bluuebunny/crossref_metadata_2025_split huggingface dataset:
Melphalan/hepatic delivery system versus best available care in patients with unresectable metastatic uveal melanoma: Randomized FOCUS trial results.
Authors: Zager Jonathan S. , Orloff Marlana M. , Ferrucci Pier Francesco , Choi Junsung , Eschelman David J. , Glazer Evan Scott , Ejaz Aslam , Richtig Erika , Ochsenreither Sebastian , Reddy Sunil A. , Lowe Michael C. , Beasley Georgia , Gesierich Anja Heike , Gschnell Martin , Dummer Reinhard , Arance Ana Maria , Fenwick Stephen William , John Johnny , Wheater Matthew , Ottensmeier Christian H.H ,   FOCUS Trial Authors
Published: July 2024

9556 Background: Metastatic uveal melanoma (mUM) has a poor prognosis, with liver metastases typically presenting a therapeutic challenge. Melphalan/Hepatic Delivery System (melphalan/HDS) is a drug/medical device combination used for liver-directed treatment of unresectable mUM patients. The purpose of the FOCUS study, an open label, multicenter randomized Phase 3 study, was to assess efficacy and safety of melphalan/HDS versus best alternative care (BAC). Methods: Eligible patients with unresectable mUM were randomized 1:1 to treatment with melphalan/HDS (3.0 mg/kg ideal body weight) once every 6-8 weeks for a maximum of 6 cycles or BAC. The primary endpoint was overall survival (OS). The planned study size was 240 patients; due to slow enrollment and patient reluctance to receive BAC treatment, the study design was amended to a single-arm melphalan/HDS study, and all efficacy analyses of the randomized study were treated as exploratory. Results: From February 2016 to October 2018 a total of 129 patients were screened and 85 were enrolled at 22 centers in the US and Europe; eligible patients were randomized to receive melphalan/HDS (N=43) or BAC (N=42) and 72 patients received study treatment. Exploratory analyses of efficacy endpoints showed numerical differences consistently favoring the melphalan/HDS arm vs. BAC (median OS: 18.5 vs 14.5 months; median progression free survival: 9.1 vs 3.3 months; objective response rate: 27.5% vs 9.4%; and disease control rate: 80.0% vs 46.9%). Serious adverse events (SAEs) occurred in 51.2% of melphalan/HDS and in 21.9% of BAC patients. Most common (>5%) SAEs included thrombocytopenia (19.5%), and neutropenia (9.8%), leukopenia (9.8%) and febrile neutropenia (7.3%) in melphalan/HDS patients and cholecystitis, nausea and vomiting (6.3% each) in BAC patients. No treatment-related deaths were observed. Conclusions: Treatment with melphalan/HDS shows clinically meaningful efficacy and demonstrates a favorable benefit-risk profile in patients with unresectable mUM as compared to best alternative care. Clinical trial information: NCT02678572 .
Antigen-specific profiling for neoadjuvant anti-PD-1 therapy in melanoma.
Authors: Yoon Daniel , Wang Guanning , Nandi Ajeya , Kim Justin , Nickie Aaron , Park Stella , Carberry Mary , Giles Lydia , Patel Khushboo , Amaravadi Ravi K. , Schuchter Lynn M. , Karakousis Giorgos Constantine , Xu Xiaowei , Mitchell Tara C. , Huang Alexander C. 
Published: July 2024

9576 Background: Anti-PD-1 therapy (aPD-1) has had significant clinical success in extending survivability of melanoma patients. However, two-third of the patients do not achieve long-lasting benefits, and currently, there exists no reliable method for predicting clinical response. We test whether monitoring melanoma-specific CD8 T cells in blood, lymph node, and tumor enables us to gain insights into the mechanism of clinical resistance, and identify potential predictive biomarkers. Methods: We leveraged a phase 2 clinical trial of neoadjuvant PD-1 blockade at University of Pennsylvania where patients with stage III melanoma patients receive a pre-treatment biopsy, treatment with a single dose of the aPD-1 therapy, followed by tumor and lymph node resection 4 weeks later, allowing for access to paired blood and tumor samples. We used a combinatorial tetramer system to track panels of 10 HLA-restricted melanoma and viral-specific CD8 T cell populations simultaneously. Results: Out of 35 patients analyzed, 53% of patients had detectable melanoma-specific CD8 T cells. Notably, these cells exhibited exhausted phenotypes both in blood and tumor, whereas viral-specific T cells displayed features resembling effector and memory CD8 T cells in blood and tumor, respectively. Thus. the presence of tumor antigen emerges as a crucial determinant in shaping the phenotype of melanoma-specific CD8 T cells, above that of the tissue microenvironment. Analysis of resected lymph node samples following PD-1 blockade reveals their supportive role in activating and proliferating anti-tumor T cells. Finally, pathologic responders to PD-1 blockade are characterized by both a higher quantity and a less exhausted phenotype of tumor-specific CD8 T cells. This suggests that assessing both the quantity and quality of these T cells can serve as a predictive indicator to distinguish responders from non-responders. Conclusions: These findings highlight the feasibility of antigen-specific profiling in a clinical trial setting, the importance of melanoma-specific CD8 T cells in checkpoint blockade responses, and their potential use an early on-treatment biomarker of clinical outcomes.
Neoadjuvant pembrolizumab and lenvatinib in resectable mucosal melanoma: NeoPlus study update.
Authors: Mao Lili , Dai Jie , Bai Xue , Kong Yan , Cui Chuanliang , Chi Zhihong , Sheng Xinan , Lian Bin , Tang Bixia , Yan Xieqiao , Wang Xuan , Li Siming , Zhou Li , Wei Xiaoting , Li Juan , Li Caili , Wu Xiaowen , Guo Jun , Si Lu ,   Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Melanoma and Sarcoma, Peking University Cancer Hospital and Institute, Beijing, China
Published: July 2024

9580 Background: Combination therapy of anti-PD1 agent with VEGFR inhibitor is a promising therapeutic approach in unresectable or metastatic mucosal melanoma. We conducted this study evaluating neoadjuvant lenvatinib and pembrolizumab in pts with resectable mucosal melanoma. Methods: This was a single-arm, open-label, single-center, phase 2 study conducted from Sep 2021. Eligible pts were adults (18-75 yr) with histologically confirmed, resectable mucosal melanoma. Pts received lenvatinib 20mg qd and pembrolizumab 200mg q3w for 2 cycles, followed by surgery. Pembrolizumab (200mg q3w) continued post operatively for further 15 cycles. The primary endpoint was complete pathologic response (pCR). Secondary endpoints were Relapse free survival (RFS, time from surgery to any event), Overall survival (OS) and safety. Results: Between Sep 2021 and Apr 2023, 26 pts were enrolled, median age was 57 yrs(range: 49-75), 19 were female. Primary sites included: 11 female genital, 8 ano-rectal, 5 head & neck (1 nasal, 4 oral),2 esophageal. 15 pts (58%) were localized disease,11 (42%) were regional lymphatic disease. BRAF V600, NRAS or KIT mutations were presented in 1, 3 and 2 pts, respectively. 21 pts underwent surgery, 2 pts had a pCR (9.5%), 2 near PCR, 4 pPR, with a pathologic response rate of 38% (8/21,95%CI 18-62%). 5 pts did not proceed with planned surgery for pts preference. As of Dec 2023, 12 of 21 resected pts had relapsed (9/11 in female genital,2/4 in ano-rectal, 1/5 in head & neck). Median follow up time was 19.1 months (95%CI 13.7-24.5). Median RFS was 12.4 months (95%CI 4.0-20.8), no difference was observed among these primary sites (female genital: 6.6 months, ano-rectal: 14.1 months, head & neck: not reached). Median DMFS was not reached. IHC data of the resected tumor showed higher CD8+ T cells density in responders (R: pCR+near PCR+ pPR) than non-responders (NR: pNR) (p = 0.046). Tertiary lymphoid structures were detected in 9 pts. Most common TRAEs were hypertension (13, 50%), proteinuria (12, 46%), LDH increased (9,35%), hypothyroidism (8, 31%). Three pts experienced a dose reduction and 5 experienced a dose interruption due to an AE. No grade 4-5 toxicities were observed. Conclusions: Updated results confirmed that the combination of pembrolizumab plus lenvatinib as neoadjuvant therapy had moderate anti-tumor efficacy in resectable mucosal melanoma. Increased CD8+ T cell infiltration was observed in tumor with pathologic response, supporting further investigation in mucosal melanoma.
Characterization of driver oncogenic mutations of in-transit melanoma metastases.
Authors: El Moheb Mohamad , Kim Susan , Cao Chunyan , Zhang Yunwei , Shafiei Mahnoush S , Shen Chengli , Haden Kathleen , Dengel Lynn T , Fallahi-Sichani Mohammad , Tsung Allan , Slingluff Craig , Witt Russell G 
Published: July 2024

9586 Background: In-transit melanoma (ITM) is a distinctive form of melanoma metastasis, marked by aggressive locoregional progression and characterized by the entrapment of tumor cells within the lymphatic channels before reaching regional lymph nodes (LN). The mechanisms leading to lymphatic trapping rather than progression to distant metastasis are not well-understood. Previous research indicates a clonal origin for ITM, suggesting specific early-stage genetic alterations may drive this clinical phenotype. In this study, we sought to identify driver oncogenic mutations specific to ITM that may serve as potential targets. Methods: We analyzed data from the MSK-IMPACT database, which includes targeted sequencing of 341-468 genes for patients with cutaneous melanoma. Patients were stratified into four groups based on the type of sample sequenced: in-transit, primary tumor, regional LN, and distant metastases. We examined the prevalence of driver mutations and genetic variants across these groups, adjusting for multiple comparisons. Results: A total of 528 patients were included, of which 74 were in the ITM, 103 in the primary, 133 in the regional LN, and 218 in the metastatic group. The mean age of the cohort was 59 years (SD = 16) and 67% were male. Among the in-transit samples, 68% were treatment-naïve at the time of sequencing, 36% received anti-PD1 monotherapy, and 12% received anti-PD-1 combination therapy. None of the patients received targeted therapy. NRAS Q61 driver mutations were significantly more common in ITM than all other groups (all p<0.05). NF-1 driver mutations were significantly less common in ITM than distant metastasis (p=0.007) (Table). Comparative analysis across all genes showed a lower incidence of NF-1 mutations in ITM relative to metastatic samples (12% vs 38%, p=0.007). Gene interaction analysis showed mutual exclusivity between NRAS and PAK5 mutations in ITM (p=0.02), but not in other groups (p>0.05). Conclusions: This study reveals distinct driver oncogenic mutations specific to ITM, characterized by a high incidence of NRAS mutations, retained NF-1 function and the novel finding of mutual exclusivity between NRAS and PAK5. Closer examination of the interplay between NRAS, NF-1 and PAK5 interactions in ITM may provide deeper insights into the molecular mechanisms of ITM and offer potential therapeutic targets for ITM. [Table: see text]
The 15-gene expression profile test is independent from PRAME and 7-gene next-generation sequencing: Results from 3,267 clinically tested uveal melanomas.
Authors: Cook Robert W. , Alsina Katherina , Siegel Jennifer J. , Oelschlager Kristen M. , Borman Sherri 
Published: July 2024

9598 Background: The 15-gene expression profile (15-GEP) test is the gold standard in the US for metastatic risk prediction in uveal melanoma (UM). Studies have shown that the 15-GEP is superior to and independent of other clinicopathologic and molecular risk factors, including PRAME expression status and BAP1 mutation status. Supplemental tests for PRAME and the 7-gene NGS panel ( BAP1, SF3B1, EIF1AX, GNA11, GNAQ, CYSLTR2, PLCB4)are validated and can now be run clinically from the same biopsy specimen. However, the discordance between 15-GEP, PRAME and NGS in clinical specimens is unknown. This study aimed to determine whether PRAME status or DNA mutation status could be used to predict the 15-GEP result. Methods: Data from fine-needle aspiration biopsy or formalin-fixed paraffin-embedded UM specimens submitted for routine comprehensive clinical testing with all three commercial tests (15-GEP, PRAME, and NGS) between February 2018 and December 2023 were collected through an Institutional Review Board-approved protocol. Results: Overall, 3267 tumors with comprehensive molecular testing were analyzed. 15-GEP testing yielded 65.9% (n=2152/3267) Class 1 and 34.1% (n=1115) Class 2 tumors. While Class 2 tumors were more than twice as likely to be PRAME(+) vs Class 1, 54.3% (606/1115) of Class 2 cases were PRAME(–), and 20.9% (450/2152) of Class 1 cases were PRAME(+) resulting in a PRAME/15-GEP discordance rate of 32.3% (10-56/3267). Mutations in genes associated with increasing metastatic risk ( EIF1AX, SF3B1, and BAP1, respectively) were identified in 58.7% (1918/3267) of cases. Most EIF1AX mutations (569/623, 91.3%) occurred in Class 1 tumors that were PRAME(–), while most SF3B1mutations were found in Class 1, PRAME(+) tumors (244/404, 60.4%). Most BAP1 mutations (863/976, 88.4%) occurred in Class 2 (high risk) tumors, of which 53.9% (465/863) were PRAME(–). Importantly, 56.0% (1205/2152) of Class 1 tumors did not harbor detectable EIF1AX or SF3B1 mutations, and 22.6% (252/1115) of Class 2 tumors did not harbor a detectable BAP1 mutation, yielding an NGS/15-GEP discordance rate of 44.6% (1457/3267). Conclusions: The validated PRAME and NGS tests described here, which can be performed from the same initial biopsy sample taken for 15-GEP testing, provide results that are not systematically associated with 15-GEP class. Given that the 15-GEP has been shown to be superior to both PRAME and NGS in predicting metastatic outcomes, it is recommended that these supplemental tests only be considered in the context of a 15-GEP test result to prevent potentially over or under identifying high-risk biology. An ongoing prospective study with long term outcomes for over 1700 UM patients led by the Collaborative Ocular Oncology Group (COOG2) will provide insight into how best to effectively integrate these supplementary biomarkers with the 15-GEP class result.
Exosome-delivered microRNAs confer adriamycin-resistance through modulating the immune and metabolism-related gene PTEN in HER2-negative breast cancer.
Authors: Yang Sujin , Zhu Bei , Wu Jia-hao , Cheng Tian-cheng , Zheng Lin , Chen Wei-xian 
Published: July 2024

e12500 Background: Anthracycline is widely used in breast cancer (BCa) chemotherapy, but acquired drug resistance remains a challenge. Increasing evidence suggests that changes in the tumour immune microenvironment (TIME) consistently contribute to the development of chemoresistance. Methods: TIME scores and tumor-infiltrating immune cells (TICs) scores were used to investigate the prognosis, characteristics and gene transcriptomic profiling of HER2-negative BCa patients who received anthracycline chemotherapy. Exosomes from MCF/7-ADR (ADR-exos) and MCF/7-S cell lines were characterized. Dysregulated miRNAs were obtained by using miRNA microarray analysis on BCa cells and their corresponding exosomes. Protein profiling was performed to identify differentially expressed proteins in up- and down-regulated miR-222 cells. Ability of ADR-exos to transfer drug-resistance mediated by miR-222 was assessed by immunofluorescence assay and flow cytometry. Conditions to load miR-222 mimic or inhibitor into exosomes were optimized. Influence of miR-222 inhibitor-containing exosomes on the downstream pathway of miR-222 and the potential therapeutic effects were evaluated. Relationship between miR-222/PTEN and drug resistance in circulating exosomes from mice after doxorubicin chemotherapy was investigated. Results: Firstly, we discovered the complicated and heterogeneous TICs subtypes and their unique biological behaviors in HER2-negative BCa. Then, we identified 85 differentially expressed immunologic signature gene sets and 7202 corresponding immune-related genes in three subtypes quantified by gene set variation analysis. We identified 12 up-regulated and 13 down-regulated genes using miRNA microarray analysis in doxorubicin-resistant cells and their exosomes. Mass spectrometry found 45 differentially expressed proteins affected by miR-222. Moreover, we successfully established miRNA mimic/inhibitor-containing exosomes to explore the solo function of exosomal miR-222 in doxorubicin-resistance both in vitro and in vivo. For the first time, we detected the levels of miR-222 and its target gene PTEN in circulating exosomes from mice after doxorubicin-based chemotherapy and explored the potential clinical implications of miR-222/PTEN-containing exosomes in chemotherapy and immune suppression of BCa. Conclusions: Doxorubicin-resistant cells can transmit drug-resistance to sensitive cells via delivering miR-222 by modulating the immune- and metabolism-related gene PTEN without interference from other relevant drug-resistance factors in exosomes. Therefore, miR-222-containing exosomes and their target gene PTEN may be a promising biomarker for predicting chemotherapy efficacy and tumor immunity regulation in BCa patients receiving anthracycline chemotherapy.
Breast cancer recurrence rate after mastectomy in young females.
Authors: Sahib Hamsa , Azhar Waqas , Saini Nitin , Robinson Kathy J , Delfino Kristin , Rao Krishna A. 
Published: July 2024

e12591 Background: Breast cancer is the most commonly diagnosed female cancer worldwide and the most common cause of cancer mortality in women. Surgical treatment of early breast cancer includes lumpectomy or mastectomy with or without reconstruction. Despite the surgeon’s best effort to perform a radical resection of the breast tissue during mastectomy to achieve locoregional control, residual fibroglandular tissue was found in 20% of breasts on postoperative breast MRI, which carries a risk of recurrence. Younger women with breast cancer have inferior survival rates despite receiving more aggressive therapy. Tumors in young women are more likely to be poorly differentiated, hormone receptor-negative, have a high proliferation index, and more lymphovascular invasion, which is partially explained by patients’ genetic profile. Another factor that could contribute to poor outcomes is the advanced stage at the time of diagnosis, including larger tumor size and higher rates of axillary lymph node positivity. This knowledge has motivated us to conduct this study that is dedicated to looking at the recurrence rate in young females following mastectomy. Methods: This is a retrospective study that collected data from young female patients who were diagnosed with breast cancer between January 2010 and August 2018, had an age at diagnosis of 18-45 years old, and underwent unilateral or bilateral mastectomy with or without reconstruction. The study also looked at the patient’s risk factors and genetic profile. Results: A total of 115 patients were diagnosed with early-stage breast cancer between January 2010 and August 2018 and underwent mastectomy. 81.74% were Caucasian females, and 8.7% were African American females. The mean age of diagnosis was 36.9 years. The mean BMI was 30.5 kg/m2. 59.13% of patients had a family history of breast cancer. The most common genetic mutations were BRCA1 at 7.83% and BRCA2 at 8.7%. 71% of patients underwent a bilateral mastectomy. 76% of patients had reconstruction. 77% of tumors were ER-positive, 68% PR-positive, and 26% HER2-positive. 49.4% of tumors were Nottingham grade 3. 52% of patients had no nodal involvement, while 35% had N1 disease. 34.6% had lymphovascular invasion. We found that 18/115 patients had recurrence of breast cancer following mastectomy. 5/17 patients had locoregional recurrence, while 12/17 patients had a distant recurrence; 1 patient’s recurrence data was unavailable. The median time to recurrence was 1147.5 days (335 to 3107). The 5-year recurrence free survival rate is 86% ± 3%. Conclusions: Our study found that 15.65% of young females had recurrence after mastectomy. To our knowledge, this is the first dedicated study to look at the recurrence rate after mastectomy in this young, high-risk patient population. Our study aims to encourage larger studies in young females with breast cancer to help tailor the treatment plan in this population.
3D cell cultures exhibit increased drug resistance, particularly to taxanes.
Authors: Maestri Chiara , Kumar Jahanvi , Nitiyanandan Rajeshwar , Trus Ivan , Parker Ricardo , Apfel Brigitte , Apfel Christian 
Published: July 2024

e12599 Background: Cell culture platforms could be categorized into two main types: 2D and 3D. 3D cell cultures, known for mimicking the physiological cellular environment, are commonly preferred by researchers to assess drug responses as they accurately reproduce aspects of the in vivo cell behavior. We hypothesized that dose-response curves of 2D and 3D platforms may be drug dependent, with some being more sensitive or resistant depending on the platform. Methods: MCF-7 cancer cells were cultured and plated using a 2D flat bottom well plate platform or using a matrix-based and a matrix-free 3D platform. Cells were treated with chemotherapies and targeted therapies for four days and cellular sensitivity was assessed through a viability assay. Four-parameter logistic (4PL) dose response curves were generated and IC50 values (µM/Cmax) were quantified to understand the differences in dose response curves between the 2D and 3D cellular platforms. Results: While the dose-response curves generally correlate between 2D vs. 3D matrix-based (r2=0.82, p<0.001) and 2D vs. 3D matrix-free methods (r2=0.78, p<0.001), noteworthy variations were observed for certain drugs, particularly paclitaxel (2D IC50= 66; 3D matrix-based IC50 = ≥100; 3D matrix-free IC50 = ≥100) and docetaxel (2D IC50 = ≥34; 3D matrix-based IC50 = ≥100; 3D matrix-free IC50 = ≥100). Additionally, a general increase in resistance was evident when cells formed 3D structures compared to the 2D monolayer condition, as indicated by regression analysis (Y-intercept = 0.55, CI95% 0.32 to 0.78; slope = 0.47, CI95% 0.20 to 0.75). Conclusions: Our findings reveal that taxanes such as paclitaxel and docetaxel exhibit distinctive resistance patterns in 3D structures. In addition, a substantial increase in cellular resistance is observed in 3D cellular models when compared to the 2D assay for most drugs. Despite the overall correlation, these drug-specific differences should be considered. Thus, the next generation of an extreme drug resistance assay, aimed at enhancing the quality of life for patients by avoiding ineffective therapies, might preferentially employ a 3D platform to tailor patients’ cancer therapies.