Proposal of the novel predictive model for postoperative pancreatic fistula in distal pancreatectomy for pancreatic tumor based on preoperative imaging parameters and stapler handling.

BACKGROUND: Distal pancreatectomy (DP) using linear staplers is widely performed; however, postoperative pancreatic fistulas (POPF) remain an issue. This study aimed to analyze preoperative risk factors for POPF and assess stapler handling. METHODS: We retrospectively analyzed consecutive patients who underwent DP for pancreatic tumors using a linear stapler between 2014 and 2022. Preoperative measurements included pancreas-to-muscle signal intensity ratio (SIR) on fat-suppressed T1-weighted magnetic resonance imaging (MRI). The main outcome was clinically relevant POPF of the 2016 International Study Group of Pancreatic Fistulas definition. The predictive ability of the model was compared with the distal fistula risk score (D-FRS) by using the area under the receiver operating characteristic curve (AUROC). RESULTS: Among the 81 patients, POPF occurred in 31 (38.2%). Multivariate analysis identified computed tomography-measured pancreatic thickness (odds ratio [OR] 1.30, 95% confidence interval [CI] 1.05-1.61, p = 0.009) and SIR on T1-weighted MRI (OR 6.85, 95% CI 1.71-27.4, p = 0.002) as preoperative predictors. A novel preoperative model, "Thickness × MRI (TM)"-index, was established by multiplying these two variables. The TM-index exhibited the highest predictability preoperatively (AUROC 0.757, 95% CI 0.649-0.867). In the intraoperative variable analyses, TM-index (p < 0.001), thin cartridge application (p = 0.032), and short pre-firing compression (p = 0.047) were identified as significant risk factors for POPF. The model's AUROC combined with these two stapler handling methods was higher than D-FRS (0.851 vs. 0.660, p = 0.006). CONCLUSIONS: The novel preoperative model exhibited excellent predictability. Thick cartridge use and long pre-firing compression were protective factors against POPF. This model may facilitate preventive surgical strategy development to reduce POPF.

Management of Patients Receiving Antiplatelet Therapy During Gastroenterological Surgery: A Multicenter Prospective Cohort Study (GSATT).

OBJECTIVE: This study aimed to evaluate the effect of continuing preoperative aspirin monotherapy on surgical outcomes in patients receiving antiplatelet therapy (APT). SUMMARY BACKGROUND DATA: The effectiveness of continuing preoperative aspirin monotherapy in patients undergoing APT in preventing thromboembolic consequences is mostly unknown. METHODS: This prospective multicenter cohort study on the Safety and Feasibility of Gastroenterological Surgery in Patients Undergoing Antithrombotic Therapy (GSATT study) conducted at 14 clinical centers enrolled and screened patients between October 2019 and December 2021. The participants (n=1,170) were assigned to the continued APT group, discontinued APT group, or non-APT group, and the surgical outcomes of each group were compared. Propensity score matching was performed between the continued and discontinued APT groups to investigate the effect of continuing preoperative aspirin therapy on thromboembolic complications. RESULTS: The rate of thromboembolic complications in the continued APT group was substantially lower than that in the non-APT or discontinued APT groups (0.5% vs. 2.6% vs. 2.9%; P=0.027). Multivariate investigation of the entire cohort revealed that discontinuation of APT (P<0.001) and chronic anticoagulant use (P<0.001) were independent risk factors for postoperative thromboembolism. The post-matching evaluation demonstrated that the rates of thromboembolic complications were significantly different between the continued and discontinued APT groups (0.6% vs. 3.3%; P=0.012). CONCLUSIONS: APT discontinuation following elective gastroenterological surgery increases the risk of thromboembolic consequences, whereas continuing preoperative aspirin greatly reduces this risk. The continuation of preoperative aspirin therapy in APT-received patients is considered one of the best alternatives for preventing thromboembolism during elective gastroenterological surgery.

Identification of patient subgroups with low risk of postoperative local recurrence for whom total mesorectal excision surgery alone is sufficient: a multicenter retrospective analysis.

PURPOSE: For rectal cancer, a multimodality approach is mandatory including neoadjuvant chemoradiotherapy, neoadjuvant chemotherapy, and lateral pelvic lymph node (LPLN) dissection, in addition to the total mesorectal excision (TME). However, these treatments are associated with adverse events. It is important to select patients who do or do not need these treatments. METHODS: We retrospectively analyzed patients with cStage II and III rectal cancer who underwent curative resection at three hospitals. Recurrence patterns were classified into three types; pelvic cavity, LPLN, and distant recurrences, and the risk factors for each pattern of recurrence were compared. We then analyzed the risk of recurrence in the patients who underwent TME alone. RESULTS: In total, 506 patients were enrolled in this study. Pelvic cavity recurrence was significantly associated with clinical assumption of circumferential resection margin involvement (cCRM) (p < 0.001), distant recurrence was associated with cN positivity (p < 0.001), and LPLN recurrence was associated with pretreatment LPLN swelling ≥ 5 mm (p < 0.001), lower tumor location (p = 0.016), and serum CEA level > 5 ng/mL (p = 0.008). In patients without cCRM and swollen LPLN, the local recurrence rate was extremely low even if they underwent TME alone; the 5-year recurrence rates of pelvic cavity and LPLN were 2.2% and 1.9%, respectively. CONCLUSION: Additional treatments to TME for rectal cancer need to be performed based on the risk factors for each recurrence pattern.

Differences in clinical and cost-effectiveness between cefmetazole and flomoxef for the prevention of surgical site infection in elective colorectal surgery: A single-center, retrospective cohort study.

INTRODUCTION: Surgical site infection (SSI) is associated with increased morbidity and mortality rates, postoperative length of stay (pLOS), and medical costs. In colorectal surgery, cefmetazole (CMZ) and flomoxef (FMOX) are predominantly used in Japan, and they have almost the same spectrum of antibiotic activity against SSI pathogens, and an approximately four-fold cost difference (CMZ: ∼4$, FMOX: ∼16$). However, the difference between these antibiotics in SSI prophylaxis in colorectal surgery remains poorly understood. METHODS: We performed a single-center retrospective cohort study to investigate the prophylactic effects of these antibiotics, pLOS, and hospitalization costs. Patients who underwent elective colorectal surgery between April 2016 and March 2020 were considered for this study. RESULTS: Of the 634 patients, 316 (49.8%) were eligible. The SSI rates in the CMZ and FMOX groups were 14.7% and 12.5%, respectively. The incidence of organ/space SSI was approximately two-fold lower in the CMZ group than in the FMOX group (4.4% vs. 9.4%). Multivariable regression analysis revealed that CMZ was not significantly related to SSI, with an adjusted odds ratio of 1.21 (95% confidence interval [CI]: 0.52-2.82) and did not induce a significant difference in pLOS (difference ratio: 0.951 [95% CI: 0.868-1.041]). Hospitalization costs were reduced in the CMZ group (difference ratio, 0.951 [95% CI: 0.907-0.998], p = 0.042). The sensitivity analysis also showed results similar to the above findings. CONCLUSION: Our study showed that CMZ could be a cost-effective antibiotic with similar efficacy for SSI prophylaxis in colorectal surgery, compared with FMOX.

Impact of vascular abnormality on contrast-enhanced CT and high C-reactive protein levels on postoperative pancreatic hemorrhage after pancreaticoduodenectomy: A multi-institutional, retrospective analysis of 590 consecutive cases.

BACKGROUND: /Objectives: This study aimed to elucidate the efficacy of CT findings and perioperative characteristics to predict post-pancreatectomy hemorrhage (PPH): a critical complication after pancreaticoduodenectomy. METHODS: The records of 590 consecutive patients who underwent pancreaticoduodenectomy at three institutes between 2012 and 2018 were included. The presence of a vascular wall abnormality or ascites with high density (vascular abnormality) on postoperative day (POD) 5-10 contrast-enhanced CT (early CT), perioperative characteristics, and any PPH or pseudoaneurysm formation (PPH events) were analyzed through a multivariate analysis. RESULTS: PPH events occurred in 48 out of 590 patients (8%). The vascular abnormality on early CT and the C-reactive protein (CRP) value on POD 3 were independent risk factors for PPH events after POD5 (vascular abnormality: odds ratio 6.42, p = 0.001; CRP on POD 3: odds ratio 1.17, p = 0.016). The sensitivity of vascular abnormality for PPH events was 24% (7/29), and the positive predictive value was 30% (7/23). The combination of vascular abnormality and a high CRP value (≥15.5 mg/dL) on postoperative day 3 had a higher positive predictive value of 64% (7/11) than the vascular abnormality alone. None of the seven PPH events that occurred more than one month after surgery were foreseen via early CT. CONCLUSION: The combination of vascular abnormality and high CRP value was associated with increasing risk of PPH events after pancreaticoduodenectomy, but the low sensitivity of early CT must be noted as an important shortcoming. The normal findings on early CT could not eliminate the risk of late PPH.

[Locally Advanced Gastric Cancer Showing Marked Tumor Shrinkage after the First Dose of Nivolumab for Fourth-Line Chemotherapy].

We report a case of locally advanced gastric cancer, which showed marked tumor shrinkage after the first dose of nivolumab. A 75-year-old woman was diagnosed with locally advanced gastric cancer with pancreatic invasion and pyloric stenosis. We performed gastrojejunostomy before chemotherapy. The first-line, second-line, and third-line chemotherapies were not effective, resulting in tumor progression and necrosis with abdominal wall penetration. Her performance status was good, so we started nivolumab therapy as the fourth-line chemotherapy. Nine days after the first dose of nivolumab, she had a severe abdominal pain and a sense of fatigue. CT imaging showed a remarkable degree of tumor necrosis just beneath the skin. We diagnosed progressive disease and discontinued the chemotherapy. However, her general condition gradually improved and CT imaging 4 months after the first dose of nivolumab showed marked tumor shrinkage. We restarted nivolumab therapy and she has been alive for 2 years 10 months since the introduction of chemotherapy. It was suggested that a single dose of nivolumab only could lead to marked tumor shrinkage in chemotherapy for advanced gastric cancer.

[Curative resection for Stage IV advanced gastric cancer that responded to combination chemotherapy with docetaxel, cisplatin, and S-1].

A 50-year-old man was diagnosed with advanced gastric cancer(Borrmann type 3)accompanied with N3.Staging laparoscopy revealed invasion to the transverse mesocolon and positive cytology from peritoneal washing (CY1). After the patient underwent gastrojejunostomy, we administered DCS combination chemotherapy consisting of docetaxel (40 mg/m² intravenously on day 1), cisplatin(60 mg/m² intravenously on day 1), and S-1 (orally 80 mg/m² on days 1 to 14).Four courses of this treatment were provided every 4 weeks, and it resulted in a partial response (PR).We performed curative distal gastrectomy with transverse mesocolon resection and D2 plus 14v lymph node dissection. Cytological analysis of the samples obtained after peritoneal washing showed negative results.Histopathologically, no variable cancer cells remained in the primary lesion, but a few degenerated cancer cells remained in one of the lymph nodes.Pathological features were classified as Grade 3 for the primary lesion and Grade 2 for the lymph node lesions.S -1 and S-1/cisplatin were administered as adjuvant chemotherapy.One year and 6 months after surgery, the patient is alive and free of disease.

[A case of stage IV rectal cancer successfully resected after chemotherapy (mFOLFOX6 plus panitumumab)].

A 6 6-year-old woman with hematochezia was admitted to our hospital. A colonoscopy detected KRAS wild-type rectal cancer. An abdominal computed tomography (CT) scan revealed a liver metastasis, and invasion to the uterus was suspected. The patient underwent a laparotomy, and intraoperative cytology and peritoneal dissemination proved positive. The tumor had invaded the uterus. We administered chemotherapy consisting of 5-fluorouracil, Leucovorin, and oxaliplatin(mFOL FOX6)plus panitumumab. A CT scan and colonoscopy performed after 10 courses of chemotherapy indicated remarkable tumor regression. An abdominal CT scan did not detect any liver metastases, and we performed a laparoscopic low anterior resection. In the second operation, peritoneal dissemination and washing cytology were negative. The pathological diagnosis of the surgically resected specimen was ypStageII. The patient is recurrence-free 7 months after surgery.

[A case of resection for a huge pancreatic acinar cell carcinoma with tumor thrombus in the portal vein].

A 6 3-year-old man with a huge pancreatic tumor was referred to our hospital. Abdominal computed tomography revealed a heterogeneously enhanced encapsulated mass, 14 cm in diameter, in the pancreas head. The tumor thrombus extended to the bifurcation of the portal vein. The tumor, which had invaded the descending duodenum, was diagnosed as a probable case of acinar cell carcinoma, based on the biopsy results. Prior to resection, we prepared an ileocecal vein-umbilical vein bypass. Initially, we planned to perform a pancreatoduodenectomy, however, a total pancreatectomy had to be performed due to the atrophy of the residual pancreas tail. Since the tumor thrombus was visible, floating up from the portal vein wall at the upper level of pancreas, we dissected the portal vein at this level. The thrombus was extracted after securing the main tract and both (right and left) branches of the portal vein with vessel tape. About 5 cm of portal vein was resected and reconstructed. Since patients who undergo resection of acinar cell carcinoma have a better prognosis and long-term survival is often reported for cases of resected tumor thrombus of the portal vein, it is advisable to resect acinar cell carcinomas even in cases as advanced as reported here.

[A case of advanced gastric cancer successfully treated with trastuzumab, capecitabine, and Cisplatin therapy followed by curative resection].

We report a case of human epidermal growth factor receptor 2(HER2)-positive advanced gastric cancer successfully treated with combination therapy of trastuzumab, capecitabine, and cisplatin, followed by a curative resection. A 23-year-old woman was diagnosed with advanced type 3 gastric cancer, and the clinical findings were T3N0M0, StageIIA. A laparoscopic exploration revealed that it was a CY1 unresectable StageIV cancer. Initially, docetaxel, cisplatin, and S-1 therapy was chosen. However, the patient's HER2 status proved to be positive (IHC 3+), and so trastuzumab, capecitabine and cisplatin therapy was administered. After four cycles, the tumor significantly decreased in size, suggesting a partial response(PR). A further laparoscopic exam showed no apparent dissemination or metastatic cancer cells. We performed a curative resection consisting of a laparoscopic distal gastrectomy and D2 lymphadenectomy. The patient's postoperative course has been uneventful. She has been alive for 4 months and is receiving adjuvant chemotherapy comprising trastuzumab and S-1.

Delayed-Onset Immune-Related Colitis Following Pancreaticoduodenectomy in Patients With Gastric Cancer and Pancreatic Invasion Treated With Immune Checkpoint Inhibitors.

Immune checkpoint inhibitors (ICIs) have been approved for treating various advanced malignancies. Immune-related adverse events (irAEs) can manifest diversely and at varying times. However, postoperative diarrhea is a common complication in pancreaticoduodenectomy (PD). This case report presents a unique instance of delayed-onset irAE colitis occurring one year after PD in a patient with gastric cancer who received neoadjuvant nivolumab, a monoclonal antibody targeting human programmed death 1. A 54-year-old male developed severe diarrhea and weight loss, ultimately diagnosed with irAE colitis, which responded to steroid therapy. This report underscores the importance of extended monitoring, recognizing the potential for late-onset toxicities associated with ICIs, and differentiating from PD-related diarrhea.

Esophagogastrostomy Versus Double Tract Reconstruction for Laparoscopic Proximal Gastrectomy: Short-term Outcomes Based on Nutritional Parameters and Skeletal Muscle Index.

BACKGROUND/AIM: The optimal reconstruction method for laparoscopic proximal gastrectomy (LPG) remains controversial. The present study aimed to compare short-term outcomes, including assessment of nutritional parameters and skeletal muscle, between two different methods, double-tract reconstruction (DTR) versus esophagogastrostomy (EG). PATIENTS AND METHODS: Data from patients who underwent LPG for gastric tumor(s) between 2018 and 2021, were retrospectively analyzed. Patients were divided into two group: DTR (n=11) and EG (n=17). Since 2020, the authors have applied the modified side overlap with fundoplication by Yamashita (mSOFY) method as the EG technique. RESULTS: Compared with DTR, EG was associated with a shorter reconstruction time (p=0.003). Complications of grade ≥3 occurred only in the EG group [n=4 (23.5%)] and the incidence of abnormal endoscopic findings after surgery was numerically higher in the EG group (n=2 vs. n=9; p=0.047). Across virtually all data points on the line graph, the EG group exhibited greater changes in post-discharge nutritional parameters, with Skeletal Muscle Index also demonstrating significant superiority (0.83 vs. 0.89; p=0.045). CONCLUSION: Among reconstruction methods for LPG, EG demonstrated superiority over DTR in preserving nutritional parameters and skeletal muscle mass. However, further research, including larger cohorts and longer-term follow-up, is necessary to validate this finding.

Safety and Limitations of Laparoscopic Total Gastrectomy for Gastric Cancer: A Comparative Analysis of Short and Long-term Outcomes With Open Surgery.

BACKGROUND/AIM: Laparoscopic gastrectomy is a standard treatment strategy for gastric cancer (GC); however, the clinical impact of laparoscopic total gastrectomy (LTG) on survival outcomes remains unclear. We compared the short- and long-term results of LTG with those of open total gastrectomy (OTG). PATIENTS AND METHODS: Patients undergoing total gastrectomy with lymph node dissection for Stage I/II/III GC between 2010 and 2020 were retrospectively analyzed. Patients were classified into those undergoing LTG (n=143, LTG group) and OTG (n=173, OTG group). The primary outcome was relapse-free survival (RFS). RESULTS: The LTG group exhibited a higher prevalence of early T and N factors, with pStage I/II/III distribution skewed toward early-stage in a ratio of 86/24/33 compared to 38/65/69 in the OTG group (p<0.001), respectively. Longer operation time (p<0.001), less blood loss (p<0.001), fewer grade 3-4 complications (p<0.001), and shorter hospital stay (p<0.001) were observed in the LTG than in the OTG group. LTG was associated with survival benefits for patients without indication for adjuvant chemotherapy [5-year RFS rate, 96.3% vs. 73.2%; hazard ratio (HR)=0.24; 95% confidence interval (CI)=0.10-0.56; p<0.001]. Among the eligibility criteria for adjuvant chemotherapy (Stage II/III excluding pT1 and pT3N0), while the LTG group received more frequently doublet-agent administration (56.5% vs. 11%, p<0.001), conversely, the OTG group exhibited slightly better long-term survival rates (5-year RFS rate, 33.9% vs. 50.2%; HR=1.31; 95%CI=0.82-2.10; p=0.251). CONCLUSION: LTG contributed to favorable short-term outcomes and demonstrated improved long-term outcomes in early-stage GC; however, careful consideration of indications is warranted for advanced GC cases.

Clinical Implications and Risk Factors of Dilatation of Remnant Pancreatic Duct at 1 Year After Pancreatoduodenectomy: A Prospective, Japanese, Multicenter, Observational Cohort Study (DAIMONJI-Study).

BACKGROUND: To determine the precise frequency of main pancreatic duct (MPD) dilatation within the remnant pancreas at 1 year after pancreatoduodenectomy (PD) and its clinical implications, a prospective multicentre cohort study was performed in patients without MPD dilatation before PD (Registry number; UMIN000029662). METHODS: Between October 2017 and July 2020, patients with MPD diameter <3mm who were planned to undergo PD for periampullary lesions at 21 hospitals were enrolled. The primary endpoints were frequency of MPD dilatation at 1 year after PD, and the relationship between MPD dilatation and pancreatic endo- and exocrine function, nutritional status, and fatty liver. Secondary endpoints were risk factors for MPD dilatation at 1 year after PD and time-course change in MPD diameter. RESULTS: Of 200 registered patients, 161 patients were finally analyzed. Pancreatic fistula was the most frequent complication (n=76; 47.2%). MPD dilatation (MPD>3mm) at 1 year after PD was seen in 35 patients (21.7%). Pancreatic exocrine function, assessed by steatorrhea, was significantly impaired in patients with MPD dilatation. However, endocrine function, nutrition status and fatty liver development were comparable between the two groups. In multivariate analysis, the serum toral protein level≥7.3g/dl was an independent predictor for MPD dilatation at 1 year after PD (OR; 3.12, 95%CI; 1.31-7.15). A mean MPD diameter significantly increased at 6 months after PD and kept plateau thereafter. CONCLUSIONS: MPD dilatation at 1 year after PD was seen in 21.7% of patients and significantly associated with exocrine function impairment but not with endocrine function, nutrition status, or development of fatty liver.

[A case of recurrent colon cancer developed thrombosis in superior mesenteric vein after chemotherapy].

A 48-year-old man was administered bevacizumab+FOLFOX for lymph node recurrence of colon cancer in the abdominal cavity, and developed serious thrombosis of the portal system after 6 courses of the chemotherapy. We discontinued it promptly and anticoagulant therapy with urokinase was started immediately, but a complete dissolution was not achieved. Preservation therapy using anticoagulants for a long duration was effective for controling the of clinical symptom of thrombosis. The result of 6 courses of chemotherapy was CR, and the effect continues today, without further treatment 2 years later.

Clinical Impact of Laparoscopic Surgery on the Long-term Survival of Advanced Gastric Cancer Patients With Regard to Facilitating Doublet Adjuvant Chemotherapy.

BACKGROUND/AIM: The impact of laparoscopic gastrectomy (LG), a standard gastric cancer (GC) management strategy, in advanced GC cases involving doublet adjuvant chemotherapy remains unclear. This study was aimed at comparing short- and long-term LG and open gastrectomy (OG) results. PATIENTS AND METHODS: Patients who underwent gastrectomy with D2 lymph node dissection for stage II/III GC between 2013 and 2020 were retrospectively analyzed. Patients were divided into two groups: patients undergoing LG (n=96, LG-group) and OG (n=148, OG-group). The primary outcome was relapse-free survival (RFS). RESULTS: Compared with the OG group, the LG group was associated with a longer operation time (373 vs. 314 min, p<0.001), less blood loss (50 vs. 448 ml, p<0.001), fewer grade 3-4 complications (5.2 vs. 17.1%, p=0.005), and a shorter hospital stay (12 vs. 15 days, p<0.001). More lymph nodes were dissected in the LG group (49 vs. 40, p<0.001). The intergroup difference in prognosis was insignificant [5-year RFS: 60.4% (LG) vs. 63.1% (OG), p=0.825]. The LG group more frequently received doublet adjuvant chemotherapy (46.8 vs. 12.7%, p<0.001) and started treatments within 6 weeks after surgery (71.1% vs. 38.9%, p=0.017), and the completion rate of doublet AC was significantly higher in the LG group (85.4% vs. 58.8%, p=0.027). Compared to OG, LG for stage III GC tended to be associated with improved prognosis (HR=0.61, 95%CI=0.33-1.09, p=0.096). CONCLUSION: LG for advanced GC may facilitate doublet regimens due to favorable postoperative outcomes and its intervention may contribute to survival benefits.

Successful neoadjuvant treatment with radiochemotherapy and systemic chemotherapy for the locally advanced pancreatic head cancer: report of a case.

A 49-year-old man was admitted to the hospital for the upper abdominal pain and was diagnosed as unresectable pancreatic head cancer because of the invasion around the superior mesenteric artery. He was treated with radiochemotherapy, followed by systemic gemcitabine alone for 3 courses. He was further treated with systemic gemcitabine plus S­1 combination therapy for 5 courses. CT examination after these treatments showed a dramatic reduction of the tumor at the head of the pancreas and a pancreatoduodenectomy was performed. Pathologically, there was no residual malignant tumor. He has had no recurrent tumor up until now. Several studies of gemcitabine plus S-1 combination therapy show higher response rates for unresectable tumors. The current case indicates the effectiveness of the radiochemotherapy and gemcitabine plus S­1 combination therapy for locally advanced pancreatic head cancer as a neoadjuvant setting. We consider that multidisciplinary treatment including gemcitabine plus S­1 therapy may prolong the survival time by curative operation.

Effect of IVIG administration on complement activation and HLA antibody levels.

The objective of the present study was to determine if there are changes on complement (C) activation and concentration of HLA antibodies (Abs) in patients treated with intravenous immunoglobulin (IVIG). The patients evaluated were given IVIG as treatment of Ab-mediated rejection or desensitization. The patients' sera obtained before and after IVIG administration were tested for their effects on the deposition of both IgG (HLA Abs) and C3b (C activation) as measured by flow cytometry on T cells. IVIG consistently inhibited C activation when measured shortly after IVIG infusion but returned to the initial levels at 2-4 weeks, when total serum IgG also returned to pre-infusion levels. C inhibition was more pronounced with higher IVIG doses and the degree of inhibition was inversely proportional to the HLA Ab concentrations. IVIG did not block the binding of HLA Abs immediately after administration, although levels were slightly but consistently lower after several monthly IVIG infusions. The data show that C inhibition by IVIG is short-lived and that IVIG induces only a mild reduction of HLA Abs, seen not immediately but after months of treatment. These results may explain the inconsistent results of IVIG to achieve desensitization.

Activation-induced cytidine deaminase links bile duct inflammation to human cholangiocarcinoma.

UNLABELLED: Chronic inflammation plays a critical role in oncogenesis in various human organs. Epidemiological studies have demonstrated that patients with primary sclerosing cholangitis have a predisposition to develop cholangiocarcinoma (CC). However, the molecular mechanisms that account for the development of bile duct carcinomas are not well defined. We recently provided evidence that activation-induced cytidine deaminase (AID), a member of the DNA/RNA editing enzyme family, is implicated in human tumorigenesis via its mutagenic activity. We found here that ectopic AID production is induced in response to tumor necrosis factor-alpha (TNF-alpha) stimulation via the IkappaB kinase-dependent nuclear factor-kappaB (NF-kappaB) activation pathway in human cholangiocarcinoma-derived cells. Aberrant expression of AID in biliary cells resulted in the generation of somatic mutations in tumor-related genes, including p53, c-myc, and the promoter region of the INK4A/p16 sequences. In human tissue specimens, real-time reverse transcription polymerase chain reaction (RT-PCR) analyses revealed that AID was increased significantly in 28 of 30 CC tissues (93%), whereas only trace amounts of AID were detected in the normal liver. Immunohistochemistry showed that all of the CC tissue samples examined showed overproduction of endogenous AID protein in cancer cells. Moreover, immunostaining for AID was detectable in 16 of 20 bile epithelia in the tissues underlying primary sclerosing cholangitis. CONCLUSION: The proinflammatory cytokine-induced aberrant production of AID might link bile duct inflammation to an enhanced genetic susceptibility to mutagenesis, leading to cholangiocarcinogenesis.

Transplantation of embryonic stem cell-derived endodermal cells into mice with induced lethal liver damage.

ESCs are a potential cell source for cell therapy. However, there is no evidence that cell transplantation using ESC-derived hepatocytes is therapeutically effective. The main objective of this study was to assess the therapeutic efficacy of the transplantation of ESC-derived endodermal cells into a liver injury model. The beta-galactosidase-labeled mouse ESCs were differentiated into alpha-fetoprotein (AFP)-producing endodermal cells. AFP-producing cells or ESCs were transplanted into transgenic mice that expressed diphtheria toxin (DT) receptors under the control of an albumin enhancer/promoter. Selective damage was induced in the recipient hepatocytes by the administration of DT. Although the transplanted AFP-producing cells had repopulated only 3.4% of the total liver mass 7 days after cell transplantation, they replaced 32.8% of the liver by day 35. However, these engrafted cells decreased (18.3% at day 40 and 7.9% at day 50) after the cessation of DT administration, and few donor cells were observed by days 60-90. The survival rate of the AFP-producing cell-transplanted group (66.7%) was significantly higher in comparison with that of the sham-operated group (17.6%). No tumors were detected by day 50 in the AFP-producing cell-transplanted group; however, splenic teratomas did form 60 days or more after transplantation. ESC transplantation had no effect on survival rates; furthermore, there was a high frequency of tumors in the ESC-transplanted group 35 days after transplantation. In conclusion, this study demonstrates, for the first time, that ESC-derived endodermal cells improve the survival rates after transplantation into mice with induced hepatocellular injury. Disclosure of potential conflicts of interest is found at the end of this article.