Safety and Feasibility of Minimally Invasive Inguinal Lymph Node Dissection in Patients With Melanoma (SAFE-MILND): Report of a Prospective Multi-institutional Trial.

BACKGROUND: Minimally invasive inguinal lymph node dissection (MILND) is a novel approach to inguinal lymphadenectomy. SAFE-MILND (NCT01500304) is a multicenter, phase I/II clinical trial evaluating the safety and feasibility of MILND for patients with melanoma in a group of surgeons newly adopting the procedure. METHODS: Twelve melanoma surgeons from 10 institutions without any previous MILND experience, enrolled patients into a prospective study after completing specialized training including didactic lectures, participating in a hands-on cadaveric laboratory, and being provided an instructional DVD of the procedure. Complications and adverse postoperative events were graded using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events Version 4.0. RESULTS: Eighty-seven patients underwent a MILND. Seventy-seven cases (88.5%) were completed via a minimally invasive approach. The median total inguinal lymph nodes pathologically examined (SLN + MILND) was 12.0 (interquartile range 8.0, 14.0). Overall, 71% of patients suffered an adverse event (AE); the majority of these were grades 1 and 2, with 26% of patients experiencing a grade 3 AE. No grade 4 or 5 AEs were observed. CONCLUSIONS: After a structured training program, high-volume melanoma surgeons adopted a novel surgical technique with a lymph node retrieval rate that met or exceeded current oncologic guidelines and published benchmarks, and a favorable morbidity profile.

Laparoscopic skill assessment of practicing surgeons prior to enrollment in a surgical trial of a new laparoscopic procedure.

BACKGROUND: Outcomes of surgical trials hinge on surgeon selection and their underlying expertise. Assessment of expertise is paramount. We investigated whether surgeons' performance measured by the fundamentals of laparoscopic surgery (FLS) assessment program could predict their performance in a surgical trial. METHODS: As part of a prospective multi-institutional study of minimally invasive inguinal lymphadenectomy (MILND) for melanoma, surgical oncologists with no prior MILND experience underwent pre-trial FLS assessment. Surgeons completed MILND training, began enrolling patients, and submitted videos of each MILND case performed. Videos were scored with the global operative assessment of laparoscopic skills (GOALS) tool. Associations between baseline FLS scores and participant's trial performance metrics were assessed. RESULTS: Twelve surgeons enrolled patients; their median total baseline FLS score was 332 (range 275-380, max possible 500, passing >270). Participants enrolled 87 patients in the study (median 6 per surgeon, range 1-24), of which 72 (83%) videos were adequate for scoring. Baseline GOALS score was 17.1 (range 9.6-21.2, max possible score 30). Inter-rater reliability was excellent (ICC = 0.85). FLS scores correlated with improved GOALS scores (r = 0.57, p = 0.05) and with decreased operative time (r = -0.6, p = 0.02). No associations were found with the degree of patient recruitment (r = 0.02, p = 0.7), lymph node count (r = 0.01, p = 0.07), conversion rate (r = -0.06, p = 0.38) or major complications(r = -0.14, p = 0.6). CONCLUSIONS: FLS skill assessment of surgeons prior to their enrollment in a surgical trial is feasible. Although better FLS scores predicted improved operative performance and operative time, other trial outcome measures showed no difference. Our findings have implications for the documentation of laparoscopic expertise of surgeons in practice and may allow more appropriate selection of surgeons to participate in clinical trials.

Pediatric melanoma: analysis of an international registry.

BACKGROUND: The management of pediatric melanoma (PM) has largely been extrapolated from adult data. However, the behavior of PM appears to differ from its adult counterparts. Therefore, an international PM registry was created and analyzed. METHODS: Twelve institutions contributed deidentified clinicopathologic and outcome data for patients diagnosed with PM from 1953 through 2008. RESULTS: Overall survival (OS) data were reported for 365 patients with invasive PM who had adequate follow-up data. The mean age of the patients was 16 years (range 1 year-21 years). The 10-year OS rate, 80.6%, tended to vary by patient age: 100% for those aged birth to 10 years, 69.7% for those aged > 10 years to 15 years, and 79.5% for those aged > 15 years to 20 years (P = .147). Patients with melanomas measuring ≤ 1 mm had a favorable prognosis (10-year OS rate of 97%), whereas survival was lower but similar for patients with melanomas measuring > 1 mm to 2 mm, > 2 mm to 4 mm, and > 4 mm (70%, 78%, and 80%, respectively; P = .0077). Ulceration and lymph node metastasis were found to be correlated with worse survival (P = .022 and P = .017, respectively). The 10-year OS rate was 94.1% for patients with American Joint Committee on Cancer stage I disease, 79.6% for those with stage II disease, and 77.1% for patients with stage III disease (P < .001). CONCLUSIONS: Tumor thickness, ulceration, lymph node status, and stage were found to be significant predictors of survival in patients with PM, similar to adult melanoma. There is a trend toward increased survival in children aged ≤ 10 years versus adolescents aged > 10 years. Further analyses are needed to probe for potential biological and behavioral differences in pediatric versus adult melanoma.

Combined analysis of phase III trials evaluating [99mTc]tilmanocept and vital blue dye for identification of sentinel lymph nodes in clinically node-negative cutaneous melanoma.

BACKGROUND: [(99m)Tc]Tilmanocept is a CD206 receptor-targeted radiopharmaceutical designed for sentinel lymph node (SLN) identification. Two nearly identical nonrandomized phase III trials compared [(99m)Tc]tilmanocept to vital blue dye. METHODS: Patients received [(99m)Tc]tilmanocept and blue dye. SLNs identified intraoperatively as radioactive and/or blue were excised and histologically examined. The primary end point, concordance, was the proportion of blue nodes detected by [(99m)Tc]tilmanocept; 90 % concordance was the prespecified minimum concordance level. Reverse concordance, the proportion of radioactive nodes detected by blue dye, was also calculated. The prospective statistical plan combined the data from both trials. RESULTS: Fifteen centers contributed 154 melanoma patients who were injected with both agents and were intraoperatively evaluated. Intraoperatively, 232 of 235 blue nodes were detected by [(99m)Tc]tilmanocept, for 98.7 % concordance (p < 0.001). [(99m)Tc]Tilmanocept detected 364 nodes, for 63.7 % reverse concordance (232 of 364 nodes). [(99m)Tc]Tilmanocept detected at least one node in more patients (n = 150) than blue dye (n = 138, p = 0.002). In 135 of 138 patients with at least one blue node, all blue nodes were radioactive. Melanoma was identified in the SLNs of 22.1 % of patients; all 45 melanoma-positive SLNs were detected by [(99m)Tc]tilmanocept, whereas blue dye detected only 36 (80 %) of 45 (p = 0.004). No positive SLNs were detected exclusively by blue dye. Four of 34 node-positive patients were identified only by [(99m)Tc]tilmanocept, so 4 (2.6 %) of 154 patients were correctly staged only by [(99m)Tc]tilmanocept. No serious adverse events were attributed to [(99m)Tc]tilmanocept. CONCLUSIONS: [(99m)Tc]Tilmanocept met the prespecified concordance primary end point, identifying 98.7 % of blue nodes. It identified more SLNs in more patients, and identified more melanoma-containing nodes than blue dye.

Factors predictive of the status of sentinel lymph nodes in melanoma patients from a large multicenter database.

BACKGROUND: Numerous predictive factors for cutaneous melanoma metastases to sentinel lymph nodes have been identified; however, few have been found to be reproducibly significant. This study investigated the significance of factors for predicting regional nodal disease in cutaneous melanoma using a large multicenter database. METHODS: Seventeen institutions submitted retrospective and prospective data on 3463 patients undergoing sentinel lymph node (SLN) biopsy for primary melanoma. Multiple demographic and tumor factors were analyzed for correlation with a positive SLN. Univariate and multivariate statistical analyses were performed. RESULTS: Of 3445 analyzable patients, 561 (16.3%) had a positive SLN biopsy. In multivariate analysis of 1526 patients with complete records for 10 variables, increasing Breslow thickness, lymphovascular invasion, ulceration, younger age, the absence of regression, and tumor location on the trunk were statistically significant predictors of a positive SLN. CONCLUSIONS: These results confirm the predictive significance of the well-established variables of Breslow thickness, ulceration, age, and location, as well as consistently reported but less well-established variables such as lymphovascular invasion. In addition, the presence of regression was associated with a lower likelihood of a positive SLN. Consideration of multiple tumor parameters should influence the decision for SLN biopsy and the estimation of nodal metastatic disease risk.

Melanoma in pediatric, adolescent, and young adult patients.

The family practitioner, pediatrician, and dermatologist all have potential roles in the primary prevention, diagnosis, and treatment of localized thin melanomas. Surgical and medical oncologists are often involved when controversy arises over the nature of the skin lesion or whether sentinel lymph node (SLN) biopsies and adjuvant therapy are to be contemplated. This overview of melanoma will deal with the primary and nodal pathology, surgery, and medical therapy of melanoma in pediatric, adolescent, and young adult patients--and will raise areas of controversy that are only recently being addressed in databases of cases from this age group.

Training High-Volume Melanoma Surgeons to Perform a Novel Minimally Invasive Inguinal Lymphadenectomy: Report of a Prospective Multi-Institutional Trial.

BACKGROUND: Minimally invasive inguinal lymphadenectomy (MILND) is a novel procedure with the potential to decrease surgical morbidity compared with the traditional open approach. The current study examined the feasibility of a combined didactic and hands-on training program to prepare high-volume melanoma surgeons to perform this procedure safely and proficiently. STUDY DESIGN: A select group of melanoma surgeons with no MILND experience were recruited. After completing a structured training program, surgeons enrolled patients with melanoma who required inguinal lymphadenectomy and performed the procedure in the minimally invasive fashion. A proficiency score composed of lymph node yield, operative time, and blood loss (or adverse events) was assigned for each case. After performing six cases, surgeons meeting a threshold score were considered proficient in the procedure. RESULTS: Twelve surgeons from 10 institutions enrolled 88 patients. The majority of surgeons were deemed proficient within 6 cases (83%). No differences in operative time or lymph node yield were noted during the course of the study. The rate of conversion was higher during an individual surgeon's early experience (9 of 49 [18%]), and only 1 procedure was converted in the 39 cases performed after a surgeon had performed 5 cases (late conversion rate, 3%; p = 0.038); however, this did not remain significant after controlling for surgeon. CONCLUSIONS: After a structured training program, experienced melanoma surgeons adopted a novel surgical technique with acceptable operative times, conversions, and lymph node yield. Eighty-four percent of the surgeons who completed at least 6 MILND procedures were considered proficient based on our predetermined definition.

A long-term analysis of 1018 patients with melanoma by classic Cox regression and tree-structured survival analysis at a major referral center: Implications on the future of cancer staging.

BACKGROUND: Traditional statistical analysis of 2 surgeons' experiences with resectable malignant melanoma during a 30-year period (November 1970-July 2000) was compared with new tree-structured recursive partitioning regression analysis. METHODS: A total of 1018 consecutive patients were registered and 983 patients were evaluable. Disease-free survival (DFS) and melanoma survival (MS) were calculated by Kaplan-Meier method for stage, thickness, ulceration, site, lymph node involvement, age, sex, and type; and compared with log-rank tests. Cox proportional hazards model was used for multivariate analysis. Multivariate predictors were used to analyze DFS and MS with a classification and regression tree model that partitioned patients into progressively more homogenous prognostic groups with significantly different Kaplan-Meier curves. RESULTS: Multivariate correlations were with thickness (millimeters), ulceration, age (per year), type, and sex in predicting DFS (relative risk = 1.18, 2.10, 1.05, 1.71, and 1.71, respectively). Thickness, ulceration, age, and type remained significant predictors of MS (relative risk = 1.14, 3.02, 1.02, and 2.30, respectively). Classification and regression tree analysis showed thickness, age, ulceration, and sex affected DFS. Only thickness and ulceration were significant in predicting MS. CONCLUSION: The Cox model is an important tool for analysis of clinical data but has flaws. New statistical technology to predict outcome should be considered. Classification and regression tree analysis of larger published series may reveal new predictors useful for staging, prognosis, and guiding clinical decisions.

Antitumor effects of Flt3 ligand in transplanted murine tumor models.

Administration of Flt3 ligand (FL) to mice causes dendritic and natural killer cells to increase but certain solid tumors to regress. Depending on the particular tumor model used, T cells and natural killer cells have been implicated in the protective immune response induced by FL. The current study examined the effects of FL administration on tumor establishment and progression in metastatic and primary tumor models to correlate anatomic location with immunotherapeutic efficacy. FL mediated significant (p < or = 0.05) therapeutic activity against pulmonary metastases of the murine MC-38 colon adenocarcinoma, particularly when cytokine administration was initiated before tumor inoculation. However, progressive intraabdominal tumors sometimes were observed even in the relative absence of pulmonary metastases. Significant, although less dramatic, antimetastatic effects were observed with MCA-205 and MCA-102 sarcomas and D5 (B16BL6) melanoma. In contrast, FL was ineffective against subcutaneous MC-38 tumors or against several intracranial tumors. This suggests that besides the administration dose, the efficacy of this cytokine depends on the tumor type and possibly the location of the inoculated tumor. Antitumor activities of FL were abolished by whole-body irradiation (500 cGy) and partially abolished by systemic depletion of CD8, CD4, or natural killer cells. The results indicate that optimization of FL immunotherapy of tumors will require a firmer understanding of the relative contributions of tumor burden, location, immune system requirements, and other factors.

Immunogenicity and therapeutic efficacy of dendritic-tumor hybrid cells generated by electrofusion.

Dendritic cells (DCs) are potent antigen-presenting cells capable of inducing strong immune responses to weak tumor-associated antigens. Among various DC-based approaches, cancer immunotherapy with DC-tumor fusion hybrids offers advantages of polyclonal stimulation of a diverse array of tumor antigens. However, prevalent fusion methods using chemical fusogens such as polyethylene glycol often result in toxicity and low fusion efficiency. In this article, we describe an electrofusion technique, applicable to processing large numbers of cells with consistent and high fusion efficiency. Generation of fusion hybrids was verified by unequivocal experimental evidence. In animal models, fusion hybrids expressed the mature DC-like phenotype. They stimulated both CD4 and CD8 tumor-specific T cells to secrete interferon-gamma in vitro. In immunotherapy, a single vaccination with DC-tumor fusion cells along with interleukin-12 as an adjuvant eradicated tumors established in the skin nd lung. These results provide an impetus for treating cancer patients with similarly generated cells.