Epidemiological analysis of a large enterohaemorrhagic Escherichia coli O111 outbreak in Japan associated with haemolytic uraemic syndrome and acute encephalopathy.

A large outbreak of enterohaemorrhagic Escherichia coli (EHEC) O111 and O157 occurred in Japan in April 2011. We conducted an unmatched case-control study and trace-back investigation to determine the source of EHEC O111 infection and risk factors for severe complications. Pulsed-field gel electrophoresis was performed to help define cases. A total of 86 individuals met the case definition. Of these, 40% experienced haemolytic uraemic syndrome (HUS), 24% acute encephalopathy, and 6% died. Illness was significantly associated with eating the raw beef dish yukhoe (odds ratio 19·64, 95% confidence interval 7·03-54·83), the likely food vehicle. EHEC O111 and its closely related stx-negative variants were found in the beef. HUS occurred most frequently in individuals aged 5-9 years, and this age group was significantly associated with acute encephalopathy. The prevalence of HUS and acute encephalopathy was higher than in previous non-O157-related outbreaks, indicating a high risk of severe complications.

Early surgery for treatment of spontaneous hemopneumothorax.

PURPOSE: Spontaneous hemopneumothorax (SHP) is a rare life threatening disorder. We retrospectively investigated patients with SHP who were treated with video- assisted thoracic surgery (VATS), and report our results. METHODS: From January 1993 to July 2006, 239 patients with spontaneous pneumothorax were treated, among whom 11 (4.6%) were diagnosed with SHP. RESULTS: All 11 patients had a collapsed lung condition worse than moderate and a chest tube inserted, of whom 10 underwent an emergency operation. The points of hemorrhaging, each of which were in the apical portion of the lung, were easily revealed during VATS, and we were able to distinguish between brisk flow and seepage. Hemostasis was acquired using VATS in all surgery cases, while the other was treated with tube drainage. The single patient who did not undergo surgical treatment had recurrent spontaneous pneumothorax 3 months later. CONCLUSION: It is important to perform surgery for SHP at the appropriate time. VATS was found to be an easily performed and safe procedure for initial treatment in patients with active hemorrhaging and massive blood clotting in the thorax. The long-term outcome of our patients with early surgical indication was excellent and we recommend early surgical treatment for SHP.

[Uncontrollable midbrain hemorrhage due to brain metastasis of pulmonary pleomorphic carcinoma].

A 54-year-old man who had been treated hypertension admitted our hospital due to midbrain hemorrhage. Pulmonary abnormal shadow was also found by chest radiological examinations and it was diagnosed as stage IB (T2N0M0) non-small-cell lung cancer. Right upper lobectomy with combined resection of azygos vein and parietal pleura facing to the tumor was conducted because the direct invasion of the tumor was strongly suspected. Pathological diagnosis was pleomorphic carcinoma. Although, postoperative course was uneventful, midbrain hemorrhage recurred 3rd postoperative day. Since the hemorrhage continued in spite of the conservative treatment, the craniotomy was performed on the 13th postoperative day. The pathological examination revealed the hemorrhage to be caused by the brain metastasis.

The sentinel node concept in prostate cancer: Present reality and future prospects.

A sentinel node (SN) is defined as the first site where cancer cells are carried by lymph flow from a tumor. If this definition (SN concept) correctly reflects the clinical reality, intraoperative SN biopsy would facilitate precise nodal staging. In malignant melanoma, a prolonged survival has been evidenced by a large-scale randomized controlled study. On the contrary, research on SN concept in deeply located cancers including prostate cancer, is still investigative, and no concrete data from clinical trials are yet available. Since 1993, several investigators have demonstrated that the SN concept could be applied in prostate cancer patients as well with high accuracy. Although promising and technically feasible in pre-clinical settings, many hurdles remain to be cleared before clinical application can be recommended. This review addresses the current status and related issues of the SN concept in prostate cancer, and discusses the future directions.

[Diaphragmatic hernia following pneumonectomy; report of a case].

We report a case of diaphragmatic hernia following left pleuropneumonectomy. A 70-year-old man was referred to our hospital after tube drainage for 3 months due to left pyothorax. He had a past history of left lung tuberculosis. Pleuropneumonectomy with partial resection of the muscle layer of the diaphragm was performed because adhesion of pleurae was severe. On the 19th postoperative day, he started to develop a slight fever. Chest X-ray and computed tomography (CT) demonstrated diaphragmatic hernia. On the 22nd postoperative day, we performed surgery because panperitonitis developed. At laparotomy, the transverse colon was pierced by the cut end of the rib. We successfully repaired the diaphragm and established transverse colostomy. The patient has been in good health for more than 10 years after the surgery.

[Mediastinal lymph node metastasis of thyroid cancer occurring 15 years after the initial operation; report of a case].

A 71-year-old woman was found to have an abnormal shadow on a chest X-ray. Fifteen years earlier she had undergone a subtotal thyroidectomy for thyroid cancer without any lymph node metastasis. Chest computed tomography (CT) revealed a mediastinal tumor with full of blood stream. Since the positron emission tomography (PET) disclosed an increased uptake of fluoro-2-deoxy-D-glucose (FDG) in the tumor, a malignant lymphatic tumor was therefore suspected. An immunohistological examination of biopsy specimens taken by thoracoscopic procedure demonstrated tumor to be lymph node metastasis of the previous thyroid cancer. After a tumor resection by means of a thoracotomy and total thyroidectomy, the patient was scheduled to receive radioiodine therapy. The previously reported cases are also herein reviewed.

Automatic border detection identifies subclinical anthracycline cardiotoxicity in children with malignancy.

BACKGROUND: Anthracycline drugs for cancer therapy often cause functional myocardial impairment even in relatively low doses. We investigated the left ventricular function in asymptomatic anthracycline-treated children by automatic border detection (ABD) to assess its clinical usefulness for unmasking latent anthracycline-induced myocardial damage. METHODS AND RESULTS: Thirty-four children (0.7 to 17.6 years old) during or after anthracycline chemotherapy (26 to 1100 mg/m2) for malignancy (Chemo group) were studied, and 40 children (2.8 to 15.6 years old) without cardiac involvement served as normal control subjects (Control group). All patients underwent complete echocardiographic examination, including M-mode, Doppler, and ABD. Conventional echocardiography disclosed no difference between groups with regard to ejection fraction and the ratio of early to late transmitral flow velocity. In marked contrast, an investigation using ABD revealed that the Chemo group appeared to have some anthracycline-induced myocardial damage. In the apical 4-chamber view, peak filling rate in the Chemo group [2.3+/-0.4 end-diastolic area (EDA)/s] was significantly lower than that in the Control group (3.1+/-0.5 EDA/s) (P<0.0001), and time to peak filling rate in the Chemo group (106+/-31 ms) was clearly prolonged compared with that in the Control group (74+/-22 ms) (P<0.0001). CONCLUSIONS: Echocardiographic ABD may be a sensitive and useful noninvasive approach for evaluating subclinical anthracycline cardiotoxicity.

[New technique to determine graft length using the proximal anastomotic system during off-pump coronary artery bypass grafting].

For determining the graft length for an aortic connector, grafts to the circumflex (Cx) and the posterior descending (PD) regions often present problems. Difficulties in determining the appropriate distance between the aorta and coronary artery have been reported to be due to changes in the morphology of the heart following the evolution of Cx and PD. We set an intermediate point (IMP) in advance and then determine graft distance in 2 steps. When using the IMP method, determination of the graft length in the Cx region is not difficult. However, attention should be paid to determine the distance between the IMP and anastomosed site without deforming the heart, as the graft length becomes shorter if the heart as a whole is pulled up by traction of the diaphragm during evolution to the PD region.

[Sternal metastasis of breast cancer; report of a case].

A 51-year-old woman presented with a painful sternal lump. Nine years earlier she had undergone right modified mastectomy for breast cancer, followed by chemotherapy. Computed tomography and bone scintigraphy demonstrated a solitary sternal bone metastasis. The patient was treated by partial sternectomy. Thereafter, the sternal defect was reconstructed with Marlex mesh and rectus abdominis myocutaneous flap. The postoperative course was uneventful. The patient subsequently developed brain metastasis and died within 52 months after sternal resection. The stability of the chest wall was well preserved for the duration of follow-up.

Longterm effects of cryosurgery in the sheep heart.

This study concerns the longterm effects of both epicardial and endocardial cryosurgery with particular reference to the coronary arteries. Sheep were subjected to epicardial cryosurgery without cardiopulmonary bypass, and to endocardial application with bypass. In both groups the heart was kept beating throughout the operation. Neither cardioplegia nor aortic cross-clamping was used. In the first group applications were made for 5 min directly over or adjacent to a major branch of the left coronary artery. In the second, the cryoprobe was applied for 5 min or until atrioventricular dissociation occurred. No sheep developed late arrhythmias or evidence of myocardial ischaemia. Only minimal arterial changes were observed and all the major coronary arteries remained widely patent. Cryothermia to the heart produced a small discrete lesion without complication. Bright fluorescence of necrotic myocytes was observed in all the immature lesions when sections stained with haematoxylin and eosin were examined under ultraviolet light. This vivid fluorescence clearly delineated the extent of the lesions and persisted while cytoplasmic elements remained. Our results indicate that cryosurgery provides a safe and permanent technique for the surgical treatment of arrhythmias in man, and may safely be used even in proximity to the coronary arteries. Cardioplegia is contraindicated.

Solitary lung tumors and their spontaneous metastasis in athymic nude mice orthotopically implanted with human non-small cell lung cancer.

We examined the tumorigenic and metastatic potentials of three human non-small cell lung cancer (NSCLC) cell lines, PC-14, A549 or Lu-99 cell lines suspended in Matrigel-containing phosphate-buffered saline were orthotopically implanted into the lungs of nude mice. The formation of a solitary tumor nodule in the lung was observed after the implantation of all cell lines. Intrapulmonary implantation of PC-14 or Lu-99 cells resulted in spontaneous distant metastases. In contrast, A549 cells caused multiple intrapulmonary metastases to the right and left lobes of the lung without producing visible lymphatic metastasis. We also investigated the expression of matrix metalloproteinases (MMPs), urokinase-type plasminogen activator (u-PA), u-PA receptor (u-PAR) and c-MET in these cell lines in vitro and in vivo. Reverse transcription polymerase chain reaction (RT-PCR) analysis showed that the expression of MMP-2 and membrane-type 1 MMP (MT1-MMP) was elevated in PC-14 as compared with the other two cell lines. In contrast, stronger expression of c-MET was observed in A549 than in PC-14 or Lu-99. These results indicate that differential patterns of metastasis of lung cancer might be associated with differential expression of metastasis-associated molecules. Our orthotopic implantation models display clinical features resembling those of NSCLC, and may provide a useful basis for lung cancer research.

Effects of rat gamma- and non-gamma-interferons on the expression of Ia antigen, growth, and differentiated functions of FRTL5 cells.

We undertook the present studies with several objectives in mind: 1) to determine whether recombinant rat gamma-interferon (r gamma IFN) would induce expression of the class II major histocompatibility antigen (Ia) in rat thyroid follicular cells (FRTL5) in culture as human gamma IFN does in cultured human thyrocytes; 2) to characterize the properties of this response, if it does indeed occur; 3) to ascertain whether r gamma IFN has any effect on the growth or differentiated function of FRTL5 cells; and 4) to determine how, if at all, effects of r gamma IFN on the growth and function of FRTL5 cells might be related to expression of the Ia antigen. At concentrations between 1 and 30 U/ml, r gamma IFN induced expression of Ia antigen in a concentration-dependent manner. With a supramaximal concentration of r gamma IFN, Ia antigen first appeared between 4 and 16 h and reached a maximum concentration at about 36 h. After removal of r gamma IFN, the Ia antigen concentration remained constant for about 24 h and then declined, becoming undetectable by 72 h. Induction could not be detected in FRTL5 cells cultured with human gamma IFN, rat non-gamma IFN, Concanavalin-A, phytohemagglutinin, or bovine TSH (bTSH). Over the same range of concentrations that induced the Ia antigen, r gamma IFN proved to be a potent inhibitor of the growth of FRTL5 cells induced by a variety of agents. It produced a concentration-dependent inhibition of the stimulation of [3H] thymidine incorporation and cell replication in FRTL5 cells induced by bTSH. This effect was unaccompanied by any inhibition of either the binding of bTSH to FRTL5 cells or the bTSH-induced increase in cellular cAMP concentration induced therein. However, r gamma IFN did inhibit the stimulation of [3H] thymidine incorporation into DNA induced by (Bu)2cAMP. r gamma IFN also inhibited the stimulation of DNA synthesis and cell replication induced by insulin-like growth factor I (IGF-I) without affecting the specific binding of IGF-I, and decreased the extent of stimulation of [3H]thymidine incorporation induced by the phorbol ester tetradecanoyl phorbol acetate (TPA). Thus, r gamma IFN inhibited both the cAMP-dependent pathway of growth activated by TSH, doing so at some post-cAMP locus, and the cAMP-independent pathways of growth regulation that are activated by IGF-I and TPA.(ABSTRACT TRUNCATED AT 400 WORDS)

Thyrotropin receptor antibodies in hypothyroid Graves' disease.

To clarify the relation of TSH receptor antibody (TRAb) to Graves' ophthalmopathy and thyroid function, the activities of TSH binding inhibitor immunoglobulins, thyroid-stimulating antibodies, and thyroid stimulation-blocking antibodies were measured in five patients with hypothyroid Graves' disease. The diagnosis was based on the presence of Graves' ophthalmopathy and either permanent or transient hypothyroidism without a history of treatment for hyperthyroid Graves' disease. TSH binding inhibitor immunoglobulins and thyroid-stimulating antibodies were detected in all five patients. Thyroid stimulation-blocking antibodies results indicated that a blocking type of TRAb was not a cause of hypothyroidism. Destructive changes in the thyroid were probably responsible for hypothyroidism, since 1) high antibody titers against thyroglobulin and thyroid microsomal antigen, 2) diffuse hypoechogenicity of the thyroid on ultrasonography, 3) absent or impaired responses of serum T3 after TRH or TSH stimulation, and 4) histological findings similar to those in Hashimoto's thyroiditis were observed. In all patients except one, thyroid function was changeable, with euthyroid and even subclinical hyperthyroid episodes occurring during the course of the illness. It is conceivable that such unstable thyroid function may be attributable to subtle changes in the balance between the effects of destructive changes in the thyroid and the stimulatory effects of TRAb. In conclusion, all patients had TRAb, suggesting a possible relationship between such antibodies and Graves' ophthalmopathy. Patients develop euthyroidism or subclinical hyperthyroidism during the course of the illness with high frequency.

Inhibition of thyrotropin-stimulated iodide uptake in FRTL-5 thyroid cells by crude immunoglobulin fractions from patients with goitrous and atrophic autoimmune thyroiditis.

We studied the effects of crude immunoglobulin (Ig) fractions of serum from patients with goitrous and atrophic autoimmune thyroiditis on TSH-, thyroid-stimulating immunoglobulin (TSI)-, forskolin-, and dibutyryl cAMP-stimulated 125I uptake by FRTL-5 thyroid cells. TSH-stimulated 125I uptake was inhibited by the Ig fractions from 15 patients with atrophic thyroiditis who had serum TSH binding inhibitor Igs (TBII), 10 (62.5%) of 16 TBII-negative patients with atrophic thyroiditis, 7 (43.8%) of 16 hypothyroid patients with goitrous thyroiditis who had no TBII activity, and only 2 (15.4%) of 13 euthyroid patients with goitrous thyroiditis who were negative for TBII. The mean inhibition of TSH-stimulated 125I uptake produced by the crude Igs from the former 3 groups of hypothyroid patients was statistically significant (P less than 0.001, P less than 0.001, and P less than 0.01, respectively) and correlated closely with the ability of the Ig fractions to inhibit TSI-stimulated 125I uptake (r = 0.882) and TSH-stimulated cAMP accumulation (r = 0.929). The inhibition of TSH- or TSI-stimulated 125I uptake by Ig samples containing TBII correlated significantly with the TBII activities. On the other hand, in the presence of Igs from TBII-negative hypothyroid patients, the inhibition of TSH-stimulated 125I uptake correlated significantly with that of forskolin-stimulated 125I uptake (r = 0.685). Although 6 (12.8%) of 47 Ig samples from hypothyroid patients inhibited dibutyryl cAMP-stimulated 125I uptake, the activities were marginal. These findings suggest that at least 2 types of antibodies are involved in the inhibition of TSH- or TSI-stimulated 125I uptake: 1 being a competitive inhibitor of TSH binding to its receptors, and another exerting influence on a step subsequent to TSH or TSI binding, presumably through adenylate cyclase inhibition.

A sensitive and practical assay for thyroid-stimulating antibodies using crude immunoglobulin fractions precipitated with polyethylene glycol.

A simple, sensitive, and practical assay for thyroid-stimulating autoantibodies (TSAb) was developed in which cryopreserved porcine thyroid cells were incubated with crude immunoglobulin fractions sedimented from serum with polyethylene glycol. In the assay, 1.4- to 2.0-fold and 6- to 12-fold increases in cAMP released into Hank's medium without NaCl were found at 1 and 10 microU/ml bovine TSH, respectively. TSAb were detected in 41 (97.6%) of 42 patients with untreated hyperthyroid Graves' disease, 29 (55.8%) of 52 patients with hyperthyroid Graves' disease who were euthyroid while taking antithyroid drugs, 22 (78.6%) of 28 patients with euthyroid Graves' disease, and none of the patients with simple goiter, adenomatous goiter, thyroid adenoma, or thyroid cancer tested. TSAb activities measured using porcine thyroid cells significantly correlated with those measured using human thyroid adenoma cells (r = 0.908; n = 46; P less than 0.001). Thyroid-stimulating activity was also detected in 11 (28.9%) of 38 patients with Hashimoto's thyroiditis. However, the activity was considered to be due to TSH in the patients' sera, because it was completely abolished by pretreatment with anti-TSH antibodies. Serum TSH concentrations lower than 50 microU/ml did not affect the assay result. In Graves' disease after cessation of antithyroid drugs, 85.7% (12 of 14) of TSAb-positive patients relapsed, while 77.8% (14 of 18) of TSAb-negative patients remained in remission. Thus, the assessment of TSAb was useful as an index to predict prognosis.

Supranormal stimulation of deoxyribonucleic acid synthesis in FRTL5 cells by serum from patients with untreated acromegaly.

Insulin-like growth factor I (IGF-I) is one of a number of mitogenic factors in the serum of animals and humans. We demonstrated previously that IGF-I is a potent mitogen for FRTL5 cells, a line of rat thyroid follicular cells. In this study, we assessed the relevance of this finding with respect to the levels of IGF-I found in human serum by comparing the effects of normal serum and serum from patients with untreated acromegaly or hypopituitarism on DNA synthesis in quiescent FRTL5 cells. As expected, when added to cells maintained in Coon's modified Ham's F-12 medium containing 0.1% BSA, but devoid of insulin, transferrin, TSH, or calf serum, normal serum produced a dose-dependent stimulation of [3H]thymidine incorporation into DNA. A similar, but more marked, effect was produced by the addition of serum from patients with untreated acromegaly. In multiple experiments, a standard concentration (0.5%) of acromegaly serum was more stimulatory to DNA synthesis than was normal serum. In a single experiment designed to eliminate interassay variation and define the relationship between the ability of serum to stimulate DNA synthesis and its IGF-I concentration, studies were performed with 0.5% concentrations of serum from 9 normal subjects, 15 patients with untreated acromegaly, and 3 patients with panhypopituitarism. On the average, [3H]thymidine incorporation in the presence of serum from patients with acromegaly was approximately 3 times, and that in the presence of serum from patients with hypopituitarism only one fourth, that in the presence of serum from normal subjects; there was no overlap of individual values in the three groups. For the entire study group, we found a highly significant correlation (r = 0.86) between the serum IGF-I concentration and the ability of that serum to stimulate thymidine incorporation into the DNA of FRTL5 cells. The stimulatory effects of serum from both normal and acromegalic subjects were decreased or abolished by the addition of a monoclonal antibody against IGF-I. In hypophysectomized rats, GH increases the thyroid to body weight ratio and enhances the effect of TSH to promote thyroid growth. Further, an inordinate frequency of nontoxic goiter in patients with acromegaly has been reported. Taken together with these observations, our findings suggest that the effect of IGF-I to promote thyroid cell growth in vitro has a counterpart in the living animal or patient.

Inhibition of thyrotropin-induced growth of rat thyroid cells, FRTL-5, by immunoglobulin G from patients with primary myxedema.

We studied thyroid growth-blocking activity in immunoglobulin G (IgG) fractions of serum from 24 patients with primary myxedema, 24 patients with goitrous Hashimoto's thyroiditis, and 18 normal subjects by measuring the ability of their IgG to inhibit TSH-induced [3H]thymidine incorporation into DNA in a rat thyroid cell line, FRTL-5. Both groups of patients were receiving T4 when studied. [3H]Thymidine incorporation induced by 0.1 mU/ml bovine TSH was significantly inhibited by the addition of 2 mg/ml IgG from patients with primary myxedema (P less than 0.01), while it was not affected by IgG from the normal subjects or 23 of the 24 patients with goitrous Hashimoto's thyroiditis. IgG from patients with primary myxedema also inhibited the [3H]thymidine incorporation induced by Graves' IgG, but not that induced by forskolin, cholera toxin, (Bu)2cAMP or phorbol-12-myristate-13-acetate. The inhibition of TSH-induced [3H]thymidine incorporation by IgGs from patients with primary myxedema was significantly correlated with their inhibitory activities against both TSH-induced cAMP generation and TSH binding (P less than 0.001). These data indicate that these growth-blocking antibodies are directed against the TSH receptor and might be one of the causes of the thyroid atrophy in patients with primary myxedema.

Inhibition of thyrotropin-induced adenosine 3'5'-monophosphate increase by immunoglobulins from patients with primary myxedema.

Immunoglobulin G (IgG) fractions prepared from the serum of 18 patients with primary myxedema, 9 patients with goitrous Hashimoto's thyroiditis, and 14 normal controls were tested for their ability to alter TSH stimulation of cAMP production in cultured human thyroid cells and the binding of TSH to its receptor. When compared with the cAMP increase induced by 0.1 mU/ml bovine TSH in the presence of normal IgG, cAMP accumulation was significantly inhibited (P less than 0.005) by the addition of IgG from patients with primary myxedema. TSH-induced cAMP accumulation was not affected by IgG from patients with goitrous thyroiditis. IgG from patients with primary myxedema also inhibited the cAMP increase induced by thyroid-stimulating immunoglobulins, but not against the increase induced by prostaglandin E1. None of the IgG tested affected the basal level of cAMP. Two potent inhibitory IgG were strongly positive for TSH-binding inhibitor immunoglobulins. Excluding these, no significant correlation was found between the thyroid stimulation-blocking activity and the TSH-binding inhibitory activity. These data suggest the presence of at least two different types of antibodies in primary myxedema which block adenylate cyclase stimulation by TSH and might be responsible for thyroid dysfunction and atrophy.

Role of thyrotropin receptor antibodies in the development of hyperthyroidism: follow-up studies on nine patients with Graves' disease.

TSH binding inhibitor immunoglobulin (TBII) and thyroid-stimulating antibody (TSAb) activities were measured serially for 4-32 months in nine patients before and during development of hyperthyroidism due to Graves' disease. Initially, all were euthyroid, seven had thyroid enlargement, one had proptosis, and seven had high serum titers of antithyroid microsomal antibodies. The occurrence of hyperthyroidism was preceded by detection of both TBII and TSAb in four patients and detection of TSAb alone in four patients. One patient had neither TBII nor TSAb when euthyroid. The mean initial TBII and TSAb activities were 10.2 +/- 15.2% (+/- SD) and 2677 +/- 4620%, respectively, when these patients were euthyroid. When they became hyperthyroid, both TBII and TSAb activities increased in all patients. At that time, TBII was detected in all but one (eight of nine subjects; 88.9%), with a mean activity of 58.8 +/- 23.4% (+/- SD), and TSAb was detected in all nine patients, with a mean value of 4508 +/- 4429%. These findings not only indicate the crucial role of TSH receptor antibodies in the development of hyperthyroidism due to Graves' disease, but also suggest that a certain period of subclinical Graves' disease exists before the onset of overt hyperthyroidism in most patients, in the sense that they have TSH receptor antibodies, especially TSAb, in their serum even though they are euthyroid.

Regulation of activator protein-1 activity in the mediastinal lymph node metastasis of lung cancer.

Orthotopic implantation of a metastatic cell line of Lewis lung carcinoma (LLC-MLN), which was isolated by an in vivo selection method, resulted in greater metastatic growth in mediastinal lymph nodes as compared with that of the original LLC cells. LLC-MLN cells also had increased invasive ability and activator protein-1 (AP-1) transcriptional activity as compared with the original LLC cells. This is well consistent with the previously reported finding that overexpression of AP-1 is associated with lymphatic metastasis in lung cancer patients. Oral administration of curcumin, which downregulates AP-1 transcription, significantly inhibited the mediastinal lymph node metastasis of orthotopically implanted LLC cells in a dose-dependent manner, but did not affect the tumor growth at the implantation site. Combined treatment with curcumin and an anti-cancer drug, cis-diamine-dichloroplatinum (CDDP), resulted in a marked inhibition of tumor growth at the implanted site and of lymphatic metastasis, and a significant prolongation of the survival time. The downregulation of transcriptional AP-1 activity by curcumin as seen in the dual luciferase assay caused inhibition of LLC cell invasion through the repression of expression of the mRNAs for urokinase-type plasminogen activator (u-PA) and its receptor (u-PAR). Inhibition of AP-1 transcriptional activity may offer improved therapeutic efficacy for lung cancer patients with lymphatic metastasis.