[Case of Resected Retroperitoneal Dedifferentiated Liposarcoma Extending to the Posterior Mediastinum].

A 71-year-old woman visited our hospital for the examination and treatment of retroperitoneal tumor. CT showed a retroperitoneal tumor extending to the posterior mediastinum; the tumor pressed the IVC and widely abutted the aorta. On MRI, the tumor showed low intensity on T1WI and high intensity on T2WI and DWI. However, the tumor did not show signal reduction on an ADC map. PET-CT showed high accumulation at the tumor. The patient was diagnosed with sarcoma arising from the retroperitoneum. The tumor located on a part of the diaphragm was resected. Histological examination revealed spindle cells with atypical nuclear and multinuclear cells. There were no lesions of well-differentiated liposarcoma. Both CDK4 and MDM2 tested positive on immunohistological staining. Histopathologically, the tumor was diagnosed as dedifferentiated liposarcoma without any well-differentiated liposarcoma component. The postoperative course was uneventful, and she was discharged on the 13th day after surgery. Two months after surgery, no recurrence has been detected.

[Two Cases of Complete Response to Trastuzumab Combined with Chemotherapy for Recurrence of HER2-Positive Gastric Cancer].

Case 1: A 67-year-old male underwent distal gastrectomy for advanced gastric cancer. Postoperative histopathological examination indicated pT2a, pN2, M0, pStage ⅢA. He received 4 courses of TS-1 with paclitaxel chemotherapy and TS-1 chemotherapy for 2 years. Three years and 5 months after surgery, computed tomography suggested lymph node metastasis of the mediastinum, so TS-1 with cisplatin(CDDP)therapy was administered. Five years and 10 months after surgery, recurrence occurred and docetaxel and CPT-11 were administered with no response. Since HER2 was overexpressed in the primary tumor, he was treated with capecitabine, CDDP, and trastuzumab(XPT)therapy. After 1 year and 6 months, the patient was considered to have achieved a complete response(CR), and after further trastuzumab therapy for half a year, CR was maintained for 12 years and 3 months after surgery. Case 2: A 59-year-old female underwent total gastrectomy for advanced gastric cancer. Postoperative histopathological examination indicated pT3, pN3a, M0, pStageⅢB. She received TS-1 chemotherapy for 1 year and 8 months. Computed tomography suggested paraaortic lymph node metastasis, and XPT therapy was administered. The patients responded well, and alternate administration of XPT and capecitabine and docetaxel(XT) was performed. Three years and 5 months after surgery, recurrence of lymphadenopathy occurred and intensity-modulated radiation therapy in addition to XPT/XT alternate therapy was introduced, leading to a CR 5 years and 8months after surgery. XT therapy was continued afterward, and CR was maintained for 9 years and 2 months after surgery.

[A Resected Case of UR-LA Pancreatic Tail Cancer with Aortic Invasion after Chemoradiotherapy].

A 70-year-old male was referred to our hospital because of weight loss and epigastric discomfort. CT showed an irregularshaped, low-density tumor, 12 cm in diameter in the tail of the pancreas. This tumor widely invaded to the left kidney and to the anterior and left lateral sides of the aorta in spite of no involvement of celiac and superior mesenteric arteries. Moreover, it closely contacted with the stomach and the spleen. EUS-fine-needle aspiration biopsy of the tumor detected adenocarcinoma. Thus, he was diagnosed with UR-LA pancreatic cancer with aortic invasion. He received combination chemotherapy(S-1 plus gemcitabine[GEM])and 50.4 Gy 3-dimensional conformal radiation therapy, but this therapy had no expected effect. We changed the regimen to GEM plus nab-PTX. After 1 course of changed regimen, the tumor ruptured into the stomach and endoscopic debridement of the necrotic tissue was performed. Twenty-six days later, We performed distal pancreatectomy with splenectomy, total gastrectomy, left nephrectomy, left adrenalectomy, and segmental resection of the colon. The tumor was detached from the aorta as much as possible. The final diagnosis was pT3N0M0, pStage II A. Fifty-nine days after operation, we restarted GEM plus nab-PTX therapy. However, a cerebral infarction suddenly occurred, and we discontinued the chemotherapy. Five months after the operation, he died of cancerous peritonitis.

[A Case of Small Intestinal Neuroendocrine Tumor Detected One Year after Resection of Liver Metastasis].

A 49-year-old woman received a detailed examination for a myoma uteri, and a hepatic tumor was detected incidentally. A CT scan showed a tumor 6 cm in diameter in the posterior segment, which was irregularly enhanced. The tumor showed a low signal intensity on T1WI MRI and a slightly high intensity with high-density spots on T2WI. The tumor showed a low signal intensity in the hepatobiliary phase of the EOB-enhanced MRI. Percutaneous liver biopsy proved that this tumor was a grade 1 neuroendocrine tumor(NET G1). We examined her whole body in detail but found no primary lesions. Therefore, we made a diagnosis of primary hepatic NET or hepatic metastasis of an unknown origin and performed right hepatectomy. A year after the operation, a tumor was found in the jejunum. We made a diagnosis of NET by using endoscopic biopsy and performed partial intestinal resection. Histological findings showed NET G2(Ki-67 labeling index: 3.5%), which had venous invasion and one lymph node metastasis, suggesting that the jejunum was a primary lesion of NET. Three years and 2 months after the first operation, multiple liver metastases were found, and bland TAE was performed three times. Four years and 6 months after the first operation, we started sustained-release somatostatin analogues for tumor progression. She is still alive 5 years and 6 months after the first operation.

Transgenic rat model of childhood-onset dermatitis by overexpressing telomerase reverse transcriptase (TERT).

Childhood-onset dermatitis is one of the most common skin disorders in children. Although various mouse models that mirror aspects of dermatitis have become available, there is still a need for an animal model that develops dermatitis in childhood and is more suitable for performing tissue transplantation experiments. There is emerging evidence that peripheral blood T lymphocytes from patients with dermatitis have significantly increased telomerase activity. Here, we developed telomerase reverse transcriptase (TERT)-expressing transgenic (Tg) rats that spontaneously developed eczematous skin inflammation in childhood. Newborn TERT-Tg rats developed visible dermatitis in 56 % of cases, and the skin lesions microscopically showed spongiosis and acanthosis with infiltration of lymphocytes, eosinophils and mast cells. TERT-Tg rats with dermatitis exhibited increased CD4 (2.5-fold) and CD8 (fivefold) T cell numbers compared with dermatitis-free TERT-Tg rats. Stronger TERT activity was observed in the peripheral lymphocytes of dermatitis-positive TERT-Tg rats than those of dermatitis-free TERT-Tg rats. RT-PCR analysis revealed that IL-4 was markedly elevated in the spleen of dermatitis-positive TERT-Tg rats, and that interferon-gamma was increased in the dermatitis lesions. Moreover, skin grafting of TERT-Tg rats with dermatitis onto T cell-deficient nude rats demonstrated that the inflamed skin lesions could not be maintained. Taken together, the results suggest that TERT activation in T lymphocytes is one of the potential predisposing factors for dermatitis. Moreover, our results demonstrated that the TERT-Tg rats mirror aspects of human childhood-onset dermatitis and that these animals represent a potential animal model system for studying childhood-onset dermatitis.

[A Case of Primary Peritoneal Cancer Successfully Treated with Debulking Surgery and Postoperative Chemotherapy].

A 52-year-old woman with abdominal pain and a feeling of incomplete evacuation visited a local clinic. Enlargement of the right ovary was detected, and the patient was referred to the gynecological department of our hospital. CT and MRI revealed a round-shaped mass, 8 cm in diameter, with cystic and solid components in the Douglas pouch. The patient underwent a laparotomy under the diagnosis of ovarian cancer. Intraoperatively, both the ovaries appeared normal and the tumor strongly adhered to the rectum and uterus. An exploratory laparotomy was performed; the tumor was identified as unresectable, and the patient was referred to our department after the surgery. PET-CT revealed nodules in the liver and peritoneum, in addition to the main tumor. Gastrointestinal endoscopy and immunohistochemical examination of a needle biopsy of the main tumor did not lead to the identification of the primary lesion. Thus, debulking surgery was performed to alleviate the patient's complaints. Histologically, the tumor was diagnosed as a primary peritoneal clear cell carcinoma. One month after surgery, multiple liver metastases and swelling of the peritoneal lymph nodes occurred. Six courses of dose-dense TC therapy were administered, and the patient achieved a complete response. At 8 months after surgery, the patient is still alive without tumor recurrence.

A natural tetrahydropyrimidine, ectoine, ameliorates ischemia reperfusion injury after intestinal transplantation in rats.

BACKGROUND/AIMS: Ischemia reperfusion (I/R) injury after small bowel transplantation leads to inflammatory reactions and loss of structural integrity with subsequent graft contractile dysfunction in the early postoperative phase. The natural tetrahydropyrimidine ectoine (1-,4-,5-,6-tetrahydro-2-methyl-4-pyrimidine carboxylic acid; THP) protects the ileal mucosa and muscularis against effects of I/R injury in an experimental model of isolated graft reperfusion. The effects of THP treatment were evaluated in an established experimental intestinal transplant model. METHODS: Isogenic, orthotopic small bowel transplantation was performed in Lewis rats (6 h cold ischemia time). Perioperative THP treatment (intraluminal/intravascular) groups were compared to vehicle-treated animals (after 3 and 24 h) and non-transplanted controls (n = 5/group). Park's score defined the effects of I/R injury. The infiltration of neutrophils, monocytes and macrophages, mRNA expression of IL-6 and TNF-α, serum levels of IL-6 and NO and smooth muscle contractility were evaluated. RESULTS: Improved graft outcome after intraluminal and intravascular THP treatment was defined by considerably ameliorated neutrophil infiltration and less histological signs of I/R injury (p ≤ 0.05). In the presence of THP, mRNA expression of IL-6 and TNF-α and IL-6 and NO serum levels were reduced and smooth muscle function was improved. CONCLUSION: THP treatment offers protection against the effects of I/R injury in intestinal transplantation in vivo, however, only as supplementary treatment option.

Immunological aspects in late phase of living donor liver transplant patients: usefulness of monitoring peripheral blood CD4+ adenosine triphosphate activity.

AIM: To evaluate whether the combination of the peripheral blood CD4+ adenosine triphosphate activity (ATP) assay (ImmuKnow assay: IMK assay) and cytochrome P450 3A5 (CYP3A5) genotype assay is useful for monitoring of immunological aspects in the patient followup of more than one year after living donor liver transplantation (LDLT). METHODS: Forty-nine patients, who underwent LDLT more than one year ago, were randomly screened by using IMK assay from January 2010 to December 2011, and the complete medical records of each patient were obtained. The CYP3A5 genotypes were examined in thirty-nine patients of them. RESULTS: The mean ATP level of the IMK assay was significantly lower in the patients with infection including recurrence of hepatitis C (HCV) (n = 10) than in those without infection (n = 39): 185 versus 350 ng/mL (P < 0.001), while it was significantly higher in the patients with rejection (n = 4) than in those without rejection (n = 45): 663 versus 306 ng/mL (P < 0.001). The IMK assay showed favorable sensitivity/specificity for infection (0.909/0.842) as well as acute rejection (1.0/0.911). CYP3A5 genotypes in both recipient and donor did not affect incidence of infectious complications. CONCLUSIONS: In the late phase of LDLT patients, the IMK assay is very useful for monitoring immunological aspects including bacterial infection, recurrence of HCV, and rejection.

An approach to the intra-thoracic inferior vena cava through the abdominal cavity preparing for total hepatic vascular exclusion by sagittal diaphragmotomy.

BACKGROUND/AIMS: For resection of advanced liver tumors with tumor thrombus/invasion extending into the intra-thoracic inferior vena cava (IVC) above the diaphragm as well as huge liver tumors located at the root of hepatic vein, an appropriate approach to the intra-thoracic IVC through the abdominal cavity is the key to control the intraoperative massive bleeding. SURGICAL TECHNIQUE: The pericardium and diaphragm are separated by using fingers without injury of the pericardium. From just below the xiphoid process to the IVC, the diaphragm is vertically dissected without cutting the pericardium and doing median sternotomy. Then the intra-thoracic IVC is exposed easily and encircled with an umbilical tape. RESULTS: This technique was applied in four patients (hepatocellular carcinoma: n = 3, cholangiocellular carcinoma: n = 1). The mean patient's age was 69 (59-81) year old, and three were male. The median duration of surgery and blood loss was 490 min and 3600 mL, respectively. The median peaked aspartate aminotransferase and total bilirubin was 428 IU/mL and 2.75 mg/dL, respectively. The median duration of hospital stay was 22 days. CONCLUSIONS: This approach to intra-thoracic IVC through the abdominal cavity is very beneficial and helpful for many liver surgeons.

Dual cytoprotective effects of splenectomy for small-for-size liver transplantation in rats.

The problems associated with small-for-size liver grafts (ie, high mortality rates, postoperative complications, and acute rejection) remain critical issues in partial orthotopic liver transplantation (OLT). In association with partial OLT, splenectomy (SP) is a procedure used to reduce the portal pressure. However, the precise effects of SP on partial OLT have been unclear. In this study, using small-for-size liver grafts in rats, we examined the cytoprotective effects of SP on OLT. Liver grafts were assigned to 2 groups: a control group (OLT alone) and an SP group (OLT after SP). SP significantly increased animal survival and decreased liver damage. SP exerted the following cytoprotective effects: (1) it improved hepatic microcirculation and prevented increases in the portal pressure after OLT, (2) it suppressed the hepatic infiltration of neutrophils and macrophages through the direct elimination of splenic inflammatory cells before OLT, (3) it decreased the hepatic expression of tumor necrosis factor α and interleukin-6, (4) it attenuated sinusoidal endothelial injury, (5) it decreased plasma endothelin 1 levels and increased hepatic heme oxygenase 1 expression, (6) it suppressed hepatocellular apoptosis through the down-regulation of hepatic caspase-3 and caspase-8 activity, and (7) it increased hepatic regeneration. In conclusion, SP for small-for-size grafts exerts dual cytoprotective effects by preventing excessive portal vein hepatic inflow and eliminating splenic inflammatory cell recruitment into the liver; this in turn inhibits hepatocellular apoptosis and improves liver regeneration.

Pancreaticoduodenectomy with resection of the splenic artery and splenectomy for pancreatic double cancers after total gastrectomy. Preservation of the pancreatic function via the blood supply from the posterior epiploic artery: report of a case.

The patient was a 56-year-old man who had previously undergone a total gastrectomy without splenectomy, and was diagnosed with pancreatic head and body cancers and primary solitary lung cancer. The pancreas body tumor invaded the origin of the splenic artery, and if the origin of the splenic artery were resected there would be no blood flow to the pancreas tail, resulting in a need for total pancreatectomy. However, we focused on the posterior epiploic artery (PEA), which is a less well known blood supply from the mesocolon to pancreatic body and tail, and planned to preserve the pancreatic tail as long as the resected margin of the pancreas was not malignant, considering his limited life expectancy. We performed a pancreaticoduodenectomy with resection of the origin of the splenic artery and splenectomy, preserving the pancreatic tail and PEA. The patient has been free from insulin therapy for blood sugar control, and has been well for 10 months after the surgery.

Research of masticatory function using hemiplegia simulator equipment.

BACKGROUND AND OBJECTIVE: Hemiplegic patients often exhibit a characteristic condition called Wernicke-Mann contracture. Therefore, the occlusal pattern in hemiplegic patients is considered to be adapted to stress because of this characteristic limb position. We created a sham Wernicke-Mann contracture in healthy individuals using hemiplegia simulator equipment and compared the functional occlusion in this position with that in the normal state to evaluate dynamic adaptive responses. METHODS: Wernicke-Mann contracture was simulated using a device to create sham hemiplegia (Manabi-tai, Hemiplegia Experiencing Set; Tokushu-iryo, Inc.). In addition to the measurement of the occlusal force using Dental Prescale(®) and Occluzer(®), the occlusion was evaluated using an electromyogram and stabilometer. RESULTS: There was a significant difference in the occlusal force between the normal state and during simulated hemiplegia. The surface electromyo-potential of the masseter muscle showed significantly higher values during simulated hemiplegia. It is significantly higher during simulated hemiplegia than in the normal state on the paralysed side, but not for the normal state on the non-paralysed side. The position and velocity vectors changed in the antero-posterior direction in the normal state but in the lateral direction during simulated hemiplegia. CONCLUSIONS: The hemiplegia simulator equipment is useful for research on hemiplegia, and that the occlusal balance is disturbed in the posture characteristic of hemiplegia.

The cytoprotective effects of addition of activated protein C into preservation solution on small-for-size grafts in rats.

Small-for-size liver grafts are a serious obstacle for partial orthotopic liver transplantation. Activated protein C (APC), a potent anticoagulant serine protease, is known to have cell-protective properties due to its anti-inflammatory and antiapoptotic activities. This study was designed to examine the cytoprotective effects of a preservation solution containing APC on small-for-size liver grafts, with special attention paid to ischemia-reperfusion injury and shear stress in rats. APC exerted cytoprotective effects, as evidenced by (1) increased 7-day graft survival; (2) decreased initial portal pressure and improved hepatic microcirculation; (3) decreased levels of aminotransferase and improved histological features of hepatic ischemia-reperfusion injury; (4) suppressed infiltration of neutrophils and monocytes/macrophages; (5) reduced hepatic expression of tumor necrosis factor alpha and interleukin 6; (6) decreased serum levels of hyaluronic acid, which indicated attenuation of sinusoidal endothelial cell injury; (7) increased hepatic levels of nitric oxide via up-regulated hepatic endothelial nitric oxide synthesis expression together with down-regulated hepatic inducible nitric oxide synthase expression; (8) decreased hepatic levels of endothelin 1; and (9) reduced hepatocellular apoptosis by down-regulated caspase-8 and caspase-3 activities. These results suggest that a preservation solution containing APC is a potential novel and safe product for small-for-size liver transplantation, alleviating graft injury via anti-inflammatory and antiapoptotic effects and vasorelaxing conditions.

Cholecystohepatic duct detected during laparoscopic cholecystectomy: a case report.

BACKGROUND: The cholecystohepatic duct is a rare form of an aberrant hepatic duct that connects to the gallbladder. Although cholecystohepatic duct is reported to be a very rare anomaly, injury of cholecystohepatic duct during cholecystectomy may result in serious complications. Herein, we present a case of cholecystohepatic duct in the ventral branch of the right posterior inferior segmental bile duct detected during laparoscopic cholecystectomy. CASE PRESENTATION: A 77-year-old woman with cholecystolithiasis had been referred to our hospital for surgery. Drip infusion cholecystocholangiography-computed tomography revealed a bile duct branch without communication between the intra- and extrabiliary systems, although the existence of this aberrant hepatic duct was not suspected preoperatively. A 4-port laparoscopic cholecystectomy was performed. After critical view of safety was confirmed, the cystic artery and duct were divided after double clipping. During antegrade mobilization of the gallbladder from the gallbladder bed, a thin, white cord-like material connecting the gallbladder neck and bed was detected. After clipping and dividing it, a cholecystohepatic duct injury was recognized through rechecking the results of the preoperative examinations. Biliary reconstruction was considered unnecessary because of the lesion's small drainage area. The postoperative course was uneventful, and an enhanced computed tomography performed 6 months after the surgery revealed a dilation in the ventral branch of the right posterior inferior segmental bile duct. The patient's liver function remained normal, and she had no symptoms of cholangitis 42 months after the surgery. CONCLUSIONS: Although cholecystohepatic duct is a rare anomaly compared to other aberrant hepatic ducts, surgeons performing cholecystectomy should always keep its existence in mind to avoid serious postoperative complications. Ideally, preoperative detection of cholecystohepatic duct is preferable, but even if it is detected during surgery, the appropriate management according to the drainage area is also important.

Activated protein C prevents hepatic ischaemia-reperfusion injury in rats.

BACKGROUND: Hepatic ischaemia-reperfusion injury (IRI) is a serious complication of liver surgery, especially extended hepatectomy and liver transplantation. Activated protein C (APC), a potent anticoagulant serine protease, has been shown to have cell-protective properties by virtue of its anti-inflammatory and anti-apoptotic activities. METHODS: The present study was designed to examine the cytoprotective effects of APC in a 60-min warm-IRI rat model. RESULTS: Following a single intravenous injection of APC before reperfusion, APC exerted cytoprotective effects 4 h after reperfusion, as evidenced by: (i) decreased levels of transaminase and improved histological findings of IRI, (ii) reduced infiltration and activation of neutrophils, macrophages and T cells, (iii) reduced expression of tumour necrosis factor-alpha, (iv) reduced expression of P-selectin and intracellular adhesion molecule-1, (v) inhibited coagulation and attenuated sinusoidal endothelial cell injury, (vi) improved hepatic microcirculation and (vii) decreased transferase-mediated dUTP nick end-labelling-positive cells. These effects of APC were observed 4 h but not 24 h after reperfusion. However, multiple injections of APC after reperfusion significantly decreased the levels of transaminase and the activity of myeloperoxidase, and improved histological findings of IRI 24 h after reperfusion. CONCLUSION: These results suggest that APC is a promising therapeutic option for hepatic warm-IRI; however, multiple injections of APC are necessary to maintain its cell-protective action over the long term.

Assessment of liver graft function and regeneration by galactosyl-human serum albumin (99mTc-GSA) liver scintigraphy in adult living-donor liver transplantation.

BACKGROUND: In adult living-donor liver transplantation (LDLT), the assessment of the graft functional reserve is very important. We evaluated the graft functional reserve by technetium-99m-diethylenetriaminepenta-acetic acid-galactosyl-human serum albumin ((99m)Tc-GSA) liver scintigraphy. PATIENTS AND METHOD: From May 2003 to September 2006, (99m)Tc-GSA studies were performed in 27 adult recipients on two, four wk after LDLT, the receptor index [ratio of liver to heart-plus-liver radioactivity at 15 minutes (LHL15)] (LHL15) was calculated. Recipients were divided into two groups according to LHL15 on two wk after LDLT (group H; >0.935, group L; <0.935). Liver functional tests and recipients' background parameters were evaluated between the two groups. RESULT: Group L accompanied higher preoperative model for end-stage liver disease (MELD) score (p = 0.038), lower graft-recipient weight ratio (GRWR) (p = 0.032) and older donor age (p = 0.003) compared with group H. There was no significant difference in the graft regeneration rate between two groups. The three-yr cumulative survival rate was 76.1% in group L and 88.9% in group H. CONCLUSION: In LDLT, LHL15 has the potential to assess the graft function and predict the recipients' outcome. Graft function after LDLT may be related closely to the pretransplant MELD score, GRWR, and donor age.

Successful laparoscopic splenectomy after living-donor liver transplantation for thrombocytopenia caused by antiviral therapy.

Although interferon (IFN) based therapy for recurrent hepatitis C virus (HCV) infection after liver transplantation has been widely accepted, it induces various adverse effects such as thrombocytopenia, resulting in its interruption. Recently, concomitant splenectomy at the time of living donor liver transplantation (LDLT) has been tried to overcome this problem, but this procedure leads to several complications such as excessive intraoperative bleeding and serious infection. A 60-year-old female received LDLT using a left lobe graft from her second son for liver failure caused by hepatitis C-related cirrhosis. Six months after LDLT, she was diagnosed as recurrent HCV infection by liver biopsy. IFN monotherapy was started from 7 mo after LDLT and her platelet count decreased to less than 50,000/microL, which thus made it necessary to discontinue the treatment. We decided to attempt laparoscopic splenectomy (LS) under general anesthesia. Since intra-abdominal findings did not show any adhesion formations around the spleen, LS could be successfully performed. After LS, since her platelet count immediately increased to 225,000/microL 14 d after operation, IFN therapy was restarted and we could convert the combination therapy of IFN and ribavirin, resulting in no detectable viral marker. In conclusion, LS can be performed safely even after LDLT, and LS after LDLT is a feasible and less invasive modality for thrombocytopenia caused by antiviral therapy.

Control of cyclosporine A-induced tumor progression using 15-deoxyspergualin for rat cardiac transplantation.

Immunosuppressive therapy increases the risk of recurrence of initial cancers in organ transplant patients, and compelling therapeutic protocols are needed to suppress the malignancy and protect the allograft. We examined the potential use of 15-deoxyspergualin (DSG) in relation to organ transplantation and cancer. The effect of DSG on established liver metastatic tumors in recipient rats bearing a heart allograft was evaluated using an in vivo luminescent technique with luciferase-expressing RCN-H4 rat colon cancer cells. The inhibition of cell growth by DSG was correlated with NF-kappa B activity and caspase-3/7 activity in vitro. In the cyclosporine A (CsA)-induced cancer progression model of rats, DSG treatment (3 mg/kg) blocked the increase in tumor-derived luciferase activity, while CsA (15 mg/kg) facilitated luciferase activity up to around day 20 after cardiac transplantation. Our data suggest that DSG may be a therapeutic candidate for the control of tumor growth in transplant patients.

In vivo luminescent imaging of cyclosporin A-mediated cancer progression in rats.

BACKGROUND: Immunosuppressed individuals undergoing organ transplantation are at increased risk of recurrences of initial cancers, although how immunosuppressive therapy increases early cancer metastasis remains unclear. METHODS: The metastatic fate of luciferase-expressing rat metastatic colon cancer cells (luc-RCN-H4) injected intravenously into the liver of syngeneic and allogeneic rats was examined in the presence of the immunosuppressant cyclosporin A (CsA) by in vivo luminescent technique. With respect to potential tumor-progressing factors, contribution of chemokine receptors and transforming growth factor (TGF)-beta1 to early metastasis was evaluated using their specific signaling inhibitors. RESULTS: F344 rats injected in the liver with luc-RCN-H4 cells did not always exhibit the formation of tumors and showed a dormant state as long as 60 days after inoculation without CsA. However, CsA released early luc-RCN-H4 cells from dormancy within 2 weeks at nearly 100% in liver and preferentially promoted metastasis to the lymph nodes (approximately 40%). A similar dissemination occurred even in minor histocompatibility complex-disparate hosts. As a tumor-progressing factor, RCN-H4 cells aberrantly expressed chemokine receptors CXCR4 and CCR7. The chemokine receptor (CXC) R4-specific antagonist AMD3100 decreased early metastasis of luc-RCN-H4 cells in rats with ischemic liver conditions (P<0.05), but CsA treatment did not enhance early adhesion. Use of CsA was able to facilitate TGF-beta1 expression and the subsequent TGF-beta-mediated random migration was blocked by the use of the specific signaling inhibitor SB431542 in vitro. CONCLUSIONS: Whereas the chemokine receptor expression by cancer cells is implicated with early organotropic dissemination even under CsA-mediated immune suppression, rather, CsA enhances the late-phase progression after tumor adhesion through TGF-beta1 expression.

The novel guanylhydrazone CPSI-2364 ameliorates ischemia reperfusion injury after experimental small bowel transplantation.

BACKGROUND: Resident macrophages within the tunica muscularis are known to play a crucial role in initiating severe inflammation in response to ischemia reperfusion injury after intestinal transplantation contributing to graft dysmotility, bacterial translocation, and possibly, acute rejection. The p38 mitogen-activated protein kinase is a key player in the signaling of proinflammatory cytokine synthesis in macrophages. Therefore, we investigated the effects of CPSI-2364, an apparent macrophage-specific inhibitor of the p38 mitogen-activated protein kinase pathway in an isogenic intestinal rat transplantation model. METHODS: Recipient and donor animals were treated perioperatively with CPSI-2364 (1 mg/kg, intravenously) or vehicle solution. Nontransplanted animals served as control. Animals were killed 30 min, 3 hr, and 18 hr after reperfusion. RESULTS: CPSI-2364 treatment resulted in significantly less leukocyte infiltration and significantly improved graft motor function (18 hr). Messenger RNA expression of proinflammatory cytokines (interleukin 6) and kinetic active mediators (NO) was reduced by CPSI-2364 in the early phase after transplantation. Histologic evaluation revealed the protective effects of CPSI-2364 treatment by a significantly less destruction of mucosal integrity at all time points. Perioperative treatment with CPSI-2364 improves graft motor function through impaired inflammatory responses to ischemia reperfusion injury by inhibition of proinflammatory cytokines and suppression of nitric oxide production in macrophages. CONCLUSIONS: CPSI-2364 presents as a promising complementary pharmacological approach preventing postoperative dysmotility for clinical intestinal transplantation.