Pancreatic cancer is a highly lethal disease, for which mortality closely parallels incidence. Most patients with pancreatic cancer remain asymptomatic until the disease reaches an advanced stage. There is no standard programme for screening patients at high risk of pancreatic cancer (eg, those with a family history of pancreatic cancer and chronic pancreatitis). Most pancreatic cancers arise from microscopic non-invasive epithelial proliferations within the pancreatic ducts, referred to as pancreatic intraepithelial neoplasias. There are four major driver genes for pancreatic cancer: KRAS, CDKN2A, TP53, and SMAD4. KRAS mutation and alterations in CDKN2A are early events in pancreatic tumorigenesis. Endoscopic ultrasonography and endoscopic ultrasonography-guided fine-needle aspiration offer high diagnostic ability for pancreatic cancer. Surgical resection is regarded as the only potentially curative treatment, and adjuvant chemotherapy with gemcitabine or S-1, an oral fluoropyrimidine derivative, is given after surgery. FOLFIRINOX (fluorouracil, folinic acid [leucovorin], irinotecan, and oxaliplatin) and gemcitabine plus nanoparticle albumin-bound paclitaxel (nab-paclitaxel) are the treatments of choice for patients who are not surgical candidates but have good performance status.

The Tokyo Guidelines 2013 (TG13) for acute cholangitis and cholecystitis were globally disseminated and various clinical studies about the management of acute cholecystitis were reported by many researchers and clinicians from all over the world. The 1 st edition of the Tokyo Guidelines 2007 (TG07) was revised in 2013. According to that revision, the TG13 diagnostic criteria of acute cholecystitis provided better specificity and higher diagnostic accuracy. Thorough our literature search about diagnostic criteria for acute cholecystitis, new and strong evidence that had been released from 2013 to 2017 was not found with serious and important issues about using TG13 diagnostic criteria of acute cholecystitis. On the other hand, the TG13 severity grading for acute cholecystitis has been validated in numerous studies. As a result of these reviews, the TG13 severity grading for acute cholecystitis was significantly associated with parameters including 30-day overall mortality, length of hospital stay, conversion rates to open surgery, and medical costs. In terms of severity assessment, breakthrough and intensive literature for revising severity grading was not reported. Consequently, TG13 diagnostic criteria and severity grading were judged from numerous validation studies as useful indicators in clinical practice and adopted as TG18/TG13 diagnostic criteria and severity grading of acute cholecystitis without any modification. Free full articles and mobile app of TG18 are available at: http:// www.jshbps.jp/modules/en/index.php?content_id=47. Related clinical questions and references are also included.

Despite recent efforts to dissect the inter-tumor heterogeneity of pancreatic ductal adenocarcinoma (PDAC) by determining prognosis-predictive gene expression signatures for specific subtypes, their functional differences remain elusive. Here, we established a pancreatic tumor organoid library encompassing 39 patient-derived PDACs and identified 3 functional subtypes based on their stem cell niche factor dependencies on Wnt and R-spondin. A Wnt-non-producing subtype required Wnt from cancer-associated fibroblasts, whereas a Wnt-producing subtype autonomously secreted Wnt ligands and an R-spondin-independent subtype grew in the absence of Wnt and R-spondin. Transcriptome analysis of PDAC organoids revealed gene-expression signatures that associated Wnt niche subtypes with GATA6-dependent gene expression subtypes, which were functionally supported by genetic perturbation of GATA6. Furthermore, CRISPR-Cas9-based genome editing of PDAC driver genes (KRAS, CDKN2A, SMAD4, and TP53) demonstrated non-genetic acquisition of Wnt niche independence during pancreas tumorigenesis. Collectively, our results reveal functional heterogeneity of Wnt niche independency in PDAC that is non-genetically formed through tumor progression.

Despite its longer procedure time and higher perforation rate, ESD resulted in higher en bloc resection and curative rates compared with EMR and all ESD perforations were successfully managed by conservative endoscopic treatment.

We propose a new flowchart for the treatment of acute cholecystitis (AC) in the Tokyo Guidelines 2018 (TG18). Grade III AC was not indicated for straightforward laparoscopic cholecystectomy (Lap-C). Following analysis of subsequent clinical investigations and drawing on Big Data in particular, TG18 proposes that some Grade III AC can be treated by Lap-C when performed at advanced centers with specialized surgeons experienced in this procedure and for patients that satisfy certain strict criteria. For Grade I, TG18 recommends early Lap-C if the patients meet the criteria of Charlson comorbidity index (CCI) ≤5 and American Society of Anesthesiologists physical status classification (ASA-PS) ≤2. For Grade II AC, if patients meet the criteria of CCI ≤5 and ASA-PS ≤2, TG18 recommends early Lap-C performed by experienced surgeons; and if not, after medical treatment and/or gallbladder drainage, Lap-C would be indicated. TG18 proposes that Lap-C is indicated in Grade III patients with strict criteria. These are that the patients have favorable organ system failure, and negative predictive factors, who meet the criteria of CCI ≤3 and ASA-PS ≤2 and who are being treated at an advanced center (where experienced surgeons practice). If the patient is not considered suitable for early surgery, TG18 recommends early/urgent biliary drainage followed by delayed Lap-C once the patient's overall condition has improved. Free full articles and mobile app of TG18 are available at:

The JPN Guidelines 2015 were prepared using the most up-to-date methods, and including the latest recommended medical treatments, and we are confident that this will make them easy for many clinicians to use, and will provide a useful tool in the decision-making process for the treatment of patients, and optimal medical support. The free mobile application and calculator for the JPN Guidelines 2015 is available via http://www.jshbps.jp/en/guideline/jpn-guideline2015.html.

Although the diagnostic and severity grading criteria on the 2013 Tokyo Guidelines (TG13) are used worldwide as the primary standard for management of acute cholangitis (AC), they need to be validated through implementation and assessment in actual clinical practice. Here, we conduct a systematic review of the literature to validate the TG13 diagnostic and severity grading criteria for AC and propose TG18 criteria. While there is little evidence evaluating the TG13 criteria, they were validated through a large-scale case series study in Japan and Taiwan. Analyzing big data from this study confirmed that the diagnostic rate of AC based on the TG13 diagnostic criteria was higher than that based on the TG07 criteria, and that 30-day mortality in patients with a higher severity based on the TG13 severity grading criteria was significantly higher. Furthermore, a comparison of patients treated with early or urgent biliary drainage versus patients not treated this way showed no difference in 30-day mortality among patients with Grade I or Grade III AC, but significantly lower 30-day mortality in patients with Grade II AC who were treated with early or urgent biliary drainage. This suggests that the TG13 severity grading criteria can be used to identify Grade II patients whose prognoses may be improved through biliary drainage. The TG13 severity grading criteria may therefore be useful as an indicator for biliary drainage as well as a predictive factor when assessing the patient's prognosis. The TG13 diagnostic and severity grading criteria for AC can provide results quickly, are minimally invasive for the patients, and are inexpensive. We recommend that the TG13 criteria be adopted in the TG18 guidelines and used as standard practice in the clinical setting. Free full articles and mobile app of TG18 are available at: http://www.jshbps.jp/modules/en/index.php?content_id=47. Related clinical questions and references are also included.

Since its publication in 2007, the Tokyo Guidelines for the management of acute cholangitis and cholecystitis (TG07) have been widely adopted. The validation of TG07 conducted in terms of clinical practice has shown that the diagnostic criteria for acute cholecystitis are highly reliable but that the definition of definite diagnosis is ambiguous. Discussion by the Tokyo Guidelines Revision Committee concluded that acute cholecystitis should be suspected when Murphy's sign, local inflammatory findings in the gallbladder such as right upper quadrant abdominal pain and tenderness, and fever and systemic inflammatory reaction findings detected by blood tests are present but that definite diagnosis of acute cholecystitis can be made only on the basis of the imaging of ultrasonography, computed tomography or scintigraphy (HIDA scan). These proposed diagnostic criteria provided better specificity and accuracy rates than the TG07 diagnostic criteria. As for the severity assessment criteria in TG07, there is evidence that TG07 resulted in clarification of the concept of severe acute cholecystitis. Furthermore, there is evidence that severity assessment in TG07 has led to a reduction in the mean duration of hospital stay. As for the factors used to establish a moderate grade of acute cholecystitis, such as leukocytosis, ALP, old age, diabetes, being Electronic supplementary material The online version of this article