Indian Pediatric Oncology Group (InPOG) – Collaborative research in India comes of age

AbstractTreatment of children with cancer on clinical trials, often in the context of national and international co-operative groups, is one of the cornerstones of pediatric oncology treatment and has been shown to improve outcomes of children with cancer. While enrolling children with cancer in prospective multi-centre trials has become the norm in high-income countries, it has remained an exception in low and middle-income countries until recently. In this article, we briefly review the global landscape of pediatric oncology co-operative groups and then discuss the Indian scenario including more recent developments of the formation and galvanization of the Indian Pediatric Oncology Group (InPOG). The mission of InPOG is to improve the outcomes of children with cancer in India by collaborative research. A roadmap for the development and conduct of an InPOG study has been created and 21 disease-specific subcommittees have been formed. Multi-centre studies on Hodgkin lymphoma and acute lymphoblastic leukemia are currently recruiting and several others are under development

Intramedullary spinal cord lesions in children

Paediatric intramedullary spinal cord lesions are uncommon pathologies, prone to result in dismal prognosis if not managed promptly and aggressively. While children usually present in good functional grades compared to adults, early recognition and treatment is important to improve outcomes. In this review, we present tumour demographics, patient factors, and treatment modalities of intramedullary spinal cord lesions in paediatric patients

A randomized, prospective open labeled study of oral amoxicillin-clavulanate and levofloxacin with intravenous ceftriaxone and amikacin in chemotherapy induced low risk febrile neutropenia

Background : We compared the efficacy of oral antibiotics with intravenous antibiotics in low risk febrile neutropenia. Design : A prospective, randomized study Methods: Between April 2004 - December 2005, 55 patients with low risk febrile neutropenia (expected neutropenia duration < 7 days with no co-morbid features) between 15 and 75 years of age, were randomized to receive either oral amoxicillin-clavulanate 625mg twice daily and levofloxacin -500mg once daily OR intravenous (i.v.) ceftriaxone 2g and amikacin 15mg/kg once daily. Most patients were treated on out patient basis. The primary end point was response to therapy, defervescence of fever within 72 hours with improvement in any clinical manifestation of infection and no recurrence of fever for 48 hours without use of antipyretics. Use of growth factors was not permitted except in treatment failure. Results: A total of 64 febrile episodes were recorded (mean 1.20 ); 33 in the IV group and 31 in the oral antibiotics group. Both groups were equally matched for age (median 25 years in the IV group and 19 years in the oral group), gender, type of cancer, baseline absolute neutrophil count (median 200/cmm in both arms) and duration of neutropenia (5 days and 4 days in the IV and oral groups, respectively). A focus of infection was identified clinically in 15% of episodes and microbiologically in 11% of episodes; 57% of which were Gram positive organisms and the rest Gram negative. 72% in the IV arm and 77% in the oral arm responded to therapy (p=ns). One patient in IV group had one episode of seizure. Non-responding patients received second line IV antibiotics. There was no mortality in either group. Age > 60 years, neutropenia lasting > 7 days after the onset of fever and positive blood culture were predictors for lack of response to antibiotics on multivariate analysis. Conclusion: Oral antibiotics have comparable efficacy as IV antibiotics in the management of low risk febrile neutropenia

Extraocular retinoblastoma in Indian children:clinical, imaging and histopathological features

AIM: To study eyes with extraocular dissemination (EORB), with the following aims:first to establish the mean lag period and to understand various reasons for delayed presentation, second to study their imaging profiles and third to analyze histopathological features of eyes enucleated after neoadjuvant chemotherapy.METHODS: Prospective study of clinical and imaging features of EORBs (stage Ⅲ and Ⅳ International Retinoblastoma Staging System) presenting to a tertiary eye care centre. Histopathological features of eyes enucleated after receiving neoadjuvant chemotherapy were analyzed. A pictorial illustration of the varied imaging profile of EORB was also presented.RESULTS: Over a period of one year, 97 eyes were diagnosed with retinoblastoma; 32 children (36 eyes) (37.1%) had EORB. Mean age 3.6±1.9 years, 71.9% males, 71.9% unilateral, 3.1% with positive family history and 40.6% with metastasis. On imaging, there was extrascleral involvement in 22.2%, involvement of orbital part of optic nerve in 33.3%, involvement of central nervous system in 27.8% and orbital wall involvement in 2.9% eyes. On histopathological analysis of eyes enucleated after neoadjuvant chemotherapy, 25.0% had no residual viable tumour tissue and rest all tumours were poorly differentiated.CONCLUSION:There are very few human malignancies where definitive treatment is started without any confirmed histopathological diagnosis and imaging plays an important role in diagnosis and appropriate staging of the disease. Chemotherapy has a variable effect on EORB, 75.0% of eyes with EORB had residual viable tumour tissue when enucleated after receiving neoadjuvant chemotherapy

A health care labyrinth: perspectives of caregivers on the journey to accessing timely cancer diagnosis and treatment for children in India.

BACKGROUND: Cure rates for children with cancer in India lag behind that of high-income countries. Various disease, treatment and socio-economic related factors contribute to this gap including barriers in timely access of diagnostic and therapeutic care. This study investigated barriers to accessing care from symptom onset to beginning of treatment, from perspectives of caregivers of children with cancer in India. METHODS: Semi-structured in-depth interviews were conducted with caregivers of children (< 18 years) diagnosed with cancer in seven tertiary care hospitals across New Delhi and Hyderabad. Purposive sampling to saturation was used to ensure adequate representation of the child's gender, age, cancer type, geographical location and socioeconomic status. Interviews were audio recorded after obtaining informed consent. Thematic content analysis was conducted and organised using NVivo 11. RESULTS: Thirty-nine caregivers were interviewed, where three key themes emerged from the narratives: time intervals to definitive diagnosis and treatment, the importance of social supportive care and the overall accumulative impacts of the journey. There were two phases encapsulating the experiences of the family: referral pathways taken to reach the hospital and after reaching the hospital. Most caregivers, especially those from distant geographical areas had variable and inconsistent referral pathways partly due to poor availability of specialist doctors and diagnostic facilities outside major cities, influence from family or friends, and long travel times. Upon reaching the hospital, families mostly from public hospitals faced challenges navigating the hospital facilities, finding accommodation, and comprehending the diagnosis and treatment pathway. Throughout both phases, financial constraint was a recurring issue amongst low-income families. The caregiver's knowledge and awareness of the disease and health system, religious and social factors were also common barriers. CONCLUSION: This qualitative study highlights and explores some of the barriers to childhood cancer care in India. Our findings show that referral pathways are intrinsically linked to the treatment experience and there should be better recognition of the financial and emotional challenges faced by the family that occur prior to definitive diagnosis and treatment. This information would help inform various stakeholders and contribute to improved interventions addressing these barriers

IKZF1 Deletions with COBL Breakpoints Are Not Driven by RAG-Mediated Recombination Events in Acute Lymphoblastic Leukemia

IKZF1 deletion (ΔIKZF1) is an important predictor of relapse in both childhood and adult B-cell precursor acute lymphoblastic leukemia (B-ALL). Previously, we revealed that COBL is a hotspot for breakpoints in leukemia and could promote IKZF1 deletions. Through an international collaboration, we provide a detailed genetic and clinical picture of B-ALL with COBL rearrangements (COBL-r). Patients with B-ALL and IKZF1 deletion (n = 133) were included. IKZF1 ∆1-8 were associated with large alterations within chromosome 7: monosomy 7 (18%), isochromosome 7q (10%), 7p loss (19%), and interstitial deletions (53%). The latter included COBL-r, which were found in 12% of the IKZF1 ∆1-8 cohort. Patients with COBL-r are mostly classified as intermediate cytogenetic risk and frequently harbor ETV6, PAX5, CDKN2A/B deletions. Overall, 56% of breakpoints were located within COBL intron 5. Cryptic recombination signal sequence motifs were broadly distributed within the sequence of COBL, and no enrichment for the breakpoint cluster region was found. In summary, a diverse spectrum of alterations characterizes ΔIKZF1 and they also include deletion breakpoints within COBL. We confirmed that COBL is a hotspot associated with ΔIKZF1, but these rearrangements are not driven by RAG-mediated recombination

Recurrent hemorrhagic pericardial effusion in a child due to diffuse lymphangiohemangiomatosis: a case report

<p>Abstract</p> <p>Introduction</p> <p>Recurrent hemorrhagic pericardial effusion in children with no identifiable cause is a rare presentation.</p> <p>Case presentation</p> <p>We report the case of a 4-year-old Indian girl who presented with recurrent hemorrhagic pericardial effusion. Diffuse lymphangiomatosis was suspected when associated pulmonary involvement, soft tissue mediastinal mass, and lytic bone lesions were found. Pericardiectomy and lung biopsy confirmed the diagnosis of diffuse lymphangiohemangiomatosis. Partial clinical improvement occurred with thalidomide and low-dose radiotherapy, but our patient died from progressive respiratory failure.</p> <p>Conclusion</p> <p>Diffuse lymphangiohemangiomatosis should be considered in the differential diagnosis of hemorrhagic pericardial effusion of unclear cause.</p

A proposed methodology for detecting the malignant potential of pulmonary nodules in sarcoma using computed tomographic imaging and artificial intelligence-based models

The presence of lung metastases in patients with primary malignancies is an important criterion for treatment management and prognostication. Computed tomography (CT) of the chest is the preferred method to detect lung metastasis. However, CT has limited efficacy in differentiating metastatic nodules from benign nodules (e.g., granulomas due to tuberculosis) especially at early stages (&lt;5 mm). There is also a significant subjectivity associated in making this distinction, leading to frequent CT follow-ups and additional radiation exposure along with financial and emotional burden to the patients and family. Even 18F-fluoro-deoxyglucose positron emission technology-computed tomography (18F-FDG PET-CT) is not always confirmatory for this clinical problem. While pathological biopsy is the gold standard to demonstrate malignancy, invasive sampling of small lung nodules is often not clinically feasible. Currently, there is no non-invasive imaging technique that can reliably characterize lung metastases. The lung is one of the favored sites of metastasis in sarcomas. Hence, patients with sarcomas, especially from tuberculosis prevalent developing countries, can provide an ideal platform to develop a model to differentiate lung metastases from benign nodules. To overcome the lack of optimal specificity of CT scan in detecting pulmonary metastasis, a novel artificial intelligence (AI)-based protocol is proposed utilizing a combination of radiological and clinical biomarkers to identify lung nodules and characterize it as benign or metastasis. This protocol includes a retrospective cohort of nearly 2,000–2,250 sample nodules (from at least 450 patients) for training and testing and an ambispective cohort of nearly 500 nodules (from 100 patients; 50 patients each from the retrospective and prospective cohort) for validation. Ground-truth annotation of lung nodules will be performed using an in-house-built segmentation tool. Ground-truth labeling of lung nodules (metastatic/benign) will be performed based on histopathological results or baseline and/or follow-up radiological findings along with clinical outcome of the patient. Optimal methods for data handling and statistical analysis are included to develop a robust protocol for early detection and classification of pulmonary metastasis at baseline and at follow-up and identification of associated potential clinical and radiological markers

The Association between Patient Characteristics and the Efficacy and Safety of Selinexor in Diffuse Large B-Cell Lymphoma in the SADAL Study.

Selinexor, an oral selective inhibitor of nuclear export, was evaluated in the Phase 2b SADAL study in patients with diffuse large B-cell lymphoma (DLBCL) who previously received two to five prior systemic regimens. In post hoc analyses, we analyzed several categories of patient characteristics (age, renal function, DLBCL subtype, absolute lymphocyte count, transplant status, number of prior lines of therapy, refractory status, Ann Arbor disease stage, and lactate dehydrogenase) at baseline, i.e., during screening procedures, to determine their potential contributions to the efficacy (overall response rate [ORR], duration of response [DOR], overall survival [OS]) and tolerability of selinexor. Across most categories of characteristics, no significant difference was observed in ORR or DOR. OS was significantly longer for patients ULN. The most common adverse events (AEs) across the characteristics were thrombocytopenia and nausea, and similar rates of grade 3 AEs and serious AEs were observed. With its oral administration, novel mechanism of action, and consistency in responses in heavily pretreated patients, selinexor may help to address an important unmet clinical need in the treatment of DLBCL

The Association between Patient Characteristics and the Efficacy and Safety of Selinexor in Diffuse Large B-Cell Lymphoma in the SADAL Study.

Selinexor, an oral selective inhibitor of nuclear export, was evaluated in the Phase 2b SADAL study in patients with diffuse large B-cell lymphoma (DLBCL) who previously received two to five prior systemic regimens. In post hoc analyses, we analyzed several categories of patient characteristics (age, renal function, DLBCL subtype, absolute lymphocyte count, transplant status, number of prior lines of therapy, refractory status, Ann Arbor disease stage, and lactate dehydrogenase) at baseline, i.e., during screening procedures, to determine their potential contributions to the efficacy (overall response rate [ORR], duration of response [DOR], overall survival [OS]) and tolerability of selinexor. Across most categories of characteristics, no significant difference was observed in ORR or DOR. OS was significantly longer for patients ULN. The most common adverse events (AEs) across the characteristics were thrombocytopenia and nausea, and similar rates of grade 3 AEs and serious AEs were observed. With its oral administration, novel mechanism of action, and consistency in responses in heavily pretreated patients, selinexor may help to address an important unmet clinical need in the treatment of DLBCL