bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Targeting Alpha-Fetoprotein (AFP)–MHC Complex with CAR T-Cell Therapy for Liver Cancer
Authors: Liu Hong , Xu Yiyang , Xiang Jingyi , Long Li , Green Shon , Yang Zhiyuan , Zimdahl Bryan , Lu Jingwei , Cheng Neal , Horan Lucas H. , Liu Bin , Yan Su , Wang Pei , Diaz Juan , Jin Lu , Nakano Yoko , Morales Javier F. , Zhang Pengbo , Liu Lian-xing , Staley Binnaz K. , Priceman Saul J. , Brown Christine E. , Forman Stephen J. , Chan Vivien W. , Liu Cheng
Published: April 2023

Abstract
Purpose: The majority of tumor-specific antigens are intracellular and/or secreted and therefore inaccessible by conventional chimeric antigen receptor (CAR) T-cell therapy. Given that all intracellular/secreted proteins are processed into peptides and presented by class I MHC on the surface of tumor cells, we used alpha-fetoprotein (AFP), a specific liver cancer marker, as an example to determine whether peptide–MHC complexes can be targets for CAR T-cell therapy against solid tumors.

Experimental Design: We generated a fully human chimeric antigen receptor, ET1402L1-CAR (AFP-CAR), with exquisite selectivity and specificity for the AFP158–166 peptide complexed with human leukocyte antigen (HLA)-A*02:01.

Results: We report that T cells expressing AFP-CAR selectively degranulated, released cytokines, and lysed liver cancer cells that were HLA-A*02:01+/AFP+ while sparing cells from multiple tissue types that were negative for either expressed proteins. In vivo, intratumoral injection of AFP-CAR T cells significantly regressed both Hep G2 and AFP158-expressing SK-HEP-1 tumors in SCID-Beige mice (n = 8 for each). Moreover, intravenous administration of AFP-CAR T cells in Hep G2 tumor-bearing NSG mice lead to rapid and profound tumor growth inhibition (n = 6). Finally, in an established intraperitoneal liver cancer xenograft model, AFP-CAR T cells showed robust antitumor activity (n = 6).

Conclusions: This study demonstrates that CAR T-cell immunotherapy targeting intracellular/secreted solid tumor antigens can elicit a potent antitumor response. Our approach expands the spectrum of antigens available for redirected T-cell therapy against solid malignancies and offers a promising new avenue for liver cancer immunotherapy. Clin Cancer Res; 23(2); 478–88. ©2016 AACR.
Data from FDA Approval Summary: Tisagenlecleucel for Treatment of Patients with Relapsed or Refractory B-cell Precursor Acute Lymphoblastic Leukemia
Authors: O'Leary Maura C. , Lu Xiaobin , Huang Ying , Lin Xue , Mahmood Iftekhar , Przepiorka Donna , Gavin Denise , Lee Shiowjen , Liu Ke , George Bindu , Bryan Wilson , Theoret Marc R. , Pazdur Richard
Published: April 2023

Abstract
Tisagenlecleucel (Kymriah; Novartis Pharmaceuticals) is a CD19-directed genetically modified autologous T-cell immunotherapy. On August 30, 2017, the FDA approved tisagenlecleucel for treatment of patients up to 25 years of age with B-cell precursor acute lymphoblastic leukemia (ALL) that is refractory in second or later relapse. Approval was based on the complete remission (CR) rate, durability of CR, and minimal residual disease (MRD) <0.01% in a cohort of 63 children and young adults with relapsed or refractory ALL treated on a single-arm trial (CCTL019B2202). Treatment consisted of fludarabine and cyclophosphamide followed 2 to 14 days later by a single dose of tisagenlecleucel. The CR rate was 63% (95% confidence interval, 50%–75%), and all CRs had MRD <0.01%. With a median follow-up of 4.8 months, the median duration of response was not reached. Cytokine release syndrome (79%) and neurologic events (65%) were serious toxicities reported in the trial. With implementation of a Risk Evaluation and Mitigation Strategy, the benefit–risk profile was considered acceptable for this patient population with such resistant ALL. A study of safety with 15 years of follow-up is required as a condition of the approval.

See related commentary by Geyer, p. 1133
Data from Research Priorities, Measures, and Recommendations for Assessment of Tobacco Use in Clinical Cancer Research
Authors: Land Stephanie R. , Toll Benjamin A. , Moinpour Carol M. , Mitchell Sandra A. , Ostroff Jamie S. , Hatsukami Dorothy K. , Duffy Sonia A. , Gritz Ellen R. , Rigotti Nancy A. , Brandon Thomas H. , Prindiville Sheila A. , Sarna Linda P. , Schnoll Robert A. , Herbst Roy S. , Cinciripini Paul M. , Leischow Scott J. , Dresler Carolyn M. , Fiore Michael C. , Warren Graham W.
Published: April 2023

Abstract
There is strong evidence that cigarette smoking causes adverse outcomes in people with cancer. However, more research is needed regarding those effects and the effects of alternative tobacco products and of secondhand smoke, the effects of cessation (before diagnosis, during treatment, or during survivorship), the biologic mechanisms, and optimal strategies for tobacco dependence treatment in oncology. Fundamentally, tobacco is an important source of variation in clinical treatment trials. Nevertheless, tobacco use assessment has not been uniform in clinical trials. Progress has been impeded by a lack of consensus regarding tobacco use assessment suitable for cancer patients. The NCI-AACR Cancer Patient Tobacco Use Assessment Task Force identified priority research areas and developed recommendations for assessment items and timing of assessment in cancer research. A cognitive interview study was conducted with 30 cancer patients at the NIH Clinical Center to evaluate and improve the measurement items. The resulting Cancer Patient Tobacco Use Questionnaire (C-TUQ) includes “Core” items for minimal assessment of tobacco use at initial and follow-up time points, and an “Extension” set. Domains include the following: cigarette and other tobacco use status, intensity, and past use; use relative to cancer diagnosis and treatment; cessation approaches and history; and secondhand smoke exposure. The Task Force recommends that assessment occur at study entry and, at a minimum, at the end of protocol therapy in clinical trials. Broad adoption of the recommended measures and timing protocol, and pursuit of the recommended research priorities, will help us to achieve a clearer understanding of the significance of tobacco use and cessation for cancer patients. Clin Cancer Res; 22(8); 1907–13. ©2016 AACR.
Data from Fractionated Radiation Therapy Stimulates Antitumor Immunity Mediated by Both Resident and Infiltrating Polyclonal T-cell Populations when Combined with PD-1 Blockade
Authors: Dovedi Simon J. , Cheadle Eleanor J. , Popple Amy L. , Poon Edmund , Morrow Michelle , Stewart Ross , Yusko Erik C. , Sanders Catherine M. , Vignali Marissa , Emerson Ryan O. , Robins Harlan S. , Wilkinson Robert W. , Honeychurch Jamie , Illidge Timothy M.
Published: April 2023

Abstract
Purpose: Radiotherapy is a highly effective anticancer treatment forming part of the standard of care for the majority of patients, but local and distal disease recurrence remains a major cause of mortality. Radiotherapy is known to enhance tumor immunogenicity; however, the contribution and mechanisms of radiotherapy-induced immune responses are unknown.

Experimental Design: The impact of low-dose fractionated radiotherapy (5 × 2 Gy) alone and in combination with αPD-1 mAb on the tumor microenvironment was evaluated by flow cytometry and next-generation sequencing of the T-cell receptor (TCR) repertoire. A dual-tumor model was used, with fractionated radiotherapy delivered to a single tumor site to enable evaluation of the local and systemic response to treatment and ability to induce abscopal responses outside the radiation field.

Results: We show that fractionated radiotherapy leads to T-cell infiltration at the irradiated site; however, the TCR landscape remains dominated by polyclonal expansion of preexisting T-cell clones. Adaptive resistance via the PD-1/PD-L1 pathway restricts the generation of systemic anticancer immunity following radiotherapy, which can be overcome through combination with αPD-1 mAb leading to improved local and distal tumor control. Moreover, we show that effective clearance of tumor following combination therapy is dependent on both T cells resident in the tumor at the time of radiotherapy and infiltrating T cells.

Conclusions: These data provide evidence that radiotherapy can enhance T-cell trafficking to locally treated tumor sites and augment preexisting anticancer T-cell responses with the capacity to mediate regression of out-of-field tumor lesions when delivered in combination with αPD-1 mAb therapy. Clin Cancer Res; 23(18); 5514–26. ©2017 AACR.
Data from Molecular Profiling of Appendiceal Adenocarcinoma and Comparison with Right-sided and Left-sided Colorectal Cancer
Authors: Tokunaga Ryuma , Xiu Joanne , Johnston Curtis , Goldberg Richard M. , Philip Philip A. , Seeber Andreas , Naseem Madiha , Lo Jae Ho , Arai Hiroyuki , Battaglin Francesca , Puccini Alberto , Berger Martin D. , Soni Shivani , Zhang Wu , Hwang Jimmy J. , Shields Anthony F. , Marshall John L. , Baba Hideo , Korn W. Michael , Lenz Heinz-Josef
Published: April 2023

AbstractPurpose:
The natural history and prognosis of appendiceal adenocarcinomas differ from those of adenocarcinomas arising in other large bowel sites. We aimed to compare the molecular profiles exhibited by appendiceal adenocarcinomas and colorectal cancers, or between the histopathologic subtypes of appendiceal adenocarcinoma.
Experimental Design:
A total of 183 samples from appendiceal adenocarcinoma [46 adenocarcinoma, not otherwise specified (NOS), 66 pseudomyxoma peritonei (PMP), 44 mucinous adenocarcinoma (MU), and 27 signet ring cell carcinoma (SR)], 994 from right-sided colorectal cancer (R-CRC), and 1,080 from left-sided CRC (L-CRC) were analyzed by next-generation sequencing (NGS) and IHC markers. Microsatellite instability (MSI) and tumor mutational burden (TMB) were tested by NGS, and programmed death ligand 1 (PD-L1) by IHC.
Results:
We observed high mutation rates in appendiceal adenocarcinoma samples for KRAS (55%), TP53 (40%), GNAS (31%), SMAD4 (16%), and APC (10%). Appendiceal adenocarcinoma exhibited higher mutation rates in KRAS and GNAS, and lower mutation rates in TP53, APC, and PIK3CA (6%) than colorectal cancers. PMP exhibited much higher mutation rates in KRAS (74%) and GNAS (63%), and much lower mutation rates in TP53 (23%), APC (2%), and PIK3CA (2%) than NOS. Alterations associated with immune checkpoint inhibitor response (MSI-high, TMB-high, PD-L1 expression) showed similar frequency in appendiceal adenocarcinoma compared with L-CRC, but not R-CRC, and those of NOS were higher than other subtypes of appendiceal adenocarcinoma and L-CRC.
Conclusions:
Molecular profiling of appendiceal adenocarcinoma revealed different molecular characteristics than noted in R-CRC and L-CRC, and molecular heterogeneity among the histopathologic subtypes of appendiceal adenocarcinoma. Our findings may be critical to developing an individualized approach to appendiceal adenocarcinoma treatment.
Data from Expression of Five Neuroblastoma Genes in Bone Marrow or Blood of Patients with Relapsed/Refractory Neuroblastoma Provides a New Biomarker for Disease and Prognosis
Authors: Marachelian Araz , Villablanca Judith G. , Liu Cathy W. , Liu Betty , Goodarzian Fariba , Lai Hollie A. , Shimada Hiroyuki , Tran Hung C. , Parra Jaime A. , Gallego Richard , Bedrossian Nora , Young Sabrina , Czarnecki Scarlett , Kennedy Rebekah , Weiss Brian D. , Goldsmith Kelly , Granger Meaghan , Matthay Katherine K. , Groshen Susan , Asgharzadeh Shahab , Sposto Richard , Seeger Robert C.
Published: April 2023

Abstract
Purpose: We determined whether quantifying neuroblastoma-associated mRNAs (NB-mRNAs) in bone marrow and blood improves assessment of disease and prediction of disease progression in patients with relapsed/refractory neuroblastoma.

Experimental Design: mRNA for CHGA, DCX, DDC, PHOX2B, and TH was quantified in bone marrow and blood from 101 patients concurrently with clinical disease evaluations. Correlation between NB-mRNA (delta cycle threshold, ΔCt, for the geometric mean of genes from the TaqMan Low Density Array NB5 assay) and morphologically defined tumor cell percentage in bone marrow, 123I-meta-iodobenzylguanidine (MIBG) Curie score, and CT/MRI-defined tumor longest diameter was determined. Time-dependent covariate Cox regression was used to analyze the relationship between ΔCt and progression-free survival (PFS).

Results: NB-mRNA was detectable in 83% of bone marrow (185/223) and 63% (89/142) of blood specimens, and their ΔCt values were correlated (Spearman r = 0.67, P < 0.0001), although bone marrow Ct was 7.9 ± 0.5 Ct stronger than blood Ct. When bone marrow morphology, MIBG, or CT/MRI were positive, NB-mRNA was detected in 99% (99/100), 88% (100/113), and 81% (82/101) of bone marrow samples. When all three were negative, NB-mRNA was detected in 55% (11/20) of bone marrow samples. Bone marrow NB-mRNA correlated with bone marrow morphology or MIBG positivity (P < 0.0001 and P = 0.007). Bone marrow and blood ΔCt values correlated with PFS (P < 0.001; P = 0.001) even when bone marrow was morphologically negative (P = 0.001; P = 0.014). Multivariate analysis showed that bone marrow and blood ΔCt values were associated with PFS independently of clinical disease and MYCN gene status (P < 0.001; P = 0.055).

Conclusions: This five-gene NB5 assay for NB-mRNA improves definition of disease status and correlates independently with PFS in relapsed/refractory neuroblastoma. Clin Cancer Res; 23(18); 5374–83. ©2017 AACR.
Data from MAVERICC, a Randomized, Biomarker-stratified, Phase II Study of mFOLFOX6-Bevacizumab versus FOLFIRI-Bevacizumab as First-line Chemotherapy in Metastatic Colorectal Cancer
Authors: Parikh Aparna R. , Lee Fa-Chyi , Yau Linda , Koh Han , Knost James , Mitchell Edith P. , Bosanac Ivan , Choong Nicholas , Scappaticci Frank , Mancao Christoph , Lenz Heinz-Josef
Published: April 2023

AbstractPurpose:
MAVERICC compared the efficacy and safety of modified leucovorin/5-fluorouracil/oxaliplatin plus bevacizumab (mFOLFOX6-BV) with leucovorin/5-fluorouracil/irinotecan plus bevacizumab (FOLFIRI-BV) in patients with previously untreated metastatic colorectal cancer (mCRC).

Patients and Methods: MAVERICC was a global, randomized, open-label, phase II study. Primary objectives were to assess associations between (i) excision repair cross-complementing 1 (ERCC1) expression with progression-free survival (PFS), and (ii) plasma VEGF A (VEGF-A) with PFS in patients with previously untreated mCRC receiving mFOLFOX6-BV or FOLFIRI-BV. Before randomization, patients were stratified by tumoral ERCC1/β-actin mRNA expression level and region.
Results:
Of 376 enrolled patients, 188 each received mFOLFOX6-BV and FOLFIRI-BV. PFS and overall survival (OS) were comparable between FOLFIRI-BV and mFOLFOX6-BV, with numerically higher PFS [HR = 0.79; 95% CI (confidence interval): 0.61–1.01; P = 0.06] and OS (HR = 0.76; 95% CI: 0.56–1.04; P = 0.09) observed for FOLFIRI-BV. In the high ERCC1 subgroup, PFS and OS were comparable between treatment groups (PFS, HR = 0.84; 95% CI: 0.56–1.26; P = 0.40; OS, HR = 0.80; 95% CI: 0.51–1.26; P = 0.33). Across treatment groups, high plasma VEGF-A levels (>5.1 pg/mL) were observed with shorter PFS (HR = 1.19; 95% CI: 0.93–1.53; P = 0.17) and significantly shorter OS (HR = 1.64; 95% CI: 1.20–2.24; P < 0.01) versus low levels (≤5.1 pg/mL). Safety findings for FOLFIRI-BV or mFOLFOX6-BV were comparable with those reported previously.
Conclusions:
First-line FOLFIRI-BV and mFOLFOX6-BV had comparable PFS and OS, similar to results in patients with high baseline tumor ERCC1 levels. There were no new safety signals with these bevacizumab-containing regimens.
Data from Phase II Study of Radiotherapy and Temsirolimus versus Radiochemotherapy with Temozolomide in Patients with Newly Diagnosed Glioblastoma without MGMT Promoter Hypermethylation (EORTC 26082)
Authors: Wick Wolfgang , Gorlia Thierry , Bady Pierre , Platten Michael , van den Bent Martin J. , Taphoorn Martin J.B. , Steuve Jonathan , Brandes Alba A. , Hamou Marie-France , Wick Antje , Kosch Markus , Weller Michael , Stupp Roger , Roth Patrick , Golfinopoulos Vassilis , Frenel Jean-Sebastien , Campone Mario , Ricard Damien , Marosi Christine , Villa Salvador , Weyerbrock Astrid , Hopkins Kirsten , Homicsko Krisztian , Lhermitte Benoit , Pesce Gianfranco , Hegi Monika E.
Published: April 2023

Abstract
Purpose: EORTC 26082 assessed the activity of temsirolimus in patients with newly diagnosed glioblastoma harboring an unmethylated O6 methylguanine-DNA-methyltransferase (MGMT) promoter.

Experimental Design: Patients (n = 257) fulfilling eligibility criteria underwent central MGMT testing. Patients with MGMT unmethylated glioblastoma (n = 111) were randomized 1:1 between standard chemo-radiotherapy with temozolomide or radiotherapy plus weekly temsirolimus (25 mg). Primary endpoint was overall survival at 12 months (OS12). A positive signal was considered >38 patients alive at 12 months in the per protocol population. A noncomparative reference arm of 54 patients evaluated the assumptions on OS12 in a standard-treated cohort of patients. Prespecified post hoc analyses of markers reflecting target activation were performed.

Results: Both therapies were administered per protocol with a median of 13 cycles of maintenance temsirolimus. Median age was 55 and 58 years in the temsirolimus and standard arms, the WHO performance status 0 or 1 for most patients (95.5%). In the per protocol population, 38 of 54 patients treated with temsirolimus reached OS12. The actuarial 1-year survival was 72.2% [95% confidence interval (CI), 58.2–82.2] in the temozolomide arm and 69.6% (95% CI, 55.8–79.9) in the temsirolimus arm [hazard ratio (HR) 1.16; 95% CI, 0.77–1.76; P = 0.47]. In multivariable prognostic analyses of clinical and molecular factors, phosphorylation of mTORSer2448 in tumor tissue (HR 0.13; 95% CI, 0.04–0.47; P = 0.002), detected in 37.6%, was associated with benefit from temsirolimus.

Conclusions: Temsirolimus was not superior to temozolomide in patients with an unmethylated MGMT promoter. Phosphorylation of mTORSer2448 in the pretreatment tumor tissue may define a subgroup benefitting from mTOR inhibition. Clin Cancer Res; 22(19); 4797–806. ©2016 AACR.
Data from Individualized Molecular Analyses Guide Efforts (IMAGE): A Prospective Study of Molecular Profiling of Tissue and Blood in Metastatic Triple-Negative Breast Cancer
Authors: Parsons Heather A. , Beaver Julia A. , Cimino-Mathews Ashley , Ali Siraj M. , Axilbund Jennifer , Chu David , Connolly Roisin M. , Cochran Rory L. , Croessmann Sarah , Clark Travis A. , Gocke Christopher D. , Jeter Stacie C. , Kennedy Mark R. , Lauring Josh , Lee Justin , Lipson Doron , Miller Vincent A. , Otto Geoff A. , Rosner Gary L. , Ross Jeffrey S. , Slater Shannon , Stephens Philip J. , VanDenBerg Dustin A. , Wolff Antonio C. , Young Lauren E. , Zabransky Daniel J. , Zhang Zhe , Zorzi Jane , Stearns Vered , Park Ben H.
Published: April 2023

Abstract
Purpose: The clinical utility of next-generation sequencing (NGS) in breast cancer has not been demonstrated. We hypothesized that we could perform NGS of a new biopsy from patients with metastatic triple-negative breast cancer (TNBC) in a clinically actionable timeframe.

Experimental Design: We planned to enroll 40 patients onto a prospective study, Individualized Molecular Analyses Guide Efforts (IMAGE), to evaluate the feasibility of obtaining a new biopsy of a metastatic site, perform NGS (FoundationOne), and convene a molecular tumor board to formulate treatment recommendations within 28 days. We collected blood at baseline and at time of restaging to assess cell-free circulating plasma tumor DNA (ptDNA).

Results: We enrolled 26 women with metastatic TNBC who had received ≥1 line of prior chemotherapy, and 20 (77%) underwent NGS of a metastatic site biopsy. Twelve (60%) evaluable patients received treatment recommendations within 28 days of consent. The study closed after 20 patients underwent NGS, based on protocol-specified interim futility analysis. Three patients went on to receive genomically directed therapies. Twenty-four of 26 patients had genetic alterations successfully detected in ptDNA. Among 5 patients, 4 mutations found in tumor tissues were not identified in blood, and 4 mutations found in blood were not found in corresponding tumors. In 9 patients, NGS of follow-up blood samples showed 100% concordance with baseline blood samples.

Conclusions: This study demonstrates challenges of performing NGS on prospective tissue biopsies in patients with metastatic TNBC within 28 days, while also highlighting the potential use of blood as a more time-efficient and less invasive method of mutational assessment. Clin Cancer Res; 23(2); 379–86. ©2016 AACR.
Data from SNP rs16906252C>T Is an Expression and Methylation Quantitative Trait Locus Associated with an Increased Risk of Developing MGMT-Methylated Colorectal Cancer
Authors: Kuroiwa-Trzmielina Joice , Wang Fan , Rapkins Robert W. , Ward Robyn L. , Buchanan Daniel D. , Win Aung Ko , Clendenning Mark , Rosty Christophe , Southey Melissa C. , Winship Ingrid M. , Hopper John L. , Jenkins Mark A. , Olivier Jake , Hawkins Nicholas J. , Hitchins Megan P.
Published: April 2023

Abstract
Purpose: Methylation of the MGMT promoter is the major cause of O6-methylguanine methyltransferase deficiency in cancer and has been associated with the T variant of the promoter enhancer SNP rs16906252C>T. We sought evidence for an association between the rs16906252C>T genotype and increased risk of developing a subtype of colorectal cancer featuring MGMT methylation, mediated by genotype-dependent epigenetic silencing within normal tissues.

Experimental Design: By applying a molecular pathologic epidemiology case–control study design, associations between rs16906252C>T and risk for colorectal cancer overall, and colorectal cancer stratified by MGMT methylation status, were estimated using multinomial logistic regression in two independent retrospective series of colorectal cancer cases and controls. The test sample comprised 1,054 colorectal cancer cases and 451 controls from Sydney, Australia. The validation sample comprised 612 colorectal cancer cases and 245 controls from the Australasian Colon Cancer Family Registry (ACCFR). To determine whether rs16906252C>T was linked to a constitutively altered epigenetic state, quantitative allelic expression and methylation analyses were performed in normal tissues.

Results: An association between rs16906252C>T and increased risk of developing MGMT-methylated colorectal cancer in the Sydney sample was observed [OR, 3.3; 95% confidence interval (CI), 2.0–5.3; P < 0.0001], which was replicated in the ACCFR sample (OR, 4.0; 95% CI, 2.4–6.8; P < 0.0001). The T allele demonstrated about 2.5-fold reduced transcription in normal colorectal mucosa from cases and controls and was selectively methylated in a minority of normal cells, indicating that rs16906252C>T represents an expression and methylation quantitative trait locus.

Conclusions: We provide evidence that rs16906252C>T is associated with elevated risk for MGMT-methylated colorectal cancer, likely mediated by constitutive epigenetic repression of the T allele. Clin Cancer Res; 22(24); 6266–77. ©2016 AACR.
Data from Complementary Value of Contralateral Parenchymal Enhancement on DCE-MRI to Prognostic Models and Molecular Assays in High-risk ER+/HER2− Breast Cancer
Authors: van der Velden Bas H.M. , Elias Sjoerd G. , Bismeijer Tycho , Loo Claudette E. , Viergever Max A. , Wessels Lodewyk F.A. , Gilhuijs Kenneth G.A.
Published: April 2023

Abstract
Purpose: To determine whether markers of healthy breast stroma are able to select a subgroup of patients at low risk of death or metastasis from patients considered at high risk according to routine markers of the tumor.

Experimental Design: Patients with ER+/HER2− breast cancer were consecutively included for retrospective analysis. The contralateral parenchyma was segmented automatically on dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), where upon the average of the top-10% late enhancement was calculated. This contralateral parenchymal enhancement (CPE) was analyzed with respect to routine prognostic models and molecular assays (Nottingham Prognostic Index, Dutch clinical chemotherapy-selection guidelines, 70-gene signature, and 21-gene recurrence score). CPE was split in tertiles and tested for overall and distant disease-free survival. CPE was adjusted for patient and tumor characteristics, as well as systemic therapy, using inverse probability weighting (IPW). Subanalyses were performed in patients at high risk according to prognostic models and molecular assays.

Results: Four-hundred-and-fifteen patients were included, constituting the same group in which the association between CPE and survival was discovered. Median follow-up was 85 months, 34/415(8%) patients succumbed. After IPW-adjustment for patient and tumor characteristics, patients with high CPE had significantly better overall survival than those with low CPE in groups at high risk according to the Nottingham Prognostic Index [HR (95% CI): 0.08 (0.00–0.40), P < 0.001]; Dutch clinical guidelines [HR (95% CI): 0.22 (0.00–0.81), P = 0.021]; and 21-gene recurrence score [HR (95% CI): 0.14 (0.00–0.84), P = 0.030]. One group showed a trend [70-gene signature: HR (95% CI): 0.25 (0.00–1.02), P = 0.054].

Conclusions: In patients at high risk based on the tumor, subgroups at relatively low risk were identified using pretreatment enhancement of the stroma on breast DCE-MRI. Clin Cancer Res; 23(21); 6505–15. ©2017 AACR.
Data from Screening of Conditionally Reprogrammed Patient-Derived Carcinoma Cells Identifies ERCC3–MYC Interactions as a Target in Pancreatic Cancer
Authors: Beglyarova Natalya , Banina Eugenia , Zhou Yan , Mukhamadeeva Ramilia , Andrianov Grigorii , Bobrov Egor , Lysenko Elena , Skobeleva Natalya , Gabitova Linara , Restifo Diana , Pressman Max , Serebriiskii Ilya G. , Hoffman John P. , Paz Keren , Behrens Diana , Khazak Vladimir , Jablonski Sandra A. , Golemis Erica A. , Weiner Louis M. , Astsaturov Igor
Published: April 2023

Abstract
Purpose: Even when diagnosed prior to metastasis, pancreatic ductal adenocarcinoma (PDAC) is a devastating malignancy with almost 90% lethality, emphasizing the need for new therapies optimally targeting the tumors of individual patients.

Experimental Design: We first developed a panel of new physiologic models for study of PDAC, expanding surgical PDAC tumor samples in culture using short-term culture and conditional reprogramming with the Rho kinase inhibitor Y-27632, and creating matched patient-derived xenografts (PDX). These were evaluated for sensitivity to a large panel of clinical agents, and promising leads further evaluated mechanistically.

Results: Only a small minority of tested agents was cytotoxic in minimally passaged PDAC cultures in vitro. Drugs interfering with protein turnover and transcription were among most cytotoxic. Among transcriptional repressors, triptolide, a covalent inhibitor of ERCC3, was most consistently effective in vitro and in vivo causing prolonged complete regression in multiple PDX models resistant to standard PDAC therapies. Importantly, triptolide showed superior activity in MYC-amplified PDX models and elicited rapid and profound depletion of the oncoprotein MYC, a transcriptional regulator. Expression of ERCC3 and MYC was interdependent in PDACs, and acquired resistance to triptolide depended on elevated ERCC3 and MYC expression. The Cancer Genome Atlas analysis indicates ERCC3 expression predicts poor prognosis, particularly in CDKN2A-null, highly proliferative tumors.

Conclusions: This provides initial preclinical evidence for an essential role of MYC–ERCC3 interactions in PDAC, and suggests a new mechanistic approach for disruption of critical survival signaling in MYC-dependent cancers. Clin Cancer Res; 22(24); 6153–63. ©2016 AACR.
Data from Cytokines Produced by Dendritic Cells Administered Intratumorally Correlate with Clinical Outcome in Patients with Diverse Cancers
Authors: Subbiah Vivek , Murthy Ravi , Hong David S. , Prins Robert M. , Hosing Chitra , Hendricks Kyle , Kolli Deepthi , Noffsinger Lori , Brown Robert , McGuire Mary , Fu Siquing , Piha-Paul Sarina , Naing Aung , Conley Anthony P. , Benjamin Robert S. , Kaur Indreshpal , Bosch Marnix L.
Published: April 2023

Abstract
Purpose: Dendritic cells (DC) initiate adaptive immune responses through the uptake and presentation of antigenic material. In preclinical studies, intratumorally injected activated DCs (aDCs; DCVax-Direct) were superior to immature DCs in rejecting tumors from mice.

Experimental Design: This single-arm, open-label phase I clinical trial evaluated the safety and efficacy of aDCs, administered intratumorally, in patients with solid tumors. Three dose levels (2 million, 6 million, and 15 million aDCs per injection) were tested using a standard 3 + 3 dose-escalation trial design. Feasibility, immunogenicity, changes to the tumor microenvironment after direct injection, and survival were evaluated. We also investigated cytokine production of aDCs prior to injection.

Results: In total, 39 of the 40 enrolled patients were evaluable. The injections of aDCs were well tolerated with no dose-limiting toxicities. Increased lymphocyte infiltration was observed in 54% of assessed patients. Stable disease (SD; best response) at week 8 was associated with increased overall survival. Increased secretion of interleukin (IL)-8 and IL12p40 by aDCs was significantly associated with survival (P = 0.023 and 0.024, respectively). Increased TNFα levels correlated positively with SD at week 8 (P < 0.01).

Conclusions: Intratumoral aDC injections were feasible and safe. Increased production of specific cytokines was correlated with SD and prolonged survival, demonstrating a link between the functional profile of aDCs prior to injection and patient outcomes. Clin Cancer Res; 24(16); 3845–56. ©2018 AACR.
Data from Functional Ex Vivo Assay Reveals Homologous Recombination Deficiency in Breast Cancer Beyond BRCA Gene Defects
Authors: Meijer Titia G. , Verkaik Nicole S. , Sieuwerts Anieta M. , van Riet Job , Naipal Kishan A.T. , van Deurzen Carolien H.M. , den Bakker Michael A. , Sleddens Hein F.B.M. , Dubbink Hendrikus-Jan , den Toom T. Dorine , Dinjens Winand N.M. , Lips Esther , Nederlof Petra M. , Smid Marcel , van de Werken Harmen J.G. , Kanaar Roland , Martens John W.M. , Jager Agnes , van Gent Dik C.
Published: April 2023

AbstractPurpose:
Tumors of germline BRCA1/2 mutated carriers show homologous recombination (HR) deficiency (HRD), resulting in impaired DNA double-strand break (DSB) repair and high sensitivity to PARP inhibitors. Although this therapy is expected to be effective beyond germline BRCA1/2 mutated carriers, a robust validated test to detect HRD tumors is lacking. In this study, we therefore evaluated a functional HR assay exploiting the formation of RAD51 foci in proliferating cells after ex vivo irradiation of fresh breast cancer tissue: the recombination REpair CAPacity (RECAP) test.
Experimental Design:
Fresh samples of 170 primary breast cancer were analyzed using the RECAP test. The molecular explanation for the HRD phenotype was investigated by exploring BRCA deficiencies, mutational signatures, tumor-infiltrating lymphocytes (TIL), and microsatellite instability (MSI).
Results:
RECAP was completed successfully in 125 of 170 samples (74%). Twenty-four tumors showed HRD (19%), whereas six tumors were HR intermediate (HRi; 5%). HRD was explained by BRCA deficiencies (mutations, promoter hypermethylation, deletions) in 16 cases, whereas seven HRD tumors were non-BRCA related. HRD tumors showed an increased incidence of high TIL counts (P = 0.023) compared with HR proficient (HRP) tumors and MSI was more frequently observed in the HRD group (2/20, 10%) than expected in breast cancer (1%; P = 0.017).
Conclusions:
RECAP is a robust functional HR assay detecting both BRCA1/2-deficient and BRCA1/2-proficient HRD tumors. Functional assessment of HR in a pseudo-diagnostic setting is achievable and produces robust and interpretable results.
Data from Distinct Biological Types of Ocular Adnexal Sebaceous Carcinoma: HPV-Driven and Virus-Negative Tumors Arise through Nonoverlapping Molecular-Genetic Alterations
Authors: Tetzlaff Michael T. , Curry Jonathan L. , Ning Jing , Sagiv Oded , Kandl Thomas L. , Peng Bo , Bell Diana , Routbort Mark , Hudgens Courtney W. , Ivan Doina , Kim Tae-Boom , Chen Ken , Eterovic Agda Karina , Shaw Kenna , Prieto Victor G. , Yemelyanova Anna , Esmaeli Bita
Published: April 2023

AbstractPurpose:
Ocular adnexal (OA) sebaceous carcinoma is an aggressive malignancy of the eyelid and ocular adnexa that frequently recurs and metastasizes, and effective therapies beyond surgical excision are lacking. There remains a critical need to define the molecular-genetic drivers of the disease to understand carcinomagenesis and progression and to devise novel treatment strategies.
Experimental Design:
We present next-generation sequencing of a targeted panel of cancer-associated genes in 42 and whole transcriptome RNA sequencing from eight OA sebaceous carcinomas from 29 patients.
Results:
We delineate two potentially distinct molecular-genetic subtypes of OA sebaceous carcinoma. The first is defined by somatic mutations impacting TP53 and/or RB1 [20/29 (70%) patients, including 10 patients whose primary tumors contained coexisting TP53 and RB1 mutations] with frequent concomitant mutations affecting NOTCH genes. These tumors arise in older patients and show frequent local recurrence. The second subtype [9/29 (31%) patients] lacks mutations affecting TP53, RB1, or NOTCH family members, but in 44% (4/9) of these tumors, RNA sequencing and in situ hybridization studies confirm transcriptionally active high-risk human papillomavirus. These tumors arise in younger patients and have not shown local recurrence.
Conclusions:
Together, our findings establish a potential molecular-genetic framework by which to understand the development and progression of OA sebaceous carcinoma and provide key molecular-genetic insights to direct the design of novel therapeutic interventions.
Data from Phase Ib Study of Utomilumab (PF-05082566), a 4-1BB/CD137 Agonist, in Combination with Pembrolizumab (MK-3475) in Patients with Advanced Solid Tumors
Authors: Tolcher Anthony W. , Sznol Mario , Hu-Lieskovan Siwen , Papadopoulos Kyriakos P. , Patnaik Amita , Rasco Drew W. , Di Gravio Donna , Huang Bo , Gambhire Dhiraj , Chen Ying , Thall Aron D. , Pathan Nuzhat , Schmidt Emmett V. , Chow Laura Q.M.
Published: April 2023

Abstract
Purpose: This phase Ib study (NCT02179918) evaluated the safety, antitumor activity, pharmacokinetics, and pharmacodynamics of utomilumab, a fully human IgG2 mAb agonist of the T-cell costimulatory receptor 4-1BB/CD137 in combination with the humanized, PD-1–blocking IgG4 mAb pembrolizumab in patients with advanced solid tumors.

Experimental Design: Utomilumab (0.45–5.0 mg/kg) and pembrolizumab (2 mg/kg) were administered intravenously every 3 weeks. Utomilumab dose escalation was conducted using the time-to-event continual reassessment method.

Results: Twenty-three patients received combination treatment with no dose-limiting toxicities. Treatment-emergent adverse events were mostly grades 1 to 2, without any treatment-related discontinuations. Six patients (26.1%) had confirmed complete or partial responses. Pharmacokinetics and immunogenicity of utomilumab and pembrolizumab were similar when administered alone or in combination. A trend toward higher levels of activated memory/effector peripheral blood CD8+ T cells was observed in responders versus nonresponders.

Conclusions: The safety, tolerability, and clinical activity demonstrated by utomilumab in combination with pembrolizumab support further investigation in patients with advanced solid tumors. Clin Cancer Res; 23(18); 5349–57. ©2017 AACR.

See related commentary by Pérez-Ruiz et al., p. 5326
Data from C8orf76 Promotes Gastric Tumorigenicity and Metastasis by Directly Inducing lncRNA DUSP5P1 and Associates with Patient Outcomes
Authors: Wang Xiaohong , Liang Qiaoyi , Zhang Lianhai , Gou Hongyan , Li Ziyu , Chen Huarong , Dong Yujuan , Ji Jiafu , Yu Jun
Published: April 2023

AbstractPurpose:
We identified for the first time that C8orf76 (chromosome 8 open reading frame 76) is preferentially amplified in gastric cancer. We elucidated its role and clinical significance in gastric carcinogenesis.
Experimental Design:
The clinical impact of C8orf76 was assessed in 592 patients with gastric cancer. The biological function of C8orf76 was studied in vitro, in vivo, and in gastric cancer patient-derived organoid models. C8orf76 downstream effector and pathways were identified by RNA sequencing, chromatin immunoprecipitation sequencing, luciferase reporter, and electrophoretic mobility shift assay.
Results:
C8orf76 was upregulated in 69.74% and 65.71% of two independent cohorts of gastric cancers and was positively associated with C8orf76 amplification. Multivariate analysis showed that gastric cancer patients with C8orf76 amplification (cohort I, n = 129; cohort II, n = 107) or overexpression (n = 356) had a significantly shortened survival. C8orf76 significantly promoted gastric cancer cell proliferation, cell-cycle transformation, and migration/invasion, but suppressed cell apoptosis. Silencing C8orf76 expression exerted opposite effects in vitro and significantly inhibited xenograft tumor growth, lung metastasis, and liver metastasis in nude mice. Silencing C8orf76 also significantly suppressed the growth of patient-derived organoids. Mechanically, C8orf76 activated MAPK/ERK signaling cascade. C8orf76 directly bound to the promoter region of lncRNA dual specificity phosphatase 5 pseudogene 1 (DUSP5P1) with a binding motif of AGGCTG and activated DUSP5P1 transcription. DUSP5P1 induced MAPK/ERK signaling and promoted gastric tumorigenesis. Knockdown DUSP5P1 abrogated the effect of C8orf76 in activating MAPK/ERK cascade and the tumor-promoting function.
Conclusions:
C8orf76 directly binds to oncogenic lncRNA DUSP5P1 to induce its expression and activates MAPK signaling. C8orf76 plays a pivotal oncogenic role in gastric carcinogenesis and is an independent prognostic factor for gastric cancer patients.
Data from Keyboard: A Novel Bayesian Toxicity Probability Interval Design for Phase I Clinical Trials
Authors: Yan Fangrong , Mandrekar Sumithra J. , Yuan Ying
Published: April 2023

Abstract
The primary objective of phase I oncology trials is to find the MTD. The 3+3 design is easy to implement but performs poorly in finding the MTD. A newer design, such as the modified toxicity probability interval (mTPI) design, provides better accuracy to identify the MTD but tends to overdose patients. We propose the keyboard design, an intuitive Bayesian design that conducts dose escalation and de-escalation based on whether the strongest key, defined as the dosing interval that most likely contains the current dose, is below or above the target dosing interval. The keyboard design can be implemented in a simple way, similar to the traditional 3+3 design, but provides more flexibility for choosing the target toxicity rate and cohort size. Our simulation studies demonstrate that compared with the 3+3 design, the keyboard design has favorable operating characteristics in terms of identifying the MTD. Compared with the mTPI design, the keyboard design is safer, with a substantially lower risk of treating patients at overly toxic doses, and has the better precision to identify the MTD, thereby providing a useful upgrade to the mTPI design. Software freely available at http://www.trialdesign.org facilitates the application of the keyboard design. Clin Cancer Res; 23(15); 3994–4003. ©2017 AACR.

See related commentary by Paoletti et al., p. 3977
Data from Tumor-Infiltrating and Peripheral Blood T-cell Immunophenotypes Predict Early Relapse in Localized Clear Cell Renal Cell Carcinoma
Authors: Giraldo Nicolas A. , Becht Etienne , Vano Yann , Petitprez Florent , Lacroix Laetitia , Validire Pierre , Sanchez-Salas Rafael , Ingels Alexandre , Oudard Stephane , Moatti Audrey , Buttard Benedicte , Bourass Sarah , Germain Claire , Cathelineau Xavier , Fridman Wolf H. , Sautès-Fridman Catherine
Published: April 2023

Abstract
Purpose: The efficacy of PD-1 checkpoint blockade as adjuvant therapy in localized clear cell renal cell carcinoma (ccRCC) is currently unknown. The identification of tumor microenvironment (TME) prognostic biomarkers in this setting may help define which patients could benefit from checkpoint blockade and uncover new therapeutic targets.

Experimental Design: We performed multiparametric flow cytometric immunophenotypic analysis of T cells isolated from tumor tissue [tumor-infiltrating lymphocytes (TIL)], adjacent non-malignant renal tissue [renal-infiltrating lymphocytes (RIL)], and peripheral blood lymphocytes (PBL), in a cohort of patients (n = 40) with localized ccRCC. Immunophenotypic data were integrated with prognostic and histopathologic variables, T-cell receptor (TCR) repertoire analysis of sorted CD8+PD-1+ TILs, tumor mRNA expression, and digital quantitative immunohistochemistry.

Results: On the basis of TIL phenotypic characterization, we identified three dominant immune profiles in localized ccRCC: (i) immune-regulated, characterized by polyclonal/poorly cytotoxic CD8+PD-1+Tim-3+Lag-3+ TILs and CD4+ICOS+ cells with a Treg phenotype (CD25+CD127−Foxp3+/Helios+GITR+), that developed in inflamed tumors with prominent infiltrations by dysfunctional dendritic cells and high PD-L1 expression; (ii) immune-activated, enriched in oligoclonal/cytotoxic CD8+PD-1+Tim-3+ TILs, that represented 22% of the tumors; and (iii) immune-silent, enriched in TILs exhibiting RIL-like phenotype, that represented 56% of patients in the cohort. Only immune-regulated tumors displayed aggressive histologic features, high risk of disease progression in the year following nephrectomy, and a CD8+PD-1+Tim-3+ and CD4+ICOS+ PBL phenotypic signature.

Conclusions: In localized ccRCC, the infiltration with CD8+PD-1+Tim-3+Lag-3+ exhausted TILs and ICOS+ Treg identifies the patients with deleterious prognosis who could benefit from adjuvant therapy with TME-modulating agents and checkpoint blockade. This work also provides PBL phenotypic markers that could allow their identification. Clin Cancer Res; 23(15); 4416–28. ©2017 AACR.
Data from Long Noncoding RNA LBCS Inhibits Self-Renewal and Chemoresistance of Bladder Cancer Stem Cells through Epigenetic Silencing of SOX2
Authors: Chen Xu , Xie Ruihui , Gu Peng , Huang Ming , Han Jinli , Dong Wen , Xie Weibin , Wang Bo , He Wang , Zhong Guangzheng , Chen Ziyue , Huang Jian , Lin Tianxin
Published: April 2023

AbstractPurpose:
Chemoresistance and tumor relapse are the leading cause of deaths in bladder cancer patients. Bladder cancer stem cells (BCSCs) have been reported to contribute to these pathologic properties. However, the molecular mechanisms underlying their self-renewal and chemoresistance remain largely unknown. In the current study, a novel lncRNA termed Low expressed in Bladder Cancer Stem cells (lnc-LBCS) has been identified and explored in BCSCs.
Experimental Design:
Firstly, we establish BCSCs model and explore the BCSCs-associated lncRNAs by transcriptome microarray. The expression and clinical features of lnc-LBCS are analyzed in three independent large-scale cohorts. The functional role and mechanism of lnc-LBCS are further investigated by gain- and loss-of-function assays in vitro and in vivo.
Results:
Lnc-LBCS is significantly downregulated in BCSCs and cancer tissues, and correlates with tumor grade, chemotherapy response, and prognosis. Moreover, lnc-LBCS markedly inhibits self-renewal, chemoresistance, and tumor initiation of BCSCs both in vitro and in vivo. Mechanistically, lnc-LBCS directly binds to heterogeneous nuclear ribonucleoprotein K (hnRNPK) and enhancer of zeste homolog 2 (EZH2), and serves as a scaffold to induce the formation of this complex to repress SRY-box 2 (SOX2) transcription via mediating histone H3 lysine 27 tri-methylation. SOX2 is essential for self-renewal and chemoresistance of BCSCs, and correlates with the clinical severity and prognosis of bladder cancer patients.
Conclusions:
As a novel regulator, lnc-LBCS plays an important tumor-suppressor role in BCSCs’ self-renewal and chemoresistance, contributing to weak tumorigenesis and enhanced chemosensitivity. The lnc-LBCS–hnRNPK–EZH2–SOX2 regulatory axis may represent a therapeutic target for clinical intervention in chemoresistant bladder cancer.
Data from The CD98 Heavy Chain Is a Marker and Regulator of Head and Neck Squamous Cell Carcinoma Radiosensitivity
Authors: Digomann David , Kurth Ina , Tyutyunnykova Anna , Chen Oleg , Löck Steffen , Gorodetska Ielizaveta , Peitzsch Claudia , Skvortsova Ira-Ida , Negro Giulia , Aschenbrenner Bertram , Eisenhofer Graeme , Richter Susan , Heiden Stephan , Porrmann Joseph , Klink Barbara , Schwager Christian , Dowle Adam A. , Hein Linda , Kunz-Schughart Leoni A. , Abdollahi Amir , Lohaus Fabian , Krause Mechthild , Baumann Michael , Linge Annett , Dubrovska Anna
Published: April 2023

AbstractPurpose:
The heavy chain of the CD98 protein (CD98hc) is encoded by the SLC3A2 gene. Together with the light subunit LAT1, CD98hc constitutes a heterodimeric transmembrane amino acid transporter. High SLC3A2 mRNA expression levels are associated with poor prognosis in patients with head and neck squamous cell carcinoma (HNSCC) treated with radiochemotherapy. Little is known regarding the CD98hc protein–mediated molecular mechanisms of tumor radioresistance.
Experimental Design:
CD98hc protein expression levels were correlated with corresponding tumor control dose 50 (TCD50) in HNSCC xenograft models. Expression levels of CD98hc and LAT1 in HNSCC cells were modulated by siRNA or CRISPR/Cas9 gene editing. HNSCC cell phenotypes were characterized by transcription profiling, plasma membrane proteomics, metabolic analysis, and signaling pathway activation. Expression levels of CD98hc and LAT1 proteins were examined by IHC analysis of tumor tissues from patients with locally advanced HNSCC treated with primary radiochemotherapy (RCTx). Primary endpoint was locoregional tumor control (LRC).
Results:
High expression levels of CD98hc resulted in an increase in mTOR pathway activation, amino acid metabolism, and DNA repair as well as downregulation of oxidative stress and autophagy. High expression levels of CD98hc and LAT1 proteins were significantly correlated and associated with an increase in radioresistance in HNSCC in vitro and in vivo models. High expression of both proteins identified a poor prognosis subgroup in patients with locally advanced HNSCC after RCTx.
Conclusions:
We found that CD98hc-associated signaling mechanisms play a central role in the regulation of HNSCC radioresistance and may be a promising target for tumor radiosensitization.