BACKGROUND: Systemic inflammation such as rheumatoid arthritis (RA) and Crohn's disease (CD) may be responsible for vascular comorbidity. TNF-alpha blockade was expected to lower these comorbidities but several cases of arterial and venous thromboembolic events (TE) have been reported. OBJECTIVES: The aim of this work was to study retrospectively the main characteristics of spontaneously notified TNF-alpha blockers related TE over a 7-year period. METHODS: TE related to infliximab, etanercept and adalimumab spontaneously notified to the French adverse drug reporting system database between January 2000 and December 2006 were analyzed. Separate analysis of arterial TE and venous TE was performed. Risk factors for each category of TE were assessed with consensual criteria. RESULTS: 85 TE were analyzed, representing 4.5% of all the spontaneously notified adverse reactions of the 3 TNF-alpha blockers in the database. 42 were arterial events and 43 were venous events. The incidence was not significantly different between the 3 TNF-alpha blockers. Mean delay of TE onset after treatment initiation was 10.6 months. It was significantly shorter for etanercept (6.1 months, p=0.001) especially for venous TE (2.4 months). 16 among the 42 patients with arterial TE had 2 or more risk factors whereas 39 among the 43 patients with venous TE had no RF or only one. Most of patients (79/85) received concomitant systemic corticosteroids and/or methotrexate and/or COX-2 selective inhibitors. 23 patients had been investigated for autoimmunity, 13 had antinuclear and/or antiphospholipid antibodies. Main limitations of this study were underreporting and heterogeneous report contents. CONCLUSION: Despite its limitations, this study suggests that venous TE could be favoured by TNF-alpha blockers therapy since they occurred in patients with no or few risk factors for venous thrombosis. However, this needs to be more evaluated by controlled studies. less...

Primary cutaneous CD30+ T-cell lymphoproliferative disorders (PCLPDs) are the second most common type of cutaneous T-cell lymphoma. These disorders comprise a spectrum of clinically benign lymphomatoidpapulosis (LyP) and primary cutaneous anaplastic large-cell lymphoma (ALCL). The peak incidence of LyP is in the 5th decade of life, and the incidence of primary cutaneous ALCL peaks in the 6th decade, but children are also affected. Both LyP and primary cutaneous ALCL have an excellent prognosis. However, LyP is associated with development of malignant lymphoma (mycosis fungoides, Hodgkin lymphoma, or ALCL) in 20% of cases, and also with an increased risk of non-lymphoid cancers. The diagnosis of LyP is difficult and often delayed. Primary cutaneous ALCL must be distinguished from secondary skin lesions in systemic ALCL, which confer a poor prognosis. Correlation of clinical findings with histopathology and immunopathology (stains for ALK kinase, epithelial membrane antigen, and cutaneous lymphocyte antigen) are important to achieve a correct diagnosis. When a diagnosis of CD30+ PCLPD is established, minimal clinical staging is required. Low-dose methotrexate (10-25 mg weekly) is the most effective therapy for PCLPD but is usually reserved for aggressive cases of LyP and multifocal lesions of cutaneous ALCL Many patients with LyP can be followed expectantly, with special attention to changes in character of the skin lesions or development of lymphadenopathy. Patients with localized cutaneous ALCL can be treated with irradiation. Extracutaneous spread of disease is an indication for multiagent chemotherapy. Other treatment alternatives are discussed. less...

The change of protein vibrations on ligand binding is of functional and thermodynamic importance. Here, this process is characterized using a simple analytical "ball-and-spring" model and all-atom normal-mode analysis (NMA) of the binding of the cancer drug, methotrexate (MTX) to its target, dihydrofolate reductase (DHFR). The analytical model predicts that the coupling between protein vibrations and ligand external motion generates entropy-rich, low-frequency vibrations in the complex. This is consistent with the atomistic NMA which reveals vibrational softening in forming the DHFR-MTX complex, a result also in qualitative agreement with neutron-scattering experiments. Energy minimization of the atomistic bound-state (B) structure while gradually decreasing the ligand interaction to zero allows the generation of a hypothetical "intermediate" (I) state, without the ligand force field but with a structure similar to that of B. In going from I to B, it is found that the vibrational entropies of both the protein and MTX decrease while the complex structure becomes enthalpically stabilized. However, the relatively weak DHFR:MTX interaction energy results in the net entropy gain arising from coupling between the protein and MTX external motion being larger than the loss of vibrational entropy on complex formation. This, together with the I structure being more flexible than the unbound structure, results in the observed vibrational softening on ligand binding. less...

Gefitinib is an orally active, selective epidermal growth factor receptor-tyrosine kinase inhibitor. The present study was aimed at evaluating the antitumor activity of gefitinib alone or in combination with other antitumor agents. Gefitinib showed higher cytotoxicity against five human tumor cell lines (HSC-2, HSC-3, HSC-4, T98G and U87MG) than against three human normal oral cells (gingival fibroblast HGF, pulp cell HPC and periodontal ligament fibroblast HPLF). Gefitinib showed little or no growth stimulation effects at lower concentrations (so-called hormetic effect). Non-cytotoxic concentration of gefitinib effectively enhanced the cytotoxicity of docetaxel against HSC-2 and T98G cell, but failed to enhance the cytotoxicity of other antitumor agents (mitoxantrone, doxorubicin, methotrexate, cisplatin, sodium ascorbate, sodium fluoride) or herbal extracts (Drynaria baronii, Angelica sinensis and Cornus officinalis Sieb. et Zucc). Gefitinib alone and combined with docetaxel induced internucleosomal DNA fragmentation and caspase-3 activation in human promyelocytic leukemia HL-60 cells, but not in HSC-2 or T98G cells. Combination treatment with gefitinib and docetaxel induced the formation of acidic organelles (stained with acridine orange) and mitochondrial shrinkage, vacuolization and production of autophagosome and the loss of cell surface microvilli, without destruction of cell surface and nuclear membranes in HSC-2 and T98G cells (demonstrated by transmission electron microscopy), suggesting the induction of autophagy in HSC-2 and T98G cells. less...

OBJECTIVE: To investigate the effects of antiproliferative drugs (anastrozole, methotrexate, and 5-fluorouracil [5-FU]) on the proliferation of endometriotic cells in vitro and in vivo. DESIGN: Ex vivo study on human endometrial and endometriotic cells in culture; establishment of a murine model using mice implanted with human endometriosis. SETTING: University research center. PATIENT(S): Ten patients with ovarian endometrioma, 10 patients with deep infiltrating endometriosis, and 10 patients without endometriosis. INTERVENTION(S): Stromal and epithelial cells were extracted from endometrial and endometriotic biopsies from patients with endometriosis and from patients without endometriosis. Cells were treated in vitro with anastrozole, methotrexate, progesterone, or 5-FU. Human endometriotic lesions were implanted in nude mice. Mice were treated with 5-FU or phosphate-buffered saline during 4 weeks before sacrifice and extraction of the endometriotic implants. MAIN OUTCOME MEASURE(S): Stromal and epithelial cell proliferation and pathology score of endometriotic implants. RESULT(S): Although anastrozole, methotrexate, and progesterone were ineffective, 5-FU significantly decreased the proliferation of endometriotic cells in vitro and controlled the growth of both cells from ovarian endometrioma and deep infiltrating endometriosis. CONCLUSION(S): Considering common features between endometriotic cells and tumor cells, the use of 5-FU could be an option in the management of severe endometriosis. less...

PURPOSE: To evaluate the effect of rituximab in poor prognosis patients with diffuse large B-cell lymphoma (DLBCL), a multicenter phase II trial combining rituximab with chemotherapy followed by high-dose therapy (HDT) with autologous stem cell transplant (ASCT) was conducted by the Groupe Ouest-Est des Leuc�mies et des Autres Maladies du Sang (GOELAMS). PATIENTS AND METHODS: Patients were aged 18 to 60, with newly diagnosed CD20-expressing DLBCL, and at least two adverse risk factors as defined by the age-adjusted International Prognostic Index (aa-IPI). The treatment consisted of two courses of high-dose CHOP-like regimen on day 1 and 15 and one course of methotrexate and cytarabine on day 36. Four doses of rituximab (375mg/m(2)) were infused on days 1, 15, 22, and 36. For patients who achieved at least a PR, HDT followed by ASCT was performed on day 66. RESULTS: From 04/2002 to 05/2003, 42 patients were eligible. Half were high aa-IPI risk patients. Thirty-eight patients (90%) completed the treatment. Treatment-related mortality was 7% and no toxic death was related to rituximab. Complete response rate after the end of the full treatment was 67%. With a median follow-up of 66 months, event-free survival and overall survival rates were 55% and 74%, respectively. Median survival was not reached. CONCLUSION: First-line HDT with rituximab offers promising results for young adults with intermediate high or high aa-IPI high-grade lymphoma. Immediate and late toxicities were low. This treatment is being randomly compared prospectively with CHOP-14-rituximab in young adults with DLBCL (GOELAMS 075 trial). less...

AIM: In several commonly used regimens, chemotherapy doses are split across different days of the cycle. We aimed to determine the feasibility of growth factor support with once-per-cycle pegfilgrastim in this setting. METHODS: This phase II study in breast cancer patients assessed the utility of a single 6 mg subcutaneous dose of pegfilgrastim administered on day 9 of an intravenous (IV) "split" CMF (cyclophosphamide 600 mg/m(2), methotrexate 40 mg/m(2) and 5-fluorouracil 600 mg/m(2)) chemotherapy regimen administered on days 1 and 8 and repeated every 28 days for 6 cycles. RESULTS: Fifty-eight patients were enrolled, with 49 completing the study. For the primary endpoint, 48 patients (83%) received >or=85% of the relative dose intensity (RDI) of chemotherapy over all 6 cycles (95% confidence interval [CI], 71-91%). Across all chemotherapy cycles, 41 patients (71%) received all scheduled cycles on time and most patients (n=49, 84%) received >or=85% of the planned dose of all chemotherapy agents in all cycles. In total, 295/319 cycles (92%) were delivered on schedule and >or=85% of the planned dose of all chemotherapy agents were administered in 309/319 cycles (97%). Febrile neutropenia was reported in only 2 patients (3%). There were no grade 4 adverse events related to pegfilgrastim. DISCUSSION: Day 9 pegfilgrastim administration was well tolerated and provided effective protection against neutropenia in patients receiving IV CMF on days 1 and 8, allowing chemotherapy to be delivered on time and at the scheduled dose in most patients. less...

The effects of direct hemoperfusion with polymyxin B-immobilized fiber (PMX-DHP) treatment for acute exacerbation of interstitial pneumonia have been reported. Here, we report 3 severe cases of drug-induced interstitial lung disease (DI-ILD) that were treated with PMX-DHP. Two DI-ILD cases were caused by methotrexate, and the third case was caused by the herbal medicine sanmotsu-ogon-to. The arterial oxygen tension/inspiratory oxygen fraction ratio improved during PMX-DHP treatment in all 3 patients. Finally, 2 patients survived and 1 died. The study findings indicate that PMX-DHP treatment is a viable option for the management of acute respiratory failure in patients with DI-ILD. less...

Junayet, a nine years and six months old boy was admitted to the hospital because of back pain and vertebral compression fractures. The boy had been well until two months earlier, when he began to have back pain after falling on his back along with occasional fever. The pain was intermittent initially but gradually it became constant. One month before admission, he fell again and the back pain became deteriorated. He was mildly pale, liver was palpable, skin survey revealed normal, BCG scar mark was present. He had bone pain, cervical lymphadenopathy and a tender swelling on the lumbusacral region. Two weeks before admission, the hematological findings were suggestive of leukemia of lymphoblastic type. Biochemical values were normal except high level of serum lactate dehydrogenase (LDH). Cerebrospinal fluid (CSF) examination was free of malignant cell. Skeletal survey showed diffuse osteopenia of the thoracic and lumber spine with multiple compression fracture of the vertebral bodies of D7, D8, D12 and L1, L3 and L5 with increased disc space. Radiograph of the chest also showed diffuse osteopenia of ribs. Magnetic resonance (MRI) showed uniform signal intensity in the marrow throughout the spine with compressed fracture of the same vertebrae. Bone marrow morphology study and the cytochemistry of the aspirated marrow were consistent with acute lymphoblastic leukemia (ALL-L2). Then, he was started protocol based chemotherapy for induction of remission, consolidation, high dose methotrexate and maintenance therapy. Now, he is on regular follow up with repeated hematological and radiological examinations. Following six month of chemotherapy the boy was found with significant improvement of his physical, hematological and radiological abnormalities. less...

Fewer than 1 in 5 patients comply with the established follow-up protocol to treat presumed ectopic pregnancy medically in an urban clinic population. Institutions should consider tracking their patient compliance with follow-up to determine the efficacy of their treatment decisions. less...