Home >> Tag Archives: Molecular pathology/diagnostics (see also Polymerase chain reaction technology and AMP molecular case reports)

Tag Archives: Molecular pathology/diagnostics (see also Polymerase chain reaction technology and AMP molecular case reports)

AMP case report: Identification of multiple germline cancer predisposing gene variants in a single patient during tumor sequencing analysis

October 2023—Next-generation sequencing of tumor tissue has important implications in solid and hematologic malignancies because it can identify genomic variants that provide diagnostic, prognostic, and predictive information to guide clinical management. Variants identified on tumor sequencing can be classified as somatic (acquired after conception) or inherited through germline.

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AMP case report: Lung micropapillary adenocarcinomas revisited

September 2023—CAP TODAY and the Association for Molecular Pathology have teamed up to bring molecular case reports to CAP TODAY readers. AMP members write the reports using clinical cases from their own practices that show molecular testing’s important role in diagnosis, prognosis, and treatment. The following report comes from Henry Ford Hospital. If you would like to submit a case report, please send an email to the AMP at amp@amp.org. For more information about the AMP and all previously published case reports, visit www.amp.org.

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AMP case report: Small intragenic structural variants in SATB2-associated syndrome

CAP TODAY and the Association for Molecular Pathology have teamed up to bring molecular case reports to CAP TODAY readers. AMP members write the reports using clinical cases from their own practices that show molecular testing’s important role in diagnosis, prognosis, and treatment. The following report comes from Washington University School of Medicine in St. Louis.

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AMP case report: A germline GATA2 c.121C>G (p.P41A) variant in a patient with an unusual acute promyelocytic leukemia

July 2023—A germline GATA2 c.121C>G (p.P41A) variant in a patient with an unusual acute promyelocytic leukemia CAP TODAY and the Association for Molecular Pathology have teamed up to bring molecular case reports to CAP TODAY readers. AMP members write the reports using clinical cases from their own practices that show molecular testing’s important role in diagnosis, prognosis, and treatment. The following report comes from Emory University School of Medicine. If you would like to submit a case report, please send an email to the AMP at amp@amp.org. For more information about the AMP and all previously published case reports, visit www.amp.org.

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Adequacy in cytopathology: focus on cytology specimen use in molecular testing

May 2023—In the first article in our series on adequacy in cytology, published in January 2023 (bit.ly/3MDNVzr), we summarized current approaches to defining adequacy for the purpose of primary diagnosis in the majority of specimen types encountered routinely in cytology practice. As we saw, while the essence of adequacy is constant across reporting systems, the technical definitions can vary significantly by specimen type.

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New paths through hematologic neoplasms

March 2023—Updated classifications for hematologic neoplasms are here. Let the complications continue. As with other specialties, hematopathology has been absorbing advances gleaned from molecular and genetic data. In some cases, this can tilt diagnosis away from primarily immunophenotypic approaches. It might lead to splits in what was formerly a single entity. On occasion, it might suggest further testing options that could be of value to patients now, or possibly at a date down the road. Or it might just leave pathologists and their clinical colleagues peering at a lack of data, knowing they have to make decisions nonetheless. Two groups—the World Health Organization and the International Consensus Classification—have put forth classifications to help physicians sort through the complexities. The WHO published a beta version of the fifth edition of its Classification of Haematolymphoid Tumours in July 2022.

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Breast cancer biomarkers, classic and new

February 2023—Like a thriving expat, Deborah Dillon, MD, is comfortable moving within worlds both old and new. Specifically, as a breast and molecular pathologist at Brigham and Women’s Hospital, she appreciates the biomarkers she and her colleagues grew up with, so to speak, as well as those that are part of a more recently arrived-at scenery. Not everyone finds both worlds equally riveting. “A lot of people are much more interested in, and excited by, new markers,” she says. “When I talk to people from pharma, this is what they want to hear about.” So do many pathologists, oncologists, and patients—new markers and new therapies have a way of updating hopes. Dr. Dillon understands the persistent thrill of the new, why people want her to talk the language of PIK3CA, PARP inhibitors, MMR, NTRK fusions, ESR1, and the like. But as an in-demand speaker as well as in a recent interview with CAP TODAY, she also advocates for making the old—the longstanding trinity of ER, PR, and HER2—seem new again.

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New starts: rapid-molecular pullback, fentanyl screen

January 2023—Respiratory viruses were up in most states when Compass Group members met online Dec. 6 with CAP TODAY publisher Bob McGonnagle, and some were looking to centralize their now decentralized rapid molecular testing. At least one system had already done so. In California, a new law requires fentanyl screening be included in drug screens in all general acute-care hospital lab settings.

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Close-up on HER2 alterations in advanced NSCLC

August 2022—HER2 is a known oncogenic driver and emerging biomarker in non-small cell lung cancer, and while the therapeutic implication is not yet fully known in NSCLC, “we need to pay attention to it,” said Fred R. Hirsch, MD, PhD, executive director of the Mount Sinai Center for Thoracic Oncology and associate director, Tisch Cancer Institute, in a CAP TODAY webinar sponsored by Daiichi-Sankyo and AstraZeneca.

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Molecular oncology tumor board: Pathologist, oncologist dip into head and neck case

February 2022—Up first in a CAP21 molecular oncology tumor board session was an unusual case of head and neck cancer, one that raises questions about what salivary duct carcinoma is and the role of next-generation sequencing. Justin Bishop, MD, the Jane B. and Edwin P. Jenevein, MD, distinguished chair in pathology and professor and chief of anatomic pathology, UT Southwestern, along with Saad Khan, MD, assistant professor of medicine (oncology) at Stanford, teamed up to present the case, along with a second case that will be reported in the March issue. (Dr. Khan practiced at one time at UT Southwestern, so this wasn’t their first tumor board together.)

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AMP case report: A case of a rare myeloid neoplasm presenting with features mimicking primary myelofibrosis

February 2022—Myeloproliferative neoplasms (MPNs) are a group of clonal hematopoietic stem cell disorders characterized by increased proliferation of myeloid cells of one or more lineage. The most common MPNs include chronic myeloid leukemia (CML), polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). CML is defined by the BCR-ABL1 fusion, which typically results from the t(9;22)(q34;q11.2) rearrangement.

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AMP case report: Rhinoscleroma in Southern California—diagnosis made by multidisciplinary investigation

January 2022—A 33-year-old male with progressive hoarseness and shortness of breath was given a purported diagnosis of laryngeal papillomatosis and referred to our institution in November 2020 for a higher level of care. On presentation, the patient reported no recent upper respiratory infection-like systemic symptoms but had cough, nasal congestion, throat discomfort, dysphonia, and worsening dyspnea.

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AMP case report: Identification of encephalomyocarditis virus using metagenomic NGS in a patient with acute febrile illness

December 2021—Clinical metagenomic next-generation sequencing (mNGS), the comprehensive analysis of microbial and host genetic material (DNA and RNA) in patient samples, is increasingly available in clinical laboratories. At present, for various reasons including test complexity, cost, and turnaround time, this technology is generally limited to difficult-to-diagnose conditions where conventional microbiological testing methods may not lead to a definitive diagnosis in selected patients, such as those with meningoencephalitis of unknown etiology.

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A sizable shift in CNS tumor classification

November 2021—Much has changed since the last WHO classification of central nervous system tumors was published five years ago. Case in point: When the group of authors met in Utrecht, the Netherlands, in late 2019, everyone anticipated two more WHO meetings in Europe to work further on the 2021 classification. Arie Perry, MD, a coauthor on both classifications, says the group photo was cheery. “Everybody was smiling.” The later trips to Europe were canceled because of the pandemic and the group met instead by Zoom. “Now everybody looked grumpy,” he says of a screen shot. Fortunately, “We got everything done, even if it wasn’t quite as pleasant,” says Dr. Perry, professor of pathology and neurological surgery, Department of Pathology, Division of Neuropathology, University of California, San Francisco. The result is the latest WHO classification, which offers dramatic changes of its own. “I’m really excited about the new WHO,” he says. “At first it takes a little getting used to”—like, say, a face mask—“but I think it’s another major advance, just like we had last time.”

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Molecular or morphology? Challenges in pathologic diagnoses

October 2021—Recent molecular genetic advances have dramatically expanded diagnostic options, thus revolutionizing the diagnosis of many tumor types, especially those of soft tissue and bone. Advances in the discovery of molecular alterations underlying neoplastic pathogenesis have also provided insights into novel therapeutic targets and prognostic biomarkers. These improvements have led to the reclassification of a growing list of previously established tumor types, resulting in significant challenges for practicing pathologists, as exemplified herein.

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AMP case report: Celiac genetic health risk screening by NGS in the family of a child with clinical findings of dermatitis herpetiformis and gluten sensitivity

August 2021—Dermatitis herpetiformis (DH) is an autoimmune skin disorder associated with celiac disease and characterized by pruritic, blistering lesions mainly on the elbows, knees, buttocks, lower back, and scalp. Immunopathogenesis is attributed to IgA TG3 antibody immune complexes in the papillary dermis originating from subclinical celiac disease in the gut. Onset occurs at any age, but DH is diagnosed most often in young adults and rarely in children. Individuals of northern European heritage represent the most frequently affected population for DH, with an estimated incidence reported by the National Organization for Rare Disorders of 75.3 per 100,000 people. First-degree family members of patients with DH are at increased risk for both DH and celiac disease.

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AMP case report: MYC amplification identified in an EML4-ALK-positive lung adenocarcinoma with primary resistance to targeted therapy

July 2021—The advent of genomically targeted therapy and immunotherapy has greatly altered the clinical management of advanced non-small cell lung cancer (NSCLC). Molecular testing is recommended for sensitizing EGFR mutations, ALK fusions, ROS1 fusions, BRAF V600E, NTRK fusions, RET fusions, and MET exon 14 skipping alterations.

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Higher stakes in systemic mastocytosis​

June 2021—Mastocytosis is not for quitters. Not at any point, from considering the possible diagnosis, to doing a complement of stains, to looking for mutations beyond KIT D816V, to being curious about the presence of mast cells even after making a diagnosis of another myeloid disease. Patients have already learned this grueling lesson. They can easily spend years seeking answers before their disease is properly identified. Pathologists can speed up that process—and the time to do so is now, says Tracy George, MD, chief medical officer and incoming president of ARUP Laboratories, and medical director of hematopathology. Notes Dr. George: “There’s some exciting stuff going on with systemic mastocytosis.” New targeted KIT inhibitors appear to be quite effective, including at least one agent for advanced systemic mastocytosis that has been submitted to the Food and Drug Administration. “We anticipate there’s going to be approval by the FDA this summer,” says Dr. George, who’s been involved in the clinical trials for avapritinib (Blueprint Medicines).

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Looming unknowns with SARS-CoV-2 variants

March 2021—Listening to experts and others make predictions about the pandemic, it’s easy to think they’re obsessed with surfing: How will we deal with the next wave? The dangers are real. With SARS-CoV-2, the next wave might be swept in by emerging variants, with their uncertain but worrisome impact on transmission, severity of illness, treatments, and vaccine effectiveness.

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AMP case report: A CLL/SLL case with distinctive molecular and cytogenetic changes during different stages of disease progression

March 2021—Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) is one of the most common lymphoproliferative diseases. It is a CD5-positive B-cell neoplasm of monomorphic small mature B cells. One of the characteristics of CLL/SLL is its heterogeneity, not only among individuals but also within individual patients.1 The cytogenetic and molecular variants are dynamic during disease progression and in response to targeted therapies.

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Markers, methods remake the NSCLC map

February 2021—Absorbing new biomarkers into lung cancer workups makes for a complicated diplomacy. How best to balance so many rivals? Does it make the most sense for laboratories to try to do everything at once, a full-court press involving next-generation sequencing panels? Or is it more practical to add a new marker only as a new targeted therapy receives approval? Where do RNA-based assays fit in? What about IHC? When do you make the switch? Or do you? And how best to handle cell-free DNA tests (which seem to be the rogue states in all this)? How do you weight external factors, such as reimbursement, existing equipment and capital expenditures, and physician expertise? Driving this all are medical breakthroughs. As with all forms of statecraft, the latest incident can change everything. For lung cancer, the most recent advance comes from the ADAURA trial, which showed a significant benefit of using osimertinib to treat stage IB to IIIA EGFR-mutation positive non-small-cell lung cancer.

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AMP case report: 18-month-old female with poorly differentiated cerebellar tumor harboring BCOR internal tandem duplication

January 2021—Central nervous system high-grade neuroepithelial tumor with BCOR alteration (CNS HGNET-BCOR) is a rare and genetically distinct CNS neoplasm that occurs predominantly in the pediatric population. Previously, these tumors had been categorized as primitive neuroectodermal tumors of the central nervous system (CNS-PNET).

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AMP case report: NGS as the tiebreaker in tumors with similar morphology and equivocal immunophenotype

May 2020—Traditionally, histopathologic diagnosis has been regarded as the gold standard for most disease processes including cancer. However, in certain circumstances, a final histopathologic diagnosis cannot be rendered despite extensive conventional ancillary testing such as immunohistochemistry. In recent years, molecular testing has revealed specific variant signatures for many tumors, which can be used to determine a final diagnosis.

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In CML, BCR-ABL monitoring takes on new importance

March 2020—Three decades ago, when Jerald Radich, MD, started doing BCR-ABL testing, the process was highly hands-on. In those days, “we used water baths to do PCR,” said Dr. Radich, an oncologist and director of the molecular oncology lab and member of the Clinical Research Division, Fred Hutchinson Cancer Research Center, in a recent CAP TODAY webinar.

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ME multiplex panel: debating the tradeoffs

June 2019—Meningitis and encephalitis have been called by some the most terrifying diseases in medicine, in part because of the difficulty of diagnosing their underlying pathology. The clinical stakes of laboratory testing are high for diagnosing and treating the inflammation that meningitis/encephalitis (ME) causes within the central nervous system.

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Bladder cancer detection and surveillance: How urine cell-free DNA stacks up against cytology

June 2019—A high-throughput sequencing panel was found to be more than 90 percent sensitive in detecting urinary tumor DNA in early-stage bladder cancer and in post-treatment surveillance. The approach, reported in April in Cancer Discovery, overcomes some of the challenges urinary cell-free DNA analysis poses, said one of its developers, and is far more sensitive than cytology and cystoscopy.

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Lung guideline goals: more tests, treatment

March 2018—Among the many never-ending chores that humans undertake—paying bills, filing taxes, flossing—writing medical guidelines can seem like an especially perpetual task. Just ask the architects of an updated document on molecular testing for lung cancer, issued by the CAP, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology.

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Next-gen sequencing finds further clinical utility in oncology

January 2018—One of the plenary sessions at the 2017 meeting of the Association for Molecular Pathology—“High Impact Molecular Diagnostics for Cancer and Inherited Diseases”—was a virtual mini-course in the latest and most useful applications of next-generation sequencing to detect germline and somatic mutations in cancer. Both speakers zeroed in on the clinical utility of their innovative diagnostic techniques.

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New molecular road map for CRC

April 2017—Molecular testing for colorectal cancer is not for the faint of heart. While that’s not news to Stan Hamilton, MD—he’s head, Division of Pathology and Laboratory Medicine, and the Frederick F. Becker distinguished chair in cancer research, University of Texas MD Anderson Cancer Center—he was reminded of this fact recently when a friend looked at the multipage molecular pathology report on his own tumor.

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‘A marriage of virtual and real bronchoscopy’

February 2017—The molecular testing guidelines have been having a significant impact on surgical practices since they were issued, said thoracic surgeon Min Kim, MD, another webinar panelist. As practice at his institution, Houston Methodist Hospital, has evolved, Dr. Kim said, there has been an increasing need for minimally invasive ways of obtaining tissue from lung cancer patients.

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What molecular diagnostics laboratory systems offer

December 2016—As personalized and predictive medicine have progressed from not-in-my-lifetime to now available, health care information technology vendors have faced the challenge of how to manage a mass of molecular data and direct molecular testing processes. CAP TODAY asked vendors of molecular diagnostics lab information systems to explain what their products contribute to the flourishing field of molecular testing. Here are their responses.

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Diagnosing polycythemia vera: conventional tools amid molecular options—case report and brief review

April 2016—Case. The patient presented in May 2013 at age 42 with a two-year history of fatigue and pruritus of his legs. He smoked one pack of cigarettes per day as he had for 25 years and had about five to six alcoholic drinks daily. Physical exam was unremarkable with no rash or palpable splenomegaly. Height was 74 inches and weight 189 pounds.

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Roads cross in clonal hematopoiesis and stem cell studies

March 2016—At the annual meeting of the Association for Molecular Pathology in November 2015, one plenary session was called “Exciting Times for Translational Research in Molecular Hematology.” In accord with the title, Margaret Goodell, PhD, gave an exciting talk about how hematopoietic stem cells are regulated in mice. While Dr. Goodell’s basic research was impressive, what was most remarkable was how it meshed with and anticipated research in human hematopoietic malignancies from other laboratories.

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In genetics, stay open to the unexpected

July 2015—When Uta Francke, MD, received the Association for Molecular Pathology Award for Excellence in Molecular Diagnostics at the 2014 AMP meeting, she titled her lecture “Adventures in Disease Gene Identification and Characterization of Mutations.” Her title was appropriate for a research clinician who, during her 35-year career, while working on several major human genetic disease challenges, contributed in significant ways to our understanding of important genetic disease mechanisms and whose laboratory identified the gene for Wiskott-Aldrich syndrome.

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Workflow, regulatory unknowns tax molecular IT

April 2015—Alexis Carter, MD, immediate past president of the Association for Pathology Informatics, isn’t under any illusion about how well information technology is meeting the needs of molecular diagnostics. “Laboratory information systems right now do a fairly decent job of getting samples to the right lab, tracking the sample, and reporting results,” Dr. Carter says. But when it comes to molecular diagnostics laboratories, “LISs are really not where they should be. They’re kind of moving at a turtle’s pace to keep up.”

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With molecular MPN testing, think positive

March 2015—If molecular tests for myeloproliferative neoplasms ever decide to write their autobiography, they could easily do a riff on the business bestseller Getting to Yes. For myeloproliferative neoplasms, morphologic and clinical findings should guide molecular analysis, which can often be a helpful way to clinch the diagnosis, says Dr. David Czuchlewski (left), of TriCore Reference Laboratories, with Mohammad Vasef, MD, TriCore’s director of molecular diagnostics.

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Medical genetics labs shine in 10-year proficiency test data

January 2015—Molecular genetics laboratories in the U.S. are doing a great job. Ten-year data from the molecular genetics Surveys in the CAP proficiency testing program show that U.S. clinical laboratories are making extremely accurate calls using molecular genetics assays. At the 2014 meeting of the Association for Molecular Pathology, Karen E. Weck, MD, and Iris Schrijver, MD, presented results from seven of the proficiency Surveys that the CAP/ACMG Biochemical and Molecular Genetics Resource Committee oversees. Dr. Weck is the chair of the committee; Dr. Schrijver is past chair.

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From tumor board, an integrated diagnostic report

December 2014—The handling of molecular information bears a certain resemblance to Wall Street’s bundling of mortgages in recent years. You can slice ’em, dice ’em, and repackage them in all sorts of ways. In medicine, however, this is being done—one would hope—without the ensuing meltdown. The goal is to shape personalized medicine, using the results of next-generation sequencing and other technologies to evaluate genetic information ranging from single gene to whole exome or whole genome, with proteomics possibly not too far behind.

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Is molecular AP testing in sync with guidelines?

November 2014—Molecular testing, on a steep growth curve in anatomic pathology, is increasingly providing decisive guidance for treatment of cancer patients. But while guidelines on clinical relevance and performance of common molecular tests are available and widely used in theory, to date there has been limited information on how well requests for molecular testing in AP laboratories are adhering to the guidelines.

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Molecular tumor boards: fixture or fad?

October 2014—Along with everything else the genomics revolution has wrought, there’s this: Molecular testing is threatening to turn medicine into an ongoing episode of “Hoarders.” So much information and so many possible uses for it—including, in some cases, none at all. The expansion of molecular testing is also upending the role of the traditional tumor board.

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AML molecular testing a map with many paths

July 2014—When it comes to molecular testing for acute myeloid leukemia, the approach seems more Montessori than military school. There are some basic steps physicians should take, to be sure. Cytogenetics still shepherds patients into three prognostic groups: favorable, intermediate, and unfavorable. And several gene mutations—NPM1, CEBPA, FLT3, and KIT—alone or in combination, and with various cytogenetic associations, provide additional prognostic and therapeutic guidance.

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Molecular testing platforms a land of plenty

October 2013—If you’ve ever seen what happens when someone accidentally puts regular liquid soap in a dishwasher, you’ll have a good mental image of just how vigorously the automated molecular testing market is bubbling over with new assays. HCV genotyping, rifampin resistance, group A Streptococcus—vendors are pouring these and many other tests into a market that, by all accounts, is more than eager for them.

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With molecular testing, better infection control

September 2013—Rapid and accurate molecular assays have gradually infiltrated the field of bacterial diagnosis. For several potentially lethal nosocomial pathogens—Clostridium difficile, vancomycin-resistant enterococcus, Mycobacterium tuberculosis, and methicillin-resistant Staphylococcus aureus—FDA-approved molecular assays are making a difference. Not only have they improved the accuracy of diagnosis, benefiting patients and clinicians, they have also been a boon to infection control practitioners.

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HCV, CMV viral load—treatment, testing, timing

April 2013—Treatment for hepatitis C virus infection turned a corner in 2011 when direct-acting antiviral inhibitors were approved and combined with dual therapy—pegylated interferon and ribavirin. Cure rates shot up from about 45 percent to 70 to 75 percent. With antivirals that are even more potent in late-stage clinical trials now, “Use of oral antiviral therapy without interferon appears to be a real possibility for the near future,” said Mitchell L. Shiffman, MD, director of the Liver Institute of Virginia at Bon Secours Health System in Richmond and Newport News, in an Association for Molecular Pathology session at the 2012 annual meeting, where he spoke about viral load monitoring for HCV.

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New guidance on lung cancer testing

April 2013—It was a monumental task: create a molecular testing guideline for lung cancer. Among other tasks, those involved (representing the CAP, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology) reviewed 1,533 abstracts and read, in detail, 521 full-text articles. There was extensive evidence grading; naturally, new literature was published in the interim, which required even more reviews. The payoff was the first international, evidence-based, multidisciplinary guideline for this part of lung cancer care. It contains 37 items addressing 14 subjects, including 15 recommendations (evidence grade A/B).

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AMP case report: Multilocus sequencing for rapid identification of molds

February 2013—CAP TODAY and the Association for Molecular Pathology have teamed up to bring molecular case reports to CAP TODAY readers, starting this month. AMP members will write the reports using clinical cases from their own practices that show molecular testing’s important role in diagnosis, prognosis, treatment, and more. We aim to publish a few a year. The first such report comes from the University of Washington Medical Center, Seattle. (If you would like to submit a case report, please e-mail the AMP at amp@amp.org. For more information about the AMP, visit www.amp.org.)

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Building the case for PGx testing

January 2013—Mammals have a striking range of gestation periods, from the 12 days and 31 days of the opossum and rabbit to the 266 days and 360 days of the human and whale. Laboratory tests, too, take shorter or longer amounts of time to be delivered into routine clinical practice, with pharmacogenomics beginning to look like the elephant—more than 600 days’ gestation—of laboratory testing. Our first major discussion of this topic was in 2005, and the clinical pathology world had been “expecting” its arrival for some time before that.

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