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BACKGROUND: 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). METHODS: The biological impact of hyperglycaemia on malignant behaviour in PDAC was examined by in vitro and in vivo experiments. RESULTS: 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. CONCLUSION: 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.
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Carcinoma Ductal Pancreático , Hiperglicemia , Neoplasias Pancreáticas , Humanos , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas Hedgehog/genética , Proteínas de Sinalização YAP , Fatores de Transcrição/genética , Transativadores/genética , Transição Epitelial-Mesenquimal , Neoplasias Pancreáticas/patologia , Carcinoma Ductal Pancreático/patologia , Fenótipo , Microambiente Tumoral , Neoplasias PancreáticasRESUMO
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.
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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.
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Aim: The aim of this study was to evaluate risk factors for nonalcoholic fatty liver disease (NAFLD) after pancreaticoduodenectomy (PD), with a special focus on remnant pancreatic volume (RPV) as assessed using computed tomography (CT). Methods: From February 2004 to June 2017, 101 patients who underwent PD in our institution were enrolled. We defined a CT attenuation value of less than 40 HU as hepatic steatosis and measured RPV at 7 days, 3 months, and 1 year after PD using the SYNAPSE VINCENT system. The incidence of NAFLD and RPV were compared between the two groups according to reconstruction with pancreaticogastrostomy (PG) or pancreaticojejunostomy (PJ). Results: The incidence of NAFLD at 3 months after PD was 39.6% (40/101). The RPV ratio (RPV at 3 months or 1 year divided by RPV at 7 days after PD) at both 3 months and 1 year was significantly smaller in the PG group than in the PJ group (59% vs 73%, P < .001 and 53% vs 67% P < .01, respectively). A positive correlation between the RPV ratio and liver CT value at 3 months was found. The multivariate analysis identified three independent risk factors for NAFLD: female sex (odds ratio [OR] 8.16, 95% confidence interval [95% CI] 2.27-35.9, P < .001), PG reconstruction (OR 3.87, 95% CI 1.04-15.6, P = .04), and RPV ratio ≤60% (OR 3.44, 95% CI 1.06-11.8, P = .001). Conclusion: Atrophic change in the remnant pancreas is significantly associated with the development of NAFLD, and PJ reconstruction may be superior to PG from the viewpoint of NAFLD development.
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Prediction of hepatocellular carcinoma (HCC) risk is an urgent unmet need in patients with nonalcoholic fatty liver disease (NAFLD). In cohorts of 409 patients with NAFLD from multiple global regions, we defined and validated hepatic transcriptome and serum secretome signatures predictive of long-term HCC risk in patients with NAFLD. A 133-gene signature, prognostic liver signature (PLS)-NAFLD, predicted incident HCC over up to 15 years of longitudinal observation. High-risk PLS-NAFLD was associated with IDO1+ dendritic cells and dysfunctional CD8+ T cells in fibrotic portal tracts along with impaired metabolic regulators. PLS-NAFLD was validated in independent cohorts of patients with NAFLD who were HCC naïve (HCC incidence rates at 15 years were 22.7 and 0% in high- and low-risk patients, respectively) or HCC experienced (de novo HCC recurrence rates at 5 years were 71.8 and 42.9% in high- and low-risk patients, respectively). PLS-NAFLD was bioinformatically translated into a four-protein secretome signature, PLSec-NAFLD, which was validated in an independent cohort of HCC-naïve patients with NAFLD and cirrhosis (HCC incidence rates at 15 years were 37.6 and 0% in high- and low-risk patients, respectively). Combination of PLSec-NAFLD with our previously defined etiology-agnostic PLSec-AFP yielded improved HCC risk stratification. PLS-NAFLD was modified by bariatric surgery, lipophilic statin, and IDO1 inhibitor, suggesting that the signature can be used for drug discovery and as a surrogate end point in HCC chemoprevention clinical trials. Collectively, PLS/PLSec-NAFLD may enable NAFLD-specific HCC risk prediction and facilitate clinical translation of NAFLD-directed HCC chemoprevention.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Hepatopatia Gordurosa não Alcoólica , Linfócitos T CD8-Positivos , Carcinoma Hepatocelular/complicações , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Humanos , Cirrose Hepática/complicações , Cirrose Hepática/patologia , Neoplasias Hepáticas/complicações , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/genética , Fatores de RiscoRESUMO
BACKGROUND AND AIM: Early recurrence (ER) is a strong predictor of poor prognosis in patients with hepatocellular carcinoma (HCC) after hepatectomy. The aim of this study was to examine manageable factors associated with ER. METHODS: Overall, 475 consecutive patients with primary HCC who underwent curative hepatectomy were included (R0/R1). We defined ER as recurrence within 2 years after hepatectomy and analyzed predictors for ER. We also defined postoperative complication as Clavien-Dindo classification grade III or IV. RESULTS: ER after hepatectomy was observed in 209 cases (44.0%). Patients with ER had a significantly poor prognosis compared with those with late recurrence (log-rank p < 0.0001) and were more likely to be diagnosed with extrahepatic metastasis (p = 0.009). Significant predictors for ER were des-γ-carboxyprothrombin > 40 mAU/mL (odds ratio (OR) 2.06, 95% confidence interval (CI) 1.36-3.14, p = 0.001), multiple tumors (OR 2.80 95%CI 1.83-4.32, p < 0.0001), cirrhosis (OR 1.53, 95%CI 1.01-2.32, p = 0.043), and postoperative complications (OR 1.72, 95% CI 1.05-2.85, p = 0.032). Blood loss (OR 1.09, 95%CI 1.05-1.13, p < 0.0001) and cirrhosis (OR 1.74, 95%CI 1.05-2.86, p = 0.031) were significant predictors for postoperative complications. CONCLUSIONS: We should pay close attention to surgical associated- and disease-specific factors in hepatectomy for HCC to prevent ER.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/cirurgia , Hepatectomia/efeitos adversos , Humanos , Cirrose Hepática/cirurgia , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/cirurgia , Recidiva Local de Neoplasia/patologia , Complicações Pós-Operatórias/etiologia , Prognóstico , Estudos Retrospectivos , Fatores de RiscoRESUMO
BACKGROUND: Laparoscopic surgery has been introduced as a minimally invasive technique for the treatment of various field. However, there are few reports that have scientifically investigated the minimally invasive nature of laparoscopic liver resection (LLR). AIM: To investigate whether LLR is scientifically less invasive than open liver resection. METHODS: During December 2011 to April 2015, blood samples were obtained from 30 patients who treated with laparoscopic (n = 10, 33%) or open (n = 20, 67%) partial liver resection for liver tumor. The levels of serum interleukin-6 (IL-6) and plasma thrombospondin-1 (TSP-1) were measured using ELISA kit at four time points including preoperative, immediate after operation, postoperative day 1 (POD1) and POD3. Then, we investigated the impact of the operative approaches during partial hepatectomy on the clinical time course including IL-6 and TSP-1. RESULTS: Serum level of IL-6 on POD1 in laparoscopic hepatectomy was significantly lower than those in open hepatectomy (8.7 vs 30.3 pg/mL, respectively) (P = 0.003). Plasma level of TSP-1 on POD3 in laparoscopic hepatectomy was significantly higher than those in open hepatectomy (1704.0 vs 548.3 ng/mL, respectively) (P = 0.009), and have already recovered to preoperative level in laparoscopic approach. In patients with higher IL-6 Levels on POD1, plasma level of TSP-1 on POD3 was significantly lower than those in patients with lower IL-6 Levels on POD1. Multivariate analysis showed that open approach was the only independent factor related to higher level of IL-6 on POD1 [odds ratio (OR), 7.48; 95% confidence interval (CI): 1.28-63.3; P = 0.02]. Furthermore, the higher level of serum IL-6 on POD1 was significantly associated with lower level of plasm TSP-1 on POD3 (OR, 5.32; 95%CI: 1.08-32.2; P = 0.04) in multivariate analysis. CONCLUSION: In partial hepatectomy, laparoscopic approach might be minimally invasive surgery with less IL-6 production compared to open approach.
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BACKGROUND: The albumin-bilirubin (ALBI) grade was developed to predict the prognosis of patients with hepatocellular carcinoma (HCC), which can stratify the prognosis even in HCC patients with Child-Pugh A. We evaluated the prognostic efficacy of the ALBI grade and Child-Pugh classification in HCC patients with Child-Pugh A stratified by the presence or absence of advanced fibrosis or a preoperative biomarker for advanced fibrosis. METHODS: We retrospectively analyzed 490 consecutive HCC patients with Child-Pugh A who underwent initial hepatectomies. The accuracy of prognostic prediction using both models was compared by the presence or absence of advanced fibrosis (F3-4) and its predictor, the preoperative platelet count (PLT). RESULTS: The prognostic accuracy of the ALBI grade was better in patients without advanced fibrosis (F3-4; likelihood ratio: 4.39, corrected Akaike information criterion [AICc]: 453.0, P = .074), but Child-Pugh score was better in the advanced fibrosis group (likelihood ratio: 10.67, AICc: 915.2, P = .0014). In the high PLT group (≥140 × 103/µL), the prognostic accuracy using the ALBI grade was better in overall survival (OS) and relapse-free survival (RFS), but in the low PLT group, the Child-Pugh score was the more accurate model in OS and RFS. CONCLUSIONS: Depending on the degree of fibrosis or preoperative PLT, the ALBI grade and Child-Pugh score may provide more accurate prognoses after initial hepatectomy in HCC patients with Child-Pugh A.
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Diagnosis of gastrointestinal (GI) amyloidosis is often very difficult because of its nonspecific symptoms. However, a few reports have indicated that serious symptoms such as fatal GI bleeding and obstruction or perforation sometimes lead to a diagnosis of GI amyloidosis. A 79-year-old man was transported to our emergency department with a 1-week history of worsening abdominal pain. Abdominal contrast-enhanced computed tomography showed extravasation from part of the transverse colon wall and moderate ascites. Because intra-abdominal bleeding was suspected, the patient urgently underwent partial resection of the transverse colon, which was the source of the bleeding. Postoperative pathological examination of the tissue specimens led to a diagnosis of amyloid transthyretin amyloidosis. This is the first reported case in which intra-abdominal bleeding led to a diagnosis of GI amyloidosis. We should consider the possibility of GI amyloidosis when intraperitoneal bleeding is observed in elderly patients.
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Neuropatias Amiloides Familiares , Gastroenteropatias , Idoso , Neuropatias Amiloides Familiares/complicações , Neuropatias Amiloides Familiares/diagnóstico , Gastroenteropatias/diagnóstico , Hemorragia Gastrointestinal/etiologia , Humanos , MasculinoRESUMO
BACKGROUND: Liver inflammation is a reaction to disease-causing stress in the liver that induces fibrosis and cirrhosis. However, its prognostic impact after hepatectomy remains unclear. This study aimed to evaluate the prognostic and oncologic impacts of liver inflammation on patients after curative hepatectomy for hepatocellular carcinoma (HCC). METHODS: The study enrolled 500 consecutive patients with primary HCC who underwent curative and primary hepatectomy. Patient characteristics and prognoses were evaluated according to histologic liver inflammation assessed by the New Inuyama Classification. RESULTS: Severe liver inflammation (A3) was observed in 97 patients (19.4%) and nonsevere liver inflammation (A0-2) in 403 patients (80.6%). The patients with A3 had a significantly poorer prognosis than those with A0-2 in terms of relapse-free survival (p < 0.0001, log-rank) and overall survival (p = 0.0013, log-rank). The study showed that A3 is an independent poor prognostic factor (hazard ratio, 1.36; 95% confidence interval [Cl], 1.02-1.81; p = 0.039), and that Child-Pugh grade B and multiple tumors are associated with relapse-free survival. Furthermore, The significant predictors of early recurrence (within 2 years after hepatectomy) were A3 (odds ratio, 2.10; 95% CI, 1.25-3.55; p = 0.005), a des-γ-carboxyprothrombin level higher than 40 mAU/mL, and multiple tumors. CONCLUSIONS: Severe liver inflammation was associated with poor short- and long-term prognoses independently of cirrhosis. Controlling liver inflammation in the perioperative period may be essential to improving the prognosis of patients with HCC after hepatectomy.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Carcinoma Hepatocelular/cirurgia , Hepatectomia/efeitos adversos , Humanos , Inflamação/etiologia , Neoplasias Hepáticas/cirurgia , Recidiva Local de Neoplasia , Prognóstico , Estudos RetrospectivosRESUMO
BACKGROUND: Large numbers of synchronous colorectal liver metastases are associated with poor prognosis. CASE REPORT: A 47-year-old male patient with rectal cancer and unresectable colorectal liver metastases (over 15 cm in diameter and over 30 metastases) was treated with a multidisciplinary treatment including systemic chemotherapy with mFOLFOX6/panitumumab and surgical therapies (colostomy, modified associating liver partition and portal vein ligation for staged hepatectomy together with radiofrequency ablation). For solitary recurrent colorectal liver metastases, percutaneous radiofrequency ablation with chemoembolization and open radiofrequency ablation in combination with the same systemic chemotherapy was performed. Since the diagnosis 3 years ago, he has been leading a good quality of life, free of any tumor or treatment. CONCLUSION: For patients with far-advanced but liver-only colorectal liver metastases, surgical therapy, systemic chemotherapy, and interventional treatment can be important for achieving good prognosis.
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Adenocarcinoma/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Colorretais/patologia , Hepatectomia , Neoplasias Hepáticas/terapia , Terapia Neoadjuvante , Veia Porta/cirurgia , Ablação por Radiofrequência , Adenocarcinoma/diagnóstico por imagem , Adenocarcinoma/secundário , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Quimioterapia Adjuvante , Colostomia , Humanos , Ligadura , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/secundário , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Resultado do TratamentoRESUMO
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.
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Carcinoma Ductal Pancreático/patologia , Ácidos Glicéricos/metabolismo , Neoplasias Pancreáticas/patologia , Fosfoglicerato Desidrogenase/fisiologia , Serina/biossíntese , Animais , Linhagem Celular Tumoral , Ilhas de CpG , Metilação de DNA , Indução Enzimática , Humanos , Camundongos , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/metabolismo , Fosfoglicerato Desidrogenase/antagonistas & inibidores , Fosfoglicerato Desidrogenase/genética , Fosfoglicerato Mutase/fisiologiaRESUMO
Chronic liver disease and hepatocellular carcinoma (HCC) are life-threatening diseases with limited treatment options. The lack of clinically relevant/tractable experimental models hampers therapeutic discovery. Here, we develop a simple and robust human liver cell-based system modeling a clinical prognostic liver signature (PLS) predicting long-term liver disease progression toward HCC. Using the PLS as a readout, followed by validation in nonalcoholic steatohepatitis/fibrosis/HCC animal models and patient-derived liver spheroids, we identify nizatidine, a histamine receptor H2 (HRH2) blocker, for treatment of advanced liver disease and HCC chemoprevention. Moreover, perturbation studies combined with single cell RNA-Seq analyses of patient liver tissues uncover hepatocytes and HRH2+, CLEC5Ahigh, MARCOlow liver macrophages as potential nizatidine targets. The PLS model combined with single cell RNA-Seq of patient tissues enables discovery of urgently needed targets and therapeutics for treatment of advanced liver disease and cancer prevention.
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Descoberta de Drogas , Fígado/patologia , Modelos Biológicos , Animais , Carcinogênese/patologia , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Quimioprevenção , Estudos de Coortes , AMP Cíclico/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Modelos Animais de Doenças , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células HEK293 , Hepacivirus/fisiologia , Hepatite C/genética , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Hepatócitos/patologia , Humanos , Vigilância Imunológica/efeitos dos fármacos , Inflamação/patologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Cirrose Hepática/patologia , Neoplasias Hepáticas/patologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Macrófagos/patologia , Masculino , Camundongos Knockout , Nizatidina/farmacologia , Prognóstico , Transdução de Sinais/efeitos dos fármacos , Transcriptoma/genéticaRESUMO
Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer mortality worldwide. Although advances in systemic chemotherapy for PDAC have improved survival outcomes for patients with the disease, chemoresistance is a major treatment issue for unselected PDAC patient populations. The existence of heterogeneity caused by a mixture of tumor cells and stromal cells produces chemoresistance and limits the targeted therapy of PDAC. Advances in precision medicine for PDACs according to the genetics and molecular biology of this disease may represent the next alternative approach to overcome the heterogeneity of different patients and improve survival outcomes for this poor prognostic disease. The genetic alteration of PDAC is characterized by four genes that are frequently mutated (KRAS, TP53, CDKN2A, and SMAD4). Furthermore, several genetic and molecular profiling studies have revealed that up to 25% of PDACs harbor actionable alterations. In particular, DNA repair dysfunction, including cases with BRCA mutations, is a causal element of sensitivity to platinum-based anti-cancer agents and poly-ADP ribose polymerase (PARP) inhibitors. A deep understanding of the molecular and cellular crosstalk in the tumor microenvironment helps to establish scientifically rational treatment strategies for cancers that show specific molecular profiles. Here, we review recent advances in genetic analysis of PDACs and describe future perspectives in precision medicine according to molecular subtypes or actionable gene mutations for patients with PDAC. We believe the breakthroughs will soon emerge to fight this deadly disease.
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Primary carcinosarcoma of the liver is extremely rare. Here, we report an unusual case of carcinosarcoma of the liver containing combined hepatocellular carcinoma and cholangiocarcinoma. A 66-year-old man with a history of viral hepatitis B was admitted for investigation of multiple liver masses. Dynamic computed tomography revealed a mostly hypoenhancing main tumor with a peripheral ring enhancement and several satellite nodules. After transcatheter arterial chemoembolization and portal vein embolization, an extended right posterior sectionectomy was performed. The resected tumor was macroscopically a simple nodular type, 4.3 × 4.2 cm in diameter, with a dense fibrous capsule. The pathological findings showed that both carcinomatous and sarcomatous elements were present, and diagnosis of carcinosarcoma of the liver was confirmed. The carcinomatous element consisted of hepatocellular carcinoma and cholangiocarcinoma. The sarcomatous element was composed of spindle cells. Immunohistochemical studies demonstrated that cytokeratin AE1/AE3, human serum albumin, cytokeratin 7, and Arginase-1 were partially positive in tumor cells of the carcinomatous element but not in tumor cells of the sarcomatous element. Follow-up for 30 months after surgery has shown no signs of recurrence.
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Neoplasias dos Ductos Biliares , Carcinoma Hepatocelular , Carcinossarcoma , Quimioembolização Terapêutica , Colangiocarcinoma , Neoplasias Hepáticas , Idoso , Neoplasias dos Ductos Biliares/cirurgia , Ductos Biliares Intra-Hepáticos , Carcinoma Hepatocelular/diagnóstico por imagem , Carcinoma Hepatocelular/cirurgia , Carcinossarcoma/cirurgia , Humanos , Masculino , Recidiva Local de NeoplasiaRESUMO
BACKGROUND: The objective of this study was to describe the detailed technique and clinical outcomes of portal vein embolization via the round ligament (RL-PVE) prior to major hepatectomy. METHODS: Between January 2010 and March 2020, a total of 50 portal vein embolization (PVE) procedures were performed in 50 patients. Of them, seven patients who underwent RL-PVE were enrolled in this study. Percutaneous transhepatic portal vein embolization (PTPE) was not indicated due to the following reasons: bile duct dilation (n = 4), difficulty in visualizing the portal vein on ultrasonography because of severe fatty liver (n = 1), large tumor size (n = 1), and combined surgery with staging laparoscopy (n = 1). The following were reasons for avoiding trans-ileocecal PVE: past laparotomy (n = 5), difficulty in accessing the portal vein due to a large tumor (n = 1), and purpose of preventing small intestinal adhesions before hepatopancreatoduodenectomy (n = 1). The percentage of functional hepatic remnant rates was calculated before and after RL-PVE. RESULTS: Technical success was achieved in all cases. Five patients underwent embolization of the right portal vein, while two underwent embolization of the left portal vein. The median operative time and blood loss during RL-PVE were 181 min and 33 g, respectively. Morbidity and mortality related to RL-PVE were not observed. The median functional hepatic remnant rate before and after PVE was 55.6% and 63.2%, respectively. Liver functions including Child-Pugh classification were equivalent before and after RL-PVE. CONCLUSIONS: The RL-PVE technique may be useful in elective cases for which it is difficult to safely perform PTPE or trans-ileocecal approaches.
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Embolização Terapêutica , Neoplasias Hepáticas , Ligamentos Redondos , Feminino , Hepatectomia , Humanos , Neoplasias Hepáticas/cirurgia , Veia Porta/diagnóstico por imagem , Cuidados Pré-Operatórios , Resultado do TratamentoRESUMO
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.
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Carcinoma Hepatocelular , Proteína 7 com Repetições F-Box-WD , Neoplasias Hepáticas , MicroRNAs , Carcinoma Hepatocelular/genética , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Proteína 7 com Repetições F-Box-WD/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Hepáticas/genética , MicroRNAs/genética , Oncogenes , Prognóstico , Ubiquitina-Proteína Ligases/genéticaRESUMO
Focal nodular hyperplasia (FNH) is a relatively common benign liver tumor with rare indications to surgery. Budd-Chiari syndrome is a rare condition caused by interrupted hepatic venous outflow in the hepatic veins and inferior vena cava (IVC). A 42-year-old woman was referred to our department with a hepatic tumor. Patient's chief complaint was leg edema. Because of this symptom, it was difficult for the patient to stand for more than 20 min in the evening. Computed tomography (CT) showed a hypervascular mass compressing IVC in the caudate lobe of the liver. Fine needle aspiration was performed, and preoperative diagnosis was focal nodular hyperplasia (FNH). Hepatic resection of the right caudate lobe was performed. Postoperative histological examination revealed that the tumor was FNH. After surgery, the patient's leg edema disappeared, and postoperative CT revealed that severe IVC stenosis was improved. Although there have been several reports of giant FNH causing Budd-Chiari syndrome, this case shows the stenosis of IVC below the root of hepatic veins causing Budd-Chiari-like syndrome without portal hypertension. The location of the tumor considerably attributed to the congestion of venous flow in IVC causing various symptoms and intrahepatic inferior right hepatic vein-right hepatic vein bypass. The surgical indication of FNH is limited in most cases; however, the current report alerts that the location of FNH should be taken into account when monitoring it.
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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.
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BACKGROUND: An accurate diagnosis of the primary cancer or metastatic tumor is quite important because misdiagnosis may lead to the selection of incorrect adjuvant therapy and worse long-term outcomes after surgery. Here, we present a rare case with an unusual metastatic pattern mimicking a hilar cholangiocarcinoma originated from colon cancer CASE PRESENTATION: A 69-year-old man was referred to our hospital because of an upper bile duct stenosis. He had the past history of the sigmoidectomy for the primary colon cancer and the partial hepatectomy with radiofrequency ablation (RFA) for synchronous liver metastases 4 years ago. After 2 years from the initial operation, he had experienced the local recurrence of post-RFA lesion and had undergone a partial hepatectomy. According to the radiological findings of the bile duct stenosis, we diagnosed a hilar cholangiocarcinoma (Bismuth type II), and then he underwent the extended right hepatectomy with extrahepatic bile duct resection. Histological findings including the immune-histochemical examinations (CK7-, CK20+, CDX2+ and SATB2+) uncovered the metastatic tumor into extrahepatic bile duct originated from the primary colon cancer. CONCLUSION: We experienced an extremely rare case with a colon cancer metastasis mimicking a hilar cholangiocarcinoma. In this case with a past history of colon cancer, an immunohistochemical staining led us to distinguish the primary hilar cholangiocarcinoma and the mimicking tumor.