Outcome In Melanoma Research Articles

Systematic review of risk prediction tools for primary cutaneous melanoma outcomes and validation of sentinel lymph node positivity prediction in a UK tertiary cohort.

It is difficult for clinicians to make predictions for cancer progression or outcomes based on AJCC staging for individual patients. Models individualising risk prediction for clinical outcomes are developed using patient level data, advanced statistical techniques, and artificial intelligence. A systematic search identified cutaneous melanoma prognostic prediction tools published between January 1985-March 2023. Population comparisons of key clinico-pathological variables, external prediction of receiver operating characteristics and calibration analysis are applied to an unselected group of patients undergoing sentinel lymph node biopsy in a UK University hospital setting (n = 1564). Twenty-nine models were identified which predicted survival, disease recurrence or sentinel lymph node positivity (Internal validation n = 19 and external validation n = 14). 3 out of 7 tools for sentinel node positivity were contemporaneous with available characteristics for external validation. External validation of models by Lo et al. Friedman et al. & Bertolli et al. highlighted good discriminative performance (AUC 68.1% (64.5-71.8%), 77.1% (66.8-85.7%) & 68.6% (63.3-74.1%) respectively) but were sub-optimally calibrated for the UK patient cohort (Calibration intercept & slope Friedman: -4.01 & 32.92, Lo: -1.17 & 0.44, Bertolli: -2.75 & 4.88). This work highlights the complexity of predictive modelling and the rigorous validation process necessary to ensure accurate predictions. Our search highlights a tendency to focus on discriminative performance over calibration, and the possibility for inconsistent predictions when tools are applied to populations with differing characteristics.

Body mass index and type 2 diabetes mellitus as metabolic determinants of immune checkpoint inhibitors response in melanoma

BackgroundImmune checkpoint inhibitors (ICIs) have improved survival outcomes in melanoma. Studies exploring the correlations between body mass index (BMI), type 2 diabetes (T2DM) and the outcomes of ICI treatment have...

Exploring resistance to immune checkpoint inhibitors and targeted therapies in melanoma.

Melanoma is the most aggressive form of skin cancer, characterized by a poor prognosis, and its incidence has risen rapidly over the past 30 years. Recent therapies, notably immunotherapy and targeted therapy, have significantly improved the outcome of patients with metastatic melanoma. Previously dismal five-year survival rates of below 5% have shifted to over 50% of patients surviving the five-year mark, marking a significant shift in the landscape of melanoma treatment and survival. Unfortunately, about 50% of patients either do not respond to therapy or experience early or late relapses following an initial response. The underlying mechanisms for primary and secondary resistance to targeted therapies or immunotherapy and relapse patterns remain not fully identified. However, several molecular pathways and genetic factors have been associated with melanoma resistance to these treatments. Understanding these mechanisms paves the way for creating novel treatments that can address resistance and ultimately enhance patient outcomes in melanoma. This review explores the mechanisms behind immunotherapy and targeted therapy resistance in melanoma patients. Additionally, it describes the treatment strategies to overcome resistance, which have improved patients' outcomes in clinical trials and practice.

Is pancreaticoduodenectomy justified for metastatic melanoma to the ampulla of Vater?

Metastatic melanoma of the ampulla of Vater is rare. The purpose of this study was to summarize the characteristics and outcomes of metastatic melanoma in the ampulla of Vater and highlight the impact of surgery on the prognosis of patients with metastatic melanoma. Pooled data from a case encountered at our institution and from all sporadic cases published on PubMed and MEDLINE between 1996 and 2023 were analyzed. Fourteen patients with metastatic melanoma in the ampulla of Vater were enrolled. Seventy-three percent of primary melanomas were cutaneous and 27% were mucosal. Jaundice was the most common symptom (86%). The size of metastatic melanoma to the ampulla ranged from 1.5 cm to 8 cm, with a median of 2.75 cm. Concomitant metastasis to other organs occurred in 82% of the patients at the time of diagnosis, most commonly in the brain, lungs, and liver (36% each). Among the reported cases, pancreaticoduodenectomy was performed in five patients. The overall 1-year survival rate was 27.3%, with a median survival of four months. Wide excision of the primary lesion and chemotherapy significantly improved survival rates (p= 0.048). There is a trend toward improved survival in patients undergoing pancreaticoduodenectomy followed by chemotherapy. Given the availability of effective systemic therapies, metastatic melanoma of the ampulla of Vater does not necessarily preclude major surgeries.

Immunohistochemistry-Assisted Mohs Surgery for Invasive Eyelid and Periorbital Cutaneous Melanoma.

Prior studies describe wide local excision and "slow Mohs" outcomes for periocular melanoma. Mohs micrographic surgery (MMS) with immunohistochemistry maximizes tissue preservation and offers same-day comprehensive margin evaluation, which facilitates expedited repair, and coordination of oculoplastic reconstruction when necessary. To describe oncologic and reconstructive outcomes of invasive periocular cutaneous melanoma treated with immunohistochemistry-assisted MMS. Invasive melanoma cases affecting the eyelids or periorbital region treated with MMS between 2008 and 2018 were reviewed. Eyelid tumors and those in adjacent subunits were compared. Main outcome measures were recurrence, melanoma-specific death, and postreconstructive complications. Of 42 cases, 28 were classified as periorbital and 14 as eyelid involving. Most were T1 (37, 88.1%). There was 1 local recurrence in a patient with persistent positive conjunctival margin (2.4%). No local recurrences were observed in cases where negative Mohs margins were achieved, and no melanoma-related deaths occurred. Eyelid tumors were more likely to result in lid margin involving defects and require oculoplastic reconstruction. Eyelid complications developed in 10 cases (23.8%), and 5 (11.9%) required revision surgery. Mohs micrographic surgery for periocular melanoma results in low rates of local recurrence and melanoma-specific death. Initial tumor location can aid in reconstructive planning.

Exploring the Frequency and Risk Factors of Hyperprogressive Disease in Patients with Advanced Melanoma Treated with Immune Checkpoint Inhibitors.

Hyperprogressive disease (HPD) is described as the unexpected rapid growth of a tumour accompanied by a decline in performance status. While immune checkpoint inhibitors (ICIs) have improved outcomes in advanced melanoma, HPD remains a significant challenge in a subset of patients. Although HPD has been extensively studied in various solid tumours, research specifically focusing on advanced melanoma remains limited. We analysed 158 advanced melanoma patients, with 66.5% (n = 105) receiving anti-PD-1 and 33.5% (n = 53) receiving nivolumab plus ipilimumab. The median overall survival was 4.9 months for patients with HPD compared to 8.9 months for those with progressive disease without HPD (p = 0.014). Factors associated with HPD included liver metastasis (p = 0.002), three or more metastatic sites (p < 0.001), elevated lactate dehydrogenase levels (p = 0.004), and Eastern cooperative oncology group performance status ≥2 (p = 0.023). Multivariate analysis identified the Royal Marsden Hospital score (HR 3.675, 95% CI: 1.166-11.580, p = 0.026) as an independent risk factor for HPD, with the MDA-ICI score also trending towards significance (HR 4.466, 95% CI: 0.947-21.061, p = 0.059). This study provides valuable insights into the frequency and factors associated with HPD in advanced melanoma patients treated with ICIs, highlighting the relevance of clinical markers and scoring systems in predicting HPD risk.

Impact of Adjuvant Interferon Therapy on Survival Outcomes for Cutaneous Melanoma With Parotid Involvement.

To determine the relative 5-year overall survival (OS) and 5-year recurrence-free survival (RFS) outcomes for adjuvant interferon therapy in the treatment of head and neck cutaneous melanoma (HNCM) with parotid gland involvement. A retrospective cohort study was conducted at a single tertiary care institution to analyze patients undergoing parotidectomy for cutaneous head and neck melanoma involving the parotid gland from 2000 to 2014. Time-to-event analyses were performed using Kaplan-Meier curves with log-rank p-values and Cox proportional hazards models. The sample consisted of 82 patients who underwent surgical resection of stage III HNCM with parotid involvement. The mean follow-up was 67.8 months (SD 65) after diagnosis. Twenty-one patients received adjuvant interferon therapy, 12 patients received adjuvant radiation therapy, and 49 patients received no adjuvant therapy. Crude 5-year OS rates were 95.0% for interferon therapy, 33.3% for adjuvant RT, and 40.4% for no adjuvant therapy. Crude 5-year RFS rates were 75.2%, 19.5%, and 40.8% respectively. In the fully adjusted model, adjuvant interferon therapy was associated with improved 5-year OS compared to adjuvant RT (HR 0.10, 95% CI 0.011-0.837; p = 0.034). There was no significant association between adjuvant interferon therapy and 5-year RFS in the fully adjusted model. Adjuvant interferon therapy for surgically resected stage III cutaneous melanoma with parotid gland involvement may be associated with improved survival outcomes. These findings support the growing evidence for the use of immunotherapy in melanoma, and potentially a unique role for when melanoma involves the lymphatic-rich parotid gland. 3 Laryngoscope, 2024.

Immunotherapy after progression to double immunotherapy: pembrolizumab and lenvatinib versus conventional chemotherapy for patients with metastatic melanoma after failure of PD-1/CTLA-4 inhibition.

Programmed cell death 1 receptor (PD-1) inhibition as monotherapy followed by Cytotoxic T-lymphocyte associated protein 4 (CTLA-4) inhibition in case of progression or as upfront double co-inhibition has drastically improved the survival outcomes of metastatic melanoma. Still, many patients develop primary or acquired resistance to both agents, relapse soon, and survive less. For these patients, the therapeutic options are very limited, and for many years, conventional chemotherapy (CC) was the standard of care. Recently, the phase II LEAP-004 trial supported that pembrolizumab/lenvatinib could potentially overcome anti-PD-1/anti-CTLA-4 immunotherapy refractoriness. In the absence of any prospective comparative study and to evaluate in a real-world context the clinical benefit of re-administering a PD-1 inhibitor (pembrolizumab 200 mg i.v. every 3 weeks, Q3W) with a multi-kinase inhibitor (lenvatinib, but at a reduced dose 10 mg p.o. daily due to its known toxicity) in this frail population of unmet need, we conducted here a retrospective comparison of LEAP-004-proposed combination with CC (carboplatin 4 AUC and dacarbazine 850 mg/m2 i.v. Q3W) in melanoma patients who relapsed to both checkpoint inhibitors, either in combinatorial or in sequential setting, between July 2022 and January 2024. Baseline demographics, disease characteristics, and treatment outcomes (objective response rate (ORR), progression-free survival (PFS), and overall survival (OS)) were recorded. Survival analyses were performed using the Kaplan-Meier method. All patients were also considered for safety analysis. A total of 84 patients were included in the effectiveness and safety analysis (pembrolizumab/lenvatinib, n=39 and CC, n=45). The median age was 67 (45-87) years and 64 (34-87) years, and men were 33.3% and 46.7%, respectively. The distribution of their metastatic sites was comparable, including 12.8% and 20% with brain involvement. Most patients had a good PS<2 (69.9% and 56.5%), increased lactate dehydrogenase (LDH) (71.8% and 84.4%), BRAF-wild status (82.1% and 84.8%), and received ≥2 previous systemic therapies (61.5% and 53.3%). The median follow-up was 18 months. The ORR was 23.1% and 11.1% (p<0.0001), the median PFS was 4.8 months and 3.8 months [HR (95%CI), 0.57 (0.36-0.92); p=0.017], and the median OS was 14.2 months and 7.8 months [HR (95%CI), 0.39 (0.22-0.69), p=0.0009] in pembrolizumab/lenvatinib and CC arms, respectively. Grade 3-5 treatment-related adverse events were documented in 48.7% (pembrolizumab/lenvatinib) and 75.6% (CC) of patients (p=0.034), which led to treatment discontinuation in 10.3% and 17.8% of cases, respectively. This is the first comparative study in patients with metastatic melanoma refractory to PD-1/CTLA-4 inhibition and showed significantly longer outcomes in cases treated with pembrolizumab/lenvatinib versus CC.

Trends in Melanoma Incidence, Prevalence, Stage at Diagnosis, and Survival: An Analysis of the United States Cancer Statistics (USCS) Database.

Background and objectives Melanoma, a major skin cancer, has seen varying trends in incidence, prevalence, stage atdiagnosis, and survival. This study examines these trends using the United States CancerStatistics (USCS) database, covering the period from 1999 to 2021. Methods We extracted data from the USCS database, which integrates the National Cancer Institute's (NCI) Surveillance, Epidemiology, and End Results (SEER) program and the Centers for Disease Control and Prevention's (CDC) National Program of Cancer Registries (NPCR). The analysis included new melanoma cases, prevalence estimates (using a 20-year limited duration), stage at diagnosis, and five-year relative survival rates. Incidence rates were adjusted for age using the 2000 United States standard population. Descriptive and trend analyses were performed using IBM SPSS Statistics software, version 29 (IBM Corp., Armonk, NY). Results The analysis of melanoma trends from 1999 to 2021 reveals a significant increase in the annual age-adjusted incidence rate, rising from 15.1 per 100,000 (95% CI: 14.9- 15.2) in 1999 to 23.0 per 100,000 (95% CI: 22.8- 23.1) in 2021. This upward trend is consistent across gender and racial/ethnic groups. The prevalence of melanoma over a 20-year period was 0.279 (95% CI: 0.276-0.282), with males showing a higher prevalence (0.302, 95% CI: 0.298-0.306) compared to females (0.256, 95% CI: 0.252-0.260). The distribution of melanoma stage at diagnosis indicated that 77% of cases were localized (95% CI: 76.5-77.5%), 9.5% regional (95% CI: 9.2-9.8%), 4.7% distant (95% CI: 4.4-5.0%), and 8.8% unstaged (95% CI: 8.5-9.1%). Survival analysis showed a five-year relative survival rate of 99.4% (95% CI: 99.2-99.6%) for localized melanoma and 35.6% (95% CI: 33.7-37.6%) for distant melanoma, highlighting significant disparities in survival based on stage at diagnosis. Conclusions The study highlights a rising incidence of melanoma and emphasizes the critical role of early detection in improving survival outcomes. The findings underscore the effectiveness of early diagnosis and the necessity for ongoing efforts to improve melanoma outcomes across diverse populations.

Tumor characteristics and outcomes of malignant melanomas on the genitalia.

Tumor characteristics and outcomes of malignant melanomas on the genitalia.

Longitudinal analysis of the gut microbiota during anti-PD-1 therapy reveals stable microbial features of response in melanoma patients

Immune checkpoint inhibitors (ICIs) improve outcomes in advanced melanoma, but many patients are refractory or experience relapse. The gut microbiota modulates antitumor responses. However, inconsistent baseline predictors point to heterogeneity in responses and inadequacy of cross-sectional data. We followed patients with unresectable melanoma from baseline and during anti-PD-1 therapy, collecting fecal and blood samples that were surveyed for changes in the gut microbiota and immune markers. Varying patient responses were linked to different gut microbiota dynamics during ICI treatment. We select complete responders by their stable microbiota functions and validate them using multiple external cohorts and experimentally. We identify major histocompatibility complex class I (MHC class I)-restricted peptides derived from flagellin-related genes of Lachnospiraceae (FLach) as structural homologs of tumor-associated antigens, detect FLach-reactive CD8+ Tcells in complete responders before ICI therapy, and demonstrate that FLach peptides improve antitumor immunity. These findings highlight the prognostic value of microbial functions and therapeutic potential of tumor-mimicking microbial peptides.

Pregnancy-associated melanoma (PAM): A single institution retrospective review between 2005 and 2023.

30 Background: Melanoma is the most prevalent cancer during pregnancy, representing 31% of all gestational cancers, with its incidence rates rising globally. Pregnancy-associated melanoma (PAM) presents unique challenges in diagnosis and management due to maternal physiological and hormonal changes, as well as consideration of fetal impact. This study aims to understand the impact of pregnancy on melanoma outcomes to optimize patient care. Methods: We conducted a retrospective study of patients diagnosed with PAM at The University of Texas MD Anderson Cancer Center between 2005 and 2023. Eligible patients were diagnosed either during pregnancy or within one year of delivery. Frequencies and percentages were used to describe the study population. Our primary outcome was to describe melanoma characteristics and prognosis, and our secondary outcome was to investigate melanoma’s impact on obstetrical outcomes. Results: The study included 76 patients with a mean age of 31.3 ± 4.4 years, 93.4% of whom were of white or Caucasian origin. The median follow-up was 39.8 months. Diagnoses included Stage 0 (7.9%), Stage I (36.8%), Stage II (3.9%), Stage III (22.4%), and Stage IV (25%) melanoma. The mean Breslow Thickness was 2.1± 4.7 mm. Primary diagnoses occurred in 76.6% of patients, while 21.9% experienced recurrent episodes during pregnancy. At the time of their PAM event, 47.4% had localized disease, and 48.7% had metastatic disease. The average mean time from diagnosis to first surgery was 2.1 months in patients diagnosed during pregnancy (group 1) and 0.9 months in patients diagnosed after pregnancy (group 2). The average time from diagnosis to systemic therapy was 3.3 ± 2.8 months in group 1 and 1 ± 0.7 months in group 2. Patients diagnosed during pregnancy had an average gestational age of 17.8 weeks: 30.65% were diagnosed in the first trimester, 54.84% in the second, and 14.52% in the third trimester. Thirty-three (43.4%) patients had term deliveries, while fifteen (19.7%) patients gave birth prematurely. There were 75.0% live births, 5.3% spontaneous abortions and 3.9% elective terminations. Conclusions: Our findings contribute to the limited literature on PAM outcomes, emphasizing the importance of a collaborative approach in managing these patients. Close surveillance of pregnant patients with melanoma is essential to prevent treatment delays and ensure optimal maternal and fetal outcomes.

Pediatric Melanoma Outcomes by Race and Socioeconomic Factors

Pediatric Melanoma Outcomes by Race and Socioeconomic Factors

Pregnancy and survival-related outcomes of uveal melanoma treated with brachytherapy in women of reproductive age

BackgroundTo examine if pregnancy affects the prognosis of uveal melanoma (UM) patients undergoing plaque brachytherapy (PBT) and to assess if PBT has any subsequent impact on pregnancy outcomes.MethodsA retrospective, single-center study was carried out at Beijing Tongren Hospital, focusing on women of childbearing age diagnosed with UM and treated with iodine-125 plaque brachytherapy. Both the outcomes of pregnancies and the health status of the fetuses were monitored. Survival analyses were conducted using the Kaplan-Meier method, with endpoints being metastasis and death.ResultsA total of 13 patients who had full-term pregnancies and 96 non-pregnant women matched by age and tumor size were included. The mean follow-up time was 67.0 ± 27.7 months (median:66.0 months, range:21.0 to 116.0 months). In the pregnant group, two patients developed metastases, one of whom died shortly after delivery; local recurrence of UM occurred in 2 patients after or during delivery, and 2 other patients developed secondary glaucoma due to radiation retinopathy. None of the other pregnant patients reported any signs of disease progression. In the control group, 18 metastasis cases including 12 deaths were documented. Pregnant patients and matched control subjects showed no statistical difference in both Metastasis-free survival (hazard ratio (HR): 0.66, 95% confidence interval (CI): 0.15–2.86; P = 0.576) and overall survival (HR: 0.48, 95% CI: 0.06–3.66; P = 0.464). All pregnant patients carried the pregnancy to term and delivered healthy children with no report of placental or infant metastases to date.ConclusionPregnancy does not appear to negatively impact the prognosis of UM patients undergoing PBT. PBT showed no observable detriment to maternal fertility and exhibited no teratogenic effects on the fetus. However, the long-term implications of PBT on pregnancy remain uncertain, necessitating additional, prolonged follow-up studies.

Chondroitin Sulfate Proteoglycan 4 (CSPG4) as an Emerging Target for Immunotherapy to Treat Melanoma

Immunotherapies, including checkpoint inhibitor antibodies, have precipitated significant improvements in clinical outcomes for melanoma. However, approximately half of patients do not benefit from approved treatments. Additionally, apart from Tebentafusp, which is approved for the treatment of uveal melanoma, there is a lack of immunotherapies directly focused on melanoma cells. This is partly due to few available targets, especially those expressed on the cancer cell surface. Chondroitin sulfate proteoglycan 4 (CSPG4) is a cell surface molecule overexpressed in human melanoma, with restricted distribution and low expression in non-malignant tissues and involved in several cancer-promoting and dissemination pathways. Here, we summarize the current understanding of the expression and functional significance of CSPG4 in health and melanoma, and we outline immunotherapeutic strategies. These include monoclonal antibodies, antibody–drug conjugates (ADCs), chimeric-antigen receptor (CAR) T cells, and other strategies such as anti-idiotypic and mimotope vaccines to raise immune responses against CSPG4-expressing melanomas. Several showed promising functions in preclinical models of melanoma, yet few have reached clinical testing, and none are approved for therapeutic use. Obstacles preventing that progress include limited knowledge of CSPG4 function in human cancer and a lack of in vivo models that adequately represent patient immune responses and human melanoma biology. Despite several challenges, immunotherapy directed to CSPG4-expressing melanoma harbors significant potential to transform the treatment landscape.

Evaluation of the efficacy of combined immune checkpoint inhibitors in advanced melanoma treatment - Long term outcomes and emerging therapeutic perspectives: a narrative review

Combination therapy with immune checkpoint inhibitors, specifically CTLA-4 and PD-1 blockade, has shown promise in treating advanced melanoma. However, this approach often results in increased toxicity, necessitating a careful evaluation of both efficacy and safety. This review explores clinical outcomes, survival rates, and adverse events associated with these therapies. A systematic review of PubMed, Scopus, and clinical trial databases was conducted for studies published from 2014 to 2024. Studies assessing the combined use of CTLA-4 and PD-1 inhibitors in melanoma patients were included, focusing on overall survival (OS), progression-free survival (PFS), and treatment-related adverse events (AEs). The combination of CTLA-4 and PD-1 inhibitors significantly improved clinical outcomes in advanced melanoma. In trials like CheckMate 067, the five-year overall survival rate reached 52%, with a notable improvement in progression-free survival. However, these benefits came with substantial toxicity, as approximately 55% of patients experienced grade 3 or 4 treatment-related adverse events, including colitis, hepatitis, and pneumonitis. Despite these challenges, combination therapy led to durable responses in a subset of patients, underscoring its efficacy. The review emphasizes the need for balancing efficacy with toxicity management in clinical practice. While CTLA-4 and PD-1 inhibitor combinations improve survival in advanced melanoma, increased toxicity presents challenges. Further research is needed to optimize treatment strategies and enhance patient selection to balance efficacy and safety.

Recent Advancements in Cell-Based Therapies in Melanoma.

Malignant melanoma outcomes have drastically changed in recent years due to the introduction of immune checkpoint inhibitors (ICIs). However, many patients still experience intolerable side effects, therapy resistance, and disease progression on ICI therapy. Therefore, there remains a need for novel therapeutics that address this gap in treatment options. Cell-based therapies have gained wide attention as a therapeutic option that could address this gap in treatment options for advanced melanoma. These therapies work by extracting certain cell types produced in the human body such as T-cells, modifying them based on a specific target, and transfusing them back into the patient. In the realm of cancer therapy, cell-based therapies utilize immune cells to target tumor cells while sparing healthy cells. Recently, the Food and Drug Administration (FDA) has approved the usage of lifileucel, a tumor-infiltrating lymphocyte (TIL) therapy, in advanced melanoma. This came following recent results from the C-144-01 study (NCT02360579), which demonstrated the efficacy and safety of TILs in metastatic melanoma patients who otherwise failed on standard ICI/targeted therapy. Thus, the results of this trial as well as the recent FDA approval have proven the viability of utilizing cell-based therapies to fill the gap in treatment options for patients with advanced melanoma. This review aims to provide a comprehensive overview of major cell-based therapies that have been utilized in melanoma by delineating results of the most recent multi-center phase II/ III clinical trials that evaluate the efficacy and safety of major cell-based therapies in melanoma. Additionally, we provide a summary of current limitations in each cell-based therapeutic option as well as a future direction of how to further extrapolate these cell-based therapies in advanced melanoma.

Comparison of clinicopathological features and treatment outcomes for cutaneous melanomas of the head and neck and melanomas arising at other sites: Implications for systemic therapy

Melanoma is increasingly recognized as a heterogeneous disease, with conflicting evidence regarding whether cutaneous head and neck melanoma (CHNM) represents a distinct entity. Comparison of clinicopathological features and treatment outcomes of CHNM and cutaneous melanomas of other sites (CMOS). Patients with CHNM and CMOS diagnosed between 2000 and 2018 were included. Locoregional control, distant metastasis-free survival, melanoma-specific survival (MSS), and overall survival (OS) were described using the Kaplan-Meier method. Cox regression analyses were performed to examine associations between prognostic factors and outcomes. Additional analyses of survival from time of stage IV disease diagnosis were undertaken, stratified by receipt of BRAF-targeted therapy and immune checkpoint inhibitor immunotherapy. Of 3007 CHNM and 10,637 CMOS patients, CHNM had more adverse pathological features (median age 65.9 vs 58.5, P<.001; median Breslow thickness 1.7mm vs 1.2mm, P<.001; and ulceration 21.2% vs 18.2%, P<.001). CHNM had worse locoregional control (hazard ratio (HR) 1.17, P<.001) and distant metastasis-free survival (HR 1.25, P<.001) but there were no significant differences in MSS or OS. Among stage IV patients who received immune checkpoint inhibitor, CHNM had better MSS (HR 0.56, P=.001) and OS (HR 0.57, P<.001) on multivariable analyses. Retrospective study, offset by prospective data collection. CHNM is associated with a distinct clinicopathological and prognostic profile.

Efficacy of PARP inhibitor therapy after targeted BRAF/MEK failure in advanced melanoma

Modern advancements in targeted therapy and immunotherapy have significantly improved survival outcomes for advanced melanoma; however, there remains a need for novel approaches to overcome disease progression and treatment resistance. In recent years, PARPi therapy has shown great promise both as a single regimen and in combination with other therapeutics in melanoma. Here, we describe three unique cases of advanced BRAF V600 mutated melanoma that progressed on targeted BRAF/MEK agents that subsequently exhibited partial to near-complete responses to combinatory PARPi and BRAF/MEK inhibitors. This highlights both a potential synergy underlying this combinatory approach and its efficacy as a treatment option for patients with advanced melanoma refractory to targeted and/or immunotherapies. Prospective clinical trials are needed to explore this synergic effect in larger melanoma cohorts to investigate this combination for treating refractory advanced melanoma.

Polypyrrole/iron-glycol chitosan nanozymes mediate M1 macrophages to enhance the X-ray-triggered photodynamic therapy for bladder cancer by promoting antitumor immunity

X-ray Photodynamic Therapy (XPDT) is an emerging, deeply penetrating, and non-invasive tumor treatment that stimulates robust antitumor immune responses. However, its efficacy is often limited by low therapeutic delivery and immunosuppressant within the tumor microenvironment. This challenge can potentially be addressed by utilizing X-ray responsive iron-glycol chitosan-polypyrrole nanozymes (GCS-I-PPy NZs), which activate M1 macrophages. These nanozymes increase tumor infiltration and enhance the macrophages' intrinsic immune response and their ability to stimulate adaptive immunity. Authors have designed biocompatible, photosensitizer-containing GCS-I-PPy NZs using oxidation/reduction reactions. These nanozymes were internalized by M1 macrophages to form RAW-GCS-I-PPy NZs. Authors' results demonstrated that these engineered macrophages effectively delivered the nanozymes with potentially high tumor accumulation. Within the tumor microenvironment, the accumulated GCS-I-PPy NZs underwent X-ray irradiation, generating reactive oxygen species (ROS). This ROS augmentation significantly enhanced the therapeutic effect of XPDT and synergistically promoted T cell infiltration into the tumor. These findings suggest that nano-engineered M1 macrophages can effectively boost the immune effects of XPDT, providing a promising strategy for enhancing cancer immunotherapy. The ability of GCS-I-PPy NZs to mediate M1 macrophage activation and increase tumor infiltration highlights their potential in overcoming the limitations of current XPDT approaches and improving therapeutic outcomes in melanoma and other cancers.