bluuebunny/crossref_metadata_2025 huggingface dataset:
Supplementary Figure S7 from Estrogen Therapy Induces Receptor-Dependent DNA Damage Enhanced by PARP Inhibition in ER+ Breast Cancer
Authors: Traphagen Nicole A. , Schwartz Gary N. , Tau Steven , Roberts Alyssa M. , Jiang Amanda , Hosford Sarah R. , Marotti Jonathan D. , Goen Abigail E. , Romo Bianca A. , Johnson Anneka L. , Duffy Emily-Claire K. , Demidenko Eugene , Heverly Paul , Mosesson Yaron , Soucy Shannon M. , Kolling Fred , Miller Todd W.
Published: September 2023

Supplementary Figure S7- Single-channel fluorescence images of tumors from patients treated with E2.
Supplementary Figure S2 from Estrogen Therapy Induces Receptor-Dependent DNA Damage Enhanced by PARP Inhibition in ER+ Breast Cancer
Authors: Traphagen Nicole A. , Schwartz Gary N. , Tau Steven , Roberts Alyssa M. , Jiang Amanda , Hosford Sarah R. , Marotti Jonathan D. , Goen Abigail E. , Romo Bianca A. , Johnson Anneka L. , Duffy Emily-Claire K. , Demidenko Eugene , Heverly Paul , Mosesson Yaron , Soucy Shannon M. , Kolling Fred , Miller Todd W.
Published: September 2023

Supplementary Figure S2- E2 induces DNA damage in LTED and ER-overexpressing cells.
Supplementary Figure S15 from Estrogen Therapy Induces Receptor-Dependent DNA Damage Enhanced by PARP Inhibition in ER+ Breast Cancer
Authors: Traphagen Nicole A. , Schwartz Gary N. , Tau Steven , Roberts Alyssa M. , Jiang Amanda , Hosford Sarah R. , Marotti Jonathan D. , Goen Abigail E. , Romo Bianca A. , Johnson Anneka L. , Duffy Emily-Claire K. , Demidenko Eugene , Heverly Paul , Mosesson Yaron , Soucy Shannon M. , Kolling Fred , Miller Todd W.
Published: September 2023

Supplementary Figure S15- Individual growth curves of WHIM16 tumors from mice treated with a second cycle of E2 ± olaparib.
Supplementary Figure S1 from Estrogen Therapy Induces Receptor-Dependent DNA Damage Enhanced by PARP Inhibition in ER+ Breast Cancer
Authors: Traphagen Nicole A. , Schwartz Gary N. , Tau Steven , Roberts Alyssa M. , Jiang Amanda , Hosford Sarah R. , Marotti Jonathan D. , Goen Abigail E. , Romo Bianca A. , Johnson Anneka L. , Duffy Emily-Claire K. , Demidenko Eugene , Heverly Paul , Mosesson Yaron , Soucy Shannon M. , Kolling Fred , Miller Todd W.
Published: September 2023

Supplementary Figure S1- E2 induces changes in overlapping sets of genes in HCC-1428 and HCC-1428/LTED cells.
Supplementary Table S9 from Lorazepam Stimulates IL6 Production and Is Associated with Poor Survival Outcomes in Pancreatic Cancer
Authors: Cornwell Abigail C. , Tisdale Arwen A. , Venkat Swati , Maraszek Kathryn E. , Alahmari Abdulrahman A. , George Anthony , Attwood Kristopher , George Madison , Rempinski Donald , Franco-Barraza Janusz , Seshadri Mukund , Parker Mark D. , Cortes Gomez Eduardo , Fountzilas Christos , Cukierman Edna , Steele Nina G. , Feigin Michael E.
Published: September 2023

Supplementary Table S9. Head and neck cancer patient characteristics, median survival, and Multivariate Cox Regression Modeling
Supplementary Figure S2 from Targeting Replication Stress and Chemotherapy Resistance with a Combination of Sacituzumab Govitecan and Berzosertib: A Phase I Clinical Trial
Authors: Abel Melissa L. , Takahashi Nobuyuki , Peer Cody , Redon Christophe E. , Nichols Samantha , Vilimas Rasa , Lee Min-Jung , Lee Sunmin , Shelat Meenakshi , Kattappuram Robbie , Sciuto Linda , Pinkiert Danielle , Graham Chante , Butcher Donna , Karim Baktiar , Sharma Ajit Kumar , Malin Justin , Kumar Rajesh , Schultz Christopher W. , Goyal Shubhank , del Rivero Jaydira , Krishnamurthy Manan , Upadhyay Deep , Schroeder Brett , Sissung Tristan , Tyagi Manoj , Kim Jung , Pommier Yves , Aladjem Mirit , Raffeld Mark , Figg William Douglas , Trepel Jane , Xi Liqiang , Desai Parth , Thomas Anish
Published: September 2023

Pharmacokinetic assessment
Supplementary Table S6 from Lorazepam Stimulates IL6 Production and Is Associated with Poor Survival Outcomes in Pancreatic Cancer
Authors: Cornwell Abigail C. , Tisdale Arwen A. , Venkat Swati , Maraszek Kathryn E. , Alahmari Abdulrahman A. , George Anthony , Attwood Kristopher , George Madison , Rempinski Donald , Franco-Barraza Janusz , Seshadri Mukund , Parker Mark D. , Cortes Gomez Eduardo , Fountzilas Christos , Cukierman Edna , Steele Nina G. , Feigin Michael E.
Published: September 2023

Supplementary Table S6. Brain cancer patient characteristics, median survival, and Multivariate Cox Regression Modeling
Supplementary Data S1 from Targeting Replication Stress and Chemotherapy Resistance with a Combination of Sacituzumab Govitecan and Berzosertib: A Phase I Clinical Trial
Authors: Abel Melissa L. , Takahashi Nobuyuki , Peer Cody , Redon Christophe E. , Nichols Samantha , Vilimas Rasa , Lee Min-Jung , Lee Sunmin , Shelat Meenakshi , Kattappuram Robbie , Sciuto Linda , Pinkiert Danielle , Graham Chante , Butcher Donna , Karim Baktiar , Sharma Ajit Kumar , Malin Justin , Kumar Rajesh , Schultz Christopher W. , Goyal Shubhank , del Rivero Jaydira , Krishnamurthy Manan , Upadhyay Deep , Schroeder Brett , Sissung Tristan , Tyagi Manoj , Kim Jung , Pommier Yves , Aladjem Mirit , Raffeld Mark , Figg William Douglas , Trepel Jane , Xi Liqiang , Desai Parth , Thomas Anish
Published: September 2023

Trial protocol dose limiting toxicity criteria
Supplementary Table S3 from Lorazepam Stimulates IL6 Production and Is Associated with Poor Survival Outcomes in Pancreatic Cancer
Authors: Cornwell Abigail C. , Tisdale Arwen A. , Venkat Swati , Maraszek Kathryn E. , Alahmari Abdulrahman A. , George Anthony , Attwood Kristopher , George Madison , Rempinski Donald , Franco-Barraza Janusz , Seshadri Mukund , Parker Mark D. , Cortes Gomez Eduardo , Fountzilas Christos , Cukierman Edna , Steele Nina G. , Feigin Michael E.
Published: September 2023

Supplementary Table S3. Pancreatic cancer patient characteristics by alprazolam prescription records
Supplementary Table S1 from Lorazepam Stimulates IL6 Production and Is Associated with Poor Survival Outcomes in Pancreatic Cancer
Authors: Cornwell Abigail C. , Tisdale Arwen A. , Venkat Swati , Maraszek Kathryn E. , Alahmari Abdulrahman A. , George Anthony , Attwood Kristopher , George Madison , Rempinski Donald , Franco-Barraza Janusz , Seshadri Mukund , Parker Mark D. , Cortes Gomez Eduardo , Fountzilas Christos , Cukierman Edna , Steele Nina G. , Feigin Michael E.
Published: September 2023

Supplementary Table S1. Pancreatic cancer patient characteristics by benzodiazepine prescription records.
Table 1 from Integrated Multimodal Analyses of DNA Damage Response and Immune Markers as Predictors of Response in Metastatic Triple-Negative Breast Cancer in the TNT Trial (NCT00532727)
Authors: Tovey Holly , Sipos Orsolya , Parker Joel S. , Hoadley Katherine A. , Quist Jelmar , Kernaghan Sarah , Kilburn Lucy , Salgado Roberto , Loi Sherene , Kennedy Richard D. , Roxanis Ioannis , Gazinska Patrycja , Pinder Sarah E. , Bliss Judith , Perou Charles M. , Haider Syed , Grigoriadis Anita , Tutt Andrew , Cheang Maggie Chon U.
Published: September 2023

Patient characteristics.
Supplementary Figure S1 from Integrated Multimodal Analyses of DNA Damage Response and Immune Markers as Predictors of Response in Metastatic Triple-Negative Breast Cancer in the TNT Trial (NCT00532727)
Authors: Tovey Holly , Sipos Orsolya , Parker Joel S. , Hoadley Katherine A. , Quist Jelmar , Kernaghan Sarah , Kilburn Lucy , Salgado Roberto , Loi Sherene , Kennedy Richard D. , Roxanis Ioannis , Gazinska Patrycja , Pinder Sarah E. , Bliss Judith , Perou Charles M. , Haider Syed , Grigoriadis Anita , Tutt Andrew , Cheang Maggie Chon U.
Published: September 2023

Additional associations between signatures.
A. Distribution of CIN70 by HRD score and genomic scars (NtAI tertiles, AiCna tertiles and HLAMP). B Distribution of RPS by HRD score and genomic scars (NtAI tertiles, AiCna tertiles and HLAMP). C. Distribution of PARPi7 by HRD score and genomic scars (NtAI tertiles, AiCna tertiles and HLAMP). D. Distribution of TILs by HRD score, E. Distribution of ConcensusTME average score by HRD score F. ConsensusTME cell type estimates are highly correlated excluding fibroblasts.Correlation assessed using Spearman correlation. HRD<42 = HRD low; HRD≥42 = HRD high.
Supplemental Figure 5 from Transcriptomic Signatures of MSI-High Metastatic Colorectal Cancer Predict Efficacy of Immune Checkpoint Inhibitors
Authors: Gallois Claire , Landi Matteo , Taieb Julien , Sroussi Marine , Saberzadeh-Ardestani Bahar , Cazelles Antoine , Lonardi Sara , Bergamo Francesca , Intini Rossana , Maddalena Giulia , Pietrantonio Filippo , Corti Francesca , Ambrosini Margherita , Martinetti Antonia , Germani Marco Maria , Boccaccio Chiara , Vetere Guglielmo , Mouillet-Richard Sophie , de Reynies Aurélien , Sinicrope Frank A. , Cremolini Chiara , Laurent-Puig Pierre
Published: September 2023

Kaplan Meier curves for progression-free survival according to the three unsupervised clusters in the validation cohort
Figure 3 from Integrated Multimodal Analyses of DNA Damage Response and Immune Markers as Predictors of Response in Metastatic Triple-Negative Breast Cancer in the TNT Trial (NCT00532727)
Authors: Tovey Holly , Sipos Orsolya , Parker Joel S. , Hoadley Katherine A. , Quist Jelmar , Kernaghan Sarah , Kilburn Lucy , Salgado Roberto , Loi Sherene , Kennedy Richard D. , Roxanis Ioannis , Gazinska Patrycja , Pinder Sarah E. , Bliss Judith , Perou Charles M. , Haider Syed , Grigoriadis Anita , Tutt Andrew , Cheang Maggie Chon U.
Published: September 2023

Association of biomarkers of interest with clinical outcomes by treatment group. A, Association of biomarkers with objective response. Odds ratios for each biomarker are presented from univariable logistic regression models. B, Association of biomarkers with PFS. Model coefficients of each biomarker are presented from linear regression of restricted mean PFS. Ninety-five percent confidence intervals are shown. Response rates are also presented by Baylor subtypes (C) and TNBC subtypes (D).
Figure 2 from Integrated Multimodal Analyses of DNA Damage Response and Immune Markers as Predictors of Response in Metastatic Triple-Negative Breast Cancer in the TNT Trial (NCT00532727)
Authors: Tovey Holly , Sipos Orsolya , Parker Joel S. , Hoadley Katherine A. , Quist Jelmar , Kernaghan Sarah , Kilburn Lucy , Salgado Roberto , Loi Sherene , Kennedy Richard D. , Roxanis Ioannis , Gazinska Patrycja , Pinder Sarah E. , Bliss Judith , Perou Charles M. , Haider Syed , Grigoriadis Anita , Tutt Andrew , Cheang Maggie Chon U.
Published: September 2023

Overview of the characterization of DNA damage/repair and immune features in TNT samples and their association with each other. A, Distribution of DNA damage repair features by BRCA1/2 status and Baylor subtype. B, Distribution of average immune infiltration features by BRCA1/2 status and Baylor subtype. C, Correlation matrix of all signatures of interest.
Supplemental Figure 3 from Transcriptomic Signatures of MSI-High Metastatic Colorectal Cancer Predict Efficacy of Immune Checkpoint Inhibitors
Authors: Gallois Claire , Landi Matteo , Taieb Julien , Sroussi Marine , Saberzadeh-Ardestani Bahar , Cazelles Antoine , Lonardi Sara , Bergamo Francesca , Intini Rossana , Maddalena Giulia , Pietrantonio Filippo , Corti Francesca , Ambrosini Margherita , Martinetti Antonia , Germani Marco Maria , Boccaccio Chiara , Vetere Guglielmo , Mouillet-Richard Sophie , de Reynies Aurélien , Sinicrope Frank A. , Cremolini Chiara , Laurent-Puig Pierre
Published: September 2023

Tumor mutational burden and diagnosed Lynch syndrome in patients with MSI-high status determined by only one method
Supplementary Appendix 1 from A Phase I, Multicenter, Open-Label, First-in-Human Study of DS-6157a in Patients with Advanced Gastrointestinal Stromal Tumor
Authors: George Suzanne , Heinrich Michael C. , Somaiah Neeta , Oppelt Peter , McLeod Robert , Nishioka Satoshi , Kundu Madan G. , Qian Xiaozhong , Kumar Prasanna , Laadem Abderrahmane , Lau Yvonne , Tran Brittany P. , Fallon Maura , Dosunmu Ololade , Shi Julia , Naito Yoichi
Published: September 2023

Supplementary Appendix
Supplementary Figure S4 from A Phase I/IIa Trial of Yttrium-90 Radioembolization in Combination with Durvalumab for Locally Advanced Unresectable Hepatocellular Carcinoma
Authors: Lee Yun Bin , Nam Joon Yeul , Cho Eun Ju , Lee Jeong-Hoon , Yu Su Jong , Kim Hyo-Cheol , Paeng Jin Chul , Yoon Jung-Hwan , Kim Yoon Jun
Published: September 2023

Supplementary Figure S4. Kaplan–Meier estimates of time to progression and overall survival according to etiology in the intent-to-treat population. (A) Time to progression. (B) Overall survival. (C) Progression-free survival.
Supplementary Table S6A from Trackable Intratumor Microdosing and Spatial Profiling Provide Early Insights into Activity of Investigational Agents in the Intact Tumor Microenvironment
Authors: Derry Jonathan M.J. , Burns Connor , Frazier Jason P. , Beirne Emily , Grenley Marc , DuFort Christopher C. , Killingbeck Emily , Leon Michael , Williams Claire , Gregory Mark , Houlton Jeffrey , Clayburgh Daniel , Swiecicki Paul , Huszar Dennis , Berger Allison , Klinghoffer Richard A.
Published: September 2023

Enrichment analysis for genes upregulated by Subasumstat
Supplementary Figure S2 from A Phase I/IIa Trial of Yttrium-90 Radioembolization in Combination with Durvalumab for Locally Advanced Unresectable Hepatocellular Carcinoma
Authors: Lee Yun Bin , Nam Joon Yeul , Cho Eun Ju , Lee Jeong-Hoon , Yu Su Jong , Kim Hyo-Cheol , Paeng Jin Chul , Yoon Jung-Hwan , Kim Yoon Jun
Published: September 2023

Supplementary Figure S2. Kaplan–Meier estimates of time to progression and overall survival according to BCLC stage in the intent-to-treat population. (A) Time to progression. (B) Overall survival. (C) Progression-free survival.
Supplementary Figure S1 from A Phase I/IIa Trial of Yttrium-90 Radioembolization in Combination with Durvalumab for Locally Advanced Unresectable Hepatocellular Carcinoma
Authors: Lee Yun Bin , Nam Joon Yeul , Cho Eun Ju , Lee Jeong-Hoon , Yu Su Jong , Kim Hyo-Cheol , Paeng Jin Chul , Yoon Jung-Hwan , Kim Yoon Jun
Published: September 2023

Supplementary Figure S1. Kaplan–Meier estimates of time to progression and overall survival in the per-protocol population. (A) Time to progression. (B) Overall survival. (C) Progression-free survival.
Supplementary Table S2 from Trackable Intratumor Microdosing and Spatial Profiling Provide Early Insights into Activity of Investigational Agents in the Intact Tumor Microenvironment
Authors: Derry Jonathan M.J. , Burns Connor , Frazier Jason P. , Beirne Emily , Grenley Marc , DuFort Christopher C. , Killingbeck Emily , Leon Michael , Williams Claire , Gregory Mark , Houlton Jeffrey , Clayburgh Daniel , Swiecicki Paul , Huszar Dennis , Berger Allison , Klinghoffer Richard A.
Published: September 2023

Primary Antibody Information
Supplementary Table S9 from CD49d Expression Identifies a Biologically Distinct Subtype of Chronic Lymphocytic Leukemia with Inferior Progression-Free Survival on BTK Inhibitor Therapy
Authors: Alsadhan Anfal , Chen Jonathan , Gaglione Erika M. , Underbayev Chingiz , Tuma Pamela L. , Tian Xin , Freeman Lita A. , Baskar Sivasubramanian , Nierman Pia , Soto Susan , Itsara Andy , Ahn Inhye E. , Sun Clare , Bibikova Elena , Hartmann Tanja Nicole , Mhibik Maissa , Wiestner Adrian
Published: September 2023

Supplementary Table S9. Gene Signatures
Supplementary Table S1 from Trackable Intratumor Microdosing and Spatial Profiling Provide Early Insights into Activity of Investigational Agents in the Intact Tumor Microenvironment
Authors: Derry Jonathan M.J. , Burns Connor , Frazier Jason P. , Beirne Emily , Grenley Marc , DuFort Christopher C. , Killingbeck Emily , Leon Michael , Williams Claire , Gregory Mark , Houlton Jeffrey , Clayburgh Daniel , Swiecicki Paul , Huszar Dennis , Berger Allison , Klinghoffer Richard A.
Published: September 2023

ISH Probe Information
Supplementary Table S5 from CD49d Expression Identifies a Biologically Distinct Subtype of Chronic Lymphocytic Leukemia with Inferior Progression-Free Survival on BTK Inhibitor Therapy
Authors: Alsadhan Anfal , Chen Jonathan , Gaglione Erika M. , Underbayev Chingiz , Tuma Pamela L. , Tian Xin , Freeman Lita A. , Baskar Sivasubramanian , Nierman Pia , Soto Susan , Itsara Andy , Ahn Inhye E. , Sun Clare , Bibikova Elena , Hartmann Tanja Nicole , Mhibik Maissa , Wiestner Adrian
Published: September 2023

Supplementary Table S5: CD49d samples used for the RNAseq analysis
Supplementary Table S4 from CD49d Expression Identifies a Biologically Distinct Subtype of Chronic Lymphocytic Leukemia with Inferior Progression-Free Survival on BTK Inhibitor Therapy
Authors: Alsadhan Anfal , Chen Jonathan , Gaglione Erika M. , Underbayev Chingiz , Tuma Pamela L. , Tian Xin , Freeman Lita A. , Baskar Sivasubramanian , Nierman Pia , Soto Susan , Itsara Andy , Ahn Inhye E. , Sun Clare , Bibikova Elena , Hartmann Tanja Nicole , Mhibik Maissa , Wiestner Adrian
Published: September 2023

Supplementary Table S4. Mutations status of patients with disease progression on BTKis
Supplementary Figure S4 from Trackable Intratumor Microdosing and Spatial Profiling Provide Early Insights into Activity of Investigational Agents in the Intact Tumor Microenvironment
Authors: Derry Jonathan M.J. , Burns Connor , Frazier Jason P. , Beirne Emily , Grenley Marc , DuFort Christopher C. , Killingbeck Emily , Leon Michael , Williams Claire , Gregory Mark , Houlton Jeffrey , Clayburgh Daniel , Swiecicki Paul , Huszar Dennis , Berger Allison , Klinghoffer Richard A.
Published: September 2023

Subasumstat induces IFN response genes in CIVO micro-injected tumors
Supplementary Table S2 from CD49d Expression Identifies a Biologically Distinct Subtype of Chronic Lymphocytic Leukemia with Inferior Progression-Free Survival on BTK Inhibitor Therapy
Authors: Alsadhan Anfal , Chen Jonathan , Gaglione Erika M. , Underbayev Chingiz , Tuma Pamela L. , Tian Xin , Freeman Lita A. , Baskar Sivasubramanian , Nierman Pia , Soto Susan , Itsara Andy , Ahn Inhye E. , Sun Clare , Bibikova Elena , Hartmann Tanja Nicole , Mhibik Maissa , Wiestner Adrian
Published: September 2023

Supplementary Table 2. Baseline characteristics of ibrutinib treated patients
Supplementary Table S1 from CD49d Expression Identifies a Biologically Distinct Subtype of Chronic Lymphocytic Leukemia with Inferior Progression-Free Survival on BTK Inhibitor Therapy
Authors: Alsadhan Anfal , Chen Jonathan , Gaglione Erika M. , Underbayev Chingiz , Tuma Pamela L. , Tian Xin , Freeman Lita A. , Baskar Sivasubramanian , Nierman Pia , Soto Susan , Itsara Andy , Ahn Inhye E. , Sun Clare , Bibikova Elena , Hartmann Tanja Nicole , Mhibik Maissa , Wiestner Adrian
Published: September 2023

Supplementary Table S1. Baseline characteristics of acalabrutinib treated patients
Supplementary Figure S2 from CD49d Expression Identifies a Biologically Distinct Subtype of Chronic Lymphocytic Leukemia with Inferior Progression-Free Survival on BTK Inhibitor Therapy
Authors: Alsadhan Anfal , Chen Jonathan , Gaglione Erika M. , Underbayev Chingiz , Tuma Pamela L. , Tian Xin , Freeman Lita A. , Baskar Sivasubramanian , Nierman Pia , Soto Susan , Itsara Andy , Ahn Inhye E. , Sun Clare , Bibikova Elena , Hartmann Tanja Nicole , Mhibik Maissa , Wiestner Adrian
Published: September 2023

Supplementary Figure S2. In vivo effect of acalabrutinib on the expression of CD49d
Supplementary Figure S12 from Trackable Intratumor Microdosing and Spatial Profiling Provide Early Insights into Activity of Investigational Agents in the Intact Tumor Microenvironment
Authors: Derry Jonathan M.J. , Burns Connor , Frazier Jason P. , Beirne Emily , Grenley Marc , DuFort Christopher C. , Killingbeck Emily , Leon Michael , Williams Claire , Gregory Mark , Houlton Jeffrey , Clayburgh Daniel , Swiecicki Paul , Huszar Dennis , Berger Allison , Klinghoffer Richard A.
Published: September 2023

Correlation of Percentage of cell types in TME to Percent of Cells MIL113 Positive
Supplementary Figure S11 from Trackable Intratumor Microdosing and Spatial Profiling Provide Early Insights into Activity of Investigational Agents in the Intact Tumor Microenvironment
Authors: Derry Jonathan M.J. , Burns Connor , Frazier Jason P. , Beirne Emily , Grenley Marc , DuFort Christopher C. , Killingbeck Emily , Leon Michael , Williams Claire , Gregory Mark , Houlton Jeffrey , Clayburgh Daniel , Swiecicki Paul , Huszar Dennis , Berger Allison , Klinghoffer Richard A.
Published: September 2023

Interferon Signature Expression closely matches MIL113 staining
Supplementary Figure S10 from Trackable Intratumor Microdosing and Spatial Profiling Provide Early Insights into Activity of Investigational Agents in the Intact Tumor Microenvironment
Authors: Derry Jonathan M.J. , Burns Connor , Frazier Jason P. , Beirne Emily , Grenley Marc , DuFort Christopher C. , Killingbeck Emily , Leon Michael , Williams Claire , Gregory Mark , Houlton Jeffrey , Clayburgh Daniel , Swiecicki Paul , Huszar Dennis , Berger Allison , Klinghoffer Richard A.
Published: September 2023

Percentages of Cells identified by UMAP analysis from Tumors 7 and 8
Supplementary Figure S3 from Evaluation of Somatic Mutations in Urine Samples as a Noninvasive Method for the Detection and Molecular Classification of Endometrial Cancer
Authors: Costas Laura , Onieva Irene , Pelegrina Beatriz , Marin Fátima , Carmona Álvaro , López-Querol Marta , Frias-Gomez Jon , Peremiquel-Trillas Paula , Martínez José Manuel , Dorca Eduard , Brunet Joan , Pineda Marta , Ponce Jordi , Matias-Guiu Xavier , de Sanjosé Silvia , Bosch Francesc Xavier , Alemany Laia , Paytubi Sonia
Published: September 2023

Variant allele frequency of all variants in supernatant urine from cases and controls and in tumor samples from cases
Supplementary Figure S2 from Evaluation of Somatic Mutations in Urine Samples as a Noninvasive Method for the Detection and Molecular Classification of Endometrial Cancer
Authors: Costas Laura , Onieva Irene , Pelegrina Beatriz , Marin Fátima , Carmona Álvaro , López-Querol Marta , Frias-Gomez Jon , Peremiquel-Trillas Paula , Martínez José Manuel , Dorca Eduard , Brunet Joan , Pineda Marta , Ponce Jordi , Matias-Guiu Xavier , de Sanjosé Silvia , Bosch Francesc Xavier , Alemany Laia , Paytubi Sonia
Published: September 2023

Heat map of mutations according to the highest variant allele frequency per gene in urine samples from cases and controls
Supplementary Figure S1 from Evaluation of Somatic Mutations in Urine Samples as a Noninvasive Method for the Detection and Molecular Classification of Endometrial Cancer
Authors: Costas Laura , Onieva Irene , Pelegrina Beatriz , Marin Fátima , Carmona Álvaro , López-Querol Marta , Frias-Gomez Jon , Peremiquel-Trillas Paula , Martínez José Manuel , Dorca Eduard , Brunet Joan , Pineda Marta , Ponce Jordi , Matias-Guiu Xavier , de Sanjosé Silvia , Bosch Francesc Xavier , Alemany Laia , Paytubi Sonia
Published: September 2023

This graph shows a summary of the study
Supplementary Figure 2 from Development and Multicenter Case–Control Validation of Urinary Comprehensive Genomic Profiling for Urothelial Carcinoma Diagnosis, Surveillance, and Risk-Prediction
Authors: Salari Keyan , Sundi Debasish , Lee Jason J. , Wu Shulin , Wu Chin-Lee , DiFiore Gabrielle , Yan Q. Robert , Pienkny Andrew , Lee Chi K. , Oberlin Daniel , Barme Greg , Piser Joel , Kahn Robert , Collins Edward , Phillips Kevin G. , Caruso Vincent M. , Goudarzi Mahdi , Garcia-Ransom Monica , Lentz Peter S. , Evans-Holm Martha E. , MacBride Andrew R. , Fischer Daniel S. , Haddadzadeh Iden J. , Mazzarella Brian C. , Gray Joe W. , Koppie Theresa M. , Bicocca Vincent T. , Levin Trevor G. , Lotan Yair , Feldman Adam S.
Published: September 2023

Supplemental Figure 2. uCGP Predicted Recurrence Risk by Subgroup.
Data from Targeting Replication Stress and Chemotherapy Resistance with a Combination of Sacituzumab Govitecan and Berzosertib: A Phase I Clinical Trial
Authors: Abel Melissa L. , Takahashi Nobuyuki , Peer Cody , Redon Christophe E. , Nichols Samantha , Vilimas Rasa , Lee Min-Jung , Lee Sunmin , Shelat Meenakshi , Kattappuram Robbie , Sciuto Linda , Pinkiert Danielle , Graham Chante , Butcher Donna , Karim Baktiar , Sharma Ajit Kumar , Malin Justin , Kumar Rajesh , Schultz Christopher W. , Goyal Shubhank , del Rivero Jaydira , Krishnamurthy Manan , Upadhyay Deep , Schroeder Brett , Sissung Tristan , Tyagi Manoj , Kim Jung , Pommier Yves , Aladjem Mirit , Raffeld Mark , Figg William Douglas , Trepel Jane , Xi Liqiang , Desai Parth , Thomas Anish
Published: September 2023

AbstractPurpose:
Despite promising preclinical studies, toxicities have precluded combinations of chemotherapy and DNA damage response (DDR) inhibitors. We hypothesized that tumor-targeted chemotherapy delivery might enable clinical translation of such combinations.
Patients and Methods:
In a phase I trial, we combined sacituzumab govitecan, antibody–drug conjugate (ADC) that delivers topoisomerase-1 inhibitor SN-38 to tumors expressing Trop-2, with ataxia telangiectasia and Rad3-related (ATR) inhibitor berzosertib. Twelve patients were enrolled across three dose levels.
Results:
Treatment was well tolerated, with improved safety over conventional chemotherapy-based combinations, allowing escalation to the highest dose. No dose-limiting toxicities or clinically relevant ≥grade 4 adverse events occurred. Tumor regressions were observed in 2 patients with neuroendocrine prostate cancer, and a patient with small cell lung cancer transformed from EGFR-mutant non–small cell lung cancer.
Conclusions:
ADC-based delivery of cytotoxic payloads represents a new paradigm to increase efficacy of DDR inhibitors.

See related commentary by Berg and Choudhury, p. 3557
Data from Driving Diversity and Inclusion in Cancer Drug Development – Industry and Regulatory Perspectives, Current Practices, Opportunities, and Challenges
Authors: Fashoyin-Aje Lola A. , Tendler Craig , Lavery Bea , Ghiorghiu Serban , Gerald Brittany , Kalidas Chitkala , Richie Nicole , Winson Kathleen , Warren Nicholas J.H. , Tellman Tristen V. , Retzlaff Jon , Foti Margaret , Pazdur Richard
Published: September 2023

Abstract
In April 2022, the FDA issued draft guidance to help industry develop strategies to improve diversity in clinical trials. Historically, clinical trial sponsors have not systematically incorporated efforts to promote diversity, equity, and inclusion (DEI), particularly during the early design stages of clinical development plans and operational strategies. Unfortunately, a retrospective approach to DEI often results in clinical trial participants not being reflective of the diversity of patients intended to be treated with new therapies. A shift to prospective, intentional DEI strategies for clinical trials, including long-term engagement with diverse patients and communities throughout the development life cycle, is necessary to maximize the benefits and minimize the risks of new drugs and devices for all patients. Sponsors’ current practices and opportunities for improving DEI address four major topics: institutional commitment, culture change, and governance; clinical development strategy; setting enrollment goals to ensure trial participant diversity; and development and implementation of the operational strategy. As DEI practices gain wider adoption in clinical trials, shared learning and collaboration among stakeholders on an ongoing and noncompetitive basis will lead to sustainable change. Prioritization of enrollment of diverse populations as an integral part of study start-up planning, clinical trial design, and recruitment capabilities will enhance the clinical development process for oncology therapies. Importantly, these efforts will help provide equitable access to clinical trials and innovative cancer therapies.
Data from Lorazepam Stimulates IL6 Production and Is Associated with Poor Survival Outcomes in Pancreatic Cancer
Authors: Cornwell Abigail C. , Tisdale Arwen A. , Venkat Swati , Maraszek Kathryn E. , Alahmari Abdulrahman A. , George Anthony , Attwood Kristopher , George Madison , Rempinski Donald , Franco-Barraza Janusz , Seshadri Mukund , Parker Mark D. , Cortes Gomez Eduardo , Fountzilas Christos , Cukierman Edna , Steele Nina G. , Feigin Michael E.
Published: September 2023

AbstractPurpose:
This research investigates the association between benzodiazepines (BZD) and cancer patient survival outcomes, the pancreatic cancer tumor microenvironment, and cancer-associated fibroblast (CAF) signaling.
Experimental Design:
Multivariate Cox regression modeling was used to retrospectively measure associations between Roswell Park cancer patient survival outcomes and BZD prescription records. IHC, H&E, Masson's trichrome, RNAscope, and RNA sequencing were used to evaluate the impact of lorazepam (LOR) on the murine PDAC tumor microenvironment. ELISA and qPCR were used to determine the impact of BZDs on IL6 expression or secretion by human-immortalized pancreatic CAFs. PRESTO-Tango assays, reanalysis of PDAC single-cell sequencing/TCGA data sets, and GPR68 CRISPRi knockdown CAFs were used to determine the impact of BZDs on GPR68 signaling.
Results:
LOR is associated with worse progression-free survival (PFS), whereas alprazolam (ALP) is associated with improved PFS, in pancreatic cancer patients receiving chemotherapy. LOR promotes desmoplasia (fibrosis and extracellular matrix protein deposition), inflammatory signaling, and ischemic necrosis. GPR68 is preferentially expressed on human PDAC CAFs, and n-unsubstituted BZDs, such as LOR, significantly increase IL6 expression and secretion in CAFs in a pH and GPR68-dependent manner. Conversely, ALP and other GPR68 n-substituted BZDs decrease IL6 in human CAFs in a pH and GPR68-independent manner. Across many cancer types, LOR is associated with worse survival outcomes relative to ALP and patients not receiving BZDs.
Conclusions:
We demonstrate that LOR stimulates fibrosis and inflammatory signaling, promotes desmoplasia and ischemic necrosis, and is associated with decreased pancreatic cancer patient survival.
Abstract IA05: Nodal and systemic Immune effects of radiation in HNSCC
Authors: Darragh Laurel B. , Gadwa Jacob , Boss Keara , Karam Sana D.
Published: September 2023

When combined with immunotherapy, HPV-unrelated HNSCC has a high incidence of local and regional recurrence. Since nodal metastasis remains a common pattern of spread for HNSCC, elective nodal irradiation (ENI) is commonly employed to eradicate potential microscopic disease in non-involved lymph nodes. Given our developing understanding that (1) immune cells are highly radio-sensitive, and (2) that anti-tumor T cell priming, and expansion, occur in the draining lymph nodes (DLNs), we tested whether RT directed at gross tumor only could increase the effectiveness of immunotherapies. Using preclinical models and samples from canine and human trials, we tested the effects of RT with or without ENI. Immune cell differences in the tumor tissue, DLNs, and blood were characterized with flow cytometry. We found that tumor only irradiation decreased local and distant tumor growth and increased survival but increased regional recurrence. Sentinel lymph node resection or irradiation was effective at reducing regional metastasis. We show that the effectiveness of tumor only RT is likely mediated via induction of a systemic immune response dependent on antigen recognition by T cells in the DLNs. These data support the hypothesis that effective anti-tumor immunotherapy treatment requires a systemic, antigen-dependent immune response which is primed in the DLNs.

Citation Format: Laurel B. Darragh, Jacob Gadwa, Keara Boss, Sana D. Karam. Nodal and systemic Immune effects of radiation in HNSCC [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Innovating through Basic, Clinical, and Translational Research; 2023 Jul 7-8; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2023;29(18_Suppl):Abstract nr IA05.
Abstract PO-047: A novel saliva miRNA panel of promising diagnostic biomarkers for oral cancer: The association of miR-21 with smoking history
Authors: Vageli Dimitra , Doukas Panagiotis G. , Judson Benjamin L.
Published: September 2023

Introduction: Tobacco use is implicated in the carcinogenesis of oral squamous cell carcinoma (OSCC), which is associated with poor survival if not diagnosed early. It is urgent to develop a novel non-invasive and highly sensitive risk assessment and diagnostic method to screen OSCC. Here, we explored salivary miRNAs as a screening method for OSCC in a high-risk group of patients, such as smokers. Materials and methods: Saliva was collected from 44 individuals (23 HPV-negative OSCC; 21 controls; an equal number of smokers and non-smokers). Twenty head and neck cancer-related miRNA markers were analyzed by qPCR, using dual-labeled probes (miR-20A, miR-21, miR-27B, miR-29A, miR-29B, miR-29C, miR-31, miR-34a, miR-99a, miR-125a, miR-136, miR-139, miR-155, miR-192, miR-200A, miR-375, miR-425A, miR-451a, miR-504, miR-3928; RNU6 control), and by Welch’s t-test and ROC (receiver operating characteristic) curve; GraphPad Prism 7.0. Results: A panel of 4 miRNA markers (miR-21, miR-136, miR-3928, miR-29B) was found to be significantly overexpressed in the saliva of OSCC versus healthy controls with a diagnostic ability (p<0.05 by Welch’s t-test; AUC (area under the ROC curve): 64-85%, sensitivity: 50-67%, specificity: 32-38%; 95% confidence interval; by ROC curve analysis). “Oncomir” miR-21 levels (miR-21/RNU6) were found to be significantly higher in the saliva of OSCC patients with a smoking history (mean ± SD: 0.17 ± 0.19) versus never-smokers (mean ± SD: 0.0056 ± 0.0075) (p<0.05; by t-test) with a diagnostic ability (AUC: 90%, sensitivity: 68%, specificity: 30%; 95% confidence interval). Conclusions: We provide a novel panel of non-invasive, easy-to-apply, and sensitive biomarkers, for the diagnosis of oral cancer, including miR-21 in individuals with a smoking history, encouraging their validation in a large group of head and neck cancer patients.

Citation Format: Dimitra Vageli, Panagiotis G. Doukas, Benjamin L. Judson. A novel saliva miRNA panel of promising diagnostic biomarkers for oral cancer: The association of miR-21 with smoking history [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Innovating through Basic, Clinical, and Translational Research; 2023 Jul 7-8; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2023;29(18_Suppl):Abstract nr PO-047.
Abstract PO-077: High-throughput 3D-spheroid invasion assay: A powerful tool to identify novel drugs targeting tumor micro-environment in HNSCC
Authors: Karve Kunal , Poon Stephanie , Prinos Panagiotis , Ailles Laurie
Published: September 2023

Cancer metastasis is a complex cascade that involves activation of cancer cell invasion and migration. This activation is greatly attributed by multiple factors, including the tumor-microenvironment (TME). Cancer-associated fibroblasts (CAF), a prominent cell type within the TME, have been shown to promote cancer cell invasion and migration, causing metastasis in various cancers including head and neck squamous cell carcinoma (HNSCC). The molecular mechanisms of how CAFs promote HNSCC invasion remain elusive. Our research goal is to understand how CAFs influence HNSCC cells to become invasive and potentially metastatic. Using a top-down research approach, our aim is to identify novel therapeutic chemical probe/drug regimens that potentially target CAF-dependent HNSCC cancer cell-invasion. In-order to perform high-throughput small molecule screens, we have established a 384-well format, three-dimensional (3D) spheroid invasion assay, as a powerful tool to study CAF-dependent HNSCC cancer cell invasion. This platform is currently being used to screen small molecule libraries and identify putative molecular targets, providing insights into underlying mechanisms of CAF-induced cancer cell invasion and candidate therapeutic strategies.

Citation Format: Kunal Karve, Stephanie Poon, Panagiotis Prinos, Laurie Ailles. High-throughput 3D-spheroid invasion assay: A powerful tool to identify novel drugs targeting tumor micro-environment in HNSCC [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Innovating through Basic, Clinical, and Translational Research; 2023 Jul 7-8; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2023;29(18_Suppl):Abstract nr PO-077.
Which Small Molecule? Selecting Chemical Probes for Use in Cancer Research and Target Validation
Authors: Mader Mary M. , Rudolph Joachim , Hartung Ingo V. , Uehling David , Workman Paul , Zuercher William
Published: September 2023

Small-molecule chemical “probes” complement the use of molecular biology techniques to explore, validate, and generate hypotheses on the function of proteins in diseases such as cancer. Unfortunately, the poor selection and use of small-molecule reagents can lead to incorrect conclusions. Here, we illustrate examples of poor chemical tools and suggest best practices for the selection, validation, and use of high-quality chemical probes in cancer research. We also note the complexity associated with tools for novel drug modalities, exemplified by protein degraders, and provide advice and resources to facilitate the independent identification of appropriate small-molecule probes by researchers.

Significance:

Validation of biological targets and pathways will be aided by a shared understanding of the criteria of potency, selectivity, and target engagement associated with small-molecule reagents (“chemical probes”) that enable that work. Interdisciplinary collaboration between cancer biologists, medicinal chemists, and chemical biologists and the awareness of available resources will reduce misleading data generation and interpretation, strengthen data robustness, and improve productivity in academic and industrial research.
TABLE 2 from EphA2 Proteolytic Fragment as a Sensitive Diagnostic Biomarker for Very Early-stage Pancreatic Ductal Carcinoma
Authors: Sato Shinya , Nakagawa Masatoshi , Terashima Takeshi , Morinaga Soichiro , Miyagi Yohei , Yoshida Eisaku , Yoshimura Toru , Seiki Motoharu , Kaneko Shuichi , Ueno Makoto , Yamashita Taro , Koshikawa Naohiko
Published: September 2023

Univariate and multivariate Cox regression analyses of prognostic factor of pancreatic cancer
TABLE 1B from EphA2 Proteolytic Fragment as a Sensitive Diagnostic Biomarker for Very Early-stage Pancreatic Ductal Carcinoma
Authors: Sato Shinya , Nakagawa Masatoshi , Terashima Takeshi , Morinaga Soichiro , Miyagi Yohei , Yoshida Eisaku , Yoshimura Toru , Seiki Motoharu , Kaneko Shuichi , Ueno Makoto , Yamashita Taro , Koshikawa Naohiko
Published: September 2023

Comparison of clinical background in the validation cohort (Kanagawa Cancer Center)
TABLE 1A from EphA2 Proteolytic Fragment as a Sensitive Diagnostic Biomarker for Very Early-stage Pancreatic Ductal Carcinoma
Authors: Sato Shinya , Nakagawa Masatoshi , Terashima Takeshi , Morinaga Soichiro , Miyagi Yohei , Yoshida Eisaku , Yoshimura Toru , Seiki Motoharu , Kaneko Shuichi , Ueno Makoto , Yamashita Taro , Koshikawa Naohiko
Published: September 2023

Comparison of clinical background in the test cohort (Kanazawa University)
Supplementary Table S6 from EphA2 Proteolytic Fragment as a Sensitive Diagnostic Biomarker for Very Early-stage Pancreatic Ductal Carcinoma
Authors: Sato Shinya , Nakagawa Masatoshi , Terashima Takeshi , Morinaga Soichiro , Miyagi Yohei , Yoshida Eisaku , Yoshimura Toru , Seiki Motoharu , Kaneko Shuichi , Ueno Makoto , Yamashita Taro , Koshikawa Naohiko
Published: September 2023

Median survival time of PC patients treated with surgical resection and chemotherapy after classification into serum EphA2-NF high (≥50 pg / ml) and low (<50 pg / ml) groups.
Supplementary Table S3 from EphA2 Proteolytic Fragment as a Sensitive Diagnostic Biomarker for Very Early-stage Pancreatic Ductal Carcinoma
Authors: Sato Shinya , Nakagawa Masatoshi , Terashima Takeshi , Morinaga Soichiro , Miyagi Yohei , Yoshida Eisaku , Yoshimura Toru , Seiki Motoharu , Kaneko Shuichi , Ueno Makoto , Yamashita Taro , Koshikawa Naohiko
Published: September 2023

Serum EphA2-NF and CA19-9 in the validation cohort of patients with PC (n = 472), intraductal papillary mucinous neoplasms (IPMNs) (n = 16), and pancreatic neuroendocrine tumors (PNETs) (n = 19). The cutoff value for EphA2-NF and CA19-9 was defined as 50.0 pg / ml and 100 U / ml, respectively, from the test cohort analysis.
Supplementary Fig. S5 from EphA2 Proteolytic Fragment as a Sensitive Diagnostic Biomarker for Very Early-stage Pancreatic Ductal Carcinoma
Authors: Sato Shinya , Nakagawa Masatoshi , Terashima Takeshi , Morinaga Soichiro , Miyagi Yohei , Yoshida Eisaku , Yoshimura Toru , Seiki Motoharu , Kaneko Shuichi , Ueno Makoto , Yamashita Taro , Koshikawa Naohiko
Published: September 2023

Comparison for the positive and negative ratios of CA19-9 and/or EphA2-NF in early-stage and late-stage PCs.
Supplementary Fig. S4 from EphA2 Proteolytic Fragment as a Sensitive Diagnostic Biomarker for Very Early-stage Pancreatic Ductal Carcinoma
Authors: Sato Shinya , Nakagawa Masatoshi , Terashima Takeshi , Morinaga Soichiro , Miyagi Yohei , Yoshida Eisaku , Yoshimura Toru , Seiki Motoharu , Kaneko Shuichi , Ueno Makoto , Yamashita Taro , Koshikawa Naohiko
Published: September 2023

Dot blot analysis of PNET, IPMN and PC cases combined with test and validation cohorts. It became clear that serum EphA2-NF over the cutoff value existed in the benign pancreatic disease sera.
Supplementary Fig. S3 from EphA2 Proteolytic Fragment as a Sensitive Diagnostic Biomarker for Very Early-stage Pancreatic Ductal Carcinoma
Authors: Sato Shinya , Nakagawa Masatoshi , Terashima Takeshi , Morinaga Soichiro , Miyagi Yohei , Yoshida Eisaku , Yoshimura Toru , Seiki Motoharu , Kaneko Shuichi , Ueno Makoto , Yamashita Taro , Koshikawa Naohiko
Published: September 2023

Correlation between serum EphA2-NF and pancreatic duct size in IPMN including IPMC.
Supplementary Fig. S1 from EphA2 Proteolytic Fragment as a Sensitive Diagnostic Biomarker for Very Early-stage Pancreatic Ductal Carcinoma
Authors: Sato Shinya , Nakagawa Masatoshi , Terashima Takeshi , Morinaga Soichiro , Miyagi Yohei , Yoshida Eisaku , Yoshimura Toru , Seiki Motoharu , Kaneko Shuichi , Ueno Makoto , Yamashita Taro , Koshikawa Naohiko
Published: September 2023

(A) Schematic of recombinant EphA2-FL, EphA2-NF and stem portion. FLAG-tag was added at C-terminus. (B) These recombinant proteins were detected by anti-FLAG mAb and anti-EphA2-N-termius pAb.
FIGURE 5 from EphA2 Proteolytic Fragment as a Sensitive Diagnostic Biomarker for Very Early-stage Pancreatic Ductal Carcinoma
Authors: Sato Shinya , Nakagawa Masatoshi , Terashima Takeshi , Morinaga Soichiro , Miyagi Yohei , Yoshida Eisaku , Yoshimura Toru , Seiki Motoharu , Kaneko Shuichi , Ueno Makoto , Yamashita Taro , Koshikawa Naohiko
Published: September 2023

Clinical analysis of serum EphA2-NF levels for patients with pancreatic cancer treated with surgical resection or chemotherapy. Kaplan–Meier analyses of patients with pancreatic cancer treated with surgical resection (A) and chemotherapy (B) after classification into serum EphA2-NF–high (≥50 pg/mL) and –low (<50 pg/mL) groups. Kaplan–Meier analyses of patients with pancreatic cancer treated with surgical resection (C) and chemotherapy (D) classified into CA19-9–high (≥37 U/mL) and –low (<37 U/mL) groups. Kaplan–Meier analyses of patients with pancreatic cancer treated with GnP (E) and modified FOLFIRINOX (oxaliplatin, irinotecan, and 5-fluorouracil, mFFX) (F) after classification into serum EphA2-NF (≥50 pg/mL) and low (<50 pg/mL) groups. Kaplan–Meier analyses of patients with pancreatic cancer treated with GnP (G) and mFFX (F) classified into CA19-9–high (≥37 U/mL) and –low (<37 U/mL) groups.
FIGURE 4 from EphA2 Proteolytic Fragment as a Sensitive Diagnostic Biomarker for Very Early-stage Pancreatic Ductal Carcinoma
Authors: Sato Shinya , Nakagawa Masatoshi , Terashima Takeshi , Morinaga Soichiro , Miyagi Yohei , Yoshida Eisaku , Yoshimura Toru , Seiki Motoharu , Kaneko Shuichi , Ueno Makoto , Yamashita Taro , Koshikawa Naohiko
Published: September 2023

EphA2-NF is an independent diagnostic biomarker for pancreatic cancer from CA19-9. A and B, The ROC curves of serum EphA2-NF and CA19-9 to differentiate pancreatic cancer and HDs divided into high (A) and low (B) CA19-9 groups. The AUC for the diagnosis of pancreatic cancer by serum EphA2-NF (vs. test cohort HDs) for CA19-9 high or low was 0.87. C, There was no significant correlation between serum EphA2-NF and CA19-9 levels. D, Dot plot analysis of serum EphA2-NF in CA19-9–negative patients. E, ROC curves of serum EphA2-NF for pancreatic cancer with CA19-9 ≤2.0 U/mL.
FIGURE 3 from EphA2 Proteolytic Fragment as a Sensitive Diagnostic Biomarker for Very Early-stage Pancreatic Ductal Carcinoma
Authors: Sato Shinya , Nakagawa Masatoshi , Terashima Takeshi , Morinaga Soichiro , Miyagi Yohei , Yoshida Eisaku , Yoshimura Toru , Seiki Motoharu , Kaneko Shuichi , Ueno Makoto , Yamashita Taro , Koshikawa Naohiko
Published: September 2023

Diagnostic performance of EphA2-NF and CA19-9 for pancreatic cancer in the validation cohort. Dot plots of serum EphA2-NF (A) and CA19-9 (B) in the validation cohort of patients with pancreatic cancer (n = 472), IPMNs (n = 16), and PNETs (n = 19). The cut-off value for EphA2-NF and CA19-9 was defined as 50.0 pg/mL and 37 U/mL, respectively, from the test cohort analysis. Dot plots of EphA2-NF (C) and CA19-9 (D) in pancreatic cancer sera from the validation cohort by stage. E–G, ROC curves of serum EphA2-NF and CA19-9 levels for differentiating pancreatic cancer (left, stage I/II/III/IV), early-stage pancreatic cancer (center, stage I/II), late-stage pancreatic cancer (right, stage III/IV), and HD.
Data from EphA2 Proteolytic Fragment as a Sensitive Diagnostic Biomarker for Very Early-stage Pancreatic Ductal Carcinoma
Authors: Sato Shinya , Nakagawa Masatoshi , Terashima Takeshi , Morinaga Soichiro , Miyagi Yohei , Yoshida Eisaku , Yoshimura Toru , Seiki Motoharu , Kaneko Shuichi , Ueno Makoto , Yamashita Taro , Koshikawa Naohiko
Published: September 2023

Cleavage of erythropoietin-producing hepatocellular ephrin receptor A2 (EphA2) triggers malignant progression and yields an N-terminal fragment (EphA2-NF) detectable in sera from patients with pancreatic ductal carcinoma. We established a quantitative automated chemiluminescence immunoassay for EphA2-NF and evaluated serum EphA2-NF levels as a biomarker to diagnose pancreatic ductal carcinoma in the test and validation cohorts. The EphA2-NF value was elevated (above the cutoff: mean ± SD) in more than half of the patients with stage I/II pancreatic ductal carcinoma. Among patients receiving standard chemotherapy for pancreatic ductal carcinoma [gemcitabine plus nab-paclitaxel (GnP)], the median survival time of patients with elevated serum EphA2-NF was half that of patients with values below the cutoff. Patients with intraductal papillary mucinous neoplasm (IPMN), a precancerous pancreatic ductal carcinoma lesion, also show high serum EphA2 levels, which are associated with an increase in pancreatic duct size and the development of pancreatic ductal carcinoma in some cases. IHC showed loss of EphA2-NF staining in IPMN with pancreatic ductal carcinoma, but not in the normal epithelium or IPMN without pancreatic ductal carcinoma, regardless of the histologic grade. These results suggest that EphA2 cleavage is an essential event that occurs very early in pancreatic ductal carcinoma development, and that the consequent release of EphA2-NF can be detected in the serum. Thus, serum EphA2-NF could be a diagnostic biomarker for very early-stage pancreatic ductal carcinoma and pancreatic ductal carcinoma development from high-risk IPMN and as a prognostic biomarker after chemotherapy with GnP.
Significance:
EphA2 N-terminus deletion is involved in pancreatic ductal carcinoma development from high-risk IPMN and EphA2-NF produced by cleavage can be used as a serum biomarker to diagnose pancreatic ductal carcinoma and predict pancreatic ductal carcinoma development from high-risk IPMN.