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1.  A Case of Severe Sepsis Presenting Marked Decrease of Neutrophils and Interesting Findings on Dynamic CT 
Patient: Male, 60
Final Diagnosis: Sepsis
Symptoms: Fever • shock
Medication: Sivelestat sodium hydrate
Clinical Procedure: PMX-DHP • CHDF
Specialty: Infectious Diseases
Unusual clinical course
In a patient with severe sepsis, we sometimes observe immediate decrease of the counts of white blood cells (WBCs) and neutrophils, which is known as an indicator for poor prognosis. We observed marked decrease of white blood cells and neutrophils on blood examination and interesting findings on dynamic CT. Here, we present the case of a patient with severe postoperative sepsis occurring after major abdominal surgery and we discuss the mechanism of such clinical presentations.
Case Report:
A 60-year-old man received pancreatoduodenectomy with colectomy for pancreatic cancer. He developed a high fever on postoperative day 3. We observed marked decrease of WBCs and neutrophils on blood examination. We also observed slight swelling of the liver, inhomogeneous enhancement of liver parenchyma in arterial phase, and periportal low density in the Glisson capsule in portal phase, without any findings indicating infectious complications on dynamic CT. WBCs and neutrophils increased above normal range in just 6 hours. Blood culture examination performed while the patient had a high fever was positive for Aeromonas hydrophila. After receiving intensive care, he promptly recovered from severe sepsis. The CT findings disappeared on second dynamic CT examination performed 3 days after the first examination.
We treated a patient with severe sepsis after major abdominal surgery who presented very rapid change of the counts of WBCs and neutrophils and interesting CT findings in the liver. We rescued him from a critical situation by prompt and intensive treatment. Research is needed to accumulate and analyze data from more patients who present a similar clinical course to better understand their pathophysiological conditions.
PMCID: PMC4460910  PMID: 26020838
Multidetector Computed Tomography; Neutrophils; Sepsis
2.  Randomized Phase II trial of paclitaxel plus valproic acid vs paclitaxel alone as second-line therapy for patients with advanced gastric cancer 
OncoTargets and therapy  2015;8:939-941.
The standard regimen of second-line chemotherapy for patients with unresectable gastric cancer has not been established. However, weekly paclitaxel (wPTX) has become the preferable second-line chemotherapy in Japan. Histone deacetylase (HDAC) inhibitors have been shown to have antiproliferative activity through cell-cycle arrest, differentiation, and apoptosis in gastric cancer cells. One HDAC inhibitor, valproic acid (VPA), also inhibits tumor growth by inducing apoptosis, and enhances the efficacy of paclitaxel in a mouse xenograft model of gastric cancer. wPTX plus VPA as a second-line chemotherapy is expected to improve survival in gastric cancer patients. A multicenter randomized Phase II study was conducted to compare the effects of wPTX plus VPA and wPTX alone. A total of 66 patients participated in this study. The primary end point of the study was overall survival, and secondary end points were progression-free survival, response rate, and assessment of peripheral neuropathy.
PMCID: PMC4410891  PMID: 25960665
valproic acid; paclitaxel; second-line therapy; advanced gastric cancer
3.  Multiple liver metastases of pancreatic solid pseudopapillary tumor treated with resection following chemotherapy and transcatheter arterial embolization: A case report 
Oncology Letters  2015;9(4):1733-1738.
A 33-year-old female was diagnosed with a solid pseudopapillary tumor (SPT) of the pancreas and multiple liver metastases at the Department of Gastroenterological Surgery, Ishikawa Prefectural Central Hospital (Kanazawa, Japan). Distal pancreatectomy and postoperative systemic chemotherapy with gemcitabine (GEM) and S-1, an oral fluoropyrimidine derivative, was administered, however, liver metastases became enlarged and local recurrence occurred. Therefore, the patient was referred to the Department of Gastroenterologic Surgery at the Graduate School of Medicine (Kanazawa, Japan) for hepatic arterial infusion (HAI) chemotherapy. Oral S-1 (80 mg/m2) was administered as well as HAI chemotherapy with GEM (1,000 mg/standard liver volume). Following 18 cycles, tumor sizes were reduced and 18-fluorodeoxyglucose positron emission tomography (18FDG-PET) examination revealed obvious reduction of tumor FDG uptake. Transarterial tumor embolization (TAE) was performed for the previously unresectable right subphrenic liver tumor, and the other tumors were surgically resected. The resected tumors were diagnosed as liver metastases and a local recurrence of SPT in the postoperative pathological examination, which revealed that the resected tumors were composed of sheets of bland cells, which were positive for CD10, CD56, vimentin, neuron-specific enolase and α-antitrypsin. The postoperative course was uneventful, and the patient is currently under observation at an outpatient clinic; postoperative adjuvant chemotherapy with oral S-1 has continued, and additional TAE is planned. In the future, if the middle segment of the liver becomes enlarged, surgery for the residual right lobe tumor may be possible. This case demonstrates one method of SPT treatment: Preoperative HAI chemotherapy with GEM, plus oral S-1 and TAE. If complete resection can be achieved, the majority of patients with SPT have a favorable prognosis. In patients with unresectable metastases from SPT, it is crucial to conduct systematic multimodal treatment to maximize treatment success.
PMCID: PMC4356297  PMID: 25789032
solid pseudopapillary tumor; liver metastasis; resection; hepatic arterial infusion; transarterial tumor embolization; chemotherapy
4.  Oxaliplatin-based chemotherapy induces extravasated platelet aggregation in the liver 
Molecular and Clinical Oncology  2015;3(3):555-558.
Oxaliplatin-based chemotherapy plays a central role in the treatment of patients with colorectal liver metastasis (CRLM). This treatment, however, has been associated with hepatic sinusoidal obstruction syndrome (SOS), a clinically important adverse effect characterized by a bluish hue of the liver, splenomegaly and thrombocytopenia, resulting in liver dysfunction. The significant association between the sinusoidal endothelium and platelets has suggested that oxaliplatin-based chemotherapy affects platelets in the liver. This study compared platelet counts in patients who did and did not receive oxaliplatin-based neoadjuvant chemotherapy (NAC). The peripheral blood platelet count was significantly lower in the NAC group (n=17) compared to that in the non-NAC, or control group (n=15) (P<0.05). The spleen index was also higher in the NAC group, although the difference was not significant. However, the spleens of the patients in the NAC group were significantly enlarged following treatment (P<0.01). Immunostaining for the platelet surface marker CD42b (glycoprotein Ib), revealed more platelets in the liver in the NAC compared to the control group, particularly in the centrilobular zone III, adjacent to the hepatic central vein and in contact with hepatocytes (P<0.01). The platelets present in the spaces of Disse, referred to as extravasated platelet aggregation (EPA), secrete a number of growth factors, including transforming growth factor-β, vascular endothelial growth factor-A, plasminogen activator inhibitor-1 and thromboxane A2. In conclusion, EPA may play an important role in the development of hepatic SOS. Moreover, antiplatelet drugs may prevent the onset of SOS and hepatic injury in patients treated with oxaliplatin-based chemotherapy for CRLM.
PMCID: PMC4471568  PMID: 26137266
colorectal liver metastasis; extravasated platelet aggregation; sinusoidal obstruction syndrome; oxaliplatin
5.  Extravasated platelet aggregation in liver zone 3 may correlate with the progression of sinusoidal obstruction syndrome following living donor liver transplantation: A case report 
Sinusoidal obstruction syndrome (SOS), previously known as veno-occlusive disease, is relatively rare subsequent to liver transplantation (LT). SOS refractory to medical therapy, however, can result in centrilobular fibrosis, portal hypertension and liver failure. Although sinusoidal endothelial cell damage around central venules (zone 3) occurs early in the development of SOS, the detailed mechanism of SOS development and its association with thrombocytopenia are not yet completely understood. The present report describes a patient who experienced SOS with unexplained thrombocytopenia following living donor LT. The progression of SOS resulted in graft dysfunction and the patient succumbed. The presence of platelets in the liver allograft was assayed immunohistochemically using antibody to the platelet marker cluster of differentiation 42b (platelet glycoprotein Ib). Platelet aggregates were found attached to hepatocytes along the sinusoid and within the cytoplasm of hepatocytes, particularly in zone 3. By contrast, no staining was observed in zone 1. These findings suggested that extravasated platelet aggregation in the space of Disse and the phagocytosis of platelets by hepatocytes were initiated by sinusoidal endothelial cell damage due to the toxicity of the immunosuppressant tacrolimus or a corticosteroid pulse, and that platelet activation and degranulation may be at least partially involved in the mechanism responsible for SOS.
PMCID: PMC4353807  PMID: 25780397
platelet; aggregation; cluster of differentiation 42b; sinusoidal obstruction syndrome; veno-occlusive disease; liver transplantation
6.  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
7.  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
8.  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
9.  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
10.  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
11.  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
12.  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
13.  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
14.  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
15.  Bone marrow derived “fibrocytes” contribute to tumor proliferation and fibrosis in gastric cancer 
Gastric Cancer  2014;18(2):306-313.
Cancer-associated fibroblasts (CAFs) in the stroma are considered to play important roles for gastric cancer proliferation, invasion, and fibrosis, but the source of CAFs and their interaction with cancer cells in the microenvironment have not been fully determined. Here we elucidated the role of bone marrow-derived cells, fibrocytes, in development of gastric cancers, as represented by scirrhous gastric cancer.
Materials and methods
In co-culturing MKN45 gastric cancer cells and purified fibrocytes from healthy volunteers, migration and endothelial mesenchymal transition associated gene expression were evaluated using western blot analysis. Also, mouse xenograft models of MKN45 with or without fibrocytes were conducted to investigate their tumorigenicity and immunohistological differences of tumors.
Co-culture of fibrocytes with MKN45 resulted in morphological changes from cobblestone-shape to spindle-shape and enhanced expression of α-SMA and collagen type I in fibrocytes, suggesting that co-culture with gastric cancer cells may have induced the differentiation of fibrocytes to myofibroblasts. Furthermore, enhanced expression of SDF-1 in MKN45 and CXCR4 in fibrocytes were also determined. Mouse xenograft models inoculated with MKN45 and fibrocytes revealed significantly larger tumors than those inoculated with MKN45 cells alone, and the stroma in co-inoculated tumors consisted of myofibroblasts and fibrosis. Mouse-derived cells expressing both CD45 and type I collagen were also observed in co-inoculated tumors.
Fibrocytes derived from bone marrow may migrate into the microenvironment of gastric cancer by SDF-1/CXCR4 system, and enhance the tumor proliferation and fibrosis as CAFs.
PMCID: PMC4371822  PMID: 24792410
Fibrocytes; Bone marrow-derived cell; Cancer associated fibroblasts; Cancer stroma; Gastric cancer
16.  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
17.  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
18.  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
19.  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
20.  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
21.  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
22.  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
23.  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
24.  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
25.  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

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