Pediatric cancer-associated thrombosis: Analysis from a tertiary care cancer center in India.

BACKGROUND AND AIMS: Thrombotic events (TEs) have been extensively studied in adult cancer patients, but data in children are limited. We prospectively analyzed pediatric cancer-associated thrombosis (PCAT) in children with malignancies. METHODS: Children below 15 years of age with confirmed malignancies, treated at a large tertiary cancer center in India from July 2015 to March 2020 developing any TE were eligible. A standardized approach for detection and management was followed. Data were collected after informed consent. RESULTS: Of 6132 eligible children, 150 (2.44%) had 152 TEs, with median age 8.5 years and male:female of 1.83:1. Most TEs occurred on chemotherapy: 111 (74.0%). The most common site was central nervous system (CNS) 59 (39.3%), followed by upper-limb venous system 37 (24.7%). Hemato-lymphoid (HL) malignancies were more prone to PCAT than solid tumors (ST) (incidence 3.23% vs. 1.58%; odds ratio [OR] = 2.06, 95% confidence interval [CI] [1.36-2.88]; p < .001). Malignancies associated with PCAT were acute lymphoblastic leukemia (ALL) 2.94%, acute myeloid leukemia (AML) 6.66%, and non-Hodgkin lymphomas 5.35%. Response imaging done in 106 (70.7%) children showed complete to partial resolution in almost 90% children. Death was attributable to TE in seven (4.66%) children. Age above 10 years (OR 2.33, 95% CI [1.59-3.41]; p < .001), AML (OR 4.62, 95% CI [1.98-10.74]; p = .0062), and non-Hodgkin lymphoma (OR 4.01, 95% CI [1.15-14.04]; p = .029) were significantly associated with TEs. In ALL, age more than 10 years (OR 1.86, 95% CI [1.06-3.24]; p < .03), T-ALL (OR 3.32, 95% CI [1.69-6.54]; p = .001), and intermediate-risk group (OR 4.97, 95% CI [1.12-22.02]; p = .035) were significantly associated with thrombosis. The 2-year event-free survival (EFS) for HL malignancies with PCAT was 55.3% versus 72.1% in those without PCAT (p = .05), overall survival (OS) being 84.6% versus 80.0% (p = .32). CONCLUSION: Incidence of PCAT was 2.4%, and occurred predominantly in older children with hematolymphoid malignancies early in treatment. Most resolved completely with low molecular weight heparin (LMWH) and mortality was low. In hematolymphoid malignancies, PCAT reduce EFS, highlighting the need for prevention.

Outcomes of relapsed/refractory extracranial germ cell tumors treated on conventional salvage chemotherapy without stem cell rescue: Experience from a tertiary cancer center.

BACKGROUND AND AIMS: Data on the outcome and prognostic indicators in extracranial relapsed/refractory germ cell tumors (rel/ref-GCTs) in children are limited to a few studies. This study looks at remission rates and outcomes of rel/ref-GCTs treated with conventional salvage chemotherapy (SC) regimens without stem cell rescue at a single center in the developing world. METHODS: Patients treated at our center from January 2009 to December 2018 were included. Risk at primary presentation was stratified as all completely excised teratomas and stage I gonadal tumors being low risk (LR); stage IV ovarian, stage III-IV extragonadal GCTs as high risk (HR), and the remaining as intermediate risk (IR). SC regimens were: vinblastine-ifosfamide-cisplatin/carboplatin or paclitaxel-ifosfamide-cisplatin/carboplatin, or cisplatin/carboplatin-etoposide-bleomycin. Local therapy was either surgery and/or radiotherapy. RESULTS: The analyzable cohort comprised 50 patients (44 = rel-GCTs; 6 = ref-GCTs) with a median age of 3.8 years and male:female ratio of 1.27:1. Primary location was ovary in 16 (32%), testicular in 10 (20%), and extragonadal in the rest (48%). Local, metastatic, and combined progression was noted in 28 (56%), 14 (28%), and eight (16%) patients, respectively, at a median time of 8.5 months. At a median follow-up of 60 months, the 5-year event-free survival (EFS) and overall survival (OS) of the entire cohort (n = 50) were 42.4% and 50.0%, respectively. In patients previously exposed to platinum analogs (n = 38), 5-year-EFS and OS were 27.7% and 31.7%, respectively. Local relapses did better when compared to metastatic and combined relapses (5-year EFS: 64% vs. 23% vs. 0%; p = .009). LR and IR tumors did better compared to HR (5-year EFS: 81.5% vs. 49.3% vs. 6.5%; p = .002). Patients with normalization of tumor markers after two cycles had a superior EFS (57.6% vs. 0%; p < .001). Relapsed tumors fared better than primary refractory GCTs (5-year EFS: 48.6% vs. 0%; p < .001). CONCLUSIONS: Primary refractory GCTs, extragonadal rel-GCTs, and rel/ref-GCTs with a poor biochemical response did poorly with conventional SC and need alternative treatment strategies. The rel/ref-testicular GCTs had the best chance of salvage despite a second recurrence (5-year EFS and OS: 28.60% and 42.90%, respectively).

Can 18 F-FDG-Positron Emission Tomography be a Prognostic Tool in Children With Rhabdomyosarcoma Treated With Definitive Radiotherapy?

BACKGROUND: 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 18 F-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. MATERIALS AND METHODS: Children 15 years old or below with Group III/IV RMS who received only definitive radiotherapy for local control from June 2013 to December 2018, and had 18 F-FDG-PET CT at 3 months post-RT were retrospectively analyzed for outcomes and other prognostic factors. RESULTS: Sixty-three children were eligible (Group III-55, Group IV-8). 18 F-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)]. CONCLUSIONS: 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.

Psychological distress in primary caregivers of children with cancer during COVID-19 pandemic-A single tertiary care center experience.

OBJECTIVE: Families of children with cancer undergoing treatment during COVID-19 pandemic represent a vulnerable population for psychological distress and early identification and remedial measures are imperative for wellbeing of both the children and the caregivers. This article reports the results of assessment of psychological distress in primary caregivers of children with cancer undergoing treatment at a tertiary care center. METHODS: Primary caregivers of children with cancer (≤15 years) taking treatment at our institute during the period of July 2020 to August 2020 were prospectively evaluated for psychological distress using Patient Health Questionnaire-9 (PHQ-9) and Generalized Anxiety Disorder-7 (GAD-7) tools over a telephonic call. There were 2 cohorts, A and B (50 participants each) depending on whether child was diagnosed with COVID-19 or not respectively during the study period. RESULTS: The assessment tool, PHQ-9 showed a score of ≥10 in 13% (n = 13) participants (95%CI:7.1%-21.2%) in the entire cohort and in 16% (n = 8, 95%CI:5.8%-26.2%) and 10% (n = 5, 95%CI:1.7%-18.3%) participants in cohort A and cohort B respectively. GAD-7 showed a score of ≥8 in 18% (n = 18) participants (95%CI:11.0%-27.0%) in the entire cohort and in 20% (n = 10, 95%CI:8.9%-31.1%) and 16% (n = 8, 95%CI:5.8%-26.2%) participants in cohort A and cohort B respectively. All participants were assessed, and supportive psychotherapeutic interventions administered over telephonic call. CONCLUSIONS: Primary caregivers should be assessed and followed up for psychological distress irrespective of other co-existing factors. Robust support systems built over time could help withstand the exceptional strain of a major surge during a pandemic.

Outcomes and prognostic variables of extracranial germ cell tumors in children and adolescents treated over a decade: A developing world perspective.

BACKGROUND: 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. METHODS: 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]). RESULTS: 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. CONCLUSIONS: 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.

Safety and efficacy of concurrent carboplatin during full-dose craniospinal irradiation for high-risk/metastatic medulloblastoma in a resource-limited setting.

PURPOSE: To assess the safety and efficacy of concurrent carboplatin during craniospinal irradiation (CSI) in high-risk/metastatic medulloblastoma defined as either residual tumor >1.5 cm2 or leptomeningeal metastases. METHODS: This single-arm combined prospective (2005-2011) and retrospective (2011-2019) study was undertaken at a tertiary care cancer center in India. Following surgery, patients with newly diagnosed high-risk/metastatic medulloblastoma received concurrent carboplatin (35 mg/m2 ) for 15 days (day 1 to day 15) during CSI plus posterior fossa/tumor bed boost, followed by six cycles of standard adjuvant chemotherapy. RESULTS: All 97 patients completed their planned course of radiotherapy without interruptions, except for two (2.1%) patients who had brief gaps due to treatment-related toxicity. Grade 3-4 anemia, neutropenia, thrombocytopenia, and febrile neutropenia were seen in four (4.1%), 41 (42.2%) 21 (21.6%), and 18 (18.6%) patients, necessitating packed cell transfusion, granulocyte colony-stimulating factor, and platelet support in five (5.1%), 41 (42.2%), and five (5.1%) patients, respectively, during the concurrent phase. Following myelorecovery, 92 (94.9%) patients completed the planned six cycles of standard adjuvant systemic chemotherapy. There were no treatment-related deaths during the concurrent chemo-radiotherapy phase, while three (3.1%) toxic deaths were ascribed to adjuvant chemotherapy-related complications. At a median follow-up of 82 months, the 5-year Kaplan-Meier estimates of progression-free survival and overall survival were 60.2% and 62.1%, respectively. On univariate analysis, leptomeningeal metastases (M0/M1 vs. M2/M3) and histological subtype (large cell/anaplastic vs. others) emerged as significant prognostic factors for survival. CONCLUSION: Addition of concurrent carboplatin to RT as radiosensitizing chemotherapy is a simple and effective way of treatment intensification in high-risk/metastatic medulloblastoma.

Efficacy of ready-to-use therapeutic food in malnourished children with cancer: Results of a randomized, open-label phase 3 trial.

BACKGROUND: The adverse influence of undernutrition in children with cancer may be remediated by early nutritional intervention. This study assessed the efficacy of ready-to-use therapeutic food (RUTF) in improving nutritional status and reducing treatment-related toxicities (TRTs) in such children. METHODS: In a randomized controlled phase-3 open-label trial, severely and moderately undernourished children with cancer were randomized 1:1 to receive standard nutritional therapy (SNT) or SNT+RUTF for 6 weeks. The primary outcome (weight gain >10%) and secondary outcomes (improved/maintained nutritional status, improved body composition) were assessed after 6 weeks. TRTs were assessed over 6 months. RESULTS: Between July 2015 and March 2018, 260 subjects were enrolled, 126 were analyzable in both arms at 6 weeks. More children on RUTF had weight gain (98 [77.8%] vs. 81 [64.2%], p = .025) with a greater increase in fat mass as a percentage of body mass (median 2% [IQR -0.12 to 4.9] vs. 0.5% [IQR -1.45 to 2.27, p = .005]) but a greater loss of lean mass (median -1.86% [IQR -4.4 to 0.50] vs. -0.4% [IQR -2.4 to 1.4, p = .007]) compared to the SNT arm. Fewer subjects on the RUTF arm had episodes of severe infection (10.6% vs. 31%, p < .0001), treatment delays (17.7% vs. 39%, p < .0001), and severe mucositis (11% vs. 23.8%, p = .006) compared to the SNT arm. The odds of developing TRTs on the RUTF arm were lower even after adjusting for improvement in nutritional status. CONCLUSIONS: RUTF is efficacious in improving weight gain and nutritional status in undernourished children with cancer and decreases TRTs. Incorporating RUTF into a healthy, balanced diet should be considered in undernourished children with cancer.

Development of paediatric non-stage prognosticator guidelines for population-based cancer registries and updates to the 2014 Toronto Paediatric Cancer Stage Guidelines.

Population-based cancer registries (PBCRs) generate measures of cancer incidence and survival that are essential for cancer surveillance, research, and cancer control strategies. In 2014, the Toronto Paediatric Cancer Stage Guidelines were developed to standardise how PBCRs collect data on the stage at diagnosis for childhood cancer cases. These guidelines have been implemented in multiple jurisdictions worldwide to facilitate international comparative studies of incidence and outcome. Robust stratification by risk also requires data on key non-stage prognosticators (NSPs). Key experts and stakeholders used a modified Delphi approach to establish principles guiding paediatric cancer NSP data collection. With the use of these principles, recommendations were made on which NSPs should be collected for the major malignancies in children. The 2014 Toronto Stage Guidelines were also reviewed and updated where necessary. Wide adoption of the resultant Paediatric NSP Guidelines and updated Toronto Stage Guidelines will enhance the harmonisation and use of childhood cancer data provided by PBCRs.

Outcomes with nondose-dense chemotherapy for Ewing sarcoma: A practical approach for the developing world.

BACKGROUND: The current multidisciplinary approach in the treatment of Ewing sarcoma has improved cure rates, with contemporary dose-dense chemotherapy attaining 5-year event-free survival (EFS) of 73% in localized cases. Dose-intense and dose-dense chemotherapy is difficult in the majority of resource-limited settings with limited access to optimal supportive care. We report on patients with Ewing sarcoma treated on EFT-2001, a nondose-dense chemotherapy protocol. PROCEDURE: A retrospective analysis was conducted of patients (<15 years) with Ewing sarcoma treated with curative intent during January 2013-June 2017 with an institutional ethics committee-approved nondose-dense protocol (EFT-2001). Local therapy was planned after 9-12 weeks of chemotherapy with metastatic sites addressed with radiotherapy. The study assessed outcomes and prognostic factors. RESULTS: We analysed 200 patients with M:F ratio of 1.27:1 and metastases in 41 patients (20.5%). At a median follow up of 41.5 months (range 4.5-81.8 months), respective 3-year EFS and overall survival (OS) of the whole cohort is 65.3% (95% confidence interval [CI]: 58.1-71.7%) and 79.3% (95% CI: 72.8-84.5%); for localized and metastatic cohort, 70.9% (95% CI: 62.9-77.5%) and 82.8% (95% CI: 75.7-89.0%); and for metastatic cohort, 42.8% (95% CI: 28.0-58.6%) and 65.3% (95% CI: 47.7-78.3%). Presence of residual disease (morphologic/metabolic) on positron emission tomography-computed tomography scan done 3 months post definitive radiotherapy (hazard ratio [HR] 7.92 [95% CI: 3.46-18.14]) and delay in any form of local control >4 months (HR 3.42 [95% CI: 1.32-8.89]) affected outcomes. Nonrelapse mortality during treatment was 6.5%, mainly due to cardiomyopathy (3.0%) and bacterial sepsis (1.5%). Cardiotoxicity was seen in 11.5% of patients. CONCLUSIONS: Nondose-dense chemotherapy provides good outcomes with manageable toxicities in a multidisciplinary treatment approach, while reducing cumulative drug exposures in the developing world where dose-intense or dose-dense chemotherapy could potentially increase toxicity, and hence seems a feasible approach in resource-limited settings. Presence of any residual disease post definitive radiotherapy or delay in local control portends poor outcome.

Clinicopathologic, immunohistochemical, molecular cytogenetic profile with treatment and outcomes of 34 cases of Ewing sarcoma with epithelial differentiation, including 6 cases with "Adamantinoma-like" features, diagnosed at a single institution, India.

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.

Pediatric NUT Carcinoma Is a Rare and Challenging Tumor: Single Center Experience of Five Children.

BACKGROUND: Nuclear protein of the testis (NUT) carcinoma is a rare and aggressive malignancy associated with rearrangements of the nuclear protein of the testis (NUT) gene on chromosome 15q14. Because of its rarity, this tumor is often underdiagnosed and underreported, and there is limited literature regarding its biology and optimal management. METHODS AND RESULTS: We report our experience of five patients with pediatric NUT carcinoma, all of whom presented with midline head and neck mass. In spite of aggressive multimodality treatment, only one patient survives. CONCLUSION: NUT carcinoma has a dismal prognosis in spite of aggressive multimodality management (surgery and adjuvant chemotherapy and/or radiation). Novel strategies are required to improve outcomes of patients with this tumor.

Holistic support coupled with prospective tracking reduces abandonment in childhood cancers: A report from India.

BACKGROUND: High cure rates of over 80% in childhood cancers reported from high-income countries (HICs) are not replicated in low- and middle-income countries (LMICs). Treatment abandonment (TxA) is an important reason for this poorer outcome. We assessed the effect of a holistic support group approach coupled with prospective tracking on TxA in children with cancer in a limited-resources environment. METHODS: In 2010, all existing nongovernmental organizations (NGOs) working with childhood cancer at our hospital were brought together to form a pediatric cancer foundation with the aim of providing holistic support to the patient and family, including financial, psychosocial, lodging, educational, and bereavement support. Simultaneously, prospective tracking of all children with a Time-Responsive Electronic Abandonment Tracking (TREAT) system was also established. The impact of these measures on TxA over the 2009-2016 period was compared using the log-rank test. RESULTS: The annual rate of abandonment reduced from 20% in 2009 to 10.4% in 2010 and 5.2% in 2011. It has been consistently between 3% and 6% from 2012 to 2016 (P -0.04). TxA after the initiation of treatment dropped from 9% in 2009 to 1% in 2016 (P -0.02), while refusal to initiate treatment dropped from 11% to 2.7% (P -0.23) over the same period. CONCLUSIONS: A holistic support group consisting of the hospital team, as well as existing NGOs and governmental organizations, along with a systematic and prospective tracking system significantly reduced abandonment in a resource-constrained setting. This cost-effective holistic support group may be applicable in other LMICs with similar healthcare systems.

Customized approach for upfront or delayed resection using radiological criteria in unilateral, nonmetastatic pediatric renal tumors: A prospective study.

BACKGROUND: The availability of robust, equivalent data regarding outcomes for upfront or delayed surgery for renal tumors in children leads to a dilemma in selecting the initial treatment. Imaging criteria associated with the probability of rupture or incomplete resection may provide a more objective assessment for customization for the timing of surgery. PROCEDURE: Eighty-three children with unilateral, nonmetastatic renal tumors were enrolled between January 2012 and April 2018. Upfront nephrectomy was performed in the absence or delayed surgery (after a biopsy and chemotherapy) in the presence of one or more imaging-based high-risk features, including perinephric spread or adjacent organ infiltration, tumors crossing the midline, intravascular thrombus, and extensive adenopathy. Post hoc analysis for interobserver concordance for high-risk imaging features was also performed. RESULTS: The upfront surgery group (19) had predominantly stage I or II diseases (89%) and the histological types were Wilms (13), non-Wilms (5) renal tumor, and an inflammatory lesion. The delayed surgery group had 60% with stage I or II diseases and the histological types were Wilms (60) and non-Wilms (4) tumor. In addition, high-risk pathology was identified in nine patients. Overall, 27 patients with Wilms tumors required radiotherapy and anthracycline because of stage III disease, including one in the immediate surgery group. The event-free and overall survival (OS) at a median follow-up of 39 months for Wilms tumor are 88% (95% confidence interval [CI]: 78.5-94.9%) and 89% (95% CI: 81.4-96.6%), 85.1% (95% CI: 73.8-93.4%) and 86.5% (95% CI: 77.4-95.8%) for the delayed, and 100% event-free survival as well as OS (P = .1) in the upfront surgery group. CONCLUSION: A customized approach pivoted on image-based high-risk features facilitates identification of patients with early-stage renal tumor when the timing of surgery is tailored. Moreover, non-Wilms tumor and high-risk pathology are also identified.

Osteosarcoma journey over two decades in India: Small steps, big changes.

BACKGROUND: The management of osteosarcoma is challenging especially in lower-income and middle-income countries, and there is an unmet need to evolve efficient and sustainable chemotherapy regimens. METHODS: We compared the outcomes in nonmetastatic osteosarcoma patients treated with three sequential non-high-dose methotrexate-based combination chemotherapy protocols at a single tertiary care center over two decades. The first protocol, OGS-99, involved dose-intense, alternating dyads of three drugs: doxorubicin (Dox), cisplatin (CDDP), and ifosfamide (Ifo). The second protocol, OGS-99 enhanced, included OGS-99 drugs with etoposide and enhanced supportive care. The OGS-12 protocol involved dose-dense administration of eight sequential dyads of Dox, CDDP and Ifo, universal growth factor prophylaxis and targeted nutritional support. Event-free survival (EFS), overall survival (OS), and toxicity were reported using a retrospective chart review in the OGS-99 and OGS-99 enhanced protocols and prospectively in the OGS-12 protocol. RESULTS: A total of 41, 94, and 385 treatment-naïve, consecutive, nonmetastatic patients with extremity osteosarcoma were treated with the OGS-99 (2000-2005), OGS-99 enhanced (2010), and OGS-12 (2011-2016), respectively. At a median follow-up of 19, 86, and 39 months, the five-year EFS rates were 38%, 50%, and 62% in the OGS-99, OGS-99 enhanced, and OGS-12, respectively. The corresponding rates of five-year OS were nonevaluable, 60% and 77%, respectively, with acceptable rates of grade 3-4 toxicities: febrile neutropenia (40%), thrombocytopenia (36%), anemia (51%), and 1% deaths related to toxicity. CONCLUSIONS: Sequential selection of an intelligent, dose-dense chemotherapy regimen together with enhanced supportive care resulted in marked improvement in outcomes of nonmetastatic osteosarcoma and this "small steps-big changes" model deserves wider recognition and usage.

Parvoviral disease in childhood cancer: Clinical outcomes and impact on therapy at a tertiary cancer center in India.

BACKGROUND AND AIM: Parvovirus-B19 disease in immunocompromised children can cause myelosuppression and therapeutic delays. We studied the clinical profiles of children having symptoms suggestive of parvoviral disease at our institution, a large tertiary cancer center. METHODS: Children below age 15 years undergoing treatment for malignancies with clinical features suggestive of parvoviral infection, and/or unexplained drop in hemoglobin, and/or prolonged cytopenia were screened for parvovirus infection using DNA-PCR for parvovirus-B19 (PB19) in the peripheral blood. Patients testing positive from September 2014 till February 2017 were studied. RESULTS: Of the 59 patients (36 patients with hematolymphoid malignancies, 23 with solid tumors) screened for suspected parvoviral infections, 27 tested positive. Median age was 9.6 years (2.25-15 years), 18 (66%) had hematolymphoid malignancies, while 7 (33%) had solid tumors. Six patients (26%) were on intensive phases, 16 (60%) patients developed the symptoms during maintenance chemotherapy, and 4 (15%) after completion of therapy. Isolated anemia was the commonest feature seen in 10 patients (37%) while bicytopenia and pancytopenia were noticed in 8 (30%) and 9 (33%) patients respectively. Fifty percent of patients those who received rituximab (3/6) developed persistent parvoviremia (>4 weeks) as compared with 24% (5/21) of those who did not. Two patients (7%) developed hemophagocytic lymphohistiocytosis (HLH). Treatment delay by more than 14 days was encountered in a majority (62%), with 5 patients requiring treatment modification or even suspension. CONCLUSIONS: Parvoviral infection in children who are on or have recently completed chemotherapy can lead to multiple cytopenias and significant treatment delays. Rituximab exposure may lead to persistent parvoviral disease (p < 0.05). HLH, though occasional, can be a serious complication.

Interstitial brachytherapy for pediatric soft tissue sarcoma: Evolving practice over three decades and long-term outcomes.

PURPOSE: Evaluate long-term clinical outcomes, adverse effects, and evolving practice of interstitial brachytherapy (BT) for pediatric soft tissue sarcomas (STS). METHODS: From September 1984 to December 2014, 105 children (median age 10 years) were included. There were 60 males and 45 females. The majority (74%) had primary lesions. Synovial sarcoma (22%) was the most frequent histology. Treatment included wide local excision and BT with or without external beam radiotherapy (EBRT). Eighty-five (81%) received BT alone. RESULTS: After a median follow-up of 65 months, local control (LC), disease-free survival (DFS), and overall survival (OS) at 10 years were 83, 66, and 73%, respectively. On univariate analysis, LC was superior with tumors <5 cm versus >5 cm (93% vs. 75%, P = 0.10), Grade I/II versus Grade III tumors (97% vs. 73%, P = 0.01), nonround cell versus round cell histology (89% vs. 72%, P = 0.03), and trunk/extremity versus head and neck/genitourinary sites (87% vs. 57%, P = 0.0001). On multivariate analysis tumor size (P = 0.03) and location (P = 0.002) retained significance. Children receiving BT alone had comparable LC to those receiving BT and EBRT (84% vs. 80%, P = 0.43). There was no difference in LC between LDR versus HDR BT (86% vs. 83%, P = 0.30). Wound complications were seen in 6%. Subcutaneous fibrosis (25%), limb edema (6%), skeletal abnormalities (3%), and neuropathy (1%) were the late complications. One child (0.9%) developed a second malignancy after 7 years. CONCLUSION: Interstitial BT with or without EBRT results in excellent outcomes. Radical BT alone, when used judiciously, results in excellent local control and function with minimal treatment-related morbidity.

Clinicopathologic features of 300 rhabdomyosarcomas with emphasis upon differential expression of skeletal muscle specific markers in the various subtypes: A single institutional experience.

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 and <0.001, 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.

Outcomes and complications of surgery in patients with intermediate-risk neuroblastoma: experience from an Indian tertiary Cancer Centre.

PURPOSE: The treatment of intermediate risk (IR) neuroblastoma has evolved with the focus now on reducing the drugs, dosage, and duration of chemotherapy. The aim of this study is to present the outcomes of treatment and the complications of surgery in patients with IR neuroblastoma treated at a tertiary cancer center in India. METHODS: All eligible patients with IR neuroblastoma treated between April 2005 and August 2016 were identified. The presence and number of image-defined risk factors (IDRF) before and after neoadjuvant chemotherapy were retrospectively analyzed as were the extent of surgery, complications, and outcomes. RESULTS: Of 282 neuroblastoma patients treated during the study period, 54 had IR neuroblastoma. Complete excision was achieved in 25 patients. There were 26 surgical complications in 22 patients with a similar incidence in patients with complete (n = 13) or incomplete (n = 13) resection (p = 0.78). After a median follow-up of 47 months, the 4-year overall and event-free survival was 91.5% and 75%, respectively. There was no difference in survival between patients who underwent complete resection versus those with incomplete resection (p = 0.9). CONCLUSION: Outcomes of IR neuroblastoma are favorable. The extent of resection does not affect the survival and complications can occur even when the resection is incomplete.

Pulmonary cement embolism in a child following total elbow replacement for primitive neuroectodermal tumour (PNET) of the humerus.

Pulmonary bone cement embolism (PCE) is an uncommon event occurring after implantation of polymethylmethacrylate (PMMA) in orthopaedic surgeries involving adult patients, more so in the elderly. Its incidence in the paediatric population is extremely rare. We herein describe a case of PCE in a 15-year-old girl, 9 days after she underwent total elbow replacement with PMMA placement for a primitive neuroectodermal tumour (PNET) of the distal humerus. This report describes the occurrence of a common post-operative complication of bone cement embolism in an uncommon scenario of total elbow replacement for a bone tumour in a child, which masqueraded initially as acute pneumonitis.

Paediatric cancer stage in population-based cancer registries: the Toronto consensus principles and guidelines.

Population-based cancer registries generate estimates of incidence and survival that are essential for cancer surveillance, research, and control strategies. Although data on cancer stage allow meaningful assessments of changes in cancer incidence and outcomes, stage is not recorded by most population-based cancer registries. The main method of staging adult cancers is the TNM classification. The criteria for staging paediatric cancers, however, vary by diagnosis, have evolved over time, and sometimes vary by cooperative trial group. Consistency in the collection of staging data has therefore been challenging for population-based cancer registries. We assembled key experts and stakeholders (oncologists, cancer registrars, epidemiologists) and used a modified Delphi approach to establish principles for paediatric cancer stage collection. In this Review, we make recommendations on which staging systems should be adopted by population-based cancer registries for the major childhood cancers, including adaptations for low-income countries. Wide adoption of these guidelines in registries will ease international comparative incidence and outcome studies.