Prognostic impact of lymphovascular invasion in lymph node-negative superficial esophageal squamous cell carcinoma.

The relationship between lymphovascular invasion (LVI) and prognosis in patients with superficial esophageal squamous cell carcinoma (SESCC) is unclear. The aim of this study is to evaluate prognostic factors in patients with lymph node-negative SESCC. A total of 195 patients with pathologically confirmed T1a-MM, T1b, and lymph node-negative SESCC were retrospectively reviewed in this study. Overall, the disease-free survival (DFS) rate was poorer in the lymphatic invasion-positive group than in the lymphatic invasion-negative group (p = 0.002) and a multivariate analysis suggested that lymphatic invasion was the only independent prognostic factor of DFS in patients with lymph node-negative SESCC (HR = 4.075, p = 0.005). Distant organ recurrence occurred in one patient (1/52, 1.9%) in the T1b-SM2 group and in six patients (6/61, 9.7%) in the T1b-SM3 group; all of these patients had LVI. LVI-positive patients had a poorer DFS than invasion-negative patients in the T1b-SM2 and SM3 groups (p = 0.026), and a multivariate analysis suggested that LVI was the only independent prognostic factor of DFS in patients with lymph node-negative SM2 and SM3 SESCC (HR = 5.165, p = 0.031). Lymph node-positive patients had a significantly poorer DFS rate than lymph node negative and LVI positive patients among the SM2 and SM3 SESCC patients (p = 0.018). The present results suggested that LVI was an independent prognostic factor in patients with SM2 and SM3 lymph node-negative SESCC; however their prognosis was not worse than that of patients with lymph node-positive SM2 and SM3 SESCC, for whom adjuvant therapy is indicated as a standard treatment.

Impact of body mass index on postoperative complications and long-term survival in patients with esophageal squamous cell cancer.

Undernutrition and cachexia have been suggested to be risk factors for postoperative complications and survival in cancer patients. The aim of this study was to investigate whether body mass index (BMI) is related to the short-term and long-term outcomes in patients who undergo an esophagectomy for the resection of esophageal squamous cell cancer (ESCC). Three hundred forty patients who underwent an esophagectomy for the resection of ESCC between 2003 and 2008 were retrospectively reviewed. The patients were divided into two groups: an L-BMI group characterized by a BMI < 18.5 kg/m(2) and an N-BMI group characterized by a BMI ≥ 18.5 kg/m(2). Clinical and pathological outcome were compared between groups. The study included 40 patients in the L-BMI group and 300 patients in the N-BMI group. A clinicopathological assessment showed that nodal involvement was seen more frequently in the L-BMI group (P = 0.016). Pulmonary complications seemed to occur more frequently in the L-BMI group (P = 0.006). The 5-year overall survival rate was higher in the N-BMI group (63.6%) than in the L-BMI group (32.3%) (P < 0.001). The 5-year disease-free survival rate was also higher in the N-BMI group (58.0%) than in the L-BMI group (33.6%) (P = 0.001). In multivariate analysis, the BMI (hazard ratio, 2.154; 95% CI, 1.349-3.440, P = 0.001) was found to be an independent prognostic factor for overall survival. Our data suggested that a lower BMI not only increased pulmonary complications but also impaired overall and disease-free survival after an esophagectomy for the resection of ESCC.

Clinicopathological significance of laminin-5γ2 chain expression in superficial esophageal cancer.

The glycoprotein laminin 5γ2 chain (LN-5γ2) has recently become a focus of increased interest and investigation as a marker of invasion in gastrointestinal malignancies. We investigated the significance of LN-5γ2 expression as a prognostic factor in superficial esophageal cancer. The study population consisted of 87 patients who had undergone a transthoracic esophagectomy and three-field lymphadenectomy for the treatment of superficial esophageal cancer at Tokai University Hospital. Formalin-fixed, paraffin-embedded sections of the resected specimens were examined using immunohistochemical staining and hematoxylin and eosin staining to assess the correlations between the LN-5γ2 expression pattern and the clinicopathological factors (age, sex, T-factor, N-factor, ly-factor, v-factor, degree of differentiation, infiltrative growth pattern, tumor node metastasis classification of malignant tumors [TNM] stage, etc.) and the patient outcome. The expression pattern of LN-5γ2 was classified into an extracellular type (E type), characterized by the staining of extracellular matrix such as the basement membrane and the stroma (31 cases, 35.6%), and a cytoplasmic type (C type), characterized by the staining of the cytoplasm in the cancer cells (56 cases, 64.6%). The expression pattern was not correlated with any of the clinicopathological factors that were assessed. However, univariate analyses of the survival analysis data showed that the N-factor (P = 0.011), TNM stage (P = 0.011), and LN-5γ2 C type (P = 0.017) were prognostic factors. A multivariate analysis revealed that the N-factor (P = 0.049) and LN-5γ2 C type (P = 0.048) were prognostic factors. In the survival analysis, a univariate analysis of the 75 T1b cases also showed that the N-factor (P = 0.048), TNM stage (P = 0.048), and LN-5γ2 C type (P = 0.029) were prognostic factors, while a multivariate analysis showed that the LN-5γ2 C type (P = 0.035) was a prognostic factor. The C type expression of LN-5γ2, i.e. confined to the cytoplasm, was correlated with an unfavorable outcome among the patients with superficial esophageal cancer in the present series. Observation of the LN-5γ2 expression pattern may be useful for the diagnosis of highly malignant tumors.

[Lymph node metastasis in superficial squamous carcinoma of the esophagus]. / Lymphknotenmetastasen bei Plattenepithelfrühkarzinomen des Ösophagus.

The definition of early carcinoma of the esophagus has changed with time on the basis of new data. As from 2007 an early carcinoma is defined as an intramucosal carcinoma with or without metastasis. In the subclassification based on invasion depth, m1 and m2 squamous cell carcinomas have no metastasis and are considered curable by endoscopic resection alone, whereas less than 10% of m3 carcinomas and some 20% of sm1 squamous cell carcinomas have lymph node metastasis. In this article the relationship between various histopathological findings and the incidence of lymph node metastasis is reviewed. The m3 and sm1 superficial squamous cell carcinomas showing 0-I and 0-III types, large tumors over 50 mm in size or those showing vessel permeation have higher incidences of lymph node metastasis. In the field of gastrointestinal surgical pathology pathologists are now expected to not only diagnose the presence or absence of malignancy but also to investigate in detail many of the histological factors related to the prevalence of lymph node metastasis.

Phase I/II study of twenty-four-hour infusion of irinotecan in combination with oral UFT plus leucovorin for metastatic colorectal cancer.

OBJECTIVE: Irinotecan has, in general, been administered as a 90-min infusion. However, several studies have demonstrated that continuous infusion seems to be a promising method of delivering irinotecan. This phase I/II trial was performed to evaluate the efficacy and safety of continuous infusion of irinotecan combined with UFT plus leucovorin (LV) for metastatic colorectal cancer. METHODS: Escalating doses of irinotecan (90-110 mg/m(2)) were administered by 24-hour infusion on day 1. UFT 300 mg/m(2)/day and LV 75 mg/day were administered orally, in 3 divided daily doses, on days 3-7 and 10-14. The treatment cycles were repeated every 2 weeks. RESULTS: In the phase I study, the maximum tolerated dose of irinotecan was 110 mg/m(2) and the recommended dose for the phase II study was determined to be 100 mg/m(2). Thirty-six patients, including 3 patients at the recommended dose in the phase I study, were evaluated in the phase II study. The common grade 3/4 toxicities were leucopenia, neutropenia, diarrhea and anorexia. The response rate was 63.9%, and the median progression-free and overall survival times were 8.3 and 24.6 months, respectively. CONCLUSION: A 24-hour infusion of irinotecan combined with UFT/LV is feasible and active for metastatic colorectal cancer.

Local VEGF administration enhances healing of colonic anastomoses in a rabbit model.

BACKGROUND/AIMS: Many studies report the role of vascular endothelial growth factor (VEGF) in wound healing, but few describe local VEGF administration to the digestive tract. Leakage from colonic anastomoses, including those due to ischemia, represents a major complication causing increased mortality and morbidity. Angiogenesis is crucial to anastomotic healing and restoration of blood supply, and VEGF is a potent angiogenic factor showing improved healing in various models of reconstruction and anastomosis. Here, we examine the effects of local VEGF-A(165) administration on postoperative rabbit colon anastomosis. METHODS: Two colotomies per animal were made in the sinistral colon on opposite sides of the mesentery. Randomly assigned VEGF (10 microg/0.1 ml) or saline (0.1 ml) was injected into the muscularis propria on both sides of each colonic anastomosis before closing the access laparotomy using single-layer sutures. On postoperative days 3, 4 and 7, the bursting pressure of partially healed anastomoses was measured. On postoperative day 4, anastomotic tissues were examined for the following: hydroxyproline; histopathologically for inflammatory infiltrate and tissue organization and immunohistochemically for capillary proliferation and density; vessel density of midzone collaterals around anastomoses by microangiography. RESULTS: Compared to saline, VEGF administration significantly improved bursting pressure (p = 0.014, paired t test) and increased hydroxyproline (p = 0.027, paired t test) on postoperative day 4. Inflammatory cell infiltration and fibroblast proliferation were prominent, and submucosal capillary vascular counts were significantly higher for VEGF. CONCLUSIONS: Administration of VEGF to colonic anastomosis accelerates wound healing and strengthens the anastomosis by increased angiogenesis.

[Coronary artery bypass grafting in patients with carotid artery disease; indication and early clinical outcome of coronary artery bypass grafting concomitant with carotid endarterectomy].

The purpose of this study is to assess the clinical results of coronary artery bypass grafting (CABG) in patients with carotid artery disease, especially concomitant with carotid endarterectomy (CEA). Between April 1993 and April 2008, 77 patients (aged 69.5 +/- 7.1 years, 77.9% male) with carotid artery stenotic disease underwent CABG. Cerebral hemodynamics in all patients was examined with single photon emission computerized tomography (SPECT). Treatment course was decided after through diagnostic evaluation and strategic discussion with brain surgeons. Among these, 12 patients required CEA simultaneously, because both coronary and carotid artery diseases were too serious for safe staged operation. Hospital death occurred in 3 patients (3.9%). Two patients (2.6%) had postoperative stroke, but were discharged without neurological deterioration. In 12 patients receiving CABG and CEA simultaneously, there was no intraoperative stroke or hospital death. One patient had hyperperfusion syndrome after CEA, and required adequate rehabilitation exercise. CABG concomitant with CEA is an acceptable and feasible procedure in patients with significant coronary and carotid artery diseases. In order to improve surgical outcome of combined cases, it is important to prevent occurrence or aggravation of cerebral hyperperfusion syndrome.

[Paraplegia associated with acute aortic dissection complicated with pulmonary embolism and re-dissection].

Paraplegia associated with acute aortic dissection is one of the most serious complications. We experienced a case of Stanford type A acute aortic dissection with paraplegia and cardiac tamponade because the dissection was already thrombosed, conservative therapy was chosen. After drainage of pericardial effusion, a spinal drainage tube was inserted. Eleven days later, pulmonary embolism and re-dissection occurred, and an emergency operation was performed. Although the operation was successful, paraplegia did not improve. Even if type A acute aortic dissection is complicated with paraplegia, early surgical repair of aortic dissection should be considered, when paraplegia does not improve rapidly in spite of treatment.

[Treatment of a persistent postoperative chylothorax with octreotide].

Chylothorax is a serious postoperative complication in the field of thoracic surgery. To treat refractory chylothorax, various methods including surgery are employed. In this study, we report a patient with refractory chylothorax in whom treatment with octreotide acetate was successful, although the chylorrhea site could not be determined during additional thoracotomy.

[Ruptured aneurysm of the sinus of Valsalva with severe liver dysfunction; report of a case].

The patient is a 59-year-old male who complained of acute palpitation, shivering and chest oppression. His laboratory data showed severe liver dysfunction (AST 3,445 IU/l, ALT 2,937 IU/l, and LDH 3,200 IU/l). By echocardiography, abnormal shunt flow was detected in the right atrium, and it was diagnosed as a ruptured aneurysm of the Valsalva sinus (Konno type IV). Suture closure of the fistula was performed from the right atrial side, and then, patch closure was performed from the aortic side with auto-pericardium to cover the whole non-coronary sinus, which was heavily calcified. The liver function rapidly restored to a normal range postoperatively. In a case of severe liver dysfunction, such cardiac disease should also be considered.

Automated diagnosis of heart disease in patients with heart murmurs: application of a neural network technique.

This study was conducted to test a three-layered artificial neural network analysis of phonocardiogram recordings to diagnose, automatically and objectively, the condition of the heart in patients with heart murmurs. The data were recorded simultaneously in each of 49 patients with a heart murmur through eight microphones attached to the skin surface with adhesive tape, and were analysed by computer. The diagnosis was automated using a three-layered neural network technique. The neural network generated correct answers in over 70% of cases. Furthermore, about 80% of cases of two concurrent diseases were identified correctly. However, ventricular septal defects were incorrectly classified as aortic stenosis or aortic regurgitation, and patent ductus arteriosus was not diagnosed correctly. Accurate diagnoses can frequently be obtained using a neural network, but accuracy can be improved with further data accumulation.

Mosaicism in the expression of tumor-associated carbohydrate antigens in human colonic and gastric cancers.

Serial sequential sections from a single tumor were examined by immunohistological staining with several monoclonal antibodies directed, respectively, to different tumor-associated carbohydrate epitopes. Staining patterns were compared with those of conventional staining with hematoxylin-eosin or periodate/Schiff's reagent. Each tumor showed different areas of staining with different antibodies, and the combined staining map shows a clear mosaicism of antigen expression within the same tumor. For example, some areas of a given tumor were stained by FH4 (defining dimeric Le(x)), while other complementary areas were strongly stained, in a mutually exclusive manner, by SH1 (defining Le(x)), AH6 (defining Le(y)), FH6 (defining sialosyl dimeric (Le(x)), or TKH2 (defining sialosyl-Tn). Some areas were stained by two or three of these antibodies. Comparisons of the mosaic-staining patterns with cytohistological properties of tumor cells within specific areas suggested that the pattern of antigen expression is correlated with degree of differentiation; e.g., poorly-differentiated cells with severe dysplasia did not express high levels of Le(x) or Le(y) but did express sialyl-Le(x) or dimeric Le(x); on the other hand, moderately or well-differentiated tumor cells in some areas expressed high levels of Le(x) or Le(y) but lower levels of sialyl-Le(x). Areas showing strong expression of sialyl-Tn in their secretions were consistently correlated with presence of well-differentiated tumor cells, whereas secretions from normal mucosae were consistently characterized by lack of sialyl-Tn expression. It is postulated that the original in situ tumors (which had homogeneous glycosylation patterns) evolved into several spatially discrete cell populations displaying different degrees of glycosylation, reflecting stages of tumor cell differentiation and progression.

[Thoracoabdominal aortic aneurysm combined with inferior mesenteric artery aneurysm and occlusion of celiac and superior mesenteric arteries].

A 56-year-old man with thoracoabdominal aortic aneurysm combined with inferior mesenteric artery aneurysm and occlusion of celiac and superior mesenteric arteries is presented. Contrast-enhanced computed tomography (CT) and aortography revealed thoracoabdominal aortic aneurysm of 6 cm in diameter, accompanied by inferior mesenteric aneurysm of 3 cm in diameter. Severe calcification of the abdominal aorta and occlusion of the celiac and the superior mesenteric arteries were also noted, whose territories were perfused by collateral circulation of the inferior mesenteric artery. At the operation, orifice of the left renal artery was stenosed by severe calcification, which was resected. Because of severe adhesion around the origins of celiac and superior mesenteric arteries, they were left unrevascularized. The thoracoabdominal aortic aneurysm was replaced with an Dacron tube graft, whose side branch was anastomosed to the inferior mesenteric artery after resection of its aneurysm. The postoperative course was uneventful, and no symptoms of intestinal ischemia were noted. As blood supply to the abdominal viscera mostly depends on the inferior mesenteric artery, careful follow-up is necessary.

[Ball thrombus in the right atrium: report of a case].

A 63-year-old man visited our hospital because of intermittent claudication due to an embolic episode in the left femoral artery. He had a long history of arterial fibrillation but had received no anticoagulant therapy. Echocardiography showed a large floating ball-shaped shadow in the right atrium, without any sign of tricuspid stenosis. Pulmonary perfusion scintigram was normal. At the operation, the thrombus which attached to the superior atrial septum with a thin string was removed. The thrombus was 54 x 40 x 25 mm in size and 23.8 g in weight, whose cut surface was in layers. There was neither atrial septal defect nor foramen ovale to suggest possibility of paradoxical embolism. The postoperative course was uneventful and he was discharged on the 9th postoperative day. Although the mechanism of the thrombus formations is unknown, it is considered to be important to continue anticoagulant therapy to avoid reccurence of intracardiac thrombus.

Short-term follow-up after endoscopic mucosectomy of early esophageal cancer and aldehyde dehydrogenase-2 genotype in Japanese alcoholics.

The risk of the future development of primary esophageal cancer after endoscopic esophageal mucosal resection of esophageal cancer is not known; hence, there are no established guidelines for follow-up surveillance programs. Simultaneous occurrence of multiple cancers associated with esophageal cancer is common among heavy drinkers who have the inactive form of aldehyde dehydrogenase-2 (ALDH2) as a risk factor. Thirty-four Japanese male alcoholics with intraepithelial or mucosal squamous cell carcinoma in the esophagus were treated by endoscopic esophageal mucosal resection, followed by endoscopy and esophageal iodine staining, to find the additional development of primary esophageal cancer. Primary esophageal squamous cell carcinoma was detected in nine patients (26.5%) at 3-21 months after the first cancer diagnosis. Cancer occurred more frequently in patients with inactive ALDH2 than it did in those with active ALDH2 [42.1% (8 of 19) versus 6.7% (1 of 15), P = 0.047], and it occurred more frequently in those with multiple esophageal cancers than it did in those without them [60.0% (6 of 10) versus 12.5% (3 of 24), P = 0.009]. Kaplan-Meier estimates of the proportions of patients with additional primary esophageal cancers showed that patients with inactive ALDH2 (P = 0.024) or multiple esophageal cancers (P = 0.007) had a significantly increased likelihood of the development of additional cancer. Close follow-up examinations using endoscopy and iodine staining are needed for such high-risk patients.

Potentiation of antitumor effect of NKT cell ligand, alpha-galactosylceramide by combination with IL-12 on lung metastasis of malignant melanoma cells.

The combined therapeutic effect of natural killer T (NKT) cell ligand alpha-galactosylceramide (alpha-GalCer) and IL-12 against highly metastatic B16-BL6-HM melanoma cells was investigated. In comparison with a single administration of alpha-GalCer or IL-12, the combined treatment of tumor-bearing mice with alpha-GalCer plus IL-12 caused a super-induction of serum IFN-gamma levels, though alpha-GalCer-induced IL-4 production was rather inhibited. In parallel with the augmented IFN-gamma production, the natural killing activity against YAC-1 cells and syngeneic B16-BL6-HM melanoma was greatly augmented by the combined therapy. The major effector cells responsible for natural killing activity induced by alpha-GalCer plus IL-12 were enriched in both NK1.1+ TCRalphabeta+ NKT cells and NK1.1+ TCRalphabeta- NK cells. The preventing effect of alpha-GalCer or IL-12 alone against lung metastasis of B16-BL6-HM was also enhanced by the combination therapy. The antitumor activity of alpha-GalCer was totally abolished in NKT-deficient mice. However, IL-12-induced antitumor activity was not eliminated in NKT-deficient mice though it was inhibited by anti-asialo GM1 Ab treatment. These findings suggested that alpha-GalCer synergistically act with IL-12 to activate both NKT cells and NK cells, which may play a critical role in the strong prevention of distant tumor metastasis at early stages of tumor-bearing. These data will provide a novel tool for the prevention of tumor metastasis using NKT-specific ligands alpha-GalCer and IL-12.

Late development of an aneurysm of a saphenous vein used as an aortocoronary conduit.

A case of a large saphenous vein aortocoronary aneurysm that developed late after coronary artery bypass grafting is presented. This is the first case of a large saphenous vein aortocoronary aneurysm identified by serial angiography and 3-dimensional computed tomographic scanning.

Stromal CEA immunoreactivity is correlated with lymphatic invasion of human esophageal carcinoma.

Carcinoembryonic antigen (CEA) is a good marker of colorectal cancer. Recent studies have demonstrated that CEA may function as a metastatic potentiator by different pathways; i.e. modulation of immune responses, facilitation of intercellular adhesion and cellular migration. However, expression patterns of CEA have not yet been established in human esophageal carcinomas. In this study, we examined CEA expression in human esophageal squamous cell carcinoma and its clinicopathological significance. CEA immunoreactivity was frequently detected in the cancer cells (cytoplasmic type; 81.1%, 43/53) as well as in the cancer stroma (stromal type; 32.1%, 17/53), regardless of the depth of tumor invasion. Lymphatic invasion of cancer cells was frequently found in the stromal CEA-positive esophageal cancer (44.4%, 16/36), compared to stromal CEA-negative cancer (5.9%, 1/17) (p<0.05). These observations suggested that stromal CEA expression plays important roles in lymphatic invasion of human esophageal squamous cell carcinoma.

Frequent expression of inducible nitric oxide synthase in esophageal squamous cell carcinomas.

Nitric oxide (NO) plays important biological roles in cardiovascular, nervous and immune systems, and is synthesized by nitric oxide synthase (NOS). Intracellular NO is known to cause DNA damage as a mutagen. We examined the expression of cytokine-inducible NOS (iNOS) in human esophageal squamous cell carcinomas. Weak iNOS immunoreactivity was seen in the basal and parabasal layers of non-neoplastic esophageal stratified squamous epithelium. iNOS expression was detected in 50 (87.7%) of the 57 esophageal squamous cell carcinomas, regardless of the depth of tumor invasion, histological differentiation and lymph node status. Early-stage cancers, i.e. mucosal squamous cell carcinomas, also showed significant iNOS expression. We speculate that increased iNOS expression is associated with the carcinogenesis of human esophageal cancer.

Frequent expression of sialyl Le(a) in human esophageal squamous cell carcinoma.

Sialyl Le(a) antigen (CA19-9), a member of a family of high molecular weight glycoproteins, was originally described as a gastrointestinal- and pancreatic-specific tumor marker. Recent studies have demonstrated that sialyl Le(a) is a ligand for E-selectin and may play an important role in tumor metastasis. However, expression patterns of sialyl Le(a) have not yet been established in human esophageal carcinomas. In this study, we examined sialyl Le(a) expression and its histopathological localization in human esophageal squamous cell carcinoma. Sialyl Le(a) immunoreactivity was detected in 28 (51.9%) of the 54 esophageal squamous cell carcinomas, regardless of the depth of tumor invasion, vascular invasion or lymph nodal status. In 13 cases (29.5%), significant sialyl Le(a) expression was detected not only in the intramucosal carcinoma components, but also in the invasive carcinoma components. These observation suggested that sialyl Le(a) expression is associated with early-stage cancer progression.