William F. McCarthy

Age-Specific Reference Ranges for Serum Prostate-Specific Antigen in Black Men

BACKGROUND The detection of prostate cancer by screening for prostate-specific antigen (PSA) in serum is improved when age-specific reference ranges are used, but these ranges have been derived from white populations. We determined the distribution of PSA and age-specific reference ranges in black men both with and without prostate cancer. METHODS From January 1991 through May 1995, we measured serum PSA in 3475 men with no clinical evidence of prostate cancer (1802 white and 1673 black) and 1783 men with prostate cancer (1372 white and 411 black). We studied the data as a function of age and race to determine the usefulness of measuring PSA in diagnosing prostate cancer. RESULTS Serum PSA concentrations in black men (geometric mean in controls, 1.48 ng per milliliter; in patients, 7.46) were significantly higher than those in white men (geometric mean in controls, 1.33 ng per milliliter; in patients, 6.28). The values in the controls correlated directly with age. The area under the receiver-operating-characteristic curve was 0.91 for blacks and 0.94 for whites. If traditional age-specific reference ranges were used in screening black men, with the test specificity kept at 95 percent, 41 percent of cases of prostate cancer would be missed. For the test to have 95 percent sensitivity among black men, the following normal reference ranges should be used: for men in their 40s, 0 to 2.0 ng of PSA per milliliter (test specificity, 93 percent); for men in their 50s, 0 to 4.0 ng per milliliter (specificity, 88 percent); for men in their 60s, 0 to 4.5 ng per milliliter (specificity, 81 percent); and for men in their 70s, 0 to 5.5 ng per milliliter (specificity, 78 percent). CONCLUSIONS Serum PSA concentrations can be used to discriminate between men with prostate cancer and those without it among both blacks and whites. Over 40 percent of cases of prostate cancer in black men would not be detected by tests using traditional age-specific reference ranges, which maintain specificity at 95 percent. In this high-risk population, the alternative approach--maintaining sensitivity at 95 percent--may be used with acceptable decrements in specificity.

Merkel cell carcinoma: Analysis of clinical, histologic, and immunohistologic features of 132 cases with relation to survival

BACKGROUND Merkel cell carcinoma (MCC) is an uncommon malignancy of the skin and has a high rate of recurrence and metastasis. There have been few large studies of the biologic behavior of MCC. OBJECTIVE Our purpose was to determine whether there were clinical or histologic features of MCC that predict its biologic behavior. METHODS We reviewed 132 cases of MCC. Clinical and histologic features were correlated with follow-up information to determine whether any of these were associated with prognosis. RESULTS Clinical information was available on 126 patients; 57 were alive, 1 was alive with tumor, 28 died of tumor, 27 died from other causes, and 14 were lost to follow-up. MCC on the buttock/thigh area or trunk had the worst prognosis, and those on the distal extremities had the best prognosis; however, the difference was not statistically significant. Sex and age were not significant factors. Small cell size, high mitotic rate, and large tumor size were associated with a low survival rate. When cell size was excluded, male sex and depth of invasion were associated with a worse survival, although these were not statistically significant. CONCLUSION Cell size, mitotic rate, and tumor size are significant factors in relation to the biologic behavior of MCC.

Black Race is an Adverse Prognostic Factor for Prostate Cancer Recurrence Following Radical Prostatectomy in an Equal Access Health Care Setting

PURPOSE We determined if black men with clinically localized adenocarcinoma of the prostate have the same recurrence-free outcome following radical prostatectomy, and whether they have similar preoperative, operative and pathological characteristics as white men in an equal access health care environment. MATERIALS AND METHODS We studied consecutive single hospital case series of 366 white and 107 black patients who underwent radical prostatectomy between 1975 and February 29, 1995. Evaluation included comprehensive retrospective chart review, prospective data collection and proactive followup. Univariate and multivariate statistical analyses were done of preoperative, operative, pathological and recurrence data by race. RESULTS Although the incidences of hypertension and diabetes, pretreatment prostate specific antigen (PSA) and serum creatinine measurements, elevated PSA as an indication for biopsy and clinical stage were greater in black men, the operative variables of blood loss, operative time and performance of a nerve sparing procedure were not different. The incidence of margin positivity was greater in black patients but pathological stage, Gleason score and seminal vesicle or nodal involvement were not different. Black race was an adverse prognostic factor for recurrence following radical prostatectomy after multivariate adjustment for pretreatment PSA and acid phosphatase, organ confinement status and tumor grade. CONCLUSIONS The poorer recurrence-free outcome for black patients even after multivariate adjustment suggests a potentially more aggressive variant of prostate cancer in this population, the etiology of which is unknown. Race should be a stratification factor in clinical trials, especially those including radical prostatectomy and using recurrence-free outcome as an end point.

Epithelial noncarcinoid tumors and tumor‐like lesions of the appendix. A clinicopathologic study of 184 patients with a multivariate analysis of prognostic factors

Background. The current understanding of appendiceal epithelial tumors is based on series composed of relatively small numbers of patients and on case reports. The aim of this study was to perform clinicopathologic correlation, particularly concerning prognosis, on a relatively large series of patients with epithelial tumors and tumor‐like lesions of the human vermiform appendix.

Topical Paromomycin with or without Gentamicin for Cutaneous Leishmaniasis

BACKGROUND There is a need for a simple and efficacious treatment for cutaneous leishmaniasis with an acceptable side-effect profile. METHODS We conducted a randomized, vehicle-controlled phase 3 trial of topical treatments containing 15% paromomycin, with and without 0.5% gentamicin, for cutaneous leishmaniasis caused by Leishmania major in Tunisia. We randomly assigned 375 patients with one to five ulcerative lesions from cutaneous leishmaniasis to receive a cream containing 15% paromomycin-0.5% gentamicin (called WR 279,396), 15% paromomycin alone, or vehicle control (with the same base as the other two creams but containing neither paromomycin nor gentamicin). Each lesion was treated once daily for 20 days. The primary end point was the cure of the index lesion. Cure was defined as at least 50% reduction in the size of the index lesion by 42 days, complete reepithelialization by 98 days, and absence of relapse by the end of the trial (168 days). Any withdrawal from the trial was considered a treatment failure. RESULTS The rate of cure of the index lesion was 81% (95% confidence interval [CI], 73 to 87) for paromomycin-gentamicin, 82% (95% CI, 74 to 87) for paromomycin alone, and 58% (95% CI, 50 to 67) for vehicle control (P<0.001 for each treatment group vs. the vehicle-control group). Cure of the index lesion was accompanied by cure of all other lesions except in five patients, one in each of the paromomycin groups and three in the vehicle-control group. Mild-to-moderate application-site reactions were more frequent in the paromomycin groups than in the vehicle-control group. CONCLUSIONS This trial provides evidence of the efficacy of paromomycin-gentamicin and paromomycin alone for ulcerative L. major disease. (Funded by the Department of the Army; ClinicalTrials.gov number, NCT00606580.).

Primaquine failure and cytochrome P-450 2D6 in Plasmodium vivax malaria.

Primaquine is used to eradicate the hepatic or hypnozoite form of Plasmodium vivax that may lead to relapse of infection. Host genetic factors may play a role in the activity of primaquine therapy.

Diagnostic considerations in molar gestations

Hydatidiform moles (HMs) are classified as partial or complete based on a combination of gross, histologic, and karyotypic features. Adherence to strict and reproducible diagnostic criteria is needed to ensure accurate diagnosis and minimize interpathologist variability. Using the kappa statistic as a measure of agreement, the morphologic, flow cytometric, and clinical features of 80 cases of HM or suspected HM were analyzed sequentially by three pathologists to evaluate intrapathologist and interpathologist variability. Poor interpathologist agreement was obtained when histology alone was used for diagnosis. The combination of gross morphology and histology resulted in poor to good agreement. Good interpathologist agreement was obtained, however, when objective data (DNA content determined by flow cytometry) were included in the analysis. Our data indicate that pathologist concordance is maximized when the diagnosis is based on a combination of morphology and DNA content.

Immunohistochemical Expression of P53 Tumor Suppressor Gene Protein in Adult Germ Cell Testis Tumors: Clinical Correlation in Stage I Disease

P53 tumor suppressor gene protein immunostaining was evaluated in the primary tumor of adult testicular germ cell cancer to assess if P53 expression would serve as a clinically useful tumor marker. Representative archival tissues from 152 orchiectomy specimens were studied for P53 immunohistochemistry. Seminoma and nonseminomatous germ cell tumor constituents revealed P53 expression via immunohistochemistry in 90% and 94% of the cases, respectively. For seminoma, there was a trend toward decreased P53 expression with advancing stage. For nonseminomatous germ cell tumor, although all cellular components showed variable P53 expression, P53 expression in embryonal carcinoma constituents increased among stages of disease. A third of pathological stage I cancer patients exhibited 2+ or greater P53-embryonal staining compared with 61% with stage II (p = 0.0670) and 67% with stage III (p = 0.0815) disease, respectively (Kruskal-Wallis, 2-sided test). As a secondary objective, we wanted to determine if P53 immunohistochemistry would be useful to predict occult disease in clinical stage I nonseminomatous germ cell tumor. This group was studied for P53-embryonal immunohistochemistry, the presence of vascular invasion and the quantitative determination of percentage of embryonal carcinoma in the primary tumor in a multivariate fashion to assess if these tests could be clinically useful to predict occult disease. Degree of P53 immunostaining of the embryonal component in the primary tumor was statistically greater for stage II by univariate logistic regression analysis (p = 0.0362). Similarly, the per cent embryonal cancer (p = 0.0002) and vascular invasion (p = 0.0005) were highly significant as predictors of occult stage II disease via the univariate testing. By multivariate logistic regression analysis, the model consisting of per cent embryonal cancer and vascular invasion provided the best prediction of occult disease in the clinical stage I cohort. In addition, this model had the highest sensitivity and specificity of all multivariate models considered. The addition of P53-embryonal staining did not improve predictability nor sensitivity/specificity. The P53 tumor suppressor gene protein is expressed to some degree in most testicular germ cell tumors and degree of staining/expression varies according to stage of disease. From the standpoint of a clinically useful primary tumor risk factor for predicting occult disease, vascular invasion by the tumor and percentage of embryonal carcinoma component in the tumor are more useful than P53 immunohistochemistry.

HMB45 negative spindle cell malignant melanoma.

Desmoplastic malignant melanoma (DMM) and spindle cell malignant melanoma (SCMM) form a continuum without a discrete separation. One feature characteristic of DMM is a negative reaction for HMB45, a marker for premelanosomes. Fifty-six cases of SCMM were stained with HMB45. The clinical features, histologic features, and survival data for HMB45(+) and HMB45(-) SCMM were compared. Thirty cases were HMB45(-), and 26 were HMB45(+). In the HMB45(-) cases, there was a 1.4:1 ratio of males to females, and in the HMB45(+) cases the ratio was 1:1.5. Only 12.9% of the HMB45(-) cases occurred on the trunk compared with 40% of the HMB45(+) cases. The average ages for the HMB45(-) and the HMB45(+) cases were 65.6 and 61 years, respectively. Follow-up was obtained on 22 cases: 11 HMB45(-) and 11 HMB45(+). Of the 11 HMB45(-) cases, four had a 5-year disease-free survival. Of the 11 HMB45(+) cases, only one had a 5-year disease free survival. HMB45(-) SCMM appear to have a less aggressive biologic potential than HMB45(+) SCMM.

Flow Cytometric and Quantitative Histological Parameters to Predict Occult Disease in Clinical Stage I Nonseminomatous Testicular Germ Cell Tumors

The goal of this study was to determine if deoxyribonucleic acid (DNA) flow cytometric and quantitative histological parameters could predict occult metastases in clinical stage I nonseminomatous testicular cancer. Archival paraffin primary tumor tissue was available from 36 clinical stage I nonseminomatous germ cell testicular cancer patients who all had retroperitoneal lymphadenectomy and followup defining 2 groups: pathological stage I (23) and occult pathological stage II (13). Archival blocks were microdissected and individual histological components were subjected to flow cytometry. In addition, the primary histology was reevaluated for vascular invasion and per cent composition of histological components of embryonal carcinoma and other histologies. For flow cytometry parameters, no tumor was uniformly diploid, and the DNA index and per cent S phase cells were not useful in differentiating stages. Although mean per cent S phase for the aneuploid cell population and proliferative index were significantly greater for stage II cases by univariate logistic regression analysis, they are approximately 70% accurate in predicting occult disease as single tests and were not significant by multivariate analysis. The calculation of per cent embryonal carcinoma was also significantly greater in stage II cancer by univariate logistic regression testing and remained significant by multivariate analysis. Vascular invasion was marginally predictive of occult disease but was also not significant by multivariate analysis. Calculating the percentage of embryonal carcinoma of a primary testicular tumor may be a useful method to assess clinical stage I cancer patients for risk of occult disease. A larger study is needed to confirm the importance of per cent embryonal carcinoma and to clarify further if flow cytometry in combination is useful.