Showing papers in "American Journal of Clinical Pathology in 2015"
TL;DR: Findings further articulate that breast cancer subtypes differ not only in tumor characteristics but also in their metastatic behavior, thus raising the possibility that this knowledge could potentially be used in determining the appropriate strategy for follow-up of patients with newly diagnosed breast cancer.
Abstract: Objectives: The distant organs to which breast cancer preferentially metastasizes are of significant clinical importance.
Methods: We explored the relationship between the clinicopathologic factors and the common sites of distant metastasis in 531 consecutive patients with advanced breast cancer.
Results: Breast cancer subtype as a variable was significantly associated with all five common sites of relapse by multivariate analysis. The luminal tumors were remarkable for their significant bone-seeking phenotype and were less frequently observed in lung, brain, and pleural metastases and less likely to be associated with multiorgan relapse. The HER2 subtype demonstrated a significant liver-homing characteristic. African Americans were significantly less likely to have brain-only metastasis in patients with brain relapse.
Conclusions: These findings further articulate that breast cancer subtypes differ not only in tumor characteristics but also in their metastatic behavior, thus raising the possibility that this knowledge could potentially be used in determining the appropriate strategy for follow-up of patients with newly diagnosed breast cancer.
180 citations
TL;DR: Strong nuclear STAT6 is largely specific for SFTs, and Physiologic low-level cytoplasmic/nuclear expression is common in mesenchymal neoplasia and is of uncertain significance.
Abstract: Objectives: Expression of strong nuclear STAT6 is thought to be a specific marker for solitary fibrous tumors (SFTs). Little is known about subtle expression patterns in other mesenchymal lesions.
Methods: We performed immunohistochemical studies against the C-terminus of STAT6 in tissue microarrays and whole sections, comprising 2366 mesenchymal lesions.
Results: Strong nuclear STAT6 was expressed in 285 of 2,021 tumors, including 206 of 240 SFTs, 49 of 408 well-differentiated/dedifferentiated liposarcomas, eight of 65 unclassified sarcomas, and 14 of 184 desmoid tumors, among others. Expression in SFTs was predominately limited to the nucleus. Other positive tumors typically expressed both nuclear and cytoplasmic STAT6. Complete absence of STAT6 was most common in pleomorphic liposarcoma and alveolar soft part sarcoma (60% and 72% cases negative, respectively).
Conclusions: Strong nuclear STAT6 is largely specific for SFTs. Physiologic low-level cytoplasmic/nuclear expression is common in mesenchymal neoplasia and is of uncertain significance.
160 citations
TL;DR: In normal adult tissue that INSM1 expression was highly restricted to nuclei of NE cells and tissues, and among midgut GI-NENs, neoplasms with known metastases showed significantly higher expression than those that had not yet metastasized.
Abstract: Objectives Neuroendocrine neoplasms (NENs) are heterogeneous neoplasms, which are sometimes malignant, although predicting metastasis is difficult. INSM1 is a transcription factor expressed transiently in embryonic neuroendocrine (NE) tissue, thought to coordinate termination of cell division with differentiation of NE and neuroepithelial cells. In adult tissues, INSM1 has been identified in multiple tumors of NE or neuroepithelial origin but has not been thoroughly investigated as a potential neoplastic marker. Methods We evaluated INSM1 as a semiquantitative immunohistochemical (IHC) marker for NE and neuroepithelial neoplasms and as a quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) marker for gastrointestinal NENs (GI-NENs). Results Using IHC, we found in normal adult tissue that INSM1 expression was highly restricted to nuclei of NE cells and tissues. INSM1 was not detected in any adult nonneoplastic, non-NE tissue. In neoplastic tissue, INSM1 was detectable by IHC in 88.3% of 129 NEN specimens. In contrast, INSM1 was detected by IHC in only one of 27 neoplasms without a neuroepithelial or NE component. Using qRT-PCR, we evaluated INSM1 gene expression in 113 GI-NEN specimens. Conclusions INSM1 expression was significantly increased in neoplastic vs nonneoplastic tissue. Furthermore, among midgut GI-NENs, neoplasms with known metastases showed significantly higher expression than those that had not yet metastasized.
132 citations
TL;DR: It is important to recognize ETP-ALL, because these patients have a poor prognosis if treated with standard therapy and a consensus immunophenotype has been developed to aid in the recognition of these cases.
Abstract: Objectives To review important concepts from the 2013 Society for Hematopathology/European Association for Haematopathology Workshop session on T-acute lymphoblastic leukemia/T-lymphoblastic lymphoma (T-ALL/T-LBL).
Methods Twenty-one submitted cases are reviewed and summarized, with emphasis on key diagnostic or biologic points, and supplemented with relevant literature citations.
Results Early T-cell precursor (ETP)-ALL represented about one-third of all cases submitted. It is important to recognize ETP-ALL, because these patients have a poor prognosis if treated with standard therapy. A consensus immunophenotype has been developed to aid in the recognition of these cases. Other cases submitted illustrated rare entities, including two cases of Philadelphia chromosome–positive T-ALL, two cases of T-ALL associated with MYC translocations, and single cases illustrating various diseases. A subset of cases submitted illustrated issues related to differential diagnosis of T-ALL/T-LBL.
Conclusions In view of the growing importance of molecular genetic analysis in the diagnosis and prognosis of T-ALL/T-LBL, it is important for pathologists to keep abreast of these developments. Currently, routine histopathology, immunophenotyping, conventional cytogenetic analysis, fluorescence in situ hybridization, and clonality testing are usually adequate to establish the diagnosis. However, as therapies become more targeted, assessment for relevant genetic abnormalities, either through candidate gene or broad-scale unbiased approaches, may become necessary.
114 citations
TL;DR: Endocrine pathologists are reconsidering whether tumors characterized as noninvasive follicular variant of papillary thyroid carcinoma (NFVPTC) warrant a diagnosis of carcinoma, and a change in terminology would affect cytology diagnoses; thus, the preceding fine-needle aspiration diagnoses of this group of tumors were studied.
Abstract: Objectives Endocrine pathologists are reconsidering whether tumors characterized as noninvasive follicular variant of papillary thyroid carcinoma (NFVPTC) warrant a diagnosis of carcinoma. A change in terminology would affect cytology diagnoses; thus, our aim was to study the preceding fine-needle aspiration (FNA) diagnoses of this group of tumors. Methods We evaluated the FNA diagnoses of a primary cohort of 72 consecutively resected NFVPTCs and the cytologic and molecular features of an additional cohort of 39 tumors that included both NFVPTCs and classical papillary thyroid carcinomas (cPTCs). Results For our primary cohort, the preceding FNA diagnosis associated with the highest risk of malignancy was suspicious for PTC in nearly half (48.6%) of cases. In contrast to the majority of cPTCs, no NFVPTCs in our second cohort had papillae or pseudoinclusions on cytologic evaluation of the FNA specimens, and none harbored a BRAF V600E mutation. Conclusions If NFVPTCs were no longer termed carcinomas, this would affect the rate of malignancy of FNA diagnostic categories. Cytologic and molecular features could aid in identifying NFVPTCs at the time of FNA diagnosis.
104 citations
TL;DR: Salivary gland FNA categorization into commonly encountered morphologic categories provides risk stratification, which translates to a simplified classification scheme of benign, NUMP, suspicious, and positive for malignancy similar to the paradigm in other organ systems.
Abstract: Objectives: Fine-needle aspiration (FNA) is useful in the evaluation of salivary gland tumors, but currently no standard terminology or risk stratification model exists.
Methods: FNA smears were reviewed and categorized based on cytonuclear features, stromal characteristics, and background characteristics. Risk of malignancy was calculated for each category. Classifications as benign, neoplasm of uncertain malignant potential (NUMP), suspicious for malignancy, and positive for malignancy were used to aggregate categories into similar risk groups.
Results: Categorization of salivary gland aspirates into morphologic categories resulted in the expected risk stratification. Grouping of categories maintained risk stratification, providing classes with malignancy risk as follows: benign, 2%; NUMP, 18%; suspicious for malignancy, 76%; and positive for malignancy, 100%.
Conclusions: Salivary gland FNA categorization into commonly encountered morphologic categories provides risk stratification, which translates to a simplified classification scheme of benign, NUMP, suspicious, and positive for malignancy similar to the paradigm in other organ systems.
103 citations
TL;DR: The average percent CV for fingerprick blood was up to 5 times higher for hemoglobin than venous blood measured using a point-of-care hemoglobinometer, which suggests caution when using measurements from a single drop of fingerprack blood.
Abstract: Objectives Blood obtained via fingerprick is commonly used in point-of-care assays, but few studies have assessed variability in parameters obtained from successive drops of fingerprick blood, which may cause problems for clinical decision making and for assessing accuracy of point-of-care tests.
Methods We used a hematology analyzer to analyze the hemoglobin concentration, total WBC count, three-part WBC differential, and platelet count in six successive drops of blood collected from one fingerprick from each of 11 donors, and we used a hemoglobinometer to measure the hemoglobin concentration of 10 drops of fingerprick blood from each of 7 donors.
Results The average percent coefficient of variation (CV) for successive drops of fingerprick blood was higher by up to 3.4 times for hemoglobin, 5.7 times for WBC count, 3 times for lymphocyte count, 7.7 times for granulocyte count, and 4 times for platelets than in venous controls measured using a hematology analyzer. The average percent CV for fingerprick blood was up to 5 times higher for hemoglobin than venous blood measured using a point-of-care hemoglobinometer. Fluctuations in blood parameters with increasing volume of fingerprick blood are within instrument variability for volumes equal to or greater than 60 to 100 μL.
Conclusions These data suggest caution when using measurements from a single drop of fingerprick blood.
97 citations
TL;DR: Abundant TILs and the absence of lymphovascular invasion were found to be good, independent prognostic factors for disease-free survival in patients with HR-/HER2+ breast cancer.
Abstract: Objectives: Tumor-infiltrating lymphocytes (TILs) have prognostic significance in breast cancer. The tertiary lymphoid structure (TLS) is related to the influx of TILs, and expression of major histocompatibility complex (MHC) I in tumor cells is necessary for the effective action of TILs.
Methods: We retrospectively evaluated the relationship of TILs and TLS and the expression of MHC I in 447 HER2-positive breast cancers treated with chemotherapy and 1 year of trastuzumab.
Results: TILs were more abundant in hormone receptor (HR)−/HER2+ tumors than in HR+/HER2+ tumors. HR−/HER2+ breast cancers with abundant TILs showed a higher histologic grade, the absence of lymphovascular invasion, the presence of peritumoral lymphocytic infiltration, moderate to abundant TLSs in adjacent tissue, and stronger HLA-ABC and HLA-A expression. Abundant TILs and the absence of lymphovascular invasion were found to be good, independent prognostic factors for disease-free survival in patients with HR−/HER2+ breast cancer. The level of TILs was not associated with the patients’ prognosis in HR+ tumors.
Conclusions: Abundant TILs are an independent prognostic factor in HR−/HER2+ breast cancers. Evaluation of TILs in HR−/HER2+ breast cancers may provide valuable information regarding the prognosis of patients treated using adjuvant chemotherapy and trastuzumab.
92 citations
TL;DR: When paraffin-embedded tissue is used for molecularTesting of lung cancer, CNB specimens are more likely than FNA specimens to provide adequate tissue for molecular testing.
Abstract: Objectives: Molecular testing of lung adenocarcinomas for epidermal growth factor ( EGFR ) mutations and an anaplastic lymphoma kinase ( ALK ) translocation is important to guide directed therapy with tyrosine kinase inhibitors. The goal of this study was to determine whether transthoracic computed tomography–guided core needle biopsy (CNB) and fine-needle aspiration (FNA) biopsy specimens were equally suitable for molecular testing.
Methods: We determined the percentage of 52 CNB and 120 FNA specimens that contained sufficient paraffin-embedded tumor tissue for EGFR , KRAS , and ALK testing over a period of 2 years. We correlated sample sufficiency with the sampling method, tumor size, biopsy operator, pathologist assessing the adequacy of the sample, and the number of FNA passes performed.
Results: Univariate analysis showed that CNB specimens provided a significantly higher number of samples sufficient for molecular testing than did FNA specimens (67% vs 46%; P = .007) and that one operator achieved a significantly higher percentage of sufficient FNA specimens. Binomial logistic regression found sufficiency of FNA samples to correlate with tumor size ( P = .015) but not operator.
Conclusions: When paraffin-embedded tissue is used for molecular testing of lung cancer, CNB specimens are more likely than FNA specimens to provide adequate tissue for molecular testing. Obtaining a sufficient FNA specimen depends on the tumor size and the individual performing the biopsy.
78 citations
TL;DR: Whole-genome sequencing and array studies may identify genetic abnormalities, such as those affecting TP53, which may provide prognostic information.
Abstract: Objectives: Acute myeloid leukemia with myelodysplasia-related changes (AML-MRC) is a heterogeneous disorder defined by morphologic, genetic, or clinical features. Genetic abnormalities associated with AML-MRC are often associated with adverse prognostic features, and many cases are preceded by a myelodysplastic syndrome (MDS) or a myelodysplastic/myeloproliferative neoplasm.
Methods: Although the criteria of 20% or more blasts in blood or bone marrow and multilineage dysplasia affecting 50% or more of cells in two or more of the myeloid lineages seem straightforward for AML-MRC, identification of morphologic dysplasia among observers is not always consistent, and there is morphologic overlap with other leukemic disorders such as acute erythroleukemia.
Results: Session 3 of the workshop cases displayed heterogeneity as expected within AML-MRC, yet several cases suggested that recently recognized entities may exist within this category, such as familial MDS/AML predisposition syndromes and rare cases of high-risk AML associated with the cryptic t(5;11)(q35;p15); NUP98-NSD1 that may masquerade as a del(5q). However, most cases of AML-MRC were usually associated with adverse genetic abnormalities, particularly −5/del(5q), −7/del(7q), and/or complex karyotypes.
Conclusions: Whole-genome sequencing and array studies may identify genetic abnormalities, such as those affecting TP53, which may provide prognostic information.
78 citations
TL;DR: CALR mutations were frequently observed in the JAK2-negative MPNs, most frequently in MPN-U, and the prognostic significance of CALR mutations likely differs among the MPN subtypes.
Abstract: Objectives: We investigated mutation profiles of CALR , JAK2 , and MPL in 199 Korean patients with myeloproliferative neoplasms (MPNs).
Methods: In total, 199 patients with MPN (54 primary myelofibrosis [PMF], 79 essential thrombocythemia [ET], 58 polycythemia vera [PV], and eight MPN-unclassifiable [MPN-U]) and 4 patients with acute panmyelosis with myelofibrosis (APMF) were retrospectively subjected to Sanger sequencing for CALR , JAK2 , and MPL .
Results: The overall frequency of CALR mutations was 12.6% (type 1 mutation, 16 patients; type 2 mutation, nine patients): most frequent in MPN-U (37.5%), followed by ET (17.7%) and PMF (14.8%). CALR mutations were not found in PV or APMF. CALR and JAK2 or MPL mutations were mutually exclusive. In PMF, the CALR mutations were associated with lower levels of leukocytes, lower bone marrow cellularity, and higher number of megakaryocytes. Patients with CALR -mutated ET more frequently progressed to the accelerated or blast phases compared with patients with JAK2 mutations. CALR mutations were frequently observed in the JAK2 -negative MPNs, most frequently in MPN-U.
Conclusions: The prognostic significance of CALR mutations likely differs among the MPN subtypes.
TL;DR: In the era of targeted therapy and sophisticated risk stratification, every attempt must be made to perform a complete workup on MS cases (or concurrent AML) since the diagnosis of MS, in itself, is no longer adequate for patient management.
Abstract: Objectives: This session of the 2013 Society of Hematopathology/European Association for Haematopathology workshop focused on extramedullary manifestations of myeloid neoplasms.
Methods: We divided the submitted cases into four subgroups: (1) isolated myeloid sarcoma (MS); (2) MS with concurrent acute myeloid leukemia (AML), with a focus on karyotypic and molecular findings; (3) extramedullary relapse of AML, including relapse in the posttransplant setting; and (4) blast phase/transformation of a myeloproliferative neoplasm or chronic myelomonocytic leukemia.
Results: Establishing a diagnosis of isolated MS requires a high index of suspicion and use of immunophenotypic methods. Recurrent cytogenetic abnormalities or gene mutations that occur in MS mirror those known to occur in AML.
Conclusions: In the era of targeted therapy and sophisticated risk stratification, every attempt must be made to perform a complete workup on MS cases (or concurrent AML) since the diagnosis of MS, in itself, is no longer adequate for patient management. Cases of blastic plasmacytoid dendritic cell neoplasm were also included and discussed in this session.
TL;DR: This study demonstrates that EBUS-TBNA can be effectively used not just for diagnosis but also for complete mutational testing, comparing the results with a series of patients who underwent diagnostic surgical procedures in the same institution.
Abstract: Objectives: Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is a minimally invasive procedure that has revolutionized the diagnosis and staging of lung cancer. The goal of the present study was to investigate the yield and applicability of molecular testing in the specimens obtained by EBUS-TBNA from patients with advanced non–small cell lung cancer (NSCLC), comparing the results with a series of patients who underwent diagnostic surgical procedures in the same institution.
Methods: The study followed 306 consecutive patients with clinically diagnosed primary lung cancer who had the EBUS-TBNA procedure. EGFR and KRAS mutations were evaluated on cytologic specimens by Sanger sequencing and Cobas real-time polymerase chain reaction, whereas ALK rearrangement was tested by fluorescence in situ hybridization. The results were compared with those obtained from a series of 1,000 NSCLC surgical samples routinely analyzed.
Results: Molecular testing was possible in 96.9% of the samples obtained by EBUS-TBNA. EGFR (exons 18–21) mutations were found in 16.9%, KRAS mutation (exons 2–3) in 31.6%, and ALK rearrangement in 3.9% of the cases. In the surgical series, the mutations’ distribution were 14.8%, 29.0%, and 3.4%, respectively. There were no statistical differences between the two series .
Conclusions: Our study demonstrates that EBUS-TBNA can be effectively used not just for diagnosis but also for complete mutational testing.
TL;DR: The results from this study provide crucial guidelines for future investigations using complement biomarkers to define the role of complement system in disease.
Abstract: Objectives Recent studies have shown that complement hyperactivation contributes to development of thrombotic microangiopathy. The evaluation of complement biomarkers is known to be influenced by inappropriate specimen handling. However, there has been no study fully addressing this topic. Methods Blood from each donor was subjected to 62 different handling conditions prior to complement assays. Results Complement biomarkers (C4d/C3a/factor Bb/C5a/C5b-9) are stable at room temperature (RT) for up to 4 hours in whole blood containing citrate or EDTA. However, under similar conditions, levels of C4d and C3a were significantly higher in serum than those in plasma. Thawing of the samples on ice or at RT had no significant effect on complement levels. In contrast, thawing at 37°C resulted in striking increases in levels of the complement system in serum and citrated plasma but not in EDTA plasma. Up to four freeze/thaw cycles on ice or RT did not substantially increase the levels of C3a, factor Bb, C5a, and C5b-9 but had a significant effect on C4d. Long-term storage of citrated plasma at -80°C for up to 6 years had no significant effect on levels of complement factors. Conclusions The results from this study thus provide crucial guidelines for future investigations using complement biomarkers to define the role of complement system in disease.
TL;DR: Intratumoral and intertumoral Ki-67 heterogeneity is common and positively correlated with tumor size, and the presence of one or more grade 3 liver lesions predicts a worse prognosis.
Abstract: Objectives: We examined Ki-67 heterogeneity within single and between synchronous liver metastases of small intestine neuroendocrine tumors.
Methods: There were 27 patients (10 men and 17 women) with two or more liver metastases. The Ki-67 index was used to classify the tumors into World Health Organization grade 1, 2, or 3. The association between Ki-67 heterogeneity and tumor size of liver metastases was analyzed. Correlation of tumor grade with patient survival was also evaluated.
Results: Primary tumors from 20 patients were graded, including 17 grade 1 and three grade 2. A total of 188 liver metastases were resected, including 122 (65%) grade 1, 47 (25%) grade 2, and 19 (10%) grade 3. The highest tumor grade was grade 1 in 10 (37%), grade 2 in nine (33%), and grade 3 in eight (30%) patients. Patients with one or more grade 3 liver lesions had a shorter progression-free survival compared with those with grade 1/2 tumors ( P < .001). A positive association was found between tumor size and Ki-67 index ( P = .04), as well as between tumor size and intratumoral Ki-67 heterogeneity ( P < .001).
Conclusions: Intratumoral and intertumoral Ki-67 heterogeneity is common and positively correlated with tumor size. The presence of one or more grade 3 liver lesions predicts a worse prognosis.
TL;DR: Overall certification rates are highest among laboratory personnel in cytogenetics, hematology/coagulation, and flow cytometry departments and lowest among phlebotomy, specimen processing, and anatomic pathology.
Abstract: Since 1988, the American Society for Clinical Pathology (ASCP) has conducted its Vacancy Survey to determine the extent and distribution of workforce shortages within the nation’s clinical laboratories. This confidential survey has been administered every 2 years and has served as the primary source of information for academic, government, and industry labor analysts. Results from past surveys show that laboratory medicine is a rapidly evolving field. Although ASCP recognizes the importance of continuity, each administration of the Wage and Vacancy Survey represents an opportunity to improve its methodology to collect the most current relevant data while maximizing survey participation. The Survey has evolved in response to changes within the profession; new questions were added to the 2012 Survey to examine some of the factors affecting wage and vacancy rates. The ASCP continues to gather questions, comments, and suggestions from our members regarding the profession with the goal of addressing them through this important survey.
TL;DR: Provider education and reminders can reduce the frequency of daily blood tests ordered by providers for hospitalized patients, which can decrease health care costs and may reduce the risk of complications such as anemia.
Abstract: Objectives: During hospitalizations, blood is drawn for diagnostic laboratory tests to help guide patient care. Often, blood tests continue to be ordered even in the face of clinical and laboratory stability. Blood draws are painful and costly, and they may be associated with anemia. We hypothesized that provider education could reduce the frequency of daily blood tests ordered for hospitalized patients.
Methods: During a 2-month intervention period, internal medicine providers were educated through flyers displayed in providers’ offices and periodic email communications reminding them to order daily blood tests only if the results would change patient care. Two-month preintervention data from 982 patients and 2-month postintervention data from 988 patients were analyzed. The primary outcome measured was the number of daily blood tests ordered per patient per day.
Results: Mean orders of CBC decreased from 1.46 to 1.37 tests per patient per day ( P < .05) after the intervention. Basic metabolic panel orders were reduced from 0.91 to 0.83 tests per patient per day ( P < .05). Cost analyses showed a reduction of $6.33 per patient day based on the decrease in the number of daily laboratory tests ordered.
Conclusions: Provider education and reminders can reduce the frequency of daily blood tests ordered by providers for hospitalized patients. This can decrease health care costs and may reduce the risk of complications such as anemia.
TL;DR: Edoxaban concentration-dependently inhibited thrombin generation, with a more potent effect seen in PPP than in PRP, and aPTT could be used as a conventional and convenient test with a smaller variation among reagents.
Abstract: Objectives: Edoxaban, an oral direct factor Xa inhibitor, does not require routine monitoring. However, assessment of the anticoagulant effects may be required in certain situations.
Methods: We investigated the effects of edoxaban on prothrombin time (PT), activated partial thromboplastin time (aPTT), and thrombin generation using human platelet-poor plasma (PPP) or platelet-rich plasma (PRP).
Results: Edoxaban concentration-dependently prolonged PT and aPTT. There was a considerable variation in the magnitude of PT prolongation among the reagents used. The variability in aPTT prolongation among the reagents was smaller than that of PT. Edoxaban concentration-dependently inhibited thrombin generation, with a more potent effect seen in PPP than in PRP. Thrombin generation assay was three times more sensitive to edoxaban than PT and aPTT.
Conclusions: PT had disadvantages of a large variability among different PT reagents. aPTT could be used as a conventional and convenient test with a smaller variation among reagents. Thrombin generation was the most sensitive assay.
TL;DR: Structural and process changes that require laboratory contact and justification for duplicate testing are more effective than interventions that allow providers to bypass alerts without justification at point of computerized physician order entry.
Abstract: Objectives: Unnecessary duplicate laboratory testing is common and costly. Systems-based means to avert unnecessary testing should be investigated and employed.
Methods: We compared the effectiveness and cost savings associated with two clinical decision support tools to stop duplicate testing. The Hard Stop required telephone contact with the laboratory and justification to have the duplicate test performed, whereas the Smart Alert allowed the provider to bypass the alert at the point of order entry without justification.
Results: The Hard Stop alert was significantly more effective than the Smart Alert (92.3% vs 42.6%, respectively; P < .0001). The cost savings realized per alert activation was $16.08/alert for the Hard Stop alert vs $3.52/alert for the Smart Alert.
Conclusions: Structural and process changes that require laboratory contact and justification for duplicate testing are more effective than interventions that allow providers to bypass alerts without justification at point of computerized physician order entry.
TL;DR: These results support the use of AHPV as a safe and effective adjunctive cervical cancer screening method and suggest a very low risk of CIN2+ in women negative by either human papillomavirus test after 3 years of follow-up.
Abstract: Objectives This study determined the longitudinal clinical performance of a high-risk human papillomavirus (HR-HPV) E6/E7 RNA assay (Aptima HPV [AHPV]; Hologic, San Diego, CA) compared with an HR-HPV DNA assay (Hybrid Capture 2 [HC2]; Qiagen, Gaithersburg, MD) as an adjunctive method for cervical cancer screening. Methods Women 30 years or older with a negative result for intraepithelial lesions or malignancy cytology (n = 10,860) positive by AHPV and/or HC2 assays and randomly selected women negative by both assays were referred to colposcopy at baseline. Women without baseline cervical intraepithelial neoplasia (CIN) grade 2 or higher (CIN2+) continued into the 3-year follow-up. Results The specificity of AHPV for CIN2 or lower was significantly greater at 96.3% compared with HC2 specificity of 94.8% (P Conclusions These results support the use of AHPV as a safe and effective adjunctive cervical cancer screening method.
TL;DR: In this article, the authors compared histologic features of inflammatory bowel disease (IBD) with STI colitis caused by syphilis and lymphogranuloma venereum.
Abstract: Objectives Sexually transmitted infectious (STI) colitis often raises concern for inflammatory bowel disease (IBD). In this study, we compare histologic features of IBD with STI colitis caused by syphilis and lymphogranuloma venereum.
Methods The STI colitis group included 10 unique colorectal biopsy specimens in patients with clinically confirmed syphilis and/or lymphogranuloma venereum. The STI biopsy specimens were compared with patients matched for age, sex, and site with Crohn disease (n = 10) or ulcerative colitis (n = 10). All IBD controls had an established history of IBD (up to 276 months of follow-up, mean follow-up = 102 months).
Results Discriminating features ( P .05) included rectal bleeding, endoscopic appearance, skip lesions, ulcerations, aphthoid lesions, granulomata, foreign body giant cells, neural hyperplasia, fibrosis, and lymphoid aggregates.
Conclusions While STI colitis shares many overlapping features with IBD, histologic and clinical discriminating features may be helpful when confronted with that differential diagnosis.
TL;DR: The 2013 ASCO/CAP guidelines increased the number of HER2 FISH positive and equivocal results, and the equvocal group is substantially different, posing a dilemma for clinical management.
Abstract: Objectives: Human epidermal growth factor receptor 2 (HER2, ERBB2) testing is an important prognostic/predictive marker in breast cancer management, especially in selecting HER2-targeted treatment. American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines address HER2 status and were recently revised in 2013, replacing the 2007 version. For in situ hybridization interpretation, 2013 guidelines return to the prior threshold of a HER2/CEP17 ratio of 2.0 or greater for positive and eliminate 1.8 to 2.2 as the equivocal range. Also, the HER2 signal/nucleus ratio is accounted for, with 6.0 or greater for positive and 4.0 to less than 6.0 for equivocal, even in cases with a HER2/CEP17 ratio less than 2.0.
Methods: With institutional review board approval, we reviewed our 2006 to 2012 HER2 fluorescence in situ hybridization (FISH) results and classified them according to both the 2007 and 2013 guidelines as negative, positive, or equivocal.
Results: Of 717 HER2 FISH results, 55 (7.7%) changed category when reassessed by 2013 guidelines. Nineteen of 25 results in the 2007 equivocal category were reassigned as positive (n = 13) or negative (n = 6). Thirty-five previously negative cases became equivocal in the 2013 scheme, 12 of these with 1+ immunohistochemistry. The positive category increased from 71 to 85.
Conclusions: The 2013 ASCO/CAP guidelines increased the number of HER2 FISH positive and equivocal results. The equivocal group is substantially different, posing a dilemma for clinical management.
TL;DR: CFD measured using a simple fluorometric assay has shown good correlation to stage and enhanced sensitivity to locally advanced disease and a large prospective study is warranted to evaluate if inclusion of this method as a decisive marker before mammography is advantageous.
Abstract: Objectives: To evaluate circulating cell-free DNA (CFD) measured by a simple fluorescent assay as a biomarker of breast cancer.
Methods: We enrolled 38 patients with breast cancer before surgery, two patients with noncancerous breast lesions, nine patients after surgery, 16 healthy participants, and 29 control women admitted to the hospital emergency ward and released without hospitalization. CFD levels were measured by a direct fluorescence assay.
Results: Presurgery patients with cancer had elevated CFD levels (1,010 ± 642 ng/mL), which were higher than those measured in the healthy control group (395 ± 248 ng/mL, P < .001), the noncancer breast lesion group (386 ± 40 ng/mL), the nonhospitalized control group (492 ± 193 ng/mL, P < .001), and the postsurgery cancer group (398 ± 162 ng/mL, P < .01). The area under the receiver operating characteristic curve of the presurgery vs healthy patient group was 0.83. CFD levels correlated with tumor size ( P = .03, ρ = 0.36), nodal involvement ( P = .0003, ρ = 0.56), and TNM stage ( P = .0002, ρ = 0.56). All patients with axillary node involvement had a CFD value greater than 600 ng/mL.
Conclusions: CFD measured using a simple fluorometric assay has shown good correlation to stage and enhanced sensitivity to locally advanced disease. A large prospective study is warranted to evaluate if inclusion of this method as a decisive marker before mammography is advantageous.
TL;DR: Relatively inexpensive interventions can have a prompt and dramatic impact on reducing blood wastage with regard to both cost and resource savings.
Abstract: Objectives: Blood component waste is an important issue at all hospitals. As an initiative of the patient blood management program at a regional health care system, the causes and extent of blood product wastage were identified, and targeted interventions to effect a reduction were implemented.
Methods: Multiple low-cost interventions, including educational outreach, print and digital messaging, and improved transportation and component identification modalities, were implemented beginning in January 2013. The impact on reducing RBC, platelet (PLT), and plasma wastage in the 16 months after intervention implementation was compared with the wastage rates in the 16 months before these interventions had been implemented.
Results: Overall, the RBC wastage rate as a percentage of the number of units issued decreased from 0.67% to 0.56% ( P = .001) after the interventions were implemented, while the PLT wastage rate decreased from 3.71% to 2.81% ( P < .001). The plasma wastage rate increased from 1.14% to 1.40% ( P < .001). The initial cost of these interventions was approximately $310. The net cost savings of the reduced waste was estimated at $131,520, excluding intervention costs.
Conclusions: Relatively inexpensive interventions can have a prompt and dramatic impact on reducing blood wastage with regard to both cost and resource savings.
TL;DR: The presented statistical algorithm is shown to be an accurate and practical tool for reference interval calculations and compared with published peer-reviewed studies that used direct sampling.
Abstract: Objectives: To describe the application of a data-mining statistical algorithm for calculation of clinical laboratory tests reference intervals.
Methods: Reference intervals for eight different analytes and different age and sex groups (a total of 11 separate reference intervals) for tests that are unlikely to be ordered during routine screening of disease-free populations were calculated using the modified algorithm for data mining of test results stored in the laboratory database and compared with published peer-reviewed studies that used direct sampling. The selection of analytes was based on the predefined criteria that include comparability of analytical methods with a statistically significant number of observations.
Results: Of the 11 calculated reference intervals, having upper and lower limits for each, 21 of 22 reference interval limits were not statistically different from the reference studies.
Conclusions: The presented statistical algorithm is shown to be an accurate and practical tool for reference interval calculations.
TL;DR: The method reaches a high precision in the recognition of five different types of lymphoid cells and could allow for the design of a diagnosis support tool in the future.
Abstract: Objectives The objective was the development of a method for the automatic recognition of different types of atypical lymphoid cells. Methods In the method development, a training set (TS) of 1,500 lymphoid cell images from peripheral blood was used. To segment the images, we used clustering of color components and watershed transformation. In total, 113 features were extracted for lymphocyte recognition by linear discriminant analysis (LDA) with a 10-fold cross-validation over the TS. Then, a new validation set (VS) of 150 images was used, performing two steps: (1) tuning the LDA classifier using the TS and (2) classifying the VS in the different lymphoid cell types. Results The segmentation algorithm was very effective in separating the cytoplasm, nucleus, and peripheral zone around the cell. From them, descriptive features were extracted and used to recognize the different lymphoid cells. The accuracy for the classification in the TS was 98.07%. The precision, sensitivity, and specificity values were above 99.7%, 97.5%, and 98.6%, respectively. The accuracy of the classification in the VS was 85.33%. Conclusions The method reaches a high precision in the recognition of five different types of lymphoid cells and could allow for the design of a diagnosis support tool in the future.
TL;DR: Implementation of the 2013 ASCO/CAP HER2 guideline updates resulted in an increase in HER2 FISH equivocal results, which can be attributed to HER2 copy number, regardless of the HER2/CEP17 ratio.
Abstract: Objectives: The 2013 American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guideline updates lowered the threshold for HER2 positivity and altered the equivocal category The goal of this study was to evaluate the impact of these changes on the distribution of HER2 fluorescence in situ hybridization (FISH) status The utility of reflex HER2 immunohistochemistry (IHC) for FISH equivocal cases was also examined
Methods: We retrospectively reviewed all invasive breast cancers analyzed for HER2 via dual-probe FISH (PathVysion; Abbott Laboratories Abbott Park, IL) 12 months before and after the HER2 guidelines updates were implemented Reflex HER2 IHC results were recorded for HER2 FISH equivocal cases
Results: There was a significant increase in the number of HER2 FISH equivocal results after the guideline updates (49% vs 14%, P = 0087) that was independent of specimen type (core vs surgical, P = 6) All 17 FISH equivocal cases after the updates had reflex HER2 IHC: two (12%) of 17 were positive, 12 (71%) of 17 remained equivocal, and three (18%) of 17 were negative
Conclusions: Implementation of the 2013 ASCO/CAP HER2 guideline updates resulted in an increase in HER2 FISH equivocal results, which can be attributed to HER2 copy number, regardless of the HER2 /CEP17 ratio Reflex IHC for FISH equivocal cases is of limited utility; however, IHC does assign HER2 positivity or negativity in a small percentage of cases
TL;DR: Objective definitions based on repeated testing identified 16% of six studied tests as inappropriate, delineating a subset of inappropriate testing that is well suited to automated identification and intervention and that provides a likely lower bound on the true burden of inappropriateTesting.
Abstract: Objectives To identify inappropriate repeats of six common laboratory tests in a population sample of patients, using highly specific criteria based only on repeat time and test value.
Methods We used a laboratory informatics database to conduct a retrospective cohort study using a population sample of 103,000 patients in the city of Calgary with an index test in 2010 and uniform follow-up of 1 year. We examined six tests (cholesterol, hemoglobin A1c, thyroid-stimulating hormone, vitamin B12, vitamin D, and ferritin) with consensus-based or easily justified criteria for inappropriate repeats based solely on time to repeat and the index test value.
Results The percentages of tests repeated at 3, 6, and 12 months were 11%, 23%, and 41%, respectively. In total, 16% of these six tests were inappropriately repeated, representing an annual internal cost of $0.6 to $2.2 million Canadian dollars and corresponding to population-scaled national estimates for Canada and the United States of $160 million and $2.4 billion, respectively.
Conclusions Objective definitions based on repeated testing identified 16% of six studied tests as inappropriate, delineating a subset of inappropriate testing that is well suited to automated identification and intervention and that provides a likely lower bound on the true burden of inappropriate testing.
TL;DR: Evaluation of intratumoral heterogeneity, especially in cases with hormone receptor positivity, may be valuable for assessing the prognosis of HER2-positive patients anticipating treatment with adjuvant systemic therapy and trastuzumab.
Abstract: Objectives Although intratumoral heterogeneity of human epidermal growth factor receptor 2 ( HER2 ) gene amplification has been associated with a poor prognosis for primary HER2-positive breast cancer and metastatic HER2-positive breast cancer treated with trastuzumab, the clinicopathologic significance in a setting involving trastuzumab treatment as an adjuvant treatment has not been studied in patients.
Methods We retrospectively investigated 443 patients with HER2-positive breast cancer treated with surgery, adjuvant chemotherapy, and 1 year of trastuzumab. Three areas that showed different levels of HER2 protein expression were chosen, and silver in situ hybridization was performed.
Results HER2 regional and genetic heterogeneity was found in 6.2% and 6.8% of tumors, respectively. Both types of heterogeneity were significantly associated with hormone receptor positivity, HER2 immunohistochemistry score of 2+, a low level of HER2 gene amplification, and absence of an extensive intraductal component. Genetic heterogeneity also showed strong correlation with a lower histologic grade. In the hormone receptor–positive group, the regional heterogeneity affected disease-free survival of patients (hazard ratio, 4.869; 95% confidence interval, 1.424–16.646; P = .005), whereas genetic heterogeneity did not.
Conclusions Evaluation of intratumoral heterogeneity, especially in cases with hormone receptor positivity, may be valuable for assessing the prognosis of HER2-positive patients anticipating treatment with adjuvant systemic therapy and trastuzumab.
TL;DR: Distinct molecular events may occur in relatively early stages of tumorigenesis of endometriosis-associated OEMCas and OCCCas and significant differences in the expression of pAkt, hepatocyte nuclear factor 1β, hypoxia-inducible factor 1α, p65, and inducible nitric oxide synthase were evident between the two types of tumors and their coexisting endometiosis.
Abstract: Objectives We focused on the differences in molecular mechanisms in the early stages of endometriosis-associated ovarian endometrioid carcinoma (OEMCa) and ovarian clear cell carcinoma (OCCCa). Methods Alterations in the β-catenin and PIK3CA genes, as well as expression of their associated markers, were investigated. Results Mutations in exon 3 of the β-catenin gene were identified in 21 (60%) of 35 OEMCas. The mutations were also detected in the coexisting nonatypical (52.4%) and atypical (73.3%) endometriosis, and the single-nucleotide substitutions were identical in most cases. In contrast, the mutations were not identified in any of the OCCCas and their coexisting endometriosis. PIK3CA mutations were observed in 11 (31.4%) of 35 OEMCas and 10 (35.7%) of 28 OCCCas. Ten of 11 OEMCas had PIK3CA mutations in exon 9, and eight of 10 OCCCas had them in exon 20. The same mutations were also detected in the coexisting nonatypical and/or atypical endometriosis in three OEMCas and four OCCCas. In addition, significant differences in the expression of pAkt, hepatocyte nuclear factor 1β, hypoxia-inducible factor 1α, p65, and inducible nitric oxide synthase were evident between the two types of tumors and their coexisting endometriosis. Conclusions Distinct molecular events may occur in relatively early stages of tumorigenesis of endometriosis-associated OEMCas and OCCCas.