Royal Adelaide Hospital

BACKGROUND: In 1986, the European Organization for Research and Treatment of Cancer (EORTC) initiated a research program to develop an integrated, modular approach for evaluating the quality of life of patients participating in international clinical trials. PURPOSE: We report here the results of an international field study of the practicality, reliability, and validity of the EORTC QLQ-C30, the current core questionnaire. The QLQ-C30 incorporates nine multi-item scales: five functional scales (physical, role, cognitive, emotional, and social); three symptom scales (fatigue, pain, and nausea and vomiting); and a global health and quality-of-life scale. Several single-item symptom measures are also included. METHODS: The questionnaire was administered before treatment and once during treatment to 305 patients with nonresectable lung cancer from centers in 13 countries. Clinical variables assessed included disease stage, weight loss, performance status, and treatment toxicity. RESULTS: The average time required to complete the questionnaire was approximately 11 minutes, and most patients required no assistance. The data supported the hypothesized scale structure of the questionnaire with the exception of role functioning (work and household activities), which was also the only multi-item scale that failed to meet the minimal standards for reliability (Cronbach's alpha coefficient > or = .70) either before or during treatment. Validity was shown by three findings. First, while all interscale correlations were statistically significant, the correlation was moderate, indicating that the scales were assessing distinct components of the quality-of-life construct. Second, most of the functional and symptom measures discriminated clearly between patients differing in clinical status as defined by the Eastern Cooperative Oncology Group performance status scale, weight loss, and treatment toxicity. Third, there were statistically significant changes, in the expected direction, in physical and role functioning, global quality of life, fatigue, and nausea and vomiting, for patients whose performance status had improved or worsened during treatment. The reliability and validity of the questionnaire were highly consistent across the three language-cultural groups studied: patients from English-speaking countries, Northern Europe, and Southern Europe. CONCLUSIONS: These results support the EORTC QLQ-C30 as a reliable and valid measure of the quality of life of cancer patients in multicultural clinical research settings. Work is ongoing to examine the performance of the questionnaire among more heterogenous patient samples and in phase II and phase III clinical trials.

BACKGROUND: Trials of endovascular therapy for ischemic stroke have produced variable results. We conducted this study to test whether more advanced imaging selection, recently developed devices, and earlier intervention improve outcomes. METHODS: We randomly assigned patients with ischemic stroke who were receiving 0.9 mg of alteplase per kilogram of body weight less than 4.5 hours after the onset of ischemic stroke either to undergo endovascular thrombectomy with the Solitaire FR (Flow Restoration) stent retriever or to continue receiving alteplase alone. All the patients had occlusion of the internal carotid or middle cerebral artery and evidence of salvageable brain tissue and ischemic core of less than 70 ml on computed tomographic (CT) perfusion imaging. The coprimary outcomes were reperfusion at 24 hours and early neurologic improvement (≥8-point reduction on the National Institutes of Health Stroke Scale or a score of 0 or 1 at day 3). Secondary outcomes included the functional score on the modified Rankin scale at 90 days. RESULTS: The trial was stopped early because of efficacy after 70 patients had undergone randomization (35 patients in each group). The percentage of ischemic territory that had undergone reperfusion at 24 hours was greater in the endovascular-therapy group than in the alteplase-only group (median, 100% vs. 37%; P<0.001). Endovascular therapy, initiated at a median of 210 minutes after the onset of stroke, increased early neurologic improvement at 3 days (80% vs. 37%, P=0.002) and improved the functional outcome at 90 days, with more patients achieving functional independence (score of 0 to 2 on the modified Rankin scale, 71% vs. 40%; P=0.01). There were no significant differences in rates of death or symptomatic intracerebral hemorrhage. CONCLUSIONS: In patients with ischemic stroke with a proximal cerebral arterial occlusion and salvageable tissue on CT perfusion imaging, early thrombectomy with the Solitaire FR stent retriever, as compared with alteplase alone, improved reperfusion, early neurologic recovery, and functional outcome. (Funded by the Australian National Health and Medical Research Council and others; EXTEND-IA ClinicalTrials.gov number, NCT01492725, and Australian New Zealand Clinical Trials Registry number, ACTRN12611000969965.).

BACKGROUND: Imatinib, a selective inhibitor of the BCR-ABL tyrosine kinase, produces high response rates in patients with chronic-phase chronic myeloid leukemia (CML) who have had no response to interferon alfa. We compared the efficacy of imatinib with that of interferon alfa combined with low-dose cytarabine in newly diagnosed chronic-phase CML. METHODS: We randomly assigned 1106 patients to receive imatinib (553 patients) or interferon alfa plus low-dose cytarabine (553 patients). Crossover to the alternative group was allowed if stringent criteria defining treatment failure or intolerance were met. Patients were evaluated for hematologic and cytogenetic responses, toxic effects, and rates of progression. RESULTS: After a median follow-up of 19 months, the estimated rate of a major cytogenetic response (0 to 35 percent of cells in metaphase positive for the Philadelphia chromosome) at 18 months was 87.1 percent (95 percent confidence interval, 84.1 to 90.0) in the imatinib group and 34.7 percent (95 percent confidence interval, 29.3 to 40.0) in the group given interferon alfa plus cytarabine (P<0.001). The estimated rates of complete cytogenetic response were 76.2 percent (95 percent confidence interval, 72.5 to 79.9) and 14.5 percent (95 percent confidence interval, 10.5 to 18.5), respectively (P<0.001). At 18 months, the estimated rate of freedom from progression to accelerated-phase or blast-crisis CML was 96.7 percent in the imatinib group and 91.5 percent in the combination-therapy group (P<0.001). Imatinib was better tolerated than combination therapy. CONCLUSIONS: In terms of hematologic and cytogenetic responses, tolerability, and the likelihood of progression to accelerated-phase or blast-crisis CML, imatinib was superior to interferon alfa plus low-dose cytarabine as first-line therapy in newly diagnosed chronic-phase CML.

BACKGROUND: The cause of chronic myeloid leukemia (CML) is a constitutively active BCR-ABL tyrosine kinase. Imatinib inhibits this kinase, and in a short-term study was superior to interferon alfa plus cytarabine for newly diagnosed CML in the chronic phase. For 5 years, we followed patients with CML who received imatinib as initial therapy. METHODS: We randomly assigned 553 patients to receive imatinib and 553 to receive interferon alfa plus cytarabine and then evaluated them for overall and event-free survival; progression to accelerated-phase CML or blast crisis; hematologic, cytogenetic, and molecular responses; and adverse events. RESULTS: The median follow-up was 60 months. Kaplan-Meier estimates of cumulative best rates of complete cytogenetic response among patients receiving imatinib were 69% by 12 months and 87% by 60 months. An estimated 7% of patients progressed to accelerated-phase CML or blast crisis, and the estimated overall survival of patients who received imatinib as initial therapy was 89% at 60 months. Patients who had a complete cytogenetic response or in whom levels of BCR-ABL transcripts had fallen by at least 3 log had a significantly lower risk of disease progression than did patients without a complete cytogenetic response (P<0.001). Grade 3 or 4 adverse events diminished over time, and there was no clinically significant change in the profile of adverse events. CONCLUSIONS: After 5 years of follow-up, continuous treatment of chronic-phase CML with imatinib as initial therapy was found to induce durable responses in a high proportion of patients. (ClinicalTrials.gov number, NCT00006343 [ClinicalTrials.gov].)

BACKGROUND: Multimorbidity and the associated use of multiple medicines (polypharmacy), is common in the older population. Despite this, there is no consensus definition for polypharmacy. A systematic review was conducted to identify and summarise polypharmacy definitions in existing literature. METHODS: The reporting of this systematic review conforms to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) checklist. MEDLINE (Ovid), EMBASE and Cochrane were systematically searched, as well as grey literature, to identify articles which defined the term polypharmacy (without any limits on the types of definitions) and were in English, published between 1st January 2000 and 30th May 2016. Definitions were categorised as i. numerical only (using the number of medications to define polypharmacy), ii. numerical with an associated duration of therapy or healthcare setting (such as during hospital stay) or iii. Descriptive (using a brief description to define polypharmacy). RESULTS: A total of 1156 articles were identified and 110 articles met the inclusion criteria. Articles not only defined polypharmacy but associated terms such as minor and major polypharmacy. As a result, a total of 138 definitions of polypharmacy and associated terms were obtained. There were 111 numerical only definitions (80.4% of all definitions), 15 numerical definitions which incorporated a duration of therapy or healthcare setting (10.9%) and 12 descriptive definitions (8.7%). The most commonly reported definition of polypharmacy was the numerical definition of five or more medications daily (n = 51, 46.4% of articles), with definitions ranging from two or more to 11 or more medicines. Only 6.4% of articles classified the distinction between appropriate and inappropriate polypharmacy, using descriptive definitions to make this distinction. CONCLUSIONS: Polypharmacy definitions were variable. Numerical definitions of polypharmacy did not account for specific comorbidities present and make it difficult to assess safety and appropriateness of therapy in the clinical setting.

Publicado também em: https://repositorio.unifesp.br/handle/11600/53933

A review of the medical records of over 14,000 admissions to 28 hospitals in New South Wales and South Australia revealed that 16.6% of these admissions were associated with an "adverse event", which resulted in disability or a longer hospital stay for the patient and was caused by health care management; 51% of the adverse events were considered preventable. In 77.1% the disability had resolved within 12 months, but in 13.7% the disability was permanent and in 4.9% the patient died.

BACKGROUND: Catheter ablation is less successful for persistent atrial fibrillation than for paroxysmal atrial fibrillation. Guidelines suggest that adjuvant substrate modification in addition to pulmonary-vein isolation is required in persistent atrial fibrillation. METHODS: We randomly assigned 589 patients with persistent atrial fibrillation in a 1:4:4 ratio to ablation with pulmonary-vein isolation alone (67 patients), pulmonary-vein isolation plus ablation of electrograms showing complex fractionated activity (263 patients), or pulmonary-vein isolation plus additional linear ablation across the left atrial roof and mitral valve isthmus (259 patients). The duration of follow-up was 18 months. The primary end point was freedom from any documented recurrence of atrial fibrillation lasting longer than 30 seconds after a single ablation procedure. RESULTS: Procedure time was significantly shorter for pulmonary-vein isolation alone than for the other two procedures (P<0.001). After 18 months, 59% of patients assigned to pulmonary-vein isolation alone were free from recurrent atrial fibrillation, as compared with 49% of patients assigned to pulmonary-vein isolation plus complex electrogram ablation and 46% of patients assigned to pulmonary-vein isolation plus linear ablation (P=0.15). There were also no significant differences among the three groups for the secondary end points, including freedom from atrial fibrillation after two ablation procedures and freedom from any atrial arrhythmia. Complications included tamponade (three patients), stroke or transient ischemic attack (three patients), and atrioesophageal fistula (one patient). CONCLUSIONS: Among patients with persistent atrial fibrillation, we found no reduction in the rate of recurrent atrial fibrillation when either linear ablation or ablation of complex fractionated electrograms was performed in addition to pulmonary-vein isolation. (Funded by St. Jude Medical; ClinicalTrials.gov number, NCT01203748.).

OBJECTIVE: To update the findings of the 2005 systematic review of population-based studies assessing the epidemiology of gastro-oesophageal reflux disease (GERD). DESIGN: PubMed and Embase were screened for new references using the original search strings. Studies were required to be population-based, to include ≥ 200 individuals, to have response rates ≥ 50% and recall periods <12 months. GERD was defined as heartburn and/or regurgitation on at least 1 day a week, or according to the Montreal definition, or diagnosed by a clinician. Temporal and geographic trends in disease prevalence were examined using a Poisson regression model. RESULTS: 16 studies of GERD epidemiology published since the original review were found to be suitable for inclusion (15 reporting prevalence and one reporting incidence), and were added to the 13 prevalence and two incidence studies found previously. The range of GERD prevalence estimates was 18.1%-27.8% in North America, 8.8%-25.9% in Europe, 2.5%-7.8% in East Asia, 8.7%-33.1% in the Middle East, 11.6% in Australia and 23.0% in South America. Incidence per 1000 person-years was approximately 5 in the overall UK and US populations, and 0.84 in paediatric patients aged 1-17 years in the UK. Evidence suggests an increase in GERD prevalence since 1995 (p<0.0001), particularly in North America and East Asia. CONCLUSIONS: GERD is prevalent worldwide, and disease burden may be increasing. Prevalence estimates show considerable geographic variation, but only East Asia shows estimates consistently lower than 10%.

A systematic review of the epidemiology of gastro-oesophageal reflux disease (GORD) has been performed, applying strict criteria for quality of studies and the disease definition used. The prevalence and incidence of GORD was estimated from 15 studies which defined GORD as at least weekly heartburn and/or acid regurgitation and met criteria concerning sample size, response rate, and recall period. Data on factors associated with GORD were also evaluated. An approximate prevalence of 10-20% was identified for GORD, defined by at least weekly heartburn and/or acid regurgitation in the Western world while in Asia this was lower, at less than 5%. The incidence in the Western world was approximately 5 per 1000 person years. A number of potential risk factors (for example, an immediate family history and obesity) and comorbidities (for example, respiratory diseases and chest pain) associated with GORD were identified. Data reported in this systematic review can be interpreted with confidence as reflecting the epidemiology of "true" GORD. The disease is more common in the Western world than in Asia, and the low rate of incidence relative to prevalence reflects its chronicity. The small number of studies eligible for inclusion in this review highlights the need for global consensus on a symptom based definition of GORD.

BACKGROUND: We evaluated the contribution of sentinel-node biopsy to outcomes in patients with newly diagnosed melanoma. METHODS: Patients with a primary cutaneous melanoma were randomly assigned to wide excision and postoperative observation of regional lymph nodes with lymphadenectomy if nodal relapse occurred, or to wide excision and sentinel-node biopsy with immediate lymphadenectomy if nodal micrometastases were detected on biopsy. RESULTS: Among 1269 patients with an intermediate-thickness primary melanoma, the mean (+/-SE) estimated 5-year disease-free survival rate for the population was 78.3+/-1.6% in the biopsy group and 73.1+/-2.1% in the observation group (hazard ratio for recurrence[corrected], 0.74; 95% confidence interval [CI], 0.59 to 0.93; P=0.009). Five-year melanoma-specific survival rates were similar in the two groups (87.1+/-1.3% and 86.6+/-1.6%, respectively). In the biopsy group, the presence of metastases in the sentinel node was the most important prognostic factor; the 5-year survival rate was 72.3+/-4.6% among patients with tumor-positive sentinel nodes and 90.2+/-1.3% among those with tumor-negative sentinel nodes (hazard ratio for death, 2.48; 95% CI, 1.54 to 3.98; P<0.001). The incidence of sentinel-node micrometastases was 16.0% (122 of 764 patients), and the rate of nodal relapse in the observation group was 15.6% (78 of 500 patients). The corresponding mean number of tumor-involved nodes was 1.4 in the biopsy group and 3.3 in the observation group (P<0.001), indicating disease progression during observation. Among patients with nodal metastases, the 5-year survival rate was higher among those who underwent immediate lymphadenectomy than among those in whom lymphadenectomy was delayed (72.3+/-4.6% vs. 52.4+/-5.9%; hazard ratio for death, 0.51; 95% CI, 0.32 to 0.81; P=0.004). CONCLUSIONS: The staging of intermediate-thickness (1.2 to 3.5 mm) primary melanomas according to the results of sentinel-node biopsy provides important prognostic information and identifies patients with nodal metastases whose survival can be prolonged by immediate lymphadenectomy. (ClinicalTrials.gov number, NCT00275496 [ClinicalTrials.gov].).

BACKGROUND: Cyclophosphamide induction regimens for antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis are effective in 70 to 90% of patients, but they are associated with high rates of death and adverse events. Treatment with rituximab has led to remission rates of 80 to 90% among patients with refractory ANCA-associated vasculitis and may be safer than cyclophosphamide regimens. METHODS: We compared rituximab with cyclophosphamide as induction therapy in ANCA-associated vasculitis. We randomly assigned, in a 3:1 ratio, 44 patients with newly diagnosed ANCA-associated vasculitis and renal involvement to a standard glucocorticoid regimen plus either rituximab at a dose of 375 mg per square meter of body-surface area per week for 4 weeks, with two intravenous cyclophosphamide pulses (33 patients, the rituximab group), or intravenous cyclophosphamide for 3 to 6 months followed by azathioprine (11 patients, the control group). Primary end points were sustained remission rates at 12 months and severe adverse events. RESULTS: The median age was 68 years, and the glomerular filtration rate (GFR) was 18 ml per minute per 1.73 m(2) of body-surface area. A total of 25 patients in the rituximab group (76%) and 9 patients in the control group (82%) had a sustained remission (P=0.68). Severe adverse events occurred in 14 patients in the rituximab group (42%) and 4 patients in the control group (36%) (P=0.77). Six of the 33 patients in the rituximab group (18%) and 2 of the 11 patients in the control group (18%) died (P=1.00). The median increase in the GFR between 0 and 12 months was 19 ml per minute in the rituximab group and 15 ml per minute in the control group (P=0.14). CONCLUSIONS: A rituximab-based regimen was not superior to standard intravenous cyclophosphamide for severe ANCA-associated vasculitis. Sustained-remission rates were high in both groups, and the rituximab-based regimen was not associated with reductions in early severe adverse events. (Funded by Cambridge University Hospitals National Health Service Foundation Trust and F. Hoffmann-La Roche; Current Controlled Trials number, ISRCTN28528813.)

OBJECTIVE: This clinical practice guideline addresses the diagnosis and treatment of primary adrenal insufficiency. PARTICIPANTS: The Task Force included a chair, selected by The Clinical Guidelines Subcommittee of the Endocrine Society, eight additional clinicians experienced with the disease, a methodologist, and a medical writer. The co-sponsoring associations (European Society of Endocrinology and the American Association for Clinical Chemistry) had participating members. The Task Force received no corporate funding or remuneration in connection with this review. EVIDENCE: This evidence-based guideline was developed using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system to determine the strength of recommendations and the quality of evidence. CONSENSUS PROCESS: The evidence used to formulate recommendations was derived from two commissioned systematic reviews as well as other published systematic reviews and studies identified by the Task Force. The guideline was reviewed and approved sequentially by the Endocrine Society's Clinical Guidelines Subcommittee and Clinical Affairs Core Committee, members responding to a web posting, and the Endocrine Society Council. At each stage, the Task Force incorporated changes in response to written comments. CONCLUSIONS: We recommend diagnostic tests for the exclusion of primary adrenal insufficiency in all patients with indicative clinical symptoms or signs. In particular, we suggest a low diagnostic (and therapeutic) threshold in acutely ill patients, as well as in patients with predisposing factors. This is also recommended for pregnant women with unexplained persistent nausea, fatigue, and hypotension. We recommend a short corticotropin test (250 μg) as the "gold standard" diagnostic tool to establish the diagnosis. If a short corticotropin test is not possible in the first instance, we recommend an initial screening procedure comprising the measurement of morning plasma ACTH and cortisol levels. Diagnosis of the underlying cause should include a validated assay of autoantibodies against 21-hydroxylase. In autoantibody-negative individuals, other causes should be sought. We recommend once-daily fludrocortisone (median, 0.1 mg) and hydrocortisone (15-25 mg/d) or cortisone acetate replacement (20-35 mg/d) applied in two to three daily doses in adults. In children, hydrocortisone (∼8 mg/m(2)/d) is recommended. Patients should be educated about stress dosing and equipped with a steroid card and glucocorticoid preparation for parenteral emergency administration. Follow-up should aim at monitoring appropriate dosing of corticosteroids and associated autoimmune diseases, particularly autoimmune thyroid disease.

BACKGROUND: Nilotinib has been shown to be a more potent inhibitor of BCR-ABL than imatinib. We evaluated the efficacy and safety of nilotinib, as compared with imatinib, in patients with newly diagnosed Philadelphia chromosome-positive chronic myeloid leukemia (CML) in the chronic phase. METHODS: In this phase 3, randomized, open-label, multicenter study, we assigned 846 patients with chronic-phase Philadelphia chromosome-positive CML in a 1:1:1 ratio to receive nilotinib (at a dose of either 300 mg or 400 mg twice daily) or imatinib (at a dose of 400 mg once daily). The primary end point was the rate of major molecular response at 12 months. RESULTS: At 12 months, the rates of major molecular response for nilotinib (44% for the 300-mg dose and 43% for the 400-mg dose) were nearly twice that for imatinib (22%) (P<0.001 for both comparisons). The rates of complete cytogenetic response by 12 months were significantly higher for nilotinib (80% for the 300-mg dose and 78% for the 400-mg dose) than for imatinib (65%) (P<0.001 for both comparisons). Patients receiving either the 300-mg dose or the 400-mg dose of nilotinib twice daily had a significant improvement in the time to progression to the accelerated phase or blast crisis, as compared with those receiving imatinib (P=0.01 and P=0.004, respectively). No patient with progression to the accelerated phase or blast crisis had a major molecular response. Gastrointestinal and fluid-retention events were more frequent among patients receiving imatinib, whereas dermatologic events and headache were more frequent in those receiving nilotinib. Discontinuations due to aminotransferase and bilirubin elevations were low in all three study groups. CONCLUSIONS: Nilotinib at a dose of either 300 mg or 400 mg twice daily was superior to imatinib in patients with newly diagnosed chronic-phase Philadelphia chromosome-positive CML. (ClinicalTrials.gov number, NCT00471497.)

BACKGROUND: It is unclear whether decompressive craniectomy improves the functional outcome in patients with severe traumatic brain injury and refractory raised intracranial pressure. METHODS: From December 2002 through April 2010, we randomly assigned 155 adults with severe diffuse traumatic brain injury and intracranial hypertension that was refractory to first-tier therapies to undergo either bifrontotemporoparietal decompressive craniectomy or standard care. The original primary outcome was an unfavorable outcome (a composite of death, vegetative state, or severe disability), as evaluated on the Extended Glasgow Outcome Scale 6 months after the injury. The final primary outcome was the score on the Extended Glasgow Outcome Scale at 6 months. RESULTS: Patients in the craniectomy group, as compared with those in the standard-care group, had less time with intracranial pressures above the treatment threshold (P<0.001), fewer interventions for increased intracranial pressure (P<0.02 for all comparisons), and fewer days in the intensive care unit (ICU) (P<0.001). However, patients undergoing craniectomy had worse scores on the Extended Glasgow Outcome Scale than those receiving standard care (odds ratio for a worse score in the craniectomy group, 1.84; 95% confidence interval [CI], 1.05 to 3.24; P=0.03) and a greater risk of an unfavorable outcome (odds ratio, 2.21; 95% CI, 1.14 to 4.26; P=0.02). Rates of death at 6 months were similar in the craniectomy group (19%) and the standard-care group (18%). CONCLUSIONS: In adults with severe diffuse traumatic brain injury and refractory intracranial hypertension, early bifrontotemporoparietal decompressive craniectomy decreased intracranial pressure and the length of stay in the ICU but was associated with more unfavorable outcomes. (Funded by the National Health and Medical Research Council of Australia and others; DECRA Australian Clinical Trials Registry number, ACTRN012605000009617.).

BACKGROUND: Enzalutamide, an androgen-receptor inhibitor, has been associated with improved overall survival in men with castration-resistant prostate cancer. It is not known whether adding enzalutamide to testosterone suppression, with or without early docetaxel, will improve survival in men with metastatic, hormone-sensitive prostate cancer. METHODS: In this open-label, randomized, phase 3 trial, we assigned patients to receive testosterone suppression plus either open-label enzalutamide or a standard nonsteroidal antiandrogen therapy (standard-care group). The primary end point was overall survival. Secondary end points included progression-free survival as determined by the prostate-specific antigen (PSA) level, clinical progression-free survival, and adverse events. RESULTS: A total of 1125 men underwent randomization; the median follow-up was 34 months. There were 102 deaths in the enzalutamide group and 143 deaths in the standard-care group (hazard ratio, 0.67; 95% confidence interval [CI], 0.52 to 0.86; P = 0.002). Kaplan-Meier estimates of overall survival at 3 years were 80% (based on 94 events) in the enzalutamide group and 72% (based on 130 events) in the standard-care group. Better results with enzalutamide were also seen in PSA progression-free survival (174 and 333 events, respectively; hazard ratio, 0.39; P<0.001) and in clinical progression-free survival (167 and 320 events, respectively; hazard ratio, 0.40; P<0.001). Treatment discontinuation due to adverse events was more frequent in the enzalutamide group than in the standard-care group (33 events and 14 events, respectively). Fatigue was more common in the enzalutamide group; seizures occurred in 7 patients in the enzalutamide group (1%) and in no patients in the standard-care group. CONCLUSIONS: Enzalutamide was associated with significantly longer progression-free and overall survival than standard care in men with metastatic, hormone-sensitive prostate cancer receiving testosterone suppression. The enzalutamide group had a higher incidence of seizures and other toxic effects, especially among those treated with early docetaxel. (Funded by Astellas Scientific and Medical Affairs and others; ENZAMET (ANZUP 1304) ANZCTR number, ACTRN12614000110684; ClinicalTrials.gov number, NCT02446405; and EU Clinical Trials Register number, 2014-003190-42.).

BACKGROUND: Sentinel-node biopsy, a minimally invasive procedure for regional melanoma staging, was evaluated in a phase 3 trial. METHODS: We evaluated outcomes in 2001 patients with primary cutaneous melanomas randomly assigned to undergo wide excision and nodal observation, with lymphadenectomy for nodal relapse (observation group), or wide excision and sentinel-node biopsy, with immediate lymphadenectomy for nodal metastases detected on biopsy (biopsy group). Results No significant treatment-related difference in the 10-year melanoma-specific survival rate was seen in the overall study population (20.8% with and 79.2% without nodal metastases). Mean (± SE) 10-year disease-free survival rates were significantly improved in the biopsy group, as compared with the observation group, among patients with intermediate-thickness melanomas, defined as 1.20 to 3.50 mm (71.3 ± 1.8% vs. 64.7 ± 2.3%; hazard ratio for recurrence or metastasis, 0.76; P=0.01), and those with thick melanomas, defined as >3.50 mm (50.7 ± 4.0% vs. 40.5 ± 4.7%; hazard ratio, 0.70; P=0.03). Among patients with intermediate-thickness melanomas, the 10-year melanoma-specific survival rate was 62.1 ± 4.8% among those with metastasis versus 85.1 ± 1.5% for those without metastasis (hazard ratio for death from melanoma, 3.09; P<0.001); among patients with thick melanomas, the respective rates were 48.0 ± 7.0% and 64.6 ± 4.9% (hazard ratio, 1.75; P=0.03). Biopsy-based management improved the 10-year rate of distant disease-free survival (hazard ratio for distant metastasis, 0.62; P=0.02) and the 10-year rate of melanoma-specific survival (hazard ratio for death from melanoma, 0.56; P=0.006) for patients with intermediate-thickness melanomas and nodal metastases. Accelerated-failure-time latent-subgroup analysis was performed to account for the fact that nodal status was initially known only in the biopsy group, and a significant treatment benefit persisted. CONCLUSIONS: Biopsy-based staging of intermediate-thickness or thick primary melanomas provides important prognostic information and identifies patients with nodal metastases who may benefit from immediate complete lymphadenectomy. Biopsy-based management prolongs disease-free survival for all patients and prolongs distant disease-free survival and melanoma-specific survival for patients with nodal metastases from intermediate-thickness melanomas. (Funded by the National Cancer Institute, National Institutes of Health, and the Australia and New Zealand Melanoma Trials Group; ClinicalTrials.gov number, NCT00275496.).

BACKGROUND: A frequent complication of anticancer treatment, oral and gastrointestinal (GI) mucositis, threatens the effectiveness of therapy because it leads to dose reductions, increases healthcare costs, and impairs patients' quality of life. The Multinational Association of Supportive Care in Cancer and the International Society for Oral Oncology assembled an international multidisciplinary panel of experts to create clinical practice guidelines for the prevention, evaluation, and treatment of mucositis. METHODS: The panelists examined medical literature published from January 1966 through May 2002, presented their findings at two separate conferences, and then created a writing committee that produced two articles: the current study and another that codifies the clinical implications of the panel's findings in practice guidelines. RESULTS: New evidence supports the view that oral mucositis is a complex process involving all the tissues and cellular elements of the mucosa. Other findings suggest that some aspects of mucositis risk may be determined genetically. GI proapoptotic and antiapoptotic gene levels change along the GI tract, perhaps explaining differences in the frequency with which mucositis occurs at different sites. Studies of mucositis incidence in clinical trials by quality and using meta-analysis techniques produced estimates of incidence that are presented herein for what to our knowledge may be a broader range of cancers than ever presented before. CONCLUSIONS: Understanding the pathobiology of mucositis, its incidence, and scoring are essential for progress in research and care directed at this common side-effect of anticancer therapies.

Catheter ablation of AF is a very commonly performed procedure in hospitals throughout the world. Surgical ablation of AF, although less widely available than catheter-based AF ablation, is also an important therapeutic option for patients with AF at many major medical centers. This document provides an up-to-date review of the indications, techniques, and outcomes of catheter and surgical ablation of AF. Areas for which a consensus can be reached concerning AF ablation are identified, and a series of consensus definitions have been developed for use in future clinical trials of AF ablation. Also included within this document are recommendations concerning indications for AF ablation, technical performance of this procedure, and training. It is our hope to improve patient care by providing a foundation for those involved with care of patients with AF as well as those who perform AF ablation. It is recognized that this field continues to evolve rapidly and that this document will need to be updated. Successful AF ablation programs optimally should consist of a cooperative team of cardiologists, electrophysiologists, and surgeons to ensure appropriate indications, procedure selection, and follow-up.

PURPOSE: To examine the efficacy of ACE inhibitors for treatment of nondiabetic renal disease. DATA SOURCES: 11 randomized, controlled trials comparing the efficacy of antihypertensive regimens including ACE inhibitors to the efficacy of regimens without ACE inhibitors in predominantly nondiabetic renal disease. STUDY SELECTION: Studies were identified by searching the MEDLINE database for English-language studies evaluating the effects of ACE inhibitors on renal disease in humans between May 1977 (when ACE inhibitors were approved for trials in humans) and September 1997. DATA EXTRACTION: Data on 1860 nondiabetic patients were analyzed. DATA SYNTHESIS: Mean duration of follow-up was 2.2 years. Patients in the ACE inhibitor group had a greater mean decrease in systolic and diastolic blood pressure (4.5 mm Hg [95% CI, 3.0 to 6.1 mm Hg]) and 2.3 mm Hg [CI, 1.4 to 3.2 mm Hg], respectively) and urinary protein excretion (0.46 g/d [CI, 0.33 to 0.59 g/d]). After adjustment for patient and study characteristics at baseline and changes in systolic blood pressure and urinary protein excretion during follow-up, relative risks in the ACE inhibitor group were 0.69 (CI, 0.51 to 0.94) for end-stage renal disease and 0.70 (CI, 0.55 to 0.88) for the combined outcome of doubling of the baseline serum creatinine concentration or end-stage renal disease. Patients with greater urinary protein excretion at baseline benefited more from ACE inhibitor therapy (P = 0.03 and P = 0.001, respectively), but the data were inconclusive as to whether the benefit extended to patients with baseline urinary protein excretion less than 0.5 g/d. CONCLUSION: Antihypertensive regimens that include ACE inhibitors are more effective than regimens without ACE inhibitors in slowing the progression of nondiabetic renal disease. The beneficial effect of ACE inhibitors is mediated by factors in addition to decreasing blood pressure and urinary protein excretion and is greater in patients with proteinuria. Angiotensin-converting inhibitors are indicated for treatment of nondiabetic patients with chronic renal disease and proteinuria and, possibly, those without proteinuria.