Factors Affecting Nonfunctioning Small Pancreatic Neuroendocrine Neoplasms and Proposed New Treatment Strategies.

BACKGROUND & AIMS: Despite previously reported treatment strategies for nonfunctioning small (≤20 mm) pancreatic neuroendocrine neoplasms (pNENs), uncertainties persist. We aimed to evaluate the surgically resected cases of nonfunctioning small pNENs (NF-spNENs) in a large Japanese cohort to elucidate an optimal treatment strategy for NF-spNENs. METHODS: In this Japanese multicenter study, data were retrospectively collected from patients who underwent pancreatectomy between January 1996 and December 2019, were pathologically diagnosed with pNEN, and were treated according to the World Health Organization 2019 classification. Overall, 1490 patients met the eligibility criteria, and 1014 were included in the analysis cohort. RESULTS: In the analysis cohort, 606 patients (59.8%) had NF-spNENs, with 82% classified as grade 1 (NET-G1) and 18% as grade 2 (NET-G2) or higher. The incidence of lymph node metastasis (N1) by grade was significantly higher in NET-G2 (G1: 3.1% vs G2: 15.0%). Independent factors contributing to N1 were NET-G2 or higher and tumor diameter ≥15 mm. The predictive ability of tumor size for N1 was high. Independent factors contributing to recurrence included multiple lesions, NET-G2 or higher, tumor diameter ≥15 mm, and N1. However, the independent factor contributing to survival was tumor grade (NET-G2 or higher). The appropriate timing for surgical resection of NET-G1 and NET-G2 or higher was when tumors were >20 and >10 mm, respectively. For neoplasms with unknown preoperative grades, tumor size >15 mm was considered appropriate. CONCLUSIONS: NF-spNENs are heterogeneous with varying levels of malignancy. Therefore, treatment strategies based on tumor size alone can be unreliable; personalized treatment strategies that consider tumor grading are preferable.

Inhibition of dopamine receptor D1 signaling promotes human bile duct cancer progression via WNT signaling.

Bile duct cancer (BDC) frequently invades the nerve fibers, making complete surgical resection difficult. A single tumor mass contains cells of variable malignancy and cell-differentiation states, with cancer stem cells (CSCs) considered responsible for poor clinical outcomes. This study aimed to investigate the contribution of autosynthesized dopamine to CSC-related properties in BDC. Sphere formation assays using 13 commercially available BDC cell lines demonstrated that blocking dopamine receptor D1 (DRD1) signaling promoted CSC-related anchorage-independent growth. Additionally, we newly established four new BDC patient-derived organoids (PDOs) and found that blocking DRD1 increased resistance to chemotherapy and enabled xenotransplantation in vivo. Single-cell analysis revealed that the BDC PDO cells varied in their cell-differentiation states and responses to dopamine signaling. Further, DRD1 inhibition increased WNT7B expression in cells with bile duct-like phenotype, and it induced proliferation of other cell types expressing Wnt receptors and stem cell-like signatures. Reagents that inhibited Wnt function canceled the effect of DRD1 inhibition and reduced cell proliferation in BDC PDOs. In summary, in BDCs, DRD1 is a crucial protein involved in autonomous CSC proliferation through the regulation of endogenous WNT7B. As such, inhibition of the DRD1 feedback signaling may be a potential treatment strategy for BDC.

Controversy Over Liver Transplantation or Resection for Neuroendocrine Liver Metastasis: Tumor Biology Cuts the Deal.

BACKGROUND: In patients with neuroendocrine liver metastasis (NELM), liver transplantation (LT) is an alternative to liver resection (LR), although the choice of therapy remains controversial. In this multicenter study, we aim to provide novel insight in this dispute. METHODS: Following a systematic literature search, 15 large international centers were contacted to provide comprehensive data on their patients after LR or LT for NELM. Survival analyses were performed with the Kaplan-Meier method, while multivariable Cox regression served to identify factors influencing survival after either transplantation or resection. Inverse probability weighting and propensity score matching was used for analyses with balanced and equalized baseline characteristics. RESULTS: Overall, 455 patients were analyzed, including 230 after LR and 225 after LT, with a median follow-up of 97 months [95% confidence interval (CI): 85-110 months]. Multivariable analysis revealed G3 grading as a negative prognostic factor for LR [hazard ratio (HR)=2.22, 95% CI: 1.04-4.77, P =0.040], while G2 grading (HR=2.52, 95% CI: 1.15-5.52, P =0.021) and LT outside Milan criteria (HR=2.40, 95% CI: 1.16-4.92, P =0.018) were negative prognostic factors in transplanted patients. Inverse probability-weighted multivariate analyses revealed a distinct survival benefit after LT. Matched patients presented a median overall survival (OS) of 197 months (95% CI: 143-not reached) and a 73% 5-year OS after LT, and 119 months (95% CI: 74-133 months) and a 52.8% 5-year OS after LR (HR=0.59, 95% CI: 0.3-0.9, P =0.022). However, the survival benefit after LT was lost if patients were transplanted outside Milan criteria. CONCLUSIONS: This multicentric study in patients with NELM demonstrates a survival benefit of LT over LR. This benefit depends on adherence to selection criteria, in particular low-grade tumor biology and Milan criteria, and must be balanced against potential risks of LT.

Loss of Arid1a and Pten in Pancreatic Ductal Cells Induces Intraductal Tubulopapillary Neoplasm via the YAP/TAZ Pathway.

BACKGROUND & AIMS: Pancreatic ductal adenocarcinoma (PDAC) arises from several types of premalignant lesions, including intraductal tubulopapillary neoplasm (ITPN); however, the molecular pathogenesis of ITPN remains unknown. METHODS: We performed studies with Hnf1b-CreERT2; Ptenf/f; Arid1af/f mice to investigate the consequence of genetic deletion of Arid1a in adult pancreatic ductal cells in the context of oncogenic PI3K/Akt pathway activation. RESULTS: Simultaneous deletion of Arid1a and Pten in pancreatic ductal cells resulted in the development of ITPN, which progressed to PDAC, in mice. Simultaneous loss of Arid1a and Pten induced dedifferentiation of pancreatic ductal cells and Yes-associated protein 1/Transcriptional coactivator with PDZ-binding motif (YAP/TAZ) pathway activation. Consistent with the mouse data, TAZ expression was found elevated in human ITPNs and ITPN-derived PDACs but not in human intraductal papillary mucinous neoplasms, indicating that activation of the TAZ pathway is a distinctive feature of ITPN. Furthermore, pharmacological inhibition of the YAP/TAZ pathway suppressed the dedifferentiation of pancreatic ductal cells and development of ITPN in Arid1a and Pten double-knockout mice. CONCLUSION: Concurrent loss of Arid1a and Pten in adult pancreatic ductal cells induced ITPN and ITPN-derived PDAC in mice through aberrant activation of the YAP/TAZ pathway, and inhibition of the YAP/TAZ pathway prevented the development of ITPN. These findings provide novel insights into the pathogenesis of ITPN-derived PDAC and highlight the YAP/TAZ pathway as a potential therapeutic target.

Preoperative Endoscopic Minor Papilla Sphincterotomy for Pancreas Divisum in a Patient with Pancreatic Cancer Who Underwent Laparoscopic Distal Pancreatectomy.

BACKGROUND: Pancreas divisum (PD) is a congenital anomaly that occurs due to failure of fusion of the dorsal and ventral pancreatic ductal systems.1-3 In PD, pancreatic juice drains mainly through the minor papilla via the dorsal duct, leading to high intraductal pressure, which can cause pancreatitis.1-3 We report a case of PD that underwent preoperative decompression using endoscopic minor papilla sphincterotomy (EMPS) before laparoscopic distal pancreatectomy (LDP) for pancreatic cancer.3 METHODS: The patient was a 74-year-old woman with pancreatic tail cancer, measuring 35 mm in size, in PD with an entirely dilated dorsal duct, implying high, intraductal pressure caused by minor papillary dysfunction. We performed EMPS to prevent postoperative pancreatitis and pancreatic fistula before LDP using a left-posterior approach, as previously described.4 As the pancreatic transection margin was positive for high-grade pancreatic intraepithelial neoplasia on intraoperative pathology, an additional resection of the pancreatic head to the right side of the portal vein was performed after the liberation of the gastroduodenal artery with both the dorsal and ventral pancreatic ducts ligated and divided. RESULTS: The operative time was 421 min, and blood loss was 70 mL. The postoperative course was uneventful, with no evidence of pancreatitis or pancreatic fistula. The patient was discharged on postoperative Day 10. Postoperative computed tomography revealed reduced dilatation of the dorsal duct. CONCLUSIONS: Preoperative EMPS may be effective in preventing pancreatic fistula after LDP in patients with PD.

Propensity Score Matching Analysis of the Safety of Completion Total Pancreatectomy for Remnant Pancreatic Tumors Versus that of Initial Total Pancreatectomy for Primary Pancreatic Tumors.

BACKGROUND: The safety and feasibility of completion total pancreatectomy (TP) for remnant pancreatic neoplasms remain controversial and are rarely compared with that of initial TP. Thus, we aimed to compare the safety of these two procedures inducing a pancreatic state. METHODS: Patients who underwent TP for pancreatic neoplasms between 2006 and 2018 at our institution were included in this study. Tumor pathologies were classified into three subgroups according to survival curves. We used 1:1 propensity score matching (PSM) to analyze age, sex, Charlson Comorbidity Index, and tumor stage. Finally, we analyzed the primary outcome Clavien-Dindo classification (CDC) grade, risks of other safety-related outcomes, and the survival rate of patients with invasive cancer. RESULTS: Of 54 patients, 16 underwent completion TP (29.6%) and 38 (70.4%) underwent initial TP. Before PSM analysis, age and Charlson Comorbidity Index were significantly higher, and T category and stage were significantly lower for the completion TP group. Upon PSM analysis, these two groups were equivalent in CDC grade [initial TP vs. completion TP: 71.4% (10/14) vs. 78.6% (11/14); p = 0.678] and other safety-related outcomes. Additionally, while the overall survival and recurrence-free survival of patients with invasive cancer were not significantly different between these two groups, the T category and stage tended to be remarkably severe in the initial TP group. CONCLUSIONS: PSM analysis for prognostic factors showed that completion TP and initial TP have similar safety-related outcomes that can be used as a decision-making reference in the surgery of pancreatic tumors.

Is frequent measurement of tumor markers beneficial for postoperative surveillance of colorectal cancer?

PURPOSE: To determine whether frequent measurement of tumor markers triggers early detection of colorectal cancer recurrence. METHODS: Of 1,651 consecutive patients undergoing colorectal cancer surgery between 2010 and 2016, 1,050 were included. CEA and CA 19-9 were considered to be postoperative tumor markers and were measured every 3 months for 3 years, and then every 6 months for 2 years. Sensitivity analysis of elevated CEA and CA19-9 levels and multivariate analysis of factors associated with elevated CEA and CA19-9 levels were performed. The proportion of triggers for detecting recurrence was determined. RESULTS: The median follow-up period was 5.3 years. After applying the exclusion criteria, 1,050 patients were analyzed, 176 (16.8%) of whom were found to have recurrence. After excluding patients with persistently elevated CEA and CA19-9 levels before and after surgery from the 176 patients, 71 (43.6%) of 163 patients had elevated CEA levels and 35 (20.2%) of 173 patients had elevated CA19-9 levels. Sensitivity/positive predictive values for elevated CEA and CA19-9 levels at recurrence were 43.6%/32.3% and 20.2%/32.4%, respectively. Lymph node metastasis was a factor associated with both elevated CEA and CA19-9 levels at recurrence. Of the 176 patients, computed tomography triggered the detection of recurrence in 137 (78%) and elevated tumor marker levels in 13 (7%); the diagnostic lead interval in the latter 13 patients was 1.7 months. CONCLUSION: Tumor marker measurements in surveillance after radical colorectal cancer resection contribute little to early detection, and frequent measurements are unnecessary for stage I patients with low risk of recurrence.

Increased Expressions of Programmed Death Ligand 1 and Galectin 9 in Transplant Recipients Who Achieved Tolerance After Immunosuppression Withdrawal.

Programmed death 1 (PD1)/its ligand PD-L1 concomitant with T cell immunoglobulin and mucin domain-containing protein 3 (TIM-3)/its ligand galectin 9 (Gal-9) and the forkhead box P3 (FOXP3) might be involved in tolerance after liver transplantation (LT). Liver biopsies from 38 tolerant, 19 nontolerant (including 16 samples that triggered reintroduction of immunosuppression [IS] and 19 samples after IS reintroduction), and 38 control LT patients were studied. The expressions of PD1, PD-L1, Gal-9, and FOXP3 were determined by immunohistochemical and immunofluorescence (IF) staining. The success period of IS withdrawal was calculated using Kaplan-Meier curve analysis. Tolerant and control patients exhibited higher PD-L1, Gal-9, and FOXP3 levels than nontolerant patients at the moment of triggering IS reintroduction. High expressions of PD-L1 and Gal-9 were associated with prolonged success of tolerance (83.3% versus 36.7% [P < 0.01] and 73.1% versus 42.9% [P = 0.03]). A strong correlation between PD-L1 and Gal-9 expression levels was detected (Spearman r = 0.73; P ≤ 0.001), and IF demonstrated colocalization of PD-L1 and Gal-9 in the cytoplasm of hepatocytes. In conclusion, the present study demonstrated that increased expressions of PD-L1 and Gal-9 were associated with sustained tolerance after IS withdrawal in pediatric liver transplantation.

Impact of Preoperative CEA Uptrend on Survival Outcomes in Patients with Colorectal Liver Metastasis After Hepatectomy.

BACKGROUND: Preoperative carcinoembryonic antigen (CEA) has been reported as a prognostic factor in patients with colorectal liver metastasis (CRLM) after hepatectomy. However, the impact of a preoperative "CEA uptrend" on prognosis after hepatectomy in these patients remains unknown. This study assessed the impact of CEA uptrend on prognosis in patients undergoing hepatectomy for CRLM. METHODS: Consecutive patients with CRLM who underwent hepatectomy between 2009 and 2018 were retrospectively analyzed. Patients with CRLM for whom CEA was measured both around 1 month before (CEA-1m) and within 3 days (CEA-3d) before hepatectomy were enrolled. A CEA-3d higher than both the upper limit of normal (5 ng/ml) and CEA-1m was defined as a CEA uptrend. RESULTS: Study participants comprised 212 patients with CRLM. Of these, 88 patients (41.5%) showed a CEA uptrend. CEA uptrend indicated better discriminatory ability (corrected Akaike information criteria, 733.72) and homogeneity (likelihood ratio chi-square value, 18.80) than CEA-3d or CEA-1m. Patients with CEA uptrend showed poorer overall survival than those without CEA uptrend (p < 0.001). After adjusting for known prognostic factors, the prognostic significance of CEA uptrend retained (hazard ratio 2.63, 95% confidence interval 1.63-4.26, p < 0.001). In subgroup analyses, the prognostic significance of CEA uptrend was retained irrespective of the status of RAS mutation or response to preoperative chemotherapy. CONCLUSIONS: CEA uptrend offers better prediction of survival outcomes than conventional CEA measurements in patients undergoing hepatectomy for CRLM.

Establishment of patient-derived organoids and a characterization-based drug discovery platform for treatment of pancreatic cancer.

BACKGROUND: Pancreatic cancer is one of the most lethal tumors. The aim of this study is to provide an effective therapeutic discovery platform for pancreatic cancer by establishing and characterizing patient-derived organoids (PDOs). METHODS: PDOs were established from pancreatic tumor surgical specimens, and the mutations were examined using a panel sequence. Expression of markers was assessed by PCR, immunoblotting, and immunohistochemistry; tumorigenicity was examined using immunodeficient mice, and drug responses were examined in vitro and in vivo. RESULTS: PDOs were established from eight primary and metastatic tumors, and the characteristic mutations and expression of cancer stem cell markers and CA19-9 were confirmed. Tumorigenicity of the PDOs was confirmed in subcutaneous transplantation and in the peritoneal cavity in the case of PDOs derived from disseminated nodules. Gemcitabine-sensitive/resistant PDOs showed consistent responses in vivo. High throughput screening in PDOs identified a compound effective for inhibiting tumor growth of a gemcitabine-resistant PDO xenograft model. CONCLUSIONS: This PDO-based platform captures important aspects of treatment-resistant pancreatic cancer and its metastatic features, suggesting that this study may serve as a tool for the discovery of personalized therapies.

Impact of neoadjuvant intensity-modulated radiation therapy on borderline resectable pancreatic cancer with arterial abutment; a prospective, open-label, phase II study in a single institution.

BACKGROUND: Borderline resectable pancreatic cancer (BRPC) is a category of pancreatic cancer that is anatomically widely spread, and curative resection is uncommon with upfront surgery. Intensity-modulated radiation therapy (IMRT) is a form of radiation therapy that delivers precise radiation to a tumor while minimizing the dose to surrounding normal tissues. Here, we conducted a phase 2 study to estimate the curability and efficacy of neoadjuvant chemoradiotherapy using IMRT (NACIMRT) for patients with BRPC with arterial abutment (BRPC-A). METHODS: A total of 49 BRPC-A patients were enrolled in this study and were treated at our hospital according to the study protocol between June 2013 and March 2021. The primary endpoint was microscopically margin-negative resection (R0) rates and we subsequently analyzed safety, histological effect of the treatment as well as survivals among patients with NACIMRT. RESULTS: Twenty-nine patients (59.2%) received pancreatectomy after NACIMRT. The R0 rate in resection patients was 93.1% and that in the whole cohort was 55.1%. No mortality was encountered. Local therapeutic effects as assessed by Evans classification showed good therapeutic effect (Grade 1, 3.4%; Grade 2a, 31.0%; Grade 2b, 48.3%; Grade 3, 3.4%; Grade 4, 3.4%). Median disease-free survival was 15.5 months. Median overall survival in the whole cohort was 35.1 months. The only independent prognostic pre-NACIMRT factor identified was serum carbohydrate antigen 19-9 (CA19-9) > 400 U/ml before NACIMRT. CONCLUSIONS: NACIMRT showed preferable outcome without significant operative morbidity for BRPC-A patients. NACIMRT contributes to good local tumor control, but a high initial serum CA19-9 implies poor prognosis even after neoadjuvant treatment. TRIAL REGISTRATION: UMIN-CTR Clinical Trial: https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000011776 Registration number: UMIN000010113. Date of first registration: 01/03/2013.

Preoperative risk stratification of lymph node metastasis for non-functional pancreatic neuroendocrine neoplasm: An international dual-institutional study.

BACKGROUND: /Objectives: Although the presence of lymph node metastasis (LNM) defines malignant potential, preoperative prediction of LNM has not been established for non-functional pancreatic neuroendocrine neoplasm (NF-PNEN). We sought to develop a prediction system using only preoperatively available factors that would stratify the risk of LNM for NF-PNEN. METHODS: We retrospectively reviewed patients who underwent R0/1 resection of NF-PNEN at Kyoto University (2007-2019) and the University of California, San Francisco (2010-2019). Risk stratification of LNM was developed using preoperative factors by the logistic regression analysis. Long-term outcomes were compared across the risk groups. RESULTS: A total of 131 patients were included in this study. Lymph nodes were pathologically examined in 116 patients, 23 (20%) of whom had LNM. Radiological tumor size [1.5-3.5 cm (odds ratio: 13.5, 95% confidence interval: 1.77-398) and >3.5 cm (72.4, 9.06-2257) against ≤1.5 cm], <50% cystic component (8.46 × 10^6, 1.68 × 10^106-), and dilatation of main pancreatic duct ≥5 mm (31.2, 3.94-702) were independently associated with LNM. When patients were classified as the low-risk (43 patients), intermediate-risk (44 patients), and high-risk groups (29 patients), proportions of LNM differed significantly across the groups (0%, 14%, and 59%, respectively). Recurrence-free survival (RFS) of the low- and intermediate-risk groups were significantly better than that of the high-risk group (5-year RFS rates of 92.2%, 85.4%, and 47.1%, respectively). CONCLUSIONS: The prediction system using preoperative radiological factors stratifies the risk of LNM for NF-PNEN. This stratification helps to predict malignant potential and determine the surgical procedure and necessity of regional lymphadenectomy.

Nationwide registry for patients with neuroendocrine neoplasm of pancreas, gastrointestinal tract, lungs, bronchi, or thymus in Japan.

BACKGROUND: Neuroendocrine neoplasm (NEN) is a comparatively rare tumor that has been considered indolent. Due to these characteristics, detailed epidemiological data have not been analyzed in Japan. To elucidate the present status of NEN diagnosis and treatment in Japan, we started a registry cohort study in January 2015. METHODS: Patients pathologically diagnosed with NENs of the pancreas, gastrointestinal tract, lungs, bronchi, or thymus after January 2012 were enrolled in this registry after the date of ethics review committee approval in each hospital or institute. Follow-up was continued for enrolled patients. RESULTS: During 5 years of enrollment between January 2015 and December 2019, a total of 1526 participants from 63 departments were enrolled in this registry (mean, 305.2 participants/year), covering approximately 5.8% of the annual incidence of NENs in Japan. For pancreatic NEN, 41.9% of patients had metastasis and the dominant metastatic site was the liver, at twice the rate of lymph node metastasis in the current registry. In contrast, the frequency of lymph node metastasis from gastrointestinal (GI)-NEN was similar to that of the liver. The distribution of WHO 2019-based grades varied according to the primary site. Low-to-intermediate grade (G1-G2) was dominant for duodenal, jejunal/ileal, rectal, and pancreatic NENs, whereas high grade (G3 or NEC) was dominant for esophageal, stomach, and colon NENs. For PanNENs, G3 and NEC accounted only for 1.6% and 2.9%, respectively. CONCLUSIONS: These cohort data provide crucial information for clinical research to clarify the characteristics of NENs in Japan.

Potential impact of the adoption of food loss reduction technologies in Indonesia.

This study tried to assess the impact of the food loss reduction on Indonesia's economy and environment. The simulation utilises the Computable General Equilibrium (CGE) model, which simulates the effect of food loss technologies adoption in food crops and livestock sectors. The simulation results indicate that the food loss reduction potentially has a positive impact economically and environmentally. From an economic perspective, applying technology to reduce food loss is estimated to increase Indonesia's GDP by 0.37% (around 88 trillion IDR) by 2030 compared to the BAU level. This economic improvement is mostly driven by the increase in household consumption, which can be increased by around 0.47% by 2030. This result follows that around 40% of household incomes in Indonesia are spent on food expenditure. Food loss reduction holds an important key to increasing food availability and household consumption of foods. Our simulation also indicated some positive effects of food loss reduction on the environment. By reducing the food loss, around 14.19 Mt CO2eq of GHG can also be reduced by 2030, while the cropland needed for food crop cultivation can also be reduced by 3.37% by 2030. Finally, this result highlights the importance of food loss reduction for Indonesia's economy and environment. It is recommended that the government pay serious attention to applying food loss reduction technologies to all food crops in the country.

How ICT can contribute to realize a sustainable society in the future: a CGE approach.

Many information and communications technology (ICT) services have become commonplace worldwide and are certain to continue to spread faster than before, particularly along with the commercialization of 5G and movement restrictions in response to the COVID-19 Pandemic. Although there is a concern that ICT equipment usage may increase power consumption and emit greenhouse gas (GHG) emissions, ICT has also been contributing to reducing GHG emissions through improved productivity and reduced mobility. This research targeted the main ICT services used in Japan and adopted a dynamic national computable general equilibrium model to quantitatively analyze future impacts on economic growth and GHG emission reduction until 2030 by using these ICTs, while considering both the increase in power consumption of ICT itself and the reduction in environmental load in other sectors. The results showed that the spread of ICT services, especially some artificial intelligence-based services, can improve productivity in most sectors through labor-saving and contribute to improving overall gross domestic product (GDP). Additionally, increased efficiency of logistics and manufacturing can greatly reduce the input of oil and coal products and so greatly contribute to GHG emission reduction. In 2030, compared with the baseline scenario in which all technology levels are fixed at current levels, at least 1% additional GDP growth and 4% GHG emission reduction can be expected by the targeted introduction of ICT in the ICT accelerated scenario in which the technology level of ICT accelerates. This also means ICT can potentially decouple the economy from the environment.

SNAIL2 contributes to tumorigenicity and chemotherapy resistance in pancreatic cancer by regulating IGFBP2.

Pancreatic cancer has an extremely poor prognosis because of its resistance to conventional therapies. Cancer stem cell (CSC)-targeted therapy is considered a promising approach for this disease. Epithelial-mesenchymal transition-inducing transcription factors (EMT-TFs) contribute to CSC properties in some solid tumors; however, this mechanism has not been fully elucidated in pancreatic cancer. Zinc finger protein, SNAIL2 (also known as SLUG), is a member of the SNAIL superfamily of EMT-TFs and is commonly overexpressed in pancreatic cancer. Patients exhibiting high SNAIL2 expression have a poor prognosis. In this study, we showed that the suppression of SNAIL2 expression using RNA interference decreased tumorigenicity in vitro (sphere formation assay) and in vivo (xenograft assay) in 2 pancreatic cancer cell lines, KLM1 and KMP5. In addition, SNAIL2 suppression resulted in increased sensitivity to gemcitabine and reduced the expression of CD44, a pancreatic CSC marker. Moreover, experiments on tumor spheroids established from surgically resected pancreatic cancer tissues yielded similar results. A microarray analysis revealed that the mechanism was mediated by insulin-like growth factor (IGF) binding protein 2. These results indicate that IGFBP2 regulated by SNAIL2 may represent an effective therapeutic target for pancreatic cancer.

Liver Transection-First Approach in Hepatopancreatoduodenectomy for Hilar Cholangiocarcinoma: A Safe and Secure Technique for the Early Assessment of Curable Resection and Vascular Reconstruction.

BACKGROUND: Hepatopancreatoduodenectomy (HPD) is often indicated in the resection of cholangiocarcinoma but is associated with high mortality.1-3 From a risk-benefit perspective, HPD can be justified only when curative resection is achievable.4-6 METHODS: A liver transection-first approach is a surgical technique in which liver transection precedes pancreatoduodenectomy (PD) and skeletonization of the hepatoduodenal ligament in HPD. This approach enables an early assessment of resectability and curability. RESULTS: A 64-year-old with jaundice had a tumor located mainly in the proximal bile duct, spreading from the confluence of hepatic ducts (dominant in the left hepatic duct) to the intrapancreatic bile duct. The right hepatic artery and portal vein existed in close proximity to the tumor. HPD (left hemi-hepatectomy and subtotal stomach-preserving PD) with vascular resection was performed. After liver transection along the Cantlie line, the right Glissonean pedicle was collectively secured inside the liver. The right hepatic artery, right portal vein, and right hepatic duct (RHD) were isolated, and the feasibility of vascular reconstruction was confirmed. After the RHD was divided and the negative margin was confirmed, we proceeded to perform PD. The portal vein was reconstructed between the right portal vein and the portal vein trunk. The right hepatic artery was anastomosed to the second jejunal artery of the jejunal loop with the right gastroepiploic artery as an interposition graft. CONCLUSION: The liver transection-first technique in HPD facilitates early assessment of curability and resectability as well as a safe and secure manipulation and reconstruction of the hepatic artery and portal vein.

Impact of vascular abnormality on contrast-enhanced CT and high C-reactive protein levels on postoperative pancreatic hemorrhage after pancreaticoduodenectomy: A multi-institutional, retrospective analysis of 590 consecutive cases.

BACKGROUND: /Objectives: This study aimed to elucidate the efficacy of CT findings and perioperative characteristics to predict post-pancreatectomy hemorrhage (PPH): a critical complication after pancreaticoduodenectomy. METHODS: The records of 590 consecutive patients who underwent pancreaticoduodenectomy at three institutes between 2012 and 2018 were included. The presence of a vascular wall abnormality or ascites with high density (vascular abnormality) on postoperative day (POD) 5-10 contrast-enhanced CT (early CT), perioperative characteristics, and any PPH or pseudoaneurysm formation (PPH events) were analyzed through a multivariate analysis. RESULTS: PPH events occurred in 48 out of 590 patients (8%). The vascular abnormality on early CT and the C-reactive protein (CRP) value on POD 3 were independent risk factors for PPH events after POD5 (vascular abnormality: odds ratio 6.42, p = 0.001; CRP on POD 3: odds ratio 1.17, p = 0.016). The sensitivity of vascular abnormality for PPH events was 24% (7/29), and the positive predictive value was 30% (7/23). The combination of vascular abnormality and a high CRP value (≥15.5 mg/dL) on postoperative day 3 had a higher positive predictive value of 64% (7/11) than the vascular abnormality alone. None of the seven PPH events that occurred more than one month after surgery were foreseen via early CT. CONCLUSION: The combination of vascular abnormality and high CRP value was associated with increasing risk of PPH events after pancreaticoduodenectomy, but the low sensitivity of early CT must be noted as an important shortcoming. The normal findings on early CT could not eliminate the risk of late PPH.

Potential impact of introducing emission mitigation policies in Indonesia: how much will Indonesia have to spend?

Under the Nationally Determined Commitment (NDC), Indonesia voluntarily reduces GHG emission by 29% compared to the BAU level in 2030. While the national economics itself is still growing and advancing, the mitigation policies are expected to slow down the economy at some level. This study is trying to examine the potential impact of the emission mitigation policies on the Indonesian economy by utilizing a dynamic computable general equilibrium (CGE). The simulation result showed that the implementation of comprehensive mitigation technology would cause a GDP loss of around 1.7% by 2030 compared to the BAU level. If we look at the sectoral GDP, the agriculture sector is projected to experiencing the most significant shock by the emission mitigation policies (- 13.4% compared to BAU level by 2030). But the energy sector might become a sector experiencing higher GDP under the mitigation action (3.5% compared to BAU level by 2030). It also showed that the utilization of renewable energies for power generation would increase significantly, especially after 2025, but still cannot fully replace the dominance of fossil fuel sources. There are several policy recommendations based on our simulation results, including that the government also needs to increase efficiency in using fossil fuels, especially coal and gas, during the process of building infrastructure for renewable energy utilization. In terms of employment, the government needs to prepare other sectors to absorb labor, especially from the agricultural sector. Another crucial thing is that considering the possible economic impact, especially in the mid-term period, the government needs to implement necessary mitigation policies immediately. Otherwise, the government may need to prepare more expenditure to introduce more technologies and policies in the future.

Recent epidemiology of patients with gastro-entero-pancreatic neuroendocrine neoplasms (GEP-NEN) in Japan: a population-based study.

BACKGROUND: The worldwide prevalence and incidence of neuroendocrine neoplasms (NEN) have been increasing recently, although few studies have analyzed data on the current situation of NENs in Japan. Here, the Japan Neuroendocrine Tumor Society (JNETS) planned to investigate the recent incidence and distribution of these tumors using data from the national cancer registry started in 2016. This study examined the incidence and distribution of primary sites as well as rate of advanced disease from this population-based registry. METHODS: A retrospective, population-based study using data from the national cancer registry in Japan (NCR) was conducted to evaluate patients with gastro-entero-pancreatic NEN (GEP-NEN) in 2016. Associated population data were used to determine annual age-adjusted incidences. RESULTS: A total of 6735 individuals were diagnosed with GEP-NEN in Japan in 2016. Annual onset incidence was 0.70/100,000 for pancreatic NEN and 2.84/100,000 for gastrointestinal NEN. NEN in the ileum accounted for only 1% of total GEP-NENs in Japan. Most NENs in the esophagus or lungs were neuroendocrine carcinomas (NECs), while the majority of those in the duodenum, ileum, appendix and rectum were grade 1 neuroendocrine tumors (NETs). Median age at initial diagnosis was in between 60 to 65. Tumors in the duodenum, appendix and rectum were mostly limited to local, while those in the esophagus, stomach and colon tended to show distant metastasis. In Japan, initial treatment for GEP-NENs was resection even if the tumor was NEC. CONCLUSIONS: This is the first report of a national registry-based incidence and distribution of GEP-NEN in Japan. These data will serve as an important first step to determining the exact etiology and trends for this pathology in Japan.