[A Case of Locally Advanced Adenosquamous Carcinoma of the Pancreas Accompanied by Hepatic Metastasis Treated by Resection of the Primary Lesion as Palliative Care].

A 61-year-old man presented to our hospital with appetite loss. Gastroscopy revealed a tumor on the upper body of the stomach. Persistent bleeding was observed from the tumor; therefore, the patient was immediately hospitalized. An abdominal CT scan revealed that the tumor arose from the pancreas and invaded the spleen, stomach, and transverse colon. Furthermore, a hepatic tumor was observed at the posterior segment and blood tests showed increased CA19-9 level. Therefore, the tumor was diagnosed as pancreatic cancer with invasion of the adjacent organs and hepatic metastasis. Although the tumor was classified as unresectable for the distant metastasis, resection of the primary lesion was performed to control the bleeding and obstruction at the invasion sites. The pathological diagnosis of the tumor was adenosquamous carcinoma. The patient subsequently underwent chemotherapy and was discharged from the hospital on postoperative day 34. The patient was able to spend time at home and was treated at an outpatient clinic until postoperative day 110, when his generalcondition deteriorated. In this case, resection of the primary lesion was ineffectual for a life prognosis but was beneficial for palliative care.

[A Case of Solitary Lymph Node Recurrence Accompanied by Metachronous Multiple Lesion after Definitive Chemoradiotherapy for Esophageal Cancer].

A 53-year-old man was diagnosed with squamous cell carcinoma of the upper thoracic esophagus in cT3N1M0, cStage III (UICC 6th edition). The patient underwent definitive chemoradiotherapy(dCRT)and achieved a complete response in May 2008. Five and a half years after dCRT, swelling of the cardiac lymph node was detected on CT. Frequent check-up was performed in the subsequent 1 year and 10 months, during which the recurrent lesion was revealed as solitarybyPET -CT. No signs of recurrence were detected at the site of the primarylesion byendoscopic examination; however, another superficial cancer was found at a different site. Endoscopic submucosal dissection was performed for the esophageal lesion, and laparoscopic lymphadenectomy was applied to the cardiac lymph node. We herein report a case of a male patient who underwent minimal invasive locoregional treatments for both metachronous multiple lesions and solitaryly mph node recurrence after dCRT.

Overexpression of IL-6 by gene transfer stimulates IL-8-mediated invasiveness of KYSE170 esophageal carcinoma cells.

Interleukin-6 (IL-6) has been associated with disease progression and poor prognosis in esophageal carcinoma. The aim of this study was to investigate the possible influence of IL-6 on the biological activities of esophageal carcinoma cells in terms of invasiveness. The human esophageal carcinoma cell line, KYSE170, was transfected with a plasmid vector expressing IL-6, and a stable transfectant overexpressing IL-6 was established. Invasiveness was evaluated by an invasion assay and compared between IL-6 and control transfectants. The invasiveness of the IL-6 transfectant was significantly higher than that of the control transfectant, and was significantly reduced by IL-6-specific siRNA. In reverse transcriptase-polymerase chain reaction (RT-PCR) analysis, IL-8 expression was significantly higher in the IL-6 transfectant than in the control transfectant, whereas the expression of Hepatocyte growth factor (HGF) and Vascular endothelial growth factor (VEGF) was not different. IL-8 expression in the IL-6 transfectant was significantly inhibited by IL-8-specific siRNA, whereas IL-6 expression was not. In addition, the invasiveness of the IL-6 transfectant was significantly reduced by IL-8-specific siRNA. These results indicate that the overexpression of IL-6 increases the invasiveness of KYSE170 esophageal carcinoma cells and IL-6-induced IL-8 plays a predominant role in increasing invasiveness.

COX-2 overexpression Induced by gene transfer reduces sensitivity of TE13 esophageal carcinoma cells to 5-fluorouracil and cisplatin.

Previous clinicopathological studies demonstrated that overexpression of cyclooxygenase-2 (COX-2) is associated with a poor treatment response of esophageal carcinoma. The aim of this study was to elucidate the role of COX-2 overexpression in the chemosensitivity of esophageal carcinoma cells. TE13 human esophageal squamous cell carcinoma cells were transfected with a COX-2 constitutive expression vector, and stable transfectants overexpressing COX-2 were established. COX-2 overexpression in COX-2 transfectants was confirmed with western blotting and prostaglandin-E(2) (PGE(2)) assay. Chemosensitivity testing revealed that sensitivity of COX-2 transfectants to 5-fluorouracil and cisplatin was significantly lower than in control vector-only transfectants, and that sensitivity of COX-2 transfectants was restored by the transfection of COX-2-specific siRNA. In addition, expression of antiapoptotic B-cell lymphoma-extra large (BCL-xL) and myeloid cell leukaemia-1 (MCL-1) was increased in COX-2 transfectants. These results indicate that COX-2 overexpression may reduce the chemosensitivity of esophageal carcinoma cells through up-regulation of the expression of antiapoptotic BCL-2 family proteins.

Risk factors for postoperative respiratory complications following esophageal cancer resection.

The development of surgical and postoperative management techniques has improved the treatment outcomes of esophageal cancer resection. However, respiratory morbidity is still the most frequent complication after esophagectomy. The objective of the present study was to identify risk factors for respiratory complications following resection for esophageal cancer. This study included 96 patients with esophageal cancer who had undergone esophagectomy with lymph node dissection. The patients were divided into 2 groups according to the presence (20 patients, 17 had pneumonia and 3 had acute respiratory distress syndrome) or absence (76 patients) of postoperative respiratory complications (PRC). The two groups were compared with respect to their preoperative clinical variables, such as age, body mass index, smoking history, serum albumin, serum C-reactive protein (CRP), number of lymphocytes, %VC, FEV1.0% and FEV1.0. Furthermore, multiple logistic regression analyses were used to estimate relative risk factors for respiratory complications. Results of the univariate analysis showed that smoking history (+/-, patients with PRC, 19/1 and without PRC, 53/23), serum CRP (≥1.0 mg/dl/<1.0 mg/dl, patients with PRC, 6/14 and without PRC, 6/70) and FEV1.0% (≥60%/<60%, patients with PRC, 16/4 and without PRC, 73/3) were significantly different between the two groups. Multiple logistic regression analysis showed that FEV1.0% was the strongest predictor of PRC. FEV1.0%, serum CRP and smoking history are reliable predictors of the risk of respiratory complications following esophageal cancer resection. For patients with these factors, perioperative management for the prevention of postoperative respiratory complications should be considered.

Prediction of histologic regression on the basis of colonoscopic findings in patients with locally advanced middle and lower rectal cancer who receive preoperative chemoradiotherapy.

OBJECTIVE: Preoperative chemoradiotherapy significantly reduces local recurrence in patients with locally advanced rectal cancer (LARC). Various biomarkers have been proposed as predictors of the response to chemoradiotherapy, but their reliability remains uncertain. METHODS: Surgery in combination with preoperative radiation and UFT- or S-1-based chemotherapy was used to treat 102 patients with LARC. Colonoscopy was performed before the start of chemoradiotherapy and immediately before surgery. Patients in whom the tumor mound flattened remarkably or disappeared were evaluated as responders. The endoscopic response was compared with histologic regression and the degree of tumor shrinkage. RESULTS: Histologic regression was marked in 59.8% of patients according to the Tumor Regression Grade criteria and 44.1% according to the Japanese Classification of Colorectal Carcinoma criteria. The degree of tumor shrinkage was 34.3% on average. Marked histologic regression was present in a significantly higher proportion of responders than non-responders (p = 0.01). The degree of tumor shrinkage was significantly greater in responders (38.8%) than in non-responders (30.9%; p < 0.01). T-downstaging was significantly more common among responders (64.3%) than non-responders (26.7%; p = 0.04). CONCLUSIONS: Morphologic changes on colonoscopy were associated with the degree of tumor shrinkage, histologic regression, and T-downstaging, suggesting that such findings can be used to predict the response to preoperative chemoradiotherapy.

Gastrointestinal stromal tumor of the rectum: report of three cases.

Gastrointestinal stromal tumors (GISTs) account for about 0.2% of all malignancy of gastrointestinal tumors and rarely arise in the rectum. We experienced three patients with large GISTs in the rectum. Case 1 (66-year-old man) underwent abdominoperineal resection (APR) for intrapelvic mass. The tumor was 90 mm and diagnosed to be a Kit-positive GIST. Case 2 (81-year-old woman) underwent right hemicolectomy for concurrent ascending colon cancer by a local physician. In our Hospital, APR was performed for intrapelvic mass. The tumor was 90 mm and diagnosed to be a Kit-positive GIST. Ten months after surgery, multiple liver tumors developed. She received oral imatinib for metastases. Case 3 (83-year-old woman) was yielded a diagnosis of Kit-positive GIST by a percutaneous biopsy. Imatinib was given preoperatively. However, adverse reactions occurred and the drug was withdrawn. APR was performed. The tumor was 70 mm. At present, Case 1 and 3 patients are alive without recurrence.

Overexpression of Interleukin-6 suppresses cisplatin-induced cytotoxicity in esophageal squamous cell carcinoma cells.

Interleukin-6 (IL-6) expression at local tumor sites or in systemic circulation is associated with disease progression and poor prognosis of esophageal cancer. The aim of this study was to investigate the possible influence of IL-6 on biological activities of esophageal cancer cells in terms of chemosensitivity. Human esophageal cancer cell lines TE13 and KYSE170 were transfected with a plasmid vector expressing IL-6 and stable transfectants overexpressing IL-6 were thus established. The sensitivity of IL-6 transfectants to cisplatin was evaluated using a WST-8 assay and cell-cycle analysis. In addition, the inhibitory effects of IL-6-specific siRNAs were investigated. IL-6 transfectants showed significantly reduced sensitivity to cisplatin compared to control transfectants. In addition, the reduced cisplatin sensitivity of IL-6 transfectants was restored by pretreatment with IL-6-specific siRNA. These results suggest that intracellular IL-6 expression in tumor cells may acts as a resistance factor against cisplatin-based treatments for esophageal cancer.

Elevated serum CRP levels after induction chemoradiotherapy reflect poor treatment response in association with IL-6 in serum and local tumor site in patients with advanced esophageal cancer.

BACKGROUND AND OBJECTIVES: Elevated serum CRP levels are associated with tumor progression and poor prognosis of esophageal cancer. The aim of this study was to clarify the clinical significance of CRP in relation to response to chemoradiotherapy in patients with esophageal cancer. METHODS: The relationship between serum CRP levels and response to chemoradiotherapy and prognosis was analyzed in 34 patients with advanced esophageal squamous cell carcinoma who underwent induction chemoradiotherapy followed by surgery. The relationship between response to chemoradiotherapy and interleukin-6 (IL-6) expression in sera and tumor tissues was also analyzed. RESULTS: Although elevated serum CRP levels were associated with poor response to chemoradiotherapy, significant difference in CRP levels between pathological responders (n = 18) and non-responders (n = 16) was observed after chemoradiotherapy, but not before. Patients with elevated CRP levels had shorter cause-specific survival, but significant difference was observed only after chemoradiotherapy. In addition, serum levels of IL-6 were also associated with poor treatment response following chemoradiotherapy and were correlated with residual tumor volume. IL-6 expression was detected in residual tumor tissues by immunohistochemistry. CONCLUSIONS: Elevated serum CRP levels after chemoradiotherapy may predict poor response to chemoradiotherapy more accurately than before chemoradiotherapy, and IL-6 may be a possible target associated with chemoradiotherapy resistance.

[Early prediction of treatment response by serum CRP levels in patients with advanced esophageal cancer who underwent definitive chemoradiotherapy].

Serum CRP has been shown to be associated with the progression of esophageal cancer. The purpose of this study was to examine the relationship between treatment response and serum CRP levels in time course during definitive chemoradiotherapy (CRT) in terms of early prediction of CRT response by serum CRP. The subjects of this study were 36 patients with cT3/cT4 esophageal squamous cell carcinoma who underwent definitive CRT in our hospital. Serum CRP levels during definitive CRT (pretreatment, 1W, 2W and 3W after CRT initiation) were compared between CR and non-CR group. In addition, partition model was constructed to discriminate CR with non-CR and the prediction accuracy was evaluated. The patients were consisted of 28 males and 8 females. At pretreatment diagnosis, tumors were categorized as T3 (n=21) and T4 (n=15). Thirty four patients received FP-based chemotherapy and 2 patients received docetaxel-based chemotherapy. Treatment responses were categorized as CR (n=8), PR (n=14), NC (n=2) and PD (n=12). Serum CRP levels at the time of 2W after CRT initiation (CRT2W) in CR group were low compared to those in non-CR group (p=0.071). The partition model was constructed based on CRP levels at CRT2W. The prediction accuracies to discriminate CR from non-CR by CRP≤0.1 were 50%, 82%, and 75% in sensitivity, specificity and accuracy, respectively. Serum CRP is a useful biomarker for an early prediction of CRT response.

[Surgically resected local recurrence after endoscopic submucosal dissection of esophageal cancer--a case report].

We report a case of surgically resected esophageal cancer which was locally recurred after endoscopic submucosal dissection. A 66-year-old man was admitted to our hospital because of further examination and a treatment of superficial esophageal cancer. A type 0-IIb+IIa cancer occupying the whole circumference of the lumen of the middle to lower esophagus was revealed. The depth of the invasion was judged to be T1a-EP or LPM by endoscopic ultrasonography, and no metastasis to other organs or lymph nodes was detected. Endoscopic submucosal dissection (ESD) was performed. However, macroscopic residual cancer didn't seem to exist. Pathological diagnosis was squamous cell carcinoma, moderately differentiated, the depth of tumor invasion was T1a-LPM. The presence of the residual cancer of the horizontal cut margin could not be judged because en bloc resection could not be achieved. After that, endoscopic balloon dilatation of the esophageal stenosis was performed repeatedly for about one year. Then, he was diagnosed as the local recurrence of the squamous cell carcinoma of the esophagus. Thoraco-abdominal esophagectomy reconstructed by stomach tube via a retrosternal route was undergone. The final stage of the lesion was judged T3N1M0 (Stage III, UICC) by the histological examination from the resected specimen. After the operation, he is receiving adjuvant chemotherapy and alive without recurrence. When endoscopic resection of the esophageal cancer is performed to the lesion, which relatively indicated to endoscopic resection or outside the guideline criteria for endoscopic resection, it is important that we choose the appropriate treatment protocol obtaining an informed consent from the patient sufficiently.

[Radiofrequency ablation for postoperative recurrent of metastatic lesions of esophageal cancer].

Radiofrequency ablation (RFA) was performed for the postoperative recurrent of metastatic lesions of esophageal cancer in 6 patients. All patients were males, and the median age was 59. Surgical curativities were A (3 cases), B (2) and C (1). The recurrent sites were intramediastinal omentum of gastric tube (2 cases), rt lung (2), rt adrenal grand (1) and liver (1). Four cases had a single recurrent lesion and the two had multiple lesions consisted of a single lesion as RFA target, and the lesions in a different site that were simultaneously treated by other therapeutic modalities. The median time of recurrence was 12 months after esophagectomy. RFA was performed once in the 3 cases, and twice in the other 3 cases. Therapeutic effect evaluated by CT was CR (2 cases), PR (3) and SD (1). No serious complications associated with RFA procedure were observed. Three patients died due to cancer recurrence within 7 months after RFA. However, RFA-treated lesions were well controlled to the end. RFA are safe and minimally invasive, thus, can be repeatedly performed technique that can induce a good local control of the target lesion equivalent to surgical resection. RFA is applicable as an effective local therapy for the recurrent or metastatic lesions of esophageal cancer.

[PSK-mediated growth suppression and enhancement of 5-FU/docetaxel-induced cytotoxicity in human esophageal cancer cell lines].

PSK, a protein-bound polysaccharide, is widely used for treating cancer patients as an immunostimulant. However, its direct action on cancer cells is not fully understood. In the present study, we investigated direct effects of PSK alone or in combination with 5-FU, CDDP and docetaxel on tumor growth by using esophageal cancer cell lines, KYSE170 and TE13. Cells were incubated with different concentrations of PSK for 72 hour, and cell viability was determined by WST-8 assay, and cell cycle was analyzed by flow cytometry. As a result, PSK of 100 microg/mL induced growth suppression dose-dependently in the both cell lines, and flow cytometric analysis showed a PSK dose-dependent increase of sub-G1 cells indicating apoptotic cells. In addition, when cells were incubated with different concentrations of 5-FU and docetaxel in the presence of PSK at the dose of 5 microg/mL showing no growth suppression, cytotoxicity induced by 5-FU and docetaxel was significantly enhanced. These results indicate that PSK not only shows tumor growth suppression by apoptosis induction, but also enhances 5-FU and docetaxel-induced cytotoxicity.

[The IL-6 and COX-2 expression related to sensitivity of chemoradiotherapy and prognosis in esophageal carcinoma].

Chemoradiation therapy (CRT) for esophageal cancer induces inflammatory responses within tumor tissues. Inflammatory cells infiltrated into the tumor tissues may modulate the CRT responses via inflammation-related molecules such as IL-6 or COX-2. In the present study, we investigated a relationship between IL-6/COX-2 expression and CRT responses for esophageal cancer. A surgical resection following CRT was performed, and the specimens from the patients with cT3/T4 esophageal squamous cell examined for IL-6/COX-2 expression in both residual cancer and stromal cells by immunohistochemical staining. CRT responses were divided into responder group (Grade 1b and Grade 2) and non-responder group (Grade 1a). COX-2 in cancer cells and IL-6 in stromal cells were associated with non-responder and responder, respectively. In addition, IL-6 in stromal cells was significantly correlated with overall survival. Our data suggest that inflammatory responses concomitant with CRT responses could play a role in chemoradiation responses and prognosis.

[A case of multiple hepatic metastases of gastric cancer that showed complete regression by systemic chemotherapy using paclitaxel and UFT-E].

We report a case of gastric cancer with simultaneous multiple liver metastasis that was successfully treated by paclitaxel and UFT-E. A 54-year-old man with gastric cancer was admitted to our hospital for further examination and treatment. A type III gastric cancer was located in the lower to middle part of the gastric body. Abdominal CT revealed multiple liver metastases and lymph node metastases. Then, we performed distal gastrectomy and cholecystectomy. Postoperative pathological diagnosis was stage IV(a type 3 tumor( 78x65 mm), pT3, por 2, INF g, ly3, v0, pN2(+)(26/ 28), H1(bilobular multiple metastases), CY0, P0). Postoperatively, he was treated with S-1 po at 100 mg/body/day as first-line chemotherapy. Thirteen days after S-1 initiation, he was readmitted due to grade 3 diarrhea, and S-1 was immediately stopped. After his general condition was improved, paclitaxel was administered biweekly at a dose of 80 mg/m2. He was discharged after twice administration, and the regimen was continued at an outpatient clinic. Four months after the operation, abdominal computed tomography(CT)showed a remarkable reduction of the multiple liver metastases, and the serum levels of tumor markers(CEA, CA19-9)were reduced. Five months after the operation, the serum levels of tumor markers elevated again. Then, additional administration of UFT-E po(300 mg/body daily) was started. Seven months after the operation, abdominal CT showed a complete regression of the multiple liver metastasis, and the serum levels of tumor markers were also reduced within the normal range. During chemotherapy at an outpatient clinic, critical adverse effects did not appear. Paclitaxel or paclitaxel combined with UFT-E might be an effective regimen as second- or third-line chemotherapy for the liver metastases of gastric cancer.

Long-term complete response of multiple hepatic metastases from carcinoma of the papilla of Vater using intrahepatic infusion of 5-FU with low-dose cisplatin following pancreaticoduodenectomy.

Of all distant metastases from carcinoma of the papilla of Vater (CPV), the liver is the most frequent site (more than 60%) and should be specifically targeted in the effort to improve the prognosis. However, the optimal chemotherapy regimen for nonresectable liver metastasis has not been clearly established. In this preliminary report, we note a patient with multiple hepatic metastases from CPV successfully treated using intrahepatic infusion of 5-fluorouracil (FU) with low-dose cisplatin. A 62-year-old woman underwent curative pylorus-preserving pancreaticoduodenectomy for CPV. Four months after surgery, followup computed tomography (CT) demonstrated multiple liver metastases. Weekly intrahepatic arterial infusion chemotherapy of 5-FU, 350 mg/m(2), with low-dose cisplatin (7 mg/m(2)) was started. Ten months after starting chemotherapy, a complete response was obtained. To date, the patient continues to receive this weekly hepatic arterial infusion chemotherapy without any side effects, and she has successfully maintained a long-term complete response for 20 months. The patient remains well and was able to proceed with daily activity at the last follow up 30 months after starting this chemotherapy regimen. This regimen is safe and effective and is recommended as one of the treatment choices for liver metastases from CPV.

Novel interventional treatment technique for intractable pancreatic fistula due to dehiscence of pancreatico-jejunal anastomosis following pancreaticoduodenectomy.

Despite recent technological advances in the treatment of hepatobiliary pancreatic disease, intractable external pancreatic fistula is still a major critical complication after pancreaticoduodenectomy, and the treatment strategy is not well defined. We report here a case that was successfully treated by our novel interventional internal drainage technique. A 62-year-old woman underwent pylorus-preserving pancreaticoduodenectomy for carcinoma of the papilla of Vater, with reconstruction by a modified Child's procedure. One year later, she was readmitted to our hospital because of external pancreatic fistula. Both computed tomography and fistulography demonstrated a pancreatic fistula derived from dehiscence of the pancreatico-jejunal anastomosis. The pancreatic fistula persisted for 1 week with conservative management. Therefore, we performed repeated fistulography and cannulation, using two comparatively stiff guidewires introduced into the main pancreatic duct and stenotic anastomosed jejunal lumen, respectively, and we placed an endoprosthesis, using bilateral guidewires to connect the two lumens. Consequently, the pancreatic fistula was successfully closed within a few days. Our novel technique is simple, rapid, and not costly. Therefore, it should be considered an effective treatment strategy for persistent pancreatic fistula following pancreaticoduodenectomy that fails to respond to initial conservative management and an endoscopic approach. Also, this technique is applicable to other intractable fistulous situations.