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PurposeFor locally advanced pathological T4 (pT4) colon cancer, the safety and feasibility of laparoscopic procedures remain controversial. Therefore, this study aimed to assess short-term and long-term outcomes and to identify the prognostic factors in laparoscopic surgery for pT4 colon cancer.MethodsThe study group included 130 patients who underwent laparoscopic radical resection for pT4 colon and rectosigmoid cancer from January 2004 through December 2012. The short-term outcomes, long-term outcomes, and prognostic factors in pT4 colon cancer were analyzed.ResultsThe median operative time was 205 min, with a median blood loss of 10 ml. The conversion rate was 3.8%, and 13 patients (10.0%) had postoperative complications. The radial resection margin was positive in 1 patient (0.8%). The median follow-up time was 73 months. The 5-year overall survival (OS) and recurrence-free survival (RFS) were 77.2 and 63.5%, respectively. On a multivariate analysis, a male sex [hazard ratio (HR) 3.09, p < 0.001], lymph node ratio ≥ 0.06 (HR 2.35, p = 0.021), tumor diameter < 38 mm (HR 2.57, p = 0.007), and right-sided colon cancer (HR 2.11, p = 0.047) were significantly related to a poor OS.ConclusionsThese results suggest that laparoscopic surgery for pT4 colon cancer is safe and feasible, and the oncological outcomes are acceptable. Based on the present findings, select patients with locally advanced colon cancer should not be excluded from laparoscopic surgery.

PurposeThe aim of this prospective multi-center registry was to evaluate the safety and clinical performance of INTERCEED® in laparoscopic colorectal surgery.MethodsThis study was a prospective, multi-center, single-arm registry wherein patients who received INTERCEED® in laparoscopic colorectal surgery were registered consecutively (UMIN-CTR 00001872). The primary outcome was the incidence rate of postoperative adhesive small intestinal obstruction within 6 months. The secondary outcomes were reoperation related to postoperative bleeding and anastomotic leak, surgical site infection (SSI) and anastomotic leak.ResultsBetween March 2012 and March 2015, a total of 202 patients were enrolled from six institutions. INTERCEED® was not applied in two patients, so 200 patients were analyzed using the full analysis set population. The incidence rate of postoperative adhesive intestinal obstruction was 1.0% (2/200). The total SSI rate was 3.5% (7/200), the deep incisional SSI rate was 0.0% (0/200), and the organ SSI rate was 0.0% (0/200). The incidence of anastomotic leak was 1.0% (2/200). Reoperation was performed in two cases: one for anastomotic leak and the other as cardiac surgery due to heart disease.ConclusionsUsing INTERCEED® in laparoscopic colorectal surgery is safe and may be useful for preventing postoperative adhesive small intestinal obstruction.

PurposeTo clarify the risk factors for complications after diverting ileostomy closure in patients who have undergone rectal cancer surgery.MethodsThe study group comprised 240 patients who underwent a diverting ileostomy at the time of lower anterior resection or internal anal sphincter resection, in our department, between 2004 and 2015. Univariate and multivariate analyses of 18 variables were performed to establish which of these are risk factors for postoperative complications.ResultsThe most common complications were intestinal obstruction and wound infection. Univariate analysis showed that an age of 72 years or older (p = 0.0028), an interval between surgery and closure of 6 months or longer (p = 0.0049), and an operation time of 145 min or longer (p = 0.0293) were significant risk factors for postoperative complications. Multivariate analysis showed that age (odds ratio, 3.4236; p = 0.0025), the interval between surgery and closure (odds ratio, 3.4780; p = 0.0039), and operation time (odds 2.5179; p = 0.0260) were independent risk factors.ConclusionsAge, interval between surgery and closure, and operation time were independent risk factors for postoperative complications after diverting ileostomy closure. Thus, temporary ileostomy closure should be performed within 6 months after surgery for rectal cancer.

Apoptosis and necroptosis are two regulated cell death mechanisms; however, the interaction between these cell death pathways in vivo is unclear. Here we used cerebral ischemia/reperfusion as a model to investigate the interaction between apoptosis and necroptosis. We show that the activation of RIPK1 sequentially promotes necroptosis followed by apoptosis in a temporally specific manner. Cerebral ischemia/reperfusion insult rapidly activates necroptosis to promote cerebral hemorrhage and neuroinflammation. Ripk3 deficiency reduces cerebral hemorrhage and delays the onset of neural damage mediated by inflammation. Reduced cerebral perfusion resulting from arterial occlusion promotes the degradation of TAK1, a suppressor of RIPK1, and the transition from necroptosis to apoptosis. Conditional knockout of TAK1 in microglial/infiltrated macrophages and neuronal lineages sensitizes to ischemic infarction by promoting apoptosis. Taken together, our results demonstrate the critical role of necroptosis in mediating neurovascular damage and hypoperfusion-induced TAK1 loss, which subsequently promotes apoptosis and cerebral pathology in stroke and neurodegeneration.

Aim The aim of this study was to compare the outcomes of GM142, a newly developed gelatin film with a concave and convex structure to a commercially available conventional film, hyaluronate‐carboxymethylcellulose. Methods Patients with primary rectal cancer who were scheduled for diverting ileostomy during laparoscopic surgery were eligible for this study. Patients were randomized before surgery and an antiadhesion film was applied under the umbilical incision. The primary outcome was the incidence of adhesion under the midline incision confirmed by second‐look surgery for diverting ileostomy closure. The secondary outcomes were the adhesion severity score, the extent of adhesion score, the presence of intestinal obstruction, and the success of all patching. Results A total of 146 patients were enrolled. A total of 123 patients were included in the full analysis set. The primary outcome of “no adhesion” was observed in 66.1% in the GM142 group and 55.7% in the conventional film group. The noninferiority of GM142 to conventional film was confirmed (P = .0005). The secondary outcomes were similar between the groups. For the safety evaluation, there were no safety concerns regarding allergic reactions to gelatin or increased gelatin‐specific IgE antibody titers. Conclusions The noninferiority of GM142 to conventional film was shown. GM142 showed no major safety issues. The clinical safety profiles of GM142 suggested certain physiological benefits of the gelatin film as an adhesion barrier. This randomized controlled trial revealed the noninferiority of a newly developed absorbable adhesion barrier (GM142) to conventional film. GM142 showed no major safety issues. The clinical safety profiles of GM142 suggested certain physiological benefits of the gelatin film as an adhesion barrier.

PurposeThis study compared the results of laparoscopic surgery for colon cancer in obese patients with a body-mass index (BMI) of 25 kg/m2 or higher with those in nonobese patients (BMI <25 kg/m2) who were matched for clinicohistopathological factors.MethodsThe oncologic outcomes were compared between 140 patients with a BMI of 25 kg/m2 or higher (obese group) and 140 patients with a BMI of <25 kg/m2 (nonobese group) that were matched for sex, tumor location, date of operation, and pTNM stage.ResultsThe proportion of patients with postoperative complications was significantly higher in the obese group (15 %) than in the nonobese group (6 %). The disease-free survival rate and overall survival rate in patients with stage I or II disease were similar in the obese group (98.6 and 98.8 %, respectively) and the nonobese group (97.8 and 97.8 %, respectively). The disease-free survival rate and overall survival rate in patients with stage III disease also did not differ significantly between the obese group (77.2 and 79.4 %, respectively) and the nonobese group (83.4 and 84.9 %, respectively).ConclusionsPostoperative complications and long-term oncologic outcomes were similar in obese and nonobese patients who underwent laparoscopic colectomy for colon cancer in this hospital.

Cell death in human diseases is often a consequence of disrupted cellular homeostasis. If cell death is prevented without restoring cellular homeostasis, it may lead to a persistent dysfunctional and pathological state. Although mechanisms of cell death have been thoroughly investigated 1 – 3 , it remains unclear how homeostasis can be restored after inhibition of cell death. Here we identify TRADD 4 – 6 , an adaptor protein, as a direct regulator of both cellular homeostasis and apoptosis. TRADD modulates cellular homeostasis by inhibiting K63-linked ubiquitination of beclin 1 mediated by TRAF2, cIAP1 and cIAP2, thereby reducing autophagy. TRADD deficiency inhibits RIPK1-dependent extrinsic apoptosis and proteasomal stress-induced intrinsic apoptosis. We also show that the small molecules ICCB-19 and Apt-1 bind to a pocket on the N-terminal TRAF2-binding domain of TRADD (TRADD-N), which interacts with the C-terminal domain (TRADD-C) and TRAF2 to modulate the ubiquitination of RIPK1 and beclin 1. Inhibition of TRADD by ICCB-19 or Apt-1 blocks apoptosis and restores cellular homeostasis by activating autophagy in cells with accumulated mutant tau, α-synuclein, or huntingtin. Treatment with Apt-1 restored proteostasis and inhibited cell death in a mouse model of proteinopathy induced by mutant tau(P301S). We conclude that pharmacological targeting of TRADD may represent a promising strategy for inhibiting cell death and restoring homeostasis to treat human diseases. The adaptor protein TRADD is a regulator of both cellular homeostasis and apoptosis, and represents a potential therapeutic target for human diseases.

Loss-of-function mutations in NEK1 gene, which encodes a serine/threonine kinase, are involved in human developmental disorders and ALS. Here we show that NEK1 regulates retromer-mediated endosomal trafficking by phosphorylating VPS26B. NEK1 deficiency disrupts endosomal trafficking of plasma membrane proteins and cerebral proteome homeostasis to promote mitochondrial and lysosomal dysfunction and aggregation of α-synuclein. The metabolic and proteomic defects of NEK1 deficiency disrupts the integrity of blood–brain barrier (BBB) by promoting lysosomal degradation of A20, a key modulator of RIPK1, thus sensitizing cerebrovascular endothelial cells to RIPK1-dependent apoptosis and necroptosis. Genetic inactivation of RIPK1 or metabolic rescue with ketogenic diet can prevent postnatal lethality and BBB damage in NEK1 deficient mice. Inhibition of RIPK1 reduces neuroinflammation and aggregation of α-synuclein in the brains of NEK1 deficient mice. Our study identifies a molecular mechanism by which retromer trafficking and metabolism regulates cerebrovascular integrity, cerebral proteome homeostasis and RIPK1-mediated neuroinflammation. NEK1 mutations promote lethality early in life and ALS late in life via unknown mechanisms. Here, the authors show that NEK1 mutation disrupts retromer-mediated trafficking and promotes RIPK1 activation, connecting retromer trafficking and metabolism to neuroinflammation by dietary intervention.

Poorly differentiated adenocarcinoma of colorectal carcinoma (CRC) is a rare condition with poor prognosis. In this report, we describe a case of a 69-year-old man who underwent laparoscopic low anterior resection after being diagnosed with stage IIIB CRC. At 10 months post-operation, he developed fever and loss of appetite. Laboratory examination revealed > 120.0 μg/dL fibrin degradation products and > 60.0 μg/dL D-dimer. Bone marrow (BM) examination showed malignant epithelioid infiltrate with CK20 and CDX2 expression, leading to diagnosis of disseminated carcinomatosis of BM, which is rare in CRC and indicative of widespread disease throughout the body. Furthermore, immunohistochemistry revealed high expression of receptor activator of nuclear factor κB ligand (RANKL) in tumor cells, including budding cells of CRC and BM tissues. Thus, RANKL expression, which is known to indicate metastatic behavior of cancer cells, may play a critical role in promoting osteoclast formation, which has been associated with the pathogenesis of BM lesions.

PurposeThe short- and long-term outcomes of laparoscopic surgery for right-sided colon cancer remain largely uninvestigated. This study was undertaken to compare the morbidity and mortality after either a laparoscopic right hemicolectomy (LRHC) or an open right hemicolectomy (ORHC) for this type of tumor.MethodsThe study group included 100 patients who underwent an LRHC and 100 patients who underwent an ORHC for right-sided colon cancer from 1990 through 2004. The two groups were retrospectively well matched with respect to sex, age (±5 years), and pathological tumor-node-metastasis (TNM) stage.ResultsThe median follow-up period was 83 months in the LRHC group and 105 months in the ORHC group. The LRHC group had a lower volume of intraoperative bleeding (P < 0.001), a lower rate of wound infection (P = 0.019) or postoperative intestinal obstruction (P = 0.013), and a shorter hospital stay (P < 0.001) than the ORHC group. The rate of recurrence did not differ significantly between the LRHC group (19%) and the ORHC group (22%). In patients with TNM stage I or II, the disease-free survival (DFS) rate (94.9% vs 95.1%) and overall survival (OS) rate (95.8% vs 95.0%) did not differ significantly between the two groups. A similar tendency was observed in patients with stage III with the rates for DFS (71.3% vs 60.4%) and OS (73.6% vs 64.1%), respectively.ConclusionsAn LRHC for right-sided colon cancer has the advantage over an ORHC of better short-term outcomes, and both groups have similar long-term oncologic outcomes. An LRHC is thus an acceptable alternative to an ORHC for the treatment of this type cancer.