tbuckley/cabot-search huggingface dataset:
Efficacy and safety of avelumab plus axitinib (A + Ax) versus sunitinib (S) in elderly patients with advanced renal cell carcinoma (aRCC): Extended follow-up results from JAVELIN Renal 101.
Authors: Yoshihiko Tomita, Robert J. Motzer, Toni K. Choueiri, Brian I. Rini, Hideaki Miyake, Hirotsugu Uemura, Laurence Albiges, Yosuke Fujii, Yoshiko Umeyama, Jing Wang, Mariangela Mariani, Manuela Schmidinger
Journal: Journal of Clinical Oncology (2021)

301 Background: In the phase III JAVELIN Renal 101 trial (NCT02684006), A + Ax demonstrated significantly longer progression-free survival (PFS) and a higher objective response rate (ORR) vs S in patients with previously untreated aRCC. The role of immune checkpoint + VEGFR inhibition in elderly patients remains unclear. Here we report the efficacy of A + Ax vs S by age group from the second interim analysis (IA) of overall survival (OS) and the safety of A + Ax by age group from the first IA. Methods: Patients were randomized 1:1 to receive A 10 mg/kg intravenously every 2 wk + Ax 5 mg orally twice daily or S 50 mg orally once daily for 4 wk (6-wk cycle). PFS and ORR per independent central review (RECIST 1.1), OS, and safety by age group (&lt;65, ≥65 to &lt;75, and ≥75 y) were assessed. Results: A total of 271/138/33 and 275/128/41 patients in each age group (&lt;65, ≥65 to &lt;75, and ≥75 y, respectively) were randomized to the A + Ax or S arm, respectively. The proportion of IMDC risk groups was generally well balanced between the A + Ax and S arm in each age group, although in the ≥75 y age group, the frequency of patients with intermediate risk was slightly higher in the A + Ax arm, and that of patients with favorable risk was slightly higher in the S arm. The percentages of patients with favorable/intermediate/poor risk in each age group were 19%/61%/19%, 28%/58%/13%, and 12%/76%/12% in the A + Ax arm vs 20%/63%/16%, 23%/60%/16%, and 24%/61%/15% in the S arm. At data cut-off (Jan 2019) for the second IA, median follow-up for OS and PFS was 19.3 vs 19.2 mo and 16.8 vs 15.2 mo for the A + Ax vs S arm, respectively. The table shows OS, PFS, and ORR by age group. In the A + Ax arm, the most common treatment-emergent adverse events (AEs) were diarrhea (62%/68%/42%), hypertension (49%/49%/55%), palmar-plantar erythrodysesthesia syndrome (37%/31%/15%), fatigue (37%/53%/30%), and nausea (34%/37%/21%) in each age group. Grade ≥3 treatment-emergent AEs and immune-related AEs were observed in 69%/74%/73% and 39%/40%/24% of patients in each age group, respectively. Conclusions: A + Ax demonstrated favorable efficacy across age groups, including patients aged ≥75 y. OS was still immature; follow-up for the final analysis is ongoing. The safety profile was generally consistent between age groups. Clinical trial information: NCT02684006 . [Table: see text]
Real-world treatment patterns and sequencing for metastatic renal cell carcinoma (mRCC): Results from the Flatiron database.
Authors: Saby George, Jillian Faccone, Stephen Huo, Ying Zhang, Brian Stwalley, Melissa Hamilton, Trong Kim Le, Flavia Ejzykowicz
Journal: Journal of Clinical Oncology (2021)

286 Background: RCC accounts for ~80%‒90% of all kidney cancers worldwide. The mRCC treatment landscape is rapidly changing with the approval of new therapies; data describing real-world (RW) treatment patterns and sequencing are limited. This study investigates the characteristics, treatment patterns, and sequencing for mRCC patients in the RW (December 2015‒May 2020) and post-dual immuno-oncology therapy (IO-IO) approval in the United States (April 2018‒May 2020). Methods: Adults diagnosed with mRCC between December 2015 and May 2020 were selected from the Flatiron electronic medical record database for this retrospective study. The study cohort was required to have ≥ 1 month of medical data from the initial mRCC diagnosis date (index date). We used descriptive statistics to analyze baseline patient characteristics, treatment patterns, and sequencing. Results: Of 3,524 patients with mRCC (overall cohort, December 2015–May 2020), most were male (68.5%) and had clear cell histology (68.2%). The median age at metastatic diagnosis was 68 years (range, 23–85) and the median follow-up from index date was 328 days. Based on IMDC risk score, 75.8% of patients were categorized as intermediate/poor risk and 23.2% as favorable risk (1% missing). Systemic therapy for RCC was initiated in 79.1% (N = 2788) of patients. The most common treatments for first-line (1L) therapy were tyrosine kinase inhibitor (TKI) monotherapy (mono; 56.4%), IO-IO (19.1%), IO-TKI (9.5%), IO mono (6.9%), and others (8.1%). Second-line (2L) therapy was received by 1303 patients; treatment sequences are presented in the table below. Among patients who received IO-based therapy in the 1L (N = 990), 11% were retreated with IO on any subsequent line. When stratified by clear cell and non-clear cell histology, similar treatment patterns and sequences were observed. Among patients who initiated 1L treatment post-April 2018 (N = 1395), the most common treatments for 1L therapy were IO-IO (36.9%) and TKI mono (32.7%). Among patients who received 2L treatment after initiating 1L post-April 2018 (N = 486), TKI mono followed by IO mono, and IO-IO followed by TKI mono were the most prescribed sequences (Table). Conclusions: Following approval of IO-based therapies for 1L, RW treatment patterns for mRCC are evolving; IO-IO has become the most common 1L therapy received by all patients initiating treatment for mRCC. [Table: see text]
Anticancer effect of SN-38 on colon cancer cell lines with different metastatic potential
Authors: Asa Wallin, Xiao-Feng Sun, Joar Svanvik
Journal: Cancer Research (2005)

5321  SN-38 functions as an active metabolite of the topoisomerase-I (topo-I) inhibitor irinotecan. Mechanism behind its antitumor effect in colorectal cancer has not been fully understood. In this study, we examined response of the colon cancer cell lines with different metastatic potential to SN-38 (the active metabolite of irinotecan). The parental human colon cancer cell line KM12C and its two highly metastatic derivatives KM12SM and KM12L4a were cultivated in 5% CO2 at 37°C for 24 hours, and then exposed to SN-38 (2.5 μg/ml) at 37°C for 4, 24 and 48 hours, respectively. Cell cycle was measured by flow cytometry, apoptotic activity was determined by flow cytometry and immunocytochemistry, and expression of Topo 1, Bax and survivin proteins was examined by Western blot. Results show that the cells exposed to SN-38 induced S-phase and G2 arrest (P
Modelling the intervention effect of opioid agonist treatment on multiple mortality outcomes in people who inject drugs: a three-setting analysis
Authors: Jack Stone, Louisa Degenhardt, Jason Grebely, Sarah Larney, Frederick L Altice, Pavlo Smyrnov, Afarin Rahimi-Movaghar, Maryam Alavi, April M Young, Jennifer R Havens, William C Miller, Matthew Hickman, Peter Vickerman
Journal: The Lancet Psychiatry (2021)
Releasing the brakes of tumor immunity with anti-PD-L1 and pushing its accelerator with L19–IL2 cures poorly immunogenic tumors when combined with radiotherapy
Authors: Veronica Olivo Pimentel, Damiënne Marcus, Alexander MA van der Wiel, Natasja G Lieuwes, Rianne Biemans, Relinde IY Lieverse, Dario Neri, Jan Theys, Ala Yaromina, Ludwig J Dubois, Philippe Lambin
Journal: Journal for ImmunoTherapy of Cancer (2021)

Background Poorly immunogenic tumors are hardly responsive to immunotherapies such as immune checkpoint blockade (ICB) and are, therefore, a therapeutic challenge. Combination with other immunotherapies and/or immunogenic therapies, such as radiotherapy (RT), could make these tumors more immune responsive. We have previously shown that the immunocytokine L19–IL2 combined with single-dose RT resulted in 75% tumor remission and a 20% curative abscopal effect in the T cell-inflamed C51 colon carcinoma model. This treatment schedule was associated with the upregulation of inhibitory immune checkpoint (IC) molecules on tumor-infiltrating T cells, leading to only tumor growth delay in the poorly immunogenic Lewis lung carcinoma (LLC) model. Methods We aimed to trigger curative therapeutic responses in three tumor models (LLC, C51 and CT26) by “pushing the accelerator” of tumor immunity with L19–IL2 and/or “releasing the brakes” with ICB, such as antibodies directed against cytotoxic T lymphocyte associated protein 4 (CTLA-4), programmed death 1 (PD-1) or its ligand (PD-L1), combined with single-dose RT (10 Gy or 5 Gy). Primary tumor endpoint was defined as time to reach four times the size of tumor volume at start of treatment (4T×SV). Multivariate analysis of 4T×SV was performed using the Cox proportional hazards model comparing each treatment group with controls. Causal involvement of T and natural killer (NK) cells in the anti-tumor effect was assessed by in vivo depletion of T, NK or both cell populations. Immune profiling was performed using flow cytometry on single cell suspensions from spleens, bone marrow, tumors and blood. Results Combining RT, anti-PD-L1 and L19–IL2 cured 38% of LLC tumors, which was both CD8 + T and NK cell dependent. LLC tumors were resistant to RT +anti-PD-L1 likely explained by the upregulation of other IC molecules and increased T regulatory cell tumor infiltration. RT+L19–IL2 outperformed RT+ICB in C51 tumors; effects were comparable in CT26 tumors. Triple combinations were not superior to RT+L19–IL2 in both these models. Conclusions This study demonstrated that combinatorial strategies rationally designed on biological effects can turn immunotherapy-resistant tumors into immunologically responsive tumors. This hypothesis is currently being tested in the international multicentric randomized phase 2 trial: ImmunoSABR ( NCT03705403 ).
Abstract 17357: Direct Cardiac Reprogramming Using Combinatorial Modified mRNA
Authors: Keerat Kaur, Asharee Mahmoud, Hanna Girard, Ann Anu Kurian, Magdalena Zak, Elena Chepurko, Efrat Eliyahu, Roger Hajjar, Shahin Rafii, Lior Zangi
Journal: Circulation (2020)

Introduction: Despite various clinical modalities, ischemic heart disease remains among the leading causes of mortality and morbidity worldwide. The elemental problem is the immense loss of cardiomyocytes (CMs) post-myocardial infarction (MI). Reprogramming non- cardiomyocytes (non-CMs) into cardiomyocyte (CM)-like cells in vivo is a promising strategy for cardiac regeneration: however, the traditional viral delivery method hampered its application into clinical settings due to low and erratic transduction efficiency. Methods: We used a modified mRNA (modRNA) gene delivery platform to deliver different stoichiometry of cardiac-reprogramming genes (Gata4, Mef2c, Tbx5 and Hand2) together with reprogramming helper genes (Dominant Negative (DN)-TGFβ, DN- Wnt8a and Acid ceramidase (AC)), named 7G, to induce direct cardiac reprogramming post myocardial infarction (MI). Results: Here, we identified 7G modRNA cocktail as an important regulator ofthe cardiac reprogramming. Cardiac transfection with 7G modRNA doubled cardiac reprogramming efficiency (57%) in comparison to Gata4, Mef2C and Tbx5 (GMT) alone (28%) in vitro . By inducing MI in our lineage tracing model, we showed that one-time delivery of the 7G-modRNA cocktail reprogrammed ~25% of the non-CMs in the scar area to CM- like cells. Furthermore, 7G modRNA treated mice showed significantly improved cardiac function, longer survival, reduced scar size and greater capillary density than control mice 28 days post-MI. We attributed the improvement in heart function post modRNA delivery of 7G or 7G with increased Hand2 ratio (7G-GMT Hx2) to significant upregulation of 15 key angiogenic factors without any signs of angioma or edema. Conclusions: 7G or 7G GMT HX2 modRNA cocktails boosts de novo CM-like cells and promotes cardiovascular regeneration post-MI. Thus, we highlight that this gene delivery approach not only has high efficiency but also high margin of safety for translation to clinics.
The De-adoption of Low-Value Health Care—Reply
Authors: Brian W. Powers, Sachin H. Jain, William H. Shrank
Journal: JAMA (2021)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
COVID-19 impact on Surgical Training and Recovery Planning (COVID-STAR) - A cross-sectional observational study
Authors: Joshua Michael Clements, Josh Burke, Deirdre Nally, Mohamed Rabie, Elizabeth Kane, Emma Barlow, Walid Mohamed, Martin King, Liusaidh McClymont, Manish George, Sotonye Tolofari, Siobhan McKay, Ashan Jayasekera, Duncan Steele, Abdul Badran, Dominic Summers, Deena Harji, Gina Weston-Petrides, Omar Nasher, Benjamin Baker, Shaneel Patel, Raghuram Boyapati, Adam Peckham-Cooper, Anthony Bashyam, Matthew Stovell, Catherine Zhang, Rachel Thomas, Panchali Sarmah, Alexander Wilkins, Radhika Dua, Vimal Gokani, George Dovell, Sophie Rintoul-Hoad
Journal: International Journal of Surgery (2021)
Epicutaneous Staphylococcus aureus induces IL-36 to enhance IgE production and ensuing allergic disease
Authors: Garrett J. Patrick, Haiyun Liu, Martin P. Alphonse, Dustin A. Dikeman, Christine Youn, Jack C. Otterson, Yu Wang, Advaitaa Ravipati, Momina Mazhar, George Denny, Roger V. Ortines, Emily Zhang, Robert J. Miller, Carly A. Dillen, Qi Liu, Sabrina J. Nolan, Kristine Nguyen, LeeAnn Marcello, Danh C. Do, Eric M. Wier, Yan Zhang, Gary Caviness, Alexander C. Klimowicz, Diane V. Mierz, Jay S. Fine, Guangping Sun, Raphaela Goldbach-Mansky, Alina I. Marusina, Alexander A. Merleev, Emanual Maverakis, Luis A. Garza, Joshua D. Milner, Peisong Gao, Meera Ramanujam, Ernest L. Raymond, Nathan K. Archer, Lloyd S. Miller
Journal: Journal of Clinical Investigation (2021)

IgE induced by type 2 immune responses in atopic dermatitis is implicated in the progression of atopic dermatitis to other allergic diseases, including food allergies, allergic rhinitis, and asthma. However, the keratinocyte-derived signals that promote IgE and ensuing allergic diseases remain unclear. Herein, in a mouse model of atopic dermatitis-like skin inflammation induced by epicutaneous Staphylococcus aureus exposure, keratinocyte release of IL‑36α along with IL-4 triggered B cell IgE class-switching, plasma cell differentiation, and increased serum IgE levels-all of which were abrogated in IL-36R-deficient mice or anti-IL‑36R-blocking antibody-treated mice. Moreover, skin allergen sensitization during S. aureus epicutaneous exposure-induced IL-36 responses was required for the development of allergen-specific lung inflammation. In translating these findings, elevated IL‑36 cytokines in human atopic dermatitis skin and in IL‑36 receptor antagonist-deficiency patients coincided with increased serum IgE levels. Collectively, keratinocyte-initiated IL‑36 responses represent a key mechanism and potential therapeutic target against allergic diseases.
In chronic noncancer illness, palliative care reduces symptoms and health care use but does not improve QoL
Authors: Alicia Topoll, Robert Arnold
Journal: Annals of Internal Medicine (2021)

Source Citation Quinn KL, Shurrab M, Gitau K, et al. Association of receipt of palliative care interventions with health care use, quality of life, and symptom burden among adults with chronic noncancer illness: a systematic review and meta-analysis. JAMA. 2020;324:1439-50. 33048152
Randomized phase II trial of radium-223 (RA) plus enzalutamide (EZ) versus EZ alone in metastatic castration-refractory prostate cancer (mCRPC): Final efficacy and safety results.
Authors: Adam Kessel, Taylor Ryan McFarland, Nicolas Sayegh, Kathryn Morton, Deepika Sirohi, Manish Kohli, Umang Swami, Roberto Nussenzveig, Neeraj Agarwal, Benjamin Louis Maughan
Journal: Journal of Clinical Oncology (2021)

135 Background: We previously reported that treatment with EZ+RA was associated with a decline in serum bone metabolism markers (BMM), which correlated with improved outcomes compared to EZ alone (Agarwal N et al, Clinical Cancer Research, 2020, PMID 31937614). Here we report the final efficacy and safety results for this trial. Methods: In this phase 2 trial (NCT02199197), patients (pts) with progressive mCRPC were treated with EZ (160 mg daily) ±RA (standard dose of 55 kBq/kg IV Q4 weeks x 6), until disease progression or unacceptable toxicities. Primary objectives of change in bone markers and safety have been reported previously. Secondary objectives included comparison of PSA progression free survival (PFS), overall survival (OS), and long term safety in all pts receiving RA+EZ vs EZ alone. Post hoc analysis included comparison of PSA-PFS2 (defined as time from start of protocol therapy to PSA progression on subsequent therapy or death whichever occurred earlier), time to subsequent/next therapy (TTNT), and long term safety. Survival analysis and log-rank tests was performed using the R statistical package v.4.0.2 ( https://www.r-project.org ). Statistical significance was defined as P&lt;0.05. Results: Between 08/2014 and 11/2017, 47 pts were eligible and enrolled. Median follow up was 22 months (range 3.2-71.5). Thirty-five pts received RA+EZ and 12 pts received EZ alone. Receipt of prior abiraterone was allowed and was balanced between two groups: 60% in RA+EZ vs. 64% in EZ pts. Final efficacy results: TTNT, PSA-PFS2 were significantly improved in the RA+EZ pts over EZ alone pts, and all other efficacy parameters were numerically improved in RA+EZ pts (Table). Final safety results: none of the 12 EZ alone pts had any fracture; two of 35 RA+EZ pts were found to have incidental grade 1 asymptomatic fracture at the site of bone metastasis on routine imaging, at 15 and 31 months respectively after the last dose of RA, and did not require any intervention. No patients developed bone marrow disorders during the follow-up period. Efficacy and safety data will be elaborated during the meeting. Conclusions: In our study, EZ+RA resulted in significant long-term clinical benefit over EZ alone in pts with mCRPC without compromising safety. * NA&amp;BLM; equal contribution. Clinical trial information: NCT02199197. [Table: see text]
Osteonecrosis in Adults With Acute Lymphoblastic Leukemia: An Unmet Clinical Need
Authors: Michaela Kuhlen, Marina Kunstreich, Nicola Gökbuget
Journal: HemaSphere (2021)

Osteonecrosis is a serious complication of antileukemic therapy associated with severe pain and reduced mobility, ultimately leading to joint destruction and significant long-term morbidity. The 5-year cumulative incidence of osteonecrosis ranges from 11% to 20% in adolescents and young adults to 3% to 8% in patients aged 30 years and older. Most symptomatic patients have multiple joints affected, which in turn poses a risk factor for developing severe osteonecrosis. Osteonecrosis has a multifactorial genesis. Treatment-associated risk factors for developing osteonecrosis depend on the therapeutic context including the use of glucocorticosteroids and the simultaneous and/or intensified use of asparaginase (ASP) which may, among others, exert its effect on blood supply to the bone through hypertriglyceridemia, hypercholesterolemia, and hypertension. Allogeneic hematopoietic stem cell transplantation, bloodstream infections, and genetic factors may additionally impact the risk of osteonecrosis. In this article, the authors used the best available evidence in the literature to develop management recommendations for the use in the context of steroid and asparaginase containing regimens. These considerations may be helpful for similar treatment approaches.
Association Between Resident Duty Hours and Self-study Time Among Postgraduate Medical Residents in Japan
Authors: Kazuya Nagasaki, Yuji Nishizaki, Tomohiro Shinozaki, Hiroyuki Kobayashi, Yasuharu Tokuda
Journal: JAMA Network Open (2021)

This cross-sectional study uses information from the General Medicine In-Training Examination survey in Japan to assess the association between resident duty hours and self-study time.
Asthma-related sudden death in athletes: a retrospective analysis of the US NCCSIR database (1982–2018)
Authors: Oliver J. Price, Kristen L. Kucera, Hannah M. Price, Jonathan A. Drezner, Andrew Menzies-Gow, James H. Hull
Journal: European Respiratory Journal (2021)

<b>Asthma remains a rare but important cause of sudden death in young athletes. Approximately one athlete with asthma died per year, thus highlighting that with appropriate medical management, sports participation for people with asthma is generally safe.</b>https://bit.ly/3r9dE5t
Extracellular vesicles shed by follicular lymphoma B cells promote polarization of the bone marrow stromal cell niche
Authors: Erwan Dumontet, Céline Pangault, David Roulois, Matthis Desoteux, Simon Léonard, Tony Marchand, Maelle Latour, Patricia Legoix, Damarys Loew, Florent Dingli, Joelle Dulong, Erwan Flecher, Cédric Coulouarn, Guillaume Cartron, Thierry Fest, Karin Tarte
Journal: Blood (2021)
Genomic Alterations in <i>PIK3CA</i>-Mutated Breast Cancer Result in mTORC1 Activation and Limit the Sensitivity to PI3Kα Inhibitors
Authors: Yanyan Cai, Guotai Xu, Fan Wu, Flavia Michelini, Carmen Chan, Xuan Qu, Pier Selenica, Erik Ladewig, Pau Castel, Yuanming Cheng, Alison Zhao, Komal Jhaveri, Eneda Toska, Marta Jimenez, Alexandra Jacquet, Alicia Tran-Dien, Fabrice Andre, Sarat Chandarlapaty, Jorge S. Reis-Filho, Pedram Razavi, Maurizio Scaltriti
Journal: Cancer Research (2021)

Abstract PI3Kα inhibitors have shown clinical activity in PIK3CA-mutated estrogen receptor-positive (ER+) patients with breast cancer. Using whole genome CRISPR/Cas9 sgRNA knockout screens, we identified and validated several negative regulators of mTORC1 whose loss confers resistance to PI3Kα inhibition. Among the top candidates were TSC1, TSC2, TBC1D7, AKT1S1, STK11, MARK2, PDE7A, DEPDC5, NPRL2, NPRL3, C12orf66, SZT2, and ITFG2. Loss of these genes invariably results in sustained mTOR signaling under pharmacologic inhibition of the PI3K–AKT pathway. Moreover, resistance could be prevented or overcome by mTOR inhibition, confirming the causative role of sustained mTOR activity in limiting the sensitivity to PI3Kα inhibition. Cumulatively, genomic alterations affecting these genes are identified in about 15% of PIK3CA-mutated breast tumors and appear to be mutually exclusive. This study improves our understanding of the role of mTOR signaling restoration in leading to resistance to PI3Kα inhibition and proposes therapeutic strategies to prevent or revert this resistance. Significance: These findings show that genetic lesions of multiple negative regulators of mTORC1 could limit the efficacy of PI3Kα inhibitors in breast cancer, which may guide patient selection strategies for future clinical trials.