Epigenetic silencing of retinoblastoma gene regulates pathologic differentiation of myeloid cells in cancer.

Two major populations of myeloid-derived suppressor cells (MDSCs), monocytic MDSCs (M-MDSCs) and polymorphonuclear MDSCs (PMN-MDSCs) regulate immune responses in cancer and other pathologic conditions. Under physiologic conditions, Ly6C(hi)Ly6G(-) inflammatory monocytes, which are the normal counterpart of M-MDSCs, differentiate into macrophages and dendritic cells. PMN-MDSCs are the predominant group of MDSCs that accumulates in cancer. Here we show that a large proportion of M-MDSCs in tumor-bearing mice acquired phenotypic, morphological and functional features of PMN-MDSCs. Acquisition of this phenotype, but not the functional attributes of PMN-MDSCs, was mediated by transcriptional silencing of the retinoblastoma gene through epigenetic modifications mediated by histone deacetylase 2 (HDAC-2). These data demonstrate a new regulatory mechanism of myeloid cells in cancer.

CD4 Phenotypes Are Associated with Reduced Expansion of Tumor-Infiltrating Lymphocytes in Melanoma Patients Treated with Adoptive Cell Therapy.

Tumor-infiltrating lymphocyte (TIL) adoptive cell therapy is effective in treating malignant melanoma, but its success relies on the adequate ex vivo expansion of TIL. To assess correlates of TIL expansion, CD4+ and CD8+ TIL were analyzed by RNA sequencing (RNA-seq) and chromatin immunoprecipitation sequencing of acetylated histone 3. Patients were grouped into "TIL high" and "TIL low" based on division at the median number of TIL infused. Greater numbers of TIL infused correlated with longer overall survival, and increased frequencies of CD4+ cells infused were negatively correlated with the number of TIL infused. RNA-seq analysis of CD4+ TIL showed increases in Th2/Th17/regulatory T cell-related transcripts and pathways in the TIL-low group. Analysis of a public single-cell RNA-seq dataset validated findings that increased frequencies of CD4+ cells were negatively correlated with the number of TIL infused. TIL-low patients had significantly increased frequencies of CD4+ cells expressing ETS2 and OSM and trended toward increased expression of TNFRSF18.

Radar-Guided Localization and Resection for Metastatic Nodal and Soft Tissue Melanoma: A Single-Institution Retrospective Study.

BACKGROUND: Radar-guided localization (RGL) offers a wire-free, nonradioactive surgical guidance method consisting of a small percutaneously-placed radar reflector and handheld probe. This study investigates the feasibility, timing, and outcomes of RGL for melanoma metastasectomy. METHODS: We retrospectively identified patients at our cancer center who underwent RGL resection of metastatic melanoma between December 2020-June 2023. Data pertaining to patients' melanoma history, management, reflector placement and retrieval, and follow-up was extracted from patient charts and analyzed using descriptive statistics. RESULTS: Twenty-three RGL cases were performed in patients with stage III-IV locoregional or oligometastatic disease, 10 of whom had reflectors placed prior to neoadjuvant therapy. Procedures included soft tissue nodule removals (8), index lymph node removals (13), and therapeutic lymph node dissections (2). Reflectors were located and retrieved intraoperatively in 96% of cases from a range of 2 to 282 days after placement; the last reflector was not able to be located during surgery via probe or intraoperative ultrasound. One retrieved reflector had migrated from the index lesion, thus overall success rate of reflector and associated index lesion removal was 21 of 23 (91%). All RGL-localized and retrieved index lesions that contained viable tumor (10) had microscopically negative margins. There were no complications attributable to reflector insertion and no unexpected complications of RGL surgery. CONCLUSION: In our practice, RGL is a safe and effective surgical localization method for soft tissue and nodal melanoma metastases. The inert nature of the reflector enables implantation prior to neoadjuvant therapy with utility in index lymph node removal.

There are a variety of tools available to localize melanoma that had spread to deep layers of the skin or lymph nodes that can guide surgeons to the cancer when the tumor cannot be felt. We evaluated a marker that reflects radar signals that has been studied in breast surgery but not in melanoma. The marker was placed in the tumor before surgery and was located during surgery using a handheld probe, guiding the surgeon to the correct location. An advantage of the radar-reflecting marker we studied is that since it is safe to stay in the body, it can be placed ahead of the use of cancer medications and can keep track of the tumor as it responds to treatment. In a review of 23 surgeries in which the radar-reflecting marker was used, there was one case where the marker migrated away from the tumor and one case where the marker was not able to be located. Monitoring or alternative definitive treatment was provided in each of these cases. Overall, we found the marker to be an effective tumor localization tool for surgeons and safe for patients. Other marker options available are unable or less suitable to be placed a long time in advance of surgery due to either technical or safety reasons, so the radar-reflecting marker is especially useful when it is placed in a tumor ahead of medical treatment leading up to planned surgical treatment.

International Center-Level Variation in Utilization of Completion Lymph Node Dissection and Adjuvant Systemic Therapy for Sentinel Lymph Node-Positive Melanoma at Major Referral Centers.

OBJECTIVE: The aim of this study was to determine overall trends and center-level variation in utilization of completion lymph node dissection (CLND) and adjuvant systemic therapy for sentinel lymph node (SLN)-positive melanoma. SUMMARY BACKGROUND DATA: Based on recent clinical trials, management options for SLN-positive melanoma now include effective adjuvant systemic therapy and nodal observation instead of CLND. It is unknown how these findings have shaped practice or how these contemporaneous developments have influenced their respective utilization. METHODS: We performed an international cohort study at 21 melanoma referral centers in Australia, Europe, and the United States that treated adults with SLN-positive melanoma and negative distant staging from July 2017 to June 2019. We used generalized linear and multinomial logistic regression models with random intercepts for each center to assess center-level variation in CLND and adjuvant systemic treatment, adjusting for patient and disease-specific characteristics. RESULTS: Among 1109 patients, performance of CLND decreased from 28% to 8% and adjuvant systemic therapy use increased from 29 to 60%. For both CLND and adjuvant systemic treatment, the most influential factors were nodal tumor size, stage, and location of treating center. There was notable variation among treating centers in management of stage IIIA patients and use of CLND with adjuvant systemic therapy versus nodal observation alone for similar risk patients. CONCLUSIONS: There has been an overall decline in CLND and simultaneous adoption of adjuvant systemic therapy for patients with SLN-positive melanoma though wide variation in practice remains. Accounting for differences in patient mix, location of care contributed significantly to the observed variation.

Atypical Fibroxanthoma: Outcomes from a Large Single Institution Series.

BACKGROUND: Atypical fibroxanthomas (AFX) are rare malignant cutaneous neoplasms. Unfortunately, limited clinicopathologic and outcomes data on this cancer exists. OBJECTIVE: We report the clinical, pathologic, and treatment characteristics, as well as oncologic outcomes in this single-institution retrospective analysis. METHODS: This retrospective cohort study compiled clinical, pathologic, treatment, and outcome data for all patients with AFX on definitive excision diagnosed, evaluated, and treated primarily by surgical resection at a single institution between 2000-2020. Descriptive statistics evaluated clinical and pathologic characteristics. Kaplan-Meier method and Cox proportional-hazards models were used to evaluate overall survival and recurrence-free survival. RESULTS: 78 patients with AFX were identified. The majority were elderly, immunocompetent, Caucasian men. 85% of tumors were located on the head and neck. 63% of patients were correctly diagnosed only after complete resection of the index lesion. The median surgical margin was 1.0 cm. Overall, only 1.3% (1/78) of patients developed a local recurrence (RFS). No patients died of disease. CONCLUSION: This study suggests that resection margins of 1 cm achieve excellent local control with close to 99% RFS and 100% disease-specific survival.

Oncologic Outcomes of Multi-Institutional Minimally Invasive Inguinal Lymph Node Dissection for Melanoma Compared with Open Inguinal Dissection in the Second Multicenter Selective Lymphadenectomy Trial (MSLT-II).

BACKGROUND: Minimally invasive inguinal lymphadenectomy (MILND) is safe and feasible, but limited data exist regarding oncologic outcomes. METHODS: This study performed a multi-institutional retrospective cohort analysis of consecutive MILND performed for melanoma between January 2009 and June 2016. The open ILND (OILND) comparative cohort comprised patients enrolled in the second Multicenter Selective Lymphadenectomy Trial (MSLT-II) between December 2004 and March 2014.The pre-defined primary end point was the same-basin regional nodal recurrence, calculated using properties of binomial distribution. Time to events was calculated using the Kaplan-Meier method. The secondary end points were overall survival, progression-free survival, melanoma-specific survival (MSS), and distant metastasis-free survival (DMFS). RESULTS: For all the patients undergoing MILND, the same-basin regional recurrence rate was 4.4 % (10/228; 95 % confidence interval [CI], 2.1-7.9 %): 8.2 % (4/49) for clinical nodal disease and 3.4 % (6/179) for patients with a positive sentinel lymph node (SLN) as the indication. For the 288 patients enrolled in MSLT-II who underwent OILND for a positive SLN, 17 (5.9 %) had regional node recurrence as their first event. After controlling for ulceration, positive LN count and positive non-SLNs at the time of lymphadenectomy, no difference in OS, PFS, MSS or DMFS was observed for patients with a positive SLN who underwent MILND versus OILND. CONCLUSION: This large multi-institutional experience supports the oncologic safety of MILND for melanoma. The outcomes in this large multi-institutional experience of MILND compared favorably with those for an OILND population during similar periods, supporting the oncologic safety of MILND for melanoma.

Talimogene Laherparepvec (T-VEC) for the Treatment of Advanced Locoregional Melanoma After Failure of Immunotherapy: An International Multi-Institutional Experience.

BACKGROUND: Talimogene laherparepvec (T-VEC) is an oncolytic virus approved for the treatment of unresectable, recurrent melanoma. The role of T-VEC after progression on systemic immunotherapy (IO) remains undefined. The goal of this study was to characterize the efficacy of T-VEC after failure of IO in patients with unresectable metastatic melanoma. METHODS: An international, multi-institutional review of AJCC version 8 stage IIIB-IV melanoma patients treated with T-VEC after failure of IO was performed at six centers from October 2015-December 2020. Primary outcome was in-field response; secondary outcomes included analyses of in-field and overall progression-free survival (PFS) and in-field and overall disease-free survival (DFS) after a complete response. Subset analysis of T-VEC initiation sequentially after or concurrently with IO was performed. RESULTS: Of 112 patients, median age at T-VEC initiation was 69 years (range 21-93); 65 (58%) were male. Before T-VEC, 57% patients received one IO regimen, 42% received two or more, with most patients (n = 74, 66%) receiving T-VEC sequential to IO. Most were stage 3C (n = 51, 46%) at T-VEC initiation, 29 (26%) received injections to nodal disease. Over median follow-up of 14 months, in-field response at final T-VEC injection was 37% complete (CR), 14% partial (PR). T-VEC initiation sequentially or concurrently did not significantly affect in-field response (p = 0.26). Median in-field PFS was 15 months (95% confidence interval 4.6-NE). Median overall DFS after CR was 32 months (95% confidence interval 17-NE). CONCLUSIONS: T-VEC after failure of IO is effective in unresectable, metastatic stage IIIB-IV melanoma. T-VEC initiation sequentially or concurrently did not significantly affect in-field response.

Intratumoral Activation of 41BB Costimulatory Signals Enhances CD8 T Cell Expansion and Modulates Tumor-Infiltrating Myeloid Cells.

The activation of 41BB costimulatory signals by agonistic Abs enhances the expansion and function of tumor-infiltrating lymphocytes (TILs) for treating cancer patients with adoptive cell therapy. However, the impact of 41BB agonism is not limited to enhancing the activity of T cells, and the mechanism by which additional activation of this costimulatory axis in tumor-associated myeloid cells is poorly understood. In this study, we describe that the intratumoral administration of 41BB agonistic Abs led to increases in CD8 T cell infiltration followed by tumor regression in murine models. We found that granulocytes and monocytes rapidly replaced macrophages and dendritic cells in tumors following administration of anti-41BB Abs. Overall, myeloid cells from anti-41BB-treated tumors had an improved capacity to stimulate T cells in comparison with control-treated tumors. In human coculture systems, we demonstrated that the agonism of the 41BB-41BBL axis enhanced costimulatory signals and effector functions among APC and autologous TILs. Overall, these findings suggest that the effect of 41BB agonistic Abs are supported by additional costimulatory signals from tumor-associated myeloid cells,v leading to enhanced TIL expansion and function.

Active surveillance of patients who have sentinel node positive melanoma: An international, multi-institution evaluation of adoption and early outcomes after the Multicenter Selective Lymphadenectomy Trial II (MSLT-2).

BACKGROUND: For patients with sentinel lymph node (SLN)-positive cutaneous melanoma, the Second Multicenter Selective Lymphadenectomy trial demonstrated equivalent disease-specific survival (DSS) with active surveillance using nodal ultrasound versus completion lymph node dissection (CLND). Adoption and outcomes of active surveillance in clinical practice and in adjuvant therapy recipients are unknown. METHODS: In a retrospective cohort of SLN-positive adults treated at 21 institutions in Australia, Europe, and the United States from June 2017 to November 2019, the authors evaluated the impact of active surveillance and adjuvant therapy on all-site recurrence-free survival (RFS), isolated nodal RFS, distant metastasis-free survival (DMFS), and DSS using Kaplan-Meier curves and Cox proportional hazard models. RESULTS: Among 6347 SLN biopsies, 1154 (18%) were positive and had initial negative distant staging. In total, 965 patients (84%) received active surveillance, 189 (16%) underwent CLND. Four hundred thirty-nine patients received adjuvant therapy (surveillance, 38%; CLND, 39%), with the majority (83%) receiving anti-PD-1 immunotherapy. After a median follow-up of 11 months, 220 patients developed recurrent disease (surveillance, 19%; CLND, 22%), and 24 died of melanoma (surveillance, 2%; CLND, 4%). Sixty-eight patients had an isolated nodal recurrence (surveillance, 6%; CLND, 4%). In patients who received adjuvant treatment without undergoing prior CLND, all isolated nodal recurrences were resectable. On risk-adjusted multivariable analyses, CLND was associated with improved isolated nodal RFS (hazard ratio [HR], 0.36; 95% CI, 0.15-0.88), but not all-site RFS (HR, 0.68; 95% CI, 0.45-1.02). Adjuvant therapy improved all-site RFS (HR, 0.52; 95% CI, 0.47-0.57). DSS and DMFS did not differ by nodal management or adjuvant treatment. CONCLUSIONS: Active surveillance has been adopted for most SLN-positive patients. At initial assessment, real-world outcomes align with randomized trial findings, including in adjuvant therapy recipients. LAY SUMMARY: For patients with melanoma of the skin and microscopic spread to lymph nodes, monitoring with ultrasound is an alternative to surgically removing the remaining lymph nodes. The authors studied adoption and real-world outcomes of ultrasound monitoring in over 1000 patients treated at 21 centers worldwide, finding that most patients now have ultrasounds instead of surgery. Although slightly more patients have cancer return in the lymph nodes with this strategy, typically, it can be removed with delayed surgery. Compared with up-front surgery, ultrasound monitoring results in the same overall risk of melanoma coming back at any location or of dying from melanoma.

Surveillance of Sentinel Node-Positive Melanoma Patients Who Receive Adjuvant Therapy Without Undergoing Completion Lymph Node Dissection.

INTRODUCTION: Adjuvant therapy trials required completion lymph node dissection (CLND) for sentinel lymph node (SLN)-positive melanoma prior to systemic treatment, but nodal surveillance without CLND is now common. For patients receiving adjuvant therapy without CLND, patterns of recurrence are unknown and the value of regional nodal ultrasound alongside cross-sectional imaging is not well-defined. METHODS: In a retrospective cohort of SLN-positive melanoma patients managed with nodal surveillance from June 2014 to June 2019, we evaluated the association between adjuvant treatment and location of first recurrence (locoregional, nodal, distant, or multisite) using Chi-square tests. We compared methods of recurrence detection and cost by surveillance intensity using Chi-square and Dunn's tests. RESULTS: Among 177 nodal surveillance patients, 66 (37%) received adjuvant therapy. Median follow-up was 24 months, during which 48 patients (27%) recurred. Adjuvant treatment did not alter patterns of initial recurrence (p = 0.76). Adjuvant therapy recipients more often had both nodal ultrasound and cross-sectional imaging surveillance (p < 0.01). Among 13 isolated nodal recurrences, 85% were within the first year and 85% were detected by examination and/or ultrasound. Increasing surveillance intensity was not associated with recurrence detection rates but increased overall cost and cost per detected recurrence. CONCLUSION: Regardless of adjuvant treatment, most nodal recurrences occurred in the first year and were initially detected clinically or by ultrasound. Findings support continued use of examination and nodal basin ultrasound in addition to any planned cross-sectional imaging surveillance.

Intralesional injection of rose bengal augments the efficacy of gemcitabine chemotherapy against pancreatic tumors.

BACKGROUND: Chemotherapy regimens that include the utilization of gemcitabine are the standard of care in pancreatic cancer patients. However, most patients with advanced pancreatic cancer die within the first 2 years after diagnosis, even when treated with standard of care chemotherapy. This study aims to explore combination therapies that could boost the efficacy of standard of care regimens in pancreatic cancer patients. METHODS: In this study, we used PV-10, a 10% solution of rose bengal, to induce the death of human pancreatic tumor cells in vitro. Murine in vivo studies were carried out to examine the effectiveness of the direct injection of PV-10 into syngeneic pancreatic tumors in causing lesion-specific ablation. Intralesional PV-10 treatment was combined with systemic gemcitabine treatment in tumor-bearing mice to investigate the control of growth among treated tumors and distal uninjected tumors. The involvement of the immune-mediated clearance of tumors was examined in immunogenic tumor models that express ovalbumin (OVA). RESULTS: In this study, we demonstrate that the injection of PV-10 into mouse pancreatic tumors caused lesion-specific ablation. We show that the combination of intralesional PV-10 with the systemic administration of gemcitabine caused lesion-specific ablation and delayed the growth of distal uninjected tumors. We observed that this treatment strategy was markedly more successful in immunogenic tumors that express the neoantigen OVA, suggesting that the combination therapy enhanced the immune clearance of tumors. Moreover, the regression of tumors in mice that received PV-10 in combination with gemcitabine was associated with the depletion of splenic CD11b+Gr-1+ cells and increases in damage associated molecular patterns HMGB1, S100A8, and IL-1α. CONCLUSIONS: These results demonstrate that intralesional therapy with PV-10 in combination with gemcitabine can enhance anti-tumor activity against pancreatic tumors and raises the potential for this strategy to be used for the treatment of patients with pancreatic cancer.

Reactive Myelopoiesis Triggered by Lymphodepleting Chemotherapy Limits the Efficacy of Adoptive T Cell Therapy.

Adoptive T cell therapy (ACT) in combination with lymphodepleting chemotherapy is an effective strategy to induce the eradication of tumors, providing long-term regression in cancer patients. Despite that lymphodepleting regimens condition the host for optimal engraftment and expansion of adoptively transferred T cells, lymphodepletion concomitantly promotes immunosuppression during the course of endogenous immune recovery. In this study, we have identified that lymphodepleting chemotherapy initiates the mobilization of hematopoietic progenitor cells that differentiate to immunosuppressive myeloid cells, leading to a dramatic increase of peripheral myeloid-derived suppressor cells (MDSCs). In melanoma and lung cancer patients, MDSCs rapidly expanded in the periphery within 1 week after completion of a lymphodepleting regimen and infusion of autologous tumor-infiltrating lymphocytes (TILs). This expansion was associated with disease progression, poor survival, and reduced TIL persistence in melanoma patients. We demonstrated that the interleukin 6 (IL-6)-driven differentiation of mobilized hematopoietic progenitor cells promoted the survival and immunosuppressive capacity of post-lymphodepletion MDSCs. Furthermore, the genetic abrogation or therapeutic inhibition of IL-6 in mouse models enhanced host survival and reduced tumor growth in mice that received ACT. Thus, the expansion of MDSCs in response to lymphodepleting chemotherapy may contribute to ACT failure, and targeting myeloid-mediated immunosuppression may support anti-tumor immune responses.

Robotic-Assisted Pelvic Lymphadenectomy for Metastatic Melanoma Results in Durable Oncologic Outcomes.

BACKGROUND: Robotic pelvic lymphadenectomy (rPLND) has been demonstrated to be a safe and effective minimally invasive approach for patients with metastatic melanoma to the iliac nodes. However, the long-term oncologic benefit of this procedure remains poorly defined. METHODS: A single-institutional study comparing perioperative outcomes and survival [recurrence-free (RFS) and overall survival (OS)] between rPLND and open PLND (oPLND) for metastatic melanoma was conducted. RESULTS: From 2006 to 2018, a total of 63 PLND cases were identified: 22 rPLND and 41 oPLND. Evidence of isolated pelvic metastasis was the most common indication for PLND in both groups (rPLND: 64%, oPLND: 85%). There was no difference in median pelvic lymph node yield (11 vs. 9 nodes, p = 0.65). Neither treatment group experienced a Clavien-Dindo complication ≥ 3. rPLND was associated with a shorter length of stay compared with oPLND (2 vs. 4 days, p < 0.001). With a median follow-up of 37 months, there was no difference in RFS (14.4 vs. 9.6 months, p = 0.47) and OS (43 vs. 50 months, p = 0.58) between rPLND and oPLND, respectively. In basin recurrence was low with 1 (4.5%) and 3 (7.3%) patients in the rPLND and oPLND cohorts, respectively, experiencing an event (p = 0.9). CONCLUSIONS: rPLND for metastatic melanoma is a safe, minimally invasive treatment strategy that appears to result in similar intermediate term recurrence and survival rates as oPLND but shorter hospital stays.

Management of Sentinel Lymph Node Metastasis in Merkel Cell Carcinoma: Completion Lymphadenectomy, Radiation, or Both?

BACKGROUND: Approximately 30% of patients with clinically localized Merkel cell carcinoma (MCC) show nodal involvement on sentinel lymph node biopsy (SLNB). Optimal management of SLNB-positive disease has not been defined. This study compared outcomes after completion lymphadenectomy (CLND), radiation, and combined CLND plus radiation after a positive SLNB. METHODS: All patients treated at a single institution for SLNB-positive MCC (1998-2015) were retrospectively evaluated, with examination of patient demographics, clinicopathologic characteristics, outcomes, and regional toxicity. RESULTS: The study identified 71 evaluable patients with SLNB-positive disease. The median age of these patients was 76 years, and 76.1% were men. Of the 71 patients, 11 (15.5%) underwent CLND, 40 (56.3%) received radiation, and 20 (28.2%) underwent CLND plus postoperative radiation. Lymphovascular invasion was significantly more common in the radiation-alone cohort (p = 0.04). For the three cohorts, the median percentages of nodal involvement were respectively 2, 10, and 30% (p = 0.06). After a median follow-up period of 22.3 months, four patients had recurrence in their regional nodal basin (3 radiation-alone patients and 1 CLND + radiation patient). The three cohorts did not differ significantly in the development of distant metastases (p = 0.68) or overall survival (p = 0.72). Six patients experienced surgical-site infections (2 CLND and 4 CLND + radiation patients), and three patients experienced symptomatic lymphedema (1 CLND patient and 2 CLND + radiation patients). CONCLUSIONS: Regional failure was infrequent (≤ 10%) regardless of treatment, and morbidity appeared to be low with all approaches. Given that multiple treatment approaches can be successful in treating micrometastatic MCC, future efforts should be directed at refining criteria for allocating patients to a specific method, or possibly no further nodal basin treatment, in an effort to maximize regional control at the lowest cost and morbidity.

Talimogene Laherparepvec (TVEC) for the Treatment of Advanced Melanoma: A Single-Institution Experience.

BACKGROUND: Talimogene laherparepvec (TVEC) is an oncolytic herpes virus used as intralesional therapy for patients with unresectable stage IIIB through IV melanoma. We reviewed the standard of care treatment of TVEC at a single institution. METHODS: All patients treated with TVEC for advanced melanoma were retrospectively evaluated from 2015 to 2018. Patient demographics, clinicopathologic characteristics, treatment response, and toxicity were reviewed. RESULTS: Twenty-seven patients underwent therapy with TVEC. Median age was 75 years, and 63% of patients were female. Seventeen (63.0%) patients underwent injections on the lower extremity, four (14.8%) on the upper extremity, four (14.8%) on the head and neck, and two (7.4%) on the trunk. Median number of injections was five. Median follow-up was 8.6 months. Of the 27 patients, 23 patients met the criteria for response analysis with at least 8 weeks follow-up. Ten (43.5%) patients experienced a complete response (CR), three (13.1%) experienced a partial response (PR), and five (21.7%) had stable disease (SD) for an overall response rate of 56.5% (CR + PR) and a disease control rate of 78.3% (CR + PR + SD). Adverse events were mostly limited to mild constitutional symptoms within 48 h of injection. Two patients developed cellulitis treated with oral antibiotics, and one patient underwent excision of a lesion for ulceration and bleeding during therapy. DISCUSSION: TVEC is an effective and well-tolerated intralesional therapy for patients with unresectable stage IIIB through IV melanoma. A CR was achieved in almost half of patients treated. Disease control is seen in the vast majority.

Resection Margins in Merkel Cell Carcinoma: Is a 1-cm Margin Wide Enough?

BACKGROUND: Guidelines regarding specific resection margins for primary Merkel cell carcinoma (MCC) are not well established. The current National Comprehensive Cancer Network (NCCN) guidelines recommend 1- to 2-cm resection margins. This study aimed to determine the impact of margin width on local recurrence (LR), disease-specific survival (DSS), overall survival (OS), and type of wound closure. METHODS: All patients who underwent resection of primary MCC at a single institution from 2000 to 2015 were reviewed. Patient demographics, clinicopathologic characteristics, treatments, and outcomes were reviewed. RESULTS: A total of 240 patients underwent resection of primary MCC with resection margin width identified in the operative report. The median age was 76 years, and 65.8% of the patients were men. Of the 240 patients, 85 (35.4%) had head and neck primaries, 140 (58.3%) had extremity primaries, and 15 (6.3%) had trunk primaries. In terms of margins, 69 patients (28.8%) had a margin of 1 cm, 36 patients (15%) had a margin of 1.1-1.9 cm, and 135 patients (56.2%) had a margin of 2 cm or more. The median follow-up period was 21 months. The LR rate was 2.9% for a margin of 1 cm, 2.8% for a margin of 1.1-1.9 cm, and 5.2% for a margin of 2 cm or more (p = 0.80). The 5-year OS was 63.6% for a margin of 1 cm, 59.7% for a margin of 1.1-1.9, and 70.7% for a margin of 2 cm or more (p = 0.66). The 5-year DSS was 80.3% for a margin of 1 cm, 66.2% for a margin of 1.1-1.9 cm, and 91.8% for a margin of 2 cm or more (p = 0.28). For wound closure, 43.5, 50, and 65.9% of the patients respectively required a flap or graft with a margin of 1, 1.1-1.9, and 2 cm or more (p = 0.006). CONCLUSIONS: A 1-cm resection margins did not increase the risk of LR. Margin width did not make a significant difference in DSS or OS. Larger resection margins increase the need for a graft or flap closure.

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.

Comparison of Single-Photon Emission Computed Tomography-Computed Tomography (SPECT/CT) and Conventional Planar Lymphoscintigraphy for Sentinel Node Localization in Patients with Cutaneous Malignancies.

BACKGROUND: Accurate preoperative lymphoscintigraphy is vital to performing sentinel lymph node biopsy (SLNB) for cutaneous malignancies. Potential advantages of single-photon emission computed tomography with integrated computed tomography (SPECT/CT) include the ability to readily identify aberrant drainage patterns as well as provide the surgeon with three-dimensional anatomic landmarks not seen on conventional planar lymphoscintigraphy (PLS). METHODS: Patients with cutaneous malignancies who underwent SLNB with preoperative imaging using both SPECT/CT and PLS from 2011 to 2014 were identified. RESULTS: Both SPECT/CT and PLS were obtained in 351 patients (median age, 69 years; range, 5-94 years) with cutaneous malignancies (melanoma = 300, Merkel cell carcinoma = 33, squamous cell carcinoma = 8, other = 10) after intradermal injection of 99mtechnetium sulfur colloid (median dose 300 µCi). A mean of 4.3 hot spots were identified on SPECT/CT compared to 3.0 on PLS (p < 0.001). One hundred fifty-three patients (43.6 %) had identical findings between SPECT/CT and PLS, while 172 (49 %) had additional hot spots identified on SPECT/CT compared to only 24 (6.8 %) additional on PLS. SPECT/CT demonstrated additional nodal basins in 103 patients (29.4 %), compared to only 11 patients (3.1 %) with additional basins on PLS. CONCLUSIONS: SPECT/CT is a useful adjunct that can help with sentinel node localization in challenging cases. It identified additional hot spots not seen on PLS in almost 50 % of patients. Because PLS identified hot spots not seen on SPECT/CT in 6.8 % of patients, we recommend using both modalities jointly. Long-term follow-up will be required to validate the clinical significance of the additional hot spots identified by SPECT/CT.

Regional Radiation Therapy Impacts Outcome for Node-Positive Cutaneous Melanoma.

Background: Regional radiation therapy (RT) has been shown to reduce the risk of regional recurrence with node-positive cutaneous melanoma. However, risk factors for regional recurrence, especially in the era of sentinel lymph node biopsy (SLNB), are less clear. Our goals were to identify risk factors associated with regional recurrence and to determine whether a radiosensitivity index (RSI) gene expression signature (GES) could identify patients who experience a survival benefit with regional RT. Methods: A single-institution, Institutional Review Board-approved study was performed including 410 patients treated with either SLNB with or without completion lymph node dissection (LND; n=270) or therapeutic LND (n=91). Postoperative regional RT was delivered to the involved nodal basin in 83 cases (20.2%), to a median dose of 54 Gy (range, 30-60 Gy) in 27 fractions (range, 5-30). Primary outcomes were regional control and overall survival by RSI GES status. Results: Median follow-up was 69 months (range, 13-180). Postoperative regional RT was associated with a reduced risk of regional recurrence among all patients on univariate (5-year estimate: 95.0% vs 83.3%; P=.036) and multivariate analysis (hazard ratio[HR], 0.15; 95% CI, 0.05-0.43; P<.001). Among higher-risk subgroups, regional RT was associated with a lower risk of regional recurrence among patients with clinically detected lymph nodes (n=175; 5-year regional control: 94.1% vs 69.5%; P=.003) and extracapsular extension (ECE) present (n=138; 5-year regional control: 96.7% vs 62.2%; P<.001). Among a subset of radiated patients with gene expression data available, a low RSI GES (radiosensitive) tumor status was associated with improved survival compared with a high RSI GES (5-year: 75% vs 0%; HR, 10.68; 95% CI, 1.24-92.14). Conclusions: Regional RT was associated with a reduced risk of regional recurrence among patients with ECE and clinically detected nodal disease. Gene expression data show promise for better predicting radiocurable patients in the future. In the era of increasingly effective systemic therapies, the value of improved regional control potentially takes on greater significance.