Medicinal chemistry advances in targeting class I histone deacetylases.

Histone deacetylases (HDACs) are a class of zinc (Zn)-dependent metalloenzymes that are responsible for epigenetic modifications. HDACs are largely associated with histone proteins that regulate gene expression at the DNA level. This tight regulation is controlled by acetylation [via histone acetyl transferases (HATs)] and deacetylation (via HDACs) of histone and non-histone proteins that alter the coiling state of DNA, thus impacting gene expression as a downstream effect. For the last two decades, HDACs have been studied extensively and indicated in a range of diseases where HDAC dysregulation has been strongly correlated with disease emergence and progression-most prominently, cancer, neurodegenerative diseases, HIV, and inflammatory diseases. The involvement of HDACs as regulators in these biochemical pathways established them as an attractive therapeutic target. This review summarizes the drug development efforts exerted to create HDAC inhibitors (HDACis), specifically class I HDACs, with a focus on the medicinal chemistry, structural design, and pharmacology aspects of these inhibitors.

Maintaining professional activity during breast cancer treatment.

The question of returning to work and pursuing professional activity during cancer treatment is an increasingly important consideration. The present work focuses on factors affecting the feasibility of maintaining professional activity during treatment for breast cancer, for women who wished to do so. Written questionnaires were collected from 216 patients between March and November 2012. Since the onset of their treatment, 31.4% of the women (68/216) had not been on sick-leave. The main factors associated with the pursuit of professional activity were: considering the availability of their physician to answer questions as unimportant [OR = 18.83 (3.60-98.53); P ≤ 0.05]; considering the diagnosis of cancer as likely to have a weak impact on career perspectives [OR = 4.07 (2.49-6.64); P ≤ 0.05]; not having any children in the household [OR = 3.87 (2.38-6.28); P ≤ 0.05]; being in a managerial position [OR = 3.13 (1.88-5.21); P ≤ 0.05]. Negative predictive factors were: physician mentioning adverse effects of the treatment [OR = 0.31 (0.16-0.58); P ≤ 0.05], and patient rating workload as high [OR = 0.26 (0.15-0.46); P ≤ 0.05]. As a result of advances in therapeutic strategies, more patients will expect healthcare professionals, as well as employers and occupational health societies, to prioritise issues pertaining to the maintenance of professional activities during cancer treatment.

[Clonal eosinophilia revealed by recurrent Staphylococcus aureus infection]. / Hyperéosinophilie clonale révélée par une infection récurrente à Staphylococcus aureus.

Acquired eosinophilia is currently classified into secondary (reactional to underlying diseases), clonal (presence of a bone marrow histological, cytogenetic or molecular marker of a myeloid malignancy) and idiopathic (neither secondary nor clonal) categories. We report the case of a 47-year-old male who was admitted to the hospital for Staphylococcus aureus recurring infections. An hypereosinophilia was discovered and led to molecular analysis. The identification of FIP1L1-PDGFRA fusion gene permitted the diagnostic of clonal eosinophilia. Treatment by imatinib mesylate induced an haematological remission, the control of the infection and thoracotomy cicatrization. This case is original because of its infectious presentation and the efficacy of imatinib mesylate to control the infectious process.

Phase II study of UFT with leucovorin and irinotecan (TEGAFIRI): first-line therapy for metastatic colorectal cancer.

This phase II trial was performed to evaluate the efficacy and tolerability of oral tegafur-uracil (UFT) with leucovorin (LV) combined with intravenous (i.v.) irinotecan every 3 weeks (TEGAFIRI) as first-line treatment for patients with metastatic colorectal cancer (mCRC). Patients received oral UFT 250 mg m(-2) day(-1) and LV 90 mg day(-1) in three divided daily doses for 14 days followed by a 1-week rest and i.v. irinotecan 250 mg m(-2) as a 90-min infusion every 3 weeks. Tumour responses, assessed every two cycles using RECIST criteria, were reviewed by an independent review committee. In 52 evaluable patients, the best overall response rate was 33% (95% confidence intervals (CI) 20-47%; 1 complete and 16 partial responses). The median time to progression was 5.4 months (95% CI 3.02-7.52 months) and median overall survival was 14.9 months (11.73-17.97 months). A total of 307 cycles were administered, with a median number of five cycles per patient (range: 1-10). The most common grade 3/4 toxicities were neutropenia (25% of patients), diarrhoea (22%), vomiting (11%) and anaemia (11%). The TEGAFIRI regimen is a feasible, well-tolerated and convenient treatment option for patients with non-resectable mCRC.

[Sarcoma of the spermatic cord. Report of 2 cases. Review of the literature]. / Sarcomes du cordon spermatique. Rapport de 2 cas. Revue de la littérature.

Illustrated by a case of rapidly fatal rhabdomyosarcoma in a child and a leiomyosarcoma in an adult, the authors differentiate the various histological types of sarcomas affecting the spermatic cord. Based on a review of the literature, they stress the great variety and various clinical courses related to the histological type. The predominant role of the histologist is stressed. The most widely used classifications are reviewed, leading to treatments in which primary surgery should be as complete as possible and combined with lymph node dissection or radiotherapy and chemotherapy. At the present time, the use of chemotherapy appears to be the decisive step in the improvement of the survival rates. The lymphophilic nature of rhabdomyosarcomas, which are embryonal in 95% of cases in children, can be schematically contrasted with the haematogenous nature of other sarcomas. The current approach to sarcomas of the spermatic cord, a minor site in comparison with the frequency of other soft tissue sarcomas, consists of an aggressive multidisciplinary treatment.

Interim report of phase II study of new nitrosourea S 10036 in disseminated malignant melanoma.

Thirty-three patients with disseminated malignant melanoma were entered in a phase II study of the new nitrosourea S 10036 using a 100-mg/m2 weekly induction schedule for 3-4 consecutive weeks. Patients who responded to this treatment were followed with a maintenance therapy every 3 weeks. Toxic effects were mainly hematological and consisted of delayed thrombocytopenia and leukopenia. Among 30 patients who could be evaluated, eight partial responses were observed (response rate, 26.67%); among seven patients with cerebral metastasis, two partial responses were observed. This multicentric study is currently being continued to confirm this interim report.

[Breast cancer induced by estrogens in a prostate cancer patient]. / Cancer du sein induit par les oestrogènes chez un cancéreux prostatique.

The authors report a case of malignant breast tumour induced by oestrogens in a patient treated for 7 years for carcinoma of the prostate. They review the literature on the subject and stress the important diagnostic and prognostic role of hormonal receptor assays. These allow the much more numerous cases of mammary metastases of prostatic cancer to be distinguished and, in cases of primary malignant tumour, they permit the choice of the best possible hormone therapy available.

[Apparently primary malignant secreting renal lymphoma (immunocytoma)]. / Lymphome malin sécrétant (immunocytome) rénal d'apparence primitive.

The authors report a case of renal lymphoma which secreted a monoclonal Ig M kappa immunoglobulin (immunocytoma) and which was diagnosed on the basis of its secretion. They analyse the problems posed by the indication for surgery, the histological nature, the management and the prognosis.