bluuebunny/crossref_metadata_2025_split huggingface dataset:
Re-irradiation in recurrent glioblastoma: PET- or MRI-based? Results of a prospective randomized clinical trial.
Authors: Popp Ilinca , Weber Wolfgang A. , Graf Erika , Mix Michael , Wiehle Rolf , Nestle Ursula , Schimek-Jasch Tanja , Niyazi Maximilian , Belka Claus , Paulsen Frank , Eckert Franziska , Eble Michael J. , König Liane , Giordano Frank Anton , Sperk Elena , Momm Felix , Spehl Irina , Combs Stephanie E. , Bernhardt Denise , Grosu Anca L. ,   GLIAA Study Group
Published: June 2024

2021 Background: Re-irradiation is an important treatment option for recurrent glioblastoma (rGBM). Here, we aimed to compare the oncological outcome of a re-irradiation target volume delineation based on O-(2-[18F]fluoroethyl)-L-tyrosine (FET) positron emission tomography (PET) with the one of a treatment based on contrast enhanced T1-weighted magnetic resonance imaging (T1Gd-MRI). Methods: GLIAA was a prospective, multicenter, randomized trial (NOA 10/ARO 2013-1, DKTK-a.). Patients with rGBM recurrence of 1-6 cm following initial radiotherapy were recruited at 14 centers in Germany and randomized 1:1 between a FET-PET- (arm A) and a T1Gd-MRI-based target volume delineation (arm B). The treatment consisted in a high-precision stereotactic re-irradiation with 39 Gy in 13 fractions. The primary endpoint was progression-free survival (PFS) from randomization. Secondary endpoints included overall survival (OS), local tumor control, and toxicity. Results: From November 26, 2013, to September 2, 2021, 271 patients were assessed for eligibility and 200 were randomized. 98 patients in the FET-PET arm and 97 patients in the T1Gd-MRI arm were treated per protocol. Median PFS was 4.0 months (95% confidence interval [CI] 3.7-5.2) in the FET-PET arm and 4.9 months (95% CI 3.7-6.0) in the GdT1-MRI arm (one-sided stratified log-rank test p=0.98; adjusted HR for the experimental versus the control arm 1.14 [95% CI 0.85-1.52], p=0.39). Median OS was 9.4 months (95% CI 7.8-11.1) in arm A and 9.0 months (95% CI 7.6-10.5) in arm B (HR 1.01 [95% CI 0.75-1.37], p=0.92). Local control rate at 12 months was 22% in the FET-PET arm (95% CI 14%-31%) and 20% in the GdT1-MRI arm (95% CI 12%-29%). Radiation necrosis as adverse event was documented in 25.5% of cases in arm A and in 21.6% in arm B. Of the 239 patients who received the FET tracer, 3 reported 5 severe adverse events in the timespan of 7 days after PET. No event was related to the application of the tracer. Conclusions: In this trial, FET-PET-based re-irradiation of rGBM was not superior to the GdT1-MRI-based treatment. Consequently, both options remain valid in this setting. Stereotactic re-irradiation with 39 Gy in 3 Gy fractions was shown to be safe and the FET-PET investigation was well tolerated in all cases. Due to the inclusion of FET-PET-positive patients only, our results do not impact the known diagnostic role of FET-PET in differentiating rGBM progression from post-therapeutic changes. Clinical trial information: NCT01252459 .
Genomic biomarkers of CNS-specific outcomes in patients with breast cancer brain metastases.
Authors: Khatri Ishaani S. , Eichholz Jordan , Boe Lillian A , Safonov Anton , Smith Deborah Ruth , Ferraro Emanuela , Shen Junchao , Imber Brandon S. , Yu Yao , Yamada Yoshiya , Miao Emily , Moss Nelson S. , Wilcox Jessica , Walch Henry S. , Chatila Walid Khaled , Schultz Nikolaus , Razavi Pedram , Pike Luke R. G. 
Published: June 2024

2028 Background: The diagnosis of brain metastasis (BM) is a life- and prognosis-altering event for patients with breast cancer (BC). The standard of care for the management of limited BM remains ablation with stereotactic radiosurgery (SRS). There are no established genomic biomarkers to guide CNS-directed treatment among patients with breast cancer brain metastases (BCBM). Methods: We retrospectively reviewed clinical and genomic features of a cohort of patients who received SRS for newly diagnosed BCBM between 2010 and 2021 at Memorial Sloan Kettering Cancer Center (MSK). Next-generation genomic sequencing (NGS) was performed using the MSK-IMPACT assay, covering all exonic and selected intronic regions for up to 505 genes. Time-to-CNS progression (TTCP) and overall survival (OS) were analyzed using multivariable Fine-Gray and Cox proportional hazards models, respectively, adjusted for clinically relevant factors. Relevant clinical factors and genomic alterations present at an instance at 5% or greater were included in the univariate and multivariate analyses, completed for the overall cohort and BC receptor subtypes. Results: From 2010-2021, 260 patients were identified; 123 (47%), 74 (28%), and 63 (24%) patients had hormone receptor-positive (HR+), HER2+, and triple-negative (TN) disease, respectively. 116 (45%) patients had 1 BM and 184 (71%) patients had at least 1 BM greater than 1 cm in axial diameter. Median follow up for the overall cohort was 18 months (Interquartile range (IQR) 9, 36). Among patients who progressed, median TTCP was 6 (IQR 4, 13) and 6 (4, 13), 11 (5, 18), and 4(3, 8) months for the overall cohort, and HR+, HER2+, and TN subgroups, respectively. Median OS was 19 (95% CI 16, 23) and 15 (13, 21), 58 (39, --), and 13 (11, 20), for the overall cohort, and HR+, HER2+, and TN subgroups, respectively. In the overall cohort, shorter TTCP was associated with TN subtype, >5 BMs, and pathogenic alterations in MYC, AGO2, PTEN, AURKA, and NF1 (p < 0.05); decreased OS was associated with non-HER2+ subtype, presence of extracranial metastatic disease, and oncogenic alterations in TP53, CDH1 and NF1 (p < 0.05). In stratified analyses by receptor subtype, shorter TTCP was associated with oncogenic alterations in GAB2 and PTEN in the HR+ subgroup, AURKA, DDR2, and NF1 in the HER2+ subgroup, and with MYC and RB1 in the TN subgroup (p < 0.05). Conclusions: In this large clinico-genomic analysis of CNS-specific outcomes in BC, we identified clinical and putative genomic biomarkers associated with BCBM receiving SRS that could be used to risk stratify patients and optimize treatment strategies.
Effect of novel autologous immune training platform on end-stage patients with cancer.
Authors: Pulford John F , Lederer James A. , Murzin E , Younger D , Goh Jeffrey C. , Kitchenadasse Ganessan , Atkinson Victoria , Joubert Warren Lance , Kwatra Vineet , Okera Meena , Bishnoi Sarwan K. , Gargosky Sharron , Borriello Frank , Joshi Rohit 
Published: June 2024

2546 Background: SUPLEXA therapeutic cells are the initial autologous and non-engineered candidate to emerge from the novel ENLIST cells training platform. Manufacturing is robust, reproducible and with an acceptable cost of goods. The method requires 35 days to produce multiple doses. Multiple mechanisms of SUPLEXA therapeutic cells have been delineated and all appear to complement that of immune checkpoint inhibitors (ICIs) with SUPLEXA cells serving to enhance the number of primed anti-tumor host T cells while ICIs serve to increase the durability of primed T cells by blocking their premature down-regulation. Methods: A 35 patient Phase 1 single-agent study survey study is currently ongoing in Australia to test the safety and clinical activity of SUPLEXA cells in end-stage patients with various tumor types. No chemo preconditioning or concomitant cytokine treatment was employed. CYTOF analysis of longitudinal peripheral blood is used to monitor changes to the host immune system. Results: To date, SUPLEXA therapeutic cells have demonstrated safety and significant clinical benefit with an observed CR, PR, and many durable SD in approximately half the patients. Several solid tumor patients remain on study beyond 1 year and doing well. Longitudinal analysis of PBMCs from SUPLEXA cell treated cancer patients demonstrated durable changes in the composition of myeloid immune cell subsets in SUPLEXA treated patients, impacting the anti-tumor bias of the host immune system. Specifically, we identified a dramatic decrease in the number of peripheral myeloid derived suppressor cells (MDSCs), within 3 weeks of SUPLEXA treatment. In patients with CR and PR, we also identified stable increases in activated classical CD14+ blood monocytes. Conclusions: SUPLEXA therapeutic cells are a highly differentiated approach to cellular therapy. The first-in-human experience demonstrated a pristine safety profile and strong clinical benefit as a single-agent. The pharmacodynamic decrease of in the number of MDSCs, known to suppress the anti-tumor immune response and limit immune checkpoint inhibitors (ICIs) efficacy, supports the further clinical testing to test the hypothesis that the multiple mechanisms of SUPLEXA cells will enhance the clinical activity of ICIs. Clinical trial information: NCT05237206 .
Combinatorial cellular therapy in pediatric solid tumors with natural killer (NK) and genetically engineered myeloid cells (GEMys).
Authors: Li Kathy Pei , Cronk James , Kaczanowska Sabina , Pereira Marcelo , Sato Noriko , Nakkula Robin , Chen Yun , Choyke Peter , Lee Dean Anthony , Kaplan Rosandra N. 
Published: June 2024

2561 Background: Early human studies with Natural Killer (NK) cells have shown promise, harnessing their ability to infiltrate into tumors and be tumoricidal. However, these effects can be limited by adenosine, reactive oxygen species, and TGF-β in the highly immune suppressive tumor microenvironment (TME). TGF-β and downstream SMAD3 signaling in Natural Killer (NK) cells have been shown to cause decreased cytokine production, downregulation of activating cell surface receptors, and attenuated cytotoxic function against solid tumors. Exposure to TGF-β during cell culture generates expanded NK cells with increased resistance to TGF-β signaling, dubbed TGF-β imprinted NK cells. In vitrostudies have shown that these cells have increased cytokine production and cytotoxic function in the presence of TGF-β. However, their in vivo trafficking, modulation of the TME, and therapeutic efficacy remain understudied. Our lab has previously shown that when given to tumor-bearing mice, myeloid cells modified to produce IL-12 (IL-12-Genetically Engineered Myeloid cells, aka IL-12 GEMys) are effective at homing to tumor and metastatic sites and, via IL-12 secretion and TME modulation, increase NK cell presence and activation in these sites. They hold great promise as combination therapy, enhancing the effectiveness of other cellular therapies such as NK cell therapy. A current clinical trial exploring TGF-β Imprinted, Ex Vivo Expanded, Universal Donor NK Cell Infusions in relapsed sarcomas is underway (NCT05634369). Methods: In vitro experiments were conducted with the xCELLigence real-time cell analysis system. The human osteosarcoma cell line 143B and human rhabdomyosarcoma cell line RH-30 were evaluated for cell death after co-culture with healthy donor NK cells or TGF-β imprinted NK cells (E:T ratio of 5:1) in isolation and in combination with IL-12 GEMys (E:T ratio of 2:1). Results: TGF-β imprinted NK cells are significantly more effective at tumor cell killing of both 143B and RH30 cell lines in-vitro compared to regular expanded NK cells (WT NK cells), with >90% decrease in cell index compared to 50-60%, respectively, after 48 hours of co-culture. IL-12 GEMys also significantly enhance the cytotoxic effects of WT NK cells, increasing cell killing to 70-80% compared to co-culture with untransduced GEMy controls. Conclusions: These initial in-vitro experiments provide insight into the promising effectiveness of NK-myeloid cell combination therapies in the treatment of pediatric sarcomas. Ongoing in vitroexperiments include cytokine quantification by ELISA and flow cytometric analysis of NK cell activation and proliferation markers. Our preliminary results provide rationale to continue studying the in vivo efficacy of TGF-β imprinted NK cell monotherapy and in combination with IL-12 GEMys in the treatment of tumor-bearing NSG mice.
Genetic drivers of severe skin toxicity with immune checkpoint inhibitors (ICIs) in Asian patients.
Authors: Yoshimine Kohei , Goto Hiroki , Yamada Kana , Fukuyama Tamaki , Oda Tetsuro , Iwakami Runa , Takahashi Koji , Kaul Monika Dulloo , Chandler G Scott , Mohindra Rajat , Madjar Katrin 
Published: June 2024

2667 Background: ICIs may cause severe skin toxicity associated with significant patient (pt) impact. Published data suggests Asian pts might be at higher risk of skin immune-related adverse events (SirAEs). Variation in human leukocyte antigen (HLA) is known to predispose to autoimmune (AI) conditions, but there is limited data to understand genetic drivers of severe SirAEs. Methods: The incidence of severe SirAEs was correlated with 30 HLA alleles of interest in 2 cohorts totaling 18 Asian pts (Dermatitis bullous n=4, Erythema multiforme n=10, Stevens-Johnson syndrome n=3, Toxic skin eruption n=1) treated with atezolizumab (A) across tumor types as monotherapy or as part of combinations- 8 Japanese pts received A in a non-interventional study (trial ID: UMIN000048702) and 10 Asian pts were enrolled in Roche trials with A. Data from the 18 cases was compared to 3 different controls of Asian pts identified from Roche trials with A (i.e. pts without any irAEs n=148, pts without SirAEs n=225, pts without severe SirAEs n=390). For each HLA allele, positive predictive value (PPV), negative predictive value (NPV), sensitivity, specificity, (unadjusted) odds ratio (OR) and corresponding 95%-confidence interval (CI) were evaluated. Case-control populations were obtained by risk-set sampling with exact matching on indication, treatment arm and sex, and used in age-adjusted conditional logistic regression models to assess associations between each HLA allele and severe SirAEs. Results: There was an association between some HLA alleles and severe SirAEs, but sensitivity was low (<30%) and 1-NPV was only slightly smaller than background prevalence. Results for five HLA alleles with OR>1.5 in either the unadjusted or adjusted analysis compared to controls without severe SirAEs are presented in table. Results were consistent across the three control populations. Conclusions: Five HLA alleles previously reported in AI disorders were associated with severe SirAEs in Asian pts receiving A. Although the effect size is insufficient to be considered clinically relevant, further research is warranted to better characterize the pt-level drivers of severe SirAEs in Asians pts. Clinical trial information: UMIN000048702 . [Table: see text]
Acquired gene alteration patterns and post-progression survival: PARADIGM study analysis.
Authors: Uetake Hiroyuki , Yamashita Riu , Shitara Kohei , Yoshino Takayuki , Watanabe Jun , Yasui Hirofumi , Ohori Hisatsugu , Shiozawa Manabu , Muro Kei , Yamazaki Kentaro , Oki Eiji , Sato Takeo , Naitoh Takeshi , Komatsu Yoshito , Kato Takeshi , Soeda Junpei , Yamamoto Kouji , Akagi Kiwamu , Ochiai Atsushi , Tsuchihara Katsuya 
Published: June 2024

3507 Background: In the phase 3 PARADIGM trial (NCT02394795), adding panitumumab (PAN) to FOLFOX6 improved overall survival (OS) compared with bevacizumab (BEV) in patients (pts) with RASWT mCRC. In this exploratory analysis, we investigated the role of acquired gene alterations in pts who experienced progressive disease (PD) and the impact of these alterations on post-progression survival (PPS). Methods: PPS was defined as the interval from PD to death. Pre- and post-treatment cell-free DNA (cfDNA) was analyzed using the custom PlasmaSELECT-R 91 PGDx panel (NCT02394834). PFS, OS, and PPS were compared by patterns of acquired gene alterations. Results: Among the enrolled 802 pts, 390 discontinued treatment due to PD, of which 276 (70.8%) had evaluable pre- and post-treatment cfDNA samples (PAN, 126; BEV, 150). PAN pts with acquired RTK/RAS alterations had shorter PPS than those without alterations (13.2 vs 18.8 mo, HR 1.88 [95% CI: 1.28–2.76]) with the same trend in OS. BEV pts with acquired CIMP pathway alterations had shorter PPS than those without (14.9 vs 18.6 mo; HR 1.58 [1.09–2.29]); OS had similar results. Co-occurrence of gene alterations was more frequent in PAN vs BEV (overall 52.4% vs 43.3%, RTK/RAS gene co-alterations 25% vs 10%). Co-occurrence of gene alterations resulted in shorter PPS only in PAN pts. Conclusions: Distinctive patterns of acquired gene alterations were observed in PAN- and BEV-treated pts with PD. Co-occurrence of gene alterations, particularly in the RTK/ RAS pathway, was more prevalent with PAN than BEV. Clinical trial information: NCT02394834 .
Clonal hematopoiesis of indeterminate potential (CHIP): Outcomes and adverse events in patients with solid tumors.
Authors: Krishnan Tharani , Solar Vasconcelos Joao Paulo , Titmuss Emma , Topham James T. , Vanner Robert , Schaeffer David F. , Karsan Aly , Lim Howard J , Ho Cheryl , Brown Carl J. , Gill Sharlene , Kennecke Hagen Fritz , Jonker Derek J. , Chen Eric Xueyu , Renouf Daniel John , O'Callaghan Christopher J. , Loree Jonathan M. 
Published: June 2024

3521 Background: CHIP is the clonal expansion of hematopoietic stem cells following acquisition of somatic mutations. It is a common incidental finding in cell-free DNA (cfDNA). We investigated the incidence of CHIP in cfDNA from patients with solid tumors and explored its association with outcomes and adverse events (AEs). Methods: We reviewed cfDNA results from a local prospective solid tumor cohort (PREDICT-L) and two randomized trials: CCTG CO.26 (durvalumab + tremelimumab [D+T] or best supportive care [BSC] in metastatic colorectal cancer [mCRC]) and CCTG PA.7 (gemcitabine and nab-paclitaxel [GN] +/- D+T in metastatic pancreatic adenocarcinoma [mPDAC]). CHIP+ was defined as any mutation in DNMT3A, TET2, ASXL1or ATM with a variant allele frequency (VAF) 2% or higher. Variants were considered germline if the VAF was >40%, or were annotated as germline by respective assays. The first line of treatment after cfDNA was reviewed for grade 3 or higher and dose-limiting AEs. Results: The prevalence of CHIP was 10%-21% and was more common in older patients (p=0.003). There was no association between CHIP and sex (p=0.80) or ECOG status (p=0.31). The VAF of CHIP variants was similar across all panels, and DNMT3A was the gene most frequently mutated in all cohorts. Patients with CHIP in PA.7 treated with immunotherapy (IO) had improved progression-free survival (PFS) versus patients without CHIP (p=0.036, p-interaction=0.061 [multivariable]). However, patients with CHIP treated with chemotherapy (Chemo) showed a trend towards worse overall survival (OS) in the PREDICT-L cohort (p=0.057). There was no significant difference in the rates of AEs between the CHIP+ versus CHIP- groups for those treated with Chemo or IO. Conclusions: CHIP is common in patients with solid tumors. Although not appearing to impact rates of AEs, CHIP may impact outcomes from Chemo or IO. [Table: see text]
Characterization of necroptosis activators in colorectal cancer.
Authors: Ashouri Karam , Xiu Joanne , Yang Yan , Millstein Joshua , Soni Shivani , Algaze Sandra , Mittal Pooja , Wong Alexandra , Lo Jae Ho , Torres-Gonzalez Lesly , Shields Anthony F. , Goldberg Richard M. , Lou Emil , Weinberg Benjamin Adam , Marshall John , Hoffmann Alexander , Zhang Lin , Yu Jian , Battaglin Francesca , Lenz Heinz-Josef 
Published: June 2024

3522 Background: Necroptosis is a pro-inflammatory form of programmed cell death triggered by cellular stresses and extrinsic cytokines. It is a potential therapeutic target for immunotherapy (IO) in colorectal cancer (CRC). Here, we present comprehensive clinical and molecular characterization of key necroptosis regulators in CRC. Methods: 24,257 samples of CRC tested at Caris Life Sciences (Phoenix, AZ) with WTS (Illumina NovaSeq), NextGen DNA sequencing (NextSeq, 592 Genes and NovaSEQ, WES), and PD-L1 expression (22C3 clone; TPS ≥1%) were analyzed. Expression of activators in the necroptosis pathway ( RIPK3, MLKL, CYLD, and ZBP1) was categorized as either high (H) or low (L) using median expression as the cutoff. CRCs with high expression of all four activators were considered to have high propensity for necroptosis activity (NA-H, N=4595) compared to tumors with low expression in all activators (NA-L, N = 4946). RNA deconvolution analysis with QuantiSEQ estimated immune cell infiltration in the tumor microenvironment (TME). Differences in overall survival (OS) were analyzed from insurance claims data and calculated from treatment initiation using Kaplan-Meier estimates. Statistical significance was set as a P-value adjusted for multiple comparisons ( q<0.05). Results: NA-H was associated with increased PD-L1 positivity (4.0% vs 2.3%), immune cell infiltration, and T-cell inflamed score (all q<0.001). TP53 mutations were more frequent in NA-H, while SMAD2, SMAD4, KRAS, and NRAS mutations were associated with NA-L (all q<0.01). NA-H was associated with activation of KRAS signaling, allograft rejection, inflammatory/interferon gamma response, and pancreatic beta cell function pathways (all q<0.05). NA-H showed significantly improved OS in FOLFOX/FOLFIRI (F/F) (NA-L: 34.3 vs NA-H: 39.6 months [mo], P < 0.001; HR = 0.83, 95% CI 0.77 – 0.90) and those treated with IO (15.3 vs 22.4 mo, P = 0.018; HR = 0.77, 95% CI 0.62– 0.96) treated CRC patients. The benefit remained in TP53-mutated CRC treated with F/F (34.6 vs 41.0 mo, P < 0.001; HR = 0.82, 95% CI 0.74-0.90) and IO (10.0 vs 21.8 mo, P = 0.027; HR = 0.68, 95% CI 0.48-0.96) but not in the TP53-wild-type subgroup. Improved OS was observed with increased expression of CYLD and ZBP1(Table). The benefit remained in TP53-mutated CRC but not in the TP53 wildtype subgroup. Conclusions: This is the largest molecular and clinical characterization of necroptotic genes in CRC. Our data shows that activation of the necroptosis pathway is associated with immune cell infiltration/pathway activation, PD-L1 expression, and improved OS on F/F and IO. This benefit is more pronounced in TP53-mutated CRC, suggesting possible novel therapeutic targets.[Table: see text]