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.

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.

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.

The effect of delay time between primary melanoma biopsy and sentinel lymph node dissection on sentinel node status, recurrence, and survival.

For primary melanoma, there is a delay between the initial skin biopsy and sentinel lymph node dissection, which may cause anxiety for the patient. The consequences of this delay on disease progression are unknown. The goal of this study was to determine whether delay time for sentinel node dissection from the initial cutaneous melanoma biopsy affects patient outcomes. A retrospective analysis of 492 patients with melanoma who underwent a sentinel node dissection between 1993 and 1999 was carried out. The endpoints assessed were sentinel node tumor status, recurrence, and mortality. Time to sentinel node dissection was compared between patients with positive and negative sentinel nodes. Long-term survival and recurrence were evaluated in relation to the time between the cutaneous biopsy and the sentinel node dissection (delay time), comparing less than 40 days with at least 40 days. In total, 15.9% of patients had positive sentinel nodes. The median follow-up was 11.7 years. Positive sentinel node patients had a median delay of 35 days between the primary melanoma biopsy and the sentinel node dissection compared with 41 days for negative sentinel node patients (P=0.5). Kaplan-Meier survival curves showed that a delay time of less than 40 days versus at least 40 days was not related to recurrence of melanoma (log-rank P=0.13) or overall survival (log-rank P=0.14). On multivariate analysis of age, thickness, ulceration, and sentinel node status, there was no difference in disease-free survival (P=0.58) or overall survival (P=0.53) between the less than 40 days and the at least 40 days groups. A modest delay in sentinel node dissection from the initial melanoma biopsy does not adversely affect sentinel node status, recurrence, nor survival.

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.

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.

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.

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.

Refining outcomes in dorsal hand coverage: consideration of aesthetics and donor-site morbidity.

BACKGROUND: With high success rates, flap survival should no longer be the sole criterion in judging success in dorsal hand and wrist reconstruction. The authors sought to determine the best flap for dorsal hand coverage in terms of aesthetic appearance, donor-site morbidity, and minimization of revision surgery. METHODS: A retrospective review of all free flaps for dorsal hand and wrist coverage from 2002 to 2008 was performed. Flaps were divided into four groups: muscle, fasciocutaneous, fascial, and venous flaps. Outcomes assessed included need for debulking, blinded grading of aesthetic outcomes, and flap and donor-site complications. RESULTS: A total of 125 flaps were performed with no flap losses. There was no difference in partial loss or infection among the different flap groups. There was a significant range in the need for future debulking procedures, with debulking required in 67 percent of fasciocutaneous, 32 percent of muscle, 5.8 percent of fascial, and 0 percent of venous flaps. There was a significant difference in aesthetic outcomes: venous flaps had the best overall aesthetic outcomes; fascia and muscle flaps scored equally in terms of overall aesthetics, color, and contour match; and fasciocutaneous flaps had significantly worse aesthetic, contour, and color match results compared with all other flap types. Fasciocutaneous flaps had greater donor-site morbidity in terms of need for skin grafting and wound breakdown. CONCLUSION: The aesthetic outcome of dorsal hand reconstruction is dependent on flap choice, with statistically significant differences in revision surgeries and aesthetics among flap types.

Sepsis after autologous fat grafting.

Autologous fat grafting is an increasingly popular technique, with numerous examples of excellent results. Adherence to key principles, including sterile technique and low-volume injection throughout layers of tissue, appears to be critical to obtaining good results. Reports of adverse outcomes are infrequent, but several case reports document both infectious and aesthetic complications. This case report represents an extreme complication, including abscess formation, life-threatening sepsis, and residual deformity. It serves as yet another reminder that early adoption of surgical procedures by those without a sound understanding of the underlying principles and techniques can have disastrous consequences. Furthermore, physicians operating on any patient must understand the potential for complications and be able to manage these appropriately when they occur.

Reconstrucción de extremidad inferior / Reconstruction of the lower extremity

La reconstrucción de la extremidad inferior es parte esencial de la cirugía plástica y se concentra en el tratamiento de heridas y defectos causados por trauma, cáncer, o procesos de enfermedades crónicas. Durante los últimos 25 años, los avances en técnicas de cirugía plástica tales como latransferencia libre de tejidos tecnologías más avanzadas de cuidado de heridas han revolucionado este campo, permitiendo salvar extremidades que de otro modo habrían sido amputadas. Este documento analizará el campo de la reconstrucción de extremidades inferiores concentrándose en la evaluación de defectos y heridas de pierna y las variadas opciones de tratamiento.

Pulsed dye laser in burn scars: current concepts and future directions.

Hypertrophic scarring after partial-thickness burns is common, resulting in raised, erythematous, pruritic, and contracted scars. Treatment of hypertrophic scars, especially on the face, is challenging and has high failure rates. Excisional treatment has morbidity and can create iatrogenic deformities. After an extensive experience over 10 years with laser therapy for the treatment of difficult scars, the pulsed dye laser (PDL) has emerged as a successful alternative to excision in patients with hypertrophic burn scars. Multiple studies have shown its ability to decrease scar erythema and thickness while significantly decreasing pruritus and improving the cosmetic appearance of the scar. The history of laser therapy and the mechanism of action and results of the PDL in burn scars will be reviewed. The PDL should become an integral part of the management of burn scarring and will significantly decrease the need for excisional surgery.

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.

A review of local and regional flaps for distal leg reconstruction.

Reconstruction of defects or wounds of the distal third of the leg with exposed bone, tendon, or hardware is challenging. Free tissue transfer has allowed limb salvage in many cases but requires a relatively healthy and stable patient, long operative times, and a significant expense. Small and moderate-size wounds of the distal leg may be better served by the use of local and regional flaps. Due to a better understanding of leg vascular anatomy and angiosomes, as well as more sophisticated and varied flap designs, local and regional flaps have been described and successfully used in distal leg wounds. The goal is choosing the most appropriate flap given the patient's anatomy and wound characteristics. The following review will detail the available local and regional flaps for reconstruction of the distal third of the leg with an emphasis on decision making, anatomy, flap design, and technique.

An algorithm for treatment of nasal defects.

Nasal defects are common after cancer resection, and the goal of treatment is to appropriately define the defect and then to select the best reconstructive options. The plastic surgeon must reestablish all deficient layers of the nose (support, lining, and external cover). The authors' algorithm is based on defect location and orientation, with the nose divided transversely into three zones, and then into subunits. In this article, using the aforementioned algorithm, the authors simplify the complex topic of nasal reconstruction, concentrating on local and regional flap reconstruction. The appropriate treatment for full-thickness defects, including options for reconstruction of lining and support, is also discussed.

Risk analysis for the reverse sural fasciocutaneous flap in distal leg reconstruction.

BACKGROUND: The reverse sural fasciocutaneous flap provides the potential for simple and efficient closure of distal leg, ankle, and foot defects. In young patients with traumatic injuries, low complication rates have been reported. The authors hypothesize that extending its use to older patients with comorbidities results in a higher complication rate. METHODS: The authors retrospectively reviewed 58 consecutive reverse sural fasciocutaneous flap in 57 patients for distal leg reconstruction. Outcomes were compared between patients with no comorbidities (n = 31) and those with a history of smoking, diabetes mellitus, or peripheral arterial disease (n = 26). Standard statistical analyses were performed, including logistic regression. RESULTS: Patients had a mean age of 53 years and a median follow-up of 20 months. Fifty percent of flaps had postoperative complications, with nine (16 percent) major complications (three total flap losses and six partial losses), 17 (29 percent) minor complications, and three infections. In patients without comorbidities, there were no major complications and five minor complications (16 percent). Significantly higher major and minor complication rates were seen in older patients and patients with a history of smoking, obesity, diabetes, or peripheral arterial disease. Multivariate regression analysis identified smoking as the risk factor most independently associated with any reverse sural fasciocutaneous flap complication. Importantly, surgical delay procedures were associated with decreased ischemic flap complications in patients with comorbidities. CONCLUSIONS: Although the reverse sural fasciocutaneous flap is reliable in young healthy patients, it has significant complication rates in patients with comorbidities, especially smokers. In such patients, the reverse sural fasciocutaneous flap requires multiple operative revisions and a surgical delay should be considered.