In recent years, effective systemic therapies have emerged for patients with metastatic melanoma. These therapies have also made their way to the perioperative setting, demonstrating improved recurrence-free survival for subsets of individuals with stage III and IV disease that received therapy after having undergone surgical resection. While adjuvant therapy is recommended for certain patients with stage II, III, and IV disease, patient selection can be nuanced. Adjuvant therapies are not without their own risks, and an individual's ability to tolerate treatment must be weighed. We review key adjuvant therapy trials, recommendations for its use in contemporary practice, and future directions.

Disease progression is closely linked to shifts in the expression levels of specific genes within molecular pathways. While gene set enrichment analysis is a widely employed method for identifying key disease markers, it has been underutilized in survival analysis. Here, we introduce a novel computational approach that adapts gene set enrichment analysis for survival analysis. The proposed approach considers a gene set, computes a single-sample gene set enrichment score, and, based on this score, splits the samples into cohorts. It then scores the gene sets by evaluating the differences in survival rates between the resulting cohorts. We aim to find gene sets that can lead to cohorts with significantly different survival probabilities. Utilizing gene expression data from The Cancer Genome Atlas and gene sets from the Molecular Signature Database, our results demonstrate that existing empirical research consistently supports the top gene sets our approach associates with survival prognosis. The proposed method broadens gene set enrichment analysis applications to include information on survival, bridging the gap between alterations in molecular pathways and their implications on survival.

Pathogenic BRAF mutations drive constitutive MAPK pathway activation in melanoma, and targeted therapies with dabrafenib plus trametinib have improved outcomes in the adjuvant setting. However, the optimal duration of adjuvant therapy remains unclear. This retrospective study examined whether extending dabrafenib plus trametinib beyond 1 year offers additional clinical benefit in Chinese patients with resected Stage III melanoma.

Medical records from six centers were reviewed for adults with BRAF V600E/K-positive, completely resected Stage III melanoma who received at least 12 months of adjuvant dabrafenib plus trametinib. Patients were divided into a 1-year therapy group and a more-than-1-year therapy group. Relapse-free survival (RFS) was the primary end point; adverse events were also assessed.

Of the 122 patients included, 77 received more than 1 year of adjuvant therapy. The more-than-1-year group experienced significantly better RFS (log-rank p = 0.04), and longer therapy independently reduced recurrence risk in multivariate analysis (HR, 2.42; p = 0.035). Adverse event profiles did not differ between groups, and toxicity-related treatment modifications occurred primarily within the first year.

Extending dabrafenib plus trametinib beyond 1 year may provide improved RFS without increasing toxicity. Further prospective trials are warranted to confirm the impact on overall survival and identify optimal patient subsets for prolonged therapy.

Cancer immunotherapy, encompassing both experimental and standard-of-care therapies, has emerged as a promising approach to harnessing the immune system for tumor suppression. Experimental strategies, including novel immunotherapies and preclinical models, are actively being explored, while established treatments, such as immune checkpoint inhibitors (ICIs), are widely implemented in clinical settings. This comprehensive review examines the historical evolution, underlying mechanisms, and diverse strategies of cancer immunotherapy, highlighting both its clinical applications and ongoing preclinical advancements. The review delves into the essential components of anticancer immunity, including dendritic cell activation, T cell priming, and immune surveillance, while addressing the challenges posed by immune evasion mechanisms. Key immunotherapeutic strategies, such as cancer vaccines, oncolytic viruses, adoptive cell transfer, and ICIs, are discussed in detail. Additionally, the role of nanotechnology, cytokines, chemokines, and adjuvants in enhancing the precision and efficacy of immunotherapies were explored. Combination therapies, particularly those integrating immunotherapy with radiotherapy or chemotherapy, exhibit synergistic potential but necessitate careful management to reduce side effects. Emerging factors influencing immunotherapy outcomes, including tumor heterogeneity, gut microbiota composition, and genomic and epigenetic modifications, are also examined. Furthermore, the molecular mechanisms underlying immune evasion and therapeutic resistance are analyzed, with a focus on the contributions of noncoding RNAs and epigenetic alterations, along with innovative intervention strategies. This review emphasizes recent preclinical and clinical advancements, with particular attention to biomarker-driven approaches aimed at optimizing patient prognosis. Challenges such as immunotherapy-related toxicity, limited efficacy in solid tumors, and production constraints are highlighted as critical areas for future research. Advancements in personalized therapies and novel delivery systems are proposed as avenues to enhance treatment effectiveness and accessibility. By incorporating insights from multiple disciplines, this review aims to deepen the understanding and application of cancer immunotherapy, ultimately fostering more effective and widely accessible therapeutic solutions.

In the phase 3 CheckMate 76 K trial, adjuvant nivolumab significantly improved recurrence-free survival and distant metastasis-free survival versus placebo in patients with resected stage IIB/C melanoma. We report patient-reported outcomes from CheckMate 76 K.

Change from baseline to week 53 in health-related quality of life (HRQoL), as measured using the EORTC QLQ-C30 and EQ-5D-5L utility index and visual analog scale (VAS), was compared between treatment groups using linear mixed-effect models. Time to confirmed deterioration (TTCD) in HRQoL was assessed using Cox regression. Bother from side effects, as measured by the FACIT-GP5, was descriptively compared between treatment groups.

There were no clinically meaningful differences in change from baseline between treatment groups in EORTC QLQ-C30 subscales, including global health status (GHS)/quality of life (QoL; least squares mean [LSM] difference: -1.3; 95 % confidence interval [CI]: -2.9, 0.4), and EQ-5D-5L utility index (LSM difference: -0.011; 95 % CI: -0.025, 0.004) and VAS (LSM difference: -1.3; 95 % CI: -2.6, 0.0). There was no difference in TTCD for nivolumab versus placebo in EORTC QLQ-C30 GHS/QoL (hazard ratio [HR]: 1.10; 95 % CI: 0.88, 1.36) or EQ-5D-5L utility index (HR: 1.10; 95 % CI: 0.86, 1.42); however, TTCD in EQ-5D-5L VAS was longer with placebo (HR: 1.92; 95 % CI: 1.39, 2.64). Proportions of patients reporting severe side effect bother ("quite a bit"/"very much") were minimal (nivolumab: 1 %-4 %; placebo: 0 %-2 %).

Patients with resected stage IIB/C melanoma treated with adjuvant nivolumab demonstrated stable HRQoL and minimal bother from side effects.

NCT04099251.

As essential immune system regulators, cytokines are essential for modulating both innate and adaptive immunological responses. They have become important tools in cancer immunotherapy, improving the immune system's capacity to identify and destroy tumor cells. This article examines the background, workings, and therapeutic uses of cytokines, such as interleukins, interferons, and granulocyte-macropHage colony-stimulating factors, in the management of cancer. It examines the many ways that cytokines affect immune cell activation, signaling pathways, tumor development, metastasis, and prognosis by modifying the tumor microenvironment. Despite the limited effectiveness of cytokine-based monotherapy, recent developments have concentrated on new fusion molecules such as immunocytokines, cytokine delivery improvements, and combination techniques to maximize treatment efficacy while reducing adverse effects. Current FDA-approved cytokine therapeutics and clinical trial results are also included in this study, which offers insights into how cytokines might be used with other therapies including checkpoint inhibitors, chemotherapy, and radiation therapy to address cancer treatment obstacles. This study addresses the intricacies of cytokine interactions in the tumor microenvironment, highlighting the possibility for innovative treatment methods and suggesting fresh techniques for enhancing cytokine-based immunotherapies. PEGylation, viral vector-mediated cytokine gene transfer, antibody-cytokine fusion proteins (immunocytokines), and other innovative cytokine delivery techniques are among the novelties of this work, which focuses on the most recent developments in cytokine-based immunotherapy. Additionally, the study offers a thorough examination of the little-reviewed topic of cytokine usage in conjunction with other treatment techniques. It also discusses the most recent clinical studies and FDA-approved therapies, providing a modern perspective on the developing field of cancer immunotherapy and suggesting creative ways to improve treatment effectiveness while lowering toxicity. BACKGROUND: Cytokines are crucial in cancer immunotherapy for regulating immune responses and modifying the tumor microenvironment (TME). However, challenges with efficacy and safety have driven research into advanced delivery methods and combination therapies to enhance their therapeutic potential.

Cutaneous melanoma is a common cancer in Australia and New Zealand, Europe, and North America, and its incidence is still increasing in many regions. Ultraviolet (UV) radiation exposure (for example, through excessive sunlight exposure) remains the primary risk factor for melanoma; however, public awareness campaigns have led to a marked reduction in mortality. In addition to genetic damage from UV radiation, specific genetic alterations have been linked to melanoma. The stage of the tumour at the time of diagnosis is of greater importance for melanoma prognosis than in almost any other cancer. Context-dependent genetic mutations that attenuate tumour-suppressive mechanisms or activate growth-promoting signalling pathways are crucial factors in the development of cutaneous melanoma. In addition to external factors such as UV radiation, the tumour microenvironment can contribute to melanoma progression, invasion and metastasis. Cutaneous melanoma treatment has improved considerably over the past decade with the discovery and development of immune checkpoint inhibitors and therapy targeting BRAF and MEK. Over the next decade, several priorities are likely to influence melanoma research and management, including the continued advance of precision medicine methods to identify the most suitable patients for the most effective treatment, with the aim of improving clinical outcomes.

Neoadjuvant immunotherapy is emerging as an effective approach for resectable stage III/IV melanoma, showing improvements in disease response and survival outcomes.

This review summarizes findings from neoadjuvant treatment trials in melanoma patients. Using the PubMed search engine and including the keywords 'neoadjuvant,' 'immunotherapy,' and 'melanoma,' we selected 18 trials that showed efficacy in patients with melanoma, mainly testing checkpoint inhibitors alone or in combination. Across all trials examined, treatments showed objective disease responses, which frequently translated into improved disease-free survival.

Additional phase III studies comparing neoadjuvant and adjuvant therapies are needed to establish the optimal standard of care. The variety of regimens and dosing schedules investigated highlights the need for further research to determine the most appropriate treatments in this clinical setting. Advances in the study of biomarkers that can identify specific subgroups of patients will guide future research in this field.

BackgroundIn 2022, SWOG S1801 was the first trial to demonstrate that single-agent anti-PD-1 checkpoint inhibition used as neoadjuvant-adjuvant therapy leads to significantly improved outcomes compared to adjuvant-only therapy. Endpoints in trials comparing neoadjuvant-adjuvant to adjuvant strategies need special consideration to ensure that event measurement timing is appropriately accounted for in analyses to avoid biased comparisons artificially favoring one arm over another.MethodsThe S1801 trial is used a case study to evaluate the issues involved in selecting endpoints for trials comparing neoadjuvant-adjuvant versus adjuvant-only strategies.ResultsDefinitions and timing of measurement of events is provided. Trial scenarios when recurrence-free versus event-free survival should be used are provided.ConclusionsIn randomized trials comparing neoadjuvant-adjuvant to adjuvant-only strategies, event-free survival endpoints measured from randomization are required for unbiased comparison of the arms. The time at which events can be measured on each arm needs to be carefully considered. If measurement of events occurs at different times on the randomized arms, modified definitions of event-free survival must be used to avoid bias.

Immunotherapy has surfaced as a promising therapeutic modality for gastric cancer (GC). A comprehensive review of advancements, current status, and research trends in GC immunotherapy is essential to inform future investigative efforts.

To delineate the trends, advancements, and focal points in immunotherapy for GC.

We performed a bibliometric analysis of 2906 articles in English concerning GC immunotherapy published from 2000 to December 20, 2023, indexed in the Web of Science Core Collection. Data analysis and visualization were facilitated by CiteSpace (6.1.6R), VOSviewer v.1.6.17, and GraphPad Prism v8.0.2.

There has been an increase in the annual publication rate of GC immunotherapy research. China leads in publication volume, while the United States demonstrates the highest citation impact. Fudan University is notable for its citation frequency and publication output. Co-citation analysis and keyword frequency revealed and highlighted a focus on GC prognosis, the tumor microenvironment (TME), and integrative immunotherapy with targeted therapy. Emerging research areas include gastroesophageal junction cancer, adoptive immunotherapy, and the role of Treg cell in immunotherapy.

GC immunotherapy research is an expanding field attracting considerable scientific interest. With the clinical adoption of immunotherapy in GC, the primary goals are to enhance treatment efficacy and patient outcomes. Unlike hematological malignancies, GC's solid TME presents distinct immunological challenges that may attenuate the cytotoxic effects of immune cells on cancer cells. For instance, although CAR-T therapy is effective in hematological malignancies, it has underperformed in GC settings. Current research is centered on overcoming immunosuppression within the TME, with a focus on combinations of targeted therapy, adoptive immunotherapy, Treg cell dynamics, and precise prognosis prediction in immunotherapy. Additionally, immunotherapy's role in treating gastroesophageal junction cancer has become a novel research focus.

Melanoma has become the poster child for transformative outcomes in advanced malignancy from the use of immunotherapy over the last 10-15 years with median survival improving from ~ 1 to > 5 years. With the increasing repertoire of immune checkpoint inhibitors (ICI) and other novel immunotherapeutic approaches, integrating and sequencing treatments to create new paradigms has gained prominence, with focus on optimizing toxicity management and complex scenarios such as immunotherapy resistance, brain metastases, fertility, and duration of follow-up.

In this review, we summarize the progress and emerging evidence in melanoma treatments to date and consider management and possible future directions to improve outcomes for above-mentioned specific patient cohorts.

Personalized care with integration of novel prognostic and predictive biomarkers is the way forward in tailoring not only patient selection and choice of therapy, but also duration of treatment and surveillance to allow for early recurrence detection and access to newer therapies such as tumor infiltrating lymphocytes (TIL) to maximize the curative fraction of melanoma patients. Further research is needed in optimizing ICI and other immunotherapy toxicity management, including reducing steroid exposure for better patient outcomes and preserving quality of life.

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, 135:1098-1104, 2025.

Over the years, extensive research has been dedicated to performing in-depth analysis of cancer to uncover the intricate details of its nature - including the types of cancer, causative agents, stimulators of disease progression, factors contributing to poor prognosis, and efficient therapies to restrict the metastatic aggressiveness. This chapter highlights the mechanisms through which different arms of the host immune system - namely cytokines, lymphocytes, antigen-presenting cells (APCs) -can be mobilized to eradicate cancer. Most malignant tumors are either poorly immunogenic, or are harbored in a highly immuno-suppressive microenvironment. This is why reinforcing the host's anti-tumor defenses, through infusion of pro-inflammatory cytokines, tumor antigen-loaded APCs, and anti-tumor cytotoxic cells has emerged as a viable treatment option against cancer. The chapter also highlights the ongoing preclinical and clinical studies in different malignancies and the outcome of various therapies. Although these methods are not foolproof, and antigen escape variants can still evade or develop resistance to customized therapies, they achieve disease stabilization in several cases when conventional treatments fail. In many instances, combination therapies involving cytokines, T cells, and vaccinations prove more effective than monotherapies. The limitations of the current therapies are also discussed, along with ongoing modifications aimed at improving efficacy.

Primary pulmonary malignant melanoma is an extremely rare non-epithelial malignancy. Literature is merely limited to a few anecdotal case reports. Herein we present a case of a 74-year-old female who was diagnosed with primary malignant melanoma of the lung. To fully appraise the available evidence, we have sought to perform narrative review of the existing literature.

Interferon-alpha1b (IFN-α1b) has shown remarkable therapeutic potential as adjuvant therapy for melanoma. This study aimed to develop five machine learning models to evaluate the efficacy of postoperative IFN-α1b in patients with advanced melanoma.

We retrospectively analyzed 113 patients with the American Joint Committee on Cancer (AJCC) stage III-IV melanoma who received postoperative IFN-α1b therapy between July 2009 and February 2024. Recurrence-free survival (RFS) and overall survival (OS) were assessed using Kaplan-Meier analysis. Five machine learning models (Decision Tree, Cox Proportional Hazards, Random Forest, Support Vector Machine, and LASSO regression) were developed and compared for their capacity to predict the outcomes of patients. Model performance was evaluated using concordance index (C-index), time-dependent receiver operating characteristic (ROC) curves, and decision curve analysis.

The 1-year, 2-year, and 3-year RFS rates were 71.10%, 43.10%, and 31.10%, respectively. For OS, the 1-year, 2-year, and 3-year OS rates were 99.10%, 82.30%, and 75.00%, respectively. The Decision Tree (DT) model demonstrated superior predictive performance with the highest C-index of 0.792. Time-dependent ROC analysis for predicting 1-, 2-, and 3-year RFS based on the DT model is 0.77, 0.79 and 0.76, respectively. Serum albumin emerged as the important predictor of RFS.

Our study demonstrates the considerable efficacy DT model for predicting the efficacy of adjuvant IFN-α1b in patients with advanced melanoma. Serum albumin was identified as a key predictive factor of the treatment efficacy.

There are many Bayesian design methods allowing for the incorporation of historical data for sample size determination (SSD) in situations where the outcome in the historical data is the same as the outcome of a new study. However, there is a dearth of methods supporting the incorporation of data from a previously completed clinical trial that investigated the same or similar treatment as the new trial but had a primary outcome that is different. We propose a simulation-based Bayesian SSD framework using the partial-borrowing scale transformed power prior (straPP). The partial-borrowing straPP is developed by applying a novel scale transformation to a traditional power prior on the parameters from the historical data model to make the information better align with the new data model. The scale transformation is based on the assumption that the standardized parameters (i.e., parameters multiplied by the square roots of their respective Fisher information matrices) are equal. To illustrate the method, we present results from simulation studies that use real data from a previously completed clinical trial to design a new clinical trial with a primary time-to-event endpoint.

Modern systemic therapy has dramatically improved outcomes for many patients with advanced metastatic melanoma. The success of these therapies has attracted much scientific interest while these therapies have made their way into the treatment of earlier stages of disease. Randomized trials have led to the approval of adjuvant immunotherapy and targeted therapy for resected stage III melanoma. However, most recently, these therapies have gained traction in the neoadjuvant setting. Promising early results led to randomized controlled trials that have now established neoadjuvant therapy as standard of care in advanced melanoma patients. Questions remain regarding the optimal choice of therapy, duration and timing of neoadjuvant therapy, extent of surgery, and the need for additional adjuvant therapy for patients who received neoadjuvant therapy. Herein we provide an overview of neoadjuvant therapy for melanoma and dilemmas to its broader applications.

Although meningiomas are the most common primary brain tumor, there are limited treatment options for recurrent or aggressive lesions. Compared to other brain tumors, meningiomas may be uniquely amenable to immunotherapy by virtue of their location outside the blood-brain barrier.

This review describes our current understanding of the immunology of the meninges, as well as immune cell infiltration and immune signaling in meningioma. Current literature on meningioma immunology and immunotherapy was comprehensively reviewed and summarized by a comprehensive search of MEDLINE (1/1/1990-6/1/2024). Further, we describe the current state of immunotherapeutic approaches, as well as potential future targets. Potential immunotherapeutic approaches include immune checkpoint inhibition, CAR-T approaches, tumor vaccine therapy, and immunogenic molecular markers.

Meningioma immunotherapy is in early stages, as no immunotherapies are currently included in treatment guidelines. There is substantial heterogeneity in immune cell infiltration, immunogenicity, and immune escape across tumors, even within tumor grade. Furthering our understanding of meningioma immunology and tumor classification will allow for careful selection of tumors and patient populations that may benefit from primary or adjunctive immunotherapy for meningioma.

Acral melanoma presents distinct biological characteristics compared to cutaneous melanoma. While adjuvant therapeutic strategies for high-risk resected acral melanoma closely resemble those for cutaneous melanoma, the evidence supporting the clinical application of adjuvant therapy for acral melanoma remains inadequate. Our aim was to systematically analyze the efficacy and safety profile of adjuvant therapy in acral melanoma.

This systematic review adhered to a pre-registered protocol. We comprehensively searched four electronic databases and reference lists of included articles to identify eligible studies. The primary outcome was therapeutic efficacy, and the secondary outcome was adverse events (AEs).

This systematic review included 11 studies with 758 acral melanoma patients undergoing adjuvant therapy. High-dose interferon α-2b (IFN) regimens showed no significant difference in recurrence-free survival (RFS), though the longer regimen was linked to increased hepatotoxicity. Adjuvant anti-PD-1 therapy demonstrated varying efficacy, with improved RFS in patients who experienced immune-related AEs. Targeted therapy with dabrafenib plus trametinib achieved high 12-month RFS in patients with BRAF-mutated acral melanoma. Comparative studies suggested that adjuvant anti-PD-1 therapy is similarly effective to IFN in prolonging survival for high-risk acral melanoma patients. Additionally, prior treatment with pegylated IFN enhanced RFS in patients receiving adjuvant pembrolizumab.

High-dose IFN was widely used as adjuvant therapy for acral melanoma, but serious AEs prompted the search for alternatives. Adjuvant anti-PD-1 therapy shows promise, though it may be less effective than in non-acral melanoma. Further prospective studies are needed to determine the optimal adjuvant treatment for acral melanoma.

Anorectal mucosal melanoma (AMM) is a rare and highly aggressive malignancy. It frequently presents with nonspecific symptoms, often resulting in delayed diagnosis and poor prognosis. This report describes the case of a 60-year-old male who presented with a painful para-anal papule that progressed to a fistula. Histopathological and immunohistochemical analyses confirmed AMM. Imaging revealed a locally advanced tumor without distant metastasis. Due to the locally advanced nature of the disease, a multidisciplinary team recommended neoadjuvant radiotherapy. This case highlights the diagnostic and therapeutic challenges associated with AMM and emphasizes the importance of a tailored, multidisciplinary approach. Surgical resection remains the cornerstone of treatment, with neoadjuvant therapy potentially improving surgical outcomes in advanced cases.

Recombinant cytokine products have emerged as a promising avenue in cancer therapy due to their capacity to modulate and enhance the immune response against tumors. However, their clinical application is significantly hindered by systemic toxicities already at low doses, thus preventing escalation to therapeutically active regimens. One promising approach to overcoming these limitations is using antibody-cytokine fusion proteins (also called immunocytokines). These biopharmaceuticals leverage the targeting specificity of antibodies to deliver cytokines directly to the tumor microenvironment, thereby reducing systemic exposure and enhancing the therapeutic index. This review comprehensively examines the development and potential of antibody-cytokine fusion proteins in cancer therapy. It explores the molecular characteristics that influence the performance of these fusion proteins, and it highlights key findings from preclinical and clinical studies, illustrating the potential of immunocytokines to improve treatment outcomes in cancer patients. Recent advancements in the field, such as novel engineering strategies and combination strategies to enhance the efficacy and safety of immunocytokines, are also discussed. These innovations offer new opportunities to optimize this class of biotherapeutics, making them a more viable and effective option for cancer treatment. As the field continues to evolve, understanding the critical factors that influence the performance of immunocytokines will be essential for successfully translating these therapies into clinical practice.

Cytokines are small proteins that modulate the activity of the immune system. Because of their potent immunomodulatory properties, some recombinant cytokines have undergone clinical development and have gained marketing authorization for the therapy of certain forms of cancer. Recombinant cytokines are typically administered at ultralow doses, as many of them can cause substantial toxicity even at submilligram quantities. In an attempt to increase the therapeutic index, fusion proteins based on tumor-homing antibodies (also called "immunocytokines") have been considered, and some products in this class have reached late-stage clinical trials. While antibody-cytokine fusions, which preferentially localize in the neoplastic mass, can activate tumor-resident leukocytes and may be more efficacious than their nontargeted counterparts, such products typically conserve an intact cytokine activity, which may prevent escalation to curative doses. To further improve tolerability, several strategies have been conceived for the development of antibody-cytokine fusions with "activity-on-demand", acting on tumors but helping spare normal tissues from undesired toxicity. In this article, we have reviewed some of the most promising strategies, outlining their potential as well as possible limitations.

Melanoma is defined as the most aggressive and deadly form of skin cancer. The treatment of melanoma depends on the disease stage, tumor location, and extent of its spread from its point of origin. Melanoma treatment has made significant advances, notably in the context of targeted and immunotherapies. Surgical resection is the main therapeutic option for earlystage melanoma, and it provides favourable outcomes. With disease metastasis, systemic treatments such as immunotherapy and targeted therapy become increasingly important. The identification of mutations that lead to melanoma has influenced treatment strategies. Targeted therapies focusing on these mutations offer improved response rates and fewer toxicities than conventional chemotherapy. Furthermore, developing immunotherapies, including checkpoint inhibitors and tumor-infiltrating lymphocyte (TIL) therapies, has demonstrated encouraging outcomes in effectively combating cancer cells. These therapeutic agents demonstrate superior effectiveness and a more tolerable side-effect profile, improving the quality of life for patients receiving treatment. The future of melanoma treatment may involve a multimodal approach consisting of a combination of surgery, targeted therapy, and immunotherapy adapted to each patient's profile. This approach may improve survival rates and health outcomes.

Cytokines are critical in regulating immune responses and cellular behavior, playing dual roles in both normal physiology and the pathology of diseases such as cancer. These molecules, including interleukins, interferons, tumor necrosis factors, chemokines, and growth factors like TGF-β, VEGF, and EGF, can promote or inhibit tumor growth, influence the tumor microenvironment, and impact the efficacy of cancer treatments. Recent advances in targeting these pathways have shown promising therapeutic potential, offering new strategies to modulate the immune system, inhibit tumor progression, and overcome resistance to conventional therapies. In this review, we summarized the current understanding and therapeutic implications of targeting cytokine and chemokine signaling pathways in cancer. By exploring the roles of these molecules in tumor biology and the immune response, we highlighted the development of novel therapeutic agents aimed at modulating these pathways to combat cancer. The review elaborated on the dual nature of cytokines as both promoters and suppressors of tumorigenesis, depending on the context, and discussed the challenges and opportunities this presents for therapeutic intervention. We also examined the latest advancements in targeted therapies, including monoclonal antibodies, bispecific antibodies, receptor inhibitors, fusion proteins, engineered cytokine variants, and their impact on tumor growth, metastasis, and the tumor microenvironment. Additionally, we evaluated the potential of combining these targeted therapies with other treatment modalities to overcome resistance and improve patient outcomes. Besides, we also focused on the ongoing research and clinical trials that are pivotal in advancing our understanding and application of cytokine- and chemokine-targeted therapies for cancer patients.

Melanoma is commonly diagnosed in a younger population than most other solid malignancies and, in Australia and most of the world, is the leading cause of skin-cancer-related death. Melanoma is a cancer type with high immunogenicity; thus, immunotherapies are used as first-line treatment for advanced melanoma patients. Although immunotherapies are working well, not all the patients are benefitting from them. A lack of a comprehensive understanding of immune regulation in the melanoma tumour microenvironment is a major challenge of patient stratification. Overexpression of CD155 has been reported as a key factor in melanoma immune regulation for the development of therapy resistance. A more thorough understanding of the actions of current immunotherapy strategies, their effects on immune cell subsets, and the roles that CD155 plays are essential for a rational design of novel targets of anti-cancer immunotherapies. In this review, we comprehensively discuss current anti-melanoma immunotherapy strategies and the immune response contribution of different cell lineages, including tumour endothelial cells, myeloid-derived suppressor cells, cytotoxic T cells, cancer-associated fibroblast, and nature killer cells. Finally, we explore the impact of CD155 and its receptors DNAM-1, TIGIT, and CD96 on immune cells, especially in the context of the melanoma tumour microenvironment and anti-cancer immunotherapies.

This study investigates the differential expression of miRNA gene subtypes in tumoral versus benign nevi in individuals with melanoma, aiming to identify clinically significant correlations that could serve as reliable markers for assessing tumor stage and progression. Conducted between 2019 and 2022, this descriptive, quantitative observational research analyzed 90 formalin-fixed paraffin-embedded (FFPE) samples from the Pius Brinzeu County Emergency Clinical Hospital, Timisoara, including 45 samples of advanced-stage melanoma and 45 samples of pigmented nevi. miRNA purification and analysis were performed using the miRNeasy Kit and the Human Cancer PathwayFinder miScript miRNA PCR Array, with statistical analysis (including logistic regression) to determine associations with cancer staging, such as high Breslow index risk, number of mitoses, and vascular invasion. After the analysis and comparison of 180 miRNA gene subtypes, we selected 10 of the most upregulated and 10 most downregulated genes. The results revealed that hsa-miR-133b, hsa-miR-335-5p, hsa-miR-200a-3p, and hsa-miR-885-5p were significantly upregulated in melanoma samples, with fold changes ranging from 1.09 to 1.12. Conversely, hsa-miR-451a and hsa-miR-29b-3p showed notable downregulation in melanoma, with fold changes of 0.90 and 0.92, respectively. Additionally, logistic regression analysis identified hsa-miR-29b-3p (OR = 2.51) and hsa-miR-200a-3p (OR = 2.10) as significantly associated with an increased risk of a high Breslow index, while hsa-miR-127-3p and hsa-miR-451a were associated with a reduced risk. Conclusively, this study underscores the significant alterations in miRNA expression in melanoma compared to benign nevi and highlights the potential of specific miRNAs as biomarkers for melanoma progression. The identification of miRNAs with significant associations to melanoma characteristics suggests their utility in developing non-invasive, cost-effective diagnostic tools and in guiding therapeutic decisions, potentially improving patient outcomes in melanoma management.

Melanoma is the most aggressive and deadly form of skin cancer due to its high propensity to metastasize to distant organs. Significant progress has been made in the last few decades in melanoma therapeutics, most notably in targeted therapy and immunotherapy. These approaches have greatly improved treatment response outcomes; however, they remain limited in their abilities to hinder disease progression due, in part, to the onset of acquired resistance. In parallel, intrinsic resistance to therapy remains an issue to be resolved. In this review, we summarize currently available therapeutic options for melanoma treatment and focus on possible mechanisms that drive therapeutic resistance. A better understanding of therapy resistance will provide improved rational strategies to overcome these obstacles.

Inflammation has accompanied human beings since the emergence of wounds and infections. In the past decades, numerous efforts have been undertaken to explore the potential role of inflammation in cancer, from tumor development, invasion, and metastasis to the resistance of tumors to treatment. Inflammation-targeted agents not only demonstrate the potential to suppress cancer development, but also to improve the efficacy of other therapeutic modalities. In this review, we describe the highly dynamic and complex inflammatory tumor microenvironment, with discussion on key inflammation mediators in cancer including inflammatory cells, inflammatory cytokines, and their downstream intracellular pathways. In addition, we especially address the role of inflammation in cancer development and highlight the action mechanisms of inflammation-targeted therapies in antitumor response. Finally, we summarize the results from both preclinical and clinical studies up to date to illustrate the translation potential of inflammation-targeted therapies.

Biliary tract cancers (BTC), a heterogeneous disease with poor prognosis, including gallbladder cancer (GBC), intrahepatic cholangiocarcinoma (ICC), and extrahepatic cholangiocarcinoma (ECC). Although surgery is currently the primary regimen to treat BTC, most BTC patients are diagnosed at an advanced stage and miss the opportunity of surgical eradication. As a result, non-surgical therapy serves as the main intervention for advanced BTC. In recent years, immunotherapy has emerged as one of the most promising therapies in a number of solid cancers, and it includes immune checkpoint inhibitors (ICIs) monotherapy or combined therapy, tumor vaccines, oncolytic virus immunotherapy, adoptive cell therapy (ACT), and cytokine therapy. However, these therapies have been practiced in limited clinical settings in patients with BTC. In this review, we focus on the discussion of latest advances of immunotherapy in BTC and update the progress of multiple current clinical trials with different immunotherapies.

Patients with stage III resectable melanoma carry a high risk of melanoma recurrence that ranges from approximately 40% to 90% at 5 years following surgical management alone. Postoperative systemic adjuvant therapy targets residual micrometastatic disease that could be the source of future recurrence and death from melanoma. Randomized phase III adjuvant trials reported significant improvements in overall survival with high-dose interferon α in 2 of 3 studies (compared with observation and GMK ganglioside vaccine) and with anti-cytotoxic T-lymphocyte antigen 4 ipilimumab at 10 mg/kg compared with placebo and ipilimumab 3 mg/kg compared with high-dose interferon α. In the modern era, more recent phase III trials demonstrated significant recurrence-free survival improvements with anti-programmed cell death protein 1, pembrolizumab, and BRAF-MEK inhibitor combination dabrafenib-trametinib (for BRAF mutant melanoma) versus placebo. Furthermore, anti-programmed cell death protein 1, nivolumab and pembrolizumab have both been shown to significantly improve recurrence-free survival as compared with ipilimumab 10 mg/kg. For melanoma patients with clinically or radiologically detectable locoregionally advanced disease, emerging data support an important role for preoperative systemic neoadjuvant therapy. Importantly, a recent cooperative group trial (S1801) reported superior event-free survival rates with neoadjuvant versus adjuvant therapy. Collectively, current data from neoadjuvant immunotherapy and targeted therapy trials support a future change in clinical practice in favor of neoadjuvant therapy for eligible melanoma patients.

Tumor progression and eradication have long piqued the scientific community's interest. Recent discoveries about the role of chemokines and cytokines in these processes have fueled renewed interest in related research. These roles are frequently viewed as contentious due to their ability to both suppress and promote cancer progression. As a result, this review critically appraised existing literature to discuss the unique roles of cytokines and chemokines in the tumor microenvironment, as well as the existing challenges and future opportunities for exploiting these roles to develop novel and targeted treatments. While these modulatory molecules play an important role in tumor suppression via enhanced cancer-cell identification by cytotoxic effector cells and directly recruiting immunological effector cells and stromal cells in the TME, we observed that they also promote tumor proliferation. Many cytokines, including GM-CSF, IL-7, IL-12, IL-15, IL-18, and IL-21, have entered clinical trials for people with advanced cancer, while the FDA has approved interferon-alpha and IL-2. Nonetheless, low efficacy and dose-limiting toxicity limit these agents' full potential. Conversely, Chemokines have tremendous potential for increasing cancer immune-cell penetration of the tumor microenvironment and promoting beneficial immunological interactions. When chemokines are combined with cytokines, they activate lymphocytes, producing IL-2, CD80, and IL-12, all of which have a strong anticancer effect. This phenomenon opens the door to the development of effective anticancer combination therapies, such as therapies that can reverse cancer escape, and chemotaxis of immunosuppressive cells like Tregs, MDSCs, and TAMs.

Therapeutic lymphadenectomy (TLND) is still performed in most melanoma patients to treat nodal recurrences after initial negative lymph node biopsy (-SLNB), despite the lack of evidence for survival benefit. We sought to compare melanoma-specific survival (MSS) and distant metastasis-free survival (DMFS) of patients who underwent TLND versus no TLND using our institutional and MSTL-1 databases.

We identified 146 patients with nodal recurrence following -SLNB: 132 underwent TLND and 14 did not. DMFS and MSS were evaluated for the cohorts followed by a matched-pair analysis between the cohorts.

No difference was observed in five-year DMFS (p ​= ​0.454) and five-year MSS (p ​= ​0.945) between the two groups. The matched-pair analysis showed similar results (p ​= ​0.329 and p ​= ​0.363 for DMSF and MSS, respectively).

From this limited retrospective study, TLND for nodal recurrence after a -SLNB does not appear to improve DMFS or MSS in melanoma patients compared to no TLND.

Glioblastoma is an aggressive primary brain tumor that poses many therapeutic difficulties because of the high rate of proliferation, genetic variability, and its immunosuppressive microenvironment. The theory of cancer immunoediting, which includes the phases of elimination, equilibrium, and escape, offers a paradigm for comprehending interactions between the immune system and glioblastoma. Immunoediting indicates the process by which immune cells initially suppress tumor development, but thereafter select for immune-resistant versions leading to tumor escape and progression. The tumor microenvironment (TME) in glioblastoma is particularly immunosuppressive, with regulatory T cells and myeloid-derived suppressor cells being involved in immune escape. To achieve an efficient immunotherapy for glioblastoma, it is crucial to understand these mechanisms within the TME. Existing immunotherapeutic modalities such as chimeric antigen receptor T cells and immune checkpoint inhibitors have been met with some level of resistance because of the heterogeneous nature of the immune response to glioblastoma. Solving these issues is critical to develop novel strategies capable of modulating the TME and re-establishing normal immune monitoring. Further studies should be conducted to identify the molecular and cellular events that underlie the immunosuppressive tumor microenvironment in glioblastoma. Comprehending and modifying the stages of immunoediting in glioblastoma could facilitate the development of more potent and long-lasting therapies.

Pancreatic ductal adenocarcinoma cancer (PDAC) is projected to become the second leading cause of cancer-related death in the United States by 2030. Patients are often diagnosed with advanced disease, which explains the dismal 5-year median overall survival rate of ~12%. Immunotherapy has been successful in improving outcomes in the past decade for a variety of malignancies, including gastrointestinal cancers. However, PDAC is historically an immunologically "cold" tumor, one with an immunosuppressive environment and with restricted entry of immune cells that have limited the success of immunotherapy in these tumors. The microbiome, the intricate community of microorganisms present on and within humans, has been shown to contribute to many cancers, including PDAC. Recently, its role in tumor immunology and response to immunotherapy has generated much interest. Herein, the current state of the interaction of the microbiome and immunotherapy in PDAC is discussed with a focus on needed areas of study in order to harness the immune system to combat pancreatic cancer.

Anorectal melanoma (ARM) is an exceedingly rare and very aggressive malignancy. It originates from the melanocytic cells in the anorectal mucosa, which produces melanin. Other mucosal melanomas commonly found in the mucosa of the oral cavity, vulvovaginal, pharynx and urinary tract. Patients usually present with bleeding per rectum, perianal pain and difficulty in defaecation. Distinction of primary anorectal melanoma from other tumours of this region is difficult because of the lack of common imaging features. MRI is the modality of choice for its better tissue characterisation and resolution. There is no standard treatment protocol available mainly due to scarcity of data. Surgery is the mainstay therapy. Herein we present a case of a male patient in his 30s who presented with rectal bleeding and perianal pain. Haematological analysis revealed normocytic normochromic anaemia. MRI detected a mass lesion in the anorectal region. Contrast enhanced CT revealed multiple metastases in the liver, lungs, periportal, mesorectal and inguinal lymph nodes. The diagnosis of the ulcerated anorectal melanoma was established on histopathological examination. The patient underwent abdominoperineal resection (APR) followed by chemotherapy. Afterward the patient presented to the emergency room with respiratory distress for which he was on ventilator support. Sadly, the patient died after four days.

Anorectal mucosal melanoma (AMM) is an infrequent and highly aggressive form of mucosal melanoma. Its rarity makes it challenging to clinically diagnose, and its initial symptoms are typically nonspecific such as rectal/anal bleeding (the most common symptom), anal pain, or the presence of an anal mass. The prognosis for this condition is generally poor, and its incidence appears to be increasing each year. AMMs often go undetected and/or are already metastasized at the time of diagnosis. We present a case report of a patient who initially presented with nonspecific symptoms of anemia and blood per rectum, and was later found to have stage IV melanoma of the anorectal region. There is a notable scarcity of literature on this disease, resulting in a lack of a comprehensive understanding of its nature. Most available information consists of isolated case reports rather than comprehensive studies. Although surgical resection remains the primary treatment approach, the majority of patients (over 80%) will die due to distant metastasis within five years after undergoing surgery. The five-year survival rate for anorectal melanoma is estimated to be between 6% and 22%.

Melanoma had long been considered to be particularly addressable with immunotherapy, but that reputation was built on modestly effective cytokine-based immunotherapy. CTLA-4 antibody therapy reinforced this legacy, but PD-1 antibodies transformed the melanoma treatment landscape and lead the way for immunotherapy to become standard treatment for more than half of the advanced cancer population. BRAF mutations were discovered in 8% of all cancer and nearly 50% of melanomas. Successful development of BRAF inhibitors and BRAF/MEK combination therapy in melanoma preceded regulatory approval across all cancer types. No cancer type saw outcomes improved by the same margin as melanoma in the decade of the 2010s.

Conventional type 1 dendritic cells (cDC1s) are superior in antigen cross-presentation and priming CD8+ T cell anti-tumor immunity and thus, are a target of high interest for cancer immunotherapy. Type I interferon (IFN) is a potent inducer of antigen cross-presentation, but, unfortunately, shows only modest results in the clinic given the short half-life and high toxicity of current type I IFN therapies, which limit IFN exposure in the tumor. CD8+ T cell immunity is dependent on IFN signaling in cDC1s and preclinical studies suggest targeting IFN directly to cDC1s may be sufficient to drive anti-tumor immunity. Here, we engineered an anti-XCR1 antibody (Ab) and IFN mutein (IFNmut) fusion protein (XCR1Ab-IFNmut) to determine whether systemic delivery could drive selective and sustained type I IFN signaling in cDC1s leading to anti-tumor activity and, in parallel, reduced systemic toxicity. We found that the XCR1Ab-IFNmut fusion specifically enhanced cDC1 activation in the tumor and spleen compared to an untargeted control IFN. However, multiple treatments with the XCR1Ab-IFNmut fusion resulted in robust anti-drug antibodies (ADA) and loss of drug exposure. Using other cDC1-targeting Ab-IFNmut fusions, we found that localizing IFN directly to cDC1s activates their ability to promote ADA responses, regardless of the cDC1 targeting antigen. The development of ADA remains a major hurdle in immunotherapy drug development and the cellular and molecular mechanisms governing the development of ADA responses in humans is not well understood. Our results reveal a role of cDC1s in ADA generation and highlight the potential ADA challenges with targeting immunostimulatory agents to this cellular compartment.

Advances in our understanding of melanoma biology and the role of immune checkpoint blockade and targeted therapy have ushered in a new and rapidly evolving era of multidisciplinary care for patients with melanoma. Based on efficacy for patients with metastatic melanoma, these systemic treatment approaches have been introduced into the adjuvant and, more recently, the neoadjuvant landscape. This report highlights the results of key clinical studies published or initially presented in 2021 that have informed our evidence-based approach to melanoma multidisciplinary care, primarily related to adjuvant and neoadjuvant approaches for patients with resectable or resected stage III or high-risk stage II melanoma and their impact on clinical care. Knowledge concerning these areas of active clinical investigation is critical for surgical oncologists who care for melanoma patients as the treatment landscape continues to evolve.

Since the first approval for immune checkpoint inhibitors (ICIs) for the treatment of cutaneous melanoma more than a decade ago, immunotherapy has completely transformed the treatment landscape of this chemotherapy-resistant disease. Combination regimens including ICIs directed against programmed cell death protein 1 (PD-1) with anti-cytotoxic T lymphocyte antigen-4 (CTLA-4) agents or, more recently, anti-lymphocyte-activation gene 3 (LAG-3) agents, have gained regulatory approvals for the treatment of metastatic cutaneous melanoma, with long-term follow-up data suggesting the possibility of cure for some patients with advanced disease. In the resectable setting, adjuvant ICIs prolong recurrence-free survival, and neoadjuvant strategies are an active area of investigation. Other immunotherapy strategies, such as oncolytic virotherapy for injectable cutaneous melanoma and bispecific T-cell engager therapy for HLA-A*02:01 genotype-positive uveal melanoma, are also available to patients. Despite the remarkable efficacy of these regimens for many patients with cutaneous melanoma, traditional immunotherapy biomarkers (ie, programmed death-ligand 1 expression, tumor mutational burden, T-cell infiltrate and/or microsatellite stability) have failed to reliably predict response. Furthermore, ICIs are associated with unique toxicity profiles, particularly for the highly active combination of anti-PD-1 plus anti-CTLA-4 agents. The Society for Immunotherapy of Cancer (SITC) convened a panel of experts to develop this clinical practice guideline on immunotherapy for the treatment of melanoma, including rare subtypes of the disease (eg, uveal, mucosal), with the goal of improving patient care by providing guidance to the oncology community. Drawing from published data and clinical experience, the Expert Panel developed evidence- and consensus-based recommendations for healthcare professionals using immunotherapy to treat melanoma, with topics including therapy selection in the advanced and perioperative settings, intratumoral immunotherapy, when to use immunotherapy for patients with BRAFV600-mutated disease, management of patients with brain metastases, evaluation of treatment response, special patient populations, patient education, quality of life, and survivorship, among others.

Inflammatory processes are increased by stress and contribute to the pathology of mood disorders. Stress is thought to primarily induce inflammation through peripheral and central noradrenergic neurotransmission. In healthy individuals, these pro-inflammatory effects are countered by glucocorticoid signaling, which is also activated by stress. In chronically stressed individuals, the anti-inflammatory effects of glucocorticoids are impaired, allowing pro-inflammatory effects to go unchecked. Mechanisms underlying this glucocorticoid resistance are well understood, but the precise circuits and molecular mechanisms by which stress increases inflammation are not as well known. In this narrative review, we summarize the mechanisms by which chronic stress increases inflammation and contributes to the onset and development of stress-related mood disorders. We focus on the neural substrates and molecular mechanisms, especially those regulated by noradrenergic signaling, that increase inflammatory processes in stressed individuals. We also discuss key knowledge gaps in our understanding of the communication between nervous and immune systems during stress and considerations for future therapeutic strategies. Here we highlight the mechanisms by which noradrenergic signaling contributes to inflammatory processes during stress and how this inflammation can contribute to the pathology of stress-related mood disorders. Understanding the mechanisms underlying crosstalk between the nervous and immune systems may lead to novel therapeutic strategies for mood disorders and/or provide important considerations for treating immune-related diseases in individuals suffering from stress-related disorders.

The consideration of systemic adjuvant therapy is recommended for patients with stage IIB-IV melanoma who have undergone surgical resection due to a heightened risk of experiencing melanoma relapse and mortality from melanoma. Adjuvant therapy options tested over the past three decades include high-dose interferon-α, immune checkpoint inhibitors (pembrolizumab, nivolumab), targeted therapy (dabrafenib-trametinib for BRAF mutant melanoma), radiotherapy and chemotherapy. Most of these therapies have been demonstrated to enhance relapse-free survival (RFS) but with limited to no impact on overall survival (OS), as reported in randomized trials. In contemporary clinical practice, the adjuvant treatment approach for surgically resected stage III-IV melanoma has undergone a notable shift towards the utilization of nivolumab, pembrolizumab, and BRAF-MEK inhibitors, such as dabrafenib plus trametinib (specifically for BRAF mutant melanoma) due to the significant enhancements in RFS observed with these treatments. Pembrolizumab has obtained regulatory approval in the United States to treat resected stage IIB-IIC melanoma, while nivolumab is currently under review for the same indication. This review comprehensively analyzes completed phase III adjuvant therapy trials in adjuvant therapy. Additionally, it provides a summary of ongoing trials and an overview of the main challenges and future directions with adjuvant therapy.

Advanced melanoma accounts for the majority of skin cancer-associated deaths. Over the past 15 years, there has been a dramatic change in the treatment options and prognosis for patients with advanced melanoma secondary to the development of novel systemic immunotherapies (IO) and targeted therapies. In addition to these novel systemic therapies, regional therapies (intralesional and perfusional) also continue to play a major role in the management of these patients.

In this article, we review recent updates in the management of advanced melanoma via Medline (PubMed) and Google Scholar, including recently published trials in the metastatic, adjuvant, and neoadjuvant settings. We also review recently published trials for regional therapies and discuss future directions in the management of patients with advanced melanoma.

A significant portion of patients with advanced melanoma will develop recurrent or progressive disease following treatment with IO or targeted therapy. Therefore, identifying not only the appropriate therapeutic agent but also the sequence and duration of treatment is pivotal for these patients.