tbuckley/cabot-search huggingface dataset:
An umbrella study of biomarker-driven targeted therapy in patients with platinum-resistant recurrent ovarian cancer (KGOG 3045, AMBITION).
Authors: JUNG-YUN LEE, Byoung-Gie Kim, Jae-Weon Kim, Jung Bok Lee, Eunhyang Park, Sung Hoon Kim, Chel Hun Choi, Hee Seung Kim
Journal: Journal of Clinical Oncology (2021)

5520 Background: Heavily treated platinum-resistant ovarian cancer remains a therapeutic challenge. Although standard therapy includes non-platinum single agent chemotherapy (CT), prognoses are very poor in this setting. Anticancer therapies based on molecular biomarkers have improved dramatically. We report data from an umbrella study of biomarker-driven targeted therapy (olaparib, O; cediranib, C; durvalumab, D; tremelimumab, T) in platinum-resistant recurrent ovarian cancer (NCT03699449). Methods: Patients with platinum-resistant ovarian cancer with ≥ two lines of prior chemotherapy and ECOG 0/1 were eligible for this study. In the screening phase, archival tumor samples were tested for HRD and PD-L1 status. Treatment arms were allocated according to the test results. For HRD+ patients, we tested the synergistic effects of O with other agents: patients were randomly allocated to arm 1, O+C (O 200mg bid + C 30mg qd); or arm 2, O+D (O 300mg bid + D 1500mg q4w). For HRD- patients, we tested the role of biomarker-driven immunotherapy according to PD-L1 expression: arm 3, D+CT (D 1500mg q4w + PLD or topotecan or weekly paclitaxel [6 cycles]) in patients with high PD-L1 expression; arm 4, D+T75+CT (D 1500mg q4w + T 75mg q4w [4 doses] + PLD or topotecan or weekly paclitaxel [4 cycles]) in patients with low PD-L1 expression; or arm 5, D+T300+CT (D 1500mg q4w + T 300mg [1 dose] + weekly paclitaxel [60mg/m 2 D1,8,15 q4w for 4 cycles]) in patients with low PD-L1 expression. Recruitment to arm 5 was initiated after completion in arm 4. The primary endpoint was objective response rates (ORR) according to RECIST 1.1. Results: Between Dec 2018 and Oct 2020, 70 patients were allocated to treatment as follows: arm 1 (n = 16), arm 2 (n = 14), arm 3 (n = 5), arm 4 (n = 18), and arm 5 (n = 17). Median age was 57 years (range 34-77) and median prior lines of treatment was 3 (range: 2-10). Among all patients, the ORR was 35.7% (25/70, 95% CI: 24.6%-48.0%); complete response was observed in two patients. The ORRs (95% CI) for each treatment arm were shown (Table). Treatment-related grade 3/4 adverse events were reported in 37.5%, 35.7%, 20%, 66.7%, and 35.3% of patients in each treatment arm, respectively. No treatment-related adverse events (TRAEs) leading to discontinuation of treatment and no grade 5 TRAEs were observed. Conclusions: This is the first biomarker-driven umbrella study conducted in patients with platinum-resistant recurrent ovarian cancer. This umbrella study provides preliminary evidence on the clinical benefit of biomarker-driven targeted therapy. All regimens were manageable, without unexpected toxicities. Clinical trial information: NCT03699449. [Table: see text]
Ruxolitinib for refractory large granular lymphocyte leukemia
Authors: Aline Moignet, Cédric Pastoret, Guillaume Cartron, Paul Coppo, Thierry Lamy
Journal: American Journal of Hematology (2021)

from teaching and research institutions in France or abroad, or from public or private research centers.L'archive ouverte pluridisciplinaire HAL, est destinée au dépôt et à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.
Patient-reported efficacy and toxicity in CAR T-cell therapy for multiple myeloma via Internet-based platforms.
Authors: Nathan W. Sweeney, Eduardo Franco Hernandez, Nolan Cole, Scott Ryan Goldsmith, Zachary Crees, Jenny Ahlstrom
Journal: Journal of Clinical Oncology (2021)

e20024 Background: Chimeric antigen receptor (CAR) T-cell therapies are in clinical development for multiple myeloma (MM). Patient-reported outcomes (PRO) can provide valuable insights into how patients perceive the relative risks and benefits of these new therapies. This study aimed to evaluate CAR T-cell therapy in relapsed/refractory MM (RRMM) patients. Methods: We utilized HealthTree Cure Hub for Multiple Myeloma to analyze patient-reported data from 17 patients who participated in CAR T-cell clinical trials. In this study, we examined total prior lines of therapy, time to next treatment (TNT), overall survival (OS), patient-reported toxicity and severity, and patient-reported outcomes (myeloma reduction or no myeloma reduction). The Kaplan-Meier model was used to calculate overall survival. The severity of toxicity was assessed using a 1 to 10 scale (1 = minimal and 10 = severe). Results: Our analysis of the 17 patients found a median of 10 lines of therapy prior to CAR T-cell treatment. Ten patients had no new treatments to report at the time of this study, 5 patients reported new treatment with a median TNT of 15.9 months, and for 2 patients we did not have data. The median OS was 24 months (95% CI 21-30 months). The probability that a patient remained alive at 2 years was 0.48 (95% CI: 0.195, 1). Four of the 17 patients died with a median of 22.5 months post-CAR T-cell therapy. Two of these patients died without reporting a change in treatment. There was a total of 36 different side effects reported by patients as a result of the therapy. Table lists the side effects experienced by 2 or more patients and the corresponding average severity. Finally, 76% of patients treated with CAR T-cell therapy reported a reduction in their myeloma, four of these patients had m-protein levels reported and saw an average decrease of 93%. Of the remaining patients, three (18%) reported little to no reduction in their myeloma, and one patient (6%) did not know their response at the time of this analysis. Conclusions: Our investigation of patient-reported results suggests an emerging and viable immunotherapy treatment option for RRMM, with encouraging outcomes and manageable side effects. Future directions include analysis of genetics and treatment options post CAR T-cell therapy. These data highlight the expedited benefit of using PROs via an online platform, like HealthTree Cure Hub, to assess new therapeutics in the research community.[Table: see text]
Plasma from patients with bacterial sepsis or severe COVID-19 induces suppressive myeloid cell production from hematopoietic progenitors in vitro
Authors: Miguel Reyes, Michael R. Filbin, Roby P. Bhattacharyya, Abraham Sonny, Arnav Mehta, Kianna Billman, Kyle R. Kays, Mayra Pinilla-Vera, Maura E. Benson, Lisa A. Cosimi, Deborah T. Hung, Bruce D. Levy, Alexandra-Chloe Villani, Moshe Sade-Feldman, Rebecca M. Baron, Marcia B. Goldberg, Paul C. Blainey, Nir Hacohen
Journal: Science Translational Medicine (2021)

Bacterial sepsis and severe COVID-19 share similar clinical manifestations and are both associated with dysregulation of the myeloid cell compartment. We previously reported an expanded CD14
Abstract MP85: Lifestyle and Biologic Factors and Risk for Recurrent Coronary Heart Disease Events
Authors: John N Booth, Emily B Levitan, Todd M Brown, Michael Farkouh, Monika Safford, Paul Muntner
Journal: Circulation (2013)

The 2011 American Heart Association guidelines recommend lifestyle modification and risk factor management for secondary coronary heart disease (CHD) prevention. We determined the association of lifestyle behaviors and clinical management risk factors with recurrent CHD events among participants with electrocardiographic evidence or self-reported CHD history from the REasons for Geographic and Racial Differences in Stroke (REGARDS) study (n=30,239). Ideal health factors (normal waist circumference, physical activity ≥4 times/week, DASH diet adherence, not smoking, systolic/diastolic blood pressure (BP) &lt; 120 / 80 mmHg and LDL-cholesterol (LDL-C) &lt; 70 mg/dL) were assessed through questionnaires and an in home study visit. Of the 4,174 REGARDS participants with CHD history, the mean age was 68.8 (SD=8.9) years, 35.1% were women and 34.1% were black. Over a median follow up of 4.3 (maximum=6.9) years, 447 (10.7%) participants had a nonfatal or fatal recurrent CHD event. After adjustment for demographics, clinical factors, and co-morbid conditions, participating in physical activity ≥4 times/week versus no activity and not smoking versus current smoking were associated with a reduced risk for recurrent CHD events (hazard ratio [95% confidence interval] 0.48 (0.34-0.68) and 0.45 (0.35-0.56), respectively). In contrast, DASH diet consistency, normal waist circumference, LDL-C and normal BP were not associated with statistically significant reductions in risk for recurrent CHD events. More ideal health factors were associated with a lower risk for recurrent CHD events (Figure). The hazard ratio for each additional ideal health factor was 0.76 (95% CI: 0.69-0.84). If these observations are causal, then if all people with established CHD participated in physical activity 4+ times/week and did not smoke, 40.5% (95% CI: 11.0-63.4) of recurrent CHD events could be avoided. This analysis suggests that secondary prevention to lower the risk of recurrent CHD events should emphasize physical activity and smoking cessation.
Bioelectrical impedance analysis-guided fluid management promotes primary fascial closure after open abdomen: a randomized controlled trial
Authors: Kai Wang, Shi-Long Sun, Xin-Yu Wang, Cheng-Nan Chu, Ze-Hua Duan, Chao Yang, Bao-Chen Liu, Wei-Wei Ding, Wei-Qin Li, Jie-Shou Li
Journal: Military Medical Research (2021)

Fluid overload (FO) after resuscitation is frequent and contributes to adverse outcomes among postinjury open abdomen (OA) patients. Bioelectrical impedance analysis (BIA) is a promising tool for monitoring fluid status and FO. Therefore, we sought to investigate the efficacy of BIA-directed fluid resuscitation among OA patients. A pragmatic, prospective, randomized, observer-blind, single-center trial was performed for all trauma patients requiring OA between January 2013 and December 2017 to a national referral center. A total of 140 postinjury OA patients were randomly assigned in a 1:1 ratio to receive either a BIA-directed fluid resuscitation (BIA) protocol that included fluid administration with monitoring of hemodynamic parameters and different degrees of interventions to achieve a negative fluid balance targeting the hydration level (HL) measured by BIA or a traditional fluid resuscitation (TRD) in which clinicians determined the fluid resuscitation regimen according to traditional parameters during 30 days of ICU management. The primary outcome was the 30-day primary fascial closure (PFC) rate. The secondary outcomes included the time to PFC, postoperative 7-day cumulative fluid balance (CFB) and adverse events within 30 days after OA. The Kaplan-Meier method and the log-rank test were utilized for PFC after OA. A generalized linear regression model for the time to PFC and CFB was built. A total of 134 patients completed the trial (BIA, n = 66; TRD, n = 68). The BIA patients were significantly more likely to achieve PFC than the TRD patients (83.33% vs. 55.88%, P < 0.001). In the BIA group, the time to PFC occurred earlier than that of the TRD group by an average of 3.66 days (P < 0.001). Additionally, the BIA group showed a lower postoperative 7-day CFB by an average of 6632.80 ml (P < 0.001) and fewer complications. Among postinjury OA patients in the ICU, the use of BIA-guided fluid resuscitation resulted in a higher PFC rate and fewer severe complications than the traditional fluid resuscitation strategy.
Loss of <i>Yap/Taz</i> in cardiac fibroblasts attenuates adverse remodelling and improves cardiac function
Authors: Masum M Mia, Dasan Mary Cibi, Siti Aishah Binte Abdul Ghani, Anamika Singh, Nicole Tee, Viswanathan Sivakumar, Hanumakumar Bogireddi, Stuart A Cook, Junhao Mao, Manvendra K Singh
Journal: Cardiovascular Research (2021)

Fibrosis is associated with all forms of adult cardiac diseases including myocardial infarction (MI). In response to MI, the heart undergoes ventricular remodelling that leads to fibrotic scar due to excessive deposition of extracellular matrix mostly produced by myofibroblasts. The structural and mechanical properties of the fibrotic scar are critical determinants of heart function. Yes-associated protein (Yap) and transcriptional coactivator with PDZ-binding motif (Taz) are the key effectors of the Hippo signalling pathway and are crucial for cardiomyocyte proliferation during cardiac development and regeneration. However, their role in cardiac fibroblasts, regulating post-MI fibrotic and fibroinflammatory response, is not well established.Using mouse model, we demonstrate that Yap/Taz are activated in cardiac fibroblasts after MI and fibroblasts-specific deletion of Yap/Taz using Col1a2Cre(ER)T mice reduces post-MI fibrotic and fibroinflammatory response and improves cardiac function. Consistently, Yap overexpression elevated post-MI fibrotic response. Gene expression profiling shows significant downregulation of several cytokines involved in post-MI cardiac remodelling. Furthermore, Yap/Taz directly regulate the promoter activity of pro-fibrotic cytokine interleukin-33 (IL33) in cardiac fibroblasts. Blocking of IL33 receptor ST2 using the neutralizing antibody abrogates the Yap-induced pro-fibrotic response in cardiac fibroblasts. We demonstrate that the altered fibroinflammatory programme not only affects the nature of cardiac fibroblasts but also the polarization as well as infiltration of macrophages in the infarcted hearts. Furthermore, we demonstrate that Yap/Taz act downstream of both Wnt and TGFβ signalling pathways in regulating cardiac fibroblasts activation and fibroinflammatory response.We demonstrate that Yap/Taz play an important role in controlling MI-induced cardiac fibrosis by modulating fibroblasts proliferation, transdifferentiation into myofibroblasts, and fibroinflammatory programme.
Real-world evidence of cancer immunotherapy (CIT) combination treatment in first-line (1L) extensive-stage small cell lung cancer (ES-SCLC).
Authors: Eric S. Nadler, Anupama Vasudevan, Kalatu Davies, Yunfei Wang, Ann Johnson, Sarika Ogale
Journal: Journal of Clinical Oncology (2021)

8561 Background: Atezolizumab plus chemotherapy was the first CIT combination regimen approved for 1L treatment of ES-SCLC in 2019. This study investigated patient characteristics and treatment patterns for patients with ES-SCLC receiving this regimen in the real-world community oncology setting. Methods: This was a retrospective study including adult patients diagnosed with ES-SCLC between 01-Oct-2018 (after IMpower 133 publication in NEJM Sep-2018) and 31-Dec-2019, with follow-up through 31-March-2020 using The US Oncology Network electronic health records data. Descriptive analyses of patient characteristics and treatment patterns were conducted, with Kaplan-Meier (K-M) methods used to assess time to treatment discontinuation (TTD) and time to next treatment/death (TTNT). Results: Of the 408 patients included in this study, 267 (71.4%) received atezo+carboplatin+etoposide (Atezo+Chemo), 80 (21.4%) received carboplatin+etoposide (Chemo only) and the rest received other regimens. The Atezo+Chemo patients in the real-world cohort compared with the IMpower 133 trial (n = 201) were older (median age 68 vs. 64 years) and included fewer males (45% vs. 64%), fewer white race (73% vs. 81%), more patients with brain metastases at baseline (23% vs. 9%), and more patients with worse ECOG (2/3) performance-status score (24% vs. 0%). The median follow-up, TTD, and TTNT in months (mo) for the real-world cohort are presented in the table alongside the best comparable measures reported for the trial. Conclusions: Most patients in this real-world ES-SCLC cohort received the Atezo+Chemo regimen in the 1L setting. While the follow-up was much shorter and patients had worse baseline characteristics (age, brain metastases, ECOG) in the real-world setting compared to the IMpower 133 trial, the real-world median TTD in this descriptive analysis was found to be in line with the median duration of treatment in the trial. Further research with longer follow-up comparing the real-world effectiveness of the CIT and chemo regimens is needed.[Table: see text]
Mouse Lymphoma Model-Based Senescence Exploitation to Predict Treatment Outcome of DLBCL Patients
Authors: Kolja Schleich, Julia Kase, Jan R. Dörr, Saskia Trescher, Animesh Battacharya, Yong Yu, Philipp Lohneis, Dido Lenze, Dorothy Ngo-Yin Fan, Michael Hummel, Ulf Leser, Clemens A. Schmitt
Journal: Blood (2017)
Baseline neutrophil-to-lymphocyte ratio and absolute lymphocyte count in patients with HER2-negative breast cancer treated with eribulin may predict overall survival.
Authors: Shigeto Maeda, Keisei Anan, Kenichiro Koga, Sayaka Kuba, Hiroshi Yano, Yuichiro Kai, Reiki Nishimura, Uhi Toh, Miki Yamaguchi, Kohjiro Mashino, Shoshu Mitsuyama, Kazuo Tamura, Toshihiro Tanaka, Hirotaka Iwase
Journal: Journal of Clinical Oncology (2021)

e13005 Background: In Japan, eribulin has been approved for inoperative or recurrent breast cancer, following treatment with an anthracyclines and a taxanes. We reported the efficacy and safety of eribulin as a first-line to third-line treatment in patients with advanced/metastatic breast cancer (MBC) previously treated with anthracylinsanthracyclines and taxanes (Breast 2017). Briefly, the main inclusion criteria were as follows: no history of eribulin administration; an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 to 2,; human epidermal growth factor receptor 2 (HER2)-negative,; 20–75 years; ≥4 weeks from the last dose of chemotherapy, or ≥2 weeks from the last dosing of endocrine or radiation therapy; measurable lesion based on Response Evaluation Criteria in Solid Tumors (RECIST) ver. 1.1; sufficient organ function; life expectancy of ≥3 months; and no significant abnormalities on electrocardiogram. Patients in this clinical trial were enrolled between December 1, 2011, and November 30, 2013. Eribulin was administered intravenously at a dose of 1.4 mg/m2 during a 2-5 min infusion on days 1 and 8 every 3 weeks. In contrast, baseline neutrophil-to-lymphocyte ratio (NLR) and absolute lymphocyte count (ALC) were reported to predict progression-free survival (PFS) or overall survival (OS). However, these reports were mainly retrospective analysis. Therefore, retrospective evaluation of NLR/ALC in a prospective clinical trial is important to understand the association between NLR/ALC and OS/PFS. Methods: Of 47 prospectively enrolled patients in a previous trial, 45 patients were retrospectively evaluated for baseline NLR/ACL and at the time of 3 cycles of eribulin. The association between NLR/ALC and OS/PFS was also were analyzed for association with OS/PFS. The Kaplan-Meier method was used to estimate the OS/PFS distribution. The cut-off values for baseline NLR and ALC were set at 3 and 1500 /ul, respectively. Results: The median OS of patients with a baseline NLR &lt; 3 was significantly longer than that of patients with a baseline NLR ≥ ≧3 (769 days vs. 409 days; log-rank test p = 0.0333). The median OS of patients with a baseline ALC ≥ ≧1500 was also significantly longer than that of patients with a baseline ALC &lt; 1500 (964 days vs.vs 427 days; log-rank test p = 0.0425). Association between baseline NLR/ALC and PFS were not seen, and also association between at the time of 3 cycles of NLR/ALC and OS/PFS were not seen neither. Conclusions: Baseline NLR and ALC in the patients with HER2- negative breast cancer who plan to treat eribulin may predict overall survival. Clinical trial information: UMIN000007121.
EMBR-04. BET INHIBITION TARGETS RADIOTHERAPY RESISTANCE IN H3K27ME3-DEFICIENT GROUP 3 MEDULLOBLASTOMA
Authors: Nishanth Gabriel, Kumaresh Balaji, Matthew Inkman, Kay Jayachandran, Jin Zhang, Sonika Dahiya, Michael Goldstein
Journal: Neuro-Oncology (2021)

Abstract Medulloblastoma has been categorized into four subgroups based on genetic, epigenetic and transcriptional profiling. However, molecular pathways determining radiotherapy response in this tumor remain elusive. Here, we investigated the role of the EZH2-dependent histone H3K27 tri-methylation in radiotherapy response in medulloblastoma. We demonstrate that 47.2% of group 3 and 4 medulloblastoma patients have H3K27me3-deficient tumors. Loss of H3K27me3 was associated with a radioresistant phenotype, high relapse rates and poor overall survival. We show that an epigenetic switch from H3K27me3 to H3K27ac occurs at specific genomic loci in H3K27me3-deficient medulloblastoma cells altering the transcriptional profile. The resulting up-regulation of EPHA2 (ephrin type-A receptor 2) stimulates an excessive activation of the pro-survival AKT signaling pathway leading to radiotherapy resistance. We show that BET inhibition targets radiation resistance in H3K27me3-deficient medulloblastoma by suppressing H3K27ac levels, blunting EPHA2 overexpression and mitigating the excessive AKT signaling. Additionally, BET inhibition sensitizes medulloblastoma cells to radiation by enhancing apoptotic response through suppression of Bcl-XL and up-regulation of Bim expression. Our work demonstrates a novel mechanism of radiation resistance in medulloblastoma and identifies an epigenetic marker predictive of radiotherapy response. Based on these findings we propose an epigenetically guided treatment approach targeting radiotherapy resistance in medulloblastoma patients.
Living with the enemy: from protein-misfolding pathologies we know, to those we want to know
Authors: Abdul-Hamid Emwas, Mawadda Alghrably, Manel Dhahri, Abeer Sharfalddin, Rawiah Alsiary, Mariusz Jaremko, Gavino Faa, Marcello Campagna, Terenzio Congiu, Monica Piras, Marco Piludu, Giuseppina Pichiri, Pierpaolo Coni, Joanna Izabela Lachowicz
Journal: Ageing Research Reviews (2021)

Conformational diseases are caused by the aggregation of misfolded proteins. The risk for such pathologies develops years before clinical symptoms appear, and is higher in people with alpha-1 antitrypsin (AAT) polymorphisms. Thousands of people with alpha-1 antitrypsin deficiency (AATD) are underdiagnosed. Enemy-aggregating proteins may reside in these underdiagnosed AATD patients for many years before a pathology for AATD fully develops. In this perspective review, we hypothesize that the AAT protein could exert a new and previously unconsidered biological effect as an endogenous metal ion chelator that plays a significant role in essential metal ion homeostasis. In this respect, AAT polymorphism may cause an imbalance of metal ions, which could be correlated with the aggregation of amylin, tau, amyloid beta, and alpha synuclein proteins in type 2 diabetes mellitus (T2DM), Alzheimer's and Parkinson's diseases, respectively.