bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Distinguishing Tumor from Associated Fibrosis to Increase Diagnostic Biopsy Yield with Polarization-Sensitive Optical Coherence Tomography
Authors: Hariri Lida P. , Adams David C. , Applegate Matthew B. , Miller Alyssa J. , Roop Benjamin W. , Villiger Martin , Bouma Brett E. , Suter Melissa J.
Published: April 2023

AbstractPurpose:
With recent advancements in personalized medicine, biopsies must contain sufficient tumor for histologic diagnosis and molecular testing. However, inadvertent biopsy of tumor-associated fibrosis compromises tumor yield, resulting in delayed diagnoses and/or repeat procedures when additional tumor is needed. The ability to differentiate tumor from fibrosis intraprocedurally during biopsy could significantly increase tumor yield. Polarization-sensitive optical coherence tomography (PS-OCT) is an imaging modality that is endoscope- and/or needle-compatible, and provides large volumetric views of tissue microstructure with high resolution (∼10 μm) while simultaneously measuring birefringence of organized tissues such as collagen. We aim to determine whether PS-OCT can accurately detect and distinguish tumor-associated fibrosis from tumor.
Experimental Design:
PS-OCT was obtained ex vivo in 64 lung nodule samples. PS-OCT birefringence was measured and correlated to collagen content in precisely matched histology, quantified on picrosirius red (PSR) staining.
Results:
There was a strong positive correlation between PS-OCT measurement of birefringent fibrosis and total collagen content by PSR (r = 0.793; P < 0.001). In addition, PS-OCT was able to accurately classify tumor regions with >20% fibrosis from those with low fibrosis (≤20%) that would likely yield higher tumor content (P < 0.0001).
Conclusions:
PS-OCT enables accurate fibrosis detection and can distinguish tumor regions with low fibrosis. PS-OCT has significant potential for clinical impact, as the ability to differentiate tumor from fibrosis could be used to guide intraprocedural tissue sampling in vivo, or for rapid biopsy adequacy assessment ex vivo, to increase diagnostic tumor yield essential for patient care and research.
Data from Phase II Trial of Alisertib in Combination with Irinotecan and Temozolomide for Patients with Relapsed or Refractory Neuroblastoma
Authors: DuBois Steven G. , Mosse Yael P. , Fox Elizabeth , Kudgus Rachel A. , Reid Joel M. , McGovern Renee , Groshen Susan , Bagatell Rochelle , Maris John M. , Twist Clare J. , Goldsmith Kelly , Granger M. Meaghan , Weiss Brian , Park Julie R. , Macy Margaret E. , Cohn Susan L. , Yanik Greg , Wagner Lars M. , Hawkins Randall , Courtier Jesse , Lai Hollie , Goodarzian Fariba , Shimada Hiroyuki , Boucher Najee , Czarnecki Scarlett , Luo Chunqiao , Tsao-Wei Denice , Matthay Katherine K. , Marachelian Araz
Published: April 2023

AbstractPurpose:
In phase I testing, alisertib tablets with irinotecan and temozolomide showed significant antitumor activity in patients with neuroblastoma. This study sought to confirm activity of this regimen; evaluate an alisertib oral solution; and evaluate biomarkers of clinical outcomes.
Patients and Methods:
We conducted a two-stage phase II trial of alisertib tablets (60 mg/m2/dose × 7 days), irinotecan (50 mg/m2/dose i.v. × 5 days), and temozolomide (100 mg/m2/dose orally × 5 days) in patients with relapsed or refractory neuroblastoma. The primary endpoint was best objective response. A separate cohort was treated with alisertib at 45 mg/m2 using oral solution instead of tablets. Exploratory analyses sought to identify predictors of toxicity, response, and progression-free survival (PFS) using pooled data from phase I, phase II, and oral solution cohorts.
Results:
Twenty and 12 eligible patients were treated in the phase II and oral solution cohorts, respectively. Hematologic toxicities were the most common adverse events. In phase II, partial responses were observed in 19 evaluable patients (21%). The estimated PFS at 1 year was 34%. In the oral solution cohort, 3 patients (25%) had first cycle dose-limiting toxicity (DLT). Alisertib oral solution at 45 mg/m2 had significantly higher median Cmax and exposure compared with tablets at 60 mg/m2. Higher alisertib trough concentration was associated with first cycle DLT, whereas MYCN amplification was associated with inferior PFS.
Conclusions:
This combination shows antitumor activity, particularly in patients with MYCN nonamplified tumors. Data on an alisertib oral solution expand the population able to be treated with this agent.
Data from Loss of Function of Canonical Notch Signaling Drives Head and Neck Carcinogenesis
Authors: Nyman Patrick E. , Buehler Darya , Lambert Paul F.
Published: April 2023

AbstractPurpose:
Head and neck squamous cell carcinoma (HNSCC), a common cancer worldwide, is etiologically associated with tobacco use, high alcohol consumption, and high-risk human papillomaviruses (HPV). The Notch signaling pathway, which is involved in cell differentiation decisions with differential downstream targets and effects depending on tissue type and developmental stage, has been implicated in human HNSCC. NOTCH1 is among the most frequently mutated genes in both HPV-positive and HPV-negative HNSCC. These mutations are predicted to inactivate the function of Notch. Other studies have argued the opposite—Notch signaling is increased in HNSCC.
Experimental Design:
To assess the role of Notch signaling in HPV-positive and HPV-negative HNSCC, we utilized genetically engineered mouse (GEM) models for conventional keratinizing HNSCC, in which either HPV16 E6 and E7 oncoproteins or a gain-of-function mutant p53 are expressed, and in which we inactivated canonical Notch signaling via expression of a dominant negative form of MAML1 (DNMAML1), a required transcriptional coactivator of Notch signaling.
Results:
Loss of canonical Notch signaling increased tumorigenesis in both contexts and also caused an increase in nuclear β-catenin, a marker for increased tumorigenic potential. When combined with loss of canonical Notch signaling, HPV oncogenes led to the highest frequency of cancers overall and the largest number of poorly differentiated (high-grade) cancers.
Conclusions:
These findings inform on the contribution of loss of canonical Notch signaling in head and neck carcinogenesis.
Data from Glycosyltransferase Gene Expression Identifies a Poor Prognostic Colorectal Cancer Subtype Associated with Mismatch Repair Deficiency and Incomplete Glycan Synthesis
Authors: Noda Masaru , Okayama Hirokazu , Tachibana Kazunoshin , Sakamoto Wataru , Saito Katsuharu , Thar Min Aung Kyi , Ashizawa Mai , Nakajima Takahiro , Aoto Keita , Momma Tomoyuki , Katakura Kyoko , Ohki Shinji , Kono Koji
Published: April 2023

Abstract
Purpose: We aimed to discover glycosyltransferase gene (glycogene)-derived molecular subtypes of colorectal cancer associated with patient outcomes.

Experimental Design: Transcriptomic and epigenomic datasets of nontumor, precancerous, cancerous tissues, and cell lines with somatic mutations, mismatch repair status, clinicopathologic and survival information were assembled (n = 4,223) and glycogene profiles were analyzed. IHC for a glycogene, GALNT6, was conducted in adenoma and carcinoma specimens (n = 403). The functional role and cell surface glycan profiles were further investigated by in vitro loss-of-function assays and lectin microarray analysis.

Results: We initially developed and validated a 15-glycogene signature that can identify a poor-prognostic subtype, which closely related to deficient mismatch repair (dMMR) and GALNT6 downregulation. The association of decreased GALNT6 with dMMR was confirmed in multiple datasets of tumors and cell lines, and was further recapitulated by IHC, where approximately 15% tumors exhibited loss of GALNT6 protein. GALNT6 mRNA and protein was expressed in premalignant/preinvasive lesions but was subsequently downregulated in a subset of carcinomas, possibly through epigenetic silencing. Decreased GALNT6 was independently associated with poor prognosis in the IHC cohort and an additional microarray meta-cohort, by multivariate analyses, and its discriminative power of survival was particularly remarkable in stage III patients. GALNT6 silencing in SW480 cells promoted invasion, migration, chemoresistance, and increased cell surface expression of a cancer-associated truncated O-glycan, Tn-antigen.

Conclusions: The 15-glycogene signature and the expression levels of GALNT6 mRNA and protein each serve as a novel prognostic biomarker, highlighting the role of dysregulated glycogenes in cancer-associated glycan synthesis and poor prognosis. Clin Cancer Res; 24(18); 4468–81. ©2018 AACR.
Data from A Biological Signature for Breast Ductal Carcinoma In Situ to Predict Radiotherapy Benefit and Assess Recurrence Risk
Authors: Bremer Troy , Whitworth Pat W. , Patel Rakesh , Savala Jess , Barry Todd , Lyle Stephen , Leesman Glen , Linke Steven P. , Jirström Karin , Zhou Wenjing , Amini Rose-Marie , Wärnberg Fredrik
Published: April 2023

AbstractPurpose:
Ductal carcinoma in situ (DCIS) patients and their physicians currently face challenging treatment decisions with limited information about the individual's subsequent breast cancer risk or treatment benefit. The DCISionRT biological signature developed in this study provides recurrence risk and predicts radiotherapy (RT) benefit for DCIS patients following breast-conserving surgery (BCS).
Experimental Design:
A biological signature that calculates an individualized Decision Score (DS) was developed and cross-validated in 526 DCIS patients treated with BCS ± RT. The relationship was assessed between DS and 10-year risk of invasive breast cancer (IBC) or any ipsilateral breast event (IBE), including IBC or DCIS. RT benefit was evaluated by risk group and as a function of DS.
Results:
The DS was significantly associated with IBC and IBE risk, HR (per 5 units) of 4.2 and 3.1, respectively. For patients treated without RT, DS identified a Low Group with 10-year IBC risk of 4% (7% IBE) and an Elevated Risk Group with IBC risk of 15% (23% IBE). In analysis of DS and RT by group, the Elevated Risk Group received significant RT benefit, HR of 0.3 for IBC and IBE. In a clinicopathologically low-risk subset, DS reclassified 42% of patients into the Elevated Risk Group. In an interaction analysis of DS and RT, patients with elevated DS had significant RT benefit over baseline.
Conclusions:
The DS was prognostic for risk and predicted RT benefit for DCIS patients. DS identified a clinically meaningful low-risk group and a group with elevated 10-year risks that received substantial RT benefit over baseline.
Data from Glioblastoma-Derived IL6 Induces Immunosuppressive Peripheral Myeloid Cell PD-L1 and Promotes Tumor Growth
Authors: Lamano Jonathan B. , Lamano Jason Balquidera , Li Yuping D. , DiDomenico Joseph D. , Choy Winward , Veliceasa Dorina , Oyon Daniel E. , Fakurnejad Shayan , Ampie Leonel , Kesavabhotla Kartik , Kaur Rajwant , Kaur Gurvinder , Biyashev Dauren , Unruh Dusten J. , Horbinski Craig M. , James C. David , Parsa Andrew T. , Bloch Orin
Published: April 2023

AbstractPurpose:
Upregulation of programmed death-ligand 1 (PD-L1) on circulating and tumor-infiltrating myeloid cells is a critical component of GBM-mediated immunosuppression that has been associated with diminished response to vaccine immunotherapy and poor survival. Although GBM-derived soluble factors have been implicated in myeloid PD-L1 expression, the identity of such factors has remained unknown. This study aimed to identify factors responsible for myeloid PD-L1 upregulation as potential targets for immune modulation.
Experimental Design:
Conditioned media from patient-derived GBM explant cell cultures was assessed for cytokine expression and utilized to stimulate naïve myeloid cells. Myeloid PD-L1 induction was quantified by flow cytometry. Candidate cytokines correlated with PD-L1 induction were evaluated in tumor sections and plasma for relationships with survival and myeloid PD-L1 expression. The role of identified cytokines on immunosuppression and survival was investigated in vivo utilizing immunocompetent C57BL/6 mice bearing syngeneic GL261 and CT-2A tumors.
Results:
GBM-derived IL6 was identified as a cytokine that is necessary and sufficient for myeloid PD-L1 induction in GBM through a STAT3-dependent mechanism. Inhibition of IL6 signaling in orthotopic murine glioma models was associated with reduced myeloid PD-L1 expression, diminished tumor growth, and increased survival. The therapeutic benefit of anti-IL6 therapy proved to be CD8+ T-cell dependent, and the antitumor activity was additive with that provided by programmed death-1 (PD-1)-targeted immunotherapy.
Conclusions:
Our findings suggest that disruption of IL6 signaling in GBM reduces local and systemic myeloid-driven immunosuppression and enhances immune-mediated antitumor responses against GBM.
Data from Immune Suppression by PD-L2 against Spontaneous and Treatment-Related Antitumor Immunity
Authors: Tanegashima Tokiyoshi , Togashi Yosuke , Azuma Koichi , Kawahara Akihiko , Ideguchi Ko , Sugiyama Daisuke , Kinoshita Fumio , Akiba Jun , Kashiwagi Eiji , Takeuchi Ario , Irie Takuma , Tatsugami Katsunori , Hoshino Tomoaki , Eto Masatoshi , Nishikawa Hiroyoshi
Published: April 2023

AbstractPurpose:
To evaluate the detailed immunosuppressive role(s) of PD-L2 given that its detailed role(s) remains unclear in PD-1 signal blockade therapy in animal models and humans.
Experimental Design:
We generated mouse cell lines harboring various status of PD-L1/PD-L2 and evaluated the tumor growth and phenotypes of tumor-infiltrated lymphocytes using several PD-1 signal blockades in animal models. In humans, the correlation between immune-related gene expression and CD274 (encoding PD-L1) or PDCD1LG2 (encoding PD-L2) was investigated using The Cancer Genome Atlas (TCGA) datasets. In addition, PD-L1 or PD-L2 expression in tumor cells and CD8+ T-cell infiltration were assessed by IHC.
Results:
In animal models, we showed that PD-L2 expression alone or simultaneously expressed with PD-L1 in tumor cells significantly suppressed antitumor immune responses, such as tumor antigen–specific CD8+ T cells, and was involved in the resistance to treatment with anti-PD-L1 mAb alone. This resistance was overcome by anti-PD-1 mAb or combined treatment with anti-PD-L2 mAb. In clinical settings, antitumor immune responses were significantly correlated with PD-L2 expression in the tumor microenvironment in renal cell carcinoma (RCC) and lung squamous cell carcinoma (LUSC).
Conclusions:
We propose that PD-L2 as well as PD-L1 play important roles in evading antitumor immunity, suggesting that PD-1/PD-L2 blockade must be considered for optimal immunotherapy in PD-L2–expressing cancers, such as RCC and LUSC.
Data from Enhanced Intratumoral Delivery of SN38 as a Tocopherol Oxyacetate Prodrug Using Nanoparticles in a Neuroblastoma Xenograft Model
Authors: Nguyen Ferro , Alferiev Ivan , Guan Peng , Guerrero David T. , Kolla Venkatadri , Moorthy Ganesh S. , Chorny Michael , Brodeur Garrett M.
Published: April 2023

Abstract
Purpose: Currently, <50% of high-risk pediatric solid tumors like neuroblastoma can be cured, and many survivors experience serious or life-threatening toxicities, so more effective, less toxic therapy is needed. One approach is to target drugs to tumors using nanoparticles, which take advantage of the enhanced permeability of tumor vasculature.

Experimental Design: SN38, the active metabolite of irinotecan (CPT-11), is a potent therapeutic agent that is readily encapsulated in polymeric nanoparticles. Tocopherol oxyacetate (TOA) is a hydrophobic mitocan that was linked to SN38 to significantly increase hydrophobicity and enhance nanoparticle retention. We treated neuroblastomas with SN38-TOA nanoparticles and compared the efficacy with the parent prodrug CPT-11 using a mouse xenograft model.

Results: Nanoparticle treatment induced prolonged event-free survival (EFS) in most mice, compared with CPT-11. This was shown for both SH-SY5Y and IMR-32 neuroblastoma xenografts. Enhanced efficacy was likely due to increased and sustained drug levels of SN38 in the tumor compared with conventional CPT-11 delivery. Interestingly, when recurrent CPT-11–treated tumors were re-treated with SN38-TOA nanoparticles, the tumors transformed from undifferentiated neuroblastomas to maturing ganglioneuroblastomas. Furthermore, these tumors were infiltrated with Schwann cells of mouse origin, which may have contributed to the differentiated histology.

Conclusions: Nanoparticle delivery of SN38-TOA produced increased drug delivery and prolonged EFS compared to conventional delivery of CPT-11. Also, lower total dose and drug entrapment in nanoparticles during circulation should decrease toxicity. We propose that nanoparticle-based delivery of a rationally designed prodrug is an attractive approach to enhance chemotherapeutic efficacy in pediatric and adult tumors. Clin Cancer Res; 24(11); 2585–93. ©2018 AACR.
Data from Comparison of Longitudinal CA125 Algorithms as a First-Line Screen for Ovarian Cancer in the General Population
Authors: Blyuss Oleg , Burnell Matthew , Ryan Andy , Gentry-Maharaj Aleksandra , Mariño Inés P. , Kalsi Jatinderpal , Manchanda Ranjit , Timms John F. , Parmar Mahesh , Skates Steven J. , Jacobs Ian , Zaikin Alexey , Menon Usha
Published: April 2023

Abstract
Purpose: In the United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS), women in the multimodal (MMS) arm had a serum CA125 test (first-line), with those at increased risk, having repeat CA125/ultrasound (second-line test). CA125 was interpreted using the “Risk of Ovarian Cancer Algorithm” (ROCA). We report on performance of other serial algorithms and a single CA125 threshold as a first-line screen in the UKCTOCS dataset.

Experimental Design: 50,083 post-menopausal women who attended 346,806 MMS screens were randomly split into training and validation sets, following stratification into cases (ovarian/tubal/peritoneal cancers) and controls. The two longitudinal algorithms, a new serial algorithm, method of mean trends (MMT) and the parametric empirical Bayes (PEB) were trained in the training set and tested in the blinded validation set and the performance characteristics, including that of a single CA125 threshold, were compared.

Results: The area under receiver operator curve (AUC) was significantly higher (P = 0.01) for MMT (0.921) compared with CA125 single threshold (0.884). At a specificity of 89.5%, sensitivities for MMT [86.5%; 95% confidence interval (CI), 78.4–91.9] and PEB (88.5%; 95% CI, 80.6–93.4) were similar to that reported for ROCA (sensitivity 87.1%; specificity 87.6%; AUC 0.915) and significantly higher than the single CA125 threshold (73.1%; 95% CI, 63.6–80.8).

Conclusions: These findings from the largest available serial CA125 dataset in the general population provide definitive evidence that longitudinal algorithms are significantly superior to simple cutoff values for ovarian cancer screening. Use of these newer algorithms requires incorporation into a multimodal strategy. The results highlight the importance of incorporating serial change in biomarker levels in cancer screening/early detection strategies. Clin Cancer Res; 24(19); 4726–33. ©2018 AACR.
Data from Early Reduction in ctDNA Predicts Survival in Patients with Lung and Bladder Cancer Treated with Durvalumab
Authors: Raja Rajiv , Kuziora Michael , Brohawn Philip Z. , Higgs Brandon W. , Gupta Ashok , Dennis Phillip A. , Ranade Koustubh
Published: April 2023

AbstractPurpose:
Immunotherapy has transformed the treatment of many solid tumors, with some patients deriving long-term benefit, but how to identify such patients remains unclear. Somatic mutations detected in circulating tumor DNA (ctDNA) from plasma can be an indicator of disease progression, response to therapy, and clonality of primary and metastatic lesions. Hence, ctDNA analysis can provide a valuable noninvasive and tumor-specific marker for longitudinal monitoring of tumor burden. We explored the use of ctDNA to predict survival on durvalumab, an anti-PD-L1 therapy.
Experimental Design:
Variant allele frequencies (VAF) of somatic mutations in 73 genes were assessed in ctDNA using targeted sequencing in a discovery cohort consisting of 28 patients with non–small cell lung cancer (NSCLC) and two validation NSCLC and urothelial cancer (UC) cohorts of 72 and 29 patients, respectively, to correlate ctDNA changes with clinical outcomes.
Results:
Somatic variants were detected in 96% of patients. Changes in VAF preceded radiographic responses, and patients with reduction in VAF at 6 weeks had significantly greater reduction in tumor volume, with longer progression-free and overall survival.
Conclusions:
ctDNA VAF changes are strongly correlated with duration of treatment, antitumor activity, and clinical outcomes in NSCLC and UC. Early on-treatment reduction in ctDNA VAF may be a useful predictor of long-term benefit from immunotherapy. Prospective studies should validate these findings and the value of utilizing early changes in ctDNA for therapeutic decision making by identifying nonresponders to checkpoint inhibitor monotherapies and guiding combination therapies.
Data from Safety and Antitumor Activity of Pembrolizumab in Patients with Estrogen Receptor–Positive/Human Epidermal Growth Factor Receptor 2–Negative Advanced Breast Cancer
Authors: Rugo Hope S. , Delord Jean-Pierre , Im Seock-Ah , Ott Patrick A. , Piha-Paul Sarina A. , Bedard Philippe L. , Sachdev Jasgit , Tourneau Christophe Le , van Brummelen Emilie M.J. , Varga Andrea , Salgado Roberto , Loi Sherene , Saraf Sanatan , Pietrangelo Dina , Karantza Vassiliki , Tan Antoinette R.
Published: April 2023

Abstract
Purpose: We investigated the safety and antitumor activity of the anti–programmed death 1 monoclonal antibody pembrolizumab in patients with estrogen receptor–positive (ER+)/human epidermal growth factor receptor 2–negative (HER2−) advanced breast cancer with programmed death ligand 1–positive (PD-L1–positive) tumors in the phase Ib open-label, multicohort KEYNOTE-028 (NCT02054806) study.

Patients and Methods: Patients with ER+/HER2− advanced breast cancer with PD-L1–positive tumors (combined positive score ≥1) received pembrolizumab (10 mg/kg every 2 weeks) up to 2 years or until confirmed progression/intolerable toxicity. Primary endpoints were safety and overall response rate (ORR), based on Response Evaluation Criteria in Solid Tumors, version 1 (RECIST v1.1) as assessed by investigator review.

Results: Between April 2014 and January 2015, 25 patients were enrolled. Median number of prior therapies for breast cancer, including endocrine agents, was 9 (range, 3–15). Median follow-up was 9.7 months (range, 0.7–31.8 months). Three patients experienced partial response (PR) and none experienced complete response (CR), resulting in an ORR of 12.0% (95% CI, 2.5%–31.2%); 16% of patients had stable disease (SD) and clinical benefit rate (CR + PR + [SD for ≥24 weeks]) was 20% (95% CI, 7–41). Median duration of response was 12.0 months (range, 7.4–15.9 months). The incidence of treatment-related adverse events was 64%; nausea (20%) and fatigue (12%) were most common and were predominantly grade 1/2. No treatment-related discontinuations or deaths occurred.

Conclusions: Pembrolizumab was well tolerated with modest but durable overall response in certain patients with previously treated, advanced, PD-L1–positive, ER+/HER2− breast cancer. Clin Cancer Res; 24(12); 2804–11. ©2018 AACR.
Data from Tumor-Derived GM-CSF Promotes Granulocyte Immunosuppression in Mesothelioma Patients
Authors: Khanna Swati , Graef Suzanne , Mussai Francis , Thomas Anish , Wali Neha , Yenidunya Bahar Guliz , Yuan Constance , Morrow Betsy , Zhang Jingli , Korangy Firouzeh , Greten Tim F. , Steinberg Seth M. , Stetler-Stevenson Maryalice , Middleton Gary , De Santo Carmela , Hassan Raffit
Published: April 2023

Abstract
Purpose: The cross-talk between tumor cells, myeloid cells, and T cells can play a critical role in tumor pathogenesis and response to immunotherapies. Although the etiology of mesothelioma is well understood, the impact of mesothelioma tumor cells on the surrounding immune microenvironment is less well studied. In this study, the effect of the mesothelioma tumor microenvironment on circulating and infiltrating granulocytes and T cells is investigated.

Experimental Design: Tumor tissues and peripheral blood from mesothelioma patients were evaluated for presence of granulocytes, which were then tested for their T-cell suppression potential. Different cocultures of granulocytes and/or mesothelioma tumor cells and/or T cells were set up to identify the mechanism of T-cell inhibition.

Results: Analysis of human tumors showed that the mesothelioma microenvironment is enriched in infiltrating granulocytes, which inhibit T-cell proliferation and activation. Characterization of the whole blood at diagnosis identified similar, circulating, immunosuppressive CD11b+CD15+HLADR− granulocytes at increased frequency compared with healthy controls. Culture of healthy-donor granulocytes with human mesothelioma cells showed that GM-CSF upregulates NOX2 expression and the release of reactive oxygen species (ROS) from granulocytes, resulting in T-cell suppression. Immunohistochemistry and transcriptomic analysis revealed that a majority of mesothelioma tumors express GM-CSF and that higher GM-CSF expression correlated with clinical progression. Blockade of GM-CSF with neutralizing antibody, or ROS inhibition, restored T-cell proliferation, suggesting that targeting of GM-CSF could be of therapeutic benefit in these patients.

Conclusions: Our study presents the mechanism behind the cross-talk between mesothelioma tumors and the immune microenvironment and indicates that targeting GM-CSF could be a novel treatment strategy to augment immunotherapy in patients with mesothelioma. Clin Cancer Res; 24(12); 2859–72. ©2018 AACR.
Data from Prognostic Value of Methylator Phenotype in Stage III Colon Cancer Treated with Oxaliplatin-based Adjuvant Chemotherapy
Authors: Gallois Claire , Taieb Julien , Le Corre Delphine , Le Malicot Karine , Tabernero Josep , Mulot Claire , Seitz Jean-François , Aparicio Thomas , Folprecht Gunnar , Lepage Côme , Mini Enrico , Van Laethem Jean-Luc , Emile Jean-François , Laurent-Puig Pierre
Published: April 2023

Abstract
Purpose: There are conflicting results concerning the prognostic value of the CpG island methylator phenotype (CIMP) in patients with nonmetastatic colon cancer. We studied this phenotype in stage III colon cancer characterized for mismatch repair (MMR), RAS, and BRAF status, and treated with adjuvant FOLFOX-based regimen.

Experimental Design: Tumor samples of 1,907 patients enrolled in the PETACC-8 adjuvant phase III trial were analyzed. The method used was methylation-specific PCR, where CIMP+ status was defined by methylation of at least 3 of 5 following genes: IGF2, CACNA1G, NEUROG1, SOCS1, and RUNX3. Association between CIMP status and overall survival (OS), disease-free survival (DFS), and survival after recurrence (SAR), was assessed by Cox model adjusted for prognostic factors and treatment arm (FOLFOX4 ± cetuximab).

Results: CIMP status was successfully determined in 1,867 patients (97.9%): 275 (14.7%) tumors were CIMP+. Compared with CIMP− patients, CIMP+ patients were more frequently older (P = 0.002), females (P = 0.04), with right-sided (P < 0.0001), grade 3–4 (P < 0.0001), pN2 (P = 0.001), dMMR (P < 0.0001), BRAF mutated (P < 0.0001), and RAS wild-type (P < 0.0001) tumors. In multivariate analysis, CIMP+ status was associated with shorter OS [HR, 1.46; 95% confidence interval (CI), 1.02–1.94; P = 0.04] and SAR [HR, 1.76; 95% CI, 1.20–2.56; P < 0.0004]; but not DFS [HR, 1.15; 95% CI, 0.86–1.54; P = 0.34]. A nonsignificant trend of detrimental effect of cetuximab was observed in patients with CIMP+ tumors for OS, DFS, and SAR.

Conclusions: In a large cohort of well-defined patients with stage III colon cancer, CIMP+ phenotype is associated with a shorter OS and SAR but not to DFS. Clin Cancer Res; 24(19); 4745–53. ©2018 AACR.
Data from Phase I Trial of ALT-803, A Novel Recombinant IL15 Complex, in Patients with Advanced Solid Tumors
Authors: Margolin Kim , Morishima Chihiro , Velcheti Vamsidhar , Miller Jeffrey S. , Lee Sylvia M. , Silk Ann W. , Holtan Shernan G. , Lacroix Andreanne M. , Fling Steven P. , Kaiser Judith C. , Egan Jack O. , Jones Monica , Rhode Peter R. , Rock Amy D. , Cheever Martin A. , Wong Hing C. , Ernstoff Marc S.
Published: April 2023

Abstract
Purpose: IL15 induces the activation and proliferation of natural killer (NK) and memory CD8+ T cells and has preclinical antitumor activity. Given the superior activity and favorable kinetics of ALT-803 (IL15N72D:IL15RαSu/IgG1 Fc complex) over recombinant human IL15 (rhIL15) in animal models, we performed this first-in-human phase I trial of ALT-803 in patients with advanced solid tumors.

Patients and Methods: Patients with incurable advanced melanoma, renal cell, non–small cell lung, and head and neck cancer were treated with ALT-803 0.3 to 6 μg/kg weekly intravenously or 6 to 20 μg/kg weekly subcutaneously for 4 consecutive weeks, every 6 weeks. Immune correlates included pharmacokinetics, immunogenicity, and lymphocyte expansion and function. Clinical endpoints were toxicity and antitumor activity.

Results: Twenty-four patients were enrolled; 11 received intravenous and 13 received subcutaneous ALT-803. Of these patients, nine had melanoma, six renal, three head and neck, and six lung cancer. Although total lymphocyte and CD8+ T-cell expansion were modest, NK cell numbers rose significantly. Neither anti–ALT-803 antibodies nor clinical activity were observed. Overall, ALT-803 was well tolerated, with adverse effects including fatigue and nausea most commonly with intravenous administration, whereas painful injection site wheal was reported most commonly with subcutaneous ALT-803.

Conclusions: Subcutaneous ALT-803 produced the expected NK cell expansion and was well tolerated with minimal cytokine toxicities and a strong local inflammatory reaction at injection sites in patients with advanced cancer. These data, together with compelling evidence of synergy in preclinical and clinical studies, provide the rationale for combining ALT-803 with other anticancer agents. Clin Cancer Res; 24(22); 5552–61. ©2018 AACR.
Data from Integrated Genomic Classification of Melanocytic Tumors of the Central Nervous System Using Mutation Analysis, Copy Number Alterations, and DNA Methylation Profiling
Authors: Griewank Klaus G. , Koelsche Christian , van de Nes Johannes A.P. , Schrimpf Daniel , Gessi Marco , Möller Inga , Sucker Antje , Scolyer Richard A. , Buckland Michael E. , Murali Rajmohan , Pietsch Torsten , von Deimling Andreas , Schadendorf Dirk
Published: April 2023

Abstract
Purpose: In the central nervous system, distinguishing primary leptomeningeal melanocytic tumors from melanoma metastases and predicting their biological behavior solely using histopathologic criteria may be challenging. We aimed to assess the diagnostic and prognostic value of integrated molecular analysis.

Experimental Design: Targeted next-generation sequencing, array-based genome-wide methylation analysis, and BAP1 IHC were performed on the largest cohort of central nervous system melanocytic tumors analyzed to date, including 47 primary tumors of the central nervous system, 16 uveal melanomas, 13 cutaneous melanoma metastases, and 2 blue nevus–like melanomas. Gene mutation, DNA-methylation, and copy-number profiles were correlated with clinicopathologic features.

Results: Combining mutation, copy-number, and DNA-methylation profiles clearly distinguished cutaneous melanoma metastases from other melanocytic tumors. Primary leptomeningeal melanocytic tumors, uveal melanomas, and blue nevus–like melanoma showed common DNA-methylation, copy-number alteration, and gene mutation signatures. Notably, tumors demonstrating chromosome 3 monosomy and BAP1 alterations formed a homogeneous subset within this group.

Conclusions: Integrated molecular profiling aids in distinguishing primary from metastatic melanocytic tumors of the central nervous system. Primary leptomeningeal melanocytic tumors, uveal melanoma, and blue nevus–like melanoma share molecular similarity with chromosome 3 and BAP1 alterations, markers of poor prognosis. Clin Cancer Res; 24(18); 4494–504. ©2018 AACR.
Data from Myocarditis in Cynomolgus Monkeys Following Treatment with Immune Checkpoint Inhibitors
Authors: Ji Changhua , Roy Marc D. , Golas Jonathan , Vitsky Allison , Ram Sripad , Kumpf Steven W. , Martin Matthew , Barletta Frank , Meier William A. , Hooper Andrea T. , Sapra Puja , Khan Nasir K. , Finkelstein Martin , Guffroy Magali , Buetow Bernard S.
Published: April 2023

AbstractPurpose:
Immune checkpoint inhibitors (ICI) targeting PD1, PDL1, or CTLA4 are associated with immune-related adverse events (irAE) in multiple organ systems including myocarditis. The pathogenesis and early diagnostic markers for ICI-induced myocarditis are poorly understood, and there is currently a lack of laboratory animal model to enhance our understanding. We aimed to develop such a model using cynomolgus monkeys.
Experimental Design:
Chinese-origin cynomolgus monkeys were dosed intravenously with vehicle or nivolumab 20 mg/kg plus ipilimumab 15 mg/kg once weekly and euthanized on day 29.
Results:
Multiple organ toxicities were observed in cynomolgus monkeys, and were characterized by loose feces, lymphadenopathy, and mononuclear cell infiltrations of varying severity in heart, colon, kidneys, liver, salivary glands, and endocrine organs. Increased proliferation of CD4+ and CD8+ T lymphocytes as well as an increase in activated T cells and central memory T cells in the blood, spleen, and lymph nodes, were observed. Transcriptomic analysis suggested increased migration and activation of T cells and increased phagocytosis and antigen presentation in the heart. Mononuclear cell infiltration in myocardium was comprised primarily of T cells, with lower numbers of macrophages and occasional B cells, and was associated with minimal cardiomyocyte degeneration as well as increases in cardiac troponin-I and NT-pro-BNP. Morphologically, cardiac lesions in our monkey model are similar to the reported ICI myocarditis in humans.
Conclusions:
We have developed a monkey model characterized by multiple organ toxicities including myocarditis. This model may provide insight into the immune mechanisms and facilitate biomarker identification for ICI-associated irAEs.
Data from Validation of the 16-Gene Recurrence Score in Patients with Locoregional, High-Risk Renal Cell Carcinoma from a Phase III Trial of Adjuvant Sunitinib
Authors: Rini Brian I. , Escudier Bernard , Martini Jean-Francois , Magheli Ahmed , Svedman Christer , Lopatin Margarita , Knezevic Dejan , Goddard Audrey D. , Febbo Phillip G. , Li Rachel , Lin Xun , Valota Olga , Staehler Michael , Motzer Robert J. , Ravaud Alain
Published: April 2023

Abstract
Purpose: Adjuvant sunitinib prolonged disease-free survival (DFS; HR, 0.76) in patients with locoregional high-risk renal cell carcinoma (RCC) in the S-TRAC trial (ClinicalTrials.gov NCT00375674). The 16-gene Recurrence Score (RS) assay was previously developed and validated to estimate risk for disease recurrence in patients with RCC after nephrectomy. This analysis further validated the prognostic value of RS assay in patients from S-TRAC and explored the association of RS results with prediction of sunitinib benefit.

Patients and Methods: The analysis was prospectively designed with prespecified genes, algorithm, endpoints, and analytical methods. Primary RCC was available from 212 patients with informed consent; primary analysis focused on patients with T3 RCC. Gene expression was quantitated by RT-PCR. Time to recurrence (TTR), DFS, and renal cancer–specific survival (RCSS) were analyzed using Cox proportional hazards regression.

Results: Baseline characteristics were similar between patients with and those without RS results, and between the sunitinib and placebo arms among patients with RS results. RS results predicted TTR, DFS, and RCSS in both arms, with the strongest results observed in the placebo arm. When high versus low RS groups were compared, HR for recurrence was 9.18 [95% confidence interval (CI), 2.15–39.24; P < 0.001) in the placebo arm; interaction of RS results with treatment was not significant.

Conclusions: The strong prognostic performance of the 16-gene RS assay was confirmed in S-TRAC, and the RS assay is now supported by level IB evidence. RS results may help identify patients at high risk for recurrence who may derive higher absolute benefit from adjuvant therapy. Clin Cancer Res; 24(18); 4407–15. ©2018 AACR.
Data from A Visually Apparent and Quantifiable CT Imaging Feature Identifies Biophysical Subtypes of Pancreatic Ductal Adenocarcinoma
Authors: Koay Eugene J. , Lee Yeonju , Cristini Vittorio , Lowengrub John S. , Kang Ya'an , Lucas F. Anthony San , Hobbs Brian P. , Ye Rong , Elganainy Dalia , Almahariq Muayad , Amer Ahmed M. , Chatterjee Deyali , Yan Huaming , Park Peter C. , Rios Perez Mayrim V. , Li Dali , Garg Naveen , Reiss Kim A. , Yu Shun , Chauhan Anil , Zaid Mohamed , Nikzad Newsha , Wolff Robert A. , Javle Milind , Varadhachary Gauri R. , Shroff Rachna T. , Das Prajnan , Lee Jeffrey E. , Ferrari Mauro , Maitra Anirban , Taniguchi Cullen M. , Kim Michael P. , Crane Christopher H. , Katz Matthew H. , Wang Huamin , Bhosale Priya , Tamm Eric P. , Fleming Jason B.
Published: April 2023

AbstractPurpose:
Pancreatic ductal adenocarcinoma (PDAC) is a heterogeneous disease with variable presentations and natural histories of disease. We hypothesized that different morphologic characteristics of PDAC tumors on diagnostic computed tomography (CT) scans would reflect their underlying biology.
Experimental Design:
We developed a quantitative method to categorize the PDAC morphology on pretherapy CT scans from multiple datasets of patients with resectable and metastatic disease and correlated these patterns with clinical/pathologic measurements. We modeled macroscopic lesion growth computationally to test the effects of stroma on morphologic patterns, hypothesizing that the balance of proliferation and local migration rates of the cancer cells would determine tumor morphology.
Results:
In localized and metastatic PDAC, quantifying the change in enhancement on CT scans at the interface between tumor and parenchyma (delta) demonstrated that patients with conspicuous (high-delta) tumors had significantly less stroma, higher likelihood of multiple common pathway mutations, more mesenchymal features, higher likelihood of early distant metastasis, and shorter survival times compared with those with inconspicuous (low-delta) tumors. Pathologic measurements of stromal and mesenchymal features of the tumors supported the mathematical model's underlying theory for PDAC growth.
Conclusions:
At baseline diagnosis, a visually striking and quantifiable CT imaging feature reflects the molecular and pathological heterogeneity of PDAC, and may be used to stratify patients into distinct subtypes. Moreover, growth patterns of PDAC may be described using physical principles, enabling new insights into diagnosis and treatment of this deadly disease.
Data from Combination Approach for Detecting Different Types of Alterations in Circulating Tumor DNA in Leiomyosarcoma
Authors: Przybyl Joanna , Chabon Jacob J. , Spans Lien , Ganjoo Kristen N. , Vennam Sujay , Newman Aaron M. , Forgó Erna , Varma Sushama , Zhu Shirley , Debiec-Rychter Maria , Alizadeh Ash A. , Diehn Maximilian , van de Rijn Matt
Published: April 2023

Abstract
Purpose: The clinical utility of circulating tumor DNA (ctDNA) monitoring has been shown in tumors that harbor highly recurrent mutations. Leiomyosarcoma represents a type of tumor with a wide spectrum of heterogeneous genomic abnormalities; thus, targeting hotspot mutations or a narrow genomic region for ctDNA detection may not be practical. Here, we demonstrate a combinatorial approach that integrates different sequencing protocols for the orthogonal detection of single-nucleotide variants (SNV), small indels, and copy-number alterations (CNA) in ctDNA.

Experimental Design: We employed Cancer Personalized Profiling by deep Sequencing (CAPP-Seq) for the analysis of SNVs and indels, together with a genome-wide interrogation of CNAs by Genome Representation Profiling (GRP). We profiled 28 longitudinal plasma samples and 25 tumor specimens from 7 patients with leiomyosarcoma.

Results: We detected ctDNA in 6 of 7 of these patients with >98% specificity for mutant allele fractions down to a level of 0.01%. We show that results from CAPP-Seq and GRP are highly concordant, and the combination of these methods allows for more comprehensive monitoring of ctDNA by profiling a wide spectrum of tumor-specific markers. By analyzing multiple tumor specimens in individual patients obtained from different sites and at different times during treatment, we observed clonal evolution of these tumors that was reflected by ctDNA profiles.

Conclusions: Our strategy allows for the comprehensive monitoring of a broad spectrum of tumor-specific markers in plasma. Our approach may be clinically useful not only in leiomyosarcoma but also in other tumor types that lack recurrent genomic alterations. Clin Cancer Res; 24(11); 2688–99. ©2018 AACR.
Data from KIM-1 as a Blood-Based Marker for Early Detection of Kidney Cancer: A Prospective Nested Case–Control Study
Authors: Scelo Ghislaine , Muller David C. , Riboli Elio , Johansson Mattias , Cross Amanda J. , Vineis Paolo , Tsilidis Konstantinos K. , Brennan Paul , Boeing Heiner , Peeters Petra H.M. , Vermeulen Roel C.H. , Overvad Kim , Bueno-de-Mesquita H. Bas , Severi Gianluca , Perduca Vittorio , Kvaskoff Marina , Trichopoulou Antonia , La Vecchia Carlo , Karakatsani Anna , Palli Domenico , Sieri Sabina , Panico Salvatore , Weiderpass Elisabete , Sandanger Torkjel M. , Nøst Therese H. , Agudo Antonio , Quirós J. Ramón , Rodríguez-Barranco Miguel , Chirlaque Maria-Dolores , Key Timothy J. , Khanna Prateek , Bonventre Joseph V. , Sabbisetti Venkata S. , Bhatt Rupal S.
Published: April 2023

Abstract
Purpose: Renal cell carcinoma (RCC) has the potential for cure with surgery when diagnosed at an early stage. Kidney injury molecule-1 (KIM-1) has been shown to be elevated in the plasma of RCC patients. We aimed to test whether plasma KIM-1 could represent a means of detecting RCC prior to clinical diagnosis.

Experimental Design: KIM-1 concentrations were measured in prediagnostic plasma from 190 RCC cases and 190 controls nested within a population-based prospective cohort study. Cases had entered the cohort up to 5 years before diagnosis, and controls were matched on cases for date of birth, date at blood donation, sex, and country. We applied conditional logistic regression and flexible parametric survival models to evaluate the association between plasma KIM-1 concentrations and RCC risk and survival.

Results: The incidence rate ratio (IRR) of RCC for a doubling in KIM-1 concentration was 1.71 [95% confidence interval (CI), 1.44–2.03, P = 4.1 × 10−23], corresponding to an IRR of 63.3 (95% CI, 16.2–246.9) comparing the 80th to the 20th percentiles of the KIM-1 distribution in this sample. Compared with a risk model including known risk factors of RCC (age, sex, country, body mass index, and tobacco smoking status), a risk model additionally including KIM-1 substantially improved discrimination between cases and controls (area under the receiver-operating characteristic curve of 0.8 compared with 0.7). High plasma KIM-1 concentrations were also associated with poorer survival (P = 0.0053).

Conclusions: Plasma KIM-1 concentrations could predict RCC incidence up to 5 years prior to diagnosis and were associated with poorer survival. Clin Cancer Res; 24(22); 5594–601. ©2018 AACR.
Data from Clinically Relevant and Minimally Invasive Tumor Surveillance of Pediatric Diffuse Midline Gliomas Using Patient-Derived Liquid Biopsy
Authors: Panditharatna Eshini , Kilburn Lindsay B. , Aboian Mariam S. , Kambhampati Madhuri , Gordish-Dressman Heather , Magge Suresh N. , Gupta Nalin , Myseros John S. , Hwang Eugene I. , Kline Cassie , Crawford John R. , Warren Katherine E. , Cha Soonmee , Liang Winnie S. , Berens Michael E. , Packer Roger J. , Resnick Adam C. , Prados Michael , Mueller Sabine , Nazarian Javad
Published: April 2023

AbstractPurpose:
Pediatric diffuse midline glioma (DMG) are highly malignant tumors with poor clinical outcomes. Over 70% of patients with DMG harbor the histone 3 p.K27M (H3K27M) mutation, which correlates with a poorer clinical outcome, and is also used as a criterion for enrollment in clinical trials. Because complete surgical resection of DMG is not an option, biopsy at presentation is feasible, but rebiopsy at time of progression is rare. While imaging and clinical-based disease monitoring is the standard of care, molecular-based longitudinal characterization of these tumors is almost nonexistent. To overcome these hurdles, we examined whether liquid biopsy allows measurement of disease response to precision therapy.
Experimental Design:
We established a sensitive and specific methodology that detects major driver mutations associated with pediatric DMGs using droplet digital PCR (n = 48 subjects, n = 110 specimens). Quantification of circulating tumor DNA (ctDNA) for H3K27M was used for longitudinal assessment of disease response compared with centrally reviewed MRI data.
Results:
H3K27M was identified in cerebrospinal fluid (CSF) and plasma in 88% of patients with DMG, with CSF being the most enriched for ctDNA. We demonstrated the feasibility of multiplexing for detection of H3K27M, and additional driver mutations in patient's tumor and matched CSF, maximizing the utility of a single source of liquid biome. A significant decrease in H3K27M plasma ctDNA agreed with MRI assessment of tumor response to radiotherapy in 83% (10/12) of patients.
Conclusions:
Our liquid biopsy approach provides a molecularly based tool for tumor characterization, and is the first to indicate clinical utility of ctDNA for longitudinal surveillance of DMGs.
Data from 89Zr-labeled Bispecific T-cell Engager AMG 211 PET Shows AMG 211 Accumulation in CD3-rich Tissues and Clear, Heterogeneous Tumor Uptake
Authors: Moek Kirsten L. , Waaijer Stijn J.H. , Kok Iris C. , Suurs Frans V. , Brouwers Adrienne H. , Menke-van der Houven van Oordt C. Willemien , Wind Thijs T. , Gietema Jourik A. , Schröder Carolien P. , Mahesh Shekar V.K. , Jorritsma-Smit Annelies , Lub-de Hooge Marjolijn N. , Fehrmann Rudolf S.N. , de Groot Derk Jan A. , de Vries Elisabeth G.E.
Published: April 2023

AbstractPurpose:
Biodistribution of bispecific antibodies in patients is largely unknown. We therefore performed a feasibility study in 9 patients with advanced gastrointestinal adenocarcinomas to explore AMG 211 biodistribution (also known as MEDI-565), an approximately 55 kDa bispecific T-cell engager (BiTE®) directed against carcinoembryonic antigen (CEA) on tumor cells and cluster of differentiation 3 (CD3) on T-cells.
Experimental Design:
89Zr-labeled AMG 211 as tracer was administered alone or with cold AMG 211, for PET imaging before and/or during AMG 211 treatment.
Results:
Before AMG 211 treatment, the optimal imaging dose was 200-μg 89Zr-AMG 211 + 1,800-μg cold AMG 211. At 3 hours, the highest blood pool standardized uptake value (SUV)mean was 4.0, and tracer serum half-life was 3.3 hours. CD3-mediated uptake was clearly observed in CD3-rich lymphoid tissues including spleen and bone marrow (SUVmean 3.2 and 1.8, respectively), and the SUVmean decreased more slowly than in other healthy tissues. 89Zr-AMG 211 remained intact in plasma and was excreted predominantly via the kidneys in degraded forms. Of 43 visible tumor lesions, 37 were PET quantifiable, with a SUVmax of 4.0 [interquartile range (IQR) 2.7–4.4] at 3 hours using the optimal imaging dose. The tracer uptake differed between tumor lesions 5-fold within and 9-fold between patients. During AMG 211 treatment, tracer was present in the blood pool, whereas tumor lesions were not visualized, possibly reflecting target saturation.
Conclusions:
This first-in-human study shows high, specific 89Zr-AMG 211 accumulation in CD3-rich lymphoid tissues, as well as a clear, inter- and intraindividual heterogeneous tumor uptake.