Takahiro Yamanaka

Association of RAB5 overexpression in pancreatic cancer with cancer progression and poor prognosis via E-cadherin suppression

Pancreatic cancer is a common type of cancer with poor prognosis worldwide. Postoperative survival depends on the existence of metastasis. Elucidation of the mechanism underlying cancer progression is important to improve prognosis. The RAS-associated protein RAB5 activates intracellular membrane trafficking, and RAB5 expression is correlated to progression and epithelial mesenchymal transition in various cancers. The expression of RAB5 and E-cadherin in 111 pancreatic cancer samples was investigated by immunohistochemical staining, and the relationship among RAB5 expression, clinicopathological factors, and E-cadherin expression was assessed. Furthermore, RAB5 suppression analysis by siRNA was performed to determine the roles of RAB5 in morphological change, proliferation potency, cell migration ability, and invasiveness of the pancreatic cancer cell line. High RAB5 expression correlated with the presence of lymphatic invasion and venous invasion and low E-cadherin expression. Patients with high RAB5 expression had a poorer prognosis than those with low RAB5 expression. RAB5 suppression in pancreatic cancer cells enhanced E-cadherin expression; changed cell morphology from spindle to round; and inhibited proliferation, invasion, and cell migration. RAB5 contributes to poor prognosis and progression in pancreatic cancer patients. It may be a promising candidate for individualized therapy in refractory pancreatic cancer.

Perioperative management of hepatectomy in patients with interstitial pneumonia: a report of three cases and a literature review

PurposeInterstitial pneumonia (IP) is a progressive and irreversible fibrosis and can be fatal if acute exacerbation (AE) occurs. While a useful risk-scoring system has been established for lung surgery, no risk evaluation exists for AE of IP related to non-pulmonary surgery. The objective of this review is to describe the management for patients with IP.MethodsWe experienced three hepatectomy cases with IP. The first was a 72-year-old male patient diagnosed with hepatocellular carcinoma. Preoperative computed tomography (CT) revealed IP with reticular shadow at the base of both lungs. After hepatectomy, his IP became acutely exacerbated and did not improve with steroid or sivelestat treatment. The second was a 74-year-old male patient diagnosed with hepatocellular carcinoma, and the third was a 75-year-old male patient with liver metastasis. In both these cases, CT revealed a reticular shadow in the lung fields, with increased serum KL-6 levels. We administered pirfenidone for perioperative management, during which time no respiratory complications occurred.ResultsPerioperative management with pirfenidone for hepatectomy accompanied by IP was successful in our cases.ConclusionWe reviewed reports on the perioperative prevention, intraoperative risk factors, and treatment of postoperative AE of IP and summarized the perioperative management techniques for IP patients undergoing non-pulmonary surgery.

Fairly rare clear cell adenocarcinoma mimicking liver cancer: a case report

BackgroundClear cell carcinoma commonly occurs in the ovary and kidney, and clear cell cholangiocarcinoma was rarely reported. Differential diagnosis which the origin of the tumor located on the liver surface is intrahepatic or extrahepatic was difficult. Herein, we report a case of clear cell adenocarcinoma mimicking liver cancer.Case presentationThis was a 55-year-old female who had the tumor with cystic component in the liver. She was performed hepatectomy and diagnosed as clear cell adenocarcinoma. Histopathological evaluation revealed intra-cystic clear cell adenocarcinoma. The tumor has ductal structure including mucin and atypical nuclear with clear cytoplasm. The tumor was separated from the liver and the diaphragm. The expression of Pax8 was positive, but the expression CK7 and HNF1β was positive and that of CD10 and ER was negative, which indicate that the tumor has the feature of clear cell carcinoma of ovary, not renal cell carcinoma nor cholangiocarcinoma.ConclusionsOur experience with this patient suggests that this tumor may originate from the endometriosis onto the diaphragm from the detailed results of immunohistochemical staining.

The Feature of Solitary Small Nodular Type of Hepatic Epithelioid Hemangioendothelioma

Hepatic epithelioid hemangioendothelioma (HEHE) is a rare tumor. Preoperative diagnosis of HEHE is difficult because it does not manifest specific symptoms or tumor markers. We report a resected case of small and solitary HEHE. The patient, a 74-year-old man, had undergone surgical resection for left renal cell carcinoma 20 years ago. During follow-up, a tumor approximately 1.3 cm in diameter was detected by computed tomography (CT) at liver segment VIII. It showed isodensity in the arterial phase, low density in the portal venous phase, and homogeneous enhancement in the late phase on CT and magnetic resonance imaging (MRI). We performed hepatic resection of the right hepatic vein drainage area. A pathological diagnosis of HEHE was made. Although small and solitary HEHE is rare, an enhancement pattern in each phase on CT and MRI, using contrast media, can yield clues for the diagnosis of HEHE.

Conophylline suppresses pancreatic cancer desmoplasia and cancer‐promoting cytokines produced by cancer‐associated fibroblasts

Despite recent advances in cancer treatment, pancreatic cancer is a highly malignant tumor type with a dismal prognosis and it is characterized by dense desmoplasia in the cancer tissue. Cancer‐associated fibroblasts (CAF) are responsible for this fibrotic stroma and promote cancer progression. We previously reported that a novel natural compound conophylline (CnP) extracted from the leaves of a tropical plant reduced liver and pancreatic fibrosis by suppression of stellate cells. However, there have been no studies to investigate the effects of CnP on CAF, which is the aim of this work. Here, we showed that CAF stimulated indicators of pancreatic cancer malignancy, such as proliferation, invasiveness, and chemoresistance. We also showed that CnP suppressed CAF activity and proliferation, and inhibited the stimulating effects of CAF on pancreatic cancer cells. Moreover, CnP strongly decreased the various cytokines involved in cancer progression, such as interleukin (IL)‐6, IL‐8, C‐C motif chemokine ligand 2 (CCL2), and C‐X‐C motif chemokine ligand 12 (CXCL12), secreted by CAF. In vivo, CAF promoted tumor proliferation and desmoplastic formation in a mouse xenograft model, CnP reduced desmoplasia of tumors composed of pancreatic cancer cells + CAF, and combination therapy of CnP with gemcitabine remarkably inhibited tumor proliferation. Our findings suggest that CnP is a promising therapeutic strategy of combination therapy with anticancer drugs to overcome refractory pancreatic cancers.

High expression of forkhead box protein C2 is associated with aggressive phenotypes and poor prognosis in clinical hepatocellular carcinoma

BackgroundHepatocellular carcinoma (HCC) is one of the major causes of tumor death; thus, the identification of markers related to its diagnosis and prognosis is critical. Previous studies have revealed that epithelial-to-mesenchymal transition (EMT) is involved in tumor invasion and metastasis, and the forkhead box protein C2 (FOXC2) has been shown to promote tumor cell proliferation, invasion, and EMT. In the present study, we examined the clinicopathological significance of FOXC2 and EMT-related markers in clinical HCC specimens and identified factors related to the diagnosis and prognosis of HCC.MethodsThe expression of FOXC2 and EMT-related markers was evaluated by immunohistochemistry in 84 cases of hepatocellular carcinoma.ResultsA high expression of FOXC2 was observed in 26 of 84 cases, and expression was significantly correlated with background liver cirrhosis, poor tumor differentiation, high serum AFP, and elevated cell proliferation markers. In addition, this high expression was related to the induction of the Cadherin switch and vimentin expression and was an independent predictor for poor prognosis.ConclusionThe high expression of FOXC2 in HCC is correlated with tumor malignancy and poor prognosis, suggesting that FOXC2 may be an important prognostic factor for HCC.

Skeletal Muscle Volume and Intramuscular Adipose Tissue Are Prognostic Predictors of Postoperative Complications After Hepatic Resection

Background/Aim: Recently, skeletal muscle quality was important in patients with malignant tumors to predict the surgical outcome. The relationship between postoperative complications of Clavien–Dindo grade III or more and prognosis in patients who have undergone hepatic resection for hepatic malignancies were investigated. Patients and Methods: Patient data were retrospectively collected for 146 consecutive patients who underwent curative hepatic resection in the Department of Hepatobiliary and Pancreatic Surgery, Gunma University, Japan, for hepatic malignancy. The patients were assigned to two groups according to the presence of postoperative complications. The clinicopathological and surgical outcomes were analyzed. Skeletal muscle area (SMA) and intramuscular adipose tissue content (IMAC) were also evaluated. Results: No hospital deaths occurred. Postoperative complications were identified in 12 patients (8.2%). Univariate and multivariate analyses revealed that the independent risk factors for postoperative complications were hemodialysis, psychiatric disorder, high CONUT (controlling nutritional status) score and patients both with low SMA and high IMAC. Conclusion: Intensive surgical care is necessary for high-risk patients with hemodialysis, psychiatric disorder, high CONUT count and/or low skeletal muscle quality to reduce postoperative complication.

Reduced FBXW7 expression in pancreatic cancer correlates with poor prognosis and chemotherapeutic resistance via accumulation of MCL1

Pancreatic cancer is a highly malignant tumor type with poor outcomes, and elucidation of the mechanisms involved in cancer progression and therapeutic resistance is critical. FBXW7 is a key regulator of tumor malignant potential, and its substrate MCL1 regulates therapeutic resistance in human malignancies. Therefore, determination of the relevance of FBXW7 expression is critical for improving patient outcomes. In this study, we investigated the function and clinical significance of FBXW7 in pancreatic cancer. FBXW7 expression was evaluated by immunohistochemistry in 122 pancreatic cancer tissues. Reduced FBXW7 expression was significantly associated with advanced venous invasion, high MCL1 expression, enhanced Ki-67 expression, and poor prognosis and was an independent poor prognostic factor. Among patients who underwent gemcitabine treatment after surgery, reduced FBXW7 expression was also significantly associated with poor prognosis. Knockdown of FBXW7 in vitro enhanced cell proliferation, and migration, and invasion abilities and promoted gemcitabine and nab-paclitaxel chemoresistance in pancreatic cancer cells. Moreover, FBXW7-knockdown cells showed accumulation of MCL1, and the enhanced chemoresistance observed in FBXW7-knockdown cells was eliminated by MCL1 suppression. These results suggested that FBXW7 was associated with cancer progression and mediated sensitivity to gemcitabine and nab-paclitaxel via MCL1 accumulation in pancreatic cancer. Thus, the FBXW7/MCL1 axis may be a promising therapeutic tool to overcome refractory pancreatic cancer.

Internal Hernia into the Treitz Fossa after Pancreaticoduodenectomy

The development of an internal hernia into the Treitz fossa after pancreaticoduodenectomy has not been previously reported. We herein present such a case with a brief review of the literature. A 43-year-old man who had undergone pancreaticoduodenectomy with reconstruction of the digestive tract by the Child method at our hospital 7 months previously presented with abdominal pain. Computed tomography showed intestinal ileus with formation of a small intestinal loop that was suspected to be an internal hernia. Intraoperatively, we found that the dilated small intestine had entered the upper side of the abdomen from the ligament of Treitz. We detached the intestine from the hernia and placed it in its normal position. The ligament of Treitz at the hernia orifice was closed with sutures. The patient remained in good health and was discharged from the hospital 18 days after the second operation. Suturing of the Treitz fossa at the time of pancreaticoduodenectomy may be important to prevent the formation of an internal hernia.

Carcinoma of the Papilla of Vater after Diversion Operation for Pancreaticobiliary Maljunction

Pancreaticobiliary maljunction (PBM) is a congenital malformation that is associated with biliary cancer development. When patients are diagnosed with PBM, a diversion operation is recommended. Although a risk remains for developing residual bile duct carcinoma following diversion, the development of a carcinoma of the ampulla of Vater after a diversion operation for PBM is rare. We present a treated case of carcinoma of the ampulla of Vater after a diversion operation for PBM. A 65-year-old woman presented with abdominal pain. She had undergone extrahepatic bile duct resection and cholecystectomy 2 years 9 months previously for the treatment of type Ic PBM according to the Todani classification. At the current admission for evaluation of the abdominal pain, computed tomography and magnetic resonance imaging showed only dilation of the main pancreatic duct. However, gastrointestinal endoscopy showed a tumor at the papilla of Vater, and biopsy revealed adenocarcinoma of the papilla of Vater. We performed pylorus-preserving pancreaticoduodenectomy, and the pathological diagnosis was moderately differentiated tubular adenocarcinoma of the papilla of Vater with no metastasis to the lymph nodes. The patient remained in good health for 3 years postoperatively. Carcinoma of the papilla of Vater after a diversion operation for PBM is rare. In this case, a diagnosis could not be made by computed tomography or magnetic resonance imaging; the definitive diagnosis was obtained with gastrointestinal endoscopy. Careful postoperative follow-up with gastrointestinal endoscopy in addition to imaging examination may be needed after a diversion operation for PBM.