Systemic chemotherapy is the main treatment option for patients with advanced intrahepatic cholangiocarcinoma (iCCA), however, its efficacy is limited. Herein, we report a young patient with NRAS-mutated chemoresistant metastatic iCCA, who received second-line therapy with a combination of trametinib (MEK1/2 inhibitor), hydroxychloroquine (autophagy inhibitor), and bevacizumab (angiogenesis inhibitor). A significant response was achieved during therapy, resulting in a 25% decrease in the size of tumor lesions after 2 months of treatment and an improvement in the patient\'s condition. The duration of this response was 4 months, but the patient died 10 months after the initiation of this triple therapy. This case report and the analysis of other available studies warrant further investigations on combined MEK and autophagy inhibition in RAS-mutated tumors.

Mutations in the NRAS gene are common alterations in malignant melanoma. However, there are no specific treatment options approved for NRAS-mutated melanoma patients besides immune checkpoint inhibition. Since preclinical data suggests a synergistic effect of a MEK inhibitor (MEKi) and the oncolytic virus talimogene laherparepvec (T-VEC), we have treated three melanoma patients with this combination. All of the three patients had been suffering from recurring cutaneous and subcutaneous in-transit metastases. Upon treatment one patient (case 1) presented full regression of locoregional metastases and remained progression-free until date, for almost three years. The second patient (case 2) showed a partial regression of painful gluteal satellite metastases but died from brain metastases. The third patient (case 3) showed a durable response of locoregional metastases for seven months. The combination treatment was well tolerated with common adverse events known for each single agent. This report is the first case series presenting a clinical benefit of the combined T-VEC and MEKi treatment. We suggest the combination of T-VEC and MEKi as an off-label treatment option for patients with NRAS mutations, especially with recurrent in-transit or satellite metastases.

Despite recent advances in treatment and surveillance, metastatic melanoma still carries a poor prognosis. Large/giant congenital melanocytic nevi (CMNs) constitute a known risk factor for the condition, with the greatest risk for malignant transformation thought to be during childhood (median age at diagnosis of 3 years in a previous cohort). Herein, we present the case of a 30-year-old male who, after undergoing multiple excision/grafting procedures for a giant CMN as a child, was diagnosed with an NRAS-mutant, MDM2-amplified metastatic melanoma more than 20 years later. Response to ipilimumab/nivolumab immunotherapy, cisplatin/vinblastine/temozolomide chemotherapy, and nivolumab/relatlimab immunotherapy was poor. This case highlights the importance of lifetime monitoring with once-yearly dermatological examination (including lymph node palpation) in large/giant CMN patients, as well as the need for further clinical trials evaluating novel therapies for NRAS-mutant melanoma.

Congenital melanocytic nevus syndrome (CMNS) is a rare condition characterized by pigmented skin lesions that are usually present at birth and are associated with an increased risk of neurological abnormalities and malignant melanoma. It mostly results from a post-zygotic NRAS mutation of neural-derived crest cells, leading to uncontrolled cell growth. Because of the increased knowledge of the genetics underlying CMNS, targeted therapy becomes a promising treatment option. We present a case of CMNS in a newborn. Physical examination at birth showed a giant congenital melanocytic nevus, extending from the occipital to the lower lumbar region. A magnetic resonance imaging scan revealed multiple cerebral and cerebellar parenchymal lesions. Genetic analysis of the cutaneous lesions showed the presence of an NRAS Q61R mutation. The patient was treated with dermabrasion to reduce the color intensity of the nevus. However, this was complicated by recurrent wound infections and laborious wound healing. At the age of 1 year, the patient had an age-appropriate psychomotor development, without neurological deficits.

Anaplastic thyroid carcinoma (ATC) is a rare and highly aggressive fatal tumor. Most ATC patients using traditional surgery or radio-chemotherapy have poor prognosis and experience recurrence in a very short time. There is no optimal therapy for ATC, and the median survival time is about 5 months. We report a 67-year-old ATC patient, who experienced rapid local recurrence after radical thyroidectomy. The resected tumor tissue was sent for immunohistochemistry analysis and targeted next-generation sequencing. The results indicated high PD-L1 expression, a tumor mutation burden of 0.48 muts/Mb, microsatellite stable, and somatic mutations of TERT promoter, EIF1AX, NRAS and TP53. However, none of the mutations indicated corresponding target therapy. An immediate operation was unsuitable because of rapid recurrence after surgery. The patient was also not in a condition to tolerate chemotherapy. Based on the high expression of PD-L1, an optimum strategy was used, combining immunotherapeutic agent, sintilimab, with an anti-angiogenesis drug, anlotinib. The patient obtained remarkable tumor shrinkage and an 18.3-month-sustained remission period. This is an effective case of using immunotherapy and anti-angiogenesis agent in the first-line treatment of ATC. It demonstrates a feasible and novel therapeutic option for future treatment of ATC patients.

BACKGROUND: Primary malignant melanoma of the lung (PML) is extremely rare. No precursor lesions of PML have been identified, and little is known about the genetic mutations associated with the disease. Typically, 15-20% of malignant melanomas possess NRAS gene mutations, but no cases of NRAS-mutated PML have been reported in the English literature. We present a case of PML involving an NRAS mutation.
METHODS: Clinical summary A 74-year-old Japanese female presented with worsening dyspnea and was admitted to hospital. Computed tomography (CT) revealed a right lung (S10) mass and pleural dissemination. Cytology of the pleural effusion in the right lung was performed, and malignant melanoma or clear cell sarcoma was suspected. A dermatological examination and gallium scintigraphy were conducted to determine the primary tumor site, but no suspicious lesions, expect for the right lung mass, were found. After admission, CT showed complicating bilateral pneumonia, and an antibiotic drug was administered, but the pleural effusion got worse. About 2 weeks later, the patient died of respiratory failure and cardiac arrest. An autopsy was performed to determine the histological diagnosis. Autopsy findings A 26x15x20-mm black and pale yellow mass was found in the right lower lobe. Many disseminated nodules were found in the right lobe. The tumor had invaded the right diaphragm. Subcarinal lymph node metastasis was also detected. Immunohistochemically, the tumor cells exhibited positivity for S-100 and HMB45 staining. The patient was diagnosed with malignant melanoma. Sanger sequencing of the tumor detected an NRAS mutation.
CONCLUSIONS: We found an NRAS D54N mutation in PML, which has not been reported previously anywhere in the world. Previous reports indicated that most cases of PML can be classified into the triple-wild-type, but BRAF mutation status was only analyzed in a few cases. We should analyze the mutation patterns of PML to determine whether any subtypes other than the triple-wild-type exist. PML might be a form of de novo cancer.

BACKGROUND: A giant congenital melanocytic nevus (GCMN) is found in 0.1% of live-born infants. If present, the lesion has a chance of about 6% to develop into malignant melanoma. Both children and adults can be affected by malignant melanoma arising in a giant congenital nevus. Up to 95% of GCMNs harbor NRAS mutations, and mutations in the BRAF, MC1R, TP53, and GNAQ genes have also been described. The individualization of therapy is required, but diagnostic and prognostic criteria remain controversial.
METHODS: We report two cases: 1) melanoma arising in a giant congenital nevus during the first month of life complicated with neurocutaneous melanosis (NCM), and 2) melanoma arising in a giant congenital nevus during the first 6 months of life. Pathology, immunohistochemistry, and genetic analyses of tumor tissue were performed. The first case revealed only a non-pathogenic P72R polymorphism of the TP53 gene in the homozygote condition. For the second case, a Q61K mutation was detected in the NRAS gene.
CONCLUSIONS: Malignant melanoma associated with GCMN is rare and therefore poorly understood. Outcomes have been linked to the stage at diagnosis, but no additional pathological prognostic factors have been identified. The most frequent genetic event in giant CMNs is NRAS mutations, which was discovered in one of our cases. To accumulate evidence to improve disease prognosis and outcomes, children with congenital melanocytic nevus should be included in a systemic follow-up study from birth.

BACKGROUND: The follicular variant of papillary thyroid cancer (FVPTC) can be noninvasive or invasive. The invasive form of FVPTC commonly harbors BRAF mutations whereas RAS mutations are more often associated with noninvasive FVPTC and a favorable clinical outcome.
METHODS: A 47-year-old man presented with a metastasis to his right iliac bone as the initial manifestation of a 1.6cm invasive FVPTC. After total thyroidectomy, the patient underwent additional treatment, including thyroid hormone suppressive treatment to non-detectable TSH levels, repeated courses of radioiodine treatment, external beam radiation, and treatment with the tyrosine kinase inhibitor sorafenib. Despite these therapeutic efforts, the disease progressed with growth of the iliac mass and additional metastatic spread to cervical and lumbar vertebrae causing increasing pain and disability. The patient succumbed to the disease four years after presentation. Retrospective next-generation sequencing of the primary tumor using a pan-cancer targeted mutation and gene fusion panel revealed NRAS Q61K mutation and no other oncogenic alterations.
CONCLUSIONS: The study challenges the concept that thyroid neoplasms with isolated RAS mutations are often associated with favorable clinical behavior and may be candidates for conservative management.
CONCLUSIONS: An isolated RAS mutation in invasive FVPTC may be associated with an aggressive clinical behavior.

Congenital melanocytic nevus syndrome (CMNS) is the result of an abnormal proliferation of melanocytes in the skin and central nervous system caused by progenitor-cell mutations during embryonic development. Mutations in the NRAS gene have been detected in many of these cells. We present 5 cases of giant congenital melanocytic nevus, 3 of them associated with CMNS; NRAS gene mutation was studied in these 3 patients. Until a few years ago, surgery was the treatment of choice, but the results have proved unsatisfactory because aggressive interventions do not improve cosmetic appearance and only minimally reduce the risk of malignant change. In 2013, trametinib was approved for use in advanced melanoma associated with NRAS mutations. This drug, which acts on the intracellular RAS/RAF/MEK/pERK/MAPK cascade, could be useful in pediatric patients with CMNS. A better understanding of this disease will facilitate the development of new strategies.