The Daily Sign-Out

CFTR: cystic fibrosis and beyond

Excellent recent review of the role of the cystic fibrosis transmembrane conductance regulator in cystic fibrosis.

http://erj.ersjournals.com/content/early/2014/06/12/09031936.00228013.abstract

Download WebPage.pdf

The Role of Vascular Endothelial Growth Factor in Pulmonary Arterial Hypertension: The Angiogenesis Paradox

Current review focusing on the enigmatic role of VEGF in the pathogenesis of pulmonary arterial hypertension from American Journal of Respiratory Cell and Molecular Biology published online last month.

Abstract

Pulmonary arterial hypertension (PAH) is characterized by dysfunctional angiogenesis leading to lung vessel obliteration. PAH is widely considered a pro-angiogenic disease, however, the role of angiogenic factors such as the vascular endothelial factor (VEGF) and its receptors in the pathobiology of PAH remains incompletely understood. This review attempts to untangle some of the complex multilayered actions of VEGF, in order to provide a VEGF-centered perspective of PAH. Furthermore, we provide a cogent explanation for the paradox of VEGF receptor blockade-induced pulmonary hypertension that characterizes the SU5416-hypoxia rat model of PAH and attempt to translate the knowledge gained from the experimental model to the human disease by postulating the potential role of endogenous (SU5416-like) VEGF inhibitors. The main objective of this review is to promote discussion and investigation of the opposing and complementary actions of VEGF in PAH. Understanding the balance between angiogenic and anti-angiogenic factors and their role in the pathogenesis of PAH will be necessary before anti-angiogenic drugs can be considered for the treatment of PAH.

http://www.atsjournals.org/doi/abs/10.1165/rcmb.2014-0045TR?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed#.U8xkMlYqT4E

Unopposed Cathepsin G, Neutrophil Elastase, and Proteinase 3 Cause Severe Lung Damage and Emphysema

Interesting abstract from American Journal of Pathology showing evidence for involvement of neutrophils serine proteinases in pathogenesis of emphysema.

Abstract

Cigarette smoking is a major factor for the development of pulmonary emphysema because it induces abnormal inflammation and a protease-rich local milieu that causes connective tissue breakdown of the lungs. As a result of its capacity to degrade lung tissue and the high risk of patients lacking α1-antitrypsin to develop emphysema, much interest has focused on neutrophil elastase (NE). Two similar neutrophil serine proteases (NSPs), cathepsin G and proteinase 3, coexist with NE in humans and mice, but their potential tissue-destructive role(s) remains unclear. Using a gene-targeting approach, we observed that in contrast to their wild-type littermates, mice deficient in all three NSPs were substantially protected against lung tissue destruction after long-term exposure to cigarette smoke. In exploring the underlying basis for disrupted wild-type lung air spaces, we found that active NSPs collectively caused more severe lung damage than did NE alone. Furthermore, NSP activities unleashed increased activity of the tissue-destructive proteases macrophage elastase (matrix metalloproteinase-12) and gelatinase B (matrix metalloproteinase-9). These in vivo data provide, for the first time, compelling evidence of the collateral involvement of cathepsin G, NE, and proteinase 3 in cigarette smoke–induced tissue damage and emphysema. They also reveal a complex positive feed-forward loop whereby these NSPs induce the destructive potential of other proteases, thereby generating a chronic and pathogenic protease-rich milieu.

http://ajp.amjpathol.org/article/S0002-9440(14)00276-4/abstract

Multifocal Micronodular Pneumocyte Hyperplasia Mimicking Miliary TB

Saturday morning interesting case report!

Download Multifocal pneumocyte hyperplasia mimicking miliary TB case report Lee 2014

 

SNAI1 functional variant associated with decreased risk for lung cancer

This is an abstract from the January 15, 2014 issue of American Journal of Respiratory and Critical Care Medicino that I just re-discovered this week and relates to one of my ongoing (and unrequited) obsession with epithelial-mesenchymal transition in lung cancer.

It appears that there are five major EMT regulatory genes (SNAI1, SLUG, ZEB1, ZEB2, and TWIST1) involved in EMT.  But--the relative contribution and importance of each of these genes in the development and progression of non-small cell lung cancer is not clear.

 This article adds another layer of complexity and I post it (rather belatedly) now because I find in it such an intriguing finding that a variant protein could have functional consequences that are observable as a clinical outcome with regard to COPD and NSCLC.  Moreover, this variant was discovered to attenuate Snai1’s ability to specifically up-regulate mesenchymal biomarkers (i.e., fibronectin and vimentin) expression, and to promote EMT-like changes, including morphologic changes, cell migration, and invasion.

Web-based Tool for Assessing Transfusion Reactions

The Hemovigilance Module of the CDC's National Healthcare Safety Network has an open access Web application for assessing transfusion reactions that is available at www.trddx.com.  This tool is based on the NHSN Hemovigilance Module Surveillance Protocol (itself an essential resource).  This would be especially useful for general pathologists who infrequently have to assess transfusion reactions.  This is also a wonderful educational tool for pathology residents and internal medicine residents rotating through hematology-oncology services.

Other features include a table showing which diagnoses have been ruled-in, excluded or not yet tested; optional questions for assigning severity and imputability for each diagnosis; a written summary with supporting evidence of which diagnoses were established as well as those that were excluded. Finally, the user has the ability to email the written summary as a PDF document. 

I've really come to rely on this as a final check on myself and a first reference to guide pathology residents through the evaluation of a transfusion reaction.

NHLBI Workshop Report: Matrix Biology in Idiopathic Pulmonary Fibrosis

The June 2014 issue of American Journal of Pathology has this state-of-the-art review, based on a recent NHBLI workshop, of the various attributes of the lung extracellular matrix and its role in normal lung and in the development of IPF.

This is an "open access' (FREE) article and you can get CME for it too!

Here's a choice figure that nicely summarizes the biochemical and mechanical interactions between the fibroblast and the ECM:

Major Driver Mutations in Adenosquamous Lung Carcinomas

The June 2014 issue of Journal of Thoracic Oncology (abstract) features a thorough study of major known driver mutations (EGFR, KRAS, ERBB2, BRAF, PIK3CA, AKT1, RET, and ALK) in a series of 76 patients from Fudan University Shanghai Cancer Center with resected adenosquamous lung carcinoma (AdSqLC) by Wang et al. and compared this group with a group of 646 patients with resected adenocarcinoma (ADC) during the same study period.  This is a nifty paper that will serve well as a useful contemporary reference when you next encounter a patient with adenosquamous lung carcinoma.

From their "Table 1" data, it is of note that they found significantly higher smokers in AdSqLC versus ADC.

Known mutant kinases were demonstrated in 57% (43/76) patients.  EGFR mutations were the most common found (32%, 24/76) but were significantly lower compared to the ADC "control" group.  EGFR mutation was significantly higher in never smokers compared to smokers as expected, but it is notable that the frequency of EGFR mutation was higher in glandular dominant AdSqLC than squamous dominant AdSqLC.  Other gene mutations were similar to those found in ADC.  While the frequency of driver mutations was similar between "classical" AdSqLC and poorly-differentiated ADC, the frequency of RET and ALK fusion genes was higher in solid growth glandular component-predominant AdSqLC versus classical AdSqLC.

Microdissection of 13 tumors showed the same mutation in both glandular and squamous components in 9 tumors but 4 of 13 cases showed mutations (KRAS-2, HER2, EGFR) only in the glandular component.

Survival data including 58 AdSqLC and 246 ADC patients showed no significant difference in relapse-free survival between classical AdSqLC, poorly-differentiated ADC, and solid-predominant AdSqLC.  Both classical- and solid-types AdSqLC showed worse overall survival compared to well- and moderately-differentiated ADC.

 

Ancient account of physician subspecialization

This is a follow-up to my recent post on Herodotus describing 6th-century BC Babylonians relying on "social networking" for health care.

In Book 2 of The Histories, Herodotus comments on Egyptian medicine (ca. 500 BC).  In opposition to Babylonian health care, Herodotus notes that in Egypt each physician just treats one illness.  He comments dryly that "Doctors are everywhere."

Hmmm.

Extratumoral lymphatic permeation as prognostic marker in NSCLC

Matsumura and colleagues from the National Cancer Center Hospital East in Chiba, Japan recently reported in the Journal of Thoracic Oncology (abstract) their study of the location of lymphatic permeation in relation to the tumor and the effect on outcome.

Since 2001, this group has been classifying lymphatic permeation in patients with resected NSCLC into 3 catagories: no lymphatic permeation (ly0), intratumoral permeation (ly1), and extratumoral permeation (ly2).  This is a follow-up to a previous study reported in 2007 that found that NSCLC patients with ly2 developed more recurrence than patients with ly1--but long-term follow-up was short.

A couple of practical notes from their methods--

All cut surfaces containing the main tumor were submitted for histology.  Victoria blue/van Gieson stain was performed on all tumor sections to evaluate for vascular invasion, lymphatic invasion, and pleural invasion and lymphatic invasion was confirmed by immunohistochemical staining for podoplanin (D2-40).

One thing that makes this study valuable is that 67% of patients included in this study were pT1, although it is noted that the median tumor size was 2.8 cm.  Another is that median follow-up was 85 months.

5-year overall survival (5yOS) was significantly worse for ly2 (34%) versus ly0 (75%) and ly1 (63%).  Both recurrence-free survival (RFS) and cancer-specific survival were also similarly worse between ly2 and ly0 and ly1 groups.  Similar significant results in 5yOS were also observed when analyzed by pStage I: ly0--83%, ly1--79%, ly2--47%.  But, unexpectedly (to me, anyhow), ly2 was still a significant prognostic factor in pStage II and pStageIII.

By multivariate analysis, worse 5yOS was associated with age ≥ 70, pT2-4, pN1-2, pleural invasion, intrapulmonary metastasis, vascular invasion, and ly2.  Notably, ly2 had a higher HR (1.73) than pT2-4 (1.37), pN1-2 (1.63), and VPI (1.62).

The authors show that extratumoral lymphatic permeation has a marked negative prognostic impact on the recurrence-free period, disease-free survival, and overall survival.  They opine that this feature should be evaluated for every case and included in the lung cancer staging system.