Downregulation of thrombomodulin contributes to ischemia-reperfusion injury in mice with steatotic liver.

AIM: Ischemia-reperfusion (IR) injury is one of the most critical complications commonly associated with liver surgery, including liver transplantation. Steatotic livers are particularly vulnerable to IR injury. However, the underlying mechanisms of this increased susceptibility have not fully been understood. In the present study, we used heterogeneous thrombomodulin (TM)-knockout (KO) (TM+/- ) mice, which express about 50% functional activity of TM as compared with wild type, to investigate whether dysregulation of TM enhances IR injury in steatotic livers. METHODS: Steatotic livers were induced using choline-deficient diets (CDD) in mice. The biological activity of TM was assessed using the productivity of protein C. Susceptibility to IR injury was compared between steatotic livers and non-steatotic livers and also assessed in TM-KO mice. We investigated whether recombinant TM (rTM) and the lectin-like domain of TM (rTM-D1) ameliorated IR injury in steatotic livers. RESULTS: Protein C activity was significantly decreased to less than 20% in CDD-fed mice compared with mice with non-steatotic livers. Steatotic livers showed exaggerated IR injury compared with non-steatotic livers. Recombinant TM (rTM) and the lectin-like domain of TM (rTM-D1), which has anti-inflammatory effects, ameliorated IR injury in steatotic livers. TM+/- mice showed increased susceptibility to IR injury, and rTM ameliorated the increased IR injury in TM+/- mice. CONCLUSION: We conclude that downregulation of TM increases susceptibility to hepatic IR injury in steatotic livers and that rTM ameliorates hepatic IR injury through anti-inflammatory action.

Clinical indicators for the incidence of postoperative ileus after elective surgery for colorectal cancer.

BACKGROUND: The occurrence of postoperative ileus leads to increased patient morbidity, longer hospitalization, and higher healthcare costs. No clear policy on postoperative ileus prevention exists. Therefore, we aim to evaluate the clinical factors involved in the development of postoperative ileus after elective surgery for colorectal cancer. METHODS: We retrospectively analyzed patients who underwent elective surgery involving bowel resection with or without re-anastomosis for colon cancer between April 2015 and March 2020. The primary readout was the presence or absence of postoperative ileus. Univariate and multivariate analyses were used to identify pre- and intraoperative risk factors, and the incidence of postoperative ileus was assessed using independent factors. RESULTS: Postoperative ileus occurred in 48 out of 356 patients (13.5%). In multivariate analysis, male sex poor performance status, and intraoperative in-out balance per body weight were independently associated with postoperative ileus development. The incidence of postoperative ileus was 2.5% in the cases with no independent factors; however, it increased to 36.1% when two factors were observed and 75.0% when three factors were matched. CONCLUSIONS: We discovered that male gender, poor performance status, and intraoperative in-out balance per body weight were associated with the development of postoperative ileus. Of these, intraoperative in-out balance per body weight is a controllable factor. Hence it is important to control the intraoperative in-out balance to lower the risk for postoperative ileus.

Antithrombin attenuates the progression of hepatocellular carcinoma by regulating neutrophil/interleukin-8 signaling.

AIM: Inflammation plays an important role in hepatocellular carcinoma (HCC) progression. Here, we examined whether antithrombin (AT) plays a role in attenuating HCC progression, via its anti-inflammatory effects. METHODS: HCCs were developed in AT-insufficient (AT+/- ) mice and wild-type (AT+/+ ) mice treated with diethyl nitrosamine and carbon tetrachloride. AT was administered to AT+/- mice. The development of HCC was compared between the three groups. In vitro study, migration assay was performed. The association of the prognosis of patients with HCC and plasma AT values was clinically examined. RESULTS: AT suppressed the release of interleukin (IL)-8 from lipopolysaccharide (LPS)-stimulated human neutrophils in vitro. Huh-7 cells that were co-cultured with neutrophils and stimulated with LPS showed significantly enhanced migration; however, Huh-7 cells co-cultured with LPS/AT-stimulated neutrophils showed significantly decreased migration. Moreover, the addition of anti-IL-8 antibodies to LPS-stimulated Huh-7 cells co-cultured with neutrophils also suppressed migration. AT+/- mice (AT plasma activity: 64%) promoted liver cancer, as compared with wild-type mice (AT plasma activity: 135%); AT administration attenuated liver cancer in AT+/- mice. Patients with HCC with a preoperative AT level of ≥70% showed better outcomes after liver resection, as compared with those with an AT level of <70%. IL-8 expression and neutrophil infiltration in HCC tissues were negatively correlated with the AT level. CONCLUSIONS: AT attenuates HCC progression by regulating neutrophil/IL-8 signaling.

Antithrombin Insufficiency Promotes Susceptibility to Liver Tumorigenesis.

BACKGROUND: Antithrombin (AT) is not only a major regulator of hemostasis, but it shows anti-inflammatory properties as well. We aimed to investigate whether AT-insufficient mice increase susceptibility to liver tumorigenesis. METHODS: We induced the development of liver tumor in AT-insufficient (AT+/-) mice and wild-type (AT+/+) mice by treating them with diethylnitrosamine (DEN) and CCl4. The development of liver tumors and liver inflammation were compared between these mouse groups. Following this, AT was administered to the AT-insufficient mice treated with DEN and CCl4. RESULTS: Tumor size and the number of DEN and CCl4-induced liver tumors significantly increased in AT-insufficient mice compared with the wild-type mice. Serum transaminase levels, cell death, and the expression of cleaved caspase-3 in liver were increased in AT+/-. Furthermore, hepatic neutrophil infiltrations and serum interleukin 6 and tumor necrosis factor-α levels were significantly elevated in AT-insufficient mice. The levels of 8-OHdG, oxidative DNA damage marker, in liver were significantly increased in AT-insufficient mice. Administration of AT led to a significant decrease in DEN- and CCl4-induced liver injury and inflammation in AT-insufficient mice, compared with the wild-type group. CONCLUSIONS: AT insufficiency led to increased susceptibility to liver tumorigenesis by increasing hepatic inflammation.

Vitamin A-coupled liposomal Rho-kinase inhibitor ameliorates liver fibrosis without systemic adverse effects.

AIM: Rho-kinase (ROCK) inhibitor could ameliorate liver fibrosis by suppressing hepatic stellate cell (HSC) activation. However, because systemic administration of ROCK inhibitor causes serious adverse effects, we developed a drug delivery system selectively delivering ROCK inhibitor to HSCs. Here, we examined whether our developed vitamin A (VA)-coupled liposomal ROCK inhibitor reduced liver fibrosis in rats without causing systemic adverse effects. METHODS: LX-2 HSCs were analyzed for morphological changes and the expression of profibrotic proteins. The inhibitory effects of VA-coupled liposomal ROCK inhibitor on liver fibrosis were confirmed in a rat model of liver fibrosis induced by i.p. injection of carbon tetrachloride. The degree of liver fibrosis, biochemical changes, and survival rates were also investigated. RESULTS: Vitamin A-coupled liposomal ROCK inhibitor had an effect at approximately 1/100 the amount of the free ROCK inhibitor for inhibiting the activation of LX-2 cells and caused significant decreases in the expression levels of α-smooth muscle actin (SMA) and transforming growth factor (TGF)-ß1. The degree of liver fibrosis was suppressed by treatment with VA-coupled liposomal ROCK inhibitor, and the expression of α-SMA and TGF-ß1 in liver tissues was also significantly suppressed. In addition, serum levels of alanine aminotransferase and hyaluronic acid were significantly reduced, and there was no decline in kidney function, which has been noted as a systemic adverse effect of ROCK inhibitor. Furthermore, VA-coupled liposomal ROCK inhibitor improved survival rates in rats with liver fibrosis. CONCLUSION: Vitamin A-coupled liposomal ROCK inhibitor efficiently suppressed liver fibrosis without causing systemic adverse effects.

Prediction of recurrence following hepatectomy in patients with hepatitis C virus infection-related hepatocellular carcinoma who achieved a sustained virological response.

AIM: The risk of hepatitis C virus infection-related hepatocellular carcinoma (HCC) is lower, with a better prognosis, in patients who achieve a sustained virological response (SVR) than in those who do not. We aimed to identify risk factors of post-hepatectomy HCC recurrence in patients who achieved a SVR. METHODS: This retrospective study included 349 HCC patients who underwent an initial radical hepatectomy at our institution between January 2005 and December 2014. Sixty-eight patients had achieved a SVR (the SVR group) and 281 patients had not (the non-SVR group). Clinical characteristics and long-term outcomes were compared between the two groups. Univariate and multivariate analyses identified variables associated with recurrence-free survival in the SVR group. RESULTS: Post-hepatectomy overall and recurrence-free survival rates were significantly higher in the SVR group than the non-SVR group (P < 0.01 and <0.05, respectively). Univariate analysis of post-hepatectomy recurrence-free survival in the SVR group revealed multiple significant factors: aspartate aminotransferase, 25 IU/L or more (P = 0.01); indocyanine green retention rate at 15 min, 20.0% or less (P < 0.05); hepatic vascular invasion (P < 0.05); and an interval of months or less between achieving a SVR and hepatectomy (P < 0.01). Multivariate analysis confirmed an interval of 30 months or less between achieving a SVR and hepatectomy as an independent prognostic factor of recurrence-free survival (hazard ratio, 2.30; 95.0% confidence interval, 1.04-5.13; P < 0.05). CONCLUSION: The interval between achieving a SVR and hepatectomy is an important predictor of recurrence in hepatitis C virus infection-related HCC patients who achieved a SVR.

[Estimation of peritoneal dissemination in patients with unresectable advanced or recurrent colorectal cancer who underwent curative resection after combination chemotherapy].

In a group of 209 colorectal cancer patients with unresectable tumors, 10 patients underwent curative resection after combination chemotherapy at our hospital between 2006 and 2012. Of these 10 patients, 5 presented with peritoneal dissemination at the start of chemotherapy. With the exception of 1 patient with peritoneal recurrence, peritoneal dissemination and liver metastasis were observed in all patients at the time of diagnosis of colorectal cancer. Computed tomography (CT) and/ or positron emission tomography-CT examination revealed disappearance of peritoneal dissemination in response to chemotherapy, except in 1 patient with peritoneal recurrence. After combination chemotherapy, surgical resection of liver metastases and peritoneal dissemination was performed. Pathological and intraoperative findings indicated disappearance of peritoneal dissemination in 3 patients and P2 grade peritoneal dissemination in 1 patient. In the patient with peritoneal recurrence, 1 tumor was completely resected. Interestingly, none of the 3 patients that exhibited complete disappearance of peritoneal dissemination showed peritoneal recurrence, although 1 patient exhibited metastases in the lung and non-regional lymph nodes. In contrast, the patient with P2 grade peritoneal dissemination showed peritoneal recurrence and lung metastasis. All 5 patients survived (duration from diagnosis of colorectal cancer, 31-83 months). Herein, we report the use of combination chemotherapy to achieve the disappearance of peritoneal dissemination, changing unresectable colorectal cancer with peritoneal dissemination into resectable cancer.

[A case of triple-negative breast cancer responding to multidisciplinary treatment containing bevacizumab].

We report a case of a 64-year-old woman with Stage IV breast cancer who responded well to chemotherapy containing bevacizumab. She noticed a left breast tumor with acute progression and was diagnosed as having Stage IV, estrogen receptor( ER)(-), progesterone receptor(PgR)(-), human epidermal growth factor receptor 2(HER2)(-)breast cancer (T4cN3cM1[lymph nodes]). She received 5 courses of adriamycin(60mg/m / 2)plus cyclophosphamide(600mg/m2)(AC therapy)and 4 courses of weekly paclitaxel(PTX 90mg/m / 2)plus bevacizumab(AVA 10 mg/m2)as systemic therapy. Computed tomography(CT)and magnetic resonance imaging(MRI)revealed a complete response(CR). After local resection of the breast tumor and radiation to the breast and regional lymph nodes, capecitabine therapy was initiated. Currently, at 5 months after surgery, no new lesion has been detected.

Comparison of postoperative outcomes in cases achieving sustained virological response with direct-acting antiviral and interferon therapy.

BACKGROUND/PURPOSE: The effect of direct-acting antiviral agents (DAAs) on hepatocellular carcinoma (HCC) recurrence after curative hepatectomy remains uncertain. This retrospective study aimed to evaluate the effect of sustained virological response (SVR) with DAAs or interferon (IFN) therapy on recurrence and overall survival (OS) after hepatectomy. METHODS: We enrolled 593 patients who underwent curative resections between January 2010 and December 2017. Among them, 186 achieved SVR before hepatectomy: a total of 51 (27.4%) in the DAA-SVR group and 132 (72.6%) in the IFN-based SVR group. RESULTS: SVR before hepatectomy was an independent predictor of OS, and the 5-year OS rate was significantly higher in the SVR group than that in the non-SVR group (82.2% vs. 63.9%). There were no significant differences in the recurrence rates or OS between DAA and IFN treatments in achieving SVR before hepatectomy, regardless of poor hepatic function in the DAA therapy group. CONCLUSIONS: There was no significant difference in OS and recurrence-free survival (RFS) between the preoperative SVR achieved with DAA and IFN groups in this study, although liver function was significantly worse at the time of surgery in the DAA group compared to the IFN group.

Validation of appendiceal stump invagination in laparoscopic appendectomy.

INTRODUCTION: There are various methods for appendiceal stump dissection, but the necessity for stump invagination remains unclear. This study aimed to assess the efficacy of appendiceal stump invagination in patients with acute appendicitis after laparoscopic appendectomy (LA). METHODS: We enrolled 327 patients with acute appendicitis who underwent LA between 2012 and 2020. Perioperative variables and surgical outcomes were analyzed between the invagination of the appendiceal stump and noninvagination groups. Propensity score-matched analysis (PSM) was performed. RESULTS: More patients experienced severe inflammation and severe intra-abdominal contamination in the noninvagination group than in the invagination group. Patients in the noninvagination group had an older age, higher body mass index, and poorer American Society of Anesthesiologists physical status than the invagination group. Severe inflammation in the noninvagination group was associated with longer hospital stays and poorer postoperative complications than in the invagination group. PSM analysis was performed to minimize bias in the two groups. After PSM analysis, there were no significant differences in surgical site infection, postoperative intra-abdominal abscess, Clavien-Dindo class ≥IIIa, or postoperative stay between the two groups. During the follow-up period, the postoperative adhesive ileus was not significantly different between the invagination and noninvagination groups. CONCLUSION: Invagination of the appendiceal stump during LA is not necessary to prevent short- and long-term complications. Even in cases dissected using a laparoscopic endostapler, the appendiceal stump per se is not related to postoperative adhesive ileus.

Duodenal diverticula perforation caused by an impacted bezoar successfully treated by endoscopic drainage and lithotripsy: A case report and literature review.

Duodenal diverticula perforation due to an impacted bezoar is a rare disease. Surgical treatment is associated with high rates of complications and mortality; therefore, treatment strategies must be carefully decided. Endoscopic treatment offers significant benefits to patients over surgery.

Branching form of celiac artery to be aware of in laparoscopic surgery: A case report using MDCT angiography.

The anomalies of the celiac artery have been reported and reviewed in literature. Hence, it is not uncommon to clinically encounter its various types. This report presents the case of a 76-year-old male who underwent laparoscopic distal gastrectomy. Preoperative abdominal contrast-enhanced computed tomography showed an anomaly of the celiac artery, which was extremely rare, with various other anomalies of the artery.

Imaging diagnosis of aberrant proper hepatic and gastroduodenal arteries prior to pancreaticoduodenectomy: A case report.

In hepatobiliary and pancreatic surgery, an understanding of hepatic artery anomalies is of great importance to surgeons. Cases of the proper hepatic artery originating from the superior mesenteric artery and the gastroduodenal artery originating from the celiac trunk are extremely rare. To our knowledge, there are no reports of these arterial variants being diagnosed before hepatobiliary and pancreatic surgery. A 73-year-old woman underwent subtotal stomach-preserving pancreaticoduodenectomy and lymphadenectomy for duodenal carcinoma. Preoperative vascular construction with 3-dimensional computed tomography showed variants of the proper hepatic artery and gastroduodenal artery. The proper hepatic artery originated from the superior mesenteric artery, and the gastroduodenal artery originated from the celiac trunk. Intraoperative findings and preoperative vascular construction from 3-dimensional computed tomography were found to be matched exactly; both the proper hepatic artery and gastroduodenal artery were preserved. By diagnosing a rare arterial variant preoperatively, we were able to perform the surgery safely. In hepatobiliary and pancreatic surgery, understanding any potential variation of the hepatic artery before surgery is crucial to ensure the best patient outcomes.

Laparoscopic resection of schwannoma in the hepatoduodenal ligament: a case report.

BACKGROUND: The occurrence of schwannomas in the hepatoduodenal ligament is rare, and its preoperative accurate diagnosis is difficult. Only few cases have been treated with laparoscopic surgery. CASE PRESENTATION: A 54-year-old man visited our hospital following abnormal abdominal computed tomography findings. He had no complaints, and his laboratory investigations were normal. Abdominal contrast-enhanced computed tomography revealed a tumor with enhancement at the margin of the hepatoduodenal ligament. The abdominal magnetic resonance imaging findings of the tumor showed hypointensity on the T1-weighted images and mixed hypointensity and hyperintensity on the T2-weighted fat-suppression images. Positron emission tomography showed localized accumulation of fludeoxyglucose only in the hepatoduodenal ligament tumor. The patient underwent laparoscopic tumor resection for accurate diagnosis. Histopathologically, the tumor was mainly composed of spindle cells, which were strongly positive for S-100 protein on immunohistochemical staining. The patient was discharged without any postoperative complications on day 5. CONCLUSIONS: Complete tumor resection is essential for schwannomas to avoid recurrence. Laparoscopic surgery is useful for schwannomas occurring in the hepatoduodenal ligament and can be performed safely by devising an appropriate surgical method.

Anomalous origin of the middle colic artery from the ileocecal artery affecting laparoscopic ascending colon cancer resection.

The anomalies of the middle colic artery have rarely been reported and reviewed in literature. However, in case such anomalies are observed in clinical practice, surgery must still be performed safely. This report presents the case of a 78-years-old female who underwent ileocecal resection and hepatectomy due to ascending colon cancer with liver metastasis. Preoperative abdominal contrast-enhanced computed tomography showed an anomaly of the middle colic artery. Since such anomaly is extremely rare, preoperative evaluation of vascular structure is important for safely performing the surgery.

Appendicitis with submucosal fecalith mimicking a submucosal tumor: a case report.

BACKGROUND: Submucosal fecalith(s) mimicking submucosal tumors of the gastrointestinal lumen are rare. Moreover, accurate preoperative diagnosis of these entities is exceedingly difficult, and the mechanism(s) of their formation remains unclear. CASE PRESENTATION: A 40-year-old woman visited the authors' hospital due to lower abdominal pain and diarrhea. She had previously been treated for endometriosis. Laboratory investigation revealed increased C-reactive protein levels. Abdominal contrast-enhanced computed tomography revealed thickening of the appendix wall and dilation of the small intestine. The patient was diagnosed with paralytic ileus caused by appendicitis, and interval appendectomy was scheduled. She underwent laparoscopic-assisted appendectomy after conservative treatment. Partial cecal resection was selected due to the presence of an elastic mass in the cecum. The final pathological diagnosis was submucosal fecalith, not submucosal tumor. On day 5, the patient was discharged without any postoperative complications. CONCLUSIONS: In cases of appendicitis with fecalith(s) that appear as submucosal tumor(s) on colonoscopy, submucosal fecalith mimicking submucosal tumor should be considered in the differential diagnosis.

Risk Factors for Anastomotic Leakage after Colorectal Surgery with Double-staple Technique Anastomosis: Impact of the Agatston Score.

OBJECTIVES: Anastomotic leakage is associated with severe morbidity, mortality, and functional defects. Its risk factors remain unclear. However, blood perfusion may be a potential major risk factor. It has been reported that the Agatston score is an index for blood flow perfusion evaluation. Therefore, we evaluated the clinical indicators associated with anastomotic leakage, including the Agatston score, in patients who underwent colorectal surgery. METHODS: We retrospectively analyzed 147 patients who underwent elective colorectal surgery with the double-staple technique anastomosis for colorectal cancer between April 2015 and March 2020. The primary outcome was the presence or absence of anastomotic leakage. Univariate and multivariate analyses were employed to identify pre- and intraoperative risk factors. RESULTS: Of the 147 patients analyzed, anastomotic leakage occurred in 12 (8.16%). Male gender, history of angina and myocardial infarction, preoperative white blood cell count, the Agatston score, extent of bleeding, operation time, and intraoperative fluid volume were significantly related to a higher incidence of anastomotic leakage in univariate analysis. Multivariate analysis demonstrated that the incidence of anastomotic leakage was high in patients with a high Agatston score. CONCLUSIONS: The Agatston score can predict the incidence of anastomotic leakage in patients following colorectal surgery. Thus, perioperative measures to prevent anastomotic leakage are recommended when a high Agatston score is observed. A prospective trial is required to demonstrate, with a high level of evidence, that the Agatston score can be useful as a risk score for anastomotic leakage following colorectal surgery.

Large hydrocele of the canal of Nuck diagnosed and treated using conventional and laparoscopic methods.

A 49-year-old woman presented to the hospital with a right inguinal swelling. On examination, we suspected hydrocele of the canal of Nuck (HCN) or an appendiceal or retroperitoneal tumor. Surgery for diagnosis and removal of the mass revealed that it was large and located in the preperitoneal cavity, extending into the inguinal ring; so, it was difficult to observe the entire outline of the mass solely using the laparoscopic approach. Therefore, we added the conventional approach with an inguinal incision. This combination of conventional and laparoscopic approaches helped in safe removal of the tumor. The HCN is an unusual developmental condition in women among whom it might cause an inguinal swelling infrequently. In a case with a large HCN, a combined approach using conventional and laparoscopic methods is suggested for better observation of the abdomen and successful resection without perforation of the mass than when using a single approach.

Mixed neuroendocrine-non-neuroendocrine neoplasms of ascending colon: A case report.

INTRODUCTION: Neuroendocrine tumor (NET) that develops in the right-sided colon is relatively rare. Coexistence of adenocarcinoma and NET is extremely rare, and such cases are called mixed neuroendocrine-non-neuroendocrine neoplasm (MiNEN). PRESENTATION OF CASE: Colonoscopy in an 85-year-old woman for an anemia examination indicated laterally spreading tumor-nongranular (LST-NG) in the transverse colon. Colonoscopy and endoscopic ultrasonography (EUS) showed that the depth of the tumor invasion was deep submucosal. The tumor localization was diagnosed as transverse colon close to the hepatic curvature by enema. Computed tomography (CT) showed no obvious lymph node or distant metastasis. Based on these findings, laparoscopic transverse colectomy with D2 lymphadenectomy was performed. Pathologically, most of the tumor was well-differentiated tubular adenocarcinoma, but some solid follicles of polygonal tumor cells with poor nuclear atypia were observed. Immunostaining was positive for synaptophysin and diagnosed as NET G1. This tumor consisted of adenocarcinoma and neuroendocrine tumor, so we diagnosed it as MiNEN and classified the tumor as fT1N0M0 fStage I (TNM Classification of Malignant Tumors, 8th Edition). Since it was an early stage cancer, postoperative adjuvant therapy was not performed. No recurrence has yet been noted. DISCUSSION: Although MiNEN is extremely rare, the detailed pathological specimen observation and diagnosis are important because long-term follow-up after surgery is needed, as is the adequate selection of postoperative adjuvant therapy. CONCLUSION: It is important to elucidate the mechanisms involved in the coexistence of NET and adenocarcinoma and to apply these findings to future medical care.

Rectal Arteriovenous Malformation Treated by Transcatheter Arterial Embolization.

An 86-year-old man who presented with frequent hematochezia with mild anemia on blood tests was admitted to our hospital. Colonoscopy exhibited a submucosal tumor-like lesion in the lower rectum. CT and MRI showed blood flow into the lesion, but not tumor component. Angiography of the superior rectal artery and left internal iliac artery showed vascular hyperplasia and nidus. Thus, rectal arteriovenous malformation was diagnosed. If bleeding from arteriovenous malformation was out of control, surgical resection was necessary. However, due to the age of the patient, we performed transcatheter arterial embolization and abdominoperineal resection was not needed. Embolization from the left superior rectal artery, middle rectal artery and inferior rectal artery was performed to control the bleeding and to avoid surgery. After embolization, he was followed up for 10 months in our hospital without recurrence.