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A disintegrin and metalloproteinase domain-containing protein 12 (ADAM12) has been reported to influence tumor progression and chemosensitivity in human cancers. We assessed the prognostic impact of ADAM12 and its predictive value for neoadjuvant chemotherapy (NAC) in patients with pancreatic ductal adenocarcinoma (PDAC) treated with surgical resection.ADAM12 expression was immunohistochemically examined in 428 patients with PDAC who underwent surgical resection. The association of ADAM12 expression with clinicopathological factors and survival was also analyzed.Patients with high ADAM12 expression exhibited significantly shorter median disease-free survival (DFS) (high ADAM12: 17.8 vs. low ADAM12: 37.9 months; P 0.001) and overall survival (OS) (high ADAM12: 33.1 vs. low ADAM12: 65.0 months; P 0.001). A multivariate analysis revealed that high ADAM12 expression was an independent risk factor for poor DFS (P 0.001) and OS (P 0.001) in all eligible patients. Of 100 patients who received neoadjuvant chemotherapy (NAC), high ADAM12 expression was significantly associated with poor DFS in a subset of patients treated with the nab-paclitaxel (PTX) neoadjuvant regimen (P = 0.03), whereas the prognostic value of ADAM12 was not evident in patients not treated with nab-PTX (P = 0.12).A negative prognostic value of high ADAM12 expression was observed in patients with PDAC treated with surgical resection, which was enhanced in patients treated with NAC, including nab-PTX. These results suggested that ADAM12 expression can predict nab-PTX chemosensitivity in PDAC and reflect PDAC progression.

Background The prognosis of patients with borderline resectable pancreatic cancer with arterial contact (BRPC-A) is extremely poor, and effective preoperative treatment is indispensable. We evaluated the clinical efficacy and safety of neoadjuvant chemotherapy, including gemcitabine, nab-paclitaxel and S-1 (GAS), for patients with BRPC-A. Material and methods A multicentre, single-arm, phase II study was performed. Patients were administered 1000 mg/m2 gemcitabine on day 1, 125 mg/m2 nab-paclitaxel on day 1 and 60–100 mg/day S-1 on days 1–7 during a 14-day cycle. Patients were then assessed for resectability and response to treatment after six cycles. The primary end-points were 2-year overall survival (OS) rate and median OS time (trial registration: jRCTs061180045, UMIN000016630). Results Forty-seven patients with BRPC-A were eligible for the present study. Six courses of neoadjuvant GAS regimen were completed in all eligible patients. The rate of grade III/IV toxicities occurred in 14 (30%) patients during the neoadjuvant GAS regimen. The response and disease control rates were 43% and 96%, respectively. Forty-five (96%) patients received potentially curative pancreatectomy, whereas two did not owing to disease progression. R0 resection was performed in 40 (86%) of 47 eligible patients. Eleven (24%) patients experienced postoperative major complications (>grade III), including one mortality. The 2-year OS rate and median OS time among 47 eligible patients were 70.1% and 41.0 months, respectively. Conclusions The neoadjuvant GAS chemotherapy regimen for BRPC-A showed good efficacy with mild toxicity, resulting in a high R0 resection rate and prolonged survival in patients with BRPC-A.

The prognostic value of peritoneal lavage cytology (CY) for pancreatic ductal adenocarcinoma (PDAC) remains controversial. We assessed the prognostic impact of CY status stratified by resectability in PDAC patients treated with surgical resection. Clinical data from 440 patients with PDAC who underwent surgical resection were retrospectively analyzed to examine the association of CY status with clinicopathological factors and survival. Positive CY status (CY+) was found in 30 patients (7%). These patients had significantly worse overall survival in both the resectable (R) (P = 0.002) and borderline resectable (BR) (P < 0.001) groups. The median survival time of CY+ patients in the R and BR groups was 25.6 and 6.7 months, respectively. Multivariate analysis revealed that CY+ was an independent prognostic factor in the BR group (P < 0.001) but not in the R group (P = 0.08). In the R group, CY+ patients who received adjuvant chemotherapy had significantly longer overall survival than those without adjuvant chemotherapy (34.3 vs. 9.8 months, respectively; P < 0.001). The prognosis of CY+ patients in the BR group was extremely poor. In the R group, surgical resection combined with adjuvant chemotherapy may improve the prognosis of CY+ patients.

Preoperative biliary drainage is commonly performed in Japan for patients with cancer of the pancreatic head accompanied by obstructive jaundice due to concerns about liver dysfunction, susceptibility to infection, and hemorrhagic tendency. Therefore, biliary drainage was performed for all patients with preoperative obstructive jaundice in this study. Given the purpose of identifying preoperative risk factors for poor prognosis, separate evaluation of cancers of the pancreatic head versus body/tail might have decreased the statistical power because of the small number of eligible patients. Therefore, we did not separate data based on tumor location in this study. Since examining Lewis antigen status for all patients with pancreatic cancer is impractical, we stratified patients by CA19-9 value without including information about Lewis antigen status. Only 150 (56%) patients were followed for 5 years in this study, so long-term analysis might have had insufficient statistical power. Future studies involving larger numbers of patients with long-term (5 years) follow-up data are required to enhance the results of this study. Since we focused only on preoperative factors in this study, we did not exclude any patients based on information available only after surgery.

The clinical importance of peritoneal washing cytology (PWC) for cholangiocarcinoma patients remains unclear. The clinical data of 137 extrahepatic cholangiocarcinoma patients who received PWC and curative surgery were retrospectively analyzed. Among the 137 patients analyzed, five (3.6%) had positive PWC, and 132 (96.4%) had negative PWC. The median survival time in patients with negative PWC was 6.45 years, and the overall 1-, 2-, and 5-year survival rates were 86.5%, 75.3%, and 51.6%, respectively. The median survival time in patients with positive PWC was 2.56 years, and the overall 1-, 2-, and 5-year survival rates were 60.0%, 60.0%, and 40.0%, respectively. A multivariate analysis revealed that positive lymph node metastasis (P

This study aims to investigate the positivity rate of the nerve plexus (NPL) around the common hepatic artery (CHA), as well as the impact of dissecting the NPL-CHA, during surgical resection of pancreatic cancer. Clinicopathological factors, including hematoxylin and eosin (H&E) staining and immunohistochemistry, were compared between the resectable pancreatic cancer (RPC) and borderline resectable PC (BRPC) groups. Moreover, the relationship between the NPL-CHA status and overall survival (OS) was investigated. In this study, 136 eligible patients were divided into the RPC (72) and BRPC (64) groups. In the RPC group, all patients were negative for H&E staining and microinvasion, whereas 13 (20%) and five patients (8%) were positive for H&E staining and microinvasion, respectively, in the BRPC group. The median OS times in the NPL-CHA–positive and –negative groups were 29.8 and 60.2 months, respectively (p = 0.088). The multivariate analysis of OS indicated an elevated initial carbohydrate antigen 19-9, lymph node (LN) metastasis, and lack of adjuvant chemotherapy (AC), which independently predicted poor outcomes. In the BRPC subgroup, contact with the CHA on preoperative computed tomography (CT) was a high-risk factor for NPL-CHA positivity. NPL-CHA positivity was only present in the BRPC group. In the absence of CT evidence of CHA contact, NPL-CHA dissection may not have survival benefits.

The clinical implications of pre- and postoperative KRAS-mutated circulating tumor DNA (ctDNA) present in patients with pancreatic ductal adenocarcinoma (PDAC) have remained an unresolved issue. This study sought to investigate the clinical significance of pre- and postoperative ctDNA analyses and their impact on the prognosis of PDAC patients. Digital droplet polymerase chain reaction detected ctDNA in pre- and postoperative plasma samples prospectively obtained from patients with resectable and borderline-resectable PDAC. Its associations with recurrence-free survival (RFS) and overall survival (OS) were analyzed. The patients were sorted according to the presence of pre- and postoperative ctDNA, and its ability to stratify prognosis was evaluated. The study analyzed 97 patients. Both pre- and postoperative ctDNA were detected in 9 patients, and neither was detected in 55 patients. Whereas 15 patients harbored only preoperative ctDNA, 18 patients had only postoperative ctDNA. The multivariate analysis showed that the presence of preoperative ctDNA was associated with poorer OS (P = 0.008) and that postoperative ctDNA was not associated with either RFS or OS. Survival did not differ significantly between the patients with a positive shift in ctDNA status and those without detectable pre- or postoperative ctDNA. For the patients with PDAC, the presence of preoperative ctDNA was significantly associated poor OS, whereas postoperative ctDNA was not associated with poor survival. A positive change in ctDNA did not affect patients’ survival.

Aim and Background TJ-100 is a traditional Japanese medicine that affects inflammation and gastrointestinal motility, and is used as a preventive and treatment for paralytic ileus. This study aims at determining the effect of TJ-100 on the peritoneal levels of IFN-γ/IL-9, cytokines related to ileus, after pancreaticoduodenectomy (PD) in a clinical setting. Methods This was a subsidiary study of the clinical trial investigating the effect of TJ-100 on postoperative bowel function. Ascites was collected from 180 patients using an abdominal drainage tube on postoperative day 1 and 3 after PD (POD 1 or POD 3) and used to measure 27 cytokines. We performed univariate and multivariate analyses using several perioperative variables and administration of TJ-100/placebo to determine the effect of TJ-100 on the levels of IFN-γ and IL-9. Results Peritoneal levels of IL-9 and IFN-γ decreased between POD 1 and 3 (Wilcoxon signed-rank test p

The clinical characteristic differences at the initial recurrence site after resection for pancreatic ductal adenocarcinoma (PDAC) remain unknown. We investigated the clinical characteristics in patients with lung recurrence after surgical resection and evaluated the outcome of resection for isolated lung recurrence.Of 442 consecutive PDAC patients who underwent surgical resection between 2002 and 2018, 229 had recurrence on imaging. Initial recurrence sites were the liver, lung, local, peritoneal, multiple organs, and others. We analyzed the clinicopathologic factors and outcomes, comparing by initial recurrence site, and investigated the outcomes of resection for isolated lung recurrence.Liver recurrences were the most frequent (n = 60, 26%), followed by lung recurrence (n = 48, 21%). The interval from surgery to recurrence was significantly longer in lung recurrence (P = 0.0001). Patients with lung recurrence had significantly longer overall survival after diagnosis (P 0.0001). Patients who underwent surgical resection of lung recurrence had a significantly prolonged overall survival rate after recurrence diagnosis (P = 0.004).Patients with lung recurrence had significantly prolonged survival than those with other recurrence patterns. Resection for isolated lung recurrence represented relatively good prognosis, and possibly may be beneficial in highly-selected patients.

Aim To validate a Japanese version of the Gastrointestinal Quality of Life Index (GIQLI) in patients with symptomatic gallstone disease. Methods We investigated responsiveness, reliability, and convergent validity of the translated GIQLI in patients who underwent elective laparoscopic cholecystectomy. Questionnaire scores were compared with the Gastrointestinal Symptom Rating Scale (GSRS) to verify convergent validity. Results There were 120 patients originally enrolled in the study; three were excluded after their surgery as they no longer met the inclusion criteria. Questionnaires were collected from the remaining 117 patients (100% response rate). At 2 weeks post‐surgery, total GIQLI score increased significantly from pre‐surgery levels, suggesting high responsiveness. Cronbach's alpha ranged from 0.901 to 0.934 for the total score, while a comparison of scores at 2 vs 6 weeks post‐surgery yielded an intraclass correlation coefficient of 0.843; thus, the Japanese version of the questionnaire was reliable. Correlations with GSRS ranged between −0.459 and −0.679, indicating fair to good convergent validity. Conclusion The Japanese GIQLI had high responsiveness and reliability to assess how surgery for symptomatic gallstone disease influenced patient quality of life.

This study aimed to reassess the duration of neoadjuvant therapy (NAT) for patients with borderline resectable pancreatic cancer (BRPC). The medical records of patients with BRPC who received NAT before intended curative resection were retrospectively reviewed. Patient demographics, clinicopathological factors, and prognostic factors for overall survival were analyzed. The serum carbohydrate antigen (CA) 19-9 level was examined monthly during NAT. A total of 118 patients with BRPC were enrolled. The median survival time and 5-year overall survival were 28.0 months and 31%, respectively. Three months after NAT, the CA19-9 levels were normal in 57% of the patients, and 92% underwent resection. Multivariate analysis showed that radiological partial response (hazard ratio (HR), 0.53; 95% confidence interval (CI), 0.26–0.99; p = 0.047); a normal CA19-9 level after NAT (HR, 0.30; 95% CI, 0.22–0.66; p = 0.006); and tumor resection (HR, 0.29; 95% CI, 0.13–0.67; p = 0.005) were independent predictors of better survival. The median CA19-9 level and the rate of normal CA19-9 levels before and after NAT were 256 (interquartile range (IQR), 23–1197) U/mL and 33%, and 27 (IQR, 7–176) U/mL and 57%, respectively. A normal CA19-9 level after NAT was an independent predictor of better survival in patients with BRPC. A longer NAT duration might contribute to improved prognosis of patients with elevated CA19-9 levels.

An aortic graft-duodenal fistula commonly requires graft replacement and duodenectomy. However, the appropriate surgical approach to the duodenum with aortic graft fistula remains unclear. Herein, we describe the case of an 85-year-old male patient who underwent a pancreas-preserving partial duodenectomy using the mesenteric approach for aortic graft-duodenal fistula. The patient presented with hemorrhagic shock and duodenal bleeding 2 years after undergoing open aortic graft replacement. He first underwent emergent endovascular aortic repair with an artificial vascular graft to achieve hemostasis. Although his general condition stabilized following endovascular treatment, duodenal endoscopy revealed an aortic graft-duodenal fistula, exposing the artificial vascular graft via the third portion of the duodenum. As the radical treatment for aortic graft-duodenal fistula, open graft replacement and pancreas-preserving partial duodenectomy were performed using the mesenteric approach which helps to divide the pancreas and duodenum. The patient recovered without any major complications, such as postoperative pancreatic fistula, and was discharged. In conclusion, the mesenteric approach in partial duodenectomy for aortic graft-duodenal fistula could be safely performed. This procedure is useful to approach the duodenum fixed by fistula formation, which may help reduce intraoperative blood loss, operative time, and surgical invasiveness.

The long-term survival of patients with locally advanced, unresectable pancreatic cancer is extremely poor. We present our experience with a 67-year-old woman who had a 40-mm mass in the body of the pancreas. Tumor infiltration reached the gastroduodenal artery, celiac artery, common hepatic artery, and splenic artery. After 10 courses of FOLFIRINOX, 2 courses of gemcitabine plus nab-paclitaxel, and 6 courses of gemcitabine alone, we performed distal pancreatectomy with celiac axis resection and hepatic artery reconstruction. The bifurcation of the gastroduodenal artery and the proper hepatic artery had to be resected, after which we created 2 anastomoses: proper hepatic-to-middle colic artery, and second jejunal-to-right gastroepiploic artery. Histopathologic examination revealed an Evans grade IIb histologic response to prior treatment and verified the R0 resection status. The patient was discharged on postoperative day 30 after treatment of a grade B pancreatic fistula and is still alive, without recurrence, more than 5 years after initiation of treatment. This patient with locally advanced, unresectable pancreatic cancer achieved long-term survival through perioperative multidisciplinary treatment, including distal pancreatectomy with celiac axis resection and hepatic artery reconstruction. This aggressive procedure could be a treatment option for patients with locally advanced, unresectable pancreatic cancer.

The preoperative risk factors for positive peritoneal lavage cytology (CY) are unknown, especially in patients who received neoadjuvant therapy. In addition, the optimal indications for staging laparoscopy (SL) are still unclear. The aim of this study was to investigate the preoperative risk factors of CY positivity in patients with pancreatic ductal adenocarcinoma (PDAC) treated with surgical resection and to determine the optimal indications for SL.We retrospectively analyzed 493 patients with PDAC, including 356 treated with upfront surgery and 137 treated with neoadjuvant chemotherapy (NAC). The preoperative risk factor for CY positivity was investigated along with stratification according to NAC.Among the 493 patients, 36 (7.3%) were CY-positive. The CY-positive frequency in patients who received and did not receive NAC was 9 (6.6%) and 27 (7.6%), respectively. In the multivariate analyses, no independent preoperative predictive factor was found in patients who received NAC, whereas body and tail PDAC were identified as an independent risk factor for CY positivity in patients who did not receive NAC.The preoperative risk factors of CY-positive PDAC are body and tail PDAC in 356 patients who did not receive NAC. However, there is no useful predictive factor for CY positivity in patients treated with NAC. Based on these results, it was difficult to determine the optimal indication for SL especially in NAC cases.

In recent trend of preoperative chemotherapy, postoperative clostridium difficile infection (CDI) might be increasing in pancreatic ductal adenocarcinoma (PDAC) patients. This study aimed to elucidate the inducement of postoperative CDI in the new era of preoperative chemotherapy.Eligible patients were those who received pancreaticoduodenectomy for PDAC. Patients were classified into two groups according to the presence or absence of postoperative CDI, and the independently associated factors for postoperative CDI were investigated. Additionally, eligible patients were classified using the identified associated factors, and the duration of preoperative antimicrobial administration and incidence of CDI were compared between the groups.Two hundred PDAC patients were eligible for this study, and postoperative CDI was detected in 15 (7.5%) patients. Multivariate analysis revealed that preoperative biliary tract infection (BTI) and chemotherapy (Chemo) were independently associated with postoperative CDI (OR, 4.05; 95% CI, 1.25-13.1; p = 0.0200 and OR, 3.64; 95% CI, 1.14-11.6; p = 0.0209, respectively). The patients were classified into four groups according to the presence or absence of preoperative BTI and Chemo (BTI-/Chemo-, BTI-/Chemo+, BTI+/Chemo- and BTI+/Chemo + group). The median durations of preoperative antimicrobial administration were 0, 2, 8 and 15 days in each group, respectively. Postoperative CDI was detected in 3.7%, 10.0%, 10.5% and 31.3% in each group, respectively, and patients in BTI+/Chemo + group suffered CDI more frequently compared to those in BTI-/Chemo-group (p = 0.00778).Preoperative BTI and chemotherapy might induce postoperative CDI for PDAC patients.

Introduction: The aim of this study was to identify preoperative risk factors for poor survival in patients with resectable pancreatic ductal adenocarcinoma (PDAC) treated with upfront surgery. Methods: Medical records of 268 patients with resectable PDAC defined by resectability status who underwent upfront surgery were reviewed retrospectively. Multivariate analyses were performed to identify preoperative risk factors for recurrence-free survival (RFS) and overall survival (OS). Moreover, a binary logistic regression model was built to determine preoperative independent risk factors of 2- and 3-year recurrence and survival. Results: Multivariate analyses identified CA19-9 (≥100 U/mL, p < 0.001) as an independent risk factor for poor RFS, and worse performance status (1 or 2, p = 0.03), platelet:lymphocyte ratio (p = 0.04), and preoperative CA19-9 (≥100 U/mL, p < 0.001) as independent risk factors for poor OS. Moreover, preoperative CA19-9 (≥100 U/mL) was the only independent risk factor identified for 2- and 3-year recurrence and survival. Discussion/Conclusion: Preoperative CA19-9 (≥100 U/mL) was the most reliable preoperative predictive factor for poor survival in resectable PDAC treated with upfront surgery. These findings warrant further clinical trials investigating efficacy of neoadjuvant therapy targeting the subset of patients with resectable PDAC who have elevated preoperative CA19-9, namely, those with high risk of poor prognosis.

The survival benefit associated with distal pancreatectomy with en bloc celiac axis resection (DP-CAR) for patients with borderline resectable or locally advanced pancreatic body carcinoma is controversial. The aim of this study was to evaluate the impact of DP-CAR following neoadjuvant chemotherapy on survival in patients with borderline resectable or locally advanced pancreatic body carcinoma.Medical records of patients with pancreatic ductal adenocarcinoma who underwent distal pancreatectomy (DP, n = 102) and DP-CAR following neoadjuvant chemotherapy (n = 32) between 2008 and 2019 were analyzed retrospectively. Short- and long-term outcomes were compared between the two groups.All patients who underwent DP-CAR had tumor contact with the celiac axis. Of these, 30 patients underwent preoperative embolization of the common hepatic artery. The pretreatment tumor size of patients who underwent DP-CAR was larger (P 0.001), and rates of blood transfusion (P = 0.003) and postoperative complications (P = 0.016) were higher in patients who underwent DP-CAR compared with patients who underwent DP. The 5-year survival rate of patients who underwent DP and DP-CAR were 50.6% and 41.1%, respectively (median survival time, 65.9 vs 37.0 months). For all 134 patients, pretreatment serum CA19-9 levels (P 0.001), adjuvant chemotherapy (P 0.001), and lymph node status (P = 0.035) were independent prognostic factors of overall survival by multivariate analysis.DP-CAR following neoadjuvant chemotherapy for patients with borderline resectable or locally advanced pancreatic body carcinoma may bring the same survival impact as DP, despite increased morbidity.

The Frey procedure, which involves longitudinal pancreaticojejunostomy with coring-out of the pancreatic head, is considered the ideal surgical procedure for chronic pancreatitis with pancreas head stone. Long-term relief from abdominal pain after the Frey procedure was reported to reach about 90%, and this is the most common surgical procedure for chronic pancreatitis in Japan. However, coring-out has the potential risk of severe complications such as bile duct injury, pancreatic fistula, and postoperative hemorrhage. Therefore, we introduce a new lithotripsy technique using laparoscopic coagulation shear without coring-out.

Although postoperative adjuvant chemotherapy for pancreatic ductal adenocarcinoma (PDAC) improves survival, its efficacy varies among individuals. Identification of biomarkers that can predict the efficacy of adjuvant chemotherapy for PDAC is essential.To investigate the predictive value of secreted protein acidic and rich in cysteine (SPARC) expression in patients with PDAC treated with adjuvant gemcitabine in combination with S-1 (adjuvant GS) or adjuvant gemcitabine alone (adjuvant G alone).Stromal SPARC and cytoplasmic SPARC were examined immunohistochemically in 211 PDAC patients treated with adjuvant GS or G alone after resection. The association of SPARC expression with clinicopathological factors, disease-free survival (DFS) and overall survival (OS) were analyzed.In multivariate analysis, borderline resectable with arterial contact (BR-A) (P = .002), higher preoperative CA 19-9 level (≥91 U/ml) (P = .005), moderately or poorly (P = .003), presence of lymph node metastasis (P = .012) and high stromal SPARC expression (P = .013) were independent predictors of poor DFS. Moreover, BR-A (P = .003), higher preoperative CA 19-9 level (≥91 U/ml) (P = .007) and high stromal SPARC expression (P .001) were identified as independent predictors of poor OS. In contrast, cytoplasmic SPARC expression did not affect DFS and OS.High stromal SPARC expression was an independent predictor of poor DFS and OS in patients treated with adjuvant GS or G alone. Stromal SPARC expression could be a relevant biomarker for prediction of prognosis in PDAC patients after resection treated with adjuvant GS or G alone.

Background The frequency and prognosis of resected deficient mismatch repair (dMMR) pancreatic ductal adenocarcinoma (PDAC) remain unclear. This study was designed to assess the frequency of dMMR and its clinicopathological relevance in Japanese patients with PDAC treated with surgical resection. Methods A total of 400 consecutive patients with PDAC who underwent surgical resection at Hiroshima University were enrolled. Immunohistochemical staining with four antibodies including MLH1, MSH2, MSH6, and PMS2 was used to determine the presence of dMMR in PDAC specimens. Statistical analyses were applied to evaluate the frequency and clinical outcomes of these patients. Results Of these 400 patients, five (1.3%) had dMMR (two had MLH1 deficiency, two had PMS2 deficiency, and one had MSH2 deficiency). We found a significantly different histological differentiation pattern between patients with dMMR and those with proficient mismatch repair (pMMR) (P = .03). Univariate survival analysis revealed no significant differences between dMMR and pMMR in recurrence-free survival (P = .268) or overall survival (P = .173). Conclusions The incidence of dMMR in Japanese patients with resected PDAC is low, and we found no ethnic-specific differences when comparing the incidence to that in Caucasian patients. In the current study, no significant difference was found in recurrence-free and overall survival between patients with dMMR and pMMR.

PURPOSE The aim of this study was to assess the validity of surgical resection for patients with pancreatic ductal adenocarcinoma (PDAC) aged ≥80 years stratified by resectability status. METHODS Medical records of 245 patients with resectable (R) and 169 with borderline resectable/unresectable (BR/UR) PDAC were reviewed retrospectively. Of the total of 414 patients, 56 (14%) were ≥80 years. The prognostic impact of age ≥80 years was analyzed with stratification by resectability status. RESULTS No significant difference was found in the incidence of major complications between patients aged ≥80 versus

Although metastasis in lymph nodes along the left side of superior mesenteric artery (SMA-LNs-lt) is sometimes found, survival benefit of SMA-LN-lt dissection for pancreatic head cancer is still unclear. The purpose of this study is to evaluate the prognostic significance of SMA-LN-lt metastasis and micrometastasis. A total of 166 patients with pancreatic head cancer who underwent pancreatectomy with lymphadenectomy including SMA-LNs-lt between 2002 and 2017 were reviewed retrospectively. Micrometastasis was evaluated by immunohistochemistry. Twenty patients (12%) had SMA-LN-lt metastasis detected by hematoxylin and eosin (HE) staining, and eight patients (5%) had micrometastasis. Patients with SMA-LN-lt HE-positive or micrometastasis group experienced significantly shorter overall survival (OS) than those without (p = .015). In multivariate analysis, SMA-LN-lt HE-positive or micrometastasis (p = .034), portal vein resection (p = .002), histologic grade 2/3 (p = .046), LN metastasis (p = .002), and lack of adjuvant chemotherapy (p

Background Although serum carbohydrate antigen 19-9 (CA19-9), s-pancreas antigen-1 (SPan-1), and duke pancreatic monoclonal antigen type 2 (DUPAN-II) are commonly utilized tumor markers in pancreatic ductal adenocarcinoma (PDAC), it is still unclear which is the most useful for predicting prognosis after surgical resection. Here, we aimed to compare the prognostic impact of pre- and post-operative serum CA19-9, SPan-1, and DUPAN-II levels in patients with resectable PDAC. Methods Pre-operative CA19-9, SPan-1, and DUPAN-II levels were analyzed to compare their prognostic values for resectable PDAC in 198 patients whose pre-operative tumor markers were available. The relationships of clinicopathological factors, including pre- and postoperative CA19-9, SPan-1, and DUPAN-II levels, with overall survival (OS) were analyzed using univariate and multivariate analyses in 149 patients for whom both pre- and postoperative tumor markers were available. Results Elevated pre-operative CA19-9 (≥37 U/mL), SPan-1 (≥30 U/mL), and DUPAN-II (≥150 U/mL) levels were found in 113 (60%), 96 (51%), and 82 (43%) patients, respectively. In multivariate analysis, absence of adjuvant chemotherapy (hazard ratio [HR], 4.17; p = 0.001), R1 resection (HR, 1.90; p = 0.03), higher histological grade (HR, 1.99; p = 0.02), advanced UICC T factor (HR, N/A; p = 0.04) and elevated postoperative CA19-9 (HR, 3.39; p = 0.009) were identified as independent predictors for worse OS. Conclusion When the prognostic impacts of pre- and post-operative serum CA19-9, SPan-1, and DUPAN-II levels in patients with resectable PDAC were compared, elevated postoperative CA19-9 was the strongest predictive marker of poor survival in the pre- and post-operative period.

Background/Objectives The loss of skeletal muscle mass (sarcopenia) is associated with the poor prognosis of pancreatic cancer. It has been reported pancreatic exocrine insufficiency (PEI) is associated with serum nutritional markers in chronic pancreatitis. However, there has been no report about the relationship between sarcopenia and PEI. The aim of this study is to determine whether body composition, including skeletal muscle (SM), subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT), intramuscular adipose tissue content (IMAC), and serum nutritional markers are associated with pancreatic exocrine function in patients with pancreatic disease. Methods Data were collected prospectively on 132 patients with pancreatic disease. SM, SAT, VAT and IMAC were assessed by computed tomography. Patients underwent a 13 C-labeled mixed triglyceride breath test to measure pancreatic exocrine function. Serum nutritional markers were measured at the same time of 13 C-labeled mixed triglyceride breath test. Patients were stratified by quartiles according to each body component, and for each component the lowest group was defined as the lowest quartile, treating men and women separately. The lowest group for SM was defined as sarcopenia. PEI was defined as a percentage 13 CO 2 cumulative dose at 7 h below 5%. Results Sarcopenia was associated with PEI in both men (P Conclusions Sarcopenia is independently associated with PEI in patients with pancreatic disease.

Pancreatectomy, including pancreatoduodenectomy and distal pancreatectomy, often causes postoperative pancreatic exocrine insufficiency (PEI). Our aim was to clarify a relationship between remnant pancreatic volume and postoperative PEI.A total of 227 patients who underwent pancreatoduodenectomy or distal pancreatectomy were enrolled in this study. All patients underwent a (13)C-labeled mixed triglyceride breath test to assess pancreatic exocrine function and abdominal dynamic computed tomography for assessing remnant pancreatic volume after pancreatectomy at a median of 7 months postoperatively. The percent (13)CO2 cumulative dose at 7 hours (% dose (13)C cum 7 h)5% on the (13)C-labeled mixed triglyceride breath test was considered diagnostic of postoperative PEI. Relationships between postoperative PEI and clinicopathologic factors including remnant pancreatic volume were analyzed.Pancreatoduodenectomy and distal pancreatectomy were performed in 174 (76.7%) and 53 (23.3%) patients, respectively. Of the 227 patients, 128 (56.3%) developed postoperative PEI. Postoperative % dose (13)C cum 7 h was strongly correlated with remnant pancreatic volume (r = .509, P.001). The cut-off value of remnant pancreatic volume for predicting postoperative PEI was 24.1 mL by receiver operating characteristic curve analysis. Multivariate analysis revealed that remnant pancreatic volume24.1 mL was the only independent predictive factor for the development of postoperative PEI in patients who underwent pancreatectomy (P.001, hazard ratio; 5.94, 95% confidence interval; 2.96-12.3).Remnant pancreatic volume is associated closely with postoperative PEI after pancreatectomy. Remnant pancreatic volume may predict postoperative PEI in patients who undergo pancreatectomy.

Our previous study aimed to examine the effect of TJ-100, a widely used herbal medicine, on intestinal function following pancreaticoduodenectomy (PD) in a multicenter, randomized, double-blinded, placebo-controlled manner (JAPAN-PD study). This concomitant study investigated the effect of TJ-100 on serum cytokine levels in patients who underwent PD. Due to the fact that several clinical variables can affect the absolute values of baseline serum cytokine levels, the ratios of the cytokine levels on postoperative day (POD)3 to those on POD1 were also used for analysis. The present study enrolled 180/224 randomized patients, of whom 91 received TJ-100 and 89 received placebo. As the main findings of the analysis, Wilcoxon signed-rank test revealed no significant difference in the levels of serum cytokines between the groups; however, patients in the TJ-100 group without severe inflammatory complications exhibited significantly higher ratios of interleukin (IL)-4 (n=123), IL-9 (n=72), IL-10 (n=97), PDGF-BB (n=143) and tumor necrosis factor-α (n=135), compared with patients in the Placebo Group (P

Although the presence of perineural invasion has been recognized as a poor prognostic factor in extrahepatic cholangiocarcinoma, the molecular mechanisms of perineural invasion in extrahepatic cholangiocarcinoma remain unclear. Nerve growth factor has been reported to be a candidate predictive biomarker of perineural invasion in some cancers. To investigate the impact of intratumoral nerve growth factor expression in resected extrahepatic cholangiocarcinoma on survival. Intratumoral nerve growth factor expression was investigated immunohistochemically in 112 patients with resected extrahepatic cholangiocarcinoma. Associations between nerve growth factor expression and clinicopathological factors were statistically evaluated, and risk factors for poor survival were analyzed using univariate and multivariate analyses. High and low nerve growth factor expression was observed in 62 (55 %) and 50 (45 %) patients, respectively. For all 112 patients, no significant correlation was found between nerve growth factor expression and presence of perineural invasion (P = 0.942). Moreover, nerve growth factor expression was not associated with recurrence-free survival (P = 0.861) and overall survival (P = 0.973). In multivariate analysis, lymph node metastasis (P = 0.004) was identified as an independent risk factor for early recurrence and the presence of perineural invasion (P = 0.002) and lymph node metastasis (P

Background and objectives The aim of this study was to investigate the prognostic impact of postoperative complications after pancreatoduodenectomy (PD) for pancreatic ductal adenocarcinoma (PDAC) stratified by resectability status. Methods Medical records of 226 patients with pancreatic head carcinoma who underwent PD, including 115 with resectable (R) and 111 with borderline resectable/unresectable (BR/UR) PDAC, were reviewed retrospectively. Major complications were defined as grade III or IV based on the Clavien-Dindo classification system. The prognostic impact of major complications on overall survival (OS) was analyzed using univariate and multivariate analyses with stratification by resectability status. Results A multivariate analysis in the BR/UR group identified R1 resection (P = 0.03), T 3/4 stage (P = 0.03), and incidence of major complications (P = 0.03) as independent risk factors for poor survival, whereas major complications did not affect survival in the R group. Initiation of adjuvant gemcitabine plus S-1 chemotherapy occurred significantly less frequently for patients with major complications than for those without major complications in the BR/UR group (P = 0.02). Conclusion A negative prognostic impact of postoperative major complications after PD was observed in patients with BR/UR PDAC, whereas the prognostic impact was unclear in patients with R PDAC.

There are only a few reports concerning long-term exocrine function after pancreaticoduodenectomy (PD), although the number of long-term survivors has increased. We assessed pancreatic exocrine function after PD in 189 patients to identify risk factors for pancreatic exocrine insufficiency. We evaluated patients’ exocrine function by using the 13C-labeled mixed triglyceride breath test, a noninvasive test feasible in outpatient service units. The present study included 99 patients that underwent pancreaticojejunostomy (PJ) at Wakayama Medical University Hospital and 90 patients that underwent pancreaticogastrostomy (PG) at Hiroshima University Hospital, the standard reconstruction techniques during PD at the respective hospitals. We also analyzed long-term morphological changes of remnant pancreas by computed tomography (main pancreatic duct dilation and parenchymal atrophy), nutritional status, and endocrine function. Independent risk factors for exocrine insufficiency after PD include hard pancreas (P = 0.003, odds ratio; 3.157) and PG reconstruction (P = 0.040, odds ratio; 2.321). Breath test results correlated significantly with post-operative morphological changes, nutritional status, and endocrine function. Atrophic changes of the remnant pancreas in the PG group were more severe than those in the PJ group. Furthermore, for patients with a soft pancreas, postoperative body weight changes, prognostic nutritional index, serum total protein levels as well as exocrine test were worse in the PG group, compared with the PJ group. Our results showed that PJ reconstruction might be superior to PG during PD, from the viewpoint of long-term pancreatic exocrine function, although further prospective studies are needed.

Pancreatic fistula (PF) is one of the leading complications after pancreatic resection for pancreatic carcinoma. The aim of this study was to determine whether PF was associated with deterioration of long-term outcomes in patients with pancreatic carcinoma after surgical resection. Medical records of 210 patients with pancreatic carcinoma who underwent tumor resection were reviewed retrospectively. PF was defined as grade B or C PF according to the criteria of the International Study Group on Pancreatic Fistula. Clinicopathological factors including overall survival were compared between patients with and without PF by univariate and multivariate analyses. Thirty-one patients (15 %) developed postoperative PF, and 179 (85 %) did not. The 31 cases of PF consisted of 27 grade B PF and 4 grade C PF. There were no differences in the use of adjuvant chemotherapy, tumor differentiation, lymph node status, surgical margin status, or UICC stage between groups. Overall 5-year survival rates for patients with and without PF were 25 and 27 %, respectively. There was no significant difference in overall survival between the two groups (P = 0.743). Multivariate analysis demonstrated that the use of postoperative adjuvant chemotherapy (P

Although bile contamination caused by preoperative biliary drainage (PBD) is a risk factor for infectious complications after pancreatoduodenectomy, the appropriate perioperative antibiotic regimen remains unclear. We evaluated a perioperative antibiotic strategy targeting bile contamination associated with PBD procedures for preventing abdominal infectious complications after pancreatoduodenectomy. Consecutive patients (n = 254) underwent pancreatoduodenectomy at a single center. Perioperative antibiotics were mainly cefazolin in non-PBD cases (n = 116) and cefozopran in internal-PBD cases (n = 87). They were based on preoperative bile cultures in 51 of the external-PBD cases. Intraoperative bile cultures were examined prospectively. Morbidity and abdominal infectious complication rates were evaluated. The incidence of positive intraoperative bile cultures was significantly higher in the internal-PBD (85 %) and external-PBD (90 %) cases than in the non-PBD cases (26 %) (p

Background In recent years, nonalcoholic fatty liver disease (NAFLD) after pancreatoduodenectomy (PD) has become increasingly problematic. Our aims were to clarify the relationship between NAFLD and postoperative pancreatic exocrine function and to identify the risk factors for NAFLD after PD. Methods Patients who underwent PD (n = 104) were assessed with abdominal unenhanced computed tomography (CT) to determine the fatty liver changes and were given a 13C-labeled mixed triglyceride breath test to measure pancreatic exocrine function. The percent 13CO2 cumulative dose at 7 hr (% dose 13C cum 7 hr)

Background and Objectives Identification of prognostic markers is important to establish a perioperative therapeutic strategy for resectable cholangiocarcinoma (CC). The aim of this study was to investigate whether perioperative serum carbohydrate antigen 19-9 (CA19-9) levels can predict survival of patients who underwent surgical resection for CC. Methods The study included 106 patients who underwent surgical resection for CC. Serum CA19-9 levels were measured preoperatively after biliary drainage and postoperatively about 4 weeks after surgery. The association of clinicopathological factors (including perioperative serum CA19-9 levels) with overall survival (OS) was analyzed with univariate and multivariate analyses. Results Differences in OS were significant between groups divided on the basis of two preoperative CA19-9 cutoff values (in U/ml) of 37 and 200 and three postoperative CA19-9 cutoff values (in U/ml) of 37, 100, and 200. In multivariate analysis, absence of postoperative adjuvant chemotherapy (P = 0.002), lymph node metastasis (P = 0.0002), preoperative CA19-9 (≥200 IU/ml) (P = 0.03), and postoperative CA19-9 (≥37 IU/ml) (P

Background and objective Very few studies have revealed the dynamics of meropenem penetration into the pancreas or pancreatic juice in humans. This study of the clinical pharmacokinetics and pharmacodynamics of meropenem in human pancreatic juice was performed to establish a basis for the validation of dosing regimens for pancreatic infections. Methods Ten patients with endoscopic naso-pancreatic drainage received 500 mg meropenem over 0.5 h via intravenous infusion. Venous blood and pancreatic juice samples were collected post-infusion for up to 5.0 h and used to obtain measures of meropenem concentration. The probability of attaining the pharmacodynamic target (40% of the time above the minimum inhibitory concentration [MIC]) in pancreatic juice against MIC distributions for clinical isolates of Gram-negative bacteria was determined using a Monte Carlo simulation. Results The mean maximum concentration of meropenem in pancreatic juice was 2.08 ± 0.94 μg/mL at 1.025 ± 0.18 h. The pancreatic juice/plasma ratio was 0.055 ± 0.028. A 0.5-h infusion of 500 mg meropenem every 8 h achieved a 99.4% probability of target attainment against Escherichia coli , 96.4% against Klebsiella species, 94.3% against Enterobacter species and 96.2% against Proteus species, but only 41.3% against Pseudomonas aeruginosa isolates. Conclusion Intravenous meropenem exhibits low penetrance into pancreatic juice. However, a dosing regimen of 500 mg meropenem (0.5-h infusion) every 8 h provides sufficient drug-exposure time in pancreatic juice against the four common Gram-negative bacteria populations.

Secreted protein acidic and rich in cysteine (SPARC) is a matricellular protein that influences chemotherapy effectiveness and prognosis. The aim of this study was to investigate whether SPARC expression correlates with the postoperative survival of patients treated with surgical resection for biliary carcinoma. SPARC expression in resected biliary carcinoma specimens was investigated immunohistochemically in 175 patients. The relationship between SPARC expression and prognosis after surgery was evaluated using univariate and multivariate analyses. High SPARC expression in peritumoral stroma was found in 61 (35%) patients. In all patients, stromal SPARC expression was significantly associated with overall survival (OS) (P = 0.006). Multivariate analysis revealed that high stromal SPARC expression was an independent risk factor for poor OS (HR 1.81, P = 0.006). Moreover, high stromal SPARC expression was independently associated with poor prognosis in a subset of 118 patients treated with gemcitabine-based adjuvant chemotherapy (HR 2.04, P = 0.010) but not in the 57 patients who did not receive adjuvant chemotherapy (P = 0.21). Stromal SPARC expression correlated with the prognosis of patients with resectable biliary carcinoma, and its significance was enhanced in patients treated with adjuvant gemcitabine-based chemotherapy.

Para-aortic nodal dissection in patients with biliary carcinoma has not been performed routinely worldwide. Therefore, the prognostic impact of para-aortic lymph node metastasis in biliary carcinoma has not yet been evaluated. The aim of this study was to clarify the prognostic impact of para-aortic lymph node metastasis in biliary carcinoma. Of 113 patients with biliary adenocarcinoma who underwent surgical resection with regional and para-aortic lymph node dissection, para-aortic lymph node metastasis was found in 17 patients (15%) by final pathological examination. Relationships between clinicopathological factors, including para-aortic lymph node metastasis, and survival were analyzed by univariate and multivariate analyses. Overall survival rates for the 113 patients were 82% at 1 year, 65% at 2 years, 58% at 3 years, and 52% at 5 years. Univariate analysis revealed that better tumor differentiation (P = 0.044), negative lymph node metastasis (P

The prognosis for patients with advanced gallbladder carcinoma is dismal despite aggressive surgical resection. The aim of this study is to determine useful prognostic factors for patients with gallbladder carcinoma following aggressive surgical resection. Medical records of 62 patients with gallbladder carcinoma who underwent surgical resection were retrospectively reviewed. Univariate and multivariate models were used to analyze the effect of clinicopathological factors on long-term survival. According to the UICC staging system, ten (16%), 11 (18%), eight (13%), 16 (25%), nine (15%), and eight patients (13%) were diagnosed with stages I, II, IIIA, IIIB, IVA, and IVB disease, respectively. Partial hepatectomy and pancreatoduodenectomy were performed for 43 (69%) and 11 (18%) patients, respectively. Overall survival rates of all 62 and 41 patients with UICC stages III and IV disease were 71% and 56% at 1 year, 48% and 23% at 3 years, and 48% and 23% at 5 years, respectively (median survival time, 15.8 and 12.7 months, respectively). Multivariate analysis revealed that independent prognostic factors included tumor differentiation (p = 0.006), hepatic invasion (p = 0.002), lymph node metastasis (p = 0.009), and surgical margin status (p = 0.002) for all patients, and adjuvant chemotherapy (p = 0.005), tumor differentiation (p = 0.008), hepatic invasion (p = 0.001), and surgical margin status (p = 0.022) for patients with UICC stages III and IV disease. R0 resection and adjuvant chemotherapy are significant prognostic factors in advanced gallbladder carcinoma and should be performed to improve survival.

The prognosis of patients with cholangiocarcinoma is unsatisfactory. Therefore, evaluation of prognostic factors and establishment of new therapeutic strategies are needed to improve their long-term survival. The aim of this study was to identify useful prognostic factors for patients with intrahepatic, hilar, and distal cholangiocarcinoma. Records of 127 patients with cholangiocarcinoma (21 with intrahepatic cholangiocarcinoma, 50 with hilar cholangiocarcinoma, and 56 with distal cholangiocarcinoma) who underwent surgical resection were reviewed retrospectively. Relationships between survival and clinicopathological factors including patient demographics and tumor characteristics were evaluated using univariate and multivariate analysis. For all 127 patients, overall 1-, 3-, 5-year survival rates were 80, 51, and 40%, respectively. Univariate analysis revealed that adjuvant chemotherapy (P = .049), tumor differentiation (P = .014), lymph node metastasis (P

This study examined the penetration of meropenem into pancreatic juice in patients who had undergone hepato-biliary-pancreatic surgery. The patients received a 0.5-h infusion of 500 mg meropenem. The observed maximum concentration (mean ± standard deviation, n = 5) was 39.1 ± 11.2 μg/ml at 0.5 h in plasma and 2.12 ± 0.73 μg/ml at 1.10 ± 0.14 h in pancreatic juice. The pancreatic juice/plasma ratio was 0.06 ± 0.02. The area under the drug concentration–time curve was 73.0 ± 37.5 μg•h/ml in plasma and 4.24 ± 2.77 μg•h/ml in pancreatic juice. The pancreatic juice/plasma ratio was 0.06 ± 0.01. The mean drug-exposure times above 0.125 μg/ml and 0.25 μg/ml (the minimum inhibitory concentrations (MIC) for common pathogens) in pancreatic juice were 99.4% and 87.3%, respectively, for 500 mg meropenem 3 times daily. This commonly used regimen for pancreatitis achieved the drug-exposure time target (40% of the time above the MIC) at the action site, despite the low penetrability of meropenem.