Diagnostic center for primary care patients with nonspecific symptoms and suspected cancer: compliance to workflow and accuracy of tests and examinations.

OBJECTIVE: To evaluate compliance to workflow and accuracy of tests in Sweden's first fast-track referral pathway for patients with nonspecific symptoms and suspected cancer (SCAN). DESIGN: Prospective cohort study with consecutive inclusion of patients referred to the diagnostic center (DC). SETTING: Patients with nonspecific symptoms were examined in primary care according to a protocol including two test packages and diagnostic imaging. If symptoms were not explained, patients were referred to the DC and a DC-test package was taken. At the DC, further investigations resulted in diagnosis/no diagnosis. SUBJECTS: A total of 290 patients, median age 69 years (interquartile range [IQR] 59-76), 48% men, participated. A total of 64 (22%) were diagnosed with cancer, 186 (64%) with non-malignant disease and 40 (14%) had no new disease. MAIN OUTCOME MEASURE: Compliance was estimated by percentage of compulsory tests taken. Test accuracy was assessed by likelihood ratios (LRs) regarding cancer. RESULTS: A total of 23 (8%) patients had taken both primary care packages, whereas 150 (52%) patients went through entire diagnostic imaging. Abnormal pulmonary X-ray, peak expiratory flow (PEF) and calcium had the highest LRs in primary care (3.5; 3.2; 2.7). A total of 105 (36%) took the complete DC-package, of which bilirubin and cytomegalovirus had the highest LRs (11.5; 10.9). The median number (IQR) of abnormal primary care tests was 5 (3-6) for cancer, 3 (2-6) for other diagnoses and 1 (0-3) for no diagnosis. CONCLUSIONS: Compliance to test packages in primary care was low, which warrants review of the workflow. Few single tests had high accuracy regarding cancer, but the number of abnormal tests can provide guidance in complicated investigations of suspected malignancies.KEY POINTSFast-track referral pathways for patients with nonspecific serious symptoms have been implemented in several countries and are part of the national cancer strategy in all of Scandinavia.Compliance with compulsory tests in primary care was modest in this study; 8% of the patients had taken the entire compulsory test packages.Few single compulsory tests had high accuracy regarding subsequent cancer, which warrants a review of tests and examinations. However, patients diagnosed with cancer had a higher number of abnormal test results compared to the other groups.

Time Intervals Under the Lens at Sweden's First Diagnostic Center for Primary Care Patients With Nonspecific Symptoms of Cancer. A Comparison With Matched Control Patients.

INTRODUCTION: Fast-track referral pathways for patients with nonspecific, serious symptoms have been implemented in several countries. Our objective was to analyze time intervals in the diagnostic routes of patients diagnosed with cancer at Sweden's first Diagnostic Center (DC) for nonspecific symptoms and compare with time intervals of matched control patients. METHODS: Adult patients with nonspecific symptoms that could not be explained by an initial investigation in primary care were eligible for referral to the DC. Patients diagnosed with cancer were matched with patients at another hospital within the same healthcare organization. We aimed for two control patients per DC-patient and matched on tumor type, age and sex. Five time intervals were compared: 1) patient interval (first symptom-primary care contact), 2) primary care interval (first visit-referral to the DC/secondary care), 3) diagnostic interval (first visit-cancer diagnosis), 4) information interval (cancer diagnosis-patient informed) and 5) treatment interval (cancer diagnosis-treatment start). Comparisons between groups and matched cohort analyses were made. RESULTS: Sixty-four patients (22.1%) were diagnosed with cancer at the DC, of which eight were not matchable. Forty-two patients were matched with two controls and 14 were matched with one control. There were no significant differences in patient-, primary care-, or diagnostic intervals between the groups. The information interval was shorter at the DC compared to the control group (difference between matched pairs 7 days, p = 0.001) and the treatment interval was also shorter at the DC with significant differences in the matched analysis (difference between matched pairs 13 days, p = 0.049). The findings remained the same in four sensitivity analyses, made to compensate for differences between the groups. CONCLUSIONS: Up to diagnosis, we could not detect significant differences in time intervals between the DC and the control group. However, the shorter information and treatment intervals at the DC should be advantageous for these patients who will get timely access to treatment or palliative care. Due to limitations regarding comparability between the groups, the results must be interpreted with caution and further research is warranted. TRIAL REGISTRATION: ClinicalTrials.gov-ID: NCT01709539. Registration-date: October 18, 2012.

Diagnostic spectrum and time intervals in Sweden's first diagnostic center for patients with nonspecific symptoms of cancer.

BACKGROUND: Fast-track referral is an increasingly used method for diagnostic evaluation of patients suspected of having cancer. This approach is challenging and not used as often for patients with only nonspecific symptoms. In order to expedite the diagnostics for these patients, we established Sweden's first Diagnostic Center (DC) focusing on outcomes related to diagnoses and diagnostic time intervals. MATERIAL AND METHODS: The study was designed as a prospective cohort study. Patients aged ≥18 years who presented in primary care with nonspecific symptoms of a serious disease were eligible for referral to the DC after having completed an initial investigation. Acceptable diagnostic time intervals were defined to be a maximum of 15 days in primary care and 22 days at the DC. Diagnostic outcome, length of diagnostic time intervals and patient satisfaction were evaluated. RESULTS: A total of 290 patients were included in the study. Cancer was diagnosed in 22.1%, other diseases in 64.1%, and no diagnosis was identified in 13.8% of these patients. Patients diagnosed with cancer were older, had shorter patient interval (time from first symptom to help-seeking), shorter DC-interval (time from referral decision in primary care to diagnosis) and showed a greater number of symptoms compared to patients with no diagnosis. The median primary care interval was 21 days and the median DC interval was 11 days. Few symptoms, no diagnosis, female sex, longer patient interval, and incomplete investigations were associated with prolonged diagnostic time intervals. Patient satisfaction was high; 86% of patients reported a positive degree of satisfaction with the diagnostic procedures. CONCLUSIONS: We demonstrated that the DC concept is feasible with a diagnosis reached in 86.2% of the patients in addition to favorable diagnostic time intervals at the DC and a high degree of patient satisfaction.

Genetic variation in KLK2 and KLK3 is associated with concentrations of hK2 and PSA in serum and seminal plasma in young men.

BACKGROUND: Genetic variants in KLK2 and KLK3 have been associated with increased serum concentrations of their encoded proteins, human kallikrein-related peptidase 2 (hK2) and prostate-specific antigen (PSA), and with prostate cancer in older men. Low PSA concentrations in seminal plasma (SP) have been associated with low sperm motility. To evaluate whether KLK2 and KLK3 genetic variants affect physiological prostatic secretion, we studied the association of SNPs with hK2 and PSA concentrations in SP and serum of young, healthy men. METHODS: Leukocyte DNA was extracted from 303 male military conscripts (median age 18.1 years). Nine SNPs across KLK2-KLK3 were genotyped. We measured PSA and hK2 in SP and serum using immunofluorometric assays. The association of genotype frequencies with hK2 and PSA concentrations was tested with the Kruskal-Wallis test. RESULTS: Four KLK2 SNPs (rs198972, rs198977, rs198978, and rs80050017) were strongly associated with hK2 concentrations in SP and serum, with individuals homozygous for the major alleles having 3- to 7-fold higher concentrations than the intermediate concentrations found in other homozygotes and heterozygotes (all P < 0.001). Three of these SNPs were significantly associated with percentage of free PSA (%fPSA) in serum (all P < 0.007). Three KLK3 SNPs showed associations with PSA in SP, and the rs1058205 SNP was associated with total PSA in serum (P = 0.001) and %fPSA (P = 0.015). CONCLUSIONS: Associations observed in young, healthy men between the SP and serum concentrations of hK2 and PSA and several genetic variants in KLK2 and KLK3 could be useful to refine models of PSA cutoff values in prostate cancer testing.

Polymorphisms at the Microseminoprotein-beta locus associated with physiologic variation in beta-microseminoprotein and prostate-specific antigen levels.

BACKGROUND: rs10993994, a single nucleotide polymorphism (SNP) at the genetic locus encoding beta-microseminoprotein (beta-MSP), is associated with both prostate cancer risk and levels of blood prostate-specific antigen (PSA), a biomarker used in prostate cancer screening. Therefore, we wished to determine the association between SNPs at MSMB, the gene encoding beta-MSP, and the levels of prostate-produced biomarkers beta-MSP, PSA, and human kallikrein 2 (hK2) in blood and semen. METHODS: Blood and semen from 304 healthy young Swedish men (ages 18-21) were assayed for beta-MSP, PSA, and hK2. SNPs around MSMB were genotyped from matched DNA and analyzed for quantitative association with biomarker levels. Empirical P values were multiple test-corrected and the independence of each SNP's effect was determined. RESULTS: rs10993994 was significantly associated with the blood and semen levels of beta-MSP (both P < 1.0 x 10(-7)) and PSA (P = 0.00014 and P = 0.0019), and semen levels of hK2 (P = 0.00027). Additional copies of the prostate cancer risk allele resulted in lower beta-MSP but higher PSA levels, and singly explained 23% and 5% of the variation seen in semen beta-MSP and PSA, respectively. Additional SNPs at MSMB are associated with beta-MSP and PSA independently of rs10993994. CONCLUSIONS: SNPs at MSMB correlate with physiologic variation in beta-MSP and PSA levels in the blood and semen of healthy young Swedish men. In particular, rs10993994 has a strong effect on beta-MSP levels. IMPACT: Our results suggest a mechanism by which rs10993994 might predispose to prostate cancer and raise the possibility that genetic variation might need to be considered in interpreting the levels of these biomarkers.

Beta-microseminoprotein in serum correlates with the levels in seminal plasma of young, healthy males.

Beta-microseminoprotein (MSP) is one of the most abundant proteins secreted by the prostate gland. Because MSP is also synthesized in nonreproductive organs, the establishment of a solid relationship between the levels of MSP in serum and semen is crucial for future studies connecting MSP with aging or diseases of the prostate gland. We developed a specific, competitive, europium-based immunoassay to measure MSP in serum and seminal plasma. We also produced recombinant MSP in insect cells using baculo virus and purified it to homogeneity by a novel approach with ethanol extraction and gel filtration. The median values of MSP in 205 young men were 12 microg/L (2.5-97.5 percentile, 4.9-26 microg/L) in serum and 0.53 g/L (2.5-97.5 percentile, 0.13-2.0 g/L) or 1.8 mg (2.5-97.5 percentile, 0.32-6.6 mg) in seminal plasma. MSP in serum showed significant correlation to MSP in seminal plasma (r = .50, P < .001). Significant correlations were also found in seminal plasma between MSP and prostate-specific antigen (PSA) (r = .65, P < .001) and between MSP and Zn(2+) (r = .54, P < .001). The yield of recombinant MSP in culture medium was 35 mg/L or higher, and recovery following ethanol extraction was 80%-90%. MSP in serum reflects the prostate secretion of MSP, and correlations were also found in seminal plasma between MSP and PSA and Zn(2+). This suggests that MSP in serum can be used as a marker of prostate secretion, despite the contribution from extra prostatic tissues.

Blood levels of free-PSA but not complex-PSA significantly correlates to prostate release of PSA in semen in young men, while blood levels of complex-PSA, but not free-PSA increase with age.

BACKGROUND: The proportion of free- and complex-prostate specific antigen (PSA) in serum is used for differentiating between benign and malignant prostate disease. To further understand the physiological relationship between PSA in seminal plasma and blood, we have analyzed free-PSA (fPSA) and complex-PSA (cPSA) in blood and PSA in seminal plasma in young healthy men. We also compared age-related changes of PSA-forms in blood from young versus older men. METHODS: Total-PSA (tPSA), fPSA, and cPSA were measured in (i) blood and semen from 289 male conscripts (mean age 18.1 years) and in (ii) blood from a representative population of 1,389 men (mean age 46.5 years) without diagnosis of prostate cancer (PCa) during long-term follow-up. RESULTS: fPSA in serum (r = 0.40, P < 0.0001) but not cPSA (r = 0.09, P = 0.11), correlates to PSA in seminal fluid. fPSA levels in blood in young (geometric mean: 0.20 ng/ml) versus middle-aged men (geometric mean: 0.18 ng/ml) was not different (P = 0.06), whereas cPSA in middle-aged men (geometric mean: 0.38 ng/ml) was higher (P < 0.0001) than in young men (geometric mean: 0.28 ng/ml). CONCLUSIONS: fPSA in blood, but not cPSA, is associated to PSA in semen ( approximately 17% co-variation). In blood cPSA, but not fPSA, increase with age in healthy men, which may reflect an increasing incidence of prostate disease.