William R. Bamlet

Genome-wide association study identifies variants in the ABO locus associated with susceptibility to pancreatic cancer

We conducted a two-stage genome-wide association study of pancreatic cancer, a cancer with one of the lowest survival rates worldwide. We genotyped 558,542 SNPs in 1,896 individuals with pancreatic cancer and 1,939 controls drawn from 12 prospective cohorts plus one hospital-based case-control study. We conducted a combined analysis of these groups plus an additional 2,457 affected individuals and 2,654 controls from eight case-control studies, adjusting for study, sex, ancestry and five principal components. We identified an association between a locus on 9q34 and pancreatic cancer marked by the SNP rs505922 (combined P = 5.37 × 10−8; multiplicative per-allele odds ratio 1.20; 95% confidence interval 1.12–1.28). This SNP maps to the first intron of the ABO blood group gene. Our results are consistent with earlier epidemiologic evidence suggesting that people with blood group O may have a lower risk of pancreatic cancer than those with groups A or B.

Validation of a new coma scale: The FOUR score

The Glasgow Coma Scale (GCS) has been widely adopted. Failure to assess the verbal score in intubated patients and the inability to test brainstem reflexes are shortcomings. We devised a new coma score, the FOUR (Full Outline of UnResponsiveness) score. It consists of four components (eye, motor, brainstem, and respiration), and each component has a maximal score of 4. We prospectively studied the FOUR score in 120 intensive care unit patients and compared it with the GCS score using neuroscience nurses, neurology residents, and neurointensivists. We found that the interrater reliability was excellent with the FOUR score (κw = 0.82) and good to excellent for physician rater pairs. The agreement among raters was similar with the GCS (κw = 0.82). Patients with the lowest GCS score could be further distinguished using the FOUR score. We conclude that the agreement among raters was good to excellent. The FOUR score provides greater neurological detail than the GCS, recognizes a locked‐in syndrome, and is superior to the GCS due to the availability of brainstem reflexes, breathing patterns, and the ability to recognize different stages of herniation. The probability of in‐hospital mortality was higher for the lowest total FOUR score when compared with the lowest total GCS score. Ann Neurol 2005;58:585–593

Prevalence and Clinical Profile of Pancreatic Cancer–Associated Diabetes Mellitus

BACKGROUND & AIMS Information on the clinical profile of pancreatic cancer (PaC) associated diabetes (DM) is limited. We compared the prevalence and clinical characteristics of DM in subjects with and without PaC. METHODS We prospectively recruited 512 newly diagnosed PaC cases and 933 controls of similar age, who completed demographic and clinical questionnaires and had fasting blood glucose (FBG) levels measured at recruitment and after pancreaticoduodenectomy (n = 105). Subjects with a FBG level >126 mg/dL or who were on antidiabetic treatment were classified as having DM. RESULTS DM was more prevalent (47% vs 7%; P < .001) and predominantly of new onset (<2-year duration) (74% vs 53%; P = .002) among cases compared with controls. Among PaC cases, those with DM (n = 243) were older (68 +/- 10 vs 64 +/- 12 years; P < .001), reported higher usual adult body mass index (30 +/- 6 vs 27 +/- 5 kg/m(2); P < .001), and had a greater frequency of family history of DM (47% vs 31%; P < .001) compared with those without DM (n = 269). After pancreaticoduodenectomy, while DM resolved in 17 of 30 patients (57%) with new-onset DM, its prevalence was unchanged in patients with long-standing DM (n = 11) (P = .009). CONCLUSIONS PaC is a powerful diabetogenic state; DM associated with PaC is often new-onset, resolves following cancer resection, and appears to be associated with conventional risk factors for DM. New-onset DM in patients with PaC is likely induced by the tumor.

Dual-Chamber Versus Single-Chamber Detection Enhancements for Implantable Defibrillator Rhythm Diagnosis The Detect Supraventricular Tachycardia Study

Background— Delivery of inappropriate shocks caused by misdetection of supraventricular tachycardia (SVT) remains a substantial complication of implanted cardioverter/defibrillator (ICD) therapy. Whether use of optimally programmed dual-chamber ICDs lowers this risk compared with that in single-chamber ICDs is not clear. Methods and Results— Subjects with a clinical indication for ICD (n=400) at 27 participating centers received dual-chamber ICDs and were randomly assigned to strictly defined optimal single- or dual-chamber detection in a single-blind manner. Programming minimized ventricular pacing. The primary end point was the proportion of SVT episodes inappropriately detected from the time of programming until crossover or end of study. On a per-episode basis, 42% of the episodes in the single-chamber arm and 69% of the episodes in the dual-chamber arm were due to SVT. Mortality (3.5% in both groups) and early study withdrawal (14% single-chamber, 11% dual-chamber) were similar in both groups. The rate of inappropriate detection of SVT was 39.5% in the single-chamber detection arm compared with 30.9% in the dual-chamber arm. The odds of inappropriate detection were decreased by almost half with the use of the dual-chamber detection enhancements (odds ratio, 0.53; 95% confidence interval, 0.30 to 0.94; P=0.03). Conclusions— Dual-chamber ICDs, programmed to optimize detection enhancements and to minimize ventricular pacing, significantly decrease inappropriate detection.

Incidence and Risk Factors of Prosthetic Joint Infection After Total Hip or Knee Replacement in Patients With Rheumatoid Arthritis

OBJECTIVE Prosthetic joint infection is one of the most dreaded complications after total joint arthroplasty, a common procedure in patients with rheumatoid arthritis (RA). We conducted a study to evaluate potential risk factors of prosthetic joint infection and to clarify if RA is an independent predictor of this complication. METHODS This study included all patients with RA who underwent total hip or knee replacement at the Mayo Clinic Rochester between January 1996 and June 2004. The association of potential risk factors with prosthetic joint infection was examined using Cox models. A matched cohort of patients with osteoarthritis (OA) was assembled to determine whether RA is an independent risk factor for prosthetic joint infection. RESULTS We identified 462 patients with RA who underwent a total of 657 hip or knee replacements. Overall, 23 (3.7%) joint arthroplasties were complicated by an infection during a mean +/- SD followup of 4.3 +/- 2.4 years. Revision arthroplasty (hazard ratio [HR] 2.99, 95% confidence interval [95% CI] 1.02-8.75) and a previous prosthetic joint infection of the replaced joint (HR 5.49, 95% CI 1.87-16.14) were significant predictors of postoperative prosthetic joint infection. Comparison of RA patients with a matched cohort of OA patients identified an increased risk of prosthetic joint infections (HR 4.08, 95% CI 1.35-12.33) in patients with RA. CONCLUSION Patients with RA who undergo total hip or knee replacement are at increased risk of prosthetic joint infection, which is further increased in the setting of revision arthroplasty and a previous prosthetic joint infection. These findings highlight the importance of perioperative prophylactic measures and vigilance during the postoperative period.

Anthropometric Measures, Body Mass Index and Pancreatic Cancer: a Pooled Analysis from the Pancreatic Cancer Cohort Consortium (PanScan)

BACKGROUND Obesity has been proposed as a risk factor for pancreatic cancer. METHODS Pooled data were analyzed from the National Cancer Institute Pancreatic Cancer Cohort Consortium (PanScan) to study the association between prediagnostic anthropometric measures and risk of pancreatic cancer. PanScan applied a nested case-control study design and included 2170 cases and 2209 control subjects. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using unconditional logistic regression for cohort-specific quartiles of body mass index (BMI [calculated as weight in kilograms divided by height in meters squared]), weight, height, waist circumference, and waist to hip ratio as well as conventional BMI categories (underweight, <18.5; normal weight, 18.5-24.9; overweight, 25.0-29.9; obese, 30.0-34.9; and severely obese, > or = 35.0). Models were adjusted for potential confounders. RESULTS In all of the participants, a positive association between increasing BMI and risk of pancreatic cancer was observed (adjusted OR for the highest vs lowest BMI quartile, 1.33; 95% CI, 1.12-1.58; P(trend) < .001). In men, the adjusted OR for pancreatic cancer for the highest vs lowest quartile of BMI was 1.33 (95% CI, 1.04-1.69; P(trend) < .03), and in women it was 1.34 (95% CI, 1.05-1.70; P(trend) = .01). Increased waist to hip ratio was associated with increased risk of pancreatic cancer in women (adjusted OR for the highest vs lowest quartile, 1.87; 95% CI, 1.31-2.69; P(trend) = .003) but less so in men. CONCLUSIONS These findings provide strong support for a positive association between BMI and pancreatic cancer risk. In addition, centralized fat distribution may increase pancreatic cancer risk, especially in women.

Subcutaneous IGF-1 is not beneficial in 2-year ALS trial

Background: Previous human clinical trials of insulin-like growth factor type I (IGF-1) in amyotrophic lateral sclerosis (ALS) have been inconsistent. This phase III, randomized, double-blind, placebo-controlled study was undertaken to address whether IGF-1 benefited patients with ALS. Methods: A total of 330 patients from 20 medical centers were randomized to receive 0.05 mg/kg body weight of human recombinant IGF-1 given subcutaneously twice daily or placebo for 2 years. The primary outcome measure was change in their manual muscle testing score. Secondary outcome measures included tracheostomy-free survival and rate of change in the revised ALS functional rating scale. Intention to treat analysis was used. Results: There was no difference between treatment groups in the primary or secondary outcome measures after the 2-year treatment period. Conclusions: Insulin-like growth factor type I does not provide benefit for patients with amyotrophic lateral sclerosis. GLOSSARY: ALS = amyotrophic lateral sclerosis; ALSFRS-r = revised ALS functional rating scale; AUC = area under the curve; DVT = deep venous thromboses; IGF-1 = insulin-like growth factor type I; MMT = manual muscle testing; PE = pulmonary embolisms.

Cigarette smoking and pancreatic cancer: an analysis from the International Pancreatic Cancer Case-Control Consortium (Panc4)

BACKGROUND To evaluate the dose-response relationship between cigarette smoking and pancreatic cancer and to examine the effects of temporal variables. METHODS We analyzed data from 12 case-control studies within the International Pancreatic Cancer Case-Control Consortium (PanC4), including 6507 pancreatic cases and 12 890 controls. We estimated summary odds ratios (ORs) by pooling study-specific ORs using random-effects models. RESULTS Compared with never smokers, the OR was 1.2 (95% confidence interval [CI] 1.0-1.3) for former smokers and 2.2 (95% CI 1.7-2.8) for current cigarette smokers, with a significant increasing trend in risk with increasing number of cigarettes among current smokers (OR=3.4 for ≥35 cigarettes per day, P for trend<0.0001). Risk increased in relation to duration of cigarette smoking up to 40 years of smoking (OR=2.4). No trend in risk was observed for age at starting cigarette smoking, whereas risk decreased with increasing time since cigarette cessation, the OR being 0.98 after 20 years. CONCLUSIONS This uniquely large pooled analysis confirms that current cigarette smoking is associated with a twofold increased risk of pancreatic cancer and that the risk increases with the number of cigarettes smoked and duration of smoking. Risk of pancreatic cancer reaches the level of never smokers ∼20 years after quitting.

Alcohol consumption and pancreatic cancer: A pooled analysis in the International Pancreatic Cancer Case-Control Consortium (PanC4)

BACKGROUND Heavy alcohol drinking has been related to pancreatic cancer, but the issue is still unsolved. METHODS To evaluate the role of alcohol consumption in relation to pancreatic cancer, we conducted a pooled analysis of 10 case-control studies (5585 cases and 11,827 controls) participating in the International Pancreatic Cancer Case-Control Consortium. We computed pooled odds ratios (ORs) by estimating study-specific ORs adjusted for selected covariates and pooling them using random effects models. RESULTS Compared with abstainers and occasional drinkers (< 1 drink per day), we observed no association for light-to-moderate alcohol consumption (≤ 4 drinks per day) and pancreatic cancer risk; however, associations were above unity for higher consumption levels (OR = 1.6, 95% confidence interval 1.2-2.2 for subjects drinking ≥ 9 drinks per day). Results did not change substantially when we evaluated associations by tobacco smoking status, or when we excluded participants who reported a history of pancreatitis, or participants whose data were based upon proxy responses. Further, no notable differences in pooled risk estimates emerged across strata of sex, age, race, study type, and study area. CONCLUSION This collaborative-pooled analysis provides additional evidence for a positive association between heavy alcohol consumption and the risk of pancreatic cancer.

Polymorphisms in DNA Repair Genes, Smoking, and Pancreatic Adenocarcinoma Risk

Base excision repair and nucleotide excision repair are vital responses to multiple types of DNA damage, including damage from tobacco exposure. Single-nucleotide polymorphisms (SNP) in these pathways may affect DNA repair capacity and therefore influence risk for cancer development. We performed a clinic-based, case-control study comprising 481 consecutive patients with confirmed pancreatic adenocarcinoma and 625 healthy controls. Allele and genotype frequencies for 16 SNPs in DNA repair genes ERCC1, XPD/ERCC2, XPC, XPF/ERCC4, OGG1, and XRCC1 were compared after adjusting for age, sex, and smoking history. Subgroup analysis by sex and smoking history was performed. Carriers of one or two XPF/ERCC4 minor alleles at R415Q had decreased risk of pancreatic adenocarcinoma compared with those who had two major alleles [odds ratio (OR), 0.59; 95% confidence interval (95% CI), 0.40-0.85]. Heavy smokers (>40 pack-years) had increased risk for cancer if they were carriers of at least one minor allele for XPD/ERCC2 at D312N (OR, 2.78; 95% CI, 1.28-6.04) or D711D (OR, 2.19; 95% CI, 1.01-4.73). No other significant differences in risk were identified. Minor alleles in DNA repair genes XPF/ERCC4 and XPD/ERCC2 were associated with altered risk for pancreatic cancer.