tbuckley/cabot-search huggingface dataset:
Discovery and validation of a genomic signature to identify women with early-stage invasive breast cancer who may safely omit adjuvant radiotherapy after breast-conserving surgery.
Authors: Martin Sjöström, S. Laura Chang, Linda Hartman, Erik Holmberg, Felix Y Feng, Corey Wayne Speers, Lori J. Pierce, Per Malmström, Mårten Fernö, Per Karlsson
Journal: Journal of Clinical Oncology (2021)

512 Background: Adjuvant radiotherapy (RT) is currently the standard of care for women with early-stage invasive breast cancer (BC) treated with breast conserving surgery (BCS). However, some women may have very low risk of recurrence and could safely be spared RT. This study aimed to identify these women using a molecularly-based approach. Methods: We performed an analysis of the SweBCG91-RT cohort, a trial randomizing women with node-negative stage I-II invasive BC +/- RT following breast conserving surgery, with sparse use of adjuvant systemic therapy. Only patients with ER+, HER2- tumors, and not treated with adjuvant systemic therapy, were included in this analysis. Transcriptome-wide profiling of tumors was performed using the Affymetrix Human Exon 1.0 ST microarray. The SweBCG91-RT cohort was divided into a training cohort of 243 patients and a validation cohort of 354 patients. Biological gene sets and individual genes related to locoregional recurrence in patients not receiving RT of the training set were identified, and a 16-gene signature was trained using elastic net regression. The signature, named Profile for the Omission of Local Adjuvant Radiation (POLAR), was locked prior to validation. Results: In the validation cohort, POLAR was prognostic for locoregional recurrence (LRR) in patients not treated with RT (multivariable Cox model adjusting for age, grade, tumor size, and luminal A vs luminal B: HR = 1.7 [1.2,2.3], p &lt; 0.001). Patients categorized as POLAR low-risk had a 10-year locoregional recurrence rate of 7% in the absence of RT. Notably, there was no significant benefit from RT for these POLAR low-risk patients (HR = 1.1 [0.38,3.3], p = 0.83), whereas patients categorized as POLAR high-risk had a significant decreased risk of locoregional recurrence when treated with RT (recurrence rate without RT at 10-years 19%, HR = 0.43 [0.24,0.78], p = 0.0053). Conclusions: These data suggest that the novel POLAR genomic signature based on LRR biology can not only identify patients who have a low risk of LRR without adjuvant RT after BCS but who also would not benefit from RT, thus being prime candidates for RT omission.
Association Between Treatment Adherence and Response Among Patients With Chronic Myeloid Leukemia (CML) Receiving First-Line TKIs In The Community Setting
Authors: Nicholas J. Di Bella, Debajyoti Bhowmik, Menaka Bhor, Mark Yap, Brooke Middlebrook, Debra Rembert, Rahul Dhanda, Zachary Cain, Tony Okoro, Bjorn Bolinder, Elias J. Jabbour
Journal: Blood (2013)
Acute and chronic cancer-related distress among multiple myeloma patients during the COVID-19 pandemic.
Authors: Jenny Ahlstrom, Thomas H. Molina, Nathan W. Sweeney
Journal: Journal of Clinical Oncology (2021)

e20025 Background: Patients with multiple myeloma (MM) are uniquely susceptible to viral and bacterial illnesses. In addition, MM and its treatments lead to immune deficiency, putting patients at a high risk for infection, including the novel coronavirus (COVID-19). The emotional impact of COVID-19 on high-risk groups, such as MM patients, remains unclear. The purpose of this project was to understand psychosocial distress and unmet needs among patients with active MM during the acute and chronic phase of COVID-19 and its impact in the United States. Methods: We utilized the HealthTree Cure Hub (healthtree.org) and invited patients with active MM cancer or precursor conditions to participate in an online CancerSupportSource distress screening questionnaire by the Cancer Support Community. Participants were asked to rate their level of concern (Not at All to Very Seriously) on 12 items assessing physical, psychosocial, and practical needs during the acute and chronic phase of the COVID-19 pandemic. De-identified responses were aggregated and reviewed. Results: 1,079 MM patients analyzed during the acute phase of the pandemic (April 15, 2020, to June 8, 2020) and 246 were analyzed during the chronic phase (January 8, 2021, to February 12, 2021). The percent of patients responding moderately to very seriously concerned are reported here. While eating and nutrition increased 3% from acute (71%) to chronic (74%) phases, physical needs overall decreased 2%. Psychosocial needs (worrying about the future, family concerns, feeling irritable, sad, nervous, or lonely, and relationship concerns) decreased 4% between the two phases, despite the 2% increase in problems with your spouse/partner. Additionally, practical needs (health insurance or money worries) decreased 4% between the acute and chronic phases of the pandemic. Conclusions: Respondents to our survey maintain a concern for eating and nutrition during the acute and chronic phases of the pandemic. Between the three types of needs examined in this survey, physical needs had the smallest change over time. This information can inform patients and medical professionals of the type of distress experienced by patients and help investigators assess the needs of the patient community to enhance patient outcomes.[Table: see text]
Dual-targeted therapy with pyrotinib and trastuzumab for HER2-positive advanced colorectal cancer: Preliminary results from a multicenter phase 2 trial.
Authors: Ying Yuan, Xianhua Fu, Jieer Ying, Liu Yang, Weijia Fang, Weidong Han, Suzhan Zhang
Journal: Journal of Clinical Oncology (2021)

e15554 Background: HER2 is an emerging treatment target for colorectal cancer (CRC). Previous phase 2 trials have demonstrated the promising antitumor activity of dual HER2 inhibition with trastuzumab plus lapatinib or pertuzumab in HER2-positive metastatic CRC. Pyrotinib, a novel irreversible HER2/EGFR dual tyrosine kinase inhibitor, has been approved for breast cancer in 2018 in China. The antitumor effect of pyrotinib was also shown in other solid tumors, such as lung cancer and gastric cancer. The randomized phase 3 PHOEBE trial proved that the efficacy of pyrotinib was better than lapatinib when in combination with capecitabine in HER2-positive local relapsed or metastatic breast cancer. We reported preliminary results of pyrotinib plus trastuzumab in patients with HER2-positive advanced CRC from an ongoing multicenter phase 2 trial (NCT04380012). Methods: Patients with confirmed recurrent/metastatic CRC, HER2-positive disease, and ECOG performance status 0-2, received oral pyrotinib 400 mg once a day plus intravenous trastuzumab 8 mg/kg loading dose followed by 6 mg/kg once every 3 weeks. The primary endpoint was objective response rate (ORR), as assessed according to the Response Evaluation Criteria In Solid Tumors version 1.1. The data cutoff date was December 24, 2020. Results: From December 2019 to November 2020, a total of 11 patients were enrolled. The median age was 57 (range, 44-70) years and 73% (8/11) of patients were male. The number of prior therapy lines was 0, 1, and ≥2 in 1 (9%), 2 (18%), and 8 (73%) patients, respectively. One (9%) patient only showed HER2 overexpression, 7 (64%) showed HER2 amplification and overexpression, and 3 (27%) showed HER2 mutation and overexpression. The detection of co-mutations showed that 5 (45%) patients had KRAS mutations, 1 (9%) had NRAS mutation, and none had BRAF mutation. Three patients achieved partial response, with an ORR of 27% (3/11) in the total population, 50% (3/6) in KRAS wild-type patients, and 60% (3/5) in patients with wild type of both KRAS and NRAS, respectively. The disease control rate was 45% (5/11). The most common (occurring in at least 2 patients) grade ≥3 adverse event was diarrhea (73% [8/11]). Dose interruption owing to diarrhea occurred in 7 (64%) patients, and 5 (45%) patients reduced the dose to 320 mg due to diarrhea. No treatment-related death was observed. Conclusions: Pyrotinib combined with trastuzumab showed promising ORR with acceptable safety in patients with HER2-positive advanced CRC, suggesting a potential treatment option, especially in those without co-mutations. Clinical trial information: NCT04380012.
Abstract 17144: Cardioprotective Effect of Beta Blockers in Patients With Breast Cancer Undergoing Chemotherapy and Radiation Therapy: Is It a Myth or Reality?
Authors: Alexander Ivanov, Pragnan Kancharla
Journal: Circulation (2018)

Background: Breast cancer is the leading cause of cancer in women worldwide. Cardiotoxicity is a common complication of anthracycline based regimens. It has been suggested that use of beta blockers (BB) may have cardioprotective effect in patients with breast cancer undergoing therapy. Methods: A systematic search of 3 electronic databases was performed for all randomized clinical trials between 1990 and 2018 comparing BB and placebo in patients with breast cancer undergoing chemotherapy. Primary outcome was change in left ventricular ejection fraction (LVEF) , secondary outcome was change in LV diastolic function measured as difference in early (E) to late (A) ventricular filling velocities (E/A ratio). We used Cohen method for this meta-analysis. Results: Total of 6 studies evaluating 614 females, with mean age of 49 (±7) years were included. These patients were receiving anthracyclines with or without transtuzumab over weighted mean follow up of 8 (±3) months. There was a smaller LVEF decline in patients treated with BB compared to placebo with standardized mean difference (SMD) of 0.34% (0.18%-0.5%), p&lt;0.01 and significant heterogeneity I 2 86%, p&lt;0.01(Figure 1). There were only 3 studies reporting on e/a ratio. There was a significantly lower decline in e/a with BB therapy , SMD of 0.46 (0.23-0.7), p&lt;0.01, with high heterogeneity I 2 85%, p&lt;0.01 (Figure 2). Conclusion: Beta blockers can preserve left ventricular systolic and diastolic function in patient with breast cancer undergoing chemotherapy. Observed high heterogeneity indicates the need for larger trials.
Follicular helper-T cells restore CD8<sup>+</sup>-dependent antitumor immunity and anti-PD-L1/PD-1 efficacy
Authors: Julie Niogret, Hélène Berger, Cédric Rebe, Romain Mary, Elise Ballot, Caroline Truntzer, Marion Thibaudin, Valentin Derangère, Christophe Hibos, Léa Hampe, David Rageot, Théo Accogli, Philippe Joubert, Bertrand Routy, James Harker, Frederique Vegran, Francois Ghiringhelli, Fanny Chalmin
Journal: Journal for ImmunoTherapy of Cancer (2021)

Background T follicular helper cells (Tfh) are essential to shape B cell response during germinal center formation. Tfh accumulation has been reported in various human cancers, with positive or negative prognostic roles. However, the mechanisms explaining the accumulation of Tfh and their role in cancer remain obscure. Methods In vitro differentiated and mouse cell sorted Tfh phenotype was evaluated by flow cytometry and quantitative PCR (qPCR). Antitumor effect of Tfh was evaluated by adoptive transfer in different tumor-bearing mice models. The involvement of immune cells, cytokines and chemokines was evaluated, using depleting antibodies. Chemokines and cytokines expression and production were evaluated by qPCR and ELISA. In human, the impact of immune cells and chemokines on survival was evaluated by analyzing transcriptomic data from public databases and from our own patient cohorts. Results In this study, we show that Tfh exert an antitumor immune effect in a CD8 + -dependent manner. Tfh produce interleukin-21, which sustains proliferation, viability, cytokine production and cytotoxic functions of exhausted T cells. The presence of Tfh is required for efficacy of antiprogrammed cell death ligand-1 therapy. Tfh accumulate in the tumor bed and draining lymph nodes in different mouse cancer models. This recruitment is due to the capacity of transforming growth factor β to drive Chemokine (C-X-C motif) Ligand 13 expression, a chemoattractant of Tfh, by intratumor CD8 + T cells. Accumulation of Tfh and exhausted CD8 + T cells predicts cancer outcome in various cancer types. In patients treated with anti-programmed cell death-1 mAb, accumulation of Tfh and CD8 + at the tumor site is associated with outcome. Conclusion This study provides evidence that CD8 + /Tfh crosstalk is important in shaping antitumor immune response generated by immunotherapy.
A medication acquisition program to facilitate access to nonstandard targeted oncologic therapies.
Authors: Vicki Doctor, Maurie Markman, Ankur Rasik Parikh, Bellinda Conte
Journal: Journal of Clinical Oncology (2021)

e13505 Background: Precision oncology provides targeted approaches to cancer diagnosis and treatment, but also carries significant risks to reimbursement and patient access. A recent survey found that up to 60% of authorization denials are due to the therapy being off-label and experimental. The Cancer Treatment Centers of America's Medication Acquisition Program (CTCA-MAP) was initiated in October 2015 with the goal of helping patients successfully navigate a medication acquisition process following prior authorization denials for off-label therapy. Methods: A consecutive series of cancer patients who were non-responsive to standard-of-care, and for whom off-label targeted therapies have been matched to a potentially actionable genetic or molecular variant were enrolled into CTCA-MAP following the denial of payer preauthorization. The CTCA-MAP appeals payer denials, and simultaneously coordinates applications to patient assistance programs. Each payer appeal is customized to the patient's disease profile and unique tumor genomics and is based on any available evidence supporting the therapy’s use and safety in the patient’s tumor type. Results: A total of 825 patients (338 males and 487 females; median age 57 years) were enrolled into the program from October 2015 to October 2020. The most common tumor types were breast (n = 157), colorectal (n = 96), pancreas (n = 72), lung (n = 68), ovarian (n = 35) and prostate (n = 35). 682 (82.7%) patients were able to access therapy through patient assistance programs (n = 548), overturned payer appeals (n = 133) or conversion from patient assistance to insurance (n = 1) within a median of 16 days from the date of program referral. Only 5 (0.6%) patients were unable to access therapy through payer appeals or philanthropic programs. The remaining 138 (16.7%) patients could not complete the program due to disease progression or death. The overturned payer appeals led to insurance coverage for an estimated USD 7.95 million in drugs (calculated as the multiplication of drug cost per cycle and the number of cycles received). Conclusions: The CTCA-MAP provides a mechanism through which cancer patients with potentially actionable genetic variants can acquire access to existing off-label targeted therapies when standard-of-care is no longer effective, or when they are ineligible for a clinical trial. This program's outcomes to date demonstrate a need for a concerted advocacy effort to increase accessibility for cancer patients to these innovative targeted therapies.
Epidemiology, Treatments, and Vaccine Development for Antimicrobial-Resistant Neisseria gonorrhoeae: Current Strategies and Future Directions
Authors: Eric Y Lin, Paul C Adamson, Jeffrey D. Klausner
Journal: Drugs (2021)

Neisseria gonorrhoeae is the second most common bacterial sexually transmitted infection in the world after Chlamydia trachomatis. The pathogen has developed resistance to every antibiotic currently approved for treatment, and multidrug-resistant strains have been identified globally. The current treatment recommended by the World Health Organization is ceftriaxone and azithromycin dual therapy. However, resistance to azithromycin and ceftriaxone are increasing and treatment failures have been reported. As a result, there is a critical need to develop novel strategies for mitigating the spread of antimicrobial-resistant N. gonorrhoeae through improved diagnosis and treatment of resistant infections. Strategies that are currently being pursued include developing molecular assays to predict resistance, utilizing higher doses of ceftriaxone, repurposing older antibiotics, and developing newer agents. In addition, efforts to discover a vaccine for N. gonorrhoeae have been reignited in recent years with the cross-protectivity provided by the N. meningitidis vaccine, with several new strategies and targets. Despite the significant progress that has been made, there is still much work ahead to combat antimicrobial-resistant N. gonorrhoeae globally.
Sulindac, a Nonselective NSAID, Reduces Breast Density in Postmenopausal Women with Breast Cancer Treated with Aromatase Inhibitors
Authors: Patricia A. Thompson, Chuan Huang, Jie Yang, Betsy C. Wertheim, Denise Roe, Xiaoyue Zhang, Jie Ding, Pavani Chalasani, Christina Preece, Jessica Martinez, H.-H. Sherry Chow, Alison T. Stopeck
Journal: Clinical Cancer Research (2021)

Abstract Purpose: To evaluate the effect of sulindac, a nonselective anti-inflammatory drug (NSAID), for activity to reduce breast density (BD), a risk factor for breast cancer. Experimental Design: An open-label phase II study was conducted to test the effect of 12 months' daily sulindac at 150 mg twice daily on change in percent BD in postmenopausal hormone receptor–positive breast cancer patients on aromatase inhibitor (AI) therapy. Change in percent BD in the contralateral, unaffected breast was measured by noncontrast magnetic resonance imaging (MRI) and reported as change in MRI percent BD (MRPD). A nonrandomized patient population on AI therapy (observation group) with comparable baseline BD was also followed for 12 months. Changes in tissue collagen after 6 months of sulindac treatment were explored using second-harmonic generated microscopy in a subset of women in the sulindac group who agreed to repeat breast biopsy. Results: In 43 women who completed 1 year of sulindac (86% of those accrued), relative MRPD significantly decreased by 9.8% [95% confidence interval (CI), −14.6 to −4.7] at 12 months, an absolute decrease of −1.4% (95% CI, −2.5 to −0.3). A significant decrease in mean breast tissue collagen fiber straightness (P = 0.032), an investigational biomarker of tissue inflammation, was also observed. MRPD (relative or absolute) did not change in the AI-only observation group (N = 40). Conclusions: This is the first study to indicate that the NSAID sulindac may reduce BD. Additional studies are needed to verify these findings and determine if prostaglandin E2 inhibition by NSAIDs is important for BD or collagen modulation.
Root cause determination of intraperitoneal catheter obstructions: Insulin amyloid aggregates vs foreign body reaction
Authors: Jia He, Eric Renard, Peter Lord, Don Cohen, Eleazere Cem-Duranty, Jerome Place, Bing Gu, Xiaoyi Wang, Gowtham Yenduri, Diane J. Burgess
Journal: Journal of Controlled Release (2021)
Study did not take account of confounders
Authors: A. Haycox, S. Barton, T. Walley
Journal: BMJ (1996)

Cost effectiveness of lowering cholesterolCost consequence analysis may be more useful to decision makers EDrroR,-If economic analyses are to provide guidance on population health strategies they should consider all relevant costs and consequences associated with medical interventions.We have identified five methodological deficien- cies in the economic analysis of P D P Pharoah and W Hollingworth.'
Multi-site practice and physician travel burden by oncology specialty.
Authors: Zachary AK Frosch, Katherine Hicks-Courant, Justin E. Bekelman, Emily Meichun Ko, Genevieve P. Kanter
Journal: Journal of Clinical Oncology (2021)

e13513 Background: Having physicians who practice at multiple sites may increase patients’ access to care, but also burden physicians Gynecologic oncologists (GO) are increasingly practicing at more sites across a larger geographic area, but the degree to which medical oncologists (MO), surgical oncologists (SO) or radiation oncologists (RO) are also doing so is unknown. Methods: We conducted a retrospective, observational study using data from the 2020 Physician Compare National Dataset. We included GO, MO, SO, RO, as determined by self-reported specialty. Practice sites with incomplete street addresses were excluded. For each specialty, we calculated the number of practice sites per physician, geographic practice dispersion (median driving distance required to go to each practice site), and temporal practice dispersion (median travel time required to go to each practice site). We used linear regression to compare the number of practice sites, geographic practice dispersion, and temporal practice dispersion by specialty. Results: The number of physicians, mean number of practice sites, along with geographic and temporal practice dispersion by specialty are shown in the table. MO practiced at a smaller number of practice sites compared to GO (p&lt;0.001) and RO (p&lt;0.001). Compared to MO, SO had a smaller geographic dispersion (median driving distance 22 miles vs. 38 miles, p=&lt;0.001) and temporal practice dispersion (median driving time 27 minutes vs. 43 minutes, p&lt;0.001), whereas RO had a larger geographic dispersion (median RO driving distance 58 minutes, p&lt;0.001) and temporal practice dispersion (median RO driving time 63 minutes, p&lt;0.001). Conclusions: Oncologic specialties vary in the number of practice sites and practice dispersion per oncologist. In particular, GO and RO practice at more sites than MO, with MO practices more geographically concentrated than RO practices. While SO practice at a similar number of practice sites compared to MO, their practices are the most geographically concentrated. While these practice patterns may represent increased patient access to specialty oncology care, the impact on quality of care and physician wellness is unknown.[Table: see text]