'Anticancer Res'[jour]; +67 new citations

a.sfakia shared this article with you from Inoreader Message: 1 Review Anticancer Res 2020 Nov;40(11):6009-6015. doi: 10.21873/anticanres.14622. Role of Oncogenes and Tumor-suppressor Genes in Carcinogenesis: A Review Emmanuel N Kontomanolis 1, Antonios Koutras 2, Athanasios Syllaios 3, Dimitrios Schizas 3, Aikaterini Mastoraki 3, Nikolaos Garmpis 4, Michail Diakosavvas 2, Kyveli Angelou 2, Georgios Tsatsaris 1, Athanasios Pagkalos 5, Thomas Ntounis 2, Zacharias Fasoulakis 2 Affiliations expand PMID: 33109539 DOI: 10.21873/anticanres.14622 Abstract Cancer is a medical condition which has a molecular basis. Proto-oncogenes are the first regulatory factors of this biological process. They act in transmitting signals, resulting as growth factors. Modifications of these genes, called oncogenes, lead to the appearance of cancer cells. The activation process leading to proto-oncogenes are chromosomal translocation, point mutation, and gene amplification. Concerning the clonal theory of oncogenesis, it is believed that a tumor starts from a cell. Furthermore, there is close association between tumor development and inhibition of apoptosis or programmed cell death, providing cell immortality. Angiogenesis and angiogenic factors found to be expressed in tumors and may play a key role in tumor formation and development. Tumor-suppressor genes block the growth of cancer and contribute to the normal development of cells. This article highlights the evidence that neoplasms develop as the after-effect of the increase of acquired and physical genetic variations in proto-oncogenes and tumor-suppressor genes; these form a target group in the cells of neoplasms. Tumor formation and development are characterized by individual processes, working synergistically, and an understanding of each individual process may provide a better basis for further anticancer research. Keywords: Oncogenes; carcinogenesis; review; signaling pathways; tumor-suppressor genes. Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved. supplementary info Publication typesexpand full-text links full-text provider logo Proceed to details Cite Share 2 Anticancer Res 2020 Oct;40(10):5869-5875. doi: 10.21873/anticanres.14606. Radical Surgical Procedures in Advanced Ovarian Cancer and Differences Between Primary and Interval Debulking Surgery Vasilis Mitsopoulos 1, Anni Innamaa 1, Jonathan Lippiatt 1, Nikolaos Plevris 1, Ioannis Biliatis 2 Affiliations expand PMID: 32988917 DOI: 10.21873/anticanres.14606 Abstract Background/aim: We aimed to identify differences in cytoreduction rates and procedures performed in patients with advanced ovarian cancer undergoing primary (PDS) or interval debulking surgery (IDS). Patients and methods: Data were collected prospectively on 110 consecutive patients from June 2016 to Mar 2020. Results: Forty-nine patients (44.5%) underwent diaphragmatic peritonectomy (34 in PDS and 15 in IDS, p=0.005), while 38 (34.5%) underwent large bowel resection (29 in PDS and 9 in IDS, p<0.001). Complete cytoreduction was achieved in 39 patients in PDS and 29 in IDS (65% vs. 58%, p=0.22). Longer operations with more blood loss and extended hospital stay were performed in the PDS group. Ten patients (9.1%) experienced severe complications and in eight patients (7.2%) chemotherapy was delayed. Conclusion: More bowel resections and diaphragmatic stripping were performed in the PDS group. End surgical results were similar between groups, with a trend for more complete cytoreduction in PDS. Keywords: Debulking for ovarian cancer; complete cytoreduction; interval debulking surgery; morbidity; primary debulking; upper abdominal surgery. Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved. supplementary info MeSH termsexpand full-text links full-text provider logo Proceed to details Cite Share 3 Anticancer Res 2020 Oct;40(10):5405-5409. doi: 10.21873/anticanres.14549. Expression of ATP-binding Cassette Transporter 11 (ABCC11) Protein in Colon Cancer Yasufumi Yamada 1, Kazuhiko Yoshimatsu 2, Hajime Yokomizo 1, Sachiyo Okayama 1, Shunichi Shiozawa 1 Affiliations expand PMID: 32988860 DOI: 10.21873/anticanres.14549 Abstract Aim: To investigate the clinical significance of ATP-binding cassette transporter 11 (ABCC11) protein expression in colon cancer. Materials and methods: One hundred thirty nine patients with colon cancer resection between 2009 and 2011 were enrolled. The relationship with immunohistochemical ABCC11 staining and clinicopathological factors was retrospectively analyzed. Results: Median age was 70 years including 67 males and 72 females. The patients with Stage 0, 1, 2, 3a and 4 were 4, 20, 43, 35, 7 and 30, respectively. The patients with curability (Cur) A, B and C were 109, 11 and 19, respectively. Positive expression of ABCC11 was observed in 31 patients (22.3%). There were no significant differences regarding age, gender, location, serum tumor markers, T category, lymphatic invasion and stage in relation to ABCC11 protein expression. Cases with node metastasis and venous invasion as well as unresectable cases were significantly more often found negative for ABCC11 protein (p=0.0246, 0.0285 and 0.0422, respectively). Concerning the 3 year disease free survival (DFS) and the 5 year overall survival (OS) in Stage 2/3 and in Stage 3 with adjuvant chemotherapy, no significant differences were found. However, OS in ABCC11 negative cases was 81.1%, which was significantly lower compared to positive cases, where OS was 96.2%. Conclusion: There was significant correlation with ABCC11 expression and lymph node metastasis, venous invasion and curability. The prognosis in ABCC11 negative cases was poor because of increased cases without curative resection. Keywords: 5-fluorouracil; ATP-binding cassette transporter 11; Colon cancer; prognosis. Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved. supplementary info MeSH terms, Substancesexpand full-text links full-text provider logo Proceed to details Cite Share 4 Anticancer Res 2020 Oct;40(10):5735-5738. doi: 10.21873/anticanres.14588. Utility of Bone Scintigraphy and PET-CT in the Surgical Staging of Skeletal Chondrosarcoma Joshua D Johnson 1, William G Rainer 1, Peter S Rose 1, Matthew T Houdek 2 Affiliations expand PMID: 32988899 DOI: 10.21873/anticanres.14588 Abstract Background/aim: Surgical staging is paramount to treatment of primary bone sarcomas. Often, bone scintigraphy and/or positron emission tomography-computed tomography (PET-CT) are used to exclude skeletal metastases; however, skeletal metastases in chondrosarcoma are rare. The purpose of this study was to assess the utility of these staging methods in patients with chondrosarcoma. Patients and methods: We reviewed 138 (87 males, 51 female) patients, mean age 54±20 years, with a chondrosarcoma, who had completed a bone scintigraphy or PET/CT as part of surgical staging. Sensitivity, specificity, and positive/negative predictive value of the scans was calculated. Results: Seventeen (12%) patients had a positive bone scintigraphy or PET-CT for skeletal metastases. In cases of bone scintigraphy (n=11), 6 were benign and 5 were skeletal metastases. In cases of PET-CT, 6 were skeletal metastases, 3 were positive and 3 benign. All positive cases regarded dedifferentiated chondrosarcoma. The overall sensitivity and specificity of a bone scan or PET-CT was 100% and 93.1%; with a positive and negative predictive value of 47.1% and 100%, respectively. Conclusion: Skeletal metastases at presentation of chondrosarcoma are rare and associated with dedifferentiated chondrosarcoma. Bone scintigraphy or PET-CT should only be performed in cases of high grade and dedifferentiated histology. Keywords: Chondrosarcoma; PET-CT; bone scintigraphy; skeletal metastases; staging. Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved. supplementary info MeSH terms, Substancesexpand full-text links full-text provider logo Proceed to details Cite Share 5 Anticancer Res 2020 Oct;40(10):5667-5671. doi: 10.21873/anticanres.14580. Expression Analysis of Tyrosine Phosphatase Genes at Different Stages of Renal Cell Carcinoma Izabela Laczmanska 1, Lukasz Laczmanski 2, Maria M Sasiadek 1 Affiliations expand PMID: 32988891 DOI: 10.21873/anticanres.14580 Abstract Background: Renal cell carcinoma (RCC) is a common urological cancer, and its risk correlates with environmental factors such as obesity, smoking and hypertension. Microarray technology enables analysis of the expression pattern of the whole phosphatome, members of which are involved in many cellular pathways and may act as either tumour suppressors or oncogenes in cancers. Materials and methods: We analysed data for the expression level of 87 out of 107 known protein phosphatase genes included in the Hugo Gene Nomenclature Committee Website for 72 RCC tissues and paired healthy tissues obtained from the GEO Database. Results: Our analysis revealed overexpression of DUSP1, DUSP4, PTP4A3, PTPRC and PTPRE genes at all examined stages of RCC. Moreover, we found overexpression of PTPN12 at stage 2, overexpression of CDKN3 at stages 3 and 4, and overexpression of DUSP10 and PTPN22 at stages 2, 3 and 4. Lower expression of DUSP9, PTPR9 and PTPRO was also observed at all stages. Conclusion: Significant changes in expression patterns of protein tyrosine phosphatase genes confirm the involvement of this group in crucial carcinogenesis pathways underlying RCC. Thus, we postulate that protein tyrosine phosphatases play an important role in RCC promotion and progression, and may be considered as potential therapeutic targets. Keywords: PTPs; Protein tyrosine phosphatases; RCC; expression; renal cell carcinoma. Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved. supplementary info MeSH terms, Substancesexpand full-text links full-text provider logo Proceed to details Cite Share 6 Anticancer Res 2020 Oct;40(10):5621-5630. doi: 10.21873/anticanres.14575. FGF Expression in HPV16-positive and -negative SCC After Treatment With Small-molecule Tyrosine Kinase Inhibitors and Everolimus Lena Huber 1, Richard Birk 2, Manuel Knuettel 3, Nicole Rotter 3, Christoph Aderhold 3, Claudia Scherl 3, Anne Lammert 3, Frederic Jungbauer 3, Benedikt Kramer 3 Affiliations expand PMID: 32988886 DOI: 10.21873/anticanres.14575 Abstract Background: Targeted therapies in the treatment of head and neck squamous cell carcinoma (HNSCC) are subject to extensive research. Different mutations of genes belonging to the fibroblast growth factor (FGF) family have been detected in HNSCC. In this study, we examined the expression of FGF1 and FGF2 after treatment with small-molecule tyrosine kinase inhibitors (TKIs) and an inhibitor of mechanistic target of rapamycin (mTOR) in vitro using human papillomavirus (HPV)-positive and -negative SCC lines. Materials and methods: Cells of two human HPV-negative cell lines (UMSCC-11A/-14C) and one HPV-positive cell line (CERV196) were incubated with 20 μmol/l of erlotinib, gefitinib, nilotinib, dasatinib, or everolimus for 24-96 h. Cell proliferation was assessed by proliferation assay and the protein concentrations of FGF1 and FGF2 by sandwich enzyme-linked immunosorbent assay. For statistical analysis, the results were compared with those for untreated HPV-negative SCC cells. Results: FGF1 and FGF2 were detected in all three tested cell lines. The tested TKIs significantly (p<0.05 reduced) FGF1 expression in the UMSCC-11A cell line within the first 24 h. At later time points, the tested TKIs and everolimus significantly (p<0.05) increased FGF1 and FGF2 expression in HPV-negative and -positive cancer cell lines. The effect was stronger in the HPV-positive cell line. Conclusion: Alterations in FGF signalling are considered to be relevant drivers of tumourigenesis in some HNSCCs. Our results show that the expression of FGF1 and -2 can be influenced effectively by small-molecule TKIs and everolimus. Based on our data, future research should include combinations of specific FGF inhibitors, mTOR inhibitors and other TKIs in the treatment of HNSCC and research on FGF-mediated drug escape mechanisms. Keywords: FGF; Fibroblast growth factor; HNSCC; HPV; everolimus; head and neck squamous cell carcinoma; mTOR inhibitors; tyrosine kinase inhibitors. Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved. supplementary info MeSH terms, Substancesexpand full-text links full-text provider logo Proceed to details Cite Share 7 Anticancer Res 2020 Oct;40(10):5411-5416. doi: 10.21873/anticanres.14550. Double Negativity for Expression of YAP1 and CDX2 Defines an Aggressive Type of Colitis-associated Cancer Feng Yin 1, Hao Xie 2, Jinping Lai 3, Yuanhong Chen 4, Jixin Dong 4, Xuefeng Zhang 5, Xiuli Liu 6 Affiliations expand PMID: 32988861 DOI: 10.21873/anticanres.14550 Abstract Background: Patients with inflammatory bowel disease have markedly increased risk for developing colitis-associated colorectal adenocarcinoma (CAC). There is no established prognostic biomarker for CAC. Materials and methods: A retrospective study was performed on a cohort of 57 CACs. Expression of caudal type homeobox transcription factor 2 (CDX2) and YES-associated protein 1 (YAP1) expression was correlated with clinicodemographic and histopathological features. Results: Neither YAP1 nor CDX2 expression alone was significantly associated with tumor invasion beyond the muscularis propria or lymph node status. However, a subgroup of CAC with double negativity for expression of YAP1 and CDX2 was more frequently found in younger patients, and more frequently associated with higher pathological tumor stage and nodal metastasis. Furthermore, a positive correlation between CDX2 and YAP1 expression was identified in CAC and sporadic colorectal adenocarcinoma. Conclusion: Our study demonstrates that double negativity for expression of YAP1 and CDX2 defines a subgroup of CAC with early onset and aggressive clinical features. Keywords: CDX2; Colitis-associated colorectal cancer; YAP1; prognosis. Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved. supplementary info MeSH terms, Substancesexpand full-text links full-text provider logo Proceed to details Cite Share 8 Anticancer Res 2020 Oct;40(10):5877-5881. doi: 10.21873/anticanres.14607. Diagnostic Accuracy of Pleural Fluid Cytology, Carcinoembryonic Antigen and C-Reactive Protein Together in Patients With Pulmonary Metastases and Malignant Pleural Effusion Stefano M M Basso 1, Alessandro Del Conte 2, Umberto Zuccon 3, Sandro C Sulfaro 4, Giovanni Fanti 5, Federica Maffeis 5, Paolo Ubiali 5, Mario Ermani 6, Franco Lumachi 7 Affiliations expand PMID: 32988918 DOI: 10.21873/anticanres.14607 Abstract Background/aim: Pleural effusion (PE) has a heterogeneous aetiology, and differential diagnosis between benign and malignant disease may require invasive procedures in up to 60% of cases. The sensitivity of pleural cytology is limited, and several strategies have been tested to reduce the need of invasive diagnostic approaches. The aim of this study was to evaluate the usefulness of pleural fluid cytology, compared to, and combined with, carcinoembryonic antigen (CEA), C reactive protein (CRP), and lactate dehydrogenase (LDH) assay of pleural fluid (PF) in patients with a history of cancer, exudative non-purulent PE, and suspicion of malignant PE on imaging studies. Patients and methods: The medical records of 40 patients with pulmonary metastases and malignant PE, and 57 controls with benign exudative PE were reviewed. All the patients underwent pleural cytology and CEA, CRP, and LDH assay before VATS-guided biopsy. Results: The sensitivity and specificity were 55.0% and 98.2% (cytology), 35.0% and 98.2% (CEA), 92.5% and 71.9% (CRP), 70.0% and 54.4% (LDH). The multivariate analysis excluded LDH, and the final AUC (cytology+CEA+CRP) was 0.894. Conclusion: In all patients with a history of cancer and PE of uncertain origin, the combination of PF cytology plus pleural CEA and CRP assay together should be suggested to recognize malignant plural effusion (MPE), minimising the use of unnecessary invasive investigations. Keywords: CEA; CRP; LDH; Pleural effusion; pleural cytology; predictive model; pulmonary metastases. Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved. supplementary info MeSH terms, Substancesexpand full-text links full-text provider logo Proceed to details Cite Share 9 Anticancer Res 2020 Oct;40(10):5463-5469. doi: 10.21873/anticanres.14557. Promotion of Chondrosarcoma Cell Survival, Migration and Lymphangiogenesis by Periostin Ji Yun Jeong 1, Wonju Jeong 2, Ha-Jeong Kim 3 4 Affiliations expand PMID: 32988868 DOI: 10.21873/anticanres.14557 Abstract Background/aim: Periostin exists as an extracellular matrix protein in several carcinomas and is related to metastasis and poor prognosis. It is mainly secreted from cancer associated fibroblasts, and not from carcinoma cells. As a tumor microenvironment component, periostin usually mediates tumor cell stemness, metastasis, angiogenesis and lymphangiogenesis. This study aimed to examine the role of periostin in chondrosarcoma. Materials and methods: To evaluate the effect of periostin on the proliferation of chondrosarcoma cells, MTT assay was performed on SW1353 cells and periostin knockdown SW1353 cells. Migration activity was examined using Boyden chamber. Results: Periostin, secreted from chondrosarcoma cells, was found to support proliferation, and maintain stemness and migration of chondrosarcoma cells. Periostin also induced proliferation and migration of lymphatic endothelial cells. Conclusion: Periostin plays an important role in chondrosarcoma development and disease progression. Keywords: Periostin; angiogenesis; carcinoma; chondrosarcoma; lymphangiogenesis; metastasis; stemness. Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved. supplementary info MeSH terms, Substancesexpand full-text links full-text provider logo Proceed to details Cite Share 10 Anticancer Res 2020 Oct;40(10):5503-5508. doi: 10.21873/anticanres.14562. Association of Caspase-8 Genotypes With the Risk for Nasopharyngeal Carcinoma in Taiwan Liang-Chun Shih 1 2 3, Chia-Wen Tsai 1 3, Wen-Shin Chang 1 3, Te-Chun Shen 3, Yun-Chi Wang 1 3, Jia-Sing Yang 3 4, Meng-Liang Lin 5, Zhi-Hong Wang 6, DA-Tian Bau 7 3 8 Affiliations expand PMID: 32988873 DOI: 10.21873/anticanres.14562 Abstract Background/aim: Accumulating evidence shows that caspase-8 (Cas-8) rs3834129 genotypes determine susceptibility to various cancers, but their association with nasopharyngeal carcinoma (NPC) has not been examined. We aimed at investigating the association of Cas-8 rs3834129 with NPC risk. Materials and methods: Cas-8 rs3834129 genotypes and their associations with NPC risk were investigated among 176 NPC patients and 352 non-cancer subjects by the PCR-RFLP method. Additionally, the interaction of Cas-8 rs3834129 genotypes with smoking was examined. Results: The II, ID and DD frequencies were 56.8, 36.9 and 6.3% among NPC patients and 54.8, 38.1 and 7.1% among control subjects (ptrend=0.8830). Allelic frequency distribution analysis also indicated that the D allele is not a risk factor for NPC (p=0.6183). There was no interaction between Cas-8 rs3834129 and smoking and NPC risk (p=0.8305). Conclusion: Cas-8 rs3834129 genotypes play a minor role in the risk for NPC. Keywords: Case–control study; Taiwan; caspase-8; genotype; nasopharyngeal carcinoma; polymorphism. Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved. supplementary info MeSH terms, Substancesexpand full-text links full-text provider logo Proceed to details Cite Share 11 Review Anticancer Res 2020 Oct;40(10):5351-5354. doi: 10.21873/anticanres.14542. De-escalation of Axillary Surgery in the Neoadjuvant Chemotherapy (NACT) Setting for Breast Cancer: Is it Oncologically Safe? Umar Wazir 1, Kefah Mokbel 2 3 Affiliations expand PMID: 32988853 DOI: 10.21873/anticanres.14542 Erratum in Erratum. [No authors listed] Anticancer Res. 2020 Nov;40(11):6571. PMID: 33109599 No abstract available. Abstract Background/aim: The treatment of breast cancer has progressed considerably over the years, with a significant de-escalation from radical mastectomies to the current paradigm of breast conserving surgery (BCS) and neoadjuvant chemotherapy (NACT). We aimed to appraise the literature regarding the feasibility of de-escalation of treatment of axillary disease in the context of NACT. Materials and methods: We appraised studies and guidelines published regarding this topic and discussed them in this mini-review. Results and conclusion: The SNB following NACT is oncologically safe in patients with clinically node negative disease and in patients with biopsy proven axillary node involvement at presentation provided that the dual technique is used and the clipped pathological node is harvested. Keywords: Breast cancer; axillary disease; neo-adjuvant chemotherapy; review; sentinel node biopsy. Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved. supplementary info Publication types, MeSH termsexpand full-text links full-text provider logo Proceed to details Cite Share 12 Anticancer Res 2020 Oct;40(10):5557-5566. doi: 10.21873/anticanres.14568. Differential Expression of E-Cadherin and P-Cadherin in Breast Cancer Molecular Subtypes Madalin Marius Margan 1, Anca Maria Cimpean 2 3, Amalia Raluca Ceausu 4 3, Marius Raica 4 3 Affiliations expand PMID: 32988879 DOI: 10.21873/anticanres.14568 Abstract Background/aim: E- and P-cadherin (E-cadh, P-cadh) control tumor cell invasion, metastatic or stemness potential and chemotherapy resistance. The study aimed to assess E- and P-cadherin expression in breast cancer molecular subtypes. Materials and methods: Immunohistochemistry for E-cadh and P-cadh was performed for 97 breast cancer cases. Membrane (M), cytoplasmic (C) or mixed (MC) patterns of E-cadh and P-cadh were considered in our evaluation. Results: E-cadh and P-cadh C pattern was significantly correlated in the HER2 subtype (p=0.031). P-cadh M pattern was highly specific for the HER2 subtype (p=0.002). Only P-cadh C characterized the triple negative breast cancer subtype (p=0.015). For Luminal B/HER2 cases, P-cadh M pattern was strongly coexpressed with the E-cadh MC pattern (p=0.012). Progesterone receptor (PR) expression influenced E-cadh M pattern in the Luminal B/HER2 subtype (p=0.042). Conclusion: E- and P-cadherins define distinct subgroups within breast cancer molecular subtypes. Our findings support the inclusion of E- and P-cadherin into breast cancer molecular classification. Keywords: Breast cancer; E-cadherin; P-cadherin; molecular subtypes. Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved. supplementary info MeSH terms, Substancesexpand full-text links full-text provider logo Proceed to details Cite Share 13 Anticancer Res 2020 Nov;40(11):6017-6028. doi: 10.21873/anticanres.14623. WNT Signaling Driven by R-spondin 1 and LGR6 in High-grade Serous Ovarian Cancer Sanghoon Lee 1, John Jun 2, William J Kim 2, Pablo Tamayo 2, Stephen B Howell 3 Affiliations expand PMID: 33109540 DOI: 10.21873/anticanres.14623 Abstract Background/aim: R-spondins control WNT signaling and RSPO1 and LGR6, two of its receptors, are uniquely expressed at high levels in high-grade serous ovarian cancer (HGSOC). The aim of this study was to assess the interrelations between the expression of the RSPOs and LGRs in HGSOC and in the ovarian surface (OSE) and fallopian tube surface epithelium (FTSE) from which HGSOC arises. Materials and methods: Analysis of TCGA (HGSOC), CCLE (ovary), and other publicly accessed RNA-Seq data using UC San Diego Computational Cancer Analysis Library (CCAL) to perform differential expression analysis, association studies, and gene set inspection using the single-sample GSEA method. Additionally, we employed multiple publicly available databases including StringDB, Human Protein Atlas, and cBioPortal to aid the investigation. Results: Among normal tissues, expression of RSPO1, LGR5 and LGR6 was highest in the fallopian tube. The relative levels of expression of the RSPOs and LGRs in the OSE and FTSE matched those in HGSOC. RSPO1 and LGR6 were highly co-expressed in all three tissues. Gene set enrichment analysis (GSEA) showed that expression of RSPO1 was strongly linked to the enrichment of three separate WNT-driven GO pathways. Analysis of genes that impacted overall survival identified two other immediately adjacent genes that control WNT signaling, KREMEN1 and ZNRF3 whose expression and copy number were coordinately linked. Conclusion: RSPO1 and LGR6 are coordinately expressed in HGSOC and the two normal tissues from which this tumor arises, and their expression is linked to WNT signaling pathways known the control cell fate and proliferation. Keywords: R-spondin 1; ovarian cancer; spondins; wnt signaling. Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved. full-text links full-text provider logo Proceed to details Cite Share 14 Anticancer Res 2020 Oct;40(10):5577-5582. doi: 10.21873/anticanres.14570. A Novel System to Detect Circulating Tumor Cells Using Two Different Size-selective Microfilters Tomoaki Sonoda 1 2, Noriko Yanagitani 1, Kanako Suga 3, Takahiro Yoshizawa 1 4, Shingo Nishikawa 1 5, Satoru Kitazono 1, Atsushi Horiike 1 6, Kiyotaka Shiba 3, Tamotsu Ishizuka 2, Makoto Nishio 1, Satoshi Matsusaka 7 8 Affiliations expand PMID: 32988881 DOI: 10.21873/anticanres.14570 Abstract Background/aim: Clusters of circulating tumor cells (CTCs) increase metastatic potential compared to single CTC. However, conventional technologies have been unable to generate an accurate analysis of single and cluster CTCs in the peripheral blood. We propose an effective strategy to detect and isolate both single and cluster CTCs using two size-selective microfilters. Materials and methods: Five ml of whole blood were collected from 10 patients with epidermal growth factor receptor mutation-positive non-small cell lung cancer. Single and cluster CTCs were identified using precision microfiltration membranes with two distinct pore sizes together with anti-EpCAM antibody labeling. Results: Single and cluster CTCs were detected by simultaneously using two size-selective microfilters. The EGFR-L858R mutation was detected in the DNA from cells captured using both microfilters. Conclusion: Our method can be used to detect and isolate single and cluster CTCs in the whole blood and may facilitate the development of a liquid biopsy strategy. Keywords: Size-selective microfilters; circulating tumor cell; circulating tumor cell cluster; non-small cell lung cancer. Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved. supplementary info MeSH terms, Substancesexpand full-text links full-text provider logo Proceed to details Cite Share 15 Anticancer Res 2020 Oct;40(10):5457-5462. doi: 10.21873/anticanres.14556. The Interplay Between Innate Immunity (TLR-4) and sCD40L in the Context of an Animal Model of Colitis-associated Cancer Anastasios Angelou 1, Apostolos E Papalois 2 3, Efstathios Antoniou 1, Jaeyun Wang 4, Neda Amini 4, Anastasia Pikouli 5, Nikolaos Andreatos 4, Stefan Buettner 4, Muhammad Munir 4, Georgios Theodoropoulos 6, Georgios C Zografos 6, Panagiotis Sarantis 7, Alessandra Pulvirenti 8, Carsten Kamphues 9, Stamatios Theocharis 7, Emmanouil Pikoulis 5, Georgios Antonios Margonis 10 Affiliations expand PMID: 32988867 DOI: 10.21873/anticanres.14556 Abstract Background/aim: Several studies have found elevated soluble CD40 Ligand (sCD40L) in the serum of patients with malignancies as well as those with inflammatory bowel disease (IBD). Our goal was to determine the possible causal role of sCD40L in colitis-associated colorectal cancer (CAC) by using the well-established azoxymethane/dextran sulfate sodium (AOM/DSS) protocol. Materials and methods: Twelve wild type (WT) and twelve TLR4 knock out (KO) female C57BL6 mice were divided into 4 experimental groups. Six WT and six TLR4 KO mice were treated with a single intraperitoneal dose (10 mg/kg of body weight) of AOM followed by three 7-day cycles of oral 2.5% DSS. The other two groups included 6 WT and 6 TLR4 KO mice that received only water and served as the control groups. The mice were sacrificed after 84 days. Results: All mice in the AOM/DSS WT group developed CAC while all mice from the AOM/DSS TLR4 KO group were protected from CAC. We measured the serum and pathologic tissue levels of sCD40L with quantitative sandwich enzyme-linked immunoassay (ELISA) and found that serum sCD40L was significantly higher in wild-type mice that developed CAC compared to their healthy counterparts (wild-type and TLR-4 KO controls). In comparison, serum sCD40L levels were comparable between TLR-4 KO mice, which are protected from developing CAC, and their healthy counterparts (wild-type and TLR-4 KO controls). Of note, tissue levels of sCD40L were not affected by the development of CAC. Conclusion: Our findings point to the presence of an axis between TLR-4 and sCD40L, which may lead to decreased immunosurveillance and the subsequent development of colitis-associated cancer. Keywords: AOM/DSS; Colitis associated cancer; IBD; animal model; carcinogenesis; colorectal cancer. Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved. supplementary info MeSH terms, Substancesexpand full-text links full-text provider logo Proceed to details Cite Share 16 Anticancer Res 2020 Oct;40(10):5437-5443. doi: 10.21873/anticanres.14554. Expression and Clinical Significance of Neuropilin-1 in Patients With Multiple Myeloma Agnieszka Karczmarczyk 1, Sylwia Bilska 2, Maciej Korpysz 3, Joanna Purkot 1, Norbert GrzĄŚko 1 4, Marek Hus 2, Krzysztof Giannopoulos 5 4 Affiliations expand PMID: 32988865 DOI: 10.21873/anticanres.14554 Abstract Background: Neuropilin-1 (NRP1) is a receptor for vascular endothelial growth factor A (VEGFA), and has been reported to be overexpressed in several malignancies. Since angiogenesis plays an important role in pathogenesis of multiple myeloma (MM) and the role of NRP1 in MM has not been studied yet, we characterized the expression of NRP1 in this disease. Materials and methods: The expression level of NRP1 was measured in 140 patients newly diagnosed with MM and 28 healthy controls by flow cytometry and quantitative reverse transcriptase polymerase chain reaction. Results: Expression of NRP1 was significantly reduced on plasma cells (median=2.05%) compared to that on B-cells (median=10.05%, p<0.0001) in bone marrow of patients with MM. In MM, the expression of NRP1 was high on plasmacytoid dendritic cells (median=85.85%) and low on regulatory T-cells (median=0.6%). Conclusion: In MM, NRP1 is regulated differentially as compared to other B-cell malignancies at both the RNA and protein level. Keywords: Multiple myeloma; PDCs; Tregs; neuropilin-1. Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved. supplementary info MeSH terms, Substancesexpand full-text links full-text provider logo Proceed to details Cite Share 17 Anticancer Res 2020 Oct;40(10):5861-5868. doi: 10.21873/anticanres.14605. Bladder-conserving Approach in Radical Treatment of Patients With Bladder Cancer - A Single-institution Experience Wojciech Majewski 1, Jaroslaw Nieckula 2, Tomasz Dworzecki 3, Leszek Miszczyk 3 Affiliations expand PMID: 32988916 DOI: 10.21873/anticanres.14605 Abstract Aim: To evaluate our experience with radical radiotherapy and chemotherapy in patients with muscle-invasive bladder cancer. Patients and methods: The study consisted of 27 patients treated with cisplatin-based chemoradiation (CCRT), 48 treated with radiation alone (RT), and 42 with locally advanced disease treated with neoadjuvant chemotherapy and radiation (neoCRT). Results: The incidence of acute grade 3 or more genitourinary (GU) toxicity in the RT, CCRT and neoCRT groups was: 25%, 11% and 19%, respectively (p=0.029). The 3-year freedom from grade 2 or more GU toxicity was: 81%, 89%, 54%, respectively (p=0.36). The long-term outcomes of 3-year local control, overall survival, and disease-free survival were as follows: RT group: 74%, 61% and 55%; CCRT group: 76%, 76% and 56%; neoCRT group: 31%, 43% and 18%, respectively. Conclusion: The preferable bladder-conserving approach is CRT, however RT alone might also be an option for appropriately selected patients. NeoCRT for those with locally advanced tumors remain unsatisfactory; adequate selection of patients for radical treatment is of importance. Keywords: Bladder cancer; bladder sparing; chemoradiotherapy; neoadjuvant chemotherapy; radiotherapy. Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved. supplementary info MeSH terms, Substancesexpand full-text links full-text provider logo Proceed to details Cite Share 18 Anticancer Res 2020 Nov;40(11):6265-6271. doi: 10.21873/anticanres.14647. Synergistic Antiproliferative Effect of Ribociclib (LEE011) and 5-Fluorouracil on Human Colorectal Cancer Pai-Mei Lin 1 2, Hui-Ming Lee 3 4, Chung-I Huang 5, Tzong-Shyuan Tai 6, Jian-Han Chen 7 8 9, Chih-I Chen 1 4 9, Yu-Chieh Su 10 11 Affiliations expand PMID: 33109564 DOI: 10.21873/anticanres.14647 Abstract Background/aim: Colorectal cancer (CRC) is one of the most common malignant tumors in the world. This study aimed to investigate the anticancer effect of the combination treatment of Ribociclib (LEE011) and 5-Fluorouracil (5-FU) on CRC cells. Materials and methods: HT-29 and SW480 cells were treated with LEE011, 5-FU, or the combination of LEE011 and 5-FU. Cell viability and cycle were investigated through 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium assay and flow cytometry. The expression of cell cycle-related proteins was determined through western blot. Results: The combined treatment of LEE011 with 5-FU synergistically reduced cell viability in HT-29 and SW480 cells. Specifically, it induced cell cycle arrest at the G1 phase, down-regulated the phosphorylation of retinoblastoma protein and the expression of p53. Conclusion: LEE011 exhibited potential as an effective therapeutic inhibitor for the combination treatment of CRC patients. Keywords: 5-fluorouracil; Ribociclib; human colorectal cancer. Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved. full-text links full-text provider logo Proceed to details Cite Share 19 Review Anticancer Res 2020 Oct;40(10):5343-5349. doi: 10.21873/anticanres.14541. Systematic Review on the Controlling Nutritional Status (CONUT) Score in Patients Undergoing Esophagectomy for Esophageal Cancer Kosei Takagi 1 2, Stefan Buettner 3, Jan N M Ijzermans 3, Bas P L Wijnhoven 3 Affiliations expand PMID: 32988852 DOI: 10.21873/anticanres.14541 Abstract Background/aim: The present study aimed to examine the association of the controlling nutritional status (CONUT) score with outcomes in patients undergoing esophagectomy for esophageal cancer (EC). Materials and methods: A systematic literature review was carried out to investigate the impact of the CONUT score in EC. Next, meta-analysis of long-term outcomes was performed. Results: The search found six eligible retrospective studies, and five studies with 952 patients were included in the meta-analysis. Meta-analysis found a significant association of the CONUT score with outcomes including overall survival [hazard ratio (HR)=2.51, 95% confidence interval (CI)=1.75-3.60, p<0.001], cancer-specific survival (HR=2.60, 95%CI=1.53-4.41, p<0.001), and recurrence free survival (HR=2.08, 95%CI=1.39-3.12, p<0.001). Conclusion: The CONUT score may be an independent predictor associated with prognosis in patients undergoing esophagectomy for EC. However, further studies are needed to clarify the association of the CONUT score with postoperative outcomes in EC patients. Keywords: Controlling nutritional status score; esophageal cancer; esophagectomy; outcome; review. Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved. supplementary info Publication types, MeSH termsexpand full-text links full-text provider logo Proceed to details Cite Share 20 Anticancer Res 2020 Oct;40(10):5909-5917. doi: 10.21873/anticanres.14611. Incidence of CMV Replication and the Role of Letermovir Primary/Secondary Prophylaxis in the Early Phase After Allogeneic Hematopoietic Stem Cell Transplantation - A Single Centre Study Ursina Studer 1, Nina Khanna 2, Karoline Leuzinger 3 4, Hans H Hirsch 2 3 4, Dominik Heim 1, Claudia Lengerke 1, Dimitrios A Tsakiris 1, Joerg Halter 1, Sabine Gerull 1, Jakob Passweg 1, Michael Medinger 5 6, Malena Gwerder 1 Affiliations expand PMID: 32988922 DOI: 10.21873/anticanres.14611 Abstract Background/aim: Cytomegalovirus (CMV) replication may cause life-threatening complications after allogeneic haematopoietic stem cell transplantation (allo-HSCT). The aim of the study was to characterize CMV events, and the outcome of letermovir (LTV) CMV prophylaxis. Patients and methods: In this retrospective analysis of patients treated with an allo-HSCT between 2010 and 2020, we determined plasma CMV events, as well as associated risk factors. Results: We identified 423 patients who had undergone allo-HSCT between 2010 and 2020. CMV DNAemia was found in 130/423 (30.7%) of patients. CMV reactivation rate was significantly higher in patients with acute graft-versus-host disease, HLA mismatch, and CMV IgG seropositivity of donors and recipients. Among 42 patients receiving LTV prophylaxis those, 5 (11.9%) showed CMV DNAemia under LTV versus 87/353 (24.6%) in a control group. Conclusion: Despite the development of better approaches with weekly monitoring and early treatment initiation, CMV reactivations play an important role after allo-HSCT. Keywords: Cytomegalovirus; allogeneic hematopoietic stem cell transplantation; letermovir. Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved. supplementary info MeSH terms, Substancesexpand full-text links full-text provider logo Proceed to details Cite Share 21 Anticancer Res 2020 Oct;40(10):5417-5421. doi: 10.21873/anticanres.14551. Genomic Database Analysis for Head and Neck Cancer Prevention Targets: MTOR Signal Transduction Pathway Cynthia Koenigsberg 1, Frank G Ondrey 2 Affiliations expand PMID: 32988862 DOI: 10.21873/anticanres.14551 Abstract Background: Type II diabetes agents have anticancer effects on head and neck squamous cell carcinoma (HNSCC). The mechanistic target of rapamycin (MTOR) pathway represents a putative target. Materials and methods: We interrogated an Affymetrix HNSCC dataset for MTOR-related gene expression. Results: MTOR expression itself was unchanged, but various related genes demonstrated differential expression. Pathway promoters ras homolog (RHEB), MTOR-associated protein (MLST8), and ribosomal protein S6 kinase B1 (RPS6KB1) were up-regulated. Expression of growth suppressors tuberous sclerosis complex 2 (TSC2), programmed cell death 4 (PDCD4), and BCL2 apoptosis regulator-associated agonist of cell death (BAD) were reduced in HNSCC. Upstream, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), AKT serine/threonine kinase 1 (AKT1), and phosphatase and tensin homolog (PTEN) were up-regulated in cancer. Conclusion: Several MTOR pathway promoters and tumor suppressors were found to be differentially expressed, favoring MTOR pathway up-regulation in HNSCC. Genomic databases can be interrogated to identify intervention targets and endpoints in HNSCC trials. Keywords: MTOR; chemoprevention; head and neck squamous carcinoma. Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved. supplementary info MeSH terms, Substancesexpand full-text links full-text provider logo Proceed to details Cite Share 22 Anticancer Res 2020 Oct;40(10):5497-5502. doi: 10.21873/anticanres.14561. Differences in Linear Energy Transfer Affect Cell-killing and Radiosensitizing Effects of Spread-out Carbon-ion Beams Shintaro Shiba 1 2, Masaru Wakatsuki 3, Tatsuya Ohno 4, Takashi Nakano 1 Affiliations expand PMID: 32988872 DOI: 10.21873/anticanres.14561 Abstract Background/aim: The cell-killing and radiosensitizing effects of carbon-ion (C-ion) beams with low linear energy transfer (LET) are underexplored. We aimed to demonstrate the cell-killing effects of 60Co gamma rays and C-ion beams at various LET values and the radiosensitizing effect of C-ion beams at various LET and cisplatin levels. Materials and methods: Human uterine cervical cancer cells were irradiated with 60Co gamma rays and C-ion beams at different levels of LET, with and without cisplatin treatment. Results: Low-LET C-ion beams had a superior cell-killing effect compared to 60Co gamma rays. Survival curves under low-LET C-ion beams were more similar to that of 60Co gamma rays than that of high-LET C-ion beams. Cisplatin significantly reduced cell survival after 1, 2, and 3 Gy C-ion beam irradiations at LET values of 13/30/70 keV/μm, 13/30 keV/μm, and 13 keV/μm, respectively. Conclusion: Low-LET C-ion beams combined with cisplatin have higher radiosensitizing effects than high-LET C-ion beams. Keywords: Carbon-ion beams; HeLa cells; cell-killing effect; linear energy transfer; radiosensitizing effect. Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved. supplementary info MeSH terms, Substancesexpand full-text links full-text provider logo Proceed to details Cite Share 23 Anticancer Res 2020 Oct;40(10):5701-5706. doi: 10.21873/anticanres.14584. The Induction of Antioxidant Catalase Enzyme With Decrease of Plasma Malonidialdehyde: An Important Reactive Oxidative Species Inhibiting Mechanism Maiju Ruottinen 1, Viivi Kaaronen 1, Iina Saimanen 1, Viivi Kuosmanen 1, Jari KÄrkkÄinen 1, Tuomas Selander 2, Samuli Aspinen 1, Matti Eskelinen 3 Affiliations expand PMID: 32988895 DOI: 10.21873/anticanres.14584 Abstract Background/aim: The simultaneous increase of antioxidant CAT (catalase) enzyme and plasma MDA (malonidialdehyde) concentrations versus the numeric rating scale (NRS) pain score following surgery is unknown. Patients and Methods: The study included 114 patients with gallstone disease and 29 patients in the cancer group. Results: Following surgery, the plasma CAT concentrations increased and plasma MDA concentrations decreased in all patients and especially in cancer patients. The linear mixed model time-effect was statistically significant in CAT and MDA (p<0.001 and p=0.02, respectively). In addition, a significant correlation between NRS pain score values and plasma MDA median concentrations in cancer patients was identified (r=0.430, p<0.001). Conclusion: The plasma MDA concentrations decreased and CAT concentrations increased significantly in all patients and especially in cancer patients following surgery. The simultaneous increase of antioxidant CAT enzyme with the decrease of plasma MDA may be an important ROS inhibiting mechanism to help patients return to normal antioxidant-oxidant status. Keywords: Gallstone disease; NRS pain score; cancer; plasma CAT; plasma MDA; surgery. Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved. supplementary info MeSH terms, Substancesexpand full-text links full-text provider logo Proceed to details Cite Share 24 Anticancer Res 2020 Oct;40(10):5895-5899. doi: 10.21873/anticanres.14609. Prognostic Significance of Oligometastatic Disease Classification by the ESTRO/EORTC of Cancer for Patients With Lung Cancer Treated With Definitive Radical Radiotherapy Hung-Jen Chen 1 2, Chih-Yen Tu 1 2, Te-Chun Hsia 1 2 3, Hsin-Yuan Fang 2 4, Chia-Hung Chen 1 2, Shuo-Chueh Chen 1, Chia-Hsiang Li 1, Yu-Min Liao 5, Ching-Yun Hsieh 5, Ming-Yu Lein 2 5, Ji-An Liang 2 6, Chun-Ru Chien 7 6 8 Affiliations expand PMID: 32988920 DOI: 10.21873/anticanres.14609 Abstract Background: Randomized controlled trials had demonstrated local therapy, such as radiotherapy, can improve outcomes of patients with lung cancer with oligometastatic disease (OMD). However, the definition of OMD is not uniform and the European Society for Radiotherapy and Oncology (ESTRO) and European Organisation for Research and Treatment of Cancer (EORTC) proposed a new classification in 2020 comprising nine subtypes. Therefore, we aimed to investigate the prognostic significance of this European classification for patients with lung OMD treated with definitive radical radiotherapy. Patients and methods: We identified eligible patients via an in-house database. Patient, disease, and treatment characteristics, as well as outcomes, were obtained via chart review plus peer review. Overall and progression-free survival were estimated via the Kaplan-Meier method. Log-rank test was used in univariate analysis and Cox regression in multivariable analyses to investigate the prognostic significance of the subtypes of OMD. Results: We identified 35 eligible patients with six different OMD subtypes treated from 2011 to 2019. After a median follow-up of 23 (range=2-88) months, the median progression-free and overall survival were 11 and 38 months, respectively. The prognosis for patients with the subtype 'induced oligoprogression' was statistically worse than for those without in both univariate (p=0.02) and multivariate (adjusted hazard ratio for death=4.8, 95% confidence interval=1.4-16.2, p=0.01) analyses. Conclusion: We found the subtype with induced oligoprogression in the European classification to be associated with worse survival. Further studies are needed to confirm our finding. Keywords: EORTC; ESTRO; oligometastatic disease. Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved. supplementary info MeSH termsexpand full-text links full-text provider logo Proceed to details Cite Share 25 Anticancer Res 2020 Nov;40(11):6063-6073. doi: 10.21873/anticanres.14627. In Vitro Analyses of Interactions Between Colonic Myofibroblasts and Colorectal Cancer Cells for Anticancer Study Marahaini Musa 1, Djamila Ouaret 2, Walter F Bodmer 2 Affiliations expand PMID: 33109544 DOI: 10.21873/anticanres.14627 Abstract Background/aim: Interactions between colorectal cancer (CRC) cells and myofibroblasts govern many processes such as cell growth, migration, invasion and differentiation, and contribute to CRC progression. Robust experimental tests are needed to investigate the nature of these interactions for future anticancer studies. The purpose of the study was to design and validate in vitro assays for studying the communication between myofibroblasts and CRC epithelial cell lines. Materials and methods: The influence of co-culture of myofibroblasts and CRC cell lines is discussed using various in vitro assays including direct co-culture, transwell assays, Matrigel-based differentiation and cell invasion experiments. Results: The results from these in vitro assays clearly demonstrated various aspects of the crosstalk between myofibroblasts and CRC cell lines, which include cell growth, differentiation, migration and invasion. Conclusion: The reported in vitro assays provide a basis for investigating the factors that control the myofibroblast-epithelial cell interactions in CRC in vivo. Keywords: Neoplasms; colon; tumour heterogeneity; tumour microenvironment. Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved. full-text links full-text provider logo Proceed to details Cite Share 26 Clinical Trial Anticancer Res 2020 Oct;40(10):5687-5700. doi: 10.21873/anticanres.14583. Highly Activated Ex Vivo-expanded Natural Killer Cells in Patients With Solid Tumors in a Phase I/IIa Clinical Study Kazuhiro Nagai 1, Yui Harada 2, Hiroshi Harada 3, Katsunori Yanagihara 4, Yoshikazu Yonemitsu 2, Yasushi Miyazaki 3 5 Affiliations expand PMID: 32988894 DOI: 10.21873/anticanres.14583 Abstract Background: We previously developed a novel technique for expanding highly activated and purified natural killer (NK) cells able to maximize the theoretical activation potential of NK cells; thus, we named this cell population zenithal-NK (ZNK). Aim: To evaluate the safety, feasibility, and preliminary efficacy of autologous ZNK cells in patients with different types of advanced cancer with measurable solid lesions. Patients and methods: In this phase I/IIb first-in-human, open-label, dose-escalation study (trial registration ID: UMIN-000011555), eligible patients received ZNK cells intravenously starting from 106 to 108 cells/patient/dose at 2-week dosing intervals. A maximum of six cycles were allowed. Safety and survival analyses were also carried out for cases that were excluded and never administered ZNK cells. Results: As of April 20, 2017, a total of nine patients were enrolled in this study, with one recruited twice. Overall, neither grade 2 or higher toxicities (Common Terminology Criteria for Adverse Events v5.0) caused by cell administration, nor adverse events causing discontinuation of protocol treatment were found. In four cases, the number of administered ZNK cells was increased to 108 cells/body/dose without any serious dose-limiting toxicity; the maximally tolerated dose was therefore considered to be at least 108 cells. The overall response rate was 40.0% in 10 net cases, one of partial response and three of stable disease, and the patient with partial response is still alive after 4 year's observation. Conclusion: These results demonstrate that autologous ZNK cells are safe and well-tolerated in patients with different types of advanced solid tumors. Clinical studies using similarly active ZNK cells from human leukocyte antigen/killer cell immunoglobulin-like receptor-mismatched healthy donors under Good Manufacturing Practice-compliant manufacturing, and with modified treatment regimen, i.e. doses and frequencies, are warranted for further investigation to show the potential of ZNK cells in such patients. Keywords: Zenithal natural killer cells; cancer; immune cell therapy; phase I/IIa study. Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved. supplementary info Publication types, MeSH termsexpand full-text links full-text provider logo Proceed to details Cite Share 27 Anticancer Res 2020 Oct;40(10):5649-5657. doi: 10.21873/anticanres.14578. The Relationship of GATA3 and Ki-67 With Histopathological Prognostic Parameters, Locoregional Recurrence and Disease-free Survival in Invasive Ductal Carcinoma of the Breast Emine Yildirim 1, Sibel Bektas 2, Ozgecan Gundogar 3, Deniz Findik 4, Serap Alcicek 4, Kivilcim Orhun Erdogan 4, Mete Yildiz 5 Affiliations expand PMID: 32988889 DOI: 10.21873/anticanres.14578 Abstract Background: In recent years, GATA-binding protein 3 (GATA3) has been indicated as a marker showing good prognosis in breast cancer. In luminal breast cancer, which has good a prognosis, it shows more significant elevation in small-sized and low-grade tumors. In contrast, Ki-67 is defined as a poor prognostic factor. The aim of this study was to emphasise the prognostic importance of GATA3 and the inverse relationship with Ki-67. Materials and methods: In our study, 90 patients with invasive ductal breast cancer were immunohistochemically evaluated for Ki-67 and GATA3 expression. The relationship between GATA3 and Ki-67 expression was examined. In addition, the relationship between these two factors with estrogen, progesterone, human epidermal growth factor 2 receptor antibodies and other prognostic parameters such as disease-free survival and local recurrence was investigated. We accepted the level of ≥5% nüclear reaction as positive for GATA 3. A Ki-67 cut-off value of 20% was accepted as positive. Results: In GATA3 positive breast cancers, good prognostic parameters were seen including high estrogen receptor (ER) positivity, progesterone receptor (PR) positivity, small tumor size and low histological grade as well as low Ki-67 expression. In breast cancers showing high Ki-67 expression, ER, PR, and GATA3 positivity were lower and there was higher human epidermal growth factor receptor 2 (HER2) positivity and high histological grade while the tumor size was larger. Conclusion: Our study has revealed that GATA3 has an inverse relationship with Ki-67, whereas it has a positive releationship with good prognostic factors. Keywords: Breast cancer; GATA3; Ki-67; prognostic parameters. Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved. supplementary info MeSH terms, Substancesexpand full-text links full-text provider logo Proceed to details Cite Share 28 Clinical Trial Anticancer Res 2020 Oct;40(10):5883-5893. doi: 10.21873/anticanres.14608. Predictive Role of TP53, PIK3CA and MLL2 in ER+ HER2+ Breast Bancer: Biomarker Analysis of Neo-ALL-IN [NCT 01275859] Ji Hyun Park 1 2, Jin-Hee Ahn 1, Jeong Eun Kim 1, Kyung Hae Jung 1, Gyungyub Gong 3, Hee Jin Lee 3, Byung-Ho Son 4, Sei-Hyun Ahn 4, Hak-Hee Kim 5, Hee Jung Shin 5, Dae-Hyuk Moon 6, Deokhoon Kim 7, Sung-Bae Kim 8 Affiliations expand PMID: 32988919 DOI: 10.21873/anticanres.14608 Abstract Background/aim: Somatic mutations were investigated in 21 patients with postmenopausal estrogen receptor (ER)-positive and human epidermal growth factor receptor-2 (HER-2)-positive (ER+HER2+) breast cancer (BC) treated with neoadjuvant letrozole and lapatinib, to identify their distinct molecular landscape. Patients and methods: We used tissue samples of 21 patients from phase II Neo ALL-IN cohort, and somatic alterations were examined using targeted exome sequencing performed in Foundation Medicine, Inc. (FMI). Results: TP53 (61.9%) and PIK3CA (57.1%) were the two most frequently mutated genes that were inter-correlated (p=0.026). They were associated with unfavorable clinical outcomes, particularly when accompanying PIK3CA mutations at exon 9 in helical domains. Meanwhile, MLL2 alteration was negatively associated with mutations of TP53 or PIK3CA, and it tended to be present in patients with low KI-67 levels and no initial nodal involvement. Moreover, patients with MLL2 mutations numerically showed more favorable overall response rates (ORR) (80% vs. 56.2%) and better 5-year event-free survival (EFS) rates (100% vs. 87.5%) compared to the wild-type. Conclusion: Mutations in TP53 and PIK3CA hotspot at exon 9 may be potential negative predictors of ER+HER2+ BC treated with neoadjuvant letrozole and lapatinib, while MLL2 inactivating mutation might confer therapeutic benefit in these patients. Keywords: ER+/HER2+; MLL2; Neo-ALL-IN; PIK3CA; next-generation sequencing; triple-positive breast cancer. Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved. supplementary info Publication types, MeSH terms, Substancesexpand full-text links full-text provider logo Proceed to details Cite Share 29 Anticancer Res 2020 Oct;40(10):5539-5544. doi: 10.21873/anticanres.14566. Mxi-2 Dependent Regulation of p53 in Prostate Cancer Barbara KÖditz 1 2, Jochen W U Fries 2, Heike GÖbel 3, Pia Paffenholz 2, Konstantin Richter 2, Axel Heidenreich 2, Melanie VON Brandenstein 4 Affiliations expand PMID: 32988877 DOI: 10.21873/anticanres.14566 Abstract Background/aim: Endothelin-1 (ET-1) is overexpressed in many types of cancer, inhibiting the release of the microRNA 15a (miR-15a) and inducing the production of Mxi-2. Our aim was to identify a molecular complex regulating p53 activity in prostate cancer (PCa). Materials and methods: DU145 cells were treated with ET-1, MAPK p38 inhibitor, Endothelin A receptor inhibitor (ETAR inhibitor) and Endothelin B receptor inhibitor (ETBR inhibitor). Extracts were analysed using Western Blot, immunoprecipitation and qRT-PCR. Furthermore, prostate cancer patient samples were analysed using qRT-PCR and ELISA. Results: The hypothesised molecular complex was identified, with miR-15a, microRNA 1285 (miR-1285) and Mxi-2 levels up-regulated in patients in relation to increasing aggressiveness of PCa. Conclusion: A complex composed of Argonaut 2 (Ago2)/Mxi-2/miR-1285 is involved in PCa. The expression of Mxi-2 correlates with increasing PCa aggressiveness and might be used as a non-invasive marker for the diagnosis and progression of PCa. Keywords: Ago2; Endothelin-1; Mxi-2; Prostate cancer; p53. Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved. supplementary info MeSH terms, Substancesexpand full-text links full-text provider logo Proceed to details Cite Share 30 Anticancer Res 2020 Oct;40(10):5939-5947. doi: 10.21873/anticanres.14615. Oncological and Reproductive Outcomes of Abdominal Radical Trachelectomy A I Yoshino 1, Eiji Kobayashi 2, Michiko Kodama 1, Kae Hashimoto 1, Yutaka Ueda 1, Kenjiro Sawada 1, Takuji Tomimatsu 1, Tadashi Kimura 1 Affiliations expand PMID: 32988926 DOI: 10.21873/anticanres.14615 Abstract Background/Aim: There is an increasing demand for preserving the fertility of young women impacted with early-stage cervical cancer. The aim of this study is to evaluate the oncological and reproductive outcomes of abdominal radical trachelectomy (ART). Patients and Methods: We retrospectively reviewed patients with FIGO stageIA2-IB1 cervical cancer who underwent ART from 2007 to 2018. We also compared the oncological prognosis between the patients who underwent ART and radical hysterectomy (RH). Results: A total of 42 patients underwent ART. During median follow-up 62.5 months, there were 4 (9.5%) recurrences and 1 (2.4%) death. As for tumors ≤2 cm, the 5-year recurrence-free survival (RFS) rate and overall survival (OS) rate for patients who underwent ART was similar to those who underwent RH (89.8% vs. 92.7%, p=0.42 and 97.3% vs. 95.0%, p=0.44, respectively). Nineteen patients attempted to conceive and seven of them were successful. There was one case of a first-trimester miscar riage, two cases of preterm delivery, three cases of full-term delivery and one ongoing pregnancy. Conclusion: ART could be a feasible alternative to RH for patients with tumors ≤2 cm with comparable oncological outcome. Keywords: Abdominal radical trachelectomy; cervical cancer; fertility preservation; fertility-sparing; radical hysterectomy. Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved. supplementary info MeSH termsexpand full-text links full-text provider logo Proceed to details Cite Share 31 Review Anticancer Res 2020 Nov;40(11):5989-5994. doi: 10.21873/anticanres.14619. Potential for Treatment of Glioblastoma: New Aspects of Superparamagnetic Iron Oxide Nanoparticles Dana Marekova 1 2, Karolina Turnovcova 1, Tolga H Sursal 3, Chirag D Gandhi 3, Pavla Jendelova 4 2, Meena Jhanwar-Uniyal 5 Affiliations expand PMID: 33109536 DOI: 10.21873/anticanres.14619 Abstract Glioblastoma (GB) is a highly aggressive and infiltrative brain tumor characterized by poor outcomes and a high rate of recurrence despite maximal safe resection, chemotherapy, and radiation. Superparamagnetic iron oxide nanoparticles (SPIONs) are a novel tool that can be used for many applications including magnetic targeting, drug delivery, gene delivery, hyperthermia treatment, cell tracking, or multiple simultaneous functions. SPIONs are studied as a magnetic resonance imaging tumor contrast agent by targeting tumor cell proteins or tumor vasculature. Drug delivery to GB tumor has been targeted with SPIONs in murine models. In addition to targeting tumor cells for imaging or drug-delivery, SPION has also been shown to be effective at targeting for hyperthermia. Along with animal models, human trials have been conducted for a number of different modes of SPION utilization, with important findings and lessons for further preclinical and clinical experiments. SPIONs are opening up s everal new avenues for monitoring and treatment of GB tumors; here, we review the current research and a variety of possible clinical applications. Keywords: SPION; Superparamagnetic iron oxide nanoparticles; drug-delivery; glioblastoma; review. Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved. supplementary info Publication typesexpand full-text links full-text provider logo Proceed to details Cite Share 32 Anticancer Res 2020 Oct;40(10):5379-5391. doi: 10.21873/anticanres.14546. Toll-Iike Receptor-3 Activation Enhances Malignant Traits in Human Breast Cancer Cells Through Hypoxia-inducible Factor-1α Francesca Scatozza 1, Antonella D'Amore 1, Rosaria Anna Fontanella 1, Paola DE Cesaris 2, Francesco Marampon 3, Fabrizio Padula 1, Elio Ziparo 1, Anna Riccioli 4, Antonio Filippini 1 Affiliations expand PMID: 32988857 DOI: 10.21873/anticanres.14546 Abstract Background/aim: Hypoxia-inducible factor 1 (HIF1) inhibitors have been proposed as therapeutic agents for several tumor types. HIF1α is induced by hypoxia and by pathogens in normoxia through toll-like receptors (TLRs). The TLR3 activator polyinosinic:polycytidylic acid [poly(I:C)] induces apoptosis in various types of cancer but not in the most aggressive breast cancer cell lines. We hypothesized that the failure of TLR3 stimulation to induce apoptosis in these cells might be due to an elevated HIF1α level and this link might be exploited. Materials and methods: Poly(I:C)-induced signaling pathway and expression of HIF1α and HIF1α targets were studied in MDA MB-231 and MCF-7 breast cancer cell lines by western blot. Flow cytometry was used for apoptotic responses and vasculogenic mimicry as bioassay. Results: Poly(I:C) increased expression of HIF1α and its targets BCL2 apoptosis regulator and c-MYC. Moreover, using pharmacological or genetic HIF1 inhibition, reduction of poly(I:C)-induced expression of HIF1α was paralleled by lowering of c-MYC and increased sensitivity to poly(I:C)-induced apoptosis, demonstrating the crucial role of this factor. We provide the first evidence in breast cancer cells that TLR3 stimulation induces HIF1α-dependent vasculogenic mimicry. By using specific inhibitors, we identified a signaling cascade upstream of HIF1α induction. Conclusion: Combined treatment with poly(I:C) and HIF1 inhibitors deserves consideration as an effective strategy in breast cancer therapy. Keywords: HIF1 inhibitors; HIF1α; acriflavine; apoptosis; vasculogenic mimicry. Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved. supplementary info MeSH terms, Substancesexpand full-text links full-text provider logo Proceed to details Cite Share 33 Review Anticancer Res 2020 Oct;40(10):5329-5341. doi: 10.21873/anticanres.14540. The Development of Next-generation PBMC Humanized Mice for Preclinical Investigation of Cancer Immunotherapeutic Agents Y Maurice Morillon 2nd 1, Ariana Sabzevari 1, Jeffrey Schlom 2, John W Greiner 1 Affiliations expand PMID: 32988851 DOI: 10.21873/anticanres.14540 Abstract Investigation of the efficacy and mechanisms of human immuno-oncology agents has been hampered due to species-specific differences when utilizing preclinical mouse models. Peripheral blood mononuclear cell (PBMC) humanized mice provide a platform for investigating the modulation of the human immune-mediated antitumor response while circumventing the limitations of syngeneic model systems. Use of humanized mice has been stymied by model-specific limitations, some of which include the development of graft versus host disease, technical difficulty and cost associated with each humanized animal, and insufficient engraftment of some human immune subsets. Recent advances have addressed many of these limitations from which have emerged humanized models that are more clinically relevant. This review characterizes the expanded usage, advantages and limitations of humanized mice and provides insights into the development of the next generation of murine humanized models to further inform clini cal applications of cancer immunotherapeutic agents. Keywords: PBMCs; cancer; humanized mice; immuno-oncology; immunotherapy; review. Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved. supplementary info Publication types, MeSH terms, Substancesexpand full-text links full-text provider logo Proceed to details Cite Share 34 Anticancer Res 2020 Nov;40(11):6137-6150. doi: 10.21873/anticanres.14634. Heat Shock Protein 90 Inhibitors AUY922, BIIB021 and SNX5422 Induce Bim-mediated Death of Thyroid Carcinoma Cells Si Hyoung Kim 1, Yun Kyung Cho 1, Ji Hye Huh 1, Jun Goo Kang 1, Sung-Hee Ihm 1, Moon Gi Choi 1, Seong Jin Lee 2 Affiliations expand PMID: 33109551 DOI: 10.21873/anticanres.14634 Abstract Background/aim: Heat shock protein 90 (HSP90) controls maturation of oncogenic client proteins of cancer cells, and thus we studied the effect of HSP 90 inhibitors on cell survival and survival-related mediators in thyroid carcinoma cells. Materials and methods: Human TPC-1 and SW1736 thyroid carcinoma cells were utilized. Cell viability, cytotoxic activity and apoptosis were estimated using CCK-8 assay, cytotoxicity assay and FACS analysis, respectively. Results: AUY922, BIIB021 and SNX5422 decreased cell viability, and increased cytotoxic activity and the proportion of apoptotic cells. The protein levels of cleaved PARP, cleaved caspase-3, Bax and Bim were elevated, and Bcl2 protein levels were reduced. Knockdown of Bax did not change cell viability, cytotoxic activity, the proportion of apoptotic cells and cleaved caspase-3 protein levels. Meanwhile, knockdown of Bim enhanced cell viability, and diminished cytotoxic activity, the proportion of apoptotic cells and cleaved caspase-3 protein levels. AUY922, BIIB021 and SNX5422 increased the protein levels of phospho-AMPK, and decreased those of phospho-ERK1/2, and total and phospho-AKT. Conclusion: AUY922, BIIB021 and SNX5422 induce cytotoxicity by modulating Bim and ERK1/2, AKT and AMPK signaling in thyroid carcinoma cells. Keywords: AUY922; BIIB021; Bim; HSP90 inhibitor; SNX5422; Thyroid carcinoma. Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved. full-text links full-text provider logo Proceed to details Cite Share 35 Anticancer Res 2020 Oct;40(10):5583-5592. doi: 10.21873/anticanres.14571. A Psychometric Validation of the Decisional Conflict Scale in Italian Cancer Patients Scheduled for Insertion of Central Venous Access Devices Maria Rosaria Esposito 1, Assunta Guillari 2, Francesco Giancamilli 3, Teresa Rea 2, Michela Piredda 4, Maria Grazia DE Marinis 4, Andrea Chirico 3 5 Affiliations expand PMID: 32988882 DOI: 10.21873/anticanres.14571 Abstract Background/aim: In oncological settings, high-quality decision-making takes place when an adaptive pattern of cognitive and behavioural processes occurs, potentially limiting post-decisional regret and leading to an increment of adherence to the final decision. An example of a choice that requires a patient's involvement in the decision-making during cancer treatment occurs when the insertion of Central Vascular Access Device (CVAD) is proposed for chemotherapy administration. The aim of the current study was to develop and evaluate the psychometric properties of an Italian version of the Decisional Conflict Scale (DCS), including its factorial structure and its accuracy in discriminating the level of uncertainty in a sample of cancer patients during their decision-making process for the insertion of a CVAD for intravenous (IV) chemotherapy administration. Materials and methods: The study included 264 cancer patients with different diagnoses. To test the structural and psychometric properties of the Italian version of the DCS (DCS-ITA), exploratory factorial analysis was conducted followed by traditional classical test theory assessments of internal reliability and criterion validity. Results: The Italian version of the DCS (DCS-ITA) demonstrated good internal consistency, acceptable construct validity, which was tested with exploratory factorial analysis, and good criterion validity, demonstrated by the ability of the scale to differentiate between patients who declared themselves certain about their choice and patients expressing uncertainty about the choice to make. Conclusion: Overall, the results of the study showed that the DCS-ITA is a psychometrically sound instrument that easily discriminates between patients who are experiencing a decisional conflict and those who are not. The DCS-ITA can be used as a valid and easy-to-use tool for the screening of the decisional conflict in oncological settings. Keywords: Decisional conflict scale; central vascular access devices; psychometrics; validation study. Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved. supplementary info MeSH termsexpand full-text links full-text provider logo Proceed to details Cite Share 36 Anticancer Res 2020 Oct;40(10):5593-5600. doi: 10.21873/anticanres.14572. Prognostic Significance of TYRO3 Receptor Tyrosine Kinase Expression in Gastric Cancer Chihiro Uejima 1, Masaki Morimoto 2, Manabu Yamamoto 1, Kazushi Hara 1, Wataru Miyauchi 1, Ken Sugezawa 1, Yoichiro Tada 1, Akimitsu Tanio 1, Kyoichi Kihara 1, Tomoyuki Matsunaga 1, Naruo Tokuyasu 1, Teruhisa Sakamoto 1, Soichiro Honjo 1, Yoshihisa Umekita 3, Yoshiyuki Fujiwara 1 Affiliations expand PMID: 32988883 DOI: 10.21873/anticanres.14572 Abstract Background: Despite improved treatment for gastric cancer (GC), the prognosis of advanced disease remains poor. Further investigation of the oncogenic sequence for GC is needed. Materials and methods: The expression of TYRO3 protein tyrosine kinase in five GC cell lines was confirmed using western blotting. TYRO3 knockdown in GC cells, and bromodeoxyuridine and Transwell assays were used to examine the functions of TYRO3 in tumor proliferation and invasion. Finally, TYRO3 expression in 138 patients who underwent curative gastric resection for advanced GC (Union for International Cancer Control stage II/III) was tested by immunohistochemistry, and the association between prognosis and TYRO3 expression was analyzed. Results: TYRO3 was detected at various levels in all the tested GC cell lines. Deleting TYRO3 significantly suppressed proliferation and invasion. Immunohistochemistry revealed TYRO3 expression was an independent prognostic factor for overall survival in patients with GC. Conclusion: TYRO3 appears to mediate tumor progression and predict prognosis of patients with GC. Keywords: TAM; TYRO3; gastric cancer; prognostic factor. Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved. supplementary info MeSH terms, Substancesexpand full-text links full-text provider logo Proceed to details Cite Share 37 Anticancer Res 2020 Oct;40(10):5361-5369. doi: 10.21873/anticanres.14544. Activation of Toll-Like Receptor 2 Promotes Proliferation of Human Lung Adenocarcinoma Cells Anna K Gergen 1, Patrick D Kohtz 2, Alison L Halpern 2, Anqi Li 2, Xianzhong Meng 2, T Brett Reece 2, David A Fullerton 2, Michael J Weyant 2 Affiliations expand PMID: 32988855 DOI: 10.21873/anticanres.14544 Abstract Background/aim: The aim of this study was to evaluate the role of toll-like receptor 2 (TLR2) in the proliferation of human lung cancer cells and identify the signaling pathway that mediates this effect. Materials and methods: Adenocarcinoma (A549 and H1650) and adenosquamous (H125) cells were treated with increasing doses of Pam3CSK4, a TLR2 agonist. Cell proliferation and NF-ĸB activation were evaluated. NF-ĸB was inhibited prior to treatment with Pam3CSK4 and proliferation was assessed. Results: TLR2 expression was significantly higher in A549 and H1650 cells compared to H125 cells (p<0.001). TLR2 stimulation induced proliferation in adenocarcinoma cells only and led to a corresponding increase in NF-ĸB activity (p<0.05). Inhibition of NF-ĸB prior to treatment with Pam3CSK4 attenuated this proliferative response. Conclusion: TLR2 activation induced proliferation of lung adenocarcinoma cells through activation of NF-ĸB. Thus, the TLR2 signaling pathway may be a potential therapeutic target in lung adenocarcinoma. Keywords: Lung cancer; lung adenocarcinoma; non-small cell lung cancer; nuclear factor-kappa B; proliferation; toll-like receptor 2. Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved. supplementary info MeSH terms, Substancesexpand full-text links full-text provider logo Proceed to details Cite Share 38 Anticancer Res 2020 Oct;40(10):5777-5785. doi: 10.21873/anticanres.14594. Expression of Insulin-like Growth Factor II mRNA-binding Protein 3 in Gallbladder Carcinoma Sung Joo Kim 1, So-Woon Kim 2, Chi Hyuck Oh 3, Mikyoung Hong 4, Sung-Im DO 5, Youn Wha Kim 2, Hyun-Soo Kim 6, Kiyong Na 7 Affiliations expand PMID: 32988905 DOI: 10.21873/anticanres.14594 Abstract Background/aim: Emerging evidence suggests that Insulin-like growth factor II mRNA-binding protein 3 (IMP3) promotes tumor progression in several human malignancies. We investigated whether IMP3 expression has clinicopathological and prognostic significance in gallbladder adenocarcinoma (GBAC). Patients and methods: We examined immunohistochemical IMP3 expression in 204 GBACs and its associations with clinicopathological parameters and patient outcomes. Results: The majority (87.7%) of GBACs exhibited at least focal cytoplasmic and membranous IMP3 immunoreactivity. Tumor-specific IMP3 expression highlighted proper muscle invasion, which was not detected in the corresponding hematoxylin and eosin-stained slides. This finding upgraded pathological tumor stage (pT) from pT1a to pT1b in four well-differentiated GBACs. High IMP3 expression was associated with high histological grade, advanced stage, and lymphatic invasion, as well as worse overall survival. Conclusion: Tumor-specific IMP3 expression in GBAC is helpful in determining the tumor extent, especially in well-differentiated tumors. High IMP3 expression reflects aggressive oncogenic behavior of GBAC. IMP3 expression may be used as a diagnostic and prognostic marker in GBAC. Keywords: Gallbladder; IMP3; carcinoma; immunohistochemistry; prognosis. Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved. supplementary info MeSH terms, Substancesexpand full-text links full-text provider logo Proceed to details Cite Share 39 Anticancer Res 2020 Oct;40(10):5925-5932. doi: 10.21873/anticanres.14613. Characterization of Paired Box 8 (PAX8)-expressing Metastatic Breast Carcinoma So-Woon Kim 1, Hyun-Soo Kim 2, Kiyong Na 3 Affiliations expand PMID: 32988924 DOI: 10.21873/anticanres.14613 Abstract Background/aim: Paired box 8 (PAX8) is an organ-specific marker discriminating Müllerian and breast carcinomas. Recent studies have described PAX8 expression in a small subset of breast carcinomas, which may cause a diagnostic pitfall in the determination of cancer origin. The aim of this study was to investigate characteristics of PAX8-expressing metastatic breast carcinomas (MBCs) to help elucidate the primary site of occurrence. Patients and methods: Using immunohistochemistry, we examined PAX8 status in 80 MBCs and 52 matched primary breast carcinomas (PBCs). Results: A total of 20% of MBCs displayed PAX8 expression and the concordance rate of PAX8 expression between MBCs and PBCs was 92.3%. In MBCs, PAX8 expression was significantly associated with high-grade features (p=0.042), estrogen and progesterone receptor negativities (p=0.005 and p=0.017, respectively). Conclusion: PAX8 may be identified in MBCs with high-grade and non-luminal molecular subtypes. Careful assessment is needed when designating a primary site relying principally on PAX8 positivity. Keywords: Breast cancer; PAX8; immunohistochemistry. Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved. supplementary info MeSH terms, Substancesexpand full-text links full-text provider logo Proceed to details Cite Share 40 Anticancer Res 2020 Nov;40(11):6205-6212. doi: 10.21873/anticanres.14640. Protherapeutic Effects and Inactivation of Mammary Carcinoma Cells by a Medical Argon Plasma Device Matthias B Stope 1, Rim Benouahi 2, Caroline Sander 2, Lyubomir Haralambiev 2 3, Andreas Nitsch 2, Eva Egger 4, Alexander Mustea 4 Affiliations expand PMID: 33109557 DOI: 10.21873/anticanres.14640 Abstract Background/aim: Mammary carcinoma (MC) remains one of the leading causes of morbidity and mortality in the female population worldwide. Cold physical plasma at atmospheric pressure (CAP) has an antioncogenic effect on tumor cells, and its anticancer properties may complement or even extend existing treatment options. In the present study, the efficacy of CAP was characterized on an MC in vitro cell culture system. Materials and methods: MC cells (MCF-7, MDA-MB-231) were directly treated with CAP or incubated with CAP-treated cell culture medium. Cell growth, cell mobility and apoptosis were subsequently analyzed. Results: A single treatment of MC cells with CAP and CAP treated medium led to a treatment-time dependent reduction of cell growth. Furthermore, CAP exposure led to a loss of cellular motility and induced apoptosis. Conclusion: Due to its anticancer properties, CAP treatment is an innovative and promising physical approach to expand and complement the treatment options for MC. In particular, a combination of CAP application with surgical and/or chemotherapeutic interventions might significantly improve the therapeutic outcomes. Keywords: Plasma oncology; cold atmospheric plasma; mammary carcinoma; physical therapy; plasma surgery. Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved. full-text links full-text provider logo Proceed to details Cite Share 41 Anticancer Res 2020 Oct;40(10):5517-5527. doi: 10.21873/anticanres.14564. Azidothymidine (AZT) Inhibits Proliferation of Human Ovarian Cancer Cells by Regulating Cell Cycle Progression Yeunting Hsieh 1, Jenn-Jhy Tseng 2 Affiliations expand PMID: 32988875 DOI: 10.21873/anticanres.14564 Abstract Background/aim: Drug resistance is a significant cause of high mortality in ovarian cancer (OC) patients. The reverse transcriptase inhibitor azidothymidine (AZT) has been utilized as a treatment for tumors, but its role in OC treatment has not been revealed. The aim of the present in vitro study was to examine the influence of AZT on the growth of human OC cells and the involved proteins. Materials and methods: The proliferation, cell cycle distribution, extent of apoptosis, mitotic index, and terminal restriction fragment length were examined in three OC cell lines, CaOV3, TOV112D, and TOV21G, treated with AZT. Results: AZT inhibited growth of the TOV21G and CaOV3 cell lines by regulating cell cycle distribution. Specifically, AZT caused G2/M phase arrest on TOV21G cells and S phase arrest on CaOV3 cells. In addition, AZT treatment induced up-regulation of p21 and p16 in the TOV21G and CaOV3 cell line, respectively. Conclusion: AZT inhibited cell proliferation in serous and clear cell OC via the regulation of cell cycle distribution. Keywords: AZT; cell cycle arrest; chemotherapy; ovarian cancer; p16; p21. Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved. supplementary info MeSH terms, Substancesexpand full-text links full-text provider logo Proceed to details Cite Share 42 Anticancer Res 2020 Nov;40(11):6285-6293. doi: 10.21873/anticanres.14649. Overexpression of Pyruvate Carboxylase Is Correlated With Colorectal Cancer Progression and Supports Growth of Invasive Colon Cancer HT-29 Cell Line Jarunya Ngamkham 1, Chanitra Thuwajit 2, Peti Thuwajit 2, Peerapat Khamwachirapithak 3, Kornkamon Lertsuwan 3, Varodom Charoensawan 3 4 5, Sarawut Jitrapakdee 6 Affiliations expand PMID: 33109566 DOI: 10.21873/anticanres.14649 Abstract Background/aim: Pyruvate carboxylase (PC) is a major anaplerotic enzyme for generating oxaloacetate for the TCA cycle and also a key enzyme in gluconeogenesis, de novo fatty acid and amino acid synthesis in normal cells. Recent studies have identified PC overexpression in different cancers, such as breast and lung. However, the involvement of PC in colorectal cancer (CRC) is unclear. Our purpose was to investigate the PC expression levels and its correlations with potentially relevant clinical-pathological parameters in CRC. Materials and methods: PC expression levels in tissues from 60 Thai CRC patients were investigated by immunohistochemistry while a clonogenic assay was performed for determining cell growth of HT-29 cells with PC knockdown. Results: Our results showed for the first time that high PC expression levels were significantly correlated with late stage of the cancer, perineural invasion and lymph node metastasis. The overexpression of PC was also significantly associated with poor overall and disease-free survival times of CRC patients. In addition, suppression of cancer cell growth was found in PC-deficient cell lines using CRISPR-Cas9. Conclusion: The overexpression levels of PC were correlated with CRC progression and survival times. Therefore, PC might serve as a potential clinical prognostic marker for colorectal cancer. Keywords: Pyruvate carboxylase; anaplerotic enzyme; colorectal cancer. Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved. full-text links full-text provider logo Proceed to details Cite Share 43 Anticancer Res 2020 Oct;40(10):5471-5480. doi: 10.21873/anticanres.14558. MDA-MB-157 Cell Line Presents High Levels of MAD2L2 and Dysregulated Mitosis Nomi Pernicone 1, Limor Peretz 1, Shira Grinshpon 1, Tamar Listovsky 2 3 4 Affiliations expand PMID: 32988869 DOI: 10.21873/anticanres.14558 Abstract Background/aim: Accurate regulation of the spindle assembly checkpoint (SAC) and anaphase promoting complex/cyclosome (APC/C) are essential for the correct execution of mitosis. In this work, we focused on MAD2L2 (REV7), a central translesion (TLS) protein, which also functions as a mitotic regulator by inhibiting APC/C in prometaphase. Materials and methods: Using bioinformatics analysis, live cell imaging and APC/C protein binding and degradation assays, we explored the influence of MAD2L2 over-expression in breast cancer. Results: A significant over-expression of MAD2L2 was found in triple negative breast cancers (TNBC), compared to other breast cancers, correlating to poor patient prognosis. We also identified significant over-expression of MAD2L2 in the MDA-MB-157 triple negative (TN) cell line. A high percentage of MDA-MB-157 cells failed to complete mitosis and died during mitosis or shortly after. In addition, these cells completed mitosis at a significantly slower rate than control cells. MDA-MB-157 cells present high levels of mitotic slippage upon nocodazole treatment and acute dysregulation in APC/C function and substrate degradation. Moreover, silencing of MAD2L2 in the MDA-MB-157 cell line improved mitotic phenotypes. Conclusion: MAD2L2 over-expression supports the carcinogenic phenotype of MDA-MB-157 cells by promoting uncontrolled mitosis. Keywords: APC/C; MAD2L2; TNBC. Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved. supplementary info MeSH terms, Substancesexpand full-text links full-text provider logo Proceed to details Cite Share 44 Anticancer Res 2020 Oct;40(10):5853-5860. doi: 10.21873/anticanres.14604. Upfront Radiotherapy in Patients With Asymptomatic Incurable Rectal Cancer: A Retrospective Cohort Study Gabriel Jonsson 1, Louise Philipson 2, Kenneth Villman 3, Antonis Valachis 4 Affiliations expand PMID: 32988915 DOI: 10.21873/anticanres.14604 Abstract Background/aim: The optimal treatment sequencing for asymptomatic de novo metastatic rectal cancer is unclear. The aim of this study was to investigate the role of upfront radiotherapy, with or without chemotherapy on risk for local complications, in patients with asymptomatic advanced metastatic rectal cancer treated with palliative intention. Patients and methods: All patients with de novo metastatic rectal cancer diagnosed between January 2008 and December 2017 in two healthcare regions in Sweden (Örebro län, Sörmland) were identified and data were extracted from electronic medical records. Patients were divided into 3 groups based on treatment sequence: upfront radiotherapy, upfront chemotherapy, and only palliative surgery. Results: In total, 102 patients were included in the study cohort, 30 patients in upfront radiotherapy group, 54 in upfront chemotherapy, and 18 in only palliative surgery group. Patients with only upfront CT [odds ratio (OR)= 5.10; 95% confidence interval (CI)=1.24-20.91, p=0.024] had a higher risk to suffer from a local complication compared to those who received upfront radiotherapy. Cause-specific Cox regression analysis among patients who received oncological therapy revealed that female patients [cause-specific hazard ratio (csHR)=3.61; 95% confidence interval (CI)=1.67-7.81] and upfront chemotherapy [csHR=1.85; 95% CI=1.11-3.77] were associated with increased cumulative incidence of local complication over time, whereas primary surgery with ostomy or stent with lower risk [csHR=0.45; 95% CI=0.21-0.99]. Conclusion: Patients who received upfront radiotherapy, with or without chemotherapy, had fewer local complications due to primary tumor compared to patients who only received chemotherapy. This could indicate that radiotherapy to the primary tumor could be discussed with the patients as a first treatment option for asymptomatic metastatic rectal cancer to prevent local complications later during the disease. Keywords: Stage IV rectal cancer; chemotherapy; local complication; radiotherapy. Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved. supplementary info MeSH termsexpand full-text links full-text provider logo Proceed to details Cite Share 45 Published Erratum Anticancer Res 2020 Nov;40(11):6571. Erratum No authors listed PMID: 33109599 No abstract available Erratum for De-escalation of Axillary Surgery in the Neoadjuvant Chemotherapy (NACT) Setting for Breast Cancer: Is it Oncologically Safe? Wazir U, Mokbel K. Anticancer Res. 2020 Oct;40(10):5351-5354. doi: 10.21873/anticanres.14542. PMID: 32988853 Review. supplementary info Publication typesexpand full-text links full-text provider logo Proceed to details Cite Share 46 Published Erratum Anticancer Res 2020 Oct;40(10):5949. Erratum No authors listed PMID: 32988927 No abstract available Erratum for Double-negative T Cells Inhibit Proliferation and Invasion of Human Pancreatic Cancer Cells in Co-culture. Lu Y, Hu P, Zhou H, Yang Z, Sun YU, Hoffman RM, Chen J. Anticancer Res. 2019 Nov;39(11):5911-5918. doi: 10.21873/anticanres.13795. PMID: 31704815 supplementary info Publication typesexpand full-text links full-text provider logo Proceed to details Cite Share 47 Anticancer Res 2020 Oct;40(10):5611-5620. doi: 10.21873/anticanres.14574. Role of PrP C in Cancer Stem Cell Characteristics and Drug Resistance in Colon Cancer Cells Gyeongyun Go 1, Chul Won Yun 2, Yeo Min Yoon 2, Ji Ho Lim 2, Jun Hee Lee 1 3 4, Sang Hun Lee 5 2 Affiliations expand PMID: 32988885 DOI: 10.21873/anticanres.14574 Abstract Background/aim: Cancer stem cell characteristics and drug resistance of colorectal cancer are associated with failure of cancer treatment. In this study, we investigated the effects of PrPC on cancer stem cell characteristics, migration, invasion, and drug resistance of 5FU-resistant CRC cells. Materials and methods: PrPC negative and PrPC positive cells were isolated from 5FU-resistant CRC cells using magnetic activated cell sorting. Sphere formation, cancer stem cell marker expression, migration, invasion, and drug resistance were analyzed. Results: PrPC positive cells showed increased sphere formation capacity and increased expression of cancer stem cell markers compared to PrPC negative cells. In addition, PrPC positive cells showed increased migration, invasion and drug resistance compared to PrPC negative cells. Furthermore, knockdown of PrPC abolished these effects. Conclusion: PrPC expression is important in CRC cell behavior, such as sphere formation, migration, invasion, and drug resistance. PrPC is an important therapeutic target for the treatment of CRC. Keywords: PrPC; Prion protein; anti-cancer drug resistance; cancer stem cell characteristics; colorectal cancer. Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved. supplementary info MeSH terms, Substancesexpand full-text links full-text provider logo Proceed to details Cite Share 48 Anticancer Res 2020 Nov;40(11):6443-6456. doi: 10.21873/anticanres.14666. Longitudinal Changes in Health-related Quality of Life After 125 I Low-dose-rate Brachytherapy for Localized Prostate Cancer Naoyuki Ogasawara 1 2, Makoto Nakiri 3, Hirofumi Kurose 3, Kosuke Ueda 3, Katsuaki Chikui 3, Kiyoaki Nishihara 3, Mitsunori Matsuo 3, Shigetaka Suekane 3, Kenta Murotani 4, Koichiro Muraki 5, Chikayuki Hattori 5, Etsuyo Ogo 5, Tukasa Igawa 3, Tatsuya Ishitake 2 Affiliations expand PMID: 33109583 DOI: 10.21873/anticanres.14666 Abstract Background/aim: The factors associated with longitudinal changes in health-related quality of life (HRQOL) are unclear. In this study we aimed to evaluate the longitudinal changes and predictors of HRQOL after 125I low-dose-rate brachytherapy (LDB) for localised prostate cancer (PCA). Patients and methods: We evaluated 180 patients with localised PCA treated with LDB. The HRQOL was evaluated at 3 weeks before LDB and at 1, 3, 6, 12, 18, 24, 36, and 48 months after LDB using the International Prostate Symptom Score, Medical Outcome Study 8-Items Short Form Health Survey (SF-8), and University of California Los Angeles Prostate Cancer Index (UCLA-PCI). Results: All HRQOL scores, except for UCLA-PCI sexual function and SF-8 mental component summary (MCS), were improved to baseline after an early transient deterioration. In contrast, the sexual function did not return to baseline after early deterioration. Meanwhile, the MCS scores showed no significant decline after implantation and trended upward. The prostate V100 and baseline UCLA-PCI sexual function scores predicted a clinically significant decrease in sexual function in the late post-implantation period. Conclusion: Most aspects of the HRQOL of PCA patients who underwent LDB improved to baseline. The results that V100 and baseline sexual function were predictors of late post-LDB may provide more accurate information for patients with preserved sexual function before treatment and for their partners. Keywords: Prostate cancer; brachytherapy; health-related quality of life. Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved. full-text links full-text provider logo Proceed to details Cite Share 49 Anticancer Res 2020 Oct;40(10):5807-5813. doi: 10.21873/anticanres.14598. Is it Necessary to Confirm Negative Margins in Gastrectomy for Peritoneal Lavage Cytology-positive Gastric Cancer? Shunji Endo 1, Yoshinori Fujiwara 2, Tomoki Yamatsuji 3, Kazuhiro Nishikawa 4, Kazumasa Fujitani 5, Masakazu Ikenaga 6, Junji Kawada 7, Yuko Okamoto 2, Hisako Kubota 2, Masaharu Higashida 2, Tomio Ueno 2 Affiliations expand PMID: 32988909 DOI: 10.21873/anticanres.14598 Abstract Background/aim: The survival benefit of negative resection margins in patients who undergo gastrectomy with positive peritoneal lavage cytology (CY1) is unknown. Patients and methods: We reviewed the medical records of 128 patients with CY1 but no other distant metastases who had undergone R1 gastrectomy, 21 of whom had positive margins. We compared overall survival (OS) according to margin status. Results: The positive-margin group had poorer performance status scores (p=0.02), higher number of patients had undergone limited lymphadenectomy (p=0.01), had type 4 tumors (p=0.01), and undifferentiated type (p=0.02). Median OS was 19.0 and 16.9 months in the groups with negative and positive margins, respectively (HR=1.26, 95%CI=0.75-2.12, p=0.39). An inverse probability of treatment weighted analysis showed an OS of 13.1 and 11.9 months for the groups with negative and positive margins, respectively (HR=0.83, 95%CI=0.43-1.63, p=0.59). Conclusion: The prognoses of patients with CY1 and negative or positive margins may be equivalent. Keywords: Cell biology; margins of excision; stomach neoplasms. Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved. supplementary info MeSH termsexpand full-text links full-text provider logo Proceed to details Cite Share 50 Anticancer Res 2020 Oct;40(10):5567-5575. doi: 10.21873/anticanres.14569. Relationship Between Stage-specific Embryonic Antigen-4 and Anti-cancer Effects of Neoadjuvant Hormonal Therapy in Prostate Cancer Tsutomu Yuno 1, Yasuyoshi Miyata 2, Tomohiro Matsuo 1, Yuta Mukae 1, Asato Otsubo 1, Kensuke Mistunari 1, Kojiro Ohba 1, Tetsuji Suda 3, Seiichi Saito 3, Hideki Sakai 1 Affiliations expand PMID: 32988880 DOI: 10.21873/anticanres.14569 Abstract Background/aim: Stage-specific embryonic antigen-4 (SSEA-4) expression is associated with malignant aggressiveness and is useful as a marker for identifying cancer stem cells. Our aim was to assess the relationship between hormonal therapy and SSEA-4 expression in prostate cancer (PC). Materials and methods: SSEA-4 expression in paired specimens from PC patients who underwent neoadjuvant hormonal therapy (NHT) and radical prostatectomy (60 pre-NHT specimens and 60 post-NHT specimens) was evaluated using immunohistochemistry. Proliferation index (PI) and apoptotic index (AI) were also evaluated. Results: Post-NHT tissues had significantly elevated SSEA-4 expression whereas anti-tumor effects of NHT were inversely correlated with SSEA-4 expression level. SSEA-4 expression in post-NHT tissues was significantly associated with biochemical recurrence-free survival. SSEA-4 expression in the post-NHT tissues was positively associated with PI and negatively done with AI. Conclusion: SSEA-4 is a potential therapeutic target for limiting the malignant potential in hormone-naïve PC when considering the use of NHT. Keywords: SSEA-4; biochemical recurrence; histological effect; neoadjuvant hormonal therapy; prostate cancer. Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved. supplementary info MeSH terms, Substancesexpand full-text links full-text provider logo Proceed to details Cite Share "Anticancer Res"[jour]; +67 new citations Via anticancer res 67 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results: "Anticancer Res"[jour] These pubmed results were generated on 2020/10/29 PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.