Normal Risk Ovarian Screening Study: 21-Year Update.

PURPOSE: The Normal Risk Ovarian Screening Study (NROSS) tested a two-stage screening strategy in postmenopausal women at conventional hereditary risk where significantly rising cancer antigen (CA)-125 prompted transvaginal sonography (TVS) and abnormal TVS prompted surgery to detect ovarian cancer. METHODS: A total of 7,856 healthy postmenopausal women were screened annually for a total of 50,596 woman-years in a single-arm study (ClinicalTrials.gov identifier: NCT00539162). Serum CA125 was analyzed with the Risk of Ovarian Cancer Algorithm (ROCA) each year. If risk was unchanged and <1:2,000, women returned in a year. If risk increased above 1:500, TVS was undertaken immediately, and if risk was intermediate, CA125 was repeated in 3 months with a further increase in risk above 1:500 prompting referral for TVS. An average of 2% of participants were referred to TVS annually. RESULTS: Thirty-four patients were referred for operations detecting 15 ovarian cancers and two borderline tumors with 12 in early stage (I-II). In addition, seven endometrial cancers were detected with six in stage I. As four ovarian cancers and two borderline tumors were diagnosed with a normal ROCA, the sensitivity for detecting ovarian and borderline cancer was 74% (17 of 23), and 70% of ROCA-detected cases (12 of 17) were in stage I-II. NROSS screening reduced late-stage (III-IV) disease by 34% compared with UKCTOCS controls and by 30% compared with US SEER values. The positive predictive value (PPV) was 50% (17 of 34) for detecting ovarian cancer and 74% (25 of 34) for any cancer, far exceeding the minimum acceptable study end point of 10% PPV. CONCLUSION: While the NROSS trial was not powered to detect reduced mortality, the high specificity, PPV, and marked stage shift support further development of this strategy.

Autoantibodies, antigen-autoantibody complexes and antigens complement CA125 for early detection of ovarian cancer.

BACKGROUND: Multiple antigens, autoantibodies (AAb), and antigen-autoantibody (Ag-AAb) complexes were compared for their ability to complement CA125 for early detection of ovarian cancer. METHODS: Twenty six biomarkers were measured in a single panel of sera from women with early stage (I-II) ovarian cancers (n = 64), late stage (III-IV) ovarian cancers (186), benign pelvic masses (200) and from healthy controls (502), and then split randomly (50:50) into a training set to identify the most promising classifier and a validation set to compare its performance to CA125 alone. RESULTS: Eight biomarkers detected ≥ 8% of early stage cases at 98% specificity. A four-biomarker panel including CA125, HE4, HE4 Ag-AAb and osteopontin detected 75% of early stage cancers in the validation set from among healthy controls compared to 62% with CA125 alone (p = 0.003) at 98% specificity. The same panel increased sensitivity for distinguishing early-stage ovarian cancers from benign pelvic masses by 25% (p = 0.0004) at 95% specificity. From 21 autoantibody candidates, 3 AAb (anti-p53, anti-CTAG1 and annt-Il-8) detected 22% of early stage ovarian cancers, potentially lengthening lead time prior to diagnosis. CONCLUSION: A four biomarker panel achieved greater sensitivity at the same specificity for early detection of ovarian cancer than CA125 alone.

Combination of Prostate Cancer Antigen 3 and Prostate-Specific Antigen Improves Diagnostic Accuracy in Men at Risk of Prostate Cancer.

CONTEXT: - Prostate cancer antigen 3 (PCA3) is a noncoding RNA that is highly overexpressed in prostate cancer (PCa) tissue and excreted in urine in patients with PCa. OBJECTIVE: - To assess the clinical utility of urinary PCA3 in men at risk of PCa. DESIGN: - We retrospectively reviewed a cohort of 271 men (median age, 63 years) with elevated prostate-specific antigen (PSA), and/or strong family history, and/or abnormal digital rectal examination findings. Diagnostic sensitivity, specificity, positive and negative predictive values (PPV, NPV), positive and negative likelihood ratios (LR+, LR-), and diagnostic odds ratio (DOR), and area under the receiver-operating characteristic curves (AUC) were evaluated. RESULTS: - PCA3 score was a significant predictor of prostate biopsy outcome ( P < .001). A PCA3 score of 30 was the optimal cutoff for our study cohort, with a diagnostic sensitivity of 72.7%, specificity of 67.5%, PPV of 47.1%, NPV of 86.2%, LR+ of 2.24, LR- of 0.40, and DOR of 5.55. At this cutoff score, the PCA3 assay could avoid 57.4% of unnecessary invasive biopsies in the overall study cohort and 70.3% in the subgroup with PSA level in the "gray zone" (4-10 ng/mL). A logistic regression algorithm combining PCA3 with PSA increased the AUC from 0.571 for PSA-only to 0.729 ( P < .001). The logistic combined marker gained the ability to discriminate low-grade from high-grade cancers. CONCLUSIONS: - Our data suggest that PCA3 improves the diagnostic sensitivity and specificity of PSA and that the combination of PCA3 with PSA gives better overall performance in identification of PCa than serum PSA alone in the high-risk population.

Causes and impact of specimen rejection in a clinical chemistry laboratory.

BACKGROUND: Pre-analytical errors necessitate specimen rejection and negatively affect patient safety. Our purpose was to investigate the factors leading to specimen rejection and its impact. METHODS: Specimen rejections in a clinical chemistry laboratory during a 1-year period were reviewed retrospectively and analyzed for frequency, cause, circumstances, and impact. RESULTS: Of the 837,862 specimens received, 2178 (0.26%) were rejected. The most common reasons for specimen rejection were contamination (n=764, 35.1%), inappropriate collection container/tube (n=330, 15.2%), quantity not sufficient (QNS) (n=329, 15.1%), labeling errors (n=321, 14.7%), hemolyzed specimen (n=205, 9.4%), and clotted specimen (n=203, 9.3%). The analytes most often affected were glucose (n=192, 8.8%); calcium (n=152, 7.0%), magnesium (n=148, 6.8%), potassium (n=137, 6.3%), creatinine (n=100, 4.6%), and blood urea nitrogen (n=97, 4.4%). Outpatient service and blood draw by phlebotomists were associated with low rejection rates (536/493,501 or 0.11% and 368/586,503 or 0.06%, respectively). Recollection due to specimen rejection increased the turnaround time by an average of 108min. The total cost for the recollection was around $43,210 USD with an average cost around $21.9 USD. CONCLUSIONS: The factors associated with rejection are remediable by improved training and quality assurance measures. Policies and procedures specific to specimen collection, transportation, and preparation should be strictly followed.

Circulating tumor cells as early predictors of metastatic spread in breast cancer patients with limited metastatic dissemination.

INTRODUCTION: Traditional factors currently used for prognostic stratification do not always adequately predict treatment response and disease evolution in advanced breast cancer patients. Therefore, the use of blood-based markers, such as circulating tumor cells (CTCs), represents a promising complementary strategy for disease monitoring. In this retrospective study, we explored the role of CTC counts as predictors of disease evolution in breast cancer patients with limited metastatic dissemination. METHODS: A total of 492 advanced breast cancer patients who had a CTC count assessed by CellSearch prior to starting a new line of systemic therapy were eligible for this analysis. Using the threshold of 5 CTCs/7.5 ml of blood, pretreatment CTC counts were correlated in the overall population with metastatic site distribution, evaluated at baseline and at the time of treatment failure, using Fisher's exact test. Time to visceral progression and time to the development of new metastatic lesions and sites were estimated in patients with nonvisceral metastases and with single-site metastatic disease, respectively, by the Kaplan-Meier method. Survival times were compared between groups according to pretreatment CTC count by logrank test. RESULTS: In the overall population, a pretreatment level ≥5 CTCs/7.5 ml was associated with an increased baseline number of metastatic sites compared with <5 CTCs/7.5 ml (P = 0.0077). At the time of treatment failure, patients with ≥5 CTCs/7.5 ml more frequently developed new metastatic lesions and sites compared with those with <5 CTCs/7.5 ml (development of new lesions: P = 0.0002; development of new sites: P = 0.0031). Among patients with disease originally confined to nonvisceral sites, ≥5 CTCs/7.5 ml was associated with remarkably shorter time to visceral metastases (P = 0.0021) and overall survival (P = 0.0006) compared with <5 CTCs/7.5 ml. In patients with single-site metastatic disease, ≥5 CTCs/7.5 ml was associated with a significant reduction of the time to development of new metastatic sites (P = 0.0051) and new lesions (P = 0.0002) and with worse overall survival (P = 0.0101). CONCLUSION: Our results suggest that baseline CTC counts can be used as an early predictor of metastatic potential in breast cancer patients with limited metastatic dissemination.

Elevated serum P1NP predicts development of bone metastasis and survival in early-stage breast cancer.

Bone is the most common site of metastasis of breast cancer, affecting most women with advanced disease. Procollagen type I N-terminal propeptide (P1NP), osteocalcin, CTX, and IL-6 are markers of bone turnover. Our objective was to determine whether serum levels of these proteins have clinical utility as predictors of breast cancer metastasis to bone. Blood was collected before treatment from 164 patients with stage I-III breast cancer from September 2001 to December 2008. Serum levels of P1NP, CTX, IL-6, and OC were measured using an automated immunoassay system. Correlations of the levels of these markers with time to bone metastasis development and with overall survival (OS) rate were assessed using Cox proportional hazards regression analysis and the Kaplan-Meier method. Fifty-five patients with stage I-III disease at the time of blood sample collection subsequently experienced metastasis to bone. A baseline P1NP level of at least 75 ng/mL predicted increased risk of bone metastasis (hazard ratio, 2.7 [95 % confidence interval, 1.2-6.0]; P = 0.031) and a poor OS rate (P = 0.031). Serum P1NP levels at or above 75 ng/mL correlate with a short time to development of bone metastasis and low overall survival in patients with stage I-III breast cancer.

Circulating tumor cells as prognostic and predictive markers in metastatic breast cancer patients receiving first-line systemic treatment.

INTRODUCTION: Circulating tumor cells (CTCs) represent an independent predictor of outcome in patients with metastatic breast cancer (MBC). We assessed the prognostic impact of CTCs according to different first-line systemic treatments, and explored their potential predictive value in MBC patients. METHODS: We retrospectively evaluated 235 newly diagnosed MBC patients, treated at the University of Texas MD Anderson Cancer Center. All patients had a baseline CTC assessment performed with CellSearch(®). Progression-free survival and overall survival were compared with the log-rank test between groups, according to CTC count (< 5 vs. ≥ 5) and type of systemic therapy. We further explored the predictive value of baseline CTCs in patients receiving different treatments. RESULTS: At a median follow-up of 18 months, the CTC count was confirmed to be a robust prognostic marker in the overall population (median progression-free survival 12.0 and 7.0 months for patients with CTC < 5 and ≥ 5, respectively; P < 0.001). Conversely, in patients with human epidermal growth factor receptor-2-overexpressed/amplified tumors receiving trastuzumab or lapatinib, the baseline CTC count was not prognostic (median progression-free survival 14.5 months for patients with CTC < 5 and 16.1 months for those with CTC ≥ 5; P = 0.947). Furthermore, in patients with human epidermal growth factor receptor-2 normal tumors, a baseline CTC count ≥ 5 identified subjects who derived benefit from more aggressive treatments, including combination chemotherapy and chemotherapy plus bevacizumab. CONCLUSIONS: This analysis suggests that the prognostic information provided by CTC count may be useful in patient stratifications and therapeutic selection, particularly in the group with positive CTCs, in which various therapeutic choices may procure differential palliative benefit.

18F-FDG PET/CT findings and circulating tumor cell counts in the monitoring of systemic therapies for bone metastases from breast cancer.

UNLABELLED: Our objective was to compare the predictive significance of (18)F-FDG PET/CT findings and circulating tumor cell (CTC) count in patients with bone metastases from breast cancer treated with standard systemic therapy. METHODS: Breast cancer patients with progressive bone-only metastatic disease without visceral metastases starting a new line of systemic therapy underwent (18)F-FDG PET/CT and had CTC counts determined before and during treatment. Disease status was reassessed by CTC count (> or = 5 vs. < 5 CTC/7.5 mL of blood) and (18)F-FDG PET/CT approximately 2-4 mo after initiation of the new systemic therapy. RESULTS: CTC counts at follow-up agreed with the (18)F-FDG PET/CT assessment in 43 (78%) of the 55 evaluable patients. Of the 12 patients with discordant CTC and (18)F-FDG PET/CT results, 8 (66%) had > or = 5 CTCs, with no evidence of progressive disease at the time of the (18)F-FDG PET/CT study, whereas 4 (33%) had < 5 CTCs, with evidence of progressive disease by (18)F-FDG PET/CT. (18)F-FDG PET/CT findings and follow-up CTC counts were found to be significantly associated with both progression-free survival (P = 0.02 and P < 0.0001, respectively) and overall survival (P = 0.02 and P = 0.01, respectively). In multivariate analysis, the (18)F-FDG PET/CT assessment remained as the only predictive factor for progression-free survival (P < 0.0001), whereas estrogen receptor status was the only predictive factor for overall survival (P = 0.01). CONCLUSION: (18)F-FDG PET/CT is a useful tool for therapeutic monitoring in patients with bone metastases from breast cancer. Prospective studies are needed to define the role of (18)F-FDG PET/CT and CTC in the setting of response discordance to establish bone-dominant disease as a tumor-response measurable disease.

Circulating tumor cells and [18F]fluorodeoxyglucose positron emission tomography/computed tomography for outcome prediction in metastatic breast cancer.

PURPOSE: Circulating tumor cells (CTCs) and [(18)F]fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) are two new promising tools for therapeutic monitoring. In this study, we compared the prognostic value of CTC and FDG-PET/CT monitoring during systemic therapy for metastatic breast cancer (MBC). PATIENTS AND METHODS: A retrospective analyses of 115 MBC patients who started a new line of therapy and who had CTC counts and FDG-PET/CT scans performed at baseline and at 9 to 12 weeks during therapy (midtherapy) was performed. Patients were categorized according to midtherapy CTC counts as favorable (ie, < five CTCs/7.5 mL blood) or unfavorable (> or = five CTCs/7.5 mL blood) outcomes. CTC counts and FDG-PET/CT response at midtherapy were compared, and univariate and multivariate analyses were performed to identify factors associated with survival. RESULTS: In 102 evaluable patients, the median overall survival time was 14 months (range, 1 to > 41 months). Midtherapy CTC levels correlated with FDG-PET/CT response in 68 (67%) of 102 evaluable patients. In univariate analysis, midtherapy CTC counts and FDG-PET/CT response predicted overall survival (P < .001 and P = .001, respectively). FDG-PET/CT predicted overall survival (P = .0086) in 31 (91%) of 34 discordant patients who had fewer than five CTCs at midtherapy. Only midtherapy CTC levels remained significant in a multivariate analysis (P = .004). CONCLUSION: Detection of five or more CTCs during therapeutic monitoring can accurately predict prognosis in MBC beyond metabolic response. FDG-PET/CT deserves a role in patients who have fewer than five CTCs at midtherapy. Prospective trials should evaluate the most sensitive and cost-effective modality for therapeutic monitoring in MBC.

Lymphoid neoplasms associated with IgM paraprotein: a study of 382 patients.

We identified 382 consecutive patients with lymphoid neoplasms associated with serum monoclonal IgM paraprotein and classified each neoplasm according to World Health Organization criteria. Lymphoplasmacytic lymphoma/Waldenström macroglobulinemia (LPL/WM) was most common, 225 cases (median serum IgM level, 2.2 g/dL; range, 0.2-10.9 g/dL). For 157 cases, classification and median (and range in g/dL) IgM levels were as follows: chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL; n = 77), 0.9 (0.1-2.1); marginal zone lymphoma (n = 27), 0.5 (0.1-2.4); follicular lymphoma (n = 18), 0.4 (0.1-1.6); mantle cell lymphoma (n = 11), 0.4 (0.2-1.3); diffuse large B-cell lymphoma (DLBCL; n = 7), 0.5 (0.2-1.0); DLBCL associated with low-grade lymphoma (n = 5), 0.9 (0.4-3.0); angioimmunoblastic T-cell lymphoma (n = 4), 0.8 (0.8); and CD5+CD23- low-grade B-cell lymphoma, unclassified (n = 8), 0.5 (0.3-2.9). The results show IgM paraproteinemia was associated most commonly with LPL/WM (58.9%), followed by CLL/SLL (20.2%). Although serum IgM levels greater than 3 g/dL were restricted to patients with LPL/WM, most patients with LPL/WM had paraprotein levels less than 3 g/dL. Thus, serum IgM paraprotein level is not a reliable discriminator in differential diagnosis.

Chronic lymphocytic leukemia/small lymphocytic lymphoma associated with IgM paraprotein.

We studied the clinicopathologic, immunophenotypic, and cytogenetic features of 26 patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) associated with serum IgM paraprotein. The study group (16 men; 10 women; median age, 64 years; range, 40-82 years) represents approximately 2.5% of CLL/SLL cases at our institution. The paraprotein level ranged from 1 to 14 g/L (median, 4 g/L). Neoplasms in bone marrow were composed of small round lymphocytes arranged in nodular (n = 6), diffuse (n = 5), interstitial (n = 5), or mixed (n = 10) patterns. All cases were positive for monotypic surface immunoglobulin light chain, IgM/IgD, CD5, CD19, CD20, and CD23. CD11c (14/20 [70%]), CD79b (11/19 [58%]), FMC-7 (11/26 [42%]), CD22 (8/20 [40%]), and ZAP-70 (6/19 [32%]) were expressed in subsets of cases. Of 17 bone marrow specimens assessed by conventional cytogenetics, 6 were abnormal and 11 were diploid. The overall survival of this group (median follow-up, 24 months) was not significantly different from that for an age-, sex-and stage-matched group of 52 CLL/SLL patients without IgM paraprotein (P = .60). We conclude that CLL/SLL cases with serum IgM paraprotein are similar to other CLL/SLL cases in their clinicopathologic and immunophenotypic features.