John L. Zapas

The risk of regional lymph node metastases in patients with melanoma less than 1.0 mm thick: recommendations for sentinel lymph node biopsy

BACKGROUND Lymphatic mapping and sentinel lymph node biopsy can upstage patients with intermediate thickness (1.0 to 4.0 mm) melanoma. Currently, there are no strict guidelines for sentinel lymph node biopsy in patients with melanoma <1.0 mm thick. STUDY DESIGN A retrospective review of our patient database (598 patients treated at two institutions in Baltimore, MD, between January 1970 and June 2002) was performed to identify patients with primary cutaneous melanoma <1.0 mm thick who developed recurrent disease. This cohort of patients with > or =5 years of followup from the date of diagnosis was compared with patients with primary melanoma of similar thickness and similar followup intervals without recurrent disease. RESULTS A total of 114 patients with primary cutaneous melanoma <1.0 mm thick were identified, 17 of whom developed disease recurrence. In 13 patients, the site of first recurrence was the regional lymph nodes and in 4 patients disease recurred with distant metastases. The median time to lymph node recurrence was 55 months (range 2 to 112) months. Patients with regional lymph node recurrences had a significant (p = 0.02) difference in median primary tumor thickness of 0.80 mm versus 0.45 mm in patients without recurrent disease; there was no association of Clark level of invasion to recurrence (p = 0.42). In all, 35% of patients (7 of 20) presenting with melanoma 0.80 to 0.99 mm thick developed lymph node recurrence a median of 41 months (range 8 to 112 months) after surgical treatment. CONCLUSIONS Sentinel lymph node biopsy can be justified for patients with melanoma > or =0.8 mm thick provided that the technique would detect metastatic disease years before it becomes clinically evident.

Sequential Administration of GM-CSF (Sargramostim®) and IL-2 ± Autologous Vaccine as Adjuvant Therapy in Cutaneous Melanoma : An Interim Report of a Phase II Clinical Trial

Granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-2 (IL-2) are 2 cytokines with distinct mechanisms of action that complement one another in the adjuvant management of melanoma. Forty-five patients with high-risk melanoma were enrolled in an open-label, single-arm, phase II clinical trial to examine the safety, tolerability, and effectiveness of this combination. After potentially curative surgery, each patient received 12 months of GM-CSF 125 microg/m2/d subcutaneously (SC) for 14 days followed by IL-2, 9 million IU/m2/d SC for 4 days (given every other cycle from months 7-12), followed by 10 days of no treatment. In addition, patients who had tumors yielding an adequate number of live cells received autologous melanoma vaccines. For months 13-24, patients received only GM-CSF 250 microg/m2 twice weekly. This is an interim analysis based on the 45 enrolled patients with a median of 15.9 months follow-up (range, 1-50 months). Thirty-two patients are alive: 9 of 13 with stage IV resected melanoma, 16 of 25 with stage III disease, and 7 of 7 with stage II disease. Twelve died of the disease, and one due to stroke. Adjuvant use of sequential GM-CSF and IL-2 +/- autologous vaccine was well tolerated with good patient compliance and seemed to benefit high-risk patients with surgically resected melanoma.

Clinical Impact of a Value-Based Decision: A Surgical Case Study

BACKGROUND Value is an economic utility defined by quality and cost, with the maximum benefit achieved by improving quality and reducing cost simultaneously. Health care systems are using value-based analysis to identify the best practices (BPs) that accomplish this goal. STUDY DESIGN We chose a clinical condition, deep venous thrombophlebitis (DVT) to test this hypothesis by identifying the BPs available in the literature; determining the usual practice for DVT prophylaxis at each of 8 hospitals (ie, community, tertiary, and a university hospital) in an integrated system; measuring clinical outcomes (mortality and morbidity) for each hospital; determining cost for each treatment algorithm in each hospital; and measuring the savings opportunity if a single BP was used by all of the hospitals. RESULTS The literature suggests that the BPs for DVT prophylaxis consist of sequential compression devices for short-stay procedures; unfractionated heparin for inpatient procedures, and low molecular weight heparin for thrombotic events. Four of the hospitals were using these BPs; the others relied on sequential compression devices and low molecular weight heparin for prophylaxis. Outcomes were identical and value-based analysis suggested a savings opportunity of nearly

Using Value-Based Analysis to Influence Outcomes in Complex Surgical Systems

4 million if a single BP was adopted. CONCLUSIONS There were substantial variations in the type of DVT prophylaxis used by the hospitals with no difference in outcomes. A single BP increased value and resulted in savings of

Abstract 1097: Immunohistochemical expression of growth factor receptors in different stages of human cutaneous melanoma

1.5 million, with a savings opportunity of nearly

Abstract 1921: Nonadherent human melanoma cell lines from lymph node metastases coexpress B cell markers and melanoma antigens

4 million.

Dendritic cell counts in the peripheral blood of healthy adults

BACKGROUND Value-based analysis (VBA) is a management strategy used to determine changes in value (quality/cost) when a usual practice (UP) is replaced by a best practice (BP). Previously validated in clinical initiatives, its usefulness in complex systems is unknown. To answer this question, we used VBA to correct deficiencies in cardiac surgery at Memorial Healthcare System. STUDY DESIGN Cardiac surgery is a complex surgical system that lends itself to VBA because outcomes metrics provided by the Society of Thoracic Surgeons provide an estimate of quality; cost is available from Centers for Medicare and Medicaid Services and other contemporary sources; the UP can be determined; and the best practice can be established. RESULTS Analysis of the UP at Memorial Healthcare System revealed considerable deficiencies in selection of patients for surgery; the surgery itself, including choice of procedure and outcomes; after care; follow-up; and control of expenditures. To correct these deficiencies, each UP was replaced with a BP. Changes included replacement of most of the cardiac surgeons; conversion to an employed physician model; restructuring of a heart surgery unit; recruitment of cardiac anesthesiologists; introduction of an interactive educational program; eliminating unsafe practices; and reducing cost. CONCLUSIONS There was a significant (p < 0.01) reduction in readmissions, complications, and mortality between 2009 and 2013. Memorial Healthcare System was only 1 of 17 (1.7%) database participants (n = 1,009) to achieve a Society of Thoracic Surgeons 3-star rating in all 3 measured categories. Despite substantial improvements in quality, the cost per case and the length of stay declined. These changes created a savings opportunity of

In Vivo Effects of Sequential Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF) and Interleukin-2 (IL-2) on Circulating Dendritic Cells (DC) in Patients with Surgically Resected High Risk Cutaneous Melanoma

14 million, with actual savings of

Perioperative adjuvant biotherapy in high-risk resected cutaneous melanoma: the results of 5 years of follow-up.

10.4 million. These findings suggest that VBA can be a powerful tool to enhance value (quality/cost) in a complex surgical system.

Inhibition of proliferation of early passage human melanoma cell lines by curcumin

Background: Melanoma is an aggressive and chemoresistant tumor.High risk melanoma is minimally susceptible to current treatment strategies.These treatment strategies have not yielded much appreciable survival benefits. It is now clearly evident that cell-surface receptors play a pivotal role in transmitting extracellular signals to intracellular effectors. Trophic factors exert profound influence on the tumor micro-environment through auto or paracrine signaling mechanisms in the course of coordinated activation of their cognate receptors.This in turn orchestrates tumor growth, survival and invasion. Melanoma cells utilize a cascade of multiple trophic factors which modulate tumor progression through autocrine growth mechanisms by activating specific receptor tyrosine kinases (RTKs). Melanoma progression is preceded with certain types of cells oscillating in response to changing micro-environment signals. Therefore, growth factor receptor activation in melanoma cells may have important implications in tumor progression and tumor cell homing to metastatic sites.The aim of present investigation was to assess synergistic expression of EGF-R, FGF-R,VEGF-R, PDGF-R, IGF-1R,TGFβ-RII at various stages of cutaneous melanoma by Immunohisto-chemistry in order to identify factors that might be applied to early diagnosis, prognosis or for emerging targeted therapies. Methods: FFPE tissues were selected from patients with primary melanoma (n=39), metastatic melanoma (n=19) and 11 patients with benign nevi. Five micron thick sections of FFPE tissues from each case were subjected individually for Immunohistochemical staining using monoclonal / polyclonal antibodies to EGFR, phosphoEGFR, FGF-R, VEGF-R3, PDGF-Rβ, IGF1R, TGFβ-RII. Immunoexpression patterns of various growth factor receptors were evaluated with a semi-quantitative scoring system for the intensity of staining on tumor cells.Fisher9s exact test was utilized to determine significant variance in the study group. Results: Tissues from patients with metastatic melanoma revealed significant overexpression of IGF1-R, TGF-β RII when compared with primary melanoma (p Conclusions: The study revealed overexpression of TGFβ-RII, IGF1R, FGFR1 and phosho-EGF-R which are suggestive of the markers of receptor tyrosine kinase dependent progression of metastatic lesions through activation of multiple signaling pathways. Multi-targeted therapeutics will be a better paradigm for effective clinical management of high risk cutaneous melanoma. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1097. doi:10.1158/1538-7445.AM2011-1097