tbuckley/cabot-search huggingface dataset:
Melflufen plus dexamethasone (dex) in patients (pts) with relapsed/refractory multiple myeloma (RRMM) exposed/refractory to prior alkylators: A pooled analysis of the O-12-M1 and HORIZON studies.
Authors: Paula Rodríguez-Otero, Maria-Victoria Mateos, Albert Oriol, Alessandra Larocca, Joan Blade, Michele Cavo, Xavier Leleu, Omar Nadeem, John W. Hiemenz, Hani Hassoun, Cyrille Touzeau, Adrian Alegre, Agne Paner, Christopher Maisel, Amitabha Mazumder, Anastasios Raptis, Marcus Thuresson, Johan Harmenberg, Olof Harlin, Paul G. Richardson
Journal: Journal of Clinical Oncology (2021)

8048 Background: Melphalan flufenamide (melflufen) is a first-in-class peptide-drug conjugate (PDC) that leverages aminopeptidases and rapidly releases alkylating agents inside tumor cells. Melflufen has a mechanism of action distinct from other alkylating agents (Slipicevic et al. AACR 2020. Abs. 1843). In the O-12-M1 (NCT01897714) and HORIZON (OP-106; NCT02963493) studies, melflufen plus dex showed meaningful efficacy and a clinically manageable safety profile in pts with RRMM (Richardson et al. Lancet Haematol. 2020;7:5; Richardson et al. J Clin Oncol. 2020;Dec 9 [Epub]). This pooled analysis examines pts from these studies exposed to prior alkylators. Methods: Both the O-12-M1 and HORIZON studies included pts with RRMM who received ≥ 2 prior lines of therapy (LoTs) and had a primary endpoint of overall response rate (ORR). Secondary endpoints included progression-free survival (PFS) and safety. Data from the 2 studies were pooled and analyzed according to previous exposure and refractoriness to alkylators before study entry. Refractoriness to prior alkylator therapy was defined as disease that failed to achieve a minimal response or progressed while on therapy, or within 60 d of last therapy. Results: Of 202 pts (HORIZON: n = 157, cutoff January 14, 2020; O-12-M1: n = 45, cutoff October 29, 2019), 178 (88%) had been exposed to alkylators in ≥ 1 prior LoT (see Table for subgroups). Pts exposed and refractory to alkylators in ≥ 2 LoTs had the highest number of pts refractory to an alkylator in the last LoT (61%), and 82% were refractory to an alkylator within 12 mo of study entry. Meaningful response rates were seen in all subgroups, except for pts who were exposed and refractory to alkylators in ≥ 2 prior LoTs (see Table). PFS trended toward being shorter with higher exposure and refractoriness to prior alkylators. Results should be interpreted with caution due to limited pt numbers. Grade 3/4 adverse events (AEs) were similar between pts exposed to prior alkylators (O-12-M1: 85%; HORIZON: 89%) and the overall population (O-12-M1: 84%; HORIZON: 89%). The most common AEs were hematologic, but were mostly reversible and clinically manageable. Nonhematologic AEs were infrequent and primarily grade 1/2. Conclusions: Melflufen in combination with dex showed meaningful efficacy and a clinically manageable safety profile in pts with RRMM exposed/refractory to prior alkylators. Clinical trial information: NCT02963493 and NCT01897714. [Table: see text]
Safety and efficacy study of retifanlimab and epacadostat in combination with radiation and bevacizumab in patients with recurrent glioblastoma.
Authors: Jian Li Campian, Christopher Abraham, Jingqin Luo, Grayson Talcott, Ruth Katumba, Albert H Kim, Gavin P. Dunn, George Ansstas, Tanner Michael Johanns, Matthew A Ciorba, Milan G Chheda, Jiayi Huang
Journal: Journal of Clinical Oncology (2021)

TPS2070 Background: Recurrent glioblastoma (rGBM) after chemoradiotherapy has a dismal outcome with very limited treatment options. Addition of reirradiation to bevacizumab appears to improve progression-free survival (PFS) but does not improve overall survival (OS). Immune checkpoint inhibitors of programmed cell death-1 (PD-1) pathway appear to have limited single-agent activity for rGBM due to its immunesuppressive microenvironment. Indoleamine 2,3 dioxygenase 1 (IDO1) is an inducible and rate-limiting enzyme that catabolizes tryptophan (Trp) into kynurenine (Kyn). IDO1 is over-expressed in 50̃90% of GBM patients, and high IDO1 levels correlate with reduced OS. Epacadostat is a highly potent and selective oral inhibitor of IDO1 and may increase tumor sensitivity to anti-PD-1 blockade. Retifanlimab is a humanized anti-PD-1 monoclonal antibody directed against PD-1. The purpose of this study is to evaluate the safety and efficacy of combining retifanlimab plus or minus epacadostat with reirradiation and bevacizumab for rGBM patients. Methods: This is an open-label nonrandomized phase II study of two sequential cohorts for bevacizumab-naïve adults with rGBM: retifanlimab + bevacizumab+ radiation (cohort A), and retifanlimab + epacadostat + bevacizumab + radiation (cohort B). Each cohort will enroll 24 evaluable patients. Key eligibility criteria include candidates for reirradiation and bevacizumab, age ≥ 18 years, Karnofsky performance status ≥ 60%, and dexamethasone dose ≤ 4 mg/day. The primary endpoint is OS. Secondary endpoints include PFS, neurologic functions, and toxicity. The correlative endpoints include studies assess the anti-glioma immune response, serum Kyn/Trp ratio, and RNA expression of IDO1 and PD-L1 from available tissue. The trial is actively enrolling. At the time of abstract submission, 16 of the planned 24 patients in Cohort A have been enrolled. Clinical trial information: NCT03532295. [Table: see text]
Heterogeneity between core needle biopsy and synchronous axillary lymph node metastases in early breast cancer patients: Comparison of HER2, estrogen and progesterone receptor expression profiles during primary treatment regime.
Authors: Laura Weydandt, Ivonne Nel, Anne Kreklau, Lars-Christian Horn, Bahriye Aktas
Journal: Journal of Clinical Oncology (2021)

e12565 Background: Therapeutic decisions for the primary treatment of breast cancer is commonly based on the expression profiles of estrogen (ER), progesterone (PR) and the human epidermal growth factor 2 (HER2) receptors. However, breast cancer is a very heterogeneous disease, and receptor changes were manifold reported during progression. Little is known about receptor discordance in the primary setting. Here, we compared receptor expression profiles between core needle biopsy (CNB) of the breast tumor tissue and synchronous axillary lymph node metastases (LNM) not at recurrence, but at the primary treatment. Methods: In a German single center study, we retrospectively analyzed 175 breast cancer patients with axillary synchronous LNM. 69,7% of our patients were without any upfront therapy. Profiles of ER, PR and HER2 were immunohistochemically analyzed using the common cut-off at 10% positive tumor cells vs. the controversially discussed low-positive cut-off at 1%. Receptor status was compared between CNB specimens of the primary tumor tissue and axillary LNM. Further, clinicopathological characteristics were correlated to receptor changes. Results: The discordance rates between CNB and axillary LNM were 12.7% for HER2, 6.9% for ER and 22.6% for PR using the ≥1% cut-off, respective 7.5% for ER and 25.6% for PR when using the ≥10% cut-off-level. The most frequently occurring change was a PR loss. Analysis of clinical parameters revealed a significant association of ER change between CNB and LNM in younger patients (p &lt; 0.01) with increased proliferation marker Ki-67 (p = 0.04). Conclusions: Receptor discordance between CNB and synchronous axillary LNM appears to exist at the primary setting already. Hence, receptor profiles of the tumor tissue and the synchronous axillary LNM should be considered for treatment decision.
Retrospective real-world comparison of clinical and economic burden between first-generation and second-generation tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia (CML).
Authors: T. Alexander Smith, Sumit Verma, Yi Liu, Slaven Sikirica, Nora Anita Janjan
Journal: Journal of Clinical Oncology (2021)

e19030 Background: TKIs are the standard of care for the treatment of chronic phase CML under National Comprehensive Cancer Network (NCCN) guidelines. Imatinib is recommended as a first-generation TKI (1GTKI), and bosutinib, dasatinib, nilotinib, and ponatinib are recommended as second-generation TKIs (2GTKIs). TKIs are associated with high healthcare resource utilization (HRU) and costs, although literature is limited comparing 1GTKI and 2GTKIs in a U.S. population. Methods: Using the Veteran’s Health Administration (VHA) database between April 1, 2013 and March 31, 2018, the study included patients aged ≥18 years with ≥1 medical claim for CML and ≥1 prescription claim for a TKI on or after the initial CML diagnosis date during the identification period (October 1, 2014 to September 30, 2017); the first TKI prescription claim was defined as the index date. Inverse probability of treatment weighting (IPTW) minimized potential confounding; included variables were age, race, Quan-Charlson Comorbidity Index (CCI) score, and CHA2DS2-VASc Score. Medication possession ratio (MPR) assessed adherence to index TKI; optimal adherence was defined as MPR ≥80%. Results: 944 patients were included: 78.9% on 1GTKI and 21.1% on 2GTKI. Mean age was 62.21 years (SD:18.8); 77.2% were white. At baselinetients on 1GTKI had a higher comorbidity burden than 2GTKIs: COPD (19.7% vs. 8%; p &lt; 0.01), anemia (17.7% vs. 11.1%; p = 0.02), GI symptoms (28.5% vs. 18.6%; p &lt; 0.01), cardiac dysrhythmias (15.6% vs. 7.5%; p &lt; 0.01), coronary artery disease (26.3% vs. 13.6%; p &lt; 0.01), hypertension (55.7% vs. 43.2%; p &lt; 0.01) and CHA2DS2-VASc Score (2.2 vs 1.6; p &lt; 0.01). Optimal adherence was higher with 1GTKI (69.6% vs. 62.2%; p = 0.04), although this was not statistically significant when mean MPR was compared. During follow-up, no difference between 1GTKI and 2GTKIs patients occurred with cardiac-related risk factors or CHA2DS2-VASc Score. Compared to 1GTKI, 2GTKIs had lower medical (inpatient and outpatient) costs ($3,162 vs. $3,906; p = 0.04) but higher all-cause pharmacy cost ($7,214 vs. $3,895; p &lt; 0.01) due to imatinib becoming a generic drug during the study period. CML-related ($2,260 vs. $1,640, p &lt; 0.01) and cardiac-related medical costs ($1,365 vs. $665, p &lt; 0.01) were significantly higher in 1GTKI vs. 2GTKIs patients. Conclusions: Adherence to TKI therapy was suboptimal for both 1GTKI and 2GTKIs. 2GTKIs incurred lower medical cost in comparison to 1GTKI. Differences in total all-cause cost was primarily driven by pharmacy cost of TKIs. These results show that, beyond the cost of the TKI, using a 2GTKIs in the first-line can lead to cost offsets when compared to imatinib.
RARE-07. EFFICACY AND SAFETY OF LAROTRECTINIB IN PEDIATRIC PATIENTS WITH TROPOMYOSIN RECEPTOR KINASE (TRK) FUSION-POSITIVE PRIMARY CENTRAL NERVOUS SYSTEM (CNS) TUMORS
Authors: Sébastien Perreault, François Doz, Birgit Geoerger, Karsten Nysom, Ingrid Øra, Valentina Boni, Julia Chisholm, Steven G DuBois, Nicolas U Gerber, Hiroaki Goto, Juneko E Grilley-Olson, Jordan R Hansford, Hyoung Jin Kang, Michael Capra, Johannes H Schulte, Joanna Stefanowicz, Makoto Tahara, David S Ziegler, Ricarda Norenberg, Laura Dima, Esther De La Cuesta, Theodore W Laetsch, Cornelis M van Tilburg
Journal: Neuro-Oncology (2021)

Abstract Background NTRK gene fusions are oncogenic drivers in various CNS and non-CNS tumors. Larotrectinib is a highly selective TRK inhibitor approved to treat patients with TRK fusion cancer, with an objective response rate (ORR) of 78% across multiple non-CNS cancers (McDermott et al, ESMO 2020). We report updated data on pediatric patients with TRK fusion-positive primary CNS tumors. Methods Patients aged &amp;lt;18 years with primary CNS tumors harboring an NTRK gene fusion enrolled in two clinical trials (NCT02637687, NCT02576431) were identified. Larotrectinib was administered until disease progression, withdrawal, or unacceptable toxicity. Response was investigator assessed. Results By July 2020, 26 pediatric patients with TRK fusion-positive CNS tumors were treated. Tumor histologic subtypes included high-grade glioma (n=13), low-grade glioma (n=7), glioneuronal tumor (n=2), neuroepithelial tumor (n=2), CNS neuroblastoma (n=1), and small round blue cell tumor (n=1). Median age was 7.0 years (range 1.3–16.7). The ORR was 38% (95% CI 20–59%): 3 complete responses, 7 partial responses (including 2 pending confirmation), 14 stable disease, and 2 progressive disease. The ORR in patients with high-grade glioma was 38% (95% CI 14–68%). Nineteen of 21 patients (90%) with measurable disease had tumor shrinkage. The 24-week disease control rate was 77% (95% CI 56–91%). Median duration of response (DoR), PFS and overall survival (OS) were not reached. The 12-month rates for DoR, PFS and OS were 75%, 65%, and 86%, respectively. Duration of treatment ranged from 1.2 to 31.3+ months. Treatment-related adverse events were reported for 15 patients (58%) and were Grade 3–4 in 3 patients (12%), with no discontinuations related to larotrectinib. Conclusions In pediatric patients with TRK fusion-positive CNS tumors, larotrectinib demonstrated durable responses, high disease control rate, and good tolerability. These results support testing for NTRK gene fusions in pediatric patients with CNS tumors.
Real-world quality of life (QoL) in black, indigenous and people of color (BIPOC) treated with palbociclib (PAL) and endocrine therapy for hormone receptor–positive (HR+)/human epidermal growth factor receptor 2–negative (HER2–) advanced breast cancer (ABC): A subgroup analysis from POLARIS.
Authors: Gabrielle Betty Rocque, Joanne Lorraine Blum, Aldemar Montero, Meghan Sri Karuturi, Kenneth Manning, Lloyd Shabazz, Christopher Gallagher, Lara Zuberi, Joseph C Cappelleri, Marc Drucker, Yao Wang, Debu Tripathy
Journal: Journal of Clinical Oncology (2021)

1071 Background: Racial disparities in breast cancer incidence, mortality, and care are well documented. PAL plus endocrine therapy is indicated for patients (pts) with HR+/HER2− ABC. Findings from the PALOMA clinical trials have shown that pts receiving PAL maintained stable QoL; however, limited QoL data are available from real-world settings for BIPOC receiving PAL. Methods: POLARIS is a noninterventional, prospective, primarily US-based study in pts with HR+/HER2– ABC receiving PAL. QoL was assessed with the European Organisation for Research and Treatment of Cancer Quality-of-Life Questionnaire Core 30 (EORTC QLQ-C30) at baseline, monthly for the first 3 mo of treatment (Tx) with PAL, and then every 3 mo. In this interim analysis, we report Tx patterns and QoL assessments at baseline and at 6 mo and 12 mo in BIPOC from POLARIS. Results: Of 1280 pts treated with PAL as November 10, 2020, 233 were included in the BIPOC subgroup of whom 159 (68.2%) completed PAL Tx for ≥6 mo and 112 (48.1%) for ≥12 mo. In the BIPOC cohort, 59.2% of pts were black, 35.2% Hispanic, 3.4% American Indian or Alaskan native, 2.1% Pacific Islander. PAL in combination with letrozole/anastrozole was received by 116 pts, 94 received PAL plus fulvestrant, 13 received PAL plus exemestane, and 10 received PAL plus another Tx; 175 pts (75.1%) received PAL as first-line Tx. Mean EORTC QLQ-C30 global health QoL and functional scales scores remained stable over the first 12 mo of PAL Tx, without any changes at or above the 10-point threshold considered clinically meaningful, and were similar to those previously reported in an earlier analysis of the entire POLARIS population (Table and Rocque et al SABCS 2019). Symptom scales scores, including nausea and vomiting, pain, dyspnea, insomnia, appetite loss, constipation, and diarrhea, also remained stable over 12 mo. Conclusions: In this subgroup analysis, PAL had no significant adverse impact on QOL in BIPOC with HR+/HER2– ABC, consistent with previous findings from the total POLARIS study population. Pfizer (NCT03280303). Clinical trial information: NCT03280303 .[Table: see text]
The role of social determinants on overall survival in advanced-stage non-small cell lung cancer patients.
Authors: Andreas Bello, Neeharika Srivastava Makani
Journal: Journal of Clinical Oncology (2021)

e21117 Background: Non-small cell lung cancer (NSCLC) is the most prevalent form of lung cancer. Many studies have evaluated the association of social determinants with outcomes in early-stage NSCLC. These studies have shown statistically and clinically significant associations between overall survival (OS) and other social factors (e.g marital status, educational attainment). The aim of our study was to better understand the role of various social determinants of health (SDH) on OS in advanced-stage NSCLC patients in a community oncology practice in Florida. Methods: In this retrospective study, 125 patients with stage III and IV NSCLC were recruited between January 1st, 2014 until December 31st, 2018. We performed both categorical and continuous analyses (Pearson’s chi-square and Kruskal-Wallis test, respectively) to evaluate the association between median OS and several independent variables, including; gender, race, marital status, insurance status, living status, receiving financial assistance (FA), alcohol use, and smoking histories. OS is defined as the date of diagnosis up to the date of death. Other confounders that were analyzed included histology, treatment modality, comorbidities, and performance status of the patients. Results: Of the total study population (n = 125), 60% identified as male with a mean age of 73 years for the study population. The majority of patients (89%) identified as white; 56% were married, and 81% lived with someone. 66% of patients had an HMO insurance plan, and 51% of patients obtained FA to help with treatment care costs. 47% of patients identified as former smokers and 54% denied any alcohol use. The median OS for the patient population was 0.756 years. Chi-square analyses revealed that patients who received FA were more likely to live longer than median OS as opposed to patients that did not receive FA (OR = 2.41, 95% CI [1.18, 4.96], p = 0.050). Kruskal-Wallis analyses demonstrated that patients receiving FA had nearly a two-fold increase in median OS compared to patients without financial assistance (median OS = 1.01 years vs. 0.545 years, respectively; p = 0.013). However, other social determinants evaluated did not have a significant impact on relative OS in advanced-stage NSCLC. Conclusions: Ultimately, our study concludes that receiving FA has a significant association with increased OS in advanced-stage NSCLC patients. This study highlights the importance of reducing the financial burden of advanced-stage NSCLC patients and how FA impacts patient outcomes. Future prospective cohort studies with a larger sample size are warranted to identify other SDH, as well as the underlying mechanisms affecting median OS, in patients with advanced-stage NSCLC.
Racial Diversity Among American Cardiologists: Implications for the Past, Present, and Future
Authors: Amber E. Johnson, Mehret Birru Talabi, Eliana Bonifacino, Alison J. Culyba, Esa M. Davis, Paula K. Davis, Laura M. De Castro, Utibe R. Essien, Alda Maria Gonzaga, MaCalus V. Hogan, Alaina J. James, Charles R. Jonassaint, Naudia L. Jonassaint, Loreta Matheo, Melonie A. Nance, G. Sarah Napoé, Oladipupo Olafiranye, Sylvia Owusu-Ansah, Tomar N. Pierson-Brown, A.J. Conrad Smith, Tomeka L. Suber, Orquidia Torres, Rickquel Tripp, Eloho Ufomata, J. Deanna Wilson, Jeannette E. South-Paul
Journal: Circulation (2021)

In the United States, race-based disparities in cardiovascular disease care have proven to be pervasive, deadly, and expensive. African American/Black, Hispanic/Latinx, and Native/Indigenous American individuals are at an increased risk of cardiovascular disease and are less likely to receive high-quality, evidence-based medical care as compared with their White American counterparts. Although the United States population is diverse, the cardiovascular workforce that provides its much-needed care lacks diversity. The available data show that care provided by physicians from racially diverse backgrounds is associated with better quality, both for minoritized patients and for majority patients. Not only is cardiovascular workforce diversity associated with improvements in health care quality, but racial diversity among academic teams and research scientists is linked with research quality. We outline documented barriers to achieving workforce diversity and suggest evidence-based strategies to overcome these barriers. Key strategies to enhance racial diversity in cardiology include improving recruitment and retention of racially diverse members of the cardiology workforce and focusing on cardiovascular health equity for patients. This review draws attention to academic institutions, but the implications should be considered relevant for nonacademic and community settings as well.
Survey on Main Drive Methods Used in Humanoid Robotic Upper Limbs
Authors: Yiwei Wang, Wenyang Li, Shunta Togo, Hiroshi Yokoi, Yinlai Jiang
Journal: Cyborg and Bionic Systems (2021)

Humanoid robotic upper limbs including the robotic hand and robotic arm are widely studied as the important parts of a humanoid robot. A robotic upper limb with light weight and high output can perform more tasks. The drive system is one of the main factors affecting the weight and output of the robotic upper limb, and therefore, the main purpose of this study is to compare and analyze the effects of the different drive methods on the overall structure. In this paper, we first introduce the advantages and disadvantages of the main drive methods such as tendon, gear, link, fluid (hydraulic and pneumatic), belt, chain, and screw drives. The design of the drive system is an essential factor to allow the humanoid robotic upper limb to exhibit the structural features and functions of the human upper limb. Therefore, the specific applications of each drive method on the humanoid robotic limbs are illustrated and briefly analyzed. Meanwhile, we compared the differences in the weight and payload (or grasping force) of the robotic hands and robotic arms with different drive methods. The results showed that the tendon drive system is easier to achieve light weight due to its simple structure, while the gear drive system can achieve a larger torque ratio, which results in a larger output torque. Further, the weight of the actuator accounts for a larger proportion of the total weight, and a reasonable external placement of the actuator is also beneficial to achieve light weight.
TMBIM1 is an inhibitor of adipogenesis and its depletion promotes adipocyte hyperplasia and improves obesity-related metabolic disease
Authors: Guang-Nian Zhao, Zheng-Wei Tian, Tian Tian, Zhi-Peng Zhu, Wen-Jie Zhao, Han Tian, Xu Cheng, Feng-Jiao Hu, Man-Li Hu, Song Tian, Ting Ding, Siping Chen, Yan-Xiao Ji, Peng Zhang, Xiao-Jing Zhang, Zhi-Gang She, Yufeng Yuan, Wenping Chen, Lan Bai, Hongliang Li
Journal: Cell Metabolism (2021)