Participant selection for lung cancer screening by risk modelling (the Pan-Canadian Early Detection of Lung Cancer [PanCan] study): a single-arm, prospective study.

BACKGROUND: Results from retrospective studies indicate that selecting individuals for low-dose CT lung cancer screening on the basis of a highly predictive risk model is superior to using criteria similar to those used in the National Lung Screening Trial (NLST; age, pack-year, and smoking quit-time). We designed the Pan-Canadian Early Detection of Lung Cancer (PanCan) study to assess the efficacy of a risk prediction model to select candidates for lung cancer screening, with the aim of determining whether this approach could better detect patients with early, potentially curable, lung cancer. METHODS: We did this single-arm, prospective study in eight centres across Canada. We recruited participants aged 50-75 years, who had smoked at some point in their life (ever-smokers), and who did not have a self-reported history of lung cancer. Participants had at least a 2% 6-year risk of lung cancer as estimated by the PanCan model, a precursor to the validated PLCOm2012 model. Risk variables in the model were age, smoking duration, pack-years, family history of lung cancer, education level, body-mass index, chest x-ray in the past 3 years, and history of chronic obstructive pulmonary disease. Individuals were screened with low-dose CT at baseline (T0), and at 1 (T1) and 4 (T4) years post-baseline. The primary outcome of the study was incidence of lung cancer. This study is registered with ClinicalTrials.gov, number NCT00751660. FINDINGS: 7059 queries came into the study coordinating centre and were screened for PanCan risk. 15 were duplicates, so 7044 participants were considered for enrolment. Between Sept 24, 2008, and Dec 17, 2010, we recruited and enrolled 2537 eligible ever-smokers. After a median follow-up of 5·5 years (IQR 3·2-6·1), 172 lung cancers were diagnosed in 164 individuals (cumulative incidence 0·065 [95% CI 0·055-0·075], incidence rate 138·1 per 10 000 person-years [117·8-160·9]). There were ten interval lung cancers (6% of lung cancers and 6% of individuals with cancer): one diagnosed between T0 and T1, and nine between T1 and T4. Cumulative incidence was significantly higher than that observed in NLST (4·0%; p<0·0001). Compared with 593 (57%) of 1040 lung cancers observed in NLST, 133 (77%) of 172 lung cancers in the PanCan Study were early stage (I or II; p<0·0001). INTERPRETATION: The PanCan model was effective in identifying individuals who were subsequently diagnosed with early, potentially curable, lung cancer. The incidence of cancers detected and the proportion of early stage cancers in the screened population was higher than observed in previous studies. This approach should be considered for adoption in lung cancer screening programmes. FUNDING: Terry Fox Research Institute and Canadian Partnership Against Cancer.

Remembering Dr. Frederick Griffith Pearson.

SUMMARY: Canada has lost a remarkable surgeon and leader. Dr. Frederick Griffith "Griff" Pearson, aged 90, died in Kitchener, Ont., on Aug. 10, 2016, surrounded by his wife, Hilppa Pearson, and his family.

Alveolar macrophage proteinase/antiproteinase expression in lung function and emphysema.

Alveolar macrophages play an important role in chronic obstructive pulmonary disease via production of matrix metalloproteinases (MMPs) and cathepsins as well as their inhibitors, tissue inhibitors of metalloproteinases and cystatin C. We hypothesised that expression levels of these molecules by alveolar macrophages at baseline and after stimulation would be influenced by genotype and associated with chronic obstructive pulmonary disease phenotypes. Quantitative PCR and ELISAs/gelatine zymography were used to investigate expression levels of mRNA and protein, respectively. The relationships of expression with genotype, pulmonary function and emphysema were analysed. The results showed that basal expression level of MMP12 mRNA was inversely related to the diffusing capacity of the lung for carbon monoxide/alveolar volume and to forced expiratory volume in 1 s/forced vital capacity after correction for multiple comparisons. The expression level of MMP12 protein stimulated with lipopolysaccharide was also inversely related to the diffusing capacity of the lung for carbon monoxide/alveolar volume and was positively related to the extent of emphysema. The basal expression of MMP1 mRNA was positively correlated with the extent of emphysema. Cathepsin L protein level was positively associated with forced expiratory volume in 1 s % predicted. We conclude that increased MMP12 and MMP1 expression may play a role in the pathogenesis of emphysema. Cathepsin L and MMP9 may be involved in the development of airflow limitation.

Expression of matrix metalloproteinase-1 in alveolar macrophages, type II pneumocytes, and airways in smokers: relationship to lung function and emphysema.

BACKGROUND: An imbalance between proteolytic enzymes and their inhibitors is thought to be involved in the pathogenesis of chronic obstructive pulmonary disease. Matrix metalloproteinase-1, also known as interstitial collagenase, has been implicated as a potentially important proteinase in the genesis of chronic obstructive pulmonary disease and, more specifically, emphysema. METHODS: We performed quantitative immunohistochemical assessment of matrix metalloproteinase-1 expression in the resected lung of 20 smokers/ex-smokers who had varying severity of airflow obstruction and emphysema and compared this with the lungs of 5 nonsmokers. Emphysema was measured using a morphometric measure of the lungs' surface area/volume ratio and with qualitative and quantitative computed tomography (CT) measures of emphysema. RESULTS: There were significantly more matrix metalloproteinase-1-expressing alveolar macrophages and type II pneumocytes as well as a greater percentage of small airways that stained positively for matrix metalloproteinase-1 in the lungs of smokers than in those of nonsmokers (p < 0.0001, p < 0.0001, and p = 0.0003, respectively). The extent of staining of type II pneumocytes and airways for matrix metalloproteinase-1 was significantly related to the extent of smoking (p = 0.012 and p = 0.013, respectively). In addition, the extent of matrix metalloproteinase-1 staining of alveolar macrophages was related to the lung surface area/volume ratio and to qualitative estimates of emphysema on CT. CONCLUSION: These findings suggest that cigarette smoking increases expression of matrix metalloproteinase-1 in alveolar macrophages as well as in alveolar and small airway epithelial cells. Smokers who develop emphysema have increased alveolar macrophage expression of matrix metalloproteinase-1.

Lung nodules: CT-guided placement of microcoils to direct video-assisted thoracoscopic surgical resection.

PURPOSE: To prospectively assess the safety and effectiveness of computed tomography (CT)-guided placement of fiber-coated microcoils used to guide video-assisted thoracoscopic surgical (VATS) excision of small peripheral lung nodules, with successful excision as the primary outcome and successful CT-guided microcoil placement and procedural complications as secondary outcomes. MATERIALS AND METHODS: The institutional review board approved the study protocol. Informed consent was obtained from all 69 enrolled patients (30 men, 39 women; mean age, 60.7 years +/- 10.1 [standard deviation]) with 75 nodules. At CT, one end of an 80-mm long, 0.018-inch-diameter fiber-coated microcoil was placed deep to the small peripheral lung nodule, and the other end was coiled in the pleural space. VATS excision of lung tissue, nodules, and the microcoil was performed with fluoroscopic guidance. RESULTS: Seventy-three (97%) 4-24-mm nodules were successfully removed at fluoroscopically guided VATS excision; two nodules could not be removed. CT-guided microcoil placement was successful in all cases; however, two (3%) of 75 coils were displaced at VATS excision. Pneumothorax requiring chest tube placement occurred in two (3%) patients, and asymptomatic hemothorax occurred in one (1%) patient. The microcoil did not impede intraoperative frozen-section histopathologic analysis, which facilitated accurate clinical management in all patients. For 19 (28%) patients, the preoperative treatment plan based on bronchoscopy, needle biopsy, and positron emission tomography findings changed after VATS excision. CONCLUSION: Microcoil localization of small peripheral lung nodules enabled fluoroscopically guided VATS resection of 97% of the nodules, with a low rate of intervention (3%) for procedural complications.

Strategic faculty recruitment increases research productivity within an academic university division.

BACKGROUND: Research is an important mandate for academic surgical divisions. However, there is widespread concern that the current health care climate is leading to a decline in research activity. A University of British Columbia (UBC) academic surgical division attempted to address this concern by strategically recruiting PhD research scientists to prioritize research and develop collaborative research programs. The objective of our study was to determine whether this strategy resulted in increased research productivity. METHODS: We reviewed the UBC Department of Surgery database to assess research funding obtained by the Division of General Surgery for the years 1994-2004. We searched MEDLINE for peer-reviewed publications by faculty members during this period. RESULTS: Research funding increased from a mean of Can$417,292 per year in the 5 years (1994/95-1998/99) before the recruitment of dedicated PhD scientists to a mean of Can$1.3 million per year in the 5 years following the recruitment strategy (1999/2000-2003/04; p = 0.012). Funding for the initial 5 years was Can$2.1 million, including 1 Canadian Institutes of Health Research (CIHR) grant. Funding increased to Can$6.8 million, including 22 CIHR grants over the subsequent 5 years (p < 0.001). Collaborative research led to the awarding of multidisciplinary grants exceeding Can$4 million with divisional members as principle or coprinciple investigators. From 1994/05 to 1998/99, the total number of peer-reviewed publications was 116 (mean 23.2, standard deviation [SD] 7 per year), increasing to 144 from 1999/2000 to 2003/04 (mean 28.8, SD 13 per year). The trend was for publications in journals with higher impact factors in the latter 5-year period. CONCLUSION: Strategic recruitment resulted in increased and sustained research productivity. Interactions between research scientists and clinicians resulted in successful program grant funding support. These results have implications for sustaining the research mission within academic departments of surgery.

Practical approaches to the surgical management of achalasia.

Achalasia is a primary motor disorder of the esophagus characterized by an abnormal hypertensive, nonrelaxing lower esophageal sphincter (LES) and nonfunctioning, aperistaltic esophageal body resulting in significant regurgitation and dysphagia. The primary goal of treatment is palliation of symptoms. At present, all treatment techniques are directed at relieving the functional obstruction at the level of the LES by disruption or paralysis of the esophageal muscle constituting the LES. Destruction of the LES function also places the patient at risk for pathologic gastroesophageal reflux disease. Therefore, the treatment of patients with achalasia must strike a balance between the relief of dysphagia and potential creation of pathologic gastroesophageal reflux. The advent of laparoscopic esophageal myotomy for the treatment of achalasia over the past decade has resulted in most patients with the disease being referred to surgeons for definitive treatment. At the time of consultation the patient may present with a myriad of symptoms, investigative results, and previous treatments. Based on our experience of over 300 patients treated with surgery at our institution between 1990 and 2007, this review will address the practical problems encountered in the surgical management of achalasia.

CT-Directed microcoil localization of small peripheral lung nodules: a feasibility study in pigs.

Platinum microcoils were placed in porcine lungs to determine the feasibility for use as a lung nodule marker. Using computed tomography (CT) guidance, the microcoils were successfully deployed in 17 out of 19 attempts. Coil deployment depth ranged from 7 mm to 34 mm below the pleural surface. Moderate pneumothorax was detected after 3 of 19 microcoil insertions. No hemothorax or significant pulmonary hemorrhage was noted. Fluoroscopic guided thoracoscopic resection was successful in 10 of 12 attempts. Platinum microcoils can be safely and easily deployed into the lung parenchyma with minimal complication risk, and can be used to guide subsequent thoracoscopic wedge resection.

Preoperative computed tomography-guided microcoil localization of small peripheral pulmonary nodules: a prospective randomized controlled trial.

OBJECTIVES: Growing, small, peripheral, pulmonary nodules in patients at high risk for lung cancer lead to requests for video-assisted thoracoscopic (VATS) resection for pathologic diagnosis. The purpose of this randomized controlled trial was to determine if preoperative localization using percutaneously placed computed tomography (CT)-guided platinum microcoils decreases the need for thoracotomy or VATS anatomic resection (segmentectomy/lobectomy) for diagnosis. METHODS: Patients with undiagnosed nodules of 15 mm or less were randomized to either no localization or preoperative microcoil localization. Coils were placed with the distal end deep to the nodule and the superficial end coiled on the visceral pleural surface with subsequent visualization by intraoperative fluoroscopy and VATS. Nodules were removed by VATS wedge excision using endostaplers. The primary outcome was a VATS wedge excision for pathologic diagnosis of the nodule without the need for either thoracotomy or VATS anatomic resection. RESULTS: Sixty patients were randomized and 56 underwent surgery between March 2010 and June 2012. Twenty-nine underwent microcoil localization and 27 did not. The baseline characteristics (age, sex, forced expiratory volume in the first second of expiration, nodule size/depth) were similar. The coil group had a higher rate of successful diagnosis with VATS wedge resection alone (27/29 vs 13/27; P < .001), decreased operative time to nodule excision (37 ± 39 vs 100 ± 67 minutes; P < .001), and reduced stapler firings (3.7 ± 2.0 vs 5.9 ± 31; P = .003) with no difference in total costs. Pathologic diagnoses included 14 benign nodules, 32 primary lung malignancies, and 10 metastases. There were no clinically significant complications related to the coil placement or wedge resection. CONCLUSIONS: Preoperative CT-guided microcoil localization decreases the need for thoracotomy or VATS anatomic resection for the diagnosis of small peripheral pulmonary nodules.

Resource utilization and costs during the initial years of lung cancer screening with computed tomography in Canada.

BACKGROUND: It is estimated that millions of North Americans would qualify for lung cancer screening and that billions of dollars of national health expenditures would be required to support population-based computed tomography lung cancer screening programs. The decision to implement such programs should be informed by data on resource utilization and costs. METHODS: Resource utilization data were collected prospectively from 2059 participants in the Pan-Canadian Early Detection of Lung Cancer Study using low-dose computed tomography (LDCT). Participants who had 2% or greater lung cancer risk over 3 years using a risk prediction tool were recruited from seven major cities across Canada. A cost analysis was conducted from the Canadian public payer's perspective for resources that were used for the screening and treatment of lung cancer in the initial years of the study. RESULTS: The average per-person cost for screening individuals with LDCT was $453 (95% confidence interval [CI], $400-$505) for the initial 18-months of screening following a baseline scan. The screening costs were highly dependent on the detected lung nodule size, presence of cancer, screening intervention, and the screening center. The mean per-person cost of treating lung cancer with curative surgery was $33,344 (95% CI, $31,553-$34,935) over 2 years. This was lower than the cost of treating advanced-stage lung cancer with chemotherapy, radiotherapy, or supportive care alone, ($47,792; 95% CI, $43,254-$52,200; p = 0.061). CONCLUSION: In the Pan-Canadian study, the average cost to screen individuals with a high risk for developing lung cancer using LDCT and the average initial cost of curative intent treatment were lower than the average per-person cost of treating advanced stage lung cancer which infrequently results in a cure.

Matrix metalloproteinase expression by human alveolar macrophages in relation to emphysema.

An abnormal increase in proteolytic enzymes is thought to play a key role in pulmonary emphysema. Alveolar macrophage proteolytic enzymes include cathepsin L, cathepsin S, matrix metalloproteinase 1, 9, and 12, and a number of studies have implicated these proteinases in the alveolar destruction that characterizes emphysema. The aim of this study was to investigate cathepsin L, cathepsin S, matrix metalloproteinase 1, 9, and 12 mRNA expression in alveolar macrophages isolated from patients with varying degrees of emphysema and to correlate their level of expression with measures of emphysema. Alveolar macrophages were isolated from fifty-four patients who underwent surgical resection for lung carcinoma. The level of mRNA expression was determined using real-time PCR. Emphysema was quantified using high-resolution CT scans. Alveolar macrophages were also cultured for 24 h and 48 h; the effect of proinflammatory mediators and promoter polymorphisms on expression was analyzed. There was a significant correlation between matrix metalloproteinase 1 mRNA expression and emphysema. A higher level of matrix metalloproteinase 1 mRNA was associated with more severe emphysema. Matrix metalloproteinase 12 mRNA expression was increased in current smokers as compared with former smokers. Furthermore, there was a negative correlation between matrix metalloproteinase 12 gene expression and carbon monoxide diffusing capacity. The matrix metalloproteinase 9 C-1562T polymorphism significantly influenced matrix metalloproteinase 9 mRNA expression in alveolar macrophages. These results suggest that alveolar macrophage matrix metalloproteinase 1 and 12 may have a role in the lung structural changes leading to the development of emphysema. Furthermore, these data provide evidence to support the concept that multiple proteinases, causing both elastin and collagen degradation, are important in the pathogenesis of pulmonary emphysema.

Defining the optimal treatment of locally advanced esophageal cancer: a systematic review and decision analysis.

BACKGROUND: The objective of this study was to combine systematic review and decision analytic techniques to determine the optimal treatment strategy for patients with locally advanced esophageal cancer. METHODS: We performed a systematic review of all randomized trials of patients with locally advanced esophageal cancer that included one of the following strategies compared with surgery alone: chemoradiotherapy followed by surgery, chemotherapy followed by surgery, or surgery with adjuvant chemoradiotherapy. Using the estimates of relative risk for mortality and overall quality of life we constructed a decision model. The outcome of interest was expected quality-adjusted life-years (QALY). RESULTS: The meta-analysis showed for the first year, the relative risk (95% confidence interval) of death for treatments compared with surgery were 0.87 (0.75 to 1.02) for chemoradiotherapy followed by surgery, 0.94 (0.82 to 1.08) for chemotherapy followed by surgery, and 1.33 (0.93 to 1.93) for surgery with adjuvant chemoradiotherapy. The QALYs gained for surgery alone, chemoradiotherapy followed by surgery, chemotherapy followed by surgery, and surgery with adjuvant chemoradiotherapy strategies were 2.07, 2.18, 2.14, and 1.99, respectively. If the reduction in utility for multimodality treatment was increased to 21%, the QALYs gained for surgery alone, chemoradiotherapy followed by surgery, chemotherapy followed by surgery, and surgery with adjuvant chemoradiotherapy were 2.07, 2.03, 1.99, and 1.85, respectively. CONCLUSIONS: Chemoradiotherapy followed by surgery appears to be associated with the best survival and the largest expected gain in QALYs. However, the improvement in quality-adjusted life expectancy is modest at 40 days, and surgery alone becomes the preferred strategy if the reduction in utility associated with multimodality treatment is increased to 21%.

The practice of thoracic surgery in Canada.

The objective of the consensus conference of the Canadian Association of Thoracic Surgeons (CATS) was to define the scope of thoracic surgery practice in Canada, to develop standards of practice, to define training and resource requirements for the practice of thoracic surgery in Canada and to determine appropriate waiting times for thoracic surgery care. A meeting of the CATS membership was held in September 2001 to address issues facing thoracic surgeons practising in Canada. The discussion was facilitated by an expert panel of surgeons and supplemented by a survey. At the end of the meeting, consensus was reached by the membership regarding the issues outline above. The membership agreed that the scope of practice includes diagnosis and management of conditions of the lungs, mediastinum, pleura and foregut. They agreed that appropriate training in thoracic surgery included completion and certification in general or cardiac surgery prior to completing a 2-year program in thoracic surgery. The membership supported the Canadian Society of Surgical Oncology recommendations for management of cancer patients that new patients should be seen within 2 weeks of referral and cancer therapy initiated within 2 weeks of consultation. Thoracic surgical care is best delivered by 2 or 3 fully certified thoracic surgeons, in regional centres linked to a cancer centre and trauma unit. The establishment of a critical mass of thoracic surgeons in each centre would lead to improved quality and delivery of care and allow for adequate coverage for on-call and continuing medical education.

Peripheral lung nodules: fluoroscopically guided video-assisted thoracoscopic resection after computed tomography-guided localization using platinum microcoils.

OBJECTIVES: We sought to test the safety and efficacy of fluoroscopically guided, video-assisted, thoracoscopic resection after computed tomography (CT)-guided localization using platinum microcoils. SUMMARY BACKGROUND DATA: Video-assisted thoracoscopic (VATS) resection of small pulmonary nodules >5 mm deep to the visceral pleura fails to locate the nodule and requires conversion to open thoracotomy in two thirds of cases. Therefore, we developed a new technique for intraoperative localization of these nodules using CT-guided placement of platinum microcoils. This study tests the safety and efficacy of this technique in a Phase I human study. METHODS: Twelve patients with undiagnosed growing pulmonary nodules <20 mm were marked preoperatively using percutaneously placed CT-guided platinum microcoils. The coil was deployed adjacent to the nodule with the distal end of the coil placed deep to the nodule and the superficial end coiled on the pleural surface. The nodule and coil were excised using endostaplers guided by VATS and fluoroscopy. Histopathologic diagnosis was performed immediately after resection. RESULTS: CT-guided microcoil localization was successful in all patients. A small hemothorax and a pneumothorax requiring a chest tube occurred in 2 patients. Mean distance from visceral pleura to the deep edge of the nodule was 30.9 +/- 15.4 mm. VATS resection of the nodules (size = 11.8 +/- 3.2 mm) was successful in all patients. Mean microcoil localization, fluoroscopy, and operative times were 42 +/- 14, 3.1 +/- 2.0, and 67 +/- 27 minutes. A diagnosis of primary nonsmall cell bronchogenic carcinoma was made in 6 patients who then received a completion lobectomy. Six patients (hamartoma: 2, reactive lymph node: 1, bronchoalveolar cell carcinoma: 2, metastatic sarcoma: 1) did not receive further resections. CONCLUSIONS: Preoperative localization of pulmonary nodules using percutaneous CT-guided platinum microcoil insertion combined with operative fluoroscopic visualization is a safe, effective technique that increases the success rate of VATS excision.