Biomedical subjects

Richard J Zarbo

Publications and source records attributed to Richard J Zarbo.

At least 19 recordsLinked to original sources

PubMed2006

NF-kappaB in breast cancer cells promotes osteolytic bone metastasis by inducing osteoclastogenesis via GM-CSF.

Advanced breast cancers frequently metastasize to bone, resulting in osteolytic lesions, yet the underlying mechanisms are poorly understood. Here we report that nuclear factor-kappaB (NF-kappaB) plays a crucial role in the osteolytic bone metastasis of breast cancer by stimulating osteoclastogenesis. Using an in vivo bone metastasis model, we found that constitutive NF-kappaB activity in breast cancer cells is crucial for the bone resorption characteristic of osteolytic bone metastasis. We identified the gene encoding granulocyte macrophage-colony stimulating factor (GM-CSF) as a key target of NF-kappaB and found that it mediates osteolytic bone metastasis of breast cancer by stimulating osteoclast development. Moreover, we observed that the expression of GM-CSF correlated with NF-kappaB activation in bone-metastatic tumor tissues from individuals with breast cancer. These results uncover a new and specific role of NF-kappaB in osteolytic bone metastasis through GM-CSF induction, suggesting that NF-kappaB is a potential target for the treatment of breast cancer and the prevention of skeletal metastasis.

Animals↗

PubMed2006

The "Big Dog" effect: variability assessing the causes of error in diagnoses of patients with lung cancer.

PURPOSE: The frequency of diagnostic error in patients who have a lung mass and a pathology specimen is as high as 15%. This study examined the role of inter-pathologist agreement in identifying the cause of error in these patients. METHODS: Pathologists from six institutions reviewed the slides of 40 patients who had a pulmonary specimen false-negative diagnosis. The initial assessment of error cause arose from cytologic-histologic correlation slide review of discrepant diagnostic samples in patients who had both a bronchial brushing cytologic and surgical specimen. The cause of error was attributed either to clinical sampling (diagnostic material obtained in one but not the other sample) or interpretation (pathologist failed to identify the salient diagnostic features). The pairwise kappa (kappa) statistic was used to calculate interobserver agreement between the review and original diagnoses and between the separate review diagnoses. RESULTS: The pairwise kappa statistic ranged widely from -0.154 to 1.0, and the pairwise kappa statistic of the slides from one institution was undetermined because that institutional pathologist never made the assessment that error was secondary to interpretation. Agreement for observers within the same institution was better than agreement between observers from different institutions. CONCLUSION: Pathologists exhibit poor agreement in determining the cause of error for pulmonary specimens sent for cancer diagnosis. We developed a psychosocial hypothesis (the "Big Dog" Effect) that partially explains biases in error assessment. This lack of agreement precludes confident targeting of these errors for quality improvement interventions with prospects of success across a variety of institutions.

Bronchi↗

PubMed2006

Detection of non-maternal components of gestational choriocarcinoma by PCR-based microsatellite DNA assay.

OBJECTIVE: Gestational and non-gestational choriocarcinomas have distinctly different tissues of origin, parental genotypes, natural histories, and responses to therapy. Our objective was to develop a convenient, fast, and reliable assay that would, using only patient tissue, allow separation of gestational from non-gestational choriocarcinomas. METHOD: Benign and malignant tissues, preserved in paraffin blocks and separated by microdissection, were examined using a commercial PCR-based tissue identity assay (ABI AmpFlSTR Profiler Plus Kit and ABI 377 DNA sequencer) to detect genetic profiles of 9 microsatellite markers, along with X and Y chromosome markers. Cases included 6 choriocarcinomas. Controls included eight non-germ cell reproductive tract tumors and two hydatidiform moles. RESULTS: The microsatellite markers identified the five choriocarcinomas diagnosed on clinical and histological grounds as gestational, to be of genetically non-maternal (androgenic) origin. The neoplasm previously classified as a non-gestational choriocarcinoma was demonstrated to be of maternal origin, as were the non-germ cell reproductive tract tumors. Samples from hydatidiform moles contained either androgenic markers only or a mix of maternal and androgenic markers, as previously seen in complete and partial moles, respectively. CONCLUSION: A commercially available microsatellite DNA diagnostic assay is a quick and convenient way to discriminate between gestational and non-gestational choriocarcinoma.

Alleles↗

PubMed2006

Use of a new method in reaching consensus on the cause of cytologic-histologic correlation discrepancy.

Pathologists exhibit very poor agreement in adjudicating the cause of cytologic-histologic correlation discrepancies, which contributes to problems in designing interventions to reduce discrepancy frequency. In this observational study, we developed a visual method of adjudicating discrepancy cause, termed the No-Blame Box method, which consisted of initially assessing specimen interpretability by separately evaluating specimen quality and the presence of tumor. Five pathologists blindly adjudicated the cause of discrepancy in pulmonary specimens from 40 patients. The kappa statistic of all pathologist pairs in adjudicating discrepancy cause using the No-Blame Box method ranged from 0.400 to 0.796, indicating acceptable to excellent agreement. Pathologists ranged in their assessment of specimen interpretability from 13% to 20%, and in no case did all 5 pathologists concur that a specimen was interpretable. Most discrepancies resulted from pathologists diagnosing noninterpretable samples. Pathologists who used the No-Blame Box showed significant agreement in the adjudication of discrepancy cause.

Consensus↗

PubMed2006

Errors in thyroid gland fine-needle aspiration.

Scant published data exist on redesigning pathology practice based on error data. In this first step of an Agency for Healthcare Research and Quality patient safety project, we measured the performance metrics of thyroid gland fine-needle aspiration, performed root cause analysis to determine the causes of error, and proposed error-reduction initiatives to address specific errors. Eleven cytologists signed out 1,543 thyroid gland aspirates in 2 years, and surgical pathology follow-up was obtained in 364 patients. Of the 364 patients, 91 (25.0%) had a false-negative diagnosis and 36 (9.9%) a false-positive diagnosis. Root cause analysis showed that major sources of error were pre-analytic (poor specimen quality) and analytic (interpretation of unsatisfactory specimens as nonneoplastic and lack of diagnostic category standardization). We currently are evaluating the effectiveness of error reduction initiatives that target pre-analytic and analytic portions of the diagnostic pathway.

Biopsy, Fine-Needle↗

PubMed2006

Double slide viewing as a cytology quality improvement initiative.

Few studies have measured the effect of pre-sign out double viewing of cytology cases as a means to decrease error. Three Agency for Healthcare Research and Quality-funded project sites performed pre-sign out double viewing of 431 pulmonary cytology cases. Two-step or more differences in diagnosis were arbitrated as interpretive errors, and the effect of double viewing was measured by comparing the frequency of cytologic-histologic correlation-detected errors in the previous 2 years with the double-viewing period. The number of interpretive errors detected by double viewing for the 3 institutions was 2.7%, 0% and 1.9%, respectively. Double viewing did not lower the frequency of cytologic-histologic correlation false-negative errors. We conclude that double viewing detects errors in up to 1 of every 37 cases and that biases in the double-viewing process limit error detection.

Carcinoma, Small Cell↗

PubMed2006

Angioimmunoblastic T-cell lymphoma with supervening Epstein-Barr virus-associated large B-cell lymphoma.

Patients with angioimmunoblastic T-cell lymphoma can have profound immune dysfunction and immunodeficiency. Epstein-Barr virus-driven B-cell lymphoid proliferation can occur in angioimmunoblastic T-cell lymphoma, as in other immunodeficiency states. However, few cases of Epstein-Barr virus-positive B-cell lymphoma arising in patients with preexisting angioimmunoblastic T-cell lymphoma have been reported. We report a case of angioimmunoblastic T-cell lymphoma in which diffuse large B-cell lymphoma developed 56 months after the diagnosis of angioimmunoblastic T-cell lymphoma. The patient survived for 9 years after the initial diagnosis of angioimmunoblastic T-cell lymphoma, and molecular studies performed on multiple biopsy specimens during this period revealed the dynamic nature of clonal lymphoid expansion. Epstein-Barr virus latent membrane protein 1 and Epstein-Barr virus-encoded RNA were detected in the diffuse large B-cell lymphoma, suggesting that Epstein-Barr virus may have played a role in the pathogenesis of the diffuse large B-cell lymphoma.

Aged↗

PubMed2006

The value of monitoring frozen section-permanent section correlation data over time.

CONTEXT: The effectiveness of the long-term monitoring of errors detected by frozen section-permanent section correlation is unknown. OBJECTIVE: To determine factors important in laboratory improvement in frozen section-permanent section discordant and deferral rates by participation in a multi-institutional continuous quality improvement program. DESIGN: Participants in the College of American Pathologists Q-Tracks program self-reported the number of anatomic pathology frozen-permanent section discordant and deferred cases in their laboratories by prospectively performing secondary review of intraoperative consultations. Laboratories participated in the program for 1 to 5 years and reported their data every quarter. We calculated mean and median discordant and deferred case frequencies and used mixed linear modeling to determine if length of participation in the program was associated with improved performance. PARTICIPANTS: One hundred seventy-four laboratories self-reported data. MAIN OUTCOME MEASURES: Mean frozen-permanent section discordant and deferred diagnostic frequencies and changes in these frequencies over time were measured. RESULTS: The mean and median frozen-permanent section discordant frequencies were 1.36% and 0.70%, respectively. The mean and median deferred diagnostic frequencies were 2.35% and 1.20%, respectively. Longer participation in the Q-Tracks program was significantly associated (P = .04) with lower discordant frequencies; 4- or 5-year participation showed a decrease in discordant frequency of 0.99%, whereas 1-year participation showed a decrease in discordant frequency of 0.84%. Longer participation in the Q-Tracks monitor was associated with lower microscopic sampling frequencies for discordant diagnoses (P = .04). Increased length of participation in the Q-Tracks program was significantly associated (P = .04) with lower deferred diagnostic frequencies. CONCLUSIONS: Long-term monitoring of frozen-permanent section correlation is associated with sustained improvement in performance.

Diagnostic Errors↗

PubMed2006

Use of microsatellite analysis in detection of tumor lineage as a cause of death in a liver transplant patient.

Malignant tumors are a significant cause of long-term morbidity and mortality in allograft recipients. Most solid tumors in transplant recipients are assumed to arise de novo in the setting of chronic immunosuppressive therapy; however, there have been instances in which malignant tumors have been transplanted in donated tissue from apparently healthy donors. We report a case of a 49-year-old liver transplant patient who presented with metastatic melanoma 9 months after transplantation for hepatocellular carcinoma and who later succumbed to the disease. To investigate the possibility that melanoma was derived from the donor liver, we used a commercially available polymerase chain reaction-based microsatellite marker assay to perform tissue identity testing. The genetic profiles of the patient's original hepatocellular carcinoma and the melanoma from the autopsy specimen were compared with the profile of the normal donor liver tissue, which was still available for testing. The pattern of microsatellite allelic expression strongly suggested that the melanoma detected at autopsy originated from the transplanted liver.

DNA Fingerprinting↗

PubMed2006

Determining customer satisfaction in anatomic pathology.

CONTEXT: Measurement of physicians' and patients' satisfaction with laboratory services has become a standard practice in the United States, prompted by national accreditation requirements. Unlike other surveys of hospital-, outpatient care-, or physician-related activities, no ongoing, comprehensive customer satisfaction survey of anatomic pathology services is available for subscription that would allow continual benchmarking against peer laboratories. Pathologists, therefore, must often design their own local assessment tools to determine physician satisfaction in anatomic pathology. OBJECTIVE: To describe satisfaction survey design that would elicit specific information from physician customers about key elements of anatomic pathology services. DESIGN: The author shares his experience in biannually assessing customer satisfaction in anatomic pathology with survey tools designed at the Henry Ford Hospital, Detroit, Mich. Benchmarks for physician satisfaction, opportunities for improvement, and characteristics that correlated with a high level of physician satisfaction were identified nationally from a standardized survey tool used by 94 laboratories in the 2001 College of American Pathologists Q-Probes quality improvement program. RESULTS: In general, physicians are most satisfied with professional diagnostic services and least satisfied with pathology services related to poor communication. CONCLUSIONS: A well-designed and conducted customer satisfaction survey is an opportunity for pathologists to periodically educate physician customers about services offered, manage unrealistic expectations, and understand the evolving needs of the physician customer. Armed with current information from physician customers, the pathologist is better able to strategically plan for resources that facilitate performance improvements in anatomic pathology laboratory services that align with evolving clinical needs in health care delivery.

Consumer Behavior↗

PubMed2005

Clinical impact and frequency of anatomic pathology errors in cancer diagnoses.

BACKGROUND: To the authors' knowledge, the frequency and clinical impact of errors in the anatomic pathology diagnosis of cancer have been poorly characterized to date. METHODS: The authors examined errors in patients who underwent anatomic pathology tests to determine the presence or absence of cancer or precancerous lesions in four hospitals. They analyzed 1 year of retrospective errors detected through a standardized cytologic-histologic correlation process (in which patient same-site cytologic and histologic specimens were compared). Medical record reviews were performed to determine patient outcomes. The authors also measured the institutional frequency, cause (i.e., pathologist interpretation or sampling), and clinical impact of diagnostic cancer errors. RESULTS: The frequency of errors in cancer diagnosis was found to be dependent on the institution (P < 0.001) and ranged from 1.79-9.42% and from 4.87-11.8% of all correlated gynecologic and nongynecologic cases, respectively. A statistically significant association was found between institution and error cause (P < 0.001); the cause of errors resulting from pathologic misinterpretation ranged from 5.0-50.7% (the remainder were due to clinical sampling). A statistically significant association was found between institution and assignment of the clinical impact of error (P < 0.001); the aggregated data demonstrated that for gynecologic and nongynecologic errors, 45% and 39%, respectively, were associated with harm. The pairwise kappa statistic for interobserver agreement on cause of error ranged from 0.118-0.737. CONCLUSIONS: Errors in cancer diagnosis are reported to occur in up to 11.8% of all reviewed cytologic-histologic specimen pairs. To the authors' knowledge, little agreement exists regarding whether pathology errors are secondary to misinterpretation or poor clinical sampling of tissues and whether pathology errors result in serious harm.

Diagnostic Errors↗

PubMed2005

Error detection in anatomic pathology.

OBJECTIVES: To define the magnitude of error occurring in anatomic pathology, to propose a scheme to classify such errors so their influence on clinical outcomes can be evaluated, and to identify quality assurance procedures able to reduce the frequency of errors. DESIGN: (a) Peer-reviewed literature search via PubMed for studies from single institutions and multi-institutional College of American Pathologists Q-Probes studies of anatomic pathology error detection and prevention practices; (b) structured evaluation of defects in surgical pathology reports uncovered in the Department of Pathology and Laboratory Medicine of the Henry Ford Health System in 2001-2003, using a newly validated error taxonomy scheme; and (c) comparative review of anatomic pathology quality assurance procedures proposed to reduce error. RESULTS: Marked differences in both definitions of error and pathology practice make comparison of error detection and prevention procedures among publications from individual institutions impossible. Q-Probes studies further suggest that observer redundancy reduces diagnostic variation and interpretive error, which ranges from 1.2 to 50 errors per 1000 cases; however, it is unclear which forms of such redundancy are the most efficient in uncovering diagnostic error. The proposed error taxonomy tested has shown a very good interobserver agreement of 91.4% (kappa = 0.8780; 95% confidence limit, 0.8416-0.9144), when applied to amended reports, and suggests a distribution of errors among identification, specimen, interpretation, and reporting variables. CONCLUSIONS: Presently, there are no standardized tools for defining error in anatomic pathology, so it cannot be reliably measured nor can its clinical impact be assessed. The authors propose a standardized error classification that would permit measurement of error frequencies, clinical impact of errors, and the effect of error reduction and prevention efforts. In particular, the value of double-reading, case conferences, and consultations (the traditional triad of error control in anatomic pathology) awaits objective assessment.

Diagnostic Errors↗

PubMed2005

Anatomic pathology databases and patient safety.

CONTEXT: The utility of anatomic pathology discrepancies has not been rigorously studied. OBJECTIVE: To outline how databases may be used to study anatomic pathology patient safety. DESIGN: The Agency for Healthcare Research and Quality funded the creation of a national anatomic pathology errors database to establish benchmarks for error frequency. The database is used to track more frequent errors and errors that result in more serious harm, in order to design quality improvement interventions intended to reduce these types of errors. In the first year of funding, 4 institutions (University of Pittsburgh, Henry Ford Hospital, University of Iowa, and Western Pennsylvania Hospital) reported cytologic-histologic correlation error data after standardizing correlation methods. Root cause analysis was performed to determine sources of error, and error reduction plans were implemented. PARTICIPANTS: Four institutions self-reported anatomic pathology error data. MAIN OUTCOME MEASURES: Frequency of cytologic-histologic correlation error, case type, cause of error (sampling or interpretation), and effect of error on patient outcome (ie, no harm, near miss, and harm). RESULTS: The institutional gynecologic cytologic-histologic correlation error frequency ranged from 0.17% to 0.63%, using the denominator of all Papanicolaou tests. Based on the nongynecologic cytologic-histologic correlation data, the specimen sites with the highest discrepancy frequency (by project site) were lung (ranging from 16.5% to 62.3% of all errors) and urinary bladder (ranging from 4.4% to 25.0%). Most errors detected by the gynecologic cytologic-histologic correlation process were no-harm events (ranging from 10.7% to 43.2% by project site). Root cause analysis identified sources of error on both the clinical and pathology sides of the process, and error intervention programs are currently being implemented to improve patient safety. CONCLUSIONS: A multi-institutional anatomic pathology error database may be used to benchmark practices and target specific high-frequency errors or errors with high clinical impact. These error reduction programs have national import.

Benchmarking↗

PubMed2004

Prognostic implications of loss of heterozygosity at 8p21 and 9p21 in head and neck squamous cell carcinoma.

Loss of heterozygosity (LOH) in chromosomal regions that harbor tumor suppressor genes from tumor tissue may lead to decreased survival time in cancer patients with squamous cell carcinoma of the head and neck (HNSCC). We studied 8 regions frequently lost in HNSCC in 150 patients having a primary diagnosis of HNSCC. Tumor and normal tissue DNA were genotyped for microsatellite repeat markers in 8 unlinked chromosomal regions. The association between LOH and death from HNSCC was investigated, weighted by number of informative markers per region and adjusted for age at diagnosis, self-reported race, tumor stage and current smoking status. LOH at 3 chromosomal regions were independently associated with reduced survival. A greater risk for cancer mortality was observed for LOH at chromosomal regions 3p24.3-p14.3 (p = 0.02), 8p21.3-p11.21 (p = 0.02) and 9p24.2-p21.2 (p = 0.03). In these regions, LOH at one or more markers was observed in 66.9%, 43.3% and 60.6% of patients, respectively. Survival times were significantly shorter for those with LOH at marker NEFL on 8p21.2 (relative risk = 6.15; p = 0.0002) and at D9S126 on 9p21.2 (relative risk = 5.96; p = 0.0003). Our results indicate that LOH at several chromosomal sites may offer additional independent prognostic information beyond traditional indicators such as tumor stage and age.

Adult↗

PubMed2004

Defining the role of myoepithelium in salivary gland neoplasia.

Neoplastic myoepithelium is considered to be the key cellular participant in morphogenetic processes responsible for the variable histologic appearances of many salivary gland tumors. Nevertheless, controversy still exists concerning its participation in some types of salivary gland neoplasms. This has been largely due to the difficulty in fully characterizing the wide spectrum of morphologic and immunophenotypic expressions of neoplastic myoepithelium compared with the normal counterpart. However, in recent years, our understanding regarding the phenotypic, immunophenotypic, ultrastructural, and biochemical properties of myoepithelium has advanced. Here we discuss the role of neoplastic myoepithelium in the scope of salivary gland neoplasia and present this information from a practical diagnostic standpoint.

Animals↗

PubMed2004

The diagnostic utility of p63, CK5/6, CK 7, and CK 20 in distinguishing primary cutaneous adnexal neoplasms from metastatic carcinomas.

BACKGROUND: Distinguishing primary cutaneous adnexal neoplasms (PCANs) from metastatic carcinomas (MCs) can be difficult. We study the utility of p63, CK 5/6, CK 7, and 20 expression in PCAN vs. MC. METHODS: Twenty-one PCAN with sweat gland differentiation (six benign, 15 malignant), one sebaceous carcinoma, and 15 MC (14 adenocarcinomas, one urothelial carcinoma) to skin were retrieved from the pathology files. Immunostains for p63, CK 5/6, CK 7, and CK 20 were performed and graded as follows: 1, <10; 2, 11-50; and 3 >50% of tumor cells stained. RESULTS: Twenty of 22 PCAN expressed p63 and CK 5/6. Four of 15 and two of 15 MC were positive for CK 5/6 and p63, respectively. Thirteen of 22 PCAN and 13 of 15 MC were positive for CK 7, respectively. All PCAN were negative for CK 20, two of 15 MC were positive. The sensitivity and specificity for the diagnosis of PCAN were 91 and 73% for CK 5/6, 91 and 100% for p63, and 60 and 13% for CK 7, respectively. CONCLUSIONS: For distinguishing PCAN from MC: (1) positivity for p63 and CK 5/6 are relatively specific and sensitive for PCAN, (2) CK 7 and 20 are neither sensitive nor specific, and (3) CK 7 positivity in PCAN was focal with a specific pattern in contrast to the diffuse positivity for MC.

Biomarkers, Tumor↗

PubMed2004

Use of physician extenders in surgical pathology practice.

CONTEXT: Use of a variety of nonphysician personnel for surgical pathology gross examination is generally known to be increasing, although detailed information regarding nonphysician use is currently unavailable. OBJECTIVE: To measure and describe the use of nonphysician personnel for surgical pathology gross examination in order to gain a better understanding of the current surgical pathology workforce. DESIGN: A voluntary, mailed questionnaire containing items related to the use of multiple nonphysician personnel types in surgical pathology was distributed to (1) a cross-sectional sample (n = 968) of US pathologists and (2) a purposive sample of pathologist directors of surgical and/or anatomic pathology (n = 77) located at teaching institutions. Responses were analyzed using descriptive statistics, correlation analyses, the chi2 test, and 1-way analysis of variance. Staffing ratios were calculated for multiple nonphysician personnel types. RESULTS: The overall response rate was 22% (n = 225). Of the US sample, 56% of respondents reported using nonphysician laboratory personnel to perform gross examinations, compared with 91% of the directors' sample. The most frequently reported personnel type for both samples was pathologists' assistants, but multiple other personnel types were used as well. Significant associations existed between certain practice types and personnel types used, as well as differences in the scope of responsibilities between personnel types. Calculated staffing ratios were variable across personnel types and were highest for pathologists' assistants. CONCLUSIONS: The use of a variety of nonphysician laboratory personnel for surgical pathology gross examination is common, particularly in academic pathology practice. Further studies are needed to examine the impact of physician extenders on laboratory efficiency and quality of care.

Pathology, Surgical↗

PubMed2004

Chondroid syringoma. Cytokeratin 20 immunolocalization of Merkel cells and reappraisal of apocrine folliculo-sebaceous differentiation.

CONTEXT: Chondroid syringoma (CS) is a benign cutaneous adnexal tumor with epithelial and stromal components. Epithelial components derived from folliculo-sebaceous-apocrine germ are evident in apocrine but not in eccrine CS. OBJECTIVES: To further characterize pilosebaceous differentiation and to identify the presence of Merkel cells in the areas of follicular differentiation. DESIGN: Histologic type, folliculo-sebaceous differentiation, character of stroma, and presence or absence of Merkel cells by cytokeratin (CK) 20 immunoreactivity were evaluated in 25 CSs (22 apocrine and 3 eccrine) from the surgical pathology files of Henry Ford Hospital (Detroit, Mich). RESULTS: Most CSs occurred in the head and neck region of patients aged 40 years or older. We found no significant difference in sex, age, or location between apocrine and eccrine types. The stroma varied from myxoid (100%) to chondroid (59%), with various amounts of fat (59%) and ossification identified in 2 cases (9%) of apocrine type, but was homogeneously myxoid in the eccrine type. Follicular and sebaceous differentiation was found in 64% and 32% of apocrine CSs, respectively. Only 2 (14%) apocrine CSs with follicular differentiation were positive for CK20 (a few scattered cells in one case and numerous grouped cells in the other in association with follicular epithelium). No correlation was found between type of stroma and the presence of Merkel cells. Scattered Merkel cells were identified in 83% of normal hair follicles and in 33.3% of normal epidermis. CONCLUSION: A high proportion of apocrine CSs show folliculo-sebaceous differentiation. The presence of Merkel cells in foci of follicular differentiation of CS supports the hypothesis that Merkel cells may be an integral constituent of follicles. To our knowledge, the presence of Merkel cells in CS, particularly in proliferative form, has not been described previously in the literature.

Adenoma, Pleomorphic↗