bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Phase 1 Study of Tabalumab, a Human Anti-B-Cell Activating Factor Antibody, and Bortezomib in Patients with Relapsed/Refractory Multiple Myeloma
Authors: Raje Noopur S. , Faber Edward A. , Richardson Paul G. , Schiller Gary , Hohl Raymond J. , Cohen Adam D. , Forero Andres , Carpenter Susan , Nguyen Tuan S. , Conti Ilaria , Kaiser Christopher J. , Cronier Damien M. , Wooldridge James E. , Anderson Kenneth C.
Published: April 2023

Abstract
Purpose: Tabalumab, a human mAb that neutralizes B-cell–activating factor (BAFF), demonstrated antitumor activity in xenograft models of multiple myeloma. Here we report on a phase I study of relapsed/refractory multiple myeloma patients in which the primary objective was to identify a tolerable and potentially efficacious dose of tabalumab when combined with bortezomib.

Experimental Design: Forty-eight patients were enrolled; 20 to the dose-escalation cohort, and 28 to cohort expansion in which a dose of 100 mg of tabalumab was evaluated. All patients had received either prior bortezomib or an immunomodulatory drug; the median number of prior therapies was 3. Bortezomib was administered intravenously on days 1, 4, 8, and 11 of a 21-day schedule. Tabalumab was given every 21 days for 3 cycles, then every 42 days thereafter.

Results: The most common grade 3/4 toxicities included thrombocytopenia, neutropenia, pneumonia, and peripheral sensory neuropathy. There were no dose-limiting toxicities, and the maximum tolerated dose was not reached. Pharmacokinetic data suggested serum exposure increased in a greater than dose-proportional manner up to a dose of 100 mg. Out of 46 evaluable patients, 20 had confirmed responses. The median time to progression (9 patients censored) was 4.8 months, and the median response duration (4 patients censored) was 7.2 months.

Conclusions: A dose of 100 mg tabalumab in combination with bortezomib was well tolerated and active and is currently under further investigation. Clin Cancer Res; 22(23); 5688–95. ©2016 AACR.
Data from Inhibition of ID1–BMPR2 Intrinsic Signaling Sensitizes Glioma Stem Cells to Differentiation Therapy
Authors: Jin Xiong , Jin Xun , Kim Leo J.Y. , Dixit Deobrat , Jeon Hee-Young , Kim Eun-Jung , Kim Jun-Kyum , Lee Seon Yong , Yin Jinlong , Rich Jeremy N. , Kim Hyunggee
Published: April 2023

Abstract
Purpose: Normal stem cells tightly control self-renewal and differentiation during development, but their neoplastic counterparts, cancer stem cells (CSCs), sustain tumorigenicity both through aberrant activation of stemness and evasion of differentiation. Although regulation of CSC stemness has been extensively studied, the molecular mechanisms suppressing differentiation remain unclear.

Experimental Design: We performed in silico screening and in vitro validation studies through Western blotting, qRT-PCR for treatment of WNT and SHH signaling inhibitors, and BMP signaling inducer with control and ID1-overexpressing cells. We also performed in vivo drug treatment assays with Balb/c nude mice.

Results: Inhibitor of differentiation 1 (ID1) abrogated differentiation signals from bone morphogenetic protein receptor (BMPR) signaling in glioblastoma stem cells (GSCs) to promote self-renewal. ID1 inhibited BMPR2 expression through miRNAs, miR-17 and miR-20a, which are transcriptional targets of MYC. ID1 increases MYC expression by activating WNT and SHH signaling. Combined pharmacologic blockade of WNT and SHH signaling with BMP treatment significantly suppressed GSC self-renewal and extended survival of tumor-bearing mice.

Conclusions: Collectively, our results suggested that ID1 simultaneously regulates stemness through WNT and SHH signaling and differentiation through BMPR-mediated differentiation signaling in GSCs, informing a novel therapeutic strategy of combinatorial targeting of stemness and differentiation. Clin Cancer Res; 24(2); 383–94. ©2017 AACR.
Data from First-in-Human Study of AMG 820, a Monoclonal Anti-Colony-Stimulating Factor 1 Receptor Antibody, in Patients with Advanced Solid Tumors
Authors: Papadopoulos Kyriakos P. , Gluck Larry , Martin Lainie P. , Olszanski Anthony J. , Tolcher Anthony W. , Ngarmchamnanrith Gataree , Rasmussen Erik , Amore Benny M. , Nagorsen Dirk , Hill John S. , Stephenson Joe
Published: April 2023

Abstract
Purpose: Binding of colony-stimulating factor 1 (CSF1) ligand to the CSF1 receptor (CSF1R) regulates survival of tumor-associated macrophages, which generally promote an immunosuppressive tumor microenvironment. AMG 820 is an investigational, fully human CSF1R antibody that inhibits binding of the ligands CSF1 and IL34 and subsequent ligand-mediated receptor activation. This first-in-human phase I study evaluated the safety, pharmacokinetics, pharmacodynamics, and antitumor activity of AMG 820.

Experimental Design: Adult patients with relapsed or refractory advanced solid tumors received intravenous AMG 820 0.5 mg/kg once weekly or 1.5 to 20 mg/kg every 2 weeks until disease progression, adverse event (AE), or consent withdrawal.

Results: Twenty-five patients received ≥1 dose of AMG 820. AMG 820 was tolerated up to 20 mg/kg; the MTD was not reached. One dose-limiting toxicity was observed (20 mg/kg; nonreversible grade 3 deafness). Most patients (76%) had treatment-related AEs; the most common were periorbital edema (44%), increased aspartate aminotransferase (AST; 28%), fatigue (24%), nausea (16%), increased blood alkaline phosphatase (12%), and blurred vision (12%). No patients had serious or fatal treatment-related AEs; 28% had grade ≥3 treatment-related AEs. Grade 3 AST elevations resolved when treatment was withheld. AMG 820 showed linear pharmacokinetics, with minimal accumulation (<2-fold) after repeated dosing. Pharmacodynamic increases in serum CSF1 concentrations and reduced numbers of skin macrophages were observed. Best response was stable disease in 8 patients (32%).

Conclusions: AMG 820 was tolerated with manageable toxicities up to 20 mg/kg every 2 weeks. Pharmacodynamic response was demonstrated, and limited antitumor activity was observed. Clin Cancer Res; 23(19); 5703–10. ©2017 AACR.
Data from Clinical Utility of Risk Models to Refer Patients with Adnexal Masses to Specialized Oncology Care: Multicenter External Validation Using Decision Curve Analysis
Authors: Wynants Laure , Timmerman Dirk , Verbakel Jan Y. , Testa Antonia , Savelli Luca , Fischerova Daniela , Franchi Dorella , Van Holsbeke Caroline , Epstein Elisabeth , Froyman Wouter , Guerriero Stefano , Rossi Alberto , Fruscio Robert , Leone Francesco PG , Bourne Tom , Valentin Lil , Van Calster Ben
Published: April 2023

Abstract
Purpose: To evaluate the utility of preoperative diagnostic models for ovarian cancer based on ultrasound and/or biomarkers for referring patients to specialized oncology care. The investigated models were RMI, ROMA, and 3 models from the International Ovarian Tumor Analysis (IOTA) group [LR2, ADNEX, and the Simple Rules risk score (SRRisk)].

Experimental Design: A secondary analysis of prospectively collected data from 2 cross-sectional cohort studies was performed to externally validate diagnostic models. A total of 2,763 patients (2,403 in dataset 1 and 360 in dataset 2) from 18 centers (11 oncology centers and 7 nononcology hospitals) in 6 countries participated. Excised tissue was histologically classified as benign or malignant. The clinical utility of the preoperative diagnostic models was assessed with net benefit (NB) at a range of risk thresholds (5%–50% risk of malignancy) to refer patients to specialized oncology care. We visualized results with decision curves and generated bootstrap confidence intervals.

Results: The prevalence of malignancy was 41% in dataset 1 and 40% in dataset 2. For thresholds up to 10% to 15%, RMI and ROMA had a lower NB than referring all patients. SRRisks and ADNEX demonstrated the highest NB. At a threshold of 20%, the NBs of ADNEX, SRrisks, and RMI were 0.348, 0.350, and 0.270, respectively. Results by menopausal status and type of center (oncology vs. nononcology) were similar.

Conclusions: All tested IOTA methods, especially ADNEX and SRRisks, are clinically more useful than RMI and ROMA to select patients with adnexal masses for specialized oncology care. Clin Cancer Res; 23(17); 5082–90. ©2017 AACR.
Data from CD31 Expression Determines Redox Status and Chemoresistance in Human Angiosarcomas
Authors: Venkataramani Vivek , Küffer Stefan , Cheung Kenneth C.P. , Jiang Xuejun , Trümper Lorenz , Wulf Gerald G. , Ströbel Philipp
Published: April 2023

Abstract
Purpose: Angiosarcomas are soft tissue sarcomas with endothelial differentiation and vasoformative capacity. Most angiosarcomas show strong constitutive expression of the endothelial adhesion receptor CD31/PECAM-1 pointing to an important role of this molecule. However, the biological function of CD31 in angiosarcomas is unknown.

Experimental Design: The expression levels of CD31 in angiosarcoma cells and its effects on cell viability, colony formation, and chemoresistance were evaluated in human angiosarcoma clinical samples and in cell lines through isolation of CD31high and CD31low cell subsets. The redox-regulatory CD31 function linked to YAP signaling was determined using a CD31-blocking antibody and siRNA approach and was further validated in CD31-knockout endothelial cells.

Results: We found that most angiosarcomas contain a small CD31low cell population. CD31low cells had lost part of their endothelial properties and were more tumorigenic and chemoresistant than CD31high cells due to more efficient reactive oxygen species (ROS) detoxification. Active downregulation of CD31 resulted in loss of endothelial tube formation, nuclear accumulation of YAP, and YAP-dependent induction of antioxidative enzymes. Addition of pazopanib, a known enhancer of proteasomal YAP degradation resensitized CD31low cells for doxorubicin resulting in growth suppression and induction of apoptosis.

Conclusions: Human angiosarcomas contain a small aggressive CD31low population that have lost part of their endothelial differentiation programs and are more resistant against oxidative stress and DNA damage due to intensified YAP signaling. Our finding that the addition of YAP inhibitors can resensitize CD31low cells toward doxorubicin may aid in the rational development of novel combination therapies to treat angiosarcomas. Clin Cancer Res; 24(2); 460–73. ©2017 AACR.
Data from Increases in Absolute Lymphocytes and Circulating CD4+ and CD8+ T Cells Are Associated with Positive Clinical Outcome of Melanoma Patients Treated with Ipilimumab
Authors: Martens Alexander , Wistuba-Hamprecht Kilian , Yuan Jianda , Postow Michael A. , Wong Phillip , Capone Mariaelena , Madonna Gabriele , Khammari Amir , Schilling Bastian , Sucker Antje , Schadendorf Dirk , Martus Peter , Dreno Brigitte , Ascierto Paolo A. , Wolchok Jedd D. , Pawelec Graham , Garbe Claus , Weide Benjamin
Published: April 2023

Abstract
Purpose: To investigate changes of peripheral blood biomarkers and their impact on clinical outcome following treatment with ipilimumab in advanced melanoma patients.

Experimental Design: Changes in blood counts and the frequency of circulating immune cell populations analyzed by flow cytometry were investigated in 82 patients to compare baseline values with different time-points after starting ipilimumab. Endpoints were overall survival (OS) and best clinical response. Statistical calculations were done by Wilcoxon-matched pairs tests, Fisher exact test, Kaplan–Meier analysis, and Cox regression analysis.

Results: Increases in absolute lymphocyte counts (ALC) 2 to 8 weeks (P = 0.003) and in percentages of CD4+ and CD8+ T cells 8 to 14 weeks (P = 0.001 and P = 0.02) after the first dose of ipilimumab were correlated with improved survival. These associations did not meet significance criteria, when conservatively adjusted for multiple testing, but were additionally correlated with clinical responses (all P < 0.05). However, validation is required. Increases in all three factors were observed in 36% of patients, who had a favorable outcome and survival probabilities of 93.3% and 63.8% at 12 and 24 months, respectively. A partial or complete response was observed in 71% of these patients compared with only 8% in patients with decreases in ≥1 of the 3 factors, respectively. Changes of regulatory T cells or myeloid-derived suppressor cells were not associated with OS.

Conclusions: Increases of ALC observed 2 to 8 weeks after initiation of ipilimumab and delayed increases in CD4+ and CD8+ T cells reflect changes associated with positive outcome. These changes represent surrogate marker candidates and warrant further validation. Clin Cancer Res; 22(19); 4848–58. ©2016 AACR.
Data from Exposure–Response of Veliparib to Inform Phase II Trial Design in Refractory or Relapsed Patients with Hematological Malignancies
Authors: Mehrotra Shailly , Gopalakrishnan Mathangi , Gobburu Jogarao , Ji Jiuping , Greer Jacqueline M. , Piekarz Richard , Karp Judith E. , Pratz Keith W. , Rudek Michelle A.
Published: April 2023

Abstract
Purpose: A phase I trial of veliparib in combination with topotecan plus carboplatin (T+C) demonstrated a 33% objective response rate in patients with hematological malignancies. The objective is to perform exposure–response analysis to inform the phase II trial design.

Experimental Design: Pharmacokinetic, efficacy, and safety data from 95 patients, who were administered 10 to 100 mg b.i.d. doses of veliparib for either 8, 14, or 21 days with T+C, were utilized for exposure–efficacy (objective response and overall survival) and exposure–safety (≥grade 3 mucositis) analysis. Multivariate cox proportional hazards and logistic regression analyses were conducted. The covariates evaluated were disease status, duration of treatment, and number of prior therapies.

Results: The odds of having objective response were 1.08-fold with 1,000 ng/hr/mL increase in AUC, 1.8-fold with >8 days treatment, 2.8-fold in patients with myeloproliferative neoplasms (MPN), and 0.5-fold with ≥2 prior therapies. Based on analysis of overall survival, hazard of death decreased by 1.5% for 1,000 ng/hr/mL increase in AUC, 39% with >8 days treatment, 44% in patients with MPN, while increased by 19% with ≥2 prior therapies. The odds of having ≥grade 3 mucositis increased by 29% with 1,000 ng.h/mL increase in AUC.

Conclusions: Despite shallow exposure–efficacy relationship, doses lower than 80 mg do not exceed veliparib single agent preclinical IC50. Shallow exposure–mucositis relationship also supports the 80-mg dose. Based on benefit/risk assessment, veliparib at a dose of 80 mg b.i.d. for at least 14 days in combination with T+C is recommended to be studied in MPN patients. Clin Cancer Res; 23(21); 6421–9. ©2017 AACR.
Data from PI3K/Akt/mTOR Signaling and Plasma Membrane Proteins Are Implicated in Responsiveness to Adjuvant Dendritic Cell Vaccination for Metastatic Colorectal Cancer
Authors: Qian David C. , Xiao Xiangjun , Byun Jinyoung , Suriawinata Arief A. , Her Stephanie C. , Amos Christopher I. , Barth Richard J.
Published: April 2023

Abstract
Purpose: We have previously demonstrated that patients with metastatic colorectal cancer who exhibit immune responses to a dendritic cell (DC) vaccine have superior recurrence-free survival following surgery, compared with patients in whom responses do not occur. We sought to characterize the patterns of T-lymphocyte infiltration and somatic mutations in metastases that are associated with and predictive of response to the DC vaccine.

Experimental Design: Cytotoxic, memory, and regulatory T cells in resected metastases and surrounding normal liver tissue from 22 patients (11 responders and 11 nonresponders) were enumerated by immunohistochemistry prior to vaccine administration. In conjunction with tumor sequencing, the combined multivariate and collapsing method was used to identify gene mutations that are associated with vaccine response. We also derived a response prediction score for each patient using his/her tumor genotype data and variant association effect sizes computed from the other 21 patients; greater weighting was placed on gene products with cell membrane–related functions.

Results: There was no correlation between vaccine response and intratumor, peritumor, or hepatic densities of T-cell subpopulations. Associated genes were found to be enriched in the PI3K/Akt/mTOR signaling axis (P < 0.001). Applying a consistent prediction score cutoff over 22 rounds of leave-one-out cross-validation correctly inferred vaccine response in 21 of 22 patients (95%).

Conclusions: Adjuvant DC vaccination has shown promise as a form of immunotherapy for patients with metastatic colorectal cancer. Its efficacy may be influenced by somatic mutations that affect pathways involving PI3K, Akt, and mTOR, as well as tumor surface proteins. Clin Cancer Res; 23(2); 399–406. ©2016 AACR.
Data from Extracellular HMGA1 Promotes Tumor Invasion and Metastasis in Triple-Negative Breast Cancer
Authors: Méndez Olga , Peg Vicente , Salvans Cándida , Pujals Mireia , Fernández Yolanda , Abasolo Ibane , Pérez José , Matres Ana , Valeri Marta , Gregori Josep , Villarreal Laura , Schwartz Simó , Ramon y Cajal Santiago , Tabernero Josep , Cortés Javier , Arribas Joaquín , Villanueva Josep
Published: April 2023

AbstractPurpose:
The study of the cancer secretome suggests that a fraction of the intracellular proteome could play unanticipated roles in the extracellular space during tumorigenesis. A project aimed at investigating the invasive secretome led us to study the alternative extracellular function of the nuclear protein high mobility group A1 (HMGA1) in breast cancer invasion and metastasis.
Experimental Design:
Antibodies against HMGA1 were tested in signaling, adhesion, migration, invasion, and metastasis assays using breast cancer cell lines and xenograft models. Fluorescence microscopy was used to determine the subcellular localization of HMGA1 in cell lines, xenograft, and patient-derived xenograft models. A cohort of triple-negative breast cancer (TNBC) patients was used to study the correlation between subcellular localization of HMGA1 and the incidence of metastasis.
Results:
Our data show that treatment of invasive cells with HMGA1-blocking antibodies in the extracellular space impairs their migration and invasion abilities. We also prove that extracellular HMGA1 (eHMGA1) becomes a ligand for the Advanced glycosylation end product-specific receptor (RAGE), inducing pERK signaling and increasing migration and invasion. Using the cytoplasmic localization of HMGA1 as a surrogate marker of secretion, we showed that eHMGA1 correlates with the incidence of metastasis in a cohort of TNBC patients. Furthermore, we show that HMGA1 is enriched in the cytoplasm of tumor cells at the invasive front of primary tumors and in metastatic lesions in xenograft models.
Conclusions:
Our results strongly suggest that eHMGA1 could become a novel drug target in metastatic TNBC and a biomarker predicting the onset of distant metastasis.
Data from The Highly Metastatic Nature of Uterine Cervical/Endometrial Cancer Displaying Tumor-Related Leukocytosis: Clinical and Preclinical Investigations
Authors: Sasano Tomoyuki , Mabuchi Seiji , Kozasa Katsumi , Kuroda Hiromasa , Kawano Mahiru , Takahashi Ryoko , Komura Naoko , Yokoi Eriko , Matsumoto Yuri , Hashimoto Kae , Sawada Kenjiro , Morii Eiichi , Kimura Tadashi
Published: April 2023

Abstract
Purpose: The aim of this study was to investigate the metastatic potential of uterine cervical and endometrial cancer displaying tumor-related leukocytosis (TRL).

Experimental Design: Clinical data on uterine cervical (N = 732) and endometrial cancer (N = 900) were collected, and the metastatic potential of TRL-positive cancer was evaluated in univariate and multivariate analyses. Tumor and blood samples obtained from patients with cervical cancer, cervical cancer cell lines, and a mouse model of cervical cancer were used to examine the mechanisms underlying the highly metastatic nature of TRL-positive cancer, focusing on tumor-derived G-CSF and the myeloid-derived suppressor cell (MDSC)-mediated premetastatic niche.

Results: Pretreatment TRL was significantly associated with visceral organ metastasis in patients with uterine cervical or endometrial cancer. The patients with TRL-positive cervical cancer displayed upregulated tumor G-CSF expression, elevated G-CSF levels, and increased MDSC frequencies in the peripheral blood compared with the TRL-negative patients. In vitro and in vivo investigations revealed that MDSCs produced in response to tumor-derived G-CSF are involved in premetastatic niche formation, which promotes visceral organ metastasis of TRL-positive cancer. The depletion of MDSCs attenuated this premetastatic niche formation and effectively inhibited the visceral organ metastasis of TRL-positive cancer.

Conclusions: Uterine cervical/endometrial cancer displaying TRL is a distinct clinical entity with high metastatic potential. Tumor-derived G-CSF and the MDSC-mediated premetastatic niche are responsible for the highly metastatic nature of this type of cancer. MDSC-targeting therapy might represent a potential strategy for combating metastasis derived from TRL-positive uterine cancer. Clin Cancer Res; 24(16); 4018–29. ©2018 AACR.
Data from Clinical Significance of Four Molecular Subtypes of Gastric Cancer Identified by The Cancer Genome Atlas Project
Authors: Sohn Bo Hwa , Hwang Jun-Eul , Jang Hee-Jin , Lee Hyun-Sung , Oh Sang Cheul , Shim Jae-Jun , Lee Keun-Wook , Kim Eui Hyun , Yim Sun Young , Lee Sang Ho , Cheong Jae-Ho , Jeong Woojin , Cho Jae Yong , Kim Joohee , Chae Jungsoo , Lee Jeeyun , Kang Won Ki , Kim Sung , Noh Sung Hoon , Ajani Jaffer A. , Lee Ju-Seog
Published: April 2023

Abstract
Purpose: The Cancer Genome Atlas (TCGA) project recently uncovered four molecular subtypes of gastric cancer: Epstein–Barr virus (EBV), microsatellite instability (MSI), genomically stable (GS), and chromosomal instability (CIN). However, their clinical significances are currently unknown. We aimed to investigate the relationship between subtypes and prognosis of patients with gastric cancer.

Experimental Design: Gene expression data from a TCGA cohort (n = 262) were used to develop a subtype prediction model, and the association of each subtype with survival and benefit from adjuvant chemotherapy was tested in 2 other cohorts (n = 267 and 432). An integrated risk assessment model (TCGA risk score) was also developed.

Results: EBV subtype was associated with the best prognosis, and GS subtype was associated with the worst prognosis. Patients with MSI and CIN subtypes had poorer overall survival than those with EBV subtype but better overall survival than those with GS subtype (P = 0.004 and 0.03 in two cohorts, respectively). In multivariate Cox regression analyses, TCGA risk score was an independent prognostic factor [HR, 1.5; 95% confidence interval (CI), 1.2–1.9; P = 0.001]. Patients with the CIN subtype experienced the greatest benefit from adjuvant chemotherapy (HR, 0.39; 95% CI, 0.16–0.94; P = 0.03) and those with the GS subtype had the least benefit from adjuvant chemotherapy (HR, 0.83; 95% CI, 0.36–1.89; P = 0.65).

Conclusions: Our prediction model successfully stratified patients by survival and adjuvant chemotherapy outcomes. Further development of the prediction model is warranted. Clin Cancer Res; 23(15); 4441–9. ©2017 AACR.
Data from Vulvar Squamous Cell Carcinoma (VSCC) as Two Diseases: HPV Status Identifies Distinct Mutational Profiles Including Oncogenic Fibroblast Growth Factor Receptor 3
Authors: Weberpals Johanne I. , Lo Bryan , Duciaume Marc M. , Spaans Johanna N. , Clancy Aisling A. , Dimitroulakos Jim , Goss Glenwood D. , Sekhon Harman S.
Published: April 2023

Abstract
Purpose: Patients with advanced or recurrent invasive vulvar squamous cell carcinoma (VSCC) have limited treatment options and a grave prognosis. Understanding the genomic landscape may facilitate the identification of new therapies and improve clinical outcomes.

Experimental Design: A retrospective chart review and molecular analysis of patients with VSCC from 2000 to 2016 was performed at the Ottawa Hospital Research Institute. The presence of oncogenic human papillomavirus (HPV) was determined by nested PCR and amplified DNA was sequenced using the Ion AmpliSeq Cancer Hotspot v2 Panel. The patients were divided into two groups according to HPV status (HPV-positive versus HPV-negative) and clinical outcome correlated with mutation status using descriptive statistics.

Results: In 43 VSCC patients, there was a high mutation rate in both HPV-positive (73%) and HPV-negative (90%) disease with the two subgroups expressing distinct genetic profiles. HPV-positive tumors were characterized by oncogenic mutations in PIK3CA (27%), FGFR3 (14%), and PTEN (9%), whereas HPV-negative tumors were found to have mutations in TP53 (57%), HRAS (24%), PI3KCA (19%), and CDKN2A (14%). Mutation S249C in FGFR3 occurred in 14% of HPV-positive tumors. While there were notable differences in the occurrence of TP53, HRAS, PTEN, and FGFR3 mutations according to HPV status, only the rate of TP53 mutations was statistically significant (P = 0.0004). No significant difference in prognosis was found between patients with HPV-positive and HPV-negative VSCC.

Conclusions: HPV-positive VSCC is characterized by oncogenic FGFR3 mutations that helps classify this subtype as a separate disease. Inhibitors of FGFR3 merit consideration as a therapeutic strategy in this neglected cancer in women. Clin Cancer Res; 23(15); 4501–10. ©2017 AACR.
Data from Multiplexed (18-Plex) Measurement of Signaling Targets and Cytotoxic T Cells in Trastuzumab-Treated Patients using Imaging Mass Cytometry
Authors: Carvajal-Hausdorf Daniel E. , Patsenker Jonathan , Stanton Kelly P. , Villarroel-Espindola Franz , Esch Amanda , Montgomery Ruth R. , Psyrri Amanda , Kalogeras Konstantine T. , Kotoula Vassiliki , Foutzilas George , Schalper Kurt A. , Kluger Yuval , Rimm David L.
Published: April 2023

AbstractPurpose:
Imaging mass cytometry (IMC) uses metal-conjugated antibodies to provide multidimensional, objective measurement of protein targets. We used this high-throughput platform to perform an 18-plex assessment of HER2 ICD/ECD, cytotoxic T-cell infiltration and other structural and signaling proteins in a cohort of patients treated with trastuzumab to discover associations with trastuzumab benefit.
Experimental Design:
An antibody panel for detection of 18 targets (pan-cytokeratin, HER2 ICD, HER2 ECD, CD8, vimentin, cytokeratin 7, β-catenin, HER3, MET, EGFR, ERK 1–2, MEK 1–2, PTEN, PI3K p110 α, Akt, mTOR, Ki67, and Histone H3) was used with a selection of trastuzumab-treated patients from the Hellenic Cooperative Oncology Group 10/05 trial (n = 180), and identified a case–control series.
Results:
Patients that recurred after adjuvant treatment with trastuzumab trended toward a decreased fraction of HER2 ECD pixels over threshold compared with cases without recurrence (P = 0.057). After exclusion of the lowest HER2 expressers, 5-year recurrence events were associated with reduced total extracellular domain (ECD)/intracellular domain (ICD) ratio intensity in tumor (P = 0.044). These observations are consistent with our previous work using quantitative immunofluorescence, but represent the proof on identical cell content. We also describe the association of the ECD of HER2 with CD8 T-cell infiltration on the same slide.
Conclusions:
The proximity of CD8 cells as a function of the expression of the ECD of HER2 provides further evidence for the role of the immune system in the mechanism of action of trastuzumab.
Data from CD103 and Intratumoral Immune Response in Breast Cancer
Authors: Wang Zhi-Qiang , Milne Katy , Derocher Heather , Webb John R. , Nelson Brad H. , Watson Peter H.
Published: April 2023

Abstract
Purpose: CD103 is expressed in several immune cell types but in the context of the intratumoral immune response may be most important as a marker of antigen-activated CD8 T cells.

Methods: We have examined the prognostic significance of CD103 TILs in breast cancer by IHC in a cohort of 424 breast cancer patients.

Results: CD103 TILs were present in all subtypes but were more abundant in ER-negative tumors where CD103 TILs were preferentially localized to the intraepithelial compartment. CD103 was associated with tumor size, tumor grade, and ER/PR status (P < 0.05). CD103 TIL density and the epithelial to stromal ratio was highest in the basal-like tumors. Intraepithelial CD103 but not intrastromal CD103 was associated with better relapse-free and overall survival in basal-like subtype tumors [HR = 0.28; 95% confidence interval (CI), 0.17–0.72; P = 0.0047 and HR = 0.25; 95% CI, 0.17–0.66; P = 0.0017, respectively). CD8 status showed similar but less significant associations, but the combination of dual CD103+CD8+ TIL status was the most strongly prognostic combination for relapse-free and overall survival (HR = 0.10; 95% CI, 0.07–0.62; P = 0.006 and HR = 0.09; 95% CI, 0.07–0.57; P = 0.003, respectively).

Conclusions: CD103 TILs are indicative of a good prognosis specifically within the basal-like subtype of breast cancer. Clin Cancer Res; 22(24); 6290–7. ©2016 AACR.
Data from Dual NAMPT and BTK Targeting Leads to Synergistic Killing of Waldenström Macroglobulinemia Cells Regardless of MYD88 and CXCR4 Somatic Mutation Status
Authors: Cea Michele , Cagnetta Antonia , Acharya Chirag , Acharya Prakrati , Tai Yu-Tzu , Yang Cao , Lovera Davide , Soncini Debora , Miglino Maurizio , Fraternali-Orcioni Giulio , Mastracci Luca , Nencioni Alessio , Montecucco Fabrizio , Monacelli Fiammetta , Ballestrero Alberto , Hideshima Teru , Chauhan Dharminder , Gobbi Marco , Lemoli Roberto M. , Munshi Nikhil , Treon Steven P. , Anderson Kenneth C.
Published: April 2023

Abstract
Purpose: Nicotinamide phosphoribosyltransferase (Nampt) regulates intracellular NAD+ pool and is highly expressed in a number of malignancies. FK866, a selective inhibitor of Nampt, depletes intracellular NAD+ levels, thereby blocking cellular metabolism and triggering sensitization to other drugs and cell death. Here we characterized the antitumor effects of Nampt inhibition in Waldenström macroglobulinemia.

Experimental Design: We investigated Nampt role in MW cells using both mRNA and protein expression analyses. We have also used loss-of-function approaches to investigate the growth and survival effects of Nampt on MW cells and further tested the anti-MW activity of dual Nampt and BTK inhibition in vitro and in vivo.

Results: We found that Waldenström macroglobulinemia cells exhibit high levels of Nampt compared with normal B cells. Loss of function studies suggested a potential oncogenic role of Nampt in Waldenström macroglobulinemia cells, and BTK-inhibitor ibrutinib and FK866 resulted in a significant and synergistic anti-Waldenström macroglobulinemia cell death, regardless of MYD88 and CXCR4 mutational status. Cell death was associated with: (i) activation of caspase-3, PARP and downregulation of Mcl-1, (ii) enhanced intracellular ATP and NAD+ depletion, (iii) inhibition of NF-κB signaling, and (iv) inhibition of multiple prosurvival signaling pathways. In a murine xenograft Waldenström macroglobulinemia model, low-dose combination FK866 and ibrutinib is well tolerated, significantly inhibits tumor growth, and prolongs host survival.

Conclusions: Our results show intracellular NAD+ level as crucial for proliferation and survival of Waldenström macroglobulinemia cells, and provides the mechanistic preclinical rationale for targeting Nampt, either alone or with Ibrutinib, to overcome drug resistance and improve patient outcome in Waldenström macroglobulinemia. Clin Cancer Res; 22(24); 6099–109. ©2016 AACR.
Data from Dichotomous ALK-IHC Is a Better Predictor for ALK Inhibition Outcome than Traditional ALK-FISH in Advanced Non–Small Cell Lung Cancer
Authors: van der Wekken A.J. , Pelgrim R. , 't Hart N. , Werner N. , Mastik M.F. , Hendriks L. , van der Heijden E.H.F.M. , Looijen-Salamon M. , de Langen A.J. , Staal-van den Brekel J. , Riemersma S. , van den Borne B.E. , Speel E.J.M. , Dingemans A-M.C. , Hiltermann T.J.N. , van den Berg A. , Timens W. , Schuuring E. , Groen H.J.M.
Published: April 2023

Abstract
Purpose: ALK rearrangement detection using FISH is the standard test to identify patients with non–small cell lung carcinoma (NSCLC) eligible for treatment with ALK inhibitors. Recently, ALK protein expression in resectable NSCLC showed predictive value. We evaluated tumor response rate and survival after crizotinib treatment of patients with advanced NSCLC with ALK activation using both dichotomous immunohistochemical (IHC) staining and FISH.

Experimental Design: Patients with stage IV NSCLC treated with crizotinib were selected. Tumor response was assessed. ALK rearrangements were detected by FISH (Vysis ALK-break-apart FISH-Probe KIT) and IHC [Ventana ALK (D5F3) CDx assay]. Cohorts of patients with ALK-FISH–positive advanced NSCLC from four other hospitals were used for validation.

Results: Twenty-nine consecutive patients with ALK-positive advanced NSCLC diagnosed by FISH and/or IHC on small biopsies or fine-needle aspirations (FNA) were treated with ALK inhibitors. All ALK-IHC–positive patients responded to crizotinib except three with primary resistance. No tumor response was observed in 13 ALK-FISH–positive but ALK-IHC–negative patients. This was confirmed in an external cohort of 16 patients. Receiver operator characteristic (ROC) curves for ALK-IHC and ALK-FISH compared with treatment outcome showed that dichotomous ALK-IHC outperforms ALK-FISH [tumor response area under the curve: (AUC), 0.86 vs. 0.64, P = 0.03; progression-free survival (PFS): AUC 0.86 vs. 0.36, P = 0.005; overall survival (OS): AUC, 0.78 vs. 0.41, P = 0.01, respectively].

Conclusions: Dichotomous ALK-IHC is superior to ALK-FISH on small biopsies and FNA to predict tumor response and survival to crizotinib for patients with advanced NSCLC. Our data strongly suggest adapting the guidelines and using dichotomous ALK-IHC as standard companion diagnostic test to select patients with NSCLC who benefit from ALK-targeting therapy. Clin Cancer Res; 23(15); 4251–8. ©2017 AACR.
Data from Phase Ib Pilot Study to Evaluate Reparixin in Combination with Weekly Paclitaxel in Patients with HER-2–Negative Metastatic Breast Cancer
Authors: Schott Anne F. , Goldstein Lori J. , Cristofanilli Massimo , Ruffini Pier Adelchi , McCanna Susan , Reuben James M. , Perez Raymond P. , Kato Giraldo , Wicha Max
Published: April 2023

Abstract
Purpose: Chemokine receptor 1 (CXCR1) is recognized as an actionable receptor selectively expressed by breast cancer stem cells (BCSCs). Reparixin is an investigational allosteric inhibitor of chemokine receptors 1 and 2 (CXCR1/2), and demonstrates activity against BCSCs in human breast cancer xenografts. This phase Ib clinical trial examined dose, safety, and pharmacokinetics of paclitaxel plus reparixin therapy, and explored effects of reparixin on BCSCs in patients with metastatic breast cancer (MBC) (trial registration ID: NCT02001974).

Experimental Design: Eligible patients had MBC and were candidates for paclitaxel therapy. Study treatment included a 3-day run-in with reparixin oral tablets three times a day, followed by paclitaxel 80 mg/m2/week (days 1, 8, and 15 for 28-day cycle) + reparixin tablets three times a day for 21/28 days; three dose cohorts were examined in a 3+3 dose escalation schema. Additional patients were recruited into an expansion cohort at the recommended phase II dose to further explore pharmacokinetics, safety, and biological effects of the combination therapy.

Results: There were neither G4–5 adverse events nor serious adverse events related to study therapy and no interactions between reparixin and paclitaxel to influence their respective pharmacokinetic profiles. A 30% response rate was recorded, with durable responses >12 months in two patients. Exploratory biomarker analysis was inconclusive for therapy effect on BCSCs.

Conclusions: Weekly paclitaxel plus reparixin in MBC appeared to be safe and tolerable, with demonstrated responses in the enrolled population. Dose level 3, 1200 mg orally three times a day, was selected for further study in a randomized phase II trial (NCT02370238). Clin Cancer Res; 23(18); 5358–65. ©2017 AACR.
Data from Successful Transfer of Umbilical Cord Blood CD34+ Hematopoietic Stem and Progenitor-derived NK Cells in Older Acute Myeloid Leukemia Patients
Authors: Dolstra Harry , Roeven Mieke W.H. , Spanholtz Jan , Hangalapura Basav N. , Tordoir Marleen , Maas Frans , Leenders Marij , Bohme Fenna , Kok Nina , Trilsbeek Carel , Paardekooper Jos , van der Waart Anniek B. , Westerweel Peter E. , Snijders Tjeerd J.F. , Cornelissen Jan , Bos Gerard , Pruijt Hans F.M. , de Graaf Aniek O. , van der Reijden Bert A. , Jansen Joop H. , van der Meer Arnold , Huls Gerwin , Cany Jeannette , Preijers Frank , Blijlevens Nicole M.A. , Schaap Nicolaas M.
Published: April 2023

Abstract
Purpose: Older acute myeloid leukemia (AML) patients have a poor prognosis; therefore, novel therapies are needed. Allogeneic natural killer (NK) cells have been adoptively transferred with promising clinical results. Here, we report the first-in-human study exploiting a unique scalable NK-cell product generated ex vivo from CD34+ hematopoietic stem and progenitor cells (HSPC) from partially HLA-matched umbilical cord blood units.

Experimental Design: Ten older AML patients in morphologic complete remission received an escalating HSPC-NK cell dose (between 3 and 30 × 106/kg body weight) after lymphodepleting chemotherapy without cytokine boosting.

Results: HSPC-NK cell products contained a median of 75% highly activated NK cells, with <1 × 104 T cells/kg and <3 × 105 B cells/kg body weight. HSPC-NK cells were well tolerated, and neither graft-versus-host disease nor toxicity was observed. Despite no cytokine boosting being given, transient HSPC-NK cell persistence was clearly found in peripheral blood up to 21% until day 8, which was accompanied by augmented IL15 plasma levels. Moreover, donor chimerism up to 3.5% was found in bone marrow. Interestingly, in vivo HSPC-NK cell maturation was observed, indicated by the rapid acquisition of CD16 and KIR expression, while expression of most activating receptors was sustained. Notably, 2 of 4 patients with minimal residual disease (MRD) in bone marrow before infusion became MRD negative (<0.1%), which lasted for 6 months.

Conclusions: These findings indicate that HSPC-NK cell adoptive transfer is a promising, potential “off-the-shelf” translational immunotherapy approach in AML. Clin Cancer Res; 23(15); 4107–18. ©2017 AACR.
Data from Cerdulatinib Pharmacodynamics and Relationships to Tumor Response Following Oral Dosing in Patients with Relapsed/Refractory B-cell Malignancies
Authors: Coffey Greg P. , Feng Jiajia , Betz Andreas , Pandey Anjali , Birrell Matt , Leeds Janet M. , Der Kenneth , Kadri Sabah , Lu Pin , Segal Jeremy , Wang Y. Lynn , Michelson Glenn , Curnutte John T. , Conley Pamela B.
Published: April 2023

AbstractPurpose:
Preclinical studies suggest SYK and JAK contribute to tumor-intrinsic and microenvironment-derived survival signals. The pharmacodynamics of cerdulatinib, a dual SYK/JAK inhibitor, and associations with tumor response were investigated.
Patients and Methods:
In a phase I dose-escalation study in adults with relapsed/refractory B-cell malignancies, cerdulatinib was administered orally to sequential dose-escalation cohorts using once-daily or twice-daily schedules. The study enrolled 8 patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), 13 with follicular lymphoma, 16 with diffuse large B-cell lymphoma (DLBCL), and 6 with mantle cell lymphoma. Correlation of tumor response with pharmacodynamic markers was determined in patients with meaningful clinical responses.
Results:
Following cerdulatinib administration, complete SYK and JAK pathway inhibition was achieved in whole blood of patients at tolerated exposures. Target inhibition correlated with serum cerdulatinib concentration, and IC50 values against B-cell antigen receptor (BCR), IL2, IL4, and IL6 signaling pathways were 0.27 to 1.11 μmol/L, depending on the phosphorylation event. Significant correlations were observed between SYK and JAK pathway inhibition and tumor response. Serum inflammation markers were reduced by cerdulatinib, and several significantly correlated with tumor response. Diminished expression of CD69 and CD86 (B-cell activation markers), CD5 (negative regulator of BCR signaling), and enhanced expression of CXCR4 were observed in 2 patients with CLL, consistent with BCR and IL4 suppression and loss of proliferative capacity.
Conclusions:
Cerdulatinib potently and selectively inhibited SYK/JAK signaling at tolerated exposures in patients with relapsed/refractory B-cell malignancies. The extent of target inhibition in whole-blood assays and suppression of inflammation correlated with tumor response. (ClinicalTrials.gov ID:NCT01994382).
Data from Prognostic Value of RANKL/OPG Serum Levels and Disseminated Tumor Cells in Nonmetastatic Breast Cancer
Authors: Rachner Tilman D. , Kasimir-Bauer Sabine , Göbel Andy , Erdmann Kati , Hoffmann Oliver , Browne Andrew , Wimberger Pauline , Rauner Martina , Hofbauer Lorenz C. , Kimmig Rainer , Bittner Ann-Kathrin
Published: April 2023

AbstractPurpose:
We assessed serum concentrations of the receptor activator of NFκB ligand (RANKL) and its decoy receptor, osteoprotegerin (OPG), two proteins implicated in the development and progression of breast cancer, in 509 patients with primary, nonmetastatic breast cancer. Then the results were evaluated with regards to the occurrence of bone metastases, the presence of disseminated tumor cells (DTC) in the bone marrow, survival, and risk of developing metastatic disease.
Experimental Design:
Before surgery, two bone marrow aspirates were analyzed for DTC using density centrifugation followed by immunocytochemistry (pan-cytokeratin antibody A45-B/B3). RANKL and OPG levels in the serum were measured by ELISA.
Results:
RANKL levels were significantly lower in women >60 years (P < 0.0001) and RANKL/OPG ratios higher in lymph node–positive patients (P < 0.05). High OPG serum levels were associated with a higher risk of death from breast cancer [HR 1.94; 95% confidence interval (CI) 1.23–3.07; P = 0.005] and OPG was an independent prognostic marker for breast cancer–specific survival (BCSS; multivariate analyses, P = 0.035). RANKL levels were 33% higher (P < 0.0001) in DTCpos patients (41%), whereas high levels were associated with a significantly better BCSS in DTCneg patients as compared with low levels (HR 0.524; 95% CI 0.30–0.95; P = 0.04). RANKL serum levels were significantly increased in patients who developed bone metastases (P = 0.01) and patients within the highest quartile of RANKL had a significantly increased risk of developing bone metastases compared with those in the lowest (HR 4.62; 95% CI 1.49–14.34; P = 0.03).
Conclusions:
These findings warrant further investigation as they provide a rationale for novel diagnostic or therapeutic approaches.
Data from Differential Expression and Significance of PD-L1, IDO-1, and B7-H4 in Human Lung Cancer
Authors: Schalper Kurt A. , Carvajal-Hausdorf Daniel , McLaughlin Joseph , Altan Mehmet , Velcheti Vamsidhar , Gaule Patricia , Sanmamed Miguel F. , Chen Lieping , Herbst Roy S. , Rimm David L.
Published: April 2023

Abstract
Purpose: To determine the expression level, associations, and biological role of PD-L1, IDO-1, and B7-H4 in non–small cell lung cancer (NSCLC).

Experimental Design: Using multiplexed quantitative immunofluorescence (QIF), we measured the levels of PD-L1, IDO-1, B7-H4, and different tumor-infiltrating lymphoycte (TIL) subsets in 552 stages I–IV lung carcinomas from two independent populations. Associations between the marker levels, TILs, and major clinicopathologic variables were determined. Validation of findings was performed using mRNA expression data from The Cancer Genome Atlas (TCGA) and in vitro stimulation of lung adenocarcinoma A549 cells with IFNγ and IL10.

Results: PD-L1 was detected in 16.9% and 21.8% of cases in each population. IDO-1 was expressed in 42.6% and 49.8%; and B7-H4 in 12.8% and 22.6% of cases, respectively. Elevated PD-L1 and IDO-1 were consistently associated with prominent B- and T-cell infiltrates, but B7-H4 was not. Coexpression of the three protein markers was infrequent, and comparable results were seen in the lung cancer TCGA dataset. Levels of PD-L1 and IDO-1 (but not B7-H4) were increased by IFNγ stimulation in A549 cells. Treatment with IL10 upregulated B7-H4 but did not affect PD-L1 and IDO-1 levels.

Conclusions: PD-L1, IDO-1, and B7-H4 are differentially expressed in human lung carcinomas and show limited co-expression. While PD-L1 and IDO-1 are associated with increased TILs and IFNγ stimulation, B7-H4 is not. The preferential expression of discrete immune evasion pathways in lung cancer could participate in therapeutic resistance and support design of optimal clinical trials. Clin Cancer Res; 23(2); 370–8. ©2016 AACR.
Data from Genetic and Modifiable Risk Factors Contributing to Cisplatin-induced Toxicities
Authors: Trendowski Matthew R. , El Charif Omar , Dinh Paul C. , Travis Lois B. , Dolan M. Eileen
Published: April 2023

Abstract
Effective administration of traditional cytotoxic chemotherapy is often limited by off-target toxicities. This clinical dilemma is epitomized by cisplatin, a platinating agent, which has potent antineoplastic activity due to its affinity for DNA and other intracellular nucleophiles. Despite its efficacy against many adult-onset and pediatric malignancies, cisplatin elicits multiple off-target toxicities that can not only severely impact a patient's quality of life but also lead to dose reductions or the selection of alternative therapies that can ultimately affect outcomes. Without an effective therapeutic measure by which to successfully mitigate many of these symptoms, there have been attempts to identify a priori those individuals who are more susceptible to developing these sequelae through studies of genetic and nongenetic risk factors. Older age is associated with cisplatin-induced ototoxicity, neurotoxicity, and nephrotoxicity. Traditional genome-wide association studies have identified single-nucleotide polymorphisms in ACYP2 and WFS1 associated with cisplatin-induced hearing loss. However, validating associations between specific genotypes and cisplatin-induced toxicities with enough stringency to warrant clinical application remains challenging. This review summarizes the current state of knowledge with regard to specific adverse sequelae following cisplatin-based therapy, with a focus on ototoxicity, neurotoxicity, nephrotoxicity, myelosuppression, and nausea/emesis. We discuss variables (genetic and nongenetic) contributing to these detrimental toxicities and currently available means to prevent or treat their occurrence.