tbuckley/cabot-search huggingface dataset:
Long-term survival outcomes with immune checkpoint inhibitors (ICI) in metastatic uveal melanoma (MUM).
Authors: Cha Len Lee, Naomi Walsh, Fergus Keane, Emer Lynch, Tadhg Reddan, Helen Craig, Aileen O'Meara, Deirdre Smith, Valerie O'Neill, Noel Horgan, Susan Kennedy, Giuseppe Gullo, John Crown
Journal: Journal of Clinical Oncology (2021)

e21585 Background: The treatment of MUM remains highly unsatisfactory. Single agent ICI produce low response rates. Two recent phase II trials of combination Ipilimumab and Nivolumab yielded response rates of 12% and 18%. We report the long-term survival results of MUM patients (pts) treated with ICI in our institution. Methods: We conducted a retrospective analysis of all pts with a diagnosis of MUM in St Vincent’s University Hospital. Overall survival (OS) was calculated from time of first systemic relapse to death or latest follow-up. One-way ANOVA is used with p &lt; 0.05 considered statistically significant. Results: Out of 244 pts with UM registered in our clinics between April 2008 to October 2020, 52 developed MUM. Median age at initial diagnosis 63 years. 26(50%) are females. Median duration of follow-up of the MUM pts is 35.1 months [2.71-123.2]. Median duration of follow-up from initiation of ICI therapy is 9.1 months [1.6-84.2]. First sites of metastases: liver only 71%, liver plus extrahepatic 17%, and extrahepatic only 12%. Fifteen pts (29%) underwent radical metastasectomy as initial treatment. Thirty-seven (71%) had non-resectable MUM and received systemic treatment (23 total: ICI = 18, chemotherapy = 4, BRAF inhibitors = 1), non-surgical locoregional therapies (5 total: chemosaturation = 3, radiofrequency ablation = 2) or supportive/palliative care (9) as first-line. An additional 22 pts received ICI as second or subsequent treatment, for a total of 40 treated with ICI. Of these, 17 received single agents ICI (Ipilimumab = 11, Pembrolizumab = 6), 13 received sequential Ipilimumab and anti-PD1, and 10 received combination Ipilimumab /Nivolumab. At the time of analysis on 31 st October 2020, 9 out of 52 pts (17%) are alive at 2.6, 5.0,5.4,8.9,17.3, 54.7, 77.5, 83.1 and 121.7 months (the 6 longest all had ICI). The median OS is 14.3 months [0.6-121.7]. Pts treated with ICI demonstrated longer OS than pts who did not receive ICI [15.0 months, 5.0-121.7 vs 7.2 months, 0.6-34.6; p = 0.089]. The median OS is 24.9 months (sequential Ipilimumab and anti-PD1) vs 15.0 months (combination Ipilimumab/Nivolumab) vs 13.4 months (single agents). Of the three pts remain alive &gt; 5 years, one is currently disease-free. Conclusions: Prolonged survival beyond five years is achieved by a minority of pts with MUM who receive ICI during their treatment history, although durable initial ICI-induced remission is very rare. Our data suggest that pts who receive two ICI drugs during their illness may have longer survival compared to those who receive only a single ICI.
Anti-proliferative effect of a novel purine-template based dual Src/Abl tyrosine kinase inhibitor AP23464 on native and Imatinib-resistant Bcr-Abl cell lines
Authors: Azam Mohammad, Valentina Nardi, Chester A. Metcalf, William C. Shakespeare, Tomi K. Sawyer, George Q. Daley
Journal: Cancer Research (2004)

4641  Bcr-Abl is a dysregulated tyrosine kinase that causes chronic myeloid leukemia and is targeted by the signal transduction inhibitor Imatinib mesylate (IM). Imatinib is an effective treatment choice for Bcr-Abl-positive malignancies. However, resistance toward IM develops frequently in advanced-stage (Blast crisis), and is even observed in chronic-phase of leukemia. Point mutations within the ABL kinase and SH3 domain emerged as a major mechanism of resistance toward imatinib. Frequently, mutations occur at positions that determine specific contacts of imatinib to the ATP-binding site. However, an interesting class of mutants appears to act allosterically by influencing the confirmation of the kinase domain. These mutants alter the “breathing” of the N-lobe of the kinase domain relative to the C-lobe. Emergence of resistance to IM warrants the exploration of novel well-tolerated anticancer agents. We evaluated a novel purine template-based dual Src/Abl kinase inhibitor AP23464 (ARIAD Pharmaceuticals) for their potential to overcome resistance in various imatinib-resistant cell lines. This compound effectively suppressed the activity of 30 different kinase domain mutants resistant to IM. The common P-loop mutants are sensitive to AP23464, and only the L267R (type Ib) remains resistant. Interestingly, the most frequent and robust mutant T334I (type Ib) was effectively suppressed; whereas, F336L (type Ib) is 30 fold resistant over native Bcr-Abl. Surprisingly, eight of the 30 kinase domain mutants (D295V, E300K, V308S, E311Q, Q319H, T334S, G340W and M370T; type Ib) were highly sensitive as compared to the native Bcr-Abl. These observations led us to conclude that AP23464 is an effective compound against most of the frequently observed mutations of Bcr-Abl in connection with IM resistance. Understanding the underlying molecular mechanisms involved in drug sensitivity is important to exploiting this novel Src/Abl kinase inhibitor and its analogs. Moreover, combination studies of AP23464 and other drugs may also be a promising therapeutic strategy to overcome IM resistance. Our data support the development of AP23464 for the treatment of CML and provide impetus to test AP23464 in combination with other drugs relative to further understanding the molecular mechanisms involved in Bcr-Abl-positive malignancies.
Ovarian function suppression in premenopausal patients with concurrent endocrine therapy use.
Authors: Nicole Margo Grogan, Yajing Li, Kelley M. Kidwell, Norah Lynn Henry
Journal: Journal of Clinical Oncology (2021)

6574 Background: The addition of ovarian function suppression (OFS) to endocrine therapy (ET) for premenopausal women with high risk, hormone receptor-positive breast cancer improves disease outcomes. However, in the SOFT-EST study, up to 17% of patients receiving gonadotropin-releasing hormone agonists (GnRHa) did not have appropriate ovarian suppression within the first year of treatment. Few studies have explored the long-term effectiveness of OFS to maintain estrogen suppression. Guidelines for estradiol monitoring during OFS therapy are not clearly defined. Methods: We performed a retrospective, single institution review of all patients who received concurrent GnRHa injections and ET since 2010. Only estradiol concentrations that were assessed during OFS treatment were abstracted from the medical record and included in the analysis. The primary endpoint was the percentage of patients with a non-suppressed estradiol concentration (defined as standard estradiol or high-sensitivity estradiol ≥ 10 pg/ml) identified during OFS cycle 2 ( &gt; 35 days after OFS initiation) and/or later cycles. The secondary endpoint, which included only those patients with estradiol assessment within 35 days of OFS initiation, was the percentage of patients with a non-suppressed estradiol level when measured within the first 35 days after OFS initiation. For both cohorts, differences in age, body mass index (BMI), and previous chemotherapy use were summarized via multivariable logistic regression. Results: 148 patients received concurrent OFS and ET. Patients were excluded because of lack of estradiol assessment during OFS therapy (n = 13) and non-compliance with GnRHa injections (n = 4). The average age and BMI were 43.1 years and 29.1 kg/m 2 , respectively. 35 of 131 patients (26.7%) had at least one non-suppressed estradiol level during OFS cycle 2 and/or later cycles. The median time to detection of non-suppression was 250 days (range: 53 – 2573 days). Patients whose estradiol concentration remained suppressed throughout treatment with OFS and ET were more likely to be older (OR 1.12 [95% CI 1.05-1.22], p =.02), have a lower BMI (OR 0.88 [95% CI 0.82-0.94], p &lt;.001), and have received chemotherapy (OR 6.30 [95% CI 2.06-20.8], p =.002). For the secondary endpoint, 20 of 83 patients (24.1%) had a non-suppressed estradiol level within 35 days of OFS initiation. Lower BMI was associated with achieving ovarian suppression by 35 days (OR 0.85 [95% CI 0.77-0.93], p &lt;.001); no association was noted for age or chemotherapy. Conclusions: More than one-fourth of patients in this “real world” population had at least one non-suppressed estradiol level during treatment, both the month after the initial OFS dose and at later time points. Patients on OFS, especially those on aromatase inhibitor therapy and those at increased risk of non-suppression, may require frequent and long-term estradiol monitoring during treatment.
Differential modulation of polyunsaturated fatty acids in patients with myocardial infarction treated with ticagrelor or clopidogrel
Authors: Karla N. Samman, Pamela Mehanna, Emad Takla, Jean-Christophe Grenier, Mark Y. Chan, Renato D. Lopes, Megan Lee Neely, Tracy Y. Wang, L. Kristin Newby, Richard C. Becker, Marie Lordkipanidzé, Matthieu Ruiz, Julie G. Hussin, E. Marc Jolicœur
Journal: Cell Reports Medicine (2021)

Untargeted metabolomics is used to refine the development of biomarkers for the diagnosis of cardiovascular disease. Myocardial infarction (MI) has major individual and societal consequences for patients, who remain at high risk of secondary events, despite advances in pharmacological therapy. To monitor their differential response to treatment, we performed untargeted plasma metabolomics on 175 patients from the platelet inhibition and patient outcomes (PLATO) trial treated with ticagrelor and clopidogrel, two common P2Y12 inhibitors. We identified a signature that discriminates patients, which involves polyunsaturated fatty acids (PUFAs) and particularly the omega-3 fatty acids docosahexaenoate and eicosapentaenoate. The known cardiovascular benefits of PUFAs could contribute to the efficacy of ticagrelor. Our work, beyond pointing out the high relevance of untargeted metabolomics in evaluating response to treatment, establishes PUFA metabolism as a pathway of clinical interest in the recovery path from MI.
Incorporating HER2/HER3 targeted therapies across solid tumors: Assessing the impact of digital education on clinician practice patterns.
Authors: Tariqa Ackbarali, Wendy Turell, Elizabeth L. del Nido, Adam Brufsky, Stephen V. Liu
Journal: Journal of Clinical Oncology (2021)

11036 Background: Improved understanding of the interactions between HER2 and HER3, the heterogeneity of HER-expressing disease, and mechanisms of resistance to anti-HER2 therapy has led to increasing number of treatment options to address clinical needs. Tumor types of interest, impacted by HER2/HER3 expression and pathophysiology were breast cancer, non-small cell lung cancer (NSCLC), gastric cancer, and colorectal cancer (CRC). Increasing competency in these areas is deemed critical to clinician’s ability to individualize treatment plans and improve patient outcomes. Methods: A 2-hour CME activity was broadcast live-online in September 2020 and remains on-demand through September 2021 at OMedLive.com. The educational initiative was divided into one hour addressing HER2 and HER3, testing guidelines, resistance mechanisms and emerging data elucidating recent and ongoing clinical trials across NSCLC, gastric cancer, and CRC. The second hour focused on individualizing metastatic HER2+ breast cancer, HER2-low breast cancer as an emerging subtype, and management of side effects. Knowledge and competence questions were administered pre-, immediate post-, and 2 mos. post-activity. Behavioral impact questions were also asked at follow-up. Data from these questions were analyzed to determine engagement and clinical impact. Results: To date, 448 clinicians participated in the activity. Across the seven CME test questions, improvements in knowledge and competence were observed in the clinical applications of HER2-directed agents and HER3 antibody drug conjugates (ADCs), first-line standard of care for HER2+ breast cancer, and adverse event management for HER2 ADCs. At 2-mos. follow-up, 67% reported improved behavioral impact on both clinical practice and patient experience and outcomes. Clinicians provided specific write-in examples of these changes, noting improved patient-reported outcomes, improved treatment adherence, improved competence developing treatment plans, and increased understanding of HER2/HER3 pathophysiology. Updated and expanded results will be shared. Conclusions: The activity was successful in improving clinician understanding of the relationship between HER2/HER3, pathophysiology across tumor types, and applications of emerging targeted therapies. Open-ended responses to behavioral impact questions illustrated clear improvements in clinician-reported patient experience and outcomes, clinical practice management, and knowledge of emerging HER2/HER3 therapies and their uses across multiple solid tumors.
The impact of an expert exchange-based educational initiative on urologist confidence and knowledge in implementing immunotherapy for bladder cancer.
Authors: Susan H. Gitzinger, Bryan Carson Taylor, Joan B. Fowler, Vanessa Carranza, Rebecca Weaver
Journal: Journal of Clinical Oncology (2021)

e23001 Background: The rapid and robust emergence of the immunotherapy era in bladder cancer has prompted a paradigmatic shift in both early and late-stage bladder cancer management. Given this change, it is imperative that members of the bladder cancer care team, most notably urologists, medical oncologists, and urologic oncologists, be well-equipped to safely and effectively integrate immune checkpoint inhibitors into the treatment armamentarium. Methods: CEC Oncology delivered education at select meetings throughout 2019-2021 including ASCO GU, AUA, and SUO Annual Meetings; in addition to live presentations, the content was streamed live and on-demand on www.ceconceptslive.com and endured on myCME.com. Learning and knowledge was objectively assessed by analyzing pre- and post-test results before and after the educational activities. To determine retention of knowledge over time, follow-up assessments were sent to participants after each live activity. Assessment questions in the form of case studies were utilized to gauge whether participants translated knowledge into practice at follow-up. Statistical testing between pre- and post-tests and from pre-test to follow-up were conducted via chi square analysis with a priori significance set at 0.05. Results: Executed five live educational activities and a spin-off enduring component hosted on myCME.com. 765 total clinicians educated across the live elements of the curriculum. Across the curriculum, over 70% of attendees indicated at post-activity assessment that they would use systemic immunotherapy either primarily or exclusively in their practice compared to just 25% at pre-activity. Among urologists practicing at academic medical centers, confidence in appropriate implementation of immunotherapy increased for all participants, and more specifically, for clinicians practicing at academic medical centers (on a 4-point scale, All Participants demonstrated a confidence increase from 2.70 to 2.91; Academic Medical Center clinicians demonstrated an increase of 2.75 to 3.00); 97% said that the initiative increased their knowledge of ongoing ICI clinical trials in bladder cancer; Attendee ability to appropriately manage an irAE increased substantially from pre-test to post-test assessment (37% vs. 63%; P=.057). Clinicians practicing in community settings are the only attendees who did not exhibit an increase in mean confidence in appropriately implementing immunotherapy at post-activity assessment. Conclusions: Our Expert Exchange Bladder Cancer Curriculum precipitated substantive practice advances related to appropriate implementation of ICI therapy. Many of these advances, however, were specific to academic urologists and urologic oncologists; outcomes analyses have revealed tangible educational gaps among community-based urologists.
Comparing phase 3 “go” decisions (Ph3-GO) between single arm trials with real-world external control (SAT+rwEC) versus randomized phase 2 trials (rPh2).
Authors: Brian Hobbs, Thanh Ton, Xiao Li, David S. Hong, Rebecca A. Hubbard, Pam K. Mangat, William Capra, Shengchun Kong, Herbert Pang, Meghna Samant, Brian D. Segal, Liz Garrett-Mayer
Journal: Journal of Clinical Oncology (2021)

e13564 Background: Traditional rPh2 trials have limitations that may yield suboptimal Ph3-GO. Compared to a rPh2 of equivalent sample size, SAT+rwEC allows more patients to receive experimental therapies while preserving the ability to compare experimental and control groups. Bias arising from measurement error and confounding in the rwEC, however, poses challenges to statistical inference. Preliminary studies suggest higher response rates are observed in rwEC than randomized controls. We compared Ph3-GO decisions between SAT+rwEC and rPh2. Methods: Ph3-GO probability was compared using simulation studies that resembled the oncology setting with objective response rate (ORR) endpoint. rPh2 simulated parameters were: sample size (60-120) with 1:1 randomization, ORR in rPh2 control (15%-50%), true treatment effect (ΔORR: 0-50). For each rPh2 of a given sample size, we evaluated an SAT+rwEC that re-allocated all rPh2 control patients to the experimental arm (i.e., doubling the sample size of the experimental arm) and added an rwEC. SAT+rwEC were simulated with assumptions for size (rwEC to SAT ratio: 0.5 to 2) and net bias (-10 to +10), which was simulated as a composite representing ORR measurement error plus residual confounding after multivariable adjustment. Positive direction of net bias corresponds to higher ORR in the rwEC. Ph3-GO thresholds varied from 10-30%. Ph3-GO was considered “False-GO” when true treatment effect &lt; threshold, and “True-GO” when true treatment effect ≥ threshold. Results: With positive net bias of +10, SAT+rwEC had lower False-GO and True-GO decisions compared to rPh2. With negative net bias of -10, both False-GO and True-GO probabilities were higher for the SAT+rwEC. When net bias=0, the increased size of SAT+rwEC resulted in observable Ph3-GO improvements with lower False-GO and higher True-GO than corresponding rPh2. Conclusions: An interactive dashboard was developed for users. The magnitude and direction of net bias relative to the decision threshold affect the performance of SAT+rwEC. The relative sample size of rwEC to rPh2 may also impact performance. The dashboard can provide quantitative guidance for Ph3-GO if net bias can be estimated by independent studies. Further work to quantify net bias and refine Ph3-GO criteria can help reduce the currently high False-GO rates while increasing opportunities for patients to receive experimental therapies through the SAT+rwEC design. Ph3-GO probability for rPh2 vs. SAT+rwEC with threshold=15%, baseline ORR=20% (select scenarios).[Table: see text]
Dedicated clinical trial tissue tracking database to improve turn-around time at high-volume center.
Authors: Peter Blankenship, David DeLaRosa, Marc Burris, Steven Cusson, Kayla Hendricks, Christopher Earwood, Suzanne Fields Jones, Erika P. Hamilton, Melissa Lynne Johnson, Howard A. Burris III, Johanna C. Bendell, Meredith McKean
Journal: Journal of Clinical Oncology (2021)

1543 Background: Tissue requirements in oncology clinical trials are increasingly complex due to prescreening protocols for patient selection and serial biopsies to understand molecular-level treatment effects. Novel solutions for tissue processing are necessary for timely tissue procurement. Based on these needs, we developed a Tissue Tracker (TT), a comprehensive database for study-related tissue tasks at our high-volume clinical trial center. Methods: In this Microsoft Access database, patients are assigned an ID within the TT that is associated with their name, medical record number, and study that follows their request to external users: pathology departments, clinical trial coordinators and data team members. To complete tasks in the TT, relevant information is required to update the status. Due to the high number of archival tissue requests from unique pathology labs, the TT has a “Follow-Up Dashboard” that organizes information needed to conduct follow-up on all archival samples with the status “Requested”. This results in an autogenerated email and pdf report sent to necessary teams. The TT also includes a kit inventory system and a real-time read only version formatted for interdepartmental communication, metric reporting, and other data-driven efforts. The primary outcome in this study was to evaluate our average turnaround time (ATAT: average time from request to shipment) for archival and fresh tissue samples before and after TT development. Results: Before implementing the TT, between March 2016 and March 2018, we processed 2676 archival requests from 235 unique source labs resulting in 2040 shipments with an ATAT of 19.29 days. We also processed 1099 fresh biopsies resulting in 944 shipments with an ATAT of 7.72 days. After TT implementation, between April 2018 and April 2020, we processed 2664 archival requests from 204 unique source labs resulting in 2506 shipments (+28.0%) with an ATAT of 14.78 days (-23.4%). During that same period, we processed 1795 fresh biopsies (+63.3%) resulting in 2006 shipments (+112.5%) with an ATAT of 6.85 days (-11.3%). Conclusions: Oncology clinical trials continue to evolve toward more extensive tissue requirements for prescreening and scientific exploration of on-treatment molecular profiling. Timely results are required to optimize patient trial participation. During the intervention period, our tissue sample volume and shipments increased, but the development and implementation of an automated tracking system allowed improvement in ATAT of both archival and fresh tissue. This automation not only improves end-user expectations and experiences for patients and trial sponsors but this allows our team to adapt to the increasing interest in tissue exploration.
COVID‐19 outcomes in patients with autoimmune blistering disease
Authors: E. Hwang, M.M. Tomayko
Journal: British Journal of Dermatology (2021)

Autoimmune blistering diseases (AIBD) are often treated with immunosuppressive medications, including rituximab, yet the implications of these approaches during the COVID-19 pandemic are not fully understood. COVID-19 outcome studies in AIBD patients are limited by small sample sizes and interpretation complicated by advanced ages and comorbidities common in this population.