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I myocardial matrix metalloproteinase (MMP) activity has been reported to occur in clinical and experimental forms of dilated cardiomyopathy.1–3 Proinflammatory cytokines, such as tumor necrosis factor(TNF), are important regulators of MMP gene expression. Previous experimental studies have shown that TNFstimulates myocardial MMP activity and can lead to degradation of the extracellular matrix in the myocardium.4 However, few clinical studies of the relation between circulating MMP and TNFlevels in idiopathic dilated cardiomyopathy (IDC) have been conducted. Recently, we reported the presence of increased circulating TNFin patients with IDC, and that blockers could reduce the increased circulating TNFlevels in IDC.5,6 The present study further clarifies the relation between circulating levels of MMPs and TNFin patients with IDC. • • • We studied 34 consecutive patients with IDC between January 1999 and December 2001. The diagnosis of IDC was based on patient history, physical examination, electrocardiogram, echocardiogram, and cardiac catheterization. All patients underwent coronary angiography during the study period, and patients with epicardial coronary artery disease were excluded. Patients who had clinical or laboratory evidence of infections, neoplasms, autoimmune disease, or liver or renal dysfunction were also excluded from this study. Ten age-matched subjects who had no evidence of organic cardiac disease and no cardiac dysfunction were retrospectively selected as the control group. All subjects participated in this study after giving informed consent, and the protocol was approved by the Human Investigations Committee of our institution. In 20 patients who were poor responders to treatment with angiotensin-converting enzyme inhibitors or angiotensin II type-1 receptor blockers for 6 months, carvedilol, a nonselective blocker, was administered orally in addition to combination therapy after their hospital admission. In 18 patients with New York Heart Association functional class II or III congestive heart failure, the initial dosage was 2.5 mg twice daily; the doses were increased at weekly intervals for 8 weeks. In 2 patients in New York Heart Association functional class IV, the initial dosage was 1.0 mg twice daily; the doses were increased at weekly intervals for 12 weeks. The target dose was 25 mg/day, considering the weight of patients in this study of 75 kg. If a decrease in systolic blood pressure to 90 mm Hg or a decrease in heart rate at rest to 60 beats/min occurred, increments in dose were discontinued. As a result, the mean final dose of carvedilol was 19.2 mg. Maintenance of final doses was continued for an additional 6 months. Blood samples from patients were collected for measurement before and 6 months after initiation of carvedilol therapy. After bed rest for 30 minutes, peripheral venous blood samples were collected into chilled tubes and immediately centrifuged at 4°C. The serum samples were stored at 80°C until assay. Serum levels of TNFwere measured by enzyme-linked immunosorFrom The Second Department of Internal Medicine, Ehime University School of Medicine, Shigenobu, Onsen-gun, Ehime, Japan. Dr. Ohtsuka’s address is: The Second Department of Internal Medicine, Ehime University School of Medicine, Shigenobu, Onsen-gun, Ehime 7910295, Japan. E-mail: tohtsuka@m.ehime-u.ac.jp. Manuscript received October 24, 2002; revised manuscript received and accepted December 30, 2002. FIGURE 1. Serum levels of TNF, MMP-1, MMP-3, and MMP-9 in 10 age-matched normal control subjects (NC) and in 34 patients with IDC. *p

A 70-year-old man referred for treatment of a left lower lung tumor was shown in chest computed tomography to have a homogeneous round tumor 45 mm in diameter with an enhanced thin wall in the lower lobe of the left lung. No specific finding was seen in material obtained by transbronchial and computed tomography (CT)-guided lung tissue biopsy, so the presumptive diagnosis was a lung abscess. Despite antibiotics administered for 2 weeks, radiography showed the tumor had grown, necessitating left lower lobectomy. The permanent section was diagnosed as diffuse large B-cell lymphoma. Because CT findings for the tumor suggested a lung abscess and the central part of the tumor consisted of fibrotic and necrotic tissue, we had difficulty establishing a final diagnosis. The literature showed primary pulmonary lymphomas yielded a variety of findings radiographically, making surgery paramount for ascertaining a final diagnosis.

We reviewed the clinical courses of 25 patients who underwent pulmonary resection for metastatic lesions from colorectal cancer between January 1991 and December 2001. The cumulative survivals at 3 and 5 years were 72% and 63%, respectively. Sex, site of the primary tumor, presence of extrapulmonary metastases, disease-free interval, location of pulmonary metastases (PM), number of PM, size of PM, mode of operation, pre-thoracotomy serum carcinoembryonic antigen level, and post-thoracotomy chemotherapy were not found to be statistically significant prognostic factors. Age (70 yearsor =) was a predictor of a shorter survival duration by univariate analysis (p = 0.02). Recurrence was observed in 19 patients, 11 of which were lung recurrences. Eight patients underwent repeated pulmonary resection. The median survival in these 8 patients was 23 months after second pulmonary operation. Surgical treatment for pulmonary metastases from colorectal cancer in selected patients might improve prognosis.

The overexpression of eukaryotic initiation factor 4E (eIF4E), a key regulator of protein synthesis, is involved in the malignant progression of various human cancers. We investigated eIF4E expression in atypical adenomatous hyperplasia (AAH) and adenocarcinomas of the human peripheral lung. On the basis of the WHO criteria with minor modifications, adenocarcinomas were classified as bronchioloalveolar carcinoma (BAC), mixed subtypes with a bronchioloalveolar pattern and minor invasion (early MX), and mixed subtypes with a papillary pattern and marked invasion (overt MX). eIF4E immunohistochemistry was performed in 143 tissue samples (31 AAH, 38 BAC, 43 early MX, and 31 overt MX). Both tumoral and stromal eIF4E levels were elevated from AAH, BAC, and early MX to overt MX and significantly associated with histological grade (P0.001 and P0.001, respectively). Tumoral and stromal eIF4E staining intensities were significantly correlated (P0.01). Immunoblot analysis of 51 tissue samples (2 AAH, 11 BAC, 18 early MX, and 20 overt MX) demonstrated that eIF4E expression in adenocarcinomas was 3.4-7.4-fold higher than in normal lung and that its expression progressively increased in the following order: AAH (lowest expression), BAC, early MX, and overt MX (highest expression). Multiple regression analysis revealed that both tumoral and stromal eIF4E expressions were significant independent factors for the histological subtype (P0.01 and P0.01, respectively). These results suggest that translational control is dysregulated during the development of peripheral lung adenocarcinoma and that progressive increases of tumoral and stromal eIF4E may be part of a positive feedback loop for malignant progression.

A multi-center trial of exemestane 25 mg, an oral aromatase irreversible inactivator, was conducted to evaluate its efficacy and safety in 33 postmenopausal patients, and to investigate the pharmacokinetics/serum hormone levels in 16 postmenopausal patients, respectively, with breast cancer and anti-estrogen resistance. Exemestane 25 mg was given once daily for up to 48 weeks (maximum). The objective of this study was to confirm the reproducibility of the results shown in two studies in other countries with similar patients, to investigate the possibility of extrapolating the overseas data to Japanese. The response rate (CR + PR) was 24.2% (8.33%), which exceeded the minimum number (6 cases) required to evaluate efficacy. The response rate in this study was very similar to that observed in the two international open studies. Adverse events (subjective/objective symptoms), in which a causal relationship with exemestane administration could not be excluded, were observed in 26 cases (78.8%). Of these, hot flushes, increased sweating, fatigue, and insomnia occurred in more than 10% of patients, which was similar to that observed in the two international open studies. Abnormal laboratory results occurring in more than 10% of patients, in which a causal relationship with exemestane administration could not be excluded, were as follows: lymphocyte count decrease, alkaline phosphate increase, GOT increase, GPT increase, gamma-GTP increase, triglyceride increase, and inorganic phosphate increase, most of which were either grade 1 or 2. A remarkable decrease in serum hormone concentration was observed only for estrogen. The values of AUC0-infinity at day 1 and AUC0-24 h at day 29 (steady state) were similar, suggesting no accumulative effect of exemestane. These results demonstrate the anti-tumor effect and safety of exemestane in postmenopausal anti-estrogen resistant breast cancer patients. The reproducibility of the results of the two foreign studies was verified in Japanese patients, and it is concluded that the foreign trial data on exemestane can be extrapolated to Japanese.

This study sought to clarify the relationship between magnesium (Mg) deficiency and coronary artery spasm provoked by pharmacologic agents in patients with a recent acute myocardial infarction (AMI). Twenty-three consecutive patients suffering from AMI were investigated with a Mg retention test (Mg: 0.1 mmol/kg for 4 h) in both the acute phase (within I week (3+/-2 days) of onset) and the subacute phase (3-4 weeks (24+/-6 days) of the onset). Early coronary arteriography was performed in all patients. Coronary stenosis in the infarct-related artery was less than 90% in all patients in the subacute phase. The spasm provocation test was performed in the subacute phase and coronary spasm was defined as transient subtotal or total occlusion in association with angina or electrocardiographic ST-segment deviation. Coronary artery spasm was provoked in only 13 of the 23 patients. Compared with the control subjects (12 patients without coronary artery disease or coronary spasm), the 24-h Mg retention was significantly higher in patients with AMI (acute phase: 78+/-27%, subacute phase: 66+/-32%, vs control: 48+/-12%, p

A 28-year-old man was admitted to hospital for investigation of a 2-week history of angina occurring on exertion. Coronary angiography showed an isolated left coronary ostial stenosis and left main trunk plasty was performed 2 weeks later. The pathological diagnosis of the left coronary ostial stenosis was fibromuscular dysplasia, which makes this a rare case.

We describe two cases of atypical carcinoid of the thymus. One was an 82-year-old woman with complaints of nonproductive cough and back pain, and the other a 64-year-old woman with no symptoms. Computed tomography scans of the chest in both cases revealed a large mass in the anterior mediastinum. Multiple metastases to bone and liver were also noted in the former case. Histological examination of their tumors revealed that the tumor cells were arranged in a nested, trabecular, or pseudorosette pattern, with increased numbers of mitoses, nuclear pleomorphism, and presence of necrosis. In addition, immunohistochemically, the cells stained for neuron-specific enolase, synaptophysin and chromogranin A. Combination chemotherapy consisting of carboplatin and etoposide was performed as initial chemotherapy in the former case and as adjuvant therapy in the latter. The former patient achieved a short-term partial response. It is important to differentiate atypical carcinoid from other thymic tumors, since such tumors including thymoma have a much better prognosis than does atypical carcinoid.

Background . Whether video-assisted thoracic surgery (VATS) improves postoperative pulmonary function is still controversial. We compared postoperative pulmonary function after VATS lobectomy and standard lobectomy. Methods . Eleven patients who had undergone standard lobectomy and 10 patients who had undergone VATS lobectomy were studied. Arterial blood gas analyses were performed on the 4th, 7th, and 14th postoperative days. Pulmonary function, including forced vital capacity (FVC), forced expiratory volume in 1 second (FEV 1.0 ), and peak flow rate (PFR) were measured on the 7th and 14th postoperative days (early phase), and approximately 1 year after surgery (late phase). Results . Pulmonary function, as assessed with arterial oxygen partial pressure (PaO 2 ) ( p = 0.054), arterial oxygen saturation (O 2SAT ) ( p = 0.063), FVC ( p = 0.10), and FEV 1.0 ( p = 0.08), was better after VATS lobectomy than after thoracotomy on the 7th postoperative day. PFR was significantly better after VATS on both the 7th and 14th postoperative days ( p = 0.008 and p = 0.03, respectively). Conclusions . VATS lobectomy had advantages on early postoperative pulmonary function. We conclude that VATS lobectomy is a beneficial alternative to standard thoracotomy, especially for patients with poor pulmonary reserve.

Since there are no large-scale surveys of how cancer patients perceive unproven therapy in Japan, we wanted to clarify this issue by means of a cross-sectional questionnaire conducted among cancer patients. The survey revealed that 32% of cancer patients used unproven therapy without having sufficient information about it. There was a lack of communication between cancer patients and their physicians on topics relating to alternative medicine. Issues that we have to solve are concerned with the education of cancer patients, lay people and physicians on the meaning and role of alternative medicine and on the necessity for scientific evaluation of medical treatments in Japan.

A 66-year-old woman with a 7-year history of Parkinsons' disease was admitted to our hospital because of a high fever and disturbance of consciousness. She had been treated with levodopa/benserazide hydrochloride and trihexyphenidyl hydrochloride until admission. On admission, the patient was comatose, her temperature was 40.5 degrees C, her blood pressure was 54/-mmHg, and her pulse rate was 130 beats/min. Laboratory tests showed leukocytosis, a high level of creatine kinase in serum and evidence of hyperosmolar non-ketotic diabetic coma (blood glucose, 1,080 mg/dl) and of disseminated intravascular coagulation (DIC). A continuous insulin infusion, antibiotics, nafamostat mesilate, and urinastatin were given, after which the DIC, hyperglycemia, and the level of consciousness were improved. However, levels of creatine kinase, myoglobin, transaminase, and amylase in serum continued to increase, and multiple organ failure was suspected. Furthermore, she became less responsive, diaphoretic, and tremulous; fever and mild rigidity developed. The peak creatine kinase and myoglobin were 11,095 U/l and 12,520 ng/ml, respectively. A diagnosis of malignant syndrome was made, and treatment with levodopa/carbidopa and dantrolene was begun. Within several days, the clinical and laboratory findings improved. We report here a rare case of malignant syndrome associated with DIC followed by diabetic coma in an elderly patient with Parkinsons' disease during L-dopa therapy. Timely diagnosis and treatment of malignant syndrome are important in the management of elderly patients with Parkinsons' disease, because DIC and multiple organ failure may occur in the early stages of malignant syndrome.

Platelet-derived endothelial cell growth factor may play a role in tumor development through its angiogenic action. To clarify the relationship between expression of platelet-derived endothelial cell growth factor and microvessel density in the development of human colon carcinoma, we examined 80 early-stage colon carcinomas using microscopy and immunohistochemistry. Localization of platelet-derived endothelial cell growth factor was assessed by immunocytochemistry, while microvessel count was evaluated by either HE staining or Factor VIII immunostaining. Among the examined carcinomas, 35 were classified as m carcinomas including carcinoma in situ, whereas 45 were sm carcinomas. Fifteen (42.9%) of the 35 m and 30 (66.7%) of the 45 sm carcinomas demonstrated high vascular density, whereas 20 (57.1%) m and 15 (33.3%) sm carcinomas showed moderate or low vascular density. Vascular density was higher in sm carcinomas than in m carcinomas and there was a significant correlation between depth of invasion and vascular density. Of the 45 highly vascularized carcinomas, 44 expressed platelet-derived endothelial cell growth factor. There was a statistically significant correlation between the frequency of platelet-derived endothelial cell growth factor expression and microvessel density (P = 0.012). These data demonstrate that microvessel density may be associated with the depth of cancer invasion and that platelet-derived endothelial cell growth factor may play an important role in the early stage of colon cancer development through angiogenesis.

A 47-year-old man was admitted to our hospital for abrupt onset of hemoptysis and dyspnea. Chest roentgenography revealed a left lower mass shadow with obstruction of the left main bronchus. However, on the third hospital day, he expectorated a coagulum-like substance which resembled bronchial tree, and his symptoms then dramatically subsided. Except for small amounts of bleeding from left B10a, the endobronchus was intact on bronchoscopic examination, and the pathologic diagnosis of the tumor using resected material was fibrous histiocytoma of low-grade malignancy. In addition, given the similarity in histologic findings between the expectorated substance and resected tumor, the expectorated substance was considered to be a part of the tumor which had grown along the endobronchial tree.(Internal Medicine 35: 724-727, 1996)

We describe an 87-year-old woman with a large ileal gastrointestinal stromal tumor (GIST) causing hemoperitoneum. A CT scan demonstrated a large heterogeneous mass measuring about 13 cm multiply 11 cm in the pelvis and hemoperitoneum, with a non-uniform enhancement pattern. The mass was diagnosed as a GIST originating from the gastrointestinal tract. She underwent an urgent laparotomy and an ileal GIST with a rupture was found 130 cm from the anal to the Treitz's ligament. Hemoperitoneum caused by ileal GIST rupture is a rare condition. Bleeding in the large tumor leading to rupture of the capsule might cause hemoperitoneum in the present case.

漿膜露出胃癌の腹膜再発防止の目的でRecombinant interferon-β (IFN-β) の術後腹腔内投与を試みた.胃癌癌性腹水10例では著効2例, 有効4例 (奏効率60%) を得た. 特に低分化腺癌, 印環細胞癌に強い効果を認めた. 発熱以外の重篤な副作用はなく, 剖検例の検索で癒着を促進するような刺激作用は認めなかった. 漿膜露出胃癌13例に対する術後腹腔内投与では, 縫合不全, イレウスなどの合併症は無く治癒手術例では腹膜再発を認めていない.S2, 肉眼的治癒手術例を対象にIFN-βの術後腹腔内投与の有無での比較試験を行っており, 術後補助療法としての本法の評価を明らかにしたいと考えている.

The effect was studied of a local anesthetic, dibucaine, and an inhalation anesthetic, methoxyflurane, on the ATPase activity and the membrane fluidity in the surface membrane, pellicle, of Tetrahymena pyriformis NT-I. Both anesthetics were observed to inhibit ATPase activity and to lower its transition temperature (28° → 21°). It was also found that these anesthetics exerted fluidizing and depression of the phase transition temperature and that the disordering effect by methoxyflurane was much greater than that by dibucaine. These results have demonstrated that the anesthetic-induced alterations in the physical property of the pellicular membrane lead to inhibition of ATPase activity bound to the membrane, thus providing evidence suggesting the relationship between the function and physical state of the biological membrane.