tbuckley/cabot-search huggingface dataset:
Association of perioperative acute kidney injury with oncological outcomes in patients who undergo radical cystectomy: A multicenter retrospective study.
Authors: Naoki Fujita, Masaki Momota, Toshikazu Tanaka, Shogo Hosogoe, Shingo Hatakeyama, Takahiro Yoneyama, Yasuhiro Hashimoto, Chikara Ohyama
Journal: Journal of Clinical Oncology (2024)

660 Background: Acute kidney injury (AKI) is a frequent complication in patients with muscle-invasive bladder cancer (MIBC) who undergo radical cystectomy (RC). Previous studies have reported that AKI during cancer treatment was associated with poor oncological outcomes in several malignancies. Moreover, we previously have reported the negative impact of neoadjuvant chemotherapy-induced AKI on oncological outcomes in patients with MIBC. However, the impact of perioperative AKI on oncological outcomes in patients who undergo RC remains unclear. Methods: This multi-institutional retrospective study included 798 patients with MIBC who underwent RC. AKI was defined according to the KDIGO criteria. Stage 1 AKI was diagnosed with an increase in serum creatinine by just 0.3 mg/dL. Patients were divided into two groups: patients who developed AKI after RC (AKI group) and patients who did not (non-AKI group). Multivariable Cox-proportional hazards regression analyses were performed to evaluate the impact of perioperative AKI on recurrence-free survival (RFS), cancer-specific survival (CSS), and overall survival (OS). Results: The median age and follow-up period were 70 years and 64 months, respectively. Of the 798 patients, 408 (51%) developed AKI after RC. Approximately 73% AKI were stage 1 AKI. RFS, CSS, and OS in the AKI group were significantly shorter than those in the non-AKI group ( P = 0.003, P = 0.035, and P &lt; 0.001, respectively). After adjustment for confounding variables, AKI was significantly associated with shorter RFS (hazard ratio [HR] 1.357, P = 0.019), CSS (HR 1.345, P = 0.042), and OS (HR 1.344, P = 0.009). Conclusions: Perioperative AKI was associated with poor oncological outcomes in patients with MIBC who underwent RC. [Table: see text]
Activity of antibody-drug conjugates (ADCs) with radiation in preclinical bladder cancer models.
Authors: Vincent D'Andrea, Yuzhen Zhou, Surish P Shanmugam, Rea Chroneos, Isabella Stelter, Timothy Hanlon, Raie Bekele, William Anderson, Filipe L.F. Carvalho, Joaquim Bellmunt, Kent William Mouw
Journal: Journal of Clinical Oncology (2024)

664 Background: Antibody-drug conjugates (ADCs) are a novel class of therapeutics that combine a tumor cell targeting antibody with a cytotoxic payload. Two ADCs are currently approved in the US for treatment of advanced bladder cancer: enfortumab vedotin (EV) and sacituzumab govitecan (SG). Radiation therapy (RT) plays a central role in trimodality therapy (TMT), a curative treatment approach for muscle-invasive bladder cancer (MIBC). However, the biological activity of ADCs combined with RT in preclinical MIBC models has not been reported. Methods: We use a molecularly annotated panel of human MIBC preclinical models to test the impact of RT on expression of ADC targets and define the combined activity of EV and SG with RT. We also test the in vivo activity of combining ADCs with image-guided, fractionated RT in bladder cancer flank xenograft mouse models. Results: Radiation has variable impact on expression levels of nectin-4 and trop-2, the targets of EV and SG, respectively, as determined by immunoblot, immunofluorescence microscopy, and immunohistochemistry (IHC). Whereas modest dose-dependent increases in nectin-4 and/or trop-2 levels were observed in some models, no significant changes were observed in other models. Importantly, RT did not lead to a significant decrease in nectin-4 or trop-2 expression in any of the models. EV and SG showed additive or synergistic cell killing when combined with RT across preclinical models in vitro. Combining EV or SG with fractionated RT in vivo was well-tolerated, showed improved tumor control, and prolonged survival in bladder cancer flank xenograft mouse models compared to either ADC or RT alone. Conclusions: ADCs demonstrate combination activity with RT across a panel of molecularly diverse bladder cancer preclinical models. These studies provide preclinical data supporting clinical trials to investigate the safety and efficacy of combining ADCs with RT as a bladder-preserving therapy for MIBC.
The role of androgen response pathway in association with tumor biology and response to neoadjuvant immune-checkpoint inhibitors (ICI) in muscle-invasive urothelial bladder carcinoma (MIBC).
Authors: Valentina Tateo, Ewan Gibb, Chiara Mercinelli, Daniele Raggi, Antonio Cigliola, Damiano Alfio Patanè, Emanuele Crupi, Patrizia Giannatempo, Maurizio Colecchia, Marco Moschini, Giulio Avesani, Alberto Briganti, Francesco Montorsi, Daniele Santini, Andrea Necchi
Journal: Journal of Clinical Oncology (2024)

662 Background: Emerging findings from ICI trials are suggestive of differential outcomes in females compared with males. Sex-specific differences in tumor biology, microbiome, and outcomes in MIBC are well-established. Conversely, limited data are available regarding the role of the androgen response pathway in explaining subtype differences between males and females and, most importantly, response to ICI. Methods: We retrospectively evaluated the biomarker findings of the transurethral resection of the bladder tumors (TURBT) and baseline clinical characteristics of patients (pts) with cT2-4N0M0 MIBC who received neoadjuvant pembrolizumab and radical cystectomy (RC) in the PURE-01 study. Transcriptome-wide expression profiling was performed on 102 TURBT samples. We focused on androgen receptor (AR) gene expression and the hallmark androgen response pathway expression quantifying 117 different genes related to the androgen response pathway as previously reported (PMID: 26771021). Pt and tumor characteristics were compared between subgroups using χ2 tests and two-sided Wilcoxon rank-sum tests. Kaplan-Meier curves and log rank tests evaluated gene expression and signature scores in association with the event-free survival (EFS), calculated from start of pembrolizumab treatment. Signature scores were analyzed as continuous values and were split by median and quartile values. Results: Pts received pembrolizumab and RC from 2017 to 2022. There were 87 (85.3%) males and 15 (14.7%) females. AR gene expression was not significantly different between males and females (p = 0.5), whereas androgen response signature was significantly higher in male (p = 0.03). The AR gene expression and androgen response signature scores were more highly expressed in luminal tumors vs rest of molecular subtypes (p = 0.005 and p &lt; 0.001). Despite AR gene expression was not associated with ypT0N0 response (p = 0.425), hallmark androgen response signature scores were significantly lower in ypT0N0 responders (p = 0.033). Higher hallmark androgen response signature scores were statistically significantly associated with shorter EFS (p = 0.028), whereas AR gene expression was not (p = 0.152). Conclusions: For the first time to our knowledge, we reported the androgen response pathway expression to be a potential biomarker of ICI benefit in MIBC. This signature was also associated with a luminal subtype, linked to inferior responsiveness to ICI. If confirmed at a larger scale these analyses will strengthen the need for sex-specific approaches and potentially new combination therapies in MIBC.
Germline mutations in patients with metastatic prostate cancer: A prospective cohort study in South Korea (KCSG GU20-19).
Authors: Joo-Hwan Park, Inkeun Park, Jinju Kim, Chang Seon Lee, Kwonoh Park, Jin Young Kim, Se Hyun Kim, Il Hwan Kim, Hyo Jin Lee, Woo Kyun Bae, Seok Jae Huh, Miso Kim, Min-Young Lee, Seong Hoon Shin, Ho Young Kim, Byeong Seok Sohn, In-Ho Kim, Jae-Lyun Lee
Journal: Journal of Clinical Oncology (2024)

193 Background: Several clinical guidelines recommend screening for hereditary prostate cancer in high-risk groups for metastatic prostate cancer. However, despite the recent increase in the diagnosis of prostate cancer in Korea, genetic testing for hereditary prostate cancer is not being performed, making it impossible to know the frequency of hereditary prostate cancer. This study aimed to determine the prevalence of germline mutations in unselected Korean patients with metastatic prostate cancer. Methods: Between July 2021 and December 2022, metastatic prostate cancer patients were enrolled prospectively, without any specific selection based on age or family history. Germline mutation analysis was performed on DNA from blood via next generation sequencing using SOLIDaccuTestTM DNA HRD (NgeneBio, Korea). Results: A total of 301 patients were enrolled and the prevalence of germline mutation was analyzed. At diagnosis, the median age was 67 (46-91 years old), and the median PSA was 150 ng/mL (3.07-5000). 250 patients had a Gleason score of 8 or higher. 36 patients (12.0 %) carried a pathogenic (14/301, 4.6 %)/likely pathogenic (22/301, 7.3 %) variant in a germline mutation. Of these patients, 11 patients (3.65 %) had BRCA2 mutations. ATM (6/301, 1.99 %) was the second most frequently mutated gene, followed by FH (4/301, 1.33 %), FANCA, FANCD2, MRE11, SLFN11, SMO (0.66 % of each, 2/301), BLM, CHEK2, ERBB3, MAP2K1, and VHL (0.33 % of each, 1/301). Further analysis will be conducted to evaluate the impact of germline mutations on somatic mutation results, treatment patterns, and clinical outcomes. Conclusions: The prevalence of pathogenic germline mutations among unselected Korean patients with metastatic prostate cancer was 12.0 %. Germline mutation prevalence in this cohort was comparable to previous reported results. This study provides the framework for the development of preventive and treatment strategies based on hereditary genetic factors for prostate cancer in the Korean population. [Table: see text]
Predictive roles of NETs and IgG in neoadjuvant chemotherapy for muscle-invasive bladder cancer.
Authors: Bing-Qing Shang, Zhaoru Gu, Honglei Cui, Rui-Yang Xie, Jie Wu, Hongzhe Shi, Xin-Gang Bi, Wang Qu, Wen Zhang, Aiping Zhou, Kaitai Zhang, Lin Feng, Jianzhong Shou
Journal: Journal of Clinical Oncology (2024)

659 Background: Cisplatin-based chemotherapy is the recommended therapy for muscle-invasive bladder cancer (MIBC), in the neoadjuvant setting. However, the efficacy of MIBC for chemotherapy is only about 40%. Therefore, predictors of therapy response are urgently needed. Neutrophils form neutrophil extracellular traps (NETs), a network structure, and growing evidence indicated that it could be a prognostic and predictive marker in cancer. Besides, NETs and IgG could reflect the immune response, even may induce immune tolerance. In MIBC, the predictive role of NETs or IgG in chemotherapy resistance is unclear. Methods: This study included 54 patients with MIBC undergoing neoadjuvant chemotherapy. Immunohistochemical staining with NETs was performed on tumor primary lesions before chemotherapy, and the staining intensity was scored. Serum IgG levels in the pre-treatment baseline and 1 month after chemotherapy were also measured for these patients. Results: Citrullinated histone H3 (H3Cit) as a hallmark of NETs, was an independent predictor of chemotherapy resistance as determined by the multivariate logistic regression analyses [OR=5.94, 95% CI 1.20–45.50, P=0.045]. Additionally, in patients with favorable chemotherapy response, serum IgG levels significantly decreased after 1 month of treatment (P=0.0018), while in those with poor response, there was no significant change. Conclusions: The baseline levels of NETs and the change of IgG after 1-month treatment demonstrated predictive capabilities during neoadjuvant chemotherapy, possibly reflecting the immune status. MIBC patients with high NETs and IgG levels were resistant to neoadjuvant chemotherapy, providing new insights into the treatment of MIBC. However, these results require further validation through larger sample studies. Further validation of our findings could provide a theoretical basis regarding NETs inhibitors or IgG antibodies combined with chemotherapy strategy.
The feasibility of an educational and monitoring smartphone application for patients with advanced renal cell carcinoma undergoing combination immunotherapy.
Authors: Gabriel Roman Souza, Mahati Paravathaneni, Filip Ionescu, Keerthi Gullapalli, Sarah Raymond, Ghazal Jameel, Juskaran Chadha, Rohit K. Jain, Gillian Trujillo, Amayla M. Budet DeJesus, Brandon J. Manley, Amy Schneider, Youngchul Kim, Adele Semaan, Heather S.L. Jim, Philippe E. Spiess, Jad Chahoud
Journal: Journal of Clinical Oncology (2024)

413 Background: Renal Cell Carcinoma (RCC) is a global public health burden with over 400,000 new cases and over 175,000 deaths annually. Immune checkpoint inhibitors (ICI) in combination with vascular endothelial growth factor tyrosine kinase inhibitors (VEGF-TKI) has become an integral part of the management of patients with advanced RCC which requires adaptation of healthcare systems to provide information and optimize the management of drug-related adverse events. This study aims to improve the education on therapy-related symptoms and the quality of life of patients with RCC treated with these drugs. Methods: We created a smartphone application (mHealth) that combines educational data, patient-reported outcomes, and peer-to-peer interactions. We aim to assess the feasibility of expansion of this pilot study. We prospectively enrolled stage IV RCC patients (n=20) undergoing treatment with combination ICI and VEGF-TKI. Therapy-related symptom education, knowledge PRO questionnaires, and peer-to-peer support were provided at baseline and at different time points throughout this study duration (Table 1). Time-course data of PROs were visualized using line plots and then compared with paired t-tests. The study's primary endpoint was to assess acceptability and feasibility of mHealth, defined as acceptable if 50% of patients offered participation agree to be enrolled and feasible if 50% of enrolled patients complete the intervention with 70% of these completing at least 50% of survey instruments. Results: Eighty percent of patients were male, 80% were white, 75% had at least some college education, 70% were married, and the mean age of the cohort was 66 years.A total of 22 patients were approached for the study with an acceptance rate of 90%. Sixty percent of patients completed every questionnaire and knowledge assessment at every timepoint of the intervention and 75% of those completed at least 50% of instruments. PROs data showed no significant difference compared to baseline in global health status, functional scales, and symptom scales across the 24 weeks. We noticed an improvement in the patients' knowledge assessment on symptom management after completion of the mHealth knowledge component. Conclusions: Our pilot study was considered acceptable and feasible, showing preliminary evidence of improvement in patient knowledge with mHealth. Our future direction will be to assess, in a larger randomized study, the efficacy of mHealth in improving the quality of life of patients with advanced RCC treated with ICI and VEGF-TKI. Clinical trial information: NCT05579847 . [Table: see text]
Nonadherence to medications for chronic conditions and risk of nonadherence to androgen receptor signaling inhibitors (ARSIs) in patients with prostate cancer.
Authors: Morgan RL Lichtenstein, Rohit R. Raghunathan, Alexander Z Wei, Boris Gershman, Mark N. Stein, Dawn L. Hershman
Journal: Journal of Clinical Oncology (2024)

92 Background: While ARSIs have become a cornerstone in treatment for prostate cancer, nonadherence to these oral medications is common. We investigated the association between patterns of prior nonadherence to medications for chronic conditions with ARSI nonadherence. Methods: In this retrospective cohort study, the MarketScan database was searched for patients &gt;18 years old with a prostate cancer claim between 1/1/2014 and 12/31/2019 and who filled &gt;2 ARSI prescriptions between 9/1/2013 and 12/31/2020. Nonadherence to medications for 4 chronic conditions (hypertension, hyperlipidemia, diabetes, benign prostatic hypertrophy (BPH)) in the 12 months before diagnosis was defined as a medication possession ratio (MPR) &lt;80%. Nonadherence to ARSIs was defined as an MPR &lt;80% between the first and last ARSI prescription up to 1 year. We used logistic regression to examine the relationship between nonadherence to prior medications and nonadherence to ARSIs. Results: Among 4,898 patients, 967 (19.7%) were nonadherent to ARSIs. Regarding prior medication nonadherence, of the patients prescribed hypertension medications (n=2602), 15.4% (n=402) were nonadherent to hypertension medications, of those prescribed hyperlipidemia medications (n=2234), 18.8% (n=419) were nonadherent to hyperlipidemia medications, of those prescribed diabetes mediations (n=826), 19.1% (n=158) were nonadherent to diabetes mediations, and of those prescribed BPH medications (n=1827), 13.4% (n=245) were nonadherent to BPH medications. Among those without prior medications (n=1031 [21.1%]), 21.3% of patients were nonadherent to ARSIs. Compared to those without prior medications, those who used at least 1 medication prior to ARSI and were adherent to all of them (n=2919 [59.6%]) had a 17.2% nonadherence rate to ARSI treatment (OR: 0.77; 95% CI: 0.64, 0.91; p: 0.003). Those who used at least 1 medication prior to ARSI and were nonadherent to 1 of them (n=722 [14.7%]) had a 24.0% nonadherence rate to ARSI (OR: 1.16; 95% CI: 0.93,1.46; p: 0.195), while those who used at least 1 medication prior to ARSI and were nonadherent to &gt;2 (n=226 [4.6%]) had a 30.5% nonadherence rate to ARSI (OR: 1.62; 95% CI: 1.18,2.23; p: 0.003). Conclusions: Nonadherence to medications for chronic conditions prior to ARSI treatment is common and associated with greater nonadherence to ARSIs in patients with prostate cancer. History of medication nonadherence could serve a marker to target a high-risk population for adherence interventions. [Table: see text]
Association of DAZL expression with risk of recurrence in clinical stage 1 testicular germ cell tumors.
Authors: Alok Tewari, Anis Hamid, Jiaming Huang, Caiwei Zhong, Wanling Xie, Emily Rothmann, Peter Nicholls, Nathan Walk, Iva Brcic, Angelika Terbuch, Eliezer Mendel Van Allen, Christopher Sweeney
Journal: Journal of Clinical Oncology (2024)

523 Background: One model for testicular germ cell tumor (TGCT) formation posits that these tumors arise from a failure of germ cell determination characterized by persistent pluripotency and apoptotic escape. Risk assessment for relapse in clinical stage 1 (CS1) TGCT is dictated by clinical factors; molecular biomarkers to improve patient stratification for post-orchiectomy care are lacking. In this study, we examined the relationship between protein expression of pluripotency and apoptosis factors and risk of relapse in clinical stage 1 TGCT. Methods: Orchiectomy specimens from 73 patients treated for clinical stage 1 TGCT at one institution (27 seminoma, 46 non-seminoma) were subjected to immunohistochemistry (IHC) to assess protein expression of DAZL, POU5F1, BAK1, DDX4, NANOG, and PMAIP1. Samples were dichotomized as negative or positive for target protein expression. Patients with CS1 TGCT managed with surveillance were annotated for baseline clinical characteristics and whether they experienced relapse within two years of orchiectomy. Exact logistic regression estimated odds ratios (OR) and 95% confidence intervals were calculated for the association between protein expression and relapse. Results: At two years, 17% of patients in our cohort experienced relapse. DAZL expression (score &gt; 0) was detected in 43% of seminoma samples and 13% of embryonal carcinomas. After adjusting for histology, tumors negative for DAZL expression were more likely to recur within two years (adjusted OR for recurrence 0.08, 95% CI 0 – 0.81, p = 0.03). The direction of this relationship was consistent in seminoma when adjusted for tumor size (adjusted OR 0.14, 95% CI 0-1.83, p = 0.18) and non-seminoma after adjustment for embryonal predominance and lymphovascular invasion (adjusted OR 0.53, 95% CI 0-3.10, p = 0.30). No notable findings were observed for POU5F1, BAK1, DDX4, NANOG, and PMAIP1. Validation studies in two independent cohorts from other institutions are ongoing. Conclusions: The absence of DAZL expression by IHC is associated with a greater risk of relapse in CS1 TGCT. As DAZL promotes germ cell commitment by suppressing the pluripotency program, absence of DAZL expression may promote an oncogenic germ cell phenotype and more aggressive tumor behavior. Validation in larger patient cohorts is required to credential DAZL as a biomarker for clinical stage 1 relapse on surveillance.
Prognostic value of PSMA-extracellular vesicles in oligometastatic castration-sensitive prostate cancer treated with stereotactic ablative radiotherapy: A multi-center observational study.
Authors: Fabrice Lucien, Jack R. Andrews, Yohan J Kim, Edlira Horjeti, Ali Arafa, Philip Sutera, Aurélie De Bruycker, Carole Mercier, Ryan Phillips, Daniel Song, Ana Ponce Kiess, Piet Ost, Phuoc T. Tran, Daniel S Childs, A. Oliver Sartor, Jacob Orme, Sean Sunghun Park
Journal: Journal of Clinical Oncology (2024)

191 Background: Two randomized clinical trials have demonstrated that SABR can prolong time to progression in oligometastatic castration-sensitive prostate cancer (omCSPC) patients. However, there is a need for predictive tools to identify patients who will benefit from SABR alone or with systemic therapy. We investigated the prognostic value of PSMA-positive extracellular vesicles (PSMA+EVs) in a blinded observational study using blood samples from three independent patient cohorts. Methods: We obtained plasma samples from 157 omCSPC patients treated with SABR from the ORIOLE cohort (N=30, JHU) and STOMP-like cohorts (N=80, UGhent; N=47, Iridium Net). Baseline PSMA+EV levels (EV/ml) were measured by nanoscale flow cytometry. Primary clinical endpoints were biochemical progression (bPFS) and radiographic progression (rPFS). Optimal cutoffs for PSA (ng/ml) and PSMA+EV (EVs/ml) were defined as the point with the most significant log-rank test split. Kaplan-Meier curves and univariate Cox regression models were used to determine the association of PSMA+EV levels with clinical outcomes. Results: Twenty percent of patients (N=157 total) were diagnosed with bone scan, 79% with PET imaging, and 1% with other modalities. Ninety-four percent of patients presented with ≤3 metastases on imaging. In the pooled STOMP-like cohorts, median bPFS was 27.9 and 18.0 months for PSMA+EV low and high groups, respectively (p=0.039). Median rPFS was 36.0 versus 27.0 months (p=0.029). In the ORIOLE cohort, median bPFS was 24.3 and 5.9 months in PSMA+EV low and high, respectively (p=0.021). Median rPFS was 36.0 versus 11.1 months (p=0.019). High baseline PSMA+EV levels were associated with higher risk of both biochemical and radiographic progression (Table). Combination of baseline PSA low and PSMA+EV low outperformed either biomarker alone and better predicted risk of disease progression after SABR. Conclusions: While prospective biomarker-guided trials are warranted, a PSMA+EV blood test can aid patient selection by identifying omCSPC patients who may have durable responses to SABR without ADT. [Table: see text]