Primary hypertrophic osteoarthropathy (PHO), or pachydermoperiostosis, is characterized by a clinical association including digital clubbing, periostosis and pachydermia. SLCO2A1 and HPGD genes are both responsible for PHO. The pathology is classically defined as an autosomal recessive disorder with clinical variability ranging from a mild to more severe phenotype. However, the hypothesis for an autosomal dominant form suggested for a long time was only demonstrated for the first time in 2021 for SLCO2A1. We aimed to detect a second pathogenic variant by a deep sequencing of the entire SLCO2A1 and HPGD genes, associated with functional transcription analysis in PHO patients harboring only one heterozygous variant. Among 10 PHO patients, 4 presented a single pathogenic or probably pathogenic novel variant in SLCO2A1 in heterozygous status (NM_005630.3: c.234+1G > A, c.1523_1524delCT, c.1625G > A and c.31delC), and the others carried homozygous pathogenic variants. For heterozygous forms, we found no additional pathogenic variant in HPGD or SLCO2A1. PHO can be a dominant form with age at disease onset later than that for the recessive form. This dominant form is not exceptional in young adults. In conclusion, both modes of inheritance of PHO explain the clinical variability and the difference in age at disease onset. Molecular analysis is especially required in the incomplete form to distinguish it from secondary hypertrophic osteoarthropathy.

Diffuse large B cell lymphoma (DLBCL) is a heterogeneous disease treated with anti-CD20-based immuno-chemotherapy (R-CHOP). We identified that low levels of GAPDH predict a poor response to R-CHOP treatment. Importantly, we demonstrated that GAPDH(low) lymphomas use OxPhos metabolism and rely on mTORC1 signaling and glutaminolysis. Consistently, disruptors of OxPhos metabolism(phenformin) or glutaminolysis (L-asparaginase) induce cytotoxic responses in GAPDH(low) B cells and improve GAPDH(low) B cell-lymphoma-bearing mice survival, while they are low or not efficient on GAPDH(high) B cell lymphomas. Ultimately, we selected four GAPDH(low) DLBCL patients, who were refractory to all anti-CD20-based therapies, and targeted DLBCL metabolism-using L-asparaginase (K), mTOR inhibitor (T), and metformin (M) (called KTM therapy). Three out of the four patients presented a complete response upon one cycle of KTM. These findings establish that the GAPDH expression level predicts DLBCL patients' response to R-CHOP treatment and their sensitivity to specific metabolic inhibitors.

Caloric restriction (CR) is proposed to decrease tumorigenesis through a variety of mechanisms including effects on glycolysis. However, the understanding of how CR affects the response to cancer therapy is still rudimentary. Here, using the Eµ-Myc transgenic mouse model of B-cell lymphoma, we report that by reducing protein translation, CR can reduce expression of the prosurvival Bcl-2 family member Mcl-1 and sensitize lymphomas to ABT-737-induced death in vivo. By using Eµ-Myc lymphoma cells lacking p53, we showed that CR mimetics such as 2-deoxyglucose led to a decrease in Mcl-1 expression and sensitized lymphoma cells to ABT-737-induced death independently of p53. In keeping with this, Eµ-Myc lymphoma cells lacking the BH3-only proapoptotic members Noxa, Puma, or Bim were also sensitized by CR mimetics to ABT-737-induced death. Remarkably, neither the loss of both Puma and Noxa, the loss of both Puma and Bim, nor the loss of all three BH3-only proteins prevented sensitization to ABT-737 induced by CR mimetics. Thus, CR can influence Mcl-1 expression and sensitize cells to BH3 mimetic-induced apoptosis, independently of the main BH3-only proteins and of p53. Exploiting this may improve the efficiency of, or prevent resistance to, cancer therapy.

Objective TNF-alpha antagonists have changed the outcome of various chronic inflammatory diseases. Their use has spread widely and many patients receive those treatments for years. Previous reports found that the use of TNF-alpha antagonists may be associated with an increased risk of serious bacterial infections. We report 47 prospective bacteremia cases from the RATIO registry. Methods A national prospective study was conducted in France between 2004 and 2007 to collect severe bacterial infections in patients receiving TNF-alpha antagonists. All reported cases of bacteremia were validated by an expert committee. Results Forty-seven bacteremic episodes were reported. Staphylococcus aureus represented the most frequent causative pathogen (40%) and was mostly associated with bones and/or joints infections (68%) and with a worse outcome compared to that observed with other bacterial pathogens. Conclusions Patients receiving TNF-alpha antagonists may develop bacteremia and S. aureus has to be included in the spectrum of the initial empiric antimicrobial therapy.

Objective. To evaluate the response to treatment in a large cohort of patients with systemic lupus erythematosus (SLE) associated with autoimmune thrombocytopenia.Methods. Response to treatment was assessed retrospectively in 59 patients with SLE, either definite (n = 44) or incomplete (n = 15), associated with frank autoimmune thrombocytopenia (defined as platelet count < 50 x 10(9)/l). Response to treatment was classified as complete (CR: platelet count > 150 x 10(9)/l), partial (PR: platelet count > 50 x 10(9)/l), or failure (FR) in the other cases.Results. Oral prednisone alone was used in 50 of the 59 patients (mean initial dose 1 mg/kg body weight/day). A response was obtained in 80% of cases (CR in 28, PR in 12) but only 11 (22%) had a sustained response (CR, n = 7; PR, n = 4). In contrast, combined treatment with prednisone and either danazol (n = 18) or hydroxychloroquine (n = 11) resulted in 50% (7 CR, 2 PR) and 64% (4 CR, 3 PR) longterm responses, respectively, allowing prednisone to be withdrawn or the dose tapered below 0.2 mg/kg body weight/day. High dose methylprednisolone pulses (n = 10) and intravenous immunoglobulin (IVIG) (n = 31) resulted in positive responses in 60% (4 CR, 2 PR) and 65% (12 CR, 8 PR) of cases, respectively, but the response was transient in each case. Splenectomy (n = 17) resulted in 65% longterm responses (10 CR, I PR). Only 2 longterm partial responses, were obtained with the 22 immunosuppressant-containing regimens administered to 14 patients. At the end of the study, a response was observed in 52 (88%) patients [CR: 36 (61%), PR: 16 (27%)], mainly as a result of splenectomy or combined treatment with prednisone and either danazol or hydroxychloroquine.Conclusion. Longterm remission was obtained in the majority of patients. The major treatments inducing remission were splenectomy and prednisone combined with danazol or hydroxychloroquine.

INTRODUCTION:The antiphospholipid syndrome includes recurrent thrombotic manifestations related to antiphospholipid antibodies. Adrenal insufficiency is a rare complication of the antiphospholipid syndrome.EXEGESIS:We report a case of acute adrenal insufficiency secondary to bilateral adrenal hemorrhage in a 45-year-old man. The finding of antiphospholipid antibodies and 6 months later of a polymetastatic bronchopulmonary cancer led us to diagnose a paraneoplasic antiphospholipid syndrome.CONCLUSION:We discuss the role of coagulation disorders in the pathogenesis of tumor growth and rapid metastatic spread. Assessment of the high risk for thrombosis may be of prognostic and therapeutic value in patients with evolutive bronchopulmonary cancer. Early anticoagulation treatment in association with classical treatment of cancer may contribute to prevent malignant process from extending and avoid metastatic spread.

Introduction. - The antiphospholipid syndrome includes recurrent thrombotic manifestations related to antiphospholipid antibodies. Adrenal insufficiency is a rare complication of the antiphospholipid syndrome. Exegesis. - We report a case of acute adrenal insufficiency secondary to bilateral adrenal hemorrhage in a 45-year-old man. The finding of antiphospholipid antibodies and 6 months later of a polymetastatic bronchopulmonary cancer led us to diagnose a paraneoplasic antiphospholipid syndrome. Conclusion, - We discuss the role of coagulation disorders in the pathogenesis of tumor growth and rapid metastatic spread. Assessment of the high risk for thrombosis may be of prognostic and therapeutic value in patients with evolutive bronchopulmonary cancer. Early anticoagulation treatment in association with classical treatment gf cancer may contribute to prevent malignant process from extending and avoid metastatic spread. (C) 1999 Elsevier, Paris.

Cancer and HIV infection: As the HIV epidemic advances, the spectrum of non-AIDS defining malignancy is expanding, Recent reports suggest an increased incidence of skin cancers, squamous cell carcinomas of the anus, and Hodgkin's disease in HIV-infected patients. Other neoplasms encountered in this setting include oral mucosa, head and neck carcinoma without evidence of increased incidence. Particular features: The natural history of lung, testicle and skin cancer (excepting Kaposi sarcoma) as well as ENT cancer appears to be modified in HIV-infected patients, The main problem raised by these tumors is confounding infection which may lead to late diagnosis or an error in tumor staging.

La leucémie à tricholeucocytes est un syndrome lymphoprolifératif de phénotype B rare. Elle survient habituellement chez les hommes de plus de 50 ans. Jusqu'en 1984, les moyens thérapeutiques étaient très décevants et la plupart des patients décédaient des complications liées à la cytopénie. L'introduction de l'interféron et plus récemment des analogues des bases puriques (pentostatine et 2-chlorodéoxyadénosine) a transformé le pronostic de cette affection. Néanmoins, si des rémissions complètes sont quelquefois obtenues par l'interféron et de façon plus fréquente grâce aux analogues des bases puriques, aucun de ces traitements ne semble faire disparaître complètement les tricholeucocytes. Il convient donc de traiter ces patients souvent âgés en fonction des effets secondaires de ces médicaments et de leurs bénéfices attendus.Hairy cell leukemia is a rare lymphoproliferative B disorder. It usually occurs in men older than 50 years. Until 1984, therapeutic approaches had been disappointing and most of the patients died from complications of cytopenia. The introduction of Interferon and, more recently of purine analogues (pentostatin and 2-chlorodeoxyadenosine) improved outcome of this disease. Nevertheless, if complete remissions may be achieved sometimes with Interferon and more frequently with purine analogues, none of these treatments seems able to remove hairy cells. So, therapeutic decision has to be made according to the efficacy and the potential adverse effects of these drugs.

CANCER AND HIV INFECTION: As the HIV epidemic advances, the spectrum of non-AIDS defining malignancy is expanding. Recent reports suggest an increased incidence of skin cancers, squamous cell carcinomas of the anus, and Hodgkin's disease in HIV-infected patients. Other neoplasms encountered in this setting include oral mucosa, head and neck carcinoma without evidence of increased incidence. PARTICULAR FEATURES: The natural history of lung, testicle and skin cancer (excepting Kaposi sarcoma) as well as ENT cancer appears to be modified in HIV-infected patients. The main problem raised by these tumors is confounding infection which may lead to late diagnosis or an error in tumor staging.

The tyrosine kinase family includes growth factor receptor and cytoplasmic enzymes. It plays a key role in normal cell division and abnormal cell proliferation and differentiation. The most common tyrosine kinases are the epidermal-growth factor (EGFR) and platelet-derived growth factor (PDGF) receptors, and a chromosome Philadelphia product, the Bcr-abl oncogene. Many studies have attempted to correlate clinical evolution of tumors with tyrosine kinase expression. However, clinical application of these new pronostic factors has not yet been demonstrated. More recently, tyrosine-phosphorylation inhibitors (tyrphostin) have been developed in phase I studies. Results that were obtained show some objective responses in patients with glioblastoma and polymetastic cancer. Another approach to block tyrosine kinase expression is the use of monoclonal antibodies. Trials using such antibodies have shown interesting preliminary results. (C) 1998, Elsevier, Paris.