MRI-detected extramural vascular invasion (mrEMVI) as the best predictive factor to identify candidates to total neoadjuvant therapy in locally advanced rectal cancer.

BACKGROUND AND OBJECTIVES: Chemotherapy in locally advanced rectal cancer (LARC) is shifting from an adjuvant setting to a total neoadjuvant therapy (TNT) strategy, that relies on distant metastases (DM) risk prediction. This study aims to assess the accuracy of magnetic resonance imaging-detected extramural vascular invasion (mrEMVI) as predictive factor for DM in LARC, compared with other MRI-detected and pathologic factors. METHODS: This retrospective single-center study analyzed data extracted from a series of consecutive patients curatively resected for rectal cancer at Mauriziano Hospital in Turin (Italy) from January 2013 to December 2018. RESULTS: Data from 69 patients were analyzed. MrEMVI was detected in 31 (44.9%) cases. Median follow-up was 39.9 months. DM and local recurrence occurred in 19 (27.5%) and 4 (5.8%) patients. One- and 3-year cumulative incidence of DM were 32.3% (95% confidence interval [CI]: 0.17-0.49) and 56.8% (95% CI: 0.35-0.74) in the mrEMVI-positive group and 5.4% (95% CI: 0.01-0.16) and 14.0% (95% CI: 0.05-0.27) in the mrEMVI-negative group (log-rank test, p < 0.001). In the multivariate analysis of MRI factors, mrEMVI was the only independent predictor of DM (HR: 3.59, CI: 1.21-10.69, p = 0.02). CONCLUSIONS: This study confirmed that mrEMVI is a powerful predictor of DM in LARC. It should be routinely reported and considered during multidisciplinary care strategy planning.

A close adherence to a stoma-therapeutic pathway improves immediate stoma-related outcomes and reduces the length of hospital stay.

PURPOSE: New stoma creation is related to a wide range of implications and stoma-related complications could occur frequently. The aim was to assess the impact of a close stoma-therapeutic-care pathway (STCP) in terms of length of stay, autonomy in the management of the pouch, readmission rate, and stoma-related complications. METHODS: Patients undergoing surgery for colorectal disease and first stoma creation from January 2017 to December 2020 were analyzed. All patients enrolled had joined the Enhanced Recovery after Surgery (ERAS) protocol. RESULTS: Among 143 enrolled, 56 (40%) did not completely follow the STCP (group A), whereas 87 (60%) demonstrated strict compliance (group B). The hospital stay lasted 8 days in group B and 11.5 in group A (p = 0.001). The first look at the stoma needed 1 day in group B and 3 days in group A (p < 0.001), emptying the pouch 2 days in group B and 5 days in group A (p < 0.001). Finally, the ability to change the pouch was 3 days in group B and 6 days in group A (p < 0.001). Nine (16.1%) stoma-related complications were counted in group A and 16 (18.4%) in group B, and 30-day readmission was 10.1% in group B and 11.5% in group A (p = 0.82 and p = 1, respectively, not significant). CONCLUSIONS: The STCP has been shown to reduce the hospital stay and to have a protective role making the patient autonomous in the management of the stoma.

Negativization of viremia prior to liver transplant reduces early allograft dysfunction in hepatitis C-positive recipients.

Although early allograft dysfunction (EAD) negatively impacts survival from the first months following liver transplantation (LT), direct-acting antiviral agents (DAAs) have revolutionized hepatitis C virus (HCV) therapy. We investigated the EAD definition best predicting 90-day graft loss and identified EAD risk factors in HCV-positive recipients. From November 2002 to June 2016, 603 HCV-positive patients (hepatocellular carcinoma, 53.4%) underwent a first LT with HCV-negative donors. The median recipient Model for End-Stage Liver Disease (MELD) score was 15, and the median donor age was 63 years. At LT, 77 (12.8%) patients were HCV RNA negative; negativization was achieved and maintained by pre-LT antiviral therapy (61 patients) or pre-LT plus a pre-emptive post-LT course (16 patients); 60 (77.9%) patients received DAAs and 17 (22.1%) interferon. We compared 3 different EAD definitions: (1) bilirubin ≥ 10 mg/dL or international normalized ratio ≥ 1.6 on day 7 after LT or aspartate aminotransferase or alanine aminotransferase > 2000 IU/L within 7 days of LT; (2) bilirubin > 10 mg/dL on days 2-7 after LT; and (3) MELD ≥ 19 on day 5 after LT. EAD defined by MELD ≥ 19 on day 5 after LT had the lowest negative (0.1) and the highest positive (1.9) likelihood ratio to predict 90-day graft loss. At 90 days after LT, 9.2% of recipients with EAD lost their graft as opposed to 0.7% of those without EAD (P < 0.001). At multivariate analysis, considering variables available at LT, MELD at LT of >25 (OR = 7.4) or 15-25 (OR = 3.2), graft macrovesicular steatosis ≥ 30% (OR = 6.7), HCV RNA positive at LT (OR = 2.7), donor age > 70 years (OR = 2.0), earlier LT era (OR = 1.8), and cold ischemia time ≥ 8 hours (OR = 1.8) were significant risk factors for EAD. In conclusion, in HCV-positive patients, MELD ≥ 19 on day 5 after LT best predicts 90-day graft loss. Preventing graft infection by pre-/peri-LT antiviral therapy reduces EAD incidence and could be most beneficial in high-MELD patients and recipients of suboptimal grafts. Liver Transplantation 23 915-924 2017 AASLD.

Laparoscopic right colectomy reduces short-term mortality and morbidity. Results of a systematic review and meta-analysis.

PURPOSE: While definitive long-term results are not yet available, the global safety and oncologic adequacy of laparoscopic surgery for right colectomy remain controversial. The aim of the study was to evaluate differences in safety of laparoscopic right colectomy, compared with open surgery, with particular attention to cancer patients. METHODS: A systematic review from 1991 to 2014 was performed searching the MEDLINE and EMBASE databases (PROSPERO Registration number: CRD42014015256). We included randomised and controlled clinical studies comparing laparoscopic and open resection for rectal cancer. Primary endpoints were 30 days mortality and overall morbidity. Then, a meta-analysis was conducted by a fixed-effect model, performing a sensitivity analysis by a random-effect model. Relative risk (RR) was used as an indicator of treatment effect; a RR less than 1.0 was in favour of laparoscopy. Publication bias was assessed by funnel plot, heterogeneity by the I (2) test and subgroup analysis on oncologic patients. RESULTS: Twenty-seven studies, representing 3049 patients, met the inclusion criteria; only 2 were randomised for a total of 211 patients. Mortality was observed in 1.2 % of patients in the laparoscopic group and in 3.4 % of patients in the open group. The overall RR was 0.45 (95 % CI 0.21-0.93, p = 0.031). The raw incidence of overall complications was significantly lower in the laparoscopic group (16.8 %) compared to the open group (24.2 %). The overall RR was 0.81 (95 % CI 0.70-0.95, p = 0.007). CONCLUSIONS: Based on the evidence of few randomised and mostly controlled series, mortality and morbidity were significantly lower after laparoscopy compared to open surgery.

Ulcerative enteritis. How the extension of ulcerative colitis to small bowel may jeopardize postcolectomy course: a case report and literature review.

Intestinal involvement in ulcerative colitis is generally limited to the colon and rectum. We describe a life-threatening case of ulcerative enteritis occurring after colectomy. Other 53 similar cases are reported in the literature. The aim of this narrative review was to focus on ulcerative enteritis characteristics and diagnostic workup. A 25-year-old boy affected by ulcerative colitis underwent a total colectomy in an urgent setting for septic shock. Postoperative course was characterized by elevated ileostomy output, raised up to 10 L/day. Critical clinical conditions required resuscitation therapy. After exclusion of surgical complications, intestinal infections, and histologic specimen revision, the patient underwent endoscopic examination. Ileal biopsies revealed ileal localization of ulcerative colitis. Steroid treatment was finally effective. After literature revision, we classified all cases of ulcerative enteritis in three groups, according to intestinal involvement pattern and timing of clinical manifestation after operation. Out of 54 cases, 18 occurred within 1 month since colectomy (early ileitis), 10 later on (late ileitis) and 26 do not involve ileus (nonileitis). Clinical manifestation is generally severe in the first group and mild and chronic in the others. Differential diagnoses of ulcerative enteritis are represented by infectious, immunological, toxic, and ischemic disorders. Those conditions excluded, ulcerative enteritis can be easily detected by endoscopic biopsies and treated with immunosuppressive agents. Long term surveillance seems important since recurrences are described. In conclusion, clinicians should suspect ulcerative enteritis in all patients with previous colectomy history that develop unexplained gastrointestinal syndromes, in order to avoid therapeutic delay.

A novel patient-centered protocol to reduce hospital readmissions for dehydration after ileostomy.

Early hospital readmission for dehydration represents a relevant problem among patients with diverting or terminal ileostomy. The aim of the study was to evaluate the efficacy of a new multidisciplinary individualized multistep protocol in terms of reduction of hospital readmission for dehydration. Since January 2016, our institution adopted a new protocol for patients with ileostomy. Protocol key points were: preoperative personalized education in stoma management; early recognition of dehydration symptoms; multidisciplinary counseling; patient autonomy in stoma management through post-operative recall schedule. The study compared a series of consecutive patients treated before (2014-2015) and after (2016-2017) the protocol application. The primary endpoint was hospital readmission rate after protocol use. The secondary endpoint was the identification of possible risk factors for readmission. The entire cohort was composed of 296 patients, 129 in the protocol group and 167 in the control one. The two groups were homogeneous for baseline characteristics. Hospital readmission rate within 30 days post-discharge for dehydration dropped from 9 to 3.9% after protocol application. Specifically, the number of avoided potential readmissions was 29/129 (22.4%). The number needed to treat (NNT) was 20. Univariate analysis identified three relevant variables: patient comorbidities, diuretics use as risk factors and protocol application as the protective one. The multivariate analysis confirmed patient comorbidity as the risk factor. Dehydration related to ileostomy is a potentially avoidable problem, by employing preventive strategies, especially in high-risk patients. Our new protocol could be a simple and cost-saving method, effective in preventing hospital readmissions.

Hypothermic Oxygenated Machine Perfusion for Liver Transplantation: An Initial Experience.

OBJECTIVES: Due to widespread exploitation of extended criteria donors, machine perfusion is emerging as an alternative to static cold storage for organ preservation. Hypothermic oxygenated machine perfusion has been associated with improved outcomes after liver transplant, both in laboratory and clinical settings. Here, we present our initial experience with hypothermic oxygenated machine perfusion, evaluating incidence of postreperfusion syndrome, early allograft dysfunction, and long-term biliary complications. MATERIALS AND METHODS: End-ischemic dual (hepatic artery and portal vein) hypothermic oxygenated machine perfusion was carried out for 150 to 200 minutes before organ implantation in 4 liver transplants considered at increased risk due to donor, recipient, or matching issues. RESULTS: No device malfunction occurred. Theatre logistics were minimally affected. Incidences of post-reperfusion syndrome and early allograft dysfunction were 25% and 50%. At 6-month follow-up, all patients were alive with normal hepatic function and no evidence of ischemic cholangiopathy. CONCLUSIONS: In our experience, hypothermic oxygenated machine perfusion appeared safe and logistically simple. Further studies are needed to assess the real value of this technique and to identify which subset of patients would benefit from its implementation.

Identification and Validation of the Predictive Capacity of Risk Factors and Models in Liver Transplantation Over Time.

BACKGROUND: Outcome after liver transplantation (LT) is determined by donor, transplant and recipient risk factors. These factors may have different impact on either patient or graft survival (outcome type). In the literature, there is wide variation in the use of outcome types and points in time (short term or long term). Objective of this study is to analyze the predictive capacity of risk factors and risk models in LT and how they vary over time and per outcome type. METHODS: All LTs performed in the Netherlands from January 1, 2002, to December 31, 2011, were analyzed with multivariate analyses at 3-month, 1-year, and 5-year for patient and (non-)death-censored graft survival. The predictive capacity of the investigated risk models was compared with concordance indices. RESULTS: Recipient age, model for end-stage liver disease sodium, ventilatory support, diabetes mellitus, hepatocellular carcinoma, previous malignancy, hepatitis C virus antibody, hepatitis B virus antibody, perfusion fluid, and Eurotransplant donor risk index (ET-DRI) had significant impact on outcome (graft or patient survival) at 1 or multiple points in time. Significant factors at 3-month patient survival (recipient age, model for end-stage liver disease sodium, ventilatory support) were used to compose a concept model. This model, had a higher c-index than the balance-of-risk score, DRI, ET-DRI, donor-recipient model and simplified recipient risk index for long-term patient and non-death-censored graft survival. CONCLUSIONS: In this study, the effects of recipient risk factors and models on different outcome types and time points were shown. Short-term patient survival mainly depends on recipient risk factors, long-term graft survival on donor risk factors and is more difficult to predict. Next to the concept model, the donor-recipient model has a higher predictive capacity to other risk models for (long-term) patient and non-death-censored graft survival. The DRI and ET-DRI best predicted death-censored graft survival. Knowledge about risk factors and models is critical when using these for waitlist management and/or help in organ allocation and decision-making.

Extracellular Vesicles from Human Liver Stem Cells Reduce Injury in an Ex Vivo Normothermic Hypoxic Rat Liver Perfusion Model.

BACKGROUND: The gold standard for organ preservation before transplantation is static cold storage, which is unable to fully protect suboptimal livers from ischemia/reperfusion injury. An emerging alternative is normothermic machine perfusion (NMP), which permits organ reconditioning. Here, we aimed to explore the feasibility of a pharmacological intervention on isolated rat livers by using a combination of NMP and human liver stem cells-derived extracellular vesicles (HLSC-EV). METHODS: We established an ex vivo murine model of NMP capable to maintain liver function despite an ongoing hypoxic injury induced by hemodilution. Livers were perfused for 4 hours without (control group, n = 10) or with HLSC-EV (treated group, n = 9). Bile production was quantified; perfusate samples were collected hourly to measure metabolic (pH, pO2, pCO2) and cytolysis parameters (AST, alanine aminotransferase, lactate dehydrogenase). At the end of perfusion, we assessed HLSC-EV engraftment by immunofluorescence, tissue injury by histology, apoptosis by terminal deoxynucleotidyl transferase dUTP nick-end labeling assay, tissue hypoxia-inducible factor 1-α, and transforming growth factor-beta 1 RNA expression by quantitative reverse transcription-polymerase chain reaction. RESULTS: During hypoxic NMP, livers were able to maintain homeostasis and produce bile. In the treated group, AST (P = 0.018) and lactate dehydrogenase (P = 0.032) levels were significantly lower than those of the control group at 3 hours of perfusion, and AST levels persisted lower at 4 hours (P = 0.003). By the end of NMP, HLSC-EV had been uptaken by hepatocytes, and EV treatment significantly reduced histological damage (P = 0.030), apoptosis (P = 0.049), and RNA overexpression of hypoxia-inducible factor 1-α (P < 0.0001) and transforming growth factor-beta 1 (P = 0.014). CONCLUSIONS: HLSC-EV treatment, even in a short-duration model, was feasible and effectively reduced liver injury during hypoxic NMP.

A rare case of IgG4-related systemic disease manifesting with pancreatic head mass mimicking borderline resectable cancer.

INTRODUCTION: Autoimmune pancreatitis (AIP) is a rare pancreatic disorder among chronic pancreatitis that can mimick pancreatic cancer (PC). Patients with type 1 AIP usually present obstructive jaundice associated with high level of IgG4 in serum and a pancreatic mass at radiological imaging; these disorders may be associated with other organs lesions presenting the same histopathological features, and in these cases AIP should be considered a pancreatic localization of an IgG4-related systemic disease. PRESENTATION OF CASE: We report the case of a young man with initial suspect of PC to be treated with surgery, and final diagnosis of AIP in the context of an IgG4-related systemic disease. DISCUSSION: Because of its similar features, several algorithms have been proposed for AIP diagnosis, based on combination of clinical/serological and radiological criteria. However, histology represents the only way to obtain definitive diagnosis, even if sometimes it is difficult to obtain biological samples. CONCLUSION: IgG4-related systemic disease must be taken into account among differential diagnosis during the workup for PC, in order to avoid unnecessary surgery.

Genetic and expression analysis of MET, MACC1, and HGF in metastatic colorectal cancer: response to met inhibition in patient xenografts and pathologic correlations.

PURPOSE: We determined the gene copy numbers for MET, for its transcriptional activator MACC1 and for its ligand hepatocyte growth factor (HGF) in liver metastases from colorectal carcinoma (mCRC). We correlated copy numbers with mRNA levels and explored whether gain and/or overexpression of MET and MACC1 predict response to anti-Met therapies. Finally, we assessed whether their genomic or transcriptional deregulation correlates with pathologic and molecular parameters of aggressive disease. EXPERIMENTAL DESIGN: One hundred three mCRCs were analyzed. Copy numbers and mRNA were determined by quantitative PCR (qPCR). Thirty nine samples were implanted and expanded in NOD (nonobese diabetic)/SCID (severe combined immunodeficient) mice to generate cohorts that were treated with the Met inhibitor JNJ-38877605. In silico analysis of MACC1 targets relied on genome-wide mapping of promoter regions and on expression data from two CRC datasets. RESULTS: No focal, high-grade amplifications of MET, MACC1, or HGF were detected. Chromosome 7 polysomy and gain of the p-arm were observed in 21% and 8% of cases, respectively, and significantly correlated with higher expression of both Met and MACC1. Met inhibition in patient-derived xenografts did not modify tumor growth. Copy number gain and overexpression of MACC1 correlated with unfavorable pathologic features better than overexpression of Met. Bioinformatic analysis of putative MACC1 targets identified elements besides Met, whose overexpression cosegregated with aggressive forms of colorectal cancer. CONCLUSIONS: Experiments in patient-derived xenografts suggest that mCRCs do not rely on Met genomic gain and/or overexpression for growth. On the basis of pathologic correlations and bioinformatic analysis, MACC1 could contribute to CRC progression through mechanisms other than or additional to Met transcriptional upregulation.