Influence of lymph node degeneration on metastases in prostate cancer: or why we must look for a needle in a haystack.

BACKGROUND: To evaluate the incidence of lymph node degeneration and its association with nodal metastatic pattern in prostate cancer. METHODS: A retrospective analysis of the submitted lymph node specimen of 390 prostatectomies in 2011 was performed. All lymph nodes were histologically re-evaluated and the degree of lymph node degeneration e.g. lipomatous atrophy, capsular and framework fibrosis, and calcifications as well as the lymph node size were recorded. Lymph node degeneration was compared in the anatomic regions of the pelvis as well as in lymph nodes with and without metastases of prostatic cancer. RESULTS: Eighty-one of 6026 lymph nodes demonstrated metastases. Complete histologic examination with analysis of a complete cross-section was possible in 5173 lymph nodes including all lymph nodes with metastases. The incidence of lymph node degeneration was different across the various landing sites. Lymph node metastases were primarily detected in less degenerative and therefore more functional lymph nodes. In metastatic versus non-metastatic lymph nodes low lipomatous atrophy was reported in 84.0% versus 66.7% (p = 0.004), capsular fibrosis in 14.8% versus 35.4% (p < 0.001), calcifications in 35.8% versus 46.1% (p = 0.072) and framework fibrosis in 69.8% versus 75.3% (p = 0.53). Metastases were also identified more frequently in larger than in smaller lymph nodes (63.0% vs. 47.5%; p = 0.007). CONCLUSIONS: Degenerative changes in pelvic lymph nodes are commonly detectable but occur with variable frequency in the various nodal landing sites in the pelvis. The degree of lymph node degeneration of single lymph nodes has a significant influence on whether a lymph node is infiltrated by tumor cells and may harbour metastases.

A SWOT (Strengths, Weaknesses, Opportunities, and Threats) Analysis of ChatGPT in the Medical Literature: Concise Review.

BACKGROUND: ChatGPT is a 175-billion-parameter natural language processing model that is already involved in scientific content and publications. Its influence ranges from providing quick access to information on medical topics, assisting in generating medical and scientific articles and papers, performing medical data analyses, and even interpreting complex data sets. OBJECTIVE: The future role of ChatGPT remains uncertain and a matter of debate already shortly after its release. This review aimed to analyze the role of ChatGPT in the medical literature during the first 3 months after its release. METHODS: We performed a concise review of literature published in PubMed from December 1, 2022, to March 31, 2023. To find all publications related to ChatGPT or considering ChatGPT, the search term was kept simple ("ChatGPT" in AllFields). All publications available as full text in German or English were included. All accessible publications were evaluated according to specifications by the author team (eg, impact factor, publication modus, article type, publication speed, and type of ChatGPT integration or content). The conclusions of the articles were used for later SWOT (strengths, weaknesses, opportunities, and threats) analysis. All data were analyzed on a descriptive basis. RESULTS: Of 178 studies in total, 160 met the inclusion criteria and were evaluated. The average impact factor was 4.423 (range 0-96.216), and the average publication speed was 16 (range 0-83) days. Among the articles, there were 77 editorials (48,1%), 43 essays (26.9%), 21 studies (13.1%), 6 reviews (3.8%), 6 case reports (3.8%), 6 news (3.8%), and 1 meta-analysis (0.6%). Of those, 54.4% (n=87) were published as open access, with 5% (n=8) provided on preprint servers. Over 400 quotes with information on strengths, weaknesses, opportunities, and threats were detected. By far, most (n=142, 34.8%) were related to weaknesses. ChatGPT excels in its ability to express ideas clearly and formulate general contexts comprehensibly. It performs so well that even experts in the field have difficulty identifying abstracts generated by ChatGPT. However, the time-limited scope and the need for corrections by experts were mentioned as weaknesses and threats of ChatGPT. Opportunities include assistance in formulating medical issues for nonnative English speakers, as well as the possibility of timely participation in the development of such artificial intelligence tools since it is in its early stages and can therefore still be influenced. CONCLUSIONS: Artificial intelligence tools such as ChatGPT are already part of the medical publishing landscape. Despite their apparent opportunities, policies and guidelines must be implemented to ensure benefits in education, clinical practice, and research and protect against threats such as scientific misconduct, plagiarism, and inaccuracy.

[Prostate cancer in older men : Special features of the diagnostics and treatment]. / Prostatakarzinom beim älteren Mann : Besonderheiten der Diagnostik und Therapie.

Prostate cancer is the most frequent cancer in men. For localized prostate cancer, surgery and radiotherapy are the standard treatment, with active surveillance also used in low-risk cases. For advanced/metastatic disease, androgen deprivation treatment is carried out. Further options include inhibitors of the androgen receptor axis and taxane-based chemotherapy. The avoidance of side effects should be considered, e.g., by dose adjustment. New options include poly(ADP-ribose) polymerase (PARP) inhibitors, and radioligand treatment. The existing guidelines only provide a few treatment recommendations for older patients; however, the treatment of older patients should primarily consider not only chronological age but also the patient's psychological and physical condition and preferences. In this context, the geriatric assessment represents an important instrument for determining the treatment strategy.

Effectiveness and Safety of a Modified Technique of Transvesical Obturator Nerve Block to Avoid Adductor Contractions during Transurethral Resection of Bladder Tumors.

INTRODUCTION: The aim of the study was to evaluate the effectiveness of a modified transvesical obturator nerve block (ONB) in the prevention of obturator nerve reflex and consecutive bladder perforations (BPs) during transurethral resection of bladder tumors (TURBTs). MATERIALS AND METHODS: A retrospective analysis of all patients resected in 2014-2015 due to a bladder tumor of the lateral walls, including a follow-up period until December 2018, was performed. Two groups were defined: in the first group, all patients underwent TURBT with a modified transvesical ONB. The second group underwent conventional TURBT with intermittent resection. Primary endpoints were the rates of adductor contractions and BPs. RESULTS: Ninety-four out of 1,145 resected patients presented with tumors on the lateral wall of the bladder and a complete dataset including a long-term follow-up. Thirty-six patients were treated in the ONB group, and 58 patients comprised the control group. The median age in the 2 groups was 70.8 and 71.8 years in the first and second groups, respectively. Adductor spasms were reported in 8.33 versus 25.86% (p = 0.057) and perforation in 2.78 versus 17.24% (p = 0.047) in groups 1 and 2, respectively. After a median follow-up of 32.5 months, there was no significant difference in recurrence rates (52.78 vs. 51.72%, p = 0.672). In a subgroup analysis, lower perforation rates were recorded for the ONB group in patients with tumors <3 cm (0/30 vs. 8/46, p = 0.076) and in patients with unifocal tumors (0/12 vs. 5/23, p = 0.141). DISCUSSION/CONCLUSION: The simplified approach of transvesical ONB demonstrated in this study appears to be an inexpensive, safe, effective, and simple-to-use technique.

Extra nodular metastasis is a poor prognostic factor for overall survival in node-positive patients with colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) is the second leading cause for cancer-related death in industrialized nations. Nodal involvement has been identified as a relevant prognostic feature in CRC. Extra nodal metastasis (ENM) describes the spread of malignant cells beyond the nodal capsule. ENM is thought to be an independent risk factor for poor survival. This study examined ENM as an independent risk factor for poor overall survival in patients with node-positive CRC. MATERIALS AND METHODS: Data from a prospectively maintained CRC database was retrospectively analyzed. Blinded slides of patients with stage III and IV CRC following radical surgical resection were re-examined for the presence of ENM. The effect of ENM on overall survival was examined using Kaplan-Meier curves. RESULTS: One hundred forty-seven cases with node-positive CRC (UICC stages III and IV) including 78 cases with ENM were included for analysis. ENM was seen in 60 patients with colon cancer (58.8%) and in 18 patients with rectal cancer (40%), p = 0.033. ENM-positive patients had a significantly higher odd for cancer-related death compared to ENM-negative patients ratio of [OR 0.44: 0.22-0.88, CI 95%, p = 0.021], p = 0.02. The median overall survival was significantly longer in patients without ENM, 51.0 ± 33 vs. 30.5 ± 42 months, p = 0.02. CONCLUSION: Extra nodal metastasis is an independent prognostic factor in patients with node-positive colorectal cancer. Extra nodal metastasis is associated with high odds of tumor-related mortality and poor overall survival.

Calprotectin could be a potential biomarker for acute appendicitis.

BACKGROUND: Acute appendicitis is a common cause for a visit to the emergency department and appendectomy represents the most common emergency procedure in surgery. The rate of negative appendectomy however has remained high despite modern diagnostic apparatus. Therefore, there is need for a better preoperative screening of patients with suspected appendicitis. Calprotectin represents a predominant protein in the cytosol of neutrophil granulocytes and has been extensively investigated with regard to bowel pathologies. This study investigates the expression of calprotectin in the lumen of the vermiform appendix of patients undergoing appendectomy for suspected appendicitis. METHODS: Appendix specimens from patients undergoing emergency appendectomy for suspected acute appendicitis were examined. Acute appendicitis was confirmed on histopathology. The qualitative expression of calprotectin in the vermiform appendix specimens was analyzed using specific calprotectin antibodies. RESULTS: Vermiform appendix specimens from 52 patients (22 female and 30 male) including 11 with uncomplicated and 41 with complicated appendicitis were analyzed. Strong immunostainings were achieved with calprotectin antibody in the lumen of all specimens irrespective of the extent of appendicitis. Immunostaining was negative in the uninflamed appendix. CONCLUSIONS: High calprotectin activity could be demonstrated within the lumen of vermiform appendix specimens following appendectomy for acute appendicitis. The high luminal accumulation of calprotectin-carrying cells could be interpreted as an invitation to study the expression of calprotectin in stool as a new diagnostic aid in patients with suspected appendicitis.

Integrative Pathway Analysis of Metabolic Signature in Bladder Cancer: A Linkage to The Cancer Genome Atlas Project and Prediction of Survival.

PURPOSE: We used targeted mass spectrometry to study the metabolic fingerprint of urothelial cancer and determine whether the biochemical pathway analysis gene signature would have a predictive value in independent cohorts of patients with bladder cancer. MATERIALS AND METHODS: Pathologically evaluated, bladder derived tissues, including benign adjacent tissue from 14 patients and bladder cancer from 46, were analyzed by liquid chromatography based targeted mass spectrometry. Differential metabolites associated with tumor samples in comparison to benign tissue were identified by adjusting the p values for multiple testing at a false discovery rate threshold of 15%. Enrichment of pathways and processes associated with the metabolic signature were determined using the GO (Gene Ontology) Database and MSigDB (Molecular Signature Database). Integration of metabolite alterations with transcriptome data from TCGA (The Cancer Genome Atlas) was done to identify the molecular signature of 30 metabolic genes. Available outcome data from TCGA portal were used to determine the association with survival. RESULTS: We identified 145 metabolites, of which analysis revealed 31 differential metabolites when comparing benign and tumor tissue samples. Using the KEGG (Kyoto Encyclopedia of Genes and Genomes) Database we identified a total of 174 genes that correlated with the altered metabolic pathways involved. By integrating these genes with the transcriptomic data from the corresponding TCGA data set we identified a metabolic signature consisting of 30 genes. The signature was significant in its prediction of survival in 95 patients with a low signature score vs 282 with a high signature score (p = 0.0458). CONCLUSIONS: Targeted mass spectrometry of bladder cancer is highly sensitive for detecting metabolic alterations. Applying transcriptome data allows for integration into larger data sets and identification of relevant metabolic pathways in bladder cancer progression.

Aquaporin-1 and 8 expression in the gallbladder mucosa might not be associated with the development of gallbladder stones in humans.

BACKGROUND: Cholecystolithiasis is a highly prevalent condition in the Western world. Gallbladder stone-related conditions represent the second most common gastrointestinal pathology. Cholesterol stones represent over 80% of gallstones. Cholesterol stones develop secondary to crystallization of bile cholesterol. Water resorption from gallbladder bile via aquaporin in the gallbladder mucosa might play a role in the development of cholesterol stones. This study investigated the expression of Aquaporin-1 (AQP1) and Aquaporin-8 (AQP8) in the human gallbladder mucosa and their possible association with the formation of gallbladder stones. METHODS: The expression of AQP1 and AQP8 in the gallbladder mucosa was examined via immunohistochemical staining. The expression of both AQP1 and AQP8 in the gallbladder mucosa of stone carriers (study group) was compared to that of nonstone carriers (control group). RESULTS: Eighty-four gallbladder specimens from 44 male (52·2%) and 40 female (47·6%) patients were analysed. The study group included 47 specimens from stone carriers, while 37 specimens from stone-free gallbladders were included in the control group. Immunostaining for both AQP1 and AQP8 was positive in 80 cases. AQP1 was expressed both over the apical and intercellular membrane, while AQP8 was expressed only over the apical membrane. A similar distribution was recorded in specimens from the cystic duct. Immunostaining with AQP1 was generally stronger in comparison with AQP8. No significant (P > 0·05) relationship was found between aquaporin expression and the presence or absence of gallbladder stones. CONCLUSION: AQP1 and AQP8 are both expressed in the gallbladder and cystic duct mucosa. However, their role in the development of gallbladder stones is still to be proven.

Microsatellite instability is highly prevalent in older patients with colorectal cancer.

Background: Clinical guidelines suggest screening of colorectal cancer (CRC) for microsatellite instability (MSI). However, microsatellite instability-high (MSI-H) CRC is not rare in older patients. This study aimed to investigate the prevalence of MSI-H CRC in an unselected population in an age-based manner. Material and methods: A retrospective analysis of data from patients undergoing radical surgery for CRC was performed. Only cases with results from MSI testing using immunochemistry (IHC) were analyzed. Age-based analyses were performed using two cut-off ages: 50 years. as stated in Amsterdam II guidelines, and 60 years. as outlined in the revised Bethesda criteria. Results: The study population included 343 (146 female and 197 male) patients with a median age of 70 years (range 21-90 years). The prevalence of MSI-H tumors in the entire cohort was 18.7%. The prevalence of MSI-H CRC was 22.5% in the group ≤50 years vs. 18.2% in the group >50 years using the age limit in the Amsterdam II guidelines. MSI-H CRC was present in 12.6% of the group aged ≤60 years compared to 20.6% in the control group >60 years. Conclusion: MSI screening of CRC based on age alone is associated with negative selection of a relevant number of cases. MSI-H CRC is also common in elderly patients, who may be negatively selected secondary to an age-based screening algorithm. Following the results of this study, screening based on clinical criteria should be omitted in favor of systematic screening as is already internationally practiced.

Family history as a major prerequisite for microsatellite instability screening in colorectal cancer is a poor selection tool.

Background: Deficient mismatch repair (MMR) leading to microsatellite instability (MSI) in tumors is thought to be present in over 15% of colorectal cancer (CRC) cases. Testing CRC for MSI has traditionally been recommended following the fulfillment of clinical criteria. However, the performance of clinical criteria, especially the family history, as a selection tool for MSI screening in CRC is questionable. Methods: We retrospectively investigated the incidence of high degree MSI (MSI-H) tumors in an unselected population of CRC patients and compared its prevalence between individuals with and without family history of cancers within the spectrum of MSI-H tumors as defined in the revised Bethesda criteria. Results: The study population included 274 patients, 70 with positive and 204 without family history of MSI-H tumors with complete data including findings from MSI analysis. The overall incidence of MSI-H CRC was 18.98%. There was no statistically significant difference in the incidence of MSI-H CRC amongst both groups. The sensitivity and specificity of family history with regard to the presence of an MSI-H tumor in this collective was 36.5% and 77.5%, respectively. Conclusions: A relevant number of cases with high MSI-H CRC may be missed secondary to screening based on clinical criteria like family history alone. Thus, systematic screening independent of clinical characteristics, especially family history of cancer should be recommended in all cases with CRC.

Degenerative Changes in Aging Human Pelvic Lymph Nodes-A Reason to Rethink Staging and Therapy of Regional Malignancies?

Lymph node metastases are common in pelvic urological tumors, and the age-related remodeling process of the pelvic lymph nodes influences metastatic behavior. The aim of this work is to characterize age-related degenerative changes in the pelvic lymph nodes with respect to their occurrence and extent. A total of 5173 pelvic lymph nodes of 390 patients aged 44 to 79 years (median 68 years, IQR 62-71 years) were histologically examined for degenerative structural changes. Lymph node size, lipomatous atrophy, capsular fibrosis, framework fibrosis, and calcifications were recorded semi-quantitatively and evaluated by age group. Significantly more lymph nodes <10 mm were found in older patients (p = 0.001). The incidence of framework fibrosis, capsular fibrosis, and calcifications increased significantly with increasing patient age (p < 0.001). In lipomatous atrophy, an increase in mild to moderate lipomatous atrophy was observed with increasing age (p < 0.001). In this, the largest study to date on this topic, age-related degenerative changes in pelvic lymph nodes were proven. Due to the consecutive decrease in hte filtration function of pelvic lymph nodes with increasing age, staging and therapy of metastatic pelvic urologic carcinomas should be reconsidered.

Manual and Mechanical Induced Peri-Resuscitation Injuries-Post-Mortem and Clinical Findings.

(1) Background: Injuries related to resuscitation are not usually systematically recorded and documented. By evaluating this data, conclusions could be drawn about the quality of the resuscitation, with the aim of improving patient care and safety. (2) Methods: We are planning to conduct a multicentric, retrospective 3-phased study consisting of (1) a worldwide literature review (scoping review), (2) an analysis of anatomical pathological findings from local institutions in North Rhine-Westphalia, Germany to assess the transferability of the review data to the German healthcare system, and (3) depending on the results, possibly establishing potential prospective indicators for resuscitation-related injuries as part of quality assurance measures. (3) Conclusions: From the comparison of literature and local data, the picture of resuscitation-related injuries will be focused on and quality indicators will be derived.

The natural history of muscle-invasive bladder cancer in geriatric patients undergoing transurethral resection only: Outcome and cost.

PURPOSE: Bladder cancer is predominant in the elderly. Up to 70% of geriatric patients with muscle-invasive bladder cancer do not receive curative treatment. We analyzed the outcome of patients managed only by transurethral resection of bladder tumor (TURBT) without chemo- or radio-therapy, and performed a cost analysis of the cumulative inpatient interventions throughout the course of the disease. METHODS: From 2010 to 2016 81 patients ≥75 years with de novo muscle-invasive bladder cancer who were not eligible for curative treatment options were analyzed retrospectively. All patients were treated only with TURBT. Overall survival (OS) was measured by Kaplan-Meier plots (log-rank test) and clinical parameters predicting OS by a multivariate analysis. The cost analysis was based on actual billing from the hospital provider and referenced standardized pricing in Germany for bladder cancer treatment. RESULTS: The median age was 83 years. The OS was 11 months, the 1-year OS was 42%. In the multivariate model Charlson Comorbidity Index <8 (P = 0.016), tumor size ≤3 cm (P = 0.011), complete (T0) tumor resection (P = 0.003), normal C-reactive protein level (P = 0.010), and initial elective surgery (P = 0.035) were shown to be independent predictors of longer OS in palliative TURBT regimes. Median treatment cost for the TURBT regimen was $16,175 vs. $16,467 for a salvage radical cystectomy in this cohort. CONCLUSIONS: In a TURBT-only concept elective surgery, tumor size, Charlson Comorbidity Index, C-reactive protein level and complete TURBT are independent predictors of OS. The treatment-related cumulative cost appears to be higher in patients not managed by cystectomy.

Diode-pumped neodymium:yttrium aluminum garnet laser effects on the visceral pleura in an ex vivo porcine lung model†.

OBJECTIVES: Resection of tumour spread on a very thin visceral pleura might be challenging, and collateral damage to the lung parenchyma might occur. We aimed to develop an operative technique, which might facilitate the parenchyma-sparing destruction of the visceral pleura. This experimental work investigated the effects of a neodymium:yttrium aluminum garnet (Nd:YAG) laser on the visceral pleura in an ex vivo porcine lung model. METHODS: We used a diode-pumped Nd:YAG laser (Limax® 120, KLS Martin, Tuttlingen, Germany) to investigate the effects on the visceral pleural in 20 porcine lungs. The laser was applied on a standardized length in 4 different settings: Group I (80 W, 6 s), Group II (80 W, 12 s), Group III (120 W, 6 s) and Group IV (120 W, 12 s). All specimens were analysed histologically. RESULTS: The mean thickness of the visceral pleura was 81 ± 10 µm. Increasing power levels and longer application duration resulted in significantly enhanced laser destruction effects. The mean depths of the carbonization zone were 142 ± 42 µm, 378 ± 137 µm, 607 ± 155 µm and 1371 ± 271 µm for Groups I-IV, respectively (P < 0.001). The ratio of carbonization zone to pleural thickness was measured for each section (C/P ratio) to quantify the thermal effects. The corresponding C/P ratio for Groups I-IV were 1.72 ± 0.55, 4.98 ± 1.96, 7.11 ± 1.61 and 17.35 ± 4.35, respectively (P < 0.001). CONCLUSIONS: Our study showed that increasing power levels and application duration of the laser lead to a significantly increased carbonization and destruction zones. Further in vivo human studies should evaluate the feasibility of laser application for a potential translational relevance for human use.

Extensive screening of microRNA populations identifies hsa-miR-375 and hsa-miR-133a-3p as selective markers for human rectal and colon cancer.

MicroRNAs (miRNAs) are ∼22-nt molecules exerting control of protein expression in cancer tissues. The current study determined the full spectrum of miRNA dysregulation in freshly isolated human colon or rectal cancer biopsies as well as in controls of healthy adjacent tissue (total of n = 100) using an Illumina sequencing technology. In this work, we aimed to identify miRNAs that may serve as future marker to discern between these two subtypes. DESeq2 analysis revealed 53 significantly dysregulated miRNAs in colon cancer, 67 miRNAs in rectal cancer, and 97 miRNAs in both at a Padj value < 0.05 and ≥ 10 read counts. 65% of miRNAs were upregulated in colon as well as rectal cancer. Highest significant dysregulation (Padj < 0.00001) was detected for hsa-miR-21-5p, -215-5p and -378a in both colon and rectal cancer. Among the group of miRNAs with Padj < 0.05 and more than 2-fold expression differences, hsa-miR-375 was detected in rectal cancer only, and hsa-miR-133a-3p only in colon cancer. Receiver operating characteristic (ROC) analysis confirmed highly distinct sensitivities for hsa-miR-375 to detect rectal cancer (area under the curve (AUC): 0.9), while hsa-miR-133a-3p (AUC: 0.89) had the highest sensitivity for detecting colon cancer. We conclude that hsa-miR-375 and hsa-miR-133a-3p may serve as new markers of rectal or colon cancer and should be further investigated to search for different etiologies of colorectal cancer.

Advanced gallbladder inflammation is a risk factor for gallbladder perforation in patients with acute cholecystitis.

Background: Acute perforated cholecystitis (APC) is probably the most severe benign gallbladder pathology with high rates of morbidity and mortality. The cause of APC has not been fully understood. We postulated that APC is a complication of advanced gallbladder inflammation. The aim of this study was to investigate the extent of gallbladder inflammation in patients with APC. Methods: Patients with intraoperative and histopathologic diagnosis of APC were compared with cases with acute cholecystitis without perforation with respect to the extent of inflammation on histopathology as well as surgical outcomes. Results: Fifty patients with APC were compared to 150 cases without perforation. Advanced age > 65 years and elevated CRP were confirmed on multivariate analysis as independent risk factors for APC. Advanced gallbladder inflammation was seen significantly more often in patients with APC (84.0 vs. 18.7%). Surgery lasted significantly longer 131.3 ± 55.2 min vs. 100.4 ± 47.9 min; the rates of conversion (22 vs. 4%), morbidity (24 vs. 7%), and mortality (8 vs. 1%) were significantly higher in patients with APC. ICU management following surgery was needed significantly more often in the APC group (56 vs. 15%), and the overall length of stay (11.2 ± 12.0 days vs. 5.8 ± 6.5 days) was significantly longer compared to the group without perforation. Conclusion: Acute gallbladder perforation in patients with acute cholecystitis represents the most severe complication of cholecystitis. Acute perforated cholecystitis is a sequela of advanced gallbladder inflammation like empyematous and gangrenous cholecystitis and is associated with poor outcome compared to non-perforated cases.

A Review of Molecular Predictors of Response to Neoadjuvant Chemotherapy in Muscle-invasive Bladder Cancer.

Locally advanced, muscle-invasive urothelial carcinoma of the bladder (MIBC) may be definitively treated with either radiotherapy or radical cystectomy (RC) with urinary diversion. Neoadjuvant chemotherapy (NAC) is typically administered prior to treatment with either modality. Receiving NAC prior to RC might confer a survival advantage compared to undergoing RC alone. However, its usefulness has been questioned due to concerns about over treatment and toxicity. Having the ability to predict whether individual patients would benefit from or be harmed by NAC would be an important tool in precision medicine. Unfortunately, to date no prognostic or predictive molecular markers have been validated for this purpose. In this manuscript, we review the current state of molecular markers in MIBC treatment and outline how recent advances in whole-genome sequencing may soon improve the selection of precisely targeted therapeutics for the benefit of individual patients.

Distinct Lipidomic Landscapes Associated with Clinical Stages of Urothelial Cancer of the Bladder.

BACKGROUND: The first global lipidomic profiles associated with urothelial cancer of the bladder (UCB) and its clinical stages associated with progression were identified. OBJECTIVE: To identify lipidomic signatures associated with survival and different clinical stages of UCB. DESIGN, SETTING, AND PARTICIPANTS: Pathologically confirmed 165 bladder-derived tissues (126 UCB, 39 benign adjacent or normal bladder tissues). UCB tissues included Ta (n=16), T1 (n=30), T2 (n=43), T3 (n=27), and T4 (n=9); lymphovascular invasion (LVI) positive (n=52) and negative (n=69); and lymph node status N0 (n=28), N1 (n=11), N2 (n=9), N3 (n=3), and Nx (n=75). RESULTS AND LIMITATIONS: UCB tissues have higher levels of phospholipids and fatty acids, and reduced levels of triglycerides compared with benign tissues. A total of 59 genes associated with altered lipids in UCB strongly correlate with patient survival in an UCB public dataset. Within UCB, there was a progressive decrease in the levels of phosphatidylserine (PS), phosphatidylethanolamines (PEs), and phosphocholines, whereas an increase in the levels of diacylglycerols (DGs) with tumor stage. Transcript and protein expression of phosphatidylserine synthase 1, which converts DGs to PSs, decreased progressively with tumor stage. Levels of DGs and lyso-PEs were significantly elevated in tumors with LVI and lymph node involvement, respectively. Lack of carcinoma in situ and treatment information is the limitation of our study. CONCLUSIONS: To date, this is the first study describing the global lipidomic profiles associated with UCB and identifies lipids associated with tumor stages, LVI, and lymph node status. Our data suggest that triglycerides serve as the primary energy source in UCB, while phospholipid alterations could affect membrane structure and/or signaling associated with tumor progression. PATIENT SUMMARY: Lipidomic alterations identified in this study set the stage for characterization of pathways associated with these altered lipids that, in turn, could inform the development of first-of-its-kind lipid-based noninvasive biomarkers and novel therapeutic targets for aggressive urothelial cancer of the bladder.

Tobacco-Specific Carcinogens Induce Hypermethylation, DNA Adducts, and DNA Damage in Bladder Cancer.

Smoking is a major risk factor for the development of bladder cancer; however, the functional consequences of the carcinogens in tobacco smoke and bladder cancer-associated metabolic alterations remain poorly defined. We assessed the metabolic profiles in bladder cancer smokers and non-smokers and identified the key alterations in their metabolism. LC/MS and bioinformatic analysis were performed to determine the metabolome associated with bladder cancer smokers and were further validated in cell line models. Smokers with bladder cancer were found to have elevated levels of methylated metabolites, polycyclic aromatic hydrocarbons, DNA adducts, and DNA damage. DNA methyltransferase 1 (DNMT1) expression was significantly higher in smokers than non-smokers with bladder cancer. An integromics approach, using multiple patient cohorts, revealed strong associations between smokers and high-grade bladder cancer. In vitro exposure to the tobacco smoke carcinogens, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone and benzo[a]pyrene (BaP) led to increase in levels of methylated metabolites, DNA adducts, and extensive DNA damage in bladder cancer cells. Cotreatment of bladder cancer cells with these carcinogens and the methylation inhibitor 5-aza-2'-deoxycytidine rewired the methylated metabolites, DNA adducts, and DNA damage. These findings were confirmed through the isotopic-labeled metabolic flux analysis. Screens using smoke-associated metabolites and DNA adducts could provide robust biomarkers and improve individual risk prediction in bladder cancer smokers. Noninvasive predictive biomarkers that can stratify the risk of developing bladder cancer in smokers could aid in early detection and treatment. Cancer Prev Res; 10(10); 588-97. ©2017 AACR.