bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Recurrent TRIO Fusion in Nontranslocation–Related Sarcomas
Authors: Delespaul Lucile , Lesluyes Tom , Pérot Gaëlle , Brulard Céline , Lartigue Lydia , Baud Jessica , Lagarde Pauline , Le Guellec Sophie , Neuville Agnès , Terrier Philippe , Vince-Ranchère Dominique , Schmidt Susanne , Debant Anne , Coindre Jean-Michel , Chibon Frédéric
Published: April 2023

Abstract
Purpose: Despite various differences, nontranslocation-related sarcomas (e.g., comprising undifferentiated pleomorphic sarcoma, leiomyosarcoma, myxofibrosarcoma) are unified by their complex genetics. Extensive analysis of the tumor genome using molecular cytogenetic approaches showed many chromosomal gains, losses, and translocations per cell. Genomic quantitative alterations and expression variations have been extensively studied by adapted high-throughput approaches, yet translocations still remained unscreened. We therefore analyzed 117 nontranslocation-related sarcomas by RNA sequencing to identify fusion genes.

Experimental design: We performed RNA sequencing and applied a bioinformatics pipeline dedicated to the detection of fusion transcripts. RT-PCR and Sanger sequencing were then applied to validate predictions and to search for recurrence and specificity.

Results: Among the 6,772 predicted fusion genes, 420 were in-frame. One recurrent rearrangement, consistently involving TRIO with various partners, was identified in 5.1% of cases. TRIO translocations are either intrachromosomal with TERT or interchromosomal with LINC01504 or ZNF558. Our results suggest that all translocations led to a truncated TRIO protein either directly or indirectly by alternative splicing. TRIO rearrangement is associated with a modified transcriptomic program to immunity/inflammation, proliferation and migration, and an increase in proliferation.

Conclusions: TRIO fusions have been identified in four different sarcoma histotypes, likely meaning that they are not related to a primary oncogenic event but rather to a secondary one implicated in tumor progression. Moreover, they appear to be specific to nontranslocation-related sarcomas, as no such rearrangement was identified in sarcomas with simple genetics. More cases could lead to a significant association of these fusions to a specific clinical behavior. Clin Cancer Res; 23(3); 857–67. ©2016 AACR.
Data from Inhibition of HER2 Increases JAGGED1-dependent Breast Cancer Stem Cells: Role for Membrane JAGGED1
Authors: Shah Deep , Wyatt Debra , Baker Andrew T. , Simms Patricia , Peiffer Daniel S. , Fernandez Michelle , Rakha Emad , Green Andrew , Filipovic Alexandra , Miele Lucio , Osipo Clodia
Published: April 2023

Abstract
Purpose: HER2-positive breast cancer is driven by cells possessing stem-like properties of self-renewal and differentiation, referred to as cancer stem cells (CSC). CSCs are implicated in radiotherapy, chemotherapy resistance, and tumor recurrence. NOTCH promotes breast CSC survival and self-renewal, and overexpression of NOTCH1 and the NOTCH ligand JAGGED1 predict poor outcome. Resistance to anti-HER2 therapy in HER2+ breast cancer requires NOTCH1, and that combination of trastuzumab and a gamma secretase inhibitor (GSI) prevents tumor relapse in xenograft models.

Experimental Design: The current study investigates mechanisms by which HER2 tyrosine kinase activity regulates NOTCH-dependent CSC survival and tumor initiation.

Results: Lapatinib-mediated HER2 inhibition shifts the population of HER2+ breast cancer cells from low membrane JAGGED1 expression to higher levels, independent of sensitivity to anti-HER2 treatment within the bulk cell population. This increase in membrane JAGGED1 is associated with higher NOTCH receptor expression, activation, and enrichment of CSCs in vitro and in vivo. Importantly, lapatinib treatment results in growth arrest and cell death of JAGGED1 low-expressing cells while the JAGGED1 high-expressing cells continue to cycle. High membrane JAGGED1 protein expression predicts poor overall cumulative survival in women with HER2+ breast cancer.

Conclusions: These results indicate that higher membrane JAGGED1 expression may be used to either predict response to anti-HER2 therapy or for detection of NOTCH-sensitive CSCs posttherapy. Sequential blockade of HER2 followed by JAGGED1 or NOTCH could be more effective than simultaneous blockade to prevent drug resistance and tumor progression. Clin Cancer Res; 24(18); 4566–78. ©2018 AACR.
Data from Orthoxenografts of Testicular Germ Cell Tumors Demonstrate Genomic Changes Associated with Cisplatin Resistance and Identify PDMP as a Resensitizing Agent
Authors: Piulats Josep M. , Vidal August , García-Rodríguez Francisco J. , Muñoz Clara , Nadal Marga , Moutinho Catia , Martínez-Iniesta María , Mora Josefina , Figueras Agnés , Guinó Elisabet , Padullés Laura , Aytés Àlvaro , Molleví David G. , Puertas Sara , Martínez-Fernández Carmen , Castillo Wilmar , Juliachs Merce , Moreno Victor , Muñoz Purificación , Stefanovic Milica , Pujana Miguel A. , Condom Enric , Esteller Manel , Germà Josep R. , Capella Gabriel , Farré Lourdes , Morales Albert , Viñals Francesc , García-del-Muro Xavier , Cerón Julián , Villanueva Alberto
Published: April 2023

Abstract
Purpose: To investigate the genetic basis of cisplatin resistance as efficacy of cisplatin-based chemotherapy in the treatment of distinct malignancies is often hampered by intrinsic or acquired drug resistance of tumor cells.

Experimental Design: We produced 14 orthoxenograft transplanting human nonseminomatous testicular germ cell tumors (TGCT) in mice, keeping the primary tumor features in terms of genotype, phenotype, and sensitivity to cisplatin. Chromosomal and genetic alterations were evaluated in matched cisplatin-sensitive and their counterpart orthoxenografts that developed resistance to cisplatin in nude mice.

Results: Comparative genomic hybridization analyses of four matched orthoxenografts identified recurrent chromosomal rearrangements across cisplatin-resistant tumors in three of them, showing gains at 9q32-q33.1 region. We found a clinical correlation between the presence of 9q32-q33.1 gains in cisplatin-refractory patients and poorer overall survival (OS) in metastatic germ cell tumors. We studied the expression profile of the 60 genes located at that genomic region. POLE3 and AKNA were the only two genes deregulated in resistant tumors harboring the 9q32-q33.1 gain. Moreover, other four genes (GCS, ZNF883, CTR1, and FLJ31713) were deregulated in all five resistant tumors independently of the 9q32-q33.1 amplification. RT-PCRs in tumors and functional analyses in Caenorhabditis elegans (C. elegans) indicate that the influence of 9q32-q33.1 genes in cisplatin resistance can be driven by either up- or downregulation. We focused on glucosylceramide synthase (GCS) to demonstrate that the GCS inhibitor DL-threo-PDMP resensitizes cisplatin-resistant germline-derived orthoxenografts to cisplatin.

Conclusions: Orthoxenografts can be used preclinically not only to test the efficiency of drugs but also to identify prognosis markers and gene alterations acting as drivers of the acquired cisplatin resistance. Clin Cancer Res; 24(15); 3755–66. ©2018 AACR.
Data from Radiomics Analysis for Evaluation of Pathological Complete Response to Neoadjuvant Chemoradiotherapy in Locally Advanced Rectal Cancer
Authors: Liu Zhenyu , Zhang Xiao-Yan , Shi Yan-Jie , Wang Lin , Zhu Hai-Tao , Tang Zhenchao , Wang Shuo , Li Xiao-Ting , Tian Jie , Sun Ying-Shi
Published: April 2023

Abstract
Purpose: To develop and validate a radiomics model for evaluating pathologic complete response (pCR) to neoadjuvant chemoradiotherapy in patients with locally advanced rectal cancer (LARC).

Experimental Design: We enrolled 222 patients (152 in the primary cohort and 70 in the validation cohort) with clinicopathologically confirmed LARC who received chemoradiotherapy before surgery. All patients underwent T2-weighted and diffusion-weighted imaging before and after chemoradiotherapy; 2,252 radiomic features were extracted from each patient before and after treatment imaging. The two-sample t test and the least absolute shrinkage and selection operator regression were used for feature selection, whereupon a radiomics signature was built with support vector machines. Multivariable logistic regression analysis was then used to develop a radiomics model incorporating the radiomics signature and independent clinicopathologic risk factors. The performance of the radiomics model was assessed by its calibration, discrimination, and clinical usefulness with independent validation.

Results: The radiomics signature comprised 30 selected features and showed good discrimination performance in both the primary and validation cohorts. The individualized radiomics model, which incorporated the radiomics signature and tumor length, also showed good discrimination, with an area under the receiver operating characteristic curve of 0.9756 (95% confidence interval, 0.9185–0.9711) in the validation cohort, and good calibration. Decision curve analysis confirmed the clinical utility of the radiomics model.

Conclusions: Using pre- and posttreatment MRI data, we developed a radiomics model with excellent performance for individualized, noninvasive prediction of pCR. This model may be used to identify LARC patients who can omit surgery after chemoradiotherapy. Clin Cancer Res; 23(23); 7253–62. ©2017 AACR.
Data from Dual mTOR Kinase Inhibitor MLN0128 Sensitizes HR+/HER2+ Breast Cancer Patient-Derived Xenografts to Trastuzumab or Fulvestrant
Authors: Hsu Pei-Yin , Wu Victoria Shang , Kanaya Noriko , Petrossian Karineh , Hsu Hang-Kai , Nguyen Duc , Schmolze Daniel , Kai Masaya , Liu Chun-Yu , Lu Hannah , Chu Peiguo , Vito Courtney A. , Kruper Laura , Mortimer Joanne , Chen Shiuan
Published: April 2023

Abstract
Purpose: Therapeutic strategies against hormonal receptor–positive (HR+)/HER2+ breast cancers with poor response to trastuzumab need to be optimized.

Experimental Design: Two HR+/HER2+ patient-derived xenograft (PDX) models named as COH-SC1 and COH-SC31 were established to explore targeted therapies for HER2+ breast cancers. RNA sequencing and RPPA (reverse phase protein array) analyses were conducted to decipher molecular features of the two PDXs and define the therapeutic strategy of interest, validated by in vivo drug efficacy examination and in vitro cell proliferation analysis.

Results: Estrogen acted as a growth driver of trastuzumab-resistant COH-SC31 tumors but an accelerator in the trastuzumab-sensitive COH-SC1 model. In vivo trastuzumab efficacy examination further confirmed the consistent responses between PDXs and the corresponding tumors. Integrative omics analysis revealed that mammalian target of rapamycin (mTOR) and ERα signaling predominantly regulate tumor growth of the two HR+/HER2+ PDXs. Combination of the dual mTOR complex inhibitor MLN0128 and anti-HER2 trastuzumab strongly suppressed tumor growth of COH-SC1 PDX accompanied by increasing ER-positive cell population in vivo. Instead, MLN0128 in combination with antiestrogen fulvestrant significantly halted the growth of HR+/HER2+ cancer cells in vitro and trastuzumab-resistant COH-SC31 as well as trastuzumab-sensitive COH-SC1 tumors in vivo.

Conclusions: Compared with the standard trastuzumab treatment, this study demonstrates alternative therapeutic strategies against HR+/HER2+ tumors through establishment of two PDXs coupled with integrative omics analyses and in vivo drug efficacy examination. This work presents a prototype of future “co-clinical” trials to tailor personalized medicine in clinical practice. Clin Cancer Res; 24(2); 395–406. ©2017 AACR.
Data from Use of Expansion Cohorts in Phase I Trials and Probability of Success in Phase II for 381 Anticancer Drugs
Authors: Bugano Diogo D.G. , Hess Kenneth , Jardim Denis L.F. , Zer Alona , Meric-Bernstam Funda , Siu Lillian L. , Razak Albiruni R.A. , Hong David S.
Published: April 2023

Abstract
Purpose: Evaluate the association between the use of phase I expansion cohorts (ECs) and drug performance in phase II as well as time to approval by the FDA.

Experimental Design: We performed a systematic search of MEDLINE for single-agent dose-finding adult oncology phase I trials published in 2006 to 2011 and subsequent phase II trials. Successful phase II trials were those that met their primary endpoints. Dates of approval were obtained from the Drugs@FDA website in April 2014. A logistic regression model was used to determine the associations between variables and success in phase II.

Results: We identified 533 phase I trials evaluating 381 drugs; 112 drugs had at least one phase I trial with an expansion cohort. Phase I trials with expansion cohorts of two to 20 patients were associated with a higher rate of successful phase II trials than those with no expansion cohort [48% vs. 27%; OR, 2.1; 95% confidence interval (CI), 1.1–4.0; P = 0.037]. Phase II success rates were the same for expansion cohort with two to 20 and more than 20 patients (48% vs. 52%). Other positive associations were disease-specific trials (OR, 1.7; 95% CI, 1.0–2.9; P = 0.037), industry sponsorship (OR, 2.9; 95% CI, 1.5–5.7; P = 0.0024), and response rate of 6% to 20% (OR, 2.89; 95% CI, 1.6–5.2; P = 0.0007). Drugs tested in phase I trials with expansion cohorts had a higher rate of 5-year approval (19% vs. 5%; HR, 4.4; 95% CI, 2.2–8.8; P < 0.001).

Conclusions: The use of expansion cohorts in phase I trials was associated with success of subsequent phase II trials. However, confounders may play a role in this association. Clin Cancer Res; 23(15); 4020–6. ©2017 AACR.
Data from An Anti–CLL-1 Antibody–Drug Conjugate for the Treatment of Acute Myeloid Leukemia
Authors: Zheng Bing , Yu Shang-Fan , del Rosario Geoffrey , Leong Steven R. , Lee Genee Y. , Vij Rajesh , Chiu Cecilia , Liang Wei-Ching , Wu Yan , Chalouni Cecile , Sadowsky Jack , Clark Vanessa , Hendricks Angela , Poon Kirsten Achilles , Chu Wayne , Pillow Thomas , Schutten Melissa M. , Flygare John , Polson Andrew G.
Published: April 2023

AbstractPurpose:
The treatment of acute myeloid leukemia (AML) has not significantly changed in 40 years. Cytarabine- and anthracycline-based chemotherapy induction regimens (7 + 3) remain the standard of care, and most patients have poor long-term survival. The reapproval of Mylotarg, an anti-CD33–calicheamicin antibody–drug conjugate (ADC), has demonstrated ADCs as a clinically validated option to enhance the effectiveness of induction therapy. We are interested in developing a next-generation ADC for AML to improve upon the initial success of Mylotarg.
Experimental Design:
The expression pattern of CLL-1 and its hematopoietic potential were investigated. A novel anti–CLL-1-ADC, with a highly potent pyrrolobenzodiazepine (PBD) dimer conjugated through a self-immolative disulfide linker, was developed. The efficacy and safety profiles of this ADC were evaluated in mouse xenograft models and in cynomolgus monkeys.
Results:
We demonstrate that CLL-1 shares similar prevalence and trafficking properties that make CD33 an excellent ADC target for AML, but lacks expression on hematopoietic stem cells that hampers current CD33-targeted ADCs. Our anti–CLL-1-ADC is highly effective at depleting tumor cells in AML xenograft models and lacks target independent toxicities at doses that depleted target monocytes and neutrophils in cynomolgus monkeys.
Conclusions:
Collectively, our data suggest that an anti–CLL-1-ADC has the potential to become an effective and safer treatment for AML in humans, by reducing and allowing for faster recovery from initial cytopenias than the current generation of ADCs for AML.
Data from Hyperspectral Imaging for Resection Margin Assessment during Cancer Surgery
Authors: Kho Esther , de Boer Lisanne L. , Van de Vijver Koen K. , van Duijnhoven Frederieke , Vrancken Peeters Marie-Jeanne T.F.D. , Sterenborg Henricus J.C.M. , Ruers Theo J.M.
Published: April 2023

AbstractPurpose:
Complete tumor removal during cancer surgery remains challenging due to the lack of accurate techniques for intraoperative margin assessment. This study evaluates the use of hyperspectral imaging for margin assessment by reporting its use in fresh human breast specimens.
Experimental Design:
Hyperspectral data were first acquired on tissue slices from 18 patients after gross sectioning of the resected breast specimen. This dataset, which contained over 22,000 spectra, was well correlated with histopathology and was used to develop a support vector machine classification algorithm and test the classification performance. In addition, we evaluated hyperspectral imaging in clinical practice by imaging the resection surface of six lumpectomy specimens. With the developed classification algorithm, we determined if hyperspectral imaging could detect malignancies in the resection surface.
Results:
The diagnostic performance of hyperspectral imaging on the tissue slices was high; invasive carcinoma, ductal carcinoma in situ, connective tissue, and adipose tissue were correctly classified as tumor or healthy tissue with accuracies of 93%, 84%, 70%, and 99%, respectively. These accuracies increased with the size of the area, consisting of one tissue type. The entire resection surface was imaged within 10 minutes, and data analysis was performed fast, without the need of an experienced operator. On the resection surface, hyperspectral imaging detected 19 of 20 malignancies that, according to the available histopathology information, were located within 2 mm of the resection surface.
Conclusions:
These findings show the potential of using hyperspectral imaging for margin assessment during breast-conserving surgery to improve surgical outcome.
Data from Targeting Galectin-1 Impairs Castration-Resistant Prostate Cancer Progression and Invasion
Authors: Shih Tsung-Chieh , Liu Ruiwu , Wu Chun-Te , Li Xiaocen , Xiao Wenwu , Deng Xiaojun , Kiss Sophie , Wang Ting , Chen Xiao-Jia , Carney Randy , Kung Hsing-Jien , Duan Yong , Ghosh Paramita M. , Lam Kit S.
Published: April 2023

Abstract
Purpose: The majority of patients with prostate cancer who are treated with androgen-deprivation therapy (ADT) will eventually develop fatal metastatic castration-resistant prostate cancer (mCRPC). Currently, there are no effective durable therapies for patients with mCRPC. High expression of galectin-1 (Gal-1) is associated with prostate cancer progression and poor clinical outcome. The role of Gal-1 in tumor progression is largely unknown. Here, we characterized Gal-1 functions and evaluated the therapeutic effects of a newly developed Gal-1 inhibitor, LLS30, in mCRPC.

Experimental Design: Cell viability, colony formation, migration, and invasion assays were performed to examine the effects of inhibition of Gal-1 in CRPC cells. We used two human CRPC xenograft models to assess growth-inhibitory effects of LLS30. Genome-wide gene expression analysis was conducted to elucidate the effects of LLS30 on metastatic PC3 cells.

Results: Gal-1 was highly expressed in CRPC cells, but not in androgen-sensitive cells. Gal-1 knockdown significantly inhibited CRPC cells' growth, anchorage-independent growth, migration, and invasion through the suppression of androgen receptor (AR) and Akt signaling. LLS30 targets Gal-1 as an allosteric inhibitor and decreases Gal-1–binding affinity to its binding partners. LLS30 showed in vivo efficacy in both AR-positive and AR-negative xenograft models. LLS30 not only can potentiate the antitumor effect of docetaxel to cause complete regression of tumors, but can also effectively inhibit the invasion and metastasis of prostate cancer cells in vivo.

Conclusions: Our study provides evidence that Gal-1 is an important target for mCRPC therapy, and LLS30 is a promising small-molecule compound that can potentially overcome mCRPC. Clin Cancer Res; 24(17); 4319–31. ©2018 AACR.
Data from Comprehensive Safety Analysis of Venetoclax Monotherapy for Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia
Authors: Davids Matthew S. , Hallek Michael , Wierda William , Roberts Andrew W. , Stilgenbauer Stephan , Jones Jeffrey A. , Gerecitano John F. , Kim Su Young , Potluri Jalaja , Busman Todd , Best Andrea , Verdugo Maria E. , Cerri Elisa , Desai Monali , Hillmen Peter , Seymour John F.
Published: April 2023

Abstract
Purpose: The oral BCL-2 inhibitor venetoclax is an effective therapy for patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL), including disease with high-risk genomic features such as chromosome 17p deletion [del(17p)] or progressive disease following B-cell receptor pathway inhibitors.

Patients and Methods: We conducted a comprehensive analysis of the safety of 400 mg daily venetoclax monotherapy in 350 patients with CLL using an integrated dataset from three phase I/II studies.

Results: Median age was 66 years and 60% had del(17p). Patients had received a median of three prior therapies (range: 0–15); 42% previously received ibrutinib or idelalisib. Median duration of exposure to venetoclax was 16 months (0–56). In the pooled analysis, the most common adverse events (AE) of any grade were diarrhea (41%), neutropenia (40%), nausea (39%), anemia (31%), fatigue (28%), and upper respiratory tract infection (25%). The most common grade 3/4 AEs were neutropenia (37%), anemia (17%), and thrombocytopenia (14%). With the current 5-week ramp-up dosing, the incidence of laboratory TLS was 1.4% (2/166), none had clinical sequelae, and all of these patients were able to ramp-up to a daily dose of 400 mg. Grade 3/4 neutropenia was manageable with growth factor support and dose adjustments; the incidence of serious infections in these patients was 15%. Ten percent of patients discontinued venetoclax due to AEs and 8% died while on study, with the majority of deaths in the setting of disease progression.

Conclusions: Venetoclax as a long-term continuous therapy is generally well tolerated in patients with R/R CLL when initiated with the current treatment algorithm. Clin Cancer Res; 24(18); 4371–9. ©2018 AACR.
Data from Clinically Relevant Cytotoxic Immune Cell Signatures and Clonal Expansion of T-Cell Receptors in High-Risk MYCN-Not-Amplified Human Neuroblastoma
Authors: Wei Jun S. , Kuznetsov Igor B. , Zhang Shile , Song Young K. , Asgharzadeh Shahab , Sindiri Sivasish , Wen Xinyu , Patidar Rajesh , Najaraj Sushma , Walton Ashley , Auvil Jaime M. Guidry , Gerhard Daniela S. , Yuksel Aysen , Catchpoole Daniel , Hewitt Stephen M. , Sondel Paul M. , Seeger Robert , Maris John M. , Khan Javed
Published: April 2023

Abstract
Purpose: High-risk neuroblastoma is an aggressive disease. DNA sequencing studies have revealed a paucity of actionable genomic alterations and a low mutation burden, posing challenges to develop effective novel therapies. We used RNA sequencing (RNA-seq) to investigate the biology of this disease, including a focus on tumor-infiltrating lymphocytes (TIL).

Experimental Design: We performed deep RNA-seq on pretreatment diagnostic tumors from 129 high-risk and 21 low- or intermediate-risk patients with neuroblastomas. We used single-sample gene set enrichment analysis to detect gene expression signatures of TILs in tumors and examined their association with clinical and molecular parameters, including patient outcome. The expression profiles of 190 additional pretreatment diagnostic neuroblastomas, a neuroblastoma tissue microarray, and T-cell receptor (TCR) sequencing were used to validate our findings.

Results: We found that MYCN-not-amplified (MYCN-NA) tumors had significantly higher cytotoxic TIL signatures compared with MYCN-amplified (MYCN-A) tumors. A reported MYCN activation signature was significantly associated with poor outcome for high-risk patients with MYCN-NA tumors; however, a subgroup of these patients who had elevated activated natural killer (NK) cells, CD8+ T cells, and cytolytic signatures showed improved outcome and expansion of infiltrating TCR clones. Furthermore, we observed upregulation of immune exhaustion marker genes, indicating an immune-suppressive microenvironment in these neuroblastomas.

Conclusions: This study provides evidence that RNA signatures of cytotoxic TIL are associated with the presence of activated NK/T cells and improved outcomes in high-risk neuroblastoma patients harboring MYCN-NA tumors. Our findings suggest that these high-risk patients with MYCN-NA neuroblastoma may benefit from additional immunotherapies incorporated into the current therapeutic strategies. Clin Cancer Res; 24(22); 5673–84. ©2018 AACR.
Data from Deviation from the Proportional Hazards Assumption in Randomized Phase 3 Clinical Trials in Oncology: Prevalence, Associated Factors, and Implications
Authors: Rahman Rifaquat , Fell Geoffrey , Ventz Steffen , Arfé Andrea , Vanderbeek Alyssa M. , Trippa Lorenzo , Alexander Brian M.
Published: April 2023

AbstractPurpose:
Deviations from proportional hazards (DPHs), which may be more prevalent in the era of precision medicine and immunotherapy, can lead to underpowered trials or misleading conclusions. We used a meta-analytic approach to estimate DPHs across cancer trials, investigate associated factors, and evaluate data-analysis approaches for future trials.

Experimental Design: We searched PubMed for phase III trials in breast, lung, prostate, and colorectal cancer published in a preselected list of journals between 2014 and 2016 and extracted individual patient-level data (IPLD) from Kaplan–Meier curves. We re-analyzed IPLD to identify DPHs. Potential efficiency gains, when DPHs were present, of alternative statistical methods relative to standard log-rank based analysis were expressed as sample-size requirements for a fixed power level.
Results:
From 152 trials, we obtained IPLD on 129,401 patients. Among 304 Kaplan–Meier figures, 75 (24.7%) exhibited evidence of DPHs, including eight of 14 (57%) KM pairs from immunotherapy trials. Trial type [immunotherapy, odds ratio (OR), 4.29; 95% confidence interval (CI), 1.11–16.6], metastatic patient population (OR, 3.18; 95% CI, 1.26–8.05), and non-OS endpoints (OR, 3.23; 95% CI, 1.79–5.88) were associated with DPHs. In immunotherapy trials, alternative statistical approaches allowed for more efficient clinical trials with fewer patients (up to 74% reduction) relative to log-rank testing.
Conclusions:
DPHs were found in a notable proportion of time-to-event outcomes in published clinical trials in oncology and was more common for immunotherapy trials and non-OS endpoints. Alternative statistical methods, without proportional hazards assumptions, should be considered in the design and analysis of clinical trials when the likelihood of DPHs is high.
Data from Brentuximab Vedotin plus Chemotherapy in North American Subjects with Newly Diagnosed Stage III or IV Hodgkin Lymphoma
Authors: Ramchandren Radhakrishnan , Advani Ranjana H. , Ansell Stephen M. , Bartlett Nancy L. , Chen Robert , Connors Joseph M. , Feldman Tatyana , Forero-Torres Andres , Friedberg Jonathan W. , Gopal Ajay K. , Gordon Leo I. , Kuruvilla John , Savage Kerry J. , Younes Anas , Engley Gerald , Manley Thomas J. , Fenton Keenan , Straus David J.
Published: April 2023

AbstractPurpose:
To evaluate safety and efficacy outcomes for subjects on the ECHELON-1 study treated in North America (NA).
Patients and Methods:
ECHELON-1 is a global, open-label, randomized phase III study comparing doxorubicin, vinblastine, and dacarbazine in combination with brentuximab vedotin (A+AVD) versus ABVD (AVD + bleomycin) as first-line therapy in subjects with stage III or IV classical Hodgkin lymphoma (cHL; NCT01712490). Subjects were randomized 1:1 to receive A+AVD or ABVD intravenously on days 1 and 15 of each 28-day cycle for up to 6 cycles.
Results:
The NA subgroup consisted of 497 subjects in the A+AVD (n = 250) and ABVD (n = 247) arms. Similar to the primary analysis based on the intent-to-treat population, the primary endpoint [modified progression-free survival (PFS) per independent review] demonstrated an improvement among subjects who received A+AVD compared with ABVD (HR = 0.60; P = 0.012). For PFS, the risk of progression or death was also reduced (HR = 0.50; P = 0.002). Subsequent anticancer therapies were lower in the A+AVD arm. Grade 3 or 4 adverse events (AEs) were more common, but there were fewer study discontinuations due to AEs in the A+AVD arm as compared with ABVD. Noted differences between arms included higher rates of febrile neutropenia (20% vs. 9%) and peripheral neuropathy (80% vs. 56%), but lower rates of pulmonary toxicity (3% vs. 10%) in subjects treated with A+AVD versus ABVD.
Conclusions:
The efficacy benefit and manageable toxicity profile observed in the NA subgroup of ECHELON-1 support A+AVD as a frontline treatment option for patients with stage III or IV cHL.
Data from Multispecific Targeting with Synthetic Ankyrin Repeat Motif Chimeric Antigen Receptors
Authors: Balakrishnan Ashwini , Rajan Anusha , Salter Alexander I. , Kosasih Paula L. , Wu Qian , Voutsinas Jenna , Jensen Michael C. , Plückthun Andreas , Riddell Stanley R.
Published: April 2023

AbstractPurpose:
The outgrowth of antigen-negative variants is a significant challenge for adoptive therapy with T cells that target a single specificity. Chimeric antigen receptors (CAR) are typically designed with one or two scFvs that impart antigen specificity fused to activation and costimulation domains of T-cell signaling molecules. We designed and evaluated the function of CARs with up to three specificities for overcoming tumor escape using Designed Ankyrin Repeat Proteins (DARPins) rather than scFvs for tumor recognition.
Experimental Design:
A monospecific CAR was designed with a DARPin binder (E01) specific for EGFR and compared with a CAR designed using an anti-EGFR scFv. CAR constructs in which DARPins specific for EGFR, EpCAM, and HER2 were linked together in a single CAR were then designed and optimized to achieve multispecific tumor recognition. The efficacy of CAR-T cells bearing a multispecific DARPin CAR for treating tumors with heterogeneous antigen expression was evaluated in vivo.
Results:
The monospecific anti-EGFR E01 DARPin conferred potent tumor regression against EGFR+ targets that was comparable with an anti-EGFR scFv CAR. Linking three separate DARPins in tandem was feasible and in an optimized format generated a single tumor recognition domain that targeted a mixture of heterogeneous tumor cells, each expressing a single antigen, and displayed synergistic activity when tumor cells expressed more than one target antigen.
Conclusions:
DARPins can serve as high-affinity recognition motifs for CAR design, and their robust architecture enables linking of multiple binders against different antigens to achieve functional synergy and reduce antigen escape.
Data from Effective Delivery of a Microtubule Polymerization Inhibitor Synergizes with Standard Regimens in Models of Pancreatic Ductal Adenocarcinoma
Authors: Eberle-Singh Jaime A. , Sagalovskiy Irina , Maurer H. Carlo , Sastra Stephen A. , Palermo Carmine F. , Decker Amanda R. , Kim Min Jung , Sheedy Josephine , Mollin Anna , Cao Liangxian , Hu Jianhua , Branstrom Arthur , Weetall Marla , Olive Kenneth P.
Published: April 2023

AbstractPurpose:
Pancreatic ductal adenocarcinoma (PDA) is a deadly cancer that is broadly chemoresistant, due in part to biophysical properties of tumor stroma, which serves as a barrier to drug delivery for most classical chemotherapeutic drugs. The goal of this work is to evaluate the preclinical efficacy and mechanisms of PTC596, a novel agent with potent anticancer properties in vitro and desirable pharmacologic properties in vivo.

Experimental Design: We assessed the pharmacology, mechanism, and preclinical efficacy of PTC596 in combination with standards of care, using multiple preclinical models of PDA.
Results:
We found that PTC596 has pharmacologic properties that overcome the barrier to drug delivery in PDA, including a long circulating half-life, lack of P-glycoprotein substrate activity, and high systemic tolerability. We also found that PTC596 combined synergistically with standard clinical regimens to improve efficacy in multiple model systems, including the chemoresistant genetically engineered “KPC” model of PDA. Through mechanistic studies, we learned that PTC596 functions as a direct microtubule polymerization inhibitor, yet a prior clinical trial found that it lacks peripheral neurotoxicity, in contrast to other such agents. Strikingly, we found that PTC596 synergized with the standard clinical backbone regimen gemcitabine/nab-paclitaxel, yielding potent, durable regressions in a PDX model. Moreover, similar efficacy was achieved in combination with nab-paclitaxel alone, highlighting a specific synergistic interaction between two different microtubule-targeted agents in the setting of pancreatic ductal adenocarcinoma.
Conclusions:
These data demonstrate clear rationale for the development of PTC596 in combination with standard-of-care chemotherapy for PDA.
Data from Breast Phyllodes Tumors Recruit and Repolarize Tumor-Associated Macrophages via Secreting CCL5 to Promote Malignant Progression, Which Can Be Inhibited by CCR5 Inhibition Therapy
Authors: Nie Yan , Huang Hongyan , Guo Mingyan , Chen Jiewen , Wu Wei , Li Wende , Xu Xiaoding , Lin Xiaorong , Fu Wenkui , Yao Yandan , Zheng Fang , Luo Man-Li , Saw Phei Er , Yao Herui , Song Erwei , Hu Hai
Published: April 2023

AbstractPurpose:
Malignant phyllodes tumor (PT) is a fast-progression neoplasm derived from periductal stromal cells of the breast, which currently still lack effective treatment strategies. Our previous studies showed that the high density of tumor-associated macrophages (TAM) plays an important role in the malignant progression of PTs. TAMs secreted large amount of CCL18 to promote myofibroblast differentiation and invasion via binding to its receptor PIPTNM3 on myofibroblasts. Herein, we investigate the mechanism of how TAMs are recruited and repolarized by PTs to drive the malignant progression.
Experimental Design:
The cytokines secreted by PTs were identified by the cytokine array. The clinical and pathologic correlations of the cytokine with PTs were estimated with IHC. The mechanisms of the cytokine that recruited and polarized the macrophage were explored with a coculture model of primary PT cells and macrophages in vitro and in vivo. The patient-derived xenografts (PDX) of malignant PTs were used to evaluate the therapeutic effect of CCR5 inhibitor.
Results:
A high level of malignant PT-secreted CCL5 correlated with poor outcome of PTs and could be an independent prognostic factor of PTs. CCL5 bound to its receptor, CCR5, on macrophages thus activated AKT signaling to recruit and repolarize TAMs. Subsequently, the TAMs released CCL18 to further promote the aggressive phenotype of malignant PTs by enhancing and maintaining the myofibroblast differentiation and invasion in vitro and in vivo. In a murine PDX model of human malignant PTs, the CCL5–CCR5 axis blocked by maraviroc, an FDA-proved CCR5 inhibitor, prevented recruitment of monocytes to the tumor and dramatically suppressed tumor growth.
Conclusions:
Our findings indicate that malignant PTs recruit and repolarize TAMs through a CCL5-CCR5–driven signaling cascade. Thus, a positive feedback loop of CCL5-CCR5 and CCL18-PIPTNM3 between myofibroblast and TAMs is constituted to drive the malignant progression of PTs. Furthermore, targeting CCR5 with maraviroc represents a potential clinically available strategy to treat malignant PTs.
Data from CAR T Cells Targeting B7-H3, a Pan-Cancer Antigen, Demonstrate Potent Preclinical Activity Against Pediatric Solid Tumors and Brain Tumors
Authors: Majzner Robbie G. , Theruvath Johanna L. , Nellan Anandani , Heitzeneder Sabine , Cui Yongzhi , Mount Christopher W. , Rietberg Skyler P. , Linde Miles H. , Xu Peng , Rota Christopher , Sotillo Elena , Labanieh Louai , Lee Daniel W. , Orentas Rimas J. , Dimitrov Dimiter S. , Zhu Zhongyu , Croix Brad St , Delaidelli Alberto , Sekunova Alla , Bonvini Ezio , Mitra Siddhartha S. , Quezado Martha M. , Majeti Ravindra , Monje Michelle , Sorensen Poul H.B. , Maris John M. , Mackall Crystal L.
Published: April 2023

AbstractPurpose:
Patients with relapsed pediatric solid tumors and CNS malignancies have few therapeutic options and frequently die of their disease. Chimeric antigen receptor (CAR) T cells have shown tremendous success in treating relapsed pediatric acute lymphoblastic leukemia, but this has not yet translated to treating solid tumors. This is partially due to a paucity of differentially expressed cell surface molecules on solid tumors that can be safely targeted. Here, we present B7-H3 (CD276) as a putative target for CAR T-cell therapy of pediatric solid tumors, including those arising in the central nervous system.
Experimental Design:
We developed a novel B7-H3 CAR whose binder is derived from a mAb that has been shown to preferentially bind tumor tissues and has been safely used in humans in early-phase clinical trials. We tested B7-H3 CAR T cells in a variety of pediatric cancer models.
Results:
B7-H3 CAR T cells mediate significant antitumor activity in vivo, causing regression of established solid tumors in xenograft models including osteosarcoma, medulloblastoma, and Ewing sarcoma. We demonstrate that B7-H3 CAR T-cell efficacy is largely dependent upon high surface target antigen density on tumor tissues and that activity is greatly diminished against target cells that express low levels of antigen, thus providing a possible therapeutic window despite low-level normal tissue expression of B7-H3.
Conclusions:
B7-H3 CAR T cells could represent an exciting therapeutic option for patients with certain lethal relapsed or refractory pediatric malignancies, and should be tested in carefully designed clinical trials.
Data from Autologous Dendritic Cell-Cytokine Induced Killer Cell Immunotherapy Combined with S-1 Plus Cisplatin in Patients with Advanced Gastric Cancer: A Prospective Study
Authors: Qiao Guoliang , Wang Xiaoli , Zhou Lei , Zhou Xinna , Song Yuguang , Wang Shuo , Zhao Lei , Morse Michael A. , Hobeika Amy , Song Jin , Yi Xin , Xia Xuefeng , Ren Jun , Lyerly Herbert Kim
Published: April 2023

AbstractPurpose:
We have assessed the combination of DC–CIK with S-1 plus cisplatin chemotherapy in advanced gastric cancer (AGC) and the role of mutational analysis of circulating tumor DNA (ctDNA) and T-cell receptor (TCR) repertoire in predicting clinical outcomes.
Patients and Methods:
Consecutive patients (n = 63) with AGC were allocated to treatment with S-1 alone, S-1 plus cisplatin, DC–CIK combined with S-1 or DC–CIK combined with S-1 plus cisplatin. The primary endpoints were progression-free survival (PFS) and overall survival (OS) at 1 year; the secondary endpoints were disease control rate and analysis of ctDNA and TCR repertoire.
Results:
The DC–CIK infusions were well tolerated with no serious adverse events. The disease control rates (CR+PR+SD) were 5.6%, 33.3%, 47.1%, and 76.9% in the S-1 alone, the S-1 plus cisplatin, DC–CIK combined with S-1 and DC–CIK combined with the S-1 plus cisplatin groups, respectively (P = 0.001). After adjusting for competing risk factors, treatment with DC-CIK combined with S-1 plus cisplatin was confirmed to be an independent predictor of PFS and OS (P = 0.001). A decrease in the frequency and number of mutations in ctDNA was observed in 19 patients (63.3%) following the DC–CIK infusions. Decreased ctDNA mutational frequency and restored TCR repertoire were associated with improved PFS and OS (P = 0.001).
Conclusions:
DC–CIK combined with S-1 plus cisplatin provided a favorable PFS and OS in patients with AGC and the combination therapy was safe with tolerable toxicities. Clinical efficacy correlated with decreases in ctDNA mutational profiles and restored TCR repertoire.
Data from Voxel Forecast for Precision Oncology: Predicting Spatially Variant and Multiscale Cancer Therapy Response on Longitudinal Quantitative Molecular Imaging
Authors: Bowen Stephen R. , Hippe Daniel S. , Chaovalitwongse W. Art , Duan Chunyan , Thammasorn Phawis , Liu Xiao , Miyaoka Robert S. , Vesselle Hubert J. , Kinahan Paul E. , Rengan Ramesh , Zeng Jing
Published: April 2023

AbstractPurpose:
Prediction of spatially variant response to cancer therapies can inform risk-adaptive management within precision oncology. We developed the “Voxel Forecast” multiscale regression framework for predicting spatially variant tumor response to chemoradiotherapy on fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) imaging.
Experimental Design:
Twenty-five patients with locally advanced non–small cell lung cancer, enrolled on the FLARE-RT phase II trial (NCT02773238), underwent FDG PET/CT imaging prior to (PETpre) and during week 3 (PETmid) of concurrent chemoradiotherapy. Voxel Forecast was designed to predict tumor voxel standardized uptake value (SUV) on PETmid from baseline patient-level and voxel-level covariates using a custom generalized least squares (GLS) algorithm. Matérn covariance matrices were fit to patient- specific empirical variograms of distance-dependent intervoxel correlation. Regression coefficients from variogram-based weights and corresponding standard errors were estimated using the jackknife technique. The framework was validated using statistical simulations of known spatially variant tumor response. Mean absolute prediction errors (MAEs) of Voxel Forecast models were calculated under leave-one-patient-out cross-validation.
Results:
Patient-level forecasts resulted in tumor voxel SUV MAE on PETmid of 1.5 g/mL while combined patient- and voxel-level forecasts achieved lower MAE of 1.0 g/mL (P < 0.0001). PETpre voxel SUV was the most important predictor of PETmid voxel SUV. Patients with a greater percentage of under-responding tumor voxels were classified as PETmid nonresponders (P = 0.030) with worse overall survival prognosis (P < 0.001).
Conclusions:
Voxel Forecast multiscale regression provides a statistical framework to predict voxel-wise response patterns during therapy. Voxel Forecast can be extended to predict spatially variant response on multimodal quantitative imaging and may eventually guide optimized spatial–temporal dose distributions for precision cancer therapy.
Data from CKAP4, a DKK1 Receptor, Is a Biomarker in Exosomes Derived from Pancreatic Cancer and a Molecular Target for Therapy
Authors: Kimura Hirokazu , Yamamoto Hideki , Harada Takeshi , Fumoto Katsumi , Osugi Yoshihito , Sada Ryota , Maehara Natsumi , Hikita Hayato , Mori Soichiro , Eguchi Hidetoshi , Ikawa Masahito , Takehara Tetsuo , Kikuchi Akira
Published: April 2023

AbstractPurpose:
The survival rate of pancreatic ductal adenocarcinoma (PDAC) is poor; thus, novel molecularly targeted therapy and companion diagnostics are required. We asked whether cytoskeleton-associated protein 4 (CKAP4), a novel Dickkopf1 (DKK1) receptor, is a candidate for PDAC diagnosis and therapy.

Experimental Design: Whether CKAP4 can be secreted with small extracellular vesicles (SEV) from PDAC cells was examined. It was also investigated whether CKAP4 can be detected in sera from patients with PDAC by ELISA using newly generated anti-CKAP4 mAbs and whether anti-CKAP4 mAbs can show antitumor activity in vivo.
Results:
CKAP4 was secreted with SEVs from PDAC cells, and the SEVs exhibited the characteristics of exosomes. The secretion of CKAP4-containing exosomes was mediated by DKK1-dependent endocytosis routes and required exosome biogenesis molecules. Two ELISAs capable of detecting tumor-secreted CKAP4 were developed. The serum CKAP4 levels were higher in patients with PDAC than healthy control individuals. CKAP4 was highly detected in the sera of pancreatic tumor-bearing xenografted mice and patients with PDAC, whereas CKAP4 was barely detectable in sera from normal mice and postoperative patients. Anti-CKAP4 mAbs with different epitopes demonstrated the inhibitory activities for the binding of DKK1 and CKAP4, AKT activity, and proliferation and migration of PDAC cells. Anti-CKAP4 mAbs also suppressed xenograft tumor formation in immunodeficient mice and extended the survival of mice receiving intraperitoneal or orthotopic injection of PDAC cells.
Conclusions:
CKAP4 secreted in exosomes may represent a biomarker for PDAC. Anti-CKAP4 mAbs can contribute to the development of novel diagnostic methods and therapeutics.
Data from Activated Natural Killer Cells in Combination with Anti-GD2 Antibody Dinutuximab Improve Survival of Mice after Surgical Resection of Primary Neuroblastoma
Authors: Barry Wesley E. , Jackson Jeremy R. , Asuelime Grace E. , Wu Hong-Wei , Sun Jianping , Wan Zesheng , Malvar Jemily , Sheard Michael A. , Wang Larry , Seeger Robert C. , Kim Eugene S.
Published: April 2023

AbstractPurpose:
Immunotherapy of neuroblastoma that remains after myeloablative chemotherapy with anti-GD2 antibody dinutuximab has increased the two-year event-free and overall survival of high-risk neuroblastoma patients; however, 40% of patients develop recurrent disease during or after this treatment. To determine the potential of such antibody-based immunotherapy earlier in treatment, a mouse model was developed in which surgical resection of the primary tumor was followed by therapy of residual disease with dinutuximab combined with ex vivo–activated human natural killer (aNK) cells.
Experimental Design:
The effect of combining dinutuximab with human aNK cells was determined in vitro with cellular cytotoxicity and Matrigel invasion assays. The in vivo efficacy of dinutuximab and aNK cells against neuroblastoma was assessed following resection of primary tumors formed by two cell lines or a patient-derived xenograft (PDX) in immunodeficient NOD-scid gamma mice.
Results:
In vitro, the combination of aNK cells and dinutuximab caused cytotoxicity and decreased invasiveness of three human neuroblastoma cell lines. Treatment of mice with dinutuximab combined with aNK cells after surgical resection of primary intrarenal tumors formed by two cell lines or a PDX decreased tumor cells in liver and bone marrow as evaluated by histopathology and bioluminescence imaging. Survival of mice after resection of these tumors was most significantly increased by treatment with dinutuximab combined with aNK cells compared with that of untreated mice.
Conclusions:
The combination of dinutuximab and adoptively transferred human aNK cells following surgical resection of primary neuroblastomas significantly improves survival of immunodeficient mice.
Data from The Advantage of FLASH Radiotherapy Confirmed in Mini-pig and Cat-cancer Patients
Authors: Vozenin Marie-Catherine , De Fornel Pauline , Petersson Kristoffer , Favaudon Vincent , Jaccard Maud , Germond Jean-François , Petit Benoit , Burki Marco , Ferrand Gisèle , Patin David , Bouchaab Hanan , Ozsahin Mahmut , Bochud François , Bailat Claude , Devauchelle Patrick , Bourhis Jean
Published: April 2023

AbstractPurpose:
Previous studies using FLASH radiotherapy (RT) in mice showed a marked increase of the differential effect between normal tissue and tumors. To stimulate clinical transfer, we evaluated whether this effect could also occur in higher mammals.
Experimental Design:
Pig skin was used to investigate a potential difference in toxicity between irradiation delivered at an ultrahigh dose rate called “FLASH-RT” and irradiation delivered at a conventional dose rate called “Conv-RT.” A clinical, phase I, single-dose escalation trial (25–41 Gy) was performed in 6 cat patients with locally advanced T2/T3N0M0 squamous cell carcinoma of the nasal planum to determine the maximal tolerated dose and progression-free survival (PFS) of single-dose FLASH-RT.
Results:
Using, respectively, depilation and fibronecrosis as acute and late endpoints, a protective effect of FLASH-RT was observed (≥20% dose-equivalent difference vs. Conv-RT). Three cats experienced no acute toxicity, whereas 3 exhibited moderate/mild transient mucositis, and all cats had depilation. With a median follow-up of 13.5 months, the PFS at 16 months was 84%.
Conclusions:
Our results confirmed the potential advantage of FLASH-RT and provide a strong rationale for further evaluating FLASH-RT in human patients.

See related commentary by Harrington, p. 3