Treatment outcomes in patients with Ewing sarcoma of the spine in a resource-challenged setting: 17-year experience from a single center in India.

Ewing sarcoma (ES) of the spine is a rare childhood cancer with sparse literature on treatment outcomes. We aimed to describe survival outcomes and prognostic factors in patients with spinal ES treated at a single institute in a resource-challenged setting. We conducted a retrospective analysis of patients with spinal ES registered at a tertiary care oncology center between 2003-2019. Clinical patient data was retrieved from hospital records. Cox regression analysis was used to identify the association of baseline clinical parameters with event free survival (EFS) and overall survival (OS). A cohort of 85 patients was analyzed including 38 (45%) patients with metastatic disease. The median age was 15 years with 73% being male. Local therapy was administered in 62 (72.9%) patients with surgery alone in 8 (9.4%), radiotherapy alone in 36 (42.4%) and both in 18 (21.2%) patients. A higher proportion of males received local therapy than females (80.3% versus 59.1%; p = 0.049). The median EFS and OS were 20.1 and 28.6 months, respectively. On univariable analysis, age ≤ 15 years, female sex, serum albumin ≤3.5 g/dL and hemoglobin ≤11 g/dL were associated with inferior EFS while younger age, female sex, hypoalbuminemia and metastatic disease were associated with inferior OS. On multivariable analysis, only hypoalbuminemia was predictive for inferior EFS (HR:2.41; p = 0.005) while hypoalbuminemia (HR:2.06;p = 0.033) and female sex (HR:1.83; p = 0.046) were associated with inferior OS. We concluded that hypoalbuminemia confers poor prognosis in ES spine. Survival outcomes are poorer in females treated in our setting, possibly due to prevailing sex-based biases.

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.

Determinants and impact of diagnostic interval in bone sarcomas: A retrospective cohort study.

BACKGROUND: Diagnostic delays in cancers are frequent in developing countries due to poor health infrastructure. Existing literature from developed countries suggests that diagnostic interval in bone sarcomas is primarily dictated by tumour biology with no impact on survival. This study evaluates the social and biological determinants of the diagnostic interval in bone sarcomas in a resource-challenged setting and assesses its impact on treatment outcomes. METHODS: A retrospective single-institutional study was conducted on patients with high-grade bone sarcomas recorded in the sarcoma clinic database between 2003 and 2018. Baseline clinical characteristics and treatment outcomes were recorded. Logistic regression was performed to assess the impact of baseline clinical and social characteristics (distance from treating centre and rural vs. urban residence) on the diagnostic interval. Further, the impact of diagnostic interval on histologic response to neoadjuvant chemotherapy, amputation requirement in extremity sarcomas and survival was evaluated. RESULTS: A total of 1227 patients were included for analysis. The median diagnostic interval was 4 months (3-7 months). Age above 18 years, Ewing sarcoma (ES) diagnosis, absence of fever at presentation and tumour size above 7.5 cm were predictors of a longer diagnostic interval (>4 months). The length of the diagnostic interval did not impact amputation requirement or survival outcomes. However, the proportion of patients with good necrosis post-neoadjuvant chemotherapy was lower among patients with longer diagnostic intervals (25% vs. 34·16%; p-value = .04). CONCLUSION: Tumour characteristics rather than social factors determined the diagnostic interval. Diagnostic interval did not impact survival outcomes even in a resource-constrained setting.

The impact of COVID-19 pandemic on access to treatment for children with cancer in India and treating center practices.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic led the Indian government to announce a nationwide lockdown on March 23, 2020. This study aimed to explore the impact of the pandemic on the accessibility of care for children with cancer and to view strategies adopted by hospitals for service delivery. METHODS: Weekly average of childhood cancer (≤18 years) patient registrations during pre-lockdown period (January 1 to March 23, 2020) were compared with post-lockdown period (March 24 to May 31, 2020). The effect on the scheduled treatment was investigated for post-lockdown period. A survey of health care providers was conducted to determine centers' adopted strategies. RESULTS: In 30 participating centers, 1146 patients with childhood cancer (797 pre-lockdown period and 349 post-lockdown period) were registered. The weekly average registration was 67.3 and 35.5 patients during pre-lockdown and post-lockdown respectively (decline of 47.9%). Although most centers experienced this decline, there were 4 that saw an increase in patient registrations. The distribution of patients registered post-lockdown was found significantly different by age (lesser older age, P = .010) and distance (lesser travel distance, P = .001). 36.1% of patients, who were scheduled for any of the treatment modalities (chemotherapy, surgery, radiotherapy, and hematopoietic stem cell transplantation) during the post-lockdown period, experienced delays. Centers adopted several strategies including modifications to treatment protocols, increased use of growth factors, and increased support from social organizations. CONCLUSIONS: This multicenter study from India suggests that the COVID-19 pandemic and the lockdown impacted 2 out of 3 children with cancer. The effect of this on survival is yet to be established.

Prognostic utility of key copy number alterations in T cell acute lymphoblastic leukemia.

T-cell acute lymphoblastic leukemia (T-ALL) is a genetically heterogeneous disease, characterized by an abnormal transformation of T cells into highly proliferative leukemic lymphoblasts. Identification of common genetic alterations has provided promising opportunities for better risk stratification in T-ALL. Current treatment in T-ALL still poses the major challenge of integrating the knowledge of molecular alterations in the clinical setting. We utilized the Multiplex Ligation Dependent Probe Amplification (MLPA) method to determine the frequency of common copy number alterations (CNAs) in 128 newly diagnosed T-ALL patients. We also studied the association of these CNAs with patient's clinical characteristics and survival. The highest frequency of deletion was observed in CDKN2A (59.38%), followed by CDKN2B (46.88%), LMO1 (37.5%), and MTAP (28.12%). PTPN2 (22.66%), PHF6 (14.06%), and MYB (14.06%) had the highest number of duplication events. A total of 89.06% patients exhibited CNAs. STIL::TAL1, NUP214::ABL1, and LMO2::RAG2 fusions were observed in 5.47%, 3.12%, and 0.78% of patients, respectively. CDKN2A, CDKN2B, and PTPN2 gene deletions were mainly observed in pediatric patients, while CNAs of NF1 and SUZ12 were observed more frequently in adults. In pediatric patients, alterations in CDKN2B, CASP8AP2, and AHI1 were associated with poor prognosis, while SUZ12 and NF1 CNAs were associated with favorable prognosis. In adult patients, ABL1 CNA emerged as an independent indicator of poor prognosis. The observed molecular heterogeneity in T-ALL may provide the basis for variations observed in clinical response in T-ALL and MLPA based CNA detection may help in risk stratification of these patients.

Autologous Hematopoietic Stem Cell Transplant: A Potential Option for Relapsed Pediatric Acute Myeloid Leukemia With Lack of Matched Sibling Donor and Resource Challenge.

Though allogeneic hematopoietic stem cell transplant (HSCT) is standard for relapsed pediatric acute myeloid leukemia, often it may not be accessible due to donor unavailability and resource limitations. We retrospectively analyzed outcomes of 26 children (mean age: 10.9±4.5 y) who underwent autologous HSCT in complete remission 2. Three-year event-free survival and overall survival were 50.1±10.7% and 63.3±9%, respectively; with 1 treatment-related death and 46% relapse rate. Notwithstanding the retrospective study design and somewhat favorable patient characteristics, the outcomes are comparable with those of other series and our own allogeneic HSCT data. Autologous HSCT is a potential alternative to allogeneic HSCT, especially in countries with poorly maintained donor registries.

Characteristics & outcomes of cancer patients with COVID-19: A multicentre retrospective study from India.

Background & objectives: High mortality has been observed in the cancer population affected with COVID-19 during this pandemic. We undertook this study to determine the characteristics and outcomes of cancer patients with COVID-19 and assessed the factors predicting outcome. Methods: Patients of all age groups with a proven history of malignancy and a recent diagnosis of SARS-CoV-2 infection based on nasal/nasopharyngeal reverse transcriptase (RT)-PCR tests were included. Demographic, clinical and laboratory variables were compared between survivors and non-survivors groups, with respect to observed mortality. Results: Between May 11 and August 10, 2020, 134 patients were included from the three centres and observed mortality was 17.1 per cent. The median age was 53 yr (interquartile range 39-61 yr) and thirty four patients (25%) were asymptomatic. Solid tumours accounted for 69.1 per cent and breast cancer was the most common tumour type (20%). One hundred and five patients (70.5%) had received chemotherapy within the past four weeks and 25 patients (19.3%) had neutropenia at presentation. On multivariate analysis, age [odds ratio (OR) 7.99 (95% confidence interval [CI] 1.18-54.00); P=0.033], haemoglobin [OR 6.28 (95% CI 1.07-37.04); P=0.042] neutrophil-lymphocyte ratio [OR 12.02 (95% CI 2.08-69.51); P=0.005] and baseline serum albumin [OR 18.52 (95% CI 2.80-122.27); P=0.002], were associated with higher mortality. Recent chemotherapy, haematological tumours type and baseline neutropenia did not affect the outcome. Interpretation & conclusions: Higher mortality in moderate and severe infections was associated with baseline organ dysfunction and elderly age. Significant proportion of patients were asymptomatic and might remain undetected.

Oral metronomic chemotherapy is a cost effective alternative to pazopanib in advanced soft tissue sarcoma.

INTRODUCTION: Soft tissue sarcoma(STS) is a rare and heterogeneous group of disorders with dismal outcomes in metastatic setting. Pazopanib and oral metronomic chemotherapy (OMT) have been evaluated as therapeutic options in this cohort. MATERIALS AND METHODS: We conducted a retrospective, single center study evaluating 45 patients with unresectable and/or metastatic STS, who received pazopanib or oral metronomic regimen as per instituitonal protocol between January 2013 and December 2019. An informal cost minimisation analysis was conducted for both OMT and pazopanib arms, considering equivalent outcomes for both (PFS and OS). RESULTS: Median PFS in OMT and Pazopanib groups was 4.13 months and 3.53 months,respectively (HR1.31, 95% CI:0.68-2.51, p = 0.41) Only one patient in the OMT group achieved an objective response (partial response) and no objective response was noted in the pazopanib group. The incidence of grade III/IVtoxicities was higher with pazopanib than with OMT (p = 0.08). There were no toxicity related deaths noted in either arm. CONCLUSIONS: Our study demonstrates that OMT have a similar progression free survival (PFS) and overall survival (OS) in metastatic STS. This study raises the possibility that OMT might be an equally efficacious and less toxic alternative to pazopanib, without compromising survival outcome especially in LMIC.

Cytomorphological and immunophenotypic characteristics of blastic plasmacytoid dendritic cell neoplasm involving central nervous system: a case report and review of literature.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare, aggressive hematopoietic neoplasm derived from precursors of plasmacytoid dendritic cells. We describe cytomorphological and immunophenotypic features of BPDCN in cerebrospinal fluid (CSF) in a 66-year-old patient who presented with delayed central nervous system relapse. Morphological examination showed dense infiltration by monotonous population of intermediate-sized cells, resembling blasts. Nuclei had irregular contour with fine chromatin and prominent nucleoli. The cells had scant, pale blue, agranular cytoplasm. In some cells, intracytoplasmic vacuoles were also seen. No lymphoglandular bodies were seen. No mitosis or karyorrhexis were observed. On immunophenotyping, these cells were positive for CD45dim, CD123dim, HLA-DR, CD56, CD36bright, TCL1, CD4, CD117, CD38dim and negative for CD13, CD33, CD34, CD14, CD64 and CD16. The relevance of clinical suspicion, cytological recognition, and inclusion of BPDCN specific immunophenotypic markers is emphasized.

Allogeneic hematopoietic stem cell transplant in pediatric acute myeloid leukemia: Lessons learnt from a tertiary care center in India.

There is paucity of data on outcomes of MSD-HSCT in children with relapsed or high-risk AML from developing countries, which have unique challenges including adverse host factors and resource constraints. We retrospectively reviewed records of children (age ≤ 18 years) who underwent MSD-HSCT for AML at our center from 2009 to 2019 to evaluate clinical outcome and its predictors using Cox proportional hazards model. There were 46 children (36 boys and 10 girls) with mean age 10.7 ± 4.8 years. Indication for HSCT was relapsed AML in CR2 (n = 37), primary refractory (n = 3), or relapsed refractory disease (n = 3); high-risk (n = 1) or secondary (n = 2) AML in CR1. Five-year EFS and OS were 33.3 ± 7.2% and 36.3 ± 7.6%, respectively. On multivariate analysis, CR1 duration less than 12 months, presence of active disease at transplant, and use of bone marrow stem cell graft were associated with poorer EFS and OS. There was one (2.2%) TRM, while disease relapse occurred in 20/40 patients who underwent HSCT in remission. Though the 5-year EFS and OS were inferior to results reported from high-income countries, relapse (and not TRM) was the major cause of treatment failure. A well-sustained CR1, achievement of disease remission, and use of peripheral blood allograft seem imperative to a successful transplant. Targeted therapy along with HSCT may be the option for those with early relapse.

Impact of microbial contamination of haematopoietic stem cells on post-transplant outcomes: A retrospective study from tertiary care centre in India.

BACKGROUND: Haematopoietic stem cells (HSC) may act as a source of infection for the recipient due to manipulation at multiple levels from collection to infusion. Due to the high risk of contamination cultures are usually taken during multiple steps. The clinical significance of microbial contamination of HSC on the post-transplant course and the role of prophylactic antibiotics is relatively unknown. AIMS AND METHODS: The aim of our study is to investigate the incidence of microbial contamination of haematopoietic stem cell and to assess its impact on the post-transplant febrile neutropenia, engraftment kinetics, hospitalisation and day 100 mortality. Details of all patients admitted in the bone marrow transplantation unit of a tertiary care centre in India between January 2014 and December 2018 were collected from case records. RESULTS: Of the 1306 stem cell harvests from 503 patients sent for culture, 17 harvests (1.3%) were found to have a culture positive report. Sixteen patients had undergone autologous transplant. Multiple myeloma was most common indication of HSC transplant followed by Non-Hodgkin Lymphoma (NHL). Twelve of 17 HSC cultures were positive at the time of infusion and five were positive at the time of harvest. The five HSC that were culture positive at the time of harvest were culture negative at the time of infusion. Gram-positive organisms were isolated in six cultures and gram-negative in rest. All patients developed febrile neutropenia post-transplantation between day 1 and day 7. The median time of onset of fever was day +5 (1-7), the median duration of fever was 4 days (2-7), the median duration of antibiotic use was 11 days (9-16). Median day for neutrophil engraftment was 11 days (9-16), the median day for platelet engraftment was 14 days (10-25) and median duration of hospitalisation was 15 days (12-78). All patients were alive at day 100 of transplant. CONCLUSION: This study shows that there appears to be minimal impact of culture positive HSC on transplant related outcomes in terms of engraftment kinetics, duration of hospitalisation and day 100 mortality. Discarding of contaminated HSC may not be required, though on development of febrile neutropenia appropriate antibiotics should be administered based on sensitivity pattern of HSC culture. Larger prospective studies are needed to determine the clinical relevance of such contaminations. Emphasis should be laid on better infection control practices to minimise contamination rates.

Management of advanced melanoma in the current era: A medical oncology perspective for the Indian scenario.

Malignant melanoma is an aggressive malignancy with high recurrence rates after curative surgery and in advanced stages is characterized by resistance to conventional chemotherapy. With better understanding of the genomic landscape and mutational signature of these tumours over the past decade, there has been a paradigm shift in management of melanoma using immunotherapy (anti-PD-1 and anti-CTLA-4 antibodies) and targeted drugs against BRAF and MEK. These drugs have shown survival benefits in both adjuvant and metastatic setting with patients being eligible for immunotherapy irrespective of any biomarker. However, these drugs have varying toxicity profiles and there are no studies comparing these two classes of drugs in either the adjuvant or metastatic setting leaving the question of sequencing open to clinical judgement. Moreover, availability and cost are issues that need to be considered before use of these drugs in the Indian setting.

Concerns of Health Care Professionals Managing non-COVID Patients during The COVID-19 Pandemic: A Descriptive Cross- Sectional Study.

CONTEXT: The coronavirus pandemic has put an unprecedented burden on the health-care workers who are the cornerstone of the work system, preparing to mitigate its effects. Due to the lack of protective equipments, guidelines for managing patients, or proper training and education regarding the same, health care professionals (HCPs) working in non-COVID areas may face even greater problems than those working in COVID areas of a hospital. Our aim was to find out the concerns of HCPs working in non-COVID areas. SUBJECTS AND METHODS: After obtaining institutional ethics approval, a descriptive cross-sectional study was planned. An online Google-based questionnaire was rolled out to all doctors through various social media platforms who were dealing with COVID-negative patients. RESULTS: We received a total of 110 responses. 84.5% of participants were concerned about the risk of infection to self and family, 67.3% were concerned by the disruption of their daily activities. 56.4% of HCPs were disturbed by the lack of any concrete protocol for patient management. Less staff availability, delay in discharging duties toward their patients, and increased workload were other concerns. More than half of the doctors received N-95 masks whenever required and were trained in donning and doffing of Personal protective equipment. Sixty-eight percemt of our respondents labeled their current quality of life as stressful. CONCLUSION: It is the need of the hour to develop a comprehensive strategy focussing on the above challenges that HCPs working in non-COVID areas are facing. This will go a long way in not only providing holistic care to the patients but also in controlling this pandemic.

Paediatric chronic myeloid leukaemia: Is it really a different disease?

Paediatric chronic myeloid leukaemia (CML) has biological and clinical differences from adult CML. Management of paediatric CML presents unique challenges in growing children, and there are no specific guidelines for paediatric CML. This review focusses on the clinical characteristics, diagnostic issues and management of paediatric CML. Major studies that provide the basis of managing paediatric CML are summerized here. Studies conducted on adult CML patients were used to guide the management of places where studies were lacking in paediatric CML. Recently, dasatinib and nilotinib have been approved for treatment of paediatric CML, and their role has been discussed in the current management perspective. Allogeneic transplant, fertility and vaccination in paediatric CML, have also been discussed.

Association of absolute lymphocyte count and peripheral blood lymphocyte subsets percentage with minimal residual disease at the end of induction in pediatric B cell acute lymphoblastic leukemia.

Absolute lymphocyte count (ALC) has been associated with overall survival (OS) and event-free survival, but we do not know if ALC is associated with minimal residual disease (MRD) at the end of induction (EOI) and whether it can be used as surrogate marker in resource limited settings. Immunological differences between MRD-positive and MRD-negative B ALL patients at the EOI are not known at present. This prospective study evaluated the association of ALC and peripheral blood lymphocyte subset percentage at the EOI with MRD. ALC was done at baseline, day 8, and day 15 and at EOI. Assessment for MRD and peripheral blood lymphocyte subset was done at EOI. In 2-year study duration, 197 B cell acute lymphoblastic leukemia (ALL) patients were recruited out of which 150 were analyzed. Peripheral lymphocyte subset percentage was available for 58 patients. We found that ALC at baseline, day 8, day 15, and EOI was not associated with MRD. Day 8 ALC was significantly higher in poor steroid responders (day 8 blasts > 1 × 109 cells/l) (p < 0.0001). At the EOI, CD4-CD8+ cell percentage in peripheral blood were significantly higher in MRD-positive patients than MRD-negative patients (p = 0.01). Our study suggests that ALC at any point is not a surrogate marker for MRD. Immunologically MRD-positive and MRD-negative patients differ in CD4-CD8+ cells. The role of CD8+T and TCRαßCD3+T cells in eliminating residual leukemic cells need to be studied further by functional assays.