bluuebunny/crossref_metadata_2025 huggingface dataset:
An immunogenomic signature for molecular classification in melanoma.
Authors: Liu Yang , Wang Qian , Xiao Shanshan , Wang Tao
Published: June 2023

e21562

Background: Melanoma is one of the most aggressive tumors in the world, characterized by an increasing incidence and high mortality with half of the patients dying from the advanced tumors. The melanoma tumor is very heterogenous and the appropriate classification of subtypes is the key to guide precision treatment. Previous studies have revealed the important roles of immune cells in melanoma. Therefore, the better classification method and comprehensive analysis of immune cells and immune-related genes can help to better understand the tumor progression and develop effective treatment strategies in melanoma. Methods: Two datasets containing RNA sequencing data and paired patient information with melanoma were collected in this study. The first dataset of skin cutaneous melanoma patients downloaded from The Cancer Genome Atlas database (n = 204) was used as the training set, and the second dataset from a published study was used as internal validation set (n = 102). Single sample gene enrichment analysis (ssGSEA), ESTIMATE, CIBERSORT and k-means analysis were used to classify melanoma patients into two different immune clusters. We then constructed a molecular signature with nine immune related genes that could predict the overall survival (OS) of melanoma patients by LASSO regression and Cox regression analysis. The accuracy of the risk signature was then verified in eight independent cancer types. Results: The melanoma patients were divided into two different immune clusters, the high-immune cell infiltration cluster (Immunity_H) and low-immune cell infiltration cluster (Immunity_L). 1,556 and 1445 differentially expressed genes (DEGs) between the Immunity_H and Immunity_L were detected in the training set and validation set, respectively. Accordingly, 677 and 147 genes associated with overall survival (OS) was further selected by Univariate Cox regression analysis. 59 genes were shared between the 677 and 147 OS related genes. Eventually, 9 DEGs (CST7, CSF2RB, SPARC, SPOCK2, PLA2G2D, MYO1G, NCF1, ICOS and HSH2D) were screened out by LASSO regression analysis and were then subjected to multivariate Cox regression analysis to further construct the prognostic signature. Patients were divided into high-risk and low-risk groups based on the computed risk threshold. Kaplan-Meier analysis indicated that patients in the high-risk group had a significantly worse OS. Finally, 8 independent external pan-cancer cohorts were used to validate the robustness of the model. Conclusions: This study identified two immune-related clusters and a risk signature based on nine immune-related genes was constructed, which could predict the melanoma cancer OS and the constructed model can be used as prognosis predictor in melanoma.
Impact of adjuvant immunotherapy in resected stage II/III/IV melanoma: A single center experience.
Authors: Sevillano Tripero Alberto Rafael , Ortiz Carolina , Lostes Julia , Bodet Domingo , Ferrandiz Carla , Bassas Patricia , Chiquillo Paula , Villacampa Guillermo , Vega-Cano Kreina Sharela , García-Patos Vicente , Recio Juan , Muñoz-Couselo Eva
Published: June 2023

e21565

Background: The incidence of malignant melanoma (MM) in Mediterranean countries is estimated at 3- 5/100.000 inhabitants/year with a predicted rising trend. MM is responsible for over 90% skin cancer deaths due to its tendency to metastasize early. Surgical excision is the treatment of choice for early-stage melanoma, however, 40-60% of patients with high recurrence risk melanoma, thick ulcerated primary melanomas (Stage IIC) and those with lymph node involvement (Stage III), experience a tumor relapse. Adjuvant therapy in resected high-risk melanomas has shown improved Relapse-Free-Survival (RFS), although no Overall Survival (OS) benefit has been observed to date. This retrospective observational study, conducted in one center, aims to evaluate effectiveness and safety of adjuvant therapies for resected high-risk melanoma. Methods: Single center cross-sectional study that included patients with a resected high-risk melanoma candidate for adjuvant treatment, at 2015-2022 period. Convenience sampling 48 patients recruited. Median follow up 55,4 months. Results: Median age was 54y, 52% were male and 93’6 is cutaneous melanoma. 53% were BRAF WT. Median Breslow (mm) was 3’85, median num/mm2 mitosis are 4 and 62’5% had ulceration. 15% presented satelosis or intransit metastasis and 55% had a lymphadenectomy. Melanoma stage: 9%IIB, 11%IIC, 11%IIIA, 25%IIIB, 38%IIIC, 2% IIID and 2% IV. Adjuvant treatment: 22% nivolumab, 20% ipilimumab+nivolumab, 12% ipilimumab, 16% interferon.75% of patients completed adjuvant treatment, 14% stopped for toxicity and 9% presented disease relapse (21% loca, 64% systemic). Best treatment response in relapse was 12% partial response, 37% progression. Toxicity: 18% presented grad ¾ toxicity. Efficacy: median RFS was 78’8m and median OS was NR. Conclusions: Adjuvant treatment is associated with an increased DFI in resected high risk melanoma patients. Adjuvant therapy was generally well tolerated, with manageable adverse events, consistent in type and incidence to those seen in clinical trials that allowed the approval for these compounds in adjuvant and metastatic scenarios. Prospective studies are needed to determine new biomarkers for the selection of those patients who could benefit to a greater extent from adjuvant therapies in resected high-risk melanoma.
The current state and future of neoadjuvants in resectable melanoma: Review of phase II/III studies conducted between 2018-2022.
Authors: Lee Chan Mi , Mirsky Matthew M , Wang Margaret , Mangla Ankit
Published: June 2023

e21568

Background: Adjuvant therapy with single agent anti-PD1 and BRAF/MEK-inhibitors (BRAF/MEKi) is approved for patients diagnosed with high-risk stage III melanoma. The goal of adjuvant therapy is to prevent the growth of the occult metastasis to distant organs. The premise of neoadjuvant therapy in clinical stage III melanoma is to allow for a better antigen exposure when checkpoint inhibitors are administered. We aimed to get an overview of the current state of neoadjuvant therapy in resectable melanoma. Methods: A systematic literature search was conducted in November 2022, using PubMed, American Society of Clinical Oncology (ASCO) Journal of Clinical Oncology and European Society for Medical Oncology (ESMO) abstract databases. Eligible studies included Phase 2 and 3 randomized controlled trials (RCT), single-arm trials, pooled analyses, and planned future trials published between 2018-2022 looking at the efficacy of neoadjuvants in resectable melanoma. Two individuals (CL and MM) screened all the studies, and 3 individuals (CM, MM, MW) went over the list of Abstracts. Primary outcomes and secondary outcomes, as well as median duration of follow up and Grade 3 or above adverse effects (AEs) were recorded. Abstracts with more recent findings or final publications were excluded in the final analysis. Results: A total of 14 published studies (4 RTCs, 5 single-arm, 2 OpACIN-neo and 3 related sub-analysis studies) and 16 abstracts (5 ESMO, 11 ASCO) were identified, representing 34 unique Neoadjuvant arms and a total of 1,496 patients. Thirteen of 27 trials making 71% of patients (n = 1061) tested immune checkpoint inhibitors (ICIs). Four of 27 trials of total n = 112 tested BRAF/MEKi. All ongoing or future studies (7 trials) tested combination of ICI with BRAF/MEKi or other molecules such as MDM2 inhibitors, interferon-α, or oncolytic viruses. Most of studies (54% of ICI studies, 50% of BRAF/MEK inhibitor trials, and 80% of other studies) used pathological response as their primary outcome. Other primary end points included event-free survival (EFS) and relapse-free survival (RFS), and 13/14 published studies and 13/16 abstracts met the primary end point. A pooled analysis of complete pathologic response (pCR) revealed an estimate of 38.3% ± 19.7 (mean ± SD) from 16 unique ICI neoadjuvant arms, 51.9% ± 5.3 for BRAF/MEKi (from 3 data points), and 21.0% ± 7.2 for other agents/combinations (from 3 data points). Rate of ≥ Grade 3 AEs was 28.7% ± 31.0 (from 11 data points) for studies testing ICI, 32.5% ± 14.1 (from 6 data points) for BRAF/MEKi, and 23.6% ± 20.2 (from 3 data points) from studies testing other agents/combinations. Conclusions: Recent studies have shown that neoadjuvant in resectable melanoma can offer increased therapeutic efficacy. While past studies have focused on PD-1 and CTLA-4 inhibitors, ongoing and future studies are beginning to test newer agents and novel molecular targets.
Sun exposure and associated risks: Insight from an international survey with a focus on the population with past medical history of skin cancers.
Authors: Dreno Brigitte , Passeron Thierry , Puig Susana , Goh Cl , Lim Henry , Ly Fatimata , Kang H. , Morita A. , Ocampo Jorge , Schalka Sergio , Wei L. , Lefloch Caroline , Demessant Anne-Laure , Kerob Delphine , Krutmann Jean
Published: June 2023

e21575

Background: This survey investigates knowledge and behaviors regarding sun exposure among population who have been treated for skin cancer (melanoma/non melanoma) or pre-cancerous lesions in 17 countries. Methods: The survey (N = 17,001) was conducted online in 17 countries (5 continents) from 28 September-18 October 2021. Automated selection from the Ipsos online Panel ensured samples of 1,000 individuals in each country fit the quotas method based on gender, age, employment status, and country regions. Data covered demographics, phototype, exposure habits and practices, knowledge and understanding of risks. The current focus in this abstract was defined as individuals with a history of melanoma/non melanoma skin cancer, pre-cancerous lesions. Results: This sub population represents 8% of the general population (n = 1372), it comprised 54% men, average age was 49.9 years (SD:17.6) and 58% were of phototype 1-2. 90% were aware of sun-related skin-health issues (vs 88% in the general population). 79% did know that sun protection is useful when the weather is overcast, a better knowledge compared to the general population (61%). However, 34% indicated it was safe to expose themselves without protection when already tanned, a larger misconception compared to the general population (23%). 54% did not understand the difference between UVA and UVB vs 70% in the general population. Only 28% systematically/often use all protections measures during exposure; still a higher practice compared to the general population (12%). However, 42% said they protected from the sun all year round, a better habit compared to the general population (23%). During sun exposure, among the 91% who declared using sunscreen, 74% applied sunscreen only once or twice a day, a similar practice among general population (74%). And when already tanned 38% decreased frequency of application and/or used lower protection (44% among general population). 82% regretted not having previously used better protection, a much stronger regret compared to the general population (57%). Conclusions: Although individuals who have been treated for skin cancer or pre-cancerous lesions had better knowledge and behavioral attitudes compared to the general population, this survey shows that even a population at high risk of melanoma and having a regular medical follow-up does not sufficiently perceive the importance of photoprotection in a prevention objective. This leads to discuss the implementation of new information tools with more impact.
Prognostic biomarkers for survival in mucosal melanoma.
Authors: Thierauf Julia Cara , Kaluziak Stefan T. , Codd Elizabeth , Dybel Stacey , Jobaggy Soma , Purohit Rashi , Farahani Alex , Dedeilia Aikaterini , Naranbhai Vivek , Hoang Mai , Fisch Adam , Ritterhouse Lauren , Boland Genevieve Marie , Lennerz Jochen K. , Iafrate A. John
Published: June 2023

e21576

Background: Mucosal Melanoma is a rare subtype of melanoma with a more aggressive clinical course when compared to cutaneous melanoma. In cutaneous melanoma, the absence of pigmentation and presence of NRAS/KRAS mutations are known as biomarkers indicating an aggressive clinical course with significantly shorter overall survival times. Similar data for mucosal melanoma are currently missing. Here, we present real world outcome data in a large cohort of genotyped mucosal melanoma patients and assessed the prognostic relevance of pigmentation- and NRAS/KRAS mutation status. Methods: We correlated pathological reports and clinical data with overall survival of patients with mucosal melanoma. Furthermore, we performed clinically integrated molecular genotyping and analyzed real world treatment regimens for covariates associated with clinical outcome. For institutional data analysis, we ran a source query and only included patients with the diagnosis of mucosal melanoma, available genotyping data and comprehensive clinical information. As a population-based reference and to directly compare overall survival differences we first queried the National Cancer Institute’s Surveillance, Epidemiology and End Results (SEER) database. Pigmentation status was assessed by pathological review. Treatment regimens were identified by chart review. Results: We identified a cohort of 39 patients with mucosal melanoma where clinical and molecular data was available. Patients with amelanotic mucosal melanoma had a significantly shorter overall survival ( p = 0.003). In addition, the presence of a NRAS or KRAS mutation was significantly associated with poor overall survival (NRAS or KRAS p = 0.024). Therapeutic regimens were heterogeneous with a mean of 5 treatment lines per patient. Patients with low stage tumors who received immunotherapy had a significantly shorter overall survival (p < 0.001), although numbers were small. Conclusions: The absence of pigmentation and the presence of NRAS or KRAS mutations are poor prognostic indicators for survival in CM. Both biomarkers are have been described in MM. Currently, it is unknown if the same prognostic relevance for the lack of pigmentation and RAS mutations exists in MM. Here we analyzed a cohort of MM for outcome measures and determined that two known prognostic biomarkers for CM are in fact novel prognosticators for MM.
Sun exposure and associated risks: Insight from an international survey with a focus on the organ transplant recipient population.
Authors: Kerob Delphine , Dreno Brigitte , Passeron Thierry , Puig Susana , Goh Cl , Lim Henry , Ly Fatimata , Kang H. , Morita A. , Ocampo Jorge , Schalka Sergio , Wei L. , Lefloch Caroline , Demessant Anne-Laure , Krutmann Jean
Published: June 2023

e21578

Background: This survey investigates knowledge and behaviors regarding sun exposure among population who have been treated with immunosuppressive anti-graft rejection drugs because of an organ transplantation. Methods: The survey (N = 17,001) was conducted online in 17 countries (5 continents) from 28 September-18 October 2021. Automated selection from the Ipsos online Panel ensured samples of 1,000 individuals in each country fit the quotas method based on gender, age, employment status, and country regions. Data covered demographics, phototype, exposure habits and practices, knowledge and understanding of risks. The current focus in this abstract was defined as individuals who have been treated with immunosuppressive anti-graft rejection drugs because of an organ transplantation. Results: This sub population represents 3% of the general population (n = 434), it comprised 65% men, average age was 39.7 years (SD:14.6) and 57% were of phototype 1-2. 85% were aware of sun-related skin-health issues, a similar awareness among general population (88%). 79% did know that sun protection is useful when the weather is overcast, a better knowledge compared to the general population (61%). Furthermore, 75% did understand the difference between UVA and UVB vs 30% in the general population. But, 69% indicated it was safe to expose themselves without protection when already tanned, a much larger misconception compared to the general population (23%). Only 46% systematically/often use all protections measures during exposure; still a higher practice compared to the general population (12%). And, 63% said they protected from the sun all year round, a better habit compared to the general population (23%). However, during sun exposure, among the 93% who declared using sunscreen, 85% applied sunscreen only once or twice a day, a worse practice compared to the general population (74%). And when already tanned 37% decreased frequency of application and/or used lower protection (44% among general population). 89% regretted not having previously used better protection, a much stronger regret compared to the general population (57%). Conclusions: Although individuals who have been treated with immunosuppressive anti-graft rejection drugs because of an organ transplantation had better knowledge and behavioral attitudes compared to the general population, this survey shows that even a population at high risk of skin cancers and having a regular medical follow-up does not sufficiently perceive the importance of photoprotection in a prevention objective. This leads to discuss the implementation of new information tools with more impact.
Tebentafusp (tebe) in a real-world cohort of 72 French metastatic uveal melanoma (UM) patients (pts).
Authors: Piperno-Neumann Sophie , Mailly-Giacchetti Leah , Ramtohul Toulsie , Saint-Ghislain Mathilde , Pracht Marc , Thery Jean Christophe , Combe Pierre , Litrowski Noemie , Martin Hélène , Dutriaux Caroline , Garcia Agathe , de Koning Leanne , Servois Vincent , Rodrigues Manuel
Published: June 2023

e21583

Background: Up to 50% of UM pts will develop metastases with poor overall survival (OS) and limited treatment options. Tebe, a bispecific T-cell engager binding CD3 and the gp100 protein presented by the HLA A*02-01, recently showed a benefit in overall response rate (ORR), progression-free survival (PFS) and OS in HLA A*02-01pos metastatic UM (mUM) pts in the IMCgp100-202 phase III trial. Prior to the EMA approval, French Health Authorities allowed an early access to tebe in May 2021 to UM metastatic pts. We here report our real-world experience with tebe in metastatic UM pts. Methods: Ongoing ambispective cohort of mUM pts treated with tebe in France. Metastases are evaluated according to RECIST 1.1 with assessments every 12 weeks (liver MRI +/- CT-scan). ORR, PFS, OS and toxicities are retrieved. Results: 72 pts started tebe between May 26th 2021 and December 12th 2022 (29 men and 43 women). Median age was 61 yo (32-78). Thirty, 34 and 7 patients underwent enucleation proton beam therapy or brachytherapy, respectively (one pt did not receive local treatment). The median time to first metastasis was 24 months (0-276). Tebe was prescribed in first-line in 46 patients, in second-line or more in 26 patients. Metastatic sites at tebe initiation were liver, lung, skin, bone and muscle in 71, 4, 2, 3 and 2 patients, respectively. Liver was the sole metastatic site in 63/72 patients (87.5%). With a median follow-up of 44 weeks, patients received a median of 36 weeks of tebe. Thirty patients discontinued tebe because of disease progression, two because of poor health status and none for toxicity. Of 60 assessable pts, 33 (55%) pts showed stable disease and 5 (8%) showed partial response as best response according to RECIST 1.1. Median PFS was 28 weeks (confidence interval 95% [CI95%]: 8-56) in the global cohort. OS at 12 months was 74% ([CI95%] = 0.62-0.89) in the global cohort, 73% ([CI95%] = 0.55-0.99) and 74% ([CI95%] = 0.57-0.97) in 1st and 2nd line and more, respectively. To date, 13 pts died. Circulating tumor DNA analyses and monitoring of peripheral blood leukocytes are ongoing and will be available by June 2023. Conclusions: In this ongoing, real-world, cohort of metastatic UM pts, tebe is associated with similar clinical outcomes as in the IMCgp100-202, phase III trial. Translational studies on blood and tumor samples are ongoing to identify predictive biomarkers of clinical benefit to this drug.
Community outreach in vulnerable populations: Skin cancer screening for firefighters.
Authors: Fay Christopher , Rice Shauna , Krueger Steven , St John Jessica
Published: June 2023

e21587

Background: Firefighters have both an increased risk (21%) and 20-year younger median age (42) at diagnosis of melanoma compared to the general population. The World Health Organization classifies firefighters’ occupational exposures as "carcinogenic to humans," but there is limited knowledge regarding sun protection habits, skin cancer history, and community outreach in this at-risk population. Methods: Free, full-body skin examinations conducted by board-certified dermatologists using the American Academy of Dermatology’s SPOT Skin CancerTM screening form were offered to firefighters from 26 cities and towns in Massachusetts on two separate days in August 2021 and October 2022. Data from the screening form and subsequent skin biopsy results were obtained and reported. Results: Of 195 firefighters screened, 30 (15.4%) were referred for biopsy. All were white males, mean age was 44.7 years, 26.7% had prior tanning bed exposure, 80% had prior blistering sunburns, 20% used sunscreen regularly, 86.7% did not have a regular dermatologist, and 6.7% had a history of keratinocyte-based skin cancer. Nineteen (63.3%) had biopsies, most frequently on the back or face, which resulted in three nodular basal cell carcinomas and 11 dysplastic nevi (seven moderate-to-severe). Conclusions: Firefighters are an underrecognized vulnerable population for the development of skin cancer. Community outreach in the form of free skin cancer screenings is a successful model for increasing awareness and early diagnosis of skin cancer among this population. In addition to providing access to care, community screenings offer tailored educational opportunities that promote skin cancer prevention in this high-risk group.
Comparing PD-L1 scores for predicting pembrolizumab efficacy in first-line treatment of unresectable cutaneous squamous cell carcinomas.
Authors: Maubec Eve , Boubaya Marouane , Deschamps Lydia , Beylot-Barry Marie , Petrow Peter , Scheer-Senyarich Isabelle , Basset-Seguin Nicole , Grob Jean-Jacques , Dreno Brigitte , Bloch-Queyrat Coralie , Leccia Marie Thérèse , Stefan Andreea Raluca , Saiag Philippe , Grange Florent , Meyer Nicolas , Dalac Sophie , Alloux Céline , Lopez Isabelle , Tibi Annick , Lévy Vincent
Published: June 2023

e21593

Background: In the CARSKIN study (NCT02883556), 1L pembrolizumab demonstrated promising activity with durable responses and manageable safety in patients (pts) with unresectable locally advanced or metastatic CSCC. Here we report best ORR and survival endpoints of the entire cohort by PD-L1 status. Methods: The imaging assessment per RECIST v1.1 was blinded with independent central review. Best ORR, PFS, DOR OS, in the overall sample and by PD-L1 status was centrally assessed by 2 blinded independent pathologists, one using the anti–PD-L1 E1L3N clone (TPSE1L3N), the other using the 22C3 antibody (TPS22C3 and CPS22C3). Among 57 pts, 6 were excluded from the analysis: 2 untreated pts, 1 early unrelated death and 3 pts tested only with 1 assay). ROC curve analysis was used to compare assays. Results: With a median follow-up of 26 mo, best ORR was 51% with 14 PR (27%) and 12 CR (24%). Relapse occurred in 3 PR and 1 PD-L1 – CR pts. Respective median PFS, DOR, and OS were 13.7, NR, and 25.3 mo; respective 1-year PFS, DOR and OS were 50% [38-66], 80% [65-97] and 73% [61-86]. With a cutoff of 1%, best ORR was higher either for TPSE1L3N + pts vs TPSE1L3N – pts (60% vs 18%, p = 0.02) and for CPS22C3 + pts (59% vs 20%, p = 0.038), but not TPS22C3 + pts (p = 0.76). The optimal cutoff of CPS22C3 for ORR using a ROC curve was estimated to be ≥ 7% with a sensitivity of 0.70 and a specificity of 0.75. For best ORR, area under the ROC curve was higher for CPS22C3 (0.72) than TPSE1L3N (0.62) but the difference was not significant (P = 0.21). Pts with TPSE1L3N ≥ 1% had a higher 1-y PFS (57% vs 27%, p = 0.004) and OS (82% vs 42%, P = 0.01). Pts with CPS22C3 ≥ 1%, had a better 1-y OS (79% vs 50%, p = 0.03), but not 1y-PFS. Conclusions: CPS22C3 ≥ 7% appeared equivalent to TPSE1L3N ≥ 1% for predicting ORR and OS in pts receiving pembrolizumab in 1L treatment of advanced or metastatic CSCCs. Replications are warranted for validation. Pts with low scores might beneficiate from combined treatments. Clinical trial information: NCT02883556 .
Dissecting the relationship between ethnicity and response to checkpoint inhibitors in patients with acral melanoma.
Authors: Kreidieh Firas Y. , Simien Rinata , John Ida , Rodgers Theresa , Abdel-Wahab Noha , Abdel-Wahab Reham , Diab Adi , Ludford Kaysia
Published: June 2023

e21597

Background: Aral lentiginous melanoma (ALM) constitutes the most common subtype of cutaneous melanoma (CM) among people with pigmented skin, accounting to up to 70% of cases. In a prior study of 44 patients with advanced, unresectable ALM treated with checkpoint inhibitors, we demonstrated differential response to checkpoint inhibitors by ethnicity with Hispanic patients having a higher response to therapy compared to non-Hispanic patients. Accumulating evidence suggests that tumor mutation burden (TMB) can predict the efficacy of immune checkpoint inhibitors (ICI) in solid malignancies, including cutaneous melanoma. ALM however has significantly lower TMB compared to cutaneous melanoma suggesting that there are other mechanisms outside of TMB driving this response. Here, expanding upon our prior work, we will examine outcomes in over 130 patients and report for the first time, the correlation between ethnicity and response to checkpoint inhibitors in the largest dataset to our knowledge of acral melanoma patients. Methods: This was a retrospective analysis of all advanced and metastatic ALM patients treated with anti-CTLA4 (ipilimumab) or anti-PD1 (pembrolizumab or nivolumab) ICI between March 2011 and January 2019 at the University of Texas MD Anderson Cancer Center, Texas. Clinical response, progression free and overall survival outcomes (PFS and OS) and their correlation to ethnicity and TMB will be evaluated. Objective response will be measured using RECIST 1.1. OS and PFS will be estimated using the Kaplan-Meier method, and differences between groups assessed using the log-rank test. Associations between OS and PFS and measures of interest will be determined using Cox proportional hazards regression models. Results: 132 patients with Stages III-IV ALM (III: 27% and IV: 73%) were included in the analysis. Median age was 66.6 years old (15.8-92.5) and 58% were men. 28 (21.2%) self-identified as Hispanic, 101 (76.5%) were non-Hispanic, and 3 (2.3%) did not provide their ethnicity. The best objective response rate (ORR) was 27 (20.4%), with 9 (6.8%) showing complete response (CR) and 18 (13.6%) showing partial response (PR). 48 (36.4%) patients received anti-PD1 based- therapy while 57 (43.2%) received anti-CTLA4 only. We will present immune phenotyping of both adaptive and innate immune arms to investigate further mechanisms of differential response. Conclusions: The data from our prior small retrospective study suggested that non-Hispanic patients with ALM had low response rates to CPI presumably due to low TMB while interestingly, Hispanic patients, despite relatively low TMB have high response rates paralleling those seen in the overall cutaneous melanoma population. This data will provide the rationale to design prospective studies to investigate further how tumor micro-environment varies with ethnicity.
Clinical outcomes of extramammary Paget’s disease in Korea: A multicenter, retrospective study.
Authors: Sohn Byeong Seok , Kim Jeong Eun , Kim Miso , Hong Jung Yong , Lee Jieun , Park Song Ee , Kim Hyojeong , Lee Hyo Jin , Kang Eun Joo , Lee Soon Il , Lee In Hee , Huh Seok Jae , Jo Jeong Min , Lim Sung-nam , Kim Ho Young
Published: June 2023

e21599

Background: Extramammary Paget’s disease (EMPD) is very rare disease. Due to its rarity, there have been few clinical trials and no standard therapy to date. In this multicenter retrospective study, we investigated the treatment patterns and outcomes of Korean patients with advanced/metastatic extramammary Paget’s disease. Methods: As a retrospective multicenter study, we searched the medical record from 15 centers participating Rare Cancer Committee in Korean Cancer Study Group (KCSG). Results: A total of 54 patients were identified, and 11 patients who refused or did not receive treatments were excluded. In remaining 43 patients, 9 patients received locoregional therapy as first-line treatment and 34 patients initially received systemic chemotherapy. In 34 patients who received systemic chemotherapy as first-line treatment, cisplatin plus 5-fluorouracil was the most frequently used chemotherapy regimen (n = 19). Cisplatin plus 5-fluorouracil regimen achieved an objective response rate of 42.1% and a median PFS of 7.9 months. The next frequently used chemotherapy regimen was docetaxel monotherapy (n = 6). Docetaxel monotherapy achieved an objective response rate of 50.0% and a median PFS of 8.5 months. There was no statistical difference between the two treatments (p = 0.29). Two patients received trastuzumab plus paclitaxel regimen as first-line therapy. Both obtained partial response, with PFS of 13.0+ and 8.2+ months respectively. Seventeen patients received second-line chemotherapy for disease progression. In 17 patients who received systemic chemotherapy as second-line treatment, docetaxel monotherapy was the most frequently used chemotherapy regimen (n = 6). Docetaxel monotherapy achieved an objective response rate of 50.0% and a median PFS of 4.5 months. Two patients received trastuzumab plus paclitaxel regimen as second-line therapy. Both obtained partial response, with PFS of 8.7 and 12.7 months respectively. In 4 patients received trastuzumab plus paclitaxel during first- and second-line chemotherapy, trastuzumab plus paclitaxel achieved an objective response rate of 100% and a median PFS of 10.7+ months. Overall, most patients with advanced/metastatic extramammary Paget’s disease could receive up to median two lines of chemotherapy and obtained median overall survival of 20.8 months. Conclusions: Due to its rarity, advanced or metastatic EMPD still has no established standard treatment. Results of our study indicate that there is no significant difference between cisplatin plus 5-fluorouracil and docetaxel treatment in the first-line treatment. The combination of trastuzumab with paclitaxel has longer survival than conventional cytotoxic chemotherapy only.
Synergistic activity of JAK2 and BCL-2 inhibition against B-cell acute lymphoblastic leukemia.
Authors: Rinella Sean , Hess Nicholas , Bell Haley , Shi Lei , Rui Lixin , Capitini Christian
Published: June 2023

e22002

Background: Treatment of relapsed/refractory B cell acute lymphoblastic leukemia (B-ALL) remains a challenge particularly in patients who do not respond to traditional chemotherapy. The objective of this study was to assess the efficacy of fedratinib, a semi selective JAK2 inhibitor and venetoclax, a selective BCL-2 inhibitor, on a model of B-ALL using the human cell line RS4;11 in vitro and in vivo. While select studies have examined the efficacy of these drugs on hematologic disorders as single agents, data is lacking on whether these drugs work optimally as single agents or in combination. Methods: RS4;11 cells were treated with either vehicle (DMSO), single agent fedratinib or venetoclax, or the combination of both inhibitors for 48 and 72 hours. Live/dead discrimination was performed using flow cytometry and a 72-hour MTS assay to assess proliferation. Drug synergy was calculated using CompuSyn software to generate combination index (CI) scores, with a CI score less than 1 reflecting synergy. RS4;11 was then used in a cell line derived xenograft model using NSG mice. Peripheral blood was obtained via retroorbital bleeds on days +10 (engraftment), +21 (treatment start), and +35 (post treatment) to assess B-ALL disease burden. Mice were randomized to one of the following groups: untreated, single agent venetoclax, fedratinib, or combination therapy. Mice were treated for 14 days with 6.25 mg/kg venetoclax IP and 100 mg/kg fedratinib via gavage. Results: In vitro, the combination of 7.5 nM venetoclax and 700 nM fedratinib significantly increased cell death compared to single agent venetoclax (p = 0.0186) and fedratinib (p = 0.0035). Furthermore, the combination significantly decreased leukemia cell proliferation compared to single agent venetoclax (p = 0.0183) and fedratinib (p = < 0.0001). Synergy between venetoclax and fedratinib was seen in combination (CI = 0.40517). In vivo, peripheral blood counts post treatment showed a significant decrease in leukemic burden in combination compared to both single agent venetoclax (p = 0.016770) and fedratinib (p = 0.00002). Flow cytometry analysis of peripheral blood also showed a significant increase in CD19 MFI expression in samples from mice that received either venetoclax or combination therapy. Conclusions: The combination of fedratinib and venetoclax synergistically combined to treat B-ALL in vitro. The combination also was effective at significantly reducing leukemic disease burden in a cell line derived xenograft model. Finally, the significant increase in CD19 MFI expression post treatment suggests this combination therapy may be useful as a bridge to other CD19 targeted cell therapies.
Novel biomarkers to predict chronic kidney disease and hypertension at 3 and 12 months post-cisplatin.
Authors: Huang Ryan S T , McMahon Kelly , Wang Stella , Chui Hayton , Lebel Asaf , Lee Jasmine , Cockovski Vedran , Rassekh Shahrad Rod , Schultz Kirk R. , Blydt-Hansen Tom D. , Cuvelier Geoffrey D. E , Mammen Cherry , Pinsk Maury , Carleton Bruce C. , Tsuyuki Ross T. , Ross Colin , Palijan Ana , Zappitelli Michael
Published: June 2023

e22003

Background: Urine kidney injury biomarkers measured during cisplatin therapy may help identify patients at risk for adverse long-term kidney outcomes. In children treated for cancer, we examined associations of urine tubular injury biomarkers collected during two cisplatin cycles, with chronic kidney disease (CKD) and hypertension at 3 and 12 months post-cisplatin. Methods: We analyzed data from the Applying Biomarkers to Minimize Long-Term Effects of Childhood/Adolescent Cancer Treatment (ABLE) Nephrotoxicity Study: a twelve-center prospective cohort of 159 children receiving cisplatin. Urine tubular injury biomarkers (by ELISA: neutrophil gelatinase-associated lipocalin [NGAL]; kidney injury molecule-1 [KIM-1]; tissue inhibitor of metalloproteinase-2 [TIMP-2]; insulin-like growth factor-binding protein-7 [IGFBP-7]) were measured at three timepoints (pre-infusion; 12-24 hours post-infusion; discharge after cisplatin cycle) during an early cisplatin cycle (EarlyCisP: first or second cycle of therapy) and a later cycle (LateCisP: last or second-to-last cycle). Area under the curve (AUC) for biomarkers to predict CKD (estimated glomerular filtration rate below normal or urine albumin/creatinine above normal for age, per international definition) and hypertension (3 blood pressures; per American Academy of Pediatrics guidelines) at 3 and 12 months post-cisplatin was calculated. AUC change from adding biomarkers to a published clinical prediction model for 3-month outcomes was evaluated (DeLong method). Results: 156 patients were available for analysis (mainly solid tumors). 3-month (median 90 days) outcomes were 52/118 (44%) CKD; 17/125 (14%) hypertension. 12-month (median 335 days) outcomes were 47/118 (40%) CKD; 15/125 (12%) hypertension. AUCs for all biomarkers to predict 3 and 12-month CKD and hypertension were poor to modest (best AUC = 0.70, 95% CI 0.60-0.80 for pre-infusion EarlyCisP TIMP-2*IGFBP-7 to predict 3-month hypertension). Biomarkers did not improve the clinical prediction model for 3-month CKD (AUC change not statistically significant with vs. without biomarkers). Adding pre-infusion EarlyCisP NGAL and TIMP-2*IGFBP-7 to the clinical prediction model for 3-month hypertension led to AUC change from 0.81 (0.72-0.91) to 0.89 (0.83-0.95) (p < 0.05). Conclusions: Tubular injury biomarkers we studied were individually not strong predictors of 3 or 12-month post-cisplatin kidney outcomes. Adding biomarkers to existing clinical prediction models may help predict post-therapy hypertension development or identify higher kidney-risk patients.
Recursive partitioning analysis to identify risk stratification for pediatric rhabdomyosarcoma: A real-world data retrospective cohort study based on the SEER database.
Authors: Lin Zhuangbin , Qiu Shuping , Li Xiaobo , Song Jianyuan , Li Anchuan , Xu Benhua
Published: June 2023

e22005

Background: For pediatric rhabdomyosarcoma (RMS), IRSG risk stratification is based on two distinct staging systems that differ according to whether surgery is performed. Its complexity hinders its effective clinical application to a certain extent. We aimed to develop a simple, practical, and reproducible risk stratification model to offer treatment guidance for RMS. Methods: We conducted a retrospective study based on the Surveillance, Epidemiology, and End Results (SEER) database obtained from SEER*Stat software, version 8.4.0. Multivariate Cox regression analysis was used to identify independent prognostic factors in RMS. Later, prognostic factors were integrated to construct an OS prediction nomogram. Recursive partitioning analysis (RPA) was performed to stratify the risk of the patients. Results: A total of 223 patients with pediatric RMS were ultimately included in this study. All patients received chemotherapy, and most received radiotherapy (98.2%). The median follow-up time was 93.0 months, and the overall median survival time was not reached. Multivariate Cox analysis revealed that histology (hazard ratio [HR] = 2.2374, P = 0.031), tumor size (HR = 3.403, P = 0.008), and M classification (HR = 2.060, P = 0.028) were independent factors for OS in RMS. A nomogram was constructed to predict accuracy toward individual OS with a training C-index of 0.698 and a validation C-index of 0.781. Compared to the IRSG risk stratification, the risk groups stratified by RPA allowed for significant distinction between survival curves in our cohort (for 3-y OS, IDI = 0.04454772, P = 0.022; for 5-y OS, IDI = 0.05452665, P = 0.015). Conclusions: The risk stratification model constructed by RPA could help clinicians to identify patients with poor outcomes and assist them in making treatment and surveillance decisions.
Deep multi-omic analyses to identify targetable pathways in desmoplastic small round cell tumor (DSRCT) with opportunities for clinical intervention.
Authors: Zhu Limin , Keck Jamie , Stommel Jayne , Johnson Brett , Corless Christopher L. , Ryan Christopher W. , Mills Gordon B. , Davis Lara E.
Published: June 2023

e22006

Background: DSRCT is an extremely rare and highly aggressive soft-tissue sarcoma affecting adolescents and young adults with male predominance. The 5-year overall survival is < 25% despite intensive multi-modality treatment including aggressive surgical resection, radiotherapy, chemotherapy, and targeted therapy. Therefore, more effective and innovative therapeutic options are urgently needed. Recent advances in genomic, epigenomic, proteomic, and immune profiling have uncovered a large number of therapeutic targets that are transforming the field of cancer medicine. This study aimed to identify novel targetable pathways in DSRCT using a deep multi-omics-based platform. Methods: Three patients with biopsy proven metastatic DSRCT were enrolled under an IRB-approved observational study within the “Serial Measurements of Molecular and Architectural Responses to Therapy” (SMMART) program at OHSU. Biopsies taken at enrollment were analyzed with targeted DNA sequencing, whole transcriptome sequencing, immunohistochemistry (IHC), NanoString GeoMx digital spatial profiling (DSP) multiplexed proteomics, single cell cyclic immunofluorescence (Cyc-IF), and reverse phase protein array (RPPA). Results: Multiple clinically relevant targets were identified, including HER2, androgen receptor (AR), elevated DNA damage response, and MAPK and mTOR signaling pathways. All three DSRCTs expressed HER2: clinical IHC identified HER2 low (1+) to HER2 equivocal (2+) expression; DSP analysis showed high HER2 and phospho-HER2 expression; and HER2 RNA expression was elevated compared to the TCGA sarcoma cohort. Two of the three patients displayed high AR protein expression, assessed by clinical IHC (90-100% positive cells) and DSP (top quartile compared to a 20 mixed-subtype breast cancer cohort). Strong evidence of DNA damage response was demonstrated at both RNA and protein levels, and RPPA revealed high PARP1, PAR, p-ATM, p-RPA32, and RAD51. Within cell signaling pathways, one DSRCT exhibited high total and phospho-ERK1/2 protein across all clinical and exploratory assays, while another patient displayed evidence of elevated mTOR pathway signaling by RPPA. Conclusions: Overall, this multi-omic analysis provided new insights into possible therapeutic targets for this rare and difficult to treat sarcoma subtype. Results from this study will be further validated in vivo using patient-derived xenograft (PDX) models, providing support for development of multiple early phase trials.
Clinical trends of children with primary cardiac tumors: 15-year experience from a single center.
Authors: Patel Nishant , Dong Dan , Ding Peicheng , Wu Kede , Yang Zhaocong , Mo Xuming
Published: June 2023

e22008

Background: Clinical presentation of pediatric primary cardiac tumors is exceptionally rare throughout the world. The purpose of our study is to evaluate clinical intervention by following up on children with primary cardiac tumors. Methods: Our study retrospectively enrolled 97 children diagnosed with primary cardiac tumors from Jan 2005 to Dec 2020 in a single center, Children’s Hospital of Nanjing Medical University by confirming with clinicoradiological and non-invasive diagnostic procedures. Primary outcome was to measure clinical trends and interventions while secondary was to analyze survival of 26 (26.80%) operative and 71 (73.19%) non-operative patients. Surgical intervention patients were followed for 6 Mo in the first postoperative year, then every year. Meanwhile, non-serious, asymptomatic, and no hemodynamic changes patients were treated non-operatively and followed up every year regularly. Results: In primary outcome, median age of children was 4.72±4.10 years (1d~16y), and median follow-up was 5.60±4.97 years (1m~15y). Most enrolled children were younger than 1 year old at the time of diagnosis. Primary cardiac tumors patients consisting of 60 rhabdomyoma (61.85%), 11 myxomas (11.34%), 7 fibromas (7.21%), 3 lymphangiomas (3.09%), 2 lipomas (2.06%), 9 unclassified tumors (9.27%) and 5 malignant tumors (5.15%) were retrospectively analyzed. Major 75 patients (77.31%) were diagnosed during various treatments of clinical symptoms, whereas 18 (18.55%) were diagnosed with routine investigation and 14 (14.43%) were diagnosed by prenatal fetal echocardiography. Herein, 26 children with critical symptoms and serious hemodynamic alteration had undergone surgical intervention in our hospital. Among them, 6 (23.07%) patients had postoperative complications; 2 (7.7%) patients were unable to survive due to post-operative arrhythmia and low cardiac output syndrome; While 2 (7.7%) patients with myxomas had a reoccurrence, and 2 (7.7%) patients had been diagnosed with another rhabdomyoma after intervention, others recovered well. Meanwhile, 71 children had non-surgical management, where 8 (11.26%) were lost to follow-up; 3 (4.22%) patients with malignant tumors were unable to survive after discharge due to unknown causes, and other patients had no serious symptoms or growth of tumors during follow-up. In secondary outcome, survival between operative and non-operative patients had no significant difference ( P > 0.05). Conclusions: Clinical intervention of pediatric primary cardiac tumors may be performed one-on-one by accounting presentations, symptoms, and emergence even though majority of primary cardiac tumors in children are benign in nature, and postoperative reoccurrence is feasible, particularly for rhabdomyoma. Meanwhile, the primary goal of surgical intervention is to reinstate normal hemodynamics, and preserve significant structures and cardiac tissues.
Pelvic Ewing sarcoma in children: Multimodal treatment, long term outcome and prognostic factors.
Authors: Kebudi Rejin , Yildirim Ulku Miray Miray , Iribas Ayca , Salduz Ahmet , Zulfikar Bulent , Bilgiç Bilge
Published: June 2023

e22010

Background: The pelvis is one of the primary sites of Ewing sarcoma (ES) and is associated with a higher rate of local recurrence and poorer prognosis, compared with nonpelvic sites. Due to the rarity of this disease and limited data available, the prognostic factors of pelvic ES remain controversial. This study aims to assess the demographic, clinical features, treatment approach, outcome and prognostic factors in children with pelvic Ewing Sarcoma. Methods: Files of 264 children and adolescents with Ewing sarcoma diagnosed and treated between 1990-2022 in our center were retrospectively reviewed, of these 42 (15.9 %) were located in the pelvis. All recieved a COG modified chemotherapy regimen of ifosfamide-etoposide, alternating with vincristin, adriamisin/actinomycinD and cyclophosphamide (IE/VAC) every three weeks (every two weeks since 2012). Local treatment was discussed in each patient in the tumor board. Variables including age, gender, tumor stage, local and systemic treatment, outcome were analyzed using the Kaplan-Meier method and log rank test. Results: The median age of the 42 (23 male, 19 female) patients was 12.5 (2-16) years. The median time to diagnosis was 4 (0.25-12) months. The primary site was skeletal in 37 and extraskeletal in 5 patients. Seventeen (%40) had metastasis at diagnosis (lung, bone, bone marrow). Radiotherapy (RT) was given to 36 patients (10 preoperatively, 5 postoperatively, 21 definitive RT), 19 underwent surgery (4 at diagnosis, 14 had additional RT ). Surgical margins were positive in 6 and negative in 13. The histopathological necrosis was <90% in 6 and ≥ 90% in 9. The median follow-up was 56 (10-370) months. At a median of 13 months (3-115), 22 patients had recurrence(9) /progression (13). The 3-year event free survival (EFS) and overall survival (OS) were 50.1% and 62.6%; in all; 62.2 and 75.3% in nonmetastatic; 31.9% ve %42.9% in metastatic patients ( p=0.048, p= 0.028) respectively. The 3-year EFS and OS were significantly higher in patients with negative surgical margins compared to ones with positive margins [(%83.9 vs 0 % (p=0.0001) and %91.7 vs %16.7 (p=0.001) respectively] . The 3-year EFS and overall survival OS were higher in patients with ≥90% necrosis [76.2 vs 33.3 % ( p=0.029); 87.5 vs 50% (p=0.13)respectively]. Age, gender, the mode of local therapy (surgery/RT/RT+surgery) was not prognostic. One patient who had recieved oral etoposide and RT at recurrence and who achieved a complete response, developed acute myeloid leukemia (AML), M5 myelomonocytic subtype, 20 months after relapse, and died. Conclusions: In our cohort of patients with pelvic Ewing sarcoma, 40% had metastasis at diagnosis. Metastasis, positive surgical margins, poor necrosois rate <90% after neoadjuvant chemotherapy were found to be poor prognostic factors for outcome. Patients with localized pelvic Ewing sarcoma had a successful outcome with multidisciplinary treatment approach.