tbuckley/cabot-search huggingface dataset:
Final analysis results from TITAN: A phase III study of apalutamide (APA) versus placebo (PBO) in patients (pts) with metastatic castration-sensitive prostate cancer (mCSPC) receiving androgen deprivation therapy (ADT).
Authors: Kim N. Chi, Simon Chowdhury, Anders Bjartell, Byung Ha Chung, Andrea Juliana Pereira de Santana Gomes, Robert Given, Álvaro Juárez Soto, Axel Stuart Merseburger, Mustafa Ozguroglu, Hirotsugu Uemura, Dingwei Ye, Spyros Triantos, Suneel Mundle, Sharon Anne McCarthy, Julie S. Larsen, Weili Sun, Katherine Bevans, Ke Zhang, Nibedita Bandyopadhyay, Neeraj Agarwal
Journal: Journal of Clinical Oncology (2021)

11 Background: TITAN evaluated APA or PBO added to ADT in pts with mCSPC. Pts with high- and low-volume disease, prior docetaxel, prior treatment for localized disease, and prior ADT (≤ 6 mos) were eligible. At the first interim analysis, with 22.7 mos median follow-up, APA significantly improved dual primary end points of overall survival (OS) (hazard ratio [HR] 0.67) and radiographic progression-free survival (rPFS) (HR 0.48) compared with PBO (Chi et al. NEJM. 2019). At that time, OS analysis was first planned interim while rPFS was final. TITAN was unblinded, allowing pts without progression who were still receiving PBO to cross over to APA. Herein, we report the final analysis of efficacy and safety results from TITAN. Methods: 1052 mCSPC pts were randomized 1:1 to receive APA (240 mg QD) or PBO plus ADT. Time-to-event end points were analyzed by Kaplan-Meier method and Cox proportional hazards model. A preplanned sensitivity analysis for OS, accounting for crossover using inverse probability censoring weighted (IPCW) log-rank test, was conducted. No formal statistical retesting was performed; nominal p values were reported without multiplicity adjustment. Change from baseline in Functional Assessment of Cancer Therapy-Prostate (FACT-P) total score was assessed using a mixed-effect repeated-measures model. Results: With 44 mos median follow-up, 405 OS events had occurred. After unblinding, 208 PBO pts (39.5%) crossed over to APA. Median treatment duration was 39.3 mos for the APA group, 20.2 mos for the entire PBO group, and 15.4 mos for the PBO→APA crossover group. OS was superior in the APA group compared with the PBO group despite crossover (Table). 48-mo survival rates were 65% (APA) vs 52% (PBO). Other end points also favored APA vs PBO (Table). Health-related quality of life (HRQoL), per total FACT-P, was maintained in the APA group through the study and was not different from the PBO group. Safety was consistent with previous reports. Conclusions: With close to 4 yrs of follow-up, the final analysis of TITAN demonstrated that in a broad population of pts with mCSPC, APA plus ADT provides an improvement in OS with a 35% reduction in risk of death, which increased to 48% reduction after adjusting for pts who crossed over from PBO to APA. In addition, there was consistent benefit with APA in other end points, including delaying castration resistance, and HRQoL continued to be maintained with an acceptable safety profile. Clinical trial information: NCT02489318. [Table: see text]
BiTE-ing into Prostate Cancer with Bispecific T-cell Engagers
Authors: Nikhil V. Kamat, Evan Y. Yu, John K. Lee
Journal: Clinical Cancer Research (2021)

Abstract Targeting prostate-specific membrane antigen (PSMA) has important therapeutic ramifications, more recently including immune oncology. Data were recently presented on the preclinical efficacy of a half-life extended bispecific T-cell engager, AMG 160, which binds PSMA and CD3 to induce T-cell–driven cytolytic activity against prostate cancer. See related article by Deegen et al., p. 2928
Preventing the next pandemic: the power of a global viral surveillance network
Authors: Dennis Carroll, Subhash Morzaria, Sylvie Briand, Christine Kreuder Johnson, David Morens, Keith Sumption, Oyewale Tomori, Supaporn Wacharphaueasadee
Journal: BMJ (2021)

Dennis Carroll and colleagues call for a global early warning system to detect viruses with pandemic potential
Markers of cardiovascular risk and their reversibility with acute oxygen therapy in Kyrgyz highlanders with high altitude pulmonary hypertension
Authors: M. Furian, T.D. Latshang, S.S. Aeschbacher, U. Sheraliev, N.H. Marazhapov, E. Mirrakhimov, S. Ulrich, T.M. Sooronbaev, K.E. Bloch
Journal: Pulmonology (2021)

High altitude pulmonary hypertension (HAPH), a chronic altitude related illness, is associated with hypoxemia, dyspnea and reduced exercise performance. We evaluated ECG and pulse wave-derived markers of cardiovascular risk in highlanders with HAPH (HAPH+) in comparison to healthy highlanders (HH) and lowlanders (LL) and the effects of hyperoxia. We studied 34 HAPH+ and 54 HH at Aksay (3250 m), and 34 LL at Bishkek (760 m), Kyrgyzstan. Mean pulmonary artery pressure by echocardiography was mean ± SD 34 ± 3, 22 ± 5, 16 ± 4 mmHg, respectively (p < 0.05 all comparisons). During quiet rest, breathing room air or oxygen in randomized order, we measured heart-rate adjusted QT interval (QTc), an ECG-derived marker of increased cardiovascular mortality, and arterial stiffness index (SI), a marker of cardiovascular disease derived from pulse oximetry plethysmograms. Pulse oximetry in HAPH+, HH and LL was, mean ± SD, 88 ± 4, 92 ± 2 and 95 ± 2%, respectively (p < 0.05 vs HAPH+, both comparisons). QTc in HAPH+, HH and LL was 422 ± 24, 405 ± 27, 400 ± 28 ms (p < 0.05 HAPH+ vs. others); corresponding SI was 10.5 ± 1.9, 8.4 ± 2.6, 8.5 ± 2.0 m/s, heart rate was 75 ± 8, 68 ± 8, 70 ± 10 bpm (p < 0.05, corresponding comparisons HAPH+ vs. others). In regression analysis, HAPH+ was an independent predictor of increased QTc and SI when controlled for several confounders. Oxygen breathing increased SI in HH but not in HAPH+, and reduced QTc in all groups. Our data suggest that HAPH+ but not HH may be at increased risk of cardiovascular mortality and morbidity compared to LL. The lack of a further increase of the elevated SI during hyperoxia in HAPH+ may indicate dysfunctional control of vascular tone and/or remodelling.
Enhanced liposomal retention of irinotecan is correlated to increases in plasma irinotecan AUC and improved efficacy against a model of colorectal cancer
Authors: Euan Ramsay, Jehan Alnajim, Malathi Anantha, Hong Yan, Marcel Bally
Journal: Cancer Research (2005)

1393  Purpose: We have previously reported that irinotecan can be encapsulated into liposomes by generation of a secondary pH gradient following addition of the ionophore A23187 to liposomes with a pre-existing divalent metal ion gradient. A23187 exchanges divalent metal ions from the liposome interior for two protons from the external buffer thus generating a low internal pH. This environment maintains encapsulated irinotecan in the clinically active lactone form and can mediate significant gains in therapeutic effect when compared to unencapsulated irinotecan (Messerer et al., Clin. Cancer Res. 10:6638-49, 2004). In this study we sought to (i) further optimise the liposomal retention of irinotecan by use of interior solutions comprising transition metal ions at low pH and (ii) determine whether improved plasma retention of irinotecan by liposomes translates into increased therapeutic activity. Methods: Irinotecan was remote loaded into DSPC/Cholesterol liposomes comprising different internal solutions ± A23187: A (buffered Cu2+, pH 7.5), B (Cu2+, pH ∼ 3.5), C (Mn2+ + A23187) and D (Cu2+ + A23187). Mice were injected i.v. with a single treatment dose and the plasma concentrations of liposomal lipid and/or irinotecan were determined over time and used to calculate plasma irinotecan-to-lipid ratio (a measure of liposomal irinotecan retention), irinotecan area-under-the-curve (AUC) and mean residence time (MRT). The therapeutic efficacy of the treatments was investigated using a s.c. murine LS180 human colorectal cancer model. Results:  Conclusion: Encapsulation of irinotecan in DSPC/Cholesterol liposomes by a remote loading procedure employing Cu2+ and A23187 results in a liposome formulation with superior plasma irinotecan retention and AUC, and improved therapeutic activity against a murine model of human colorectal cancer.
The biological fate of the polymer nanocarrier material monomethoxy poly(ethylene glycol)-block-poly(d,l-lactic acid) in rat
Authors: Xiangjun Meng, Zhi Zhang, Jin Tong, Hui Sun, John Paul Fawcett, Jingkai Gu
Journal: Acta Pharmaceutica Sinica B (2021)

Monomethoxy poly(ethylene glycol)-block-poly(d,l-lactic acid) (PEG-PLA) is a typical amphiphilic di-block copolymer widely used as a nanoparticle carrier (nanocarrier) in drug delivery. Understanding the in vivo fate of PEG-PLA is required to evaluate its overall safety and promote the development of PEG-PLA-based nanocarrier drug delivery systems. However, acquiring such understanding is limited by the lack of a suitable analytical method for the bioassay of PEG-PLA. In this study, the pharmacokinetics, biodistribution, metabolism and excretion of PEG-PLA were investigated in rat after intravenous administration. The results show that unchanged PEG-PLA is mainly distributed to spleen, liver, and kidney before being eliminated in urine over 48 h mainly (>80%) in the form of its PEG metabolite. Our study provides a clear and comprehensive picture of the in vivo fate of PEG-PLA which we anticipate will facilitate the scientific design and safety evaluation of PEG-PLA-based nanocarrier drug delivery systems and thereby enhance their clinical development.
Evaluation of germline genetic testing criteria in early-onset kidney cancer.
Authors: Hong Truong, Rania Sheikh, Ritesh Kotecha, Yelena Kemel, Aliya Khurram, Peter Reisz, Andrew Thomas Lenis, Vijai Joseph, Diana Mandelker, Chung-Han Lee, Darren R. Feldman, Martin H Voss, Jonathan Coleman, Paul Russo, Zsofia Kinga Stadler, A. Ari Hakimi, Robert J. Motzer, Kenneth Offit, Sujata Patil, Maria Isabel Carlo
Journal: Journal of Clinical Oncology (2021)

296 Background: An estimated 5% of kidney cancers are associated with hereditary RCC syndromes. Current germline genetic testing guidelines for patients with kidney cancer were developed to identify carriers of known RCC-associated genes and have evolved in the panel-testing era. We evaluated the utility of the recent National Comprehensive Cancer Network (NCCN) recommendation of testing all patients with early-onset RCC (defined as age of diagnosis ≤ 46 years) for germline variants in genes implicated in hereditary RCC syndromes. Methods: We retrospectively identified patients with RCC diagnosed at age ≤ 46 years who underwent targeted germline testing at our institution through referral to clinical genetics service (n = 68, 29%) or through broad germline testing of ≥77 cancer susceptibility genes using next generation sequencing as part of a prospective matched tumor-normal genomic profiling initiative (n = 165, 71%). Diagnostic performance of referral criteria was assessed by the presence of pathogenic/likely pathogenic (P/LP) germline variants in RCC-associated genes and incidental cancer susceptibility genes. Results: Of 233 patients, 61% were male, 74% were Caucasian, 15% had family history of RCC, 15% had RCC-syndromic features, including 9% with multifocal renal tumors. Most patients (54%) had clear cell RCC (ccRCC). P/LP germline variants were identified in 42 (18%) patients but only 21 (9%) had mutations in RCC genes (12 FH, 4 VHL, 2 SDHB, 1 each in BAP1, TSC1, and FLCN). All 21 early-onset patients with germline variants in an RCC-associated gene also had one of the following risk factors: non-ccRCC histology, family history, or syndromic features. In 91 patients (39%) with a non-RCC germline variants or no alteration, none of these three risk factors were found. Of 21 patients with non-RCC P/LP germline variants, 9 had mutations in moderate/high penetrance genes ( BRCA1 [2], ATM [2], CHEK2 [1], TP53 [2] , PALB2 [1], and RET [1]); 8/9 (89%) met standard criteria for testing for those genes independent of early-onset RCC diagnosis. Conclusions: Patients with early-onset clear cell RCC and no suspicious personal or family history are unlikely to have an RCC-associated germline mutation. RCC-gene panel testing has highest utility in early-onset patients with either non-ccRCC histology, family history of RCC, or RCC-associated syndromic features. Given the high frequency of non-RCC P/LP variants, early-onset RCC patients should be counseled regarding broader testing beyond RCC-associated genes.
Stratification of Patients With Sjögren’s Syndrome and Patients With Systemic Lupus Erythematosus According to Two Shared Immune Cell Signatures, With Potential Therapeutic Implications
Authors: Lucia Martin‐Gutierrez, Junjie Peng, Nicolyn L. Thompson, George A. Robinson, Meena Naja, Hannah Peckham, WingHan Wu, Hajar J’bari, Nyarko Ahwireng, Kirsty E. Waddington, Claire M. Bradford, Giulia Varnier, Akash Gandhi, Rebecca Radmore, Vivek Gupta, David A. Isenberg, Elizabeth C. Jury, Coziana Ciurtin
Journal: Arthritis & Rheumatology (2021)

Similarities in the clinical and laboratory features of primary Sjögren's syndrome (SS) and systemic lupus erythematosus (SLE) have led to attempts to treat patients with primary SS or SLE with similar biologic therapeutics. However, the results of many clinical trials are disappointing, and no biologic treatments are licensed for use in primary SS, while only a few biologic agents are available to treat SLE patients whose disease has remained refractory to other treatments. With the aim of improving treatment selections, this study was undertaken to identify distinct immunologic signatures in patients with primary SS and patients with SLE, using a stratification approach based on immune cell endotypes.Immunophentyping of 29 immune cell subsets was performed using flow cytometry in peripheral blood from patients with primary SS (n = 45), patients with SLE (n = 29), and patients with secondary SS associated with SLE (SLE/SS) (n = 14), all of whom were considered to have low disease activity or be in clinical remission, and sex-matched healthy controls (n = 31). Data were analyzed using supervised machine learning (balanced random forest, sparse partial least squares discriminant analysis), logistic regression, and multiple t-tests. Patients were stratified by K-means clustering and clinical trajectory analysis.Patients with primary SS and patients with SLE had a similar immunologic architecture despite having different clinical presentations and prognoses. Stratification of the combined primary SS, SLE, and SLE/SS patient cohorts by K-means cluster analysis revealed 2 endotypes, characterized by distinct immune cell profiles spanning the diagnoses. A signature of 8 T cell subsets that distinctly differentiated the 2 endotypes with high accuracy (area under the curve 0.9979) was identified in logistic regression and machine learning models. In clinical trajectory analyses, the change in damage scores and disease activity levels from baseline to 5 years differed between the 2 endotypes.These findings identify an immune cell toolkit that may be useful for differentiating, with high accuracy, the immunologic profiles of patients with primary SS and patients with SLE as a way to achieve targeted therapeutic approaches.
Racism in patient care: a call to translate concerns into actions
Authors: Wen Hui Lim, Wilson Sim, Cheng Han Ng, Yip Han Chin, Clyve Leon, Dujeepa D Samarasekera, M Kamala Devi, Chin Meng Khoo, Choon Seng Chong
Journal: The Lancet Global Health (2021)

BackgroundRacial injustices in health care lead to poor health outcomes in minority groups. Such health inequality has been exacerbated in times of COVID-19 which has seen disproportionately high mortality in minority communities. The objective of the study was to better understand the nature of racial bias in clinical settings to inspire changes in the way healthcare providers interact with their patients to improve health outcomes.MethodsWe did systematic searches of four electronic databases:, Medline, CINAHL, PsycINFO and Web of Science using the search terms "Exp Racism/ and (Exp Health Personnel/ or Exp Attitude of Health Personnel/) and Exp Qualitative Research/" in the title and abstract to identify articles published in English between Dec 1, 1978, and June 25, 2020. Titles and abstracts were sieved, followed by a full text review. Data synthesis and inductive thematic analysis were conducted using the Thomas and Harden methodology.FindingsWe included 23 articles that reported data for 1006 participants aged 24 to 89 years. Included studies were from six countries, mostly the USA (n=15, 65%) and UK (3, 13%). Perspectives from both minority patients and health-care providers were included. Three themes were generated: alienation of minority patients, labelling of minority patients and denial of racism. Alienation of patients resulted from supremacism of healthcare providers who were condescending in their attitudes (11, 48%). Health-care providers were less empathetic, as evident from their cold dispositions and body language (14, 61%). Minority patients reported being subjected to labelling and generalisations about their lower socioeconomic class, lifestyle practices and needs, which led to inadequate treatment such as denial of drug therapy (12, 52%). Providers were also fearful of minorities because of negative assumptions and stereotypes (3, 13%). By contrast, some patients and providers denied the presence of racism in health care. Providers felt that they treated all patients equally (6, 26%). They suggested that minority patients were oversensitive and shifted blame onto lack of patient compliance, rather than racism, for poor health outcomes (6, 26%).InterpretationImplicit racial bias in patient-provider interactions is pervasive, thus exacerbating health disparities in minorities. Our findings serve as a call to action for health-care institutions to implement targeted anti-racism interventions such as diversity training, anti-racism forums and increased implicit bias education. We may have underestimated the extent of racism in health care since we included only articles published in English, thus missing relevant studies of minorities published in a language other than English. The strength of this article is that it includes perspectives about racism from not only patients from minority groups but also health-care providers.FundingNone.
7O Updated results from phase I study of CC-90011 in patients (pts) with solid tumours (STs), including neuroendocrine neoplasms (NENs), and relapsed/refractory non-Hodgkin lymphoma (R/R NHL)
Authors: A. Hollebecque, J.S. de Bono, S. Salvagni, R. Plummer, P. Niccoli, J. Capdevila, G. Curigliano, V. Moreno, F. De Braud, S. Gonzalez de Villambrosía, P. Martin-Romano, E. Baudin, M. Arias, J. De Alvaro, J. Parra-Palau, T. Sánchez-Pérez, I. Aronchik, E. Filvaroff, M. Lamba, Z. Nikolova
Journal: Annals of Oncology (2021)
Abstract 17442: Myocardial Damage Assessed by Late Gadolinium Enhancement on Cardiovascular Magnetic Resonance Imaging in Cancer Patients Treated With Anthracyclines and/or Trastuzumab
Authors: Kalpit Modi, Ko-hsuan Chen, Osama Okasha, Pratik Velangi, Matthew Hooks, Prabhjot S Nijjar, Anne Blaes, Chetan Shenoy
Journal: Circulation (2020)

Aims: In cancer patients with cardiomyopathy related to anthracyclines and/or trastuzumab, data on late gadolinium enhancement (LGE) on cardiovascular magnetic resonance imaging (CMR) are conflicting, with a prevalence of 0-100%. The patterns of LGE are also poorly described. We aimed to investigate these topics in a large cohort of consecutive cancer patients with suspected cardiotoxicity from anthracyclines and/or trastuzumab. Methods and Results: We studied 298 patients, analyzed the prevalence, patterns, and correlates of LGE, and identified their causes. We compared the findings with those from 100 age-matched cancer patients who received neither anthracyclines nor trastuzumab. Overall, 31 (10.4%) patients who received anthracyclines and/or trastuzumab had LGE. The LGE had widely varying extents (3.9-34.7%) and locations (all 17 left ventricular segments were involved). It was in an ischemic pattern in 20/31 (64.5%) patients. There was an alternative explanation for the non-ischemic LGE in 7/11 (63.6%) patients. In the patients who received neither anthracyclines nor trastuzumab, the prevalence of LGE was higher at 27.0%, while the extent of LGE and the proportion with ischemic LGE were not different. Conclusions: Treatment with anthracyclines and/or trastuzumab is unlikely to be associated with LGE because LGE was present in only a minority, the LGE did not fit into a single profile that could be attributed to cancer treatment-related cardiotoxicity, the LGE had alternative explanations in almost all cases, and LGE was also present in cancer patients who received neither anthracyclines nor trastuzumab. Absence of LGE can differentiate anthracycline- or trastuzumab-related cardiomyopathy from unrelated cardiomyopathies.
Corrigendum to “Viability of endothelial cells after ultrasound-mediated sonoporation: Influence of targeting, oscillation, and displacement of microbubbles” [Journal of Controlled Release 238 (2016) 197–211]
Authors: Tom van Rooij, Ilya Skachkov, Inés Beekers, Kirby R. Lattwein, Jason D. Voorneveld, Tom J.A. Kokhuis, Deep Bera, Ying Luan, Antonius F.W. van der Steen, Nico de Jong, Klazina Kooiman
Journal: Journal of Controlled Release (2021)