Primary mucosal melanomas represent a minority of melanomas, but have a significantly worse prognosis than cutaneous melanomas. A better characterization of the molecular pathogenesis of this ...melanoma subtype could help us understand the risk factors associated with the development of mucosal melanomas and highlight therapeutic targets. Because the Mitogen-Activated Protein Kinase (MAPK) pathway plays such a significant role in melanoma development, we explore v-raf murine sarcoma viral oncogene homolog B (
and neuroblastoma RAS viral oncogene homolog (
mutations in mucosal melanoma and compare them to the mutation profiles in cutaneous melanoma and other tumors with
and
mutations. We show that in addition to being less frequent,
and
mutations are different in mucosal melanoma compared to cutaneous melanomas. Strikingly, the
and
mutation profiles in mucosal melanoma are closer to those found in cancers such as lung cancer, suggesting that mutations in mucosal melanoma could be linked to some genotoxic agents that remain to be identified. We also show that the atypical
and
mutations found in mucosal melanomas have particular effects on protein activities, which could be essential for the transformation of mucosal melanocytes.
Background Skin toxicity during low-dose methotrexate therapy is rare, ill described, and reported to have nonspecific histologic characteristics. Thus, misdiagnosis is common in patients with ...mucosal ulcers and/or skin erosions related to low-dose methotrexate. Objective We sought to describe the features of skin toxicity induced by low-dose methotrexate. Methods We evaluated the clinical and histologic features in 5 patients who experienced skin toxicity induced by low-dose methotrexate between 2011 and 2013. Results All 5 patients had acute mucosal ulcers, 4 had moderately abnormal blood cell counts, and 3 had skin erosions. In 3 patients, methotrexate dosage or dosing-schedule errors were identified. No other contributing factors (eg, renal dysfunction or interacting drugs) were identified. Mucocutaneous biopsy specimens consistently showed multiple dystrophic keratinocytes. Limitations We studied only 5 patients and obtained no sensitivity or specificity data on the diagnostic value of keratinocyte dystrophy. Conclusion Keratinocyte dystrophy may help to diagnose skin toxicity of low-dose methotrexate, even in the absence of known risk factors or methotrexate administration errors. Studies of the diagnostic performance of this histologic sign are needed.
Kaposi's sarcoma (KS) is a common neoplasm in Eastern and central Africa reflecting the spread of
8 (HHV-8), now considered a necessary causal agent for the development of KS. The endemic KS subtype ...can follow an aggressive clinical course with ulcerative skin lesions with soft tissue invasion or even bone or visceral involvement. In the latter cases, a thorough imaging work-up and better follow-up schedules are warranted. As KS is a chronic disease, the therapeutic goal is to obtain sustainable remission in cutaneous and visceral lesions and a good quality of life. Watchful monitoring may be sufficient in localized cutaneous forms. Potential therapeutic modalities for symptomatic advanced KS include systemic chemotherapies, immunomodulators, immune checkpoint inhibitors, and antiangiogenic drugs.
Sonidegib, a hedgehog pathway inhibitor, is indicated for treatment of locally advanced basal cell carcinoma, based on the results of the BOLT study. However, to date, no real-world study of ...sonidegib has been reported. An observational, retrospective, single-centre study (PaSoS study) was conducted. The primary objective was to evaluate the efficacy of sonidegib for treatment of locally advanced basal cell carcinoma in a real-world setting. Secondary objectives included modalities of use, tolerability, tumour evolution, and management after discontinuation. A total of 21 patients treated with sonidegib were included from March 2018 to January 2021. The median follow-up was 18.7 months and median exposure 7.0 months. Objective response (OR) rate was 81.0% (n = 17) including 6 (29%) patients with a complete response (CR). Disease control rate was 100%. First tumour response was rapid, with a median time of 2.3 months. Nine (43%) patients underwent surgery after sonidegib discontinuation, and no relapse was observed. All the patients experienced at least 1 adverse event (AE). Muscle spasms were the most frequent AE (n = 14; 67%), followed by dysgeusia (n = 8; 38%) and alopecia (n = 12; 57%). The efficacy and safety profile of sonidegib in this first-to-date real-life trial are consistent with prior results. Overall, real-world evidence corroborated sonidegib efficacy and tolerability as a first-line treatment for locally advanced basal cell carcinoma.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Increasing the efficacy of immune checkpoint blockade therapy while mitigating toxicity is one of the major challenges in oncology research. In this issue of Cancer Cell, Hailemichael et al. provide ...a strong rationale for the combination of IL-6 blockade and dual inhibition of CTLA-4 and PD-1 to overcome this issue.
Increasing the efficacy of immune checkpoint blockade therapy while mitigating toxicity is one of the major challenges in oncology research. In this issue of Cancer Cell, Hailemichael et al. provide a strong rationale for the combination of IL-6 blockade and dual inhibition of CTLA-4 and PD-1 to overcome this issue.
In their systematic review and meta-analysis in The Lancet Oncology, Yu Fujiwara and colleagues3 analysed the safety of adding immune checkpoint inhibitors to conventional neoadjuvant or adjuvant ...therapy in 28 randomised controlled trials involving more than 16 000 patients. The addition of immune checkpoint inhibitor to conventional neoadjuvant or adjuvant therapy was not associated with an increase in fatal treatment-related adverse events, except in the subgroup analysis comparing immune checkpoint blockade with placebo (odds ratio OR 4·02, 95% CI 1·04–15·63; p=0·044). Conversely, the occurrence of treatment-related adverse events was associated with survival benefits in the metastatic setting, and showed a benefit in relapse-free survival in the adjuvant setting,6 although such analyses are prone to immortal time biases.7 Further studies are warranted to study the association between safety and survival in the neoadjuvant or adjuvant setting.
Positron emission tomography/computed tomography with fluorodeoxyglucose (F-18) (FDG PET/CT) is increasingly used in Kaposi sarcoma (KS), but its value has not been assessed.
In this study, we aimed ...to evaluate the diagnostic accuracy of FDG PET/CT to define the extent of disease in KS.
Consecutive patients with KS referred to our department for FDG PET/CT were included. The diagnostic accuracy of FDG PET/CT for cutaneous and extra-cutaneous KS staging was assessed on a per lesion basis compared to staging obtained from clinical examination, standard imaging, endoscopy, histological analyses, and follow-up.
From 2007 to 2017, 75 patients with FDG PET/CT were analyzed. The sensitivity and specificity of FDG PET/CT for the overall detection of KS lesions were 71 and 98%, respectively. Sensitivity and specificity were 100 and 85% for lymph nodes, 87 and 98% for bone, 87 and 100% for lungs, and 100 and 100% for muscle involvement, whereas sensitivity was only 17% to detect KS digestive involvement. The sensitivity of the diagnostic for KS cutaneous involvement increased from 73 to 88% when using a whole-body examination.
FDG PET/CT showed good sensitivity and specificity for KS staging (digestive involvement excepted) and could be used for staging patients with active KS.
Because BRAF-mutated melanomas are addicted to the Mitogen Activated Protein Kinase (MAPK) pathway they show a high response rate to BRAF and MEK inhibitors. However, the clinical responses to these ...inhibitors are often short-lived with the rapid onset of resistance to treatment. Deciphering the molecular mechanisms driving resistance has been the subject of intense research. Recent in vitro and clinical data have suggested a link between expression of telomerase and resistance to targeted therapy in melanoma. TERT promoter mutations are the main mechanism for the continuous upregulation of telomerase in melanoma and co-occur frequently with BRAF alterations. To understand how TERT promoter mutations could be associated with resistance to targeted therapy in melanoma, we conducted translational and in vitro studies. In a cohort of V600E-BRAF-mutated melanoma patients, we showed that the TERT promoter mutation status and TERT expression tended to be associated with response to BRAF and MEK inhibitors. We demonstrated that TERT overexpression in BRAF-mutated melanoma cells reduced sensitivity to BRAF and MEK independently of TERT's telomer maintenance activity. Interestingly, inhibition of TERT reduced growth of BRAF-mutated melanoma including resistant cells. TERT expression in melanoma can therefore be a new biomarker for resistance to MAPK inhibitors as well as a novel therapeutic target.
Background: Immune checkpoint inhibitors (ICI) are currently the first-line treatment for patients with metastatic melanoma. We investigated the value of positron emission tomography (PET) response ...criteria to assess the therapeutic response to first-line ICI in this clinical context and explore the potential contribution of total tumor metabolic volume (TMTV) analysis. Methods: We conducted a retrospective study in patients treated with first-line ICI for advanced or metastatic melanoma, with 18F-FDG PET/CT performed at baseline and 3 months after starting treatment. Patients’ metabolic response was classified according to PERCIST5 and imPERCIST 5 criteria. TMTV was recorded for each examination. Results: Twenty-nine patients were included. The median overall survival (OS) was 51.2 months (IQR 13.6—not reached), and the OS rate at 2 years was 58.6%. Patients classified as responders (complete and partial response) had a 90.9% 2-year OS rate versus 38.9% for non-responders (stable disease and progressive disease) (p = 0.03), for PERCIST5 and imPERCIST 5 criteria. The median change in metabolic volume was 9.8% (IQR −59–+140%). No significant correlation between OS and changes in TMTV was found. Conclusion: The evaluation of response to immunotherapy using metabolic imaging with PERCIST5 and imPERCIST5 was significantly associated with OS in patients with advanced or metastatic melanoma.
Gastrointestinal toxicities of MEK inhibitors in melanoma patients are frequent. In clinical trials, the most common digestive adverse events were nausea, vomiting, and diarrhoea. However, severe ...toxicities such as colitis and gastrointestinal perforation, some with fatal outcomes, have been reported. These rare but severe adverse events are not well described. We performed a retrospective analysis of all patients with stage IV and unresectable stage III melanoma treated with a MEK inhibitors at Saint-Louis Hospital, Paris, between 1 August 2013 and 15 October 2018. Among 119 patients exposed to MEK inhibitors, 78 were treated with trametinib, 19 with cobimetinib, four with binimetinib, and 18 patients with two different MEK inhibitors at separate times. All grade digestive adverse events were observed in 39 (32.7%) patients. Grade 3 and 4 adverse events occurred in 6 (5%) patients: 2 (1.7%) developed perforations, 3 (2.5%) had colitis and 1 (0.8%) had grade 4 diarrhoea. These adverse events were all reversible following a permanent discontinuation of the MEK inhibitors, or a temporary interruption followed by resumption at a dose lower than conventional posology. There were no fatal outcomes; however one patient had a permanent ileostomy. The mechanism underlying these toxicities is not well known. Clinicians should be aware of such toxicities.
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