Mark Deffebach

Screening for Lung Cancer With Low-Dose Computed Tomography: A Systematic Review to Update the U.S. Preventive Services Task Force Recommendation

BACKGROUND Lung cancer is the leading cause of cancer-related death in the United States. Because early-stage lung cancer is associated with lower mortality than late-stage disease, early detection and treatment may be beneficial. PURPOSE To update the 2004 review of screening for lung cancer for the U.S. Preventive Services Task Force, focusing on screening with low-dose computed tomography (LDCT). DATA SOURCES MEDLINE (2000 to 31 May 2013), the Cochrane Central Register of Controlled Trials and Cochrane Database of Systematic Reviews (through the fourth quarter of 2012), Scopus, and reference lists. STUDY SELECTION English-language randomized, controlled trials or cohort studies that evaluated LDCT screening for lung cancer. DATA EXTRACTION One reviewer extracted study data about participants, design, analysis, follow-up, and results, and a second reviewer checked extractions. Two reviewers rated study quality using established criteria. DATA SYNTHESIS Four trials reported results of LDCT screening among patients with smoking exposure. One large good-quality trial reported that screening was associated with significant reductions in lung cancer (20%) and all-cause (6.7%) mortality. Three small European trials showed no benefit of screening. Harms included radiation exposure, overdiagnosis, and a high rate of false-positive findings that typically were resolved with further imaging. Smoking cessation was not affected. Incidental findings were common. LIMITATIONS Three trials were underpowered and of insufficient duration to evaluate screening effectiveness. Overdiagnosis, an important harm of screening, is of uncertain magnitude. No studies reported results in women or minority populations. CONCLUSION Strong evidence shows that LDCT screening can reduce lung cancer and all-cause mortality. The harms associated with screening must be balanced with the benefits. PRIMARY FUNDING SOURCE Agency for Healthcare Research and Quality.

A human gene coding for a membrane-associated nucleic acid-binding protein.

Studies to clone a cell-surface DNA-binding protein involved in the binding and internalization of extracellular DNA have led to the isolation of a gene for a membrane-associated nucleic acid-binding protein (MNAB). The full-length cDNA is 4.3 kilobases with an open reading frame of 3576 base pairs encoding a protein of ∼130 kDa (GenBank accession numbers AF255303 andAF255304). The MNAB gene is on human chromosome 9 with wide expression in normal tissues and tumor cells. A C3HC4 RING finger and a CCCH zinc finger have been identified in the amino-terminal half of the protein. MNAB bound DNA (K D ∼4 nm) and mutagenesis of a single conserved amino acid in the zinc finger reduced DNA binding by 50%. A potential transmembrane domain exists near the carboxyl terminus. Antibodies against the amino-terminal half of the protein immunoprecipitated a protein of molecular mass ∼150 kDa and reacted with cell surfaces. The MNAB protein is membrane-associated and primarily localized to the perinuclear space, probably to the endoplasmic reticulum or trans-Golgi network. Characterization of the MNAB protein as a cell-surface DNA-binding protein, critical in binding and internalization of extracellular DNA, awaits confirmation of its localization to cell surfaces.

Electromagnetic navigational bronchoscopy-guided fiducial markers for lung stereotactic body radiation therapy: analysis of safety, feasibility, and interfraction stability.

Background:Embolization coils as fiducial markers for pulmonary stereotactic body radiation therapy (SBRT) are perceived to be the optimal marker type, given their ability to conform and anchor within the small airways. The aim of our study was to assess retention, placement, migration, feasibility, and safety of electromagnetic navigational bronchoscopy (ENB)-guided embolization coil markers throughout courses of SBRT. Methods:Thirty-one patients with 34 nodules underwent ENB-guided fiducial placement of several 4 mm fibered platinum embolization coils before SBRT. Patient and nodule positioning was confirmed with daily pretreatment cone-beam computed tomography (CBCT). Fiducial positional characteristics were analyzed utilizing radiation treatment-planning software comparing the simulation CT with daily CBCTs. Results:Of 105 fiducials placed, 103 were identifiable on simulation CT (retention rate: 98.1%). Incidence of asymptomatic pneumothoraces was 6%. One patient experienced hemoptysis requiring hospitalization. Eighty-six percent of fiducials were placed within 1 cm of the nodule, with 52% of fiducials placed directly on the nodule surface. Throughout a 5-fraction SBRT course, fiducial displacement was <7, 5, and 2 mm in 98%, 96%, and 67% of pretreatment CBCTs. Conclusions:ENB placement of embolization coils as fiducials for lung SBRT image guidance is associated with a low rate of iatrogenic pneumothoraces, and resulted in reliable placement of the fiducials in close proximity to the lung nodule. Embolization coils retained their relative position to the nodule throughout the course of SBRT, and provide an excellent alternative to linear gold seeds.

Lung cancer stage at diagnosis: Individual associations in the prospective VITamins and lifestyle (VITAL) cohort

BackgroundLung cancer is the leading cause of cancer death in the United States. Identifying factors associated with stage of diagnosis can improve our understanding of biologic and behavioral pathways of lung cancer development and detection. We used data from a prospective cohort study to evaluate associations of demographic, health history, and health behaviors with early versus late stage at diagnosis of non-small cell lung cancer (NSCLC).MethodsWe calculated odds ratios (ORs) for the association of patient-level characteristics with advanced stage of diagnosis for NSCLC. The ORs were then adjusted for age, gender, race/ethnicity, smoking status, income, education, chronic obstructive pulmonary disease, and a comorbidity index.ResultsWe identified 612 cases of NSCLC among 77,719 adults, aged 50 to 76 years from Washington State recruited in 2000-2002, with followup through December 2007. In univariate analyses, subjects who quit smoking <10 years (OR 2.56, 95% CI 1.17 - 5.60) and were college graduates (OR 1.67, 95% CI, 1.00 - 2.76) had increased risks of being diagnosed with advanced stage NSCLC, compared to never smokers and non-college graduates, respectively. Receipt of sigmoidoscopy/colonoscopy, compared to no receipt, was associated with a decreased risk of advanced stage (OR 0.65, 95% CI, 0.43 - 0.99). The adjusted OR for receipt of sigmoidoscopy/colonoscopy was 0.55 (95% CI, 0.36 - 0.86). There was evidence that increasing the number of screening activities was associated with a decreased risk of advanced stage NSCLC (P for trend = 0.049).ConclusionsSmoking status, education, and a screening activity were associated with stage at diagnosis of NSCLC. These results may guide future studies of the underlying mechanisms that influence how NSCLC is detected and diagnosed.

Patient and Clinician Characteristics Associated with Adherence. A Cohort Study of Veterans with Incidental Pulmonary Nodules

RATIONALE Many patients are diagnosed with small pulmonary nodules for which professional societies recommend subsequent imaging surveillance. Adherence to these guidelines involves many steps from both clinicians and patients but has not been well studied. OBJECTIVES In a health care setting with a nodule tracking system, we evaluated the association of communication processes and distress with patient and clinician adherence to recommended follow up and Fleischner Society guidelines, respectively. METHODS We conducted a prospective, longitudinally assessed, cohort study of patients with incidentally detected nodules who received care at one Veterans Affairs Medical Center. We measured patient-centered communication with the Consultation Care Measure and distress with the Impact of Event Scale. We abstracted data regarding participant adherence to clinician recommendations (defined as receiving the follow-up scan within 30 d of the recommended date) and clinician adherence to Fleischner guidelines (defined as planning the follow-up scan within 30 d of the recommended interval) from the electronic medical record. We measured associations of communication and distress with adherence using multivariable-adjusted generalized estimating equations. MEASUREMENTS AND MAIN RESULTS Among 138 veterans, 39% were nonadherent at least once during follow up. Clinicians were nonadherent to Fleischner guidelines for 27% of follow-up scans. High-quality communication (adjusted odds ratio, 3.65; P = 0.02) and distress (adjusted odds ratio, 0.38; P = 0.02) were associated with increased and decreased participant adherence, respectively. Neither was associated with clinician adherence. CONCLUSIONS Patients and clinicians often do not adhere to nodule follow-up recommendations. Interventions designed to improve communication quality and decrease distress may also improve patient adherence to nodule follow-up recommendations.

Lung Cancer Screening

Screening for lung cancer in high-risk individuals with annual low-dose computed tomography has been shown to reduce lung cancer mortality by 20% and is recommended by multiple health care organizations. Lung cancer screening is not a specific test; it is a process that involves appropriate selection of high-risk individuals, careful interpretation and follow-up of imaging, and annual testing. Screening should be performed in the context of a multidisciplinary program experienced in the diagnosis and management of lung nodules and early-stage lung cancer.

Quantification of DNA binding to cell-surfaces by flow cytometry.

DNA binding to cell-surfaces has been documented in several studies. The interaction of DNA with cells has been shown to have therapeutic potential as a non-viral form of gene delivery and DNA vaccination. Recently, bacterial DNA binding and internalization has been demonstrated in some cells to trigger secretion of cytokines and cell activation. Previous studies to quantify DNA binding to cells have used radiolabeled DNA. Here we report a non-radioactive assay for quantification of cell-surface DNA binding based on the isoparametric analysis of flow cytometric data as described by Chatelier et al., Embo J., 5 (1986) 1181. This assay has the advantage over previously used procedures in not employing radioactive material and being able to discriminate viable from non-viable cells that bind DNA. With the importance of understanding the interaction of DNA with cells, this assay may have application for the identification and characterization of reagents designed to either enhance or inhibit DNA binding to cells.

“Even if I Don’t Remember, I Feel Better”. A Qualitative Study of Patients with Early-Stage Non–Small Cell Lung Cancer Undergoing Stereotactic Body Radiotherapy or Surgery

RATIONALE While surgical resection is recommended for most patients with early stage lung cancer according to the National Comprehensive Cancer Network guidelines, stereotactic body radiotherapy is increasingly being used. Provider-patient communication regarding the risks and benefits of each approach may be a modifiable factor leading to improved patient-centered outcomes. OBJECTIVES To qualitatively describe the experiences of patients undergoing either surgery or stereotactic body radiotherapy for early stage non-small cell lung cancer. METHODS We qualitatively evaluated and used content analysis to describe the experiences of 13 patients with early clinical stage non-small cell lung cancer before undergoing treatment in three health care systems in the Pacific Northwest, with a focus on knowledge obtained, communication, and feelings of distress. MEASUREMENTS AND MAIN RESULTS Although most participants reported rarely having been told about other options for treatment and could not readily recall many details about specific risks of recommended treatment, they were satisfied with their care. The patients paradoxically described clinicians as displaying caring and empathy despite not explicitly addressing their concerns and worries. We found that the communication domains that underlie shared decision making occurred infrequently, but that participants were still pleased with their role in the decision-making process. We did not find substantially different themes based on where the participant received care or the treatment selected. CONCLUSIONS Patients were satisfied with all aspects of their care, despite reporting little knowledge about risks or other treatment options, no direct elicitation of worries from providers, and a lack of shared decision making. While the development of effective communication strategies to address these gaps is warranted, their effect on patient-centered outcomes, such as distress and decisional conflict, is unclear.

Inaccuracies describing results of a lung cancer screening demonstration project

In Reply We welcome this opportunity to make some clarifications, and to direct readers to previous publications that address many of the concerns raised by Zhang et al. There has been substantial interest from the scientific community in a complete picture of the net balance of benefits and harms of intensive blood pressure control.1 Because physical function represents one component of this evaluation, our study2 examined changes in gait speed in the subgroup of SPRINT participants 75 years or older at baseline.3 While procedures for the measurement of gait speed were specified in the SPRINT protocol, the authors are correct that gait speed and mobility limitation were not prespecified as outcomes in the protocol or on clinicaltrials.gov. However, gait speed is wellestablished, well-accepted measure of physical function, and so we reject any allusion that there was selective reporting of the outcomes in our study.2 Our article2 and other SPRINT publications3 have clearly acknowledged limitations in the generalizability of SPRINT. While there are certainly segments of the adult population to which the SPRINT results may not apply, estimates from the National Health and Nutrition Examination Survey have indicated that a large segment of older adults in the United States would be eligible for SPRINT, 34.6% of adults older than 75 years, or approximately 5.8 million adults.4 SPRINT2 did not systematically collect information on hearing and visual problems or balance disorders. However, we disagree that these issues, along with functional limitations and cognitive impairment, represent a concerning source of bias. While randomization does not guarantee covariate balance, for a trial the size of SPRINT (n > 2600 for participants 75 years or older), the likelihood of an important imbalance for any given covariate, measured or unmeasured, is very small. Using cognitive function as an example, there was no difference in baseline Montreal Cognitive Assessment scores across the treatment groups (median score of 22 for both groups) within the subgroup of participants 75 years or older.3 We included self-reported information about mobility in our analyses to try to address the concern that participants with poor physical function may not be able to complete the 4-meter walk test. In addition, we used multiple imputation to examine the impact of missing gait speed measurements. These analyses did not appreciably change our results in any of the scenarios we considered. Our study2 did not present any information on serious adverse events in the subgroup of participants 75 years and older because these results have been published and discussed previously.3,5,6 Therefore we do not recapitulate those discussions here.

“It wasn’t as bad as I thought it would be”: a qualitative study of early stage non-small cell lung cancer patients after treatment

ObjectiveWhile surgical resection is recommended for most patients with early stage lung cancer, stereotactic body radiotherapy (SBRT) is being increasingly utilized. Provider-patient communication regarding risks/benefits of each approach may be a modifiable factor leading to improved patient-centered outcomes. Our objective was to determine a framework and recommended strategies on how to best communicate with patients with early stage non-small cell lung cancer (NSCLC) in the post-treatment setting. We qualitatively evaluated the experiences of 11 patients with early clinical stage NSCLC after treatment, with a focus on treatment experience, knowledge obtained, communication, and recommendations. We used conventional content analysis and a patient-centered communication theoretical model to guide our understanding.ResultsFive patients received surgery and six received SBRT. Both treatments were generally well-tolerated. Few participants reported communication deficits around receiving follow-up information, although several had remaining questions about their treatment outcome (mainly those who underwent SBRT). They described feeling anxious regarding their first surveillance CT scan and clinician visit. Overall, participants remained satisfied with care because of implicit trust in their clinicians rather than explicit communication. Communication gaps remain but may be addressed by a trusting relationship with the clinician. Patients recommend clinicians give thorough explanations and personalize when possible.