tbuckley/cabot-search huggingface dataset:
Five-year overall survival from the anti-PD1 brain collaboration (ABC Study): Randomized phase 2 study of nivolumab (nivo) or nivo+ipilimumab (ipi) in patients (pts) with melanoma brain metastases (mets).
Authors: Georgina V. Long, Victoria Atkinson, Serigne Lo, Alexander David Guminski, Shahneen Kaur Sandhu, Michael Paul Brown, Maria Gonzalez, Richard A. Scolyer, Louise Emmett, Grant A. McArthur, Alexander M. Menzies
Journal: Journal of Clinical Oncology (2021)

9508 Background: Preliminary data from the ABC (76 pts) and CheckMate 204 (94 pts) trials showed that nivo and nivo+ipi have activity in active melanoma brain metastases, with durable responses in a subset of pts. Here, we report updated 5-yr data from all pts enrolled on the ABC trial (NCT02374242). Methods: This open-label ph2 trial enrolled 3 cohorts of pts with active melanoma brain mets naïve to anti-PD1/PDL1/PDL2/CTLA4 from Nov 2014-Apr 2017. Pts with asymptomatic brain mets with no prior local brain therapy were randomised to cohort A (nivo 1mg/kg + ipi 3mg/kg, Q3Wx4, then nivo 3mg/kg Q2W) or cohort B (nivo 3mg/kg Q2W). Cohort C (nivo 3mg/kg Q2W) had brain mets i) that failed local therapy, ii) with neuro symptoms and/or iii) with leptomeningeal disease. Prior BRAF inhibitor (BRAFi) was allowed. The primary endpoint was best intracranial response (ICR) ≥wk12. Key secondary endpoints were IC PFS, overall PFS, OS, &amp; safety. Results: A total of 76 pts (med f/u 54 mo) were enrolled; median age 59y, 78% male. For cohorts A, B and C: elevated LDH 51%, 58% and 19%; V600BRAF 54%, 56% and 81%; prior BRAFi 23%, 24%, 75%. Efficacy and toxicity are shown in the table. There were no treatment-related deaths. 1/17 deaths in cohort A &amp; 4/16 in cohort B were due to IC progression only. Conclusions: Nivo monotherapy and ipi+nivo are active in melanoma brain mets, with durable responses in the majority of patients who received ipi+nivo upfront. A study of upfront ipi+nivo+/-SRS is underway (NCT03340129). Clinical trial information: NCT02374242. [Table: see text]
Compliance with germline testing in pancreatic cancer in a rural tertiary care hospital.
Authors: Catherine Travaline, Leighton Andrew Elliott, Nadia N. Ramdin, Joseph Vadakara
Journal: Journal of Clinical Oncology (2021)

10599 Background: Pancreatic cancer is the 7th most common cause of cancer death worldwide and is projected to be the second leading cause of cancer death in the next decade. Personalized care is becoming more of a reality with pharmacological regimens targeting specific genetic mutations. In March 2019, the National Comprehensive Cancer Network (NCCN) guidelines were updated to recommend germline testing (GT) in all patients with pancreatic adenocarcinoma (PDAC) considering 1 in 10 may have a germline mutation (GM). The goal of this study was to quantify compliance with these recently updated guidelines. Methods: The electronic medical records and survivorship data of all patients diagnosed with PDAC between January 1, 2017 and October 1, 2020 were reviewed. April 1, 2019 was used as the transition point (TP) for guideline updates. Descriptive statistics for all variables were determined. The rate of ordered referrals to genetic counseling (GC), as well as completion rate, was calculated. Results: A total of 304 patients were diagnosed with PDAC during the study period (223 prior to the TP). A total of 54 patients were referred for GC and 41 had GT ordered. The rate of GC referrals ordered after the TP was significantly higher than before the TP (22/81, 26.6% vs. 32/223, 14.4%; p-value 0.010). Almost 60% of patients who had genetic evaluation had private insurance. The patients who completed GT were significantly more likely to have a documented family history of cancer (61.0% vs 4.2%; p-value &lt;.0001Patients who completed GT had more problems on their problem list (median 10 vs 7, p = 0.001). The median overall survival (OS) for all patients in the study was 7.8 months (95% CI: 6.3-9.8). Conclusions: Overall compliance with the updated NCCN guidelines significantly improved; however, it was below 25%. This study showed that there may be some lingering bias toward GT in PDAC solely for those who have a family history of cancer. Although patients with stage IV PDAC have poor outcomes, GT may still improve surveillance for family members. The approval of olaparib in patients with BRCA1/2 mutations based on the POLO trial is likely to increase provider compliance as it provides a viable maintenance strategy in these patients. Patient complexity was unlikely to affect GT rate. Assessment of provider awareness was outside the scope of this study. There is need for continued advocacy for awareness and implementation of guidelines that highlight the importance of germline evaluation on prevention, surveillance, and treatment in pancreatic adenocarcinoma.
Surveillance of the Immune Repertoire of Aplastic Anemia Patients Using Deep Sequencing
Authors: Cassandra M. Hirsch, Michael J. Clemente, Valeria Visconte, Taha Bat, Bartlomiej P. Przychodzen, Tomas Radivoyevitch, Vera Adema, Yasunobu Nagata, Hetty E. Carraway, Mikkael A. Sekeres, Babal K Jha, Sudipto Mukherjee, Thomas Laframboise, Jaroslaw P. Maciejewski
Journal: Blood (2017)
Maintenance of the human memory T cell repertoire by subset and tissue site
Authors: Michelle Miron, Wenzhao Meng, Aaron M. Rosenfeld, Shirit Dvorkin, Maya Meimei Li Poon, Nora Lam, Brahma V. Kumar, Yoram Louzoun, Eline T. Luning Prak, Donna L. Farber
Journal: Genome Medicine (2021)

Abstract Background Immune-mediated protection is mediated by T cells expressing pathogen-specific T cell antigen receptors (TCR) that are maintained at diverse sites of infection as tissue-resident memory T cells (TRM) or that disseminate as circulating effector-memory (TEM), central memory (TCM), or terminal effector (TEMRA) subsets in blood and tissues. The relationship between circulating and tissue resident T cell subsets in humans remains elusive, and is important for promoting site-specific protective immunity. Methods We analyzed the TCR repertoire of the major memory CD4 + and CD8 + T cell subsets (TEM, TCM, TEMRA, and TRM) isolated from blood and/or lymphoid organs (spleen, lymph nodes, bone marrow) and lungs of nine organ donors, and blood of three living individuals spanning five decades of life. High-throughput sequencing of the variable (V) portion of individual TCR genes for each subset, tissue, and individual were analyzed for clonal diversity, expansion and overlap between lineage, T cell subsets, and anatomic sites. TCR repertoires were further analyzed for TRBV gene usage and CDR3 edit distance. Results Across blood, lymphoid organs, and lungs, human memory, and effector CD8 + T cells exhibit greater clonal expansion and distinct TRBV usage compared to CD4 + T cell subsets. Extensive sharing of clones between tissues was observed for CD8 + T cells; large clones specific to TEMRA cells were present in all sites, while TEM cells contained clones shared between sites and with TRM. For CD4 + T cells, TEM clones exhibited the most sharing between sites, followed by TRM, while TCM clones were diverse with minimal sharing between sites and subsets. Within sites, TRM clones exhibited tissue-specific expansions, and maintained clonal diversity with age, compared to age-associated clonal expansions in circulating memory subsets. Edit distance analysis revealed tissue-specific biases in clonal similarity. Conclusions Our results show that the human memory T cell repertoire comprises clones which persist across sites and subsets, along with clones that are more restricted to certain subsets and/or tissue sites. We also provide evidence that the tissue plays a key role in maintaining memory T cells over age, bolstering the rationale for site-specific targeting of memory reservoirs in vaccines and immunotherapies.
Racial, ethnic, and socioeconomic disparities in diagnosis, treatment, and survival of patients with breast cancer.
Authors: Arash Azin, Houman Tahmasebi, Amanpreet Brar, Sam Azin, Gary T. Ko, Andrea Covelli, Tulin D. Cil
Journal: Journal of Clinical Oncology (2021)

e18551 Background: Racial disparities in breast cancer are well established. However, there is a paucity of literature assessing the interaction of patient, socioeconomic, and community factors on outcomes. The objective of this study was to determine the influence of race/ ethnicity, socioeconomic status (SES), and insurance status on disease presentation, access to care, and survival in breast cancer. Methods: A retrospective analysis was performed of Non-Hispanic Black (NHB), Non-Hispanic White (NHW), and Hispanic patients with non-metastatic breast cancer in the SEER cancer registry between 2007 and 2016. Multivariable binary logistic regression and Cox regression analyses were conducted. Results: A total of 382,975 patients were identified; 289,074 (75.5%) NHW, 45,821 (12.0%) NHB, and 48,080 (12.6%) Hispanic patients. On multivariate analysis (see table), NHB (OR 1.18, 95%CI: 1.15-1.20) and Hispanic (OR 1.20, 95%CI: 1.17-1.22) patients were more likely to present with higher stage disease than NHW patients. There was an increased likelihood of not undergoing primary resection in NHB (OR 1.56, 95%CI: 1.49-1.65) and Hispanic (OR 1.41, 95%CI: 1.34-1.48) patients compared to NHWs. Similarly, NHB and Hispanic patients had increased odds of not undergoing breast reconstruction following mastectomy (OR 1.07, 95%CI: 1.03-1.11 and OR 1.60, 95%CI 1.54-1.66, respectively). NHB patients had increased hazard for all-cause mortality (HR: 1.13, 95%CI 1.10-1.16) and breast cancer-specific mortality (HR: 1.20, 95%CI 1.16-1.24). All-cause mortality increased across SES categories (lower SES: HR 1.33, 95%CI 1.30-1.37, middle SES: HR 1.20, 95%CI 1.17-1.23) in NHBs. Conclusions: This population-based analysis confirms worse disease presentation, access to surgical therapy, and survival across racial, ethnic, and socioeconomic factors. These disparities were compounded across worsening SES, suggesting structural racism may partly account for our findings.[Table: see text]
Impact of immunotherapy on survival differences in patients with melanoma and chronic lymphocytic leukemia.
Authors: Raghav Tripathi, Jeremy S. Bordeaux, Luke Rothermel, Ankit Mangla
Journal: Journal of Clinical Oncology (2021)

e21550 Background: Chronic lymphocytic leukemia (CLL) is well known to be associated with secondary malignancies like melanoma. Patients with melanoma and CLL are known to have poorer prognosis compared to patients without CLL. Checkpoint inhibitors (CPI) started gaining traction in 2011 after ipilimumab approval and are widely used in treatment of advanced melanoma. The objective of this study is to determine the survival of patients with melanoma and CLL in the era of CPI (2011 onwards) compared to previous years. Methods: We identified patients with melanoma and CLL reported to the Surveillance, Epidemiology, and End Results (SEER-18) program. We created cohorts of patients with melanoma and CLL vs. melanoma without CLL and split the cohorts into patients diagnosed from 2000-2010 and 2011-2017 to evaluate the impact of immunotherapy on overall all-cause survival. Kaplain-Meier survival curves were created for each of the four cohorts using the Ederer/direct-adjusted survival method. Standard Cox regression models adjusted for age and sex used to compare survival between subgroups. Two-sided p-values &lt; 0.05 were considered significant. Results: From 2000-2017, 536,264 patients with melanoma were included in this study. 2,945 [0.55%] patients had coexisting CLL. Most patients were male (303,477 [56.6%]), age 60-79 (235,833 [44.0%]), non-Hispanic white (499,151 [93.08%]), and diagnosed from 2000-2010 (285,292 [53.2%]) with melanoma of the trunk (156,722 [29.2%]). From 2000-2010, patients with melanoma had an average survival of 91.4 months (95% CI 88.7-94.1) and those with coexisting CLL had an average survival of 59.3 months (95% CI 58.1-60.6). From 2011-2017, patients with melanoma had an average survival of 129.1 months (95% CI 127.7-130.5) and those with coexisting CLL had an average survival of 116.0 months (95% CI 113.5-118.5). The difference in survival in patients with melanoma vs. melanoma and CLL in 2000-2010 (32.1 months) is significantly greater than that of patients from 2011-2017 (13.1 months, p &lt; 0.05). Conclusions: Although CLL continues to confer a survival disadvantage in patients with melanoma, the survival of patients with CLL and melanoma is better in the CPI-era. We also demonstrate that in the CPI era the gap between the survival of patients with melanoma and CLL and melanoma alone is also reducing significantly.
Phoenix Cancer Support Network provides non-medical assistance to reduce disparities among cancer patients.
Authors: Glen J. Weiss, Adam R. Thompson, Kathryn M. Pastuszak, Samantha R. Torre, Jeanette S. Martin
Journal: Journal of Clinical Oncology (2021)

e18502 Background: Social determinants of health (SDOH) can lead to gaps in supportive care resources and services available to cancer patients. Established in 2017, Phoenix Cancer Support Network (PCSN) is a non-profit that endeavors to empower cancer patients (clients) throughout their cancer journey by providing support, guidance, and direction while promoting and protecting the unique needs, lifestyle, and abilities of each client and their caregivers. In this study, we investigate the non-medical needs of patients that engaged with PCSN for assistance and the increases in services provided over time. Methods: All patients that applied for and were eligible to receive assistance from PCSN were included. Eligibility requirements include patients primarily residing in Arizona and are receiving cancer therapy. Non-medical services offered included transportation, groceries and meals, housecleaning, other domestic services (e.g., child care or dog walking), financial support, and household goods. Summary statistics were conducted. Results: Between December 2017 and November 2020, 188 clients (117 were female) were offered assistance by PCSN. The median age was 58 (range 23-92). The number of clients assisted was 2 in 2017, 81 in 2018, 58 in 2019, and 38 in 2020. 145 clients had a solid tumor and 131 were actively undergoing cancer treatment when seeking PCSN assistance. Of 67 clients with available income data, 55 clients earned less than $25,000/year including 41 clients that were unemployed and 21 clients without insurance coverage. Most frequently requested services were transportation (49%), groceries and meals (41%), financial support (34%), housecleaning (26%), and other domestic services (10%). Of those requested services, PCSN was able to provide assistance for 76% of transportation, 62% of meal services, 79% of financial assistance, 50% of housecleaning, and 100% of other domestic services requested. Details of total expenditures for these services by year are depicted in the Table.Transportation service has been the largest expenditure overall, followed by other domestic services and groceries and meals. Conclusions: PCSN clients have needs that span multiple non-medical resources, reflecting potential sources of improvement in reducing disparities in the cancer community. At least 25% of clients requesting non-medical assistance reported annual income below $25,000/year. The amount of services provided has increased yearly, particularly transportation services. Additional study and follow-up to understand these service gaps and the impact of SDOH is warranted.[Table: see text]
Nicotinamide mononucleotide ameliorates senescence in alveolar epithelial cells
Authors: Tingting Fang, Jingyun Yang, Li Liu, Hengyi Xiao, Xiawei Wei
Journal: MedComm (2021)

Alveolar epithelial cells (ACEs) gradually senescent as aging, which is one of the main causes of respiratory defense and function decline. Investigating the mechanisms of ACE senescence is important for understanding how the human respiratory system works. NAD+ is reported to reduce during the aging process. Supplementing NAD+ intermediates can activate sirtuin deacylases (SIRT1-SIRT7), which regulates the benefits of exercise and dietary restriction, reduce the level of intracellular oxidative stress, and improve mitochondrial function, thereby reversing cell senescence. We showed that nicotinamide mononucleotide (NMN) could effectively mitigate age-associated physiological decline in the lung of 8-10 months old C57BL/6 mice and bleomycin-induced pulmonary fibrosis in young mice of 6-8 weeks. Besides, the treatment of primary ACEs with NMN can markedly ameliorate cell senescence phenotype in vitro. These findings to improve the respiratory system function and reduce the incidence and mortality from respiratory diseases in the elderly are of great significance.
Autoimmune Cytopenias in Patients with Chronic Lymphocytic Leukemia Treated with Ibrutinib in Routine Clinical Practice at an Academic Medical Center
Authors: Paul J. Hampel, Melissa C. Larson, Brian Kabat, Timothy G. Call, Wei Ding, Saad Sirop Kenderian, Michael Conte, Susan Marie Schwager, Jose F. Leis, Asher A. Chanan-Khan, Susan L Slager, Neil E. Kay, Kari G Chaffee, Tait D. Shanafelt, Sameer A. Parikh
Journal: Blood (2017)
EMBR-06. EFFECTIVE INHIBITION OF MYC-AMPLIFIFIED GROUP 3 MEDULLOBLASTOMA BY FACT-TARGETED CURAXIN DRUG CBL0137
Authors: Jiajia Wang, Jie Ma
Journal: Neuro-Oncology (2021)

Abstract Medulloblastoma (MB) is the most common malignant pediatric brain tumor that can be categorized into four major molecular subgroups. Group 3 MB with MYC amplifification (MYCamp-G3-MB) has been shown to be highly aggressive and exhibited worst prognosis, indicating the need for novel effective therapy most urgently. A few epigenetic targeted therapeutic strategies have recently been proven to effectively treat preclinical models of MYCamp-G3-MB, including BET inhibition, HDAC inhibition and SETD8 inhibition, unveiling a promising direction for further investigation. In this study, we carried out systemic bioinformatic analyses of public-available MB datasets as well as functional genomic screening datasets of primary MYCamp-G3-MB lines to search for other potential therapeutic targets within epigenetic modulators. We identifified SSRP1, a subunit of histone-chaperone FACT complex, to be the top drug target candidate as it is highly cancer-dependent in whole-genome CRISPR-Cas9 screening across multiple MYCamp-G3-MB lines; signifificantly upregulated in MYCamp-G3-MB compared to normal cerebellum and most of the rest MB subtypes; its higher expression is correlated with worse prognosis; and it has a blood-brain-barrier penetrable targeted drug that has entered early phase human clinical trials already. Then we utilized RNA-interference approach to verify the cancer-dependency of SSRP1 in multiple MYCamp-G3-MB lines and further confifirmed the therapeutic effificacy of FACT-targeted curaxin drug CBL0137 on treating preclinical models of MYCamp-G3-MB in vitro and in vivo, including an orthotopic intracranial xenograft model. Mechanistically, transcriptome analyses showed CBL0137 preferentially suppressed cell-cycle and DNA-repair related biological processes. Moreover, it selectively disrupted transcription of MYC and NEUROD1, two critical oncogenic transcription factors of MYCamp-G3-MB, via depleting FACT complex from their promoter regions. In summary, our study demonstrates FACT-targeted CBL0137 works effectively on treating MYCamp-G3-MB, presenting another promising epigenetic-targeted therapeutic strategy against the most devastating form of MB.
Overall survival and exploratory subgroup analyses from the phase 2 CodeBreaK 100 trial evaluating sotorasib in pretreated <i>KRAS</i> p.G12C mutated non-small cell lung cancer.
Authors: Ferdinandos Skoulidis, Bob T. Li, Ramaswamy Govindan, Grace K. Dy, Geoffrey Shapiro, Joshua Bauml, Martin H. Schuler, Alfredo Addeo, Terufumi Kato, Benjamin Besse, Abraham Anderson, Agnes Ang, Gataree Ngarmchamnanrith, Qui Tran, Vamsidhar Velcheti
Journal: Journal of Clinical Oncology (2021)

9003 Background: In the registrational phase 2 CodeBreaK 100 trial, sotorasib demonstrated an objective response rate (ORR) of 37.1% (95% Cl: 28.6, 46.2) and a median progression-free survival (PFS) of 6.8 months (95% Cl: 5.1, 8.2) in patients with pretreated KRAS p.G12C mutated non-small cell lung cancer (NSCLC). Tumor response was observed in patients bearing co-mutations in STK11, a driver of poor clinical outcomes with standard of care. Here, we report efficacy across an extended set of patient subgroups by key baseline characteristics and biomarkers. Methods: Sotorasib was given orally at 960 mg once daily to eligible patients who had advanced NSCLC harboring KRAS p.G12C and received prior standard therapies. Primary endpoint was ORR assessed by central review. Key secondary endpoints included PFS, overall survival, and safety. KRAS p.G12C mutant allele frequency (MAF) and tumor mutational burden (TMB) were analyzed by next-generation sequencing (NGS) using tissue samples. Mutational status of individual genes was determined by NGS using tissue and/or plasma samples. Correlations between response and KRAS p.G12C MAF, TMB, or co-mutations were analyzed in subsets of patients who had available respective results. Association between MAF and response was reported by odds ratio (95% CI), from a logistic regression with dependent variable of log odds of being a responder and an independent variable of MAF in a unit of 10%. Results: ORR across subgroups is presented in the Table. Response was independent of KRAS p.G12C MAF in the study population (odds ratio [95% CI]: 1.11 [0.88, 1.39]). OS remained immature. Conclusions: In the exploratory analyses of the phase 2 CodeBreaK 100 trial, the clinical benefit of sotorasib was observed across patient subgroups. Overall survival and updated exploratory analyses will be presented. Clinical trial information: NCT03600883. [Table: see text]