FcγRIIB expressed on CD8+ T cells limits responsiveness to PD-1 checkpoint inhibition in cancer.

Checkpoint inhibition using Fc-containing monoclonal antibodies has emerged as a powerful therapeutic approach to augment antitumor immunity. We recently showed that FcγRIIB, the only inhibitory IgG-Fc receptor, is expressed on a population of highly differentiated effector CD8+ T cells in the tumors of mice and humans, raising the possibility that CD8+ T cell responses may be directly modulated by checkpoint inhibitor binding to T cell-expressed FcγRIIB. Here, we show that despite exhibiting strong proliferative and cytokine responses at baseline, human FcγRIIBpos CD8+ T cells exhibited reduced responsiveness to both PD-1 and CTLA-4 checkpoint inhibition as compared with FcγRIIBneg CD8+ T cells in vitro. Moreover, frequencies of FcγRIIBpos CD8+ T cells were reduced after treatment of patients with melanoma with nivolumab in vivo. This reduced responsiveness was FcγRIIB dependent, because conditional genetic deletion of FcγRIIB on tumor-specific CD8+ T cells improved response to checkpoint blockade in B16 and LLC mouse models of cancer. The limited responsiveness of FcγRIIBpos CD8+ T cells was also dependent on an intact Fc region of the checkpoint inhibitor, in that treatment with Fc-devoid anti-PD-1 F(ab) fragments resulted in increased proliferation of FcγRIIBpos CD8+ T cells, without altering the response of FcγRIIBneg CD8+ T cells. Last, the addition of FcγRIIB blockade improved efficacy of PD-1 checkpoint inhibition in mouse models of melanoma, lung, and colon cancer. These results illuminate an FcγRIIB-mediated, cell-autonomous mechanism of CD8+ T cell suppression, which limits the efficacy of checkpoint inhibitors during antitumor immune responses in vivo.

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.

Outcomes with adjuvant anti-PD-1 therapy in patients with sentinel lymph node-positive melanoma without completion lymph node dissection.

Until recently, most patients with sentinel lymph node-positive (SLN+) melanoma underwent a completion lymph node dissection (CLND), as mandated in published trials of adjuvant systemic therapies. Following multicenter selective lymphadenectomy trial-II, most patients with SLN+ melanoma no longer undergo a CLND prior to adjuvant systemic therapy. A retrospective analysis of clinical outcomes in SLN+ melanoma patients treated with adjuvant systemic therapy after July 2017 was performed in 21 international cancer centers. Of 462 patients who received systemic adjuvant therapy, 326 patients received adjuvant anti-PD-1 without prior immediate (IM) CLND, while 60 underwent IM CLND. With median follow-up of 21 months, 24-month relapse-free survival (RFS) was 67% (95% CI 62% to 73%) in the 326 patients. When the patient subgroups who would have been eligible for the two adjuvant anti-PD-1 clinical trials mandating IM CLND were analyzed separately, 24-month RFS rates were 64%, very similar to the RFS rates from those studies. Of these no-CLND patients, those with SLN tumor deposit >1 mm, stage IIIC/D and ulcerated primary had worse RFS. Of the patients who relapsed on adjuvant anti-PD-1, those without IM CLND had a higher rate of relapse in the regional nodal basin than those with IM CLND (46% vs 11%). Therefore, 55% of patients who relapsed without prior CLND underwent surgery including therapeutic lymph node dissection (TLND), with 30% relapsing a second time; there was no difference in subsequent relapse between patients who received observation vs secondary adjuvant therapy. Despite the increased frequency of nodal relapses, adjuvant anti-PD-1 therapy may be as effective in SLN+ pts who forego IM CLND and salvage surgery with TLND at relapse may be a viable option for these patients.

An Internally Validated Prognostic Risk-Score Model for Disease-Specific Survival in Clinical Stage I and II Merkel Cell Carcinoma.

BACKGROUND: Merkel cell carcinoma (MCC) is a rare cutaneous malignancy for which factors predictive of disease-specific survival (DSS) are poorly defined. METHODS: Patients from six centers (2005-2020) with clinical stage I-II MCC who underwent sentinel lymph node (SLN) biopsy were included. Factors associated with DSS were identified using competing-risks regression analysis. Risk-score modeling was established using competing-risks regression on a training dataset and internally validated by point assignment to variables. RESULTS: Of 604 patients, 474 (78.5%) and 128 (21.2%) patients had clinical stage I and II disease, respectively, and 189 (31.3%) had SLN metastases. The 5-year DSS rate was 81.8% with a median follow-up of 31 months. Prognostic factors associated with worse DSS included increasing age (hazard ratio [HR] 1.03, p = 0.046), male sex (HR 3.21, p = 0.021), immune compromise (HR 2.46, p = 0.013), presence of microsatellites (HR 2.65, p = 0.041), and regional nodal involvement (1 node: HR 2.48, p = 0.039; ≥2 nodes: HR 2.95, p = 0.026). An internally validated, risk-score model incorporating all of these factors was developed with good performance (AUC 0.738). Patients with ≤ 4.00 and > 4.00 points had 5-year DSS rates of 89.4% and 67.2%, respectively. Five-year DSS for pathologic stage I/II patients with > 4.00 points (n = 49) was 79.8% and for pathologic stage III patients with ≤ 4.00 points (n = 62) was 90.3%. CONCLUSIONS: A risk-score model, including patient and tumor factors, based on DSS improves prognostic assessment of patients with clinically localized MCC. This may inform surveillance strategies and patient selection for adjuvant therapy trials.

Do Oncologic Outcomes From Head and Neck Versus Truncal and Extremity Melanoma Differ? A Single-Institution Single-Subspecialty Experience.

BACKGROUND: Outcomes are thought to be worse in head and neck (H&N) melanoma patients. However, definitive evidence of inferior outcomes in H&N melanoma in the modern era is lacking. We sought to ascertain whether H&N melanomas carry a worse prognosis than melanomas of other sites. METHODS: All patients who underwent excision for primary melanoma by fellowship-trained surgical oncologists at a single institution from 2014 to 2020 were queried from the electronic medical record. Patients who had AJCC eighth edition stage I-III disease were included. RESULTS: Of 1127 patients, 28.7% had primary H&N melanoma. H&N patients were more likely to be male, older, and present with more advanced AJCC stage. Median follow-up was 20.0 months (IQR 26.4). On multivariable analyses controlling for other variables, H&N melanoma was associated with worse RFS. Notably, H&N melanoma was not associated with worse MSS, DMFS, or OS on univariate or multivariable analyses. Among patients who recurred, H&N patients were significantly more likely to recur locally compared to non-H&N patients. On subgroup analysis, scalp melanoma was also associated with worse RFS compared to patients with melanoma in locations other than the scalp. When patients with scalp melanoma were excluded from analysis, non-scalp H&N RFS was not significantly different from the non-H&N group on univariate or multivariable analyses. DISCUSSION: In this series from a high-volume tertiary referral center, the differences in rates and sites of recurrence between H&N and non-H&N melanoma do not impact melanoma-specific or overall survival, suggesting that H&N melanoma patients should be treated similarly with respect to regional and systemic therapies.

Intersection of FcγRIIB, the microbiome, and checkpoint inhibitors in antitumor immunity.

Fc receptors (FcRs) and the microbiome are both known to have an effect on the development and progression of cancers. Checkpoint inhibitors are a novel class of therapeutics which are used to combat cancer and are integrally linked to both FcRs and the microbiome. The use of checkpoint inhibitors has grown exponentially over the past decade, although many host factors affect both the efficacy and the safety of these therapeutics. Some of these host factors, including the microbiome and the expression of FcRs, are currently being investigated. Here we discuss the current understanding of FcRs (particularly the inhibitory FcγRIIB) and the microbiome in context of T cell immunity, inflammation, cancer, and checkpoint inhibition.

Predictors of False Negative Sentinel Lymph Node Biopsy in Clinically Localized Merkel Cell Carcinoma.

BACKGROUND: Sentinel lymph node biopsy (SLNB) is routinely recommended for clinically localized Merkel cell carcinoma (MCC); however, predictors of false negative (FN) SLNB are undefined. METHODS: Patients from six centers undergoing wide excision and SLNB for stage I/II MCC (2005-2020) were identified and were classified as having either a true positive (TP), true negative (TN) or FN SLNB. Predictors of FN SLNB were identified and survival outcomes were estimated. RESULTS: Of 525 patients, 28 (5.4%), 329 (62.7%), and 168 (32%) were classified as FN, TN, and TP, respectively, giving an FN rate of 14.3% and negative predictive value of 92.2% for SLNB. Median follow-up for SLNB-negative patients was 27 months, and median time to nodal recurrence for FN patients was 7 months. Male sex (hazard ratio [HR] 3.15, p = 0.034) and lymphovascular invasion (LVI) (HR 2.22, p = 0.048) significantly correlated with FN, and increasing age trended toward significance (HR 1.04, p = 0.067). The 3-year regional nodal recurrence-free survival for males >75 years with LVI was 78.5% versus 97.4% for females ≤75 years without LVI (p = 0.009). Five-year disease-specific survival (90.9% TN vs. 51.3% FN, p < 0.001) and overall survival (69.9% TN vs. 48.1% FN, p = 0.035) were significantly worse for FN patients. CONCLUSION: Failure to detect regional nodal microscopic disease by SLNB is associated with worse survival in clinically localized MCC. Males, patients >75 years, and those with LVI may be at increased risk for FN SLNB. Consideration of increased nodal surveillance following negative SLNB in these high-risk patients may aid in early identification of regional nodal recurrences.

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

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.

The impact of axillary node surgery on outcomes following immediate breast reconstruction.

Immediate breast reconstruction (IBR) has become the most common method for postmastectomy reconstruction. Axillary lymph node dissection is performed for the staging of patients, but the impact of IBR with nodal surgery on postoperative complications remains elusive. The present study aims to investigate the impact of concomitant axillary lymph node surgery on postoperative complications. We conducted a retrospective study of patients who underwent IBR from 2000 to 2014. We recorded and analyzed patient data to determine the association between nodal surgery and postsurgical complications. Univariate and multivariate analyses were utilized to elucidate the risk of a complication given nodal surgery, sentinel lymph node biopsy (SLNB) or axillary lymph node dissection (ALND), and type of incision for nodal access. A total of 986 breast reconstructions were included for analysis. Overall incidence of postoperative complications per breast that received nodal surgery was 35.9% (n = 230/642), compared to 25.6% (n = 88/344) in breasts that did not have concomitant nodal surgery (P = .001). Nodal surgery was found to increase risk of all complications with an odds ratio of 1.62 (P = .001). Moreover, complications were significantly higher in patients whose nodes were accessed via mastectomy incision (39.4%) when compared to a separate incision (33.5%). Multivariate analysis showed that nodal sampling through the mastectomy incision is a significant risk factor for seroma, with an odds ratio of 3.60 (P = .002). We did not observe differences in breast complications in patients who underwent SLNB vs ALND. These factors should be taken into account in the approach to breast reconstruction during lymphadenectomy.

Current Opinion on the Oncoplastic Approach in the USA.

The management of women with breast cancer who wish to preserve their breasts often includes partial reconstruction at the time of tumor resection. This is referred to as the oncoplastic approach and has been shown to improve outcomes. The purpose of this review was to better understand the current surgeon mindset relative to the oncoplastic approach. A survey was designed to understand demographics and opinions on partial breast reconstruction at the time of tumor resection. This was disseminated to the registered members of the American Society of Breast Surgeons as well the American Society of Plastic Surgeons (ASPS) through an online system and comparisons were made. There were 422 responders in the ABS and 214 responders in the ASPS for a response rate of 14.8% and 9.1%, respectively. Most (69.7%) breast surgeons felt that partial breast reconstruction following lumpectomy was not limited in their practice. Fifty percent of plastic surgeons felt that it was limited because they were not getting the referrals. Both groups agreed that complex partial reconstructions were best performed using the team approach. Margin involvement was a major concern in both groups, and the groups agreed that the aesthetic benefits were a major driving force. Future adoption of these techniques will rely on increased training and increased awareness of these procedures. There tends to be general agreement surrounding the concerns and benefits of immediately reconstructing the partial mastectomy defect. Disparity does exist between the two groups in terms of delivery likely due to the system-based inadequacies in the USA. This represents an area for improvement.

A pyrosequencing-based assay for the rapid detection of the 22q11.2 deletion in DNA from buccal and dried blood spot samples.

The 22q11.2 deletion syndrome is one of the most common deletion syndromes in newborns. Some affected newborns may be diagnosed shortly after birth because of the presence of heart defects, palatal defects, or severe immune deficiencies. However, diagnosis is often delayed in patients presenting with other associated conditions that would benefit from early recognition and treatment, such as speech delays, learning difficulties, and schizophrenia. Fluorescence in situ hybridization (FISH) is the gold standard for deletion detection, but it is costly and time consuming and requires a whole blood specimen. Our goal was to develop a suitable assay for population-based screening of easily collectible specimens, such as buccal swabs and dried blood spots (DBS). We designed a pyrosequencing assay and validated it using DNA from FISH-confirmed 22q11 deletion syndrome patients and normal controls. We tested DBS from nine patients and paired buccal cell and venous blood specimens from 20 patients. Results were 100% concordant with FISH assay results. DNA samples from normal controls (n = 180 cell lines, n = 15 DBS, and n = 88 buccal specimens) were negative for the deletion. Limiting dilution experiments demonstrated that accurate results could be obtained from as little as 1 ng of DNA. This method represents a reliable and low-cost alternative for detection of the common 22q11.2 microdeletions and can be adapted to high-throughput population screening.