tbuckley/cabot-search huggingface dataset:
Analysis of Repeated Measurements of Serum Carotenoid Levels and All-Cause and Cause-Specific Mortality in Japan
Authors: Ryosuke Fujii, Yoshiki Tsuboi, Keisuke Maeda, Yuya Ishihara, Koji Suzuki
Journal: JAMA Network Open (2021)

<h3>Importance</h3> The associations of levels of diverse serum carotenoids ascertained via repeated measurements with all-cause, cancer, and cardiovascular disease (CVD) mortality risk have not been considered in previous prospective studies. <h3>Objective</h3> To investigate the association between repeated measurement of serum carotenoid levels and all-cause and cause-specific mortality risk. <h3>Design, Setting, and Participants</h3> This cohort study's baseline data were collected using information from physical examinations from 1990 to 1999. Eligible participants were followed up until December 2017, with a median (interquartile range) follow-up period of 22.3 (15.5-25.3) years. Included individuals were age 40 years or older at the baseline data collection, were residents of the study site in the town of Yakumo, Hokkaido, Japan, and participated in a physical examination at least once from 1990 to 1999. Among eligible participants, after excluding 332 individuals, 3116 individuals were included in the analysis. Data analysis was conducted in April 2020. <h3>Exposures</h3> Repeated measurements of 6 serum carotenoid levels and 4 associated indices. <h3>Main Outcomes and Measures</h3> All-cause, cancer, and CVD mortality, categorized by<i>International Classification of Diseases, Ninth Revision</i>and<i>International Statistical Classification of Diseases and Related Health Problems, Tenth Revision</i>codes, were recorded. A time-dependent Cox regression model was performed to examine associations between time-varying serum carotenoid levels and mortality. <h3>Results</h3> Among 3116 individuals who received physical examinations, the mean (SD) age was 54.7 (10.6) years and 1883 (60.4%) were women. During the follow-up period, 762 deaths from all causes, 253 deaths from cancer, and 210 deaths from CVD were ascertained. In a time-dependent Cox regression analysis, for every 25% higher serum levels of total carotenoids, risks were statistically significantly lower for all-cause mortality (hazard ratio [HR], 0.85; 95% CI, 0.82-0.87;<i>P</i> &lt; .001), cancer mortality (HR, 0.82; 95% CI, 0.78-0.87;<i>P</i> &lt; .001), and CVD mortality (HR, 0.86; 95% CI, 0.81-0.91;<i>P</i> &lt; .001). Using only baseline measures, for every 25% higher serum levels of total carotenoids, risks were also statistically significantly lower for all-cause mortality (HR, 0.92; 95% CI, 0.89-0.95;<i>P</i> &lt; .001), cancer mortality (HR, 0.87; 95% CI, 0.83-0.93;<i>P</i> &lt; .001), and CVD mortality (HR, 0.93; 95% CI, 0.88-0.99;<i>P</i> = .03) but with larger HRs than those associated with repeated measurements. <h3>Conclusions and Relevance</h3> This study found that higher levels of serum carotenoids in analysis using repeated measurements were associated with significantly lower all-cause and cause-specific mortality over a follow-up period of 25 years.
Expanded access and early access provision: Awareness, educational needs and opportunities to improve access to care.
Authors: Andriy Krendyukov, Sanjay Singhvi, Yianick Green-Morrison, Markus Zabransky
Journal: Journal of Clinical Oncology (2021)

e18507 Background: An unmet medical need exists for many oncology patients who cannot be treated satisfactorily by available therapeutics. Despite notable efforts made by FDA and EMA to expedite development, review and approval of Innovative Medicinal Products (InMPs), there may still be a lengthy delay before oncology patients can gain access to new therapies. Expanded access (EA) in the USA and compassionate use (CU) in the European Union are pathways endorsed to improve patient access to InMPs. Recently reported data from CDER and CBER revealed that applications for EA pathways dealing with patient cohorts remain low, despite high approval rates. The challenges that practicing oncologists may face when dealing with EA or other early access provision (EAP), together with limited education, may influence the access of oncology patients to care. Methods: An on-line, fully anonymous survey reaching out to more than 3,258 practicing physicians was initiated between November 2020- January 2021. Participants were asked questions about their knowledge and understanding of EA/EAP, level of experience, decision process, interest for further educational activities and opportunities to improve process, both in general and specifically during COVID 19 pandemic. Attributes were rated on a 5-point scale. Results: Analysis of first respondents showed that 70% of practicing physicians rated their own understanding and knowledge about EA/EAP as above average (good or very good). However, only 60% of responders answered specific knowledge-based question correctly. At the same time, only 44% of practicing oncologists reported notable experience with EA/EAP in daily practice. The majority of respondents (90%) felt that availability of clinical efficacy data from comparative phase III RCTs would be considered of high importance; other evidence and study types (e.g. clinical safety, PK/PD, preclinical data) were rated substantially lower. The need for further education around better understanding of the processes and regulatory requirements, roles and responsibilities, and data collection was emphasized by 61%, 36% and 30% of respondents, respectively. During current COVID 19 pandemic, majority of respondents highlighted the need to improve and substantially adapt EA with regard to application process and documentation, InMP supply and logistics, and safety reporting process. Conclusions: Results from this survey suggest that challenges posed by the EA process, together with a lack of education, might contribute to the under-utilization of EA/EAP for oncology patients. Continuous educational efforts are required to better inform and support practicing oncologists during the EA application process and regulatory framework. Competent authorities should consider optimization and implementation of digital tools to facilitate EA applications and follow up during the COVID 19 pandemic.
Demographic, Clinical and Laboratory Features, Management and Outcome of Immune Thrombocytopenia (ITP) in Greece: The National ITP Registry of the Hellenic Society of Hematology
Authors: Charalampos Pontikoglou, Emily Stavroulaki, Vassilis Tzikoulis, Peggy Kanellou, Maria Kaparou, Vasileia Kaliafentaki, Panayiotis Panayiotidis, Nora-Athina Viniou, Marina Matzourani, Panayiotis Tsaftaridis, Vassiliki Bartzi, Athanassios Galanopoulos, George Kanavos, Spyros Hontropoulos, Evridiki Michali, Nikolaos Anagnostopoulos, Argiris Symeonidis, Alexandra Kourakli, Polyxeni Lampropoulou, Dimitra Liapi, Aikaterini Palla, Achilles Anagnostopoulos, Antonia Syrigou, Aikaterini Megalakaki, Efthymia Vlachaki, Maria Papaioannou, Georgia Kaiafa, Stavroula Giannouli, Ioannis Kotsianidis, Despoina Kyriakou, Maria Protopappa, Eleftheria Hatzimichael, Panagiotis Zikos, George Chalkiadakis, Helen A. Papadaki
Journal: Blood (2017)
Prostate-specific antigen testing in the disabled population: A cross-sectional analysis of the Health Information National Trends Survey (HINTS).
Authors: Joon Yau Leong, Ruben Pinkhasov, Thenappan Chandrasekar, Oleg Shapiro, Michael Daneshvar, Thomas Sanford, Gennady Bratslavsky, Hanan Goldberg
Journal: Journal of Clinical Oncology (2021)

e17000 Background: Disabled patients are a unique minority population that may have lower literacy levels and difficulty communicating with physicians. Furthermore, their knowledge for cancer prevention recommendations is unknown. Herein, we aim to compare prostate-specific antigen (PSA) testing rates and associated predictors among disabled men and non-disabled men in the USA. Methods: We performed a cross-sectional study utilizing the Health Information National Trends Survey (HINTS) to analyze factors predicting PSA testing rates in men with disabilities (disabled, deaf, blind). Multivariable logistic regression models were used to determine clinically significant predictors of PSA testing in men with disabilities compared to that of the healthy cohort. Results: A total of 782 (14.6%) disabled men were compared to 4,569 (85.4%) non-disabled men. Disabled men were older with a mean age of 65.0 ± 14.2 vs. 55.0 ± 15.9 years (p &lt; 0.001). On multivariable analysis, after adjusting for all available confounders including race, age, geographical region, survey year, marital status, health insurance, healthcare provider, amongst others, men with any disability were less likely to undergo PSA screening (OR 0.772, 95% CI 0.623-0.956, p = 0.018). Variables associated with increased PSA screening rates included age, having a healthcare provider or health insurance, and living with a partner. Although prostate cancer detection rates were shown to be higher among disabled men, this did not reach statistical significance. Conclusions: Our data suggests that significant inequalities in PSA screening exist among men with disabilities in the USA, with disabled men, especially the deaf and the blind, being less likely to be offered PSA screening. There is a clear need to implement strategies to reduce existing gaps in the care of disabled men and strive to reach equality in PSA screening in this unique population.
FOLFOX plus panitumumab or FOLFOX alone as additive therapy following R0/1 resection of RAS wild-type colorectal cancer liver metastases: The PARLIM trial (AIO KRK 0314).
Authors: Dominik Paul Modest, Meinolf Karthaus, Stefan Kasper, Nicolas Moosmann, Verena Keitel, Alexander Kiani, Ludwig Fischer von Weikersthal, Jens Uhlig, Lutz Jacobasch, Martin Fuchs, Florian Kaiser, Christian A. Lerchenmuller, Christian Junghanss, Swantje Held, Kathrin Heinrich, Andreas Jung, Arndt Stahler, Sebastian Stintzing, Volker Heinemann
Journal: Journal of Clinical Oncology (2021)

3553 Background: This trial investigates the addition of panitumumab to chemotherapy with fluorouracil/ folinic acid and oxaliplatin (FOLFOX) in a 2:1 randomized, controlled, open label, phase II trial in RAS wild-type colorectal cancer patients with R0/1-resected liver metastases. Methods: The primary endpoint was progression-free survival (PFS) two years after randomisation. The experimental arm (12 wks of biweekly mFOLFOX6 plus panitumumab followed by 12 wks of panitumumab alone) was considered active if the 2-year-PFS rate was ≥65%. Based on historical data, a 2-year-PFS rate of 50% was estimated in the control arm (12 wks of biweekly FOLFOX). The trial was performed with a power of 80% and an alpha of 0.05. Secondary endpoints included overall survival (OS) and toxicity. The trial is registered with ClinicalTrials.gov, NCT01384994. Results: The full analysis set consists of 70 patients (pts) in the experimental arm and 36 pts in the control arm. The 2-year-PFS rate was 34.3% with FOLFOX plus panitumumab and failed to meet the primary endpoint. The 2-year-PFS rate in the control arm was 25%. In the experimental arm, a more favourable outcome was observed with regard to PFS (HR: 0.72, 95%CI 0.45-1.17; P = 0.18) and OS (HR: 0.76 (95% CI 0.34-1.71, P = 0.51) which did, however, not reach the level of significance. Updated data including toxicity and subgroup analyses might be presented at the meeting Conclusions: The PARLIM trial clearly failed to demonstrate a PFS rate of 65% after resection of colorectal liver metastases 2 years after randomisation, potentially indicating that the generally high frequency of recurrence and the choice of primary endpoint did not correspond in this study population. However, a trend for improved PFS and OS by the addition of panitumumab to 12 wks of FOLFOX followed by 12 wks panitumumab maintenance therapy may support future trials with ant-EGFR antibodies in this specific treatment setting. Clinical trial information: NCT01384994.
Pan-Canadian cohort of immune checkpoint inhibitor-induced insulin-dependent diabetes mellitus (CANDIED).
Authors: Thiago Pimentel Muniz, Daniel Vilarim Araujo, Kerry J. Savage, Tina Cheng, Moumita Saha, Xinni Song, Sabrina Gill, Jose Gerard Monzon, Debjani Grenier, Sofia Genta, Anna Spreafico, David Hogg
Journal: Journal of Clinical Oncology (2021)

2640 Background: Endocrine immune-related adverse events (irAEs) are frequent with immune checkpoint inhibitors (ICIs); however, ICI-related insulin-dependent diabetes mellitus (IDDM) is a rare but serious endocrine irAE. We describe the characteristics of patients who developed ICI-related IDDM across five academic Canadian cancer centres. Methods: In this multicentre, retrospective study, we included both patients who developed IDDM and patients with non-IDDM (NIDDM) or pre-DM who became insulin-dependent while on treatment with ICI. We collected data on primary tumor type, ICI regimen (single agent or combination), time to development of IDDM from ICI initiation, comorbidities, laboratory parameters at the time of IDDM diagnosis, tumor response and survival. A p value &lt; 0.05 was considered statistically significant. Results: We identified 27 patients between July 2016 and August 2019. Median age was 60 (39-79) years, 20 (74%) were male, 15 (55%) had melanoma and 4 each (15%) non-small cell lung cancer (NSCLC) and renal cell carcinoma. Seven (26%) patients had prior NIDDM or pre-DM; 5 (18%) had an auto-immune disease (2 psoriasis, 2 inflammatory bowel disease, and 1 systemic lupus erythematosus). Laboratory parameters at presentation and management of IDDM are presented in the Table. Mean A1c was not statistically different between patients with or without prior NIDDM or pre-DM (8.4% vs. 8.6%; p = 0.9). All IDDM events were irreversible; 1 (4%) patient died of diabetic ketoacidosis. At time of IDDM diagnosis, 17 (63%) patients were receiving single agent anti-PD1 and 10 (37%) anti-PD1-based combinations (7 anti-CTLA-4, and 3 other compounds). Median time for development of IDDM from ICI initiation was 2.7 months (95% CI 0.2-5.3). Patients receiving combination ICI developed IDDM earlier than those treated with single agent (1.4 vs 4.8 months; p = 0.05). Amongst patients with metastatic disease (n = 24), 9 (38%) had a complete response and 7 (29%) had a partial response. Two patients (8%) were treated in the adjuvant setting; 1 (4%) received consolidation ICI. IDDM led to ICI discontinuation in 12 (44%) patients. After a median follow up of 21 months from ICI initiation, median survival was 30 months (95% CI NE) and was not reached in patients with melanoma and NSCLC. Conclusions: ICI-related IDDM is a rare and typically irreversible irAE that occurs early in the course of treatment and develops earlier with combination ICI. In this cohort, patients who developed ICI-related IDDM had a high tumor response rate and prolonged survival, especially melanoma and NSCLC patients. Prospective evaluation of autoantibodies to predict development of IDDM is ongoing.[Table: see text]
Age (≤75 years) and Not Choice of First-Line Therapy Improves Overall Survival in Transplant Ineligible NDMM Patients: Results from a Large UK Real-World Dataset
Authors: Faouzi Djebbari, Faye A Sharpley, Connor Sweeney, Grant Vallance, Andy Peniket, Lisa Ferguson, Susan McLain-Smith, Jaimal Kothari, Karthik Ramasamy
Journal: Blood (2017)
The Evolving Challenge of Infections in Cirrhosis
Authors: Jasmohan S. Bajaj, Patrick S. Kamath, K. Rajender Reddy
Journal: New England Journal of Medicine (2021)

Patients with cirrhosis are at increased risk for serious infections, including spontaneous bacterial peritonitis, multidrug-resistant infection, and infection with gut microorganisms. In-hospital mortality exceeds 50%. Empirical antibiotic coverage is used until a precise diagnosis can be made.
Genetic ancestry and clinical outcomes to immune checkpoint inhibitors among seven common cancers.
Authors: Amin Nassar, Elio Adib, Sarah Abou Alaiwi, Elie Akl, Talal El Zarif, Pier Vitale Nuzzo, Tarek H. Mouhieddine, Habib El-Khoury, Stefan Groha, Guru P. Sonpavde, Robert I. Haddad, Kent William Mouw, Marios Giannakis, Guruprasad Ananda, Matthew L. Freedman, David J. Kwiatkowski, Laura E MacConaill, Toni K. Choueiri, Alexander Gusev
Journal: Journal of Clinical Oncology (2021)

10536 Background: Prior studies and clinical trials report associations between self-reported race and clinical outcomes to Immune Checkpoint Inhibitors (ICIs). However, comprehensive studies of ancestry-associated differences in clinical outcomes have not been performed. We derived genetic ancestry scores and assessed clinical outcomes in 1341 patients with cancer treated with ICIs. Methods: Patients at the Dana-Farber Cancer Institute treated with ICIs only and with relevant cancer types and targeted exome sequencing data (Oncopanel) were included. Relevant cancer types included colorectal adenocarcinoma (CRC), esophagogastric adenocarcinoma (EGC), head and neck squamous cell carcinoma (HNSCC), melanoma, non-small cell lung cancer (NSCLC), renal cell carcinoma (RCC), and urothelial carcinoma (UC). We developed a bioinformatics pipeline to infer fine-scale genetic ancestry for each patient (n=1341) directly from tumor sequencing data by leveraging off and on-target sequenced reads and external ancestry reference panels. Three ancestry scores were determined (African, East Asian, European). Overall survival (OS) and time-to-treatment failure (TTF) were compared by Cox logistic regression between ancestral populations. Hazard ratio (HR) was derived using multivariable analysis, adjusted for single versus combination therapy, prior lines of therapy, and tumor mutational burden (TMB, as percentiles). Results: Median follow-up was 37.8 months (m; interquartile range: 35.7-39.5m). Common cancer types included CRC (n=52), EGC (n=114), HNSCC (n=88), melanoma (n=274), NSCLC (n=571), RCC (n=99), and UC (n=143). A higher East Asian ancestry (EAS) was significantly associated with worse OS ( p=0.03) and TTF ( p=0.002) in patients with RCC, independent of the histologic subtype (Table). There was no significant association between any of the three ancestral populations and clinical outcomes in the other 6 cancer types. Conclusions: We described clinical outcomes to ICIs across three global populations in 7 cancers. As the medical field re-evaluates the use of self-reported race in clinical decision-making, we utilize a novel ancestry pipeline that can be readily applied to tumor-only sequencing panels and better characterize non-white populations. We find no ancestry differences in clinical outcomes except in patients with RCC treated with ICIs which will require future validation. We plan to analyze genomic correlates of response by ancestry in each of the cancer types to better understand these diverge clinical behaviors.[Table: see text]
Frequency of homologous recombination repair alterations in ovarian cancer in Chinese population.
Authors: Tongtong Yang, Huanhuan Liu, Mingwei Li, Yanrui Zhang, Yun Zhang, Xiayuan Liang, Tao Zhou, Feng Lou, Shanbo Cao, Huina Wang
Journal: Journal of Clinical Oncology (2021)

e17531 Background: Ovarian Cancer (OC) is the most lethal cancer of all gynecological malignancies.Circulating tumor DNA (ctDNA) has received substantial attention in recent years resulting from the non-invasive, safe and effective method with considerable potential for clinical diagnosis and treatment management in patients with OC. Here, we assessed the mutational feature in homologous recombination repair (HRR) using ctDNA in OC. Methods: Plasma ctDNA was isolated from blood of patients and then was analyzed by AcornMed Biotechnology NGS-based assay for 808 genes panel for genomic alterations. The somatic and germline pathogenic mutations were identified in 12 HRR genes (ATM, BRCA1, BRCA2, BRIP1, CHEK1, CHEK2, FANCA, PALB2, RAD51B, RAD51C, RAD51D, RAD54L). Results: At our institution, 85 patients underwent NGS analysis of ovarian cancer specimens. The median age was 57 (range from 26 to 83). Twenty-six patients(42.34%) harbored a mutation in at least 1 of the HRR genes in their tumor. The most commonly altered HRR gene was BRCA1 (18.25%), followed by BRCA2 (8.76%), ATM (5.84%), RAD51D(3.65%), CHEK2 (2.92%), FANCA(2.19%) and RAD51C (0.73%). To determine the difference of mutation landscape in HRR between Chinese and western populations, we compared prevalence and spectrum in cases between our cohort and the cohort of Heeke et al 1 (Table). Prevalence of HRR were different from the Western cases(42.34% vs 20%, P＜0.05). Of note, BRCA1, BRCA2, ATM and CHEK2 alterations rate was higher in our cohort, and BRIP1 and PALB2 were only detected in the western cohort. Conclusions: CtDNA can characterize the mutational feature of HRR in OC. Around 42.3% of patients with OC harbour germline or somatic HRR mutations. The expanded use of PARP inhibitors in HRR deficient tumours using a signature of HRR by ctDNA in clinical practice requires validation.[Table: see text]
Choosing the right dose and regimen PK/PD modeling of tumor response of trastuzumab-MCC-DM1 using mouse models
Authors: Nelson Jumbe, Jay tibbitts, Leipold Doug, Mark Sliwkowski, Debra Dugger, Lisa Crocker, Mike Reich, Paul Fielder
Journal: Cancer Research (2007)

1554  The treatment of cancer requires the optimal administration of the therapeutic drug; choosing both dose and dose regimen to achieve maximal efficacy with manageable toxicity. For drugs being considered for use in the clinic, studies to determine the most efficacious dose and regimen can be conducted in rodent models and the resulting data used to inform clinical trial design. The relationship between dose, regimen, and response can be modeled using pharmacokinetic/pharmacodynamic (PK/PD) methods. In this work, we describe the PK/PD of an antibody drug conjugate (ADC) being studied for the treatment of metastatic breast cancer.  Trastuzumab-MCC-DM1 (Tmab-MCC-DM1) is an ADC consisting of the HER2 antibody Trastuzumab (Tmab) linked to a maytansinoid drug, DM1. Tmab-MCC-DM1, like Tmab, binds to the HER2 receptor and delivers a potent chemotherapeutic into HER2 positive cancer cells via normal receptor internalization and cycling.  Immunocompromised mice bearing Tmab-insensitive, HER2 overexpressing mammary tumors (BT474EEI or Founder 5 [Fo5]) were administered intravenous (IV) doses of Tmab-MCC-DM1 at 1, 2, or 3 week intervals with total doses from 0-90 mg/kg. Animals were observed and tumor volumes measured for 120 days following initiation of dosing. In separate studies, the PK of Tmab-MCC-DM1 were determined following an IV bolus dose of Tmab-MCC-DM1 at doses from 0.3-15 mg/kg. A non-linear tumor-kill PK/PD model was used to describe Tmab-MCC-DM1 anti-tumor activity.  A dose-response relationship was observed in tumor volume following dosing with Tmab-MCC-DM1 with pronounced tumor regression at the highest doses. The PK/PD model captured well the features of tumor growth and the activity of the ADC, and resulted in good estimates of PD parameters. The Fo5 tumor grew more rapidly than BT474EEI in the absence of drug, but also had a higher maximum cell kill rate. The more rapid growth of Fo5 balanced in part by the greater activity of the drug in this tumor resulted in higher PD stasis concentrations for Fo5 than BT474EEI (32.3 vs. 7.94 µg/mL, respectively). Of note was the finding that efficacy did not depend on dose schedule; efficacy of Tmab-MCC-DM1 was driven by AUC/PD stasis concentration.  This study indicates that Tmab-MCC-DM1 is efficacious in the treatment of Tmab-insensitive, HER2 overexpressing tumor models, and efficacy is dependent on tumor sensitivity and tumor growth rate. In addition, efficacy was not substantially affected by dose regimen. Tmab-MCC-DM1 is currently under evaluation in Phase I trials of HER2 positive metastatic breast cancer.