BACKGROUND:Neoadjuvant therapy with immune checkpoint inhibitors (ICIs) is increasingly used in advanced or recurrent melanoma based on outcomes observed in clinical trials. The efficacy and toxicity of this in a real-world setting remain unclear. STUDY DESIGN:We conducted a retrospective review of adults with cutaneous melanoma who received neoadjuvant ICI as first line therapy at our institution between 2019 and 2024. Patients had advanced melanoma that was surgically resectable and treated with neoadjuvant intent. The primary outcome was pathological response, with a secondary outcome of immune-related toxicity. RESULTS:In total, 81 patients were identified. The median age was 64 (range: 21-86). There were 48 males. Most patients received 2 cycles (n = 53) prior to resection (range: 1-7 cycles). Dual ICI was the most common approach (n = 62). Disease stage ranged from IIC to IV, with 57% IIIC. Half were pathologic non-responders (n = 41). Pathologic complete response (pCR) was seen in 25% (n = 20), near-pCR in 2% (n = 2) and partial PR in 10% (n = 8). Ten (12%) patients had a discrepant PR between two or more resected sites. Immune related adverse events were observed in 34 (42%) patients; 21 (26%) grade 1-2, and 13 (16%) grade 3-4. Overall survival trended towards significance (p = 0.07) for those with mPR. CONCLUSIONS:Non-trial use of neoadjuvant ICI therapy is associated with a less favourable pathological response than reported in clinical trials and similar risks of toxicity.

INTRODUCTION:Ventral hernia repair in oncologic patients is challenging due to poor tissue quality, immunosuppression, malnutrition, and prior operations. Limited data exists comparing the outcomes of biosynthetic (Poly-4-hydroxybutyrate) and synthetic mesh in this population. This study aims to assess the outcomes in patients who undergo hernia repair using one of two mesh types. METHODS:Patients undergoing ventral hernia repair by the Plastic and Reconstructive Surgery service and general surgery after oncologic resection from 2010 to 2023 were included, with patient records reviewed and cases identified in a prospectively maintained database by the Plastic and Reconstructive Service. Repairs were done in a retrorectus, underlay, or onlay fashion with either biosynthetic or synthetic mesh. Primary endpoints included complication rates (hematoma, infection/cellulitis, wound dehiscence, abscess, seroma) and hernia recurrence. RESULTS:207 patients underwent repair (102 biosynthetic, 105 synthetic) and were included. Baseline demographics were similar between groups. No significant difference was observed in complication rates (biosynthetic: 24%, synthetic: 18%; p=0.3). Hernia recurrence was noted in 8.8% of biosynthetic and 6.7% of synthetic mesh cases (p>0.6). Subgroup analysis of wound classes II-IV showed consistent results. Up to two years postoperatively, synthetic mesh did not significantly reduce hernia recurrence risk compared to biosynthetic mesh (Subdistribution Hazard Ratio (sHR): 0.66; 95% CI, 0.27-1.59; p=0.4). Bilateral external abdominal oblique release (sHR: 0.31; 95% CI, 0.11-0.87, p=0.026) and retromuscular mesh placement (sHR: 0.08; 95% CI, 0.02, 0.35, p<0.001) exhibited a protective role. CONCLUSION:Biosynthetic mesh can be considered a reasonable alternative to synthetic mesh in this high-risk population.

9557 Background: While inpatient toxicity associated with tumor infiltrating lymphocyte (TIL) therapy and IL-2 administration is well characterized, risks facing patients after hospital discharge are less understood. Better characterization of outpatient adverse effects (AEs) could guide the optimal frequency and duration of follow up for this growing patient population. Methods: We conducted a retrospective analysis of all patients with advanced melanoma discharged from Memorial Sloan Kettering Cancer Center after receiving investigational or commercial lifileucel from October 2020 to October 2024. We reviewed incidence and timing of new Grade 3+ treatment-related AEs (TRAEs), blood product administration, and readmission among all patients from the time of hospital discharge to the time of the start of a subsequent systemic therapy or death. Results: Fifty-three patients successfully discharged after lifileucel administration were identified; patient demographics are included in Table 1 . The median follow up time from discharge in survivors was 5 months (interquartile range (IQR): 3, 18). Two patients (4%) developed new Grade 3+ TRAEs following hospital discharge, including new Grade 3 neutropenia 73 days after discharge and new Grade 3 hypoxia 104 days from discharge. Hypoxia was secondary to pleural effusions that developed in the setting of renal thrombotic microangiopathy. Four patients (7.5%) were readmitted for TRAEs including cytopenias, dyspnea, and syncope while 7 patients (13%) were readmitted for melanoma progression. Readmissions occurred a median of 85 (IQR: 39, 128) days after lifileucel infusion and 69 days (IQR: 19, 98) after initial discharge. Twelve patients (23%) received at least one outpatient blood product transfusion, including packed red blood cells (PRBCs; 10 patients) and platelets (6 patients). Within 30 days of initial discharge, six patients (11%) received at least one PRBC transfusion and 3 patients (5.7%) received at least one platelet transfusion. The median number of transfused PRBC units was 2 (IQR: 1,4) and the median number of platelet transfusions was 4 (IQR: 2, 4). Conclusions: Rates of new severe toxicity and treatment-related readmissions were low among patients discharged post-lifileucel. About one in four patients required blood products after discharge. Identification of risk factors for the development of outpatient TRAEs may inform personalized care following lifileucel administration. Patient demographics. Characteristic N = 53 1 Age at TIL infusion 61 (42, 66) Sex Male 29 (55%) Female 24 (45%) Melanoma subtype Cutaneous 19 (36%) Uveal 9 (17%) Acral 8 (15%) Unknown primary 8 (15%) Mucosal 5 (9.4%) Other 4 (7.5%) BRAF status Mutated 13/51 (25%) Wild type 38/51 (75%) Treatment setting Investigational 45 (85%) Standard of care 8 (15%) 1. N (%); Median (interquartile range).

Hernia repair following cancer surgery is often challenging due to prior radiation therapy, malnutrition, and immunosuppression. Poly-4-hydroxybutyrate (P4HB) is a biosynthetic mesh that balances strength and biocompatibility, potentially optimizing outcomes in this high-risk population. This study aimed to evaluate recurrence and surgical site complications associated with P4HB mesh in oncologic patients undergoing incisional hernia repair and to identify surgical techniques related to improved outcomes. Patients with previous oncologic abdominal or pelvic surgery who developed an incisional hernia and underwent surgical repair using P4HB from January 2018 to December 2023 were identified. Patients were analyzed according to wound classification. Primary outcomes included hernia recurrence and surgical site complications (hematoma, infection/cellulitis, superficial wound dehiscence, and abscess formation). 102 patients [median (IQR) age 63 (55–69) years; median BMI 26 (23–30) kg/m2] were included, with a median follow-up of 26.1 (15.1–40.1) months. The overall recurrence rate was 8.8

INTRODUCTION:Merkel cell carcinoma (MCC) is an uncommon neuroendocrine cutaneous malignancy considered to have a high risk of local recurrence (LR). We investigated the true risk of LR in patients with MCC treated by surgical excision alone. PATIENTS AND METHODS:Patients with clinically localized MCC excised with pathologically negative surgical margins were identified from a prospectively maintained single-institution database from November 1980 through December 2022. The cumulative incidence of LR, defined as recurrence within 5 cm of the surgical scar, was estimated using death as a competing event. RESULTS:Among 447 patients, 393 (88%) were treated with surgery alone, and 54 (12%) also received adjuvant radiotherapy (RT) to the primary site. LR occurred in eight patients, with seven recurrences detected within 12 months of treatment. All recurrences occurred in patients treated with surgery alone for a 1-year LR rate of 1.8% (95% confidence interval [CI] 0.8-3.6%). At a median follow-up of 8.8 years (95% CI 7.6-10) from presentation, of the six patients with LR alone, all treated with surgery and/or RT, four patients had no evidence of disease and two died of other causes. Two patients developed distant metastases at the time of LR; both received systemic therapy and died of disease. The low incidence of LR precluded analysis of risk factors. CONCLUSIONS:Negative-margin surgery without adjuvant RT provides excellent local control, with an LR rate of 1.8%. LR was effectively treated with surgery and/or RT. These data do not support the routine use of adjuvant RT for all patients after complete excision of primary MCC.

The treatment of metastatic melanoma has been revolutionized with the introduction of immune checkpoint inhibitors, though approximately 50% of patients will progress at 12 months even with the most robust immunotherapy combinations. As these drugs are now first-line treatment for advanced melanoma, it is imperative to define the role and benefits of multimodal therapy adjunct to systemic therapy. This case describes a patient with v-Raf murine sarcoma viral oncogene homolog B (BRAF) mutant stage IV melanoma who has been treated for over 9 years with a combination of systemic and local therapeutics: anti-Cytotoxic T-lymphocyte associated protein 4 (CTLA4), anti-programmed cell death protein 1 receptor (PD1), and targeted therapies, stereotactic radiosurgery, and multiple metastasectomies. Through multidisciplinary care with the help of genomic analysis, this patent’s survival has been extended far past conventional estimates. Molecular profiling revealed an acquired NRAS mutation, which helped explain clinical findings and allowed for a more tailored therapeutic regimen. This report demonstrates that effective surgical resection of nonresponding or progressing lesions can lead to long-term survival even in patients with severe disease burden. Continuous clinical and molecular monitoring can also help shape patients’ treatment courses. The effectiveness of multimodal treatment, incorporating local therapies with molecular profiling in conjunction with systemic therapies, should be considered by interdisciplinary care teams to strive for durable survival in patients with historically grim prognoses.

Merkel cell carcinoma (MCC) is a rare, cutaneous malignancy with a propensity for nodal metastasis, for which prognostic factors remain poorly characterized. All patients treated from April 1996 through December 2022 by wide excision and sentinel lymph node (SLN) biopsy for clinically localized MCC at a single institution were included. Logistic regression was used to evaluate factors associated with a positive SLN, recurrence, and disease-specific death (DSD). Cumulative incidence functions estimated recurrence and DSD with death from other causes as a competing risk. Of 342 patients with MCC, 140 (41

9513 Background: Neoadjuvant (neoadj) immune checkpoint blockade (ICB) is standard of care for patients (pts) with resectable stage III/IV melanoma. A single ICB dose induces substantial peripheral immune activation and 1 dose of neoadj pembrolizumab has promising activity. The efficacy of 1 dose of combination ICB is unknown and clinically important to describe given the toxicity of sequential combination ICB. Methods: In this phase II single-arm trial, pts with resectable stage IIIB-IV melanoma received 1 dose of neoadj nivolumab (nivo) 1mg/kg and ipilimumab (ipi) 3mg/kg 4 weeks prior to resection. The primary endpoint is major pathologic response (MPR), defined as pathologic complete response (pCR) or near CR (≤10% viable tumor). Using a Simon minimax two-stage design, MPR < 30% is deemed not promising and > 50% promising; positive if >12 MPR in 28 pts. Secondary endpoints were response rate (RECIST 1.1), recurrence free survival (RFS), and safety. CD8-PET imaging was done pre-ICB and pre-surgery, using 89 Zr-radiolabeled crefmirlimab to evaluate association with MPR. Autoradiography and CD8 cell infiltrate by IHC were used to verify the on-target binding of crefmirlimab in surgical specimens. Results: Stage I successfully met the interim efficacy threshold with 5 of 12 pts demonstrating an MPR, thus advancing to stage II. Here we report interim results of the 19 pts enrolled by data cut-off 01/02/2025. Baseline stages were IIIB (53%, n = 10), IIIC (42%, n = 8) and IV (5%, n = 1); 80% cutaneous, 10% acral and 10% unknown primary melanoma. An MPR was observed in 53% (95% CI: 29,76) of pts (n = 10, 7 pCR, 3 near pCR), partial pathologic response (PR) in 21% (n = 4), and non-response in 26% (n = 5). Of the 18 evaluable, RECIST response was 28% (n = 5, all PR), 61% (n = 11) had stable disease, and 11% (n = 2) progressive disease (PD). The rate of grade >3 treatment-related adverse events (TRAE), in neoadj and adjuvant setting, was 11% (n = 2); 1 pt was hospitalized with adrenal insufficiency, no grade 5 events occurred on study. All pts proceeded to surgery with median time to surgery of 29 days (IQR 26,31). 14 pts (74%) received adjuvant therapy; 13 anti-PD-1 and 1 BRAF targeted therapy. Median follow-up was 16 months (IQR 8;23) and 12-month RFS from surgery was 91% (95% CI: 75, 100). Of the 3 pts with recurrent or progressive disease; 0 had an MPR and 2 died from progressive melanoma. CD8-PET was completed in 19 pts pre-ICB and 17 pts pre-surgery. SUVmax pre-ICB, pre-surgery and the percent change over-time was not significantly associated with MPR. CD8-PET tracer evaluation by autoradiography correlated with CD8+ cell infiltrate on IHC by pathologist assessment. Conclusions: C-IT-Neo is the first study evaluating a single dose of combination ICB in the neoadjuvant setting. Interim results show one dose has low grade 3+ TRAE and high efficacy with MPR of 53%. The trial is actively enrolling, with ongoing analysis of CD8-PET imaging and immune biomarkers. Clinical trial information: NCT05289193 .

9563 Background: Patients undergoing surgical resection of Stage III/IV melanoma after response to ICIs show favorable survival, particularly with pathologic complete response (pCR). However, long-term outcomes of such patients stratified by ICI response remain undescribed. As surgery is increasingly employed in both PD-1 sensitive and refractory settings (e.g. tumor-infiltrating lymphocytes (TIL) therapy), better-defined outcomes and a clearer understanding of surgery's role are much needed. Methods: Patients treated with ICI (2003-2023) followed by metastasectomy were identified from a prospectively maintained database. Pre-surgery ICI response was assessed radiographically, and patients were categorized as having either stable/responding disease (R), an isolated site of disease progression (IP), or multiple progressing sites of disease (MP) for which surgery was pursued due to acute symptoms or palliative intent. Clinicopathologic factors examined included response to ICI, resection to no evidence of disease (NED), and pCR. Kaplan-Meier analyses with log-rank tests were used to compare disease-specific survival (DSS) from surgery date. Cox proportional hazards models identified independent predictors of DSS. Results: Among 513 patients, 426 (83%) had stage IV and 87 (17%) had stage III disease at ICI initiation. Patients were categorized as either R (n=76), IP (n=227), or MP (n=210). Fifty-three percent of patients received subsequent systemic therapy including 20 TIL patients, 12 of whom were in the MP group. Median follow-up after surgery among survivors was 2.51 years (IQR 0.93, 6.72). Median DSS following surgery was 4.1 years (95% CI: 2.5, NR). Resection to NED at the first operation post-ICI (n = 202, 39%) was associated with improved 5-year DSS [81% (75%, 88%) vs. 26% (20%, 33%); p < 0.001], with similar findings in only Stage IV patients (n = 426) [75% (67%, 84%) vs. 24% (19%, 32%); p<0.001]. Patients who underwent resection for an R or IP tumor had a 5-yr DSS of 89% (80%, 98%) or 62% (55%, 70%), respectively, compared to 20% (14%, 28%) for MP lesions (p < 0.001). Independent predictors of DSS also included NED resection and pCR (Table 1). Conclusions: Disease control after metastasectomy following ICI is durable, especially in patients with responding, stable, or isolated progressing disease, in addition to those achieving resection to NED or pCR. Alternative therapeutic strategies should be considered for patients with MP tumors as DSS remains poor after surgery alone. Multivariate model of DSS. p-value HR [95% CI] NED Status <0.001 0.31 [0.20, 0.49] Pre-operative Neutrophil-Lymphocyte Ratio 0.014 1.02 [1.01, 1.04] Response to ICI (R, IP, MP) <0.001 1.31 [0.65, 2.65] (R v. IP) 2.75 [1.35, 5.63] (R v. MP) pCR Status <0.001 0.22 [0.08, 0.65] Surgery Site 0.074 1.33 [0.97,1.83] Time from ICI Initiation to Surgery 0.006 0.85 [0.76, 0.97] M Stage 0.003 2.01 [1.21, 3.34]

This review explores T-cell immunotherapy for melanoma, highlighting immune checkpoint inhibitors (anti-CTLA-4, anti-PD-1, anti-LAG-3), tumor-infiltrating lymphocytes (TILs), and emerging therapies that engineer T cells with specific receptors or T-cell receptors, such as CAR-T and TCR cells, and RNA vaccines. We discuss the history of T-cell immunotherapy, mechanisms of action, and future directions for improving patient outcomes.

While CD40 agonism is an attractive approach for activating antigen-presenting cells and initiating antitumor responses, previous attempts have encountered limited clinical efficacy coupled with toxicity. We previously demonstrated that interactions between the antibody Fc domain and the inhibitory receptor FcγRIIB are critical for enhanced antitumor activity. Here, we present the results of a phase 1 study on intratumoral administration of an anti-CD40 agonistic antibody (2141-V11) Fc-engineered to enhance FcγRIIB binding. Primary endpoints included safety, maximum tolerated dose (MTD), and recommended phase 2 dose. Secondary objectives included preliminary clinical activity and correlative studies from biospecimens. 2141-V11 was well-tolerated without dose-limiting toxicities and MTD was not reached. In ten evaluable patients with metastatic cancer, the overall response rate was 20%, with complete responses in two patients (melanoma and breast carcinoma) and stable disease in six patients. 2141-V11 induced tumor regression in injected and non-injected lesions, with increased leukocyte infiltration and tertiary lymphoid structures (TLS) formation in post-treatment biopsies. In a humanized mouse model for CD40 and FcγRs, 2141-V11 induced TLS formation in mice bearing orthotopic breast carcinoma, correlating with local and abscopal antitumor effects, systemic immune activation, and immune memory. These findings support the safety and efficacy of 2141-V11, warranting phase 2 studies and suggesting a unique mechanism of action for this Fc-enhanced immunotherapy (NCT04059588).

9587 Background: NST with immune checkpoint blockade (ICB) improves clinical outcomes over upfront surgery followed by adjuvant treatment (tx) in patients (pts) with stage III, surgically resectable melanoma. The NST platform also provides an opportunity for deep translational analysis to identify baseline (BL) biomarkers predicting pathologic response and to gain insights into resistance. BL biomarkers, including gene expression signatures (GES) such as IFN-γ/ tumor mutational burden, tumor infiltrating lymphocytes, and presence of tertiary lymphoid structures, have been associated with pathologic response to NST with anti-PD1 and/or anti-CTLA4 antibodies. These studies have not evaluated the newest ICB combination, nivo (anti-PD1) + rela (anti-LAG3), which achieved a major pathologic response rate (MPR) (≤10% viable tumor) of 63% in a Ph II study (NCT02519322). Here we report GES analysis from BL and longitudinal tumor tissues obtained on this study and correlations with outcomes. Methods: Longitudinal tissue was collected from 30 pts treated on the clinical trial and available RNA analyzed using the NanoString nCounter PanCancer IO360 panel. Clinical outcomes, including recurrence and event-free survival, were also updated with longer follow-up. Pts were grouped into MPR and non- major pathologic responders (non MPR). Normalization, differential expression / GES evaluation was performed using nSolver Advanced Analysis software. Differential expression is fit on a per signatures basis using a linear model for analysis. P-values were adjusted within each analysis and on the grouping variable level difference t-test using the Benjamini and Yekutieli False Discovery Rate adjustment to account for correlations amongst the tests. BL analysis was grouped based on pathologic response, MPR vs non-MPR. Results: Of the 30 pts (median follow up 44 months), 53 RNA samples from 26 patients (9 NR and 17 R) were included in the full analysis. Immune GES with significantly higher (adjusted p< 0.05) differences at BL in MPR vs non-MPR included: B cells, CD45, CD-8+ T cells, TIGIT, IDO1, and IFN-γ. Significantly higher B7-H3 GES at BL was associated with non MPR. Additional analyses (i.e., cell population changes over time) and association with event outcomes are underway. Conclusions: To our knowledge, this is the first longitudinal RNA analysis reported from pts treated with nivo+rela. BL immune features associated with major pathologic response include higher GES of B cells, CD45+ cells, CD8 T cells, and increased expression of TIGIT, IDO and IFN-y. Additionally, higher B7-H3 in non MPR pts may indicate a clinically actionable strategy for further evaluation. Ongoing analyses of longitudinal samples and correlations with clinical outcomes are underway and will be presented. Clinical trial information: NCT02519322 .

BACKGROUND: For patients with melanoma, the decision to perform sentinel lymph node biopsy (SLNB) is based on the estimated risk of lymph node metastasis. We assessed 3 melanoma SLNB risk-prediction models’ statistical performance and their ability to improve clinical decision making (clinical utility) on a cohort of melanoma SLNB cases. STUDY DESIGN: Melanoma patients undergoing SLNB at a single center from 2003 to 2021 were identified. The predicted probabilities of sentinel lymph node positivity using the Melanoma Institute of Australia, Memorial Sloan Kettering Cancer Center (MSK), and Friedman nomograms were calculated. Receiver operating characteristic and calibration curves were generated. Clinical utility was assessed via decision curve analysis, calculating the net SLNBs that could have been avoided had a given model guided selection at different risk thresholds. RESULTS: Of 2,464 melanoma cases that underwent SLNB, 567 (23.0%) had a positive sentinel lymph node. The areas under the receiver operating characteristic curves for the Melanoma Institute of Australia, MSK, and Friedman models were 0.726 (95% CI, 0.702 to 0.750), 0.720 (95% CI, 0.697 to 0.744), and 0.721 (95% CI, 0.699 to 0.744), respectively. For all models, calibration was best at predicted positivity rates below 30%. The MSK model underpredicted risk. At a 10% risk threshold, only the Friedman model would correctly avoid a net of 6.2 SLNBs per 100 patients. The other models did not reduce net avoidable SLNBs at risk thresholds of ≤10%. CONCLUSIONS: The tested nomograms had comparable performance in our cohort. The only model that achieved clinical utility at risk thresholds of ≤10% was the Friedman model.

2639 Background: Talimogene laherparepvec (T-VEC) is an oncolytic immunotherapy made from a modified herpes virus expressing granulocyte-macrophage colony-stimulating factor and is FDA approved for the treatment of advanced melanoma. Laboratory studies suggest radiotherapy (RT) may interact with oncolytic immunotherapy to facilitate an immune-mediated anticancer response. We hypothesized that the combination of T-VEC+RT would produce tumor responses in distant (non-irradiated and non-injected) metastases. Methods: A prospective phase II, randomized, Simon two-stage clinical trial of T-VEC with or without RT was conducted with the primary objective of determining if the response rate of the largest non-injected and non-irradiated metastasis was ≥27%. Eligible patients had ≥1 cutaneous metastasis from a solid tumor amenable to T-VEC and RT and 1 measurable metastasis that would not be treated with T-VEC or RT. Using type I and II error probabilities of 10% and 20%, it was calculated that 9 patients would be enrolled in each arm, and if at least 1 of 9 patients subjects exhibited a response, then 6 additional patients would be enrolled in the second stage. Tumor and overall response was assessed using modified World Health Organization (mWHO) and immune related response criteria (irRC). Treatment-emergent and treatment-related adverse events (TEAEs and TRAEs) were characterized using CTCAE v4.0. Results: 19 patients were enrolled and randomized to receive T-VEC alone (n=9) or T-VEC+RT (n=10). One patient in each arm demonstrated a complete response in the largest non-irradiated and non-injected metastasis but progressed in new metastases. The composite response rate in target tumors not injected or irradiated was 13% and 0% in the T-VEC alone and T-VEC+RT arms, respectively. The composite response rate in target tumors treated with T-VEC alone or T-VEC+RT was 7% and 22%, respectively. Because no patient exhibited an overall mWHO or irRC defined response and due to slow accrual, the trial was closed after the first stage of enrollment despite meeting the prespecified response rate to continue enrollment in the second stage. Grade 3-4 TEAEs and TRAEs occurred in 9 and 2 patients, with similar frequencies between study arms. The most common AE was fever and occurred in 47% of patients. Peripheral blood-based immunologic analyses will be presented. Conclusions: The response rate in the largest non-injected or non-irradiated metastasis following T-VEC with or without RT given to a cutaneous metastasis from solid tumor could be ≥27% but was not determined in this trial due to premature closure, in part due to slow accrual rate and no observed mWHO defined overall responses. Cutaneous metastases responded more often after TVEC+RT than T-VEC alone, but the response in non-injected and non-irradiated tumors was more frequent after T-VEC alone. Clinical trial information: NCT02819843 .

Summary: Patients undergoing extensive lymph node dissection and radiation are at high risk for not only lymphedema but also painful contracture. In a standard lymphadenectomy, immediate lymphatic reconstruction using a lymphovenous bypass is effective in reconstructing the lymphatic defect. However, a more aggressive nodal clearance leaves the patient with a large cavity and skeletonized neurovascular structures, often resulting in severe contracture, pain, cosmetic deformity, and venous stricture. Adjuvant radiotherapy to the nodal bed can lead to severe and permanent disability despite physical therapy. Typically, these patients are referred to us after the fact, where surgery will rarely restore the patient to normal function. In an effort to avoid lymphedema and contracture, we have been reconstructing both the lymphatic and soft tissue defect during lymphadenectomy, using vascularized omentum lymphatic transplant (VOLT). A total of 13 patients underwent immediate reconstruction with VOLT at the time of axillary (n = 8; 61.5%) or groin (n = 5; 38.5%) dissection. No postoperative complications were observed. The mean follow-up time was 15.1 ± 12.5 months. Only one lower extremity patient developed mild lymphedema (11% volume differential), with excellent scores in validated patient-reported outcomes. All patients maintained full range of motion with no pain. None of the 13 patients required a compression garment. Immediate lymphatic reconstruction with VOLT is a promising procedure for minimizing the risk of lymphedema and contracture in the highest risk patients undergoing particularly extensive lymph node dissection and radiotherapy.