (91 bulky sites; 1 ERA < CR). At a median follow-up of 31 months (range, 17-62), three-year event-free survival (EFS) and overall survival (OS) were both 100% for LR, and 94.4% (95% CI, 66.0%-99.2%) for IR, whereas for HR it was 90.3% (95% CI, 82.2%-94.8%) and 92.6% (95% CI, 85.2%-96.4%), respectively. CONCLUSIONS: Children with HL have favorable outcomes with manageable toxicities when treated on a risk-stratified and adapted approach. A high proportion of AHL have bulky disease necessitating IFRT, a concern that will have to be factored in future strategies.

Common malignant brain tumors: can 18F-FDG PET/CT aid in differentiation?

OBJECTIVES: The objectives of this study were to evalute the metabolic characteristics of common malignant space-occupying lesions (SOL) of the brain and to determine the utility of fluorine-18-fluorodeoxyglucose (F-FDG) PET/CT in differentiating between the common types of malignant brain SOL. PATIENTS AND METHODS: All patients with brain SOL who were referred for an F-FDG PET/CT scan by a multidisciplinary team were included in this retrospective study. The metabolic characteristics of the brain lesions in the form of maximum standardized uptake value (SUVmax) along with tumor-to-background activity ratios were determined and differences were compared using nonparametric statistical tests. Histopathological confirmation was used as the gold standard in all patients. Receiver operating characteristic curve analysis was used to find the optimal SUVmax cutoff to differentiate the tumor types. RESULTS: Glioblastoma multiforme (GBM; n=30), lymphoma (n=25), and metastases (n=46) accounted for most malignant tumors (95.2%). Lymphomas showed a significantly high metabolic uptake (median SUVmax=20.3, range: 8.1-46.3) compared with GBM ( median SUVmax=10.3, range: 2.6-21.7) and metastases (median SUVmax=11.5, range: 2.9-19.6) (P=0.00). The tumor-to-background activity ratios for lymphomas were also significantly higher. There was an overlap in the metabolic uptake of GBM and metastases, with no significant difference between their SUVmax values (P=0.245). A SUVmax more than 15.5 showed an 84% sensitivity and an 80% specificity to diagnose lymphomas (area under the curve=0.876, P=0.00). Four patients with brain lymphoma had extracranial disease on F-FDG PET. Lung cancer was the most common primary malignancy in patients with brain metastases. CONCLUSION: Central nervous system lymphomas can be differentiated from GBM and metastases by their higher metabolic activity. In addition, F-FDG PET/CT can potentially impact therapeutic decisions by detecting primary malignancy in patients with metastatic brain lesions and extracranial disease sites in patients with brain lymphoma.

Radiation-induced homotypic cell fusions of innately resistant glioblastoma cells mediate their sustained survival and recurrence.

Understanding of molecular events underlying resistance and relapse in glioblastoma (GBM) is hampered due to lack of accessibility to resistant cells from patients undergone therapy. Therefore, we mimicked clinical scenario in an in vitro cellular model developed from five GBM grade IV primary patient samples and two cell lines. We show that upon exposure to lethal dose of radiation, a subpopulation of GBM cells, innately resistant to radiation, survive and transiently arrest in G2/M phase via inhibitory pCdk1(Y15). Although arrested, these cells show multinucleated and giant cell phenotype (MNGC). Significantly, we demonstrate that these MNGCs are not pre-existing giant cells from parent population but formed via radiation-induced homotypic cell fusions among resistant cells. Furthermore, cell fusions induce senescence, high expression of senescence-associated secretory proteins (SASPs) and activation of pro-survival signals (pAKT, BIRC3 and Bcl-xL) in MNGCs. Importantly, following transient non-proliferation, MNGCs escape senescence and despite having multiple spindle poles during mitosis, they overcome mitotic catastrophe to undergo normal cytokinesis forming mononucleated relapse population. This is the first report showing radiation-induced homotypic cell fusions as novel non-genetic mechanism in radiation-resistant cells to sustain survival. These data also underscore the importance of non-proliferative phase in resistant glioma cells. Accordingly, we show that pushing resistant cells into premature mitosis by Wee1 kinase inhibitor prevents pCdk1(Y15)-mediated cell cycle arrest and relapse. Taken together, our data provide novel molecular insights into a multistep process of radiation survival and relapse in GBM that can be exploited for therapeutic interventions.