Mary Sue Brady

Resection of metastatic renal cell carcinoma.

PURPOSE Resection of solitary metastases from renal cell carcinoma (RCC) is associated with a 5-year survival rate of 35% to 50%. Selection criteria are not well defined. PATIENTS AND METHODS We retrospectively analyzed our experience with 278 patients with recurrent RCC from 1980 to 1993. RESULTS One hundred forty-one of 278 patients underwent a curative metastectomy for their first recurrence (44% 5-year overall survival [OS] rate), 70 patients underwent noncurative surgery (14% 5-year OS rate), and 67 patients were treated nonsurgically (11% 5-year OS rate). Favorable features for survival were a disease-free interval (DFI) greater than 12 months versus 12 months or less (55% v 9% 5-year OS rate; P < .0001), solitary versus multiple sites of metastases (54% v 29% 5-year OS rate; P < .001), and age younger than 60 years (49% v 35% 5-year OS rate; P < .05). Among 94 patients with a solitary metastasis, lung (n = 50; 54% 5-year OS rate) was more favorable than brain (n = 11; 18% 5-year OS rate; P < .05). Survival rates after curative resection of second and third metastases were not different compared with initial metastectomy (46% and 44%, respectively, v 43% 5-year OS rates; P = nonsignificant). Favorable predictors of survival by multivariate analysis included a single site of first recurrence, curative resection of first metastasis, a long DFI, a solitary site of first metastasis, and a metachronous presentation with recurrence. CONCLUSION Selected patients with recurrent RCC who can undergo a curative resection of their disease have a good opportunity for long-term survival, particularly those with a single site of recurrence and/or a long DFI.

Multivariate prognostic model for patients with thick cutaneous melanoma: Importance of sentinel lymph node status

BackgroundThe overall prognosis of patients with thick cutaneous melanoma (TCM) is generally thought to be poor. Surgically staging these patients with sentinel lymph node (SLN) biopsy remains controversial. This study was performed to determine whether SLN status improved our ability to predict outcome over other known prognostic factors and to develop a model incorporating independent prognostic factors to estimate the risk of recurrence for an individual patient.MethodsA prospective database identified patients with TCM (>4.0 mm or Clark level V) and clinically negative nodes who underwent SLN biopsy. Univariate and multivariate analyses were performed.ResultsFrom 1991 to 2001, 126 patients were identified; 75 (60%) were male. The median age was 60 years. The median tumor thickness was 5.5 mm, and 43% were ulcerated. Thirty percent of patients had a positive SLN. Recurrence was seen in 50 patients (40%). Median follow-up, relapse-free survival, and overall survival were 25, 50, and 68 months, respectively. Factors independently predictive of recurrence were age ≥60 years, depth >5.5 mm, ulceration, and SLN positivity. SLN status was the most significant prognostic factor (P< .001). The relative risk of recurrence for an individual patient ranged from 1 in patients for whom no adverse factors were present to 29.4 when all factors were present.ConclusionsSLN status was the strongest independent predictor of outcome in patients with TCM. However, patients with TCM are prognostically heterogeneous, and all independently predictive factors should be considered when an individual patient’s risk of recurrence is assessed.

Sentinel Lymph Node Biopsy for Patients With Cutaneous Desmoplastic Melanoma

Background: Although desmoplastic melanoma (DM) often presents at a locally advanced stage, nodal metastases are rare. We describe our experience with lymphatic mapping and sentinel lymph node biopsy (SLNB) in patients with DM to characterize the biological behavior of these tumors.Methods: Twenty-seven patients with cutaneous DM underwent wide excision and attempted SLNB between 1996 and 2001. All pathology was reviewed by a single dermatopathologist (KB). Clinical and histological features were recorded.Results: There were 20 male and 7 female patients. The median age was 64 years (range, 35–83 years). The head and neck was the most commonly involved anatomical region (n = 14). The median Breslow thickness was 2.2 mm. Twenty-four patients underwent successful SLNB. No patient had a positive sentinel node. At a median follow-up of 27 months, five patients recurred (four systemic and one local); all five had undergone successful SLNB. Two of these patients died of disease, two are alive with disease, and one remains alive and disease free. No patient experienced failure in a regional nodal basin.Conclusions:DM is a biologically distinct form of melanoma, with a very low incidence of regional lymph node metastases, either at presentation or in long-term follow-up. This biology should be considered when designing rational treatment strategies for these patients.

Prognostic implication of sentinel lymph node biopsy in cutaneous head and neck melanoma

Current therapy for intermediate thickness melanoma involves wide local excision with sentinel lymph node biopsy (SLNB). SLNB provides important prognostic information and immediate regional lymphadenectomy for a positive sentinel lymph node (SLN) may improve survival and identifies patients who are candidates for adjuvant therapy and/or clinical trials. The head and neck site is unique because of its complex lymphatic drainage pattern to multiple nodal basins and because of the risk of site‐specific morbidity associated with regional lymphadenectomy when compared to other body sites. The goal of this study is to report the results of SLNB for head and neck cutaneous melanoma in locating the sentinel node and to report on the prognostic implications of SLNB for this cohort of patients.

Identification of distinct nanoparticles and subsets of extracellular vesicles by asymmetric flow field-flow fractionation

The heterogeneity of exosomal populations has hindered our understanding of their biogenesis, molecular composition, biodistribution and functions. By employing asymmetric flow field-flow fractionation (AF4), we identified two exosome subpopulations (large exosome vesicles, Exo-L, 90–120 nm; small exosome vesicles, Exo-S, 60–80 nm) and discovered an abundant population of non-membranous nanoparticles termed ‘exomeres’ (~35 nm). Exomere proteomic profiling revealed an enrichment in metabolic enzymes and hypoxia, microtubule and coagulation proteins as well as specific pathways, such as glycolysis and mTOR signalling. Exo-S and Exo-L contained proteins involved in endosomal function and secretion pathways, and mitotic spindle and IL-2/STAT5 signalling pathways, respectively. Exo-S, Exo-L and exomeres each had unique N-glycosylation, protein, lipid, DNA and RNA profiles and biophysical properties. These three nanoparticle subsets demonstrated diverse organ biodistribution patterns, suggesting distinct biological functions. This study demonstrates that AF4 can serve as an improved analytical tool for isolating extracellular vesicles and addressing the complexities of heterogeneous nanoparticle subpopulations.Lyden and colleagues use asymmetric flow field-flow fractionation to classify nanoparticles derived from cell lines and human samples, including previously uncharacterized large, Exo-L and small, Exo-S, exosome subsets.

Prognosis of Mucosal, Uveal, Acral, Nonacral Cutaneous, and Unknown Primary Melanoma From the Time of First Metastasis

BACKGROUND Subtypes of melanoma, such as mucosal, uveal, and acral, are believed to result in worse prognoses than nonacral cutaneous melanoma. After a diagnosis of distant metastatic disease, however, the overall survival of patients with mucosal, uveal, acral, nonacral cutaneous, and unknown primary melanoma has not been directly compared. MATERIALS AND METHODS We conducted a single-center, retrospective analysis of 3,454 patients with melanoma diagnosed with distant metastases from 2000 to 2013, identified from a prospectively maintained database. We examined melanoma subtype, date of diagnosis of distant metastases, age at diagnosis of metastasis, gender, and site of melanoma metastases. RESULTS Of the 3,454 patients (237 with mucosal, 286 with uveal, 2,292 with nonacral cutaneous, 105 with acral cutaneous, and 534 with unknown primary melanoma), 2,594 died. The median follow-up was 46.1 months. The median overall survival for those with mucosal, uveal, acral, nonacral cutaneous, and unknown primary melanoma was 9.1, 13.4, 11.4, 11.7, and 10.4 months, respectively. Patients with uveal melanoma, cutaneous melanoma (acral and nonacral), and unknown primary melanoma had similar survival, but patients with mucosal melanoma had worse survival. Patients diagnosed with metastatic melanoma in 2006-2010 and 2011-2013 had better overall survival than patients diagnosed in 2000-2005. In a multivariate model, patients with mucosal melanoma had inferior overall survival compared with patients with the other four subtypes. CONCLUSION Additional research and advocacy are needed for patients with mucosal melanoma because of their shorter overall survival in the metastatic setting. Despite distinct tumor biology, the survival was similar for those with metastatic uveal melanoma, acral, nonacral cutaneous, and unknown primary melanoma. IMPLICATIONS FOR PRACTICE Uveal, acral, and mucosal melanoma are assumed to result in a worse prognosis than nonacral cutaneous melanoma or unknown primary melanoma. No studies, however, have been conducted assessing the overall survival of patients with these melanoma subtypes starting at the time of distant metastatic disease. The present study found that patients with uveal, acral, nonacral cutaneous, and unknown primary melanoma have similar overall survival after distant metastases have been diagnosed. These findings provide information for oncologists to reconsider previously held assumptions and appropriately counsel patients. Patients with mucosal melanoma have worse overall survival and are thus a group in need of specific research and advocacy.

Primary genitourinary melanoma

OBJECTIVES To describe the presentation, management, and clinical outcome of patients with genitourinary melanoma. METHODS We identified 14 patients with genitourinary melanoma treated at Memorial Sloan-Kettering Cancer Center, New York and Tripler Army Medical Center, Honolulu, Hawaii. The presentation, surgical treatment, disease progression, and outcome of these patients were reviewed. Survival was analyzed, using the Kaplan-Meier product limit method. RESULTS The presentation and management of patients with genitourinary melanoma were varied. Overall, the prognosis was poor, with a median survival of 43 months, and only 3 patients were alive, without disease, at last follow-up. Our findings confirm a poor prognosis in patients with this rare disease. CONCLUSIONS Genitourinary melanoma is a rare form of the disease with an unfavorable clinical outcome. Less than one third of patients survive long term, although patients with scrotal melanomas may have a better prognosis.

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.

History of regional chemotherapy for cancer of the extremities

Patients with recurrent cutaneous or soft tissue malignancies of the extremity provide a unique opportunity to evaluate therapy targeted to the isolated limb. The most common clinical presentation of recurrent extremity malignancy occurs in patients with melanoma. The extremity is the site of primary melanoma in half of patients with the disease 1, and of those with a primary melanoma of Breslow depth ≥1.5 mm, 15% will develop a local or in-transit recurrence 2. Palliation of extremity disease is important in these patients, as median survival after diagnosis of in-transit or locally recurrent disease >2 years 34. Radical approaches to eradication of extremity recurrence are rarely used, although in a highly selected group of patients undergoing amputation, 42% 5-year survival was reported 5. As greater recognition of the palliative nature of extremity therapy has evolved, an emphasis on preservation of limb function has supplanted cure as a more realistic therapeutic goal. While occasional cure can be observed, it would be misleading to propose this as the likely outcome of eradication of recurrent extremity melanoma. Isolated limb perfusion (ILP) was developed as an alternative to amputation in patients with recurrent cancer of the extremity. The concept was that vascular isolation of the limb would allow delivery of higher (and potentially more effective) doses of chemotherapy to the disease in the limb than could be achieved with systemic therapy.

Randomized, placebo-controlled trial of dietary supplementation of α-tocopherol on mutagen sensitivity levels in melanoma patients: a pilot trial

We evaluated the effects of vitamin E (dl-α-tocopherol) on mutagen sensitivity levels in a randomized placebo-controlled pilot trial. In brief, a dietary supplement of 1000 mg/day vitamin E or a placebo was randomly administered for 3 months to melanoma outpatients clinically free of the disease. Plasma vitamin E and mutagen sensitivity levels were measured at baseline and at the end of the trial after 3 months. At baseline, we found no significant differences in plasma vitamin E and mutagen sensitivity levels between the two groups. We also measured dietary intake at baseline and found dietary vitamin E to be a poor predictor of plasma levels of vitamin E. After 3 months of supplementation, we found that plasma levels of α-tocopherol increased significantly (P = 0.0005) in the vitamin E compared to the placebo group. We also found a non-significant, but consistent decrease in plasma γ-tocopherol concentrations in the vitamin E supplemented compared to the placebo group. We did not find any significant difference between the vitamin E and placebo groups in mutagen sensitivity levels either at baseline or after 3 months of supplementation. We conclude that short term vitamin E supplementation, although it causes increased blood levels of α-tocopherol, does not provide protection against bleomycin-induced chromosome damage.