[A case of advanced gastric cancer with multiple bone metastases and disseminated intravascular coagulation successfully treated by combination chemotherapy of S-1 plus docetaxel].

Advanced gastric cancer (AGC) accompanied by disseminated intravascular coagulation(DIC)has a poor prognosis, and has no established therapy. Here, we report a case of a 69-year-old woman referred to our hospital due to severe anemia and thrombocytopenia. Esophagogastroduodenoscopy demonstrated an AGC in the cardiac part of the stomach, which was histologically diagnosed as poorly-differentiated adenocarcinoma. Bone scintigraphy showed multiple metastases to the bone marrow. Her diagnosis was DIC resulting from AGC, with multiple bone metastases. She underwent chemotherapy with the following regimen: 60mg/m2 docetaxel(DOC)infusion on day 1 and daily oral administration of 100 mg/m2 S-1 for two weeks every three weeks. DIC subsided rapidly after initiation of the therapy and resolved in 12 days. She was discharged from the hospital 56 days after admission and survived 303 days. To our knowledge, this is the first case of AGC reported in the Japanese and English literature to obtain long-term survival in this setting. Combined chemotherapy of S-1 plus DOC may play an important role in the treatment of AGC developing DIC.

Experimental pulmonary granuloma mimicking sarcoidosis induced by Propionibacterium acnes in mice.

Propionibacterium acnes has been implicated as an etiologic agent of sarcoidosis since the isolation of this bacterium from sarcoid lesions. We experimentally produced a murine pulmonary granuloma model using P. acnes with several features that simulate sarcoidosis. Mice were sensitized with heat-killed P. acnes and complete Freund's adjuvant and were subsequently challenged with heat-killed P. acnes at 2-week intervals. P. acnes-challenged mice developed epitheloid cell granulomas in the lungs. These mice showed a pulmonary immune response characterized by an increased number of T-lymphocytes, especially CD4+ cells, and the ratio of CD4+/CD8+ in bronchoalveolar lavage (BAL) fluid also increased. Furthermore, significant elevations in both angiotensin-converting enzyme (ACE) serum levels and antibody titers against P. acnes were observed. Mice sensitized with P. acnes without complete Freund's adjuvant were capable of forming pulmonary granulomas, which appeared to be caused by indigenous P. acnes. The genome of P. acnes was found in the lungs, BAL cells, hilar lymph nodes, liver, and spleen in non-sensitized mice, which were thought to be germ-free. These results suggest that the immune response against indigenous P. acnes may play an important role in the pathogenesis of granuloma formation in a murine model.

Induction of CXC and CC chemokines by all-trans retinoic acid in acute promyelocytic leukemia cells.

We previously reported the induction of interleukin-8 (IL-8), one of the CXC chemokines, by all-trans retinoic acid (ATRA) in PL-21 and NB4 human myeloid leukemia cells, which may be implicated in APL differentiation syndrome that is a relatively frequent complication in patients with acute promyelocytic leukemia (APL) during treatment with ATRA. We, therefore, further investigated the effects of ATRA on the expression of chemokine family in NB4 cells and APL cells prepared from two APL patients. The RNase protection assay using a multi-probe template set for human chemokines revealed that ATRA induced gene expressions of a number of CC chemokines, such as monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory protein (MIP)-1alpha and MIP-1beta in NB4 cells. Their antigen levels were also increased in the cultured media. APL cells prepared from two APL patients showed gene expression of chemokines, such as IL-8, MCP-1, MIP-1alpha, and MIP-1beta when stimulated with ATRA in vitro. Furthermore, serum levels of IL-8, MIP-1beta and RANTES were increased during the course of ATRA treatment in both APL patients who developed APL differentiation syndrome. These chemokines are all chemoattractants of particular inflammatory cell types, including neutrophils, monocytes and lymphocytes; therefore, the simultaneous induction of these chemokines after stimulation with ATRA may exacerbate the hyper-inflammation observed in ATRA-induced APL differentiation syndrome.

First presenting signs or symptoms of sarcoidosis in a Japanese population.

PURPOSE: To determine the first presenting signs or symptoms or other reasons leading to the diagnosis of sarcoidosis. METHODS: A retrospective review was made of the records of 123 consecutive Japanese patients with histopathological diagnosis of sarcoidosis seen at a referral-based university hospital. RESULTS: At the first presentation, eye symptoms in 32 patients, abnormal chest X-ray findings in 52 patients, common cold-like symptoms in 12 patients, lymphadenopathy in 6 patients, skin lesions in 14 patients, and examinations for other diseases in 4 patients led to the final diagnosis. Overall, uveitis was detected in 60 patients (50%) during the follow-up. CONCLUSIONS: Mass screening programs of chest X-rays are the major way sarcoidosis is detected in Japan. Uveitis is seen in about half the patients during the course of sarcoidosis, and eye symptoms are frequent first presentations of sarcoidosis. These facts emphasize the role of ophthalmologists in the diagnosis and management of sarcoidosis.

Propionibacterium acnes DNA detected in bronchoalveolar lavage cells from patients with sarcoidosis.

BACKGROUND AND AIM OF THE WORK: The causes of sarcoidosis are unknown. Propionibacterium acnes is so far the only bacterium to be found in sarcoid lymph nodes. We attempted to detect P. acnes DNA in cells recovered by bronchoalveolar lavage (BAL) from patients with sarcoidosis. METHODS: BAL cells from 30 patients with histologically proven sarcoidosis and 30 controls with other lung diseases were examined by a nested polymerase chain reaction (PCR) for 16S rRNA of P. acnes. BAL cells from three recent sarcoid patients and two control patients were also examined by in situ PCR to locate P. acnes DNA. Clinical findings in sarcoid patients with and without positive results by PCR were compared. RESULTS: P. acnes DNA was detected in BAL cells from 21 (70%) sarcoid patients and 7 (23%) control patients. In situ signals of P. acnes DNA were detected in the cytoplasm of 0.2% to 2.8% of alveolar macrophages from sarcoid patients, but from no cells of the control patients. Gallium-67 uptake by lung parenchyma was found in about half of the sarcoid patients with P. acnes DNA, but in none of the other sarcoid patients. More of these patients with such DNA had lung parenchymal shadows in chest X-ray films and were in more advanced stages of the disease than the other sarcoid patients. CONCLUSIONS: Detection of P. acnes DNA in BAL cells was significantly more common in the patients with confirmed sarcoidosis. Detection was associated with some indices of disease activity in the lung.

Camptothecin induces urokinase-type plasminogen activator gene-expression in human RC-K8 malignant lymphoma and H69 small cell lung cancer cells.

We previously reported that anthracyclines, which could generate reactive oxygen species (ROS), could induce the urokinase-type plasminogen activator (uPA) gene expression in human RC-K8 malignant lymphoma cells and in H69 small cell lung cancer (SCLC) cells. In screening other uPA-inducible anti-cancer agents, we found that camptothecin (CPT) and its derivative, SN38, could induce uPA in RC-K8 and H69 cells. CPT and SN38, which are also used for the treatment of lymphoma and SCLC, significantly increased the uPA accumulation in the conditioned media of both cells in a dose-dependent manner. The maximum induction of uPA mRNA levels was observed 24 h after stimulation. Pretreatment with pyrrolidine dithiocarbamate (PDTC), an anti-oxidant, inhibited the CPT-induced uPA mRNA expression. Thus, CPT induces uPA through gene expression, and, therefore, CPT may influence the tumor-cell biology by up-regulating the uPA/plasmin system.

[The concept, definition and diagnostic criteria of sarcoidosis].

The definition of sarcoidosis in the past international conference on sarcoidosis is introduced. Furthermore, the diagnostic criteria proposed by Japanese Research Committee for Diffuse Lung Diseases of the Japan Ministry of Welfare was discussed upon the problem.

Sarcoidosis occurring after interferon-alpha therapy for chronic hepatitis C: report of two cases.

We report two patients who were diagnosed with sarcoidosis after receiving interferon (IFN)-alpha therapy for chronic hepatitis C, and conduct a review the relevant literature. The first patient was a 52-year-old female who developed multiple subcutaneous nodules 2 months after finishing IFN-alpha therapy. A skin biopsy from subcutaneous nodules on the right elbow joint revealed sarcoid granulomata. These lesions resolved spontaneously 4 months later. The second patient, a 57-year-old male, developed bilateral hilar and mediastinal lymph node enlargement 2 years after finishing IFN-alpha 2a therapy. A transbronchial lung biopsy demonstrated sarcoid granulomata. In addition, he had uveitis and left ulnar nerve involvement. His eye and nerve involvement gradually improved over 20 months. It is feasible that IFN therapy has been a trigger for sarcoidosis in these patients.

Induction of IL-8 and monoclyte chemoattractant protein-1 by doxorubicin in human small cell lung carcinoma cells.

We previously demonstrated doxorubicin-induced urokinase expression in human H69 SCLC cells by the microarray technique using Human Cancer CHIP version 2 (Takara Shuzo, Kyoto, Japan), in which 425 human cancer-related genes were spotted on glass plates (Kiguchi et al., Int J Cancer 2001;93:792-7). Microarray analysis also revealed significant induction of IL-8, a member of the CXC chemokines. We have, therefore, extended the observation by testing the effects of doxorubicin on expression of the chemokine family and provide here definitive evidence that doxorubicin induces IL-8 and MCP-1, one of the CC chemokines, at least in 2 human SCLC cells, H69 and SBC-1. IL-8 antigen levels, measured by ELISA, were markedly increased in both H69 and SBC-1 conditioned media after doxorubicin treatment, in parallel with mRNA levels; and this was dependent on the dose of doxorubicin. The ribonuclease protection assay, using a multiprobe template set for human chemokines, revealed induction of not only IL-8 but also MCP-1 in doxorubicin-treated H69 cells. MCP-1 antigen levels increased approximately 100-fold in doxorubicin-treated H69 cells. RT-PCR using specific primers for MCP-1 suggested that doxorubicin also induced MCP-1 expression in SBC-1 and SBC-3 SCLC cells. Futhermore, CAT analysis using IL-8 promoter implicated the PEA3 transcriptional factor, whose binding site was located immediately upstream of the AP-1 and NF-kappaB binding sites. Thus, it is suggested that doxorubicin induces IL-8 and MCP-1 chemokines in human SCLC cells by activating gene expression, in which at least PEA3 is involved. IL-8 and MCP-1 are major chemoattractants for neutrophils and monocytes/macrophages, respectively; therefore, extensive induction of IL-8 and MCP-1 may provoke the interaction between inflammatory/immune cells and tumor cells under doxorubicin stimulation and influence many aspects of tumor cell biology.

Simultaneous induction of matrix metalloproteinase-9 and interleukin 8 by all-trans retinoic acid in human PL-21 and NB4 myeloid leukaemia cells.

All-trans retinoic acid (ATRA) has been shown to induce differentiation of human acute promyelocytic leukaemia (APL) cells and eventual elimination of the malignant clone. Matrix metalloproteinase-9 (MMP-9) is produced by neutrophils and its expression appears to be linked with myeloid cell differentiation. We investigated effects of ATRA on MMP expression in two human myeloid leukaemia cell lines, PL-21 and NB4. Both cells could differentiate into neutrophils after exposure to ATRA. Both the activity and antigen levels of MMP-9 were much higher in NB4 cells than in PL-21 cells. Stimulation with ATRA significantly increased MMP-9 levels approximately three- to fivefold in both PL-21 and NB4-conditioned media. MMP-9 mRNA levels increased in ATRA-treated cells and was almost in parallel with the increase in MMP-9 activity, suggesting that ATRA induced MMP-9 by activating its gene expression. ATRA can induce interleukin 8 (IL-8) in APL cells. IL-8, chemokine for neutrophils and a potent inducer of MMP-9, was also induced by ATRA in PL-21 cells. However, recombinant IL-8 did not induce MMP-9 expression. In addition, a neutralizing antibody against IL-8 did not inhibit ATRA-induced MMP-9 expression in either cell type. These observations suggest that ATRA can induce both MMP-9 and IL-8, but IL-8 is not involved in ATRA-induced MMP-9 expression. As MMP-9 can truncate and activate IL-8, simultaneous induction of MMP-9 and IL-8 by ATRA could activate leucocytes excessively, causing the hyper-inflammatory events in retinoic acid syndrome.