Clinical Utility of Melanoma Sentinel Lymph Node Biopsy Nomograms.

BACKGROUND: For patients with melanoma, the decision to perform sentinel lymph node biopsy (SLNB) is based on the estimated risk of lymph node metastasis. We assessed 3 melanoma SLNB risk-prediction models' statistical performance and their ability to improve clinical decision making (clinical utility) on a cohort of melanoma SLNB cases. STUDY DESIGN: Melanoma patients undergoing SLNB at a single center from 2003 to 2021 were identified. The predicted probabilities of sentinel lymph node positivity using the Melanoma Institute of Australia, Memorial Sloan Kettering Cancer Center (MSK), and Friedman nomograms were calculated. Receiver operating characteristic and calibration curves were generated. Clinical utility was assessed via decision curve analysis, calculating the net SLNBs that could have been avoided had a given model guided selection at different risk thresholds. RESULTS: Of 2,464 melanoma cases that underwent SLNB, 567 (23.0%) had a positive sentinel lymph node. The areas under the receiver operating characteristic curves for the Melanoma Institute of Australia, MSK, and Friedman models were 0.726 (95% CI, 0.702 to 0.750), 0.720 (95% CI, 0.697 to 0.744), and 0.721 (95% CI, 0.699 to 0.744), respectively. For all models, calibration was best at predicted positivity rates below 30%. The MSK model underpredicted risk. At a 10% risk threshold, only the Friedman model would correctly avoid a net of 6.2 SLNBs per 100 patients. The other models did not reduce net avoidable SLNBs at risk thresholds of ≤10%. CONCLUSIONS: The tested nomograms had comparable performance in our cohort. The only model that achieved clinical utility at risk thresholds of ≤10% was the Friedman model.

Neoadjuvant therapy for melanoma: A critical appraisal.

The treatment of advanced melanoma has significantly changed since the development of targeted and immune therapy. To date, these agents have primarily been used in the adjuvant or metastatic setting. Given several theoretical advantages, there is increased interest in the use of these new therapeutics in the neoadjuvant setting. In this review, we detail the potential benefits and pitfalls of neoadjuvant therapy for melanoma, review the currently available data, and describe ongoing neoadjuvant trials.

Neoadjuvant immunotherapy for melanoma.

Clinical trials have demonstrated the efficacy of immunotherapy, especially checkpoint blockade inhibitors, in the treatment of patients with metastatic melanoma. More recently, improvements in survival have been reported in patients with high-risk resectable melanoma when these agents are used in the adjuvant setting. Increasing interest in neoadjuvant immunotherapy for high-risk resectable melanoma has been fueled by early reports of significant efficacy. We review the rationale and data behind utilizing neoadjuvant immunotherapy.

Sentinel Lymph Node Biopsy for T1b Melanoma: Balancing Prognostic Value and Cost.

BACKGROUND: The purpose of this study is to report the additional prognostic information and cost associated with sentinel lymph node biopsy (SLNB) for patients with T1b melanoma. PATIENTS AND METHODS: An institutional database was queried for patients with T1b melanoma (0.8-1.0 mm or < 0.8 mm with ulceration) with at least 5 years of follow-up. Results of SLNB, completion lymphadenectomy (CLND), recurrence, and melanoma-specific survival (MSS) were assessed. Institutional costs of melanoma care were converted to Medicare proportional dollars. A Markov model was created to estimate long-term costs. RESULTS: Among the total 392 patients, 238 underwent SLNB. Median follow-up was 10.5 years. SLNB was positive in 19 patients (8.0%). Patients who underwent SLNB had higher 10-year nodal recurrence-free survival (98.6% vs. 91.2%, p < 0.001) but not MSS (94.4% vs. 93.2%, p = 0.55). Ulceration (HR 4.7, p = 0.022) and positive sentinel node (HR 11.5, p < 0.001) were associated with worse MSS. Estimates for 5-year costs reflect a fourfold increase in total costs of care associated with SLNB. However, a treatment plan that forgoes adjuvant therapy for resected stage IIIA melanoma but offers systemic therapy for a node-basin recurrence would nullify the additional cost of SLNB. CONCLUSIONS: SLNB is prognostic for T1b melanoma. Its impact on the overall cost of melanoma care is intimately tied to systemic therapy in the adjuvant and recurrent settings.

Survival Outcomes After Metastasectomy in Melanoma Patients Categorized by Response to Checkpoint Blockade.

INTRODUCTION: Checkpoint inhibitors have improved outcomes in metastatic melanoma, with 4-year overall survival (OS) of 46% for anti-PD-1 alone or 53% in combination with anti-CTLA-4. However, the median progression free survival is 6.9 and 11.5 months, respectively. Many who progress have gone on to alternative treatments, including surgery, yet the outcome of patients selected for surgery after checkpoint blockade remains unclear. METHODS: Patients who were treated with checkpoint blockade from 2003 to 2017, followed by metastasectomy, were identified from a prospectively maintained institutional melanoma database. Response to immunotherapy was assessed at the time of surgery. Patients were categorized as having responding, isolated progressing, or multiple progressing lesions. RESULTS: Of the 237 total patients identified, 208 (88%) had stage IV disease, and 29 (12%) had unresectable stage III disease at the start of immunotherapy. Median OS following first resection was 21 months. Median follow-up among survivors was 23 months. Complete resection at the first operation (n = 87, 37%) was associated with improved survival compared with patients with incomplete resection (n = 150, 63%) [median OS not reached (NR) vs. 10.8 months, respectively; 95% CI: 7.3, 14.8; p < 0.0001]. Patients resected for an isolated progressing or responding tumor had a longer median survival compared with those with multiple progressing lesions (NR vs. 7.8 months, 95% CI: 6.2, 11.2; p < 0.0001). CONCLUSIONS: Patients selected for surgical resection following checkpoint blockade have a relatively favorable survival, especially if they had a response to immunotherapy and undergo complete resection of isolated progressing or responding disease.

Clinical implications of the eighth edition of the American Joint Committee on Cancer melanoma staging.

The new edition of the American Joint Committee on Cancer staging system for melanoma builds on the foundation of prior editions but has several important improvements. The availability of regional nodal staging using sentinel lymph node biopsy (with subsequent follow-up) has resulted in more accurate prognostication for patients and clinicians. This facilitates identification of those at higher risk for recurrence, and allows for the appropriate selection of patients for new adjuvant therapy and clinical trials. Although more complex than previous editions, the eighth edition will provide granularity to outcome analysis based on more precise risk stratification.

Parastomal hernia repair using the "top hat" technique - An initial experience in 30 patients at Memorial Sloan Kettering Cancer Center.

Parastomal hernia repair remains a significant surgical challenge. Recurrence after standard "keyhole" or primary suture repair is common. We adopted and modified a new technique using a construct shaped like an inverted top hat. We review our experience over the last six years in the first 30 patients (31 consecutive procedures). Of these 31 procedures, six (19%) resulted in a parastomal hernia recurrence with a median follow-up of 31 months (range 0.5-80). Four of the recurrences occurred in our initial experience, when we constructed the top hat of xenograft alone. When the technique was modified, using a synthetic composite mesh for the underlay portion of the hat, there were only two subsequent recurrences in 16 patients (13%) with a median follow-up of 22 months. One of these "recurrences" was secondary to infection of the top hat construct, which had to be removed. This initial success in preventing recurrence of parastomal hernia is probably due to the design of the construct, for it occludes the vulnerable stoma/fascial angle, through which most parastomal hernia recurrences occur.

Transected thin melanoma: Implications for sentinel lymph node staging.

BACKGROUND AND OBJECTIVES: Indications for sentinel lymph node (SLN) biopsy in patients with thin melanoma (≤1 mm thick) are controversial. We asked whether deep margin (DM) positivity at initial biopsy of thin melanoma is associated with SLN positivity. METHODS: Cases were identified using prospectively maintained databases at two melanoma centers. Patients who had undergone SLN biopsy for melanoma ≤1 mm were included. DM status was assessed for association with SLN metastasis in univariate and multivariate analyses. RESULTS: 1413 cases were identified, but only 1129 with known DM status were included. 39% of patients had a positive DM on original biopsy. DM-positive and DM-negative patients did not differ significantly in primary thickness, ulceration, or mitotic activity. DM-positive and DM-negative patients had similar incidence of SLN metastasis (5.7% vs 3.5%; P = 0.07). Positive DM was not associated with SLN metastasis on univariate analysis (OR 1.69, 95% CI: 0.95-3.00, P = 0.07) or on multivariate analysis adjusted for Breslow depth, Clark level, mitotic rate, and ulceration (OR = 1.59, 95% CI: 0.89-2.85; P = 0.12). CONCLUSIONS: For patients with thin melanoma, a positive DM on initial biopsy is not associated with risk of SLN metastasis, so DM positivity should not be considered an indication for SLN staging in an otherwise low-risk patient.

Elevated Blood Neutrophil-to-Lymphocyte Ratio: A Readily Available Biomarker Associated with Death due to Disease in High Risk Nonmetastatic Melanoma.

BACKGROUND: Elevated peripheral blood neutrophil-to-lymphocyte ratio (NLR) is associated with poor oncologic outcomes in patients with stage IV melanoma and other solid tumors, but its impact has not been characterized for patients with high-risk, nonmetastatic melanoma. METHODS: Retrospective review of a melanoma database identified patients with high-risk melanoma who underwent operation with curative intent at a single institution. NLR was calculated from blood samples obtained within 2 weeks before operation. Multiple primary melanomas and concurrent hematologic or other metastatic malignancies were excluded. Cumulative incidence of death due to disease was estimated, and Gray's test was used to examine the effect of NLR on melanoma disease-specific death (DOD). Multivariable competing risks regression models assessed associated factors. RESULTS: Data on 1431 patients with high-risk, nonmetastatic melanoma were analyzed. Median follow-up for survivors was 4 years. High NLR (≥3 or as continuous variable) was associated with older age, male sex, thicker primaries, higher mitotic index, and more advanced nodal status. On multivariate analysis, high NLR (≥3 or as a continuous variable), older age, male sex, ulcerated primary, lymphovascular invasion, and positive nodal status were all independently associated with worse DOD. CONCLUSIONS: NLR is a readily available blood test that was independently associated with DOD in patients with high-risk, nonmetastatic melanoma. It is unclear whether high NLR is a passive indicator of poor prognosis or a potential therapeutic target. Further studies to evaluate the prognostic role of NLR to potentially identify those more likely to benefit from adjuvant immunotherapy may prove informative.

Patterns and Timing of Initial Relapse in Pathologic Stage II Melanoma Patients.

PURPOSE: Pathologic stage II melanoma patients have variable outcomes when divided by substage. We hypothesized that an understanding of the patterns of initial relapse by substage will better inform follow-up guidelines. METHODS: We performed a retrospective review of 738 adult patients with pathologic stage II cutaneous melanoma treated at Memorial Sloan Kettering Cancer Center between 1993 and 2013. Clinical records were reviewed to determine time, location, and method of detection of initial relapse. RESULTS: At a median follow-up of 52 months, 219 patients relapsed. Relapses were detected more frequently in higher substages. Initial relapses were most commonly local/in-transit for IIA and IIB and systemic for IIC. Lung and brain were the most frequent sites of systemic relapse. Patient-detection was the most common method of relapse detection (59%) in all substages. The 5-year cumulative incidence for patient-detected relapse was 13.6% for IIA, 18.9% for IIB, and 23.3% for IIC and for image-detected relapse was 3.4, 7.9, and 16.6%, respectively. The 5-year cumulative incidence for physician-detected relapse was less than 10% across all substages and leveled off at 3 years for stage IIA and IIB and 2 years for stage IIC. CONCLUSIONS: Relapses were most frequently patient-detected in all stage II substages, highlighting the importance of patient education and self-examination. The highest yield for routine imaging is in stage IIC patients during the first 4 years. Physician examination is unlikely to detect relapses beyond 3 years for stage IIA and IIB and beyond 2 years for stage IIC patients.

Lymph nodes and the melanoma surgeon: re-defining a long-term relationship.

Surgeons now have an enhanced ability to stage patients with clinically localized cutaneous melanoma using sentinel lymph node biopsy. Despite this, the weight of clinical evidence is tilting in favor of a measured approach to pre-emptive lymph node removal. Careful consideration of whether traditional surgical approaches to the regional nodes, whether done in the name of 'staging' or pre-emptive removal of a potential site of relapse, really 'benefit' the patient is paramount for optimal care.

Sentinel Lymph Node Biopsy for Cutaneous Head and Neck Melanoma: Mapping the Parotid Gland.

BACKGROUND: Sentinel lymph node biopsy (SLNB) for primary cutaneous head and neck melanoma (CHNM) has been shown to be successful and is the current standard of care for intermediate-thickness melanoma. We evaluated our experience with CHNM associated with SLNB mapping to the region of the parotid gland. METHODS: Retrospective review of a prospectively collected melanoma database identified 1014 CHNMs. Two-hundred twenty-three patients underwent SLNB, and 72 (32%) had mapping in the region of the parotid gland between May 1995 and June 2003. RESULTS: The mean number of SLNs per patient was 2.5. A sentinel lymph node (SLN) was successfully identified in 94% of patients, and in 12%, the SLN was positive for metastatic disease. Biopsy of intraparotid SLNs was performed in 51.4% and of periparotid SLNs in 26.4%, and a superficial parotidectomy was performed in 22.2%. Ten patients were found to have lymph nodes in the parotid region with metastatic disease (eight identified by SLNB), and two (20%) patients developed intraparotid lymph node recurrence in the setting of a negative SLNB. Same-basin recurrence in SLN-negative patients was 3.3% with a median follow-up of 26 months. Facial nerve dysfunction was identified in seven (10%) patients. Facial nerve function returned to preoperative status in all patients. CONCLUSIONS: SLNB for patients with primary CHNM mapping to the parotid gland can be performed with a high degree of accuracy and a low morbidity consisting of temporary facial nerve paresis.

Tumour exosome integrins determine organotropic metastasis.

Ever since Stephen Paget's 1889 hypothesis, metastatic organotropism has remained one of cancer's greatest mysteries. Here we demonstrate that exosomes from mouse and human lung-, liver- and brain-tropic tumour cells fuse preferentially with resident cells at their predicted destination, namely lung fibroblasts and epithelial cells, liver Kupffer cells and brain endothelial cells. We show that tumour-derived exosomes uptaken by organ-specific cells prepare the pre-metastatic niche. Treatment with exosomes from lung-tropic models redirected the metastasis of bone-tropic tumour cells. Exosome proteomics revealed distinct integrin expression patterns, in which the exosomal integrins α6ß4 and α6ß1 were associated with lung metastasis, while exosomal integrin αvß5 was linked to liver metastasis. Targeting the integrins α6ß4 and αvß5 decreased exosome uptake, as well as lung and liver metastasis, respectively. We demonstrate that exosome integrin uptake by resident cells activates Src phosphorylation and pro-inflammatory S100 gene expression. Finally, our clinical data indicate that exosomal integrins could be used to predict organ-specific metastasis.