Measuring Faculty Effort: A Quantitative Approach That Aligns Personal and Institutional Goals in Pathology at Yale.

US medical schools increasingly seek ways to reduce costs and improve productivity. One aspect of this effort has been the development of performance-based incentives for individual faculty. A myriad of such plans exist. Typically, they incentivize clinical revenue generation but vary widely in how teaching, investigation, and administrative contributions are recognized. In Pathology at Yale, we have developed a transparent metrically driven approach that recognizes all missions and allows faculty significant control over their career path. Although some metrics derive from traditional measures such as workload relative value units and one's level of grant support, the key concept underpinning our approach is to define one's contributions not in terms of the revenue generated, but rather on the effort devoted to each of our missions, benchmarked against national or local standards. Full-time faculty are paid a competitive rank-based salary and are expected to contribute at least 100% effort in support of the school's missions: clinical, research, education, administration, and professional service. Metrics define the effort assigned to each activity. Faculty achieving greater than 100% effort receive bonus compensation in proportion to their excess effort. By codifying explicitly how such effort is recognized into a single metric (% effort), we achieve a process that better aligns the professional and personal goals of faculty with the aims of the school. To facilitate its implementation, we have developed a web-based software platform called SWAY (Standardized Workload Analysis at Yale) that enables faculty to monitor their progress and record their activities in real time.

Enumeration and molecular characterization of circulating tumor cells as an innovative tool for companion diagnostics in breast cancer.

INTRODUCTION: Circulating tumor cells (CTC) and more recently, CTC clusters are implicated as a fundamental mechanism by which tumor cells break away from the primary site and travel to distant sites. Enumeration of CTC and CTC clusters represents a new approach to prognosis, prediction, and response to therapy in patients with early and metastatic breast cancer. Several recent studies have shown the predictive importance of monitoring CTCs levels in progression-free and overall survival in breast cancer patients. This review will focus on CTC enumeration and characterization in breast cancers. AREAS COVERED: We will provide a historical perspective and clinical background of CTC detection in peripheral blood. The current methodologies for studying CTCs and newer technologies for CTC detection will be reviewed together with the current state of the art of CTCs as a biomarker in risk stratification and prognostication in breast cancers. EXPERT OPINION: Currently, there is an FDA approved CTC assessment method for clinical use. While CTC enumeration, is a marker for prognostication and survival, molecular characterization of CTC, may be more accurate in monitoring response to treatment due to tumor heterogeneity rather than the tumor phenotype at the primary or metastatic sites.

Detection and genotype of high-risk human papillomavirus in fine-needle aspirates of patients with metastatic squamous cell carcinoma is helpful in determining tumor origin.

OBJECTIVES: Recent studies have shown that human papillomavirus (HPV) is associated with a certain subset of head and neck squamous cell carcinoma (HNSCC)-namely, those arising in the oropharynx. The objective of this study is to determine the efficacy, detection, and genotype of high-risk (HR) HPV using the Roche cobas 4800 system (Roche Molecular System, Pleasanton, CA). METHODS: Forty-two fine-needle aspirate (FNA) specimens from 37 patients with cervical (n = 36) or mediastinal (n = 5) lymphadenopathy or a left parapharyngeal mass (n =1) were included in this prospective study. HR-HPV testing was performed on residual FNA material after direct smear preparation and, if positive, was further delineated into HPV 16/18 genotypes using the Roche cobas 4800 system. Follow-up included review of histologic material and/or electronic health records. RESULTS: Among those HNSCCs that were positive for HR-HPV, 18 (100%) of 18 originated from the oropharynx, whereas only two (13%) of 15 HR-HPV-negative HNSCCs originated from the oropharynx (χ(2) test, P < .05). p16 immunohistochemical assay and HPV 16 in situ hybridization on corresponding histologic specimens were concordant with cytologic HR-HPV results. CONCLUSIONS: HR-HPV detection and genotyping can be performed on lymph node FNAs with metastatic squamous cell carcinoma using the Roche cobas 4800 system. The presence of HR-HPV and/or HPV 16 is a reliable indicator of the metastatic squamous cell carcinoma originating from the oropharynx.

Implementation of FocalPoint GS location-guided imaging system: experience in a clinical setting.

BACKGROUND: Recently, the Food and Drug Administration approved the use of the location-guided imaging system FocalPoint GS (FPGS), on SurePath Papanicolaou (Pap) tests for primary screening. The objective of the current study was to evaluate the impact of FPGS on the following: distribution of diagnostic categories; rate of high-risk human papillomavirus (HR-HPV)-positive ASC-US cases; and quality control (QC) data before and after FPGS implementation. METHODS: A search of the laboratory information system was performed to identify all SurePath Pap tests processed in our laboratory for the first 19 months after FPGS implementation. We also retrieved all SurePath specimens from a 16-month period prior to FPGS implementation to serve as the control. During the period from Janaury 2008 to April 2009, the FocalPoint Slide Profiler was used. RESULTS: Implementation of FPGS resulted in a significantly higher percentage of LSIL and ASC-US interpretations, as well as a significant increase in the detection of candidiasis and bacterial vaginosis. The ASC-to-SIL ratio was 1.4 and 1.9 before and after FPGS implementation, respectively. There was a decrease in the HR-HPV positive rate in ASC-US cases, and a decrease in the estimated false-negative fraction after FPGS implementation. CONCLUSIONS: In conclusion, our study seems to demonstrate a favorable performance of FPGS in the routine clinical setting. FPGS may have the potential to be a promising screening tool for gynecologic cytology in a low-risk patient population.

Thyroid follicular lesion of undetermined significance: Evaluation of the risk of malignancy using the two-tier sub-classification.

The Bethesda 2007 Thyroid Cytology Classification defines follicular lesion of undetermined significance as a heterogeneous category of cases that are not convincingly benign nor sufficiently atypical for a diagnosis of follicular neoplasm or suspicious for malignancy. In our institution, we refer to these cases as indeterminate, and they are further sub-classified into two: (1) low cellularity with predominant microfollicular architecture and absence of colloid (IN(a)) and (2) nuclear features not characteristic of benign lesions (nuclear atypia) (IN(b)). We reviewed these indeterminate cases to document the follow-up trend using this two-tier classification. A search of the cytology records was performed for the period between January 2008 and June 2009. All thyroid fine-needle aspiration (FNA) cases were reviewed and the ones diagnosed as indeterminate were identified. Correlating follow-up FNA and/or surgical pathology reports were reviewed. The percentage of cases showing a malignancy was calculated. One hundred and seventy-one indeterminate cases were identified, representing 2.8% of the 6,205 thyroid FNA cases examined during the time under review (107 IN(a), 64 IN(b)). Records of follow-up procedures were available in 106 (61%) cases. Malignancy was identified in 27% of all indeterminate cases. This was disproportionately more in the IN(b) (56%) compared to the IN(a) (7%) cases. A diagnosis of "IN(a)" does not carry the same implication as that of "IN(b)". The IN(b) category needs a more aggressive follow-up than the IN(a) category and may justify an immediate referral for lobectomy. Despite the vague morphologic criteria for this diagnostic category, the indeterminate rate remains relatively low and falls within the NCI recommendation (<7%).

Pleomorphic adenoma arising in an incidental midline isthmic thyroid nodule: a case report and review of the literature.

Ectopic salivary gland tissue is common in the head and neck, usually associated with lymph nodes in lateral areas. It is rarely noted in the thyroid gland. Here we report the first case of a pleomorphic adenoma presenting as a midline nodule in the isthmus of thyroid in a 66-year-old man. We propose the possibility of origin in ectopic salivary gland tissue that may have aberrantly migrated with the median anlage from the foramen cecum in the base of the tongue during embryogenesis.

Littoral cell angioma of the spleen diagnosed by endoscopic ultrasound-guided fine-needle aspiration biopsy.

Littoral cell angiomas are uncommon primary vascular neoplasms that arise from the sinusoidal lining or littoral cells of the splenic red pulp, and hence are unique to the spleen. We report a case of littoral cell angioma in 34-year-old woman, which was diagnosed by endoscopic ultrasound-guided fine needle aspiration biopsy (EUS-FNAB). The cytologic features of littoral cell angiomas have been described only in three previous case reports, one of which was a bench-top aspirate. In our case, we have utilized the fine-needle aspiration samples obtained by a linear endoscopic ultrasound examination for establishing the diagnosis. The characteristic cytologic features identified on the smears along with immunohistochemical analysis performed on the compact cellblock prepared from the aspirate aided in the confirmation of the diagnosis. We suggest that EUS-FNAB is a safe and reliable method in the diagnosis of vascular lesions of the spleen.

Comparative prognostic value of epidermal growth factor quantitative protein expression compared with FISH for head and neck squamous cell carcinoma.

PURPOSE: Epidermal growth factor receptor (EGFR) overexpression correlates with recurrence and with treatment resistance in head and neck squamous cell carcinoma (HNSCC). The aim of this study was to evaluate the relationship of EGFR gene copy number utilizing FISH and protein expression with automated quantitative analysis (AQUA) and to correlate those with patient outcome. EXPERIMENTAL DESIGN: A tissue microarray composed of 102 HNSCC treated with (chemo)radiation was constructed and analyzed for EGFR copy number by FISH (Vysis; Abbott Laboratories) and EGFR protein expression using AQUA analysis of EGFR staining scored on a scale of 0 to 255. We evaluated associations of EGFR FISH status and AQUA score with clinicopathologic parameters and survival prognosis. RESULTS: Eleven (17.2%) of 64 tumors with FISH results showed EGFR high polysomy and/or gene amplification (FISH positive). Protein levels assessed by AQUA in FISH-positive cases were significantly higher (P = 0.04) than in FISH-negative cases. Using the continuous AQUA scores for EGFR expression, AQUA and FISH showed significant agreement (Pearson's ρ = 0.353, P = 0.04). Patients with high tumor EGFR protein expression had inferior 5-year overall survival (27.7%) compared with those with low tumor EGFR expression (54%; P = 0.029). There was no significant association between EGFR FISH status and overall survival (P = 0.201). In the multivariate model, high tumor EGFR protein expression status remained an independent prognostic factor for overall survival (P = 0.047). CONCLUSIONS: EGFR protein content correlates with gene copy number if protein content is quantitated and automatically analyzed, as with AQUA. EGFR protein levels assessed by AQUA strongly predict for patient outcome in HNSCC, whereas EGFR FISH status does not provide prognostic information.

Defining molecular phenotypes of human papillomavirus-associated oropharyngeal squamous cell carcinoma: validation of three-class hypothesis.

OBJECTIVE: The purpose of this study was to determine if oropharyngeal squamous cell carcinoma (OSCC) classified into three groups based on human papillomavirus (HPV) 16 DNA presence and p16 expression display different protein expression patterns. STUDY DESIGN: Cross-sectional study. SETTING: A laboratory-based study of patients with OSCC treated at a tertiary care academic medical center. SUBJECTS AND METHODS: Paraffin-embedded OSCC specimens from 77 patients classified into the three-class model (HPV negative, HPV inactive [HPV16+/p16-], and HPV active [HPV16+/p16+]) were queried for the expression of 14 tumor progression proteins using AQUA (HistoRx, New Haven CT). Protein expression between groups was assessed by analysis of variance. Global expression patterns were determined by unsupervised hierarchical clustering. RESULTS: There were significant differences in expression of beta-catenin (P = 0.009), epidermal growth factor receptor (P = 0.009), and vascular endothelial growth factor (P = 0.028) between groups. HPV-active tumors had overexpression of beta-catenin. Hierarchical clustering showed HPV-negative and HPV-inactive tumors displayed association patterns distinct from HPV-active tumors. CONCLUSIONS: Tumors classified by HPV DNA presence and p16 expression have different molecular phenotypes. This is the first demonstration of overexpression of beta-catenin (also found in HPV-caused cervical cancer) in HPV-active OSCC. HPV-active OSCC may share a similar ontogeny to HPV-caused cervical cancer.

Loss of epigenetic silencing in tumors preferentially affects primate-specific retroelements.

Close to 50% of the human genome harbors repetitive sequences originally derived from mobile DNA elements, and in normal cells, this sequence compartment is tightly regulated by epigenetic silencing mechanisms involving chromatin-mediated repression. In cancer cells, repetitive DNA elements suffer abnormal demethylation, with potential loss of silencing. We used a genome-wide microarray approach to measure DNA methylation changes in cancers of the head and neck and to compare these changes to alterations found in adjacent non-tumor tissues. We observed specific alterations at thousands of small clusters of CpG dinucleotides associated with DNA repeats. Among the 257,599 repetitive elements probed, 5% to 8% showed disease-related DNA methylation alterations. In dysplasia, a large number of local events of loss of methylation appear in apparently stochastic fashion. Loss of DNA methylation is most pronounced for certain members of the SVA, HERV, LINE-1P, AluY, and MaLR families. The methylation levels of retrotransposons are discretely stratified, with younger elements being highly methylated in healthy tissues, while in tumors, these young elements suffer the most dramatic loss of methylation. Wilcoxon test statistics reveals that a subset of primate LINE-1 elements is demethylated preferentially in tumors, as compared to non-tumoral adjacent tissue. Sequence analysis of these strongly demethylated elements reveals genomic loci harboring full length, as opposed to truncated elements, while possible enrichment for functional LINE-1 ORFs is weaker. Our analysis suggests that, in non-tumor adjacent tissues, there is generalized and highly variable disruption of epigenetic control across the repetitive DNA compartment, while in tumor cells, a specific subset of LINE-1 retrotransposons that arose during primate evolution suffers the most dramatic DNA methylation alterations.

Expression and prognostic significance of kallikrein-related peptidase 8 protein levels in advanced ovarian cancer by using automated quantitative analysis.

Kallikrein-related peptidases, a subgroup of the serine protease enzyme family, are considered to be important prognostic biomarkers in cancer. In this study we sought to determine the prognostic value of kallikrein-related peptidase 8 (KLK8, hK8, KLK-8) in ovarian cancer using a novel method of compartmentalised in situ protein analysis. A tissue array composed of 150 advanced stage ovarian cancers, uniformly treated with surgical debulking followed by platinum-paclitaxel combination chemotherapy, was constructed. For the evaluation of kallikrein-related peptidase 8 protein expression, we used an immunofluorescence-based method of automated in situ quantitative protein analysis (AQUA). Mean follow-up time of the cohort was 34.35 months. One hundred twenty-six of 150 cases had sufficient tissue for AQUA analysis. There were significant correlations between tumour mask KLK8 protein expression levels and clinicopathological variables, including grade (p = 0.0011), residual disease (p = 0.0063) and clinical response to chemotherapy(p = 0.0346). In univariate survival analysis there was a significant correlation between KLK8 tumour mask expression and five years progression-free survival, meanwhile it was not associated with five-year overall survival (p = 0.0694). Specifically, low KLK8 expression correlated with better outcome (top vs. bottom quartile, p = 0.0319). In multivariate survival analysis, adjusting for well-characterised prognostic variables, tumour KLK8 expression level retained its prognostic significance for progression-free survival (95%CI: 0.341-1.027, p = 0.045). The possibility that KLK8 may be a suitable candidate as a diagnostic and prognostic marker warrants further investigation.

Prognostic value of kallikrein-related peptidase 6 protein expression levels in advanced ovarian cancer evaluated by automated quantitative analysis (AQUA).

Kallikrein-related peptidases, a subgroup of the serine protease enzyme family, are considered important prognostic biomarkers in cancer. In the present study, we sought to determine the prognostic value of kallikrein-related peptidase 6 (KLK6) in ovarian cancer using a novel method of compartmentalized in situ protein analysis. A tissue array composed of 150 advanced stage ovarian cancers, uniformly treated with surgical debulking followed by platinum-paclitaxel combination chemotherapy, was constructed. For evaluation of KLK6 protein expression, we used an immunofluorescence-based method of automated in situ quantitative measurement of protein analysis (AQUA). Mean follow-up time of the cohort was 34.35 months. One hundred and thirty-five of 150 cases had sufficient tissue for AQUA analysis. In univariate survival analysis, low tumor KLK6 expression was associated with better outcome for overall survival over 3 years (P = 0.019). There was no association between tumor KLK6 expression and progression-free survival (P = 0.128). In multivariate survival analysis, adjusting for well-characterized prognostic variables, low tumor KLK6 expression level was one of the most significant predictor variable for overall survival (95% confidence interval, 1.19-3.50; P = 0.009). High tumor KLK6 protein expression is associated with inferior patient outcome in ovarian cancer. KLK6 may represent a promising disease biomarker and therapeutic target in ovarian cancer.

Correlates and determinants of nuclear epidermal growth factor receptor content in an oropharyngeal cancer tissue microarray.

BACKGROUND: We have previously reported nuclear localization of epidermal growth factor receptor (EGFR) protein in oropharyngeal cancer tissue. Nuclear EGFR levels were inversely correlated with survival and response to radiotherapy. Here, we sought to identify the determinants and correlates of nuclear EGFR content. METHODS: We analyzed an oropharyngeal cancer tissue microarray for the expression of the key molecules of the EGFR signaling cascade using an automated image analysis technique (AQUA) scored on a scale of 0 to 255, which permits protein quantitation and subcellular localization. Patients with oropharyngeal squamous cell cancer treated with radiotherapy or surgery and radiotherapy were eligible. Data were analyzed using Spearman correlations and multiple linear regression with robust SEs. RESULTS: Of the 95 tumors included in this study, 72 (75%) had sufficient tissue for analysis of nuclear EGFR. Nuclear EGFR levels were associated with membranous/cytoplasmic EGFR levels (rho = 0.82, P < 0.001), nuclear extracellular signal-regulated kinase-2 (rho = 0.30, P = 0.01), and nuclear proliferating cell nuclear antigen (PCNA; rho = 0.36, P = 0.003). Nuclear phosphorylated-Akt, cyclin D1, phosphatase and tensin homolog (mutated in multiple cancers 1) (PTEN), p53, and proliferation marker Ki-67 levels did not correlate with nuclear EGFR level. In multivariable analysis, only PCNA retained its significant association (P = 0.01). CONCLUSIONS: These results are consistent with preclinical data showing that EGFR may function as a tyrosine kinase in the nucleus, phosphorylating and stabilizing PCNA. The nuclear activity of EGFR may constitute a novel therapeutic target.

Phosphorylation of Akt (Ser473) predicts poor clinical outcome in oropharyngeal squamous cell cancer.

BACKGROUND: Several lines of laboratory evidence support a role of persistent activation of Akt pathway in oropharyngeal squamous cell carcinoma (OSCC) progression. Loss of phosphatase PTEN is one of the proposed mechanisms of Akt activation. We sought to determine the prognostic significance of Akt activation in a cohort of patients with OSCC as well as the association between phosphorylated (activated) Akt and PTEN levels. METHODS: Using a novel system of in situ quantitative protein expression analysis (AQUA), we studied the protein expression levels of phosphorylated Akt (p-Akt) and PTEN on a tissue microarray. The array included 79 OSCCs with a mean follow-up of 36 months. RESULTS: Patients with tumors expressing low tumor p-Akt levels had lower 5-year local recurrence rates (5% versus 38%). Additionally, these patients had improved 5-year overall survival rates (45% versus 27%). This survival effect was likely due to disease recurrence, as there was no difference in death without recurrence between low- and high-expressing groups. In adjusted analysis, tumor p-Akt expression was a strong predictor of local recurrence. A significant inverse relationship was found between nuclear p-Akt and nuclear PTEN: Tumors with high nuclear p-Akt had low nuclear PTEN and vice versa. CONCLUSIONS: Akt activation in OSCC is associated with adverse patient outcome, indicating that Akt is a promising molecular target in OSCC. PTEN loss may be one of the mechanisms of Akt activation in OSCC.

Evaluation of the prognostic value of cellular inhibitor of apoptosis protein in epithelial ovarian cancer using automated quantitative protein analysis.

PURPOSE: The cellular inhibitor of apoptosis protein (cIAP) is regarded as an important prognostic biomarker in cancer. Here, we sought to determine the prognostic value of cIAP protein levels in epithelial ovarian cancer using a novel method of compartmentalized in situ protein analysis. METHODS: A tissue array composed of 150 advanced-stage ovarian cancers, treated with surgical debulking followed by platinum/paclitaxel-based combination chemotherapy, was constructed. For evaluation of protein expression, we used an immunofluorescence-based method of automated in situ quantitative measurement of protein analysis. RESULTS: The mean follow-up time for the entire cohort was 34.4 months. Patients with tumors bearing high cIAP membranous expression had a 3-year survival rate of 31% compared with 73% for patients with low cIAP expressing tumors (P = 0.0020). In multivariable analysis, adjusting for well-characterized prognostic variables, low membranous cIAP expression level was the only significant prognostic factor for overall survival. CONCLUSIONS: Our results indicate that cIAP protein levels have prognostic value in ovarian cancer patients. Modulation of cIAP levels may improve clinical outcome in ovarian cancer.

Solitary fibrous tumor of the larynx: a case report and review of the literature.

Solitary fibrous tumors are relatively rare mesenchymal neoplasms that were originally described as pleural- or peritoneal-based lesions. Although they were considered a form of mesothelioma, subsequent investigation failed to reveal mesothelial differentiation. Characterization of their histologic and immunohistochemical features, as well as identification in a multitude of nonmesothelial-based locations has further served to distinguish these lesions from the more diffuse and aggressive mesothelioma. Reports of solitary fibrous tumor in the larynx are extremely rare. We report a case of solitary fibrous tumor of the larynx in a 38-year-old man.

Molecular classification identifies a subset of human papillomavirus--associated oropharyngeal cancers with favorable prognosis.

PURPOSE: We sought to determine the prevalence of biologically relevant human papillomavirus (HPV) in oropharyngeal squamous cell carcinoma (OSCC). Retinoblastoma (Rb) downregulation by HPV E7 results in p16 upregulation. We hypothesized that p16 overexpression in OSCC defines HPV-induced tumors with favorable prognosis. METHODS: Using real-time polymerase chain reaction for HPV16, we determined HPV16 viral load in a cohort of 79 OSCCs annotated with long-term patient follow-up. A tissue microarray including these cases was also analyzed for p53, p16, and Rb utilizing in situ quantitative protein expression analysis. Seventy-seven tumors were classified into a three-class model on the basis of p16 expression and HPV-DNA presence: class I, HPV-, p16 low; class II, HPV+, p16 low; and class III, HPV+, p16 high. RESULTS: Sixty-one percent of OSCCs were HPV16+; HPV status alone was of no prognostic value for local recurrence and was barely significant for survival times. Overall survival was improved in class III (79%) compared with the other two classes (20% and 18%; P = .0095). Disease-free survival for the same class was 75% versus 15% and 13% (P = .0025). The 5-year local recurrence was 14% in class III versus 45% and 74% (P = .03). Only patients in class III had significantly lower p53 and Rb expression (P = .017 and .001, respectively). Multivariable survival analysis confirmed the prognostic value of the three-class model. CONCLUSION: Using this system for classification, we define the molecular profile of HPV+ OSCC with favorable prognosis, namely HPV+/p16 high (class III). This study defines a novel classification scheme that may have value for patient stratification for clinical trials testing HPV-targeted therapies.

Effect of epidermal growth factor receptor expression level on survival in patients with epithelial ovarian cancer.

BACKGROUND: Several lines of laboratory evidence support the epidermal growth factor receptor (EGFR) as an adverse prognostic indicator in ovarian cancers. However, different methods of immunohistochemical assessment have yielded conflicting results. Here, we sought to determine the prognostic value of EGFR in ovarian cancer using a novel method of compartmentalized in situ protein analysis. METHODS: A tissue array composed of 150 advanced-stage ovarian cancers uniformly treated, with surgical debulking followed by platinum-paclitaxel combination chemotherapy, was constructed. For evaluation of EGFR protein expression, we used an immunofluorescence-based method of automated in situ quantitative measurement of protein analysis (AQUA). RESULTS: Mean follow-up time for the entire cohort was 34.4 months. Eighty-one of 150 cases had sufficient tissue for AQUA analysis. High tumor EGFR expression was associated with poor outcome for overall survival (P=0.0001) and disease-free survival (P=0.0005) at 3 years. In multivariable analysis, adjusting for well-characterized prognostic variables, EGFR expression status was the most significant prognostic factor for disease-free and overall survival. CONCLUSION: The conflicting results in the literature regarding the prognostic value of EGFR may be due to the technical difficulties inherent in assessing EGFR with immunocytochemistry. In the present study, we show that measurement of EGFR protein levels in ovarian cancer using AQUA is feasible and can give important prognostic information.

Subcellular localization and protein levels of cyclin-dependent kinase inhibitor p27 independently predict for survival in epithelial ovarian cancer.

PURPOSE: p27 protein is regarded as a valuable prognostic biomarker in cancer with a potential use as a molecular target. However, different methods of immunohistochemical assessment have yielded conflicting results. Here, we sought to determine the prognostic value of p27 in ovarian cancer using a novel method of compartmentalized in situ protein analysis. EXPERIMENTAL DESIGN: A tissue array composed of 150 advanced stage ovarian cancers uniformly treated, with surgical debulking followed by platinum-paclitaxel combination chemotherapy, was constructed. For evaluation of p27 protein expression, we used an immunofluorescence-based method of automated in situ quantitative measurement of protein analysis [automated quantitative analysis (AQUA)]. RESULTS: The mean follow-up time of the patients was 34.3 months. Patients with low Fédération Internationale des Gynaecologistes et Obstetristes stage were more likely to have low nuclear p27 expression (P = 0.008). Low nuclear p27 expression was associated with improved 3-year overall survival (66% versus 20%, P = 0.0047) and disease-free survival (27% versus 12%, P = 0.022). In multivariable analysis, adjusting for well-characterized prognostic variables, low nuclear p27 expression level was the most significant prognostic factor for both disease-free and overall survival. CONCLUSIONS: Our results indicate that quantitative assessment of nuclear p27 expression level by automated in situ quantitative analysis is a strong predictor for outcome in ovarian cancer.

Early metastasizing spindle epithelial tumor with thymus-like differentiation (SETTLE) of the thyroid.

Spindle epithelial tumor with thymus-like elements is a rare thyroid lesion of children and young adults thought to be derived from branchial pouch remnants or foci of ectopic thymus. The lesion is poorly understood, and although it was originally believed to follow an indolent clinical course, its potential for late metastasis is becoming generally acknowledged. We have recently seen a unique case of this rare tumor in an 11-year-old boy, in which an unexpected and salient feature is the presence of a micrometastasis in a single lymph node at presentation. With the exception of 1 case with extensively infiltrative tumor and metastatic disease at the time of onset, in all other cases dissemination occurred years after surgical resection of the primary lesion. We review all previously reported cases and provide a detailed study of the histologic and ultrastructural appearances of this lesion.