ABSTRACT
Malignant ascites accompanied by peritoneal dissemination contain various factors and cell populations as well as cancer cells; however, how the tumor microenvironment is shaped in ascites remains unclear. Single-cell proteomic profiling and a comprehensive proteomic analysis are conducted to comprehensively characterize malignant ascites. Here, we find defects in immune effectors along with immunosuppressive cell accumulation in ascites of patients with gastric cancer (GC) and identify five distinct subpopulations of CD45(-)/EpCAM(-) cells. Mesothelial cells with mesenchymal features in CD45(-)/EpCAM(-) cells are the predominant source of chemokines involved in immunosuppressive myeloid cell (IMC) recruitment. Moreover, mesothelial-mesenchymal transition (MMT)-induced mesothelial cells strongly express extracellular matrix (ECM)-related genes, including tenascin-C (TNC), enhancing metastatic colonization. These findings highlight the definite roles of the mesenchymal cell population in the development of a protumorigenic microenvironment to promote peritoneal dissemination.
Subject(s)
Ascites , Peritoneal Neoplasms , Humans , Ascites/pathology , Epithelial Cell Adhesion Molecule , Proteomics , Peritoneum/pathology , Peritoneal Neoplasms/pathology , Cell Line, Tumor , Tumor MicroenvironmentABSTRACT
Glycolysis is highly enhanced in pancreatic ductal adenocarcinoma (PDAC) cells; thus, glucose restrictions are imposed on nontumor cells in the PDAC tumor microenvironment (TME). However, little is known about how such glucose competition alters metabolism and confers phenotypic changes in stromal cells in the TME. Here, we report that cancer-associated fibroblasts (CAFs) with restricted glucose availability utilize lactate from glycolysis-enhanced cancer cells as a fuel and exert immunosuppressive activity in the PDAC TME. The expression of lactate dehydrogenase A (LDHA), which regulates lactate production, was a poor prognostic factor for patients with PDAC, and LDHA depletion suppressed tumor growth in a CAF-rich murine PDAC model. Coculture of CAFs with PDAC cells revealed that most of the glucose was taken up by the tumor cells and that CAFs consumed lactate via monocarboxylate transporter 1 to enhance proliferation through the TCA cycle. Moreover, lactate-stimulated CAFs upregulated IL-6 expression and suppressed cytotoxic immune cell activity synergistically with lactate. Finally, the LDHA inhibitor FX11 reduced tumor growth and improved antitumor immunity in CAF-rich PDAC tumors. Our study provides insight regarding the crosstalk among tumor cells, CAFs, and immune cells mediated by lactate and offers therapeutic strategies for targeting LDHA enzymatic activity in PDAC cells.
Subject(s)
Cancer-Associated Fibroblasts , Carcinoma, Pancreatic Ductal , Pancreatic Neoplasms , Humans , Mice , Animals , Cancer-Associated Fibroblasts/metabolism , Lactic Acid/metabolism , Pancreatic Neoplasms/pathology , Carcinoma, Pancreatic Ductal/pathology , Glucose/metabolism , Tumor Microenvironment , Pancreatic NeoplasmsABSTRACT
Fibroblast activation protein (FAP) generally shows low or undetectable expression in most normal tissues but is highly expressed in fibroblasts in almost all carcinomas. FAP is one of the potential molecules to detect activated fibroblasts and has multiple roles in tumour progression. We generated transgenic mice that specifically expressed tdTomato along with FAP promoter activity. Coculturing a mouse gastric cancer cell line and FAP-tdTomato transgenic mouse-derived fibroblasts showed that tdTomato expression was elevated in the cocultured fibroblasts. Moreover, stomach wall transplanted tumours in mice also showed FAP-tdTomato expression in fibroblasts of the stomach and each metastatic legion. These results indicated that FAP-tdTomato expression in fibroblasts was elevated by stimulation through the interaction with cancer cells. Functionally, collagen production was increased in FAP/tdTomato-positive fibroblasts cocultured with mouse cancer cells. These FAP-tdTomato transgenic mice have the potential to be used to investigate real-time FAP dynamics and the importance of FAP expression in tumour development.
Subject(s)
Cancer-Associated Fibroblasts , Stomach Neoplasms , Animals , Mice , Serine Endopeptidases/genetics , Serine Endopeptidases/metabolism , Endopeptidases/genetics , Endopeptidases/metabolism , Mice, Transgenic , Cancer-Associated Fibroblasts/metabolism , Membrane Proteins/genetics , Membrane Proteins/metabolism , Fibroblasts/metabolism , Stomach Neoplasms/pathology , Red Fluorescent ProteinABSTRACT
Excess stroma and cancer-associated fibroblasts (CAF) enhance cancer progression and facilitate immune evasion. Insights into the mechanisms by which the stroma manipulates the immune microenvironment could help improve cancer treatment. Here, we aimed to elucidate potential approaches for stromal reprogramming and improved cancer immunotherapy. Platelet-derived growth factor C (PDGFC) and D expression were significantly associated with a poor prognosis in patients with gastric cancer, and PDGF receptor beta (PDGFRß) was predominantly expressed in diffuse-type gastric cancer stroma. CAFs stimulated with PDGFs exhibited markedly increased expression of CXCL1, CXCL3, CXCL5, and CXCL8, which are involved in polymorphonuclear myeloid-derived suppressor cell (PMN-MDSC) recruitment. Fibrotic gastric cancer xenograft tumors exhibited increased PMN-MDSC accumulation and decreased lymphocyte infiltration, as well as resistance to anti-PD-1. Single-cell RNA sequencing and spatial transcriptomics revealed that PDGFRα/ß blockade reversed the immunosuppressive microenvironment through stromal modification. Finally, combining PDGFRα/ß blockade and anti-PD-1 treatment synergistically suppressed the growth of fibrotic tumors. These findings highlight the impact of stromal reprogramming on immune reactivation and the potential for combined immunotherapy for patients with fibrotic cancer. SIGNIFICANCE: Stromal targeting with PDGFRα/ß dual blockade reverses the immunosuppressive microenvironment and enhances the efficacy of immune checkpoint inhibitors in fibrotic cancer. See related commentary by Tauriello, p. 655.
Subject(s)
Receptor, Platelet-Derived Growth Factor alpha , Stomach Neoplasms , Humans , Receptor, Platelet-Derived Growth Factor alpha/genetics , Fibrosis , Immunotherapy , Tumor MicroenvironmentABSTRACT
BACKGROUND: Remodeling the tumor microenvironment (TME) to benefit cancer cells is crucial for tumor progression. Although diffuse-type gastric cancer (DGC) preferentially interacts with the TME, the precise mechanism of the complicated network remains unknown. This study aimed to investigate the mutual activation mechanism underlying DGC progression. METHODS: Mass cytometry analysis of co-cultured macrophages, noncancerous fibroblasts (NFs), and DGC cells was performed. RNA sequencing was applied to examine gene expression in fibroblasts. DGC cells were treated with cytokines to examine their effect on characteristic changes. The TCGA and Kumamoto University cohorts were used to evaluate the clinical relevance of the in vitro findings. RESULTS: Cohort analysis revealed that DGC patients had a poor prognosis. The fibroblasts and macrophages interacted with DGC cells to form a cell cluster in the invasive front of DGC tissue. The original 3D triple co-culture system determined the promotional effects of nonmalignant cells on DGC invasive growth. We notably identified a mixed-polarized macrophage cell type with M1/M2 cell surface markers in a triple co-culture system. IL-1ß from mixed-polarized macrophages induced the conversion of NFs to cancer-associated fibroblast-like (CAF-like) cells, promoting the malignant phenotype of DGC cells by inducing the secretion of IL-6, IL-24, and leukemia inhibitory factor (LIF). Moreover, IL-6 and colony stimulating factor 2 (GM-CSF) cooperated to maintain the stable state of mixed-polarized macrophages. Finally, we found that mixed-polarized macrophages were frequently detected in DGC tissues. CONCLUSION: These findings demonstrated that mixed-polarized macrophages exist as a novel subtype through the reciprocal interaction between DGC cells and nonmalignant cells.
Subject(s)
Interleukin-6 , Stomach Neoplasms , Humans , Interleukin-6/metabolism , Interleukin-6/pharmacology , Tumor Microenvironment , Stomach Neoplasms/pathology , Macrophages/metabolism , FibroblastsABSTRACT
INTRODUCTION: Pancreatic ductal adenocarcinoma (PDAC) is characterized by abundant stroma and cancer-associated fibroblasts (CAFs) provide a favorable tumor microenvironment. Smad4 is known as tumor suppressor in several types of cancers including PDAC, and loss of Smad4 triggers accelerated cell invasiveness and metastatic potential. The thrombospondin-1 (TSP-1) can act as a major activator of latent transforming growth factor-ß (TGF-ß) in vivo. However, the roles of TSP-1 and the mediator of Smad4 loss and TGF-ß signal activation during PDAC progression have not yet been addressed. The aim is to elucidate the biological role of TSP-1 in PDAC progression. METHODS AND RESULTS: High substrate stiffness stimulated TSP-1 expression in CAFs, and TSP-1 knockdown inhibited cell proliferation with suppressed profibrogenic and activated stroma-related gene expressions in CAFs. Paracrine TSP-1 treatment for PDAC cells promoted cell proliferation and epithelial mesenchymal transition (EMT) with activated TGF-ß signals such as phosphorylated Akt and Smad2/3 expressions. Surprisingly, knockdown of DPC4 (Smad4 gene) induced TSP-1 overexpression with TGF-ß signal activation in PDAC cells. Interestingly, TSP-1 overexpression also induced downregulation of Smad4 expression and enhanced cell proliferation in vitro and in vivo. Treatment with LSKL peptide, which antagonizes TSP-1-mediated latent TGF-ß activation, attenuated cell proliferation, migration and chemoresistance with enhanced apoptosis in PDAC cells. CONCLUSIONS: TSP-1 derived from CAFs stimulates loss of Smad4 expression in cancer cells and accelerates malignant behavior by TGF-ß signal activation in PDAC. TSP-1 could be a novel therapeutic target, not only for CAFs in stiff stroma, but also for cancer cells in the PDAC microenvironment.
ABSTRACT
BACKGROUND: Although PNENs generally have a better prognosis than pancreatic cancers, some PNENs display malignant behavior including lymph node (LN) metastasis. Complete tumor resection can be the only potentially curative treatment for patients with resectable PNENs. However, the indications for LN dissection are still controversial. Over the last decade, minimally invasive surgery such as laparoscopic pancreatic surgery (LPS) has been increasingly performed for pancreatic tumors including PNENs. AIM: To investigate the risk factors for LN metastasis in PNENs and to select appropriate patients for limited surgery by LPS. METHODS: From April 2001 to December 2019, 92 patients underwent pancreatic resection for PNENs at Kumamoto University Hospital. Finally, 82 patients were enrolled in this study. Using perioperative factors, we examined the predictive factors for LN metastasis in PNENs. RESULTS: Among the 82 patients, the percentage of LN metastasis according to the pathological findings was 12% (10/82 cases). The median tumor size was 12 mm (range: 5-90 mm). The median tumor size in the LN-positive group (37 mm) was significantly larger than that in the LN-negative group (12 mm) (P = 0.0001). Multivariate analyses revealed that larger tumor size (≥ 20 mm) was an independent risk factor for LN metastasis (odds ratio 16.8, P = 0.0062). In patients with small tumors (≤ 10 mm), LN metastasis was not found. CONCLUSION: Larger tumor size (≥ 20 mm) is an independent risk factor for LN metastasis in PNENs. In smaller PNENs (≤ 10 mm), we may be able to choose limited surgery without LN dissection.
ABSTRACT
The arachidonic acid cascade is a major inflammatory pathway that produces prostaglandin E2 (PGE2). Although inhibition of 15-hydroxyprostaglandin dehydrogenase (15-PGDH) is reported to lead to PGE2 accumulation, the role of 15-PGDH expression in the tumor microenvironment remains unclear. We utilized Panc02 murine pancreatic cancer cells for orthotopic transplantation into wild-type and 15-pgdh+/- mice and found that 15-pgdh depletion in the tumor microenvironment leads to enhanced tumorigenesis accompanied by an increase in cancer-associated fibroblasts (CAFs) and the promotion of fibrosis. The fibrotic tumor microenvironment is widely considered to be hypovascular; however, we found that the angiogenesis level is maintained in 15-pgdh+/- mice, and these changes were also observed in a genetically engineered PDAC mouse model. Further confirmation revealed that fibroblast growth factor 1 (FGF1) is secreted by pancreatic cancer cells after PGE2 stimulation, consequently promoting CAF proliferation and vascular endothelial growth factor A (VEGFA) expression in the tumor microenvironment. Finally, in 15-pgdh+/- Acta2-TK mice, depletion of fibroblasts inhibited angiogenesis and cancer cell viability in orthotopically transplanted tumors. These findings highlighted the role of 15-pgdh downregulation in enhancing PGE2 accumulation in the pancreatic tumor microenvironment and in subsequently maintaining the angiogenesis level in fibrotic tumors along with CAF expansion.
Subject(s)
Pancreatic Neoplasms , Vascular Endothelial Growth Factor A , Animals , Arachidonic Acid , Cell Line, Tumor , Dinoprostone/metabolism , Dinoprostone/pharmacology , Fibroblast Growth Factor 1 , Fibrosis , Hydroxyprostaglandin Dehydrogenases/genetics , Hydroxyprostaglandin Dehydrogenases/metabolism , Mice , Pancreatic Neoplasms/genetics , Tumor Microenvironment , Vascular Endothelial Growth Factor A/genetics , Pancreatic NeoplasmsABSTRACT
BACKGROUND: Signet ring cell carcinoma (SRCC) is a particular histologic variant of gastric cancer (GC). However, the critical factor related to the aggressive characteristics of SRCC has not been determined. METHODS: We collected surgically resected tissues from 360 GC patients in the Kumamoto University cohort and generated survival curves via the Kaplan-Meier method. In vitro, we identified the specific transcript variant of MUC20 in SRCC cells by direct sequencing and investigated the role of MUC20 in GC progression using GC cells with MUC20 silencing and forced expression. In vivo, we examined chemoresistance using MUC20 variant 2 (MUC20v2)-overexpressing non-SRCC cells to construct a xenograft mouse model. RESULTS: We analyzed a comprehensive GC cell line database to identify the specifically expressed genes in gastric SRCC. We focused on MUC20 and investigated its role in GC progression. Survival analysis revealed that GC patients with high MUC20 expression exhibited a poor prognosis and that MUC20 expression was significantly correlated with SRCC histological type. Moreover, we found that gastric SRCC cells specifically expressed MUC20v2, which was dominantly expressed in the cytoplasm. Silencing MUC20v2 caused cell death with characteristic morphological changes in gastric SRCC cells. To further determine the types of cell death, we examined apoptosis, pyroptosis and ferroptosis by detecting cleaved PARP, gasdermin E-N-terminal (GSDME-N), and lipid reactive oxygen species (ROS) levels, respectively. We found that apoptosis and pyroptosis occurred in MUC20-silenced gastric SRCC cells. In addition, MUC20v2-overexpressing GC cells exhibited chemoresistance to cisplatin (CDDP) and paclitaxel (PTX). RNA sequencing revealed that the pathways involved in intracellular calcium regulation were significantly upregulated in MUC20v2-overexpressing GC cells. Notably, forced expression of MUC20v2 in the cytoplasm of GC cells led to the maintenance of mitochondrial calcium homeostasis and mitochondrial membrane potential (MMP), which promoted cell survival and chemoresistance by suppressing apoptosis and pyroptosis. Finally, we investigated the significance of MUC20v2 in a xenograft model treated with CDDP and showed that MUC20v2 overexpression caused chemoresistance by inhibiting cell death. CONCLUSION: These findings highlight the novel functions of MUC20v2, which may confer cell survival and drug resistance in GC cells. SIGNIFICANCE: MUC20v2 protects GC cells from apoptosis and pyroptosis by maintaining mitochondrial calcium levels and mitochondrial membrane potential and subsequently induces drug resistance.
Subject(s)
Carcinoma, Signet Ring Cell , Stomach Neoplasms , Animals , Calcium/therapeutic use , Carcinoma, Signet Ring Cell/pathology , Cisplatin , Drug Resistance , Heterografts , Homeostasis , Humans , Mice , Mucins , Stomach Neoplasms/drug therapy , Stomach Neoplasms/genetics , Stomach Neoplasms/metabolismABSTRACT
Cancer cells craftily adapt their energy metabolism to their microenvironment. Nutrient deprivation due to hypovascularity and fibrosis is a major characteristic of pancreatic ductal adenocarcinoma (PDAC); thus, PDAC cells must produce energy intrinsically. However, the enhancement of energy production via activating Kras mutations is insufficient to explain the metabolic rewiring of PDAC cells. Here, we investigated the molecular mechanism underlying the metabolic shift in PDAC cells under serine starvation. Amino acid analysis revealed that the concentrations of all essential amino acids and most nonessential amino acids were decreased in the blood of PDAC patients. In addition, the plasma serine concentration was significantly higher in PDAC patients with PHGDH-high tumors than in those with PHGDH-low tumors. Although the growth and tumorigenesis of PK-59 cells with PHGDH promoter hypermethylation were significantly decreased by serine starvation, these activities were maintained in PDAC cell lines with PHGDH promoter hypomethylation by serine biosynthesis through PHGDH induction. In fact, DNA methylation analysis by pyrosequencing revealed that the methylation status of the PHGDH promoter was inversely correlated with the PHGDH expression level in human PDAC tissues. In addition to PHGDH induction by serine starvation, PDAC cells showed enhanced serine biosynthesis under serine starvation through 3-PG accumulation via PGAM1 knockdown, resulting in enhanced PDAC cell growth and tumor growth. However, PHGDH knockdown efficiently suppressed PDAC cell growth and tumor growth under serine starvation. These findings provide evidence that targeting the serine biosynthesis pathway by inhibiting PHGDH is a potent therapeutic approach to eliminate PDAC cells in nutrient-deprived microenvironments.
Subject(s)
Carcinoma, Pancreatic Ductal/pathology , Glyceric Acids/metabolism , Pancreatic Neoplasms/pathology , Phosphoglycerate Dehydrogenase/physiology , Serine/biosynthesis , Animals , Cell Line, Tumor , CpG Islands , DNA Methylation , Enzyme Induction , Humans , Mice , Pancreatic Neoplasms/drug therapy , Pancreatic Neoplasms/metabolism , Phosphoglycerate Dehydrogenase/antagonists & inhibitors , Phosphoglycerate Dehydrogenase/genetics , Phosphoglycerate Mutase/physiologyABSTRACT
BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSION: 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.
Subject(s)
Frailty , Pancreatic Neoplasms , Humans , Pancreatic Neoplasms/surgery , Prognosis , Proportional Hazards Models , Retrospective StudiesABSTRACT
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.
Subject(s)
Ascites/metabolism , Carcinoma, Pancreatic Ductal/metabolism , Pancreatic Neoplasms/metabolism , Proteomics/methods , Ascites/pathology , Biomarkers, Tumor/metabolism , Carcinoma, Pancreatic Ductal/pathology , Gene Expression Regulation, Neoplastic , Humans , Pancreatic Neoplasms/pathologyABSTRACT
BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: miR-25 may promote tumor progression in HCC patients by repression of Fbxw7 and could serve as a promising molecular target for HCC treatment.
Subject(s)
Carcinoma, Hepatocellular , F-Box-WD Repeat-Containing Protein 7 , Liver Neoplasms , MicroRNAs , Carcinoma, Hepatocellular/genetics , Cell Cycle Proteins/genetics , Cell Cycle Proteins/metabolism , Cell Line, Tumor , Cell Proliferation , F-Box-WD Repeat-Containing Protein 7/genetics , Gene Expression Regulation, Neoplastic , Humans , Liver Neoplasms/genetics , MicroRNAs/genetics , Oncogenes , Prognosis , Ubiquitin-Protein Ligases/geneticsABSTRACT
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 = .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 = .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.
Subject(s)
Anti-Bacterial Agents , Bile , Pancreaticoduodenectomy , Anti-Bacterial Agents/therapeutic use , Bile/microbiology , Drainage , Humans , Postoperative Complications/prevention & control , Retrospective StudiesABSTRACT
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.
Subject(s)
Adenocarcinoma , Pancreatic Neoplasms , Humans , Neoplasm Recurrence, Local , Pancreatic Neoplasms/surgery , Prognosis , Retrospective Studies , Survival RateABSTRACT
Postpancreaticoduodenectomy (PD) bleeding, which is reported to occur in 5-7%, is a major complication that often causes life-threatening secondary events. A transarterial catheter technique with coil embolization is a widespread procedure that could potentially cause massive hepatic infarction and subsequent sepsis with hepatic abscess, which can be a fatal complication. Here, we introduce a new transarterial technique that uses a hemostat with a stent graft, which successfully rescued a patient had suffered post-PD bleeding.
ABSTRACT
BACKGROUND: An outbreak of cholangiocarcinoma in Japan has led to widespread concern among workers in printing plants. In March 2013, the Japanese Ministry of Health, Labour and Welfare, confirmed a causal relationship between cholangiocarcinoma and long-term exposure to dichloromethane (DCM) and 1,2-dichloropropane (DCP), which were widely used in printing plants. We herein report a rare case of successful radical resection of multiple cholangiocarcinomas in the intrahepatic and extrahepatic bile ducts caused by past exposure to DCM. CASE PRESENTATION: A 54-year-old man developed brown urine 22 years after his last exposure to DCP and DCM. He had an 11-year history of working at a printing plant from the age of 21 to 31 years and dealt with organic solvents during his employment. Enhanced computed tomography revealed a thickened distal bile duct wall with upstream biliary dilatation and multiple intrahepatic cholangiocarcinomas located in liver segments III, VI, and VIII. Biopsy of the distal bile duct wall revealed adenocarcinoma, and a diagnosis of distal cholangiocarcinoma was made. Tumor marker levels were within the reference range (carcinoembryonic antigen, 3.3 ng/mL; carbohydrate antigen 19-9, 25.4 U/mL; SPAN-1, 13 U/mL; and DUPAN-2, 33 U/mL). The multiple intrahepatic and extrahepatic bile duct cancers were treated by subtotal stomach-preserving pancreatoduodenectomy and partial hepatectomy of segments III, VI, and VIII. Pathological examination of the surgical specimens revealed multiple cholangiocarcinomas with well-differentiated adenocarcinoma in the biliary tree. The patient was still alive without recurrence 17 months after the operation. CONCLUSIONS: We experienced a rare case of multiple cholangiocarcinomas in the intrahepatic and extrahepatic bile ducts that developed 22 years after the patient's last exposure to DCP and DCM. Long-term and careful follow-up is required for workers with an occupational history of exposure to organic solvents because of the risk of development of cholangiocarcinoma.
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BACKGROUND: Whether perioperative allogeneic blood transfusion (PABT) negatively influences patient survival after hepatectomy (HR) for hepatocellular carcinoma (HCC) remains controversial. METHODS: 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. RESULTS: 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). CONCLUSION: Using propensity score matching, we found that PABT does not influence patient survival after HR for HCC.
Subject(s)
Carcinoma, Hepatocellular/surgery , Erythrocyte Transfusion , Liver Neoplasms/surgery , Neoplasm Recurrence, Local , Plasma , Platelet Transfusion , Aged , Allogeneic Cells , Carcinoma, Hepatocellular/pathology , Female , Hepatectomy , Humans , Liver Neoplasms/pathology , Male , Middle Aged , Neoplasm Recurrence, Local/pathology , Neoplasm Staging , Operative Time , Perioperative Care , Propensity Score , Retrospective Studies , Survival RateABSTRACT
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, Pâ¯=â¯.019), des-γ-carboxy prothrombin >200 mAU/mL (hazard ratio 3.36, Pâ¯=â¯.045), and red blood cell transfusion (hazard ratio 11.03, Pâ¯=â¯.0008) were independent prognostic factors for overall survival. Male sex (hazard ratio 3.74, Pâ¯=â¯.029), bilobar tumor distribution (hazard ratio 3.65, Pâ¯=â¯.004), and red blood cell transfusion (hazard ratio 6.22, Pâ¯=â¯.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.
Subject(s)
Carcinoma, Hepatocellular/therapy , Embolization, Therapeutic , Hepatectomy , Liver Neoplasms/therapy , Portal Vein , Adult , Aged , Aged, 80 and over , Carcinoma, Hepatocellular/mortality , Disease Progression , Female , Humans , Liver Neoplasms/mortality , Male , Middle AgedABSTRACT
BACKGROUND: Extramedullary plasmacytomas account for 4% of all plasma cell tumors and occur mainly in the upper respiratory tract; gastrointestinal system involvement is rare. Extramedullary plasmacytoma of the colon with perforation has not been reported. CASE PRESENTATION: A 77-year-old woman with a 1-year history of lower abdominal pain and nausea was admitted to our hospital. An abdominal computed tomography scan revealed a sigmoid tumor with perforation. The patient underwent emergency surgery. Pathological examination led to a diagnosis of plasmacytoma of the colon. The patient did not undergo postoperative adjuvant chemotherapy. She has had no recurrence in 14 months of regular follow-up. CONCLUSIONS: We have herein described a rare case of extramedullary plasmacytoma of the gastrointestinal tract with perforation involving the sigmoid colon.