Luteinising hormone-releasing hormone antagonists in prostate cancer therapy

The introduction of androgen blockade therapy using luteinising hormone-releasing hormone (LHRH)/gonadotropin-releasing hormone analogues alone or in combination with non-steroidal antiandrogens has a major impact in both survival and quality of life of patients with locally advanced and metastatic prostate cancer. The effect of LHRH agonists is based on the continuous binding to the LHRH receptor (LHRH-R) on the gonadotrope cells of the pituitary, which although initially stimulate LH release, consequently downregulates the LHRH-R, thereby suppressing serum LH, testosterone levels and 5alpha-dihydrotestosterone levels. Because this initial surge of LH and testosterone can cause adverse consequences in these patients (the so-called flare-up symptoms), immediate inhibition of LH release and testosterone production is desirable and this can be achieved with the use of the LHRH antagonists. In addition, there exist data to support a direct anticancer effect of LHRH antagonists on prostate cancer cells. This review summarises the potential clinical use of the LHRH antagonists in prostate cancer patients.     

Is the screening for celiac disease useful in anorexia nervosa?

The main objective of the study was to prospectively assess if the prevalence of celiac disease (CD) in patients with anorexia nervosa (AN) is higher than that reported in the general population to require a regular screening program. The study was conducted at the Neuropsychiatry Unit of “Bambino Gesù” Children’s Hospital in Rome from January 2005 to December 2010. All patients with diagnosis of AN according to the Diagnostic and Statistical Manual of Mental Disorders 4th edition criteria were screened for CD. One hundred and seventy-seven patients (33 males and 144 females) were enrolled. Only one patient was found to be affected with CD as confirmed by intestinal biopsy. The overall prevalence of CD in AN patients was 0.6 % which is similar to that observed in the general population. In conclusion, AN patients do not seem to require a regular screening program for CD. The screening for CD may be useful in selected AN patients in which the symptoms are only partially responding to psychiatric interventions.     

Mechanistic associations of a mild phenotype of immunodysregulation, polyendocrinopathy, enteropathy, x-linked syndrome.

BACKGROUND & AIMS: The syndrome of immunodysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) is a rare disorder resulting in the expression of multiple autoimmune and allergic features. Early onset enteropathy and type 1 diabetes (T1D) are the most common clinical features. The IPEX syndrome is caused by mutations of the FOXP3 gene, which is essential for the development of regulatory T cells (Treg). We describe 2 unrelated patients with IPEX syndrome with a mild clinical phenotype and with novel FOXP3 mutations and the phenotypic and functional characterization of their Treg cells. METHODS: The FOXP3 gene was analyzed by sequencing amplimers from genomic DNA. Treg cells were characterized by evaluating the number of CD4+CD25+ T cells and their functional ability to suppress the proliferation of autologous CD4+CD25- effector T cells stimulated with anti-CD3 and anti-CD28 antibodies. RESULTS: A 7-year-old boy and a 24-year-old man presented with autoimmune enteropathy characterized by early onset persistent diarrhea not associated with T1D or other endocrinopathies. These 2 patients carry novel FOXP3 mutations that do not abrogate the function of the forkhead domain. They have normal numbers of CD4+CD25+ T lymphocytes, however, these show severely defective suppressive function in vitro. CONCLUSIONS: Our 2 patients show that IPEX patients may present with early onset enteropathy and long-term survival without T1D or other endocrinopathies. This milder phenotype may be associated with FOXP3 mutations that do not abrogate the function of the forkhead domain.     

Clinical accuracy of anti-tissue transglutaminase as screening test for celiac disease under 2 years

Aim: To investigate, in patients with suspected celiac disease (CD) younger than 2 years, the clinical value of anti‐tissue transglutaminase (tTG) in diagnostic work‐up of CD. Methods: Between June 2005 and June 2009, 169 patients aged <2 years, with symptoms suggestive of CD, were submitted to biopsy. CD diagnosis was based on the revised criteria of the European Society for Pediatric Gastroenterology, Hepatology and Nutrition. Results: Of the 169 patients enrolled, 155 were included: 108 of them showed mucosal atrophy and 47 negative histology. Sensitivity and specificity of tTG, at the cut‐off of 8 AU/mL, were 0.96 (CI 0.91–0.99) and 0.91 (CI 0.80–0.98), respectively, with likelihood ratio (LR) of 11.31; at the cut‐off of 16 AU/mL, they were 0.79 (CI 0.70–0.86) and 1.00, respectively (CI 0.92–1.00), with LR 4.50. Conclusions: In patients younger than 2 years, suspected for CD, tTG is very valuable in selecting for small intestinal biopsy.     

Prevalence of life-threatening complications in pediatric patients affected by intestinal failure

Intestinal failure (IF) is defined as the reduction of functional gut mass necessary to maintain health and growth in children. Causes of IF include short bowel syndrome (SBS), neuromuscular intestinal disorders (NID), and severe protracted diarrhea (SPD). If patients require long-term parenteral nutrition (PN); they can now be discharged on home PN (HPN), thus improving their quality of life. Children requiring long-term PN are at high risk of developing life-threatening IF complications that hinder HPN, namely, IF associated liver disease (IFALD), catheter-related infections (CRI), and thrombosis. The goal of our study was to retrospectively evaluate the prevalence of life-threatening complications among IF patients according to the HPN indication. From January 1989 to May 2006, 60 IF patients (41 boys and 19 girls) underwent prolonged HPN. Total program duration was 46,391 days (127 total years, mean 2.1 years per patient). Indications for HPN were SBS in 36 cases, SPD in 19 cases, or NID in 5 cases. In our experience patients affected by SBS displayed a significantly higher prevalence of life-threatening complications than patients with other IF causes. Sixteen (27%) among 60 patients developed IFALD. CRI and thrombosis prevalence were 1.4/1000 central venous catheter (CVC) days and 0.2/1000 CVC days respectively. SBS seemed to lead to life-threatening complications more often than other HPN indications. SBS patients on long-term PN therefore require careful management to identify complications early, and they seem to be the candidates for early referral to small bowel transplantation centers.     

B cell modulation strategies in autoimmunity: the SLE example

The paradigm that T cells are the prime effectors of autoimmune diseases has been recently challenged by growing evidence that B-lymphocytes play a role in the development, re-activation and persistence of autoimmune disorders. B-cells of different subsets may play different roles in autoimmune pathologies due to their ability to secrete antibodies, produce cytokines, present antigen and form ectopic germinal centers. Thus, a given therapeutic approach or drug may have distinct outcomes depending on which specific B cell subset is targeted. Immunosuppressive therapies such as azathioprine (AZA), cyclophosphamide (CyC) or methotrexate (MTX) are conventionally used in autoimmune diseases with the aim of reducing disease activity and improving the patient's general health conditions. These treatments do not target a specific cellular type or subset and have substantial side effects, such as impairment of liver function and fertility. Moreover, autoimmune patients may be refractory to immunosuppressive therapy. In these cases finding an effective treatment becomes a challenge. The fast evolution in antibody technology is leading to the production of a wide array of humanized monoclonal antibodies, targeting specific cell types or pathways, initiating a new era in the treatment of autoimmune disorders. In addition, the recent discovery that toll like receptors (TLRs) activation can fire up autoimmunity in humans and maintain disease gives the grounds for the development of new drugs targeting the TLR/MyD88 pathway. In contrast to conventional immune-suppression, the availability of drugs interfering with B-cell specific pathogenetic pathways gives the possibility to choose therapies tailored to each disease and, possibly, to each patient.