The Daily Sign-Out

AABB SmartBrief: Mismatched cord blood transplants can be effective

Studies: Mismatched cord blood, marrow transplants can be effective
Results of transplants with unrelated umbilical cord blood or mismatched bone marrow were comparable with results of transplants that used fully matched tissue, according to two studies involving patients with advanced leukemia or lymphoma. The studies, reported in Blood, found that the one-year survival rate for those who had unrelated cord-blood transplant was 54% and 62% for those who underwent mismatched bone marrow transplant. "Taken together, these results set the stage for a multicenter, randomized phase III trial to evaluate the relative risks and benefits" of such regimens, the researchers said. MedPage Today (7/9)

Stem cells and pluripotency articles in Development

Development has updated review articles on stem cells and pluripotency that I think would be of general interest for everyone and are available to download for free.  I really found the article on stem cell biology from a systems perspective especially cool. 

New Pathology blog: StemPath

Welcome to Dr. David Braxton and his new pathology weblog  StemPath which will focus on stem cell biology.  Best of luck to Dr. Braxton--make sure y'all check up on this one regularly as he gets off the ground.

Japanese team discovers new type of stem cells in human skin, bone marrow

Tohoku University team discovers new type of stem cells in human skin, bone marrow

This work will be reported in the April 20, 2010 of PNAS.  The authors have identified a compartment f extremely rare pluripotent stem cells, called Muse cells, that are capable of differentiating into muscle, nerve, and liver cells but, unlike embryonic or induced stem cells, demonstrate limited proliferation capability.  After being implanted into damaged mouse muscle, nerve, or liver tissue, the Muse cells transformed into the appropriate tissue where they were transplanted--but stopped multiplying after about two weeks.  Another apparent difference from other types of stem cells is an very limited capability of becoming malignant.  Interesting stuff!

Notable abstracts from 6th Biennial Pulmonary Pathology Society Meeting 2009

This month's Archives of Pathology & Laboratory Medicine (February 2010) publishes abstracts from the meeting we had last June in Portland.  This was one of the best meetings I have ever attended!  The presentations were all current summaries of the state-of-the-art in a variety of lung and pleura topics.  I want to call attention to 3 notable abstracts in Archives.

The first one is actually notable to avoid (in a way) but I want to comment on because I think it could be done better and be more helpful the pathologists who "daily sign out" lung cases.  "Interobserver Reproducibility for the 2004 World Health Organization Classification of Non-Small Cell Lung Cancer."  This study takes 12 "expert pathologists" (EP) and 12 "community pathologists" (CP) and measured the interobserver reproducibility (IOR) by the kappa statistic using H&E "virtual slides" from 96 lung tumors based on the 2004 WHO classification.  The authors report comparisons between various major classes (SqCa versus non-SqCa, AdCa versus non-AdCa, EP versus CP) and categories accounting for "grade" (non-poorly differentiated SqCa versus non-SqCa, pdSqCa versus non-SqCa, non-pdAdCa versus non-AdCa, pdAdCa versus non-AdCa).  Not surprisingly, EPs have a higher degree of agreement than CPs in every category, although even in the "basic" binary comparisons (SqCa vs. non-SqCa and AdCa vs. non-AdCa), the "best" agreement is relatively modest (for EPs kappa 0.64 for SqCa vs. non-SqCa, 0.69 for AdCa vs. non-AdCa) and slightly more than a coin-toss for all.

I realize that this is an abstract but, if this has been written for publication as a paper, I hope that the reviewers look past the reputations of the authors and consider (and push them) on some of these points.  My overarching objection to these sorts of "studies" is that they are "fake."  They do not re-create or represent what one encounters in daily practice.  Yet it would be and is very valuable to appreciate the variability and reproducibility of diagnostic categories First, how were the specimens selected and by whom?  A study of consecutive, unselected cases would most faithfully represent actual practice.  Also, the type of specimens studied is crucial: are these CT-guided needle biopsies, bronchoscopic specimens, resected tumors, mediastinoscpic node specimens?  It would be valuable to compare the diagnostic agreement both within and between these different types of specimens so that we could communicate the diagnostic uncertainty with better precision to clinicians address issues related to specimen adequacy regarding the most basic decision-point for NSCLC (SqCa vs. AdCa).  The IOR doesn't surprise me if the sample includes small samples but I would expect more agreement for resected specimens that were adequately sampled.  Also, the number and type of "virtual slides" needs to be specified.  Does anyone make a diagnosis, virtual or real, on one slide?  Again, the study does not reflect actual practice.  Second, the idea of incorporating the idea of "grade" (i.e. "poorly-differentiated") into the diagnostic categories needs to be junked or radically de-emphasized.  "Grading" of NSCLC is totally subjective and, unless the WHO folks or an expert panel or another ad hoc group wants to define and validate a grading system, the authors should just leave this alone.  Again, since there is no defined, validated grading system for NSCLC (I'm thinking here of something like the Nottingham system for invasive ductal carcinoma of the breast where grading is related to survival), one CP's "poorly-differentiated (fill-in-blank) carcinoma" is a EPs "moderately-differentiated (fill-in-the-other-blank) carcinoma" (or vice versa!).  Double-down the above point since this study is based just on apparently just one H&E slide--does anyone actually practice like this?!  Finally, the conclusion that "IOR improvement may be possible (my emphasis) with reflex screening  for mucin and type-specific immunophenotypes."  May be possible?!  Are you serious?!  Doesn't everyone already reflexively do mucin and p63/TTF-1 for any case that doesn't show unequivocal squamous or glandular differentiation--especially in small biopsies?  I consider this standard of care in 2010.  Here is the study I think we need:  a large unselected series of consecutive diagnostic NSCLC lung tumor surgical pathology biopsies (CT-guided, endo- or transbronchial biopsies, wedge resections, lobectomies) from statistically representative community hospitals and tertiary care hospitals (so it will be weighted toward community settings where the vast majority of lung cancers are diagnosed) using WHO 2004 classifications, digitized slides from all slides of the tumor, and mucin/p63/TTF-1 (on all cases? or all cases with exclusive solid pattern? or all cases not definitively showing squamous or adenocarcinoma features?) and compare the diagnoses between a different group of EPs and CPs not from these institutions.  This would give us information on the diagnostic agreement and uncertainty based on present practice, on small biopsy versus resected diagnostic specimens, the effect of the presence of solid pattern on diagnostic agreement in adenocarcinoma, and info on the sensitivity, specificity, PPV and NPV of the special stains and a benchmark for other IHC stains in the future.

SInce this post is already way too long and a bit of a rant, I do want to briefly end with two other interesting abstracts that you might keep an eye out for subsequent papers:

"Stem Cell Marker Expression in Pulmonary Carcinoma Associated with Histologic Type and Differentiation"  Stem cell marker expression is obviously a rapidly developing and exciting area right now not only for lung but other solid organ carcinomas as well.  This study looks at Mushashi-1 as a marker which I've not seen elsewhere in the literature.

"Anaplastic Mesothelioma: A Nonrecognized Histologic Pattern."  Not anymore.  I like the conclusions to this abstract--simple, straight-forward--"The presence of high-grade or anaplastic features in either sarcomatoid or epithelioid tumors of the pleura should not prompy a diagnosis of sarcoma or carcinoma or discourage a diagnosis of malignant mesothelioma."  Bam!  I would love to see this published as a paper with good illustrations.

Evidence for stem/progenitor cells in mouse lung model

I came across this excellent paper and summarized my "top 10 list" of points from the paper.  The role of stem/progenitor cells in cancer is a crazy-active area in current research.  If you catch some of the details, you can probably guess the technical challenges to this work.

 

Evidence of an epithelial stem/progenitor cell hierarchy in the adult mouse lung

Jonathan L. McQualtera, Karen Yuena, Brenda Williams, and Ivan Bertoncello

PNAS 2010; 107:1414-1419.

1. Mesenchymal progenitor cells (EpCAM^neg Sca-1^pos) regulate the growth of EpCAM^pos lung progenitor/stem cells in in vitro matrigel cultures.
2. Fibroblast growth factor-10 and hepatocyte growth factor regulate epithelial cfus even in stromal-free cultures and appear to act synergistically, while the addition of mesenchymal growth factors [bone morphogenic protein (BMP-4), TGF-beta1, or platelet-derived growth factor (PDGF)-AA] resulted in a significant reduction or complete inhibition of epithelial colony growth.
3. Lung epithelial cells comprise less than 0.05% of lung epithelial cells and are predominantly restricted to the EpCAM^hi CD49f^pos (α-6-integrin) cell fraction.
4. The EpCAM^hi cell fraction was exclusively CD104^pos (β-4 integrin).
5. In the adult mouse lung, immunofluorescent staining demonstrated that CD104 has a distinct localization to endothelial cells and the basal plasma membrane of virtually all epithelial cells in the bronchi and most cells in the terminal bronchioles.
6. Further enrichment of epithelial cfus in the EpCAMhi cell fraction was achieved by selecting on the basis of high or low expression of CD24 (heat-stable antigen) the incidence of colony formation is directly proportional to the number of CD24low cells plated and that the cloning efficiency of this population is only about 4.5%
7. Only CD24low cells demonstrate cfu potential, suggesting that only a restricted subpopulation of EpCAM^hi CD49f^pos CD104^pos CD24^low bronchiolar epithelial cells have the capacity to serve as stem/progenitor cells
1. This is at variance with previous reports suggesting that the majority of Clara cells in the bronchioles can self-renew and generate differentiated progeny (13). The relation of the authors EpCAMhi CD24low population to the Clara or variant Clara cell is unclear (3) and will require identification of previously undescribed Clara cell markers for further subsetting.
8. Lung epithelial cfus are clonally derived and a subset of EpCAM^hi CD104^pos epthelial cfus possess the capacity for in vitro self-renewal after serial passage.
9. Lung epithelial cfus also contain three distinct subtypes of epithelial colonies:
1. Large airway-like cystic spaces with well-defined lumens: express MUC5AC but not proSP-C and genes encoding airway lineage markers (Foxj1, P63, MUC5AC, CFTR), observe cilia in cells in inner lumen--cells of airway origin
2. Small dense saccular colonies: express proSP-C but not MUC5AC and genes encoding alveolar markers (ABCA3, CEBP/alpha, SP-C, SP-A)--alveolar AEC II cells
3. Clara cell marker (CCSP) overexpressed in cystic and mixed colonies but also detected in saccular colonies
4. Colonies of mixed phenotype with distinct budding: express both MUC5AC and proSP-C (but only at tips of buds)
10. Evidence of adult lung epithelial stem/progenitor cell in adult mouse lung is forthcoming and mostly inferential.