Evaluation of Heterogeneity in the Coding Region of BRAF, MAP2K1, and MAP2K2 Genes in Primary and Metastatic Melanomas.

Introduction: The incidence of melanoma has been increasing in recent decades. BRAF mutations appear in 50%-70% of melanomas. The BRAF-targeted therapy increased the disease-free survival of patients with metastatic melanoma, but this response may be short, due to several resistance mechanisms, such as the presence of other subclones with mutations.

Multiplatform Analysis of Intratumoral PTEN Heterogeneity in Melanoma.

Loss of protein expression of the tumor suppressor PTEN is associated with increased cancer aggressiveness, decreased tumor immune infiltration, and resistance to immune and targeted therapies in melanoma. We assessed a unique cohort of eight melanoma samples with focal loss of PTEN protein expression to understand the features and mechanisms of PTEN loss in this disease. We compared the PTEN-negative (PTEN[-]) areas to their adjacent PTEN-positive (PTEN[+]) areas using DNA sequencing, DNA methylation, RNA expression, digital spatial profiling, and immunohistochemical platforms.

The immunogenomic landscape of resected intrahepatic cholangiocarcinoma.

Background And Aims: Cholangiocarcinoma (CCA) is a deadly and highly therapy-refractory cancer of the bile ducts, with early results from immune checkpoint blockade trials showing limited responses. Whereas recent molecular assessments have made bulk characterizations of immune profiles and their genomic correlates, spatial assessments may reveal actionable insights.

Approach And Results: Here, we have integrated immune checkpoint-directed immunohistochemistry with next-generation sequencing of resected intrahepatic CCA samples from 96 patients.

Immune profiling of uveal melanoma identifies a potential signature associated with response to immunotherapy.

Background: To date, no systemic therapy, including immunotherapy, exists to improve clinical outcomes in metastatic uveal melanoma (UM) patients. To understand the role of immune infiltrates in the genesis, metastasis, and response to treatment for UM, we systematically characterized immune profiles of UM primary and metastatic tumors, as well as samples from UM patients treated with immunotherapies.

Methods: Relevant immune markers (CD3, CD8, FoxP3, CD68, PD-1, and PD-L1) were analyzed by immunohistochemistry on 27 primary and 31 metastatic tumors from 47 patients with UM.

Intrahepatic Cholangiocarcinoma: Genomic Heterogeneity Between Eastern and Western Patients.

Purpose: Intrahepatic cholangiocarcinoma (IHCCA), a global health problem, is increasing in incidence and has differing etiologies worldwide. Next-generation sequencing (NGS) is rapidly being incorporated into the clinical management of biliary cancers. IHCCA is enriched with actionable mutations, and there are several promising targeted therapies under development.

IMP dehydrogenase rod/ring structures in acral melanomas.

Acral lentiginous melanoma (ALM) is a rare subtype of melanoma with aggressive behavior. IMPDH enzyme, involved in de novo GTP biosynthesis, has been reported to assemble into large filamentary structures called rods/rings (RR) or cytoophidium (cellular snakes). RR assembly induces a hyperactive state in IMPDH, usually to supply a high demand for GTP nucleotides, such as in highly proliferative cells.

BRAFV600E and KIT immunoexpression in early-stage melanoma.

Melanoma is widely known as the most lethal skin cancer. Specific tumor-related mortality can be significantly reduced if diagnosis and treatment are properly performed during initial phases of the disease. The current search for biomarkers in early-stage melanomas is a high-priority challenge for physicians and researchers.

Intratumor Heterogeneity of KIT Gene Mutations in Acral Lentiginous Melanoma.

Melanoma is an aggressive skin malignancy, and the acral lentiginous melanoma (ALM) subtype affects non-sun-exposed sites such as the volar surface of the hands and feet and the subungual region and is most common in Asians, Hispanics, and Afro-descendants. The presence of different clones within the same tumor seems to influence the aggressiveness of tumors. Patients with mutations in the KIT gene have shown a good response to tyrosine kinase inhibitor therapy.

Long term safety of targeted internalization of cell penetrating peptide crotamine into renal proximal tubular epithelial cells in vivo.

Activated proximal tubular epithelial cells (PTECs) play a crucial role in progressive tubulo-interstitial fibrosis in native and transplanted kidneys. Targeting PTECs by non-viral delivery vectors might be useful to influence the expression of important genes and/or proteins in order to slow down renal function loss. However, no clinical therapies that specifically target PTECs are available at present.

Molecular Profiling Reveals Unique Immune and Metabolic Features of Melanoma Brain Metastases.

There is a critical need to improve our understanding of the pathogenesis of melanoma brain metastases (MBM). Thus, we performed RNA sequencing on 88 resected MBMs and 42 patient-matched extracranial metastases; tumors with sufficient tissue also underwent whole-exome sequencing, T-cell receptor sequencing, and IHC. MBMs demonstrated heterogeneity of immune infiltrates that correlated with prior radiation and post-craniotomy survival.

A Preexisting Rare Subpopulation Confers Clinical Resistance to MEK plus CDK4/6 Inhibition in Melanoma and Is Dependent on S6K1 Signaling.

Combined MEK and CDK4/6 inhibition (MEKi + CDK4i) has shown promising clinical outcomes in patients with -mutant melanoma. Here, we interrogated longitudinal biopsies from a patient who initially responded to MEKi + CDK4i therapy but subsequently developed resistance. Whole-exome sequencing and functional validation identified an acquired mutation as conferring drug resistance.

Oral treatment with a rattlesnake native polypeptide crotamine efficiently inhibits the tumor growth with no potential toxicity for the host animal and with suggestive positive effects on animal metabolic profile.

The efficacy of crotamine as antitumoral was first demonstrated by daily intraperitoneal (IP) injections of low doses of this toxin in an animal model bearing melanoma tumors. Significant inhibition of tumor growth and increased lifespan of mice bearing tumor was also noticed after 21 consecutive days of this daily IP administration of crotamine. However, due to the limited acceptance of treatments by IP route in clinical conditions, herein, we evaluated the antitumor effect of this native polypeptide employing the oral route.

Increased Angiogenesis and Lymphangiogenesis in Metastatic Sentinel Lymph Nodes Is Associated With Nonsentinel Lymph Node Involvement and Distant Metastasis in Patients With Melanoma.

Lymph node angio- and lymphangio-genesis have been shown to play an important role in the premetastatic niche of sentinel lymph nodes. In the current study we have investigated the association of angio- and lympangio-genesis related parameters in metastatic sentinel lymph nodes of patients with melanoma with the presence of nonsentinel and distant organ metastasis. Peritumoral and intratumoral relative blood and lymphatic vessel areas (evaluated by Chalkley method), blood and lymphatic microvessel densities, and the rates of blood and lymphatic vessel proliferation were assessed in primary tumors and sentinel lymph node metastasis of 44 patients with melanoma using CD34/Ki-67 and D240/Ki-67 immunohistochemical double staining.

Peritumoral D2-40 Chalkley score independently predicts metastases and survival in patients with cutaneous malignant melanoma.

Background: Many observational studies investigated the prognostic significance of angiogenesis and lymphangiogenesis in patients with melanoma. However, the obtained results are rather contradictory, probably due to the lack of the consensus methodology.

Methods: To investigate the prognostic significance of angiogenesis and lymphangiogenesis-related parameters in patients with melanoma, we performed a retrospective investigation following the consensus recommendations for angiogenesis and lymphangiogenesis quantification in solid tumors and reporting recommendations for tumor marker (REMARK) criteria for reporting the results.

Melanomas arising on skin with chronic sun-induced damage exhibit low degree of angiogenesis and lymphangiogenesis.

Differences in gene expression between melanomas arising on skin intermittently and chronically sun-exposed areas were described. Additionally, several studies have shown differences in clinical characteristics and prognosis, suggesting distinct biological pathways in the development of these tumors. We performed a retrospective investigation aimed on evaluation of the differences in angiogenesis and lymphangiogenesis between melanomas arising on skin with and without signs of chronic sun-induced damage.

Squamous cell carcinomas of the skin explore angiogenesis-independent mechanisms of tumour vascularization.

Aims. To evaluate the vascularization in basal cell carcinomas (BCCs) and squamous cell carcinomas (SCCs) of the skin. Methods.

Lymphangiogenesis: implications for diagnosis, treatment, and prognosis in patients with melanoma.

Disease course in melanoma often cannot be accurately predicted by means of the prognostic factors usually considered in patients with melanoma; therefore, new factors are clearly needed. Increasingly robust scientific evidence shows that tumor lymph vessels play a key role in melanoma that metastasizes by lymphatic and hematogenous pathways. We review current knowledge and examine the implications of lymphangiogenesis in the diagnosis, treatment, and prognosis of patients with melanoma.

Mechanisms of tumour vascularization in cutaneous malignant melanoma: clinical implications.

Malignant melanoma represents < 10% of all skin cancers but is responsible for the majority of skin-cancer-related deaths. Metastatic melanoma has historically been considered as one of the most therapeutically challenging malignancies. Fortunately, for the first time after decades of basic research and clinical investigation, new drugs have produced major clinical responses.