Daniel W. Lin

Disseminated Tumor Cells in Prostate Cancer Patients after Radical Prostatectomy and without Evidence of Disease Predicts Biochemical Recurrence

Purpose: Men with apparently localized prostate cancer often relapse years after radical prostatectomy. We sought to determine if epithelial-like cells identified from bone marrow in patients after radical prostatectomy, commonly called disseminated tumor cells (DTC), were associated with biochemical recurrence. Experimental Design: We obtained bone marrow aspirates from 569 men prior to radical prostatectomy and from 34 healthy men with prostate-specific antigens <2.5 ng/mL to establish a comparison group. Additionally, an analytic cohort consisting of 98 patients with no evidence of disease (NED) after radical prostatectomy was established to evaluate the relationship between DTC and biochemical recurrence. Epithelial cells in the bone marrow were detected by magnetic bead enrichment with antibodies to CD45 and CD61 (negative selection) followed by antibodies to human epithelial antigen (positive selection) and confirmation with FITC-labeled anti-BerEP4 antibody. Results: DTC were present in 72% (408 of 569) of patients prior to radical prostatectomy. There was no correlation with pathologic stage, Gleason grade, or preoperative prostate-specific antigens. Three of 34 controls (8.8%) had DTC present. In patients with NED after radical prostatectomy, DTC were present in 56 of 98 (57%). DTC were detected in 12 of 14 (86%) NED patients after radical prostatectomy who subsequently suffered biochemical recurrence. The presence of DTC in NED patients was an independent predictor of recurrence (hazard ratio 6.9; 95% confidence interval, 1.03-45.9). Conclusions: Approximately 70% of men undergoing radical prostatectomy had DTC detected in their bone marrow prior to surgery, suggesting that these cells escape early in the disease. Although preoperative DTC status does not correlate with pathologic risk factors, persistence of DTC after radical prostatectomy in NED patients was an independent predictor of recurrence.

Influence of Surgical Manipulation on Prostate Gene Expression: Implications for Molecular Correlates of Treatment Effects and Disease Prognosis

PURPOSE Measurements of tissue gene expression are increasingly used for disease stratification, clinical trial eligibility, and assessment of neoadjuvant therapy response. However, the method of tissue acquisition alone could significantly influence the expression of specific transcripts or proteins. This study examines whether there are transcript alterations associated with surgical resection of the prostate gland by radical retropubic prostatectomy. MATERIALS AND METHODS Twelve patients with clinically localized prostate cancer underwent immediate in situ prostate biopsy after induction of anesthesia for radical prostatectomy. Ex vivo prostate biopsies were performed immediately after surgical removal. Prostate epithelium was acquired by laser-capture microdissection, and transcript abundance levels were quantitated by cDNA microarray hybridization and confirmed by quantitative polymerase chain reaction. Data were analyzed by paired, two-sample t test using Statistical Analysis of Microarray algorithms, and linear models were fit as a function of clinical characteristics. RESULTS Of 5,753 cDNAs with measurable expression in prostate epithelium, 88 (1.5%) were altered as a result of surgery (false-discovery rate < or = 10%), representing 62 unique genes. These included transcripts encoding acute phase response proteins, IER2 and JUNB, and regulators of cell proliferation, p21Cip1 and KLF6. Of the clinical characteristics examined, including patient age, prostate volume, serum prostate-specific antigen, blood loss, and operative time, only gland volume was significantly and negatively associated with the magnitude of gene expression difference between pre- and postsurgical specimens. CONCLUSION Surgical manipulation results in significant gene expression changes. Molecular analyses of surgical samples should recognize that transcript alterations occur rapidly, and these results are important when designing and analyzing molecular correlates of clinical studies.

Olanzapine for the treatment of borderline personality disorder: variable dose 12-week randomised double-blind placebo-controlled study

BACKGROUND Despite the prevalence and clinical significance of borderline personality disorder, its treatment remains understudied. AIMS To evaluate treatment with variably dosed olanzapine in individuals with borderline personality disorder. METHOD In this 12-week randomised, double-blind trial, individuals received olanzapine (2.5-20 mg/day; n=155) or placebo (n=159) (trial registry: NCT00091650). The primary efficacy measure was baseline to end-point change on the Zanarini Rating Scale for Borderline Personality Disorder (ZAN-BPD) using last-observation-carried-forward methodology. RESULTS Both olanzapine and placebo groups showed significant improvements but did not differ in magnitude at end-point (-6.56 v. -6.25, P=0.661). Response rates (50% reduction in ZAN-BPD) were 64.7% with olanzapine and 53.5% with placebo (P=0.062); however, time to response was significantly shorter for olanzapine (P=0.022). Weight gain was significantly greater (2.86 v. -0.35 kg, P<0.001), with higher incidence of treatment-emergent abnormal high levels of prolactin for the olanzapine group. CONCLUSIONS Individuals treated with olanzapine and placebo showed significant but not statistically different improvements on overall symptoms of borderline personality disorder. The types of adverse events observed with olanzapine treatment appeared similar to those observed previously in adult populations.

The critical role of the pathologist in determining eligibility for active surveillance as a management option in patients with prostate cancer: consensus statement with recommendations supported by the College of American Pathologists, International Society of Urological Pathology, Association of Directors of Anatomic and Surgical Pathology, the New Zealand Society of Pathologists, and the Prostate Cancer Foundation.

CONTEXT Prostate cancer remains a significant public health problem. Recent publications of randomized trials and the US Preventive Services Task Force recommendations have drawn attention to overtreatment of localized, low-risk prostate cancer. Active surveillance, in which patients undergo regular visits with serum prostate-specific antigen tests and repeat prostate biopsies, rather than aggressive treatment with curative intent, may address overtreatment of low-risk prostate cancer. It is apparent that a greater awareness of the critical role of pathologists in determining eligibility for active surveillance is needed. OBJECTIVES To review the state of current knowledge about the role of active surveillance in the management of prostate cancer and to provide a multidisciplinary report focusing on pathologic parameters important to the successful identification of patients likely to succeed with active surveillance, to determine the role of molecular tests in increasing the safety of active surveillance, and to provide future directions. DESIGN Systematic review of literature on active surveillance for low-risk prostate cancer, pathologic parameters important for appropriate stratification, and issues regarding interobserver reproducibility. Expert panels were created to delineate the fundamental questions confronting the clinical and pathologic aspects of management of men on active surveillance. RESULTS Expert panelists identified pathologic parameters important for management and the related diagnostic and reporting issues. Consensus recommendations were generated where appropriate. CONCLUSIONS Active surveillance is an important management option for men with low-risk prostate cancer. Vital to this process is the critical role pathologic parameters have in identifying appropriate candidates for active surveillance. These findings need to be reproducible and consistently reported by surgical pathologists with accurate pathology reporting.

Influence of Publication of US and European Prostate Cancer Screening Trials on PSA Testing Practices

In 2009, results from the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial indicated no difference in mortality between the screening and the control groups (rate ratio = 1.13, 95% confidence interval = 0.75 to 1.70), whereas those from the European Randomized study of Screening for Prostate Cancer trial indicated a 20% reduction in mortality among the screening group (rate ratio = 0.80, 95% confidence interval = 0.65 to 0.98). In this study, we examined whether prostate-specific antigen (PSA) testing has changed following these publications. The primary outcome measure was the proportion of men seen at least once in a primary care or urology clinic between August 1, 2004, and March 31, 2010, who received a PSA test. Following the publications, PSA use declined slightly-by 3.0 percentage points and 2.7 percentage points among men aged 40-54 and 55-74 years, respectively. PSA testing among men older than 75 years initially declined slightly following the recommendations by the US Preventive Services Task Force in 2008 and continued to decline after the trial publications.

Baseline characteristics and outcomes in patients with first episode or multiple episodes of acute mania.

OBJECTIVE Previous studies have reported differential responses to therapeutic interventions depending on the patients history with bipolar disorder, which highlights the importance of understanding the longitudinal nature of the disorder. The goal of the present analyses was to describe and compare the baseline characteristics, response to treatment, and medication patterns in adult patients experiencing a first episode versus multiple episodes of mania. METHOD The European Mania in Bipolar Longitudinal Evaluation of Medication (EMBLEM) study was a 2-year prospective, observational study to evaluate outcomes in patients experiencing a DSM-IV- or ICD-10-diagnosed manic or mixed episode. The study was conducted from December 2002 to June 2004. RESULTS Among 3,115 patients, 256 (8.2%) enrolled with a first manic or mixed episode. Relative to multiple-episode patients, first-episode patients were younger and had a lower body mass index (BMI), a higher incidence of past or current cannabis abuse, significantly higher baseline Young Mania Rating Scale total and Clinical Global Impressions-Bipolar Disorder (CGI-BP) mania scores, and lower CGI-BP depression and Hamilton Depression Rating Scale (5-item version) total scores. At the 12-week endpoint, rates of recovery and remission were greater for first-episode patients, and times to recovery and remission were shorter. CONCLUSIONS Limitations of the study were that entry of patients into this study with an acute manic or mixed episode was determined by clinical interview but not confirmed with a structured diagnostic interview. That information on the course of illness prior to entry into the study was obtained retrospectively. First-episode patients presented with different baseline illness characteristics and achieved recovery and remission more rapidly than multiple-episode patients.

Low-Fat, Low-Glycemic Load Diet and Gene Expression in Human Prostate Epithelium: A Feasibility Study of Using cDNA Microarrays to Assess the Response to Dietary Intervention in Target Tissues

Purpose: We examined the feasibility of using gene expression changes in human prostate epithelium as a measure of response to a dietary intervention. Materials and Methods: Eight men with newly diagnosed prostate cancer were randomized to a low-fat/low-glycemic load intervention arm (<20% energy from fat and total daily glycemic load <100) or a “standard American” control arm (≈35% energy from fat and total daily glycemic load >200). Prostate tissue was collected before randomization and ∼6 weeks later, at the time of radical prostatectomy. Epithelium was acquired by laser capture microdissection, and transcript abundance levels were measured by cDNA microarray hybridization and confirmed by quantitative reverse transcription-PCR. Results: Men in the intervention arm consumed 39% less total energy (P = 0.004) and the difference in weight change between intervention and control arms was −6.1 kg (P = 0.02). In the intervention arm, 23 (0.46%) of 5,711 cDNAs with measurable expression were significantly altered (P < 0.05; false discovery rate, ≤10%). In the control arm, there were no significant changes in transcript expression, even when using a false discovery rate as high as 50%. Conclusions: A 6-week, low-fat/low-glycemic load diet was associated with significant gene expression changes in human prostate epithelium. These results show the feasibility of using prostate tissues collected at diagnosis and at surgery to study the effects of dietary manipulation on prostate tissue, which may give insight into the molecular mechanisms underlying the associations of diet and obesity with the development or progression of prostate cancer. (Cancer Epidemiol Biomarkers Prev 2007;16(10):2150–4)

Differential Gene Expression in Benign Prostate Epithelium of Men with and without Prostate Cancer: Evidence for a Prostate Cancer Field Effect

Background: Several malignancies are known to exhibit a “field effect,” whereby regions beyond tumor boundaries harbor histologic or molecular changes that are associated with cancer. We sought to determine if histologically benign prostate epithelium collected from men with prostate cancer exhibits features indicative of premalignancy or field effect. Experimental Design: Prostate needle biopsies from 15 men with high-grade (Gleason 8-10) prostate cancer and 15 age- and body mass index–matched controls were identified from a biospecimen repository. Benign epithelia from each patient were isolated by laser capture microdissection. RNA was isolated, amplified, and used for microarray hybridization. Quantitative PCR was used to determine the expression of specific genes of interest. Alterations in protein expression were analyzed through immunohistochemistry. Results: Overall patterns of gene expression in microdissected benign prostate-associated benign epithelium (BABE) and cancer-associated benign epithelium (CABE) were similar. Two genes previously associated with prostate cancer, PSMA and SSTR1, were significantly upregulated in the CABE group (false discovery rate <1%). Expression of other prostate cancer–associated genes, including ERG, HOXC4, HOXC5, and MME, were also increased in CABE by quantitative reverse transcription-PCR, although other genes commonly altered in prostate cancer were not different between the BABE and CABE samples. The expression of MME and PSMA proteins on immunohistochemistry coincided with their mRNA alterations. Conclusion: Gene expression profiles between benign epithelia of patients with and without prostate cancer are very similar. However, these tissues exhibit differences in the expression levels of several genes previously associated with prostate cancer development or progression. These differences may comprise a field effect and represent early events in carcinogenesis. Clin Cancer Res; 16(22); 5414–23. ©2010 AACR.

A Dose Comparison of Olanzapine for the Treatment of Borderline Personality Disorder: A 12-Week Randomized, Double-Blind, Placebo-Controlled Study

OBJECTIVE To examine the efficacy and safety of olanzapine at low and moderate doses for the treatment of borderline personality disorder. METHOD In this 12-week randomized double-blind placebo-controlled trial, 451 outpatients aged 18-65 years with DSM-IV borderline personality disorder received olanzapine 2.5 mg/d (n = 150), olanzapine 5-10 mg/d (n = 148), or placebo (n = 153). The trial was conducted from February 2004 through January 2006 at 59 community-based and academic study centers in 9 countries (United States, Italy, Poland, Romania, Turkey, Chile, Peru, Argentina, and Venezuela). The primary efficacy measure was mean change from baseline to last-observation-carried-forward endpoint on the Zanarini Rating Scale for Borderline Personality Disorder (ZAN-BPD) total score. Secondary measures included the Montgomery-Asberg Depression Rating Scale, the Modified Overt Aggression Scale, the Global Assessment of Functioning, the Symptom Checklist-90-Revised, and the Sheehan Disability Scale. RESULTS An overall mean baseline ZAN-BPD total score of 17.2 (SD = 4.9) indicated moderate symptom severity. Only treatment with olanzapine 5-10 mg/d was associated with significantly greater mean change from baseline to endpoint in ZAN-BPD total score relative to placebo (-8.5 vs -6.8, respectively; P = .010; effect size = 0.29; 95% CI, 0.06-0.52). Response rates (response indicated by ≥ 50% decrease from baseline in ZAN-BPD total score) were significantly higher for olanzapine 5-10 mg/d (73.6%) versus olanzapine 2.5 mg/d (60.1%; P = .018) and versus placebo (57.8%; P = .006). Time to response was also significantly shorter for patients taking olanzapine 5-10 mg/d than for placebo-treated patients (P = .028). Treatment-emergent adverse events reported significantly more frequently among olanzapine-treated patients included somnolence, fatigue, increased appetite, and weight increase (all P values < .05). Mean weight change from baseline to endpoint was significantly greater for olanzapine-treated than for placebo-treated patients (olanzapine 2.5 mg/d: 2.09 kg; olanzapine 5-10 mg/d: 3.17 kg; placebo: 0.02 kg; P < .001). The overall completion rate for the 12-week double-blind treatment period was 65.2% (ie, 64.7% for olanzapine 2.5 mg/d, 69.6% for olanzapine 5-10 mg/d, and 61.4% for placebo). CONCLUSIONS Olanzapine 5-10 mg/d showed a clinically modest advantage over placebo in the treatment of overall borderline psychopathology. This advantage in effectiveness should be weighed against the risk of adverse events (particularly weight gain), which were consistent with the known safety profile of olanzapine. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00088036.

Characteristics of two alternative schizophrenia remission definitions: Relationship to clinical and quality of life outcomes

BACKGROUND The goal of these secondary analyses of clinical trial data was to characterize clinical outcomes in patients with schizophrenia who met symptom severity or duration thresholds for two alternative definitions of remission, and to explore their relationships to improvement duration and quality of life outcomes. METHODS Definition 1 used threshold criteria for selected PANSS items sustained over at least 6-months Definition 2 used Brief Psychiatric Rating Scale (BPRS) % change, a threshold score for the Clinical Global Improvement-Severity (CGI-S) maintained for at least 8 weeks, and threshold scores for selected BPRS items. Positive and Negative Symptom Scale (PANSS) and Quality of Life scale (QLS) total scores were pooled from 6 clinical trials. The extent to which the alternative severity thresholds from these two definitions and duration of clinical improvement were associated with different clinical and QLS outcomes was explored. Regression analysis also assessed the relative contribution of each of the components of the two definition severity thresholds to improvements in QLS Total score. RESULTS Increases in QLS scores were greater for those patients who met either threshold criteria relative to those who met neither (p<.0001). Significantly greater improvements in QLS scores were observed for patients who met either threshold criteria at the 8-, 16- and 24-week visits relative to those who met criteria at weeks 16 and 24, or at week 24 only (p<0.001), as well as for the subset of patients who met threshold criteria at both 24 and 52 weeks relative to those who met criteria at only one of these 2 time points. Only 31% to 47% of patients meeting threshold criteria for either definition at the 8-, 16- or 24-week visits remained in remission at the 52-week visit. Among the severity threshold components analyzed, BPRS total % change from baseline was the strongest predictor of improvement in QLS scores. CONCLUSIONS Quality of life improved most for patients who achieved severity thresholds associated with either remission criteria and who stayed improved for longer periods. Total BPRS change scores accounted for the greatest percentage of the QLS scores variance. Only a fraction of patients who meet severity criteria for either remission definition early in treatment will remain at that level of improvement within the subsequent 9-12 months.