Utility of GnRH-Agonists for Fertility Preservation in Women with Operable Breast Cancer: Is It Protective?

Breast cancer is the most common type of malignancy in reproductive-age women. Breast cancer chemotherapy is associated with premature ovarian failure, infertility, and negative psychosocial effects related to these reproductive changes. As a result of this, fertility preservation becomes highly critical in this group of women. Besides the fertility preservation methods that utilize assisted reproductive technologies such as embryo, oocyte, and ovarian tissue cryopreservation, another suggested strategy for fertility preservation is suppression of ovarian ovulatory function by gonadotropin-releasing hormone agonist (GnRHa) administration before and during chemotherapy. However, both the efficacy and safety of GnRH agonists for prevention of ovarian damage are unproven and the preponderance of evidence indicates that this is an ineffective strategy. This review details the most recent information and studies on this controversial topic.     

Combination of Doxazosin and Sildenafil Exerts an Additive Relaxing Effect Compared with Each Compound Alone on Human Cavernosal and Prostatic Tissue

IntroductionPhosphodiesterase 5 inhibitors (PDE5) such as sildenafil are first-line treatment for erectile dysfunction (ED). Alpha1 (α1)-adrenoceptor antagonists such as doxazosin are indicated for the treatment of patients with lower urinary tract symptoms (LUTS)/benign prostatic hyperplasia (BPH). ED and LUTS/BPH are conditions that are often associated. Accordingly, α1-adrenoceptor antagonists and PDE5 inhibitors will be often prescribed in real life setting together.AimTo evaluate the effects of the combination of sildenafil and doxazosin on human cavernosal and prostatic tissue.MethodsProstatic and erectile tissues were obtained from nine to 12 patients, respectively. Patients underwent cystoprostatectomy for infiltrating bladder cancer or penile surgery for penile implant, congenital curvature or Peyronie's disease.Main Outcome MeasuresIn organ baths, prostatic and cavernosal strips were submitted to either concentration-response curves (CRC) to phenylephrine (Phe) or norepinephrine (NE), respectively, in presence of vehicle, sildenafil (10^?6 M, 10^?5 M), doxazosin (10^?8 M, 3.10^?8 M, or 10^?7 M), or a combination of both. Continuous electrical field stimulation (EFS; 32 Hz, 5 ms, 5 seconds, 300 mA) was performed on prostatic strips which were incubated with sildenafil 10^?6 M or vehicle before the successive addition of doxazosin (10^?7 M, 10^?6 M) or vehicle. Cavernosal strips were pre-incubated with doxazosin (10^?9 M, 10^?8 M) or vehicle, then CRC to sildenafil were constructed on NE (3.10^?6 M) precontracted cavernosal strips.ResultsCombination of sildenafil and doxazosin exerted a greater relaxing effect on CRC to Phe or NE compared with each compound alone in both tissues. Sildenafil significantly enhanced the relaxing effect of doxazosin on EFS-induced contractions in prostatic strips. Doxazosin significantly increased the ability of sildenafil to inhibit NE-induced contractions in cavernosal strips.ConclusionsSildenafil and doxazosin reduced adrenergic tone of prostatic and cavernosal smooth muscle and their combination provided a significant benefit when targeting relaxation of both tissues. These experiments provide support for further clinical evaluation of the sildenafil and doxazosin combination in ED patients with LUTS/BPH. Oger S, Behr-Roussel D, Gorny D, Lecoz O, Lebret T, Denoux Y, Faix A, Leriche A, Wayman C, Alexandre L, and Giuliano F. Combination of doxazosin and sildenafil exerts an additive relaxing effect compared with each compound alone on human cavernosal and prostatic tissue. J Sex Med 2009;6:836–847.     

Angiotensin II-receptor antagonist in the treatment of hypertension

Effective treatment of high blood pressure levels represents a crucial point in reducing global cardiovascular risk, and several studies have clearly demonstrated a significant reduction in cardiovascular and renal morbidity and mortality with a more intensive blood pressure-lowering treatment. Other factors beyond blood pressure control may be important in reducing the risk related to hypertension. Pharmacologic agents blocking the renin-angiotensin system, in particular the angiotensin II-receptor blocker (ARB), a novel class of antihypertensive agents, represent an important addition to the therapeutic options for hypertension management, and recent large, international, randomized, trials have demonstrated that ARBs have clinical benefits across the spectrum of disease severity. In this article, we provide some evidence derived from these trials, supporting a role for ARBs in primary and secondary prevention of cardiovascular and renal disease, beyond blood pressure control.     

Predictors of cognitive improvement after reality orientation in Alzheimer's disease

BACKGROUND: there is increasing evidence to support the efficacy of reality orientation in cognitive deficits in patients with Alzheimer's disease. The clinical characteristics of patients who respond to reality orientation are poorly understood; this knowledge could be important, given that the provision of reality orientation therapy is labour-intensive and may provoke emotional distress. AIM: to evaluate retrospectively which demographic and clinical characteristics of Alzheimer's patients predict cognitive outcomes. METHOD: we analysed 38 mild-to-moderately demented outpatients who regularly attended a one-month formal reality orientation programme. The mini mental state examination score changes from baseline-and immediately after-reality orientation were correlated with demographic and pre-treatment clinical characteristics by a linear regression analysis. RESULTS: short-term responsiveness to reality orientation was significantly predicted by a lower level of cognitive functioning (as measured by the mini mental state examination) at baseline and by the absence of euphoria, accounting together for 57.6% of variance. CONCLUSION: a lower mini mental state examination and the absence of euphoric behaviour in patients with mild-to-moderate Alzheimer's disease may predict a good cognitive outcome of reality orientation therapy.     

Effectiveness of alendronate treatment in postmenopausal women with osteoporosis: relationship with BsmI vitamin D receptor genotypes

OBJECTIVE: To assess whether there is a relationship between the effectiveness of alendronate treatment in postmenopausal women with osteoporosis and BsmI vitamin D receptor (VDR) genotypes. DESIGN: Prospective baseline-controlled clinical trial. PATIENTS: Sixty-eight Italian osteoporotic women were enrolled and treated with alendronate at a dose of 10 mg/day for 12 months. MEASUREMENTS: At entry and after treatment, lumbar bone mineral density (BMD) and serum osteocalcin (OC) and urinary deoxypyridinoline/creatinine ratio (DPD-Cr) levels were evaluated. DNA was extracted from blood and analysed for the BsmI polymorphism of the VDR gene. RESULTS: The mean percentage (% +/- SD) change from baseline in lumbar BMD was significantly higher (P < 0.01) in bb than in BB BsmI VDR genotypes (7.92 +/- 4.31 vs. 3.40 +/- 1.81). No significant difference in lumbar BMD was observed in Bb VDR patients (6.01 +/- 3.89) in comparison with other groups. The mean percentage of change in serum OC and urinary DPD-Cr levels was significantly (P < 0.01) lower in individuals with bb than in those with BB BsmI VDR genotypes (-14.34 +/- 2.87 vs.-10.39 +/- 1.43 and -9.61 +/- 5.56 vs.-4.61 +/- 2.31). No significant difference in serum OC and urinary DPD-Cr levels was observed in Bb VDR patients (-12.31 +/- 2.11 and -6.52 +/- 2.65) in comparison with other groups. CONCLUSION: The different BsmI vitamin D receptor genotypes modify the pharmacological response to alendronate treatment in postmenopausal women with osteoporosis.     

Radioiodine treatment with 30 mCi after recombinant human thyrotropin stimulation in thyroid cancer: effectiveness for postsurgical remnants ablation and possible role of iodine content in L-thyroxine in the outcome of ablation

The main steps in the management of differentiated thyroid cancer are thyroidectomy, treatment with iodine-131 ((131)I), and follow-up with whole-body scanning (WBS) and serum thyroglobulin (Tg) determination. Both (131)I treatment and follow-up require maximum stimulation of normal or pathological thyroid remnants by TSH. The use of recombinant human TSH (rhTSH) has been shown to be useful for follow-up, whereas previous reports are not univocal regarding the use of (131)I postsurgical ablation of thyroid remnants, at least when low doses (30 mCi) of (131)I are administered. A possible explanation for the diminished effectiveness of (131)I treatment after rhTSH may be the interference of iodine content of L-thyroxine (L-T4) therapy during the protocol of administration of rhTSH. We have evaluated the effectiveness of stimulation by rhTSH for radioiodine ablation of postsurgical remnants, stopping L-T4 the day before the first injection of rhTSH and restarting L-T4 the day after (131)I. The study included two groups of patients: group 1 included 16 patients with differentiated thyroid cancer (15 papillary cancers and 1 follicular cancer, stages I and II), who were treated with 30 mCi (131)I with the aid of rhTSH, using the standard protocol but stopping L-T4 as stated previously; and group 2 included 24 patients with the same features (histology and stage) of disease treated with 30 mCi in the hypothyroid state after L-T4 withdrawal. In both groups, serum TSH reached a very good stimulation level [76-210 U/liter (mean, 112 +/- 11 SE) and 38-82 U/liter (mean, 51 +/- 3 SE), respectively]. At the first WBS (after (131)I treatment), all patients showed thyroid remnants. Furthermore, two patients of the first group and three patients of the second group showed lymph node metastases. After 1 yr, all patients were studied again and underwent WBS with a tracer dose of (131)I and serum Tg measurement using rhTSH with the same protocol in both groups. The percentage of ablation (undetectable Tg and a negative WBS) was higher, although not reaching statistical significance, in patients treated with rhTSH: 81.2% in patients treated by rhTSH withdrawal and 75.0% in patients treated by L-T4 withdrawal, respectively. No patient experienced symptoms of hypothyroidism during the 4 d of L-T4 interruption, and serum T4 remained in the normal range. Urinary iodine was analyzed in both groups and compared with a control group of patients who received, for diagnostic purposes, rhTSH without stopping L-T4. In the first group, urinary iodine was 47.2 +/- 4.0 microg/liter (mean +/- SE; P = 0.21 vs. the second group, P = 0.019 vs. control group). In the second group, urinary iodine was 38.6 +/- 4.0 microg/liter (mean +/- SE; P < 0.001 vs. control group); urinary iodine in the control group was 76.4 +/- 9.3 microg/liter (mean +/- SE). Our data show that rhTSH, as administered in the protocol stated previously, allows at least the same rate of ablation of thyroid remnants when low doses (30 mCi) of (131)I are used. The possible role of interference of iodine content in L-T4 is not surprising if we consider that the amount of iodine in 30 mCi is negligible (5 microg) compared with the amount of iodine content in a daily dose of T(4) ( approximately 50 microg). The cost of rhTSH seems modest compared with the high cost of complex therapeutic regimens in other areas of oncology and in consideration of the well-being of patients and of the high level of effectiveness of the treatment.     

Mutations of the Imprinted CDKN1C Gene as a Cause of the Overgrowth Beckwith–Wiedemann Syndrome: Clinical Spectrum and Functional Characterization

Beckwith–Wiedemann syndrome (BWS) is an imprinting disorder associating macroglossia, abdominal wall defects, visceromegaly, and a high risk of childhood tumor. Molecular anomalies are mostly epigenetic; however, mutations of CDKN1C are implicated in 8% of cases, including both sporadic and familial forms. We aimed to describe the phenotype of BWS patients with CDKN1C mutations and develop a functional test for CDKN1C mutations. For each propositus, we sequenced the three exons and intron–exon boundaries of CDKN1C in patients presenting a BWS phenotype, including abdominal wall defects, without 11p15 methylation defects. We developed a functional test based on flow cytometry. We identified 37 mutations in 38 pedigrees (50 patients and seven fetuses). Analysis of parental samples when available showed that all mutations tested but one was inherited from the mother. The four missense mutations led to a less severe phenotype (lower frequency of exomphalos) than the other 33 mutations. The following four tumors occurred: one neuroblastoma, one ganglioneuroblastoma, one melanoma, and one acute lymphoid leukemia. Cases of BWS caused by CDKN1C mutations are not rare. CDKN1C sequencing should be performed for BWS patients presenting with abdominal wall defects or cleft palate without 11p15 methylation defects or body asymmetry, or in familial cases of BWS.