The Daily Sign-Out

Digital pathology article in "CAP Today"

Dr. Keith Kaplan at Digital Pathology Blog pointed this one out as a good article discussing the recent FDA meeting regarding whole-slide imaging (WSI) technology.  And he has some informed insights quoted in the article.  The online version of CAP Today has been out and I (again) urge you to check it out--although the hard copy version is probably sitting on your desk somewhere.

I reckon that you're take on this article might depend on your reaction to the quote from Ole Eichhorn ot Aperio:

"Eichhorn believes that the FDA fears that if it doesn't "get out in front" of digital pathology, there could be a proliferation of non-cleared/non-approved WSI systems "because these devices are useful and valuable.  By the way, that's what we have with the microscope"."(my emphasis)

If a device is already "useful and valuable" (as judged by me, a practicing pathologist or as judged by the marketplace of laboratories and pathologists), shouldn't the FDA just let us use these for making our diagnoses--like we already do with microscopes?  As in golf (with a similar governing body deciding what is allowable equipment and what is not), it's not the club, it's the player that makes the shot and records the score.  If I'm a crap player (okay, I admit it), it won't matter whether I have an approved or non-approved club, ball, grip-warmer, etc.--I'll still be a crap player!  The imager and software is NOT making the diagnosis, the pathologist is!  And I'll freely admit that the instrument/software might (sorry, I'd still like proof) be better at counting stainable events at statistically important cut-offs or at least doing it faster.  BUT I would also submit that whether a breast cancer is positive for ER at 21.38% or 25% to 50%, the clinician is going to look at my Allred score to determine treatment (sorry, Keith, that's where I slightly disagree with your statement as it is in the article).  The "precision" offered by these instruments for this use is a little disingenuous and adds a patina of "scientificity" that really isn't that clinically meaningful.

If the FDA wants to collaborate with CAP and industry groups to provide guidance on how we should validate these instruments in our own labs, I'm definitely on board with that. 

I think too that you really have to also keep in mind the various people at the table and ask what their own vested interests are in this process--not that I'm cynical or anything, but still. 

It seems that the CAP has taken a reasonable position, as articulated by Dr. Valenstein, but I would like to review the actual consensus position--which I cannot find on our (the CAP) website.  Can anyone else?  We really need real pathologists out there expressing their opinions on this stuff to the CAP and to these regulatory agencies.

Genetic variation and susceptibility to COPD

The Dec. 17 New England Journal of Medicine has an interesting article exploring genetic susceptibility to COPD.   Having just recently finished my lung pathology course to second-year medical students, I can confess to the awkward feeling I have when the inevitable question arises as to why doesn't everyone who smokes get COPD (or lung cancer, for that matter).  My (somewhat feeble) reply is to ascribe this to "individual differences" or "genetic variation."  This paper tries to investigate specifically how genetic variation might be with associated with susceptibility to COPD.

The rationale for the study is that matrix metalloproteinase-12, produced by alveolar macrophages, is essential for the development of emphysema in mouse models and is increased by up to a factor of 9 in alveolar macrophages from smokers compared to non-smokers.  Further, production of MMP12 in lower airways leads to destruction of elastic fibers in alveolar walls--the resulting increase in elastin fragments recruits more macrophages thus setting up a reinforcing feedback loop that amplifies this process.  The authors' hypothesis is that MMP12 variants influence lung function and the development of COPD.  Their study tested for an association between SNPs in MMP12 and lung function test (FEV1) in different cohorts including children with asthma and adults with and without COPD.

They found a positive association between the minor allele of SNP rs2276109 and FEV1 in all cohorts and, in adult cohorts, a 35% reduction in the risk of developing COPD in smokers.  Conversely, they observed a 54% increased in risk of COPD in smokers in the absence of the minor allele (i.e. homozygous for the major allele).  It is noted that the minor allele of SNP rs2276109 is a functional polymorphism is associated with decreased promoter activity through less efficient binding of AP-1 in murine and human monocytic cell lines.  Further, deletion of the AP-1 binding site abrogates both baseline and stimulated MMP12 expression.  There are some important limitations to this study but this is a fascinating insight into "individual variation" due to genetic variability in SNPs and an association between smoking and the development of COPD.

New therapeutic approaches for small cell lung cancer

I am currently working on a project with our lung cancer research group at Rush University Medical Center in Chicago in which we are looking at expression of the BCL-2 family protein, MCL-1.  MCL-1 is interesting because it can either be anti- or pro-apoptotic depending on alternative splicing.  So I was interested in this nice review article that explores the role of novel targeted agents in SCLC.  This article specifically discusses agents targeting the bcl-2 protein family.  The prognosis for SCLC remains pretty dismal but there is a lot of interest in this malignancy because of the better understanding of pathways involved in SCLC and the development of "targeted" therapies.

Hurwitz J, McCoy F, Scullin P, Fennell D. New advances in the second-line treatment of small cell lung cancer. Oncologist. 2009;14(10):986-994.

Leave well enough alone? The role of resection in asymptomatic metastatic CRC

The standard of care for treatment of mCRC has been surgical resection followed by adjuvant chemotherapy.  In patients presenting with symptomatic mCRC, palliative surgery is performed for bleeding, obstruction, or perforation, while in patients presenting with non-emergent symptoms and limited disease, surgery may be undertaken with a curative intent.  The role and value of surgery in patients with unresectable stage 4 colon cancer and a synchronous asymptomatic primary tumor is being currently investigated by the National Surgical Adjuvant Breast and Bowel Project in a prospective phase II study (NSABP C-10).  Current recommendations for treatment of mCRC are:

1. Patients with evidence of significant obstruction, perforation, or uncontrolled bleeding should undergo resection of the symptomatic lesion.
2. Patients who are unfit for surgery, or who decline surgery, should undergo endoscopic management with stents or ablation to palliate symptoms.
3. Patients with potentially resectable metastases should undergo resections of both the primary tumor and the metastases (typically, sequentially).
   1. Chemotherapy may be administered preoperatively to assess the natural history of the underlying malignancy.
   2. If disease controlled is obtained with chemotherapy, resection of primary and secondary lesions should be considered.
4. In patients who have diffuse, metastatic CRC with unresectable metastases, modern polychemotherapy with targeted agents will offer disease control without the mortality and morbidity of surgery directed at the primary lesion.

The hypothesis of this study is that, given the dramatic improvement in response rates with current regimens incorporating oxaliplatin and irinotecan with biologics such as bevacizumab and cetuximab, systemic chemotherapy without resection of the primary tumor is a reasonable alternative to the standard approach in these patients.  This approach takes into account the morbidity and mortality associated with colectomy in these patients compared to the potential survival benefit in an incurable disease where <10% of patients survive 5 years. 

Patients  will be treated with 5-fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) plus bevacizumab. The goal is to determine if this approach leads to an increase in “major morbidity” defined as any event related to the intact primary tumor necessitating surgery or resulting in patient death. The results of this study should be very interesting and could represent a real change in thinking about how we treat primary tumors. Oncologist. 2009;14(10):963-969.

More recommendations for lymph node adequacy in CRC

The Dutch National Working Group on Gastrointestinal Cancers has recently released colorectal cancer guidelines which includes a recommendation of a minimum of 10 lymph nodes to establish a negative lymph node status.  At the same time, the group states that "determining the lymph node status of a patient requires evaluation as many lymph nodes as possible using conventional techniques." (emphasis mine

The discussion of this recommendation states that "no definitive criteria were found in the literature regarding the minimum number of examined lymph nodes.  There is no evidence to support 12 lymph nodes, as recommended by TNM." (emphasis mine)

Furthermore, they specifically do not recommend using immunohistochemistry to detect metastases or pre-treatment of mesenteric fat with GEWF-type solutions.  While using the former to detect micrometastases is not common practice, as least in the U.S., the latter is not only fairly common, if not routine in many places (mine included!).  Also, the recent literature also supports the use of these solutions to increase lymph node retrieval, although the utility of the raw node count has been questioned with the data regarding the percentage or proportion of positive:negative nodes (whole other discussion!).

MicroRNAs as a predictive marker for stage 2 colorectal cancer

This is an interesting abstract presented at the recent 2009 Association for Molecular Pathology annual meeting which is highlighted in Medscape.  Finding the magic markers that will predict which stage 2 CRC patients will progress without chemotherapy is an intense area of research, as is research into the importance of microRNAs in various diseases.

This abstract by Dr. Elizabeth Mambo et al. from Asuragen, Inc. is a small case-matched paired study but demonstrates that 11 microRNAs could potentially be prognostic for CRC recurrence.  Interestingly, they found that most microRNAs associated with CRC recurrence were downregulated but microRNA-21 and microRNA-31 were significantly upregulated compared to tumor specimens from CRC stage 2 patients who did not experience recurrence. 

I wonder which cells are exactly showing these changes given changes in the tumor microenvironment, specifically, neoangiogenic endothelial cells, myofibroblastic cells, and inflammatory cells.  I don't know much specifically about this type of testing, but I think it is a leap to assume that the test is measuring purely the carcinoma compartment of the tumor.

Still following the miRNA story. . .

Pink puffer versus blue bloater

One of the students wished for clarification between the clinical phenotypes of "pink puffer" versus "blue bloater" in COPD.

A "pink puffer" is a person where emphysema is the primary underlying pathology. As you recall, emphysema results from destruction of the airways distal to the terminal bronchiole--which also includes the gradual destruction of the pulmonary capillary bed and thus decreased inability to oxygenate the blood.  So, not only is there less surface area for gas exchange, there is also less vascular bed for gas exchange--but less ventilation-perfusion mismatch than blue bloaters.  The body then has to compensate by hyperventilation (the "puffer" part).  Their arterial blood gases (ABGs) actually are relatively normal because of this compensatory hyperventilation.  Eventually, because of the low cardiac output, people afflicted with this disease develop muscle wasting and weight loss.  They actually have less hypoxemia (compared to blue bloaters) and appear to have a "pink" complexion and hence "pink puffer".  Some of the pink appearance may also be due to the work (use of neck and chest muscles) these folks put into just drawing a breath.

A "blue bloater" is a person where the primary underlying lung pathology is chronic bronchitis. Just a reminder, chronic bronchitis is caused by excessive mucus production with airway obstruction resulting from hyperplasia of mucus-producing glands, goblet cell metaplasia, and chronic inflammation around bronchi.  Unlike emphysema, the pulmonary capillary bed is undamaged. Instead, the body responds to the increased obstruction by decreasing ventilation and increasing cardiac output. There is a dreadful ventilation to perfusion mismatch leading to hypoxemia and polycythemia.  In addition, they also have increased carbon dioxide retention (hypercapnia).  Because of increasing obstruction, their residual lung volume gradually increases (the "bloating" part).  They are hypoxemic/cyanotic because they actually have worse hypoxemia than pink puffers and this manifests as bluish lips and faces--the "blue" part.

Exosomes and nanoscale messenging

This month's Laboratory Investigation has an interesting free article by Hood et al. exploring exosomes--nanoparticles formed by inward budding of microvesiclar bodies and released into the extracellular matrix as part of a nanoscale messenger system.  The size of these particles (30-100nm) facilitates their penetration into cells at the invasive tumor front and they have been shown to participate in cell to cell communication such as morphogen and RNA transport between cells.

The authors' hypothesis is that melanoma exosomes act as "nanovehicles" (I love this term!) to prepare the microenvironment for tumor cell implantation.  This article describes a unique in vitro angiogenesis assay system to study exosomes and their influence on endothelial cell tubulogenesis (i.e., early anagiogenic changes) and spheroid sprouting (a later stage of angiogenesis).  This system also incorporates a novel method of tracking the trafficking of exosomes.

I know this is "out there" but I was not familiar with this topic at all and thought it fascinating.

P.S. Sorry for my recent prolonged absence from posting--teaching the second-year medical students some lung pathology.

New CAP Today online version available!

If you haven't done so, check out the new CAP Today online edition.  Although I try to read as much as I can in an electronic or online format, sometimes I fatigue trying to navigate through things since I find that I don't necessarily read things in a front-to-back manner.  The new CAP Today version is wonderfully easy to navigate and you can customize a comfortable size to read.  It is also pretty intuitive to use (you don't need an instruction manual).  Definitely a score for CAP!  And it takes up less shelf-space than the ledger size print edition.

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