Solitary Metastases Presentation from Uveal Melanoma: Report of 3 Cases and a Comprehensive Review of the Literature.

Introduction: Uveal melanoma (UM) is a rare condition accounting for only 5% of all primary melanoma cases. Still, it is the most frequently diagnosed primary intraocular malignant tumor in adults. UM is an aggressive malignancy that originates from melanocytes in the eye. UMs are usually initiated by a mutation in GNAQ or GNA11, and rarely harbor a BRAF or NRAS mutations like cutaneous melanomas. Even if the primary tumor has been successfully treated with radiation or surgery, up to half of all UM patients will eventually develop metastatic disease. The liver is the most frequent metastatic site, and solitary metastases are rare, especially without hepatic or other organs (such as lung or skin/soft tissue) involvement. Most of treatment options to the metastatic UM are still inadequate in preventing a fatal outcome. Methods: A chart review of patients diagnosed with UM between January 1998 and December 2018 at the Instituto Português de Oncologia de Lisboa Francisco Gentil was performed. Results: Three patients with solitary metastases several years after primary UV treatment without any other organ involvement were identified. Patient 1 and 2 showed a very long overall survival and progression-free survival after complete surgical removal of the isolated metastatic lesion from colon and spleen, respectively. The third patient presented with a single brain metastasis from choroidal melanoma harboring the BRAF V600E mutation, a condition rarely reported in UM. Discussion: The cases highlight long relapse-free survival of UM; hence, a regular long-term follow-up should be mandatory. In addition, solitary metastases from UM should be treated, whenever possible, with a surgical approach, with complete removal as a goal.

Adjuvant Chemotherapy De-Escalation with Genomic Assay Protocol in Patients with Early Breast Cancer: A Single-Centre Prospective Cohort Study.

INTRODUCTION: Genomic assays are useful tools for tailoring adjuvant treatment in early breast cancer. We aimed to analyse the role of an institutional protocol of a genomic assay for chemotherapy de-escalation. MATERIAL AND METHODS: Prospective cohort study of all consecutive women diagnosed with hormone receptor-positive and human epidermal growth factor receptor 2-negative early breast cancer, tested with the 21-gene Recurrence Score (RS) assay from August 2015 to July 2018 at a Portuguese cancer centre. For being tested, patients should meet at least one of the pre-defined inclusion criteria: i) luminal A-like, pT2pN0; ii) luminal A-like, 1 - 3 positive nodes and comorbidities with higher risk of chemotherapy-induced toxicity; iii) pT1-2pN0, progesterone receptor ≤ 20% and/or Ki67 14% - 40%. Adjuvant treatment was de-escalated to isolated endocrine therapy if RS was less than 18. We measured the reduction in chemotherapy prescribing and its clinical impact, the RS association with pathologic features, and the protocol feasibility. RESULTS: We tested 154 women with a median age of 61 years old (range: 25 - 79), 69% postmenopausal. Tumours were mainly pT1 (55%), pN0 (82%), invasive ductal (73%), G2 (86%), luminal B-like (69%) and stage IA (85%). We obtained a RS less than 18 in 60% of women, with an overall adjuvant chemotherapy reduction of 65%. Seven (95% confidence interval: 5 - 10) patients needed to be screened with the 21-gene RS assay to prevent one clinically relevant adverse event during the first six months of adjuvant treatment. Considering the currently used RS cut-off, only 9% of node-negative and 11% of node-positive patients had RS over 25. We found no relevant associations between RS and pathologic features. The protocol was feasible and did not compromise the adequate timing for adjuvant treatment. CONCLUSION: These criteria allowed the de-escalation of adjuvant systemic treatment in at least six out of ten women.

Vismodegib for treatment of periocular basal cell carcinoma - 6-year experience from a tertiary cancer center

Abstract Background: The treatment of advanced periocular basal cell carcinomas becomes a challenge as surgery may involve highly mutilating procedures. Vismodegib is the first selective hedgehog inhibitor approved for the treatment of locally advanced tumors or metastatic disease. Objective: Analyze the results of treatment with vismodegib for advanced periocular basal cell carcinomas in a real-life setting of a reference center between 2014 and 2020. Methods: Retrospective longitudinal study. The patient's demographic profile, comorbidities, tumor characteristics, and treatment outcomes were analyzed. Results: A total of 13 patients were included. Median follow-up and treatment duration were 15.9 and 10.5 months, respectively. Objective clinical response rate was 76.9%: 30.8% had a complete response and 46.2% a partial response. The median duration of response was 13 months. Progressive disease was observed in 38.5% of cases, with a median of 19 months after the beginning of treatment. Eighty-four percent of the patients had at least one adverse event, and 61.54% needed to interrupt treatment temporarily or permanently to increase tolerability. Study limitations: Being a retrospective study in a real-life setting, the evaluation of objective clinical response was subjective to physician appreciation. Conclusion: Vismodegib is a safe and effective treatment for locally advanced basal cell carcinoma. To prevent recurrences, the drug should be used continually when tolerated. The role of neoadjuvant vismodegib before surgery is being investigated and might add an important step in searching for a definitive treatment for these cases.

Vismodegib for treatment of periocular basal cell carcinoma - 6-year experience from a tertiary cancer center.

BACKGROUND: The treatment of advanced periocular basal cell carcinomas becomes a challenge as surgery may involve highly mutilating procedures. Vismodegib is the first selective hedgehog inhibitor approved for the treatment of locally advanced tumors or metastatic disease. OBJECTIVE: Analyze the results of treatment with vismodegib for advanced periocular basal cell carcinomas in a real-life setting of a reference center between 2014 and 2020. METHODS: Retrospective longitudinal study. The patient's demographic profile, comorbidities, tumor characteristics, and treatment outcomes were analyzed. RESULTS: A total of 13 patients were included. Median follow-up and treatment duration were 15.9 and 10.5 months, respectively. Objective clinical response rate was 76.9%: 30.8% had a complete response and 46.2% a partial response. The median duration of response was 13 months. Progressive disease was observed in 38.5% of cases, with a median of 19 months after the beginning of treatment. Eighty-four percent of the patients had at least one adverse event, and 61.54% needed to interrupt treatment temporarily or permanently to increase tolerability. STUDY LIMITATIONS: Being a retrospective study in a real-life setting, the evaluation of objective clinical response was subjective to physician appreciation. CONCLUSION: Vismodegib is a safe and effective treatment for locally advanced basal cell carcinoma. To prevent recurrences, the drug should be used continually when tolerated. The role of neoadjuvant vismodegib before surgery is being investigated and might add an important step in searching for a definitive treatment for these cases.

A Rare Form of Metastatic Melanoma in an HIV-Infected Patient - A Diagnosis to Remember.

Malignant melanoma (MM), which is amongst the rarest skin cancers, still remains one of the deadliest and most likely to spread, and, in human immunodeficiency virus (HIV)-infected patients, generally has a more aggressive behaviour. Although gastrointestinal (GI) tract metastases are frequent, secondary symptomatic colonic disease is rare. We present the case of a 76-year-old HIV-infected patient, with a 15-month history of GI and constitutional symptoms and a previous diagnosis of malignant melanoma. Diagnostic workup revealed metastatic involvement of the cecum. This case highlights the need to bear in mind the metastatic involvement of the GI tract by MM, and MM itself, especially in HIV-infected patients.

Challenges of New Approaches in Metastatic Merkel Cell Carcinoma.

Merkel cell carcinoma is a rare and aggressive cutaneous tumor, and the use of checkpoint inhibitors immunotherapy is a recent indication in its metastatic setting, both first and second line. However, the widespread use of immunotherapy is associated with an increase of acute and late immune-mediated adverse events. We present a case of an elderly fit patient with metastatic Merkel cell carcinoma treated with pembrolizumab who developed diabetic ketoacidosis, a severe immune-mediated adverse event. A multidisciplinary approach was crucial to overcome the life-threatening event. Even with early treatment stop, the patient had a significant and durable response to the treatment for 15 months. Meanwhile, a progressive pan-cerebellar syndrome emerged, possible due to a paraneoplastic syndrome with a negative onco-neuronal antibody panel, although an autoimmune etiology associated with immunotherapy could not be excluded. Unfortunately, the situation was irreversible and refractory to immunomodulatory treatment. Despite the unpredictable toxicity, it is important to note the efficacy profile, with a progression-free survival of 15 months, which is higher than the one reported in reference clinical trials in this setting.

Using a cancer registry to capture signals of adverse events following immune and targeted therapy for melanoma.

Background Toxicity of oncology treatments in real-life patients is frequently disregarded and hence underreported. Objective To characterize adverse events (AEs) of immunotherapy and targeted therapy reported in patients with locally advanced or metastatic melanoma. Setting District Hospital for Cancer treatment (Instituto Português de Oncologia de Lisboa Francisco Gentil). Method A retrospective cohort of melanoma patients was established, comprising adult patients diagnosed with malignant melanoma treated with immunotherapy or targeted therapy. Exposure was characterized by nature, time and intensity of exposure. To account for different exposure periods, person-time was used as unit of analysis. Main outcomes measure Occurrence of AEs. Results Data from 111 patients included in the cohort indicates the majority received immunotherapy regimens (CTLA-4, anti-PD-1 and combination therapy; (n = 70; 63.1%), among which anti-PD-1 were the predominant treatment. Pembrolizumab was the most frequently prescribed drug (n = 30; 45.7%). Three hundred and seventy-one AEs were extracted. The incidence of AEs was lower in the anti-PD-1 mAc group (54 AEs per 1000 person.months) and the number of AEs/patient was also lower (3.1 ± 2.0). Grade 3 to 4 AEs occurred in 15.3% (n = 17) of the cohort, being more common in the targeted therapy group. Forty-two (11.6%) of the extracted AEs were not described in the Summary of Product Characteristics of the drugs under study. Conclusion This study suggests various known and unknown AEs of immunotherapy and targeted therapy may be identified using the Cancer Registry database. These events should be considered as signals worth further investigation for assessment of causality as the underreporting of AEs in cancer may have potential implications for the patient's quality of life.

Systemic Treatment of Metastatic Conjunctival Melanoma.

Conjunctival melanoma (CM) is an exceptionally rare tumor, with a propensity for local and distant recurrence, with the lungs, skin, liver, and brain being the most common sites of metastasis. Recent progress in systemic treatments, with checkpoint inhibitors and targeted therapies blocking BRAF and MEK, has redefined the standard of care of advanced unresectable and metastatic melanoma. Although most trials did not include patients with conjunctival melanoma, its close molecular and genetic relationship to cutaneous melanoma might suggest a similar response to these novel agents. The authors describe two uncommon cases of metastatic conjunctival melanomas with distinct genetic profiles and, as such, submitted to different systemic treatments.

Right cardiac intracavitary metastases from a primary intracranial myxofibrosarcoma.

Primary intracranial myxofibrosarcoma is exceedingly rare, with less than 10 cases published. We present a case of a 23-year-old man with previous history of a primary low grade myxofibrosarcoma of the left parietal-occipital convexity resected in March 1999. He subsequently underwent several interventions for multiple local recurrent disease until March 2004. At that time, complete remission was documented. About 8 years later, in February 2012, the patient was admitted to the emergency room with refractory acute pulmonary oedema. On work up, sustained monomorphic ventricular tachycardia and hyperechoic myocardial mass with invasion of the right ventricular cavity were detected. Electrical cardioversion was unsuccessful and irreversible cardiac arrest followed. The autopsy confirmed multiple bilateral lung metastases, malignant pulmonary embolism and myocardial invasion by the primary tumour, with intracavitary cardiac thrombosis and absence of intracranial disease. To the best of our knowledge, this is the first report of extracranial metastases of this neoplasm.

Paraneoplastic leukemoid reaction in a patient with BRAF V600E-mutated metastatic malignant melanoma.

A paraneoplastic leukemoid reaction is a rare condition of extreme leucocytosis in patients with solid malignancies. The differential diagnosis is often a true challenge. We present a case of a 56-year old woman with a history of stage IIIA malignant melanoma resected in 2004 that was diagnosed in May 2013 with BRAF V600E-mutated metastatic disease (left arm mass, lungs and adrenal glands). The laboratory findings revealed leucocytosis with granulocytosis that increased progressively to values up to 120.0 × 10(9)/L. After a diagnostic work-up, a diagnosis of a paraneoplastic leukemoid reaction was established. We report the response of leucocytosis to radiation and BRAF inhibitor therapy, albeit short-lived. To the best of our knowledge, this is the first case report of a paraneoplastic leukemoid reaction in metastatic melanoma with characterisation of BRAF V600 mutation status. It remains unclear whether the aggressive tumour phenotype is related to the leukemoid reaction and whether this is related to the BRAF mutation.