tbuckley/cabot-search huggingface dataset:
Novel elements of value in the context of oncology.
Authors: Sachin Kamal-Bahl, Justin Puckett, Amitabh Singh, Richard Willke
Journal: Journal of Clinical Oncology (2021)

e18823 Background: Over the past decade, perhaps no single area of the health sector has seen as much groundbreaking innovation as pharmaceuticals. This has been especially true in oncology, where promising curative treatments have been initially celebrated by the media only for access and cost challenges to limit their impact. A narrative has emerged that many of these breakthroughs are not priced according to the value they provide. This thinking has been reinforced by traditional approaches to cost-effectiveness analysis (CEA) that fail to incorporate critically relevant dimensions of value for innovative oncology therapies. What might a broader conception of value in oncology look like? To answer that question, this study reviews oncology-specific considerations when assessing elements of value. Methods: We first review the background on the nature and development of quality-adjusted life years (QALYs) as a part of cost-effectiveness analyses and some of their key limitations. This is followed by a review of “novel” elements of value, which capture specific aspects of patient and societal preferences not included in QALYs, and their applicability to oncology, including discussion on areas where further thought and research might be needed. We conclude with a potential checklist of novel elements of value that should be considered when designing value assessment strategies for products in oncology. Results: Key novel value elements not captured in QALYs under traditional CEA that can be relevant for oncology include value of hope (for a cure), value of insurance (reducing health and financial risk), value of treating very severe diseases, and, real option value (for treatments extending survival enough to allow the option of future cures). The novel value elements of reduced diagnostic uncertainty and the value of knowing are also directly relevant for oncology products with companion diagnostics. Other relevant novel value elements within the context of oncology include scientific spillovers and equity. Few studies have measured these value elements with applications in oncology. Conclusions: Our key takeaways include: (1) since cancer is often a severe disease that is expensive to treat, the potential for novel value elements to be important in economic evaluations of oncology products is high; (2) while some elements of value have been explored in specific economic evaluations, there has been limited adoption of novel elements of value in oncology; (3) the conceptual justification for use of novel value elements in oncology is strong, but standards for their measurement are evolving and further experience with their use would be beneficial; and (4) given the lower prioritization of many of them from the payer perspective, barriers to payer acceptance also seem significant, implying attention must also be paid to establishing the relevance of those elements to payer decision-making.
Molecular determinants of disease severity in urinary tract infection
Authors: Ines Ambite, Daniel Butler, Murphy Lam Yim Wan, Therese Rosenblad, Thi Hien Tran, Sing Ming Chao, Catharina Svanborg
Journal: Nature Reviews Urology (2021)

The most common and lethal bacterial pathogens have co-evolved with the host. Pathogens are the aggressors, and the host immune system is responsible for the defence. However, immune responses can also become destructive, and excessive innate immune activation is a major cause of infection-associated morbidity, exemplified by symptomatic urinary tract infections (UTIs), which are caused, in part, by excessive innate immune activation. Severe kidney infections (acute pyelonephritis) are a major cause of morbidity and mortality, and painful infections of the urinary bladder (acute cystitis) can become debilitating in susceptible patients. Disease severity is controlled at specific innate immune checkpoints, and a detailed understanding of their functions is crucial for strategies to counter microbial aggression with novel treatment and prevention measures. One approach is the use of bacterial molecules that reprogramme the innate immune system, accelerating or inhibiting disease processes. A very different outcome is asymptomatic bacteriuria, defined by low host immune responsiveness to bacteria with attenuated virulence. This observation provides the rationale for immunomodulation as a new therapeutic tool to deliberately modify host susceptibility, control the host response and avoid severe disease. The power of innate immunity as an arbitrator of health and disease is also highly relevant for emerging pathogens, including the current COVID-19 pandemic.
Exposures associated with SARS-CoV-2 infection in France: A nationwide online case-control study
Authors: Simon Galmiche, Tiffany Charmet, Laura Schaeffer, Juliette Paireau, Rebecca Grant, Olivia Chény, Cassandre Von Platen, Alexandra Maurizot, Carole Blanc, Annika Dinis, Sophie Martin, Faïza Omar, Christophe David, Alexandra Septfons, Simon Cauchemez, Fabrice Carrat, Alexandra Mailles, Daniel Levy-Bruhl, Arnaud Fontanet
Journal: The Lancet Regional Health - Europe (2021)
Preliminary efficacy of a community-based, group-mediated cognitive behavioral lifestyle intervention among breast cancer survivors.
Authors: Marcy Haynam, Ciaran Fairman, Jessica Bowman, Victoria DeScenza, Zachary Chaplow, Megan Kilar, Kathryn Dispennette, Stephanie Hohn, Xiaochen Zhang, Maryam B. Lustberg, Brian Focht
Journal: Journal of Clinical Oncology (2021)

e24035 Background: Post-treatment weight gain places breast cancer (BCa) survivors at heightened risk for cardiovascular disease, metabolic syndrome, and functional decline. Lifestyle weight management (LWM) interventions combining exercise and dietary weight loss represents an effective approach to mitigating the adverse cardiometabolic and functional effects frequently observed in BCa survivors. Unfortunately, community access to cost-effective, sustainable, LWM interventions among BCa survivors remains limited. The purpose of this study is to determine the preliminary efficacy of a community-based LWM intervention in BCa survivors on select body composition (BC), physical function, and social cognitive outcomes of the first wave of participants in the Healthy New Albany Breast Cancer (HNABC) pilot trial. Methods: The 24-week, community-based pilot trial promotes lifestyle behavior changes through a group-mediated cognitive behavioral (GMCB) approach driven by Social Cognitive Theory. The measures analyzed were BC done via Dual-energy X-ray Absorptiometry, physical function via the 400m walk test, and social cognitive outcomes via satisfaction with function and appearance and perceived competence with exercise and diet at 6-months via effect size calculations using Cohen’s d. Results: Meaningful changes were observed in fat mass ( d= -0.46), percent lean mass ( d= 0.33), lean mass ( d= -0.45), and physical function ( d= -0.59), some of which reached clinical relevance. Select self-reported outcomes also saw meaningful improvements from this LWM intervention. Conclusions: Findings from this study demonstrate the preliminary efficacy of implementing a GMCB-based LWM intervention among overweight or obese BCa survivors. Given the meaningful impact that successful weight management has on reducing risk for chronic diseases, these results highlight the utility of implementing a LWM intervention in the community for BCa survivors in an effort to extend the access, reach, and scalability of supportive care approaches during BCa survivorship.
CD44 loss of function sensitizes AML cells to the BCL-2 inhibitor venetoclax by decreasing CXCL12-driven survival cues
Authors: Xiaobing Yu, Leonel Munoz-Sagredo, Karolin Streule, Patricia Muschong, Elisabeth Bayer, Romina J. Walter, Julia C. Gutjahr, Richard Greil, Miguel L. Concha, Carsten Müller-Tidow, Tanja N. Hartmann, Véronique Orian-Rousseau
Journal: Blood (2021)
Minimal residual disease by circulating tumor DNA analysis for colorectal cancer patients receiving radical surgery: An initial report from CIRCULATE-Japan.
Authors: Hiroki Yukami, Yoshiaki Nakamura, Jun Watanabe, Masahito Kotaka, Kentaro Yamazaki, Keiji Hirata, Yasunori Emi, Mitsuru Yokota, Kentaro Kato, Tatsuro Yamaguchi, Masataka Ikeda, Alexey Aleshin, Daisuke Kotani, Saori Mishima, Hiromichi Shirasu, Eiji Oki, Ichiro Takemasa, Takeshi Kato, Hiroya Taniguchi, Takayuki Yoshino
Journal: Journal of Clinical Oncology (2021)

3608 Background: Circulating tumor DNA (ctDNA) analysis can be used to predict the risk of recurrence by detecting molecular residual disease (MRD) in patients with colorectal cancer (CRC). We are conducting a prospective observational study to monitor MRD status in patients with clinical stage II–IV or relapsed CRC amenable to radical surgical resection (GALAXY study), as part of the CIRCULATE-Japan, a nationwide ctDNA-guided precision adjuvant therapy project. Methods: Analysis of ctDNA is being performed at pre- and post-surgery timepoints and will continue periodically for up to 2 years using Signatera, a personalized, tumor-informed ctDNA assay that is designed to track 16 patient-specific somatic variants based on whole-exome sequencing of tumor tissue. The association of peri-operative ctDNA status with clinicopathological characteristics was investigated. Results: As of January 13, 2021, 941 patients have been enrolled in the GALAXY study, of which 400 patients had their pre-operative ctDNA status evaluated. Of the 400 patients, baseline ctDNA was detected in 92% (367/400) of the patients: consisting of 35 patients with pathological stage (pStage) I, 135 with pStage II, 152 with pStage III, and 78 with pStage IV or relapsed disease (pStage IV/R). Patient-specific Signatera assays targeting 16 variants were designed for 100% of the patients. Out of the 6400 designed variants 99.3% passed quality control in the plasma analysis and produced the final results. Among 4425 genes selected for 400 patients, 3330 genes were selected for only one patient, while TP53 was the most commonly selected in 113 patients (28%). Median ctDNA levels, measured in mean tumor molecules per mL of plasma and ctDNA detection rate, stratified by stage are presented in table. Positive ctDNA status post-surgery was significantly associated with advanced pStage, pT and pN, and lymphovascular invasion. Of the 13 patients with recurrence, 10 were detected with a positive ctDNA at 4-weeks post-surgery, before confirmation of recurrence by the radiological imaging. Conclusions: Preoperative ctDNA detection rates were observed to be in &gt;90% in patients with pStage II–III by personalized ctDNA assay based on unique somatic variants, specific to each patient. ctDNA- based MRD detected post-surgery (4W) was significantly associated with certain known clinicopathological factors for recurrence with ctDNA positivity associated with a very short-term of recurrence. Clinical trial information: 000039205. [Table: see text]
Neuroendocrine differentiation in metastatic breast cancer following CDK 4/6 inhibitors.
Authors: Sakina Sekkate, Laure Ladrat, Christelle Pouliquen, Celine Callens, Jean Francois Geay, Philippe Beuzeboc
Journal: Journal of Clinical Oncology (2021)

e13029 Background: First-line treatment with a CDK4/6 inhibitor in combination with an aromatase inhibitor for HR+/HER2- postmenopausal metastatic breast cancer (mBC) is considered as a standard of care based on the compelling data across all landmark trials. Methods: We report our experience about two cases with metastatic breast cancer treated by CDK4/6 inhibitor in combination with an aromatase inhibitor, which develop neuroendocrine differentiation. After observing an unusual massive progression, a biopsy of the metastasis was performed in both patients. Both histological analysis confirmed a lobular breast cancer with small cell neuroendocrine features and a high proliferation index (KI 67 90%). An NGS (Next generation sequencing) profile was realized on primary and metastatic tumors to detect new acquired genomic alterations. Results: The comparative analysis of the NGS results of primary and metastatic tumors revealed the occurrence of several events in both patients under treatment. For one patient, we identified new mutations in the genes CDH1, FANCG, PIK3CA, PTEN and TP53, which did not exist initially. For the second patient, we found an amplification of the segment containing FGFR1, CCND1, FGF4, FGF3, FADD genes and the deletion of the segment containing RB1 andTP53 genes. Such events were not observed on the primary tumor. Conclusions: Prostate adenocarcinoma may develop neuroendocrine features in later stages of castration-resistant prostate cancer but neuroendocrine differentiation is atypical in breast carcinoma. In case of unusual rapidly progressive disease after CDK4/6 inhibitor, biopsy of new metastases should be recommanded to search neuroendocrine differentiation, or druggable mutations to guide the treatment.
Denosumab after total hip arthroplasty – Authors' reply
Authors: Mohit M Mahatma, Raveen L Jayasuriya, David Hughes, Nigel Hoggard, Simon C Buckley, Andrew Gordon, Andrew J Hamer, Mohammed W Tomouk, Robert M Kerry, Richard Eastell, Jeremy M Wilkinson
Journal: The Lancet Rheumatology (2021)
Changes in chronic disease medication adherence following oral anticancer agent initiation in patients with multiple myeloma.
Authors: Justin Gatwood, Ankur Dashputre, Alex Wallace, Katie S. Gatwood, Karen B. Farris, Emily R. Mackler, Amna Rizvi-Toner, Abhijeet Rajpurohit, Joel Farley
Journal: Journal of Clinical Oncology (2021)

e18760 Background: Improvements in treatment options for multiple myeloma (MM) have led to double-digit increases in 5-year survival rates over the past 40 years. Such extended survival has increased emphasis for the management of comorbid chronic conditions. Initial analyses suggest that oral anticancer agent (OAA) initiation for MM may correspond to significant reductions in adherence to chronic disease medications. Methods: This was a retrospective cohort study of adults diagnosed with and being treated for MM between 2013-2018 using data from the IBM MarketScan Commercial Claims and Encounters databases and a 20% sample of Medicare claims data. Adults (18 years and older) were included if they were diagnosed with and had at least two claims for an OAA indicated for MM, had continuous enrollment for 12 months both before and after OAA initiation, and were previously diagnosed with two chronic conditions and had prescription fills for select chronic conditions. Medication adherence was determined using the proportion of days covered (PDC) metric and was compared for the 12 months before and after the OAA initiation by Wilcoxon signed-rank tests, McNemar’s tests, and difference-in-differences (DinD) models. Results: A slight majority of the 2,765 patients (total N from both databases) were male (52.3%), and hypertension (94.5%) and hyperlipidemia (69.2%) were the most common comorbid conditions. Mean OAA adherence in the first year of therapy was 55.8% (SD: 23.5) and 63.5% (SD: 26.9) for commercial and Medicare patients, respectively. PDCs for comorbid therapies declined in the first year after OAA initiation, irrespective of payer (table), and the proportion adherent to these therapies (PDC &gt; 80%) also declined consistently. OAA adherence tended to align with the direction of changes in comorbid therapy adherence with those nonadherent to their OAA (PDC &lt; 80%) demonstrating general declines in comorbid therapy PDCs post-OAA initiation (p&lt;0.05 in 4 of 6 DinD models). Conclusions: Among adults with MM and multiple chronic conditions, the pre-OAA initiation level of adherence appears to dictate chronic disease medication use patterns after OAA initiation. The starting of OAA therapy facilitates an opportunity for providers to reinforce the need for total regimen adherence to improve the odds of positive cancer- and non-cancer-related outcomes. [Table: see text]
The Effect of 5-Azacitidine Treatment on the Biologic Characteristics of Bone Marrow Mesenchymal Stem Cells in Patients with Myelodysplastic Syndromes
Authors: Ioannis Liapis, Aristea Batsali, Anastasios Mitrakos, Elisavet Kouvidi, Athanasios Galanopoulos, Charalampos Pontikoglou, Emmanouil Kanavakis, Helen A. Papadaki
Journal: Blood (2017)
Differences in U.S. Rural-Urban Trends in Diabetes ABCS, 1999–2018
Authors: Carla I. Mercado, Kai McKeever Bullard, Edward W. Gregg, Mohammed K. Ali, Sharon H. Saydah, Giuseppina Imperatore
Journal: Diabetes Care (2021)

To examine changes in and the relationships between diabetes management and rural and urban residence.Using National Health and Nutrition Examination Survey (1999-2018) data from 6,372 adults aged ≥18 years with self-reported diagnosed diabetes, we examined poor ABCS: A1C >9% (>75 mmol/mol), Blood pressure (BP) ≥140/90 mmHg, Cholesterol (non-HDL) ≥160 mg/dL (≥4.1 mmol/L), and current Smoking. We compared odds of urban versus rural residents (census tract population size ≥2,500 considered urban, otherwise rural) having poor ABCS across time (1999-2006, 2007-2012, and 2013-2018), overall and by sociodemographic and clinical characteristics.During 1999-2018, the proportion of U.S. adults with diabetes residing in rural areas ranged between 15% and 19.5%. In 1999-2006, there were no statistically significant rural-urban differences in poor ABCS. However, from 1999-2006 to 2013-2018, there were greater improvements for urban adults with diabetes than for rural for BP ≥140/90 mmHg (relative odds ratio [OR] 0.8, 95% CI 0.6-0.9) and non-HDL ≥160 mg/dL (≥4.1 mmol/L) (relative OR 0.45, 0.4-0.5). These differences remained statistically significant after adjustment for race/ethnicity, education, poverty levels, and clinical characteristics. Yet, over the 1999-2018 time period, minority race/ethnicity, lower education attainment, poverty, and lack of health insurance coverage were factors associated with poorer A, B, C, or S in urban adults compared with their rural counterparts.Over two decades, rural U.S. adults with diabetes have had less improvement in BP and cholesterol control. In addition, rural-urban differences exist across sociodemographic groups, suggesting that efforts to narrow this divide may need to address both socioeconomic and clinical aspects of care.
The role of ifosfamide-doxorubicin chemotherapy in the treatment histology-specific, high grade, locally advanced soft tissue sarcoma: A 14-year experience.
Authors: Barry W Goy
Journal: Journal of Clinical Oncology (2021)

e23529 Background: To compare long-term outcomes of high grade, locally advanced, primary soft tissue sarcoma (STS), using Ifosfamide-Doxorubicin vs local therapy alone, in histology-specific sarcomas. Methods: Retrospective analysis was performed on 127 patients from 2005 to 2018, who had STS of extremity or trunk, &gt; 5cm, that were either Synovial Cell, Dedifferentiated Liposarcoma (DDL), Myxofibrosarcoma, Round Cell Liposarcoma (RCLS), Undifferentiated Pleomorphic Sarcoma (UPS), or Undifferentiated Sarcoma not otherwise specified (NOS), with central pathology review. Ifosfamide-doxorubicin was generally given neoadjuvant, followed by radiation and wide excision, with chemotherapy given in 38 patients, while 89 received local therapy alone. Multi-variable analysis of prognostic factors was performed, and local-recurrence-free-survival (LRFS), distant-metastases-free-survival (DMFS), disease-specific-survival (DSS), and overall-survival(OS) were estimated using Kaplan-Meier. Results: Median follow-up was 4.5 years. Younger age (p &lt; 0.0001) and Synovial histology (p = 0.0002) had significantly higher rates of receiving chemotherapy. Size &gt; 10cm and trunk location were poor prognostic features on multivariable analysis (MVA) affecting DMFS, DSS, and OS, while DDL histology had a more favorable effect; although size, trunk location, and DDL histology were not significantly different between treatment groups. Ifosfamide-Doxorubicin vs local therapy alone improved 5-year DMFS at 70.2% vs 49.5% ,p = 0.02, DSS 83.5% vs 57.9%, p = 0.009, and OS 80.6% vs 53.8%, p = 0.002. Sub-analysis of non-synovial histologies still showed a significant improvements in favor of chemotherapy in DMFS,(p = 0.04), DSS (p = 0.02), and OS (p = 0.003). Conclusions: Ifosfamide-Doxorubicin chemotherapy benefits younger patients with &gt; 5cm, high grade, STS of the trunk or extremity, with histologies of Synovial Cell, DDL, Myxofibrosarcoma, RCLS, UPS, or Undifferentiated Sarcoma NOS.
Association between timely targeted therapy initiation and clinical outcomes in patients with advanced HER2+ gastroesophageal adenocarcinoma.
Authors: Kelsey S. Lau-Min, Yimei Li, Jennifer Rachel Eads, Ronac Mamtani, Kelly D. Getz
Journal: Journal of Clinical Oncology (2021)

e16048 Background: Delayed treatment initiation is associated with increased mortality in early-stage cancers. Few studies have examined the impact of timely initiation in advanced cancers. Timely targeted therapy initiation can be especially challenging due to the additional biomarker testing required to identify patients eligible for these treatments. We examined the impact of timely targeted therapy initiation on survival among patients with metastatic HER2+ gastroesophageal adenocarcinoma (GEA). Methods: We performed a retrospective cohort study of patients with metastatic HER2+ GEA treated with first line systemic therapy between 1/2011 and 12/2017 using the nationwide Flatiron Health EHR-derived deidentified database. Timely targeted therapy, defined as initiation of the anti-HER2 monoclonal antibody trastuzumab up to 14 days after first line chemotherapy initiation, was entered as a time-varying exposure on the day of initiation. Patients who initiated trastuzumab after the 14-day cut point or who lacked documentation of having received trastuzumab were classified as having non-timely targeted therapy initiation. Extended Cox regression models were used to compare progression-free (PFS) and overall survival (OS) from the date of first line treatment initiation, adjusted for potential confounders. Pre-planned sensitivity analyses assessed alternative “timeliness” definitions as well as the impact of any trastuzumab administration, regardless of the timing of initiation. Results: We included 459 patients with metastatic HER2+ GEA; 293 (63.8%) received trastuzumab, of whom 223 (76.1%) initiated in a timely manner. The median age was 65.0 years, and patients were predominantly male (82.4%) and non-Hispanic White (78.2%) with an ECOG performance status of 0-1 (85.9%). Relative to non-timely initiation, timely targeted therapy was associated with significantly higher OS (2-year OS 29.6% vs 14.6%; adjusted HR 0.72, 95% CI 0.57-0.91, p = 0.006) and PFS (2-year PFS 8.3% vs 3.9%; adjusted HR 0.78, 95% CI 0.62-0.98, p = 0.030). Results remained similar in sensitivity analyses 1) using alternative “timeliness” definitions (up to 70 days after chemotherapy initiation), and 2) comparing any trastuzumab administration, regardless of the timing of initiation, to no trastuzumab administration (OS - adjusted HR 0.75, 95% CI 0.60-0.95, p = 0.018; PFS - adjusted HR 0.81, 95% CI 0.64-1.02, p = 0.069). Conclusions: OS and PFS were higher among patients with metastatic HER2+ GEA treated with trastuzumab, regardless of the timing of targeted therapy initiation. Although our results provide reassurance to clinicians that delays in targeted therapy may not be detrimental to patient outcomes, efforts should still be made to ensure that all patients with metastatic HER2+ GEA receive first line trastuzumab.