Renin-Angiotensin Inhibitor, Captopril, Attenuates Growth of Patient-Derived Colorectal Liver Metastasis Organoids.

The recurrence of colorectal liver metastasis (CRLM) following liver resection is common; approximately 40% of patients will experience tumor recurrence post-surgery. Renin-angiotensin inhibitors (RASis) have been shown to attenuate the growth and progression of CRLM in pre-clinical models following liver resection. This study examined the efficacy of the RASi captopril on patient-derived colorectal liver metastasis organoids. Patient-derived organoids (PDOs) were established using fresh samples of colorectal liver metastasis from appropriately consented patients undergoing liver resection. To mimic the regenerating liver post-CRLM liver resection, PDOs were cultured under hepatocyte regeneration conditions in vitro. CRLM PDOs were established from three patients' parent tissue. CRLM PDOs and parent tissue expressed markers of colorectal cancer, CDX2 and CK20, consistently. Furthermore, CRLM PDOs treated with captopril showed a dose dependent reduction in their expansion in vitro. In conclusion, CRLM PDOs recapitulate in vivo disease and displayed a dose-dependent response to treatment with captopril. RASis may be an additional viable treatment for patients with CRLM.

Assessment of Pre-Clinical Liver Models Based on Their Ability to Predict the Liver-Tropism of Adeno-Associated Virus Vectors.

The liver is a prime target for in vivo gene therapies using recombinant adeno-associated viral vectors. Multiple clinical trials have been undertaken for this target in the past 15 years; however, we are still to see market approval of the first liver-targeted adeno-associated virus (AAV)-based gene therapy. Inefficient expression of the therapeutic transgene, vector-induced liver toxicity and capsid, and/or transgene-mediated immune responses reported at high vector doses are the main challenges to date. One of the contributing factors to the insufficient clinical outcomes, despite highly encouraging preclinical data, is the lack of robust, biologically and clinically predictive preclinical models. To this end, this study reports findings of a functional evaluation of 6 AAV vectors in 12 preclinical models of the human liver, with the aim to uncover which combination of models is the most relevant for the identification of AAV capsid variant for safe and efficient transgene delivery to primary human hepatocytes. The results, generated by studies in models ranging from immortalized cells, iPSC-derived and primary hepatocytes, and primary human hepatic organoids to in vivo models, increased our understanding of the strengths and weaknesses of each system. This should allow the development of novel gene therapies targeting the human liver.

Prophylactic negative pressure wound dressings reduces wound complications following emergency laparotomies: A systematic review and meta-analysis.

BACKGROUND: Wound complications are a common cause of postoperative morbidity and incur significant healthcare costs. Recent studies have shown that negative pressure wound dressings reduce wound complication rates, particularly surgical site infections, after elective laparotomies. The clinical utility of prophylactic negative pressure wound dressings for closed emergency laparotomy incisions remains controversial. This meta-analysis investigated the rates of wound complications after emergency laparotomy when a negative pressure wound dressing was applied. METHODS: A systematic review and meta-analysis were performed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. PubMed, Embase, Cochrane Registry, Web of Science, and Clinialtrials.gov databases were searched from January 1, 2005, to April 1, 2022. All studies comparing negative pressure wound dressings to standard dressings on closed emergency laparotomy incisions were included. RESULTS: A total of 1,199 (negative pressure wound dressings: 566, standard dressing: 633) patients from 7 (prospective: 4, retrospective: 3) studies were identified. Overall, the surgical site infection (superficial/deep) rate was 13.6% (77/566) vs 25.1% (159/633) in the negative pressure wound dressing versus standard dressing groups, respectively (odds ratio 0.43, 95% confidence interval 0.30-0.62). Wound breakdown (skin/fascial dehiscence) was significantly lower in the negative pressure wound dressing (7.7%) group compared to the standard dressing (16.9%) group (odds ratio 0.36, 95% confidence interval 0.19-0.72). The incidence of overall wound complications was significantly lower in the negative pressure wound dressing (15.9%) group compared to the standard dressing (30.4%) group (odds ratio 0.41, 95% confidence interval 0.28-0.59). No significant differences were found in hospital length-of-stay and readmission rates. CONCLUSION: Prophylactic negative pressure wound dressings for closed emergency laparotomy incisions were associated with a significant reduction in surgical site infections, wound breakdown, and overall wound complications, thus supporting its clinical use.

Captopril, a Renin-Angiotensin System Inhibitor, Attenuates Tumour Progression in the Regenerating Liver Following Partial Hepatectomy.

(1) Liver regeneration following partial hepatectomy for colorectal liver metastasis (CRLM) has been linked to tumour recurrence. Inhibition of the renin−angiotensin system (RASi) attenuates CRLM growth in the non-regenerating liver. This study investigates whether RASi exerts an antitumour effect within the regenerating liver following partial hepatectomy for CRLM and examines RASi-induced changes in the tumour immune microenvironment; (2) CRLM in mice was induced via intrasplenic injection of mouse colorectal tumour cells, followed by splenectomy on Day 0. Mice were treated with RASi captopril (250 mg/kg/day), or saline (control) from Day 4 to Day 16 (endpoint) and underwent 70% partial hepatectomy on Day 7. Liver and tumour samples were characterised by flow cytometry and immunofluorescence; (3) captopril treatment reduced tumour burden in mice following partial hepatectomy (p < 0.01). Captopril treatment reduced populations of myeloid-derived suppressor cells (MDSCs) (CD11b+Ly6CHi p < 0.05, CD11b+Ly6CLo p < 0.01) and increased PD-1 expression on infiltrating hepatic tissue-resident memory (TRM)-like CD8+ (p < 0.001) and double-negative (CD4-CD8-; p < 0.001) T cells; (4) RASi reduced CRLM growth in the regenerating liver and altered immune cell composition by reducing populations of immunosuppressive MDSCs and boosting populations of PD-1+ hepatic TRMs. Thus, RASi should be explored as an adjunct therapy for patients undergoing partial hepatectomy for CRLM.

Captopril, a Renin-Angiotensin System Inhibitor, Attenuates Features of Tumor Invasion and Down-Regulates C-Myc Expression in a Mouse Model of Colorectal Cancer Liver Metastasis.

(1) Background: Recent clinical and experimental data suggests that the liver's regenerative response following partial hepatectomy can stimulate tumor recurrence in the liver remnant. The Wnt/ß-catenin pathway plays important roles in both colorectal cancer carcinogenesis and liver regeneration. Studies have shown that the Wnt/ß-catenin pathway regulates multiple renin-angiotensin system (RAS) genes, whilst RAS inhibition (RASi) reduces tumor burden and progression. This study explores whether RASi attenuates features of tumor progression in the regenerating liver post-hepatectomy by modulating Wnt/ß-catenin signaling. (2) Methods: Male CBA mice underwent CRLM induction, followed one week later by 70% partial hepatectomy. Mice were treated daily with captopril, a RASi, at 250 mg/kg/day or vehicle control from experimental Day 4. Tumor and liver samples were analyzed for RAS and Wnt signaling markers using qRT-PCR and immunohistochemistry. (3) Results: Treatment with captopril reduced the expression of down-stream Wnt target genes, including a significant reduction in both c-myc and cyclin-D1, despite activating Wnt signaling. This was a tumor-specific response that was not elicited in corresponding liver samples. (4) Conclusions: We report for the first time decreased c-myc expression in colorectal tumors following RASi treatment in vivo. Decreased c-myc expression was accompanied by an attenuated invasive phenotype, despite increased Wnt signaling.

Liver regeneration and liver metastasis.

Surgical resection for primary and secondary hepatic neoplasms provides the best chance of cure. Advanced surgical techniques such as portal vein embolisation, two-staged hepatectomy and associated liver partition and portal vein ligation for staged-hepatectomy (ALPPS) have facilitated hepatic resection in patients with previously unresectable, bi-lobar disease. These techniques are frequently employed to ensure favourable clinical outcomes and avoid potentially fatal post-operative complications such as small for size syndrome and post-hepatectomy liver failure. However, they rely on the innate ability of the liver to regenerate. As our knowledge of liver organogenesis, liver regeneration and hepatocarcinogenesis has expanded in recent decades it has come to light that liver regeneration may also drive tumour recurrence. Clinical studies in patients undergoing portal vein embolisation indicate that tumours may progress following the procedure in concordance with liver regeneration and hypertrophy, however overall survival in these patients has not been shown to be worse. In this article, we delve into the mechanisms underlying liver regeneration to better understand the complex ways in which this may affect tumour behaviour and ultimately inform clinical decisions.

A systematic review of small for size syndrome after major hepatectomy and liver transplantation.

BACKGROUND: Major hepatectomy (MH) and particular types of liver transplantation (LT) (reduced size graft, living-donor and split-liver transplantation) lead to a reduction in liver mass. As the portal venous return remains the same it results in a reciprocal and proportionate rise in portal venous pressure potentially resulting in small for size syndrome (SFSS). The aim of this study was to review the incidence, diagnosis and management of SFSS amongst recipients of LT and MH. METHODS: A systematic review was performed in accordance with the 2010 Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines. The following terms were used to search PubMed, Embase and Cochrane Library in July 2019: ("major hepatectomy" or "liver resection" or "liver transplantation") AND ("small for size syndrome" or "post hepatectomy liver failure"). The primary outcome was a diagnosis of SFSS. RESULTS: Twenty-four articles met the inclusion criteria and could be included in this review. In total 2728 patients were included of whom 316 (12%) patients met criteria for SFSS or post hepatectomy liver failure (PHLF). Of these, 31 (10%) fulfilled criteria for PHLF following MH. 8 of these patients developed intractable ascites alongside elevated portal venous pressure following MH indicative of SFSS. CONCLUSION: SFSS is under-recognised following major hepatectomy and should be considered as an underlying cause of PHLF. Surgical and pharmacological therapies are available to reduce portal congestion and reverse SFSS.

Searching for the link; mechanisms underlying liver regeneration and recurrence of colorectal liver metastasis post partial hepatectomy.

Despite excellent treatment of primary colorectal cancer, the majority of deaths occur as a result of metastasis to the liver. Recent population studies have estimated that one quarter of patients with colorectal cancer will incur synchronous or metachronous colorectal liver metastasis. However, only one quarter of these patients will be eligible for potentially curative resection. Tumor recurrence occurs in reportedly 60% of patients undergoing hepatic resection, and the majority of intrahepatic recurrence occurs within the first 6 months of surgery. The livers innate ability to restore its homeostatic size, and volume facilitates major hepatic resection that currently offers the only chance of cure to patients with extensive hepatic metastases. Experimental and clinical evidence supports the notion that following partial hepatectomy, liver regeneration (LR) paradoxically drives tumor progression and increases the risk of recurrence. It is becoming increasingly clear that the processes that drive liver organogenesis, regeneration, and tumor progression are inextricably linked. This presents a major hurdle in the management of colorectal liver metastasis and other hepatic malignancies because therapies that reduce the risk of recurrence without hampering LR are sought. The processes and pathways underlying these phenomena are multiple, complex, and cross-communicate. In this review, we will summarize the common mechanisms contributing to both LR and tumor recurrence.

Laparoscopic treatment of a patent ductus venosus and the use of indocyanine green to monitor perioperative hepatic function.

Patent ductus venosus (PDV) is an uncommon but important congenital portocaval shunt that can lead to numerous complications if untreated. This case describes the successful management of a 17-year-old male with symptomatic PDV. Doppler ultrasonography and contrast-enhanced computed tomography (CT) confirmed a large communication between the left portal vein and the inferior vena cava. Angiography demonstrated a large and high flow PDV which precluded its therapeutic embolization. Based on these findings, laparoscopic closure of the PDV was elected and successfully performed. Perioperative indocyanine green (ICG) clearance was performed and marked improvement was observed following the occlusion of the PDV. The patient showed immediate resolution of symptoms post-operatively and remains asymptomatic 2 years after his surgery. Laparoscopic approach to the management of PDV is feasible. ICG clearance, for the first time, was demonstrated in this setting to be a useful and rapid bedside test for the real-time assessment of liver function.

Gastric adenocarinoma of the upper oesophagus: A literature review and case report.

BACKGROUND: Ectopic gastric mucosa (EGM) otherwise termed gastric heterotopia or gastric inlet patch occurs in approximately 2.5% of the population. Adenocarcinoma uncommonly involves the upper oesophagus, rarely arising from gastric heterotopia or submucosal glands. Currently, there are 58 cases in the literature of oesophageal adenocarcinoma arising within areas of EGM. To date no paper has differentiated between gastric or intestinal type adenocarcinoma. This case, which describes adenocarcinoma arising within EGM, exhibited a different immunophenotype reminiscent of gastric type glands, in the absence of intestinal metaplasia. This case should be regarded as a different type of carcinoma, consistent with a non-Barrett's oesophagus-associated adenocarcinoma. CLINICAL PRESENTATION: A 63year old female presented with a three month history of progressive cervical dysphagia with no associated weight loss or general malaise. Gastroscopy revealed a suspicious lesion at the cricopharyngeus. Positron emission tomography demonstrated a metabolically active primary lesion without evidence of distant disease. The patient received neo-adjuvant chemotherapy followed by a three stage total oesophagectomy. Histology demonstrated a moderately differentiated adenocarcinoma with gastric immunophenotype and background changes of gastric heterotopia. CONCLUSION: EGM is common but scarcely biopsied for evidence of dysplasia or adenocarcinoma. Whilst malignant progression is rare it is important that endoscopists are aware of the potential. Determining the exact type of adenocarcinoma may have implications for therapeutic approaches. Recognition of EGM at endoscopy may identify patients at greater risk of developing adenocarcinomas of the proximal oesophagus, however, this relationship and the necessity for screening requires more study.

Acute appendicitis with unusual dual pathology.

INTRODUCTION: Meckel's diverticulum is a rare congenital abnormality arising due to the persistence of the vitelline duct in 1-3% of the population. Clinical presentation is varied and includes rectal bleeding, intestinal obstruction, diverticulitis and ulceration; therefore diagnosis can be difficult. PRESENTATION OF CASE: We report a case of acute appendicitis complicated by persistent post operative small bowel obstruction. Further surgical examination of the bowel revealed an non-inflamed, inverted Meckel's diverticulum causing intussusception. DISCUSSION: Intestinal obstruction in patients with Meckel's diverticulum may be caused by volvulus, intussusception or incarceration of the diverticulum into a hernia. Obstruction secondary to intussusception is relatively uncommon and frequently leads to a confusing and complicated clinical picture. CONCLUSION: Consideration of Meckel's diverticulum although a rare diagnosis is imperative and this case raises the question "should surgeons routinely examine the bowel for Meckel's diverticulum at laparoscopy?"