LCZ696, an angiotensin receptor-neprilysin inhibitor, ameliorates epithelial-mesenchymal transition of peritoneal mesothelial cells and M2 macrophage polarization.

AIMS: To investigate the effects and mechanisms of LCZ696, an angiotensin receptor-neprilysin inhibitor (ARNI), on epithelial-mesenchymal transition (EMT) of peritoneal mesothelial cells and on macrophage M2 polarization. METHODS: We examined the effects of LCZ696 in a 4.25% high glucose peritoneal dialysis fluid (PDF)-induced peritoneal fibrosis (PF) mouse model, and explored the mechanisms of LCZ696 on human peritoneal mesothelial cells (HPMCs) stimulated by TGF-ß1 (5 ng/mL) and on Raw264.7 cells stimulated by IL-4 (10 ng/mL). To further elucidate the mechanism, we treated HPMCs with the conditioned medium of Raw264.7 cells. RESULTS: LCZ696 effectively improved PF and inhibited the process of EMT in PDF mice. In vitro, LCZ696 also significantly alleviated the EMT of TGF-ß1 induced HPMCs, although there was no statistically significant difference when compared to the Valsartan treatment group. Moreover, LCZ696 ameliorates the increased expression of Snail and Slug, two nuclear transcription factors that drive the EMT. Mechanistically, TGF-ß1 increased the expression of TGFßRI, p-Smad3, p-PDGFRß and p-EGFR, while treatment with LCZ696 abrogated the activation of TGF-ß/Smad3, PDGFRß and EGFR signaling pathways. Additionally, exposure of Raw264.7 to IL-4 results in increasing expression of Arginase-1, CD163 and p-STAT6. Treatment with LCZ696 inhibited IL-4-elicited M2 macrophage polarization by inactivating the STAT6 signaling pathway. Furthermore, we observed that LCZ696 inhibits EMT by blocking TGF-ß1 secretion from M2 macrophages. CONCLUSION: Our study demonstrated that LCZ696 improves PF and ameliorates TGF-ß1-induced EMT of HPMCs by blocking TGF-ß/Smad3, PDGFRß and EGFR pathways. Meanwhile, LCZ696 also inhibits M2 macrophage polarization by regulating STAT6 pathway.

The Peritoneum: Anatomy, Pathologic Findings, and Patterns of Disease Spread.

Disease spread in the abdomen and pelvis generally occurs in a predictable pattern in relation to anatomic landmarks and fascial planes. Anatomically, the abdominopelvic cavity is subdivided into several smaller spaces or compartments by key ligaments and fascial planes. The abdominal cavity has been traditionally divided into peritoneal, retroperitoneal, and pelvic extraperitoneal spaces. Recently, more clinically relevant classifications have evolved. Many pathologic conditions affect the abdominal cavity, including traumatic, inflammatory, infectious, and neoplastic processes. These abnormalities can extend beyond their sites of origin through various pathways. Identifying the origin of a disease process is the first step in formulating a differential diagnosis and ultimately reaching a final diagnosis. Pathologic conditions differ in terms of pathways of disease spread. For example, simple fluid tracks along fascial planes, respecting anatomic boundaries, while fluid from acute necrotizing pancreatitis can destroy fascial planes, resulting in transfascial spread without regard for anatomic landmarks. Furthermore, neoplastic processes can spread through multiple pathways, with a propensity for spread to noncontiguous sites. When the origin of a disease process is not readily apparent, recognizing the spread pattern can allow the radiologist to work backward and ultimately arrive at the site or source of pathogenesis. As such, a cohesive understanding of the peritoneal anatomy, the typical organ or site of origin for a disease process, and the corresponding pattern of disease spread is critical not only for initial diagnosis but also for establishing a road map for staging, anticipating further disease spread, guiding search patterns and report checklists, determining prognosis, and tailoring appropriate follow-up imaging studies. ©RSNA, 2024 Supplemental material is available for this article.

Transabdominal pre-peritoneal (TAPP) versus totally extraperitoneal (TEP) laparoscopic techniques for inguinal hernia repair.

BACKGROUND: An inguinal hernia occurs when part of the intestine protrudes through the abdominal muscles. In adults, this common condition is much more likely in men than in women. Inguinal hernia can be monitored by 'watchful waiting', but if symptoms persist or worsen, surgery is usually required, which can be open or laparoscopic. Laparoscopic (keyhole) repair of inguinal hernias in adults is generally performed using either the transabdominal preperitoneal (TAPP) or the totally extraperitoneal (TEP) method. Both methods include the use of mesh placed in front of the peritoneal lining of the abdominal wall, but for the TAPP technique, the abdominal cavity needs to be entered to place the mesh, and for the TEP technique, the whole procedure is done on the outside of the peritoneal lining of the abdominall wall. Whether one method is superior to the other has not been established, and there is debate about their relative benefits and harms. An advantage of TEP is its avoidance of the abdominal cavity; the downside is that it requires a steeper learning curve for clinicians. TAPP is considered simpler and makes it possible to inspect the contralateral side, but TAPP may have a higher risk of visceral injury compared to TEP. This is an update of a Cochrane review first published in 2005. OBJECTIVES: To compare the benefits and harms of laparoscopic TAPP technique versus laparoscopic TEP technique for inguinal hernia repair in adults. SEARCH METHODS: On 25 October 2022, the authors searched the Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library; Ovid MEDLINE(R) Epub Ahead of Print, In-Process & Other Non-Indexed Citations, Ovid MEDLINE(R) Daily, and Ovid MEDLINE(R); and Ovid Embase, for published randomised controlled trials. To identify studies in progress, we searched ClinicalTrials.gov and the WHO International Clinical Trial Registry Platform (ICTRP). SELECTION CRITERIA: All prospective randomised, quasi-randomised, and cluster-randomised trials that compared the laparoscopic TAPP technique with the laparoscopic TEP technique for inguinal hernia repair in adults were eligible for inclusion. We included studies that involved a mix of different types of groin hernia if we could extract data for the inguinal hernias. Studies may have also included a group of participants receiving hernia repair by open surgery, but these groups were not included in our review. DATA COLLECTION AND ANALYSIS: Both review authors independently evaluated trial eligibility, extracted data from included studies, and assessed the risk of bias in the included studies. The review's primary outcomes were serious adverse events, chronic pain (persisting for at least six months after surgery), and hernia recurrence. We also assessed a variety of secondary outcomes at perioperative, early postoperative, and late postoperative time points. We performed statistical analyses using the random-effects model, and expressed the results as odds ratios (ORs) for dichotomous outcomes and mean differences (MDs) for continuous outcomes, with their respective 95% confidence intervals (CIs). We used GRADE to assess the certainty of evidence for key outcomes as high, moderate, low or very low. MAIN RESULTS: We included 23 studies in this review update, which randomised 1156 people to TAPP and 1110 people to TEP, all requiring repair of inguinal hernias. Study sample sizes varied from 40 to 316 participants. The vast majority of study participants were male. We judged most studies to be at 'high' or 'unclear' risk of bias. Our judgements of the certainty of the evidence were low or very low for all outcomes we assessed. There may be little to no difference between TAPP and TEP laparoscopic techniques for serious adverse events (0.4% versus 0.7%; OR 0.58, 95% CI 0.15 to 2.32, P = 0.45, I2 = 0%; 19 studies, 1735 participants; low certainty of evidence); and hernia recurrence (1.2% versus 1.1%; OR 1.14, 95% CI 0.49 to 2.62, P = 0.97, I2 = 0%; 17 studies, 1712 participants; low certainty of evidence). The evidence is very uncertain about the effects of TAPP versus TEP techniques on chronic pain (OR 0.62, 95% CI 0.20 to 1.97, P = 0.68, I2 = 0%; 6 studies, 860 participants; very low certainty of evidence). In terms of secondary outcomes, the evidence is very uncertain for TAPP versus TEP techniques for perioperative visceral and vascular injury (15 studies, 1523 participants; very low certainty of evidence), and for haematoma or seroma during the early (≤ 30 days) postoperative phase (OR 0.86, 95% CI 0.54 to 1.37, P = 0.3861, I2 = 0%; 15 studies, 1423 participants; very low certainty of evidence). TEP technique may carry a higher risk of conversion to another hernia repair method (either TAPP technique or open surgery) when compared to TAPP (2.5% versus 0.7%; OR 0.28, 95% CI 0.09 to 0.84, P = 0.02, I2 = 0%; 13 studies, 1178 participants; low certainty of evidence). Only two studies (474 participants) reported quality of life in the late (> 30 days) postoperative phase; overall, there was an improvement in quality of life from the pre- to post-operative assessment, but the evidence suggests little to no difference between the techniques (low certainty of evidence). AUTHORS' CONCLUSIONS: This review update found that there may be little to no difference between the TAPP and TEP techniques for serious adverse events, hernia recurrence, or chronic pain (low- to very-low-certainty evidence). Decisions about which method to use will most likely reflect surgeon and patient preference until high-certainty evidence becomes available. There may be a higher risk of needing to convert from TEP to TAPP or open surgery when compared to the risk of needing to convert from TAPP to open surgery (low-certainty evidence). If surgeons opt for TEP as their standard laparoscopic method, they could consider having a strategy for how to handle the potential need for conversion. This might include proficiency in the TAPP approach or having informed the patient about the risk of conversion to open surgery. For surgeons or surgical departments, the choice of a laparoscopic technique should involve shared decision-making with patients and their families or carers. Future research could focus on patient-reported outcomes, such as quality of life.

Development and validation of a high-quality simulator with exchangeable peritoneum for transabdominal preperitoneal laparoscopic inguinal hernia repair.

INTRODUCTION: Practical simulation training with proper haptic feedback and the fragility of the human body is required to overcome the long learning curve associated with laparoscopic inguinal hernia repair (LIHR). However, few hernia models accurately reflect the texture and fragility of the human body. Therefore, in this study, we developed a novel model for transabdominal preperitoneal (TAPP) LIHR training and evaluated its validity. METHODS: We developed a high-quality mock peritoneum with a hydrated polyvinyl alcohol layer and a unique two-way crossing cellulose fiber layer. To complete the simulation, the peritoneum was adhered to a urethane foam inguinal base with surgical landmarks. Participants could perform all the procedures required for the TAPP LIHR. Twenty-four surgeons performed TAPP LIHR simulation using a novel simulator. Their opinions were rated on a 5-point Likert scale. Additionally, 6 surgical residents and 10 surgical experts performed the procedure. Their performance was evaluated using the TAPP checklist score and procedure time. RESULTS: Most participants strongly agreed that the TAPP LIHR simulator with an exchangeable peritoneum model was useful. The participants agreed on the model fidelity for tactile sensation, forceps handling, and humanlike anatomy. In comparisons between surgical residents and experts, the experts had significantly higher scores (10.6 vs. 17.2, p < 0.05) and shorter procedure times (92.3 vs. 55.9 min; p < .05) than did surgical residents. CONCLUSIONS: We developed a high-quality exchangeable peritoneal model that mimics the human peritoneum's texture and fragility. This model enhances laparoscopic simulation training, potentially shortening TAPP LIHR learning curves.

Propensity score matched comparison of transperitoneal laparoscopic ureterolithotomy and percutaneous nephrolithotomy for management of large impacted proximal ureteral stones with long-term follow-up.

Impacted proximal ureteral stones (IPUS) present challenging clinical scenarios due to their persistent nature and associated complications. While ureterorenoscopy (URS) lithotripsy is recommended as the primary treatment, controversies exist regarding the optimal management of such stones. In this retrospective analysis, we compared the operative outcomes and long-term results of transperitoneal laparoscopic ureterolithotomy (LU) and percutaneous nephrolithotomy (PCNL) for IPUS larger than 15 mm. Propensity score matching (PSM) was employed to mitigate potential selection biases. Following PSM, 83 patients in each cohort exhibited comparable baseline characteristics. LU demonstrated a superior surgical success rate (100% vs. 96.4%, p = 0.244) and significantly lower perioperative hemoglobin decline (0.6 ± 0.4 g/dL vs. 1.5 ± 0.7 g/dL, p = 0.036) compared to PCNL. Additionally, LU exhibited a higher stone-free rate after 2 months (100% vs. 91.6%, p = 0.043), but a longer duration of catheterization (7.4 ± 1.2 days vs. 3.5 ± 2.2 days vs., p = 0.011). Conversely, PCNL was associated with a higher incidence of total complications (21.7% vs. 9.6%, p = 0.033) and stone recurrence during a mean period of 40-month follow-up (20.5% vs. 8.4%, p = 0.027). Transperitoneal LU and PCNL represent effective interventions for managing IPUS exceeding 15 mm. Notably, LU emerges as a preferable option over PCNL, offering superior stone clearance rates, reduced perioperative complications, and lower recurrence rates.

High peritoneal incision approach in endoscopic transabdominal preperitoneal patch plasty (TAPP) for inguinal hernia after radical prostatectomy.

BACKGROUND: Inguinal hernia develops as one of the common complications after robotic or laparoscopic radical prostatectomy (RP). Transabdominal preperitoneal patch plasty (TAPP) for an inguinal hernia after RP is difficult to perform due to postoperative severe adhesions in the preperitoneal cavity. We have introduced a high peritoneal incision approach (HPIA) in TAPP for inguinal hernia patients in whom peritoneal dissection is difficult due to severe adhesions after RP. We evaluate the safety and efficacy of TAPP with a HPIA for patients with an inguinal hernia after robot-assisted RP (RARP). METHODS: Patients characteristics and surgical outcome were evaluated by a retrospective analysis. RESULTS: From January 2014 to December 2017, 21 consecutive patients underwent TAPP for an inguinal hernia after RARP. Twenty-four lesions were the type 3b and three were type 3a according to the Nyhus classification. A circular incision TAPP was performed for 10 hernia lesions in eight patients and TAPP with HPIA was utilized for 17 lesions in 13 patients. The mean operation time for the unilateral hernia in the HPIA (137.8 ± 20.7 min) was significantly shorter than that (182.2 ± 42.0 min) in the circular incision TAPP (p = .038). The HPIA was complete in all patients, while the circular incision TAPP was converted to intraperitoneal onlay mesh (IPOM)intraperitoneal onlay mesh in five patients (55.6%, p = .008) due to dense adhesions with difficult dissection. No recurrent was observed after follow-up period of 48 months in both groups. CONCLUSIONS: The TAPP with HPIA is feasible and a safe and reliable treatment of choice in patients with an inguinal hernia after RARP.

Modifications of surgical techniques in laparoscopic percutaneous extraperitoneal closure of inguinal ring for childhood inguinal hernia to achieve zero recurrence and zero subcutaneous stitch granuloma.

PURPOSE: To present our technical modifications of single incision laparoscopic percutaneous extraperitoneal closure (SILPEC) of the internal inguinal ring (IIR) for pediatric inguinal hernia (PIH). METHODS: The prospectively collected data of all children diagnosed with PIH undergoing SILPEC at our center from 2016 to 2023 were reviewed and divided into two groups for result comparison: Group A: before and Group B: after the implementation of full modifications. Our modifications included using a nonabsorbable monofilament suture, creating a peritoneal thermal injury at the internal inguinal ring (IIR), employing a cannula to ensure the suture at the IIR ligates only the peritoneum, and double ligation of the IIR in selected cases. RESULTS: 1755 patients in group A and in group B (1 month to 14 years old) were enrolled. There were no significant differences regarding baseline patient characteristics between the two groups. At a median follow-up of 40 months, the rate of recurrent CIH and subcutaneous stitch granuloma (SSG) was 2.3% and 1.5% in group A vs. 0% and 0% in group B (p < 0.001). There were no hydroceles, no ascended or atrophic testis. CONCLUSIONS: Our SILPEC technical modifications can achieve zero recurrence and zero SSG for PIH.

Protective effect of Cyclo(His-Pro) on peritoneal fibrosis through regulation of HDAC3 expression.

Peritoneal dialysis is a common treatment for end-stage renal disease, but complications often force its discontinuation. Preventive treatments for peritoneal inflammation and fibrosis are currently lacking. Cyclo(His-Pro) (CHP), a naturally occurring cyclic dipeptide, has demonstrated protective effects in various fibrotic diseases, yet its potential role in peritoneal fibrosis (PF) remains uncertain. In a mouse model of induced PF, CHP was administered, and quantitative proteomic analysis using liquid chromatography-tandem mass spectrometry was employed to identify PF-related protein signaling pathways. The results were further validated using human primary cultured mesothelial cells. This analysis revealed the involvement of histone deacetylase 3 (HDAC3) in the PF signaling pathway. CHP administration effectively mitigated PF in both peritoneal tissue and human primary cultured mesothelial cells, concurrently regulating fibrosis-related markers and HDAC3 expression. Moreover, CHP enhanced the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) while suppressing forkhead box protein M1 (FOXM1), known to inhibit Nrf2 transcription through its interaction with HDAC3. CHP also displayed an impact on spleen myeloid-derived suppressor cells, suggesting an immunomodulatory effect. Notably, CHP improved mitochondrial function in peritoneal tissue, resulting in increased mitochondrial membrane potential and adenosine triphosphate production. This study suggests that CHP can significantly prevent PF in peritoneal dialysis patients by modulating HDAC3 expression and associated signaling pathways, reducing fibrosis and inflammation markers, and improving mitochondrial function.

Pressure induces peritoneal fibrosis and inflammation through CD44 signaling.

Peritoneal dialysis (PD) is a widely used sustainable kidney replacement therapy. Prolonged use of PD fluids is associated with mesothelial-mesenchymal transition, peritoneal fibrosis, and eventual ultrafiltration (UF) failure. However, the impact of pressure on the peritoneum remains unclear. In the present study, we hypothesized increased pressure is a potential contributing factor to peritoneal fibrosis and investigated the possible mechanisms. In vitro experiments found that pressurization led to a mesenchymal phenotype, the expression of fibrotic markers and inflammatory factors in human mesothelial MeT-5A cells. Pressure also increased cell proliferation and augmented cell migration potential in MeT-5A cells. The mouse PD model and human peritoneum equilibrium test (PET) data both showed a positive association between higher pressure and increased small solute transport, along with decreased net UF. Mechanistically, we found that significant upregulation of CD44 in mesothelial cells upon pressurization. Notably, the treatment of CD44 neutralizing antibodies prevented pressure-induced phenotypic changes in mesothelial cells, while a CD44 inhibitor oligo-fucoidan ameliorated pressure-induced peritoneal thickening, fibrosis, and inflammation in PD mice. To conclude, intraperitoneal pressure results in peritoneal fibrosis in PD via CD44-mediated mesothelial changes and inflammation. CD44 blockage can be utilized as a novel preventive approach for PD-related peritoneal fibrosis and UF failure.

Ascites microenvironment conditions the peritoneal pre-metastatic niche to promote the implantation of ovarian tumor spheroids: Involvement of fibrinogen/fibrin and αV and α5ß1 integrins.

At least one-third of patients with epithelial ovarian cancer (OC) present ascites at diagnosis and almost all have ascites at recurrence especially because of the propensity of the OC cells to spread in the abdominal cavity leading to peritoneal metastasis. The influence of ascites on the development of pre-metastatic niches, and on the biological mechanisms leading to cancer cell colonization of the mesothelium, remains poorly understood. Here, we show that ascites weakens the mesothelium by affecting the morphology of mesothelial cells and by destabilizing their distribution in the cell cycle. Ascites also causes destabilization of the integrity of mesothelium by modifying the organization of cell junctions, but it does not affect the synthesis of N-cadherin and ZO-1 by mesothelial cells. Moreover, ascites induces disorganization of focal contacts and causes actin cytoskeletal reorganization potentially dependent on the activity of Rac1. Ascites allows the densification and reorganization of ECM proteins of the mesothelium, especially fibrinogen/fibrin, and indicates that it is a source of the fibrinogen and fibrin surrounding OC spheroids. The fibrin in ascites leads to the adhesion of OC spheroids to the mesothelium, and ascites promotes their disaggregation followed by the clearance of mesothelial cells. Both αV and α5ß1 integrins are involved. In conclusion ascites and its fibrinogen/fibrin composition affects the integrity of the mesothelium and promotes the integrin-dependent implantation of OC spheroids in the mesothelium.

Empagliflozin attenuates epithelial-to-mesenchymal transition through senescence in peritoneal dialysis.

Epithelial-to-mesenchymal transition (EMT) is considered as one of the senescence processes; reportedly, antisenescence therapies effectively reduce EMT. Some models have shown antisenescence effects with the use of sodium-glucose cotransporter 2 (SGLT2) inhibitor. Therefore, our study investigated the antisenescence effects of empagliflozin as an SGLT2 inhibitor in a peritoneal fibrosis model and their impact on EMT inhibition. For in vitro study, human peritoneal mesothelial cells (HPMCs) were isolated and grown in a 96-well plate. The cell media were exchanged with serum-free M199 medium with d-glucose, with or without empagliflozin. All animal experiments were carried out in male mice. Mice were randomly classified into three treatment groups based on peritoneal dialysis (PD) or empagliflozin. We evaluated changes in senescence and EMT markers in HPMCs and PD model. HPMCs treated with glucose transformed from cobblestone to spindle shape, resulting in EMT. Empagliflozin attenuated these morphological changes. Reactive oxygen species production, DNA damage, senescence, and EMT markers were increased by glucose treatment; however, cotreatment with glucose and empagliflozin attenuated these changes. For the mice with PD, an increase in thickness, collagen deposition, staining for senescence, or EMT markers of the parietal peritoneum was observed, which, however, was attenuated by cotreatment with empagliflozin. p53, p21, and p16 increased in mice with PD compared with those in the control group; however, these changes were decreased by empagliflozin. In conclusion, empagliflozin effectively attenuated glucose-induced EMT in HPMCs through a decrease in senescence. Cotreatment with empagliflozin improved peritoneal thickness and fibrosis in PD.NEW & NOTEWORTHY Epithelial-to-mesenchymal transition (EMT) is considered one of the senescence processes. Antisenescence therapies may effectively reduce EMT in peritoneal dialysis models. Human peritoneal mesothelial cells treated with glucose show an increase in senescence and EMT markers; however, empagliflozin attenuates these changes. Mice undergoing peritoneal dialysis exhibit increased senescence and EMT markers, which are decreased by empagliflozin. These findings suggest that empagliflozin may emerge as a novel strategy for prevention or treatment of peritoneal fibrosis.

Surgical outcomes of novel retroperitoneal low anterior vs posterior and transperitoneal access in single-port partial nephrectomy.

PURPOSE: Single-Port Robot-Assisted Partial Nephrectomy (SP-RAPN) can be performed by transperitoneal and retroperitoneal approaches. However, there is a lack of surgical outcomes for novel Retroperitoneal Low Anterior Access (LAA) in SP-RAPN. The study compared outcomes of the standard approach (SA), considering transperitoneal (TP) and posterior retroperitoneal (RP) access vs LAA in SP-RAPN series. METHODS: 102 consecutive patients underwent SP-RAPN between 2019 and 2023 at a tertiary referral robotic center were identified. Baseline characteristics, peri- and post-operative outcomes were collected. Patients were stratified according to surgical approach into standard (RP or TP) vs LAA and, subsequently, RP vs LAA. Multivariable logistic regression analysis was used to test the probability of the same-day discharge adjusting for comorbidity indexes. RESULTS: Overall, 102 consecutive patients were included in this study (68 SA - 26 TP and 42 posterior RP vs 34 LAA). Median age was 60 (IQR 51.5-66) years and median BMI was 31 (IQR 26.3-37.6). No baseline differences were observed. LAA exhibited significantly shorter length of stay (LOS) (median 10 [IQR 8-12] vs 24 [IQR 12-30.2.] hours, p < .0001), reduced post-operative pain (p < .0001) and decreased narcotic use on 0-1 PO Day (p < .001) compared to SA and RP only. Multivariate analysis, adjusting for comorbidities, identified LAA as a strong predictor for Same-Day Discharge. CONCLUSION: LAA is an effective approach as well as RP and TP, regardless of the renal mass location, whether it is anterior or posterior, upper/mid or lower pole, yielding favorable outcomes in LOS, post-operative pain and decreased narcotics use compared to SA in SP-RAPN.

Survival and its relationship with the type of peritoneal solute transfer rate, in patients with chronic kidney disease incident on peritoneal dialysis therapy in RTS Colombia between the years 2007-2017.

INTRODUCTION: In some studies, the peritoneal solute transfer rate (PSTR) through the peritoneal membrane has been related to an increased risk of mortality. It has been observed in the literature that those patients with rapid diffusion of solutes through the peritoneal membrane (high/fast transfer) and probably those with high average transfer characterized by the Peritoneal Equilibrium Test (PET) are associated with higher mortality compared to those patients who have a slow transfer rate. However, some authors have not documented this fact. In the present study, we want to evaluate the (etiological) relationship between the characteristics of peritoneal membrane transfer and mortality and survival of the technique in an incident population on peritoneal dialysis in RTS Colombia during the years 2007-2017 using a competing risk model. MATERIALS AND METHODS: A retrospective cohort study was carried out at RTS Colombia in the period between 2007 and 2017. In total, there were 8170 incident patients older than 18 years, who had a Peritoneal Equilibration Test (PET) between 28 and 180 days from the start of therapy. Demographic, clinical, and laboratory variables were evaluated. The (etiological) relationship between the type of peritoneal solute transfer rate at the start of therapy and overall mortality and technique survival were analyzed using a competing risk model (cause-specific proportional hazard model described by Royston-Lambert). RESULTS: Patients were classified into four categories based on the PET result: Slow/Low transfer (16.0%), low average (35.4%), high average (32.9%), and High/Fast transfer (15.7%). During follow-up, with a median of 730 days, 3025 (37.02%) patients died, 1079 (13.2%) were transferred to hemodialysis and 661 (8.1%) were transplanted. In the analysis of competing risks, adjusted for age, sex, presence of DM, HTA, body mass index, residual function, albumin, hemoglobin, phosphorus, and modality of PD at the start of therapy, we found cause-specific HR (HRce) for high/fast transfer was 1.13 (95% CI 0.98-1.30) p = 0.078, high average 1.08 (95% CI 0.96-1.22) p = 0.195, low average 1.09 (95% CI 0.96-1.22) p = 0.156 compared to the low/slow transfer rate. For technique survival, cause-specific HR for high/rapid transfer of 1.22 (95% CI 0.98-1.52) p = 0.66, high average HR was 1.10 (95% CI 0.91-1.33) p = 0.296, low average HR of 1.03 (95% CI 0.85-1.24) p = 0.733 compared with the low/slow transfer rate, adjusted for age, sex, DM, HTA, BMI, residual renal function, albumin, phosphorus, hemoglobin, and PD modality at start of therapy. Non-significant differences. CONCLUSIONS: When evaluating the etiological relationship between the type of peritoneal solute transfer rate and overall mortality and survival of the technique using a competing risk model, we found no etiological relationship between the characteristics of peritoneal membrane transfer according to the classification given by Twardowski assessed at the start of peritoneal dialysis therapy and overall mortality or technique survival in adjusted models. The analysis will then be made from the prognostic model with the purpose of predicting the risk of mortality and survival of the technique using the risk subdistribution model (Fine & Gray).

Effect of cellular senescence on the response of human peritoneal mesothelial cells to TGF-ß.

Transforming growth factor ß (TGF-ß) is implicated in both mesothelial-to-mesenchymal transition (MMT) and cellular senescence of human peritoneal mesothelial cells (HPMCs). We previously showed that senescent HPMCs could spontaneously acquire some phenotypic features of MMT, which in young HPMCs were induced by TGF-ß. Here, we used electron microscopy, as well as global gene and protein profiling to assess in detail how exposure to TGF-ß impacts on young and senescent HPMCs in vitro. We found that TGF-ß induced structural changes consistent with MMT in young, but not in senescent HPMCs. Of all genes and proteins identified reliably in HPMCs across all treatments and states, 4,656 targets represented overlapping genes and proteins. Following exposure to TGF-ß, 137 proteins and 46 transcripts were significantly changed in young cells, compared to 225 proteins and only 2 transcripts in senescent cells. Identified differences between young and senescent HPMCs were related predominantly to wound healing, integrin-mediated signalling, production of proteases and extracellular matrix components, and cytoskeleton structure. Thus, the response of senescent HPMCs to TGF-ß differs or is less pronounced compared to young cells. As a result, the character and magnitude of the postulated contribution of HPMCs to TGF-ß-induced peritoneal remodelling may change with cell senescence.

[Influence of neoadjuvant chemoradiotherapy on peritoneal wound healing after abdominoperineal resection].

Objective: To study the influence of neoadjuvant chemoradiotherapy on peritoneal wound recovery after abdominoperineal resection (APR). Methods: This was a retrospective cohort study of data of 219 patients who had been pathologically diagnosed with low rectal cancer and undergone APR in the Union Hospital of Tongji Medical College of Huazhong University of Science and Technology between January 2018 and December 2021. Of these patients, 158 had undergone surgery without any pre-surgical treatment (surgery group), 35 had undergone surgery after neoadjuvant chemotherapy (neoadjuvant chemotherapy group), and 26 had undergone surgery after neoadjuvant chemoradiotherapy (neoadjuvant chemoradiotherapy group). The primary outcome was perineal wound complications occurring within 30 days. The status of wound healing was classified into the following three levels: Level A: abnormal wound seepage that improved after wound discharge; Level B: wound infection and dehiscence; and Level C: Level B plus fever. The patients' general condition, tumor status, perianal wound healing level, and intra- and post-operative recovery were recorded. Results: None of the study patients had any complications during surgery. The duration of surgery was 240.0 (180.0-300.0) minutes, 240.0 (225.0-270.0) minutes and 270.0 (240.0-356.2) minutes in the surgery, neoadjuvant chemotherapy, and neoadjuvant chemoradiotherapy groups, respectively (H=6.508, P=0.039). The rates of perineal wound complications were 34.6% (9/26) and (22.9%, 8/35)in the neoadjuvant chemoradiotherapy group and the neoadjuvant chemotherapy group, being significantly higher than that in the surgery group (10.1%, 16/158). After adjusting for patient age and sex using a logistic regression model, the risk of complications was still higher in the neoadjuvant chemoradiotherapy than in the surgery group (OR=4.6, 95%CI: 1.7-12.7; OR=2.6, 95%CI: 1.0-6.8), these differences being statistically significant (both P<0.05). The duration of hospital stay was 9.5 (7.0-12.0) days, 10.0 (8.0-17.0) days and 11.5 (9.0-19.5) days for patients in the surgery, neoadjuvant chemotherapy, and neoadjuvant chemoradiotherapy groups, respectively (H=0.569, P=0.752). However, after adjusting for patient age and sex by using a generalized linear model, hospital stay was longer in the neoadjuvant chemoradiotherapy than in the surgery group (ß [95% CI]: 4.4 [0.5-8.4], P=0.028). After surgery, 155 of 219 patients required further adjuvant chemotherapy. A higher proportion of patients with than without wound complications did not attend for follow-up (32.2% [10/31] vs. 16.1% [20/124]); this difference is statistically significant (χ2=4.133, P=0.023). Conclusions: In patients with low rectal cancer, neoadjuvant radiotherapy may be associated with an increased risk of perineal wound infection and non-healing.

Selective therapeutic efficacy of tyrosine kinase inhibitor sorafenib on the restoration of methylglyoxal-induced peritoneal fibrosis.

Peritoneal fibrosis, a common complication observed in long-term peritoneal dialysis patients, can gradually lead to ultrafiltration failure and the development of encapsulating peritoneal sclerosis. Although mechanisms of peritoneal fibrosis have been proposed, effective therapeutic options are unsatisfactory. Recently, several tyrosine kinase inhibitors have proven to be anti-fibrosis in rodent models. To assess the potential therapeutic effects of tyrosine kinase inhibitors on peritoneal fibrosis in the larger animal model, a novel porcine model of peritoneal fibrosis induced by 40 mM methylglyoxal in 2.5 % dialysate was established, and two different doses (20 mg/kg and 30 mg/kg) of sorafenib were given orally to evaluate their therapeutic efficacy in this study. Our results showed that sorafenib effectively reduced adhesions between peritoneal organs and significantly diminished the thickening of both the parietal and visceral peritoneum. Angiogenesis, vascular endothelial growth factor A production, myofibroblast infiltration, and decreased endothelial glycocalyx resulting from dialysate and methylglyoxal stimulations were also alleviated with sorafenib. However, therapeutic efficacy in ameliorating loss of mesothelial cells, restoring decreased ultrafiltration volume, and improving elevated small solutes transport rates was limited. In conclusion, this study demonstrated that sorafenib could potentially be used for peritoneal fibrosis treatment, but applying sorafenib alone might not be sufficient to fully rescue methylglyoxal-induced peritoneal defects.

Step-by-step Peritoneal Bladder Flap Bunching (PBFB) technique: an innovative approach following lymph node dissection in robotic radical prostatectomy.

INTRODUCTION: Robot-assisted radical prostatectomy (RARP) has become a popular surgical approach for localized prostate cancer due to its favorable oncological and functional outcomes, as well as lower morbidity. In cases of intermediate- and high-risk prostate cancer, bilateral pelvic lymphadenectomy (PLND) is recommended as an adjunct to RARP (1-3). Despite its benefits, PLND can lead to surgical complications, with postoperative lymphocele formation being the most common. Most postoperative lymphoceles are clinically insignificant with variable incidence, reaching up to 60% of cases 4. However, a small percentage of patients 2-8% may experience symptomatic lymphoceles (SL), which can cause significant morbidity (4, 5). SURGICAL TECHNIQUE: We perform our RARP technique with our standard approach in all patients (6). After vesicourethral anastomosis a modified PF created to prevent symptomatic lymphocele. We start by suturing the peritoneal fold on the right side, medially to the vas deferens, followed by a similar stitch on the left side to approximate the edges in the midline. A running suture bunches the bladder peritoneum from both sides, passing through the pubic bone periosteum to secure it in place (7). This approach keeps the lateral pelvic gutters open for lymphatic drainage, while allowing fluid drainage from the true pelvis into the abdomen. A pelvic ultrasound was done for all patients at 6 weeks post operative, and additional clinical follow-up was carried out at 3 months following surgery. CONSIDERATIONS: We have demonstrated a modified technique of peritoneal flap (PBFB) with an initial decrease in postoperative symptomatic lymphoceles, the technique is feasible, safe, does not add significant morbidity, and does not require a learning curve.

Perioperative outcomes and platinum resistant recurrence in patients undergoing systematic, protocol-based, total parietal peritonectomy during interval cytoreductive surgery for advanced ovarian cancer: results of the TORPEDO study.

OBJECTIVE: The TORPEDO (CTRI/2018/12/016789) is the single-arm, prospective, interventional study evaluating the role of a total parietal peritonectomy (TPP) in patients undergoing interval cytoreductive surgery (iCRS). In this manuscript, we report the perioperative outcomes and platinum resistant recurrence (PRR) in 218 patients enrolled in the study. METHODS: A TPP was performed in all patients undergoing iCRS irrespective of the residual disease extent. hyperthermic intraperitoneal chemotherapy (HIPEC) was performed as per the clinician's discretion with 75 mg/m² of cisplatin. Maintenance therapy was also used at the discretion of the treating clinicians. RESULTS: From 9th December 2018 to 31st July 2022 (recruitment complete), 218 patients were enrolled at 4 medical centers in India. The median surgical peritoneal cancer index was 14 and a complete gross resection was achieved in 95.8%. HIPEC was performed in 130 (59.6%) patients. The 90-day major morbidity was 17.4% and 2.7% patients died within 90 days of surgery. Adjuvant chemotherapy was delayed beyond 6 weeks in 7.3%. At a median follow-up of 19 months (95% confidence interval [CI]=15.9-35 months), 101 (46.3%) recurrences and 19 (8.7%) deaths had occurred. The median progression-free survival was 22 months (95% CI=17-35 months) and the median overall survival (OS) not reached. Platinum resistant recurrence was observed in 6.4%. The projected 3-year OS was 81.5% and in 80 patients treated before may 2020, it was 77.5%. CONCLUSION: The morbidity and mortality of TPP with or without HIPEC performed during iCRS is acceptable. The incidence was of PRR is low. Early survival results are encouraging and warrant conduction of a randomized controlled trial comparing TPP with conventional surgery.

The Impact of Positive Peritoneal Cytology on the Survival Rates of Early-Stage-Disease Endometrial Cancer Patients: Systematic Review and Meta-Analysis.

Background and Objectives: The impact of positive peritoneal cytology has been a matter of controversy in early-stage endometrial cancer for several years. The latest staging systems do not take into consideration its presence; however, emerging evidence about its potential harmful effect on patient survival outcomes suggests otherwise. In the present systematic review and meta-analysis, we sought to accumulate current evidence. Materials and Methods: Medline, Scopus, the Cochrane Central Register of Controlled Trials CENTRAL, Google Scholar and Clinicaltrials.gov databases were searched for relevant articles. Effect sizes were calculated in Rstudio using the meta function. A sensitivity analysis was carried out to evaluate the possibility of small-study effects and p-hacking. Trial sequential analysis was used to evaluate the adequacy of the sample size. The methodological quality of the included studies was assessed using the Newcastle-Ottawa scale. Results: Fifteen articles were finally included in the present systematic review that involved 19,255 women with early-stage endometrial cancer. The Newcastle-Ottawa scale indicated that the majority of included studies had a moderate risk of bias in their selection of participants, a moderate risk of bias in terms of the comparability of groups (positive peritoneal cytology vs. negative peritoneal cytology) and a low risk of bias concerning the assessment of the outcome. The results of the meta-analysis indicated that women with early-stage endometrial cancer and positive peritoneal cytology had significantly lower 5-year recurrence-free survival (RFS) (hazards ratio (HR) 0.26, 95% CI 0.09, 0.71). As a result of the decreased recurrence-free survival, patients with positive peritoneal cytology also exhibited reduced 5-year overall survival outcomes (HR 0.50, 95% CI 0.27, 0.92). The overall survival of the included patients was considerably higher among those that did not have positive peritoneal cytology (HR 12.76, 95% CI 2.78, 58.51). Conclusions: Positive peritoneal cytology seems to be a negative prognostic indicator of survival outcomes of patients with endometrial cancer. Considering the absence of data related to the molecular profile of patients, further research is needed to evaluate if this factor should be reinstituted in future staging systems.

Sterile inflammation of peritoneal membrane caused by peritoneal dialysis: focus on the communication between immune cells and peritoneal stroma.

Peritoneal dialysis is a widely used method for treating kidney failure. However, over time, the peritoneal structure and function can deteriorate, leading to the failure of this therapy. This deterioration is primarily caused by infectious and sterile inflammation. Sterile inflammation, which is inflammation without infection, is particularly concerning as it can be subtle and often goes unnoticed. The onset of sterile inflammation involves various pathological processes. Peritoneal cells detect signals that promote inflammation and release substances that attract immune cells from the bloodstream. These immune cells contribute to the initiation and escalation of the inflammatory response. The existing literature extensively covers the involvement of different cell types in the sterile inflammation, including mesothelial cells, fibroblasts, endothelial cells, and adipocytes, as well as immune cells such as macrophages, lymphocytes, and mast cells. These cells work together to promote the occurrence and progression of sterile inflammation, although the exact mechanisms are not fully understood. This review aims to provide a comprehensive overview of the signals from both stromal cells and components of immune system, as well as the reciprocal interactions between cellular components, during the initiation of sterile inflammation. By understanding the cellular and molecular mechanisms underlying sterile inflammation, we may potentially develop therapeutic interventions to counteract peritoneal membrane damage and restore normal function.