Pharmacotherapy of hormone refractory prostate cancer: new developments and challenges

Hormone refractory prostate cancer (HRPC) remains a challenge in the management of prostate cancer patients. With the widespread use of PSA (prostate specific antigen), recurrent disease after local treatment for localised prostate cancer is usually diagnosed long before evidence of metastatic disease. In many cases, hormonal manipulations are started at the time of biochemical relapse and therefore, patients become 'hormone refractory' earlier in the course of their disease, frequently with a good performance status, often with no evidence of metastatic disease, and they still face a considerably long life expectancy. Despite these changes, the need for more options in the treatment of HRPC is obvious. The pharmacological treatments that are in use and those that are under investigation for this group of patients will be discussed and include: cytotoxic agents including the microtubule inhibitors, alone and in combination with other conventional or experimental therapies such as calcitriol or thalidomide; treatment with epothilone analogues; endothelin receptor antagonists; palliative therapy with bisphosphonates, bone-targeted radiopharmaceuticals and other developing treatments such as vaccines, gene therapies and monoclonal antibodies.     

Epidermolysis bullosa simplex in Israel: clinical and genetic features

BACKGROUND: Epidermolysis bullosa simplex (EBS) is the most common form of epidermolysis bullosa. The disease is characterized by intraepidermal blistering due in most cases to mutations in cytokeratin genes 5 (K5) or 14 (K14). Extensive studies in the United States and Europe have shown that EBS is almost always inherited in an autosomal dominant fashion. OBJECTIVE: To assess the possibility that the molecular features of EBS may differ according to the type of population studied. DESIGN: We assessed 10 Israeli families diagnosed as having EBS and compared their clinical and genetic features with previous observations. Affected individuals underwent complete clinical evaluation. DNA from all family members was assessed for mutations in K5 or K14 using polymerase chain reaction amplification, direct sequencing, and subsequent mutation verification. In addition, specific cases were genotyped using a panel of microsatellite markers spanning the K14 locus. RESULTS: Eight distinct pathogenic mutations in K5 (3 mutations) and K14 (5 mutations) were identified. Six of these mutations are novel. The mutations included 2 nonsense mutations and 6 missense mutations. A third of the affected families inherited EBS in a recessive fashion, in contrast with previous observations in Europe and the United States. In addition, we identified a unique case that resulted from compound heterozygosity for a missense and a nonsense mutation in K14. Homozygous nonsense mutations were strongly associated with a severe phenotype. CONCLUSION: The present study demonstrates a unique mutation spectrum and a strikingly different pattern of inheritance for EBS in a series of Israeli families compared with families of European or US extraction.     

Extrapancreatic autoimmune manifestations in type 1 diabetes patients and their first-degree relatives: a multicenter study

OBJECTIVE: To investigate the prevalence of autoimmune diseases in young patients (probands) with type 1 diabetes and their first-degree relatives, and to determine the spectrum of extrapancreatic manifestations in these subjects. RESEARCH DESIGN AND METHODS: The study population included 109 probands age 13 +/- 4.9 years and 412 first-degree relatives age 28.7 +/- 16.2 years. The prevalence rates of autoimmune thyroiditis and celiac disease were determined in all probands and in 100 of the 412 first-degree relatives. Control groups included 78 subjects age 14.9 +/- 10.4 years for the prevalence of autoimmune thyroiditis and 120,000 youth ages 16-17 years for the prevalence of celiac disease. Thyroiditis and celiac disease were diagnosed by abnormally high thyroid peroxidase (TPO), thyroglobulin (TG), antigliadin, and antiendomysial antibody titers. Celiac was confirmed by biopsy. A questionnaire was used to interview probands and relatives to determine the spectrum of autoimmune manifestations. RESULTS: The prevalence of autoimmune thyroiditis determined by high TPO and/or TG titers was 27 and 25% for probands and relatives, respectively. These rates were higher than those for control subjects (P < 000.1). The prevalence of celiac disease among probands and screened relatives was 8.3 and 6%, respectively. These rates were higher than those for control subjects and the 312 family members interviewed only (0.1 and 0.3%, respectively; P < 0.0001). Interviews of participants revealed a wide range of associated autoimmune diseases. The risk of developing an autoimmune disease was higher (P < 0.001) in families with a proband who had an additional autoimmune manifestation. CONCLUSIONS: Screening for autoimmune thyroiditis and celiac disease should be performed in patients with type 1 diabetes and their first-degree relatives, especially when the probands have an additional autoimmune manifestation.     

Effect of modern pacing algorithms on generator longevity: a predictive analysis

Pulse generator (PG) longevity is of major importance to the quality of care of pacemaker patients. A series of automatic algorithms affect PG longevity. This study investigated the individual and combined effects of three algorithms incorporated in the Medtronic Kappa 700 pacemaker series: Capture Management periodically measures the stimulation threshold and adjusts the PG output, Sinus Preference allows the sinus rate to prevail in a specified range below the sensor rate, and Search AV allows an extension of the AV interval if spontaneous conduction is observed. The effects of Capture Management, Sinus Preference, and Search AV on device longevity were studied in 21 consecutive patients treated in the VDD and DDDR modes. Patients were followed for 1 year. The data were analyzed using an equation provided by the manufacturer. Capture Management was activated in 20 patients. For 11 PGs at the basic settings, longevity was extended by 5.2%, whereas reprogrammed PGs had no gain. Sinus Preference was active in four DDDR patients, who gained 12.0 +/- 5.3%atrial sensing from it, with a resultant longevity gain of1.4 +/- 0.45 months(NS). Search AV was active in 19 patients and 8 responders gained 7.8 +/- 4.4 months PG longevity. The overall longevity in this study was 106.3 +/- 8.4 months with all features as programmed, whereas the longevity without Capture Management and Search AV algorithms would be 98.2 +/- 4.9 months, saving 8.1 +/- 5.8 months(range 0-18) of battery life. Thus, two algorithms: Capture Management and Search AV, have clinical relevance in the extension of PG longevity.