Ole Dan Jørgensen

Randomised study of screening for colorectal cancer with faecal-occult-blood test

BACKGROUND Case-control studies and a voluntary-based follow-up study have suggested that repeated screening with faecal-occult-blood (FOB) tests can lead to a reduction in mortality from colorectal cancer (CRC). The aim of this randomised study was to compare mortality rates after FOB tests every 2 years during a 10-year period with those of unscreened similar controls. METHODS 140,000 people aged 45-75 years lived in Funen, Denmark, in August, 1985, and were considered for inclusion in our study. Before randomisation we excluded individuals who had CRC or precursor adenomas and those who had taken part in a previous pilot study. Randomisation of 137,485 people in blocks of 14 allocated three per 14 to the screening group (30,967), three per 14 to the control group (30,966), and eight not to be enrolled in the study (75,552). Controls were not told about the study and continued to use health-care facilities as normal. Hemoccult-II blood tests (with dietary restrictions but without rehydration) were sent to screening-group participants. Only those participants who completed the first screening round were invited for further screening--five rounds of screening during a 10-year period. Participants with positive tests were asked to attend to full examination and were offered colonoscopy whenever possible. The primary endpoint was death from CRC. FINDINGS Of the 30,967 screening-group participants, 20,672 (67%) completed the first screening round and were invited for further screening; more than 90% accepted repeated screenings. During the 10-year study, 481 people in the screening group had a diagnosis of CRC, compared with 483 unscreened controls. There were 205 deaths attributable to CRC in the screening group, compared with 249 deaths in controls. CRC mortality, including deaths attributable to complications from CRC treatment, was significantly lower in the screening group than in controls (mortality ratio 0.82 [95% CI 0.68-0.99]) p = 0.03). INTERPRETATION Our findings indicate that biennial screening by FOB tests can reduce CRC mortality. This study is being continued to improve its statistical power and to assess the effect of the removal of more precursor adenomas in the screening-group participants than in controls on CRC incidence.

A randomised study of screening for colorectal cancer using faecal occult blood testing: results after 13 years and seven biennial screening rounds

Background: Three randomised trials have demonstrated reduction in mortality from colorectal cancer (CRC) by repeated screening with faecal occult blood tests, including the trial presented here, which is the only one still in progress. Aims: To evaluate reduction in mortality after seven screening rounds and the possible influence of compliance on mortality from CRC. Methods: At Funen in Denmark, random allocation to biennial screening with Hemoccult-II in 30 967 subjects aged 45–75 years and 30 966 controls was performed in 1985 from a population of 137 485 of the same age. Only participants who completed the first screening round were invited for further screening. Colonoscopy was offered if the test was positive. The primary end point was death from CRC, and the 10 year results were published in 1996. Results: From the beginning of the first screening to the seventh round, mean age increased from 59.8 to 70.0 years in the screening and control groups, and the male/female ratio decreased from 0.92 to 0.81. Those who accepted screening were younger than non-responders. Positivity rates varied from 0.8% to 3.8%, the cumulative ratio of a positive test was 5.1% after seven rounds, and 4.8% of patients had at least one colonoscopy. Mortality from CRC was significantly less in the screening group (relative risk (RR) 0.82 (0.69–0.97)), and the reduction in mortality was most pronounced above the sigmoid colon. After seven rounds, RR was reduced to less than 0.70 compared with controls. Mortality rates from causes other than CRC did not differ. Non-responders had a significantly increased risk of death from CRC compared with those who accepted the full programme. Subjects who accepted the first screening, but not subsequent ones, demonstrated a tendency towards increased risk. Conclusions: The persistent reduction in mortality from CRC in a biennial screening program with Hemoccult-II, and a reduction in RR to less than 0.70 in those adhering to the programme, support attempts to introduce larger scale population screening programmes. The smaller effect on mortality from CRC in the rectum and sigmoid colon suggests evaluation by additional flexible sigmoidoscopy with longer intervals.

Complications after cardiac implantable electronic device implantations: an analysis of a complete, nationwide cohort in Denmark

Aims Complications after cardiac implantable electronic device (CIED) treatment, including permanent pacemakers (PMs), cardiac resynchronization therapy devices with defibrillators (CRT-Ds) or without (CRT-Ps), and implantable cardioverter defibrillators (ICDs), are associated with increased patient morbidity, healthcare costs, and possibly increased mortality. Methods and results Population-based cohort study in all Danish patients who underwent a CIED procedure from May 2010 to April 2011. Data on complications were gathered on review of all patient charts while baseline data were obtained from the Danish Pacemaker and ICD Register. Adjusted risk ratios (aRRs) with 95% confidence intervals were estimated using binary regression. The study population consisted of 5918 consecutive patients. A total of 562 patients (9.5%) experienced at least one complication. The risk of any complication was higher if the patient was a female (aRR 1.3; 1.1–1.6), underweight (aRR 1.5; 1.1–2.3), implanted in a centre with an annual volume <750 procedures (0–249 procedures: aRR 1.6; 1.1–2.2, 250–499: aRR 2.0; 1.6–2.7, 500–749: aRR 1.5; 1.2–1.8), received a dual-chamber ICD (aRR 2.0; 1.4–2.7) or CRT-D (aRR 2.6; 1.9–3.4), underwent system upgrade or lead revision (aRR 1.3; 1.0–1.7), had an operator with an annual volume <50 procedures (aRR 1.9; 1.4–2.6), or underwent an emergency, out-of-hours procedure (aRR 1.5; 1.0–2.3). Conclusion CIED complications are more frequent than generally acknowledged. Both patient- and procedure-related predictors may identify patients with a particularly high risk of complications. This information should be taken into account both in individual patient treatment and in the planning of future organization of CIED treatment.

Infection after pacemaker implantation: infection rates and risk factors associated with infection in a population-based cohort study of 46299 consecutive patients

Aims Infection is a serious complication of pacemaker (PM) systems. Although the rate of infection has been debated, the figures are largely unknown. We therefore studied the incidence of PM infection and its associated risk factors in the Danish population. Methods and results Since 1982, all PM implantation and removal procedures performed in Denmark have been prospectively recorded in the Danish Pacemaker Register. All patients (n = 46299) who underwent implantation between 1982 and 2007 were included. The total length of surveillance was 236 888 PM-years. The incidence of infection was calculated according to the total number of PM-years. The incidence of surgical site infection (≤365 days after PM implantation) was compared with later infection in first implant and replacement procedures. Multiple-record and multiple-event-per-subject proportional hazards analyses were used to identify the independent risk factors of PM infection. Surgical site infection occurred in 192 cases after first implantation (incidence rate 4.82/1000 PM-years), and in 133 cases after replacement (12.12/1000 PM-years). Infections occurring more than 365 days after the first implantation occurred in 153 cases (1.02/1000 PM-years), and in 118 cases after replacement (3.26/1000 PM-years). Independent factors associated with an increased risk of PM infection were a greater number of PM operations (including replacements), male sex, younger age, implantation during the earliest part of the study period, and absence of antibiotics (P< 0.001). Conclusion The overall risk of infection after PM implantation was low. A greater number of operations augmented the risk of infection. This should be taken into account when considering revisions of PM systems.

The Funen Adenoma Follow-up Study: Incidence and Death from Colorectal Carcinoma in an Adenoma Surveillance Program

The results of a prospective randomized study of 1056 patients with colorectal adenomas are presented. After initial polypectomy from 1978 to 1992, patients were allocated at random to different follow-up intervals varying from 6 to 48 months, except 53 patients who were allocated to intervals of 6 months. The examinations were mainly done by colonoscopy. Ten patients developed colorectal carcinoma, a number similar to that expected (7.96), when compared with a sex- and age-matched normal Danish population. The expected number of carcinomas was also calculated from adenoma to carcinoma conversion rates estimated in other studies and compared with that observed. If all carcinomas develop in large (> or = 10 mm) adenomas or adenomas with severe dysplasia, the expected number of carcinomas would have been 62 and 110, respectively, indicating a significant reduction of carcinomas in the present study. One patient died of colorectal carcinoma, which is significantly lower than the number expected (7.58). Two patients died of complications from therapeutic and diagnostic colonoscopy--that is, 2 deaths in 3959 colonoscopies. In conclusion, the follow-up strategy has resulted in a mortality from colorectal carcinoma which is reduced when compared with the normal population, in spite of an apparently similar incidence of carcinoma. However, previous suggested adenoma-carcinoma conversion rates indicate that a major reduction of incidence actually has taken place.

A national study of nodal upstaging after thoracoscopic versus open lobectomy for clinical stage I lung cancer.

BACKGROUND Nodal upstaging after surgical intervention for non-small cell lung cancer (NSCLC) occurs when unsuspected lymph node metastases are found during the final evaluation of surgical specimens. Recent data from The Society of Thoracic Surgery (STS) database demonstrated significantly lower nodal upstaging after thoracoscopic (VATS) lobectomy than after thoracotomy. STS data, however, may be biased from voluntary reporting, and survival was not investigated. We used a complete national registry to compare nodal upstaging and survival after lobectomy by VATS or thoracotomy. METHODS The Danish Lung Cancer Registry was used to identify patients who underwent lobectomy for clinical stage I NSCLC from 2007 to 2011. Patient demographics, comorbidity, preoperative staging, surgical approach, number of lymph nodes harvested, final pathology, and survival were evaluated. Nodal upstaging was identified by comparing cT N M with pT N M. RESULTS Lobectomy for clinical stage I NSCLC was performed in 1,513 patients: 717 (47%) by VATS and 796 (53%) by thoracotomy. Nodal upstaging occurred in 281 patients (18.6%) and was significantly higher after thoracotomy for N1 upstaging (13.1% vs 8.1%; p<0.001) and N2 upstaging (11.5% vs 3.8%; p<0.001). Overall unadjusted survival was significantly higher after VATS, but after adjusting for differences in sex, age, comorbidity, and pT N M by Cox regression analysis, we found no difference between VATS and thoracotomy (hazard ratio, 0.98; 95% confidence interval, 0.80 to 1.22, p=0.88). CONCLUSIONS National data confirm that nodal upstaging was lower after VATS than after open lobectomy for clinical stage I NSCLC. Multivariate survival analysis, however, showed no difference in survival, indicating that differences in nodal upstaging result from patient selection for reasons not captured in our registry.

Possible Advantages and Drawbacks of Adding Flexible Sigmoidoscopy to Hemoccult-II in Screening for Colorectal Cancer: A Randomized Study

BACKGROUND Flexible sigmoidoscopy (FS) has been recommended as a screening method to reduce mortality from colorectal cancer (CRC). The present study evaluates the effect of adding FS to the fecal occult blood test Hemoccult-II (H-II) on diagnostic yield of colorectal neoplasia. METHODS A total of 10,978 normal persons aged 50-75 years were invited to participate, 5495 persons being allocated at random to H-II and FS and 5483 to H-II alone. RESULTS In spite of a lower compliance (40% versus 56%) for the combined procedure, the diagnostic yield of colorectal neoplasia was higher than for H-II alone (12 CRC versus 4 CRC, and 72 large adenomas versus 14). Within 24-62 months after screening there were fewer CRCs detected after H-II + FS than after H-II alone. The stage distribution was less favorable than in screen-detected cases. CONCLUSION One FS may not be an optimal way of screening, but FS deserves to be evaluated in randomized population studies including repeated H-II tests in the control arm.

A Randomized Surveillance Study of Patients with Pedunculated and Small Sessile Tubular and Tubulovillous Adenomas: The Funen Adenoma Follow-up Study

BACKGROUND We wanted to assess the influence of various surveillance intervals on the risk of new neoplasia after removal of pedunculated and small sessile tubular and tubulovillous adenomas. METHODS After initial colonoscopic polypectomy patients were randomized to surveillance with either 2 years (group A) or 4 years (group B) between colorectal examinations. RESULTS The cumulated risk of a patient having new adenomas was 35.0% (28.7-41.4%) in group A and 35.5% (28.4-42.7%) in group B after 48 months. The risk increased to 44.9% (36.0-53.9%) and 60.1% (48.5-71.7%), respectively, after 96 months. The risk of significant neoplasia (carcinoma or adenoma with villous structure, severe dysplasia, or diameter > 10 mm) was 5.2% (2.3-8.1%) and 8.6% (3.8-13.3%) after 48 months and 8.6% (4.2-13.0%) and 17.4% (7.6-27.2%) after 96 months. More than one adenoma at first examination was associated with higher risk of new adenomas. Furthermore, we found a tendency for age above 60 years and male gender to be associated with higher risk of new adenomas. More than two adenomas at first examination was the only factor found to be associated with a higher risk of new significant neoplasia. One patient in group A and two patients in group B developed cancer, which is not significantly different from the number expected (3.43) in the average Danish population (RR = 0.9, 0.2-2.6). CONCLUSION After colonoscopy with removal of all polyps, colorectal examination at 4 years resulted in a similar risk of new adenomas compared with examinations at 2 and 4 years. However, new significant neoplasia tended to be more frequent when first surveillance was at 4 years. Extending the surveillance to 8 years also tended to increase the risk more in the group being examined every 4 years, but reduction of the number of surveillance examinations by more than 50% and a probable reduction of complications from surveillance examinations themselves may justify a recommendation for the longest interval.

Postoperative pain and quality of life after lobectomy via video-assisted thoracoscopic surgery or anterolateral thoracotomy for early stage lung cancer: a randomised controlled trial

BACKGROUND Video-assisted thoracoscopic surgery (VATS) is used increasingly as an alternative to thoracotomy for lobectomy in the treatment of early-stage non-small-cell lung cancer, but remains controversial and worldwide adoption rates are low. Non-randomised studies have suggested that VATS reduces postoperative morbidity, but there is little high-quality evidence to show its superiority over open surgery. We aimed to investigate postoperative pain and quality of life in a randomised trial of patients with early-stage non-small-cell lung cancer undergoing VATS versus open surgery. METHODS We did a randomised controlled patient and observer blinded trial at a public university-based cardiothoracic surgery department in Denmark. We enrolled patients who were scheduled for lobectomy for stage I non-small-cell lung cancer. By use of a web-based randomisation system, we assigned patients (1:1) to lobectomy via four-port VATS or anterolateral thoracotomy. After surgery, we applied identical surgical dressings to ensure masking of patients and staff. Postoperative pain was measured with a numeric rating scale (NRS) six times per day during hospital stay and once at 2, 4, 8, 12, 26, and 52 weeks, and self-reported quality of life was assessed with the EuroQol 5 Dimensions (EQ5D) and the European Organisation for Research and Treatment of Cancer (EORTC) 30 item Quality of Life Questionnaire (QLQ-C30) during hospital stay and 2, 4, 8, 12, 26, and 52 weeks after discharge. The primary outcomes were the proportion of patients with clinically relevant moderate-to-severe pain (NRS ≥3) and mean quality of life scores. These outcomes were assessed longitudinally by logistic regression across all timepoints. Data for the primary analysis were analysed by modified intention to treat (ie, all randomised patients with pathologically confirmed non-small-cell lung cancer). This trial is registered with ClinicalTrials.gov, number NCT01278888. FINDINGS Between Oct 1, 2008, and Aug 20, 2014, we screened 772 patients, of whom 361 were eligible for inclusion and 206 were enrolled. We randomly assigned 103 patients to VATS and 103 to anterolateral thoracotomy. 102 patients in the VATS group and 99 in the thoracotomy group were included in the final analysis. The proportion of patients with clinically relevant pain (NRS ≥3) was significantly lower during the first 24 h after VATS than after anterolateral thoracotomy (VATS 38%, 95% CI 0·28-0·48 vs thoracotomy 63%, 95% CI 0·52-0·72, p=0·0012). During 52 weeks of follow-up, episodes of moderate-to-severe pain were significantly less frequent after VATS than after anterolateral thoracotomy (p<0·0001) and self-reported quality of life according to EQ5D was significantly better after VATS (p=0·014). By contrast, for the whole study period, quality of life according to QLQ-C30 was not significantly different between groups (p=0·13). Postoperative surgical complications (grade 3-4 adverse events) were similar between the two groups, consisting of prolonged air leakage over 4 days (14 patients in the VATS group vs nine patients in the thoracotomy group), re-operation for bleeding (two vs none), twisted middle lobe (one vs three) or prolonged air leakage over 7 days (five vs six), arrhythmia (one vs one), or neurological events (one vs two). Nine (4%) patients died during the follow-up period (three in the VATS group and six in the thoracotomy group). INTERPRETATION VATS is associated with less postoperative pain and better quality of life than is anterolateral thoracotomy for the first year after surgery, suggesting that VATS should be the preferred surgical approach for lobectomy in stage I non-small-cell lung cancer. FUNDING Simon Fougner Hartmanns Familiefond, Guldsmed AL & D Rasmussens Mindefond, Karen S Jensens legat, The University of Southern Denmark, The Research Council at Odense University Hospital, and Department of Cardiothoracic Surgery, Odense University Hospital.

The value of mediastinal staging with endobronchial ultrasound-guided transbronchial needle aspiration in patients with lung cancer

OBJECTIVE To evaluate the diagnostic yield, the learning curve and the safety of endobronchial ultrasound-guided transbronchial needle biopsy (EBUS-TBNA) in mediastinal staging of patients with lung cancer. METHODS Mediastinal staging was performed with EBUS-TBNA according to the Danish national guidelines in patients fulfilling one or more of the following criteria: (1) central tumour; (2) enlarged (>10 mm) mediastinal lymph nodes on computed tomography; or (3) positron emission tomography (PET)-positive mediastinal lymph nodes. The study period began in January 2006 when EBUS-TBNA was introduced in the department and ended in December 2007. All records were reviewed retrospectively. None of the four examiners had any previous experience with EBUS-TBNA or ultrasound when the study began. All examinations were performed under general anaesthesia. Patients without useful cytological material from the EBUS-TBNA were subjected to a supplementary standard cervical mediastinoscopy if the mediastinal lymph nodes were found to be enlarged (>10 mm), PET positive or if the examiner was insecure of the result of the EBUS-TBNA. Patients with mediastinal lymph node involvement, detected by EBUS-TBNA or standard cervical mediastinoscopy, were referred to oncological treatment, while those without mediastinal lymph node involvement underwent--if they were otherwise eligible for surgery--resection and systematic lymph node sampling either by thoracotomy or by video-assisted thoracoscopy. Final mediastinal staging was defined as positive if mediastinal lymph node involvement was detected by EBUS-TBNA, standard cervical mediastinoscopy or surgery, or defined as negative otherwise. RESULTS A total of 157 patients were included in the study. N2/N3 disease was found in 67 patients (42.6%). EBUS-TBNA missed the mediastinal spread in 10 patients. Five of the ten patients had lymph node metastases in station 5, 6 or 8--out of reach of EBUS-TBNA or standard cervical mediastinoscopy. EBUS-TBNA had a sensitivity of 0.85 (0.74-0.93) and a negative predictive value of 0.90 (0.82-0.95). No complications occurred from EBUS-TBNA. The number of supplementary standard cervical mediastinoscopies decreased significantly in the study period. CONCLUSION The results of this study suggest that staging of the mediastinum with EBUS-TBNA is safe and easy to learn--even without previous experience with ultrasound. The diagnostic yield of EBUS-TBNA is in accordance with the yield of standard cervical mediastinoscopy reported in the literature. We do not find any indications in the present study of the recommended necessity for mediastinoscopy in all EBUS-TBNA-negative patients.