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BMC Cancer ◽  
2022 ◽  
Vol 22 (1) ◽  
John Sharp ◽  
Vinay Prasad

Abstract Importance It is unknown whether and to what degree trials submitted to the US FDA to support drug approval adhere to NCCN guideline-recommended care in their baseline and surveillance CNS imaging protocols. Objective We sought to characterize the frequency with which the trials cited in US FDA drug approvals for first line advanced NSCLC between 2015 and 2020 deviated from NCCN guideline-recommended care for baseline and surveillance CNS imaging. Design, setting, and participants Retrospective observational analysis using publicly available data of (1) list of trials cited by the FDA in drug approvals for first line advanced NSCLC from 2015 to 2020 (2) individual trial protocols (3) published trial data and supplementary appendices (4) archived versions of the NCCN guidelines for NSCLC from 2009 to 2018 (the years during which the trials were enrolling). Main outcomes and measures Estimated percentage of trials for first line advanced NSCLC leading to FDA approval which deviated from NCCN guideline-recommended care with regards to CNS baseline and surveillance imaging. Results A total of 14 studies that had been cited in FDA drug approvals for first line advanced NSCLC met our inclusion criteria between January 1, 2015 and September 30, 2020. Of these trials, 8 (57.1%) deviated from NCCN guidelines in their baseline CNS imaging requirement. The frequency of re-assessment of CNS disease was variable amongst trials as well, with 9 (64.3%) deviating from NCCN recommendations. Conclusions and relevance The trials supporting US FDA drug approvals in first line advanced NSCLC often have CNS imaging requirements that do not adhere to NCCN guidelines. Many trials permit alternative, substandard methods and the proportion of patients undergoing each modality is uniformly not reported. Nonstandard CNS surveillance protocols are common. To best serve patients with advanced NSCLC in the US, drug approvals by the FDA must be based on trials that mirror clinical practice and have imaging requirements consistent with current US standard of care.

2022 ◽  
Vol 17 (1) ◽  
Hiroshi Mayahara ◽  
Kazuyuki Uehara ◽  
Aya Harada ◽  
Keiji Kitatani ◽  
Tomonori Yabuuchi ◽  

Abstract Background Concurrent chemoradiotherapy (CCRT) followed by durvalumab is the standard of care for unresectable locally-advanced non-small cell carcinoma (LA-NSCLC). However, a major concern about administration of durvalumab after CCRT is whether the incidence of symptomatic radiation pneumonitis (RP) may increase or not. In the present analysis, we report the initial results of CCRT followed by durvalumab in patients with LA-NSCLC in a real-world setting with focus on predicting factors for symptomatic RP. Methods Patients who were pathologically diagnosed as NSCLC and initiated treatment with CCRT followed by durvalumab between July 2018 to December 2019 were eligible for this study. Patients were included if they completed the planned CRT course and administered at least one course of durvalumab. We retrospectively investigated the preliminary survival outcome and incidence and predicting factors for symptomatic RP. Results Of the 67 patients who planned CCRT, 63 patients completed the entire CCRT course. Of these, 56 patients proceeded to consolidation with durvalumab. The median time to eternal discontinuation of durvalumab was 9.7 months. The cumulative proportion of the patients who exhibited symptomatic RP was 30, 40 and 44% at 3, 6 and 12 months, respectively. In multivariate analyses, pulmonary fibrosis score and lung V40 were significant predictive factors for symptomatic RP (p < 0.001, HR: 7.83, 95% CI: 3.38–18.13, and p = 0.034, HR: 3.17, 95% CI: 1.09–9.19, respectively). Conclusions Pulmonary fibrosis sore and lung V40 were significant predictive factors for symptomatic RP. We should be cautious about the administration of durvalumab for patients having subclinical pulmonary fibrosis. To our best knowledge, this is one of the first report showing the predictive value of high dose volumes to the lung in patients with LA-NSCLC who received CCRT followed by durvalumab.

2022 ◽  
Vol 20 (1) ◽  
Gihan Hamdy Elsisi ◽  
Ayman Afify ◽  
Ashraf Abgad ◽  
Ibtissam Zakaria ◽  
Nabil Nasif ◽  

Abstract Introduction Type 2 diabetes mellitus causes a sizable burden globally from both health and economic points of view. This study aimed to assess the budget impact of substituting sitagliptin with liraglutide versus other glucose-lowering drugs from the private health insurance perspective in Egypt over a 3-year time horizon. Methods Two budget impact models were compared with the standard of care (metformin, pioglitazone, gliclazide, insulin glargine, repaglinide, and empagliflozin) administered in addition to liraglutide or sitagliptin versus the standard of care with placebo. A gradual market introduction of liraglutide or sitagliptin was assumed, and the existing market shares for the other glucose-lowering drugs were provided and validated by the Expert Panel. The event rates were extracted from the LEADER and TECOS trials. Direct and mortality costs were measured. Sensitivity analyses were performed. Results The estimated target population of 120,574 type 2 diabetic adult patients was associated with cardio vascular risk. The budget impact per patient per month for liraglutide is EGP29 ($6.7), EGP39 ($9), and EGP49 ($11.3) in the 1st, 2nd, and 3rd years, respectively. The budget impact per patient per month for sitagliptin is EGP11 ($2.5), EGP14 ($3.2), and EGP18 ($4.1) in the 1st, 2nd, and 3rd years, respectively. Furthermore, adoption of liraglutide resulted in 203 fewer deaths and 550 avoided hospitalizations, while sitagliptin resulted in 43 increased deaths and 14 avoided hospitalizations. The treatment costs of liraglutide use are mostly offset by substantial savings due to fewer cardiovascular-related events, avoided mortality and avoided hospitalizations over 3 years. Conclusion Adding liraglutide resulted in a modest budget impact, suggesting that the upfront drug costs were offset by budget savings due to fewer cardiovascular-related complications and deaths avoided compared to the standard of care. Sitagliptin resulted in a small budget impact but was associated with increased deaths and fewer hospitalizations avoided.

2022 ◽  
Vol 17 (1) ◽  
Indrawati Hadi ◽  
Chukwuka Eze ◽  
Stephan Schönecker ◽  
Rieke von Bestenbostel ◽  
Paul Rogowski ◽  

Abstract Background and purpose Chemoradiotherapy (CRT) followed by a brachytherapy (BT) boost is the standard of care for patients with locally advanced or recurrent gynecological cancer (LARGC). However, not every patient is suitable for BT. Therefore, we investigated the feasibility of an MR-guided SBRT boost (MRg-SBRT boost) following CRT of the pelvis. Material and methods Ten patients with LARGC were analyzed retrospectively. The patients were not suitable for BT due to extensive infiltration of the pelvic wall (10%), other adjacent organs (30%), or both (50%), or ineligibility for anesthesia (10%). Online-adaptive treatment planning was performed to control for interfractional anatomical changes. Treatment parameters and toxicity were evaluated to assess the feasibility of MRg-SBRT boost. Results MRg-SBRT boost was delivered to a median total dose of 21.0 Gy in 4 fractions. The median optimized PTV (PTVopt) size was 43.5ccm. The median cumulative dose of 73.6Gy10 was delivered to PTVopt. The cumulative median D2ccm of the rectum was 63.7 Gy; bladder 72.2 Gy; sigmoid 65.8 Gy; bowel 59.9 Gy (EQD23). The median overall treatment time/fraction was 77 min, including the adaptive workflow in 100% of fractions. The median duration of the entire treatment was 50 days. After a median follow-up of 9 months, we observed no CTCAE ≥ °II toxicities. Conclusion These early results report the feasibility of an MRg-SBRT boost approach in patients with LARGC, who were not candidates for BT. When classical BT-OAR constraints are followed, the therapy was well tolerated. Long-term follow-up is needed to validate the results.

2022 ◽  
Vol 8 (4) ◽  
pp. 291-297
M.S. Madhu ◽  
S.M. Ahmed ◽  
Raghavendra. K.V.

There are no approved drugs to treat COVID-19, and the vaccine is likely to be ready by early 2021. Many clinical studies are ongoing around the globe to find a cure or prevention of the disease. The objective of the proposed study is to determine the efficacy and safety profile of Mulmina Mango as an adjunct to standard of care treatment on COVID-19 positive subjects undergoing treatment for COVID-19 in Hospital Quarantine. Settings and Design: The enrolled subjects were randomized into either of the two treatment arms in the ratio of 1:1. The freshly diagnosed (24-48 hrs.) COVID-19 positive Male or Female is aged 20 to 65 years (both inclusive) hospitalized patients were approached and checked for their eligibility. They were recruited after signing the written informed consent form. The number of patients included in the study is 48. In efficacy, both the treatment arms and the reduction in clinical symptom scale value and ordinal scale value are seen on day 7. On the ordinal scale, 41.7% of subjects in Treatment arm A showed a reduction of 2 points on the day, and 16.7% of subjects show 2 points reduction in Treatment arm B. In Safety results, there was no clinically significant finding in safety parameters in Treatment arm B. Mulmina Mango showed encouraging results concerning RTPCR, CRP, Dopamine, IgG, CD4, and CD8 parameters. The properties of Mulmina Mango are highlighted below, along with the parameters for each property. Mulmina Mango, COVID-19, Treatment Arm A, Treatment Arm B, MoHFW (Ministry of Health and Family Welfare)

2022 ◽  
Rong Chen ◽  
Dmitry Gultyaev ◽  
Johanna Lister ◽  
Rong Han ◽  
Nan Hu ◽  

Abstract Background: Long-term prophylactic therapy is considered the standard of care for hemophilia A patients. This study models the long-term clinical and cost outcomes of two factor VIII (FVIII) products using a pharmacokinetic (PK) simulation model in a Chinese population. Methods: Head-to-head PK profile data of BAY 81-8973 (KOVALTRY®) and antihemophilic factor (recombinant) plasma/albumin-free method (rAHF-PFM, ADVATE®) were applied to a two-state (alive and dead) Markov model to simulate blood FVIII concentrations at a steady state in prophylactically-treated patients with hemophilia A. Worsening of the Pettersson score was simulated and decline was associated with the probability of having orthopaedic surgery. The only difference between the compounds was FVIII concentration at a given time; each subject was treated with 25 IU/kg every 3 days. The model used a lifetime horizon, with cycle lengths of 1 year. Results: Cumulative bleeding events, joint bleeding events, and major bleeding events were reduced by 19.3%, 9.3% and 19.3%, respectively for BAY 81-8973 compared to rAHF-PFM. Hospitalizations and hospitalization days were also reduced by 19.3% for BAY 81-8973 compared to rAHF-PFM. BAY 81-8973 resulted in both cost savings and a gain in quality adjusted life years (QALYs) compared to rAHF-PFM. Conclusion: Based on modeled head-to-head comparisons, differences in PK-properties between BAY 81-8973 and rAHF-PFM result in a reduced number of bleeding events, leading to reduced costs and increased quality of life for BAY 81-8973. These results should be used to inform clinical practice in China when caring for patients with severe hemophilia A.

2022 ◽  
Vol 2 ◽  
Sarah Alonzi ◽  
Thomas J. Caruso ◽  
Sayantani B. Sindher ◽  
Shu Cao ◽  
Sara Varadharajulu ◽  

Phlebotomy procedures required in food allergy (FA) diagnosis and clinical trials often induce fear and anxiety for pediatric patients. The primary aim of this study was to determine whether virtual reality (VR) applications were effective in reducing anxiety for pediatric FA patients undergoing phlebotomy during FA clinical trials. Secondary aims assessed fear, pain, procedural compliance, and adverse events. Participants undergoing phlebotomy were enrolled and randomized to a VR group or standard of care (SOC) group for this prospective pilot randomized, pragmatic study. Participants in the VR group played interactive applications on a customized Samsung Gear VR headset and those in the SOC group received the standard of care. Participants' anxiety, fear, and pain were assessed with the Children's Anxiety Meter, Children's Fear Scale, and FACES pain scale pre, during, and post phlebotomy procedure. Compliance was assessed using the modified Induction Compliance Checklist during the procedure and compared between two groups. Forty-nine participants were randomized to VR (n = 26) and SOC (n = 23) groups. Although both the VR and SOC groups experienced a decrease in anxiety and fear from pre- to post-procedure, those in the VR group experienced less anxiety and fear during the procedure than SOC participants. Similarly, both groups experienced an increase in pain from pre- to post-procedure; however, the VR group reported less pain during the procedure than SOC. Fewer symptoms of procedural non-compliance were reported in the VR group. Interactive VR applications may be an effective tool for reducing fear, anxiety, and pain during phlebotomy for FA clinical trials.

Alana Ju ◽  
Sabrina Sedano ◽  
Kathleen Mackin ◽  
Joyce Koh ◽  
Ashwini Lakshmanan ◽  

BACKGROUND: Family-centered rounds (FCR) is the standard of care in inpatient pediatrics. Results of studies have revealed that Spanish-speaking families can experience communication challenges and decreased empowerment on rounds. In our study, we aim to identify variation in FCR practices for Spanish-speaking compared to English-speaking families and factors contributing to these disparities. METHODS: This is a cross-sectional observational study performed by secondary analysis of a quality improvement initiative conducted at a quaternary children’s hospital. Data were collected from June 2019 to March 2020 by using observational audits. Encounters were analyzed to compare key elements of FCR (including rounds location, elicitation of family questions, involvement in discharge planning) for English-speaking and Spanish-speaking families. Multivariable logistic regression was used to compare family involvement in FCR. A sensitivity analysis was conducted to evaluate unmeasured confounding. RESULTS: Rounding encounters included 394 families (261 English-speaking and 133 Spanish-speaking). Fewer Spanish-speaking families were included in the medical team’s discussion on rounds (64.7% vs 76.3%, P = .017), were asked about questions at the start of rounds (44.4% vs 56.3%, P = .025), or were involved in discussion of discharge criteria (72.2% vs 82.8%, P = .018) when compared to English-speaking families. These differences were magnified for resident teams rounding with subspecialists. The finding of decreased family involvement in the discussion on rounds persisted after adjusting for patient age and team type. CONCLUSIONS: Spanish-speaking families were less likely to be involved in FCR compared to English-speaking families. Further investigation is needed to explore the root causes of this practice variation and to develop interventions to address disparities.

2022 ◽  
Guangrong Lu ◽  
Mayank Rao ◽  
Ping Zhu ◽  
Nadine Linendoll ◽  
Maximilian L. Buja ◽  

Abstract Purpose Systemic monotherapy with temozolomide (TMZ) or bevacizumab (BEV); two-drug combinations, such as Irinotecan (IRI) and BEV, TMZ and BEV and a three-drug combination with TMZ, IRI and BEV (TIB) have been used in treating patients with progressive high-grade gliomas including glioblastoma. Most patients tolerated these regimens well with well-established sides effects of hypertension, proteinuria, and reversible clinical myelosuppression (CM). However, organ-specific toxicities have never been examined by postmortem studies. Methods Postmortem tissues (from all major organs) were prospectively collected and examined by standard institution autopsy and brain cutting procedures from 76 decedents, including gliomas (N=68, 44/M, and 24/F) and brain metastases (N=8, 5/M, and 3/F) between 2009 and 2019. Standard hematoxylin and eosin (H&E) were performed on all major organs and brain samples harvested. Electronic microscopic (EM) study was carried on selected subjects kidney samples per standard EM protocol. Results Twenty-four glioma subjects were treated with TIB [median: 5.5 (range: 1-25) cycles] at glioma recurrence. Exposure to IRI significantly increased the frequency of CM (p=0.05). No unexpected adverse events were detected clinically or permenant end-organ damage by postmortem examination among subjects who received TIB compared to subjects who received standard of care (SOC) therapies. Among glioma decedents, the most common causes of death (COD) were tumor progression (63.2%, N=43), followed by aspiration pneumonia (48.5%, N=33). No COD was attributed to acute toxicity from TIB. The study also demonstrated that postmortem kidney specimen is unsuitable for studying renal ultrastructural pathological changes due to autolysis. Conclusion IRI, but not the extended use of TMZ, significantly increased CM in recurrent glioma patients. There is no permanent organ-specific toxicity among glioma decedents who received prolonged BEV, TMZ or TIB regimen based chemotherapies except expected occasional myelosuppresson. COD are most commonly resulted from glioma tumor progression and aspiration pneumonia.

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