SOX10 immunohistochemistry in sweat ductal/glandular neoplasms.

BACKGROUND: SOX10 is a newer Schwannian and melanocytic marker that has generated great interest for its relative sensitivity and specificity in the diagnosis of neural crest-derived tumors. Previous studies with SOX10 have shown positive immunohistochemical expression in cutaneous eccrine glands and negative expression in eccrine ducts, apocrine glands and hair follicles. Thus, we hypothesized that some sweat gland tumors of presumed eccrine origin would be positive for SOX10, whereas apocrine-derived sweat gland tumors would not. METHODS: A mouse monoclonal anti-SOX10 (clone BC34: Biocare Medical; Concord, California) immunohistochemical antibody was performed on various sweat gland tumors and basal cell carcinoma. RESULTS: SOX10 showed positivity in spiradenomas (13/13), cylindromas (9/10), hidradenoma papilliferum (10/10), syringocystadenoma papilliferum (8/10), apocrine adenomas (8/10), and negativity in poromas (0/12), syringomas (0/10), and basal cell carcinomas (0/13). There was mixed staining of hidradenomas (6/15). CONCLUSIONS: SOX10 immunohistochemistry may be of utility in distinguishing some of the varying adnexal tumors from each other, and from basal cell carcinoma (BCC), but given the staining of both apocrine and eccrine tumors, does not seem to provide information as to their origins as either eccrine or apocrine tumors.

Molecular Analysis of Low Grade Prostate Cancer Using a Genomic Classifier of Metastatic Potential.

PURPOSE: We determined how frequently histological Gleason 3 + 3 = 6 tumors have the molecular characteristics of disease with metastatic potential. MATERIALS AND METHODS: We analyzed prostatectomy tissue from 337 patients with Gleason 3 + 3 disease. All tissue was re-reviewed in blinded fashion by genitourinary pathologists using 2005 ISUP (International Society of Urological Pathology) Gleason grading criteria. A previously validated Decipher® metastasis signature was calculated in each case based on a locked model. To compare patient characteristics across pathological Gleason score categories we used the Fisher exact test or the ANOVA F test. The distribution of Decipher scores among different clinicopathological groups was compared with the Wilcoxon rank sum test. The association of Decipher score with adverse pathology features was examined using logistic regression models. The significance level of all statistical tests was 0.05. RESULTS: Of men with Gleason 3 + 3 = 6 disease only 269 (80%) had a low Decipher score with intermediate and high scores in 43 (13%) and 25 (7%), respectively. Decipher scores were significantly higher among pathological Gleason 3 + 3 = 6 specimens from cases with adverse pathological features such as extraprostatic extension, seminal vesicle involvement or positive margins (p <0.001). The median Decipher score in patients with margin negative pT2 disease was 0.23 (IQR 0.09-0.42) compared to 0.30 (IQR 0.17-0.42) in patients with pT3 disease or positive margins (p = 0.005). CONCLUSIONS: Using a robust and validated prognostic signature we found that a small but not insignificant proportion of histological Gleason 6 tumors harbored molecular characteristics of aggressive cancer. Molecular profiling of such tumors at diagnosis may better select patients for active surveillance at diagnosis and trigger appropriate intervention during followup.

Utilization of a Genomic Classifier for Prediction of Metastasis Following Salvage Radiation Therapy after Radical Prostatectomy.

BACKGROUND: Despite salvage radiation therapy (SRT) for recurrent prostate cancer (PCa) after radical prostatectomy (RP), some patients still progress to metastases. Identifying these men would allow them to undergo systemic therapy including testing novel therapies to reduce metastases risk. OBJECTIVE: To test whether the genomic classifier (GC) predicts development of metastatic disease. DESIGN, SETTING, AND PARTICIPANTS: Retrospective multi-center and multi-ethnic cohort study from two academic centers and one Veterans Affairs Medical Center in the United States involving 170 men receiving SRT for recurrent PCa post-RP. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Time from SRT to development of metastatic disease tested using Cox regression, survival c-index, and decision curve analysis. Performance of GC was compared to the Cancer of the Prostate Risk Assessment Score and Briganti risk models based on these metrics. RESULTS AND LIMITATIONS: With a median 5.7 yr follow-up after SRT, 20 patients (12%) developed metastases. On multivariable analysis, for each 0.1 unit increase in GC (scaled from 0 to 1), the hazard ratio for metastasis was 1.58 (95% confidence interval 1.16-2.17; p=0.002). Adjusting for androgen deprivation therapy did not materially change the results. The c-index for GC was 0.85 (95% confidence interval 0.73-0.88) versus 0.63-0.65 for published clinico-pathologic risk models. The 5-yr cumulative incidence of metastasis post-SRT in patients with low, intermediate, and high GC scores was 2.7%, 8.4%, and 33.1%, respectively (p<0.001). CONCLUSIONS: While validation in larger, prospectively collected cohorts is required, these data suggest GC is a strong predictor of metastases among men receiving SRT for recurrent PCa post-RP, accurately identifying men who are excellent candidates for systemic therapy due to their very high-risk of metastases. PATIENT SUMMARY: Genomic classifier and two clinico-pathologic risk models were evaluated on their ability to predict metastases among men receiving salvage radiation therapy for recurrent prostate cancer. Genomic classifier was able to identify candidates for further therapies due to their very high-risk of metastases.

Validation of a Genomic Classifier for Predicting Post-Prostatectomy Recurrence in a Community Based Health Care Setting.

PURPOSE: We determined the value of Decipher®, a genomic classifier, to predict prostate cancer outcomes among patients after prostatectomy in a community health care setting. MATERIALS AND METHODS: We examined the experience of 224 men treated with radical prostatectomy from 1997 to 2009 at Kaiser Permanente Northwest, a large prepaid health plan in Portland, Oregon. Study subjects had aggressive prostate cancer with at least 1 of several criteria such as preoperative prostate specific antigen 20 ng/ml or greater, pathological Gleason score 8 or greater, stage pT3 disease or positive surgical margins at prostatectomy. The primary end point was clinical recurrence or metastasis after surgery evaluated using a time dependent c-index. Secondary end points were biochemical recurrence and salvage treatment failure. We compared the performance of Decipher alone to the widely used CAPRA-S (Cancer of the Prostate Risk Assessment Post-Surgical) score, and assessed the independent contributions of Decipher, CAPRA-S and their combination for the prediction of recurrence and treatment failure. RESULTS: Of the 224 patients treated 12 experienced clinical recurrence, 68 had biochemical recurrence and 34 experienced salvage treatment failure. At 10 years after prostatectomy the recurrence rate was 2.6% among patients with low Decipher scores but 13.6% among those with high Decipher scores (p=0.02). When CAPRA-S and Decipher scores were considered together, the discrimination accuracy of the ROC curve was increased by 0.11 compared to the CAPRA-S score alone (combined c-index 0.84 at 10 years after radical prostatectomy) for clinical recurrence. CONCLUSIONS: Decipher improves our ability to predict clinical recurrence in prostate cancer and adds precision to conventional pathological prognostic measures.

A newly developed mouse monoclonal SOX10 antibody is a highly sensitive and specific marker for malignant melanoma, including spindle cell and desmoplastic melanomas.

CONTEXT: Recent immunohistochemical studies have demonstrated Sry-related HMG-Box gene 10 (SOX10) expression in malignant melanomas, malignant peripheral nerve sheath tumors, a subset of breast carcinomas, and gliomas. SOX10 has shown important clinical utility in its ability to detect desmoplastic and spindle cell melanomas. To date, most publications have employed a research use-only goat polyclonal SOX10 antibody for immunohistochemical staining. OBJECTIVE: To describe the development of a new mouse monoclonal SOX10 antibody (BC34) and evaluate its immunohistochemical staining profile in a wide range of normal and neoplastic tissues, with an emphasis on melanoma. DESIGN: SOX10 antibody was optimized for staining using a polymer detection system and visualization with diaminobenzidine. RESULTS: In normal tissues, SOX10 was expressed in skin melanocytes and eccrine cells, breast myoepithelial and lobular epithelial cells, salivary gland myoepithelial cells, peripheral nerve Schwann cells, and central nervous system glial cells. SOX10 was expressed in 238 of 257 melanomas (92.6%), including 50 of 51 of both spindle cell and desmoplastic melanomas (98%). SOX10 was expressed in 100% of nevi (20 of 20) and schwannomas (28 of 28). In other neoplasms, SOX10 was expressed in 18 of 109 invasive ductal breast carcinomas (16.5%). All other carcinomas were negative for SOX10. SOX10 was identified in 25 of 52 central nervous system neoplasms, primarily in astrocytomas (22 of 41; 53.7%), and in 4 of 99 various sarcomas examined (4.0%). CONCLUSIONS: The newly developed mouse monoclonal SOX10 antibody BC34 is highly sensitive and specific for malignant melanoma, including desmoplastic and spindle cell variants, and appears highly suitable for clinical use.

Diagnostic Reasoning across the Medical Education Continuum.

We aimed to study linguistic and non-linguistic elements of diagnostic reasoning across the continuum of medical education. We performed semi-structured interviews of premedical students, first year medical students, third year medical students, second year internal medicine residents, and experienced faculty (ten each) as they diagnosed three common causes of dyspnea. A second observer recorded emotional tone. All interviews were digitally recorded and blinded transcripts were created. Propositional analysis and concept mapping were performed. Grounded theory was used to identify salient categories and transcripts were scored with these categories. Transcripts were then unblinded. Systematic differences in propositional structure, number of concept connections, distribution of grounded theory categories, episodic and semantic memories, and emotional tone were identified. Summary concept maps were created and grounded theory concepts were explored for each learning level. We identified three major findings: (1) The "apprentice effect" in novices (high stress and low narrative competence); (2) logistic concept growth in intermediates; and (3) a cognitive state transition (between analytical and intuitive approaches) in experts. These findings warrant further study and comparison.

Leukemia cutis in association with cutaneous epidermal malignancies.

BACKGROUND: Epidermal malignancies developing in association with hematolymphoid malignancies are exceptional. Only one prior case of myeloid leukemia cutis with a cutaneous epidermal malignancy has been reported. METHODS: We report two cases; one occurred in association with squamous cell carcinoma (SCC) and another with basal cell carcinoma (BCC). RESULTS: Both patients were 83-year-old males without established histories of systemic hematopoietic disorders; one presented with an erythematous papule on the right upper back and the other with a nodule on the left wrist. One biopsy revealed nodular BCC with an associated perivascular myeloid leukemic infiltrate showing immunohistochemical positivity for CD43 and CD45. The other biopsy showed SCC associated with a leukemic infiltrate in sheets with myeloid blasts, eosinophilic myelocytes and maturing myeloid precursors. The myeloid cells showed immunohistochemical expression of CD43, CD68, CD33, CD117 and myeloperoxidase. Both patients had myeloblasts on peripheral blood smear. One patient declined further treatment and died of disease 5 weeks after the initial biopsy. The other patient underwent chemotherapy and is alive after 6 months. CONCLUSION: Although most inflammatory infiltrates associated with cutaneous epidermal malignancies are reactive, careful examination is necessary to exclude systemic hematopoietic disease, especially in elderly patients.

Comparative efficacy of rapid-release nicotine gum versus nicotine polacrilex gum in relieving smoking cue-provoked craving.

AIMS: Most relapse episodes occur when smokers are confronted with craving provoked by situational cues. Current nicotine gum can help relieve cue-provoked cravings, but faster effects may result in more rapid relief. We tested a prototype formulation of a new rapid-release nicotine gum (RRNG) that provides more rapid release and absorption of nicotine, for its ability to provide faster and better craving relief compared to current nicotine polacrilex gum (NPG). DESIGN: Random assignment to RRNG or NPG, used during a smoking cue provocation procedure. Participants and setting A total of 319 smokers were exposed to a smoking cue in the laboratory by being asked to light but not smoke a cigarette of their preferred brand. Subjects then chewed a piece of 2 mg RRNG (n = 159) or 2 mg NPG (n = 160) according to randomized assignment. MEASUREMENTS: Craving assessments were completed at regular intervals before and after cue exposure (baseline, pre-cue, and 3, 6, 9, 12, 15, 18, 21, 25, 30 and 35 minutes after the cue). FINDINGS: Smokers chewing RRNG showed significantly lower craving than NPG subjects starting with the first assessment at 3 minutes (P < 0.025). Repeated-measures ANOVA revealed a significant treatment x time interaction (P < 0.05)-craving scores dropped more rapidly in RRNG subjects compared to NPG subjects. Survival analyses also indicated superiority of RRNG in achieving more rapid self-reported meaningful relief (P < 0.05) and complete relief (P < 0.05) of craving. CONCLUSIONS: Rapid-release nicotine gum reduced cue-provoked craving more rapidly compared to NPG, and thus merits further study in cessation efficacy trials.