bluuebunny/crossref_metadata_2025_split huggingface dataset:
Skin cancer and deep learning for dermoscopic images classification: A pilot study.
Authors: Belaala Abir , Bourezane Yazid , Terrissa Labib Sadek , Al Masry Zeina , Zerhouni Noureddine 
Published: May 2020

e22018 Background: The prevalence of skin cancer is increasing worldwide. According to World Health Organization (WHO),there is one in every three cancers diagnosed in US is a skin cancer. Traditional ways for skin cancer diagnosis have shown many limitations: inadequate accuracy, consume much time, and effort. In order to assist dermatologists for earlier and accurate diagnosis, we propose to develop a computer aided diagnosis systems for automatic classification of skin lesions. Deep learning architectures are used in this area based on a new convolutional neural network that can classify skin lesions with improved accuracy. Methods: A public dataset of skin lesions HAM10000 ("Human Against Machine with 10000 training images") is used for training and testing. For the validation of our work, a private dataset is collected from a dermatology office in Besançon (France). This dataset contains 45 different dermatoscopic images of skin lesions (Basal cell carcinoma, squamous cell carcinoma and Actinic keratosis) with their histology results. In this research, a three-phase approach was proposed and implemented: Phase one is preprocessing the data; by amputate missing values using the mean filling method. The dermoscopy images in the dataset were downscaled to 224X224 pixels. Then, data augmentation was applied to solve the imbalanced data problem. Finally, the ten-fold cross-validation method was applied to compare the performance of three CNN architectures used in literature: DenseNet 201, ResNet 152, and VGGNet with our proposed architecture. Results: Results obtained with our model show the highest classification accuracy 0.95, a sensitivity of 0, 96, a specificity of 0.94, and outperforms other algorithms in classifying these skin lesions. Conclusions: Our research improves the performance of computer aided diagnosis systems for skin lesions by giving an accurate classification. The use of this system helps dermatologists to make accurate classification with lower time, cost, and effort. Our future work will focus on generalizing the domain by developing a model that can classify various lesions using various types of data (dermoscopic images, histological images, clinical data, sensors data...etc) using the advanced techniques in literature of transfer learning and adaptors models.
Second primary melanoma in advanced melanoma patients treated with anti-PD-1 monoclonal antibodies.
Authors: Funck-Brentano Elisa , Charvet Estelle , Chaplain Louise , Gantzer Amelie , Kassem Oula , Longvert Christine , Blom Astrid , Dupin Nicolas , Aractingi Sélim , Hamon Maxime , Zimmermann Ute , Emile Jean-François , Sohier Pierre , Kramkimel Nora , Saiag Philippe 
Published: May 2020

e22025 Background: Development of a second primary melanoma (SCPM) has not been reported in melanoma patients treated with anti-PD-1 monoclonal antibodies (mAb), in contrast with those reported in BRAF-inhibitor-treated patients. Our aim was to report arising SCPM in patients with advanced melanoma treated with anti-PD-1 therapy. Methods: Retrospective study, conducted in 2 referral centres, including advanced melanoma patients who developed a SCPM after anti-PD-1 mAb initiation, between September 2010 and May 2019. BRAF or NRAS mutational status was assessed by targeted NGS panels, real-time PCR, and immunohistochemistry. Results: Among a total of 509 patients treated with anti-PD-1 mAb, 4 had a SCPM (incidence: 0.8%; 95%CI: 0.02-1.57%). All patients were treated with nivolumab, in first (N = 3) or second line after progression with BRAF + MEK inhibitors (N = 1). No immune-related adverse event greater than grade 2 according to Common Terminology Criteria for Adverse Events version 5.0. was observed in these 4 cases; a vitiligo-like depigmentation (grade 1) was observed in two patients. The median time from the first nivolumab infusion to the SCPM diagnosis was 17.5 months (range: 5-21). All patients developed the SCPM after achieving a complete response. Nivolumab administration had been discontinued (4 months prior) in one patient. Histology revealed 4 superficial spreading melanomas (SSM): one invasive (without BRAFV600 mutation) and 3 intraepidermal melanomas (2 with a BRAFV600E mutation and one with a NRASQ61H mutation). 3 patients had risk factors for developing multiple melanomas: a dysplastic nevus syndrome, a high number of nevi (≥100 nevi), and a family history of melanoma in first-degree relatives and constitutional heterozygous mutation of exon 2 of the CDKN2A gene. Occurrence of SPCM did not alter advanced melanoma treatment. With a median follow-up of 29 months [range: 18-41] from the first anti-PD-1 mAb infusion, all patients had prolonged CR, and treatment was discontinued in all patients, without relapse after a median 11.5 months [0-18] off therapy. The median duration of nivolumab treatment was 15.5 months [10-24]. Conclusions: Although anti-PD-1 mAb could theoretically decrease the risk of developing another melanoma in metastatic melanoma patients, we found 4 such cases, highlighting the importance of regular clinical screenings for new primary melanoma in patients with metastatic melanoma even when responsive to anti-PD-1 therapy. Immune checkpoint inhibitors do not totally prevent the risk of occurrence a SCPM.
A process mining approach to real-world advanced melanoma treatments.
Authors: Gerard Camille Lea , Tavazzi Erica , Gatta Roberto , Delyon Julie , Cuendet Michel A , Michielin Olivier 
Published: May 2020

e22040 Background: Process Mining (PM) is an emerging discipline with promising potential in oncology, which offers a time-oriented perspective on the clinical events that define the patient’s (pts) path of care, from diagnosis to follow-up. PM enables us to 1) build unsupervised models that automatically discover frequent patterns and detect unexpected behaviors, and 2) show the pts flow through predefined models, allowing quantitative assessments of conformance/divergence between reality and expected behaviors or medical guidelines. Methods: We explored the potential of PM to analyze treatments in a real-world melanoma cohort of 212 advanced melanoma pts treated with tyrosine kinase inhibitors (TKI), chemotherapy, or immunotherapy (IO) since 2010. 44% of pts are BRAF mutated, 24% NRAS mutated, and 16% WT. Using PM, we characterize the sequences of treatment according to type of drugs, order and timing of consecutive lines. We use kernel density estimations, Fisher or Wilcoxon tests to assess differences between groups. As main endpoint we assess the overall survival (OS) with respect to specific patterns of care followed by the pts using Kaplan-Meier analysis with log-rank test. Results: This approach provides important self-consistency checks for data and reveals the most frequent treatment sequences, and the associated outcome. The 324 administered treatments, characterized in terms of type and occurrence, are: TKI (23%), antiCTLA4 + antiPD1 (22%), antiPD1 (21%), and antiCTLA4 (20%). The overall 3-year OS is 56.9% (95% CI: 49.2 – 65.8). We identified 50 distinct patterns, which can be further aggregated into relevant cohorts to provide real-world answers to medical questions. Among others, we probed the influence of treatment order: IO single (any BRAF status), IO → TKI, TKI → IO (see table). Preliminary results suggest that pts treated with TKI → IO had shorter OS despite balance prognostic factors to IO → TKI group. IO → TKI provides short-term benefits with 1.5-year OS similar to IO alone, but degraded 3-year OS. Conclusions: The PM approach enables fast and efficient visual inspection of the data, emphasizing treatment sequences over time and allowing stratification at different levels. More population attributes and outcomes will be included to further characterize treatment sequences and provide real-world insights into future personalized care options. [Table: see text]
Circulating tumor DNA (ctDNA) in patients (pts) with metastatic uveal melanoma (UM) treated with protein kinase C inhibitor (PKCi).
Authors: Park John J. , Diefenbach Russell J. , Byrne Natalie , Kefford Richard , Long Georgina V. , Scolyer Richard A. , Gray Elin , Carlino Matteo S. , Rizos Helen 
Published: May 2020

e22054 Background: UM is the most common primary intraocular malignancy. About 50% of pts with UM will develop metastatic disease and currently there is no effective treatment in metastatic UM. Nearly 95% of UM harbour mutually exclusive activating mutations in GNAQ, GNA11, CYSTLR2 and PLCb4. We sought to evaluate ctDNA in metastatic UM pts receiving experimental early phase clinical trial of LXS196, a PKCi, using digital droplet PCR (ddPCR) and targeted ion torrent next generation sequencing (NGS). Methods: 17 pts with metastatic UM were identified from a single institution. Pt characteristics including mutation status, disease volume using sum of product of disease (SPOD), best response and clinical benefit defined as partial response (PR) or stable disease (SD) > 6 months were assessed. Plasma samples at baseline and early on treatment (EOT) (14 – 30 days on treatment) were analysed for ctDNA using mutation specific ddPCR. A custom made NGS panel covering 95% of UM mutations was used on plasma ctDNA samples at baseline and on treatment. The allele frequency (AF) of activating mutations identified using ion torrent NGS analysis were then validated using ddPCR. Results: Using ddPCR, 16/17 pts had a +ve ctDNA at baseline with baseline ctDNA copies correlating with LDH (n = 17, p = < 0.001, Spearman’s rank r = 0.8015) and SPOD (n = 17, p = 0.005, r = 0.6642). 16/17 pts had paired samples at baseline and EOT and only 4/16 pts were undetectable at EOT. These 4 pts were GNA11 Q209L positive, had below median SPOD (median 5986, range 200 – 16782), and low numbers of liver metastases (median 9, range 1 – 49). Of these 4 pts, one had PR and three had SD (two with SD > 6 months) as best response. A further 8 pts had +ve ctDNA at baseline and showed a reduction in EOT (reduction range 46 – 99%). Of these 8 pts, one had PR, four had SD (two with SD > 6 months) and three had progressive disease (PD) as best response. The remaining 4 pts showed increasing ctDNA from baseline to EOT and all had SD/PD. Using ROC analysis, EOT ctDNA predicted clinical benefit to PKCi (AUC 0.84, [95% confidence interval, 0.65-1.0, p = 0.026]). AF of ion torrent NGS correlated significantly with ddPCR AF (n = 30, p = < 0.001, r = 0.968). Ion torrent NGS was able to detect additional mutations implicated in UM prognosis including SF3B1 mutations in 4 pts. Conclusions: Baseline ctDNA correlates with baseline LDH level and disease volume. EOT ctDNA predicted clinical benefit to PKCi. The ctDNA AF derived from ddPCR and NGS was comparable and targeted ion torrent NGS was useful in detecting driver as well as additional mutations in UM.
Open label, phase II study of axitinib, a selective inhibitor of vascular endothelial growth factor receptors, in patients with stage III malignant melanoma.
Authors: Zhuang Eric , Jakowatz James G. , Yamamoto Maki , Fruehauf John P. 
Published: May 2020

e22062 Background: This open-label, phase II study investigated the clinical activity and safety profile of axitinib, a potent and selective second-generation inhibitor of vascular endothelial growth factor receptors (VEGFR) in patients with stage III melanoma. Methods: Eligible patients had histology proven stage III melanoma, at least 1 target lesion as defined by RECIST, and no prior systemic therapy. Primary end point was objective response rate (ORR) according to RECIST v1.1; response was also considered if there was a ≥ 25% reduction in the involved nodal basin specific uptake value (SUV) on PET/CT. Secondary endpoints included duration of response (DOR), progression free survival (PFS), and overall survival (OS). Axitinib 5mg was given orally twice each day; treatment continued until tumor progression, unmanageable toxicity, or if the patient withdrew consent. After two months of therapy, patients then underwent definitive surgical resection of their involved nodal basins; one month after surgery patients would restart axitinib. In the 1st stage, 18 patients were to be enrolled; if there was ≥ 1 response, then the study would proceed to the 2nd stage with enrollment of additional 14 patients. At the end of the study, if there were at least 4 confirmed responses, then axitinib would be recommended for further studies in this patient population. Results: Fifteen patients were screened, and eleven patients were initiated on protocol therapy. Median age was 63 years (range 37-88). Three patients (27%) had BRAF mutations. Objective response rate was 45.5% [95% confidence interval (CI), 16.7-76.6], comprised of one complete and four partial responses, with two patients ongoing. Median duration of response was 8 months (95% CI, 3.5-13.3). Stable disease was observed in one patient, with an overall disease control rate of 54.5% (95% CI, 23.3-83.2]. Median progression free survival was 4 months [95% CI, 2.8-8.5]. Median overall survival was 59 months [95% CI, 29.6-67.5]. The most frequently reported ( > 15%) nonhematologic, treatment-related adverse effects were hypertension, fatigue, and diarrhea. Conclusions: Axitinib showed single-agent activity among patients with stage III melanoma and had favorable effect as a neoadjuvant therapy. Axitinib was well tolerated and safety profiles were consistent with previous reports from previous studies in patients with melanoma. Axitinib alone or combined with other therapies merits further research. Clinical trial information: NCT01321437.
Effectiveness of PD1-inhibitors in advanced Merkel cell carcinoma: Real life data in a Swedish cohort.
Authors: Bjorn-Andtback Hannah , Masucci Giuseppe V. , Villabona Lisa Elena Esther 
Published: May 2020

e22063 Background: Merkel Cell Carcinoma (MCC) is a highly aggressive neuroendocrine skin cancer that affects the elderly. Most cases are associated with the Merkel cell polyomavirus. It has previously been shown in clinical trials that MCC respond to immunotherapy with PD1 and PDL1-inhibition. PD1-inhibitiors have been used to treat MCC at Karolinska University Hospital in Sweden since 2016. The aim of this study is to describe the PD1-MCC-cohort at Karolinska. Methods: Patients with inoperable MCC that were treated with PD1-inhibitor at the oncology dept between August 2016 and February 2020 at Karolinska were included in the study, and response data was assessed retrospectively. Response was assessed clinically and through CT-scans. Results: Among 12 treated pts, median age was 75 yrs, 8 male and 4 female, 10 were treatment naive, 2 with prior chemotherapy. 10 pts received pembrolizumab and 2 pts nivolumab. No pts discontinued treatment due to side-effects. Comorbidities seen in the cohort were amongst others Atrial fibrillation (4 pts), Systemic Lupus Erythematosus (1), Hypertension (6), COPD (1), Aortic stenosis (2) and congestive heart failure (1). Follow-up time was median 10 months (range 2-43). First evaluation varied between 2-4 months with the majority at ~3 months. At first evaluation ORR was 75% and PFS and OS was 75% and 100% respectively. At 10 months, PFS and OS rates were 58% and 67% respectively. At study end mean PFS was 15,4 months and mean OS 17,8 months. 6 pts (50%) were still in response. Conclusions: PD1-inhibitors in clinical use in this cohort induced rapid and durable tumor responses in patients with advanced MCC, and the treatment was well tolerated. Our conclusion is that a PD1-inhibitor is a feasible and effective treatment for advanced Merkel Cell Carcinoma in the clinical setting.
Cutaneous melanoma mutation pathways and driver mutations as racially biased.
Authors: Sanchez Margaret I , Grichnik James Michael 
Published: May 2020

e22066 Background: Cutaneous melanoma (CM) demonstrates differences in its clinical prevalence in different racial groups. CM generally exhibits a high tumor mutational burden (TMB) and mutually exclusive driving mutations in NRAS, BRAF or KIT. TMB may be driven by different pathways including ultraviolet radiation (UVR), oxidation and deamination. UVR is the most common mutational signature found in CMs, but deamination and oxidation are also present. Methods: We analyzed 321 CMs exome data from The Cancer Genome Atlas network. BRAF, NRAS, KIT and those without (WT) were used to divide the melanomas. Germline SNPs with racial information (Caucasian, African and Asian) that were enriched in melanomas with a particular driving mutation were identified. Results: We compared the 3 racial groups across the 4 driving mutation types, Asian SNPs were significantly higher in KIT, African in WT and Caucasian in BRAF and NRAS. The melanomas were also evaluated by the type of substitution mutations including CC > TT for UV, G > T for oxidative damage and (G/A)C (G) > (G/A)T(G) for deamination. UV and deamination appeared inversely proportional, while oxidative damage appeared to be independent. UV signal was more prominent in BRAF and NRAS groups. KIT had a greater percentage of deamination while WT revealed more oxidative damage. We further compared UV and non-UV (CC > TT absence) KIT subgroups for racial differences. Asian SNPs were greatly increased in non-UV subgroup whereas Caucasian SNPs were in UV subgroup. Further, the non-UV KIT subgroup was divided into deamination and oxidative damage subgroups to compare racial differences. Deamination was significantly increased in Asians whereas oxidative damage was higher in Caucasians. In the case of the WT group, African SNPs were significantly higher in the non UV subgroup and were primarily correlated with oxidative damage. Conclusions: This study suggests that racial genetic background may predispose the distinctive mutational and genetic environments of melanoma development.
Efficacy and safety of IO103 a novel anti PD-L1 vaccine in basal cell carcinoma.
Authors: Jørgensen Nicolai Grønne , Kaae Jeanette , Grauslund Jacob Handlos , Met Özcan , Svane Inge Marie , Ehrnrooth Eva , Andersen Mads Hald , Zachariae Claus , Skov Lone 
Published: May 2020

e22070 Background: Basal cell carcinoma (BCC) is the most frequent malignancy. Case reports have described effect of immune checkpoint blocking antibodies (ICB) against PD-1 in BCC (Cannon et al. 2018, Chang et al. 2017, Ikeda et al. 2016, Winkler et al. 2017). Autoimmune side effects of ICB are well known and limits a wider use in BCC. IO103 is a peptide vaccine against major programmed death (PD) ligand 1 (PD-L1). In a first-in-man study of IO103 in patients with multiple myeloma (NCT03042793) regression of co-existing BCC was observed in two patients which prompted the current study. Methods: A single arm phase IIa study of subcutaneous IO103 (q2w six times followed optionally by q4w an additional 3 times) with the adjuvant Montanide for patients with BCC (NCT03714529). Eligible patients had at least one biopsy verified BCC suitable for sequential biopsies, and no severe autoimmune comorbidity. The primary endpoints were categorical clinical responses of target tumors, percent change in largest diameter of target tumor and immune responses to the vaccine. Secondary endpoint was safety. One tumor per patient was designated target tumor, if more than one tumor the remaining were designated non-target tumors. Only target tumors were sequentially biopsied during vaccinations. Results: Ten patients were included at the department of Dermatology, Herlev and Gentofte Hospital, Denmark between November 19th, 2018 and October 21st, 2019. Based on target lesion assessment, one patient achieved partial response. Two additional patients achieved CR in non-target lesions, including one lesion that had recurred after previous surgery. Categorical clinical responses are given in table. Adverse events were max CTCAE Grade 2 and related events were only CTCAE Grade 1 reversible reactions. Vaccine induced immune responses against PD-L1 were detected in blood samples from eight of ten patients and vaccine specific skin-infiltrating lymphocytes from five of eight tested patients. Conclusions: In this exploratory study, one target tumor achieved partial response. Nonetheless, the two clearances and one partial response of non-target tumors suggest that IO103 may be effective against BCCs. The vaccine was well tolerated. Understanding the underlying molecular mechanisms would be needed to select patients for further studies with IO103. Clinical trial information: NCT03714529. [Table: see text]
Prospective observational trial of low-dose skin electron therapy in mycosis fungoides using rotational technique.
Authors: Newman Neil , Kirschner Austin Noah , Patel Chirayu 
Published: May 2020

e22077 Background: Low dose total skin electron therapy (TSET) utilizing 12 Gy in 12 fractions has been shown to provide a durable treatment response for dermal lesions caused by mycosis fungoides secondary to cutaneous T cell lymphoma (CTCL). We sought to prospectively assess the durability of response and quality of life (QOL) for patients receiving low dose TSET using the rotational technique technique. Methods: We prospectively enrolled patients with CTCL on an IRB approved study from 2016 to 2019 who had pathologically confirmed CTCL from stage IB-III. Patients completed a baseline validated Skindex-29 survey encompassing 29 questions assessing QOL. Physicians graded the appearance of the skin using the modified severity-weighted assessment tool (mSWAT) at baseline. Patients received 12 Gy in 12 Fractions on consecutive dates and patients were treated with a dual field rotational technique. The mSWAT was reassessed on ensuing follow-up visits along with the Skindex. The primary outcome was overall response rate with the secondary outcomes being time to treatment response, duration of clinical benefit (time to requiring an additional intervention), as well as improvements in Skindex questionnaire items. Results: We enrolled 20 patients and recorded an overall response rate (ORR) of 90% with four complete responses. The time to treatment response was 9.7 weeks. While the baseline mSWAT was 55.6 it declined to a median mSWAT of 2.2 at last follow-up (p < 0.001) with there being a median decline of nearly 97% in the scores. The median duration of clinical benefit was 15.7 months. There was a precipitous decline in the Skindex total score and every subdomain when comparing each follow-up visit (p = 0.004) with post-hoc analysis demonstrating the decline between the baseline visit and first follow-up as the primary driver of the decline (p < 0.0001). Conclusions: This prospective study demonstrates the subjective and objective clinical benefits of utilizing low dose TSE with a dual beam rotational technique. This control rates and QOL will continue to be observed for ongoing feasibility as a treatment modality.