Alfred A. Bartolucci

Efficacy of an elective regional lymph node dissection of 1 to 4 mm thick melanomas for patients 60 years of age and younger

OBJECTIVE A prospective multi-institutional randomized surgical trial involving 740 stage I and II melanoma patients was conducted by the Intergroup Melanoma Surgical Program to determine whether elective (immediate) lymph node dissection (ELND) for intermediate-thickness melanoma (1-4 mm) improves survival rates compared with clinical observation of the lymph nodes. A second objective was to define subgroups of melanoma patients who would have a higher survival with ELND. METHODS The eligible patients were stratified according to tumor thickness, anatomic site, and ulceration, and then were prerandomized to either ELND or nodal observation. Femoral, axillary, or modified neck dissections were performed using standardized surgical guidelines. RESULTS The median follow-up was 7.4 years. A multifactorial (Cox regression) analysis showed that the following factors independently influenced survival: tumor ulceration, trunk site, tumor thickness, and patient age. Surgical treatment results were first compared based on randomized intent. Overall 5-year survival was not significantly different for patients who received ELND or nodal observation. However, the 552 patients 60 years of age or younger (75% of total group) with ELND has a significantly better 5-year survival. Among these patients, 5-year survival was better with ELND versus nodal observation for the 335 patients with tumors 1 to 2 mm thick, the 403 patients without tumor ulceration, and the 284 patients with tumors 1 to 2 mm thick and no ulceration. In contrast, patients older than 60 years of age who had ELND actually had a lower survival trend than those who had nodal observation. When survival rates were compared based on treatment actually received (i.e., including crossover patients), the patients with significantly improved 5-year survival rates after ELND included those with tumors 1 to 2 mm thick, those without tumor ulceration, and those 60 years of age or younger with tumors 1 to 2 mm thick or without ulceration. CONCLUSION This is the first randomized study to prove the value of surgical treatment for clinically occult regional metastases. Patients 60 years or age or younger with intermediate-thickness melanomas, especially with nonulcerative melanoma and those with tumors 1 to 2 mm thick, may benefit from ELND. However, because some patients still are developing distant disease, these results should be considered an interim analysis.

Efficacy of 2-cm surgical margins for intermediate-thickness melanomas (1 to 4 mm). Results of a multi-institutional randomized surgical trial.

BACKGROUND A prospective, multi-institutional, randomized surgical trial involving 486 localized melanoma patients was conducted to determine whether excision margins for intermediate-thickness melanomas (1.0 to 4.0 mm) could be safely reduced from the standard 4-cm radius. METHODS Patients with 1- to 4-mm-thick melanomas on the trunk or proximal extremities were randomly assigned to receive either a 2- or 4-cm surgical margin. RESULTS The median follow-up time was 6 years. The local recurrence rate was 0.8% for 2-cm margins and 1.7% for 4-cm margins (p value not significant [NS]). The rates of in-transit metastases were 2.1% and 2.5%, respectively (p = NS). Of the six patients with local recurrences, five have died. Recurrence rates did not correlate with surgical margins, even among stratified thickness groups. The overall 5-year survival rate was 79.5% for the 2-cm margin patients and 83.7% for the 4-cm margin patients (p = NS). The need for skin grafting was reduced from 46% with 4-cm surgical margins to 11% with 2-cm surgical margins (p < 0.001). The hospital stay was shortened from 7.0 days for patients receiving 4-cm surgical margins to 5.2 days for those receiving 2-cm margins (p = 0.0001). This reduction was largely due to reduced need for skin grafting, since the hospital stay for those who had a skin graft was 2.5 days longer than that for those who had a primary wound closure (p < 0.01). CONCLUSION Margins of excision can be safely reduced to 2 cm for patients with intermediate-thickness melanomas. The narrower margins significantly reduced the need for skin grafting and shortened the hospital stay.

Ten-year disease free survival after transperineal sonography-guided iodine-125 brachytherapy with or without 45-Gray external beam irradiation in the treatment of patients with clinically localized, low to high Gleason grade prostate carcinoma.

The authors report observed 10‐year brachytherapy results in the treatment of 152 consecutive patients with clinically organ‐confined prostate carcinoma.

Systemic lupus erythematosus in three ethnic groups: III A comparison of characteristics early in the natural history of the LUMINA cohort

Aim: To determine and contrast the socioeconomic-demographic and clinical features of patients with recent onset (5 y) systemic lupus erythematosus (SLE) from three ethnic groups, Hispanic, African-American and Caucasian (H, AA, C). Subjects and methods: SLE cases (American College of Rheumatology criteria) (incident (n ‘ 56), prevalent (n ‘ 173)), were enrolled in a longitudinal study at The University of Alabama at Birmingham, The University of Texas-Houston Health Science Center and The University of Texas Medical Branch at Galveston. Socioeconomic-demographic, clinical, immunological, behavioral and psychological data were obtained using validated instruments and standard laboratory techniques, and compared. Results: 70 H, 88 AA and 71 C SLE patients constitutethis cohort. H and AA patients were younger and of lower socioeconomic-demographic status. They also had evidence of more frequent organ system involvement (renal, cardiovascular), more auto-antibodies, more active disease (after adjusting for discrepant socioeconomic-demographic features), lower levels of social support and more abnormal illness-related behaviors (more in H than in AA). H also were more likely to have an abrupt disease onset; C were more likely to be on antimalarials but less likely to be on corticosteroids. H, AA, and C used health care resources comparably. They had similar levels of pain and physical and mental functioning after adjusting for age, disease duration, income, education, social support, illness-related behaviors, and Systemic Lupus Activity Measure or SLAM scores. Conclusions: H and AA patients have more active SLE, at an earlier age of onset, and a less favorable socioeconomic-demographic structure (worse among the H than AA) which predispose them to a less favorable natural history.

Systemic lupus erythematosus in three ethnic groups. IX. Differences in damage accrual.

OBJECTIVE To determine the factors predictive of damage in a multiethnic (Hispanic, African American, and Caucasian) LUMINA (lupus in minority populations, nature versus nurture) cohort of patients with systemic lupus erythematosus (SLE) with disease duration of < or =5 years at enrollment (T0). METHODS Variables (socioeconomic/demographic, clinical, immunologic, immunogenetic, behavioral, and psychological) were measured at T0 and annually thereafter. Disease damage was measured with the Systemic Lupus International Collaborating Clinics Damage Index (SDI), and disease activity was measured with the Systemic Lupus Activity Measure. The relationship between the different variables and the SDI at the last visit (TL) was examined (mean followup from diagnosis to TL 61 months; adjusted for disease duration). Poisson regression was used to identify the independent association between the different variables and SDI scores at TL. RESULTS Seventy-two Hispanics, 104 African Americans, and 82 Caucasians were included. One-half of patients had not accrued any damage. Caucasians had the lowest SDI scores at T0, and Hispanics had the highest scores at TL. Renal damage occurred more frequently among Hispanics and African Americans, while integument damage was more frequent among African Americans. Neuropsychiatric (20%), renal (16%), and ocular (15%) damage occurred most frequently among all patients. Independent predictors of SDI at TL were age, corticosteroid use (maximum dose at T0), number of American College of Rheumatology (ACR) criteria met, disease activity, and abnormal illness-related behaviors. Other variables were less consistently associated with damage accrual (poverty in African Americans, lack of HLA-DRB1*0301 in Hispanics, presence of HLA-DQB1*0201 and acute onset of SLE in Caucasians). CONCLUSION Damage in SLE occurs from the outset in some, but not all, patients; Hispanics accrue damage more rapidly. Disease factors (corticosteroid use, number of ACR criteria met, disease activity, and acute-onset type) are important, but age and abnormal illness-related behaviors also contribute to overall damage in SLE.

Local recurrence in malignant melanoma: Long-term results of the multiinstitutional randomized surgical trial

AbstractBackground: In the past, radical margins of excision were prescribed for cutaneous melanoma based on preconceived notions rather than on hard clinical evidence. Methods: In a prospective study of 742 patients with intermediate-thickness melanoma (1–4 mm), 470 patients with trunk or proximal extremity lesions were randomized into a 2-or 4-cm margin. Patients with distal extremity or head and neck lesions (n=272) received uniformly a 2-cm margin. Results: The overall rate of local recurrence was 3.8%. This rate in the randomized portion (n=470) was 2.1% for the 2-cm margin and 2.6% for the 4-cm margin (p=0.72). A progressive increase in local recurrence rates was observed with thickness: 2.3% for lesions 1.0–2.0 mm, 4.2% for those 2.01–3.0 mm, and 11.7% for those 3.01–4.0 mm thick (p=0.001). Local recurrence occurred in 1.5% of those without ulceration and in 10.6% of those with ulceration of the primary lesion (p=0.001). The local recurrence rate was not significantly affected by the margin of resection even among the thicker or ulcerated lesions. It also was not affected significantly by the method of closure of the primary site or management of the regional nodes, or the age or gender of the patients. Conclusions: A 2-cm margin is as effective as a 4-cm margin in local control and survival of intermediate-thickness melanomas. The local recurrence rate is significantly affected by the thickness of the primary lesion and the presence or not of ulceration.

Thoracic Radiotherapy Does Not Prolong Survival in Patients with Locally Advanced, Unresectable Non-Small Cell Lung Cancer

STUDY OBJECTIVE To compare the survival of patients with locally advanced non-small cell lung cancer treated with single-agent vindesine, thoracic radiotherapy, or both treatment modalities. DESIGN Randomized, prospective, phase III trial. SETTING Multi-institutional, university-based national cooperative oncology group. PATIENTS The study included 319 patients with locally advanced, unresectable non-small cell lung cancer who had no evidence of extrathoracic metastases. All patients were ambulatory and had measurable disease. Some patients could not have surgery because of coexisting medical conditions. INTERVENTION Patients were randomly assigned to receive vindesine, 3 mg/m2 body surface area weekly; standard thoracic radiotherapy, 60 Gy over 6 weeks; or both vindesine and thoracic radiotherapy. Vindesine was administered for 6 weeks and then every other week to patients who had no disease progression. Patients who developed progressive disease while receiving vindesine or radiotherapy alone were crossed over to radiotherapy or vindesine, respectively. Response assessment took place at week 6. RESULTS The overall response rate was superior in the radiotherapy arms (radiotherapy alone, 30%; radiotherapy plus vindesine, 34%; vindesine alone, 10%; P = 0.001). However, with a minimum follow-up of 42 months, no improvement in survival has been seen with radiotherapy. The median survival was 8.6 months for patients receiving radiotherapy alone, 9.4 months for those receiving radiotherapy plus vindesine, and 10.1 months for those receiving vindesine (P = 0.58). Radiotherapy also failed to improve long-term survival. The 5-year survivals were 3%, 3%, and 1%, respectively (P = 0.56). CONCLUSION Patients with non-small cell lung cancer who have inoperable, nonmetastatic disease gain no clinically meaningful survival advantage with immediate thoracic irradiation, even when modern megavoltage radiation therapy techniques and equipment are used.

Systemic lupus erythematosus in three ethnic groups. II. Features predictive of disease activity early in its course

Objective To determine the factors associated with disease activity in patients with recent-onset (≤5 years) systemic lupus erythematosus (SLE) who were of Hispanic, African-American, or Caucasian ethnicity. Methods Incident and prevalent cases of SLE, as defined by the American College of Rheumatology criteria for SLE, among the 3 ethnic groups were identified in Alabama (The University of Alabama at Birmingham) and Texas (The University of Texas-Houston Health Science Center and The University of Texas Medical Branch at Galveston). Variables from the sociodemographic, clinical, immunologic, immunogenetic, behavioral, and psychological domains were obtained using validated instruments. Disease activity was ascertained with the Systemic Lupus Activity Measure (SLAM). Stepwise domain regressions with SLAM score as the dependent variable were performed. Final ethnic-specific and overall regression models were obtained by entering variables that were retained in the domain regressions. Results SLAM scores at study entry were higher in the African Americans (mean ± SD 12.6 ± 6.9) and Hispanics (11.0 ± 6.2) than in the Caucasians (8.5 ± 3.7) (P ≤ 0.001). The final overall regression model (R2 = 28%) for higher SLAM score included the following variables: African-American ethnicity, lack of private health insurance, abrupt disease onset, presence of anti-Ro antibodies, absence of HLA-DRB1*0301, higher levels of helplessness, and abnormal illness-related behaviors. Conclusion Socioeconomic, immunologic, immunogenetic, behavioral, and psychological variables were all predictive of disease activity early in the course of SLE, irrespective of ethnic group. However, there remain ethnic group differences in disease activity that were not explained by these factors.

Deficiency in the Inhibitory Serine-Phosphorylation of Glycogen Synthase Kinase-3 Increases Sensitivity to Mood Disturbances

Bipolar disorder, characterized by extreme manic and depressive moods, is a prevalent debilitating disease of unknown etiology. Because mood stabilizers, antipsychotics, antidepressants, and mood-regulating neuromodulators increase the inhibitory serine-phosphorylation of glycogen synthase kinase-3 (GSK3), we hypothesized that deficient GSK3 serine-phosphorylation may increase vulnerability to mood-related behavioral disturbances. This was tested by measuring behavioral characteristics of GSK3α/β21A/21A/9A/9A knockin mice with serine-to-alanine mutations to block inhibitory serine-phosphorylation of GSK3. GSK3 knockin mice displayed increased susceptibility to amphetamine-induced hyperactivity and to stress-induced depressive-like behaviors. Furthermore, serine-phosphorylation of GSK3 was reduced during both mood-related behavioral responses in wild-type mouse brain and in blood cells from patients with bipolar disorder. Therefore, proper control of GSK3 by serine-phosphorylation, which is targeted by agents therapeutic for bipolar disorder, is an important mechanism that regulates mood stabilization, and mice with disabled GSK3 serine-phosphorylation may provide a valuable model to study bipolar disorder.

Prevalence of adrenal androgen excess in patients with the polycystic ovary syndrome (PCOS)

Objective  To determine the prevalence of adrenal androgen (AA) excess in the polycystic ovary syndrome (PCOS) using age‐ and race‐specific normative values.