Quantitative analysis of redox proteome reveals oxidation-sensitive protein thiols acting in fundamental processes of developmental hematopoiesis.

Fetal and adult hematopoietic stem and progenitor cells (HSPCs) are characterized by distinct redox homeostasis that may influence their differential cellular behavior in normal and malignant hematopoiesis. In this work, we have applied a quantitative mass spectrometry-based redox proteomic approach to comprehensively describe reversible cysteine modifications in primary mouse fetal and adult HSPCs. We defined the redox state of 4,438 cysteines in fetal and adult HSPCs and demonstrated a higher susceptibility to oxidation of protein thiols in fetal HSPCs. Our data identified ontogenic changes to oxidation state of thiols in proteins with a pronounced role in metabolism and protein homeostasis. Additional redox proteomic analysis identified oxidation changes to thiols acting in mitochondrial respiration as well as protein homeostasis to be triggered during onset of MLL-ENL leukemogenesis in fetal HSPCs. Our data has demonstrated that redox signaling contributes to the regulation of fundamental processes of developmental hematopoiesis and has pinpointed potential targetable redox-sensitive proteins in in utero-initiated MLL-rearranged leukemia.

Vismodegib in patients with advanced basal cell carcinoma: Primary analysis of STEVIE, an international, open-label trial.

BACKGROUND: The SafeTy Events in VIsmodEgib study (STEVIE, ClinicalTrials.gov, NCT01367665), assessed safety and efficacy of vismodegib-a first-in-class Hedgehog pathway inhibitor demonstrating clinical benefit in advanced basal cell carcinoma (BCC)-in a patient population representative of clinical practice. Primary analysis data are presented. PATIENTS AND METHODS: Patients with locally advanced or metastatic BCC received oral vismodegib 150 mg/d until progressive disease, unacceptable toxicity, or withdrawal. Primary objective was safety. Efficacy variables were assessed as secondary end-points. RESULTS: Evaluable adult patients (N = 1215, 1119 locally advanced; 96 metastatic BCC) from 36 countries were treated; 147 patients (12%) remained on study at time of reporting. Median (range) treatment duration was 8.6 (0-44) months. Most patients (98%) had ≥1 treatment-emergent adverse event (TEAE). The incidence of the most common TEAEs was consistent with reports in previous analyses. No association between creatine phosphokinase (CPK) abnormalities and muscle spasm was observed. Serious TEAEs occurred in 289 patients (23.8%). Exposure ≥12 months did not lead to increased incidence or severity of new TEAEs. The majority of the most common TEAEs ongoing at time of treatment discontinuation resolved by 12 months afterwards, regardless of Gorlin syndrome status. Response rates (investigator-assessed) in patients with histologically confirmed measurable baseline disease were 68.5% (95% confidence interval (CI) 65.7-71.3) in patients with locally advanced BCC and 36.9% (95% CI 26.6-48.1) in patients with metastatic BCC. CONCLUSIONS: The primary analysis of STEVIE demonstrates that vismodegib is tolerable in typical patients in clinical practice; safety profile is consistent with that in previous reports. Long-term exposure was not associated with worsening severity/frequency of TEAEs. Investigator-assessed response rates showed high rate of tumour control. CLINICALTRIALS.GOV: NCT01367665.

Dabrafenib plus trametinib versus dabrafenib monotherapy in patients with metastatic BRAF V600E/K-mutant melanoma: long-term survival and safety analysis of a phase 3 study.

BACKGROUND: Previous analysis of COMBI-d (NCT01584648) demonstrated improved progression-free survival (PFS) and overall survival (OS) with combination dabrafenib and trametinib versus dabrafenib monotherapy in BRAF V600E/K-mutant metastatic melanoma. This study was continued to assess 3-year landmark efficacy and safety after ≥36-month follow-up for all living patients. PATIENTS AND METHODS: This double-blind, phase 3 study enrolled previously untreated patients with BRAF V600E/K-mutant unresectable stage IIIC or stage IV melanoma. Patients were randomized to receive dabrafenib (150 mg twice daily) plus trametinib (2 mg once daily) or dabrafenib plus placebo. The primary endpoint was PFS; secondary endpoints were OS, overall response, duration of response, safety, and pharmacokinetics. RESULTS: Between 4 May and 30 November 2012, a total of 423 of 947 screened patients were randomly assigned to receive dabrafenib plus trametinib (n = 211) or dabrafenib monotherapy (n = 212). At data cut-off (15 February 2016), outcomes remained superior with the combination: 3-year PFS was 22% with dabrafenib plus trametinib versus 12% with monotherapy, and 3-year OS was 44% versus 32%, respectively. Twenty-five patients receiving monotherapy crossed over to combination therapy, with continued follow-up under the monotherapy arm (per intent-to-treat principle). Of combination-arm patients alive at 3 years, 58% remained on dabrafenib plus trametinib. Three-year OS with the combination reached 62% in the most favourable subgroup (normal lactate dehydrogenase and <3 organ sites with metastasis) versus only 25% in the unfavourable subgroup (elevated lactate dehydrogenase). The dabrafenib plus trametinib safety profile was consistent with previous clinical trial observations, and no new safety signals were detected with long-term use. CONCLUSIONS: These data demonstrate that durable (≥3 years) survival is achievable with dabrafenib plus trametinib in patients with BRAF V600-mutant metastatic melanoma and support long-term first-line use of the combination in this setting.

More than 5000 patients with metastatic melanoma in Europe per year do not have access to recommended first-line innovative treatments.

BACKGROUND: Despite the efficacy of innovative treatments for metastatic melanoma, their high costs has led to disparities in cancer care among different European countries. We analysed the availability of these innovative therapies in Europe and estimated the number of patients without access to first-line recommended treatment per current guidelines of professional entities such as the European Society for Medical Oncology (ESMO), the European Organisation for Research and Treatment of Cancer (EORTC), the European Association of Dermato-Oncology (EADO), and European Dermatology Forum (EDF). MATERIALS AND METHODS: Web-based online survey was conducted in 30 European countries with questions about the treatment schedules from 1st May 2015 to 1st May 2016: number of metastatic melanoma patients, registration and reimbursement of innovative medicines (updated data, as of 1st October 2016), percentage of patients treated and availability of clinical studies and compassionate-use programmes. RESULTS: The recommended BRAF inhibitor (BRAFi) + MEK inhibitor (MEKi) combination was both registered and fully reimbursed in 9/30 (30%) countries, and in 13/30 (43%) (all from Eastern Europe) not reimbursed. First-line immunotherapy with anti-PD1 antibodies was registered and fully reimbursed in 14/30 (47%) countries, while in 13/30 (43%) (all from Eastern Europe) not reimbursed. It was estimated that in Europe 19,600 patients with metastatic melanoma are treated, and 5238 (27%) do not have access to recommended first-line therapy. Significant correlation was found between human development index (HDI, UNDP report 2015), (r = 0.662; p < 0.001), health expenditure per capita (r = 0.695; p < 0.001) and the Mackenbach score of health policy performance (r = 0.765; p < 0.001) with the percentage of patients treated with innovative medicines and a number of reimbursed medicines. CONCLUSIONS: Great discrepancy exists in metastatic melanoma treatment across Europe. It is crucial to increase the awareness of national and European policymakers, oncological societies, melanoma patients' associations and pharma industry.

Surgical outcomes in patients with cutaneous malignant melanoma in Europe - a systematic literature review.

There is limited comparative evidence of the outcomes of different types of surgical management in patients with malignant melanoma in Europe. To address that gap we conducted a systematic literature review to summarize studies reporting outcomes of surgical procedures in patients with malignant melanoma in Europe. Medline was searched for European studies published in English, between 2004 and 2014 reporting surgical outcomes in adults with cutaneous malignant melanoma. We identified 23 studies that evaluated 18 332 patients treated surgically between 1979 and 2009 from 11 European countries. Most of the studies (21/23) were observational; the two remaining studies were randomized controlled trials (RCTs). Studies compared the effect of a range of surgical interventions on a range of clinical outcomes, more commonly overall survival (OS) and disease-free survival (DFS)/recurrence-free survival (RFS). Wider excisions were not associated with improved survival in patients with melanoma thickness ≥2 mm in both studies (RCTs), however, recent results based on long-term follow-up data associate 3 cm excision margins (vs. 1 cm) with favourable survival outcomes. There was some evidence that complete lymph node dissection after positive sentinel lymph node offers survival benefits over therapeutic lymph node dissection. Sentinel lymph node biopsy was not shown to be associated with significant OS benefits, however, it was overly related with higher rates of DFS/RFS. This review highlights the difficulties of making comparisons between different types of surgical procedures for malignant melanoma. As surgery remains the main treatment, this is an important field, and further evidence, particularly from RCTs, is needed.

Trends in cutaneous malignant melanoma in Sweden 1997-2011: thinner tumours and improved survival among men.

BACKGROUND: Both patient survival and the proportion of patients diagnosed with thin cutaneous malignant melanoma (CMM) have been steadily rising in Sweden as in most Western countries, although the rate of improvement in survival appears to have declined in Sweden at the end of the last millennium. OBJECTIVES: To analyse the most recent trends in the distribution of tumour thickness (T category) as well as CMM-specific survival in Swedish patients diagnosed during 1997-2011. METHODS: This nationwide population-based study included 30,590 patients registered in the Swedish Melanoma Register (SMR) and diagnosed with a first primary invasive CMM during 1997-2011. The patients were followed through 2012 in the national Cause of Death Register. RESULTS: Logistic and Cox regression analyses adjusting for age at diagnosis, tumour site and healthcare region were carried out. The odds ratio for being diagnosed with thicker tumours was significantly reduced (P < 0·001) and the CMM-specific survival significantly improved in men diagnosed during 2007-2011 compared with men diagnosed during 1997-2001 (hazard ratio = 0·81; 95% confidence interval 0·72-0·91; P < 0·001), while the corresponding differences for women were not significant. Women were diagnosed with significantly thicker tumours during 2002-2006 and a tendency towards decreased survival was observed compared with those diagnosed earlier (during 1997-2001) and later (during 2007-2011). CONCLUSIONS: In Sweden, the CMMs of men are detected earlier over time and this seems to be followed by an improved CMM-specific survival for men. Women are still diagnosed with considerably thinner tumours and they experience a better survival than men.

Prognostic factors in localized invasive primary cutaneous malignant melanoma: results of a large population-based study.

BACKGROUND: The prognostic impact of several histopathological prognostic features in cutaneous malignant melanoma (CMM) remains controversial. OBJECTIVES: To assess the independent prognostic value of mitotic rate, regression, tumour-infiltrating lymphocytes (TILs) and growth phase in primary stage I and II CMMs. METHODS: Clinicohistopathological data were obtained from the Stockholm-Gotland registry for 4237 patients diagnosed with an incident primary stage I or II CMM followed up to December 2011. The risk of CMM-specific death was evaluated by a Cox regression model. RESULTS: A mitotic rate of 1-10 mitoses per mm(2) [hazard ratio (HR) 1·69, 95% confidence interval (CI) 1·16-2·45] and > 10 mitoses per mm(2) (HR 2·27, 95% CI 1·46-3·52) were significant; TILs and regression were not. A more detailed analysis of data assessed between 1989 and 1995 confirmed significantly increased HRs for the presence vs. absence of mitoses (HR1-5/mm² 2·25, 95% CI 1·36-3·76; HR6-10/mm² 2·34, 95% CI 1·23-4·44; HR> 10/mm² 2·64, 95% CI 1·39-4·99). Other prognosticators were increasing T-stage vs. T1, presence of ulceration and presence of vertical growth phase (VGP). In T1 CMMs, an increasing tumour thickness vs. < 0·7 mm (HR0·7-0·8 mm 2·24, 95% CI 1·24-4·04; HR>0·8 mm  2·92, 95% CI 1·57-5·43) and presence of ulceration were significantly associated with higher HRs; mitotic rate, TILs, regression and growth phase were not. CONCLUSIONS: Determinants of increased risk of CMM death in stage I and II CMMs were increasing T-stage, presence of ulceration, presence of mitoses and VGP. This was not found for TILs or regression.

Proteomics analysis of melanoma metastases: association between S100A13 expression and chemotherapy resistance.

BACKGROUND: Disseminated cutaneous malignant melanoma (CMM) is commonly unresponsive to standard chemotherapies, and there are as yet no predictive markers of therapy response. METHODS: In the present study we collected fresh-frozen pretreatment lymph-node metastasis samples (n=14) from melanoma patients with differential response to dacarbazine (DTIC) or temozolomide (TMZ) chemotherapy, to identify proteins with an impact on treatment response. We performed quantitative protein profiling using tandem mass spectrometry and compared the proteome differences between responders (R) and non-responders (NR), matched for age, gender and histopathological type of CMM. RESULTS: Biological pathway analyses showed several signalling pathways differing between R vs NR, including Rho signalling. Gene expression profiling data was available for a subset of the samples, and the results were compared with the proteomics data. Four proteins with differential expression between R and NR were selected for technical validation by immunoblotting (ISYNA1, F13A1, CSTB and S100A13), and CSTB and S100A13 were further validated on a larger sample set by immunohistochemistry (n=48). The calcium binding protein S100A13 was found to be significantly overexpressed in NR compared with R in all analyses performed. CONCLUSIONS: Our results suggest that S100A13 is involved in CMM resistance to DTIC/TMZ.

Snus (Swedish smokeless tobacco) use and risk of stroke: pooled analyses of incidence and survival.

BACKGROUND: Snus is a moist smokeless tobacco product with high nicotine content. Its use has a short-term effect on the cardiovascular system, but the relationship between snus use and stroke is unclear. OBJECTIVE: The aim of this study was to assess the associations between use of snus and incidence of and survival after stroke, both overall and according to subtypes. METHODS: Pooled analyses of eight Swedish prospective cohort studies were conducted, including 130 485 men who never smoked. We estimated hazard ratios (HRs) with 95% confidence intervals (CIs) of incidence and death after diagnosis using Cox proportional hazard regression models and case fatality and survival using logistic regression and Kaplan-Meier methods, respectively. RESULTS: No associations were observed between the use of snus and the risk of overall stroke (HR 1.04, 95% CI 0.92-1.17) or of any of the stroke subtypes. The odds ratio (OR) of 28-day case fatality was 1.42 (95% CI 0.99-2.04) amongst users of snus who had experienced a stroke, and the HR of death during the follow-up period was 1.32 (95% CI 1.08-1.61). CONCLUSION: Use of snus was not associated with the risk of stroke. Hence, nicotine is unlikely to contribute importantly to the pathophysiology of stroke. However, case fatality was increased in snus users, compared with nonusers, but further studies are needed to determine any possible causal mechanisms.

KIT, NRAS and BRAF mutations in sinonasal mucosal melanoma: a study of 56 cases.

BACKGROUND: Mucosal melanomas in the head and neck region are most frequently located in the nasal cavity and paranasal sinuses. Sinonasal mucosal melanoma (SNMM) comprises <1% of all melanomas. The aim was to determine the KIT, NRAS and BRAF mutation frequencies in a large series of primary SNMMs. METHODS: Laser capture microdissection was used to isolate tumour cells from 56 formalin-fixed paraffin-embedded tumours. The tumour cells were screened for KIT, NRAS and BRAF mutations by direct sequencing. RESULTS: Overall, 21% (12 out of 56) of SNMMs harboured KIT, NRAS or BRAF mutations. Mutations in these oncogenes occurred in a mutually exclusive manner. Both KIT and BRAF mutations were identified at a similar frequency of 4% each (2 out of 56), whereas NRAS mutations were detected in 14% (8 out of 56) of the SNMMs. Four of the NRAS mutations were located in exon 1. Mutations in these oncogenes were significantly more common in melanomas located in the paranasal sinuses than in nasal cavity (P=0.045). In a multivariate analysis, patients with melanomas in the nasal cavity had a significantly better overall survival than those with tumours in the paranasal sinuses (P=0.027). CONCLUSION: Our findings show that KIT and BRAF mutations, which are accessible for present targeted therapies, are only rarely present in SNMMs, whereas NRAS mutations seem to be relatively more frequent. The data show that majority of SNMMs harbour alterations in genes other than KIT, NRAS and BRAF.

Low level of education is associated with later stage at diagnosis and reduced survival in cutaneous malignant melanoma: a nationwide population-based study in Sweden.

BACKGROUND: A worse outcome has been reported for cutaneous malignant melanoma (CMM) patients with low socioeconomic status. We have investigated the association between level of education, clinical stage at diagnosis (stage at diagnosis) and CMM-specific survival in Sweden. METHODS: We identified 27,235 patients from the Swedish Melanoma Register diagnosed with a primary invasive CMM between 1990 and 2007 and linked data to nationwide, population-based, health and census registers with a follow-up to 2010. RESULTS: The odds ratio (OR) of higher disease stage at diagnosis was significantly increased in lower education groups (OR stage II versus I=1.6; 95% confidence interval (CI)=1.5-1.7. OR stage III-IV versus I=2.3; 95% CI=1.8-2.9). The risk of dying of CMM, was significantly increased in patients with low (hazard ratio (HR) low versus high=2.02; 95% CI=1.80-2.26; p<0.0001) and intermediate (HR intermediate versus high=1.35; 95% CI=1.20-1.51; p<0.0001) level of education. After adjustment for age, gender, stage at diagnosis and other known prognostic factors, the HRs remained significant for low versus high (HR=1.13; 95% CI=1.01-1.27; p=0.04) but not for intermediate versus high (HR=1.11; 95% CI=0.99-1.24; p=0.08) education. The HR associated with low level of education was significantly higher among female patients, patients <55 years, patients with truncal tumours and during the first 5 years after diagnosis. CONCLUSION: Lower level of education is associated with reduced CMM-specific survival, which may at least partially be attributed to a more advanced stage at diagnosis. These results emphasise the need for improved early detection strategies.

Primary sinonasal malignant melanoma: a nationwide study of the Swedish population, 1960-2000.

OBJECTIVE: To establish population-based trends for sinonasal mucosal melanoma (SNMM) in Sweden. METHODS: We identified 186 patients from the Swedish National Cancer Registry diagnosed with primary melanomas arising from the nasal cavity, paranasal sinuses, or both, during the period 1960 through 2000. Incidence, gender and age, primary anatomical sites, geographic distribution, treatment and survival were investigated. RESULTS: The age-standardized incidence of SNMM increased significantly during the 41-year-period, with a higher overall incidence for females than males, but with a more rapid increase for males than for females. The incidence increased with age, peaking after the eightieth year in both genders. About 70 % of the cases were clinically amelanotic. The most common primary treatment was surgery. Five-year, disease-specific survival rates were poor for all these patients, but women had a significantly better survival time than men. For both genders the survival rate lengthened during the study period, irrespective of therapeutic strategy. CONCLUSION: SNMM is a rare disease, but the incidence in Sweden has increased significantly from 1960 through 2000, although not at the same pace as that of cutaneous malignant melanoma. Both the incidence and the survival were significantly higher in females than in males, but the reason for these gender differences is unknown.

Prognostic subclassifications of T1 cutaneous melanomas based on ulceration, tumour thickness and Clark's level of invasion: results of a population-based study from the Swedish Melanoma Register.

BACKGROUND: Survival and prognostic factors for thin melanomas have been studied relatively little in population-based settings. This patient group accounts for the majority of melanomas diagnosed in western countries today, and better prognostic information is needed. OBJECTIVES: The aim of this study was to use established prognostic factors such as ulceration, tumour thickness and Clark's level of invasion for risk stratification of T1 cutaneous melanoma. METHODS: From 1990 to 2008, the Swedish Melanoma Register included 97% of all melanomas diagnosed in Sweden. Altogether, 13,026 patients with T1 melanomas in clinical stage I were used for estimating melanoma-specific 10- and 15-year mortality rates. The Cox regression model was used for further survival analysis on 11,165 patients with complete data. RESULTS: Ulceration, tumour thickness and Clark's level of invasion all showed significant, independent, long-term prognostic information. By combining these factors the patients could be subdivided into three risk groups: a low-risk group (67·9% of T1 cases) with a 10-year melanoma-specific mortality rate of 1·5% (1·2-1·9%); an intermediate-risk group (28·6% of T1 cases) with a 10-year mortality rate of 6·1% (5·0-7·3%); and a high-risk group (3·5% of T1 cases) with a 10-year mortality rate of 15·6% (11·2-21·4%). The high- and intermediate-risk groups accounted for 66% of melanoma deaths within T1. CONCLUSIONS: Using a population-based melanoma register, and combining ulceration, tumour thickness and Clark's level of invasion, three distinct prognostic subgroups were identified.

Health-related quality of life in patients with high-risk melanoma randomised in the Nordic phase 3 trial with adjuvant intermediate-dose interferon alfa-2b.

PURPOSE: To compare health-related quality of life (HRQoL) and side-effects in patients with high-risk melanoma participating in a randomised phase III trial of adjuvant interferon alfa-2b (IFN). PATIENTS AND METHODS: A total of 855 patients with histologically verified resected cutaneous melanoma in AJCC stage IIb (T4 N0 M0) or stage III (Tx N1-3 M0) were randomised to: Arm A: observation only (n = 284); Arm B: 1-year treatment: induction: IFN alfa-2b, 10 MU (flat dose), SC, 5 days/week, 4 weeks, maintenance: IFN alfa-2b, 10 MU (flat dose), SC, 3 days/week for 12 months (n = 285); or Arm C: 2 years of same treatment as Arm B. HRQoL was assessed using The European Organisation for Research and Treatment of Cancer Core Questionnaire (EORTC QLQ-C30) before randomisation and at 8 pre-defined time-points during 2 years. IFN-related side-effects were assessed by a study-specific questionnaire. RESULTS: > 80% of eligible patients returned questionnaires at the different assessment points. Statistically significant interactions between randomisation arm and time after randomisation were found for almost all EORTC QLQ-30 variables. While patients in Arm A improved or remained at baseline levels; patients in Arms B and C reported decreased functioning and quality of life, and an increase in side-effects during their treatment. Patients in Arm B improved after the 12th month assessment, when IFN treatment was scheduled to end, to the 16th month assessment (p < 0.001). The same pattern of improvement was found for 5 of 7 interferon-related side-effects. CONCLUSION: A significant negative impact on HRQoL of IFN treatment was demonstrated, however the impact were reversible when treatment was stopped.

Association of MC1R variants and host phenotypes with melanoma risk in CDKN2A mutation carriers: a GenoMEL study.

BACKGROUND: Carrying the cyclin-dependent kinase inhibitor 2A (CDKN2A) germline mutations is associated with a high risk for melanoma. Penetrance of CDKN2A mutations is modified by pigmentation characteristics, nevus phenotypes, and some variants of the melanocortin-1 receptor gene (MC1R), which is known to have a role in the pigmentation process. However, investigation of the associations of both MC1R variants and host phenotypes with melanoma risk has been limited. METHODS: We included 815 CDKN2A mutation carriers (473 affected, and 342 unaffected, with melanoma) from 186 families from 15 centers in Europe, North America, and Australia who participated in the Melanoma Genetics Consortium. In this family-based study, we assessed the associations of the four most frequent MC1R variants (V60L, V92M, R151C, and R160W) and the number of variants (1, ≥2 variants), alone or jointly with the host phenotypes (hair color, propensity to sunburn, and number of nevi), with melanoma risk in CDKN2A mutation carriers. These associations were estimated and tested using generalized estimating equations. All statistical tests were two-sided. RESULTS: Carrying any one of the four most frequent MC1R variants (V60L, V92M, R151C, R160W) in CDKN2A mutation carriers was associated with a statistically significantly increased risk for melanoma across all continents (1.24 × 10(-6) ≤ P ≤ .0007). A consistent pattern of increase in melanoma risk was also associated with increase in number of MC1R variants. The risk of melanoma associated with at least two MC1R variants was 2.6-fold higher than the risk associated with only one variant (odds ratio = 5.83 [95% confidence interval = 3.60 to 9.46] vs 2.25 [95% confidence interval = 1.44 to 3.52]; P(trend) = 1.86 × 10(-8)). The joint analysis of MC1R variants and host phenotypes showed statistically significant associations of melanoma risk, together with MC1R variants (.0001 ≤ P ≤ .04), hair color (.006 ≤ P ≤ .06), and number of nevi (6.9 × 10(-6) ≤ P ≤ .02). CONCLUSION: Results show that MC1R variants, hair color, and number of nevi were jointly associated with melanoma risk in CDKN2A mutation carriers. This joint association may have important consequences for risk assessments in familial settings.

Use of snus and risk for cardiovascular disease: results from the Swedish Twin Registry.

OBJECTIVE: To study the association between snus use and the risk for cardiovascular disease, i.e. ischemic heart disease and stroke. DESIGN: Cohort study. SETTING: Sweden. SUBJECTS: Sixteen thousand six hundred and forty-two male Swedish twins participating in the Screening Across the Lifespan Twin Study, conducted in 1998- 2002, were followed for incident cardiovascular disease. Participants were without a history of cardiovascular disease at baseline and incident cases were identified via the Swedish Cause of Death Register and Hospital Discharge Register. RESULTS: Overall, there was no association between use of snus and risk for cardiovascular disease. Current snus users, without a smoking history, had a relative risk of 1.00 (95% confidence interval 0.69-1.46) for cardiovascular disease as compared to non users. Corresponding relative risks for ischemic heart disease and stroke were 0.85 (95% confidence interval 0.51-1.41) and 1.18 (95% confidence interval 0.67-2.08), respectively. In smoking adjusted models, risk estimates for ischemic heart disease in relation to snus use were all close to unity regardless of timing or intensity of snus use. However, current heavy snus users (consuming more than four cans week(-1)) had a relative risk for stroke of 1.75 (95% confidence interval 0.95-3.21). CONCLUSION: These data do not support any strong association between snus use and risk for cardiovascular disease.

Randomized clinical trial of antibiotic therapy versus appendicectomy as primary treatment of acute appendicitis in unselected patients.

BACKGROUND: A trial in selected men suggested that antibiotic therapy could be an alternative to appendicectomy in appendicitis. This study aimed to evaluate antibiotic therapy in unselected men and women with acute appendicitis. METHODS: Consecutive patients were allocated to study (antibiotics) or control (surgery) groups according to date of birth. Study patients received intravenous antibiotics for 24 h and continued at home with oral antibiotics for 10 days. Control patients had a standard appendicectomy. Follow-up at 1 and 12 months was carried out according to intention and per protocol. RESULTS: Study and control patients were comparable at inclusion; 106 (52.5 per cent) of 202 patients allocated to antibiotics completed the treatment and 154 (92.2 per cent) of 167 patients allocated to appendicectomy had surgery. Treatment efficacy was 90.8 per cent for antibiotic therapy and 89.2 per cent for surgery. Recurrent appendicitis occurred in 15 patients (13.9 per cent) after a median of 1 year. A third of recurrences appeared within 10 days and two-thirds between 3 and 16 months after hospital discharge. Minor complications were similar between the groups. Major complications were threefold higher in patients who had an appendicectomy (P < 0.050). CONCLUSION: Antibiotic treatment appears to be a safe first-line therapy in unselected patients with acute appendicitis. REGISTRATION NUMBER: NCT00469430 (http://www.clinicaltrials.gov).

Postoperative adverse events and long-term survival after cytoreductive surgery and intraperitoneal chemotherapy.

BACKGROUND: Peritoneal carcinomatosis (PC) is fatal without special combined cytoreductive surgery (CRS) and intraperitoneal chemotherapy (IPC). This study was designed to identify factors that may increase the risk of postoperative morbidity and mortality from combined CRS and IPC interventions for PC. Survival based on primary tumour type and extent of surgery is reported. METHODS: Between May 1991 and November 2004, 123 patients were treated with CRS and IPC for PC. Based on the National Cancer Institute Common Toxicity Criteria for grade 3 and 4, data on 30 days postoperative morbidity and 90 days mortality were analysed. RESULTS: Grade 3-4 adverse events were observed in 51 patients (41%) and were associated with stoma formation, duration of surgery, peroperative blood loss and peritoneal cancer index (PCI). Excision, or electrocautery evaporation, of tumour from small bowel surface was correlated to bowel morbidity. Five patients had treatment-related mortality (4%) within 90 days. Survival was associated with macroscopic radical surgery, prior surgical score, PCI and primary tumour type. CONCLUSIONS: CRS and IPC for PC are associated with high morbidity and mortality. However, in light of the potential benefit indicated by long-term survival, the adverse event from this treatment is considered acceptable.