Genetic and Functional Drivers of Diffuse Large B Cell Lymphoma.

Diffuse large B cell lymphoma (DLBCL) is the most common form of blood cancer and is characterized by a striking degree of genetic and clinical heterogeneity. This heterogeneity poses a major barrier to understanding the genetic basis of the disease and its response to therapy. Here, we performed an integrative analysis of whole-exome sequencing and transcriptome sequencing in a cohort of 1,001 DLBCL patients to comprehensively define the landscape of 150 genetic drivers of the disease. We characterized the functional impact of these genes using an unbiased CRISPR screen of DLBCL cell lines to define oncogenes that promote cell growth. A prognostic model comprising these genetic alterations outperformed current established methods: cell of origin, the International Prognostic Index comprising clinical variables, and dual MYC and BCL2 expression. These results comprehensively define the genetic drivers and their functional roles in DLBCL to identify new therapeutic opportunities in the disease.

Quality indicators for evaluating cancer care in low-income and middle-income country settings: a multinational modified Delphi study.

This Policy Review sourced opinions from experts in cancer care across low-income and middle-income countries (LMICs) to build consensus around high-priority measures of care quality. A comprehensive list of quality indicators in medical, radiation, and surgical oncology was identified from systematic literature reviews. A modified Delphi study consisting of three 90-min workshops and two international electronic surveys integrating a global range of key clinical, policy, and research leaders was used to derive consensus on cancer quality indicators that would be both feasible to collect and were high priority for cancer care systems in LMICs. Workshop participants narrowed the list of 216 quality indicators from the literature review to 34 for inclusion in the subsequent surveys. Experts' responses to the surveys showed consensus around nine high-priority quality indicators for measuring the quality of hospital-based cancer care in LMICs. These quality indicators focus on important processes of care delivery from accurate diagnosis (eg, histologic diagnosis via biopsy and TNM staging) to adequate, timely, and appropriate treatment (eg, completion of radiotherapy and appropriate surgical intervention). The core indicators selected could be used to implement systems of feedback and quality improvement.

Treatment challenges and outcomes of older patients with acute myeloid leukemia from India.

Globally, overall survival (OS) of older patients with AML continues to be suboptimal with very little data from India. In a multicenter registry analysis, we evaluated 712 patients with AML older than 55 years. Only 323 (45.3%) underwent further treatment, of which 239 (74%) received HMAs, and 60 (18%) received intensive chemotherapy (IC). CR was documented in 39% of those receiving IC and 42% after HMAs. Overall, 100 (31%) patients died within 60 days of diagnosis, most commonly due to progressive disease (47%) or infections (30%). After a median follow-up of 176 days, 228 (76%) of patients had discontinued treatment. At one year from diagnosis, 211 (65%) patients had died, and the median OS was 186 days (IQR, 137-234). Only 12 (3.7%) patients underwent stem cell transplantation. Survival was significantly lower for those older than 60 years (p < 0.001). Patients who died had a higher median age (p = .027) and baseline WBC counts (p = .006). Our data highlights suboptimal outcomes in older AML patients, which are evident from 55 years of age onwards, making it necessary to evaluate HMA and targeted agent combinations along with novel consolidation strategies to improve survival in this high-risk population.

Design of a clinical trial using generalized pairwise comparisons to test a less intensive treatment regimen.

BACKGROUND/AIMS: Showing "similar efficacy" of a less intensive treatment typically requires a non-inferiority trial. Yet such trials may be challenging to design and conduct. In acute promyelocytic leukemia, great progress has been achieved with the introduction of targeted therapies, but toxicity remains a major clinical issue. There is a pressing need to show the favorable benefit/risk of less intensive treatment regimens. METHODS: We designed a clinical trial that uses generalized pairwise comparisons of five prioritized outcomes (alive and event-free at 2 years, grade 3/4 documented infections, differentiation syndrome, hepatotoxicity, and neuropathy) to confirm a favorable benefit/risk of a less intensive treatment regimen. We conducted simulations based on historical data and assumptions about the differences expected between the standard of care and the less intensive treatment regimen to calculate the sample size required to have high power to show a positive Net Treatment Benefit in favor of the less intensive treatment regimen. RESULTS: Across 10,000 simulations, average sample sizes of 260 to 300 patients are required for a trial using generalized pairwise comparisons to detect typical Net Treatment Benefits of 0.19 (interquartile range 0.14-0.23 for a sample size of 280). The Net Treatment Benefit is interpreted as a difference between the probability of doing better on the less intensive treatment regimen than on the standard of care, minus the probability of the opposite situation. A Net Treatment Benefit of 0.19 translates to a number needed to treat of about 5.3 patients (1/0.19 ≃ 5.3). CONCLUSION: Generalized pairwise comparisons allow for simultaneous assessment of efficacy and safety, with priority given to the former. The sample size required would be of the order of 300 patients, as compared with more than 700 patients for a non-inferiority trial using a margin of 4% against the less intensive treatment regimen for the absolute difference in event-free survival at 2 years, as considered here.

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.

Global application of National Comprehensive Cancer Network resource-stratified guidelines for systemic treatment of colon cancer: a population-based, customisable model for cost, demand, and procurement.

BACKGROUND: Resource-stratified guidelines (RSGs) can inform systemic treatment decisions in the face of limited resources. The objective of this study was to develop a customisable modelling tool to predict the demand, cost, and drug procurement needs of delivering National Comprehensive Cancer Network (NCCN) RSG-based systemic treatment for colon cancer. METHODS: We developed decision trees for first-course systemic therapy for colon cancer based on the NCCN RSGs. Decision trees were merged with data from the Surveillance, Epidemiology, and End Results programme, the International Agency for Research on Cancer's GLOBOCAN 2020 national estimates for colon cancer incidence, country-level income data, and data on drug costs from Redbook (USA), the Pharmaceutical Benefits Scheme (Australia), and the Management Sciences for Health 2015 International Medical Products price guide to estimate global treatment needs and costs, and forecast drug procurement. Simulations and sensitivity analyses were used to explore the effect of scaling up services globally and the effect of alternative stage distributions on treatment demand and cost. We generated a customisable model, in which estimates can be tailored to local incidence, epidemiological, and costing data. FINDINGS: First-course systemic therapy is indicated in 608 314 (53·6%) of 1 135 864 colon cancer diagnoses in 2020. Indications for first-course systemic therapy are projected to rise to 926 653 in 2040; the indications in 2020 might be as high as 826 123 (72·7%), depending on stage distribution assumptions. Adhering to NCCN RSGs, patients with colon cancer in low-income and middle income countries (LMICs) would constitute 329 098 (54·1%) of 608 314 global systemic therapy demands, but only 10% of global expenditure on systemic therapies. The total cost of NCCN RSG-based first-course systemic therapy for colon cancer in 2020 would be between about US$4·2 and about $4·6 billion, depending on stage distribution. If all patients with colon cancer in 2020 were treated according to maximal resources, global expenditure on systemic therapy for colon cancer would rise to around $8·3 billion. INTERPRETATION: We have developed a customisable model that can be applied at global, national, and subnational levels to estimate systemic treatment needs, forecast drug procurement, and calculate expected drug costs on the basis of local data. This tool can be used to plan resource allocation for colon cancer globally. FUNDING: None.

Allocation of authorship and patient enrollment among global clinical trials in oncology.

BACKGROUND: Oncology randomized controlled trials (RCTs) are increasingly global in scope. Whether authorship is equitably shared between investigators from high-income countries (HIC) and low-middle/upper-middle incomes countries (LMIC/UMIC) is not well described. The authors conducted this study to understand the allocation of authorship and patient enrollment across all oncology RCTs conducted globally. METHODS: A cross-sectional retrospective cohort study of phase 3 RCTs (published 2014-2017) that were led by investigators in HIC and recruited patients in LMIC/UMIC. FINDINGS: During 2014-2017, 694 oncology RCTs were published; 636 (92%) were led by investigators from HIC. Among these HIC-led trials, 186 (29%) enrolled patients in LMIC/UMIC. One-third (33%, 62 of 186) of RCTs had no authors from LMIC/UMIC. Forty percent (74 of 186) of RCTs reported patient enrollment by country; in 50% (37 of 74) of these trials, LMIC/UMIC contributed <15% of patients. The relationship between enrollment and authorship proportion is very strong and is comparable between LMIC/UMIC and HIC (Spearman's ρ LMIC/UMIC 0.824, p < .001; HIC 0.823, p < .001). Among the 74 trials that report country enrollment, 34% (25 of 74) have no authors from LMIC/UMIC. CONCLUSIONS: Among trials that enroll patients in HIC and LMIC/UMIC, authorship appears to be proportional to patient enrollment. This finding is limited by the fact that more than half of RCTs do not report enrollment by country. Moreover, there are important outliers as a significant proportion of RCTs had no authors from LMIC/UMIC despite enrolling patients in these countries. The findings in this study reflect a complex global RCT ecosystem that still underserves cancer control outside high-income settings.

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.

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.

Navigating the neutropenic abyss with granulocyte transfusions: Retrospective single-center analysis of effectiveness and safety in India.

BACKGROUND: Hemato-oncologic patients receiving intensive chemotherapy may develop severe neutropenia and serious bacterial and/or fungal infections. Granulocyte transfusions (GTs) may be beneficial as a bridging therapy in hemato-oncologic patients with febrile neutropenia. AIM: To evaluate the clinical effectiveness of GTs in hemato-oncologic patients with febrile neutropenia. MATERIALS AND METHODS: This retrospective study evaluated the effectiveness of 150 GTs in 88 hemato-oncologic patients. Donors were mobilized with granulocyte colony-stimulating factors and dexamethasone. Patients' hematological parameters (pre- and post-GT) and safety and effectiveness of GTs were analyzed. RESULTS: The safety and effectiveness of GTs were assessed in the patients with various underlying conditions, including 78% with acute myeloid leukemia. In total, 150 GTs were administered, mostly during the chemotherapy induction phase. The GTs were well-tolerated by the patients, and a significant increment in white blood cell count and absolute neutrophil count (ANC) was noticed in 95% of patients after the transfusion. The granulocyte dose was positively correlated with ANC after the transfusion. The average time to neutrophil recovery from the last day of GT was 6.7 days, and the 30-day survival rate was 77%. The donors were all men, and a significant increase in WBC count was observed post-mobilization. The median granulocyte yield was 2.28 × 1010 /unit. All granulocyte products were crossmatched and irradiated before the transfusion. CONCLUSION: GTs can be a useful adjunctive treatment for febrile neutropenia in hemato-oncologic patients with multidrug-resistant sepsis. However, additional studies are required for confirming their effectiveness and establishing guidelines for their use.

Access to cancer medicines deemed essential by oncologists in 82 countries: an international, cross-sectional survey.

BACKGROUND: The WHO Essential Medicines List (EML) identifies priority medicines that are most important to public health. Over time, the EML has included an increasing number of cancer medicines. We aimed to investigate whether the cancer medicines in the EML are aligned with the priority medicines of frontline oncologists worldwide, and the extent to which these medicines are accessible in routine clinical practice. METHODS: This international, cross-sectional survey was developed by investigators from a range of clinical practice settings across low-income to high-income countries, including members of the WHO Essential Medicines Cancer Working Group. A 28-question electronic survey was developed and disseminated to a global network of oncologists in 89 countries and regions by use of a hierarchical snowball method; each primary contact distributed the survey through their national and regional oncology associations or personal networks. The survey was open from Oct 15 to Dec 7, 2020. Fully qualified physicians who prescribe systemic anticancer therapy to adults were eligible to participate in the survey. The primary question asked respondents to select the ten cancer medicines that would provide the greatest public health benefit to their country; subsequent questions explored availability and cost of cancer medicines. Descriptive statistics were used to compare access to medicines between low-income and lower-middle-income countries, upper-middle-income countries, and high-income countries. FINDINGS: 87 country-level contacts and two regional networks were invited to participate in the survey; 46 (52%) accepted the invitation and distributed the survey. 1697 respondents opened the survey link; 423 were excluded as they did not answer the primary study question and 326 were excluded because of ineligibility. 948 eligible oncologists from 82 countries completed the survey (165 [17%] in low-income and lower-middle-income countries, 165 [17%] in upper-middle-income countries, and 618 [65%] in high-income countries). The most commonly selected medicines were doxorubicin (by 499 [53%] of 948 respondents), cisplatin (by 470 [50%]), paclitaxel (by 423 [45%]), pembrolizumab (by 414 [44%]), trastuzumab (by 402 [42%]), carboplatin (by 390 [41%]), and 5-fluorouracil (by 386 [41%]). Of the 20 most frequently selected high-priority cancer medicines, 19 (95%) are currently on the WHO EML; 12 (60%) were cytotoxic agents and 13 (65%) were granted US Food and Drug Administration regulatory approval before 2000. The proportion of respondents indicating universal availability of each top 20 medication was 9-54% in low-income and lower-middle-income countries, 13-90% in upper-middle-income countries, and 68-94% in high-income countries. The risk of catastrophic expenditure (spending >40% of total consumption net of spending on food) was more common in low-income and lower-middle-income countries, with 13-68% of respondents indicating a substantial risk of catastrophic expenditures for each of the top 20 medications in lower-middle-income countries versus 2-41% of respondents in upper-middle-income countries and 0-9% in high-income countries. INTERPRETATION: These data demonstrate major barriers in access to core cancer medicines worldwide. These findings challenge the feasibility of adding additional expensive cancer medicines to the EML. There is an urgent need for global and country-level policy action to ensure patients with cancer globally have access to high priority medicines. FUNDING: None.

The International Collaboration for Research methods Development in Oncology (CReDO) workshops: shaping the future of global oncology research.

Low-income and middle-income countries (LMICs) have a disproportionately high burden of cancer and cancer mortality. The unique barriers to optimum cancer care in these regions necessitate context-specific research. The conduct of research in LMICs has several challenges, not least of which is a paucity of formal training in research methods. Building capacity by training early career researchers is essential to improve research output and cancer outcomes in LMICs. The International Collaboration for Research methods Development in Oncology (CReDO) workshop is an initiative by the Tata Memorial Centre and the National Cancer Grid of India to address gaps in research training and increase capacity in oncology research. Since 2015, there have been five CReDO workshops, which have trained more than 250 oncologists from India and other countries in clinical research methods and protocol development. Participants from all oncology and allied fields were represented at these workshops. Protocols developed included clinical trials, comparative effectiveness studies, health services research, and observational studies, and many of these protocols were particularly relevant to cancer management in LMICs. A follow-up of these participants in 2020 elicited an 88% response rate and showed that 42% of participants had made progress with their CReDO protocols, and 73% had initiated other research protocols and published papers. In this Policy Review, we describe the challenges to research in LMICs, as well as the evolution, structure, and impact of CReDO and other similar workshops on global oncology research.

Impact of COVID-19 on cancer care in India: a cohort study.

BACKGROUND: The COVID-19 pandemic has disrupted health-care systems, leading to concerns about its subsequent impact on non-COVID disease conditions. The diagnosis and management of cancer is time sensitive and is likely to be substantially affected by these disruptions. We aimed to assess the impact of the COVID-19 pandemic on cancer care in India. METHODS: We did an ambidirectional cohort study at 41 cancer centres across India that were members of the National Cancer Grid of India to compare provision of oncology services between March 1 and May 31, 2020, with the same time period in 2019. We collected data on new patient registrations, number of patients visiting outpatient clinics, hospital admissions, day care admissions for chemotherapy, minor and major surgeries, patients accessing radiotherapy, diagnostic tests done (pathology reports, CT scans, MRI scans), and palliative care referrals. We also obtained estimates from participating centres on cancer screening, research, and educational activities (teaching of postgraduate students and trainees). We calculated proportional reductions in the provision of oncology services in 2020, compared with 2019. FINDINGS: Between March 1 and May 31, 2020, the number of new patients registered decreased from 112 270 to 51 760 (54% reduction), patients who had follow-up visits decreased from 634 745 to 340 984 (46% reduction), hospital admissions decreased from 88 801 to 56 885 (36% reduction), outpatient chemotherapy decreased from 173634 to 109 107 (37% reduction), the number of major surgeries decreased from 17 120 to 8677 (49% reduction), minor surgeries from 18 004 to 8630 (52% reduction), patients accessing radiotherapy from 51 142 to 39 365 (23% reduction), pathological diagnostic tests from 398 373 to 246 616 (38% reduction), number of radiological diagnostic tests from 93 449 to 53 560 (43% reduction), and palliative care referrals from 19 474 to 13 890 (29% reduction). These reductions were even more marked between April and May, 2020. Cancer screening was stopped completely or was functioning at less than 25% of usual capacity at more than 70% of centres during these months. Reductions in the provision of oncology services were higher for centres in tier 1 cities (larger cities) than tier 2 and 3 cities (smaller cities). INTERPRETATION: The COVID-19 pandemic has had considerable impact on the delivery of oncology services in India. The long-term impact of cessation of cancer screening and delayed hospital visits on cancer stage migration and outcomes are likely to be substantial. FUNDING: None. TRANSLATION: For the Hindi translation of the abstract see Supplementary Materials section.

Role of cytogenetic abnormalities detected by fluorescence in situ hybridization as a prognostic marker: Pathogenesis & clinical course in patients with B-chronic lymphocytic leukaemia.

BACKGROUND & OBJECTIVES: B-cell chronic lymphocytic leukaemia (B-CLL) is one of the most common forms of adult leukaemia, with a highly variable clinical course. Specific chromosomal and genetic aberrations are used clinically to predict prognosis, independent from conventional clinical markers. Molecular cytogenetic methods such as fluorescence in situ hybridization (FISH) detect aberrations in up to 80 per cent B-CLL patients. This study was conducted to score the frequencies of recurrent aberrations, i.e., del(13q14), trisomy 12, del(11q22), del(17p13), del(6q21) and IgH (immunoglobulin heavy chain) translocations and to understand their role in prognostication and risk stratification. METHODS: FISH studies were performed on bone marrow aspirate or peripheral blood of 280 patients using commercially available disease-specific probe set. The data were correlated with clinical and haematological parameters such as low haemoglobin, splenomegaly and lymphadenopathy. RESULTS: Chromosomal aberrations were detected in 79 per cent of patients, with del(13q14) (57%) as the most common cytogenetic aberration, followed by trisomy 12 (27%), del(11q22) (22%), t(14q32) (19%), del(17p13) (18%) and del(6q21) (9%). Single or in coexistence with other aberration del(13q14) had a favourable outcome in comparison to del(11q22), t(14q32), del(17p13) and del(6q21) which were associated with advanced stages of the disease. Trisomy 12 had a variable clinical course. INTERPRETATION & CONCLUSIONS: FISH was found to be a sensitive and efficient technique in detecting the prevalence of recurrent cytogenetic abnormalities. Each of these aberrations is an important independent predictor of disease progression and survival which aids in designing risk-adapted treatment strategies for better disease management.

Drug Interactions between Antimicrobial and Immunosuppressive Agents in Solid Organ Transplant Recipients.

The number of allogeneic solid organ and bone marrow transplants is increasing all over the world. To prevent transplant rejection and treat acute rejection of transplant, immunosuppressant drugs are used. The outcomes of solid organ transplants have dramatically improved over last 30 years, due to availability of multiple immunosuppressive agents, with varied mechanisms of action. The use of intense immunosuppression makes the individual having undergone solid organ transplant at the risk of several serious infections, which may prove fatal. To prevent and treat these infections (when they occur), patients are often given antimicrobial prophylaxis and therapy. The use of antimicrobials can interfere with the metabolism of the immunosuppressants, and may put the patient at risk of developing severe adverse effects due to unwanted increase or decrease in the serum levels of immunosuppressive agents. Knowledge of these interactions is essential for successful management of solid organ transplant patients. We therefore decided to review the literature and present the interactions that commonly occur between these two life-saving groups of drugs. How to cite this article: Bhagat V, Pandit RA, Ambapurkar S, Sengar M, Kulkarni AP. Drug Interactions between Antimicrobial and Immunosuppressive Agents in Solid Organ Transplant Recipients. Indian J Crit Care Med 2021;25(1):67-76.

Investigating the clinical, hematological and cytogenetic profile of endoreduplicated hypodiploids in BCP-ALL.

Ploidy, besides known translocations in lymphoblasts, is a strong predictor of prognosis in B- cell progenitor acute lymphoblastic leukemia (BCP-ALL). While hyperdiploidy with >50 chromosomes shows a favourable outcome, hypodiploidy with <45 chromosomes have a dismal clinical outcome. However, there exists a small subset where both the hypodiploid and hyperdiploid clones are apparent either by cytogenetics or flow cytometry and are defined partially masked hypodiploids or mosaics based on the percentage of clonal population. These patients are essentially hypodiploids, and show the hyperdiploid clone as a consequence of endoreduplication of the primary hypodiploid clone- A phenomenon of successive replication of genome without mitosis (cytokinesis) resulting in increased ploidy. In the current study, we present the complete clinical, hematological and cytogenetic profile of 11 such newly diagnosed mosaics or partially masked hypodiploid BCP-ALL cases.

Over expression of brain and acute leukemia, cytoplasmic and ETS-related gene is associated with poor outcome in acute myeloid leukemia.

The high expression of brain and acute leukemia, cytoplasmic (BAALC) and ETS-related gene (ERG) has been reported to influence the outcome in acute myeloid leukemia (AML), but due to limited prospective studies, their role as prognostic factors is unclear. At diagnosis, the prognostic value of BAALC and ERG expression with respect to other cytogenetic and molecular markers was analyzed in 149 AML patients. Patients were divided into quartiles which resulted in the formation of four groups (G1-G4) based on expression values of BAALC and ERG and clinical response defined across groups. Groups with similar survival probabilities were merged together and categorized subsequently as high versus low expressers. Patients with high BAALC and ERG expression had significantly lower overall survival (OS; BAALC: p = 0.001 at 5 years 29.4% vs. 69.8%; ERG: p < 0.0001 at 5 years 4% vs. 50.4%) and disease-free survival (BAALC: p = 0.001 at 5 years 19.5% vs. 69.8%; ERG: p < 0.0001 at 5 years 4.2% vs. 47%). Patients were further stratified combining BAALC and ERG expression in an integrative prognostic risk score (IPRS). After a median follow-up of 54 months (95% CI 45-63 months) among survivors, IPRS for high versus low expressers was a significant predictor for OS (BAALC + ERG: 4% vs. 71.6%, p < 0.0001) and DFS (BAALC + ERG: 4.5% vs. 74.1%, p < 0.0001). In a multivariate model, IPRS of BAALC + ERG expression retained prognostic significance for OS (hazard ratio [HR] 2.96, 95%CI 1.91-4.59, p < 0.001) and DFS (HR 3.61, 95%CI 2.26-5.76, p < 0.001).

A survey of clinical practices among oncologists regarding hepatitis B screening in patients with cancer.

Background & objectives: Screening for hepatitis B prior to the initiation of chemotherapy in patients with cancer is recommended by all major hepatology and oncology societies. This study was aimed to determine the screening practices for hepatitis B among oncologists from India and their experience with hepatitis B reactivation. Methods: A questionnaire-based survey was conducted among oncologists attending the Evidence-Based Medicine Conference at Tata Memorial Centre, Mumbai, India. The questionnaire was developed in keeping with the recent guidelines for hepatitis B reactivation on chemotherapy, with questions regarding demographics, years in practice and hepatitis B screening practices and management. There was 78 per cent response rate to the questionnaire. Results: Most respondents were <35 yr of age (69%), with < five years of experience (39%), practicing in an academic institution (81%). Seventy four per cent respondents always screened their patients with cancer for hepatitis prior to chemotherapy, whereas 19 per cent in special settings and seven per cent never screened; 96 per cent respondents used hepatitis B surface antigen (HBsAg) as a screening test, while 17 per cent also used antibody to hepatitis B core antigen. Sixty one per cent respondents used entecavir or tenofovir for prophylaxis; 70 per cent continued prophylaxis till 6-12 months after completion of chemotherapy, while 21 per cent continued only till the end of chemotherapy. Interpretation & conclusions: More than 25 per cent of the oncologists were not screening their patients with cancer for viral hepatitis prior to cancer-directed therapy, and only 17 per cent of the oncologists used the recommended tests for screening. Better training of oncologists regarding viral hepatitis screening and management is needed.

Luminescence Sensitization of Eu(III) Complexes with Aromatic Schiff Base and N,N'-Donor Heterocyclic Ligands: Synthesis, Luminescent Properties and Energy Transfer.

Five luminescent Eu(III)-4-fluoro-N-salicylideneaniline (Fsa) complexes with different N,N'- donor heterocyclic ligands (L) were synthesized (where L = 2,2'-bipyridine (bipy), 4,4'-dimethoxy-2,2'-bipyridine (dmbp), 1,10-phenanthroline (phen), 2,9-dimethyl-1,10-phenanthroline (neo) and 2,2'-biquinoline (biq)) and characterized by structural, thermal and spectroscopic analyses. The photophysical studies of the complexes viz. UV-Vis absorption spectra, emission spectra, lifetime decay curve, radiative, non-radiative transition rates and quantum yields were investigated. The photophysical properties indicated that fluorine substituted salicylideneaniline acts as a better sensitizer for Eu3+ ion after involvement of ancillary ligands which leads to efficient energy transfer resulted in bright red emission due to 5D0 → 7F2 transition. The highest overall quantum yield (32.78%) and sensitization efficiency (75.30%) of [Eu(Fsa)3neo] showed that it is a potential candidate in optical field. Graphical Abstract Sensitization of europium(III)-Schiff base complexes by antenna effect.

Indian Antimicrobial Prescription Guidelines in Critically Ill Immunocompromised Patients.

How to cite this article: Kulkarni AP, Sengar M, Chinnaswamy G, Hegde A, Rodrigues C, Soman R, Khilnani GC, Ramasubban S, Desai M, Pandit R, Khasne R, Shetty A, Gilada T, Bhosale S, Kothekar A, Dixit S, Zirpe K, Mehta Y, Pulinilkunnathil JG, Bhagat V, Khan MS, Narkhede AM, Baliga N, Ammapalli S, Bamne S, Turkar S, Bhat KV, Choudhary J, Kumar R, Divatia JV. Indian Journal of Critical Care Medicine 2019;23(Suppl 1): S64-S96.