Tomas Gudbjartsson

A Variant Associated with Nicotine Dependence, Lung Cancer and Peripheral Arterial Disease

Smoking is a leading cause of preventable death, causing about 5 million premature deaths worldwide each year. Evidence for genetic influence on smoking behaviour and nicotine dependence (ND) has prompted a search for susceptibility genes. Furthermore, assessing the impact of sequence variants on smoking-related diseases is important to public health. Smoking is the major risk factor for lung cancer (LC) and is one of the main risk factors for peripheral arterial disease (PAD). Here we identify a common variant in the nicotinic acetylcholine receptor gene cluster on chromosome 15q24 with an effect on smoking quantity, ND and the risk of two smoking-related diseases in populations of European descent. The variant has an effect on the number of cigarettes smoked per day in our sample of smokers. The same variant was associated with ND in a previous genome-wide association study that used low-quantity smokers as controls, and with a similar approach we observe a highly significant association with ND. A comparison of cases of LC and PAD with population controls each showed that the variant confers risk of LC and PAD. The findings provide a case study of a gene–environment interaction, highlighting the role of nicotine addiction in the pathology of other serious diseases.

Sequence variants at the TERT-CLPTM1L locus associate with many cancer types

The common sequence variants that have recently been associated with cancer risk are particular to a single cancer type or at most two. Following up on our genome-wide scan of basal cell carcinoma, we found that rs401681[C] on chromosome 5p15.33 satisfied our threshold for genome-wide significance (OR = 1.25, P = 3.7 × 10−12). We tested rs401681 for association with 16 additional cancer types in over 30,000 cancer cases and 45,000 controls and found association with lung cancer (OR = 1.15, P = 7.2 × 10−8) and urinary bladder, prostate and cervix cancer (ORs = 1.07−1.31, all P < 4 × 10−4). However, rs401681[C] seems to confer protection against cutaneous melanoma (OR = 0.88, P = 8.0 × 10−4). Notably, most of these cancer types have a strong environmental component to their risk. Investigation of the region led us to rs2736098[A], which showed stronger association with some cancer types. However, neither variant could fully account for the association of the other. rs2736098 corresponds to A305A in the telomerase reverse transcriptase (TERT) protein and rs401681 is in an intron of the CLPTM1L gene.

Tracheobronchial transplantation with a stem-cell-seeded bioartificial nanocomposite: a proof-of-concept study

BACKGROUND Tracheal tumours can be surgically resected but most are an inoperable size at the time of diagnosis; therefore, new therapeutic options are needed. We report the clinical transplantation of the tracheobronchial airway with a stem-cell-seeded bioartificial nanocomposite. METHODS A 36-year-old male patient, previously treated with debulking surgery and radiation therapy, presented with recurrent primary cancer of the distal trachea and main bronchi. After complete tumour resection, the airway was replaced with a tailored bioartificial nanocomposite previously seeded with autologous bone-marrow mononuclear cells via a bioreactor for 36 h. Postoperative granulocyte colony-stimulating factor filgrastim (10 μg/kg) and epoetin beta (40,000 UI) were given over 14 days. We undertook flow cytometry, scanning electron microscopy, confocal microscopy epigenetics, multiplex, miRNA, and gene expression analyses. FINDINGS We noted an extracellular matrix-like coating and proliferating cells including a CD105+ subpopulation in the scaffold after the reseeding and bioreactor process. There were no major complications, and the patient was asymptomatic and tumour free 5 months after transplantation. The bioartificial nanocomposite has patent anastomoses, lined with a vascularised neomucosa, and was partly covered by nearly healthy epithelium. Postoperatively, we detected a mobilisation of peripheral cells displaying increased mesenchymal stromal cell phenotype, and upregulation of epoetin receptors, antiapoptotic genes, and miR-34 and miR-449 biomarkers. These findings, together with increased levels of regenerative-associated plasma factors, strongly suggest stem-cell homing and cell-mediated wound repair, extracellular matrix remodelling, and neovascularisation of the graft. INTERPRETATION Tailor-made bioartificial scaffolds can be used to replace complex airway defects. The bioreactor reseeding process and pharmacological-induced site-specific and graft-specific regeneration and tissue protection are key factors for successful clinical outcome. FUNDING European Commission, Knut and Alice Wallenberg Foundation, Swedish Research Council, StratRegen, Vinnova Foundation, Radiumhemmet, Clinigene EU Network of Excellence, Swedish Cancer Society, Centre for Biosciences (The Live Cell imaging Unit), and UCL Business.

Atrial fibrillation following cardiac surgery: risk analysis and long-term survival

BackgroundWe studied potential risk factors for postoperative atrial fibrillation (POAF) in a large cohort of patients who underwent open-heart surgery, evaluating short- and long-term outcome, and we developed a risk-assessment model of POAF.MethodsA retrospective study of 744 patients without prior history of AF who underwent CABG (n = 513), OPCAB (n = 207), and/or AVR (n = 156) at Landspitali Hospital in 2002–2006. Logistic regression analysis was used to study risk factors for POAF, comparing patients with and without POAF.ResultsThe rate of POAF was 44%, and was higher following AVR (74%) than after CABG (44%) or OPCAB (35%). In general, patients with POAF were significantly older, were more often female, were less likely to be smokers, had a lower EF, and had a higher EuroSCORE. The use of antiarrythmics was similar in the groups but patients who experienced POAF were less likely to be taking statins. POAF patients also had longer hospital stay, higher rates of complications, and operative mortality (5% vs. 0.7%). In multivariate analysis, AVR (OR 4.4), a preoperative history of cardiac failure (OR 1.8), higher EuroSCORE (OR 1.1), and advanced age (OR 1.1) were independent prognostic factors for POAF. Overall five-year survival was 83% and 93% for patients with and without POAF (p <0.001).ConclusionPOAF was detected in 44% of patients, which is high compared to other studies. In the future, our assessment score will hopefully be of use in identifying patients at high risk of POAF and lower complications related to POAF.

Deep sternal wound infections following open heart surgery in Iceland. A population-based study

Objective. The aim of this nationwide case-control study was to study the epidemiology and identify risk factors of deep sternal wound infections (DSWI) in Iceland. Patients and methods. Between 1997–2004, 1 650 adults underwent open cardiac surgery in Iceland. For every infected patient four control subjects were chosen (n =163), matched for time of operation. The groups were compared by multivariable logistic regression analysis. Results. Forty one patients (2.5%) developed DSWI, most often following CABG (76%). The most common pathogens were Staphylococcus aureus (39%) and coagulase-negative staphylococci (24%). All except two patients underwent debridement and rewiring of the sternum. Length of hospital stay was significantly longer in the DSWI group with a trend for increased hospital mortality and significantly greater 1-year mortality (17% vs. 5%, p =0.02). History of stroke (OR 5.12), peripheral arterial disease (OR 5), corticosteroid use (OR 4.25), smoking (OR 3.66) and re-operation for bleeding (OR 4.66) were the strongest independent predictors for DSWI. Conclusion. Incidence of DSWI in Iceland (2.5%) is comparable to other recently published studies, with similar risk factors and significantly reduced survival at one year following the infection.

Diagnostic Surgical Lung Biopsies for Suspected Interstitial Lung Diseases: A Retrospective Study

BACKGROUND Current guidelines for interstitial lung disease support a surgical biopsy for optimal diagnosis and treatment, yet only a minority of patients undergo such biopsy. Our objectives were to address the properties of a surgical lung biopsy for suspected interstitial lung disease, the diagnostic yield of the procedure, and whether it resulted in changes in diagnosis and treatment. METHODS A retrospective nationwide study including 73 patients (mean age, 57.3 years; 58% males) who underwent a surgical lung biopsy for suspected interstitial disease in Iceland between 1986 and 2007 was conducted. Patient records and histologic specimens were reviewed. Before the surgical biopsy a transbronchial or computed tomography-guided biopsy had been performed in two thirds of the patients. RESULTS The complication rate for surgical lung biopsy was 16%, and 30-day operative mortality was 2.7%, both significantly higher in patients with preoperative respiratory failure. After the procedure, a definite histopathologic diagnosis was obtained in 81% of the patients. Usual interstitial pneumonia was the most common diagnosis (31%). The clinical diagnosis was changed for 73% of the patients, and in 53% of the patients the biopsy resulted in changes in treatment. CONCLUSIONS Surgical lung biopsy is a powerful tool for diagnosis of suspected interstitial lung disease. It results in a specific diagnosis for the majority of patients and changes in treatment for more than half. Operative morbidity and mortality are low but still significant, so patients should be carefully selected for the procedure, especially those with respiratory failure.

Oesophageal perforations in Iceland : a whole population study on incidence, aetiology and surgical outcome

BACKGROUND Oesophageal perforation is a rare but life-threatening condition with a significant morbidity and mortality. In this retrospective, nationwide study, the results of oesophageal perforation are reported for a well defined cohort, with special emphasis on the incidence, aetiology and results of surgical treatment. MATERIAL AND METHODS 29 consecutive patients (16 males) were diagnosed with perforation of the oesophagus at Landspitali University Hospital between 1980 and 2007. Patients had a mean age of 61 years (range: 7 months-90 years). Type of surgery, complications and survival were recorded. Average follow-up was 76 months. RESULTS Age-standardised incidence of oesophageal perforation was 3.1/1,000,000 per year during the study period. Out of 29 patients diagnosed with oesophageal perforation, the diagnosis was missed in 5 cases (17%) and first made at autopsy. Iatrogenic injury was the most frequent cause (52%), followed by spontaneous perforation (24%) and foreign body ingestion (17%). Thoracic perforations were seen in 73% of patients, and 14 patients had an underlying oesophageal disease. Nineteen patients were treated surgically, in 16 cases with drainage of the mediastinum via thoracotomy and insertion of chest tubes. The median time from perforation to surgery was 6.5 h and median length of hospital stay was 15 days (range: 9-83). All surgically treated patients survived surgery, and the 5-year overall survival rate was 69%. CONCLUSION More than half of all oesophageal injuries in Iceland are caused by a iatrogenic injury. Mortality is significant and is related to a missed diagnosis. Patients treated surgically all survived surgery; however, complications were frequent and their hospital stay was long.

Incidental Detection of Renal Cell Carcinoma is an Independent Prognostic Marker: Results of a Long-Term, Whole Population Study

PURPOSE The true effect of incidental detection on the survival of patients with renal cell carcinoma has been debated. We used centralized databases in Iceland to study prognostic factors of survival, focusing on the effect of incidental detection. MATERIALS AND METHODS This retrospective study included all living patients diagnosed with renal cell carcinoma in Iceland from 1971 to 2005. Hospital charts and histology were reviewed. Incidentally diagnosed renal cell carcinomas were compared to symptomatic tumors and prognostic factors were evaluated using Cox multivariate analysis. RESULTS Of the 910 patients 254 (27.9%) were diagnosed incidentally, most often by abdominal ultrasound (29.5%) or computerized tomography (28.3%). The incidental detection rate increased from 11.1% in 1971 through 1975 to 39.2% in 2001 through 2005 (p <0.001). During the same period the incidence increased significantly in males but in females only during the last 5 study years. Mortality remained unchanged for each gender. Incidentally detected tumors were an average of 2.6 cm smaller and diagnosed at lower stage and lower grade than symptomatic tumors. Age and histology were similar in each group. TNM stage was by far the strongest independent prognostic factor of survival but age, calendar year of diagnosis and ESR were also significant. After correcting for confounders patients with symptomatic renal cell carcinoma had worse survival than those diagnosed incidentally. CONCLUSIONS With increased incidence and unchanged mortality the survival of patients with renal cell carcinoma has improved. This is mainly related to a steep increase in incidental detection. Incidental detection affects survival favorably and to a greater extent than can be explained by lower stage compared to the survival of patients diagnosed with symptoms.

Renal oncocytoma: a clinicopathological analysis of 45 consecutive cases.

To evaluate the clinical behaviour and pathology of renal oncocytoma in a well‐defined population over a 30‐year period.

Triclosan-coated sutures reduce surgical site infection after open vein harvesting in coronary artery bypass grafting patients: a randomized controlled trial †

OBJECTIVES The incidence of surgical site infection (SSI) after open vein harvesting in coronary artery bypass grafting (CABG) patients ranges in different studies between 2 and 20%. Triclosan is an antibacterial substance that reduces the growth of bacteria by inhibiting fatty acid synthesis. We hypothesized that wound closure with triclosan-coated sutures would reduce SSI after open vein harvesting. METHODS An investigator-initiated prospective randomized double-blind single-centre study was performed with 374 patients, randomized to subcutaneous and intracutaneous leg-wound closure with either triclosan-coated sutures (Vicryl Plus® and Monocryl Plus®, Ethicon, Somerville, NJ, USA) (n = 184) or identical sutures without triclosan (n = 190) from the same manufacturer. All patients were followed up after 30 days (clinical visit) and 60 days (telephone interview). Primary endpoint was SSI within 60 days after surgery according to the definition of Center for Disease Control. Predefined secondary endpoints included culture-proven and antibiotic-treated SSI. RESULTS The primary endpoint occurred in 23 patients (12.5%) with triclosan-coated sutures and in 38 patients (20.0%) in the group without triclosan (P = 0.0497, risk ratio 0.63, (95% confidence interval 0.39–1.00). Corresponding figures for culture-proven infections were 7.6 vs 12.1%, (P = 0.15), and for antibiotic-treated infections, 10.9 vs 18.4%, (P = 0.039). Staphylococcus aureus and coagulase-negative staphylococci were the most common pathogens in both groups. Insulin-treated diabetes and vein-harvesting time were associated with SSI after vein harvesting. CONCLUSIONS Leg-wound closure with triclosan-coated sutures in CABG patients reduces SSIs after open vein harvesting. (ClinicalTrials.gov number NCT01212315).