The Daily Sign-Out

Abstracts and Posters Accepted Now for Pathology Visions 2012

As a courtesy to the Digital Pathology Association, I am passing along this information regarding the 2012 Pathology Visions conference in Baltimore, Maryland from October 28-31, 2012.  Please consider submitting an abstract for oral presentation and/or poster presentation.  This is a great conference to attend!

  

ABSTRACT SUBMISSION DEADLINE FOR PATHOLOGY VISIONS 2012 APPROACHING

What’s the best way to stay in the loop on the most pressing and intriguing topics in the field of digital pathology? By attending and speaking at the Digital Pathology Association’s (DPA) annual meeting, Pathology Visions.

Pathology Visions will be held October 28 – 31, 2012 at the Hilton Baltimore. The Pathology Visions Conference will give you the opportunity to present and learn about real world, practical applications in the ever evolving field of digital pathology. In addition, Pathology Visions will give you direct access to industry leaders, the opportunity to earn CME credits, your choice of cutting-edge workshops with distinguished trade visionaries, the chance to see the latest product solutions, and much more!

The DPA is currently accepting oral presentation abstracts and poster presentation abstracts. The oral abstracts, submissions which provide researchers the opportunity to present for 30 minutes on a topic related to digital pathology, will be due on June 1, 2012. The poster presentation abstracts, allowing attendees the opportunity to display a poster for two days during Pathology Visions, will be due August 1, 2012.

Submitted abstracts will be reviewed by the Pathology Visions Program Committee and chosen presenters will be provided a conference registration pass (valued at $699), economy class round trip airfare, and lodging expenses for a maximum of 3 nights (October 28 - 31) at the host hotel.

Accepted presenters will be notified by June 15, 2012. To submit your abstract please now please click here. For more information regarding Pathology Visions please click here.

 

About the DPA

The Digital Pathology Association, located in Indianapolis, IN, was founded in 2009. Its mission is to facilitate education and awareness of digital pathology applications in healthcare and life sciences. Members will be encouraged to share best practices and promote the use of technology among colleagues in order to demonstrate efficiencies, awareness, and its ultimate benefits to patient care.

 

New proposal for histological grading in colorectal carcinoma

I find it surprising that histological grading for two of the most common adult malignancies--colon and lung--lacks any kind of consensus criteria for grading elements let alone clinical validation as a prognostic marker.  I have previously blogged on proposals for grading for lung adenocarcinoma but the February 2012 issue of American Journal of Surgical Pathology has an intriguing proposal for criteria for grading of colorectal cancer by Hideki Ueno et al. (abstract).

I am most familiar with Dr. Ueno's previous work on tumor budding in colon cancer (you should be too!) and this work builds on and expands on this work.  In contrast to tumor budding, defined as invasive single cells and/or clusters with <5 cells, this work describes and defines the significance of "poorly differentiated clusters" for grading.  Poorly differentiated clusters are defined by these authors as "cancer clusters in the stroma composed of >5 cancer cells and lacking a gland-like structure."  These clusters are identified at low power and then counted per 20X (1-mm diameter) field.  The color illustrations included in the text are particularly well-selected and beautifully reproduced.  Grading was also assessed independently by assessing quantitatively the area of the tumor involved by poorly differentiated clusters and by tumor budding.

Although this is a single institution study, it included 500 consecutive patients with stage 2 or stage 3 CRC who underwent curative resection and had follow-up on 97% (!) of these patients (483 patients) for a median of 68 months for the 378 surviving patients.

Three things stand out from the results.  First, there was excellent separation in 5-Year DFS using quantity of poorly differentiated clusters as the criterion for grading: grade 1--96%, grade 2--85%, grade 3--59%.  Second, tumor grading based on poorly differentiated clusters, T and N stages, and venous invasion were independent prognostic parameters related to survival on mutlivariate analysis.  FInally, the authors measured intra- and inter-observer variability in tumorg grading based on poorly differentiated clusters.

This is an interesting and status quo-challenging article that should provoke some good discussion amongst GI specialist and general pathologists.

The new IASLC/ATS/ERS Lung Adencarcinoma Classification is a Stage-Independent Predictor of Survival

 I blogged on this new classification over a year ago when it was first published, but now papers are rolling out showing its utility.  My take on this recent paper below is that it confirms the idea of histologically grading lung ADC according to the predominant different subtypes (lepidic predominant grade 1 "well-differentiated" versus solid predominant being grade 3 "poorly-differentiated".  Moreover, it asserts that it is sufficient to regard only the predominant histologic type with regard to survival--which is a relief from going through the tedious task of estimating percentages of different minor subtypes after complete histologic examination.  Get this article--good for discussion with surgeons, oncologists, tumor conference, etc. 

The Novel Histologic International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society Classification System of Lung Adenocarcinoma Is a Stage-Independent Predictor of Survival.

New biomarkers for mesothelioma

Today is a first for this blog--a guest post!  I recently was contacted by Danielle DiPietro, National Awareness Director for the Mesothelioma Center at Asbestos.com to see if I might be interested in a guest blog.  What follows is a brief review of new biomarkers for mesothelioma.  It seems that the search for novel (and better) biomarkers for mesothelioma, especially for early diagnosis and pathological confirmation, has been going on for years.  It has.  And mesothelioma hasn't gotten any easier to diagnose.  And it continues to be have a miserable prognosis.  Michelle Llamas, a writer for the Mesothelioma Center, wrote what follows and I hope that you all find this informative.  I invite you, whether you may be a physician, patient, or interested person to explore their Website--I find it very informative and hopeful.  On behalf of the Mesothelioma Center and myself, we would appreciate any comments that you might generously offer.

New Mesothelioma Biomarkers

Mesothelioma remains incredibly difficult to diagnose and treat. While a biopsy is the most accurate method of diagnosing mesothelioma, biomarkers are being researched for the purposes of improving early stage diagnosis and for evaluating the effectiveness of treatment.

There are several mesothelioma biomarkers currently being studied. Each biomarker is tested for sensitivity and specificity in detecting the mesothelioma cancer cells. Some of the current markers include:

• BerEp4
• CA-125
• calretinin (CALB2)
• cytokeratin 5
• epithelial membrane antigen (EMA)
• GLUT-1
• megakaryocyte potentiating factor (MKPF)
• mesothelin
• MOC-31
• osteopontin (OPN)
• thrombomodulin

According to a panel of expert pathologists from the International Mesothelioma Interest Group, guidelines for diagnosing mesothelioma and differentiating it from adenocarcinoma or other tumors requires use of a marker with a sensitivity of 80 percent or more. Unfortunately, the majority of biomarkers lack sensitivity. Some research suggests using a combination of biomarkers to achieve better sensitivity and specificity.

In recent studies mesothelin and CA-125 have proven to be among the most promising biomarkers with implications for both diagnosis and treatment.

Mesothelin

Perhaps one of the most significant recent developments in biomarker research has been the discovery of elevated mesothelin levels in malignant mesothelioma patients. Found in normal mesothelial cells, mesothelin is a cell-surface glycoprotein.

In studies that compared mesothelin to osteopontin and megakaryocyte potentiating factor, mesothelin was found to be the best biomarker for mesothelioma.

Assays of mesothelin may be used as an indicator of disease progression since higher levels of this marker are present in more advanced stages of the disease. Testing for mesothelin levels in a patient’s blood cannot currently replace biopsy or cytologic diagnosis, but this type of testing may be applicable when a patient’s health precludes them as a biopsy candidate.

CA-125

CA-125 is an antigen that is shed by tumors. Though this marker has no benefit in differentiating mesothelioma from other forms of cancer, several studies have shown that it can be valuable as a method to gauge effectiveness of treatments as well as track the progression of the disease.

In a study of patients that underwent debulking surgery, the levels of CA-125 fell sharply in contrast to those who did not undergo the surgery. Furthermore, levels of the marker increased in patients who developed progressive disease after surgery and other treatments.

Advances in Mesothelioma Treatment Using Biomarkers

Biomarker research continues to yield promising advances for the treatment of mesothelioma.

One such advancement is the use of mesothelin to develop the first commercially marketed in vitro diagnostic test for mesothelioma, the MESOMARK® test. This manual enzyme-linked immunosorbent test measures the levels of Soluble Mesothelin-Related Peptides (SMRP) released by cancer cells, improving the chances for early diagnosis.

In 2010, the results of a Phase I clinical trial revealed that a mouse-human chimeric monoclonal antibody called MORAb-009 could kill mesothelin-expressing cell lines through creating cellular cytotoxicity.

The study also suggested that mesothelin was a receptor for CA-125 and that the binding of these two markers may signal tumor metastasis. Applying the MORAb-009 antibody to these cells prevents binding which may also inhibit tumor metastasis to improve patient survival rates.

Bio: Michelle Y. Llamas is a writer for the Mesothelioma Center. She is committed to generating mesothelioma awareness and providing information regarding breakthroughs in mesothelioma treatment.

Sources:

Fujirebio Diagnostics, Inc. (2008). Mesomark. Retrieved from http://www.fdi.com/mesomark/world/home.html

Hassan, R., Schweizer, C., Lu, K. F., Schuler, B., Remaley, A. T., Weil, S. C., & Pastan, I. (2010). Inhibition of mesothelin-CA-125 interaction in patients with mesothelioma by the anti-mesothelin monoclonal antibody MORAb-009: Implications for cancer therapy. Retrieved from http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2864325/?tool=pubmed

Mott, F. E. (2012). Mesothelioma: A review. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/22438785

Pass, H. I., Vogelzang, N. J., & Carbon, M. (Eds.). (2005). Malignant mesothelioma: Advances in pathogenesis, diagnosis, and translational therapies. New York: Springer.

Tannapfel, A. (Ed.). 2011. Malignant mesothelioma: Recent results in cancer research. New York: Springer.

 

The new paternalism in American medicine

It has taken me awhile to get to this article by Hartzband and Groopman, "Rise of the Medical Expertocracy," from the March 31, 2011 Wall Street Journal.  If you happened to miss it, it is quite thought-provoking.

Whether you are coming from the left or right perspective on health care reform, there is an underlying singular assumption that there is a "best practices" or "evidence-based solution for every difficult problem in medicine and health care delivery.  This may be naive wishful thinking or a zealous belief in the power of science, but, either way, this assumption is pervasive amongst physicians, "experts" in various medical disciplines, as well as politicians and policymakers.  I aver that this is a pernicious and dangerous assumption for both medical practice and health care policy.

One interesting part of this article is the authors' discussion of the results of their study interviewing how patients process and act upon "expert" advice and information.  Perhaps not surprisingly, there is indeed a wide range of how patients make medical decisions--which is also reflected in the range in how members of expert "consensus" panels also view the same evidence and arrive at different, indeed, opposite conclusions.

The authors' observation of the rise of the industry supplying metrics and report cards to doctors, health plans and hospitals is particularly insightful--and disturbing.  How much of the health care dollar goes to companies measuring and benchmarking health care hospitals' own data?  I know my hospital spends a lot--as well as spending on how to remediate or improve to get where the experts say we need to be in the 90th percentile.  To me, this seems to stifle the trial-and-error, locally-based approach that might truly provide innovation that could be appropriated or adopted elsewhere.

I will confess an inherent skepticism and distrust of experts (especially those panels that are buddy-appointed), but the authors make what should be obvious points:

For patients and experts alike, there is a subjective core to every medical decision. The truth is that, despite many advances, much of medicine still exists in a gray zone where there is not one right answer. . .Patients and doctors can differ with experts and not be ignorant or irrational. Policy makers need to abandon the idea that experts know what is best. In medical care, the "right" clinical decisions turn out to be those that are based on a patient's goals and values.

Institute of Medicine Report on Omics-based Testing

The IOM released the report “Evolution of Translational Omics: Lessons Learned and the Path Forward,” last month which includes recommendations for using test models based on “omics” technologies to predict clinical outcomes, and ways to ensure adoption and adherence to the evaluation process.

Many of the IOM report’s recommendations align with those in “Accelerating Progress Against Cancer: ASCO’s Blueprint for Transforming Clinical and Translational Research,” which was released in November 2011.

Institute of Medicine Report on Omics-based Testing Bolsters ASCO’s Blueprint for Transforming Cancer Research - The ASCO Post.

Exosomes as Possible Biomarker for Tuberculosis

I have previously posted on exosomes in the context of cancer.  Here is a very interesting and brief video from Dr. Jeffrey Schorey regarding exosomes in the pathogenesis of tuberculosis and their possible use as a biomarker for infection.  It's only 5 minutes--go ahead and enjoy!

Possible false positive interpretation of Napsin A staining in evaluating lung non-small cell carcinomas

Dr. Nelson Ordonez (MD Anderson Cancer Center, Houston) published a brief and very helpful article in the March 2012 American Journal of Surgical Pathology (abstract) that addresses a very practical issue of using IHC staining for Napsin A in evaluating primary lung NSCLC for confirmation of adenocarcinoma type.

Napsin A is normally expressed in type II alveolar pneumocytes but may also be localized immunohistochemically in intraalveolar macrophages presumably from phagocytosis.  The expression of both Napsin A and pro-surfactant protein B (ProSP-B) are regulated by thyroid transcription factor-1 (TTF-1), which is one of the common IHC stains initially performed on NSCLC not diagnostic for adenocarcinoma on routine H&E.  Napsin A is localized to lamellar bodies with ProSP-B and is thought to be involved in post-translational processing of ProSP-B.

This paper must be understood in the context of new IASLC lung adenocarcinoma classification and the algorithm recommended to histological type NSCLC.  Napsin A has emerged as a useful adjunct IHC stain, such as, in those cases in which a tumor is negative or equivocal for initial screening markers for both adenocarcinoma (ADC) and squamous cell carcinoma (SQC).  Until recently, Napsin A was found to be highly specific for lung ADC.  But, as Dr. Ordonez points out, several recent publications have found Napsin A positivity in lung squamous cell carcinomas and, thus, cast doubt over the high degree of specificity of Napsin A for lung adenocarcinoma and utility of this marker in this context.

Dr. Ordonez studied Napsin A expression by IHC in 90 primary lung SQC, including whole section and biopsy specimens, and 64 non-pulmonary SQC.  None of the primary lung SQC or the non-pulmonary SQC showed Napsin A positive staining in the malignant cells.

The key observation is the identification of entrapped type 2 pneumocytes and/or intraalveolar macrophages in desmoplastic areas adjacent to the tumor and in small clusters within the tumor--which could be a source of false-positive interpretation in SQC.  Dr. Ordonez found 5 biopsies in which these entrapped cells were difficult to distinguish from malignant cells and CK 5/6 was used in 2 of these cases to rule out the possibility that these were Napsin A-positive malignant squamous cells.

This is a critical distinction and very welcome contribution to the lung cancer pathology literature.  The reader should keep point this in mind, especially when evaluating biopsy material.  The illustrations are excellent in demonstrating these points and should also be kept close at hand.  Congratulations to Dr. Nelson Ordonez for an excellent paper.

Biomarkers in COPD

Chronic obstructive lung disease (COPD) is defined functionally as airflow limitation that is not fully reversible.  It is a MAJOR cause of morbidity and mortality in the U.S. and worldwide.  COPD has two distinct major, but often coexisting, forms that represent different manifestations of COPD: emphysema and chronic bronchitis.  Emphysema can be defined morphologically, either by radiography or pathology, while chronic bronchitis is defined clinically based upon the duration of productive cough and exclusion of other causes.  Treatment is focused on preventing progression of disease and the development of acute exacerbations, which are a major cause of hospitalizations, morbidity and mortality.  Common to both major forms is small airways inflammation and an abnormal inflammatory response either in large airways (chronic bronchitis) or in alveoli (emphysema).

COPD is also associated with low-grade systemic inflammation and biomarkers that could predict increased risk for mortality from progressive disease or acute exacerbations might be greatly beneficial in providing more intesive surveillance and treatment of this group.  A team of researchers led by Tufts University School of Medicine screened blood samples from people in the ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints) to see if inflammatory biomarkers could predict disease outcome (abstract).  The study included 1843 patients who were followed for 3 years.  168 of the 1843 patients (9.1%) died.  Serum or plasma levels of fibrinogen, chemokine ligand 18, surfactant protein D, C-reative protein, Clara cell secretory protein-16, interleukin-6, IL-8, and tumor necrosis factor-alpha were measured at recruitment and at subsequent visits.

The addtion of a panel of biomarkers significantly improved predictive power and was able to better predict outcomes compared with current clinical variables, including age, BODE index, and hospitalization history. The addition of IL-6 provided the most improvement of discriminatory power, but this was improved further with the addition of all biomarkers measured.

Medscape Interview with NIH Director

Medscape recently produced a fascinating interview with Dr. Francis Collins, Director of the National Intitutes of Health that focuses on genomics but ranges broadly over several areas, including medical education and preventative medicine.  It's not that long and there is also a text format if you don't want to watch the interview.  Highly recommended.  This a thought-provoking interview.

I think Dr. Collins is overly optimistic about the impact of genomics on day-to-day patient care.  Pharmacogenomics, for one example he uses, has not made any impact thus far in my experience.  While it is a tool, perhaps, for demonstrating why a patient may not be responding to a particular drug, the use of pharmacogenomic testing before initiating treatment has not been prospectively studied to my knowledge in any trials, for any drug.  This leaves aside the further studies regarding cost-benefit analyses as well as the issue of payment/reimbursement.  Right now, it seems cheaper and tried to put a patient on a standard dose and see what happens.

Another example is the idea of genomic sequencing of cancers.  It sounds good because it provides a "personalized" profile of a cancer.  What about tumor heterogeneity?  Do we sequence the primary tumor or metastasis?  Which part of the primary tumor?  Which metastasis?  Finally, how does one compare "unique" tumor genotypes and develop groups to statistically compare treatment responses?  At some point, patients have to be lumped together (and thus muddying up personalized differences) in order to find appropriate guidelines for treatment and provide some prognostic information.

Lots more to think about!