The effects of ezetimibe on non-alcoholic fatty liver disease and glucose metabolism: a randomised controlled trial.

AIMS/HYPOTHESIS: The cholesterol absorption inhibitor ezetimibe has been shown to ameliorate non-alcoholic fatty liver disease (NAFLD) pathology in a single-armed clinical study and in experimental animal models. In this study, we investigated the efficacy of ezetimibe on NAFLD pathology in an open-label randomised controlled clinical trial. METHODS: We had planned to enrol 80 patients in the trial, as we had estimated that, with this sample size, the study would have 90% power. The study intervention and enrolment were discontinued because of the higher proportion of adverse events (significant elevation in HbA(1c)) in the ezetimibe group than in the control group. Thirty-two patients with NAFLD were enrolled and randomised (allocation by computer program). Ezetimibe (10 mg/day) was given to 17 patients with NAFLD for 6 months. The primary endpoint was change in serum aminotransferase level. Secondary outcomes were change in liver histology (12 control and 16 ezetimibe patients), insulin sensitivity including a hyperinsulinaemic-euglycaemic clamp study (ten control and 13 ezetimibe patients) and hepatic fatty acid composition (six control and nine ezetimibe patients). Hepatic gene expression profiling was completed in 15 patients using an Affymetrix gene chip. Patients and the physician in charge knew to which group the patient had been allocated, but people carrying out measurements or examinations were blinded to group. RESULTS: Serum total cholesterol was significantly decreased in the ezetimibe group. The fibrosis stage and ballooning score were also significantly improved with ezetimibe treatment. However, ezetimibe treatment significantly increased HbA1c and was associated with a significant increase in hepatic long-chain fatty acids. Hepatic gene expression analysis showed coordinate downregulation of genes involved in skeletal muscle development and cell adhesion molecules in the ezetimibe treatment group, suggesting a suppression of stellate cell development into myofibroblasts. Genes involved in the L-carnitine pathway were coordinately downregulated by ezetimibe treatment and those in the steroid metabolism pathway upregulated, suggestive of impaired oxidation of long-chain fatty acids. CONCLUSIONS/INTERPRETATION: Ezetimibe improved hepatic fibrosis but increased hepatic long-chain fatty acids and HbA1c in patients with NAFLD. These findings shed light on previously unrecognised actions of ezetimibe that should be examined further in future studies. TRIAL REGISTRATION: University Hospital Medical Information Network (UMIN) Clinical Trials Registry UMIN000005250. FUNDING: The study was funded by grants-in-aid from the Ministry of Education, Culture, Sports, Science and Technology, Japan, and research grants from MSD.

Selenoprotein P as a diabetes-associated hepatokine that impairs angiogenesis by inducing VEGF resistance in vascular endothelial cells.

AIMS/HYPOTHESIS: Impaired angiogenesis induced by vascular endothelial growth factor (VEGF) resistance is a hallmark of vascular complications in type 2 diabetes; however, its molecular mechanism is not fully understood. We have previously identified selenoprotein P (SeP, encoded by the SEPP1 gene in humans) as a liver-derived secretory protein that induces insulin resistance. Levels of serum SeP and hepatic expression of SEPP1 are elevated in type 2 diabetes. Here, we investigated the effects of SeP on VEGF signalling and angiogenesis. METHODS: We assessed the action of glucose on Sepp1 expression in cultured hepatocytes. We examined the actions of SeP on VEGF signalling and VEGF-induced angiogenesis in HUVECs. We assessed wound healing in mice with hepatic SeP overexpression or SeP deletion. The blood flow recovery after ischaemia was also examined by using hindlimb ischaemia model with Sepp1-heterozygous-knockout mice. RESULTS: Treatment with glucose increased gene expression and transcriptional activity for Sepp1 in H4IIEC hepatocytes. Physiological concentrations of SeP inhibited VEGF-stimulated cell proliferation, tubule formation and migration in HUVECs. SeP suppressed VEGF-induced reactive oxygen species (ROS) generation and phosphorylation of VEGF receptor 2 (VEGFR2) and extracellular signal-regulated kinase 1/2 (ERK1/2) in HUVECs. Wound closure was impaired in the mice overexpressing Sepp1, whereas it was improved in SeP (-/-)mice. SeP (+/-)mice showed an increase in blood flow recovery and vascular endothelial cells after hindlimb ischaemia. CONCLUSIONS/INTERPRETATION: The hepatokine SeP may be a novel therapeutic target for impaired angiogenesis in type 2 diabetes.

Combination immunohistochemistry for CK5/6, p63, GATA6, and HNF4a predicts clinical outcome in treatment-naïve pancreatic ductal adenocarcinoma.

Although sequence-based studies show that basal-like features lead to worse prognosis and chemotherapy-resistance compared to the classical subtype in advanced pancreatic ductal adenocarcinoma (PDAC), a surrogate biomarker distinguishing between these subtypes in routine diagnostic practice remains to be identified. We aimed to evaluate the utility of immunohistochemistry (IHC) expression subtypes generated by unsupervised hierarchical clustering based on staining scores of four markers (CK5/6, p63, GATA6, HNF4a) applied to endoscopic ultrasound-guided fine needle aspiration biopsy (EUS-FNAB) materials. EUS-FNAB materials taken from 190 treatment-naïve advanced PDAC patients were analyzed, and three IHC patterns were established (Classical, Transitional, and Basal-like pattern). Basal-like pattern (high co-expression of CK5/6 and p63 with low expression of GATA6 and HNF4a) was significantly associated with squamous differentiation histology (p < 0.001) and demonstrated the worst overall survival among our cohort (p = 0.004). IHC expression subtype (Transitional, Basal vs Classical) was an independent poor prognosticator in multivariate analysis [HR 1.58 (95% CI 1.01-2.38), p = 0.047]. Furthermore, CK5/6 expression was an independent poor prognostic factor in histological glandular type PDAC [HR 2.82 (95% CI 1.31-6.08), p = 0.008]. Our results suggest that IHC expression patterns successfully predict molecular features indicative of the Basal-like subgroup in advanced PDAC. These results provide the basis for appropriate stratification for therapeutic selection and prognostic estimation of advanced PDAC in a simplified manner.

Specific COVID-19 risk behaviors and the preventive effect of personal protective equipment among healthcare workers in Japan.

As coronavirus disease 2019 (COVID-19) outbreaks in healthcare facilities are a serious public health concern, we performed a case-control study to investigate the risk of COVID-19 infection in healthcare workers. We collected data on participants' sociodemographic characteristics, contact behaviors, installation status of personal protective equipment, and polymerase chain reaction testing results. We also collected whole blood and assessed seropositivity using the electrochemiluminescence immunoassay and microneutralization assay. In total, 161 (8.5%) of 1,899 participants were seropositive between August 3 and November 13, 2020. Physical contact (adjusted odds ratio 2.4, 95% confidence interval 1.1-5.6) and aerosol-generating procedures (1.9, 1.1-3.2) were associated with seropositivity. Using goggles (0.2, 0.1-0.5) and N95 masks (0.3, 0.1-0.8) had a preventive effect. Seroprevalence was higher in the outbreak ward (18.6%) than in the COVID-19 dedicated ward (1.4%). Results showed certain specific risk behaviors of COVID-19; proper infection prevention practices reduced these risks.

Pharmacokinetics and pharmacodynamics of insulin aspart in patients with type 2 diabetes: assessment using a meal tolerance test under clinical conditions.

1. Few studies have evaluated the pharmacokinetics of rapid-acting insulin analogues in patients with Type 2 diabetes, especially under clinical conditions. The aim of the present study was to assess both the pharmacokinetics and pharmacodynamics of insulin aspart in Type 2 diabetic patients who were being treated with the analogue alone. 2. Meal tolerance tests with and without self-injection of a customary dose of insulin aspart (0.05-0.22 U/kg) were conducted in 20 patients in a randomized cross-over study. 3. The dose of insulin aspart (per bodyweight) was significantly correlated with both the maximum concentration (r(2) = 0.59; P < 0.01) and area under the concentration-time curve for insulin aspart (r(2) = 0.53; P < 0.01). However, the time to maximum concentration (T(max)), which varied widely from < 60 to ≥ 120 min, was not associated with either dosage (r(2) = 0.02; P = 0.51) or body mass index (r(2) = 0.02; P = 0.57). Injection of insulin aspart exacerbated delayed hyperinsulinaemia after meal loading, mainly in patients with T(max) ≥ 120 min. With regard to pharmacodynamics, insulin aspart had favourable effects on postprandial hyperglycaemia, hyperglucagonaemia and hyperlipidaemia. 4. The T(max) for this insulin analogue differed greatly between individuals and delayed hyperinsulinaemia was particularly exacerbated in patients with higher T(max) values. Identification of the factors contributing to interindividual variation in the absorption lag time is essential for improving the efficacy and safety of insulin aspart.

Duodenal adenocarcinoma with neuroendocrine features in a patient with acromegaly and thyroid papillary adenocarcinoma: a unique combination of endocrine neoplasia.

A 67-year-old woman with familial clustering of thyroid papillary adenocarcinoma was diagnosed with acromegaly due to pituitary macroadenoma. She had multiple skin vegetations, but had no parathyroid and pancreas diseases. Before transsphenoidal surgery, she was further diagnosed as having a duodenal tumor and multiple hypervascular liver nodules. Biopsy specimens from the duodenal tumor and liver nodules were diagnosed histologically as moderately differentiated adenocarcinoma. Immunohistochemically, the tumor cells were positive for chromogranin, synaptophysin and somatostatin receptor 2a, suggestive for neuroendocrine features. After surgery, the patient was not in biochemical remission, and octreotide treatment was initiated. The duodenal cancer was treated with chemotherapy (neoadjuvant cisplatin and S-1). After 24 months, the patient's insulin-like growth factor I level had been normalized, and her liver tumors had not progressed macroscopically. This is a rare case of acromegaly associated with multiple endocrine tumors, not being categorized as conventional multiple endocrine neoplasia. Octreotide treatment might have had beneficial effects on our patient's duodenal adenocarcinoma and liver metastases, both directly via SSTR2a and indirectly via GH suppression, thereby contributing to their slow progression.

An annular pancreas associated with carcinoma of the papilla of Vater: report of a case.

An annular pancreas is an uncommon congenital anomaly that usually presents early in childhood. Malignancy in the setting of an annular pancreas is unusual. We herein report a case of annular pancreas with carcinoma of the papilla of Vater. A 59-year-old man presented with epigastric discomfort and was referred to us after gastroduodenal endoscopy showed a tumor of the papilla of Vater. Preoperative imaging showed the pancreatic parenchyma encircling the descending duodenum and a tumor at the papilla of Vater. A pancreaticoduodenectomy was performed for the annular pancreas and the ampullary tumor. Histological examination confirmed a complete annular pancreas and carcinoma in situ of the papilla of Vater. We also provide a review of the reported cases of an annular pancreas with periampullary neoplasms and discuss the clinical characteristics of this anomaly.

Associations of Plasma Concentration Profiles of Dapagliflozin, a Selective Inhibitor of Sodium-Glucose Co-Transporter Type 2, with Its Effects in Japanese Patients with Type 2 Diabetes Mellitus.

This study was conducted to evaluate the long-term plasma concentration profiles of dapagliflozin and its effects on the glycated hemoglobin (HbA1c) level, body weight, and estimated glomerular filtration rate (eGFR) in 72 Japanese outpatients with type 2 diabetes mellitus (T2DM) receiving metformin and a dipeptidyl peptidase-4 inhibitor. At baseline, HbA1c level, body weight, and eGFR were 6.9 ± 0.6%, 77.9 ± 13.5 kg, and 78.8 ± 20.7 mL/min/1.73 m2, respectively. A once-daily oral dose of 5 mg dapagliflozin was administered, and its trough plasma concentrations were evaluated at 1, 3, 6, 9, and 12 months. In this study, the patients with stable dapagliflozin concentrations were defined, based on a well-organized clinical trial, as those with average plasma concentrations of 2-5 ng/mL with a coefficient of variation <30%; these values were achieved if patients complied with their once-daily dosage. Multivariate analysis showed a significant decrease in the HbA1c levels among patients with stable concentrations (-0.6 ± 0.4%, p < 0.01), which was greater than the mean change among all 72 patients (-0.2 ± 0.5%, p < 0.01). The patients' mean body weight also decreased (-2.3 ± 4.0 kg, p = 0.060). Average plasma concentrations ranged from 1.6 to 11.8 ng/mL; however, multivariate analysis indicated it was unrelated to the HbA1c-lowering effect. In conclusion, the long-term stability of plasma dapagliflozin concentration was important in lowering HbA1c level, and a once-daily oral dose of 5 mg was sufficient in achieving this effect.

Management of postoperative arterial hemorrhage after pancreato-biliary surgery according to the site of bleeding: re-laparotomy or interventional radiology.

BACKGROUND/PURPOSE: Intra-abdominal arterial hemorrhage is still one of the most serious complications after pancreato-biliary surgery. We retrospectively analyzed our experiences with 15 patients in order to establish a therapeutic strategy for postoperative arterial hemorrhage following pancreato-biliary surgery. METHODS: Between August 1981 and November 2007, 15 patients developed massive intra-abdominal arterial bleeding after pancreato-biliary surgery. The initial surgery of these 15 patients were pylorus-preserving pancreatoduodenectomy (PPPD) (7 patients), hemihepatectomy and caudate lobectomy with extrahepatic bile duct resection or PPPD (4 patients), Whipple's pancreatoduodenectomy (PD) (3 patients), and total pancreatectomy (1 patient). Twelve patients were managed by transcatheter arterial embolization and three patients underwent re-laparotomy. RESULTS: Patients were divided into two groups according to the site of bleeding: SMA group, superior mesenteric artery (4 patients); HA group, stump of gastroduodenal artery, right hepatic artery, common hepatic artery, or proper hepatic artery (11 patients). In the SMA group, re-laparotomy and coil embolization for pseudoaneurysm were performed in three and one patients, respectively, but none of the patients survived. In the HA group, all 11 patients were managed by transcatheter arterial embolization. None of four patients who had major hepatectomy with extrahepatic bile duct resection survived. Six of seven patients (85.7%) who had pancreatectomy survived, although hepatic infarction occurred in four. CONCLUSIONS: Management of postoperative arterial hemorrhage after pancreato-biliary surgery should be done according to the site of bleeding and the initial operative procedure. Careful consideration is required for indication of interventional radiology for bleeding from SMA after pancreatectomy and hepatic artery after major hepatectomy with bilioenteric anastomosis.

Effects of metformin and alogliptin on body composition in people with type 2 diabetes.

AIMS/INTRODUCTION: The aim of the present study was to investigate the effects of metformin and a dipeptidyl peptidase-4 inhibitor, alogliptin, on body composition in a 12-week randomized add-on trial in Japanese participants with type 2 diabetes. MATERIALS AND METHODS: A total of 84 participants with poorly controlled type 2 diabetes undergoing antidiabetic therapy were randomly assigned to receive alogliptin (25 mg, once daily) or metformin (1,000 mg, twice daily) for 12 weeks. The primary efficacy end-point was body composition. The secondary end-points included factors associated with decreased bodyweight. RESULTS: Compared with the baseline values, alogliptin significantly increased bodyweight (66.5 ± 19.2 to 67.6 ± 19.3 kg), body mass index (BMI; 25.4 ± 6.1 to 25.8 ± 6.3 kg/m2 ) and fat mass (20.3 ± 12.8 to 21.8 ± 14.5 kg), whereas metformin had no significant effect on body composition. Alogliptin was inferior to metformin in reducing bodyweight (0.84 ± 1.57 vs -0.35 ± 1.53 kg, P = 0.002), BMI (0.34 ± 0.69 to -0.15 ± 0.56 kg/m2 , P = 0.002) and fat mass (1.49 ± 5.06 vs -0.04 ± 1.81 kg, P = 0.042). BMI at baseline was associated with changes in bodyweight negatively in the metformin group and positively in the alogliptin group. CONCLUSIONS: Metformin and alogliptin exert opposite effects on bodyweight in type 2 diabetes patients who are overweight. The higher the BMI, the more metformin reduces bodyweight and alogliptin increases weight.

Mealtime dosing of a rapid-acting insulin analog reduces glucose variability and suppresses daytime cardiac sympathetic activity: a randomized controlled study in hospitalized patients with type 2 diabetes.

OBJECTIVE: Glucose variability induces endothelial dysfunction and cardiac autonomic nerve abnormality. Here we compared the effects of mealtime insulin aspart and bedtime insulin detemir on glucose variability, endothelial function, and cardiac autonomic nerve activity among Japanese patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: Forty hospitalized patients received either mealtime insulin aspart or bedtime insulin detemir treatment for 2 weeks. We assessed glucose variability indices, including M-value, SD of blood glucose level, and mean blood glucose (MBG) level. Flow-mediated dilation (FMD) of the brachial artery was measured as an index of endothelial function. Low-frequency power, high-frequency power, and the low-frequency to high-frequency power ratio (LF:HF ratio) derived via heart rate variability analysis using a Holter ECG were employed as indices of cardiac autonomic nerve function. RESULTS: M-values and MBG levels showed a considerably greater decrease in the insulin aspart group than in the insulin detemir group (p=0.006 vs p=0.001); no change in FMD was observed in either group. Daytime LF:HF ratio significantly decreased in the insulin aspart group but not in the insulin detemir group. Total insulin dose at endpoint in the insulin aspart group was significantly higher than that in the insulin detemir group (p<0.001). CONCLUSIONS: Mealtime insulin aspart reduced glucose variability to a greater extent than bedtime insulin detemir in patients with type 2 diabetes. Despite the need for higher insulin doses, insulin aspart decreased daytime cardiac sympathetic nerve activity. These properties may subsequently help reduce cardiovascular risks. TRIAL REGISTRATION NUMBER: UMIN000008369.

Ursodeoxycholic acid potentiates dipeptidyl peptidase-4 inhibitor sitagliptin by enhancing glucagon-like peptide-1 secretion in patients with type 2 diabetes and chronic liver disease: a pilot randomized controlled and add-on study.

OBJECTIVE: We evaluated the effects of ursodeoxycholic acid (UDCA) on glucagon-like peptide-1 (GLP-1) secretion and glucose tolerance in patients with type 2 diabetes with chronic liver disease. RESEARCH DESIGN AND METHODS: Japanese patients with type 2 diabetes (glycated hemoglobin (HbA1c) levels ≥7.0%) and chronic liver disease were included in this study. Sixteen patients (HbA1c level, 7.2%±0.6%(55.2 mmol/mol)) were randomized to receive 900 mg UDCA for 12 weeks followed by 50 mg sitagliptin add-on therapy for 12 weeks (UDCA-first group; n=8) or 50 mg sitagliptin for 12 weeks followed by 900 mg UDCA add-on therapy for 12 weeks (sitagliptin-first group; n=8). All patients underwent a liquid high-fat meal test before and after 12 or 24 weeks of treatment. RESULTS: The baseline characteristics were similar between the UDCA-first and sitagliptin-first groups. There was a decrease in body weight (72.5±8.4 to 70.6±8.6 kg; P=0.04) and the HbA1c level (7.0%±0.3% to 6.4%±0.5%(53.0 to 46.4 mmol/mol); P=0.01) in the UDCA-first group. The HbA1c level decreased further after sitagliptin administration (6.4%±0.5% to 6.0%±0.4%(46.4 to 42.1 mmol/mol); P<0.01). Although there were no initial changes in the weight and HbA1c level in the sitagliptin-first group, the HbA1c level decreased after UDCA addition (7.1%±1.1% to 6.6%±0.9%(54.1 to 48.6 mmol/mol); P=0.04). UDCA alone increased the area under the curve0-30 for GLP-1 response (115.4±47.2 to 221.9±48.9 pmol·min/L; P<0.01), but not the glucose-dependent insulinotropic polypeptide response, in the UDCA-first group. CONCLUSIONS: UDCA treatment resulted in a greater reduction in HbA1c levels, and an increased early phase GLP-1 secretion. TRIAL REGISTRATION NUMBER: NCT01337440.

A case of peribiliary cysts accompanying bile duct carcinoma.

A rare case of peribiliary cysts accompanying bile duct carcinoma is presented. A 54-year-old man was diagnosed as having lower bile duct carcinoma and peribiliary cysts by diagnostic imaging. He underwent pylorus preserving pancreatoduodenectomy. As for the peribiliary cysts, a course of observation was taken. Over surgery due to misdiagnosis of patients with biliary malignancy accompanied by peribiliary cysts should be avoided.

The lethal toxicity of pancreatic ascites fluid in severe acute necrotizing pancreatitis.

BACKGROUND/AIMS: The pathogenesis and the molecular mechanisms of the development and progression of the acute pancreatitis (AP) are not clearly understood. Ascites fluid is known to be important in the clinical progression of AP. We present the lethal toxicity of human pancreatic ascites fluid for experimental pancreatitis, with the therapeutic course of severe necrotizing AP. METHODOLOGY: The material was in a 33-year-old male admitted with epigastric pain. An abdominal CT revealed that his pancreas was swollen and contained pancreatic fluid collection extending to the pelvic cavity. He had complicated acute renal failure, sepsis, and DIC, and received hemodialysis, and continuous arterial infusion therapy (CAI). The peripancreatic infection was acquired, and percutaneous interventional radiology (IVR) was performed for the abscess drainage. The drained liquid around the pancreas contained high molecular cytokines, protease, and bacterial contamination. To evaluate the toxicity of the ascites fluid, we gave it intraperitoneally to rats in which pancreatitis had been induced and rats that had undergone a sham operation; these rats died immediately. The consistent irrigation and drainage of the abscess was administered and the patient's general condition improved. At this time, we gave the drained material intraperitoneally to other rats with induced pancreatitis and sham operation, but all these rats survived. RESULTS: These experimental results suggested that pancreatitis-associated ascites fluid contained a lethal toxicity. For curing this disease, elimination of these potential toxic mediators was essential. Our intensive IVR-based therapy improved the patient's prognosis. CONCLUSIONS: Downregulating this inflammatory process leads to a decrease in the mortality of severe acute pancreatitis.

[Trend in the management of pancreatic adenocarcinoma--Japan vs. US and Europe].

Pancreatic adenocarcinoma remains to have poor prognosis. Most of all patients have locally advanced disease with or without distant disease when diagnosed. Current rationale for the treatment of pancreatic adenocarcinoma in the US and European countries consists of the following formula: (1) accurate staging by improved imaging. (2) a balanced-resection which means not too extensive not too limited. (3) centralized treatment in high-volume center with minimal surgical mortality. (4) surgery alone is not enough for cure and need more radical adjuvant or neoadjuvant therapy. On the other hands, Japanese surgeons had challenged to improve outcome by radical resections but did not show their advantages in terms of survival benefit as shown in recent randomized controlled trials. Now we should look back to surgical role and think 'who can benefit by surgical resection'. The efficacy of "Japanese" radical resection including vascular resection or pancreatic nerve plexus resection should be evaluated, although the devise of novel diagnostic modalities and more effective adjuvant or neoadjuvant therapy are crucial to improve prognosis of this disease.

Pleiotropic effects of sitagliptin versus voglibose in patients with type 2 diabetes inadequately controlled via diet and/or a single oral antihyperglycemic agent: a multicenter, randomized trial.

PURPOSE: A step-up strategy for diet therapy and/or single oral antihyperglycemic agent (OHA) regimens has not yet been established. The aim of this study was to evaluate hemoglobin A1c (HbA1c) as a primary end point, and the pleiotropic effects on metabolic and cardiovascular parameters as secondary end points, of sitagliptin versus voglibose in patients with type 2 diabetes with inadequate glycemic control while on diet therapy and/or treatment with a single OHA. METHODS: In this multicenter, randomized, open-label, parallel-group trial, a total of 260 patients with inadequately controlled type 2 diabetes (HbA1c levels >6.9%) were randomly assigned to receive either sitagliptin (50 mg, once daily) or voglibose (0.6 mg, thrice daily) for 12 weeks. The primary end point was HbA1c levels. RESULTS: Patients receiving sitagliptin showed a significantly greater decrease in HbA1c levels (-0.78±0.69%) compared with those receiving voglibose (-0.30±0.78%). Sitagliptin treatment also lowered serum alkaline phosphatase levels and increased serum creatinine, uric acid, cystatin-C and homeostasis model assessment-ß values. Voglibose increased low-density lipoprotein-cholesterol levels and altered serum levels of several fatty acids, and increased Δ-5 desaturase activity. Both drugs increased serum adiponectin. The incidence of adverse events (AEs) was significantly lower in the sitagliptin group, due to the decreased incidence of gastrointestinal AEs. CONCLUSIONS: Sitagliptin shows superior antihyperglycemic effects compared with voglibose as a first-line or second-line therapy. However, both agents possess unique pleiotropic effects that lead to reduced cardiovascular risk in Japanese people with type 2 diabetes. TRIAL REGISTRATION NUMBER: UMIN 000003503.

Exceptional ultra-late recurrence of papilla Vater carcinoma after pancreaticoduodenectomy: two cases at 17 and 25 years.

Curative resection does not always equate with long-term survival. Cancer of the papilla Vater can remain clinically quiescent for decades prior to regional or distant recurrence. Nevertheless, late and ultra-late recurrence (respectively 10 and 15 years after initial treatment) are exceptional events. This protracted disease-free interval challenges the concept of a "cure" for cancer of the papilla Vater. In the first case reported here, a 74-year-old female underwent pancreaticoduodenectomy in 1985 for cancer of the papilla Vater revealed histologically as a well-differentiated papillotubular adenocarcinoma, stage IA (UICC classification). Multiple hepatic recurrences were found 17 years after the operation; hepatic biopsy showed histologically well to moderately differentiated papillotubular adenocarcinoma. She died about 17.5 years after the original operation. The second case is that of an 82-year-old female who underwent pancreaticoduodenectomy in 1974 for cancer of the papilla Vater, histologically a well-differentiated adenocarcinoma, stage IA. In the 25.5 years after the operation, the cancer recurred at the choledochoduodenal anastomosis and involved the liver hilus. Autopsy showed histologically well to moderately differentiated adenocarcinoma at the locations indicated, together with lung and lymph node metastases. The ultra-late recurrences (>15 years) in these cases are highly exceptional and, to our knowledge, this is the first report of such recurrences in cancer of the papilla Vater. It can occur in any patient, with or without identifiable risk factors. Because cancer of the papilla Vater can recur in many prognostically favorable cases after prolonged disease-free intervals, the possibility of delayed recurrence should not be ignored.

MPR-hCT imaging of the pancreatic fluid pathway to Grey-Turner's and Cullen's sign in acute pancreatitis.

Subcutaneous manifestations (Grey Turner's sign and Cullen's sign) of severe acute pancreatitis (SAP) are often discussed but rarely observed in a daily clinic setting. This paper will demonstrate the anatomic pathways followed by the extravasated pancreatic enzymes and how their effects lead to these ecchymoses by multiplanar reformation (MPR) images obtained by helical computed tomography (hCT). A 34-year-old female was admitted with SAP. A hCT scan revealed a swollen pancreas and cholecystolithiasis. The fluid collection around the pancreas extended to the pelvic cavity, infiltrating subcutaneous tissue in the left anterior and lateral abdominal wall. She was treated with interventional endoscopy (IVE) and continuous arterial infusion (CAI) therapy immediately following admission, she survived the SAP and these ecchymoses resolved within 7 days of presentation. MPR images obtained by hCT revealed that, the infiltration of the extra-pancreatic fluid collection between the leaves of the anterior renal fascia through the anterior and posterior pararenal space had reached into a relationship with the subcutaneous tissues in the left flank at the clinical site of discoloration as the pathway of extension to Grey Turner's sign, and also revealed anterior extension from the inflamed gastrohepatic ligament and across the falciform ligament to Cullen's sign.