bluuebunny/crossref_metadata_2025_split huggingface dataset:
Validation of the 31-gene expression profile test to stratify melanoma-specific survival in an unselected, prospectively tested cohort of patients with stage IIB-III cutaneous melanoma.
Authors: Hong Young , Kurley Sarah J. , Bailey Christine N. , Martin Brian , Goldberg Matthew S. , Petkov Valentina I. , Covington Kyle R. , Zakharia Yousef 
Published: June 2022

e21538 Background: Given recent FDA extended approval of Pembrolizumab for stage IIB-IIC cutaneous melanoma (CM) patients, it is critical to risk-stratify patients to balance potential benefits versus toxicities of adjuvant therapy. The 31-gene expression profile (31-GEP) is a validated test for CM for risk of recurrence or metastasis prognosis in patients with stage I-III CM. A low-risk (Class 1A) 31-GEP result is associated with lower recurrence risk and higher melanoma-specific survival than an intermediate (Class 1B/2A) or high-risk (Class 2B) result. To validate the 31-GEP’s ability to stratify patients’ risk in an unselected, prospectively tested cohort of therapy-eligible CM patients, we collaborated with the National Cancer Institute and the Surveillance, Epidemiology, and End Results (SEER) program. Methods: A linkage was conducted between SEER registries’ CM cases diagnosed 2012-2018, and 31-GEP tested patients between 2013-2020. A de-identified dataset was used for the analysis. Kaplan-Meier analysis with log-rank test was used to analyze patient melanoma-specific survival (MSS) in the overall cohort and the subset of patients with potential adjuvant therapy access: stage IIB-III melanoma (n = 615). Results: In the overall cohort of patients (N = 5,225), those with a 31-GEP Class 1A result had higher 3-year MSS than patients with a Class 2B result (99.7% vs. 90.4%, p < 0.001). In multivariable Cox regression analysis, a Class 2B result was an independent significant predictor of MSS (HR = 5.71, p = 0.01), as were age (HR = 1.05, p < 0.001), SLN positivity (HR = 2.42, p = 0.02), and T2b (HR = 8.29, p = 0.025) and T4b (HR = 11.99, p = 0.009) tumors. In the subset of patients with stage IIB-III melanoma, those with a 31-GEP Class 1A result had higher 3-year MSS (98.8% vs. 82.4%, p = 0.02) than patients with a Class 2B result. Patients with a Class 2B result had a five and a half times higher event rate than those with a Class 1A result for MSS (5.5% [21/382] vs. 1.0% [1/105]). Conclusions: In a large, unselected, prospectively tested cohort of patients with stage I-III CM, the 31-GEP stratified patient risk of dying from melanoma, validating previous studies. While the 31-GEP identified a subgroup (Class 1A) of traditionally high-risk patients (stage IIB-III CM) who had a > 98% MSS over three years, it can also facilitate identifying patients who could warrant earlier adjuvant therapy with a higher 31-GEP class designation.
Cemiplimab in advanced cutaneous squamous cell carcinoma: A real-world experience of outcomes and safety.
Authors: Badami Sunil , Mazloom Anita , Howard John Harrison , Liles J. Spencer , Alkharabsheh Omar , Persing Brian Edward , Cameron Daniel , Huddleston Adam , Gilbert Robert , Venkatesh Kshithi , Prodduturvar Pranitha 
Published: June 2022

e21545 Background: Nearly 1.5 million cases of cutaneous squamous cell cancer (cSCC) are diagnosed annually in the United States. Approximately 1% of cases are in the advanced unresectable stage. The standard of care in unresectable advanced disease is immunotherapy with anti-PD-1 agents. Cemiplimab, an anti-PD-1 antibody, was approved by the Food and Drug Administration in 2018. We present real-world clinical data from a single institution on outcomes and safety for patients treated with cemiplimab for metastatic and unresectable cSCC. Methods: We conducted a retrospective cohort analysis of patients treated with cemiplimab (350 mg every 3 weeks) for advanced cSCC from September 2018 until December 2021. Data included patient demographics, tumor characteristics, and treatment course. Patients who received at least 1 dose of cemiplimab and one clinic follow-up were included for analysis. Clinical response and adverse events (AE) were evaluated. Results: Of the 26 patients treated, 84% were male (n = 22), and 16% were female (n = 4) with a median age of 74 years (39-94). Twenty-three (23) patients were included in the final analysis as 3 patients transferred care to an outside facility and were not available for follow-up. Nineteen (19) patients (73%) had locally advanced disease and 7 (27%) had metastatic disease. The most common site of the primary tumor was head/neck (85%, n = 22) with all remaining cases on the trunk/extremities (15%, n = 4). Patients received a median of 7 doses of cemiplimab (range 1- 46). The median time to first response was 1.7 months which required a median of 2.5 doses. An objective clinical response defined as complete response (CR) or partial response (PR) was seen in 18/23 (78%) patients, of whom 8/23(35%) were CR and 10/23 (44%) PR. The ongoing response was noted in 6/23 (27%) with continued treatment. Treatment was well-tolerated with 6/23 (26%) adverse events (AE) all of which were grade 1 or 2: 1 (4%) grade 1 pruritus, 5 (21.7%) grade 2. Of the 5 grade 2 AEs, 1 was infusion-related, 2 hypothyroidism, 1 dermatitis, 1 rheumatoid arthritis flare. No grade 3-5 AEs were noted. Conclusions: To the best of our knowledge, this is the first real-world outcomes study of advanced cSCC patients treated with cemiplimab in the United States. The overall efficacy, response rate, and safety profile were better in comparison to the results of the EMPOWER-CSCC-1 trial.[Table: see text]
Long-term toxicities with immune checkpoint inhibitor (ICI) in melanoma patients.
Authors: Tong Justin , Kartolo B. Adi , Yeung Cynthia , Hopman Wilma M. , Baetz Tara D. 
Published: June 2022

e21549 Background: The incorporation of ICI into the treatment of melanoma has greatly improved patient outcomes, but this benefit has come at the cost of exposing patients to immune-related adverse events (irAEs). A wide spectrum of irAE types has been described, and severity is known to vary from minor to life-threatening; however, the literature to date on the chronicity of irAEs is limited. Objectives: To characterize the long-term and permanent irAEs associated with ICI treatment in patients with melanoma, the treatment of irAEs and the association with survival outcomes. Methods: We performed a retrospective chart review of 161 adult patients with melanoma treated with at least one cycle of ICI regimen in the adjuvant or metastatic setting: 129 patients received PD-1 inhibitor monotherapy and 32 received dual immunotherapy. Patients were grouped by duration of irAE: permanent (no complete resolution), long-term (resolution over a period ≥6 months), transient (resolution over a period < 6 months), or no irAEs. Overall survival was evaluated for those patients that were treated in the metastatic setting with PD1 inhibitor monotherapy. Results: Thirty-eight patients were treated in the adjuvant setting and 123 patients were treated in the metastatic setting. A total of 279 irAEs were reported in the whole patient population. Sixty-six (41.0%) patients developed permanent irAEs, 15 (9.3%) experienced long-term irAEs as their longest-lasting toxicity, 34 (21.1%) developed transient irAEs only, and 46 (28.6%) experienced no irAEs. Permanent irAEs occurred in 21 (65.6%) patients treated with dual immunotherapy and in 45 (34.9%) patients treated with monotherapy. The majority of permanent irAEs were endocrine-related (35.5%) or skin-related (32.7%). Grade ≥3 permanent irAEs occurred in 20 (12.4%) patients and included toxicities such as adrenal insufficiency, myocarditis, and myelitis. Fifty-three (32.9%) patients were still on treatment for long-term or permanent irAEs 6 months or more following completion of ICI therapy, including 23 patients on thyroid replacement and 22 on oral steroids. ICI treatment was temporarily interrupted for 63 (22.6%) irAEs and permanently discontinued due to irAE in 38 (13.6%) patients. Subgroup analysis of patients who received single-agent ICI in the first-line palliative setting reveals that those with longer-duration irAEs had a significantly longer median overall survival. Conclusions: Despite the significant benefits, treatment with ICIs in melanoma is associated with a wide range of toxicities that can be permanent and may have long-lasting impacts on patients. The risk of long-term toxicity should therefore be discussed when obtaining consent for treatment. As these treatments are being used more commonly in the adjuvant setting, the impact of survivorship and the long-term management of these toxicities is increasingly important.
Melanoma: Morphological essays of energetic tumor death under the influence of live mitochondria.
Authors: Shikhlyarova Alla I. , Frantsiyants Elena M. , Kaplieva Irina V. , Neskubina Irina V. , Cheryarina Natalia D. , Trepitaki Lidia K. , Surikova Ekaterina I. , Bandovkina Valeria A. , Przhedetskiy Yuriy V. , Pozdnyakova Viktoria V. , Przhedetskaya Viktoria Yu , Zakharova Natalia A. , Khokhlova Olga , Kit Oleg I. 
Published: June 2022

e21561 Background: Global trials form a new mitochondrial paradigm for suppressing the growth of malignant tumors. The unique role of mitochondria (MC) in the processes of metabolism, proliferation, and cell death was proven by the establishment of signaling pathways and critical conditions for the self-organization and degradation of MC. There are still many unsolved problems in the development of a new strategy, including the absence of an integral picture of morphological changes in the tumor under the influence of mitochondrial therapy (MCT), and this determined the purpose of the study. Methods: The study included male and female Balb/c Nude mice weighing 21-22 g. B16/F10 melanoma was transplanted to mice subcutaneously, and suspension of live liver MC was injected intraperitoneally. MC were isolated by differential centrifugation (Avanti J-E high-speed centrifuge, BECKMAN COULTER, USA). After an MCT cycle, the melanoma structure was examined with hematoxylin and eosin staining and light microscopy (LEICA DM LS2). Results: Control samples of melanoma (without MCT) showed abundant vascularization with dense growth of epithelial-like cells with branched cytoplasm, an eccentric nucleus and a moderate content of melanin pigment. Massive hypoxic death, autolysis and autoxidation of tumor cells were registered in male mice after MCT, as well as matrix hyalinosis, pronounced subcutaneous tissue edema with segregation and necrotization of fat accumulations. The formation of a large cavity filled with detritus indicated signs of total tumor necrosis and ischemia. The accumulation of hyperchromic granules indicated the activation of granulocytic and phagocytic elements in the mechanism of tumor regression. Female mice showed rare small areas of necrosis, as well as pronounced fragmentation of nuclei and cytoplasm of cells in most fields of view induced by bioenergetic hypoxia, with the formation of apoptotic bodies. Along the edge of the cells subjected to autophagocytosis, melanin accumulated as it left the cells and accumulated as large granules, while small ones filled the space of the vessels. The process of melanoma regression was confirmed by a significant increase in free fibrous areas, where only faint cell shadows remained. Conclusions: The initial state of melanoma degrades under the influence of MCT inducing bioenergetic hypoxia in male and female Balb/c Nude mice in different ways. Gender, in fact, hormonal differences determine the dominance of different ways of cell death, necrosis (in males) and apoptosis (in females), while maintaining the MCT access to the processes of preventing tumor growth.
Mitochondrial therapy can inhibit melanoma development.
Authors: Frantsiyants Elena M. , Neskubina Irina V. , Shikhlyarova Alla I. , Cheryarina Natalia D. , Surikova Ekaterina I. , Bandovkina Valeria A. , Nemashkalova Ludmila A. , Kaplieva Irina V. , Trepitaki Lidia K. , Kachesova Polina S. , Kuchkina Ludmila P. , Volkova Viktoriya L. , Engibaryan Marina A. , Ulianova Yulia V. , Kit Oleg I. 
Published: June 2022

e21571 Background: Mitochondria of tumor cells undergo adaptive changes for even more active reproduction of tumor cells in the acidic and hypoxic microenvironment of tumor tissue. The purpose of this study was to evaluate antitumor effect of mitochondrial therapy in BALB/c Nude mice of both genders with B16/F10 melanoma growth. Methods: Male (n = 10) and female (n = 10) BALB/c Nude mice were injected subcutaneously with 0.5 ml of a suspension of B16/F10 mouse melanoma tumor cells in saline at a dilution of 1:20. Mitochondria (MC) were isolated from rat liver. 24 hours after subcutaneous transplantation of B16/F10 melanoma, mice were intraperitoneally injected with freshly isolated mitochondria (3.3 mg of protein per animal in 0.3 ml of saline). Further, mitochondrial therapy (MC therapy) was carried out according to the scheme on days 3, 5, 9, 13, 16, 19, 21. Male BALB/c Nude mice with subcutaneous inoculation of B16/F10 melanoma receiving intraperitoneal injections with 0.3 ml of saline served as controls. Results: Subcutaneous tumors in mice of both genders could be determined on the 5th day from the moment of tumor transplantation. In males, the regressive effect of MC therapy was recorded from the 8th day of tumor growth. The average tumor volume in males with MC therapy on day 8 was 3.0 times less than in the control group. On days 12 and 15, the regressive difference in tumor volumes between the groups was 1.8 times (p < 0.05) (MC therapy). On day 19, a slower tumor growth was recorded in the group with MC therapy, where the tumor volume was 2 times lower compared to the control volumes. At the end of the experiment on day 22, the difference in the average tumor volumes was 3.2 times, i.e. a significant inhibition of tumor growth was determined in males treated with MC therapy. A sizeable tumor node in females treated with MC therapy formed longer than in males, remaining as a flat tumor spot for up to 8 days. The inhibition of the growth of a large tumor node was determined on day 12 of melanoma growth, and the difference with the control values was 1.8 times (p < 0.05). On day 15, the tumor volumes in females with MC therapy decreased by 2.2 times compared with the control values, on day 19 - by 2.1 times. As a result, by the end of the experiment (day 22), the difference with the control group was 2.7 times. Conclusions: MC therapy inhibits the growth of B16/F10 melanoma in male and female BALB/c Nude mice. Formation of a sizeable tumor node and the start the tumor growth inhibition differs in time depending on the gender of experimental animals.
Evaluation of treatment patterns in patients with BRAF-mutant cutaneous melanoma in adjuvant setting in real practice.
Authors: Samoylenko Igor , Stroganova Anna , Shakhray Ekaterina , Orlova Kristina V. , Akhmetianova Angelina , Demidov Lev V. 
Published: June 2022

e21573 Background: Mutation in BRAF is a crucial biomarker for treatment choice in patient with locally advanced or metastatic melanoma. In patient with BRAF wild-type (WT) melanoma aPD1 is the preferred treatment regimen. In patients with BRAF V600 mutant melanoma combined targeted therapy (cTT) could also be chosen as adjuvant treatment, which significantly improves OS. Methods: We conducted a retrospective continuous study of all melanoma patients, who were tested for BRAF mutation by RT-PCR in 2020 (COIVD-19 pandemic year) in our institution and analyzed adjuvant therapy options they received. Patient demographics, mutational status, disease stage, treatment regimens and treatment outcomes were collected from electronic medical records. Results: Between January 2020 and December 2020, tumor samples from 297 pts were tested for BRAF mutations. The mean pts age was 58.2 years (95% CI 51.2 to 60.3) and 130 (43.7%) were male. BRAF mutations were detected in 147 (49.5%) patients. Most common mutation was V600E (140 out of 147 samples, 88.4%) and V600K (13 out of 147, 8.84%). We also found K601N, K601E, L597R and V600M mutations (in one sample each). Among 150 BRAF wild type samples 44 were also tested for NRAS mutations and in 13 (29.54%) pts NRAS mutations were detected: Q61R – in 6 (46.15%) pts, Q61L – in 2 (15.38%) pts, Q61K – in 3 (23.08%) pts, G12E – in 1 (7.69%) pt, and G12D - in 1 (7.69%) pt . Also among 150 BRAF wild type samples 56 were tested for KIT mutations and only one sample were found to harbour D186V mutation . Among BRAF-positive pts at time of the genetic test performed stage I CM had 11 (7.48%) out of 147 pts, stage II - 13 (8.84%) pts, stage III - 67 (45.57%) pts, and stage IV - 43 (29.25%) pts. In 13 (8.84%) pts stage could not be clearly identified. In most cases (32 out of 67, 47.76%) monotherapy with aPD1 was given as adjuvant treatment in stage III pts where as only 6 (8.95%) patients received cTT, 7 pts (10.41%) received IFN-alfa and 22 pts (32.84%) received no or were given with other treatment (Table). Median DFS did not differ significantly between treatment cohorts. Conclusions: In our retrospective study we found that among stage III BRAF-mutant patients monotherapy with aPD1 was the most common adjuvant treatment regimen. In some patients with stage III disease IFN-alfa is still given. More studies are needed to define best adjuvant treatment for BRAF mutant stage III melanoma pts.[Table: see text]
A single arm phase 2 study of talimogene laherparepvec in patients with low-risk invasive cutaneous squamous cell cancer. interim analysis.
Authors: Curiel Clara N , Stratton Delaney , Cui Haiyan , Roe Denise , Arif Tiwari Hina , Sundararajan Srinath 
Published: June 2022

e21583 Background: A compromised immune-surveillance plays an important role in the pathogenesis of cutaneous squamous cell carcinoma (cSCC). Talimogene laherparepvec (TVEC) is an HSV-1 oncolytic immunological agent FDA approved for the local treatment of unresectable recurrent melanoma. It is proposed that T-VEC directly destroys cancer cells, and induces production of GM-CSF to enhance systemic antitumor immune recognition. This proposed mechanism of action supports the innovative approach to implement TVEC in the management of cSCC. Methods: Immunocompetent patients > 18 years of age and diagnosed with at least one > 0.5 cm to < 5.0 cm, primary and histologically confirmed well-moderate differentiated cSCC, without evidence of perineural or vascular invasion were eligible to participate. Unresectable lesions or patients unable/unwilling to undergo standard of care treatment were eligible to participate. Study lesions include target injected lesions (TILs) and target non-injected lesions (TNILs). A total of up to 5 TILs were selected per subject. If feasible, target non-injected lesions (TNILs) were also selected in eligible participants to evaluate for abscopal effect. Every TIL was injected up to 4 times based lesion diameter according to current TVEC approved protocol administration and followed for 1yr after the 1st injection. The primary endpoint of the study was to evaluate the overall response rate (ORR), defined as the proportion of subjects who achieved complete response (CR) and partial response (PR) in the TILs. Safety and adverse effect profile (AEs), duration of ORR, time to response (TTR), durable response rate, and time to progression, were the secondary endpoints included. A Simon 2 stage design was used. Total sample size was calculated to be 20 subjects. Seven subjects were recruited for stage 1 with a plan to recruit an additional 13 patients if five or more subjects met the primary endpoint in stage 1. Results: The interim analysis was conducted after the 7th participant completed Visit 8 (352-266 days from study initiation). For the primary endpoint, all 7 participants achieved an overall complete response (100%; 95% CI: 59.0-100%). NCI CTCAE (v. 4.0) was used to assess the safety and adverse effect profile. All AEs ranged from grades 1-2, and most commonly experienced transient fatigue (n = 3/7), flu like symptoms (n = 2/7) and headaches (n = 2/7). The mean time to response was 43.4 (SD 31.6) days and for duration of ORR 190.0 days (SD 39.3) at the time of analysis. The 2 TNILs evaluated in the interim analysis also demonstrated 100% CR (95% CI: 15.8-100%). Conclusions: TVEC showed extremely impressive ORR for patients with cSCC with a 100% CR in stage 1 of our pilot study. AE profile of TVEC was mild and was well tolerated. Completion of the study will further assess this high response rate. Clinical trial information: 03714828.
Age associated mutations in cutaneous squamous cell carcinomas (CSCC).
Authors: Kumar Priyanka , Brazel Danielle , Doan Hung , Moyers Justin Tyler 
Published: June 2022

e21592 Background: Cutaneous squamous cell carcinoma is the second most common skin cancer globally. However, advanced or metastatic disease is rare and is primarily a disease of the elderly or immunocompromised. The relationship between age and the presence and frequency of poor prognostic indicators (TP53 or TERT promoter mutations) and therapeutic targets (ERBB4) is unknown. Methods: We queried the American Association for Cancer Research (AACR) Project GENIE for cutaneous squamous carcinomas accessed through cBioPortal. We gathered genomic alterations and demographic data by age groups at time of tumor sequencing (< 65years, 66-80 years, > 81 years). Genomic alterations were assessed for function by OncoKB. Descriptive variables were presented as frequencies and compared by Chi squared method. Results: Among 1,025 non-melanoma skin cancer samples, 285 total CSCC samples were identified within the database. By age groups, 104 (36%) samples were from those 65 or younger, 127 (45%) in those 66-80 years, and 54 (19%) in those older than 80 years. Prevalence of TP53 mutations increased with age, 72% in < 65, 88% in 66-80, and 93% in > 80 (p < 0.001). Nearly all TP53 mutations were functional (96%; 228/237). ROS1 mutations also significantly increased in prevalence with older age, 27% in those < 65, 37% in 66-80, and 48% in > 80, respectively (p = 0.03). However, all ROS1 alterations were variants of unknown significance (VUS). TERT alterations also increased in frequency with more advanced age, with 32% in those < 65, 45% in 66-80, and 46% in > 80 (p = 0.078). ERBB4 alterations also increased in prevalence with age, 28% in those < 65, 30% in 66-80, 33% in > 80 groups (p = 0.71), however only 9/130 (6.9%) were known oncogenic alterations. Conclusions: Tumor suppressor genes (such as TP53, TERT, KMT2D, NOTCH1, NOTCH2, and FAT1) were frequently altered in CSCC among the AACR GENIE population, while actionable mutations and gain of function driver mutations (such as ERBB4) were infrequent.