Wednesday, December 21, 2011

From U Texas Southwestern Med: Preneoplasia of lung cancer

Cancer Biomark. 2011;9(1-6):385-96.
Preneoplasia of lung cancer.
Gazdar AF, Brambilla E.
Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical School, Dallas, TX, USA.

As with other epithelial cancers, lung cancer develops over a period of several years or decades via a series of progressive morphological changes accompanied by molecular alterations that commence in histologically normal epithelium. However the development of lung cancer presents certain unique features that complicates this evaluation. Anatomically the respiratory tree may be divided into central and peripheral compartments having different gross and histological anatomies as well as different functions. In addition, there are three major forms of lung cancer and many minor forms. Many of these forms arise predominantly in either the central or peripheral compartments. Squamous cell and small cell carcinomas predominantly arise in the central compartment, while adenocarcinomas predominantly arise peripherally. Large cell carcinomas are not a single entity but consist of poorly differentiated forms of the other types and, possibly, some truly undifferentiated "stem cell like" tumors. The multistage origin of squamous cell carcinomas, because of their central location, can be followed more closely than the peripherally arising adenocarcinomas. Squamous cell carcinomas arise after a series of reactive, metaplastic, premalignant and preinvasive changes. However, long term observations indicate that not all tumors follow a defined histologic course, and the clinical course, especially of early lesions, is difficult to predict. Peripheral adenocarcinomas are believed to arise from precursor lesions known as atypical adenomatous hyperplasias and may have extensive in situ growth before becoming invasive. Small cell carcinomas are believed to arise from severely molecularly damaged epithelium without going through recognizable preneoplastic changes. The molecular changes that occur prior to the onset on invasive cancers are extensive. As documented in this chapter, they encompass all of the six classic Hallmarks of Cancer other than invasion and metastasis, which by definition occur beyond preneoplasia. A study of preinvasive lung cancer has yielded much valuable biologic information that impacts on clinical management.

From Respirology: Frontiers in Bronchoscopic Imaging

Respirology. 2011 Nov 29. doi: 10.1111/j.1440-1843.2011.02108.x. [Epub ahead of print]
Frontiers in Bronchoscopic Imaging.
Ohtani K, Lee AM, Lam S.
Department of Surgery, Tokyo Medical University, Tokyo, Japan & Visiting Fellow, Cancer Imaging Unit, Integrative Oncology Department, British Columbia Cancer Agency Research Centre, British Columbia, Canada Cancer Imaging Unit, Integrative Oncology Department, British Columbia Cancer Agency Research Centre & the University of British Columbia, British Columbia, Canada.

Bronchoscopy is a minimally-invasive method for diagnosis of diseases of the airways and the lung parenchyma. Standard bronchoscopy uses the reflectance/scattering properties of white light from tissue to examine the macroscopic appearance of airways. It does not exploit the full spectrum of the optical properties of bronchial tissues. Advances in optical imaging such as optical coherence tomography (OCT), confocal endomicroscopy, autofluorescence imaging and laser Raman spectroscopy are at the forefront to allow in-vivo high resolution probing of the microscopic structure, biochemical compositions and even molecular alterations in disease states. OCT can visualize cellular and extracellular structures at and below the tissue surface with near histologic resolution as well as to provide three-dimensional imaging of the airways. Cellular and sub-cellular imaging can be achieved using confocal endomicroscopy or endocytoscopy. Contrast associated with light absorption by hemoglobin can be used to highlight changes in microvascular structures in the sub-epithelium using narrow band imaging. Blood vessels in the peribronchial space can be displayed using Doppler OCT. Biochemical compositions can be analyzed with laser Raman spectroscopy, autofluorescence or multi-spectral imaging. Clinically, autofluorescence and narrow band imaging have been found to be useful for localization of pre-neoplastic and neoplastic bronchial lesions. OCT can differentiate carcinoma in-situ versus micro-invasive cancer. Endoscopic optical imaging is a promising technology that can expand the horizon for studying the pathogenesis and progression of airway diseases such as COPD and asthma as well as to evaluate the effect of novel therapy.

Nice article on how TKIs work in targeted cancer therapy

Biol Pharm Bull. 2011;34(12):1774-80.
Receptor tyrosine kinases and targeted cancer therapeutics.
Takeuchi K, Ito F.
Department of Biochemistry, Faculty of Pharmaceutical Sciences, Setsunan University.

The majority of growth factor receptors are composed of extracellular, transmembrane, and cytoplasmic tyrosine kinase (TK) domains. Receptor tyrosine kinase (RTK) activation regulates many key processes including cell growth and survival. However, dysregulation of RTK has been found in a wide range of cancers, and it has been shown to correlate with the development and progression of numerous cancers. Therefore, RTK has become an attractive therapeutic target. One way to effectively block signaling from RTK is inhibition of its catalytic activity with small-molecule inhibitors. Low-molecular-weight TK inhibitors (TKIs), such as imatinib, targeting tumors with mutant c-Kit, and gefitinib, targeting non-small cell lung cancer with mutant epidermal growth factor receptor (EGFR), have received marketing approval in Japan. MET, fibroblast growth factor receptor (FGFR), and insulin-like growth factor-I receptor (IGF-IR) are frequently genetically altered in advanced cancers. TKIs of these receptors have not yet appeared on the market, but many anticancer drug candidates are currently undergoing clinical trials. Most of these TKIs were designed to compete with ATP at the ATP-binding site within the TK domain. This review will focus on small-molecule TKIs targeting MET, FGFR, and IGF-IR and discuss the merits and demerits of two types of agents, i.e., those with only one or a few targets and those directed at multiple targets. Targeting agents specifically inhibiting the target kinase were previously searched for based on the hypothesis that a narrow target window might reduce unexpected side effects, but agents with multiple targets have been recently developed to overcome tumors resistant against a single-targeting agent.

From Johns Hopkins: Molecular changes in smoking-related lung cancer

Expert Rev Mol Diagn. 2012 Jan;12(1):93-106.
Molecular changes in smoking-related lung cancer.
Begum S.
Department of Pathology, Johns Hopkins University School of Medicine, Bond Street Building Room 311, 417 North Caroline Street, Baltimore, MD 21231, USA.

To elucidate the effect of cigarette smoke on developing lung cancer among individuals, numerous genetic and epigenetic factors related to cigarette smoke-induced lung cancers have been widely investigated and a various genes, loci and pathways have been identified as candidates to date. However, the importance of these molecular alterations in the initiation and progression of lung cancer still remains imprecise and different molecules altered in lung cancer are being used for stratification of patients for targeted therapy. There are a number of molecular pathways involved in the development of lung cancer, and environmental factors related to these alterations are still unclear. Furthermore, various genetic alterations determined by candidate gene approach have not been re-evaluated for their functional significance together with epigenetic alterations in the same population. Accumulated evidence suggested that lung cancer in ever smokers and never smokers follow distinct molecular pathways and may therefore respond to distinct therapy. Therefore, additional studies will be essential to re-evaluate the individual risk of developing lung cancer based on the combination of genetic and epigenetic alterations and to set up a guideline to assess the individual risk for lung cancer and for its prevention.

Getting the most information from a small tissue biopsy of lung cancer

Lung Cancer. 2011 Dec 2. [Epub ahead of print]
The challenge of NSCLC diagnosis and predictive analysis on small samples. Practical approach of a working group.
Thunnissen E, Kerr KM, Herth FJ, Lantuejoul S, Papotti M, Rintoul RC, Rossi G, Skov BG, Weynand B, Bubendorf L, Katrien G, Johansson L, López-Ríos F, Ninane V, Olszewski W, Popper H, Jaume S, Schnabel P, Thiberville L, Laenger F.
Department of Pathology, VU Medical Center, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands.

Until recently, the division of pulmonary carcinomas into small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) was adequate for therapy selection. Due to the emergence of new treatment options subtyping of NSCLC and predictive testing have become mandatory. A practical approach to the new requirements involving interaction between pulmonologist, oncologist and molecular pathology to optimize patient care is described. The diagnosis of lung cancer involves (i) the identification and complete classification of malignancy, (ii) immunohistochemistry is used to predict the likely NSCLC subtype (squamous cell vs. adenocarcinoma), as in small diagnostic samples specific subtyping is frequently on morphological grounds alone not feasible (NSCLC-NOS), (iii) molecular testing. To allow the extended diagnostic and predictive examination (i) tissue sampling should be maximized whenever feasible and deemed clinically safe, reducing the need for re-biopsy for additional studies and (ii) tissue handling, processing and sectioning should be optimized. Complex diagnostic algorithms are emerging, which will require close dialogue and understanding between pulmonologists and others who are closely involved in tissue acquisition, pathologists and oncologists who will ultimately, with the patient, make treatment decisions. Personalized medicine not only means the choice of treatment tailored to the individual patient, but also reflects the need to consider how investigative and diagnostic strategies must also be planned according to individual tumour characteristics.

From Lung Cancer: More on the best molecular test for ALK in lung cancer

Lung Cancer. 2011 Dec 6. [Epub ahead of print]
Histologic subtypes, immunohistochemistry, FISH or molecular screening for the accurate diagnosis of ALK-rearrangement in lung cancer: A comprehensive study of Caucasian non-smokers.
Just PA, Cazes A, Audebourg A, Cessot A, Pallier K, Danel C, Vacher-Lavenu MC, Laurent-Puig P, Terris B, Blons H.
APHP, Université Paris Descartes, Groupe Hospitalier Cochin-Broca-Hôtel Dieu, Service d'anatomie et de cytologie pathologiques, Paris, F-75014, France; APHP, Hôpital européen Georges Pompidou, Service de biochimie, Paris, F-75015, France.

EML4-ALK adenocarcinomas constitute a new molecular subgroup of lung tumours that respond very well to crizotinib, an ALK inhibitor. However, the diagnosis of ALK rearrangement in lung cancer is challenging. The aim of this study was to compare the diagnostic accuracy of five different methods in a series of 20 EGFR(wt/wt) lung adenocarcinomas from non- or light- smokers. Multiplex RT-PCR was considered as gold standard and identified four ALK-rearranged tumours among the 20 tested tumours. qRT-PCR got an interpretability rate of 100% and accurately typed all 20 tumours. qRT-PCR from corresponding formalin-fixed paraffin-embedded (FFPE) specimens got an interpretability rate of 65%. Out of the four previously identified ALK-rearranged cases, three were interpretable and two were retrieved using FFPE qRT-PCR. ALK break-apart FISH got an interpretability rate of 60% and accurately typed all of the twelve remaining cases. Anti-ALK immunohistochemistry (IHC) accurately typed all twenty tumours using a cut-off value of strong staining of 100% tumour cells. The 16 non ALK-rearranged tumours got no/light staining in 13 cases, and a moderate staining of 80-100% tumour cells in 3 cases. We then analysed four solid signet-ring lung adenocarcinomas. FFPE qRT-PCR, FISH and immunohistochemistry were concordant in three cases, with positive and negative results in respectively one and two cases. The fourth case, which was positive by FISH and immunohistochemistry but negative by RT-PCR, was shown to have a non-EML4-ALK ALK-rearrangement. As various factors such as RNA quality, fixation quality and type of ALK rearrangement may impede ALK screening, we propose a combined FISH/molecular biology diagnostic algorithm in which anti-ALK immunohistochemistry is used as a pre-screening step.

From NCI: Laser capture microdissection for lung cancer cytology molecular analysis

Mod Pathol. 2011 Dec 9. doi: 10.1038/modpathol.2011.184. [Epub ahead of print]
EGFR and KRAS mutation analysis in cytologic samples of lung adenocarcinoma enabled by laser capture microdissection.
Chowdhuri SR, Xi L, Pham TH, Hanson J, Rodriguez-Canales J, Berman A, Rajan A, Giaccone G, Emmert-Buck M, Raffeld M, Filie AC.
Laboratory of Pathology, National Cancer Institute, Bethesda, MD, USA.

The discovery of activating mutations in EGFR and KRAS in a subset of lung adenocarcinomas was a major advance in our understanding of lung adenocarcinoma biology, and has led to groundbreaking studies that have demonstrated the efficacy of tyrosine kinase inhibitor therapy. Fine-needle aspirates and other cytologic procedures have become increasingly popular for obtaining diagnostic material in lung carcinomas. However, frequently the small amount of material or sparseness of tumor cells obtained from cytologic preparations limit the number of specialized studies, such as mutation analysis, that can be performed. In this study we used laser capture microdissection to isolate small numbers of tumor cells to assess for EGFR and KRAS mutations from cell block sections of 19 cytology samples from patients with known lung adenocarcinomas. We compared our results with previous molecular assays that had been performed on either surgical or cytology specimens as part of the patient's initial clinical work-up. Not only were we able to detect the identical EGFR or KRAS mutation that was present in the patient's prior molecular assay in every case, but we were also able to consistently detect the mutation from as few as 50 microdissected tumor cells. Furthermore, isolating a more pure population of tumor cells resulted in increased sensitivity of mutation detection as we were able to detect mutations from laser capture microdissection-enriched cases where the tumor load was low and traditional methods of whole slide scraping failed. Therefore, this method can not only significantly increase the number of lung adenocarcinoma patients that can be screened for EGFR and KRAS mutations, but can also facilitate the use of cytologic samples in the newly emerging field of molecular-based personalized therapies.Modern Pathology advance online publication, 9 December 2011; doi:10.1038/modpathol.2011.184.

From Moffitt: Malignancy-Risk Gene Signature in Lung Cancer

J Natl Cancer Inst. 2011 Dec 8. [Epub ahead of print]
Prognostic and Predictive Value of a Malignancy-Risk Gene Signature in Early-Stage Non-Small Cell Lung Cancer.
Chen DT, Hsu YL, Fulp WJ, Coppola D, Haura EB, Yeatman TJ, Cress WD.
Affiliations of authors: Department of Biostatics (D-TC, WJF), Department of Pathology (DC), Department of Molecular Oncology (EBH, WDC), Department of Surgery and Interdisciplinary Oncology (TJY), Moffitt Cancer Center & Research Institute, Tampa, FL; Department of Applied Mathematics and Institute of Statistics, National Chung Hsing University, Taiwan (Y-LH).

The malignancy-risk gene signature is composed of numerous proliferative genes and has been applied to predict breast cancer risk. We hypothesized that the malignancy-risk gene signature has prognostic and predictive value for early-stage non-small cell lung cancer (NSCLC) patients.

The ability of the malignancy-risk gene signature to predict overall survival (OS) of early-stage NSCLC patients was tested using a large NSCLC microarray dataset from the Director's Challenge Consortium (n = 442) and two independent NSCLC microarray datasets (n = 117 and 133, for the GSE13213 and GSE14814 datasets, respectively). An overall malignancy-risk score was generated by principal component analysis to determine the prognostic and predictive value of the signature. An interaction model was used to investigate a statistically significant interaction between adjuvant chemotherapy (ACT) and the gene signature. All statistical tests were two-sided.

The malignancy-risk gene signature was statistically significantly associated with OS (P < .001) of NSCLC patients. Validation with the two independent datasets demonstrated that the malignancy-risk score had prognostic and predictive values: Of patients who did not receive ACT, those with a low malignancy-risk score had increased OS compared with a high malignancy-risk score (P = .007 and .01 for the GSE13212 and GSE14814 datasets, respectively), indicating a prognostic value; and in the GSE14814 dataset, patients receiving ACT survived longer in the high malignancy-risk score group (P = .03), and a statistically significant interaction between ACT and the signature was observed (P = .02).

The malignancy-risk gene signature was associated with OS and was a prognostic and predictive indicator. The malignancy-risk gene signature could be useful to improve prediction of OS and to identify those NSCLC patients who will benefit from ACT.

IASLC CT Screening Workshop 2011 Report

J Thorac Oncol. 2012 Jan;7(1):10-19.
International Association for the Study of Lung Cancer Computed Tomography Screening Workshop 2011 Report.
Field JK, Smith RA, Aberle DR, Oudkerk M, Baldwin DR, Yankelevitz D, Pedersen JH, Swanson SJ, Travis WD, Wisbuba II, Noguchi M, Mulshine JL; IASLC CT Screening Workshop 2011 Participants.
*Roy Castle Lung Cancer Research Programme, The University of Liverpool Cancer Research Centre, Department of Molecular and Clinical Cancer Medicine, Institute of Translational Medicine, The University of Liverpool, Liverpool, United Kingdom; †American Cancer Society, Atlanta, GA; ‡Department of Radiological Sciences, David Geffen School of Medicine at UCLA, Los Angeles, California; §Centre for Medical Imaging EB45, University Medical Centre Groningen, Groningen, The Netherlands; ∥Respiratory Medicine Unit, David Evans Centre, Nottingham City Hospital Campus, Nottingham University Hospitals, Nottingham, United Kingdom; ¶Department of Radiology, Mount Sinai School of Medicine, New York, New York; #Department of Cardiothoracic Surgery, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark; **Department of Surgery, Brigham and Women's Hospital & Harvard Medical School, Boston, Massachusetts; ††Memorial Sloan Kettering Cancer Center, New York, New York; ‡‡Departments of Pathology and Thoracic/Head and Neck Medical Oncology, The University of Texas, M. D. Anderson Cancer Center, Houston, Texas; §§Department of Pathology, Institute of Basic Medical Sciences, University of Tsukuba, Tsukuba, Japan; and ∥∥Rush University Medical Center, Chicago, Illinois.

The International Association for the Study of Lung Cancer (IASLC) Board of Directors convened a computed tomography (CT) Screening Task Force to develop an IASLC position statement, after the National Cancer Institute press statement from the National Lung Screening Trial showed that lung cancer deaths fell by 20%. The Task Force's Position Statement outlined a number of the major opportunities to further improve the CT screening in lung cancer approach, based on experience with cancer screening from other organ sites.The IASLC CT Screening Workshop 2011 further developed these discussions, which are summarized in this report. The recommendation from the workshop, and supported by the IASLC Board of Directors, was to set up the Strategic CT Screening Advisory Committee (IASLC-SSAC). The Strategic CT Screening Advisory Committee is currently engaging professional societies and organizations who are stakeholders in lung cancer CT screening implementation across the globe, to focus on delivering guidelines and recommendations in six specific areas: (i) identification of high-risk individuals for lung cancer CT screening programs; (ii) develop radiological guidelines for use in developing national screening programs; (iii) develop guidelines for the clinical work-up of "indeterminate nodules" resulting from CT screening programmers; (iv) guidelines for pathology reporting of nodules from lung cancer CT screening programs; (v) recommendations for surgical and therapeutic interventions of suspicious nodules identified through lung cancer CT screening programs; and (vi) integration of smoking cessation practices into future national lung cancer CT screening programs.

Wow. Sequential use of different EGFR-TKIs to improve lung cancer survival?

J Thorac Oncol. 2011 Dec 14. [Epub ahead of print]
EGFR-Mutant Lung Adenocarcinomas Treated First-Line with the Novel EGFR Inhibitor, XL647, Can Subsequently Retain Moderate Sensitivity to Erlotinib.
Chmielecki J, Pietanza MC, Aftab D, Shen R, Zhao Z, Chen X, Hutchinson K, Viale A, Kris MG, Stout T, Miller V, Rizvi N, Pao W.
*Weill Cornell Graduate School of Medical Sciences, New York, New York; †Department of Medicine, Thoracic Oncology Service, Division of Solid Tumor Oncology, Memorial Sloan-Kettering Cancer Center and the Weill Medical College of Cornell University, New York, New York; ‡Exelixis, South San Francisco, California; §Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, New York; ∥Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee; ¶Vanderbilt-Ingram Cancer Center, Nashville, Tennessee; and #Genomics Core Laboratory, Memorial Sloan-Kettering Cancer Center, New York, New York.

EGFR-mutant lung cancers are sensitive to EGFR tyrosine kinase inhibitors (TKIs). Unfortunately, they develop resistance, often due to acquisition of a second-site mutation (T790M). Current EGFR TKIs select for T790M in preclinical models of acquired resistance. We explored whether all EGFR TKIs similarly select for the T790M mutation using data from early clinical trials and established in vitro models of acquired resistance.
We analyzed the clinical characteristics of eight patients with metastatic EGFR-mutant lung adenocarcinoma who were treated first-line with XL647 and then progressed. XL647 is an ATP-competitive inhibitor of EGFR, HER2, KDR, and EPHB4. Additional molecular preclinical studies were performed to characterize resistance.
Four patients displayed confirmed partial responses (PRs), three patients had unconfirmed PRs, and one patient displayed stable disease. Only one of five patients' tumor samples available for analysis after disease progression harbored the T790M mutation. Eight patients subsequently received erlotinib, with (n = 3) or without (n = 5) chemotherapy. Three of five patients treated with single-agent erlotinib derived additional benefit, staying on drug up to 9 months. EGFR-mutant PC-9 cells with acquired resistance to XL647 did not harbor the T790M mutation, displayed a distinct mRNA profile from PC-9 cells with T790M-mediated resistance, and were moderately sensitive to erlotinib in growth inhibition assays. Crystal structure analyses of XL647/EGFR T790M did not reveal a different binding mode from that of erlotinib.
The findings of this exploratory study suggest that different EGFR TKIs may select for distinct mechanisms of resistance. These results raise the possibility that different EGFR TKIs could be sequentially used to improve outcomes in patients with EGFR-mutant lung cancer. Further work investigating this hypothesis is warranted.

From National Jewish-Denver: Evaluating and treating lung cancer

Med Clin North Am. 2011 Nov;95(6):1041-54.
Evaluation and treatment of patients with non-small cell lung cancer.
Carr LL, Finigan JH, Kern JA.
Division of Oncology, National Jewish Health, Denver, CO 80206, USA.
Lung cancer is the most common cause of cancer-related death in the United States; however, recent clinical advances may change this outcome. New data on low-dose computed tomography for lung cancer screening, and technologic advances in surgery and radiation, have improved outcomes for those with early-stage disease. Identification of driver mutations in lung cancer has led to the development of molecular targeted therapy to improve survival of subsets of patients with metastatic disease. These advances now allow for treatment of many patients with lung cancer with comorbidities or poor performance status who would have had limited options in the past.

From U S Carolina: Personalized therapy for advanced lung cancer

Lung Cancer. 2011 Dec 14. [Epub ahead of print]
The role of molecular analyses in the era of personalized therapy for advanced NSCLC.
Tanner NT, Pastis NJ, Sherman C, Simon GR, Lewin D, Silvestri GA.
Division of Pulmonary and Critical Care Medicine, Medical University of South Carolina, PO Box 250630, Charleston, SC 29425, United States.

Platinum-based doublet chemotherapy is the traditional treatment of choice for advanced non-small cell lung cancer (NSCLC); however, the efficacy of these regimens has reached a plateau. Increasing evidence demonstrates that patients with sensitizing mutations in the epidermal growth factor receptor (EGFR) experience improved progression-free survival and response rates with first-line gefitinib or erlotinib therapy relative to traditional platinum-based chemotherapy, while patients with EGFR-mutation negative tumors gain greater benefit from platinum-based chemotherapy. These results highlight the importance of molecular testing prior to the initiation of first-line therapy for advanced NSCLC. Routine molecular testing of tumor samples represents an important paradigm shift in NSCLC therapy and would allow for individualized therapy in specific subsets of patients. As these and other advances in personalized treatment are integrated into everyday clinical practice, pulmonologists will play a vital role in ensuring that tumor samples of adequate quality and quantity are collected in order to perform appropriate molecular analyses to guide treatment decisions. This article provides an overview of clinical trial data supporting molecular analysis of NSCLC, describes specimen acquisition and testing methods currently in use, and discusses future directions of personalized therapy for patients with NSCLC.

Interventional pulmonology-minimally invasive

Med Clin North Am. 2011 Nov;95(6):1095-114. Epub 2011 Oct 5.
Interventional pulmonology.
Hsia D, Musani AI.
Division of Respiratory and Critical Care Physiology and Medicine, Harbor-University of California, Los Angeles Medical Center, Torrance, CA 90509, USA.

Interventional pulmonology is a rapidly growing field of pulmonary medicine. It is a procedure-based subspecialty focusing on minimally invasive advanced diagnostic and therapeutic interventions. Current interventions include advanced bronchoscopic imaging, guidance methods for diagnostic bronchoscopy, therapeutic modalities for central airway obstructions, pleural interventions, and novel therapies for asthma and chronic obstructive pulmonary disease. This article is an introduction to pertinent interventions within the context of the diseases encountered by the trained interventional pulmonologist.

Guidelines for mediastinal staging of lung cancer

Curr Oncol. 2011 Dec;18(6):e304-10.
Invasive mediastinal staging of non-small-cell lung cancer: a clinical practice guideline.
Darling GE, Dickie AJ, Malthaner RA, Kennedy EB, Tey R.
Division of Thoracic Surgery, Toronto General Hospital, Toronto, ON.

In non-small-cell lung cancer (nsclc), invasive mediastinal staging is typically used to guide treatment decision-making. Here, we present clinical practice guideline recommendations for invasive mediastinal staging in nsclc patients who have been staged T1-4, N0-3, with no distant metastases.
Draft recommendations were formulated based on the best available evidence gathered by a systematic review and a consensus of expert opinion. The draft recommendations underwent an internal review by clinical and methodology experts, and an external review by clinical practitioners through a survey assessing the clinical relevance and overall quality of the guideline. Feedback from the internal and external reviews was integrated into the clinical practice guideline.
In general, most clinical experts agreed with the guideline, approving it for methodologic rigour. More than 80% of the surveyed practitioners gave it a high quality rating. The expert reviewers also provided written comments, with some of the suggested changes being incorporated into the final version of the guideline.
In the clinical practice guideline, invasive mediastinal staging of nsclc is recommended in all cases except those involving patients with normal-sized lymph nodes, negative combine positron-emission tomography and computed tomography, and peripheral clinical stage 1A tumour. When performing mediastinoscopy, 5 nodal stations (2R/L, 4R/L, and 7) should routinely be examined.

Wednesday, December 7, 2011

From J Grad Med Edu: Educating medical students about the law

J Grad Med Educ. 2010 Dec;2(4):595-9.
Medico-legal education: a pilot curriculum to fill the identified knowledge gap.
Evans A, Refrow-Rutala D.

We sought to determine if a medico-legal educational curriculum designed to increase physicians' familiarity with the legal system in a nonthreatening environment-a didactic and interactive educational seminar-would positively influence learners' knowledge base and self-awareness.

Because neither the Accreditation Council for Graduate Medical Education nor its Residency Review Committees specifically addresses medico-legal liability education, we designed a 2-day intensive medico-legal educational curriculum and piloted it in 2007 and 2008 at a large academic tertiary-referral medical center. Postcurriculum evaluations and precurriculum and postcurriculum testing were used to identify areas of common and/or persisting knowledge deficit.

A total of 50 graduating residents, fellows, and community practitioners participated in the course. Common areas of knowledge deficit were "privilege," "discovery," statutes of limitations, and basic legal procedure. Discordance in physician interpretation of patient perspective and misunderstanding among physicians of the impact of the legal suit were evident.

Concentrated legal education at selected times during medical training may support physicians' motivations to improve the assurance of quality and continuity of care. We continue to revise the curriculum to address issues of lecturer style, lecture content, and overall attitudinal values related to clinical practice, legal education, long-term impact on practice patterns, job satisfaction and its effect on attention to quality and continuity-of-care issues, and health care provider attitudes about the provider's role within the legal system and the community. We plan to conduct follow-up of participants to assess retention and subsequent use of this knowledge.

From U Michigan: Health care rationing--not if, but when (and more importantly, how)

J Am Coll Radiol. 2011 Dec;8(12):830-7.
Rationing and health care reform: not a question of if, but when.
Kelly AM, Cronin P.
Department of Radiology, Division of Cardiothoracic Radiology, University of Michigan Medical Center, Ann Arbor, Michigan.

Evidence-based medicine and rationing have been increasingly discussed in the context of health care reform recently. Both concepts are frequently the source of heated debate, leading to polarization of different health care practitioners and public parties. In some public arenas, rationing has become a dirty word. The term evidence-based medicine is perceived as being used as a "cover" for rationing. However, rationing is widespread, whether explicit or implicit, and exists within health care. Evidence-based medicine (or imaging) and rationing overlap considerably, and it looks like both are here to stay, given the current state of developed-world health care systems and the proposed reforms. The authors review these entities and argue that evidence-based medicine (or imaging) is one form of health care rationing. Rationing already occurs, and it is important that it be done in a way that provides the greater good for the majority. This article reviews the history of rationing and evidence-based medicine, the reasons evidence-based medicine and rationing are necessary, examples of rationing that already exist (economic), proposed forms of rationing (age based), the need for physicians (radiologists) to be at the forefront of any rationing efforts, and the basis (cost and comparative effectiveness research and evidence-based medicine) and principles of physician decision rationing (optimum outcome-based rationing) in the context of proposed health care reforms.

From U Penn: Childrens' decision-making involvement in chronic diseases

J Pediatr Psychol. 2011 Dec 2. [Epub ahead of print]
Measuring Children's Decision-Making Involvement Regarding Chronic Illness Management.
Miller VA, Harris D.
Department of Anesthesiology and Critical Care Medicine, The Children's Hospital of Philadelphia and Perelman School of Medicine at the University of Pennsylvania and Center for the Integration of Genetic Healthcare Technologies, Perelman School of Medicine at the University of Pennsylvania.

To develop a measure of decision-making involvement in children and adolescents with cystic fibrosis, diabetes, and asthma.

Parent-child dyads completed the Decision-Making Involvement Scale (DMIS) and measures of locus of control and family communication. DMIS items were subjected to exploratory and confirmatory factor analysis (CFA). Temporal stability and construct validity were assessed.

The parent form was reduced to 20 items representing five factors. CFA showed that the five factors were an acceptable fit to the parent- and child-report data. Internal consistency values ranged from 0.71 to 0.91. Temporal stability was supported by moderate-substantial intraclass correlation coefficients. DMIS subscales were associated with child age, child locus of control, and family communication.

The DMIS can be used to inform our understanding of the transition to greater independence for illness management. Additional research is needed to examine outcomes of decision-making involvement, including treatment adherence and responsibility.

From U Tasmania: The relation of childhood physical activity to adult physical activity

Br J Sports Med. 2011 Dec 5. [Epub ahead of print]
Which domains of childhood physical activity predict physical activity in adulthood? A 20-year prospective tracking study.
Cleland V, Dwyer T, Venn A.
Menzies Research Institute Tasmania, University of Tasmania, Hobart, Australia.

It is important to examine how childhood physical activity is related to adult physical activity in order to best tailor physical activity-promotion strategies. The time- and resource-intensive nature of studies spanning childhood into adulthood means the understanding of physical activity trajectories over this time span is limited. This study aimed to determine whether childhood domain-specific physical activities predict domain-specific physical activity 20 years later in adulthood, and whether age and sex play a role in these trajectories.

In 1985, 6412 children of age 9-15 years self-reported frequency and duration of discretionary sport and exercise (leisure activity), transport activity, school sport and physical education (PE) in the past week and number of sports played in the past year. In 2004-2006, 2201 of these participants (aged 26-36 years) completed the long International Physical Activity Questionnaire and/or wore a Yamax pedometer. Analyses included partial correlation coefficients and log-binomial regression.

Childhood and adult activity were weakly correlated (r=-0.08-0.14). Total weekly physical activity in childhood did not predict adult activity. School PE predicted adult total weekly physical activity and daily steps (older females), while school sport demonstrated inconsistent associations. Leisure and transport activity in childhood predicted adult leisure activity among younger males and older females, respectively. Childhood past year sport participation positively predicted adult physical activity (younger males and older females).

Despite modest associations between childhood and adult physical activity that varied by domain, age and sex, promoting a range of physical activities to children of all ages is warranted.

From Johns Hopkins: More on ALK and lung cancer

Oncology (Williston Park). 2011 Jun;25(7):597-601.
ALK-targeted therapy for lung cancer: ready for prime time.
Husain H, Rudin CM.
Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD 21231, USA.

Lung cancer remains the leading cause of cancer-related death in the United States. Ongoing research into the molecular basis of lung cancer has yielded insight into various critical pathways that are deregulated in lung tumorigenesis, and in particular key driver mutations integral to cancer cell survival and proliferation. One of the most recent examples of this has been definition of translocations and functional dysregulation of the anaplastic lymphoma kinase (ALK) gene in a subset of patients with non-small-cell lung cancer. The pace of research progress in this area has been remarkable: chromosomal rearrangements involving this gene in lung cancer were first reported in 2007 by a team of investigators in Japan. Less than 3 years later, an early-phase clinical trial of a targeted ALK inhibitor has yielded impressive responses in patients with advanced lung cancer containing ALK rearrangements, and mechanisms of acquired resistance to ALK-targeted therapy are being reported. A definitive study randomizing patients with ALK-mutant lung cancer to crizotinib (also known as PF-02341066 or 1066) versus standard therapy has recently completed enrollment.Taken together, these data describe a trajectory of research progress from basic discovery science to real-world implementation that should serve as a model for future integration of preclinical and clinical therapeutic research.

Night eating syndrome

Clin Psychol Rev. 2011 Nov 9;32(1):49-59. [Epub ahead of print]
Night eating syndrome: A critical review of the literature.
Vander Wal JS.

Clinical psychologists are increasingly called to participate in the treatment of obesity, a condition that affects about one-third of adults in the United States. A disorder gaining increased recognition for its role in the development and maintenance of obesity is Night Eating Syndrome (NES), a relatively novel disorder involving morning anorexia, evening hyperphagia and/or nocturnal ingestions, and insomnia. NES affects men and women from various racial groups and tends to run in families. NES tends to co-occur with mood, anxiety, eating, sleep, and substance use disorders and may have implications for weight and diabetes management. Relatively little is known about the successful treatment of NES. Limited evidence suggests that serotonergic-based pharmacological treatments may be beneficial. Psychological interventions, such as psychoeducation, eating modification, relaxation strategies, sleep hygiene, cognitive restructuring, physical activity, and social support facilitation may also yield beneficial results. The purpose of the present paper is to provide an introduction to NES, including diagnosis, clinical presentation, assessment, comorbidities, clinical implications, and pharmacological and psychological treatment approaches. Areas for further study and development are discussed. NES is an emerging area for clinical description, evaluation, and intervention.

From Mount Sanai: Clinico-histologic conferences to enhance medical students' education

Anat Sci Educ. 2011 Dec 5. doi: 10.1002/ase.1252. [Epub ahead of print]
Clinico-Histologic Conferences: Histology and disease.
Shaw PA, Friedman ES.
Center of Anatomy and Functional Morphology, Mount Sinai School of Medicine, New York, New York; Department of Medical Education, Mount Sinai School of Medicine, New York, New York.

Providing a context for learning information and requiring learners to teach specific content has been demonstrated to enhance knowledge retention. To enhance students' appreciation of the role of science and specifically histology in clinical reasoning, disease diagnosis, and treatment, a new teaching format was created to provide clinical context, promote integration and application of science knowledge, and to foster peer teaching and learning: the Clinico-Histologic Conference (CHC) for the Mount Sinai School of Medicine Histology course. Teams of six students were each assigned specific disease processes and were charged with creating oral presentations and handouts that taught their classmates about the clinical manifestations, etiopathogeneses, diagnoses, and treatments of the assigned processes, along with comparisons of normal histology to the pathology of the disease. Each team also created four questions, some of which were used on Histology written examinations. The physician facilitator evaluated the presentation and handouts. About two-thirds of students agreed the CHC enhanced appreciation of the importance of histology, provided a context for integration and application of basic science to patient care and enhanced their ability to teach their peers. Student feedback demonstrated that the CHCs were successful in promoting teamwork, peer teaching, and the application of histology to diagnose diseases. The authors believe that teaching basic science content in this new format enhanced student learning and application of medical knowledge, and that this new teaching format can be adopted by other medical school courses. Anat Sci Educ. © 2011 American Association of Anatomists.

DNA methylation biomarkers for lung cancer

Tumour Biol. 2011 Dec 6. [Epub ahead of print]
DNA methylation biomarkers for lung cancer.
Rauch TA, Wang Z, Wu X, Kernstine KH, Riggs AD, Pfeifer GP.
Division of Biology, Beckman Research Institute of the City of Hope, Duarte, CA, 91010, USA.

Changes in DNA methylation patterns are an important characteristic of human cancer including lung cancer. In particular, hypermethylation of CpG islands is a signature of malignant progression. Methylated CpG islands are promising diagnostic markers for the early detection of cancer. However, the full extent and sequence context of DNA hypermethylation in lung cancer has remained unknown. We have used the methylated CpG island recovery assay and high-resolution microarray analysis to find hypermethylated CpG islands in squamous cell carcinomas (SCC) and adenocarcinomas of the lung. Each tumor contained several hundred hypermethylated CpG islands. In an initial microarray screen, 36 CpG islands were methylated in five of five (=100%) of the SCC tumors tested and 52 CpG islands were methylated in at least 75% of the adenocarcinomas tested (n = 8). Using sodium-bisulfite-based approaches, 12 CpG islands (associated with the BARHL2, EVX2, IRX2, MEIS1, MSX1, NR2E1, OC2, OSR1, OTX1, PAX6, TFAP2A, and ZNF577 genes) were confirmed to be methylated in 85% to 100% of the squamous cell carcinomas and 11 CpG islands (associated with the CHAD, DLX4, GRIK2, KCNG3, NR2E1, OSR1, OTX1, OTX2, PROX1, RUNX1, and VAX1 genes) were methylated in >80% of the adenocarcinomas. From the list of genes that were methylated in lung adenocarcinomas, we identified the gene FAT4 and found that this gene was methylated in 39% of the tumors. FAT4 is the closest mammalian homologue of the Drosophila tumor suppressor Fat which is an important component of the Hippo growth control pathway. Many of these newly discovered methylated CpG islands hold promise for becoming biomarkers for the early detection of lung cancer.

What are safe margins of resection for invasive and in situ breast cancer?

Oncology (Williston Park). 2011 Sep;25(10):890-5.
What are safe margins of resection for invasive and in situ breast cancer?
Revesz E, Khan SA.
Lynn Sage Comprehensive Breast Center and Department ofSurgery, Feinberg School of Medicine of Northwestern University, Chicago, Illinois 60614, USA.

Adequate surgical margins in breast-conserving surgery are an important predictor of local recurrence (LR) rates. The definition of tumor-free margins in National Surgical Adjuvant Breast and Bowel Project (NSABP) trials requires that tumor cells do not touch ink, but subsequent retrospective single-institution studies have suggested that wider margins confer greater protection against LR. Particularly wide margins have been proposed for ductal carcinoma in situ. However, wider margin requirements lead to higher re-excision rates, with attendant economic, psychological, and cosmetic costs, and perhaps increased mastectomy rates. Juxtaposed against these concerns about optimal margin width, a meta-analysis of clinical trials has demonstrated the survival value of minimizing LR. We are therefore at a juncture where a reduction of LR may be achieved by tumor resection with wide margins, but data regarding optimal margin width are conflicting and the risk/benefit balance of tumorectomy with wide margins has not been demonstrated. A randomized trial of reexcision for close margins inserted into trials of systemic therapy could be considered but seems unlikely. Alternatively, detailed longitudinal data need to balance the value and the cost of wide margins. Until better data are available, the desirable margin width will vary depending on individual circumstances, including age, histology, and patient preference.

Gender-related cardiovascular risk and stress management

Int J Behav Med. 2011 Dec 6. [Epub ahead of print]
Cardiovascular Risk: Gender Differences in Lifestyle Behaviors and Coping Strategies.
Martin LA, Critelli JW, Doster JA, Powers C, Purdum M, Doster MR, Lambert PL.
University of La Verne, La Verne, CA, USA,

Although cardiovascular disease (CVD) does not occur until mid to late life for most adults, the presence of risk factors, such as high blood pressure (BP) and cholesterol, has increased dramatically in young adults.

The present study examined the relationships between gender and coping strategies, lifestyle behaviors, and cardiovascular risks.

The sample consisted of 297 (71% female) university students. Participants completed a survey to assess demographics, lifestyle behaviors, and coping strategies, and a physiological assessment including lipid and blood pressure (BP) measurements. Data collection occurred from January 2007 to May 2008.

Analyses revealed that age, ethnicity, greater body mass index (BMI), greater use of social support, and less frequent exercise were associated with higher cholesterol, while gender, age, greater BMI, and less frequent exercise were associated with higher systolic BP. There were two significant interactions: one between gender and avoidant coping and the other between gender and exercise on systolic BP, such that for men greater use of avoidant coping or exercise was associated with lower systolic BP.

Understanding how young adults manage their demands and cope with stress sets the stage for understanding the developmental process of CVD. Both coping strategies and lifestyle behaviors must be considered in appraising gender-related cardiovascular risk at an early age before the disease process has begun.

Management of sarcopenic obesity

Am J Nurs. 2011 Dec;111(12):38-44.
Sarcopenic Obesity: Strategies for Management.
Benton MJ, Whyte MD, Dyal BW.
Melissa J. Benton is an associate professor, and Maria D. Whyte and Brenda W. Dyal are assistant professors, at Valdosta State University College of Nursing, Valdosta, GA. Contact author: Melissa J. Benton, Melissa J. Benton participated in a program sponsored by Abbott Nutrition, a maker of nutritional products, and received an honorarium for her participation. The other authors have disclosed no potential conflicts of interest, financial or otherwise. AJN's peer review process has determined this article to be objective and free of commercial bias.
OVERVIEW: Sarcopenia is the age-related loss of muscle mass. Sarcopenic obesity, which describes the process of muscle loss combined with increased body fat as people age, is associated with loss of strength and function, reduced quality of life, and early death. This article describes the clinical significance of sarcopenia and sarcopenic obesity, their pathophysiology, and management strategies for healthy older adults. Both diet and exercise are essential for preventing and reversing loss of muscle and gains in fat. Dietary approaches include protein supplementation and a high protein diet. Exercise strategies promote resistance training in order to maintain muscle mass and maximize energy expenditure.Nurses should be knowledgeable about this condition and its management and routinely educate older patients on the benefits of resistance training and dietary protein to prevent or reverse sarcopenia and sarcopenic obesity. KEYWORDS: aging, high-protein diet, obesity, resistance training, sarcopenia, sarcopenic obesity.

Consensus statement on effective communication in surgical pathology and cytopathology

Arch Pathol Lab Med. 2011 Oct 13. [Epub ahead of print]
Consensus Statement on Effective Communication of Urgent Diagnoses and Significant, Unexpected Diagnoses in Surgical Pathology and Cytopathology From the College of American Pathologists and Association of Directors of Anatomic and Surgical Pathology.
Nakhleh RE, Myer JL, Allen TC, Deyoung BR, Fitzgibbons PL, Funkhouser WK, Mody DR, Lynn A, Fatheree LA, Smith AT, Lal A, Silverman JF.

Context.-Recognizing the difficulty in applying the concept of critical values to anatomic pathology diagnoses, the College of American Pathologists and the Association of Directors of Anatomic and Surgical Pathology have chosen to reevaluate the concept of critical diagnoses. Objective.-To promote effective communication of urgent and significant, unexpected diagnoses in surgical pathology and cytology. Design.-A comprehensive literature search was conducted and reviewed by an expert panel. Results.-A policy of effective communication of important results in surgical pathology and cytology is desirable to enhance patient safety and to address multiple regulatory requirements. Conclusions.-Each institution should create its own policy regarding urgent diagnoses and significant, unexpected diagnoses in anatomic pathology. This policy should be separate from critical results or panic-value policies in clinical pathology, with the expectation of a different time frame for communication. Urgent diagnosis is defined as a medical condition that, in most cases, should be addressed as soon as possible. Significant, unexpected diagnosis is defined as a medical condition that is clinically unusual or unforeseen and should be addressed at some point in the patient's course. Further details of this statement are provided.

Kevin Leslie's intriguing hypothesis as to the cause of idiopathic pulmonary fibrosis

Arch Pathol Lab Med. 2011 Dec 2. [Epub ahead of print]
Idiopathic Pulmonary Fibrosis May Be a Disease of Recurrent, Tractional Injury to the Periphery of the Aging Lung: A Unifying Hypothesis Regarding Etiology and Pathogenesis.
Leslie KO.

Context.-Idiopathic pulmonary fibrosis is a progressive, fatal lung disease occurring in older individuals. Despite 50 years of accrued data about the disease, little progress has been made in slowing functional loss or in decreasing patient mortality. Objective.-To present a novel hypothesis on the etiology and pathogenesis of idiopathic pulmonary fibrosis. Design.-Published data are reviewed regarding the epidemiology, clinical presentation, natural history, radiologic findings, and pathologic findings in patients with idiopathic pulmonary fibrosis. Results.-Patients with idiopathic pulmonary fibrosis may be predisposed genetically to tractional injury to the peripheral lung. The result is recurrent damage to the epithelial-mesenchymal interface, preferentially at the outer edges of the basilar lung lobules where tractional stress is high during inspiration, compliance is relatively low, and there is a greater tendency for alveolar collapse at end-expiration. A distinctive "reticular network of injury" (the fibroblast focus) forms, attended by a prolonged phase of wound repair (tear and slow repair). Discrete areas of alveolar collapse are observed in scar at the periphery of the lung lobules. The cycle repeats over many years resulting in progressive fibrous remodeling and replacement of the alveoli in a lobule by bronchiolar cysts surrounded by scar (honeycomb lung). Abnormalities in surfactant function are proposed as a potential mechanism of initial lung damage. Age of onset may be a function of a required threshold of environmental exposures (eg, cigarette smoking) or other comorbid injury to the aging lung. Conclusions.-Evidence supporting this hypothesis is presented and potential mechanisms are discussed. A potential role for contributing cofactors is presented.

Monday, November 28, 2011

Health care reform: impact on innovation and new technology

Gastrointest Endosc Clin N Am. 2012 Jan;22(1):109-20. Epub 2011 Oct 20.
The impact of health care reform on innovation and new technology.
Ganz RA.
Minnesota Gastroenterology, PA, Old Shakopee Road, Bloomington, MN, USA; University of Minnesota, Minneapolis, MN, USA.

Health care reform has created special challenges and hurdles to the introduction of new technology and innovative medical devices in gastroenterology and other medical fields. The implication of new regulations will be enormous as we begin to see venture-capital funding flee our specialty for more lucrative and "sure bets." This article, written by an experienced entrepreneur and practicing gastroenterologist, outlines some of the implications of this emerging challenge. Few other sources of information are available that truly articulate the insider view of coming changes.

From Johns Hopkins: Quality and safety in anesthesiology

Best Pract Res Clin Anaesthesiol. 2011 Dec;25(4):557-67.
A novel approach to implementation of quality and safety programmes in anaesthesiology.
Schwengel DA, Winters BD, Berkow LC, Mark L, Heitmiller ES, Berenholtz SM.
Department of Anesthesiology, Critical Care and Pediatrics, Johns Hopkins University, 600 N. Wolfe St., Blalock 1412, Baltimore, MD 21287, USA.

Far too many patients suffer preventable harm from medical errors that add to needless suffering and cost of care. Underdeveloped residency training programmes in patient safety are a major contributor to preventable harm. Consequently, the Institute of Medicine has called for health professionals to reform their educational programmes to advance health-care safety and quality. Additionally, the Accreditation Council for Graduate Medical Education (ACGME) now requires education in 'systems-based practice' and 'practice-based learning and improvement' as core competencies of residency training programmes. The specific aim of this article is to describe the implementation of a novel programme designed to enhance residency education, meet ACGME core competencies and improve quality and safety education in one residency programme at an academic medical institution.

From Brown U: Cardiovascular disease and risk in primary care settings

Am J Cardiol. 2011 Nov 21. [Epub ahead of print]
Cardiovascular Disease and Risk in Primary Care Settings in the United States.
Ndumele CD, Baer HJ, Shaykevich S, Lipsitz SR, Hicks LS.
Program in Public Health, Alpert School of Medicine, Brown University, Providence, Rhode Island.

Primary care site may play an important role in cardiovascular disease prevalence; however, the distribution of risk factors and outcomes across care sites is not known. In this study, a cross-sectional analysis of 21,778 adult participants from the National Health and Nutrition Examination Survey (NHANES; 1999 to 2008) using multivariate logistic regression was conducted to assess the relation between site of usual care and disease prevalence. Patients' self-reported histories of several chronic conditions (hypertension, diabetes, and hypercholesterolemia), awareness of chronic conditions, and associated cardiovascular events (angina, coronary heart disease, cardiovascular disease, myocardial infarction, and stroke) were examined. After adjustment for demographic and health care utilization characteristics, there were no significant differences in the prevalence of diabetes or hypercholesterolemia among patients receiving usual care at private doctors' offices, hospital outpatient clinics, community-based clinics, and emergency rooms (ER). However, participants without usual sources of care and those receiving usual care at ERs had significantly lower awareness of their chronic conditions than participants at other sites. The odds of having a history of each of the adverse cardiovascular events ranged from 2.21 to 4.18 times higher for patients receiving usual care at ERs relative to private doctors' offices. In conclusion, participants who report using ERs as their usual sites of care are disproportionately more likely to have histories of poor cardiovascular outcomes and are more likely to be unaware of having hypertension or hypercholesterolemia. As health care reform takes place and millions more begin seeking care, it is imperative to ensure access to longitudinal care sites designed for continuous disease management.

Childhood obesity: Parents fear being blamed. MDs must be sensitive and nonjudgmental

Fam Pract. 2011 Nov 24. [Epub ahead of print]
Parents' views and experiences of childhood obesity management in primary care: a qualitative study.
Turner KM, Salisbury C, Shield JP.
Academic Unit of Primary Health Care, School of Social and Community Medicine, University of Bristol, Canynge Hall, 39 Whatley Road, Bristol BS8 2PS.

Primary care has been viewed as an appropriate setting for childhood obesity management. Little is known about parents' views and experiences of obesity management within this clinical setting. These views and experiences need to be explored, as they could affect treatment success.

To explore parents' views and experiences of primary care as a treatment setting for childhood obesity.

In-depth interviews were held with 15 parents of obese children aged 5-10 years, to explore their views and experiences of primary care childhood obesity management. Parents were contacted via a hospital-based childhood obesity clinic, general practices and Mind, Exercise, Nutrition … Do it! (MEND) groups based in Bristol, England. The interviews were audio-taped transcribed verbatim and analysed thematically.

Parents viewed primary care as an appropriate setting in which to treat childhood obesity but were reluctant to consult due to a fear of being blamed for their child's weight and a concern about their child's mental well-being. They also questioned whether practitioners had the knowledge, time and resources to effectively manage childhood obesity. Parents varied in the extent to which they had found consulting a practitioner helpful, and their accounts suggested that GPs and school nurses offer different types of support.

Parents need to be reassured that practitioners will address their child's weight in a non-judgemental sensitive manner and are able to treat childhood obesity effectively. A multidisciplinary team approach might benefit a child, as different practitioners may vary in the type of care they provide.

Annual CT screening for lung cancer: This study shows 20% reduced mortality

Expert Rev Anticancer Ther. 2011 Dec;11(12):1833-6.
Finding needles in a haystack: annual low-dose computed tomography screening reduces lung cancer mortality in a high-risk group.
Duke SL, Eisen T.
Department of Oncology, Cambridge University Health Partners, Hills Road, Cambridge, CB2 0QQ, UK.

Evaluation of: Aberle DR, Adams AM, Berg CD et al.; National Lung Screening Trial Research Team. Reduced lung-cancer mortality with low-dose computed tomographic screening. N. Engl. J. Med. 365(5), 395-409 (2011). Lung cancer is a global health issue. Compared with other common malignancies, the prognosis is poor as many patients present with advanced disease. The National Lung Screening Trial (NLST) aimed to identify and treat early lung cancers using annual low-dose computed tomography (CT) screening in a high-risk group. When compared with chest x-ray screening, low-dose CT screening reduced lung cancer mortality by 20%; the NLST is the first lung cancer screening trial to demonstrate such a mortality benefit. However, we must wait for cost-effectiveness data from the NLST, as well as the results of ongoing European studies comparing low-dose CT with observation alone, before firm conclusions can be drawn regarding the overall benefits of introducing a CT screening program to clinical practice.

Treating facial trauma: The otolaryngologists' experience

Otolaryngol Head Neck Surg. 2011 Nov 16. [Epub ahead of print]
The Otolaryngologist's Cost in Treating Facial Trauma: American Academy of Otolaryngology--Head and Neck Surgery Survey.
McCusker SB, Schmalbach CE.
Yokota Air Base, Japan.

Objectives. (1) To define practice patterns and perceptions of junior otolaryngologists treating maxillofacial/neck trauma. (2) To identify manners in which the American Academy of Otolaryngology-Head and Neck Surgery (AAO-HNS) can meet future trauma needs.Study Design. Cross-sectional survey.Setting. Academic and private otolaryngology practices.

Methods. A 26-question survey was designed to identify demographics, practice patterns, perceptions, and areas for improvement in maxillofacial/neck trauma care. It was distributed anonymously to AAO-HNS members completing residency from 2005 to 2009. Analysis included descriptive statistics and χ(2) comparisons.

Results. Of 1343 otolaryngologists, 444 (33%) responded. A total of 85% of responding physicians treat maxillofacial/neck trauma, and 64% identify trauma as an ideal part of their practice. Sense of duty (54%), institutional requirements (33%), and enjoyment (32%) are the most common reasons for treating trauma. Major deterrents include patient noncompliance (60%) and lifestyle limitations (47%). Five respondents (3.1%) have been involved in a trauma-related lawsuit. While insufficient reimbursement is a major deterrent to treating trauma (52%), only 36% would increase their volume if reimbursement improved. Increased educational opportunities represent the most common request to the AAO-HNS (59%), followed by AAO-HNS focus on improved reimbursement and tort reform (28%).

Conclusion. Most junior otolaryngologists treat maxillofacial/neck trauma on a monthly basis. A total of 64% identify trauma as a component of their ideal practice. They report being well to very well trained in all facets of trauma, with the exception of vascular and laryngotracheal injuries; but they desire additional education, such as courses and panels. Universal concerns include inadequate reimbursement, limited pool of treating physicians, and lack of practice guidelines.

From Sarah Feldman: Making sense of cervical cancer screening guidelines

N Engl J Med. 2011 Nov 23. [Epub ahead of print]
Making Sense of the New Cervical-Cancer Screening Guidelines.
Feldman S.
From the Department of Obstetrics, Gynecology, and Reproductive Biology, Brigham and Women's Hospital, Boston.

"Health care is a limited resource, and providing the best care at the best price will become increasingly important. We need to use and understand actual data about risk and the long-term effects and costs of various strategies. Experts are often in the best position to review the data and make recommendations, but different expert panels may interpret data differently and emphasize different results in making their decisions. And even with the best consensus guidelines, some clinical judgment and personalized attention to each patient remains necessary."

Friday, November 18, 2011

Reforming Big Pharma-Physician Financial Relationships

J Law Med Ethics. 2011 Dec;39(4):662-670. doi: 10.1111/j.1748-720X.2011.00633.x.
Reforming Pharmaceutical Industry-Physician Financial Relationships: Lessons from the United States, France, and Japan.
Rodwin MA.
Edmond J. Safra Research Lab Fellow at Harvard University and Professor of Law at Suffolk University Law School, is the author of Conflicts of Interest and the Future of Medicine: The United States, France and Japan (Oxford, 2011) and Medicine, Money and Morals: Physicians' Conflicts of Interest (1993).

This article compares the means that the United States, France, and Japan use to oversee pharmaceutical industry-physician financial relationships. These countries rely on professional and/or industry ethical codes, anti-kickback laws, and fair trade practice laws. They restrict kickbacks the most strictly, allow wide latitude on gifts, and generally permit drug firms to fund professional activities and associations. Consequently, to avoid legal liability, drug firms often replace kickbacks with gifts and grants. The paper concludes by proposing reforms that address problems that persist when firms replace kickbacks with gifts and grants based on the experience of the three countries.

© 2011 American Society of Law, Medicine & Ethics, Inc.

COPD and Hypoxemia

Int J Chron Obstruct Pulmon Dis. 2011;6:199-208. Epub 2011 Mar 14.
Hypoxemia in patients with COPD: cause, effects, and disease progression.
Kent BD, Mitchell PD, McNicholas WT.
Pulmonary and Sleep Disorders Unit, St. Vincent's University Hospital, Dublin, Ireland.

Chronic obstructive pulmonary disease (COPD) is a leading cause of death and disability internationally. Alveolar hypoxia and consequent hypoxemia increase in prevalence as disease severity increases. Ventilation/perfusion mismatch resulting from progressive airflow limitation and emphysema is the key driver of this hypoxia, which may be exacerbated by sleep and exercise. Uncorrected chronic hypoxemia is associated with the development of adverse sequelae of COPD, including pulmonary hypertension, secondary polycythemia, systemic inflammation, and skeletal muscle dysfunction. A combination of these factors leads to diminished quality of life, reduced exercise tolerance, increased risk of cardiovascular morbidity, and greater risk of death. Concomitant sleep-disordered breathing may place a small but significant subset of COPD patients at increased risk of these complications. Long-term oxygen therapy has been shown to improve pulmonary hemodynamics, reduce erythrocytosis, and improve survival in selected patients with severe hypoxemic respiratory failure. However, the optimal treatment for patients with exertional oxyhemoglobin desaturation, isolated nocturnal hypoxemia, or mild-to-moderate resting daytime hypoxemia remains uncertain.

Delivering mental health services within primary care: Best practices

Clin Med Res. 2011 Nov;9(3-4):171.
PS1-32: Psychology in Primary Care: An Evaluation of Best Practices.
Phillips K, Smith E, Stevens A.

Integrating psychology and mental health professionals into primary care settings has emerged as a means to improve the access to and utilization of mental health services. Three main delivery models of psychology in primary care settings have emerged: referring a patient to a psychologist/mental health professional located in a facility outside of the primary care physician's (PCP) office; referring a patient to a co-located psychologist/mental health professional who does not directly interface with PCP; integrated and co-located model where the PCP and the psychologist/ mental health professional discuss the patient's health. The overall purpose of this project was to compare patient utilization of psychology/mental health services across the Scott & White Health care system.

Using electronic medical records and the virtual data warehouse (VDW), mental health clinics/facilities were categorized into one of the three main psychology models. Patients that had depression, anxiety or ADHD DRG codes in their EMR and were aged 18 and older (n=37,310) were included in the analysis. The following additional variables were controlled for: gender, race/ethnicity, and chronic physical health conditions (i.e. arthritis, lung disease, heart disease, diabetes, hypertensive disease, and osteoporosis). ANOVA/ANCOVA analyses were performed to determine the differences across the three models in the length of time between the PPC referral and the first appointment with the psychologist/mental health professional.

Patients that were seen by psychologist in facilities with integrated co-located models of care experienced a shorter amount of time between their referral and their first appointment with the psychologist/mental health professional, compared to the other two models of care.

These initial results begin to inform best practices for delivering mental health services within primary care and provide physicians and health care systems with data on issues that facilitate integrated, person-centered care.

Does PPACA disincentivize comprehensive primary care?

J Am Board Fam Med. 2011 Nov;24(6):637-638.
Rewarding Family Medicine While Penalizing Comprehensiveness? Primary Care Payment Incentives and Health Reform: the Patient Protection and Affordable Care Act (PPACA).
Petterson S, Bazemore AW, Phillips RL, Xierali IM, Rinaldo J, Green LA, Puffer JC.
The Robert Graham Center.

Family physicians' scope of work is exceptionally broad, particularly with increasing rurality. Provisions for Medicare bonus payment specified in the health care reform bill (the Patient Protection and Affordable Care Act) used a narrow definition of primary care that inadvertently offers family physicians disincentives to delivering comprehensive primary care.

From LA Review of Books: Steven Brint's The Education Lottery

"The American education gospel is built around four core beliefs. First, it teaches that access to higher levels of education should be available to everyone, regardless of their background or previous academic performance. Every educational sinner should have a path to redemption. (Most of these paths now run through community colleges.) Second, the gospel teaches that opportunity for a better life is the goal of everyone and that education is the primary — and perhaps the only — road to opportunity. Third, it teaches that the country can solve its social problems — drugs, crime, poverty, and the rest — by providing more education to the poor. Education instills the knowledge, discipline, and the habits of life that lead to personal renewal and social mobility. And, finally, it teaches that higher levels of education for all will reduce social inequalities, as they will put everyone on a more equal footing."

"...we will need to turn our backs on assumptions of our most fervent boosters of universal higher education: that access alone is the primary purpose, and that when students and teachers are co-present, education occurs..."

Federal health care reform and the Necessary and Proper Clause

Bad News for Professor Koppelman: The Incidental Unconstitutionality of the Individual Mandate
Gary Lawson & David B. Kopel
Tuesday, 08 November 2011

In Bad News for Mail Robbers: The Obvious Constitutionality of Health Care Reform, Professor Andrew Koppelman argues that the individual mandate in the Patient Protection and Affordable Care Act is constitutionally authorized by the Necessary and Proper Clause. This view is fundamentally wrong. The Necessary and Proper Clause is based on eighteenth-century agency law, including the fundamental agency doctrine of principals and incidents. Accordingly, the Clause only allows Congress to exercise powers that are incident to—meaning subordinate to or less “worthy” than—its principal enumerated powers. The power to compel private persons to engage in commercial transactions with other private persons is not an incidental power. Thus, the mandate is not authorized by the Necessary and Proper Clause, whether or not such a power is “necessary and proper for carrying into Execution” other powers. In addition, eighteenth-century public law carried administrative law principles—including the fiduciary norms at the heart of agency law—into delegations of power to political actors. One of the most basic of these fiduciary norms is the obligation to treat multiple principals equally. That equal treatment requirement is violated by the individual mandate, which compels transactions with a favored oligopoly of insurance companies. In short, the mandate is not an exercise of incidental power within the scope of the Necessary and Proper Clause, nor is the mandate “proper.”

Preferred citation: Gary Lawson & David B. Kopel, Bad News for Professor Koppelman: The Incidental Unconstitutionality of the Individual Mandate, 121 YALE L.J. ONLINE 267 (2011),

Tuesday, November 15, 2011

Sarcopenia and genetics

Age (Dordr). 2011 Oct 27. [Epub ahead of print]
Genes and the ageing muscle: a review on genetic association studies.
Garatachea N, Lucía A.
University of Zaragoza, Huesca, Spain,

Western populations are living longer. Ageing decline in muscle mass and strength (i.e. sarcopenia) is becoming a growing public health problem, as it contributes to the decreased capacity for independent living. It is thus important to determine those genetic factors that interact with ageing and thus modulate functional capacity and skeletal muscle phenotypes in older people. It would be also clinically relevant to identify 'unfavourable' genotypes associated with accelerated sarcopenia. In this review, we summarized published information on the potential associations between some genetic polymorphisms and muscle phenotypes in older people. A special emphasis was placed on those candidate polymorphisms that have been more extensively studied, i.e. angiotensin-converting enzyme (ACE) gene I/D, α-actinin-3 (ACTN3) R577X, and myostatin (MSTN) K153R, among others. Although previous heritability studies have indicated that there is an important genetic contribution to individual variability in muscle phenotypes among old people, published data on specific gene variants are controversial. The ACTN3 R577X polymorphism could influence muscle function in old women, yet there is controversy with regards to which allele (R or X) might play a 'favourable' role. Though more research is needed, up-to-date MSTN genotype is possibly the strongest candidate to explain variance among muscle phenotypes in the elderly. Future studies should take into account the association between muscle phenotypes in this population and complex gene-gene and gene-environment interactions.

From U Mich and Western Mich U: Gender-related differences among med school faculty

Health Care Manag (Frederick). 2011 Oct;30(4):334-41.
An empirical investigation of the differences between male and female medical school physicians.
Deshpande SS, Deshpande SP.
Author Affiliations: Section of Plastic Surgery, Department of Surgery, University of Michigan, Ann Arbor (S. S. Deshpande), and Department of Management, Haworth College of Business, Western Michigan University, Kalamazoo (Dr S. P. Deshpande).

The purpose of this research was to investigate gender-related differences among medical school faculty in a variety of areas such as information technology, medical malpractice, compensation, patient care, and carrier satisfaction. The Center for Studying Health System Change's 2008 Health Tracking Physician survey data consisting of 326 medical school faculty belonging to the American Medical Association were used in this study. t Tests indicate that female physicians practicing in medical schools were younger, had less experience, reported lower compensation, and were more likely to be primary care physicians. Male medical school physicians were significantly more concerned about being involved in a malpractice lawsuit. They reported a significantly higher percentage on income based on productivity-related factors. Male physicians also reported getting a significantly higher level of goods and services from drug companies. They also provided more hours of medical service for no or reduced fee in the previous month and higher levels of career satisfaction. Implications of this research are discussed.

From U Milan: Time for new performance classification for high level male marathon runners?

J Strength Cond Res. 2011 Nov 10. [Epub ahead of print]
Is It Time to Consider a New Performance Classification for High-Level Male Marathon Runners?
Torre AL, Vernillo G, Agnello L, Berardelli C, Rampinini E.
1Department of Sport, Nutrition and Health Sciences, University of Milan, Milan, Italy; 2Faculty of Exercise Sciences, University of Milan, Milan, Italy; 3Department of Basic and Applied Medical Sciences, Chieti-Pescara University, Chieti Pescara, Italy; and 4Human Performance Laboratory, Mapei Sport Research Center, Castellanza, Varese, Italy.

Studies have attempted to describe human running performances by the analysis of world-record times. However, to date, no study has analyzed the evolution of high-level marathon performances over time. Thus, the purpose of this study was to analyze these performances across the past 42 years with the aim of delineating a time-based classification. To identify the nature of the phenomenon represented by the sequence of observations, we examined the data collected (i.e., 8,400 times from 1969 to 2010) as a time series. The leading time (LT) and the mean 200 times (T200) per year underwent a nonlinear but significant decrement (r = -0.92, p < 0.001 and r = -0.98, p < 0.001, respectively). In fact, from 1969 to 2010, the mean time differences were 3 minutes 20 seconds ± 1 minute 59 seconds and 7 minutes 1 second ± 2 minutes 48 seconds, corresponding to an improvement of 5 and 10 seconds per year for LT and T200, respectively. Furthermore, trend analysis suggested a disruption in marathon time improvements, indicating the presence of 3 points in the time series in which the performance significantly improved with respect to that of the previous years, corresponding to the years 1983-1984 (p < 0.001), 1997-1998 (p < 0.003), and 2003 (p < 0.001). In conclusion, despite the trend in high-level marathon performances being better explained by a nonlinear tendency, significant improvements in the ability of the high-level marathon runners to complete the distance were observed. These improvements are likely to be related to sociological, environmental, physiological, and training-method factors. Researchers and coaches should take into account these enhancements by using the time classification proposed in this study to better reflect the marathon performance profile of their athletes.

"The especially high rates of obesity in Texas have a profound impact on personal health and may result in increased health care costs that threaten public programs as well."

J Health Care Poor Underserved. 2011;22(4):1190-204.
Predictors of Body Mass Index among Low-Income Community-Dwelling Older Adults.
Ahn S, Huber C, Smith ML, Ory MG, Phillips CD.

Abstract:This study investigated demographic, behavioral, and functional predictors of overweight and obesity, using secondary data from 705 community-dwelling individuals aged 65 years and older receiving or seeking Medicaid personal care services. Half of the participants were obese, while an additional 28% were overweight. The relationships between body mass index (BMI) levels and selected independent variables were analyzed. Females were more likely to be obese, while those who were older (75 years or older), more cognitively impaired, and smoked were less likely to obese. Comparing obesity with being overweight, being female and reporting more pain symptoms increased the odds of being obese, whereas being older (75 years or older) and being more cognitively impaired decreased the odds. The especially high rates of obesity in Texas have a profound impact on personal health and may result in increased health care costs that threaten public programs as well.

From U Wisc-Madison: 14 factors causing a missed diagnosis of Cystic Fibrosis on newborn screening

Pediatr Pulmonol. 2011 Dec;46(12):1166-74. doi: 10.1002/ppul.21509. Epub 2011 Aug 24.
Factors accounting for a missed diagnosis of cystic fibrosis after newborn screening.
Rock MJ, Levy H, Zaleski C, Farrell PM.
School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin.

Newborn screening is a public health policy program involving the centralized testing laboratory, infant and their family, primary care provider, and subspecialist for confirmatory testing and follow-up of abnormal results. Cystic fibrosis (CF) newborn screening has now been enacted in all 50 states and the District of Columbia and throughout many countries in the world. Although CF neonatal screening will identify the vast majority of infants with CF, there are many factors in the newborn screening system that can lead to a missed diagnosis of CF. To inform clinicians, this article summarizes the CF newborn screening system and highlights 14 factors that can account for a missed diagnosis of CF. Care providers should maintain a high suspicion for CF if there are compatible symptoms, regardless of the results of the newborn screening test. These factors in newborn screening programs leading to a missed diagnosis of CF present opportunities for quality improvement in specimen collection, laboratory analysis of immunoreactive tryspinogen (IRT) and CF mutation testing, communication, and sweat testing. Pediatr Pulmonol. 2011; 46: 1166-1174. © 2011 Wiley Periodicals, Inc.

Trauma networks and the reform of trauma care in England

BMC Med. 2011 Nov 11;9(1):121. [Epub ahead of print]
Trauma networks: present and future challenges.
Kanakaris NK, Giannoudis PV.

ABSTRACT: In England, trauma is the leading cause of death across all age groups, with over 16,000 deaths per year. Major trauma implies the presence of multiple, serious injuries that could result in death or serious disability. Successive reports have documented the fact that the current ad hoc unstructured management of this patient group is associated with considerable avoidable death and disability. The reform of trauma care in England, especially of the severely injured patient, has already begun. Strong clinical leadership is embraced as the way forward. The present article summarises the steps that have been made over the last decade that led to the recent decision to move towards a long anticipated restructure of the National Health Service (NHS) trauma services with the introduction of Regional Trauma Networks (RTNs). While, for the first time, a genuine political will and support exists, the changes required to maintain the momentum for the implementation of the RTNs needs to be marshalled against arguments, myths and perceptions from the past. Such an approach may reverse the disinterest attitude of many, and will gradually evolve into a cultural shift of the public, clinicians and policymakers in the fullness of time.

From SUNY Downstate: Med mal from failure to notify test results

J Am Coll Radiol. 2011 Nov;8(11):776-9.
Failure to notify reportable test results: significance in medical malpractice.
Gale BD, Bissett-Siegel DP, Davidson SJ, Juran DC.
Department of Radiology, SUNY Downstate Medical Center, Brooklyn, New York.

Diagnostic physicians generally acknowledge their responsibility to notify referring clinicians whenever examinations demonstrate urgent or unexpected findings. During the past decade, clinicians have ordered dramatically greater numbers of diagnostic examinations. One study demonstrated that between 1996 and 2003, malpractice payments related to diagnosis increased by approximately 40%. Communication failures are a prominent cause of action in medical malpractice litigation. The aims of this study were to (1) define the magnitude of malpractice costs related to communication failures in test result notification and (2) determine if these costs are increasing significantly.

Linear regression analysis of National Practitioner Data Bank claims data from 1991 to 2009 suggested that claims payments increased at the national level by an average of $4.7 million annually (95% confidence interval, $2.98 million to $6.37 million). Controlled Risk Insurance Company/Risk Management Foundation claims data for 2004 to 2008 indicate that communication failures played a role, accounting for 4% of cases by volume and 7% of the total cost.

Faile communication of clinical data constitutes an increasing proportion of medical malpractice payments. The increase in cases may reflect expectations of more reliable notification of medical data. Another explanation may be that the remarkable growth in diagnostic test volume has led to a corresponding increase in reportable results. If notification reliability remained unchanged, this increased volume would predict more failed notifications.

There is increased risk for malpractice litigation resulting from diagnostic test result notification. The advent of semiautomated critical test result management systems may improve notification reliability, improve workflow and patient safety, and, when necessary, provide legal documentation.

Lung cancer and methylation profiling

Int J Oncol. 2011 Nov 7. doi: 10.3892/ijo.2011.1253. [Epub ahead of print]
Methylation profiling in non-small cell lung cancer: Clinical implications.
Morán A, Fernández-Marcelo T, Carro J, De Juan C, Pascua I, Head J, Gómez A, Hernando F, Torres AJ, Benito M, Iniesta P.
Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Complutense University, 28040-Madrid, Spain.

The aim of this study was to identify a panel of methylation markers that distinguish non-small cell lung cancers (NSCLCs) from normal lung tissues. We also studied the relation of the methylation profile to clinicopathological factors in NSCLC. We collected a series of 46 NSCLC samples and their corresponding control tissues and analyzed them to determine gene methylation status using the Illumina GoldenGate Methylation bead array, which screens up to 1505 CpG sites from 803 different genes. We found that 120 CpG sites, corresponding to 88 genes were hypermethylated in tumor samples and only 17 CpG sites (16 genes) were hypomethylated when compared with controls. Clustering analysis of these 104 genes discriminates almost perfectly between tumors and normal samples. Global hypermethylation was significantly associated with a worse prognosis in stage IIIA NSCLC patients (P=0.012). Moreover, hypermethylation of the CALCA and MMP-2 genes were statistically associated to a poor clinical evolution of patients, independently of TNM tumor stage (P=0.06, RR=2.64; P=0.04, RR=2.96, respectively). However, hypermethylation of RASSF1 turned out to be a protective variable (P=0.02; RR=0.53). In conclusion, our results could be useful for establishing a gene methylation pattern for the detection and prognosis of NSCLC.

From U Exeter: Radon gas and skin cancer?

Epidemiology. 2011 Nov 10. [Epub ahead of print]
Radon and Skin Cancer in Southwest England: An Ecologic Study.
Wheeler BW, Allen J, Depledge MH, Curnow A.
From the European Centre for Environment & Human Health, Peninsula College of Medicine & Dentistry, University of Exeter, Knowledge Spa, Royal Cornwall Hospital, Truro, United Kingdom.

Radon, a naturally occurring radioactive gas, is a carcinogen that causes a small proportion of lung cancers among exposed populations. Theoretical models suggest that radon may also be a risk factor for skin cancer, but epidemiologic evidence for this relationship is weak. In this study, we investigated ecologic associations between environmental radon concentration and the incidence of various types of skin cancer.

We analyzed data for 287 small areas (postcode sectors) in southwest England for the years 2000-2004. Poisson regression was used to compare registration rates of malignant melanoma, basal cell carcinoma, and squamous cell carcinoma across mean indoor radon concentrations from household surveys. Analyses were adjusted for potentially confounding factors, including age, sex, population socioeconomic status, and mean hours of bright sunshine.

No association was observed between mean postcode sector radon concentration and either malignant melanoma or basal cell carcinoma registration rates. However, sectors with higher radon levels had higher squamous cell carcinoma registration rates, with evidence of an exposure-response relationship. Comparing highest and lowest radon categories, postcode sectors with mean radon ≥230 Bq/m had registration rates 1.76 (95% confidence interval = 1.46-2.11) times those with mean radon 0-39 Bq/m. Associations persisted after adjustment for potential confounders.

This ecologic study suggests that environmental radon exposure may be a risk factor for squamous cell carcinoma. Further study is warranted to overcome ecologic design limitations and to determine whether this relationship is generalizable to national and international settings.

From UNC: Cancer staging and grading

Methods Mol Biol. 2012;823:1-18.
Tumor staging and grading: a primer.
Cowherd SM.
Internal Medicine, University of North Carolina School of Medicine, Chapel Hill, NC, USA,

Cancer staging and grading are used to predict the clinical behavior of malignancies, establish appropriate therapies, and facilitate exchange of precise information between clinicians. The internationally accepted criteria for cancer staging, the tumor-node-metastasis (TNM) system, includes: (1) tumor size and local growth (T); (2) extent of lymph node metastases (N); and (3) occurrence of distant metastases (M). Clinical stage is established before initiation of therapy and depends on the physical examination, laboratory findings, and imaging studies. Pathologic stage is determined following surgical exploration of disease spread and histological examination of tissue. The TNM classification system has evolved over 50 years to accommodate increasing knowledge about cancer biology. Efforts are ongoing to keep the system both synchronized with the most sophisticated cancer technology and simple for ease of clinician/patient use. Upcoming molecular technologies, such as genomic and proteomic profiling of tumors, microRNA profiling, and even ex vivo living tumor tissue treatment, could improve the current TNM staging system. This chapter describes the current TNM system using breast, lung, ovarian, and prostate cancer examples.

Tuesday, November 8, 2011

From U Texas Southwestern Med: Molecular biology of lung cancer

Clin Chest Med. 2011 Dec;32(4):703-40. Epub 2011 Oct 7.
Molecular biology of lung cancer: clinical implications.
Larsen JE, Minna JD.
Hamon Center for Therapeutic Oncology Research, Simmons Cancer Center, 6000 Harry Hines Boulevard, University of Texas Southwestern Medical Center, Dallas, TX 75390-8593, USA.

Lung cancer is a heterogeneous disease clinically, biologically, histologically, and molecularly. Understanding the molecular causes of this heterogeneity, which might reflect changes occurring in different classes of epithelial cells or different molecular changes occurring in the same target lung epithelial cells, is the focus of current research. Identifying the genes and pathways involved, determining how they relate to the biological behavior of lung cancer, and their utility as diagnostic and therapeutic targets are important basic and translational research issues. This article reviews current information on the key molecular steps in lung cancer pathogenesis, their timing, and clinical implications.

From Yale: Revised staging system for lung cancer

Clin Chest Med. 2011 Dec;32(4):741-8.
The revised stage classification system for primary lung cancer.
Boffa DJ.
Thoracic Surgery, Yale University School of Medicine, 330 Cedar Street, BB205, 208062, New Haven, CT 06520, USA.

The revised stage classification system has improved the ability of clinicians to estimate prognosis based on specific staging determinations. Several important questions have been addressed, although many remain and will likely fuel the discussion for subsequent revisions. Perhaps more than previous revisions, the current iteration may cause confusion because of the emphasis on stage-specific treatment recommendations. However, prognosis is only 1 of the factors in a multidisciplinary treatment plan, and clinicians are encouraged to apply randomized trial data whenever possible. This global staging effort is testament to the progress that is possible through international collaboration.

From Keck Med: Lung cancer-use/misuse of PET scans

Clin Chest Med. 2011 Dec;32(4):749-62.
The use and misuse of positron emission tomography in lung cancer evaluation.
Chang CF, Rashtian A, Gould MK.
Department of Medicine, Division of Pulmonary and Critical Care Medicine, Keck School of Medicine of USC, 2020 Zonal Avenue, IRD Room 723, Los Angeles, CA 90033, USA.

This article discusses the potential benefits and limitations of positron emission tomography (PET) for characterizing lung nodules, staging the mediastinum, identifying occult distant metastasis, determining prognosis and treatment response, guiding plans for radiation therapy, restaging during and after treatment, and selecting targets for tissue sampling. The key findings from the medical literature are presented regarding the capabilities and fallibilities of PET in lung cancer evaluation, including characterization of pulmonary nodules and staging in patients with known or suspected non-small-cell lung cancer. The discussion is limited to PET imaging with fluorodeoxyglucose.

From Yale: Lung cancer-diagnostic/therapeutic interventions

Clin Chest Med. 2011 Dec;32(4):763-71. Epub 2011 Oct 7.
The Pulmonologist's Diagnostic and Therapeutic Interventions in Lung Cancer.
Puchalski J, Feller-Kopman D.
Division of Pulmonary and Critical Care Medicine, Yale University School of Medicine, Boardman Building 205, 330 Cedar Street, New Haven, CT 06510, USA.

Diagnostic and therapeutic strategies for lung cancer have improved with advancing technology and the acquisition of the necessary skills by bronchoscopists to fully use these advanced techniques. The diagnostic yield for lung cancer has significantly increased with the advent of technologies such as endobronchial ultrasound, navigational systems, and improved imaging modalities. Similarly, the therapeutic benefit of bronchoscopy in advanced lung cancer has begun to be understood for its impact on quality and quantity of life. This article highlights the pulmonologists' diagnostic advances and therapeutic options, with an emphasis on outcomes.

From U Stellenbosch-SA: Functional evaluation before lung resection

Clin Chest Med. 2011 Dec;32(4):773-82.
Functional Evaluation before Lung Resection.
von Groote-Bidlingmaier F, Koegelenberg CF, Bolliger CT.
Division of Pulmonology, Department of Medicine, University of Stellenbosch, PO Box 19063, Tygerberg 7505, Cape Town, South Africa.

Lung cancer is the leading cause of cancer-related death worldwide, and lung resection remains the only curative approach. In the Western world, lung cancer is one of the main indications for lung resection, despite only 15% to 25% of all lung cancers being operable at the time of presentation. In most cases of operable lung cancer, a substantial part of functional lung tissue has to be resected, leading to a permanent loss of pulmonary function. Resection in patients with insufficient pulmonary reserves can result in permanent respiratory disability. This article reviews the current standards of preoperative assessment.