bluuebunny/crossref_metadata_2025 huggingface dataset:
KRAS mutation detection and cfDNA in liquid biopsy as prognostic factors in pancreatic adenocarcinoma.
Authors: Fabregat-Franco Carles , Matito Judit , Martin Agatha , Verdaguer Helena , Castet Florian , Aymar Josep Maria Miquel , Castillo Gloria , Sierra Alexandre , Vivancos Ana , Macarulla Teresa
Published: June 2022

e16302

Background: Approximately 80% of pancreatic ductal adenocarcinoma (PDAC) patients present with advanced disease at diagnosis, with a 5-year survival rate of less than 5%. According to molecular profiling, mutations in KRAS have been described in 90% of PDAC patients, and correlated with poor prognosis. Nevertheless, the invasiveness of tumor biopsy and the difficulties in obtaining quality samples in some patients remains a concern. Circulating free DNA (cfDNA) is considered a surrogate marker of tumor burden and may also act as a prognostic factor that can be used independently from tumor biopsy. In this study, we aim to explore molecular prognostic biomarkers using plasma samples. Methods: Patients with metastatic PDAC harboring KRAS mutation in tissue samples and treated with first-line chemotherapy were identified at Vall d’Hebron University Hospital. Clinical features and plasma samples were collected before starting any treatment. DNA mutations were analyzed in plasma and compared with tissue samples. In plasma, detection of KRAS mutation and total cfDNA concentration were evaluated for clinical significance. A cfDNA minimum 100 genome equivalent threshold was proposed based on results and utility. A Chi-square test was planned to prove the independence between cfDNA levels and KRAS detection in plasma. Survival analysis was performed using the Kaplan-Meier method. Results: We included 33 PDAC patients with a median age of 66.1 years old, 57% were women. All of them were treated with gemcitabine and Nab-paclitaxel. At the final analysis cut-off, 31 patients had died . KRAS mutation was detected in 25 patients’ blood samples (75.8%) and cfDNA-High levels were considered for 20 patients (60.6%). 19 of 20 (95%) patients with cfDNA-High correlated with KRAS blood detection, showing significant dependence (p-value 0.001). Median overall survival (OS) was 10.5 months in the KRAS detected group compared with 22.6 months in the KRAS non-detected group (HR for death 4.70; confidence interval (CI) 1.70-12.98, p-value 0.002). Better separation was seen using cfDNA where median OS was 9.8 months in the cfDNA-High group compared with 21.0 months in the cfDNA-Low group (HR for death 5.38; CI 2.17-13.31, p-value < 0.001). Conclusions: Liquid biopsy can provide quality prognostic information in metastatic PDAC patients. On account of this, the cfDNA level is proposed as a prognostic factor. However, prospective cohorts to validate this information are needed.[Table: see text]
A multivariate logistic model to predict odds of small bowel cancer by various risk factors.
Authors: Franco Diana , Farooq Umer , Rehman Mohammad Ebad Ur , Ma Irene
Published: June 2022

e16307

Background: Small bowel cancer (SBC) is a rare malignancy, and current epidemiologic literature consists of small single-center studies describing various etiologic associations. Therefore, we evaluated the strength of association of various SBC risk factors using a nationally representative patient sample. Methods: We investigated the National Inpatient Sample 2019 employing International Classification of Diseases-10 (ICD-10) codes to include adult patients with SBC. Odds of SBC were tested for various risk factors individually using univariate logistic regression. In addition, a multivariate regression model was developed to test the odds of developing SBC while controlling for all other risk factors. Analyses were performed using STATA (v 14.2), considering 2 sided P< 0.05 as statistically significant. Results: Out of 30,200,000 adult hospitalized patients in 2019, 9,629 had a diagnosis of SBC. Each one-year increase in age predicted a 4% increased odds of SBC. Males had 28% higher odds compared to females. Compared to whites, Blacks and Asians had higher odds of SBC while Hispanics did not. Smoking, alcohol, HIV, and low socioeconomic status were associated with higher odds of SBC while controlling for all other risk factors ( P < 0.05). Disorders of lipid metabolism, hormone replacement therapy, prior cholecystectomy, celiac disease were associated with lower odds. Crohn’s disease, familial adenomatous polyposis (FAP), and Lynch syndrome were not significantly associated with higher odds of SBC ( P > 0.05). Conclusions: FAP and Lynch syndrome appear to increase the risk of polyp formation in the small intestine but not SBC. The lower odds mentioned for certain variables are merely an association and do not imply a protective effect. The reliance on ICD-10 codes and the inability to distinguish between various cancer subtypes limits our conclusion and needs to be addressed in future studies.[Table: see text]
Identification of molecular feature in tumor immune microenvironment of bladder cancer patients.
Authors: Cao Ming , Xue Wei , Zhang Jiali
Published: June 2022

e16500

Background: Bladder cancer (BC) is the most common malignant tumor of the urinary system, with various heterogeneity. Immunotherapy has become one of the hot areas of cancer research. Tumor immune microenvironment is closely related to prognosis and immunotherapy effect. Therefore, Immune cell infiltration analysis is necessary for the prognosis and treatment of BC. Methods: In this study, we analyzed IMvigor210 dataset, which included complete expression data and detailed clinical information from a cohort associated with Bladder Urothelial Carcinoma (BLCA) immunotherapy. The dataset was divided into two groups based on tumor remission after immunotherapy, including 68 remission samples and 230 stable samples. The CIBERSORT program package was used for immune invasion analysis to compute the relative proportion of immune cells in the tumor tissue from tissue gene expression profiles. Results: Significant results of differentially immune cells proportion were obtained in 126 BC patients by CIBERSORT analysis ( p< 0.05). Compared with the stable group, the number of resting memory CD4+ T cells decreased and the number of CD8+T cells increased in the remission group. The relative proportion of immune cells in tumor microenvironment has certain influence on the occurrence and development of tumor. Conclusions: Memory CD4+ T cells in the resting state did not promote the activation and proliferation of CD8+ T cells, whereas resting memory CD4+ T cells were associated with poor outcome. The increased level of CD8+ T cells in tumor microenvironment was associated with the anti-tumor effect and improved prognosis of various cancers. The results indicate that resting memory CD4+ T cells and CD8+ T cells may be the target of immunotherapy.
Real-world outcomes in advanced renal cancer patients treated with stereotactic radiosurgery for intracranial metastases.
Authors: Fatimilehin Abiola , Mahabubabinta Hossain , Stephen Kennedy , Pillai Manon Rhys , Charnley Natalie
Published: June 2022

e16516

Background: The proportion of metastatic renal cancer (mRC) patients with intracranial involvement is 8%, and 2% develop brain secondaries exclusively [1]. Although renal cancer is generally regarded as relatively radioresistant, studies have shown patients treated with stereotactic radiosurgery (SRS) demonstrate a local progression free survival (PFS) rate of 79-84% at 1 year and median overall survival (OS) of 9.6 – 13.9 months [2,3]. We evaluate the outcomes of patients with mRC who have received SRS to intracranial metastases at two tertiary centres in the North West of England. Methods: Patients who received SRS from January 2017 to July 2019 at Royal Preston Hospital, and from May 2016 to March 2021 at the Christie were retrospectively identified from the database of the respective hospitals. Clinical records were used to obtain demographics, therapies received and follow up data. Results: A total of 41 patients were identified. 31 patients (76%) were male and the average age at treatment was 59.6 years. 5 patients received treatment on >1 occasion, but only the first episode was considered for analysis. 80.4% had a performance status of 0-1 and most patients had clear cell histology. 19 patients (46.3%) had lesions treated bilaterally. The median follow up time was 11 months. Prescribed doses ranged between 18Gy to 30Gy in 1-5 fractions. 11 patients (26.8%) progressed during the follow up period, with a median time to progression of 5 months. The longest time to progression was 17 months, in a patient who received Nivolumab following SRS. 28 patients (68.3%) died during the follow up period with a median time to death of 9.1 months. Median OS was 11 months, with 19 out of the 28 patients (67.9%) dying within the first year. The 1 year survival rate was 52.6% and 2 year survival rate was 16.2%. A range of systemic agents were used pre and post SRS including immunotherapy. 6 patients (23%) commenced immunotherapy following SRS (nivolumab +/- ipilimumab), with OS ranging from 6 – 49 months (average 25.5 months). Conclusions: We found that outcomes in this cohort of patients treated with SRS were comparable to previous findings. A subgroup who commenced Nivolumab following SRS demonstrated an average survival of over 2 years.[Table: see text]
Effect of adrenergic receptor antagonists on clinical outcomes in metastatic renal cell carcinoma.
Authors: Ganta Teja , Tsao Che-Kai
Published: June 2022

e16520

Background: Adrenergic receptors (ADR) have a well-established role in kidney physiology, suggesting a possible role of ADR signaling in renal cell carcinoma (RCC). Preclinical studies have shown a possible anti-tumor effect of both alpha-adrenergic blockers (AB) and beta-adrenergic blockers (BB) on renal cancer cells. However, the literature is conflicting regarding the effect on clinical outcomes. In addition, there is no comprehensive analysis of what role these medications have specifically in RCC patients with metastatic disease. In this single health system retrospective study, we evaluate the effect of AB or BB prescription on cancer-specific outcomes in patients with metastatic RCC. Methods: Clinical data was abstracted from the electronic health record and the institutional cancer registry at The Mount Sinai Health System to include patients with RCC diagnosed with metastatic disease ( de novo or relapsed) between 2016-2020. Follow up data was recorded until a data lock of 4/1/2021. Multivariate Cox regression was used to evaluate the association of AB and BB prescription on overall survival (OS) for the entire cohort and progression free survival (PFS) for patients who received any first line therapy. Multivariate logistic regression was used to evaluate association of these medications with overall response rate (ORR) of first line therapies with available data on initial response. Analyses were controlled for clinical risk factors including age at diagnosis, sex, race, treatment plan including immunotherapy, and medical history of benign prostatic hyperplasia, hypertension, or heart failure. Data was analyzed using R version 4.1.0. Results: 133 patients were identified for inclusion in the study. 61% of cases are de novo metastatic and 39% are relapsed from previously resected disease. 71% are clear cell histology, 3.8 % are papillary, and the rest are unspecified/other. 84 patients (63%) received at least a 1st line systemic therapy. AB or BB prescription alone is not associated with OS, PFS, or ORR. However, prescription of both AB and BB is associated with worse OS (HR 2.94 95% CI 1.13-7.68), worse PFS (HR 7.70 95% CI 1.80-33.0), and decreased odds of responding to 1st line therapy (OR 0.06 95% CI 0.00-0.55) on multivariate analysis. Conclusions: The data suggests that the concurrent use of both an AB and BB in patients with metastatic RCC leads to worse clinical outcomes. What remains unclear is if there is a negative synergistic effect of these medications on RCC pathophysiology or if the prescription of these medications is associated with another negative confounding clinical factor. Since these medications are commonly utilized for cardiovascular disease, multivariate analyses attempted to control for these comorbidities. Future studies may add to this data by cataloging the severity of heart failure and doses of AB and BB medications used in a RCC cohort.
Fumarate hydratase-deficient renal cell carcinoma: The real-world experience at Dana-Farber Cancer Institute and Moores Cancer Center.
Authors: Saliby Renee Maria , Labaki Chris , Xie Wanling , Nonato Taylor , Schmidt Andrew Lachlan , Bakouny Ziad , Xu Wenxin , Ravi Praful , Braun David A. , Hirsch Michelle S. , McKay Rana R. , Choueiri Toni K. , McGregor Bradley Alexander
Published: June 2022

e16522

Background: Fumarate hydratase (FH)-deficient renal cell carcinoma (RCC) is a rare and aggressive tumor with limited clinical trials dedicated to therapeutics for this disease. This retrospective study aimed to report a multi-center experience in the systemic treatment of FH-deficient RCC. Methods: The medical records of patients undergoing systemic therapy for advanced or metastatic FH-deficient RCC at Dana-Farber Cancer Institute and Moores Cancer Center were reviewed from 2012 to 2021. Demographic, histologic, molecular, and survival parameters were collected. Response was assessed using RECIST 1.1 criteria. A confirmative initial diagnosis of FH-RCC was made utilizing FH/2SC immunohistochemistry (n = 12) and/or the presence of an FH mutation (n = 6). The primary endpoint of this study was to characterize patients with FH-deficient RCC in the modern era. Results: 18 patients were included; median age at diagnosis was 45 (interquartile range [IQR]: 40-55) years. All patients had a Karnofsky Performance Status (KPS) ≥ 80. Among 14 patients with evaluable IMDC criteria, 1 (7.4%) had favorable-risk disease, while 10 (71.4%) and 3 (21.4%) had intermediate- and poor-risk disease, respectively. Tumors at diagnosis were stage III (n = 6, 33.3%), and IV (n = 12, 66.7%). Median time from diagnosis to the start of systemic therapy was 2.8 months. Six types of regimens were given as first-line therapy (Table). Fourteen patients (78%) developed disease progression on frontline therapy and received subsequent therapy; two patients, initially treated with an mTOR inhibitor and combined vascular endothelial growth factor (VEGF) inhibitor and immune checkpoint inhibitor (ICI), are off therapy and still under surveillance with no recurrence to date; one patient passed away while on frontline therapy; and one patient has limited follow-up. For a median follow-up of 22 months (IQR:6.4-49), the 18-month-overall survival estimate was 81% (95% confidence interval [CI]: 53%-94%) and median progression-free survival (PFS) was 6.7 months (95%CI: 5.0-17.0). Conclusions: This study shows considerable heterogeneity in the treatment for FH deficient-RCC, with disparate clinical outcomes. Dedicated trials and guidelines on the management of FH-deficient RCC are needed.[Table: see text]
Clinical effectiveness of second-line TKI plus PD-1 following targeted therapy in patients with metastatic non-clear cell renal cell carcinoma: A real-world study.
Authors: Wang Jun , Zhang Zhiling , Wei Wensu , Li Zhiyong , Han Hui , Guo Shengjie , Li Zhiyong , Dong Pei
Published: June 2022

e16523

Background: Non-clear cell renal carcinoma (nccRCC) usually had a poorer response to tyrosine kinase inhibitors (TKIs) due to its heterogeneity and rarity. The combination of immunotherapy with TKIs has shown promising efficacy in ccRCC. However, for nccRCC failed standard first-line TKI therapy, the second-line option is still limited. This real-world study aimed to evaluate the efficacy of immune-targeted combination therapy versus TKI monotherapy as the second-line regimen in patients with metastatic nccRCC who failed first-line TKI therapy. Methods: Demographic and clinicopathological data of patients with metastatic nccRCC who were admitted into the Sun Yat-sen University Cancer Center between October, 2011 and September, 2020 were retrospectively collected. All patients failed in first-line TKI therapy and received second-line TKI alone (TKI group) or TKI plus PD-1 therapy (combination group). Efficacy including the objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS) and overall survival (OS) was calculated. The differences on baseline characteristics and efficacy between the two groups were compared. Results: Totally 67 patients were included, with a median age of 50 (interquartile 37-60) years. The median follow-up time was 32.7 (interquartile 21.6-53.0) months. The overall ORR, DCR was 37.3% and 56.7%, respectively. The overall second-line PFS was 7.2 (95% CI: 5.8-8.5) months and OS was 53.2 (18.4-88.0) months. Baseline characteristics between the combination group (n = 45) and the TKI group (n = 22) did not differ significantly except that the combination group had more proportion of liver metastasis (20.9% vs 4.5%, P = 0.025). The combination group had a significantly longer PFS compared with the TKI group [median PFS (95% CI): 9.2 (6.4-12.0) vs 5.2 (2.9-7.5) months, P = 0.001]. Similarly, ORR (48.9% vs 13.6, P = 0.005) and DCR (71.1% vs 27.3%, P = 0.001) was remarkably improved in the combination group. The superior efficacy over TKI monotherapy was more prominent in the younger (< 60 years), male, and patients with lower KPS, IMDC intermediate/poor-risk, non-hereditary RCC and multiple metastatic sites. Conclusions: Immune-targeted combination therapy was effective in the treatment of metastatic nccRCC who failed first-line TKIs.[Table: see text]
Exploratory analysis on crosstalk between intra-tumor immunity and FGF/FGFR pathway in clear cell renal cell carcinoma.
Authors: Narisawa Takafumi , Naito Sei , Mitsuda Yoshihide , Oe Rintaro , Sato Hidenori , Kobayashi Chizuru , Fukuda Mizuki , Kitaoka Takumi , Miyano Yuki , Ito Hiromi , Kimura Mizuki , Hamaguchi Makoto , Aoshima Ken , Futakuchi Mitsuru , Tsuchiya Norihiko
Published: June 2022

e16525

Background: Clear cell renal cell carcinoma (ccRCC) patients classically show good response to VEGFR inhibitors; however, the biological basis by which FGFR inhibition provides tumor response was not well understood. Here, we performed an exploratory analysis of the relationship between the FGF/FGFR pathway and intra-tumor immunity to support the effectiveness of FGFR inhibitors for ccRCC. Methods: We used whole transcriptome data and immunohistochemistry with metastatic clear cell RCC specimens from patients who were treated at the Yamagata University Hospital (n = 57). FFPE samples were prepared from the primary lesions of treatment-naive metastatic ccRCC patients. FFPE was sliced by a pathologist to evaluate the immunological microenvironment. RNA extraction and immunostaining were performed at the same site. Immuno-histological quantification was performed by automatically analysis system HALO in digital whole slide imaging. Hierarchical clustering was performed, and the cohort was divided based on the profile of the FGF and immune cells. We analyzed the cancer-specific survival based on the FGF cluster classification and investigated the relationship between FGF-FGFR expression and immune cell infiltration that were evaluated histologically. Results: RNA transcriptome data showed that FGF2 and FGF7 were widely expressed in ccRCC. Hierarchical cluster analysis based on the FGF expression profile (intrinsic FGFs were excluded) revealed that metastatic ccRCC had three distinct patterns. Cluster1 showed low FGFs expression, except for FGF2 and 7, while Cluster2 and 3 expressed multiple FGFs. Survival analysis showed Cluster2and 3 had a poor cancer-specific survival rate than Cluster1 (Logrank test, p = 0.05). However, no association was detected between the FGF cluster classification and the infiltration of immune cell count in immunohistological analysis. In comparison of the expression of each FGF subfamily and the positive cells of CD4, CD8, CD68 and CD31 (Mann–Whitney U test, p < 0.05), CD4 and CD8 were higher in the cases expressing FGF20. While most FGF subfamilies have been suggested to be less associated with immune cell infiltration (excluding FGF20), further analysis among FGF receptor expression and immune signatures are ongoing. Conclusions: Our study demonstrates the possibility of intra-tumor interaction between FGF/FGFR axis and immune infiltration in ccRCC.
Toxicities of anti-VEGF therapies used in metastatic renal cell carcinoma: A real-world experience.
Authors: Master Samip R. , Findakly Dawood
Published: June 2022

e16533

Background: Tumor endothelial proliferation inhibition using vascular endothelial growth factor-tyrosine kinase inhibitors (VEGF-TKIs) have revolutionized metastatic renal cell carcinoma (mRCC) therapy. We retrospectively analyzed data on various anti-VEGF adverse events (AEs) utilizing the FDA Adverse Events Reports System (FAERS). Methods: We examined the FAERS public dashboard data on VEGF inhibitors’ reported AEs for the years 2019-2021. Data analyzed using descriptive statistics. Results: A total of 34,651 AEs were identified for anti-VEGF therapies, of which 29,328 (84.6%) were serious and 5,830 (16.82%) reported deaths (Table). Lenvatinib has most reported serious hemorrhagic events and thyroid impairment in 5.5% and 1.2%, respectively, and least (3.4%) reported dermatologic toxicity (including Hand-foot skin reaction, depigmentation, and rash. Cabozantinib has most (2.8%) reported gastrointestinal (GI) perforation and fistula. Pazopanib has most bone marrow suppression (BMS)—neutropenia, leukopenia, thrombocytopenia, and anemia (43.3%), dermatologic toxicity (25.8%), hepatotoxicity—jaundice, elevated transaminases, hyperbilirubinemia, hepatic encephalopathy, coagulopathy, ascites, and/or hepatorenal syndrome (23.9%), arterial thromboembolic events (ATE)—comprising cerebral infarction, ischemic stroke, transient ischemic attack, myocardial infarction, angina (19.8%), proteinuria and nephrotic syndrome (NS; 10.4%), pulmonary toxicity—interstitial lung disease, and pneumonitis (7.2%), posterior reversible encephalopathy syndrome (PRES; 4.9%), cardiotoxicity—cardiac failure (3.1%), and tumor lysis syndrome (TLS; 0.9%). Sunitinib has most reported osteonecrosis of the jaw AEs (ONJ; 37.3%), QT Prolongation and various arrhythmias (11.9%), severe hypertension (SHTN—including accelerated, urgency, and emergency; 10.0%), and aortic complications—including aortic aneurysm, dissection, and rupture (3.1%). Conclusions: Pazopanib has most while axitinib has least reported BMS, ATE, and pulmonary AEs. Cabozantinib has most reported GI AEs and sunitinib has most reported ONJ, SHTN, QT prolongation, arrhythmias, and aortic complications. With expanding treatment landscape for mRCC, this study helps shed light on the different anti-VEGF toxicity profiles and would therefore support treatment decision making.
Single-nucleus RNA-sequencing analysis reveals transcriptome differences in TIGIT+ exhausted T-cell associated with poor prognosis in muscle-invasive bladder cancer (MIBC).
Authors: Xiao Shanshan , Wang QI , Zheng Liuqing , Wang Qian , Wang Tao ,   Hangzhou Repugene Technology Co,.Ltd
Published: June 2022

e16544

Background: Compared with single-cell RNA-sequencing (scRNA-seq), Single-nuclei RNA-sequencing(snRNA-seq) can detect more genes with higher sensitivity, and it is more robust in identifying cellular markers. TIGIT+ exhausted T cells were reported significantly associated with poor prognosis in muscle invasive bladder cancer(MIBC) by flow cytometry. We aimed to evaluate unique markers of TIGIT+ exhausted T cells in MIBC via snRNA-seq and to construct a potential prognostic survival model. Methods: We collected snRNA-seq data from 25 MIBC and 4 non-MIBC patients in GSE169379, including 57 cancer tissues and 4 distant normal tissues. Meanwhile, expression profiling data and clinical information of 402 Bladder Urothelial Carcinoma(BLCA) patients were collected in The Cancer Genome Atlas (TCGA). Firstly, the snRNA-seq data was preprocessed and filtered. Next, We re-clustered T-cell subsets and abstracted TIGIT+ exhausted T cells (TIGIT+Tex), then screened out the genes uniquely expressed in TIGIT+Tex subsets by differential expression analysis. We further evaluate the correlations between uniquely expressed genes and the exhausted T cell markers, identified significantly correlated differential expressed genes, constructed a prognostic model based on multivariate cox regression analysis and exploited the patient's overall survival and disease-free survival to confirm our findings. Results: Top 10 genes (CNTN1, CTPS1, EYA1, GRIK2, FOXP2, YBX1, DACH1, SYT1, NOL4, TRIT1) of unparalleled differential up-regulation were identified from TIGIT+ exhausted T cells via snRNA-seq data. Based on the correlation analysis of TCGA expression profile data, six genes (CNTN1, CTPS1, EYA1, GRIK2, FOXP2, YBX1) that were significantly positively correlated with exhausted T cells were obtained. Next, we constructed a regression prediction model consisting of 5 genes (CNTN1, CTPS1, EYA1, GRIK2, FOXP2) through multivariate cox regression analysis based on patients’ clinical information. The model was associated with significantly poor prognosis overall survival (OS) (P < 0.01,HR = 2) and disease-free survival (DFS) (P < 0.01,HR = 1.6) in BLCA patients. Conclusions: In our study, Single-nuclei RNA expression profiling data revealed transcriptome differences between TIGIT+ exhausted T cells and other types of T cells. The regression model for potential prognostic survival was constructed using TCGA expression profiling data. These results demonstrated that distinctive differentially high expressed genes associated with TIGIT+ exhausted T cells may act as potential markers for predicting prognosis outcomes in bladder cancer patients.
Assessment of changes in the international prostate symptom score for patients enrolled in a phase I trial of intravesical bacillus Calmette-Guérin combined with intravenous pembrolizumab for recurrent or persistent high-grade non-muscle-invasive bladder cancer after previous bacillus Calmette-Guérin treatment.
Authors: Montgomery Jazzmyne T. , Sana Sherjeel , El-Zawahry Ahmed , Peabody James O. , Pearce Tiffany , Adams Nicole , Deebajah Mustafa , Dynda Danuta , Babaian Kara N. , Crabtree Jane , Delfino Kristin , McVary Kevin , Robinson Kathy , Rao Krishna A. , Alanee Shaheen Riadh
Published: June 2022

e16553

Background: We conducted the first phase I dose-escalation trial (NCT02324582) of intravesical Bacillus Calmette-Guérin (BCG) in combination with systemic pembrolizumab in patients with high-grade non-muscle-invasive bladder cancer who had persistent or recurrent disease after prior intravesical therapy with BCG. The International Prostate Symptom Score (IPSS) were administered to assess subjects’ urinary bother during the trial. Methods: Eighteen subjects were consented for the study, 13 were treated. The study population was comprised of 11 males, 2 females, with age range 42 - 92 years. The IPSS was assessed at pre-treatment, Week 10 (during combined BCG and pembrolizumab treatment), and at 3 and 6 months from treatment completion. IPSS outcomes were analyzed using a mixed-model repeated measures analysis with p-value < 0.05 considered statically significant. Results: For each time point, there was no significant change in any of the component variables of the IPSS. There was no increase in reported bother symptoms over the course of treatment, given median IPSS scores of 9, 11, 7, and 8 (IQR 1.75) for each time point, respectively. Furthermore, quality of life measurements demonstrated no significant change in subjective burden with 75% of subjects reporting that they were “mostly satisfied” with treatment outcomes, followed by 13% reporting “delighted” or “pleased” at 6 month follow-up. Conclusions: There is no significant change in quality of life or the perceived bother of symptoms indicated in the component variables of the IPSS for our study population before, during or after treatment.
Blood-based miRNA, exosomal PD-L1, and immune profiling analysis as predictive biomarkers for immune checkpoint inhibitor treatment response in urothelial cancer.
Authors: Kim Joori , Kim In-Ho , Shin Sun , Kim Ok Ran , Park Juyeon , Kang Nahyeon , Shin Kabsoo
Published: June 2022

e16559

Background: Predicting response to immune checkpoint inhibitor (ICI) is difficult and adequate biomarkers are lacking. PD-L1 expression of tumor cells (TC) and tumor-infiltrating immune cells (IC) has limitations. We hypothesized that peripheral blood analysis would provide systemic insights about the immune responses induced by therapies blocking the PD-1/PD-L1 pathway. Methods: First, plasma samples from urothelial cancers (N = 30) with matched paired samples (N = 27) at baseline, after 1 week of PD-L1 inhibitor administration, and at response evaluation were analyzed. Exosomes were extracted and the expression of plasma-derived exosomal PD-L1 (exo PD-L1) and cytokine levels (IFN-γ, IL-10, TGF-ß, granzyme B) were determined with ELISA. Peripheral blood mononuclear cells (PBMCs) were analyzed with FACS. Samples were stained with anti-CD3, CD8, CD69, and PD1. Secondly, small RNA-sequencing was done using plasma samples from 8 patients and samples from 4 normal ones to identify differentially expressed miRNAs (DE-miRNAs) between treatment responders and non-responders. Expressions of selected DE-miRNAs were validated in a separate patient cohort of 54 patients. Results: In all of patients’ samples tested, exoPD-L1 was detected. Pretreatment level of exoPD-L1 was significantly higher in patients with objective tumor response (P = 0.010). For both clinical responders and non-responders, the level of exoPD-L1 expression increased at treatment day 8. A lower fold change (< 18) in plasma exoPD-L1 was associated with a better rate of response to the anti-PD-L1 therapy (P = 0.032). Compared to non-responder group, the PD1+CD8+T-cell fraction was significantly lower at baseline (p = 0.005) and increased at treatment day 8 in the responder group (p = 0.018). At baseline, the IL-10 level was significantly higher in the responder group (p = 0.005). Decreased levels of immune-suppressive cytokines, TGF-beta1/2 and IL-10, at post-treatment day 8 indicated better response (p = 0.005 and 0.020, respectively). From small RNA sequencing analysis, two upregulated (miR-451a and let-7i-5p) and eight downregulated (miR-1290, miR-151a-3p, miR-10b-5p, miR-148a-3p, miR-10a-5p, miR-1246, miR-34c-3p, let-7b-3p) differentially expressed miRNA in responders were identified. Conclusions: Our findings suggested that the higher expression of exoPD-L1, early peripheral PD1+CD8+T-cell response, and decrease of immunosuppressive cytokines could serve as blood-based predictive biomarkers for responses to ICI treatment and that miRNAs could act as regulators in these processes.
Survival in patients with prostate cancer and history of autoimmune disease.
Authors: Dedousis Demitrios , Zhang Annie , Vassiliou Anastasia , Cao Shufen , Yammani Deepthi , Kyasaram Ravi Kumar , Shanahan John , Keinath Melissa C. , Hsu Melinda Laine , Fu Pingfu , Dowlati Afshin , Garcia Jorge A.
Published: June 2022

e17001

Background: Prostate cancer is thought of as an immunologically cold tumor, however a small proportion of patients treated with immunotherapy have impressive responses. Studies into the effect of autoimmune disease on risk of prostate cancer have yielded contradictory results and little is known about the survival of patients with concurrent autoimmune disease and prostate cancer. This study compared outcomes in patients with prostate cancer with and without autoimmune disease. Methods: This study was a retrospective analysis of patients from the SEER-Medicare databases from 2007-2014 with prostate cancer. Patients with a history of autoimmune disease were identified using ICD-9 codes. The effects of autoimmune disease on overall survival (OS) and cancer-specific survival (CSS) were estimated using multivariable Cox regression and Gray’s method respectively controlling the effects of age, race and chronic kidney disease (CKD). The cumulative CSS was estimated taking death as a competing risk. Results: The overall prevalence of investigated autoimmune diseases among the 172,061 patients with prostate cancer was 23.74%. The most common autoimmune diseases identified were rheumatoid arthritis (RA) (20.93%), psoriasis (2.43%) and ulcerative colitis (UC) (0.91%). In stage IV prostate cancer, OS (p = 0.018) and CSS (p < 0.001) were significantly higher in patients with autoimmune disease, with a median OS of 55 months compared to 48 months in patients without autoimmune disease. After adjusting for the effects of age, race, and CKD, autoimmune disease was still predictive of higher OS (HR: 1.41, 95% CI: 1.33 – 1.5, p < 0.0001) and CSS (HR: 1.30, 95% CI: 1.21 – 1.39, p < 0.0001). Patients with autoimmune disease and stage II and III prostate cancer had lower OS (p values < 0.0001) compared to patients without autoimmune disease. Conclusions: The study showed higher prevalence of RA, Crohn disease, UC, and systemic lupus erythematosus in patients with prostate cancer compared to cohorts of similar age ranges in the general population. History of autoimmune disease predicted significantly higher OS and CSS in patients with stage IV prostate cancer even when age, race and CKD were controlled for. It is possible that an improvement in OS with a history of autoimmune disease was evident in stage IV but not in stages II and III because anti-tumor autoimmune activity plays a larger role when prostate cancer effects regional lymph nodes or has distant metastases.
Racial differences in genomic profiling of prostate cancer at the durham veterans affairs medical center.
Authors: Labriola Matthew , Bitting Rhonda L.
Published: June 2022

e17002

Background: Black men are underrepresented in precision oncology studies. Mahal et al. found that black men with metastatic PCa who had genomic profiling (GP) more commonly had mutations in DNA damage repair (DDR) and actionable genes, although only 8.5% of men in the study were black. [i] Here, we examine racial differences in GP in men with PCa at the Durham Veterans Affairs Medical Center (DVAMC). Methods: Men with PCa who had GP completed by Foundation Medicine at DVAMC from 2/2019-2/2022 were included. Reports were analyzed for mutations of interest. Biopsy site and patient demographics were extracted on chart review. Results: 155 men had GP at the DVAMC during the study period. Importantly 88 (57%) men were black and 67 (43%) were white. Sequencing was performed on the primary tumor (n = 80, 52%), metastatic site (n = 25, 16%), or circulating tumor (ct) DNA (n = 50, 32%). GP was performed on both tissue and ctDNA in 8% of patients, 58% had concordant findings. Racial differences in actionable mutations, DDR mutations, and mutations approved for PARP inhibitor use are noted in Table. The most commonly altered gene is TP53 (n = 59), more prevalent in black men (n = 36, 61%). ATM mutations are more common in black men, 10/14 (71%), however 85% of these are identified on ctDNA and n = 5 had an allele fraction of < 1% suggestive of clonal hematopoiesis of indeterminate potential (CHIP). In contrast, 8/9 (89%) of PIK3CA mutations and 25/36 (69%) of TMPRSS fusions were found in white men. Conclusions: Black men comprised a majority of the patients with PCa who had GP at the DVAMC. We found no statistically significant differences between black and white men in incidence of actionable mutations, DDR mutations, or mutations approved for PARP inhibitor use. PIK3CA alterations and TMPRSS fusions are enriched in white men, consistent with published literature, however, ATM and TP53 mutations are enriched in black men, discordant with findings from Mahal et al,raising the possibility that GP in veterans differs due to environmental exposures. ATM mutations are predominantly found in ctDNA, which may represent CHIP. Expansion of the above analysis could offer insight into racial differences in tumor biology.[Table: see text]
Early discontinuation of abiraterone acetate/prednisone (AA/P) in localized prostate cancer.
Authors: Asif Samia , Schissel Makayla , Teply Benjamin A.
Published: June 2022

e17003

Background: Data from STAMPEDE trial supporting systemic therapy intensification with long course AA/P was first presented in 2017. Overall survival benefit was confirmed in 2021. Our institution proceeded with early adoption of addition of 24 months of AA/P to ADT and radiotherapy (RT) in patients with high-risk localized or regional prostate cancer in 2017. In STAMPEDE, only 17% patients discontinued AA/P prior to completion of planned course. Outside of a clinical trial, whether patients adhere to this intense combination therapy that is associated with toxicities and expense is unknown. We hypothesized that adherence to long course AA/P in real-world practice in definitively treated prostate cancer would be poor. Methods: We performed a retrospective study for patients with clinically localized prostate cancer treated with AA/P combined with standard ADT and RT who had at least 6 months of follow-up data. Primary endpoint was rate of early discontinuation (prior to the 24mo) of AA/P. Secondary outcomes included rates of RT completion and disease recurrence and toxicity of intensive therapy. Reasons for early discontinuation were analyzed. Fisher's Exact, Chi-square analysis and Mann-Whitney tests were used to compare variables. SAS 9.4 was used for statistical analysis. Results: We identified 77 patients who met inclusion criteria, including 2 (2%) with high-risk, 30 (39%) with very high-risk, 19 (25%) with regional risk and 26 (34%) with locally recurrent disease after prostatectomy. AA/P was discontinued in 29 (38%) patients prior to completion of 24mo. Among those with early discontinuation, median duration of AA/P was 12.1 mo [0.1-21.7] and median duration of ADT was 17 mo[3.5-32.2]. Common reasons for early AA/P discontinuation included refractory hypokalemia (n = 4), diarrhea (n = 3), heart failure and fluid retention (n = 2 each) and quality of life deterioration (n = 8). Other reasons included hepatotoxicity, arrhythmia, osteoporotic fracture and financial toxicity (n = 1 each). All patients completed definitive RT. Only 1 of 77 patients had disease recurrence and had discontinued AA/P after 14 mo. A statistically significant association between age at diagnosis and treatment completion was noted(p = 0.01); each 1-year increase in age was associated with 9.4% decrease in odds of completing AA/P. Median age at diagnosis in those completing vs not completing AA/P was 65 vs 71 years. Conclusions: Very high rates of early discontinuation of AA/P were observed among patients with localized prostate cancer receiving definitive RT. Patients were less tolerant of toxicity in adjuvant setting compared to in a clinical trial or advanced disease. Shorter durations of AA/P appeared more acceptable but whether similar benefit is derived with a truncated course of AA/P is unknown. Future studies need to explore an optimal duration of AA/P that will reduce toxicity without compromising survival benefit.
Oncologic outcomes of primary retroperitoneal lymph node dissection (RPLND) for stage II seminoma: Indiana University experience.
Authors: Tachibana Isamu , Alabd Andre , Piroozi Alex , Mahmoud Mohammad , Kern Sean , Tong Yan , Masterson Timothy A. , Adra Nabil , Foster Richard , Hanna Nasser H. , Einhorn Lawrence H. , Cary Clint
Published: June 2022

e17012

Background: Stage II seminoma is typically treated with radiotherapy or chemotherapy based on NCCN guidelines. Primary RPLND has demonstrated efficacy as first-line therapy for retroperitoneal (RP)-only disease. Our aim was to study recurrences of patients undergoing primary RPLND for Stage IIa or IIb seminoma to identify clinicopathologic factors affecting outcomes. Methods: Using our prospectively maintained database, we identified patients that had primary RPLND for seminoma from 2014-2021. All patients had at least 6 months of follow up. Patients were clinical stage IIa or IIb at the time of surgery and underwent open RPLND. We used Kaplan-Meier analysis for recurrence free survival (RFS) and compared clinicopathologic factors. Results: We identified 67 patients that underwent RPLND for RP only seminoma. Table shows the clinical characteristics of patients experiencing recurrences (median follow up - 22.4 months) and excludes 2 patients that had adjuvant chemotherapy. The 2-year RFS rate was 80.2%. Eleven patients (16.4%) experienced recurrences. Kaplan Meier analysis demonstrated improved survival in patients that had an RPLND after 12 months of surveillance (p = 0.02). Fifty-six patients were presumably cured with surgery alone at time of last follow-up. No patients died of testis cancer. One patient had a recurrence within the surgical field. Two patients had contralateral recurrences that may have been cured with bilateral RP template dissection. Seven patients that had a bilateral template dissection had disease on the contralateral side, of which 4 patients had visible nodes on pre-operative scans. In total, 9 out of 67 patients had disease on the contralateral side suggesting that bilateral RP template could confer higher cure rates. Recurrences were successfully treated with BEPx3 (9 pts), Redo RPLND then BEPx3 (1 pt), BEPx3 then High Dose chemotherapy (1 pt), and EPx4 (1 pt). Conclusions: Primary RPLND for low volume RP disease is effective with over 80% chance of surgical cure. Recurrences were cured almost exclusively with induction chemotherapy. Patients with delayed RP only recurrences had improved surgical success. Further investigation in larger trials may help standardize bilateral templates in seminoma and surveillance protocols in the post-operative setting. [Table: see text]
Phase II study of disulfiram (D) and cisplatin (P) in refractory germ cell tumors (GCTs).
Authors: Mego Michal , Svetlovska Daniela , Schmidtova Silvia , Kalavska Katarina , Obertova Jana , Palacka Patrik , De Angelis Valentina , Lesko Peter , Orszaghova Zuzana , Rejlekova Katarina , Reckova Maria , Sycova-Mila Zuzana , Mardiak Jozef , Chovanec Michal , Kucerova Lucia
Published: June 2022

e17013

Background: Multiple relapsed/refractory GCTs patients have extremely poor prognosis, therefore, new treatment strategies are warranted. Previously, we showed, that cisplatin resistant testicular GCTs overexpress aldehyde-dehydrogenase (ALDH) isoforms and inhibition of ALDH activity by disulfiram is associated with reconstitution of cisplatin sensitivity in vitro as well as in animal model. This study aimed to determine the efficacy and toxicity of ALDH inhibitor disulfiram in combination with cisplatin in patients with multiple relapsed/refractory germ cell cancer. Methods: Twelve patients with multiple relapsed/refractory GCTs were enrolled in the phase II study from May 2019 to September 2021. All patients were pretreated with at least 2 cisplatin-based therapies (median 4, range 2 – 7); 6 tumors (50.0%) were absolutely refractory to cisplatin and 9 patients (75.0%) had visceral non-pulmonary metastases. Disulfiram was administered at a dose of 400 mg daily until progression or unacceptable toxicity, cisplatin was administered at dose 50 mg/m2 day 1 and 2, every 3 weeks. Twelve evaluable patients had to be enrolled into the first cohort, and if 0 of 12 patients had treatment response, the study was to be terminated. The results of the first stage of the trial are presented in the this report. Results: Median age was 36 years (range: 29 – 48 years). Median number of treatment cycles was 2 (range 1 – 6). During a median follow-up period of 3.1 months (range: 1.3 – 13.9), all (100%) patients experienced disease progression and died. None of patients achieved objective response to treatment, therefore the study was terminated in first stage. Median progression-free survival (PFS) was 1.4 months, 95% CI (0.7 – 1.5 months), and median overall survival (OS) was 2.9 months 95% CI (1.5 – 4.7 months). Disease stabilization for at least 6 months was observed in 2 (16.7%) patients. Treatment was well tolerated, however, 5 (41.7%) of patients experienced grade 3/4 fatigue, 4 (33.3%) thrombocytopenia, 3 (25.0%) anemia, while 2 (16.7%) experienced neutropenia, nausea and infection. Conclusions: This study failed to achieve its primary end point and our data suggest limited efficacy of disulfiram in restoring sensitivity to cisplatin in multiple relapsed/refractory germ cell tumors. Clinical trial information: NCT03950830.
Genomic landscape and homologous recombination repair (HRR) genes analysis in Chinese prostate cancer (PCa) patients.
Authors: Liu Jianhua , Lu Jiantang , Wang Jian , Hu Yuan , Li Binbin , Zhong Xuefeng , Huang Mengli
Published: June 2022

e17020

Background: HRR gene mutations have been proven to be effective biomarkers for PARP inhibitor (PARPi) therapy in metastatic castration resistant PCa. The epidemiological data of genomic variation and the characteristic of HRR gene alterations in Chinese population is still insufficient. Methods: Tumor tissue samples (including surgical and biopsy samples) and blood samples from 250 pathologically confirmed PCa patients were collected and analyzed using next generation sequencing (733-gene panel). Tumor mutation burden (TMB) was defined as total number of somatic non-synonymous mutations in coding region. Homologous recombination deficiency (HRD) was evaluated by the sum of the loss of heterozygosity, telomeric allelic imbalance and large-scale state transition. Somatic or germline alterations (including copy number reduction, CNV-loss) of HRR pathway genes were classified as HRR-altered positive. Results: In total, the top three alteration frequency somatic genes were FOXA1 (24.9%), TP53 (15.2%) and MYC (13.6%) while the top three alteration frequency germline genes were DPYD (17.1%), UGT1A1 (13.2%) and SLX4 (4.3%). In HRR pathway genes, the top three alteration frequency somatic genes were CDK12 (9.7%), ATM (4.7%) and BRCA2 (3.9%) while the top three alteration frequency germline genes were BRCA2 (3.1%), PALB2 (1.9%) and BRCA1 (1.6%). 25.6% (64/250) cases carried HRR gene alterations. Among HRR-altered positive cases with HRD score, only 8.9% (4/45) carried more than one HRR gene alteration and most carried a single HRR gene alteration (40.0% [18/45] in CDK12, 17.8% [8/45] in ATM or BRCA2, 11.1% [5/45] in BRCA1 and 2.2% [1/45] in PALB2 or FANCA). 61 HRR gene alterations were detected in these 45 cases and the commonly alteration types of HRR genes were single base substitution (47.5%, 29/61). The alteration type of CNV-loss (14.8%, 9/61) was only detected in somatic samples. The HRD score of HRR-altered group was significantly higher than wild group (median HRD socre, altered-type vs. wild-type = 23.5 vs. 19.0, P= 0.0097). And there was no significant difference in HRD score between CNV-loss and other alteration types. Moveover, the TMB level of HRR-altered group tended to be higher than wild group (median TMB, altered-type vs. wild-type = 4.5 vs. 2.8 Muts/Mb, P= 0.5). Conclusions: The results illustrated the molecular characteristics of HRR gene in Chinese PCa and indicated that HRR gene alterations (including CNV-loss) were associated with higher HRD score. These data provide further evidence for the clinical management of PARPi personalized therapy.