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1.  Clinical and radiological feature of lymphoepithelial cyst of the pancreas 
World Journal of Gastroenterology : WJG  2014;20(45):17247-17253.
A lymphoepithelial cyst (LEC) of the pancreas is a rare benign lesion. Because patients with LEC of the pancreas have a good prognosis, it is important that these lesions are accurately differentiated from other more aggressive pancreatic neoplasms for an appropriate treatment strategy. Previous studies have reported that a definitive diagnosis of LEC often cannot be obtained based solely on the findings of preoperative imaging (e.g., Computed tomography or Magnetic resonance imaging). In this study, we reviewed four cases of pancreatic LECs to investigate the feature of LECs. We reviewed these cases with regard to symptoms, imaging findings, surgical procedures, and other clinical factors. We found that LEC was associated with unique characteristics on imaging findings. A preoperative diagnosis of LEC may be possible by comprehensively evaluating its clinical and imaging findings.
PMCID: PMC4258598  PMID: 25493042
Lymphoepithelial cyst; Preoperative diagnosis; Magnetic resonance imaging
2.  Protein-bound polysaccharide K suppresses tumor fibrosis in gastric cancer by inhibiting the TGF-β signaling pathway 
Oncology Reports  2014;33(2):553-558.
Peritoneal carcinomatosis (PC) is the most frequent metastatic pattern of gastric cancer and its prognosis is extremely poor. PC is characterized by rich fibrosis and the development of obstructive disorders such as ileus, jaundice and hydronephrosis. Epithelial-mesenchymal transition (EMT) is one of the major causes of tissue fibrosis and transforming growth factor β (TGF-β) has a pivotal function in the progression of EMT. Protein-bound polysaccharide K (PSK) is a biological response modifier that can modulate the TGF-β/Smad signaling pathway in vitro. In the present study, we established a fibrotic tumor model using human peritoneal mesothelial cells (HPMCs) and a human gastric cancer cell line to evaluate whether PSK attenuates tumor fibrosis. HPMCs exposed to PSK did not undergo the morphological change from a cobblestone-like pattern to a spindle-shape pattern normally induced by treatment with TGF-β. Immunofluorescence further demonstrated that PSK suppressed TGF-β-induced overexpression of α-SMA in the HPMCs. We further showed that HPMCs contributed to the proliferation of tumor fibrosis by using a mouse xenograft model. Additionally, PSK treatment of these mice significantly reduced the area of observable tumor fibrosis. These results suggest that seeded cancer cells transformed HPMCs into myofibroblast-like cells through their release of TGF-β in the microenvironment, facilitating the development of fibrous tumors in organs covered with HPMCs. Therefore, our study indicates that PSK has potential utility as an anti-fibrotic agent in the treatment of gastric cancer patients with PC.
PMCID: PMC4306268  PMID: 25435013
protein-bound polysaccharide; transforming growth factor β; gastric cancer; cancer-associated fibroblast
3.  A Case of Living Donor Liver Transplant Recipient Treated With Novel Blood Purification “Plasma Diafiltration” 
International Surgery  2013;98(4):428-431.
Blood purification therapy is indispensable for liver transplant recipients. The case of a living donor liver transplant recipient who represented graft insufficiency and was supported by novel blood purification “plasma diafiltration” immediately after operation is presented. A 60-year-old woman was referred for living donor liver transplant because of liver cirrhosis due to hepatitis C. Elective living donor liver transplant was performed, but the graft was small for size. Thus, the signs of graft insufficiency appeared immediately after the operation, and plasma diafiltration was used as a bridge to graft regeneration. After plasma diafiltration was started, the recipient recovered promptly, and withdrawal was performed 35 hours after induction without any complications. Plasma diafiltration is a useful and safe liver support for liver transplant recipients, including immediately after liver transplantation.
PMCID: PMC3829076  PMID: 24229036
Artificial organ support; Graft insufficiency; Liver support; Small-for-size graft syndrome
4.  Pioglitazone inhibits the proliferation and metastasis of human pancreatic cancer cells 
Oncology Letters  2014;8(6):2709-2714.
Proliferator-activated receptor-γ (PPAR-γ) is a nuclear receptor that acts as a transcription factor in several types of tissue. PPAR-γ ligands are known to inhibit numerous cancer cell processes, including pancreatic cancer cell proliferation through terminal differentiation. Previous studies concerning the inhibitory effect of PPAR-γ ligands derived from thiazolidinediones (TZDs) on the metastatic potential of cancer cells have been reported. The present study aimed to investigate whether pioglitazone, a prescription TZD class drug and a ligand of PPAR-γ, inhibits the proliferation and metastasis of pancreatic cancer cells. The inhibitory effect of pioglitazone on the proliferation of the Capan-1, Aspc-1, BxPC-3, PANC-1 and MIApaCa-2 pancreatic cancer cell lines was analyzed. Alterations in carcinoembryonic antigen (CEA), interleukin-8 (IL-8) and cyclooxygenase-2 (COX-2) mRNA expression levels subsequent to pioglitazone treatment were examined in BxPC-3 cells by quantitative reverse transcription polymerase chain reaction. In addition, whether the oral administration of pioglitazone prevents tumorigenesis and spontaneous BxPC-3 cell lymph node and lung metastases was investigated using a rectal xenograft model. Pioglitazone treatment resulted in the inhibition of proliferation in all five pancreatic cancer cell lines in vitro. Pioglitazone induced CEA mRNA expression, suppressed IL-8 and COX-2 mRNA expression in vitro, and inhibited BxPC-3 xenograft growth. Pioglitazone also reduced BxPC-3 cell lymph node and lung metastasis in the rectal xenograft model. These results suggest that pioglitazone treatment inhibited the proliferation and metastasis of pancreatic cancer cells through the induction of differentiation and the inhibition of angiogenesis-associated protein expression.
PMCID: PMC4214501  PMID: 25364454
pioglitazone; lymph node metastasis; lung metastasis; pancreatic cancer; differentiation; rectal xenograft model
5.  Barrett’s esophagus and animal models 
Concise summaries
Significant progress has been made in the last few decades using animal models to recreate the esophagitis–metaplasia–carcinoma sequence similar to that seen in human Barrett’s esophagus (BE) and EAC. More recent works focus on molecular pathways associated with intestinal metaplasia and carcinogenesis, as well as similarities between genetic mutations occurring in humans and animal models, mouse, rat, pig, rabbit, guinea pig, dog, cat, ferret, and possum.
Despite the lack of a perfect model, there is still significant potential in using these models to clarify the contribution of different types of reflux (gastric, biliary, and pancreatic) to esophageal adenocarcinoma and to determine how the different types of refluxate interact.
Refluxed duodenal contents cause gastric and esophageal carcinoma in rats without exposure to carcinogens, and several rat duodenal contents reflux models have been developed. BE in the animal models has well-developed goblet cells positive forMUC2, gastric pyloric-type mucins positive for MUC6, and sometimes intermingled with gastric foveolar-type mucins positive for MUC5AC.
A gut regenerative cell lineage, characterized by pyloric–foveolar metaplasia followed by the appearance of goblet cells, occurs in the regenerative process in response to chronic inflammation.
High animal-fat dietary intake causes severe obesity, resulting in the development of increased abdominal pressure and increased refluxate, particularly of the duodenal contents. The N-nitroso bile acid conjugates, which have mutagenecity, play an important role in Barrett’s carcinogenesis, and are stabilized by gastric acid.
Experiments have been made in a rodent duodeno-esophageal reflux model using thioproline or cyclooxygenase-2 inhibitor to prevent the inflammation–metaplasia– adenocarcinoma sequence. Thioproline is one of the nitrite scavengers, which reduce the production of carcinogenic nitroso-compounds. Celecoxib could postpone the sequence itself, whereas thioproline could only prevent the evolution of Barrett’s esophagus to cancer.
The Levrat’s surgical model of esophago-duodenal anatomosis in rats has been shown to induce gastroduodenojejunal reflux. This in vivo model reproduces the sequence of histologic and molecular events that lead to the development of BE and esophageal adenocarcinoma in humans and, as such, provides a realistic and translatable model for development of therapeutics for EAC.
A pilot study using proteomics to evaluate for differentially expressed markers in the progression from metaplasia to dysplasia and ultimately adenocarcinoma in human tissues has been conducted.
Differential expression of cytokeratin 20 in specimens from human patients and the Levrat’s model substantiated the hypothesis that the animal model is representative of human cancer and, hence, further supporting the basis for its utilization.
Furthermore, if this data is confirmed, the Levrat’s approach may serve as a model for preclinical drug development. Up to ten potential novel target regimens identified and selected through the proteomics screen will be tested in a multi-arm study in rats.
PMCID: PMC4091915  PMID: 21950831
esophageal neoplasm; Barrett’s esophagus; duodenogastric reflux; bile reflux; carcinoma; histogenesis; gut regenerative cell lineage; pyloric–foveolar metaplasia; fat intake; DNA adducts; N-nitroso bile acids; chemoprevention; duodenoesophageal reflux; thioproline; cyclooxygenase-2 inhibitor
6.  Lymph node spread of gallbladder cancer from the perspective of embryologically-based anatomy and significance of the lymphatic basin along the embryonic right hepatic artery 
Molecular and Clinical Oncology  2014;2(6):963-967.
Lymph node metastasis from gallbladder cancer is often found in the pericholedochal area; however, these regional lymph nodes are not typically accompanied by arteries. We hypothesized that the artery accompanying pericholedochal lymph nodes was either the regressed embryonic right hepatic artery (eRHA) or an aberrant right hepatic artery (aRHA) remaining without regression. This study aimed to determine the artery supplying pericholedochal lymph nodes. We obtained serial tissue sections of resected specimens from 10 patients who underwent pancreaticoduodenectomy with combined resection of the superior mesenteric artery and vein and investigated the association between the distribution of enlarged lymph nodes and the course of blood vessels in each section. In 2 cases with aRHA, enlarged lymph nodes were distributed in the posterosuperior area, pancreaticoduodenal region and retroportal area along this artery. By contrast, no blood vessels accompanied enlarged lymph nodes in 8 patients exhibiting a normal hepatic artery branching pattern, although these nodes exhibited a distribution pattern similar to that of patients with the aRHA. Thus, the artery supplying pericholedochal lymph nodes appears to be either the regressed eRHA or an aRHA persisting without regression.
PMCID: PMC4179785  PMID: 25279182
right hepatic artery; embryonic right hepatic artery; lymph node metastasis; gallbladder cancer; lymphadenectomy; pericholedochal lymph node
7.  Colonic stenosis caused by infection of an intraperitoneal access port system: a rare complication of intraperitoneal chemotherapy for gastric cancer with peritoneal metastasis 
Intraperitoneal (IP) chemotherapy is garnering attention as an effective treatment for gastric cancer with peritoneal metastasis. We report the case of a patient who developed colonic stenosis caused by infection of an IP access port system during IP chemotherapy. It was difficult to differentiate whether the extrinsic colonic stenosis arose from a catheter infection or peritoneal metastasis of the gastric cancer.
Case presentation
A 66-year-old Japanese man underwent total gastrectomy for gastric cancer. Because the intraoperative findings revealed peritoneal metastasis, a port system was implanted for subsequent IP chemotherapy. Two months after initiation of chemotherapy, he complained of vomiting and abdominal pain. A computed tomography scan revealed marked thickening of the sigmoid colon wall adjacent to the catheter of the IP access port system. A barium enema demonstrated extrinsic irregular stenosis of the sigmoid colon. Although it was difficult to distinguish whether infection or peritoneal metastasis had caused the colonic stenosis, we removed the port system to obtain a therapeutic diagnosis. Coagulase-negative staphylococci were detected by catheter culture. The wall thickening and stenosis of the sigmoid colon completely resolved after removal of the port system.
We report the case of a rare complication in association with an IP access port system. Infection of the port system should be considered as a differential diagnosis when colonic stenosis adjacent to the catheter is observed during IP chemotherapy.
PMCID: PMC4050104  PMID: 24893606
Intraperitoneal chemotherapy; Gastric cancer; Peritoneal metastasis; Port complication
8.  Impact of histone deacetylase 1 and metastasis-associated gene 1 expression in esophageal carcinogenesis 
Oncology Letters  2014;8(2):758-764.
Animal models are important for the development of novel therapies for esophageal cancer. Histone deacetylase 1 (HDAC1)/metastasis-associated gene (MTA1) complexes inhibit p53 acetylation and thus, inhibit p53-induced apoptosis. The aim of the present study was to evaluate HDAC1 and MTA1 expression in esophageal carcinogenesis in rats. The rats underwent a total gastrectomy followed by esophagojejunostomy to induce chronic duodenal content reflux esophagitis. The rats were sacrificed sequentially at 20, 30, 40 and 50 weeks post-surgery and the esophagi were examined. Immunohistochemical analysis was conducted to assess the expression and localization of HDAC1 and MTA1. At 20 weeks post-surgery, squamous proliferative hyperplasia and Barrett’s metaplasia (BM) were observed. While, adenocarcinoma-associated BM and squamous cell carcinoma were observed at 30–50 weeks post-surgery. The nuclear expression of HDAC1 and MTA1 was observed in all of the stages of squamous carcinogenesis and adenocarcinogenesis, although not in the normal esophageal epithelium. The expression of HDAC1 and MTA1 may be involved in duodenoesophageal reflux-induced neoplastic transformation of the esophageal mucosa into cancer cells with squamous and adeno differentiation.
PMCID: PMC4081431  PMID: 25009653
metastasis-associated gene; histone deacetylases; esophageal carcinogenesis; esophageal adenocarcinoma; Barrett’s esophagus
9.  Clinicopathological characterization of so-called “cholangiocarcinoma with intraductal papillary growth” with respect to “intraductal papillary neoplasm of bile duct (IPNB)” 
Cholangiocarcinoma (CC) of the biliary tract occasionally presents a predominant intraductal papillary growth in the bile ducts, called as biliary tract carcinoma (BTC) of papillary growth (PG) and intrahepatic CC (ICC) of intraductal growth (IG) type. Recently, intraductal papillary neoplasm of bile duct (IPNB) has been proposed as a pre-invasive biliary neoplasm. This study was performed to characterize pathologically BTC of PG type and ICC of IG type with respect to IPNB. It was found that 126 of such 154 CCs (81.8%) fulfilled the criteria of IPNB, while the remaining 28 cases showed different histologies, such as tubular adenocarcinoma and carcinosarcoma. These IPNBs occurred in old aged patients with a male predominance, and the left lobe was rather frequently affected in the liver. A majority of these cases were high grade IPNB (43 cases) and invasive IPNB (77 cases), while low grade IPNB was rare (6 cases). Pancreatobiliary type was predominant (48 cases) followed by gastric (30 cases), intestinal (29 cases) and oncocytic (19 cases) types. Mucus hypersecretion was found in 45 cases, and this was frequent in IPNB at the intrahepatic large bile duct and hilar bile ducts but rare at the extrahepatic bile ducts. Interestingly, 36 cases of high grade and invasive IPNBs contained foci of moderately differentiated adenocacinoma within the intraductal papillary tumor. In conclusion, a majority of ICC of IG type and BTC of PG type could be regarded as a IPNB lineage, and clinically detectable IPNBs were already a malignant papillary lesion.
PMCID: PMC4097227  PMID: 25031730
Biliary tree; intraductal papillary neoplasm; intraductal cholangiocarcinoma; papillary cholangiocarcinoma; phenotype
10.  A Modification of Radical Antegrade Modular Pancreatosplenectomy for Adenocarcinoma of the Left Pancreas: Significance of En Bloc Resection Including the Anterior Renal Fascia 
World Journal of Surgery  2014;38(9):2448-2454.
Radical antegrade modular pancreatosplenectomy (RAMPS) has theoretical advantages for curative resection of adenocarcinomas of the left pancreas. The anterior renal fascia is a key structure, and resection planes should run posterior to this fascia. However, it is difficult to delineate this fascia and set a precise dissection plane. We modified RAMPS to achieve such a precise dissection plane with ease.
After clamping the splenic artery, the third duodenal portion was mobilized from the left to the right to locate the inferior vena cava, which was covered by the anterior renal fascia. Here, the anterior renal fascia was incised while approaching the dissection plane. Dissection then continued cephalad, with this plane along the inferior vena cava, and then turned along the left renal vein at the confluence of the left renal vein toward the renal hilum. At this point, dissection continued along the coronal plane to the superior edge of the pancreas.
Between July 2007 and December 2012, a total of 24 pancreatic adenocarcinoma patients underwent modified RAMPS. Tumor extension beyond the pancreatic parenchyma (T3) and lymph node metastases was confirmed in 17 and 13 cases, respectively. Histologically clear surgical margins were achieved (R0 resection) in 21 patients (88 %). The 5-year overall survival rate was 53 %. Six patients survived for over 5 years without recurrence.
This modification of RAMPS is advantageous for en bloc resection while actually including removal of the anterior renal fascia. It is associated with satisfactory survival rates for patients with distal pancreatic carcinomas.
PMCID: PMC4124261  PMID: 24752361
11.  Isolated adrenocorticotropic hormone deficiency development during chemotherapy for gastric cancer: a case report 
Isolated adrenocorticotropic hormone deficiency is an endocrinological disorder characterized by loss of adrenocorticotropic hormone and resultant adrenal insufficiency. Affected patients often present with fatigue, anorexia, and hyponatremia. Although the number of reported cases has been recently increasing, isolated adrenocorticotropic hormone deficiency combined with malignant neoplasia is very rare. Here we describe a patient with gastric cancer who developed unexpected isolated adrenocorticotropic hormone deficiency during chemotherapy.
Case presentation
A 72-year-old Japanese man was admitted to our hospital because of febrile neutropenia due to chemotherapy for gastric cancer recurrence. Although the neutropenia and fever immediately improved, he became unable to take any oral medications and was bedridden 1 week after admission. His serum sodium level abruptly decreased to 122mEq/L on the fifth day of hospitalization. We performed endocrinological studies to investigate the cause of his hyponatremia and plasma hyposmolality. His plasma adrenocorticotropic hormone and cortisol levels were very low. However, his serum levels of all other anterior pituitary hormones were slightly elevated. We then performed a corticotropin-releasing hormone test, which showed that neither his plasma adrenocorticotropic hormone nor cortisol level responded to corticotropin-releasing hormone stimulation. We definitively diagnosed isolated adrenocorticotropic hormone deficiency based on these findings. Hydrocortisone replacement therapy was begun at 20mg/day, resulting in a marked improvement in his anorexia and general fatigue within a few days. His serum sodium level was also normalized immediately after the administration of hydrocortisone. He was discharged from our hospital on the 50th day of hospitalization.
The present case is the second report of a patient with concurrent isolated adrenocorticotropic hormone deficiency and gastric cancer and the first report of a patient diagnosed with isolated adrenocorticotropic hormone deficiency during the course of chemotherapy for a solid malignant neoplasm. Although the symptoms and signs described in the present report are common observations during chemotherapy, it is important to consider not only the adverse effects of antineoplastic agents, but also isolated adrenocorticotropic hormone deficiency as a differential diagnosis. Hydrocortisone replacement therapy for isolated adrenocorticotropic hormone deficiency effectively avoids the unnecessary cessation of chemotherapy.
PMCID: PMC3976173  PMID: 24597969
Chemotherapy; Gastric cancer; Hyponatremia; Isolated ACTH deficiency
12.  En bloc vascular resection for the treatment of borderline resectable pancreatic head carcinoma 
Molecular and Clinical Oncology  2014;2(3):369-374.
Borderline resectable (BR) pancreatic head carcinoma (PhC) is an advanced disease, presenting with infiltration of major vessels. Major vascular resection (VR), particularly arterial resection, to achieve microscopic no residual tumor (R0) is a controversial approach, due to the potential complications. In this study, we aimed to clarify the benefit of en bloc R0 resection with VR for PhC by retrospectively evaluating 78 PhC patients who underwent pancreatoduodenectomy at our institute. The patients were divided into 4 groups as follows: R, resectable (n=20); BR-V, BR involving the superior mesenteric vein or portal vein (PV) (n=28); BR-SMA, BR involving the superior mesenteric artery (n=21); and BR-HA, BR involving the hepatic artery (n=9). In total, 65 patients underwent VR, with 63, 21 and 9 patients undergoing PV, SMA and HA resection, respectively. The R0 rates were as follows: R group, 85%; BR-V, 82%; BR-SMA, 71%; and BR-HA, 33%. The median survival time and 5-year survival rate for R0 resection were 31 months and 25% in the R group, 22 months and 28% in the BR-V group, 17 months and 27% in the BR-SMA group and 10 months and 0% in the BR-HA group, respectively. The prognosis was comparable among the BR-V, BR-SMA and R groups, but was significantly poorer in the BR-HA group. In total, 5 patients (6.4%) died perioperatively (4 from postoperative hemorrhage and 1 from suffocation due to failure of expectoration, without pneumonia or asthma). Of the 4 patients who succumbed to hemorrhage, 3 had undergone arterial resection. Therefore, en bloc resection with major VR for R0 may be suitable for BR-V and BR-SMA PhC patients.
PMCID: PMC3999123  PMID: 24772302
borderline resectable; pancreatic head carcinoma; en bloc arterial resection; meso-pancreatoduodenum; superior mesenteric artery
13.  Pancreatic body adenocarcinoma with neuroendocrine tumor characteristics: A case report 
Oncology Letters  2014;7(4):1049-1052.
A 61-year-old female with pancreatic body cancer underwent a distal pancreatectomy. The tumor was a moderately- to poorly-differentiated adenocarcinoma. Tumor growth filled the dilated main pancreatic duct (MPD) and infiltrated the surrounding area. Six months later, metastases to the left diaphragm and MPD of the remnant pancreatic head were detected. Chemoradiotherapy was administered, but the patient succumbed 22 months after surgery. An autopsy demonstrated that a moderately- to poorly-differentiated adenocarcinoma had arisen from the pancreatic head and infiltrated the duodenum and bile duct. Huge liver metastases and multiple peritoneal disseminations were also present. Microscopically, a portion of the tumor had a pseudo-rosette appearance in the adenocarcinoma component, while another section showed characteristics of a neuroendocrine tumor (NET) immunohistochemically. The original surgically-resected tumor also showed NET characteristics immunohistochemically. It is therefore necessary to search for NET components in pancreatic cancer with atypical growth and metastases, even when adenocarcinoma has been diagnosed histologically.
PMCID: PMC3961464  PMID: 24944667
pancreatic adenocarcinoma; neuroendocrine tumor; immunohistochemistry
14.  A case report of anaplastic carcinoma of the pancreas with remarkable intraductal tumor growth into the main pancreatic duct 
We herein report a case of anaplastic carcinoma of the pancreas with remarkable intraductal tumor growth into the main pancreatic duct. A 76-year-old male was referred to our hospital for treatment of a pancreatic tumor. Preoperative examinations revealed a poorly defined tumor in the main pancreatic duct in the body of the pancreas, accompanied with severe dilatation of the main pancreatic duct, which was diagnosed as an intraductal papillary-mucinous neoplasm. We performed distal pancreatectomy and splenectomy. The pathological examination revealed that the tumor consisted of a mixture of anaplastic carcinoma (giant cell type) and adenocarcinoma in the pancreas. There was a papillary projecting tumor composed of anaplastic carcinoma in the dilated main pancreatic duct. The patient is now receiving chemotherapy because liver metastasis was detected 12 mo after surgery. In this case, we could observe a remarkable intraductal tumor growth into the main pancreatic duct. We also discuss the pathogenesis and characteristics of this rare tumor with specific tumor growth.
PMCID: PMC3921494  PMID: 24574758
Anaplastic carcinoma; Giant cell carcinoma; Intraductal tumor growth; Papillary projecting tumor
15.  Treatment of capecitabine-induced hand-foot syndrome using a topical retinoid: A case report 
Oncology Letters  2013;7(2):444-448.
Capecitabine is a chemotherapeutic drug used in patients with breast, colon and gastric cancer. Hand-foot syndrome (HFS) is a type of dermatitis that frequently occurs as a reaction to capecitabine. To date, no effective strategies have been found to prevent or reverse HFS. Furthermore, chemotherapy induces an elevation in the expression of heparin-binding epidermal growth factor-like growth factor (HB-EGF), and this activation represents a critical mechanism for the induction of chemotherapeutic resistance. Adapalene is a third-generation synthetic retinoid. Topical retinoids are important therapeutic anti-aging agents for managing photodamaged skin, and are known to increase HB-EGF levels, which is important for skin wound healing. Accordingly, the current report focused on the topical retinoids that increase HB-EGF expression in the skin, and we hypothesized that these topical retinoids induce local chemotherapeutic resistance in the skin of patients receiving chemotherapy and consequently, decrease the cutaneous side-effects of chemotherapy. This report presents a case of the successful treatment of refractory HFS induced by capecitabine using the topical application of adapalene. Topical adapalene was applied for 3 months and significantly reduced inflammation and pain following chemotherapy. Topical retinoids may have the potential to effectively treat capecitabine-induced HFS by increasing HB-EGF expression and decreasing cutaneous side-effects. Further studies are required to establish the therapeutic efficacy of topical retinoids on HFS.
PMCID: PMC3881915  PMID: 24396465
retinoid; adapalene; hand-foot syndrome; capecitabine; heparin-binding epidermal growth factor-like growth factor; chemotherapeutic resistance
16.  VEGF is a target molecule for peritoneal metastasis and malignant ascites in gastric cancer: prognostic significance of VEGF in ascites and efficacy of anti-VEGF monoclonal antibody 
OncoTargets and therapy  2013;6:1445-1451.
In gastric cancer, poor prognosis is associated with peritoneal dissemination, which often accompanies malignant ascites. We searched for a target molecule in peritoneal metastasis and investigated its clinical utility as a biomarker.
Biopsy specimens from both primary lesions and peritoneal metastasis, and if possible, malignant ascites, were obtained from 40 patients with gastric cancer. Vascular endothelial growth factor (VEGF) expression was analyzed by immunohistochemical staining and enzyme-linked immunosorbent assay.
VEGF expression was seen in 70% of peritoneal samples. Of the 40 patients, 35 had malignant ascites. These 35 patients were divided into two groups: 15 with ascites found beyond the pelvic cavity (large group) and 20 whose ascites were within the pelvic cavity (small group). The two groups did not significantly differ by serum VEGF levels, but ascites VEGF levels in the large group were significantly higher than in the small group (P < 0.0001). Serum VEGF and ascites VEGF levels were highly correlated in the large group (r = 0.686). A high ascites VEGF level was found to be a risk factor for survival (P = 0.045). We include a report of a patient with chemoresistant refractory gastric cancer and symptomatic ascites who obtained 8 months of palliation from systemic bevacizumab.
Anti-VEGF therapies are promising, and the ascites VEGF level is an important marker in managing patients with gastric cancer and peritoneal metastasis.
PMCID: PMC3804591  PMID: 24204159
vascular endothelial growth factor; malignant ascites; peritoneal metastasis; gastric cancer; bevacizumab
17.  Duodenal ulcer penetration into the liver at the previous left hemihepatectomy site☆ 
Duodenal ulcer penetration into the liver is a rare, but serious complication. Its frequency was thought to have decreased owing to advances in therapies for peptic ulcers. However, we encountered a case in which the duodenal ulcer had penetrated into a previous hemihepatectomy site.
A 69-year-old man with a history of left hemihepatectomy 20 months previously presented to the emergency room with sudden-onset abdominal pain and nausea. An upper gastrointestinal examination with a fiberscope revealed a giant ulcer in the duodenal bulb. In addition, a foreign body was detected at the ulcer floor and was strongly suspected of being a ligature from previous hemihepatectomy.
The presence of a gas-filled liver mass and bowel wall thickening with inflammatory changes are important imaging findings for prompt diagnosis of such a condition, but in this case, none of these were reported. Further, no definite abscess was found. Thus, the patient was treated conservatively with a proton pump inhibitor.
This case demonstrates the importance of using absorbable suture materials, adequate lavage in the postoperative peritoneal space and gastroduodenal mucosal protection postoperatively.
PMCID: PMC3860026  PMID: 24240081
Hepatectomy; Duodenal ulcer; Proton pump inhibitor; Penetration; Hepatoduodenal fistula
18.  Internal Hernia in a Liver Transplant Recipien: A Case Report 
Case Reports in Surgery  2013;2013:923647.
Biliary complications have great importance for liver transplant recipients because of affecting long-term prognosis. In rare situations, an internal hernia of the Roux-en-Y loop cause graft injury. A 42-year-old woman with a history of living donor liver transplantation 6 years ago presented with prolonged graft injury during the past 6 months. She suddenly developed ileus of the small bowel with internal hernia through the defect of the mesentery around the Roux-en-Y limb of the hepaticojejunostomy. Emergent surgery was performed to reduce the hernia and volvulus; also the mesenteric rent was closed with interrupted suture of silk. Internal hernia of the small bowel after liver transplantation is rare but causes graft injury due to associated biliary complications and rapid deterioration of patient's condition.
PMCID: PMC3789415  PMID: 24159411
19.  Low-dose paclitaxel inhibits the induction of epidermal-mesenchymal transition in the human cholangiocarcinoma CCKS-1 cell line 
Oncology Letters  2013;6(4):915-920.
Epidermal-mesenchymal transition (EMT) confers an advantage to cancer cells by improving their invasive capacity and metastatic potential. This phenomenon by which epidermal cells change into mesenchymal cells and therefore acquire a higher ability to automaticity, is considered a key process in cancer development. Transforming growth factor-β (TGF-β) is a significant factor for accelerating EMT through the activation of proteins, including members of the Smad pathway. Furthermore, previous studies have shown that low-dose paclitaxel (PTX) inhibits EMT in certain cell lines, including those of cancer cells. The present study determined whether low-dose PTX was able to inhibit EMT in a human cholangiocarcinoma CCKS-1 cell line that had been treated with TGF-β1. First, the cytotoxic concentration of PTX for the CCKS-1 cells was identified to be ~5 nM by MTT assay and dead cell staining. Therefore, the concentrations of PTX were set as 1 nM, 2.5 nM and 5 nM for the subsequent experiments. In the morphological investigation, the CCKS-1 cells changed into a spindle morphology and became separated by the administration of TGF-β1. However, low-dose PTX inhibited these changes and the morphology resembled the control cells in a dose-dependent manner. Similarly, immunofluorescence and immunoblotting investigations revealed that the CCKS-1 cells expressed mesenchymal markers following the administration of TGF-β1. However, low-dose PTX inhibited the expression of the mesenchymal markers and the CCKS-1 cells expressed the epithelial marker, E-cadherin. In particular, a concentration-dependent effect was observed in the immunoblotting experiments. These results show that PTX may be able to inhibit EMT in cancer cells, depending on the dose concentration.
PMCID: PMC3796399  PMID: 24137436
cholangiocarcinoma; paclitaxel; epidermal-mesenchymal transition
20.  Hepatic arterial infusion chemotherapy with gemcitabine and 5-fluorouracil or oral S-1 improves the prognosis of patients with postoperative liver metastases from pancreatic cancer 
Molecular and Clinical Oncology  2013;1(5):869-874.
Hepatic metastasis is a common cause of treatment failure following resection of pancreatic cancer. In this study, we report our results of hepatic arterial infusion (HAI) chemotherapy with gemcitabine (GEM) plus 5-fluorouracil (5-FU) or oral S-1 treatment for postoperative liver metastases from pancreatic cancer. Seven patients with postoperative liver metastases from pancreatic cancer received HAI with GEM plus 5-FU or oral S-1 between October, 2008 and September, 2010 at Kanazawa University Hospital (Kanazawa, Japan). Three out of the 7 cases exhibited a partial response (PR) according to Response Evaluation Criteria in Solid Tumors (RECIST) and stable disease (SD) was achieved in 3 out of the 7 cases (response rate, 85.7%). A decrease in serum tumor marker CA 19-9 levels was observed after 10 HAI treatment cycles in 5 out of the 7 cases. The median time to treatment failure was 8 months (range, 0–17 months). Adverse events included grade 3 leukocytopenia in 1 case and anemia in all 7 cases, although 5 out of the 7 patients were anemic prior to HAI therapy. Grade 2 thrombocytopenia was also observed in 2 cases. Non-hematological events, such as nausea, diarrhea, liver injury or neuropathy and life-threatening toxicities were not reported; however, 6 patients (85.7%) developed catheter-related complications and the HAI catheter and subcutaneous implantable port system had to be removed. These findings demonstrated that HAI may deliver high doses of chemotherapeutic agents directly into the tumor vessels, producing increased regional levels with greater efficacy and a lower incidence/severity of systemic side effects. In conclusion, HAI chemotherapy is a safe and effective treatment for liver metastases from pancreatic cancer.
PMCID: PMC3916203  PMID: 24649263
pancreatic cancer; liver metastasis; hepatic arterial infusion; gemcitabine; 5-fluorouracil; S-1
21.  Evaluation of eligibility criteria in living donor liver transplantation for hepatocellular carcinoma by α-SMA-positive cancer-associated fibroblasts 
Oncology Reports  2013;30(4):1561-1574.
The eligibility criteria of liver transplantation (LT) for hepatocellular carcinoma (HCC) must clearly confirm the prognosis not only from pathological diagnosis but also from pre-operative imaging diagnosis. In the present study, we evaluated published eligibility criteria for LT based on both pre-operative imaging diagnosis and pathological diagnosis using living donor liver transplantation (LDLT) recipients at our hospital by α-smooth muscle actin (SMA)-positive cancer-associated fibroblasts (CAFs) in HCC. The Up-to-seven (Up-to-7), Asan and Tokyo criteria were evaluated, in both overall survival and HCC disease-free survival, to be statistically significantly beneficial criteria to define post-LDLT prognosis. Recipients only within Up-to-7 criteria based on both pre-operative imaging diagnosis and pathological diagnosis survived without HCC recurrence. Recipients with proliferation of α-SMA-positive CAFs in HCC had significantly poorer prognosis. All survival recipients without HCC recurrence, who were above the Up-to-7 criteria in pathological diagnosis, had no proliferation of α-SMA-positive CAFs. As a result of multivariate analysis, the significant independent factors defining prognosis of recipients after LDLT for HCC were Up-to-7 criteria and proliferation of α-SMA-positive CAFs. The ideal eligibility criteria for LDLT with HCC is Up-to-7 criteria and α-SMA-positive CAFs was considered to be an important factor in HCC recurrence. LDLT should be limited to recipients within Up-to-7 criteria or without proliferation of α-SMA-positive CAFs.
PMCID: PMC3810217  PMID: 23863893
living donor liver transplantation; hepatocellular carcinoma; cancer-associated fibroblast; Up-to-seven criteria; α-smooth muscle actin
22.  Intraductal papillary neoplasm of the bile duct accompanying biliary mixed adenoneuroendocrine carcinoma 
We present the first case of an intraductal papillary neoplasm of the bile duct (IPNB) accompanying a mixed adenoneuroendocrine carcinoma (MANEC). A 74-year-old woman presented with fever of unknown cause. Laboratory data revealed jaundice and liver injury. Contrast-enhanced computed tomography revealed a 20 mm polypoid tumor in the dilated distal bile duct, which exhibited early enhancement and papillary growth. Upper gastrointestinal endoscopy revealed mucus production from the papilla of Vater, characterized by its protruding and dilated orifice. Endoscopic ultrasonography visualized the polypoid tumor in the distal bile duct, but no invasive region was suggested by diagnostic imaging. Therefore, the initial diagnosis was IPNB. After endoscopic nasobiliary drainage, a pylorus-preserving pancreaticoduodenectomy was performed. Pathological examination of the resected bile duct revealed papillary proliferation of biliary-type cells with nuclear atypia, indicating pancreaticobiliary-type IPNB. In addition, solid portions comprised of tumor cells with characteristic salt-and-pepper nuclei were evident. Immunohistochemistry revealed expression of the neuroendocrine marker synaptophysin in this solid component, diagnosing it as a neuroendocrine tumor (NET). Furthermore, the MIB-1 proliferation index of NET was higher than that of IPNB, and microinvasion of the NET component was found, indicating neuroendocrine carcinoma (NET G3). This unique case of MANEC, comprising IPNB and NET, provides insight into the pathogenesis of biliary NET.
PMCID: PMC3662959  PMID: 23716999
Neuroendocrine tumor; Intraductal papillary neoplasm of bile duct; Intraductal papillary neoplasm of the bile duct; Bile duct
23.  A phase I study of neoadjuvant chemotherapy with gemcitabine plus oral S-1 for resectable pancreatic cancer 
Molecular and Clinical Oncology  2013;1(4):768-772.
The aim of this study was to determine the maximum-tolerated dose (MTD), the dose-limiting toxicity (DLT) and the recommended dose (RD) of neoadjuvant chemotherapy (NAC) with gemcitabine (GEM) plus oral S-1 in patients with resectable pancreatic cancer. Thirteen patients with radiologically proven resectable pancreatic cancer were included in this study. S-1 was administered orally for 14 consecutive days, and GEM was administered on days 8 and 15 for two pre-operative cycles. The dose of S-1 in this study was planned with fixed doses of GEM (1,000 mg/m2): 20, 30 and 40 mg/day for levels 0, 1 and 2, respectively. Treatment was initiated at level 1 in 3 patients, while adverse events occurred in 2 patients during the second course, leading to a dose reduction to level 0 for the 8 remaining patients. Two of the 10 patients enrolled at level 0 were excluded. Of the remaining 8 patients, GEM administration was terminated due to DLT on day 15, during the first course in 3 patients, while level 0 dosage reached MTD. Surgery was performed for the remaining 11 patients included in the study. Post-operative complications included pancreatic fistulas in 5 patients and Pseudomonas aeruginosa sepsis in 1 patient. Two of the 11 patients exhibited a partial response and 9 patients stable disease. Eight of the 11 tumor specimens showed histopathological evidence of tumor cell injury. In conclusion, NAC with GEM and S-1 was not well-tolerated in this study. However, pre-operative chemotherapy may be effective against pancreatic cancer. Therefore, it is necessary to reconsider NAC regimens for pancreatic cancer.
PMCID: PMC3915328  PMID: 24649244
pancreatic cancer; gemcitabine; S-1; neoadjuvant chemotherapy; phase I
24.  The retropancreatic fusion fascia acts as a barrier against infiltration by pancreatic carcinoma 
Molecular and Clinical Oncology  2013;1(3):418-422.
Although pancreatic carcinoma frequently extends posteriorly beyond the pancreatic parenchyma, retroperitoneal organs such as the inferior vena cava (IVC) and the adrenal gland are rarely involved. The fusion fascia lies between the pancreas and these retroperitoneal organs. This study investigated the role of the fusion fascia in the prevention of infiltration of retroperitoneal structures by pancreatic carcinoma. This study was conducted on 140 patients who underwent pancreatic carcinoma resection at our hospital. Retropancreatic infiltration was divided into three grades as follows: Grade 0, carcinoma confined within the pancreatic parenchyma; grade 1, carcinoma infiltrating beyond the parenchyma but within the fusion fascia; and grade 2, infiltration of retroperitoneal tissues beyond the fusion fascia. Grade 0 was found in 24%, grade 1 in 73% and grade 2 in 3% of the cases. There was no significant difference in the prevalence of grade 2 between pancreatoduodenectomy (PD) and distal pancreatectomy (DP). Pancreatic carcinoma infiltrated posteriorly beyond the parenchyma in over 70% of our cases; however, grade 2 infiltration was a rare finding and tumor invasion was confined within the fusion fascia in almost all the cases. Thus, the fusion fascia may act as a barrier against retroperitoneal tissue infiltration by pancreatic carcinoma.
PMCID: PMC3915679  PMID: 24649185
pancreatic carcinoma; retropancreatic infiltration; retropancreatic fusion fascia
25.  Low-dose paclitaxel modulates tumour fibrosis in gastric cancer 
International Journal of Oncology  2013;42(4):1167-1174.
Various treatments have been used for peritoneal dissemination, which is the most common mode of metastasis in gastric cancer, but sufficiently good clinical outcomes have not yet been obtained because of the presence of rich fibrous components and acquired drug resistance. Epithelialmesenchymal transition (EMT) is one of the major causes of tissue fibrosis and transforming growth factor-β (TGF-β) has a pivotal function in the progression of EMT. Smad proteins play an important role in the TGF-β signalling pathway. The TGF-β/Smad signalling pathway can be modulated by stabilising microtubules with paclitaxel (PTX). Here, we investigated whether paclitaxel can modulate TGF-β/Smad signalling in human peritoneal methothelial cells (HPMCs). To determine the cytostatic concentrations of antineoplastic agents in HPMCs, a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was performed using PTX, 5-fluorouracil and cisplatin. The minimum concentration that caused significant inhibition of TGF-β1-induced morphological changes in human peritoneal methothelial cells on pre-treatment with PTX was 5 nM at 48 h (cell viability: 87.1±1.5%, P<0.01). The TGF-β signalling cascade and the status of various fibrous components were evaluated by immunofluorescence staining, real-time quantitative PCR and western blotting. TGF-β signalling induced morphological changes, α-SMA expression and collagen I synthesis in HPMCs and PTX treatment suppressed these EMT-like changes. Moreover, PTX treatment markedly suppressed Smad2 phosphorylation. These data suggest that at a low-dose, PTX can significantly suppress the TGF-β/Smad signalling pathway by inhibiting Smad2 phosphorylation in the human peritoneum and that this can reduce stromal fibrosis.
PMCID: PMC3622657  PMID: 23443842
gastric cancer; human peritoneal mesothelial cell; paclitaxel; epithelial-mesenchymal transitions; fibrosis

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