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.