Jo Ann V. Antenor

Serial Biopsy Results in Prostate Cancer Screening Study

PURPOSE We evaluated prostate biopsy results in men with elevated prostate specific antigen (PSA) levels and/or suspicious digital rectal examination whose initial biopsies did not reveal cancer. MATERIALS AND METHODS A total of 2,526 volunteers 40 years old or older underwent 1 or more prostate biopsies for serum PSA concentrations greater than 4.0 ng./ml. (before May 1995) or greater than 2.5 ng./ml. (after May 1995), or digital rectal examination suspicious of cancer. We evaluated compliance with the biopsy recommendation and the cancer detection rate with regard to digital rectal examination results and increasing PSA levels. RESULTS Of the men who underwent up to 10 biopsy procedures the serial cancer detection rates were 29%, 17%, 14%, 11%, 9% and 7%, respectively, on biopsy procedures 1 through 6. No significant difference in the yield of cancer on serial biopsies was observed between the groups using the greater than 4.0 ng./ml. and greater than 2.5 ng./ml. cutoff. There was a trend for more cancers detected through serial screening to be organ confined compared with those detected on initial screening (78% versus 69%, p = 0.05). Also, more cancers detected using the greater than 2.5 ng./ml. cutoff were organ confined (80% versus 66%, p = 0.004). Only approximately 1% of the cancers fulfilled the published criteria for clinically insignificant tumors. CONCLUSIONS Nearly a quarter of prostate cancers detected in this screening study were missed by the initial biopsy. Of the 962 prostate cancers detected 77% were detected with 1, 91% with 2, 97% with 3 and 99% with 4 biopsy procedures. Serial biopsies detect more organ confined cancers without over detecting clinically unimportant tumors. Future studies are needed to determine whether obtaining more biopsy cores initially would provide earlier prostate cancer detection and avoid unnecessary repeat biopsies.

[18F]FDOPA PET and clinical features in parkinsonism due to manganism

Manganese exposure reportedly causes a clinically and pathophysiologically distinct syndrome from idiopathic Parkinsons disease (PD). We describe the clinical features and results of positron emission tomography with 6‐[18F]fluorodopa ([18F]FDOPA PET) of a patient with parkinsonism occurring in the setting of elevated blood manganese. The patient developed parkinsonism associated with elevated serum manganese from hepatic dysfunction. [18F]FDOPA PET demonstrated relatively symmetric and severely reduced [18F]FDOPA levels in the posterior putamen compared to controls. The globus pallidum interna had increased signal on T1‐weighted magnetic resonance imaging (MRI) images. We conclude that elevated manganese exposure may be associated with reduced striatal [18F]FDOPA uptake, and MRI may reveal selective abnormality within the internal segment of the pallidum. This case suggests that the clinical and pathophysiological features of manganese‐associated parkinsonism may overlap with that of PD.

Screening for Prostate Cancer in High Risk Populations

PURPOSE Black men and men with a family history of prostate cancer are at higher risk for this disease and may have an earlier age of onset. Consequently, screening at a younger age has been recommended for high risk men, however, there are limited data on actual screening results in young, high risk populations. MATERIALS AND METHODS In men 50 years old or older we compared screening results in 1,224 black men, 1,227 men with a positive family history and 63 men who were both with those of 15,964 nonblack men with no known family history. In high risk men in their forties we also evaluated the percent with abnormal screening tests, the positive predictive value of screening tests, cancer detection rates and the prognostic features of tumors detected. RESULTS In men 50 years old or older prostate cancer detection rates were 6.4% for controls compared with 10.3%, 10.5% and 17.5%, respectively, for the high risk groups. Among high risk men screened in their forties 8% had suspicious screening tests and approximately 55% who underwent a biopsy had cancer detected. Of tumors detected 80% were organ confined and all but 1 were of moderate Gleason grade 5 years old or older. Only 1 tumor (7%) fulfilled the published criteria for a possibly harmless cancer. CONCLUSIONS Black men and men with a family history of prostate cancer are at a 75% to 80% higher risk for prostate cancer. On initial screening of high risk men in their fourth decade only 8% have positive screening tests; however, approximately 55% of these men have tumors, most of which are medically important with favorable prognostic features.

Robustness of free prostate specific antigen measurements to reduce unnecessary biopsies in the 2.6 to 4.0 ng./ml. range

PURPOSE Prostate specific antigen (PSA) cutoffs lower than 4.0 ng./ml. are being evaluated more frequently but lower PSA cutoffs increase the number of prostatic biopsies. PSA exists in several forms free and complexed to proteins. Percent free PSA is lower in men with prostate cancer. Accordingly, free PSA and complexed PSA have been used to distinguish between cancer and benign disease in the diagnostic gray zone of 4 to 10 ng./ml. to eliminate unnecessary biopsies. There are limited data on the robustness of free PSA measurements in the 2.6 to 4.0 ng./ml. total PSA range. MATERIALS AND METHODS We evaluated percent free PSA measurements to discriminate between cancer and benign conditions in 965 consecutive volunteers in a prostate cancer screening study who underwent prostatic biopsy for a PSA of 2.6 to 4.0 ng./ml. and had benign digital rectal examination. RESULTS Overall 25% of men had cancer detected. A 25% free PSA cutoff detected 85% of cancers and avoided 19% of negative (cancer-free) biopsies, while a 30% free PSA cutoff detected 93% of cancers and avoided only 9% of negative biopsies. Of those men who underwent radical prostatectomy 132 (80%) had pathologically organ confined tumors. Only 5% of these tumors fulfilled the published pathological criteria for possibly clinically unimportant tumors. CONCLUSIONS Percent free PSA provides risk assessment but does not eliminate many unnecessary prostatic biopsies while maintaining a high sensitivity in the narrow total PSA range of 2.6 to 4.0 ng./ml.

Pathological characteristics of prostate cancer detected through prostate specific antigen based screening.

PURPOSE Since the introduction of PSA testing for CaP, there has been an increase in CaP detection. However, it is uncertain to what extent clinically insignificant tumors are being diagnosed and treated. In a large, community based population we determined the pathological characteristics of screening detected cancers. MATERIALS AND METHODS From 1989 to 2001, 35,661 men were enrolled in a longitudinal prostate cancer screening study. Data were available on 3,492 of the 3,568 men (98%) diagnosed with CaP during this study period. Radical prostatectomy was performed in 2,254 men (63%). Clinical stage, Gleason score and pathological analysis were recorded and analyzed in the context of preoperative PSA, digital rectal examination findings, PSA velocity and the year of cancer detection. RESULTS CaP was detected in 10% of men. Virtually all cases were clinically localized (99.8%) and approximately 70% treated with radical prostatectomy were pathologically organ confined disease. Fewer than 10% of tumors would be considered clinically insignificant based on 2 previously published pathological criteria. CONCLUSIONS Compared to the high prevalence of CaP found in autopsy studies there is a lower detection rate using current screening protocols. Although the outcomes are unknown if these tumors had been left untreated, the majority met pathological criteria for significant cancer.

Pathophysiology of parkinsonism due to hydrocephalus

We report a patient with hydrocephalus who developed levodopa responsive parkinsonism and severe bradyphrenia associated with shunt malfunction and revision. Magnetic resonance imaging revealed periaqueductal edema involving medial substantia nigra. [18F]dopa positron emission tomography demonstrated reduced uptake in the caudate and putamen with relative sparing of the posterior putamen. Hydrocephalus associated with shunt malfunction can cause a distinct parkinsonian syndrome with greater dysfunction of projections from the medial substantia nigra to anterior striatum than in idiopathic Parkinson’s disease.

[18F]FDOPA PET as an endophenotype for Parkinson's Disease linkage studies

Parkinson disease (PD) is a late onset disorder with age‐dependent penetrance that may confound genetic studies, since affected individuals may not demonstrate clinical manifestations at the time of evaluation. The use of endophenotypes, biologic surrogates for clinical disease diagnoses, may permit more accurate classification of at‐risk subjects. Positron emission tomography (PET) measurements of 6‐[18F]fluorodopa ([18F]FDOPA) uptake indicate nigrostriatal neuronal integrity and may provide a useful endophenotype for PD linkage studies. We performed [18F]FDOPA PET in 11 members of a large, multi‐incident Amish family with PD, 24 normals and 48 people with clinically definite idiopathic PD (PD controls). Clinical diagnoses in the Amish were clinically definite PD in four, clinically probable in one, clinically possible in five, and normal in one. Abnormal [18F]FDOPA posterior putamen uptake was defined as less than 3 standard deviations below the normal mean. The criteria were applied to the Amish sample to determine a PET endophenotype for each. We performed genetic simulations using SLINK to model the effect phenoconversion with the PET endophenotype had on logarithm of odds (LOD) scores. PET endophenotype confirmed the status of two clinically definite subjects. Two clinically definite Amish PD subjects had normal PETs. Two possible PD were converted to “PET definite PD.” The remainder had normal PETs. The average maximum LOD score with the pre‐PET was 6.14 ± 0.84. Simulating phenoconversion of subjects with unknown phenotypes increased the LOD score to 7.36 ± 1.23. The [18F]FDOPA PET endophenotype permits phenoconversion in multi‐incident PD families and may increase LOD score accuracy and power of an informative pedigree.