tbuckley/cabot-search huggingface dataset:
Treatment duration and response of advanced renal cell carcinoma (aRCC) patients (pts) who have completed first-line (1L) treatment (tx): Results from a cross-sectional real-world study.
Authors: Giovanni Zanotti, Ruth Kim, Stan Krulewicz, Jennifer P. Hall, Andrea Leith, Abigail Bailey, Frank Xiaoqing Liu, Mairead Kearney
Journal: Journal of Clinical Oncology (2020)

643 Background: In 2019, there was an estimated 73,820 new cases of kidney cancers in the US. The tx landscape for aRCC is changing rapidly. Recently approved txs for 1L aRCC include new targeted agents and immuno-oncology (IO) therapies. We examine outcomes for pts who completed 1L tx. Methods: Real-world data were drawn from the RCC Disease Specific Programme; a cross-sectional survey administered to US oncologists, nephrologists and urologists. Physicians completed pt record forms (PRFs) for up to the next 8 consulting aRCC pts receiving drug tx, from February - September 2019, plus additional optional PRFs for pts receiving/who had received either 1L tx of nivolumab/ipilimumab combination or cabozantinib, where these pts were available. Results: Physicians (n=82) provided data on 687 pts; 230 had progressed from 1L tx and were on 2L tx at time of data collection. Of those receiving 2L tx, 61% male; mean age was 66.4 years (SD=11.0); 43% stage IV at diagnosis. At 1L, 72% (n=165) had received tyrosine kinase inhibitor (TKI) monotherapy; 16% (n=37) IO+IO, 3% (n=7) TKI+IO and 9% (n=20) other regimens. Mean 1L duration was 10.3 months (SD=9.4) and mean time to 2L initiation was 13.7 months (SD=21.1). 1L treatment responses were: 6% complete response, 21% partial response, 16% stable disease, and the remainder relapsed/progressed (44%) or unknown response (13%). Most common 2L regimens were TKI (37%) or IO (34%) monotherapy. 47% of 1L TKI monotherapy pts received 2L IO monotherapy. 86% of 1L IO+IO pts received 2L TKI monotherapy. Conclusions: Some pts with aRCC progress to 2L; many experience poor clinical outcomes with 1L txs, highlighting high unmet need in 1L for more efficacious txs. Optimal tx strategy (and sequencing) continues to evolve. Approval of IO+TKI therapies, approved during the fieldwork period, has broadened the therapeutic landscape for 1L aRCC. Whilst the proportion of 1L pts receiving IO+TKI therapies is still low, the adoption of these in 1L is likely to transform the management of aRCC. Further research is needed to determine the optimum tx sequence in these pts with high unmet need.
Activation of Estrogen Receptor G Protein–Coupled Receptor 30 Enhances Cholesterol Cholelithogenesis in Female Mice
Authors: Helen H. Wang, Ornella de Bari, Christopher K. Arnatt, Min Liu, Piero Portincasa, David Q.‐H. Wang
Journal: Hepatology (2020)

Background and Aims Estrogen is an important risk factor for cholesterol gallstone disease because women are twice as likely as men to form gallstones. The classical estrogen receptor α (ERα), but not ERβ, in the liver plays a critical role in the formation of estrogen‐induced gallstones in female mice. The molecular mechanisms underlying the lithogenic effect of estrogen on gallstone formation have become more complicated with the identification of G protein–coupled receptor 30 (GPR30), an estrogen receptor. Approach and Results We investigated the biliary and gallstone phenotypes in ovariectomized female GPR30 −/− , ERα −/− , and wild‐type mice injected intramuscularly with the potent GPR30‐selective agonist G‐1 at 0 or 1 μg/day and fed a lithogenic diet for 8 weeks. The activation of GPR30 by G‐1 enhanced cholelithogenesis by suppressing expression of cholesterol 7α‐hydroxylase, the rate‐limiting enzyme for the classical pathway of bile salt synthesis. These metabolic abnormalities led to an increase in biliary cholesterol concentrations in company with hepatic hyposecretion of biliary bile salts, thereby inducing cholesterol‐supersaturated gallbladder bile and accelerating cholesterol crystallization. G‐1 also impairs gallbladder emptying, leading to sluggish gallbladder motility and promoting the development of biliary sludge in the early stage of gallstone formation. The prevalence rates of gallstones were 80% in wild‐type and ERα −/− mice treated with G‐1 compared to 10% in wild‐type mice receiving no G‐1. However, no gallstones were formed in GPR30 −/− mice treated with G‐1. Conclusions GPR30 produces additional lithogenic actions, working independently of ERα, to increase susceptible to gallstone formation in female mice; both GPR30 and ERα are potential therapeutic targets for cholesterol gallstone disease, particularly in women and patients exposed to high levels of estrogen.
Re: Ola Bratt, Erik Holmberg, Ove Andrén, et al. The Value of an Extensive Transrectal Repeat Biopsy with Anterior Sampling in Men on Active Surveillance for Low-risk Prostate Cancer: A Comparison from the Randomised Study of Active Monitoring in Sweden (SAMS). Eur Urol 2019;76:461–6
Authors: Francesco Montorsi, Giorgio Gandaglia, Nicola Fossati, Andrea Salonia, Alberto Briganti
Journal: European Urology (2020)
Corrigendum re “Extracorporeal Shock Wave Therapy for the Treatment of Chronic Pelvic Pain Syndrome in Males: A Randomised, Double-Blind, Placebo-Controlled Study” [Eur Urol 2009;56:418–24]
Authors: Reinhold Zimmermann, Alin Cumpanas, Florin Miclea, Günter Janetschek
Journal: European Urology (2020)
The impact of surgical resection on circulating tumor-reactive cytotoxic T cells for patients with renal tumors.
Authors: Vignesh T. Packiam, Bimal Bhindi, Henan Zhang, Christine M. Lohse, Paras H. Shah, Matvey Tsivian, Lance C. Pagliaro, Brian Addis Costello, R. Houston Thompson, Stephen A. Boorjian, John Cheville, Haidong Dong, Bradley C. Leibovich
Journal: Journal of Clinical Oncology (2020)

725 Background: The impact of surgical resection of renal tumors on peripheral immune related cells is not well characterized, and has potential implications as biomarkers for systemic immune therapy are being developed. We sought to assess the effect of surgical resection on circulating cytotoxic T-cells (CTLs) for patients with renal tumors. Methods: We prospectively enrolled 40 patients undergoing partial, radical, or cytoreductive nephrectomy (PN, RN, CN) for unilateral primary renal tumors between 2016 and 2018. Blood draws were performed pre-op, 1 day post-op, and 3 months post-op. Flow cytometry was performed on peripheral blood mononuclear cells (PBMCs). The % of PBMCs expressing CD11a/CD8 (CTLs) were assessed. The % of CTLs expressing PD-1, Bim (a downstream PD-1 pathway pro-apoptotic mediator), CX3CR1/GZMB (an effector memory T-cell phenotype), and Ki67 (a proliferation marker) were assessed. Median changes in % of CTLs were evaluated with the Wilcoxon signed rank test. Comparisons between aggressive (pT3-4, N1, M1, or aggressive histology (high-grade, coagulative necrosis, sarcomatoid dedifferentiation, or specific RCC-variant histologies)) versus indolent tumors were assessed using the Wilcoxon rank sum test. Results: Twenty, 12, and 8 patients underwent RN, PN, and CN, respectively. Thirty, 7, and 3 patients had clear-cell RCC, non-clear cell RCC, and oncocytoma, respectively. Twenty-three and 17 patients had aggressive and indolent tumors, respectively. While there was no significant change at 1 day, by 3 months there were significantly increased CTLs among PBMCs (+1.3%; p=0.004). There was significant decrease in CX3CR1+GZMB+ CTLs (-2.9%; p&lt;0.001) and significant increase in Bim+ CTLs (+3.0%; p=0.03) at 1 day but not 3 months. Interestingly, Ki67+ CTLs increased at day 1 (+0.6%; p&lt;0.001) but decreased by 3 months (-0.6%; p=0.001). There were no significant changes in PD-1+ CTLs at either time point. There were no significant changes in any CTL characteristics at 1 day or 3 months between aggressive and indolent tumors. Conclusions: These findings characterize changing CTL profiles over time with surgical resection of renal tumors which may help guide biomarker development.
A Slice of FPIES (food protein-induced enterocolitis syndrome): Insights on demographics, risk factors, foods avoided, and management from 441 children with FPIES
Authors: Lisa Bartnikas, Michelle Maciag, Scott Sicherer, Linda Herbert, Michael Young, Fallon Matney, Amity Westcott-Chavez, Carter Petty, Wanda Phipatanakul, Theresa Bingemann
Journal: Journal of Allergy and Clinical Immunology (2020)
Abstract 15733: Comparison of Efficacy and Safety Between Direct Oral Anticoagulant and Warfarin in Patients With Chronic Thromboembolic Pulmonary Hypertension
Authors: Hiroya Hayashi, Akihiro Tsuji, Jin Ueda, Shigefumi Fukui, Takeshi Ogo, Satoshi Yasuda
Journal: Circulation (2018)

Introduction: Oral vitamin K antagonists such as warfarin has been used as an anticoagulation for chronic thromboembolic pulmonary hypertension (CTEPH) to prevent in situ pulmonary artery thrombosi...
Evaluation of brain metastasis in JAVELIN Renal 101: Efficacy of avelumab + axitinib (A+Ax) versus sunitinib (S).
Authors: Eric Jonasch, Elshad Hasanov, Robert J. Motzer, Subramanian Hariharan, Toni K. Choueiri, Bo Huang, John B. A. G. Haanen, Laurence Albiges, Balaji Venugopal, Manuela Schmidinger, James M. G. Larkin, Marc-Oliver Grimm, Sylvie Negrier, Jing Wang, Mariangela Mariani, Aleksander Chudnovsky, Alessandra di Pietro, Brian I. Rini
Journal: Journal of Clinical Oncology (2020)

687 Background: Patients (pts) with brain metastasis from renal cell carcinoma (RCC) have poor prognosis and are often excluded from randomized registrational trials. The phase 3 JAVELIN Renal 101 trial (NCT02684006) demonstrated significantly improved progression-free survival (PFS) for A+Ax vs S in pts with advanced RCC (Motzer NEJM 2019). The activity of A+Ax in pts with brain metastasis enrolled in JAVELIN Renal 101 is presented. Methods: PFS was compared between treatment arms for the subgroup of pts randomized in JAVELIN Renal 101 with brain metastases at enrollment (pts with brain disease site prior to randomization by blinded independent central review [BICR] or by investigator assessment). PFS time was summarized per BICR assessment by treatment arm using the Kaplan-Meier method. The Cox proportional hazards model was fitted to compute the hazard ratio (HR) and the corresponding CI. In addition, time to brain metastasis was assessed for pts without brain metastasis by BICR at enrollment after treating death as a competing risk. Results: Of all randomized pts (A+Ax arm, N=442; S, N=444), 23 in each arm (5.2%) had asymptomatic brain metastasis at enrollment; of these, pts assigned to A+Ax had a PFS of 4.9 mo (95% CI: 1.6, 5.7) vs 2.8 mo (95% CI: 2.3, 5.6) for pts assigned to S (HR: 0.90; 95% CI: 0.43, 1.88). Among pts without brain metastasis at enrollment, 8 pts on the A+Ax arm and 10 on the S arm developed brain metastasis during the trial, based on BICR assessment; 17/18 occurred ≤12 mo from randomization. The cumulative incidence rate of brain metastasis at 18 mo was 2% (95% CI: 0.6, 3.3) for the A+Ax arm and 3% (95% CI: 1.1, 4.8) for the S arm. Conclusions: In this post hoc exploratory analysis of JAVELIN Renal 101, the observed PFS among pts with brain metastasis at enrollment was similar between the two arms, with HR and median PFS numerically favoring A+Ax. Pts on the S arm had a numerically higher incidence of new brain metastases on trial. Outcomes are poor in pts with advanced RCC and brain metastasis; more effective treatments are needed. Clinical trial information: NCT02684006.
Single residue in CD28-costimulated CAR-T cells limits long-term persistence and antitumor durability
Authors: Sonia Guedan, Aviv Madar, Victoria Casado-Medrano, Carolyn Shaw, Anna Wing, Fang Liu, Regina M. Young, Carl H. June, Avery D. Posey
Journal: Journal of Clinical Investigation (2020)

Chimeric antigen receptor-T (CAR-T) cell therapies can eliminate relapsed and refractory tumors, but the durability of antitumor activity requires in vivo persistence. Differential signaling through the CAR costimulatory domain can alter the T cell metabolism, memory differentiation, and influence long-term persistence. CAR-T cells costimulated with 4-1BB or ICOS persist in xenograft models but those constructed with CD28 exhibit rapid clearance. Here, we show that a single amino acid residue in CD28 drove T cell exhaustion and hindered the persistence of CD28-based CAR-T cells and changing this asparagine to phenylalanine (CD28-YMFM) promoted durable antitumor control. In addition, CD28-YMFM CAR-T cells exhibited reduced T cell differentiation and exhaustion as well as increased skewing toward Th17 cells. Reciprocal modification of ICOS-containing CAR-T cells abolished in vivo persistence and antitumor activity. This finding suggests modifications to the costimulatory domains of CAR-T cells can enable longer persistence and thereby improve antitumor response.
Immediate Hypersensitivity Reaction to Chemotherapy in Pediatric Malignancies
Authors: Chanaphorn Mokkhamakkun, Jassada Buaboonnam, Witchaya Srisuwatchari, Orathai Piboonpocanun, Nualanong Visitsunthorn, Punchama Pacharn
Journal: Journal of Allergy and Clinical Immunology (2020)
Abiraterone acetate (AA) with or without cabazitaxel (CBZ) in treatment of chemotherapy naive metastatic castration-resistant prostate cancer (mCRPC).
Authors: Susan F. Slovin, Karen E. Knudsen, Susan Halabi, Mark T. Fleming, Ana M. Molina, Steven Paul Wolf, Renee de Leeuw, Celina Fernandez, Praneet Kang, Traci Southwell, Carol L. Jones, Escarleth Fernandez, William Kevin Kelly
Journal: Journal of Clinical Oncology (2020)

84 Background: Loss of retinoblastoma tumor suppressor (RB) function has been shown to lead to CRPC and is strongly associated with poor outcome. RB functions as a transcriptional repressor; as such, loss of RB causes de-repression of pro-tumorigenic gene networks, including deregulation of the androgen receptor (AR) locus, excessive AR production, and castration-resistant (ligand independent) AR activity that can bypass hormone therapy. Our hypothesis is that leveraging RB status can direct treatment decisions. The primary objective of the trial (NCT02218606) was to determine the radiographic progression free survival (rPFS) of AA/prednisone (AAP) with and without CBZ in mCRPC patients (pts) that have progressed on primary androgen deprivation therapy and no prior AR directed therapy or chemotherapy. Methods: This is a multicenter non-comparative randomized phase 2 trial. Pts were randomized 1:1 to AAP with crossover to CBZ upon AAP failure (Arm 1), or the combination of AAP + CBZ (Arm 2). Randomization was stratified by the CALGB 90401 prognostic risk groups. The primary endpoint was rPFS (time from randomization to radiographic progression or death, whichever occurs first). Arms were analyzed separately. Results: Between October 2014 and March 2019, 93 pts were accrued; 81 were randomized. Median age was 68 years and ECOG performance status was 0 or 1. Endpoints are shown in Table. Therapies were well tolerated. Conclusions: Results of AAP + CBZ (Arm 2) in chemotherapy naïve pts suggest that men may derive benefit from the earlier use of CBZ with acceptable toxicity, supporting further study of this combination in mCRPC pts. Circulating Tumor Cells are being analyzed for changes in RB/AR expression. Managed by: Prostate Cancer Clinical Trials Consortium; Funding: Sanofi US; Support: Prostate Cancer Foundation. Clinical trial information: NCT02218606. [Table: see text]
Investigating the role of the innate immune response in relapse or blast crisis in chronic myeloid leukemia
Authors: Weiqi Huang, Bin Liu, Elizabeth A. Eklund
Journal: Leukemia (2020)

Abstract Chronic myeloid leukemia (CML) is characterized by expression of the tyrosine kinase oncogene, Bcr–abl. Tyrosine kinase inhibitors (TKI) induce prolonged remission in CML, and therapy discontinuation is an accepted approach to patients with reduction in Bcr–abl transcripts of four logs or greater. Half such individuals sustain a therapy free remission, but molecular mechanisms predicting relapse are undefined. We found relative calpain inhibition in CML cells with stabilization of calpain substrates, including βcatenin and Xiap1. Since the Survivin gene is activated by βcatenin, this identified two apoptosis-resistance mechanisms. We found that Survivin impaired apoptosis in leukemia stem cells (LSCs) and Xiap1 in CML granulocytes. Consistent with this, we determined treatment with an inhibitor of Survivin, but not Xiap1, prevented relapse during TKI treatment and after therapy discontinuation in a murine CML model. By transcriptome profiling, we identified activation of innate immune response pathways in murine CML bone marrow progenitors. This was increased by TKI treatment alone, but normalized with addition of a Survivin inhibitor. We found that activation of the innate immune response induced rapid blast crisis in untreated CML mice, and chronic phase relapse during a TKI discontinuation attempt. These results suggest that extrinsic stress exerts adverse effects on CML-LSCs.
In patients admitted with COPD exacerbation, adding azithromycin to standard care did not reduce treatment failure
Authors: Matthew B. Stanbrook
Journal: Annals of Internal Medicine (2020)

Source Citation Vermeersch K, Gabrovska M, Aumann J, et al. Azithromycin during acute chronic obstructive pulmonary disease exacerbations requiring hospitalization (BACE). A multicenter, randomized, double-blind, placebo-controlled trial. Am J Respir Crit Care Med. 2019;200:857-68. 31046405
Clinical characteristics and imaging manifestations of the 2019 novel coronavirus disease (COVID-19):A multi-center study in Wenzhou city, Zhejiang, China
Authors: Wenjie Yang, Qiqi Cao, Le Qin, Xiaoyang Wang, Zenghui Cheng, Ashan Pan, Jianyi Dai, Qingfeng Sun, Fengquan Zhao, Jieming Qu, Fuhua Yan
Journal: Journal of Infection (2020)

Little is known about COVID-19 outside Hubei. The aim of this paper was to describe the clinical characteristics and imaging manifestations of hospitalized patients with confirmed COVID-19 infection in Wenzhou, Zhejiang, China.In this retrospective cohort study, 149 RT-PCR confirmed positive patients were consecutively enrolled from January 17th to February 10th, 2020 in three tertiary hospitals of Wenzhou. Outcomes were followed up until Feb 15th, 2020.A total of 85 patients had Hubei travel/residence history, while another 49 had contact with people from Hubei and 15 had no traceable exposure history to Hubei. Fever, cough and expectoration were the most common symptoms, 14 patients had decreased oxygen saturation, 33 had leukopenia, 53 had lymphopenia, and 82 had elevated C-reactive protein. On chest computed tomography (CT), lung segments 6 and 10 were mostly involved. A total of 287 segments presented ground glass opacity, 637 presented mixed opacity and 170 presented consolidation. Lesions were more localized in the peripheral lung with a patchy form. No significant difference was found between patients with or without Hubei exposure history. Seventeen patients had normal CT on admission of these, 12 had negative findings even10 days later.Most patients presented with a mild infection in our study. The imaging pattern of multifocal peripheral ground glass or mixed opacity with predominance in the lower lung is highly suspicious of COVID-19 in the first week of disease onset. Nevetheless, some patients can present with a normal chest finding despite testing positive for COVID-19.We did not receive any fundings.
Laparoscopic Gastrectomy After Neoadjuvant Chemotherapy—Reply
Authors: Fei Shan, Ziyu Li, Jiafu Ji
Journal: JAMA Surgery (2020)

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Checkpoint kinase inhibition in prostate cancer cells resistant to poly ADP-ribose polymerase inhibitors.
Authors: Mohammad Omar Atiq, Goutam Chakraborty, Subhiksha Nandakumar, Ying Zhang Mazzu, Konrad H. Stopsack, Yuki Yoshikawa, Gwo-Shu Mary Lee, Philip W. Kantoff
Journal: Journal of Clinical Oncology (2020)

150 Background: Poly ADP-ribose polymerase inhibitors (PARPi) have shown promise in the treatment of metastatic castration-resistant prostate cancer patients with DNA damage response defects . The phase 3 PROfound trial showed olaparib delayed the time to radiographic progression or death as compared with abiraterone or enzalutamide. In addition to olaparib, three other PARPi are in Phase 3 trials in prostate cancer (PC): rucaparib, talazoparib, and niraparib. Despite responses, resistance is common and treatment options for PARPi-resistant patients are limited. In this study, we observed de novo activation of checkpoint kinases (CHEK) in talazoparib-resistant (TR) PC cells. Therefore, we hypothesized that targeting CHEK may mitigate resistance to PARPi in PC. Methods: We developed TR human prostate cancer PC3 (low BRCA2 protein due to heterozygous deletion of BRCA2) cells. We performed phosphoproteomic analysis to identify possible mechanisms of talazoparib resistance in PC3 cells and validated the results with Western blot. Results: TR-PC3 cells proliferated slower and had a significant increase in the phosphorylation of CHEK2 compared to parental (p) PC3. Treatment with a CHEK2-selective inhibitor, CCT241533, did not affect cell growth in TR-PC3 cells. Conversely, treatment with a CHEK 1/2 inhibitor, prexasertib, led to significant cell growth inhibition in TR-PC3 at a much lower IG 50% concentration compared to pPC3. RNAi-mediated knockdown validated the superior efficacy of combined CHEK1 and CHEK2 inhibition since this combination produced the greatest cell growth inhibition seen in both TR-PC3 and de novo PARPi-resistant p22RV1. Treatment of pPC-3 and p22RV1 with combinations of talazoparib and prexasertib showed greater cell growth inhibition compared to either drug alone. Conclusions: Resistance to PARPi in PC cells with deletion of BRCA2 may potentially be overcome with CHEK inhibition. Moreover, our preliminary data suggested that the effect of PARPi and CHEK inhibitors on PARPi/CHEK inhibitor-naïve PC cells was greatest when used together, indicating that patients with PC may experience greatest anti-tumor activity of the two drugs when they are used in combination.
Matt Morgan: When nothing is the right thing to say
Authors: Matt Morgan
Journal: BMJ (2020)

I slept dreadfully that night. I fought with my pillow and perched on the narrow corner ledge of my mattress, almost falling to the floor despite the adequate space next to me. The next day I found myself trying to cheat my circadian rhythm with a double espresso in my favourite cafe, contemplating a trip to the gym to short circuit my tiredness.

The previous night I had arrived home from work after midnight, when the children were dreaming, the dog was snoring, and even the lampposts had been extinguished. But my turmoil was completely insignificant when …