Ten-year follow-up of outcomes, patterns of care, and psychosocial burden in adolescent and young adult (AYA) patients with bone sarcomas from a large cohort in a low-income and middle-income country (LMIC).

BACKGROUND: The care of adolescents and young adults (AYAs) with bone sarcomas involves unique challenges. The objectives of this study were to identify challenges and evaluate long-term outcomes of these patients from India who received treatment with novel protocols. METHODS: This prospective cohort study included AYA patients (aged 15-39 years) with osteosarcoma and Ewing sarcoma (ES), who were treated uniformly at the authors' institute using unique protocols (OGS-12 and EFT-2001) from 2011 to 2021 and from 2013 to 2018, respectively. RESULTS: The cohorts included 688 of 748 (91.9%) treatment-naive AYA patients with osteosarcoma and 126 of 142 (88.7%) treatment-naive AYA patients with ES. Among 481 of 561 patients (85.7%) who had nonmetastatic osteosarcoma treated according to protocol, at a median follow-up of 59.7 months, the 5-year event-free survival (5-EFS) rate was 58.6% (95% confidence interval, 54.1%-63.5%) and for 142 patients (20.6%) who had metastatic osteosarcoma, the 5-EFS rate was 18.7%. The 5-EFS rate was 66.4% and 21.9% for 104 patients (73%) with nonmetastatic ES and 38 patients (27%) with metastatic ES, respectively. Treatment-naive patients had better outcomes, similar to compliance in the form of protocol completion (hazard ratio, 1.93 [p = .0043] and 2.66 [p < .0001], respectively. Only 230 of 377 (61.0%) male patients and 10 of 134 (7.4%) female patients reached out to fertility specialists. In addition, 17 of 161 (10.6%) eligible male survivors and 14 of 61 (22.9%) eligible female survivors got married posttreatment. Furthermore, 14 of 17 (82.4%) males and 14 of 14 (100%) females conceived. Among 311 patients who were working or attending school during diagnosis, greater than 90% had interruptions. CONCLUSIONS: Homogenous treatment with the OGS-12 and EFT-2001 protocols resulted in internationally comparable long-term outcomes in the cohorts with nonmetastatic and metastatic AYA bone sarcomas. Treatment compliance, timely referral to sarcoma reference centers (avoiding prior inadvertent treatment), and streamlining fertility-preservation practices constitute unmet needs that demand prioritization.

Long-term clinical outcomes of combined modality therapy for advanced-stage Hodgkin lymphoma in the PET era: A retrospective study.

BACKGROUND OBJECTIVES: The role of consolidation radiation therapy (CRT) after complete metabolic response to chemotherapy in advanced-stage (stage III and IV) Hodgkin lymphoma (HL) is controversial. This study was undertaken to assess the clinical outcomes in terms of event free survival, local failure free survival and overall survival in individuals with advanced HL treated with chemotherapy and CRT. METHODS: A retrospective review was conducted to study the long-term clinical outcomes in individuals diagnosed with HL and treated with chemotherapy and CRT from 2012 to 2016 at a tertiary cancer care hospital in India. RESULTS: Data from 203 study participants with advanced-stage HL were analyzed. Positron emission tomography-computed tomography (PET-CT) was done at baseline and after 2 cycles for response assessment. The median age at presentation was 32 yr [interquartile range (IQR): 26-46]. Early metabolic response (after 2 cycles) and delayed metabolic response (after 4 or 6 cycles) were observed in 74.4 and 25.6 per cent of individuals, respectively. With a median follow up of 52 months (IQR: 40-67), the five-year event-free survival (EFS), local failure-free survival (LFFS) and overall survival (OS) were 83.2, 95.1 and 94.6 per cent, respectively. On univariate analysis, extranodal disease was associated with inferior EFS (P=0.043). Haemoglobin <10.5 g/dl (P=0.002) and Hasenclever index >3 (P=0.00047) were associated with poorer OS. Relapses were observed in 28/203 (13.8%) study participants with predominance at central nodal stations. The median time to relapse was 19.4 months (IQR: 13-33). Local relapse alone (at the irradiated site) was observed in 5/28 study participants, systemic (distant) relapse in 14/28 individuals, while both systemic and local relapse was observed in 9/28 participants. Extranodal disease (P=0.05), bulky disease (P=0.005) and haemoglobin concentration ≤10.5 g/dl (P=0.036) were significant predictors for disease relapse. INTERPRETATION CONCLUSIONS: Individuals with advanced-stage HL treated with anthracycline-based chemotherapy (anthracycline-based chemotherapy with doxorubicin, bleomycin, vinblastine and dacarbazine regimen) and CRT had excellent long-term outcomes. As isolated infield failures are uncommon, selective consolidation with conformal RT to high-risk sites improves final disease outcomes.

Accuracy of contrast-enhanced CT in liver neoplasms in children under 2 years age.

BACKGROUND: Multiple differentials exist for pediatric liver tumors under 2 years. Accurate imaging diagnosis may obviate the need for tissue sampling in most cases. OBJECTIVE: To evaluate the imaging features and diagnostic accuracy of computed tomography (CT) in liver tumors in children under 2 years. METHODS: Eighty-eight children under 2 years with treatment naive liver neoplasms and baseline contrast-enhanced CT were included in this institutional review board approved retrospective study. Two blinded onco-radiologists assessed these tumors in consensus. Findings assessed included enhancement pattern, lobulated appearance, cystic change, calcifications, central scar-like appearance, and metastases. The radiologists classified the lesion as hepatoblastoma, infantile hemangioma, mesenchymal hamartoma, rhabdoid tumor, or indeterminate, first based purely on imaging and then after alpha-fetoprotein (AFP) correlation. Multivariate analysis and methods of comparing means and frequencies were used for statistical analysis wherever applicable. Diagnostic accuracy, sensitivity, and positive predictive values were analyzed. RESULTS: The mean age of the sample was 11.4 months (95% CI, 10.9-11.8) with 50/88 (57%) boys. The study included 72 hepatoblastomas, 6 hemangiomas, 4 mesenchymal hamartomas, and 6 rhabdoid tumors. Presence of calcifications, multilobular pattern of arterial enhancement, lobulated morphology, and central scar-like appearance was significantly associated with hepatoblastomas (P-value < 0.05). Fourteen out of eighty-eight lesions were called indeterminate based on imaging alone; six lesions remained indeterminate after AFP correlation. Pure radiology-based diagnostic accuracy was 81.8% (95% CI, 72.2-89.2%), which increased to 92.1% (95% CI, 84.3-96.7%) (P-value > 0.05) after AFP correlation, with one hepatoblastoma misdiagnosed as a rhabdoid tumor. If indeterminate lesions were excluded for biopsy, the accuracy would be 98.8% (95% CI, 93.4-99.9%). CONCLUSION: CT had high accuracy for diagnosing liver neoplasms in the under 2-year age population after AFP correlation. Certain imaging features were significantly associated with the diagnosis of hepatoblastoma. A policy of biopsying only indeterminate lesions after CT and AFP correlation would avoid sampling in the majority of patients.

Phase II trial of a novel chemotherapy regimen CVEP (cyclophosphamide, vinblastine, etoposide and prednisolone) for acquired immunodeficiency syndrome (AIDS)-associated lymphomas.

Management of acquired immunodeficiency syndrome (AIDS)-related diffuse large B-cell (DLBCL) and plasmablastic lymphomas (PBL) poses significant challenges. The evidence supports use of dose-adjusted EPOCH (etoposide, prednisone, vincristine, cyclophosphamide and doxorubicin) with or without rituximab as first-line therapy. The need for central venous access, growth factors and significant toxicities limits its use in resource-constrained settings. To address these challenges, we have developed a novel regimen, CVEP (cyclophosphamide, vinblastine, etoposide, and prednisolone) based on the pharmacodynamic principles of dose-adjusted EPOCH. This single-centre phase II study evaluated the efficacy and safety of CVEP regimen in patients with de novo systemic AIDS-related DLBCL and PBL. The primary objective was complete response (CR) rates as assessed by positron emission tomography-computed tomography. The secondary objectives were incidence of Grade 3/4 toxicities, toxicities requiring hospitalisation, and disease-free survival. From May 2011 to February 2017, 42 patients were enrolled. At the end of therapy the CR rates were 69% (29/42) in the intention-to-treat population and 80.5% (29/36) in evaluable patients. At a median follow-up of 69 months, the 5-year disease-free survival was 65.3%. Out of 217 cycles administered, febrile neutropenia occurred in 19.3% and hospitalisation was required in 18.3% of cycles. There were two treatment-related deaths. The CVEP regimen is an active and safe regimen for AIDS-related DLBCL and PBL.

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).

Treatment outcomes and prognostic factors in children with hepatoblastoma using a risk-stratified approach.

BACKGROUND: Not all the significant progress made in the management of children with hepatoblastoma (HB) has translated into improved outcomes in limited-resource settings. There are limited data on outcomes in children with HB from India. METHODS: All patients diagnosed with HB between July 2013 and December 2020 were risk-stratified and treated as per International Liver Tumor Strategy Group (SIOPEL). Patients with standard-risk HB received cisplatin monotherapy and those with high-risk HB received alternating cycles of cisplatin and the combination of carboplatin plus doxorubicin. Data regarding demographic details, chemotherapy, surgery, liver transplantation, outcomes, prognostic factors, and toxicity were collected. RESULTS: Of 157 patients with HB, 117 (74%) were high risk, 31 (20%) were standard risk, and nine (6%) unknown. Patients with standard-risk disease had excellent outcomes, with 3-year event-free survival (EFS) and overall survival (OS) of 96% and 100%, respectively. Among high-risk HB, six underwent orthotopic liver transplantation of which four were alive at last follow-up. The 3-year EFS and OS of patients with high-risk disease was 56% and 66%, respectively. Outcomes of patients with PRETEXT IV (3-year EFS: 42%, 3-year OS: 50%) and metastatic disease (3-year EFS: 30%, 3-year OS: 50%) were dismal. Patients with serum alpha-fetoprotein (AFP) reduction greater than 90% following two courses of chemotherapy had favorable outcomes; 3-year EFS: 80% versus 58% (p = .013) and 3-year OS: 95% vs. 68% (p < .01). Only two (6%) of 31 patients with relapse/refractory HB were alive at a median follow-up of 36 months, and both had received salvage chemotherapy and surgery. CONCLUSIONS: While children with standard-risk HB had excellent outcomes, those with high-risk disease continue to do poorly. Serial monitoring of serum AFP values is a cost-effective and reliable predictor of outcomes. Orthotopic liver transplantation remains a viable option for inoperable disease in resource-limited settings as well.

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.

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.

Clinical outcomes and prognostic factors in children with B-cell lymphoblastic lymphoma (LBL) treated according to on modified BFM-90 protocol: Experience from a Tertiary cancer care center in India.

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.

Adolescent-adult nonmetastatic Ewing sarcoma-Experience from a large developing country.

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 naïve (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.

Giant cell tumors of the sacrum: is non-operative treatment effective?

PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: This study offers a non-surgical management option that provides good mid-term local control while preserving neurological function in these complex lesions.

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.

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.

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.

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.

Osteoclast-rich, proximal-type epithelioid sarcoma: clinicopathologic features of 3 unusual cases expanding the histomorphological spectrum.

Epithelioid sarcoma (ES) displays a wide clinicopathologic spectrum. On histopathology, osteoclast-like giant cells have been rarely described in these tumors. A 45-year-old gentleman presented with a perineal swelling of 6-month duration. Radiologic imaging disclosed a large, highly vascular tumor mass in his perineal region that was diagnosed elsewhere as pigmented villonodular synovitis. A 58-year-old lady presented with a recurrent tumor in her right inguinolabial region for which she underwent multiple tumor resections in the past. A 33-year-old lady presented with a right inguinal swelling of 1-month duration that was diagnosed elsewhere as a non-Hodgkin lymphoma on fine needle aspiration cytology. Histopathologic examination of tumors in all the 3 cases revealed epithelioid to "rhabdoid-like" cells arranged in a diffuse pattern interspersed with many osteoclast-like giant cells. The first tumor also revealed focal pseudoangiosarcomatous areas and heterotopic bone formation. By immunohistochemistry, tumor cells in all 3 cases were positive for AE1/AE3, epithelial membrane antigen, and CD34 and were completely negative for INI1/SMARCB1. CD68 immunostaining in 2 tumors highlighted osteoclast-like giant cells. Osteoclast-rich, proximal-type ES are unusual tumors, indicative of an expanding spectrum of ESs. Awareness of this histopathologic pattern and diagnostic confirmation with necessary immunohistochemical stains is crucial to avoid misinterpretation, as these tumors are clinically aggressive and are treated with wide local excision and optional adjuvant radiation therapy.

Assessment of pencil beam scanning proton therapy beam delivery accuracy through machine learning and log file analysis.

PURPOSE: Comprehensive Quality Assurance (QA) protocols are necessary for complex beam delivery systems like Pencil Beam Scanning (PBS) proton therapy. This study focuses on automating the evaluation of beam delivery accuracy using irradiation log files and machine learning (ML) models. METHODS: Irradiation log files of 935 clinical treatment fields and routine QA beams were analysed to evaluate spot parameters and Monitor Unit (MU) accuracy. ML models predicted spot size along the X, Y, major, and minor axes. In-house scripts automated log file analysis and spot size predictions. Predicted spot sizes were compared with expected baselines, and the accuracy of spot position, symmetry, and MU for each spot in the beam was evaluated. RESULTS: More than 99.5 % of spot positions were accurate within a 1 mm. The mean and Standard Deviation (SD) of X positional error were -0.021 mm (SD: 0.181 mm), and for Y positional error, they were -0.002 mm (SD: 0.132 mm). ML models accurately predicted spot sizes, with over 95 % of spots demonstrating size variations within 10 % of the baseline. The Root Mean Squared Error (RMSE) of X and Y spot size differences were 0.15 mm and 0.16 mm, respectively. Spot symmetry was within 10 %, and MU accuracy showed 95 % of spots with MU per spot variation less than 2 %. CONCLUSION: This method can validate the vendor's beam delivery safety interlock system and serve as a quick alternative to patient-specific QA in adaptive treatment, where time is limited, as well as for routine QA spot parameter evaluations.