[A Case of Long-Term Response to Chemotherapy in Mucinous Carcinoma of the Duodenum with Multiple Distant Metastases].

Primary carcinoma of the duodenum, especially mucinous carcinoma of the duodenum, is extremely rare. We present a case of a long-term response to chemotherapy in mucinous carcinoma of the duodenum with multiple distant metastases. A 60-year-old man was admitted to our hospital with epigastric pain and jaundice. CT showed a thickening of the duodenal wall; extensive lymphadenopathy around the head of the pancreas, in the para-aortic region and the mediastinum; suspected peritoneal dissemination; lung metastases; and bone metastases. An upper gastrointestinal endoscopy revealed a duodenal stenosis in the descending limb with irregular mucosa, and a diagnosis of mucinous carcinoma of the duodenum was made on the basis of the histological analysis of the biopsy sample. Double bypass surgery involving a choledochojejunostomy and gastrojejunostomy were performed for obstruction of the duodenum and common bile duct. After FOLFOXIRI therapy was initiated, the tumors were reduced markedly. Despite withdrawal after 28 courses of chemotherapy, the patient achieved a long-term response for 10 years after the initiation of chemotherapy.

Development of an ultralow-latency communication system using shared internet access: promoting the implementation of telemedicine.

Telemedicine is becoming increasingly important to address the shortage of gastrointestinal surgeons and disparities in domestic and international treatment outcomes for patients with colorectal cancer. The development of a low-latency communication system using existing communication infrastructure (shared internet access: SIA) is necessary to promote the use of telemedicine. The aim of this study was to develop a low-latency communication system using SIA. We conducted an experiment between Sapporo and Tokyo using an ultralow-latency communication system for remote medical education (TELEPRO®). The latency was measured using 2000 annotations from a monitor in Sapporo, which confirmed a median latency of 27.5 ms. A low-latency communication system based on SIA with latency lower than the maximum allowable latency for telemedicine was developed successfully.

DENEB: Development of new criteria for curability after local excision of pathological T1 colorectal cancer using liquid biopsy.

According to the current international guidelines, high-risk patients diagnosed with pathological T1 (pT1) colorectal cancer (CRC) who underwent complete local resection but may have risk of developing lymph node metastasis (LNM) are recommended additional intestinal resection with lymph node dissection. However, around 90% of the patients without LNM are exposed to the risk of being overtreated due to the insufficient pathological criteria for risk stratification of LNM. Circulating tumor DNA (ctDNA) is a noninvasive biomarker for molecular residual disease and relapse detection after treatments including surgical and endoscopic resection of solid tumors. The CIRCULATE-Japan project includes a large-scale patient-screening registry of the GALAXY study to track ctDNA status of patients with stage II to IV or recurrent CRC that can be completely resected. Based on the CIRCULATE-Japan platform, we launched DENEB, a new prospective study, within the GALAXY study for patients with pT1 CRC who underwent complete local resection and were scheduled for additional intestinal resection with lymph node dissection based on the standard pathologic risk stratification criteria for LNM. The aim of this study is to explore the ability of predicting LNM using ctDNA analysis compared with the standard pathological criteria. The ctDNA assay will build new evidence to establish a noninvasive personalized diagnosis in patients, which will facilitate tailored/optimal treatment strategies for CRC patients.

Clinical Utility and Characteristics of the LARS Score Compared to the CCIS.

PURPOSE: The low anterior resection syndrome (LARS) score (LS) has been widely validated and has become an international tool for evaluating postoperative bowel dysfunction. However, many physicians still use the conventional incontinence scores in LARS treatment. Moreover, interpretation of LS and its relationship with conventional incontinence scores are not yet well understood. Here we compared the LS with the Cleveland Clinic Incontinence Score (CCIS) to clarify the clinical utility and characteristics of the LARS score. METHODS: We performed a multicentre observational study, recruiting 246 rectal cancer patients following sphincter-preserving surgery. Patients completed the LS, CCIS, and SF36 questionnaires. RESULTS: The response rate was 76.4%, and a total of 180 patients were analysed. The LS was strongly correlated with the CCIS (P < 0.001, rs = 0.727). However, among 116 patients determined to not have incontinence (CCIS 0-5), 51 (44%) were diagnosed with LARS (29 with minor LARS and 22 with major LARS). Among 68 patients without LARS, only 3 were diagnosed as having incontinence (CCIS > 6). In comparison with background factors, aging and elapsed time were associated with only LS. High LS and CCIS both showed significant quality-of-life impairment as assessed by the SF-36. CONCLUSION: This is the first study to determine the difference in the numeric values between the CCIS and LS. The LS can be a convenient tool for LARS screening, identifying a wide range of patients with LARS, including those with incontinence evaluated by CCIS. Assessment using the CCIS may often underestimate LARS.

Feasibility of the semi-opened method of specimen resection for a circumferential resection margin in rectal cancer surgery: a multicenter study.

PURPOSE: A circumferential resection margin (CRM) > 1 mm is a surrogate marker of oncologic outcomes in rectal cancer patients. In Japan, because the mesentery is removed from the rectum, the CRM cannot be measured. This multicenter prospective study evaluates the feasibility of a resected specimen processing method that allows CRM measurement. METHODS: Fifty patients with rectal cancer were enrolled. Resected specimens were processed as previously reported. The primary outcomes were CRM measurement and the rate of CRM positivity. The secondary outcomes were the quality of total mesorectal excision, the possibility to visualize and sample the tumor, the number of harvested lymph nodes, and comparison between the pathological CRM and preoperative mesorectal fascia (MRF) involvement. This study was registered in the University Hospital Medical Information Network (UMIN) Clinical Trials Registry under identification number UMIN000031735. RESULTS: The CRM was measurable in all patients and found to be positive in three (6%). We confirmed tumor localization, sampled the tumor, and measured the distal margin in all patients. A median of 20 lymph nodes were harvested. The concordance rate between preoperative MRF involvement and pathological CRM status was 90%. CONCLUSION: A semi-opened rectal specimen with transverse slicing is a feasible method for measuring the CRM.

Timing of indocyanine green injection prior to laparoscopic colorectal surgery for tumor localization: a prospective case series.

BACKGROUND: Accurate identification of tumor sites during laparoscopic colorectal surgery helps to optimize oncological clearance. We aimed to assess the timing of the local injection preoperatively and clarify the usefulness and limitation of tumor site marking using indocyanine green (ICG) fluorescence imaging. METHODS: Consecutive patients who underwent primary colorectal cancer surgery from September 2017 to January 2019 were included. Preoperatively, lower endoscopy was used to inject the ICG solution into the submucosal layer near the tumor. During laparoscopic surgery, ICG fluorescence marking as the tumor site marking was detected using a laparoscopic near-infrared camera system. The detection rate and factors associated with successful intraoperative ICG fluorescence visualization including the interval between local injection and surgery were evaluated. RESULTS: One hundred sixty-five patients were enrolled. Using the laparoscopic near-infrared system, the intraoperative detection rates of ICG marking were 100% for ICG injection within 6 days preoperatively, 60% for injection between 7 and 9 days preoperatively, and 0% for injection earlier than 10 days preoperatively. There were no complications associated with ICG marking. Additionally, this method did not disturb the progress of the surgical procedure because injected ICG in the submucosal layer did not cause any tissue inflammation, and if ICG spilled into the serosa, it was invisible by white light. CONCLUSION: Advantages of ICG fluorescence tumor site marking were high visibility of infrared imaging during laparoscopic colorectal surgery and minimal adverse events of surgery. One of the most important findings regarding practical use was a rapid decrease in fluorescence marking visibility if one week passed from the time of ICG local injection.

Perspectives for circulating tumor DNA in clinical management of colorectal cancer.

Growing evidence has demonstrated that circulating tumor DNA (ctDNA) detection in colorectal cancer might be a promising approach to address current important clinical questions. During chemotherapy for metastatic colorectal cancer, tumor cells acquire potential resistance by generating additional somatic mutations related to therapeutic resistance. ctDNA can capture the tumor landscape, including heterogeneity, which might provide the opportunity for additional treatment options. Moreover, ctDNA detection is advantageous, because it can monitor tumor heterogeneity serially, in a non-invasive manner. ctDNA is considered valid for detecting minimal residual disease after a curable resection. By utilizing ctDNA detection, adjuvant chemotherapy for patients with stage II-III colorectal cancer might be omitted for patients at low risk of recurrence; or conversely, adjuvant chemotherapy might be highly recommended for patients at high risk, based on ctDNA findings. During multidisciplinary treatments for locally advanced rectal cancer, it is essential to monitor the responses to sequential treatments to make appropriate decisions. Currently, these decisions are mainly based on radiological or pathological findings. ctDNA can add value by providing the real-time status of locally advanced rectal cancer. In this review, we summarized the current evidence and discussed future strategies for using ctDNA in the treatment of colorectal cancer.

Surgical anatomy of the pelvis for total pelvic exenteration with distal sacrectomy: a cadaveric study.

PURPOSE: Intraoperative bleeding from the pelvic venous structures is one of the most serious complications of total pelvic exenteration with distal sacrectomy. The purpose of this study was to investigate the topographic anatomy of these veins and the potential source of the bleeding in cadaver dissections. METHODS: We dissected seven cadavers, focusing on the veins in the surgical resection line for total pelvic exenteration with distal sacrectomy. RESULTS: The presacral venous plexus and the dorsal vein complex are thin-walled, plexiform, and situated on the line of resection. The internal iliac vein receives blood from the pelvic viscera and the perineal and the gluteal regions and then crosses the line of resection as a high-flow venous system. It has abundant communications with the presacral venous plexus and the dorsal vein complex. CONCLUSION: The anatomical features of the presacral venous plexus, the dorsal vein complex, and the internal iliac vein make them highly potential sources of bleeding. Surgical management strategies must consider the anatomy and hemodynamics of these veins carefully to perform this procedure safely.

MRI-detected extramural vascular invasion potentiates the risk for pathological metastasis to the lateral lymph nodes in rectal cancer.

PURPOSE: Multidisciplinary treatment for locally advanced rectal cancer requires an accurate assessment of the risk of metastasis to the lateral lymph nodes (LNs). We herein aimed to stratify the risk of pathological metastasis to lateral LNs based on the preoperatively detected malignant features. METHODS: All patients with rectal cancer who underwent surgery from January 2016 to July 2020 were identified. We recorded the TNM factors; perirectal and lateral LN sizes; and MRI findings, including mesorectal fascia involvement, extramural vascular invasion (EMVI), tumor site, and tumor distance from the anal verge. RESULTS: 101 patients underwent rectal resection with lateral lymph node dissection, of whom 16 (15.8%) exhibited pathological metastases to the lateral LNs. Univariate analyses demonstrated that lateral LN metastasis was significantly correlated with mrEMVI positivity (p = 0.0023) and a baseline lateral LN short-axis length of ≥ 5 mm (p < 0.0001). These significant associations were confirmed by a multivariate analysis (p = 0.0254 and 0.0027, respectively). The lateral LN metastasis rate was as high as 44% in cases bearing both risk factors, compared to 0% in cases lacking both risk factors. CONCLUSION: The results elucidated in this study may contribute to risk stratification, which can be used when determining the indications for lateral lymph node dissection.

Emergency surgery for hemobilia due to hepatic artery pseudoaneurysm rupture complicated by Mirizzi syndrome type II: a case report.

BACKGROUND: Hemobilia refers to bleeding into the biliary tract. Hepatic artery pseudoaneurysm (HAP) rupture is an uncommon cause of hemobilia, and cases of HAP associated with Mirizzi syndrome are extremely rare. Although transarterial embolization is recommended as the first-line treatment for hemobilia, surgery is sometimes required. CASE PRESENTATION: A 76-year-old woman was referred to our hospital with epigastric pain. She was febrile and had conjunctival icterus and epigastric tenderness. Laboratory tests revealed abnormal white blood cell count and liver function. An abdominal computed tomography (CT) revealed multiple calculi in the gallbladder, an incarcerated calculus in the cystic duct, and a slightly dilated common hepatic duct. Based on examination findings, she was diagnosed with Mirizzi syndrome type I, complicated by cholangitis. Intravenous antibiotics were administered, and we performed endoscopic retrograde cholangiopancreatography (ERCP) to place a drainage tube. The fever persisted; therefore, contrast-enhanced CT (CECT) was performed. This revealed portal vein thrombosis and hepatic abscesses; therefore, heparin infusion was administered. The following day, she complained of melena, and laboratory tests showed that she was anemic. ERCP was performed to change the drainage tube in the bile duct; however, bleeding from the papilla of Vater was observed. CECT demonstrated a right HAP with high-density fluid in the gallbladder and gallbladder perforation. Finally, she was diagnosed with hemobilia caused by HAP rupture, and emergency surgery was performed to secure hemostasis and control the infection. During laparotomy, we found that a right HAP had ruptured into the gallbladder. The gallbladder made a cholecystobiliary fistula, which indicated Mirizzi syndrome type II. Although we tried to repair the right hepatic artery, we later ligated it due to arterial wall vulnerability. Then, we performed subtotal cholecystectomy and inserted a T-tube into the common bile duct. There were no postoperative complications except for minor leakage from the T-tube insertion site. The patient was discharged after a total hospital stay of 7 weeks. CONCLUSIONS: We experienced an extremely rare case of emergency definitive surgery for hemobilia due to HAP rupture complicated by Mirizzi syndrome type II. Surgery might be indicated when controlling underlying infections was required.

[Three Cases of No. 16 Lymph Node Metastasis-Positive Gastric Cancer Successfully Treated with Chemotherapy and Para-Aortic Lymph Node Dissection].

Chemotherapy is standard treatment for Stage Ⅳ advanced gastric cancer(AGC)positive for No. 16 lymph node(LN) metastasis, but the significance of conversion surgery remains unclear. S-1 plus CDDP(SP), primary lesion resection+ para-aortic LN dissection(PAND), and postoperative recurrence-free survival are reported. Case 1: A 70-year-old woman had AGC with para-aortic LN metastases(tub1, HER2 score 3+, cT3N2M1, cStage Ⅳ). Four courses of SP plus trastuzumab were administered, which shrank the primary tumor and metastatic LNs. She underwent distal gastrectomy with D2+PAND (No. 16a2 int-b1 int). Histopathology showed metastasis to No. 16 LN, with Grade 2 histological effect. She underwent adjuvant chemotherapy with S-1 and 4-year recurrence-free follow-up. Case 2: An 80-year-old man with AGC rand para- aortic LN metastases(por, cT3N2M1, cStage Ⅳ)underwent 4 courses of SP, which shrank the primary tumor and metastatic LNs. He underwent total gastrectomy with D2+PAND(No. 16a2 lat)dissection. Histopathology showed no residual tumor cells in LNs. Follow-up for 3 years has shown no recurrence without chemotherapy. Case 3: A 50-year-old woman with epigastric pain and anemia had AGC with para-aortic LN metastases(tub2, cT3N3M1, cStage Ⅳ). She underwent distal gastrectomy with D2+PAND(No. 16a2 int-b1 lat). After 1-year chemotherapy with SP, follow-up for 5 years showed no recurrence. In AGC with para-aortic LN metastases, long-term survival can be expected by combining selective PAND with SP therapy.

Efficacy of indocyanine green fluorescence angiography in preventing anastomotic leakage after laparoscopic colorectal cancer surgery.

PURPOSE: Some recent studies have suggested that fluorescence angiography with indocyanine green (ICG) might be useful for preventing anastomotic leakage (AL) after laparoscopic colorectal surgery. However, its efficacy has not been proven. We evaluated whether intraoperative ICG fluorescence angiography could decrease the AL rate with laparoscopic colorectal cancer surgery. METHODS: This retrospective study included patients with colorectal cancer who underwent laparoscopic surgery at our institution between March 2014 and December 2018. Patients were divided into two groups: with or without ICG fluorescence angiography. The primary outcome was the rate of AL. RESULTS: A total of 488 patients were included: 223 patients in the ICG group and 265 patients in the no-ICG group. In the ICG group, the transection line was changed to a more proximal location in seven patients (3.1%), including one patient with transverse colon surgery and six with rectal surgery. None of these seven patients developed AL. There were 18 ALs (3.7%) overall. The AL rate was 1.8% in the ICG group and 5.3% in the no-ICG group. For colon cancer, there were no significant differences in the AL rate between the groups (p = 0.278). In rectal cancer, the AL rate was significantly lower in the ICG group than in the no-ICG group (3.5% vs. 10.5%, p = 0.041). After propensity score matching, the AL rate was also significantly lower in the ICG group for rectal cancer (p = 0.044). CONCLUSION: ICG fluorescence angiography can potentially reduce the AL rate with laparoscopic rectal cancer surgery.

Evaluation of negative-pressure wound therapy for surgical site infections after ileostomy closure in colorectal cancer patients: a prospective multicenter study.

PURPOSE: Surgical site infection (SSI) occurs at a high rate after ileostomy closure. The effect of preventive negative-pressure wound therapy (NPWT) on SSI development in closed wounds remains controversial. We conducted a prospective multicenter study to evaluate the usefulness of preventive NPWT for SSI after ileostomy closure. METHODS: From January 2018 to November 2018, 50 patients who underwent closure of ileostomy created after surgery for colorectal cancer participated in this study. An NPWT device was applied to each wound immediately after surgery and then treatment was continued for 3 days. The primary endpoint was 30-day SSI, and the secondary endpoints were the incidence of seroma, hematoma, and adverse events related to NPWT. RESULTS: No patients developed SSI, seroma, or hematoma. Adverse events that may have been causally linked with NPWT were contact dermatitis in two patients and wound pain in one patient, and there were no cases of discontinuation or decompression of NPWT. CONCLUSION: The use of NPWT following ileostomy closure may be useful for reducing the development of SSI in colorectal cancer patients. This is a prospective multicenter pilot study and we are planning a comparative study based on these successful results. TRAIL REGISTRATION: Registration number: UMIN000032053 ( https://www.umin.ac.jp/ ).

Transplantation of Thy1+ Cells Accelerates Liver Regeneration by Enhancing the Growth of Small Hepatocyte-Like Progenitor Cells via IL17RB Signaling.

Small hepatocyte-like progenitor cells (SHPCs) transiently form clusters in rat livers treated with retrorsine (Ret)/70% partial hepatectomy (PH). When Thy1+ cells isolated from d-galactosamine-treated rat livers were transplanted into the livers of Ret/PH-treated rats, the mass of the recipient liver transiently increased during the first 30 days after transplantation, suggesting that liver regeneration was enhanced. Here we addressed how Thy1+ cell transplantation stimulates liver regeneration. We found that the number and size of SHPC clusters increased in the liver at 14 days after transplantation. GeneChip analysis revealed that interleukin 17 receptor b (IL17rb) expression significantly increased in SHPCs from livers transplanted with Thy1+ cells. We subsequently searched for ligand-expressing cells and found that sinusoidal endothelial cells (SECs) and Kupffer cells expressed Il17b and Il25, respectively. Moreover, extracellular vesicles (EVs) separated from the conditioned medium of Thy1+ cell culture induced IL17b and IL25 expression in SECs and Kupffer cells, respectively. Furthermore, EVs enhanced IL17rb expression in small hepatocytes (SHs), which are hepatocytic progenitor cells; in culture, IL17B stimulated the growth of SHs. These results suggest that Thy1-EVs coordinate IL17RB signaling to enhance liver regeneration by targeting SECs, Kupffer cells, and SHPCs. Indeed, the administration of Thy1-EVs increased the number and size of SHPC clusters in Ret/PH-treated rat livers. Sixty days post-transplantation, most expanded SHPCs entered cellular senescence, and the enlarged liver returned to its normal size. In conclusion, Thy1+ cell transplantation enhanced liver regeneration by promoting the proliferation of intrinsic hepatic progenitor cells via IL17RB signaling. Stem Cells 2017;35:920-931.

Reappraisal of the lateral rectal ligament: an anatomical study of total mesorectal excision with autonomic nerve preservation.

PURPOSE: The term "lateral rectal ligament" in surgery for rectal cancer has caused confusion regarding its true existence and contents. In previous studies, investigators claimed the existence of the ligament and described its topographical features as neurovascular structures and their surrounding connective tissues located at the anterolateral aspect of the distal rectum or the posterolateral aspect of the middle rectum. The purpose of this study is to evaluate the structure of the so-called "lateral rectal ligament" in cadaver dissections. METHODS: Dissection was performed in nine cadavers (eight males and one female, aged 73 to 94 years) in accordance with typical total mesorectal excision techniques. During dissection, structures related to "the ligament" were examined and images recorded. RESULTS: At the anterolateral aspect of the distal rectum, the middle rectal artery was noted to be crossing the fusion of Denonvilliers' fascia and the proper rectal fascia. At the posterolateral aspect of the middle rectum, there was a structure which consisted of the rectal nerves running through the fusion of the pelvic fasciae. Although called "ligaments," neither structure contained discrete strong connective tissue fixing the rectum to the pelvic wall. CONCLUSIONS: The proper rectal fascia and surrounding pelvic fasciae fuse firmly anterolaterally and posterolaterally where neurovascular structures course toward the rectum. During a total mesorectal excision, the surgical dissection plane coincides with the fused part of the fasciae, which had long been considered the "lateral rectal ligament."

Effectiveness of Pelvic Floor Rehabilitation for Bowel Dysfunction After Intersphincteric Resection for Lower Rectal Cancer.

BACKGROUND: The aim of this study was to evaluate the effectiveness of pelvic floor rehabilitation (PFR) for patients with bowel dysfunction after intersphincteric resection (ISR) and to compare the treatment response to that of patients after low anterior resection (LAR). METHODS: Thirty patients with postoperative bowel dysfunction for more than 6 months were enrolled and treated with PFR for 6 months. RESULTS: In the ISR group, significant improvements in the number of bowel movements and the use of antidiarrheal medications were observed, but no significant improvement was observed in the Wexner score (WS) and the fecal incontinence severity index (FISI). Meanwhile, in the LAR group, WS and FISI were better post-treatment than pre-treatment (WS: 10.7-5.7; p = 0.01, FISI: 28-11; p = 0.01). In the assessment of fecal incontinence quality of life (FIQL), only the Coping/Behavior category was improved in the ISR group (1.56 before, 2.16 after PFR; p = 0.01), while all four categories were improved significantly in the LAR group. The anorectal manometric examination showed no significant increase in sphincter pressure and the tolerable volume in patients after ISR. CONCLUSIONS: PFR improved several clinical symptoms of patients after ISR. Compared with patients after LAR, patients after ISR showed an insufficient response to PFR in improving fecal incontinence. Considering the result of the generalized assessment of the quality of life scale, PFR may offer a therapeutic effect for several symptoms of patients after ISR.

Validation of the Japanese Version of the Low Anterior Resection Syndrome Score.

BACKGROUND: The low anterior resection syndrome (LARS) score is a patient-reported outcome measure to evaluate the severity of bowel dysfunction after rectal cancer surgery by scoring the major symptoms of LARS. The aim of this study was to translate the English version of the LARS score into Japanese and to investigate the validity and reliability of the LARS score. METHODS: The LARS score was translated in Japanese following current international recommendations. A total of 149 rectal cancer patients completed the LARS score questionnaire and were also asked a single question assessing the impact of bowel function on quality of life (QoL). A total of 136 patients answered the LARS score questionnaire twice. RESULTS: The Japanese LARS score showed high convergent validity, based on its good correlation between the LARS score and QoL (p < 0.001). The LARS score was able to discriminate between patients according to the tumor distance to anal verge (p < 0.001), type of surgery (p < 0.001), and time since surgery (p = 0.001). Patients after ultra-low anterior resection and intersphincteric resection showed especially high scores. The score also had high test-retest reliability (intraclass correlation coefficient: 0.87). CONCLUSION: The Japanese LARS score is a valid and reliable tool for measuring LARS. The LARS score is appropriate for assessments in postoperative bowel function and international comparison. Using this score, patient-reported outcome measures of LARS in Japanese patients can be shared internationally. Additional validation reports from non-English speaking countries can support the LARS score as a worldwide assessment tool for postoperative bowel dysfunction.

Intrahepatic bile ducts are developed through formation of homogeneous continuous luminal network and its dynamic rearrangement in mice.

UNLABELLED: The intrahepatic bile duct (IHBD) is a highly organized tubular structure consisting of cholangiocytes, biliary epithelial cells, which drains bile produced by hepatocytes into the duodenum. Although several models have been proposed, it remains unclear how the three-dimensional (3D) IHBD network develops during liver organogenesis. Using 3D imaging techniques, we demonstrate that the continuous luminal network of IHBDs is established by 1 week after birth. Beyond this stage, the IHBD network consists of large ducts running along portal veins (PVs) and small ductules forming a mesh-like network around PVs. By analyzing embryonic and neonatal livers, we found that newly differentiated cholangiocytes progressively form a continuous and homogeneous luminal network. Elongation of this continuous network toward the liver periphery was attenuated by a potent Notch-signaling inhibitor N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester. Subsequent to this first step, the fine homogenous network is reorganized into the mature hierarchical network consisting of large ducts and small ductules. Between E17 and E18, when the homogenous network is radically reorganized into the mature hierarchical network, bile canaliculi rapidly extend and bile flow into IHBDs may increase. When formation of bile canaliculi was blocked between E16 and E18 by a multidrug resistance protein 2 inhibitor (benzbromarone), the structural rearrangement of IHBDs was significantly suppressed. CONCLUSION: Establishment of the mature IHBD network consists of two sequential events: (1) formation of the continuous luminal network regulated by the Notch-signaling pathway and (2) dynamic rearrangement of the homogeneous network into the hierarchical network induced by increased bile flow resulting from the establishment of hepatobiliary connections. (Hepatology 2016;64:175-188).

Liver Progenitors Isolated from Adult Healthy Mouse Liver Efficiently Differentiate to Functional Hepatocytes In Vitro and Repopulate Liver Tissue.

It has been proposed that tissue stem cells supply multiple epithelial cells in mature tissues and organs. However, it is unclear whether tissue stem cells generally contribute to cellular turnover in normal healthy organs. Here, we show that liver progenitors distinct from bipotent liver stem/progenitor cells (LPCs) persistently exist in mouse livers and potentially contribute to tissue maintenance. We found that, in addition to LPCs isolated as EpCAM+ cells, liver progenitors were enriched in CD45- TER119- CD31- EpCAM- ICAM-1+ fraction isolated from late-fetal and postnatal livers. ICAM-1+ liver progenitors were abundant by 4 weeks (4W) after birth. Although their number decreased with age, ICAM-1+ liver progenitors existed in livers beyond that stage. We established liver progenitor clones derived from ICAM-1+ cells between 1 and 20W and found that those clones efficiently differentiated into mature hepatocytes (MHs), which secreted albumin, eliminated ammonium ion, stored glycogen, and showed cytochrome P450 activity. Even after long-term culture, those clones kept potential to differentiate to MHs. When ICAM-1+ clones were transplanted into nude mice after retrorsine treatment and 70% partial hepatectomy, donor cells were incorporated into liver plates and expressed hepatocyte nuclear factor 4α, CCAAT/enhancer binding protein α, and carbamoylphosphate synthetase I. Moreover, after short-term treatment with oncostatin M, ICAM-1+ clones could efficiently repopulate the recipient liver tissues. Our results indicate that liver progenitors that can efficiently differentiate to MHs exist in normal adult livers. Those liver progenitors could be an important source of new MHs for tissue maintenance and repair in vivo, and for regenerative medicine ex vivo. Stem Cells 2016;34:2889-2901.

Pancreatic regeneration: basic research and gene regulation.

Pancreatic regeneration (PR) is an interesting phenomenon that could provide clues as to how the control of diabetes mellitus might be achieved. Due to the different regenerative abilities of the pancreas and liver, the molecular mechanism responsible for PR is largely unknown. In this review, we describe five representative murine models of PR and thirteen humoral mitogens that stimulate ß-cell proliferation. We also describe pancreatic ontogenesis, including the molecular transcriptional differences between α-cells and ß-cells. Furthermore, we review 14 murine models which carry defects in genes related to key transcription factors for pancreatic ontogenesis to gain further insight into pancreatic development.