A Novel Approach to Orthotopic Hepatocyte Transplantation Engineered With Liver Hydrogel for Fibrotic Livers, Enhancing Cell-Cell Interaction and Angiogenesis.

Hepatocyte transplantation (HCT) is a potential bridging therapy or an alternative to liver transplantation. Conventionally, single-cell hepatocytes are injected via the portal vein. This strategy, however, has yet to overcome poor cell engraftment and function. Therefore, we developed an orthotopic HCT method using a liver-derived extracellular matrix (L-ECM) gel. PXB cells (flesh mature human hepatocytes) were dispersed into the hydrogel solution in vitro, and the gel solution was immediately gelated in 37°C incubators to investigate the affinity between mature human hepatocyte and the L-ECM gel. During the 3-day cultivation in hepatocyte medium, PXB cells formed cell aggregates via cell-cell interactions. Quantitative analysis revealed human albumin production in culture supernatants. For the in vivo assay, PXB cells were encapsulated in the L-ECM gel and transplanted between the liver lobes of normal rats. Pathologically, the L-ECM gel was localized at the transplant site and retained PXB cells. Cell survival and hepatic function marker expression were verified in another rat model wherein thioacetamide was administered to induce liver fibrosis. Moreover, cell-cell interactions and angiogenesis were enhanced in the L-ECM gel compared with that in the collagen gel. Our results indicate that L-ECM gels can help engraft transplanted hepatocytes and express hepatic function as a scaffold for cell transplantation.

Preoperative predictive factors for positive peritoneal cytology results in patients with pancreatic ductal adenocarcinomas: a retrospective study.

BACKGROUND: The clinical importance of positive peritoneal cytology results in patients with pancreatic ductal adenocarcinomas remains controversial. We evaluated the prognosis of these patients and the predictive preoperative risk factors for positive peritoneal cytology results. METHODS: We retrospectively reviewed patients who underwent curative-intent surgery at our institution between May 2010 and June 2020. Preoperative risk factors for positive peritoneal cytology results were identified using logistic regression analysis. A scoring model was constructed using the total number of significant independent predictors for positive peritoneal cytology results. RESULTS: Of 233 patients, 18 (7.7%) had positive peritoneal cytology results. The recurrence-free survival and cancer-specific survival were markedly worse in patients with positive peritoneal cytology results than in those with negative peritoneal cytology results (recurrence-free survival: 6.0 months vs. 16.6 months, p = 0.050; cancer-specific survival: 19.4 months vs. 47.5 months, p = 0.034). Tumor location (odds ratio: 3.760, 95% confidence interval: 1.099-11.818, p = 0.023), tumor size > 25 mm (odds ratio: 3.410, 95% confidence interval: 1.031-11.277, p = 0.046), preoperative serosal invasion (odds ratio: 5.193, 95% confidence interval: 1.099-24.531, p = 0.038), and preoperative carcinoembryonic antigen level > 5.6 ng/mL (odds ratio: 3.816, 95% confidence interval: 1.248-10.667, p = 0.019) were identified as significant independent predictive factors. Our predictive model's optimal cutoff and positive predictive values for positive peritoneal cytology results were 3 and 27.9%, respectively. CONCLUSIONS: The indications for curative-intent surgery should be considered carefully in patients with high-risk factors for positive peritoneal cytology results.

Next­generation sequencing to identify genetic mutations in pancreatic cancer using intraoperative peritoneal washing fluid.

The efficacy of next-generation sequencing (NGS) of tumor-derived DNA from intraoperative peritoneal washing fluid (IPWF) of patients with pancreatic ductal adenocarcinoma (PDAC) who intend to undergo curative resection remains unclear. The aim of the present study was to evaluate whether genomic mutations in tumor-derived DNA from IPWF samples of patients with PDAC who intend to undergo curative resection could be detected using NGS. A total of 12 such patients were included in this study. Cytology of IPWF (CY) was assessed and NGS of genomic tumor-derived DNA from the IPWF was performed to determine whether genomic mutations could be detected in these patient samples. A total of 2 patients (16.7%) had a CY(+) status and 1 patient (8.3%) showed intraoperative macro-peritoneal dissemination; 11 patients underwent radical surgery. Actionable gene alterations were detected in 8 (80.0%) out of the 10 patients with CY(-) status based on NGS of IPWF samples, and 3 (37.5%) patients among those with actionable gene mutations identified from IPWF samples underwent peritoneal dissemination after surgery within ~12 months. The most common genomic mutation was in KRAS (9 patients, 75.0%), followed by TP53 (3 patients, 25.0%), SMAD4 (1 patient, 8.3%) and CDKN2A (1 patient, 8.3%). These findings indicated that the genomic mutations identified in tumor-derived DNA from IPWF samples of patients with PDAC with a CY(-) status who intend to undergo curative resection are potential biomarkers for predicting the recurrence of early peritoneal dissemination.

Impact of the COVID-19 pandemic on the number and short-term outcomes in hepatectomy for hepatocellular carcinoma: Results from the Japanese National Clinical Database, 2018-2021.

AIM: The coronavirus disease 2019 (COVID-19) pandemic has significantly impacted the allocation of medical resources, including cancer screening, diagnosis, and treatment. We aimed to investigate the effects of the pandemic on morbidity and mortality following hepatectomy for hepatocellular carcinoma (HCC). METHODS: We identified patients who underwent hepatectomy for HCC between 2018 and 2021 from the Japanese National Clinical Database (NCD). The number of surgical cases, the use of intensive care units, and the incidence of morbidity were assessed. The standardized morbidity / mortality ratio (SMR) was used to evaluate the rates of morbidity (bile leakage and pneumonia) and mortality in each month, which compares the observed incidence to the expected incidence calculated by the NCD's risk calculator. RESULTS: The study included a total of 10 647 cases. The number of patients undergoing hepatectomy for HCC gradually decreased. The proportion of patients aged 80 years or older increased and that of cases with T1 stage decreased. The proportion of patients who were admitted to the intensive care unit did not change between the pre- and postpandemic period. The mean actual incidence rates of bile leakage, pneumonia, 30-day mortality, and surgical mortality were 9.2%, 2.3%, 1.4%, and 2.1%, respectively. The SMR for the mortalities and morbidities in each month did not increase mostly throughout the COVID-19 pandemic. CONCLUSIONS: The present study showed the decreasing number of resected cases for HCC, while the surgical safety for hepatectomy was enough to be maintained by managing medical resources in Japan.

Impact of COVID-19 pandemic on short-term outcomes after low anterior resection in patients with rectal cancer: Analysis of data from the Japanese National Clinical Database.

Aim: The Coronavirus Disease 2019 (COVID-19) pandemic affected the allocation of various medical resources to several areas, including intensive care units (ICUs). However, currently, its impact on the short-term postoperative outcomes of gastrointestinal cancer surgeries remains unclear. We aimed to evaluate the impact of the pandemic on the incidence of complications occurring after low anterior resection in patients with rectal cancer in Japan. Methods: Data from the Japanese National Clinical Database between 2018 and 2021 were retrospectively examined. The primary outcome of the study was the postoperative morbidity and mortality rates before and after COVID-19 pandemic. Moreover, the postoperative ICU admission rate was assessed. Morbidity and mortality rates were also assessed using a standardized morbidity/mortality ratio (SMR, the ratio of the actual number of incidences to the expected number of incidences calculated by the risk calculator). Results: This study included 74 181 patients, including 43 663 (58.9%) from COVID-19 epidemic areas. The mean actual incidences of anastomotic leakage (AL) and pneumonia during the study period were 9.2% and 0.9%, respectively. The SMRs of these complications did not increase during the pandemic but those of AL declined gradually. The mean 30-day mortality and operative mortality rates were 0.3% and 0.5%, respectively. Moreover, SMRs did not change significantly in the pandemic or regional epidemic status. The ICU admission rate temporarily decreased, especially in the epidemic areas. Conclusion: Although the pandemic temporarily decreased the ICU admission rate, its impact on short-term outcomes following low anterior resection in patients with rectal cancer was insignificant in Japan.

Comparison Between Plastic and Metallic Biliary Stent Placement for Preoperative Patients with Pancreatic Head Cancer: A Systematic Review and Meta-Analysis.

BACKGROUND: Optimal preoperative biliary drainage for patients with pancreatic cancer before pancreatoduodenectomy remains unclear. This study aimed to investigate the comparison of efficacy and safety between a metallic stent (MS) and a plastic stent (PS). METHODS: Comparative studies on the use of MS and PS for pancreatic cancer before pancreatoduodenectomy were systematically searched using the MEDLINE and Web of Science databases. Pre- and postoperative data also were extracted. Random-effects meta-analyses were performed to compare post-endoscopic retrograde cholangiopancreatography (ERCP) complications as well as intra- and postoperative outcomes between the two arms of the study, and pooled odds ratios (ORs) or mean differences (MDs) were calculated with 95 percent confidence intervals (CIs). RESULTS: The study analyzed 12 studies involving 683 patients. Insertion of MS was associated with a lower incidence of re-intervention (OR, 0.06; 95% CI 0.03-0.15; P < 0.001), increased post-ERCP adverse events (OR, 2.22; 95% CI 1.13-4.36; P = 0.02), and similar operation time (MD, 18.0 min; 95% CI -29.1 to 65.6 min; P = 0.46), amount of blood loss (MD, 43.0 ml; 95% CI -207.1 to 288.2 ml; P = 0.73), and surgical complication rate (OR, 0.78; 95% CI 0.53-1.15; P = 0.21). The cumulative stent patency rate after 3 months was higher in the MS group than in the PS group (70-100 % vs 30.0-45.0 %). CONCLUSION: For biliary drainage in patients with pancreatic cancer during this era of multidisciplinary treatment, MS use might be the first choice because MS provides a more durable biliary drainage and a similar risk of postoperative outcomes compared with PS.

The impact of COVID-19 for postoperative outcomes using a nationwide Japanese database of patients undergoing distal gastrectomy for gastric cancer.

Background: The coronavirus disease 2019 (COVID-19) pandemic had resulted in either failure to provide required medical resources or delayed treatment for gastric cancer patients. This study aimed to investigate the impact of COVID-19 on the incidence of postoperative complications using a nationwide Japanese database of patients undergoing distal gastrectomy for gastric cancer. Methods: We collected the data of patients who underwent distal gastrectomy from January 2018 to December 2021 from the National Clinical Database (NCD), a web-based surgical registration system in Japan. The number of surgical cases, the use of intensive care units, and the incidence of morbidity per month were analyzed. We also calculated the standardized mortality ratio (SMR), defined as the ratio of the number of observed patients to the expected number of patients calculated using the risk calculator established in the NCD, for several morbidities, including pneumonia, sepsis, 30-day mortality, and surgical mortality. Results: A decrease of 568 gastrectomies was observed from April 2020 to May 2020. Although the absolute number of patients admitted to intensive care units had declined since 2020, the proportion of patients admitted to the ICU did not change before and after the pandemic. Mortality and critical morbidity (such as pneumonia and sepsis) rates were not worse during the pandemic compared to pre-pandemic periods per the SMR. Conclusions: Surgical management was conducted adequately through the organized efforts of the entire surgery department in our country even in a pandemic during which medical resources and staff may have been limited.

Long-term survival after surgical resection for bone metastasis from pancreatic cancer: A case report.

INTRODUCTION: Pancreatic cancer (PC) is highly malignant and metastatic; however, bone metastases are rare. Although the effectiveness of conversion surgery for distant metastases of PC has been reported in a few cases, there are no reports on surgical resection for bone metastases. Here, we report a case of long-term survival after resection of bone metastasis from PC. PATIENT CONCERNS: A 60-year-old woman underwent pancreaticoduodenectomy after neoadjuvant chemoradiotherapy for pancreatic head cancer. At 28 months after surgery, multiple lung metastases from PC were diagnosed, and chemotherapy was administered. After 59 months, chemotherapy was terminated because all target lesions had disappeared on imaging. DIAGNOSIS: At 77 months after the initial surgery, bone metastasis in the left 9th rib was detected by positron emission tomography/computed tomography, which was performed due to elevated carbohydrate antigen 19-9 levels. INTERVENTIONS: Chemotherapy was readministered as the initial treatment. Subsequently, due to the long-term well-controlled status of the recurrence site and the absence of other metastases, thoracoscopic-assisted partial resection of the left 9th rib was performed 128 months following pancreaticoduodenectomy. Pathological examination revealed adenocarcinoma metastasis from PC. OUTCOMES: The patient is currently alive without recurrence 44 months after resection for bone metastasis and 172 months after the initial surgery. CONCLUSION: Surgical resection may be favorable in patients with bone metastasis of PC that is well-controlled with chemotherapy.

Analysis of the short-term outcomes after esophagectomy for esophageal cancer during the COVID-19 pandemic using data from a nationwide Japanese database.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic had adversely impacted cancer screening, diagnosis, and treatment. We investigated the change in medical resource, such as the intensive care unit use, and short-term outcomes after esophagectomy during the pandemic. METHODS: Data of patients who underwent esophagectomy for esophageal cancer registered in the National Clinical Database (NCD) in Japan from January 2018 to December 2021 were analyzed. The time series change in the number of surgical cases; usage of intensive care unit; incidence of morbidity and mortality; standardized mortality and morbidity ratio (SMR) for 30-days mortality; surgical mortality; and morbidities for pneumonia, sepsis, unplanned intubation, and anastomotic leakage were evaluated. RESULTS: The annual number of patients undergoing esophagectomy remained similar from 2018 to 2021. The negative impact of the pandemic on medical resources was strongly identified in the patients from an epidemic area where there is a higher cumulative number of infections per population as compared to all prefectures. The proportions of patients admitted to the intensive care unit were 91.4%, 93.0%, 91.6%, and 90.5% in 2018, 2019, 2020, and 2021, respectively. Moreover, 93.3%, 94.0%, 92.0%, and 90.9% patients who underwent surgery in an epidemic area were admitted to the intensive care unit in 2018, 2019, 2020, and 2021, respectively. However, the morbidity and mortality rates during the pandemic did not worsen according to the SMR values. CONCLUSIONS: Esophagectomy was performed during the pandemic despite limited medical resources by a systematic endeavor of the entire surgical department in Japan, without increasing the incidence rate of worse outcome.

Clinical characteristics and predictive factors of postoperative intra-abdominal abscess after distal pancreatectomy.

PURPOSE: The postoperative mortality rate of distal pancreatectomy is lower than that of pancreaticoduodenectomy, although persistent complications may occur after distal pancreatectomy. Fluid collection (FC) is frequently observed after distal pancreatectomy; however, FC may occasionally progress to postoperative intra-abdominal abscess (PIAA), which requires conservative or progressive interventional treatment. This study aimed to compare the status between patients with or without PIAA, identify predictive factors for PIAA and clinically relevant postoperative pancreatic fistula, and investigate the clinical characteristics of patients with PIAA with interventional drainage. METHODS: We retrospectively reviewed data of patients who underwent distal pancreatectomy between January 2012 and December 2019 at two high-volume centers, where hepatobiliary-pancreatic surgeries were performed by expert specialist surgeons. Logistic regression analysis was performed to determine the predictive factors for PIAA. RESULTS: Overall, 242 patients were analyzed, among whom 49 (20.2%) had PIAA. The median postoperative period of PIAA formation was 9 (range: 3-49) days. Among the 49 patients with PIAA, 25 (51.0%) underwent percutaneous ultrasound, computed tomography, or endoscopic ultrasound-guided interventions for PIAA. In the univariate analysis, preoperative indices representing abdominal fat mass (i.e., body mass index, subcutaneous fat area, and visceral fat area) were identified as predictive factors for PIAA; in the multivariate analysis, C-reactive protein (CRP) level (continuous variable) on postoperative day (POD) 3 (odds ratio: 1.189, 95.0% confidence interval: 1.111 - 1.274; P < 0.001) was the only independent and significant predictive factor for PIAA. CONCLUSIONS: CRP level on POD 3 was an independent and significant predictive factor for PIAA after distal pancreatectomy.

Prognostic impact of preoperative skeletal muscle change from diagnosis to surgery in patients with perihilar cholangiocarcinoma.

Background: Loss of skeletal muscle mass is a prognostic factor after surgery for gastrointestinal cancers. The treatment for perihilar cholangiocarcinoma (PHC) is a highly invasive surgery. Biliary drainage and portal vein embolization, which can prolong the preoperative waiting time (PWT), are often required before surgery. Assuming that the skeletal muscle mass can change during PWT, we investigated the clinical effect of skeletal muscle change on surgical outcomes of PHC. Methods: We retrospectively reviewed the medical records of 89 patients who underwent curative surgery for PHC from January 2013 to December 2019. We defined the psoas muscle area (PMA) at the third lumbar vertebra as the skeletal muscle mass. The PMA just before surgery was divided by that at the time of diagnosis, and we defined it as the rate of change of PMA (CPMA). Patients were divided into two groups according to CPMA: wasting (n = 44, below the median CPMA) and no-change (n = 45, above the median CPMA). Results: The median PWT was 63 d, and CPMA was 96.1%. The median recurrence-free survival and overall survival were significantly shorter in the wasting group than in the no-change group (8.0 vs 33.2 mo, P = 0.001 and 14.2 vs 48.7 mo, P < 0.001, respectively). Multivariate analysis revealed that histological differentiation, R1 resection, lymph node metastasis, and preoperative skeletal muscle wasting were independent prognostic factors of PHC. Conclusion: This study suggests that preoperative skeletal muscle wasting in patients with PHC has a negative effect on survival outcomes.

Combinational Treatment Involving Decellularized Extracellular Matrix Hydrogels With Mesenchymal Stem Cells Increased the Efficacy of Cell Therapy in Pancreatitis.

Cell transplantation using mesenchymal stem cells (MSCs) has emerged as a promising approach to repairing and regenerating injured or impaired organs. However, the survival and retention of MSCs following transplantation remain a challenge. Therefore, we investigated the efficacy of co-transplantation of MSCs and decellularized extracellular matrix (dECM) hydrogels, which have high cytocompatibility and biocompatibility. The dECM solution was prepared by enzymatic digestion of an acellular porcine liver scaffold. It could be gelled and formed into porous fibrillar microstructures at physiological temperatures. MSCs expanded three-dimensionally in the hydrogel without cell death. Compared to the 2-dimensional cell culture, MSCs cultured in the hydrogel showed increased secretion of hepatocyte growth factor (HGF) and tumor necrosis factor-inducible gene 6 protein (TSG-6), both of which are major anti-inflammatory and anti-fibrotic paracrine factors of MSCs, under TNFα stimulation. In vivo experiments showed that the co-transplantation of MSCs with dECM hydrogel improved the survival rate of engrafted cells compared to those administered without the hydrogel. MSCs also demonstrated therapeutic effects in improving inflammation and fibrosis of pancreatic tissue in a dibutyltin dichloride (DBTC)-induced rat pancreatitis model. Combinational use of dECM hydrogel with MSCs is a new strategy to overcome the challenges of cell therapy using MSCs and can be used for treating chronic inflammatory diseases in clinical settings.

Extrahepatic approach for taping the common trunk of the middle and left hepatic veins or the left hepatic vein alone in laparoscopic hepatectomy (with videos).

BACKGROUND: Outflow control is difficult, and techniques required for effectively handling intraoperative hemorrhage during laparoscopic hepatectomy have not previously been adequately reported. METHODS: Sixteen patients underwent surgery, of which 15 underwent laparoscopic left hepatectomy and one underwent laparoscopic partial hepatectomy of the caudate lobe. Encircling and taping of the common trunk of the middle (MHV) and left hepatic veins (LHV) was performed in 12 patients, and that of the LHV alone in four patients. Surgical techniques based on anatomical landmarks and histological findings are presented with videos. Histological confirmation of the anatomical landmarks for these procedures was performed in fresh cadavers to understand the anatomical structures and layers involved. RESULTS: The median procedure duration was 15 (6-25) minutes. All procedures were performed safely with no major bleeding. Histological findings showed fibrous connective tissue between the tunica adventitia of the inferior vena cava (IVC) and the Laennec's capsule of the liver. The layer of dissection was along the tunica adventitia of the IVC. CONCLUSIONS: The surgical techniques for encircling and taping of the common trunk of the MHV and LHV and the LHV alone based on anatomical landmarks were feasible and could allow for efficient outflow control in laparoscopic hepatectomy.

Standardized upfront Glissonean approach and liver hanging maneuver reduces bile leakage from the hepatic hilum in living donors.

Biliary complications after hepatectomy in living donors have yet to be eradicated. We hypothesized that a standardized upfront Glissonean approach and liver hanging maneuver (GH) would prevent mechanical and thermal injuries to the hilar plate of the remnant liver by determining the point of bile duct division and the final destination of hepatectomy preceding liver parenchymal transection (safety) and facilitate liver transection deep within the parenchyma and allow maximum length of hilar structures (rationality). GH was implemented in 2016 and its incidence of bile leakage was retrospectively compared against the conventional technique. GH comprises six steps: (1) development of the retrohepatic avascular plane between the right hepatic vein (RHV) and the middle hepatic vein (MHV) and isolation of the hepatic vein(s); (2) isolation of the right or left Glissonean pedicle with the corresponding Glissonean pedicles of the caudate lobe; (3) for right liver grafts and left liver grafts with the caudate lobe, passage of the tape for the liver hanging maneuver along the retrohepatic avascular plane and above the hilar plate, and for left liver grafts without the caudate lobe and for left lateral section grafts, passage of the tape from between the RHV and the MHV, along the Arantius ligament, and to the right of the umbilical portion; (4) liver transection; (5) isolation of hilar structures; and (6) graft procurement. Until 2020, 62 consecutive living donors underwent GH (success rate, 100%). The incidence of bile leakage from the hepatic hilum (0%) was significantly lower than that among 59 donors who underwent the conventional technique in 2011-2015 (9%; p = 0.01). In conclusion, GH is highly effective in reducing bile leakage from the hepatic hilum in living donors.

Reconsideration of operative indications in pancreatic neuroendocrine neoplasms.

BACKGROUND: The incidence of pancreatic neuroendocrine neoplasm (PNEN) has been increasing. Resection is typically indicated for PNEN, regardless of its size; however, the indications for its resection are controversial. This study aimed to evaluate the treatment results of surgical resection of PNEN at our institute. METHODS: In this single-center, retrospective, case-control study, 87 patients who underwent PNEN resection and 17 patients with PNEN who did not undergo surgical resection between 1993 and 2020 were included in this study. Clinical characteristics and outcomes were reviewed and statistically compared. Survival was also estimated for the patients in each cohort. RESULTS: Seventeen patients who underwent resection (20%) had lymph node metastasis. Tumors measuring ≥ 2.0 cm and multiple lesions were identified as independent predictors for lymph node metastasis (odds ratio [OR] 17.3, 95% confidence interval [CI] 3.0-100.0, p = 0.001 and OR 8.7, 95% CI 1.5-52.0, p = 0.018, respectively). There was a significant difference in the survival curves depending on the presence or absence of lymph node metastasis (5-year overall survival 74.7% vs. 94.3%, p < 0.001; 5-year recurrence-free survival: 66.3% vs. 93.6%, p < 0.001). All 17 PNEN cases under observation with a median 8 mm (range 5-23) tumor size for a median of 34 (range 2.4-114) months showed slight morphological change with a median tumor growth rate of 0.15 mm (range 0-3.33) per year. CONCLUSION: Patients with tumors measuring ≥ 2.0 cm have a high probability of lymph node metastasis or recurrence, thereby requiring resection. PNEN measuring < 1.0 cm may be acceptable for observation.

Association Between Clinical Backgrounds and Malignant Progression of Suspected Intraductal Papillary Mucinous Neoplasm.

OBJECTIVES: Some intraductal papillary mucinous neoplasms (IPMNs) have malignant potential and can become pancreatic cancer. The mechanism behind the malignant progression of IPMN remains unknown. We aimed to identify the risk factors and interactions between backgrounds for IPMN. METHODS: We retrospectively enrolled 980 patients of pancreatic cancer or suspected IPMN (sIPMN) who underwent endoscopic ultrasound or retrograde cholangiopancreatography. We classified them into pancreatic cancer, high-risk sIPMN, and low-risk sIPMN, and investigated the risk factors for high-risk sIPMN. RESULTS: Smoking habits (odds ratio [OR], 3.74; 95% confidence interval [CI], 2.04-6.85; P < 0.001), serum carbohydrate antigen 19-9 ≥37 U/mL (OR, 6.30; 95% CI, 2.88-13.80; P < 0.001), and family history of cancers (OR, 2.38; 95% CI, 1.30-4.37; P = 0.005) were independent risk factors for high-risk suspected IPMN. Odds ratios of diabetes and neutrophil-to-lymphocyte ratio of 2.45 or greater were significantly higher in patients with a family history of cancer than those without a family history of cancer (OR, 3.28; 95% CI, 0.52-20.80 vs 1.85; 95% CI, 0.78-4.41; OR, 2.44; 95% CI, 0.81-7.34 vs 1.24; 95% CI, 0.67-2.30, respectively). CONCLUSIONS: Understanding the interactions between background factors can effectively prevent IPMNs' malignant transformation.

KRAS variant allele frequency, but not mutation positivity, associates with survival of patients with pancreatic cancer.

KRAS mutation is a major driver of pancreatic carcinogenesis and will likely be a therapeutic target. Due to lack of sensitive assays for clinical samples of pancreatic cancer with low cellularity, KRAS mutations and their prognostic association have not been fully examined in large populations. In a multi-institutional cohort of 1162 pancreatic cancer patients with formalin-fixed paraffin-embedded tumor samples, we undertook droplet digital PCR (ddPCR) for KRAS codons 12/13/61. We examined detection rates of KRAS mutations by clinicopathological parameters and survival associations of KRAS mutation status. Multivariable hazard ratios (HRs) and 95% confidence intervals (CIs) for disease-free survival (DFS) and overall survival (OS) were computed using the Cox regression model with adjustment for potential confounders. KRAS mutations were detected in 1139 (98%) patients. The detection rate did not differ by age of tissue blocks, tumor cellularity, or receipt of neoadjuvant chemotherapy. KRAS mutations were not associated with DFS or OS (multivariable HR comparing KRAS-mutant to KRAS-wild-type tumors, 1.04 [95% CI, 0.62-1.75] and 1.05 [95% CI, 0.60-1.84], respectively). Among KRAS-mutant tumors, KRAS variant allele frequency (VAF) was inversely associated with DFS and OS with HRs per 20% VAF increase of 1.27 (95% CI, 1.13-1.42; ptrend <0.001) and 1.31 (95% CI, 1.16-1.48; ptrend <0.001), respectively. In summary, ddPCR detected KRAS mutations in clinical specimens of pancreatic cancer with high sensitivity irrespective of parameters potentially affecting mutation detections. KRAS VAF, but not mutation positivity, was associated with survival of pancreatic cancer patients.

Decellularized Organ-Derived Scaffold Is a Promising Carrier for Human Induced Pluripotent Stem Cells-Derived Hepatocytes.

Human induced pluripotent stem cells (hiPSCs) are a promising cell source for elucidating disease pathology and therapy. The mass supply of hiPSC-derived cells is technically feasible. Carriers that can contain a large number of hiPSC-derived cells and evaluate their functions in vivo-like environments will become increasingly important for understanding disease pathogenesis or treating end-stage organ failure. hiPSC-derived hepatocyte-like cells (hiPSC-HLCs; 5 × 108) were seeded into decellularized organ-derived scaffolds under circumfusion culture. The scaffolds were implanted into immunodeficient microminiature pigs to examine their applicability in vivo. The seeded hiPSC-HLCs demonstrated increased albumin secretion and up-regulated cytochrome P450 activities compared with those in standard two-dimensional culture conditions. Moreover, they showed long-term survival accompanied by neovascularization in vivo. The decellularized organ-derived scaffold is a promising carrier for hiPSC-derived cells for ex vivo and in vivo use and is an essential platform for regenerative medicine and research.

Genomic analysis of familial pancreatic cancers and intraductal papillary mucinous neoplasms: A cross-sectional study.

Environmental and genetic factors play a critical role in the pathogenesis of pancreatic cancer, which is likely to follow a multistep process that includes intraductal papillary mucinous neoplasm. The pathogenesis of familial pancreatic cancer has been reported; however, epidemiological characteristics and causative genes remain unclear. This study aimed to determine the relationship between the family history of pancreatic cancer and tumor malignancy and identify novel susceptible germline variants of pancreatic cancer. We performed an epidemiologic study at our institute on a cohort of 668 patients with intraductal papillary mucinous neoplasm and 242 with pancreatic cancer but without associated intraductal papillary mucinous neoplasm stratified by family history of pancreatic cancer. Whole-exome sequencing was conducted for 10 patients from seven families with familial pancreatic cancer and intraductal papillary mucinous neoplasm. We found that patients who had intraductal papillary mucinous neoplasm with positive family history of pancreatic cancer within first-degree relatives were more likely to develop malignancy in a shorter period than those without family history. Duplicate frameshift variants in TET2 c.3180dupG (p.Pro1061fs) and ASXL1 c.1934dupG (p.Gly646fs) in one family and POLN c.1194dupT (p.Glu399fs) in another were identified as pathogenic truncating germline variants which were previously recognised susceptibility genes. Moreover, PDIA2 c.1403C>T (p.Pro468Leu) and DPYSL4 c.926C>A (p.Pro309Gln) were shared in four and two patients, respectively. In particular, PDIA2 was identified as a novel candidate for one of the deleterious variants of familial pancreatic cancer.

Reappraisal of liver transplantation for erythropoietic protoporphyria: A deadly combination of disease recurrence and biliary complication.

BACKGROUND: Erythropoietic protoporphyria (EPP) is a rare inherited disorder that causes the accumulation of protoporphyrin in the erythrocytes, skin, and liver. Severe protoporphyric hepatopathy results in liver failure, requiring both liver and bone marrow transplantation as a life-saving procedure and to correct the underlying enzymatic defect, respectively. CASE PRESENTATION: We report a 20-year-old man who underwent split liver transplantation using a right trisegment and caudate lobe graft for EPP-induced liver failure, but succumbed to a deadly combination of early relapse of EPP and subsequent, intractable, late-onset bile leakage from the cut surface of segment 4. EPP recurrence most likely created a high-risk situation for bile leakage from the non-communicating bile ducts of segment 4; therefore, this case shed light on the potential relationship between EPP recurrence and biliary complications. CONCLUSION: Physicians should recognize the potentially rapid and life-threatening progression of protoporphyric hepatopathy that leads to liver failure. For young patients with EPP, LT and sequential BMT should thoroughly be considered by a multidisciplinary team as soon as hepatic reserve deterioration becomes evident. Split liver transplantation should preferably be avoided and appropriate post-transplant management is critical before protoporphyrin depositions to the bile duct and hepatocyte causes irreversible damage to the liver graft.