Simultaneous and sequential combination of genetic and epigenetic biomarkers for the presence of high-grade dysplasia in patients with pancreatic cyst: Discovery in cyst fluid and test in pancreatic juice.

BACKGROUND/OBJECTIVES: Screening patients with intraductal papillary mucinous neoplasms (IPMN) has the primary goal of identifying potentially curable noninvasive precursors. We aimed to evaluate the diagnostic impact of genetic and epigenetic biomarkers in the presence of noninvasive precursors. METHODS: Mutated KRAS/GNAS and methylated SOX17/TBX15/BMP3/TFPI2 DNA were assessed by droplet digital PCR in a discovery cohort of 70 surgically aspirated cyst fluids, and diagnostic performances for differentiating high-grade dysplasia (HGD) from low-grade dysplasia (LGD) was evaluated. We then tested these markers using an independent test cohort consisting of 156 serially collected pancreatic juice samples from 30 patients with IPMN. RESULTS: Mutated KRAS and GNAS are specific for IPMNs but are not helpful for the prediction of histological grades. Cyst fluids from IPMN with HGD showed higher methylation levels of SOX17 (median, 0.141 vs. 0.021; P = 0.086) and TBX15 (median, 0.030 vs. 0.003; P = 0.028) than those with LGD. The combination of all tested markers yielded a diagnostic performance with sensitivity of 69.6%, and specificity of 90.0%. Among the 30 pancreatic juice samples exhibiting the highest abundance of KRAS/GNAS mutations in each patient in the test cohort, patients with histologically proven HGD due to pancreatic resection had a significantly higher prevalence (100% vs. 31%, P = 0.018) and abundance (P = 0.037) of methylated TBX15 than those without cytohistological diagnosis undergoing surveillance. CONCLUSIONS: A simultaneous and sequential combination of mutated and methylated DNA markers in pancreatic cyst fluid and juice sample markers can help detect noninvasive pancreatic precursor neoplasms.

Pancreaticoduodenectomy following total occlusion of the superior mesenteric artery: a case report and literature review.

BACKGROUND: Patients with chronic occlusion of the celiac artery and superior mesenteric artery (SMA) are often asymptomatic, and occlusion may be caused by arteriosclerosis or median arcuate ligament compression. Pancreaticoduodenectomy (PD) is occasionally performed for patients with celiac artery occlusion; however, reports on patients with SMA occlusion are rare. We report a patient with cholangiocarcinoma and total atherosclerotic occlusion of the SMA without preoperative stenting or bypass. CASE PRESENTATION: A 73-year-old man suspected to have lower bile duct carcinoma was admitted to our hospital for further treatment. Three-dimensional computed tomography (3DCT) showed a common bile duct tumor and total occlusion of the SMA with collateral circulation of the gastroduodenal artery (GDA) and inferior mesenteric artery (IMA). We performed a PD. During the operation, we used test clamping of the GDA, which revealed no bowel ischemia. The postoperative course was uneventful, and the patient was discharged on postoperative day (POD) 30. 3DCT on POD 98 and POD 307 showed development of collateral circulation between the IMA and SMA. CONCLUSION: Here, we report the case of a patient with total occlusion of the SMA who subsequently underwent PD. 3DCT was instrumental in gathering vascular collateral information and thus we conclude that the assessment of collateral circulation before surgery is important.

Massive retroperitoneal hematoma following colonoscopy: A case report.

RATIONALE: Colonoscopy has been used for screening and treatment of diseases worldwide. Endoscopic mucosal resection (EMR) has many major complications such as colon perforation and bleeding. However, cases of minor complications have also been reported. Here, we present a case of massive retroperitoneal hematoma, as a minor complication, after colonoscopy. PATIENT CONCERNS: A 57-year-old man was admitted to our hospital because of abdominal pain. He had no past medical history relating to his present condition, and he received EMR at another hospital 11 days before his admission. Dynamic computed tomography (CT) was performed, which showed a massive retroperitoneal hematoma near the third portion of the duodenum. DIAGNOSIS: The patient had a superior mesenteric vein injury after the colonoscopy. OUTCOMES: The patient did not complain of nausea or vomiting and was discharged after 43 days. LESSONS: Although massive retroperitoneal hematoma is a minor complication after colonoscopy, it can be life threatening; thus, we need to know more about this complication. Dynamic CT may be useful in detecting whether the bleeding occurs from the artery or not.

Incidentally detected splenogonadal fusion in a laparoscopic transabdominal preperitoneal hernia repair operation: A case report.

INTRODUCTION: Splenogonadal fusion (SGF) is a rare congenital malformation in which the spleen is connected to the gonad. Few SGF cases have been reported in the English scientific literature, and we are unaware of any previous case reports of SGF with inguinal hernia by laparoscopic transabdominal preperitoneal hernia repair (TAPP). Here, we report a case of SGF that was incidentally detected during a TAPP procedure, with an uneventful postoperative course without complications. PRESENTATION OF CASE: A 76-year-old male presented with a 10-year history of left inguinal swelling. He was diagnosed with a left inguinal hernia, and we performed TAPP. Laparoscopy revealed the left inguinal hernia and two reddish-purple masses, one located close to the left inguinal ring. A cord of soft tissue extended cranially from the mass to the spleen, and passed through the left internal inguinal ring caudally. We cut the cord for mesh placement and to make an accurate diagnosis of the mass. Pathological and intraoperative findings indicated a diagnosis of continuous SGF. DISCUSSION: We observed two important clinical issues in this case. First, the potential for incidental diagnoses of SGF may be increasing. Second, to our knowledge, this is the first case report of a patient with SGF identified by TAPP. Such a therapeutic strategy for incidentally detected SGF has not been described; here we report a successful experience. CONCLUSION: To our knowledge, this is the first report of a patient with SGF diagnosed by a TAPP procedure. The postoperative course was uneventful using our method.

Is it possible to define early distal cholangiocarcinoma?

PURPOSE: The feasibility of defining early cholangiocarcinoma has not been adequately evaluated. The surgical outcomes of patients who had undergone pancreatoduodenectomy (PD) for pathological T1 (pT1) distal cholangiocarcinoma (DCC) were evaluated to determine whether it is possible to define early DCC. METHODS: The clinicopathological data of 18 patients with pT1 DCC who had undergone PD were reviewed retrospectively. Depth of fibromuscular (fm) layer invasion was divided into two categories: fm1 and fm2 (without adventitia fascia invasion and with adventitia fascia invasion). Comparative analyses were performed according to the depth of invasion. RESULTS: Disease-specific survival rates of patients with five mucosal tumors and 13 fm-invasive tumors were 80 and 61.9 % at 5 years and 80 and 41.2 % at 10 years, respectively. There was no significant difference in disease-specific survival rates between the two groups (P = 0.244). Disease-specific survival rates of patients with 7 fm1-invasive tumors and 6 fm2-invasive tumors were 85.7 and 40 % at 5 years and 85.7 and 0 % at 10 years. A significant difference in disease-specific survival rates was observed between mucosal tumors and fm2-invasive tumors (P = 0.043), and disease-specific survival rates of mucosal tumors and fm1-invasive tumors were similar (P = 0.968). CONCLUSIONS: Defining early DCC as carcinoma confined to the fm of the bile duct might be inappropriate; early DCC should be limited to the mucosal carcinoma.

Diffusion-weighted MR imaging of pancreatic cancer and inflammation: Prognostic significance of pancreatic inflammation in pancreatic cancer patients.

BACKGROUND: Pancreatic cancer often accompanies chronic obstructive pancreatitis (COP) due to obstruction of the main pancreatic duct, and the inflammatory environment may enhance cancer progression. The purpose of this study is to evaluate COP using the apparent diffusion coefficient (ADC) value measured by diffusion-weighted MR imaging (DWI), and to assess its prognostic significance in pancreatic cancer. METHODS: Twenty-eight patients (16 men, 12 women; mean age 67.1 years) with pancreatic cancers who underwent DWI followed by curative surgery were evaluated. The ADC value of pancreatic parenchyma upstream to the tumor (upstream pancreas) was measured and compared with the upstream pancreatic duct dilatation to assess whether DWI could reflect COP. The ADC values of tumor and upstream portion were compared with overall survival (OS) using Cox regression and Kaplan-Meier analysis. RESULTS: The ADC value of upstream pancreas was significantly lower in patients with greater dilated pancreatic duct than those with less (P = 0.03). In univariate Cox regression analysis, the ADC value of upstream pancreas showed a significant association with OS (P = 0.01), but that of tumor did not (P = 0.06). In Kaplan-Meier analysis, patients with lower ADC value of upstream pancreas (<1.36 × 10(-3) mm(2)/s) were significantly associated with poor OS (P = 0.0006). In multivariate analysis, the ADC value of upstream pancreas was identified as an independent prognostic factor (P = 0.01; hazards ratio, 0.05; 95% CI, 0.004-0.59). CONCLUSIONS: The ADC value of upstream pancreas was an independent prognostic factor for OS in pancreatic cancer patients. Inflammatory environment may play an important role in pancreatic cancer progression.

Biweekly gemcitabine plus S-1 for locally advanced and metastatic pancreatic cancer: a preliminary feasibility study.

BACKGROUND: Chemotherapy for unresectable pancreatic cancer should not only prolong survival but maintain quality of life, considering its limited life expectancy. To achieve these goals, biweekly gemcitabine plus S-1 was assessed in the clinical practice setting. METHODS: Fifty-two patients with either locally advanced or metastatic pancreatic cancer who received biweekly gemcitabine plus S-1 as a first-line anti-cancer treatment were included in this study. Treatment delivery, toxicity, response, and survival were reviewed to assess the feasibility and efficacy. RESULTS: The completion rate of treatment delivery was 95.1%, with relative dose intensity of 97.1% for gemcitabine and 97.3% for S-1. Overall, grade 3 or worse adverse events were rare, with hematologic toxicities occurring in 5.8%. The objective response rate was 30.8%, and more than a 50% reduction of CA19-9 was observed in 77.1%. Surgical conversion was completed with a margin-negative resection in four patients whose tumor had shrunk for at least 6 months. The median progression-free and overall survivals were 10.4 and 18.2 months, respectively. Reduction of CA19-9 was associated with longer survival. CONCLUSIONS: Biweekly gemcitabine plus S-1 may be a good alternative to current standard chemotherapies for unresectable pancreatic cancer with less toxicity and less treatment burden without losing efficacy.

Evaluation of portal vein invasion of distal cholangiocarcinoma as borderline resectability.

BACKGROUND: The concept of borderline resectability has not yet been introduced for extrahepatic cholangiocarcinoma (ECC). In this study, the surgical results of ECC patients were analyzed to clarify the implications of surgery for distal ECC with portal vein (PV) invasion as a preliminary step for the introduction of the concept of borderline resectability. METHODS: The clinicopathological data of 129 patients who had undergone pancreatoduodenectomy of distal ECC were reviewed retrospectively. Combined PV resection was performed in 10 patients. The clinicopathological variables were evaluated using univariate and multivariate analyses. RESULTS: Pathological PV invasion was observed in eight of the 129 patients. The survival rates of patients with PV invasion were significantly poorer than those of patients without PV invasion: 3 and 5 years after surgery, 17% and 0% versus 50% and 39% (P < 0.001), respectively. Presence of pancreatic or PV invasion, tumor progression, nodal status, and residual tumor were significant prognostic factors on univariate analysis. On multivariate analysis, PV invasion was the only significant independent predictive factor of a poor prognosis. CONCLUSIONS: PV invasion of distal ECC should be regarded as indicating borderline resectability.

Long-term surgical outcomes of patients with type 1 autoimmune pancreatitis.

BACKGROUND: Although pancreatectomy has sometimes been performed for patients with autoimmune pancreatitis (AIP) presenting atypical radiologic findings under the diagnosis of pancreatobiliary malignancy, the long-term surgical outcome of these patients had not yet been fully elucidated. METHODS: The long-term surgical outcomes of 13 patients with pathologically diagnosed type 1 AIP with immunohistochemical staining for immunoglobulin G4 (IgG4) were retrospectively compared with those of 34 patients with conventional chronic pancreatitis to evaluate the residual pancreatic function. RESULTS: A definite relapse of AIP in terms of the clinical manifestations and diagnostic imaging was not found in any of the patients, although one patient experienced an attack of acute pancreatitis caused by pancreatic stones, and stricture of the hepaticojejunostomy occurred in one patient. The overall body weight decreased significantly more in patients with AIP than in patients with conventional chronic pancreatitis (p < 0.05); however, there was no difference in the preoperative nondiabetic patients. Refractory diarrhea occurred in only one patient with AIP. The cumulative new-onset rates of diabetes mellitus of the ten patients with AIP and 24 patients with conventional chronic pancreatitis at 5 years after the surgery were 32.5 and 26.1 %, respectively (p = 0.70). CONCLUSIONS: Careful long-term follow-up is needed for patients undergoing pancreatectomy for type 1 AIP because remnant pancreatic function can deteriorate as severely as that of patients who undergo pancreatectomy for conventional chronic pancreatitis. In the present series, however, there were few definite manifestations indicating relapse or the persistent existence of AIP.

Correlation of apparent diffusion coefficient measured by diffusion-weighted MRI and clinicopathologic features in pancreatic cancer patients.

BACKGROUND/PURPOSE: The aim of this study was to evaluate the clinical usefulness of diffusion-weighted magnetic resonance imaging (DWI) in patients with pancreatic cancer by comparing the apparent diffusion coefficient (ADC) value with clinicopathologic features. METHODS: Twenty-two consecutive patients (12 men, 10 women; mean age 64.4 years) with pancreatic cancer underwent DWI before surgery. We retrospectively investigated the correlations between tumor ADC value and clinicopathologic features. RESULTS: Apparent diffusion coefficient value was significantly lower for pancreatic cancer than for noncancerous tissue (P < 0.001). Receiver operating characteristic analysis yielded an optimal ADC cutoff value of 1.21 × 10(-3) mm(2)/s to distinguish pancreatic cancer from noncancerous tissue. There was a significant negative correlation between ADC value and tumor size (r = -0.59, P = 0.004) and between ADC value and number of metastatic lymph nodes (r = -0.56, P = 0.007). Tumors with low ADC value had a significant tendency to show high portal venous system invasion (P = 0.02) and extrapancreatic nerve plexus invasion (P = 0.01). CONCLUSIONS: Apparent diffusion coefficient value appears to be a promising parameter for detecting pancreatic cancer and evaluating the degree of malignancy of pancreatic cancer.

Whereabouts of an internal short stent placed across the pancreaticojejunostomy following pancreatoduodenectomy.

BACKGROUND/PURPOSE: It is generally thought that an internal short stent placed across the pancreaticojejunostomy (PJ) following pancreatoduodenectomy (PD) usually passes spontaneously through the rectum thereafter; however, we experienced some patients who presented with pancreatitis and cholangitis owing to delayed defecation of the stent. The purpose of this study was to clarify when the stent eventually became detached from the PJ and how it passed through the body until it was finally defecated. In addition, we also investigated the factors that may prevent such detachment and defecation. METHODS: This study retrospectively analyzed 57 patients who had had internal short stents placed across the PJ following PD. Defecation from the body, detachment from the PJ, and distal migration of the stent was confirmed by X-ray or computed tomography (CT) during the postoperative course. The cumulative rates of defecation and detachment of the stents, complications in relation to delayed defecation of the stents, and factors predictive of the delayed defecation, delayed detachment, and distal migration of the stents were analyzed. RESULTS: Defecation of the stent was confirmed in 35 patients. The median time to defecation after PD and the cumulative defecation rate at 1 year were 454 days and 41 %, respectively. Acute pancreatitis occurred in 2 patients with the stent remaining in the pancreatic duct. One patient experienced acute cholangitis owing to migration of the stent to the bile duct. Multivariate analysis showed that ≥5 stitches in the duct-to-mucosa anastomosis, stent size of ≥5 Fr, and pancreatic fistula classified as either Grade B or C were independent predictive factors for delayed defecation of the stent. Five or more stitches in the duct-to-mucosa anastomosis was an independent predictive factor for delayed detachment of the stent. A stent size of ≥5 Fr was a risk factor for distal migration of the stent. CONCLUSION: In more than half of the study patients, internal short stents were not defecated within 1 year. Retrieval of the stent should be considered following the migration of an internal short stent. A stent size of ≥5 Fr was an independent predictive factor for delayed defecation and distal migration of a stent. Five or more stitches in the duct-to-mucosa anastomosis was an independent predictive factor for delayed defecation and detachment of a stent.

Portal vein resection in pancreaticoduodenectomy (with video).

Superior mesenteric vein (SMV) resection during pancreaticoduodenectomy (PD) for pancreatic cancer was first reported by Moore in 1951. In Japan, utilization of portal vein resection (PVR) became popular beginning in the late 1970s and has resulted in an improved resection rate for pancreatic cancer. Outcomes of PVR differ according to the reported year and institution. In a recent report of meta-analysis, there was no difference in outcomes after PVR if R0 (negative surgical margins) resection was possible. Pancreatic surgery including vascular resection must be re-evaluated in light of recent advances in diagnostic imaging and surgical techniques, lower mortality and morbidity after PVR, and improvements in adjuvant and neo-adjuvant therapy. Isolated portal vein involvement should not be a contraindication to resection. Portal vein resection should be considered after appropriate patient selection based on an accurate diagnosis, provided that safe R0 resection is possible. We describe technical details and considerations for PVR during PD in this paper.

Small nodules which could indicate the early phase of autoimmune pancreatitis.

We present a case with small pancreatic nodules, which could indicate the early phase of autoimmune pancreatitis (AIP). A 68-year-old man was referred to our hospital for further diagnostic evaluation of a pancreatic mass detected on abdominal ultrasonography screening for epigastric discomfort. Abdominal ultrasonography and endoscopic ultrasonography revealed a low echoic lesion measuring approximately 1 cm with an irregular margin in the body of the pancreas. Computed tomography revealed a tumor in the portal venous phase of enhancement; hence, a distal pancreatectomy was performed. On histology, a marked lymphocyte- and plasma cell-dominant inflammatory cell infiltrate was observed in the nodule. There was another smaller nodule consisting of moderate lymphoplasmacytic infiltration in the 2-cm distal portion of the pancreas. Lymphoplasmacytic infiltration was also observed around the main pancreatic duct in the pancreatic stump. In the parenchyma, other than these 3 portions, the normal lobular structure was well preserved. Little storiform fibrosis and obliterative phlebitis were observed in the resected specimen. On immunohistochemical staining, plasma cells showing strong immunoreactivity for immunoglobulin G4 were observed within these two nodules and around the main pancreatic duct at the cut surface. This case could indicate the early phase and multicentricity of AIP.

Arterio-biliary fistula as rare complication of chemoradiation therapy for intrahepatic cholangiocarcinoma.

Significant hemobilia due to arterio-biliary fistula is a very rare complication of chemoradiation therapy (CRT) for unresectable intrahepatic cholangiocarcinoma (ICC). Here we report a case of arterio-biliary fistula after CRT for unresectable ICC demonstrated by angiographic examinations. This fistula was successfully treated by endovascular embolization. Hemobilia is a rare complication, but arterio-biliary fistula should be considered after CRT of ICC.

New prognostic factor influencing long-term survival of patients with advanced gallbladder carcinoma.

BACKGROUND: Although the safety of operations has generally improved in recent years, the mortality of extended operations for advanced gallbladder carcinoma (GBC) remains high, and the outcomes of patients with advanced GBC requiring major surgery are poor. In this study, a newly formulated original stage classification of advanced GBC was evaluated to clarify prognostic factors affecting long-term survival. METHODS: A total of 149 patients with resected GBC infiltrating beyond the propria muscle layer were analyzed retrospectively. These patients were classified into F0 (n = 50), F1 (n = 38), F2 (n = 38), and F3 (n = 23) according to the number of positive histopathologic factors, consisting of direct invasion to the liver, invasion to the hepatoduodenal ligament, and lymph node metastasis. Overall survival rates were compared with the Union Internationale Contre le Cancer TNM classification (6th edition). RESULTS: Overall 5-year survival rates of patients with F0, F1, F2, and F3 were 60%, 35%, 5%, and 0%, respectively. Significant differences were observed, except between F2 and F3. In 38 patients with F1, there were no significant differences between 13 patients with direct invasion to the liver, 4 patients with invasion to the hepatoduodenal ligament, and 21 patients with lymph node metastasis. Multivariate analysis revealed that F classification was the most important independent risk factor to predict survival. CONCLUSION: Patients with advanced GBC are expected to survive long if only 1 of hepatic invasion, hepatoduodenal ligament invasion, or lymph node metastasis is positive.

Eleven cases of postoperative hepatic infarction following pancreato-biliary surgery.

BACKGROUND: Postoperative hepatic infarction is rare; therefore, clinical characteristics and outcomes of postoperative hepatic infarction after pancreatobiliary surgery have not been obvious. METHODS: Eleven patients encountered hepatic infarction after pancreato-biliary surgery. Management, clinical course, and outcome of these 11 patients were retrospectively analyzed. RESULTS: Possible causes of the hepatic infarction were inadvertent injury of the hepatic artery during lymph node dissection in five patients, right hepatic artery ligation in two patients, long-term clamp of the hepatic artery during hepatic arterial reconstruction in two patients, suturing for bleeding from the right hepatic artery in one patient, and celiac axis compression syndrome in one patient. Five of the 17 infarcts extended for one whole section of the liver, and distribution of the other 12 was less than one section. Ten patients discharged from hospital; however, one patient died of sepsis of unknown origin. CONCLUSIONS: Attention should be paid to inadvertent injury of hepatic artery to prevent hepatic infarction. Hepatic infarctions after pancreato-biliary surgery seldom extend to the entire liver and most of them are able to be treated without intervention.

Cutting-edge information for the management of acute pancreatitis.

Considering that the Japanese (JPN) guidelines for the management of acute pancreatitis were published in Takada et al. (J HepatoBiliary Pancreat Surg 13:2-6, 2006), doubts will be cast as to the reason for publishing a revised edition of the Guidelines for the management of acute pancreatitis: the JPN guidelines 2010, at this time. The rationale for this is that new criteria for the severity assessment of acute pancreatitis were made public on the basis of a summary of activities and reports of shared studies that were conducted in 2008. The new severity classification is entirely different from that adopted in the 2006 guidelines. A drastic revision was made in the new criteria. For example, about half of the cases that have been assessed previously as being 'severe' are assessed as being 'mild' in the new criteria. The JPN guidelines 2010 are published so that consistency between the criteria for severity assessment in the first edition and the new criteria will be maintained. In the new criteria, severity assessment can be made only by calculating the 9 scored prognostic factors. Severity assessment according to the contrast-enhanced computed tomography (CT) grade was made by scoring the poorly visualized pancreatic area in addition to determining the degree of extrapancreatic progress of inflammation and its extent. Changes made in accordance with the new criteria are seen in various parts of the guidelines. In the present revised edition, post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis is treated as an independent item. Furthermore, clinical indicators (pancreatitis bundles) are presented to improve the quality of the management of acute pancreatitis and to increase adherence to new guidelines.