Cyclic Cushing's syndrome: an overview

Cyclic Cushing's syndrome (CS) is a disorder in which glucocorticoid levels are alternately normal and high, the latter occurring in episodes that can last from a few days to several months. It is more common in children than in adults. Cyclic CS may be either of the two different forms of CS (ACTH-dependent or -independent CS). Clinically, it may present with one or many symptoms, depending on the duration of disease activity and the timing of the fluctuations. A serotoninergic influence, cyclic changes in central dopaminergic tone, spontaneous episodic hemorrhage in the tumor, and the action of inflammatory cytokines with antitumor properties are some of the mechanisms suggested to explain the physiopathology of this phenomenon but the exact mechanism remains to be clarified. The cyclic pattern of hypercortisolism can delay the final diagnosis of CS and make it difficult to interpret the results of dynamic tests. Patients may have paradoxical responses to dexamethasone that can reflect increasing or decreasing levels of endogenous activity. Hormone assessments have to be repeated periodically when a diagnosis of CS is suspected. The cyclic pattern can also interfere with medical treatment because patients may show unexpected clinical and biochemical signs of hypocortisolism when cortisol secretion cyclically returns to normal, so an accurate follow-up is mandatory in these patients.     

Expression of connective tissue growth factor (CTGF/CCN2) in a mouse model of rhabdomyosarcomagenesis

Connective tissue growth factor (CTGF/CCN2) is a cysteine-rich matricellular protein that belongs to the CCN (CYR61, CTGF, NOV) protein family. It is highly expressed by human rhabdomyosarcoma cells and sustains their survival. In this study we investigated CCN2 expression in a mouse model of spontaneous rhabdomyosarcomagenesis that combines HER-2/neu oncogene activation and p53 oncosuppressor gene inactivation (BALB-p53neu mice). Murine rhabdomyosarcoma cells showed a 4-26 fold increase in CCN2 mRNA expression regarding to normal thigh muscle. Moreover, they expressed CCN2 protein at levels comparable to human rhabdomyosarcoma cells. Therefore BALBp53neu mice might be useful for the evaluation of the role played by CCN2 in rhabdomyosarcoma in vivo.     

Fruit and vegetable consumption and lymphoma risk in the European Prospective Investigation into Cancer and Nutrition (EPIC)

Introduction Lymphomas are a heterogeneous group of malignant diseases of cells of the immune system. The best-established risk factors are related to dys-regulation of immune function, and evidence suggests that factors such as dietary or lifestyle habits may be involved in the etiology. Material and methods In the European Prospective Investigation into Cancer and Nutrition (EPIC), 849 lymphoma cases were identified in a median follow-up period of 6.4 years. Fruit and vegetable consumption was estimated from validated dietary questionnaires. Cox proportional hazard models were used to examine the association between fruit and vegetable intake with the risk of lymphomas overall and subentities. Results There was no overall association between total fruit and vegetable consumption and risk of lymphoma [hazard ratio (HR) = 0.95, 95% confidence interval (CI) 0.78–1.15 comparing highest with lowest quartile]. However, the risk of diffuse large B-cell lymphomas (DLBCL) tended to be lower in participants with a high intake of total vegetables (HR = 0.49, 95% CI 0.23–1.02). Conclusion In this large prospective study, an inverse associations between fruit and vegetable consumption and risk of lymphomas overall could not be confirmed. Associations with lymphoma subentities such as DLBCL warrant further investigation. The work described in this article was carried out with the financial support of: Europe Against Cancer Program of the European Commission (SANCO); Deutsche Krebshilfe, Deutsches Krebsforschungszentrum, German Federal Ministry of Education and Research; Danish Cancer Society; Health Research Fund (FIS) of the Spanish Ministry of Health, Spanish Regional Governments of Andalucia, Asturia, Basque Country, Murcia and Navarra; the ISCIII Network RCESP (C03/09), Spain; Cancer Research UK; Medical Research Council, United Kingdom; Stroke Association, United Kingdom; British Heart Foundation; Department of Health, United Kingdom; Food Standards Agency, United Kingdom; Wellcome Trust, United Kingdom; Greek Ministry of Health; Greek Ministry of Education; Italian Association for Research on Cancer (AIRC); Italian National Research Council, Fondazione-Istituto Banco Napoli, Italy; Compagnia di San Paolo; Dutch Ministry of Public Health, Welfare and Sports; World Cancer Research Fund; Swedish Cancer Society; Swedish Scientific Council; Regional Government of Sk?ne, Sweden; Norwegian Cancer Society; Research Council of Norway; French League against Cancer (LNCC); National Institute for Health and Medical Research (INSERM), France; Mutuelle Générale de l’Education Nationale (MGEN), France; 3M Co, France; Gustave Roussy Institute (IGR), France; and General Councils of France.     

Occurrence of both bladder and prostate cancer in five cancer registries in Belgium, The Netherlands and the United Kingdom

ObjectiveTo assess the occurrence of both bladder and prostate tumours in five well defined cancer registries.MethodsAnonymous data were provided from each cancer registry on all male bladder and prostate cancers (invasive and non-invasive). Poisson regression was used to model the rate of developing the second primary tumour and generated incidence rate ratios (RRs) with 95% confidence intervals.ResultsFor bladder cancer and prostate cancer as first diagnosis, there was an excess risk to develop the second neoplasm. The RR decreased with increasing age of the patients. No effect of the initial treatment of the first neoplasm was found.ConclusionThis analysis found an excess risk to develop prostate cancer in bladder cancer patients younger than 70 years and the first year of follow-up after the diagnosis of bladder cancer. This may be due to detection bias, although a common aetiology may also be present.     

International Society of Geriatric Oncology (SIOG) clinical practice recommendations for the use of bisphosphonates in elderly patients

A society of geriatric oncology (SIOG) task force reviewed information from the literature (in PubMed) on bisphosphonates in elderly patients with bone metastases until December 2005. Additional pertinent data were obtained from the manufacturers. Bisphosphonates are recommended in the elderly with bone metastases to prevent skeletal-related events. Intravenous formulations are preferred for the treatment of hypercalcaemia. It has been recognised that zoledronic acid, ibandronate and pamidronate can effectively contribute in relieving metastatic bone pain. Creatinine clearance should be monitored in every patient, and a less renally toxic agent should be used where evidence of similar efficacy is available. The assessment and optimisation of hydration status is recommended. Due to the risk from osteonecrosis of the jaw, routine oral examination and treatment of dental problems by a dental team is recommended before bisphosphonates. Physicians should choose the most appropriate bisphosphonate. Safety precautions are particularly important in elderly patients. Further research is needed in this population.     

Reduced intensity conditioning with thiotepa, fludarabine, and melphalan is effective in advanced multiple myeloma

Fifty-three patients with multiple myeloma (MM) underwent an allogeneic stem cell transplant (HSCT) from their HLA identical siblings using a reduced-intensity conditioning consisting of thioteopa 5 mg/kg, fludarabine 90 mg/m(2), and melphalan 80 mg/m(2). Their median age was 52 years (range 38 - 68) and the interval from diagnosis 12 months. Forty-three patients (82%) had advanced disease and 33 had previously been treated with high-dose therapy with one (N = 21), or more (N = 12) autologus transplants. Ten (18%) had their allograft programmed after induction chemotherapy. The majority (N = 44) received peripheral blood as stem cell source. Acute graft-versus-host disease (GVHD) grade II - IV developed in 45%, but grade III - IV in only 5%. Cumulative incidence of chronic GVHD was 64%. Sixty-two per cent were in complete remission (CR) following transplantation. Transplant-related mortality was 13%. Relapse incidence was 32%. With a median follow-up of 22 months, 3-year overall survival is 45% and progression free survival (PFS) 37%. The thiotepa, fludarabine, and melphalan conditioning regimen can produce remissions in the majority of MM patients with a limited transplant mortality rate. When used as first line treatment the results of transplantation appear even more encouraging.     

Adjunctive risperidone in the treatment of generalized anxiety disorder: a double-blind, prospective, placebo-controlled, randomized trial

Background:Residual symptoms despite treatment are common in generalized anxiety disorders (GAD). The Patient-Rated Troubling Symptoms for Anxiety (PaRTS-A) is a newly created and validated instrument that measures the symptoms most troublesome to each individual patient and was used to test the hypothesis that adjunctive risperidone improves residual GAD symptoms. Methods: Primary care and psychiatry clinicians enrolled adults (n = 417) with GAD and a Clinical Global Impressions of Severity rating >/=4 despite >/=8 weeks of anxiolytic treatment. Subjects were randomized to adjunctive risperidone or placebo. The primary endpoint was change from baseline to week 4 endpoint in PaRTS-A. Results: Improvement from baseline to week 4 endpoint in PaRTS-A total score (mean +/-SE) was similar between treatment groups (-8.54 [0.63] and -7.61 [0.64] for adjunctive risperidone and placebo, respectively; P = .265). Patients in each treatment group exhibited significant improvements from baseline in nearly all patient- and clinician-rated measures. A post-hoc analysis of PaRTS-A symptoms of moderate to severe severity at baseline suggested greater improvement with risperidone than placebo (P = .04). Headache, weight increase, and increased appetite were the most frequently reported adverse events in both groups. Conclusions: Residual GAD symptoms assessed by the PaRTS-A improved with either adjunctive risperidone or placebo. Alternative analyses or scoring approaches may improve the ability of the PaRTS-A to provide clinically meaningful information on patient-rated symptoms. Further exploration of the benefits of risperidone in patients with more severe GAD may be indicated.     

Pharmacokinetics of 852A, an imidazoquinoline Toll-like receptor 7-specific agonist, following intravenous, subcutaneous, and oral administrations in humans

852A is an imidazoquinoline Toll-like receptor 7 agonist undergoing evaluation for the systemic treatment of cancer. 852A was administered to 6 healthy subjects as 3 rising subcutaneous doses (0.5 to 1.0 to 2.0 mg), to 6 subjects as 3 oral doses (10.0 to 20.0 to 15.0 mg, the third dose being a de-escalation), and to 6 subjects as a 2.0-mg dose by the subcutaneous, intravenous, and oral routes in crossover fashion. The subcutaneous and intravenous doses were well tolerated. One subject withdrew following the 20.0-mg oral dose because of hypotension. The 2.0-mg subcutaneous dose had 80.5% +/- 12.8% (mean +/- SD) bioavailability and gave serum concentrations comparable to intravenous administration by 30 minutes. Linear kinetics and an interferon-alpha dose response were observed for the 3 subcutaneous doses. Serum concentrations following the 2.0-mg oral dose were always lower than those following the same intravenous dose, and the oral route had a bioavailability of 26.5% +/- 7.84%. Concentrations appeared to increase with oral dose; however, large variabilities in both the rate and extent of absorption were seen between individuals. Approximately 40% of an absorbed dose was excreted unchanged in the urine. Overall, the study suggests that subcutaneous administration may be an acceptable method to deliver 852A for systemic applications.     

Changes in the in vitro pharmacodynamic properties of metoprolol in atria isolated from spontaneously hypertensive rats

1. The present study addressed possible changes in the dissociation constant of metoprolol and its inverse agonist activity in spontaneously hypertensive rats (SHR). In addition, a possible correlation between cardiac hypertrophy and the inverse agonist activity of metoprolol was explored. 2. In order to determine the dissociation constant (expressed as the pKb) of metoprolol, a cumulative concentration-response curve to noradrenaline was constructed in the absence or presence of metoprolol (0.1, 1 or 10 micromol/L). In a second experiment, a cumulative concentration-response curve to metoprolol was constructed to determine its inverse agonist activity. 3. The ventricular weight of SHR was significantly greater compared with Wistar-Kyoto (WKY) rats. A rightward shift of the concentration-response curve to noradrenaline was observed in SHR compared with WKY rats. The pKb of metoprolol was smaller in SHR compared with WKY rats (6.35 +/- 0.14 vs 6.99 +/- 0.12, respectively; P < 0.05). No difference was observed in the maximal response (Emax) of the concentration-time effect of metoprolol in WKY rats and SHR (-29.1 +/- 7.1 vs-28.2 +/- 8.5%, respectively; n = 6 for both). However, the concentration of metoprolol eliciting a half-maximal effect (expressed as the pEC50) was significantly smaller in SHR compared with WKY rats (4.82 +/- 0.07 vs 5.29 +/- 0.13, respectively; n = 6; P < 0.05). Although a significant correlation (r = -0.876) between the ventricular weight/bodyweight (VW/BW) ratio and the pEC50 of the chronotropic effect of metoprolol was found, no relationship (r = -0.257) was found between the VW/BW ratio and Emax. 4. In summary, the present study provides the first evidence of a change in the in vitro pharmacodynamic properties of metoprolol in SHR. The sympathetic overactivity present in SHR not only reduces the positive chronotropic effect of noradrenaline, but also diminishes the constant dissociation of metoprolol from atrial beta1-adrenoceptors and its inverse agonist activity. A significant correlation between the VW/BW ratio and the inverse agonist potency of metoprolol was found, suggesting a possible link between cardiac hypertrophy and the reduction of the inverse agonist activity of metoprolol.