Neoplasms

Skin and Connective Tissue Diseases

All Conditions

Symptoms and General Pathology

Diseases and Abnormalities at or Before Birth

Rare Diseases

Melanoma

Nevus, Pigmented

Nevus

Syndrome

Dysplastic Nevus Syndrome

Neuroendocrine Tumors

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Nerve Tissue

Nevi and Melanomas

Skin Neoplasms

Skin Diseases

Neoplastic Syndromes, Hereditary

Genetic Diseases, Inborn

Neuroendocrine Tumor

Neuroepithelioma

Melanoma-prone families from dermatology clinics.

Maria T Landi, M.D.

During the course of a case-control study of melanoma conducted at the Bufalini Hospital, Cesena, Italy in the years 1994-1996, 20 families with 2 or 3 melanoma cases were identified and studied. The area where the study was conducted showed the steepest increase in melanoma incidence in Mediterranean populations between the years 1987 and 1997.

Clinical characteristics of melanoma in the families studied were similar to those typically described in fair-skinned populations, but no relevant mutations in the coding regions of known candidate genes from melanoma have been found. Lack of findings could be due to the modest number of families and the small number of affected CMM cases examined. We cannot exclude the possibility of alterations in introns, splicing sites or promoter regions. Also epigenetic factors could affect the expression of the gene products we studied. Alternatively, germline alterations of a gene(s) other than the candidate genes we analyzed may play an important role in melanoma predisposition in this population. A large number of families is needed to test these hypotheses.

These additional families could provide an important contribution to the understanding o melanoma development. In fact, this population does not generally have the host characteristics that are usually associated with higher risk for melanoma (e.g., light skin color, red hair, blue eyes, multiple freckles, tendency to sunburn, etc.) but do have a relative high frequency of dysplastic nevi and melanoma.

The main objective of this study is to recruit more families at the Bufalini Hospital, Cesena, Italy in order to reach a larger sample size. Recently, 16 potential melanoma-prone families have been identified through patient's or physicians' referrals by the Dermatologists at the Bufalini Hospital. The dermatologists have maintained close relationships with members of these families and are confident that these subjects would be willing to participate in a study if contacted. The first goal of our study is to contact this family group and verify their willingness to participate in the study. In addition, new families could be identified and recruited.

We propose to conduct a pilot project. We estimate recruitment of approximately 25 families with 2 or more melanoma cases in first -degree relatives over a one-year period, including the 16 families already identified and approximately 10 new kindreds. At the end of the pilot phase we will determine the feasibility of continuing recruitment.

To date 557 subjects, including cases of melanoma and unaffected relatives, have been recruited in the family study of melanoma at the Bufalini Hospital, Cesena, Italy, University ofl'Aquila, L'Aquila, Italy, and the Istituto Valenciano de Oncologia, Valencia, Spain. Clinical characteristics of melanoma in the families studied were similar to those typically described in fair-skinned populations.

In the original study from the Bufalini Hospital, only 7% of the families analyzed have been shown to carry mutation in the CDKN2A gene, known candidate gene for melanoma, and no other mutation in additional susceptibility genes have been identified. The possibility of alterations in introns, splicing sites, or promoter regions cannot be excluded. Also, epigenetic factors could affect the expression of the gene products we studied. Alternatively, germline alterations of a gene(s) other than the candidate genes may play an important role in melanoma predisposition in this population. We began genome-wide scanning of the first 47 families. There was no evidence for linkage to either chromosome 9 or chromosome 1, previously shown to be susceptibility loci for melanoma. We extended the samples size also including melanoma-prone families from other Italian investigators. We have performed fine mapping of the loci that appeared interesting in the first linkage analysis. We did not confirm the previous association with the disease and published a manuscript to report the null results. Some of these families were also analyzed together with other families worldwide in linkage and genome-wide association studies with the goal of identifying loci potentially important for melanoma etiology. Moreover, some individuals from this study are being analyzed for presence of variants in susceptibility genes in pigmentation, DNA repair, and other pathways together with the melanoma samples from the case-control study (02-C- N(35). Finally, some families with three or more affected individuals are ongoing exomic sequencing with the goal of identifying novel loci associated with melanoma susceptibility. More than 100 subjects have been sequenced to date. We have identified a potentially important candidate gene for melanoma and are investigating additional families and melanoma cases to verify whether we can replicate this finding.

This protocol proposes to continue recruitment of families in order to reach a larger sample size for future analysis. The additional families could provide an important contribution to the understanding of melanoma development.

In addition, this protocol proposes to continue recruiting subjects for the tissue study subgroup at the Bufalini Hospital of Cesena, the Unviersity of I' Aquila, Italy and the Istituto Valenciano de Oncologia, Valencia, Spain. To date, 98 subjects have been enrolled in this study. The study aims at investigating the progression from nevi to melanoma in a cross sectional study of melanoma cases. The tissue study component focuses on the comparison of gene expression, somatic mutations, genetic variants, and proteomics profile in normal skin, common melanocytic nevi, dysplastic nevi, and melanoma tissue samples from the same individuals (familial or sporadic cases). Each subject completes an interview based questionnaire on sun exposure, pigmentation, sunsensitivity, family and medical history, and other melanoma risk factors and donates a blood sample.

whole blood, lymphocytes, tissue sections, plasma

Family Study of Melanoma in Italy

National Cancer Institute (NCI)

Pigmentation Disorders

Dermoscopic imaging of a lesion decided to be biopsied

Solely after the dermatologist has decided to biopsy a lesion and sent the patient to biopsy, a dermoscopic image is captured by a camera attached to a dermoscope.

dermoscopy

Avi Dascalu, MD, Ph.D.

Robert Raleigh, MBA

Avi Dascalu, MD

Avi Dascalu, MD. Ph.D.

Malignant melanoma (MM) is a deadly cancer, claiming globally about 160000 new cases per year and 48000 deaths at a 1:28 lifetime incidence (2016).

The golden standard, dermoscopy, enables Dermatologists to diagnose with a sensitivity of 40%, and a 8-12% specificity, approximately. Additional diagnostic abilities are restricted to devices which are either unproved or experimental.

A new technology of Neuronal Network Clinical Decision Support (NNCD) was developed. It uses a dermoscopic imaging device and a camera able to capture an image. The photo is transferred to a Cloud Server and further analyzed by a trained classifier. Classifier training is aimed at a high accuracy diagnosis of Dysplastic Nevi (DN), Spitz Nevi and Malignant Melanoma detection with assistance from a Deep Neuronal Learning network (DLN). Diagnosis output is an excise or do not excise recommendation for pigmented skin lesions.

A total of 80 subjects already referred to biopsy pigmented skin lesions will be examined by dermoscopy imaging in a non interventional study. Artificial Intelligence output results, as measured by 2 different dermoscopes, to be compared to ground truth biopsies, by either classifier decisions or a novel Modified Classifier Technology output decisions.

Primary endpoints are sensitivity and specificity detection of the NNCD techniques. Secondary endpoints are the positive and negative prediction ratios of NNCD techniques.

Background

Malignant melanoma (MM) is a deadly cancer, claiming globally about 160000 new cases per year and 48000 deaths \[1\]. The incidence rate for MM ascended between 1950 and 2007 more than 17-fold in men (1.9 to 33.5 per 100,000) and more than 9-fold in women (2.6 to 25.3 per 100,000) \[2\]. It is estimated that 76000 new cases and 9000 deaths are diagnosed/ year (US, only, 2017) \[3\]. European Countries yield 22000/yr. stage 4 melanomas.

MM starts de novo in about 70% of subjects, with a small 2 millimeters or more superficial skin lesion which, if left undiagnosed, might develop into a more advanced stage cancer, followed by silent lymph node spreading and invasion of vital organs such as liver and brain. MM is staged by either direct invasion into the skin, the Breslow scale in mm, or by its skin level involvement, a Clark 1-5 structural skin level of involvement. Both methods of assessment are predictors of long term survival, which is almost unchanged at a Breslow depth beneath 1 mm and much decreased beyond Clark III stage. Therefore early detection of melanoma, generally tagged as small melanoma, is critical.

Present Methodologies of MM detection

The following different methods and diagnostic means for detection of the cutaneous melanoma are currently employed as a means of diagnosis:

1. Visual recognition by an Asymmetry, Border, Color, Diameter and Evolvement (ABCDE rule). A 30 year old methodology and still running, assessing: ABCDE. It is used by part of US dermatologists who trust their clinical skills and instincts \[4\]. Due to its innate complexity and myriad of recognition patterns, dermoscopy by epiluminescence microscopy is considered as ineffective by 60% of the non users dermatologists and 30% report it as time consuming, rendering it impracticable. The abovementioned rule was reviewed in 2015 \[5\] and teaches the use of a diameter greater than 6 mm as a criteria for melanoma recognition. Consequently, it does not contribute to early detection of a melanoma, which might be life saving, since 70-80% of melanomas start de novo as small melanomas. An attempt to change the Diameter criteria, i.e. a decrease in the postulated 6 mm Diameter, leads to a major decrease in sensitivity and specificity, rendering the ABCDE ineffective for early melanoma detection. It is concluded that these basic visual criteria, although widely used, are a non effective prevention method due to their innate criteria which misses the evolving melanomas, since all melanomas start as small melanomas.
2. Epiluminescence microscopy is a 65 years old art, which is considered the golden standard of evaluation. It is highly dependent on the skills and knowledge of the diagnostician. Epiluminescence microscopy is a the bridge between clinical observation and histopathological diagnosis. It allows visualization of skin pigments up to the papillary dermis and improves detection sensitivity and specificity. Analysis is made by a clinician based on dermoscopy rules \[6\], which are based on a complicated dermoscopic pattern analysis.

   Complete dermoscopic pattern analysis of a lesion is the mainstream of diagnosis. Each of the dermoscopic patterns can diverge in extent, diameter, general or local appearance, or evolve as multi patterns with various area of expression on the same lesion and rendering the diagnosis beyond an encyclopedic task.

   Due to the complexity of the dermoscopic pattern analysis method, different modifications were proposed, such as a simplified ABCD rule, an intermediate 7 rules assessment and a 11 rules checklist. The myriad of data and its interpretation render even experts in dermoscopy to identify melanomas with a relative low ratio from 5:1 to 15:1, i.e. the number of biopsies of benign lesions performed in order to make the diagnosis of one skin melanoma.

   Furthermore, there are claims that one diagnostic sign might be more sensitive that other signs, alike the criteria of a light brown structureless area. Dermatologists commonly fail in diagnosing early small melanoma which is the critical period of growth of the tumor and most efficacious prevention.
3. Visual recognition by temporal total body photography is yet non standardized methodology, a time consuming and patient expensive procedure. It uses the human comparison assessment and is subjected to biases of pixel photo during performance of the measurement, due to lighting, background and camera position. Addition of patient assessment by artificial intelligence, an analysis based on computer evaluation of different colorimetric and geometric parameters of a lesion in real time, confer a limited advantage only, yielding sometimes more false positives compared to inexperienced or even experienced clinicians.
4. Multi Spectrometry devices, which provide measurements of melanin, collagen and hemoglobin with further use of image analysis, do not confer any advantage to epiluminescence microscopy. Although displaying a higher sensitivity, these methodologies specificity are considerably below that of simple epiluminescence microscopy in melanoma identification rate .
5. Confocal scanning microscopy, a procedure which uses a low power laser for a 3D imaging. An effective means of diagnosis. However, the use of this methodology is limited by its high cost, a prolonged (6 mo) learning curve of 2000-4000 images, and the requirement for a highly specialized and trained personal, since this methodology is highly subjected to artifacts.
6. Experimental under development methods: alike Electrical impedance spectroscopy, Optical coherence tomography, High frequency ultrasound, Laser doppler perfusion imaging, Dynamic thermal imaging, Photoacoustic microscopy, to be further developed and proved.

Clinical Requirements

It is desirable to identify a new non invasive methodology which will

1. Improve Sensitivity of diagnosis of pigmented skin lesions, alike dysplastic nevi, Spitz nevi and MM
2. Identify small MM,
3. Increase Specificity of lesions to be biopsied
4. Non invasive fast technology.

Common Practice

Commonly, a patient is evaluated by a physician due to either a skin lesion complaint or, with high risk patients, a summon to visit on a regular basis.

Only some of the dermatologists employ dermoscopy or are skilled to use it since it may seem to be time consuming. There is no international standard of degree of skill. Even a golden standard textbook of dermoscopy is not existent.

Upon recognition of suspicious lesion, patient is referred to a surgeon for biopsy.

As recently reviewed and in view of the above-mentioned, the incidence of melanoma is continuing to increase. All present methods commonly do not diagnose melanoma at an early stage and epiluminescence microscopy is highly user dependant and commonly misses the diagnosis . Early excision is the only strategy to reduce the death toll associated with melanoma. Unnecessary excision of benign lesions increases morbidity and raise healthcare costs associated with melanoma screening, resulting in recommended restrictions to a total body screening by Surgeon General (2016) and questioning the efficacy of such a screening.

The requirement for a more systemized methodology and system is obvious in view of the expected increase in melanoma incidence to a 1:15 within the next 15 years. A new device able to capture the window of opportunity of Dysplastic Nevus to small melanoma is highly useful for today healthcare systems.

Primary Study Objectives

* A Sensitivity of at least 75% for Classifier results as compared to biopsy Sensitivity is the percentage of correctly diagnosed dysplastic nevi, Spitz nevi or melanomas. \[ Designated as safety issue: No \].
* A Sensitivity of at least 85% for an Modified Classifier Technology (MCT) results as compared to biopsy. Sensitivity is the percentage of correctly diagnosed dysplastic nevi, Spitz nevi or melanomas. \[ Designated as safety issue: No \]
* A Specificity of at least 33% for Classifier results as compared to biopsy. Specificity is the percentage of correctly identified dysplastic nevi, Spitz nevi or melanomas. \[ Designated as safety issue: No \]
* A Specificity of at least 33% for MCT results as compared to biopsy. Specificity is the percentage of correctly identified dysplastic nevi, Spitz nevi or melanomas. \[ Designated as safety issue: No \]

Secondary Study Objectives

* The positive predictive value of MCT, compared to the biopsy result \[ Designated as safety issue: No \]
* The negative predictive value of MCT, \[ Designated as safety issue: No \]
* The false positive rate of MCT, \[ Designated as safety issue: No \]
* The false negative rate of MCT, \[ Designated as safety issue: No \]
* The difference between two dermoscopes, \[ Designated as safety issue: No \]
* The positive predictive value of Classifier, compared to the biopsy result \[ Designated as safety issue: No \]
* The negative predictive value of Classifier, \[ Designated as safety issue: No \]
* The false positive rate of Classifier, \[ Designated as safety issue: No \]
* The false negative rate of Classifier, \[ Designated as safety issue: No \]
* Clinical decision Sensitivity and Specificity rates.

Artificial Intelligence-assisted Evaluation of Pigmented Skin Lesions

Dermoscopy Evaluation of Pigmented Skin Lesions by a Neuronal Network Clinical Decision Support: an Open Prospective Non Interventional Study

A Sensitivity of at least 75% for Classifier results as compared to biopsy

A Sensitivity of at least 85% for Classifier results as compared to biopsy

The positive predictive value of MCT, compared to the biopsy result

The negative predictive value of MCT, compared to the biopsy result

Assuta Hospital Systems

Melanosis

Nevus, Spindle Cell

Nevus, Blue

Nevus, Epithelioid and Spindle Cell

Hyperplasia

Hyperpigmentation

Central Nervous System Depressants

All Drugs and Chemicals

Anti-Infective Agents

Anesthetics

Formaldehyde

Only data from medical records and formalin-fixed paraffin-embedded tissue blocks will be collected from patients in this cohort. Patients with skin or mucosal melanoma and dysplastic nevi which have been already excised are eligible. FFPE tissue blocks with MPATH-Dx Class 1-2 vs Class 3-5 will be collected in approximately 1:1 ratio

Only data from medical records, formalin-fixed paraffin-embedded tissue blocks and cytologic slides will be collected from patients in this cohort. Patients with skin or mucosal melanoma and dysplastic nevi which have been already excised are eligible. FFPE tissue blocks with MPATH-Dx Class 1-2 vs Class 3-5 will be collected in approximately 1:1 ratio

Patients with pigmented lesions on the skin or mucosa who are referred for excisional biopsy will be offered to apply investigated non-invasive adhesive system on their lesion just before the excisional biopsy. After biopsy cytological slides and FFPE tissue blocks will be prepared. All three types of obtained samples will be investigated separately (adhesive patches, cytologic slides and FFPE tissue blocks) for genetic markers whereas cytologic slides and FFPE tissue blocks will be processed also routinely and regular cytologic and histopathologic report will be generated.

The already registered on the market adhesive skin patch will be applied and removed for several times on the pigmented skin (or mucosal) lesion just before the preplanned excisional biopsy after local anaesthesia have been already administered. Excisional biopsy and local anaesthesia are not the part of this study and will be carried out according to local practice

Non-invasive adhesive system (patch)

Igor V Samoylenko, MD, PhD

Lev V Demidov, MD, PhD

Oxana E Garanina, MD, PhD

Irena L Shlivko, MD, PhD, DSc

Igor Samoylenko, MD, PhD

Kirill Baryshnikov, MD, PhD

Kristina V Orlova, MD, PhD

This is a multicenter, ambispective, low-interventional clinical study evaluating molecular genetic markers for non-invasive differential diagnosis of benign and malignant pigmented skin and mucosal neoplasms. In retrospective cohorts genetics markers will be identified. In prospective cohort non-invasive adhesive system will be tested to identify malignant or benign lesions with prespecified sensitivity and specificity compared to other non-invasive techniques (i.e. dermoscopy) and using histopathological examination as a "golden standard".

Ambispective study with two retrospective cohorts and one prospective cohort

Atypical MOLes and Melanoma Early Detection Study (MoleMed)

A Multicenter, Ambispective, Low-interventional Clinical Study Evaluating Molecular Genetic Markers for Non-invasive Differential Diagnosis of Benign and Malignant Pigmented Skin and Mucosal Neoplasms

•Assessment of the sensitivity and specificity of a complex of molecular genetic studies applicable for non-invasive differential diagnosis of benign and malignant melanocytic neoplasms of the skin and mucous membranes in comparison with a standard histological examination

Assessment of the sensitivity, specificity, positive and negative prognostic significance of the developed molecular genetic method for non-invasive differential diagnosis of benign and malignant pigmented neoplasms of the skin and mucous membranes in comparison with clinical diagnosis with an naked eye by an oncologist or dermatologist

Blokhin's Russian Cancer Research Center

Russian Academy of Medical Sciences

Principal Investigator, Senior Researcher, Department of Oncodermatology, MD, PhD

Immune System Diseases

Musculoskeletal Diseases

Dermatitis, Atopic

Dermatitis

Eczema

Rosacea

Psoriasis

Keratosis, Actinic

Keratosis

Acne Vulgaris

Leg Ulcer

Ulcer

Foot Ulcer

Vitiligo

Skin Diseases, Papulosquamous

Skin Diseases, Eczematous

Foot Diseases

Skin Ulcer

Precancerous Conditions

Fu-Tong Liu, M.D., Ph.D.

The purpose of the potential research study participant registry is to keep potential research subjects informed about any future research studies in which they may meet the criteria for enrollment. The purpose of this study is also to assist current and future clinical trials with recruitment of subjects.

Methods:

Subjects will self identify themselves via the UCDMC Dermatology website to complete a survey regarding their interest in learning about future dermatology clinical research projects. Subjects provide contact information and check of a list of potential topics of interest.

Procedures:

Potential participants will find a link on the UCDMC Dermatology website to our registry. The potential participant will read information about the registry. If they wish additional information, they can follow a link to the potential research registry consent form. At this stage, the potential participant may answer, "no" to the consent form and they will be redirected back to the Clinical trials website. If they answer, "yes" then they will be linked to the registry questionnaire. The potential subject would then decide if they want to participate in the registry and if so what information they want to provide. The Clinical Research Coordinators would contact potential study participants to see if they meet the eligibility criteria for any of our current studies.

Potential Research Study Participant Registry

University of California, Davis

2 mm saucerization biopsy of dysplastic nevi

Saucerization biopsy

David Polsky, MD, PhD

Non-interventional study to evaluate the utility of removing Dysplastic Nevi with a defined 2 mm margin.

This is a prospective, observational study to evaluate the utility of removing Dysplastic Nevi (DN) with a defined 2 mm margin. This is a non-interventional study that will observe the pathology results following a standard of care biopsy. Principal Investigator (PI) hypothesize that the majority of lesions removed with this technique will have margins free of nevus cells on examination of histopathological sections. Hence, pathologists will not suggest that an additional excision be performed to remove any residual nevus. PI also hypothesize that if biopsy sites are followed over time, the rate of nevus recurrence will be low, because investigators would have removed the majority, if not all of the lesion at the time of initial biopsy.

Prospective Study of 2 mm Margins for the Biopsy of Dysplastic Nevi

To determine the rate of nevus recurrence within 1 year of follow-up

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Family Study of Melanoma in Italy	NCT00339222	Melanoma Dysplastic Nevi Melanocytic Nev...		10 Years - 100 Years	National Institutes of Health Clinical Center (CC)
Artificial Intelligence-assisted Evaluation of Pigmented Skin Lesions	NCT03362138	Melanoma Pigmented Skin ... Dysplastic Nevi	dermoscopy	18 Years - 90 Years	Assuta Hospital Systems
Atypical MOLes and Melanoma Early Detection Study (MoleMed)	NCT04353050	Melanoma Melanoma (Skin) Moles Nevus Nevus, Blue Nevus, Pigmente... Nevus, Spitz Nevi, Spindle C... Nevi, Dysplasti... Dysplastic Nevu... Mucosal Melanom... Mucosal Melanos...	Non-invasive ad...	18 Years -	Russian Academy of Medical Sciences
Potential Research Study Participant Registry	NCT00710489	Acne Actinic Keratos... Dysplastic Nevi Eczema Psoriasis Skin Cancer Rosacea Leg Ulcers Foot Ulcers Atopic Dermatit...		18 Years -	University of California, Davis
Prospective Study of 2 mm Margins for the Biopsy of Dysplastic Nevi	NCT03094273	Dysplastic Nevi	Saucerization b...	18 Years -	NYU Langone Health
Artificial Intelligence-assisted Evaluation of Pigmented Skin Lesions	NCT03362138	Melanoma Pigmented Skin ... Dysplastic Nevi	dermoscopy	18 Years - 90 Years	Assuta Hospital Systems
Family Study of Melanoma in Italy	NCT00339222	Melanoma Dysplastic Nevi Melanocytic Nev...		10 Years - 100 Years	National Institutes of Health Clinical Center (CC)
Atypical MOLes and Melanoma Early Detection Study (MoleMed)	NCT04353050	Melanoma Melanoma (Skin) Moles Nevus Nevus, Blue Nevus, Pigmente... Nevus, Spitz Nevi, Spindle C... Nevi, Dysplasti... Dysplastic Nevu... Mucosal Melanom... Mucosal Melanos...	Non-invasive ad...	18 Years -	Russian Academy of Medical Sciences
Family Study of Melanoma in Italy	NCT00339222	Melanoma Dysplastic Nevi Melanocytic Nev...		10 Years - 100 Years	National Institutes of Health Clinical Center (CC)
Potential Research Study Participant Registry	NCT00710489	Acne Actinic Keratos... Dysplastic Nevi Eczema Psoriasis Skin Cancer Rosacea Leg Ulcers Foot Ulcers Atopic Dermatit...		18 Years -	University of California, Davis
Artificial Intelligence-assisted Evaluation of Pigmented Skin Lesions	NCT03362138	Melanoma Pigmented Skin ... Dysplastic Nevi	dermoscopy	18 Years - 90 Years	Assuta Hospital Systems

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