Finding the Wolf in Sheep's Clothing: The 4Kscore Is a Novel Blood Test That Can Accurately Identify the Risk of Aggressive Prostate Cancer

Better biomarkers that can discriminate between aggressive and indolent phenotypes of prostate cancer are urgently needed. In the first 20 years of the prostate-specific antigen (PSA) era, screening for prostate cancer has successfully reduced prostate cancer mortality, but has led to significant problems with overdiagnosis and overtreatment. As a result, many men are subjected to unnecessary prostate biopsies and overtreatment of indolent cancer in order to save one man from dying of prostate cancer. A novel blood test known as the 4Kscore\uae Test (OPKO Lab, Nashville, TN) incorporates a panel of four kallikrein protein biomarkers (total PSA, free PSA, intact PSA, and human kallikrein-related peptidase 2) and other clinical information in an algorithm that provides a percent risk for a high-grade (Gleason score 65 7) cancer on biopsy. In 10 peer-reviewed publications, the four kallikrein biomarkers and algorithm of the 4Kscore Test have been shown to improve the prediction not only of biopsy histopathology, but also surgical pathology and occurrence of aggressive, metastatic disease. Recently, a blinded prospective trial of the 4Kscore Test was conducted across the United States among 1012 men. The 4Kscore Test replicated previous European results showing accuracy in predicting biopsy outcome of Gleason score 65 7. In a recent case-control study nested within a population-based cohort from V\ue4sterbotten, Sweden, the four kallikrein biomarkers of the 4Kscore Test also predicted the risk for aggressive prostate cancer that metastasized within 20 years after the test was administered. These results indicate that men with an abnormal PSA or digital rectal examination result, and for whom an initial or repeat prostate biopsy is being considered, would benefit from a reflex 4Kscore Test to add important information to the clinical decision-making process. A high-risk 4Kscore Test result may be used to select men with a high probability of aggressive prostate cancer who would benefit from a biopsy of the prostate to prevent an adverse and potentially lethal outcome from prostate cancer. Men with a low 4Kscore Test result may safely defer biopsy

Robotic Partial Nephrectomy with the Da Vinci Xi

Purpose. The surgical expertise to perform robotic partial nephrectomy is heavily dependent on technology. The Da Vinci Xi (XI) is the latest robotic surgical platform with significant advancements compared to its predecessor. We describe our operative technique and experience with the XI system for robotic partial nephrectomy (RPN). Materials and Methods. Patients with clinical T1 renal masses were offered RPN with the XI. We used laser targeting, autopositioning, and a novel “in-line” port placement to perform RPN. Results. 15 patients underwent RPN with the XI. There were no intraoperative complications and no operative conversions. Mean console time was 101.3 minutes (range 44–176 minutes). Mean ischemia time was 17.5 minutes and estimated blood loss was 120 mLs. 12 of 15 patients had renal cell carcinoma. Two patients had oncocytoma and one had benign cystic disease. All patients had negative surgical margins and pathologic T1 disease. Two postoperative complications were encountered, including one patient who developed a pseudoaneurysm and one readmitted for presumed urinary tract infection. Conclusions. RPN with the XI system can be safely performed. Combining our surgical technique with the technological advancements on the XI offers patients acceptable pathologic and perioperative outcomes

Robot-assisted Radical Cystectomy Versus Open Radical Cystectomy: A Systematic Review and Meta-analysis of Perioperative, Oncological, and Quality of Life Outcomes Using Randomized Controlled Trials

CONTEXT: Differences in recovery, oncological, and quality of life (QoL) outcomes between open radical cystectomy (ORC) and robot-assisted radical cystectomy (RARC) for patients with bladder cancer are unclear. OBJECTIVE: This review aims to compare these outcomes within randomized trials of ORC and RARC in this context. The primary outcome was the rate of 90-d perioperative events. The secondary outcomes included operative, pathological, survival, and health-related QoL (HRQoL) measures. EVIDENCE ACQUISITION: Systematic literature searches of MEDLINE, Embase, Web of Science, and clinicaltrials.gov were performed up to May 31, 2022. EVIDENCE SYNTHESIS: Eight trials, reporting 1024 participants, were included. RARC was associated with a shorter hospital length of stay (LOS; mean difference [MD] 0.21, 95% confidence interval [CI] 0.03-0.39, p = 0.02) than and similar complication rates to ORC. ORC was associated with higher thromboembolic events (odds ratio [OR] 1.84, 95% CI 1.02-3.31, p = 0.04). ORC was associated with more blood loss (MD 322 ml, 95% CI 193-450, p < 0.001) and transfusions (OR 2.35, 95% CI 1.65-3.36, p < 0.001), but shorter operative time (MD 76 min, 95% CI 39-112, p < 0.001) than RARC. No differences in lymph node yield (MD 1.07, 95% CI -1.73 to 3.86, p = 0.5) or positive surgical margin rates (OR 0.95, 95% CI 0.54-1.67, p = 0.9) were present. RARC was associated with better physical functioning or well-being (standardized MD 0.47, 95% CI 0.29-0.65, p < 0.001) and role functioning (MD 8.8, 95% CI 2.4-15.1, p = 0.007), but no improvement in overall HRQoL. No differences in progression-free survival or overall survival were seen. Limitations may include a lack of generalization given trial patients. CONCLUSIONS: RARC offers various perioperative benefits over ORC. It may be more suitable in patients wishing to avoid blood transfusion, those wanting a shorter LOS, or those at a high risk of thromboembolic events. PATIENT SUMMARY: This study compares robot-assisted keyhole surgery with open surgery for bladder cancer. The robot-assisted approach offered less blood loss, shorter hospital stays, and fewer blood clots. No other differences were seen

Robot-assisted Radical Cystectomy Versus Open Radical Cystectomy: A Systematic Review and Meta-analysis of Perioperative, Oncological, and Quality of Life Outcomes Using Randomized Controlled Trials

© 2023 The Authors. Published by Elsevier B.V. on behalf of European Association of Urology. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)Context: Differences in recovery, oncological, and quality of life (QoL) outcomes between open radical cystectomy (ORC) and robot-assisted radical cystectomy (RARC) for patients with bladder cancer are unclear.  Objective: This review aims to compare these outcomes within randomized trials of ORC and RARC in this context. The primary outcome was the rate of 90-d perioperative events. The secondary outcomes included operative, pathological, survival, and health-related QoL (HRQoL) measures.  Evidence acquisition: Systematic literature searches of MEDLINE, Embase, Web of Science, and clinicaltrials.gov were performed up to May 31, 2022.  Evidence synthesis: Eight trials, reporting 1024 participants, were included. RARC was associated with a shorter hospital length of stay (LOS; mean difference [MD] 0.21, 95% confidence interval [CI] 0.03–0.39, p = 0.02) than and similar complication rates to ORC. ORC was associated with higher thromboembolic events (odds ratio [OR] 1.84, 95% CI 1.02–3.31, p = 0.04). ORC was associated with more blood loss (MD 322 ml, 95% CI 193–450, p < 0.001) and transfusions (OR 2.35, 95% CI 1.65–3.36, p < 0.001), but shorter operative time (MD 76 min, 95% CI 39–112, p < 0.001) than RARC. No differences in lymph node yield (MD 1.07, 95% CI –1.73 to 3.86, p = 0.5) or positive surgical margin rates (OR 0.95, 95% CI 0.54–1.67, p = 0.9) were present. RARC was associated with better physical functioning or well-being (standardized MD 0.47, 95% CI 0.29–0.65, p < 0.001) and role functioning (MD 8.8, 95% CI 2.4–15.1, p = 0.007), but no improvement in overall HRQoL. No differences in progression-free survival or overall survival were seen. Limitations may include a lack of generalization given trial patients.  Conclusions: RARC offers various perioperative benefits over ORC. It may be more suitable in patients wishing to avoid blood transfusion, those wanting a shorter LOS, or those at a high risk of thromboembolic events.  Patient summary: This study compares robot-assisted keyhole surgery with open surgery for bladder cancer. The robot-assisted approach offered less blood loss, shorter hospital stays, and fewer blood clots. No other differences were seen.Peer reviewe

Nox4 Mediates Renal Cell Carcinoma Cell Invasion through Hypoxia-Induced Interleukin 6- and 8- Production

Inflammatory cytokines are detected in the plasma of patients with renal cell carcinoma (RCC) and are associated with poor prognosis. However, the primary cell type involved in producing inflammatory cytokines and the biological significance in RCC remain unknown. Inflammation is associated with oxidative stress, upregulation of hypoxia inducible factor 1-alpha, and production of pro-inflammatory gene products. Solid tumors are often heterogeneous in oxygen tension together suggesting that hypoxia may play a role in inflammatory processes in RCC. Epithelial cells have been implicated in cytokine release, although the stimuli to release and molecular mechanisms by which they are released remain unclear. AMP-activated protein kinase (AMPK) is a highly conserved sensor of cellular energy status and a role for AMPK in the regulation of cell inflammatory processes has recently been demonstrated.We have identified for the first time that interleukin-6 and interleukin-8 (IL-6 and IL-8) are secreted solely from RCC cells exposed to hypoxia. Furthermore, we demonstrate that the NADPH oxidase isoform, Nox4, play a key role in hypoxia-induced IL-6 and IL-8 production in RCC. Finally, we have characterized that enhanced levels of IL-6 and IL-8 result in RCC cell invasion and that activation of AMPK reduces Nox4 expression, IL-6 and IL-8 production, and RCC cell invasion.Together, our data identify novel mechanisms by which AMPK and Nox4 may be linked to inflammation-induced RCC metastasis and that pharmacological activation of AMPK and/or antioxidants targeting Nox4 may represent a relevant therapeutic intervention to reduce IL-6- and IL-8-induced inflammation and cell invasion in RCC

Importance of prostate volume in the European Randomised Study of Screening for Prostate Cancer (ERSPC) risk calculators: results from the prostate biopsy collaborative group

OBJECTIVES: To compare the predictive performance and potential clinical usefulness of risk calculators of the European Randomized Study of Screening for Prostate Cancer (ERSPC RC) with and without information on prostate volume. METHODS: We studied 6 cohorts (5 European and 1 US) with a total of 15,300 men, all biopsied and with pre-biopsy TRUS measurements of prostate volume. Volume was categorized into 3 categories (25, 40, and 60 cc), to reflect use of digital rectal examination (DRE) for volume assessment. Risks of prostate cancer were calculated according to a ERSPC DRE-based RC (including PSA, DRE, prior biopsy, and prostate volume) and a PSA + DRE model (including PSA, DRE, and prior biopsy). Missing data on prostate volume were completed by single imputation. Risk predictions were evaluated with respect to calibration (graphically), discrimination (AUC curve), and clinical usefulness (net benefit, graphically assessed in decision curves). RESULTS: The AUCs of the ERSPC DRE-based RC ranged from 0.61 to 0.77 and were substantially larger than the AUCs of a model based on only PSA + DRE (ranging from 0.56 to 0.72) in each of the 6 cohorts. The ERSPC DRE-based RC provided net benefit over performing a prostate biopsy on the basis of PSA and DRE outcome in five of the six cohorts. CONCLUSIONS: Identifying men at increased risk for having a biopsy detectable prostate cancer should consider multiple factors, including an estimate of prostate volume

Reduced Expression of Fumarate Hydratase in Clear Cell Renal Cancer Mediates HIF-2α Accumulation and Promotes Migration and Invasion

Germline mutations of FH, the gene that encodes for the tricarboxylic acid TCA (TCA) cycle enzyme fumarate hydratase, are associated with an inherited form of cancer referred to as Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC). Individuals with HLRCC are predisposed to the development of highly malignant and lethal renal cell carcinoma (RCC). The mechanisms of tumorigenesis proposed have largely focused on the biochemical consequences of loss of FH enzymatic activity. While loss of the tumor suppressor gene von Hippel Lindau (VHL) is thought to be an initiating event for the majority of RCCs, a role for FH in sporadic renal cancer has not been explored. Here we report that FH mRNA and protein expression are reduced in clear cell renal cancer, the most common histologic variant of kidney cancer. Moreover, we demonstrate that reduced FH leads to the accumulation of hypoxia inducible factor- 2α (HIF-2α), a transcription factor known to promote renal carcinogenesis. Finally, we demonstrate that overexpression of FH in renal cancer cells inhibits cellular migration and invasion. These data provide novel insights into the tumor suppressor functions of FH in sporadic kidney cancer

Histopathologic Evaluation of Neoadjuvant Treatment Response and Tumor Regression Grade

Histopathologic response and tumor down-staging after neoadjuvant chemoradiation are major determinants of long term outcome in patients with locoregional rectal cancer. Optimal assessment of histopathologic response requires meticulous gross examination, adequate sampling of tumor bed, effective communication between operating surgeon and pathologist, and familiarity with TNM staging and different grading systems for histopathologic response/tumor regression. Several histopathologic response/tumor regression systems are described in last two decades. Almost all of them are based on semi-quantitative or quantitative assessment of fibrosis vs. residual tumor cells in rectal wall and perirectal soft tissue and generally do not include residual tumor in regional lymph nodes. Absence of residual tumor cells (complete pathology response) is associated with more than 90% 5 year recurrence free patients` survival with all grading systems. The variations among different grading systems include; assigning (or not) a numerical value to the amount of residual tumor cells or fibrosis, emphasis given more to residual tumor cells or fibrosis and number of different grades of response and availability of information about reproducibility among pathologists. American Joint Commission on Cancer has accepted 4 point tumor regression grade (TRG) system and is one of the required data point to be included in a surgical pathology report for rectal cancer resection specimen after neoadjuvant therapy

Catheter ablation for atrial fibrillation: mechanism-based curative treatment

The considerable cumulative morbidity and mortality burden resulting from atrial fibrillation has prompted renewed efforts to seek curative and widely applicable therapies. Currently used drugs are not only frequently ineffective at eliminating fibrillation, but may actually be life threatening. Extensive surgery involving both atria has shown that atrial fibrillation can be eliminated in most, if not all, patients, but at a significant cost. The recent discovery of the pivotal role that myocardial extensions into the pulmonary veins play in the initiation, and probably also the maintenance, of atrial fibrillation, has provided a relatively limited target conducive to catheter-based interventions. In experienced hands, paroxysmal atrial fibrillation can be eliminated in more than 85% of patients by a percutaneous intervention lasting less than 3 h with an attendant nonlethal complication risk of 1 to 2%. Thromboembolic complications and pulmonary vein stenosis are the principal complications that may result from this treatment, but their incidence is decreasing. Success rates in patients with persistent or permanent atrial fibrillation are lower, and it is anticipated that increased understanding of the underlying mechanisms will allow doctors to identify those subsets with the greatest potential for benefit from percutaneous catheter-based interventions. Such progress may allow doctors to extend the benefits of eliminating atrial fibrillation to the widest possible range of patients with this recalcitrant disorder

How Histopathology Affects the Management of the Multidisciplinary Team

Histopathology is critical at each stage of colorectal cancer. These include histological sub‐typing of colonic polyps for risk assessment in screening population, confirming the diagnosis of invasive carcinoma and providing prognostic indicators for patient outcome and in deciding postoperative therapy options. Histopathology and immunohistochemistry interpretation by a pathologist is important for accurate reporting of the pathological parameters and their effective applications to improve the quality of care for a colorectal cancer patient. This chapter describes histopathology parameters of colon cancer, their clinical relevance, and importance of a pathologist in the multidisciplinary care of a colorectal cancer patient