Despite the introduction of targeted (BRAFi/MEKi) and immune checkpoint inhibitors (ICIs) has significantly reduced the recurrence rate and improved the overall survival (OS) of patients with Stage ...III and IV melanoma, only a percentage will benefit of durable disease control. The aim of this study was to examine whether the levels of circulating tumour DNA (ctDNA) in plasma of advanced melanoma patients undergoing BRAFi/MEKi or ICIs vary according to the patients' survival outcomes (i.e. progression-free survival (PFS) and OS) and disease progression. Plasma samples of Stage III-IV melanoma patients were collected at baseline (treatment initiation) and thereafter every 3 months. Circulating BRAF
and NRAS
mutations were analysed through droplet digital PCR (ddPCR, Bio-Rad) in a total of 177 plasma samples from 48 melanoma patients (19 Stage III, 29 Stage IV). Baseline ctDNA concentration was significantly associated with OS (HR = 1.003, 95% CI = 1.000-1.006, p = 0.043) and PFS (HR = 1.004, 95% CI = 1.000-1.007, p = 0.029) independent of clinical-prognostic confounders. For each unit increase in the ∆ctDNA (concentration difference between the last follow-up and baseline) there was a 24% increased risk of disease progression, irrespective of treatment type and stage at diagnosis (OR = 1.24, 95% CI = 1.03-1.49, p = 0.020, AUC = 0.93). Patients with reduction of ctDNA level from baseline to the last follow-up had longer OS (HR = 0.14; 95% CI = 0.05-0.44, p = 0.001) and PFS (HR = 0.08; 95% CI = 0.03-0.27, p < 0.0001) compared to patients with increased ctDNA, including adjustment for confounding factors. Our findings suggest that variation of ctDNA over time during melanoma treatment reflects the clinical outcome and tumour response to therapy and might be helpful in clinical monitoring.
Abstract
A number of genes have been implicated in the pathogenesis of BCC in addition to the Hedgehog pathway, which is known to drive the initiation of this tumour. We performed in-depth analysis ...of 13 BCC-related genes (
CSMD1, CSMD2, DPH3
promote
r, PTCH1, SMO, GLI1, NOTCH1, NOTCH2, TP53, ITIH2, DPP10, STEAP4, TERT
promoter) in 57 BCC lesions (26 superficial and 31 nodular) from 55 patients and their corresponding blood samples.
PTCH1
and
TP53
mutations were found in 71.9% and 45.6% of BCCs, respectively. A high mutation rate was also detected in
CSMD1
(63.2%),
NOTCH1
(43.8%) and
DPP10
(35.1%), and frequent non-coding mutations were identified in
TERT
(57.9%) and
DPH3
promoter (49.1%).
CSMD1
mutations significantly co-occurred with
TP53
changes (
p
= 0.002). A significant association was observed between the superficial type of BCC and
PTCH1
(
p
= 0.018) and
NOTCH1
(
p
= 0.020) mutations. In addition,
PTCH1
mutations were significantly associated with intermittent sun exposure (
p
= 0.046) and the occurrence of single lesions (
p
= 0.021), while
NOTCH1
mutations were more frequent in BCCs located on the trunk compared to the head/neck and extremities (
p
= 0.001). In conclusion, we provide further insights into the molecular alterations underlying the tumorigenic mechanism of superficial and nodular BCCs with a view towards novel rationale-based therapeutic strategies.
Background
The COVID‐19 lockdown had a dramatic impact on primary care access and resulted in postponed skin cancer screenings. This raises concerns for a diagnostic delay on primary cutaneous ...melanomas, which can subsequently increase morbidity and mortality.
Objectives
The aim of the study was to investigate the impact of the COVID‐19‐related restrictions on the melanoma diagnosis in five European skin cancer reference centres in Switzerland, Germany, Austria and Italy.
Methods
A total of 7865 cutaneous melanoma cases were collected between 01 September 2018 and 31 August 2021. The time period was stratified into pre‐COVID (pre‐lockdown) and post‐COVID (lockdown and post‐lockdown) according to the established restrictions in each country. The data collection included demographic, clinical and histopathological data from histologically confirmed cutaneous melanomas. Personal and family history of melanoma, and presence of immunosuppression were used to assess the diagnosis delay in high‐risk individuals.
Results
There was an overall increase of the Breslow tumour thickness (mean 1.25 mm vs. 1.02 mm) during the post‐COVID period, as well as an increase in the proportion of T3‐T4 melanomas, rates of ulceration and the number of mitotic rates ≥2 (all, p < 0.001). Patients with immunosuppression and personal history of melanoma showed a decrease in the mean log10‐transformed Breslow during lockdown and post‐COVID. In the multivariate analysis, age at melanoma diagnosis (p < 0.01) and personal history of melanoma (p < 0.01) showed significant differences in the mean Breslow thickness.
Conclusions
The study confirms the diagnostic delay in cutaneous melanomas due to the COVID‐19 lockdown. High‐risk individuals, such as patients with personal history of melanoma and elderly individuals, were more hesitant to restart their regular skin cancer screenings post‐COVID. Further studies with longer follow‐up are required to evaluate the consequences of this diagnostic delay in long‐term outcomes.
Aim of this study was to systematically review the literature to assess efficacy and safety of stereotactic radiotherapy (SRT) in combination with immunotherapy for the treatment of melanoma brain ...metastases (MBM). The literature was searched using PubMed, Scopus, and Embase. Studies comparing SRT
plus
immunotherapy
versus
SRT or immunotherapy alone were deemed eligible for inclusion. Two studies showed improved overall survival after SRT
plus
immunotherapy in melanoma cancer patients with brain metastases. Three studies reported data on LC and DFS showing as SRT
plus
immunotherapy did not improve local control and DFS rates. G3-G4 toxicity was reported in only one study (20% in the SRT
plus
immunotherapy group
versus
23% in the immunotherapy group). Despite SRT
plus
concurrent immunotherapy seems associated with possible survival advantage and low ≥ G3 late toxicity rates, the quality of evidence is very low. Therefore, in patients with brain metastases from melanoma, SRT
plus
immunotherapy should be evaluated on an individual basis after discussion by a multidisciplinary team.
Kidney transplantation leads to an increased risk of cancer. Melanoma is one of the most frequent neoplasms in kidney transplant recipients. Transplanted patients were excluded from trials with ...checkpoint inhibitors in melanoma. The authors performed a systematic review regarding the use of anti-PD1 and anti-CTLA4 agents in renal transplanted patients with melanoma. Thirty-four cases were included (24 progressive disease, eight partial responses and one stable disease) but no complete response were reported. Fourteen graft rejections were observed, especially with anti-PD1 agent. The median time from the start of immune-checkpoint inhibitor and rejection was 21 days. Response rate was similar between patients with rejection and patients without rejection. The benefit of immune-checkpoint inhibitors versus the risk of allograft rejection should be carefully weighted for each patient. A multidisciplinary approach should be considered to discuss the most appropriate treatment for every case, given the aggressiveness of melanoma in these subsets of patients.
Abstract
Background
Nodular melanoma (NM) is more likely to be fatal compared with other melanoma subtypes, an effect attributed to its greater Breslow thickness.
Methods
Clinicopathological features ...of NM and superficial spreading melanoma (SSM) diagnosed in 17 centers in Europe (n = 15), the United States, and Australia between 2006 and 2015, were analyzed by multivariable logistic regression analysis, with emphasis on thin (T1 ≤ 1.0 mm) melanomas. Cox analysis assessed melanoma-specific survival. All statistical tests were two sided.
Results
In all, 20 132 melanomas (NM: 5062, SSM: 15 070) were included. Compared with T1 SSM, T1 NM was less likely to have regression (odds ratio OR = 0.46, 95% confidence interval CI = 0.29 to 0.72) or nevus remnants histologically (OR = 0.60, 95% CI = 0.42 to 0.85), and more likely to have mitoses (OR = 1.97, 95% CI = 1.33 to 2.93) and regional metastasis (OR = 1.77, 95% CI = 1.02 to 3.05). T1 NM had a higher mitotic rate than T1 SSM (adjusted geometric mean = 2.2, 95% CI = 1.9 to 2.5 vs 1.6, 95% CI = 1.5 to 1.7 per mm2, P < .001). Cox multivariable analysis showed a higher risk for melanoma-specific death for NM compared with SSM for T1 (HR = 2.10, 95% CI = 1.24 to 3.56) and T2 melanomas (HR = 1.30, 95% CI = 1.01 to 1.68), and after accounting for center heterogeneity, the difference was statistically significant only for T1 (HR = 2.20, 95% CI = 1.28 to 3.78). The NM subtype did not confer increased risk within each stratum (among localized tumors or cases with regional metastasis).
Conclusions
T1 NM (compared with T1 SSM) was associated with a constellation of aggressive characteristics that may confer a worse prognosis. Our results indicate NM is a high-risk melanoma subtype that should be considered for inclusion in future prognostic classifications of melanoma.
In the last decade, the emergence of effective systemic therapies (ESTs) in the form of both targeted and immuno-based therapies has revolutionized the treatment of patients with advanced stage III ...and stage IV melanoma. Even though lungs represent the most frequent site of melanoma metastases, only limited data are available on the role of surgery in isolated pulmonary metastases from malignant melanoma (PmMM) in the era of ESTs. The aim of this study is to describe the outcomes of patients who underwent metastasectomy of PmMM in the era of ESTs, in order to identify prognostic factors affecting survival and to provide a framework for more informed patient selection of treatmeant with lung surgery in the future. Clinical data of 183 patients who underwent metastasectomy of PmMM between June 2008 and June 2021 were collected among four Italian Thoracic Centers. The main clinical, surgical and oncological variables reviewed were: sex, comorbidities, previous oncological history, melanoma histotypes and primary site, date of primary cancer surgical treatment, melanoma growth phase, Breslow thickness, mutation pattern disease, stage at diagnosis, metastatic sites, DFI (Disease Free Interval), characteristics of lung metastases (number, side, dimension, type of resection), adjuvant therapy after lung metastasectomy, site of recurrence, disease-free survival (DFS) and cancer-specific survival (CSS; defined as the time interval between the first melanoma resection or lung metastasectomy and death from cancer). All patients underwent surgical resection of the primary melanoma before lung metastasectomy. Twenty-six (14.2%) patients already had a synchronous lung metastasis at the time of primary melanoma diagnosis. A wedge resection was performed in 95.6% of cases to radically remove the pulmonary localizations, while an anatomical resection was necessary in the remaining cases. The incidence of major post-operative complications was null, while only 21 patients (11.5%) developed minor complications (mainly air leakage followed by atrial fibrillation). The mean in-hospital stay was 4.46 ± 2.8 days. Thirty- and sixty-day mortality were null. After lung surgery, 89.6% of the population underwent adjuvant treatments (47.0% immunotherapy, 42.6% targeted therapy). During a mean FUP of 107.2 ± 82.3 months, 69 (37.7%) patients died from melanoma disease, 11 (6.0%) from other causes. Seventy-three patients (39.9%) developed a recurrence of disease. Twenty-four (13.1%) patients developed extrapulmonary metastases after pulmonary metastasectomy. The CSS from melanoma resection was: 85% at 5 years, 71% at 10 years, 54% at 15 years, 42% at 20 years and 2% at 25 years. The 5- and 10-year CSS from lung metastasectomy were 71% and 26%, respectively. Prognostic factors negatively affecting CSS from lung metastasectomy at multivariable analysis were: melanoma vertical growth (
= 0.018), previous metastatic sites other than lung (
< 0.001) and DFI < 24 months (
= 0.007). Our results support the evidence that surgical indication confirms its important role in stage IV melanoma with resectable pulmonary metastases, and selected patients can still benefit from pulmonary metastasectomy in terms of overall cancer specific survival. Furthermore, the novel systemic therapies may contribute to prolonged survival after systemic recurrence following pulmonary metastasectomy. Patients with long DFI, radial growth melanoma phase and no site of metastatization other than lung seem to be the best candidate cases for lung metastasectomy; however, to drive stronger conclusions, further studies evaluating the role of metastasectomy in patients with iPmMM are needed.
A peripheral rim of globules represents a marker of the horizontal growth phase in nevi and is a common feature in children and adolescents. The observation of melanocytic lesions with peripheral ...globules (MLPGs) in adulthood deserves more attention, since melanoma may exhibit this feature, albeit rarely. Risk-stratified management recommendations considering a global clinical approach are still missing.
To analyze current knowledge on MLPGs and propose an integrated management algorithm stratified for age groups.
We conducted a narrative review of current published data on MLPGs, analyzing clinical dermoscopic and confocal distinguishing features of melanoma from benign nevi.
The risk of finding a melanoma when removing an MLPG increases with age, especially in people >55 years old, and is significantly higher in the extremities, head/neck and in case of a single asymmetrical lesion, ≥6 mm in diameter. Dermoscopic features associated with melanoma diagnosis include atypical peripheral globules, asymmetrical distribution, multiple rims as well as the reappearance of globules after prior loss. In addition, wide blue-grey regression areas, atypical networks, eccentric blotches, tan structureless peripheral areas and vascularization are atypical dermoscopic features. Confocal worrisome findings are represented by pagetoid cells within the epidermis, architectural disarrangement and atypical cells of the dermo-epidermal junction with irregular peripheral nests.
We proposed a multi-step age-stratified management algorithm integrating clinical, dermoscopic and confocal findings that may increase the early recognition of melanoma and avoid surgical excision of benign nevi.
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