bluuebunny/crossref_metadata_2025_split huggingface dataset:
Low dose anti-PD(L)-1: A potentially effective alternative for greater accessibility in solid malignancies.
Authors: Souza Iza Andrade de A. , Netto João Pedro Homse , São José Barbara Garcia , Abdalla Kathia , Topanotti Marina , Fernandez Fabio Leite Couto , Guedes João Daniel Cardoso , Fares Aline Fusco , Araujo Daniel Vilarim 
Published: June 2023

e21523 Background: Anti-PD(L)1 agents changed the treatment landscape of multiple tumor types yielding long-term responses in a significant proportion of patients. However, these drugs are costly and not accessible to patients from most countries. Mounting data suggest that lower doses of anti-PD(L)1 can be as efficacious as label-approved doses at lower costs. Herein we compare the outcomes of patients treated with low-dose anti-PD(L)1 agents (LD) and patients treated with conventional doses (CD) at a single tertiary hospital. Methods: This is an observational historical cohort study evaluating the outcomes of patients treated with anti-PD(L)-1 agents (either at LD or CD) at Hospital de Base, São José do Rio Preto - Brazil. We included patients older than 18yo, with solid malignancies and treated with any anti-PD(L)1 agent. Patients were classified as having received LD if the dose administered at the first cycle was below the label dose. Data were abstracted from electronic medical records. Efficacy outcomes, including overall survival (OS), progression-free survival (PFS), and overall response rate (ORR), were evaluated. Log-rank test and Chi-square or Fisher's exact test were used as appropriate. A p-value of 0.05 was considered statistically significant. Results: From January 2020 to October 2022, a total of 43 patients were included: 26 (60.4%) received LD and 17 (39.6%) received CD. The mean age of LD and CD was 66.9 (SD 14.5) and 64.8 (SD 9.7), respectively. Most patients presented with ECOG 0 or 1 (64% LD and 66% CD), had metastatic disease at treatment onset (92% LD and 94.1% CD), and were treated in the first line (50% LD and 64% CD). Most frequent tumor sites were melanoma (38.5% LD, 56.3% CD) and lung (29.9% LD, 18.8% CD). Only 23.1% and 17.6% of tumours in LD and CD were tested for PD-L1 expression, of which 83% and 33% had PD-L1 > 1. Most patients from both groups were treated with pembrolizumab (92.3% LD and 82.4% CD). The mean dose of pembrolizumab was 89.6 mg (1.5 mg/kg) for LD and 171 mg (2.1 mg/kg) for CD. After a median follow-up of 23 months, there was no significant difference in median OS (mOS), mPFS, and ORR between LD and CD (Table). A sensitivity analysis with patients receiving pembrolizumab was performed and had similar results (Table). Conclusions: Our study suggests there is no difference between patients treated with LD and CD anti-PD(L)1 in terms of OS, PFS, and ORR. The numerically shorter OS and PFS in the CD group may be due to selection bias and should be interpreted cautiously. LD anti-PD(L)1 could be an alternative to expand access in places where CD is not affordable. [Table: see text]
Efficacy and safety of BRAF/MEK inhibitor rechallenge in patients with advanced melanoma: Systematic review and meta-analysis.
Authors: Priantti Jonathan N. , Vilbert Maysa , Madeira Thiago , Moraes Francisco Cezar A , Koch Hein Erica C. , Cavalcante Ludimila 
Published: June 2023

e21535 Background: Approximately 50% of patients with melanoma harbor a BRAF mutation and are eligible for targeted therapy (TT) with BRAFi/MEKi. In spite of a response rate of nearly 70%, roughly half of patients will progress within a year due to development of resistance. Rechallenging patients with BRAFi/MEKi may be an alternative to overcome resistance and improve outcomes. We conducted a systematic review and meta-analysis to evaluate the efficacy and safety of BRAFi/MEKi rechallenge in patients with advanced melanoma. Methods: PubMed, Scopus, the Cochrane Library, ASCO publications, ESMO, and AACR databases were searched for relevant studies. Rechallenge was defined as patients treated with BRAFi/MEKi that developed disease progression or had significant adverse effects and went on an interval treatment or drug holiday, before being reintroduced to BRAFi/MEKi. Efficacy was assessed by objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). Heterogeneity was examined with the I(2) statistics and random-effect model was used to pool studies. Results: Seven studies met inclusion criteria, with a total of 400 patients. The medium follow-up ranged from 6.8 to 15.7 months. Elevated LDH was seen in 48.5% (194/400) of patients, and 53% (164/310) had brain metastases (BM). Prior to rechallenge, 83% (333/400) of patients received immunotherapy as interval treatment, mainly anti-PD-1 and/or anti-CTLA-4, and 10% (40/400) were on a drug holiday. During the rechallenge, 79% (317/400) of patients were treated with the combination of BRAFi/MEKi, whereas 21% (83/400) were treated with BRAFi alone. In a pooled analysis, the median PFS was 5 months (95% CI 4.0 – 5.9), and median OS was 9.8 months (95% CI 9.3 – 20.4). The 1-year OS rate was 42.63% (95% CI 30.25 - 55.02). ORR was 34.25% (95% CI 28.50 - 40), and DCR was 65.01% (95% CI 57.31 - 72.72). Prognostic markers such as BM and elevated LDH were not statistically significant. Treatment was well tolerated without unexpected adverse events. Conclusions: This meta-analysis indicates that advanced melanoma patients with refractory disease benefit from rechallenge with BRAFi/MEKi, particularly from high DCR, with a promising effect on 1-year OS rate. Further randomized controlled trials are warranted to investigate these findings. [Table: see text]
Prognostic significance of pseudoprogression defined with lowered threshold iRECIST criteria in advanced melanoma treated with immune checkpoint inhibitor therapy.
Authors: Park Joseph S. , Janicek Milos Josef , Lerner Adam 
Published: June 2023

e21536 Background: The advent of immune checkpoint inhibitor (ICI) therapy has dramatically improved survival in advanced melanoma. Unique to ICI therapy, pseudoprogression (PP) is characterized by an initial radiographic increase in tumor size followed by shrinkage. Modifications to RECIST have been proposed in order to better distinguish this phenomenon from progressive disease (PD). In iRECIST, a > 20% initial increase in target lesions is required to define PD or PP. Here, we assessed whether lowering this threshold would enhance identification and prognostication of pseudoprogression. Methods: In this single-center retrospective cohort study, we analyzed 37 patients with stage IV melanoma treated with PD-1 or CTLA inhibitors. The outcome was overall survival. Imaging from the staging, 1st and 2nd restaging scans were blindly assessed by a radiologist and assigned summed scores of primary tumor and up to 5 metastases. In lowered threshold iRECIST (LT-iRECIST), PP was defined as score increase > 5% on 1st restaging followed by decrease < -5% on 2nd restaging. PD was defined as score increase > 5% on both 1st and 2nd restaging. Regression was defined as score decrease < -5% on both 1st and 2nd restaging. Survival odds and hazard ratios were calculated with univariate Cox regression. The analysis was repeated with the threshold set to ±20% (traditional iRECIST). Results: In the overall cohort, median survival was 861 days. Median time to 1st and 2nd restaging scans was 112 days and 214 days respectively. 5 patients (13.5%) met criteria for PP with traditional iRECIST compared to 9 (24.3%) with LT-iRECIST. Two-year survival odds for PD, PP and regression were 20%, 80% and 66.7% respectively with traditional iRECIST, and 12.5%, 88.9% and 58.3% with LT-iRECIST. Hazard ratios for PP and regression were 0.329 (p > 0.1) and 0.296 (p > 0.1) respectively with traditional iRECIST, and 0.111 (p < 0.01) and 0.269 (p < 0.05) with LT-iRECIST. Conclusions: Harnessing the first two restaging scans and lowering the threshold from 20% to 5% in iRECIST led to identification of a group of patients in whom pseudoprogression is associated with a significant survival benefit. In advanced melanoma treated with ICI, adopting this iRECIST modification may allow early discrimination of pseudoprogression and its associated favorable outcome. [Table: see text]
Multi-omics analysis of atezolizumab plus bevacizumab in patients with unresectable or metastatic mucosal melanoma.
Authors: Dai Jie , Mao Lili , Xu Tianxiao , Li Lifeng , Lin Jing , Zhang Guoliang , Chen Yu , Bai Xue , Li Caili , Si Lu , Guo Jun 
Published: June 2023

e21539 Background: A multicenter, open-label, single-arm phase II study has demonstrated that atezolizumab plus bevacizumab showed promising efficacy and manageable safety in patients with advanced mucosal melanoma, with an ORR of 45.0%. Here, we report the multi-omics analysis results with the aim of identifying potential biomarkers of response to this combination therapy. Methods: Patients with available samples were included in this study. The FFPE tissue was performed for DNA and RNA co-extraction and underwent whole exome sequencing (WES) and transcriptome sequencing. The responses were classified as complete response (CR) and partial response (PR) for responders and stable disease (SD) and progressive disease (PD) for non-responders per RECIST v1.1. Mutational signature, SNVs clonality, copy-number variations, differential expression genes, GSEA, and the immune microenvironment analysis were performed and analyzed for correlation with clinical benefits. Results: A total of 29 patients with FFPE samples underwent WES and/or transcriptome sequencing, including 1 CR, 15 PR, 9 SD, and 4 PD. As of January 11, 2023, the median follow-up time was 31 months (range, 5.0 to 37.0 months). Compared with non-reponders, responders had a significantly longer PFS (median 14.0, 95% CI 9.1 to 16.9 months vs 2.0, 95% CI 1.5 to 2.5 months, P< 0.001) and OS (median 35.0, 95% CI 20.4 to 49.6 months vs 14.0, 95% CI 5.5 to 22.5 months, P =0.005). Of the patients who underwent WES analysis, TMB and TNB were not associated with response, PFS or OS; but 53.3% (8/15) of responders harbored NRAS/PKHDL1 mutation, whereas only 16.7% (2/12) of non-reponders harbored NRAS/PKHDL1 mutation ( P= 0.112). Transcriptome analysis revealed that compared with non-reponders, responders displayed more significant angiogenesis, T cell cytotoxicity and interferon gamma response gene expression signatures. CIBERSORT analysis showed that responsders had higher proportions of cytotoxic immune cells, and non-responders had higher a higher proportion of B cells. The expression of CD274 was not associated with the response, and the expression of CD276 was significantly higher in responders than that in non-responders ( P =0.014). Weighted gene co-expression network analysis showed that the high expression of genes associated with the p38 MAPK pathway presented in cold tumor environments ( P =0.052) and was negatively correlated to the PFS ( P< 0.001) and OS ( P< 0.001). Conclusions: These molecular profiles indicated that the inflammatory cell infiltration and tumor angiogenic status was associated with response to anti-PD-L1 and anti-VEGF combination treatments, and targeting p38 MAPK pathway may further improve the survival of patients with mucosal melanoma.
Survival outcomes of metastasectomy and primary site resection in melanoma patients with isolated brain metastasis: A SEER analysis.
Authors: Fahmawi Suhib , Al-Ani Abdallah , Asfour Issa , Manthri Sukesh 
Published: June 2023

e21541 Background: Approximately 40–50% of Stage IV melanoma patients eventually develop brain metastases which is associated with poor prognosis. Breakthroughs in targeted and immunotherapies have improved long-term survival in advanced melanoma patients. In this new era, there is a paucity of evidence for the role of metastatectomy for melanoma patients with brain metastasis. Here, we investigate the survival benefit of metastasectomy and primary site resection in melanoma patients with isolated brain metastasis. Methods: A total of 636 patients with melanoma with isolated brain metastasis at diagnosis were extracted from the Surveillance, Epidemiology, and End Results (SEER) database between 2010 and 2019. Patients younger than 18 years, cases with missing information including age, gender, race, unknown stage, unknown primary site resection status, unknown metastasis site, or known metastasis to the lung, liver, or bones were excluded. Cox regression analysis estimated the prognostic value of metastasectomy and primary site resection, presented by hazard ratios (HR), among melanoma patients. Survival ratios were controlled for age, race, gender, and type of melanoma. All analyses were performed on STATA v17. Results: About 49.37% of melanoma patients with isolated brain metastasis underwent metastasectomy. Of the included sample, 25% (n = 159) underwent primary site resection. Cox regression demonstrated that metastasectomy was associated with improved survival outcomes in melanoma patients with isolated brain metastasis (HR 0.51, CI 0.42 – 0.63, p < 0.001). Pooled primary site resection procedures were associated with improved survival (HR 0.64, CI 0.49 – 0.83, p = 0.001) compared to not having a primary site resection. When stratified per procedure type, “wide excision or re-excision of lesions with margins > 1 cm and microscopically negative margins” was associated with improved survival (HR 0.27, CI 0.133 – 0.56, p < 0.001) compared to not having surgical resection, all other primary site resection procedures had no significant improvement in survival with p > 0.05. Conclusions: Metastasectomy and primary site resection significantly improved survival in melanoma patients with isolated brain metastasis. Wide excision with > 1cm negative margins presents itself as the most effective surgical treatment modality in terms of improving survival for these patients. Thus, it should be attempted whenever feasible.
A cilia-related marker predicting suitability for immunotherapy in melanoma.
Authors: Zhu Changbin , Chen Yanhua , Yu Rongshan , Xiao Xu , Kong Yan 
Published: June 2023

e21560 Background: Cilia exert tumor suppressor effects in several tumor types including melanoma, and scientists found that blocking cilia growth in drug-resistant cancer cell lines may restore cancer cells' sensitivity to immunotherapy. Therefore, we hypothesized that cilia might be used as a predictive biomarker for melanoma immunotherapy. Methods: Through literature search, a total of six sets of RNA-seq and WES data of melanoma samples receiving PD-1/CTLA-4 immunotherapy were collected. GSVA was used to obtain an enrichment score between the samples and a set of 112 ciliary genes, based on which ciliary signatures were screened for prognosis. The ciliary characteristic gene set was further optimized by LASSO regression, then a risk model was constructed by combing stepwise regression and COX regression. Log-rank test was used to verify survival differences between high and low risk groups in other independent data sets, and Wilcox test was used to explore differences in other clinical characteristics between high and low risk groups. Imaging mass spectrometry (IMC) and spatial position imaging (SPI) data were used to analyze cell states in tumor tissues. All analyses were performed by R 4.0.3. Results: A total of 10 cilia pathways related to prognosis were screened out in the training set, and 13 genes were picked out from these 10 pathways as selected features. Combining LASSO and COX regression, a risk model consisting of 5 genes were finally obtained. Patients in the high-risk (HR)group classified by this model had a significantly worse prognosis than the low-risk (LR) group in both the training and test sets (p < 0.05, respectively). In addition, by analyzing immune infiltration and pathway enrichment, it was found that LR group was in the state of immune activation, and its immune score was significantly higher than that of HR group. Further analysis showed the model had no significant correlation with other clinical features, such as pathological stage, tumor mutation burden and NF1/KRAS/BRAF gene mutations, indicating that the model was relatively independent. By IMC data analysis, it was found that the number of tumor cells in LR and HR groups were similar (107082 vs 11928), but the number of lymphocytes in LR group was significantly higher than that in HR group (71578 vs 5313). Moreover, among the 35 protein markers related to immunotherapy, 16 (45.7%) proteins were up-regulated and 0 protein was down-regulated in LR group. By analyzing SPI of multiple regions of these samples, it was also observed that tumor tissues in LR group were mostly in a state of lymphocyte infiltration, while these in HR group were in a state of immune rejection or immune desert. Conclusions: The model constructed based on cilia-related features in this study can independently identify melanomas with high risk of recurrence or progression, and provide a theoretical basis for exploring whether targeted cilia structure therapy can be used as a treatment for melanoma.
Utility of circulating tumor DNA as a tool to detect minimal residual disease in patients with metastatic cancer and durable response following treatment with immune checkpoint inhibitors.
Authors: Afzal Muhammad Zubair , Corea-Dilbert Flanklin E. , Wankel Bret , Palmer John P. , Pirruccello Jonathan P. , Kale Soham , Sharma Aditya , Lu Ziyao , Ibrahim Samer , Cao Yuanzhen , Sarwar Tayyaba , Shirai Keisuke 
Published: June 2023

e21563 Background: Circulating tumor DNA (ctDNA) is tumor-derived fragment of DNA circulating in plasma. ctDNA has been used to detect minimal residual disease (MRD) in early-stage cancers after curative intent therapy. However, ctDNA based MRD concept is not investigated in metastatic disease. There is a lack of clarity around optimal timing to stop immune checkpoint inhibitors (ICI) in melanoma and lung cancer patients who have achieved durable response (DR) and MRD may have a role here to select right patients to stop therapy at an optimal time. Methods: This is prospective study on metastatic lung cancer and melanoma patients with DR treated with ICI. DR is identified as objective response (CR/PR) by modified WHO criteria lasting ≥6 months continuously. We utilized Signatera assay by Natera. Signatera uses tissue from original biopsy of the patients and develop multiplex PCR based personalized assay to detect MRD. The level of ctDNA is reported in mean tumor molecules per mL. We obtained ctDNA assay at baseline, month 3 and month 6 at their routine follow up visits. If applicable, ctDNA assay was done at the time of progression, and 3 months after resuming treatment. Results: We identified 29 melanoma and 17 Lung cancer (both small cell and non-small cell) patients with metastases and DR. Median age was 69 years in both cohorts. Median duration of ICI was 14 months in melanoma and 24 months in lung cancer cohort. ctDNA assay was obtained in 26 melanoma and 13 lung cancer patients. One small cell lung cancer patient had detectable ctDNA at baseline, although radiographically, the patient had DR. The rest of the patients in both cohorts had undetectable ctDNA. 2 melanoma patients developed detectable ctDNA on subsequent assays and their therapies were changed. One small cell lung cancer patient has persistently detectable ctDNA on subsequent assays but remained in DR. A total of 10 patients in both cohorts decided to stop their therapy following several -ve ctDNA assay. Conclusions: The role of ctDNA needs to be investigated in advanced/metastatic settings as MRD may have a role to identify patients who may benefit from treatment break. MRD surveillance may also support radiographic assessment. [Table: see text]
Targeting Exportin 1 as treatment for cutaneous squamous cell carcinoma.
Authors: Rana Ricky , Hansen Laura A. 
Published: June 2023

e21564 Background: Cutaneous squamous cell carcinomas (cSCC) are among the most frequent solid cancers in humans and in the U.S., cSCC cases are increasing. Molecular mechanisms transitioning premalignant lesions to cancer are not well characterized. As a result, targeted therapies need to be identified to treat these lesions. Preliminary data shows that Exportin 1 (XPO1) is one of the major proteins regulating nuclear export of proteins, helping to maintain cellular homeostasis. Previous work showed that Exportin 1 modulates the nuclear:cytoplasmic ratio of signaling proteins in skin cancer; resulting in an anti-apoptotic effect by adjusting the nuclear-cytoplasmic balance of pro-survival proteins such as CDC25A and Survivin. XPO1 expression is upregulated in many cancers, thereby affecting the nuclear:cytoplasmic ratio of many pro-survival proteins and enhancing tumorigenesis. This research project was designed to investigate the effects of XPO1 inhibition on cSCC survival. Selinexor is FDA cleared for treatment of multiple myeloma patients. Selinexor is a selective inhibitor of XPO1 regulated nuclear transport causing target molecules to remain within the cell leading to decreased cancer cell growth and decreased cancer cell survival. We hypothesize that inhibiting XPO1 with Selinexor or by CRISPRi genetic knockdown of XPO1 in cSCC cells will reduce proliferation and increase apoptosis in cSCC cells. Methods: Human cSCC cell lines SCC13 and SRB12 were seeded in 96-well plates at 8,000 cells/well density and 3,000 cells/well, respectively. Cells were treated with varying concentrations of Selinexor (0.005mM – 5mM) or DMSO as vehicle control. At 24-hour intervals, cell imaging and Neutral red staining assays were conducted to determine the IC50 concentration for Selinexor in cSCC cell lines. SCC13 cells stably expressing dCas9-KRAB and a doxycycline-inducible XPO1 guide RNA were used for CRISPRi experiments. Cells were treated with doxycycline daily and apoptosis was assayed by Caspase Glo 3/7 daily for four days. CRIPSRi enabled a doxycycline inducible XPO1 knock down on SCC13 cells allowing us to disrupt the cellular transporter protein XPO1. Results: Selinexor treatment of SRB12 cells resulted in an IC50 of 1.174 μM and 0.071 μM for SCC13. In contrast, normal human keratinocyte cell lines had higher IC50 values of 2.18 μM for HaCaT and 5.29 μM for KerCT cells. Apoptosis significantly increased after 72 and 96 hours of XPO1 knock down in SCC13 cells measured by Caspase Glo. Conclusions: These results document how XPO1 inhibition reduces proliferation and is toxic to both normal keratinocytes and cSCC cells. Additionally, cSCC cells had lower IC50 values for Selinexor, suggesting cSCC may be more sensitive to XPO1 inhibition compared to normal keratinocytes. Further, targeting XPO1 also increases apoptosis in these cells. This data supports the hypothesis that targeting XPO1 may be effective in treating cSCC.