Clinicopathological characteristics of pancreatic ductal adenocarcinoma with invasive micropapillary carcinoma component with emphasis on the usefulness of PKCζ immunostaining for detection of reverse polarity.

Invasive micropapillary carcinoma (IMPC) is a rare distinct histopathological subtype, characterized by the presence of carcinoma cells displaying reverse polarity. Only limited clinicopathological information is available regarding pancreatic IMPC. The aim of the present study was to clarify the clinicopathological features of pancreatic IMPC and the usefulness of protein kinase C (PKC)ζ immunostaining for the detection of reverse polarity. We reviewed 242 consecutive surgically resected specimens of pancreatic ductal adenocarcinoma and selected samples with an IMPC component. Clinicopathological characteristics were compared between the IMPC and non-IMPC groups. Immunohistochemical staining for PKCζ was performed using an autostainer. In total, 14 cases had an IMPC component (5.8%). The extent of IMPC component ranged from 5 to 20%. There were no significant differences in tumor location, T category, lymph node metastatic status, preoperative carbohydrate antigen 19-9 level, resection status and overall survival between the IMPC and non-IMPC groups. Immunostaining for PKCζ clearly showed reverse polarity of the neoplastic cells of IMPC. Although previous reports have shown that the presence of an IMPC component (>20% of the tumor) indicated poor prognosis, the present study demonstrated that presence of IMPC <20% did not suggest a worse prognosis.

Benefits of Conversion Surgery after Multimodal Treatment for Unresectable Pancreatic Ductal Adenocarcinoma.

BACKGROUND: Traditionally, the treatment options for unresectable locally advanced (UR-LA) and metastatic (UR-M) pancreatic ductal adenocarcinoma (PDAC) are palliative chemotherapy or chemoradiotherapy. The benefits of surgery for such patients remains unknown. The present study investigated clinical outcomes of patients undergoing conversion surgery (CS) after chemo(radiation)therapy for initially UR-PDAC. METHODS: We recruited patients with UR-PDAC who underwent chemo(radiation)therapy for initially UR-PDAC between April 2006 and September 2017. We analyzed resectability of CS, predictive parameters for overall survival, and early recurrence (within six months). RESULTS: A total of 468 patients (108 with UR-LA and 360 with UR-M PDAC) were enrolled in this study, of whom, 17 (15.7%) with UR-LA and 15 (4.2%) with UR-M underwent CS. The median survival time (MST) and five-year survival of patients who underwent CS was 37.2 months and 34%, respectively; significantly better than non-resected patients (nine months and 1%, respectively, p < 0.0001). MST did not differ according to UR-LA or UR-M (50.5 vs. 29.0 months, respectively, p = 0.53). Early recurrence after CS occurred in eight patients (18.8%). Lymph node metastasis, positive washing cytology, large tumor size (>35 mm), and lack of postoperative adjuvant chemotherapy were statistically significant predictive factors for early recurrence. Moreover, the site of pancreatic lesion and administration of postoperative adjuvant chemotherapy were statistically significant prognostic factors for overall survival in the patients undergoing CS. CONCLUSION: Conversion surgery offers benefits in terms of increase survival for initially UR-PDAC for patients who responded favorably to chemo(radiation)therapy when combined with postoperative adjuvant chemotherapy.

Bile Duct Stones Predict a Requirement for Cholecystectomy in Older Patients.

BACKGROUND: The requirement for elective cholecystectomy in older patients is unclear. To determine predictors for requiring elective cholecystectomy in older patients, a prospective cohort study was performed. METHODS: All patients with gallstone disease who presented to our department from 2006 to 2018 were included if they met the following criteria: (1) age 75 years or older, (2) presentation for elective cholecystectomy, and (3) preoperative diagnosis of cholecystolithiasis. Two therapeutic options, elective surgery and a wait-and-see approach, were offered at their initial visit. Enrolled patients were assigned to one arm of the study according to their choice of the therapeutic options. The primary endpoint was the incidence of gallstone-related complications. The endpoint was compared between patients who underwent cholecystectomy (CH group) and those who chose a wait-and-see approach (No-CH group). RESULTS: During the study period, there were 344 patients in the CH group and 161 in the No-CH group. Among patients with a history of bile duct stones, the incidence of gallstone-related complications in the No-CH group was significantly higher (45% within 3 years, including two gallstone-related deaths) than that in the CH group (RR 2.66, 95% confidence interval 1.50-4.77, p = 0.0009). Among patients with no history of bile duct stones, the incidence of gallstone-related complications in the No-CH group reached only 10% over the 12 years. CONCLUSION: Cholecystectomy is recommended for older patients with both histories of cholecystolithiasis and bile duct stones, whereas a wait-and-see approach is preferable for patients with no bile duct stone history. A history of bile duct stones is a good predictor for cholecystectomy in older patients.

Prognosis in Patients With Gallbladder Edema Misdiagnosed as Cholecystitis.

BACKGROUND AND OBJECTIVES: Edema of the gallbladder may pose a diagnostic challenge because it also occurs in patients without an indication for cholecystectomy. METHODS: We evaluated all consecutive patients with gallstone disease who presented for cholecystectomy at the Department of Surgery of Kansai Medical University from January 2006 to April 2019. Using the prospectively collected database in our department, we obtained information on patients whose final diagnoses were gallbladder edema. We identified 12 patients with gallbladder edema who were misdiagnosed with acute cholecystitis among 2661 patients and who presented for cholecystectomy for benign gallbladder diseases. The outcome of these patients was assessed to prevent unnecessary cholecystectomy. RESULTS: In all 12 patients, computed tomography and ultrasonographic imaging showed gallbladder wall thickening. Acute cholecystitis was suspected, and emergent cholecystectomy was performed for the first 5 patients. Of these 5 patients, 2 patients died of liver failure postoperatively. Based on the misdiagnosis in the first 5 patients, the latter 7 patients did not undergo cholecystectomy; instead, they were treated specifically for their systemic disease. To date, no cholecystitis has occurred in these 7 patients. In all misdiagnosed cases in the present report, mesh-like wall thickening was a distinctive feature of gallbladder edema on ultrasonography. We consider this feature important for distinguishing simple gallbladder edema from cholecystitis. CONCLUSION: Careful evaluation of clinical symptoms and imaging findings, especially mesh-like wall thickening on ultrasonography, is necessary in this setting to prevent misdiagnosis and unnecessary cholecystectomy.

Clinical impact of the sequentially-checked drain removal criteria on postoperative outcomes after pancreatectomy: a retrospective study.

BACKGROUND: Strict criteria for impeccably safe drain management following pancreatectomy have not yet been developed. We evaluated the utility of the sequentially-checked drain removal criteria by comparison with conventional criteria. METHODS: Postoperative outcomes of 801 patients who underwent pancreatectomy, including 395 patients for whom drain fluid amylase (DFA) < 375U/l on postoperative day (POD) 3 (control group), were used and 406 patients for whom the sequentially-checked criteria of DFA <5,000 U/l on POD 1 and DFA <3,000 U/l on POD 3 (sequentially-checked group) were used and were retrospectively evaluated. RESULTS: DFA on POD 3 and fistula risk score did not differ between groups. Significantly more patients in the sequentially-checked group met the criteria (control, 63.8% vs. sequentially-checked, 76.1%, P < 0.001). The incidences of clinically relevant postoperative pancreatic fistula (CR-POPF) (17.0% vs. 11.1%), intra-abdominal abscess (21.0% vs. 9.1%) were significantly lower in the sequentially-checked group (all P < 0.05). Multivariate analysis revealed that use of the sequentially-checked criteria was significantly associated with CR-POPF (odds ratio 0.601, 95% confidence interval [CI] 0.389-0.929; P = 0.022). C-reactive protein <15 mg/dl at POD 3 was identified as an independent predictive factor for false positive CR-POPF results in the sequentially-checked group (odds ratio 0.872, 95% CI 0.811-0.939; P < 0.001); thus, this criterion was added to create the new triple-checked criteria. CONCLUSIONS: The sequentially-checked criteria can provide safe drain management and improve postoperative outcomes.

Adipophilin expression is an indicator of poor prognosis in patients with pancreatic ductal adenocarcinoma: An immunohistochemical analysis.

OBJECTIVE: Adipophilin is a lipid droplet-associated protein, and its expression has been correlated with aggressive clinical behavior in some types of carcinomas, though its role in pancreatic ductal adenocarcinoma (PDAC) has not been clarified. This study aimed to evaluate the role of adipophilin in PDAC. METHODS: By immunohistochemical staining using tissue microarrays, we analyzed the expression profiles of adipophilin in 181 consecutive PDAC patients who underwent macroscopic margin-negative resection from January 2008 to December 2015. Overall survival (OS) and recurrence-free survival (RFS) were compared based on adipophilin expression, and the risk factors for OS, RFS, and early recurrence (within 6 months) were analyzed. RESULTS: Of the 181 evaluated patients, 51 (28.2%) were positive for adipophilin expression. A histopathological grade of 3 (p = 0.0012), higher CA19-9 level (p = 0.0016), and R1 status (p = 0.028) were significantly associated with adipophilin-positive patients who had significantly poor OS and RFS compared to those associated with adipophilin-negative patients (p = 0.0007 and p = 0.0022, respectively). They also showed a significantly higher incidence of early recurrence (p = 0.030), based on multivariate analyses. CONCLUSIONS: Adipophilin is a potential independent prognostic marker for PDAC.

Assessment of clinical outcome of cholecystectomy according to age in preparation for the "Silver Tsunami".

BACKGROUND: Recent rapid increases in the aging population have created an impending "Silver Tsunami" in advanced countries. The overall prevalence of gallstone disease and its related complications will soon increase, and there will be a larger demand for gallbladder surgery. METHODS: We examined the outcomes of cholecystectomy according to age among patients with cholelithiasis to determine how a patient's age influences the outcome of cholecystectomy. All patients with gallstone disease who presented for cholecystectomy at our institute from January 2006 to December 2018 were analyzed. RESULTS: All perioperative outcomes (operation length, length of hospital stay, rate of open surgery, urgent surgery, postoperative complications, incidental gallbladder cancer, postoperative hospital death, concomitant bile duct stones, and total medical costs per patient) increased as patients aged. CONCLUSIONS: To prevent the progression of biliary disease, elective laparoscopic cholecystectomy is recommended before patients with cholelithiasis advance in age.

Clinicopathological and immunological features of follicular pancreatitis - a distinct disease entity characterised by Th17 activation.

AIM: Follicular pancreatitis is a recently recognised, distinct clinicopathological entity characterised by the presence of many intrapancreatic lymphoid follicles with reactive germinal centres. However, the clinicopathological and immunological features and causes have not yet been established. We assessed the clinicopathological and immunological profiles of patients with follicular pancreatitis who underwent surgery. METHODS AND RESULTS: This study included three patients with pancreatic masses (age range = 62-75 years; women:men: 1:2). A histopathological study of the resected pancreatic masses revealed abundant lymphoid follicles with reactive germinal centres in both periductal regions and diffusely within the parenchyma. No storiform fibrosis, obliterative phlebitis or granulocytic epithelial lesions were observed. The immunohistochemical examination revealed an IgG4/IgG-positive plasma cell ratio <30% in all patients. Podoplanin (Th17 marker)-expressing lymphocytes were present in the lymphoid follicles of those with follicular pancreatitis, whereas these were absent in normal lymph nodes and in lymphoid follicles of those with IgG4-related autoimmune pancreatitis (AIP). An RNA digital counting assay clearly demonstrated that the expression counts of 20 genes, including dendritic cells and lymphoid follicles markers, and related cytokines were significantly higher in follicular pancreatitis than in IgG4-related AIP (P < 0.01). The expressions of CCR6 and IL23A, which are genes related to Th17, were high. CONCLUSIONS: This study shows that follicular pancreatitis is a histopathologically and immunologically distinct disease entity of pancreatitis and is characterised by upregulated Th17 expression.

Does modified Blumgart anastomosis without intra-pancreatic ductal stenting reduce post-operative pancreatic fistula after pancreaticojejunostomy?

BACKGROUND: Post-operative pancreatic fistula (POPF) is one of the most common and serious complications after pancreaticoduodenectomy (PD). The aim of this study is to retrospectively compare clinically relevant (CR) POPF and other complications after pacreaticojejunostomy (PJ) after modified Kakita (m-Kakita) or modified Blumgart (m-Blumgart) anastomoses without stenting in a single institution. METHODS: One hundred twenty-eight patients underwent PJ using m-Kakita anastomoses (two interrupted penetrating sutures) between January 2009 and December 2011. One hundred eighteen patients underwent m-Blumgart anastomoses (two transpancreatic/jejunal seromuscular sutures to cover the pancreatic stump with jejunal serosa) between January 2014 and December 2015. Demographics, clinical characteristics, and post-operative mortality and morbidity were retrospectively compared between the two groups. RESULTS: There were no significant differences in demographics or clinical characteristics between the two groups except operative time. A significantly lower rate of CR-POPF was found in the m-Blumgart group relative to the m-Kakita group (10% vs. 19%, p = 0.038). Univariate and multivariate analyses revealed that the m-Blumgart anastomosis and fistula risk category (Negligible, Low) were independently protective against CR-POPF (p < 0.05). CONCLUSION: This retrospective single-center study demonstrated that the modified Blumgart method without pancreatic duct stenting was associated with a lower rate of CR-POPF.

Use of a piece of free omentum to prevent bile leakage after subtotal cholecystectomy.

BACKGROUND: Bile leakage after subtotal cholecystectomy (SC) is clinically serious. To prevent such leakage, we developed a new surgical technique in which a free piece of omentum is plugged into the gallbladder stump (omentum plugging technique). We evaluated whether the omentum plugging technique prevents bile leakage after subtotal cholecystectomy. METHODS: Prospectively collected data of patients who had undergone subtotal cholecystectomy without cystic duct closure in the Department of Surgery of Kansai Medical University during the 12 years from January 2006 to March 2018 were reviewed retrospectively. The outcomes of patients who had undergone subtotal cholecystectomy with the omentum plugging technique (omentum plugging technique group) were compared with those of patients who had undergone subtotal cholecystectomy without the omentum plugging technique (Control group). The outcomes of interest were perioperative data and postoperative complications including bile leakage, necessity for interventions for complications, and duration of hospitalization. RESULTS: Fifty of 2,447 consecutive patients (2.0%) had undergone subtotal cholecystectomy. Of these 50 patients, 18 were treated with the omentum plugging technique (omentum plugging technique group) and 32 were treated without the omentum plugging technique (Control group). One of 18 patients in the omentum plugging technique group and 14 of 32 in the Control group developed postoperative bile leakage. One postoperative interventional treatment for complications was performed in the omentum plugging technique group and 12 in the Control group. The duration of postoperative hospitalization was less in the omentum plugging technique group. CONCLUSION: The omentum plugging technique appears to be an effective operative technique for preventing postoperative bile leakage in selected situations when a "difficult gallbladder" is encountered.

Reappraisal of previously reported meta-analyses on antibiotic prophylaxis for low-risk laparoscopic cholecystectomy: an overview of systematic reviews.

INTRODUCTION: Many researchers have addressed overdosage and inappropriate use of antibiotics. Many meta-analyses have investigated antibiotic prophylaxis for low-risk laparoscopic cholecystectomy with the aim of reducing unnecessary antibiotic use. Most of these meta-analyses have concluded that prophylactic antibiotics are not required for low-risk laparoscopic cholecystectomies. This study aimed to assess the validity of this conclusion by systematically reviewing these meta-analyses. METHODS: A systematic review was undertaken. Searches were limited to meta-analyses and systematic reviews. PubMed and Cochrane Library electronic databases were searched from inception until March 2016 using the following keyword combinations: 'antibiotic prophylaxis', 'laparoscopic cholecystectomy' and 'systematic review or meta-analysis'. Two independent reviewers selected meta-analyses or systematic reviews evaluating prophylactic antibiotics for laparoscopic cholecystectomy. All of the randomised controlled trials (RCTs) analysed in these meta-analyses were also reviewed. RESULTS: Seven meta-analyses regarding prophylactic antibiotics for low-risk laparoscopic cholecystectomy that had examined a total of 28 RCTs were included. Review of these meta-analyses revealed 48 miscounts of the number of outcomes. Six RCTs were inappropriate for the meta-analyses; one targeted patients with acute cholecystitis, another measured inappropriate outcomes, the original source of a third was not found and the study protocols of the remaining three were not appropriate for the meta-analyses. After correcting the above miscounts and excluding the six inappropriate RCTs, pooled risk ratios (RRs) were recalculated. These showed that, contrary to what had previously been concluded, antibiotics significantly reduced the risk of postoperative infections. The rates of surgical site, distant and overall infections were all significantly reduced by antibiotic administration (RR (95% CI); 0.71 (0.51 to 0.99), 0.37 (0.19 to 0.73), 0.50 (0.34 to 0.75), respectively). CONCLUSIONS: Prophylactic antibiotics reduce the incidence of postoperative infections after elective laparoscopic cholecystectomy.

Evaluation of relative criteria for single-incision laparoscopic cholecystectomy.

BACKGROUND/OBJECTIVE: Although single-incision laparoscopic cholecystectomy (SILC) has no advantage over conventional laparoscopic cholecystectomy (LC), except for better cosmesis, few reports have discussed the criteria for SILC. The aim of this study was to evaluate the suitability of our criteria for SILC. METHODS: During the study period, SILC was performed at our institution under the following criteria. The inclusion criteria were elective surgery, age of < 60 years, and body mass index of < 30 kg/m2. The exclusion criteria were a thick gallbladder wall, history of choledocholithiasis, previous abdominal surgery, and serious concomitant disease. We reviewed data regarding consecutive patients who underwent LC at our institution from November 2009 to March 2016. The data were assessed with respect to patient characteristics, operative data, and postoperative outcomes. RESULTS: A total of 1093 patients underwent elective LC, and 232 (21.2%) of these patients underwent SILC using our criteria. Fourteen patients (6.0%) who underwent SILC required extra ports. Among the patients aged < 60 years, 50.2% (232/462) underwent SILC. There were few adverse events, including intra- and postoperative complications, among the patients who underwent SILC. CONCLUSION: The above-mentioned criteria are safe, necessary, and sufficient for SILC over conventional LC.

Clinical effect of pancreaticojejunostomy with a long-internal stent during pancreaticoduodenectomy in patients with a main pancreatic duct of small diameter.

BACKGROUND: Post-operative pancreatic fistula (POPF) is one of the most common causes of death following pancreaticoduodenectomy (PD). The aim of this study was to evaluate the clinical effect of a long-internal stent on the development of POPF in patients with a main pancreatic duct diameter of 3 mm or less. STUDY DESIGN: Patients (N = 108) with a main pancreatic duct (≤3 mm) who underwent PD were included in this single-institution historical control study. Between January 2012 and December 2013, 54 patients had undergone PJ with a long-internal stent across the duct-to-mucosa anastomosis (long-stent group), and between February 2009 and December 2011, 54 patients had undergone PJ without a stent (control). RESULTS: There was no significant difference between groups (long-stent vs control) in the incidence of POPF (70% vs. 56%, p = 0.110) and grade B/C POPF (26% vs. 26%, p = 1.000). Univariate analysis identified body mass index, extent of blood loss and soft pancreatic parenchyma as risk factors related to POPF. Multivariate analysis identified extent of blood loss and soft pancreatic parenchyma as significant risk factors. CONCLUSION: Placement of a long-internal stent during PJ did not reduce POPF after PD in patients with a main pancreatic duct of small diameter.

Comparison of surgical outcomes of three different stump closure techniques during distal pancreatectomy.

BACKGROUND: To find the appropriate method of pancreatic transection during distal pancreatectomy (DP), we retrospectively compared post-operative complications including postoperative pancreatic fistula (POPF) according to the different types of pancreatic transection. METHODS: This study included 169 patients who underwent pancreatic transection using an ultrasonic activated device (USAD) with transfixion of the pancreatic duct (DP-TF group, n = 89), USAD followed by pancreaticogastrostomy (DP-PG group, n = 44), and a reinforced linear tristapler (DP-ST, n = 36). RESULTS: Overall and POPF-related complications in DP-PG group, and delayed gastric emptying (DGE) in DP-ST group were significantly lower than DP-TF group. There were no significant difference in overall complication, length of hospitalization and operative costs between DP-PG and DP-ST groups. Operative time was significantly longer in DP-PG group than others. CONCLUSION: Both DP-PG and DP-ST are associated with better surgical outcomes. Regarding ease of surgical technique, shorter operative times, and similar medical costs, DP with a reinforced linear tristapler is a good choice during DP.

Survival benefit of intravenous and intraperitoneal paclitaxel with S-1 in pancreatic ductal adenocarcinoma patients with peritoneal metastasis: a retrospective study in a single institution.

BACKGROUND: We evaluated the clinical efficacy of intravenous (i.v.) and intraperitoneal (i.p.) paclitaxel (PTX) combined with S-1 in patients with chemotherapy-naïve pancreatic ductal adenocarcinoma (PDAC) with peritoneal metastasis. METHODS: Forty-nine patients were diagnosed with peritoneal metastasis during 2007-2014; 29 received gemcitabine or S-1-based chemo(radio)therapy from 2007 to 2011 (control group), and the remaining 20 received i.v. (50 mg/m2 ) and i.p. (20 mg/m2 ) PTX on days 1 and 8, and S-1 at 80 mg/m2 per day for 14 consecutive days, followed by 7 days of rest from 2012 to 2014 (study group). RESULTS: The median survival time in the study group was significantly longer than that in the control group (20 vs. 10 months, respectively; P = 0.004). At 1 year after initial treatment, a significant difference in ascites development on CT was found between the study (5/20 patients) and the control group (18/29 patients, P = 0.009). The frequency of objective response (9/20 patients) and conversion surgery (6/20 patients) in the study group was higher than those in the control group (8/29 and 2/29, respectively). Patients who underwent conversion surgery had improved survival in both groups. CONCLUSION: Implementation of the S-1+i.v./i.p. PTX regimen was closely associated with improved overall survival in PDAC patients with peritoneal metastasis.

Clinical outcomes of pancreatic ductal adenocarcinoma resection following neoadjuvant chemoradiation therapy vs. chemotherapy.

PURPOSE: We compared the clinical outcomes of pancreatic ductal adenocarcinoma (PDAC) resection after neoadjuvant chemoradiation therapy (NACRT) vs. chemotherapy (NAC). METHODS: The study population comprised 81 patients with UICC stage T3/4 PDAC, treated initially by NACRT with S-1 in 40 and by NAC with gemcitabine + S-1 in 41. This was followed by pancreatectomy with routine nerve plexus resection in 35 of the patients who had received NACRT and 32 of those who had received NAC. We compared the survival curves and clinical outcomes of these two groups. RESULTS: The rates of clinical response, surgical resectability, and margin-negative resection were similar. The NACRT group patients had significantly higher rates of Evans stage ≥IIB tumors (29 vs. 0 %, respectively, p = 0.010) and negative lymph nodes (49 vs. 16 %, respectively, p = 0.021) than the NAC group patients. There was no difference in disease-free survival between the groups, but the disease-specific survival of the NAC group patients was better than that of the NACRT group patients (p = 0.034). Patients undergoing pancreatectomy with nerve plexus resection following NACRT had significantly higher rates of intractable diarrhea and ascites but consequently received significantly less adjuvant chemotherapy and therapeutic chemotherapy for relapse. CONCLUSION: NACRT followed by pancreatectomy with nerve plexus resection is superior for achieving local control, but postoperative diarrhea and ascites may prohibit continuation of adjuvant chemotherapy or chemotherapy for relapse (UMIN4148).

Acute median arcuate ligament syndrome after pancreaticoduodenectomy.

Median arcuate ligament syndrome (MALS) has been reported in 2-7.6 % of patients undergoing pancreaticoduodenectomy (PD). Most of the reported cases of MALS have been diagnosed perioperatively and treated radiologically or surgically before or during PD. MALS can have an acute postoperative onset after PD even if all preoperative and intraoperative evaluations are normal particularly in young patients.In this report, we present a second case of severe hepatic cytolysis secondary to MALS that developed acutely and the first patient who required acute division of the median arcuate ligament after PD.