Clinical relevance of as-needed treatment with nalmefene in alcohol-dependent patients.

Nalmefene is the first drug approved for reduction of alcohol consumption. The aim of this study was to evaluate the clinical relevance of treatment with nalmefene in alcohol-dependent patients with a high drinking risk level from two randomised placebo-controlled 6-month studies (NCT00811720 and NCT00812461). Response criteria were based on alcohol consumption, Clinical Global Impression, and Short Form Health Survey mental component summary scores at month 6, analysed using logistic regression. The proportion of responders was higher in the nalmefene group than in the placebo group with odds ratios significantly in favour of nalmefene for all responder criteria; numbers-needed-to-treat ranged from 6 to 10. Significant differences from placebo in clinician-rated and patient-reported outcomes, and liver enzymes further supported the clinical relevance of the treatment effect. In conclusion, this study supports the clinical relevance of nalmefene treatment in patients with alcohol dependence. Nalmefene may help to reduce the alcohol-related burden and the large treatment gap, with currently less than 10% of alcohol-dependent patients in Europe receiving treatment.

Efficacy of as-needed nalmefene in alcohol-dependent patients with at least a high drinking risk level: results from a subgroup analysis of two randomized controlled 6-month studies.

AIMS: The aim of the study was to investigate the efficacy and safety of as-needed use of nalmefene 18 mg versus placebo in reducing alcohol consumption in patients who did not reduce their alcohol consumption after an initial assessment, i.e. the pooled subgroup of patients with at least a high drinking risk level (men: >60 g/day; women: >40 g/day) at both screening and randomization from the two randomized controlled 6-month studies ESENSE 1 (NCT00811720) and ESENSE 2 (NCT00812461). METHODS: Nalmefene 18 mg and placebo were taken on an as-needed basis. All the patients also received a motivational and adherence-enhancing intervention (BRENDA). The co-primary outcomes were number of heavy drinking days (HDDs) and mean total alcohol consumption (g/day) in Month 6 measured using the Timeline Follow-back method. Additionally, data on clinical improvement, liver function and safety were collected throughout the study. RESULTS: The pooled population consisted of 667 patients: placebo n = 332; nalmefene n = 335. There was a superior effect of nalmefene compared with placebo in reducing the number of HDDs [treatment difference: -3.2 days (95% CI: -4.8; -1.6); P < 0.0001] and total alcohol consumption [treatment difference: -14.3 g/day (-20.8; -7.8); P < 0.0001] at Month 6. Improvements in clinical status and liver parameters were greater in the nalmefene group compared with the placebo group. Adverse events and adverse events leading to dropout were more common with nalmefene than placebo. CONCLUSION: As-needed nalmefene was efficacious in reducing alcohol consumption in patients with at least a high drinking risk level at both screening and randomization, and the effect in this subgroup was larger than in the total population.

Extending the treatment options in alcohol dependence: a randomized controlled study of as-needed nalmefene.

BACKGROUND: There is a large treatment gap in alcohol dependence, and current treatments are only moderately effective in preventing relapse. New treatment modalities, allowing for reduction of alcohol consumption as a treatment goal are needed. This study evaluated the efficacy of as-needed use of the opioid system modulator nalmefene in reducing alcohol consumption in patients with alcohol dependence. METHODS: Six hundred and four patients (placebo = 298; nalmefene = 306),≥18 years of age, with a diagnosis of alcohol dependence,≥6 heavy drinking days, and average alcohol consumption≥World Health Organization medium drinking risk level in the 4 weeks preceding screening, were randomized (1:1) to 24 weeks of as-needed placebo or nalmefene 18 mg. RESULTS: Patients taking placebo (n = 289) and patients taking nalmefene (n = 290) were included in the efficacy analyses. At Month 6, there was a significant effect of nalmefene compared with placebo in reducing the number of heavy drinking days (-2.3 days [95% confidence interval:-3.8 to-.8]; p = .0021) and total alcohol consumption (-11.0 g/day [95% confidence interval:-16.8 to-5.1]; p = .0003). Improvements in Clinical Global Impression and liver enzymes were larger in the nalmefene group compared with placebo at Week 24. Adverse events (most mild or moderate) and dropouts due to adverse events were more common with nalmefene than placebo. The number of patients with serious adverse events was similar in the two groups. CONCLUSIONS: Nalmefene provides clinical benefit, constitutes a potential new pharmacological treatment paradigm in terms of the treatment goal and dosing regimen, and provides a method to address the unmet medical need in patients with alcohol dependence that need to reduce their alcohol consumption.

Memantine for patients with Parkinson's disease dementia or dementia with Lewy bodies: a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Previous studies have suggested that patients with Lewy-body-related dementias might benefit from treatment with the N-methyl D-aspartate receptor antagonist memantine, but further data are needed. Therefore, the efficacy and safety of memantine were investigated in patients with mild to moderate Parkinson's disease dementia (PDD) or dementia with Lewy bodies (DLB). METHODS: Patients (≥50 years of age) with mild to moderate PDD or DLB were recruited from 30 specialist centres in Austria, France, Germany, the UK, Greece, Italy, Spain, and Turkey. They were randomly assigned to placebo or memantine (20 mg per day) according to a computer-generated list. Patients and all physicians who had contact with them were masked to treatment assignment. No primary endpoint was defined. Safety analyses were done for all patients who took at least one dose of memantine or placebo, and efficacy analyses were done for all patients who had at least one valid postbaseline assessment. This trial is registered with ClinicalTrials.gov, number NCT00855686. FINDINGS: Of the 199 patients randomly assigned to treatment, 34 with DLB and 62 with PDD were given memantine, and 41 with DLB and 58 with PDD were given placebo. 159 (80%) patients completed the study: 80 in the memantine group and 79 in the placebo group. 93 patients treated with memantine and 97 patients treated with placebo were included in the efficacy analysis. At week 24, patients with DLB who received memantine showed greater improvement according to Alzheimer's disease cooperative study (ADCS)-clinical global impression of change scores than did those who received placebo (mean change from baseline 3·3 vs 3·9, respectively, difference -0·6 [95% CI -1·2 to -0·1]; p=0·023). No significant differences were noted between the two treatments in patients with PDD (3·6 with memantine vs 3·8 with placebo, -0·1 [-0·6 to 0·3]; p=0·576) or in the total population (3·5 with memantine vs 3·8 with placebo, -0·3 [-0·7 to 0·1]; p=0·120). Neuropsychiatric-inventory scores showed significantly greater improvement in the memantine group than in the placebo group (-4·3 vs 1·7, respectively, -5·9 [-11·6 to -0·2]; p=0·041) in patients with DLB, but not in those with PDD (-1·6 vs -0·1, respectively, -1·4 [-5·9 to 3·0]; p=0·522) or in the total patient population (-2·6 vs 0·4, respectively, -2·9 [-6·3 to 0·5]; p=0·092). In most of the cognitive test scores, ADCS-activities of daily living, and Zarit caregiver burden scores, there were no significant differences between the two treatment groups in any of the study populations. The incidence of adverse events and number of discontinuations due to adverse events were similar in the two groups. The most common serious adverse events were stroke (n=3 in memantine group), falls (n=2 in memantine group; n=1 in placebo group), and worsening of dementia (n=2 in memantine group). INTERPRETATION: Memantine seems to improve global clinical status and behavioural symptoms of patients with mild to moderate DLB, and might be an option for treatment of these patients. FUNDING: Lundbeck.

Effects of memantine on cognition in patients with moderate to severe Alzheimer's disease: post-hoc analyses of ADAS-cog and SIB total and single-item scores from six randomized, double-blind, placebo-controlled studies.

OBJECTIVES: The post-hoc analyses reported here evaluate the specific effects of memantine treatment on ADAS-cog single-items or SIB subscales for patients with moderate to severe AD. METHODS: Data from six multicentre, randomised, placebo-controlled, parallel-group, double-blind, 6-month studies were used as the basis for these post-hoc analyses. All patients with a Mini-Mental State Examination (MMSE) score of less than 20 were included. Analyses of patients with moderate AD (MMSE: 10-19), evaluated with the Alzheimer's disease Assessment Scale (ADAS-cog) and analyses of patients with moderate to severe AD (MMSE: 3-14), evaluated using the Severe Impairment Battery (SIB), were performed separately. RESULTS: The mean change from baseline showed a significant benefit of memantine treatment on both the ADAS-cog (p < 0.01) and the SIB (p < 0.001) total score at study end. The ADAS-cog single-item analyses showed significant benefits of memantine treatment, compared to placebo, for mean change from baseline for commands (p < 0.001), ideational praxis (p < 0.05), orientation (p < 0.01), comprehension (p < 0.05), and remembering test instructions (p < 0.05) for observed cases (OC). The SIB subscale analyses showed significant benefits of memantine, compared to placebo, for mean change from baseline for language (p < 0.05), memory (p < 0.05), orientation (p < 0.01), praxis (p < 0.001), and visuospatial ability (p < 0.01) for OC. CONCLUSION: Memantine shows significant benefits on overall cognitive abilities as well as on specific key cognitive domains for patients with moderate to severe AD.

Recurrence in patients with oral and oropharyngeal squamous cell carcinoma: human papillomavirus and other risk factors.

CONCLUSIONS: The results confirm that tumour stage influences the risk of recurrence/second primary tumour (SPT). High-risk human papillomavirus (HPV)-infected patients have a significantly higher risk of recurrence/SPT compared with high-risk HPV-negative patients. High alcohol consumption was associated with a higher risk of recurrence/SPT. In this study, the competing risk of death in intercurrent disease (DICD) was given special consideration. OBJECTIVES: The aim of the present study was to evaluate whether any of the factors which were found to increase the risk of oral and oropharyngeal squamous cell carcinoma (OOSCC) in previous analyses (smoking tobacco, alcohol, high-risk HPV infection, oral hygiene, missing teeth and dentures) have an influence on recurrence or the occurrence of a new SPT of OOSCC within the first 3 years following diagnosis. PATIENTS AND METHODS: One hundred and twenty-eight consecutive cases with planned curative treatment, who were part of a population-based case-control study carried out in southern Sweden between September 2000 and January 2004, were included. Only patients for whom the intention was curative treatment were eligible. The cases were followed to the first event of recurrence/SPT, death, loss to follow-up, 30 June 2005 or a maximum of 3 years. Time to the first event of recurrence/SPT was analysed by cumulative incidence, where DICD was a competing risk. Regression was performed on cause-specific hazard rates. RESULTS: After a median follow-up time of 22 months (range 0-36 months), 30 recurrences, 2 SPT, 12 lost to follow-up and 21 deaths before recurrence or SPT were observed. Tumour stage was associated with both a higher risk of recurrence/SPT and of DICD. In univariate analysis, patients with tonsillar carcinoma had a significantly higher risk of recurrence/SPT than patients with carcinoma at other sites, but there was no difference according to site in multivariate analyses. High alcohol consumption was associated with a higher risk of recurrence/SPT, but not of DICD. There was no increased risk of recurrence/SPT related to smoking, but there was an association between smoking and DICD. High-risk HPV-positive cases had a higher risk of recurrence/SPT, but a lower risk of DICD compared with high-risk HPV-negative cases. This seemingly higher risk should be interpreted by taking the competing risk of DICD into account.

Serum levels of uric acid and diabetes mellitus influence survival after surgery for primary hyperparathyroidism: a prospective cohort study.

BACKGROUND: Primary hyperparathyroidism (pHPT) is associated with an increased mortality attributable to cardiovascular disease (CVD), suggested to be alleviated by surgery. The exact mechanism of the beneficial influence of parathyroidectomy on survival is unknown. Furthermore, studies suggest that there is no increased mortality compared to the mortality rate in the general population during recent years. This study therefore investigated relative survival (RS), as well overall mortality associated with the clinical and biochemical variables in patients undergoing operation for sporadic pHPT. Furthermore, the influence of surgery on biochemical variables associated with pHPT was analyzed. METHODS: A group of 323 patients with sporadic pHPT operated between September 1989 and July 2003 were followed from surgery over a 10-year period. The median and mean follow-up time was 69 and 70 months, respectively (range: 1-120 months). Relative survival (RS) was calculated, and the impact of clinical and biochemical variables on overall death were evaluated. RESULTS: Postoperatively, serum levels of triglycerides and uric acid decreased. Glucose levels and glomerular filtration rate remained unchanged. A decreased RS was evident during the latter part of the 10 year follow-up period. In the multivariate Cox-analysis, diabetes mellitus (hazard ratio [HR] = 2.8, 95%; confidence interval [CI] 1.2-6.7), and the combination of an increased level of serum uric acid and cardiovascular disease (CVD) (HR = 8.6, 95%; CI 1.5-49.7) was associated with a higher mortality. The increased risk of death was evident for patients with persistently increased levels of uric acid postoperatively (HR = 4.8, 95%; CI = 1.4-16.01). CONCLUSIONS: Patients undergoing operation for pHPT had a decreased RS during a 10-year follow-up compared to the general population. This decrease in RS is associated with diabetes mellitus and increased levels of uric acid pre-and postoperatively.

Analysis of clinical characteristics, management and survival of patients with Ta T1 bladder tumours in Sweden between 1997 and 2001.

OBJECTIVE: To analyse the management and outcome of patients with Ta T1 urinary bladder cancer in a population-based national database. MATERIAL AND METHODS: Between 1997 and 2001, 94% of all newly diagnosed cases of urinary bladder cancer were registered in the Swedish National Bladder Cancer Register. Data were analysed regarding gender, healthcare region, stage and grade for patients with Ta T1 tumours. The choice of initial treatment in different regions was reviewed. Survival was analysed by calculating relative survival. RESULTS: Out of 9859 registered patients, there were 4442 Ta tumours and 2139 T1 tumours. The median age at diagnosis was 72 and 73 years for patients with Ta and T1 tumours, respectively. Seventy-six percent of the patients were men. The choice of treatment varied between different healthcare regions. A significant trend towards an increased use of intravesical therapy was seen over time. Significantly fewer older than younger patients received such therapy. There was also a tendency towards more intensive therapy in men. The bladder cancer relative 5-year survival rate was 93% for Ta and 75% for T1 tumours. Survival was similar for men and women. CONCLUSIONS: Our analysis revealed a regional variation in the treatment of bladder cancer. A large group of patients, even those at high risk, were still undertreated. However, the recent publication of guidelines may have contributed to an increased use of intravesical treatment. Urologists tended to treat TaG3 and T1G3 tumours more aggressively than T1G2 tumours. Therapeutic aggressiveness decreased as the age of the patients increased. The survival rate of patients with bladder cancer in Sweden seems to remain at the levels previously reported for the 1980s.

Oral status, oral infections and some lifestyle factors as risk factors for oral and oropharyngeal squamous cell carcinoma. A population-based case-control study in southern Sweden.

CONCLUSION: Our results show that average and poor oral hygiene and inadequate dental status are independent risk factors for oral and oropharyngeal squamous cell carcinoma (OOSCC), irrespective of tobacco and alcohol consumption. OBJECTIVE: To evaluate a possible relationship between oral cancer, oral hygiene, dental status, oral mucosal lesions and some lifestyle factors in a population-based case-control study. MATERIAL AND METHODS: Between September 2000 and January 2004, 132/165 (80%) of all incident cases of OOSCC and 320/396 (81%) of the intended eligible matched controls participated in the study. Cases and controls were subjected to an identical oral examination. A standardized protocol specially designed for the study was used. RESULTS: After adjusting for tobacco and alcohol consumption, average oral hygiene (OR 2.0; 95% CI 1.1-3.6) and poor oral hygiene (OR 5.3; 95% CI 2.5-11.3) emerged as significant risk factors for OOSCC. More than 20 lost teeth (OR 3.4; 95% CI 1.4-8.5), >5 defective teeth (OR 3.1; 95% CI 1.2-8.2) and poorly fitting or defective complete dentures (OR 3.8; 95% CI 1.3-11.4) were significant risk factors. Regular dental check-ups were associated with a decreased risk of OOSCC (OR 0.4; 95% CI 0.2-0.6).

Strong association between infection with human papillomavirus and oral and oropharyngeal squamous cell carcinoma: a population-based case-control study in southern Sweden.

CONCLUSIONS: The results of this study demonstrate a strong association between infection with high-risk types of human papillomavirus (HPV) and oral and oropharyngeal squamous cell carcinoma (OOSCC), suggesting that high-risk HPV types play a key role in carcinogenesis. The estimated proportion of OOSCC cases attributable to HPV infection was 35%. OBJECTIVE: HPV appears to have an aetiological role in OOSCC, despite the fact that the reported prevalences of HPV in both OOSCC patients and healthy individuals have varied widely. We aimed to investigate the presence and spectrum of both high- and low-risk HPVs in all consecutive cases of OOSCC in a Swedish healthcare region over a 3-year period and in population-based, matched healthy controls. MATERIAL AND METHODS: A total of 131 patients with OOSCC were studied. Samples taken from the surface of the tumour and from the tonsillar fossa using cotton-tipped swabs were investigated, together with exfoliated cells collected using a mouthwash. Tonsillar fossa and mouthwash specimens were collected in the same way from 320 matched controls. All samples were tested for HPV DNA by nested polymerase chain reaction using the primer pairs MY09/MY11 and GP5 + /GP6+, and in positive cases the HPV type was determined by DNA sequencing. RESULTS: Infection with high-risk HPV was shown to be a strong risk factor for OOSCC (OR = 63; 95% CI 14-480). Forty-seven (36%) of the cancer patients had > or =1 specimen that was positive for a high-risk HPV type (81% of which were HPV 16), while only 3 (0.94%) of the controls were positive for a high-risk HPV type. Seven (5.3%) of the cancer patients and 13 (4.1%) of the controls were positive for any of the mucosal, mucocutaneous or cutaneous low-risk HPV types.

Use of Swedish moist snuff, smoking and alcohol consumption in the aetiology of oral and oropharyngeal squamous cell carcinoma. A population-based case-control study in southern Sweden.

CONCLUSIONS: The results of this study confirm that both smoking of tobacco and alcohol consumption are risk factors for oral and oropharyngeal squamous cell carcinoma (OOSCC). The use of moist snuff had no effect on the risk of OOSCC, probably due to the low levels of tobacco-specific N-nitrosamines in Swedish moist snuff. OBJECTIVE: The aims of this population-based case-control study in southern Sweden were to establish risk estimates for cigarette and alcohol consumption and to evaluate whether Swedish moist snuff is a risk factor for OOSCC. MATERIAL AND METHODS: Between September 2000 and January 2004, 132/165 consecutive cases (80%) diagnosed with OOSCC and 320/396 matched controls (81%) were investigated. All subjects were interviewed and examined according to a standardized protocol. RESULTS: Individuals who drank > or =350 g of alcohol/week showed an increased risk of OOSCC (OR 2.6; 95% CI 1.3-5.4). Total lifetime consumption of tobacco for smoking (>250 kg) had a dose-response effect on the risk of OOSCC (OR 4.7; 95% CI 2.4-9.1). We found no increased risk of OOSCC associated with the use of Swedish moist snuff (OR 1.1; 95% CI 0.5-2.5).

The influence of surgical volume on hospital mortality and 5-year survival for carcinoma of the oesophagus and gastric cardia.

OBJECTIVE: To study the effects of hospital operation volume on hospital mortality and 5-year survival in patients treated with resection for carcinoma of the oesophagus and gastric cardia. INTRODUCTION: Surgery due to tumours of the oesophagus and gastric cardia is probably associated with the highest postoperative morbidity and mortality of all elective surgical procedures. Concentration to high-volume centres has been suggested to improve the outcome. MATERIALS AND METHODS: Between 1987 and 1996, all patients with squamous cell carcinoma or adenocarcinoma of the oesophagus or gastric cardia were identified from the Swedish Cancer Registry and the Swedish Hospital Discharge Registry. The study population was assessed according to patients operated at hospitals with a low (L-V), intermediate (I-V) or high operation volume (H-V), defined as <5 resections/year, 5-15 resections/year and >15 resections/year, respectively. We analyzed hospital mortality and 5-year survival. RESULTS: During the study period, 1429 patients were treated with resection for carcinoma of the oesophagus (n=665) or the gastric cardia (n = 764). A total of 74 hospitals were registered with at least one surgical resection, of which 90% performed <5 resections/year. The distribution of gender and age was comparable in the three groups. Hospital mortality was 10.4, 6.3 and 3.5% in the L-V, I-V and H-V groups, respectively. Overall 5-year survival was 17% (L-V), 19% (I-V) and 22% (H-V). Multivariate analysis showed an improved long-term survival for patients operated at H-V compared to L-V hospitals (p=0.02). CONCLUSION: This study supports an inverse relationship between hospital volume and hospital mortality after surgical tumour resection of the oesophagus or gastric cardia. Overall 5-year survival was significantly higher at high-volume hospitals compared to low-volume centres. We believe that concentrating these patients in high-volume hospitals is necessary to achieve high quality surgical treatment and to facilitate research aiming to improve prognosis.

Worse survival in breast cancer among women with recent childbirth: results from a Swedish population-based register study.

This study was designed to investigate how time since childbirth affects breast cancer survival using unselected population-based data linking data from the Swedish Cancer Registry, fertility register, and population census registers. A total of 14,693 parous women < or =45 years of age with breast cancer were identified. Information on deaths was collected, and 5- and 10-year survival rates were calculated according to time since most recent childbirth. Mortality during the first 10 years of follow-up was further investigated in a Cox analysis, with adjustments for age at diagnosis, time period during which the diagnosis was made, number of children, and age at the time of the first child's birth. Women with diagnosis during pregnancy had a 5-year survival rate of 52.1% (95% CI, 41.2%-61.9%) and a 10-year survival rate of 43.9% (95% CI, 33.1%-54.2%), compared with survival rates of 80.0% (95% CI, 79.6%-81.4%) and 68.6% (95% CI, 67.5%-69.7%), respectively, in women diagnosed >10 years since childbirth. In the multivariate model, we found that time since childbirth was associated with inferior survival rates in cases of diagnosis <8 years after childbirth, in which the lowest survival rates were seen in women with diagnosis during pregnancy in the first 5 years of follow-up (adjusted relative risk compared with women with >10 years since last childbirth, 2.6; 95% CI, 1.8-3.4). The adjusted hazard ratios could be described by a decreasing function of a logarithmic transformation of years since childbirth. We found that the time of follow-up was of importance, in that women with a recent pregnancy had particularly lower survival rates during the first 5 years after diagnosis. The mechanisms behind the poor survival in breast cancer for women with recent childbirth are not known, but we suggest that one explanation might be a lower proportion of hormone receptor-positive tumors.

Cancer incidence in relatives of a population-based set of cases of early-onset breast cancer with a known BRCA1 and BRCA2 mutation status.

BACKGROUND: Relatives of breast cancer cases have an increased risk of the disease. The risk increases with increasing numbers and decreasing age of onset of affected relatives. In families with a BRCA1 or a BRCA2 mutation, individual carrier status predicts the risk of breast cancer. In relatives of cases where both BRCA1 and BRCA2 mutations are excluded, the risk remains undetermined. METHODS: Standardized incidence ratios (SIRs) and cumulative cancer incidences were calculated for relatives of a population-based set of early-onset breast cancer index cases (younger than age 41 years) with a defined BRCA mutation status (n = 203). RESULTS: In first-degree relatives (FDRs) of mutation-negative cases, breast cancer incidences (SIR = 2.3), prostate cancer incidences (SIR = 1.7), cervix cancer incidences (SIR = 3.3) and nonmelanoma skin cancer incidences (SIR = 2.8) were increased. The risks of breast cancer, prostate cancer and nonmelanoma skin cancer were further increased in FDRs of breast cancer cases younger than 36 years of age. In high-risk individuals with at least one relative with breast cancer apart from the index case, but no BRCA mutation in the family, breast cancer incidence was increased (SIR = 5.3); again the prostate cancer incidence was elevated (SIR = 2.5). The cumulative incidence of breast cancer at ages 50 and 70 years for FDRs of index cases without a BRCA mutation was 3.6% and 12.8%, respectively. Similarly, the cumulative incidence of breast cancer for high-risk women was 6.3% and 21.1% at ages 50 and 70 years, and that for FDRs of BRCA mutation carriers was 17.2% and 27.7% at the same ages. CONCLUSION: The incidence of breast cancer is increased for FDRs of women with early-onset breast cancer irrespective of the BRCA status in the family. Risk increases with decreasing age and with increasing number of affected relatives. The incidences of prostate cancer, cervix cancer and nonmelanoma skin cancer are elevated for FDRs of early-onset breast cancer cases without a BRCA mutation, indicating a possible association between these cancers and early-onset breast cancer.

High proteinase 3-anti-neutrophil cytoplasmic antibody (ANCA) level measured by the capture enzyme-linked immunosorbent assay method is associated with decreased patient survival in ANCA-associated vasculitis with renal involvement.

Wegener granulomatosis (WG) and microscopic polyangiitis (MP), diseases associated with antineutrophil cytoplasmic antibodies (ANCA), had an extremely poor prognosis before the introduction of cyclophosphamide and corticosteroids for their treatment. However, there is still reduced patient survival, and some studies have documented severe side effects of the immunosuppressants used. This 10-yr follow-up study assessed 117 consecutive patients with WG or MP with biopsy-confirmed renal involvement. The cumulative relative patient survival was lower: 0.664 for women and 0.648 for men. The causes of death (n = 64) were in most cases registered as associated with the vasculitic disease. Analysis of possible predictive factors for patient survival by multiple Cox regression analysis revealed that a very high level of proteinase 3 (PR3)-ANCA measured by the capture ELISA method, a diagnosis of MP, and older age were factors predicting poorer patient survival. High levels of B-thrombocytes at time of diagnosis were associated with a better prognosis. For patients surviving the first year, remission-sustaining therapy with azathioprine for longer than 12 mo was associated with improved patient survival. Thirty-nine patients developed end-stage renal failure. Elevated serum creatinine at time of diagnosis and a very high level of PR3-ANCA by capture ELISA were factors predicting a higher risk for renal failure during follow-up. The epitope on PR3 assessed by capture ELISA needs to be further analyzed and explored: it seemed to implicate poorer patient and renal survival in WG or MP with renal involvement.

Hormone replacement therapy containing progestins and given continuously increases breast carcinoma risk in Sweden.

BACKGROUND: The authors previously reported an increased risk of breast carcinoma with longer duration of hormone replacement therapy (HRT) use. It is unclear if different types of HRT confer different risks. METHODS: In this study, a population-based cohort of 29,508 women were interviewed during 1990-1992 to determine whether there are any differences in breast carcinoma risk according to different types and duration of HRT use. RESULTS: At the end of the follow-up period in December 2001, the cohort constituted 298,649 person-years. Slightly more breast carcinoma cases were seen (n = 556) than expected (n = 508.37; standardized morbidity ratio =1.09, 95% confidence interval [CI] = 1.00-1.19). Approximately 3663 women had ever used HRT. In Cox regression models, time to breast carcinoma in relation to duration and type of HRT use was analyzed, adjusting for age at menarche, age at first full-term pregnancy, parity, age at menopause, family history of breast carcinoma, and age at interview. In women with a natural menopause, a significantly higher risk was observed for longer duration of combined continuous HRT use compared with never users (hazard ratio [HR] = 4.60, 95% CI = 2.39-8.84). Nonsignificant elevated risks also were observed for longer combined sequential (HR = 2.23, 95% CI = 0.90-5.56), gestagen only (HR = 3.74,9 5% CI = 0.94-14.97), and estriol use (HR = 1.89, 95% CI = 0.81-4.39). No increased risk was seen in women after 5 years of nonuse. When studying women who ever used only one type of HRT, even more elevated HRs for gestagen-containing preparations were seen. The highest risks were associated with the combined continuous and gestagen-only therapy in women with >/= 48 months of use. Use of estradiol without progestins did not increase breast carcinoma risk significantly. The authors estimated the cumulative risk of breast carcinoma in a 50-year-old woman with gestagen-containing therapies for >/= 48 months, with a follow-up of 10 years, to be 7% (95% CI = 5.4-11.4%) compared with 2% (95% CI = 1.6%-2.9%) for never-users of HRT. CONCLUSIONS: Longer use of HRT containing progestins significantly elevates breast carcinoma risk whereas estradiol use does not. Continued use of progestins rendered the highest risks. The yearly risk of breast carcinoma for long-term users of progestins is of the magnitude of 50% the risk of a BRCA1 mutation carrier.