tbuckley/cabot-search huggingface dataset:
Association of radical cystectomy and increased risk of skeletal-related events in bone-metastatic urothelial carcinoma.
Authors: Nima Almassi, Imaani J. Easthausen, Soleen Ghafoor, Paul J. Christos, Timothy F. Donahue, Jonathan E. Rosenberg, Azeez Farooki
Journal: Journal of Clinical Oncology (2020)

477 Background: Bone metastases are common in patients with advanced cancer of the bladder or upper urinary tract; however, few studies have assessed the morbidity of bone metastases in these patients. We sought to characterize bone-associated morbidity by measuring the frequency of skeletal-related events (SREs) and identify predictors of SREs in this population. Methods: We retrospectively identified 328 patients with bone-metastatic bladder or upper urinary tract cancer managed at Memorial Sloan Kettering between 2000 and 2018. SREs were defined as presence of spinal cord compression from bone metastasis, pathologic fracture, treatment of bone metastasis with radiotherapy or surgery, or hypercalcemia of malignancy. SRE-free survival was estimated using Kaplan-Meier analysis; competing-risks regression analysis was used to identify predictors of SREs. Results: In total, 198 patients (60%) developed ≥1 SRE, including 84 (26%) with multiple SREs. The most common SREs were bone radiotherapy (n=165 [83%]), pathologic fracture (n=73 [37%]), and orthopedic surgery (n=39 [20%]). Median SRE-free survival was 7.4 months. On competing-risks regression analysis, history of radical cystectomy (hazard ratio [HR], 1.40; 95% CI, 1.05-1.86; P=0.02) and hip involvement at the time of bone metastasis diagnosis (HR, 1.65; 95% CI, 1.12-2.42; P=0.01) were independently associated with risk of SRE. Conclusions: SREs are common among patients with bone-metastatic cancer of the bladder or upper urinary tract and typically occur soon after the development of bone metastasis. Patients with a history of radical cystectomy or with hip involvement at the time of bone metastasis diagnosis have a higher risk of SRE.
Adverse event profiles of apalutamide, enzalutamide, and darolutamide in SPARTAN, PROSPER, and ARAMIS: How confident are we about which drug is safest?
Authors: Joshua Z. Drago, Philip W. Kantoff, Konrad H. Stopsack
Journal: Journal of Clinical Oncology (2020)

318 Background: Apalutamide, enzalutamide, and darolutamide were approved for non-metastatic castration-resistant prostate cancer (nmCRPC) based on three randomized placebo-controlled trials that showed similar efficacy. Adverse event (AE) profiles have been invoked to differentiate the drugs but have only been informally compared. Methods: We accounted for baseline characteristics, AE collection and reporting, and statistical uncertainty when comparing AE risks in the drug and placebo arms of SPARTAN (NCT01946204), PROSPER (NCT02003924), and ARAMIS (NCT02200614). Results: Patients in SPARTAN, PROSPER, and ARAMIS had a similar median age (74 years in all studies), median PSA doubling time (3.7-4.7 months) and ECOG performance status (68-80% with ECOG 0). AEs were gathered consistently using CTCAE 4.0 or 4.03. However, PROSPER and ARAMIS reported AEs occurring in ≥5% of patients; SPARTAN reported AEs occurring in ≥15%. Trials also reported 5 to 14 ‘AEs of interest.’ Of 34 AE types reported overall, only 10 were reported in all three trials. Absolute risks of adverse events in the placebo arms differed considerably. Compared to the placebo arm of SPARTAN, AEs were on average 44% less common in the placebo arm of PROSPER (95% CI, 28-56%) and 54% less common in the placebo arm of ARAMIS (95% CI, 41-64%), a difference not explained by length of follow-up. With lower event numbers, relative risk estimates were less precise with wider confidence intervals. For example, comparing treatment vs. placebo arms, the relative risk for fatigue, the most common AE, was 1.45 (95% CI, 1.16-1.80) in SPARTAN, 2.37 (95% CI, 1.86-3.04) in PROSPER, and 1.39 (95% CI, 1.01-1.91) in ARAMIS. Across all AE types, compared to SPARTAN, relative risks from PROSPER were 23% less precise and relative risks from ARAMIS were 30% less precise. Conclusions: While conducted in similar patient populations, these trials had remarkable differences in AE reporting and in absolute AE risks between placebo arms. Rather than indicating better safety, low absolute adverse event numbers decrease confidence in AE profiles. Published data are insufficient to differentiate the AE profiles of these agents in nmCRPC.
Genitourinary oncology referral patterns to the cancer associated thrombosis clinic: The Cleveland Clinic experience.
Authors: Iris Yeong- Fung Sheng, Dana E Angelini, Alok A. Khorana, Timothy D. Gilligan, Brian I. Rini, Jorge A. Garcia, Moshe Chaim Ornstein, Shilpa Gupta
Journal: Journal of Clinical Oncology (2020)

583 Background: Cancer related thrombosis affects ~20% of all cancer patients. It is our standard practice to refer cancer patients with suspected venous thromboembolism (VTE) to our Cancer Associated Thrombosis (CAT) clinic. Referrals are based on a clinical suspicion of VTE or a Khorana score ≥3. We sought to evaluate the characteristics of patients with genitourinary (GU) cancer referred to the CAT clinic and their association with immunotherapy. Methods: The study population comprised of all cancer patients referred to the CAT clinic with a diagnosis of prostate cancer (Pca), bladder cancer (BC) or renal cell cancer (RCC) from August 1, 2014 to October 15, 2019. Results: Of the 147 patients with GU cancers referred to CAT clinic, 43 had a VTE (14/40 BC, 14/44 RCC, 15/63 PCa). Of which, 83% were DVT, 5% were PE, and 12% had both. The majority had stage 4 disease (98%), no prior clotting history, and ECOG 0-2 (86%). Average BMI was 28.63 and 22 patients had smoking histories (average 11 pack years). Major histology per cancer type were adenocarcinoma (100%) in PCa, 86.7% clear cell in RCC and 85.7% urothelial carcinoma in BC. Lower extremity pain or swelling (67%) was the major reason for referral. Thirty-four of the 43 patients were on active treatment; 7 patients on immunotherapy (average 4.9 months) and 13 patients on chemotherapy (average 2.6 cycles) at the time of VTE diagnosis. Of the chemotherapy regimens, patients were on the combination of gemcitabine with carboplatin (54%), docetaxel (23%), or cabazitaxel (23%). Atezolizumab was the most commonly used immunotherapy agent (57%). Other immunotherapy agents associated were nivolumab (29%) and the combination of ipilimumab with nivolumab (14 %). There was no VTE-related mortality. Conclusions: Our single center experience shows 16% of VTE events in patients with GU cancers were associated with immunotherapy and 33% were associated with cytotoxic chemotherapy. There is a growing body of literature exploring the association between thromboembolic events and immunotherapy. As more patients with GU cancers are treated with immunotherapy, it will be interesting to see how this influences the rate of CAT clinic referral and prevalence rates of VTE.
Additional holmium-166 radioembolisation after lutetium-177-dotatate in patients with neuroendocrine tumour liver metastases (HEPAR PLuS): a single-centre, single-arm, open-label, phase 2 study
Authors: Arthur J A T Braat, Rutger C G Bruijnen, Rob van Rooij, Manon N G J A Braat, Frank J Wessels, Rachel S van Leeuwaarde, Mark J C van Treijen, Wouter W de Herder, Johannes Hofland, Margot E T Tesselaar, Hugo W A M de Jong, Marnix G E H Lam
Journal: The Lancet Oncology (2020)
Discovery of the anti-angiogenesis effect of eltrombopag in breast cancer through targeting of HuR protein
Authors: Yuying Zhu, Liuqing Yang, Jiazhen Xu, Xiyan Yang, Pengwei Luan, Qianfei Cui, Pei Zhang, Feiyun Wang, Ruixiang Li, Xinyue Ding, Lixian Jiang, Guoqiang Lin, Jiange Zhang
Journal: Acta Pharmaceutica Sinica B (2020)

HuR (human antigen R), an mRNA-binding protein responsible for poor prognosis in nearly all kinds of malignancies, is a potential anti-tumor target for drug development. While screening HuR inhibitors with a fluorescence polarization (FP) based high-throughput screening (HTS) system, the clinically used drug eltrombopag was identified. Activity of eltrombopag on molecular level was verified with FP, electrophoretic mobility shift assay (EMSA), simulation docking and surface plasmon resonance (SPR). Further, we showed that eltrombopag inhibited
Using a clinical process map to identify prescribing cascades in your patient
Authors: Katrina L Piggott, Nishila Mehta, Camilla L Wong, Paula A Rochon
Journal: BMJ (2020)

### What you need to know

The adverse effects of a drug may “hide” behind common presenting symptoms.1 Prescribing cascades occur when a healthcare provider misinterprets an adverse drug event as a new medical condition and provides a second drug to address the side effect, as described in 1997 by Rochon and Gurwitz in the BMJ .2 The concept has also been expanded to include unnecessary diagnostic tests, medical devices, and over-the-counter therapies,3 which may expose the patient to risk and harm. There is no universally accepted approach to identifying whether a drug is responsible for a symptom, but by identifying prescribing cascades, clinicians can reduce the number of unnecessary medications, investigations, consultations, and harms.

To date, more than 20 prescribing cascades have been identified by cohort and population studies4 (see fig 1 for examples). These prescribing cascades are the result of medications for common conditions such as heart disease, hypertension, obstructive lung disease, diabetes, dementia, and chronic pain.356



Fig 1 
Simple clinical process maps of three common prescribing cascades



While prescribing cascades are well …
Conditional immune adverse event rate in urothelial and renal cell carcinoma patients treated with immune checkpoint inhibitors.
Authors: Pier Vitale Nuzzo, Gregory Russell Pond, Sarah Abou Alaiwi, Amin Nassar, Ronan Flippot, Catherine Curran, Kerry L. Kilbridge, Xiao X. Wei, Bradley Alexander McGregor, Lauren Christine Harshman, Toni K. Choueiri, Guru Sonpavde
Journal: Journal of Clinical Oncology (2020)

481 Background: Immune checkpoint inhibitors (ICIs) are associated with immune-related adverse events (irAEs). While the incidence and prevalence of irAEs have been well characterized in the literature, much less is known about the cumulative incidence (CI) rate of irAEs. We sought to evaluate the CI of irAEs in metastatic urothelial carcinoma (mUC) and metastatic renal cell carcinoma (mRCC) patients (pts) treated with ICIs. Methods: We identified a cohort of mUC and mRCC pts who received ICIs at DFCI. irAEs were classified using CTCAE v.5.0 guidelines. The CI rate was a defined measure that accounted for elapsed time since treatment initiation and estimated the risk of irAE development conditioned on time elapsed without experiencing an irAE, accounting for the competing risk of death. Incidence and CI of irAEs at each monthly landmark time was calculated. Prognostic factors of irAE were assessed using the Fine and Gray method. Results: A total of 470 pts was treated with ICIs between July 2013 and October 2018 [mUC: 199 (42.3%); mRCC: 271 (57.7%)]. 341 (72.6%) pts received ICI monotherapy, 86 (18.3%) received ICIs in combination with targeted therapies, and 43 (9.2%) received a combination of two ICIs. Overall, 186 pts (39.5%) experienced any irAE at any time point. Common irAEs included hypothyroidism (n=42 [22.6%]), skin (n=36 [19.4%]), colitis (n=35 [18.8%]), transaminitis (n=32 [17.2%]), and pneumonitis (n=14 [7.5%]). The risk of developing an irAE over time was as follows: 33.5% if no irAE within the 1st month(mo), 27.3% if no irAE in 3mo, 18.8% if no irAE in 6mo, and 16.4% if no irAE by 12mo. No difference was observed in CI based on type of cancer (mUC vs mRCC) or agent (PD1 vs. PD-L1). Multivariable analysis showed that ICI combined with ICI or other agents vs. ICI monotherapy (p&lt;0.001), firstline therapy (p=0.013) and PD-1 vs. PD-L1 inhibitors (p=0.008) were statistically correlated with the development of irAEs. Conclusions: This study quantitates the incidence of developing irAEs with ICI conditioned on time elapsed without irAE development. Although the incidence of irAEs decreased over time on therapy, irAEs require continuous vigilant monitoring because of the long tail in its incidence.
Abstract 13213: Anticoagulation Therapy for Atrial Fibrillation in Cancer Patients May Reduce the Incidence of Venous Thromboembolism
Authors: Pengyang Li, Mu Li, Fangcheng Wu, Ying Ning, Su Pan, Richard A Dixon, Qi Liu
Journal: Circulation (2019)

Introduction: Because patients with atrial fibrillation (AF) who have a CHA2DS2-VASc score >2 are at high risk for stroke, long-term anticoagulation therapy is recommended. Venous thromboembolism (...
Low-density lipoprotein receptor-related protein 1 deficiency in cardiomyocytes reduces susceptibility to insulin resistance and obesity
Authors: Aleyda Benitez-Amaro, Elena Revuelta-López, Olga Bornachea, Lídia Cedó, Àngela Vea, Laura Herrero, Nuria Roglans, Carolina Soler-Botija, David de Gonzalo-Calvo, Laura Nasarre, Sandra Camino-López, Eduardo García, Eugenia Mato, Francisco Blanco-Vaca, Antoni Bayes-Genis, David Sebastian, Joan Carles Laguna, Dolors Serra, Antonio Zorzano, Joan Carles Escola-Gil, Vicenta Llorente-Cortes
Journal: Metabolism (2020)
A multicenter retrospective study to evaluate real-world clinical outcomes in patients with metastatic renal cell carcinoma (mRCC) and brain metastasis treated with ipilimumab and nivolumab.
Authors: Landon Carter Brown, Kunal Desai, Chester Kao, Emily Noelle Kinsey, Patrick Healy, Julie Kephart, Michael Roger Harrison, Sundhar Ramalingam, Andrew J. Armstrong, Daniel J. George, Allison Martin, Kimberly D. Allman, Laura S. Wood, Wei Wei, Jorge A. Garcia, Timothy D. Gilligan, Shilpa Gupta, Brian I. Rini, Moshe Chaim Ornstein, Tian Zhang
Journal: Journal of Clinical Oncology (2020)

637 Background: The combination of ipilimumab &amp; nivolumab (I+N) followed by maintenance nivolumab has improved outcomes in patients (pts) with mRCC. Little is known about the outcomes in mRCC pts with brain metastasis. In this multicenter retrospective analysis, we present a real-world experience in pts with brain metastasis treated with I+N. Methods: Pts with mRCC and brain metastases treated with I+N at the Duke Cancer Institute and Cleveland Clinic were identified. Pt characteristics were summarized with descriptive statistics. Fisher’s exact test was used to determine predictors of response (alpha 0.05). Results: From 10/2017 to 2/2019, 17 pts received I+N for mRCC with brain metastases. Median age was 60; 29% were female. IMDC risk was 18%/59%/24% favorable/intermediate/poor, and 77% were clear cell histology. Pts received I+N as either first-line (65%) or ≥ second-line (35%) therapy. Of the pts evaluable for response: objective response rate (ORR) was 42% [0% CR]; with 29% achieving stable disease and 18% progressive disease as their best response. Median duration on therapy was 13 weeks. 59% of pts developed an immune-related adverse event (AE). The most common reason for treatment discontinuation was disease progression (47%) followed by AEs (18%). There were no significant predictors of any radiographic response category (PR, SD, or PD) among variables assessed (gender, IMDC risk, histology, presence of bone metastasis, line of therapy, or presence of irAE). Of note, 50% (3/6) patients treated in the second-line or greater setting experienced a PR. Conclusions: In our real-world cohort of mRCC patients with brain metastasis, I+N is clinically effective. Further investigation is warranted in this population given exclusion from prior clinical trials.
Murine cytomegalovirus dissemination but not reactivation in donor-positive/recipient-negative allogeneic kidney transplantation can be effectively prevented by transplant immune tolerance
Authors: Anil Dangi, Shuangjin Yu, Frances T. Lee, Melanie Burnette, Jiao-Jing Wang, Yashpal S. Kanwar, Zheng J. Zhang, Michael Abecassis, Edward B. Thorp, Xunrong Luo
Journal: Kidney International (2020)
Health inequalities: death by political means
Authors: Kamran Abbasi
Journal: BMJ (2020)

Austerity does not result in a fair society or healthier lives. The evidence is clear after a decade of cuts to public expenditure. “When a society is flourishing,” says Michael Marmot, “health tends to flourish” (doi:10.1136/bmj.m693).

Marmot is well placed to make this judgment. His work on social determinants of health is internationally renowned and influential. In 2008, he was commissioned by the government to review what could be done to reduce health inequalities. Fair Society, Healthy Lives , better known as the Marmot …
An open-label phase Ib study of ORIC-101 in combination with enzalutamide in patients with metastatic prostate cancer progressing on enzalutamide.
Authors: Neal D. Shore, Eleni Efstathiou, Rupal Patel, Rongda Xu, Ann Johnson, Pratik S. Multani, Michael J. Morris, Wassim Abida
Journal: Journal of Clinical Oncology (2020)

TPS253 Background: The glucocorticoid receptor (GR) has been identified as a potential antiandrogen bypass mechanism of resistance to enzalutamide treatment in prostate cancer. In an in vivo enzalutamide resistant prostate cancer model, GR activates a transcriptional program that is similar but distinguishable from AR and maintains the resistant phenotype (Arora et al 2013). In human prostate cancer cells, GR expression increases upon exposure to AR antagonists, and higher GR expression is associated with treatment resistance. These findings suggest that combined inhibition of both GR and AR may prolong the duration of response or restore sensitivity to AR antagonists such as enzalutamide or apalutamide. ORIC-101 is an oral small molecule GR antagonist that fully inhibits GR transcriptional activity and blocks proliferative and survival signals mediated by GR. Methods: This is an open-label, single arm, multicenter, dose escalation followed by dose expansion study to assess the safety, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of ORIC-101 in combination with enzalutamide in patients with PSA progression on enzalutamide (NCT04033328). Escalating dose levels of ORIC-101 will be administered orally, once daily in combination with enzalutamide 160 mg on a 28-day cycle following a modified interval (i) 3+3 design. Parallel enrollment of up to 3 additional patients presenting with GR overexpressing tumors (determined in tissue via immunohistochemistry) may be performed at each dose level. Based on the i3+3 design, the target toxicity rate for the maximum tolerated dose (MTD) is set at 25% (midpoint between 1 out of 3 and 1 out of 6) and any values between 20% and 30% can be considered as acceptable toxicity rates for the MTD. During dose expansion, patients will be stratified into 3 cohorts based on GR expression in tumor tissue: GR-high, GR-moderate, and GR-low. A Simon’s Two-Stage Optimal design will allow for early enrollment stopping in any cohort if PSA response rate is not sufficiently promising to warrant further development. Patients will continue treatment until disease progression or unacceptable toxicity. Clinical trial information: NCT04033328.
Clinical utility of diagnostic methods in respiratory allergy in pediatric patients.
Authors: Ana Prieto del Prado, Almudena Testera-Montes, Ibon Eguiluz-Gracia, Paloma Campo, Adriana Ariza Veguillas, Maria Auxiliadora Guerrero, Cristobalina Mayorga, Maria Torres Jaen, Carmen Rondon Segovia
Journal: Journal of Allergy and Clinical Immunology (2020)
The prognostic value of body fat components in metastasis renal cell carcinoma patients treated with TKIs.
Authors: Jindong Dai, Xingming Zhang, Zhenhua Liu, Tingni Song, Xudong Zhu, Haoran Zhang, Hao Zeng, Pengfei Shen
Journal: Journal of Clinical Oncology (2020)

668 Background: To assess the association between body fat components and survival status and tumor response for metastatic renal cell carcinoma (mRCC) patients treated with tyrosine kinase inhibitors (TKIs). Methods: Patients with pathologically diagnosed and radiologically indicated mRCC were enrolled into the retrospective study. Three body fat components: total fat accumulation (TFA), visceral fat accumulation (VFA) and subcutaneous fat accumulation (SFA) were measured using standard CT scans. The clinical outcomes included progression-free survival (PFS), overall survival (OS), and tumor response rates. Univariate analysis and multivariate Cox proportion hazard regression models were used to find associated parameters and to calculate the adjusted hazard ratio (HR). Results: A total of 146 patients were enrolled. The median follow-up time was 22 months. According to the univariate analysis, patients with an increased SFA and TFA had a longer PFS and OS. A similar phenomenon was observed among patients with ≥2 increasing body fat components about PFS and OS. As for multivariate analysis, SFA change (p=0.014) or the number of increasing body fat components (p=0.040) were independent indicators to predict PFS. In addition, SFA change (p=0.022) or the number of increasing body fat components (p=0.008) could independently predict OS. Moreover, a better disease control rate (p=0.028) was founded in patients with ≥2 increasing components. In the subgroup of patients with ≥2 metastasis sites, improved OS (p=0.017) and PFS (p=0.027) were found compared to those with &lt;2 increasing components. Further multivariate analysis identified the number of increasing body fat components was an independent factor in predicting PFS (p=0.018) and OS (p=0.029). Conclusions: Body fat accumulation, such as high SFA or TFA at progression, could improve the survival of patients with mRCC treated with TKIs, especially patients with higher tumor burden. It should be considered as an important parameter to predict the survival status of patients with mRCC.