Fascinating article describing a vasculopathic cutaneous and pulmonary syndrome associated with autosomal dominant mutations in TMEM173, the gene encoding stimulator of interferon genes (STING). An incredible body of work presented with numerous clinical pictures and photomicrographs in the supplementary appendix that nicely illustrate the pathologic changes. This work sheds light on an important inflammatory pathway through the description of this "experiment of nature."
Liu Y, Jesus AA, Marrero B, et al. Activated STING in a Vascular and Pulmonary Syndrome. New England Journal of Medicine published online July 16, 2014.
Studies involving children with monogenic autoinflammatory disease have provided insights into the regulation of key proinflammatory cytokine pathways and their role in causing systemic and organ-specific inflammation.1,2 We studied six patients who presented in early infancy with systemic inflammation and violaceous, scaling lesions of fingers, toes, nose, cheeks, and ears that progressed to acral necrosis in most of the patients and did not respond to therapy. A mixed histologic pattern was observed, consisting of a prominent dermal inflammatory infiltrate with features of leukocytoclastic vasculitis and microthrombotic angiopathy of small dermal vessels. Three of the patients had severe interstitial lung disease.
Although many of the genetically defined autoinflammatory diseases are associated with increased interleukin-1 signaling and have a clinical response to interleukin-1 inhibition,2 interleukin-1–inhibiting therapy was ineffective in one of the patients. A prominent interferon-response-gene signature in the peripheral blood of this participant suggested interferon dysregulation similar to that seen in other genetically defined inflammatory syndromes, including the Aicardi–Goutières syndrome,3,4 an early-onset inflammatory encephalopathy, and chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE),5,6 a proteasome-associated autoinflammatory syndrome with proposed interferon-mediated pathologic features.7,8 We detected autosomal dominant mutations in TMEM173, the gene encoding the stimulator of interferon genes (STING), in the six children we assessed, who presented with a clinical syndrome we have called STING-associated vasculopathy with onset in infancy (SAVI).
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.
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.
Interesting abstract from American Journal of Pathology showing evidence for involvement of neutrophils serine proteinases in pathogenesis of emphysema.
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.
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.
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.
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:
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.