Bromodomain inhibition overcomes treatment resistance in distinct molecular subtypes of melanoma.

Therapy of BRAF-mutant melanoma with selective inhibitors of BRAF (BRAFi) and MEK (MEKi) represents a major clinical advance but acquired resistance to therapy has emerged as a key obstacle. To date, no clinical approaches successfully resensitize to BRAF/MEK inhibition. Here, we develop a therapeutic strategy for melanoma using bromosporine, a bromodomain inhibitor. Bromosporine (bromo) monotherapy produced significant anti-tumor effects against established melanoma cell lines and patient-derived xenografts (PDXs). Combinatorial therapy involving bromosporine and cobimetinib (bromo/cobi) showed synergistic anti-tumor effects in multiple BRAFi-resistant PDX models. The bromo/cobi combination was superior in vivo to standard BRAFi/MEKi therapy in the treatment-naive BRAF-mutant setting and to MEKi alone in the setting of immunotherapy-resistant NRAS- and NF1-mutant melanoma. RNA sequencing of xenografts treated with bromo/cobi revealed profound down-regulation of genes critical to cell division and mitotic progression. Bromo/cobi treatment resulted in marked DNA damage and cell-cycle arrest, resulting in induction of apoptosis. These studies introduce bromodomain inhibition, alone or combined with agents targeting the mitogen activated protein kinase pathway, as a rational therapeutic approach for melanoma refractory to standard targeted or immunotherapeutic approaches.

Ex Vivo and In Vivo CD46 Receptor Utilization by Species D Human Adenovirus Serotype 26 (HAdV26).

Human adenovirus serotype 26 (Ad26) is used as a gene-based vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and HIV-1. However, its primary receptor portfolio remains controversial, potentially including sialic acid, coxsackie and adenovirus receptor (CAR), integrins, and CD46. We and others have shown that Ad26 can use CD46, but these observations were questioned on the basis of the inability to cocrystallize Ad26 fiber with CD46. Recent work demonstrated that Ad26 binds CD46 with its hexon protein rather than its fiber. We examined the functional consequences of Ad26 for infection in vitro and in vivo. Ectopic expression of human CD46 on Chinese hamster ovary cells increased Ad26 infection significantly. Deletion of the complement control protein domain CCP1 or CCP2 or the serine-threonine-proline (STP) region of CD46 reduced infection. Comparing wild-type and sialic acid-deficient CHO cells, we show that the usage of CD46 is independent of its sialylation status. Ad26 transduction was increased in CD46 transgenic mice after intramuscular (i.m.) injection but not after intranasal (i.n.) administration. Ad26 transduction was 10-fold lower than Ad5 transduction after intratumoral (i.t.) injection of CD46-expressing tumors. Ad26 transduction of liver was 1,000-fold lower than that ofAd5 after intravenous (i.v.) injection. These data demonstrate the use of CD46 by Ad26 in certain situations but also show that the receptor has little consequence by other routes of administration. Finally, i.v. injection of high doses of Ad26 into CD46 mice induced release of liver enzymes into the bloodstream and reduced white blood cell counts but did not induce thrombocytopenia. This suggests that Ad26 virions do not induce direct clotting side effects seen during coronavirus disease 2019 (COVID-19) vaccination with this serotype of adenovirus. IMPORTANCE The human species D Ad26 is being investigated as a low-seroprevalence vector for oncolytic virotherapy and gene-based vaccination against HIV-1 and SARS-CoV-2. However, there is debate in the literature about its tropism and receptor utilization, which directly influence its efficiency for certain applications. This work was aimed at determining which receptor(s) this virus uses for infection and its role in virus biology, vaccine efficacy, and, importantly, vaccine safety.

Pediatric ulnar artery pseudoaneurysm of the wrist after glass laceration: A case report and systematic review of the literature.

BACKGROUND: Our purpose was to explore a case of a complicated ulnar artery pseudoaneurysm and propose an algorithm to guide physicians in this scenario. We present a case of a 5-year-old boy with a pediatric ulnar artery pseudoaneurysm that developed after a wrist laceration from broken glass 6 weeks after the initial injury. The diagnosis of pseudoaneurysm was missed, and the patient was transferred to our facility in urgent need of resection and repair due to profuse bleeding. An ultrasound confirmed the suspected diagnosis of ulnar artery aneurysm with thrombosis within the vessel. An area of skin necrosis was also present. Upon exploration of the wound, the ulnar artery pseudoaneurysm was identified and resected. The defect measured six millimeters and it was repaired primarily, under the microscope, after the proximal and distal portions were freed by dissection. The patient's incision was well healed at six-week follow-up. METHOD: A systematic literature review of the English literature on ulnar artery aneurysm was conducted on PubMed/Medline, Embase, Cochrane Clinical Answers, and Cochrane Clinical Trials, without timeframe limitations. Finally, we provide an algorithm to assist the decision-making process in similar scenarios. CONCLUSION: Although ulnar artery aneurysm is rare on a pediatric patient, it should be considered in the differential diagnosis each time a patient presents with a wrist mass. In such cases, a high index of suspicion warrants examination by a hand specialist.

Microsurgical ear replantation-is venous repair necessary?-A systematic review.

BACKGROUND: A common postoperative observation after microsurgical ear replantation has been venous congestion necessitating alternate modes of decongestion, frequently in conjunction with blood transfusion. A comprehensive literature search was performed to assess the relationship between mode of vascular reconstruction and postoperative outcome as well as postoperative transfusion requirement after microsurgical ear replantation. METHODS: The search was limited to cases of microsurgical ear replantation following complete amputation. Only articles published in English and indexed in PubMed were included. RESULTS: The initial search retrieved 285 articles, which was narrowed down to 40 articles reporting on 60 cases that matched the aforementioned criteria. Reconstruction of the arterial and venous limb (Group 1) was performed in 63.3% of patients and artery-only anastomosis (Group 2) was performed in 31.7%. Among measurable outcomes, only the duration of surgery was significantly different between groups (2.6 hours longer in Group 1 than Group 2; P = 0.0042). CONCLUSION: In light of contemporary data demonstrating successful artery-only ear replantation, replantation should not be abandoned when unable to establish venous outflow microsurgically. © 2015 Wiley Periodicals, Inc. Microsurgery 36:345-350, 2016.

The safety of and indications for immediate reconstruction of head and neck melanoma defects: our early experience.

Melanoma excision requires wide margins, leaving large defects. Surgical dogma has taught that definitive reconstruction of melanoma defects be performed after permanent pathology results, with skin grafts favored. However, this results in an open wound and the need for a second operation. The advantages of immediate reconstruction with flaps are single-stage surgery, high patient satisfaction, no period of disfigurement, and cost savings. Our purpose was to evaluate rate of positive margins and local recurrence after immediate reconstruction of head and neck melanoma (HNM) defects with flaps to determine safety of this approach. We prospectively followed all patients with HNM treated at a single center from January 2010 to June 2012 and collected patient and tumor data and reconstruction type. Outcomes assessed were permanent pathology margins and local recurrence rate. Risk factors for positive margins were assessed. Seventy-six patients with HNM were treated with wide excision and immediate flap reconstruction with a mean age of 59 years. Five patients had melanoma in situ and 71 had invasive melanoma. There was a 15.4% ulceration rate. Median thickness for invasive melanoma was 2.2 mm. Mean excision margin was 1.4 cm. Median follow-up was 2 years; 5.3% of patients had positive margins on permanent pathology after reconstruction and 3 were reexcised with negative margins. Local recurrence rate was 2.6% with no recurrence in patients with previous reexcised positive margins. Significant risk factors for positive margins were melanoma in situ excised with 5-mm margins (P=0.012) and desmoplastic melanoma (P<0.02). Immediate flap reconstruction after excision of HNM can be safely performed with low positive margin and local recurrence rates. This should be offered to patients, especially those with primary melanomas with distinct borders and excision margins greater than or equal to 1 cm.

Using an unconventional perfusion pattern in ear replantation-arterialization of the venous system.

Ear amputation is a devastating injury characterized by a conspicuous deformity that is not easily concealed and can result in tremendous psychological trauma in addition to the physical insult. While numerous different approaches have been proposed, microvascular replantation is widely considered to deliver the best esthetic outcome. In this article, the authors report a case in which an unconventional perfusion pattern (i.e., arterialization of the venous system) was chosen, as intraoperative anatomic conditions precluded conventional vascular reconstruction. A 25-year-old male patient sustained a human bite resulting in subtotal amputation of his left ear. In the setting of an adequate arterial donor vessel, that is, branch of the posterior auricular artery, and a single suitable recipient vein (0.4 mm), the decision was made to perform an end-to-end arterio-venous anastomosis without the use of vein grafts. Medicinal leeches were applied postoperatively to provide for venous drainage. The ear survived and the patient was discharged after 14 days. To the best of our knowledge, this is first case of a subtotal ear amputation that was successfully replanted by arterialization of the venous system without the use of vein grafts and with preservation of the superficial temporal vessels.

Is head and neck melanoma different from trunk and extremity melanomas with respect to sentinel lymph node status and clinical outcome?

BACKGROUND: Previous studies showed conflicting and inconsistent results regarding the effect of anatomic location of the melanoma on sentinel lymph node (SLN) positivity and/or survival. This study was conducted to evaluate and compare the effect of the anatomic locations of primary melanoma on long-term clinical outcomes. METHODS: All consecutive cutaneous melanoma patients (n=2,079) who underwent selective SLN dissection (SLND) from 1993 to 2009 in a single academic tertiary-care medical center were included. SLN positive rate, disease-free survival (DFS), and overall survival (OS) were determined. Kaplan-Meier survival, univariate, and multivariate analyses were performed to determine predictive factors for SLN status, DFS, and OS. RESULTS: Head and neck melanoma (HNM) had the lowest SLN-positive rate at 10.8% (16.8% for extremity and 19.3% for trunk; P=0.002) but had the worst 5-year DFS (P<0.0001) and 5-year OS (P<0.0001) compared with other sites. Tumor thickness (P<0.001), ulceration (P<0.001), HNM location (P=0.001), mitotic rate (P<0.001), and decreasing age (P<0.001) were independent predictive factors for SLN-positivity. HNM with T3 or T4 thickness had significantly lower SLN positive rate compared with other locations (P≤0.05). Also, on multivariate analysis, HNM location versus other anatomic sites was independently predictive of decreased DFS and OS (P<0.001). By Kaplan-Meier analysis, HNM was associated significantly with the worst DFS and OS. CONCLUSIONS: Primary melanoma anatomic location is an independent predictor of SLN status and survival. Although HNM has a decreased SLN-positivity rate, it shows a significantly increased risk of recurrence and death as compared with other sites.

Processed nerve allografts for peripheral nerve reconstruction: a multicenter study of utilization and outcomes in sensory, mixed, and motor nerve reconstructions.

PURPOSE: As alternatives to autograft become more conventional, clinical outcomes data on their effectiveness in restoring meaningful function is essential. In this study we report on the outcomes from a multicenter study on processed nerve allografts (Avance® Nerve Graft, AxoGen, Inc). PATIENTS AND METHODS: Twelve sites with 25 surgeons contributed data from 132 individual nerve injuries. Data was analyzed to determine the safety and efficacy of the nerve allograft. Sufficient data for efficacy analysis were reported in 76 injuries (49 sensory, 18 mixed, and 9 motor nerves). The mean age was 41 ± 17 (18-86) years. The mean graft length was 22 ± 11 (5-50) mm. Subgroup analysis was performed to determine the relationship to factors known to influence outcomes of nerve repair such as nerve type, gap length, patient age, time to repair, age of injury, and mechanism of injury. RESULTS: Meaningful recovery was reported in 87% of the repairs reporting quantitative data. Subgroup analysis demonstrated consistency, showing no significant differences with regard to recovery outcomes between the groups (P > 0.05 Fisher's Exact Test). No graft related adverse experiences were reported and a 5% revision rate was observed. CONCLUSION: Processed nerve allografts performed well and were found to be safe and effective in sensory, mixed and motor nerve defects between 5 and 50 mm. The outcomes for safety and meaningful recovery observed in this study compare favorably to those reported in the literature for nerve autograft and are higher than those reported for nerve conduits.

Modulating Oncolytic Adenovirus Immunotherapy by Driving Two Axes of the Immune System by Expressing 4-1BBL and CD40L.

Oncolytic viruses (OVs) can have utility for direct killing of cancer cells, but may also serve to activate the immune system against cancer cells. While viruses alone can serve as immune stimulators, there is great interest in arming OVs with genes encoding immune stimulatory proteins to amplify their effects. In this work, we have tested the efficacy of conditionally-replicating adenoviruses (CRAds) with and without selected immunostimulatory payloads, murine CD40L (mCD40L) or 4-1BBL (m4-1BBL), in an immune competent mouse model of melanoma. When CRAd657-m4-1BBL and CRAd657-mCD40L were injected into B16-hCAR murine melanoma tumors, both single vectors delayed tumor growth and prolong survival compared to empty CRAd657. However, combined injection of both CRAd-m4-1BBL and CRAd-mCD40L mediated significantly better control of tumor growth. All of the payloads increased immune cell infiltration into tumors and notably reduced expression of PD-1 exhaustion marker on T cells. Tumor volumes were negatively associated with total infiltrating T cell population. We found that the payloads increased immune cell infiltration into tumors with some specificities: recruitment of CD8+ T cells was higher with m4-1BBL expression, while mCD40L expression induced more CD4+ T cell infiltration. Importantly, the combination of CRAd657-m4-1BBL and CRAd657-mCD40L induced the highest immune cells/T cell infiltration and the highest anti-TRP-2 tumor-associated antigen T cell responses than empty or single gene vector. This combination also caused depigmentation in areas adjacent to the tumor sites in more animals. These data indicate that driving two axes of the immune system with combined immune stimulatory payloads can lead to improved anticancer immune responses and better tumor control in an immune competent model of cancer.

Comparison of replicating and nonreplicating vaccines against SARS-CoV-2.

Most gene-based severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines are nonreplicating vectors. They deliver the gene or messenger RNA to the cell to express the spike protein but do not replicate to amplify antigen production. This study tested the utility of replication in a vaccine by comparing replication-defective adenovirus (RD-Ad) and replicating single-cycle adenovirus (SC-Ad) vaccines that express the SARS-CoV-2 spike protein. SC-Ad produced 100 times more spike protein than RD-Ad and generated significantly higher antibodies against the spike protein than RD-Ad after single immunization of Ad-permissive hamsters. SC-Ad-generated antibodies climbed over 14 weeks after single immunization and persisted for more than 10 months. When the hamsters were challenged 10.5 months after single immunization, a single intranasal or intramuscular immunization with SC-Ad-Spike reduced SARS-CoV-2 viral loads and damage in the lungs and preserved body weight better than vaccination with RD-Ad-Spike. This demonstrates the utility of harnessing replication in vaccines to amplify protection against infectious diseases.

Selective sentinel lymph node dissection for melanoma: importance of harvesting nodes with lower radioactive counts without the need for blue dye.

BACKGROUND: Determining how many sentinel lymph nodes (SLNs) should be removed for melanoma is important. The purpose of this study is to determine the frequency at which nodes that are less radioactive than the "hottest" node (which is negative) are positive for melanoma, how low of a radioactivity should warrant harvest, and if isosulfan blue is necessary. METHODS: We reviewed 1,152 melanoma patients who underwent lymphoscintigraphy with technetium, with or without blue dye, and SLN dissection from 1996 to 2008. SLNs with radioactivity ≥10% of the "hottest" SLN, all blue nodes, and all suspicious nodes were removed and analyzed. The miss rate was calculated as the proportion of node positive cases in which the "hottest" SLN was negative. RESULTS: SLNs were identified in 1,520 nodal basins in 1,152 patients. SLN micrometastases were detected in 218 basins (14%) in 204 patients (18%). In 16% of SLN-positive patients (33/204 patients), the positive SLN was found to have a lower radioactive count than the "hottest" SLN, which was negative. In 21 of these cases, the positive SLNs had radioactivity ≤50% of the "hottest" SLN. The 10% rule significantly reduced the miss rate to 2.5% compared with removal of only the "hottest" SLN (miss rate = 16%). Also, blue dye did not significantly decrease the miss rate compared with radiocolloid alone using the 10% rule. CONCLUSIONS: To decrease the miss rate, all SLNs with ≥10% of the ex vivo radioactivity of the "hottest" SLN should be removed and blue dye is not essential.

Prevalence of Homologous Recombination Pathway Gene Mutations in Melanoma: Rationale for a New Targeted Therapeutic Approach.

Homologous recombination DNA damage repair (HR-DDR) deficient patients with various solid tumors have been treated with PARP inhibitors. However, the clinical characteristics of patients with melanoma who have HR-DDR gene mutations and the consequences of PARP inhibition are poorly understood. We compared the commercially available next-generation sequencing data from 84 patients with melanomas from our institution with a dataset of 1,986 patients as well as 1,088 patients profiled in cBioportal. In total, 21.4% of patients had ≥1 functional HR-DDR mutation, most commonly involving BRCA1, ARID1A, ATM, ATR, and FANCA. Concurrent NF1, BRAF, and NRAS mutations were found in 39%, 39%, and 22% of cases, respectively. HR-DDR gene mutation was associated with high tumor mutational burden and clinical response to checkpoint blockade. A higher prevalence of HR-DDR mutations was observed in the datasets from Foundation Medicine (Cambridge, CA) and those from the Cancer Genome Atlas. Treatment of HR-DDR‒mutated patient-derived xenograft models of melanoma with PARP inhibitor produced significant antitumor activity in vivo and was associated with increased apoptotic activity. RNA sequencing analysis of PARP inhibitor-treated tumors indicated alterations in the pathways involving extracellular matrix remodeling, cell adhesion, and cell-cycle progression. Melanomas with HR-DDR mutations represent a unique subset, which is more likely to benefit from checkpoint blockade and may be targeted with PARP inhibitor.

Breast reduction in the irradiated breast: evidence for the role of breast reduction at the time of lumpectomy.

Given the high incidence of breast cancer in our society, it is common to encounter patients with macromastia who desire breast reduction after breast-conserving therapy by lumpectomy and radiation. We hypothesize that radiation leads to a significant increase in postoperative complications after breast reduction. All patients with a history of unilateral breast lumpectomy and radiation who subsequently underwent bilateral breast reduction by a single surgeon from 2004 to 2008 were retrospectively reviewed. Outcomes including cellulitis, wound breakdown, seroma, and need for repeat operations were compared between the radiated and nonradiated breast. The Fisher's exact test was used for statistical analysis. Twelve patients (mean age, 57 years) underwent bilateral breast reduction a mean of 86 months after unilateral lumpectomy and radiation. The nonradiated breasts had no complications postoperatively. The radiated breasts had a significant increase in complications with a total of five breasts (42%, p<0.04) having postoperative complications including cellulitis in two breasts, seroma requiring drainage in five breasts, two cases of fat necrosis, and one case of wound dehiscence. This resulted in two admissions for intravenous antibiotics and two repeat operative procedures. Additionally, three patients had significant breast asymmetry or contour deformities after reduction requiring operative revisions. Breast reduction after radiation leads to a significant increase in complications. Given this data, patients with macromastia undergoing breast conservation therapy for cancer should be considered for reduction at the time of lumpectomy and prior to radiation.

The contralateral rectus abdominis musculocutaneous flap for treatment of lower extremity lymphedema.

Lymphedema is common after inguinal lymphadenectomy or resection of groin tumors. Animal studies have shown success using the rectus abdominis musculocutaneous (RAM) flap as a treatment for lymphedema. Four patients with acquired lower extremity lymphedema were treated with a contralateral RAM flap with an inferior cutaneous pedicle left intact to facilitate lymphatic drainage into the unaffected groin. One patient also had lymphaticovenous anastomoses performed during flap transfer. All flaps survived with no postoperative complications. With a mean follow-up of 31 months, the mean reduction in limb circumference from the preoperative excess was 81% at the thigh, 70% at the calf, and 71% at the ankle. None of the patients with recurrent cellulitis had further incidences of groin cellulitis. Two patients required future flap debulking. Lymphoscintigraphy was performed in 1 patient and demonstrated reconstitution of lymphatic flow from the affected leg through the flap. According to this preliminary study, transfer of a contralateral RAM flap to the groin of a lymphedematous leg improves lymphedema and decreases the incidence of cellulitis.

The subcutaneous cervicofacial flap revisited.

The cervicofacial flap has been the reconstruction of choice for midface soft tissue defects for over 30 years. Deep plane dissection has been advocated to decrease complication rates and improve results. However, the subcutaneous approach is still widely used. Over a 20-year period, we reviewed all patients who underwent subcutaneous cervicofacial flaps for cheek defects to analyze complications and results.Thirty-two patients (mean age, 71 years) underwent 32 subcutaneous cervicofacial flaps for cheek reconstruction after Mohs micrographic excision of skin cancer. The mean defect size was 7.2 x 5.8 cm. Mean follow-up was 32 months. Only 3 of 32 patients (9%) had minor flap tip or edge necrosis, all managed without further surgery. One patient (3%) had minor long-term ectropion with upward gaze and 31 of 32 patients were happy with their results.The subcutaneous rotation-advancement cervicofacial flap remains an excellent choice for cheek reconstruction with comparable tip necrosis rates and likely lower ectropion rates when compared with the deep plane technique.

The phrenic nerve as a motor nerve donor for facial reanimation with the free latissimus dorsi muscle.

Free functional muscle transfer for acquired facial paralysis most often involves two stages. In this report, we describe single-stage free muscle transfer using the phrenic nerve as the donor motor nerve. Six patients with unilateral facial paralysis underwent single-stage facial reanimation using a free latissimus dorsi muscle with the ipsilateral phrenic nerve as the donor nerve. These cases were retrospectively studied to review technique and to determine outcomes including time to muscle reinnervation, patient satisfaction, smile symmetry, and complications. The mean age was 33 years. Five patients had complete unilateral facial paralysis and one had incomplete. There was no flap loss. The transferred muscle demonstrated active contraction in all patients at a mean of 14 weeks postoperatively (range, 12 to 16 weeks). Good dynamic symmetry was achieved by 6 to 9 months in all patients. All patients underwent rehabilitation including nerve reeducation. No clinically significant pulmonary morbidity was observed after the unilateral transection of the phrenic nerve. Using the phrenic nerve in free muscle transfer for facial paralysis allows a single-stage procedure with no requirement for nerve grafting and a rapid reinnervation time, shortening the time required for restoring facial animation.

Pulsed dye laser therapy and z-plasty for facial burn scars: the alternative to excision.

Hypertrophic scarring after partial thickness facial burns is common when epithelialization takes longer than 3 weeks. Well-healed areas continue to mature unfavorably, resulting in raised, erythematous, and contracted scars. Excisional treatment of such scars has morbidity and can create iatrogenic deformities. The flashlamp-pumped, pulsed dye laser (PDL) in combination with z-plasty can be used as a successful alternative to excision in patients with facial hypertrophic burn scars. Fifty-seven patients with hypertrophic facial burn scars (mean age 12 years; range, 2-21 years) were treated with the PDL over the past 8 years. Thirty-four patients (60%) were also treated with z-plasties to relieve scar tension. There was one complication of postoperative blistering. Patients were divided into 3 groups based on time from burn to initial laser treatment. Group I (<1 year) had 11 patients and the laser diminished scar proliferation in these patients. Group II (1-4 years) included 24 patients and treatment resulted in reversal of hypertrophic scarring and elimination of erythema. Group III (>5 years) consisted of 22 patients. The PDL was effective in treating their stable and persistent erythema as long as 17 years after burn injury. No scars required excision in this cohort of 57 patients. The PDL should become an integral part of the management of facial burn scarring and will significantly decrease the need for excisional surgery.

Selective Sentinel Lymph Node Dissection in Lower Extremity Melanoma.

BACKGROUND: There is debate as to whether deep inguinal lymph nodes should be removed with the superficial or femoral lymph nodes during sentinel lymph node biopsy for lower extremity melanoma, when both superficial and deep inguinal lymph nodes are identified by preoperative lymphoscintigraphy. This study evaluated the lymphatic drainage patterns in lower extremity melanoma to determine whether certain patterns could be used to limit the level of node removal and define the extent of dissection. METHODS: A retrospective outcomes review was performed of lower extremity melanoma patients with excision and sentinel lymph node biopsy from 1995 to 2010. Outcomes included location of sentinel lymph node drainage basins, sentinel lymph node-positivity, and disease-free and overall survival, with drainage patterns compared between above- and below-knee melanomas. RESULTS: Of 499 patients with lower extremity melanoma having sentinel lymph node biopsy, 356 had below-the-knee and 143 had above-the-knee melanoma. For below-knee melanoma, the node-positivity rate was 23 percent (63 of 271) for superficial inguinal, 0 percent (zero of three) for deep inguinal, and 50 percent (one of two) for popliteal basins. For above-knee melanoma, the positivity rate was 21 percent (24 of 113) for superficial inguinal, 33 percent (one of three) for deep inguinal basins, and 0 percent (zero of zero) for popliteal basins. Importantly, no patients with a negative superficial inguinal sentinel lymph node had a positive deep inguinal sentinel lymph node on final pathologic evaluation [corrected]. CONCLUSIONS: A difference was noted in patterns of sentinel lymph node drainage from lower extremity melanoma below and above the knee. Biopsy for deep inguinal basins may be deferred if there is simultaneous drainage to the superficial inguinal basin by preoperative lymphoscintigraphy. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, II.

Long-term results and costs of muscle flap coverage with Ilizarov bone transport in lower limb salvage.

OBJECTIVES: To determine long-term outcomes and costs of Ilizarov bone transport and flap coverage for lower limb salvage. DESIGN: Case series with retrospective review of outcomes with at least 6-year follow-up. SETTING: Academic tertiary care medical center. PATIENTS: Thirty-four consecutive patients with traumatic lower extremity wounds and tibial defects who were recommended amputation but instead underwent complex limb salvage from 1993 to 2005. INTERVENTION: Flap reconstruction and Ilizarov bone transport. MAIN OUTCOME MEASUREMENTS: Outcomes assessed were flap complications, infection, union, malunion, need for chronic narcotics, ambulation status, employment status, and need for reoperations. A cost analysis was performed comparing this treatment modality to amputation. RESULTS: Thirty-four patients (mean age: 40 years) were included with 14 acute Gustilo IIIB/C defects and 20 chronic tibial defects (nonunion with osteomyelitis). Thirty-five muscle flaps were performed with 1 flap loss (2.9%). The mean tibial bone defect was 8.7 cm, mean duration of bone transport was 10.8 months, and mean follow-up was 11 years. Primary nonunion rate at the docking site was 8.8% and malunion rate was 5.9%. All patients achieved final union with no cases of recurrent osteomyelitis. No patients underwent future amputations, 29% required reoperations, 97% were ambulating without assistance, 85% were working full time, and only 5.9% required chronic narcotics. Mean lifetime cost per patient per year after limb salvage was significantly less than the published cost for amputation. CONCLUSIONS: The long-term results and costs of bone transport and flap coverage strongly support complex limb salvage in this patient population.

Long-term prognosis and significance of the sentinel lymph node in head and neck melanoma.

OBJECTIVE: To report the long-term significance of sentinel lymph node (SLN) biopsy on prognosis, determine false-negative SLN occurrences, and determine risk factors for death and recurrence in a large series of patients with head and neck melanoma. STUDY DESIGN: Case series with tumor registry review. SETTING: Academic tertiary care medical center. SUBJECTS AND METHODS: A database review was performed of all patients who underwent SLN biopsy for head and neck melanoma from 1994 to 2009. End points assessed were SLN status, recurrence, false-negative SLN results, and survival comparing SLN-positive and SLN-negative patients and different locations. Survival curves and multivariate analyses were performed. RESULTS: SLN biopsy was performed in 365 patients. SLNs were identified in 98.6% of patients with a mean of 3.7 nodes removed from 1.6 nodal basins per patient. Median follow-up was 8 years. The SLN was positive in 40 (11%) patients. SLN-positive patients had significantly thicker melanomas, higher recurrence (P < .0001), and a significant decrease in overall survival compared with SLN-negative patients (P < .002). Scalp melanoma patients had significantly thicker melanomas and an elevated risk of SLN positivity, recurrence, and death compared with other sites. Seventeen of 365 SLN-negative patients developed regional nodal disease for a false-omission rate of 5.2% and a negative predictive value of a negative SLN to be 94.8%. Risks for false negative-SLN occurrences included thick melanomas and scalp melanomas. CONCLUSION: SLN biopsy is accurate in head and neck melanoma and provides significant prognostic data. Scalp melanoma patients present with thicker tumors with an increase in SLN positivity and false-negative SLN occurrences.