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  • Dantrolene Attenuates Cardiotoxicity of Doxorubicin Without Reducing its Antitumor Efficacy in a Breast Cancer Model
    Transl. Oncol. (IF 3.138) Pub Date : 2020-01-07
    Valentina K. Todorova; Eric R. Siegel; Yihong Kaufmann; Asangi Kumarapeli; Aaron Owen; Jeanne Y. Wei; Issam Makhoul; V. Suzanne Klimberg

    Dysregulation of calcium homeostasis is a major mechanism of doxorubicin (DOX)-induced cardiotoxicity. Treatment with DOX causes activation of sarcoplasmic reticulum (SR) ryanodine receptor (RYR) and rapid release of Ca2+ in the cytoplasm resulting in depression of myocardial function. The aim of this study was to examine the effect of dantrolene (DNT) a RYR blocker on both the cardiotoxicity and antitumor activity of DOX in a rat model of breast cancer. Female F344 rats with implanted MAT B III breast cancer cells were randomized to receive intraperitoneal DOX twice per week (12 mg/kg total dose), 5 mg/kg/day oral DNT or a combination of DOX + DNT for 3 weeks. Echocardiography and blood troponin I levels were used to measure myocardial injury. Hearts and tumors were evaluated for histopathological alterations. Blood glutathione was assessed as a measure of oxidative stress. The results showed that DNT improved DOX-induced alterations in the echocardiographic parameters by 50%. Histopathologic analysis of hearts showed reduced DOX induced cardiotoxicity in the group treated with DOX + DNT as shown by reduced interstitial edema, cytoplasmic vacuolization, and myofibrillar disruption, compared with DOX-only–treated hearts. Rats treated with DNT lost less body weight, had higher blood GSH levels and lower troponin I levels than DOX-treated rats. These data indicate that DNT is able to provide protection against DOX cardiotoxicity without reducing its antitumor activity. Further studies are needed to determine the optimal dosing of DNT and DOX in a tumor-bearing host.

  • Downregulation of CXXC Finger Protein 4 Leads to a Tamoxifen-resistant Phenotype in Breast Cancer Cells Through Activation of the Wnt/β-catenin Pathway
    Transl. Oncol. (IF 3.138) Pub Date : 2020-01-03
    Yijie Fu; Zhu Wang; Chuanxu Luo; Yu Wang; Yanping Wang; Xiaorong Zhong; Hong Zheng

    Tamoxifen is a successful endocrine therapy drug for estrogen receptor–positive (ER+) breast cancer. However, resistance to tamoxifen compromises the efficacy of endocrine treatment. In the present study, we identified potential tamoxifen resistance–related gene markers and investigated their mechanistic details. First, we established two ER + breast cancer cell lines resistant to tamoxifen, named MCF-7/TMR and BT474/TMR. Gene expression profiling showed that CXXC finger protein 4 (CXXC4) expression is lower in MCF-7/TMR cells than in MCF-7 cells. Furthermore, CXXC4 mRNA and protein expression are lower in the resistant cell lines than in the corresponding parental cell lines. We also investigated the correlation between CXXC4 and endocrine resistance in ER + breast cancer cells. CXXC4 knockdown accelerates cell proliferation in vitro and in vivo and renders breast cancer cells insensitive to tamoxifen, whereas CXXC4 overexpression inhibits cancer cell growth and increases tamoxifen sensitivity of resistant cells. In addition, we demonstrated that CXXC4 inhibits Wnt/β-catenin signaling in cancer cells by modulating the phosphorylation of GSK-3β, influencing the integrity of the β-catenin degradation complex. Silencing the CXXC4 gene upregulates expression of cyclinD1 and c-myc (the downstream targets of Wnt signaling) and promotes cell cycle progression. Conversely, ectopic expression of CXXC4 downregulates the expression of these proteins and arrests the cell cycle in the G0/G1 phase. Finally, the small-molecule inhibitor XAV939 suppresses Wnt signaling and sensitizes resistant cells to tamoxifen. These results indicate that components of Wnt pathway that are early in response to tamoxifen could be involved as an intrinsic factor of the transition to endocrine resistance, and inhibition of Wnt signaling may be an effective therapeutic strategy to overcome tamoxifen resistance.

  • VCAM-1 Upregulation Contributes to Insensitivity of Vemurafenib in BRAF-Mutant Thyroid Cancer
    Transl. Oncol. (IF 3.138) Pub Date : 2020-01-03
    Shitu Chen; Xingyun Su; Xiaoxia Jiang; Tuo Zhang; Irene Min; Yongfeng Ding; Xumeng Wang; Zhuochao Mao; Jiang Cao; Xiaodong Teng; Thomas J. Fahey; Weibin Wang; Lisong Teng

    Vemurafenib, an inhibitor of mutant BRAF activity, is a promising anticancer agent for patients with BRAF-mutant metastatic melanoma. However, it is less effective in BRAF-mutant thyroid cancer, and the reason for this discrepancy is not yet fully elucidated. By RNA sequencing analysis, we identified vascular cell adhesion molecular-1 (VCAM-1) to be highly upregulated in both time- and dose-dependent manners during BRAF inhibition (BRAFi) in a BRAF-mutant papillary thyroid cancer cell line (BCPAP). Cell cytotoxicity and apoptosis assays showed that knockdown of the induced VCAM-1 in BCPAP cells augmented the antitumor effects of vemurafenib, with decreased IC50 values of 1.4 to 0.8 μM. Meanwhile, overexpression of VCAM-1 in a BRAF-mutant anaplastic thyroid cancer cell line (FRO) reduced the sensitivity to vemurafenib, with increased IC50 values of 1.9 to 5.8 μM. Further investigation showed that PI3K-Akt-mTOR pathway was activated during BRAFi. Co-treatment with Akt signaling inhibitor MK2206 decreased the induced expression of VCAM-1 during BRAFi. This combination further improved the efficacy of vemurafenib. Moreover, VCAM-1 promoted migration and invasion in thyroid cancer cells in vitro, which was also indicated in thyroid cancer patients. The present study is the first to demonstrate that VCAM-1 is upregulated in thyroid cancer cells treated with vemurafenib and contributes to vemurafenib resistance in BRAF-mutant thyroid cancer cells. Targeting the PI3K-Akt-mTOR pathway–mediated VCAM-1 response may be an alternative strategy to sensitize BRAF-mutant thyroid cancers to vemurafenib.

  • Hallmarks and Determinants of Oncogenic Translation Revealed by Ribosome Profiling in Models of Breast Cancer
    Transl. Oncol. (IF 3.138) Pub Date : 2020-01-03
    Christos Vaklavas; Scott W. Blume; William E. Grizzle

    Gene expression is extensively and dynamically modulated at the level of translation. How cancer cells prioritize the translation of certain mRNAs over others from a pool of competing mRNAs remains an open question. Here, we analyze translation in cell line models of breast cancer and normal mammary tissue by ribosome profiling. We identify key recurrent themes of oncogenic translation: higher ribosome occupancy, greater variance of translational efficiencies, and preferential translation of transcriptional regulators and signaling proteins in malignant cells as compared with their nonmalignant counterpart. We survey for candidate RNA interacting proteins that could associate with the 5′untranslated regions of the transcripts preferentially translated in breast tumour cells. We identify SRSF1, a prototypic splicing factor, to have a pervasive direct and indirect impact on translation. In a representative estrogen receptor–positive and estrogen receptor–negative cell line, we find that protein synthesis relies heavily on SRSF1. SRSF1 is predominantly intranuclear. Under certain conditions, SRSF1 translocates from the nucleus to the cytoplasm where it associates with MYC and CDK1 mRNAs and upregulates their internal ribosome entry site–mediated translation. Our results point to a synergy between splicing and translation and unveil how certain RNA-binding proteins modulate the translational landscape in breast cancer.

  • Homologous Recombination Repair Deficiency and the Immune Response in Breast Cancer: A Literature Review
    Transl. Oncol. (IF 3.138) Pub Date : 2020-01-02
    B. Pellegrino; A. Musolino; A. Llop-Guevara; V. Serra; P. De Silva; Z. Hlavata; D. Sangiolo; K. Willard-Gallo; C. Solinas

    The success of cancer immunotherapy with immune checkpoint blockade (ICB) has demonstrated the importance of targeting a preexisting immune response in a broad spectrum of tumors. This is particularly novel and relevant for less immunogenic tumors, such as breast cancer (BC), where the efficacy of ICB was more evident in the triple-negative (TNBC) subtype, in earlier stages, and in association with chemotherapy. Tumors harboring homologous recombination DNA repair (HRR) deficiency (HRD) are supposed to have a higher number of mutations, hence a higher tumor mutational burden, which could potentially make them more sensitive to immunotherapy. However, the mechanisms involved in ICB sensitivity and patient selection are still yet to be defined in BC: whether the innate system could play a role and how the adaptive immunity could be linked with HRR pathways are the two key points of debate that we will discuss in this article. The aim of this review was to close the loop between what was found in clinical trial results so far, go back to laboratory theory and preclinical results and point out what needs to be clarified from now on.

  • Enhanced Anticancer Effect of Adding Magnesium to Vitamin C Therapy: Inhibition of Hormetic Response by SVCT-2 Activation
    Transl. Oncol. (IF 3.138) Pub Date : 2019-12-31
    Sungrae Cho; Jin Sung Chae; Hocheol Shin; Yujeong Shin; Youngwook Kim; Eui-Joon Kil; Hee-Seong Byun; Sang-Ho Cho; Seyeon Park; Sukchan Lee; Chang-Hwan Yeom

    l-Ascorbic acid (vitamin C, AA) is known as an antioxidant, but at high concentrations, AA can kill cancer cells through a prooxidant property. Sodium-dependent vitamin C transporter family-2 (SVCT-2) determines the cellular uptake of AA, and the activity of SVCT-2 is directly related to the anticancer activity of AA. Cancer cells that showed high SVCT-2 expression levels were more sensitive to AA treatment than cancer cells with low SVCT-2 expression levels. Cells with low SVCT-2 expression showed a hormetic response to a low dose of AA. Magnesium ions, which are known to activate SVCT-2, could increase the Vmax value of SVCT-2, so we investigated whether providing magnesium supplements to cancer cells with low SVCT-2 expression that had shown a hormetic response to AA would elevate the Vmax value of SVCT-2, allowing more AA to accumulate. To evaluate the effects of magnesium on cancer cells, MgSO4 and MgCl2 were screened as magnesium supplements; both forms showed synergistic anticancer effects with AA. Taken together, the results of this study suggest that magnesium supplementation enhanced the anticancer effect of AA by inhibiting the hormetic response at a low dose. This study has also demonstrated that AA treatment with magnesium supplementation provided more effective anticancer therapy than AA treatment alone.

  • Metformin Treatment for Diabetes Mellitus Correlates with Progression and Survival in Colorectal Carcinoma
    Transl. Oncol. (IF 3.138) Pub Date : 2019-12-30
    Marta K. Powell; Dana Cempirkova; Pavel Dundr; Tereza Grimmichova; Ferdinand Trebicky; Robert E. Brown; Jana Gregorova; Martina Litschmannova; Katerina Janurova; Michal Pesta; Petr Heneberg

    BACKGROUND: Diabetes mellitus is unfavorably associated with cancer risk. The purpose of this multidisciplinary project was to evaluate a possible association of diabetes mellitus and other comorbidities and their treatment with progression of colorectal cancer. PATIENTS AND METHODS: We investigated the correlation between pathological characteristics and clinical course, including comorbidities in 1004 Czech patients diagnosed and surgically treated for colorectal adenocarcinoma (CRC) between 1999 and 2016. RESULTS: In our data set, CRC patients treated with metformin due to coexisting diabetes mellitus type 2 (T2DM) developed fewer distant metastases which clinically correlates with slower CRC progression. Survival in metformin subgroup was longer, particularly in men with CRC. Osteoporosis may be a negative factor of survival in CRC patients. CONCLUSIONS: Our findings also indicate that aging, higher tumor grade and TNM stage, coexistence of selected endocrine disorders, and metabolic abnormalities may change the tumor microenvironment and impact survival in colorectal cancer, although mechanism of these observations yet to be explained. Patients with diabetes mellitus type 2 treated with metformin may represent the altered microenvironment with specifically tuned metabolic molecular responses and with various epigenetic characteristics. More awareness and increased understanding of the mechanisms underlying the positive effect of metformin on patients' survival could offer insight into new treatment methods and permit more individualized treatment plans.

  • Exquisite Tumor Targeting by Salmonella A1-R in Combination with Caffeine and Valproic Acid Regresses an Adult Pleomorphic Rhabdomyosarcoma Patient-Derived Orthotopic Xenograft Mouse Model
    Transl. Oncol. (IF 3.138) Pub Date : 2019-12-30
    Kentaro Igarashi; Kei Kawaguchi; Ming Zhao; Tasuku Kiyuna; Kentaro Miyake; Masuyo Miyake; Scott D. Nelson; Sarah M. Dry; Yunfeng Li; Norio Yamamoto; Katsuhiro Hayashi; Hiroaki Kimura; Shinji Miwa; Takashi Higuchi; Shree Ram Singh; Hiroyuki Tsuchiya; Robert M. Hoffman

    Adult pleomorphic rhabdomyosarcoma (RMS) is a rare and malignant mesenchymal tumor. Recently, we developed a patient-derived orthotopic xenograft (PDOX) model of adult pleomorphic RMS. In the present study, we evaluated the efficacy of tumor-targeting Salmonella typhimurium (S. typhimurium) A1-R combined with caffeine (CAF) and valproic acid (VPA) on the adult RMS PDOX. An adult pleomorphic RMS cell line was established from the PDOX model. Cell survival after exposure to CAF and VPA was assessed, and the IC50 value was calculated for each drug. The RMS PDOX models were randomized into five groups: untreated control; tumor treated with cyclophosphamide (CPA); tumor treated with CAF + VPA; tumor treated with S. typhimurium A1-R; and tumor treated with S. typhimurium A1-R + CAF + VPA. Tumor size and body weight was measured twice a week. VPA caused a concentration-dependent cytocidal effect. A synergistic effect of combination treatment with CAF was observed against the RMS cell line. For the in vivo study, all treatments significantly inhibited tumor growth compared with the untreated control. S. typhimurium A1-R combined with VPA and CAF was significantly more effective than CPA, VPA combined with CAF, or S. typhimurium A1-R alone and significantly regressed the tumor volume compared with day 0. These results suggest that S. typhimurium A1-R together with VPA and CAF could regresses an adult pleomorphic RMS in a PDOX model and therefore has important future clinical potential.

  • Is There an Independent Role of TERT and NF1 in High Grade Gliomas?
    Transl. Oncol. (IF 3.138) Pub Date : 2019-12-28
    Evangelia Razis; Vassiliki Kotoula; Georgia-Angeliki Koliou; Kyriaki Papadopoulou; Eleni Vrettou; Eleni Giannoulatou; Ioannis Tikas; Stefanos V. Labropoulos; Georgios Rigakos; Styliani Papaemmanoyil; Ourania Romanidou; Eugenia Bourkoula; Panagiotis Nomikos; Georgios Iliadis; George Nasioulas; Panagiotis Selviaridis; Konstantinos Polyzoidis; George Fountzilas

    BACKGROUND: High grade glioma molecular profiling is of particular interest in neurooncology. The role of telomerase reverse transcriptase (TERT) varies dependent upon other molecular parameters. We explored the role of TERT in 101 high-grade gliomas. METHODS: A total of 101 patients (pts) with grade III–IV gliomas treated with standard of care and informative tumor genotypes were included in the present study. Of 55 genes targeted with the next-generation sequencing panel, mutations (muts) were found in 37; these were included in the analysis. TERT mut were tested with Sanger sequencing. MGMT promoter methylation status was determined by methylation specific PCR. RESULTS: 270 mut were detected in 92/101 tumors (91.1%). TERT was the most frequently mutated gene (74.3%). IDH1/2 mut were mutually exclusive with mut in the neurofibromin 1 (NF1) gene. Mutated TERT was associated with wild-type (wt) IDH1/2 (p = 0.025). The 12-month overall survival (OS) rate was 74.3% (median OS: 22 months). Pts with TERT and NF1 wt had a median OS of 40.8 months, while among pts with NF1 wt/TERT mutant, the median OS was 18.5 months. NF1 and TERT mut univariately conferred shorter OS (HR = 3.19; p = 0.004 and HR = 2.28; p = 0.002). Upon multivariate analysis, mutated TERT showed marginal unfavorable prognostic significance for OS (p = 0.049), while NF1 lost its unfavorable significance (p = 0.151). CONCLUSIONS: TERT is herein proven to confer poor prognosis in high grade gliomas, independent of IDH and MGMT. NF1 seems to also confer poor prognosis although our small numbers do not allow for firm conclusions.

  • Epigenetic Regulation of RIP3 Suppresses Necroptosis and Increases Resistance to Chemotherapy in NonSmall Cell Lung Cancer
    Transl. Oncol. (IF 3.138) Pub Date : 2019-12-27
    Qiong Wang; Peipei Wang; Li Zhang; Mathewos Tessema; Lang Bai; Xiuling Xu; Qin Li; Xuelian Zheng; Bryanna Saxton; Wenshu Chen; Randy Willink; Zhiping Li; Lin Zhang; Steven A. Belinsky; Xia Wang; Bin Zhou; Yong Lin

    INTRODUCTION: The efficacy of chemotherapeutic agents in killing cancer cells is mainly attributed to the induction of apoptosis. However, the tremendous efforts on enhancing apoptosis-related mechanisms have only moderately improved lung cancer chemotherapy, suggesting that other cell death mechanisms such as necroptosis could be involved. In this study, we investigated the role of the necroptosis pathway in the responsiveness of nonsmall cell lung cancer (NSCLC) to chemotherapy. METHODS: In vitro cell culture and in vivo xenograft tumor therapy models and clinical sample studies are combined in studying the role of necroptosis in chemotherapy and mechanism of necroptosis suppression involving RIP3 expression regulation. RESULTS: While chemotherapeutic drugs were able to induce necroptotic cell death, this pathway was suppressed in lung cancer cells at least partly through downregulation of RIP3 expression. Ectopic RIP3 expression significantly sensitized lung cancer cells to the cytotoxicity of anticancer drugs such as cisplatin, etoposide, vincristine, and adriamycin. In addition, RIP3 suppression was associated with RIP3 promoter methylation, and demethylation partly restored RIP3 expression and increased chemotherapeutic-induced necroptotic cell death. In a xenograft tumor therapy model, ectopic RIP3 expression significantly sensitized anticancer activity of cisplatin in vivo. Furthermore, lower RIP3 expression was associated with worse chemotherapy response in NSCLC patients. CONCLUSION: Our results indicate that the necroptosis pathway is suppressed in lung cancer through RIP3 promoter methylation, and reactivating this pathway should be exploited for improving lung cancer chemotherapy.

  • A Real-World Study in Advanced Non–Small Cell Lung Cancer with KRAS Mutations
    Transl. Oncol. (IF 3.138) Pub Date : 2019-12-24
    Lei Lei; Wen-xian Wang; Zong-yang Yu; Xian-bin Liang; Wei-wei Pan; Hua-fei Chen; Li-ping Wang; Yong Fang; Min Wang; Chun-wei Xu; Mei-yu Fang

    BACKGROUND: KRAS gene mutations are well known as a key driver of advanced non–small cell lung cancer (NSCLC). The impact of KRAS-mutant subtypes on the survival benefit from salvage chemotherapy is controversial. Here, we present a real-world study in patients across China with advanced NSCLC with KRAS mutations using a website-based patient self-report system. METHODS: We identified a total of 75 patients diagnosed with KRAS-mutant (determined by molecular sequencing) advanced NSCLC between 2014/5/9 and 2019/5/30. KRAS mutation subtypes were divided into G12C and non-G12C groups for statistical analysis. The clinicopathological characteristics and treatment survival benefit in all patients with a KRAS mutation were evaluated. Programmed death-ligand 1 (PD-L1) expression data were collected from 30 patients in the same cohort. RESULTS: In this study, 23 patients with stage IIIB NSCLC and 52 patients with stage IV NSCLC were enrolled with 58 men and 17 women; the median age was 60 years (39–84). All patients received regular chemotherapy/radiotherapy/targeted therapy/immune therapy as per the disease condition. Four main KRAS mutation subtypes were detected: G12C (33%), G12V (19%), G12A (12%), and G12D (12%). Three predominant KRAS comutations were detected: TP53-KRAS (31%), EGFR-KRAS (11%), and STK11-KRAS (8%). Compared with the KRAS non-G12C mutation subtype, patients with the KRAS G12C mutation had potentially longer progression-free survival (PFS) after first-line chemotherapy (4.7 vs. 2.5 months, p < 0.05). Pemetrexed-based chemotherapy appeared to be superior to taxanes- and gemcitabine-based chemotherapies in all patients (PFS: 5.0 vs. 1.5 and 2.3 months, respectively, p > 0.05). Cox regression analysis showed that the KRAS G12C mutation and pemetrexed-based first-line chemotherapy were positive influencers for PFS after first-line (hazard ratios = 0.31 and 0.55, respectively, P < 0.05), but not second-line chemotherapies. CONCLUSION: The KRAS G12C mutation could be a predictive biomarker for better survival benefit from first-line chemotherapy in patients with advanced NSCLC and KRAS mutations. The first-line chemotherapy regimen could possibly influence the outcome in patients with KRAS mutations. Larger and prospective clinical trials are warranted to confirm our conclusions.

  • Prognostic and Predictive Value of Tumor-infiltrating Leukocytes and of Immune Checkpoint Molecules PD1 and PDL1 in Clear Cell Renal Cell Carcinoma
    Transl. Oncol. (IF 3.138) Pub Date : 2019-12-24
    Philipp J. Stenzel; Mario Schindeldecker; Katrin E. Tagscherer; Sebastian Foersch; Esther Herpel; Markus Hohenfellner; Gencay Hatiboglu; Juergen Alt; Christian Thomas; Axel Haferkamp; Wilfried Roth; Stephan Macher-Goeppinger

    INTRODUCTION: Immune checkpoint inhibitors (ICI) have been approved for patients with clear cell renal cell carcinoma (ccRCC), but not all patients benefit from ICI. One reason is the tumor microenvironment (TME) that has substantial influence on patient's prognosis and therapy response. Thus, we comprehensively analyzed the TME of ccRCC regarding prognostic and predictive properties. METHODS: Tumor-infiltrating CD3-positive T-cells, CD8-positive cytotoxic T-lymphocytes (CTLs), regulatory T-cells, B-cells, plasma cells, macrophages, granulocytes, programmed cell death receptor 1 (PD-1), and its ligand PD-L1 were examined in a large hospital-based series of ccRCC with long-term follow-up information (n = 756) and in another patient collective with information on response to nivolumab therapy (n = 8). Tissue microarray technique and digital image analysis were used. Relationship between immune cell infiltration and tumor characteristics, cancer-specific survival (CSS), or response to ICI was examined. RESULTS: Univariate survival analysis revealed that increased tumor-infiltrating B-cells, T-cells, and PD-1-positive cells were significantly associated with favorable CSS and high levels of intratumoral granulocytes, macrophages, cytotoxic T-cells, and PD-L1 significantly with poor CSS. High CTL or B-cell infiltration and high PD-L1 expression of ccRCC tumor cells qualified as independent prognostic biomarkers for patients' CSS. Significantly higher densities of intratumoral T-cells, CTLs, and PD-1-positive immune cells were observed in ccRCC with response to ICI compared with patients with mixed or no response (CD3: p = 0.003; CD8: p = 0.006; PD-1: p = 0.01). DISCUSSION: This study shows that subsets of tumor-infiltrating leukocytes in the TME and also PD-1/PD-L1 provide prognostic and predictive information for patients with ccRCC.

  • Bone Metastasis: Current State of Play
    Transl. Oncol. (IF 3.138) Pub Date : 2019-12-23
    Anthony Turpin; Martine Duterque-Coquillaud; Marie-Hélène Vieillard

    Bone metastasis (BM) in cancer remains a critical issue because of its associated clinical and biological complications. Moreover, BM can alter the quality of life and survival rate of cancer patients. Growing evidence suggests that bones are a fertile ground for the development of metastasis through a “vicious circle” of bone resorption/formation and tumor growth. This review aims to outline the current major issues in the diagnosis and management of BM in the most common types of osteotropic cancers and describe the mechanisms and effects of BM. First, we discuss the incidence of BM through the following questions: Are we witnessing an increase in incidence, and are we now better equipped with modern imaging techniques? Is the advent of efficient bone resorption inhibitors affecting the bigger picture of BM management? Second, we discuss the potential effects of cancer progression and well-prescribed drugs, such as multitarget tyrosine kinase inhibitors, inhibitors of the mammalian target of rapamycin, and immune checkpoint inhibitors, on BM. Finally, we examine the duality of the effects of some therapies that may help in cancer treatment but may also contribute to further BM.

  • Intermittent Versus Continuous Dosing of MAPK Inhibitors in the Treatment of BRAF-Mutated Melanoma
    Transl. Oncol. (IF 3.138) Pub Date : 2019-12-23
    Coralie Reger de Moura; Laetitia Vercellino; Fanélie Jouenne; Barouyr Baroudjian; Aurélie Sadoux; Baptiste Louveau; Julie Delyon; Kevin Serror; Lauriane Goldwirt; Pascal Merlet; Fanny Bouquet; Maxime Battistella; Céleste Lebbé; Samia Mourah

    The development of BRAF and MEK inhibitors (BRAFi/MEKi) has led to major advances in melanoma treatment. However, the emergence of resistance mechanisms limits the benefit duration and a complete response occurs in less than 20% of patients receiving BRAFi ± MEKi. In this study, we evaluated the impact of an intermittent versus continuous dosing schedule of BRAF/MEK inhibition in a melanoma model mildly sensitive to a BRAF inhibitor. The combination of a BRAFi with three different MEKi was studied with a continuous or intermittent dosing schedule in vivo, in a xenografted melanoma model and ex vivo using histoculture drug response assays (HDRAs) of patient-derived xenografts (PDX). To further understand the underlying molecular mechanisms of therapeutic efficacy, a biomarker pharmacodynamic readout was evaluated. An equal impact on tumor growth was observed in monotherapy or bitherapy regimens whether we used continuous and intermittent dosing schedules, with no significant differences in biomarkers expression between the treatments. The antitumoral effect was mostly due to modulations of expression of cell cycle and apoptotic mediators. Moreover, ex vivo studies did not show significant differences between the dosing schedules. In this context, our preclinical and pharmacodynamic results converged to show the similarity between intermittent and continuous treatments with either BRAFi or MEKi alone or with the combination of both.

  • PDZ-Binding Kinase-Dependent Transcriptional Regulation of CCNB2 Promotes Tumorigenesis and Radio-Resistance in Glioblastoma
    Transl. Oncol. (IF 3.138) Pub Date : 2019-12-23
    Ping Mao; Gang Bao; Yi-Chang Wang; Chang-Wang Du; Xiao Yu; Xiao-Ye Guo; Rui-Chun Li; Mao-De Wang

    Increasing evidence has indicated that PDZ binding kinase (PBK) promotes proliferation, invasion, and therapeutic resistance in a variety of cancer types. However, the physiological function and therapy-resistant role of PBK in GBM remain underexplored. In this study, PBK was identified as one of the most therapy-resistant genes with significantly elevated expression level in GBM. Moreover, the high expression level of PBK was essential for GBM tumorigenesis and radio-resistance both in vitro and in vivo. Clinically, aberrant activation of PBK was correlated with poor clinical prognosis. In addition, inhibition of PBK dramatically enhanced the efficacy of radiation therapy in GBM cells. Mechanically, PBK-dependent transcriptional regulation of CCNB2 was critical for tumorigenesis and radio-resistance in GBM cells. Collectively, PBK promotes tumorigenesis and radio-resistance in GBM and may serve as a novel therapeutic target for GBM treatment.

  • Pazopanib in the Treatment of Bone Sarcomas: Clinical Experience
    Transl. Oncol. (IF 3.138) Pub Date : 2019-12-23
    Ninna Aggerholm-Pedersen; Phillip Rossen; Hanne Rose; Akmal Safwat

    BACKGROUND: The effect of chemotherapy in metastatic bone sarcomas is poor and the condition is invariably fatal. Therefore, new treatment modalities are intensely needed. Pazopanib is a selective multitargeted tyrosine kinase inhibitor that has proven to be effective in the treatment of metastatic soft tissue sarcomas. The objective of this study was to evaluate the off-label use of pazopanib in patients with metastatic bone sarcomas who failed standard chemotherapy. METHODS: All patients with metastatic bone sarcomas treated with pazopanib between October 1st, 2011 and October 1st, 2017 at the Department of Oncology, Aarhus University Hospital were evaluated. Demographics, treatment, and survival outcomes were collected and analyzed. RESULTS: Nineteen patients were identified. The median age was 38 years (range 18–62). Most of the patients (50%) were diagnosed with osteosarcoma. All patients had documented disease progression at the time of initiating pazopanib treatment. The median overall survival was 11 months. Median progression free survival was 5.4 months. Out of 19 patients, 13 (68%) had either partial response or stable disease. In five patients, the dose of pazopanib was reduced because of toxicity. CONCLUSION: Off-label use of pazopanib is effective in the treatment of metastatic bone sarcomas of different histologies. Pazopanib was well tolerated in the treatment of patients with refractory bone sarcomas. Studies examining the effect of pazopanib alone or in combination with chemotherapy or other targeted therapies are needed.

  • The Somatic Mutation Hit on Top of Genetic APC mutations Cause Skin Tumor
    Transl. Oncol. (IF 3.138) Pub Date : 2019-12-23
    Ting Niu; Mingming Yang; Qing Liu; Haobin Li; Lingbi Jiang; Fanggu Li; Xiaodong He; Lijing Wang; Jiangchao Li

    Inactivation of the adenomatous polyposis coli (APC) gene is the initiating event in familial adenomatous polyposis (FAP) patients. Up to 90% of FAP patients show intestinal tumors and other extracolonic malignancies including hepatoblastomas, desmoid tumors, and brain cancer. APC mutation mice (ApcMin/+ mice) develop benign polyps in the intestinal tract. It has been reported that small numbers of ApcMin/+ mice develop breast carcinomas. Here, we found that approximately 1.6% of ApcMin/+ mice suffered skin neoplasm. The results demonstrated that these skin tumors are not derived from intestinal adenomas. Sequencing of skin tumors of ApcMin/+ mice and ApcMin/+ mice skin. The data showed that somatic mutations and gene expression levels changed greatly in skin tumors compared to control. Similarly, APC mutation accounts for 27% in the patients of nonmelanoma skin carcinomas in cancer database, and two above genes mutation coexist was observed in all patients. Furthermore, using gene mutation reagent (DMBA)–treated ApcMin/+ mice skin, the skin epithelium and glandular begin hyperplasia in ApcMin/+ mice. These findings revealed that the somatic mutation hit on the germline mutation increase the tumor incidence, suggesting that the somatic mutation should be avoided if the germline mutation exists in one body.

  • Clinical Implications of Monitoring ESR1 Mutations by Circulating Tumor DNA in Estrogen Receptor Positive Metastatic Breast Cancer: A Pilot Study
    Transl. Oncol. (IF 3.138) Pub Date : 2019-12-23
    Xuelu Li; Jiawei Lu; Lanxin Zhang; Yaoting Luo; Zuowei Zhao; Man Li

    BACKGROUND: ESR1 mutations are frequently detected in ER+ MBC, and have been reported to be associated with endocrine therapy resistance. However, there are little researches to validate whether dynamic monitoring of ESR1 mutations could serve as a predictive plasma biomarker of acquired resistance to endocrine therapy. Therefore, in this study, we performed longitudinal circulating tumor DNA (ctDNA) detection to evaluate the clinical implications of monitoring ESR1 mutations. METHODS: We performed longitudinal dynamic mutation analyses of plasma samples from 45 patients with metastatic breast cancer (MBC) and sequencing paired biopsy tissues, using a targeted NGS panel of 425 genes. These patients were treated at the Second Affiliated Hospital of Dalian Medical University between January 2017 and February 2019 with written informed consent. RESULTS: Mutations profiles were highly concordant between plasma and paired tissue samples from 45 MBC patients (r = 0.96, P < 0.0001). ESR1 mutations were enriched in ER+ MBC patients after AI therapy (17.8%, 8/45). The median time from AI endocrine therapies to the initial detection of ESR1 mutation was 39 months (95% CI 21.32–57.57). Some hotspot mutations (Y537S (n = 5), Y537N (n = 1), D538G (n = 2), E380Q (n = 2)) and several rare mutations (L345SfsX7, 24fs, G344delinsGC) were identified in our cohort. In addition, we observed that two patients obtained multiple ESR1 mutations over the course of treatment (Y537N/Y537S/D538G, L345SfsX7/24fs/E380Q). Through dynamically monitoring ESR1 mutations by ctDNA, we demonstrated that the change of allele frequency of ESR1 mutations was an important biomarker, which could predict endocrine resistance of ER+ MBC in our study. We also observed that the combination of everolimus in four cases with acquired ESR1 mutations showed longer PFS than other therapies without everolimus. CONCLUSION: The dynamic monitoring of ESR1 mutations by ctDNA is a promising tool to predict endocrine therapy resistance in ER+ MBC patients.

  • Immune Response Against Head and Neck Cancer: Biological Mechanisms and Implication on Therapy
    Transl. Oncol. (IF 3.138) Pub Date : 2019-12-21
    Francesco Perri; Franco Ionna; Francesco Longo; Giuseppina Della Vittoria Scarpati; Carmine De Angelis; Alessandro Ottaiano; Gerardo Botti; Francesco Caponigro

    Head and neck carcinoma (HNC) are diseases arising from several tracts of the aerodigestive ways. Most HNC are squamous cell carcinoma (SCCHN). Immunotherapy is a treatment strategy aimed to reinforce the immune system. Several types of immunotherapy are available in the clinical scenario. Checkpoint inhibitors were developed later in SCCHN; nivolumab and pembrolizumab have reached the clinical approval, having both drugs demonstrated to significantly improve the overall survival, if compared with the standard of treatment (according to the results of the CheckMate 141 and KEYNOTE-040 trials). Nevertheless, immunotherapy may fail because of the genetics of SCCHN. In fact, two genetically different types of SCCHN have been discovered, one virus-related (HPV) and the other mutagens-related. They seem to show in clinical trials very different responses to immunotherapy. Given the existence of a number of factors predictive of response to immunotherapy in SCCHN, a future clinical approach may be to characterize the genetic and immunologic feature of SCCHN and to perform a well-tailored immunotherapy. This review will summarize the main immunotherapy strategies available in SCCHN, discussing their real efficacy, highlighting also the ways to improve them.

  • Checkpoint Genes at the Cancer Side of the Immunological Synapse in Bladder Cancer
    Transl. Oncol. (IF 3.138) Pub Date : 2019-12-20
    Paula Dobosz; Przemysław A. Stempor; Jason Roszik; Amir Herman; Adi Layani; Raanan Berger; Dror Avni; Yechezkel Sidi; Raya Leibowitz-Amit

    Immune checkpoint inhibitors have revolutionized cancer therapy, but not all cancers respond to the currently available drugs, and even within cancers considered responsive to such modality, response rates range between 15 and 40%, depending on the cancer type, the line of treatment, and yet unknown clinical/molecular factors. Coordinated expression of checkpoint proteins was shown to occur on T cells, probably allowing fine-tuning of the signal transmitted to the cell. We performed a bioinformatic analysis of the expression of putative checkpoint mRNAs at the cancer side of the immunological synapse from the bladder cancer tumorgenome atlas (TCGA) database. Fifteen mRNAs, corresponding to both coinhibitory and costimulatory checkpoints, were shown to be expressed above a designated threshold. Of these, seven mRNAs were found to be coexpressed: CD277, PD-1L, CD48, CD86, galectin-9, TNFRSF14 (HVEM), and CD40. The expression of 2 of these mRNAs—BTN3A1 (CD277) and TNFRSF14 (HVEM)—was positively correlated with overall survival in the TCGA database. All these seven mRNA share putative binding sites of a few transcription factors (TFs). Of these, the expression of the TF BACH-2 was positively correlated with the expression of checkpoint mRNAs from the network. This suggests a joint transcriptional regulation on the expression of checkpoint mRNAs at the bladder tumor side of the immunological synapse.

  • Clinical Evaluation of BRCA1/2 Mutation in Mexican Ovarian Cancer Patients
    Transl. Oncol. (IF 3.138) Pub Date : 2019-12-20
    Dolores Gallardo-Rincón; Rosa María Álvarez-Gómez; Edgar Montes-Servín; Alfredo Toledo-Leyva; Elizabeth Montes-Servín; David Michel-Tello; Gabriela Alamilla-García; Antonio Bahena-González; Elizabeth Hernández-Nava; Veronica Fragoso-Ontiveros; Raquel Espinosa-Romero; Lucely Cetina-Pérez

    Ovarian cancer (OC) is an important cause of gynecologic cancer-related deaths. In Mexico, around 4700 new cases of OC are diagnosed per year and it represents the second cause of gynecological cancer mortality with more than 2700 deaths. Germline mutations in BRCA1/2 genes are present in 13–18% of OC cases. Few studies have evaluated the presence of mutations in BRCA genes in a population of OC Mexican patients and their relationship with clinical response and survival rates. A total of 179 OC patients were studied by molecular testing for BRCA1/2 through next-generation sequencing and multiplex ligation-dependent probe amplification. Recurrence-free survival (RFS) was estimated by the Kaplan–Meier method. BRCA mutation was detected in 33% of patients. A percentage of 66.1% were BRCA1 mutated and 33.9% were BRCA2 mutated. BRCA1 mutation carriers had a worst RFS compared with BRCA2 mutation carriers (37.6 [29–46.2] vs 72.7 [38.4–107.2]; P = 0.030). The most common mutation for BRCA1 was ex9-12del (28.2%) (Mexican founder mutation). The Mexican founder mutation had a better RFS than other BRCA1 mutations (86.1 [37.2–135.1] vs 34.5 [20.7–48.2]; P = 0.033). The presence of BRCA2 mutations in the ovarian cancer cluster region (OCCR) had a significantly better RFS than mutations in breast cancer cluster regions (BCCR) and not-related risk region (NRR) (NR vs 72.8 [39–106.6] vs 25.8 [8.3–43.2]; P = 0.013). These results demonstrate that the prevalence of BRCA1/2 positive patients in OC Mexican patients are the highest reported. Patients with mutations in BRCA2 have a better prognosis than those mutated in BRCA1. The Mexican founder mutation has an important role in clinical outcomes. These results highlight the importance to test all the HGSP (high-grade serous papillary) OC patients with or without cancer family history (CFH) in Mexican population.

  • Small-Molecule Dual PLK1 and BRD4 Inhibitors are Active Against Preclinical Models of Pediatric Solid Tumors
    Transl. Oncol. (IF 3.138) Pub Date : 2019-12-21
    Natalie Timme; Youjia Han; Shuai Liu; Hailemichael O. Yosief; Heathcliff Dorado García; Yi Bei; Filippos Klironomos; Ian C. MacArthur; Annabell Szymansky; Jennifer von Stebut; Victor Bardinet; Constantin Dohna; Annette Künkele; Jana Rolff; Patrick Hundsdörfer; Andrej Lissat; Georg Seifert; Angelika Eggert; Anton G. Henssen

    Simultaneous inhibition of multiple molecular targets is an established strategy to improve the continuance of clinical response to therapy. Here, we screened 49 molecules with dual nanomolar inhibitory activity against BRD4 and PLK1, best classified as dual kinase-bromodomain inhibitors, in pediatric tumor cell lines for their antitumor activity. We identified two candidate dual kinase-bromodomain inhibitors with strong and tumor-specific activity against neuroblastoma, medulloblastoma, and rhabdomyosarcoma tumor cells. Dual PLK1 and BRD4 inhibitor treatment suppressed proliferation and induced apoptosis in pediatric tumor cell lines at low nanomolar concentrations. This was associated with reduced MYCN-driven gene expression as assessed by RNA sequencing. Treatment of patient-derived xenografts with dual inhibitor UMB103 led to significant tumor regression. We demonstrate that concurrent inhibition of two central regulators of MYC protein family of protooncogenes, BRD4, and PLK1, with single small molecules has strong and specific antitumor effects in preclinical pediatric cancer models.

  • Expression of Alpha-type Platelet-derived Growth Factor Receptor–influenced Genes Predicts Clinical Outcome in Glioma
    Transl. Oncol. (IF 3.138) Pub Date : 2019-12-21
    Eun-A Ko; Haeyeong Lee; Kenton M. Sanders; Sang Don Koh; Tong Zhou

    BACKGROUND: Alpha-type platelet-derived growth factor receptor (PDGFRα) is a cell surface tyrosine kinase receptor for members of the platelet-derived growth factor family. PDGFRα plays an important role in the regulation of several biological processes and contributes to the pathophysiology of a broad range of human cancers, including glioma. Here, we hypothesize that the genes directly or indirectly influenced by PDGFRα might be useful for prognosis in glioma. METHODS: By comparing the genome-wide gene expression pattern between PDGFRα+ and PDGFRα− cells from human oligodendrocyte progenitor, we defined the genes potentially influenced by PDGFRα. RESULTS: The PDGFRα-influenced genes are strongly associated with cancer-related pathways. We subsequently developed a prognostic gene signature derived from the PDGFRα-influenced genes. This gene signature is able to predict clinical outcome of glioma. This signature is also independent of traditional prognostic factors of glioma. Resampling tests indicate that the prognostic power of this gene signature outperforms random gene sets selected from human genome. More importantly, this signature is superior to the random gene signatures selected from glioma related genes. CONCLUSIONS: Despite the absence of clear elucidation of molecular mechanisms, this study suggests the vital role of PDGFRα in carcinogenesis. Furthermore, the PDGFRα-based gene signature provides a promising prognostic tool for glioma and validates PDGFRα as a novel and effective therapeutic target in human cancers.

  • Does Bone-targeted Therapy Benefit Patients with Metastatic Renal Cell Carcinoma?
    Transl. Oncol. (IF 3.138) Pub Date : 2019-12-21
    Emily C.L. Wong; Anil Kapoor

    INTRODUCTION: In metastatic renal cell carcinoma (mRCC), the bone is the second most common site of metastasis and is associated with increased morbidity and poorer quality of life. Bone-targeted therapies (BTTs) such as denosumab and zoledronic acid may prevent skeletal-related events (SREs). However, the benefit of BTTs in combination with tyrosine kinase inhibitors (TKIs) remains unclear. METHODS: We performed a retrospective chart review at the Urologic Cancer Centre for Research and Innovation. Patients with mRCC were included if they had bone metastases treated with TKIs between 2010 and 2017. Our primary outcome was overall survival (OS), defined as the time elapsed from clinical diagnosis of mRCC to death, and modelled using the Kaplan–Meier method. Secondary outcomes included the median time to SRE and the analysis of prognostic factors of OS using Cox proportional hazards regression. RESULTS: In total, 230 patients with mRCC were identified; of which, 46 had bone metastases treated with TKIs and were included in the study (TKI-only, n = 37; TKI + BTT, n = 9). In the TKI + BTT cohort, patients received either denosumab (n = 5) or zoledronic acid (n = 4). At the time of analysis, 63% of patients were deceased. We observed an OS trend favouring the TKI + BTT cohort (13.8 months [95% confidence interval {CI}: 12.3–15.2] vs. 29.6 months [95% CI: 7.2–51.9], hazard ratio [HR]: 1.66 (95% CI: 0.62–4.45), P = 0.31). When patients in the TKI + BTT cohort were stratified by type of therapy (denosumab or zoledronic acid), the median time to SRE was similar between the groups (4.2 months [95% CI: 2.28–6.14] vs. 2.2 months [95% CI: not available], P = 0.71]. On univariate or multivariate analysis, it was found that age, gender, comorbidities, International metastatic RCC database consortium (IMDC) prognostic group and pathologic tumour grade were not significant predictors of worse OS. Pathologic stage 3 or 4 was an independent predictor of worse OS (HR: 5.8, 95% CI: 1.41–24.03, P = 0.015). CONCLUSION: BTTs may have a continued role in the era of targeted therapy and immunotherapy. Further prospective data are required to validate our findings.

  • Genetic Profiling of Breast Cancer with and Without Preexisting Metabolic Disease
    Transl. Oncol. (IF 3.138) Pub Date : 2019-12-21
    Wenjiang Jing; Ling Li; Xiumei Zhang; Shouxin Wu; Jiangman Zhao; Qunxing Hou; Haotian Wu; Wu Ma; Shuheng Li; Huimin Liu; Binhui Yang

    Breast cancer is the most commonly diagnosed cancer and the leading cause of cancer death among women. Various mechanisms are involved in the initiation and progression of breast cancer. Metabolic dysregulation has been associated with increasing breast cancer incidence and mortality. However, little is known about how metabolic disease regulates the development and progression of breast cancer at the molecular level. Here, using a hybridization capture-based panel including 124 cancer-associated genes, we performed targeted next-generation sequencing of tumor tissues and matched blood samples from 20 postmenopausal patients with primary breast cancer, in which 6 cases suffered from preexisting metabolic disorders including hypertension, type 2 diabetes, and coronary heart disease. We took only the protein-altering variants and identified 170 somatic mutations of 59 genes. Among these, 40 mutated genes were found in the metabolic disease group, and 33 mutated genes were found in the non–metabolic disease group. Importantly, nonsynonymous mutations of 26 genes (MSH3, BRAF, MLH3, MTOR, DDR2, ALK, etc.) were uniquely present in the metabolic disease group. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes enrichment analysis were performed to investigate biological functions and key pathways of somatic mutations. TP53, PIK3CA, and PTEN were the top three commonly mutated genes at a higher frequency compared with the Cancer Genome Atlas (TCGA) data, and several novel but infrequent mutations in other genes were also found. Although further studies are required to validate these variants, our results are the first to suggest a specific molecular profile of breast cancer with preexisting metabolic disease.

  • Ultrasound Guided Optoacoustic Tomography in Assessment of Tumor Margins for Lumpectomies
    Transl. Oncol. (IF 3.138) Pub Date : 2019-12-21
    Yonggeng Goh; Ghayathri Balasundaram; Mohesh Moothanchery; Amalina Attia; Xiuting Li; Hann Qian Lim; Neal C. Burton; Yi Qiu; Thomas Choudary Putti; Ching Wan Chan; Philip Iau; Shaik Ahmad Buhari; Mikael Hartman; Siau Wei Tang; Celene Wei Qi Ng; Yiong Huak Chan; Felicity Jane Pool; Premilla Pillay; Malini Olivo

    PURPOSE: To determine the accuracy of a handheld ultrasound-guided optoacoustic tomography (US-OT) probe developed for human deep-tissue imaging in ex vivo assessment of tumor margins postlumpectomy. METHODS: A custom-built two-dimensional (2D) US-OT–handheld probe was used to scan 15 lumpectomy breast specimens. Optoacoustic signals acquired at multiple wavelengths between 700 and 1100 nm were reconstructed using model linear algorithm, followed by spectral unmixing for lipid and deoxyhemoglobin (Hb). Distribution maps of lipid and Hb on the anterior, posterior, superior, inferior, medial, and lateral margins of the specimens were inspected for margin involvement, and results were correlated with histopathologic findings. The agreement in tumor margin assessment between US-OT and histopathology was determined using the Bland–Altman plot. Accuracy, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of margin assessment using US-OT were calculated. RESULTS: Ninety margins (6 × 15 specimens) were assessed. The US-OT probe resolved blood vessels and lipid up to a depth of 6 mm. Negative and positive margins were discriminated by marked differences in the distribution patterns of lipid and Hb. US-OT assessments were concordant with histopathologic findings in 87 of 89 margins assessed (one margin was uninterpretable and excluded), with diagnostic accuracy of 97.9% (kappa = 0.79). The sensitivity, specificity, PPV, and NPV were 100% (4/4), 97.6% (83/85), 66.7% (4/6), and 100% (83/83), respectively. CONCLUSION: US-OT was capable of providing distribution maps of lipid and Hb in lumpectomy specimens that predicted tumor margins with high sensitivity and specificity, making it a potential tool for intraoperative tumor margin assessment.

  • RUNX2/CBFB modulates the response to MEK inhibitors through activation of receptor tyrosine kinases in KRAS-mutant colorectal cancer
    Transl. Oncol. (IF 3.138) Pub Date : 2019-12-20
    Tonći Šuštić; Evert Bosdriesz; Sake van Wageningen; Lodewyk F.A. Wessels; René Bernards

    Intrinsic and acquired resistances are major hurdles preventing the effective use of MEK inhibitors for treatment of colorectal cancer (CRC). Some 35–45% of colorectal cancers are KRAS-mutant and their treatment remains challenging as these cancers are refractory to MEK inhibitor treatment, because of feedback activation of receptor tyrosine kinases (RTKs). We reported previously that loss of ERN1 sensitizes a subset of KRAS-mutant colon cancer cells to MEK inhibition. Here we show that the loss of RUNX2 or its cofactor CBFB can confer MEK inhibitor resistance in CRC cells. Mechanistically, we find that cells with genetically ablated RUNX2 or CBFB activate multiple RTKs, which coincides with high SHP2 phosphatase activity, a phosphatase that relays signals from the cell membrane to downstream pathways governing growth and proliferation. Moreover, we show that high activity of SHP2 is causal to loss of RUNX2-induced MEK inhibitor resistance, as a small molecule SHP2 inhibitor reinstates sensitivity to MEK inhibitor in RUNX2 knockout cells. Our results reveal an unexpected role for loss of RUNX2/CBFB in regulating RTK activity in colon cancer, resulting in reduced sensitivity to MEK inhibitors.

  • Whole Fruit Phytochemicals Combating Skin Damage and Carcinogenesis
    Transl. Oncol. (IF 3.138) Pub Date : 2019-12-19
    Charlotte A. Mintie; Chandra K. Singh; Nihal Ahmad

    Skin is arguably the largest organ of the body and is continuously subjected to intrinsic, extrinsic, and environmental stresses. Therefore, skin developed elaborate mechanisms to maintain homeostasis, including antioxidant, antiinflammatory, and DNA damage repair capabilities. However, repeated and excessive stresses can overwhelm these systems, causing serious cutaneous damages, including skin carcinogenesis. Phytonutrients present in the diet possess a myriad of health-promoting effects by protecting skin from damaging free radicals as well as by other mechanisms. Although many chemoprotective phytonutrients have been shown to be efficacious individually, a combination of multiple agents could have synergistic response in curtailing or preventing cutaneous damages. Here, we discuss the benefits of natural amalgamation of phytonutrients in select fruits against skin damage including carcinogenesis. However, a majority of these studies have been done in preclinical models. Therefore, clinical studies are needed to determine the human relevance of the available preclinical data, especially in the human population who are at higher risk for skin cancers (e.g., organ transplant patients). In addition, detailed well-structured preclinical animal studies in the models of high-risk skin carcinogenesis could also be useful toward informing the design for human trials.

  • Autocrine BMP4 Signaling Enhances Tumor Aggressiveness via Promoting Wnt/β-Catenin Signaling in IDH1-mutant Gliomas
    Transl. Oncol. (IF 3.138) Pub Date : 2019-12-19
    Yiqiang Zhou; Yang Liu; Junwen Zhang; Di Yu; Aiguo Li; Hua Song; Wei Zhang; Dionne Davis; Mark R. Gilbert; Fusheng Liu; Chunzhang Yang

    The isocitrate dehydrogenase (IDH1/2) mutations are frequent genetic abnormalities in the majority of WHO grade II/III glioma and secondary GBM. IDH1-mutated (IDH1Mut) glioma exhibits distinctive patterns in cancer biology and metabolism. In the present study, we showed that bone morphogenetic proteins (BMP4) are significantly upregulated in IDH1Mut glioma. Further, we demonstrated that cancer-associated BMP4 is secreted to tumor microenvironment, which enhances the tumor migration and invasion through an autocrine manner. Mechanistically, BMP4 activates its receptor and concomitant SMAD1/5/8 signaling, which potentiates Wnt/β-catenin signaling by enhancing Frizzled receptor expression. LDN-193189, a selective BMP receptor inhibitor, prolonged the overall survival of mice bearing IDH1-mutated intracranial xenografts by limiting BMP/catenin signaling. These findings demonstrate the pivotal role of BMP4 on tumor aggressiveness in IDH1Mut gliomas, suggesting a possible therapeutic strategy for this type of malignancy.

  • Inhibition of HDAC6 Attenuates Tumor Growth of Non-Small Cell Lung Cancer
    Transl. Oncol. (IF 3.138) Pub Date : 2019-12-19
    Brian Deskin; Qinyan Yin; Yan Zhuang; Shigeki Saito; Bin Shan; Joseph A. Lasky

    Histone deacetylase 6 (HDAC6) regulates cytoplasmic signaling networks through deacetylation of various cytoplasmic substrates and serves as a key member of the ubiquitin proteasome system (UPS). This study is focused on HDAC6 regulation of the Notch1 receptor that plays a crucial role in tumor growth in NSCLC. A series of cell culture experiments were employed using A549, Lewis lung carcinoma 2 (LL2), and H1299 NSCLC cell lines to investigate HDAC6-mediated regulation of the Notch1 receptor through the UPS. HDAC6 was inhibited with small molecule inhibitors tubacin and ACY1215 in vitro and in vivo. Inhibition of HDAC6 led to reduced levels of Notch1 receptor in a dose-dependent manner in all three NSCLC cell lines tested. HDAC6 inhibition with ACY1215 led to G2 arrest, increased apoptosis, and increased levels of cleaved PARP1 in A549, LL2, and H1299 cell lines. In vivo inhibition of HDAC6 with ACY1215 significantly reduced LL2 tumor growth rate. Our data show that HDAC6 in NSCLC cells supports Notch1 signaling and promotes cell survival and proliferation. Our results support clinical investigation of HDAC6 inhibitors as a potential therapeutic option for treatment of NSCLC patients.

  • PIK3CA and KRAS Amplification in Esophageal Adenocarcinoma and their Impact on the Inflammatory Tumor Microenvironment and Prognosis
    Transl. Oncol. (IF 3.138) Pub Date : 2019-12-19
    Ahlem Essakly; Heike Loeser; Max Kraemer; Hakan Alakus; Seung-Hun Chon; Thomas Zander; Reinhard Buettner; Axel M. Hillmer; Christiane J. Bruns; Wolfgang Schroeder; Florian Gebauer; Alexander Quaas

    Gene amplifications of PIK3CA or KRAS induce a downstream activation of the AKT-mTOR or RAF-ERK-pathways. Interactions of the active AKT pathway have been implicated in the inflammatory tumor microenvironment. Nothing is known about these interactions or prognostic power in esophageal adenocarcinoma (EAC). We retrospectively analyzed a large cohort of 685 EAC considering KRAS and PIK3CA gene amplification using fluorescence in situ hybridization (FISH) and immunohistochemistry. These results were correlated with clinical and molecular data as well as the inflammatory tumor microenvironment. Amplifications of KRAS were seen in 94 patients (17.1%), PIK3CA amplifications in 23 patients (5.0%). KRAS amplifications significantly correlated with nodal positive patients and poorer overall survival (OS) in the subgroup without neoadjuvant treatment (p = 0.004), coamplifications of Her2 (p = 0.027), and TP53 mutations (p = 0.016). PIK3CA amplifications significantly correlated with a high amount of tumor infiltrating T cells (p = 0.003) and showed a tendency to better OS (p = 0.068). A correlation with checkpoint makers (PD-L1, LAG3, VISTA, TIM3, IDO) could not be revealed. Our findings are the first to link the KRAS amplified genotype with lymphonodal positivity and poor prognosis and the PIK3CA-amplified genotype with a T cell–rich microenvironment in EAC. Future studies must show whether these two genotype subgroups can be therapeutically influenced. A dual inhibition of MEK and SHP2T could be effective in the subgroup of KRAS amplified EACs and an immune checkpoint blockade may prove to be particularly promising in the subgroup of PIK3CA-amplified EACs.

  • Therapy Resistance in Neoadjuvantly Treated Gastric Cancer and Cancer of the Gastroesophageal Junction is Associated with an Increased Expression of Immune Checkpoint Inhibitors—Comparison Against a Therapy Naïve Cohort
    Transl. Oncol. (IF 3.138) Pub Date : 2019-12-19
    Hauke Schoop; Anna Bregenzer; Christine Halske; Hans-Michael Behrens; Sandra Krüger; Jan-Hendrik Egberts; Christoph Röcken

    With recent studies uncovering the complex landscape of immune checkpoint regulators in gastric cancer (GC), we aimed to characterize the expression of the checkpoint proteins V-domain Ig suppressor of T-cell activation (VISTA), programmed cell death 1 ligand 1 (PD-L1), and programmed cell death protein-1 (PD-1) in a cohort of GCs following platinum-based neoadjuvant chemotherapy. A total of 141 GC samples, 93 lymph node metastases, and 15 distant metastases were assessed using immunohistochemistry. Staining results were correlated with clinicopathological patient characteristics, genetic alterations, and survival. The expression of VISTA was detected in tumor cells of 38 (30.9%) GCs and immune cells of 139 (98.6%) GCs. The expression of PD-L1 was detected in tumor cells of 27 (22.7%) GCs and immune cells of 134 (96.4%) GCs. The expression of PD-1 was only observed in lymphocyte aggregates/intratumoral lymphoid follicles of 123 (87.2%) GCs. VISTA and PD-L1 correlated in their expression and were associated with poor tumor regression. Compared with an ancient cohort of therapy naïve GCs, we observed a major increase in overall immune cell density accompanied by an over proportional increase in PD-1 and VISTA-positive immune cells. The frequency of VISTA expression in tumor cells was also found to be substantially increased. To the contrary, expression of PD-L1 was decreased in immune cells and tumor cells of neoadjuvantly treated GCs. As a result, a subset of GCs using a single (only VISTA or PD-L1) or combined (VISTA and PD-L1) immune evasion mechanisms might benefit from an anti-PD-L1/anti-VISTA–targeted therapy.

  • Combined Metabolomics and Genome-Wide Transcriptomics Analyses Show Multiple HIF1α-Induced Changes in Lipid Metabolism in Early Stage Clear Cell Renal Cell Carcinoma
    Transl. Oncol. (IF 3.138) Pub Date : 2019-12-19
    Johannes C. van der Mijn; Leiping Fu; Francesca Khani; Tuo Zhang; Ana M. Molina; Christopher E. Barbieri; Qiuying Chen; Steven S. Gross; Lorraine J. Gudas; David M. Nanus

    The accumulation of lipids is a hallmark of human clear cell renal cell carcinoma (ccRCC). Advanced ccRCC tumors frequently show increased lipid biosynthesis, but the regulation of lipid metabolism in early stage ccRCC tumors has not been studied. Here, we performed combined transcriptomics and metabolomics on a previously characterized transgenic mouse model (TRAnsgenic Cancer of the Kidney, TRACK) of early stage ccRCC. We found that in TRACK kidneys, HIF1α activation increases transcripts of lipid receptors (Cd36, ACVRL1), lipid storage genes (Hilpda and Fabp7), and intracellular levels of essential fatty acids, including linoleic acid and linolenic acid. Feeding the TRACK mice a high-fat diet enhances lipid accumulation in the kidneys. These results show that HIF1α increases the uptake and storage of dietary lipids in this early stage ccRCC model. By then analyzing early stage human ccRCC specimens, we found similar increases in CD36 transcripts and increases in linoleic and linolenic acid relative to normal kidney samples. CD36 mRNA levels decreased, while FASN transcript levels increased with increasing ccRCC tumor stage. These results suggest that an increase in the lipid biosynthesis pathway in advanced ccRCC tumors may compensate for a decreased capacity of these advanced ccRCCs to scavenge extracellular lipids.

  • Tumor Infiltrating Lymphocytes and NHERF1 Impact on Prognosis of Breast Cancer Patients
    Transl. Oncol. (IF 3.138) Pub Date : 2019-12-19
    Laura Schirosi; Concetta Saponaro; Francesco Giotta; Ondina Popescu; Maria Irene Pastena; Emanuela Scarpi; Anita Mangia

    BACKGROUND: Breast cancer (BC) is a heterogeneous disease, and patients with apparently similar clinicopathological characteristics in clinical practice show different outcome. This study evaluated in primary BCs and in the subgroup of the triple-negative breast cancers (TNBCs) the level of tumor infiltrating lymphocytes (TILs), Na+/H+ exchanger regulatory factor 1 (NHERF1) expression, and their association respect to the clinical outcome of patients. MATERIAL AND METHODS: NHERF1 expression was assessed by immunohistochemistry in 338 BC samples; the analysis of TILs was examined using hematoxylin and eosin stained slides, according to International TILs Working Group 2014. RESULTS: Multivariate analysis identified TILs as an independent prognostic factor for DFS in the entire cohort and in the TNBC subgroup (HR, 0.32; 95% CI, 0.12–0.87; P = 0.026; and HR, 0.22; 95% CI, 0.06–0.80; P = 0.022, respectively). Univariate and survival analysis by Kaplan–Meier method revealed that patients with cytoplasmic (c) NHERF1-/TILs+ expression had better DFS than other patients (P = 0.049), and this result was also found in the TNBC subgroup (P = 0.031). Moreover, TNBC patients with cNHERF1−/TILs− expression had a worse DFS and OS than other patients (P = 0.057 and P = 0.002, respectively). CONCLUSIONS: In the complex scenario of BC and in the era of tumor immunogenicity and immunotherapy, we found an association of TIL levels and cNHERF1 expression that could be useful to identify BCs and particularly TNBC patients with different prognosis and clinical outcome.

  • Predicting Therapeutic Efficacy of Vascular Disrupting Agent CA4P in Rats with Liver Tumors by Hepatobiliary Contrast Agent Mn-DPDP-Enhanced MRI
    Transl. Oncol. (IF 3.138) Pub Date : 2019-12-03
    Yewei Liu, Qiu Guan, Xiangyong Kong, Frederik De Keyzer, Yuanbo Feng, Feng Chen, Jie Yu, Jianjun Liu, Shaoli Song, Jos van Pelt, Johan Swinnen, Guy Bormans, Raymond Oyen, Shuncong Wang, Gang Huang, Yicheng Ni, Yue Li

    To evaluate hepatobiliary-specific contrast agent (CA) mangafodipir trisodium (Mn-DPDP)–enhanced magnetic resonance imaging (MRI) for predicting the therapeutic efficacy of the vascular disrupting agent combretastatin A4 phosphate (CA4P) in rats with primary and secondary liver tumors, 36 primary hepatocellular carcinomas (HCCs) were raised by diethylnitrosamine gavage in 16 male rats, in 6 of which one rhabdomyosarcomas (R1) was intrahepatically implanted as secondary liver tumors. On a 3.0T MR scanner with a wrist coil, tumors were monitored weekly by T2-/T1-weighted images (T2WI/T1WI) and characterized by Mn-DPDP-enhanced MRI. CA4P-induced intratumoral necrosis was depicted by nonspecific gadoterate meglumine (Gd-DOTA)–enhanced MRI before and 12 h after therapy. Changes of tumor-to-liver contrast (ΔT/L) on Mn-DPDP-enhanced images were analyzed. In vivo MRI findings were verified by postmortem microangiography and histopathology. Rat models of primary HCCs in a full spectrum of differentiation and secondary R1 liver tumors were successfully generated. Mn-DPDP-enhanced ΔT/L was negatively correlated with HCC differentiation grade (P < 0.01). After treatment with CA4P, more extensive tumoral necrosis was found in highly differentiated HCCs than that in moderately and poorly differentiated ones (P < 0.01); nearly complete necrosis was induced in secondary liver tumors. Mn-DPDP-enhanced MRI may help in imaging diagnosis of primary and secondary liver malignancies of different cellular differentiations and further in predicting CA4P therapeutic efficacy in primary HCCs and intrahepatic metastases.

  • Antioxidation and Antiapoptosis Characteristics of Heme Oxygenase-1 Enhance Tumorigenesis of Human Prostate Carcinoma Cells
    Transl. Oncol. (IF 3.138) Pub Date : 2019-12-03
    Kun-Chun Chiang, Ke-Hung Tsui, Yu-Hsiang Lin, Chen-Pang Hou, Kang-Shuo Chang, Hsin-Han Tsai, Yi-Syuan Shin, Chiu-Chun Chen, Tsui-Hsia Feng, Horng-Heng Juang

    Heme oxygenase-1 (HO-1) has antiinflammatory and antioxidant properties and is deemed as a tissue protector. However, effects of HO-1 in prostate cancer remain in controversy. We evaluated the role of HO-1 in prostate carcinoma in vitro and in vivo. Overexpression of HO-1 did not affect prostate cell proliferation in the normal condition but enhanced cell proliferation under serum starvation. HO-1 overexpression enhanced cell invasion of PC-3 cells through epithelial–mesenchymal transition (EMT) induction, which was supported by increased Slug, N-cadherin, and vimentin expressions. In the xenograft animal study, HO-1 overexpression enhanced PC-3 cell tumor growth in vivo. HO-1 attenuated reactive oxygen species induced by H2O2 or pyocyanin treatment in PC-3 and DU145 cells. HO-1 further reduced PC-3 and DU145 cell apoptosis induced by H2O2 or serum starvation. Our results suggested that HO-1 was able to increase prostate carcinoma cell invasion in vitro and tumor growth in vivo. The EMT induction and antioxidant and antiapoptotic effects of HO-1 in the prostate carcinoma cells may be responsible for these findings.

  • Silencing of CHFR Sensitizes Gastric Carcinoma to PARP Inhibitor Treatment
    Transl. Oncol. (IF 3.138) Pub Date : 2019-12-04
    Yuan Li, Yanyan Shi, Xiumin Wang, Xiaochun Yu, Chen Wu, Shigang Ding

    CHFR is a tumor suppressor that not only recognizes poly(ADP-ribosylation) (PARylation) signals at the sites of DNA damage but also is downregulated in many types of cancer. However, the underlying mechanism linking its role in PARylation-mediated DNA damage repair and tumor suppression is unclear. Here, we examined a panel of gastric cancer cell lines as well as primary tissue samples from gastric cancer patients, and found that CHFR expression was silenced by DNA hypermethylation in gastric cancer including 38.46% of primary gastric cancers. DNMT1 was associated with aberrant methylation of CHFR, and the expression of CHFR was restored by DNMT1 inhibitor 5-aza-2-deoxycytidine (5-aza-CdR) treatment. Moreover, we found that loss of CHFR abolished DNA damage repair and sensitized gastric tumor cells to PARP inhibitor treatment. Thus, our study reveals a potential therapeutic approach for treating gastric cancer with PARP inhibitor and lacking CHFR can serve as a biomarker for predicting the efficacy of PARP inhibitor on the gastric tumor treatment in future.

  • Inhibition of Casein Kinase II by CX-4945, But Not Yes-associated protein (YAP) by Verteporfin, Enhances the Antitumor Efficacy of Temozolomide in Glioblastoma
    Transl. Oncol. (IF 3.138) Pub Date : 2019-12-03
    Xiangyu Liu, Jieyu Chen, Wei Li, Chunhua Hang, Yuyuan Dai

    Overcoming temozolomide (TMZ) resistance in glioma cancer cells remains a major challenge to the effective treatment of the disease. Increasing TMZ efficacy for patients with glioblastoma (GBM) is urgently needed because TMZ treatment is the standard chemotherapy protocol for adult patients with glioblastoma. O6-methylguanine-DNA-methyltransferase (MGMT) overexpression is associated with TMZ resistance, and low MGMT is a positive response marker for TMZ therapy. Here, we used 3 glioma cell lines (SF767, U373, and LN229), which had different levels of TMZ sensitivity. We found TMZ sensitivity is positively correlated with MGMT expression and multidrug-resistance protein ABC subfamily G member 2 (ABCG2) in these cells. CK2-STAT3 signaling and Hippo-YAP signaling are reported to regulate MGMT expression and ABCG2 expression, respectively. We combined CK2 inhibitor CX-4945 and YAP inhibitor verteporfin with TMZ treatment. We found that CX-4945 but not verteporfin can sensitize TMZ-resistant cells SF767 to TMZ and that CX-4945 and TMZ combinational treatment was effective for glioma treatment in mouse models compared with TMZ alone. Implications A combination of CK2 inhibitor with TMZ may improve the therapeutic efficiency of TMZ toward GBM with acquired resistance.

  • Chlamydia trachomatis and Anti-MUC1 Serology and Subsequent Risk of High-Grade Serous Ovarian Cancer: A Population-Based Case–Control Study in Northern Sweden
    Transl. Oncol. (IF 3.138) Pub Date : 2019-12-02
    Sarah Jonsson, Eva Lundin, Fredrik Elgh, Ulrika Ottander, Annika Idahl

    BACKGROUND: Chlamydia trachomatis salpingitis causes inflammatory damage to the fallopian tube and could potentially cause initiation and progression of high-grade serous ovarian cancer (HGSC). Furthermore, C. trachomatis infection may stimulate mucin 1 (MUC1) protein production, possibly affecting anti-MUC1 antibody levels. The aim of this study was to examine if serology indicating past infection with C. trachomatis as well as anti-MUC1 production was associated with subsequent risk of HGSC. MATERIALS AND METHODS: In a prospective nested case–control study within the Northern Sweden Health and Disease Study and the Northern Sweden Maternity Cohort, the prevalence of chlamydial and anti-MUC1 antibodies was analyzed in blood samples drawn more than one year before diagnosis from 92 women with HGSC and 359 matched controls. Matching factors were age, date at blood draw, and sampling cohort. Plasma C. trachomatis IgG was analyzed using commercial micro-immunofluorescence test; chlamydial Heat Shock Protein 60 IgG (cHSP60) and anti-MUC1 IgG were analyzed with ELISA technique. RESULTS: The prevalence of C. trachomatis IgG and cHSP60 IgG antibodies, as well as the level of anti-MUC1 IgG was similar in women with HGSC and controls (16.3% vs. 17.0%, P = 0.87; 27.2% vs. 28.5%, P = 0.80; median 0.24 vs. 0.25, P = 0.70). Anti-MUC1 IgG and cHSP60 IgG levels were correlated (r = 0.169; P < 0.001). CONCLUSIONS: The findings of this prospective nested case–control study did not support an association between C. trachomatis infection, as measured by chlamydial serology, or anti-MUC1 IgG antibodies, and subsequent risk of HGSC.

  • The Impact of High-mobility Group Box Mutation of T-cell Factor 4 on Its Genomic Binding Pattern in Non–small Cell Lung Cancer
    Transl. Oncol. (IF 3.138) Pub Date : 2019-12-02
    Hongjian Su, Yahong Qiao, Zhuona Xi, Jifang Wang, Zhen Bao

    T-cell factor 4 (TCF-4) is determined to play a crucial role in Wnt/β-catenin signaling pathway activation. The mutations and alternative splice isoforms of TCF-4 can cause cancers and other diseases. The high-mobility group (HMG) box domain of TCF-4 contributes to interacting with DNA motif for transcriptional regulation. However, the impact of the mutations within HMG box of TCF-4 on the genomic binding pattern is poorly investigated. Herein, we generated non–small cell lung cancer (NSCLC) cell line A549 with stably overexpressed TCF-4 with HMG box hot spot mutation (10th exon partial deletion), and conducted TCF-4 and β-catenin chromatin immunoprecipitation sequence to explore the differential genomic binding patterns. Our results revealed that TCF-4 lost 19365 but gained 1724 peaks, and β-catenin lost 4035 but gained 5287 peaks upon mutant TCF-4 compared with the wild type (log2FC > 1 or < -1, FDR<0.01). The transcriptional levels of the genes associated with these differential peaks such as H3F3C, KRT1, KRT14, MMp1, and MMP15 were all found to strongly change responding to TCF-4 binding (P < 0.05). Furthermore, A549 cells with TCF-4 mutation displayed a more compromising tumor characterization on cell proliferation and invasion. Our data determined the important role of TCF-4 in gene transcription controlling and provided the gain function evidence of TCF-4 caused by the TCF-4 mutation in NSCLC.

  • Targeting Tumor Microenvironment by Small-Molecule Inhibitors
    Transl. Oncol. (IF 3.138) Pub Date : 2019-11-27
    Shangwei Zhong, Ji-Hak Jeong, Zhikang Chen, Zihua Chen, Jun-Li Luo

    The tumor microenvironment (TME) is a hypoxic, acidic, and immune/inflammatory cell–enriched milieu that plays crucial roles in tumor development, growth, progression, and therapy resistance. Targeting TME is an attractive strategy for the treatment of solid tumors. Conventional cancer chemotherapies are mostly designed to directly kill cancer cells, and the effectiveness is always compromised by their penetration and accessibility to cancer cells. Small-molecule inhibitors, which exhibit good penetration and accessibility, are widely studied, and many of them have been successfully applied in clinics for cancer treatment. As TME is more penetrable and accessible than tumor cells, a lot of efforts have recently been made to generate small-molecule inhibitors that specifically target TME or the components of TME or develop special drug-delivery systems that release the cytotoxic drugs specifically in TME. In this review, we briefly summarize the recent advances of small-molecule inhibitors that target TME for the tumor treatment.

  • Vasorin/ATIA Promotes Cigarette Smoke–Induced Transformation of Human Bronchial Epithelial Cells by Suppressing Autophagy-Mediated Apoptosis
    Transl. Oncol. (IF 3.138) Pub Date : 2019-11-21
    Wenshu Chen, Qiong Wang, Xiuling Xu, Bryanna Saxton, Mathewos Tessema, Shuguang Leng, Swati Choksi, Steven A. Belinsky, Zheng-Gang Liu, Yong Lin

    BACKGROUND: Escaping cell death pathways is an important event during carcinogenesis. We previously identified anti-TNFα-induced apoptosis (ATIA, also known as vasorin) as an antiapoptotic factor that suppresses reactive oxygen species (ROS) production. However, the role of vasorin in lung carcinogenesis has not been investigated. METHODS: Vasorin expression was examined in human lung cancer tissues with immunohistochemistry and database analysis. Genetic and pharmacological approaches were used to manipulate protein expression and autophagy activity in human bronchial epithelial cells (HBECs). ROS generation was measured with fluorescent indicator, apoptosis with release of lactate dehydrogenase, and cell transformation was assessed with colony formation in soft agar. RESULTS: Vasorin expression was increased in human lung cancer tissues and cell lines, which was inversely associated with lung cancer patient survival. Cigarette smoke extract (CSE) and benzo[a]pyrene diol epoxide (BPDE)–induced vasorin expression in HBECs. Vasorin knockdown in HBECs significantly suppressed CSE-induced transformation in association with enhanced ROS accumulation and autophagy. Scavenging ROS attenuated autophagy and cytotoxicity in vasorin knockdown cells, suggesting that vasorin potentiates transformation by impeding ROS-mediated CSE cytotoxicity and improving survival of the premalignant cells. Suppression of autophagy effectively inhibited CSE-induced apoptosis, suggesting that autophagy was pro-apoptotic in CSE-treated cells. Importantly, blocking autophagy strongly potentiated CSE-induced transformation. CONCLUSION: These results suggest that vasorin is a potential lung cancer–promoting factor that facilitates cigarette smoke–induced bronchial epithelial cell transformation by suppressing autophagy-mediated apoptosis, which could be exploited for lung cancer prevention.

  • Molecular Pathway Analysis Indicates a Distinct Metabolic Phenotype in Women With Right-Sided Colon Cancer
    Transl. Oncol. (IF 3.138) Pub Date : 2019-11-21
    Yazhi Sun, Varvara Mironova, Ying Chen, Elliott P.F. Lundh, Qian Zhang, Yuping Cai, Vasilis Vasiliou, Yawei Zhang, Rolando Garcia-Milian, Sajid A. Khan, Caroline H. Johnson

    Colon cancer is the third most commonly diagnosed cancer in the United States. Recent reports have shown that the location of the primary tumor is of clinical importance. Patients with right-sided colon cancers (RCCs) (tumors arising between the cecum and proximal transverse colon) have poorer clinical outcomes than those with left-sided colon cancers (LCCs) (tumors arising between the distal transverse colon and sigmoid colon, excluding the rectum). Interestingly, women have a lower incidence of colon cancer than men, but have a higher propensity for RCC. The reason for this difference is not known; however, identification of sex-specific differences in gene expression by tumor anatomical location in the colon could provide further insight. Moreover, it could reveal important predictive markers for response to various treatments. This study provides a comprehensive bioinformatic analysis of various genes and molecular pathways that correlated with sex and anatomical location of colon cancers using four publicly available annotated data sets housed in the National Center for Biotechnology Information's Gene Expression Omnibus. We identified differentially expressed genes in tumor tissues from women with RCC, which showed attenuated energy and nutrient metabolism when compared with women with LCC. Specifically, we showed the downregulation of 5′ AMP-activated protein kinase alpha subunit (AMPKα) and anti-tumor immune responses in women with RCC. This difference was not seen when comparing tumor tissues from men with RCC to men with LCC. Therefore, women with RCC may have a specific metabolic and immune phenotype which accounts for differences in prognosis and treatment response.

  • Concurrent Chemoradiotherapy With or Without Induction Chemotherapy for Patients with Stage II Nasopharyngeal Carcinoma: An Update
    Transl. Oncol. (IF 3.138) Pub Date : 2019-11-16
    Ting Jin, Qun Zhang, Dong-Hua Luo, Feng Jiang, Qi-Feng Jin, Yuan-Yuan Chen, Xiao-Zhong Chen, Wei-Min Mao

    PURPOSE: In contrast to other studies, our previous study showed that adding induction chemotherapy (IC) to concurrent chemoradiotherapy (CCRT) significantly worsened the prognosis of patients with stage II nasopharyngeal carcinoma (NPC). However, the population used was small; therefore, there is an urgent need to confirm the result in a larger population because IC is still widely used in certain sections of china for stage II NPC. METHODS AND MATERIALS: We retrospectively analyzed an additional 272 patients. Therefore, in total, we report the results for 445 patients with stage II NPC treated with IC + CCRT or CCRT between June 2003 to June 2016 at the Zhejiang Cancer Hospital and Sun Yat-Sen University Cancer Center. RESULTS: This study included 445 patients treated with IC + CCRT (n = 195) or CCRT (n = 250). By last analysis, 22 (11.3%) patients in the IC + CCRT group developed local-regional recurrence and 23 (11.8%) patients developed distant metastases. Twenty-four (9.6%) patients in the CCRT group developed local-regional recurrence and 12 (4.8%) patients developed distant metastases. Univariate analyses showed that adding IC to CCRT significantly decreased the 5-year disease-free survival (DFS) (80.6% vs. 88.5%, P = .043); however, there was no statistically significant difference in 5-year overall survival (OS) (90.5% vs. 95.0%, P = .375). CONCLUSION: Using a larger population, the present study showed that adding IC to CCRT had a negative effect on patients with stage II NPC, which warrants further investigation.

  • Ectonucleotidase CD39 and Checkpoint Signalling Receptor Programmed Death 1 are Highly Elevated in Intratumoral Immune Cells in Non–small-cell Lung Cancer
    Transl. Oncol. (IF 3.138) Pub Date : 2019-11-13
    Anders Tøndell, Sissel Gyrid Freim Wahl, Anne-Marit Sponaas, Sveinung Sørhaug, Magne Børset, Markus Haug

    Lung cancer is the leading cause of cancer death in both sexes worldwide and has a predicted 5-year survival rate of <20%. Immunotherapy targeting immune checkpoints such as the programmed death 1 (PD-1) signaling pathway has led to a shift of paradigm in the treatment of advanced non–small-cell lung cancer (NSCLC) but remains without effect in ∼80% of patients. Accumulating evidence suggests that several immunosuppressive mechanisms may work together in NSCLC. The contribution and cooperation between different immunosuppressive mechanisms in NSCLC remain unknown. Recently, the CD39-adenosine pathway has gained increasing attention as a crucial immunosuppressive mechanism and possible target for immunotherapy. Immune cells were extracted from lung and tumor tissue after lung resection in 12 patients by combined enzymatic and mechanical tissue disaggregation. A multiparameter flow cytometry panel was established to investigate the expression and coexpression of CD39 and PD-1 on key lymphocyte subtypes. Frequencies of CD39+, PD-1+, and CD39+/PD-1+cells were higher among both CD4+ and CD8+ T cells isolated from NSCLC tumor tissue than in T cells from normal lung tissue. Similarly, the frequency of FoxP3+ CD4+ T cells (Tregs) was highly significantly elevated in tumor tissue compared to adjacent lung tissue. The consistent upregulation of CD39 on immune cells in tumor microenvironment indicates that the CD39 signaling pathway may, in addition to the PD-1 pathway, represent another important mechanism for tumor-induced immunosuppression in NSCLC. In addition, the present study indicates that a comprehensive immune response profiling with flow cytometry may be both feasible and clinically relevant.

  • Cell Population Data–Driven Acute Promyelocytic Leukemia Flagging Through Artificial Neural Network Predictive Modeling
    Transl. Oncol. (IF 3.138) Pub Date : 2019-11-13
    Rana Zeeshan Haider, Ikram Uddin Ujjan, Tahir S. Shamsi

    A targeted and timely offered treatment can be a benefitting tool for patients with acute promyelocytic leukemia (APML). Current round of study made use of potential morphological and immature fraction–related parameters (cell population data) generated during complete blood cell count (CBC), through artificial neural network (ANN) predictive modeling for early flagging of APML cases. We collected classical CBC items along with cell population data (CPD) from hematology analyzer at diagnosis of 1067 study subjects with hematological neoplasms. For morphological assessment, peripheral blood films were examined. Statistical and machine learning tools including principal component analysis (PCA) helped in the evaluation of predictive capacity of routine and CPD items. Then selected CBC item–driven ANN predictive modeling was developed to smartly use the hidden trend by increasing the auguring accuracy of these parameters in differentiation of APML cases. We found a characteristic triad based on lower (53.73) platelet count (PLT) with decreased/normal (4.72) immature fraction of platelet (IPF) with addition of significantly higher value (65.5) of DNA/RNA content–related neutrophil (NE-SFL) parameter in patients with APML against other hematological neoplasm's groups. On PCA, APML showed exceptionally significant variance for PLT, IPF, and NE-SFL. Through training of ANN predictive modeling, our selected CBC items successfully classify the APML group from non-APML groups at highly significant (0.894) AUC value with lower (2.3 percent) false prediction rate. Practical results of using our ANN model were found acceptable with value of 95.7% and 97.7% for training and testing data sets, respectively. We proposed that PLT, IPF, and NE-SFL could potentially be used for early flagging of APML cases in the hematology-oncology unit. CBC item–driven ANN modeling is a novel approach that substantially strengthen the predictive potential of CBC items, allowing the clinicians to be confident by the typical trend raised by these studied parameters.

  • Development of a Microfluidic Culture Paradigm for Ex Vivo Maintenance of Human Glioblastoma Tissue: A New Glioblastoma Model?
    Transl. Oncol. (IF 3.138) Pub Date : 2019-11-11
    Farouk Olubajo, Shailendra Achawal, John Greenman

    BACKGROUND: One way to overcome the genetic and molecular variations within glioblastoma is to treat each tumour on an individual basis. To facilitate this, we have developed a microfluidic culture paradigm that maintains human glioblastoma tissue ex vivo. METHODS: The assembled device, fabricated using a photolithographic process, is composed of two layers of glass bonded together to contain a tissue chamber and a network of microchannels that allow continued tissue perfusion. RESULTS: A total of 128 tissue biopsies (from 33 patients) were maintained in microfluidic devices for an average of 72 hours. Tissue viability (measured with Annexin V and propidium iodide) was 61.1% in tissue maintained on chip compared with 68.9% for fresh tissue analysed at commencement of the experiments. Other biomarkers, including lactate dehydrogenase absorbance and trypan blue exclusion, supported the viability of the tissue maintained on chip. Histological appearances remained unchanged during the tissue maintenance period, and immunohistochemical analysis of Ki67 and caspase 3 showed no significant differences when compared with fresh tissues. A trend showed that tumours associated with poorer outcomes (recurrent tumours and Isocitrate Dehydrogenase - IDH wildtype) displayed higher viability on chip than tumours linked with improved outcomes (low-grade gliomas, IDH mutants and primary tumours). conclusions: This work has demonstrated for the first time that human glioblastoma tissue can be successfully maintained within a microfluidic device and has the potential to be developed as a new platform for studying the biology of brain tumours, with the long-term aim of replacing current preclinical GBM models and facilitating personalised treatments.

  • Elevated Microsatellite Alterations at Selected Tetranucleotides (EMAST) Is Not Attributed to MSH3 Loss in Stage I-III Colon cancer: An Automated, Digitalized Assessment by Immunohistochemistry of Whole Slides and Hot Spots
    Transl. Oncol. (IF 3.138) Pub Date : 2019-10-31
    Martin M Watson, Dordi Lea, Hanne R. Hagland, Kjetil Søreide

    INTRODUCTION: EMAST is a poorly understood form of microsatellite instability (MSI) in colorectal cancer (CRC) for which loss of MSH3 has been proposed as the underlying mechanism, based on experimental studies. We aimed to evaluate whether MSH3 loss is associated with EMAST in CRC. METHODS: A consecutive cohort of patients with stage I-III CRC. Digital image analysis using heatmap-derived hot spots investigated MSH3 expression by immunohistochemistry. Fragment analysis of multiplex PCR was used to assess MSI and EMAST, and results cross-examined with MSH3 protein expression. RESULTS: Of 152 patients, EMAST was found in 50 (33%) and exclusively in the colon. Most EMAST-positive cancers had instability at all 5 markers, and EMAST overlapped with MSI-H in 42/50 cases (84%). The most frequently altered tetranucleotide markers were D8S321 (38.2% of tumors) and D20S82 (34.4%). Subjective evaluation of MSH3 expression by IHC in tumor found ≤10% negative tumor cells in all samples, most being ≤5% negative. Digital analysis improved the detection but showed a similar spread of MSH3 loss (range 0.1–15.7%, mean 2.2%). Hotspot MSH3 negativity ranged between 0.1 to 95.0%, (mean 8.6%) with significant correlation with the whole slide analysis (Spearman's rho = 0.677 P < .001). Loss of MSH3 expression did not correlate with EMAST. CONCLUSIONS: In a well-defined cohort of patients with CRC, loss of MSH3 was not associated with EMAST. Further investigation into the mechanisms leading to EMAST in CRC is needed.

  • miR-888: A Novel Cancer-Testis Antigen that Targets the Progesterone Receptor in Endometrial Cancer.
    Transl. Oncol. (IF 3.138) Pub Date : 2015-05-01
    Adriann M Hovey,Eric J Devor,Patrick J Breheny,Sarah L Mott,Donghai Dai,Kristina W Thiel,Kimberly K Leslie

    Cancer-testis (CT) antigens are a large family of genes that are selectively expressed in human testis germ cells, overexpressed in a variety of tumors and predominantly located on the X chromosome. To date, all known CT antigens are protein-coding genes. Here, we identify miR-888 as the first miRNA with features characteristic of a CT antigen. In a panel of 21 normal human tissues, miR-888 expression was high in testes and minimal or absent in all other examined tissues. In situ hybridization localized miR-888 expression specifically to the early stages of sperm development within the testes. Using The Cancer Genome Atlas database, we discovered that miR-888 was predominately expressed in endometrial tumors, with a significant association to high-grade tumors and increased percent invasion. In a separate panel of endometrial tumor specimens, we validated overexpression of miR-888 by real-time polymerase chain reaction. In addition, miR-888 expression was highest in endometrial carcinosarcoma, a rare and aggressive type of endometrial tumor. Moreover, we identified the progesterone receptor (PR), a potent endometrial tumor suppressor, as a direct target of miR-888. These data define miR-888 as the first miRNA CT antigen and a potential mediator of an aggressive endometrial tumor phenotype through down-regulation of PR.

  • The Epithelial Sodium Channel (αENaC) Is a Downstream Therapeutic Target of ASCL1 in Pulmonary Neuroendocrine Tumors.
    Transl. Oncol. (IF 3.138) Pub Date : 2018-02-08
    Min He,Shanshan Liu,Sachith Gallolu Kankanamalage,Mark D Borromeo,Luc Girard,Adi F Gazdar,John D Minna,Jane E Johnson,Melanie H Cobb

    Small cell lung cancer (SCLC) is an aggressive neuroendocrine carcinoma, designated as a recalcitrant cancer by the National Cancer Institute, in urgent need of new rational therapeutic targets. Previous studies have determined that the basic helix-loop-helix transcription factor achaete-scute homolog 1 (ASCL1) is essential for the survival and progression of a fraction of pulmonary neuroendocrine cancer cells, which include both SCLC and a subset of non-SCLC. Previously, to understand how ASCL1 initiates tumorigenesis in pulmonary neuroendocrine cancer and identify the transcriptional targets of ASCL1, whole-genome RNA-sequencing analysis combined with chromatin immunoprecipitation-sequencing was performed with a series of lung cancer cell lines. From this analysis, we discovered that the gene SCNN1A, which encodes the alpha subunit of the epithelial sodium channel (αENaC), is highly correlated with ASCL1 expression in SCLC. The product of the SCNN1A gene ENaC can be pharmacologically inhibited with amiloride, a drug that has been used clinically for close to 50 years. Amiloride inhibited growth of ASCL1-dependent SCLC more strongly than ASCL1-independent SCLC in vitro and slowed growth of ASCL1-driven SCLC in xenografts. We conclude that SCNN1A/αENaC is a direct transcriptional target of the neuroendocrine lung cancer lineage oncogene ASCL1 that can be pharmacologically targeted with antitumor effects.

  • Corrigendum to "Detection of Circulating Tumor Cells and Circulating Tumor Microemboli in Gastric Cancer" [Transl Oncol 10/3 (2017) 431-441].
    Transl. Oncol. (IF 3.138) Pub Date : 2018-12-17
    Xiumei Zheng,Li Fan,Pengfei Zhou,Hong Ma,Shaoyi Huang,Dandan Yu,Lei Zhao,Shengli Yang,Jun Liu,Ai Huang,Congli Cai,Xiaomeng Dai,Tao Zhang

  • Erratum.
    Transl. Oncol. (IF 3.138) Pub Date : 2013-10-24

    [This corrects the article on p. 394 in vol. 6.].

  • Human ribonuclease with a pendant poly(ethylene glycol) inhibits tumor growth in mice.
    Transl. Oncol. (IF 3.138) Pub Date : 2013-08-03
    Thomas J Rutkoski,John A Kink,Laura E Strong,Ronald T Raines

    Human pancreatic ribonuclease (RNase 1) is a small secretory protein that catalyzes the cleavage of RNA. This highly cationic enzyme can enter human cells spontaneously but is removed rapidly from circulation by glomerular filtration. Here, this shortcoming is addressed by attaching a poly(ethylene glycol) (PEG) moiety to RNase 1. The pendant has no effect on ribonucleolytic activity but does increase persistence in circulation. The RNase 1-PEG conjugates inhibit the growth of tumors in a xenograft mouse model of human lung cancer. Both retention in circulation and tumor growth inhibition correlate with the size of the pendant PEG. A weekly dose of the 60-kDa conjugate at 1 µmol/kg inhibited nearly all tumor growth without affecting body weight. Its molecular efficacy is ∼5000-fold greater than that of erlotinib, which is a small molecule in clinical use for the treatment of lung cancer. These data demonstrate that the addition of a PEG moiety can enhance the in vivo efficacy of human proteins that act within cells and highlight a simple means of converting an endogenous human enzyme into a cytotoxin with potential clinical utility.

  • Inactivation of SAG or ROC1 E3 Ligase Inhibits Growth and Survival of Renal Cell Carcinoma Cells: Effect of BIM.
    Transl. Oncol. (IF 3.138) Pub Date : 2019-04-08
    Yu Wang,Mingjia Tan,Hua Li,Haomin Li,Yi Sun

    SAG (Sensitive to Apoptosis Gene) and ROC1 (Regulator of Cullin-1) are two family members of the RING component of CRL (Cullin RING ligase). Both members are essential for growth and survival of several types of human cancer cells; their role in renal cell carcinoma (RCC), however, remains elusive. Here we reported that compared to adjacent normal tissues, both SAG and ROC1 are overexpressed in RCC, which is positively correlated with poor patient survival, particularly for SAG. Depletion of SAG or ROC1 inhibited growth and survival of RCC cells by inducing G2/M arrest, senescence, and apoptosis likely due to accumulation of WEE1, p21, p27, NOXA, and BIM. Interestingly, simultaneous BIM knockdown in RCC cells partially rescues growth suppression triggered by depletion of SAG, but not ROC1, suggesting a differential role of BIM. Collectively, our study provides the proof-of-concept evidence that RING components of CRL are attractive candidates for targeted therapy of RCC.

  • Homoharringtonine Combined with the Heat Shock Protein 90 Inhibitor IPI504 in the Treatment of FLT3-ITD Acute Myeloid Leukemia.
    Transl. Oncol. (IF 3.138) Pub Date : 2019-04-07
    Zhaoxing Wu,Haifeng Zhuang,Qingfeng Yu,Xuzhao Zhang,Xudong Jiang,Xiaoya Lu,Ying Xu,Linlin Yang,Bowen Wu,An Ma,Lei Zhang,Xibin Xiao,Yun Liang,Ruilan Gao,Jianping Shen,Rongzhen Xu

    As a heterogeneous group of clonal disorders, acute myeloid leukemia with internal tandem duplication of fms-like tyrosine kinase 3 (FLT3-ITD) mutation usually shows an inferior prognosis. In the present study, we found that homoharringtonine (HHT), a protein translation inhibitor of plant alkaloid in China, exhibited potent cytotoxic effect against FLT3-ITD (+) cell lines and primary leukemia cells, and a remarkable synergistic anti-leukemia action was demonstrated in vitro and in vivo in xenograft mouse models when co-treated with the heat shock protein 90 inhibitor IPI504. Mechanistically, HHT combined with IPI504 synergistically inhibited the growth of leukemia cells by inducing apoptosis and G1 phase arrest. This synergistic action resulted in a prominent reduction of total and phosphorylated FLT3 (p-FLT3) as well as inhibition of its downstream signaling molecules such as STAT5, AKT, ERK and 4E-BP1. Furthermore, co-treatment of HHT and IPI504 led to a synergistic or additive effect on 55.56%(10/18) of acute myeloid leukemia cases tested, including three relapsed/refractory patients. In conclusion, our findings indicate that the combination of HHT and HSP90 inhibitor provides an alternative way for the treatment of FLT3-ITD positive acute myeloid leukemia, especially for relapsed/refractory AML.

  • Antibody-Guided In Vivo Imaging for Early Detection of Mammary Gland Tumors.
    Transl. Oncol. (IF 3.138) Pub Date : 2016-08-29
    Laura Jeffords Moore,Lopamudra Das Roy,Ru Zhou,Priyanka Grover,Shu-Ta Wu,Jennifer M Curry,Lloye M Dillon,Priya M Puri,Mahboubeh Yazdanifar,Rahul Puri,Pinku Mukherjee,Didier Dréau

    BACKGROUND Earlier detection of transformed cells using target-specific imaging techniques holds great promise. We have developed TAB 004, a monoclonal antibody highly specific to a protein sequence accessible in the tumor form of MUC1 (tMUC1). We present data assessing both the specificity and sensitivity of TAB 004 in vitro and in genetically engineered mice in vivo. METHODS Polyoma Middle T Antigen mice were crossed to the human MUC1.Tg mice to generate MMT mice. In MMT mice, mammary gland hyperplasia is observed between 6 and 10 weeks of age that progresses to ductal carcinoma in situ by 12 to 14 weeks and adenocarcinoma by 18 to 24 weeks. Approximately 40% of these mice develop metastasis to the lung and other organs with a tumor evolution that closely mimics human breast cancer progression. Tumor progression was monitored in MMT mice (from ages 8 to 22 weeks) by in vivo imaging following retro-orbital injections of the TAB 004 conjugated to indocyanine green (TAB-ICG). At euthanasia, mammary gland tumors and normal epithelial tissues were collected for further analyses. RESULTS In vivo imaging following TAB-ICG injection permitted significantly earlier detection of tumors compared with physical examination. Furthermore, TAB-ICG administration in MMT mice enabled the detection of lung metastases while sparing recognition of normal epithelia. CONCLUSIONS The data highlight the specificity and the sensitivity of the TAB 004 antibody in differentiating normal versus tumor form of MUC1 and its utility as a targeted imaging agent for early detection, tumor monitoring response, as well as potential clinical use for targeted drug delivery.

  • Variations of dynamic contrast-enhanced magnetic resonance imaging in evaluation of breast cancer therapy response: a multicenter data analysis challenge.
    Transl. Oncol. (IF 3.138) Pub Date : 2014-04-29
    Wei Huang,Xin Li,Yiyi Chen,Xia Li,Ming-Ching Chang,Matthew J Oborski,Dariya I Malyarenko,Mark Muzi,Guido H Jajamovich,Andriy Fedorov,Alina Tudorica,Sandeep N Gupta,Charles M Laymon,Kenneth I Marro,Hadrien A Dyvorne,James V Miller,Daniel P Barbodiak,Thomas L Chenevert,Thomas E Yankeelov,James M Mountz,Paul E Kinahan,Ron Kikinis,Bachir Taouli,Fiona Fennessy,Jayashree Kalpathy-Cramer

    Pharmacokinetic analysis of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) time-course data allows estimation of quantitative parameters such as K (trans) (rate constant for plasma/interstitium contrast agent transfer), v e (extravascular extracellular volume fraction), and v p (plasma volume fraction). A plethora of factors in DCE-MRI data acquisition and analysis can affect accuracy and precision of these parameters and, consequently, the utility of quantitative DCE-MRI for assessing therapy response. In this multicenter data analysis challenge, DCE-MRI data acquired at one center from 10 patients with breast cancer before and after the first cycle of neoadjuvant chemotherapy were shared and processed with 12 software tools based on the Tofts model (TM), extended TM, and Shutter-Speed model. Inputs of tumor region of interest definition, pre-contrast T1, and arterial input function were controlled to focus on the variations in parameter value and response prediction capability caused by differences in models and associated algorithms. Considerable parameter variations were observed with the within-subject coefficient of variation (wCV) values for K (trans) and v p being as high as 0.59 and 0.82, respectively. Parameter agreement improved when only algorithms based on the same model were compared, e.g., the K (trans) intraclass correlation coefficient increased to as high as 0.84. Agreement in parameter percentage change was much better than that in absolute parameter value, e.g., the pairwise concordance correlation coefficient improved from 0.047 (for K (trans)) to 0.92 (for K (trans) percentage change) in comparing two TM algorithms. Nearly all algorithms provided good to excellent (univariate logistic regression c-statistic value ranging from 0.8 to 1.0) early prediction of therapy response using the metrics of mean tumor K (trans) and k ep (=K (trans)/v e, intravasation rate constant) after the first therapy cycle and the corresponding percentage changes. The results suggest that the interalgorithm parameter variations are largely systematic, which are not likely to significantly affect the utility of DCE-MRI for assessment of therapy response.

  • Quantitative Imaging Network: Data Sharing and Competitive AlgorithmValidation Leveraging The Cancer Imaging Archive.
    Transl. Oncol. (IF 3.138) Pub Date : 2014-04-29
    Jayashree Kalpathy-Cramer,John Blake Freymann,Justin Stephen Kirby,Paul Eugene Kinahan,Fred William Prior

    The Quantitative Imaging Network (QIN), supported by the National Cancer Institute, is designed to promote research and development of quantitative imaging methods and candidate biomarkers for the measurement of tumor response in clinical trial settings. An integral aspect of the QIN mission is to facilitate collaborative activities that seek to develop best practices for the analysis of cancer imaging data. The QIN working groups and teams are developing new algorithms for image analysis and novel biomarkers for the assessment of response to therapy. To validate these algorithms and biomarkers and translate them into clinical practice, algorithms need to be compared and evaluated on large and diverse data sets. Analysis competitions, or "challenges," are being conducted within the QIN as a means to accomplish this goal. The QIN has demonstrated, through its leveraging of The Cancer Imaging Archive (TCIA), that data sharing of clinical images across multiple sites is feasible and that it can enable and support these challenges. In addition to Digital Imaging and Communications in Medicine (DICOM) imaging data, many TCIA collections provide linked clinical, pathology, and "ground truth" data generated by readers that could be used for further challenges. The TCIA-QIN partnership is a successful model that provides resources for multisite sharing of clinical imaging data and the implementation of challenges to support algorithm and biomarker validation.

  • A Virtual Clinical Trial of FDG-PET Imaging of Breast Cancer: Effect of Variability on Response Assessment.
    Transl. Oncol. (IF 3.138) Pub Date : 2014-04-29
    Robert L Harrison,Brian F Elston,Robert K Doot,Thomas K Lewellen,David A Mankoff,Paul E Kinahan

    INTRODUCTION There is growing interest in using positron emission tomography (PET) standardized uptake values (SUVs) to assess tumor response to therapy. However, many error sources compromise the ability to detect SUV changes. We explore relationships between these errors and overall SUV variability. METHODS We used simulations in a virtual clinical trial framework to study impacts of error sources from scanning and analysis effects on assessment of SUV changes. We varied tumor diameter, scan duration, pretherapy SUV, magnitude of change in SUV, image reconstruction filter, and SUV metric. Poisson noise was added to the raw data before image reconstruction. Variance from global sources of error, e.g., scanner calibration, was incorporated. Two thousand independent noisy sinograms per scenario were generated and reconstructed. We used SUVs to create receiver operating characteristic (ROC) curves to quantify ability to assess response. Integrating area under the ROC curve summarized ability to detect SUV changes. RESULTS Scan duration and image reconstruction method had relatively little impact on ability to measure response. SUVMAX is nearly as effective as SUVMEAN, especially with increased image smoothing and despite size-matched region of interest placement. For an effective variability of 15%, we found the Positron Emission Tomography Response Criteria in Solid Tumors criteria for measuring response (±30%) similar to the European Organization for Research and Treatment of Cancer criteria (±25%). CONCLUSIONS For typical PET variance levels, tumor response must be 30% to 40% to be reliably determined using SUVs. PET scan duration and image reconstruction method had relatively little effect.

  • Repeatability of quantitative MRI measurements in normal breast tissue.
    Transl. Oncol. (IF 3.138) Pub Date : 2014-04-29
    Sheye O Aliu,Ella F Jones,Ania Azziz,John Kornak,Lisa J Wilmes,David C Newitt,Sachiko A Suzuki,Catherine Klifa,Jessica Gibbs,Evelyn C Proctor,Bonnie N Joe,Nola M Hylton

    PURPOSE To evaluate the variability and repeatability of repeated magnetic resonance imaging (MRI) measurements in normal breast tissues between and within subjects. METHODS Eighteen normal premenopausal subjects underwent two contrast-enhanced MRI scans within 72 hours or during the same menstrual phase in two consecutive months. A subset of nine women also completed diffusion-weighted imaging (DWI). Fibroglandular tissue (FGT) density and FGT enhancement were measured on the contrast-enhanced MRI. Apparent diffusion coefficient (ADC) values were computed from DWI. Between- and within-subject coefficients of variation (bCV and wCV, respectively) were assessed. Repeatability of all measurements was assessed by the coefficient of repeatability (CR) and Bland-Altman plots. RESULTS The bCV of FGT density and FGT enhancement at visit 1 and visit 2 ranged from 47% to 63%. The wCV was 13% for FGT density, 22% for FGT enhancement, and 11% for ADC. The CRs of FGT density and FGT enhancement were 0.15 and 0.19, respectively, and for ADC, it was 6.1 x 10(-4) mm(2)/s. CONCLUSIONS We present an estimate of the variability and repeatability of MR measurements in normal breasts. These estimates provide the basis for understanding the normal variation of healthy breast tissue in MRI and establishing thresholds for agreement between measurements.

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上海纽约大学William Glover