tbuckley/cabot-search huggingface dataset:
Social distancing to avoid SARS-Cov-2 infection in cancer and non-cancer patients.
Authors: Goetz H. Kloecker, Jason Ellis, Leslie Korbee, Joseph Nolan, Royce Calhoun, Barbara Logan, Daniel Blake Flora, Douglas B. Flora, Philp Hartman
Journal: Journal of Clinical Oncology (2021)

e18697 Background: Social distancing has been recommended by the CDC to avoid exposure to SARS-CoV-2. Cancer patients on or after active therapy appear to be more prone to COVID being symptomatic and life threatening. When evaluating cancer patients’ risk of acquiring COVID it is essential to know the behavior of cancer patients that will affect their risk of exposure. However, it is not known to what degree social distancing is practiced by cancer patients compared to non-cancer patients and what factors lead to the decision to distance oneself. Methods: After a pilot phase using patients MyChart messaging, links to the electronic questionnaires were texted to patients using Twillio. Responses were stored on REDCap. Six questions about their social distancing behavior and mask wearing were posed and responses were compared between cancer and non-cancer patients. Demographics, comorbidities and a questionnaire about anxiety (GAD-7 scale for Generalized Anxiety Disorder) were recorded. To assess differences between cancer and non-cancer groups Bonferroni-corrected chi-square tests and proportions confidence intervals were used. Results: The pilot survey was sent in mid-2020 and the full survey followed in January 2021 during a high community COVID incidence. 387 cancer patients (32.4% responded and 503 non-cancer (22.9% responded) patients completed the survey. Questions about leaving their house, driving, shopping, friends and family indicated that patients with cancer are more cautious (p &lt; 0.001). Cancer patients were up to 20% more likely to distance themselves. No evidence of a difference was seen in wearing a mask, at least 85 % most of the time. A majority of respondents were female (63% vs 71%). Cancer patients were older ( &gt; 60 years, 69 % vs 45%) and less likely to work (52% vs 31%) or less likely to be white collar workers (21% vs 38%). There was no difference of the anxiety score in both groups (not at all anxious, 54%). Conclusions: Cancer patients’ responses revealed a distancing behavior that would likely lower the risk exposure to SARS-CoV-2. It is unclear, which of the demographic differences would account for this behavior, although remarkably anxiety was not a clear motivating factor. The high acceptance of masks is encouraging. Early publications during the pandemic and patient education suggesting a higher COVID risk for cancer patients may have reduced risk prone behavior. Considering COVID’s impact on the vulnerable cancer population and uncertainty in immunosuppressed patients about clearing the virus or adequately responding to a vaccine, further studies about health behavior and health promotion during the pandemic are needed.
Association of azole antifungals with survival in patients with non-small cell lung cancer receiving immunotherapy.
Authors: Nikhil Sebastian, William A. Stokes, Madhusmita Behera, Renjian Jiang, David Gutman, Felipe Giuste, Abigail Burns, Selvi Ramalingam, Vidula Sukhatme, Michael C. Lowe, Suresh S. Ramalingam, Vikas Sukhatme, Drew Moghanaki
Journal: Journal of Clinical Oncology (2021)

e18777 Background: Preclinical data suggest certain azole derivatives may have antitumor efficacy and modulate responses to immune checkpoint inhibitors (ICIs). Clinical evidence of synergy can support ongoing research that is investigating the role of repurposing current FDA-approved azole medications to improve outcomes in people with non-small cell lung cancer (NSCLC). We evaluated the association of concomitant azole drugs in a population of NSCLC patients treated with ICI within the Veterans Health Administration. Methods: We conducted a retrospective cohort study of veterans diagnosed with NSCLC between 2010-2018 who were treated with ICI. Receipt of azole drugs was defined as taking a systemic azole within 90 days of ICI therapy. Overall survival (OS) was measured from the start of ICI therapy using Cox-Proportional Hazard (PH) multivariable regression. Patients whose earliest azole administration occurred more than 30 days after initiation of ICI were excluded. Results: We identified 3,413 Veterans treated with ICI; of these, 324 (9.5%) were treated with an azole, most commonly clotrimazole (3.0%) and fluconazole (2.5%). Patients had predominantly stage IV disease (40.8%) at initial diagnosis, followed by stage III (27.1%), stage I-II (19.9%), and unknown stage (12.1%). There was no significant difference in OS multivariable analysis (HR = 0.93 [0.81-1.06]; p = 0.28). Propensity score-matched analysis with 324 patients in each cohort also did not measure a significant difference in OS (HR = 0.89 [0.75-1.06]; p = 0.18) between patients who received any azole versus those who did not. When evaluating specific azole agents on multivariable analysis, there was an association of higher OS with receipt of clotrimazole (HR = 0.72 [0.56 – 0.92]; p = 0.009) and more than one azole (HR = 0.71 [0.53-0.96]; p = 0.026) when compared with no azole. There was an association of shorter OS with miconazole (HR = 1.92 [1.30-2.832]; p = 0.001) and no association with itraconazole (p = 0.08), fluconazole (p = 0.20), or ketoconazole (p = 0.87). In the matched analysis of 102 clotrimazole patients versus no azole, OS was longer in patients who received clotrimazole (HR = 0.76; 95% CI 0.55 – 1.04; p = 0.087), although this effect was not statistically significant. Conclusions: This analysis demonstrated a trend towards longer survival with concomitant clotrimazole and ICI for advanced NSCLC. This association was not seen for other azole mediations.
Trastuzumab-dkst versus trastuzumab: Real-world pCR rates in patients with HER2+ breast cancer treated with neoadjuvant chemotherapy plus trastuzumab from Alberta, Canada.
Authors: Charlie Yang, Raida Khwaja, Karen King, Patricia A. Tang, Nancy Alice Nixon, Sasha M. Lupichuk
Journal: Journal of Clinical Oncology (2021)

e12569 Background: Biosimilars are defined as medical products that contains a version of the active substance with similar biological characteristics, efficacy, and safety as the original product. Differences however, exist between biosimilars and their original comparator. Unlike small-molecule drugs, identical generic versions cannot be mass produced since manufacturers often have proprietary rights to living cell lines and processes involved in producing biologics. Due to this inherent alteration in production, the potential for clinically meaningful differences may exists. These risks are reduced from bench to clinic through a minimum of one phase 1 study to demonstrate comparability of PK and PD between the biosimilar and the original product, and one phase 3 study to demonstrate equivalency for at least one indication. To date, studies have mainly looked at trastuzumab-dkst in the metastatic setting. This retrospective study compared the pathological complete response (pCR) rates of trastuzumab-dkst to trastuzumab in the neoadjuvant setting for HER2+ early breast cancer (EBC) in Alberta. Methods: Neoadjuvant patients with HER2+ EBC treated with trastuzumab from November 2018 -October 2019 and trastuzumab-dkst from December 2019 - September 2020 were identified. There was no crossover between products. Logistic regression was used to control for variables potentially associated with pCR: trastuzumab product (trastuzumab vs trastuzumab-dkst), age ( &lt; 40 vs 40+), pre-operative T (T1/2 vs T3/4) and N stage (negative vs positive), grade (I/II vs III), HR status (ER and/or PR positive vs ER/PR negative), HER2 (3+ vs SISH+), chemotherapy (anthracycline containing vs not), and chemotherapy completion (yes vs no). Results: 136 patients were identified (56% trastuzumab; 43% trastuzumab-dkst) and there were no significant differences in baseline characteristics except more patients in the trastuzumab-dkst group were clinically N negative; 39% vs 14.3% trastuzumab (p = 0.001). pCR was 35.6% for patients treated with trastuzumab-dkst versus 40.3% with trastuzumab (p = 0.598). In the logistic regression model, there was no significant difference in the odds of a pCR for patients treated with trastuzumab-dkst versus trastuzumab after controlling for the variables selected a priori (OR 1.1, 95% CI 0.5-2.4, p = 0.850). There was a trend for decreased odds of pCR for anthracycline use (OR 0.72 95% CI 0.3-1.6, p = 0.417). Conclusions: pCR rates were similar for patients treated with trastuzumab-dkst compared to trastuzumab in our real world study of HER2+ neoadjuvant EBC and comparable to pivotal phase 3 trials. For a 65 kg patient, the estimated cost savings of trastuzumab-dkst therapy is $22,000, and approximately $240-300 for a non-anthracycline chemotherapy backbone.
Abstract 3314: Opening of the Mitochondrial Permeability Transition Pore is Not Precluded With Cyclosporine A in vivo During Cardiac Arrest
Authors: Iyad M Ayoub, Jeejabai Radhakrishnan, Madhav P Upadhyaya, Raul Gazmuri
Journal: Circulation (2009)

Objective: A mechanism of mitochondrial injury during ischemia/reperfusion is Ca2+-induced opening of the mitochondrial permeability transition pore (mPTP). We examined whether cyclosporine A (CsA)...
In Memoriam: James C. Harris, MD
Authors: Joseph T. Coyle, Dost Öngür
Journal: JAMA Psychiatry (2021)

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Multimodal profiling of biliary tract cancers to detect potentially actionable biomarkers and differences in immune signatures between subtypes.
Authors: Kabir Mody, Nilofer Saba Azad, Prerna Jain, Sherif El-Refai, Rachna T. Shroff, Robin Kate Kelley, Anthony B. El-Khoueiry, Denise Lau, Gregory B. Lesinski, Mark Yarchoan
Journal: Journal of Clinical Oncology (2021)

4023 Background: Biliary tract cancers (BTC) are increasingly subtyped by molecular alterations, but little is known about the relationship between gain-of-function mutations and the RNA transcript expression of immune-related pathways. Methods: A sample of retrospective, clinicogenomic and transcriptomic data from de-identified records of patients with BTC in the Tempus database was selected. We then investigated the relationship between the mutational landscape and immune-related RNA signatures of different anatomic and genomic BTC subtypes. Results: The cohort included 455 samples of intrahepatic bile duct (IH) (n=267), gallbladder (GB) (n=153), and extrahepatic bile duct (EH) (n=35) cancer subtypes. Across all subtypes, we detected alterations in TP53 (43.8%), ARID1A (19.8%), KMT2C (18.2%), BAP1 (14.6%), KRAS (12.7%), TERT (12.0%), IDH1 (11.4%), KMT2D (11.0%), LRP1B (11.0%), and PBRM1 (10.7%), along with FGFR2 fusions (2.6%). Potentially actionable biomarkers ( FGFR2 and NTRK1-3 fusions, IDH1 and BRAF V600E mutations, tumor mutational burden [TMB]&gt;10, HER2 expression, and/or microsatellite instability) were identified in 21.1% of all BTC and 28.6% of IH samples. Mutually exclusive alterations observed between subtypes were TP53 &amp; BAP1, KRAS &amp; BAP1, TP53 &amp; IDH1, KRAS &amp; IDH1, and SMAD4 &amp; BAP1 ( P &lt; 0.001 for all). GB was more inflamed based on RNA signatures and classical immune biomarkers, including PD-L1 and TMB. RNA signature analyses revealed a higher expression of immune-related pathways in GB than IH ( P = 0.001) with no differences in comparison with EH. PD-L1 expression and continuous TMB were elevated in GB versus the other anatomical subtypes. Significant associations were noted between particular genetic mutations and immune profiling features (table). Conclusions: BTC subtypes are diverse in DNA alterations, RNA inflammatory signatures, and immune markers. Notably, potentially actionable biomarkers were identified in a sizable portion of the cohort and varied significantly between subtypes. These results provide guidance for targeted therapy development and support the use of multimodal immune profiling for BTC. For example, GB-specific clinical trials may be considered due to the relative increase in immune-related biomarkers observed in GB and the historically limited success of BTC trials.[Table: see text]
Impact of the azoximer bromide concomitant therapy on outcomes in patients with soft tissue sarcoma.
Authors: Aleksei Viktorovich Novik, Natalya Shendaleva, Anton Zozulya, Tatyana Leonidovna Nekhaeva, Anna Semenova, Gulfiya Midhatovna Teletaeva, Dilorom Khamidovna Latipova, Tatiana Semiglazova, Svetlana Protsenko, Irina Alexandrovna Baldueva
Journal: Journal of Clinical Oncology (2021)

e23534 Background: Immunomodulators are used in the management of patients with soft tissue sarcoma, (STS). However, the precise mechanism behind their benefits in anticancer therapy effects have yet to be determined. We assessed the impact of the immunomodulator azoximer bromide (AB) as a prognostic factor for survival when used concomitant with standard therapy in patients with STS. Methods: We reviewed medical history and disease outcomes in STS patients attending the Petrov National Medical Research Centre of Oncology (St Petersburg, Russia). Data were collected per protocol on treatments and patient outcomes. A Cox proportional-hazards model for time-to-progression (TTP) was constructed in SPSS v19. Known prognostic factors (TNM stage and substage, sex, age, therapy by type, and by immunologic action, as well as treatment modality), setting and AB therapy extracted from patient records were included in the model. The model employed a ‘step-forward’ method with AB therapy identified as the ‘unknown’ variable. Results: Complete patient records were available on 243 clinic attendees (from 2010 to 2020), 25 had received treatment with AB. The median follow-up was 20.9 months. Patients received single- and multi-agent chemotherapy, vaccines, cytokines, radiation therapy and/or surgery in the adjuvant or metastatic setting. Significant factors in the TTP model were current therapy type (Hazards ratios: 0.59 for surgery, 0.533 per added method for complex therapy and HR 1.689 for single-agent chemotherapy), previous systemic chemotherapy (HR: 1.451) and AB therapy (HR 0.547). Conclusions: Use of AB with standard therapy in STS emerged as an independent favorable prognostic factor. Appropriately controlled, well-designed prospective trials are needed to investigate this finding further. [Table: see text]
Pemigatinib for previously treated locally advanced/metastatic cholangiocarcinoma (CCA): Update of FIGHT-202.
Authors: Ghassan K. Abou-Alfa, Vaibhav Sahai, Antoine Hollebecque, Gina M. Vaccaro, Davide Melisi, Raed Moh'd Taiseer Al-Rajabi, Andrew Scott Paulson, Mitesh J. Borad, David H. Gallinson, Adrian Gerard Murphy, Do-Youn Oh, Efrat Dotan, Daniel Catenacci, Eric Van Cutsem, Christine Francis Lihou, Huiling Zhen, Luis Féliz, Arndt Vogel
Journal: Journal of Clinical Oncology (2021)

4086 Background: Pemigatinib (PEMI), a potent, selective, oral FGFR1-3 inhibitor, has shown efficacy and safety in patients (pts) with CCA and FGFR2 rearrangements/fusions in FIGHT-202 (NCT02924376; objective response rate [ORR], 35.5%; duration of response [DOR], 7.2 months [mo]). Overall survival (OS: 21.1 mo) was not mature in the primary report (Abou-Alfa. Lancet Oncol 2020; cutoff: Mar 22, 2019); herein we report matured efficacy and safety data from FIGHT-202 (cutoff: Apr 7, 2020). Methods: Pts (≥18 y) with known FGF/FGFR alterations and progression after ≥1 prior therapy had FGFR2 rearrangements/fusions (cohort A), other FGF/FGFR alterations (B), or no FGF/FGFR alterations (C). Pts received PEMI 13.5 mg QD (21-d cycle; 2 wks on, 1 wk off) until progression or toxicity. Primary endpoint: independent, centrally confirmed ORR (cohort A); secondary endpoints: ORR (cohorts B, C; cohorts A and B combined); DOR, disease control rate (DCR), progression free survival (PFS), OS, and safety. A post-hoc analysis in cohort A evaluated mOS in responders (pts with complete response [CR] or partial response [PR]) vs non-responders (pts with progressive disease [PD] or stable disease (SD]). Results: At cutoff, 147 pts were enrolled (cohort A, n=108; B, n=20; C, n=17; FGF/FGFR status undetermined, n=2); median follow-up was 30.4 (range, 4.9–38.7) mo and median treatment duration was 5.9 (0.2–36.5) mo. In cohort A, 9.3% of pts remained on therapy at cutoff; in cohorts B and C, all pts had discontinued. Pts discontinued mainly for PD (67.6%, 75%, and 64.7% in cohorts A, B, and C respectively). Independent, centrally confirmed ORR was 37.0%; mOS was 17.5 mo (95% CI, 14.4-22.9) in cohort A (Table 1). mOS for responders (n=40) vs non-responders (n=68) was 30.1 (95% CI, 21.5-NE) mo vs 13.7 (9.6-16.1) mo. Overall, most common all-cause treatment-emergent adverse events (TEAEs) were hyperphosphatemia (58.5%; grade ≥3, 0%), alopecia (49.7%; 0%), diarrhea (46.9%; 3.4%), fatigue (43.5%; 5.4%), nausea (41.5%; 2%), and dysgeusia (40.8%; 0%); 10.2%, 13.6% and 42.2% of pts discontinued, had dose reduction, and treatment interruption due to TEAEs, respectively. Conclusions: These results reinforce the primary data, showing continued, durable responses and sustained tolerability in pts receiving PEMI for CCA harboring FGFR2 rearrangements/fusions. Notably, the matured OS is longer than historical data; OS for responders was more than twice as long vs for non-responders. Clinical trial information: NCT02924376. [Table: see text]
Results from a phase II study of eftilagimod alpha (soluble LAG-3 protein) and pembrolizumab in patients with PD-L1 unselected metastatic non-small cell lung carcinoma.
Authors: Timothy Dudley Clay, Margarita Majem, Enriqueta Felip, Bernard Doger, Enric Carcereny Costa, Martin Forster, Matthew Krebs, Julio Antonio Peguero, Christian Mueller, Frederic Triebel
Journal: Journal of Clinical Oncology (2021)

9046 Background: Eftilagimod alpha (efti) is a soluble LAG-3 protein that binds to a subset of MHC class II molecules to mediate antigen presenting cell (APC) activation and CD8 T-cell activation. The stimulation of the dendritic cell network and subsequent T cell recruitment with efti may lead to stronger anti-tumor responses in combination than observed with pembrolizumab alone. We hereby report results of the 1st line non-small cell lung carcinoma (NSCLC) part of the phase II trial (NCT03625323). Methods: Patients (pts) with untreated, immunotherapy naïve, advanced NSCLC unselected for PD-L1 expression were recruited into part A. The study used a Simon's 2-stage design (17 pts planned for stage 1 and 19 pts for stage 2), with objective response rate (ORR) by iRECIST as the primary endpoint (EP). Secondary EPs include tolerability, disease control rate (DCR), progression free survival (PFS), overall survival (OS), PK, PD and immunogenicity. Efti is administered as 30 mg subcutaneous injection every 2 wks for 8 cycles and then every 3 wks for 9 cycles with pembrolizumab (200 mg intravenous infusion every 3 wks for up to 2 yrs). Imaging was performed every 8 weeks locally and with blinded independent central review (BICR) retrospectively. The study was approved by ethic committees and institutional review boards. Results: In total 36 pts were enrolled. At data cut-off (Jan 2021; median FU of 14 months), the median age was 69 yrs (range 53-84) and 69 % were male. The ECOG PS 0 and 1 was 42% and 58% respectively. Patients had squamous (42%) and non-squamous (58%) NSCLC and 95% presented with metastatic disease. All PD-L1 subgroups (TPS &lt; 1 %, ≥ 1 % to ≤49 %; ≥50 %) were represented with 36% pts having ≥50% TPS. Pts received a median of 7.0 (range 1 – 31) pembrolizumab and 11.5 (range 1-22) efti administrations. Responses as per BICR and local read are shown in the table. ORR (local, iRECIST) by different PD-L1 subgroups was 27% for pts with TPS&lt;1%, 39 % for TPS ≥1 %and 54% for ≥50 % TPS. Median PFS (n=36) was 8.2 months while median OS was not yet reached. The most common (&gt; 20 %) treatment emergent adverse events (AEs) were asthenia (47 %), cough (36 %), decreased appetite (36 %), dyspnea (32 %), pruritus (31 %), fatigue (28 %), diarrhea (25 %), anemia (25 %), constipation (25 %) and back pain (22%). Two patients discontinued treatment due to adverse reactions (Grade 4 immune-mediated hepatitis, Grade 3 AST+ALT increase). Conclusions: Efti in combination with pembrolizumab is safe and shows encouraging antitumor activity in 1st line advanced NSCLC patients across all PD-L1 (TPS) levels. Clinical trial information: NCT03625323. [Table: see text]
Vitamin A and Vitamin E: Will the Real Antioxidant Please Stand Up?
Authors: William S. Blaner, Igor O. Shmarakov, Maret G. Traber
Journal: Annual Review of Nutrition (2021)

Vitamin A, acting through its metabolite, all- trans-retinoic acid, is a potent transcriptional regulator affecting expression levels of hundreds of genes through retinoic acid response elements present within these genes. However, the literature is replete with claims that consider vitamin A to be an antioxidant vitamin, like vitamins C and E. This apparent contradiction in the understanding of how vitamin A acts mechanistically within the body is a major focus of this review. Vitamin E, which is generally understood to act as a lipophilic antioxidant protecting polyunsaturated fatty acids present in membranes, is often proposed to be a transcriptional regulator. The evaluation of this claim is another focus of the review. We conclude that vitamin A is an indirect antioxidant, whose indirect function is to transcriptionally regulate a number of genes involved in mediating the body's canonical antioxidant responses. Vitamin E, in addition to being a direct antioxidant, prevents the increase of peroxidized lipids that alter both metabolic pathways and gene expression profiles within tissues and cells. However, there is little compelling evidence that vitamin E has a direct transcriptional mechanism like that of vitamin A. Thus, we propose that the term antioxidant not be applied to vitamin A, and we discourage the use of the term transcriptional mediator when discussing vitamin E.