Response assessment by positron emission tomography-computed tomography as compared with contrast-enhanced computed tomography in childhood Hodgkin lymphoma can reduce the need for radiotherapy in low- and middle-income countries.

INTRODUCTION: The InPOG-HL-15-01, a multicentric prospective study, used a risk-stratified and response-based approach with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) backbone to treat children and adolescents with newly diagnosed Hodgkin lymphoma (HL) and reduce the use of radiation therapy (RT). Children/adolescents with bulky disease or inadequate response at early response assessment (ERA) after two cycles of chemotherapy were assigned to receive RT. For ERA, positron emission tomography computed tomography (PET-CT) was recommended but not mandatory in view of limited access. This study aimed to compare the impact of using contrast-enhanced computed tomography (CECT) and PET-CT on treatment decisions and outcomes. METHODOLOGY: 396 patients were enrolled and 382 had an ERA at the assigned time point. Satisfactory response was defined as Deauville score 3 or less for patients undergoing PET-CT and complete response (CR)/very good partial response (VGPR) for patients undergoing CECT. Outcomes of interest incorporate 5 year event-free survival (EFS), EFS including abandonment (EFSa), and overall survival (OS). RESULTS: At ERA, satisfactory response was documented in 277 out of 382 (72.5%) participants and this was significantly higher in PET-CT (151 out of 186, 81.2%) as compared with CECT-based assessments (126 out of 196, 64.3%) respectively (p value < .001). Amongst the 203 patients with nonbulky disease (wherein the indication for RT was entirely dependent on ERA), 96 out of 114 (84.2%) and 61 out of 89 (68.5%) patients achieved a satisfactory response according to the PET-CT and CECT (p value = .008) respectively and hence a lesser proportion of patients in the PET-CT arm received RT. Despite a lower usage of RT the 5 year OS of both groups, ERA based on CECT (91.8%) versus PET-CT (94.1%) was comparable (p value = .391) and so was the 5 year EFS (86.7 vs. 85.5%, p value = .724). CONCLUSION: Use of PET-CT as the modality for ERA is more likely to indicate a satisfactory response as compared with CECT and thereby decreases the need for RT in response-based treatment algorithm for HL-afflicted children. The reduction in the application of RT did not impact the overall outcome and plausibly would lower the risk of delayed toxic effects.

Salvage Using Polatuzumab Vedotin Based Therapy in Relapsed Refractory Large B-Cell Lymphomas: Early Experience from a Real-World Middle-Income Setting Using Named-Patient Compassionate Access Program.

Polatuzumab vedotin is a novel immunotherapy antibody-drug conjugate targeting CD79b. It has been used in relapsed/refractory (R/R) large B-cell lymphomas since its FDA approval in 2019. Presently, this drug is unaffordable or unavailable for patients in Lower-Middle Income Countries (LMIC) like India. This is a retrospective study of adult (> 18 years) patients with R/R large B-cell lymphoma failing two prior lines of therapy, who received Polatuzumab based salvage therapy on a compassionate or named-patient access program. Between May 2019 and April 2022, 10 patients received Polatuzumab vedotin, and 9 were evaluable. The most common regimen used was Polatuzumab-Bendamustine-Rituximab. Out of 43 infusions administered, the adverse event profile was manageable [One grade-2 infusion reaction, 4 patients developed grade 3-4 hematological toxicity and none had grade 3-4 non-hematological toxicities]. Ten infusions were administered in the day care service. After a median of 4.5 cycles (range 1-8), 4 patients achieved CR, 2 had partial response (PR), and 3 had progressive disease (PD). With a median follow up of 491 days (range 8-1048 days), four patients are alive (three in CR and one in PR), three patients have died and three patients were lost to follow up. Early real-world experience from a LMIC setting demonstrates feasibility and a favourable safety profile of Polatuzumab vedotin based approach, along with encouraging response rates in a subset of patients.

Intra-host variability in global SARS-CoV-2 genomes as signatures of RNA editing: implications in viral and host response outcomes

During the course of the COVID-19 pandemic, large-scale genome sequencing of SARS-CoV-2 has been useful in tracking its spread and in identifying Variants Of Concern (VOC). Besides, viral and host factors could contribute to variability within a host that can be captured in next-generation sequencing reads as intra-host Single Nucleotide Variations (iSNVs). Analysing 1, 347 samples collected till June 2020, we recorded 18, 146 iSNV sites throughout the SARS-CoV-2 genome. Both, mutations in RdRp as well as APOBEC and ADAR mediated RNA editing seem to contribute to the differential prevalence of iSNVs in hosts. Noteworthy, 41% of all unique iSNVs were reported as SNVs by 30th September 2020 in samples submitted to GISAID, which increased to [~]80% by 30th June 2021. Following this, analysis of another set of 1, 798 samples sequenced in India between November 2020 and May 2021 revealed that majority of the Delta (B.1.617.2) and Kappa (B.1.617.1) variations appeared as iSNVs before getting fixed in the population. We also observe hyper-editing events at functionally critical residues in Spike protein that could alter the antigenicity and may contribute to immune escape. Thus, tracking and functional annotation of iSNVs in ongoing genome surveillance programs could be important for early identification of potential variants of concern and actionable interventions. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=177 SRC="FIGDIR/small/417519v3_ufig1.gif" ALT="Figure 1"> View larger version (41K): org.highwire.dtl.DTLVardef@12b6ac2org.highwire.dtl.DTLVardef@16df897org.highwire.dtl.DTLVardef@dbbec2org.highwire.dtl.DTLVardef@c8de14_HPS_FORMAT_FIGEXP M_FIG C_FIG

Evaluation of in silico designed inhibitors targeting MelF (Rv1936) against Mycobacterium marinum within macrophages.

We recently identified inhibitors targeting Mycobacterium marinum MelF (Rv1936) by in silico analysis, which exhibited bacteriostatic/bactericidal activity against M. marinum and M. tuberculosis in vitro. Herein, we evaluated the effect of best four inhibitors (# 5175552, # 6513745, # 5255829, # 9125618) obtained from the ChemBridge compound libraries, on intracellular replication and persistence of bacteria within IFN-γ activated murine RAW264.7 and human THP-1 macrophages infected with M. marinum. Inhibitors # 5175552 and # 6513745 significantly reduced (p < 0.05) the intracellular replication of bacilli during day 7 post-infection (p.i.) within RAW264.7 and THP-1 macrophages infected at multiplicity of infection (MOI) of ~1.0. These observations were substantiated by electron microscopy, which revealed the protective effect of # 5175552 in clearing the bacilli inside murine macrophages. Strikingly, # 6513745 displayed synergism with isoniazid against M. marinum in murine macrophages, whereas # 5175552 significantly suppressed (p < 0.05) the persistent bacilli during day 10-14 p.i. in infected RAW264.7 and THP-1 macrophages (MOI of ~ 0.1). Moreover, # 5175552 and # 6513745 were non-cytotoxic to host macrophages at both 1X and 5X MIC. Further validation of these inhibitors against M. tuberculosis-infected macrophages and animal models has potential for development as novel anti-tubercular agents.

Deciphering foot-and-mouth disease (FMD) virus-host tropism.

The pattern of interactions between foot and mouth disease (FMD) viral protein 1 (VP1) with susceptible and resistant host integrins were deciphered. The putative effect of site-directed mutation on alteration of interaction is illustrated using predicted and validated 3D structures of VP1, mutated VP1 and integrins of Bos taurus, Gallus and Canis. Strong interactions were observed between FMDV-VP1 protein motifs at conserved tripeptide, Arg-Gly-Asp 143RGD145 and at domain 676SIPLQ680 in alpha-integrin of B. taurus. Notably, in-silico site-directed mutation in FMDV-VP1 protein led to complete loss of interaction between FMD-VP1 protein and B. taurus integrin, which confirmed the active role of arginine-glycine-aspartic acid (RGD) domain. Interestingly, in-vitro analysis demonstrates the persistence of the putative tropism site 'SIPLQ' in different cattle breeds undertaken. Thus, the attempt to decipher the tropism of FMDV at host receptor level interaction might be useful for future FMD control strategies through development of mimetic marker vaccines and/or host receptor manipulations. Communicated by Ramaswamy H. Sarma.

Angiographic predictors of success in antegrade approach of Chronic Total Occlusion interventions in a South Indian population in the contemporary era.

Chronic Total Occlusion (CTO) intervention is a challenging area in interventional cardiology. Presently about 70% of CTO interventions are successful. MATERIALS AND METHODS: This was a single center prospective study of a cohort of all patients undergoing percutaneous coronary intervention (PCI) as elective or adhoc procedure for CTO from August 2014 to June 2015. Only antegrade CTO interventions were included. In all patients the following data were recorded. RESULTS: A total of 210 (8.9% of total PCI (2353) during the study period) CTO patients were followed up. The mean age was 56.54±8.9. In the study sixty nine patients (32.9%) presented with chronic stable angina and rest of the patients had history of acute coronary syndrome of which 22.9% (n=48) had unstable angina (UA) or non ST elevation myocardial infarction (NSTEMI) and 44.2% (n=93) had ST Elevation Myocardial Infarction (STEMI). In those with history of ACS, 64.78% (n=92) had ACS during the previous year and remaining 35.22% (n=49) had ACS prior to that. Single vessel CTO was seen in 89.5% (n=188) and two vessel CTO in 10.5% (n=22). LAD was involved in 36.7% (n=77), RCA in 48.1% (n=101), and LCX in 15.2% (n=32). Procedural success in the first attempt was 68.1% (n=143), which increased to 71.42% (n=150) after the second attempt. CTO interventions were more frequently successful when the calcium was absent or minimal (p-0.05), CTO length was <10mm (p<0.01) and good distal reformation (p<0.01).

Long-term outcome of diffuse large B-cell lymphoma: Impact of biosimilar rituximab and radiation.

INTRODUCTION: Rituximab (R)-CHOP improves survival over CHOP in diffuse large B-cell lymphoma (DLBCL). The availability of biosimilar rituximab in India has increased access of this drug. We report on the impact of treatment on outcomes with special emphasis on the impact of biosimilar rituximab and radiation. METHODS: Outcomes of adults (age 15-60 years) treated with CHOP+/- Rituximab radiation were analyzed retrospectively to look at baseline features, treatment, and event-free and overall survival (EFS and OS). RESULTS: In the period 2000-2013, 444 patients (median age 47 years: 15-60; males: 288 [65%]; Stage III/IV: 224 [50%]; age-adjusted international prognostic index [aaIPI] Score 2 or 3 in 50%) received either CHOP (n = 325 [73%]) or RCHOP (n = 119 [27%]) therapy. Biosimilar rituximab and the original were used in 95 (80%) and 24 (20%) patients, respectively. Radiation was given in 134 (30%) patients (Stages I and II, 100/220 [45%] and Stages III and IV, 34/224 [15%]). After a median follow-up of 46 (0.2-126) months, the 5-year EFS and OS were 59% and 68%, respectively. The factors predicting inferior EFS and OS were age> 40 years, performance status 2-4, Stage III/IV, hemoglobin <12 g/dL, the aaIPI Score 2 or 3, and nonuse of rituximab and radiation. Radiation used in early stage disease benefitted all subgroups regardless of bulky disease, use of rituximab, or the number of cycles of chemotherapy. Addition of rituximab improved survival across all categories of aaIPI. CONCLUSION: Availability of biosimilar rituximab has increased access and survival of patients with DLBCL in India. Radiotherapy improved outcomes in early stages.

Pediatric nasopharyngeal carcinoma: Experience from a tertiary cancer center in India.

BACKGROUND: Pediatric nasopharyngeal carcinomas (NPCs) are rare tumors. There is paucity of data on outcomes in pediatric NPC from developing countries. AIM: The present study was conducted to ascertain the outcomes of children with NPC at our center. SETTINGS AND DESIGN: A retrospective analysis of case records of pediatric NPC patients treated at our hospital was performed. PATIENTS AND METHODS: We analyzed the outcomes of 37 consecutive patients <18 years of age with pediatric NPC treated between 2000 and 2015. Patients were treated with concurrent chemoradiotherapy (CTRT) with cisplatin and 5-fluorouracil (5-FU) or CTRT with cisplatin, followed by adjuvant chemotherapy with cisplatin and 5-FU. STATISTICAL ANALYSIS: Survival was analyzed using Kaplan-Meier method, and log rank test was used to compare variables. RESULTS: The median duration of follow-up was 36.6 months. The median age of the patients was 15 years, and 22/37 (59%) patients were male. The most common presenting complaint was neck mass (70%), followed by nasal bleeding (16%). The distribution of Stage I, II, III, and IV patients was 1/37 (3%), 2/37 (6%), 13/37 (35%), and 21/37 (57%), respectively. Distant metastasis at presentation was seen in 3/37 patients. Complete response was seen in 32/37 (86%) patients. The 3-year event-free survival (EFS) for the entire cohort of patients was 60.1%. No significant difference in EFS was observed with age, gender, stage, use of 5-FU with CTRT, and nutritional status. CONCLUSION: Majority of patients with pediatric NPC present with advanced stage disease at our center. No difference in outcomes was seen with the two schedules of CTRT. Local control could be achieved in majority of patients; however, distant metastasis was the most common reason for relapse.

Sensory quality of broiler breast meat influenced by low atmospheric pressure stunning, deboning time and cooking methods.

Stunning method (low atmospheric pressure stunning, LAPS and electrical stunning, ES), deboning time (0.75 h and 4 h), and cooking method (baking, frying, and sous vide) were evaluated for their impact on the descriptive sensory characteristics and consumer acceptability of breast meat (n=576, 144 birds per stunning × deboning time combination). Sensory evaluation was conducted by trained descriptive (n=8) and consumer (n=185) panels. On average, no differences (P>0.05) existed in the sensory acceptability of fried and sous vide cooked broiler breast treatment combinations. However, for oven-baking, the LAPS treatment that was deboned at 4 h was more acceptable (P<0.05) than other treatments and the ES and LAPS 4 h samples had greater (P<0.05) acceptability for texture than their ES and LAPS 0.75 h counterparts. Since consumers were highly variable in their liking of chicken breast treatments, consumers were grouped into clusters for each cooking method based on liking and preference. Cluster analysis data revealed that the largest groups of consumers liked (score≥6.0) all chicken breast treatments, but a larger proportion of consumers liked the 4 h LAPS and ES treatments when compared to the 0.75 h LAPS and ES treatments for all cooking methods. In addition, the consumers who indicated that baked chicken breast was highly acceptable preferred (P<0.05) 4 h LAPS over the 4 h ES samples. Based on sensory results, chicken breast meat from all stunning and deboning method combinations was highly acceptable to the majority of consumers, but the LAPS 4 h treatment had enhanced sensory characteristics when baked.

Phase II study of interim PET-CT-guided response-adapted therapy in advanced Hodgkin's lymphoma.

BACKGROUND: Combination chemotherapy ABVD (doxorubicin, bleomycin, vinblastine and dacarabazine) cures ∼70% of patients with advanced Hodgkin's lymphoma (aHL, stages IIB, III and IV) while more toxic escalated BEACOPP (EB, combination of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine and prednisolone) increases cure rates to 85%. Patients with a positive interim positron emission tomography-computerized tomography (PET-CT) scan after two cycles (PET-2) of ABVD have very poor outcomes with continued ABVD. Intensifying therapy with EB in PET-2-positive patients ('response-adapted therapy') may improve cure rates, whereas the negative patients can continue ABVD alone. PATIENTS AND METHODS: Eligible patients with newly diagnosed aHL received two cycles of ABVD and underwent PET-2 (scored with semi-quantitative 5-point visual criteria, 'Deauville score'). PET-2-negative patients continued four additional cycles of ABVD, whereas PET-2-positive patients received four cycles of EB. A phase II sample size of 50 was estimated keeping the lower and higher proportion of rejection of the event-free survival (EFS) as 70% and 85%, respectively. RESULTS: Fifty patients [median age 28 (12-60) years; male : female: 39 : 11; stages: IIB-3 (6%), III-29 (58%) and IV-18 (36%); International Prognostic Score (IPS): 0-3: 34 (68%); 4-7: 16 (32%)] were enrolled; 49 underwent PET-2. Eight (16%) were PET-2-positive, whereas 41 (84%) were negative. Forty-seven were evaluable for EFS and all 50 for overall survival (OS). The 2-year EFS was 76% (95% CI: 68-83) and OS was 88% (95% CI: 82-94). PET-2 was strongly prognostic-2-year EFS, negative versus positive: 82% versus 50%; P = 0.013. CONCLUSION: PET-2 response-adapted strategy could not achieve EFS of 85% in aHL. However, escalated therapy improved outcomes in PET-2-positive patients compared with historical data. TRIAL REGISTRATION: CTRI/2012/06/002741 (http://www.ctri.nic.in) and NCT01304849 (http://www.clinicaltrials.gov).

Nutritional profile of pediatric cancer patients at Cancer Institute, Chennai.

BACKGROUND: Malnutrition is widely prevalent in the pediatric population in India. There is paucity of data on the prevalence of malnutrition in pediatric cancer patients and the impact of cancer treatment on nutritional status of Indian children. AIMS: The study was conducted to look at the prevalence of malnutrition and assess the impact of treatment on nutritional status of pediatric cancer patients. SETTINGS AND DESIGN: This was a retrospective study. MATERIALS AND METHODS: Data on the weight of pediatric cancer patients <16 years of age treated at Cancer Institute, Chennai, from January 2013 to May 2014 were analyzed at systematic time points in therapy. Patients' weight were plotted on the Centre for Disease Control (CDC) growth charts. Patients were defined to be undernourished if their weight for age was ≤3rd centile in CDC growth charts and obese if their weight for age was ≥97th centile on CDC growth charts. RESULTS: A total of 295 patient case records were analyzed. Acute lymphoblastic leukemia was the most common malignancy. At diagnosis, under-nutrition was seen in 44% patients, this increased to 46% midway during treatment (end of induction in acute leukemia and completion of 50% of planned treatment in solid tumors) and decreased to 27% at the end of treatment (beginning of maintenance in acute leukemia and completion of planned treatment in solid tumors) (P = 0.0005). There was no significant difference in nutritional status between patients with hematological malignancies and solid tumors (P = 0.8). CONCLUSION: Under-nutrition is present in close to half of the pediatric cancer patients presenting to our institute. Active nutritional intervention and education were able to significantly reduce the prevalence of under-nutrition in patients at the end of treatment.

Bloodstream infections in pediatric patients at Cancer Institute, Chennai.

BACKGROUND: There is paucity of data on the epidemiology of bloodstream infections in pediatric cancer patients from India. Rationale use of antibiotics in febrile neutropenia is important for reducing morbidity and preventing the emergence of drug resistant bacteria. AIMS: The study was conducted to look at the prevalence of bloodstream bacterial infection and the antibiotic resistance profile at Cancer Institute, Chennai. SETTINGS AND DESIGN: This was a retrospective study. MATERIALS AND METHODS: Data on all blood cultures taken from pediatric cancer patients treated at Cancer Institute, Chennai, during the year 2013 were analyzed. The microbiological profile and sensitivity pattern were analyzed. RESULTS: A total of 1045 blood culture samples were taken, and there were 82/1045 (7.5%) positive blood cultures. Gram-negative organisms accounted for 50/82 (61%) of all positive cultures. Klebsiella pneumoniae (32%) was the most common Gram-negative isolate, and Staphylococcus aureus (93.5%) was the most common Gram-positive. There was high resistance to aminoglycosides and beta-lactam/beta-lactamase inhibitor antibodies. CONCLUSION: Gram-negative organisms are the predominant bacteria isolated. There is high resistance to first-line combination antibiotics used as empiric therapy for treatment of febrile neutropenia.

Aortic pulse wave velocity and its relationship with complexity of coronary artery disease based on SYNTAX score.

BACKGROUND: Aortic pulse wave velocity (APWV), a marker of arterial stiffness, was found to be a good predictor for the presence of incipient vascular disease and cardiovascular events in observational studies. APWV measured by echo Doppler is a simple and readily available method comparable with other costlier and complex modalities of APWV measurement like MRI, Complior method or applanation tonometry. AIMS AND OBJECTIVES: No previous studies have demonstrated a relationship between APWV findings and the complexity of coronary artery disease (CAD). Our aim was to examine the relationship between APWV findings and the severity of SYNTAX scores (SX scores). METHODS: 500 patients who had undergone APWV measurements and elective coronary angiography from September 2012 to June 2013 were taken. Pulsed Doppler ultrasound (6.6 MHZ) probe with ECG synchronisation was used to calculate APWV. SYNTAX scoring was performed by observers who were blinded to APWV values. RESULTS: A significant, nearly linear correlation between APWV and advancing CAD (p<0.0001) was observed. Patients with dual-vessel and triple-vessel disease had significantly higher APWV than patients without CAD. It was also found that mean APWV values were significantly more in patients with high or intermediate SX scores than in patients with low SX scores. The Fischer's linear discriminant analysis showed a cut-off value of APWV for predicting the possibility of having CAD to be >11.5 m/s. CONCLUSIONS: APWV has predictive value for the SX score. A positive relation exists between aortic stiffening and coronary atherosclerosis and APWV measured by 2D Doppler is a good predictor of advancing CAD.