A duodenal gastrointestinal stromal tumor mimicking a pancreatic neuroendocrine tumor: a case report.

BACKGROUND: Duodenal gastrointestinal stromal tumors are rare. If tumor growth is extraluminal and involves the head of the pancreas, the diagnosis of a duodenal gastrointestinal stromal tumor is difficult. CASE PRESENTATION: A 44-year-old Japanese woman was referred to our hospital with anemia. An enhanced computed tomography scan showed a hypervascular mass 30 mm in diameter, but the origin of the tumor, either the duodenum or the head of the pancreas, was unclear. Upper gastrointestinal endoscopy revealed bulging accompanied by erosion and redness in part of the duodenal bulb. Mucosal biopsy was not diagnostic. Endoscopic ultrasound fine-needle aspiration was difficult to perform because a pulsating blood vessel was present in the region to be punctured. These findings led to a diagnosis of pancreatic neuroendocrine tumor invasion to the duodenum. The patient underwent pancreaticoduodenectomy. Histologically, the tumor was made up of spindle-shaped cells immunohistochemically positive for c-Kit and CD34. The tumor was ultimately diagnosed as a duodenal gastrointestinal stromal tumor. CONCLUSION: Extraluminal duodenal gastrointestinal stromal tumors are rare and mimic pancreatic neuroendocrine tumors. Endoscopic ultrasound fine-needle aspiration is useful for preoperative diagnosis, but it is not possible in some cases. Intraoperative diagnosis based on a completely resected specimen of the tumor may be useful for modifying the surgical technique.

Locally advanced gallbladder cancer treated with effective chemotherapy and subsequent curative resection: a case report.

BACKGROUND: Surgical resection of gallbladder cancer with negative margins is the only potentially curative therapy. Most patients with gallbladder cancer are diagnosed in an advanced stage and, despite the availability of several chemotherapies, the prognosis remains dismal. We report a case of locally advanced gallbladder cancer that was successfully treated with effective cisplatin plus gemcitabine, followed by curative resection. CASE PRESENTATION: A 55-year-old Japanese female was hospitalized with right hypochondrial pain. Enhanced computed tomography revealed a 49 × 47 mm mass at the neck of the gallbladder, with suspected invasion of the liver and right hepatic artery. Endoscopic retrograde cholangiopancreatography demonstrated displacement of the upper bile duct. Intraductal ultrasonography showed irregular wall thickening and disappearance of the wall structure in bile ducts from the B4 branch to distal B2 and B3. Percutaneous transhepatic biliary biopsy revealed a poorly differentiated carcinoma. The patient was diagnosed with unresectable gallbladder cancer (T4N0M0 stage IVA). Cisplatin plus gemcitabine chemotherapy was initiated. After six courses of chemotherapy, enhanced computed tomography showed that the mass in the neck of the gallbladder had shrunk to 30 mm, Endoscopic retrograde cholangiopancreatography showed improvement of the hilar duct stenosis. A biopsy of the bile duct mucosa showed no malignant cells in the branch of the left and right hepatic ducts, the left hepatic duct, or the intrapancreatic ducts. The patient underwent conversion surgery with right and segment 4a liver resection, extrahepatic duct resection, and cholangiojejunostomy. The histopathologic diagnosis showed that the tumor cells had shrunk to 2 × 1 mm, and that R0 resection of the T2aN0M0 stage IIA tumor was successful. CONCLUSION: Although conversion surgery for gallbladder cancer is rarely possible, curative resection may offer a better prognosis, and it is important to regularly pursue possibilities for surgical resection even during chemotherapy.

Synchronous gastric cancer and carcinoma in situ of the pancreas.

Abnormal findings in the pancreatic duct without a mass may require serial pancreatic juice aspiration cytological examination. In cases of synchronous gastric cancer and stage 0 pancreatic cancer, spleen-preserving pancreatectomy may have advantage.

Anal Atresia in a Patient Who Had Undergone Hartmann Procedure.

BACKGROUND Hartmann procedure can be necessary for the treatment of rectal cancer and colonic perforation. The distal diverted intestinal tract is usually disregarded, while the proximal colon is diverted with a stoma. Most of the reported complications related to a diverted intestinal tract following Hartmann procedure include inflammation and intestinal tumors; however, there are only a few reports about postoperative anal complications. Herein, we report a rare case of anal atresia following Hartmann procedure. Anal atresia is generally considered as a congenital malformation; therefore, this was an extremely rare case, as there are no previous reports about anal atresia following Hartmann procedure. CASE REPORT An 84-year-old woman presented to our hospital with a persistent feeling of incomplete evacuation. She had undergone Hartmann procedure for diverticular disease of the sigmoid colon, with perforation, 5 years ago and had no major complications after the surgery. She had no history of anal disorders such as hemorrhoids or anal fissures. On examination, her anus was found to be closed by a thin skin, and computed tomography revealed stool retention in the diverted rectum. The anus was surgically opened to remove the stool, after which the feeling of incomplete evacuation resolved with no subsequent recurrence. CONCLUSIONS This is the first report of anal atresia in a patient following Hartmann procedure. The surgical intervention was effective in resolving the blockage and relieving the patient's feeling of incomplete evacuation.

A Case of Stage II Ascending Colon Cancer with Cardiac Tamponade Due to Pericardial Metastasis.

BACKGROUND Malignant tumors, such as lung and breast cancers, can metastasize to the heart. However, cardiac metastasis rarely occurs in colorectal cancer. Cardiac metastasis cases are typically asymptomatic and rarely cause cardiac tamponade. Heart failure due to systemic metastasis is a terminal symptom; therefore, cardiac metastasis is rarely diagnosed when a patient is alive. We report a case of stage II ascending colon cancer with cardiac tamponade due to pericardial metastasis. CASE REPORT The patient was a 63-year-old woman who underwent laparoscopic ileocecal resection for ascending colon cancer. The final pathological diagnosis was stage IIB cancer. At the time of surgery, computed tomography scans revealed no metastases to the regional lymph nodes, liver, lungs, and other organs. The patient was then referred for dyspnea 5 months after the surgery. Computed tomography revealed large quantities of pericardial effusion, and the patient was diagnosed with cardiac tamponade. The symptoms were alleviated after pericardiocentesis. Cytological examination of the pericardial fluid confirmed the diagnosis of adenocarcinoma, and by extension, cardiac metastasis of the ascending colon cancer. Anticancer agents were recommended, but the patient opted for palliative treatment. CONCLUSIONS We report a rare case of ascending colon cancer with pericardial metastasis. The advancements in chemotherapy have made the prognosis of colorectal cancer more favorable. The prevalence of pericardial metastasis is expected to increase as well. As such, it is necessary to discuss similar case encounters and establish appropriate treatment.

A liver metastasis 7 years after resection of a low-risk duodenal gastrointestinal stromal tumor.

Duodenal gastrointestinal stromal tumors (dGISTs) are rare, and a lack of consensus exists regarding their treatment, particularly for recurrent disease. We herein report a rare case of liver metastasis 7 years after resection of a low-risk duodenal gastrointestinal stromal tumor. A 45-year-old woman revealed positive fecal occult blood. Upper gastrointestinal endoscopy revealed a submucosal duodenal tumor with ulceration and oozing on the apex. Endoscopic ultrasound showed a hypoechoic mass originating in the submucosa. Contrast-enhanced abdominal computed tomography (CT) revealed a 30-mm hyper-vascular tumor in the duodenal bulb. The patient underwent partial resection of the duodenal bulb with distal gastrectomy, followed by Roux-en-Y reconstruction. Histopathological evaluation revealed a tumor comprised of spindle-shaped cells including 5 mitotic figures per 50 high-power fields. Immunohistochemical evaluation indicated that the tumor cells were positive for c-Kit and CD34 expression. The tumor was diagnosed as low-risk dGIST. Postoperative follow-up was continued, and 7 years later, CT revealed a 39-mm enhanced tumor in liver segment 4. The tumor was diagnosed as a metastatic liver tumor, and the patient underwent S4 partial hepatectomy. As a result of histological and immunohistochemical analysis, the tumor was diagnosed as a liver metastasis from dGIST. The patient has been receiving oral imatinib 400 mg daily and remains free of disease 5 years after her last surgery. Low-risk dGIST can metastasize relatively long after surgery. However, an excellent long-term prognosis may be achieved by combining complete resection and imatinib therapy in patients with recurrent liver metastases.

A multicenter randomized controlled trial comparing administration of antithrombin III after liver resection (HiSCO-05 trial).

BACKGROUND: Posthepatectomy liver failure is a poor prognostic factor after hepatectomy. Various preventive treatments have been tried; however, there are no clinical trials that use posthepatectomy liver failure as the primary endpoint, and the clinical effects of posthepatectomy liver failure have not been fully verified. The aim of this study was to investigate whether administration of antithrombin III can prevent posthepatectomy liver failure in patients with coagulopathy after hepatectomy. This study also evaluated the safety of AT-III administration after hepatectomy. METHODS: The current study enrolled 141 patients diagnosed with coagulopathy after hepatectomy between October 2015 and September 2018 at 7 hospitals in Hiroshima, Japan (HiSCO group). Patients were randomized to undergo either administration of antithrombin III (n = 64) or non-administration (n = 77). The primary endpoint was the incidence of posthepatectomy liver failure. This randomized controlled trial was registered with the University Medical Information Network Clinical Trial Registry (UMIN000018852). RESULTS: Treatment for postoperative coagulopathy was performed safely without adverse events. The incidence of posthepatectomy liver failure was similar in both treatment groups (nonadministration of antithrombin III group, 28.5%, versus administration of antithrombin III group, 28.1%; P = .953) The rate of morbidity was higher in the administration group than the non-administrated group (17.2% vs 11.7%, P = .351). Following the multivariate analysis of the whole study group, body mass index ≥25, total bilirubin ≥1.5 mg/dL, and the disseminated intravascular coagulation score ≥5 postoperatively were the independent risk factors for posthepatectomy liver failure. CONCLUSION: This study showed that the administration of antithrombin III resulted in no significant difference in preventing posthepatectomy liver failure, possibly through suppressing coagulopathy.

Inappropriate Secretion of Antidiuretic Hormone after Pancreatoduodenectomy for Pancreatic Head Cancer: A Case Report and Literature Review.

Syndrome of inappropriate secretion of antidiuretic hormone (SIADH) is a disease that leads to dilute hyponatremia through excessive secretion of antidiuretic hormone. SIADH has various causes, including ectopic ADH-producing tumors, drug properties, and can be idiopathic. But there have been very few reports of cases in which SIADH has developed after surgery for malignant tumors. In addition, few cases have been reported where this disease has developed after surgery for pancreatic cancer, because the symptoms of hyponatremia are non-specific. These symptoms are particularly gastrointestinal symptoms; therefore, it is difficult to differentiate them, even if SIADH has developed after gastrointestinal surgery. The patient in our case was an 80-year-old woman. She had persistent epigastralgia and left back pain. Imaging studies revealed a tumor in the head of the pancreas, which was diagnosed as pancreatic head cancer. We performed subtotal stomach-preserving pancreatoduodenectomy. After the operation, she complained of appetite loss and general fatigue. Her serum sodium levels decreased to 109 mEq/L on postoperative day 11. She was diagnosed with SIADH using the SIADH diagnostic criteria listed by the Japanese Ministry of Health, Labor and Welfare. We treated the patient with sodium supplementation for hyponatremia, and her symptoms ameliorated. After the event, she did not relapse with hyponatremia. This case is significant in that we performed differential diagnosis after major gastrointestinal surgery for pancreatic cancer and diagnosed SIADH at an early stage.

Alpha-fetoprotein-producing Colon Carcinoma with Rapidly Increasing Liver Metastases That Resulted in Death: A Case Report.

Alpha-fetoprotein (AFP) has been widely used as a tumor marker for detecting hepatocellular carcinoma and yolk sac tumors. Recently, cases of gastrointestinal cancer with elevated serum AFP levels have been reported. However, AFP-producing colon cancer is considered rarer than other AFP-producing gastrointestinal cancers. In this study, we report on a case of a 47-year-old woman who was diagnosed with sigmoid colon cancer and underwent sigmoidectomy and lymph node dissection. Postoperative adjuvant chemotherapy (AC) was performed after the curative surgery. After the seventh course of AC, multiple liver masses and enlarged systemic lymph nodes were detected; these were later diagnosed as liver metastases from sigmoid colon cancer. Laboratory examination revealed high AFP levels (14,657.8 ng/mL). After confirming the recurrence, her condition worsened rapidly, and she eventually died 8 months after the operation. Autopsy and histopathological findings showed that the liver mass was positive for AFP staining, but the sigmoid colon cancer tissue was not. We then determined that liver metastases of the colon cancer were more likely than germ cell carcinoma according to the clinical course and pathological findings. We assumed that colon cancer cells can rapidly expand by dedifferentiation, and we diagnosed AFP-producing colon cancer with liver metastases. Despite curative surgery and AC for AFP-producing colon cancer, the patient died of liver and systemic lymph node metastases.

A novel model for predicting posthepatectomy liver failure based on liver function and degree of liver resection in patients with hepatocellular carcinoma.

BACKGROUND: The permissible liver resection rate for preventing posthepatectomy liver failure (PHLF) remains unclear. We aimed to develop a novel PHLF-predicting model and to strategize hepatectomy for hepatocellular carcinoma (HCC). METHODS: This retrospective study included 335 HCC patients who underwent anatomical hepatectomy at eight institutions between 2013 and 2017. Risk factors, including volume-associated liver-estimating parameters, for PHLF grade B-C were analyzed in a training set (n = 122) via multivariate analysis, and a PHLF prediction model was developed. The utility of the model was evaluated in a validation set (n = 213). RESULTS: Our model was based on the three independent risk factors for PHLF identified in the training set: volume-associated indocyanine green retention rate at 15 min, platelet count, and prothrombin time index (the VIPP score). The areas under the receiver operating characteristic curve of the VIPP scores for severe PHLF in the training and validation sets were 0.864 and 0.794, respectively. In both sets, the VIPP score stratified patients at risk for severe PHLF, with a score of 3 (specificity, 0.92) indicating higher risk. CONCLUSION: Our model facilitates the selection of the appropriate hepatectomy procedure by providing permissible liver resection rates based on VIPP scores.

A safe and reliable technique for fascial closure without special devices after laparoscopic surgery.

INTRODUCTION: To prevent port-site hernia, we established a simple and low-cost closure method that uses a venous catheter needle and suture, without any other special devices. MATERIALS AND SURGICAL TECHNIQUE: We used the inner needle of a 16-G venous catheter and a 2-0 absorbable bladed suture. To evaluate the efficacy of this technique, the procedure time was noted and compared among three operators (an experienced surgeon and two inexperienced surgeons). DISCUSSION: The median suturing time was 60.5 seconds (range, 26-130 seconds) per incision. Even an unexperienced surgeon can close the fascia safely and quickly after some experience with the procedure.

Mucinous nonneoplastic cyst of the pancreas penetrates the colon causing infection: a case report.

BACKGROUND: Mucinous nonneoplastic cyst of the pancreas is a rare disease defined as a cystic lesion lined with mucinous epithelium, supported by hypocellular stroma and not communicating with the pancreatic ducts. Mucinous nonneoplastic cyst of the pancreas has no malignant potential and does not require surgical resection or surveillance. However, its preoperative differentiation from other cystic lesions of the pancreas is difficult because of several overlapping clinical, radiological, and biochemical features. We report a rare case of large mucinous nonneoplastic cyst of the pancreas in which surgery was required due to infection and the possibility of malignancy. CASE PRESENTATION: A 75-year-old Japanese man was found to have a pancreatic cyst in 2006 while undergoing postoperative evaluation for colon cancer. In 2015, the cyst ruptured, and it was treated conservatively. In 2017, he fell down on a road with a fever of 40 °C and was transported emergently to a nearby hospital. Enhanced computed tomography revealed a cystic lesion in the body of the pancreas measuring 119 mm × 100 mm and an adjacent left renal cyst measuring 63 mm in diameter. The wall of the pancreatic cyst was thickened. Magnetic resonance imaging demonstrated a liquid surface in the pancreatic cyst. Pancreatic cyst infection was diagnosed as the source of infection. However, identification of the organism was difficult. Furthermore, due to the increase in the size and wall thickness of the cyst, it was unclear whether the cystic mass was neoplastic with malignant potential. For these reasons, the patient underwent distal pancreatectomy and splenectomy with deroofing of the left renal cyst. Intraoperatively, the pancreatic cyst adhered to the descending colon, and partial resection of the colon was added. Pathologic analysis of the resected cyst demonstrated a simple cyst lined by mucinous epithelium. There was no underlying stromal condensation or epithelial dysplasia, and communication with the native pancreatic ducts was not observed. Based on the operative and histological findings, a final diagnosis of mucinous nonneoplastic cyst of the pancreas with colonic communication was made. The colonic fistula was presumed to be the source of infection. CONCLUSION: Mucinous nonneoplastic cyst of the pancreas is generally benign and requires little follow-up, but large cysts may penetrate other organs and cause severe complications.

Mixed adenoneuroendocrine carcinoma of the distal bile duct: A case report.

INTRODUCTION: Mixed adenoneuroendocrine carcinomas (MANECs) of the distal bile duct are extremely rare, and only a few cases have been reported in the English literature. PRESENTATION OF CASE: An 82-year-old man was referred to our hospital for increasing biliary enzymes. Abdominal computed tomography (CT) showed enlargement of the intrahepatic bile ducts and stenosis of the distal bile duct. Endoscopic retrograde cholangiopancreatography showed stenosis of the distal bile duct and a high-density signal at the same site on diffusion weighted imaging. PET-CT showed increased FDG accumulation (SUVmax: 4.5) at the distal bile duct stenosis. Biopsy specimens obtained by endoscopic ultrasonography-guided fine-needle aspiration revealed adenocarcinoma. The patient was diagnosed with adenocarcinoma of the distal bile duct and underwent subtotal stomach-preserving pancreaticoduodenectomy with regional lymph node dissection. The resected distal bile duct tumor was 18×14×12mm in diameter. Hematoxylin and eosin staining revealed a composite carcinoma with adenocarcinoma and non-adenocarcinoma elements. The non-adenocarcinoma component stained positive for synaptophysin and chromogranin A. The Ki-67 labeling index was 37%. The non-adenocarcinoma component was therefore diagnosed as a neuroendocrine carcinoma. The two composite carcinoma was diagnosed as MANEC of the distal bile duct. The patient was treated with surgery alone and he remained disease-free for 7 months after the surgery. DISCUSSION: The treatment of MANECs of the bile duct remains controversial and the prognosis is poor. CONCLUSIONS: There is no standard treatment for MANECs of the bile duct. Larger studies are required to establish standard treatment regimens.

Splenic hamartoma associated with thrombocytopenia: A case report.

INTRODUCTION: Hamartomas are rare, benign tumors of the spleen. Few cases of splenic hamartomas associated with thrombocytopenia have been reported. PRESENTATION OF CASE: An asymptomatic 64-year-old man with myelodysplastic syndrome was found to have a splenic tumor. Laboratory tests were significant for thrombocytopenia, with a platelet count of 7.8×104/µL. Ultrasonography showed splenomegaly (10.8×6.6cm), and a hypoechoic splenic mass (8.0×7.0cm). Color doppler ultrasound revealed blood flow within the mass, and the mass density was homogeneous on abdominal computed tomography (CT). Contrast-enhanced CT showed heterogeneous enhancement of the splenic mass during the arterial phase. Positron emission tomography (PET)-CT showed no significant fludeoxyglucose (FDG) accumulation within the mass. The differential diagnosis included splenic hamartoma, splenic hemangioma, splenomegaly associated with extramedullary hematopoiesis, and malignant tumor, including solitary splenic metastasis. A laparoscopic splenectomy was performed due to the possibility of malignancy, the presence of thrombocytopenia, and the risk of splenic rupture. The resected specimen showed a localized, well-demarcated, 8.0×7.0cm splenic mass. Histological examination revealed abnormal red pulp proliferation and the absence of normal splenic structures. The patient's post-operative course was uneventful. His platelet count improved on post-operative day 1 and he was discharged on post-operative day 9. He remained in good health with a normal platelet count one month after surgery. DISCUSSION: Making definitive preoperative diagnosis is difficult in splenic hamartomas. Surgery is necessary for diagnosis when malignancy cannot be ruled out. CONCLUSIONS: Surgery may also improve symptoms of hypersplenism, including thrombocytopenia.

[A case of advanced rectal cancer that responded to S-1 with an extended complete response].

A 78-year-old female underwent an abdomino-perineal resection for lower rectal cancer with para-aortic, right iliac artery and left inguinal lymph node metastasis. Two weeks later, an enlargement of para-aortic and right iliac artery lymph node metastasis was detected by CT. S-1 (100 mg/day for 2 weeks followed by a 1-week rest period) + CPT-11 (120 mg/m2, day 1)treatment was initially administered. However, the patient developed grade 2 anorexia so this treatment regimen was terminated. After complete recovery from the adverse reaction, the regimen was converted to S-1 administration at 100mg/day S-1 for 2 weeks followed by a 1-week rest period. Eventually, this schedule was modified to 100mg/day for 1 week followed by a 1-week rest period. A year after the operation, CT revealed the lymph node metastasis to have disappeared, and no relapse occurred for 32 months. This was a successful case in which S-1 yielded an extended complete response for advanced rectal cancer. Treatment with S-1 is an effective choice for patients who for various reasons can not tolerate the standard treatment for unresectable advanced colorectal cancer. Moreover, randomized controlled trials have to be started to evaluate the efficacy of S-1 treatment for advanced rectal cancer as soon as possible.

Large-cell neuroendocrine carcinoma of the distal bile duct.

Large-cell neuroendocrine carcinoma (LCNEC) in the distal bile duct is very rare and different from common distal bile duct adenocarcinoma. A 77-year-old man was admitted with obstructive jaundice. Severe stenosis of the distal bile duct was revealed by percutaneous transhepatic cholangiography. Subtotal stomach-preserving pancreaticoduodenectomy was performed. A tumor measuring 1.8 cm in diameter was located in the distal bile duct. Both histopathological and immunohistochemical examination of the resected specimen revealed features of LCNEC of the bile duct. The patient developed multiple liver metastases, lung metastases, and local recurrence and died of disease 3 months after the operation. The clinical behavior of LCNEC in the distal bile duct appears to be highly aggressive with early metastases and a fatal outcome.

Inhibition of tumor growth in immunocompromised hosts by restoring type-2 immunity using infusion of G-CSF-treated allogeneic CD8+ leukocytes.

Since recombinant human granulocyte colony-stimulating factor (rhG-CSF)-treated donor leukocyte infusion (G-DLI) has been shown to downregulate type-1 immunity in a heart transplant model, we examined influences of G-DLI on tumor growth in immunosuppressed hosts. F344 rats were treated with tacrolimus (8 mg/kg i.m.) and syngeneic colon adenocarcinoma RCN-9 cells (3 x 10(6)) were inoculated subcutaneously. For G-DLI, allogeneic DA rats were pretreated with rhG-CSF (250 microg/kg, days -5 to 0) and isolated leukocytes or sorted CD8(+) cells were injected intravenously to the hosts on day 0. Tumors in tacrolimus-treated hosts continuously grew over 5 weeks. G-DLI of 100 x 10(6) leukocytes attenuated tumor growth rate while direct host pretreatment with rhG-CSF did not. Notably, G-DLI of 10 x 10(6) CD8(+) cells blocked tumor expansion after day 14. Tacrolimus-induced inhibition of lymphocyte infiltration into tumors was recovered by the G-DLIs. Flow cytometry showed no detectable donor-type T cells in the tumor and circulation. Quantification of intratumor transcription levels using reverse transcription-real-time polymerase chain reaction showed recovery from tacrolimus-induced downregulation of interleukin-4 but not interferon-gamma levels. In vivo rhG-CSF-treated CD8(+) allogeneic cells demonstrate potent anti-tumor effects by restoring type-2 immunity of immunosuppressed hosts.

Regulation of T helper type-1 immunity in hapten-induced colitis by host pretreatment with granulocyte colony-stimulating factor.

Recombinant human granulocyte colony-stimulating factor (rhG-CSF) is an immunoregulatory drug whose effects include modulation of antigen-presentation. We investigated the potential ameliorative effect of pretreatment with rhG-CSF in a hapten-induced colitis animal model. Sprague-Dawley rats were given rhG-CSF (125 microg/kg subcutaneously twice a day for 5 days) before a colonic instillation of 2,4,6-trinitrobenzene sulfonic acid (TNBS) in 50% ethanol. Consequent colonic damage was evaluated pathologically, and cytokine mRNA expression levels in macroscopically inflamed sites were measured by real-time quantitative reverse transcription-polymerase chain reaction. Pretreatment with rhG-CSF remarkably attenuated both the loss of body weight and colonic wall thickening due to progressive transmural inflammation. In the control, treatment with TNBS led to a statistically significant (p < 0.05) upregulation of IFN-gamma mRNA expression in the inflammatory sites measured at post-treatment day 7. In the experimental group, pretreatment with rhG-CSF abrogated transcription of IFN-gamma (p < 0.05), but was not, however, associated with an upregulation of IL-4 or the regulatory cytokines TGF-beta and IL-10. Furthermore, transcription of IL-12p35 (a rate-limiting factor for the production of IL-12) was significantly (p < 0.05) downregulated by rhG-CSF at 24h post-TNBS instillation, whereas IL-12p40 was not affected. Pretreatment with rhG-CSF drastically attenuated the degree of TNBS-induced colitis through selective downregulation of Th1-associated cytokines.

Downregulation of interleukin-12p35 and upregulation of interleukin-12p40 mRNA expression in heart allografts by blood transfusion from granulocyte colony-stimulating factor-treated donors.

Pretransplant treatment of recipients with recombinant human granulocyte colony-stimulating factor (rhG-CSF, 250 microg/kg/day s.c. for 5 days) facilitates heart allograft acceptance in tacrolimus-treated rat recipients. We examined effectiveness of transfusion of in vivo rhG-CSF-treated blood since rhG-CSF induces immunoregulatory cells in human blood. DA heart grafts were transplanted into tacrolimus (2 mg/kg i.m. on day 0)-treated Lewis recipients. Although graft survival prolongation by blood transfusion on day 0 from rhG-CSF-treated syngeneic Lewis was comparable to that in directly rhG-CSF-pretreated recipients (p = 0.22), transfusion of rhG-CSF-treated allogeneic DA blood was much more effective (p = 0.0016). Intragraft cytokine mRNA levels were measured by reverse transcription and real-time polymerase chain reaction at 24 h after transplantation. IL-12p35 expression was downregulated by both treatments. Notably, IL-12p40 was upregulated by rhG-CSF-treated DA blood transfusion but downregulated by transfusion of rhG-CSF-treated isogeneic blood. Differential expression of IL-12 subunits was associated with facilitation of graft acceptance by rhG-CSF-treated donor blood transfusion.

Facilitation of tacrolimus-induced heart-allograft acceptability by pretransplant host treatment with granulocyte colony-stimulating factor: interleukin-12-restricted suppression of intragraft monokine mRNA expression.

BACKGROUND: Because recombinant human granulocyte colony-stimulating factor (rhG-CSF) is known to modulate function of antigen-presenting cells, we examined effects of pretransplant host treatment with rhG-CSF on allograft survival. METHODS: In DA-to-Lewis rat heart transplantation, hosts were given pretransplant injections of rhG-CSF (250 microg/kg/day subcutaneously from day -5-0) and/or posttransplant injections of tacrolimus (2 mg/kg/day intramuscularly from day 0-3). Cytokine mRNA levels in grafts were measured by real-time reverse-transcription polymerase chain reaction. RESULTS: rhG-CSF pretreatment was effective in prolonging allograft survival only in tacrolimus-treated hosts (P <0.001). Intragraft mRNA expression of interleukin (IL)-12 subunits (p35, p40) at 24 hours after transplantation was significantly (P <0.05) down-regulated by the addition of rhG-CSF and was associated with suppression of interferon-gamma levels on day 6, although other proinflammatory cytokines (tumor necrosis factor -alpha, IL-1beta, IL-6, IL-18) and anti-inflammatory cytokines (IL-10, transforming growth factor-beta) were not. CONCLUSIONS: rhG-CSF pretreatment down-regulates intragraft expression of the type-1 T-helper cell (Th1)-driving cytokine IL-12 and facilitates tacrolimus-induced graft acceptance.