tbuckley/cabot-search huggingface dataset:
Adaptation of chemotherapy to the decline tumor markers in patients with poor prognosis nonseminomatous germ cell tumors:Real-world French experience.
Authors: Marion Rolland, Sara Faouzi, Leonor Chaltiel, Clement Dumont, Lionnel Geoffrois, Marine Gross-Goupil, Brigitte Laguerre, Mathilde Guerin, Ludovic Doucet, Guilhem Roubaud, Magalie Tardy, Stephane Oudard, Aude Flechon, Diego Tosi, Hakim Mahammedi, Christine Chevreau, Damien Pouessel, Karim Fizazi
Journal: Journal of Clinical Oncology (2021)

385 Background: Personalized chemotherapy based on tumor marker decline is the new standard in poor prognosis germ-cell tumor in Europe since 2014 (GETUG 13, Lancet, Fizazi et al). The purpose of this study was to analyze the reproducibility of the princeps study in patients not selected in clinical routine between 2014 and 2018. Methods: Patients (pts) were eligible if they had at least one criteria of IGCCCG classification for poor prognosis group. They had to be treated according the study terms of GETUG 13 study and did not received prior treatment. They had to received 1 BEP (Bleomycin, Etoposide, Cisplatin). Tumor markers (HCG and AFP) were dosed between day 18 and 21. Then, they received 3 additional BEP if they had favorable tumor marker decline or intensive chemotherapy if they had unfavorable decline. Results: This retrospective study included 104 patients in 14 french centers treated between 2013 and 2018: 22,1 % (n = 23) in the favorable group (Fav), 77,9 % (n = 81) in the unfavorable group (Unfav). Thirty-two pts had PS ≥ 2. In Unfav, there were more pts with HCG &gt; 50 000 UI/L (44,2 % vs 13 %, p = 0,0067), neutrophil-to-lymphocyt ratio was also higher (median 6,4 vs 4,5, p = 0,0199). At cycle 1, all pts received BEP in Fav and 87,5 % (n = 70) in Unfav. After chemotherapy and surgery, 65,2 % in Fav and 41,3 % in Unfav obtained complete response. At 30 months (median follow-up), Fav-OS was 80,5 % (IC95% 55,8 – 92,2) and Unfav-OS was 64,4 % (IC95% 52 – 74,4). At 30 months, rates were 69,6 % (IC95% 46,6 -84,2) and 63.5 % (IC95% 51,9 – 73) respectively. In GETUG 13 study, 3-years OS was 84 % in Fav and 73 % on Unfav; 3-years PFS was 70 % and 59 % respectively. Seven pts died because of toxicity in Unfav (No one in Fav). Neuropathy, anemia and thrombopenia were more frequent in Unfav. Salvage high-dose chemotherapy with stem-cell transplant was required in 4 (66,7 %) pts in Fav and 8 (36,4 %) pts in Unfav. Conclusions: This study showed a reproducibility of the princeps study in terms of PFS and OS. Toxicity seemed more important in real world. For the congress, results will be reported with 50 additional pts.
Metabolic alterations in a rat model of takotsubo syndrome
Authors: Nadine Godsman, Michael Kohlhaas, Alexander Nickel, Lesley Cheyne, Marco Mingarelli, Lutz Schweiger, Claire Hepburn, Chantal Munts, Andy Welch, Mirela Delibegovic, Marc Van Bilsen, Christoph Maack, Dana K Dawson
Journal: Cardiovascular Research (2021)

Cardiac energetic impairment is a major finding in takotsubo patients. We investigate specific metabolic adaptations to direct future therapies.An isoprenaline-injection female rat model (vs. sham) was studied at Day 3; recovery assessed at Day 7. Substrate uptake, metabolism, inflammation, and remodelling were investigated by 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography, metabolomics, quantitative PCR, and western blot (WB). Isolated cardiomyocytes were patch-clamped during stress protocols for redox states of NAD(P)H/FAD or [Ca2+]c, [Ca2+]m, and sarcomere length. Mitochondrial respiration was assessed by seahorse/Clark electrode (glycolytic and β-oxidation substrates). Cardiac 18F-FDG metabolic rate was increased in takotsubo (P = 0.006), as was the expression of GLUT4-RNA/GLUT1/HK2-RNA and HK activity (all P < 0.05), with concomitant accumulation of glucose- and fructose-6-phosphates (P > 0.0001). Both lactate and pyruvate were lower (P < 0.05) despite increases in LDH-RNA and PDH (P < 0.05 both). β-Oxidation enzymes CPT1b-RNA and 3-ketoacyl-CoA thiolase were increased (P < 0.01) but malonyl-CoA (CPT-1 regulator) was upregulated (P = 0.01) with decreased fatty acids and acyl-carnitines levels (P = 0.0001-0.02). Krebs cycle intermediates α-ketoglutarate and succinyl-carnitine were reduced (P < 0.05) as was cellular ATP reporter dihydroorotate (P = 0.003). Mitochondrial Ca2+ uptake during high workload was impaired on Day 3 (P < 0.0001), inducing the oxidation of NAD(P)H and FAD (P = 0.03) but resolved by Day 7. There were no differences in mitochondrial respiratory function, sarcomere shortening, or [Ca2+] transients of isolated cardiomyocytes, implying preserved integrity of both mitochondria and cardiomyocyte. Inflammation and remodelling were upregulated-increased CD68-RNA, collagen RNA/protein, and skeletal actin RNA (all P < 0.05).Dysregulation of glucose and lipid metabolic pathways with decreases in final glycolytic and β-oxidation metabolites and reduced availability of Krebs intermediates characterizes takotsubo myocardium. The energetic deficit accompanies defective Ca2+ handling, inflammation, and upregulation of remodelling pathways, with the preservation of sarcomeric and mitochondrial integrity.
Sarcopenia prior to and following chemotherapy to predict morbidity in patients undergoing post-chemotherapy retroperitoneal lymphadenectomy (PC-RPLND).
Authors: Fady Baky, Solomon L. Woldu, Vitaly Margulis, Aditya Bagrodia
Journal: Journal of Clinical Oncology (2021)

381 Background: Patients undergoing post-chemotherapy retroperitoneal lymphadenectomy (PC-RPLND) are subject to variable but substantial risks. Unlike those patients undergoing other extirpative GU surgeries, patients undergoing PC-RPLND are usually younger and possess fewer co-morbidities. Despite this, the burden of metastatic disease and the effects of pre-operative chemotherapy may leave patients poorly conditioned prior to undergoing surgery. Sarcopenia has previously been demonstrated to predict adverse clinical outcomes in a variety of abdominal surgeries. We hypothesized that sarcopenia would be similarly predictive of morbidity and mortality in patients undergoing PC-RPLND. Methods: The records of all patients undergoing post-chemotherapy retroperitoneal lymphadenectomy for the treatment of metastatic germ cell tumors at both a public safety net hospital and an academic tertiary medical center were reviewed. Sarcopenia was assessed by measuring cross sectional area of the psoas muscle at the middle of the third lumbar vertebral body on pre-chemotherapy and preoperative computerized tomography. Psoas Muscle Index (PMI) was calculated by adjusting total psoas area for patient height (cm 2 /m 2 ). Univariate and multivariate analysis was performed to assess the predictive value of sarcopenia for morbidity and mortality following PC-RPLND. Results: 90 patients underwent PC-RPLND from the year 2006-2019, of whom 81 patients had both pre-chemo and preoperative cross sectional imaging available. Prior to chemotherapy the mean PMI for this cohort was 7.32 cm 2 /m 2 , and this did not significantly change following chemotherapy mean PMI = 7.06 cm 2 /m 2 (p = 0.44). Lower PMI both prior to (p = 0.05) and following chemotherapy (p = 0.03) were predictive of a higher risk of post-operative complication. There was a trend towards longer hospital length of stay in patients with more significant sarcopenia, however this was not clinically significant (p = 0.09). Conclusions: Sarcopenia was predictive of morbidity in patients undergoing PC-RPLND. Although sarcopenia did worsen following chemotherapy this was not statistically significant. Further assessment of sarcopenia and pre-operative nutritional status in this population may provide opportunities to reduce morbidity following PC-RPLND.
Improving access to health services for female entertainment workers in Cambodia: findings from the Mobile Link randomised controlled trial
Authors: Carinne Brody, Pheak Chhoun, Tuot Sovannary, Anne E Fehrenbacher, Alexander Moran, Dallas Swendeman, Siyan Yi
Journal: The Lancet Global Health (2021)

BackgroundFemale entertainment workers (FEWs) in Cambodia who work at karaoke bars, massage parlours, and beer gardens have higher rates of HIV and sexually transmitted infections (STIs), psychological distress, substance use, and gender-based violence than the general population. Reaching these workers with health education and services has been difficult because of their hidden and stigmatised status. This study evaluates the Mobile Link intervention, which aims to engage FEWs in Cambodia by connecting them to existing services for HIV, sexual and reproductive health, and gender-based violence using short message services and voice messages to ultimately improve their health.MethodsThe Mobile Link intervention consisted of text or voice messages on ten health topics, which were delivered twice a week for 10 weeks and the message topics were repeated every 10 weeks for 30 weeks (time 2) and 60 weeks (time 3). The messages were co-developed with FEWs over a 6-month period before the trial began. We used a stratified random sampling method to select 600 FEWs from a list of 4000 by age group (18–24 years old and 25–30 years old) and study sites (two sites in Phnom Penh and one site each in Battambang, Banteay Meanchey, and Siem Reap). Participants were randomly allocated to the intervention or standard-care control group. Primary outcome measures were self-reported HIV and STI testing, condom use, and contraceptive use. Secondary outcomes included contact with outreach workers, use of escorted referral services, forced drinking and gender-based violence. Intervention effects were modelled using repeated-measures multilevel mixed-effects logistic regression.FindingsBetween March, 2018, and June, 2019, we included 218 women in the intervention group and 170 in the control group in the per protocol analyses after removing dropouts. There were no differences between intervention and control groups over time for primary outcomes in fully adjusted models. However, evidence of positive intervention effects was noted for some secondary outcomes: contacting an outreach worker (group by time 2 adjusted OR: 3·288 [95% CI 1·277–8·469]), receiving an escorted referral (group by time 2, 2·861 [1·089–7·518]; group by time 3, 8·150 [1·650–40·250]), and never being forced to drink at work (group by time 3, 3·945 [1·622–9·597]).InterpretationThe Mobile Link intervention effectively connected female entertainment workers in Cambodia with outreach workers and escorted referrals and reduced rates of forced drinking at work. Longer-term messaging has the potential to increase access to services and could improve health outcomes for female entertainment workers.Funding5% Initiative through Expertise France (Grant No. 16SANIN210).
Health-related quality-of-life (HRQoL) analysis from a randomized phase II trial of androgen signaling inhibitors with or without androgen deprivation therapy (ADT) for castration-sensitive prostate cancer: LACOG 0415.
Authors: Andrey Soares, Diogo Assed Bastos, Fabio A. B. Schutz, Eduardo Cronemberger, Murilo Luz, Suelen P. S. Martins, David Queiroz Borges Muniz, Flavio Mavignier Carcano, Oren Smaletz, Fábio A Peixoto, Andrea Juliana Gomes, Felipe Melo Cruz, Fabio Andre Franke, Daniel Herchenhorn, Rosemarie Gidekel, Taiane Francieli Rebelatto, Rafaela Gomes, Vinicius Carrera Souza, Andre P. Fay, Fernando C. Maluf
Journal: Journal of Clinical Oncology (2021)

64 Background: LACOG0415 is a 3-arm randomized trial evaluating ADT with abiraterone acetate plus prednisone (ADT+AAP), apalutamide alone (APA) or apalutamide with AAP (APA+AAP) for patients with locally-advanced, high-risk biochemical recurrence or metastatic castration-sensitive prostate cancer (ASCO 2020). In this trial, ADT+AAP and APA+AAP achieved the primary endpoint of percentage of patients with PSA ≤ 0.2 ng/mL at week 25. Apalutamide alone showed a high PSA decline &gt; 50% rate, but did not achieve the pre-specified PSA threshold. Here we report patient-reported outcome data using Functional Assessment of Cancer Therapy-Prostate (FACT-P). Methods: HRQoL was measured in the overall population using the FACT-P questionnaire, comprising 5 subscales: physical wellbeing (PWB), functional wellbeing (FWB), emotional wellbeing (EWB), social/family wellbeing (SFWB), and prostate cancer subscale (PCS). Scores for each patient were measured at baseline and every four weeks until week 25. Questionnaire completion was defined as ≥ 1 question answered at an assessment time point. Analysis of HRQoL change from baseline and deterioration included only patients with baseline and ≥ 1 postbaseline score. Differences greater than 10-points in FACT-P total score and differences greater than 3-points in PWB, FWB, EWB, SFWB, and PCS scores were considered clinically significant. The time-to-event endpoint was estimated by Kaplan-Meier method and compared by stratified log-rank test. Results: 128 patients were included in LACOG0415 trial and 122 of them completed the HRQoL assessments (ranging from 95.3% at baseline to 79.7% at week 25). FACT-P and all subscales scores were similar for all three arms at baseline. There were no meaningful differences in FACT-P scores at baseline and at week 25 between the 3 arms. The subscales scores also showed no statistically differences at baseline and at week 25. Time to FACT-P deterioration did not show any statistically difference between three arms ( P=0.3371). Conclusions: ADT free alternatives with APA alone or APA+AAP did not show meaningful differences in HRQoL in patients with advanced castration-sensitive prostate cancer compared to ADT+AAP. The short follow-up period limited the ability to explore differences in HRQoL after 25 weeks. Larger studies with longer follow-up are needed to further evaluate HRQoL with ADT-free strategies. Clinical trial information: NCT02867020. [Table: see text]
Dupilumab treatment in patients with atopic dermatitis: a comparative cohort study between the Netherlands and Japan shows a discrepancy in patient‐reported outcome measures
Authors: L.E.M. de Wijs, R.F.T. Fujimoto, E.R. Andrinopoulou, T. Nijsten, D. Hijnen, Y. Kataoka
Journal: British Journal of Dermatology (2021)

Background Dupilumab was equally effective among all racial subgroups in clinical trials, but a direct comparison in daily practice is lacking. Objectives To investigate the effectiveness of dupilumab in patients with atopic dermatitis (AD) in the Netherlands and Japan over 80 weeks of treatment. Methods A longitudinal comparative cohort study was conducted in patients with AD who were treated with dupilumab in daily practice. We used linear mixed-effects models to determine changes over time. Results We found statistically significant differences in sex, disease onset, body mass index and therapeutic history between Dutch (n = 208) and Japanese (n = 153) patients. The baseline Eczema Area and Severity Index (EASI) score was higher in Japanese patients (23·8 vs. 14·8), while baseline Patient-Reported Outcome Measures (PROMs) were higher in Dutch patients. EASI scores decreased quickly to a level indicating ‘mild disease’ (EASI < 7), and remained low in both countries. However, PROMs showed different trajectories with better scores in Japan. Conclusions Dupilumab showed significant, comparable and sustained improvement of EASI scores in Japanese and Dutch patients. However, we found striking differences in the effect on PROMs between the countries, with a better outcome in Japanese patients.
Spironolactone in Patients With Heart Failure, Preserved Ejection Fraction, and Worsening Renal Function
Authors: Iris E. Beldhuis, Peder L. Myhre, Michael Bristow, Brian Claggett, Kevin Damman, James C. Fang, Jerome L. Fleg, Sonja McKinlay, Eldrin F. Lewis, Eileen O’Meara, Bertram Pitt, Sanjiv J. Shah, Orly Vardeny, Adriaan A. Voors, Marc A. Pfeffer, Scott D. Solomon, Akshay S. Desai
Journal: Journal of the American College of Cardiology (2021)
Efficacy of the PD-L1 inhibitor avelumab in neuroendocrine or aggressive variant prostate cancer: Results from a phase II, single-arm study.
Authors: Landon Carter Brown, Susan Halabi, Michael Sandon Humeniuk, Yuan Wu, Taofik Oyekunle, Jiaoti Huang, Monika Anand, Catrin Davies, Tian Zhang, Michael Roger Harrison, Daniel J. George, Andrew J. Armstrong
Journal: Journal of Clinical Oncology (2021)

89 Background: Men with metastatic neuroendocrine/small cell and aggressive variant prostate cancer (NEPC/AVPC) have poor outcomes despite platinum and taxane chemotherapy. These tumors share common features with small cell lung cancer, including higher tumor mutational burden and genomic alterations, and thus may be responsive to immunotherapy. Methods: We conducted a single arm, 2-stage phase II investigator-sponsored trial, (PICK-NEPC, NCT03179410) with the PD-L1 inhibitor avelumab in patients with NEPC/AVPC. NEPC/AVPC was defined either by histologic criteria (neuroendocrine or small cell features) by central pathology review or by aggressive variant clinical criteria (prior progression on abiraterone or enzalutamide with liver metastasis, bulky radiographic progression and low PSA, or high serum LDH). Prior chemotherapy or hormonal therapy was allowed. Avelumab 10 mg/kg IV every 2 weeks was administered until progression or unacceptable toxicity with ongoing ADT. The primary endpoint was overall response rate (ORR) defined by modified PCWG3 and iRECIST criteria. Results: We consented 19 men with AVPC/NEPC, and 15 initiated treatment with avelumab. The median age was 71 (range 51-85), and 27% had neuroendocrine or small cell histology, while 73% met AVPC clinical criteria with adenocarcinoma histology. Men had received a median of two prior systemic therapies (range 1-3) including carboplatin (27%), docetaxel (73%), enzalutamide (67%), and abiraterone (47%). Median PSA was 54 ng/mL (range 0-393) and 73% had liver metastasis. The ORR by iRECIST was 6.7% (95% CI 0-32%) with 1 CR, 0 PRs, 3 (20%) with stable disease, and 11 (73%) with progressive disease. The patient with a CR had NEPC with a CNS metastasis that was found to be MSI-high/TMB-high due to a somatic MSH2 alteration; he finished 12 months of avelumab and maintains a durable CR and undetectable PSA 6 months after completing all therapy including ADT. Median radiographic progression free survival was 1.8 months (95% CI 1.6-2.0 mo) and median time on therapy was 56 days (range 28-356). Median overall survival was 7.4 mo (85% CI 2.8-12.5 mo). Two grade 3 adverse events (abdominal pain due to hepatic disease progression versus immune hepatitis and pericarditis), and one grade 4 (immune hepatitis) adverse event were attributed to avelumab with no grade 5 adverse events. Grade 1 or 2 infusion-related reactions were experienced by 9 (60%). Conclusions: PD-L1 inhibition with avelumab demonstrated limited clinical efficacy in men with metastatic NEPC/AVPC other than in those with MSI-high disease. Further research is needed into mechanisms of immune evasion in NEPC/AVPC to develop novel immunotherapies. Clinical trial information: NCT03179410.
Abstract 16114: Statin Eligibility and Prevalence of Statin Prescriptions According to the 2013 American College of Cardiology-American Heart Association Cholesterol Guidelines in a Large Multi-Center Healthcare System
Authors: Robert Fraser, Abbey Sidebottom, Marc Vacquier, Joe Jensen, Steven Bradley, Craig Strauss, Thomas Knickelbine, Michael D Miedema
Journal: Circulation (2018)

Introduction: The 2013 ACC/AHA cholesterol guidelines represented a paradigm shift in the approach to cholesterol treatment. The degree to which these guidelines have impacted statin use warrants f...
Congruent microbiome signatures in fibrosis-prone autoimmune diseases: IgG4-related disease and systemic sclerosis
Authors: Damian R. Plichta, Juhi Somani, Matthieu Pichaud, Zachary S. Wallace, Ana D. Fernandes, Cory A. Perugino, Harri Lähdesmäki, John H. Stone, Hera Vlamakis, Daniel C. Chung, Dinesh Khanna, Shiv Pillai, Ramnik J. Xavier
Journal: Genome Medicine (2021)

Abstract Background Immunoglobulin G4-related disease (IgG4-RD) and systemic sclerosis (SSc) are rare autoimmune diseases characterized by the presence of CD4+ cytotoxic T cells in the blood as well as inflammation and fibrosis in various organs, but they have no established etiologies. Similar to other autoimmune diseases, the gut microbiome might encode disease-triggering or disease-sustaining factors. Methods The gut microbiomes from IgG4-RD and SSc patients as well as healthy individuals with no recent antibiotic treatment were studied by metagenomic sequencing of stool DNA. De novo assembly-based taxonomic and functional characterization, followed by association and accessory gene set enrichment analysis, were applied to describe microbiome changes associated with both diseases. Results Microbiomes of IgG4-RD and SSc patients distinctly separated from those of healthy controls: numerous opportunistic pathogenic Clostridium and typically oral Streptococcus species were significantly overabundant, while Alistipes , Bacteroides , and butyrate-producing species were depleted in the two diseases compared to healthy controls. Accessory gene content analysis in these species revealed an enrichment of Th17-activating Eggerthella lenta strains in IgG4-RD and SSc and a preferential colonization of a homocysteine-producing strain of Clostridium bolteae in SSc. Overabundance of the classical mevalonate pathway, hydroxyproline dehydratase, and fibronectin-binding protein in disease microbiomes reflects potential functional differences in host immune recognition and extracellular matrix utilization associated with fibrosis. Strikingly, the majority of species that were differentially abundant in IgG4-RD and SSc compared to controls showed the same directionality in both diseases. Compared with multiple sclerosis and rheumatoid arthritis, the gut microbiomes of IgG4-RD and SSc showed similar signatures; in contrast, the most differentially abundant taxa were not the facultative anaerobes consistently identified in inflammatory bowel diseases, suggesting the microbial signatures of IgG4-RD and SSc do not result from mucosal inflammation and decreased anaerobism. Conclusions These results provide an initial characterization of gut microbiome ecology in fibrosis-prone IgG4-RD and SSc and reveal microbial functions that offer insights into the pathophysiology of these rare diseases.
Poor, biased reporting of daily covid death statistics without perspective creates fear
Authors: Holly Young
Journal: BMJ (2021)

Abbasi calls for redress for the mishandling of the pandemic.1 But mainstream media outlets report daily death statistics in a way that does not support understanding or provide perspective of what is an inevitable and natural process, reinforcing the United Kingdom’s terror of death by creating fear with poor and biased reporting.

The UK’s ageing population were disproportionally affected by SARS-CoV-2, with the average age of death being 81 for men and 85 for women, compared with 79.4 and 83.1, respectively, in 2019.23 A total of 530 841 deaths occurred in …
Covid-19: Single dose of Pfizer and Oxford vaccines cuts risk of hospital admission by 80% in over 80s, data suggest
Authors: Gareth Iacobucci
Journal: BMJ (2021)

Covid-19: Single dose of Pfizer and Oxford vaccines cuts risk of hospital admission by 80% in over 80s, data suggest Gareth IacobucciBoth the Pfizer BioNTech and the Oxford AstraZeneca vaccines are highly effective in reducing covid-19 infections and protecting against severe disease in older adults, preliminary data show.