bluuebunny/crossref_metadata_2025_split huggingface dataset:
The use of PET/CT to detect early recurrence after resection of high-risk stage III melanoma, prior to the start of adjuvant therapy and during follow-up.
Authors: Van Der Hiel Bernies , Stahlie Emma H.A. , Stokkel Marcel P , Wouters Michel W.J.M. , Schrage Yvonne , van Houdt Winan J. , Van Akkooi Alexander Christopher Jonathan 
Published: May 2020

e22039 Background: To date, international consensus concerning the use of PET/CT as a surveillance tool in the follow-up of high-risk melanoma patients after complete resection of disease is lacking. Moreover, with the rise of adjuvant therapy it seems appropriate to investigate the role of this imaging modality to exclude newly developed metastases after resection and prior to starting treatment. The aim of this study was to investigate the use of PET/CT as surveillance tool in the follow-up and prior to adjuvant therapy in asymptomatic patients with complete resection of stage IIIB and IIIC melanoma. Methods: Prospectively two cohorts were set up with stage III melanoma patients with complete resection of disease. In the first cohort (stage IIIB/C AJCC 7th) surveillance PET/CT was performed 6-monthly for two years if patients stayed asymptomatic with normal serum S100B, with a final scan at three years. In the second cohort (stage IIIB/C/D AJCC 8th) patients underwent one screening PET/CT after resection and prior to starting adjuvant treatment. Results: Eighty patients entered follow-up in cohort 1. Of these, the majority did not undergo surveillance scans, because they required treatment for newly detected clinical metastases. Thirty-five patients remained asymptomatic and were included in surveillance cohort one (105 scans) with a median follow-up of 33 months. Twelve patients (34%) developed a recurrence, seven (20%) of which were detected on the first scan at six months. Seven recurrences involved stage IIIC patients, five stage IIIB patients. Sensitivity and specificity were 92% and 100% respectively. Forty-two patients were included in cohort 2. Recurrence was suspected on nine scans, four (10%) of which were true positive. One patient proceeded to undergo a node dissection and then started adjuvant therapy. The other three patients had progressed to stage IV and therefore started radiotherapy and/or systemic immunotherapy. Five (12%) scans were false positive, the suspected lesions were not related to the preceded surgery. The number of scans needed to find one asymptomatic recurrence were 8.8 and 10.5 in cohort one and two, respectively. Conclusions: This study shows that PET/CT is a useful surveillance tool for detecting recurrence in asymptomatic high-risk resected stage III melanoma patients, especially within the first six months after surgery and therefore should be considered when monitoring these patients during follow-up as well as prior to starting adjuvant therapy.
Efficacy of immune checkpoint inhibitors for the treatment of metastatic melanoma (MM) in patients with concurrent chronic lymphocytic leukemia (CLL).
Authors: Guerra Veronica , Ologun Gabriel O. , Haydu Lauren Elaine , Keung Emily Zhi-Yun , Burton Elizabeth M. , Tawbi Hussein Abdul-Hassan , Wierda William G. , Davies Michael A. , Wargo Jennifer Ann , Ferrajoli Alessandra 
Published: May 2020

e22044 Background: Patients with CLL have immune impairment with abnormalities in T-cell subset composition and immune synapse formation. The impact of these defects on response to immune checkpoint inhibitors (CPI) is not known. Given the high incidence of melanoma in patients with CLL we sought to evaluate the response to CPI in patients with concomitant MM and CLL. Methods: Retrospective analysis of 24 patients (pts) with concurrent CLL and MM who received a total of 38 CPI therapies between July 1997 and July 2019. Primary objective was to determine objective response rate (ORR), defined as complete response (CR) or partial response (PR) by RECIST1.1. Secondary outcomes included event-free survival; overall survival (OS), and duration of response (DOR). Results: The median age at CLL and melanoma diagnosis was 62 and 63 years, respectively. 71% of patients were male. Most presented with early stage CLL at diagnosis (67%), 60% had mutated IGVH, and 47% had deletion of 13q by FISH. 71% remained on observation for their CLL. Median time from melanoma diagnosis to CPI initiation was 13.5 months. 83% had stage IV MM and 17% stage III MM at the time of therapy. 17% had increased LDH. The most common melanoma mutations were BRAF(35%), BRAFV600 (26%), TP53 (30%) and NRAS (26%). Median follow up was 37 months and the ORR was 24% (Table). Median DOR was 41 months and median OS is 26.4 months. Immune-mediated adverse events occurred in 42%, including 13% fever, 11% thrombotic events, 8% endocrine dysfunction. 13 pts are alive and 11 pts died (8 pts due to MM progression). There were no significant changes in absolute lymphocyte counts during CPI therapy. 2 pts received CPI while on ibrutinib or ibrutinib+venetoclax therapy with ongoing CLL responses. Conclusions: Our experience indicates that CPIs can be effective for the treatment of MM in patients with concurrent CLL, achieving durable responses. Immuno-mediated toxicities were frequently observed. A lower ORR was observed in first-line CPI in MM, however the numbers of pts are small. Further studies are needed to determine if initial or concurrent treatment for CLL could improve CPI outcomes and survival. Additional studies evaluating T cells function and tissue infiltration in these patients are ongoing. [Table: see text]
Pathway-flux based biomarker for immunotherapy response in melanoma.
Authors: Li Jian , Mei Qi , Cheng Weiting , Hu Guangyuan , Yuan Xianglin , Mansmann Ulrich Robert 
Published: May 2020

e22064 Background: Immune checkpoint therapy (ICT) refers to therapeutic interventions that specifically target immune evasion mechanisms to restore the host immunity with anti-tumor ability. The ICT has revolutionized the immune-based treatment across > 30 different cancers including solid tumors and hematopoietic malignancies, with an ORR of 30% and a 7%-12% grades 3-5 irAEs in average. However, a substantial unmet point is the development of a biomarker with which response of ICT can be predicted before treatment for individual patients. Methods: In order to face this challenge this study developed an advanced genome-scale pathway flux analysis (GPFA) to evaluate the strength of signaling transduction and metabolic flux in immune system. The input of GPFA is the gene expression profiles of individual objects and the output of GPFA can be summarized in a index system, IM.Index, with following definition: IM.Index = 1.78E-4 * Σ flux(P) + 2.37E-4 * Σ flux(P) p ∈ signaling transduction p ∈ energy metabolism. Subsequently, the IM.Index was applied to analyze genetic data of two independent cohorts of melanoma patients treated with anti-PD-1 therapy (nivolumab a. pembrolizumab). Results: The IM.Index predicted the response of anti-PD-1 therapy (nivolumab) in the first cohort with an odds ratio (OR) of 3.14 (95%CI: 1.16-8.45; p = 3.10E-3; AUC = 0.82) and with a sensitivity 89% and specificity 76%. The prediction on overall survival (OS) of this cohort achieved an hazard ratio (HR) of 1.53 (95%CI: 1.22-1.92; p = 7.8E-3). Subsequently, the prediction result for the anti-PD-1 therapy (pembrolizumab) in the second cohort achieved an OR of 2.12 (95%CI: 1.22-3.66; p = 4.50E-4; AUC = 0.87) and the OS prediction in this cohort reached an HR of 1.24 (95%CI: 1.04-1.47; p = 1.40E-2). Comparison with other four potential biomarkers (TMB, TNB, neo-peptide load and cytolytic score) related to immunotherapy showed a comparative outcome of the IM.Index regarding diagnosis and prognosis in melanoma. For instance, IM.Index showed a superior performance on objective response rate (ORR) of 70% and AUC of 0.83. Conclusions: In conclusion this study demonstrated that a pathway flux analysis at a genome-scale may be explorative in biomarker research in immunotherapy, since this type of analysis could reflect the strength or functional status of the immune system. The IM.Index developed in this study may also be applied to investigation the treatment response of immunotherapy in other types of cancer.
Treatment of locally advanced or multiple basal cell carcinoma with vismodegib in real world setting.
Authors: Ocvirk Janja , Mesti Tanja , Leskovsek Katja 
Published: May 2020

e22065 Background: Evaluation of efficacy and safety of vismodegib (V) was done in a retrospective analysis of patients (pts) with locally advanced or multiple basal cell carcinoma (laBCC or multiple BCC) and pts with Goltz-Gorlin Syndrom (G-G Syn) in routine clinical practice. Methods: Baseline characteristics, efficacy data and treatment-related adverse events were collected from 30 laBCC or multiple BCC and 6 G-G Syn pts who were treated with V. Results: In 86-month period, 36 pts were diagnosed with laBCC (18 pts), multiple BCC (12 pts) or G-G Syn (6 pts), all inappropriate for surgery or radiotherapy. Baseline characteristics: median age was 72.6 years in laBCC + multiple BCC pts group and 51.3 years in G-G Syn pts group. Sixty percent of pts in laBCC + multiple BCC group were females; majority (70%) of pts were previously treated by surgery (S) and/or radiotherapy (RT); 43% of pts had 1 lesion with predominant localization in central face (eyes, nose, lips or ears in 84% of pts), 20% had 2-3 lesions and 37% more than 3 lesions. Fifty percent of pts in G-G Syn pts group were males; all pts were previously treated with S and/or RT. The overall response rate (ORR) was 76% in laBCC + multiple BCC and 83% in G-G Syn pts group. Disease control rate (DCR) was 93% in laBCC + multiple BCC and 100% in G-G Syn pts group. Median duration of treatment (DoT) was 7.8 months (range: 1.3-29.8) in laBCC + multiple BCC group and 27.1 months (range: 4.8-86.4) in G-G Syn group. At the time of analysis in laBCC or multiple BCC group one patient died due to other reasons than cancer, in 30% of pts treatment has been interrupted during the treatment course [in most cases due to complete response or adverse events (AEs)], 40% of pts are still on treatment. In G-G Syn group treatment has been interrupted in 50% of pts (in most cases due to adverse events), 67% of pts are still on treatment. AEs of any grade were reported in 97% of pts in laBCC or multiple BCC group and 83% in G-G Syn group. Majority of AEs in laBCC or multiple BCC group were grade 1 or 2 (96%)., 4% of AEs were grade 3: muscle cramps in 3 pts, respiratory infection, vomiting and anemia in 1 patient each. Majority of AEs in G-G Syn group were also grade 1 or 2 (87%), 13% of AEs were grade 3: muscle cramps in 2 pts, weight loss and diarrhea in 1 patient each. No grade 4 or 5 AEs were reported. Conclusions: Vismodegib has shown meaningful efficacy with manageable safety profile in pts with laBCC or multiple BCC as well as in pts with G-G Syn in real world setting.
Genomic landscape of malignant peripheral nerve sheath tumor (MPNST)-like melanoma.
Authors: Pimentel Muniz Thiago , Sorotsky Hadas , Kanjanapan Yada , Rose April A. N. , Araujo Daniel Vilarim , Fortuna Alexander , Ghazarian Danny K. , Saeed Kamil Zaid , Pugh Trevor John , Mah Michelle , Thiagarajah Madhuran , Spreafico Anna , Hogg David 
Published: May 2020

e22072 Background: Malignant Peripheral Nerve Sheath Tumor (MPNST)-like melanoma is a rare entity wherein cutaneous melanoma mimics histomorphological features of MPNST. The genomic landscape of MPNST-like melanoma has not been previously described. We report the genomic findings of 6 patients diagnosed with MPNST-like melanoma. Methods: We identified consecutive patients with confirmed histological diagnosis of MPNST-like melanoma. Archival tissue was submitted for whole exome and transcriptome sequencing analysis and genomic findings were compared to publicly available data on the genomic landscape of both melanoma and limited genetic descriptions of MPNST. Results: Six patients diagnosed with MPNST-like melanoma between November 2002 and July 2018 had archival tissue available (8 samples). Mean age at diagnosis was 60.5 years (38-74). The mean tumor mutational burden (TMB) was 35.72 mutations/exon coding megabase, ranging from 4.27 to 86.36. NF1 alterations were found in 4 (67%) of cases: one had 3 truncating mutations (W696 + X1870_splice + R1590C) associated with NF1 amplification, one had a deep deletion and another two had truncating mutations (I1908L and W696 + A1530V). Two tumors had non-V600 BRAF mutations that predict alteration in kinase function. We observed deletions of cell cycle regulators: CDKN2A and CDKN2B in 33%; and ZNF331 (19q13.42) in 83% of cases. SERPINB4 (18q21.3), described previously as a tumor suppressor in oral squamous cell carcinomas, was deleted in all samples. The patient with NF1 amplification and truncating mutations received immunotherapy due to metastatic disease and achieved a complete response; his tumor had a TMB of 72.6. Another patient who died of metastatic melanoma, treated with chemotherapy in the pre-immunotherapy era, lacked any NF1 mutation but had a Q61K NRAS mutation; the tumor had a TMB of 15. The remaining patients were treated with surgical resection alone and continue on follow-up. Conclusions: MPNST-like melanoma shares some frequently altered genes in cutaneous melanoma but possesses an excess of NF-1 mutations or deletions, in keeping with its neural-like phenotype. The high frequency of SERPINB4 alterations suggests a critical tumor suppressor role in this subtype of melanoma, warranting further investigation. Additionally, cell cycle dysregulation caused by deletion of ZNF331 and CDKN2A/B may be important in MPNST-like melanoma carcinogenesis.
Exosomal microRNA in serum is a prognostic factor in cutaneous squamous cell carcinoma.
Authors: Choi Jonggwon 
Published: May 2020

e22073 Background: Functional microRNA(miRNAs) is located in the area of the gene related to cancer, such as inside of oncogenes and tumor suppressor genes, loss of heterozygocity or fragile site. There are many studies show that abnormal increase expression of miRNAs when cancer occurs. While some miRNAs commonly suppress abnormal expression of tumors, they can also infer the orgin of tumor tissues because they are more often representative of unique miRNA depending on type of tumor. In many case, the miRNAs expression patterns provide more characteristic information about tumors than messenger RNA expression profinling. The miRNAs expression patterns, which have changed with tumor types, provide clue that can serve as a biological markers for diagnosis, determining the outcome of disease, and predicting treatment responses. Indeed, several studies have reported thatextracellular miRNA is related to the prognosis of disease in some cancers, such as colon cancer and breast cancer. However, so far, there is no study that has been no defenitive study on how exosomal miRNAsare related to progrosis in cutaneous squamous cell carcinoma. We studied the association between the patient’s prognosis and miRNAs detected in cancer tissue and blood serum. Methods: We analyzed 35 patients who have various stage of cutaneous squamous cell carcinoma. Cancer tissue and serum samples were sequentially obtained. The miRNAs were prified from serum exosome and cancer tissues, and miRNAs sequencing was performed. The miRNAs expression profiles and copy number variations were observed using next generation sequencing (Hiseq, illumina inc) in 35 cancer tissues and serum samples. We validated miRNAs change and patient’s prognosis. Results: miR-142-5p cluster expression level in serum exosome and cancer tissue was most correlated with poor prognosis of cutaneous squamous cell carcinoma. Exosomal miR-142-5p expression level in serum were significantly higher(P < 0.01) in patients with late stage than in patients with early stage. Also, the patients with recurrence showed high level of miR-142-5p. Conclusions: miR-142-5p expression level may be an important marker for predicting the patient’s prognosis and deciding whether undergo additional systemic chemotherapy after surgery.
Inhibitory effect of PAI-I in perifocal and resection line tissues on tumor growth in women with melanoma.
Authors: Rozenko Ludmila Ya. , Frantsiyants Elena M. , Bandovkina Valeria A. , Cheryarina Natalia D. , Pozdnyakova Viktoria V. , Ilchenko Maria G. , Agarkova Elena I. , Maksimova Natalia A. , Kit Oleg I. , Przhedetskiy Yuriy V. 
Published: May 2020

e22083 Background: The ability of malignant tumors to invasion and metastasis is associated with increased activity of the plasmin/plasminogen family proteases. The purpose of the study was to analyze changes in the plasmin/plasminogen system in tumors and adjacent tissues in patients with cutaneous melanoma in dependence on their gender. Methods: The study included 13 men and 22 women with cutaneous melanoma pT1-2N0M0. Levels of plasmin (PAP), content and activity of uPA, content and activity of tPA, content and activity of PAI were determined by ELISA in homogenates of melanoma (M), perifocal (P) and resection line (RL) tissues after surgical treatment. All patients gave a voluntary informed consent for the study. Skin tissues obtained from 20 non-cancer patients after plastic surgery served as the control. Results: The maximal PAP content in women was found in M – 16.5 times higher than in control, in RL – twice higher; PAP in all tissues of men was on average 7 times higher than in control. The content and activity of uPA and tPA in M were elevated in patients of both genders: in women by more than 3 times, in men by 4.9 and 3.7 times for uPA, respectively, and on average by 1.4 times for tPA. Increased content and activity of PAI-I were observed only in M of women by 74.6 and 2.3 times respectively, while PAI-I levels in men were similar to control values, and its activity was 2.9 times higher. Content and activity of PAI in P and RL tissues of men did not exceed the norm despite an increased activity of uPA and tPA, while in women they were elevated on average by 4 and 1.8 times, respectively. Conclusions: A local increase in the content and activity of the PAI-I plasminogen activator inhibitor in P and RL tissues only in women is a distinctive gender characteristics that can inhibit the spread of melanoma.
Effect of chronic neurogenic pain on blood levels of hormones in patients with melanoma depending on their gender.
Authors: Pozdnyakova Viktoria V. , Frantsiyants Elena M. , Bandovkina Valeria A. , Rozenko Ludmila Ya. , Ilchenko Maria G. , Agarkova Elena I. , Zakharova Natalia A. , Khokhlova Olga V. , Przhedetskiy Yuriy V. , Przhedetskaya Viktoria Yu. , Kit Oleg I. 
Published: May 2020

e22097 Background: Chronic neurogenic pain (CNP) as a comorbid disease is quite frequent, but its effect on malignant diseases is poorly studied. The risk of cutaneous melanoma in women is higher, but the disease course in men is more severe. The purpose of the study was to reveal the effect of CNP on the levels of sex hormones in the blood of patients with melanoma depending on their gender. Methods: Blood levels of estradiol (E2), estrone (E1), progesterone (P4), testosterone (T) and prolactin (PRL) were measured by ELISA in patients with Т3-4NxM0 melanoma (M): 21 women with CNP (pelvic pain - 7, osteochondrosis – 14), mean age 67.2±2.7 years; 17 men with CNP (osteochondrosis), mean age 65.6±3.1 years. The control group included patients with melanoma similar in age, gender and disease stages without CNP. Results: In women with M+CNP, E2 and P4 were decreased by 1.8 times, while E1 was 1.4 times, T – 2 times, PRL – 1.5 times higher, compared to controls. In men with M+CNP, blood levels of estrogens were unchanged, PRL was 2.5 times lower and P4 and T – 1.3 times higher, compared to the corresponding control levels. Conclusions: CNP upregulated blood levels of androgens in both male and female melanoma patients, and caused the inversion of estrogens only in women with the prevalence of E1 over E2. Gender differences in the CNP influence included the elevation of progesterone and a decrease of prolactin in the blood of men, and P4 deficiency with increased prolactin in women with M+CNP. The specific effect of CNP on the hormonal profile in patients with cutaneous melanoma should be considered in choosing antitumor treatment.
MAP2K1/2 and MAP3K14 as a prognostic biomarker on immunotherapy and correlated with immune infiltrates in melanoma.
Authors: Chen Jing , Ye Ting , Xie Wenzhuan , Huang Mengli , Yang Mengmei 
Published: May 2020

e22104 Background: Mitogen-activated protein kinase kinase (also known as MAP2K, MEK, MAPKK) and MAP3K are two subgroup of Mitogen-activated protein kinase cascade. MAP2K1/2 and MAP3K14 are members of two subgroup, respectively. Previous study revealed that MAP2K1/2 and MAP3K14 may be a promising therapeutic target for melanoma. However, the association between MAP2K1/2 and MAP3K14 mutant and melanoma remains elusive. In this study, we aimed to elucidate the efficacy of immunotherapy of MAP2K1/2 and MAP3K14 mutant for melanoma by integrated bioinformatics analysis. Methods: Whole-exome sequencing data for a cohort of 110 patients with metastatic melanoma from whom pre-treatment tumor biopsies were download from cBioPortal. Associations between MAP2K1/2 and MAP3K14 mutations and prognosis and TMB are analyzed, and tumor-infiltrating level (TIL) of 18 T-cell subtypes and 6 other immune cells were used to investigate the underlying mechanism. Results: Results showed that MAP2K1/2 and MAP3K14 mutations were associated with an increased progression-free survival (PFS; HR, 0.42; 95% CI, 0.18-0.96; P = 0.0342) and a superior overall survival (OS; HR, 0.28; 95% CI, 0.09-0.90; P = 0.0227) in melanoma with significance at borderline level. TMB levels in melanoma patients with MAP2K1/2 and MAP3K14 mutations were higher than in wild-type patients (P = 0.007). Moreover, TIL revealed distinct immune cells features in the different groups, where immune cells related to infiltrating levels of Neutrophil cells and natural arising regulatory T (nTreg) cells were more prominently enriched in the mutation group while the wide-type group had higher enrichment of Mucosal associated invariant T (MAIT) cells and T helper 2 (Th2) cells. Conclusions: MAP2K1/2 and MAP3K14 mutations may be a potential predictor for better prognosis in melanoma on immunotherapy. Identification of MAP2K1/2 and MAP3K14 mutations by genomic profiling provides a potentially novel and convenient approach for these patients to predict the prognosis, and refines patient’s management in clinical practice.