Ei Takahashi

Deep sequencing of cancer-related genes revealed GNAS mutations to be associated with intraductal papillary mucinous neoplasms and its main pancreatic duct dilation.

Background To clarify the genetic mutations associated with intraductal papillary mucinous neoplasms (IPMN) and IPMN-related pancreatic tumours, we conducted cancer-related gene profiling analyses using pure pancreatic juice and resected pancreatic tissues. Methods Pure pancreatic juice was collected from 152 patients [nine with a normal pancreas, 22 with chronic pancreatitis (CP), 39 with pancreatic ductal adenocarcinoma (PDAC), and 82 with IPMN], and resected tissues from the pancreas were collected from 48 patients (six IPMNs and 42 PDACs). The extracted DNA was amplified by multiplexed polymerase chain reaction (PCR) targeting 46 cancer-related genes containing 739 mutational hotspots. The mutations were analysed using a semiconductor-based DNA sequencer. Results Among the 46 cancer-related genes, KRAS and GNAS mutations were most frequently detected in both PDAC and IPMN cases. In pure pancreatic juice, GNAS mutations were detected in 7.7% of PDAC cases and 41.5% of IPMN cases (p<0.001 vs. others). All PDAC cases with GNAS mutations (n = 3) were accompanied by IPMN. Multivariate analysis revealed that GNAS mutations in IPMN cases were associated with dilated main pancreatic ducts (MPD, p = 0.016), while no statistically independent associations with clinical variables were observed for KRAS mutations. In the resected pancreatic tissues, GNAS mutations were detected in 50% of PDAC cases concomitant with IPMN, 33.3% of PDAC cases derived from IPMN, and 66.7% of IPMN cases, while no GNAS mutations were detected in cases of PDAC without IPMN. Conclusions The GNAS mutation was specifically found in the cases with IPMN and it was speculated that some PDACs might be influenced by the concomitant but separately-located IPMN in their pathogenic mechanism. Furthermore, the GNAS mutation was significantly associated with MPD dilatation in IPMN cases, suggesting its role in mucus hypersecretion.

Performance status and neutrophil-lymphocyte ratio are important prognostic factors in elderly patients with unresectable pancreatic cancer

BACKGROUND The usefulness of various prognostic factors for pancreatic cancer (PC) has been reported, but the number of elderly patients in these studies is disproportionately fewer compared with those in everyday practice. The purpose of this study was to investigate the prognostic factors for unresectable PC in elderly patients. METHODS We retrospectively analyzed 67 elderly (age ≥75 years) patients with unresectable PC who underwent chemotherapy between January 2006 and December 2014 at our hospital. Univariate and multivariate Cox regression models were applied to investigate independent prognostic factors. RESULTS Multivariate analysis revealed that an increased neutrophil-lymphocyte ratio (NLR) [hazard ratio (HR) 1.91, P=0.03] and Eastern Cooperative Oncology Group (ECOG) performance status (PS) 2 (HR 2.74, P=0.01) were independent negative prognostic factors. CONCLUSIONS The two prognostic factors identified herein are useful in the identification of patients with a poor prognosis and subsequent administration of supportive care alone, which may help avoid the unnecessary adverse effects and complications of systemic chemotherapy.

Biliary drainage strategy of unresectable malignant hilar strictures by computed tomography volumetry.

AIM To identify criteria for predicting successful drainage of unresectable malignant hilar biliary strictures (UMHBS) because no ideal strategy currently exists. METHODS We examined 78 patients with UMHBS who underwent biliary drainage. Drainage was considered effective when the serum bilirubin level decreased by ≥ 50% from the value before stent placement within 2 wk after drainage, without additional intervention. Complications that occurred within 7 d after stent placement were considered as early complications. Before drainage, the liver volume of each section (lateral and medial sections of the left liver and anterior and posterior sections of the right liver) was measured using computed tomography (CT) volumetry. Drained liver volume was calculated based on the volume of each liver section and the type of bile duct stricture (according to the Bismuth classification). Tumor volume, which was calculated by using CT volumetry, was excluded from the volume of each section. Receiver operating characteristic (ROC) analysis was performed to identify the optimal cutoff values for drained liver volume. In addition, factors associated with the effectiveness of drainage and early complications were evaluated. RESULTS Multivariate analysis showed that drained liver volume [odds ratio (OR) = 2.92, 95%CI: 1.648-5.197; P < 0.001] and impaired liver function (with decompensated liver cirrhosis) (OR = 0.06, 95%CI: 0.009-0.426; P = 0.005) were independent factors contributing to the effectiveness of drainage. ROC analysis for effective drainage showed cutoff values of 33% of liver volume for patients with preserved liver function (with normal liver or compensated liver cirrhosis) and 50% for patients with impaired liver function (with decompensated liver cirrhosis). The sensitivity and specificity of these cutoff values were 82% and 80% for preserved liver function, and 100% and 67% for impaired liver function, respectively. Among patients who met these criteria, the rate of effective drainage among those with preserved liver function and impaired liver function was 90% and 80%, respectively. The rates of effective drainage in both groups were significantly higher than in those who did not fulfill these criteria (P < 0.001 and P = 0.02, respectively). Drainage-associated cholangitis occurred in 9 patients (12%). A smaller drained liver volume was associated with drainage-associated cholangitis (P < 0.01). CONCLUSION Liver volume drainage ≥ 33% in patients with preserved liver function and ≥ 50% in patients with impaired liver function correlates with effective biliary drainage in UMHBS.

Next-Generation Sequencing Revealed TP53 Mutations to Be Malignant Marker for Intraductal Papillary Mucinous Neoplasms That Could Be Detected Using Pancreatic Juice

Objectives The aims of this study were to identify the genetic mutations associated with malignant intraductal papillary mucinous neoplasms (IPMNs) and evaluate the possibility of detecting mutations in pure pancreatic juice by next-generation sequencing. Methods Resected tissues were collected from 50 patients with IPMN, and pure pancreatic juice samples were collected from 19 patients who had a resection. The extracted DNA was amplified by multiplex polymerase chain reaction targeting 52 cancer-related genes, including KRAS, GNAS, RNF43, and TP53; the mutations were then detected by next-generation sequencing and then analyzed for correlations with the clinicopathological characteristics. Results In the resected tissues, the most frequently detected mutations were in KRAS, GNAS, TP53, and RNF43, in 88%, 76%, 36%, and 30% of cases, respectively. Univariate and multivariate analyses revealed that only TP53 mutations were associated with malignant IPMNs (P = 0.023). In the pure pancreatic juice, TP53 mutations were detected in 5 of 10 resected samples with malignant IPMN and in 4 of 5 pancreatic juice samples with mutation in resected samples. Conclusions From 52 cancer-related gene analysis, only TP53 mutation was associated with malignant IPMNs. TP53 mutation could also be detected in pure pancreatic juice, potentially making it a useful tool to diagnose malignant IPMNs preoperatively.

Hypoechoic Lesions in Submandibular Glands Are Diagnostic Markers of Type 1 Autoimmune Pancreatitis.

Routine laboratory evaluation is often unrevealing, but possible abnormalities include the following: hypercalcemia, hypercalcuria, elevated alkaline phosphatase level, elevated angiotensin-converting enzyme levels. Regarding this case, the whole body F-FDG positron emission tomography/CTand a biopsy result stands strongly for the diagnosis of pancreatic sarcoidosis. In this case, the confirmation of AIP is based on clinical, laboratory test results, radiographic, and histological findings. The pancreatic biopsy performed by EUS-FNA had sufficient tissue for both cytological and histological diagnosis. Despite radiological advances, pancreatic masses are often difficult to diagnose until operative exploration and histological examination of biopsies. There are 25 cases of pancreatic sarcoidosiswhichwere reported having performed surgical operation as a combined diagnostic and therapeutic measure. Also, such a comprehensive surgical resection is much harmful to a patient if the final result shows a benign lesion. Compared with open biopsy, EUS-FNA biopsy has a lower risk of postoperative complications. In addition, the patient in our case did not take any medication to treat his illness, sowhether the patient would react well to therapeutic diagnosis may be another way to differentiating pancreatic sarcoidosis and other pancreatic diseases. Conclusively, we report here a case showing very uncommon combination of a pancreatic sarcoidosis and type 1 AIP. They sometimes have similar presentation and possibly share the same cause but large numbers of studies are still needed. The EUS-FNAmay present an effective and relatively secure method for differentiating pancreatic sarcoidosis and chronic pancreatitis. However, whether the sensitivity and specificity of this technique in preoperative diagnosis of pancreatic diseases are higher than those of other imaging techniques, and open biopsies still need more researches to verify.

Migration of pancreatic spontaneous dislodgement stent to the appendix

The purposes of pancreatic stenting are the treatment of pancreatic duct stricture and the prevention of postendoscopic retrograde cholangiopancreatography (ERCP) pancreatitis. Here, we report a case of migration of pancreatic spontaneous dislodgement stent to the appendix, which may develop obstructive appendicitis. A 78-year-old woman was transferred to our hospital with a diagnosis of acute gallstone pancreatitis. On physical examination, she had tenderness in the upper abdomen. Laboratory data revealed leukocytosis of 13.7 ¥ 10/L and elevated C-reactive protein at 14.4 mg/dL, total bilirubin at 2.8 mg/dL, alkaline phosphatase at 626 IU/L and amylase at 1421 IU/L. ERCP was carried out to remove bile duct stones and a pancreatic spontaneous dislodgement stent was inserted to prevent post-ERCP pancreatitis. Follow-up computed tomography showed the pancreatic stent had migrated into the appendix (Fig. 1). At colonoscopy, the stent was located in the appendiceal orifice and removed with endoscopic forceps (Fig. 2).The patient did not complain of any symptoms of appendicitis throughout the clinical course. In biliary stenting, proximal or distal migrations are reported to occur. Complications of distal migration most commonly consist of enteral fistulas or overt perforation. Rare complications of appendicitis due to appendiceal obstruction by a migrated biliary stent are also reported. Pancreatic spontaneous dislodgement stent decreased the incidence of post-ERCP pancreatitis significantly in high-risk patients. To prevent post-ERCP pancreatitis, pancreatic spontaneous dislodgement stent has been frequently used in recent years. To the best of our knowledge, late complication of pancreatic spontaneous dislodgement stent has not been reported previously. It is necessary to consider the presence of this complication until the pancreatic stent is excreted from the body.

Pancreaticoduodenectomy for pancreas carcinoma occurring in the annular pancreas: report of a case.

The annular pancreas is a rare congenital anomaly in which a ring of the pancreas parenchyma surrounds the second part of the duodenum. Malignant tumors are extremely rare in patients with an annular pancreas. A 64-year-old man presented with appetite loss and vomiting. Abdominal contrast-enhanced computed tomography (CT) indicated pancreas parenchyma surrounding the second part of the duodenum, and a hypovascular area occupying lesion in the annular pancreas. Subtotal stomach-preserving pancreaticoduodenectomy was performed. Histopathology showed pancreatic carcinoma occurring in the complete annular pancreas.

Successful laparoscopic partial gastrectomy and spleen-preserving distal pancreatectomy for gastric duplication cyst connecting with the pancreatic tail

Highlights • Gastric duplication cyst(GDC) contiguous with the stomach and pancreatic tail is extremely rare.• GDCs are usually diagnosed at a younger age. In adults, they are very rare disease and the diagnosis may be difficult.• Surgical resection is considered to be the best treatment due to the difficulty of diagnosis.• Laparoscopic surgery is less invasive and should be selected whenever possible.

Clinical significance of hypoechoic submandibular gland lesions in type 1 autoimmune pancreatitis

AIM To assess the role of ultrasonography of submandibular glands (SGs) in the diagnosis of type 1 autoimmune pancreatitis (AIP). METHODS Thirty-seven patients who were definitively diagnosed with type 1 AIP according to the international consensus diagnostic criteria (ICDC) for AIP at our institution between December 1990 and April 2016 were retrospectively reviewed. Findings by physical examination, ultrasonography, and scintigraphy of SGs were analyzed to reach a diagnosis based on the ICDC for AIP. The efficacy of corticosteroid treatment in the resolution of hypoechoic lesions in SGs was also evaluated by assessment with ultrasonography before and after treatment in 18 cases. RESULTS The sensitivity of multiple hypoechoic lesions in SGs by ultrasonography for the diagnosis of sialadenitis in type 1 AIP (84%) was higher than that of physical examination (46%), scintigraphy (28%), and SGs thickness (49%). Ultrasonographic evidence of hypoechoic lesions in SGs improved the definitive diagnosis of sialadenitis and type 1 AIP by the ICDC criteria in 11 (30%) and 2 (5.4%) cases, respectively. Multiple hypoechoic lesions in SGs were resolved or disappear by corticosteroid administration in 14 of 16 cases with hypoechoic lesions in SGs, whereas the ultrasonographic findings in the remaining 2 cases with hypoechoic lesions in SGs and the 2 cases with homogenous SG parenchyma remained unchanged after corticosteroid administration. CONCLUSION SG ultrasonography to detect multiple hypoechoic lesions might be useful for type 1 AIP diagnosis by improving diagnostic accuracy together with the ICDC sialadenitis criteria.

Alterations in Cancer-related Genes Associated with Grading of Well Differentiated Pancreatic Neuroendocrine Neoplasms

Objectives: Although recent advances in next-generation sequencing (NGS) have revealed some genetic alterations in various tumors, including pancreatic neuroendocrine tumors (PanNETs), their clinical significance is not fully understood. To investigate the clinical significance of gene alteration in PanNETs, we performed genetic analysis of well differentiated PanNETs using NGS. Methods: Twenty-nine resected primary PanNET tissue samples and three samples of metastatic liver tissues, obtained from 29 PanNET patients, were analyzed. DNA was extracted from laser-captured formalin-fixed paraffinembedded tissues, and 50 cancer-associated genes, including approximately 2,800 hotspots, were amplified by multiplex PCR. Amplified libraries were sequenced using NGS, and the results were analyzed in conjunction with respective clinicopathological features. Results: Among 50 investigated genes, somatic mutations were observed in four of 29 PanNET cases. We identified APC mutations in three cases, PTEN in two, and VHL and STK11 in one. The identified mutations were observed only in NET G2 tumors. All liver metastases contained at least one mutation, such as PTEN or TP53, which was not observed in the primary tumor. Conclusion: The cancer-related gene mutations observed in PanNETs were associated with G2 grade tumors. The mutations were more frequent in PanNET liver metastasis than in the primary tumors. Our analysis of liver metastasis cases suggested that cancer-related gene mutations might raise the tumor grade and promote liver metastasis. Further studies of associations between genetic alterations and clinicopathological features should help in the cancer diagnosis and prediction of therapeutic effects of molecular-target drugs.