Laparoscopic versus open adhesiolysis for adhesive small bowel obstruction (LASSO): an international, multicentre, randomised, open-label trial.

BACKGROUND: Although laparoscopic adhesiolysis for adhesive small bowel obstruction is being done more frequently, it is not widely accepted due to the lack of supporting evidence of its superiority over an open approach and concerns regarding its benefits. We aimed to investigate whether laparoscopic adhesiolysis was a superior treatment for adhesive small bowel obstruction compared with an open approach in terms of length of postoperative hospital stay and morbidity. METHODS: In this international, multicentre, parallel, open-label trial, we randomly assigned patients (1:1) aged 18-95 years who had adhesive small bowel obstruction that had not resolved with conservative management to have either open or laparoscopic adhesiolysis. The study was done in five academic university hospitals and three community (central) hospitals in two countries (Finland [n=3 academic university hospitals; n=3 community hospitals] and Italy [n=2 academic university hospitals]). We included only patients with high likelihood of a single adhesive band in the trial; additionally, patients who had an anaesthesiological contraindication, were pregnant, living in institutionalised care, or who had a hospital stay of more than 1 week before the surgical consultation were excluded from the trial. The randomisation sequence was generated using block randomisation, with randomly varied block sizes and stratified according to centre. The primary outcome was postoperative length of hospital stay assessed at time of discharge in the modified intention-to-treat population. FINDINGS: Between July 18, 2013, and April 9, 2018, 566 patients were assessed for eligibility, of whom 104 patients were randomly assigned to the open surgery group (n=51) or to the laparoscopy group (n=53). Of these patients, 100 were included in the modified intention-to-treat analyses (49 in the open surgery group; 51 in the laparoscopy group). The postoperative length of hospital stay for open surgery group was on average 1·3 days longer than that in the laparoscopy group (geometric mean 5·5 days [range 2-19] vs 4·2 days [range 1 -20]; ratio of geometric means 1·31 [95% CI 1·06-1·61]; p=0·013). 21 (43%) patients in the open surgery group and 16 (31%) patients in the laparoscopy group had postoperative complications (Clavien-Dindo any grade) within 30 days (odds ratio 0·61 [95% CI 0·27-1·38]; p=0·23). One patient died in each group within 30 days. INTERPRETATION: Laparoscopic adhesiolysis provides quicker recovery in selected patients with adhesive small bowel obstruction than open adhesiolysis. FUNDING: Vatsatautien Tutkimussäätiö Foundation, Mary and Georg Ehrnrooth's Foundation, Martti I Turunen Foundation, and governmental (Finland) competitive research funds (EVO/VTR/TYH).

Laparoscopic versus open adhesiolysis for small bowel obstruction - a multicenter, prospective, randomized, controlled trial.

BACKGROUND: Laparoscopic adhesiolysis is emerging as an alternative for open surgery in adhesive small bowel obstruction. Retrospective studies suggest that laparoscopic approach shortens hospital stay and reduces complications in these patients. However, no prospective, randomized, controlled trials comparing laparoscopy to open surgery have been published. METHODS/DESIGN: This is a multicenter, prospective, open label, randomized, controlled trial comparing laparoscopic adhesiolysis to open surgery in patients with computed-tomography diagnosed adhesive small bowel obstruction that is not resolving with conservative management. The primary study endpoint is the length of postoperative hospital stay in days.Sample size was estimated based on preliminary retrospective cohort, which suggested that 102 patients would provide 80% power to detect a difference of 2.5 days in the length of postoperative hospital stay with significance level of 0.05. Secondary endpoints include passage of stool, commencement of enteral nutrition, 30-day mortality, complications, postoperative pain, and the length of sick leave. Tertiary endpoints consist of the rate of ventral hernia and the recurrence of small bowel obstruction during long-term follow-up. Long-term follow-up by letter or telephone interview will take place at 1, 5, and 10 years. DISCUSSION: To the best of our knowledge, this trial is the first one aiming to provide level Ib evidence to assess the use of laparoscopy in the treatment of adhesive small bowel obstruction. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01867528. Date of registration May 26th 2013.

Preoperative assessment and treatment of appendiceal mucocele complicated by acute torsion: a case report.

BACKGROUND: Mucus-producing tumours of the appendix or mucoceles can, if left untreated, lead to dissemination of its contents into the peritoneal cavity causing substantial morbidity to the patient. Symptoms for complicated mucoceles can mimic those of acute appendicitis and the final diagnosis is most likely made intraoperatively. We here present a case that is, to our knowledge, one of only ten described in the literature and the first to characterize torsion of an appendiceal mucocele with abdominal magnetic resonance imaging. CASE PRESENTATION: The patient, a 34-year-old Caucasian female presented at the emergency department with acute abdominal pain in the right lower quadrant. Initial diagnostic work-up including ultrasonography and abdominal magnetic resonance imaging showed a large tubular mass at the base of the appendix with indirect signs of torsion. A laparoscopic appendectomy was performed the following day where the finding was confirmed. The patient went on to have an uneventful recovery and was discharged from the hospital on the first postoperative day. CONCLUSIONS: Magnetic resonance imaging is a useful tool in identifying unknown lesions of the appendix and should be considered the primary imaging modality in especially younger patients requiring diagnostic imaging. In this case the preoperative imaging findings aided in choosing the correct timing and treatment option for the patient.

Vascular endothelial growth factor-B induces myocardium-specific angiogenesis and arteriogenesis via vascular endothelial growth factor receptor-1- and neuropilin receptor-1-dependent mechanisms.

BACKGROUND: New revascularization therapies are urgently needed for patients with severe coronary heart disease who lack conventional treatment options. METHODS AND RESULTS: We describe a new proangiogenic approach for these no-option patients using adenoviral (Ad) intramyocardial vascular endothelial growth factor (VEGF)-B186 gene transfer, which induces myocardium-specific angiogenesis and arteriogenesis in pigs and rabbits. After acute infarction, AdVEGF-B186 increased blood vessel area, perfusion, ejection fraction, and collateral artery formation and induced changes toward an ischemia-resistant myocardial phenotype. Soluble VEGF receptor-1 and soluble neuropilin receptor-1 reduced the effects of AdVEGF-B186, whereas neither soluble VEGF receptor-2 nor inhibition of nitric oxide production had this result. The effects of AdVEGF-B186 involved activation of neuropilin receptor-1, which is highly expressed in the myocardium, via recruitment of G-protein-alpha interacting protein, terminus C (GIPC) and upregulation of G-protein-alpha interacting protein. AdVEGF-B186 also induced an antiapoptotic gene expression profile in cardiomyocytes and had metabolic effects by inducing expression of fatty acid transport protein-4 and lipid and glycogen accumulation in the myocardium. CONCLUSIONS: VEGF-B186 displayed strikingly distinct effects compared with other VEGFs. These effects may be mediated at least in part via a G-protein signaling pathway. Tissue-specificity, high efficiency in ischemic myocardium, and induction of arteriogenesis and antiapoptotic and metabolic effects make AdVEGF-B186 a promising candidate for the treatment of myocardial ischemia.

Reevaluation of the role of VEGF-B suggests a restricted role in the revascularization of the ischemic myocardium.

OBJECTIVE: The endogenous role of the VEGF family member vascular endothelial growth factor-B (VEGF-B) in pathological angiogenesis remains unclear. METHODS AND RESULTS: We studied the role of VEGF-B in various models of pathological angiogenesis using mice lacking VEGF-B (VEGF-B(-/-)) or overexpressing VEGF-B(167). After occlusion of the left coronary artery, VEGF-B deficiency impaired vessel growth in the ischemic myocardium whereas, in wild-type mice, VEGF-B(167) overexpression enhanced revascularization of the infarct and ischemic border zone. By contrast, VEGF-B deficiency did not affect vessel growth in the wounded skin, hypoxic lung, ischemic retina, or ischemic limb. Moreover, VEGF-B(167) overexpression failed to enhance vascular growth in the skin or ischemic limb. CONCLUSIONS: VEGF-B appears to have a relatively restricted angiogenic activity in the ischemic heart. These insights might offer novel therapeutic opportunities.

The biology of vascular endothelial growth factors.

The discovery of the vascular endothelial growth factor (VEGF) family members VEGF, VEGF-B, placental growth factor (PlGF), VEGF-C and VEGF-D and their receptors VEGFR-1, -2 and -3 has provided tools for studying the vascular system in development as well as in diseases ranging from ischemic heart disease to cancer. VEGF has been established as the prime angiogenic molecule during development, adult physiology and pathology. PlGF may primarily mediate arteriogenesis, the formation of collateral arteries from preexisting arterioles, with potential future therapeutic use in for example occlusive atherosclerotic disease. VEGF-C and VEGF-D are primarily lymphangiogenic factors, but they can also induce angiogenesis in some conditions. While many studies have addressed the role of angiogenesis and the blood vasculature in human physiology, the lymphatic vascular system has until recently attracted very little attention. In this review, we will discuss recent advances in angiogenesis research and provide an overview of the molecular players involved in lymphangiogenesis.

Lymphangiogenic gene therapy with minimal blood vascular side effects.

Recent work from many laboratories has demonstrated that the vascular endothelial growth factor-C/VEGF-D/VEGFR-3 signaling pathway is crucial for lymphangiogenesis, and that mutations of the Vegfr3 gene are associated with hereditary lymphedema. Furthermore, VEGF-C gene transfer to the skin of mice with lymphedema induced a regeneration of the cutaneous lymphatic vessel network. However, as is the case with VEGF, high levels of VEGF-C cause blood vessel growth and leakiness, resulting in tissue edema. To avoid these blood vascular side effects of VEGF-C, we constructed a viral vector for a VEGFR-3-specific mutant form of VEGF-C (VEGF-C156S) for lymphedema gene therapy. We demonstrate that VEGF-C156S potently induces lymphangiogenesis in transgenic mouse embryos, and when applied via viral gene transfer, in normal and lymphedema mice. Importantly, adenoviral VEGF-C156S lacked the blood vascular side effects of VEGF and VEGF-C adenoviruses. In particular, in the lymphedema mice functional cutaneous lymphatic vessels of normal caliber and morphology were detected after long-term expression of VEGF-C156S via an adeno associated virus. These results have important implications for the development of gene therapy for human lymphedema.

Adenoviral VEGF-C overexpression induces blood vessel enlargement, tortuosity, and leakiness but no sprouting angiogenesis in the skin or mucous membranes.

Vascular endothelial growth factors (VEGFs) and their receptors (VEGFRs) are important regulators of blood and lymphatic vessel growth and vascular permeability. The VEGF-C/VEGFR-3 signaling pathway is crucial for lymphangiogenesis, and heterozygous inactivating missense mutations of the VEGFR-3 gene are associated with hereditary lymphedema. However, VEGF-C can have potent effects on blood vessels because its receptor VEGFR-3 is expressed in certain blood vessels and because the fully processed form of VEGF-C also binds to the VEGFR-2 of blood vessels. To characterize the in vivo effects of VEGF-C on blood and lymphatic vessels, we have overexpressed VEGF-C via adenovirus- and adeno-associated virus-mediated transfection in the skin and respiratory tract of athymic nude mice. This resulted in dose-dependent enlargement and tortuosity of veins, which, along with the collecting lymphatic vessels were found to express VEGFR-2. Expression of angiopoietin 1 blocked the increased leakiness of the blood vessels induced by VEGF-C whereas vessel enlargement and lymphangiogenesis were not affected. However, angiogenic sprouting of new blood vessels was not observed in response to AdVEGF-C or AAV-VEGF-C. These results show that virally produced VEGF-C induces blood vessel changes, including vascular leak, but its angiogenic potency is much reduced compared with VEGF in normal skin.

Vascular endothelial growth factor-D expression is an independent prognostic marker for survival in colorectal carcinoma.

The angiogenic factor vascular endothelial growth factor-D (VEGF-D) isa ligand for VEGF receptor-3 (VEGFR-3/Flt-4) and receptor-2 (VEGFR-2/KDR)and is implicated in the development of lymphatic vessels and promotion of lymphatic metastases. We assessed the expression of VEGF-D and VEGFR-3 in relation to microvessel density (MVD) in colorectal carcinomas (CRC), adenomas, and adjacent normal tissue by immunohistochemistry on consecutive archival sections. VEGF-D was detected in malignant and benign epithelium and in some smooth muscle of the colorectum. High-grade VEGF-D expression was observed frequently (74%) in CRC compared with adenomas (0%) and adjacent normal mucosa (22%). High-grade VEGF-D expression was not correlated with MVD, Dukes' stage (A to C), or tumor differentiation, but was associated with lymphatic involvement and patient survival. By multivariate analysis, VEGF-D expression was found to be an independent prognostic factor for both disease-free and overall survival. VEGFR-3 expression was detected in a subset of vessels, typically thin-walled and devoid of RBCs, in 89% of CRC cases examined. VEGFR-3-positive vessel densities increased progressively from normal mucosa to adenomas and carcinomas and were correlated with MVD, but not with Dukes' stage (A to C), tumor differentiation, or VEGF-D expression. VEGFR-3 expression was spatially associated with macrophage-rich inflammatory infiltrates, which were significantly more frequent among VEGFR-3-positive cases. We conclude that VEGF-D expression, but not that of its receptor VEGFR-3, is an independent prognostic indicator in CRC. VEGF-D expression may be associated with disease outcome through the promotion of lymphatic involvement/metastases.