Tuesday, January 31, 2012

From JAMA: Physician autonomy after health care reform. An important issue for patient care quality and safety.


JAMA. 2012 Jan 25;307(4):367-8.
Physician autonomy and health care reform.
Emanuel EJ, Pearson SD.
Department of Medical Ethics and Health

"Many physicians are distressed as they look toward the future. A recent survey of physicians reported that 65% thought the quality of health care will deteriorate in the future.1 Part of this malaise is driven by concerns that reforms contained in the Affordable Care Act (ACA) will further erode physicians' autonomy."

From U Auckland: "The health care sector has been slow to adopt organisational theory..."


N Z Med J. 2012 Jan 20;125(1348):79-89.
'The way things are around here': organisational culture is a concept missing from New Zealand healthcare policy, development, implementation, and research.
Scahill SL.
School of Pharmacy, University of Auckland, New Zealand. s.scahill@auckland.ac.nz.

Internationally, healthcare sectors are coming under increasing pressure to perform and to be accountable for the use of public funds. In order to deliver on stakeholder expectation, transformation will need to occur across all levels of the health system. Outside of health care it has been recognised for some time that organisational culture (OC) can have a significant influence on performance and that it is a mediator for change. The health sector has been slow to adopt organisational theory and specifically the benefits of understanding OC and impacts on performance. During a visit to health research units in the United Kingdom (UK) I realised the stark differences in the practice of health reform and its evaluation. OC is a firmly established concept within policy development, implementation and research in the UK. Unfortunately, the same cannot be said for New Zealand. There has been unrelenting reform and structural redesign, particularly of the primary healthcare sector under multiple governments over the past 20 to 30 years. However, there has been an underwhelming focus on the human aspects of organisational change. This seems set to continue and the aim of this viewpoint is to introduce the concept of OC and outline why New Zealand policy reformists and health services researchers should be thinking explicitly about OC. Culture is not solely the domain of the organisational scientist and current understandings of the influence of OC on performance are outlined in this commentary. Potential benefits of thinking about culture are argued and a proposed research agenda is presented.

From U Central Florida; Health care reform's effects on local businesses


Health Care Manag (Frederick). 2012 Jan;31(1):3-24.
The effects of national health care reform on local businesses-part 1: the law and its applicability.
Rotarius T, Liberman A, Perez B.
Author Affiliations: Graduate Program in Health Services Administration, Department of Health Management and Informatics, College of Health and Public Affairs, University of Central Florida, Orlando.

This is part 1 of a 3-part series that presents a comprehensive examination of the results that can be expected from the 2010 national Health Care Reform legislation. Political pundits have speculated endlessly on the many changes mandated by the legislation, titled the Patient Protection and Affordable Care Act. A review and assessment of this legislation at several levels (federal, state, state agency, local region, and individual business leaders) were undertaken. The results of this expanded analysis suggest strongly that members of the business community and their employees will benefit from the legislation early on (years 1-3) and then likely will be impacted adversely as the payment mechanisms driving the legislation are tightened by new federal regulations (year 4 onward). Businesses will likely be immediately impacted by the legislation, with small business owners being the prime beneficiaries of the new legislation owing to the availability of coverage to approximately 32 million individuals who previously had no access to coverage. In that regard, the soon-to-be newly-insured population also will be a prime beneficiary of the legislation as the limitations on chronic illnesses and other preexisting conditions will be reduced or eliminated by the legislation.

From Georgia Health Sciences U: Fructose and obesity in adolescents


J Nutr. 2012 Feb;142(2):251-7. Epub 2011 Dec 21.
Greater fructose consumption is associated with cardiometabolic risk markers and visceral adiposity in adolescents.
Pollock NK, Bundy V, Kanto W, Davis CL, Bernard PJ, Zhu H, Gutin B, Dong Y.
Department of Pediatrics, Georgia Health Sciences University, Augusta, GA.

Though adolescents consume more fructose than any other age group, the relationship between fructose consumption and markers of cardiometabolic risk has not been established in this population. We determined associations of total fructose intake (free fructose plus one-half the intake of free sucrose) with cardiometabolic risk factors and type of adiposity in 559 adolescents aged 14-18 y. Fasting blood samples were measured for glucose, insulin, lipids, adiponectin, and C-reactive protein. Diet was assessed with 4-7 24-h recalls and physical activity (PA) was determined by accelerometry. Fat-free soft tissue (FFST) mass and fat mass were measured by DXA. The s.c. abdominal adipose tissue (SAAT) and visceral adipose tissue (VAT) were assessed using MRI. Multiple linear regression, adjusting for age, sex, race, Tanner stage, FFST mass, fat mass, PA, energy intake, fiber intake, and socioeconomic status, revealed that fructose intake was associated with VAT (β = 0.13; P = 0.03) but not SAAT (P = 0.15). Significant linear upward trends across tertiles of fructose intake were observed for systolic blood pressure, fasting glucose, HOMA-IR, and C-reactive protein after adjusting for the same covariates (all P-trend < 0.04). Conversely, significant linear downward trends across tertiles of fructose intake were observed for plasma HDL-cholesterol and adiponectin (both P-trend < 0.03). When SAAT was added as a covariate, these trends persisted (all P-trend < 0.05). However, when VAT was included as a covariate, it attenuated these trends (all P-trend > 0.05). In adolescents, higher fructose consumption is associated with multiple markers of cardiometabolic risk, but it appears that these relationships are mediated by visceral obesity.

From Teikyo U: Fructose-enriched diets and fatty liver disease


J Nutr Biochem. 2011 Nov 28. [Epub ahead of print]
The role of fructose-enriched diets in mechanisms of nonalcoholic fatty liver disease.
Nomura K, Yamanouchi T.
Department of Hygiene and Public Health, School of Medicine, Teikyo University, Tokyo 1838605, Japan.

Nonalcoholic fatty liver disease (NAFLD) currently affects 20%-30% of adults and 10% of children in industrialized countries, and its prevalence is increasing worldwide. Although NAFLD is a benign form of liver dysfunction, it can proceed to a more serious condition, nonalcoholic steatohepatitis (NASH), which may lead to liver cirrhosis and hepatocellular carcinoma. NAFLD is accompanied by obesity, metabolic syndrome and diabetes mellitus, and evidence suggests that fructose, a major caloric sweetener in the diet, plays a significant role in its pathogenesis. Inflammatory progression to NASH is proposed to occur by a two-hit process. The first "hit" is hepatic fat accumulation owing to increased hepatic de novo lipogenesis, inhibition of fatty acid beta oxidation, impaired triglyceride clearance and decreased very-low-density lipoprotein export. The mechanisms of the second "hit" are still largely unknown, but recent studies suggest several possibilities, including inflammation caused by oxidative stress associated with lipid peroxidation, cytokine activation, nitric oxide and reactive oxygen species, and endogenous toxins of fructose metabolites.

Interleukin-8 and lung inflammation in cystic fibrosis patients


Cell Signal. 2012 Jan 17. [Epub ahead of print]
Glucocorticoids reduce inflammation in cystic fibrosis bronchial epithelial cells.
Rebeyrol C, Saint-Criq V, Guillot L, Riffault L, Corvol H, Chadelat K, Ray DW, Clement A, Tabary O, Le Rouzic P.
UPMC Univ Paris 06, CDR Saint-Antoine, Paris F-75012, France; Inserm, CDR Saint-Antoine, Paris F-75012, France.

Reduction of lung inflammation is one of the goals of cystic fibrosis (CF) therapy. Among anti-inflammatory molecules, glucocorticoids (GC) are one of the most prescribed. However, CF patients seem to be resistant to glucocorticoid treatment. Several molecular mechanisms that contribute to decrease anti-inflammatory effects of glucocorticoids have been identified in pulmonary diseases, but the molecular actions of glucocorticoids have never been studied in CF. In the cytoplasm, glucocorticoids bind to glucocorticoid receptor (GR) and then, control NF-κB and MAPK pathways through direct interaction with AP-1 and NF-κB in the nucleus. Conversely, MAPK can regulate glucocorticoid activation by targeting GR phosphorylation. Together these pathways regulate IL-8 release in the lung. Using bronchial epithelial cell lines derived from non CF and CF patients, we analyzed GR-based effects of glucocorticoids on NF-κB and MAPK pathways, after stimulation with TNF-α. We demonstrate that the synthetic glucocorticoid dexamethasone (Dex) significantly decreases IL-8 secretion and AP-1 or NF-κB activity in CF cells in a pro-inflammatory context. Moreover, we show that p38 MAPK controls IL-8 release by determining GR activation through specific phosphorylation on serine 211. Finally, we demonstrate a synergistic effect of dexamethasone treatment and inhibition of p38 inducing more than 90% inhibition of IL-8 production in CF cells. All together, these results demonstrate the good responsiveness to glucocorticoids of CF bronchial epithelial cells and the reciprocal link between glucocorticoids and p38 MAPK in the control of CF lung inflammation.

Transfusion-related acute lung injury


Curr Opin Hematol. 2011 Nov;18(6):436-42.
Recent insights into the mechanism of transfusion-related acute lung injury.
Sachs UJ.
Institute for Clinical Immunology and Transfusion Medicine, Justus Liebig University, Giessen, Germany. ulrich.sachs@med.uni-giessen.de

This review summarizes the recent clinical and experimental literature on the pathogenesis of transfusion-related acute lung injury (TRALI), with a focus on mechanistic aspects.

Mechanisms by which leukocyte antibodies induce TRALI have been unraveled, including a multistep cascade for HLA class II-induced TRALI. Significant advances have also been made in the field of recipient-related factors that contribute to the development of TRALI, both in clinical and animal studies. In contrast, TRALI associated with the transfusion of blood components that do not contain antibodies is an emerging problem, especially because the relevance of mechanisms proposed earlier is questioned by the recent findings. New mechanisms need yet to be defined. The diversity of newly described factors contributing to TRALI demonstrates that a two-hit model falls too short to explain this complex syndrome and rather supports the previously proposed threshold model of TRALI.

Activated neutrophils are central in the pathophysiology of TRALI as their interaction with the lung endothelium causes capillary leak and pulmonary edema. Typically, numerous factors must act together in order to overcome a critical activation threshold of the neutrophil. At least one of these factors originates from a transfused blood component.

From U South Carolina: Risks of transfusion


South Med J. 2011 Nov;104(11):762-9.
Risks of transfusion.
Squires JE.
Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC 29425, USA. squiresj@musc.edu

Each year, more than 4 million patients receive a blood transfusion in the United States to control symptoms associated with anemia, coagulopathy, thrombocytopenia, or some combination thereof. In each of these cases, the physician and the patient must weigh the potential benefits of the transfusion along with the associated risks. To assess accurately the risk:benefit ratio and to discuss this with the patient, the physician must be familiar with the range of adverse transfusion outcomes and the current estimates of their frequency. Most important, during the past decade the risk profile of transfusion has changed significantly. Transfusion-transmitted disease, although still a rare outcome of transfusion, is no longer an overriding concern in transfusion safety considerations; however, risks such as hemolysis, transfusion-related lung injury, and anaphylaxis continue to represent significant concerns and are relatively more common than the transmission of infectious diseases after transfusion. Against this background, the development of a national hemovigilance system, designed to evaluate more accurately transfusion adverse outcomes in the United States, will require greater precision and reliability in the assessment of adverse transfusion outcomes by clinicians if the proposed benefits of this system are to be realized.

Molecular pathways in lung cancer


Am J Cancer Res. 2012;2(1):93-103. Epub 2011 Nov 19.
Molecular signature and pathway analysis of human primary squamous and adenocarcinoma lung cancers.
Daraselia N, Wang Y, Budoff A, Lituev A, Potapova O, Vansant G, Monforte J, Mazo I, Ossovskaya VS.

Non-small cell lung cancer (NSCLC) is the most common type of lung cancer, with a poor response to chemotherapy and low survival rate. This unfavorable treatment response is likely to derive from both late diagnosis and from complex, incompletely understood biology, and heterogeneity among NSCLC subtypes. To define the relative contributions of major cellular pathways to the biogenesis of NSCLC and highlight major differences between NSCLC subtypes, we studied the molecular signatures of lung adenocarcinoma (ADC) and squamous cell carcinoma (SCC), based on analysis of gene expression and comparison of tumor samples with normal lung tissue. Our results suggest the existence of specific molecular networks and subtype-specific differences between lung ADC and SCC subtypes, mostly found in cell cycle, DNA repair, and metabolic pathways. However, we also observed similarities across major gene interaction networks and pathways in ADC and SCC. These data provide a new insight into the biology of ADC and SCC and can be used to explore novel therapeutic interventions in lung cancer chemoprevention and treatment.

Microorganisms in distal airways of lung cancer patients: Clinically relevant?


Ann Thorac Surg. 2012 Feb;93(2):413-22. Epub 2011 Dec 28.
Molecular detection of microorganisms in distal airways of patients undergoing lung cancer surgery.
D'Journo XB, Bittar F, Trousse D, Gaillat F, Doddoli C, Dutau H, Papazian L, Raoult D, Rolain JM, Thomas PA.
Department of Thoracic Surgery and Diseases of the Esophagus, Aix-Marseille University and Assistance Publique-Hôpitaux de Marseille, Hôpital Nord, Marseille, France.

Whereas proximal airways of patients undergoing lung cancer surgery are known to present specific microbiota incriminated in the occurrence of postoperative respiratory complications, little attention has been paid to distal airways and lung parenchyma considered to be free from bacteria. We have hypothesized that molecular culture-independent techniques applied to distal airways should allow identification of uncultured bacteria, virus, or emerging pathogens and predict the occurrence of postoperative respiratory complications.

Microbiological assessments were obtained from the distal airways of resected lung specimens from a prospective cohort of patients undergoing major lung resections for cancer. Microorganisms were detected using real-time polymerase chain reaction (PCR) assays targeting the bacterial 16s ribosomal RNA gene and Herpesviridae, cytomegalovirus (CMV), and herpesvirus simplex. All postoperative microbiological assessments were compared with the PCR results.

In all, 240 samples from 87 patients were investigated. Colonizing agents were exclusively Herpesviridae (CMV, n = 13, and herpesvirus simplex, n = 1). All 16s ribosomal RNA PCR remained negative. Thirteen patients (15%) had a positive CMV PCR (positive-PCR group), whereas the remaining 74 patients constituted the negative-PCR group. Postoperative pneumonia occurred in 24% of the negative-PCR group and in 69% of the positive-PCR group (p = 0.003). Upon stepwise logistic regression, performance status, percent of predicted diffusion lung capacity for carbon monoxide, and positive PCR were the risk factors of postoperative respiratory complications. The CMV PCR had a positive predictive value of 0.70 in prediction of respiratory complications.

When tested by molecular techniques, lung parenchyma and distal airways are free of bacteria, but CMV was found in a high proportion of the samples. Molecular CMV detection in distal airways should be seen as a reliable marker to identify patients at risk for postoperative respiratory complications.

From U Colorado: ALK inhibitor resistance in lung cancer


Clin Cancer Res. 2012 Jan 10. [Epub ahead of print]
Mechanisms of Resistance to Crizotinib in Patients with ALK Gene Rearranged Non-Small Cell Lung Cancer.
Doebele RC, Pilling AB, Aisner D, Kutateladze TG, Le AT, Weickhardt AJ, Kondo KL, Linderman DJ, Heasley LE, Franklin WA, Varella-Garcia M, Camidge DR.
Medicine/Medical Oncology, University of Colorado Anschutz Medical Campus.

Patients with anaplastic lymphoma kinase (ALK) gene rearrangements often manifest dramatic responses to crizotinib, a small molecule ALK inhibitor. Unfortunately, not every patient responds and acquired drug resistance inevitably develops in those that do respond. This study aimed to define molecular mechanisms of resistance to crizotinib in ALK+ non-small cell lung cancer (NSCLC) patients.

We analyzed tissue obtained from 14 ALK+ NSCLC patients demonstrating evidence of radiologic progression while on crizotinib in order to define mechanisms of intrinsic and acquired resistance to crizotinib.

Eleven patients had material evaluable for molecular analysis. Four patients (36%) developed secondary mutations in the tyrosine kinase domain of ALK. A novel mutation in the ALK kinase domain, encoding a G1269A amino acid substitution that confers resistance to crizotinib in vitro, was identified in two of these cases. Two patients, one with a resistance mutation, exhibited new onset ALK copy number gain (CNG). One patient demonstrated outgrowth of EGFR mutant NSCLC without evidence of a persistent ALK gene rearrangement. Two patients exhibited a KRAS mutation, one of which occurred without evidence of a persisting ALK gene rearrangement. One patient demonstrated the emergence of an ALK gene fusion negative tumor compared to the baseline sample, but with no identifiable alternate driver. Two patients retained ALK positivity with no identifiable resistance mechanism.

Crizotinib resistance in ALK+ NSCLC occurs through somatic kinase domain mutations, ALK gene fusion CNG, and emergence of separate oncogenic drivers.

More on circulating tumor cells and lung cancer prognosis


J Clin Oncol. 2012 Jan 17. [Epub ahead of print]
Clinical Significance and Molecular Characteristics of Circulating Tumor Cells and Circulating Tumor Microemboli in Patients With Small-Cell Lung Cancer.
Hou JM, Krebs MG, Lancashire L, Sloane R, Backen A, Swain RK, Priest LJ, Greystoke A, Zhou C, Morris K, Ward T, Blackhall FH, Dive C.
Clinical and Experimental Pharmacology Group, Paterson Institute for Cancer Research, University of Manchester, Manchester Cancer Research Centre, Manchester; Matthew G. Krebs and Fiona H. Blackhall, the Christie National Health Service Foundation Trust, Manchester, United Kingdom.

Circulating tumor cells (CTCs) may have utility as surrogate biomarkers and "virtual" biopsies. We report the clinical significance and molecular characteristics of CTCs and CTC clusters, termed circulating tumor microemboli (CTM), detected in patients with small-cell lung cancer (SCLC) undergoing standard treatment.

Serial blood samples from 97 patients receiving chemotherapy were analyzed using EpCam-based immunomagnetic detection and a filtration-based technique. Proliferation status (Ki67) and apoptotic morphology were examined. Associations of CTC and CTM number with clinical factors and prognosis were determined.

CTCs were present in 85% of patients (77 of 97 patients) and were abundant (mean ± standard deviation = 1,589 ± 5,565). CTM and apoptotic CTCs were correlated with total CTC number and were detected in 32% and 57% of patients, respectively. Pretreatment CTCs, change in CTC number after one cycle of chemotherapy, CTM, and apoptotic CTCs were independent prognostic factors. Overall survival was 5.4 months for patients with ≥ 50 CTCs/7.5 mL of blood and 11.5 months (P < .0001) for patients with less than 50 CTCs/7.5 mL of blood before chemotherapy (hazard ratio = 2.45; 95% CI, 1.39 to 4.30; P = .002). Subpopulations of apoptotic and of proliferating solitary CTCs were detected, whereas neither were observed within cell clusters (CTM), implicating both protection from anoikis and relative resistance to cytotoxic drugs for cells within CTM.

Both baseline CTC number and change in CTC number after one cycle of chemotherapy are independent prognostic factors for SCLC. Molecular comparison of CTCs to cells in CTM may provide novel insights into SCLC biology.

From UC Irvine: Better EGFR TKIs for treating lung cancer?


Crit Rev Oncol Hematol. 2012 Jan 16. [Epub ahead of print]
Second-generation irreversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs): A better mousetrap? A review of the clinical evidence.
Ou SH.
Chao Family Comprehensive Cancer Center, University of California Irvine Medical Center, Building 56, Room 241, RT81, Orange, CA 92868, United States.

The discovery of activating epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer (NSCLC) in 2004 heralded the era of molecular targeted therapy in NSCLC. First-generation small molecule, reversible tyrosine kinase inhibitors (TKIs) of EGFR, gefitinib and erlotinib, had been approved for second- or third-line treatment of NSCLC prior to the knowledge of these mutations. However, resistance to gefitinib and erlotinib invariably develops after prolonged clinical use. Two second-generation irreversible EGFR TKIs, afatinib (BIBW 2992) and dacomitinib (PF-00299804), that can potentially overcome the majority of these resistances are in late stage clinical development. Here I will review the clinical data of EGFR TKIs and discuss the appropriate future role of afatinib and dacomitinib in NSCLC: whether as replacement of erlotinib or gefitinib or only after erlotinib or gefitinib failure and whether different subgroups would benefit from different approaches.

Lung cancer and circulating tumor cells


J Thorac Oncol. 2012 Jan 17. [Epub ahead of print]
Prognostic Impact of Circulating Tumor Cells in Patients with Small Cell Lung Cancer.
Naito T, Tanaka F, Ono A, Yoneda K, Takahashi T, Murakami H, Nakamura Y, Tsuya A, Kenmotsu H, Shukuya T, Kaira K, Koh Y, Endo M, Hasegawa S, Yamamoto N.
*Division of Thoracic Oncology, Shizuoka Cancer Center, Shizuoka Prefecture; †Second Department of Surgery, University of Occupational and Environmental Health, Fukuoka Prefecture; ‡Department of Thoracic Surgery, Hyogo College of Medicine, Hyogo Prefecture; §Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, Gunma Prefecture; ‖Division of Drug Discovery and Development, Shizuoka Cancer Center Research Institute, Shizuoka Prefecture; and ¶Division of Diagnostic Radiology, Shizuoka Cancer Center, Shizuoka Prefecture, Japan.

Enumeration of circulating tumor cells (CTCs) may be valuable for prognostic assessment in lung cancer patients. In this study, we report the clinical significance of CTCs in small cell lung cancer (SCLC).

In total, 51 consecutive patients newly diagnosed as having SCLC and starting chemotherapy or chemoradiotherapy were prospectively enrolled. Blood samples were drawn at the baseline, after chemotherapy, and at relapse. CTCs were isolated using the CellSearch System (Veridex LLC). Thresholds of 1 to 100 cells at the baseline were systematically correlated with the overall survival. The optimal cutoff was determined by comparing the Cox proportional hazard ratios (HRs).

Two or more CTCs were detected at baseline in 35 patients (68.6%; 95% confidence interval, 55.0-79.7). The HR signifying the difference between the unfavorable (more than or equal to threshold) and favorable (less than threshold) groups was maximal at the threshold of 8 CTCs (HR, 3.50; 95% confidence interval, 1.45-8.60). Patients with ≥8 CTCs had worse survival than those with <8 CTCs at baseline (p = 0.0014). Patients with ≥8 CTCs posttreatment or at relapse also showed worse survival than those with <8 CTCs (p = 0.0096 and <0.0001). Patients whose baseline and posttreatment CTC levels remained <8 tended to show better survival than those whose CTC level converted from ≥8 to <8 cells (p = 0.0288) or whose posttreatment CTC level was ≥8 cells (p = 0.0047).

CTCs were highly detectable in SCLC, and higher CTC levels were strongly associated with worse survival. Consistently favorable CTC levels were associated with favorable outcomes.

Lung cancer: Molecular pathology and personalized medicine


Mod Pathol. 2012 Jan 27. doi: 10.1038/modpathol.2011.215. [Epub ahead of print]
Molecular pathology of lung cancer: key to personalized medicine.
Cheng L, Alexander RE, Maclennan GT, Cummings OW, Montironi R, Lopez-Beltran A, Cramer HM, Davidson DD, Zhang S.
Departments of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.

The majority of lung adenocarcinoma patients with epidermal growth factor receptor- (EGFR) mutated or EML4-ALK rearrangement-positive tumors are sensitive to tyrosine kinase inhibitors. Both primary and acquired resistance in a significant number of those patients to these therapies remains a major clinical problem. The specific molecular mechanisms associated with tyrosine kinase inhibitor resistance are not fully understood. Clinicopathological observations suggest that molecular alterations involving so-called 'driver mutations' could be used as markers that aid in the selection of patients most likely to benefit from targeted therapies. In this review, we summarize recent developments involving the specific molecular mechanisms and markers that have been associated with primary and acquired resistance to EGFR-targeted therapy in lung adenocarcinomas. Understanding these mechanisms may provide new treatment avenues and improve current treatment algorithms.Modern Pathology advance online publication, 27 January 2012; doi:10.1038/modpathol.2011.215.

From Kirk Jones and colleagues: Predicting lung cancer survival with a molecular assay


Lancet. 2012 Jan 26. [Epub ahead of print]
A practical molecular assay to predict survival in resected non-squamous, non-small-cell lung cancer: development and international validation studies.
Kratz JR, He J, Van Den Eeden SK, Zhu ZH, Gao W, Pham PT, Mulvihill MS, Ziaei F, Zhang H, Su B, Zhi X, Quesenberry CP, Habel LA, Deng Q, Wang Z, Zhou J, Li H, Huang MC, Yeh CC, Segal MR, Ray MR, Jones KD, Raz DJ, Xu Z, Jahan TM, Berryman D, He B, Mann MJ, Jablons DM.
University of California, San Francisco, CA, USA.

The frequent recurrence of early-stage non-small-cell lung cancer (NSCLC) is generally attributable to metastatic disease undetected at complete resection. Management of such patients depends on prognostic staging to identify the individuals most likely to have occult disease. We aimed to develop and validate a practical, reliable assay that improves risk stratification compared with conventional staging.

A 14-gene expression assay that uses quantitative PCR, runs on formalin-fixed paraffin-embedded tissue samples, and differentiates patients with heterogeneous statistical prognoses was developed in a cohort of 361 patients with non-squamous NSCLC resected at the University of California, San Francisco. The assay was then independently validated by the Kaiser Permanente Division of Research in a masked cohort of 433 patients with stage I non-squamous NSCLC resected at Kaiser Permanente Northern California hospitals, and on a cohort of 1006 patients with stage I-III non-squamous NSCLC resected in several leading Chinese cancer centres that are part of the China Clinical Trials Consortium (CCTC).

Kaplan-Meier analysis of the Kaiser validation cohort showed 5 year overall survival of 71·4% (95% CI 60·5-80·0) in low-risk, 58·3% (48·9-66·6) in intermediate-risk, and 49·2% (42·2-55·8) in high-risk patients (p(trend)=0·0003). Similar analysis of the CCTC cohort indicated 5 year overall survivals of 74·1% (66·0-80·6) in low-risk, 57·4% (48·3-65·5) in intermediate-risk, and 44·6% (40·2-48·9) in high-risk patients (p(trend)<0·0001). Multivariate analysis in both cohorts indicated that no standard clinical risk factors could account for, or provide, the prognostic information derived from tumour gene expression. The assay improved prognostic accuracy beyond National Comprehensive Cancer Network criteria for stage I high-risk tumours (p<0·0001), and differentiated low-risk, intermediate-risk, and high-risk patients within all disease stages.

Our practical, quantitative-PCR-based assay reliably identified patients with early-stage non-squamous NSCLC at high risk for mortality after surgical resection.

UCSF Thoracic Oncology Laboratory and Pinpoint Genomics.
Copyright © 2012 Elsevier Ltd. All rights reserved.

Wednesday, January 18, 2012

Faith-based initiatives and the Office of the Surgeon General

http://www.ncbi.nlm.nih.gov/pubmed/22246656 J Relig Health. 2012 Jan 13. [Epub ahead of print] A Faith-Based Prescription for the Surgeon General: Challenges and Recommendations. Levin J, Hein JF. Source Institute for Studies of Religion, Baylor University, One Bear Place #97236, Waco, TX, 76798, USA, jeff_levin@baylor.edu. Abstract This article summarizes how the Office of the Surgeon General can leverage faith-based resources to fulfill its mission and that of the Surgeon General of the United States. Such resources, personal and institutional, have been utilized historically in health promotion and disease prevention efforts and are a valuable ally for public health, an alliance that continues under the Obama Administration. This paper outlines the history and mission of the Office; details the recent history of federal faith-based initiatives; and advocates an expanded alliance between the faith-based and public health sectors sensitive to legal and professional boundaries.

HIV and pulmonary hypertension


AIDS. 2012 Jan 4. [Epub ahead of print]
Cardiopulmonary function in individuals with HIV infection in the antiretroviral therapy era.
Morris A, Gingo MR, George MP, Lucht L, Kessinger C, Singh V, Hillenbrand M, Busch M, McMahon D, Norris KA, Champion HC, Gladwin MT, Zhang Y, Steele C, Sciurba FC.

To determine relationship of echocardiographic measures of pulmonary hypertension to lung function and inflammatory biomarkers in HIV-infected individuals.

Cross-sectional study of 116 HIV-infected outpatients.

Doppler-echocardiography and pulmonary function testing were performed. Induced sputum and plasma cytokines, sputum cell counts and differentials, markers of peripheral T cell activation, and serum N-terminal pro-brain natriuretic peptide (NT-proBNP) were measured. Univariate and multivariate analyses determined relationship of echocardiographic variables to pulmonary function, inflammation, and NT-proBNP.
Mean estimated pulmonary artery systolic pressure (PASP) was 34.3 mmHg (SD 6.9) and mean tricuspid regurgitant jet velocity (TRV) was 2.5 m/sec (SD 0.32). Eighteen participants (15.5%) had PASP of at least 40 mmHg, and 9 (7.8%) had TRV of at least 3.0 m/sec. Elevated TRV was significantly associated with CD4 cell counts below 200 cells/μl and higher log HIV RNA levels. Forced expiratory volume in one second (FEV1) percent predicted, FEV1/forced vital capacity (FVC), and diffusing capacity for carbon monoxide (DLco) percent predicted were significantly lower in those with elevated PASP or TRV. Sputum interleukin-8, peripheral interleukin-8, peripheral interferon-γ levels, and CD8+ T-cell expression of CD69+ were associated increased with increasing PASP and TRV. Log NT-proBNP was significantly higher with increasing PASP and TRV. Left ventricular function was not associated with PASP or TRV.

Echocardiographic manifestations of pulmonary hypertension are common in HIV and are associated with respiratory symptoms, more advanced HIV disease, airway obstruction, abnormal DLco, and systemic and pulmonary inflammation. Pulmonary hypertension and COPD coexist in HIV and may arise secondary to common inflammatory mechanisms.

From Michael Matthay and colleagues: Transfusion-related acute lung injury


Blood. 2011 Nov 23. [Epub ahead of print]
Transfusion related acute lung injury: incidence and risk factors.
Toy P, Gajic O, Bacchetti P, Looney MR, Gropper MA, Hubmayr R, Lowell CA, Norris PJ, Murphy EL, Weiskopf RB, Wilson G, Koenigsberg M, Lee D, Schuller R, Wu P, Grimes B, Gandhi MJ, Winters JL, Mair D, Hirschler N, Sanchez Rosen R, Matthay MA.
University of California, San Francisco, San Francisco, CA, United States;

Transfusion-related acute lung injury (TRALI) is the leading cause of transfusion-related mortality. To determine TRALI incidence by prospective, active surveillance and to identify risk factors by a case-control study, two academic medical centers enrolled 89 cases and 164 transfused controls. Recipient risk factors identified by multivariate analysis were higher interleukin-8 levels, liver surgery, chronic alcohol abuse, shock, higher peak airway pressure while being mechanically ventilated, current smoking and positive fluid balance. Transfusion risk factors were receipt of plasma or whole blood from female donors (OR 4.5, 95% CI 1.85 to 11.2, p=0.001), volume of HLA Class II antibody with NBG > 27.5, (OR 1.92 per 100 mL, 95% CI 1.08 to 3.4, p=0.03), and volume of anti-HNA positive by GIFT (OR=1.71 per 100 mL, 95% CI 1.18 to 2.5, p=0.004). Little or no risk was associated with older red blood cell units, non-cognate or weak cognate Class II antibody, or Class I antibody. Reduced transfusion of plasma from female donors was concurrent with reduced TRALI incidence: 2.57 (95% CI 1.72 to3.86) in 2006 vs. 0.81 (95% CI 0.44 to1.49) in 2009 per 10,000 transfused units (p = 0.002). The identified risk factors provide potential targets for reducing residual TRALI.

From Pediatrics: Screening Newborns for Cystic Fibrosis


Pediatrics. 2012 Jan 16. [Epub ahead of print]
Comparison of the US and Australian Cystic Fibrosis Registries: The Impact of Newborn Screening.
Martin B, Schechter MS, Jaffe A, Cooper P, Bell SC, Ranganathan S.

aDepartment of Respiratory Medicine, Sydney Children's Hospital, Randwick, New South Wales, Australia;

National data registries for cystic fibrosis (CF) enable comparison of health statistics between countries. We examined the US and Australian CF data registries to compare demographics, clinical practice and outcome measures.

We compared the 2003 US and Australian registries. Differences in pulmonary and growth outcomes were assessed by creating models controlling for differences in age, gender, genotype, and diagnosis after newborn screening.

Data on 12 994 US and 1220 Australian patients aged ≤18 years were analyzed. A significant difference was noted in the proportion who had been diagnosed after newborn screening (Australian 65.8% vs United States 7.2%; P < .001). Australian children had significantly greater mean height percentile (41.0 vs 32.6; P < .001) and weight percentile (43.5 vs 36.1; P = .028) than US children. Mean forced expiratory volume in 1 second (FEV(1)) percent predicted adjusted for age, gender, and genotype was similar in the 2 countries (P = .80). Patients diagnosed after newborn screening had higher mean FEV(1) (5.3 [95% confidence interval (CI): 3.6-7.0]) percent predicted and BMI (0.26 [95% CI: 0.09-0.43]). Mean FEV(1) of Australian patients diagnosed after newborn screening was lower by 5.2 (95% CI: 2.8-7.6) percent predicted compared with US children.

Children diagnosed with CF after newborn screening benefited from better lung function and BMI than those diagnosed clinically. The benefit of newborn screening on lung function was significantly less in Australian children compared with US children. Statistical comparisons between CF registries are feasible and can contribute to benchmarking and improvements in care.

Toward better ER patient transfer communication


J Rural Health. 2012 Jan;28(1):44-53. doi: 10.1111/j.1748-0361.2011.00374.x. Epub 2011 Mar 31.
Development and testing of emergency department patient transfer communication measures.
Klingner J, Moscovice I.
Rural Health Research Center, Division of Health Policy and Management, School of Public Health, University of Minnesota, Minneapolis, Minnesota Labovitz School of Business and Economics, University of Minnesota Duluth, Duluth, Minnesota.
Communication problems are a major contributing factor to adverse events in hospitals.(1) The contextual environment in small rural hospitals increases the importance of emergency department (ED) patient transfer communication quality. This study addresses the communication problems through the development and testing of ED quality measurement of interfacility patient transfer communication.

Input from existing measures, measurement and health care delivery experts, as well as hospital frontline staff was used to design and modify ED quality measures. Three field tests were conducted to determine the feasibility of data collection and the effectiveness of different training methods and types of partnerships. Measures were evaluated based on their prevalence, ease of data collection, and usefulness for internal and external improvement.

Findings: It is feasible to collect ED quality measure data. Different data sources, data collection, and data entry methods, training and partners can be used to examine hospital ED quality. There is significant room for improvement in the communication of patient information between health care facilities.

Current health care reform efforts highlight the importance of clear communication between organizations held accountable for patient safety and outcomes. The patient transfer communication measures have been tested in a wide range of rural settings and have been vetted nationally. They have been endorsed by the National Quality Forum, are included in the National Quality Measurement Clearinghouse supported by the Agency for Health Care Research and Quality (AHRQ), and are under consideration by the Centers for Medicare and Medicaid Services for future payment determinations beginning in calendar year 2013.

From the American Hospital Association: Hospitals of the Future


World Hosp Health Serv. 2011;47(3):15-9.
Hospitals of the future.
Umbdenstock RJ, Joshi MS, Seidman J.
American Hospital Association, USA.

Hospitals and health systems face unprecedented demand to change in both the near- and longer-term future, ranging from demographic changes to increasing reliance on value-based payment, and to the uncertainty surrounding governmental reform. the American Hospital Association Board Committee on Performance Improvement embarked on an initiative to identify the top ten strategies all hospitals must adopt in order to be successful care systems of the future. As a result of the committee's survey research, four top strategies were identified: (1) Aligning hospitals, physicians, and other providers across the continuum of care; (2) Using evidenced-based practices to improve quality and patient safety; (3) Improving efficiency through productivity and financial management; and (4) Developing integrated information systems. This article summarizes ten strategies and the measures to assess the accomplishment of these strategies.

From NEJM: Health Care Reform Predictions for the New Year


N Engl J Med. 2012 Jan 11. [Epub ahead of print]
The Fate of Health Care Reform ? What to Expect in 2012.
Jones DK.
From the Department of Health Management and Policy and the Department of Political Science, University of Michigan, Ann Arbor.
The Patient Protection and Affordable Care Act of 2010 (ACA) is arguably the most significant health legislation enacted in generations. As remarkable a political and policy achievement as it was, what the reform will actually accomplish is largely yet to be determined. Whether it slows the growth of costs, increases access to care, or improves the quality of care will depend on how it is implemented. Although major components of the law do not go into effect until 2014, the fate of the ACA depends on the outcome of four key events in 2012.

From Bryan Liang: Biosimilars


Ther Clin Risk Manag. 2011;7:489-93. Epub 2011 Dec 7.
Emerging patient safety issues under health care reform: follow-on biologics and immunogenicity.
Liang BA, Mackey T.
Institute of Health Law Studies, California Western School of Law, San Diego, CA, USA.

US health care reform includes an abbreviated pathway for follow-on biologics, also known as biosimilars, in an effort to speed up access to these complex therapeutics. However, a key patient safety challenge emerges from such an abbreviated pathway: immunogenicity reactions. Yet immunogenicity is notoriously difficult to predict, and even cooperative approaches in licensing between companies have resulted in patient safety concerns, injury, and death. Because approval pathways for follow-on forms do not involve cooperative disclosure of methods and manufacturing processes by innovator companies and follow-on manufacturers, the potential for expanded immunogenicity must be taken into account from a risk management and patient safety perspective. The US Institute of Safe Medication Practices (ISMP) has principles of medication safety that have been applied in the past to high-risk drugs. We propose adapting ISMP principles to follow-on biologic forms and creating systems approaches to warn, rapidly identify, and alert providers regarding this emerging patient safety risk. This type of system can be built upon and provide lessons learned as these new drug forms are developed and marketed more broadly.

From Family Medicine: "a continual process of stigmatization"


Fam Med. 2012 Jan;44(1):39-46.
Why do some eligible families forego public insurance for their children? A qualitative analysis.
Devoe JE, Westfall N, Crocker S, Eigner D, Selph S, Bunce A, Wallace L.

Department of Family Medicine, Oregon Health & Science University.

Central to health insurance reform discussions was the recurring question: why are eligible children not enrolled in public insurance programs? We interviewed families with children eligible for public insurance to (1) learn how they view available services and (2) understand their experiences accessing care.
Semi-structured, in-depth interviews with 24 parents of children eligible for public coverage but not continuously enrolled were conducted. We used a standard iterative process to identify themes, followed by immersion/crystallization techniques to reflect on the findings.

Respondents identified four barriers: (1) confusion about insurance eligibility and enrollment, (2) difficulties obtaining public coverage and/or services, (3) limited provider availability, and (4) non-covered services and/or coverage gaps. Regardless of whether families had overcome these barriers, all had experienced stigma associated with needing and using public assistance. There was not just one point in the process where families felt stigmatized. It was, rather, a continual process of stigmatization. We present a theoretical framework that outlines how families continually experience stigma when navigating complex systems to obtain care: when they qualify for public assistance, apply for assistance, accept the assistance, and use the public benefit. This framework is accompanied by four illustrative archetypes.

This study provides further insight into why some families forego available public services. It suggests the need for a multi-pronged approach to improving access to health care for vulnerable children, which may require going beyond incremental changes within the current system.

From J Pediatric Surgery: Maintaining quality under the PPACA


J Pediatr Surg. 2012 Jan;47(1):1-9.
Health care quality, access, cost, workforce, and surgical education: the ultimate perfect storm.
Schwartz MZ.

The discussions on health care reform over the past two years have focused on cost containment while trying to maintain quality of care. Focusing on just cost and quality unfortunately does not address other very important factors that impact on our health care delivery system. Availability of a well-trained workforce, maintaining the sophisticated medical/surgical education system, and ultimately access to quality care by the public are critical to maintaining and enhancing our health care delivery system. Unfortunately, all five of these components are under at risk. Thus, we have evolving the ultimate perfect storm affecting our health care delivery system. Although not ideal and given the uniqueness of our population and their expectations, our current delivery system is excellent compared to other countries. However, the cost of our current system is rising at an alarming rate. Currently, health care consumes 17% of our gross domestic product. If our system is not revised this will continue to rise and by 2025 it will consume 48%. The dilemma, given the current state of our overall economy and rising debt, is how to address this major problem. Unfortunately, the Affordable Care Act, which is now law, does not address most of the issues and the cost was initially grossly under estimated. Furthermore, the law does not address the issues of workforce, maintaining our medical education system or ultimately, access. A major revision of our system will be necessary to truly create a system that protects and enhances all five of the components of our health care delivery system. To effectively accomplish this will require addressing those issues that lead to wasteful spending and diversion of our health care dollars to profit instead of care. Improved and efficient delivery systems that reduce complications, reduction of duplication of tertiary and quaternary programs or services within the same markets (i.e. regionalization of care), health insurance reform, and tort reform collectively could save hundreds of billion dollars per year! These changes may not be easy to accomplish politically but will be essential to save what is likely the best health care system in the world.

ADR for med mal: NPDB reporting is the deal-killer


Clin Orthop Relat Res. 2011 Dec 13. [Epub ahead of print]
Medical Malpractice Reform: The Role of Alternative Dispute Resolution.
Sohn DH, Sonny Bal B.

Department of Orthopaedic Surgery, University of Toledo Medical Center, 3000 Arlington Avenue, Toledo, OH, 43551, USA, david.sohn@utoledo.edu.

Alternative dispute resolution (ADR) refers to techniques used to resolve conflicts without going to the courtroom. As healthcare and malpractice costs continue to rise, there is growing interest in tactics such as early apology, mediation, and arbitration in the medical arena.

(1) Why is ADR needed? (2) Is ADR useful in health care? (3) What are the current legal and political developments favoring ADR? (4) What obstacles remain?
We performed MEDLINE, PubMed, and Google Scholar searches with key words "medical malpractice", "ADR", and "alternative dispute resolution" to obtain public policy studies, law review articles, case analyses, ADR surveys, and healthcare review articles.

Early apology and disclosure programs report 50% to 67% success in avoiding litigation as well as substantial reductions in the amount paid per claim. Mediation boasts 75% to 90% success in avoiding litigation, cost savings of $50,000 per claim, and 90% satisfaction rates among both plaintiffs and defendants. Arbitration is viewed as less satisfying and less efficient than mediation but still more time- and cost-effective than litigation. The current legal environment is favorable to ADR with recent court decisions upholding pretreatment arbitration clauses. The main obstacle to ADR is the mandatory reporting requirement of the National Practitioner Data Bank (NPDB).

ADR has the potential to help reform the current tort system, reducing cost and increasing both parties' satisfaction. Easing the reporting requirements for the NPDB would lead to more widespread acceptance of ADR among physicians.

From Gene Mark and colleagues: ROS1 rearrangements and lung cancer


J Clin Oncol. 2012 Jan 3. [Epub ahead of print]
ROS1 Rearrangements Define a Unique Molecular Class of Lung Cancers.
Bergethon K, Shaw AT, Ignatius Ou SH, Katayama R, Lovly CM, McDonald NT, Massion PP, Siwak-Tapp C, Gonzalez A, Fang R, Mark EJ, Batten JM, Chen H, Wilner KD, Kwak EL, Clark JW, Carbone DP, Ji H, Engelman JA, Mino-Kenudson M, Pao W, Iafrate AJ.

Kristin Bergethon, Alice T. Shaw, Ryohei Katayama, Eugene J. Mark, Julie M. Batten, Eunice L. Kwak, Jeffrey W. Clark, Jeffrey A. Engelman, Mari Mino Kenudson, and A. John Iafrate, Massachusetts General Hospital, Boston, MA; Sai-Hong Ignatius Ou and Christina Siwak-Tapp, Chao Family Comprehensive Cancer Center, University of California Irvine Medical Center, Orange; Keith D. Wilner, Pfizer, La Jolla, CA: Christine M. Lovly, Nerina T. McDonald, Pierre P. Massion, Adriana Gonzalez, David P. Carbone, and William Pao, Vanderbilt University Medical Center; Pierre P. Massion, Nashville Veterans Affairs Medical Center, Nashville, TN; Rong Fang and Hongbin Ji, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences; Haiquan Chen, Fudan University Shanghai Cancer Center; and Haiquan Chen, Shanghai Medical College, Fudan University, Shanghai, China.

Chromosomal rearrangements involving the ROS1 receptor tyrosine kinase gene have recently been described in a subset of non-small-cell lung cancers (NSCLCs). Because little is known about these tumors, we examined the clinical characteristics and treatment outcomes of patients with NSCLC with ROS1 rearrangement.

Using a ROS1 fluorescent in situ hybridization (FISH) assay, we screened 1,073 patients with NSCLC and correlated ROS1 rearrangement status with clinical characteristics, overall survival, and when available, ALK rearrangement status. In vitro studies assessed the responsiveness of cells with ROS1 rearrangement to the tyrosine kinase inhibitor crizotinib. The clinical response of one patient with ROS1-rearranged NSCLC to crizotinib was investigated as part of an expanded phase I cohort.

Of 1,073 tumors screened, 18 (1.7%) were ROS1 rearranged by FISH, and 31 (2.9%) were ALK rearranged. Compared with the ROS1-negative group, patients with ROS1 rearrangements were significantly younger and more likely to be never-smokers (each P < .001). All of the ROS1-positive tumors were adenocarcinomas, with a tendency toward higher grade. ROS1-positive and -negative groups showed no difference in overall survival. The HCC78 ROS1-rearranged NSCLC cell line and 293 cells transfected with CD74-ROS1 showed evidence of sensitivity to crizotinib. The patient treated with crizotinib showed tumor shrinkage, with a near complete response.

ROS1 rearrangement defines a molecular subset of NSCLC with distinct clinical characteristics that are similar to those observed in patients with ALK-rearranged NSCLC. Crizotinib shows in vitro activity and early evidence of clinical activity in ROS1-rearranged NSCLC.

Predictors of response to targeted therapies for GI stromal tumors


Arch Pathol Lab Med. 2012 Jan 9. [Epub ahead of print]
Predictors of Response to Targeted Therapies for Gastrointestinal Stromal Tumors.
Marrari A, Wagner AJ, Hornick JL.

Context.-The inhibition of oncogenic kinase signaling is a successful strategy to treat both hematologic and solid malignancies. Patients with chronic myelogenous leukemia, lung adenocarcinoma, renal cell carcinoma, and gastrointestinal stromal tumors are experiencing tremendous clinical benefits from targeted therapies in the form of kinase inhibitors. These drugs marked a revolution in cancer treatment, not only for their safety and efficacy, but also because they continue to expand our knowledge of the pathophysiology of cancer. Objective.-To provide a summary of the biologic predictors of gastrointestinal stromal tumor behavior and response to targeted therapies that currently help guide clinical decision making. Data Sources.-Published articles pertaining to the diagnosis, molecular genetics, prognostication, clinical behavior, and treatment of gastrointestinal stromal tumors, as well as experiences in a multidisciplinary sarcoma clinic. Conclusions.-In gastrointestinal stromal tumors, the strongest predictor of response to targeted therapies is the mutational status of KIT or PDGFRA. Patients whose tumors harbor a KIT exon 11 mutation benefit the most from imatinib mesylate therapy, in terms of response rate, progression-free survival, and overall survival. Conversely, tumors without detectable mutations in either gene ("wild-type" gastrointestinal stromal tumors) are generally not responsive to imatinib mesylate.

From Bill Travis at Sloan-Kettering: Update on small cell lung cancer


Mod Pathol. 2012 Jan;25 Suppl 1:S18-30. doi: 10.1038/modpathol.2011.150.
Update on small cell carcinoma and its differentiation from squamous cell carcinoma and other non-small cell carcinomas.
Travis WD.

Department of Pathology, Attending Thoracic Pathologist, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Small cell lung cancer (SCLC) comprises 14% of all lung cancers, and >30 000 new cases are diagnosed per year in the United States. SCLC is one of the most distinctive malignancies in the entire field of oncology with characteristic clinical properties, responsiveness to specific chemotherapy, genetic features and a highly reliable pathological diagnosis. SCLC is defined by light microscopy, and the most important stain is a good-quality hematoxylin and eosin (H&E)-stained section. The vast majority of cases can be diagnosed on H&E alone; however, in problem cases, immunohistochemistry can be very helpful in making the distinction from other tumors. Cytology is also a powerful tool, often being more definitive than small biopsies with scant tumor cells, crush artifact and/or necrosis. As virtually all SCLCs present in advanced stages, most patients are diagnosed based on small biopsy and cytology specimens. Historically, there has been significant evolution in the histological subclassification of SCLC dating from 1962 when Kreyberg proposed the oat cell and polygonal cell types. The current subclassification recognizes only two subtypes: pure SCLC and combined SCLC. Pathologists need to do their best to make a diagnosis of SCLC or other histological types of lung cancer and this can be achieved in most cases. This review will address some of the diagnostic problems that occur in the minority of cases and outline practical ways to address them. Brief reference will be made to other neuroendocrine lung tumors with an overview of the molecular pathogenesis of this spectrum of tumors.

From Seoul Natl U: Chemotherapy and brain metastases


Prog Neurol Surg. 2012;25:110-4. Epub 2012 Jan 6.
Role of chemotherapy on brain metastasis.
Lee SH.

Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea.

Cytotoxic chemotherapy has been considered ineffective for brain metastasis, traditionally because of poor penetration across the blood-brain barrier. However, cytotoxic chemotherapy could be effective in some specific situation, e.g. macroscopic brain metastasis of chemosensitive disease, such as small cell lung cancer, germ cell tumor and breast cancer. Recently, tyrosine kinase inhibitors targeting epidermal growth factor receptor (EGFR) (gefitinib and erlotinib) or human epidermal growth factor receptor 2 (HER2) (lapatinib) have a promising activity to brain metastasis of lung cancer with activating EGFR mutations or breast cancer with HER2 over expression. More molecular targeting agents will also be used against brain metastasis with the advance of understanding of molecular mechanism of cancer.

From Wistuba and colleagues: KRAS and Lung Cancer


J Natl Cancer Inst. 2012 Jan 13. [Epub ahead of print]
Effect of KRAS Oncogene Substitutions on Protein Behavior: Implications for Signaling and Clinical Outcome.

Ihle NT, Byers LA, Kim ES, Saintigny P, Lee JJ, Blumenschein GR, Tsao A, Liu S, Larsen JE, Wang J, Diao L, Coombes KR, Chen L, Zhang S, Abdelmelek MF, Tang X, Papadimitrakopoulou V, Minna JD, Lippman SM, Hong WK, Herbst RS, Wistuba II, Heymach JV, Powis G.

Affiliations of authors: Department of Experimental Therapeutics (NTI, LC, SZ, MFA, GP), Department of Thoracic Head and Neck Medical Oncology (LAB, ESK, PS, GRB, AT, XT, VP, SML, WKH, RSH, IIW, JVH), Department of Biostatistics (JJL, SL, JW, LD, KRC), and Department of Pathology (IIW); The Hamon Center for Therapeutic Oncology Research and Simmons Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX (JEL, JDM).

Mutations in the v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) play a critical role in cancer cell growth and resistance to therapy. Most mutations occur at codons 12 and 13. In colorectal cancer, the presence of any mutant KRas amino acid substitution is a negative predictor of patient response to targeted therapy. However, in non-small cell lung cancer (NSCLC), the evidence that KRAS mutation is a predictive factor is conflicting.

We used data from a molecularly targeted clinical trial for 215 patients with tissues available out of 268 evaluable patients with refractory NSCLC to examine associations between specific mutant KRas proteins and progression-free survival and tumor gene expression. Transcriptome microarray studies of patient tumor samples and reverse-phase protein array studies of a panel of 67 NSCLC cell lines with known substitutions in KRas and in immortalized human bronchial epithelial cells stably expressing different mutant KRas proteins were used to investigate signaling pathway activation. Molecular modeling was used to study the conformations of wild-type and mutant KRas proteins. Kaplan-Meier curves and Cox regression were used to analyze survival data. All statistical tests were two-sided.

Patients whose tumors had either mutant KRas-Gly12Cys or mutant KRas-Gly12Val had worse progression-free survival compared with patients whose tumors had other mutant KRas proteins or wild-type KRas (P = .046, median survival = 1.84 months) compared with all other mutant KRas (median survival = 3.35 months) or wild-type KRas (median survival = 1.95 months). NSCLC cell lines with mutant KRas-Gly12Asp had activated phosphatidylinositol 3-kinase (PI-3-K) and mitogen-activated protein/extracellular signal-regulated kinase kinase (MEK) signaling, whereas those with mutant KRas-Gly12Cys or mutant KRas-Gly12Val had activated Ral signaling and decreased growth factor-dependent Akt activation. Molecular modeling studies showed that different conformations imposed by mutant KRas may lead to altered association with downstream signaling transducers.

Not all mutant KRas proteins affect patient survival or downstream signaling in a similar way. The heterogeneous behavior of mutant KRas proteins implies that therapeutic interventions may need to take into account the specific mutant KRas expressed by the tumor.