Unraveling the role of the mitochondrial one-carbon pathway in undifferentiated thyroid cancer by multi-omics analyses.

The role of the serine/glycine metabolic pathway (SGP) has recently been demonstrated in tumors; however, the pathological relevance of the SGP in thyroid cancer remains unexplored. Here, we perform metabolomic profiling of 17 tumor-normal pairs; bulk transcriptomics of 263 normal thyroid, 348 papillary, and 21 undifferentiated thyroid cancer samples; and single-cell transcriptomes from 15 cases, showing the impact of mitochondrial one-carbon metabolism in thyroid tumors. High expression of serine hydroxymethyltransferase-2 (SHMT2) and methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) is associated with low thyroid differentiation scores and poor clinical features. A subpopulation of tumor cells with high mitochondrial one-carbon pathway activity is observed in the single-cell dataset. SHMT2 inhibition significantly compromises mitochondrial respiration and decreases cell proliferation and tumor size in vitro and in vivo. Collectively, our results highlight the importance of the mitochondrial one-carbon pathway in undifferentiated thyroid cancer and suggest that SHMT2 is a potent therapeutic target.

Mitochondrial morphology controls fatty acid utilization by changing CPT1 sensitivity to malonyl-CoA.

Changes in mitochondrial morphology are associated with nutrient utilization, but the precise causalities and the underlying mechanisms remain unknown. Here, using cellular models representing a wide variety of mitochondrial shapes, we show a strong linear correlation between mitochondrial fragmentation and increased fatty acid oxidation (FAO) rates. Forced mitochondrial elongation following MFN2 over-expression or DRP1 depletion diminishes FAO, while forced fragmentation upon knockdown or knockout of MFN2 augments FAO as evident from respirometry and metabolic tracing. Remarkably, the genetic induction of fragmentation phenocopies distinct cell type-specific biological functions of enhanced FAO. These include stimulation of gluconeogenesis in hepatocytes, induction of insulin secretion in islet ß-cells exposed to fatty acids, and survival of FAO-dependent lymphoma subtypes. We find that fragmentation increases long-chain but not short-chain FAO, identifying carnitine O-palmitoyltransferase 1 (CPT1) as the downstream effector of mitochondrial morphology in regulation of FAO. Mechanistically, we determined that fragmentation reduces malonyl-CoA inhibition of CPT1, while elongation increases CPT1 sensitivity to malonyl-CoA inhibition. Overall, these findings underscore a physiologic role for fragmentation as a mechanism whereby cellular fuel preference and FAO capacity are determined.

Development, validation, and comparison of a nomogram based on radiologic findings for predicting malignancy in intraductal papillary mucinous neoplasms of the pancreas: An international multicenter study.

BACKGROUND: Although we previously proposed a nomogram to predict malignancy in intraductal papillary mucinous neoplasms (IPMN) and validated it in an external cohort, its application is challenging without data on tumor markers. Moreover, existing nomograms have not been compared. This study aimed to develop a nomogram based on radiologic findings and to compare its performance with previously proposed American and Korean/Japanese nomograms. METHODS: We recruited 3708 patients who underwent surgical resection at 31 tertiary institutions in eight countries, and patients with main pancreatic duct >10 mm were excluded. To construct the nomogram, 2606 patients were randomly allocated 1:1 into training and internal validation sets, and area under the receiver operating characteristics curve (AUC) was calculated using 10-fold cross validation by exhaustive search. This nomogram was then validated and compared to the American and Korean/Japanese nomograms using 1102 patients. RESULTS: Among the 2606 patients, 90 had main-duct type, 900 had branch-duct type, and 1616 had mixed-type IPMN. Pathologic results revealed 1628 low-grade dysplasia, 476 high-grade dysplasia, and 502 invasive carcinoma. Location, cyst size, duct dilatation, and mural nodule were selected to construct the nomogram. AUC of this nomogram was higher than the American nomogram (0.691 vs 0.664, P = .014) and comparable with the Korean/Japanese nomogram (0.659 vs 0.653, P = .255). CONCLUSIONS: A novel nomogram based on radiologic findings of IPMN is competitive for predicting risk of malignancy. This nomogram would be clinically helpful in circumstances where tumor markers are not available. The nomogram is freely available at http://statgen.snu.ac.kr/software/nomogramIPMN.

NPFFR2 Contributes to the Malignancy of Hepatocellular Carcinoma Development by Activating RhoA/YAP Signaling.

G protein-coupled receptors (GPCRs) are a diverse family of cell surface receptors implicated in various physiological functions, making them common targets for approved drugs. Many GPCRs are abnormally activated in cancers and have emerged as therapeutic targets for cancer. Neuropeptide FF receptor 2 (NPFFR2) is a GPCR that helps regulate pain and modulates the opioid system; however, its function remains unknown in cancers. Here, we found that NPFFR2 is significantly up-regulated in liver cancer and its expression is related to poor prognosis. Silencing of NPFFR2 reduced the malignancy of liver cancer cells by decreasing cell survival, invasion, and migration, while its overexpression increased invasion, migration, and anchorage-independent cell growth. Moreover, we found that the malignant function of NPFFR2 depends on RhoA and YAP signaling. Inhibition of Rho kinase activity completely restored the phenotypes induced by NPFFR2, and RhoA/F-Actin/YAP signaling was controlled by NPFFR2. These findings demonstrate that NPFFR2 may be a potential target for the treatment of hepatocellular carcinoma.

The role of immunomodulatory metabolites in shaping the inflammatory response of macrophages.

Macrophage activation has long been implicated in a myriad of human pathophysiology, particularly in the context of the dysregulated capacities of an unleashing intracellular or/and extracellular inflammatory response. A growing number of studies have functionally coupled the macrophages' inflammatory capacities with dynamic metabolic reprogramming which occurs during activation, albeit the results have been mostly interpreted through classic metabolism point of view; macrophages take advantage of the rewired metabolism as a source of energy and for biosynthetic precursors. However, a specific subset of metabolic products, namely immune-modulatory metabolites, has recently emerged as significant regulatory signals which control inflammatory responses in macrophages and the relevant extracellular milieu. In this review, we introduce recently highlighted immuno-modulatory metabolites, with the aim of understanding their physiological and pathological relevance in the macrophage inflammatory response. [BMB Reports 2022; 55(11): 519-527].

MCL-1 is a master regulator of cancer dependency on fatty acid oxidation.

MCL-1 is an anti-apoptotic BCL-2 family protein essential for survival of diverse cell types and is a major driver of cancer and chemoresistance. The mechanistic basis for the oncogenic supremacy of MCL-1 among its anti-apoptotic homologs is unclear and implicates physiologic roles of MCL-1 beyond apoptotic suppression. Here we find that MCL-1-dependent hematologic cancer cells specifically rely on fatty acid oxidation (FAO) as a fuel source because of metabolic wiring enforced by MCL-1 itself. We demonstrate that FAO regulation by MCL-1 is independent of its anti-apoptotic activity, based on metabolomic, proteomic, and genomic profiling of MCL-1-dependent leukemia cells lacking an intact apoptotic pathway. Genetic deletion of Mcl-1 results in transcriptional downregulation of FAO pathway proteins such that glucose withdrawal triggers cell death despite apoptotic blockade. Our data reveal that MCL-1 is a master regulator of FAO, rendering MCL-1-driven cancer cells uniquely susceptible to treatment with FAO inhibitors.

Effect of Intraoperatively Detected Bacteriobilia on Surgical Outcomes After Pancreatoduodenectomy: Analysis of a Prospective Database in a Single Institute.

BACKGROUND: Bacteriobilia, the colonization of bacteria in bile, can be caused by obstructive cholangitis or preoperative biliary drainage (PBD), and is not uncommon condition in patients undergoing pancreatoduodenectomy (PD). This study aims to investigate the effect of intraoperatively detected bacteriobilia on surgical outcomes after PD. METHODS: For patients who underwent PD in Samsung Medical Center between 2018 and 2020, an intraoperative bile culture was performed prospectively, and their clinicopathological data were retrospectively reviewed. Surgical outcomes were compared between the patients, classified according to PBD and bacteriobilia. Logistic regression analysis was performed to identify factors increasing postoperative complications. RESULTS: A total of 382 patients were included, and 202 (52.9%) patients had PBD (PBD group). Bacteriobilia was significantly more common in PBD group comparing to non-PBD group (31.1% vs 75.2%, P < 0.001), but there was no difference in postoperative complications. Among PBD group, there were more patients with major complications and CR-POPF in endoscopic drainage group comparing to percutaneous drainage group (37.9% vs 14.6%, P = 0.002; 17.0% vs 4.2%, P = 0.025, respectively). In multivariable analysis, bacteriobilia increased the risk of wound complications (P = 0.041), but not the risks of other short-term adverse outcomes. CONCLUSION: Bacteriobilia itself does not exacerbate short-term postoperative outcomes after PD except for wound complication. Therefore, surgery could be performed as planned regardless of bacteriobilia, without the need to wait for negative cultures.

Prognosis of pancreatic head cancer with different patterns of lymph node metastasis.

BACKGROUND: The nodal stage of pancreatic ductal adenocarcinoma (PDAC) is revised in the AJCC 8th edition. Studies on the prognosis of PDAC according to lymph node metastasis (LNM) are still ongoing. We attempted to find the patterns of nodal involvement and to reveal its clinical significance to overall survival (OS). METHODS: We analyzed 585 patients who received pancreatic head cancer surgery diagnosed as PDAC from January 2007 to December 2016. Patients were classified into three groups: Group 1 (G1, patients without LNM), Group 2 (G2, those with LNM only in the peripancreatic area), and Group 3 (G3 those with LNM in the other area and/or peripancreatic LNM). Risk factors were analyzed by Cox-regression test and overall survival was compared by Kaplan-Meier analysis. RESULTS: LNM in peripancreatic area was the most common (88.7%). In the multivariate analysis, T stage, nuclear differentiation, adjuvant treatment, and the G2 and G3 were independent risk factors for OS (G2 over G1, HR 1.384, 95% CI 1.046-1.802; P = .036 and G3 over G1, HR 2.383, 95% CI 1.378-4.103; P = .001). G3 showed worse OS than G2 (P = .006). In the N1 status, LNM to the pericholedochal (PC) and superior mesenteric artery (SMA) areas resulted in worse OS than the G2 (P = .011 and P = .019). CONCLUSIONS: We found that LNM beyond the peripancreatic area significantly affects OS in pancreatic head cancer patients. Depending on the station of the LNM, different risk-stratification and treatment strategies will need to be considered.

Realistic Advantages of Early Surgical Drain Removal after Pancreatoduodenectomy: A Single-Institution Retrospective Study.

The latest guidelines from the Enhanced Recovery After Surgery (ERAS®) Society stated that early drain removal after pancreatoduodenectomy (PD) is beneficial in decreasing complications including postoperative pancreatic fistulas (POPFs). This study aimed to ascertain the actual benefits of early drain removal after PD. The data of 450 patients who underwent PD between 2018 and 2020 were retrospectively reviewed. The surgical outcomes were compared between patients whose drains were removed within 3 postoperative days (early removal group) and after 5 days (late removal group). Logistic regression analysis was performed to identify the risk factors for clinically relevant POPFs (CR-POPFs). Among the patients with drain fluid amylase < 5000 IU on the first postoperative day, the early removal group had fewer complications and shorter hospital stays than the late removal group (30.9% vs. 54.5%, p < 0.001; 9.8 vs. 12.5 days, p = 0.030, respectively). The incidences of specific complications including CR-POPFs were comparable between the two groups. Risk factor analysis showed that early drain removal did not increase CR-POPFs (p = 0.163). Although early drain removal has not been identified as apparently beneficial, this study showed that it may contribute to an early return to normal life without increasing complications.

The impact of portal vein resection on outcome of hilar cholangiocarcinoma.

BACKGROUNDS/AIMS: Portal vein resection (PVR) with major hepatic resection can increase the rate of curative resection for hilar cholangiocarcinoma (HC). However, the oncologic role and safety of PVR is still debatable. This study aims to analyze PVR in terms of safety and therapeutic effectiveness. METHODS: We retrospectively analyzed 235 patients who had undergone major hepatic resection for HC with curative intent, including patients with PVR (PVR, n=35) consisting of PV invasion (PVR-A, n=9), No PV invasion (PVR-B, n=26); and patients without PVR (No PVR, n=200). RESULTS: There was no significant difference in the 30-day mortality or postoperative morbidity between PVR and No PVR (2.9% vs. 1.0%; p=0.394 and 34.3% vs. 35.0%; p=0.875). The rate of advanced HC (T3: 40% vs. 12%; p<0.001 and nodal metastasis: 60% vs. 28%; p<0.001) was higher in PVR compared to No PVR. There was no significant difference in the 5-year overall survival rates and disease-free survival between PVR-A vs. PVR-B vs. No PVR. In multivariate analysis, estimated blood loss >600 ml (p=0.010), T3 diseases (p=0.001), nodal metastasis (p=0.001) and poor differentiation (p=0.002) were identified as independent risk factors for survival. CONCLUSIONS: PVR does not increase postoperative mortality or morbidity. It showed a similar oncologic outcome, despite a more advanced disease state in patients with HC. Given these findings, PVR should be actively performed if necessary, after careful patient selection.

Minimally Invasive Versus Open Pancreatectomy for Right-Sided and Left-Sided G1/G2 Nonfunctioning Pancreatic Neuroendocrine Tumors: A Multicenter Matched Analysis with an Inverse Probability of Treatment-Weighting Method.

BACKGROUND: Limited evidence exists for the safety and oncologic efficacy of minimally invasive surgery (MIS) for nonfunctioning pancreatic neuroendocrine tumors (NF-PNETs) according to tumor location. This study aimed to compare the surgical outcomes of MIS and open surgery (OS) for right- or left-sided NF-PNETs. METHODS: The study collected data on patients who underwent surgical resection (pancreatoduodenectomy, distal/total/central pancreatectomy, duodenum-preserving pancreas head resection, or enucleation) of a localized NF-PNET between January 2000 and July 2017 at 14 institutions. The inverse probability of treatment-weighting method with propensity scores was used for analysis. RESULTS: The study enrolled 859 patients: 478 OS and 381 MIS patients. A matched analysis by tumor location showed no differences in resection margin, intraoperative blood loss, or complications between MIS and OS. However, MIS was associated with a longer operation time for right-sided tumors (393.3 vs 316.7 min; P < 0.001) and a shorter postoperative hospital stay for left-sided tumors (8.9 vs 12.9 days; P < 0.01). The MIS group was associated with significantly higher survival rates than the OS group for right- and left-sided tumors, but survival did not differ for the patients divided by tumor grade and location. Multivariable analysis showed that MIS did not affect survival for any tumor location. CONCLUSION: The short-term outcomes offered by MIS were comparable with those of OS except for a longer operation time for right-sided NF-PNETs. The oncologic outcomes were not compromised by MIS regardless of tumor location or grade. These findings suggest that MIS can be performed safely for selected patients with localized NF-PNETs.

Should Lymph Nodes Be Retrieved in Patients with Intrahepatic Cholangiocarcinoma? A Collaborative Korea-Japan Study.

BACKGROUND: This study was performed to investigate the oncologic role of lymph node (LN) management and to propose a surgical strategy for treating intrahepatic cholangiocarcinoma (IHCC). METHODS: The medical records of patients with resected IHCC were retrospectively reviewed from multiple institutions in Korea and Japan. Short-term and long-term oncologic outcomes were analyzed according to lymph node metastasis (LNM). A nomogram to predict LNM in treating IHCC was established to propose a surgical strategy for managing IHCC. RESULTS: A total of 1138 patients were enrolled. Of these, 413 patients underwent LN management and 725 did not. A total of 293 patients were found to have LNM. The No. 12 lymph node (36%) was the most frequent metastatic node, and the No. 8 lymph node (21%) was the second most common. LNM showed adverse long-term oncologic impact in patients with resected IHCC (14 months, 95% CI (11.4-16.6) vs. 74 months, 95% CI (57.2-90.8), p < 0.001), and the number of LNM (0, 1-3, 4≤) was also significantly related to negative oncologic impacts in patients with resected IHCC (74 months, 95% CI (57.2-90.8) vs. 19 months, 95% CI (14.4-23.6) vs. 11 months, 95% CI (8.1-13.8)), p < 0.001). Surgical retrieval of more than four (≥4) LNs could improve the survival outcome in resected IHCC with LNM (13 months, 95% CI (10.4-15.6)) vs. 30 months, 95% CI (13.1-46.9), p = 0.045). Based on preoperatively detectable parameters, a nomogram was established to predict LNM according to the tumor location. The AUC was 0.748 (95% CI: 0.706-0.788), and the Hosmer and Lemeshow goodness of fit test showed p = 0.4904. CONCLUSION: Case-specific surgical retrieval of more than four LNs is required in patients highly suspected to have LNM, based on a preoperative detectable parameter-based nomogram. Further prospective research is needed to validate the present surgical strategy in resected IHCC.

Appraisal of 5-year recurrence-free survival after surgery in pancreatic ductal adenocarcinoma.

BACKGROUND/PURPOSE: Pancreatic ductal adenocarcinoma (PDAC) is regarded as incurable, with a limited survival rate after curative resection. The aim of this study was to explore long-term survival and late recurrence of PDAC after surgery. METHODS: Medical data of 859 patients who underwent resection between 1995 and 2014 were retrospectively examined. The clinicopathological features of the 5-year recurrence-free survivors and the patients with recurrent disease after 5 years were investigated separately. RESULTS: Among the 768 patients who were finally included in this study, elevated CA 19-9, tumor size, poor differentiation, and positive lymph node metastasis were associated with recurrence. In 89 patients with 5-year RFS, age, tumor size, differentiation, and lymph node metastasis were statistically significant predictive factors. Among these patients, disease relapse occurred in 11 patients; age was the only difference compared to those who remained free of recurrence. CONCLUSIONS: Most prognosticators failed to predict the risk of recurrence in the 5 years following surgery for PDAC, and recurrence can occur even at time points up to 100 months. Therefore, cure of PDAC cannot be guaranteed by a 5-year recurrence-free interval, and further studies into the inherent nature of PDAC are needed to develop adequate surveillance systems which may lead to improvements in survival.

Long-term outcomes following en bloc resection for pancreatic ductal adenocarcinoma of the head with portomesenteric venous invasion.

BACKGROUND: The aim of this study is to clarify the prognostic influence of venous resection of the portal vein (PV) or superior mesenteric vein (SMV) on long-term outcomes in patients with pancreatic ductal adenocarcinoma (PDAC) of the head with suspected vascular invasion. METHODS: From May 1995 to December 2014, a total of 557 patients underwent surgery with curative intent for pancreatic cancer of the head. RESULTS: Among 557 patients, 106 (19%) underwent pancreaticoduodenectomy (PD) with PV-SMV resection and 89 (75.5%) of these patients were confirmed to have true pathological invasion. The 5-year overall survival rate in patients underwent PV-SMV resection was significantly lower compared with those who did not (18.7% versus 24.3%; p = 0.002). Patients with negative resection margins who underwent PV-SMV resection had a better prognosis than those with positive resection margins who did not undergo PV-SMV resection with positive resection margins (17% versus 6.3% in 5-year overall survival rate; p = 0.003). The overall morbidity rate was not significantly different between PV-SMV resection group and no PV-SMV resection group (p = 0.064). On multivariate analysis, margin status, advanced T stage (3 or 4), lymph node metastasis, and adjuvant therapy were independent prognostic factors for survival. CONCLUSION: PV-SMV resection was related to lower overall survival. However, on multivariate analysis, margin status was a more important prognostic factor than PV-SMV resection and true pathological invasion for survival. Therefore, en bloc PV-SMV resection should be performed when PV-SMV invasion is suspected to achieve R0 resection.

Risk Factors for Recurrence in Pancreatic Neuroendocrine Tumor and Size as a Surrogate in Determining the Treatment Strategy: A Korean Nationwide Study.

INTRODUCTION: The prognostic factors of pancreatic neuroendocrine tumor (PNET) are unclear, and the treatment guidelines are insufficient. This study aimed to suggest a treatment algorithm for PNET based on risk factors for recurrence in a large cohort. METHODS: Data of 918 patients who underwent curative intent surgery for PNET were collected from 14 tertiary centers. Risk factors for recurrence and survival analyses were performed. RESULTS: The 5-year disease-free survival (DFS) rate was 86.5%. Risk factors for recurrence included margin status (R1, hazard ratio [HR] 2.438; R2, HR 3.721), 2010 WHO grade (G2, HR 3.864; G3, HR 7.352), and N category (N1, HR 2.273). A size of 2 cm was significant in the univariate analysis (HR 8.511) but not in the multivariate analysis (p = 0.407). Tumor size was not a risk factor for recurrence, but strongly reflected 2010 WHO grade and lymph node (LN) status. Tumors ≤2 cm had lower 2010 WHO grade, less LN metastasis (p < 0.001), and significantly longer 5-year DFS (77.9 vs. 98.2%, p < 0.001) than tumors >2 cm. The clinicopathologic features of tumors <1 and 1-2 cm were similar. However, the LN metastasis rate was 10.3% in 1-2-cm sized tumors and recurrence occurred in 3.0%. Tumors <1 cm in size did not have any LN metastasis or recurrence. DISCUSSION/CONCLUSION: Radical surgery is needed in suspected LN metastasis or G3 PNET or tumors >2 cm. Surveillance for <1-cm PNETs should be sufficient. Tumors sized 1-2 cm require limited surgery with LN resection, but should be converted to radical surgery in cases of doubtful margins or LN metastasis.

Risk prediction for malignant intraductal papillary mucinous neoplasm of the pancreas: logistic regression versus machine learning.

Most models for predicting malignant pancreatic intraductal papillary mucinous neoplasms were developed based on logistic regression (LR) analysis. Our study aimed to develop risk prediction models using machine learning (ML) and LR techniques and compare their performances. This was a multinational, multi-institutional, retrospective study. Clinical variables including age, sex, main duct diameter, cyst size, mural nodule, and tumour location were factors considered for model development (MD). After the division into a MD set and a test set (2:1), the best ML and LR models were developed by training with the MD set using a tenfold cross validation. The test area under the receiver operating curves (AUCs) of the two models were calculated using an independent test set. A total of 3,708 patients were included. The stacked ensemble algorithm in the ML model and variable combinations containing all variables in the LR model were the most chosen during 200 repetitions. After 200 repetitions, the mean AUCs of the ML and LR models were comparable (0.725 vs. 0.725). The performances of the ML and LR models were comparable. The LR model was more practical than ML counterpart, because of its convenience in clinical use and simple interpretability.

Prognostic Impact of Intra-Ampullary Papillary-Tubular Neoplasm versus Flat Dysplasia as Precursor Lesions of Ampullary Adenocarcinoma.

BACKGROUND: The aim of this study is to compare the prognostic impact of 2 precursor lesions of ampullary adenocarcinoma, intra-ampullary papillary-tubular neoplasm (IAPN) and flat dysplasia (FD). METHODS: From December 1994 to December 2012, a total of 359 patients underwent curative surgery for ampullary adenocarcinoma. RESULTS: The precursor lesions were IAPNs in 134 (37.3%) patients and FD in the other 225 (62.7%) patients. The FD group had more aggressive tumor biology with advanced T stage (p = 0.002), nodal involvement (p < 0.001), poor differentiation (p < 0.001), perineural and lymphovascular invasion (p < 0.001), and pancreatobiliary or mixed subtype (p < 0.001). Five-year overall survival rates were 71.1% in the IAPN group and 51.4% in the FD group (p = 0.002), respectively. Five-year disease-free survival rates were 69.7% in the IAPN group and 49.6% in the FD group (p < 0.001), respectively. The recurrence rate was also higher in the FD group (49.8 vs. 30.6%; p < 0.001). On multivariate analysis, higher levels of tumor markers including CEA and CA19-9, lymph node metastasis, poorly differentiated histology, and perineural invasion were negative predictive factors for survival. Higher levels of CEA and CA19-9, lymphovascular invasion, and FD were independent prognostic factors for recurrence. CONCLUSION: FD was significantly associated with worse prognosis and a greater tendency toward advanced disease. Further studies are needed to clarify the impacts of these precursor lesions.

Risk prediction platform for pancreatic fistula after pancreatoduodenectomy using artificial intelligence.

BACKGROUND: Despite advancements in operative technique and improvements in postoperative managements, postoperative pancreatic fistula (POPF) is a life-threatening complication following pancreatoduodenectomy (PD). There are some reports to predict POPF preoperatively or intraoperatively, but the accuracy of those is questionable. Artificial intelligence (AI) technology is being actively used in the medical field, but few studies have reported applying it to outcomes after PD. AIM: To develop a risk prediction platform for POPF using an AI model. METHODS: Medical records were reviewed from 1769 patients at Samsung Medical Center who underwent PD from 2007 to 2016. A total of 38 variables were inserted into AI-driven algorithms. The algorithms tested to make the risk prediction platform were random forest (RF) and a neural network (NN) with or without recursive feature elimination (RFE). The median imputation method was used for missing values. The area under the curve (AUC) was calculated to examine the discriminative power of algorithm for POPF prediction. RESULTS: The number of POPFs was 221 (12.5%) according to the International Study Group of Pancreatic Fistula definition 2016. After median imputation, AUCs using 38 variables were 0.68 ± 0.02 with RF and 0.71 ± 0.02 with NN. The maximal AUC using NN with RFE was 0.74. Sixteen risk factors for POPF were identified by AI algorithm: Pancreatic duct diameter, body mass index, preoperative serum albumin, lipase level, amount of intraoperative fluid infusion, age, platelet count, extrapancreatic location of tumor, combined venous resection, co-existing pancreatitis, neoadjuvant radiotherapy, American Society of Anesthesiologists' score, sex, soft texture of the pancreas, underlying heart disease, and preoperative endoscopic biliary decompression. We developed a web-based POPF prediction platform, and this application is freely available at http://popfrisk.smchbp.org. CONCLUSION: This study is the first to predict POPF with multiple risk factors using AI. This platform is reliable (AUC 0.74), so it could be used to select patients who need especially intense therapy and to preoperatively establish an effective treatment strategy.

The Beneficial Effects of Morusin, an Isoprene Flavonoid Isolated from the Root Bark of Morus.

The root bark of Morus has long been appreciated as an antiphlogistic, diuretic and expectorant drug in Chinese herbal medicine, albeit with barely known targets and mechanisms of action. In the 1970s, the development of analytic chemistry allowed for the discovery of morusin as one of 7 different isoprene flavonoid derivatives in the root bark of Morus. However, the remarkable antioxidant capacity of morusin with the unexpected potential for health benefits over the other flavonoid derivatives has recently sparked scientific interest in the biochemical identification of target proteins and signaling pathways and further clinical relevance. In this review, we discuss recent advances in the understanding of the functional roles of morusin in multiple biological processes such as inflammation, apoptosis, metabolism and autophagy. We also highlight recent in vivo and in vitro evidence on the clinical potential of morusin treatment for multiple human pathologies including inflammatory diseases, neurological disorders, diabetes, cancer and the underlying mechanisms.

Clinical outcomes of pancreaticoduodenectomy for pancreatic ductal adenocarcinoma depending on preservation or resection of pylorus.

BACKGROUNDS/AIMS: The comparative effectiveness of pylorus-resecting pancreaticoduodenectomy (PRPD) and pylorus- preserving pancreaticoduodenectomy (PPPD) in pancreatic head cancer is still disputed. The aim of this study was to analyze the data obtained from a large, single center with PPPD compared with PRPD in terms of postoperative outcomes, including blood glucose levels and survival in patients with pancreatic head cancer. METHODS: Between January 2007 and December 2016, a total of 556 patients with pancreatic head cancer underwent either PPPD or PRPD. We analyzed the clinicopathologic data to assess short- and long-term outcomes retrospectively. RESULTS: For underlying disease, patients with DM in PPPD were fewer than in PRPD (33.0% vs. 46.2%, p=0.002). The median value of CA19-9 was significantly higher in PRPD than in PPPD (129.36 vs. 86.47, p=0.037). The incidence of Clavien-Dindo grade III to V major complications in PPPD was significantly higher than in PRPD (20.4% vs. 13.4%, p=0.032). Resection of pylorus was shown to reduce complications in univariate and multivariate analyses (p=0.032 and = 0.021, respectively). The 5-year survival rates were 27.6% in the PPPD group and 22.4% in the PRPD group (p=0.015). CONCLUSIONS: The results of PPPD and PRPD showed no significant differences from those reported conventionally in previous studies. Although further well-designed studies are needed, it is more important to select the range of surgical resection for the patient's disease regardless of resection of pylorus.