226 research outputs found
Systematic review of the clinical effectiveness and cost-effectiveness, and economic evaluation, of denosumab for the treatment of bone metastases from solid tumours
Peer reviewedPublisher PD
Evidence for a schedule-dependent deleterious interaction between paclitaxel, vinblastine and cisplatin (PVC) in the treatment of advanced transitional cell carcinoma
A phase II study to evaluate the efficacy and toxicity of the combination of vinblastine, paclitaxel and cisplatin (PVC) in previously untreated patients with advanced transitional cell carcinoma. Chemotherapy naive patients with locally advanced or metastatic transitional cell carcinoma received the intravenous combination of paclitaxel 175 mg/m2 over three hours followed by cisplatin 70 mg/m2 over 3 hours on day 1 and vinblastine 3 mg/m2 as a bolus on days 1 and 8 on a 21-day cycle, to a maximum of 6 cycles. The day 8 vinblastine was omitted if the total neutrophil count was <1.0. 15 patients (13 M, 2 F) of median age 66 (54–75) received a median of 5 cycles of treatment. There were two complete responses (13%; 95% CI 2–40%) and five partial responses (33%; 95% CI 12–62%), for an overall response rate of 46% (95% CI 21–73%). Responses occurred only in those with locally recurrent tumours and/or lymph nodes involved. Neutropenia at Grade 3–4 occurred in 14 of 67 cycles (21%) resulting in 7 episodes of neutropenic sepsis. Grade 3–4 thrombocytopenia was not observed. Other Grade 3 toxicity included alopecia (10 pts), diarrhoea (2 pts), constipation resulting in bowel obstruction (2 pts), nephrotoxicity (1 pt), myalgic pain (1 pt) and peripheral neuropathy (1 pt). Six patients developed Grade 2 paraesthesia. The median time to progression was 6 months and the median survival was 11 months. The regimen PVC was both less effective against transitional cell carcinoma and less toxic than expected. This may reflect an inhibitory interaction between vinblastine and paclitaxel and this schedule cannot be recommended for further investigation. © 2000 Cancer Research Campaign http://www.bjcancer.co
A Novel Y152C KCNJ5 Mutation Responsible for Familial Hyperaldosteronism Type III
CONTEXT: Primary aldosteronism is a heterogeneous group of disorders comprising both sporadic and familial forms. Mutations in the KCNJ5 gene, which encodes the inward rectifier K(+) channel 4 (G protein-activated inward rectifier K(+) channel 4, Kir3.4), cause familial hyperaldosteronism type III (FH-III) and are involved in the pathogenesis of sporadic aldosterone-producing adenomas. OBJECTIVE: The objective of the study was to characterize the effects of a newly described KCNJ5 mutation in vitro. PATIENTS AND METHODS: The index case is a 62-year-old woman affected by primary aldosteronism, who underwent left adrenalectomy after workup for adrenal adenoma. Exon 1 of KCNJ5 was PCR amplified from adrenal tissue and peripheral blood and sequenced. Electrophysiological and gene expression studies were performed to establish the functional effects of the new mutation on the membrane potential and adrenal cell CYP11B2 expression. RESULTS: KCNJ5 sequencing in the index case revealed a new p.Y152C germline mutation; interestingly, the phenotype of the patient was milder than most of the previously described FH-III families. The tyrosine-to-cysteine substitution resulted in pathological Na(+) permeability, cell membrane depolarization, and disturbed intracellular Ca(2+) homeostasis, effects similar, albeit smaller, to the ones demonstrated for other KCNJ5 mutations. Gene expression studies revealed an increased expression of CYP11B2 and its transcriptional regulator NR4A2 in HAC15 adrenal cells overexpressing KCNJ5(Y152C) compared to the wild-type channel. The effect was clearly Ca(2+)-dependent, because it was abolished by the calcium channel blocker nifedipine. CONCLUSIONS: Herein we describe a new germline mutation in KCNJ5 responsible for FH-III
Screening of hypercortisolism among patients with hypertension: an Italian nationwide survey
Purpose Screening of Cushing Syndrome (CS) and Mild Autonomous Cortisol Secretion (MACS) in hypertensive patients is crucial for proper treatment. The aim of the study was to investigate screening and management of hypercortisolism among patients with hypertension in Italy.Methods A 10 item-questionnaire was delivered to referral centres of European and Italian Society of Hypertension (ESH and SIIA) in a nationwide survey. Data were analyzed according to type of centre (excellence vs non-excellence), geographical area, and medical specialty.Results Within 14 Italian regions, 82 centres (30% excellence, 78.790 patients during the last year, average 600 patients/year) participated to the survey. Internal medicine (44%) and cardiology (31%) were the most prevalent medical specialty. CS and MACS were diagnosed in 313 and 490 patients during the previous 5 years. The highest number of diagnoses was reported by internal medicine and excellence centres. Screening for hypercortisolism was reported by 77% in the presence of specific features of CS, 61% in resistant hypertension, and 38% in patients with adrenal mass. Among screening tests, the 24 h urinary free cortisol was the most used (66%), followed by morning cortisol and ACTH (54%), 1 mg-dexamethasone suppression test (49%), adrenal CT or MRI scans (12%), and late night salivary cortisol (11%). Awareness of referral centres with expertise in management of CS was reported by 67% of the participants, which reduced to 44% among non-excellence centres.Conclusions Current screening of hypercortisolism among hypertensive patients is unsatisfactory. Strategies tailored to different medical specialties and type of centres should be conceived
Genetic mutation screening in an Italian cohort of nonsyndromic pheochromocytoma/paraganglioma patients
To assess the prevalence of genetic mutations in nonsyndromic pheochromocytoma/paraganglioma (PHEO/PGL) patients we have performed a systematic search for mutations in the succinate dehydrogenase (SDH) B, C, and D subunits, von Hippel-Lindau (VHL), and RET genes by direct bidirectional sequencing. Patients were selected from the medical records of hypertension centers. After exclusion of syndromic patients, 45 patients with familial (F+, n=3) and sporadic (F-, n=42) cases of isolated PHEO/PGL were considered. They included 35 patients with PHEO, 7 with PGL, and 3 with head/neck PGL (hnPGL). Three patients with PHEO (2F-, 1F+) presented VHL mutations (P86A, G93C, and R167W), six with PGL (4F-, 2F+) were positive for SDH or VHL mutations (SDHB R230G in two patients, SDHB S8F, R46Q, R90Q, and VHL P81L in one subject each), and one with hnPGL carried the SDHD 348-351delGACT mutation. We have also detected missense (SDHB S163P, SDHD H50R and G12S), synonymous (SDHB A6A, SDHD S68S), and intronic mutations that have been considered nonpathological polymorphic variants. No mutation was found in SDHC or RET genes. Our data indicate that germline mutations of VHL and SDH subunits are not infrequent in familial as well as in sporadic cases of nonsyndromic PHEO/PGL (overall, 12 of 45 probands, 22%). Accordingly, screening for such mutations seems to be justified. However, a more precise characterization of the functional relevance of any observed sequence variant and of other genetic and environmental determinants of neoplastic transformation is essential in order to plan appropriate protocols for family screening and follow-up
Graz Endocrine Causes of Hypertension (GECOH) study: a diagnostic accuracy study of aldosterone to active renin ratio in screening for primary aldosteronism
<p>Abstract</p> <p>Background</p> <p>Primary aldosteronism (PA) affects approximately 5 to 10% of all patients with arterial hypertension and is associated with an excess rate of cardiovascular complications that can be significantly reduced by a targeted treatment. There exists a general consensus that the aldosterone to renin ratio should be used as a screening tool but valid data about the accuracy of the aldosterone to renin ratio in screening for PA are sparse. In the Graz endocrine causes of hypertension (GECOH) study we aim to prospectively evaluate diagnostic procedures for PA.</p> <p>Methods and design</p> <p>In this single center, diagnostic accuracy study we will enrol 400 patients that are routinely referred to our tertiary care center for screening for endocrine hypertension. We will determine the aldosterone to active renin ratio (AARR) as a screening test. In addition, all study participants will have a second determination of the AARR and will undergo a saline infusion test (SIT) as a confirmatory test. PA will be diagnosed in patients with at least one AARR of ≥ 5.7 ng/dL/ng/L (including an aldosterone concentration of ≥ 9 ng/dL) who have an aldosterone level of ≥ 10 ng/dL after the saline infusion test. As a primary outcome we will calculate the receiver operating characteristic curve of the AARR in diagnosing PA. Secondary outcomes include the test characteristics of the saline infusion test involving a comparison with 24 hours urine aldosterone levels and the accuracy of the aldosterone to renin activity ratio in diagnosing PA. In addition we will evaluate whether the use of beta-blockers significantly alters the accuracy of the AARR and we will validate our laboratory methods for aldosterone and renin.</p> <p>Conclusion</p> <p>Screening for PA with subsequent targeted treatment is of great potential benefit for hypertensive patients. In the GECOH study we will evaluate a standardised procedure for screening and diagnosing of this disease.</p
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