bluuebunny/crossref_metadata_2025_split huggingface dataset:
Leveraging longitudinal clinical annotations and panel sequencing to characterize dynamics of organotropism in metastatic melanoma.
Authors: Aprati Tyler J , Manos Michael P. , Ge Will , Tarantino Giuseppe , Bai Xue , Rahma Osama E. , Gusev Alexander , Boland Genevieve Marie , Kehl Kenneth L. , Liu David 
Published: June 2023

9526 Background: Although metastasis plays a major role in the mortality and morbidity of melanoma, patterns of metastasis and drivers of organotropism have not been well characterized clinically. Although previous efforts have been made to examine genomic drivers of organotropism, a longitudinal examination of metastasis dynamics has not been well characterized clinically. Methods: To address these questions, we leveraged a clinico-genomic dataset of patients with metastatic melanoma (Kehl et al. 2021). From this dataset, we assembled a cohort consisting of 26,143 artificial intelligence-annotated imaging reports from 879 patients with metastatic melanoma with an average of 2 years of followup after initial metastatic diagnosis. Annotated metastasis sites included brain, bone, adrenal, liver, lymph node, lung, and mesentery. All patients were evaluated at the Dana-Farber Cancer Institute, and each patient has at least one tumor biopsy sequenced with OncoPanel, a next-generation sequencing panel that identifies mutations in 447 cancer-related genes. Lifetime incidence of metastatic sites was defined as whether a patient ever had a report annotated with that site. Time-to-event analyses on metastatic sites used the acquisition of a metastatic site as the event of interest. For each patient index dates were defined as the date of the first scan with cancer present. We used cumulative incidence models to examine the incidence of each site in our cohort, and both cause-specific hazard models and Fine-Gray modeling to account for competing events and determine the effect of genomic covariates. Results: For lifetime metastasis status, the overall incidence varied by site, with LN being the most common, occurring in ~75% of patients, and mesentery the rarest, occurring in ~12% of patients. For lifetime metastasis status, patients with adrenal metastases were positively enriched for mutations in SETD2 (P < 0.005). Among the significant genes for all sites were many genes encoding epigenetic modifiers. In the time-to-event setting, the order of the cumulative incidence functions for each site matched the lifetime frequency of sites. Through time-to-event analysis we found genes whose mutant status were significantly associated with a change in risk and/or rate of certain metastatic sites. Among other results, we found that having a mutation in SETD2 is significantly positively associated with an increase rate and risk of adrenal metastases (cause-specific HR 2.4, P < 0.005, Fine-Gray HR 2.6, P < 0.005), and NRAS mutations were significantly associated with lower rate and risk of liver metastasis (cause-specific HR 0.59 P < 0.05, Fine-Gray HR 0.58 P < 0.01). Conclusions: By using time-to-event analysis with longitudinal metastatic annotations, we identify potential drivers of organotropism in melanoma patients.
Risk of further progression or death among durable progression-free survivors with melanoma in PD-1 blockade trials: Implications for imaging surveillance.
Authors: Deng Lei , Jiang Changchuan , Attwood Kristopher , Perimbeti Stuthi , Hu Chen , Puzanov Igor 
Published: June 2023

9529 Background: Durable progression-free survivors (dPFSors) over 2 years have been reported among melanoma patients treated with PD-1 blockade. However, non-negligible risk of further progression still exists and the optimal imaging surveillance interval is unknown. Methods: Individual patient data of progression-free survival (PFS) were extracted from PD-1 blockade clinical trials with follow-up of at least 5 years of PFS events. Co-treatment with anti-CTLA4 antibody was allowed. Patients with PFS of at least 2 years were considered as dPFSors. Conditional risk of progression or death with 95% CI was estimated based on a piece-wise exponential survival model, with the assumption that within each year from the beginning of the third year, the risk of progression/death (P/D) was constant. Conditional risks of P/D every 3, 4, 6, and 12 months in each subsequent year were calculated with 95% confidence interval (CI). We pre-specified three maximal risk levels – 10%, 15%, and 20% at each imaging scanning interval. An interval is considered as acceptable if the 95% CI upper bound of the risk at each scan is lower than a pre-specified risk level. Results: Of 1495 melanoma patients from 3 clinical trials, 474 (31.7%) were dPFSors. Among them, the PFS probability for additional 3 years was 76.4%. During the 3 years, no more than 5.0% of patients had P/D in any quarters. The yearly risk of P/D was 15.5% (95% CI 13.7% - 17.3%), 8.8% (6.8% - 10.8%), and 6.3% (3.8% - 8.8%) during the 3rd, 4th, and 5th year, respectively. Under risk at 10%, 15%, and 20%, melanoma dPFSors can be scanned every 6, 6, and 12 months during the 3rd year, every 6, 12, and 12 months during the 4th, and every 12, 12, and 12 months during the 5th, respectively. Conclusions: Based on their own risk tolerance level, our findings allow clinicians and dPFSors make data-driven decisions regarding imaging surveillance schedule beyond every 3 months. [Table: see text]
A prediction model for response to immune checkpoint inhibition in advanced melanoma.
Authors: van Duin Isabella A.J. , Verheijden Rik Jasper , van Diest Paul J. , van den Eertwegh Alfonsus Johannes Maria , de Groot Jan Willem , van Not Olivier Jules , Aarts Maureen J.B. , Van Den Berkmortel Franchette , Blank Christian U. , Haanen John B. A. G. , Hospers Geke , Piersma Djura , van Rijn Rozemarijn , Van Der Veldt Astrid Aplonia Maria , Vreugdenhil Gerard , Stevense - den Boer Marion , Boers-Sonderen Marye J. , Kapiteijn Ellen , Suijkerbuijk Karijn , Elias Sjoerd G. 
Published: June 2023

9532 Background: Immune checkpoint inhibition (ICI) has greatly improved the prognosis for advanced melanoma in the last decade. However, it is still difficult to predict who will benefit from treatment. We aimed to develop a multivariable prediction model for response to ICI, using clinical data including primary melanoma characteristics. Methods: We used a population-based cohort of 3525 patients with advanced cutaneous melanoma treated with anti-PD-1-based therapy, originating from the Dutch Melanoma Treatment Registry. The endpoint of the study was objective response to ICI within 6 months after treatment initiation. The model considered 15 candidate predictor variables, was developed with logistic regression using Akaike information criterion-informed backward selection, and was internally validated with bootstrap resampling. Performance evaluation included calibration and discrimination. We used multiple imputation to account for missing data. Results: Patients received anti-PD-1 monotherapy (n = 2366) or ipilimumab plus nivolumab (n = 1159) in any treatment line. Median follow-up time was 15 months and 1311 patients (39%) had an objective response within 6 months. The prediction model for response included sex, serum lactate dehydrogenase, World Health Organization performance score, type of systemic therapy, line of systemic therapy, stage of disease, location of primary melanoma, type of primary melanoma, satellites and/or in transit metastases at time of primary diagnosis, and time to first distant recurrence. The model was well-calibrated. The AUC was 0.664 (95% confidence interval [CI] 0.645-0.682), and the over-optimism adjusted AUC was 0.649 (95% CI 0.631-0.667). The range of predicted response probabilities was 6-78%. Based on these probabilities, patients were categorized into quartiles. The median predicted response probability was 25% (interquartile range [IQR] 21-28%) for the lowest quartile and 54% (IQR 50-59%) for the highest quartile. Compared to the lowest response quartile, patients in the highest quartile had a significant longer median PFS (19.9 versus 2.8 months; p < 0.001) and median OS (66.5 versus 8.4 months; p < 0.001). Conclusions: We present a model based on both clinical variables and primary melanoma characteristics capable of predicting response to ICI in patients with advanced melanoma. This model can discriminate between patients with a very good and very poor prognosis.
Interim results from a phase I/II study of duvelisib PI3Kδγ inhibitor and nivolumab in patients with advanced unresectable melanoma who have progressed on anti-PD1 therapy.
Authors: Jin Jingxiao , Rohatgi Anjali , Gabrielle Andrew , Rose Amy , Wilson Melissa , Bruno Tullia C. , Kirkwood John M. M. 
Published: June 2023

9540 Background: The majority of unresectable melanoma patients eventually progress on first-line checkpoint blockade therapy. Duvelisib is a potent phosphoinositide 3-kinase (PI3K) δ and γ isoform inhibitor approved for relapsed/refractory CLL. PI3Kγ inhibition has been shown to restore anti-PD1 activity in preclinical tumor models through conversion of tumor associated macrophages (TAMs) from an immunosuppressive to a pro-inflammatory state. PI3Kδ inactivation has been associated with impaired T regulatory cell (Treg) function and reduced intratumoral Treg numbers. We report study design and results of a phase I study to evaluate the safety and efficacy of duvelisib and nivolumab in anti-PD1 refractory patients. Methods: Utilizing a modified 3+3 design with escalating doses of duvelisib (15 mg daily, 25 mg daily, and 25 mg BID), patients with unresectable melanoma were treated with nivolumab and duvelisib until unacceptable toxicity or disease progression. Primary endpoints for the phase I portion were maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of duvelisib. Secondary endpoints include early and late toxicities and anti-tumor activity based on RECIST v1.1. Exploratory endpoints were to evaluate dose-dependent changes in the immune cell populations of peripheral blood and tumor tissue with duvelisib and nivolumab. Results: Ten patients have been enrolled (7 at dose level I, 3 at dose level II) with mean age 64. Two patients had BRAF V600E mutation and were previously treated with BRAF/MEK inhibitors. No dose limiting toxicities (DLT) were observed. Grade 3 or higher adverse events (AEs) attributable to study treatment occurred in 4 patients (40%), including G3 neutropenia (10%), G3 diarrhea (10%), G3 vomiting (10%) and G4 hepatitis (20%). Both instances of hepatitis resolved rapidly with 1-2mg/kg of prednisone. In one patient, hepatitis and nausea/vomiting led to discontinuation of treatment. Out of 6 patients who had follow-up imaging, 4 exhibited progressive disease, one stable disease, and one had partial response of 11 months duration. Given the published data on the regulation of macrophages and Tregs by PI3Kδγ inhibitors, we are utilizing multispectral imaging to measure the spatial interactions of key immune cells within the tumor microenvironment (T cells, B cells, and macrophages) in all matched pre-/post-treatment paraffin-embedded tissues, for which results will be presented. Conclusions: The combination of duvelisib and nivolumab was well-tolerated in patients with advanced unresectable melanoma refractory to ICI without DLTs to date at 15 and 25mg daily dosages. Significant anti-tumor activity was noted in one patient. Enrollment at dose level II is ongoing. Clinical trial information: NCT04688658 .
Breaking primary checkpoint inhibitor resistance: Interim analysis of a multicenter phase II study by intermittent application of an alkylating agent among patients with metastatic melanoma.
Authors: Heinzerling Lucie , Haferkamp Sebastian , Schilling Bastian , Berking Carola , Geissler Ed , Zeman Florian 
Published: June 2023

9544 Background: Patients with BRAF wildtype (wt) metastatic melanoma with primary resistance to immune checkpoint inhibitors (ICI) have a dismal prognosis. Chemotherapy has been shown to induce mutations, alter the tumor microenvironment as well as the microbiome, and modulate the immune system. This prospective phase II trial investigates whether two applications of an alkylating agent (dacarbazine/DTIC) can render ICI non-responsive patients with metastatic melanoma responsive to the same checkpoint inhibitor regime. Methods: The PROMIT trial (NCT04225390) targets patients with histologically confirmed BRAFwt metastatic melanoma showing primary resistance to ICI therapy. Applying an optimal two-step design, the uninteresting responder rate was set to 5% with an expected rate of 20%. Response is defined as complete or partial response by week 14 according to RECIST 1.1. Design foresaw 29 assessable patients at first step and 38 patients overall (alpha one-sided 5%, 90% power).After showing primary resistance to ICI, patients received 2 doses of DTIC (850 mg/m2 i.v.) on days 1 and 21, and were subsequently re-exposed to the same ICI therapy they had previously shown resistance to. Results: In total, 38 patients were screened at 4 skin cancer centers. Interim analysis was performed after 29 patients who had received at least one ICI re-exposure were assessable for efficacy. Overall response rate was 24% (90%CI 12-41%) with 7 out of 29 patients showing a partial response; disease control rate was 38%. Application was well tolerated with 16% grade 3 or more adverse events and no new safety signals. Conclusions: Interim analyses results indicate that this approach of a short-term chemotherapy can break resistance in a subgroup of patients and allows us to continue the phase II trial to assess relevance of this treatment approach for metastatic melanoma. Enrolment is ongoing. Clinical trial information: NCT04225390 .
Phase II clinical trial of camrelizumab combined with famitinib for advanced acral and mucosal melanoma.
Authors: Mao Lili , Si Lu , Li Caili , Bai Xue , Dai Jie , Wei Xiaoting , Kong Yan , Cui Chuanliang , Chi Zhihong , Sheng Xinan , Lian Bin , Wang Xuan , Tang Bixia , Li Siming , Yan Xieqiao , Zhou Li , Li Juan , Wu Xiaowen , Li Huajun , Guo Jun 
Published: June 2023

9550 Background: Acral and mucosal melanoma were rarely seen in Caucasians but common in Asians. Previous studies revealed that acral and mucosal melanoma are more aggressive than cutaneous melanoma with a high unmet need for effective treatments. Camrelizumab plus anti-angiogenic agents have shown promising antitumor activity in previously untreated melanoma. Famitinib, a selective multiple-target tyrosine kinase inhibitor that exhibits both anti-angiogenesis and antiproliferative effects via targeting VEGFR-2, PDGFR, c-kit, FGFR and so on, combined with camrelizumab had been proven effective in multiple cancers. This study aimed to assess the antitumor activity and safety of camrelizumab plus famitinib in both immunotherapy naïve and experienced advanced mucosal or acral melanoma. Methods: This single-center, open-label phase II study recruited patients (pts) with advanced acral and mucosal melanoma. Pts who were immune checkpoint inhibitors (ICI) treatment naïve were in cohort 1, while pts experienced ICI in cohort 2. In both cohorts, pts received camrelizumab (200 mg i.v. q3w) and famitinib (20 mg po qd) until disease progression or intolerable toxicity. The primary endpoint was objective response rate (ORR) per RECIST1.1. Secondary endpoints included progression free survival (PFS), disease control rate (DCR), overall survival (OS), and safety. This analysis focused on cohort 2. Results: As of January 12, 2023, 18 pts (9 mucosal and 9 acral histology subtypes) were enrolled in cohort 2. The median age of all pts was 58 yrs (ranged 38-71 yrs); 9 pts (50.0%) were female; prevalence of mutations: BRAF (11.1%), C-KIT or NRAS (16.7% each); 38.9% received ≥2 prior treatments. All pts progressed after anti-PD-1/L1 monotherapy (27.8%) or combinational therapy (66.7%), except one progressed after 4-1BB mAb monotherapy. The combination drugs included anti-LAG-3/CTLA-4 antibodies (38.9%), oncolytic viruses (11.1%), c-kit inhibitors, chemotherapy and anti-angiogenic agents (5.6% each). The median follow-up was 7.3 months (ranged 4.6-14.7 months). At the data cutoff, 5 pts remained on treatment. 17 pts were evaluable. The ORR and DCR were 17.6% and 64.7%, including two pts with confirmed PR, and one with unconfirmed PR, all of which were acral subtype. The median PFS was 6.0 months. The median OS was not reached. Of 18 pts, the incidence of treatment-related adverse events (TRAEs) was 88.9%. The most common grade 3 TRAEs was neutrophil count decreased (11.1%). No grade 4 TRAEs and no treatment-related deaths occurred. Conclusions: Camrelizumab plus famitinib showed promising antitumor activity in ICI-experienced advanced acral and mucosal melanoma pts, and was generally well tolerated. Clinical trial information: NCT05051865 .
Machine learning (ML)-based quantification of tumor-infiltrating lymphocytes (TIL) and clinical outcomes of patients with melanoma treated with immune-checkpoint inhibitors (ICI).
Authors: Adib Elio , Rakaee Mehrdad , Nassar Amin , Bou Farhat Elias , Hodi F. Stephen , Kwiatkowski David J. 
Published: June 2023

9560 Background: TIL quantification has shown promising prognostic and predictive impact in various tumors treated with ICI. More recently, TIL therapy has become an emerging treatment agent for ICI-refractory melanoma. In this work, we studied the effect of intrinsic TILs on clinical outcomes of patients with melanoma treated with ICI and quantified its utility as a biomarker in combination with tumor mutational burden (TMB). Methods: We applied a previously developed ML model to process digital whole-slide images of hematoxylin and eosin slides to quantify TIL density (TIL/mm2) in 182 metastatic melanoma samples treated with ICI at the Dana-Farber Cancer Institute. All samples underwent next-generation targeted-panel sequencing and had available TMB data (mutations/megabase). Overall survival (OS) was calculated from the data of ICI initiation to the date of death. TTF was calculated from the data of ICI initiation to the date of next line treatment or death. Alive patients were censored at the date of last follow-up. Multivariable cox regression was used to estimate adjusted hazard ratios (adj-HR) and p-values (adj-p), with TMB, prior lines of treatment and regimen type (single vs. combination ICI) used as covariates. TMB-high (TMB-H) group was defined as samples with TMB≥10. TIL-high (TIL-H) group was defined as samples with TIL density higher than the median. Results: Of 182 patients, 60% (110/182) were male and the median age at ICI start was 65.5 years. 63% (115/182) of patients received single-agent ICI (anti-PD1 or anti-CTLA4). Of 182 tumor specimens assessed for TILs, 47 (25.8%) were obtained from the primary site. There was no difference in TIL density (medians 583 vs. 817 TILs/mm2, p=0.57; 709 TIL/mm2 for full cohort) or TMB (medians 11.4 vs 12.2 mutations/megabase) between primary and metastatic samples, respectively. Moreover, there was no correlation between TIL density and TMB (pearson’s correlation coefficient = 0.92, p=1) across all samples. Compared to patients in the TIL-low (TIL-L) category, patients in TIL-H had significantly longer median TTF (33.9 [15.9-NR] versus 13.0 [7.8-18.6] months, adj-HR: 0.53 (95% CI: 0.36-0.78); adj-P=0.0012), while there was no difference in OS (P=0.57). In fact, patients in the TMB-H/TIL-H group had the longest TTF, followed by TMB-H/TIL-L, TMB-L/TIL-H then TMB-L/TIL-L (table). Conclusions: Our results support the potential use of ML-based TIL scoring as a novel and independent biomarker to predict time to failure on ICI. There is ongoing effort to validate our findings in an external dataset. [Table: see text]
Transforming growth factor-b1 and soluble co-inhibitory immune checkpoints as putative drivers of immune suppression in advanced basal cell carcinoma.
Authors: Rapoport Bernardo Leon , Anderson Ronald , Malinga Nonkululeko , Steel Helen C. , Meyer Pieter , Smit Teresa , Kgokolo Mahlatse 
Published: June 2023

9567 Background: BCC rarely metastasizes and the mortality rate is low; however, the disease is associated with substantial morbidity. Transforming growth factor-b1 (TGF-b1) is a key player in cell proliferation, differentiation, apoptosis, and immune regulation. TGF-b1 is associated with immunosuppression and resistance to immunotherapeutic drugs. Immune checkpoint proteins (ICMs) maintain self-tolerance and modulate the immune responses of effector cells. The current study compared the levels and possible associations between systemic soluble ICMs (sICMs) and a group of humoral modulators of immune suppressor cells in a cohort of patients with advanced basal cell carcinoma (BCC, n = 40) and a group of healthy control subjects (n = 20). Methods: We measured sICMs and immunosuppressive humoral modulators by using multiplex bead array or ELISA procedures, with plasma as the matrix. The sICMs comprised seven co-inhibitory (CTLA-4, BTLA, LAG-3, PD-1, PDL-1, PDL-2, and TIM-3) and eight co-stimulatory (CD27, CD28, CD40, CD80, CD86, GITR, GITRL, and ICOS) proteins, as well as the two dual-active sICPs, HVEM and TLR2. The seven humoral modulators of immunosuppressor cells included arginase 1, fibroblast activation protein (FAP), RANTES (Regulated upon Activation Normal T Cell Expressed and Presumably Secreted) also known as CCL5, interleukin-10 (IL-10), TGF-b1, and the M2-type macrophage biomarkers, soluble CD163 (sCD163) and sCD206. Ethics approval was granted by The Research Ethics Committee, Faculty of Health Sciences, University of Pretoria (Ethics Committee Approval Numbers 356/2020. Results: The plasma levels of six co-inhibitory sICPs, sCTLA-4, sLAG-3, sPD-1, sPD-L1, and sTIM-3 and sPD-L2 were significantly elevated in the cohort of BCC patients ( p< 0.001- p< 0.00001), while that of sBTLA was significantly decreased ( p< 0.006). Of the co-stimulatory sICPs, sCD27 was significantly increased ( p <0.0002) in the cohort of BCC patients, with the levels of the others essentially comparable with those of the control patients; of the dual active sICPs, sHVEM, sTLR2 was significantly elevated ( p< 0.00001) and TLR2 comparable with the control group. Although the plasma levels of the seven modulators of immune suppressor function were not significantly different between the BCC and control groups, correlation heat maps revealed selective, strong associations of TGF-b1 with seven co-stimulatory (z = 0.618468-0.768131) and 4 co-inhibitory (z = 0.674040-0.808365) sICPs, as well as with sTLR2 (z = 0.696431). Conclusions: Notwithstanding the association of BCC with selective elevations in the levels of a large group of co-inhibitory sICPs, our novel findings also imply the probable involvement of TGF-b1 in driving immunosuppression in this malignancy, possibly via activation of regulatory T cells.