Urothelial Cell Carcinoma Research Articles

Urine microbiota and bladder cancer

Urine analysis data obtained using modern microbiological methods and 16S rRNA gene sequencing technology indicate that the urinary system has its own microbial ecosystem. Individual microbiota members can play a key role in the development of cancer. Certain bacterial taxa have been revealed in bladder urothelial carcinoma cells that can affect carcinogenesis, treatment response, and the development of relapses through various mechanisms. The studies are conducted to use not only vaccine strains, but also probiotic strains and oncolytic bacteria for the treatment and prevention of relapses.

Knockdown of Keratin 6 Within Arsenite-Transformed Human Urothelial Cells Decreases Basal/Squamous Expression, Inhibits Growth, and Increases Cisplatin Sensitivity.

Urothelial carcinoma (UC) is prevalent, especially in elderly males. The high rate of recurrence, treatment regime, and follow-up monitoring make UC a global health and economic burden. Arsenic is a ubiquitous toxicant that can be found in drinking water, and it is known that exposure to arsenic is associated with UC development. Around 25% of diagnosed UC cases are muscle-invasive (MIUC) which have poor prognosis and develop chemoresistance, especially if tumors are associated with squamous differentiation (SD). The immortalized UROtsa cell line is derived from normal human urothelium and our lab has malignantly transformed these cells using arsenite (As3+). These cells represent a basal subtype model of MIUC and the tumors derived from the As3+-transformed cells histologically and molecularly resemble clinical cases of the basal subtype of MIUC that have focal areas SD and expression of the basal keratins (KRT1, 5, 6, 14, and 16). Our previous data demonstrate that KRT6 protein expression correlates to areas of SD within the tumors. For this study, we performed a lentiviral knockdown of KRT6 in As3+-transformed UROtsa cells to evaluate the effects on morphology, gene/protein expression, growth, colony formation, and cisplatin sensitivity. The knockdown of KRT6 resulted in decreased expression of the basal keratins, decreased growth, decreased colony formation, and increased sensitivity to cisplatin, the standard treatment for MIUC. The results of this study suggest that KRT6 plays a role in UC cell growth and is an exploitable target to increase cisplatin sensitivity for MIUC tumors that may have developed resistance to cisplatin treatment.

Brain Metastases from Genito-Urinary Cancers in the Canton of Geneva (Switzerland): Study of Incidence, Management and Outcomes.

Incidence of brain metastases is precisely unknown and there is no clear consensus on their management. We aimed to determine the incidence of brain metastases among patients with genito-urinary primaries, present patients' characteristics and identify prognostic factors. We identified 51 patients treated in Geneva University Hospitals between January 1992 and December 2019. We retrospectively correlated their overall survival with 23 variables. We repeated a multivariate analysis with significant variables. Overall incidence of Brain Metastases (BMs) among Genito-Urinary (GU) patients is estimated to be 1.76% (range per primary GU tumour type: 0.00-6.65%). BMs originate from germ cell tumours in two cases (3.92%), from urothelial cell carcinoma in 15 cases (29.41%), from prostate cancer in 13 cases (25.49%), and from renal cell carcinoma in 21 cases (41.18%); there are no BMs from penile cancer in our cohort. The median age at BM diagnosis is 67 years old (range: 25-92). Most patients (54%) have a stage IV disease at initial diagnosis and 11 patients (22%) have BM at initial diagnosis. Only six patients (12%) are asymptomatic at BM diagnosis. The median Overall Survival (OS) from BM diagnosis is 3 months (range: 0-127). Five patients (10%) are long survivors (OS > 24 months). OS is significantly influenced by patient performance status and administration of systemic treatment. In the absence of meningeal carcinomatosis, OS is influenced by systemic treatment and stereotactic radiosurgery. We also apply the Graded Prognostic Assessment (GPA) score to our cohort and note significant differences between groups. Brain metastases from solid tumours is not a uniform disease, with a prognosis varying a lot among patients. The optimal management for patients with genito-urinary malignancies with brain metastases remain unclear and further research is needed.

FGFR3::TACC3 fusions in head and neck carcinomas: a study of nine cases highlighting phenotypic heterogeneity, frequent HPV association, and a morphologically distinct subset in favor of a putative entity.

The FGFR3::TACC3 fusion has been reported in subsets of diverse cancers including urothelial and squamous cell carcinomas (SCC). However, the morphology of FGFR3::TACC3-positive head and neck carcinomas has not been well studied and it is unclear if this fusion represents a random event, or if it might characterize a morphologically distinct tumor type. We describe nine FGFR3::TACC3 fusion-positive head and neck carcinomas affecting six males and three females aged 38 to 89years (median, 59). The tumors originated in the sinonasal tract (n = 4), parotid gland (n = 2), and one case each in the oropharynx, submandibular gland, and larynx. At last follow-up (9-21months; median, 11), four patients developed local recurrence and/or distant metastases, two died of disease at 11 and 12months, one died of other cause, one was alive with disease, and two were disease-free. Three of six tumors harboredhigh risk oncogenic HPV infection (HPV33, HPV18, one unspecified). Histologically, three tumors revealed non-keratinizing transitional cell-like or non-descript morphology with variable mixed inflammatory infiltrate reminiscent of mucoepidermoid or DEK::AFF2 carcinoma (all were HPV-negative), and three were HPV-associated (all sinonasal) with multiphenotypic (1) and non-intestinal adenocarcinoma (2) pattern, respectively. One salivary gland tumor showed poorly cohesive large epithelioid cells with prominent background inflammation and expressed AR and GATA3, in line with a possible salivary duct carcinoma variant. Two tumors were conventional SCC. Targeted RNA sequencing revealed an in-frame FGFR3::TACC3 fusion in all cases. This series highlights heterogeneity of head and neck carcinomas harboring FGFR3::TACC3 fusions, which segregates into three categories: (1) unclassified HPV-negative category, morphologically distinct from SCC and other entities; (2) heterogeneous group of HPV-associated carcinomas; and (3) conventional SCC. A driver role of the FGFR3::TACC3 fusion in the first category (as a potential distinct entity)remains to be further studied. In the light of available FGFR-targeting therapies, delineation of these tumors and enhanced recognition is recommended.

Incidence trends, histological subtypes, and topographical distribution of bladder cancer in Iran: a study based on the Iranian National Cancer Registry during 2006-2015.

Bladder cancer (BCa) is a significant public health concern. This study aimed to analyze the incidence trends, histological subtypes, and topographical distribution of BCa in Iran over a decade. This retrospective registry-based study analyzed data on BCa patients diagnosed between March 20, 2006, and March 20, 2015. Following data quality control, age-standardized incidence rates (ASIRs) were calculated for BCa overall, by sex and histological subtype using the new World Health Organization (WHO) standard population. We identified 51,379 BCa cases (81.97% male) with a mean age of 65.10 ± 14.89 years. The overall ASIR was 8.92 per 100,000 (95% CI: 8.84-9.00). While a modest increase in ASIR was observed overall (8.77 in 2006 to 9.64 in 2015) and among males (14.13 in 2006 to 15.95 in 2015) during the study period, males consistently had a significantly higher ASIR compared to females (approximately 4.5:1 ratio). BCa incidence showed a progressive increase across older age groups, particularly those aged 40-44 to 80-84 years. Urothelial cell carcinoma (UCC) was the most prevalent histological type (ASIR: 8.19 to 7.93), followed by adenocarcinoma (AC; ASIR: 0.13 to 0.11). Squamous cell carcinoma (SCC) displayed a decreasing trend (ASIR: 0.11 to 0.06). Both UCC and AC were more frequent in males (approximately 5 and 3 times higher than females, respectively). Malignant neoplasm of the bladder, unspecified, constituted over 95% of BCa topography classifications. This study identified a modest rise in BCa incidence, with male predominance and a higher burden in older adults. Further investigation into potential risk factors contributing to this increase is warranted.

Sarcomatoid Urothelial Carcinoma Arising in Autosomal Dominant Polycystic Kidney Disease: A Case Report and Literature Review.

Autosomal dominant polycystic kidney disease (ADPKD) may be associated with various epithelial malignancies. The most reported ones are papillary renal cell carcinoma (RCC) and clear cell RCC. Only one noninvasive urothelial carcinoma arising in the renal pelvis has been previously reported in the setting of ADPKD in the English literature. A 52-year-old patient with ADPKD and a history of renal transplant presented with a poorly differentiated sarcomatoid neoplasm in his native left polycystic kidney. A recognizable urothelial or renal cell carcinoma differentiation was not identified in the resected neoplasm microscopically. The initial diagnosis for this specimen was challenging on morphology and immunohistochemistry, but targeted next-generation sequencing provided molecular evidence in support of urothelial origin, indicating a hotspot mutation -124 C > T in the TERT promoter (C228 T) and loss of heterozygosity on chromosomes 9p and 8p. This tumor is unique because, to our knowledge, this is the first report of upper tract sarcomatoid urothelial carcinoma in a patient with ADPKD.

Spectrum of Renal Tumors Other Than Renal Cell Carcinoma with Emphasis on Cytomorphological, Immunohistochemical, and Cytogenetic Study

Abstract Background: The role of fine needle aspiration cytology (FNAC) in the diagnosis of renal malignancies is established and has been getting more precise and important over a period of time. Knowledge of the pathology of uncommon renal neoplasms along with radiological and clinical correlations often aids in correct diagnosis. Aims: The present study aims to describe the cytomorphological and immunohistochemical findings in the varied spectrum of renal tumors, other than renal cell carcinomas (RCC). Materials and Methods: Data of 238 cases of ultrasound-guided renal FNAC performed in our tertiary cancer institute over 4 years were collected from the department registry. All nondiagnostic cases and cases diagnosed as RCC were excluded from the study, so 57 cases of renal tumors were reviewed along with the cell blocks and ancillary studies. Results: Out of the 57 cases, 35 cases were primary renal neoplasms, which included renal oncocytoma (3.5%), angiomyolipoma (3.5%), rhabdoid tumor (1.8%), Wilms tumor (28.0%), Ewing sarcoma (3.5%), urothelial carcinoma (8.8%), and small round cell tumor unclassified (12.3%). Twenty two cases were metastatic tumors, which included hematolymphoid neoplasm (14%) and metastatic carcinomas (24.6%) from various other primary carcinomas. Conclusion: Our study shows that renal FNAC is safe and fairly accurate in diagnosing a wide spectrum of renal tumors and has high diagnostic accuracy, when performed along with cell block and immunohistochemistry. Awareness of the pathology of uncommon renal tumors along with relevant clinical history and radiological findings may aid in identifying the type of tumor for further appropriate management.

Emodin inhibits benzidine‑enhanced survival and migration of upper urinary tract urothelial carcinoma cells by targeting the PKA/COX2 signaling pathway.

The carcinogenic effects of benzidine (BZ) on bladder cancer are well documented, but its potential for promoting upper urinary tract urothelial carcinoma (UTUC) remains unclear. The ability of emodin, a natural pharmaceutical compound, to prevent BZ‑associated UTUC has not been previously explored. To the best of our knowledge, the present study is the first to reveal that BZ significantly enhanced the survival and migration of UTUC cell lines in vitro. Furthermore, in vivo experiments demonstrated that BZ promoted an increase in the size of subcutaneous tumors in nude mice. Further investigation revealed that BZ upregulated the expression of protein kinase A (PKA) and cyclooxygenase 2 (COX2), along with downstream matrix metalloproteinase 9 (MMP9) and vascular endothelial growth factor (VEGF), in UTUC cells. Moreover, BZ increased the levels of cyclic adenosine monophosphate (cAMP) and prostaglandin E2 (PGE2) in cell lysates. By contrast, emodin reduced the PKA and COX2 expression levels compared with the BZ‑treated group. Similarly, the in vivo experiments demonstrated that emodin significantly inhibited tumor growth in BZ‑pretreated nude mice, accompanied by reductions in the cAMP, PGE2, MMP9 and VEGF levels. These findings elucidated the role of BZ in promoting UTUC progression. Additionally, emodin has emerged as a novel inhibitor of BZ‑induced UTUC development through PKA/COX2 inhibition, suggesting its potential as a natural therapeutic agent against BZ‑associated UTUC.

Role of B7-H3 in predicting response to neoadjuvant chemotherapy in muscle-invasive bladder cancer.

Neoadjuvant platinum-based chemotherapy offers a modest survival advantage in muscle-invasive bladder cancer (MIBC) for patients with pathologic response. B7-H3 (CD276), an immune checkpoint overexpressed in various cancers, including urothelial-cell carcinoma (UCC), has been associated with chemoresistance and poor oncologic outcomes. We aimed to explore if B7H3 expression on bladder biopsy samples was a predictive biomarker for pathologic response to neoadjuvant platinum-based chemotherapy. This was a retrospective cohort study among MIBC patients receiving neoadjuvant platinum-based chemotherapy followed by radical cystectomy. All patients underwent routine preoperative biopsy of their tumour. Immunohistochemistry was used to evaluate B7-H3 expression from pre-operative specimens. The primary outcome of interest was pathologic complete response (pCR). Statistical analysis included Mann-Whitney U test, Fisher's exact test, Kaplan-Meier method, and Cox regression for survival analysis. Among 87 patients analysed, high B7-H3 expression was found in 44.8% (n = 39) of patients. The median follow-up periods were similar between the high and low B7-H3 groups (high expression; 4.29 years [SD 3.04], low expression 3.94 years [SD 3.04], p = 0.60). Only 20.5% of patients with high B7-H3 expression achieved pCR, compared to 41.7% in the low expression group (p = 0.04). Cox regression showed no significant differences in recurrence-free or cancer-specific survival between the high and low B7-H3 expression groups (p > 0.05). High B7-H3 expression is associated with a reduced likelihood of achieving pCR in MIBC patients undergoing neoadjuvant chemotherapy. This suggests B7-H3's potential as a predictive biomarker for chemotherapy response. Further research is needed to explore the role of B7-H3 on platinum-based chemotherapy response in urothelial cancer.

Pan-cancer analysis reveals CCL5/CSF2 as potential predictive biomarkers for immune checkpoint inhibitors

BackgroundCurrently, there are no optimal biomarkers available for distinguishing patients who will respond to immune checkpoint inhibitors (ICIs) therapies. Consequently, the exploration of novel biomarkers that can predict responsiveness to ICIs is crucial in the field of immunotherapy.MethodsWe estimated the proportions of 22 immune cell components in 10 cancer types (6,128 tumors) using the CIBERSORT algorithm, and further classified patients based on their tumor immune cell proportions in a pan-cancer setting using k-means clustering. Differentially expressed immune genes between the patient subgroups were identified, and potential predictive biomarkers for ICIs were explored. Finally, the predictive value of the identified biomarkers was verified in patients with urothelial carcinoma (UC) and esophageal squamous cell carcinoma (ESCC) who received ICIs.ResultsOur study identified two subgroups of patients with distinct immune infiltrating phenotypes and differing clinical outcomes. The patient subgroup with improved outcomes displayed tumors enriched with genes related to immune response regulation and pathway activation. Furthermore, CCL5 and CSF2 were identified as immune-related hub-genes and were found to be prognostic in a pan-cancer setting. Importantly, UC and ESCC patients with high expression of CCL5 and low expression of CSF2 responded better to ICIs.ConclusionWe demonstrated CCL5 and CSF2 as potential novel biomarkers for predicting the response to ICIs in patients with UC and ESCC. The predictive value of these biomarkers in other cancer types warrants further evaluation in future studies.

SURVIVAL IN PATIENTS WITH HISTOLOGIC VARIANTS OF UROTHELIAL TYPE BLADDER CANCER

Objective: This study aims to determine the life expectancy of patients with histologic variants in urothelial type bladder cancer and the highest or lowest mortality rate in Hasan Sadikin Academic Medical Centre. Material & Methods: A cross-sectional study with total sampling. The samples in this study were patients with histologic variants of urothelial cell carcinoma bladder who received treatment at Hasan Sadikin Academic Medical Centre during the period of 2011 to 2022. Results: A total of 470 patients with a diagnosis of urothelial bladder cancer, 62 patients (13.19%) with histologic variants of urothelial bladder cancer treated with radical cystectomy or TURBT + intravesical chemotherapy at Hasan Sadikin Academic Medical Centre. The highest survival rate was in patients diagnosed with giant cell (66.7%) followed by small cell (50%) and glandular differentiation (40.0%). The 5-yearr survival rate of patients treated with radical cystectomy alone had a higher survival rate of 75.3% followed by radical cystectomy and adjuvant therapy, which was 75.2%. Conclusion: Histologic variants of bladder carcinoma that have the highest mortality rate are tropoblastic differentiation, nested type, micropappilary, and sarcomatoid with the lowest survival rate of 0%. Also, histologic variant of bladder carcinoma that has the lowest mortality rate is giant cell with a survival rate of 66.7%. Keywords: Bladder carcinoma, chemotherapy, trophoblastic differentiation.

Renal-Limited IgG4-Related Disease Presenting as Hypodense Lesions Found During Surveillance Imaging in a Patient With High-Grade Urothelial Cell Carcinoma.

Renal lesions as the initial presentation of IgG4-related disease (IgG4-RD) and isolated IgG4-related kidney disease (IgG4-RKD) are rare.1,2A 65-year-old male with a history of high-grade urothelial cell carcinoma in remission was found to have multiple renal lesions on surveillance imaging (Figure 1A).

Comprehensive Genomic Analysis of Puerarin in Inhibiting Bladder Urothelial Carcinoma Cell Proliferation and Migration.

Bladder urothelial carcinoma (BUC) ranks second in the incidence of urogenital system tumors, and the treatment of BUC needs to be improved. Puerarin, a traditional Chinese medicine (TCM), has been shown to have various effects such as anti-cancer effects, the promotion of angiogenesis, and anti-inflammation. This study investigates the effects of puerarin on BUC and its molecular mechanisms. Through GeneChip experiments, we obtained differentially expressed genes (DEGs) and analyzed these DEGs using the Ingenuity® Pathway Analysis (IPA®), Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) pathway enrichment analyses. The Cell Counting Kit 8 (CCK8) assay was used to verify the inhibitory effect of puerarin on the proliferation of BUC T24 cells. String combined with Cytoscape® was used to create the Protein-Protein Interaction (PPI) network, and the MCC algorithm in cytoHubba plugin was used to screen key genes. Gene Set Enrichment Analysis (GSEA®) was used to verify the correlation between key genes and cell proliferation. A total of 1617 DEGs were obtained by GeneChip. Based on the DEGs, the IPA® and pathway enrichment analysis showed they were mainly enriched in cancer cell proliferation and migration. CCK8 experiments proved that puerarin inhibited the proliferation of BUC T24 cells, and its IC50 at 48 hours was 218μmol/L. Through PPI and related algorithms, 7 key genes were obtained: ITGA1, LAMA3, LAMB3, LAMA4, PAK2, DMD, and UTRN. GSEA showed that these key genes were highly correlated with BUC cell proliferation. Survival curves showed that ITGA1 upregulation was associated with poor prognosis of BUC patients. Our findings support the potential antitumor activity of puerarin in BUC. To the best of our knowledge, bioinformatics investigation suggests that puerarin demonstrates anticancer mechanisms via the upregulation of ITGA1, LAMA3 and 4, LAMB3, PAK2, DMD, and UTRN, all of which are involved in the proliferation and migration of bladder urothelial cancer cells.

Swarms of Enzymatic Nanobots for Efficient Gene Delivery.

This study investigates the synthesis and optimization of nanobots (NBs) loaded with pDNA using the layer-by-layer (LBL) method and explores the impact of their collective motion on the transfection efficiency. NBs consist of biocompatible and biodegradable poly(lactic-co-glycolic acid) (PLGA) nanoparticles and are powered by the urease enzyme, enabling autonomous movement and collective swarming behavior. In vitro experiments were conducted to validate the delivery efficiency of fluorescently labeled NBs, using two-dimensional (2D) and three-dimensional (3D) cell models: murine urothelial carcinoma cell line (MB49) and spheroids from human urothelial bladder cancer cells (RT4). Swarms of pDNA-loaded NBs showed enhancements of 2.2- to 2.6-fold in delivery efficiency and 6.8- to 8.1-fold in material delivered compared to inhibited particles (inhibited enzyme) and the absence of fuel in a 2D cell culture. Additionally, efficient intracellular delivery of pDNA was demonstrated in both cell models by quantifying and visualizing the expression of eGFP. Swarms of NBs exhibited a >5-fold enhancement in transfection efficiency compared to the absence of fuel in a 2D culture, even surpassing the Lipofectamine 3000 commercial transfection agent (cationic lipid-mediated transfection). Swarms also demonstrated up to a 3.2-fold enhancement in the amount of material delivered in 3D spheroids compared to the absence of fuel. The successful transfection of 2D and 3D cell cultures using swarms of LBL PLGA NBs holds great potential for nucleic acid delivery in the context of bladder treatments.

Is There a Role for FAPI PET in Urological Cancers?

This work aims to investigate the utility of positron emission tomography/computed tomography (PET/CT) with fibroblast activation protein inhibitors (FAPI) in urological neoplasms, including prostate cancer, urothelial carcinoma, and renal cell carcinoma. Although the available data are very preliminary, FAPI PET showed potential for detecting primary prostate cancer with low prostate-specific membrane antigen expression, while prostate-specific membrane antigen PET/CT outperformed FAPI PET/CT in detecting biochemical recurrence. In urothelial carcinoma, FAPI PET/CT demonstrated increased detection rates compared with deoxy-2-[18F]fluoro-D-glucose PET/CT, in particular in small lymph node metastases, whose identification is still an unmet clinical need. Limited data are available for renal cell carcinoma. In conclusion, FAPI PET emerges as a promising imaging modality for urological neoplasms, in particular bladder cancer. Further research is warranted to establish its role in guiding therapeutic decisions and as a potential novel theranostic agent.

The Novel Platinum Analog Dicycloplatin Provides Reliable Growth Inhibition of Urothelial Carcinoma Cells In Vitro.

Platinum-based chemotherapies are a component of standard-of-care regimens for urothelial carcinoma (UC). These nephrotoxic drugs are often dose-limiting, with cisplatin and carboplatin being the most commonly used. Dicycloplatin (DCP) has better solubility and stability, with comparable efficacy and better tolerability. Some suggest the use of DCP as primary treatment for non-muscle-invasive bladder cancer. We exposed UC cell lines to DCP in vitro to assess its efficacy. A high grade (IV) in vitro UC cell line (TCCSUP) was exposed to varying concentrations of cisplatin (0-600 μg/ml), carboplatin (0-600 μg/ml), oxaliplatin (0-4.0 μg/ml), and DCP (0-350 μg/ml). Grade II-IV cells were exposed to varying concentrations of DCP (0-350 μg/ml) to assess time- and concentration-dependent growth inhibition, and simulate intravesical treatment. Growth inhibition was determined following 24, 48, and 72 h of exposure, using a tetrazolium dye to assess mitochondrial dehydrogenase activity. DCP, cisplatin, and carboplatin effectively achieved >90% cell kill at 72 h. Concentrations of 325 μg/ml DCP, 50 μg/ml cisplatin, and 600 μg/ml carboplatin were sufficient for >90% cell-kill, with cisplatin demonstrating the highest efficacy at the lowest concentration/time intervals. Dose- and time-dependent cell kill were demonstrated at varying concentrations of DCP in grade II-IV cell lines, including cells exposed intravesically. In vitro, DCP demonstrates cell-killing efficacy in a time- and concentration-dependent manner in grade II-IV UC cell lines, showing promise for its intravenous, oral, and intravesical use for bladder UC in both primary and adjuvant/neoadjuvant settings.

Similar genetic profile in early and late stage urothelial tract cancer

IntroductionUrothelial tract cancer (UTC) ranks as the tenth most prevalent cancer and holds the seventh position in terms of mortality worldwide. Despite its prevalence and mortality ranking, there are still gaps in the knowledge of the mutational landscape in patients with advanced disease who have limited therapeutic options after multiple lines of prior treatment. This study compares the genomic and transcriptomic landscape, and targeted treatment options between metastatic UTC (mUTC) patients treated with multiple lines of therapy compared to newly diagnosed, untreated Muscle Invasive Bladder Cancer (MIBC).MethodsWe compared genomic and clinical data from two cohorts: mUTC patients who received multiple lines of therapy and were referred to the Copenhagen Prospective Personalized Oncology (CoPPO) project at Rigshospitalet, University of Copenhagen. Data for MIBC UTC patients were acquired from the Cancer Genome Atlas Bladder Cancer (TCGA BLCA) cohort. Biopsies in CoPPO were performed at the time of enrollment. 523 highly important cancer-related genes (TrueSight Oncology-500 targeted sequencing panel) were used from both cohorts for comparative analysis. Analyses included RNA count data to compare predicted molecular subtypes in each cohort separately.ResultsPatients from the CoPPO cohort had a lower median age at first-line treatment than the TCGA BLCA cohort, with no significant gender disparity. The predominant histology was urothelial cell carcinoma in both cohorts. Genomic analysis revealed no significant difference between the top mutated genes in the two cohorts, specifically looking into DNA damage repair genes. Molecular subtyping indicated a higher frequency of neuroendocrine differentiation in the CoPPO cohort. 13% of patients in the CoPPO cohort received targeted therapy based on genomic findings, and 16% received non-targeted treatment, totaling 29% receiving CoPPO treatment (9 patients). The remaining 71% received best supportive care. Kaplan-Meier analysis showed a non-significant survival benefit for the intervention group in the CoPPO cohort.ConclusionWhen focusing on 523 highly relevant cancer genes, the mutational profile of mUTC patients who have undergone numerous treatment lines resembles that of newly diagnosed MIBC. These alterations can be targeted, indicating the potential advantage of early genomic testing for personalized treatment within clinical trials.

Structure-Based Identification of Novel Histone Deacetylase 4 (HDAC4) Inhibitors.

Histone deacetylases (HDACs) are important cancer drug targets. Existing FDA-approved drugs target the catalytic pocket of HDACs, which is conserved across subfamilies (classes) of HDAC. However, engineering specificity is an important goal. Herein, we use molecular modeling approaches to identify and target potential novel pockets specific to Class IIA HDAC-HDAC4 at the interface between HDAC4 and the transcriptional corepressor component protein NCoR. These pockets were screened using an ensemble docking approach combined with consensus scoring to identify compounds with a different binding mechanism than the currently known HDAC modulators. Binding was compared in experimental assays between HDAC4 and HDAC3, which belong to a different family of HDACs. HDAC4 was significantly inhibited by compound 88402 but not HDAC3. Two other compounds (67436 and 134199) had IC50 values in the low micromolar range for both HDACs, which is comparable to the known inhibitor of HDAC4, SAHA (Vorinostat). However, both of these compounds were significantly weaker inhibitors of HDAC3 than SAHA and thus more selective, albeit to a limited extent. Five compounds exhibited activity on human breast carcinoma and/or urothelial carcinoma cell lines. The present result suggests potential mechanistic and chemical approaches for developing selective HDAC4 modulators.

Safety and efficacy outcomes of early cessation of anti-PD1 therapy in patients 80 years or older: A retrospective cohort study

Older patients have similar immune checkpoint inhibitor efficacy and rates of adverse events as younger patients, but appear to have decreased tolerability, particularly in the oldest patient cohort (>80 years), often leading to early cessation of therapy. We aimed to determine whether early discontinuation impacts efficacy of anti-PD-1 therapy in patients ≥80 years old. In this retrospective, multicenter, international cohort study, we examined 773 patients with 4 tumor types who were at least 80 years old and treated with anti-PD-1 therapy. We determined response rate, overall survival (OS), and progression-free survival (PFS) in patients who discontinued therapy early (<12 months) for reasons other than progression or death. We used descriptive statistics for demographics, response, and toxicity rates. Survival statistics were described using Kaplan Meier curves. Median (range) age at anti-PD-1 initiation was 83.0 (75.8–97.0) years. The cancer types included were melanoma (n = 286), non-small cell lung cancer (NSCLC) (n = 345), urothelial cell carcinoma (UCC) (n = 108), and renal cell carcinoma (RCC) (n = 34). Of these, 102 met the primary endpoint of <12 months to discontinuation for reasons other than death or progression. Median PFS and OS, respectively, for these patients were 34.4 months and 46.6 months for melanoma, 15.8 months and 23.4 months for NSCLC, and 10.4 months and 15.8 months for UCC. This study suggests geriatric patients who have demonstrated therapeutic benefit and discontinued anti-PD-1 therapy at less than 12 months of duration for reasons other than progression may have durable clinical benefit without additional therapy.

Meta-analysis of perioperative immune checkpoint inhibitors in urothelial and renal cell carcinoma: Data from the latest available evidence.

Meta-analysis of perioperative immune checkpoint inhibitors in urothelial and renal cell carcinoma: Data from the latest available evidence.