Francis R. Spitz

Mitotic rate as a predictor of sentinel lymph nodepositivity in patients with thin melanomas

BackgroundLymphatic mapping and sentinel lymphadenectomy (LM/SL) provide important prognostic information for patients with early-stage melanoma. Although the use of this technique in patients with thin melanomas (≤1.00 mm) is not routine, risk factors that may predict sentinel lymph node (SLN) positivity in this patient population are under investigation. We sought to determine whether mitotic rate (MR) is associated with SLN positivity in thin-melanoma patients and, therefore, whether it may be used to risk-stratify and select patients for LM/SL.MethodsClinical and histopathologic variables were reviewed for 181 patients with thin melanomas who underwent LM/SL from January 1996 through January 2004. Univariate and multivariate logistic regression analyses were performed to identify factors associated with SLN positivity. Risk groups were defined on the basis of the development of a classification tree.ResultsThe overall SLN positivity rate was 5%. All patients with positive SLNs had an MR of >0. By univariate analysis, MR and thickness were significant predictors of SLN positivity. The association between MR and SLN positivity remained significant controlling for each of the other variables evaluated. On the basis of a classification tree, patients with an MR >0 and tumor thickness ≥.76 mm were identified as a higher-risk group, with an SLN positivity rate of 12.3%.ConclusionsIn patients with thin melanomas, MR >0 seems to be a significant predictor of SLN positivity that may be used to risk-stratify and select patients for LM/SL. To confirm these results, the predictive value of MR for SLN positivity needs to be validated in other populations of thin-melanoma patients.

Immunohistochemistry with pancytokeratins improves the sensitivity of sentinel lymph node biopsy in patients with breast carcinoma

Sentinel lymph node (SLN) biopsy is being investigated as a staging procedure for breast carcinoma. The authors evaluated whether immunohistochemical (IHC) analysis improves the sensitivity of this procedure.

Thin Primary Cutaneous Malignant Melanoma: A Prognostic Tree for 10-Year Metastasis Is More Accurate Than American Joint Committee on Cancer Staging

PURPOSE The majority of invasive primary melanomas are thin (< or = 1.00 mm). Since the current staging system imperfectly predicts outcome in patients with such lesions, we sought to develop a more effective classification scheme to better identify both patients at high risk of metastasis who are candidates for further staging and therapy and those with little risk. PATIENTS AND METHODS This prospective cohort study included 884 patients who had thin invasive melanomas. A tree-structured analysis of 10-year metastasis was used to develop a new classification scheme. RESULTS The overall 10-year metastasis rate was 6.5% (95% CI, 4.8% to 8.1%). The prognostic tree defined four risk groups: high-risk: men with vertical growth phase (VGP) lesions that had mitotic rates (MRs) greater than 0, and for whom the 10-year metastasis rate was 31% (22% to 42%; n = 90); moderate-risk: women with VGP lesions that had MRs greater than 0 and for whom the rate was 13% (9% to 18%; n = 136); low-risk: patients with VGP lesions that had MR of 0 for whom the rate was 4% (2% to 7%; n = 247); and minimal-risk: patients with invasive lesions without VGP for whom the rate was 0.5% (0% to 1.2%; n = 411). Survival curves differed significantly among the four groups (P <.001). CONCLUSION Growth phase, mitotic rate, and sex are important prognostic factors for patients with thin melanomas, and they identify subgroups at substantial risk for metastasis. After validation in other populations, the proposed prognostic tree will be useful in the design of clinical trials and clinical management.

Identification of High-Risk Patients Among Those Diagnosed With Thin Cutaneous Melanomas

PURPOSE Most patients with melanoma have microscopically thin (< or = 1 mm) primary lesions and are cured with excision. However, some develop metastatic disease that is often fatal. We evaluated established prognostic factors to develop classification schemes with better discrimination than current American Joint Committee on Cancer (AJCC) staging. PATIENTS AND METHODS We studied patients with thin melanomas from the US population-based Surveillance, Epidemiology, and End Results (SEER) cancer registry (1988 to 2001; n = 26,291) and those seen by the University of Pennsylvanias Pigmented Lesion Group (PLG; 1972 to 2001; n = 2,389; Philadelphia, PA). AJCC prognostic factors were thickness, anatomic level, ulceration, site, sex, and age; PLG prognostic factors also included a set of biologically based candidate prognostic factors. Recursive partitioning was used to develop a SEER-based classification tree that was validated using PLG data. Next, a new PLG-based classification tree was developed using the expanded set of prognostic factors. RESULTS The SEER-based classification tree identified additional criteria to explain survival heterogeneity among patients with thin, nonulcerated lesions; 10-year survival rates ranged from 89.1% to 99%. The new PLG-based tree identified groups using level, tumor cell mitotic rate, and sex. With survival rates from 83.4% to 100%, it had better discrimination. CONCLUSION Prognostication and related clinical decision making in the majority of patients with melanoma can be improved now using the validated, SEER-based classification. Tumor cell mitotic rate should be incorporated into the next iteration of AJCC staging.

Incidence of sentinel node metastasis in patients with thin primary melanoma (≤1 mm) with vertical growth phase

Background: Patients with thin primary melanomas (#1 mm) generally have an excellent prognosis. However, the presence of a vertical growth phase (VGP) adversely impacts the survival rate. We report on the rate of occurrence of nodal metastasis in patients with thin primary melanomas with a VGP who are offered sentinel lymph node (SLN) biopsy.Methods: Among 235 patients with clinically localized cutaneous melanomas who underwent successful SLN biopsy, 71 had lesions 1 mm or smaller with a VGP. The SLN was localized by using blue dye and a radiotracer. If negative for tumor by using hematoxylin and eosin staining, the SLN was further examined by immunohistochemistry.Results: The rate of occurrence of SLN metastasis was 15.2% in patients with melanomas deeper than 1 mm and 5.6% in patients with thin melanomas. Three patients with thin melanomas and a positive SLN had low-risk lesions, based on a highly accurate six-variable multivariate logistic regression model for predicting 8-year survival in stage I/II melanomas. The fourth patient had a low- to intermediate-risk lesion based on this model. At the time of the lymphadenectomy, one patient had two additional nodes with metastasis.Conclusions: VGP in a melanoma 1 mm or smaller seems to be a risk factor for nodal metastasis. The risk of nodal disease may not be accurately predicted by the use of a multivariate logistic regression model that incorporates thickness, mitotic rate, regression, tumor-infiltrating lymphocytes, sex, and anatomical site. Patients with thin lesions having VGP should be evaluated for SLN biopsy and trials of adjuvant therapy when stage III disease is found.

Predicting sentinel node status in AJCC stage I/II primary cutaneous melanoma

Sentinel lymph node (SLN) status is an important prognostic factor for survival for patients with primary cutaneous melanoma. To address the issue of selecting patients at high and low risk for a positive SLN, prognostic factors were sought that predict SLN involvement by examining characteristics of both the primary tumor and the patient within the context of a biological model of melanoma progression.

Predictors of Regional Nodal Disease in Patients With Thin Melanomas

BackgroundMost melanoma patients present with thin (≤1.0 mm) lesions. Indications for sentinel lymph node (SLN) biopsy are not well defined for this group. Previously, we reported an association between mitotic rate (MR) and SLN positivity in these patients. The study was limited by a relatively small sample size and low statistical power. In this study, we evaluated a large population of patients with thin melanoma from the pre-SLN era to identify predictors of regional nodal disease (RND) that may serve as a surrogate for SLN positivity.MethodsEight hundred eighty-two patients evaluated between 1972 and 1991 were included in the study. Univariate and multivariate regression analyses were performed by using clinical and histological data to identify factors associated with RND. A multivariate logistic regression model was developed and applied to the previously reported group of patients with thin melanomas who underwent SLN biopsy between 1996 and 2004 for validation.ResultsThirty-eight patients (4.3%) had evidence of RND. In the multivariate analysis, a MR >0, vertical growth phase (VGP), male sex, and ulceration were statistically significant predictors of RND. Patients at the highest risk according to a classification tree analysis (VGP and MR >0) had an RND rate of 11.9%. The regression model developed predicted well the SLN status in the validation sample.ConclusionsInvestigation of a large pre-SLN population identified MR >0, ulceration, VGP, and male sex as independently predictive of RND in patients with thin melanomas. These factors may help to identify subgroups of these patients that have clinically significant risks of SLN positivity.

Time of day is associated with postoperative morbidity: an analysis of the national surgical quality improvement program data.

Objective:To examine the association between surgical start time and morbidity and mortality for nonemergent procedures. Summary Background Data:Patients require medical services 24 hours a day. Several studies have demonstrated a difference in outcomes over the course of the day for anesthetic adverse events, death in the ICU, and dialysis care. The relationship between operation start time and patient outcomes is yet undefined. Methods:We performed a retrospective cohort study of 144,740 nonemergent general and vascular surgical procedures performed within the VA Medical System 2000–2004 and entered into the National Surgical Quality Improvement Program Database. Operation start time was the independent variable of interest. Logistic regression was used to adjust for patient and procedural characteristics and to determine the association between start time and, in 2 independent models, mortality and morbidity. Results:Unadjusted later start time was significantly associated with higher surgical morbidity and mortality. After adjustment for patient and procedure characteristics, mortality was not significantly associated with start time. However, after appropriate adjustment, operations starting between 4 pm and 6 pm were associated with an elevated risk of morbidity (OR = 1.25, P ≤ 0.005) over those starting between 7 am and 4 pm as were operations starting between 6 pm and 11 pm (OR = 1.60, P ≤ 0.005). Conclusions:When considering a nonemergent procedure, surgeons must bear in mind that cases that start after routine “business” hours within the VA System may face an elevated risk of complications that warrants further evaluation.

A Phase II Trial of Intraperitoneal Photodynamic Therapy for Patients with Peritoneal Carcinomatosis and Sarcomatosis

Purpose: A previous phase I trial of i.p. photodynamic therapy established the maximally tolerated dose of Photofrin (Axcan Pharma, Birmingham, AL)-mediated photodynamic therapy and showed encouraging efficacy. The primary objectives of this phase II study were to determine the efficacy and toxicities of i.p. photodynamic therapy in patients with peritoneal carcinomatosis and sarcomatosis. Experimental Design: Patients received Photofrin 2.5 mg/kg i.v. 48 hours before debulking surgery. Intraoperative laser light was delivered to the peritoneal surfaces of the abdomen and pelvis. The outcomes of interest were (a) complete response, (b) failure-free survival time, and (c) overall survival time. Photosensitizer levels in tumor and normal tissues were measured. Results: One hundred patients were enrolled into one of three strata (33 ovarian, 37 gastrointestinal, and 30 sarcoma). Twenty-nine patients did not receive light treatment. All 100 patients had progressed by the time of statistical analysis. The median failure-free survival and overall survival by strata were ovarian, 2.1 and 20.1 months; gastrointestinal cancers, 1.8 and 11.1 months; sarcoma, 3.7 and 21.9 months. Substantial fluid shifts were observed postoperatively, and the major toxicities were related to volume overload. Two patients died in the immediate postoperative period from bleeding, sepsis, adult respiratory distress syndrome, and cardiac ischemia. Conclusions: Intraperitoneal Photofrin-mediated photodynamic therapy is feasible but does not lead to significant objective complete responses or long-term tumor control. Heterogeneity in photosensitizer uptake and tumor oxygenation, lack of tumor specificity for photosensitizer uptake, and the heterogeneity in tissue optical properties may account for the lack of efficacy observed.

HIV protease inhibitor nelfinavir inhibits growth of human melanoma cells by induction of cell cycle arrest.

HIV protease inhibitors (HIV PI) are a class of antiretroviral drugs that are designed to target the viral protease. Unexpectedly, this class of drugs is also reported to have antitumor activity. In this study, we have evaluated the in vitro activity of nelfinavir, a HIV PI, against human melanoma cells. Nelfinavir inhibits the growth of melanoma cell lines at low micromolar concentrations that are clinically attainable. Nelfinavir promotes apoptosis and arrests cell cycle at G(1) phase. Cell cycle arrest is attributed to inhibition of cyclin-dependent kinase 2 (CDK2) and concomitant dephosphorylation of retinoblastoma tumor suppressor. We further show that nelfinavir inhibits CDK2 through proteasome-dependent degradation of Cdc25A phosphatase. Our results suggest that nelfinavir is a promising candidate chemotherapeutic agent for advanced melanoma, for which novel and effective therapies are urgently needed.