Antidiabetics, statins and the risk of amyotrophic lateral sclerosis.

BACKGROUND: Medications that are used for treatment of metabolic disorders have been suggested to be associated with the development of amyotrophic lateral sclerosis (ALS). METHODS: To examine the associations of antidiabetics and statins with the subsequent risk of ALS we conducted a population-based nested case-control study of 2475 Swedish residents diagnosed with ALS during July 2006 to December 2013 and 12 375 population controls (five for each ALS case). We extracted information on filled prescriptions of antidiabetics and statins for both cases and controls from the Swedish Prescribed Drug Register during the years before ALS diagnosis. Conditional logistic regression was used to calculate odds ratios (ORs) for the associations of these medications with ALS risk. RESULTS: Patients with ALS were less likely to have been prescribed with antidiabetics compared with controls [OR, 0.76; 95% confidence intervals (CI), 0.65-0.90]. Conversely, statins were not associated with ALS risk overall (OR, 1.08; 95% CI, 0.98-1.19), although a positive association was noted among women (OR, 1.28; 95% CI, 1.10-1.48). The latter association was mostly explained by ALS cases being more likely to have a first prescription of statins during the year before diagnosis compared with controls (OR, 2.54; 95% CI, 1.84-3.49). CONCLUSIONS: The inverse association of antidiabetics with ALS is consistent with the previously reported inverse association between type 2 diabetes and ALS risk. The increase in prescription of statins during the year before ALS diagnosis deserves attention because it might reflect an acceleration of the course of ALS due to statin use.

Antibiotics use and risk of amyotrophic lateral sclerosis in Sweden.

BACKGROUND AND PURPOSE: Previous animal studies have suggested a disrupted intestinal microbiome in amyotrophic lateral sclerosis (ALS). Due to the known effect of antibiotics on gut microflora, the potential role of antibiotics use on the risk of ALS deserves an investigation. METHODS: A nested case-control study was conducted using several Swedish national registers. In all, 2484 ALS patients diagnosed between 1 July 2006 and 31 December 2013 were included as cases, and five controls per case individually matched to the case by sex, birth year and area of residence were randomly selected from the general Swedish population. Information on antibiotics prescriptions before ALS diagnosis was extracted from the Prescribed Drug Register for both cases and controls. A conditional logistic regression model was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: After accounting for potential diagnostic delay in ALS by excluding all prescriptions within 1 year before diagnosis, any antibiotics use was associated with a higher risk of ALS. The ORs (95% CIs) were 1.06 (0.94-1.19), 1.13 (1.00-1.28) and 1.18 (1.03-1.35) when comparing 1, 2-3 and ≥4 prescriptions to no prescription (P for trend = 0.0069). Similar results were noted for antibiotics used for respiratory infections and urinary tract as well as skin and soft tissue infections. Amongst different individual antibiotics, the risk of ALS was especially increased in relation to more than two prescriptions of beta-lactamase sensitive penicillin (OR 1.28; 95% CI 1.10-1.50). CONCLUSIONS: Use of antibiotics, especially repeated, might be associated with a higher subsequent risk of ALS.

Comorbidity of mitochondrial disease and dementia in patients with idiopathic polyneuropathy.

BACKGROUND AND PURPOSE: Studying the comorbidities of chronic idiopathic axonal polyneuropathy (CIAP) might help to better understand its etiopathogenesis. We aimed to assess the associations of mitochondrial disease (MD), Alzheimer's disease (AD) and vascular dementia (VD) with CIAP. METHODS: In this nested case-control study we included 2659 patients with CIAP identified from the Swedish Patient Register and 13 295 age- and sex-matched controls to assess the associations of MD, AD and VD with the subsequent risk of CIAP. We also conducted a follow-up study of the cases and controls to assess the risk of MD, AD or VD among patients with CIAP in comparison to individuals without CIAP. RESULTS: Individuals with MD had an increased risk of subsequent CIAP [odds ratio (OR), 4.17; 95% confidence intervals (CI), 1.27-13.65], whereas individuals with AD and VD had a decreased risk (OR, 0.18; 95% CI, 0.06-0.59 and OR, 0.17; 95% CI, 0.04-0.69). Patients with CIAP had a ninefold increased risk of subsequent MD [hazard ratio (HR), 9.37; 95% CI, 4.00-21.93], twofold increased risk of VD (HR, 1.97; 95% CI, 1.23-3.16), but no increased risk of AD (HR, 1.33; 95% CI, 0.89-1.98) compared with individuals without CIAP. CONCLUSIONS: We found a higher risk of MD among patients with CIAP, both before and after the diagnosis of CIAP. We found a higher risk of VD, but not AD, after the diagnosis of CIAP. The lower risks of AD and VD before CIAP might be due to a reduced surveillance of CIAP symptoms among patients with dementia.

Physical and cognitive fitness in young adulthood and risk of amyotrophic lateral sclerosis at an early age.

BACKGROUND AND PURPOSE: There is a clinical impression that patients with amyotrophic lateral sclerosis (ALS) have a higher level of physical fitness and lower body mass index (BMI) than average. However, there is a lack of literature examining the relationship between cognitive fitness and ALS risk. In this study we explored the associations of both physical and cognitive fitness with future risk of ALS. METHODS: Data on physical fitness, BMI, intelligence quotient (IQ) and stress resilience were collected from 1 838 376 Swedish men aged 17-20 years at conscription during 1968-2010. Their subsequent ALS diagnoses were identified through the Swedish Patient Register. Hazard ratios (HRs) and 95% CIs from flexible parametric models were used to assess age-specific associations of physical fitness, BMI, IQ and stress resilience with ALS. RESULTS: We identified 439 incident ALS cases during follow-up (mean age at diagnosis: 48 years). Individuals with physical fitness above the highest tertile tended to have a higher risk of ALS before the age of 45 years (range of HRs: 1.42-1.75; statistically significant associations at age 41-43 years) compared with others. Individuals with BMI ≥ 25 tended to have a lower risk of ALS at all ages (range of HRs: 0.42-0.80; statistically significant associations at age 42-48 years) compared with those with BMI < 25. Individuals with IQ above the highest tertile had a statistically significantly increased risk of ALS at an age of 56 years and above (range of HRs: 1.33-1.81), whereas individuals with stress resilience above the highest tertile had a lower risk of ALS at an age of 55 years and below (range of HRs: 0.47-0.73). CONCLUSIONS: Physical fitness, BMI, IQ and stress resilience in young adulthood might be associated with the development of ALS at an early age.

Systematic review and meta-analysis on the significance of salvage esophagectomy for persistent or recurrent esophageal squamous cell carcinoma after definitive chemoradiotherapy.

The therapeutic strategy to be recommended in case of recurrent or persistent squamous cell esophageal cancer after completed definitive chemoradiotherapy (dCRT) has to be documented. Salvage esophagectomy has traditionally been recognized as a viable option, but many clinicians oppose the use of surgery due to the associated excessive morbidity and mortality. 'Second-line' chemoradiotherapy (CRT) without surgery may offer a treatment alternative in these difficult and demanding clinical situations. Until now, no comprehensive attempt has been carried out to compare the respective therapeutic options. A systematic literature search was performed focusing on studies comparing survival and treatment-related mortality in patients submitted to salvage esophagectomy or second-line CRT for recurrent or persistent esophageal squamous cell carcinoma after dCRT. Hazard ratios and risk ratios were calculated to compare the effect of these therapeutic strategies on overall survival and treatment-related mortality, respectively. Four studies containing 219 patients, with persistent or recurrent esophageal squamous cell carcinoma after dCRT, were included in the meta-analysis. The analysis revealed an overall survival benefit following salvage esophagectomy with a pooled hazard ratio for death of 0.42 (95% confidence interval 0.21-0.86, P = 0.017) compared with second-line CRT. A treatment-related mortality of 10.3% was recorded in the 36 patients who were submitted to salvage esophagectomy, while it was impossible to perform a meta-analysis comparing treatment-related mortality between the groups. Salvage esophagectomy offers significant gain in long-term survival compared with second-line CRT, although the surgery is potentially at a price of a high treatment-related mortality.

Association between diabetes and amyotrophic lateral sclerosis in Sweden.

BACKGROUND AND PURPOSE: Energy metabolism is altered in patients with amyotrophic lateral sclerosis (ALS) but the role of diabetes is largely unknown. METHODS: A population-based case-control study was conducted of 5108 ALS cases and 25,540 individually matched population controls during 1991-2010. Information on ALS and pre-existing diabetes was retrieved from the Swedish Patient Register to explore the association of ALS with diabetes overall and with insulin-dependent or non-insulin-dependent diabetes specifically. Variation of the association by diabetes duration and age was also studied. RESULTS: In total, 224 ALS cases (4.39%) and 1437 controls (5.63%) had diabetes before the index date, leading to an overall inverse association between diabetes and ALS risk [odds ratio (OR) 0.79, 95% confidence interval (CI) 0.68-0.91]. The association was strong for non-insulin-dependent diabetes (OR 0.66, 95% CI 0.53-0.81) but not for insulin-dependent diabetes (OR 0.83, 95% CI 0.60-1.15) and varied as a function of diabetes duration, with the strongest association observed around 6 years after first ascertainment of diabetes. The association was age-specific; the inverse association was noted only amongst individuals aged 70 or older. In contrast, for younger individuals (<50 years), pre-existing insulin-dependent diabetes was associated with a higher ALS risk (OR 5.38, 95% CI 1.87-15.51). CONCLUSIONS: Our study suggests that there is an association between diabetes and ALS, and highlights the importance of taking into account age, insulin dependence and diabetes duration. Future studies should explore whether the association is independent of body mass index.

Survival benefit and additional value of preoperative chemoradiotherapy in resectable gastric and gastro-oesophageal junction cancer: a direct and adjusted indirect comparison meta-analysis.

Several phase I/II studies of chemoradiotherapy for gastric cancer have reported promising results, but the significance of preoperative radiotherapy in addition to chemotherapy has not been proven. In this study, a systematic literature search was performed to capture survival and postoperative morbidity and mortality data in randomised clinical studies comparing preoperative (chemo)radiotherapy or chemotherapy versus surgery alone, or preoperative chemoradiotherapy versus chemotherapy for gastric and/or gastro-oesophageal junction (GOJ) cancer. Hazard ratios (HRs) for overall mortality were extracted from the original studies, individual patient data provided from the principal investigators of eligible studies or the earlier published meta-analysis. The incidences of postoperative morbidities and mortalities were also analysed. In total 18 studies were eligible and data were available from 14 of these. The meta-analysis on overall survival yielded HRs of 0.75 (95% CI 0.65-0.86, P < 0.001) for preoperative (chemo)radiotherapy and 0.83 (95% CI 0.67-1.01, P = 0.065) for preoperative chemotherapy when compared to surgery alone. Direct comparison between preoperative chemoradiotherapy and chemotherapy resulted in an HR of 0.71 (95% CI 0.45-1.12, P = 0.146). Combination of direct and adjusted indirect comparisons yielded an HR of 0.86 (95% CI 0.69-1.07, P = 0.171). No statistically significant differences were seen in the risk for postoperative morbidity or mortality between preoperative treatments and surgery alone, or preoperative (chemo)radiotherapy and chemotherapy. Preoperative (chemo)radiotherapy for gastric and GOJ cancer showed significant survival benefit over surgery alone. In comparisons between preoperative chemotherapy and (chemo)radiotherapy, there is a trend towards improved survival when adding radiotherapy, without increased postoperative morbidity or mortality.

No association between biopsy-verified celiac disease and subsequent amyotrophic lateral sclerosis--a population-based cohort study.

BACKGROUND AND PURPOSE: Earlier data suggest an association between amyotrophic lateral sclerosis (ALS) and autoimmune disease, but data on its association with celiac disease (CD) are limited. METHODS: The risk of ALS in 29 093 individuals with CD, according to small intestine biopsy (villous atrophy, Marsh 3) carried out at Sweden's 28 pathology departments in 1969-2008, was compared with that in 144 515 age- and sex-matched reference individuals from the general population. ALS was defined as a hospitalization or outpatient visit with ALS according to the Swedish Patient Register. We used Cox regression to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for ALS. RESULTS: During follow-up 12 (3.7/100 000 person-years) individuals with CD and 56 (3.5/100 000 person-years) reference individuals had a diagnosis of ALS. This corresponded to an HR of 1.0 (95% CI 0.5-1.8). HRs were significantly higher in the first year of follow-up (4.1; 1.2-13.4) than 1-5 years after first CD diagnosis (0.8; 0.2-2.7) or after more than 5 years of follow-up (0.5; 0.2-1.5). Relative risk estimates were similar in men and women but were higher at the end of the study period [HR for ALS in patients diagnosed with CD in year 2000 or later was 2.1 (95% CI 0.9-4.8)]. CONCLUSIONS: This study found no association between CD and ALS. Earlier reports of a positive association may be due to surveillance bias just after CD diagnosis or expedited diagnostic work-up of ALS.

Meta-analysis of postoperative morbidity and perioperative mortality in patients receiving neoadjuvant chemotherapy or chemoradiotherapy for resectable oesophageal and gastro-oesophageal junctional cancers.

BACKGROUND: The long-term survival benefits of neoadjuvant chemotherapy (NAC) and chemoradiotherapy (NACR) for oesophageal carcinoma are well established. Both are burdened, however, by toxicity that could contribute to perioperative morbidity and mortality. METHODS: MEDLINE, the Cochrane Library and Embase were searched to capture the incidence of any postoperative complications, cardiac complications, respiratory complications, anastomotic leakage, postoperative 30-day mortality, total postoperative mortality and treatment-related mortality in randomized clinical trials comparing NAC or NACR with surgery alone, or NAC versus NACR. Meta-analyses comparing NAC and NACR were conducted by using adjusted indirect comparison. RESULTS: Twenty-three relevant studies were identified. Comparing NAC or NACR with surgery alone, there was no increase in morbidity or mortality attributable to neoadjuvant therapy. Subgroup analysis of NACR for squamous cell carcinoma (SCC) suggested an increased risk of total postoperative mortality and treatment-related mortality compared with surgery alone: risk ratio 1·95 (95 per cent confidence interval 1·06 to 3·60; P = 0·032) and 1·97 (1·07 to 3·64; P = 0·030) respectively. A combination of direct comparison and adjusted indirect comparison showed no difference between NACR and NAC regarding morbidity or mortality. CONCLUSION: Neither NAC nor NACR for oesophageal carcinoma increases the risk of postoperative morbidity or perioperative mortality compared with surgery alone. There was no clear difference between NAC and NACR. Care should be taken with NACR in oesophageal SCC, where an increased risk of postoperative mortality and treatment-related mortality was apparent.