Gaps in Care Among Uncontrolled Severe Asthma Patients in the United States.

BACKGROUND: Understanding the implementation of key guideline recommendations is critical for managing severe asthma (SA) in the treatment of uncontrolled disease. OBJECTIVE: To assess specialist visits and medication escalation in US patients with SA after events indicating uncontrolled disease (EUD) and associations with health outcomes and social disparity indicators. METHODS: Patients with SA appearing in administrative claims data spanning 2015 to 2020 were indexed hierarchically on asthma-related EUD, including hospitalizations, emergency department visits with systemic corticosteroid treatment, or outpatient visits with systemic corticosteroid treatment. Patients with SA without EUD served as controls. Eligibility included age 12 or greater, 12 months enrollment before and after index, no biologic use, and no other major respiratory disease during the pre-period. Escalation of care in the form of specialist visits and medication escalation, health care resource use, costs, and disease exacerbations were assessed during follow-up. RESULTS: We identified 180,736 patients with SA (90,368 uncontrolled and 90,368 controls). Between 35% and 51% of patients with SA with an EUD had no specialist visit or medication escalation. Follow-up exacerbations ranged from 51% to 4% across EUD cohorts, compared with 13% in controls. Among uncontrolled patients with SA who were Black or Hispanic/Latino, 41% and 38%, respectively, had no specialist visit or medication escalation after EUD, compared with 33% of non-Hispanic White patients. CONCLUSIONS: A substantial proportion of uncontrolled patients with SA had no evidence of specialist visits or medication escalation after uncontrolled disease, and there was a clear relationship between uncontrolled disease and subsequent health care resource use and exacerbations. Findings highlight the need for improved guideline-based care delivery to patients with SA, particularly for those facing social disparities.

Performance of potentially inappropriate medications assessment tools in older Indian patients with cancer.

BACKGROUND: Polypharmacy and potentially inappropriate medication (PIM) use are common problems in older adults. Safe prescription practices are a necessity. The tools employed for the identification of PIM sometimes do not concur with each other. METHODS: A retrospective analysis of patients ≥60 years who visited the Geriatric Oncology Clinic of the Tata Memorial Hospital, Mumbai, India from 2018 to 2021 was performed. Beer's-2015, STOPP/START criteria v2, PRISCUS-2010, Fit fOR The Aged (FORTA)-2018, and the EU(7)-PIM list-2015 were the tools used to assess PIM. Every patient was assigned a standardized PIM value (SPV) for each scale, which represented the ratio of the number of PIMs identified by a given scale to the total number of medications taken. The median SPV of all five tools was considered the reference standard for each patient. Bland-Altman plots were utilized to determine agreement between each scale and the reference. Association between baseline variables and PIM use was determined using multiple logistic regression analysis. RESULTS: Of the 467 patients included in this analysis, there were 372 (79.66%) males and 95 (20.34%) females with an average age of 70 ± 5.91 years. The EU(7)-PIM list was found to have the highest level of agreement given by a bias estimate of 0.010, the lowest compared to any other scale. The 95% CI of the bias was in the narrow range of -0.001 to 0.022, demonstrating the precision of the estimate. In comparison, the bias (95%) CI of Beer's criteria, STOPP/START criteria, PRISCUS list, and FORTA list were -0.039 (-0.053 to -0.025), 0.076 (0.060 to 0.092), 0.035 (0.021 to 0.049), and -0.148 (-0.165 to -0.130), respectively. Patients on polypharmacy had significantly higher PIM use compared to those without (OR = 1.47 (1.33-1.63), p = <0.001). CONCLUSIONS: The EU(7)-PIM list was found to have the least bias and hence can be considered the most reliable among all other tools studied.

Geographic variation in disease burden among patients with severe persistent asthma in the United States.

BACKGROUND: In the United States, a few studies have evaluated geographic variation of severe asthma at the subnational level. OBJECTIVE: To assess state-level geographic variation in the prevalence and characteristics of severe persistent asthma in the United States. METHODS: Patients aged above or equal to 12 years with severe persistent asthma were identified using nationally representative data from IQVIA open-source Medical/Pharmacy Claims and PharMetrics Plus databases (January 2019-December 2020). The index date was defined as the patient's earliest qualifying date for a severe asthma diagnosis. Baseline characteristics were measured during the 12-month pre-index period. Outcomes including exacerbation occurrence, asthma control, and medication use were measured during the 12-month post-index period and compared across states using census-level projections. RESULTS: A total of 2,092,799 patients with asthma were identified; 496,750 (23.7%) met criteria for severe persistent asthma and all inclusion criteria. Mean age was 50.5 years; 68.4% were females. The prevalence of severe persistent asthma varied across states, ranging from 19.6% (New Mexico) to 31.9% (Alaska). Among patients with severe persistent asthma, 40.9% had more than or equal to 1 exacerbation, ranging from 34.2% (Vermont) to 45.6% (Louisiana); 21.1% had uncontrolled disease, ranging from 16.5% (Vermont) to 24.0% (Arizona). Among patients with exacerbations, 13.7% had exacerbation-related emergency department visits or hospitalizations, ranging from 7.0% (North Carolina) to 17.7% (Nevada). Among patients with severe uncontrolled asthma, 15.6% used biologics post-index, ranging from 2.2% (Hawaii) to 27.9% (Mississippi). CONCLUSION: There is significant variability in severe persistent asthma prevalence and disease burden across US states. Reasons for geographic variation may include differences in socioeconomic/environmental factors or asthma management.

Prospective Study of Incidence and Impact of Comorbidities on Breast Cancer Survival from India.

PURPOSE: To report comorbidity burden in newly-diagnosed treatment-naïve breast cancer patients and its effect on survival. METHODS: Prospective observational study in which demographic, comorbidity and outcome data from a consecutive cohort of patients diagnosed and treated between September 2019 to September 2021 were collected. Charlson Comorbidity Index (CCI) score was calculated for all and proportion of each comorbidity was determined at diagnosis (baseline), at conclusion and six-months post-treatment. Univariate and multivariate analysis was done for impact of various demographic and disease-related factors on the incidence of comorbidities as well as on progression free survival (PFS) and overall survival (OS). RESULTS: Out of five hundred patients who consented for the study, 416 patients completed planned treatment and only 206 patients had physical follow-up due to COVID-19 pandemic. Incidence of comorbidity at the three time-points was 24%, 32% and 26% respectively. The difference was significant compared to baseline at both the time-points (p<0.05). Hypertension and diabetes were the most common types (incidence 15%-21% and 12-18% respectively) of comorbidities. Advancing age, post-menopauusal status and not being married were significant factors for presence of comorbidities. Median follow-up was 27 months (95% CI 26.25-28.55 months). Presence of multiple comorbidities was a poor prognostic factor for both PFS (2-yr PFS 85% vs 77%) and OS (2-yr OS 89% vs 79%) (both p=0.04) but no such correlation for CCI score. CONCLUSION: Breast cancer treatment impacted incidence of comorbidities. Presence of multiple comorbidities had an adverse impact on survival. Hence, further research on treatment optimization is required in patients with substantial comorbidities.

Low levels of CD26 on certain cellular subtypes of donor harvest is associated with better clinical outcomes post allogeneic stem cell transplantation through regulation of NF-κB pathway and pro-inflammatory cytokines.

BACKGROUND: We had previously reported significant association of immunoectoenzyme CD26 expression on donor harvest with acute Graft-versus-Host-Disease (aGVHD) in allogeneic stem cell transplantation (ASCT) patients. The current study was aimed at analysing CD26 signaling pathway molecules and understanding their impact on immune reconstitution and clinical outcomes post-ASCT. SUBJECTS AND METHODOLOGY: The study cohort included 26 transplant donors/patients who underwent reduced intensity (n = 21), myeloablative (n = 4) and non-myeloablative (n = 1) ASCT for hematological malignancies. Donors were matched related donors (n = 19) and haploidentical donors (n = 7). Surface expression of CD26, CD73 and ADA, and various immune cell subtypes were assessed by multicolour-flow cytometry. Soluble CD26 (sCD26) and cytokine levels were measured in plasma samples by ELISA and Multiplex Luminex assay, respectively. Immune cells from healthy individuals were stimulated with phytohemagglutinin (PHA) in the presence or absence of CD26 inhibitor. Effect of CD26 inhibition on NF-κB localization in PHA stimulated cells was analysed by immunofluorescence and confocal microscopy. Pro-inflammatory cytokines from the culture supernatants were detected with Cytometric bead array flow cytometry. Association of all measured markers with clinical outcomes was evaluated using appropriate statistical tests. RESULTS: CD26 surface expression on PBSC donor harvest cells showed increased risk of chronic GVHD (cGVHD, p = 0.055). Amongst the various immune cell subtypes, decreased B cells in harvest showed significant association with aGVHD (p = 0.022) whereas increased myeloid dendritic cells and CD3+T cells at Day100 in peripheral blood of transplant recipients correlated with cGVHD (p = 0.046) and aGVHD (p = 0.035), respectively. Further, high sCD26 in transplant recipients at Day100 exhibited association with reduced event-free survival (EFS) (p = 0.011). Higher CD26 expression on more & less mature NK cells, naïve & post-switched memory B cells and Treg cells in the donor harvest (p < 0.05) led to lower EFS in transplant recipients. Mechanistically, CD26 inhibitor caused dose-dependent reduction in CD26 enzyme activity and in pro-inflammatory cytokine production in post mitogen-stimulated T cell cultures. CONCLUSION: Our study has implicated that lower CD26 expression on immune cell subtypes of the donor stem cell harvest is associated with reduced risk of GVHD and better survival. The underlying mechanism was found to be through NF-κB pathway and pro-inflammatory cytokines. Based on these observations, chemically designed or natural resources-based CD26 inhibitors can be explored further in clinical trials for improving ASCT outcomes.

Incremental cost burden among patients with severe uncontrolled asthma in the United States.

BACKGROUND: The economic burden of severe asthma and severe uncontrolled asthma (SUA) is significant. Updated assessments of health care resource utilization (HCRU) and cost are needed given the increase in treatment options and updates to guidelines in recent years. OBJECTIVE: To describe all-cause and asthma-related HCRU and costs among patients with SUA vs patients with nonsevere asthma in the United States using real-world data. METHODS: MarketScan administrative claims databases were used to select adults with persistent asthma for this retrospective analysis between January 1, 2013, and December 31, 2019. Asthma severity status was defined using the Global Initiative for Asthma step 4/5 criteria (index is the earliest date qualifying patients as severe or randomly assigned for nonsevere patients). Patients with SUA were a subset of the severe cohort meeting the following criteria: those who were hospitalized with asthma as the primary diagnosis or had at least 2 emergency department or outpatient visits with an asthma diagnosis and a steroid burst within 7 days. HCRU, costs (allcause and asthma-related defined as medical claims with an asthma diagnosis and pharmacy claims for asthma treatment), work loss, and indirect costs due to absenteeism and short-term disability (STD) were compared between patients with SUA, severe, and nonsevere asthma. Outcomes were reported during a fixed 12-month post-index period using chi-square and t-tests where appropriate. RESULTS: 533,172 patients with persistent asthma were identified (41.9% [223,610]) severe and 58.1% [309,562] nonsevere). Of the severe patients, 17.6% (39,380) had SUA. The mean (SD) all-cause total health care costs were significantly higher in patients with SUA ($23,353 [$40,817]) and severe asthma ($18,554 [$36,147]) compared with those with nonsevere asthma ($16,177 [$37,897], P < 0.001 vs nonsevere asthma). The results were consistent for asthma-related costs. In addition, although patients with severe asthma made up 41.9% of the total study population, they contributed disproportionately higher costs (60.5%) to the total asthma-related direct costs, with the effect more evident among patients with SUA (7.4% of study population contributed 17.7% of the total asthma-related costs). For the subset of patients with asthma with workplace absenteeism, patients with SUA lost more time from work (259.3 vs 236.2 hours lost, P = 0.002; 7.8 vs 5.3 STD days, P < 0.001), and had higher corresponding indirect costs ($5,944 vs $5,415, P = 0.002 for absenteeism related; $856 vs $582, P < 0.001 for STD related) compared with patients with nonsevere asthma. CONCLUSIONS: Patients with SUA have significantly higher asthma-related economic burden compared with patients with nonsevere asthma and contribute a disproportionally higher percentage of asthma-related costs. DISCLOSURES: This study was funded by Amgen and AstraZeneca. The design and analysis for this study was conducted primarily by Merative. Amgen and AstraZeneca provided funding to support protocol development, data analysis, and manuscript development activities associated with this study. Dr Burnette is on the advisory board and a consultant for GSK, a consultant and member of the advisory boards and speakers' bureaus of Sanofi, Genzyme, Regeneron, AstraZeneca, and Amgen Inc. Dr Wang, Dr Rane, Dr Lindsley, and Dr Llanos are employees and shareholders of Amgen Inc. Dr Chung and Dr Ambrose are employees and shareholders of AstraZeneca. Ms Princic and Ms Park are employees of Merative, which received funding from Amgen to conduct this study.

Validation of the Onco-MPI in predicting short-term mortality in older Indian patients with cancer.

INTRODUCTION: The number of older patients with cancer is increasing exponentially worldwide, and a similar trend has also been noted in India. The Multidimensional Prognostic Index (MPI) strongly correlates the presence of individual comorbidities with mortality, and the Onco-MPI prognosticates patients accurately for overall mortality. However, limited studies have evaluated this index in patient populations beyond Italy. We evaluated the performance of the Onco-MPI index in predicting mortality in older Indian patients with cancer. MATERIALS AND METHODS: This observational study was conducted between October 2019 and November 2021 in the Geriatric Oncology Clinic at Tata Memorial Hospital in Mumbai, India. The data of patients aged ≥60 years with solid tumors who underwent a comprehensive geriatric assessment was analysed. The study's primary aim was to calculate the Onco-MPI for patients in the study and correlate it with one-year mortality. RESULTS: A total of 576 patients aged ≥60 years were included in the study. The median age (range) of the population was 68 (60-90) years, and 429 (74.5%) were male. After a median follow-up of 19.2 months, 366 (63.7%) patients had died. The proportion of patients classified as low risk (0-0.46), moderate risk (0.47-0.63) and high risk (0.64-1.0) were 38% (219 patients), 37% (211 patients) and 25% (145 patients), respectively. There was a significant difference in one-year mortality rates between the low-risk patients compared to medium and high-risk patients (40.6% vs 53.1% vs 71.7%; p < 0.001). DISCUSSION: The current study validates the Onco-MPI as a predictive tool for estimating short-term mortality in older Indian patients with cancer. Further prospective studies need to build on this index to obtain a score with greater discrimination in the Indian population.

Long-term outcomes and prognostic factors in elderly patients with breast cancer: single-institutional experience.

Introduction: Despite advances in treatment, there is rising mortality in elderly patients with breast cancer. We aimed to conduct an audit of non-metastatic elderly breast cancer patients to understand the predictors of outcome. Methods: Data collection was done from electronic medical records. All time-to-event outcomes were analysed using Kaplan-Meier method and compared using log-rank test. Univariate and multi-variate analysis of known prognostic factors was also done. Any p-value ≤0.05 was considered statistically significant. Results: A total of 385 elderly (>70 years) breast cancer patients (range 70-95 years) were treated at our hospital from January 2013 to December 2016. The hormone receptor was positive in 284 (73.8%) patients; 69 (17.9%) patients had over-expression of HER2-neu, while 70 (18.2%) patients had triple-negative breast cancer. A large majority of women (N = 328, 85.9%) underwent mastectomy while only 54 (14.1%) had breast conservation surgery. Out of 134 patients who received chemotherapy, 111 patients received adjuvant, while the remaining 23 patients received neoadjuvant chemotherapy. Only 15 (21.7%) patients of the 69 HER2-neu receptor-positive patients received adjuvant trastuzumab. Adjuvant radiation was given to 194 (50.3%) women based on the type of surgery and disease stage. Adjuvant hormone therapy was planned using letrozole in 158 (55.6%) patients, while tamoxifen was prescribed in 126 (44.4%). At the median follow up of 71.7 months, the 5-year overall survival, relapse-free survival, locoregional relapse-free survival, distant disease-free survival, breast cancer-specific survival were 75.3%, 74.2%, 84.8%, 76.1% and 84.5%. Age, tumour size, presence of lymphovascular invasion (LVSI) and molecular subtype emerged as independent predictors of survival on multi-variate analysis. Conclusion: The audit highlights the underutilisation of breast-conserving therapy and systemic therapy in the elderly. Increasing age and tumour size, presence of LVSI and molecular subtype were found to be strong predictors of outcome. The findings from this study will help to improve the current gaps in the management of breast cancer among the elderly.

Baseline neurocognitive dysfunction is ubiquitous in intrinsic brain tumors- results from a large Indian cohort of patients and analysis of factors associated with domain-specific dysfunction.

Background: Neurocognitive function (NCF) before surgery is an important marker of baseline performance in patients with brain tumors. Increasingly, neurocognitive deficits (NCD) have been demonstrated in a high proportion of patients. Selection bias (patient, tumor, and surgical procedure related) may influence the prevalence and type of domains involved in patients with gliomas. Methods: We evaluated baseline NCF in a consecutive cohort of intra-axial tumors in Indian patients (n = 142). A comprehensive battery evaluating five domains - attention & executive function (EF), memory, language, visuospatial function and visuomotor abilities was used. Deficits were categorized as severe and mild-moderate. Factors associated with severe NCD were evaluated. Results: Severe NCD was present in 90% of the patients, 70% of them having affection of at least 2 domains. Attention-EF, memory and visuomotor speed were most affected. 132 underwent surgery (69 awake, 63 under general anesthesia - GA). The awake cohort had younger patients with lower grade gliomas and more left sided tumors. Multi-domain dysfunction was seen almost equally in awake/GA groups as well as left/right sided tumors. On multivariate analysis, older age, lower educational status and larger tumor volume adversely affected NCF in many of the domains. Only language dysfunction was location specific (temporal lobe tumors) though not laterality (left/right) specific. Conclusions: NCD were seen in a large majority of cases before surgery, including those undergoing awake surgery. Language may be affected even in tumors in the non-dominant hemisphere. Attention-EF and memory are most affected and need to be factored in while assessing patient performance intraoperatively during awake surgery as well as tailoring rehabilitative measures subsequently.

Institutional Patterns of Care of Diffuse Intrinsic Pontine Glioma.

Background and Aim: Despite recent advances, the outcomes of diffuse intrinsic pontine glioma (DIPG) remain dismal. This is a retrospective study to understand the pattern of care and its impact on DIPG patients diagnosed over 5 years in a single institute. Subjects and Methods: DIPGs diagnosed between 2015 and 2019 were retrospectively reviewed to understand the demographics, clinical features, patterns of care, and outcomes. The usage of steroids and response to treatment were analyzed as per the available records and criteria. The re-irradiation cohort was propensity matched with patients with a progression-free survival (PFS) >6 months treated with supportive care alone based on PFS and age as a continuous variable. Survival analysis was performed using the Kaplan-Meier method, and Cox regression model was used to identify any potential prognostic factors. Results: One hundred and eighty-four patients were identified with demographic profiles similar to western population-based data in the literature. Of them, 42.4% were residents from outside the state of the institution. About 75.2% of patients completed their first radiotherapy treatment, of which only 5% and 6% had worsening clinical symptoms and persistent need for steroids 1 month posttreatment. On multivariate analysis, Lansky performance status <60 (P = 0.028) and cranial nerve IX and X (P = 0.026) involvement were associated with poor survival outcomes while receiving radiotherapy with better survival (P < 0.001). In the cohort of patients receiving radiotherapy, only re-irradiation (reRT) was associated with improved survival (P = 0.002). Conclusion: Many patient families still do not choose radiotherapy treatment, although it has a consistent and significant positive association with survival and steroid usage. reRT further improves outcomes in the selective cohorts. Involvement of cranial nerves IX and X needs improved care.

A prospective, open-label, randomised, parallel design study of 4 generic formulations of intramuscular L-asparaginase in childhood precursor B-cell acute lymphoblastic leukaemia (ALL).

AIMS: L-asparaginase is an essential medicine for childhood ALL. The quality of generic L-asparaginase available in India is a matter of concern. We compared four commonly used generic formulations of L-asparaginase in India. MATERIALS AND METHODS: We conducted a prospective, open-label, randomised trial of four generic formulations of asparaginase for the treatment of patients with newly diagnosed intermediate-risk B-ALL. Patients were randomly assigned in a 1:1:1:1 ratio to receive generic asparaginase at a dose of at 10,000 IU/m 2 on days 9, 12, 15, and 18 of a 35-day cycle (Induction treatment). The primary end points were to determine the difference in the asparaginase activity and asparagine depletion. Historical patients who received L-asparaginase Medac (innovator) served as controls. RESULTS: A total of 48 patients underwent randomization; 12 patients each in the four arms. Failure to achieve predefined activity threshold of 100 IU/L was observed in 9/40 samples of Generic A (22·5%), 23/40 of Generic B (57·5%), and 43/44 (98%) each of Generic C and D. All 27 samples from seven historical patients who were administered Medac had activity > 100 IU/L. The average activity was significantly higher for Genericm A, 154 (70·3, 285·4) IU/L followed by Generic B 84·5(44·2, 289·1) IU/L, Generic C 45(14·4, 58·4) IU/L, and Generic D 20·4(13, 35) IU/L. Only 6 patients had asparaginase activity > 100 IU/L on each of the four occasions (Generic A = 5; Generic B = 1), and none of them developed Anti-Asparaginase Antibodies (AAA). On the other hand, AAA was observed in 12/36 patients who had at least one level < 100 IU/L (P < 0·05): Generic A 3/5, Generic B = 3/9, Generic D (4/11), and Generic C (5/11). CONCLUSION: Generic A and B had better trough asparaginase activity compared to Generic D and C. Overall, generic formulations had lower asparaginase activity which raises serious clinical concerns regarding their quality. Until strict regulatory enforcement improves the quality of these generics, dose adaptive approaches coupled with therapeutic drug monitoring need to be considered.

Diagnostic and prognostic role of protein and ultrastructural alterations at cell-extracellular matrix junctions in neoplastic progression of human oral malignancy.

Despite advancements in technology and increase in favorable outcomes associated with oral cancer, early detection remains the most significant factor in limiting mortality. The current study aimed to develop early diagnostic and prognostic markers for oral tumorigenesis. Protein and ultrastructural alterations at cell-extracellular matrix (ECM) adhesion junctions were examined concurrently using immunohistochemistry (IHC) and transmission electron microscopy (TEM) on progressive grade of oral carcinomas (n = 285). The expression of hemidesmosome (HD) proteins-integrin ß4, BP180, and laminin-5 increased in hyperplasia as compared to normal, and significantly increased further, as the disease progressed. TEM analysis in parallel tissues revealed a significant decrease in HD number and increase in the length of basal lamina (BL) in hyperplasia. With cancer progression, the severity of ultrastructural alterations increased gradually and significantly. Overexpression of HD proteins, decrease in HD number and increase in BL length significantly correlated with nodal metastasis, local recurrence, and recurrence-free survival of patients. Concurrent use of IHC and TEM can add value to early recognition of neoplastic changes in primary carcinomas of oral cavity. In this regard, altered expression of integrin ß4 and laminin-5, loss of HDs, and increased BL length could offer criteria for early diagnosis and prognosis of oral malignancy.

Second-line therapy in testicular germ cell tumours: results from a tertiary cancer care centre in India.

Background: Malignant testicular neoplasms constitute about 1% of all cancers in males. This is one of the most common tumours in adolescents and young adult males. After the introduction of cisplatin-based chemotherapy, the survival of germ cell tumour patients, even those with poor prognostic risk factors, has significantly improved over the years. Second-line chemotherapy in patients who have progressed over the first-line cisplatin-based chemotherapy has shown convincing 5 years of overall survival (OS). Methodology: This study is a retrospective analysis of testicular cancer patients from 2014 to 2020 who have received salvage chemotherapy treatment at Tata Memorial Centre. Patient demographics, tumour characteristics and treatment details were recorded in a specific format, and progression-free survival and OS were analysed along with response to therapy. Results: A total of 46 testicular cancer patients from 2014 to 2020, who received second-line chemotherapy, were analysed from the database maintained at our hospital. The median age at diagnosis was 29.5 (18-60) years. Most of the patients (30, 65.2%) presented with lung metastasis and 11 (23.9%) patients with liver metastasis. Most of the patients (21, 45.6%) received vinblastine, ifosfamide and cisplatin, whereas 13 (28.2%) patients received paclitaxel, ifosfamide and cisplatin regimen and 7 (15.2%) patients received GemOx regimen as the second-line chemotherapy. Median OS was observed to be 33.97 months and median progression-free survival was 29.01 months. Conclusion: Second-line chemotherapy in testicular germ cell tumours can result in long-term disease control and all patients who are fit to tolerate second-line therapy should be offered it. Patients with relapsed seminoma did better than relapsed non-seminomatous germ cell tumours.

Prevention of carcinogen-induced oral cancers by polymeric black tea polyphenols via modulation of EGFR-Akt-mTOR pathway.

The overexpression of Epidermal Growth Factor Receptor (EGFR) and dysregulation of its downstream effector pathways are important molecular hallmarks of oral cancers. Present study investigates the chemopreventive potential of polymeric black tea polyphenols (PBPs)/thearubigins (TRs) in the hamster model of oral carcinogenesis as well as determine the effect of PBPs on EGFR and the molecular players in the EGFR pathway. In dose-dependent manner, pre and concurrent treatment with PBPs (1.5%, 5%, 10%) decreased the number and volume of macroscopic tumors as well as the number and area of microscopic lesions. Interestingly, at 10% dose of PBPs, no macroscopic or microscopic tumors were observed. We observed PBPs mediated dose-dependent decrease in oxidative DNA damage (8OHdG); inflammation (COX-2); proliferation (PCNA, Cyclin D1); expression of EGFR, and its downstream signaling kinases (pAkt, Akt, and mTOR); hypoxia (HIF1α) and angiogenesis (VEGF). There was also a PBPs mediated dose-dependent increase in apoptosis (Bax). Thus, our data clearly indicate that the observed chemopreventive potential of PBPs was due to modulation in the EGFR pathway associated with cell proliferation, hypoxia, and angiogenesis. Taken together, our results demonstrate preclinical chemopreventive efficacy of PBPs and give an insight into its mechanistic role in the chemoprevention of experimental oral cancer.

Audit of principal investigator's compliance for submission of continue review application and decisions taken on lapses in validity of approval by the Institutional Ethics Committee at tertiary oncology center in Navi Mumbai.

Context: A failure to obtain continued Institutional Ethics Committee (IEC) approval for the study before the expiry date assigned by the IEC is considered as "lapse of the IEC approval" to continue the study at the site by the Investigator. Considering this, we had conducted an audit of principal investigators (PI ') compliance for Continuing Review Application (CRA) submission timelines and decision taken on the lapses in the validity of IEC approval continuation. Aim: The aim of this study is to assess the pre- and post-policy trends of non-compliance management of delayed CRA submission and compare the PI's compliance for submission of CRA between Investigator Initiated trial (IIT) and Pharma studies. Setting and Design: The present study was a retrospective audit of CRAs of ongoing projects submitted by PIs to IEC, ACTREC. Materials and Methods: The data from total 199 CRAs submitted for review to the IEC between the year January 2016 and December-2017 were collected and maintained in Microsoft Excel sheet, and later, the data were exported into the SPSS software version 21 for the analysis. Statistical Analysis: All categorical data were presented in numbers and percentage. The first primary objective was assessed by calculating the duration between the dates of approval for any study to the date of next CRA submission. The CRAs submitted after the project expiry date were considered as a lapse in following the IEC SOP. Results: This retrospective audit revealed that CRA reminder sent by the IEC to the PI played an important role in compliance w. r. t timely in following the IEC SOPof the CRA by the PI. As a result, overall, 90% of CRAs showed compliance in submitting CRAs to IEC in both IIT and Pharma study. The number of lapses were reduced to 7 in the postpolicy period as compared to 15 lapses in the prepolicy period. Conclusion: This retrospective audit reveals that CRA reminder sent by the IEC to the PI played an important role in improving the compliance of PIs in submitting CRA to IEC. Each IEC should develop the policy to minimize the delays in CRA submission by the PI and prevent lapses in following the IEC SOP.

Neurocognitive function and survival in children with average-risk medulloblastoma treated with hyperfractionated radiation therapy alone: Long-term mature outcomes of a prospective study.

Background: The purpose of this study was to report long-term neurocognitive and clinical outcomes in children treated for average-risk medulloblastoma with hyperfractionated radiation therapy (HFRT) alone. Methods: Between 2006 and 2010, 20 children with rigorously staged average-risk medulloblastoma were treated on a prospective study with HFRT without upfront adjuvant systemic chemotherapy after written informed consent. HFRT was delivered as twice-daily fractions (1 Gy/fraction, 6-8 hours apart, 5 days/week) to craniospinal axis (36 Gy/36 fractions) plus conformal tumor-bed boost (32 Gy/32 fractions). Neurocognitive function was assessed at baseline and periodically on follow-up using age-appropriate intelligence quotient (IQ) scales. Results: Median age was 8 years (range 5-14 years) with 70% being males. Mean and standard deviation (SD) scores at baseline were 90.5 (SD = 17.08), 88 (SD = 16.82) and 88 (SD = 17.24) for Verbal Quotient (VQ), Performance Quotient (PQ), and Full-Scale IQ (FSIQ) respectively. Mean scores remained stable in the short-to-medium term but declined gradually beyond 5 years with borderline statistical significance for VQ (P = .042), but nonsignificant decline in PQ (P = .259) and FSIQ (P = .108). Average rate of neurocognitive decline was <1 IQ point per year over a 10-year period. Regression analysis stratified by age, gender, and baseline FSIQ failed to demonstrate any significant impact of the tested covariates on longitudinal neurocognitive function. At a median follow-up of 145 months, 10-year Kaplan-Meier estimates of progression-free survival and overall survival were 63.2% and 74.1% respectively. Conclusion: HFRT alone without upfront adjuvant chemotherapy in children with average-risk medulloblastoma is associated with modest decline in neurocognitive functioning with acceptable long-term survival outcomes and may be most appropriate for resource-constrained settings.

Tezepelumab compared with other biologics for the treatment of severe asthma: a systematic review and indirect treatment comparison.

AIMS: To compare the efficacy of tezepelumab with other approved biologics via indirect treatment comparisons (ITCs) in patients aged ≥ 12 years with severe uncontrolled asthma. MATERIALS AND METHODS: Data from randomized controlled trials (RCTs) identified from a systematic literature review were synthesized using two different ITC approaches: network meta-analysis (NMA) and simulated treatment comparison (STC). Outcomes of interest were annualized asthma exacerbation rate (AAER) and AAER for exacerbations leading to hospitalization. To address potential heterogeneity between study populations, various subgroup analyses were performed for the NMA (based on blood eosinophil count, fractional exhaled nitric oxide level, and presence of allergic asthma), and for the STC, models were adjusted for potential treatment effect modifiers. Sensitivity analyses were performed to assess the impact of study design (exclusion of non-placebo-controlled studies and non-phase 3 or 4 studies). Results were reported as rate ratios (RRs) with 95% credible/confidence intervals and ranking statistics were computed for the NMAs. RESULTS: Sixteen RCTs were included in at least one of the ITCs. All biologics (tezepelumab, dupilumab, benralizumab, mepolizumab, reslizumab, and omalizumab) had similar efficacy, with no statistically significant RRs for either exacerbation outcome; however, tezepelumab was favorably associated with numerically lower AAERs and was ranked first in the network for both types of exacerbation outcome. This trend was consistent in the subgroup and sensitivity analyses. As with the primary NMA, the STC results did not demonstrate any significant differences between biologics, but point estimates were favorable towards tezepelumab. LIMITATIONS: Heterogeneity between trials was observed among eligibility criteria and clinically important patient characteristics; however, the impact on findings is expected to be low, based on consistency across analyses. CONCLUSIONS: Findings from both ITCs (NMA and STC) support the use of tezepelumab in a broad patient population of severe uncontrolled asthma of any phenotype.

Feasibility of therapeutic drug monitoring of sunitinib and its implications on response and toxicity in patients with metastatic renal cell cancer.

PURPOSE: Sunitinib is an oral tyrosine kinase inhibitor approved for the treatment of metastatic renal cell carcinoma (mRCC). High variability in pharmacokinetics coupled with a proven exposure-effect relationship makes sunitinib an ideal candidate for therapeutic drug monitoring (TDM). The feasibility of TDM of sunitinib in patients with mRCC was evaluated in this prospective observational study in a real-world scenario. METHODS: Seventy patients with mRCC treated with sunitinib at a fixed dose of 50 mg per day were enrolled in the study. Total trough plasma level (TTL) of sunitinib (sunitinib and its active metabolite, SU12662), was measured between days 14/15 of cycle 1. The discriminatory potential of TTL of sunitinib for the prediction of responders and occurrence of grade ≥ 3 toxicity was determined using receiver operating characteristic (ROC) curve. RESULTS: The median TTL of sunitinib was 76 ng/mL. Forty six out of 70 patients were evaluable for response, whereas 60 out of 70 patients were evaluable for toxicity. Threshold concentrations obtained from ROC analysis showed that TTL of 60.75 ng/mL and 82.3 ng/mL was discriminatory for response and occurrence of grade ≥ 3 toxicity respectively. 31/34 (91.7%) patients having TTL ≥ 60.75 ng/mL responded to treatment, while only 5/12 (41.6%) responded when TTL was < 60.75 ng/mL (P = 0.001). On the other hand, the incidence of grade ≥ 3 toxicity was 9/24 (37.7%) in patients with TTL ≥ 82.3 ng/mL compared to 4/36 (11.1%) in patients with TTL < 82.3 ng/mL (P = 0.024). CONCLUSION: The TTL range of 60.75-82.3 ng/mL was found to be optimal in terms of safety and efficacy. More than 50% of patients in our cohort attained TTL of sunitinib outside the optimal range, thus demonstrating the feasibility of TDM to improve safety and efficacy of sunitinib in mRCC.

Months and Severity Score (MOSES) in a Phase III trial (PARCER): A new comprehensive method for reporting adverse events in oncology clinical trials.

Background: Adverse event reporting in oncology trials lacks temporal description. We propose a toxicity summarizing method that incorporates time. Methods: Patients recruited in a phase III trial (NCT01279135) that compared three-dimensional conformal radiotherapy (3DCRT) and intensity modulated radiotherapy (IMRT) for late toxicity in cervical cancer were included. Adverse events were reported using Common Terminology Criteria for Adverse Events (CTCAE) v3.0 and quality of life (QOL) with EORTC QLQ-C30 and CX24. A total of six symptoms with a related QOL question (diarrhoea, abdominal pain, anorexia, urinary incontinence, frequency and fatigue) were included. Month and severity score [MOSES= ∑ (CTCAE grade x proportionate time)] was calculated. Cumulative-MOSES (C-MOSES) was calculated by summating these 6 individual MOSES. QoL was categorized as "substantially symptomatic" or "not". Receiver operator curve analysis was performed to determine the MOSES cut off that predicts for substantial QOL symptoms. CTCAE and MOSES were tested for accurately categorizing QOL impact. Findings: In the construction dataset, 201/300 patients had symptoms. MOSES > 0.20 had higher accuracy than CTCAE for predicting impact on QOL related to diarrhoea (85% vs. 69%), anorexia (61% vs 51%), abdominal pain (71% vs. 57%), urinary incontinence (72% vs. 61%) and frequency (62% vs. 59%). C-MOSES > 0·70 correlated with reduction in role functioning and global QOL. While no difference was seen in CTCAE grade ≥1 Gastrointestinal (GI) toxicity between 3DCRT or IMRT arm, 3DCRT had higher C-MOSES than IMRT (HR=0.64;95% CI 0.41-0.99, p = 0.04). Interpretation: MOSES has higher accuracy than CTCAE in categorizing symptom specific and functional QOL. These results require further external validation. Funding: None.

CD26 expression on donor harvest as a risk predictive biomarker for developing graft-versus-host disease post-allogeneic hematopoietic stem cell transplantation: A ten-year follow-up study.

BACKGROUND: Allogeneic hematopoietic stem cell transplantation (ASCT) is the preferred treatment option for patients with several hematologic disorders and immunodeficiency syndromes. Graft-versus-host disease (GVHD) is an immune mediated post-transplant complication which has a major impact on long-term transplant outcomes. OBJECTIVE: Current efforts are focused on identification of new markers that serve as potential predictors of GVHD and other post-transplant clinical outcomes. METHODS: This study includes donor harvests collected from twenty-three allogeneic donors during period 2008-2009 and respective transplant recipients followed for clinical outcomes till March 2019. Percent CD26+ and CD34+ cells in donor harvest were analyzed using flow cytometry. Percent expression and infused dose of CD26+ and CD34+ cells were evaluated for association with various clinical outcomes. RESULTS: Total 23 healthy donors with median age of 28 years (13 males), and transplant recipients with median age of 24 years (17 males) formed the study cohort. The diagnosis included malignant (n= 13) and non-malignant (n= 10) hematological disorders. Median CD34brCD45lo HSC expression was 0.57% (IQR 0.24-1.03) while median CD26 expression was 19.64% (IQR 8.96-33.56) of all nucleated cells. CD26 expression was associated with donor age (P= 0.037). CD26 percent expression correlated with WBC engraftment (P= 0.015) and with acute GVHD (P= 0.023) whereas infused CD26 cell dose correlated with WBC engraftment (P= 0.004) and risk of CMV reactivation (P= 0.020). There was no statistically significant correlation of either CD26 expression or cell dose with chronic GVHD, EFS or OS. CONCLUSIONS: Our findings suggest a role of CD26 expression on human donor harvest as a potential predictor of acute GVHD. This association warrants further exploration.