bluuebunny/crossref_metadata_2025 huggingface dataset:
Examining the effect of dementia on hospitalization outcome for GI cancer: A nationwide retrospective analysis.
Authors: Pan Chun-Wei , Pan Wei-Lin , Pinnam Bhanu Siva Mohan Pinnam
Published: June 2023

e16336

Background: Dementia is a debilitating condition affecting a significant fraction of the elderly, with far-reaching consequences. It is an active field of research, with current emphasis on modifiable risk factors as well as treatment. Considering the limitations that dementia imposes on the management of other medical conditions, we attempt to study its association with, and impact on hospitalizations for gastrointestinal (GI) cancers. Methods: We queried the National Inpatient Sample databases for the years 2016 through 2020, using International Classification of Diseases, tenth revision (ICD-10) codes to include all adult admissions with esophageal, gastric, colorectal, biliary Tract, liver, and pancreatic cancers. We further stratified this cohort based on the presence of a secondary diagnosis of dementia. STATA 17 was used to perform a multivariate regression analysis to compare outcomes in the two cohorts, while adjusting for potential confounders. Results: The study identified 280,180 patients with GI cancer, of whom 4.7% (13,135) had a secondary diagnosis of dementia. The cohort with dementia was found to have a higher proportion of females (47.0%) compared to the non-dementia cohort (40.8%) and a higher median age (77.9 years vs 66.9 years). Additionally, this cohort had a higher prevalence of other medical comorbidities, with 98.2% having a Charlson comorbidity index (CCI) greater than 3 compared to 87.8% in the non-dementia cohort. The primary outcome of the study was in-patient mortality, which was stratified by age groups. In the 41-65 years old group, the mortality rate was higher in the dementia cohort (16.3%) compared to the non-dementia cohort (8.6%), with an adjusted odds ratio (aOR) of 1.96 (95% CI: 1.10-3.48, P<0.05). In the 65-75 years old subgroup, the mortality rate was also higher in the dementia cohort (13.1%) compared to the non-dementia cohort (8.6%), with an aOR of 1.48 (95%CI: 1.14-1.93, P<0.05). In the above-75-year-old subgroup, the mortality was higher in the dementia cohort (11.7%) compared to the non-dementia cohort (8.5%) (aOR: 1.35; 95%CI: 1.16-1.58, P<0.05). Conclusions: Hospitalizations with GI cancer, with a secondary diagnosis of dementia, have higher odds of in-patient mortality compared to those without dementia. This was observed across all age groups. The dementia cohort also had a higher proportion of females and a higher median age, along with a higher prevalence of multiple comorbidities. These findings suggest that individuals with gastrointestinal cancer and dementia face a higher risk of in-patient mortality, highlighting the importance of considering dementia as a part of care planning in patients with GI cancer. [Table: see text]
Establishing functional models of peritoneal carcinomatosis using MicroOrganoSphere (MOS) technology.
Authors: Yousef Abdelrahman M.G. , McCormick Aaron , Smith Amber , Ito Ichiaki , Yousef Mahmoud M.G. , Zeineddine Mohammad A. A. , Helmink Beth A , White Michael , Fournier Keith F. , Delubac Daniel , Shen Xiling , Shen John Paul Y.C.
Published: June 2023

e16337

Background: Appendiceal adenocarcinomas (AAs) are a rare and heterogeneous mix of tumors for which few preclinical models exist for drug discovery. These tumors are commonly treated with chemotherapy according to best practices developed for colorectal cancer, despite clear evidence that the two cancers are distinctly different in their clinical behavior and molecular profiles. In this study, we created functional tumoroid models (MicroOrganoSpheres or MOS) of peritoneal carcinomatosis from appendix cancer and mesothelioma and used these MOS to test the efficacy of different chemotherapy treatments. Methods: After obtaining informed consent, fresh tumor samples were obtained from 5 patients with peritoneal carcinomatosis undergoing surgical resection at The University of Texas MD Anderson Cancer Center and 5 samples were obtained from previously established PDX models. Tissue was digested using xMRS solution and MOS culture was established. H&E was performed on tissue and paired MOS. Results: Five MOS models were successfully established, including four AA and one primary peritoneal mesothelioma (to our knowledge the first time this has been done from a peritoneal mesothelioma). Four (80%) of the 5 PDX models samples successfully generated MOS. Three out of five from the fresh samples generated p0 MOS, but only one continued to grow (20%). The MOS successfully established from fresh biopsy was a moderately differentiated mucinous adenocarcinoma with GNASR201C and KRASG12R mutation, to our knowledge the first time a Patient Derived Organoid (PDO) model of this disease has been created. Identified failure modes were delayed processing times (>48 hours after extraction in 3 out of 5 clinical samples) and low tumor content in samples. Histologically, the MOS recapitulated several important characteristics of the original patients’ tumors, including degree of differentiation, abundance of mucin, and presence of signet ring features. Response of AA MOS models to chemotherapeutic agents and regimes has been evaluated in one model thus far. AAPDX-13, derived from a low-grade mucinous adenocarcinoma, was tested against common CRC treatments: 5-FU (pIC50 5.90), Oxaliplatin (pIC50 4.51), SN-38 (pIC50 5.16). Relative to the mean from multiple CRC MOS, this was less sensitive to 5FU and more sensitive to irinotecan. Conclusions: Novel MOS models for AA and peritoneal mesothelioma were successfully established. MOS recapitulated key histologic features of AA and mesothelioma. Data acquired from this MOS system can aid in identifying appropriate chemotherapy treatments in select patients where there are no existing preclinical disease models.
C-reactive protein (CRP) as a prognostic biomarker in patients with bladder cancer: A meta-analysis.
Authors: Fujiwara Yu , Karol Alexander B. , Reford Emma , Joshi Himanshu , Doroshow Deborah Blythe , Galsky Matt D.
Published: June 2023

e16502

Background: CRP is an acute phase reactant synthesized by hepatocytes in response to inflammatory cytokines including interleukin-6. Peripheral blood CRP, a routinely measured analyte, may reflect tumor microenvironments skewed towards tumor-promoting inflammation. CRP may therefore represent an attractive biomarker to select patients with bladder cancer (BCa) more likely to benefit from therapies directed at modulating tumor-promoting inflammation. Methods: A systematic review was performed to identify studies reporting outcomes based on pre-treatment CRP values in patients with localized and advanced BCa and urothelial carcinoma (UC). The hazard ratio (HR) of overall survival (OS), cancer-specific survival (CSS), relapse-free survival (RFS), and progression-free survival (PFS) between groups with high and low CRP values as defined in each study was extracted. Meta-analysis using the random-effect model was performed to pool HR. Meta-regression analysis was conducted to assess the relationship between CRP cutoff and HR for OS. Subgroup analyses were performed according to clinical disease state and therapies administered. Heterogeneity was assessed using I2 statistics. Results: Overall, 938 articles were identified at initial screening; 22 studies comprising 2,899 patients were included in the meta-analysis. For OS, 17 datasets from 16 studies were used. High CRP levels were associated with decreased OS (HR=2.03, 95%CI:1.67-2.47, p<0.01) although high heterogeneity was observed (I2=91%). Subgroup analyses according to anticancer interventions showed that high CRP values were related to shorter OS, particularly in patients treated with immune checkpoint blockade (ICB; HR=1.78, 95%CI: 1.47-2.15, p<0.01). In meta-regression analysis, the correlation between CRP cutoff value and OS HR was not observed when all 16 studies were considered (Regression coefficient=0.03, 95%CI: -0.13-0.18, p=0.73). However, CRP cutoff value was significantly associated with the HR for OS (Regression coefficient=-0.21, 95%CI: -0.36 to -0.06, p=0.01) when the analysis was limited to eight studies assessing ICB in advanced BCa/UC. Pooled HR of CSS, RFS, and PFS is shown in Table. Conclusions: High CRP values were associated with poorer clinical outcomes in patients with BCa/UC, particularly among patients with advanced disease treated with ICB. CRP may represent an attractive biomarker to enrich populations more likely to benefit from therapies that modulate tumor-promoting inflammation. [Table: see text]
Comparison of peripheral blood markers in predicting the occurrence of immune-related adverse events in patients with metastatic genitourinary cancer treated with cabozantinib + nivolumab +/- ipilimumab.
Authors: Iannantuono Giovanni Maria , Chandran Elias , Simon Nicholas I. , Ley Lisa , Cordes Lisa M. , Wang Tzu-fang , Girardi Daniel da Motta , Gurram Sandeep , Valera Vladimir , Chalfin Heather , Parnes Howard L. , Nadal Rosa , Niglio Scot Anthony , Boudjadi Salah , Banday Abdul Rouf , Kydd Andre Rashad , Steinberg Seth M. , Apolo Andrea B.
Published: June 2023

e16506

Background: Peripheral blood markers (PBM) have been demonstrated to be prognostic and/or predictive for cancer patients (pts) treated with immune checkpoint inhibitors (ICI). Initial evidence has shown their potential role in predicting the occurrence of immune-related adverse events (IrAE) in pts treated with single-agent ICI. We explored the potential role of different PBM in predicting IrAE in metastatic genitourinary cancer (mGU) pts treated with an ICI-based combination. Methods: We retrospectively evaluated 60 mGU pts treated with Cabozantinib + Nivolumab +/- Ipilimumab (CaboNivo +/- Ipi) in a phase I study at the National Cancer Institute. We retrieved their demographics, the occurrence of IrAE, and the baseline values of different PBM (neutrophil/lymphocyte ratio [NLR], neutrophil/eosinophil ratio [NER], lymphocyte/monocyte ratio [LMR], monocyte/lymphocyte ratio [MLR], platelet/lymphocyte ratio [PLR], systemic immune-inflammation index [SII] [N/L*P], and HALP score [albumin*hemoglobin*L/P]). We evaluated PBM based on the presence or absence of IrAE using the Wilcoxon rank sum test followed by multivariable logistic regression analysis. Receiver operating characteristic (ROC) curve analyses were used to investigate an optimal cut-off for PBM suitable for prediction. Results: The median age of pts was 58.5 years (interquartile range [IQR] 46 - 67), and 13 (21.7%) were female. Twenty (33.3%) pts developed at least one IrAE. Baseline median values of PMB are summarized in the Table. A multivariable logistic regression model showed after backward elimination that only NER had the potential to predict IrAE (p = 0.033; Odds Ratio = 0.989 per unit [95% Confidence Interval 0.979 - 0.999]) and thus, we further investigated the predictive potential of NER for the development of IrAE following CaboNivo +/- Ipi. The ROC curve suggested that an optimal cut-off value for NER was 30.647 (area under the ROC = 0.6351). Accordingly, we classified pts with high NER ( > 30.647) as not having IrAE vs low NER (≤ 30.647) as having IrAE. Using this classification, 24/37 (64.9%) of those without (w/o) IrAE and 14/20 (80%) of those with an IrAE could simultaneously be correctly predicted by NER alone. Conclusions: A baseline low NER value was an independent factor associated with a higher probability of developing IrAE in mGU pts treated with CaboNivo +/- Ipi. Prospective validation on a larger cohort of pts is needed. [Table: see text]
Real-world treatment sequencing and outcomes for patients with advanced renal cell carcinoma treated with cabozantinib after first-line checkpoint inhibitor-based combination therapy: Results from the CARINA study.
Authors: Nathan Paul D. , Allison Jennifer , Charnley Natalie , Griffiths Richard , Michael Agnieszka , Moore Kathryn , Sharma Anand , Szabados Bernadett , Venugopal Balaji , Ali Jamshed , Perrot Valérie , Prendergast Áine , Klair Bhupinder , Larkin James
Published: June 2023

e16512

Background: Real-world data are required to guide the optimal sequencing of therapies for advanced renal cell carcinoma (aRCC) when first-line (1L) checkpoint inhibitor (CPI)-based combinations are used. CARINA is a retrospective, non-interventional study of treatment sequencing and outcomes in patients with aRCC who progressed to second-line (2L) treatment after 1L CPI-based combination therapy. Methods: Electronic prescribing records and hospital medical records from nine participating UK specialist centers were reviewed to identify patients (aged ≥ 18 years) with a diagnosis of aRCC who received 2L therapy after 1L CPI-based combination therapy in line with UK National Health Service funding policy. The primary objective was to describe the treatment pathways of patients with aRCC who received 1L CPI-based combination and subsequent therapy. Secondary objectives included descriptive analysis of: duration of treatment (DoT), objective response rate (ORR), progression-free survival (PFS) and overall survival (OS). Here we report a descriptive analysis of outcomes for subgroups who received 2L cabozantinib or other 2L therapies. Results: Between April 2015 and June 2022, data were collected from 281 patients (163 patients received 2L cabozantinib and 118 received other 2L therapies after 1L CPI-based therapy). Overall, mean (standard deviation [SD]) age at aRCC diagnosis was 59.4 (10.1) years, 76.5% were male and 87.5% had clear-cell aRCC (including those with a clear-cell component). In the 2L cabozantinib and other 2L therapies subgroups, the most common 1L regimens were ipilimumab + nivolumab (79.1% and 60.2%, respectively), axitinib + avelumab (9.8% and 22.0%) and pembrolizumab + axitinib (9.8% and 9.3%). Outcomes of 2L treatment for the 2L cabozantinib and other 2L therapies subgroups are shown in the Table. Conclusions: Among patients with aRCC who progressed to 2L treatment after 1L CPI-based therapy, the most common 1L therapies were ipilimumab + nivolumab followed by axitinib + avelumab. DoT and ORR were numerically better with 2L cabozantinib than with other 2L therapies, demonstrating the antitumor effect of 2L cabozantinib after 1L CPI-based therapy. Clinical trial information: NCT04957160 . [Table: see text]
Plasma KIM-1 for preoperative prediction of renal cell carcinoma versus benign renal masses, and association with clinical outcomes.
Authors: Xu Wenxin , Mukeria Anush , Gaborieau Valerie , Niman Samuel M. , Liu Xiaowen , Takakura Ayumi , Zaridze David , Freedman Matthew L. , McDermott David F. , Choueiri Toni K. , Catalano Paul J. , Sabbisetti Venkata , Maremanda Krishna , Bonventre Joseph , Pierorazio Phillip , Singla Nirmish , Brennan Paul , Bhatt Rupal Satish
Published: June 2023

e16518

Background: For patients with suspicious renal masses, it is often unclear which should receive an intervention versus initial surveillance. Both clear cell and papillary renal cell carcinoma overexpress kidney injury molecule-1 (KIM-1) due to their proximal epithelial cell of origin. We investigated whether plasma KIM-1 improves risk stratification of patients with suspicious kidney masses. Methods: Pre-nephrectomy plasma KIM-1 was measured in two independent cohorts of patients with renal masses. Cohort 1, from the prospective K2 trial, included 162 patients found to have ccRCC (cases) and 162 patients with benign renal masses (controls). Cohort 2 included 247 patients with small (cT1a) renal masses from an academic biorepository. Multivariable models were used to assess the relationship between pre-nephrectomy plasma KIM-1, surgical pathology, and subsequent clinical outcomes. Results: In cohort 1, plasma KIM-1 distinguished RCC versus benign masses with AUC-ROC 0.81 (95% CI: 0.76-0.86). In cohort 2 (cT1a renal masses), plasma KIM-1 distinguished RCC versus benign masses with AUC-ROC 0.74 (95% CI: 0.67 to 0.80). Among patients in cohort 2, the prevalence of malignancy was 97% among patients with the highest quartile of KIM-1 compared to 55% among patients with the lowest quartile of KIM-1. Plasma KIM-1 was higher in clear cell RCC and papillary RCC compared to other histologies (p<0.001 in each cohort). Cohort 1 patients had prospective long-term follow-up, and higher pre-nephrectomy KIM-1 was associated with worse metastasis free survival (multivariable MFS HR 1.29 per unit increase in log KIM-1, 95% CI 1.10-1.53) and worse overall survival (multivariable OS HR 1.31 per unit increase in log KIM-1, 95% CI 1.10-1.54). Conclusions: In two independent cohorts of patients with renal masses, elevated baseline plasma KIM-1 is associated with higher risk of malignant pathology, worse metastasis free survival, and higher risk of death. Plasma KIM-1 may be a useful risk stratification tool for patients with suspicious kidney masses.
Renal cell carcinoma with metastasis to the pancreas: Genomic signatures and clinical outcomes.
Authors: Glover Michael , Chiang Ryan S. , Hoerner Christian R. , Khan Osama A. , Kao Chia-Sui , Shah Sumit , Srinivas Sandy , Fan Alice C. , Khaki Ali Raza
Published: June 2023

e16519

Background: Renal cell carcinoma (RCC) is a diverse disease characterized by several subtypes, mutations, and a broad spectrum of sites of metastasis. Previous publications have established that RCC with pancreatic metastases (PM), a rare subpopulation, has more favorable outcomes, even when other metastases sites are involved. Outcomes in this subpopulation tend to be independent of the traditional IMDC risk stratification. We have previously explored the genomic landscape of RCC with PM. In this analysis, we explore the clinical data and correlation with NGS for a subset of patients treated at our institution. Methods: We identified patients (pts) at our institution with metastatic RCC with PM. Included pts had pathologically confirmed RCC with met to pancreas seen on imaging. All identified pts had NGS performed with Tempus xT assay (DNA-seq of 648 genes at 500x coverage). We also extracted demographic, clinicopathologic, and treatment data for included pts through chart review. We describe baseline characteristics, most prevalent gene mutations on xT and overall survival (OS) from time of diagnosis to death with particular attention of OS stratified by PBRM1 mutation. We also performed a log rank test to compare OS for those with and without PBRM1 mutation. Results: 23 pts with metastatic RCC with PM were identified. Pts included were diagnosed with RCC between 1993 and 2020, median age was 62 years (range 42-78), 48% were female, 70% of white race, 35% with smoking history. All patients had a nephrectomy and 91% had clear cell histology. 6 pts (26%) had de novo metastatic disease (3 [14%] with de novo PM). Median time to metastatic disease was 3.5 years (range 0-15.5 years) and median time to PM was 4.7 years (range 0-15.5 years). The most prevalent genes identified with mutations were VHL (70%), PBRM1 (39%), and SETD2 (32%); TP53 mutations were identified in 2 pts (9%). After a median follow-up of 16 years, 10 pts (43%) were deceased (7 due to RCC, 3 due to other causes), 11 pts were alive (5 without disease and 6 with active disease) and 2 with unknown vital status. Median [m]OS for the whole cohort was 12.7 years, which when stratified by PBRM1 mutation was 8.4 and 12.7 years for those with and without PBRM1 mutation, respectively, though this difference was not statistically significant. Conclusions: In our cohort, patients with RCC and PM had an indolent course with a prolonged survival even after diagnosis of metastatic disease. This effect was independent of PBRM1 mutations or other common mutations. As these patients presented with both de novo PM as well as later in the course, this may represent a unique population, rather than a result of survival bias.
A novel prognostic model for oligometastatic renal cell carcinoma: COMPARZ study post-hoc analysis.
Authors: Anwaier Aihetaimujiang , Zhang Hailiang , Yu Jiacui , Wan Hualin , Ong Su Miin , Tay Hao Zhe , Ye Dingwei
Published: June 2023

e16521

Background: International metastatic renal cell carcinoma database consortium (IMDC) is the most commonly used prognostic model for metastatic renal cell carcinoma (mRCC), however, its clinical application has been limited due to the cumbersome design and vague recommendation of treatment decisions for patients in the IMDC intermediate risk group. Previous studies indicated the favorable prognosis of oligometastatic RCC, but the definition of oligometastasis has not been clarified. This study aims to construct a new prognostic model of oligometastatic RCC based on the COMPARZ study cohort. Methods: Patients from the COMPARZ study (which was a randomized phase III non-inferiority study comparing pazopanib and sunitinib in advanced RCC or mRCC patients). Patients (N=1038) were divided into two cohorts for models construction respectively, Cohort A (n=293) with primary kidney tumor; Cohort B (n=745) without primary kidney tumor. Multivariate Cox regression analysis was performed to identify the independent prognostic risk factors for each model with overall survival (OS) as primary endpoint. Uno’s C-statistics was utilized to compare the novel risk model with IMDC risk. These models were then used to examine and stratify the patients in IMDC intermediate risk group. Results: In Cohort A, four risk factors were identified independent predictors for short survival. Patients were segregated into the oligo group and the non-oligo group. The concordance index (C-index) for Model A and IMDC risk model was 0.63 (95%CI: 0.59-0.67) and 0.65 (95%CI: 0.61-0.69), respectively (p=0.389). In Cohort B, three risk factors were identified as independent predictors of short survival. Patients were also divided into the oligo group and the non-oligo group. The C-index between Model B and IMDC risk model was 0.62 (95%CI: 0.59-0.64) and 0.61 (95%CI: 0.58-0.64), respectively (p=0.650). For Model A, mOS for non-oligo group was 13.4 months vs NR in oligo group (3y OS: 25.3 vs 51.8%), while for model B, mOS was 18.5 vs NR respectively (3y OS: 24.3 vs 57.5%). With the novel prognostic models, patients in the IMDC intermediate risk group could be further stratified into oligo group (mOS: NR; 3y OS: 55.6%) that had a better outcome than patients in non-oligo group (mOS: 19.2 month; 3y OS: 24.9%; p<0.001). Conclusions: Compared with the current IMDC model, the novel prognostic models of oligometastatic mRCC could well distinguish patients into favorable and poor prognostic groups with fewer risk factors and comparable predictive power. Meanwhile, the novel models can better stratify the IMDC intermediate risk group into oligo and non-oligo groups with significantly different OS outcomes, and is more conductive to the comprehensive treatment of patients with mRCC.
Camrelizumab combined with tyrosine kinase inhibitors in the treatment of patients with advanced renal cell carcinoma: A single-center prospective exploratory study.
Authors: Xu Jing , Zhu Dongyuan
Published: June 2023

e16522

Background: At present, both NCCN and CSCO guidelines recommend tyrosine kinase inhibitors (TKIs) or immunotherapy combined with TKIs as the first-line treatment of advanced renal cell carcinoma, but no large-scale clinical research data has been disclosed on the treatment of clear cell renal cell carcinoma with camrelizumab combined with TKIs. This study aims to explore the efficacy and safety of camrelizumab combined with TKIs in advanced renal cell carcinoma. Methods: Patients with stage Ⅳ renal cell carcinoma confirmed by histopathology, aged 18-75 years, with an Eastern Cooperative Oncology Group (ECOG) performance status score of 0-1, previously not received systematic treatment or only received one systematic treatment regimen were included in this study. The patients received (1) camrelizumab (200 mg/time, i.v., D1, q2w) (2) sunitinib (50mg, q.d., p.o.): 4 weeks on 2 weeks off, or pazopanib (800 mg, q.d.) or axitinib (5 mg, bid), until the disease progresses, intolerable toxicity occurs or the patient dies. The primary endpoint was the objective response rate (ORR) assessed by the Response Evaluation Criteria in Solid Tumors (RECIST v1.1), and the secondary endpoint was safety, disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). Results: Between August 21，2021，and November 10, 2022, A total of 17 patients were enrolled in the study, with an average age of 58 years old. Of all the patients included, ten (58.8%) had not received systematic treatment, and seven (41.2%) patients had received it. Of these patients, four (23.5%) patients were treated with camrelizumab combined with sunitinib, nine (52.9%) with pazopanib, four (23.5%) with axitinib. All 17 patients received at least one imaging evaluation, 11 (64.7%) patients of which had a partial response (PR) of efficacy evaluation, with an ORR of 64.7%, including 70% for first-line patients and 57.1% for second-line patients; additionally, with 3 (17.6%) cases of stable disease (SD), DCR was 82.4%; 3 (17.6%) patients of progress disease (PD). PFS has not yet been reached, with the PFS rate of 75% in 6 months and 63% in 12 months. Only three patients died, and the median OS has not reached. The main grade 3 adverse events were alanine aminotransferase (ALT) increased, Aspartate Transaminase (AST) increased, and lymphocyte count decreased, all of which were 6 cases (35.5%). No grade 4-5 adverse events occurred. Conclusions: Camrelizumab combined with TKIs in the treatment of patients with advanced renal cell carcinoma has good efficacy and controllable safety, which needs to be further verified by large-scale clinical research. Clinical trial information: ChiCTR2300068189 .
SAMHD1-induced endosomal FAK signaling promotes human renal clear cell carcinoma metastasis through activating Rac1-mediated lamellipodia protrusion.
Authors: Kim Jin Young , An Sunho , Lee Seungmee , Kim Byung Hoon , Shin Sojin , Choe Misun , Ha Eunyoung , Seo Ji Hae
Published: June 2023

e16523

Background: Human sterile α motif and HD domain-containing protein 1 (SAMHD1) has deoxyribonucleoside triphosphohydrolase (dNTPase) activity that allows it to defend against human immunodeficiency virus type I (HIV-1) infections and regulate the cell cycle. Although SAMHD1 mutations have been identified in various cancer types, their role in cancer is unclear. Here, we aimed to investigate the oncogenic role of SAMHD1 in human clear cell renal cell carcinoma (ccRCC), particularly as a core molecule promoting cancer cell migration. Methods: HK-2 (#22190, a normal kidney cell line), Caki-1 (#30046), Caki-2 (#30047), SN12C (#80025), and ACHN (#21611) cells were obtained from the Korean Cell Line Bank (Seoul, Korea). SN12C and ACHN cells were transfected with siRNA targeting SAMHD1. From the Broad GDAC Firehose database ( https://gdac.broadinstitute.org/ ), we downloaded RNA-sequencing (RNA-seq) and clinical data from the pankidney cohort (KIPAN), clear cell renal cell carcinoma (KIRC, ccRCC in the present study), renal papillary cell carcinoma (KIRP, PRCC in the present study), and kidney chromophobe (KICH, chRCC in the present study) datasets. We analyzed 20 pairs of human tissues (tumor and normal specimens) from Dongsan Hospital. The results are expressed as the mean ± SD or SEM. We used a two-tailed Student’s t test for single comparisons or two-way ANOVA for multiple comparisons. Results: We found that SAMHD1 participated in endocytosis and lamellipodia formation. Mechanistically, SAMHD1 contributed to the formation of the endosomal complex by binding to cortactin. Thereafter, SAMHD1-stimulated endosomal focal adhesion kinase (FAK) signaling activated Rac1, which promoted lamellipodia formation on the plasma membrane and enhanced the motility of ccRCC cells. Finally, we observed a strong correlation between SAMHD1 expression and the activation of FAK and cortactin in tumor tissues obtained from patients with ccRCC. Conclusions: In brief, these findings reveal that SAMHD1 is an oncogene that plays a pivotal role in ccRCC cell migration through the endosomal FAK-Rac1 signaling pathway.
Anemia in patients aged ≥75 years with metastatic clear cell renal cell carcinoma: An important IMDC prognostic factor for systemic therapy.
Authors: Mizuno Ryuichi , Tanaka Nobuyuki , Oya Mototsugu
Published: June 2023

e16524

Background: Due to an increase in life expectancy, the incidence of metastatic renal cell carcinoma (mRCC) in patients aged ≥75 years has been increasing. In this study we investigated the characteristics before treatment and the outcomes of systemic therapies for patients aged ≥75 years with mRCC and compared the results with those for patients aged < 75 years in order to determine whether differences in age influenced survival. Methods: A total of 206 consecutive Japanese patients with mRCC, including 47 patients aged ≥75 years, who received systemic therapy were included. Clinical data from medical records were retrieved and analyzed retrospectively. Differences of several factors between the two groups were analyzed by the Chi-squared and Wilcoxon tests. Matching and balancing of the empirical distributions were performed by logistic regression analyses. Survival analyses were determined using a Kaplan–Meier method, and analyzed with a log-rank test. P values less than 0.05 were judged as statistically significant. Results: Elderly patients categorized as favorable risk group based on the International Metastatic RCC Database Consortium (IMDC) stratification system were significantly lower (p = 0.0241). Among IMDC risk factors, the rate of anemia was significantly higher in elderly patients (p = 0.006). No statistically significant benefit in PFS for first (p = 0.2183) and second line treatment (p = 0.2219) was observed, whereas improvements in OS (p = 0.0082) as well as CSS (p = 0.0083) were seen in patients aged < 75 years. Furthermore, mRCC patients aged ≥75 years tend to receive BSC instead of second line active treatment. To determine the impact of higher rates of IMDC intermediate/poor risk group in patients aged ≥75 years, we used propensity score matching using IMDC risk stratification to minimize potential bias. After propensity score matching, the well-matched 46 patients in each group demonstrated similar OS (p = 0.203) and CSS (p = 0.172). Conclusions: For mRCC patients aged ≥75 years, a higher proportion of base line anemia, which resulted in higher rates of IMDC intermediate/poor risk, would be responsible for shorter OS/CSS. In addition, mRCC patients aged ≥75 years tend to receive BSC instead of second line active treatment. Overcoming under-treatment in elderly patients might help to prolong survival in mRCC.
Immune checkpoint inhibitor effects on male reproduction.
Authors: Leong Sally , Wang Christina , Onyshchenko Mykola , Ilangovan Preethi , Rock Adam , Shodiya Michael , Swerdloff Ronald , Yoon Steve , Gianoukakis Andrew G.
Published: June 2023

e16528

Background: Immune checkpoint inhibitors (ICI) have been shown to improve overall survival (OS) in patients with metastatic renal cell carcinoma (RCC) as compared to previous therapy with multi-kinase inhibitors (MKI). However, little is known about the effects of these drugs on male reproductive capacity and the current data regarding effects of MKI and ICI therapies on gonadal function and fertility are both limited and conflicting. We sought to evaluate effects of MKI and ICI on male reproductive function in patients with RCC. Methods: Male patients with RCC receiving MKI or ICI for a period of at least 3 months were identified. Inclusion criteria included age ≤ 50 years, no prior history of chemotherapy, and no prior history of medical or surgical conditions that would affect spermatogenesis such as hypogonadism, Klinefelter syndrome, or vasectomies. Patients were instructed to abstain from ejaculation 2 to 7 days prior to study collection. Follicle-stimulating hormone (FSH), luteinizing hormone (LH), morning testosterone, and a semen analysis was obtained for each patient and analyzed. Results: Of 10 patients, 5 (50%) were on ICI and 5 (50%) were on MKI. Of the patients on ICI, 2 (40%) exhibited abnormal semen morphology, motility, and sperm concentration. Of the patients on ICI, one exhibited elevated LH and FSH levels and one exhibited elevated LH levels only. Of the patients on MKI, 2 (40%) exhibited abnormal semen morphology, motility, and sperm concentration. One patient on MKI exhibited elevated LH and FSH levels. All patients had normal testosterone levels. Conclusions: Our preliminary descriptive data analysis suggests that both ICI and MKI may affect semen morphology and motility, sperm concentration, and LH and FSH levels, but does not affect testosterone levels. Due to the currently limited sample size, abnormal semen analysis and hormone levels may be attributable to confounding factors, such as performance status, the metastatic disease itself, comorbidities, etc. Study recruitment and analysis are ongoing.
Long-term liver and renal dysfunction in patients with metastatic renal cell carcinoma treated with TKI monotherapy: COMPARZ study post-hoc analysis.
Authors: Anwaier Aihetaimujiang , Zhang Hailiang , Yu Jiacui , Wan Hualin , Ong Su Miin , Tay Hao Zhe , Ye Ding-Wei
Published: June 2023

e16536

Background: Tyrosine kinase inhibitors (TKI) are currently the recommended treatment option for advanced renal cell carcinoma (aRCC) patient. Previous studies have shown some hepatorenal toxicity of TKI regimens, but differences in toxicity and long-term toxicity of TKIs have rarely been reported. This study aims to compare short- and long-term hepatorenal toxicity differences between pazopanib and sunitinib, and to explore the factors predisposing to hepatorenal toxicity. Methods: COMPARZ study was a randomized phase III non-inferiority study comparing pazopanib and sunitinib in aRCC patients. Patients without liver metastasis and with available alanine transaminase (ALT), aspartate transaminase (AST), and total bilirubin results were enrolled to evaluate the effect of TKI on liver function. Patients with available serum creatinine (Cr), blood urea nitrogen (BUN), urine protein/creatinine ratio (UPC), and creatinine clearance (CrCl) were enrolled to evaluate factors associated with abnormal renal function. Lab indicators were compared between baseline and at months 12, 24, and 36 by paired t-test respectively. Linear mixed models were used to compare the difference in changes between treatment arms. Multivariate logistic regression was performed to examine the factors associated with recorded adverse events of hepatorenal toxicities. Results: Patients with abnormal liver function tests at baseline had higher elevated ALT, AST and total bilirubin levels at 12 months after TKIs treatment compared with patients who had normal baseline results. ALT levels were not significantly different between pazopanib arm and sunitinib arm at 12, 24 and 36 months. However, patients in the sunitinib arm had significantly higher AST levels than the pazopanib arm at 12 months (p = 0.049). There was no significant difference in total bilirubin level between pazopanib and sunitinib arm. Asian race and pazopanib were two factors that was significantly associated with increased risk of developing abnormal liver function. At 12 months, Cr levels were higher in the sunitinib arm compared with the pazopanib arm . BUN levels were lower in the pazopanib arm at 12 months but conversely was higher in the sunitinib arm at 24 months. UPC levels were significantly elevated in both treatment arms at 12 months (p < 0.001) and 24 months (p = 0.008). CrCl levels decreased in both treatment arms, and was more obvious in the sunitinib group at 12 months and 24 months. Notably, male patients, Asian race, high BMI, and sunitinib were risk factors that were significantly associated with abnormal renal function. Conclusions: Compared with sunitinib, pazopanib was associated with a higher risk of hepatoxicity but lower risk of nephrotoxicity. Overall, Asian patients have a higher risk of developing abnormal liver and renal functions after TKI treatment.
Association of tumor homologous recombination deficiency (HRD) score with immune checkpoint inhibitor benefit in metastatic clear cell renal cell carcinoma.
Authors: Grigg Claud , Sha Wei , Bose Rupali , Neelands Brittany , Brown Landon Carter , Matulay Justin T. , Clark Peter E. , Burgess Earle F
Published: June 2023

e16538

Background: Genomic aberrations resulting in homologous recombination repair deficiency (HRD) can be successfully targeted with poly (ADP-ribose) polymerase (PARP) inhibitors. Tumors with HRD also have a higher tumor mutation burden (TMB) and immunogenic phenotypes, prompting PARP inhibitor + immune checkpoint inhibitor (ICI) trials across cancer types. Clear cell renal cell carcinoma (ccRCC) rarely harbors canonical genomic aberrations associated with HRD. However, a “BRCA-like” HRD phenotype can be detected from next-gen DNA- or RNA-sequencing using models trained on tumors with BRCA1/2 bi-allelic loss. We hypothesized that this novel HRD phenotype is associated with ICI benefit in metastatic ccRCC. Methods: Patients with metastatic ccRCC who underwent nephrectomy and were treated with anti-PD-1/L1 ICI monotherapy +/- ipilimumab were identified in an institutional database (N = 52), and outcomes were determined by chart review. Progression free survival (PFS) and overall survival (OS) were calculated from the start date of ICI treatment. Targeted next generation DNA and whole transcriptome sequencing were performed from archived nephrectomy specimens using the Tempus xT platform. HRD scores were calculated using DNA (HRD-DNA) and RNA (HRD-RNA) based methods as previously described (Liebowitz BD et al. BMC Cancer 2022). HRD status was analyzed as a continuous rather than binary variable, as biologically relevant cutoff thresholds have not been established for ccRCC. Multivariable Cox regression models were used to evaluate the association between HRD scores and PFS or OS when demographic/pathologic covariates were adjusted. Results: The cohort was predominantly white (n = 48; 92%) and male (n = 37; 71%) with good performance status (ECOG 0-1: n = 47; 90%). Half (n = 26) were current/former smokers; median age 67 years and BMI 28. Twenty-four (46%) nephrectomies were cytoreductive. Most tumors were staged pT3/4 (85%) and grade 3/4 (90%) including 18 (35%) with sarcomatoid histology. ICI monotherapy or ICI + ipilimumab were received by 32 (62%) and 20 (38%) patients, respectively, in the 1st (40%), 2nd (40%), 3rd (17%), or 4th (2%) line. Median PFS and OS for the cohort were 6.4 months (95% CI 4.4-11.1) and 62.7 months (95% CI 32.8-not applicable). HRD-DNA and HRD-RNA could be calculated for 47 and 46 subjects, respectively. HRD-DNA was not found to be associated with PFS nor OS. High HRD-RNA score was associated with improved PFS (HR 0.92 per unit increase; 95% CI 0.85-1.00, p = 0.052) in the multivariable model, but not OS. Conclusions: High HRD-RNA was associated with longer PFS for metastatic ccRCC patients undergoing ICI-treatment. A “BRCA-like” transcriptomic signature may be predictive of ICI benefit in ccRCC.
Genome sequencing-based prognosis, mutational analysis, and survival rate of clear cell renal cell carcinoma.
Authors: Centeno Lisa Joy , Pan Hai , Malik Preeti , Hashim Tehmina , Poursina Olia , Velez Diaz Lorena Antonella , Varma Samyukta , Bapat Prachi , Chowdhary Arsh , Alkhatib Lean , Patel Urvish , Palabindela Prasannalaxmi , Kalra Kartik , Patil Ashish , Kukreja Geetika
Published: June 2023

e16543

Background: The clear cell renal cell carcinoma (ccRCC) is the most prevalent genitourinary cancer, and carries a poor prognosis. Information regarding whole genome sequencing, a prognostic prediction system, and overall survival in ccRCC is limited. While loss of VHL is commonly implicated in ccRCC, two genes indicated in other cancers, SDHD and ARID1A, have limited literature on their correlation to ccRCC. Hence, we aimed to analyze the genomic profile, epidemiological characteristics and overall survival of ccRCC. Methods: We utilized cBioPortal cancer genomics [The Cancer Genome Atlas (TCGA) PanCancer Atlas, TCGA Firehose Legacy, and TCGA Nature 2013] to study the genetic mutations associated with ccRCC. Epidemiological characteristics and genetic profiles were evaluated, and a query was generated to calculate 5 year and 10 year survival rate with the most common mutations. Log-rank test and Kaplan–Meier estimator were used in analyzing the survival function. Patients with two or more overlapping mutations (72) were excluded. Results: We identified 761 patients with ccRCC, out of which 442 had primary ccRCC with all demographic details available. 65.8% were males, 58.1% were Caucasian, and 7.2% were African American. Majority of patients (199) were between the ages of 50-65 years. 286 (64.7%) were alive and 156 (35.3%) were deceased. The common mutations associated with reduced survival were VHL, BAP1, SDHA, SDHD, and ARID1A. Median survival of patients with VHL, BAP1, SDHA, SDHD, ARID1A mutations was 118.85, 93.04, 40.70, 2.04, and 6.02 months respectively in comparison with unaltered mutation group (78.44 months) (p < 0.0001). (Table 1) Survival was lowest amongst SDHD [2.04 months] and ARID1A [6.02 months]. (p = 3.26e-10). In survival analysis, SDHD and ARID1A were associated with lowest survival after initial diagnosis at 60 months (Figure 1) and 120 months (Figure 2). (p = 2.592e-3). Conclusions: Our study found that SDHD, ARID1A, and SDHA genes were associated with the worst prognosis in ccRCC with median survival of 2.04, 6.02, and 40.70 months. This study may provide insight for targeted therapies for ccRCC and improve the prognosis of these patients. [Table: see text]
Evaluation of a novel Re-VASC score to differentiate malignant and benign T1a renal masses.
Authors: Fateri Cameron , Roth Bradley , Rao Sriram , Peta Akhil , Danza Clifford , Wignarajah Sailesh , Park Sung-Mee , Kar Nina , Houshyar Roozbeh , Landman Jaime
Published: June 2023

e16548

Background: Early characterization of renal cell carcinoma (RCC) is pertinent for cancer prognosis and patient treatment. However, characterization of renal masses as benign or malignant on computed tomography (CT) remains a difficult clinical challenge. Angiogenesis plays a major role in RCC progression and assessing neovascularity in tumor-burdened kidneys with Re-VASC scoring has been shown to aptly predict tumor pathology and staging. In the current study, we evaluated if Re-VASC can reliably differentiate between malignant T1a ( < 4cm) RCC and benign T1a renal masses. Methods: All eligible patients had a diagnosis of T1a from pathologic or clinical evaluation. The inclusion criteria for malignant masses included a diagnosis of RCC by pathology after partial or radical nephrectomy. Our T1a benign group was comprised of patients with a diagnosis of a non-malignant renal mass (angiomyolipoma or oncocytoma) established via histopathology or CT imaging (fat containing lesions). Re-VASC score was calculated on axial preoperative contrast enhanced CT utilizing the system described below: 0 = No visible neovascularization 1 = visualized single new vessel < 3mm in diameter 2 = visualized single new vessel ≥3mm in diameter 3 = visualized multiple new vessels < 3mm in diameter 4 = visualized multiple new vessels and at least one vessel ≥3mm in diameter. Results: A total of 64 benign and 69 malignant T1a tumors were included. Comparison of the two groups demonstrated no significant differences with regards to age, sex, ASA, and BMI. The average Re- VASC scores was 0.159 and 0.753 for benign and malignant masses respectively (p < 0.001). Additionally, the tumor size for benign masses was 2.373 and for malignant masses was 2.546 (p = 0.210). There was no significant difference in Re-VASC score between the contralateral kidneys of malignant and benign kidney masses (p < 0.508). Additionally, the sensitivity, specificity and positive predictive values were 26%, 86% and 74% respectively, when utilizing a Re-VASC score of 1 as a cutoff for malignancy. Conclusions: Our results show a significantly higher Re-VASC score in T1a malignant tumors and T1a benign tumors. While biopsy remains the gold standard for confirmation of malignant tumors such as RCC, radiological evaluation with tumor scoring systems like Re-VASC may offer a useful clinical decision-making tool in a less-invasive manner. Because renal biopsy carries non-negligible risk of complications, reducing volume of biopsies among low-risk patients may lead to better overall care. The Re-VASC score shows potential as a confirmatory test with a specificity of 86%. We would like to apply the Re-VASC score to an expanded multi-center trial, in order to assess its translatability to the general population.
Frequency of pathogenic germline variants in cancer susceptibility genes in 841 renal cell carcinoma cases.
Authors: Li Mingwei , Qin Jiayue , Liang Xiayuan , Zhou Tao , Zhang Yanrui , Wang Huina , Cao Shanbo
Published: June 2023

e16551

Background: Hereditary Renal cell carcinoma (RCC) syndrome accounts for approximately 5-10% of all kidney cancers. However, the genetic architecture of susceptibility to RCC is not well defined. In this study, we investigated the prevalence and spectrum of pathogenic/likely pathogenic germline variants of cancer susceptibility genes in unselected RCC patients in the real-world Chinese population. Methods: We retrospectively profiled the germline mutations of 841 unselected RCC patients using a next-generation sequencing panel consisting of 808 cancer-related genes. Interpretation of sequence variations was classified according to the American College of Medical Genetics and Genomics guidelines. Genomic alterations include single nucleotide variations (SNV), short insertions/deletions (INDEL) and copy number variations (CNV). Results: Within 841 unselected RCC patients included in this study, 132 germline pathogenic/likely pathogenic (P/LP) variants were identified in 125 patients (14.9%), of which 114 (13.6%) were mutations of SNV/INDEL and 11 (1.3%) were CNV. Overall, 46 patients (5.5%) carried mutations of hereditary RCC syndrome-associated genes such as VHL (13, 1.5%), FH (13, 1.5%) and FLCN (8, 1.0%). Interestingly, variants in other cancer-predisposition genes not traditionally associated with RCC occurred in 9.4% of the unselected series, including 55 (6.5%) patients carried mutations in DNA damage (DDR)-related genes (e.g., MUTYH, CHEK2 and BRCA1/2) and the other 24 (2.9%) had germline mutations of non-DDR-related genes (e.g., SPINK1 and APC). The median age of patients with mutations of RCC syndrome-associated genes was 38 (range 19-77), while the median age of patients with mutations of other cancer-predisposition genes was 52(range 22-82). Furthermore, in patients older than 46 years, the prevalence of P/LP variants in RCC-associated and non–RCC-associated genes were 1.9% and 6.7%, respectively. Notably, among 125 patients with identified germline mutations, nearly half (56, 44.8%) did not meet the recommended criteria for genetic testing. Conclusions: Our findings confirm a high prevalence of pathogenic germline variants in genes associated with both hereditary RCC and other cancer predispositions in the unselected Chinese RCC population. Current guidelines recommendation for genetic testing seemed not sensitive enough to identify patients with hereditary RCC susceptibility. It is rational to promote genetic testing and expand the range of genes in RCC population with advanced age.