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Hyperglycaemia is a well-known initial symptom in patients with pancreatic ductal adenocarcinoma (PDAC). Metabolic reprogramming in cancer, described as the Warburg effect, can induce epithelial-mesenchymal transition (EMT).The biological impact of hyperglycaemia on malignant behaviour in PDAC was examined by in vitro and in vivo experiments.Hyperglycaemia promoted EMT by inducing metabolic reprogramming into a glycolytic phenotype via yes-associated protein (YAP)/PDZ-binding motif (TAZ) overexpression, accompanied by GLUT1 overexpression and enhanced phosphorylation Akt in PDAC. In addition, hyperglycaemia enhanced chemoresistance by upregulating ABCB1 expression and triggered PDAC switch into pure basal-like subtype with activated Hedgehog pathway (GLI1 high, GATA6 low expression) through YAP/TAZ overexpression. PDAC is characterised by abundant stroma that harbours tumour-promoting properties and chemoresistance. Hyperglycaemia promotes the production of collagen fibre-related proteins (fibronectin, fibroblast activation protein, COL1A1 and COL11A1) by stimulating YAP/TAZ expression in cancer-associated fibroblasts (CAFs). Knockdown of YAP and/or TAZ or treatment with YAP/TAZ inhibitor (K975) abolished EMT, chemoresistance and a favourable tumour microenvironment even under hyperglycemic conditions in vitro and in vivo.Hyperglycaemia induces metabolic reprogramming into glycolytic phenotype and promotes EMT via YAP/TAZ-Hedgehog signalling axis, and YAP/TAZ could be a novel therapeutic target in PDAC.

Pancreatic ductal adenocarcinoma (PDAC) remains the most lethal type of cancer. The 5-year survival rate for patients with early-stage diagnosis can be as high as 20%, suggesting that early diagnosis plays a pivotal role in the prognostic improvement of PDAC cases. In the medical field, the broad availability of biomedical data has led to the advent of the "big data" era. To overcome this deadly disease, how to fully exploit big data is a new challenge in the era of precision medicine. Artificial intelligence (AI) is the ability of a machine to learn and display intelligence to solve problems. AI can help to transform big data into clinically actionable insights more efficiently, reduce inevitable errors to improve diagnostic accuracy, and make real-time predictions. AI-based omics analyses will become the next alterative approach to overcome this poor-prognostic disease by discovering biomarkers for early detection, providing molecular/genomic subtyping, offering treatment guidance, and predicting recurrence and survival. Advances in AI may therefore improve PDAC survival outcomes in the near future. The present review mainly focuses on recent advances of AI in PDAC for clinicians. We believe that breakthroughs will soon emerge to fight this deadly disease using AI-navigated precision medicine.

Background/aim Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignant tumor. Research using an innovative research approach is needed to identify effective biomarkers or therapeutic targets for PDAC. We aimed to identify proteins related to the peritoneal dissemination of PDAC. Materials and methods We performed proteomic analysis using ascites samples from patients with advanced PDAC and peritoneal dissemination and patients with liver cirrhosis (LC). Proteins specific to PDAC were identified in comparison to the findings for ascites from patients with LC as a control group. Results In total, 336 proteins were identified in ascites from patients with PDAC. We identified 18 specific proteins in ascites from patients with advanced PDAC. Among these proteins, CD13, lymphatic vessel endothelial hyaluronan receptor 1, ficolin-3, and V-set and immunoglobulin domain containing 4 were the most frequently detected. In addition, these 18 proteins could be classified into four categories: extracellular matrix, immunity, metabolism, and others. Conclusion The identified proteins could be informative for developing treatment strategies for patients with PDAC and peritoneal dissemination.

Background: Pancreatic cancer is a serious life-threatening disease due to its highly invasive and metastatic potential. Hyperglycemia is a well-known initial symptom in patients with pancreatic ductal adenocarcinoma (PDAC). Metabolic reprogramming in cancer, described as the Warburg effect, can induce epithelial-mesenchymal transition (EMT). In this study, we elucidate the biological and clinical impact of hyperglycemia in PDAC progression. Methods: Biological impact of hyperglycemia on malignant behavior in PDAC was examined by in vitro and in vivoexperiment. Results: Hyperglycemia promoted EMT by inducing metabolic reprogramming into a glycolytic phenotype via yes-associated protein (YAP)/PDZ-binding motif (TAZ) overexpression, accompanied by GLUT1 overexpression and enhanced phosphorylation Akt in PDAC. In addition, hyperglycemia enhanced chemoresistance by upregulating ABCB1 expression, and triggered PDAC switch into pure-basal-like subtype with activated Hedgehog pathway (GLI1 high, GATA6 low expression) through YAP/TAZ overexpression. PDAC is characterized by abundant stroma that harbors tumor-promoting properties and chemoresistance. Hyperglycemia promotes production of collagen fiber-related proteins (fibronectin, fibroblast activation protein, COL1A1, and COL11A1) by stimulating YAP/TAZ expression in cancer-associated fibroblasts (CAFs). Knockdown of YAP and/or TAZ or treatment with YAP/TAZ inhibitor (K975) abolished EMT, chemoresistance, and a favorable tumor microenvironment even under hyperglycemic conditions in vitro and in vivo. Indeed, YAP/TAZ overexpression was significantly associated with worse prognostic outcomes in human PDAC patients. Conclusion: Hyperglycemia induce metabolic reprogramming into a glycolytic phenotype and promote EMT via the YAP/TAZ-Hedgehog signaling axis in PDAC. Hyperglycemia as an initial symptom may be the cause of highly invasive and metastatic potential by inducing YAP/TAZ overexpression, while YAP/TAZ could be a novel therapeutic target in PDAC patients. Citation Format: Zhao Liu, Hiromitsu Hayashi, Kazuki Matsumura, Yoko Ogata, Hiroki Sato, Yuta Shiraishi, Norio Uemura, Tatsunori Miyata, Takaaki Higashi, Shigeki Nakagawa, Kosuke Mima, Katsunori Imai, Hideo Baba. Hyperglycemia induces metabolic reprogramming and promotes epithelial-mesenchymal transitions in pancreatic cancer: an in vitro and in vivo experiment. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3709.

Background/aim The aim of this study was to elucidate the clinical impact of coagulation disorders on outcomes after curative resection of pancreatic ductal adenocarcinoma. Patients and methods Preoperative coagulation activity in 135 patients, who had undergone curative resections for pancreatic ductal adenocarcinoma was retrospectively evaluated and the impact on survival outcomes analyzed. Results A prolonged prothrombin time-international normalized ratio (PT-INR) (≥1.1) was detected in 23/135 patients (17%). Univariate analysis that showed prolonged PT-INR was associated with worse relapse-free (hazard ratio=1.79, p=0.044) and overall (hazard ratio=2.18, p=0.004) survival. Multivariate analyses showed prolonged PT-INR, large tumor (>30 mm), and lymph node metastasis were independent predictors of poor overall survival. Conclusion Prolonged PT-INR may be a predictor of poor prognosis in patients with pancreatic ductal adenocarcinoma who have undergone curative resection. Coagulation disorders may be a therapeutic target for improving outcomes of pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer type as it is prone to metastases and is difficult to diagnose at an early stage. Despite advances in molecular detection, its clinical prognosis remains poor and it is expected to become the second leading cause of cancer-related deaths. Approximately 85% of patients develop glucose metabolism disorders, most commonly diabetes mellitus, within three years prior to their pancreatic cancer diagnosis. Diabetes, or glucose metabolism disorders related to PDAC, are typically associated with insulin resistance, and beta cell damage, among other factors. From the perspective of molecular regulatory mechanisms, glucose metabolism disorders are closely related to PDAC initiation and development and to late invasion and metastasis. In particular, abnormal glucose metabolism impacts the nutritional status and prognosis of patients with PDAC. Meanwhile, preliminary research has shown that metformin and statins are effective for the prevention or treatment of malignancies; however, no such effect has been shown in clinical trials. Hence, the causes underlying these conflicting results require further exploration. This review focuses on the clinical significance of glucose metabolism disorders in PDAC and the mechanisms behind this relationship, while also summarizing therapeutic approaches that target glycolysis.

Whether perioperative allogeneic blood transfusion (PABT) negatively influences patient survival after hepatectomy (HR) for hepatocellular carcinoma (HCC) remains controversial. Five hundred two patients who underwent HR for initial HCC between 1994 and 2015 were enrolled in this study. All patients were divided into two groups: the PABT group and the non-PABT group. Differences of clinicopathological factors, overall survival (OS), recurrence-free survival (RFS), and the recurrence pattern between the two groups were evaluated. Using propensity score matching for tumor-related factors, liver functions, and surgical factors (total 11 factors), the survival impact of PABT was also analyzed. In the entire cohort, 78 patients (15.5%) received PABT such as red cell concentrate, fresh-frozen plasma, or platelets. OS (5-year OS: 55% vs. 76%; p = 0.0005) and RFS (2-year RFS: 47% vs. 56%; p = 0.0131) were significantly worse in the PABT group. The extrahepatic recurrence happened more frequently in the PABT group (15% vs. 5.4%; p = 0.0039). There were many significant clinicopathological differences between the two groups: more advanced tumor stage (tumor diameter, stage III or IV, microvascular invasion), worse liver functions (albumin, indocyanine green retention rate at 15 min), and more surgical stress (blood loss, operation time) in the PABT group. After propensity score matching, 43 pairs of patients were extracted. In this matched cohort, the survival curves of the PABT and non-PABT groups almost completely overlapped both in OS (5-year OS: 62% vs. 62%; p = 0.4384) and in RFS (2-year RFS: 49% vs. 47%; p = 0.8195). The significant difference of the extrahepatic recurrence rate disappeared in the matched cohort (p = 0.5789). Using propensity score matching, we found that PABT does not influence patient survival after HR for HCC.

Background Radiofrequency ablation (RFA) is widely used as a minimally invasive treatment for hepatocellular carcinoma (HCC). RFA has a low risk of complications, especially compared with liver resection. Nevertheless, various complications have been reported after RFA for HCC; however, diaphragmatic hernia (DH) is extremely rare. Case presentation A 78-year-old man underwent thoracoscopic RFA for HCC located at the medial segment adjacent to the diaphragm approximately 7 years before being transported to the emergency department due complaints of nausea and abdominal pain. Computed tomography revealed a prolapsed small intestine through a defect in the right diaphragm, and emergency surgery was performed. The cause of diaphragmatic hernia was the scar of RFA. We confirmed that the small intestine had prolapsed into the right diaphragm, and we resected the necrotic small intestine and repaired the right diaphragm. Herein, we report a case of ileal strangulation due to diaphragmatic hernia after thoracoscopic RFA. Conclusions Care should be taken when performing thoracoscopic RFA, especially for tumors located on the liver surface adjacent to the diaphragm. Patients should be carefully followed up for possible DH, even after a long postoperative interval.

With population aging, the number of frail patients with pancreatic cancer has increased. The Clinical Frailty Scale (CFS) is a simple and validated tool to assess frailty, and higher scores predict worse clinical outcomes after cardiovascular surgery. In this retrospective study, we aimed to examine the association of preoperative frailty with prognosis after resection for pancreatic cancer. We retrospectively analyzed data from 142 consecutive patients undergoing resection for pancreatic cancer between April 2010 and December 2018. We used the CFS: 1 (very fit) to 9 (terminally ill) to assess frailty and examined associations of the CFS scores with recurrence-free survival (RFS), cancer-specific survival (CSS), and overall survival (OS). Multivariable Cox proportional hazards models were used to calculate hazard ratios (HRs), controlling for potential confounders. Of the 142 patients, 113 (80%) had CFS scores of ≤ 3, 13 (9.2%) scores of 4, and 16 (11%) scores of ≥ 5. Scores of ≥ 5 on the CFS were associated with worse CSS (univariable HR: 2.62, 95% confidence interval [CI]: 1.19–5.18, P = 0.019; multivariable HR: 2.49, 95% CI 1.05–5.34, P = 0.039) and OS (univariable HR: 2.42, 95% CI 1.19–4.46, P = 0.016; multivariable HR: 2.25, 95% CI 1.05–4.43, P = 0.038). The association between CFS scores and RFS was not significant in multivariable analysis (univariable HR: 2.11, 95% CI 1.08–3.79, P = 0.030; multivariable HR: 1.47, 95% CI 0.71–2.83, P = 0.29). Higher scores on the CFS are associated with worse CSS and OS after resection for pancreatic cancer. Preoperative measurement of frailty may improve risk assessment among patients with pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal types of cancer. Despite major advances in defining the molecular mutations driving PDAC, this disease remains universally lethal with an overall 5-year survival rate of only about 7–8%. Genetic alterations in PDAC are exemplified by four critical genes (KRAS, TP53, CDKN2A, and SMAD4) that are frequently mutated. Among these, KRAS mutation ranges from 88% to 100% in several studies. Hippo signaling is an evolutionarily conserved network that plays a key role in normal organ development and tissue regeneration. Its core consists of the serine/threonine kinases mammalian sterile 20-like kinase 1 and 2 (MST1/2) and large tumor suppressor 1 and 2. Interestingly, pancreas-specific MST1/2 double knockout mice have been reported to display a decreased pancreas mass. Many of the genes involved in the Hippo signaling pathway are recognized as tumor suppressors, while the Hippo transducers Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) are identified as oncogenes. By dephosphorylation, YAP and TAZ accumulate in the nucleus and interact with transcription factors such as TEA domain transcription factor-1, 2, 3, and 4. Dysregulation of Hippo signaling and activation of YAP/TAZ have been recognized in a variety of human solid cancers, including PDAC. Recent studies have elucidated that YAP/TAZ play a crucial role in the induction of acinar-to-ductal metaplasia, an initial step in the progression to PDAC, in genetically engineered mouse models. YAP and TAZ also play a key role in the development of PDAC by both KRAS-dependent and KRAS-independent bypass mechanisms. YAP/TAZ have become extensively studied in PDAC and their biological importance during the development and progression of PDAC has been uncovered. In this review, we summarize the biological significance of a dysregulated Hippo signaling pathway or activated YAP/TAZ in PDAC and propose a role for YAP/TAZ as a therapeutic target.

Background Postoperative complications after pancreaticoduodenectomy (PD) is still a major concern. The aim of this study was to propose how to choose antibiotics, based on bacterial sensitivity profiling involved in postoperative complications after PD. Methods Two hundred and thirty patients underwent PD between 2008 and 2018 at Kumamoto University Hospital. We enrolled 121 patients who had both intraoperative bile culture and drain culture on postoperative day (POD) 3. The clinical impact of the bacterial profile on postoperative outcome was retrospectively analyzed. Results Multivariate regression analysis revealed that intraperitoneal contamination on POD3 was independently associated with postoperative complications (odds ratio 2.62, P =0.02). The bacteria in intraperitoneal drain on POD3 showed 94.9% similarity with those in bile collected during surgery. The major species were Enterococcus (44.6%) and Enterobacter (38.5%). Enterobacter species caused a higher rate of postoperative complications than others (83% vs 54%, P =0.04). Three out of five Enterococcus faecium were resistant to carbapenems that were active against all Gram-negative rods. Conclusions Intraperitoneal contamination on POD3, which had similar bacterial species as bile collected during surgery, was correlated with postoperative complications. The bacterial antibiotic sensitivity profile may help selecting optimal antibiotics against infectious postoperative complications in PD.

MicroRNA (miRNA) expression abnormalities are implicated in tumor progression. Previous reports have indicated that microRNA-25 (miR-25) acts as a tumor suppressor or oncogene in diverse cancers. However, its molecular mechanisms in hepatocellular carcinoma (HCC) are still unclear. F-box and WD repeat domain 7 (Fbxw7) is a critical tumor suppressor and is one of the most important deregulated proteins of the ubiquitin–proteasome system in cancer. Our objective was to elucidate the role of miR-25 and Fbxw7 in HCC and to clarify the mechanism by which Fbxw7 is regulated. Fbxw7 expression was estimated in 210 fixed paraffin-embedded HCC samples by immunohistochemistry, and miR-25 expression was evaluated in 142 frozen HCC tissue samples by quantitative real-time PCR. Oncogenic functions of miR-25 and its role in the regulation of Fbxw7 expression were assayed in vitro. miR-25 was overexpressed in HCC tissue compared with adjacent normal tissue and significantly correlated with a poorer prognosis. Moreover, it was inversely correlated with Fbxw7 expression in HCC tissues. Furthermore, miR-25 inhibition significantly reduced the proliferation, migration, and invasion of HCC cells in vitro. miR-25 may promote tumor progression in HCC patients by repression of Fbxw7 and could serve as a promising molecular target for HCC treatment.

Background Schwannomas originate from Schwann cells, which are constituents of peripheral nerve sheaths, and can occur anywhere in the body at any age. Most occur in soft tissues such as subcutaneous tissues and muscles, occurrence in the abdominal cavity being relatively rare. In particular, schwannomas of the gallbladder are extremely rare. We herein report a rare case of a schwannoma that coexisted with systemic sarcoidosis and presented as a steroid-resistant mass in the gallbladder wall. Case presentation A 40-year-old woman was found to have thickening of the gallbladder wall during a routine medical examination and was referred to our hospital, where she was found to have granular shadows in the lungs; mediastinal, cervical, intraperitoneal, and inguinal lymphadenopathy; parotid gland enlargement; and an erythematous skin rash. She was diagnosed as having systemic sarcoidosis by transbronchial lung biopsy and bronchoalveolar lavage. All her systemic mass lesions except for the one in the gallbladder resolved or became smaller with steroid treatment. The steroid-resistant gallbladder lesion showed enhancement on contrast-enhanced computed tomography and was shown by endoscopic ultrasonography to be a 30-mm-diameter gallbladder wall lesion. We performed laparoscopic cholecystectomy, which resulted in diagnosis of the steroid-resistant tumor as a schwannoma. Five months after surgery, the patient’s prednisolone dosage had been gradually reduced to 5 mg/day and she was doing well with no evidence of recurrence. Conclusion Resection of a steroid-resistant tumor resulted in diagnosis of schwannoma, enabling reduction in the patient’s steroid dosage for sarcoidosis.

Aim: The objective of this study was to examine the clinical and biological significance of CD44 expression in conversion hepatectomy for initially unresectable colorectal liver metastases. Methods: Fifty-four patients who received chemotherapy followed by hepatectomy (conversion hepatectomy) for initially unresectable liver metastases were enrolled. CD44 expression and its clinical significance were examined in 52 resected specimens; two specimens revealed no residual cancer cells. The biological significance of CD44 expression in the chemoresistance response to fluorouracil, oxaliplatin or irinotecan, three major anti-cancer agents for colon cancer in the clinical setting, was examined using colon cancer cell lines. Results: Membrane CD44 expression in the residual cancer cells after chemotherapy for colorectal liver metastases was detectable in 19 patients (37%), and was significantly associated with high proliferative activity represented by Ki-67 expression (P = 0.003). CD44 expression was also significantly associated with shorter disease-free survival and worse overall survival after hepatectomy (hazard ratio and P-values were 2.570, 0.007 and 3.457, 0.026, respectively). In SW480 and HT29 colon cancer cells, siRNA-mediated CD44 knockdown attenuated cell growth. Additionally, CD44 knockdown overcame chemoresistance in response to fluorouracil and oxaliplatin with enhanced apoptosis and p27 upregulation, respectively. For irinotecan, CD44 knockdown showed no additional effect in chemoresistance. Conclusions: CD44 enhances chemoresistance in response to anti-cancer drugs (fluorouracil and oxaliplatin) in colon cancer cells. CD44 expression in liver metastases after chemotherapy implies the presence of occult micrometastases and is a worse prognostic factor in patients with conversion hepatectomy for initially unresectable colorectal liver metastases.

Background Portal vein embolization has been used worldwide to induce hypertrophy of the future liver remnant and to reduce the risk of hepatic insufficiency and death after major hepatectomy. However, whether disease progression after portal vein embolization can affect long-term oncologic outcomes in patients with hepatocellular carcinoma is uncertain. Methods From a total of 107 patients who underwent portal vein embolization and subsequent hepatectomy between 2000 and 2016, 57 patients with hepatocellular carcinoma were enrolled. We evaluated their long-term oncologic outcomes and investigated whether the disease progression between portal vein embolization and subsequent hepatectomy affected survival. Results The 5-year overall survival and disease-free survival after hepatectomy were 74.5% and 31.7%, respectively. Multivariate analyses revealed that tumor number before hepatectomy ≥3 (hazard ratio 3.59, P = .019), des-γ-carboxy prothrombin >200 mAU/mL (hazard ratio 3.36, P = .045), and red blood cell transfusion (hazard ratio 11.03, P = .0008) were independent prognostic factors for overall survival. Male sex (hazard ratio 3.74, P = .029), bilobar tumor distribution (hazard ratio 3.65, P = .004), and red blood cell transfusion (hazard ratio 6.22, P = .0026) were independent prognostic factors for disease-free survival. Disease progressions after portal vein embolization, including increases in tumor size, tumor number, α-fetoprotein, lens culinaris agglutinin-reactive fraction of α-fetoprotein, and des-γ-carboxy prothrombin, were observed in 22.8%, 14.0%, 29.8%, 19.3%, and 47.4% of patients, respectively. Only an increase of tumor number significantly decreased the disease-free survival rate after hepatectomy in a univariate analysis, and none of the variables affected overall survival. Conclusion Disease progression after portal vein embolization did not affect long-term survival in patients with hepatocellular carcinoma if the planned subsequent hepatectomy could be completed.

A 62-year-old man was underwent sigmoidectomy for sigmoid colon cancer(T3N1H0P0, Stage III a). He received a postoperative systemic chemotherapy with SOX. Five months after the operation, multiple liver metastases were detected by CT scan. Systemic chemotherapy(bevacizumab and SOX, bevacizumab and FOLFIRI)did not reduce the liver metastases. So 4 courses of hepatic arterial infusion(HAI)chemotherapy with CDDP 10mg/day and 5-FU 500mg/day for 2weeks were performed without severe adverse events. All the liver metastases decreased in size remarkably, and the hepatic resection was able to be performed. We think HAI chemotherapy is one of the useful options for resistance to systemic chemotherapy for liver metastases from colorectal cancer.

Background The most common pattern of recurrence of gastric cancer (GC) is peritoneal dissemination. However, rectal metastasis via hematogenous or lymphatic spread is exceedingly rare. We present a case of a 65-year-old man with an intramucosal GC who developed a rectal recurrence, possibly via a hematogenous route. Case presentation A 65-year-old man underwent curative endoscopic submucosal dissections for the intramucosal GCs at the anterior wall of the fornix twice. The third GC at the similar location was treated by radical laparoscopic proximal gastrectomy; microscopic examination revealed well-differentiated tubular adenocarcinoma confined to the lamina propria mucosae (T1aN0M0, stage IA). Follow-up colonoscopy revealed a 30-mm submucosal mass in the rectal wall 2 years later, and a metastasis of gastric origin was suspected histopathologically. After a staging laparoscopy confirmed the absence of findings suggestive of serosal involvement or peritoneal dissemination, including negative peritoneal washing cytology, a laparoscopic low anterior resection with lymph node dissection was performed. Microscopically, the tumor was found to mainly be located in the submucosal layer and showed features of moderately differentiated tubular adenocarcinoma. The serosal surface was free of disseminated tumor. Lymph node metastases were identified. Immunohistochemically, there were foci of carcinoma cells that were positive for cytokeratin 20; however, they were negative for cytokeratin 7. Negative staining for caudal-type homeobox 2, a transcription factor indicating goblet cell differentiation, combined with absence of intramucosal carcinoma in the rectal mucosa, suggested a diagnosis of metastatic adenocarcinoma of gastric origin. The absence of evidence of peritoneal dissemination suggested hematogenous or lymphatic spread. Conclusion Although rectal metastasis from GC, particularly when attributable to hematologic or lymphatic metastasis, is very rare, metastatic gastric adenocarcinoma should be considered as a differential diagnosis for patients who present with a rectal tumor and a past history of GC, even if it is an early GC.