Robert H. Lyles

HIV-associated neurologic disease incidence changes: Multicenter AIDS Cohort Study, 1990–1998

This study examined the temporal trends in the incidence rates of HIV dementia, cryptococcal meningitis, toxoplasmosis, progressive multifocal leukoencephalopathy, and CNS lymphoma from January 1990 to December 1998 in the Multicenter AIDS Cohort Study. The incidence rates for HIV dementia, cryptococcal meningitis, and lymphoma decreased following the introduction of highly active antiretroviral therapy (HAART). The proportion of new cases of HIV dementia with a CD4 count in a higher range (i.e., 201 to 350) since 1996 may be increasing.

Extragastrointestinal (Soft Tissue) Stromal Tumors: An Analysis of 48 Cases with Emphasis on Histologic Predictors of Outcome

The clinicopathologic features of 48 tumors that were histologically similar to gastrointestinal stromal tumors but occurred in the soft tissues of the abdomen were analyzed to determine their overall similarity to their gastrointestinal counterpart, their biologic behavior, and the parameters that predict risk for adverse outcome. Classic leiomyomas and leiomyosarcomas were specifically excluded. The tumors occurred in 32 women and 16 men, who ranged in age from 31 to 82 years (mean, 58 years). Forty tumors arose from the soft tissue of the abdominal cavity, and the remainder arose from the retroperitoneum. They ranged in size from 2.1 to 32.0 cm and varied from tumors composed purely of rounded epithelioid cells to those composed of short fusiform cells set in a fine fibrillary collagenous background with some cases showing a mixed pattern. Tumors displayed variable amounts of stromal hyalinization, myxoid change, and cyst formation. The tumors expressed CD117 (c-kit receptor) (100%), CD34 (50%), neuron-specific enolase (44%), smooth muscle actin (26%), desmin (4%), and S-100 protein (4%). Tumors were evaluated with respect to several parameters: size (<10 cm or >10 cm), cellularity (low or high), mitoses (0 to 2 per 50 high-power fields, >2 per 50 high-power fields), nuclear atypia (1 to 3+), cell type (epithelioid, spindled, or mixed), and necrosis (absent or present). These parameters were then evaluated in univariate and multivariate analysis with respect to adverse or nonadverse outcome, the former defined as metastasis or death from tumor. Follow-up information was obtained for 31 patients (range, 4 to 84 months; median, 24 months). One patient presented with an adverse event and, therefore, was excluded from subsequent analysis. Twelve patients (39%) developed metastases or died of tumor. In univariate analyses, cellularity, mitotic activity (>2 per 50 high-power fields), and necrosis were associated with statistically significant increases in the risk for adverse outcome. Despite the relatively small sample size, in a multivariable analysis mitotic activity (relative risk, 7.46; P =.09) and necrosis (relative risk, 3.75; P =.07) displayed trends toward independent predictive value. No association was noted between histologic pattern and outcome. Although only 39% of tumors behaved in a malignant fashion, this figure probably represents a conservative estimate because long-term follow-up (>5 years) was available for only a limited number of patients. Stratification of patients who have extragastrointestinal stromal tumor into those with 0 to 1 adverse histologic factors versus those with 2 to 3 offers the advantage of separating patients into two groups that have a markedly different risk for adverse outcome in the short term (0.02 events versus 0.54 events per person-year; P<.001, respectively). Extragastrointestinal (soft tissue) stromal tumors are histologically and immunophenotypically similar to their gastrointestinal counterpart but have an aggressive course more akin to small intestinal than gastric stromal tumors.

Natural History of Human Immunodeficiency Virus Type 1 Viremia after Seroconversion and Proximal to AIDS in a Large Cohort of Homosexual Men

The natural history of human immunodeficiency virus type 1 (HIV-1) viremia and its association with clinical outcomes after seroconversion was characterized in a cohort of homosexual men. HIV-1 RNA was measured by reverse-transcription polymerase chain reaction (RT-PCR) in stored longitudinal plasma samples from 269 seroconverters. Subjects were generally antiretroviral drug naive for the first 3 years after seroconversion. The decline in CD4 lymphocyte counts was strongly associated with initial HIV RNA measurements. Both initial HIV RNA levels and slopes were associated with AIDS-free times. Median slopes were +0.18, +0.09, and -0.01 log10 copies/mL, respectively, for subjects developing AIDS <3, 3-7, and>7 years after seroconversion. In contrast, HIV RNA slopes in the 3 years preceding AIDS and HIV RNA levels at AIDS diagnosis showed little variation according to total AIDS-free time. HIV RNA load at the first HIV-seropositive visit ( approximately 3 months after seroconversion) was highly predictive of AIDS, and subsequent HIV RNA measurements showed even better prognostic discrimination.

Plasma viral load and CD4 lymphocytes predict HIV-associated dementia and sensory neuropathy

Objective: To determine the predictive value of plasma HIV RNA and CD4 lymphocytes for HIV-associated dementia and sensory neuropathy. Methods: A total of 1,604 AIDS-free HIV seropositive men from the Multicenter AIDS Cohort Study were followed over a 10-year period (1985 to 1995). HIV-associated dementia and sensory neuropathy were diagnosed according to standard definitions. Baseline samples were used to measure plasma HIV RNA levels with a branched DNA assay and levels of β2-microglobulin, CD4 lymphocyte counts, and hemoglobin levels. Results: Seventy-seven patients with HIV-associated dementia and 213 patients with sensory neuropathy were identified. Baseline HIV RNA levels above 3,000 copies/mL and CD4 counts below 500 cells/mm3 were predictive of both neurologic outcomes, but neither hemoglobin, body mass index, nor β2-microglobulin were independently predictive. After adjusting for age and level of education, individuals with baseline plasma HIV RNA >30,000 copies/mL had a relative hazard for dementia 8.5 times (p < 0.001) that of those with <3,000 copies/mL, and those with CD4 counts <200 cells/mm3 had a 3.5-fold (p = 0.003) greater hazard relative to those with CD4 counts >500 cells/mm3. Individuals with HIV RNA >10,000 copies/mL had a 2.3-fold (p = 0.008) greater hazard of sensory neuropathy than those with <500 copies/mL, and men with <750 CD4 cells/mm3 had a 1.4-fold (p = 0.03) greater hazard than those with >750 CD4 cells/mm3. Conclusions: High levels of systemic HIV replication may “drive” the initiation of neurologic disease; effective suppression of HIV may reduce the incidence of dementia and neuropathy. Levels of plasma HIV RNA and CD4 counts, determined before the initiation of antiretroviral therapy, were predictive of HIV-associated dementia and sensory neuropathy.

Combination antiretroviral therapy improves psychomotor speed performance in HIV-seropositive homosexual men

Background: Combination antiretroviral therapy including protease inhibitors (combo+PI) is effective in suppressing systemic viral load in HIV infection, but its impact on HIV-associated cognitive impairment is unclear. Objective: To determine whether psychomotor speed, a sensitive measure of impairment in HIV dementia, improves with combo+PI compared with other antiretroviral treatments. Methods: A total of 411 HIV-seropositive (HIV+) homosexual men (with longitudinal neuropsychological testing) in the Multicenter AIDS Cohort Study and, in a separate analysis, 282 HIV+ homosexual men with psychomotor slowing at baseline were classified by treatment into four groups: antiretroviral naïve (no antiretroviral medication treatment), monotherapy, combination antiretroviral therapy without protease inhibitors (combo-noPI), and combo+PI. We compared longitudinal performance on three tests of psychomotor speed: the Grooved Pegboard (GP) (nondominant and dominant hands), Trail Making Test B, and the Symbol Digit Modalities Test (SDMT). Results: Relative to antiretroviral-naïve and monotherapy participants, on the GP nondominant hand test, combo+PI participants with abnormal baseline neuropsychological testing showed improved performance (difference = +0.63 standard deviation [SD], p = 0.02). For the SDMT, both combo+PI participants (difference = +0.26 SD, p = 0.03) and combo-noPI participants (difference = +0.29 SD, p = 0.01) with abnormal baseline neuropsychological testing improved compared with antiretroviral-naïve and monotherapy groups. Conclusion: Combo+PI and combo-noPI are associated with improved psychomotor speed performance in HIV+ homosexual men with abnormal neuropsychological testing.

The Amount of Metastatic Melanoma in a Sentinel Lymph Node: Does It Have Prognostic Significance?

Background: The amount of metastatic disease in the sentinel lymph node (SLN) is examined as a prognostic factor in malignant melanoma.Methods: SLN mapping was performed on 592 patients with stage I and II malignant melanoma from March 1, 1994, through December 31, 1999. One hundred four patients were found to have 134 sentinel SLNs containing metastatic melanoma. The slides were reviewed, and the size of the metastatic melanoma in each SLN was measured. The size of the metastatic deposit was defined as macrometastasis (>2 mm), micrometastasis (≤2 mm), a cluster of cells (10–30 grouped cells) in the subcapsular space or interfollicular zone, or isolated melanoma cells (1 to ≥20 individual cells) in subcapsular sinuses.Results: The number of metastases in each SLN was isolated melanoma cells, n = 5 (3.7%); cluster of cells, n = 35 (26.1%); ≤2 mm, n = 45 (33.6%); and >2 mm, n = 49 (36.7%). Seventy-nine patients (76%) had a single positive SLN. The size of the largest nodal metastasis was used to stratify patients with multiple positive SLNs. The overall 3-year survival for patients with SLN micrometastases was 90%, versus 58% for patients with SLN macrometastases (P = .004).Conclusions: The amount of metastatic melanoma in an SLN is an independent predictor of survival. Patients with SLN metastatic deposits >2 mm in diameter have significantly decreased survival.

Chromophobe renal cell carcinoma: Histomorphologic characteristics and evaluation of conventional pathologic prognostic parameters in 145 cases

The aggregate literature suggests that chromophobe renal cell carcinoma (RCC) is biologically a tumor of low malignant potential with reported 5-year and 10-year survival rates of 78% to 100% and 80% to 90%, respectively. The conventional prognostic parameters that determine the outcome of the tumors that progress remain to be fully characterized. Clinicopathologic features of 145 cases were correlated with outcome. The mean age of the patients was 59 years (range, 27 to 82) and the male to female ratio was 1.1:1. Most tumors were well circumscribed and averaged 8.0 cm (range, 1.0 to 30.0 cm); multifocality and bilaterality were present in 8% and 3% of patients. Sixty (41%) were eosinophilic variant (greater than 80% eosinophilic cells), 18 (12%) were classic type (greater than 80% pale cells), and 67 (46%) were mixed (containing variable admixture of pale and eosinophilic cells). A subset of eosinophilic chromophobe RCC contained or had areas similar to renal oncocytomas. These tumors tended to be more commonly bilateral (11%) and multifocal (22%) and were not associated with necrosis or sarcomatoid change. Sarcomatoid change was present in 12/145 (8%) tumors. By histologic grade, 1%, 19%, 74%, 6% were Fuhrman nuclear grade 1, 2, 3, and 4. Nineteen percent, 21%, 28%, 13%, 4%, 1%, and 3% were pT (2002) stage pT1a, pT1b, pT2, pT3a, pT3b, pT3c, and pT4 tumors. Two percent tumors were pN1 at presentation and 2.8% tumors were M1 at presentation. Follow-up (1 to 182 mo, mean 48 mo, median 37 mo) was available in 123 cases. Disease progression (local recurrence 4, metastasis 15, and/or death 10) was seen in 20 patients. In univariable analysis, tumor size (P=0.025), pT stage (P<0.001), broad alveolar architecture (P=0.012), Fuhrman nuclear grade (P<0.001), microscopic tumor necrosis (P=0.001), vascular invasion (P=0.020), and sarcomatoid change (P≤0.001) were associated with progression. A multivariable Cox regression model revealed sarcomatoid change (P=0.013, estimated relative hazard 4.7), microscopic necrosis (P=0.020, relative hazard=3.5), and pT stage (P=0.025, relative hazard 3.4) as independent predictors of aggressive chromophobe RCC. Although the large majority of chromophobe RCCs have a favorable prognosis, a distinct subset of patients progress. The pT stage of tumor, tumor necrosis, and sarcomatoid change all predict aggressive phenotype of chromophobe RCC. The adverse presence of these features in a nephrectomy specimen with chromophobe RCC warrants active surveillance, and these patients may be candidates for adjuvant therapies as they become available.

Local Recurrence After Skin-Sparing Mastectomy: Tumor Biology or Surgical Conservatism?

Background:Long-term follow-up of the use of skin-sparing mastectomy (SSM) in the treatment of breast cancer is presented to determine the impact of local recurrence (LR) on survival.Methods:A total of 539 patients were treated for 565 cases of breast cancer by SSM and immediate breast reconstruction from January 1, 1989 to December 31, 1998. The American Joint Committee on Cancer pathological staging was stage 0 175 (31%), stage I 135 (23.9%), stage II 173 (30.6%), stage III 54 (9.6%), stage IV 8 (1.4%), and recurrent 20 (3.5%). The mean follow-up was 65.4 months (range, 23.7–86.3 months). Five patients were lost to follow-up.Results:Thirty-one patients developed a LR during the follow-up including five who received adjuvant radiation. The distribution of LR stratified by cancer stage was stage 0 1, stage I 5, stage II 17, stage III 6, and recurrent 2. The overall LR was 5.5%. Twenty-four patients (77.4%) developed a systemic relapse and 7 (22.6%) patients remained free of recurrent disease at a mean follow-up of 78.1 months. The cancer stage of those remaining disease free was stage 0 1 (100%), stage I 4 (80%), and stage II 2 (11.8%).Conclusions:LR of breast cancer after SSM is not always associated with systemic relapse.

AN EXPOSURE—ASSESSMENT STRATEGY ACCOUNTING FOR WITHIN- AND BETWEEN-WORKER SOURCES OF VARIABILITY

A strategy is presented for comparing exposures to an occupational exposure limit (OEL) and for suggesting appropriate interventions when exposures are unacceptable. The major departure from previous approaches is the explicit recognition that exposures vary both within and between workers in a given occupational group. The primary goal is to determine whether the probability of overexposure is acceptably small (a value of 0.10 or less is recommended), with overexposure being defined as the likelihood that a randomly selected workers true mean exposure exceeds the OEL. The exposure-assessment protocol contains five levels. It is suggested that at least two shift-long measurements be randomly collected from each of 10 workers for preliminary analysis. If the logged exposure data appear to be appropriate for testing (Level 1), the probability of overexposure is compared to the pre-determined value via a rigorous test of statistical significance (Level 2). Based upon published data, this test is likely to classify exposures as acceptable with 20 measurements when the group mean exposure is less than one-fifth of the OEL. However, if exposure is found to be unacceptable, re-sampling can be considered to increase the power of the test (Level 3). Otherwise, it is necessary to reduce exposures and then to re-apply the protocol. If it appears that all persons in the group have essentially the same predicted mean exposures (Level 4), then engineering or administrative controls are recommended. If, on the other hand, substantial differences appear to exist amongst these predicted mean values, regrouping and/or modifications of tasks and work practices should be considered (Level 5). Application of the protocol is illustrated with samples of data from four groups of workers exposed to inorganic nickel in the nickel-producing industry.

North American White Mitochondrial Haplogroups in Prostate and Renal Cancer

PURPOSE While the mitochondrion is known to be a key mediator of apoptosis, there has been little inquiry into the inheritance pattern of mitochondria in patients with cancer. We compared the mtDNA haplotype in patients with prostate and renal cancer to that in controls to determine if there is an association between mitochondrial genotype and cancer. MATERIALS AND METHODS Haplotyping was performed using polymerase chain reaction/digest identification of key polymorphic sites in the mitochondrial genome. A total of 121 and 221 white men with renal and prostate cancer, respectively, were identified following pathological confirmation of cancer, while 246 white controls were selected randomly from a bank of cadaveric organ donor DNA. Statistical analysis was performed and ORs were calculated. RESULTS Mitochondrial haplogroup U was a highly significant risk factor for prostate and renal cancer vs controls (16.74% and 20.66% vs 9.35%, Fishers exact test p = 0.019 and 0.005, respectively). The association remained statistically significant in renal cancer even after Bonferroni adjustment for multiple comparisons. Haplogroup U carried an OR of 1.95 for prostate cancer and an OR of 2.52 for renal cancer. CONCLUSIONS The inheritance of mitochondrial haplogroup U is associated with an approximately 2-fold increased risk of prostate cancer and 2.5-fold increased risk of renal cancer in white North American individuals. Therefore, individuals with this mitochondrial haplotype are in a high risk group. Because mitochondrial haplogroup U is found in 9.35% of the white United States population, there are more than 20 million individuals in this high risk group.