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Rationale: Several common and rare genetic variants have been associated with idiopathic pulmonary fibrosis, a progressive fibrotic condition that is localized to the lung. Objectives: To develop an integrated understanding of the rare and common variants located in multiple loci that have been reported to contribute to the risk of disease. Methods: We performed deep targeted resequencing (3.69 Mb of DNA) in cases (n = 3,624) and control subjects (n = 4,442) across genes and regions previously associated with disease. We tested for associations between disease and 1) individual common variants via logistic regression and 2) groups of rare variants via sequence kernel association tests. Measurements and Main Results: Statistically significant common variant association signals occurred in all 10 of the regions chosen based on genome-wide association studies. The strongest risk variant is the MUC5B promoter variant rs35705950, with an odds ratio of 5.45 (95% confidence interval, 4.91-6.06) for one copy of the risk allele and 18.68 (95% confidence interval, 13.34-26.17) for two copies of the risk allele (P = 9.60 × 10-295). In addition to identifying for the first time that rare variation in FAM13A is associated with disease, we confirmed the role of rare variation in the TERT and RTEL1 gene regions in the risk of IPF, and found that the FAM13A and TERT regions have independent common and rare variant signals. Conclusions: A limited number of common and rare variants contribute to the risk of idiopathic pulmonary fibrosis in each of the resequencing regions, and these genetic variants focus on biological mechanisms of host defense and cell senescence.

We performed a genome-wide association study of non-Hispanic, white individuals with fibrotic idiopathic interstitial pneumonias (IIPs; n = 1,616) and controls (n = 4,683), with follow-up replication analyses in 876 cases and 1,890 controls. We confirmed association with TERT at 5p15, MUC5B at 11p15 and the 3q26 region near TERC, and we identified seven newly associated loci (Pmeta = 2.4 × 10(-8) to 1.1 × 10(-19)), including FAM13A (4q22), DSP (6p24), OBFC1 (10q24), ATP11A (13q34), DPP9 (19p13) and chromosomal regions 7q22 and 15q14-15. Our results suggest that genes involved in host defense, cell-cell adhesion and DNA repair contribute to risk of fibrotic IIPs.

Background: Fibrotic idiopathic interstitial pneumonias (fIIP) are a group of fatal lung diseases with largely unknown etiology and without definitive treatment other than lung transplant to prolong life. There is strong evidence for the importance of both rare and common genetic risk alleles in familial and sporadic disease. We have previously used genome-wide single nucleotide polymorphism data to identify 10 risk loci for fIIP. Here we extend that work to imputed genome-wide genotypes and conduct new RNA sequencing studies of lung tissue to identify and characterize new fIIP risk loci., Results: We performed genome-wide genotype imputation association analyses in 1616 non-Hispanic white (NHW) cases and 4683 NHW controls followed by validation and replication (878 cases, 2017 controls) genotyping and targeted gene expression in lung tissue. Following meta-analysis of the discovery and replication populations, we identified a novel fIIP locus in the HLA region of chromosome 6 (rs7887 P meta  = 3.7 × 10(-09)). Imputation of classic HLA alleles identified two in high linkage disequilibrium that are associated with fIIP (DRB1*15:01 P = 1.3 × 10(-7) and DQB1*06:02 P = 6.1 × 10(-8)). Targeted RNA-sequencing of the HLA locus identified 21 genes differentially expressed between fibrotic and control lung tissue (Q < 0.001), many of which are involved in immune and inflammatory response regulation. In addition, the putative risk alleles, DRB1*15:01 and DQB1*06:02, are associated with expression of the DQB1 gene among fIIP cases (Q < 1 × 10(-16))., Conclusions: We have identified a genome-wide significant association between the HLA region and fIIP. Two HLA alleles are associated with fIIP and affect expression of HLA genes in lung tissue, indicating that the potential genetic risk due to HLA alleles may involve gene regulation in addition to altered protein structure. These studies reveal the importance of the HLA region for risk of fIIP and a basis for the potential etiologic role of auto-immunity in fIIP.

Introduction: A sublobar resection is performed on patients with non-small cell lung cancer (NSCLC) who are not candidates for a lobectomy due to reduced pulmonary function or comorbid disease. The aim of this study was to investigate the outcomes of these operations in Iceland., Material and Methods: A retrospective study of all patients with NSCLC who underwent wedge resection or segmentectomy with curative intent during 1994-2008. Data on indication, pathological TNM-stage, complications and overall survival was analyzed. All histological samples were re-evaluated., Results: Forty four patients underwent 42 wedge and 5 segmental resections (age 69.1 yrs, 55.3% female), with 38.3% of cases detected incidentally. The majority of patients (55.3%) had a history of coronary artery disease and 40.4% had chronic obstructive pulmonary disease. Mean operative time was 83 minutes (range 30-131), mean intraoperative bleeding was 260 ml (range 100-650) and median hospital stay was 9 days (range 4-24). Pneumonia (14.9%) and prolonged air leakage (12.8%) were the most common complications. Two patients had major complications and 36.2% stayed in the intensive care unit overnight. No deaths occurred within 30 days of surgery. Adenocarcinoma was the most common histological type (66.7%). Most cases were stage IA/IB (78.7%), 17.0% were stage IIA/IIB and 4.3% were stage IIIA. One and 5 year survival was 85.1% and 40.9% respectively., Conclusion: In Iceland, both survival and complication rate after sublobar resection for NSCLC are comparable to results published for lobectomies, even though a higher percentage of patients have underlying cardiopulmonary disease.

Objective: To study the impact of TNM stage and various preoperative functional parameters on survival in patients who underwent lobectomy for non-small cell lung cancer (NSCLC) in Iceland from 1999 to 2008., Materials and Methods: Retrospective study including 213 patients (mean age 66.9 yrs, equal male/female ratio) that underwent lobectomy for NSCLC. Tumors were staged by the TNM staging system, survival was estimated by the Kaplan-Meier method and prognostic factors of survival studied using the Cox proportional hazards regression model., Results: Survival at 1 year was 82.7% and 45.1% at 5 years. Operative mortality at 30 days was 0%. Most tumors were found to be in stage I (59.6%) or stage II (17.8%) and 7% were stage IIIA, whereas 14.6% were in stage IIIB or IV. Using multivariate analysis; advancing stage, increasing tumor size, reduced lung function and history of arrhythmia, predicted worse survival, whereas adenocarcinoma histology was a positive prognostic factor (HR 0.5, p=0.002) when compared to other histological types., Conclusions: Survival for patients undergoing lobectomy for operable non-small cell lung cancer in Iceland is comparable with other studies. Advanced stage, tumor size, reduced lung function and arrhythmia were negative predictors of survival, but in contrast to many but not all studies adenocarcinoma histology predicted a better prognosis compared to other tumor types.

Objective: Non small cell lung cancer (NSCLC) is the second most common cancer in Iceland. We studied the indications and surgical outcome of lobectomy for NSCLC in Iceland., Materials and Methods: 213 consecutive patients underwent lobectomy for NSCLC between 1999 and 2008. Data on indications, histology, TNM-stage and complications were analysed, and logistic regression used to assess outcome predictors., Results: The majority of patients (60%) were referred because of symptoms, whereas 40% were asymptomatic. Adenocarcinoma (62%) and squamous cell carcinoma (29%) were the most frequent histological types. Operative staging showed that 59.6% of cases were stage I, 17.8% were stage II, 7% were stage IIIA and 14.6% were stage IIIB or IV. Mediastinoscopy was performed in 13.6% of cases. Mean operative time was 128 min., operative bleeding 580 ml and median hospital stay 10 days. Sixteen patients (7.5%) had major complications and 36 (17.5%) had minor complications, such as atrial fibrillation and pneumonia. Twelve patients required reoperation, most often due to bleeding, but two had empyema and one had a bronchopleural fistula. Older patients with high ASA scores and extensive smoking history were at increased risk for complications. No patient died within 30 days of surgery whereas two (0,9%) died within 90 days of surgery., Conclusions: The results of lobectomy for NSCLC in Iceland are excellent in relation to operative mortality and short term complications.

This case report describes an 82 year old male who sought medical attention for changes in bowel habits. Colonoscopy revealed a tumor located 10 to 15cm from the anus. Biopsy showed signetring cell adenocarcinoma. The tumor was not resected due peritoneal dissemination and a tumor invasion into the urinary bladder, found intraoperatively. During hospital stay a skin lesion of the face was removed at the request of the patient. Biopsy showed metastatic signetring adenocarcinoma. Colorectal metastatic lesions to the skin are rare findings, especially metastasis to the face. Skin examination in patients with suspected or known malignancies is an important part of the clinical examination. Key words: Rectal cancer, metastases, skin.

Objective: Study the indications, complications and surgical outcome of pneumonectomy for non small cell lung cancer (NSCLC) in Iceland, Material and Methods: A retrospective study of all pneumonectomies performed for NSCLC in Iceland from 1988 to 2007. Information was obtained from medical records and data on operative indications, postoperative TNM stage, complications, survival and survival predictors was analysed., Results: 77 patients (64% males) with mean age of 62.3 yrs. were operated on, 44% on the right side. Mediastinoscopy was performed in 31% of cases. Most patients were stage I or II (58%), but 17 and 21% were stage III A and IIIB, respectively. Mean operation time was 161 min., bleeding 1.1 L and hospital stay 11 days. Atrial fibrillation (21%), pneumonia (6.5%), empyema (5.5%) and respiratory failure (5%) were the most common complications. Three (3.9%) patients died within 30 days from surgery. Five year survival was 20.7%. Age, history of COPD, adenocarcinoma histology and advanced TNM stage were independent predictors of poor survival., Conclusions: Pneumonectomies for NSCLC in Iceland have a low rate of complications and operative mortality. However, long term survival is lower than expected, and many patients (27%) were in advanced stages. This is most likely due to inadequate preoperative staging.

Objective: At the time of diagnosis, approximately 20% of renal cell carcinoma (RCC) patients have pulmonary metastasis. These patients have poor survival with less than 10% of the patients being alive 5 years after diagnosis. However, recent studies have reported 30-49% 5-year survival in selected patients that underwent pulmonary resection for RCC metastases. The aim of this study was to analyse the outcome of this patient group in Iceland over a 23 year period., Materials and Methods: This is a retrospective population-based study including all patients in Iceland that underwent pulmonary resection for RCC metastasis between 1984 and 2006. Complications were tabulated and the histology of all tumors reviewed by a pathologist. The renal tumors were classified and staged according to the TNM staging system (WHO). Crude survival was calculated using 1st of March 2007 as an endpoint, with mean follow up of 82 months., Results: A total of 14 patients were identified, 10 males and 4 females with an average age of 59 years (range 45-78). One patient had pulmonary metastases at the diagnosis of RCC. In the other patients, metastasectomy was performed on average 39 months after the nephrectomy (range 1-132 months). Most of these patients (n=11) had a single metastasis, with an average size of 27 mm (range 8-50). Lobectomy was the most common procedure (n=7), wedge resection and pulmectomy were performed in three cases each, and one patient underwent both lobectomy and wedge resection. There were no major surgical complications. and all patients survived surgery. Today, four of the 14 patients (29%) are alive with 2- and 5-year survival of 64% and 29%, respectively., Conclusion: In this retrospective study, every third patient survived five years after pulmonary resection of RCC metastases. This is a favorable survival-rate when compared to patients with metastases not operated on (9.8% survival). These operations seem to be safe and complications are most often minor. It should be kept in mind, however, that a selected cohort was studied and a well defined control group was absent.

Background and Aims: Bronchopulmonary carcinoids (BPC) are rare tumors of neuroendocrine origin. These tumors are histologically classified into two distinctive forms, typical and the more malignant atypical BPC. We evaluated the epidemiology and results of treatment for BPC in Iceland with special emphasis on how atypical vs. typical histology relates to clinical behavior., Material and Methods: This retrospective nation-wide study included all cases of BPC diagnosed in Iceland from 1955-2005. Histology of all the cases was reviewed and survival was based on data obtained from medical records and vital statistics., Results: BPC was diagnosed in 64 patients (22 males, mean age 49 yrs.), accounting for 1.9% of all lung neoplasms in Iceland. Average tumor-diameter was 2.5 cm (range 0.4-5.5), with typical histology in 54 (84%) and atypical in 10 patients (16%). Altogether 56 patients (87.5%) were operated on, most with lobectomy (82.1%). Forty eight patients were diagnosed in TNM stage I, two patients in stage II, four patients had mediastinal lymph node metastases (stage III) and distant metastases were diagnosed in 6 patients (stage IV), 2 of whom had typical histology. At follow-up, 5 out of 64 patients had died of the disease (7.8%), two of them with typical histology. Five-year disease specific survival was 96% for patients with typical and 70% with atypical histology (p<0.05)., Conclusion: BPCs usually behave as benign neoplasms, with excellent long-term survival after surgical removal. Metastases are more common in patients with atypical histology (40%), and their survival is worse. However patients with typical histology can metastasize (14.8%) and die from the disease. Therefore, histology (typical vs. atypical) can not be used with certainty to predict the clinical behaviour of these tumors.

Organising pneumonia (OP) is a relatively rare interstitial lung disease. It s definition is based on a characteristic histological pattern in the presence of certain clinical and radiological features. Organising pneumonia represents also what has been called Bronchiolitis Obliterans Organising Pneumonia (BOOP). Recently it has been recommended to call OP cryptogenic organising pneumonia (COP) when no definite cause or characteristic clinical context is found and secondary organising pneumonia (SOP) when causes can be identified such as infection or it occurs in a characteristic clinical context such as connective tissue disorder. The most common clinical symptoms are dyspnea, cough, fever and general malaise. It is common that symptoms have been present for some weeks before the diagnosis is made. Patients commonly have lowered PO2 and a mildly restrictive spirometry. Radiographic features are most often patchy bilateral airspace opacities but an interstitial pattern or focal opacities can also be seen. Most of patients respond well to steroids but relapses are quite common. The aim of this paper is to present an overview of the disease and the main results from studies on OP in Iceland. The mean annual incidence for OP in Iceland was 1.97/100,000 inhabitants. Annual incidence for COP was 1.10/100,000 and 0.87/100,000 for SOP. This is higher than in most other studies. In Iceland patients with OP had a higher standardized mortality ratio than the general population despite good clinical responses. No clinical symptoms could separate between SOP and COP.

Introduction: Historically, surgery for SP has been performed with open thoracotomy. Today video-assisted thoracoscopic surgery (VATS) has replaced open surgery for SP in most centers. Long-term results (i.e. recurrent pneumothorax) following VATS have been debated. In Iceland surgery for SP has been performed with both VATS and limited axillary thoracotomy (LAT). The aim of this study was to compare these two approaches, especially reoperations for prolonged airleakage and late recurrences., Material and Methods: This is a retrospective non-randomized study on all patients operated first time for SP at our institution between 1991-2005. Out of 210 patients that underwent 234 procedures (160 males, mean age 29 yrs.), 200 had primary SP (95%) and 10 secondary SP. The cases were divided into two groups; 134 VATS procedures and 100 thoracotomies (LAT). Three surgeons performed a LAT and four performed VATS., Results: Wedge resection was performed in all cases and mechanical pleurodesis was added in 25% of the VATS and 67% of the LAT cases. Median operation time was 20 minutes longer for VATS (p=0.006). Reoperations for late recurrent pneumothorax were 10 vs. 3 in the VATS and LAT group, and reoperations for persistent airleakage 3 vs. 0, respectively (p=0.03). Operative mortality within 30 days from surgery was 0%. Median hospital stay was one day longer after LAT., Conclusion: Reoperations following VATS for SP are more common compared to open thoracotomy, explained by a higher rate of both late recurrent pneumothoraces and prolonged early postoperative airleakage. Both approaches are safe and major complications are infrequent. Hospital stay is shorter after VATS, however, VATS takes longer and the higher reoperation rate is a shortcoming and is of concern.

Objective: The objective of the study was to describe the incidence and clinical features of chronic eosinophilic pneumonia (CEP) in Iceland and review recent literature., Material and Methods: Retrospective study where information was obtained from clinical charts from 1990-2004. Records, imaging studies and histopathology were evaluated., Results: During the study period 10 individuals were diagnosed with CEP, 7 males and 3 females. Mean age was 58 years. None of the patients was a current smoker. The incidence of CEP during the study period was 0.23 per 100,000/year but increased to 0.54 per 100,000/year during the last 5 years of the study period. Clinical symptoms were malaise, cough, dyspnea, sweating and weight loss. Sedimentation rate was 72 mm/h and C-reactive protein (CRP) 125 mg/L. Eight of the ten patients had increase in blood eosinophils. On chest auscultation crackles were heard in seven patients and wheezing in three. Forced vital capacity (FVC) was 75% of predicted value and forced expiratory volume in one second (FEV1) was 73% of predicted. Mean PO2 was 68 mmHg. All the patients had classic diffuse bilateral opacities on chest radiograph that most commonly were peripheral. All patients were treated with corticosteroids and responded well. The average initial dose of Prednisolone was 42.5 mg per day. Seven of the patients relapsed but they all responded well to repeated treatment., Conclusions: Chronic eosinophilic pneumonia is a rare disorder but it has specific radiologic and histologic features. It is important to think of the disease in patients with diffuse infiltrates that are resistant to antibiotics. CEP responds well to corticosteroids but there is a high relapse rate, which also responds to treatment.

Objective: The objective of the study was to describe case reports of organising pneumonia in Iceland induced by the drug amiodarone., Material and Methods: Retrospective study where information was obtained from clinical charts from 1984-2003. Medical records, imaging studies and histopathology were re-evaluated., Results: Described are three case reports of organising pneumonia associated with amiodarone use in two males and one female. Diagnostic methods and treatment are described and current literature is discussed., Conclusions: It is important for physicians to be aware of lung changes that amiodarone can cause and the importance of monitoring these patients.

Objective: Closed pleural biopsy is done to determine causes of pleural effusion after fluid analysis has been nondiagnostic. The aim of the study was to evaluate results of closed pleural biopsy in Iceland., Material and Methods: All pathology reports of closed pleural biopsy from 1990-1999 at the Department of Pathology were reviewed. Hospital records for these patients were screened., Results: There were 130 samples from 120 individuals. There were 74 males and 46 females. Deceased are 75/120. The most common diagnosis was pleuritis or fibrosis in 85/120, cancer in 15 and three had tuberculosis but 17/120 had other results. The sensitivity of a closed pleural biopsy for diagnosing cancer was 27%. Adding cytology increased the sensitivity to 56%. Of those that had pleuritis on initial biopsy the cause was found to be cancer in 33/85, pneumonia in 11, trauma in 5 and in 8 there were other causes. In 25/85 no etiology could be found. By doing further studies it was demonstrated that the cause for the fluid was malignancy in 55/120. Of those most had lung cancer or 24/55, and the second most common cause was breast cancer in 7. Despite further studies no cause was found in 32/85., Conclusions: Closed pleural biopsy has fairly low sensitivity for diagnosis of cancer but it can be increased by adding cytologic evaluation. It is necessary to do further investigations and follow-up in patients that have inflammation in pleural biopsy.