Germline Mutation of Bap1 Accelerates Development of Asbestos-Induced Malignant Mesothelioma
https://app.docwi.se/content/2179990/--
Sent from docwi.se – the personalized reading app for physicians on the iPad and iPhoneI decided to tackle The Histories by Herodotus this summer, after having enjoyed reading Thucydides' The Peloponnesian War last summer, and came across a fascinating description of Babylonian medicine by Herodotus in Book 1 that I connected with social networking via the Internet. In contrast to Thucydides, Herodotus, called "the father of history" by Cicero, has many little asides and colorful and curious descriptions of the people, places, and culture of the late 6th/early 5th century eastern Mediterranean and Near East world, his "Oikoumene" or inhabited world.
At 1.197, Herodotus states that the Babylonians did not use physicians, but instead took their sick into the public square and allowed people who either suffered the same illness or saw someone else who did to advise the sick person. Further, it was not considered acceptable by the Babylonians to just pass by a sick person or not ask what disease he had!
I imagine such a sick man or woman being bombarded and overwhelmed with all kinds of diagnoses and advice about how to rid themselves of whatever was ailing them--kind of like when patients go online and search for their "disease," signs, symptoms, lab results, etc., right?! I see a similar phenomenon with the myriad groups focused on patients with different syndromes and diseases. I'm certainly not disparaging these at all--they are extremely useful to patients, families, and caregivers and serve to not only a resources for information but support and advocacy. I just find it interesting and fascinating that an ancient group of people did pretty much the same thing over 2,500 years ago!
I thought this would be a nice re-entry into more regular blogging again after a bit of hiatus.
Hope to post more on a plethora of recent articles on lung pathology, cancer biology, and transfusion medicine soon.
Journal of Thoracic Oncology just issued a published ahead-of-print article that examined mutations of most frequent driver mutations seen in pulmonary adenocarcinomas in a series of 76 resected adenosquamous carcinomas of the lung.
This is an important study to note because it supports the recommendation by IASLC/ERS/ATS to send these tumors for molecular testing. Another interesting finding for pathologists is the finding of excess ALK mutations associated with those tumors with a solid pattern histologic subtype in the adenocarcinoma component.
Introduction: Genotyping for driver mutations is now routinely used to guide clinical care of patients with lung cancer. Adenosquamous lung carcinoma (AdSqLC) is a subtype of cancer that contains both adenocarcinoma and squamous cell carcinoma. However, the incidence, clinicopathologic characteristics, and prognostic implications of major driver mutations in AdSqLCs are not well established.
Methods: Seventy-six resected AdSqLCs and 646 lung adenocarcinomas were screened for known genetic alterations involving EGFR, ERBB2, KRAS, BRAF, PIK3CA, AKT1, RET, and ALK. Tumors showing acinar, lepidic, micropapillary, or papillary growth in glandular component were classified as classical AdSqLC.
Results: Of the 76 AdSqLCs, 43 (56.6%) harbored known mutant kinases, including 24 (31.6%) with EGFR mutations, eight (10.5%) with KRAS mutations, two (2.6%) with AKT1 (2.6%) mutations, one (1.3%) with ERBB2 insertion mutation, one (1.3%) with PIK3CA mutation, four (5.3%) with ALK fusions, and three (4%) with KIF5B-RET fusions. No mutation was found in BRAF. The mutational profiles and clinicopathologic characteristics of classical AdSqLC were strikingly similar to that of poorly differentiated adenocarcinoma. However, AdSqLCs with solid growth pattern in glandular component had high frequency of ALK or RET fusions and low EGFR mutation rate.
Conclusions: To our knowledge, this is the first comprehensive study investigating major oncogenic driver mutations in a large cohort of AdSqLC patients in a Chinese population. The findings suggest that it will be clinically valuable to investigate the growth pattern of glandular component in AdSqLCs.
Results of an NHBLI workshop from November, 2012 published in current American Journal of Respiratory and Critical Care Medicine (2014; Vol. 189, No. 2). Definitely worth reading the entire article, if you have any interest in ILDs.
Abstract
The median survival of patients with idiopathic pulmonary fibrosis (IPF) continues to be approximately 3 years from the time of diagnosis, underscoring the lack of effective medical therapies for this disease. In the United States alone, approximately 40,000 patients die of this disease annually. In November 2012, the NHLBI held a workshop aimed at coordinating research efforts and accelerating the development of IPF therapies. Basic, translational, and clinical researchers gathered with representatives from the NHLBI, patient advocacy groups, pharmaceutical companies, and the U.S. Food and Drug Administration to review the current state of IPF research and identify priority areas, opportunities for collaborations, and directions for future research. The workshop was organized into groups that were tasked with assessing and making recommendations to promote progress in one of the following six critical areas of research: (1) biology of alveolar epithelial injury and aberrant repair; (2) role of extracellular matrix; (3) preclinical modeling; (4) role of inflammation and immunity; (5) genetic, epigenetic, and environmental determinants; (6) translation of discoveries into diagnostics and therapeutics. The workshop recommendations provide a basis for directing future research and strategic planning by scientific, professional, and patient communities and the NHLBI.
In 2012, new publications in the Journal described both the predictive value of the new IFN-γ release assays for diagnosis of latent tuberculosis (TB), but also provided evidence that these new tests cannot be interpreted simply as positive or negative, as initially hoped. Surgical masks can reduce transmission of TB infection, but other measures such as state-wide implementation of targeted testing and treatment of latent TB or active case finding require substantial and sustained effort to successfully reduce TB morbidity and mortality. A quasiexperimental study revealed that a package of social interventions could substantially reduce risk of TB disease in heavily exposed (and infected) children in the preantibiotic era. A study in a high-TB burden setting suggested that a new rapid drug-susceptibility test for TB may be more practical for implementation than traditional culture-based phenotypic tests. And two studies of TB vaccines revealed that currently used bacillus Calmette-Guérin strains vary in their ability to affect correlates of immunogenicity, whereas a new candidate vaccine, MVA85A, was safe and immunogenic in adults. Studies of nontuberculous mycobacteria (NTM) described a rapid rise in the prevalence and spatial clustering of NTM in the United States over the past decade. Although risk factors for pulmonary NTM such as advanced age and low BMI are known, the mechanisms underlying infection and disease remain mysterious. Four studies of therapy of NTM disease highlighted the pressing need for well-designed international randomized controlled trials to improve our management of NTM disease.
Author disclosures are available with the text of this article at www.atsjournals.org.
Mary Mosquera, writing in Healthcare Finance News, outlines five broad challenges facing healthcare systems:
Among the biggest challenges that healthcare executives are confronted with this year are:
1. Pacing the shift to value-based models. Healthcare leaders continue to put infrastructure and governance practices in place to support value-based models even as providers still have significant fee-for-service revenue. However, many providers are concerned that they may be reaching a point at which the cost of building and maintaining their value-based organization is not supported by their fee-for-service reimbursement model.
2. Responding effectively to the economic dynamics of local markets. Health organizations that are migrating to value-based models must contend with the realities and limits of their local economies, the strategies of large employers for reducing their healthcare costs, concentration of the payer market and physician practice alignment.
3. Securing and growing market share. Gaining market share remains a big concern regardless of the pace of the payment model change. Providers must weigh market strategies, including consolidation and traditional and non-traditional partnership and strategic relationships, even as volume continues to drive a large share of revenue.
4. Developing alternative revenue streams. Health systems with cash reserves and strong margins are better positioned to make investments that are related to, but not necessarily directly in support of, their core patient care business. Investments that can supplement declining revenue from payers can include ambulatory care centers, telemedicine, business software development and pharmaceutical research.
5. Containing core operating costs. Health executives continue to seek approaches to rein in the costs of their core operations, reduce utilization through standardization, and manage care variations. Even high-performing organizations can obtain additional cost containment by taking a systems approach that is rigorous and transparent.
What are the implications for pathologists, especially those of us still in fee-for-service based groups? Since we are faced with these same challenges, how will we respond?
Speaking from my own recent experiences in both community hospital and academic medical center settings, pathologists are being increasingly asked to commit significant time and effort to intensively participate in reducing waste and improving appropriateness of care as it relates particularly to lab test utilization and blood utilization.
However, there is currently a disconnection between direct and specific compensation this involvement and the work involved. Hospitals improve their financial performance (more $$$) but these doesn't seem to be any simoleans coming our ways for the effort. As Ms. Mosquera reported in an article last year, only about 10% of payments to hospitals and providers are "value-based." Moreover, of these payments, less than half (43%) give providers financial incentives without risk by offering a potential bonus or added payment to support higher quality care, while 57% put providers at financial risk for their performance if they do not meet certain quality and cost goals. I wonder, "what's in it for me?" when we bill for clinical pathology professional component--and yet the hospitals are asking me to "lend" my expertise and support to help their bottom line and put my bottom out there to tell clinicans they can't have a certain expensive test or a (probably unnecessary) blood product. Oh yes, I'm also supposed to educate my clinical colleagues on appropriate test and blood utilization. I guess we're supposed to be happy that we get the measly "Part A" payment from the hospital? or just have a job?
Pathology groups also need to closely look at #2 through 5 and work through these just as the hospitals are. Unfortunately, the local markets and opportunities for growing market share have been distorted and hurt by condo labs carved out by GI, urology and dermatology groups, national labs hoovering up local groups' AP work below cost, and national-based specialty-based AP companies. With recent dramatic cuts to 88305 and 88342, there is some hope of getting some of this work back into the community but it may take awhile to play out. Meanwhile, baby needs a new pair of shoes.
Alternative revenue streams are a more realistic possibility but will require creativity on the part of leaders and managers of pathology groups. A few will grasp these opportunities. Most seems to have a deer in headlights look and hope to hang on until retirement.
Containing costs means reducing personnel for groups to me since most of our other costs are more-or-less fixed, unless groups stop offering a range of benefits and shift that onto employees and partners (probably without a compensatory change in salary).
In the words of George Bailey, "Potter's not selling! Potter's buying!"
Primary ciliary dyskinesia (PCD) is a genetically heterogeneous recessive disorder of motile cilia that leads to oto-sino-pulmonary diseases and organ laterality defects in approximately 50% of cases. The estimated incidence of PCD is approximately 1 per 15,000 births, but the prevalence of PCD is difficult to determine, primarily because of limitations in diagnostic methods that focus on testing ciliary ultrastructure and function. Diagnostic capabilities have recently benefitted from (1) documentation of low nasal nitric oxide production in PCD and (2) discovery of biallelic mutations in multiple PCD-causing genes. The use of these complementary diagnostic approaches shows that at least 30% of patients with PCD have normal ciliary ultrastructure. More accurate identification of patients with PCD has also allowed definition of a strong clinical phenotype, which includes neonatal respiratory distress in >80% of cases, daily nasal congestion and wet cough starting soon after birth, and early development of recurrent/chronic middle-ear and sinus disease. Recent studies, using advanced imaging and pulmonary physiologic assessments, clearly demonstrate early onset of lung disease in PCD, with abnormal air flow mechanics by age 6–8 years that is similar to cystic fibrosis, and age-dependent onset of bronchiectasis. The treatment of PCD is not standardized, and there are no validated PCD-specific therapies. Most patients with PCD receive suboptimal management, which should include airway clearance, regular surveillance of pulmonary function and respiratory microbiology, and use of antibiotics targeted to pathogens. The PCD Foundation is developing a network of clinical centers, which should improve diagnosis and management of PCD.
Although commonly thought of synonymous, or, at least, forming a spectrum, chronic bronchitis is distinct from COPD. This review focuses on the pathophysiology of chronic bronchitis and goblet cell hyperplasia and the association between small airways disease and worse outcomes in patients with COPD. A state-of-the-art review.
Chronic bronchitis (CB) is a common but variable phenomenon in chronic obstructive pulmonary disease (COPD). It has numerous clinical consequences, including an accelerated decline in lung function, greater risk of the development of airflow obstruction in smokers, a predisposition to lower respiratory tract infection, higher exacerbation frequency, and worse overall mortality. CB is caused by overproduction and hypersecretion of mucus by goblet cells, which leads to worsening airflow obstruction by luminal obstruction of small airways, epithelial remodeling, and alteration of airway surface tension predisposing to collapse. Despite its clinical sequelae, little is known about the pathophysiology of CB and goblet cell hyperplasia in COPD, and treatment options are limited. In addition, it is becoming increasingly apparent that in the classic COPD spectrum, with emphysema on one end and CB on the other, most patients lie somewhere in the middle. It is known now that many patients with severe emphysema can develop CB, and small airway pathology has been linked to worse clinical outcomes, such as increased mortality and lesser improvement in lung function after lung volume reduction surgery. However, in recent years, a greater understanding of the importance of CB as a phenotype to identify patients with a beneficial response to therapy has been described. Herein we review the epidemiology of CB, the evidence behind its clinical consequences, the current understanding of the pathophysiology of goblet cell hyperplasia in COPD, and current therapies for CB.
I'm a pathologist interested in pulmonary pathology and transfusion medicine.
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