Bladder Carcinoma Research Articles

Bile molecular landscape provides pathological insight and classifies signatures predictive of carcinoma of gall bladder.

Bile molecular landscape provides pathological insight and classifies signatures predictive of carcinoma of gall bladder.

TERTmonitor Efficacy and Performance in Detecting Mutations by Droplet Digital PCR

Background: The screening of TERT promoter (TERTp) mutations is essential in cancer research and diagnostics, due to its prevalence in tumours associated with low self-renewal rates. TERTmonitor is a diagnosis kit primarily designed for real-time qPCR qualitative detection of −124C>T and −146C>T TERTp mutations, which are highly prevalent in several malignancies, particularly in bladder carcinoma. Objective: This study aims to investigate TERTmonitor performance in droplet digital PCR (ddPCR) in urine samples from bladder cancer patients. Methods: A total of 45 urine samples were examined by real-time qPCR and ddPCR techniques, and their performances were compared. Results: TERTmonitor had similar performance in both real-time qPCR and ddPCR platforms. Specifically, the methods exhibited a concordance rate of 95.45% and 90% for −124C>T and −146C>T mutations, respectively. Importantly, an enhanced sensitivity in certain scenarios was exhibited by ddPCR when compared to real-time qPCR, detecting mutations that the latter failed to identify in approximately 4.55% and 10% of the samples for −124C>T and −146C>T mutations, respectively. This enhanced sensitivity of ddPCR was particularly evident in samples with low-frequency mutations. Conclusions: The findings highlight the usefulness of TERTmonitor for cancer surveillance either in real-time qPCR or ddPCR platforms.

Histopathological Profile of Cholecystectomy Specimens at a Tertiary Care Center: A Retrospective Study

Abstract Introduction: Gallbladder is one of the most frequently received specimens in any histopathology laboratory. Its diseases may present with a varied spectrum ranging from congenital anomalies, cholelithiasis, and inflammatory or noninflammatory lesions to noninvasive and invasive neoplasms. Cholelithiasis (gallstones) is the most common lesion and accounts for more than 95% of gallbladder diseases and affects 10%–20% of the adult population. The incidence is 2–4 times higher in females than in males. Aims and Objectives: This study was designed to study the histopathological spectrum of gall bladder diseases in the population, study the most common gall bladder diseases in cholecystectomy specimens, and study the frequency of gall bladder carcinoma. Methodology: This retrospective observational study was done in the Pathology department at a tertiary care hospital and research center, from September 2016 to September 2023. Tissue was fixed in 10% buffered formalin and then processed by the routine paraffin embedding techniques. Sections were cut at 4–5 μ thickness and stained with hematoxylin and eosin stains. Special stains were done if required for confirmation. All the slides were analyzed and reported by a trained histopathologist. Results: Females were affected more as compared to males. The commonest age group affected was 41-50 years. Gallstones were observed in 33.58% of patients. Gallbladder neoplasm was rare and incidental findings. Conclusion: Gallbladder disease demonstrated a diverse spectrum of histopathological changes in the cholecystectomy specimens and showed female preponderance. Gallbladder carcinoma was observed as a rare occurrence and was an incidental finding mainly. Hence, a microscopic (histopathological) examination is required for every cholecystectomy specimen.

Retracted] Propofol exhibits a tumor‑suppressive effect and regulates cell viability, migration and invasion in bladder carcinoma by targeting the microRNA‑10b/HOXD10 signaling pathway

Retracted] Propofol exhibits a tumor‑suppressive effect and regulates cell viability, migration and invasion in bladder carcinoma by targeting the microRNA‑10b/HOXD10 signaling pathway

Familial adenomatous polyposis gene MUTYH mutations are identified in anaplastic thyroid carcinoma

Abstract Introduction/Objective Anaplastic thyroid carcinoma (ATC) is a rare aggressive disease unresponsive to treatment. Next-Generation Sequencing (NGS) allows identification of targets for precision therapies, such as BRAF, with implications in treating ATC. Our prior work identified ATC clusters with characteristic gene mutations and multiple previously unreported mutations. One of these is MUTYH, which is associated with colon (CRC), ovarian, breast, bladder, and duodenal carcinomas in MUTYH-associated polyposis (MAP). Its association with ATC is not defined. Methods/Case Report Exploratory analysis of pathogenic mutations in 727 ATC cases using a 324-gene panel (FoundationOneCDx) and an interactive visualization of association rules was conducted for informative maximal frequent patterns among mutated gene combinations to identify gene clusters including genes not commonly associated with ATC. TCGA database was reviewed for frequency of MUTYH mutations. My Cancer Genome and the Drug-Gene Interaction Database were used to identify potential targeted drugs for MUTYH gene-mutated cancers. Results (if a Case Study enter NA) NGS showed MUTYH short-variant mutations in 17 cases (2.34%). Germline MUTYH variants incidence is 1.43% in normal samples. 5 cases harbored only Y165C and 7 had only G382D, with 1 case having both Y165C and G382D. The other 4 cases contained sporadic truncating events in MUTYH. All instances of Y165C and G382D were predicted to be germline. 6 patients (35%) had BRAF co-mutations, correlating with expected frequency of ATC thought to transform from papillary carcinoma (PC). One case had only MUTYH mutation while a second had MUTYH with TERT and TP53. TCGA database contained 6(0.2%) cases of PC with MUTYH mutations (total 2871 MUTYH-mutated carcinomas), but no cases of ATC or other thyroid tumors were described. Conclusion MUTYH is a DNA repair enzyme linked to CRC and other cancers. MUTYH mutations occur in 6.7% of MAP patients and 1–2.2% of sporadic CRC cases that are mutually exclusive of BRAF mutations. While MAP increases the lifetime risk of CRC by over 60%, the link of MUTYH mutations to PC has only been observed in MAP and not been described outside of it. To our knowledge this is the first description of MUTYH mutations in ATC, especially without concurrent BRAF mutation (11 cases), suggesting MUTYH may independently contribute to pathogenesis of ATC. PARP inhibitors, PD-1/PD-L1 inhibitors, and ATR inhibitors demonstrate promising results in clinical trials of MUTYH-mutated cancers, warranting further research.

Copper Nanoparticles Green-Formulated byCurcuma longa Extract Induce Apoptosis via P53 and STAT3 Signaling Pathways in Bladder Carcinoma Cell.

The study outlines the production of new copper nanoparticles infused with Curcuma longa extract to trigger apoptosis through P53 and signal transducer and activator of transcription 3 (STAT3) signaling pathways in bladder carcinoma cells. The structural characteristics of the nanoparticles that were synthesized were analyzed through various sophisticated methods such as transmission electron microscopy (TEM), field emission-scanning electron microscopy (FE-SEM), energy dispersive X-ray spectroscopy (EDX), and Fourier transform infrared spectroscopy (FT-IR). During the antioxidant evaluation, the IC50 values for copper nanoparticles and butylated hydroxytoluene (BHT) against 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radicals were found to be 116µg/mL and 31µg/mL, respectively. The cells treated with copper nanoparticles underwent evaluation through 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay for 48h to determine their anticancer properties on TCCSUP bladder carcinoma cell. The TCCSUP cell line exhibited an IC50 of 290µg/mL when exposed to copper nanoparticles. The viability of malignant cells decreased upon treatment with copper nanoparticles. Furthermore, the copper nanoparticles presence led to a 65-75% increase in cell apoptosis, along with an increase in Bax and cleaved caspase-8 and a decrease in the Bcl-2. Furthermore, the copper nanoparticles presence resulted in the suppression of colony formation. Notably, the molecular pathway analysis in cells treated with copper NPs demonstrated an increase in p53 expression, along with a decrease in the expression of both total and phosphorylated STAT3. This offers that p53 and STAT3 play a crucial role in the biological efficacies induced by the nanoparticles in human carcinoma cells. The data of our research suggest that copper NPs could have significant potential as an anticancer treatment for human bladder carcinoma cells.

Synergistic Proliferation Effects of Xanthohumol and Niflumic Acid on Merkel and Glioblastoma Cancer Cells: Role of Cell Membrane Interactions

The objective of our research was to determine the effects of xanthohumol (XN), a flavonoid isolated from hops (Humulus lupulus), and the anti-inflammatory drug niflumic acid (NA), separately and in combination with each other, on the proliferation of human cancer cells. Additionally, so as to understand the mechanism underlying the anticancer properties of the tested compounds, their effects on the biophysical parameters of a model membrane were assessed. The cells were incubated with XN and NA at various concentrations, either individually or in combination with each other. Cell proliferation was quantified using the sulforodamine B (SRB) assay. In addition, the IC50 values for niflumic acid and xanthohumol applied separately were determined by cell proliferation tests for the following human cancer cell lines: 5637 (urinary bladder carcinoma), A-431 (epidermoid carcinoma), UM-SCC-17A (head and neck squamous carcinoma), SK-MEL-3 (melanoma), MCC13 (Merkel cell cancer), and A172 (glioblastoma), in comparison with the mouse normal fibroblasts (BALB/3T3 clone A31). The results show that the two-compound combinations of XN and NA significantly decreased the proliferation of cancer cells in a dose-dependent manner, and the effects were stronger than the additive responses to XN and NA individually. The membrane studies revealed a synergistic effect on the membrane rigidity when using the mixture of XN and NA, which may explain the observed increase in anticancer activity for the combined XN and NA. Our results suggest that NSAIDs, such as niflumic acid, may be a promising strategy for co-application with xanthohumol as anticancer drugs.

Altering Trends in Pathological Spectrum of Cholecystectomy Specimen: Time to be More Vigilant

Abstract Background: Gall bladder cancer is a rare, most common and aggressive malignancy of the biliary tree, accounting for 80%–90% of biliary tract cancers. Gallstones are one of the major causes of the development of cholecystitis and long-term malignancy in developing countries. Cholecystectomy specimens have a great value in documenting various entities with clinical significance. Early detection is the most important step in improving the prognosis of gall bladder carcinoma (GBC) screening. Aim: Clinico- pathological spectrum of cholecystectomy specimen and Incidence of malignancy and its precursor lesion with gallstones. Patient and Methods: We conducted a retrospective analysis of all gall bladder specimens (cholecystectomy, laparoscopic, open or radical) from the period of January 2019–January 2022, including demographic data of the patients such as age and sex. Additional findings, such as the presence of gallstones, cholesterolosis, gastric or intestinal metaplasia, dysplasia and histopathological type of GBC, were documented. Results: A total of 1221 gall bladder specimens were received, with a higher female preponderance and a female-to-male ratio of 2.6:1. The mean age of presentation was 45 years. The most common histopathological diagnosis made was chronic cholecystitis (97%), and malignant cases accounted for 3% of the total cases. Conclusions: The high propensity of GBC with non-cholelithiasis cases, more than half of cases with metaplasia and increased incidence of adenosquamous carcinoma indicate a high burden of tumours, alerting the clinician as well as the pathologist.

Effects of Intraoperative Opioid Use and a Combined Anesthesia Protocol in Patients Undergoing Radical Cystectomy for Urothelial Carcinoma of the Bladder—A Single-Center Experience

Background: An increased intraoperative opioid dose seems to lead to worse outcomes in several types of cancer. We assessed the effect of intraoperatively administered opioids as well as the type of anesthesia on survival, recurrence rates and major perioperative outcomes in patients who underwent radical cystectomy (RC) for urothelial carcinoma of the urinary bladder. Methods: We included patients who underwent open RC at our center between 2015 and 2022. The role of the type and dosage of intraoperative opioid agents, such as remifentanil, sufentanil and morphine milligram equivalents (MME), as well as the type of anesthesia (intravenous only versus intravenous/epidural), was assessed regarding perioperative and long-term outcomes after RC. Results: A total of 508 patients with a median age of 73 years (IQR: 64–78) were included. Overall, 92 (18%) patients received intravenous anesthesia, whereas 416 (82%) received combined anesthesia. At a median follow-up of 270 days (IQR: 98–808), 108 (21%) deaths and 106 (21%) recurrences occurred. Combined anesthesia was associated with better survival (HR:0.63, 95% CI: 0.4–0.97, p = 0.037) and lower intensive care unit admission rates (OR: 0.49, 95% CI: 0.31–0.77, p = 0.002) in the univariate analysis (unadjusted). The type and dosage of intraoperative opioid agents did not affect long-term survival and recurrence rates, as well as major perioperative outcomes. Nevertheless, the findings of our study were limited by its single-center, retrospective design. Conclusion: The use of intraoperative opioids was not associated with worse outcomes in our cohort, while the use of additional epidural anesthesia seems to be beneficial in terms of overall survival and intensive care unit admissions. Nevertheless, further research is mandatory to validate the safety of opioids in patients undergoing RC.

Dynamic landscape of m6A modifications and related post-transcriptional events in muscle-invasive bladder cancer

BackgroundMuscle-invasive bladder carcinoma (MIBC) is a serious and more advanced stage of bladder carcinoma. N6-Methyladenosine (m6A) is a dynamic and reversible modifications that primarily affects RNA stability and alternative splicing. The dysregulation of m6A in MIBC can be potential target for clinical interventions, but there have been limited studies on m6A modifications in MIBC and their associations with post-transcriptional regulatory processes.MethodsPaired tumor and adjacent-normal tissues were obtained from three patients with MIBC following radical cystectomy. The additional paired tissues for validation were obtained from patients underwent transurethral resection. Utilizing Nanopore direct-RNA sequencing, we characterized the m6A RNA methylation landscape in MIBC, with a focus on identifying post-transcriptional events potentially affected by changes in m6A sites. This included an examination of differential transcript usage, polyadenylation signal sites, and variations in poly(A) tail length, providing insights into the broader impact of m6A alterations on RNA processing in MIBC.ResultsThe prognostic-related m6A genes and m6A-risk model constructed by machine learning enables the stratification of high and low-risk patients with precision. A novel m6A modification site in the 3’ untranslated region (3’UTR) of IGLL5 gene were identified, characterized by a lower m6A methylation ratio, elongated poly(A) tails, and a notable bias in transcript usage. Furthermore, we discovered two particular transcripts, VWA1-203 and CEBPB-201. VWA1-203 displayed diminished m6A methylation levels, a truncated 3’UTR, and an elongated poly(A) tail, whereas CEBPB-201 showed opposite trends, highlighting the complex interplay between m6A modifications and RNA processing. Source code was provided on GitHub (https://github.com/lelelililele/Nanopore-m6A-analysis).ConclusionsThe state-of-the-art Nanopore direct-RNA sequencing and machine learning techniques enables comprehensive identification of m6A modification and provided insights into the potential post-transcriptional regulation mechanisms on the development and progression in MIBC.

Neoadjuvant chemotherapy before radical cystectomy in patients with organ-confined and non-organ-confined urothelial carcinoma

IntroductionNeoadjuvant chemotherapy (NAC) before radical cystectomy (RC) is guideline-recommended in patients with cT2-T4N0M0 urothelial carcinoma of urinary bladder (UCUB). However, no population-based study validated the survival benefit of NAC recorded in clinical trials in a stage-specific fashion. We addressed this knowledge gap. MethodsWithin the Surveillance, Epidemiology, and End Results database (2007–2020), we identified patients with cT2-T4N0M0 UCUB treated with NAC before RC versus RC alone. Cumulative incidence plots and multivariable competing risks regression (CRR) models were fitted. Survival analyses were performed according to organ confined (OC: cT2N0M0) versus nonorgan confined stages (NOC: cT3-T4N0M0). ResultsOf 3,743 assessable patients, 1,020 (27%) underwent NAC versus 2,723 (73%) RC alone. NAC rates increased over time in OC stage (EAPC = 11.9%, P < 0.001) and NOC stage (EAPC = 8.6%, P < 0.001). In OC stage, cumulative incidence plots derived 5-year CSM was 15.6% in NAC and 19.9% in RC alone patients (P = 0.008). In multivariable CRR models, NAC independently predicted lower CSM (hazard ratio (HR): 0.74, P = 0.01). Similarly, in NOC stage, cumulative incidence plots derived 5-year CSM was 36.1% in NAC and 46.0% in RC alone patients (P = 0.01). In multivariable CRR models, NAC independently predicted lower CSM (HR: 0.66, P < 0.001). ConclusionNAC is associated with improved CSM compared to RC alone, both in OC and NOC stages. Specifically, the magnitude of the protective NAC effect was greater in NOC than OC patients. Thus, NAC should always be administered in all eligible patients before RC.

Development and validation of a novel liquid-liquid phase separation gene signature for bladder cancer

Bladder carcinoma (BLCA) represents a common urinary tract malignancy, characterized by aggressive behavior and high recurrence rates. The biological response regulation during tumor proliferation and metastasis is intimately associated with liquid-liquid phase separation (LLPS). For the purpose of enhancing early detection and treatment, this study employed transcriptomic data to examine the prognostic implications of LLPS-associated genes and formulate a predictive model. Clinical and transcriptomic data of bladder cancer patients were sourced from the GEO and TCGA databases. This study applied a clustering algorithm using non-negative matrix factorization (NMF) to classify samples, which were systematically compared based on their liquid-liquid phase separation characteristics. Prognostic models were developed using multivariate Cox regression and the Least Absolute Shrinkage Selection Operator (LASSO) algorithm to establish risk formulas for nine genes. The gene signature’s validity was tested across the entire TCGA cohort (406 cases), the TCGA testing cohort (120 cases), and the external validation dataset GSE13507. The predictive accuracy of the signature system was assessed using receiver operating characteristic (ROC) and Kaplan-Meier curves. Additionally, decision curve analysis incorporating clinicopathological parameters and the genetic signature was employed to predict individual survival. This study identified two distinct molecular subtypes, C1 and C2. Patients with the C1 subtype exhibited significantly better prognoses than those with the C2 subtype. Low-risk group patients consistently showed superior prognoses compared to high-risk groups across the entire TCGA, GEO, and TCGA training cohorts. Furthermore, the LLPS-related gene model demonstrated prognostic value independent of other clinical traits. This study identifies LLPS-associated gene clusters and establishes an independent, accurate prognostic model for BLCA. The model holds potential for clinical application in BLCA prognosis assessment.

Broad applicability of the Goldspire™ platform for the treatment of solid tumors

Goldspire™ is a personalized immunotherapy platform that combines whole tumor-derived cells with antisense oligonucleotide (IMV-001) against Insulin-Like Growth Factor-1 Receptor (IGF-1R) in biodiffusion chambers (BDCs; 0.1 μm pore). BDCs are exposed to 5–6 Gy and implanted at abdominal sites for ∼48 h to deliver an antigenic payload and immunostimulatory factors to train the immune system. Lead product IGV-001 was evaluated in newly diagnosed glioblastoma (ndGBM) patients in Phase 1a and 1b trials (NCT02507583). A Phase 2b study (NCT04485949) recently completed enrollment.Preventative treatment with tumor-specific products manufactured with Goldspire limited tumor progression and extended overall survival in mice challenged with bladder, pancreatic, ovarian, colorectal, or renal carcinomas. The benefit of this immunotherapy was enhanced with anti-PD-1; combination treatment was superior to either monotherapy in orthotopic GBM and melanoma models. Lastly, Goldspire elicited immune T cell activation and memory phenotypes against patient-derived endometrial tumor-derived products in co-cultures with matching immune cells.

Abstract C161: Rare Invasive Plasmacytoid Urothelial Carcinoma Presenting as Post-Renal Acute Kidney Injury: A Case Report

Abstract Purpose: Plasmacytoid urothelial carcinoma stands out as a rare and highly aggressive histological subtype within the spectrum of bladder carcinomas, constituting only 1-3% of all variants. Summary: In this case report, we present the case of a 72-year-old patient who initially presented with significant obstructive uropathy and hydronephrosis secondary to invasive plasmacytoid urothelial carcinoma. Admission labs were concerning for a hemoglobin level of 3.8, requiring 3 units of red blood cells for correction, potassium level of 8.8, for which urgent hemodialysis was given, and a lactate level of 5.4. The patient subsequently developed delayed hematuria one month later. Follow-up CT imaging revealed an alarming increase in the size of the bladder mass, underscoring the rapid progression of the malignancy. Discussion: The aggressive nature of this malignant neoplasm can be attributed to its diffuse pattern of infiltration and high risk of residual disease following radical surgery. Clinical manifestations often include abdominal pain, but lack early-onset hematuria and other urinary symptoms typically seen with other subtypes, leading to diagnostic delays and late-stage identification. Conclusion: This case report highlights the uncommon clinical presentation of plasmacytoid urothelial carcinoma (PUC), manifesting as obstructive nephropathy. The inherent aggressiveness associated with PUC poses a challenge in treatment due to the advanced stage of the malignancy at the time of diagnosis. The scarcity of guidelines for the management of PUC underscores the need for extensive future studies to bridge this gap. Citation Format: Andressa Uzeda, Toral Shastri, Kamilia Moalem, Kendra Van Kirk. Rare Invasive Plasmacytoid Urothelial Carcinoma Presenting as Post-Renal Acute Kidney Injury: A Case Report [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr C161.

NF-κB and TET2 promote macrophage reprogramming in hypoxia that overrides the immunosuppressive effects of the tumor microenvironment.

Macrophages orchestrate tissue homeostasis and immunity. In the tumor microenvironment (TME), macrophage presence is largely associated with poor prognosis because of their reprogramming into immunosuppressive cells. We investigated the effects of hypoxia, a TME-associated feature, on the functional, epigenetic, and transcriptional reprogramming of macrophages and found that hypoxia boosts their immunogenicity. Hypoxic inflammatory macrophages are characterized by a cluster of proinflammatory genes undergoing ten-eleven translocation-mediated DNA demethylation and overexpression. These genes are regulated by NF-κB, while HIF1α dominates the transcriptional reprogramming, demonstrated through ChIP-seq and pharmacological inhibition. In bladder and ovarian carcinomas, hypoxic inflammatory macrophages are enriched in immune-infiltrated tumors, correlating with better patient prognoses. Coculture assays and cell-cell communication analyses support that hypoxic-activated macrophages enhance T cell-mediated responses. The NF-κB-associated hypomethylation signature is displayed by a subset of hypoxic inflammatory macrophages, isolated from ovarian tumors. Our results challenge paradigms regarding the effects of hypoxia on macrophages and highlight actionable target cells to modulate anticancer immune responses.

Concurrent Urothelial Carcinoma of the Bladder and Renal Cell Carcinoma of the Kidney: A Diagnostic and Therapeutic Challenge

Concurrent Urothelial Carcinoma of the Bladder and Renal Cell Carcinoma of the Kidney: A Diagnostic and Therapeutic Challenge

The Simultaneous Use of Bladder Epicheck® and Urinary Cytology Can Improve the Sensitivity and Specificity of Diagnostic Follow-Up of Urothelial Lesions: Up-to-Date Data from a Multi-Institutional Cohort.

Background/Objectives: Bladder cancer is a prevalent urinary system malignancy and urinary cytology is widely used for its screening and follow-up. A novel diagnostic tool called Bladder Epicheck® (BE) is increasingly being used for monitoring the recurrence of non-muscle-invasive bladder cancer (NMIBC). The simultaneous use of BE and urinary cytology can increase the diagnostic performances in the follow-up of bladder neoplasms. Methods: In this multicenter study, we retrospectively evaluated the data of 322 patients in follow-up for a high-grade bladder carcinoma over a six-year period (from January 2018 to March 2024). The diagnostic performances of both cytology and BE and their combination were calculated using histology as gold standard. Results: Recurrences were diagnosed as high-grade urothelial carcinoma NMIBC in 18 cases, low-grade papillary NMIBC in 8 cases, and carcinoma in situ (CIS) in 4 cases. Cytological analysis correctly identified 26 out of 30 carcinomas, while 286 were correctly diagnosed as negative results. BE correctly identified 25 out of 30 carcinomas, 285 were correctly diagnosed as negative results. The combination of BE and urinary cytology correctly identified 29 out of 30 carcinomas, while 289 were correctly diagnosed as negative results. Conclusions: The combination of BE and cytology could be the most effective approach for follow-up diagnosis in patients with high-grade NMIBC, reducing unnecessary invasive procedures.

Enhanced Tumor-Targeted Delivery of Arginine-Rich Peptides via a Positive Feedback Loop Orchestrated by Piezo1/integrin β1 Signaling Axis.

Peptide-based drugs hold great potential for cancer treatment, and their effectiveness is driven by mechanisms on how peptides target cancer cells and escape from potential lysosomal entrapment post-endocytosis. Yet, the mechanisms remain elusive, which hinder the design of peptide-based drugs. Here hendeca-arginine peptides (R11) are synthesized for targeted delivery in bladder carcinoma (BC), investigated the targeting efficiency and elucidated the mechanism of peptide-based delivery, with the aim of refining the design and efficacy of peptide-based therapeutics. It is demonstrated that the over-activated Piezo1/integrin β1 (ITGB1) signaling axis significantly facilitates tumor-targeted delivery of R11 peptides via macropinocytosis. Furthermore, R11 peptides formed hydrogen bonds with integrin β1, facilitating targeting and penetration into tumor cells. Additionally, R11 peptides protected integrin β1 from lysosome degradation, promoting its recycling from cytoplasm to membrane. Moreover, this findings establish a positive feedback loop wherein R11 peptides activate Piezo1 by increasing membrane fusion, promoting Ca2+ releasing and resulting in enhanced integrin β1-mediated endocytosis in both orthotopic models and clinical tissues, demonstrating effective tumor-targeted delivery. Eventually, the Piezo1/integrin β1 signaling axis promoted cellular uptake and transport of peptides, establishing a positive feedback loop, promoting mechanical delivery to cancer and offering possibilities for drug modification in cancer therapy.

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 &amp; 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.

Prognostic value of nucleotide excision repair and translesion DNA synthesis proteins in muscle-infiltrating bladder carcinoma

BackgroundCisplatin (CDDP) remains a key agent in the treatment of muscle-infiltrating bladder carcinoma (MIBC). However, a proportion of MIBC patients do not respond to chemotherapy, which may be caused by the increased repair of CDDP-induced DNA damage. The purpose of this study was to explore the prognostic value of proteins involved in nucleotide excision repair (NER) and translesion DNA synthesis (TLS) in MIBC patients.MethodsThis is a retrospective analysis of 86 MIBC patients. The XPA, XPF, XPG, ERCC1, POLI, POLH and REV3L proteins were stained in primary bladder tumors and their levels were analyzed both in the total cohort and in a subgroup with metastatic urothelial carcinoma (mUC) that received gemcitabine and CDDP as a first-line therapy. Both cohorts were divided by percentage of cancer cells stained positive for each protein into subgroups with high and low expression. In the same manner, the combined expression of NER (XPA + ERCC1 + XPF + XPG) and TLS (POLI + POLH + REV3L), as the whole pathways, was analyzed.ResultsMortality was 89.5% at the median follow-up of 120.2 months. In the total cohort, patients with tumors stained positive for XPA, XPG and POLI had significantly worse overall survival (OS) compared to those with negative staining [hazard ratio (HR) = 0.60, 0.62 and 0.53, respectively]. Both XPG and POLI were independent prognostic factors in multivariate analyses (MVA). In addition, an increase in NER and TLS pathway expression was significantly associated with worse OS in the total cohort (HR = 0.54 and 0.60, respectively). In the mUC subgroup, high POLI expression was associated with significant deterioration of OS (HR = 0.56) in univariate analyses, and its independent prognostic value was shown in MVA.ConclusionsOur study showed significant correlations between the tumor expression of XPG and POLI, as well as NER and TLS as the whole pathways, and inferior OS. Hence, they could constitute prognostic biomarkers and potentially promising therapeutic targets in MIBC. However, a prospective trial is required for further validation, thereby overcoming the limitations of this study.