Causes of death and patterns of metastatic disease at the end of life for patients with advanced melanoma in the immunotherapy era.

Despite remarkable advances in immunotherapy, melanoma remains a significant cause of cancer mortality. Many factors concerning melanoma mortality are poorly understood, posing an obstacle to optimal care. We conducted a retrospective observational cohort study of 183 patients with metastatic melanoma who died following immunotherapy treatment to investigate sites of metastases at death, settings of death, and mechanisms of death. The median time from metastatic diagnosis to death was 16.1 months (range 0.3-135.1 months). Most patients experienced hospitalization within 3 months before death (80.3%), with 31.7% dying while hospitalized, 31.2% while in inpatient hospice, and 29.4% while in home hospice. The most common sites of metastases at death were distant lymph nodes (62.8%), lung (57.9%), liver (50.8%), brain (38.8%), and bone (37.7%). The most common causes of death were progressive failure to thrive (57.5%), respiratory failure (22.4%), and infection (21.8%); the vast majority (87.9%) of patients died from melanoma-specific causes. Overall, 10.9% of patients in our cohort had survival >5 years after metastatic diagnosis, and 76.2% of long-term survivors died due to melanoma. This study describes factors associated with melanoma mortality, highlighting an ongoing need for therapeutic advancements.

Characteristics and Experiences Associated with Interest in Global Surgery: What Brings US Medical Students to the Field?

INTRODUCTION: An estimated 5 billion people lack access to safe surgical care. Development and nurturing of medical student interest in global surgery can play a part in addressing this need. This study examines characteristics and experiences of medical students in the United States (US) associated with interest in global surgery. METHODS: A cross-sectional survey study of US-based medical students was performed. Student leaders from the Global Surgery Student Alliance were recruited via email and distributed the online survey to peers at their institutions. Responses from students currently training outside of the US were excluded, as were surveys with <80% completion. Descriptive statistics and multivariate analysis were performed with p < 0.05 indicating significance in R (Vienna, Austria). RESULTS: About 708 responses from students at 38 US medical schools were analyzed. 251 students (34.6%) identified as being interested in global surgery. After adjusting for covariates on multivariable regression, demographic factors significantly associated with interest in global surgery were Hispanic/Latino ethnicity (in comparison to Non-Hispanic White/Caucasian, OR = 1.30) and being born outside of the United States (OR = 1.21). Increased interest was also associated with previous clinical experiences in low or middle-income countries (OR = 1.19), public or global health experiences (OR = 1.18), and international service experiences (OR = 1.13). CONCLUSIONS: While many factors may influence student interest in global surgery, previous global health experience and nonclinical global service work are important predictors regardless of background. Our results suggest that medical educators should look to both international clinical and nonclinical collaborations as a means to cultivate and nourish global surgery interest in medical students.

Skipped sentinel lymph node basin in a patient with forearm cutaneous melanoma: A case report.

Sentinel lymph node biopsy is an important tool in the management of malignant melanoma, particularly in predicting micrometastasis to regional lymph nodes. Cases of secondary drainage to lymph nodes outside of conventional nodal basins and overall unusual lymph node localization have been reported. The present study reports a unique case of a 'skipped sentinel lymph node basin' pattern in a patient with a right forearm malignant melanoma. Lymphatic mapping using cutaneous lymphoscintigraphy revealed localization at the right supraclavicular lymph node, bypassing right axilla localization despite no prior axillary dissection or previous surgery or radiation. This unique pattern outlined in the present report adds to our understanding of disease localization and unique presentations.

Circulating Tumor Reactive KIR+CD8+ T cells Suppress Anti-Tumor Immunity in Patients with Melanoma.

Effective anti-tumor immunity is largely driven by cytotoxic CD8+ T cells that can specifically recognize tumor antigens. However, the factors which ultimately dictate successful tumor rejection remain poorly understood. Here we identify a subpopulation of CD8+ T cells which are tumor antigen-specific in patients with melanoma but resemble KIR+CD8+ T cells with a regulatory function (Tregs). These tumor antigen-specific KIR+CD8+ T cells are detectable in both the tumor and the blood, and higher levels of this population are associated with worse overall survival. Our findings therefore suggest that KIR+CD8+ Tregs are tumor antigen-specific but uniquely suppress anti-tumor immunity in patients with melanoma.

Digital spatial proteomic profiling reveals immune checkpoints as biomarkers in lymphoid aggregates and tumor microenvironment of desmoplastic melanoma.

BACKGROUND: Desmoplastic melanoma (DM) is a rare melanoma subtype characterized by dense fibrous stroma, a propensity for local recurrence, and a high response rate to programmed cell death protein 1 (PD-1) blockade. Occult sentinel lymph node positivity is significantly lower in both pure and mixed DM than in conventional melanoma, underscoring the need for better prognostic biomarkers to inform therapeutic strategies. METHODS: We assembled a tissue microarray comprising various cores of tumor, stroma, and lymphoid aggregates from 45 patients with histologically confirmed DM diagnosed between 1989 and 2018. Using a panel of 62 validated immune-oncology markers, we performed digital spatial profiling using the NanoString GeoMx platform and quantified expression in three tissue compartments defined by fluorescence colocalization (tumor (S100+/PMEL+/SYTO+), leukocytes (CD45+/SYTO+), and non-immune stroma (S100-/PMEL-/CD45-/SYTO+)). RESULTS: We observed higher expression of immune checkpoints (lymphocyte-activation gene 3 [LAG-3] and cytotoxic T-lymphocyte associated protein-4 [CTLA-4]) and cancer-associated fibroblast (CAF) markers (smooth muscle actin (SMA)) in the tumor compartments of pure DMs than mixed DMs. When comparing lymphoid aggregates (LA) to non-LA tumor cores, LAs were more enriched with CD20+B cells, but non-LA intratumoral leukocytes were more enriched with macrophage/monocytic markers (CD163, CD68, CD14) and had higher LAG-3 and CTLA-4 expression levels. Higher intratumoral PD-1 and LA-based LAG-3 expression appear to be associated with worse survival. CONCLUSIONS: Our proteomic analysis reveals an intra-tumoral population of SMA+CAFs enriched in pure DM. Additionally, increased expressions of immune checkpoints (LAG-3 and PD-1) in LA and within tumor were associated with poorer prognosis. These findings might have therapeutic implications and help guide treatment selection in addition to informing potential prognostic significance.

Immunotherapy utilization in stage IIIA melanoma: less may be more.

Background: Immunotherapy agents are approved for adjuvant treatment of stage III melanoma; however, evidence for survival benefit in early stage III disease is lacking. Current guidelines for adjuvant immunotherapy utilization in stage IIIA rely on clinician judgment, creating an opportunity for significant variation in prescribing patterns. This study aimed to characterize current immunotherapy practice variations and to compare patient outcomes for different prescribing practices in stage IIIA melanoma. Study design: Patients with melanoma diagnosed from 2015-2019 that met American Joint Committee on Cancer 8th edition criteria for stage IIIA and underwent resection were identified in the National Cancer Database. Multiple imputation by chained equations replaced missing values. Factors associated with receipt of adjuvant immunotherapy were identified. Multivariable Cox proportional hazards regression compared overall survival across groups. Results: Of 4,432 patients included in the study, 34% received adjuvant immunotherapy. Patients had lower risk-adjusted odds of receiving immunotherapy if they were treated at an academic center (OR=0.48, 95%CI=0.33-0.72, p<0.001 vs. community facility) or at a high-volume center (OR=0.69, 0.56-0.84, p<0.001 vs. low-volume). Immunotherapy receipt was not associated with risk-adjusted survival (p=0.095). Moreover, patients treated at high-volume centers experienced longer overall risk-adjusted survival than those treated at low-volume centers (HR=0.52, 0.29-0.93, p=0.030). Risk-adjusted survival trended toward being longer at academic centers than at community centers, but the difference was not statistically significant. Conclusion: Academic and high-volume centers utilize significantly less adjuvant immunotherapy in stage IIIA melanoma than community and low-volume centers without compromise in overall survival. These findings suggest that this population may benefit from more judicious immunotherapy utilization.

Immunotherapy Initiation at the End of Life in Patients With Metastatic Cancer in the US.

Importance: While immunotherapy is being used in an expanding range of clinical scenarios, the incidence of immunotherapy initiation at the end of life (EOL) is unknown. Objective: To describe patient characteristics, practice patterns, and risk factors concerning EOL-initiated (EOL-I) immunotherapy over time. Design, Setting, and Participants: Retrospective cohort study using a US national clinical database of patients with metastatic melanoma, non-small cell lung cancer (NSCLC), or kidney cell carcinoma (KCC) diagnosed after US Food and Drug Administration approval of immune checkpoint inhibitors for the treatment of each disease through December 2019. Mean follow-up was 13.7 months. Data analysis was performed from December 2022 to May 2023. Exposures: Age, sex, race and ethnicity, insurance, location, facility type, hospital volume, Charlson-Deyo Comorbidity Index, and location of metastases. Main Outcomes and Measures: Main outcomes were EOL-I immunotherapy, defined as immunotherapy initiated within 1 month of death, and characteristics of the cohort receiving EOL-I immunotherapy and factors associated with its use. Results: Overall, data for 242 371 patients were analyzed. The study included 20 415 patients with stage IV melanoma, 197 331 patients with stage IV NSCLC, and 24 625 patients with stage IV KCC. Mean (SD) age was 67.9 (11.4) years, 42.5% were older than 70 years, 56.0% were male, and 29.3% received immunotherapy. The percentage of patients who received EOL-I immunotherapy increased over time for all cancers. More than 1 in 14 immunotherapy treatments in 2019 were initiated within 1 month of death. Risk-adjusted patients with 3 or more organs involved in metastatic disease were 3.8-fold more likely (95% CI, 3.1-4.7; P < .001) to die within 1 month of immunotherapy initiation than those with lymph node involvement only. Treatment at an academic or high-volume center rather than a nonacademic or very low-volume center was associated with a 31% (odds ratio, 0.69; 95% CI, 0.65-0.74; P < .001) and 30% (odds ratio, 0.70; 95% CI, 0.65-0.76; P < .001) decrease in odds of death within a month of initiating immunotherapy, respectively. Conclusions and Relevance: Findings of this cohort study show that the initiation of immunotherapy at the EOL is increasing over time. Patients with higher metastatic burden and who were treated at nonacademic or low-volume facilities had higher odds of receiving EOL-I immunotherapy. Tracking EOL-I immunotherapy can offer insights into national prescribing patterns and serve as a harbinger for shifts in the clinical approach to patients with advanced cancer.

Case report: Metastatic Merkel cell carcinoma presenting seven years after loco-regional disease resection of primary tumor with interval in-transit and nodal metastases.

Merkel cell carcinoma (MCC) is a rare tumor with a high risk of recurrence after definitive therapy; however, the optimal duration of surveillance is unclear. First recurrences typically occur within 3 years. National guidelines recommend that patients undergo physical examination and imaging for surveillance during this time period. However, the duration of surveillance beyond this is not defined. Here, we describe a case of a patient developing a recurrence of MCC 7 years after the primary diagnosis with interval in-transit and regional lymph node metastases 15 months following the treatment of the primary MCC. Such late recurrences are rare, largely not reported, and the risk factors contributing to late recurrences are not well described. This case highlights the possibility of late recurrences of MCC after an initial in-transit and nodal recurrence and underscores the importance of identifying predictors of recurrence that may better guide the duration of surveillance.

The role of imaging and sentinel lymph node biopsy in patients with T3b-T4b melanoma with clinically negative disease.

Background: Previous studies demonstrate minimal utility of pre-operative imaging for low-risk melanoma; however, imaging may be more critical for patients with high-risk disease. Our study evaluates the impact of peri-operative cross-sectional imaging in patients with T3b-T4b melanoma. Methods: Patients with T3b-T4b melanoma who underwent wide local excision were identified from a single institution (1/1/2005 - 12/31/2020). Cross-sectional imaging was defined as body CT, PET and/or MRI in the perioperative period, with the following findings: in-transit or nodal disease, metastatic disease, incidental cancer, or other. Propensity scores were created for the odds of undergoing pre-operative imaging. Recurrence free survival was analyzed using the Kaplan-Meier method and log-rank test. Results: A total of 209 patients were identified with a median age of 65 (IQR 54-76), of which the majority were male (65.1%), with nodular melanoma (39.7%) and T4b disease (47.9%). Overall, 55.0% underwent pre-operative imaging. There were no differences in imaging findings between the pre- and post-operative cohorts. After propensity-score matching, there was no difference in recurrence free survival. Sentinel node biopsy was performed in 77.5% patients, with 47.5% resulting in a positive result. Conclusion: Pre-operative cross-sectional imaging does not impact the management of patients with high-risk melanoma. Careful consideration of imaging use is critical in the management of these patients and highlights the importance of sentinel node biopsy for stratification and decision making.

Combined Tripier and V-Y Advancement Flaps for Reconstruction of Large Lid-cheek Junction Defects.

Reconstruction of lid-cheek junction defects has a known risk of ectropion. Cervicofacial flaps require significant dissection and can still be prone to ectropion. V-Y advancement flaps have been described as less morbid, but their use is limited to moderate-size defects that do not involve the lid margin. The authors present a technique of combined Tripier and V-Y advancement flaps for reconstruction of large defects of the lid-cheek junction involving the lower eyelid. A retrospective review of patients undergoing the authors' technique was performed. A facial artery perforator flap was designed in a V-Y fashion and advanced into the cheek. An orbicularis oculi myocutaneous flap (Tripier flap) was elevated from the upper eyelid and rotated into the lower eyelid/upper cheek to meet the superior edge of the V-Y flap. A separate review of patients undergoing cervicofacial flap reconstruction was also performed. Demographics, operative details, and complications were recorded and compared. This technique was applied to five patients with large-size (19.9 ± 5.6 cm2) defects of the lid-cheek. In all cases, healing was achieved without ectropion, hematoma, infection, dehiscence, flap necrosis, or facial nerve injury. Twenty-four patients separately underwent cervicofacial flap reconstruction for defects of comparable size (15.8 ± 10.7 cm2). Two patients developed ectropion, one patient developed a hematoma, and two patients developed an infection. Combined Tripier and V-Y advancement flaps is a useful technique to reconstruct lid-cheek junction defects. This method allows for the reconstruction of large lid-cheek junction defects that involve the lid margin.

Malignant Melanoma in Older Adults: Different Patient or Different Disease?

Objective In this study, we aimed to compare the clinical outcomes between older and younger patients with melanoma and to evaluate for differences in tumor genetic makeup that might explain differences in clinical behavior between older and younger cohorts. Materials and methods A consecutive sample of patients diagnosed with melanoma at a single institution from 1984 to 2019 was categorized by age into younger, middle, and older cohorts. Tumor characteristics, melanoma-specific survival, and recurrence-free survival were assessed while accounting for differential follow-up and death from other causes using Kaplan-Meier analysis with log-rank testing. Results A total of 4378 patients were included in the study. Older patients presented with a higher incidence of T3 and T4 tumors, and a lower incidence of T1 tumors (p<0.001). The same group of patients had a lower nodal positivity at any given Breslow thickness (p<0.01). Melanoma-specific survival was lower for older patients with T2 tumors (p=0.046). There was no difference in recurrence-free survival among all age groups and tumor thicknesses (p>0.05). For patients with a given genetic profile, the melanoma-specific survival and recurrence-free survival were equivalent across ages. BRAF was the most common driver in the younger group, while NRAS and other mutations increased in prevalence as age rose. Conclusions Older adults have decreased melanoma-specific survival for T2 tumors and lower nodal positivity, suggesting a different pattern of metastatic progression. The mutational drivers of cutaneous melanoma change with age and may play a role in the different metastatic progression as well as the differential melanoma-specific survival across all age cohorts.

The Facial Artery Perforator Flap.

BACKGROUND: Reconstruction of facial melanoma defects can be challenging. Large defects of the midface, cheek, and nasolabial fold are often reconstructed using a cervicofacial flap which requires significant flap elevation and undermining. Surgeons are often hesitant to commit to such a large reconstruction without definitive pathologic evidence of negative margins. However, local perforator flaps may be used as an alternative to large flaps with less dissection and donor site morbidity and may also allow for more facile re-advancement in the event of a positive margin on final pathology. The goal of this study is to evaluate a perforator flap based on the facial artery to determine if it is a safe and cosmetically favorable option to immediately repair oncologic-related defects on the cheek and midface. METHODS: A retrospective review of all melanoma cases performed by the senior author between January 2016 and December 2021 was conducted. Patients who underwent reconstruction using a facial artery perforator flap were included. RESULTS: Sixteen patients were included in our cohort. The average age was 67.3 years and 53% (n=8) were female. Fourteen patients had the primary defect located on the cheek, 1 from the nasolabial fold, and 1 from the distal nasal sidewall. All patients received immediate reconstruction. Excisional margins ranged from 0.5 to 2 cm. Two patients had positive margins following pathology results with one undergoing treatment with imiquimod and the other opting for re-excision. No complications involving the defect or donor site were reported after an average follow-up time of 113.8 days. CONCLUSION: The facial artery perforator flap is a safe and cosmetically favorable option to immediately repair oncologic-related defects on the cheek and midface.

The Treatment of Complex Extremity Wounds Using External Tissue Expansion: A Case Series.

SUMMARY: The goal of wound reconstruction is the approximation of soft tissue and re-establishment of an acceptable appearance with minimal risk of complications. For large wound closure in the extremities, skin graft and flap reconstruction are common treatments but are associated with a variety of complications. Comparatively, tissue expansion can provide the opportunity to reconstruct large wounds with native, durable, and sensate tissue without significant donor site morbidity. External tissue expansion is less invasive and avoids complications associated with internal expansion. The authors treated 11 patients with varying extremity wound types and sizes with an external tissue expansion device. Patient age ranged from 18 to 68 years with an average age of 43.7 years (SD, ± 13.1 years). Average wound surface area was approximately 235 cm 2 (SD, ± 135.3 cm 2 ). Devices were affixed and left for 7 to 11 days before closure of the wounds. Outcomes were assessed at 2 to 36 weeks postoperative follow-up. All wounds were fully closed after treatment without need for secondary reconstructive procedures. No patient experienced major complications. All patients demonstrated intact sensation within the area of reconstruction equivalent to surrounding tissues. External tissue expansion, an excellent treatment option in extremity reconstruction, is efficacious and associated with lower complication rates compared with internal tissue expansion, skin grafts, and flap reconstruction. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

The Aesthetics of Digit Amputation.

Background: The goal of surgery, when treating a patient with a traumatized hand, is to restore function. The importance of the aesthetics on a patient's psychological well-being should also be considered. The biomechanical ideals for creating a useful hand after digit amputation have been defined; however, ideal aesthetic levels for finger amputation have not been elucidated. The purpose of this study was to determine the general population's visual preferences for different levels of digit amputation in the hand. Methods: In all, 310 participants were surveyed to identify preferences of different levels of single digit amputations in dorsal and volar views. A normal hand was digitally manipulated to simulate various levels of digit amputation. The aesthetics of amputation at the distal interphalangeal (DIP) joint, proximal interphalangeal (PIP) joint, metacarpophalangeal (MCP) joint, and ray amputation were compared to one another via rank order. Average rank for each level of amputation for a digit was determined. Results: Amputation at the DIP was favored over all other levels; however, ray amputation was the second most aesthetic, particularly in the middle and ring fingers even when compared to amputation at the PIP level. Conclusion: When presented a choice at which level to perform a completion amputation or a primary amputation of a digit, and functionality at multiple levels of amputation is equivocal, aesthetic outcomes should be considered. Amputation at the DIP joint is preferable, but ray amputation is aesthetically more pleasing than amputation at the PIP or MCP joints in the index, middle, ring, and small fingers.

Preoperative Deficiency Anemia in Digital Replantation: A Marker of Disparities, Increased Length of Stay, and Hospital Cost.

Introduction The effects of preoperative anemia have been shown to be an independent risk factor associated with poor outcomes in both cardiac and noncardiac surgery. Socioeconomic status and race have also been linked to poor outcomes in a variety of conditions. This study was designed to study iron deficiency anemia as a marker of health disparities, length of stay and hospital cost in digital replantation. Materials and Methods Digit replantations performed between 2008 and 2014 were reviewed from the National Inpatient Sample (NIS) database using the ICD-9-CM procedure codes 84.21 and 84.22. Patients with more than one code or with an upper arm (83.24) or hand replantation (84.23) code were excluded. Extracted variables included age, race, comorbidities, hospital type, hospital region, insurance payer type, and median household income quartile. Digit replantations were separated into patients with and without deficiency anemia. Demographics, comorbidities, and access to care were compared between cohorts by chi-squared and t -tests. Multivariate regressions were utilized to assess the effects of anemia on total cost and length of stay. The regression controlled for demographics, region, income, insurance, hospital type, and comorbidities. Beta coefficient was calculated for length of stay and hospital cost. The regression controlled for significant age, race, region, and comorbidities in addition to the above variables. Results In the studied patient population of those without anemia, 59.5% were Caucasian, and in patients with anemia, 46.7% were Caucasian ( p < 0.001). Whereas in the in the studied patient population of those without anemia, 6.7% were Black, and in patients with anemia, 15.7% were Black ( p < 0.001). Median household income, payer information, length of stay and total cost of hospitalization had statistically significant differences. Using regression and ß-coefficient, the effect of anemia on length of stay and cost was also significant ( p < 0.001). Regression controlled for age, race, region and comorbidities, with the ß-coefficient for effect on cost 37327.18 and on length of stay 3.96. Conclusion These data show that deficiency anemias are associated with a significant increase in length and total cost of stay in patients undergoing digital replantation. Additionally, a larger percentage of patients undergoing digital replantations and who have deficiency anemia belong to the lowest income quartile. Our findings present an important finding for public health prevention and resource allocation. Future studies could focus on clinical intervention with iron supplementation at the time of digital replantation.

Integrative molecular and clinical profiling of acral melanoma links focal amplification of 22q11.21 to metastasis.

Acral melanoma, the most common melanoma subtype among non-White individuals, is associated with poor prognosis. However, its key molecular drivers remain obscure. Here, we perform integrative genomic and clinical profiling of acral melanomas from 104 patients treated in North America (n = 37) or China (n = 67). We find that recurrent, late-arising focal amplifications of cytoband 22q11.21 are a leading determinant of inferior survival, strongly associated with metastasis, and linked to downregulation of immunomodulatory genes associated with response to immune checkpoint blockade. Unexpectedly, LZTR1 - a known tumor suppressor in other cancers - is a key candidate oncogene in this cytoband. Silencing of LZTR1 in melanoma cell lines causes apoptotic cell death independent of major hotspot mutations or melanoma subtypes. Conversely, overexpression of LZTR1 in normal human melanocytes initiates processes associated with metastasis, including anchorage-independent growth, formation of spheroids, and an increase in MAPK and SRC activities. Our results provide insights into the etiology of acral melanoma and implicate LZTR1 as a key tumor promoter and therapeutic target.