bluuebunny/crossref_metadata_2025 huggingface dataset:
Supplementary Figure S5. from Functional Homologous Recombination Assay on FFPE Specimens of Advanced High-Grade Serous Ovarian Cancer Predicts Clinical Outcomes
Authors: Pikkusaari Sanna , Tumiati Manuela , Virtanen Anni , Oikkonen Jaana , Li Yilin , Perez-Villatoro Fernando , Muranen Taru , Salko Matilda , Huhtinen Kaisa , Kanerva Anna , Koskela Heidi , Tapper Johanna , Koivisto-Korander Riitta , Joutsiniemi Titta , Haltia Ulla-Maija , Lassus Heini , Hautaniemi Sampsa , Färkkilä Anniina , Hynninen Johanna , Hietanen Sakari , Carpén Olli , Kauppi Liisa
Published: April 2023

Example images of staining patterns.
Supplementary Figure S1 from Elucidating the Genetic Landscape of Oral Leukoplakia to Predict Malignant Transformation
Authors: Wils Leon J. , Poell Jos B. , Brink Arjen , Evren Ilkay , Brouns Elisabeth R. , de Visscher Jan G.A.M. , Bloemena Elisabeth , Brakenhoff Ruud H.
Published: April 2023

Overview of the inclusion of patient samples from the consecutive oral leukoplakia cohort. lcWGS = Low coverage whole genome sequencing.
Supplementary Table S3 from Favorable Activity and Safety Profile of Memory-Enriched CD19-Targeted Chimeric Antigen Receptor T-Cell Therapy in Adults with High-Risk Relapsed/Refractory ALL
Authors: Aldoss Ibrahim , Khaled Samer K. , Wang Xiuli , Palmer Joycelynne , Wang Yan , Wagner Jamie R. , Clark Mary C. , Simpson Jennifer , Paul Jinny , Vyas Vibhuti , Chien Sheng-Hsuan , Stein Anthony , Pullarkat Vinod , Salhotra Amandeep , Al Malki Monzr M. , Aribi Ahmed , Sandhu Karamjeet , Thomas Sandra H. , Budde Lihua E. , Marcucci Guido , Brown Christine E. , Forman Stephen J.
Published: April 2023

Causes of Death
Figure S6 from LAMC2 Regulates Key Transcriptional and Targetable Effectors to Support Pancreatic Cancer Growth
Authors: Erice Oihane , Narayanan Shruthi , Feliu Iker , Entrialgo-Cadierno Rodrigo , Malinova Antonia , Vicentini Caterina , Guruceaga Elizabeth , Delfino Pietro , Trajkovic-Arsic Marija , Moreno Haritz , Valencia Karmele , Blanco Ester , Macaya Irati , Öhlund Daniel , Khatri Purvesh , Lecanda Fernando , Scarpa Aldo , Siveke Jens T. , Corbo Vincenzo , Ponz-Sarvise Mariano , Vicent Silve
Published: April 2023

Suppl. Figure 6. A. Left. Protein expression levels of phospho-ERK and ERK in HPAFII and PATU8902 cells treated with MEKi (50 nM) for 24 h. Right. Protein expression levels of phospho-AXL and AXL in HPAFII and PATU8902 cells treated with AXLi (0.2 μM) for 24 h. Quantification: pAXL levels normalized to total AXL levels and housekeeping protein levels. B. Heatmap of the Fa fraction of CAPAN2 PDAC human cell line treated with single MEKi, AXLi, or both at indicated concentrations for 72 h. C. 2D surface plot of Bliss synergy scores from B. Red regions indicate synergistic interactions.
Figure S4 from LAMC2 Regulates Key Transcriptional and Targetable Effectors to Support Pancreatic Cancer Growth
Authors: Erice Oihane , Narayanan Shruthi , Feliu Iker , Entrialgo-Cadierno Rodrigo , Malinova Antonia , Vicentini Caterina , Guruceaga Elizabeth , Delfino Pietro , Trajkovic-Arsic Marija , Moreno Haritz , Valencia Karmele , Blanco Ester , Macaya Irati , Öhlund Daniel , Khatri Purvesh , Lecanda Fernando , Scarpa Aldo , Siveke Jens T. , Corbo Vincenzo , Ponz-Sarvise Mariano , Vicent Silve
Published: April 2023

Suppl. Figure 4. A. Correlation plot of mRNA expression levels of LAMC2 and AXL in the PDAC human data set from ICGC. B. Correlation plot of mRNA expression levels of LAMC2 and AXL in the PDAC human data set from TCGA.
Figure S2 from LAMC2 Regulates Key Transcriptional and Targetable Effectors to Support Pancreatic Cancer Growth
Authors: Erice Oihane , Narayanan Shruthi , Feliu Iker , Entrialgo-Cadierno Rodrigo , Malinova Antonia , Vicentini Caterina , Guruceaga Elizabeth , Delfino Pietro , Trajkovic-Arsic Marija , Moreno Haritz , Valencia Karmele , Blanco Ester , Macaya Irati , Öhlund Daniel , Khatri Purvesh , Lecanda Fernando , Scarpa Aldo , Siveke Jens T. , Corbo Vincenzo , Ponz-Sarvise Mariano , Vicent Silve
Published: April 2023

Suppl. Figure 2. A. LAMC2 immunoblot in HPAFII after LAMC2 knockdown using 2 different sgRNAs. B. Cell proliferation assessed by MTS after LAMC2 knockdown using 2 sgRNAs. Error bars correspond to s.d. C. LAMC2 immunoblot in PM12167 after shRNA mediated Lamc2 knockdown. D. Cell proliferation assessed by MTS after shRNA mediated Lamc2 knockdown. Error bars correspond to s.d. E. Colony forming ability after shRNA mediated Lamc2 knockdown. Error bars correspond to s.d. F. Cell proliferation assessed by MTS, after shRNA-mediated LAMC2 knockdown in PATU8902 and HPAFII PDAC cell lines using a tet-inducible system. Error bars correspond to s.d.
Supplementary Data Table 3 from Bolus versus Continuous Intravenous Delivery of Doxorubicin in Soft-Tissue Sarcomas: Post Hoc Analysis of a Prospective Randomized Trial (SARC021/TH CR-406)
Authors: Cranmer Lee D. , Lu Yao , Heise Rachel S. , Ballman Karla V. , Loggers Elizabeth T. , Pollack Seth M. , Wagner Michael J. , Reinke Denise K. , Schöffski Patrick , Tap William D.
Published: April 2023

Univariable logistic regression of cardiac adverse events (n=621).
Supplementary fig 5 from Dynamic Mutational Landscape of Cerebrospinal Fluid Circulating Tumor DNA and Predictors of Survival after Proton Craniospinal Irradiation for Leptomeningeal Metastases
Authors: Wijetunga N. Ari , Goglia Alexander G. , Weinhold Nils , Berger Michael F. , Cislo Michael , Higginson Daniel S. , Chabot Kiana , Osman Ahmed M. , Schaff Lauren , Pentsova Elena , Miller Alexandra M. , Powell Simon N. , Boire Adrienne , Yang Jonathan T.
Published: April 2023

Supplemental Figure 5. Concordance between plasma and CSF ctDNA variants over time.
Supplementary Table S4 from Impact of RNA Signatures on pCR and Survival after 12-Week Neoadjuvant Pertuzumab plus Trastuzumab with or without Paclitaxel in the WSG-ADAPT HER2+/HR− Trial
Authors: Graeser Monika , Gluz Oleg , Biehl Claudia , Ulbrich-Gebauer Daniel , Christgen Matthias , Palatty Jenci , Kuemmel Sherko , Grischke Eva-Maria , Augustin Doris , Braun Michael , Potenberg Jochem , Wuerstlein Rachel , Krauss Katja , Schumacher Claudia , Forstbauer Helmut , Reimer Toralf , Stefek Andrea , Fischer Hans Holger , Pelz Enrico , zu Eulenburg Christine , Kates Ronald , Ni Hua , Kolberg-Liedtke Cornelia , Feuerhake Friedrich , Kreipe Hans Heinrich , Nitz Ulrike , Harbeck Nadia
Published: April 2023

Supplementary Table 4 shows associations between the genes in ER signaling signature and iDFS
Supplementary Table S2 from Impact of RNA Signatures on pCR and Survival after 12-Week Neoadjuvant Pertuzumab plus Trastuzumab with or without Paclitaxel in the WSG-ADAPT HER2+/HR− Trial
Authors: Graeser Monika , Gluz Oleg , Biehl Claudia , Ulbrich-Gebauer Daniel , Christgen Matthias , Palatty Jenci , Kuemmel Sherko , Grischke Eva-Maria , Augustin Doris , Braun Michael , Potenberg Jochem , Wuerstlein Rachel , Krauss Katja , Schumacher Claudia , Forstbauer Helmut , Reimer Toralf , Stefek Andrea , Fischer Hans Holger , Pelz Enrico , zu Eulenburg Christine , Kates Ronald , Ni Hua , Kolberg-Liedtke Cornelia , Feuerhake Friedrich , Kreipe Hans Heinrich , Nitz Ulrike , Harbeck Nadia
Published: April 2023

Supplementary Table 2 shows a comparison of patient characteristics between subjects with and without BC360 and all patients in the trial
Supplementary Figure 1 from ALK Amplification and Rearrangements Are Recurrent Targetable Events in Congenital and Adult Glioblastoma
Authors: Blandin Anne-Florence , Giglio Ross , Graham Maya Srikanth , Garcia Guadalupe , Malinowski Seth , Woods Jared K. , Ramkissoon Shakti , Ramkissoon Lori , Dubois Frank , Schoolcraft Kathleen , Tsai Jessica , Wang Dayle , Jones Robert , Vogelzang Jayne , Pelton Kristine , Becker Sarah , Watkinson Fiona , Sinai Claire , Cohen Elizabeth F. , Booker Matthew A. , Tolstorukov Michael Y. , Haemels Veerle , Goumnerova Liliana , Wright Karen , Kieran Mark , Fehnel Katie , Reardon David , Tauziede-Espariat Arnault , Lulla Rishi , Carcamo Benjamin , Chaleff Stanley , Charest Alain , De Smet Frederik , Ligon Azra H. , Dubuc Adrian , Pages Melanie , Varlet Pascale , Wen Patrick Y. , Alexander Brian M. , Chi Susan , Alexandrescu Sanda , Kittler Ralf , Bachoo Robert , Bandopadhayay Pratiti , Beroukhim Rameen , Ligon Keith L.
Published: April 2023

Supplementary Figure 1: Characterization of the novel LRRFIP1-ALK fusion (case ALK.223) A. Visualization of the read coverage at the fusion sites in ALK and LRRFIP1 genes using Integrative Genomic Viewer.B. Pile-up plot generated by SvABA using whole-genome sequencing data shows the breakpoint coordinates.C. Copy number ratio profile by WGS showing no somatic copy number alterations anywhere in the genome. The x-axis represents the chromosomes.D. Copy number ratio profile on chromosome 2 showing no copy number change of ALK and LRRFIP1 genes.E. Two RT-PCR products of 186bp (variant 1) and 189bp (variant 3) were detected by agarose gel electrophoresis with total RNA from tumor specimen ALK.223.F. Primer sequences of ALK-LRRFIP1 (variants 1 and 2) and LRRFIP1-ALK (variant 3) and the predicted DNA product size.G. Western Blot analysis of ALK signaling pathway in subcutaneous tumors treated with vehicle or lorlatinib. Normal brain was used as control.H. Representative 40x images and CellProfiler quantification of Cleaved Caspase 3- and Ki-67- stained subcutaneous tumors.
Supplementary Figure S4 from Loss of CDKN2A Cooperates with WWTR1(TAZ)–CAMTA1 Gene Fusion to Promote Tumor Progression in Epithelioid Hemangioendothelioma
Authors: Seavey Caleb N. , Hallett Andrea , Li Shuo , Che Kepeng , Pobbati Ajaybabu V. , Ma Shuang , Burtscher Ashley , Kanai Ryan , Lamar John M. , Rubin Brian P.
Published: April 2023

Immunohistochemistry of EHE allograft tumors
Supplementary Figure S3 from Loss of CDKN2A Cooperates with WWTR1(TAZ)–CAMTA1 Gene Fusion to Promote Tumor Progression in Epithelioid Hemangioendothelioma
Authors: Seavey Caleb N. , Hallett Andrea , Li Shuo , Che Kepeng , Pobbati Ajaybabu V. , Ma Shuang , Burtscher Ashley , Kanai Ryan , Lamar John M. , Rubin Brian P.
Published: April 2023

Validation of the EHE cell lines
Supplementary Table 1 from Crizotinib Has Preclinical Efficacy in Philadelphia-Negative Myeloproliferative Neoplasms
Authors: Gurska Lindsay M. , Okabe Rachel , Schurer Alexandra , Tong Meng Maxine , Soto Mark , Choi Daniel , Ames Kristina , Glushakow-Smith Shira , Montoya Allison , Tein Ellen , Miles Linde A. , Cheng Haiying , Hankey-Giblin Pamela , Levine Ross L. , Goel Swati , Halmos Balazs , Gritsman Kira
Published: April 2023

Supplementary Table 1
Supplementary Table S3 from Survival Outcomes, Digital TILs, and On-treatment PET/CT During Neoadjuvant Therapy for HER2-positive Breast Cancer: Results from the Randomized PREDIX HER2 Trial
Authors: Matikas Alexios , Johansson Hemming , Grybäck Per , Bjöhle Judith , Acs Balazs , Boyaci Ceren , Lekberg Tobias , Fredholm Hanna , Elinder Ellinor , Margolin Sara , Isaksson-Friman Erika , Bosch Ana , Lindman Henrik , Adra Jamila , Andersson Anne , Agartz Susanne , Hellström Mats , Zerdes Ioannis , Hartman Johan , Bergh Jonas , Hatschek Thomas , Foukakis Theodoros
Published: April 2023

Supplementary Table S3. Hazard ratios for relapse-free survival estimated using univariate and multivariable proportional hazards regression. SUVmax at cycle 2 (C2) is included as continuous variable in the regression models.
Supplementary File S1 from Survival Outcomes, Digital TILs, and On-treatment PET/CT During Neoadjuvant Therapy for HER2-positive Breast Cancer: Results from the Randomized PREDIX HER2 Trial
Authors: Matikas Alexios , Johansson Hemming , Grybäck Per , Bjöhle Judith , Acs Balazs , Boyaci Ceren , Lekberg Tobias , Fredholm Hanna , Elinder Ellinor , Margolin Sara , Isaksson-Friman Erika , Bosch Ana , Lindman Henrik , Adra Jamila , Andersson Anne , Agartz Susanne , Hellström Mats , Zerdes Ioannis , Hartman Johan , Bergh Jonas , Hatschek Thomas , Foukakis Theodoros
Published: April 2023

REMARK Checklist
Supplementary Figure S2 from Survival Outcomes, Digital TILs, and On-treatment PET/CT During Neoadjuvant Therapy for HER2-positive Breast Cancer: Results from the Randomized PREDIX HER2 Trial
Authors: Matikas Alexios , Johansson Hemming , Grybäck Per , Bjöhle Judith , Acs Balazs , Boyaci Ceren , Lekberg Tobias , Fredholm Hanna , Elinder Ellinor , Margolin Sara , Isaksson-Friman Erika , Bosch Ana , Lindman Henrik , Adra Jamila , Andersson Anne , Agartz Susanne , Hellström Mats , Zerdes Ioannis , Hartman Johan , Bergh Jonas , Hatschek Thomas , Foukakis Theodoros
Published: April 2023

Supplementary Figure S2: Probability for pathologic complete response in the four groups of the combined classification according to SUVmax at cycle 2 (median value 2.6 as cut-off) and baseline TIL (median value 10% as cut-off)
supplementary table 1 from Pilot Study of Recurrent Ewing's Sarcoma Management with Vigil/Temozolomide/Irinotecan and Assessment of Circulating Tumor (ct) DNA
Authors: Anderson Peter , Ghisoli Maurizio , Crompton Brian D. , Klega Kelly S. , Wexler Leonard H. , Slotkin Emily K. , Stanbery Laura , Manning Luisa , Wallraven Gladice , Manley Meghan , Horvath Staci , Bognar Ernest , Nemunaitis John
Published: April 2023

supplementary table
Supplementary Table S2 from Intratumoral CD16+ Macrophages Are Associated with Clinical Outcomes of Patients with Metastatic Melanoma Treated with Combination Anti-PD-1 and Anti-CTLA-4 Therapy
Authors: Lee Hansol , Ferguson Angela L. , Quek Camelia , Vergara Ismael A. , Pires daSilva Ines , Allen Ruth , Gide Tuba Nur , Conway Jordan W. , Koufariotis Lambros T. , Hayward Nicholas K. , Waddell Nicola , Carlino Matteo S. , Menzies Alexander M. , Saw Robyn P.M. , Shklovskaya Elena , Rizos Helen , Lo Serigne , Scolyer Richard A. , Long Georgina V. , Palendira Umaimainthan , Wilmott James S.
Published: April 2023

Multiplex immunohistochemical staining protocols.
Supplementary Methods from Selectively Targeting STAT3 Using a Small Molecule Inhibitor is a Potential Therapeutic Strategy for Pancreatic Cancer
Authors: Chen Huang , Zhou Wenbo , Bian Aiwu , Zhang Qiansen , Miao Ying , Yin Xuan , Ye Jiangnan , Xu Shifen , Ti Chaowen , Sun Zhenliang , Zheng Jianghua , Chen Yihua , Liu Mingyao , Yi Zhengfang
Published: April 2023

Supplementary Methods
Data from Randomized Phase II Cabazitaxel Dose Individualization and Neutropenia Prevention Trial in Patients with Metastatic Castration-Resistant Prostate Cancer
Authors: Omlin Aurelius , Cathomas Richard , von Amsberg Gunhild , Reuter Christoph , Feyerabend Susan , Loidl Wolfgang , Boegemann Martin , Lorch Anja , Heidenreich Axel , Tsaur Igor , Larcher-Senn Julian , Buck Stefan A.J. , Mathijssen Ron H.J. , Jaehde Ulrich , Gillessen Silke , Joerger Markus
Published: April 2023

AbstractPurpose:
There is ongoing controversy about the recommended dose of cabazitaxel in patients with metastatic castration-resistant prostate cancer (mCRPC).
Patients and Methods:
This multicenter phase II open-label, randomized, parallel-group study compared 3-weekly cabazitaxel at 25 mg/m2 (conventional arm A) with cabazitaxel therapeutic drug monitoring (experimental arm B) in mCRPC. The primary objective was to improve the clinical feasibility rate (CFR), defined as the absence of grade 4 neutropenia or thrombocytopenia, any thrombocytopenia with bleeding, febrile neutropenia, severe nonhematologic toxicity, withdrawal for cabazitaxel-related toxicity, or death. A total of 60 patients had to be randomized to detect a difference in CFR of 35% (power 80%, two-sided alpha 10%).
Results:
A total of 40 patients were randomized to arm A and 33 patients to arm B. CFR was 69.4% in arm A and 64.3% in arm B (P = 0.79). Week-12 PSA response was 38.5% in both arms. A radiological response by RECIST v.1.1 was seen in 3 (9.7%) patients in arm A versus 6 (23.1%) patients in arm B (P = 0.28), disease progression was higher in arm A compared with arm B (61.3% vs. 30.8%, P = 0.05). Median progression-free survival was longer in arm B compared with arm A (9.5 vs. 4.4 months; HR = 0.46; P = 0.005). Median overall survival was higher in arm B compared with arm A (16.2 vs. 7.3 months; HR = 0.33; P < 0.0001).
Conclusions:
Pharmacokinetic-guided dosing of cabazitaxel in patients with mCRPC is feasible and improves clinical outcome due to individual dose escalations in 55% of patients.
Data from COOH-Terminal Truncated HBV X Protein Plays Key Role in Hepatocarcinogenesis
Authors: Ma Ning-Fang , Lau Sze Hang , Hu Liang , Xie Dan , Wu Jun , Yang Jun , Wang Yi , Wu Meng-Chao , Fung Jackie , Bai Xueyan , Tzang Chi-Hung , Fu Li , Yang Mengsu , Su Yan An , Guan Xin-Yuan
Published: April 2023

Abstract
Purpose: X protein (HBx), a product of hepatitis B virus, has been closely associated with the development of hepatocellular carcinoma (HCC). Based on observations that the COOH-terminal truncated HBx was frequently detected in HCC, the aim of this study is to evaluate the function of COOH-terminal truncated HBx in hepatocarcinogenesis.

Experimental Design: Expression pattern of HBx was analyzed by immunohistochemistry on tissue microarray containing 194 pairs of HCCs and their matched nontumor liver tissues. MIHA and HepG2 cells transfected with full-length (X2) and COOH-terminal truncated HBx (X1) were tested for their ability to grow in soft agar and form tumors in vivo. Proliferation and apoptosis were assessed using 2,3-bis[2-methoxy-4-nitro-5-sulfophenyl]-2H-tetrazolium-5-carboxanilide inner salt and terminal deoxyribonucleotidyl transferase-mediated dUTP nick-end labeling assays, respectively. To gain additional insight, the expression profile of HepG2-X2 and HepG2-X1 were compared using cDNA microarray.

Results: COOH-terminal truncated HBx was frequently detected in HCCs (79.3%, n = 111), and our in vitro and in vivo studies showed that the truncated rather than the full-length HBx could effectively transform immortalized liver cell line MIHA. Interestingly, expression profiling revealed differential expression of key genes implicated in the control of cell cycle and apoptosis.

Conclusions: These findings strongly suggest that the COOH-terminal truncated HBx plays a critical role in the HCC carcinogenesis via the activation of cell proliferation.
Data from The Novel Expanded Porphyrin, Motexafin Gadolinium, Combined with [90Y]Ibritumomab Tiuxetan for Relapsed/Refractory Non-Hodgkin's Lymphoma: Preclinical Findings and Results of a Phase I Trial
Authors: Evens Andrew M. , Spies William G. , Helenowski Irene B. , Patton David , Spies Stewart , Jovanovic Borko D. , Miyata Sarah , Hamilton Elizabeth , Variakojis Daina , Chen Jun , Naumovski Louie , Rosen Steven T. , Winter Jane N. , Miller Richard A. , Gordon Leo I.
Published: April 2023

Abstract
Purpose: Therapeutic strategies to enhance the efficacy of radioimmunotherapy have not been explored. Motexafin gadolinium is a novel anticancer agent that targets redox-dependent pathways and enhances sensitivity of tumor cells to ionizing radiation.

Experimental Design: We did preclinical studies examining motexafin gadolinium combined with rituximab and/or radiation in lymphoma cells. We subsequently completed a phase I clinical trial combining escalating doses of motexafin gadolinium concurrently with standard [90Y]ibritumomab tiuxetan for patients with relapsed/refractory non-Hodgkin's lymphoma.

Results: In HF1 lymphoma cells, motexafin gadolinium and rituximab resulted in synergistic cytotoxicity (combination index, 0.757) through a mitochondrial-mediated caspase-dependent pathway, whereas cell death in Ramos and SUDHL4 cells was additive. Motexafin gadolinium/rituximab combined with radiation (1-3 Gy) resulted in additive apoptosis. Twenty-eight of 30 patients were evaluable on the phase I clinical trial. Median age was 65 years (47-87 years), and histologies were marginal-zone (n = 1), mantle-cell (n = 3), diffuse large cell (n = 6), and follicular lymphoma (n = 18). Of all patients, 86% were rituximab refractory. Therapy was well tolerated, and no dose-limiting toxicity was seen. Overall response rate was 57% [complete remission (CR), 43%], with median time–to–treatment failure of 10 months (1-48+ months) and median duration-of-response of 17 months. Of note, all responses were documented at 4 weeks. Furthermore, in rituximab-refractory follicular lymphoma (n = 14), overall response rate was 86% (CR, 64%), with a median time–to–treatment failure of 14 months (2-48+ months).

Conclusions: This represents the first report of a novel agent to be combined safely concurrently with radioimmunotherapy. Furthermore, tumor responses with [90Y]ibritumomab tiuxetan/motexafin gadolinium were prompt with a high rate of CRs, especially in rituximab-refractory follicular lymphoma. (Clin Cancer Res 2009;15(20):6462–71)
Data from Methylation of Tip30 Promoter Is Associated with Poor Prognosis in Human Hepatocellular Carcinoma
Authors: Lu Bin , Ma Yunchao , Wu Guobin , Tong Xin , Guo Huaizu , Liang Anmin , Cong Wenming , Liu Chang , Wang Hao , Wu Mengchao , Zhao Jian , Guo Yajun
Published: April 2023

Abstract
Purpose: To investigate Tip30 promoter methylation status in human hepatocellular carcinoma (HCC) and the correlation with clinicopathologic features and prognosis.

Experimental Design: The methylation status of CpG islands in Tip30 promoter was examined in 15 HCC cell lines as well as 59 paired HCC and adjacent nontumor tissues. The associations between Tip30 methylation status and the survival of patients were analyzed.

Results:Tip30 promoter was hypermethylated in 6 of 10 HCC cell lines with reduced Tip30 mRNA. DNA methyltransferase inhibitor, 5-aza-2′-deoxycytidine, greatly enhanced TIP30 expression and sensitized HCC cells to cytotoxic drug-induced cell death. The promoter region of Tip30 was identified and the main promoter activity was located in the -135 to -45 region sited within a CpG island. The minimal promoter element contained four Sp1 binding sites, which were hypermethylated in HCC cell-derived promoters. Moreover, analyses of Tip30 promoter methylation status in 59 paired HCC tissues showed that 47% of the cases were hypermethylated. Recurrence rate (95% versus 67%; P = 0.011) and mortality (82% versus 53%; P = 0.033) were significantly higher in patients with methylated Tip30. Disease-free survival was significantly higher in patients with unmethylated Tip30 (33.3% versus 4.5%; P = 0.036).

Conclusions: Our results show that epigenetic silencing of Tip30 gene expression by CpG island DNA hypermethylation is associated with poor prognosis in patients with HCC.
Data from Gene Expression Profiling of Papillary Thyroid Carcinoma Identifies Transcripts Correlated with BRAF Mutational Status and Lymph Node Metastasis
Authors: Oler Gisele , Camacho Cléber P. , Hojaij Flávio C. , Michaluart Pedro , Riggins Gregory J. , Cerutti Janete M.
Published: April 2023

Abstract
Purpose: To identify papillary thyroid carcinoma (PTC)–associated transcripts, we compared the gene expression profiles of three Serial Analysis of Gene Expression libraries generated from thyroid tumors and a normal thyroid tissue.

Experimental Design: Selected transcripts were validated in a panel of 57 thyroid tumors using quantitative PCR (qPCR). An independent set of 71 paraffin-embedded sections was used for validation using immunohistochemical analysis. To determine if PTC-associated gene expression could predict lymph node involvement, a separate cohort of 130 primary PTC (54 metastatic and 76 nonmetastatic) was investigated. The BRAFV600E mutational status was compared with qPCR data to identify genes that might be regulated by abnormal BRAF/MEK/extracellular signal-regulated kinase signaling.

Results: We identified and validated new PTC-associated transcripts. Three genes (CST6, CXCL14, and DHRS3) are strongly associated with PTC. Immunohistochemical analysis of CXCL14 confirmed the qPCR data and showed protein expression in PTC epithelial cells. We also observed that CST6, CXCL14, DHRS3, and SPP1 were associated with PTC lymph node metastasis, with CST6, CXCL14, and SPP1 being positively correlated with metastasis and DHRS3 being negatively correlated. Finally, we found a strong correlation between CST6 and CXCL14 expression and BRAFV600E mutational status, suggesting that these genes may be induced subsequently to BRAF activation and therefore may be downstream in the BRAF/MEK/extracellular signal-regulated kinase signaling pathway.

Conclusion:CST6, CXCL14, DHRS3, and SPP1 may play a role in PTC pathogenesis and progression and are possible molecular targets for PTC therapy.
Data from Effect of Trans-2,3-Dimethoxycinnamoyl Azide on Enhancing Antitumor Activity of Romidepsin on Human Bladder Cancer
Authors: Fan Jinhai , Stanfield Jennifer , Guo Yi , Karam Jose A. , Frenkel Eugene , Sun Xiankai , Hsieh Jer-Tsong
Published: April 2023

Abstract
Purpose: Romidepsin (FK228, depsipeptide, FR901228), a unique cyclic depsipeptide with a histone deacetylase inhibitor (HDACI) activity, is a potential cancer therapeutic agent and currently under clinical trials for several types of cancer. For bladder cancer, romidepsin seems to be a potent antitumor agent from our recent study. In this study, we further delineate a new agent that can enhance both HDACI and antitumor activity of romidepsin.

Experimental Design: We screened a chemical library to identify candidate(s) that could enhance romidepsin activity. Chemical synthesis and purification were carried out to produce pure compound to examine its biochemical and antitumor effect on bladder cancer cell lines both in vitro and in vivo.

Results: Tranilast, N-(acetoacetyl) anthranilic acid, was first identified as a lead compound from screening, and then, one of the analogues, 2,3-dimethoxycinnamoyl azide (DMCA), seems to be more potent than tranilast. Our data indicate that DMCA can potentiate the HDACI activity of romidepsin and other biological activities, such as cell cycle arrest and apoptosis; these effects were accompanied with the expression of various key cell cycle regulators in different bladder cancer cells. Consistently, DMCA can enhance the in vivo antitumor effect of romidepsin without causing any more weight loss than romidepsin alone.

Conclusion: DMCA is able to enhance the antitumor effect of romidepsin on bladder cancer from in vitro and in vivo.
Data from Impaired Tamoxifen Metabolism Reduces Survival in Familial Breast Cancer Patients
Authors: Newman William G. , Hadfield Kristen D. , Latif Ayshe , Roberts Stephen A. , Shenton Andrew , McHague Christopher , Lalloo Fiona , Howell Sacha , Evans D. Gareth
Published: April 2023

Abstract
Purpose: Tamoxifen has been the mainstay adjuvant hormonal treatment for breast cancer for many years. Conversion of tamoxifen to its active metabolite, endoxifen, is reduced by low activity of the cytochrome P450 enzyme, CYP2D6. We examined the effect of reduced CYP2D6 activity on the response to tamoxifen in patients with familial early-onset breast cancer.

Experimental Design: We conducted a case note review and genotyping for the CYP2D6*3, CYP2D6*4, CYP2D6*5, and CYP2D6*41 alleles in 115 patients (47 BRCA1, 68 BRCA2) with familial breast cancer who had been treated with 20-mg tamoxifen following surgery.

Results: Eight (7%) individuals had genotypes consistent with poor metabolizer status, and 4 (3.5%) individuals took CYP2D6 inhibitor drugs concomitant with their tamoxifen and were also considered poor metabolizer. Time to tumor recurrence, disease-free survival, and overall survival were reduced in the patient group with poor metabolizer CYP2D6 activity. However, a significant effect was confined to patients with BRCA2 mutations with a worse overall survival (median survival, 7 versus 28 years; P = 0.008; adjusted hazard ratio, 9.7).

Conclusions: Poor metabolizer status for CYP2D6 predicts worse overall survival in patients with familial breast cancer. Therefore, CYP2D6 inhibitor drugs should not be prescribed concomitantly with tamoxifen. Prospective studies should be undertaken to establish the effect of CYP2D6 status on outcome in familial breast cancer patients treated with tamoxifen.
Data from DNA Ploidy Cytometry Testing for Cervical Cancer Screening in China (DNACIC Trial): a Prospective Randomized, Controlled Trial
Authors: Tong Hua , Shen Rong , Wang ZhuMing , Kan YanJing , Wang YiQuan , Li FengShan , Wang FuZhou , Yang Jie , Guo XiRong
Published: April 2023

Abstract
Purpose: This randomized, controlled trial was designed to determine whether the DNA cytometry testing is superior to the conventional cytologic testing for mass cervical cancer screening.

Experimental Design: After approval by the institutional ethics review boards from three separate screening centers, a total of 23,993 Chinese women ages 20 to 65 years were randomly assigned into one of the two groups: a DNA cytometry testing group (11,999 women) and a cytologic testing group (11,994 women). Each woman underwent the other testing after first attending the assigned screening test. Women with positive results after assigned testing additionally underwent colposcopy and human papillomaviruses detections, and those with cervical precancerous or cancerous lesions received appropriate treatment. Sensitivity and specificity estimates were adjusted for verification bias. Analyses were by intention to treat and per protocol ways.

Results: In the cytometric DNA testing group, cervical cancer was diagnosed in 40 subjects, compared with 24 subjects in the cytologic testing group [hazard ratio for the detection of advanced cancer in the DNA cytometry testing group, 0.42; 95% confidence interval (CI), 0.27-0.60]. The sensitivity of the DNA cytometry testing for cervical cancer was 91.7% (95% CI, 64.3-95.8), whereas the sensitivity of cytologic testing was 44.5% (95% CI, 25.2-61.3; P = 0.008). The specificity was 54.1% (95% CI, 31.6-69.0) for DNA cytometry testing and 70.6% (95% CI, 46.8-82.5; P = 0.003) for cytologic testing. The sensitivity of both tests used together was 100%, and the specificity was 91.8%. A total of 187 subjects reported mild to severe adverse events after treatment with positive results in 319 women.

Conclusions: Our results highlight the benefit of the DNA cytometry testing strategy in mass cervical cancer screening with greater sensitivity and positive predicted value than the conventional cytologic testing in developing settings. (Clin Cancer Res 2009;15(20):6438–45)
Data from Intratumoral Expression of Mature Human Neutrophil Peptide-1 Mediates Antitumor Immunity in Mice
Authors: Wang Yong-sheng , Li Dan , Shi Hua-shan , Wen Yan-jun , Yang Li , Xu Ning , Chen Xian-cheng , Chen Xiang , Chen Ping , Li Jiong , Deng Hong-xin , Wang Chun-ting , Xie Gang , Huang Shan , Mao Yong-qiu , Chen Li-juan , Zhao Xia , Wei Yu-quan
Published: April 2023

Abstract
Purpose: Human neutrophil peptides (HNP1-3), small molecular antimicrobial peptides, are expressed within tumors and associated with tumor necrosis and inhibition of angiogenesis. Recent investigations have suggested that HNP1-3 are likely to be involved in the host immune responses to tumors.

Experimental Design: We used recombinant pSec-HNP1, which expresses a secretable form of HNP1, to obtain expression of HNP1 in the tumor milieu in immunocompetent mice to explore the possible roles of HNP1 in tumor immunity. The antitumor effects were investigated in established CT26 colon cancer and 4T1 breast cancer models.

Results: HNP1-mediated chemotactic and activating effects on immature dendritic cells were detected both in vitro and in vivo. Intratumoral expression of HNP1 resulted in not only significant tumor growth inhibition but also increased CTL infiltration within tumors. Adoptive transfer of splenocytes and a 51Cr release assay revealed specific cellular immune responses. Furthermore, increased antibodies were also found in sera from pSec-HNP1treated mice supporting specific humoral immune responses. Increased apoptosis and decreased angiogenesis were also shown in treated tumors.

Conclusions: These findings indicate that HNP1 can exert multiple antitumor effects through different mechanisms; more importantly, HNP1 mediates host immune responses to tumors in situ through the recruitment and subsequent activation of immature dendritic cells and thus shows promising potential in cancer therapy. (Clin Cancer Res 2009;15(22):690111)
Data from Novel Oligoamine Analogues Inhibit Lysine-Specific Demethylase 1 and Induce Reexpression of Epigenetically Silenced Genes
Authors: Huang Yi , Stewart Tracy Murray , Wu Yu , Baylin Stephen B. , Marton Laurence J. , Perkins Brandy , Jones Richard J. , Woster Patrick M. , Casero Robert A.
Published: April 2023

Abstract
Purpose: Abnormal DNA CpG island hypermethylation and transcriptionally repressive histone modifications are associated with the aberrant silencing of tumor suppressor genes. Lysine methylation is a dynamic, enzymatically controlled process. Lysine-specific demethylase 1 (LSD1) has recently been identified as a histone lysine demethylase. LSD1 specifically catalyzes demethylation of mono– and dimethyl–lysine 4 of histone 3 (H3K4), key positive chromatin marks associated with transcriptional activation. We hypothesized that a novel class of oligoamine analogues would effectively inhibit LSD1 and thus cause the reexpression of aberrantly silenced genes.

Experimental Design: Human colorectal cancer cells were treated with the oligoamines and changes in mono- and dimethyl-H3K4 and other chromatin marks were monitored. In addition, treated cells were evaluated for the reexpression of the aberrantly silenced secreted frizzled-related proteins (SFRP) Wnt signaling pathway antagonist genes. Finally, the effects of the LSD1 inhibitors were evaluated in an in vivo xenograft model.

Results: Treatment of HCT116 human colon adenocarcinoma cells in vitro resulted in increased H3K4 methylation and reexpression of silenced SFRP genes. This reexpression is also accompanied by a decrease in H3K9me2 repressive mark. Importantly, cotreatment with low doses of oligoamines and a DNA methyltransferase inhibitor highly induces the reexpression of the aberrantly silenced SFRP2 gene and results in significant inhibition of the growth of established tumors in a human colon tumor model in vivo.

Conclusions: The use of LSD1-inhibiting oligoamine analogues in combination with DNA methyltransferase inhibitors represents a highly promising and novel approach for epigenetic therapy of cancer. (Clin Cancer Res 2009;15(23):7217–28)
Data from Melanoma Cells Exhibit Variable Signal Transducer and Activator of Transcription 1 Phosphorylation and a Reduced Response to IFN-α Compared with Immune Effector Cells
Authors: Lesinski Gregory B. , Trefry John , Brasdovich Melanie , Kondadasula Sri Vidya , Sackey Korkor , Zimmerer Jason M. , Chaudhury Abhik Ray , Yu Lianbo , Zhang Xiaoli , Crespin Tim R. , Walker Michael J. , Carson William E.
Published: April 2023

Abstract
Purpose: IFN-α is administered to melanoma patients and its endogenous production is essential for immune-mediated tumor recognition. We hypothesized that a reduced capacity for signal transducer and activator of transcription (STAT) 1 activation allows melanoma cells to evade the direct actions of IFN-α.

Experimental Design: Tyr701-phosphorylated STAT1 (P-STAT1) was measured by flow cytometry in IFN-α–stimulated human melanoma cell lines, melanoma cells derived from patient tumors, and peripheral blood mononuclear cells (PBMC). Expression of other Janus-activated kinase (Jak)-STAT intermediates (STAT1, STAT2, Jak1, tyrosine kinase 2, IFN-α receptor, STAT3, and STAT5) was evaluated by flow cytometry, immunoblot, or immunohistochemistry.

Results: Significant variability in P-STAT1 was observed in human melanoma cell lines following IFN-α treatment (P < 0.05) and IFN-α–induced P-STAT1 correlated with the antiproliferative effects of IFN-α (P = 0.042). Reduced formation of P-STAT1 was not explained by loss of Jak-STAT proteins or enhanced STAT5 signaling as reported previously. Basal levels of P-STAT3 were inversely correlated with IFN-α–induced P-STAT1 in cell lines (P = 0.013). IFN-α–induced formation of P-STAT1 was also variable in melanoma cells derived from patient tumors; however, no relationship between P-STAT3 and IFN-α–induced P-STAT1 was evident. Because IFN-α acts on both tumor and immune cells, we examined the ability of IFN-α to induce P-STAT1 in patient-derived melanoma cells and PBMCs. IFN-α induced significantly lower levels of P-STAT1 in melanoma cells compared with matched PBMCs (P = 0.046). Melanoma cells and human melanocytes required 10-fold higher IFN-α doses to exert P-STAT1 levels comparable with PBMCs.

Conclusions: Melanoma cells are variable in their IFN-α responsiveness, and cells of the melanocytic lineage exhibit a lower capacity for IFN-α–induced Jak-STAT signaling compared with immune cells.
Data from The Macrophage Colony-Stimulating Factor 1 Response Signature in Breast Carcinoma
Authors: Beck Andrew H. , Espinosa Inigo , Edris Badreddin , Li Rui , Montgomery Kelli , Zhu Shirley , Varma Sushama , Marinelli Robert J. , van de Rijn Matt , West Robert B.
Published: April 2023

Abstract
Purpose: Macrophages play an important role in breast carcinogenesis. The pathways that mediate the macrophage contribution to breast cancer and the heterogeneity that exists within macrophages are incompletely understood. Macrophage colony-stimulating factor 1 (CSF1) is the primary regulator of tissue macrophages. The purpose of this study was to define a novel CSF1 response signature and to evaluate its clinical and biological significance in breast cancer.

Experimental Design: We defined the CSF1 response signature by identifying genes overexpressed in tenosynovial giant cell tumor and pigmented villonodular synovitis (tumors composed predominantly of macrophages recruited in response to the overexpression of CSF1) compared with desmoid-type fibromatosis and solitary fibrous tumor. To characterize the CSF1 response signature in breast cancer, we analyzed the expression of CSF1 response signature genes in eight published breast cancer gene expression data sets (n = 982) and did immunohistochemistry and in situ hybridization for CSF1 response genes on a breast cancer tissue microarray (n = 283).

Results: In both the gene microarray and tissue microarray analyses, a consistent subset (17-25%) of breast cancers shows the CSF1 response signature. The signature is associated with higher tumor grade, decreased expression of estrogen receptor, decreased expression of progesterone receptor, and increased TP53 mutations (P < 0.001).

Conclusions: Our data show that the CSF1 response signature is consistently seen in a subset of breast carcinomas and correlates with biological features of the tumor. Our findings provide insight into macrophage biology and may facilitate the development of personalized therapy for patients most likely to benefit from CSF1-targeted treatments.
Data from Interaction of the Multikinase Inhibitors Sorafenib and Sunitinib with Solute Carriers and ATP-Binding Cassette Transporters
Authors: Hu Shuiying , Chen Zhaoyuan , Franke Ryan , Orwick Shelley , Zhao Ming , Rudek Michelle A. , Sparreboom Alex , Baker Sharyn D.
Published: April 2023

Abstract
Purpose: To compare side-by-side the uptake of sorafenib and sunitinib in vitro by human uptake solute carriers of the SLC22A and SLCO families, the transport by and inhibition of efflux ATP-binding cassette (ABC) transporters, and the role of ABCB1 in the plasma pharmacokinetics and brain penetration of these agents.

Experimental Design: Uptake of [3H]sorafenib or [3H]sunitinib was assessed in Xenopus laevis oocytes or mammalian cells transfected with cDNAs coding for human OATP1A2, OATP1B1, OATP1B3, OCT1, OAT2, OAT3, OCTN1, or OCTN2. Efflux and inhibition experiments were conducted in cells transfected with human ABCB1, ABCG2, ABCC2, or ABCC4. In vivo pharmacokinetic studies were done in knockout mice lacking Abcb1-type transporters.

Results: Intracellular uptake was not appreciably affected by any of the studied solute carriers and was minute relative to the respective prototypical substrates. Sorafenib and sunitinib showed concentration-dependent (1 and 10 μmol/L), low to moderate affinity for ABCB1 but were not affected by the other ABC transporters. Both agents inhibited all tested ABC transporters. The absence of Abcb1 had no affect on plasma pharmacokinetics, but brain penetration was moderately increased by 1.9- and 2.9-fold for sorafenib and sunitinib, respectively, in knockout animals versus controls.

Conclusions: Unlike other tyrosine kinase inhibitors, sorafenib and sunitinib do not appear to rely on active transport to enter the cell nor are they high-affinity substrates for ABC efflux transporters. Based on these characteristics, these two drugs may be less susceptible to transporter-mediated alterations in systemic exposure and transporter-related resistance mechanisms. (Clin Cancer Res 2009;15(19):6062–9)
Data from In vitro and In vivo Anticancer Effects of the Novel Vitamin E Ether Analogue RRR-α-Tocopheryloxybutyl Sulfonic Acid in Prostate Cancer
Authors: Ni Jing , Mai Tiejun , Pang See-Tong , Haque Imranul , Huang Kaohsing , DiMaggio Matthew A. , Xie Shaozhen , James Nadine S. , Kasi Dhanalakshmi , Chemler Sherry R. , Yeh Shuyuan
Published: April 2023

Abstract
Purpose: Among derivatives of α-vitamin E, α-vitamin E succinate (VES), has attracted much attention due to its potent anti–prostate cancer activity in vitro and in vivo. However, the in vivo antitumor activity of VES might be compromised if administrated orally due to the VES hydrolysis by esterases in the gastrointestinal tract.

Experimental Design: New nonhydrolyzable VES ether analogues were synthesized and their growth inhibition was screened by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide growth assay. Among them, RRR-α-tocopheryloxybutyl sulfonic acid (VEBSA) was further characterized by terminal deoxyribonucleotidyl transferase–mediated dUTP nick end labeling apoptosis assay, soft agar assay, and in vivo tumor formation.

Results: VEBSA has potent antitumor ability, albeit to a lesser extent than VES, in in vitro cultured prostate cancer LNCaP and PC3 cells. Like VES, VEBSA induced apoptosis, repressed androgen receptor protein expression, and enhanced vitamin D receptor expression, suggesting that VEBSA can go through mechanisms similar to those used by VES to inhibit the growth of prostate cancer cells in vitro. However, 6 weeks of oral consumption of VEBSA, but not of VES, reduced the tumor burden in the xenografted prostate tumors in nude mice. Furthermore, oral intake of VEBSA for 20 weeks inhibited prostate tumor growth and progression more efficiently compared with VES in the prostate cancer tumor model of TRAMP mice.

Conclusion: Oral consumption of VEBSA allows a greater anticancer activity compared with VES. Chemoprevention prefers the oral consumption of agents; the advantage of VEBSA over VES to be administrated orally will allow VEBSA to serve as an agent for both preventive and therapeutic purposes for prostate cancer.
Data from Proteasome Enzymatic Activities in Plasma as Risk Stratification of Patients with Acute Myeloid Leukemia and Advanced-Stage Myelodysplastic Syndrome
Authors: Ma Wanlong , Kantarjian Hagop , Bekele Benjamin , Donahue Amber C. , Zhang Xi , Zhang Zhong J. , O'Brien Susan , Estey Elihu , Estrov Zeev , Cortes Jorge , Keating Michael , Giles Francis , Albitar Maher
Published: April 2023

Abstract
Purpose: Cytogenetic abnormalities are currently the most important predictors of response and clinical outcome for patients with acute myeloid leukemia (AML) or advanced-stage myelodysplastic syndrome (MDS). Because clinical outcomes vary markedly within cytogenetic subgroups, additional biological markers are needed for risk stratification.

Experimental Design: We assessed the utility of measuring pretreatment proteasome chymotrypsin-like, caspase-like, and trypsin-like activities in plasma to predict response and survival of patients with AML (n = 174) or advanced-stage MDS (n = 52).

Results: All three enzymatic activities were significantly (P < 0.001) increased in the plasma of patients with AML and MDS compared with normal controls. Both chymotrypsin-like and caspase-like activities, but not trypsin-like activity, correlated with outcome. Chymotrypsin-like and caspase-like activities, but not trypsin-like activity, predicted response in univariate analysis (P = 0.002). However, only chymotrypsin-like activity was independent predictor of response from age grouping (<70 versus ≥70 years), cytogenetics, and blood urea nitrogen in multivariate analysis. Similarly, both chymotrypsin-like and caspase-like activities, but not trypsin-like activity, were predictors of overall survival in univariate analysis (P < 0.0001), but only chymotrypsin-like activity was independent of cytogenetics, age, performance status, blood urea nitrogen, and β2-microglobulin in multivariate Cox regression models. Chymotrypsin-like activity was also a strong independent predictor of survival in patients with intermediate karyotype (n = 124).

Conclusions: Measuring plasma chymotrypsin-like activity may provide a powerful biomarker for risk stratification in patients with AML and advanced-stage MDS, including those with normal karyotype.
Data from Variable Clinical Presentations of Nasal and Waldeyer Ring Natural Killer/T-Cell Lymphoma
Authors: Li Ye-Xiong , Liu Qing-Feng , Fang Hui , Qi Shu-Nan , Wang Hua , Wang Wei-Hu , Song Yong-Wen , Lu Jiade , Jin Jing , Wang Shu-Lian , Liu Yue-Ping , Lu Ning , Liu Xin-Fan , Yu Zi-Hao
Published: April 2023

Abstract
Purpose: To determine the clinical characteristics, prognosis, and treatment outcome for patients with nasal natural killer (NK)/T-cell lymphoma (N-NKTL) and Waldeyer ring NK/T-cell lymphoma (WR-NKTL).

Experimental Design: A total of 145 patients with N-NKTL and 95 patients with WR-NKTL were compared.

Results: Compared with N-NKTL, WR-NKTL exhibited distinct differences in clinical features with a propensity for nodal involvement, more advanced stages, low elevated lactate dehydrogenase, intermediate chemosensitivity, and a favorable prognosis. Compared with patients with WR-NKTL, patients with N-NKTL were associated with a lower overall response (54% versus 89%) and higher persistent or progressive disease after initial chemotherapy (46% versus 11%; P = 0.000). The 5-year overall survival and progression-free survival rates were 67% and 56% for N-NKTL and 65% and 47% for WR-NKTL, respectively. Patients with stage II WR-NKTL showed favorable prognosis compared with those with stage II N-NKTL. Compared with radiotherapy alone, patients with early-stage WR-NKTL that received radiotherapy and chemotherapy showed a superior progression-free survival and improved overall survival. In contrast, the addition of chemotherapy to radiotherapy did not provide any survival benefit for patients with early-stage N-NKTL.

Conclusions: N-NKTL and WR-NKTL represent heterogeneous groups with variable clinical features, responses, prognosis, and treatment options.