[An autopsied case of giant small cell carcinoma of the pancreas].

A 58-year-old man who complained of an abdominal tumor was admitted to our hospital. Abdominal CT scan showed that a 15-cm tumor occupied the entire right upper abdomen and that there were ascites and liver metastases. A liver biopsy was performed. The liver biopsy showed a small cell carcinoma pattern, but no definitive origin of the tumor was determined. Considering the extensive peritoneal invasion and multiple liver metastases, he received 2 / courses of cisplatin/etoposide chemotherapy, but his tumor became larger with concomitant abdominal pain and nausea. The patient suddenly died due to multiple organ failure caused by tumor necrosis. The autopsy revealed a pathological diagnosis of primary small cell carcinoma of the pancreas.

Thyroid carcinoma with extensive tumor thrombus in the atrium.

To our knowledge, only a few cases of thyroid carcinoma with an extensive tumor thrombus in the atrium have been reported in literature. We describe a unique case of papillary carcinoma of the thyroid with extensive tumor thrombus in the atrium. A 74-year-old man consulted our hospital because of thyroid carcinoma with an extensive tumor thrombus in the atrium. Computed tomography (CT) revealed a 2-cm tumor with extensive continuous tumor thrombus in the left jugular vein, innominate vein, superior vena cava, and atrium. The tumor was resected to reduce the risk of sudden death from tumor embolism into the pulmonary arteries. Histologically, the diagnosis was papillary carcinoma of the thyroid. Thyroid carcinoma, especially papillary carcinoma, rarely develops a macroscopic tumor thrombus. Patients with an extensive tumor thrombus generally have poor prognoses and high mortality. This patient has been followed for 7 months after successful operation without recurrence.

Unresectable gastric cancer with multiple liver metastases effectively treated with combined paclitaxel and doxifluridine chemotherapy.

We report a 72-year-old man who was diagnosed by gastroscopy as having a type III poorly differentiated adenocarcinoma in the lesser curvature, with the longest diameter being 10 cm. An abdominal computed tomography (CT) scan revealed multiple liver metastases, thickening of the gastric wall, and an enlarged paraaortic lymph node. The serum carcinoembryonic antigen (CEA) level was 60 ng/ml and the carbohydrate antigen (CA) 19-9 level was 1355 U/ml. The patient received combined chemotherapy with doxifluridine (800 mg/body per day) and paclitaxel (one course comprised three weekly infusions at a dose of 70 mg/m(2) followed by 1-week rest). After the completion of three courses, the patient achieved a complete response (CR), with complete disappearance of the primary tumor, the metastatic foci in the liver, and the enlarged abdominal lymph nodes; as well, the tumor markers were normalized. Adverse effects included only mild anorexia that was limited to grade 1. He maintained a CR for 1 year and 2 months. Combination chemotherapy with paclitaxel and doxifluridine can be an effective treatment for unresectable advanced gastric carcinoma.

Significance of intraoperative monitoring of arterial blood flow velocity and hepatic venous oxygen saturation for performing minimally invasive surgery in a patient with multiple calcified pancreaticoduodenal aneurysms with celiac artery occlusion.

Even for patients with multiple pancreaticoduodenal aneurysms, successful treatment with noninvasive operative procedures can be employed, if intraoperative devices are considered. A 73-year-old man, without any symptoms, was admitted to our hospital and had computed tomography (CT) scanning to examine his liver for hepatitis C virus (HCV). Selective superior mesenteric artery (SMA) angiography confirmed multiple aneurysms in the anterior inferior pancreaticoduodenal artery (AIPDA), one aneurysm in the posterior inferior mesenteric artery (PIPDA), and another in the occluded celiac trunk, all with severe calcification. All of the aneurysms were thought to communicate with each other. With the celiac artery occlusion, the right hepatic artery (RHA) was revealed to be supplied by collateral arteries from the aneurysms in the AIPDA, and the left hepatic artery was shown to be supplied by collaterals from the left gastric artery. Intraoperative Doppler echography, at the time of the clamping of both IPDAs, demonstrated a marked decrease of blood velocity in all aneurysms (before clamping, >50 cm/s; after, <10 cm/s), although loss of pulsation and a marked decrease of flow in the RHA were inevitable. Therefore, each of these two IPDAs were ligated on the proximal side to the aneurysm, thus preserving the blood flow of the pancreas head fed by the PIPDA; bypass grafting from the AIPDA to the RHA, using the great saphenous vein, was done at the same time. After the creation of an anastomosis, the hepatic venous oxygen saturation (ShvO2) increased from 38% (at the time of ligation of the IPDAs) to 57% under ventilation. The patient's postoperative clinical course was uneventful. We describe and discuss our successful noninvasive operative management of multiple pancreaticoduodenal aneurysms, done while monitoring the blood flow and ShvO2, with some consideration of the literature.

[A randomized controlled study comparing uracil-tegafur (UFT)+tamoxifen (UFT+TAM therapy) with cyclophosphamide+adriamycin+5-fluorouracil (CAF therapy) for women with stage I , II, or IIIa breast cancer with four or more involved nodes in the adjuvant setting].

We performed a controlled study to compare the response to cyclophosphamide (CPA), adriamycin (ADM), and fluorouracil (5-FU) (CAF therapy) with that to uracil-tegafur (UFT) plus tamoxifen (TAM) (UFT+TAM therapy), when given as postoperative adjuvant therapy to women with breast cancer. The patients were registered from September 1991 through February 1995 at 51 institutions in the Kinki district of Japan. All patients had stage I, II, or IIIa breast cancer with four or more lymph-node metastases and underwent mastectomy. CAF therapy and UFT+TAM therapy were started within 4 weeks after surgery. CAF therapy consisted of CPA (100 mg/day) on days 1 to 14, followed by 2 weeks of rest, plus ADM (20 mg/m(2)/day) on days 1 and 8 and 5-FU (300 mg/m(2)/day) on days 1 and 8. A total of 6 courses were delivered. UFT+TAM therapy consisted of 3 years of UFT (400 mg/day) plus TAM (20 mg/day), given daily. CAF therapy and UFT+TAM therapy were each assigned to 82 patients. The 5-year survival rate was significantly higher in the UFT+TAM group (82.1%) than in the CAF group (66.2%; p=0.04, logrank test). The 5-year relapse-free survival rate was higher in the UFT+TAM group (61.8%) than in the CAF group (46.3%; p=0.07, logrank test). As for adverse events, the rates of leukopenia, anorexia, nausea and vomiting, general malaise, and hair loss were lower in the UFT+TAM group than in the CAF group. These results suggest that long-term treatment with UFT+TAM may be a useful alternative adjuvant therapy for the management of breast cancer, especially in elderly patients.

[Case report of advanced breast cancer responding to capecitabine and trastuzumab combination therapy].

We conducted a concomitant administration of capecitabine (2,400 mg/day for 21 days followed by a 7-day interval) and trastuzumab (2 mg/kg weekly) to a 73-year-old female patient with impaired lower limb function diagnosed with bilateral breast cancer. The patient had a complete response (CR) to pulmonary metastases, and carcinoembryonic antigen (CEA) level had normalized from 46.4 ng/ml to 0.6 ng/ml. Left mastectomy was performed in order to control bleeding from tumors. No adverse events attributable to medication were observed. The concomitant administration of capecitabine and trastuzumab is a promising therapy with the potential to greatly improve patient quality of life (QOL).

[Combined chemotherapy with weekly Paclitaxel and doxifluridine for advanced and recurrent gastric cancers].

We conducted combined therapy of weekly paclitaxel and doxifluridine (5'-DFUR) for 23 cases of advanced and recurrent gastric carcinomas to investigate their efficacy and safety. Subjects included 7 unresectable cases, 5 noncurative resection cases, and 11 recurrent cases. Twenty of the 23 subjects had a history of prior treatment with another anticancer drug. The treatment regime consisted of one course comprising 70 mg/m(2)of paclitaxel weekly for three consecutive weeks followed by one week rest, combined with 800 mg/day of 5'-DFUR orally. Results revealed a response rate of 17.6% (3/17), with 2 cases of CR, 1 case of PR, 10 cases of NC, and 4 cases of PD. One of the CR cases was an unresectable case involving a primary tumor, liver metastasis, and abdominal lymph node metastasis, while the other was a recurrent case involving abdominal lymph node metastasis. The median survival period was 387 days. The one-and two-year survival rates were 52% and 24%, respectively. In terms of adverse effects, there were only single cases of grade 3 leukopenia and grade 3 neutropenia, with no cases of grade 4 hemotoxicity. Both patients could be treated as outpatients. Combination therapy of weekly paclitaxel and 5'-DFUR can be an effective and safe therapy for advanced and recurrent gastric carcinomas.

Nitric oxide in breast cancer: induction of vascular endothelial growth factor-C and correlation with metastasis and poor prognosis.

PURPOSE: Metastasis to regional lymph nodes through the lymphatic vessels is a common step in the progression of cancer. Recent evidence suggests that tumor production of vascular endothelial growth factor-C (VEGF-C) promotes lymphagiogenesis, which in turn promotes lymphatic metastasis. Nitric oxide (NO) may also increase metastatic ability in human cancers. EXPERIMENTAL DESIGN: Nitrite/nitrate levels and VEGF-C production were assessed in MDA-MB-231 breast cancer cells after induction and/or inhibition of NO synthesis. Formation of nitrotyrosine, a biomarker for peroxynitrate formation from NO in vivo, was analyzed in primary human breast carcinoma with long-term follow-up. The relationship between nitrotyrosine levels and lymph node status, VEGF-C immunoreactivity, and other established clinicopathologic variables, as well as prognosis, was analyzed. RESULTS: Production of nitrite/nitrate and VEGF-C in MDA-MB-231 cells was increased by treatment with the NO donor DETA NONOate. The NO synthase inhibitor N(G)-nitro-l-arginine methyl ester eliminated this increase. High-grade nitrotyrosine staining was observed in 57.5% (65 of 113) of the invasive breast carcinomas. Nitrotyrosine levels were significantly correlated with VEGF-C immunoreactivity and lymph node metastasis. Survival curves determined by the Kaplan-Meier method showed that high nitrotyrosine levels were associated with reduced disease-free and overall survival. In multivariate analysis, high nitrotyrosine levels emerged as a significant independent predictor for overall survival. CONCLUSIONS: Our data showed a role for NO in stimulating VEGF-C expression in vitro. Formation of its biomarker nitrotyrosine was also correlated with VEGF-C expression and lymph node metastasis. Furthermore, high nitrotyrosine levels may serve as a significant prognostic factor for long-term survival in breast cancer.

Lymph vessel density correlates with nodal status, VEGF-C expression, and prognosis in breast cancer.

Metastasis to the regional lymph nodes through the lymphatic vessels is a common step in the progression of cancer and an important prognostic factor in many types of cancer. Recent evidence suggests that VEGF-C promotes lymphangiogenesis, and that tumor lymphangiogenesis in turn promotes lymphatic metastasis. We have studied the role of LVD in breast cancer, and examined whether LVD is associated with lymph node metastasis, VEGF-C expression, or prognosis. In addition, we examined whether VEGF-C mRNA transcript levels were associated with lymph node metastasis and LVD. We began by investigating the lymphatics in primary human breast carcinoma with long-term follow-up (113 cases of invasive ductal and other breast cancers) by quantitative immunohistochemical staining for podoplanin. We then analyzed the relationship between LVD and lymph node status as well as VEGF-C immunoreactivity and other established clinicopathological parameters. The relationship between LVD and prognosis was also studied. VEGF-C mRNA transcript levels were examined by quantitative real-time RT-PCR, in 55 invasive ductal breast carcinomas. This was followed by an analysis of the relationship between VEGF-C mRNA transcript levels and lymph node metastasis as well as LVD. Mean LVD of 'hot spots' was 10.2 +/- 7.4/each case. LVD was significantly correlated with lymph node metastasis (p < 0.0001), VEGF-C immunoreactivity (p = 0.0084), and podoplanin positive lymphatic invasion (p < 0.0001). Survival curves determined by the Kaplan-Meier method and univariate analysis demonstrated that high LVD was associated with both worse disease free survival (p = 0.0033) and overall survival (p = 0.0391). VEGF-C mRNA transcript levels were also correlated with lymph node metastasis (p = 0.0074) and LVD (p = 0.0409). Increased LVD was correlated with lymph node metastasis and VEGF-C expression. High LVD may be a significant unfavorable prognostic factor for long-term survival in breast cancer.

Resection and reconstruction of the airway in patients with advanced thyroid cancer.

The prognosis of patients with differentiated thyroid cancer is relatively fair, with a 10-year survival rate above 80%. One of the important prognostic factors is cancer invasion to the airway. For the last 25 years we have been performing combined resection of the trachea and larynx and have reported a relatively good 10-year survival (67.7%) and improved quality of life (QOL). However, operative complications associated with the procedure, especially insufficiency of the anastomosis and bleeding from large vessels, are life-threatening. Of 40 patients who underwent resection of the trachea, insufficiency of the anastomosis occurred in 4 and subsequent massive bleeding from carotid artery due to neck infection in 2. Tracheal resection should be carried out carefully by avoiding insufficiency. We have concluded that combined resection is a good treatment choice for survival and good QOL when performed for local control in patients with differentiated thyroid cancer.

Flt-4-positive vessel density correlates with vascular endothelial growth factor-d expression, nodal status, and prognosis in breast cancer.

PURPOSE: Metastasis to the regional lymph nodes through the lymphatic vessels is a common step in the progression of cancer and an important prognostic factor in many types of cancer. Recent evidence suggests that tumor lymphangiogenesis promotes lymphatic metastasis, and that the presence of Flt-4 on tumor blood and lymphatic vessels may play a important role in mediating lymphangiogenic factor-induced neovascularization. We assessed flt-4-positive vessel density (FVD) in breast cancer, and examined whether FVD associates with lymph node metastasis, VEGF-D expression, or prognosis. EXPERIMENTAL DESIGN: One hundred three invasive breast carcinomas with long-term follow-up were included in our study. Flt-4 was assessed using immunohistochemistry, then we analyzed the relationship between FVD and lymph node status, as well as VEGF-D expression and other established clinicopathological parameters. The relationship between FVD and prognosis was also investigated. RESULTS: Mean FVD of "hot spot" was 29.3 +/- 22.5 for each case. FVD was correlated significantly with lymph node metastasis (P < 0.0001), VEGF-D expression (P = 0.0019), tumor size (P = 0.0015), estrogen receptor (P = 0.0211), progesterone receptor (P = 0.0462), and c-erbB-2 (P = 0.0326). Survival curves determined by the Kaplan-Meier method and univariate analysis demonstrated that high FVD was associated with both worse disease-free survival (P = 0.0035) and overall survival (P = 0.0336). CONCLUSIONS: Increased FVD was correlated with lymph node metastasis and VEGF-D expression. High FVD may be a significant unfavorable prognostic factor for long-term survival in breast cancer. It is possible that Flt-4 becomes a target for antiangiogenic therapy to breast cancer.

Clinicopathological significance of vascular endothelial growth factor-C in breast carcinoma with long-term follow-up.

Expression of angiogenic and lymphangiogenic factors by tumors may influence the route of metastatic spread. The angiogenic factor vascular growth factor-C (VEGF-C) is implicated in the development of lymphatic vessels and promotion of lymphatic metastasis. The purpose of this study was to determine whether VEGF-C correlates with lymph node metastasis or prognosis. We assessed VEGF-C expression using immunohistochemistry in 123 invasive breast carcinomas with long-term follow-up. The relationship between VEGF-C expression and lymph node status and other established clinicopathological parameters was assessed. Whether VEGF-C expression plays a prognostic role in breast cancer was also investigated. VEGF-C expression was identified in 103 cases (83.7%). Positive VEGF-C was significantly correlated with lymph node metastasis (P = 0.0131). Survival curves determined by the Kaplan-Meier method and univariate analysis demonstrated that positive VEGF-C was associated with both disease-free survival (P = 0.0165) and overall survival (P = 0.0175). On the basis of our findings, VEGF-C plays a crucial role in lymph node metastasis and may be a significant prognostic factor for long-term survival in breast cancer.

Prognostic significance of vascular endothelial growth factor D in breast carcinoma with long-term follow-up.

PURPOSE: Expression of angiogenic and lymphangiogenic factors by tumors may influence the route of metastatic spread. The angiogenic factor vascular endothelial growth D (VEGF-D) is implicated in the development of lymphatic vessels and promotion of lymphatic metastases. The purpose of this study is to determine whether VEGF-D correlates with lymph node metastasis or prognosis. EXPERIMENTAL DESIGN: We assessed VEGF-D expression using immunohistochemistry in 105 invasive breast carcinomas with long-term follow-up. The relationship among VEGF-D expression, lymph node status, and other established clinicopathological parameters was assessed. Whether VEGF-D expression plays prognostic role in breast cancer was also investigated. RESULTS: VEGF-D expression was identified in 86 cases (81.9%). Positive VEGF-D was significantly correlated with lymph node metastasis (P = 0.0238) and high c-erbB-2 expression (P = 0.0211). Survival curves determined by the Kaplan-Meier method and univariate analysis demonstrated that positive VEGF-D was associated with both disease-free survival (P = 0.0023) and overall survival (P = 0.0222). In multivariate analysis using the Cox regression model, positive emerged as an independent indicator for disease-free survival (P = 0.0452). CONCLUSIONS: VEGF-D expression is associated with lymph node metastasis and may be a novel prognostic factor in breast cancer. VEGF-D may be useful in the treatment of breast cancer as a decision-making biomarker for aggressive treatment after operation.

Postoperative hyperbilirubinemia after surgery for gastrointestinal perforation.

PURPOSE: The aim of this study was to evaluate the risk factors and outcome of patients with hyperbilirubinemia after surgery for generalized peritonitis. METHODS: We retrospectively analyzed data from 229 patients with generalized peritonitis caused by gastrointestinal (GI) perforations. RESULTS: Postoperative hyperbilirubinemia defined as a value of > or =5 mg/dl, within 1 month, developed in 39 patients. Postoperative hyperbilirubinemia was related to age ( P = 0.0102), poor nutritional status ( P = 0.0388), decreased base excess ( P = 0.0037), delay until surgery ( P = 0.0276), preoperative serum bilirubin ( P = 0.0321) and postoperative persistent infection ( P < 0.0001). Higher mortality was seen in patients with hyperbilirubinemia (59%) than in those without hyperbilirubinemia (4%). The patients with hyperbilirubinemia who survived had decreased serum bilirubin levels after 3-5 postoperative days whereas a continuous increase was seen in the patients who ultimately died. Preoperative shock ( P = 0.0003), a decreased preoperative platelet count ( P = 0.0152), postoperative infection ( P = 0.0050), and postoperative hyperbilirubinemia ( P < 0.0001) were risk factors for overall mortality. CONCLUSION: These results indicate that postoperative hyperbilirubinemia in patients with GI perforation is related to persistent postoperative infection and associated with poor prognosis.

Heparanase: a key enzyme in invasion and metastasis of gastric carcinoma.

Previous reports have shown that the biochemical activity of heparanase is significantly correlated with the invasion and metastasis of malignant cells in vitro. Recently, it was found that the human heparanase gene was cloned and highly expressed in malignant cell lines and human solid malignant tumors. In the present study, we investigated the heparanase mRNA expression by using in situ hybridization in 116 paraffin-embedded tissues of primary gastric carcinomas. To explore its clinicopathologic significance, it was detected in the various steps of tumor progression and then compared with prognostic indicators. As a result, the heparanase expression was more prevalent in late-stage rather than early-stage carcinomas (P <.0001) and was more frequent in tumors of large size (P =.0212). Expression also correlated with lymphatic (P =.0086) and venous (P =.0171) invasion and with negative prognostic factors such as lymph nodal (P <.0001) and distant (P =.0221) metastases. However, in a multivariate analysis, messenger RNA expression of heparanase was not an independent prognostic factor. It was concluded that heparanase might play an important role in the development of invasion and metastasis of the gastric cancer. It was indicated that patients with heparanase-positive gastric carcinoma would have a greater chance of metastasis with a poor prognosis.

Responses of interleukin-6 and tumor necrosis factor during and after cardiac surgery undergoing cardiopulmonary bypass and pancreatoduodenectomy.

To evaluate the effect of cardiopulmonary bypass on immunological function, we measured interleukin-6 (IL-6) and tumor necrosis factor (TNF) in 12 patients undergoing cardiac surgery during and after cardiopulmonary bypass, and in 10 patients with pancreatoduodenectomy. Plasma IL-6 levels were determined using the Human Interleukin 6 ELISA Kit, and TNF levels were determined using a highly sensitive sandwich enzyme immunoassay. In patients with cardiac surgery, plasma levels of IL-6 and TNF increased during cardiopulmonary bypass, and in patients with pancreatoduodenectomy, IL-6 and TNF levels significantly increased at the end of intraabdominal manipulation. These results suggest that endotoxin may have activated the immune system and stimulated cytokine production after pancreatoduodenectomy and during bypass.