Its been eons since I posted.  I got lost in the throngs of studying for boards and projects.

This year one of my projects is centered on multimedia files for pathology resident education.   My first project was mainly podcasting–and the residents really liked it. I wrote a simple how-to for Mac and Windows users which i will attach to this file. 

Multimedia files are cool because you can view them on portable devices, they are easy to make, and you can incorporate sound into your images/presentations. You can share cool cases with people or send consults.  These are best for short movies (2-5 minutes).  You can also take movies with your digital cameras and import the video file into the movie maker to enhance your multimedia file.  I’m planning on learning flash this “semester” and blogging about it.

So stay TUNED!!!!!

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File attachment:
How-to for multimedia file creation (MS Word .doc format)

Pathological Findings
Microscopic examination of the liver biopsy revealed approximately five small fragments of liver tissue. There was a mild portal infiltrate of mixed inflammatory cells without evidence of limiting plate inflammation. Within the lobules, there were scattered, randomly distributed foci of hepatocyte necrosis with mixed inflammation. In a few foci, collections of epithelioid cells suggestive of poorly-formed granulomas were seen. Only rare eosinophils were present. There was one large area of inflammation and fibrosis with central necrosis.

Diagnoses
Liver tissue with microabscess formation
Mycobacterial organisms present on special stains

Discussion
In an immunosupressed patient on numerous potent medications, the differential diagnosis of multifocal lobular necrotizing granulomatous inflammation is broad. The various causes of hepatic granulomas have different histological features that help to narrow the differential diagnosis. Sarcoidosis and primary biliary cirrhosis tend to favor the portal areas, while other causes do not typically display this pattern. In granulomas caused by tuberculosis, there is often caseating necrosis, while in cat scratch disease, tularemia, and Yersinia infection, granulomas frequently have a purulent center. “Fibrin-ring” granulomas comprised of a fat vacuole surrounded by a ring of fibrin, epithelioid cells, giant cells and neutrophils may be seen Q-fever, cytomegalovirus infection, toxoplasmosis, lupus, and a few other uncommon conditions. Finally, granulomas caused by drug toxicity are sometimes associated with an eosinophilic infiltrate.¹

In this case, a broad panel of special stains for bacterial, acid-fast, and fungal organisms was ordered. In addition, less common viral causes of hepatocellular necrosis, including cytomegalovirus, adenovirus, herpes simplex virus, and varicella-zoster virus, were ruled out by immunohistochemistry. A careful search of the entire biopsy at high magnification revealed only two acid-fast organisms. Interestingly, cultures obtained from this biopsy specimen at the time of presentation were negative (though a later urine culture grew Mycobacterium tuberculosis). Based on the biopsy identification of acid-fast organisms, the patient was treated for presumptive tuberculosis and has since done well.

1. Scheuer P, Lefkowitch J. Liver Biopsy Interpretation. 7^th ed. 2006. Elsevier.

And if you haven’t been to our new site before, welcome to PathTalk, a community blog for all things pathology. We’ve only been around for a few months, and have taken a short hiatus recently, but hope to ring in the new year with more content from a specialty that is relevant to all of our medical colleagues out there. Please take a look at Gretchen’s series on lab testing, my musings on medical topics “off the stage“, and Kenneth’s great slide case studies.

So without further ado, let’s take a look around and see what medical bloggers are thinking about this week…

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Late addition secondary to my own oversight: Pearls and Dreams on eating disorders.

Dr. Toni Brayer at Everything Health wonders whether sexual misconduct complaints against doctors are being properly investigated.

Tony Chen at Hospital Impact links to an article that claims the US has too many doctors. The article’s author is Shannon Brownlee, who wrote Overtreated.

Emily at crzegrl.net relays an interesting and touching narrative from a recent adventure as a flight nurse.

The Physician Executive examines immigration laws, and to what extent health care costs play into the debate.

“The Fine Art Doctor” at In My Humble Opinion has some good rules to keep your patients out of the hospital.

Roy at Shrink Rap counts down his top 25 posts of 2007.

Bongi at Other Things Amanzi relates a story about crime, police, and the hospital in South Africa.

Kim at Emergiblog remind doctors that nurses are beholden to their own code of ethics, not the doctors they support. ERNursery chimes in.

A 23-year-old medical student at Vitum Medicinus reflects on age discrimination and maturity.

For you patients out there with back pain, Dean Moyer has some guidelines about which caregivers to see.

Allergy notes wonders whether Platelet Activating Factor will be for anaphylaxis what BNP has become for heart failure.

Clinical Cases and Images opines on the NEJM Image Challenge and the “wisdom of crowds.”

The internet is the ideal place to talk about those issues that doctors and patients may not feel the most comfortable about. Searah Deysach at ChronicBabe discusses lubricants.

For the sake of our patients, doctors must look at alternative health seriously and critically. Val Jones at Revolution Health takes a look at the plausibility of homeopathy and does not like what she sees.

Interested Participant passes along accusations that some British NHS hospitals are lying on death certificates to cover up death from hosptial-acquired infections.

In the wake of the San Francisco Zoo tragedy, Dr. Paul Auerbach of Healthline details the prevelance and health issues of large cat attacks.

Also from Healthline, JC Jones reminds that the third world struggles with diseases the developed world has conquered.

Tara Gidus explains why men, compared to women, can lose more weight faster.

Nancy Brown speaks to anyone who may be experiencing post-holiday blues.

Jolie Bookspan has some tips for improving fitness.

A volunteer ER chaplain who blogs at Rickety Contrivances of Doing Good looks at the human side of organ donation.

Ian at ImpactEDNurse.com examines the origins of the word “hysterical”. The posts title: Escaped Uterus Sparks Mass Hysteria in Emergency Department! - I think that is all I need to say.

Kolahun studies malnutrition in Darfur.

“Mother Jones” at Nurse Ratched’s Place claims that Orville Redenbacher should stick to the popcorn, and Johnson&Johnson should stick to making drugs.

Gerry at Disease Proof has everything you ever wanted to know about organic bananas.

David Williams at Health Business Blog sees that a minority of pharmaceutical samples find their way to poor patients and asks, “So what?”

The Colorado Health Insurance Insider examines the high price of becoming a doctor.

HealthBlawgs David Harlow discusses Federal ERISA laws.

Lindsay at Living With Fibromyalgia struggles with the politics of paying for drugs at Britains NHS.

A Filipino physician at Prudence MD takes a look at that country’s effort to require nutritional information on restaurant menus.

Alvaro at Sharp Brains has a roundup on brain fitness and cognitive health.

Christian at Med Journal Watch claims that for coping with stress and trauma, religion can be a double-edged sword.

Mike Feehan at InsureBlog highlights a scandal in Japan that has left 10,000 patients with Hepatitis C from fibrinogen tranfusion.

Jeffrey MD looks at the decline in physician salaries.

How To Cope With Pain has a roundup of the December Pain Blog Carnival.

Terry at Counting Sheep says that insurance companies are not covering anesthesia adequately.

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Thank you for stopping by this week for Grand Rounds, and thank you to all those who contributed. Next weeks edition will be at Sharp Brains.

If you have a submission, send to trentmcbride -at- gmail -dot- com; please have submissions by 5 PM on Monday the 7th.  There is no theme, so send whatever you’d like.

And, please, everyone stop by next Tuesday to see the best from the medical blogosphere!

Over a dinner of delicious home-cooked food, my mother, in a perpetual exercise to understand the scope of exactly what it is a pathologist does, asked me on my last visit home about laboratory testing. She wondered how her cousin, who is a high school graduate, could be involved with medical laboratory testing–including DNA test handling–without additional training. As I am not a laboratory manager and still consider myself a somewhat green resident (Will this feeling ever go away?), my first response was “?”.

It is clear that my mother’s cousin is probably performing or responsible for CLIA-waived tests, which have no routine oversight and no personnel requirements.¹ The lab is only required to obtain a certificate of waiver and pay the renewal fees on this certificate and follow manufactures test instructions when performing tests.¹ According to the Clinical Laboratory and Improvement Amendment of 1988 (CLIA), tests are classified according to complexity, and the categories are as follows: waived tests, tests of moderate complexity, and tests of high complexity.² There are seven criteria where a test will receive a score from 1 (low complexity) to 3 (high complexity), and a score of 12 or more is a high complexity test.² The general criteria are: knowledge, training/experience, reagents, characteristics of operational steps, calibration and quality control, test system trouble shooting and equipment maintenance, and interpretation and judgement.²

Specimen types fall under the general category of unprocessed specimens: whole blood, throat swab, nasal wash/swab, saliva, oral fluid, urine, stool, and gastric biopsy (for H. pylori). Approximately 1,600 test systems, representing at least 76 analytes, are waived under CLIA.¹ Sites performing only waived tests comprise 58% (105,138) of the approximately 180,000 laboratory testing sites in the United States.¹ Tables of proportion of labs performing waived tests are below.

From 1999 to 2004, the Center for Medicare and Medicaid Services (CMS) conducted multiple quality surveys on CLIA-waived labs to study the client base, personnel make up, and factors contributing to error.¹ Quality deficits were mainly attributed to failure to follow manufacturers’ instructions or failure to identify incorrect results and performing unauthorized testing.¹ There was also a high turn over rate for testing employees.¹ As a result, recommendations were released in 2005 for best practices for these CLIA-waived laboratories. A test is considered a POC test if it is a laboratory test performed and the results rendered at the location where the patient is receiving care, whether it be at the bedside, in the emergency department, at a physicians office, or at home (self monitoring, bhCG). A POC test may be a CLIA-waived test like those described above, or a test with (usually moderate) complexity, depending on the test characteristics. Examples of POC tests in the hospital setting are glucose, iSTAT (limited chemistry panel, ABG etc), PT/INR, and ACT, to list a few. POC tests performed in accredited labs fall under the same regulations as all other tests.

POC INR tests for warfarin dosing have been compared to traditional lab PT tests and the results are varied. Some studies show excellent correlations with lab results, while others show a high variability between different POC test platforms.^3-8 However, the use of POC INR tests can smoothen operations for anticoagulation clinics, where patient wait time decreases significantly, and as long as a stable test platform is used, dosing regimens and follow-up can become predictable with experience. Point of care testing is attractive in the emergency room and other settings where rapid test results are needed (e.g. intraoperative testing) because of the speed for clinical decision making, with improvements in time to decision-making ranging from 21 minutes for blood gases to 86 minutes for biochemical tests (Note: these are year 1998 minutes).^9-10 Another recent advance in POC testing is integration with the electronic medical record in the hospital, making tracking of test utilization and test results more accurate.¹¹

Obviously, one could go on to write volumes about this topic, and it is well beyond my experience to do so with any appreciable depth. The future of POC testing will be interesting to watch, with technologies emerging in the literature which suggest an expansion of the panel of possible biomarkers (and PCR?) as well as bloodless saliva-based systems.^12-14 Will this steady push to LOC extend into POC? (And possibly the most interesting question–What will the lab regulations entail? And what are the practical aspects of ensuring quality results for the best patient care?)

Tables taken from reference 1.

References
1. MMWR Nov. 11, 2005/54(RR13); 1-25
2. http://www.fda.gov/cdrh/clia/#background
3. J Am Md Dir Assoc
4. Thromb Hemost 2000; May 83(5); 698-703
5. Blood Coagul Fibrinolysis 2007; APr 18(3);287-92
6. Can J Cardiol 2007; Jan 23(1):47-50
7. AJCP 2001; Feb 115(2):280-7
8. Br J Haremotl 2005; Jan 128(2):242-7
9. Ped Merg Care 2007; Jul 23(7): 457-62
10. BMJ 1998 Apr 316(7137):1052-1057
11. CAP Today, April 2006, Feature Article
12. LabChip 2004; Auf 4(4): 310-5
13. BioMed Microdevices 2006; Sep 8(3):215-25
14. Dent Clin North Am 2005; Jul 49(3): 551-71

Construction of pathology reports using diagnostically accurate and meaningful language has been a focus of the major pathology organizations, especially the CAP, undoubtedly influenced by the IOM 1999 report and fueled by the relatively frequently cited article “Clinicians are from Mars and Pathologists are from Venus” published in the Archives in 2000¹. This article reported that surgical pathology reports were “misunderstood” 30% of the time.¹ The CAP, the Association of Directors of Anatomic and Surgical Pathology, and other organizations such as the Association for Molecular Pathology publish recommendations for pathology reporting, including the minimal requirements for specific body sites, tumor types and testing modalities. Some institutions have implemented synoptic templates for cancer reporting to ensure that all of the required elements and important features of a patient’s tumor are present in the report and to display these elements in a list-type manner so that features such as tumor size or vascular invasion are readily identifiable.

The CAP in June 2007 published guidelines for reporting of molecular tests.² The Joint Commission also issued New and Revised Molecular testing standards Jan 2007, and these standards are similar to the minimal criteria proposed by the CAP.³ Minimal criteria include (besides name of lab, patient name, ID date of collection, source, ordering doc, etc):

• List results by test name–clearly stated and obvious
• Reference range or normal range and abnormal range
• type of procedure (PCR, Southern Blot, etc)
• defined target (gene, defect, locus)

Additional recommendations include (not limited to):

• interpretation of the result
• the significance of the results in relation to the patient
• pertinent assay performance characteristics (if control has been degraded and lower detection limit is altered)
• control results
• relevant peer-reviewed literature citations
• details of procedure (kit versus home brew, non-FDA-approved test, etc)
• recommendations on genetic counseling
• residual risk of disease, or risk of disease not assessed by study

Each aspect of the above additional recommendations is a good point of discussion, and all are bound in the attempt to convey useful information to other physicians (including pathologists) for the purposes of patient care–the implementation of which is probably easier said then done. What is certain is that everyone benefits from clear reporting (i.e. the result is properly interpreted by a treating physician) and treating physicians want recommendations about clinical decision making and implications for other family member/genetic counseling bringing to light the importance of the pathologist as consultant in the “current ” testing tech-splosion^4-7 (ok getting too bloggy with blogspeak here).

Standardized acceptable terminology is another issue for accurate reporting in molecular pathology as there is a lack of a strict nomenclature.² Especially important, since a minimal requirement is to write or transcribe the target gene/protein/cDNA/mRNA/rRNA/etc. One simple example written in the recommendations is the common use of abl or bcr-abl, (all lower case) where the correct term is BCR/ABL1.² There is also no consensus on how to report what is being studied. Should we say BCR/ABL1, BCR/ABL1 transcript, ABL1/BCR fusion product? The standardization of molecular reporting would also benefit long term data storage and easier retrieval for research whether intra-institutional or collaborative between small and large groups.

Another major point of interest is the preservation or study of patient safety in molecular testing, an area which hopefully pathology informatics may support and bolster. Pre-analytical errors such as cross contamination or specimen mix up would render false results and impact patient safety tremendously. (ex= Yes this patient has a homozygous CF mutation, no this patient does not have the PML-RARA fusion transcript). A nice idea would be an internal control on new diagnoses to ensure the specimen of study is of the correct patient. This would be helpful becuase a series of microsatellite SNPs or RFLPs could be studied and filed in a database for future comparison–however, the collection and storage of reference patient DNA for future comparison for specimen result accuracy may bring up patient privacy issues.

1. Arch Pathol Lab Med 2000; 124:1040-1046
2. Arch Pathol Lab Med 2007; 131:852-863
3. Joint Commission Perspectives 2007;1
4. CAP Today 2003; 17:1-82
5. CAP Today 2004; 18:58-66
6. Genet Med 2003;5:166-171
7. NEJM 348:2526-2534

The molecular target of warfarin is the protein product of the Vitamin K epoxide Reductase Complex, subunit 1 gene (VKORC1). This gene product is inhibited by warfarin. Polymorphisms of this gene product have been extensively studied over the past several years, and variant genotypes are associated with variable response to warfarin.¹ Compared to patients with a wild-type genotype, patients with at least one variant allele had an increased risk for elevated INR (HR = 1.4) and required more time to achieve a stable dosing (median = 95 days).¹

Warfarin is eliminated via metabolism in the liver. It is stereoselectively metabolized by hepatic microsomal enzymes (cytochrome P-450).⁴ The warfarin breakdown products have minimal anticoagulant activity.⁴ The metabolites are principally excreted into the urine, and to a lesser extent into the bile.⁴ The drug is comprised of a mix of the R and S stereoisomers. The S isomer is 3 to 5 times more potent than the R isomer, and is metabolized by the cytochrome P450 family. The cytochrome P-450 isozymes involved in the metabolism of warfarin include 2C9, 2C19, 2C8, 2C18, 1A2, and 3A4.⁴

CYP2C9 is reported to be the main liver P-450 which modulates the in vivo anticoagulant activity of warfarin.⁴ Two variants of CYP2CP have been identified.¹ These variants ( the *2 allele -R144C and the *3 allele – I359L) are reportedly associated with a decrease in enzymatic activity of 30% and 80%.¹

To summarize, identified SNPs (single nucleotide polymorphisms) are associated with altered warfarin metabolism and utilization. The CYP2CP*2 and CYP2CP*3 genetic variations are associated with a need for a lower dose of warfarin. The VKORC1 genetic variation is also associated with a greater variation in warfarin dosing to maintain a stable INR.

In August 2007, the FDA issued a release in which it recommended genetic testing for these genetic variations in warfarin metabolism, and altered the drug label for warfarin to reflect this recommendation. This recommendation is a part of the Critical Path Initiative which seeks to harness new scientific knowledge in the areas of gene expression, bioinformatics, and new analytic methods in the service of product development while also emphasizing its commitment to personalized medicine. ⁵ Some institutions are beginning to implement testing for the identified polymorphisms using new testing modalities, such as methods utilizing nanoparticles for “NAT” testing or invader chemistry.

Specific dosing recommendations are not yet determined for patients with these known genetic variations. This is currently under study, but the hope is to give doctors a dosing regimen based on the presence or absence of these variations.^6-7 There are a myriad of other influences of dosing requirements for individual patients such as age, sex, weight, and diet, calling into question the utility of these tests. However, the FDA label change to reflect the push towards personalized medicine, along with the risk of fatal bleeding with overdosing and stroke/clotting with underdosing, the additional information given by the test will be helpful according to the studies published on this topic over the past few years.

1. The Pharmacogenomics Journal (2004) 4, 40–48. doi:10.1038/sj.tpj.6500220 (Published online 16 December 2003)
2. http://www.nanosphere.us/VerigeneWarfarin
MetabolismNucleicAcidTest_4472.aspx
3.http://www.fda.gov/bbs/topics/NEWS/2007/NEW01701.html
4. http://www.rxlist.com/cgi/generic/warfarin_cp.htm
5. http://www.fda.gov/cder/drug/infopage/warfarin/qa.htm
6. J Thromb Thrombolysis. 2007 Jul 29; 7. Clin Pharmacol Ther. 2006 Oct;80(4):346-55