Lymphedema in Inflammatory Breast Cancer Patients Following Trimodal Treatment.

BACKGROUND: Breast cancer-related lymphedema (BCRL) is a debilitating sequela of breast cancer treatment and is becoming a greater concern in light of improved long-term survival. Inflammatory breast cancer (IBC) is a rare and aggressive malignancy for which systemic therapy, surgery, and radiotherapy remain the standard of care, thereby making IBC patients highly susceptible to developing BCRL. This study evaluated BCRL in IBC following trimodal therapy. METHODS: IBC patients treated from 2016 to 2019 were identified from an institutional database. Patients were excluded if they presented with recurrent disease, underwent bilateral axillary surgery, did not complete trimodal therapy, or were lost to follow-up. Demographic, clinicopathologic factors, oncologic outcomes, and perometer measurements were recorded. BCRL was defined by clinician diagnosis and/or objective perometer measurements when available. Time to development of BCRL and treatment received were captured. RESULTS: Eighty-three patients were included. Median follow-up was 33 months. The incidence of BCRL was 50.6% (n = 42). Mean time to BCRL from surgery was 13 (range 2-24) months. Demographic and clinicopathologic features were similar between patients with and without BCRL with exception of higher proportion receiving delayed reconstruction in the BCRL group (38.1% vs. 14.6%, p = 0.03). Forty patients (95.2%) underwent BCRL treatment, which included physical therapy (n = 39), compression (n = 38), therapeutic lymphovenous bypass (n = 13), and/or vascularized lymph node transfer (n = 12). CONCLUSIONS: IBC patients are at high-risk for BCRL after treatment, impacting 51% of patients in this cohort. Strategies to reduce or prevent BCRL and improve real-time diagnosis should be implemented to better direct early management in this patient population.

Acral Lentiginous Melanoma: A United States Multi-Center Substage Survival Analysis.

BACKGROUND: Acral lentiginous melanoma is associated with worse survival than other subtypes of melanoma. Understanding prognostic factors for survival and recurrence can help better inform follow-up care. OBJECTIVES: To analyze the clinicopathologic features, melanoma-specific survival, and recurrence-free survival by substage in a large, multi-institutional cohort of primary acral lentiginous melanoma patients. METHODS: Retrospective review of the United States Melanoma Consortium database, a multi-center prospectively collected database of acral lentiginous melanoma patients treated between January 2000 and December 2017. RESULTS: Of the 433 primary acral lentiginous melanoma patients identified (median [range] age: 66 [8-97] years; 53% female, 83% white), 66% presented with stage 0-2 disease and the median time of follow-up for the 392 patients included in the survival analysis was 32.5 months (range: 0-259). The 5-year melanoma-specific survivals by stage were 0 = 100%, I = 93.8%, II = 76.2%, III = 63.4%, IIIA = 80.8%, and IV = 0%. Thicker Breslow depth ((HR) = 1.13; 95% CI = 1.05-1.21; P < .001)) and positive nodal status ((HR) = 1.79; 95% CI = 1.00-3.22; P = .050)) were independent prognostic factors for melanoma-specific survival. Breslow depth ((HR = 1.13; 95% CI = 1.07-1.20; P < .001), and positive nodal status (HR = 2.12; 95% CI = 1.38-3.80; P = .001) were also prognostic factors for recurrence-free survival. CONCLUSION: In this cohort of patients, acral lentiginous melanoma was associated with poor outcomes even in early stage disease, consistent with prior reports. Stage IIB and IIC disease were associated with particularly low melanoma-specific and recurrence-free survival. This suggests that studies investigating adjuvant therapies in stage II patients may be especially valuable in acral lentiginous melanoma patients.

The Impact of Obesity on Surgically Treated Locoregional Melanoma.

BACKGROUND: The impact of obesity on early-stage melanoma is poorly understood. We examined the impact of overweight and obesity on clinical outcomes in locoregional melanoma. METHODS: Adults who underwent surgery at Emory University Healthcare between 2010 and 2017 for clinically stage I-II cutaneous melanoma, with known stage, height, and weight at the time of presentation, were identified. The relationship between body mass index (BMI) and clinicopathologic characteristics was assessed. RESULTS: Of 1756 patients, 584 were obese (33.2%; BMI ≥ 30), 658 were overweight (37.5%; BMI ≥ 25 and < 30), and 514 were normal weight (29.3%; BMI < 25). Demographics associated with obesity included male sex (odds ratio [OR] 2.6, 95% confidence interval [CI] 2.1-3.3; p < 0.001) and lower income (OR 1.5, 95% CI 1.2-1.9; p = 0.003). Melanomas in obese patients were thicker (2.0 ± 0.2 mm) than in overweight (1.7 ± 0.1 mm) or normal-weight patients (1.4 ± 0.1 mm; p = 0.002). Ulceration, mitoses, BRAF status, and sentinel lymph node (SLN) status were not affected by obesity. In multivariable analysis, obesity independently predicted increased odds of pathologic stage II melanoma (vs. stage 0 or I; OR 1.9, 95% CI 1.4-2.7, p = 0.001), but not pathologic stage III melanoma (p > 0.05). At 33 months' median follow-up, obesity was not an independent predictor of stage-specific overall survival (p > 0.05). CONCLUSION: Obese patients are nearly twice as likely as their normal-weight peers to present with thicker melanomas, but they have similar stage-specific overall survival and SLN positivity. Obesity may promote more aggressive growth of the primary tumor, and barriers to preventive care in obese patients may exacerbate later-stage presentation.

FcγRIIB is a T cell checkpoint in antitumor immunity.

In the setting of cancer, T cells upregulate coinhibitory molecules that attenuate TCR signaling and lead to the loss of proliferative capacity and effector function. Checkpoint inhibitors currently in clinical use have dramatically improved mortality from melanoma yet are not effective in all patients, suggesting that additional pathways may contribute to suppression of tumor-specific CD8+ T cell responses in melanoma. Here, we show that FcγRIIB, an inhibitory Fc receptor previously thought to be exclusively expressed on B cells and innate immune cells, is upregulated on tumor-infiltrating effector CD8+ T cells in an experimental melanoma model and expressed on CD8+ T cells in patients with melanoma. Genetic deficiency of Fcgr2b resulted in enhanced tumor-infiltrating CD8+ T cell responses and significantly reduced tumor burden. Adoptive transfer experiments of Fcgr2b-/- tumor antigen-specific T cells into FcγRIIB-sufficient hosts resulted in an increased frequency of tumor-infiltrating CD8+ T cells with greater effector function. Finally, FcγRIIB was expressed on CD8+ memory T cells isolated from patients with melanoma. These data illuminate a cell-intrinsic role for the FcγRIIB checkpoint in suppressing tumor-infiltrating CD8+ T cells.

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

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.

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

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.

The Devil's in the Details: Discrepancy Between Biopsy Thickness and Final Pathology in Acral Melanoma.

PURPOSE: We hypothesized that initial biopsy may understage acral lentiginous melanoma (ALM) and lead to undertreatment or incomplete staging. Understanding this possibility can potentially aid surgical planning and improve primary tumor staging. METHODS: A retrospective review of primary ALMs treated from 2000 to 2017 in the US Melanoma Consortium database was performed. We reviewed pathology characteristics of initial biopsy, final excision specimens, surgical margins, and sentinel lymph node biopsy (SLNB). RESULTS: We identified 418 primary ALMs (321 plantar, 34 palmar, 63 subungual) with initial biopsy and final pathology results. Median final thickness was 1.8 mm (range 0.0-19.0). There was a discrepancy between initial biopsy and final pathology thickness in 180 (43%) patients with a median difference of 1.6 mm (range 0.1-16.4). Final T category was increased in 132 patients (32%), including 47% of initially in situ, 32% of T1, 39% of T2, and 28% of T3 lesions. T category was more likely to be increased in subungual (46%) and palmar (38%) melanomas than plantar (28%, p = 0.01). Among patients upstaged to T2 or higher, 71% had ≤ 1-cm margins taken. Among the 27 patients upstaged to T1b or higher, 8 (30%) did not have a SLNB performed, resulting in incomplete initial staging. CONCLUSIONS: In this large series of ALMs, final T category was frequently increased on final pathology. A high index of suspicion is necessary for lesions initially in situ or T1 and consideration should be given to performing additional punch biopsies, wider margin excisions, and/or SLNB.

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

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.

Signaling through the Inhibitory Fc Receptor FcγRIIB Induces CD8+ T Cell Apoptosis to Limit T Cell Immunity.

Effector CD8+ T cells are important mediators of adaptive immunity, and receptor-ligand interactions that regulate their survival may have therapeutic potential. Here, we identified a subset of effector CD8+ T cells that expressed the inhibitory fragment crystallizable (Fc) receptor FcγRIIB following activation and multiple rounds of division. CD8+ T cell-intrinsic genetic deletion of Fcgr2b increased CD8+ effector T cell accumulation, resulting in accelerated graft rejection and decreased tumor volume in mouse models. Immunoglobulin G (IgG) antibody was not required for FcγRIIB-mediated control of CD8+ T cell immunity, and instead, the immunosuppressive cytokine fibrinogen-like 2 (Fgl2) was a functional ligand for FcγRIIB on CD8+ T cells. Fgl2 induced caspase-3/7-mediated apoptosis in Fcgr2b+, but not Fcgr2b-/-, CD8+ T cells. Increased expression of FcγRIIB correlated with freedom from rejection following withdrawal from immunosuppression in a clinical trial of kidney transplant recipients. Together, these findings demonstrate a cell-intrinsic coinhibitory function of FcγRIIB in regulating CD8+ T cell immunity.

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

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.

Recurrence Patterns after Primary Excision of Invasive Melanoma with Melanoma in situ at the Margin.

The significance and management of melanoma in situ (MIS) at the margin of excision of invasive melanoma is debated. Patients undergoing excision of invasive melanoma from 2000 to 2016 with MIS at the margin were identified. A cohort without MIS was matched for age, gender, location, and Breslow depth. Thirty-two patients with 33 cases of MIS at the margin were identified. Melanoma was located on the head/neck (66.7%), extremities (24.2%), and trunk (9.1%). Median Breslow depth was 1.0 mm (range 0.25-10.80). Margin treatment included re-excision (45.5%), re-excision plus imiquimod (3.0%), imiquimod alone (9.1%), and observation alone (42.4%). At a median follow-up of 91 months (range 28-126), five patients (15.2%) with a median Breslow depth of 4.75 mm (range 1.10-6.70) developed local recurrence (LR). Three underwent re-excision of the positive margin and two were observed. Intervention for positive margins did not decrease LR compared with observation (P = 0.905, OR = 1.125, 95% confidence interval [CI] 0.162-7.824). All five patients with LR were alive at the last follow-up. There were two recurrences in the matched cohort (6.1%); both were alive at the last follow-up. Risk of LR is higher with MIS at the margin, but this does not seem to impact survival. Larger studies may elucidate predictive factors and interventions that decrease risk for LR.

Estimating the Reliability and Validity of the Upper Extremity Functional Index in Women After Breast Cancer Surgery.

BACKGROUND: Activity limitations as well as impairments such as pain, numbness, limitation of shoulder range of motion, and weakness are common and well documented during and after treatment for breast cancer. There is limited information regarding the measurement properties of patient-reported outcome measures of upper extremity activity limitation in this population. This study examined the reliability and validity of the Upper Extremity Functional Index (UEFI) in patients after surgery for breast cancer. PATIENTS AND METHODS: Measures of function, shoulder flexion range of motion, and pain were obtained for 53 women before and 2 weeks after surgery for breast cancer. To estimate UEFI test-retest reliability, a convenience sample of 20 patients was assessed on a second occasion within 48 hours of their 2-week postsurgery assessment. Convergent and discriminant construct validation methods were applied by examining correlations between UEFI scores and change scores with those of the shortened version of the Disabilities of the Arm, Shoulder and Hand (QuickDASH), Functional Assessment of Cancer Therapy-Breast (FACT-B) +4 items, shoulder flexion range, and pain. RESULTS: UEFI test-retest reliability was estimated to be 0.87 (95% confidence interval, 0.69, 0.94), and the standard error of measurement was 4.8 (95% confidence interval, 3.7, 7.1) scale points. The 90% confidence interval for a given UEFI score was ±7.9 and minimal detectable change at 90% confidence (MDC90) was ±11.1 points. UEFI correlations with the QuickDASH (cross-sectional -0.79 and longitudinal -0.62) were greater than with the FACT-B+4 and impairment measures. CONCLUSION: These results support and guide the use of the UEFI in patients after breast cancer surgery.

Morbidity and Outcomes Following Axillary Lymphadenectomy for Melanoma: Weighing the Risk of Surgery in the Era of MSLT-II.

BACKGROUND: Limited data exist characterizing complications after axillary lymphadenectomy for melanoma. With high rates of complications reported after dissection for breast cancer and data suggesting that completion lymphadenectomy may have limited therapeutic benefit, this study characterized morbidity to facilitate clinical decision-making. METHODS: Using a broad definition for complications, patients who underwent axillary dissection for melanoma at a single center (from 2003 to 2015) were assessed through retrospective chart review. Patients were stratified by potential risk factors for complications; outcomes were compared. RESULTS: Two hundred fifty-four axillary dissections in 239 patients were identified. Assessed risk factors for complications included age > 55 years (n = 133, 52%), body mass index (BMI) ≥ 30 kg/m2 (n = 90, 40%), diabetes (n = 40, 16%), smoking (n = 81, 32%), extremity primary (n = 71, 28%), therapeutic lymphadenectomy (n = 105, 41%), and adjuvant radiation (n = 33, 13%). Wound complications were observed in 51 patients with 38 (15%) seromas, 3 (1%) dehiscences, and 10 (4%) hematomas. There were 5 (2%) reoperations, all for hematoma. Thirty-day readmission rate was 6% (n = 14). Importantly, lymphedema occurred in only 13 (5%) patients. Wound dehiscence occurred only in smokers (p = 0.03) and was associated with adjuvant radiation (p = 0.04). Twenty-eight (11%) patients developed frozen shoulder, which was related to smoking (p = 0.02). Lymphedema was more likely in patients after therapeutic dissection (p = 0.04). All other risk factors were not associated with increased complications. CONCLUSIONS: This analysis supports historical data that axillary dissection for melanoma is a low-risk procedure, with smoking, therapeutic lymphadenectomy, and adjuvant radiation associated with increased morbidity. Although morbidity of lymphadenectomy is often cited as a reason to alter surgical approach or even forgo intervention, this may be less of a concern for axillary dissection.

A Minimally Invasive Approach for Inguinal Lymphadenectomy in Melanoma and Genitourinary Malignancy: Long-Term Outcomes in an Attempted Randomized Control Trial.

BACKGROUND: Open inguinal lymphadenectomy (OIL) has a high incidence of complications. The authors adapted and reported a minimally invasive technique [videoscopic inguinal lymphadenectomy (VIL)] for use with melanoma, subsequently pursuing a randomized, prospective trial comparing open and minimally invasive approaches in an attempt to confirm retrospective findings illustrating reduced complications with the minimally invasive approach. METHODS: A randomized, prospective trial (NCT01526486) was designed to compare outcomes for patients undergoing VIL versus OIL. Patients with a diagnosis of malignancies requiring inguinal lymphadenectomy at Emory University were enrolled in the study, and informed consent was obtained. Failure to accrue sufficient patients resulted in suspension of the randomization process. Clinicopathologic, procedural, and outcomes data on VILs were prospectively collected. The primary outcome was wound complications, and the secondary outcome was recurrence-free survival. RESULTS: The results are limited to VILs. In this study, 102 patients underwent 137 procedures. Most of the complications were Clavien-Dindo 1 or 2, accounting for 89.7% of all postoperative issues. The wound infection rate was 47.4%. Skin necrosis or wound dehiscence occurred after 13 of the procedures (9.5%). For the patients with melanoma, the median overall survival was 68.8 months, and the recurrence-free survival was 18.5 months. The median inguinal recurrence-free survival was not reached. The median stage-specific recurrence-free survival was not reached for stage IIIA, was 22.8 months for stage IIIB, and was 8.8 months for stage IIIC disease (p < 0.001). CONCLUSIONS: The long-term findings presented in this report expand on and confirm previously published results demonstrating decreased morbidity and oncologic noninferiority of VIL, further validating the technique for patients requiring lymphadenectomy.