TBK1 Suppresses RIPK1-Driven Apoptosis and Inflammation during Development and in Aging.

Aging is a major risk factor for both genetic and sporadic neurodegenerative disorders. However, it is unclear how aging interacts with genetic predispositions to promote neurodegeneration. Here, we investigate how partial loss of function of TBK1, a major genetic cause for amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) comorbidity, leads to age-dependent neurodegeneration. We show that TBK1 is an endogenous inhibitor of RIPK1 and the embryonic lethality of Tbk1-/- mice is dependent on RIPK1 kinase activity. In aging human brains, another endogenous RIPK1 inhibitor, TAK1, exhibits a marked decrease in expression. We show that in Tbk1+/- mice, the reduced myeloid TAK1 expression promotes all the key hallmarks of ALS/FTD, including neuroinflammation, TDP-43 aggregation, axonal degeneration, neuronal loss, and behavior deficits, which are blocked upon inhibition of RIPK1. Thus, aging facilitates RIPK1 activation by reducing TAK1 expression, which cooperates with genetic risk factors to promote the onset of ALS/FTD.

Modulating TRADD to restore cellular homeostasis and inhibit apoptosis.

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 investigated1-3, it remains unclear how homeostasis can be restored after inhibition of cell death. Here we identify TRADD4-6, 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.

Sequential activation of necroptosis and apoptosis cooperates to mediate vascular and neural pathology in stroke.

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.

Immunohistochemical analysis of the distribution of RANKL: a case of disseminated carcinomatosis of bone marrow as the first presentation of relapse in curatively resected colorectal cancer.

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.

[A Case of Rhabdomyolysis Caused by Oxaliplatin during Postoperative Adjuvant Chemotherapy].

The patient was a 50-year-old male. At the age of 48 years, he had undergone total gastrectomy and right hemicolectomy simultaneously for gastric and ascending colon cancers. Since adjuvant chemotherapy has become common practice for patients with ascending colon cancer, capecitabine was administered for 6 months. One year and 6 months after the surgery, he was diagnosed with recurrence of the ascending colon cancer at the anastomotic site and underwent local colectomy. Considering he was pathologically diagnosed as pT4a, mFOLFOX6 therapy was prescribed as postoperative adjuvant chemotherapy. On the day the 11th course of treatment was initiated, the patient complained of weakness; however, his blood test results showed no abnormalities; therefore, he was followed-up as an outpatient. Three days later, he presented to the hospital with exacerbated symptoms and was diagnosed with rhabdomyolysis due to a marked increase in CK(2,031 U/L). Rhabdomyolysis was determined to be the adverse effect of oxaliplatin because out of all the drugs prescribed to the patient, this condition is listed as a side effect only in oxaliplatin's package insert. Fortunately, outpatient treatment was enough to alleviate rhabdomyolysis. Subsequently, adjuvant chemotherapy was completed without oxaliplatin. The patient has been followed-up without recurrence for 9 months after the surgery.

[A Case of Extramural Growth-Type Ileocecal Colon Cancer].

A woman in her 80s was diagnosed with an abdominal mass during physical examination. Contrast-enhanced computed tomography(CT)revealed a tumor with contrast enhancement outside the ileocecal region of the intestine, and the ileocolic artery penetrated the tumor. No tumor was detected by colonoscopy. An endoscope could not be passed through due to an ileocecal valve stenosis. A biopsy of the ileocecal valve revealed only lymphocyte hyperplasia without adenocarcinoma components. Barium enema examination demonstrated no influx of the contrast medium from the cecum into the oral side of the intestine. Since a gastrointestinal stromal tumor in the ileocecal region was suspected, laparotomy was performed in the ileocecal region owing to the preoperative diagnosis of suspected malignant lymphoma, revealing a 5-cm elastic hard tumor outside the ileocecal wall. The tumor could not be separated from the intestinal tract. Histopathological examination revealed no lesion on the mucosal surface, although poorly differentiated adenocarcinoma infiltrated from the submucosa to the serosa. Thus, the patient was diagnosed with extramural growth-type ileocecal colon cancer. This disease is relatively rare but need to be kept in mind.

[A Case of Transverse Colon Cancer Complicated by Eosinophilic Granulomatosis with Polyangiitis].

A man in his 50s had undergone steroid therapy for eosinophilic granulomatosis with polyangiitis(EGPA). Since an examination for malignant tumors revealed type 0-Ⅰsp(cT1aN0M0)and type 2(cT2N0M0)lesions in the proximal and mid- transverse colon, respectively, he was referred to our department. Endoscopic resection was performed on the proximal lesion. After the confirmation of curative resection, laparoscopic partial colectomy(transverse colon)and D3 lymph node dissection were performed on the mid-transverse lesion. Because of the patient's favorable postoperative course, he was discharged from the hospital on POD17. Since steroids and immunosuppressants may cause immunological abnormalities and malignant tumors, such patients should be strictly followed up.

[An Analysis of Surgery for Colorectal Cancer Lung Metastasis].

OBJECTIVES: Resection of lung metastasis in colorectal cancer leads to a good prognosis; therefore, surgical treatment for resectable metastases is recommended by the Japanese Society for Cancer of the Colon and Rectum Guidelines for the treatment of colorectal cancer. In this study, we investigated the factors that affect the prognosis of resection of such lung cancers. RESULTS: Outcomes of 23 cases of lung resection performed from 2000 to 2019 were investigated. The 5-year overall survival rate after lung resection was 55.5%, and the 5-year relapse-free survival rate after liver resection was 27.0%. Univariate analysis identified sex(p=0.024), tumor size(p=0.0129)and complications(p=0.0129)as prognostic factors, while multivariate analysis revealed sex(p=0.0278, relative risk=5.38)to be a prognostic factor. CONCLUSION: In this study, sex was identified as a poor prognostic factor. Further evidence from cases is needed to ascertain the effects of other factors.

[Laparoscopic Partial Hepatectomy for the Liver Metastasis of Gastric Cancer after Nab-Paclitaxel plus Ramucirumab Combination Therapy-A Case Report].

We report a case of laparoscopic partial hepatectomy after nab-paclitaxel plus ramucirumab(nab-PTX plus RAM)combination therapy for postoperative liver recurrence of gastric cancer. The patient was a 50's man who underwent laparoscopic distal gastrectomy, D2 lymph node dissection, and Billroth-I reconstruction for gastric cancer. The pathological findings were L, Gre, Post, Type 3, por>tub2, pT3N3a, M1(CY1), fStage Ⅳ. Postoperative chemotherapy with S-1 was performed. The CT examination 6 months after the operation revealed a total of 3 tumors(maximum diameter of 5×4 cm)in liver segments S6, 7, and 8. We started nab-PTX plus RAM combination therapy for liver metastases and performed laparoscopic partial hepatectomy when 12 courses of the treatment were completed. The postoperative course was uneventful, and the patient was discharged on postoperative day 7. Pathological results suggested that the tumor was exposed on the cut surface, and 6 courses of nab-PTX plus RAM combination therapy were administered postoperatively. The patient has been recurrence-free 12 months after the operation.

A prospective multi-center registry concerning the clinical performance of laparoscopic colorectal surgery using an absorbable adhesion barrier (INTERCEED®) made of oxidized regenerated cellulose.

PURPOSE: The aim of this prospective multi-center registry was to evaluate the safety and clinical performance of INTERCEED® in laparoscopic colorectal surgery. METHODS: This 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. RESULTS: Between 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. CONCLUSIONS: Using INTERCEED® in laparoscopic colorectal surgery is safe and may be useful for preventing postoperative adhesive small intestinal obstruction.

[A Case of Recurrent Gastric Cancer with Clinical Complete Response after Ramucirumab plus Paclitaxel Therapy].

We report a case of a 61-year-old man who underwent open total gastrectomy and D2 lymph node dissection for gastric cancer. The pathological findings were suggestive of pT2N3M0, fStage ⅢA. S -1 was administered for 1 year post-surgery. One year and 9 months after the operation, an epigastralgia was found, and the PET-CT showed an increase of SUVmax 3.80 around the celiac artery. S -1 plus CDDP therapy was initiated. However, due to the occurrence of neutropenia, the therapy was changed to ramucirumab plus paclitaxel. After 20 courses of the same regimen, no PET-CT uptake was observed. We thus considered it cCR and discontinued further chemotherapy. The patient has been alive for 15 months without recurrence. By performing effective chemotherapy at an early stage, cCR could be observed after a secondary treatment. Therefore, longterm survival could be expected for post-operative recurrence of gastric cancer.

[A Case of Sigmoid Colon Cancer with Complete Visceral Inversion].

Complete visceral inversion occurs in 1/5,000 individuals. In 64%of cases, complete visceral inversion is complicated by the malformation of other organs. Careful attention is required when performing surgeries. In recent years, with the development of laparoscopic surgery, some cases of laparoscopic surgery with complete visceral inversion have been reported. Herein, we report a case of safely performed laparoscopic surgery for sigmoid colon cancer with complete visceral inversion along with a relevant discussion.

Laparoscopic surgery for locally advanced T4 colon cancer: the long-term outcomes and prognostic factors.

PURPOSE: For 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. METHODS: The 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. RESULTS: The 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. CONCLUSIONS: These 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.

[Chemoradiotherapy with S-1 for Recurrence Cases of Colorectal Cancer].

INTRODUCTION: Although chemotherapy is the main treatment for recurrent colorectal cancer, the utility of radiotherapy as a local treatment has been widely reported. We performed chemoradiotherapy with S-1 for cases with recurrence after surgery, and the outcomes are reported herein. MATERIALS AND METHODS: Chemoradiotherapy with S-1 was performed in 4 cases. S-1 was administered for 2 weeks during the irradiation period, and the off period provided was 1 week. RESULTS: X-ray irradiation was performed in 2 cases and proton beam irradiation in the other 2. The progression free periods of the 2 cases receiving proton beam irradiation were 31 months and 36 months. In contrast, the progression free periods of the 2 cases given X-ray irradiation were 24 months and 21 months. DISCUSSION: It is known that S-1 not only achieves a high anticancer effect via dihydropyrimidine dehydrogenase(DPD)inhibition, which is a major metabolic pathway of 5-FU, but also increases the radiation susceptibility of malignancies. S-1 is regarded as an ideal anticancer agent when used in combination with radiation therapy. Since the local control achieved in our 4 cases was good, chemoradiotherapy with S-1 was considered to be a useful treatment.

Risk factors for complications after diverting ileostomy closure in patients who have undergone rectal cancer surgery.

PURPOSE: To clarify the risk factors for complications after diverting ileostomy closure in patients who have undergone rectal cancer surgery. METHODS: The 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. RESULTS: The 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. CONCLUSIONS: Age, 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.

[Examination of Cases of Hepatectomy for Metastatic Colorectal Cancer].

OBJECTIVES: Resection of liver metastasis from colorectal cancer is known to improve prognosis; therefore, surgical treatment is recommended for resectable metastases in the Japanese Society for Cancer of the Colon and Rectum Guidelines for the Treatment of Colorectal Cancer. In this study, we investigated factors that affect the prognosis of resection of such metastatic liver tumors. RESULTS: Thirty-three cases of liver resection performed during the period from 1998 to 2017 were investigated. The 5-year overall survival rate after liver resection was 47.3%, and the 5-year recurrence-free survival rate after liver resection was 29.9%. Univariate analysis identified CA19-9(p=0.02)and operative procedure(p=0.0046)as prognostic factors, while multivariate analysis revealed operative procedure(p=0.03)to be a prognostic factor. When prognosis was examined in terms of operative procedure(ie, lobectomy, segmental resection, or partial resection), the prognosis of patients undergoing lobectomy was significantly poorer compared to those undergoing segmental resection(p=0.0092, RR=28.94)and partial resection(p=0.0092, RR=25.37). CONCLUSION: In this study, operative procedure was identified as a poor prognostic factor. The prognosis of liver metastasis requiring lobectomy is considered to be poor. Further accumulation of cases is needed to investigate the effects of other factors in the choice of operative procedure.

Interleukin enhancer-binding factor 3/NF110 is a target of YM155, a suppressant of survivin.

Survivin is responsible for cancer progression and drug resistance in many types of cancer. YM155 selectively suppresses the expression of survivin and induces apoptosis in cancer cells in vitro and in vivo. However, the mechanism underlying these effects of YM155 is unknown. Here, we show that a transcription factor, interleukin enhancer-binding factor 3 (ILF3)/NF110, is a direct binding target of YM155. The enhanced survivin promoter activity by overexpression of ILF3/NF110 was attenuated by YM155 in a concentration-dependent manner, suggesting that ILF3/NF110 is the physiological target through which YM155 mediates survivin suppression. The results also show that the unique C-terminal region of ILF3/NF110 is important for promoting survivin expression and for high affinity binding to YM155.

Laparoscopic surgery for obese patients with colon cancer: a case-matched control study.

PURPOSE: This study compared the results of laparoscopic surgery for colon cancer in obese patients with a body-mass index (BMI) of 25 kg/m(2) or higher with those in nonobese patients (BMI <25 kg/m(2)) who were matched for clinicohistopathological factors. METHODS: The oncologic outcomes were compared between 140 patients with a BMI of 25 kg/m(2) or higher (obese group) and 140 patients with a BMI of <25 kg/m(2) (nonobese group) that were matched for sex, tumor location, date of operation, and pTNM stage. RESULTS: The 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). CONCLUSIONS: Postoperative complications and long-term oncologic outcomes were similar in obese and nonobese patients who underwent laparoscopic colectomy for colon cancer in this hospital.

Laparoscopic resection of a gastrointestinal stromal tumor of the rectum after treatment with imatinib mesylate: report of a case.

This report describes the laparoscopic resection of a rectal GIST after treatment with imatinib mesylate. A 56-year-old male presented with a submucosal tumor (longest diameter, 8 cm) arising in the lower rectum. A core needle biopsy revealed that the tumor contained bundles of spindle-like cells. Immunostaining revealed that the tumor was positive for c-kit and CD34. Analysis of the c-kit gene revealed a substitution of ACA (threonine) by GCA (alanine) at codon 574 of exon 11. Imatinib mesylate (400 mg/day) was given as preoperative adjuvant therapy for 3 months, and the tumor shrank to 5 cm in diameter. Proctectomy with transanal anastomosis could be performed laparoscopically, while preserving the anus. There was no evidence of recurrence 2 years 6 months after surgery. Preoperative adjuvant chemotherapy with imatinib mesylate may permit the use of less invasive treatment procedures, allowing anal preservation.

[Neoadjuvant chemotherapy for colorectal cancer].

Surgery continues to play an important role in the curative treatment of gastrointestinal cancer. Recently, considerable progress has been made in chemotherapy and radiotherapy. In particular, chemotherapy with FOLFIRI and FOLFOX has prolonged survival in patients with colorectal cancer. Molecular-targeted agents have also enhanced the effectiveness of chemotherapy. However, radical resection offers the potential for a cure and is unsurpassed by any other treatments. Nonetheless, further improvement in survival is unlikely to be achieved by surgery alone. Studying how treatment regimens highly effective against unresectable or recurrent colorectal cancer can be adapted to patients with resectable disease is thus an important issue.