Methods of Sentinel Lymph Node Detection and Management in Urinary Bladder Cancer—A Narrative Review

© 2022 by the authors.Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/4.0/).Introduction: Detection of lymph node status in bladder cancer significantly impacts clinical decisions regarding its management. There is a wide range of detection modalities for this task, including lymphoscintigraphy, computed tomography, magnetic resonance imaging, single-photon emission computed tomography, positron emission tomography, and fluoroscopy. We aimed to study the pre- and intraoperative detection modalities of sentinel lymph nodes in urinary bladder cancer. Method: This narrative review was performed by searching the PubMed and EMBASE libraries using the following search terms: (“Transitional cell carcinoma of the bladder” OR “urothelial cancer” OR “urinary bladder cancer” OR “bladder cancer”) AND ((“sentinel lymph node”) OR (“lymphatic mapping”) OR (“lymphoscintigraphy”) OR (“lymphangiography”) OR (“lymph node metastases”)). Studies analysing the effectiveness and outcomes of sentinel lymph node detection in bladder cancer were included, while non-English language, duplicates, and non-article studies were excluded. After analysing the libraries and a further manual search of bibliographies, 31 studies were included in this paper. We followed the RAMESES publication standard for narrative reviews to produce this paper. Results: Of the 31 studies included, 7 studies included multiple detection methods; 5 studies included lymphoscintigraphy; 5 studies included computed tomography and/or single-photon emission computed tomography; 5 studies included fluoroscopy; 4 studies included magnetic resonance imaging; and 5 studies included positron emission tomography. Discussion: Anatomical, radioactive, and functional detection modalities have been studied independently and in combination. The consensus is that preoperative detection with imaging helps guide surgical management and intraoperative detection methods help capture any lymph nodes that may have been missed. Each of these types of detection represent their own set of benefits and drawbacks, but there is currently limited evidence to support any change in overall practice to replace conventional staging.Peer reviewedFinal Published versio

Comparing different pneumoperitoneum (12 vs. 15 mmHg) pressures with cytokine analysis to evaluate clinical outcomes in patients undergoing robotic‐assisted laparoscopic radical cystectomy and intracorporeal robotic urinary diversion

© 2023 The Authors. BJUI Compass published by John Wiley & Sons Ltd on behalf of BJU International Company. This is an open access article under the terms of the Creative Commons Attribution License. https://creativecommons.org/licenses/by/4.0/Background: Robotic cystectomy is the mainstay surgical intervention for treatment‐refractory non muscle‐invasive and muscle‐invasive bladder cancer. However, paralytic ileus may complicate the postoperative recovery and may be a consequence of an inflammatory response associated with transient gut ischaemia. We have therefore investigated clinical, operative and inflammatory biomarker associations between paralytic ileus in the context of robotic cystectomy and intracorporeal ileal conduit urinary diversion. Methods: Prospective consecutive patients referred for robotic cystectomy were consented and included in the study, while patients >75 years old and converted to open procedure were excluded. The pneumoperitoneum pressure (PP) for carbon dioxide insufflation required to perform the procedure efficiently and safely was recorded (12 or 15 mmHg). We also recorded the postoperative days patients passed flatus and stools, whether they developed ileus, as well as other standard clinical and demographic data. The expression of select proinflammatory and anti‐inflammatory cytokines was determined by multiplex analysis using a cytometric bead array with changes in profiles correlated with the pressures applied and with the existence of an ileus. Results: Twenty‐seven patients were recruited, but only 20 were used in the study with 10 patients in each PP group. Seven patients were excluded all of whom had an extracorporeal ileal conduit formation. There were differences in the 40‐min shorter operative time and 1 day shorter length of stay, as well as passing flatus 1 day and stools 1.5 days earlier in the 12 mmHg compared with the 15 mmHg group. More patients had ileus in the 15 mmHg group vs 12 mmHg group (30% vs. 10.0%). These were not statistically significant. Similarly, there were no statistical differences in the expression of proinflammatory cytokines at the two different pressures or between patient groups, but there were outliers, with the median indicating nonsymmetrical distribution. By comparison, anti‐inflammatory cytokines showed some significant differences between groups, with IL‐6 and IL‐10 showing elevated levels post surgery. No statistical difference was observed between pressures or the existence of an ileus, but the maximum levels of IL‐6 and IL‐10 detected in some patients reflect a pressure difference. Conclusions: The initial findings of this novel scientific study indicated a higher risk of paralytic ileus postrobotic cystectomy and robotic intracorporeal urinary diversion when a higher pressure of 15 mmHg is used compared with 12 mmHg. Although further studies are required to establish the linkage between cytokine profile expression, pressure and ileus, our initial data reinforces the advantages of lower pressure robotic cystectomy and intracorporeal urinary diversion in patient outcomes.Peer reviewe

Morbidity and mortality after robot-assisted radical cystectomy with intracorporeal urinary diversion in octogenarians: results from the European Association of Urology Robotic Urology Section Scientific Working Group

OBJECTIVES: To evaluate the postoperative complication and mortality rate following laparoscopic radical cystectomy (RARC) with intracorporeal urinary diversion (ICUD) in octogenarians. PATIENTS AND METHODS: We conducted a retrospective analysis comparing postoperative complication and mortality rates depending on age in a consecutive series of 1890 patients who underwent RARC with ICUD for bladder cancer between 2004 and 2018 in 10 European centres. Outcomes of patients aged <80 years and those aged ≥80 years were compared with regard to postoperative complications (Clavien–Dindo grading) and mortality rate. Cancer-specific mortality (CSM) and other-cause mortality (OCM) after surgery were calculated using the non-parametric Aalen-Johansen estimator. RESULTS: A total of 1726 patients aged <80 years and 164 aged ≥80 years were included in the analysis. The 30- and 90-day rate for high-grade (Clavien–Dindo grades III–V) complications were 15% and 21% for patients aged <80 years compared to 11% and 13% for patients aged ≥80 years (P = 0.2 and P = 0.03), respectively. In a multivariable logistic regression analysis adjusting for pre- and postoperative variables, age ≥80 years was not an independent predictor of high-grade complications (odds ratio 0.6, 95% confidence interval 0.3–1.1; P = 0.12). The non-cancer-related 90-day mortality was 2.3% for patients aged ≥80 years and 1.8% for those aged <80 years, respectively (P = 0.7). The estimated 12-month CSM and OCM rates for those aged <80 years were 8% and 3%, and for those aged ≥80 years, 15% and 8%, respectively (P = 0.009 and P < 0.001). CONCLUSIONS: The minimally invasive approach to RARC with ICUD for bladder cancer in well-selected elderly patients (aged ≥80 years) achieved a tolerable high-grade complication rate; the 90-day postoperative mortality rate was driven by cancer progression and the non-cancer-related rate was equivalent to that of patients aged <80 years. However, an increased OCM rate in this elderly group after the first year should be taken into account. These results will support clinicians and patients when balancing cancer-related vs treatment-related risks and benefits

Germline variation in inflammation-related pathways and risk of Barrett's oesophagus and oesophageal adenocarcinoma

Esophageal adenocarcinoma (EA) incidence has risen sharply in Western countries over recent decades. Local and systemic inflammation, operating downstream of disease-associated exposures, is considered an important contributor to EA pathogenesis. Several risk factors have been identified for EA and its precursor, Barrett’s esophagus (BE), including symptomatic reflux, obesity, and smoking. The role of inherited genetic susceptibility remains an area of active investigation. To explore whether germline variation related to inflammatory processes influences susceptibility to BE/EA, we used data from a genome-wide association study (GWAS) of 2,515 EA cases, 3,295 BE cases, and 3,207 controls. Our analysis included 7,863 single nucleotide polymorphisms (SNPs) in 449 genes assigned to five pathways: cyclooxygenase (COX), cytokine signaling, oxidative stress, human leukocyte antigen, and NFκB. A principal components-based analytic framework was employed to evaluate pathway-level and gene-level associations with disease risk. We identified a significant signal for the COX pathway in relation to BE risk (P=0.0059, FDR q=0.03), and in gene-level analyses found an association with MGST1 (microsomal glutathione-S-transferase 1; P=0.0005, q=0.005). Assessment of 36 MGST1 SNPs identified 14 variants associated with elevated BE risk (q<0.05). Of these, four were subsequently confirmed (P<5.5 × 10−5) in a meta-analysis encompassing an independent set of 1,851 BE cases and 3,496 controls. Three of these SNPs (rs3852575, rs73112090, rs4149204) were associated with similar elevations in EA risk. This study provides the most comprehensive evaluation of inflammation-related germline variation in relation to risk of BE/EA, and suggests that variants in MGST1 influence disease susceptibility

Thiopurine monotherapy is effective in ulcerative colitis but significantly less so in Crohn’s disease: long-term outcomes for 11 928 patients in the UK inflammatory bowel disease bioresource

Objective: Thiopurines are widely used as maintenance therapy in inflammatory bowel disease (IBD) but the evidence base for their use is sparse and their role increasingly questioned. Using the largest series reported to date, we assessed the long-term effectiveness of thiopurines in ulcerative colitis (UC) and Crohn’s disease (CD), including their impact on need for surgery. Design: Outcomes were assessed in 11 928 patients (4968 UC, 6960 CD) in the UK IBD BioResource initiated on thiopurine monotherapy with the intention of maintaining medically induced remission. Effectiveness was assessed retrospectively using patient-level data and a definition that required avoidance of escalation to biological therapy or surgery while on thiopurines. Analyses included overall effectiveness, time-to-event analysis for treatment escalation and comparison of surgery rates in patients tolerant or intolerant of thiopurines. Results: Using 68 132 patient-years of exposure, thiopurine monotherapy appeared effective for the duration of treatment in 2617/4968 (52.7%) patients with UC compared with 2378/6960 (34.2%) patients with CD (p<0.0001). This difference was corroborated in a multivariable analysis: after adjusting for variables including treatment era, thiopurine monotherapy was less effective in CD than UC (OR 0.47, 95% CI 0.43 to 0.51, p<0.0001). Thiopurine intolerance was associated with increased risk of surgery in UC (HR 2.44, p<0.0001); with a more modest impact on need for surgery in CD (HR=1.23, p=0.0015). Conclusion: Thiopurine monotherapy is an effective long-term treatment for UC but significantly less effective in CD

BOB CAT: a Large-Scale Review and Delphi Consensus for Management of Barrett’s Esophagus With No Dysplasia, Indefinite for, or Low-Grade Dysplasia

OBJECTIVES: Barrett’s esophagus (BE) is a common premalignant lesion for which surveillance is recommended. This strategy is limited by considerable variations in clinical practice. We conducted an international, multidisciplinary, systematic search and evidence-based review of BE and provided consensus recommendations for clinical use in patients with nondysplastic, indefinite, and low-grade dysplasia (LGD). METHODS: We defined the scope, proposed statements, and searched electronic databases, yielding 20,558 publications that were screened, selected online, and formed the evidence base. We used a Delphi consensus process, with an 80% agreement threshold, using GRADE (Grading of Recommendations Assessment, Development and Evaluation) to categorize the quality of evidence and strength of recommendations. RESULTS: In total, 80% of respondents agreed with 55 of 127 statements in the final voting rounds. Population endoscopic screening is not recommended and screening should target only very high-risk cases of males aged over 60 years with chronic uncontrolled reflux. A new international definition of BE was agreed upon. For any degree of dysplasia, at least two specialist gastrointestinal (GI) pathologists are required. Risk factors for cancer include male gender, length of BE, and central obesity. Endoscopic resection should be used for visible, nodular areas. Surveillance is not recommended for <5 years of life expectancy. Management strategies for indefinite dysplasia (IND) and LGD were identified, including a de-escalation strategy for lower-risk patients and escalation to intervention with follow-up for higher-risk patients. CONCLUSIONS: In this uniquely large consensus process in gastroenterology, we made key clinical recommendations for the escalation/de-escalation of BE in clinical practice. We made strong recommendations for the prioritization of future research

Early transcriptional response pathways in Daphnia magna are coordinated in networks of crustacean-specific genes

Natural habitats are exposed to an increasing number of environmental stressors that cause important ecological consequences. However, the multifarious nature of environmental change, the strength and the relative timing of each stressor largely limit our understanding of biological responses to environmental change. In particular, early response to unpredictable environmental change, critical to survival and fitness in later life stages, is largely uncharacterized. Here, we characterize the early transcriptional response of the keystone species Daphnia magna to twelve environmental perturbations, including biotic and abiotic stressors. We first perform a differential expression analysis aimed at identifying differential regulation of individual genes in response to stress. This preliminary analysis revealed that a few individual genes were responsive to environmental perturbations and they were modulated in a stressor and genotype-specific manner. Given the limited number of differentially regulated genes, we were unable to identify pathways involved in stress response. Hence, to gain a better understanding of the genetic and functional foundation of tolerance to multiple environmental stressors, we leveraged the correlative nature of networks and performed a weighted gene co-expression network analysis. We discovered that approximately one-third of the Daphnia genes, enriched for metabolism, cell signalling and general stress response, drives transcriptional early response to environmental stress and it is shared among genetic backgrounds. This initial response is followed by a genotype- and/or condition-specific transcriptional response with a strong genotype-by-environment interaction. Intriguingly, genotype- and condition-specific transcriptional response is found in genes not conserved beyond crustaceans, suggesting niche-specific adaptation

Polymorphisms near TBX5 and GDF7 are associated with increased risk for Barrett's esophagus.

BACKGROUND & AIMS: Barrett's esophagus (BE) increases the risk of esophageal adenocarcinoma (EAC). We found the risk to be BE has been associated with single nucleotide polymorphisms (SNPs) on chromosome 6p21 (within the HLA region) and on 16q23, where the closest protein-coding gene is FOXF1. Subsequently, the Barrett's and Esophageal Adenocarcinoma Consortium (BEACON) identified risk loci for BE and esophageal adenocarcinoma near CRTC1 and BARX1, and within 100 kb of FOXP1. We aimed to identify further SNPs that increased BE risk and to validate previously reported associations. METHODS: We performed a genome-wide association study (GWAS) to identify variants associated with BE and further analyzed promising variants identified by BEACON by genotyping 10,158 patients with BE and 21,062 controls. RESULTS: We identified 2 SNPs not previously associated with BE: rs3072 (2p24.1; odds ratio [OR] = 1.14; 95% CI: 1.09-1.18; P = 1.8 × 10(-11)) and rs2701108 (12q24.21; OR = 0.90; 95% CI: 0.86-0.93; P = 7.5 × 10(-9)). The closest protein-coding genes were respectively GDF7 (rs3072), which encodes a ligand in the bone morphogenetic protein pathway, and TBX5 (rs2701108), which encodes a transcription factor that regulates esophageal and cardiac development. Our data also supported in BE cases 3 risk SNPs identified by BEACON (rs2687201, rs11789015, and rs10423674). Meta-analysis of all data identified another SNP associated with BE and esophageal adenocarcinoma: rs3784262, within ALDH1A2 (OR = 0.90; 95% CI: 0.87-0.93; P = 3.72 × 10(-9)). CONCLUSIONS: We identified 2 loci associated with risk of BE and provided data to support a further locus. The genes we found to be associated with risk for BE encode transcription factors involved in thoracic, diaphragmatic, and esophageal development or proteins involved in the inflammatory response