CP-GEP (Merlin) gene expression profiling: can my melanoma patient forgo sentinel lymph node biopsy?

Melanoma risk stratification is crucial for both patients and physicians. Patients want to understand what to expect after diagnosis, and physicians need to decide on an appropriate treatment plan. Traditionally, risk stratification has been based on Breslow thickness and sentinel lymph node (SLN) status. However, the introduction of CP-GEP (Merlin) has provided a molecular test that can be performed on primary melanoma diagnostic biopsy tissue, offering additional risk stratification beyond established variables. In this review, we assess the utility of CP-GEP testing compared to clinicopathologic variables and SLN status and propose a multilayered approach to selecting patients for adjuvant therapy using CP-GEP technology.

New Developing Treatments for Molluscum Contagiosum.

A large variety of treatments for molluscum contagiosum (MC) are available, but none are Food and Drug Administration (FDA) approved and there is no consensus on the optimal approach, mainly owing to a lack of high-level data. Physical modalities are widely used, but require repeated outpatient visits for administration, are painful and difficult to perform in children, and are associated with the possibility of residual scarring and post-inflammatory hypo- or hyperpigmentation. Two experimental topical drugs, a new standardized preparation of topical cantharidin, called VP-102, and a topical nitric oxide (NO)-releasing product containing berdazimer, called SB206, represent promising products that have been designed to overcome the limitations of current treatments. They have recently shown good results in terms of safety and efficacy in large cohorts of patients in phase III studies and have the potential to be the first FDA-approved therapies for the treatment of MC.

Using the Merlin assay for reducing sentinel lymph node biopsy complications in melanoma: a retrospective cohort study.

BACKGROUND: The assessment of the sentinel lymph node is a cornerstone of melanoma staging. However, ~80% of sentinel lymph node biopsies (SLNB) are negative and nontherapeutic, and patients are unnecessarily exposed to surgery-related complications. Here, we gauged the potential of the Merlin assay to reduce SLNB-associated complications. The Merlin assay uses clinicopathologic variables and tumor gene expression profiling to identify low-risk patients who may forgo SLNB. METHODS: We utilized the Merlin test development cohort to determine SLNB complication rates for procedures performed between 2004 and 2018 at Mayo Clinic. Complications evaluated were lymphedema, seroma, infection/cellulitis, hematoma, and wound dehiscence. Patients who underwent a completion lymph node dissection were excluded. RESULTS: A total of 558 patients were included. The overall 90-day complication rate specific to SLNB (1 year for lymphedema) was 17.4%. The most common complications were seroma (9.3%), infection/cellulitis (4.8%), and lymphedema (4.3%). All three were more common in patients with a lower extremity primary tumor location versus other locations. With Merlin test results applied, SLNB-related complications would have decreased by 59%. CONCLUSION: SLNB is a safe procedure but carries a significant complication rate. Merlin testing might reduce the need for SLNB and its associated complications.

Clinicopathologic models predicting non-sentinel lymph node metastasis in cutaneous melanoma patients: Are they useful for patients with a single positive sentinel node?

BACKGROUND AND OBJECTIVES: Of clinically node-negative (cN0) cutaneous melanoma patients with sentinel lymph node (SLN) metastasis, between 10% and 30% harbor additional metastases in non-sentinel lymph nodes (NSLNs). Approximately 80% of SLN-positive patients have a single positive SLN. METHODS: To assess whether state-of-the-art clinicopathologic models predicting NSLN metastasis had adequate performance, we studied a single-institution cohort of 143 patients with cN0 SLN-positive primary melanoma who underwent subsequent completion lymph node dissection. We used sensitivity (SE) and positive predictive value (PPV) to characterize the ability of the models to identify patients at high risk for NSLN disease. RESULTS: Across Stage III patients, all clinicopathologic models tested had comparable performances. The best performing model identified 52% of NSLN-positive patients (SE = 52%, PPV = 37%). However, for the single SLN-positive subgroup (78% of cohort), none of the models identified high-risk patients (SE > 20%, PPV > 20%) irrespective of the chosen probability threshold used to define the binary risk labels. Thus, we designed a new model to identify high-risk patients with a single positive SLN, which achieved a sensitivity of 49% (PPV = 26%). CONCLUSION: For the largest SLN-positive subgroup, those with a single positive SLN, current model performance is inadequate. New approaches are needed to better estimate nodal disease burden of these patients.

Treatment of cradle cap in infants with a new cosmetic non-steroidal gel cream: Clinical, laboratory, and instrumental evaluation.

BACKGROUND: Cradle cap is a benign and self-limiting variant of seborrheic dermatitis (SD) that can be distressing for parents. AIMS: To assess by clinical/laboratory/instrumental evaluation the efficacy/tolerability of a gel cream containing piroctone olamine (antifungal), biosaccharide gum-2 (antifungal), stearyl glycyrrhetinate (anti-inflammatory), and zinc l-pyrrolidone carboxylate (zinc-PCA) (antiseborrheic) in the treatment of mild/ moderate cradle cap. METHODS: In this prospective, open-label trial, 10 infants, with mild/moderate cradle cap enrolled at the Dermatology University Clinic of Catania (Italy) used the tested gel cream twice daily for 30 days. Degree of erythema was evaluated clinically by a 5-point severity scale (from 0=no erythema to 4=severe erythema), at baseline, at 15 and 30 days. Desquamation was rated by dermoscopy evaluation using a 5-point scale (from 0=no desquamation to 4=severe/many large adherent white flakes), at all time points. An Investigator Global Assessment (IGA) using a 6-point scale (from -1=worsening to 4=complete response/clear) was also performed at 30 days. Five subjects, randomly selected, underwent double microbiological evaluation for bacteria and yeasts by cultures of cotton swabs at baseline and at 30 days. Tolerability/acceptability was evaluated on a 4-point scale (from 0=very poor to 3=excellent) at 15 and 30 days. Data were processed using SAS version 9. RESULTS: At baseline, a significant colony-forming unit (CFU) count for Malassezia furfur and Staphylococcus aureus was detected in 4 out of 5 selected patients. After 15 and 30 days, a statically significant reduction from baseline in erythema and desquamation severity was observed, along with a reduction in CFU count for Malassezia furfur and Staphylococcus aureus from baseline. No signs of local side effects were documented. CONCLUSIONS: Our results indicate that the tested gel cream may represent a valid option to treat mild-to-moderate forms of cradle cap and support its antifungal and antibacterial properties.

Validation of CP-GEP (Merlin Assay) for predicting sentinel lymph node metastasis in primary cutaneous melanoma patients: A U.S. cohort study.

BACKGROUND: Approximately 85% of melanoma patients who undergo a sentinel lymph node biopsy (SLNB) are node-negative. Melanoma incidence is highest in patients ≥65 years, but their SLNB positivity rate is lower than in younger patients. CP-GEP, a model combining clinicopathologic and gene expression variables, identifies primary cutaneous melanoma (CM) patients who may safely forgo SLNB due to their low risk for nodal metastasis. Here, we validate CP-GEP in a U.S. melanoma patient cohort. METHODS: A cohort of 208 adult patients with primary CM from the Mayo Clinic and West Virginia University was used. Patients were stratified according to their risk for nodal metastasis: CP-GEP High Risk and CP-GEP Low Risk. The main performance measures were SLNB reduction rate (RR) and negative predictive value (NPV). RESULTS: SLNB positivity rate for the entire cohort was 21%. Most patients had a T1b (34%) or T2a (31%) melanoma. In the T1-T2 group (153 patients), CP-GEP achieved an SLNB RR of 41.8% (95% CI: 33.9-50.1) at an NPV of 93.8% (95% CI: 84.8-98.3). Subgroup analysis showed similar performance in T1-T2 patients ≥65 years of age (51 patients; SLNB positivity rate, 9.8%): SLNB RR of 43.1% (95% CI: 29.3-57.8) at an NPV of 95.5% (95% CI: 77.2-99.9). CONCLUSION: We confirmed the potential of CP-GEP to reduce negative SLNB in all relevant age groups. Our findings are especially relevant to patients ≥65 years, where surgery is often elective. CP-GEP may guide SLNB decision-making in clinical practice.

Balloon cell nevus in children: Report of three cases of the scalp and review.

Balloon cell nevus (BCN) is a histopathological variant of cutaneous acquired melanocytic nevi characterized by junctional and/or dermal nests of large cells with a clear and foamy cytoplasm which has rarely been described in children. Three cases of BCN firstly reported on the scalp in two pediatric patients are presented along with a literature review. Dermoscopy is particularly indicated in those pigmented lesions showing a yellowish hue, in ruling out in real time those disorders that may clinically be similar such as xanthogranuloma and sebaceous nevus, and to suggest the diagnosis of BCN. The final diagnosis, however, is established by histopathological examination.

Beneficial therapeutic effects of vitamin C on recurrent respiratory tract infections in children: preliminary data.

BACKGROUND: The aim of this study was to demonstrate whether supplementation of vitamin C has a beneficial effect in the prevention of recurrent respiratory tract infections (RTIs) in children. Moreover, we evaluate the main risk factors that predispose to the development of this disease. METHODS: Sixty children have been enrolled in the study and randomized into two groups: the control group (G1 N.=33) and the group at risk of recurrent RTIs (G2 N.=27). To G2 group was administered every day 100% orange juice with the content of vitamin C 70 mg. RESULTS: Significant reduction in the incidence rate of RTIs (episodes pre-treatment: 182-6.75 episodes/child, after-treatment: 71-2.62 episodes/child, P<0.05), were observed in G2 group. CONCLUSIONS: The administration of vitamin C had a beneficial effect in our group of children with recurrent RTIs, reducing the number of infective episodes.

Identification of stage I/IIA melanoma patients at high risk for disease relapse using a clinicopathologic and gene expression model.

PURPOSE: Patients with stage I/IIA cutaneous melanoma (CM) are currently not eligible for adjuvant therapies despite uncertainty in relapse risk. Here, we studied the ability of a recently developed model which combines clinicopathologic and gene expression variables (CP-GEP) to identify stage I/IIA melanoma patients who have a high risk for disease relapse. PATIENTS AND METHODS: Archival specimens from a cohort of 837 consecutive primary CMs were used for assessing the prognostic performance of CP-GEP. The CP-GEP model combines Breslow thickness and patient age, with the expression of eight genes in the primary tumour. Our specific patient group, represented by 580 stage I/IIA patients, was stratified based on their risk of relapse: CP-GEP High Risk and CP-GEP Low Risk. The main clinical end-point of this study was five-year relapse-free survival (RFS). RESULTS: Within the stage I/IIA melanoma group, CP-GEP identified a high-risk patient group (47% of total stage I/IIA patients) which had a considerably worse five-year RFS than the low-risk patient group; 74% (95% confidence interval [CI]: 67%-80%) versus 89% (95% CI: 84%-93%); hazard ratio [HR] = 2.98 (95% CI: 1.78-4.98); P < 0.0001. Of patients in the high-risk group, those who relapsed were most likely to do so within the first 3 years. CONCLUSION: The CP-GEP model can be used to identify stage I/IIA patients who have a high risk for disease relapse. These patients may benefit from adjuvant therapy.

ß3 integrin immunohistochemistry as a method to predict sentinel lymph node status in patients with primary cutaneous melanoma.

BACKGROUND: Integrins are heterodimeric proteins composed of noncovalently linked ɑ and ß subunits which are essential for a wide range of normal physiology and also play prominent roles in cancer. Here we tested whether integrin expression in diagnostic skin biopsies is associated with sentinel lymph node (SLN) metastasis. METHODS: We utilized a cohort of 854 consecutive patients with primary cutaneous melanoma to quantify the expression of ß integrin subunits by reverse transcriptase quantitative PCR (RT-qPCR). In addition, we quantified the expression of ß3 integrin by immunohistochemistry (IHC) in a subset of 271 patients by H score. Outcome of interest was SLN biopsy metastasis within 90 days of melanoma diagnosis. Logistic regression analyses were used to develop models for the likelihood of SLN metastasis from molecular, clinical, and histologic variables. RESULTS: ß3 integrin expression quantified by IHC or RT-qPCR was associated with SLN metastasis. ß1, ß5, ß6, and ß8 integrin expression was not associated with SLN metastasis. The incremental gain in performance of a predictive model which included ß3 integrin expression as quantified by IHC in combination with established clinicopathologic variables (Breslow depth and patient age) was limited. CONCLUSIONS: ß3 integrin is the principal integrin subunit associated with sentinel lymph node biopsy (SLNb) metastasis in primary cutaneous melanoma. However, ß3 integrin H score does not significantly improve models for the likelihood of SLN metastasis over Breslow depth and patient age.

Model Combining Tumor Molecular and Clinicopathologic Risk Factors Predicts Sentinel Lymph Node Metastasis in Primary Cutaneous Melanoma.

PURPOSE: More than 80% of patients who undergo sentinel lymph node (SLN) biopsy have no nodal metastasis. Here we describe a model that combines clinicopathologic and molecular variables to identify patients with thin and intermediate thickness melanomas who may forgo the SLN biopsy procedure due to their low risk of nodal metastasis. PATIENTS AND METHODS: Genes with functional roles in melanoma metastasis were discovered by analysis of next generation sequencing data and case control studies. We then used PCR to quantify gene expression in diagnostic biopsy tissue across a prospectively designed archival cohort of 754 consecutive thin and intermediate thickness primary cutaneous melanomas. Outcome of interest was SLN biopsy metastasis within 90 days of melanoma diagnosis. A penalized maximum likelihood estimation algorithm was used to train logistic regression models in a repeated cross validation scheme to predict the presence of SLN metastasis from molecular, clinical and histologic variables. RESULTS: Expression of genes with roles in epithelial-to-mesenchymal transition (glia derived nexin, growth differentiation factor 15, integrin ß3, interleukin 8, lysyl oxidase homolog 4, TGFß receptor type 1 and tissue-type plasminogen activator) and melanosome function (melanoma antigen recognized by T cells 1) were associated with SLN metastasis. The predictive ability of a model that only considered clinicopathologic or gene expression variables was outperformed by a model which included molecular variables in combination with the clinicopathologic predictors Breslow thickness and patient age; AUC, 0.82; 95% CI, 0.78-0.86; SLN biopsy reduction rate of 42% at a negative predictive value of 96%. CONCLUSION: A combined model including clinicopathologic and gene expression variables improved the identification of melanoma patients who may forgo the SLN biopsy procedure due to their low risk of nodal metastasis.

The role of integrins in melanoma: a review.

Integrins are the major family of cell adhesion receptors in humans and essential for a wide range of normal physiology, including formation and maintenance of tissue structure integrity, cell migration, proliferation, and differentiation. Integrins also play a prominent role in tumor growth and metastasis. Translational research has tried to define the contribution of integrins to the phenotypic aggressiveness of melanoma because such knowledge is clinically useful. For example, differential expression of integrins in primary cutaneous melanoma can be used to distinguish indolent from aggressive, prometastatic melanoma. Recent studies have shown that gene expression-based testing of patient-derived melanoma tissue is feasible, and molecular tests may fully replace interventional surgical methods such as sentinel lymph node biopsies in the future. Because of their central role in mediating invasion and metastasis, integrins are likely to be useful biomarkers. Integrins are also attractive candidate targets for interventional therapy. This article focuses on the role of integrins in melanoma and highlights recent advances in the field of translational research.

Attention-deficit/hyperactivity disorder and enuresis: a study about effectiveness of treatment with methylphenidate or desmopressin in a pediatric population.

BACKGROUND: The aim of this study was to evaluate the effectiveness of treatment with methylphenidate or desmopressin (dDAVP) in patients with comorbid attention-deficit/hyperactivity disorder (ADHD) and enuresis. METHODS: We enrolled 103 patients affected by ADHD and 125 patients with monosymptomatic nocturnal enuresis (NE). Data were collected between January 2014 and December 2015. The study was carried out in compliance with the Helsinki Declaration. RESULTS: About children with ADHD, 9/103 (8.7%) were also suffering from NE; of those 8/9 followed treatment with methylphenidate and cognitive behavioral therapy. After 3 months 2/8 (25%, CI 95%: 8-65%) showed improvements, remaining 75% has been increased dosage of methylphenidate. After 6 months a response was achieved in 6/8 (75%, CI 95%: 35-96%) children and 1/8 was lost to follow-up. Furthermore the drug withdrawal showed a recurrence of symptoms both ADHD and NE in 1/7 (14.3%, CI 95%: 0.3-57%) vs. 6/7 (85.7%, CI 95%: 42-99%) that not presented recurrences. About children with NE enrolled at Campus Bio-Medico University it was found that 4/125 (3.8%) children were also suffering from ADHD; 3/4 (75%) treated with dDAVP and motivational therapy, of those 2/3 (66.7%, CI 95%: 9-99%) showed no improvements of symptoms vs. 1/3 (33.3%, CI 95%: 0.8-90%) that showed partial response with a reduction of wet-nights. CONCLUSIONS: It is important the service of recruitment of patients with NE. In fact considering NE in a Child Neuropsychiatry Service where patients belong to a diagnosis of ADHD and NE is an incidental finding, this one is not considered as the addressee of treatment, but the therapy is directed to the neuro-behavioral problem using specific drugs and therapies, which are resolutive in the enuretic disorder.

Dermatoscopy of Common Lesions in Pediatric Dermatology.

The use of dermatoscopy to assist in the diagnosis of a variety of proliferative, pigmentary, inflammatory, infectious, congenital, and genetic cutaneous and skin appendage disorders is constantly increasing, as it is effective, affordable, noninvasive, and quick to perform.