Current and future cancer staging after neoadjuvant treatment for solid tumors.

Until recently, cancer registries have only collected cancer clinical stage at diagnosis, before any therapy, and pathological stage after surgical resection, provided no treatment has been given before the surgery, but they have not collected stage data after neoadjuvant therapy (NAT). Because NAT is increasingly being used to treat a variety of tumors, it has become important to make the distinction between both the clinical and the pathological assessment without NAT and the assessment after NAT to avoid any misunderstanding of the significance of the clinical and pathological findings. It also is important that cancer registries collect data after NAT to assess response and effectiveness of this treatment approach on a population basis. The prefix y is used to denote stage after NAT. Currently, cancer registries of the American College of Surgeons' Commission on Cancer only partially collect y stage data, and data on the clinical response to NAT (yc or posttherapy clinical information) are not collected or recorded in a standardized fashion. In addition to NAT, nonoperative management after radiation and chemotherapy is being used with increasing frequency in rectal cancer and may be expanded to other treatment sites. Using examples from breast, rectal, and esophageal cancers, the pathological and imaging changes seen after NAT are reviewed to demonstrate appropriate staging.

The Eighth Edition AJCC Cancer Staging Manual: Continuing to build a bridge from a population-based to a more "personalized" approach to cancer staging.

The American Joint Committee on Cancer (AJCC) staging manual has become the benchmark for classifying patients with cancer, defining prognosis, and determining the best treatment approaches. Many view the primary role of the tumor, lymph node, metastasis (TNM) system as that of a standardized classification system for evaluating cancer at a population level in terms of the extent of disease, both at initial presentation and after surgical treatment, and the overall impact of improvements in cancer treatment. The rapid evolution of knowledge in cancer biology and the discovery and validation of biologic factors that predict cancer outcome and response to treatment with better accuracy have led some cancer experts to question the utility of a TNM-based approach in clinical care at an individualized patient level. In the Eighth Edition of the AJCC Cancer Staging Manual, the goal of including relevant, nonanatomic (including molecular) factors has been foremost, although changes are made only when there is strong evidence for inclusion. The editorial board viewed this iteration as a proactive effort to continue to build the important bridge from a "population-based" to a more "personalized" approach to patient classification, one that forms the conceptual framework and foundation of cancer staging in the era of precision molecular oncology. The AJCC promulgates best staging practices through each new edition in an effort to provide cancer care providers with a powerful, knowledge-based resource for the battle against cancer. In this commentary, the authors highlight the overall organizational and structural changes as well as "what's new" in the Eighth Edition. It is hoped that this information will provide the reader with a better understanding of the rationale behind the aggregate proposed changes and the exciting developments in the upcoming edition. CA Cancer J Clin 2017;67:93-99. © 2017 American Cancer Society.

An In Vivo Model of Human Macrophages in Metastatic Melanoma.

Despite recent therapeutic progress, advanced melanoma remains lethal for many patients. The composition of the immune tumor microenvironment (TME) has decisive impacts on therapy response and disease outcome, and high-dimensional analyses of patient samples reveal the heterogeneity of the immune TME. Macrophages infiltrate TMEs and generally associate with tumor progression, but the underlying mechanisms are incompletely understood. Because experimental systems are needed to elucidate the functional properties of these cells, we developed a humanized mouse model reconstituted with human immune cells and human melanoma. We used two strains of recipient mice, supporting or not supporting the development of human myeloid cells. We found that human myeloid cells favored metastatic spread of the primary tumor, thereby recapitulating the cancer-supportive role of macrophages. We next analyzed the transcriptome of human immune cells infiltrating tumors versus other tissues. This analysis identified a cluster of myeloid cells present in the TME, but not in other tissues, which do not correspond to canonical M2 cells. The transcriptome of these cells is characterized by high expression of glycolytic enzymes and multiple chemokines and by low expression of gene sets associated with inflammation and adaptive immunity. Compared with humanized mouse results, we found transcriptionally similar myeloid cells in patient-derived samples of melanoma and other cancer types. The humanized mouse model described here thus complements patient sample analyses, enabling further elucidation of fundamental principles in melanoma biology beyond M1/M2 macrophage polarization. The model can also support the development and evaluation of candidate antitumor therapies.

Narrow excision margins are appropriate for Merkel cell carcinoma when combined with adjuvant radiation: Analysis of 188 cases of localized disease and proposed management algorithm.

BACKGROUND: Merkel cell carcinoma (MCC) management typically includes surgery with or without adjuvant radiation therapy (aRT). Major challenges include determining surgical margin size and whether aRT is indicated. OBJECTIVE: To assess the association of aRT, surgical margin size, and MCC local recurrence. METHODS: Analysis of 188 MCC cases presenting without clinical nodal involvement. RESULTS: aRT-treated patients tended to have higher-risk tumors (larger diameter, positive microscopic margins, immunosuppression) yet had fewer local recurrences (LRs) than patients treated with surgery only (1% vs 15%; P = .001). For patients who underwent surgery alone, 7 of 35 (20%) treated with narrow margins (defined as ≤1.0 cm) developed LR, whereas 0 of 13 patients treated with surgical margins greater than 1.0 cm developed LR (P = .049). For aRT-treated patients, local control was excellent regardless of surgical margin size; only 1% experienced recurrence in each group (1 of 70 with narrow margins ≤1 cm and 1 of 70 with margins >1 cm; P = .56). LIMITATIONS: This was a retrospective study. CONCLUSIONS: Among patients treated with aRT, local control was superb even if significant risk factors were present and margins were narrow. We propose an algorithm for managing primary MCC that integrates risk factors and optimizes local control while minimizing morbidity.

Completion Dissection or Observation for Sentinel-Node Metastasis in Melanoma.

BACKGROUND: Sentinel-lymph-node biopsy is associated with increased melanoma-specific survival (i.e., survival until death from melanoma) among patients with node-positive intermediate-thickness melanomas (1.2 to 3.5 mm). The value of completion lymph-node dissection for patients with sentinel-node metastases is not clear. METHODS: In an international trial, we randomly assigned patients with sentinel-node metastases detected by means of standard pathological assessment or a multimarker molecular assay to immediate completion lymph-node dissection (dissection group) or nodal observation with ultrasonography (observation group). The primary end point was melanoma-specific survival. Secondary end points included disease-free survival and the cumulative rate of nonsentinel-node metastasis. RESULTS: Immediate completion lymph-node dissection was not associated with increased melanoma-specific survival among 1934 patients with data that could be evaluated in an intention-to-treat analysis or among 1755 patients in the per-protocol analysis. In the per-protocol analysis, the mean (±SE) 3-year rate of melanoma-specific survival was similar in the dissection group and the observation group (86±1.3% and 86±1.2%, respectively; P=0.42 by the log-rank test) at a median follow-up of 43 months. The rate of disease-free survival was slightly higher in the dissection group than in the observation group (68±1.7% and 63±1.7%, respectively; P=0.05 by the log-rank test) at 3 years, based on an increased rate of disease control in the regional nodes at 3 years (92±1.0% vs. 77±1.5%; P<0.001 by the log-rank test); these results must be interpreted with caution. Nonsentinel-node metastases, identified in 11.5% of the patients in the dissection group, were a strong, independent prognostic factor for recurrence (hazard ratio, 1.78; P=0.005). Lymphedema was observed in 24.1% of the patients in the dissection group and in 6.3% of those in the observation group. CONCLUSIONS: Immediate completion lymph-node dissection increased the rate of regional disease control and provided prognostic information but did not increase melanoma-specific survival among patients with melanoma and sentinel-node metastases. (Funded by the National Cancer Institute and others; MSLT-II ClinicalTrials.gov number, NCT00297895 .).

Managing Cancer Care During the COVID-19 Pandemic: Agility and Collaboration Toward a Common Goal.

The first confirmed case of coronavirus disease 2019 (COVID-19) in the United States was reported on January 20, 2020, in Snohomish County, Washington. At the epicenter of COVID-19 in the United States, the Seattle Cancer Care Alliance, Fred Hutchinson Cancer Research Center, and University of Washington are at the forefront of delivering care to patients with cancer during this public health crisis. This Special Feature highlights the unique circumstances and challenges of cancer treatment amidst this global pandemic, and the importance of organizational structure, preparation, agility, and a shared vision for continuing to provide cancer treatment to patients in the face of uncertainty and rapid change.

Lymphedema symptoms and limb measurement changes in breast cancer survivors treated with neoadjuvant chemotherapy and axillary dissection: results of American College of Surgeons Oncology Group (ACOSOG) Z1071 (Alliance) substudy.

PURPOSE: Lymphedema is a potential complication of breast cancer treatment. This longitudinal substudy aimed to prospectively assess arm measurements and symptoms following neoadjuvant chemotherapy and axillary dissection in the ACOSOG/Alliance Z1071 trial to characterize the optimal approach to define lymphedema. METHODS: Z1071 enrolled patients with cT0-4, N1-2, M0 disease treated with neoadjuvant chemotherapy. All patients underwent axillary dissection. Bilateral limb volumes, circumferences, and related symptoms were assessed pre-surgery, 1-2 weeks post-surgery, and semiannually for 36 months. Lymphedema definitions included volume increase ≥ 10% or limb circumference increase ≥ 2 cm. Symptoms were assessed by the Lymphedema Breast Cancer Questionnaire. RESULTS: In 488 evaluable patients, lymphedema incidence at 3 years by ≥ 10%-volume-increase was 60.3% (95% CI 55.0-66.2%) and by ≥ 2 cm-circumference increase was 75.4% (95% CI 70.8-80.2%). Symptoms of arm swelling and heaviness decreased from post-surgery for the first 18 months and then were relatively stable. The 3-year cumulative incidence of arm swelling and heaviness was 26.0% (95% CI 21.7-31.1%) and 30.9% (95% CI 26.3-36.3%), respectively. There was limited agreement between the two measurements (kappa 0.27) and between symptoms and measurements (kappa coefficients ranging from 0.05-0.09). CONCLUSIONS: Lymphedema incidence by limb volume and circumference gradually increased over 36 months post-surgery, whereas lymphedema symptoms were much lower. These findings underscore the importance of prospective surveillance and evaluation of both limb measurements and symptom assessment. Lymphedema incidence rates varied by definition. We recommend that ≥ 10% volume change criterion be used for lymphedema evaluation for referral for specialist care. TRIAL REGISTRATION: NCT00881361.

Why Thyroid Surgeons Are Frustrated with Radiologists: Lessons Learned from Pre- and Postoperative US.

Optimal treatment of thyroid cancer is highly dependent on accurate staging of the extent of disease at presentation. Preoperative ultrasonography (US) is the most sensitive method for detecting metastatic lymph nodes and is recommended as part of the standard preoperative workup. Missed findings on preoperative scans may lead to understaging and inadequate surgical management, which subsequently predispose these patients to residual disease postoperatively and a higher risk for recurrence, possibly requiring repeat surgery. Traditionally, thyroid US for pre- and postoperative staging has been performed by radiologists. However, there is a growing trend away from radiologist-performed US in favor of surgeon-performed US. Recent surgical and endocrinology literature has shown that, when compared with surgeon-performed US, radiologist-performed preoperative staging US is less accurate and is inadequate for presurgical planning, with higher local recurrence rates. This review highlights the importance of accurate preoperative US for patients with differentiated thyroid cancer, with specific attention to deficiencies that exist in general radiology department thyroid US reports. We present a standardized approach to neck US reporting that incorporates the newly updated 2015 recommendations from the American Thyroid Association and also addresses the pertinent questions for thyroid surgeons. By ensuring comprehensive preoperative assessment and improving thyroid US reporting, we seek to improve patient access to optimized care. ©RSNA, 2016.

Age as a predictor of sentinel node metastasis among patients with localized melanoma: an inverse correlation of melanoma mortality and incidence of sentinel node metastasis among young and old patients.

PURPOSE: We have previously reported that older patients with clinical stage I and II primary cutaneous. Melanoma had lower survival rates compared to younger patients. We postulated that the incidence of nodal metastasis would therefore be higher among older melanoma patients. METHODS: The expanded American Joint Committee on Cancer melanoma staging database contains a cohort of 7,756 melanoma patients who presented without clinical evidence of regional lymph node or distant metastasis and who underwent a sentinel node biopsy procedure as a component of their staging assessment. RESULTS: Although older patients had primary melanoma features associated with more aggressive biology, we paradoxically observed a significant decrease in the incidence of sentinel node metastasis as patient age increased. Overall, the highest incidence of sentinel node metastasis was 25.8 % in patients under 20 years of age, compared to 15.5 % in patients 80 years and older (p < 0.001). In contrast, 5-year mortality rates for clinical stage II patients ranged from a low of 20 % for those 20-40 years of age up to 38 % for those over 70 years of age. Patient age was an independent predictor of sentinel node metastasis in a multifactorial analysis (p < 0.001). CONCLUSIONS: Patients with clinical stage I and II melanoma under 20 years of age had a higher incidence of sentinel lymph node metastasis but, paradoxically, a more favorable survival outcome compared to all other age groups. In contrast, patients >70 years had the most aggressive primary melanoma features and a higher mortality rate compared to all other age groups but a lower incidence of sentinel lymph node metastasis.

Sentinel lymph node surgery after neoadjuvant chemotherapy in patients with node-positive breast cancer: the ACOSOG Z1071 (Alliance) clinical trial.

IMPORTANCE: Sentinel lymph node (SLN) surgery provides reliable nodal staging information with less morbidity than axillary lymph node dissection (ALND) for patients with clinically node-negative (cN0) breast cancer. The application of SLN surgery for staging the axilla following chemotherapy for women who initially had node-positive cN1 breast cancer is unclear because of high false-negative results reported in previous studies. OBJECTIVE: To determine the false-negative rate (FNR) for SLN surgery following chemotherapy in women initially presenting with biopsy-proven cN1 breast cancer. DESIGN, SETTING, AND PATIENTS: The American College of Surgeons Oncology Group (ACOSOG) Z1071 trial enrolled women from 136 institutions from July 2009 to June 2011 who had clinical T0 through T4, N1 through N2, M0 breast cancer and received neoadjuvant chemotherapy. Following chemotherapy, patients underwent both SLN surgery and ALND. Sentinel lymph node surgery using both blue dye (isosulfan blue or methylene blue) and a radiolabeled colloid mapping agent was encouraged. MAIN OUTCOMES AND MEASURES: The primary end point was the FNR of SLN surgery after chemotherapy in women who presented with cN1 disease. We evaluated the likelihood that the FNR in patients with 2 or more SLNs examined was greater than 10%, the rate expected for women undergoing SLN surgery who present with cN0 disease. RESULTS: Seven hundred fifty-six women were enrolled in the study. Of 663 evaluable patients with cN1 disease, 649 underwent chemotherapy followed by both SLN surgery and ALND. An SLN could not be identified in 46 patients (7.1%). Only 1 SLN was excised in 78 patients (12.0%). Of the remaining 525 patients with 2 or more SLNs removed, no cancer was identified in the axillary lymph nodes of 215 patients, yielding a pathological complete nodal response of 41.0% (95% CI, 36.7%-45.3%). In 39 patients, cancer was not identified in the SLNs but was found in lymph nodes obtained with ALND, resulting in an FNR of 12.6% (90% Bayesian credible interval, 9.85%-16.05%). CONCLUSIONS AND RELEVANCE: Among women with cN1 breast cancer receiving neoadjuvant chemotherapy who had 2 or more SLNs examined, the FNR was not found to be 10% or less. Given this FNR threshold, changes in approach and patient selection that result in greater sensitivity would be necessary to support the use of SLN surgery as an alternative to ALND. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00881361.

Neoantigen-specific CD4+ T cells in human melanoma have diverse differentiation states and correlate with CD8+ T cell, macrophage, and B cell function.

CD4+ T cells that recognize tumor antigens are required for immune checkpoint inhibitor efficacy in murine models, but their contributions in human cancer are unclear. We used single-cell RNA sequencing and T cell receptor sequences to identify signatures and functional correlates of tumor-specific CD4+ T cells infiltrating human melanoma. Conventional CD4+ T cells that recognize tumor neoantigens express CXCL13 and are subdivided into clusters expressing memory and T follicular helper markers, and those expressing cytolytic markers, inhibitory receptors, and IFN-γ. The frequency of CXCL13+ CD4+ T cells in the tumor correlated with the transcriptional states of CD8+ T cells and macrophages, maturation of B cells, and patient survival. Similar correlations were observed in a breast cancer cohort. These results identify phenotypes and functional correlates of tumor-specific CD4+ T cells in melanoma and suggest the possibility of using such cells to modify the tumor microenvironment.

Therapeutic Value of Sentinel Lymph Node Biopsy in Patients With Melanoma: A Randomized Clinical Trial.

Importance: Sentinel lymph node (SLN) biopsy is a standard staging procedure for cutaneous melanoma. Regional disease control is a clinically important therapeutic goal of surgical intervention, including nodal surgery. Objective: To determine how frequently SLN biopsy without completion lymph node dissection (CLND) results in long-term regional nodal disease control in patients with SLN metastases. Design, Setting, and Participants: The second Multicenter Selective Lymphadenectomy Trial (MSLT-II), a prospective multicenter randomized clinical trial, randomized participants with SLN metastases to either CLND or nodal observation. The current analysis examines observation patients with regard to regional nodal recurrence. Trial patients were aged 18 to 75 years with melanoma metastatic to SLN(s). Data were collected from December 2004 to April 2019, and data were analyzed from July 2020 to January 2022. Interventions: Nodal observation with ultrasonography rather than CLND. Main Outcomes and Measures: In-basin nodal recurrence. Results: Of 823 included patients, 479 (58.2%) were male, and the mean (SD) age was 52.8 (13.8) years. Among 855 observed basins, at 10 years, 80.2% (actuarial; 95% CI, 77-83) of basins were free of nodal recurrence. By univariable analysis, freedom from regional nodal recurrence was associated with age younger than 50 years (hazard ratio [HR], 0.49; 95% CI, 0.34-0.70; P < .001), nonulcerated melanoma (HR, 0.36; 95% CI, 0.36-0.49; P < .001), thinner primary melanoma (less than 1.5 mm; HR, 0.46; 95% CI, 0.27-0.78; P = .004), axillary basin (HR, 0.61; 95% CI, 0.44-0.86; P = .005), fewer positive SLNs (1 vs 3 or more; HR, 0.32; 95% CI, 0.14-0.75; P = .008), and SLN tumor burden (measured by diameter less than 1 mm [HR, 0.39; 95% CI, 0.26-0.60; P = .001] or less than 5% area [HR, 0.36; 95% CI, 0.24-0.54; P < .001]). By multivariable analysis, younger age (HR, 0.57; 95% CI, 0.39-0.84; P = .004), thinner primary melanoma (HR, 0.40; 95% CI, 0.22-0.70; P = .002), axillary basin (HR, 0.55; 95% CI, 0.31-0.96; P = .03), SLN metastasis diameter less than 1 mm (HR, 0.52; 95% CI, 0.33-0.81; P = .007), and area less than 5% (HR, 0.58; 95% CI, 0.38-0.88; P = .01) were associated with basin control. When looking at the identified risk factors of age (50 years or older), ulceration, Breslow thickness greater than 3.5 mm, nonaxillary basin, and tumor burden of maximum diameter of 1 mm or greater and/or metastasis area of 5% or greater and excluding missing value cases, basin disease-free rates at 5 years were 96% (95% CI, 88-100) for patients with 0 risk factors, 89% (95% CI, 82-96) for 1 risk factor, 86% (95% CI, 80-93) for 2 risk factors, 80% (95% CI, 71-89) for 3 risk factors, 61% (95% CI, 48-74) for 4 risk factors, and 54% (95% CI, 36-72) for 5 or 6 risk factors. Conclusions and Relevance: This randomized clinical trial was the largest prospective evaluation of long-term regional basin control in patients with melanoma who had nodal observation after removal of a positive SLN. SLN biopsy without CLND cleared disease in the affected nodal basin in most patients, even those with multiple risk factors for in-basin recurrence. In addition to its well-validated value in staging, SLN biopsy may also be regarded as therapeutic in some patients. Trial Registration: ClinicalTrials.gov Identifier: NCT00297895.

A new American Joint Committee on Cancer staging system for cutaneous squamous cell carcinoma: creation and rationale for inclusion of tumor (T) characteristics.

BACKGROUND: The incidence of cutaneous squamous cell carcinoma (cSCC) is increasing. Although most patients achieve complete remission with surgical treatment, those with advanced disease have a poor prognosis. The American Joint Committee on Cancer (AJCC) is responsible for the staging criteria for all cancers. For the past 20 years, the AJCC cancer staging manual has grouped all nonmelanoma skin cancers, including cSCC, together for the purposes of staging. However, based on new evidence, the AJCC has determined that cSCC should have a separate staging system in the 7th edition AJCC staging manual. OBJECTIVE: We sought to present the rationale for and characteristics of the new AJCC staging system specific to cSCC tumor characteristics (T). METHODS: The Nonmelanoma Skin Cancer Task Force of AJCC reviewed relevant data and reached expert consensus in creating the 7th edition AJCC staging system for cSCC. Emphasis was placed on prospectively accumulated data and multivariate analyses. Concordance with head and neck cancer staging system was also achieved. RESULTS: A new AJCC cSCC T classification is presented. The T classification is determined by tumor diameter, invasion into cranial bone, and high-risk features, including anatomic location, tumor thickness and level, differentiation, and perineural invasion. LIMITATIONS: The data available for analysis are still suboptimal, with limited prospective outcomes trials and few multivariate analyses. CONCLUSIONS: The new AJCC staging system for cSCC incorporates tumor-specific (T) staging features and will encourage coordinated, consistent collection of data that will be the basis of improved prognostic systems in the future.

Pathologic nodal evaluation improves prognostic accuracy in Merkel cell carcinoma: analysis of 5823 cases as the basis of the first consensus staging system.

BACKGROUND: The management of Merkel cell carcinoma (MCC) has been complicated by a lack of detailed prognostic data and by the presence of conflicting staging systems. OBJECTIVE: We sought to determine the prognostic significance of tumor size, clinical versus pathologic nodal evaluation, and extent of disease at presentation and thereby derive the first consensus staging/prognostic system for MCC. METHODS: A total of 5823 prospectively enrolled MCC cases from the National Cancer Data Base had follow-up data (median 64 months) and were used for prognostic analyses. RESULTS: At 5 years, overall survival was 40% and relative survival (compared with age- and sex-matched population data) was 54%. Among all MCC cases, 66% presented with local, 27% with nodal, and 7% with distant metastatic disease. For cases presenting with local disease only, smaller tumor size was associated with better survival (stage I, ≤2 cm, 66% relative survival at 5 years; stage II, >2 cm, 51%; P < .0001). Patients with clinically local-only disease and pathologically proven negative nodes had better outcome (76% at 5 years) than those who only underwent clinical nodal evaluation (59%, P < .0001). LIMITATIONS: The National Cancer Data Base does not capture disease-specific survival. Overall survival for patients with MCC was therefore used to calculate relative survival based on matched population data. CONCLUSION: Although the majority (68%) of patients with MCC in this nationwide cohort did not undergo pathologic nodal evaluation, this procedure may be indicated in many cases as it improves prognostic accuracy and has important treatment implications for those found to have microscopic nodal involvement.

Age-Specific Incidence of Melanoma in the United States.

Importance: Melanoma is epidemiologically linked to UV exposure, particularly childhood sunburn. Public health campaigns are increasing sun-protective behavior in the United States, but the effect on melanoma incidence is unknown. Objective: To examine the incidence of melanoma in the United States and whether any age-specific differences are present. Design, Setting, and Participants: Observational, population-based registry data were extracted on July 3, 2018, from the combined National Program of Cancer Registries-Surveillance Epidemiology and End Results United States Cancer Statistics database for 2001-2015. Deidentified data for 988 103 cases of invasive melanoma, with International Classification of Diseases for Oncology histologic categorization codes 8720 to 8790, were used for analysis. Data analysis was performed from July 1, 2018, to March 1, 2019. Main Outcomes and Measures: The annual rates of melanoma in pediatric, adolescent, young adult, and adult age groups were determined. Analyses were stratified by sex, and incidence rates were age-adjusted to the 2000 US standard population. Annual percentage change (APC) in incidence rate was calculated over the most recent decade for which data were available (2006-2015) using the weighted least squares method. Results: In 2015, 83 362 cases of invasive melanoma were reported in the United States, including 67 in children younger than 10 years, 251 in adolescents (10-19 years), and 1973 in young adults (20-29 years). Between 2006 and 2015, the overall incidence rate increased from 200.1 to 229.1 cases per million person-years. In adults aged 40 years or older, melanoma rates increased by an APC of 1.8% in both men (95% CI, 1.4%-2.1%) and women (95% CI, 1.4%-2.2%). In contrast, clinically and statistically significant decreases were seen in melanoma incidence for adolescents and young adults. Specifically, incidence rates decreased by an APC of -4.4% for male adolescents (95% CI, -1.7% to -7.0%), -5.4% for female adolescents (95% CI, -3.3% to -7.4%), -3.7% for male young adults (95% CI, -2.5% to -4.8%), and -3.6% for female young adults (95% CI, -2.8% to -4.5%). Data on skin pigmentation and sun protection history were unavailable; similar trends were observed with data limited to non-Hispanic whites. Young adult women appeared to have twice the risk of melanoma as young adult men. Conclusions and Relevance: The incidence of invasive melanoma in the United States appeared to decrease in adolescents and young adults from 2006 to 2015, and this finding contrasted with increases in older populations. These incidence trends suggest that public health efforts may be favorably influencing melanoma incidence in the United States.

Intratumoral Delivery of Plasmid IL12 Via Electroporation Leads to Regression of Injected and Noninjected Tumors in Merkel Cell Carcinoma.

PURPOSE: IL12 promotes adaptive type I immunity and has demonstrated antitumor efficacy, but systemic administration leads to severe adverse events (AE), including death. This pilot trial investigated safety, efficacy, and immunologic activity of intratumoral delivery of IL12 plasmid DNA (tavo) via in vivo electroporation (i.t.-tavo-EP) in patients with Merkel cell carcinoma (MCC), an aggressive virus-associated skin cancer. PATIENTS AND METHODS: Fifteen patients with MCC with superficial injectable tumor(s) received i.t.-tavo-EP on days 1, 5, and 8 of each cycle. Patients with locoregional MCC (cohort A, N = 3) received one cycle before definitive surgery in week 4. Patients with metastatic MCC (cohort B, N = 12) received up to four cycles total, administered at least 6 weeks apart. Serial tumor and blood samples were collected. RESULTS: All patients successfully completed at least one cycle with transient, mild (grades 1 and 2) AEs and without significant systemic toxicity. Sustained (day 22) intratumoral expression of IL12 protein was observed along with local inflammation and increased tumor-specific CD8+ T-cell infiltration, which led to systemic immunologic and clinical responses. The overall response rate was 25% (3/12) in cohort B, with 2 patients experiencing durable clinical benefit (16 and 55+ months, respectively). Two cohort A patients (1 with pathologic complete remission) were recurrence-free at 44+ and 75+ months, respectively. CONCLUSIONS: I.t.-tavo-EP was safe and feasible without systemic toxicity. Sustained local expression of IL12 protein and local inflammation led to systemic immune responses and clinically meaningful benefit in some patients. Gene electrotransfer, specifically i.t.-tavo-EP, warrants further investigation for immunotherapy of cancer.

Head and neck malignant melanoma: margin status and immediate reconstruction.

Head and neck melanoma often approaches critical structures. Therefore, excision is often limited, leading to positive margins, and increased local recurrence. Immediate reconstruction carries concern for rearrangement or concealment of cancerous tissues. Therefore, reconstruction is often delayed until confirming negative margins on permanent pathology. Our purpose is to identify variables associated with a positive margin and establish criteria for reconstruction timing. We reviewed 117 consecutive patients who underwent wide local excision of head and neck melanoma. Reconstruction was immediate for 107 and delayed for 10. Six percent of patients had a positive margin after wide local excision with no difference in incidence between immediate and delayed reconstruction (P = 0.11). Tumor characteristics associated with a positive margin were locally recurrent, ulcerated, and T4 tumors (P < 0.05); and delayed reconstruction should be considered in these circumstances. Immediate reconstruction is safe for the majority of head and neck melanoma and should be based on knowledge of tumor characteristics.