[Successful management of cold agglutinin syndrome developing subsequent to rheumatoid arthritis with immunosuppressive therapy].

A 58-year-old man was admitted with shortness of breath in September 2019. He had a severe hemolytic anemia with a high cold agglutinin (CA) titer. He also had arthralgia and finger deformation. He was diagnosed with cold agglutinin syndrome (CAS) secondary to rheumatoid arthritis (RA) based on the clinical course. Occasionally, CAS has been reported to occur in parallel with collagen disease, infectious disease, or malignant tumor. CAS developing secondary to collagen disease occurs less frequently than that to infectious disease or malignant tumors. Furthermore, CAS caused by RA is very rare, even among patients with collagen diseases. Our patient was effectively treated with immunosuppressive therapy including abatacept, which attenuated the symptoms of CAS and RA.

Hepatic Tumor Rupture in Other Iatrogenic Immunodeficiency-Associated Lymphoproliferative Disorders of the B-cell Type in a Patient With Chronic Rheumatoid Arthritis.

A 75-year-old woman on tumor necrosis factor inhibitors for rheumatoid arthritis presented with hematemesis and a gastric biopsy revealed diffuse large B-cell lymphoma with possible bulky left liver tumor involvement. On the second day of treatment with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone, the patient experienced abdominal pain followed by shock vitals. A contrast-enhanced computed tomography scan revealed a ruptured liver. Transcatheter arterial embolization (TAE) was performed to stop the bleeding. This is the first case of hepatic tumor rupture secondary to an iatrogenic immunodeficiency-associated lymphoproliferative disorder of the B-cell type that was successfully treated with TAE to achieve hemostasis.

Successful Treatment of Concomitant Pleural Mucosa-Associated Lymphoid Tissue Lymphoma and Monoclonal Gammopathy of Undetermined Significance with Lenalidomide, Rituximab, and Dexamethasone.

Concomitant plasma cell and B cell neoplasms in a single patient have been infrequently reported. It is known that the prognosis of these patients is worse than that of patients with single-disease onset. Generally, the chemotherapy specific for each disease is provided sequentially. It has been suggested that the specific chemotherapy for lymphoma could lead to the occurrence of refractory multiple myeloma (MM). We present a case with the concomitant occurrence of mucosa-associated lymphoid tissue (MALT) lymphoma and monoclonal gammopathy of undetermined significance (MGUS). MGUS does not usually require aggressive treatment. However, the potential adverse effects of MGUS on the treatment course of the B cell lymphoma were concerning. Therefore, we explored a new therapeutic approach that is simultaneously effective against both diseases. Combination therapy of lenalidomide (LEN) and rituximab (RIT) gained indication for follicular lymphoma and MALT lymphoma recently. LEN is also a key drug in MM treatment. Both diseases in our patient were effectively treated with the combination of LEN, RIT, and dexamethasone. With this combination therapy, we expect a prognostic improvement in concomitant MM and B cell lymphoma cases.

The Development of Primary Effusion Lymphoma-Like Lymphoma in a Patient with Preexisting Essential Thrombocythemia.

A 71-year-old Japanese male was diagnosed with essential thrombocythemia (ET) with the JAK2 V617F mutation variation, in April 2011. He was mainly treated with hydroxyurea following which the number of platelets was maintained within the normal limit. At age 80, he was hospitalized due to cardiac tamponade. Computed tomography showed no evidence of tumor masses or lymphadenopathy. Pericardial drainage was performed, and cytopathologic examination of the fluid revealed atypical lymphoid cells consistent with an effusion lymphoma of B cell lineage. The pericardial effusion was completely drained, and complete remission was achieved. Ultimately, the patient was diagnosed with primary effusion lymphoma-like lymphoma (PEL-LL). To the best of our knowledge, this is the first report of PEL-LL following ET.

[Secondary chronic myelogenous leukemia following postoperative TS-1 therapy for advanced gastric cancer].

A 78-year-old man received total gastrectomy for advanced gastric cancer in September 2006, and was subsequently treated with oral anti-metabolite TS-1 for 38 months. He had no evidence of recurrence of gastric cancer, although he had a continuous poor appetite due to TS-1. Leukocytosis was found in November 2008. On the basis of bone marrow findings, Philadelphia chromosome and BCR-ABL fusion gene, he was diagnosed as having chronic phase of secondary chronic myeloid leukemia (CML). Two weeks after starting imatinib therapy, skin eruption, palpebral edema and appetite loss were observed; moreover, thrombocytopenia gradually worsened. He stopped taking imatinib and hydroxyurea was subsequently started. The above symptoms disappeared and the platelet count normalized. CML is rare in secondary leukemia. Our case is the second reported case of secondary CML following TS-1 treatment and suggests that therapy for secondary CML should be selected on the basis of QOL in patients with advanced cancer.

[A case of refractory pulmonary peripheral T cell lymphoma successfully treated with Cisplatin Plus Gemcitabine Plus Solumedrol].

A 56-year-old man had an endoscopic examination for dysphagia in March 2007 which revealed tumors in the esophagus and stomach. Pathological examination of the esophagus biopsy specimens showed an unspecified peripheral T cell lymphoma. The esophagus tumor was tolerant to CHOP and EPOCH therapy. After an autologous peripheral blood stem cell transplantation, a complete response was observed in the patient. However, a lymphoma relapse was diagnosed in the lung in September 2008. The relapsed lung lymphoma was tolerant to EPOCH therapy. The refractory pulmonary peripheral T cell lymphoma was remarkably reduced by PEGS therapy. PEGS therapy is useful for relapsed peripheral T cell lymphoma cases that tolerated standard chemotherapy. An allogenic hematopoietic stem cell transplantation or new molecular target therapy might be finally selected for refractory peripheral T cell lymphoma. However, an allogenic transplantation has some severe complications. Furthermore we could not easily try phase I or II new molecular target drug treatment. We think that PEGS therapy is a useful treatment for refractory peripheral T cell lymphoma before allogenic transplantation or new molecular target drug treatment.

A case of hypereosinophilic syndrome presenting with chronic cough successfully treated with imatinib.

Chronic cough is caused by a wide variety of disease conditions, including asthma, rhino-sinusitis and gastro-oesophageal reflux. We describe the case of a 42-year-old man with hypereosinophilic syndrome presenting with chronic dry cough. The cough did not respond to inhaled corticosteroid or leucotriene receptor antagonists. Hepatosplenomegaly was noted and the patient became anaemic and thrombocytopenic. He was refractory to treatment with hydroxyurea and interferon-alpha. Administration of imatinib resulted in complete resolution of eosinophilia and cough, without the use of anti-asthma drugs. Analysis of RNA from this patient demonstrated expression of the Fip1-like 1/platelet-derived growth factor receptor-alpha (FIP1L1-PDGFRA) fusion gene. The myeloproliferative variant of hypereosinophilic syndrome may cause chronic intractable cough, and a trial of imatinib treatment may be warranted.

Long-term survival of a patient with small cell lung cancer associated with cancer-associated retinopathy.

Cancer-associated retinopathy (CAR) is a rare paraneoplastic disorder that is frequently found in patients with small cell lung cancer (SCLC); it is caused by autoantibody to the 23-kDa photoreceptor protein, recoverin. We report a 9-year survivor of SCLC after concurrent chemoradiotherapy. His anti-recoverin antibody remains positive. Long-term survival without SCLC recurrence might be related to an autoimmunity mechanism that causes CAR due to the presence of anti-recoverin antibody cross-reacting with retinal cells and tumor cells. The current literature review was conducted to evaluate the impact on overall survival according to anti-recoverin antibody status.

Establishment of a novel small cell lung carcinoma cell line with specific recoverin expression from a patient with cancer-associated retinopathy.

We analysed the biologic properties of a small cell lung carcinoma cell line (designated KK0206) established from a patient with SCLC who had cancer-associated retinopathy (CAR). Morphological and immunohistochemical studies showed that KK0206 cells have features of the classic type of SCLC. KK0206 cells grew in suspension, forming relatively small clumps of cells with a doubling time of 72 h. On light microscopy, the cells were relatively small with little cytoplasm. On immunohistochemistry using anti-bovine recoverin rabbit antibody, the cells were intensely positive for recoverin. In addition, they were positive for NSE, Ki-67, and TP53. They also expressed human recoverin, a photoreceptor protein, whose presence was confirmed by RT-PCR analysis with cDNA sequencing and Western blot analysis. The point mutation of their TP53 gene (exon 156) was detected as well. The present study demonstrates that human recoverin is expressed in SCLC cells cultured from an anti-recoverin antibody-negative patient with CAR. KK0206 might be important for further research on SCLC related retinopathy.

Effects of granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor on lung cancer: roles of cyclooxygenase-2.

We examined the effects of granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) on the lung cancer cell lines PC-9, LA-1 and A549. In addition, we examined if the effects of the cytokines on the cell lines are mediated by activation of cyclooxygenase (COX)-2. The three cell lines did not constitutively produce either G-CSF or GM-CSF. G-CSF did not influence cell growth in the three cell lines, while GM-CSF increased cell growth in the A549 and LA-1 lines. G-CSF and GM-CSF dose-dependently decreased cell death in the three cell lines. RT-PCR demonstrated GM-CSF receptor expression in the three lung cancer cell lines, whereas the G-CSF receptor exists only in the PC-9 line. We suggest that G-CSF might rescue the tumor cells from cytotoxicity due to serum deprivation through cellular pathways independent of the G-CSF receptor. G-CSF and GM-CSF increased cyclooxygenase-2 (COX-2) expression in PC-9 and LA-1 cells whereas they decreased COX-2 expression in A549 cells. The COX-2 inhibitor NS-398 increased cell death in PC-9 and LA-1 cells, whereas it decreased cell death in A549 cells. PC-9 and LA-1 clones transfected with sense G-CSF- or GM-CSF showed an increase in COX-2 expression, while COX-2 expression was decreased in transfected A549 clones. COX-2 expression was increased in anti-sense G-CSF- and GM-CSF-transfected A549 clones. Thus, although COX-2 activation seems to induce different biological behavior depending on the cell type, we propose that G-CSF and GM-CSF might accelerate tumor progression by directly regulating COX-2 expression, independently of an autocrine mechanism.

Effects of GM-CSF and M-CSF on tumor progression of lung cancer: roles of MEK1/ERK and AKT/PKB pathways.

Several studies have demonstrated that colony-stimulating factors (CSFs) are closely associated with tumor progression, metastasis and invasion through autocrine or paracrine mechanism in lung cancer. However, biologic roles of CSFs are still unknown. Elucidating the biologic roles of CSFs and the regulatory mechanisms of tumor-specific behavior by CSFs raises the possibility of having a new therapeutic approach for lung cancer. We previously established two adenocarcinoma cell lines, A924 and A964 and a large cell carcinoma cell line MI-4. MI-4 and A924 constitutively produced an abundant dose of granulocyte macrophage colony-stimulating factor (GM-CSF) and macrophage colony-stimulating factor (M-CSF). We examined the effects of GM-CSF and M-CSF on tumor growth, death, and invasion in CSF-producing (A924 and MI-4) and non-producing lung cancer cells (A549 and A964). These cell lines demonstrated both GM-CSF and M-CSF receptor mRNA expression. In our study, GM-CSF seemed to have advantage for tumor proliferation and invasion in lung cancer cells. M-CSF seemed to have advantage for tumor invasion, but not proliferation. The tumor-specific phenotypes (proliferation, invasion and survival) up-regulated by GM-CSF and M-CSF were mediated through MEK/ERK and PI3k/Akt pathways. However, when MEK/ERK was activated by transfection of active form of MEK1 cDNA, the tumor-specific behavior was promoted in CSF-non-producing cells, whereas inhibited in CSF-producing cells though MEK/ERK activation increased constitutive GM-CSF production. MEK/ERK signaling regulated differently tumor-specific behavior between CSF-producing cells and CSF-non-producing cells.

Diffuse micronodular pulmonary metastasis of lung adenocarcinoma predicts gefitinib response in association with epidermal growth factor receptor mutations.

Female, non-smoker, Asian ethnicity and adenocarcinoma histology are the major clinical predictors of gefitinib response in non-small cell lung cancer, as shown in previous studies. Recently, response to gefitinib has been associated with epidermal growth factor receptor (EGFR) mutations. Higher rates of mutation were seen in females, patients with adenocarcinomas, the Asian population and never-smokers, which may explain the clinical response predictors. The presence of diffuse micronodular pulmonary metastasis on chest imaging as a novel clinical predictor of its response is proposed here. Two cases of lung adenocarcinomas in men presenting with diffuse micronodular pulmonary metastasis were encountered. Both patients showed a major response to gefitinib. The dramatic reduction of micronodular pulmonary nodules throughout both lungs on computed tomography scans was achieved after treatment for a couple of months with 250 mg of oral gefitinib. In the molecular analysis, one patient had a heterozygous delL746-A750 mutation and the other had a heterozygous L858R EGFR mutation. In conclusion, patients with lung adenocarcinoma, even men, who presented with bilateral diffuse micronodular metastatic spread to the lungs tended to have an activated EGFR mutation. Therefore, they are most likely to receive benefits from molecular target drugs such as gefitinib and possibly erlotinib.

Role of protein kinase C in expression of granulocyte-colony stimulating factor and granulocyte macrophage-colony stimulating factor in lung cancer cells.

We examine the role of protein kinase C (PKC) pathways in the constitutive expression of granulocyte-colony stimulating factor (G-CSF) and granulocyte macrophage-colony stimulating factor (GM-CSF) in lung cancer cells. Two cell lines, OKa-C-1 and MI-4, constitutively produce an abundant dose of G-CSF and GM-CSF. The PKC activator phorbol 12-myristate 13-acetate (PMA) stimulated the production of GM-CSF in a dose-dependent manner and reduced G-CSF in the cell lines. The PKC inhibitor staurosporine had effects opposite to those of PMA in the cell lines. Another PKC activator (4beta-phorbol 12, 13-dibutyrate) and six specific PKC inhibitors (bisindolylmaleimide I, calphostin C, chelerythrine chloride, Gö 6976, PKC inhibitor 19-27, and Ro-32-0432) also worked as well as PMA and staurosporine, respectively. The induction of GM-CSF expression via PKC activation was mediated by the activation of nuclear factor-kappaB. The induction of G-CSF expression via PKC inhibition was mediated by p44/42 mitogen-activated protein kinase and c-Jun N-terminal kinase pathway signaling. GM-CSF may accelerate cell growth and inhibit cell death via PKC activation in the cell lines. G-CSF also seems to reverse growth suppression and cell death induced by PKC inhibition.

Selective COX-2 inhibitor regulates the MAP kinase signaling pathway in human osteoarthritic chondrocytes after induction of nitric oxide.

The purpose of this study was to examine the effect of cyclooxygenase-2 (COX-2) inhibitors on the mitogen-activated protein (MAP) kinase signaling pathway and synthesis of glucosaminoglycan after nitric oxide (NO) induction in articular human chondrocytes. After NO induction, the cells were divided into three groups that were treated with either ethanol (control); a selective COX-2 inhibitor (Celecoxib), or no additive, and evaluated. There were no differences in the effect of the selective COX-2 inhibitor on mitochondrial membrane potential or Annexin V levels. However, Celecoxib significantly decreased prostaglandin E2 (PGE2) production. Celecoxib also decreased the phosphorylation state of p38 and p44/42 of MAP kinase. The ratio of chondroitin-6 sulfate (C6S)/C4S was increased in response to the exposure to Celecoxib. Celecoxib did not affect apoptosis, but decreased the activation of MAP kinase in osteoarthritic chondrocytes after NO induction. NO-induced OA chondrocytes were associated with the p38 and the p44/42 MAPK signaling pathways, in a pathway that is distinct from PGE2-mediated apoptosis.

Cross talk between COX-2 inhibitor and hyaluronic acid in osteoarthritic chondrocytes.

Both hyaluronic acid (HA) and cyclooxygenase-2 (COX-2) inhibitors are used in clinical practice in the treatment of osteoarthritis. There have been no reports regarding cross-talk between HA and COX-2 inhibitors in articular human chondrocytes. The purpose of this study was to investigate whether HA, COX-2 inhibitors or a combination of COX-2 inhibitors and HA have different effects in human articular between lower and highly degenerated chondrocytes. Isolated lower and highly degenerated chondrocytes were divided into 5 groups: ethanol (used as a control for the solvents), HA, COX-2 inhibitors, COX-2 inhibitors plus HA, or no additive. After incubating for 48 h, mitochondrial membrane potential analysis and western blotting of p38 and p44/42 mitogen-activated protein kinase (MAPK) were performed. Glycosaminoglycan, nitric oxide (NO) production and prostaglandin E2 (PGE2) concentrations were assessed. A combination of COX-2 inhibitors and HA resulted in dendritic, proliferating chondrocytes with strong red fluorescence enriched in the mitochondrial membrane, and indicated reduction of apoptosis in chondrocytes. COX-2 inhibitors alone, and a combination of COX-2 inhibitor and HA inhibited the activation of p38 in highly degenerated chondrocytes. A combination of COX-2 inhibitors and HA decreased NO production in highly degenerated chondrocytes. COX-2 inhibitors decreased PGE2 production, however, HA alone had no effect on PGE2 production. The present study demonstrated that COX-2 inhibitors and HA interacted synergistically the MAPK pathway and inhibition of NO production in highly degenerated chondrocytes. Administration of COX-2 inhibitors plus HA could be used as a new alternative way of treating osteoarthritis.

Combined effects of resveratrol and paclitaxel on lung cancer cells.

Resveratrol (3,4',5-trihydroxystilbene) is a phytoalexin found in grapes and other food products that can prevent cancer. We studied the in vitro biological activity of this compound by examining its effect on proliferation and inducing apoptosis in three lung cancer cell lines (A549, EBC-1, Lu65). Resveratrol inhibited the growth of A549, EBC-1 and Lu65 lung cancer cells by 50% (ED50) at concentrations between 5-10 microM. We also examined the combined effects in these cells of resveratrol and paclitaxel, an essential chemotherapeutic agent against lung cancer. Although simultaneous exposure to resveratrol plus paclitaxel did not result in significant synergy, resveratrol (10 microM, 3 days) significantly enhanced the subsequent antiproliferative effect of paclitaxel. In addition, resveratrol as well as paclitaxel induced apoptosis in EBC-1 and Lu65 cells, as measured by TUNEL and caspase assays, as well as flow cytometry. Resveratrol (10 microM, 3 days) similarly enhanced the subsequent apoptotic effects of paclitaxel. We examined the effects of resveratrol and paclitaxel on levels of p21waf1, p27kip1, E-cadherin, EGFR and Bcl-2 in EBC-1 cells. Resveratrol (10 microM, 3 days) prior to paclitaxel induced p21waf1 expression approximately 4-fold. These results suggest that resveratrol may be a promising alternative therapy for lung cancer and that lung cancer cells exposed to resveratrol have a lowered threshold for killing by paclitaxel.

[A case of pulmonary actinomycosis with a unique finding in the chest MR image].

A 57-year old man, who was complaining of a productive cough and right shoulder pain, was admitted to our hospital because of an irregularly shaped mass located at rt. S1 on a chest radiograph. Bronchoscopy revealed no evidence suggesting lung cancer or any specific infection, either pathologically or microbiologically. CT-guided biopsy revealed changes resembling lymphocytic or plasmocytic interstitial pneumonitis with thickening of the alveolar septum and with accumulations of mononuclear cells and plasma cells, indicating the proliferation of bronchus-associated lymphoid tissue (BALT system). Since no definitive diagnosis was considered possible, a right upper lobectomy was performed. Histopathologic examination of tissue from the right upper lobe revealed sulfur granules and branching Gram-positive filamentous bacteria, and the condition was pathologically diagnosed as pulmonary actinomycosis. In the center of the mass lesion, the patient's chest MRI showed a very small area with a low signal intensity in T1- and a high signal in T2-weighted images, which suggested an accumulation of fluid in the actinomycotic abscess. As detailed MR findings in this condition have not been well described in the literature, the MRI evidence seen in this case may be useful for the diagnosis of actinomycosis.