tbuckley/cabot-search huggingface dataset:
The intraprostatic immune balance after prostate SBRT in patients.
Authors: Nicholas George Nickols, Ekambaram Ganapathy, Christine Nguyen, Nathanael Kane, Lin Lin, Silvia Diaz-Perez, Ramin Nazarian, Amar Upadhyaya Kishan, Christopher R. King, Patrick Kupelian, Matthew Rettig, Michael L. Steinberg, Minsong Cao, Beatrice Knudsen, Fang-I Chu, David Elashoff, Robert Evan Reiter, Dörthe Schaue
Journal: Journal of Clinical Oncology (2020)

339 Background: Stereotactic Body Radiotherapy (SBRT) delivers high dose per fraction radiotherapy to targets with high precision. Such hypofractionated RT appears to act as an immune adjuvant, altering the tumor infiltrating immune landscape and enriching it for lymphocytes as numerous preclinical investigations would suggest. Based on this hypothesis, hundreds of ongoing trials listed in clinicaltrials.gov currently test the combination of RT (largely SBRT) with various immunotherapies. However, studies directly measuring the representation of infiltrating immune cells after SBRT in patients are few and far between and none exist in the context of prostate cancer. We therefore sought to interrogate the tumor-immune interface after prostate SBRT using fresh tissue in patients. Methods: Fresh prostate tissue from patients (N=10) enrolled in a clinical trial of prostate SBRT (three fractions of 8 Gy directed to the prostate and seminal vesicles) in the neoadjuvant setting two weeks prior to radical prostatectomy was subjected to multicolor flow cytometry and compared to that of Gleason Grade and T stage matched controls who did not undergo neoadjuvant therapy. Results: With a threshold of significance level of 0.05 for unadjusted p-values, using two-sided two-sample t-test, myeloid cells and particularly CD14 +/hi CD16 + DR + intermediate monocytes/macrophages were enriched, while lymphocytes, including T cells and CD56 + 16 − NK cells were decreased in SBRT-treated prostates as compared to unirradiated controls. Conclusions: The immune infiltrates in prostates two weeks after SBRT demonstrates a significant lymphoid to myeloid shift consistent with a tumor microenvironment after SBRT that is likely immunosuppressive beyond what can be targeted through the PD-1/L1 or CTLA-4 axis alone. This may have implications for the design of immunotherapy trials, especially in prostate cancer, that test SBRT in combination with immunotherapies.
Gefapixant, a P2X3 receptor antagonist, for the treatment of refractory or unexplained chronic cough: a randomised, double-blind, controlled, parallel-group, phase 2b trial
Authors: Jaclyn A Smith, Michael M Kitt, Alyn H Morice, Surinder S Birring, Lorcan P McGarvey, Mandel R Sher, Yu-Ping Li, Wen-Chi Wu, Zhi Jin Xu, David R Muccino, Anthony P Ford, Jaclyn Smith, Lorcan McGarvey, Surinder Birring, James Hull, Warner W Carr, Alan B Goldsobel, Gary N Gross, John R Holcomb, Iftikhar Hussain, Mandel Sher, Selwyn Spangenthal, William Storms, Alyn Morice, David Elkayam, Gary C Steven, James Krainson, Faisal Alfonso Fakih, Jonathan Matz, Gregory Daniel Brooks, Thomas Casale, Gary D Berman, John J Condemi, Leon S Greos, Shaila U Gogate, Ellen R Sher, Jason H Friesen, Eric J Schenkel, David Isaac Bernstein, Jonathan Corren, Krishna Sundar, Mark H Gotfried, Anthony Montanaro, William R Lumry, Niran J Amar, Michael S Kaplan, Bruce M Prenner, Thomas R Murphy, James S Good, Sean Parker, Tim Harrison, Ian Pavord, Christopher Brightling, Ratko Djukanovic, Douglas McQuaid, Michael Denenberg, Neil A Ettinger, Vivek Iyer
Journal: The Lancet Respiratory Medicine (2020)
Real-world evidence of cabozantinib in metastatic renal-cell carcinoma (mRCC): Results from the Canadian Kidney Cancer Information System (CKCis).
Authors: Hanbo Zhang, Naveen S. Basappa, Isaiah Joy, Sunita Ghosh, Aly-Khan A. Lalani, Aaron Richard Hansen, Daniel Yick Chin Heng, Vincent Castonguay, Christian K. Kollmannsberger, Eric Winquist, Lori Wood, Georg A. Bjarnason, Rodney H. Breau, Frederic Pouliot, Anil Kapoor, Jeffrey Graham
Journal: Journal of Clinical Oncology (2020)

682 Background: Cabozantinib is a multitargeted tyrosine kinase inhibitor (TKI) that has demonstrated efficacy in mRCC randomized trials. Less is known about the activity of cabozantinib in patients (pts) exposed to immuno-oncology (IO) agents. We explored the real-world effectiveness of cabozantinib, including in pts who had progressed on IO therapy. Methods: Using CKCis, a prospective Canadian database, pts treated with cabozantinib monotherapy as second-line or later were identified. Baseline clinical and treatment characteristics were collected. Rates of partial response (PR), stable disease (SD), progressive disease (PD) and disease control (DCR, PR+SD) were determined along with median time to treatment failure (mTTF) and median overall survival (mOS). Results: A total of 156 pts were identified. Median age was 62 years (range 21-84), 74% of pts had clear-cell histology, and 54% had &gt; 3 sites of metastases (12% in CNS, 47% in bone). At time of cabozantinib start, 34% had KPS score &lt; 80. Outcomes are described below. Conclusions: The effectiveness of cabozantinib observed in this real-world population was consistent with results from clinical trials. Cabozantinib also appears to provide benefit to mRCC pts who have progressed on prior IO therapy, and should be incorporated into contemporary treatment algorithms. Further follow up is ongoing.[Table: see text]
Feasibility of digital pathology of circulating tumor cells with morphologic analysis in localized bladder cancer.
Authors: Heather Chalfin, Kelly Harris, Stephanie Glavaris, Michael A. Gorin, Max Kates, Megan Kearney, Adam Jendrisak, Megan Fong, Andres Matoso, Michael Hiroshi Johnson, Kenneth J. Pienta, Jean H. Hoffman-Censits, Vladimir Valera, Andrea B. Apolo, Trinity Bivalacqua, Noah M. Hahn, David James McConkey
Journal: Journal of Clinical Oncology (2020)

525 Background: Circulating tumor cells (CTCs) are promising biomarkers in metastatic urothelial cancer (UC). Unfortunately, efforts in localized disease have been unsuccessful, in part due to limitations of existing technologies that rely on counting cells and epithelial-marker expression. Here, we applied a novel selection-free digital pathology platform in a localized UC cohort. To date, this platform has associated CTC morphology with differential therapeutic response in metastatic UC and castrate-resistant prostate cancer. If feasible in localized UC, we may potentially identify best candidates for adjuvant therapy or bladder sparing, as well as enable sensitive monitoring for recurrence. Methods: N=16 consecutive UC pts included 8 (50%) metastatic controls and 8 (50%) localized (3 (37%) at TURBT and 5 (63%) at cystectomy). Peripheral blood was processed with the Epic CTC platform (pan-CK/CD45/PD-L1/DAPI staining). Approximately 3 million cells per slide were imaged. Unsupervised clustering categorized CTCs into 5 subtypes based on 11 morphologic features (nuclear solidity, speckling, nucleoli and entropy; cytokeratin speckling and ratio; and cytoplasmic/nuclear circularity, area, and convex area ratio). Results: 119 CTCs were detected from 11/16 (69%) pts (5/8 (63%) localized (2 NMIBC, 6 MIBC) and 6/8 (75%) metastatic). All MIBC pts had cystectomy (4/6 (67%) received NAC). 2/8 (25%) metastatic pts had stable disease, 3/8 (38%) were progressing, and 3/8 (38%) had newly detected M1. Median (range) CTC count/mL was similar for localized and metastatic pts (0.4 (0-58.6), 0.75 (0-1.9)). CTCs were detected in a pt with CIS, but not in a pt with TaHG disease. 1/16 (6.3%) pts had a single PD-L1+ CTC. CTCs were successfully assigned into 5 subtypes with predominant features of large, small, or linear cells, high cytoplasmic circularity, and prominent nucleoli. Conclusions: Digital pathology and subtype assignment of CTCs is feasible in localized UC. Ongoing efforts at our center include application of this technology in localized patients receiving investigational checkpoint inhibitor therapy to potentially predict best responders or conversely those at the highest risk for recurrence.
Can serum cytokeratin 19 fragments predict postoperative early progression in patients with upper urinary tract urothelial carcinoma?
Authors: Yuki Endo, Go Kimura, Naoto Hodotsuka, Hiroya Hasegawa, Shigehito Minaguchi, Hikaru Mikami, Hayato Takeda, Jun Akatsuka, Tatsuro Hayashi, Yukihiro Kondo
Journal: Journal of Clinical Oncology (2020)

557 Background: Current guidelines do not yet provide recommendations for any serum tumor markers in patients with upper tract urothelial carcinoma (UTUC) who received nephroureterectomy (NU). The criteria for adjuvant chemotherapy is also controversial. Previous studies have shown that serum cytokeratin levels (sCK) were correlated with depth of tumor invasion and metastases in patients with bladder cancer. We found that preoperative sCK was correlated with cancer specific survival(CSS) after NU. In this study we evaluated whether postoperative sCK (poCK) could predict early progression in patients who received NU. Methods: 160 patients with UTUC underwent NU from December 2003 to 2014 at our institution. The median age at diagnosis was 73 years (41-89). poCK19 had been measured in 112 patients within 8 weeks after NU. Patients were divided into two groups, a high-group and a low-group based on poCK19 levels (a cut-off value of 3.5 ng/mL). CSS and progression-free survival (PFS) were measured by Kaplan–Meier curves and log–rank test. Multivariate analysis was carried out using the Cox hazards model. Results: Of 112 patients ≤pT1 was 39 (34%), pT2 in 26 (23%), pT3 in 40 (35%), and pT4 in 7 (8%). The 5-year (5y) CSS rate was 86% and the 5yPFS rate was 60%. There were 24 (21%) patients in the high-group and 88 (79%) in the low-group. During the median follow-up period of 34.0 (1-152) months, 39 patients (35%) died. The 5yCSS rate of the high-group was 51%, which is significantly lower than the low-group (86%) (p&lt;0.001). The 1yPFS of the high-group was 66%, which was significantly lower than that of the low-group (86%) (p&lt;0.001). On univariate analysis, positive margin (HR4.0, p&lt;0.001) and poCK19 (HR3.9, p&lt;0.001) were the significant factors for 1yPFS. On multivariate analysis, poCK19 (HR5.3 95%CI (1.8-15.7), p=0.002) and positive margin (HR 4.6 95%CI (1.1-18.9), p=0.032) were also independent factors for 1yPFS. Conclusions: Our study suggests that postoperative sCK19 could predict early progression in patients with UTUC who received NU. Adjuvant chemotherapy might be indicated for patients with high postoperative sCK19 levels independent of pathological findings.
Multiple primary prostate tumors with differential drug sensitivity.
Authors: Scott C. Wilkinson, Huihui Ye, Nicholas Terrigino, Nicole Carrabba, Rayann Atway, Shana Y. Trostel, John Bright, S. Thomas Hennigan, Rosina Lis, Ross Lake, Stephanie Harmon, Baris Turkbey, Peter A. Pinto, Peter L. Choyke, Fatima Karzai, David James VanderWeele, Kathleen Kelly, William L. Dahut, Adam G. Sowalsky
Journal: Journal of Clinical Oncology (2020)

342 Background: The differential aggressiveness of potentially independent prostate cancer clones remains largely unknown. Appropriate prostate cancer staging using mpMRI and biopsy tissue can be confounded by sampling error. To date, there has been no understanding of whether clonal variability influences management decisions for localized prostate tumors. We sought to identify the sensitivity and genomic profile of distinct localized tumors from a patient following systemic intense neoadjuvant androgen deprivation therapy (ADT). Methods: A 66-year-old man with high risk prostate cancer enrolled in a Phase 2 study of intense neoadjuvant ADT (goserelin + enzalutamide; inADT). Baseline mpMRI showed a single semi-contiguous lesion encompassing the right apical-mid PZ extending into the left distal apical PZ. MR/US-fusion targeted biopsy was performed before 6 months of inADT. A second mpMRI was performed before radical prostatectomy. Whole exome sequencing on microdissected tumor foci identified somatic mutations and copy number alterations, which were further used with immunohistochemistry to assess tumor clonal architecture and genomic/phenotypic evolution of treatment resistant tumor. Results: We found two clonally independent tumors exhibited intrinsic heterogeneity at baseline which correlated with response or resistance. Biopsies of distinct left- and right-sided tumors showed differing histologies. mpMRI and pathology showed near complete response of the left-sided tumor and substantial resistance of the right-sided tumor, which exhibited a large intraductal component. Histology and whole exome data highlighted a divergence in the status of PTEN and TP53, tumor suppressor genes implicated in prostate cancer progression. Conclusions: These data highlight that even nascent prostate cancer is heterogenous and neoadjuvant therapeutic strategies will need to consider this for clinical optimization. Evolutionary trajectories that resulted in tumor heterogeneity in this case likely contributed to our observation that two independent prostate tumor nodules with distinct genetic alterations responded differently to neoadjuvant intense ADT. Clinical trial information: NCT02430480.
The impact of metastasis location on overall survival among patients with renal cell carcinoma.
Authors: Devin Patel, Fady Ghali, Margaret Meagher, Margaret Meagher, Aaron Bradshaw, Sunil Patel, Cathrine Keiner, Nathan Miller, Raksha Dutt, James Don Murphy, Ithaar Derweesh
Journal: Journal of Clinical Oncology (2020)

621 Background: Current staging guidelines define all patients with metastatic renal cell carcinoma (RCC) as a singular group. We sought to compare the impact of metastatic disease location on overall survival (OS) in patients with RCC. Methods: We queried our institutional database of consecutive patients with metastatic RCC. A confirmatory analysis was performed using the National Cancer Database (NCDB) for cases between 2010 to 2015. Only cases from which all metastatic disease location was known were used. Patients were grouped into having brain or bone metastases, liver or lung metastases or other metastases. From our institutional database, we performed a univariate analysis to determine the impact of metastasis location on OS. From the NCDB, univariable and multivariable Cox proportional hazards and Kaplan-Meier survival analysis with log-rank testing was performed. Multivariable models were adjusted for age, comorbidity, race, gender, and treatment with either palliative care, chemotherapy or immunotherapy. Results: A total of 95 patients were analyzed from our institutional database, with 30 (31.9%) having brain/bone metastases, 20 (21.3%) having lung/liver metastases, and 44 (46.8%) having other site metastases. On univariate analysis, patients with brain/bone metastases had significantly worse OS (HR 1.87; 95% CI 1.01-3.47). However, no significant difference was seen in patients with liver/lung metastases (HR 1.44; 95% CI 0.64-3.27). A total of 25,528 patients met inclusion for our NCDB analysis, of which 12,119 (47.5%) had brain/bone metastases, 10,004 (39.2%) had liver/lung metastases, and 3,405 (13.3%) had other site metastases. On univariate analysis, patients with lung/liver (HR 1.46; 95% CI 1.38-1.53) and patients with bone/brain (HR 1.69; 95% CI 1.60-1.77) had progressively worse OS with non-overlapping confidence intervals. Multivariable analysis again showed that patients with lung/liver disease (HR 1.51; 95% CI 1.43-1.59) and brain/bone disease (HR 1.66; 95% CI 1.60-1.75) had progressively worse OS. Conclusions: Our results highlight the heterogeneity of patients with metastatic renal cell carcinoma. Location of metastatic disease may drive differences in survival.
Phase II study of the oral hypoxia-inducible factor 2α (HIF-2 α) inhibitor MK-6482 in combination with cabozantinib in patients with advanced clear cell renal cell carcinoma (ccRCC).
Authors: Scott S. Tykodi, Todd Michael Bauer, David F. McDermott, Edward Arrowsmith, Naseem J. Zojwalla, Toni K. Choueiri
Journal: Journal of Clinical Oncology (2020)

TPS766 Background: Although targeting the vascular endothelial growth factor (VEGF) pathway is a valuable therapeutic option for treating advanced ccRCC, response rates are modest and patients eventually progress. The HIF-2α transcription factor is a key oncogenic driver for ccRCC. HIF-2α heterodimerizes with HIF-1β and activates the transcription of genes associated with tumor progression, including VEGFA. Targeting HIF-2α and VEGF may inhibit multiple oncogenic signaling pathways in ccRCC and improve response. MK-6482 is a potent and selective small molecule inhibitor of HIF-2α that has been found to have activity in heavily pretreated patients with ccRCC. An open-label, phase 2 study (NCT03634540) will evaluate efficacy and safety of MK-6482 in combination with the VEGF receptor inhibitor cabozantinib in patients with ccRCC. Methods: Approximately 118 patients will be enrolled to receive MK-6482 120 mg orally once daily and cabozantinib 60 mg orally once daily. Dose evaluation will be performed to find a tolerable dose. Once a recommended phase 2 dose is established, patients will be enrolled in 1 of 2 cohorts (~50 patients each): cohort 1 will comprise patients who have not received prior systemic therapy for locally advanced/metastatic RCC; cohort 2 will comprise patients who have received prior immunotherapy and no more than 2 prior regimens for locally advanced/metastatic RCC. Patients must be ≥18 years of age with a diagnosis of ccRCC, have measurable disease per RECIST v1.1, and have an ECOG PS of 0/1. Patients who stop 1 of the 2 study drugs for reasons other disease progression can continue on single-agent treatment with the other drug. Antitumor activity will be assessed by CT/MRI at baseline, week 9, every 8 weeks until year 1, and every 12 weeks thereafter. Adverse event severity will be graded per CTCAE v5.0. The primary end point is ORR per RECIST v1.1. Secondary end points are DOR, PFS, OS, and safety. Clinical trial information: NCT03634540.
Cabozantinib (C) in combination with atezolizumab (A) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC): Results of Cohort 6 of the COSMIC-021 Study.
Authors: Neeraj Agarwal, Yohann Loriot, Bradley Alexander McGregor, Robert Dreicer, Tanya B. Dorff, Benjamin Louis Maughan, William Kevin Kelly, Lance C. Pagliaro, Sandy Srinivas, Christian Michael Squillante, Ulka N. Vaishampayan, Yingjie Liu, Dominic Curran, Toni K. Choueiri, Sumanta K. Pal
Journal: Journal of Clinical Oncology (2020)

139 Background: C may enhance response to immune checkpoint inhibitors by promoting an immune-permissive microenvironment. COSMIC-021 (NCT03170960), a multinational phase 1b study, is evaluating the combination of C with A in various solid tumors. We report interim results from Cohort 6 in mCRPC. Methods: Eligible pts were required to have radiographic progression in soft tissue after enzalutamide and/or abiraterone, measurable disease, and an ECOG PS of 0 or 1. Prior chemotherapy for mCSPC was permitted. Pts received C 40 mg PO qd and A 1200 mg IV q3w. CT/MRI scans were performed q6w for 52w and q12w thereafter. Bone scans were performed q12w. The primary endpoint is ORR per RECIST 1.1. Other endpoints include safety, ORR per irRECIST, duration of response (DOR), PFS, and OS. Results: As of Oct 2019, 44 mCRPC pts were enrolled with a median follow-up of 10.6 mo (range 3.4+, 17.9). Median age was 70 y (range 49, 90), 50% had ECOG PS 1, 34% had visceral metastases, and 61% had extrapelvic lymph node metastases. 27% of pts had prior docetaxel and 52% had ≥2 prior novel hormonal therapies. The most common any grade TEAEs were fatigue (57%), nausea (48%), decreased appetite (45%), diarrhea (39%), PPE (32%), and vomiting (32%). One Grade 5 TRAE of dehydration was reported in a 90 y/o. Median duration of treatment was 5.3 mo. The ORR per RECIST 1.1 among all pts was 32% (2 CRs [4.5%] and 12 PRs [27%]); 21 (48%) pts had SD giving a disease control rate of 80% in all pts. One pt with initial PD per RECIST 1.1 had an irPR per irRECIST. ORR per RECIST 1.1 was 33% in 36 pts with high-risk clinical features (visceral and/or extrapelvic lymph node metastases). Median DOR for all pts with response per RECIST 1.1 was 8.3 mo (range 1.38+, 9.76+). In 12 responders with at least 1 post-baseline PSA evaluation, 8 (67%) had a PSA decline ≥50%. Conclusions: The combination of C+A had a tolerable safety profile and demonstrated clinically meaningful activity with durable responses in men with mCRPC. Given the encouraging activity in these pts, especially in those with visceral and/or extra pelvic lymph node metastases, further evaluation of C+A in men with mCRPC is being pursued. Clinical trial information: NCT03170960.
NIK links inflammation to hepatic steatosis by suppressing PPARα in alcoholic liver disease
Authors: Yaru Li, Mingming Chen, Yu Zhou, Chuanfeng Tang, Wen Zhang, Ying Zhong, Yadong Chen, Hong Zhou, Liang Sheng
Journal: Theranostics (2020)

Background: Inflammation and steatosis are the main pathological features of alcoholic liver disease (ALD), in which, inflammation is one of the critical drivers for the initiation and development of alcoholic steatosis. NIK, an inflammatory pathway component activated by inflammatory cytokines, was suspected to link inflammation to hepatic steatosis during ALD. However, the underlying pathogenesis is not well-elucidated. Methods: Alcoholic steatosis was induced in mice by chronic-plus-binge ethanol feeding. Both the loss- and gain-of-function experiments by the hepatocyte-specific deletion, pharmacological inhibition and adenoviral transfection of NIK were utilized to elucidate the role of NIK in alcoholic steatosis. Rate of fatty acid oxidation was assessed in vivo and in vitro. PPARα agonists or antagonists of MEK1/2 and ERK1/2 were used to identify the NIK-induced regulation of PPARα, MEK1/2, and ERK1/2. The potential interactions between NIK, MEK1/2, ERK1/2 and PPARα and the phosphorylation of PPARα were clarified by immunoprecipitation, immunoblotting and far-western blotting analysis. Results: Hepatocyte-specific deletion of NIK protected mice from alcoholic steatosis by sustaining hepatic fatty acid oxidation. Moreover, overexpression of NIK contributed to hepatic lipid accumulation with disrupted fatty acid oxidation. The pathological effect of NIK in ALD may be attributed to the suppression of PPARα, the main controller of fatty acid oxidation in the liver, because PPARα agonists reversed NIK-mediated hepatic steatosis and malfunction of fatty acid oxidation. Mechanistically, NIK recruited MEK1/2 and ERK1/2 to form a complex that catalyzed the inhibitory phosphorylation of PPARα. Importantly, pharmacological intervention against NIK significantly attenuated alcoholic steatosis in ethanol-fed mice. Conclusions: NIK targeting PPARα via MEK1/2 and ERK1/2 disrupts hepatic fatty acid oxidation and exhibits high value in ALD therapy.