John Yee

Probability of Cancer in Pulmonary Nodules Detected on First Screening CT

BACKGROUNDnMajor issues in the implementation of screening for lung cancer by means of low-dose computed tomography (CT) are the definition of a positive result and the management of lung nodules detected on the scans. We conducted a population-based prospective study to determine factors predicting the probability that lung nodules detected on the first screening low-dose CT scans are malignant or will be found to be malignant on follow-up.nnnMETHODSnWe analyzed data from two cohorts of participants undergoing low-dose CT screening. The development data set included participants in the Pan-Canadian Early Detection of Lung Cancer Study (PanCan). The validation data set included participants involved in chemoprevention trials at the British Columbia Cancer Agency (BCCA), sponsored by the U.S. National Cancer Institute. The final outcomes of all nodules of any size that were detected on baseline low-dose CT scans were tracked. Parsimonious and fuller multivariable logistic-regression models were prepared to estimate the probability of lung cancer.nnnRESULTSnIn the PanCan data set, 1871 persons had 7008 nodules, of which 102 were malignant, and in the BCCA data set, 1090 persons had 5021 nodules, of which 42 were malignant. Among persons with nodules, the rates of cancer in the two data sets were 5.5% and 3.7%, respectively. Predictors of cancer in the model included older age, female sex, family history of lung cancer, emphysema, larger nodule size, location of the nodule in the upper lobe, part-solid nodule type, lower nodule count, and spiculation. Our final parsimonious and full models showed excellent discrimination and calibration, with areas under the receiver-operating-characteristic curve of more than 0.90, even for nodules that were 10 mm or smaller in the validation set.nnnCONCLUSIONSnPredictive tools based on patient and nodule characteristics can be used to accurately estimate the probability that lung nodules detected on baseline screening low-dose CT scans are malignant. (Funded by the Terry Fox Research Institute and others; ClinicalTrials.gov number, NCT00751660.).

Protein profiles associated with survival in lung adenocarcinoma

Morphologic assessment of lung tumors is informative but insufficient to adequately predict patient outcome. We previously identified transcriptional profiles that predict patient survival, and here we identify proteins associated with patient survival in lung adenocarcinoma. A total of 682 individual protein spots were quantified in 90 lung adenocarcinomas by using quantitative two-dimensional polyacrylamide gel electrophoresis analysis. A leave-one-out cross-validation procedure using the top 20 survival-associated proteins identified by Cox modeling indicated that protein profiles as a whole can predict survival in stage I tumor patients (P = 0.01). Thirty-three of 46 survival-associated proteins were identified by using mass spectrometry. Expression of 12 candidate proteins was confirmed as tumor-derived with immunohistochemical analysis and tissue microarrays. Oligonucleotide microarray results from both the same tumors and from an independent study showed mRNAs associated with survival for 11 of 27 encoded genes. Combined analysis of protein and mRNA data revealed 11 components of the glycolysis pathway as associated with poor survival. Among these candidates, phosphoglycerate kinase 1 was associated with survival in the protein study, in both mRNA studies and in an independent validation set of 117 adenocarcinomas and squamous lung tumors using tissue microarrays. Elevated levels of phosphoglycerate kinase 1 in the serum were also significantly correlated with poor outcome in a validation set of 107 patients with lung adenocarcinomas using ELISA analysis. These studies identify new prognostic biomarkers and indicate that protein expression profiles can predict the outcome of patients with early-stage lung cancer.

Evolution of an adenocarcinoma in response to selection by targeted kinase inhibitors.

BackgroundAdenocarcinomas of the tongue are rare and represent the minority (20 to 25%) of salivary gland tumors affecting the tongue. We investigated the utility of massively parallel sequencing to characterize an adenocarcinoma of the tongue, before and after treatment.ResultsIn the pre-treatment tumor we identified 7,629 genes within regions of copy number gain. There were 1,078 genes that exhibited increased expression relative to the blood and unrelated tumors and four genes contained somatic protein-coding mutations. Our analysis suggested the tumor cells were driven by the RET oncogene. Genes whose protein products are targeted by the RET inhibitors sunitinib and sorafenib correlated with being amplified and or highly expressed. Consistent with our observations, administration of sunitinib was associated with stable disease lasting 4 months, after which the lung lesions began to grow. Administration of sorafenib and sulindac provided disease stabilization for an additional 3 months after which the cancer progressed and new lesions appeared. A recurring metastasis possessed 7,288 genes within copy number amplicons, 385 genes exhibiting increased expression relative to other tumors and 9 new somatic protein coding mutations. The observed mutations and amplifications were consistent with therapeutic resistance arising through activation of the MAPK and AKT pathways.ConclusionsWe conclude that complete genomic characterization of a rare tumor has the potential to aid in clinical decision making and identifying therapeutic approaches where no established treatment protocols exist. These results also provide direct in vivo genomic evidence for mutational evolution within a tumor under drug selection and potential mechanisms of drug resistance accrual.

Complete worldwide operative experience in laparoscopic diaphragm pacing: results and differences in spinal cord injured patients and amyotrophic lateral sclerosis patients

BackgroundDiaphragm movement is essential for adequate ventilation, and when the diaphragm is adversely affected patients face lifelong positive-pressure mechanical ventilation or death. This report summarizes the complete worldwide multicenter experience with diaphragm pacing stimulation (DPS) to maintain and provide diaphragm function in ventilator-dependent spinal cord injury (SCI) patients and respiratory-compromised patients with amyotrophic lateral sclerosis (ALS). It will highlight the surgical experiences and the differences in diaphragm function in these two groups of patients. MethodsIn prospective Food and Drug Administration (FDA) trials, patients underwent laparoscopic diaphragm motor point mapping with intramuscular electrode implantation. Stimulation of the electrodes ensued to condition and strengthen the diaphragm.Results From March of 2000 to September of 2007, a total of 88 patients (50 SCI and 38 ALS) were implanted with DPS at five sites. Patient age ranged from 18 to 74xa0years. Time from SCI to implantation ranged from 3xa0months to 27xa0years. In 87 patients the diaphragm motor point was mapped with successful implantation of electrodes with the only failure the second SCI patient who had a false-positive phrenic nerve study. Patients with ALS had much weaker diaphragms identified surgically, requiring trains of stimulation during mapping to identify the motor point at times. There was no perioperative mortality even in ALS patients with forced vital capacity (FVC) below 50% predicted. There was no cardiac involvement from diaphragm pacing even when analyzed in ten patients who had pre-existing cardiac pacemakers. No infections occurred even with simultaneous gastrostomy tube placements for ALS patients. In the SCI patients 96% were able to use DPS to provide ventilation replacing their mechanical ventilators and in the ALS studies patients have been able to delay the need for mechanical ventilation up to 24xa0months.Conclusion This multicenter experience has shown that laparoscopic diaphragm motor point mapping, electrode implantation, and pacing can be safely performed both in SCI and in ALS. In SCI patients it allows freedom from ventilator and in ALS patients it delays the need for ventilators, increasing survival.

Patient-Derived First Generation Xenografts of Non–Small Cell Lung Cancers: Promising Tools for Predicting Drug Responses for Personalized Chemotherapy

Purpose: Current chemotherapeutic regimens have only modest benefit for non–small cell lung cancer (NSCLC) patients. Cumulative toxicities/drug resistance limit chemotherapy given after the first-line regimen. For personalized chemotherapy, clinically relevant NSCLC models are needed for quickly predicting the most effective regimens for therapy with curative intent. In this study, first generation subrenal capsule xenografts of primary NSCLCs were examined for (a) determining responses to conventional chemotherapeutic regimens and (b) selecting regimens most effective for individual patients. Experimental Design: Pieces (1×3×3 mm3) of 32 nontreated, completely resected patients NSCLCs were grafted under renal capsules of nonobese diabetic/severe combined immunodeficient mice and treated with (A) cisplatin+vinorelbine, (B) cisplatin+docetaxel, (C) cisplatin+gemcitabine, and positive responses (treated tumor area ≤50% of control, P < 0.05) were determined. Clinical outcomes of treated patients were acquired. Results: Xenografts from all NSCLCs were established (engraftment rate, 90%) with the retention of major biological characteristics of the original cancers. The entire process of drug assessment took 8 weeks. Response rates to regimens A, B, and C were 28% (9 of 32), 42% (8 of 19), and 44% (7 of 16), respectively. Certain cancers that were resistant to a particular regimen were sensitive to others. The majority of responsive tumors contained foci of nonresponding cancer cells, indicative of tumor heterogeneity and potential drug resistance. Xenografts from six of seven patients who developed recurrence/metastasis were nonresponsive. Conclusions: Models based on first generation NSCLC subrenal capsule xenografts have been developed, which are suitable for quick assessment (6-8 weeks) of the chemosensitivity of patients cancers and selection of the most effective regimens. They hold promise for application in personalized chemotherapy of NSCLC patients. Clin Cancer Res; 16(5); 1442–51

Empyema: An Increasing Concern in Canada

BACKGROUNDnEmpyema is a suppurative infection of the pleural space. Without prompt treatment, it can result in significant hospital stays, more invasive treatments as it progresses, and substantial morbidity and mortality.nnnOBJECTIVESnThe primary objective of the present study was to evaluate whether there has been an increasing incidence of empyema in Canada. A secondary objective was to investigate whether this increase disproportionately affects any age group.nnnMETHODSnThe Discharge Abstract Database of the Canadian Institute for Health Information was used to evaluate national empyema data.nnnRESULTSnThere were 11,294 patients identified with empyema over the nine-year period of the present study, of whom 31% were women. The mean (+/- SD) length of stay was stable throughout the study at 21.82+/-33.88 days, and 63.4% were discharged home. The incidence rate ratio (IRR) was defined as the ratio of the incidence rate of medical empyema in 2003 divided by the incidence rate in 1995. Medical empyema increased significantly (IRR 1.30, 95% CI 1.20 to 1.41; P<0.001), as did empyema of unknown cause (IRR 1.29, 95% CI 1.08 to 1.54; P=0.005), while surgical empyema did not appear to increase (IRR 1.17, 95% CI 0.97 to 1.43; P=0.114). A Poisson regression showed an increase in the indirect age-standardized IRR during the study period (IRR 1.025, 95% CI 1.018 to 1.032; P<0.001). The IRR for patients younger than 19 years of age from 1995 to 2003 was 2.20 (95% CI 1.56 to 3.10), while the IRR in patients older than 19 years was 1.23 (95% CI 1.14 to 1.34).nnnCONCLUSIONSnThe present study demonstrates the increasing rate of empyema in Canada and shows a change in pattern of disease. The disproportionate rate change in the pediatric population suggests a high-risk group that needs to be addressed. In the adult population, while cause is unknown, it is necessary to continually educate front-line physicians to confront both the increased burden of this disease, caused by an aging population, and the underlying increasing rate of empyema in Canada.

Lung Nodules: CT-guided Placement of Microcoils to Direct Video-assisted Thoracoscopic Surgical Resection

PURPOSEnTo 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.nnnMATERIALS AND METHODSnThe 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.nnnRESULTSnSeventy-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.nnnCONCLUSIONnMicrocoil 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.

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 ± 3.2mm) 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.

Increased C-CRK proto-oncogene expression is associated with an aggressive phenotype in lung adenocarcinomas.

The C-CRK gene, cellular homolog of the avian v-crk oncogene, encodes two alternatively spliced adaptor signaling proteins, CRKI (28u2009kDa) and CRKII (40u2009kDa). Both CRKI and CRKII have been shown to activate kinase signaling and anchorage-independent growth in vitro and CRKI transformed cells readily form tumors in nude mice. Affymetrix oligonucleotide arrays were used to analyse 86 lung adenocarcinomas and 10 uninvolved lung tissues. C-CRK mRNA expression was increased in more advanced (stage III versus stage I), larger (T2–4 versus T1), and poorly differentiated tumors and in tumors from patients demonstrating poor survival (P=0.00034). An overlapping series of 93 lung adenocarcinomas (64 stage I and 29 stage III) and 10 uninvolved lung specimens were measured for quantitative differences in CRKI and CRKII protein levels using 2-D PAGE. CRK protein spots were identified using mass spectrometry and 2-D Western blotting. A significant increase in levels of the CRKI oncoprotein and the phosphorylated isoform of CRKII was observed in tumors (P<0.05). No difference in protein level was evident between stages. Concordant with mRNA expression, CRKI and CRKII were increased in poorly differentiated tumors (P<0.05). CRK immunohistochemical analysis of tumor tissue arrays using the same tumor series also demonstrated increased abundance of nuclear and cytoplasmic CRK in more proliferative tumors (P<0.05). This study provides the first quantitative analysis of discrete CRKI and CRKII protein isoforms in human lung tumors and provides evidence that the C-CRK proto-oncogene may foment a more aggressive phenotype in lung cancers.

Integrative Genomic Analyses Identify BRF2 as a Novel Lineage-Specific Oncogene in Lung Squamous Cell Carcinoma

William Lockwood and colleagues show that the focal amplification of a gene, BRF2, on Chromosome 8p12 plays a key role in squamous cell carcinoma of the lung.