Introduction of robotic pancreatoduodenectomy following phase 2a IDEAL guidelines.

BACKGROUND: Robotic pancreatoduodenectomy (RPD) is a newly introduced procedure, which is still evolving and lacks standardization. An objective assessment is essential to investigate the feasibility of RPD. The current study aimed to assess our initial ten cases of RPD based on IDEAL (Idea, Development, Exploration, Assessment, and Long-term study) guidelines. METHODS: This was a prospective phase 2a study following the IDEAL framework. Ten consecutive cases of RPD performed by two surgeons with expertise in open procedures at a single center were assigned to the study. With objective evaluation, each case was classified into four grades according to the achievements of the procedures. Errors observed in the previous case were used to inform the procedure in the next case. The surgical outcomes of the ten cases were reviewed. RESULTS: The median total operation time was 634 min (interquartile range [IQR], 594-668) with a median resection time of 363 min (IQR, 323-428) and reconstruction time of 123 min (IQR, 107-131). The achievement of the whole procedure was graded as A, "successful", in two patients. In two patients, reconstruction was performed with a mini-laparotomy due to extensive pneumoperitoneum, probably caused by insertion of a liver retractor from the xyphoid. Major postoperative complications occurred in two patients. One patient, in whom the jejunal limb was elevated through the Treitz ligament, had a bowel obstruction and needed to undergo re-laparotomy. CONCLUSIONS: RPD is feasible when performed by surgeons experienced in open procedures. Specific considerations are needed to safely introduce RPD.

Utilization of the modified Kama scoring system for predicting bail-out cholecystectomy: a valuable tool in the era of rising laparoscopic surgery prevalence.

PURPOSE: Recently, bail-out cholecystectomy (BOC) during laparoscopic cholecystectomy to avoid severe complications, such as vasculobiliary injury, has become widely used and increased in prevalence. However, current predictive factors or scoring systems are insufficient. Therefore, in this study, we aimed to test the validity of existing scoring systems and determine a suitable cutoff value for predicting BOC. METHODS: We retrospectively assessed 305 patients who underwent laparoscopic cholecystectomy and divided them into a total cholecystectomy group (n = 265) and a BOC group (n = 40). Preoperative and operative findings were collected, and cutoff values for the existing scoring systems (Kama's and Nassar's) were modified using a prospectively maintained database. RESULTS: The BOC rate was 13% with no severe complications. A logistic regression analysis revealed that the Kama's score (odds ratio, 0.93; 95% confidence interval 0.91-0.96; P < 0.01) was an independent predictor of BOC. A cutoff value of 6.5 points gave an area under the curve of 0.81, with a sensitivity of 87% and a specificity of 67%. CONCLUSIONS: Kama's difficulty scoring system with a modified cutoff value (6.5 points) is effective for predicting BOC.

Outcomes after distal pancreatectomy with or without splenectomy for intraductal papillary mucinous neoplasm: international multicentre cohort study.

BACKGROUND: International guidelines on intraductal papillary mucinous neoplasm (IPMN) recommend a formal oncological resection including splenectomy when distal pancreatectomy is indicated. This study aimed to compare oncological and surgical outcomes after distal pancreatectomy with or without splenectomy in patients with presumed IPMN. METHODS: An international, retrospective cohort study was undertaken in 14 high-volume centres from 7 countries including consecutive patients after distal pancreatectomy for IPMN (2005-2019). Patients were divided into spleen-preserving distal pancreatectomy (SPDP) and distal pancreatectomy with splenectomy (DPS). The primary outcome was lymph node metastasis (LNM). Secondary outcomes were overall survival, duration of operation, blood loss, and secondary splenectomy. RESULTS: Overall, 700 patients were included after distal pancreatectomy for IPMN; 123 underwent SPDP (17.6%) and 577 DPS (82.4%). The rate of malignancy was 29.6% (137 patients) and the overall rate of LNM 6.7% (47 patients). Patients with preoperative suspicion of malignancy had a LNM rate of 17.2% (23 of 134) versus 4.3% (23 of 539) among patients without suspected malignancy (P < 0.001). Overall, SPDP was associated with a shorter operating time (median 180 versus 226 min; P = 0.001), less blood loss (100 versus 336 ml; P = 0.001), and shorter hospital stay (5 versus 8 days; P < 0.001). No significant difference in overall survival was observed between SPDP and DPS for IPMN after correction for prognostic factors (HR 0.50, 95% c.i. 0.22 to 1.18; P = 0.504). CONCLUSION: This international cohort study found LNM in 6.7% of patients undergoing distal pancreatectomy for IPMN. In patients without preoperative suspicion of malignancy, SPDP seemed oncologically safe and was associated with improved short-term outcomes compared with DPS.

Possible Molecular Mechanisms of Hypertension Induced by Sleep Apnea Syndrome/Intermittent Hypoxia.

Intermittent hypoxia (IH) is a central characteristic of sleep apnea syndrome (SAS), and it subjects cells in the body to repetitive apnea, chronic hypoxia, oxygen desaturation, and hypercapnia. Since SAS is linked to various serious cardiovascular complications, especially hypertension, many studies have been conducted to elucidate the mechanism of hypertension induced by SAS/IH. Hypertension in SAS is associated with numerous cardiovascular disorders. As hypertension is the most common complication of SAS, cell and animal models to study SAS/IH have developed and provided lots of hints for elucidating the molecular mechanisms of hypertension induced by IH. However, the detailed mechanisms are obscure and under investigation. This review outlines the molecular mechanisms of hypertension in IH, which include the regulation systems of reactive oxygen species (ROS) that activate the renin-angiotensin system (RAS) and catecholamine biosynthesis in the sympathetic nervous system, resulting in hypertension. And hypoxia-inducible factors (HIFs), Endotheline 1 (ET-1), and inflammatory factors are also mentioned. In addition, we will discuss the influences of SAS/IH in cardiovascular dysfunction and the relationship of microRNA (miRNA)s to regulate the key molecules in each mechanism, which has become more apparent in recent years. These findings provide insight into the pathogenesis of SAS and help in the development of future treatments.

A patient alive without disease 32 months after conversion surgery following lenvatinib treatment for hepatocellular carcinoma with a tumor thrombus originating in the middle hepatic vein and reaching the right atrium via the suprahepatic vena cava: a case report.

Conversion surgery for initially unresectable hepatocellular carcinoma appears to be increasing in incidence since the advent of new molecular target drugs and immune checkpoint inhibitors; however, reports on long-term outcomes are limited and the prognostic relevance of this treatment strategy remains unclear. Herein, we report the case of a 75-year-old man with hepatocellular carcinoma, 108 mm in diameter, accompanied by a tumor thrombus in the middle hepatic vein that extended to the right atrium via the suprahepatic vena cava. He underwent conversion surgery after preceding lenvatinib treatment and is alive without disease 51 months after the commencement of treatment and 32 months after surgery. Just before conversion surgery, after 19 months of lenvatinib treatment, the main tumor had reduced in size to 72 mm in diameter, the tip of the tumor thrombus had receded back to the suprahepatic vena cava, and the tumor thrombus vascularity was markedly reduced. The operative procedure was an extended left hepatectomy with concomitant middle hepatic vein resection. The tumor thrombus was removed under total vascular exclusion via incision of the root of the middle hepatic vein. Histopathological examination revealed that more than half of the liver tumor and the tumor thrombus were necrotic.

Intermittent hypoxia increased the expression of ESM1 and ICAM-1 in vascular endothelial cells via the downregulation of microRNA-181a1.

Sleep apnea syndrome (SAS) exposes cells throughout the body to intermittent hypoxia (IH). Intermittent hypoxia is a risk factor not only for hypertension and insulin resistance but also for vascular dysfunction. We have reported correlations between IH, insulin resistance and hypertension. However, the details of why IH leads to vascular dysfunction remain unclear. In this study, we investigated inflammation-related transcripts in vascular endothelial cells (human HUEhT-1 and mouse UV2) exposed to IH by real-time RT-PCR and found that intercellular adhesion molecule-1 (ICAM-1) and endothelial cell-specific molecule-1 (ESM1) mRNAs were significantly increased. ELISA confirmed that, in the UV2 cell medium, ICAM-1 and ESM1 were significantly increased by IH. However, the promoter activities of ICAM-1 and ESM1 were not upregulated. On the other hand, IH treatment significantly decreased microRNA (miR)-181a1 in IH-treated cells. The introduction of miR-181a1 mimic but not miR-181a1 mimic NC abolished the IH-induced upregulation of Ican-1 and ESM1. These results indicated that ICAM-1 and ESM1 were upregulated by IH via the IH-induced downregulation of miR-181a1 in vascular endothelial cells and suggested that SAS patients developed atherosclerosis via the IH-induced upregulation of ICAM-1 and ESM1.

Upregulation of IL-8, osteonectin, and myonectin mRNAs by intermittent hypoxia via OCT1- and NRF2-mediated mechanisms in skeletal muscle cells.

Sleep apnoea syndrome is characterized by recurrent episodes of oxygen desaturation and reoxygenation (intermittent hypoxia [IH]) and is a risk factor for insulin resistance/Type 2 diabetes. The induction of insulin resistance in skeletal muscle is a key phenomenon to develop diabetes. However, the mechanisms linking IH stress and insulin resistance remain elusive. We exposed human RD and mouse C2C12 muscle cells to normoxia or IH and measured their mRNA levels by real-time RT-PCR. We found that IH significantly increased the mRNA and protein levels of muscle-derived insulin resistance-factors (myokines) such as IL-8, osteonectin (ON), and myonectin (MN) in muscle cells. We further analysed the IH-induced expression mechanisms of IL-8, ON, and MN genes in muscle cells. Deletion analyses of the human myokine promoter(s) revealed that the regions -152 to -151 in IL-8, -105 to -99 in ON, and - 3741 to -3738 in MN promoters were responsible for the activation by IH in RD cells. The promoters contain consensus transcription factor binding sequences for OCT1 in IL-8 and MN promoters, and for NRF2 in ON promoter, respectively. The introduction of siRNA for OCT1 abolished the IH-induced expression(s) of IL-8 and MN and siRNA for NRF2 abolished the IH-induced expression of ON.

Enteral versus parental nutrition after pancreaticoduodenectomy under enhanced recovery after surgery protocol: study protocol for a multicenter, open-label randomized controlled trial (ENE-PAN trial).

BACKGROUND: Infectious complications are the main causes of morbidity after pancreaticoduodenectomy (PD). Early enteral nutrition (EN) is a reasonable form of nutritional support that aims to mitigate the occurrence and severity of infectious complications by maintaining gut immunity. However, it remains unclear whether EN is beneficial for patients who underwent PD and are under enhanced recovery after surgery (ERAS) protocol. METHODS: A multicenter (six hospitals), open-label, randomized controlled trial will be started in July 2022. A total of 320 patients undergoing open PD will be randomly assigned to an EN group or a peripheral parental nutrition (PPN) group in a 1:1 ratio. The stratification factors will be the hospital, age (≥ 70 or not), and preoperative diagnosis (pancreatic cancer or not). In the EN group, enteral nutrition will start on postoperative day (POD) 1 at 200-300 ml/day via the percutaneous tube placed operatively. The volume of the diet will be increased to 400-600 ml/day on POD 2 and depend on the surgeon's decision from POD 3. In the PPN group, PPN will be delivered after surgery. In both groups, oral feeding will start on POD 3. Each treatment will be finished when patients' oral food intake reaches 60% of the nutritional requirement (25-30 kcal/day). The primary endpoint will be the occurrence of postoperative infectious complications within 90 days of surgery. The secondary endpoints will be all complications, including major ones such as Clavien-Dindo grade 3 or more and clinically relevant postoperative pancreatic fistula. Data will be analyzed per the intention to treat. DISCUSSION: This will be the first, large, and well-designed RCT that aims to determine whether EN is beneficial for patients who underwent PD under the ERAS protocol. According to the results of this study, either EN or PPN would be adopted as the standard nutritional support for patients undergoing PD. TRIAL REGISTRATION: jRCT1030210691. Registered on March 23, 2022.

Upregulation of Reg IV and Hgf mRNAs by Intermittent Hypoxia via Downregulation of microRNA-499 in Cardiomyocytes.

Sleep apnea syndrome (SAS) is characterized by recurrent episodes of oxygen desaturation and reoxygenation (intermittent hypoxia [IH]), and is a risk factor for cardiovascular disease (CVD) and insulin resistance/Type 2 diabetes. However, the mechanisms linking IH stress and CVD remain elusive. We exposed rat H9c2 and mouse P19.CL6 cardiomyocytes to experimental IH or normoxia for 24 h to analyze the mRNA expression of several cardiomyokines. We found that the mRNA levels of regenerating gene IV (Reg IV) and hepatocyte growth factor (Hgf) in H9c2 and P19.CL6 cardiomyocytes were significantly increased by IH, whereas the promoter activities of the genes were not increased. A target mRNA search of microRNA (miR)s revealed that rat and mouse mRNAs have a potential target sequence for miR-499. The miR-499 level of IH-treated cells was significantly decreased compared to normoxia-treated cells. MiR-499 mimic and non-specific control RNA (miR-499 mimic NC) were introduced into P19.CL6 cells, and the IH-induced upregulation of the genes was abolished by introduction of the miR-499 mimic, but not by the miR-499 mimic NC. These results indicate that IH stress downregulates the miR-499 in cardiomyocytes, resulting in increased levels of Reg IV and Hgf mRNAs, leading to the protection of cardiomyocytes in SAS patients.

Downregulation of the Cd38-Cyclic ADP-Ribose Signaling in Cardiomyocytes by Intermittent Hypoxia via Pten Upregulation.

Sleep apnea syndrome (SAS) is characterized by recurrent episodes of oxygen desaturation and reoxygenation (intermittent hypoxia, IH), and it is a risk factor for cardiovascular disease (CVD) and insulin resistance/type 2 diabetes. However, the mechanisms linking IH stress and CVD remain elusive. We exposed rat H9c2 and mouse P19.CL6 cardiomyocytes to experimental IH or normoxia for 24 h to analyze the mRNA expression of the components of Cd38-cyclic ADP-ribose (cADPR) signaling. We found that the mRNA levels of cluster of differentiation 38 (Cd38), type 2 ryanodine receptor (Ryr2), and FK506-binding protein 12.6 (Fkbp12.6) in H9c2 and P19.CL6 cardiomyocytes were significantly decreased by IH, whereas the promoter activities of these genes were not decreased. By contrast, the expression of phosphatase and tensin homolog deleted from chromosome 10 (Pten) was upregulated in IH-treated cells. The small interfering RNA for Pten (siPten) and a non-specific control RNA were introduced into the H9c2 cells. The IH-induced downregulation of Cd38, Ryr2, and Fkbp12.6 was abolished by the introduction of the siPten, but not by the control RNA. These results indicate that IH stress upregulated the Pten in cardiomyocytes, resulting in the decreased mRNA levels of Cd38, Ryr2, and Fkbp12.6, leading to the inhibition of cardiomyocyte functions in SAS patients.

Intermittent Hypoxia Increased the Expression of DBH and PNMT in Neuroblastoma Cells via MicroRNA-375-Mediated Mechanism.

Sleep apnea syndrome (SAS), characterized by recurrent episodes of oxygen desaturation and reoxygenation (intermittent hypoxia (IH)), is a risk factor for hypertension and insulin resistance. We report a correlation between IH and insulin resistance/diabetes. However, the reason why hypertension is induced by IH is elusive. Here, we investigated the effect of IH on the expression of catecholamine-metabolizing enzymes using an in vitro IH system. Human and mouse neuroblastoma cells (NB-1 and Neuro-2a) were exposed to IH or normoxia for 24 h. Real-time RT-PCR revealed that IH significantly increased the mRNA levels of dopamine ß-hydroxylase (DBH) and phenylethanolamine N-methyltransferase (PNMT) in both NB-1 and Neuro-2a. Western blot showed that the expression of DBH and PNMT in the NB-1 cells was significantly increased by IH. Reporter assays revealed that promoter activities of DBH and PNMT were not increased by IH. The miR-375 level of IH-treated cells was significantly decreased relative to that of normoxia-treated cells. The IH-induced up-regulation of DBH and PNMT was abolished by the introduction of the miR-375 mimic, but not by the control RNA. These results indicate that IH stress increases levels of DBH and PNMT via the inhibition of miR-375-mediated mRNA degradation, potentially playing a role in the emergence of hypertension in SAS patients.

Repeat Resection for Advanced Colorectal Liver Metastases-Does it have the Potential for Cure?

BACKGROUND: Although surgical resection is the only potential treatment for patients with colorectal liver metastases (CLM), the actual cure is rare in patients with advanced CLM. Repeat resection (RR) is the most effective treatment in patients with recurrence; however, whether patients with initially advanced CLM achieve cure throughout RR or experience repeated recurrence even after RR remains unclear. In this study, we analyzed whether patients with advanced CLM achieve cure after RR. METHODS: Consecutive patients who underwent initial hepatectomy with curative intent for CLM from January 1999 to August 2007 were included. Patients who were alive at 10 years from the initial hepatectomy without any evidence of recurrence were defined as cured. Cure rates were compared between patients with Fong's clinical risk score (CRS) of ≥ 3 and those with CRS of ≤ 2. RESULTS: A total of 257 patients were included and followed up. Among them, 93 (36.2%) patients achieved actual cure postoperatively. The cure rate of patients with a CRS of ≥ 3 was 32.4% (33/102), which was not different from that of patients with a CRS of ≤ 2 (38.7% [60/155]; p = 0.299), although former patients had higher recurrence rate after the initial hepatectomy than latter ones (85.3% vs. 72.3%; p = 0.014). The cure rates after the initial, second, and third resections were 23.0% (59/257), 30.0% (24/80), and 22.5% (7/31), respectively. In multivariate analysis, RR was determined as an independent favorable factor of achieving cure. CONCLUSIONS: RR had a potential to cure patients with advanced CLM, and one-third of them achieved cure.

Survival comparison of invasive intraductal papillary mucinous neoplasm versus pancreatic ductal adenocarcinoma.

BACKGROUND: The aim of this study was to assess the relevance of highlighting T1a invasive intraductal papillary mucinous carcinoma as a separate subcategory and to compare the tumor biology between invasive intraductal papillary mucinous carcinoma and pancreatic ductal adenocarcinoma. METHODS: A total of 144 and 328 consecutive patients with intraductal papillary mucinous neoplasms and pancreatic ductal adenocarcinoma, respectively, were analyzed. RESULTS: Patients with T1a invasive intraductal papillary mucinous carcinoma comprised 25% (11/44) of the overall subject population with invasive intraductal papillary mucinous carcinoma with 5-year disease-specific survival rate being 100%. None of the patients with pancreatic ductal adenocarcinoma were classified as having T1a disease. When patients with invasive intraductal papillary mucinous carcinoma and pancreatic ductal adenocarcinoma were compared after excluding patients with T1a invasive intraductal papillary mucinous carcinoma, the 5-year disease-specific survival rates were 63% vs 40% in node-negative status (P = .018); and they were 20% vs 13% in node-positive status (P = .385). Subsequent analyses revealed that this survival superiority was limited to patients without evidence of lymphatic invasion. CONCLUSION: T1a invasive intraductal papillary mucinous carcinoma is a clinical entity specifically observed in patients with intraductal papillary mucinous carcinoma, but not in patients with pancreatic ductal adenocarcinoma, and is associated with excellent postoperative survival outcomes. In the survival comparison after exclusion of patients with T1a tumors, when the analysis was limited to patients without lymphatic invasion or lymph node metastasis, the disease-specific survival rate remained higher in patients with invasive intraductal papillary mucinous carcinoma compared with those with pancreatic ductal adenocarcinoma, and this difference was considered as being attributable to the intrinsic indolent biological behavior of invasive intraductal papillary mucinous carcinoma. However, this survival advantage was lost once lymphatic invasion occurred.

Limited Prognostic Value of KRAS in Patients Undergoing Hepatectomy for Colorectal Liver Metastases.

BACKGROUND: RAS mutation status is considered a powerful prognostic factor in patients undergoing hepatectomy for colorectal liver metastases (CLM). However, whether its prognostic power is robust regardless of administration of preoperative chemotherapy or tumor burden remains unclear. METHODS: Consecutive patients who underwent initial hepatectomy for CLM from April 2010 through March 2017 in two hospitals were included. The prognostic value of KRAS was compared based on whether patients received preoperative chemotherapy and their tumor burden score (TBS). RESULTS: We included 409 patients (median follow-up 38 months). In the preoperative chemotherapy group, patients with mutant KRAS (mt-KRAS) CLM had poorer overall survival (OS) than those with wild KRAS (wt-KRAS; 5-year OS: 37.7% vs 53.8%, p = 0.024), although their OS was not different from patients undergoing upfront surgery. Similarly, patients with mt-KRAS had poorer OS than those with wt-KRAS in TBS of 3-9 (5-year OS: 33.1% vs 63.2%, p = 0.001), although their OS was not different from patients with TBS < 3 or ≥ 9. In multivariate analysis, mt-KRAS was an independent prognostic factor of OS among patients receiving preoperative chemotherapy (hazard ratio [HR] 1.61, 95% confidence interval [CI]: 1.034-2.491; p = 0.035) and patients with TBS of 3-9 (HR 1.836, 95% CI 1.176-2.866; p = 0.008). However, it was not a prognostic factor in patients who underwent upfront surgery or with TBS > 3 or ≥ 9. CONCLUSIONS: In patients undergoing hepatectomy for CLM, the prognostic value of KRAS depends on their history of preoperative chemotherapy or tumor burden.

Intermittent Hypoxia Upregulates the Renin and Cd38 mRNAs in Renin-Producing Cells via the Downregulation of miR-203.

Sleep apnea syndrome is characterized by recurrent episodes of oxygen desaturation and reoxygenation (intermittent hypoxia [IH]), and it is a known risk factor for hypertension. The upregulation of the renin-angiotensin system has been reported in IH, and the correlation between renin and CD38 has been noted. We exposed human HEK293 and mouse As4.1 renal cells to experimental IH or normoxia for 24 h and then measured the mRNA levels using a real-time reverse transcription polymerase chain reaction. The mRNA levels of Renin (Ren) and Cd38 were significantly increased by IH, indicating that they could be involved in the CD38-cyclic ADP-ribose signaling pathway. We next investigated the promotor activities of both genes, which were not increased by IH. Yet, a target mRNA search of the microRNA (miRNA) revealed both mRNAs to have a potential target sequence for miR-203. The miR-203 level of the IH-treated cells was significantly decreased when compared with the normoxia-treated cells. The IH-induced upregulation of the genes was abolished by the introduction of the miR-203 mimic, but not the miR-203 mimic NC negative control. These results indicate that IH stress downregulates the miR-203 in renin-producing cells, thereby resulting in increased mRNA levels of Ren and Cd38, which leads to hypertension.

Prognostic value of pre-treatment systemic immune-inflammation index in patients with endometrial cancer.

BACKGROUND: The systemic immune-inflammation index (SII), which is calculated using absolute platelet, neutrophil, and lymphocyte counts, has recently attracted attentions as a prognostic indicator in patients with solid malignancies. In the current study, we retrospectively investigated the prognostic significance of pre-treatment SII among patients with endometrial cancer. METHOD: Endometrial cancer patients treated at Nara medical university hospital between 2008 and 2018 were included in the current study. Receiver operating characteristic (ROC) curve was used to find the optimal SII cut-off values for 3-years progression free survival (PFS) and overall survival (OS). Then, the predictive abilities of SII and its superiority over neutrophil to lymphocyte ratio (NLR) and platelet to lymphocyte ratio (PLR) were investigated. Kaplan-Meier method was used to calculate the OS and PFS rates, and log-rank test was used to compare the survival rate between two groups. Univariate and multivariate Cox regression analysis were performed to identify risk factors for PFS and OS. RESULT: A total of 442 patients were included in the current study. The cut-off value of SII for predicting PFS and OS were defined by ROC analysis as 931 and 910, respectively. Univariate analyses showed that elevated SII was associated with significantly shorter survival (p <0.001 for both PFS and OS). Cox regression analyses revealed that an advanced FIGO stage (p <0.001 for both PFS and OS) and an elevated SII (p = 0.014 for PFS, p = 0.011 for OS) are the independent prognostic factors for survival. When SII was compared with NLR and PLR, SII showed greater area under curve for predicting survival. CONCLUSION: The SII is an independent prognostic factor in endometrial cancer patients, allowing more precise survival estimation than PLR or NLR.

Accuracy of Modern Clinical Risk Score Including RAS Status Changes Based on Whether Patients Received Perioperative Chemotherapy for Colorectal Liver Metastases.

BACKGROUND: A modified Fong clinical score (m-Fong CS) that includes the RAS mutation status has recently been proposed and offered an improved survival stratification of patients who undergo surgery and systemic chemotherapy for colorectal liver metastases (CLM). The aim of this study is to assess whether a CS that includes RAS status is influenced by whether patients receive perioperative chemotherapy. METHODS: We created a new CS using multivariate analysis of data of patients who underwent hepatectomy for CLM for the first time between 2010 and 2016 at a single hospital (n = 341, 79% received perioperative chemotherapy). The resulting CS and m-Fong CS were then validated in the patient cohort at three other hospitals (n = 309). Furthermore, the applicability of the two CS in the total cohort (n = 650) was tested according to whether the patients received perioperative chemotherapy. RESULTS: The new CS comprised mutant RAS status, ≥4 CLMs, and a CA19-9 level ≥100 U/mL (1 point per factor). Both the new CS and m-Fong CS failed to stratify the survival of the 309 patients in the validation cohort, including those who did not receive perioperative chemotherapy (29%). Both of the CS accurately stratified the survival of patients who underwent perioperative chemotherapy but not of those who underwent surgery alone. CONCLUSION: A CS that includes the RAS mutation status can stratify the survival of patients who undergo hepatectomy combined with perioperative chemotherapy, but it has limited value for patients who undergo surgery alone.

GSK-3ß mediates the effects of HNF-1ß overexpression in ovarian clear cell carcinoma.

Deubiquitinase USP28 is a target gene of the transcription factor HNF1 homeobox ß (HNF-1ß), which promotes the survival of ovarian clear cell carcinoma (OCCC) cell lines. However, the pharmacological inhibition of HNF-1ß can cause several adverse effects as it is abundantly expressed in numerous organ systems, including the kidney, liver, pancreas and digestive tract. Therefore, small interfering RNA (siRNA) screening was performed in the current study to identify other potential downstream targets of the HNF-1ß-mediated pathway. The results revealed that glycogen synthase kinase-3ß (GSK-3ß) may be a potential downstream target affecting cell viability. To further clarify the effects of GSK-3ß, two human OCCC cell lines, TOV-21G (HNF-1ß overexpressing line) and ES2 (HNF-1ß negative) were transfected with siRNA targeting GSK-3ß or control vectors. Loss-of-function studies using RNAi-mediated gene silencing indicated that HNF-1ß facilitated GSK-3ß expression, resulting in the loss of phosphorylated nuclear factor-κB (p-NFκB) and the reduction of TOV-21G cell proliferation. The cell proliferation assay also revealed that GSK-3ß inhibitors rescued the effects of HNF-1ß silencing on cell viability in a dose-dependent manner. Furthermore, the GSK-3ß inhibitor, AR-A014418, effectively inhibited tumor cell proliferation in a xenograft mouse model. In conclusion and to the best of our knowledge, the current study was the first to determine that GSK-3ß is a target gene of HNF-1ß. In addition, the results of the present study revealed the novel HNF-1ß-GSK-3ß-p-NFκB pathway, occurring in response to DNA damage. Targeting this pathway may therefore represent a putative, novel, anticancer strategy in patients with OCCC.

Conservative drain management increases the incidence of grade B postoperative pancreatic fistula without increasing serious complications: Does persistent drainage reflect the quality of pancreatic surgery or institutional policy?

BACKGROUND: Among grade B/C postoperative pancreatic fistula (POPF), the clinical burden of patients treated with persistent drainage alone was reported to be less. As the clinical difference might depend on drain management, we evaluated their clinical burden under conservative drain management. METHODS: We included 292 patients who underwent pancreaticoduodenectomy or distal pancreatectomy between 2013 and 2015. Patients with grade B POPF were categorized into those receiving persistent drainage alone (B-drain) and those receiving other treatments (B-other). The clinical burden of these groups and patients with biochemical leakage (BL) was compared. RESULTS: BL, grade B POPF, and grade C POPF occurred in 42 (14%), 93 (32%), and 4 (1.4%) patients, respectively. The B-drain group comprised 61% of grade B POPF. The overall major morbidity (Clavien-Dindo grade ≥ 3) in the B-drain group was significantly lower than in the B-other group (18% vs 50%, P = .001) but was comparable to that of the BL group (19%, P = .848). The POPF-related major morbidity in the B-drain and B-other group were 0% and 25%, respectively (P < .001). CONCLUSIONS: Under conservative drain management, patients with grade B POPF frequently experienced persistent drainage alone and the clinical burden of B-drain group and BL group was comparable.

Early Fistulography Can Predict Whether Biochemical Leakage Develops to Clinically Relevant Postoperative Pancreatic Fistula.

BACKGROUND: As complete prevention of postoperative pancreatic fistula (POPF) after pancreatic surgery remains difficult, many risk factors for clinically relevant POPF (CR-POPF) have been reported. However, their clinical impact could be limited because all previous reports included patients without biochemical leakage (BL) that rarely developed to CR-POPF. Therefore, a new strategy for identifying high-risk patients who develop delayed complications from patients with confirmed BL and for implementing interventions for such patients in the early postoperative period is required. This study aimed to examine the role of fistulography in predicting CR-POPF from confirmed BL. METHODS: Consecutive patients diagnosed with BL on postoperative day 3 after pancreaticoduodenectomy (PD) or distal pancreatectomy (DP) from January 2013 to June 2015 in our institution were included. Fistulography was performed 1 week after the operation, and the associations between findings on fistulography and delayed complications associated with POPF were evaluated. RESULTS: Eighty-four (37%) of 227 patients who underwent PD and 45 (48%) of 94 patients who underwent DP were included and divided to two groups according to fistulographic findings (simple type, n = 107, 83%; cavity type, n = 22, 17%). The latter finding was associated with a greater morbidity rate (Clavien-Dindo grade ≥ 2: 36% vs 59%, p = 0.018) and a worse final POPF grade (B/C 64% vs 95%, p = 0.003). In the multivariate analysis, cavity type on fistulography was a significant predictive factor for grade B/C POPF. CONCLUSIONS: Fistulography is a useful examination for identifying patients with a high risk of developing delayed complications associated with POPF.