Implementation of an enhanced recovery after surgery protocol for colorectal cancer in a regional hospital network supported by audit and feedback: a stepped wedge, cluster randomised trial.

BACKGROUND: Enhanced recovery after surgery (ERAS) protocols are known to potentially improve the management and outcomes of patients undergoing colorectal surgery, with limited evidence of their implementation in hospital networks and in a large population. We aimed to assess the impact of the implementation of an ERAS protocol in colorectal cancer surgery in the entire region of Piemonte, Italy, supported by an audit and feedback (A&F) intervention. METHODS: A large, stepped wedge, cluster randomised trial enrolled patients scheduled for elective surgery at 29 general surgery units (clusters). At baseline (first 3 months), standard care was continued in all units. Thereafter, four groups of clusters began to adopt the ERAS protocol successively. By the end of the study, each cluster had a period in which standard care was maintained (control) and a period in which the protocol was applied (experimental). ERAS implementation was supported by initial training and A&F initiatives. The primary endpoint was length of stay (LOS) without outliers (>94th percentile), and the secondary endpoints were outliers for LOS, postoperative medical and surgical complications, quality of recovery and compliance with ERAS items. RESULTS: Of 2626 randomised patients, 2397 were included in the LOS analysis (1060 in the control period and 1337 in the experimental period). The mean LOS without outliers was 8.5 days during the control period (SD 3.9) and 7.5 (SD 3.5) during the experimental one. The adjusted difference between the two periods was a reduction of -0.58 days (95% CI -1.07, -0.09; p=0.021). The compliance with ERAS items increased from 52.4% to 67.3% (estimated absolute difference +13%; 95% CI 11.4%, 14.7%). No difference in the occurrence of complications was evidenced (OR 1.22; 95% CI 0.89, 1.68). CONCLUSION: Implementation of the ERAS protocol for colorectal cancer, supported by A&F approach, led to a substantial improvement in compliance and a reduction in LOS, without meaningful effects on complications. Trial registration number NCT04037787.

Incidental thyroid carcinoma in an endemic goiter area in Italy: histopathological features and predictors of a common finding.

PURPOSE: The occurrence and histopathological features of incidental thyroid carcinoma (ITC) vary considerably among populations from different geographical regions. The aim of this study is to assess the prevalence and histopathological characteristics of ITC in patients who underwent thyroid surgery for apparently benign thyroid diseases in an endemic goiter area in Italy. METHODS: A total of 649 consecutive patients (531 females and 118 males; mean age, 52.9 ± 11.0 years), who underwent thyroid surgery at the Endocrine Surgery Unit of the tertiary care "Renato Dulbecco" University Hospital (Catanzaro, Italy) in the period between years 2017 and 2022, were included in this retrospective study. A comprehensive histopathological examination was performed on surgically excised thyroid tissue. Logistic regression analysis was employed to identify potential predictors of ITC. RESULTS: The histopathological examination revealed the presence of ITC in 81 patients, accounting for 12.5% of the total study population. The female to male ratio was found to be 6.4 to 1. Among the patients with ITC, 72 had papillary carcinoma (PTC), with 53 of these tumors being microcarcinomas (microPTC). Additionally, 5 patients had follicular thyroid carcinoma, 2 patients had low-risk follicular cell-derived thyroid neoplasms, 1 patient had an oncocytic carcinoma, and 1 patient had a medullary thyroid carcinoma. Logistic regression analysis demonstrated a significant association between female sex and incidental microPTC. CONCLUSIONS: These findings provide further evidence of the common occurrence of ITC, typically in the form of microPTC, among individuals who undergo thyroid surgery for apparently benign thyroid diseases.

Coexistence of Hashimoto's Thyroiditis in Differentiated Thyroid Cancer: Post-Operative Monitoring of Anti-Thyroglobulin Antibodies and Assessment of Treatment Response.

INTRODUCTION: Differentiated thyroid carcinoma (DTC) is frequently found in conjunction with autoimmune thyroid disorders, particularly Hashimoto's thyroiditis (HT). This study investigates the impact of coexisting HT on the persistence of an indeterminate response to therapy due to positive anti-thyroglobulin antibodies (AbTg), measured via competitive immunoassay, in a consecutive patient series from Calabria, Southern Italy. METHODS: This retrospective longitudinal study analyzed 259 consecutive DTC patients managed at the Endocrinology Unit of Renato Dulbecco Hospital (Catanzaro, Italy) up to 2023. Patients with medullary and undifferentiated thyroid carcinoma, partial thyroidectomy, less than six months of post-operative monitoring, or missing clinical data were excluded. Demographic information, histological findings, initial tumor stage, and ATA risk category were collected. The response to therapy was assessed based on ATA guidelines. RESULTS: Among the 259 patients, 29% had coexisting HT. Patients with HT exhibited distinct characteristics: a higher proportion of females (87.0% vs. 74.7%), a shorter post-operative monitoring duration (median 3 vs. 5 years), and a higher prevalence of papillary thyroid carcinoma (PTC) (97.4% vs. 86.3%). The tumor size, lymph node involvement, and distant metastasis were similar between the groups, with patients without HT having a higher incidence of extrathyroidal tumor extension. However, the initial TNM stage and ATA risk category did not differ significantly. At the six-month follow-up, HT patients showed a higher rate of indeterminate responses, primarily due to positive AbTg. After 12 months, the response categories aligned, with decreasing AbTg levels in the HT group. After 24 months, most patients with long-term follow-up demonstrated an excellent response to DTC therapy, irrespective of HT coexistence. CONCLUSIONS: While HT does not worsen DTC prognosis, it may result in indeterminate responses. AbTg measurements in the peri-operative period should be encouraged to facilitate post-operative monitoring, emphasizing the importance of using standardized assays. Further research in larger populations with extended follow-up is needed to comprehensively understand the HT-DTC relationship.

Metformin in Gestational Diabetes Mellitus: To Use or Not to Use, That Is the Question.

In recent years, there has been a dramatic increase in the number of pregnancies complicated by gestational diabetes mellitus (GDM). GDM occurs when maternal insulin resistance develops and/or progresses during gestation, and it is not compensated by a rise in maternal insulin secretion. If not properly managed, this condition can cause serious short-term and long-term problems for both mother and child. Lifestyle changes are the first line of treatment for GDM, but if ineffective, insulin injections are the recommended pharmacological treatment choice. Some guidance authorities and scientific societies have proposed the use of metformin as an alternative pharmacological option for treating GDM, but there is not yet a unanimous consensus on this. Although the use of metformin appears to be safe for the mother, concerns remain about its long-term metabolic effects on the child that is exposed in utero to the drug, given that metformin, contrary to insulin, crosses the placenta. This review article describes the existing lines of evidence about the use of metformin in pregnancies complicated by GDM, in order to clarify its potential benefits and limits, and to help clinicians make decisions about who could benefit most from this drug treatment.

From Euglycemia to Recent Onset of Type 2 Diabetes Mellitus: A Proof-of-Concept Study on Circulating microRNA Profiling Reveals Distinct, and Early microRNA Signatures.

Background and aim-Alterations in circulating microRNA (miRNA) expression patterns are thought to be involved in the early stages of prediabetes, as well as in the progression to overt type 2 diabetes mellitus (T2D) and its vascular complications. However, most research findings are conflicting, in part due to differences in miRNA extraction and normalization methods, and in part due to differences in the study populations and their selection. This cross-sectional study seeks to find new potentially useful biomarkers to predict and/or diagnose T2D by investigating the differential expression patterns of circulating miRNAs in the serum of patients with impaired fasting glucose (IFG) and new-onset T2D, with respect to euglycemic controls, using a high-throughput 384-well array and real-time PCR. Methods-Thirty subjects, aged 45-65 years, classified into three matched groups (of 10 participants each) according to their glycometabolic status, namely (1) healthy euglycemic controls, (2) patients with IFG and (3) patients with new-onset, uncomplicated T2D (<2 years since diagnosis) were enrolled. Circulating miRNAs were extracted from blood serum and profiled through real-time PCR on a commercial 384 well-array, containing spotted forward primers for 372 miRNAs. Data analysis was performed by using the online data analysis software GeneGlobe and normalized by the global Ct mean method. Results-Of the 372 analyzed miRNAs, 33 showed a considerably different expression in IFG and new-onset T2D compared to healthy euglycemic controls, with 2 of them down-regulated and 31 up-regulated. Stringent analysis conditions, using a differential fold regulation threshold ≥ 10, revealed that nine miRNAs (hsa-miR-3610, hsa-miR-3200-5p, hsa-miR-4651, hsa-miR-3135b, hsa-miR-1281, hsa-miR-4301, hsa-miR-195-5p, hsa-miR-523-5p and hsa-let-7a-5p) showed a specific increase in new-onset T2D patients compared to IFG patients, suggesting their possible role as early biomarkers of progression from prediabetes to T2D. Moreover, by conventional fold regulation thresholds of ±2, hsa-miR-146a-5p was down-regulated and miR-1225-3p up-regulated in new-onset T2D patients only. Whereas hsa-miR-146a-5p has a well-known role in glucose metabolism, insulin resistance and T2D complications, no association between hsa-miR-1225-3p and T2D has been previously reported. Bioinformatic and computational analysis predict a role of hsa-miR-1225-3p in the pathogenesis of T2D through the interaction with MAP3K1 and HMGA1. Conclusions-The outcomes of this study could aid in the identification and characterization of circulating miRNAs as potential novel biomarkers for the early diagnosis of T2D and may serve as a proof-of-concept for future mechanistic investigations.

The anticancer effects of Metformin in the male germ tumor SEM-1 cell line are mediated by HMGA1.

Introduction: Germ cell tumors (GCTs) are the most common type of cancer in young men. These tumors usually originate from the testis, but they can occasionally develop from extragonadal sites probably due to primordial germ cells (PGCs) migration errors. Cisplatin-based chemotherapy is usually effective for male GCTs, but the risk of toxicity is high and new therapeutic strategies are needed. Although Metformin (Met) has been widely studied as a potential cancer treatment over the past decades, there is limited evidence to support its use in treating male GCTs. Additionally, the mechanism by which it acts on tumor cells is still not entirely understood. Methods: SEM-1 cells, a newly established human cell line of extragonadal origin, were treated with Met. Cell viability was studied by MTT assay, while cell migration and invasion were studied by the wound healing assay and the transwell assay, respectively. The effect of Met on 3D spheroid formation was determined by seeding SEM-1 cells in appropriate cell suspension culture conditions, and cell cycle was characterized by flow cytometry. Factors involved in PGCs migration and GCT invasion, such as IGFBP1, IGF1R, MMP-11 and c-Kit, together with cyclin D1 (a key regulator of cell cycle progression), and the upstream factor, HMGA1, were determined by immunoblots. Results: Treatment of SEM-1 cells with Met resulted in a potent and dose-dependent reduction of cell proliferation, as evidenced by decreased nuclear abundance of cyclin D1 and cell cycle arrest in G1 phase. Also, Met prevented the formation of 3D spheroids, and blocked cell migration and invasion by reducing the expression of IGFBP1, IGF1R and MMP-11. Both, IGFBP1 and MMP-11 are under control of HMGA1, a chromatin-associated protein that is involved in the regulation of important oncogenic, metabolic and embryological processes. Intriguingly, an early reduction in the nuclear abundance of HMGA1 occurred in SEM-1 cells treated with Met. Conclusions: Our results document the antiproliferative and antimigratory effects of Met in SEM-1 cells, providing new insights into the potential treatments for male GCTs. The anticancer properties of Met in SEM-1 cells are likely related to its ability to interfere with HMGA1 and downstream targets, including cyclin D1, the IGFs system, and MMP-11.

Methods to Study Protein-Binding to Pseudogene Transcripts.

One of the most commonly described biological feature of processed pseudogenes is the ability to influence the expression of their parental coding genes. As evidenced in several studies, the high sequence similarity between these RNA pairs sets up a certain level of competition for posttranscriptional regulators, including, among others, RNA-binding proteins (RBPs). RBPs may affect, positively or negatively, the stability of bound mRNAs, so that, if an overexpressed pseudogene competes with its homologous coding gene, the downstream protein synthesis would change, with potential pathological consequences. Given these premises, a rigorous and comprehensive understanding of interactions between pseudogene-parental gene RNA pairs and RBPs could provide further insights into the biological bases of complex diseases, such as cancer, cardiovascular disease, and type 2 diabetes, identifying novel predictive and/or prognostic biomarkers.Herein, we detail easily adaptable protocols of plasmid-based molecular cloning and RNA-electrophoretic mobility shift assay (EMSA) used in our laboratory for determining the interaction between a cytoplasmatic stabilizing protein (αCP1) and the pseudogene-parental gene RNA pair HMGA1-p /HMGA1. We also offer a general overview of RNA immunoprecipitation procedures and present novel bioinformatic tools for predicting RBPs binding sites on pseudogene transcripts.

2020 WSES guidelines for the detection and management of bile duct injury during cholecystectomy.

Bile duct injury (BDI) is a dangerous complication of cholecystectomy, with significant postoperative sequelae for the patient in terms of morbidity, mortality, and long-term quality of life. BDIs have an estimated incidence of 0.4-1.5%, but considering the number of cholecystectomies performed worldwide, mostly by laparoscopy, surgeons must be prepared to manage this surgical challenge. Most BDIs are recognized either during the procedure or in the immediate postoperative period. However, some BDIs may be discovered later during the postoperative period, and this may translate to delayed or inappropriate treatments. Providing a specific diagnosis and a precise description of the BDI will expedite the decision-making process and increase the chance of treatment success. Subsequently, the choice and timing of the appropriate reconstructive strategy have a critical role in long-term prognosis. Currently, a wide spectrum of multidisciplinary interventions with different degrees of invasiveness is indicated for BDI management. These World Society of Emergency Surgery (WSES) guidelines have been produced following an exhaustive review of the current literature and an international expert panel discussion with the aim of providing evidence-based recommendations to facilitate and standardize the detection and management of BDIs during cholecystectomy. In particular, the 2020 WSES guidelines cover the following key aspects: (1) strategies to minimize the risk of BDI during cholecystectomy; (2) BDI rates in general surgery units and review of surgical practice; (3) how to classify, stage, and report BDI once detected; (4) how to manage an intraoperatively detected BDI; (5) indications for antibiotic treatment; (6) indications for clinical, biochemical, and imaging investigations for suspected BDI; and (7) how to manage a postoperatively detected BDI.

Does neoadjuvant FOLFOX chemotherapy improve the prognosis of high-risk Stage II and III colon cancers? Three years' follow-up results of the PRODIGE 22 phase II randomized multicentre trial.

AIM: Neoadjuvant chemotherapy has proven valuable in locally advanced resectable colon cancer (CC) but its effect on oncological outcomes is uncertain. The aim of the present paper was to report 3-year oncological outcomes, representing the secondary endpoints of the PRODIGE 22 trial. METHOD: PRODIGE 22 was a randomized multicentre phase II trial in high-risk T3, T4 and/or N2 CC patients on CT scan. Patients were randomized between 6 months of adjuvant FOLFOX (upfront surgery) or perioperative FOLFOX (four cycles before surgery and eight cycles after; FOLFOX perioperative). In wild-type RAS patients, a third arm testing perioperative FOLFOX-cetuximab was added. The primary endpoint was the tumour regression grade. Secondary endpoints were 3-year overall survival (OS), disease-free survival (DFS), recurrence-free survival (RFS) and time to recurrence (TTR). RESULTS: Overall, 120 patients were enrolled. At interim analysis, the FOLFOX-cetuximab arm was stopped for futility. The remaining 104 patients represented our intention-to-treat population. In the perioperative group, 96% received the scheduled four neoadjuvant cycles and all but one had adjuvant FOLFOX for eight cycles. In the control arm, 38 (73%) patients received adjuvant FOLFOX. The median follow-up was 54.3 months. Three-year OS was 90.4% in both arms [hazard ratio (HR) = 0.85], 3-year DFS, RFS and TTR were, respectively, 76.8% and 69.2% (HR=0.94), 73% and 69.2% (HR = 0.86) and 82% and 72% (HR = 0.67) in the perioperative and control arms, respectively. Forest plots did not show any subgroup with significant difference for survival outcomes. No benefit from adding cetuximab was observed. CONCLUSION: Perioperative FOLFOX has no detrimental effect on long-term oncological outcomes and may be an option for some patients with locally advanced CC.

Extracellular Matrix in Calcific Aortic Valve Disease: Architecture, Dynamic and Perspectives.

Calcific Aortic Valve Disease (CAVD) is the most common valvular heart disease in developed countries and in the ageing population. It is strongly correlated to median age, affecting up to 13% of the population over the age of 65. Pathophysiological analysis indicates CAVD as a result of an active and degenerative disease, starting with sclerosis and chronic inflammation and then leaflet calcification, which ultimately can account for aortic stenosis. Although CAVD has been firstly recognized as a passive event mostly resulting from a degenerative aging process, much evidences suggests that calcification arises from different active processes, involving both aortic valve-resident cells (valve endothelial cells, valve interstitial cells, mesenchymal stem cells, innate immunity cells) and circulating cells (circulating mesenchymal cells, immunity cells). Moreover, a role for the cell-derived "matrix vesicles" and extracellular matrix (ECM) components has also been recognized. The aim of this work is to review the cellular and molecular alterations occurring in aortic valve during CAVD pathogenesis, focusing on the role of ECM in the natural course of the disease.

Laparoscopic versus robotic right colectomy with extra-corporeal or intra-corporeal anastomosis: a systematic review and meta-analysis.

PURPOSE: The aim of the present systematic review and meta-analysis is to compare laparoscopic right colectomy (LRC) versus robotic right colectomy (RRC) using homogeneous subgroup analyses for extra-corporeal anastomosis (EA) and intra-corporeal anastomosis (IA). METHODS: MEDLINE, Scopus, and Web of Science databases were searched up to April 2020 for prospective or retrospective studies comparing LRC versus RRC on at least one short- or long-term outcome. The primary outcome was the length of hospital stay (LOS). The secondary outcomes included operative and pathological results, survival, and total costs. LRC and RRC were compared using three homogeneous subgroups: without distinction by the type of anastomosis, EA only, and IA only. Pooled data analyses were performed using mean difference (MD) and random effects model. RESULTS: Thirty-seven of 448 studies were selected. The included patients were 21,397 for the LRC group and 2796 for the RRC group. Regardless for the type of anastomosis, RRC showed shorter LOS, lower blood loss, lower conversion rate, shorter time to flatus, and lower overall complication rate compared with LRC, but longer operative time and higher total costs. In the EA subgroup, RRC showed similar LOS, longer operative time, and higher costs compared with LRC, the other outcomes being similar. In the IA subgroup, RRC showed shorter LOS and longer operative time compared with LRC, with no difference for the remaining outcomes. CONCLUSIONS: Most included articles are retrospective, providing low-quality evidence and limiting conclusions. The more frequent use of the IA seems to explain the advantages of RRC over LRC.

Extended right colectomy, left colectomy, or segmental left colectomy for splenic flexure carcinomas: a European multicenter propensity score matching analysis.

BACKGROUND: The surgical resection of the splenic flexure carcinoma (SFC) is challenging and the optimal surgical procedure for SFCs remains a matter of debate. The present study aimed to compare in a multicenter European sample of patients the short- and long-term outcomes of extended right (ERC) vs. left (LC) vs. segmental left colectomy (SLC) for SFCs. METHODS: This retrospective multicenter study analyzed the surgical and oncological outcomes of SFC patients undergoing elective curative intent surgery between 2000 and 2018. Descriptive and exploratory analyses were first conducted on the whole sample. Outcomes of the different procedures (ERC vs. LC vs. SLC) were then compared using propensity score matching for multilevel treatment. Overall (OS) and disease-free survival (DFS) were evaluated by Kaplan-Meier method. RESULTS: From a total of 399 SFC patients, 143 (35.8%) underwent ERC, 131 (32.8%) underwent LC, and 125 (31.4%) underwent SLC. Overall, 297 (74.4%) were laparoscopic procedures. An increase in operative time, time to flatus, time to regular diet, and hospital stay was observed with the progressive extension of SFC resection. ERC was associated with significantly increased risk of postoperative ileus compared to both LC and SLC. A significantly greater number of lymph nodes were retrieved by ERC, but the objective of at least 12 retrieved lymph nodes was achieved in 85% of patients, without procedure-related differences. No differences were observed in OS or DFS between ERC, LC, and SLC. CONCLUSION: The present study supports the resection of SFCs by colon-sparing surgical techniques, such as SLC.

Human Colonic Microbiota and Short-Term Postoperative Outcomes in Colorectal Cancer Patients: A Pilot Study.

Despite the advances in surgical techniques and perioperative care, the complication rates after colorectal cancer surgery have remained stable. Recently, it has been suggested that colon microbiota may be implicated in several pathways that can lead to impaired colonic homeostasis and, thereby, to the development of complications after colorectal surgery. The aim of this study was to evaluate the potential impact of colonic dysbiosis on postoperative course. This prospective human clinical study recruited patients operated on for left colon, sigmoid colon or rectal cancer. Colon mucosa and fecal samples were collected to study mucosa associated microbiota (MAM) and luminal microbiota (LM), accordingly. Preliminary analysis for the first 25 consecutive patients with V3-V4 16S rRNA metagenomic analysis was performed. Bacterial composition and abundance in patients who developed postoperative complications over a 90-day follow-up period were compared to those without postoperative complications. Abundance and distribution of genera in MAM differed significantly when compared to LM with a significant impact on neoadjuvant therapy on bacterial composition. Preliminary analysis revealed no statistically significant differences in LM nor in MAM composition when individuals with and without postoperative surgical complications were compared. In cases of postoperative complications, LM and MAM showed significantly decreased diversity. Composition of the colonic microbiota is altered by neoadjuvant therapy. Results on the impact of colonic dysbiosis on postoperative complications are pending the end of the present study, with 50 patients enrolled.

Conversions related to adhesions in abdominal surgery. Robotic versus laparoscopic approach: A multicentre experience.

BACKGROUND: An advantage of robotic surgery over laparoscopy is the lower rate of unplanned conversion. One of the implicated reasons for conversion is adhesions from previous abdominal surgeries (PASs). METHODS: A comparative analysis of 98 patients with history of open PAS treated by laparoscopic or robotic surgery was performed. Primary endpoint was the rate of conversion to open surgery related to adhesiolysis. Secondary endpoints were short-term outcomes and complications. RESULTS: Conversion rate specifically related to adhesiolysis was significantly lower in robotic group (13 for laparoscopic group vs. 2 for robotic group; p = 0.046). Conversions occurred during adhesiolysis were significantly related to severity of adhesions expressed by peritoneal adhesion index (PAI) score (p < 0.001), number of abdominal areas involved by adhesions (p < 0.001) and severity of PAI into the target area of surgical intervention (p = 0.021). CONCLUSIONS: Benefits of robotic surgery are more noticeable in performing procedures with increasing technical difficulties.

Virtual unenhanced imaging of the liver derived from 160-mm rapid-switching dual-energy CT (rsDECT): Comparison of the accuracy of attenuation values and solid liver lesion conspicuity with native unenhanced images.

OBJECTIVES: To evaluate the reliability of attenuation values of the liver parenchyma and focal liver lesions on virtual unenhanced images from arterial (VUEart) and portal venous phases (VUEport) compared to native unenhanced (NU) attenuation values in patients referred for assessment of malignant liver lesions. METHODS: Seventy-three patients with confirmed primary or metastatic liver tumors who underwent a multiphase contrast-enhanced rapid-switching kVp dual-energy CT (rsDECT) were included in this IRB-approved retrospective study. Both qualitative and quantitative analyses - including the lesion-to-liver contrast-to-noise ratio (LL-CNR) - were performed and compared between NU and both VUEart and VUEport images. RESULTS: The mean liver attenuation values were significantly lower in VUEart images (56.7 ±â€¯6.7 HU) than in NU images (59.6 ±â€¯7.5 HU, p = 0.008), and were comparable between VUEart and VUEport images (57.9 ±â€¯6 UH, p = 0.38) and between VUEport and NU images (p = 0.051). The mean liver lesions attenuation values were comparable between NU, VUEart and VUEport images (p = 0.60). Strong and significant correlations values were found both in liver lesions and tumor-free parenchyma (r = 0.82-0.91, p < 0.01). The mean LL-CNR was significantly higher in VUEart and VUEport images than in NU images (1.7 ±â€¯1 and 1.6 ±â€¯1.1 vs 0.9 ±â€¯0.6; p < 0.001), but was comparable between VUEart and VUEport images (p > 0.9). Lesion conspicuity was significantly higher in VUEport images than in NU images (p < 0.001). CONCLUSION: VUEport images derived from 3rd generation rsDECT could confidently replace NU images in patients undergoing assessment for malignant liver lesions. These images provide comparable attenuation values in both liver lesions and liver parenchyma while reducing the radiation dose and scanning time.

PDE-5i Management of Erectile Dysfunction After Rectal Surgery: A Systematic Review Focusing on Treatment Efficacy.

Erectile dysfunction (ED) is one of the main functional complications of surgical resections of the rectum due to rectal cancers or inflammatory bowel disease (IBD). The present systematic review aimed at revising ED management strategies applied after rectal resections and their efficacy in terms of improvement of the International Index of Erectile Function (IIEF) score. A literature search was conducted on Medline, EMBASE, Scopus, and Cochrane databases by two independent reviewers following the PRISMA guidelines. Randomized and nonrandomized controlled trials (RCTs, NRCTs), case-control studies, and case series evaluating medical or surgical therapies for ED diagnosed after rectal surgery for both benign and malignant pathologies were eligible for inclusion.Out of 1028 articles initially identified, only five met the inclusion criteria: two RCTs comparing oral phosphodiesterase type-5 inhibitor (PDE-5i) versus placebo; one NRCT comparing PDE-5i versus PDE-5i + vacuum erection devices (VEDs) versus control; and two before-after studies on PDE-5i. A total of 253 (82.7%) rectal cancer patients and 53 (17.3%) IBD patients were included. Based on two RCTs, PDE-5i significantly improved IIEF compared to placebo at 3 months (SMD = 1.07; 95% CI [0.65, 1.48]; p < .00001; I2 = 39%). Improved IIEF was also reported with PDE-5i + VED at 12 months. There is a paucity of articles in the literature that specifically assess efficacy of ED treatments after rectal surgery. Many alternative treatment strategies to PDE-5is remain to be investigated. Future studies should implement standardized preoperative, postoperative, and follow-up sexual function assessment in patients undergoing rectal resections.

MicroRNA-1281 as a Novel Circulating Biomarker in Patients With Diabetic Retinopathy.

Objective: Recently, the role of circulating miRNAs as non-invasive biomarkers for the identification and monitoring of diabetes microvascular complications has emerged. Herein, we aimed to: identify circulating miRNAs differentially expressed in patients with and without diabetic retinopathy (DR); examine their predictive value; and understand their pathogenic impact. Methods: Pooled serum samples from randomly selected matched patients with type 2 diabetes, either with or without DR, were used for initial serum miRNA profiling. Validation of the most relevant miRNAs was thereafter conducted by RT-qPCR in an extended sample of patients with DR and matched controls. Results: Following miRNA profiling, 43 miRNAs were significantly up- or down-regulated in patients with DR compared with controls. After individual validation, 5 miRNAs were found significantly overexpressed in patients with DR. One of them, miR-1281, was the most up-regulated and appeared to be specifically related to DR. Furthermore, secreted levels of miR-1281 were increased in high glucose-cultured retinal cells, and there was evidence of a potential link between glucose-induced miR-1281 up-regulation and DR. Conclusion: Our findings suggest miR-1281 as a circulating biomarker of DR. Also, they highlight the pathogenic significance of miR-1281, providing insights for a new potential target in treating DR.

Obesity-related hypoxia via miR-128 decreases insulin-receptor expression in human and mouse adipose tissue promoting systemic insulin resistance.

BACKGROUND: Insulin resistance in visceral adipose tissue (VAT), skeletal muscle and liver is a prominent feature of most patients with obesity. How this association arises remains poorly understood. The objective of this study was to demonstrate that the decrease in insulin receptor (INSR) expression and insulin signaling in VAT from obese individuals is an early molecular manifestation that might play a crucial role in the cascade of events leading to systemic insulin resistance. METHODS: To clarify the role of INSR and insulin signaling in adipose tissue dysfunction in obesity, we first measured INSR expression in VAT samples from normal-weight subjects and patients with different degrees of obesity. We complemented these studies with experiments on high-fat diet (HFD)-induced obese mice, and in human and murine adipocyte cultures, in both normoxic and hypoxic conditions. FINDINGS: An inverse correlation was observed between increasing body mass index and decreasing INSR expression in VAT of obese humans. Our results indicate that VAT-specific downregulation of INSR is an early event in obesity-related adipose cell dysfunction, which increases systemic insulin resistance in both obese humans and mice. We also provide evidence that obesity-related hypoxia in VAT plays a determinant role in this scenario by decreasing INSR mRNA stability. This decreased stability is through the activation of a miRNA (miR-128) that downregulates INSR expression in adipocytes. INTERPRETATION: We present a novel pathogenic mechanism of reduced INSR expression and insulin signaling in adipocytes. Our data provide a new explanation linking obesity with systemic insulin resistance. FUNDING: This work was partly supported by a grant from Nutramed (PON 03PE000_78_1) and by the European Commission (FESR FSE 2014-2020 and Regione Calabria).

Robotic Versus Laparoscopic Partial Mesorectal Excision for Cancer of the High Rectum: A Single-Center Study with Propensity Score Matching Analysis.

BACKGROUND: The role of robotic surgery for partial mesorectal excision (PME) in patients with high rectal cancer (RC) remains unexplored. This study aimed to compare the operative and postoperative outcomes of robotic (R-PME) versus laparoscopic (L-PME) PME for high RC. METHODS: This was a single-center propensity score cohort study of consecutive patients diagnosed with RC in the high rectum (>10 to 15 cm from the anal verge) who underwent surgery between September 2012 and May 2019. RESULTS: Of 131 selected patients (50 R-PME and 81 L-PME), 88 were matched using propensity score (44 per group). Operative and postoperative variables were similar between R-PME and L-PME patients, except for operative time (220 min and 190 min, respectively; p < 0.0001). No conversion was needed. Overall morbidity was 15.9%; 4 patients (4.5%) developed anastomotic leakage. The mean hospital stay was 7.25 days for R-PME vs. 7.64 days for L-PME (p = 0.597). R0 resection was achieved in 100% of R-PME and 90.9% of L-PME (p = 0.116). Only 3 patients (1 R-PME, 2 L-PME) received a permanent stoma (p = 1). No group differences were observed for overall or disease-free survival rates at 5 years. The costs of R-PME were significantly higher than those of L-PME. CONCLUSION: Minimally invasive surgery can be performed safely for PME in high RC. No difference can be detected between R-PME and L-PME for both short- and long-term outcomes, leaving the choice of the surgical approach to the surgeon's experience. Specific health economic studies are needed to evaluate the cost-effectiveness of robotic surgery for RC.