Publications by authors named "Georgia M Beasley"

70 Publications

Viral infection of cells within the tumor microenvironment mediates antitumor immunotherapy via selective TBK1-IRF3 signaling.

Nat Commun 2021 03 25;12(1):1858. Epub 2021 Mar 25.

Department of Neurosurgery, Duke University Medical School, Durham, NC, USA.

Activating intra-tumor innate immunity might enhance tumor immune surveillance. Virotherapy is proposed to achieve tumor cell killing, while indirectly activating innate immunity. Here, we report that recombinant poliovirus therapy primarily mediates antitumor immunotherapy via direct infection of non-malignant tumor microenvironment (TME) cells, independent of malignant cell lysis. Relative to other innate immune agonists, virotherapy provokes selective, TBK1-IRF3 driven innate inflammation that is associated with sustained type-I/III interferon (IFN) release. Despite priming equivalent antitumor T cell quantities, MDA5-orchestrated TBK1-IRF3 signaling, but not NFκB-polarized TLR activation, culminates in polyfunctional and Th1-differentiated antitumor T cell phenotypes. Recombinant type-I IFN increases tumor-localized T cell function, but does not mediate durable antitumor immunotherapy without concomitant pattern recognition receptor (PRR) signaling. Thus, virus-induced MDA5-TBK1-IRF3 signaling in the TME provides PRR-contextualized IFN responses that elicit functional antitumor T cell immunity. TBK1-IRF3 innate signal transduction stimulates eventual function and differentiation of tumor-infiltrating T cells.
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http://dx.doi.org/10.1038/s41467-021-22088-1DOI Listing
March 2021

ASO Author Reflections: Gene Expression-Profiling and Implications for Adjuvant Therapy in Melanoma.

Ann Surg Oncol 2021 Jan 22. Epub 2021 Jan 22.

Department of Surgery, Duke University, Durham, USA.

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http://dx.doi.org/10.1245/s10434-021-09595-7DOI Listing
January 2021

Surveillance of Sentinel Node-Positive Melanoma Patients with Reasons for Exclusion from MSLT-II: Multi-Institutional Propensity Score Matched Analysis.

J Am Coll Surg 2021 Apr 13;232(4):424-431. Epub 2020 Dec 13.

Department of Cutaneous Oncology, Moffitt Cancer Center, Tampa, FL; Department of Oncologic Sciences, University of South Florida, Tampa, FL.

Background: In sentinel lymph node (SLN)-positive melanoma, two randomized trials demonstrated equivalent melanoma-specific survival with nodal surveillance vs completion lymph node dissection (CLND). Patients with microsatellites, extranodal extension (ENE) in the SLN, or >3 positive SLNs constitute a high-risk group largely excluded from the randomized trials, for whom appropriate management remains unknown.

Study Design: SLN-positive patients with any of the three high-risk features were identified from an international cohort. CLND patients were matched 1:1 with surveillance patients using propensity scores. Risk of any-site recurrence, SLN-basin-only recurrence, and melanoma-specific mortality were compared.

Results: Among 1,154 SLN-positive patients, 166 had ENE, microsatellites, and/or >3 positive SLN. At 18.5 months median follow-up, 49% had recurrence (vs 26% in patients without high-risk features, p < 0.01). Among high-risk patients, 52 (31%) underwent CLND and 114 (69%) received surveillance. Fifty-one CLND patients were matched to 51 surveillance patients. The matched cohort was balanced on tumor, nodal, and adjuvant treatment factors. There were no significant differences in any-site recurrence (CLND 49%, surveillance 45%, p = 0.99), SLN-basin-only recurrence (CLND 6%, surveillance 14%, p = 0.20), or melanoma-specific mortality (CLND 14%, surveillance 12%, p = 0.86).

Conclusions: SLN-positive patients with microsatellites, ENE, or >3 positive SLN constitute a high-risk group with a 2-fold greater recurrence risk. For those managed with nodal surveillance, SLN-basin recurrences were more frequent, but all-site recurrence and melanoma-specific mortality were comparable to patients treated with CLND. Most recurrences were outside the SLN-basin, supporting use of nodal surveillance for SLN-positive patients with microsatellites, ENE, and/or >3 positive SLN.
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http://dx.doi.org/10.1016/j.jamcollsurg.2020.11.014DOI Listing
April 2021

Adjuvant Radiation Therapy for Clinical Stage III Melanoma in the Modern Therapeutic Era.

Ann Surg Oncol 2020 Nov 23. Epub 2020 Nov 23.

Department of Surgery, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA.

Background: Adjuvant radiation therapy (RT) can decrease lymph node basin (LNB) recurrences in patients with clinically evident melanoma lymph node (LN) metastases following lymphadenectomy, but its role in the era of modern systemic therapies (ST), immune checkpoint or BRAF/MEK inhibitors, is unclear.

Patients And Methods: Patients at four institutions who underwent lymphadenectomy (1/1/2010-12/31/2019) for clinically evident melanoma LN metastases and received neoadjuvant and/or adjuvant ST with RT, or ST alone, but met indications for RT, were identified. Comparisons were made between ST alone and ST/RT groups. The primary outcome was 3-year cumulative incidence (CI) of LNB recurrence. Secondary outcomes included 3-year incidences of in-transit/distant recurrence and survival estimates.

Results: Of 98 patients, 76 received ST alone and 22 received ST/RT. Median follow-up time for patients alive at last follow-up was 44.6 months. The ST/RT group had fewer inguinal node metastases (ST 36.8% versus ST/RT 9.1%; P = 0.04), and more extranodal extension (ST 50% versus ST/RT 77.3%; P = 0.02) and positive lymphadenectomy margins (ST 2.6% versus ST/RT 13.6%; P = 0.04). The 3-year CI of LNB recurrences was lower for the ST/RT group compared with the ST group (13.9% versus 25.2%), but this reduction was not statistically significant (P = 0.36). Groups did not differ significantly in in-transit/distant recurrences (P = 0.24), disease-free survival (P = 0.14), or melanoma-specific survival (P = 0.20).

Conclusions: In the era of modern ST, RT may still have value in reducing LNB recurrences in melanoma with clinical LN metastases. Further research should focus on whether select patient populations derive benefit from combination therapy, and optimizing indications for RT following neoadjuvant ST.
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http://dx.doi.org/10.1245/s10434-020-09384-8DOI Listing
November 2020

Characterization of Sentinel Lymph Node Immune Signatures and Implications for Risk Stratification for Adjuvant Therapy in Melanoma.

Ann Surg Oncol 2020 Nov 17. Epub 2020 Nov 17.

Department of Surgery, Duke University Medical Center, Durham, NC, USA.

Background: Although sentinel lymph node (SLN) biopsy is a standard procedure used to identify patients at risk for melanoma recurrence, it fails to risk-stratify certain patients accurately. Because processes in SLNs regulate anti-tumor immune responses, the authors hypothesized that SLN gene expression may be used for risk stratification.

Methods: The Nanostring nCounter PanCancer Immune Profiling Panel was used to quantify expression of 730 immune-related genes in 60 SLN specimens (31 positive [pSLNs], 29 negative [nSLNs]) from a retrospective melanoma cohort. A multivariate prediction model for recurrence-free survival (RFS) was created by applying stepwise variable selection to Cox regression models. Risk scores calculated on the basis of the model were used to stratify patients into low- and high-risk groups. The predictive power of the model was assessed using the Kaplan-Meier and log-rank tests.

Results: During a median follow-up period of 6.3 years, 20 patients (33.3%) experienced recurrence (pSLN, 45.2% [14/31] vs nSLN, 20.7% [6/29]; p = 0.0445). A fitted Cox regression model incorporating 12 genes accurately predicted RFS (C-index, 0.9919). Improved RFS was associated with increased expression of TIGIT (p = 0.0326), an immune checkpoint, and decreased expression of CXCL16 (p = 0.0273), a cytokine important in promoting dendritic and T cell interactions. Independent of SLN status, the model in this study was able to stratify patients into cohorts at high and low risk for recurrence (p < 0.001, log-rank).

Conclusions: Expression profiles of the SLN gene are associated with melanoma recurrence and may be able to identify patients as high or low risk regardless of SLN status, potentially enhancing patient selection for adjuvant therapy.
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http://dx.doi.org/10.1245/s10434-020-09277-wDOI Listing
November 2020

Ipilimumab and Radiation in Patients with High-risk Resected or Regionally Advanced Melanoma.

Clin Cancer Res 2021 Mar 10;27(5):1287-1295. Epub 2020 Nov 10.

Department of Radiation Oncology, Duke University, Durham, North Carolina.

Purpose: In this prospective trial, we sought to assess the feasibility of concurrent administration of ipilimumab and radiation as adjuvant, neoadjuvant, or definitive therapy in patients with regionally advanced melanoma.

Patients And Methods: Twenty-four patients in two cohorts were enrolled and received ipilimumab at 3 mg/kg every 3 weeks for four doses in conjunction with radiation; median dose was 4,000 cGy (interquartile range, 3,550-4,800 cGy). Patients in cohort 1 were treated adjuvantly; patients in cohort 2 were treated either neoadjuvantly or as definitive therapy.

Results: Adverse event profiles were consistent with those previously reported with checkpoint inhibition and radiation. For the neoadjuvant/definitive cohort, the objective response rate was 64% (80% confidence interval, 40%-83%), with 4 of 10 evaluable patients achieving a radiographic complete response. An additional 3 patients in this cohort had a partial response and went on to surgical resection. With 2 years of follow-up, the 6-, 12-, and 24-month relapse-free survival for the adjuvant cohort was 85%, 69%, and 62%, respectively. At 2 years, all patients in the neoadjuvant/definitive cohort and 10/13 patients in the adjuvant cohort were still alive. Correlative studies suggested that response in some patients were associated with specific CD4 T-cell subsets.

Conclusions: Overall, concurrent administration of ipilimumab and radiation was feasible, and resulted in a high response rate, converting some patients with unresectable disease into surgical candidates. Additional studies to investigate the combination of radiation and checkpoint inhibitor therapy are warranted.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-2452DOI Listing
March 2021

The utility of initial staging PET-CT as a baseline scan for surveillance imaging in stage II and III melanoma.

Surg Oncol 2020 Dec 2;35:533-539. Epub 2020 Nov 2.

Department of Surgery, Duke University Medical Center, Durham, NC, USA. Electronic address:

Background: This study evaluates the utility of whole-body PET-CT for the initial staging and subsequent surveillance imaging of patients with completely resected stage II and stage III melanoma.

Methods: A single-center, retrospective review of patients who received perioperative whole-body PET-CT from January 1, 2005 to December 1, 2019 within three months of initial melanoma diagnosis was performed.

Results: Of 258 total patients with completely resected melanoma who had a PET-CT within 3 months after their melanoma diagnosis, 113 had stage II and 145 had stage III melanoma. PET-CT detected distant metastasis in 3 (2.7%) of 113 stage II patients and 7 (4.8%) of 145 stage III patients. 179 of 258 patients had adequate follow-up time to determine whether they received surveillance cross-sectional imaging and whether they had a melanoma recurrence. 143 (79.9%) received subsequent surveillance imaging, 74 of whom developed a recurrence. In 64 (86.5%) of 74 cases, recurrence was detected by routine surveillance. 26 (34.2%) of 76 stage II and 65 (63.1%) of 103 stage III patients developed a recurrence. The median time to recurrence among the 179 patients for stage II and III was 16.3 and 13.0 months, respectively.

Conclusions: These findings indicate that baseline staging with whole-body PET-CT rarely provides information that changes initial management. Rather, the value of the initial PET-CT is as a baseline for subsequent surveillance scans. Therefore, it may be premature to discourage cross-sectional imaging for patients with stage II and III melanoma without supportive evidence or a reliable biomarker of recurrent disease.
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http://dx.doi.org/10.1016/j.suronc.2020.10.018DOI Listing
December 2020

Oncologic Outcomes After Isolated Limb Infusion for Advanced Melanoma: An International Comparison of the Procedure and Outcomes Between the United States and Australia.

Ann Surg Oncol 2020 Dec 11;27(13):5107-5118. Epub 2020 Sep 11.

Department of Cutaneous Oncology, Moffitt Cancer Center and Research Institute, Tampa, FL, USA.

Background: Isolated limb infusion (ILI) is a minimally invasive procedure for delivering high-dose chemotherapy to extremities affected by locally advanced or in-transit melanoma. This study compared the outcomes of melanoma patients treated with ILI in the United States of America (USA) and Australia (AUS).

Methods: Patients with locally recurrent in-transit melanoma treated with ILI at USA or AUS centers between 1992 and 2018 were identified. Demographic and clinicopathologic characteristics were collected. Primary outcomes of treatment response, in-field progression-free survival (IPFS), distant progression-free survival (DPFS), and overall survival (OS) were evaluated by the Kaplan-Meier method. Multivariable analysis evaluated whether availability of new systemic therapies affected outcomes.

Results: More ILIs were performed in AUS (n = 411, 60 %) than in the USA (n = 276, 40 %). In AUS, more ILIs were performed for stage 3B disease than in the USA (62 % vs 46 %; p < 0.001). The reported complete response rates were similar (AUS 30 % vs USA 29 %). Among the stage 3B patients, AUS patients had better IPFS (p = 0.001), whereas DPFS and OS were similar between the two countries. Among the stage 3C patients, the USA patients had better OS (p < 0.001), whereas IPFS and DPFS were similar. Availability of new systemic therapies did not affect IPFS or DPFS in either country. However, the USA patients who received ILI after ipilimumab approval in 2011 had significantly improved OS (hazard ratio, 0.62; p = 0.013).

Conclusions: AUS patients were treated at an earlier disease stage than the USA patients with better IPFS for stage 3B disease. The USA patients treated after the availability of new systemic therapies had a better OS.
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http://dx.doi.org/10.1245/s10434-020-09051-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7674259PMC
December 2020

Higher BMI, But Not Sarcopenia, Is Associated With Pembrolizumab-related Toxicity in Patients With Advanced Melanoma.

Anticancer Res 2020 Sep;40(9):5245-5254

Department of Surgery, Duke University Medical Center, Durham, NC, U.S.A.

Background/aim: To determine whether BMI and sarcopenia were related to treatment-limiting toxicity or efficacy of pembrolizumab treatment in melanoma patients.

Patients And Methods: Medical records for melanoma patients undergoing pembrolizumab treatment at Duke University from January 2014 to September 2018 were reviewed. Pre-treatment measurements such as BMI were collected. Pre-treatment CT imaging was used to determine psoas muscle index (PMI). Patients in the lowest sex-specific tertile of PMI were sarcopenic. Logistic regression measured associations with treatment toxicity and response. Kaplan-Meier analysis assessed progression-free survival (PFS) and overall survival (OS).

Results: Among 156 patients, the overall objective response rate was 46.2% and 29 patients (18.6%) experienced treatment-limiting toxicity. Sarcopenia was not significantly associated with toxicity, response, or survival. However, obese patients (BMI >30) experienced higher rates of toxicity (p=0.0007).

Conclusion: Sarcopenia did not appear to predict clinically relevant outcomes. Obesity, however, represents a readily available predictor of pembrolizumab toxicity.
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http://dx.doi.org/10.21873/anticanres.14528DOI Listing
September 2020

Retreatment with talimogene laherparepvec for advanced melanoma.

Immunotherapy 2020 Nov 25;12(16):1167-1172. Epub 2020 Aug 25.

Department of Surgery, Duke University Medical Center, Durham, NC 27710, USA.

Talimogene laherparepvec (T-VEC) is a genetically modified oncolytic herpesvirus approved for the treatment of unresectable, locoregionally advanced and recurrent melanoma. There is little relevant literature in the context of retreatment with T-VEC. We reviewed four patients aged 71-87 years old with stage IIIB-IV melanoma at treatment who were rechallenged with T-VEC after experiencing recurrence of locoregional disease or prior treatment-limiting toxicity. Cessation of initial treatment was due to one of the following reasons: severe adverse event (one case), mixed response (one case) or complete response (two cases). Three males and one female underwent T-VEC retreatment with a mean of 5.5 injection cycles. Three patients experienced a complete response to retreatment, while one experienced disease progression. Intralesional T-VEC may be effective and well-tolerated in patients who have completed prior T-VEC therapy.
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http://dx.doi.org/10.2217/imt-2020-0029DOI Listing
November 2020

Dissecting the immune landscape of tumor draining lymph nodes in melanoma with high-plex spatially resolved protein detection.

Cancer Immunol Immunother 2021 Feb 19;70(2):475-483. Epub 2020 Aug 19.

Department of Surgery, Duke University, DUMC Box 3118, Durham, NC, 27710, USA.

Background: In melanoma patients, microscopic tumor in the sentinel lymph-node biopsy (SLN) increases the risk of distant metastases, but the transition from tumor in the SLN to metastatic disease remains poorly understood.

Methods: Fluorescent staining for CD3, CD20, CD11c, and DNA was performed on SLN tissue and matching primary tumors. Regions of interest (ROI) were then chosen geometrically (e.g., tumor) or by fluorescent cell subset markers (e.g., CD11c). Each ROI was further analyzed using NanoString Digital Spatial Profiling high-resolution multiplex profiling. Digital counts for 59-panel immune-related proteins were collected and normalized to account for system variation and ROI area.

Results: Tumor regions of SLNs had variable infiltration of CD3 cells among patients. The patient with overall survival (OS) > 8 years had the most CD11c- and CD3-expressing cells infiltrating the SLN tumor region. All patients had CD11c (dendritic cell, DC) infiltration into the SLN tumor region. Selecting ROI by specific cell subtype, we compared protein expression of CD11c cells between tumor and non-tumor/normal tissue SLN regions. Known markers of DC activation such as CD86, HLA-DR, and OX40L were lowest on CD11c cells within SLN tumor for the patient with OS < 1 year and highest on the patient with OS > 8 years.

Conclusion: We demonstrate the feasibility of profiling the protein expression of CD11c cells within the SLN tumor. Identifying early regulators of melanoma control when the disease is microscopically detected in the SLN is beneficial and requires follow-up studies in a larger cohort of patients.
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http://dx.doi.org/10.1007/s00262-020-02698-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7892641PMC
February 2021

Factors predicting toxicity and response following isolated limb infusion for melanoma: An international multi-centre study.

Eur J Surg Oncol 2020 11 13;46(11):2140-2146. Epub 2020 Jul 13.

Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia; Department of Melanoma and Surgical Oncology, Royal Prince Alfred Hospital, Sydney, NSW, Australia; Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia.

Introduction: Isolated limb infusion (ILI) is a minimally-invasive procedure for delivering high-dose regional chemotherapy to treat melanoma in-transit metastases confined to a limb. The aim of this international multi-centre study was to identify predictive factors for toxicity and response.

Methods: Data of 687 patients who underwent a first ILI for melanoma in-transit metastases confined to the limb between 1992 and 2018 were collected at five Australian and four US tertiary referral centres.

Results: After ILI, predictive factors for increased limb toxicity (Wieberdink grade III/IV limb toxicity, n = 192, 27.9%) were: female gender, younger age, procedures performed before 2005, lower limb procedures, higher melphalan dose, longer drug circulation and ischemia times, and increased tissue hypoxia. No patient experienced grade V toxicity (necessitating amputation). A complete response (n = 199, 28.9%) was associated with a lower stage of disease, lower burden of disease (BOD) and thinner Breslow thickness of the primary melanoma. Additionally, an overall response (combined complete and partial response, n = 441, 64.1%) was associated with female gender, Australian centres, procedures performed before 2005, lower limb procedures and lower actinomycin-D doses. On multivariate analysis, higher melphalan dose remained a predictive factor for toxicity, while lower stage of disease and lower BOD remained predictive factors for overall response.

Conclusion: ILI is safe and effective to treat melanoma in-transit metastases. Predictive factors for toxicity and response identified in this study will allow improved patient selection and optimization of intra-operative parameters to increase response rates, while keeping toxicity low.
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http://dx.doi.org/10.1016/j.ejso.2020.06.040DOI Listing
November 2020

Overall Survival Improved for Contemporary Patients with Melanoma: A 2004-2015 National Cancer Database Analysis.

Oncol Ther 2020 Dec 28;8(2):261-275. Epub 2020 May 28.

Department of Surgery, Duke University Medical Center, Durham, NC, USA.

Introduction: Since 2011, encouraging clinical trial results have led to approval of multiple new therapies for advanced melanoma, but the impact of these therapies outside of trial populations is largely unknown. This study examines use of novel therapies and survival in contemporary patients with melanoma.

Methods: Stage I-IV melanoma patients were identified in the 2004-2015 National Cancer Database and grouped into historic (2004-2010) and contemporary (2011-2015) cohorts. Overall survival (OS) was compared using Kaplan-Meier and Cox proportional hazard modeling adjusting for patient, tumor, and facility characteristics.

Results: Of 268,668 patients, 136,828 were classified as historic and 131,840 as contemporary. Among all stages, immunotherapy utilization was significantly higher among contemporary patients (5.3% vs. 5.1%, p = 0.006). Adjusted OS was improved in the contemporary cohort (hazard ratio [HR]: 0.90 p < 0.001). There was no difference in OS among stage I/II patients between groups (HR: 0.99, p = 0.63), while OS was significantly improved for contemporary stage III/IV patients (HR: 0.85, p < 0.001). Among stage III/IV patients who received immunotherapy, OS was improved for the contemporary cohort (HR: 0.87, p = 0.014).

Conclusions: Adjusted overall survival for contemporary melanoma patients is improved. This effect is driven by improvements for those with advanced stage disease, particularly those that received immunotherapy and BRAF/MEK targeted therapies.
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http://dx.doi.org/10.1007/s40487-020-00117-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7683754PMC
December 2020

Injectable Therapies for Regional Melanoma.

Surg Oncol Clin N Am 2020 07;29(3):433-444

Department of Surgery, Duke University, DUMC Box 3118, Durham, NC 27710, USA. Electronic address:

Patients with unresectable cutaneous, subcutaneous, or nodal melanoma metastases are often candidates for injectable therapies, which are attractive for ease of intralesional delivery to superficial metastases and limited systemic toxicity profiles. Injectable or intralesional therapies can be part of multifaceted treatment strategies to kill tumor directly or to alter the tumor so as to make it more sensitive to systemic therapy. Talimogene laherparepvec is the only Food and Drug Administration-approved injectable therapy currently in wide clinical use in the United States, although ongoing trials are evaluating novel intralesional agents as well as combinations with systemic therapies, particularly checkpoint inhibitors.
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http://dx.doi.org/10.1016/j.soc.2020.02.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7274146PMC
July 2020

Adjuvant Therapy is Effective for Melanoma Patients with a Positive Sentinel Lymph Node Biopsy Who Forego Completion Lymphadenectomy.

Ann Surg Oncol 2020 Dec 20;27(13):5121-5125. Epub 2020 Apr 20.

Department of Surgery, Duke University Medical Center, Durham, NC, USA.

Background: Multiple adjuvant therapies for melanoma have been approved since 2015 based on randomized trials demonstrating improvements in recurrence-free survival (RFS) with adjuvant therapy after surgical resection of high-risk disease. Inclusion criteria for these trials required performance of a completion lymph node dissection (CLND) for positive sentinel lymph node (pSLN) disease.

Objective: We aimed to describe current practice for adjuvant therapies in patients with pSLN without CLND (active surveillance [AS]), and to evaluate recurrence in these patients.

Methods: Melanoma patients with pSLN between 2016 and 2019 were identified at two institutions. Demographic information, disease and treatment characteristics, and recurrence details were reviewed retrospectively. Patients were stratified by recurrence and patient-, treatment- and tumor-related characteristics were compared using Fisher's exact test and t test for categorical and continuous variables, respectively.

Results: Overall, 245 SLN biopsies were performed, of which 36 (14.7%) were pSLN. Of 36 pSLN, 4 underwent CLND and 32 underwent AS, of whom 22 (68.8%) received adjuvant therapy with the anti-programmed death-1 (PD1) inhibitor nivolumab (16/22), anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitor ipilimumab (3/22), or BRAF/MEK inhibitors (3/22). At a median follow up of 13.3 months, 7/32 (21.9%) patients on AS recurred, including 4/22 (18.2%) who received adjuvant therapy and 3/10 (30.0%) who did not. Tumor ulceration was significantly associated with recurrence. While not significant, acral lentiginous subtype appeared more common among those with recurrence.

Conclusion: The majority (68.8%) of patients with pSLN managed without CLND were treated with adjuvant therapy. The 1-year RFS for patients managed with adjuvant therapy without CLND was 82%, which is similar to modern adjuvant therapy trials requiring CLND.
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http://dx.doi.org/10.1245/s10434-020-08478-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7572494PMC
December 2020

Acral Melanomas of the Sole May Have Worse Prognosis Compared with Other Sites of Acral Melanoma.

Ann Surg Oncol 2020 Sep 19;27(9):3121-3122. Epub 2020 Apr 19.

Duke University, Durham, NC, USA.

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http://dx.doi.org/10.1245/s10434-020-08460-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7415581PMC
September 2020

Mind the gap: Gendered publication trends in oncology.

Cancer 2020 06 25;126(12):2859-2865. Epub 2020 Mar 25.

Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York.

Background: Investigating scientific publication trends in the field of oncology may highlight opportunities for improved representation, mentorship, collaboration, and advancement for women.

Methods: We conducted a bibliometric analysis of Annals of Surgical Oncology; Cancer; International Journal of Radiation Oncology, Biology, Physics (IJROBP); JAMA Oncology; and Journal of Clinical Oncology in 1990, 2000, 2010, and 2017. Full name and degree credentials per author role (ie, first or senior author), article type, publication year, and citation metrics were collected. First names were used to identify author gender.

Results: Across 9189 articles, female representation rose between 1990 and 2017 (first authors: 17.7% in 1990, 36.6% in 2017; senior authors: 11.7% in 1990, 28.5% in 2017). For the 50 most cited articles per year, women comprised a smaller percent of first (26.5%) and senior (19.9%) authors. The average citation count was higher for male first (44.8 per article) and senior (47.1) authors compared to female first (39.7) and senior (44.1) authors. With male senior authors, the first author was more likely male (71.4% male; 25.0% female); with female senior authors, first authors were 50.2% male and 47.6% female. IJROBP had the lowest total female representation among first (25.1%) and senior (16.7%) authors. Women had more MDs with Masters degrees, whereas men held more MDs only and more MDs with PhDs.

Conclusion: Despite positive trends, substantial gendered differences in oncology publications persist. Fostering more women in oncology research will benefit female representation at many levels of academia and improve productivity, collaboration, and recruitment, especially in technical fields such as radiation and surgical oncology.
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http://dx.doi.org/10.1002/cncr.32818DOI Listing
June 2020

International Multicenter Experience of Isolated Limb Infusion for In-Transit Melanoma Metastases in Octogenarian and Nonagenarian Patients.

Ann Surg Oncol 2020 May 9;27(5):1420-1429. Epub 2020 Mar 9.

Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia.

Background: Isolated limb infusion (ILI) is used to treat in-transit melanoma metastases confined to an extremity. However, little is known about its safety and efficacy in octogenarians and nonagenarians (ON).

Patients And Methods: ON patients (≥ 80 years) who underwent a first ILI for American Joint Committee on Cancer seventh edition stage IIIB/IIIC melanoma between 1992 and 2018 at nine international centers were included and compared with younger patients (< 80 years). A cytotoxic drug combination of melphalan and actinomycin-D was used.

Results: Of the 687 patients undergoing a first ILI, 160 were ON patients (median age 84 years; range 80-100 years). Compared with the younger cohort (n = 527; median age 67 years; range 29-79 years), ON patients were more frequently female (70.0% vs. 56.9%; p = 0.003), had more stage IIIB disease (63.8 vs. 53.3%; p = 0.02), and underwent more upper limb ILIs (16.9% vs. 9.5%; p = 0.009). ON patients experienced similar Wieberdink limb toxicity grades III/IV (25.0% vs. 29.2%; p = 0.45). No toxicity-related limb amputations were performed. Overall response for ON patients was 67.3%, versus 64.6% for younger patients (p = 0.53). Median in-field progression-free survival was 9 months for both groups (p = 0.88). Median distant progression-free survival was 36 versus 23 months (p = 0.16), overall survival was 29 versus 40 months (p < 0.0001), and melanoma-specific survival was 46 versus 78 months (p = 0.0007) for ON patients compared with younger patients, respectively.

Conclusions: ILI in ON patients is safe and effective with similar response and regional control rates compared with younger patients. However, overall and melanoma-specific survival are shorter.
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http://dx.doi.org/10.1245/s10434-020-08312-0DOI Listing
May 2020

Correction to: Characteristics Associated with Pathologic Nodal Burden in Patients Presenting with Clinical Melanoma Nodal Metastasis.

Ann Surg Oncol 2019 12;26(Suppl 3):893

Department of Surgery, Division of Endocrine and Oncologic Surgery, Hospital of the University of Pennsylvania, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.

In the original article, there is an error in the funding information. The correct funding information is as follows.
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http://dx.doi.org/10.1245/s10434-019-08046-8DOI Listing
December 2019

The Landmark Series: Regional Therapy of Recurrent Cutaneous Melanoma.

Ann Surg Oncol 2020 Jan 30;27(1):35-42. Epub 2019 Aug 30.

Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia.

In-transit melanoma represents a distinct disease pattern in which melanoma recurs as dermal or subcutaneous nodules between the primary melanoma site and the draining regional lymph node basin. The disease pattern is often not amenable to complete surgical resection. Since the 1950s, regional therapies have been explored for the treatment of this disease entity, with the goal of maximizing delivery of the therapeutic agent to the tumor while minimizing systemic toxicity. We reviewed landmark studies describing and evaluating regional chemotherapy and intralesional therapies for patients with in-transit melanoma metastases.
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http://dx.doi.org/10.1245/s10434-019-07760-7DOI Listing
January 2020

Correction to: Sentinel Lymph Node Biopsy and Completion Lymph Node Dissection for Melanoma.

Curr Treat Options Oncol 2019 Aug 29;20(10):76. Epub 2019 Aug 29.

Department of Surgery, Duke University, Durham, NC, 27710, USA.

The original version of this article, which published in Current Treatment Options in Oncology, Volume 19, Issue 11, November 2018, contained an error within the Conflict of Interest statements. It was originally stated that "Norma E. Farrow received support from an NIH T32 grant (T32-CA009111."
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http://dx.doi.org/10.1007/s11864-019-0674-xDOI Listing
August 2019

Examining Peripheral and Tumor Cellular Immunome in Patients With Cancer.

Front Immunol 2019 31;10:1767. Epub 2019 Jul 31.

Department of Surgery, Duke University, Durham, NC, United States.

Immunotherapies are rapidly being integrated into standard of care (SOC) therapy in conjunction with surgery, chemotherapy, and radiotherapy for many cancers and a large number of clinical studies continue to explore immunotherapy alone and as part of combination therapies in patients with cancer. It is evident that clinical effectiveness of immunotherapy is limited to a subset of patients and improving immunotherapy related outcomes remains a major scientific and clinical effort. Understanding the immune cell subset phenotype and activation/functional status (cellular immunome) prior to and post therapy is therefore critical to develop biomarkers that (1) will predict if a patient will respond to immunotherapy and (2) are a result of immunotherapy. In this study, we investigated local (tumor) and peripheral (blood) cellular immunome of patients with melanoma, breast cancer, and brain cancer using a rapid and reliable standardized, multiparameter flow cytometry assay. We used this approach to monitor changes in the peripheral cellular immunome in women with breast cancer undergoing SOC therapy. Our analysis is unique because it is conducted using matched fresh tumor tissue and blood from patients in real-time, within 2-3 h of sample acquisition, and provides insight into the innate and adaptive immune cell profile in blood and tumor. Specific to blood, this approach involves no manipulation and evaluates all immune subsets such as T cells, B cells, natural killer (NK) cells, monocytes, dendritic cells (DCs), neutrophils, eosinophils, and basophils using 0.5 ml of blood. Analysis of the corresponding tumor provides much needed insight into the phenotype and activation status of immune cells, especially T and B cells, in the tumor microenvironment vs. the periphery. This analysis will be used to assess baseline and therapy-mediated changes in local and peripheral cellular immunome in patients with glioblastoma, breast cancer, and melanoma in planned immunotherapy clinical studies.
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http://dx.doi.org/10.3389/fimmu.2019.01767DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6685102PMC
September 2020

Efficacy of Talimogene Laherparepvec (T-VEC) Therapy in Patients with In-Transit Melanoma Metastasis Decreases with Increasing Lesion Size.

Ann Surg Oncol 2019 Dec 14;26(13):4633-4641. Epub 2019 Aug 14.

Department of Surgery, Duke University Medical Center, Durham, NC, USA.

Background: Talimogene laherparepvec (T-VEC) is the first injectable oncolytic viral therapy approved for in-transit melanoma metastasis, with a reported overall response rate (ORR) of 25% and complete response rate (CRR) of 10%. To ascertain the role of patient selection on outcomes in routine practice, we evaluated the impact of patient, lesion, and treatment factors on clinical response.

Methods: Medical records were extracted for patients with recurrent stage IIIB-IV melanoma completing T-VEC at Duke University Medical Center between 1 January 2016 and 1 September 2018. Kaplan-Meier analysis assessed time to response and survival, while logistic regression measured associations of clinicopathologic status, lesion burden, T-VEC dosing, and use of prior and concurrent therapy with ORR and CRR.

Results: Of 27 patients, an objective response was observed in 11 (40.7%), including one patient with partial response (3.7%) and 10 with complete response (37.0%). Time to complete response and overall response was a median 22 weeks (95% confidence interval [CI] 2.0-41.9 weeks and 15.8-28.2 weeks, respectively), and median progression-free survival was 17 weeks (95% CI 0-36 weeks). Logistic regression demonstrated each millimeter increase in maximum lesion diameter predicted decreased ORR (odds ratio [OR] 0.866, 95% CI 0.753-0.995; p = 0.04). Stage IV disease (OR 0.04, 95% CI 0.00-0.74; p = 0.031) and programmed death-1 inhibitor treatment (OR 0.06, 95% CI 0.01-0.74; p = 0.028) also predicted reduced clinical response.

Conclusions: This study corroborates recent data suggesting response rates to T-VEC may be higher than reported in clinical trials, arising in part from patient selection. T-VEC lesion diameter was persistently associated with clinical response and is a readily assessed predictor of successful T-VEC therapy.
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http://dx.doi.org/10.1245/s10434-019-07691-3DOI Listing
December 2019

Characteristics Associated with Pathologic Nodal Burden in Patients Presenting with Clinical Melanoma Nodal Metastasis.

Ann Surg Oncol 2019 11 7;26(12):3962-3971. Epub 2019 Aug 7.

Department of Surgery, Division of Endocrine and Oncologic Surgery, Hospital of the University of Pennsylvania, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.

Background: Nodal observation is safe for patients with microscopic melanoma metastasis in a sentinel lymph node (LN). Complete LN dissection (CLND) remains the standard of care for patients with clinically evident LN (cLN) metastases, even though about 40% have only one pathologic LN (pLN). We sought to identify clinical features associated with having one pLN among patients with cLNs.

Methods: Patients at three melanoma centers who underwent CLND for cLNs were identified. Clinicopathologic and imaging characteristics associated with one pLN were determined by multivariable logistic regression and classification tree analysis.

Results: Of 190 patients, 90 (47.4%) had one pLN and 100 (52.6%) had more than one pLN. By multivariable logistic regression, extremity versus truncal primary (odds ratio [OR] 2.15, p = 0.012), axillary versus superficial inguinal location (OR 3.89, p = 0.009), and preoperative cross-sectional imaging demonstrating more than one versus one cLN (OR 17.1, p < 0.001) were associated with more than one pLN. The negative predictive value for additional pathologic nodal disease of preoperative imaging was 70.9%, increasing to 74.4% for positron emission tomography/computed tomography. In the subgroup of patients with one cLN, the classification tree identified two groups with < 10% risk of additional pLNs: (1) Breslow thickness > 6.55 mm (n = 17); and (2) if unknown primary or Breslow thickness ≤ 6.55 mm, then LN diameter > 1.8 cm in the inguinal location (n = 22).

Conclusion: The majority of patients with one cLN from melanoma by preoperative imaging will harbor no additional pathologic nodes on CLND. Safety of nodal observation after clinical nodal excision in these patients, particularly in an era of effective adjuvant therapies, deserves prospective evaluation.
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http://dx.doi.org/10.1245/s10434-019-07694-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6896209PMC
November 2019

Type of Organ Transplanted Impacts the Risk and Presentation of Cutaneous Squamous Cell Carcinoma in Transplant Recipients.

Exp Clin Transplant 2020 02 9;18(1):93-97. Epub 2019 Apr 9.

From the Duke University School of Medicine, Duke University Health System, Durham, North Carolina, USA.

Objectives: Transplant immunosuppression increases the risk of cutaneous squamous cell carcinoma by 65- to 200-fold. Our objective was to investigate the impact of the type of organ transplanted on the risk and presentation of cutaneous squamous cell carcinoma.

Materials And Methods: The retrospective database of the Duke University Health System was queried to identify patients who underwent an organ transplant from 1996 to 2016. Data regarding transplant outcomes, cutaneous squamous cell carcinoma, immunosuppressive regimens, and survival were recorded. We used chi-square tests, analysis of variance, and unpaired t tests to compare the incidence and presentation of cutaneous squamous cell carcinoma among organ types.

Results: Of 3652 renal, hepatic, and cardiothoracic transplant patients identified, 142 patients developed at least 1 cutaneous squamous cell carcinoma. The incidence of cutaneous squamous cell carcinoma varied by type of organ transplanted, with 46 of 1684 (2.7%) renal transplant patients developing cutaneous squamous cell carcinoma, 33 of 804 (4.1%) hepatic transplant patients, and 63 of 1164 (5.4%) cardiothoracic transplant patients over the median follow-up time of 6.5 years. Incidence in the renal transplant versus the cardiothoracic transplant group was significantly different (P < .001). The time to presentation of cutaneous squamous cell carcinoma varied significantly by group, with the renal cohort presenting at 3.8 years compared with at 2.4 years in the cardiothoracic group and 2.1 years in the hepatic group (P < .001).

Conclusions: The type of organ transplanted confers a unique risk and presentation of cutaneous squamous cell carcinoma.
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http://dx.doi.org/10.6002/ect.2018.0238DOI Listing
February 2020

Long-Term Oncologic Outcomes After Isolated Limb Infusion for Locoregionally Metastatic Melanoma: An International Multicenter Analysis.

Ann Surg Oncol 2019 Aug 25;26(8):2486-2494. Epub 2019 Mar 25.

Department of Cutaneous Oncology, Moffitt Cancer Center and Research Institute, Tampa, FL, USA.

Background: Isolated limb infusion (ILI) is a minimally invasive procedure for delivering high-dose regional chemotherapy to patients with locally advanced or in-transit melanoma located on a limb. The current international multicenter study evaluated the perioperative and long-term oncologic outcomes for patients who underwent ILI for stage 3B or 3C melanoma.

Methods: Patients undergoing a first-time ILI for stage 3B or 3C melanoma (American Joint Committee on Cancer [AJCC] 7th ed) between 1992 and 2018 at five Australian and four United States of America (USA) tertiary referral centers were identified. The primary outcome measures included treatment response, in-field (IPFS) and distant progression-free survival (DPFS), and overall survival (OS).

Results: A total of 687 first-time ILIs were performed (stage 3B: n = 383, 56%; stage 3C; n = 304, 44%). Significant limb toxicity (Wieberdink grade 4) developed in 27 patients (3.9%). No amputations (grade 5) were performed. The overall response rate was 64.1% (complete response [CR], 28.9%; partial response [PR], 35.2%). Stable disease (SD) occurred in 14.5% and progressive disease (PD) in 19.8% of the patients. The median follow-up period was 47 months, with a median OS of 38.2 months. When stratified by response, the patients with a CR or PR had a significantly longer median IPFS (21.9 vs 3.0 months; p < 0.0001), DPFS (53.6 vs 12.7 months; p < 0.0001), and OS (46.5 vs 24.4 months; p < 0.0001) than the nonresponders (SD + PD).

Conclusion: This study is the largest to date reporting long-term outcomes of ILI for locoregionally metastatic melanoma. The findings demonstrate that ILI is effective and safe for patients with stage 3B or 3C melanoma confined to a limb. A favorable response to ILI is associated with significantly longer IFPS, DPFS, and OS.
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http://dx.doi.org/10.1245/s10434-019-07288-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7771312PMC
August 2019

The Emerging Role of Surgery for Patients With Advanced Melanoma Treated With Immunotherapy.

J Surg Res 2019 04 20;236:209-215. Epub 2018 Dec 20.

Department of Surgery, Duke University, Durham, North Carolina.

Background: The emergence of immune checkpoint inhibitors (ICIs) has improved survival for patients with metastatic melanoma. The types of disease-response patterns to ICI therapy can be more complex relative to traditional chemotherapy and include mixed responses, pseudoprogression, and oligoprogression. The potential benefit of surgery after incomplete response to ICI therapy has not been explored. The purpose of this study was to explore outcomes of surgery after ICI therapy in patients with metastatic melanoma.

Methods: A retrospective study was conducted at two centers and included patients with melanoma who underwent surgery after treatment with monotherapy or combination therapy with anti-programmed cell death protein (PD) 1 and/or anti-cytotoxic T-lymphocyte associated protein (CTLA)-4 checkpoint blockade.

Results: Of 25 patients, nine received anti-CTLA-4 therapy, eight received anti-PD-1 therapy, and eight received both anti-CTLA-4 and anti-PD-1 therapies before surgery. Five patients were treated in the adjuvant setting and developed new lesions, whereas 20 patients were treated for metastatic disease and underwent surgery for persistent disease on imaging after ICI therapy. Twenty-five patients underwent 30 operations without complications. Twenty-seven of 30 masses were confirmed to be melanoma on pathology, one was a desmoid tumor and two were necrosis. At a median follow-up of 14.2 months, 2 patients died, 8 were alive with a known disease, and 15 continued to have no further evidence of disease.

Conclusions: Surgery was well tolerated in this cohort of patients receiving ICI therapy for melanoma. Surgery may benefit select patients with an oligoprogressive disease after ICI therapy. After a mixed response, surgery remains the only definitive method to render some patients free of disease.
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http://dx.doi.org/10.1016/j.jss.2018.11.045DOI Listing
April 2019