A Case of Streptozocin Monotherapy for Unresectable Duodenal Neuroendocrine Tumor G2.

BACKGROUND: Duodenal neuroendocrine tumors (NET) are rare, and few reports have demonstrated the effectiveness of chemotherapy for duodenal NET, with not many other treatment options available. Here, we present a case of unresectable duodenal NET G2 that was effectively treated with streptozocin (STZ) monotherapy. We also perform a literature review. CASE SUMMARY: A 57-year-old man presented with multiple lymph node metastasis, liver metastasis, and bone metastasis that occurred after the primary resection of the duodenal NET G2. His long-term survival was obtained; the duration of stable disease exceeded 1 year and 6 months following STZ monotherapy. In addition, his CA 19-9 levels, which previously were increasing, normalized following treatment. CONCLUSION: To our knowledge, no study has reported the effectiveness of STZ monotherapy for duodenal NET. Our findings demonstrate that for unresectable duodenal NETs, STZ should be first administered as a high volume/single dose to stabilize the disease. However, if the disease progresses, a combination therapy may be effective in obtaining a long-term prognosis of the patient. Furthermore, CA19-9 levels may be an effective factor for determining the therapeutic effect of STZ in NET with other metastases.

[The Actual State of Treatment of Gastrointestinal Cancer with Abdominal Aortic Aneurysm in Our Department over the Past Five Years].

With the aging of the population of Japan and Westernization of the dietary life, the number of cases in which cardiovascular diseases are merged in non-cardiac surgery is increasing year by year.Many of the abdominal aortic aneurysms are asymptomatic and it is not uncommon to be discovered accidentally in preoperative examination of non-cardiac surgery.When gastrointestinal surgery involves malignant diseases of the gastrointestinal tract and abdominal aortic aneurysm, the two life prognosis-related diseases are merged, depending on the severity and urgency of the disease for each case, its treatment to determine the priority order.Abdominal aortic aneurysm occurred at the time of malignant disease surgery in 14 cases of gastrointestinal cancer patients who underwent surgery at the department during the 5 years from 2012 to 2016.T he actual condition of treatment for these cases was investigated.

[Cases of Oncologic Emergency Associated with Colorectal Cancer].

The clinical condition of oncologic emergency associated with colorectal cancer includes hemorrhage, perforation and obstruction. Obstructive colorectal cancer is an oncologic emergency commonly observed in our daily clinical practice. Colonic stent placement for obstructive colorectal cancer is relatively easy and safe and may be considered as an effective treatment method that enables favorable intestinal decompression preoperatively and one-stage resection. Colonic stent use can be a bridge to surgery, enabling shorter duration of hospitalization, and reduced postoperative complications, and colostomy rates, as compared to emergency surgery. From January 2009 to December 2016, this study was designed to evaluate the clinical outcomes of 68 patients who underwent surgery for obstructive colorectal cancer. The patients were divided into 2 groups: 32 cases receiving colonic stent placement(the S group), 36 cases receiving ileus tube and emergency surgery(the NS group). There was no significant difference in terms of morbidity or survival rate between the 2 groups. For the S group, 31 out of 32 could one-stage resection(94%). The colostomy rate in the S group was significantly lower than that in the NS group(3% vs 33%). In the S group, number of dissected lymph nodes was significantly larger and the duration of postoperative stay was shorter than that in the NS Group.

[A Case of Early Gastric Cancer with Multiple Lymph Node Metastases Revealed by Additional Surgical Resection after ESD].

A 74-year-old man was referred to our hospital for further investigation of a cystic lesion in the pancreatic body, which had been detected by ultrasonography at a local hospital. He was diagnosed as intraductal papillary mucinous neoplasm(IPMN) and further preoperative examinations were conducted. Upper gastrointestinal endoscopy demonstrated a type 0-II c tumor of the greater curvature in the upper third of the stomach. Endoscopic ultrasonography showed no sign of submucosal invasion. Endoscopic submucosal dissection(ESD)was carried out and pathological examination of a specimen revealed well differentiated adenocarcinoma with submucosal invasion, which fulfilled the indication for additional gastrectomy with lymph node dissection. Laparoscopy-assisted proxymal gastrectomy with D1 plus lymph node dissection and distal pancreatectomy with splenectomy was performed. Pathological examination demonstrated intraductal papillary mucious adenoma(IPMA)in the pancreatic body and no residual gastric cancer in a specimen, however 7lymph node metastases from gastric cancer was confirmed(pN3a), including 3 metastatic lymph nodes incidentally-detected adjacent to the pancreatic parenchyma. We report a rare case of early gastric cancer with N3 lymph node metastases, with a brief literature review.

Ibuprofen enhances TRAIL-induced apoptosis through DR5 upregulation.

Numerous human chemoprevention studies have demonstrated that non-steroidal anti-inflammatory drugs (NSAIDs) possess chemopreventive effects against a variety of malignant tumors. However, there have been many clinical studies on aspirin, but not ibuprofen, even though ibuprofen is one of the most clinically and safely used NSAIDs showing potent anti-inflammatory effects. Moreover, we reported that many chemopreventive agents enhance the apoptosis-inducing effects of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), which is known to be crucial for cancer prevention. We, therefore, investigated whether ibuprofen enhances the cytocidal effect of TRAIL and found that ibuprofen markedly stimulated the apoptosis-inducing efficacy of TRAIL against human colon cancer HCT116 cells. As detected by western blot analysis and real-time RT-PCR, ibuprofen upregulated the expression of death receptor 5 (DR5), a TRAIL receptor. TRAIL-induced apoptosis enhanced by ibuprofen was effectively decreased by a caspase inhibitor and dominant-negative DR5. Noteworthy, co-treatment of ibuprofen with TRAIL did not enhance apoptosis in normal peripheral blood mononuclear cells (PBMCs). These results demonstrated that ibuprofen and TRAIL synergistically induced apoptosis in human colon cancer HCT116 cells but not in normal PBMCs, raising the possibility that ibuprofen may be promising as a safe chemopreventive agent against colon cancer.

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.

PSK induces apoptosis through the inhibition of activated STAT3 in human esophageal carcinoma cells.

PSK, a protein-bound polysaccharide, is widely used in Japan as an immunopotentiating biological response modifier for cancer patients. PSK exerts antitumor activities through stimulation of the host's immune response; however, few studies have addressed the direct actions of PSK on tumor cells. Recently, it has been found that STAT3 is aberrantly activated in various types of malignancies, and plays a crucial role in tumor cell proliferation and survival. In the present study, STAT3 was constitutively activated in KYSE170 and TE13 esophageal carcinoma cells, and PSK inhibited proliferation and induced apoptosis in these cells in a dose-dependent manner. Based on these findings, the relationship between STAT3 and apoptosis in these cells was investigated. Results showed that PSK inhibited the expression of activated STAT3 and stimulated the expression of pro-apoptotic Bax in a dose-dependent manner, without affecting the expression of anti-apoptotic Bcl-xL and Mcl-1. These results indicate that PSK may induce apoptosis in esophageal carcinoma cells by inhibiting the expression of activated STAT3.

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.