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Persisting residual masses at treatment completion are known in rhabdomyosarcoma (RMS) treated with definitive radiotherapy (RT) to the primary site, but their prognostic significance is uncertain. Tumor response as assessed by anatomic imaging is not prognostic and studies based on 18F-FDG-PET response are limited. We report the prognostic significance of persistent FDG-avidity in residual masses, assessed 3-month postdefinitive RT, in pediatric RMS.Children aged 15 years or below with Group III/IV RMS who received only definitive radiotherapy for local control from June 2013 to December 2018, and had 18F-FDG-PET CT at 3 months post-RT were retrospectively analyzed for outcomes and other prognostic factors.Sixty-three children were eligible (Group III-55, Group IV-8). 18F-FDG-PET CT scan done 3 months postradiotherapy showed FDG-avid residual masses in 10 patients (15.9%), anatomic residual in 24 (38.1%), and no anatomic/FDG-avid residual in 29(46.0%). At a median follow-up of 38 months (interquartile range, 24 to 55 mo), 3-year EFS of patients with FDG-avid residual masses was 40.0% (95% CI: 18.7% to 85.5%) versus the rest of the cohort, which was 71.9% (95% CI: 59.8% to 86.5%) (P=0.008). Three-year OS of patients with FDG-avid residual masses was 50.8% (95% CI: 25.7% to 100.0%) versus the rest of the cohort, which was 77.0% (95% CI: 65.1% to 91.0%) (P=0.037). Presence of FDG-avid residual disease persisting post-RT affected both EFS [HR-3.34 (95% CI: 1.29 to 8.68) (P=0.013)] and OS [HR-3.20 (95% CI: 1.01 to 10.12) (P=0.048)] on univariate analysis and this significance was retained for EFS in multivariate analysis [HR-3.52 (95% CI: 1.33 to 9.30) (P=0.011)].Persistent metabolic activity in residual disease post-chemoradiotherapy in RMS may portend a poorer prognosis with an increased risk of relapse. This subset of high-risk patients needs to be identified, and further trials are warranted to develop strategies to improve their outcomes.

BACKGROUND: Diagnosis of MALT lymphoma in the oral cavity is challenging. There is a great overlap in the histopathologic, immuno-histochemical and molecular features of MALT lymphoma with reactive lymphoid proliferations. The literature shows a very few case reports of primary MALT lymphoma of oral cavity. METHODS: We discuss the histopathologic, immuno-histochemical, cytogenetic features, treatment and behavior of 3 cases of primary MALT lymphoma oral cavity along with review of literature. RESULTS: The age ranged from 40 to 57 years (male to female ratio = 2:1). The sites involved were hard palate, bilateral gingivobuccal sulcus and right buccal mucosa. The most common histology was centrocyte-like (2 cases). Lymphoepithelial lesions were absent. On immunohistochemistry, all tumors showed diffuse strong CD20 and bcl2 expression with strong and diffuse MNDA staining in one case. IgH; MALT1 translocation was not seen in any of these cases. One patient received local radiotherapy, one received steroids; while the case 3 received RCHOP (Rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine and prednisone) chemotherapy. Two patients had complete remission while one had recurrence. CONCLUSION: MALT lymphoma of oral cavity shows a wide spectrum of morphology with presence of transformed cells, that may lead to misdiagnosis of DLBL. Treatment guidelines are not well established but a tendency to excise MALT lymphomas of oral cavity has been observed. Nevertheless, MALT lymphoma of oral cavity appears to be an indolent disease.

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.

Supplementary table S1: Follow-up patient's clinical details

To evaluate the efficacy and toxicity of dose-escalated image guided-intensity modulated radiation therapy (IG-IMRT) in osteosarcoma (OGS), chondrosarcoma (CS) and chordoma (CH) of head and neck (HN) and pelvis.In this prospective non-randomized study, 65 patients of HN or pelvic OGS (24), CS (7) and CH (34) mandating definitive or post-operative radiotherapy from May 2013 to December 2018 were included. Radiotherapy doses in definitive setting were 72.0 Gy for CH and 70.2 Gy for OGS and CS; while in post-operative setting it was 66.6 Gy and 64.8 Gy respectively (at 1.8 Gy per fraction).Planned doses of radiotherapy could be completed in 61 (93.8%) patients; with grade III or higher acute and late toxicities of 3% and 0% respectively. With a median follow-up of 52 (range 6-92) months, the five-year actuarial local control (LC) rates were 66% in OGS, 38.1% in CS and 75.9% in CH; while cause-specific survival (CSS) rates were 54.7%, 64.3% and 92.2% respectively. There was no statistically significant difference in outcomes for patients receiving definitive and post-operative radiotherapy. Locally controlled disease at first follow-up after radiotherapy was associated with improved CSS and OS in CS (p = 0.014) and CH (p 0.001). Radiotherapy resulted in significant and sustained improvement in Musculoskeletal tumour society (MSTS) score and reduction in pain score. Salvage re-irradiation was feasible in local progression after radiotherapy, with good outcomes and tolerability.Dose-escalated IG-IMRT results in good LCfunctional improvement with minimal toxicity in OGS, CS and CH.

Purpose: About 30%–35% of nonmetastatic and 60%–80% of metastatic Ewing Sarcoma (ES) will relapse post-treatment and outcomes after relapse continue to be poor over last several decades. Prognostic...

The purpose of this single-center study was to analyze the outcomes of extracranial germ cell tumors (GCTs) in children treated on a multimodality regimen.Retrospective study of children (18 years) with a histopathologically confirmed diagnosis of extracranial GCT over a period of 10 years (January 2009 to December 2018) treated on a uniform institution-based protocol consisting of both cisplatin- and carboplatin-based regimens. All completely excised teratomas and stage I gonadal tumors received no further therapy (low risk [LR]); stage IV ovarian, stage III-IV extragonadal GCTs received six cycles of chemotherapy (high risk [HR]), and the remaining received four cycles of chemotherapy (intermediate risk [IR]).A total of 297 children were treated with a female:male ratio of 1.72:1 and median age of 4 years. Forty-three children had pure teratomas. Gonadal GCTs (N = 180) were more common than extragonadal GCTs (N = 117) with ovary as primary site in 128 children (43%) and sacrococcygeal site being the commonest extragonadal location (N = 41; 14%). LR, IR, and HR disease were noted in 60 (20.2%), 125 (42%), and 112 (37.8%) patients, respectively. Three-fourths of ovarian tumors and half of testicular tumors operated prior to presentation needed upstaging. Forty-one patients relapsed and 43 children expired (disease-related: 33; toxic deaths: 9; unknown: 1). The 5-year event-free survival (EFS)/overall survival (OS) of malignant GCT (n = 254) was 72.50%/82.70%, respectively, with gonadal site (p = .001), LR and IR (p = .001) and nonmetastatic disease (p = .001) being favorable prognostic variables.The LR and IR GCTs in our cohort had an excellent outcome. A significant proportion of IR gonadal GCTs can be spared of systemic chemotherapy by adhering to strict surgical guidelines. In HR GCTs however, intensifying therapies to improve outcomes must be balanced against the risk of cumulative toxicity, more so in a resource-limited setting.

Background Outcome and toxicity data in adolescent-adult Ewing’s Sarcoma (AA-ES) patients is sparse and merits exploration. Methods Histopathologically confirmed, non-metastatic AA- ES patients, who received standard institutional combination chemotherapy regimen (EFT-2001) comprising of ifosfamide plus etoposide and vincristine, doxorubicin, plus cyclophosphamide, lasting a total of 12 months between 2013 and 2018, were analyzed for treatment-related toxicities, event-free survival (EFS) and overall survival (OS). Results There were 235 patients (primary safety cohort, PSC) with median age of 23 (15-61) years; 159(67.7%) were males, 155 (65.9%) had skeletal primary and 114(48.5%) had extremity tumors. 196(83.4%) were treatment naïve (primary efficacy cohort, PEC) and of these 119 (60.7%) had surgery. In PEC, at a median follow up of 36.4 (IQR 20 – 55) months, estimated 5 year EFS and OS were 60.9% (95% CI 53.1% - 69.9%) and 84.5% (95% CI 77.7% - 91.9%) respectively. Of these, 158 (80.6%) complying with intended treatment, at a median follow up of 39 (IQR 26- 57) months had an estimated 5 year EFS of 63.1% (95% CI 54.8%-72.6%). In multivariable analysis good prognostic factors included, longer symptom(s) duration (HR=0.93, 95% CI 0.86-0.994), ≥ 99% necrosis (HR=0.30, 95% CI 0.11-0.77) and treatment completion (HR=0.32, 95% CI 0.14-0.74). Among PSC, grade 3-4 toxicities were febrile-neutropenia (119, 50.6%), anemia (130,55.3%), peripheral neuropathy (37,15.7%), with 3(1.3%) chemo-toxic deaths . Conclusions The outcomes of AA non-metastatic ES patients treated with EFT-2001 regimen were comparable to those reported by others, with acceptable toxicity. This regimen could be considered a standard-of-care in AA-ES.

Treatment of Diffuse Large B-Cell Lymphoma (DLBCL) in the elderly aims to achieve disease remission while minimizing treatment-related toxicities. The use of anthracycline in the elderly is associated with increased risk of cardiotoxicity and myelosuppression. Non-anthracycline-based regimens have commonly been used in patients with cardiac contraindications or anticipated severe toxicities to anthracyclines.We retrospectively analyzed the treatment outcomes of patients, aged 60 years and above, newly diagnosed with DLBCL at our center. Of a total of 218 patients, 71 patients received the R-CHOP regimen (Rituximab, Cyclophosphamide, Doxorubicin, Vincristine and Prednisolone) and 137 received R-CE (Etoposide) OP chemotherapy. The decision to substitute etoposide for doxorubicin was based on physician's discretion depending on the performance status, cardiac comorbidities and frailty as well as available resources for supportive care.The 2-year progression-free survival (PFS) rate in the R-CHOP group was higher than that in the R-CEOP group (79.1% vs 49.6%, P-value.001) and this superiority of R-CHOP was seen in both early and advanced disease. The incidence of febrile neutropenia and grade III/IV hematological toxicities was significantly higher in the R-CHOP group in the age group of 60 to 65 years'. ECOG PS at presentation, NCCN-IPI and the chemotherapy regimen were found to be significant factors for 2-year PFS rate by multivariate analysis.Anthracycline-based regimen should be used in elderly fit patients without absolute cardiac contraindications wherever feasible with adequate access to supportive care.

The data on outcomes and toxicity in adult Ewing sarcoma (ES) patients, particularly those aged ≥40 years, is exceedingly scarce around the world, particularly in low- and middle-income countries (LMICs) and mandates research.The study involved histologically ascertained ES patients aged ≥40 years who registered at our institute from 2013 to 2018. Prospectively collected data were analysed for overall survival (OS), event-free survival (EFS) and chemotherapy-related toxicities.There were 66 patients, of which 34 were non-metastatic, and 32 were denovo metastatic, recurrent or had doubtful metastasis. At presentation, median age was 46 years, and 42 (63.6%) had extra-skeletal primary and 24 (36.3%) had extremity tumours. Curative treatment was offered to 40 (60.6%) patients. Significant grade 3/4 toxicities in non-metastatic and metastatic cohort, respectively, were febrile neutropenia (61.3%, 37.5%), anaemia (58.1%, 37.5%), thrombocytopenia (45.2%, 25.0%), peripheral neuropathy (25.8%, 12.5%) and dyselectrolytemia (25.8%, 6.25%). Chemotherapy-related toxicity led to death in three patients in the metastatic cohort, versus none in the non-metastatic patients. The 5 year EFS and OS for non-metastatic cohort were 53.8% and 67.8%, while the same for metastatic cohort were 20.7% and 27.5%, respectively. On multivariate analysis, Eastern Cooperative Oncology Group-performance status2 and metastasis at presentation predicted poorer EFS and OS. Additionally, raised lactate dehydrogenase, larger tumours (8 cm) and palliative intent treatment predicted worse EFS, while extra-skeletal primary and female gender were indicators of worse OS.Older adult ES patients benefit from aggressive multimodality treatment even in LMIC infrastructure. However, careful patient selection, close monitoring and pertinent dose modifications is imperative due to higher propensity for potential toxicities.

Giant cell tumors of sacrum in which surgery could endanger important neural components were treated with short term denosumab, angioembolisation and radiotherapy in different combinations to provide a non-operative function preserving treatment option. Between April 2013 and April 2017, 13 sacral GCTs [proximal extent of disease—S1 (10), S2 (2) and S3 (1)] were treated. Age ranged from 20 to 50 years. One patient had loss of bladder control at presentation. Treatment protocol included short term denosumab, angioembolisation and radiotherapy in different combinations. Patients were evaluated every 10–12 weeks. If disease ceased to progress no further treatment was advised. In case of progress, patient was advised additional denosumab and/or angioembolisation and/or radiotherapy till disease stopped progressing. 10 patients have non-progressive disease and are asymptomatic, 2 have non-progressive disease with occasional pain, 1 patient died. Follow-up duration (since final non-progression of disease) ranged from 15 to 54 months (mean 31 months). Total number of angio embolisation sessions ranged from 0 to 12 (mean = 4), total number of denosumab doses ranged from 5 to 16 (mean = 9). Five patients did not receive any radiotherapy, 5 received 50.4 Gy and one patient each received 50.4 + 30 + 12 Gy, 50.4 + 30 Gy and 50.4 + 12 Gy. The patient with loss of bladder control at presentation recovered. There were no other long-term complications. This study offers a non-surgical management option that provides good mid-term local control while preserving neurological function in these complex lesions.

Pediatric B-cell lymphoblastic lymphoma (LBL) is a rare entity, and appropriate treatment for pediatric B-cell LBL is not well defined. While intensive ALL type regimens achieve long term survival of 90% across Western co-operative group trials, published data from Asian studies on long term outcomes are scarce. We retrospectively analyzed the data of pediatric B-cell LBL patients treated between January 2010 and December 2017 on a uniform protocol (modified BFM 90). Kaplan-Meier method was used to estimate the survival and Cox regression models to identify prognostic factors. Of 21 patients who received treatment on the modified BFM-90 protocol, 17(81%) were alive in remission, 3(14%) had relapse, and 1(4%) had treatment-related mortality (TRM) while in remission. Two of 3 relapsed patients subsequently expired. With a median follow-up of 66 months (range 6–114), 5-year event free survival (EFS) and overall survival (OS) were 80% (95% CI:71–89%) and 91% (95% CI:85–97%), respectively. While delayed presentation from symptom onset (p=0.030), and partial response at early (D35) interim assessment (p=0.025) had inferior EFS, patients with elevated baseline LDH had a worse OS (p=0.037). Outcomes of pediatric B-cell LBL patients treated on a modified BFM-90 protocol at a single center in India were excellent. In our study, higher disease burden manifested by elevated baseline LDH and delayed presentation (≥3months) and partial interim response portend poorer survival. Supplemental data for this article is available online at https://doi.org/10.1080/08880018.2021.2005725

Introduction: Vascular endothelial growth factor (VEGF)is an angiogenic marker and implicated in carcinogenesis and prognostication of cancers. However its prognostic potential in a rare cancer-Ewing’s sarcoma merits exploration. Methods: Histopathologically confirmed consecutive ES cases registered at our institute from 2014 to 2018 were analysed. Immunohistochemical staining for VEGF was performed on tumour tissues and they were further classified based on VEGF intensity. Results: There were 105 patients including 53 non-metastatic and 52 metastatic. VEGF immunostaining in non-metastatic and metastatic cohort was negative in 20 (37.7%) and 21 (40.4%), mildly positive in 13 (24.5%) and 9 (17.3%) cases, moderately positive in 14 (26.4%) and 16 (30.8%), and was intensely positive in 6 (11.3%) and 7 (13.5%) patients, respectively. VEGF immunoexpression up to 25% was seen in 14 (13.3%) and 10 (9.5%) patients within the non-metastatic and metastatic cohort, respectively. The median EFS and OS for the entire cohort were 26.4 (95% CI 17.6-NA) and 32.5 (21.3-NA) months, respectively. Metaststatic ES patients having either VEGF immunostaining in >25% tumor cells or moderate /strong immunostaining were found to inferior EFS and OS [p= 0.017, HR-0.153; p=0.013, HR-0.109 respectively].Additionally, treatment-naïve, compliant and non-metastatic patients had superior EFS (p=0.000, 0.000, 0.020, 0.022 respectively) and OS (p=0.000, 0.000, 0.006, 0.041 respectively). Conclusion: VEGF expression and intensity were found as independent negative prognostic marker in Ewing sarcoma .This may translate to therapeutic relevance but needs validation in the subsequent, larger prospective studies.

Our aim was to assess the effect of radiation therapy (RT) dose escalation on outcomes in surgically unresectable Ewing sarcoma (ES)/primitive neuroectodermal tumor (PNET).Patients with nonmetastatic unresectable ES/PNET (excluding intracranial/chest wall) receiving vincristine, doxorubicin, cyclophosphamide, ifosfamide, and etoposide chemotherapy, planned for definitive RT, were accrued in this single-institution, open-label, phase 3 randomized controlled trial. Randomization was between standard dose RT (SDRT; 55.8 Gy/31 fractions/5 days a week) versus escalated dose RT (EDRT; 70.2 Gy/39 fractions/5 days a week) with a primary objective of improving local control (LC) by 17% (65%-82%). Secondary outcomes included disease-free survival (DFS), overall survival (OS), and functional outcomes by Musculoskeletal Tumor Society score.Between April 2005 and December 2015, 95 patients (SDRT 47 and EDRT 48) with a median age of 17 years (interquartile range, 13-23 years) were accrued. The majority of patients were male (59%). Pelvis was the most common site of primary disease (n = 60; 63%). The median largest tumor dimension (9.7 cm) and the median maximum standardized uptake value (8.2) on pretreatment fluorodeoxyglucose positron emission tomography-computed tomography were similar. At a median follow-up of 67 months, the 5-year LC, DFS, and OS for the entire cohort was 62.4%, 41.3%, and 51.9%, respectively. The 5-year LC was significantly better in EDRT compared with SDRT (76.4% vs 49.4%; P = .02). The differences in DFS and OS at 5 years (for EDRT vs SDRT) did not achieve statistical significance (DFS 46.7% vs 31.8%; P = .22 and OS 58.8% vs 45.4%; P = .08). There was a higher incidence of Radiation Therapy Oncology Group grade2 skin toxic effects (acute) in the EDRT arm (10.4% vs 2.1%; P = .08) with excellent functional outcomes (median Musculoskeletal Tumor Society score = 29) in both arms.EDRT results in improved LC with good functional outcomes without a significant increase in toxic effects. Radiation dose escalation should be considered for surgically unresectable nonmetastatic ES/PNET.

Objectives Ewing’s sarcoma is best treated using a multidisciplinary approach. We discuss the functional and oncological outcomes of clavicular Ewing’s sarcoma which has been sparsely reported in literature. Materials and Methods We retrospectively evaluated patients who underwent resections for Ewing’s sarcoma of clavicle from January 2002 to December 2017. The study end points were locoregional recurrence free survival (LRFS), disease-free survival (DFS), and overall survival (OS) at 3 and 5 years, and functional outcomes measured by Musculoskeletal Tumor Society (MSTS) scores. Statistical Analysis The LRFS, DFS, and OS were calculated and analyzed using the Kaplan–Meier method and log-rank test. Results Data of 21 patients (male: 12, female: 9) was analyzed with a mean age [range] of 15.3 [6–40] years. Total clavicle excision was done in 62% (13 of 21) while 38% (n = 8) had partial resections. Radiotherapy was administered in 15 patients (71.5%). At a median follow-up of 42 months (range: 7–198), data of 20 patients was available for follow-up. Ten patients died (due to disease: nine, other reasons: One), eight are disease free and alive, one had metastasectomy on recurrence and is disease free and, one patient is alive with disease and on palliative chemotherapy. The LRFS, DFS, and OS were 95, 59, 65% and 95, 47, 59% at 3 and 5 years, respectively. The functional evaluation done for nine patients who are free of disease showed a mean MSTS score of 29 (range: 27–30; total clavicle excision: 28.5, partial clavicle excision: 29.5). Conclusion Patients with Ewing’s sarcoma of the clavicle who underwent resection without reconstruction have acceptable local control rates and excellent functional outcomes.

Adamantinoma-like Ewing sarcoma (ALES) is a rare malignant tumor characterized by EWSR1::FLI1 related fusions and complex epithelial differentiation. ALES poses a tremendous diagnostic challenge owing to its resemblance to a wide variety of common head and neck malignancies. We aimed to study the clinicopathologic spectrum of ALES diagnosed at our institute. A retrospective review of the clinical and pathologic features of all EWSR1-rearranged ALES cases was performed after confirming the diagnosis. The cases lacking EWSR1 rearrangement were excluded. A total of 7 patients were analyzed. The median age was 27 years (range 7–42 years). There were 4 males and 3 female patients. Tumors were distributed as follows: maxilla (n = 2), parotid (n = 2), nasal cavity (n = 1), ethmoid/maxilla (n = 1), and thyroid (n = 1). Tumor size ranged from 2.2 to 5.5 cm. On microscopy, tumors displayed nested-lobular architecture, monomorphic cells, and interlobular fibrotic stroma. Other features included: palisading (n = 5), squamous differentiation (n = 2), keratinization (n = 1), colonisation of salivary ducts (n = 1) and thyroid follicles (n = 1), follicle-like cysts (n = 3), calcification (n = 2), necrosis (n = 3). Mitotic rate was 4–15/2 mm(2). On immunohistochemistry, cytokeratins (100%), p40 (100%), strong/diffuse membranous CD99 (100%), NKX2.2 (100%), Fli-1 (71%), and synaptophysin (71%) was positive. Patients received chemotherapy (n = 7) and radiotherapy (n = 4). Two patients developed recurrence at 6 and 10 months; 3 developed metastases at 0, 6, and 25 months. ALES is a rare and aggressive malignancy that mimics diverse neoplasms common in the head and neck region. Awareness of the morphologic and immunohistochemistry spectrum of this tumor is essential to avoid diagnostic errors. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s12105-022-01412-1.

Amongst the scientific frameworks powered by the Monte Carlo (MC) toolkit Geant4 (Agostinelli et al., 2003), the TOPAS (Tool for Particle Simulation) (Perl et al., 2012) is one. TOPAS focuses on providing ease of use, and has significant implementation in the radiation oncology space at present. TOPAS functionality extends across the full capacity of Geant4, is freely available to non-profit users, and is being extended into radiobiology via TOPAS-nBIO (Ramos-Mendez et al., 2018). A current "grand problem" in cancer therapy is to convert the dose of treatment from physical dose to biological dose, optimized ultimately to the individual context of administration of treatment. Biology MC calculations are some of the most complex and require significant computational resources. In order to enhance TOPAS's ability to become a critical tool to explore the definition and application of biological dose in radiation therapy, we chose to explore the use of Field Programmable Gate Array (FPGA) chips to speedup the Geant4 calculations at the heart of TOPAS, because this approach called "Reconfigurable Computing" (RC), has proven able to produce significant (around 90x) (Sajish et al., 2012) speed increases in scientific computing. Here, we describe initial steps to port Geant4 and TOPAS to be used on FPGA. We provide performance analysis of the current TOPAS/Geant4 code from an RC implementation perspective. Baseline benchmarks are presented. Achievable performance figures of the subsections of the code on optimal hardware are presented; Aspects of practical implementation of "Monte Carlo on a chip" are also discussed.

BackgroundTreatment of malignant melanoma has undergone a paradigm shift with the advent of immune checkpoint inhibitors (ICI) and targeted therapies. However, access to ICI is limited in low-middle income countries (LMICs).Patients and MethodsHistologically confirmed malignant melanoma cases registered from 2013 to 2019 were analysed for pattern of care, safety, and efficacy of systemic therapies (ST).ResultsThere were 659 patients with a median age of 53 (range 44–63) years; 58.9% were males; 55.2% were mucosal melanomas. Most common primary sites were extremities (36.6%) and anorectum (31.4%). Nearly 10.8% of the metastatic cohort were BRAF mutated. Among 368 non-metastatic patients (172 prior treated, 185 de novo, and 11 unresectable), with a median follow-up of 26 months (0–83 months), median EFS and OS were 29.5 (95% CI: 22–40) and 33.3 (95% CI: 29.5–41.2) months, respectively. In the metastatic cohort, with a median follow up of 24 (0–85) months, the median EFS for BSC was 3.1 (95% CI 1.9–4.8) months versus 3.98 (95% CI 3.2–4.7) months with any ST (HR: 0.69, 95% CI: 0.52–0.92; P = 0.011). The median OS was 3.9 (95% CI 3.3–6.4) months for BSC alone versus 12.0 (95% CI 10.5–15.1) months in any ST (HR: 0.38, 95% CI: 0.28–0.50; P < 0.001). The disease control rate was 51.55%. Commonest grade 3–4 toxicity was anemia with chemotherapy (9.5%) and ICI (8.8%). In multivariate analysis, any ST received had a better prognostic impact in the metastatic cohort.ConclusionsLarge real-world data reflects the treatment patterns adopted in LMIC for melanomas and poor access to expensive, standard of care therapies. Other systemic therapies provide meaningful clinical benefit and are worth exploring especially when the standard therapies are challenging to administer.

Radiation therapy (RT) to the head and neck (HN) region is critical in the management of various pediatric malignancies; however, it may result in late toxicity. This comprehensive review from the Pediatric Normal Tissue Effects in the Clinic (PENTEC) initiative focused on salivary dysfunction and dental abnormalities in survivors who received RT to the HN region as children.This systematic review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) method.Of the 2,164 articles identified through a literature search, 40 were included in a qualitative synthesis and 3 were included in a quantitative synthesis. The dose-toxicity data regarding salivary function demonstrate that a mean parotid dose of 35 to 40 Gy is associated with a risk of acute and chronic grade ≥2 xerostomia of approximately 32% and 13% to 32%, respectively, in patients treated with chemo-radiation therapy. This risk increases with parotid dose; however, rates of xerostomia after lower dose exposure have not been reported. Dental developmental abnormalities are common after RT to the oral cavity. Risk factors include higher radiation dose to the developing teeth and younger age at RT.This PENTEC task force considers adoption of salivary gland dose constraints from the adult experience to be a reasonable strategy until more data specific to children become available; thus, we recommend limiting the parotid mean dose to ≤26 Gy. The minimum toxic dose for dental developmental abnormalities is unknown, suggesting that the dose to the teeth should be kept as low as possible particularly in younger patients, with special effort to keep doses20 Gy in patients4 years old.

Background Outcome and toxicity data in adolescent-adult Ewing sarcoma (AA-ES) patients are sparse and merits exploration. Methods Histopathologically confirmed, nonmetastatic AA-ES patients, who received standard institutional combination chemotherapy regimen (Ewing's family of tumors-2001 [EFT-2001]) comprising of ifosfamide plus etoposide and vincristine, doxorubicin plus cyclophosphamide, lasting a total of 12 months between 2013 and 2018, were analyzed for treatment-related toxicities, event-free survival (EFS), and overall survival (OS). Results There were 235 patients (primary safety cohort [PSC]) with median age of 23 (15-61) years; 159 (67.7%) were males, 155 (65.9%) had skeletal primary and 114 (48.5%) had extremity tumors. One hundred ninety-six (83.4%) were treatment naive (primary efficacy cohort [PEC]) and of these 119 (60.7%) had surgery. In PEC, at a median follow-up of 36.4 (interquartile range [IQR] 20-55) months, estimated 3-year EFS and OS were 67.3% (95% CI 60.3-75.1%) and 91.1% (95% CI 86.7-95.7%), respectively. Of these, 158 (80.6%) complying with intended treatment, at a median follow-up of 39 (IQR 26-57) months had an estimated 3-year EFS of 68.2% (95% CI 60.3-76.1%). In multivariable analysis, good prognostic factors included longer symptom(s) duration (HR 0.93, 95% CI 0.86-0.994), ≥99% necrosis (HR 0.30, 95% CI 0.11-0.77), and treatment completion (HR 0.32, 95% CI 0.14-0.74). Among PSC, grade 3-4 toxicities were febrile neutropenia (119, 50.6%), anemia (130, 55.3%), peripheral neuropathy (37, 15.7%), with three (1.3%) chemo-toxic deaths. Conclusions The outcomes of AA nonmetastatic ES patients treated with EFT-2001 regimen were comparable to those reported by others, with acceptable toxicity. This regimen can be considered a standard of care in AA-ES.

Background Outcomes of Ewing sarcoma (ES) in low and middle income countries lags behind the rest of the world owing to multiple tumoral, logistical and socio-economic factors. The data of outcomes and toxicity in these countries is sparse, especially in the adolescent and adult (AA) population and merits exploration Procedure This was a retrospective analysis of prospectively collected data of non-metastatic AA-ES patients, who received standard institutional combination chemotherapy regimen (EFT-2001) along with surgery or definitive radiotherapy. Various cohorts were analyzed for treatment-related toxicities, event- free survival (EFS) and overall survival (OS). Results There were 235 patients (primary safety cohort, PSC) with median age of 23 years. One hundred and ninety six were treatment naïve (primary efficacy cohort, PEC) and of these 119 had surgery. In PEC, at a median follow up of 36.4 months, estimated 5 year EFS and OS were 60.9% (95% CI 53.1% - 69.9%) and 84.5% (95% CI 77.7% - 91.9%), respectively. Of these, 158 complying with intended treatment, had an estimated 5 year EFS of 63.1% (95% CI 54.8%-72.6%). In multivariate analysis, good prognostic factors included longer symptom duration, ≥ 99% necrosis and treatment completion. Among PSC, grade 3-4 toxicities were febrile-neutropenia (50.6%), anemia (55.3%), peripheral neuropathy (15.7%), with 3 (1.3%) chemo-toxic deaths. Conclusions The outcomes of AA non-metastatic ES patients treated with EFT-2001 regimen were comparable to those reported by others, with acceptable toxicity and can be considered as standard-of-care, especially in LMICs.

Background: Pediatric B-Lymphoblastic lymphoma(pB-LBL) is a rare entity, and appropriate treatment for pB-LBL is not well defined. While intensive Acute Lymphoblastic leukemia(ALL) type regimens achieve long term event free survival of 90% across western co-operative group trials, published data from Asian studies on long term outcomes in pB-LBL are scarce. We evaluated the outcomes and prognostic factors of pediatric B-LBL patients treated at our center. Methods: We retrospectively analyzed the data of pediatric B-LBL patients treated between January 2010 and December 2017 on a uniform protocol(modified BFM 90). Patients were evaluated for early response post-induction and monitored for toxicity and long term outcomes. Kaplan-Meier method was used to estimate the event free survival(EFS) and overall survival(OS). Cox regression models were performed to identify prognostic factors. Results: Of 21 patients who received treatment on the modified BFM 90 protocol, 17(81%) were alive in remission, 3(14%) had relapse, and 1(4%) had treatment-related mortality(TRM) while in remission. Two of 3 relapsed patients subsequently expired. With a median follow-up of 66 months(range 6–114), 5-year Event free survival(EFS) and overall survival(OS) were 80%(95% CI:71–89%) and 91% (95% CI:85–97%), respectively. While delayed presentation (≥3 months) had inferior EFS(p-0.030), patients with elevated baseline Lactate Dehydrogenase(LDH) had a worse OS(p-0.037). Age, gender, site of origin, stage, and post-induction response had no bearing on outcome. Conclusions: Outcomes of pB-LBL patients treated on modified BFM 90 protocol are excellent. Higher disease burden manifested by elevated baseline LDH and delayed presentation(≥3 months) portend poorer survival.

Purpose: There is lack of consensus on management of adolescent and young adult (AYA) Hodgkin lymphoma with respect to chemotherapy approach (adult or pediatric). Hence we sought to evaluate the efficacy and safety of Adriamycin, Bleomycin, Vinblastine and Dacarbazine (ABVD) chemotherapy in AYA Hodgkin lymphoma. Patients and Methods: It is a retrospective, observational, single-center study. From January 2013 to December 2016, all consecutive patients with AYA (15-25 years, all stages) were analyzed. The primary endpoint of the study was event-free survival (EFS). Secondary endpoints were complete response rates (CR) and overall survival (OS). Results: A total of 220 patients (70% men) with median age 20 years were evaluated. A significant proportion of patients had adverse features such as stage III/IV disease (63%), bulky disease (63%), extranodal involvement (37%), and marrow involvement (22%). After two cycles and end of therapy, 77% patients achieved complete response. Primary progressive disease was seen in 6% patients. With a median follow-up of 2.6 years, 19 (8.6%) patients relapsed, 1 patient developed second malignancy, and 6 patients died. Three-year EFS and OS were 81.3% and 97%, respectively. Bleomycin-induced lung injury was seen in 16% patients. On multivariate analysis stage at presentation, bone marrow involvement, partial response at interim positron emission tomography and International prognosis score (IPS) >3 were predictors of poor EFS. Conclusion: ABVD is an effective and safe regimen in AYA Hodgkin lymphoma. Advanced disease with high IPS (>3) score needs an early escalation approach to escBEACOPP regimen.

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 (

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.

To analyze clinicopathological features, including treatment profile of 34 cases of Ewing sarcomas with epithelial differentiation, including 6 cases with adamantinoma-like features. EWSR1 gene rearrangement was tested by fluorescence in-situ hybridization. Thirty-four tumors occurred in 19 males and 15 females (M:F = 1.26:1), with age ranging from 7 to 61 years (average = 24.2); in extremities (17), pelvis (5), paraspinal region (6), head and neck region (3), abdomen (2) and lung (1). Prior to molecular testing, 20/34(58.8%) cases were unequivocally diagnosed as Ewing sarcomas. Histopathologically, the most commonly observed pattern was nesting-type, comprising malignant round cells, including adamantinoma-like features, seen in 6 tumors. Immunohistochemically, tumor cells were diffusely positive (cytoplasmic membranous staining) for CD99/MIC2 (34/34), Fli1 (30/30); focally for synaptophysin (4/16) (25%); variably positive for AE1/AE3(31/32)(96.8%), including diffuse immunoexpression in 4 cases; EMA(6/8) and p40(3/8). All 34 (100%) tumors, tested for EWSR1 rearrangement, displayed positive results. According to the treatment details (available in 24/34 cases, 70.5%), most patients (13/24)(54.1%) were treated with surgical resection and a specific chemotherapy(CT) regimen (neoadjuvant or adjuvant settings), including 7 patients, who received adjuvant radiotherapy. During follow-up (16 cases, 47%), 5 patients developed recurrences and 8 developed metastasis, including a single, who developed recurrence. Finally, 10 patients were alive-with-disease (2–22 months); 6 free-of-disease (5–36 months). This constitutes one of the largest documentation of these rare tumors from our subcontinent, which are diagnostically challenging; require molecular confirmation and associated with treatment implications.

The present study was aimed at evaluating clinicopathologic and immunohistochemical (IHC) features of 300 rhabdomyosarcomas (RMSs), including differential IHC expression and prognostic value of myogenin and MyoD1 across various subtypes of RMSs. IHC expression of myogenin and MyoD1 was graded on the basis of percentage of tumor cells displaying positive intranuclear immunostaining i.e. grade 1 (1-25%); grade 2 (26-50%); grade 3 (51-76%) and grade 4 (76-100%).Clinical follow-up was available in 238 (79.3%) patients. Various clinicopathologic parameters were correlated with 3-year disease free survival (DFS) and overall survival (OS). There were 140 cases (46.7%) of alveolar RMS (ARMS), 90 of embryonal RMS (ERMS) (30%), 61 (20.3%) of spindle cell/sclerosing RMS and 9 cases (3%) of pleomorphic RMS. Most cases, barring pleomorphic RMSs, occurred in the first two decades (228 cases) (76%), frequently in males, in the head and neck region (126) (42%). By immunohistochemistry, desmin was positive in 292/299 (97.6%) tumors; myogenin in 238/267 (89.1%) and MyoD1 in 192/266 (72.2%) tumors. High myogenin expression (in ≥51% positive tumor cells) was significantly associated with ARMSs (95/121, 78.5%), as compared to other subtypes (48/117, 41%) (p value 0.001). High MyoD1 expression (≥51% tumor cells) was seen in more cases of pure sclerosing, combined with spindle cell/sclerosing RMSs (10/10, 100%), as compared to the other subtypes (91/141, 67.4%) (p = 0.032). There was no significant difference between high myogenin expression and clinical outcomes. Patients without metastasis and harbouring tumors, measuring ≤5 cm showed a significant increase in OS, with p values = 0.01 and0.001, respectively. ARMS was the most frequent subtype. There was a significant association between high myogenin expression and ARMSs and high MyoD1 expression and spindle cell/sclerosing RMSs. High myogenin expression did not correlate with clinical outcomes. Patients with smaller sized tumors and without metastasis had significantly better clinical outcomes.