Role of Interphase FISH Assay on Air-Dried Smears in Identifying Specific Structural Chromosomal Abnormalities among Pediatric Patients with Acute Leukemias.

Leukemia-associated structural chromosomal abnormalities (SCA) can be identified either by karyotyping or interphase-fluorescence in-situ hybridization (i-FISH) assays. Both karyotyping and i-FISH on mononuclear cell suspension are time, resource, and manpower-consuming assays. In this study, we have compared the results of specific leukemia-associated SCAs identified by i-FISH on air-dried bone marrow (BM)/peripheral blood (PB) smears and BM karyotyping. The study was conducted among pediatric patients (age ≤ 18 years) diagnosed with acute leukemias between January 2018 to December 2022. The results of i-FISH on air-dried BM/PB smears and BM-karyotyping for our SCA of interest (BCR::ABL1, ETV6::RUNX1, TCF3::PBX1, KMT2A rearrangement, RUNX1::RUNX1T1, CBFB::MYH11, and PML::RARA) were entered in a contingency table and the agreement of results was calculated. The strength of agreement was assessed by Cramer's V test. Among 270 patients, SCA of interest was identified among 26% and 17% of patients by i-FISH on air-dried smears and karyotyping, respectively. Excluding 53 patients with metaphase failure, the remaining 217 patients had 92% agreement (Cramer's V of 0.931 with p < 0.000) between the results for specific SCAs identified by both techniques. On excluding samples with cryptic cytogenetic aberrancies, there was 99% agreement (Cramer's V of 0.953 with p < 0.000) for gross SCA identified by both techniques. In addition, i-FISH on air-dried smears identified SCA in 30% of patients with metaphase failure. I-FISH on air-dried PB/BMA smears is a less-labor and  resource-consuming assay. It can be considered an efficient alternative to conventional karyotyping for  identifying specific SCA of interest in under-resourced laboratories. Supplementary Information: The online version contains supplementary material available at 10.1007/s12288-023-01699-2.

Management of Intraocular Retinoblastoma: ICMR Consensus Guidelines.

Retinoblastoma (RB) is the most common childhood intraocular malignancy. Delayed presentation due to a lack of awareness and advanced intraocular tumors are a common scenario in low-middle income countries (LMICs). Remarkable treatment advances have been made in the past few decades allowing globe salvage in advanced intraocular RB (IORB) including systemic chemotherapy with focal consolidation and targeted treatments like intraarterial chemotherapy and intravitreal chemotherapy. However, a lack of availability and affordability limits the use of such advances in LMICs. External beam radiotherapy, despite risk of second cancers in RB with germline mutations, still remains useful for recalcitrant RB not responding to any other treatment. When choosing conservative treatment for advanced IORB, the cost and long duration of treatment, morbidity from multiple evaluation under anesthesias (EUAs), side effects of treatment and risk of treatment failure need to be taken into account and discussed with the parents. In this article, the authors discuss the ICMR consensus guidelines on the management of IORB.

Management of Extraocular Retinoblastoma: ICMR Consensus Guidelines.

Retinoblastoma (RB) is the most common intraocular malignancy of childhood. Advanced stage presentation of RB is common in low middle-income countries (LMICs) due to lack of awareness, social taboos associated with enucleation, seeking alternative conservative treatment options, and poor accessibility to health care. Over the last few decades, there have been significant advancements in the management of extraocular RB (EORB) which have improved outcomes and helped in minimizing treatment-related toxicities. The incorporation of multimodality approaches including chemotherapy, surgery, and radiotherapy (RT) has shown promising results; however, prognosis remains poor especially in LMICs. In this article, authors have discussed the ICMR consensus guidelines on the management of EORB, including metastatic RB.

Relevance of CD20 antigen expression among paediatric patients with B-lineage acute lymphoblastic leukaemia.

Literature regarding prognostic relevance of CD20 antigen expression among paediatric B-lineage acute lymphoblastic leukaemia (B-ALL) patients is sparse and contradictory. We analysed clinical laboratory parameters and survival characteristics pertinent to CD20 expression among 224 treatment-naïve paediatric B-ALL patients. 50% patients had CD20 expression (CD20+ B-ALL). There was no difference in the clinical & laboratory presentation and end of induction measurable residual disease (EOI-MRD) status according to CD20 expression. As compared to CD20- B-ALL patients, CD20+ B-ALL patients had two times more relapse (16% vs. 29%, p = 0.034), inferior relapse-free survival (79% vs. 66%, p = 0.025) but no difference in overall survival (75% vs. 69%, p = 0.126). Similar to high-risk NCI status and EOI-MRD positivity, CD20 expression was an independent predictor for inferior relapse-free survival (HR: 1.860, 95% CI: 1.008-3.432, p = 0.047). Compared to baseline, there was a significant increase in CD20-expressing EOI-residual blasts among CD20- B-ALL patients (5% vs. 13%, p = 0.001). EOI residual blasts of both CD20+ and CD20- patients had three times increased normalized CD20 expression intensity (nCD20), with the intensity among CD20- B-ALL patients reaching the pretreatment nCD20 of CD20+ B-ALL patients (4.9 vs. 3.6, p = 0.666). Rituximab can be considered in managing EOI-MRD-positive CD20- B-ALL patients as the residual blasts of these patients have quantitative and qualitative increases in CD20 expression.

Epidemiology, Diagnosis and Genetics of Retinoblastoma: ICMR Consensus Guidelines.

Retinoblastoma (RB) is the most common intraocular tumor in childhood. It is mainly caused by mutations in both alleles of the RB1 tumor suppressor gene that is found on chromosome 13 and regulates the cell cycle. Approximately 8000 children are diagnosed with RB globally each year, with an estimated 1500 cases occurring in India. The survival rate of RB has improved to more than 90% in the developed world. Leukocoria and proptosis are the most common presenting features of RB in Asian Indian populations. Most cases of RB are diagnosed by fundus examination followed by ultrasound. The International Classification of Retinoblastoma is the most used scheme for the staging and classification of intraocular RB in India. Prenatal testing and preimplantation genetic testing for RB may be beneficial in high-risk families. Histopathologic risk factors such as massive choroidal invasion and post-laminar optic nerve help in predicting the occurrence of metastasis in children with RB, while presence of microscopic residual disease requires aggressive adjuvant treatment in eyes enucleated for group E RB. The review provides a consensus document on diagnosis and genetics of RB in India.

Factors that Impact the Outcomes in Ewing's Sarcoma: Experience from a Regional Cancer Center in Southern India.

Ewing's sarcoma family of tumors (EWSFT) is common in the second decade of life. Achieving good outcomes in EWSFT requires a multimodality approach. We report the clinico-pathological features, treatment, and survival outcomes of patients with EWSFT treated at our center. Patients diagnosed and treated for EWSFT at our center from 2009-2017 were included in this study. Data was collected from the patient's case records. Event-free survival (EFS) and overall survival (OS) were estimated using the Kaplan-Meier method. The study included 173 patients among whom 44 (25%) patients were metastatic at diagnosis. The median age of patients was 16 years. The most common site of the primary tumor was the pelvis (16.1%), followed by long bones. The median follow-up was 75 months and the 5-year EFS and OS were 43.7% and 45.1% respectively for the overall cohort whereas for the localized disease were 56.6% and 57.2% respectively. Metastatic disease, tumor volume > 200 ml, tumor diameter > 8 cm, pelvic site, hemoglobin < 10 gms%, elevated lactate dehydrogenase, positive margin, and necrosis less than 90% were significantly associated with inferior OS on univariate analysis. On multivariate analysis, metastasis disease, tumor diameter > 8 cm, and necrosis < 90% were significantly associated with inferior OS. Large tumors, advanced disease, and poor response to chemotherapy are associated with poor outcomes in EWSFT. Whether the use of dose-dense chemotherapy and/or autologous stem cell transplant would improve outcomes without increased toxicity in resource-limited settings needs to be explored. Supplementary Information: The online version contains supplementary material available at 10.1007/s13193-023-01817-6.

Profile of Childhood Cancers From Hospital-Based Cancer Registries in India, 2012-19.

OBJECTIVE: To describe the clinical pattern of childhood and adolescent cancers across India using hospital-based data in the National Cancer Registry Program. METHODS: Records of 60720 cancer cases in the 0-19 year age group for the period 2012-2019 from 96 hospital-based cancer registries were reviewed. Childhood cancers were classified based on the International Classification of Childhood Cancer (ICCC). Descriptive analysis was used to examine the distribution of cancer by five-year age groups, sex and ICCC diagnostic groups and subgroups. Data were analysed using IBM SPSS software and visualised using R software. RESULTS: 3.2% and 4.6% of all cancer cases in India were among children in the 0-14 year and 0-19 year age groups respectively. The male-to-female ratio for all cancers was 1.72 for 0-14 years and 1.73 for 0-19 years. The four leading groups of cancers among 0-14 year olds were leukemia (40%), lymphoma (12%), central nervous system tumor (11%) and bone cancer (8%). The four leading cancers among the 0-19 year age group were leukemia (36%), lymphoma (12%), bone (11%) and central nervous system tumor (10%). CONCLUSION: Cancers in the 0-14 and 0-19 age groups accounted for a considerable proportion of all cancers with significant male preponderance. Such information helps to fine-tune research and planning strategies.

Dexamethasone-Free Antiemetic Prophylaxis for Highly Emetogenic Chemotherapy: A Double-Blind, Phase III Randomized Controlled Trial (CINV POD study).

PURPOSE: The effectiveness of a dexamethasone (DEX)-free regimen for chemotherapy-induced nausea and vomiting (CINV) prophylaxis in patients receiving highly emetogenic chemotherapy (HEC) is not known. METHODS: This was a double-blind, phase III trial designed to show the noninferiority of a DEX-free regimen (olanzapine, palonosetron, and fosaprepitant [OPF]) compared with the DEX-containing regimen (olanzapine, palonosetron, and DEX [OPD]). Chemotherapy-naïve patients age 18-80 years receiving single-day HEC were randomly assigned 1:1 to receive either the OPD regimen or the OPF regimen. The primary objective was to compare complete response (CR) rates for vomiting during the overall period (start of chemotherapy to 120 hours). Secondary objectives included CR for vomiting during the acute period (0-24 hours) and delayed period (24-120 hours), CR for nausea, and comparison of toxicities and patient-reported outcomes. RESULTS: Three hundred forty-six patients received the study interventions, 174 in the OPD arm and 172 in the OPF arm. The DEX-free OPF arm had significantly higher CR rates for vomiting compared with the DEX-containing OPD arm in acute (94.7% v 85.6%; P < .004), delayed (81.9% v 50.5%; P < .001), and overall (79.6% v 48.8%; P < .001) periods. For nausea, CR rates in the OPF arm were higher in delayed (53.4% v 39.6%; P = .009) and overall (50.5% v 39.1%; P = .031) periods but not in the acute period (77.9% v 81.6%; P = .39). Fatigue (P = .009) and drowsiness (P = .002) were more in the OPF arm in the acute period and insomnia (P < .001) in the OPD arm in the overall period. CONCLUSION: This study shows that a DEX-free OPF regimen is efficacious and should be considered a standard option for acute and delayed CINV prophylaxis for HEC.

Effect of Neoadjuvant Concurrent Chemoradiation on Operability and Survival in Locally Advanced Inoperable Breast Cancer.

PURPOSE: Inoperable locally advanced breast cancers (LABCs) are treated with neoadjuvant chemotherapy. We studied the use of neoadjuvant concurrent chemoradiation (NACCRT) in patients with inoperable LABC. METHODS AND MATERIALS: From May 2017 to December 2021, the study recruited patients with stage III inoperable LABC. Treatment included 4 cycles of doxorubicin and cyclophosphamide and 4 cycles of paclitaxel, along with concurrent radiation therapy to a total dose of 46 Gy. Thereafter, all patients were evaluated for surgery, and additional treatments were given based on receptor status. The effects of NACCRT on pathologic complete response (pCR), operability, and survival were analyzed. RESULTS: The study involved 202 female patients with a median age of 52 years. Of these, 23.7% had IIIA, 65.3% had IIIB, and 10.8% had IIIC disease. Hormone receptor-positive disease was observed in 44.6% of patients, triple-negative breast cancer was observed in 24.8% of patients, and Human epidermal growth factor receptor 2 (HER2)-positive disease was observed in 30.7% of patients. Modified radical mastectomy (MRM) was performed in 88.1% of patients, 8.5% of patients remained inoperable, and 3.4% of patients declined surgery. Among the patients who underwent MRM, 36.5% of patients had a pCR. Patients who were operable and underwent MRM had complete resections and had negative margins. pCR was observed in 16% with hormone receptor-positive disease, in 45.6% with triple-negative breast cancer, and in 60.7% with HER2-positive disease. Grade 3 skin reactions were observed in 19.3% of patients. Postoperative wound morbidity requiring hospitalization was observed in 10.6% of patients. After a median follow-up of 42 months, the 4-year event-free survival and overall survival rates were 63.4% and 71.5%, respectively. HER2-positive patients who achieved a pCR had significantly improved event-free survival and overall survival. CONCLUSIONS: Our study shows that using NACCRT can improve operability and survival outcomes in patients with inoperable LABC.

2023 updated MASCC/ESMO consensus recommendations: prevention of nausea and vomiting following multiple-day chemotherapy, high-dose chemotherapy, and breakthrough nausea and vomiting.

PURPOSE: This review is an update of the MASCC/ESMO 2015 recommendations for the prophylaxis of acute and delayed nausea and vomiting induced by multiple-day chemotherapy, high-dose chemotherapy, and breakthrough nausea and vomiting. METHODS: A systematic literature search was conducted using PubMed from June 1, 2015, through February 1, 2023. RESULTS: We identified 56 references (16 were duplications or invalid), leaving 40 manuscripts for this search. The panel classified level I evidence (three manuscripts) and level II evidence (14 manuscripts). High-dose chemotherapy and stem cell transplant were discussed in four of these manuscripts, and multiple-day chemotherapy treatment in 15. Some manuscripts covered both topics. Additionally, a search for breakthrough nausea and vomiting resulted in 12 "hits." No new relevant studies were identified. CONCLUSIONS: The recommendations for patients receiving high-dose chemotherapy with stem cell transplants and patients undergoing multiple-day cisplatin were updated. For patients receiving high-dose chemotherapy for stem cell transplant, a combination of a 5-HT3 receptor antagonist with dexamethasone and aprepitant is recommended. Olanzapine could be considered part of the antiemetic regimen. Patients receiving multiple-day cisplatin should receive a 5-HT3 receptor antagonist plus dexamethasone plus aprepitant plus olanzapine. For patients experiencing breakthrough nausea and vomiting, the available evidence suggests using a single dose of olanzapine daily for 3 days.

Reducing chemotherapy dose intensity by 25% and adding rituximab improves survival in pediatric mature B-cell non-Hodgkin lymphoma in LMIC setting.

BACKGROUND AND OBJECTIVES: Pediatric B-cell non-Hodgkin lymphomas (NHL) in low- and middle-income countries (LMICs) have historically had inferior outcomes due to higher treatment-related mortality (TRM) and relapses. To address this issue, we evaluated the impact of reducing chemotherapy dose intensity by 25% and adding rituximab on outcomes in pediatric B-NHL. PATIENTS AND METHODS: Patients, less than 18 years of age with group B and C disease as per the Lymphome Malin de Burkitt (LMB) risk stratification were enrolled between September 2017 and October 2022. The LMB-89 protocol, with a 25% reduction in all chemotherapy doses and the addition of rituximab, was administered. The response was assessed using positron emission tomography with computed tomography (PET/CT) after four cycles of chemotherapy (interim) and at the end of treatment. RESULTS: The study included 25 patients with a median age of 6.9 years, among whom 20 (80%) were males. Twenty patients had group B and five had group C disease. Complete metabolic response (CMR) was achieved by 22/25 (88%) patients, and three (12%) achieved partial metabolic response (PMR) in the interim PET/CT. At the end of treatment, 22/24 (92%) patients achieved CMR, one had PMR, and one had progressive disease. The median follow-up was 45 months (range: 3-71 months). The 4-year event-free survival and overall survival were 88% and 92%, respectively. There were two deaths, one due to disease progression and the other due to sepsis. CONCLUSION: Our study demonstrates a significant improvement in outcomes in pediatric B-NHL compared to previous reports from LMICs, achieved through a 25% reduction in chemotherapy dose intensity and the addition of rituximab.

An assessment of childhood cancer care services in India - gaps, challenges and the way forward.

Background: Childhood cancers are emerging as an essential concern in India where there is lack of a specific programme component or policy to address childhood cancer control. There is limited information on the status and quality of childhood cancer care services in India. This paper describes the childhood cancer care services available at secondary and tertiary-level hospitals in India through a cross sectional study design. Methods: The survey was conducted in 137 tertiary-level and 92 secondary-level hospitals in 26 states and 4 Union Territories (UTs), ensuring a uniform representation of public and private care hospitals. The study tool collected data on the organisational infrastructure, type of oncology services, health workforce, equipment, treatment and referral protocols, and treatment guidelines. Descriptive statistics was used to primarily present the health service status and data on childhood cancer care services in proportions and mean. Findings: A dedicated pediatric oncology department was available in 41.6% of the public, 48.6% of private, and 64% Non Government Organization (NGO) managed tertiary-level hospitals. In 36 (39%) of the 92 hospitals providing secondary care, childhood cancer care was provided. The availability of bone (41.5%) and positron emission tomography (PET) scans (25.9%) was lower in public tertiary hospitals, whereas histopathology, computerised tomography (CT scan), and magnetic resonance imaging (MRI) were lower in public secondary hospitals than private and NGO managed hospitals for the corresponding level of care. Most tertiary hospitals had the required supportive care facilities except for play therapy and hospice care. Less than 50% of the public tertiary hospitals had stocks of the four categories of cancer-treating drugs and essential infrastructure for radiotherapy and chemotherapy. Most secondary-level hospitals not treating childhood cancer had referral linkages with tertiary hospitals. Interpretation: The situational analysis of childhood cancer care services in India showed the concentration of availability of childhood cancer care services at the tertiary level of health care. There were gaps in the availability of specialised pediatric oncology care in all the tertiary hospitals. The availability of childhood cancer care services was higher in private and NGO-managed hospitals than in public hospitals. Integration of childhood cancer as a part of the national cancer control response should be taken up as a matter of priority. The need of the hour is to formulate a childhood cancer policy that will enable timely access to care universally. Funding: World Health Organization, India provided funding and technical support.

A National Cancer Grid pooled procurement initiative, India.

In health systems with little public funding and decentralized procurement processes, the pricing and quality of anti-cancer medicines directly affects access to effective anti-cancer therapy. Factors such as differential pricing, volume-dependent negotiation and reliance on low-priced generics without any evaluation of their quality can lead to supply and demand lags, high out-of-pocket expenditures for patients and poor treatment outcomes. While pooled procurement of medicines can help address some of these challenges, monitoring of the procurement process requires considerable administrative investment. Group negotiation to fix prices, issuing of uniform contracts with standardized terms and conditions, and procurement by individual hospitals also reduce costs and improve quality without significant investment. The National Cancer Grid, a network of more than 250 cancer centres in India, piloted pooled procurement to improve negotiability of high-value oncology and supportive care medicines. A total of 40 drugs were included in this pilot. The pooled demand for the drugs from 23 centres was equivalent to 15.6 billion Indian rupees (197 million United States dollars (US$)) based on maximum retail prices. The process included technical and financial evaluation followed by contracts between individual centres and the selected vendors. Savings of 13.2 billion Indian Rupees (US$ 166.7million) were made compared to the maximum retail prices. The savings ranged from 23% to 99% (median: 82%) and were more with generics than innovator and newly patented medicines. This study reveals the advantages of group negotiation in pooled procurement for high-value medicines, an approach that can be applied to other health systems.

Lorsque les systèmes de santé reçoivent peu de fonds publics et que leurs processus d'achat sont décentralisés, le prix et la qualité des médicaments contre le cancer ont un impact direct sur l'accès aux traitements efficaces contre la maladie. Des facteurs tels que l'application de prix différenciés, les négociations en fonction des volumes ainsi que la confiance placée dans des génériques bon marché dont la qualité n'a pas été évaluée peuvent entraîner des décalages entre l'offre et la demande, d'énormes dépenses non remboursables pour les patients et de piètres résultats thérapeutiques. Bien que les acquisitions groupées de médicaments puissent contribuer à résoudre certains de ces problèmes, le suivi du processus d'achat requiert un engagement considérable au niveau administratif. Les négociations collectives en vue de fixer les tarifs, l'établissement de contrats types assortis de conditions générales standardisées, mais aussi les achats effectués par des hôpitaux en particulier peuvent également faire baisser les coûts et améliorer la qualité sans nécessiter d'importants investissements. Le National Cancer Grid, un réseau réunissant plus de 250 centres d'oncologie en Inde, a testé un dispositif d'achat groupé visant à assurer une meilleure négociabilité pour des médicaments et soins de soutien essentiels contre le cancer. Au total, 40 substances ont été prises en compte dans ce projet pilote. La demande groupée en médicaments émise par 23 centres équivalait à 15,6 milliards de roupies indiennes (197 millions de dollars américains) d'après le prix maximal de vente au détail. Ce processus prévoyait une évaluation technique et financière, puis des contrats entre chaque centre et les distributeurs sélectionnés. Des économies de 13,2 milliards de roupies indiennes (166,7 millions de dollars américains) ont pu être réalisées par rapport au prix maximal de vente au détail. Ces économies étaient comprises entre 23 et 99% (médiane: 82%) et concernaient davantage les médicaments génériques que les marques et les médicaments récemment brevetés. La présente étude révèle les avantages que représentent les négociations collectives lors des achats groupés de médicaments essentiels, une approche applicable à d'autres systèmes de santé.

En los sistemas sanitarios con escasa financiación pública y procesos de adquisición descentralizados, el sistema de fijación de precios y la calidad de los medicamentos contra el cáncer afectan directamente al acceso a una terapia eficaz contra dicha enfermedad. Factores como los diferentes sistemas de determinación de precios, la negociación en función del volumen y la dependencia de genéricos de bajo precio sin evaluación de su calidad pueden generar retrasos en la oferta y la demanda, elevados gastos para los pacientes y malos resultados en el tratamiento. Aunque la adquisición conjunta de medicamentos puede ayudar a abordar algunos de estos retos, el seguimiento del proceso de adquisición requiere una inversión administrativa considerable. La negociación colectiva a la hora de determinar los precios, la emisión de contratos unificados con términos y condiciones estandarizados y la adquisición por parte de algunos hospitales también reducen los costes y mejoran la calidad sin necesidad de realizar una gran inversión. La Red Nacional de Cáncer, una red que cuenta con más de 250 centros oncológicos en la India, puso a prueba la adquisición conjunta con el fin de mejorar la negociabilidad de medicamentos oncológicos y de tratamiento complementario que resultaban costosos. En esta prueba piloto se incluyó un total de 40 medicamentos. La demanda conjunta de medicamentos por parte de 23 centros fue equivalente a 15 600 millones de rupias indias (197 millones USD) según los precios minoristas máximos. El proceso incluyó una evaluación técnica y financiera, así como contratos entre centros independientes y proveedores seleccionados. Se logró un ahorro de 13 200 millones de rupias indias (166,7 millones USD) en comparación con los precios minoristas máximos. El ahorro osciló entre el 23 y el 99% (media: 82%) y fue más alto con los medicamentos genéricos que con los de marca y los recién patentados. Este estudio pone de manifiesto las ventajas de la negociación colectiva en lo que respecta a la adquisición conjunta de medicamentos costosos, un enfoque que se puede aplicar a otros sistemas sanitarios.

Management of B-cell lineage acute lymphoblastic leukemia: expert opinion from an Indian panel via Delphi consensus method.

Introduction: Currently, there are no guidelines for the management of B-cell lineage acute lymphoblastic leukemia (B-ALL) from an Indian perspective. The diagnostic workup, monitoring, and treatment of B-ALL vary among different physicians and institutes. Objective: To develop evidence-based practical consensus recommendations for the management of B-ALL in Indian settings. Methods: Modified Delphi consensus methodology was considered to arrive at a consensus. An expert scientific committee of 15 experts from India constituted the panel. Clinically relevant questions belonging to three major domains were drafted for presentation and discussion: (i) diagnosis and risk assignment; (ii) frontline treatment; and (iii) choice of therapy (optimal vs. real-world practice) in relapsed/refractory (R/R) settings. The questionnaire was shared with the panel members through an online survey platform. The level of consensus was categorized into high (≥ 80%), moderate (60%-79%), and no consensus (< 60%). The process involved 2 rounds of discussion and 3 rounds of Delphi survey. The questions that received near or no consensus were discussed during virtual meetings (Delphi rounds 1 and 2). The final draft of the consensus was emailed to the panel for final review. Results: Experts recommended morphologic assessment of peripheral blood or bone marrow, flow cytometric immunophenotyping, and conventional cytogenetic analysis in the initial diagnostic workup. Berlin-Frankfurt-Münster (BFM)-based protocol is the preferred frontline therapy in pediatric and adolescent and young adult patients with B-ALL. BFM/German Multicenter Study Group for Adult Acute Lymphoblastic Leukemia-based regimen is suggested in adult patients with B-ALL. Immunotherapy (blinatumomab or inotuzumab ozogamicin) followed by allogeneic hematopoietic cell transplantation (allo-HCT) is the optimal choice of therapy that would yield the best outcomes if offered in the first salvage in patients with R/R B-ALL. In patients with financial constraints or prior allo-HCT (real-world practice) at first relapse, standard-intensive chemotherapy followed by allo-HCT may be considered. For subsequent relapses, chimeric antigen receptor T-cell therapy or palliative care was suggested as the optimal choice of therapy. Conclusion: This expert consensus will offer guidance to oncologists/clinicians on the management of B-ALL in Indian settings.

Prevalence and prognostic significance of IKZF1 deletion in paediatric acute lymphoblastic leukemia: A systematic review and meta-analysis.

IKZF1 (IKAROS family Zinc Finger 1) alteration is an essential regulator of both T- and B-cell lineage specification with leukemogenic potential. IKZF1 deletion have been described in childhood acute lymphoblastic leukemia (ALL) with varying prevalence often influenced by underlying cytogenetics and also shown to have diverse prognostic significance. We aimed to evaluate the prevalence and prognostic significance of IKZF1 deletion among childhood ALL. Electronic databases of MEDLINE, EMBASE and SCOPUS were searched and 32 studies found eligible. Estimated prevalence of IKZF1 deletion among BCR::ABL1 negative and BCR::ABL1 positive ALL patients was 14% (95%CI:13-16%, I2 = 79%; 26 studies) and 63% (95%CI:59-68% I2 = 42%; 10 studies) respectively. Most common site of IKZF1 deletion was whole chromosome (exon1-8) deletion in 32.3% (95%CI: 23.8-40.7%) followed by exon 4-7 deletion in 28.6% (95%CI: 19.7-37.5%). A positive minimal residual disease at the end of induction was more common among patients with IKZF1 deletion, odds ratio: 3.09 (95%CI:2.3-4.16, I2 = 54%; 15 studies). Event-free survival and overall survival were significantly worse for IKZF1 deletion, hazard ratio (HR): 2.10 (95%CI:1.90-2.32, I2 = 28%; 31 studies) and HR: 2.38 (95%CI:1.93-2.93, I2 = 40; 15 studies) respectively. In summary, the current meta-analysis highlights the frequency of IKZF1 deletion and its negative impact on survival in childhood ALL. Further studies exploring the influence of IKZF1 deletion in the presence of classical cytogenetic and other copy number alterations would further help in characterising its prognostic role.

Outcomes with chemotherapy in carcinoma penis: Experience from a tertiary cancer center.

Background: Carcinoma penis is more common in India compared to the West. The role of chemotherapy in carcinoma penis is ambiguous. We analyzed the profile and outcomes of patients with carcinoma penis treated with chemotherapy. Methods: We analyzed the details of all patients with carcinoma penis treated at our institute between 2012 and 2015. We collected particulars regarding demography, clinical presentation, treatment details, toxicities, and outcomes of these patients. Event-free and overall (OS) survival were calculated from the time of diagnosis until documentation of disease relapse/progression or death for the patients with advanced carcinoma penis who were eligible for chemotherapy. Results: There were 171 patients with carcinoma penis treated at our institute during the study period including 54 (31.6%) patients with stage I, 49 (28.7%) patients with stage II, 24 (14.0%) patients with stage III, 25 (14.6%) patients with stage IV, and 19 (11.1%) patients with recurrent disease at presentation. The present study included 68 patients with advanced carcinoma penis (stages III and IV) who were eligible for chemotherapy, with a median age of 55 years (range: 27-79 years). Sixteen patients received paclitaxel and carboplatin (PC) and 26 patients cisplatin and 5-FluoroUracil (CF). Neoadjuvant chemotherapy (NACT) was given to four patients with stage III and nine patients with stage IV disease. Of the 13 patients given NACT, we observed a partial response in five (38.5%), stable disease in two (15.4%), and progressive disease in five (38.5%) evaluable patients. Six (46%) patients underwent surgery after NACT. Only 28/54 (52%) patients received adjuvant chemotherapy. After a median follow-up of 17.2 months, the 2-year OS rates were 95.8, 89, 62.7, 51.9, and 28.6% for stages I, II, III, IV, and recurrent disease, respectively. The 2-year OS of patients who were given chemotherapy versus those who were not given chemotherapy were 52.7 and 63.2%, respectively (P = 0.762). Conclusions: We report the real-world outcomes of two chemotherapeutic regimens used in consecutive patients with advanced carcinoma penis. Both PC and CF seemed effective and safe. However, approximately half of patients with advanced carcinoma penis do not receive the planned/indicated chemotherapy. We need further prospective trials regarding the sequencing, protocols and indications of chemotherapy in this malignancy.

Sex disparity in childhood cancer in India: a multi-centre, individual patient data analysis.

BACKGROUND: Sex disparity and its determinants in childhood cancer in India remain unexplored, with scarce information available through summary statistics of cancer registries. This study analysed the degree of sex bias in childhood cancer in India and its clinical and demographical associations. METHODS: In this retrospective, multicentre cohort study, we collected individual data of children (aged 0-19 years) with cancer extracted from the hospital-based records of three cancer centres in India between Jan 1, 2005, and Dec 31, 2019, and two population-based cancer registries (PBCRs; Delhi [between Jan 1, 2005, and Dec 31, 2014] and Madras Metropolitan Tumour Registry [between Jan 1, 2005, and Dec 31, 2017]). We extracted data on age, sex, and confirmed diagnosis of malignancy (according to the International Classification of Diseases-10 coding),and excluded participants if they were without a recorded diagnosis, had a benign diagnosis, had missing sex information, resided outside of India, or were a donor for haematopoietic stem cell transplantation (HSCT). The primary outcome was the male-to-female incidence rate ratio (MF-IRR) in the two PBCRs and the male-to-female ratios (MFR) from the hospital-based and the HSCT data. For PBCR data, MF-IRR was estimated by dividing the MFR by the total population at risk. MFR was analysed for patients seeking treatment at the cancer centres and for those undergoing HSCT. Logistic regression analyses were done to explore the association of clinical and demographical variables with sex of the patients seeking treatment and those undergoing HSCT in hospital-based data and multivariable analyses were done to determine independent sociodemographic predictors of sex bias. Annual time trends of MFR and MF-IRR during the 15-year study period were ascertained by time series regression analyses. FINDINGS: We included 11 375 children from PBCRs in the study. 26 891 children from hospital-based records were screened, and data from 22 893 (85·1%) were included (including 514 who underwent HSCT). Residence details were missing for 257 (1·1%) of 22 893 patients from hospital-based records. The crude MFR of children at diagnosis was in favour of boys: 2·00 (95% CI 1·92-2·09) in the Delhi PBCR and 1·44 (1·32-1·57) in Madras Metropolitan Tumour Registry. The MF-IRRs for cancer diagnosis were also skewed in favour of boys in both PBCRs (Delhi 1·69 [95% CI 1·61-1·76]; Madras Metropolitan Tumour Registry 1·37 [1·26-1·49]). The MFR for children seeking treatment from hospital-based records was 2·06 (95% CI 2·00-2·12) in favour of boys. In subgroup analyses, the proportion of boys seeking treatment was higher in northern India than southern India (p<0·0001); in private centres than in centres providing subsidised treatment (p<0·0001); in patients with haematological malignancies than those with solid malignancies (p<0·0001); in those residing 100 km or further from the hospital than those within 100 km of a hospital (p<0·0001); and those living in rural areas than those living in urban areas (p=0·0006). The MFR of 514 children who underwent HSCT was 2·81 (95% CI 2·32-3·43) in favour of boys. Time trend analysis showed that MFR did not show any significant annual change in either the overall cohort or in any of the individual centres for hospital-based data; however, the analysis did show a declining MF-IRR in the Delhi PBCR from 2005 to 2014 (p=0·031). INTERPRETATION: The sex ratio for childhood cancer in India has a bias towards boys at the level of diagnosis, which is more pronounced in northern India and in situations demanding greater financial commitment. Addressing societal sex bias and enhancing affordable health care for girls should be pursued simultaneously in India. FUNDING: None. TRANSLATION: For the Hindi translation of the abstract see Supplementary Materials section.

Empirical Antitubercular Treatment for Lymphadenopathy: Are We Missing Lymphoma?

OBJECTIVE: To evaluate the proportion of patients who received empirical treatment with antitubercular therapy (ATT) prior to the diagnosis of Hodgkin lymphoma (HL) in the first multicentric, prospective study on HL from India, and to assess its impact on extent of disease at diagnosis and outcomes. METHODS: Children < 18 y with biopsy proven HL were enrolled in InPOG-HL-15-01. Along with other clinical and epidemiological data, history of prior treatment with ATT was documented. All patients received treatment as per a risk-stratified, response-adapted strategy. RESULTS: Out of 396, 115 (29%) children had received ATT prior to establishing a definitive diagnosis of HL. This cohort presented with advanced-stage disease (p = 0.001) and B symptoms (p = 0.001) in a higher proportion of cases. Consequently, those children were more likely to receive 6 rather than 4 cycles of chemotherapy (p = 0.001). They were more likely to have infradiaphragmatic involvement (p = 0.001). Overall survival and event-free survival were not different. CONCLUSION: Empirical treatment with ATT in children presenting with lymphadenopathy continues to be practiced widely in India. The delay in diagnosis may contribute to children presenting with advanced-stage disease warranting more intensive treatment for successful outcomes.