A case of novel NFKB2 variant with hypertensive emergency and nephrotic syndrome leading to CKD 5D.

Nuclear factor kappa B (NF-κB) family plays a central role in the human immune system. Heterozygous variants in NFKB2 typically cause immunodeficiency with various degrees of central adrenal insufficiency, autoimmunity, and ectodermal dysplasia. No reported case has presented kidney failure as an initial symptom. Moreover, documentation of kidney involvement of this disease is limited. CASE DIAGNOSIS: A 2-year-old female who presented with dyspnea and hypertensive emergency in the setting of new-onset nephrotic syndrome with acute-on chronic kidney injury with resultant chronic kidney disease (CKD) was found to have a novel heterozygous N-terminal variant in NFKB2 (c.880del: p. Tyr294Ilefs*4) with mild hypogammaglobulinemia, but no adrenal insufficiency or ectodermal dysplasia. She became dialysis-dependent during her initial hospitalization and developed CKD stage 5D, requiring continued peritoneal dialysis. She is currently awaiting kidney transplantation. CONCLUSIONS: Whether nephrotic syndrome or kidney injury or failure is the primary symptom of this variant or secondary to some event remains unknown. Further case accumulation is warranted.

Clinical significance and functional role of adhesion G-protein-coupled receptors in human pancreatic ductal adenocarcinoma.

BACKGROUND: The adhesion G-protein-coupled receptors (GPCRs) play crucial roles in tumour pathogenesis, however, their clinical significance in pancreatic ductal adenocarcinoma (PDAC) remains unclear. METHODS: We analysed 796 PDAC patients, including 331 from public data sets (TCGA, ICGC and GSE57495) and 465 from independent cohorts (training: n = 321, validation: n = 144). Using in-vitro studies, we confirmed the biological function of the candidate GPCRs. RESULTS: Analysis of all 33 adhesion GPCRs, led to identify GPR115, as the only significant prognostic factor in all public data sets. The patients with high GPR115 expression exhibited significantly poorer prognosis for OS and RFS, in training (P < 0.01, P < 0.01) and validation cohort (P < 0.01, P = 0.04). Multivariate analysis indicated that GPR115 high expression was an independent prognostic factor in both cohorts (HR = 1.43; P = 0.01, HR = 2.55; P < 0.01). A risk-prediction model using Cox regression by incorporating GPR115 and clinicopathological factors accurately predicted 5-year survival following surgery. In addition, GPR115 silencing inhibited cell proliferation and migration in PDAC cells. CONCLUSION: We demonstrated that GPR115 has important prognostic significance and functional role in tumour progression; providing a rationale that this may be a potential therapeutic target in patients with PDAC.

Pre- and postoperative C-reactive protein as a risk factor of organ/space surgical site infection after hepatectomy.

BACKGROUND: Organ/space surgical site infection (SSI) is one of the most common complications of liver resection, with significant impact on morbidity and mortality, so patients at high risk should be identified early. This study aimed to determine whether pre- and postoperative C-reactive protein (CRP) levels could predict organ/space SSIs. METHODS: The hospital records of consecutive patients who underwent hepatectomy without biliary reconstruction at our institutions between 2008 and 2015 were reviewed retrospectively. Preoperative, intraoperative, and postoperative variables were compared between patients with or without organ/space SSIs. Its risk factors were also determined. RESULTS: Among 443 identified patients, 55 cases (12.5%) developed organ/space SSIs; they more frequently experienced other complications and bile leakage (47.3% vs. 16.6%, p = 0.001; 40.0% vs. 8.5%, p < 0.001, respectively). Postoperative CRP elevation from postoperative day (POD) 3 to 5 was significantly more frequent in the SSI group (21.8% vs. 4.9%, p < 0.001). Multivariate analysis identified preoperative CRP ≥ 0.2 mg/dL (odds ratio (OR), 2.01, p = 0.044], preoperative cholangitis (OR, 15.7; p = 0.020), red cell concentrate (RCC) transfusion (OR, 2.61, p = 0.018), bile leakage (OR, 9.51; p < 0.001), and CRP level elevation from POD 3 to 5 (OR, 3.81, p = 0.008) as independent risk factors for organ/space SSIs. CONCLUSIONS: Preoperative CRP elevation and postoperative CRP trajectory are risk factors for organ/space SSIs after liver resection. A prolonged CRP level elevation at POD 5 indicates its occurrence. If there were no risk factors and no CRP elevation at POD 5, its presence could be excluded.

Impact of laparoscopic liver resection on liver regeneration.

BACKGROUND: Liver regeneration after liver resection plays an important role in preventing posthepatectomy liver failure. In this study, we aimed to evaluate and compare the impact of laparoscopic liver resection (LLR) and open liver resection (OLR) on liver regeneration. METHODS: Patients who underwent curative anatomical liver resection for hepatocellular carcinoma, cholangiocellular carcinoma, and colorectal liver metastases at our institution between January 2010 and December 2018 were included in this study. The patients were divided into the OLR and LLR groups. Preoperative liver volume (PLV), future remnant liver volume, resected liver volume (RLV), liver volume at 1 month after the surgery, and liver volume at 6 months after the surgery were calculated. The liver regeneration rate was defined as the increase in the rate of RLV, and the liver recovery rate was defined as the rate of return to the PLV. RESULTS: The study included 72 patients. Among them, 43 were included in the OLR group and 29 were included in the LLR group. No differences were observed in the baseline characteristics and surgical procedures between the two groups. Moreover, no significant difference was observed in the liver regeneration rate at 1 month after the surgery (OLR vs. LLR: 68.9% vs. 69.0%, p = 0.875) and at 6 months after the surgery (91.8% vs. 93.2%, p = 0.995). Furthermore, the liver recovery rates were not significantly different between the two groups at 1 month after the surgery (90.3% vs. 90.6%, p = 0.893) and at 6 months after the surgery (96.9% vs. 98.8%, p = 0.986). CONCLUSION: Liver regeneration after liver resection is not affected by the type of surgical procedure and both laparoscopic and open procedures yield similar regeneration and recovery rates.

Clinically Relevant Late-Onset Biliary Complications After Pancreatoduodenectomy.

BACKGROUND: Late-onset biliary complications (LBC) after pancreatoduodenectomy (PD) can be serious. This study aimed to clarify the frequency and risk factors of severe LBC after PD. METHODS: We defined LBC as biliary complications occurring 3 months after PD and severe LBC as cases that required intensive care. A total of 318 patients who underwent PD between 2010 and 2018 with at least 1 year of postoperative follow-up were evaluated. RESULTS: Hospitalization for severe LBC was required in 59 patients (19%), of whom 20 had liver abscesses (6.3%); 18, acute cholangitis (5.7%); 12, biliary stones (3.8%); and 21, biliary strictures (6.6%). Interventional radiological or endoscopic treatment was required in 32 patients (10%), of whom 9 had a benign primary disease with biliary stones and/or strictures. Thirteen of the remaining 23 patients with a malignant primary disease had liver abscesses and cholangitis. Significant independent risk factors for severe LBC in patients with malignant primary disease were recurrence around the hepaticojejunostomy (odds ratio 6.5, P = 0.013) and chemotherapy (odds ratio 13.5, P < 0.001). CONCLUSIONS: Severe LBC after PD may occur regardless of whether the primary disease is benign or malignant. The course of severe LBC differs according to the primary disease, and therefore, appropriate follow-up and optimal treatment should be recommended according to the condition of the patient and the disease state.

Integrative analysis identifies activated anti-tumor immune microenvironment in lung metastasis of pancreatic cancer.

BACKGROUND: Although the prognosis of patients experiencing recurrences after surgery for pancreatic cancer is extremely poor, patients who develop recurrence in the lung have a better prognosis compared to other types of recurrence. We performed a histo-immunological analysis of the metastatic specimens to identify specific features of this patient subgroup. METHODS: We performed immunohistochemistry for CD4+, CD8+, CD45RO+, Foxp3, and PD-L1 in the lung (n = 22), peritoneal (n = 18), and liver (n = 6) metastases of pancreatic cancer. As microenvironmental and immunonutritional investigations, the tumor-stroma ratio and prognostic nutritional index (PNI) were utilized in the integrative analysis of immunological features. RESULTS: We identified significantly increased tumor-infiltrating CD4+, CD8+, and CD45RO+ cells in lung metastasis, compared with peritoneal and liver metastases (lung vs. peritoneum/liver, CD4: P < 0.001/P = 0.015, CD8: P < 0.001/P = 0.038, CD45RO: P = 0.022/P = 0.012). The CD8/Foxp3 ratio was higher in the lung than in the liver (P = 0.024). PD-L1 expression was significantly higher in lung metastasis than in peritoneal metastasis (P = 0.010). Furthermore, we found that lung metastasis had fewer cancer stroma than peritoneal metastasis (P < 0.001). A higher PNI was observed in patients with lung metastasis, and PNI was positively correlated with tumor-infiltrating lymphocytes in metastatic sites. CONCLUSION: We identified that lung metastasis revealed an immunologically "hot" tumor with increased TILs and PD-L1 expression. This specific feature suggests that patients with lung metastasis can be candidates for immunotherapy, such as immune checkpoint inhibitors; therefore, our study provides a framework for developing individualized treatment strategies for this patient subgroup.

A gene expression signature for predicting response to neoadjuvant chemoradiotherapy in pancreatic ductal adenocarcinoma.

In patients with pancreatic ductal adenocarcinoma (PDAC), optimal treatment selection, including multimodality regimens such as neoadjuvant chemoradiotherapy (NACRT), can be clinically transformative. Unfortunately, currently no predictive biomarkers are available that can guide the use of NACRT in PDAC patients. Accordingly, herein we developed a novel gene signature that can preoperatively predict NACRT-sensitivity in PDAC patients. Herein, we evaluated the performance of a 10-gene panel in 749 PDAC cases, which included two public datasets (The Cancer Genome Atlas and International Cancer Genome Consortium; n = 276), and three clinical specimen cohorts (n = 417), and a pre-NACRT endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) biopsy cohort (n = 56). The potential predictive performance of this signature was evaluated and compared to CA-19-9 levels and key clinicopathological factors. We first evaluated the prognostic potential of a 10-gene panel which significantly predicted overall survival in both public datasets (P < .01, P < .01), and two in-house patient cohorts (P < .01, P = .04). In the pre-NACRT EUS-FNA cohort, we established a radio-sensitivity gene panel (RSGP) which yielded highly robust (area under the curve [AUC] = 0.91; 95% CI: 0.81-0.97) for predicting response to gemcitabine-based NACRT. Multivariate logistic regression analysis revealed that RSGP was an independent predictor for response to NACRT (OR = 2.70; 95% CI: 1.25-5.85), and this response-prediction was even more robust when CA-19-9 levels were included into the model. In conclusion, we have validated and developed a novel gene signature that is highly robust in predicting response to NACRT, even in preoperative settings, highlighting its clinical significance for optimizing and personalizing treatment strategies in PDAC patients.

Clinical relevance of CD70 expression in resected pancreatic cancer: Prognostic value and therapeutic potential.

BACKGROUND: Aberrant expression of CD70 in several malignancies is potentially associated with poor patient prognosis and could serve as a therapeutic target. However, the clinical relevance of CD70 expression in pancreatic cancer has not been thoroughly explored. METHODS: We evaluated CD70 expression in 166 surgical specimens obtained from human patients with pancreatic cancer. We analyzed the function of CD70 in proliferation and migration using pancreatic cancer cell lines with silenced CD70 expression. RESULTS: CD70 expression was positively stained in 42 patients (25%). In the whole cohort, high CD70 expression was not associated with overall survival (OS: 33.1 vs. 40.8 months, P = 0.256), although it was significantly associated with inferior OS in a population of patients that completed adjuvant chemotherapy (OS: 45.4 vs. 63.8 months, P = 0.027). Moreover, the incidence of hematogenous metastasis was significantly higher in patients with high CD70 expression than in those with low CD70 expression (P = 0.020). This finding was also statistically significant in multivariate analyses (P = 0.001). In vitro experiments demonstrated that CD70 expression contributed to cancer cell proliferation independently of gemcitabine treatment as well as cell migration. Furthermore, real-time polymerase chain reaction analysis of frozen surgical tissues showed a correlation between the expression of CD70 and mesenchymal markers. CONCLUSIONS: CD70 expression in pancreatic cancer might be involved in hematogenous metastasis. Furthermore, our results imply that CD70 overexpression can serve as a novel prognostic factor and a potential therapeutic target in patients who have completed adjuvant chemotherapy.

Does direct invasion of peripancreatic lymph nodes impact survival in patients with pancreatic ductal adenocarcinoma? A retrospective dual-center study.

BACKGROUND: Pancreatic ductal adenocarcinoma can directly invade the peripancreatic lymph nodes; however, the significance of direct lymph node invasion is controversial, and it is currently classified as lymph node metastasis. This study aimed to identify the impact of direct invasion of peripancreatic lymph nodes on survival in patients with pancreatic ductal adenocarcinoma. METHODS: A total of 411 patients with resectable/borderline resectable pancreatic ductal adenocarcinoma who underwent pancreatic resection at two high-volume centers from 2006 to 2016 were evaluated retrospectively. RESULTS: Sixty (14.6%) patients had direct invasion of the peripancreatic lymph nodes without isolated lymph node metastasis (N-direct group), 189 (46.0%) had isolated lymph node metastasis (N-met group), and 162 (39.4%) had neither direct invasion nor isolated metastasis (N0 group). There was no significant difference in median overall survival between the N-direct group (35.0 months) and the N0 group (45.6 month) (p = 0.409), but survival was significantly longer in the N-direct compared with the N-met group (25.0 months) (p = 0.003). Similarly, median disease-free survival was similar in the N-direct (21.0 months) and N0 groups (22.7 months) (p = 0.151), but was significantly longer in the N-direct compared with the N-met group (14.0 months) (p < 0.001). Multivariate analysis identified resectability, adjuvant chemotherapy, and isolated lymph node metastasis as independent predictors of overall survival. However, direct lymph node invasion was not a predictor of survival. CONCLUSION: Direct invasion of the peripancreatic lymph nodes had no effect on survival in patients undergoing pancreatic resection for pancreatic ductal adenocarcinoma, and should therefore not be classified as lymph node metastasis.

Limited resection vs. pancreaticoduodenectomy for primary duodenal adenocarcinoma: a systematic review and meta-analysis.

It is well known that surgery is the mainstay treatment for duodenal adenocarcinoma. However, the optimal extent of surgery is still under debate. We aimed to systematically review and perform a meta-analysis of limited resection (LR) and pancreatoduodenectomy for patients with duodenal adenocarcinoma. A systematic electronic database search of the literature was performed using PubMed and the Cochrane Library. All studies comparing LR and pancreatoduodenectomy for patients with duodenal adenocarcinoma were selected. Long-term overall survival was considered as the primary outcome, and perioperative morbidity and mortality as the secondary outcomes. Fifteen studies with a total of 3166 patients were analyzed; 995 and 1498 patients were treated with limited resection and pancreatoduodenectomy, respectively. Eight and 7 studies scored a low and intermediate risk of publication bias, respectively. The LR group had a more favorable result than the pancreatoduodenectomy group in overall morbidity (odd ratio [OR]: 0.33, 95% confidence interval [CI] 0.17-0.65) and postoperative pancreatic fistula (OR: 0.13, 95% CI 0.04-0.43). Mortality (OR: 0.96, 95% CI 0.70-1.33) and overall survival (OR: 0.61, 95% CI 0.33-1.13) were not significantly different between the two groups, although comparison of the two groups stratified by prognostic factors, such as T categories, was not possible due to a lack of detailed data. LR showed long-term outcomes equivalent to those of pancreatoduodenectomy, while the perioperative morbidity rates were lower. LR could be an option for selected duodenal adenocarcinoma patients with appropriate location or depth of invasion, although further studies are required.

Phase II Study of the Triple Combination Chemotherapy of SOXIRI (S-1/Oxaliplatin/Irinotecan) in Patients with Unresectable Pancreatic Ductal Adenocarcinoma.

LESSONS LEARNED: The triple combination chemotherapy of SOXIRI (S-1/oxaliplatin/irinotecan) in patients with unresectable pancreatic ductal adenocarcinoma was an effective treatment that appeared to be better tolerated than the widely used FOLFIRINOX regimen.SOXIRI regimen may provide an alternative approach for advanced pancreatic cancer. BACKGROUND: In our previous phase I study, we determined the recommended dose of a biweekly S-1, oxaliplatin, and irinotecan (SOXIRI) regimen in patients with unresectable pancreatic ductal adenocarcinoma (PDAC). This phase II study was conducted to assess the safety and clinical efficacy in patients with unresectable PDAC. METHODS: Patients with previously untreated metastatic and locally advanced PDAC were enrolled. The primary endpoint was response rate (RR). Secondary endpoints were adverse events (AEs), progression-free survival (PFS), and overall survival (OS). Patients received 80 mg/m2 of S-1 twice a day for 2 weeks in alternate-day administration, 150 mg/m2 of irinotecan on day 1, and 85 mg/m2 of oxaliplatin on day 1 of a 2-week cycle. RESULTS: Thirty-five enrolled patients received a median of six (range: 2-15) treatment cycles. The RR was 22.8% (95% confidence interval [CI]: 10.4-40.1); median OS, 17.7 months (95% CI: 9.8-22.0); and median PFS, 7.4 months (95% CI: 4.2-8.4). Furthermore, the median OS in patients with distant metastasis was 10.1 months, whereas that in patients with locally advanced PDAC was 22.6 months. Major grade 3 or 4 toxicity included neutropenia (54%), anemia (17%), febrile neutropenia (11%), anorexia (9%), diarrhea (9%), and nausea (9%). There were no treatment-related deaths. CONCLUSION: SOXIRI is considered a promising and well-tolerated regimen in patients with unresectable PDAC.

Significance of the inflammation-based prognostic score in recurrent pancreatic cancer.

BACKGROUND: Although the prognosis of recurrent pancreatic cancer (RPC) is improving with the appearance of new anticancer drugs, prognostic indicators for RPC are still poorly understood. The aim of this study was to evaluate significance of the inflammation-based prognostic score, including modified Glasgow Prognostic Score (mGPS), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR), and Prognostic Nutritional Index (PNI), in patients with RPC. METHODS: This study reviewed 263 patients of pancreatic ductal adenocarcinoma at our institution between 2006 and 2015. A receiver operating characteristics curve analysis was performed to determine the cut-off values. The prognostic significance of the inflammation-based prognostic scores were evaluated by a multivariate analysis. RESULTS: 172 patients (65.4%) who had recurrence was included in this study. The optimal PNI for predicting 1-year survival after recurrence was 40 with higher area under receiver operating characteristics curve value (0.704) in comparison with other inflammation-based prognostic scores. A univariate and multivariate analysis revealed that liver metastasis (P < 0.001) and PNI < 40 (P < 0.001) were independently associated with the survival time after recurrence. When each of the two predictors was counted as one point and the points were calculated for all cases, a good stratified survival curve was obtained, showing the shorter survival in the higher points: median survival times of 2, 1, and 0 points were 4.3, 11.1, and 21.2 months, respectively (P < 0.001). CONCLUSIONS: Inflammation-based prognostic scores, especially PNI is useful clinical biomarker for predicting the survival time after recurrence in patients with pancreatic adenocarcinoma.

Risk Factors for Late-Onset Gastrointestinal Hemorrhage After Pancreatoduodenectomy for Pancreatic Cancer.

BACKGROUND: Late-onset gastrointestinal hemorrhage after pancreatoduodenectomy (PD) occasionally occurs repeatedly or leads to a serious condition. This retrospective study aimed to clarify its frequency and pathogenesis. METHODS: A total of 147 consecutive patients who underwent PD for pancreatic cancer between 2006 and 2014 were evaluated. Patients were divided into two groups according to the occurrence of late-onset gastrointestinal hemorrhage on postoperative day 100 or later. Furthermore, recurrence and portal vein (PV) hemodynamics were thoroughly reevaluated by computed tomography. RESULTS: Eleven patients experienced late-onset gastrointestinal hemorrhage. The bleeding sites were gastrojejunostomy in four patients, choledochojejunostomy in two, transverse colic marginal vein in one, and unknown in four. The median occurrence time of late-onset gastrointestinal hemorrhage was 13.3 months after PD. PV occlusion (63.6 vs. 8.9%; p < 0.001), no patency of PV-splenic vein (SPV) confluence (54.5 vs. 12.7%; p = 0.002), and SPV ligation (36.4 vs. 9.6%; p = 0.025) were found to be significant risk factors for late-onset gastrointestinal hemorrhage. Among 11 patients who experienced late-onset gastrointestinal hemorrhage, 7 had PV occlusion and 6 had local recurrence. CONCLUSIONS: Our data suggested for the first time that both oncologic and non-oncologic factors might contribute to late-onset gastrointestinal hemorrhage after PD for pancreatic cancer. Furthermore, PV occlusion, no PV-SPV patency, and SPV ligation were found to be significant risk factors for late-onset gastrointestinal hemorrhage. Therefore, to prevent late-onset gastrointestinal hemorrhage, we must consider various approaches to maintain the patency of the PV and SPV.

A Comparison Between Plastic and Metallic Biliary Stent Placement in Patients Receiving Preoperative Neoadjuvant Chemoradiotherapy for Resectable Pancreatic Cancer.

BACKGROUND: The optimal stent type in patients receiving preoperative neoadjuvant chemoradiotherapy (NACRT) is uncertain. The present study aimed to compare the clinical effectiveness of biliary metallic stent (MS) and plastic stent (PS) in patients undergoing preoperative NACRT for resectable pancreatic cancer. METHODS: This retrospective study included 43 patients who required either biliary MS or PS before initiating NACRT for resectable or borderline resectable pancreatic head cancer. Seventeen patients had MS (MS group), while 23 patients had PS (PS group). All patients received preoperative NACRT, including gemcitabine and concomitant three-dimensional radiation of 54 Gy, and underwent pancreatectomy. Stent patency, surgery postponement, postoperative outcomes, and cost-effectiveness were compared between these groups. RESULTS: There were no significant differences in baseline demographic or tumor characteristics between the groups. Stent patency was significantly longer in the MS group than in the PS group (p = 0.042). There were no differences in time to surgery, intraoperative characteristics, surgical complications, margin positivity, and pathological response between the groups. Furthermore, the medical cost of maintenance of biliary drainage during NACRT was similar between the groups. CONCLUSIONS: MS placement compared to PS in patients receiving preoperative NACRT provided no significant benefits during the postoperative course of pancreatectomy. However, MS placement was associated with long stent patency while showing no economic disadvantage. Therefore, MS placement may be recommended in patients receiving preoperative NACRT for resectable pancreatic cancer.

Risk Factors for Unresectable Recurrence After Up-Front Surgery for Colorectal Liver Metastasis.

BACKGROUND: There is no clear evidence that preoperative chemotherapy for resectable colorectal liver metastasis (CRLM) is superior to up-front surgery (UFS). The aim of this study was to identify the risk factors associated with poor prognosis after UFS for CRLM. METHODS: Data about consecutive patients with CRLM who underwent liver resection at Nara Medical University Hospital between January 2000 and December 2015 were retrieved from a prospective database. Recurrence that developed within 2 years after liver resection and could not be surgically resected was defined as unresectable recurrence (UR). Preoperative risk factors associated with UR after UFS were analyzed. Among the patients with the identified risk factors, the patients who were treated with UFS were compared with those who received preoperative chemotherapy via propensity score-matching analysis. RESULTS: There were 167 patients treated with UFS, and 71 of them developed UR (the UR group). The overall survival (OS) rate of the UR group was significantly worse than that of the non-UR group (5-year survival rate: 3.8 vs. 66.8%, p < 0.001). Multivariate analysis identified a primary colorectal cancer N factor of N2-3 as a risk factor for UR (hazard ratio 2.72, p = 0.004). Propensity score-matching analysis demonstrated that among patients with N2-3 primary colorectal cancer the post-initial treatment OS of the patients treated with UFS was significantly worse than that of the patients who received preoperative chemotherapy (5-year survival rate: 11.1 vs. 30.0%, p = 0.046). CONCLUSIONS: Patients with CRLM with a primary colorectal cancer N factor of N2-3 should be considered for preoperative chemotherapy.

Prognostic factors for actual long-term survival in the era of multidisciplinary treatment for pancreatic ductal adenocarcinoma.

PURPOSE: Recent advances in multidisciplinary treatments are improving the postoperative prognosis of pancreatic ductal adenocarcinoma (PDAC). However, the prognosis even after potentially curative resection remains poor. The aim of this study was to identify the clinical and pathological features of actual 5-year survivors under current circumstances. METHODS: A total of 128 patients who underwent pancreatectomy for PDAC at our institution between January 2006 and December 2011 were retrospectively analyzed. RESULTS: The actual 5-year overall survival rate for all patients was 30.9%, with a median survival time of 33.1 months. Of 128 patients, 25 (19.5%) survived for 5 years after surgery without disease recurrence. A univariate analysis showed that the pretreatment serum CA19-9 value, tumor depth, lymph node metastasis, and UICC stage at resection were significant predictive factors for the actual long-term survival. A multivariate analysis showed that a pretreatment serum CA19-9 value ≥ 110 U/mL was a significant unfavorable prognostic indicator. In addition, all subjects in the 5-year survival group completed adjuvant chemotherapy. The recurrence rate in the liver was significantly lower and that in the lung significantly higher in the long-term survival group than in the short-term survival group. CONCLUSIONS: The factors contributing to the long-term survival of PDAC were the pretreatment CA19-9 value and the completion of adjuvant chemotherapy. To achieve the actual long-term survival and cure after pancreatectomy for pancreatic cancer, further treatment strategies enhancing the completion rate of adjuvant chemotherapy are required.

Significance of bacterial culturing of prophylactic drainage fluid in the early postoperative period after liver resection for predicting the development of surgical site infections.

PURPOSES: The relationship between the results of bacterial drainage fluid cultures in the early postoperative period after liver resection and the development of surgical site infections (SSIs) is unclear. We evaluated the diagnostic value of bacterial cultures of drainage fluid obtained on postoperative day (POD) 1 after liver resection. METHODS: The cases of all consecutive patients who underwent elective liver resection from January 2014 to December 2016 were analyzed. The association between a positive culture result and the development of SSIs was analyzed. RESULTS: A total of 195 consecutive patients were studied. Positive drainage fluid cultures were obtained in 6 patients (3.1%). A multivariate analysis revealed that a positive drainage fluid culture was an independent risk factor for SSIs (odds ratio: 8.04, P = 0.035), and combined resection of the gastrointestinal tract was a risk factor for a positive drainage fluid culture (P = 0.006). Among the patients who did not undergo procedures involving the gastrointestinal tract, there was no association between drainage fluid culture positivity and SSIs. CONCLUSIONS: The detection of positive culture results for drainage fluid collected on POD 1 after liver resection was associated with SSIs. However, among patients who did not undergo procedures involving the gastrointestinal tract, it was not a predictor of SSIs.

Aicardi-Goutières syndrome is caused by IFIH1 mutations.

Aicardi-Goutières syndrome (AGS) is a rare, genetically determined early-onset progressive encephalopathy. To date, mutations in six genes have been identified as etiologic for AGS. Our Japanese nationwide AGS survey identified six AGS-affected individuals without a molecular diagnosis; we performed whole-exome sequencing on three of these individuals. After removal of the common polymorphisms found in SNP databases, we were able to identify IFIH1 heterozygous missense mutations in all three. In vitro functional analysis revealed that IFIH1 mutations increased type I interferon production, and the transcription of interferon-stimulated genes were elevated. IFIH1 encodes MDA5, and mutant MDA5 lacked ligand-specific responsiveness, similarly to the dominant Ifih1 mutation responsible for the SLE mouse model that results in type I interferon overproduction. This study suggests that the IFIH1 mutations are responsible for the AGS phenotype due to an excessive production of type I interferon.

Genetic and clinical features of cryopyrin-associated periodic syndromes in Turkish children.

OBJECTIVES: The aim of this study was to present the genetic and clinical data of the largest cohort of Turkish cryopyrin-associated periodic syndromes (CAPS) patients. METHODS: This is a two-centre descriptive study of Turkish children with clinical diagnosis of CAPS. NLRP3 analyses were performed by Sanger sequencing and by massively parallel sequencing. ASC dependent NF-κB activation and transfection-induced THP-1 cell death assays determined the functional consequences of the detected variants. Disease activity and response to anti interleukin 1 (anti-IL-1) treatment was also assessed. RESULTS: Heterozygous germline NLRP3 mutation was detected in 8 of 14 enrolled patients (57.1%). Two novel somatic mutations Y560H and G307D were found which induced both THP-1 cell death and ASC dependent NF-kB activation. With anti-IL-1 treatment the disease activity was improved in all patients except one. Except two patients with macrophage activation syndrome (MAS) attack, there were no serious adverse events requiring hospitalisation. CONCLUSIONS: CAPS should be considered in all patients with typical symptoms even if Sanger-based genetic analysis is negative, since a considerable number of patients have mosaicism. Treatment should be patient-tailored and MAS should be considered as a rare complication.