Cancer Medicine by Alexandros G.Sfakianakis,Anapafseos 5 Agios Nikolaos,Crete 72100,Greece,tel :00302841026182 & 00306932607174
Cancers, Vol. 10, Pages 52: The Epithelial-to-Mesenchymal Transition in Cancer
Cancers doi: 10.3390/cancers10020052
Authors: Joëlle Roche
The epithelial-to-mesenchymal transition (EMT) occurs during normal embryonic development, tissue regeneration, organ fibrosis, and wound healing.[...]
Cancers, Vol. 10, Pages 52: The Epithelial-to-Mesenchymal Transition in Cancer
Cancers doi: 10.3390/cancers10020052
Authors: Joëlle Roche
The epithelial-to-mesenchymal transition (EMT) occurs during normal embryonic development, tissue regeneration, organ fibrosis, and wound healing.[...]
Journal of Adolescent and Young Adult Oncology , Vol. 0, No. 0.
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Publication date: Available online 15 February 2018
Source:Cell Stem Cell
Author(s): Yuichi Hirata, Kazuhiro Furuhashi, Hiroshi Ishii, Hao Wei Li, Sandra Pinho, Lei Ding, Simon C. Robson, Paul S. Frenette, Joji Fujisaki
A crucial player in immune regulation, FoxP3+ regulatory T cells (Tregs) are drawing attention for their heterogeneity and noncanonical functions. Here, we describe a Treg subpopulation that controls hematopoietic stem cell (HSC) quiescence and engraftment. These Tregs highly expressed an HSC marker, CD150, and localized within the HSC niche in the bone marrow (BM). Specific reduction of BM Tregs achieved by conditional deletion of CXCR4 in Tregs increased HSC numbers in the BM. Adenosine generated via the CD39 cell surface ectoenzyme on niche Tregs protected HSCs from oxidative stress and maintained HSC quiescence. In transplantation settings, niche Tregs prevented allogeneic (allo-) HSC rejection through adenosine and facilitated allo-HSC engraftment. Furthermore, transfer of niche Tregs promoted allo-HSC engraftment to a much greater extent than transfer of other Tregs. These results identify a unique niche-associated Treg subset and adenosine as regulators of HSC quiescence, abundance, and engraftment, further highlighting their therapeutic utility.
Publication date: Available online 15 February 2018
Source:Cell Stem Cell
Author(s): Nigel G. Kooreman, Youngkyun Kim, Patricia E. de Almeida, Vittavat Termglinchan, Sebastian Diecke, Ning-Yi Shao, Tzu-Tang Wei, Hyoju Yi, Devaveena Dey, Raman Nelakanti, Thomas P. Brouwer, David T. Paik, Idit Sagiv-Barfi, Arnold Han, Paul H.A. Quax, Jaap F. Hamming, Ronald Levy, Mark M. Davis, Joseph C. Wu
Cancer cells and embryonic tissues share a number of cellular and molecular properties, suggesting that induced pluripotent stem cells (iPSCs) may be harnessed to elicit anti-tumor responses in cancer vaccines. RNA sequencing revealed that human and murine iPSCs express tumor-associated antigens, and we show here a proof of principle for using irradiated iPSCs in autologous anti-tumor vaccines. In a prophylactic setting, iPSC vaccines prevent tumor growth in syngeneic murine breast cancer, mesothelioma, and melanoma models. As an adjuvant, the iPSC vaccine inhibited melanoma recurrence at the resection site and reduced metastatic tumor load, which was associated with fewer Th17 cells and increased CD11b+GR1hi myeloid cells. Adoptive transfer of T cells isolated from vaccine-treated tumor-bearing mice inhibited tumor growth in unvaccinated recipients, indicating that the iPSC vaccine promotes an antigen-specific anti-tumor T cell response. Our data suggest an easy, generalizable strategy for multiple types of cancer that could prove highly valuable in clinical immunotherapy.
Gliomas are the most common primary intrinsic tumor in the brain and are classified as low- or high-grade according to the World Health Organization (WHO). Patients with high-grade gliomas (HGG) who undergo surgical resection with adjuvant therapy have a mean overall survival of 15 months and 100% recurrence. The renin-angiotensin system (RAS), the primary regulator of cardiovascular circulation, exhibits local action and works as a paracrine system. In the context of this local regulation, the expression of RAS peptides and receptors has been detected in different kinds of tumors, including gliomas. The dysregulation of RAS components plays a significant role in the proliferation, angiogenesis, and invasion of these tumors, and therefore in their outcomes. The study and potential application of RAS peptides and receptors as biomarkers in gliomas could bring advantages against the limitations of current tumoral markers and should be considered in the future. The targeting of RAS components by RAS blockers has shown potential of being protective against cancer and improving immunotherapy. In gliomas, RAS blockers have shown a broad spectrum for beneficial effects and are being considered for use in treatment protocols. This review aims to summarize the background behind how RAS plays a role in gliomagenesis and explore the evidence that could lead to their use as biomarkers and treatment adjuvants.
Gliomas are the most common primary intrinsic tumor in the brain and are classified as low- or high-grade according to the World Health Organization (WHO). Patients with high-grade gliomas (HGG) who undergo surgical resection with adjuvant therapy have a mean overall survival of 15 months and 100% recurrence. The renin-angiotensin system (RAS), the primary regulator of cardiovascular circulation, exhibits local action and works as a paracrine system. In the context of this local regulation, the expression of RAS peptides and receptors has been detected in different kinds of tumors, including gliomas. The dysregulation of RAS components plays a significant role in the proliferation, angiogenesis, and invasion of these tumors, and therefore in their outcomes. The study and potential application of RAS peptides and receptors as biomarkers in gliomas could bring advantages against the limitations of current tumoral markers and should be considered in the future. The targeting of RAS components by RAS blockers has shown potential of being protective against cancer and improving immunotherapy. In gliomas, RAS blockers have shown a broad spectrum for beneficial effects and are being considered for use in treatment protocols. This review aims to summarize the background behind how RAS plays a role in gliomagenesis and explore the evidence that could lead to their use as biomarkers and treatment adjuvants.
Publication date: Available online 15 February 2018
Source:Cancer Cell
Author(s): Ling Li, Yingchun Liang, Lei Kang, Yang Liu, Shan Gao, Siyu Chen, Ying Li, Wenye You, Qian Dong, Tian Hong, Zhifeng Yan, Shuai Jin, Tao Wang, Wei Zhao, Haixing Mai, Jun Huang, Xiao Han, Quanbo Ji, Qi Song, Chao Yang, Shixin Zhao, Xiaojie Xu, Qinong Ye
Aerobic glycolysis (the Warburg effect) facilitates tumor growth, and drugs targeting aerobic glycolysis are being developed. However, how the Warburg effect is directly regulated is largely unknown. Here we show that transcription factor SIX1 directly increases the expression of many glycolytic genes, promoting the Warburg effect and tumor growth in vitro and in vivo. SIX1 regulates glycolysis through HBO1 and AIB1 histone acetyltransferases. Cancer-related SIX1 mutation increases its ability to promote aerobic glycolysis and tumor growth. SIX1 glycolytic function is directly repressed by microRNA-548a-3p, which is downregulated, inversely correlates with SIX1, and is a good predictor of prognosis in breast cancer patients. Thus, the microRNA-548a-3p/SIX1 axis strongly links aerobic glycolysis to carcinogenesis and may become a promising cancer therapeutic target.
Publication date: Available online 15 February 2018
Source:Cancer Cell
Author(s): Ana Costa, Yann Kieffer, Alix Scholer-Dahirel, Floriane Pelon, Brigitte Bourachot, Melissa Cardon, Philemon Sirven, Ilaria Magagna, Laetitia Fuhrmann, Charles Bernard, Claire Bonneau, Maria Kondratova, Inna Kuperstein, Andrei Zinovyev, Anne-Marie Givel, Maria-Carla Parrini, Vassili Soumelis, Anne Vincent-Salomon, Fatima Mechta-Grigoriou
Carcinoma-associated fibroblasts (CAF) are key players in the tumor microenvironment. Here, we characterize four CAF subsets in breast cancer with distinct properties and levels of activation. Two myofibroblastic subsets (CAF-S1, CAF-S4) accumulate differentially in triple-negative breast cancers (TNBC). CAF-S1 fibroblasts promote an immunosuppressive environment through a multi-step mechanism. By secreting CXCL12, CAF-S1 attracts CD4+CD25+ T lymphocytes and retains them by OX40L, PD-L2, and JAM2. Moreover, CAF-S1 increases T lymphocyte survival and promotes their differentiation into CD25HighFOXP3High, through B7H3, CD73, and DPP4. Finally, in contrast to CAF-S4, CAF-S1 enhances the regulatory T cell capacity to inhibit T effector proliferation. These data are consistent with FOXP3+ T lymphocyte accumulation in CAF-S1-enriched TNBC and show how a CAF subset contributes to immunosuppression.
Publication date: Available online 15 February 2018
Source:Cancer Cell
Author(s): Ling Li, Yingchun Liang, Lei Kang, Yang Liu, Shan Gao, Siyu Chen, Ying Li, Wenye You, Qian Dong, Tian Hong, Zhifeng Yan, Shuai Jin, Tao Wang, Wei Zhao, Haixing Mai, Jun Huang, Xiao Han, Quanbo Ji, Qi Song, Chao Yang, Shixin Zhao, Xiaojie Xu, Qinong Ye
Aerobic glycolysis (the Warburg effect) facilitates tumor growth, and drugs targeting aerobic glycolysis are being developed. However, how the Warburg effect is directly regulated is largely unknown. Here we show that transcription factor SIX1 directly increases the expression of many glycolytic genes, promoting the Warburg effect and tumor growth in vitro and in vivo. SIX1 regulates glycolysis through HBO1 and AIB1 histone acetyltransferases. Cancer-related SIX1 mutation increases its ability to promote aerobic glycolysis and tumor growth. SIX1 glycolytic function is directly repressed by microRNA-548a-3p, which is downregulated, inversely correlates with SIX1, and is a good predictor of prognosis in breast cancer patients. Thus, the microRNA-548a-3p/SIX1 axis strongly links aerobic glycolysis to carcinogenesis and may become a promising cancer therapeutic target.
Publication date: Available online 15 February 2018
Source:Cancer Cell
Author(s): Ana Costa, Yann Kieffer, Alix Scholer-Dahirel, Floriane Pelon, Brigitte Bourachot, Melissa Cardon, Philemon Sirven, Ilaria Magagna, Laetitia Fuhrmann, Charles Bernard, Claire Bonneau, Maria Kondratova, Inna Kuperstein, Andrei Zinovyev, Anne-Marie Givel, Maria-Carla Parrini, Vassili Soumelis, Anne Vincent-Salomon, Fatima Mechta-Grigoriou
Carcinoma-associated fibroblasts (CAF) are key players in the tumor microenvironment. Here, we characterize four CAF subsets in breast cancer with distinct properties and levels of activation. Two myofibroblastic subsets (CAF-S1, CAF-S4) accumulate differentially in triple-negative breast cancers (TNBC). CAF-S1 fibroblasts promote an immunosuppressive environment through a multi-step mechanism. By secreting CXCL12, CAF-S1 attracts CD4+CD25+ T lymphocytes and retains them by OX40L, PD-L2, and JAM2. Moreover, CAF-S1 increases T lymphocyte survival and promotes their differentiation into CD25HighFOXP3High, through B7H3, CD73, and DPP4. Finally, in contrast to CAF-S4, CAF-S1 enhances the regulatory T cell capacity to inhibit T effector proliferation. These data are consistent with FOXP3+ T lymphocyte accumulation in CAF-S1-enriched TNBC and show how a CAF subset contributes to immunosuppression.
Chemotherapy side-effects can be substantial. There is increasing recognition that some oestrogen receptor positive (ER+ve), human epidermal growth factor receptor 2 negative (HER2–ve) patients with breast cancer derive no benefit from chemotherapy and experience only iatrogenic harm. Gene expression profiling tests help refine recurrence risk and likely chemotherapy benefit. EndoPredict® is one such test, which classifies risks of distant recurrence as low or high in patients treated with surgery and adjuvant endocrine therapy alone. We compared treatment decisions pre and post test results, patients' anxiety, decisional conflict and oncologists' confidence about the decisions made.
14 oncologists in 7 UK hospitals saw 149 pts judged to have equivocal indications for chemotherapy. Provisional treatment decisions were recorded then reconsidered when EPClin results were available. Pre and post test results, patients completed State/Trait Anxiety Inventories (STAI) and the decisional conflict scale (DCS). Oncologists also recorded basic clinical details, their agreement with, and confidence about treatment decisions.
67% patients initially prescribed endocrine alone with high risk result upgraded to endocrine+chemotherapy (E+C); 83% prescribed E+C and had low risk scores, downgraded to E. None of 46 patients initially favouring E alone, who were low risk changed decisions. Oncologists' confidence about decisions was significantly increased following the results (p=0.002). Patients with downgraded treatment decisions had significantly lower anxiety scores (p=0.045); those upgraded had increased scores (p=0.001). Overall decisional conflict and uncertainty fell significantly post-test (p<0.022).
EndoPredict scores increased oncologists' and patients' decision-making confidence, generally improving the matching of risk with therapy decisions.
Chemotherapy side-effects can be substantial. There is increasing recognition that some oestrogen receptor positive (ER+ve), human epidermal growth factor receptor 2 negative (HER2–ve) patients with breast cancer derive no benefit from chemotherapy and experience only iatrogenic harm. Gene expression profiling tests help refine recurrence risk and likely chemotherapy benefit. EndoPredict® is one such test, which classifies risks of distant recurrence as low or high in patients treated with surgery and adjuvant endocrine therapy alone. We compared treatment decisions pre and post test results, patients' anxiety, decisional conflict and oncologists' confidence about the decisions made.
14 oncologists in 7 UK hospitals saw 149 pts judged to have equivocal indications for chemotherapy. Provisional treatment decisions were recorded then reconsidered when EPClin results were available. Pre and post test results, patients completed State/Trait Anxiety Inventories (STAI) and the decisional conflict scale (DCS). Oncologists also recorded basic clinical details, their agreement with, and confidence about treatment decisions.
67% patients initially prescribed endocrine alone with high risk result upgraded to endocrine+chemotherapy (E+C); 83% prescribed E+C and had low risk scores, downgraded to E. None of 46 patients initially favouring E alone, who were low risk changed decisions. Oncologists' confidence about decisions was significantly increased following the results (p=0.002). Patients with downgraded treatment decisions had significantly lower anxiety scores (p=0.045); those upgraded had increased scores (p=0.001). Overall decisional conflict and uncertainty fell significantly post-test (p<0.022).
EndoPredict scores increased oncologists' and patients' decision-making confidence, generally improving the matching of risk with therapy decisions.
Cancers, Vol. 10, Pages 51: Next Generation Immunotherapy for Pancreatic Cancer: DNA Vaccination is Seeking New Combo Partners
Cancers doi: 10.3390/cancers10020051
Authors: Paola Cappello Claudia Curcio Giorgia Mandili Cecilia Roux Sara Bulfamante Francesco Novelli
Pancreatic Ductal Adenocarcinoma (PDA) is an almost incurable radio- and chemo-resistant tumor, and its microenvironment is characterized by a strong desmoplastic reaction associated with a significant infiltration of T regulatory lymphocytes and myeloid-derived suppressor cells (Tregs, MDSC). Investigating immunological targets has identified a number of metabolic and cytoskeletal related molecules, which are typically recognized by circulating antibodies. Among these molecules we have investigated alpha-enolase (ENO1), a glycolytic enzyme that also acts a plasminogen receptor. ENO1 is also recognized by T cells in PDA patients, so we developed a DNA vaccine that targets ENO1. This efficiently induces many immunological processes (antibody formation and complement-dependent cytotoxicity (CDC)-mediated tumor killing, infiltration of effector T cells, reduction of infiltration of myeloid and Treg suppressor cells), which significantly increase the survival of genetically engineered mice that spontaneously develop pancreatic cancer. Although promising, the ENO1 DNA vaccine does not completely eradicate the tumor, which, after an initial growth inhibition, returns to proliferate again, especially when Tregs and MDSC ensue in the tumor mass. This led us to develop possible strategies for combinatorial treatments aimed to broaden and sustain the antitumor immune response elicited by DNA vaccination. Based on the data we have obtained in recent years, this review will discuss the biological bases of possible combinatorial treatments (chemotherapy, PI3K inhibitors, tumor-associated macrophages, ENO1 inhibitors) that could be effective in amplifying the response induced by the immune vaccination in PDA.
Cancers, Vol. 10, Pages 51: Next Generation Immunotherapy for Pancreatic Cancer: DNA Vaccination is Seeking New Combo Partners
Cancers doi: 10.3390/cancers10020051
Authors: Paola Cappello Claudia Curcio Giorgia Mandili Cecilia Roux Sara Bulfamante Francesco Novelli
Pancreatic Ductal Adenocarcinoma (PDA) is an almost incurable radio- and chemo-resistant tumor, and its microenvironment is characterized by a strong desmoplastic reaction associated with a significant infiltration of T regulatory lymphocytes and myeloid-derived suppressor cells (Tregs, MDSC). Investigating immunological targets has identified a number of metabolic and cytoskeletal related molecules, which are typically recognized by circulating antibodies. Among these molecules we have investigated alpha-enolase (ENO1), a glycolytic enzyme that also acts a plasminogen receptor. ENO1 is also recognized by T cells in PDA patients, so we developed a DNA vaccine that targets ENO1. This efficiently induces many immunological processes (antibody formation and complement-dependent cytotoxicity (CDC)-mediated tumor killing, infiltration of effector T cells, reduction of infiltration of myeloid and Treg suppressor cells), which significantly increase the survival of genetically engineered mice that spontaneously develop pancreatic cancer. Although promising, the ENO1 DNA vaccine does not completely eradicate the tumor, which, after an initial growth inhibition, returns to proliferate again, especially when Tregs and MDSC ensue in the tumor mass. This led us to develop possible strategies for combinatorial treatments aimed to broaden and sustain the antitumor immune response elicited by DNA vaccination. Based on the data we have obtained in recent years, this review will discuss the biological bases of possible combinatorial treatments (chemotherapy, PI3K inhibitors, tumor-associated macrophages, ENO1 inhibitors) that could be effective in amplifying the response induced by the immune vaccination in PDA.
Previous anti-EGFR trials in unselected gastroesophageal adenocarcinoma (GEA) patients were resoundingly negative. We identified EGFR amplification in 5% (19/363) of patients at the University of Chicago, including 6% (8/140) who were prospectively screened with intention-to-treat using anti-EGFR therapy. Seven pts received >1 dose of treatment: three first line FOLFOX plus ABT-806, one second line FOLFIRI plus cetuximab, and three third/fourth line cetuximab alone. Treatment achieved objective response in 58% (4/7) and disease control in 100% (7/7) with a median progression-free survival of 10 months. Pre and post-treatment tumor NGS, serial plasma ctDNA NGS, and tumor IHC/FISH for EGFR revealed pre-existing and/or acquired genomic events including EGFR negative clones, PTEN deletion, KRAS amplification/mutation, NRAS, MYC and HER2 amplification, and GNAS mutations serving as mechanisms of resistance. Two evaluable patients demonstrated interval increase of CD3+ infiltrate, including one who demonstrated increased NKp46+, and PD-L1 IHC expression from baseline, suggesting an immune therapeutic mechanism of action. EGFR amplification predicted benefit from anti-EGFR therapy, albeit until various resistance mechanisms emerged.
Reply to 'Comment on 'Prognostic biomarkers for oral tongue squamous cell carcinoma: a systematic review and meta-analysis"
Reply to 'Comment on 'Prognostic biomarkers for oral tongue squamous cell carcinoma: a systematic review and meta-analysis", Published online: 15 February 2018; doi:10.1038/bjc.2017.491
Reply to 'Comment on 'Prognostic biomarkers for oral tongue squamous cell carcinoma: a systematic review and meta-analysis"
The predictive and prognostic potential of plasma telomerase reverse transcriptase (TERT) RNA in rectal cancer patients
The predictive and prognostic potential of plasma telomerase reverse transcriptase (TERT) RNA in rectal cancer patients, Published online: 15 February 2018; doi:10.1038/bjc.2017.492
The predictive and prognostic potential of plasma telomerase reverse transcriptase (TERT) RNA in rectal cancer patients
The Improving Rural Cancer Outcomes Trial: a cluster-randomised controlled trial of a complex intervention to reduce time to diagnosis in rural cancer patients in Western Australia
The Improving Rural Cancer Outcomes Trial: a cluster-randomised controlled trial of a complex intervention to reduce time to diagnosis in rural cancer patients in Western Australia, Published online: 15 February 2018; doi:10.1038/bjc.2017.457
The Improving Rural Cancer Outcomes Trial: a cluster-randomised controlled trial of a complex intervention to reduce time to diagnosis in rural cancer patients in Western Australia
Comment on 'Prognostic biomarkers for oral tongue squamous cell carcinoma: a systematic review and meta-analysis'
Comment on 'Prognostic biomarkers for oral tongue squamous cell carcinoma: a systematic review and meta-analysis', Published online: 15 February 2018; doi:10.1038/bjc.2017.482
Comment on 'Prognostic biomarkers for oral tongue squamous cell carcinoma: a systematic review and meta-analysis'
The predictive and prognostic potential of plasma telomerase reverse transcriptase (TERT) RNA in rectal cancer patients
The predictive and prognostic potential of plasma telomerase reverse transcriptase (TERT) RNA in rectal cancer patients, Published online: 15 February 2018; doi:10.1038/bjc.2017.492
The predictive and prognostic potential of plasma telomerase reverse transcriptase (TERT) RNA in rectal cancer patientsReply to 'Comment on 'Prognostic biomarkers for oral tongue squamous cell carcinoma: a systematic review and meta-analysis"
Reply to 'Comment on 'Prognostic biomarkers for oral tongue squamous cell carcinoma: a systematic review and meta-analysis", Published online: 15 February 2018; doi:10.1038/bjc.2017.491
Reply to 'Comment on 'Prognostic biomarkers for oral tongue squamous cell carcinoma: a systematic review and meta-analysis"The Improving Rural Cancer Outcomes Trial: a cluster-randomised controlled trial of a complex intervention to reduce time to diagnosis in rural cancer patients in Western Australia
The Improving Rural Cancer Outcomes Trial: a cluster-randomised controlled trial of a complex intervention to reduce time to diagnosis in rural cancer patients in Western Australia, Published online: 15 February 2018; doi:10.1038/bjc.2017.457
The Improving Rural Cancer Outcomes Trial: a cluster-randomised controlled trial of a complex intervention to reduce time to diagnosis in rural cancer patients in Western AustraliaComment on 'Prognostic biomarkers for oral tongue squamous cell carcinoma: a systematic review and meta-analysis'
Comment on 'Prognostic biomarkers for oral tongue squamous cell carcinoma: a systematic review and meta-analysis', Published online: 15 February 2018; doi:10.1038/bjc.2017.482
Comment on 'Prognostic biomarkers for oral tongue squamous cell carcinoma: a systematic review and meta-analysis'Angiogenesis involves dynamic interactions between specialized endothelial tip and stalk cells that are believed to be regulated in part by VEGF and Dll4-Notch signaling. However, our understanding of this process is hampered by limited knowledge of the heterogeneity of endothelial cells and the role of different signaling pathways in specifying endothelial phenotypes. Here we characterized by single cell transcriptomics the heterogeneity of mouse endothelial cells and other stromal cells during active angiogenesis in xenograft tumors as well as from adult normal heart, following pharmacologic inhibition of VEGF and Dll4-Notch signaling. We classified tumor endothelial cells into three subpopulations that appeared to correspond with tip-like, transition and stalk-like cells. Previously identified markers for tip and stalk cells were confirmed and several novel ones discovered. Blockade of VEGF rapidly inhibited cell cycle genes and strongly reduced the proportion of endothelial tip cells in tumors. In contrast, blockade of Dll4 promoted endothelial proliferation as well as tip cell markers; blockade of both pathways inhibited endothelial proliferation but preserved some tip cells. We also phenotypically classified other tumor stromal cells and found that tumor-associated fibroblasts (TAFs) responded to anti-angiogenic drug treatments by upregulating hypoxia-associated genes and producing secreted factors involved in angiogenesis. Overall, our findings better define the heterogeneity of tumor endothelial and other stromal cells and reveal the roles of VEGF and Dll4-Notch in specifying tumor endothelial phenotype, highlighting the response of stromal cells to anti-angiogenic therapies.
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Angiogenesis involves dynamic interactions between specialized endothelial tip and stalk cells that are believed to be regulated in part by VEGF and Dll4-Notch signaling. However, our understanding of this process is hampered by limited knowledge of the heterogeneity of endothelial cells and the role of different signaling pathways in specifying endothelial phenotypes. Here we characterized by single cell transcriptomics the heterogeneity of mouse endothelial cells and other stromal cells during active angiogenesis in xenograft tumors as well as from adult normal heart, following pharmacologic inhibition of VEGF and Dll4-Notch signaling. We classified tumor endothelial cells into three subpopulations that appeared to correspond with tip-like, transition and stalk-like cells. Previously identified markers for tip and stalk cells were confirmed and several novel ones discovered. Blockade of VEGF rapidly inhibited cell cycle genes and strongly reduced the proportion of endothelial tip cells in tumors. In contrast, blockade of Dll4 promoted endothelial proliferation as well as tip cell markers; blockade of both pathways inhibited endothelial proliferation but preserved some tip cells. We also phenotypically classified other tumor stromal cells and found that tumor-associated fibroblasts (TAFs) responded to anti-angiogenic drug treatments by upregulating hypoxia-associated genes and producing secreted factors involved in angiogenesis. Overall, our findings better define the heterogeneity of tumor endothelial and other stromal cells and reveal the roles of VEGF and Dll4-Notch in specifying tumor endothelial phenotype, highlighting the response of stromal cells to anti-angiogenic therapies.
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Fibroblast activation protein-α (FAPα) is a promising tumor-associated target expressed by reactive stromal fibroblasts in tumor tissue. FAPα has a postprolyl peptidase activity and can specifically cleave N-terminal benzyloxycarbonyl (Z)-blocked peptides, such as the substrate Z-Gly-Pro-AMC. Doxorubicin (DOX) is an effective antitumor drug, but its application is greatly limited by toxic adverse effects owing to poor tumor selectivity. Based on these facts, we previously designed a FAPα-targeting prodrug of doxorubicin (FTPD) which can be selectively hydrolyzed by FAPα. FTPD can retain potent antitumor efficacy and has favorable tumor targeting. The present study aimed to further evaluate the toxicological profile and the safety pharmacological property of FTPD in vitro and in vivo. The cytotoxicity assay showed that FTPD displayed markedly lower cytotoxicity to 3T3 cells and HEK-293 cells compared with DOX. In the short-term toxicity study, mice treated with 25 mg/kg of FTPD showed no obvious change in the appearance and general behavior, and no case of mortality was observed within 14 days. Unlike DOX, FTPD exhibited reduced toxicity to heart, liver, kidney, spleen as well as peripheral white blood cells in mice. Moreover, open file test and general pharmacology study were also conducted correspondingly in mice and beagle dogs. It was found that FTPD may not produce significant pharmacological effects on spontaneous locomotor activity and cardiovascular-respiratory system except for a transient decreasing in systolic blood pressure. Taken together, the results of this work suggest that FTPD has more favorable toxicological profile and better drug safety compared with its parent drug DOX.
Newcastle disease virus (NDV) can specifically kill cancer cells and has less toxicity to normal cells. The hemagglutinin–neuraminidase (HN) protein is an important structural protein in NDV pathogenesis and has been postulated as a promising candidate for antitumor therapy. The aim of this study was to investigate the anticancer potential of recombinant adenovirus Ad-HN-PEG3p-E1a. An MTS assay was performed to determine viral proliferation after viral infection, the data showed that the proliferation ability of osteosarcoma cells decreased, whereas there was no significant change in normal hepatic cells. DAPI and Annexin V experiments showed that osteosarcoma cells were killed because of apoptosis, active oxygen content, and augmented mitochondrial membrane potential loss. Caspase Activity Assay Kits were used to detect the caspase-3 activities of the treated OS-732 for increased expression. Western blot analysis showed that cytochrome C increased significantly and apoptosis of the virus was confirmed in tumor cells. In-vivo experiments show that NDV has an inhibitory effect on tumor growth. The recombinant adenovirus, which is composed of a HN protein and progressive increment promoter PEG3p, could inhibit the growth of OS-732 and promote the apoptosis of tumor cells. However, there was no clear relationship with normal cell (L02) apoptosis.
Cancer stem cells (CSCs) play an essential role in the progression of many tumors. Sonic hedgehog (Shh) and Wnt/β-catenin pathways are crucial in maintaining the stemness of CSCs. Curcumin has been shown to possess anticancer activity. However, the interventional effect of curcumin on breast CSCs has not been elucidated. In the present study, we investigated the role of Shh and Wnt/β-catenin pathway in curcumin inhibition of breast CSCs. We showed that the levels of breast CSCs markers were significantly elevated in SUM159 and MCF7 sphere-forming cells. We further illustrated that curcumin effectively decreased breast CSCs activity by inhibiting tumor sphere formation, decreasing breast CSCs markers (CD44, ALDH1A1, Nanog, and Oct4), as well as inhibiting proliferation and inducing apoptosis. Moreover, we showed that downregulation of Shh and Wnt/β-catenin activity resulted in breast CSCs inhibition; curcumin exerted an inhibitory effect on breast CSCs by suppressing both Shh and Wnt/β-catenin pathways. Taken together, these results indicated curcumin inhibition of breast CSCs by downregulation of Shh and Wnt/β-catenin pathways. Findings from this study could provide new insights into the potential therapeutic application of curcumin in breast CSCs elimination and cancer intervention.
The aim of this study was to assess the potential effects of palbociclib in combination with letrozole on QTc. PALOMA-2, a phase 3, randomized, double-blind, placebo-controlled trial, compared palbociclib plus letrozole with placebo plus letrozole in postmenopausal women with estrogen receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer. The study included a QTc evaluation substudy carried out as a definitive QT interval prolongation assessment for palbociclib. Time-matched triplicate ECGs were performed at 0, 2, 4, 6, and 8 h at baseline (Day 0) and on Cycle 1 Day 14. Additional ECGs were collected from all patients for safety monitoring. The QT interval was corrected for heart rate using Fridericia's correction (QTcF), Bazett's correction (QTcB), and a study-specific correction factor (QTcS). In total, 666 patients were randomized 2 : 1 to palbociclib plus letrozole or placebo plus letrozole. Of these, 125 patients were enrolled in the QTc evaluation substudy. No patients in the palbociclib plus letrozole arm of the substudy (N=77) had a maximum postbaseline QTcS or QTcF value of ≥ 480 ms, or a maximum increase from clock time-matched baseline for QTcS or QTcF values of ≥ 60 ms. The upper bounds of the one-sided 95% confidence interval for the mean change from time-matched baseline for QTcS, QTcF, and QTcB at all time points and at steady-state Cmax following repeated administration of 125 mg palbociclib were less than 10 ms. Palbociclib, when administered with letrozole at the recommended therapeutic dosing regimen, did not prolong the QT interval to a clinically relevant extent.
Forkhead box protein M1 (FoxM1) has been associated with cancer progression and metastasis. However, the function of FoxM1 in tongue squamous cell carcinoma (TSCC) remains largely unknown. The purpose of this study was to determine the role of FoxM1 in regulation of epithelial–mesenchymal transition (EMT) and migration of TSCC cells. We found that FoxM1 induced EMT and increased invasion/migration capacity in SCC9 and SCC25 cells. FoxM1 stimulation increased c-Met, pAKT, and vimentin levels but decreased E-cadherin level. Chromatin immunoprecipitation assay established that FoxM1 is bound to the promoter of c-Met to activate its transcription. In turn, c-Met promoted the expression of FoxM1 and pAKT. Blocking AKT signaling attenuated the invasion and migration of SCC9 and SCC25 cells stimulated by FoxM1 or c-Met. These results indicate that a positive feedback loop controls the EMT and migration of TSCC cells induced by FoxM1 and c-Met through AKT. Furthermore, the expression levels of FoxM1, pAKT, and c-Met were found to significantly increase in TSCC tissues compared with normal tissues, and these three biomarkers were concomitantly expressed in TSCC tissues. Clinical association analyses indicated that the expression of FoxM1, c-Met, and pAKT was associated with clinicopathological characteristics of patients with TSCC including tumor stage, tumor size, and lymph node metastasis. Taken together, our findings suggest that FoxM1 promotes the EMT, invasion and migration of TSCC cells, and cross-talks with c-Met/AKT signaling to form a positive feedback loop to promote TSCC development.
Genetic and laboratory studies have remodeled the conventional understanding of cancer pathogenesis by identifying different molecular alterations. Intrigued by the contribution of neurokinin-1 receptor (NK1R) network in cancer pathogenesis, we investigated the antileukemic effects of aprepitant, a nonpeptide antagonist of NK1R, in a panel of hematological cell lines. In this study, we found that aprepitant decreased the survival of all the tested cells; however, as compared with NB4, viability of the other cell lines was inhibited at higher concentrations. By increasing both p21 and p73 along with suppressing c-Myc and hTERT, aprepitant probably disordered cell distribution in the cell cycle, decreased DNA replication rate, and, thereby, impeded the proliferative capability of NB4 cells. Moreover, exposing cells to this agent led to activation of the caspase-3-dependent apoptotic pathway through altering the expression of apoptosis-related genes. Noteworthy, aprepitant also sensitized NB4 cells to the cytotoxic effects of arsenic trioxide and vincristine. Overall, it seems that pharmaceutical targeting of NK1R using aprepitant, either as a single agent or in combination, possesses novel promising potential for leukemia treatment strategies.
As a new type of anticancer drug, the effect of histone deacetylase inhibitors (HDACIs) in cancer clinical therapy is disappointing owing to drug resistance. P-glycoprotein (P-gp) is clearly recognized as a multidrug resistance protein. However, the relationship between P-gp and sodium butyrate (SB), a kind of HDACIs, has not been investigated. In this study, we found that SB increased mRNA and protein expression of P-gp in lung cancer cells and the underlying mechanisms were elucidated. We found that SB treatment enhanced the mRNA and protein expression of STAT3 rather than that of β-catenin, Foxo3a, PXR, or CAR, which were reported to directly regulate the transcription of ABCB1, a P-gp-encoding gene. Interestingly, inhibition of STAT3 expression obviously attenuated SB-increased P-gp expression in lung cancer cells, indicating that STAT3 played an important role in SB-mediated P-gp upregulation. Furthermore, we found that SB increased the mRNA stability of ABCB1. In summary, this study showed that SB increased P-gp expression by facilitating transcriptional activation and improving ABCB1 mRNA stability. This study indicated that we should pay more attention to HDACIs during cancer clinical therapy.
Histone acetylation is one of the most abundant post-translational modifications in eukaryotic cells; aberrant histone acetylation is related to a range of cancer types because of the dysregulation of histone deacetylases (HDACs). Inhibition of HDACs leads to suppression of tumor growth in multiple cancers, whereas the inhibitory effects of HDAC inhibitors remain incompletely understood in epidermal growth factor receptor (EGFR)-mutant lung cancers. In this study, the antitumor effects of HDACs inhibitor suberoylanilide hydroxamic acid (SAHA, vorinostat) were examined in EGFR-mutant lung cancer cell lines. The results of the present work showed that SAHA markedly inhibited cell viability and proliferation, induced cell apoptosis by arresting the cell cycle in the G2/M phase, and significantly reduced tumor growth in a xenograft model. Further study confirmed that the suppression function of SAHA might be mediated by regulating the ERK-dependent and/or the AKT-dependent pathway; meanwhile, angiogenesis abrogation induced by SAHA exerted effects on tumor regression in vivo. Taken together, our results identify the antitumor effects of HDACs inhibitor SAHA as an alternative therapeutic application for the epigenetic treatment of EGFR-mutant non-small-cell lung cancer.
Dioscin is a natural steroid saponin derived from several plants that shows potent anticancer effects against a variety of cancer cells. Here, we investigated the antitumor effect of dioscin against human colon cancer cells and evaluated the molecular mechanism involved in this process. The cell cytotoxicity was studied by the MTT assay and BrdU incorporation. The proapoptotic mechanism of dioscin was characterized by flow cytometry analysis. A western blot and an immunofluorescence staining were used to investigate how dioscin induces apoptosis in vitro. In our study, dioscin could significantly inhibit the growth of colon cancer cells in a time-dependent and dose-dependent manner. Dioscin induces apoptosis and reactive oxygen species (ROS) generation, promoting the disruption of mitochondrial membrane potential, Bax translocation to the mitochondria, cytochrome C release to cytosol, activations of caspase-9/3, PARP cleavage, and subsequent apoptosis. Dioscin-induced apoptosis was accompanied by sustained phosphorylation of JNK, p38-MAPK. N-acetyl-L-cysteine, a scavenger of ROS, significantly reversed dioscin-induced cell death and activation of JNK and p38. Collectively, the data indicate that the induction of apoptosis by dioscin is mediated through ROS proteins, which are critical upstream signals for JNK/p38-MAPK activation.
Adenocarcinoma (AC) is the most common type of primary pulmonary malignancy. Lung carcinoid, however, is a rare neuroendocrine tumor. Their coexistence is extremely uncommon. We report the unique case of synchronous advanced lung AC of the right upper lobe (stage IIIB) and typical endobronchial carcinoid tumor in the contralateral lower lobe in a 49-year-old white female who had never smoked. PET-computed tomography scan revealed a fluorine-18-fluorodeoxyglucose-avid AC lesion, whereas the carcinoid tumor was fluorine-18-fluorodeoxyglucose occult. After two lines of platinum-based combination chemotherapies and radiotherapy, the AC progressed, and oral tyrosine kinase inhibitor therapy with erlotinib was initiated in third line. On erlotinib, the AC remained stable for 50 months until disease progression, whereas the carcinoid completely regressed. Molecular testing of the rebronchoscopied AC revealed an exon 19 deletion mutation in the epidermal growth factor receptor (EGFR) gene, whereas the carcinoid was retrospectively EGFR mutation negative. The patient eventually succumbed to ileus caused by intra-abdominal spread of disease, surviving a remarkable 80 months with good performance status throughout most of the follow-up period. To the best of our knowledge, this is the first reported case of synchronous primary lung cancers with different EGFR mutation status, describing an unexpected response of an EGFR-wild-type carcinoid to third-line erlotinib.Fibroblast activation protein-α (FAPα) is a promising tumor-associated target expressed by reactive stromal fibroblasts in tumor tissue. FAPα has a postprolyl peptidase activity and can specifically cleave N-terminal benzyloxycarbonyl (Z)-blocked peptides, such as the substrate Z-Gly-Pro-AMC. Doxorubicin (DOX) is an effective antitumor drug, but its application is greatly limited by toxic adverse effects owing to poor tumor selectivity. Based on these facts, we previously designed a FAPα-targeting prodrug of doxorubicin (FTPD) which can be selectively hydrolyzed by FAPα. FTPD can retain potent antitumor efficacy and has favorable tumor targeting. The present study aimed to further evaluate the toxicological profile and the safety pharmacological property of FTPD in vitro and in vivo. The cytotoxicity assay showed that FTPD displayed markedly lower cytotoxicity to 3T3 cells and HEK-293 cells compared with DOX. In the short-term toxicity study, mice treated with 25 mg/kg of FTPD showed no obvious change in the appearance and general behavior, and no case of mortality was observed within 14 days. Unlike DOX, FTPD exhibited reduced toxicity to heart, liver, kidney, spleen as well as peripheral white blood cells in mice. Moreover, open file test and general pharmacology study were also conducted correspondingly in mice and beagle dogs. It was found that FTPD may not produce significant pharmacological effects on spontaneous locomotor activity and cardiovascular-respiratory system except for a transient decreasing in systolic blood pressure. Taken together, the results of this work suggest that FTPD has more favorable toxicological profile and better drug safety compared with its parent drug DOX.Newcastle disease virus (NDV) can specifically kill cancer cells and has less toxicity to normal cells. The hemagglutinin–neuraminidase (HN) protein is an important structural protein in NDV pathogenesis and has been postulated as a promising candidate for antitumor therapy. The aim of this study was to investigate the anticancer potential of recombinant adenovirus Ad-HN-PEG3p-E1a. An MTS assay was performed to determine viral proliferation after viral infection, the data showed that the proliferation ability of osteosarcoma cells decreased, whereas there was no significant change in normal hepatic cells. DAPI and Annexin V experiments showed that osteosarcoma cells were killed because of apoptosis, active oxygen content, and augmented mitochondrial membrane potential loss. Caspase Activity Assay Kits were used to detect the caspase-3 activities of the treated OS-732 for increased expression. Western blot analysis showed that cytochrome C increased significantly and apoptosis of the virus was confirmed in tumor cells. In-vivo experiments show that NDV has an inhibitory effect on tumor growth. The recombinant adenovirus, which is composed of a HN protein and progressive increment promoter PEG3p, could inhibit the growth of OS-732 and promote the apoptosis of tumor cells. However, there was no clear relationship with normal cell (L02) apoptosis.Cancer stem cells (CSCs) play an essential role in the progression of many tumors. Sonic hedgehog (Shh) and Wnt/β-catenin pathways are crucial in maintaining the stemness of CSCs. Curcumin has been shown to possess anticancer activity. However, the interventional effect of curcumin on breast CSCs has not been elucidated. In the present study, we investigated the role of Shh and Wnt/β-catenin pathway in curcumin inhibition of breast CSCs. We showed that the levels of breast CSCs markers were significantly elevated in SUM159 and MCF7 sphere-forming cells. We further illustrated that curcumin effectively decreased breast CSCs activity by inhibiting tumor sphere formation, decreasing breast CSCs markers (CD44, ALDH1A1, Nanog, and Oct4), as well as inhibiting proliferation and inducing apoptosis. Moreover, we showed that downregulation of Shh and Wnt/β-catenin activity resulted in breast CSCs inhibition; curcumin exerted an inhibitory effect on breast CSCs by suppressing both Shh and Wnt/β-catenin pathways. Taken together, these results indicated curcumin inhibition of breast CSCs by downregulation of Shh and Wnt/β-catenin pathways. Findings from this study could provide new insights into the potential therapeutic application of curcumin in breast CSCs elimination and cancer intervention.The aim of this study was to assess the potential effects of palbociclib in combination with letrozole on QTc. PALOMA-2, a phase 3, randomized, double-blind, placebo-controlled trial, compared palbociclib plus letrozole with placebo plus letrozole in postmenopausal women with estrogen receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer. The study included a QTc evaluation substudy carried out as a definitive QT interval prolongation assessment for palbociclib. Time-matched triplicate ECGs were performed at 0, 2, 4, 6, and 8 h at baseline (Day 0) and on Cycle 1 Day 14. Additional ECGs were collected from all patients for safety monitoring. The QT interval was corrected for heart rate using Fridericia's correction (QTcF), Bazett's correction (QTcB), and a study-specific correction factor (QTcS). In total, 666 patients were randomized 2 : 1 to palbociclib plus letrozole or placebo plus letrozole. Of these, 125 patients were enrolled in the QTc evaluation substudy. No patients in the palbociclib plus letrozole arm of the substudy (N=77) had a maximum postbaseline QTcS or QTcF value of ≥ 480 ms, or a maximum increase from clock time-matched baseline for QTcS or QTcF values of ≥ 60 ms. The upper bounds of the one-sided 95% confidence interval for the mean change from time-matched baseline for QTcS, QTcF, and QTcB at all time points and at steady-state Cmax following repeated administration of 125 mg palbociclib were less than 10 ms. Palbociclib, when administered with letrozole at the recommended therapeutic dosing regimen, did not prolong the QT interval to a clinically relevant extent.Forkhead box protein M1 (FoxM1) has been associated with cancer progression and metastasis. However, the function of FoxM1 in tongue squamous cell carcinoma (TSCC) remains largely unknown. The purpose of this study was to determine the role of FoxM1 in regulation of epithelial–mesenchymal transition (EMT) and migration of TSCC cells. We found that FoxM1 induced EMT and increased invasion/migration capacity in SCC9 and SCC25 cells. FoxM1 stimulation increased c-Met, pAKT, and vimentin levels but decreased E-cadherin level. Chromatin immunoprecipitation assay established that FoxM1 is bound to the promoter of c-Met to activate its transcription. In turn, c-Met promoted the expression of FoxM1 and pAKT. Blocking AKT signaling attenuated the invasion and migration of SCC9 and SCC25 cells stimulated by FoxM1 or c-Met. These results indicate that a positive feedback loop controls the EMT and migration of TSCC cells induced by FoxM1 and c-Met through AKT. Furthermore, the expression levels of FoxM1, pAKT, and c-Met were found to significantly increase in TSCC tissues compared with normal tissues, and these three biomarkers were concomitantly expressed in TSCC tissues. Clinical association analyses indicated that the expression of FoxM1, c-Met, and pAKT was associated with clinicopathological characteristics of patients with TSCC including tumor stage, tumor size, and lymph node metastasis. Taken together, our findings suggest that FoxM1 promotes the EMT, invasion and migration of TSCC cells, and cross-talks with c-Met/AKT signaling to form a positive feedback loop to promote TSCC development.Genetic and laboratory studies have remodeled the conventional understanding of cancer pathogenesis by identifying different molecular alterations. Intrigued by the contribution of neurokinin-1 receptor (NK1R) network in cancer pathogenesis, we investigated the antileukemic effects of aprepitant, a nonpeptide antagonist of NK1R, in a panel of hematological cell lines. In this study, we found that aprepitant decreased the survival of all the tested cells; however, as compared with NB4, viability of the other cell lines was inhibited at higher concentrations. By increasing both p21 and p73 along with suppressing c-Myc and hTERT, aprepitant probably disordered cell distribution in the cell cycle, decreased DNA replication rate, and, thereby, impeded the proliferative capability of NB4 cells. Moreover, exposing cells to this agent led to activation of the caspase-3-dependent apoptotic pathway through altering the expression of apoptosis-related genes. Noteworthy, aprepitant also sensitized NB4 cells to the cytotoxic effects of arsenic trioxide and vincristine. Overall, it seems that pharmaceutical targeting of NK1R using aprepitant, either as a single agent or in combination, possesses novel promising potential for leukemia treatment strategies.As a new type of anticancer drug, the effect of histone deacetylase inhibitors (HDACIs) in cancer clinical therapy is disappointing owing to drug resistance. P-glycoprotein (P-gp) is clearly recognized as a multidrug resistance protein. However, the relationship between P-gp and sodium butyrate (SB), a kind of HDACIs, has not been investigated. In this study, we found that SB increased mRNA and protein expression of P-gp in lung cancer cells and the underlying mechanisms were elucidated. We found that SB treatment enhanced the mRNA and protein expression of STAT3 rather than that of β-catenin, Foxo3a, PXR, or CAR, which were reported to directly regulate the transcription of ABCB1, a P-gp-encoding gene. Interestingly, inhibition of STAT3 expression obviously attenuated SB-increased P-gp expression in lung cancer cells, indicating that STAT3 played an important role in SB-mediated P-gp upregulation. Furthermore, we found that SB increased the mRNA stability of ABCB1. In summary, this study showed that SB increased P-gp expression by facilitating transcriptional activation and improving ABCB1 mRNA stability. This study indicated that we should pay more attention to HDACIs during cancer clinical therapy.Histone acetylation is one of the most abundant post-translational modifications in eukaryotic cells; aberrant histone acetylation is related to a range of cancer types because of the dysregulation of histone deacetylases (HDACs). Inhibition of HDACs leads to suppression of tumor growth in multiple cancers, whereas the inhibitory effects of HDAC inhibitors remain incompletely understood in epidermal growth factor receptor (EGFR)-mutant lung cancers. In this study, the antitumor effects of HDACs inhibitor suberoylanilide hydroxamic acid (SAHA, vorinostat) were examined in EGFR-mutant lung cancer cell lines. The results of the present work showed that SAHA markedly inhibited cell viability and proliferation, induced cell apoptosis by arresting the cell cycle in the G2/M phase, and significantly reduced tumor growth in a xenograft model. Further study confirmed that the suppression function of SAHA might be mediated by regulating the ERK-dependent and/or the AKT-dependent pathway; meanwhile, angiogenesis abrogation induced by SAHA exerted effects on tumor regression in vivo. Taken together, our results identify the antitumor effects of HDACs inhibitor SAHA as an alternative therapeutic application for the epigenetic treatment of EGFR-mutant non-small-cell lung cancer.Dioscin is a natural steroid saponin derived from several plants that shows potent anticancer effects against a variety of cancer cells. Here, we investigated the antitumor effect of dioscin against human colon cancer cells and evaluated the molecular mechanism involved in this process. The cell cytotoxicity was studied by the MTT assay and BrdU incorporation. The proapoptotic mechanism of dioscin was characterized by flow cytometry analysis. A western blot and an immunofluorescence staining were used to investigate how dioscin induces apoptosis in vitro. In our study, dioscin could significantly inhibit the growth of colon cancer cells in a time-dependent and dose-dependent manner. Dioscin induces apoptosis and reactive oxygen species (ROS) generation, promoting the disruption of mitochondrial membrane potential, Bax translocation to the mitochondria, cytochrome C release to cytosol, activations of caspase-9/3, PARP cleavage, and subsequent apoptosis. Dioscin-induced apoptosis was accompanied by sustained phosphorylation of JNK, p38-MAPK. N-acetyl-L-cysteine, a scavenger of ROS, significantly reversed dioscin-induced cell death and activation of JNK and p38. Collectively, the data indicate that the induction of apoptosis by dioscin is mediated through ROS proteins, which are critical upstream signals for JNK/p38-MAPK activation.Adenocarcinoma (AC) is the most common type of primary pulmonary malignancy. Lung carcinoid, however, is a rare neuroendocrine tumor. Their coexistence is extremely uncommon. We report the unique case of synchronous advanced lung AC of the right upper lobe (stage IIIB) and typical endobronchial carcinoid tumor in the contralateral lower lobe in a 49-year-old white female who had never smoked. PET-computed tomography scan revealed a fluorine-18-fluorodeoxyglucose-avid AC lesion, whereas the carcinoid tumor was fluorine-18-fluorodeoxyglucose occult. After two lines of platinum-based combination chemotherapies and radiotherapy, the AC progressed, and oral tyrosine kinase inhibitor therapy with erlotinib was initiated in third line. On erlotinib, the AC remained stable for 50 months until disease progression, whereas the carcinoid completely regressed. Molecular testing of the rebronchoscopied AC revealed an exon 19 deletion mutation in the epidermal growth factor receptor (EGFR) gene, whereas the carcinoid was retrospectively EGFR mutation negative. The patient eventually succumbed to ileus caused by intra-abdominal spread of disease, surviving a remarkable 80 months with good performance status throughout most of the follow-up period. To the best of our knowledge, this is the first reported case of synchronous primary lung cancers with different EGFR mutation status, describing an unexpected response of an EGFR-wild-type carcinoid to third-line erlotinib.Patients with a high stroma percentage within the primary tumor have a poor prognosis. In this study, we investigate whether anti-angiogenic therapy might improve survival of patients with a stroma-high profile with potentially increased angiogenesis.
Tissue samples of the primary tumor of 965 colon cancer patients participating in the QUASAR2 trial were analyzed for tumor-stroma ratio (TSR). Stroma-high (>50%) and stroma-low (≤50%) groups were evaluated with respect to survival.
Disease free survival (DFS) was significantly lower in the stroma-high group (HR 1.53, 95%CI 1.19-1.95, P = 0.001). No difference in DFS was seen with respect to treatment with capecitabine alone (CAP) or capecitabine with bevacizumab (CAPBEV) (Stroma-high HR 1.00, 95%CI 0.69-1.46, P = 0.996; stroma-low HR 1.02, 95%CI 0.75-1.41, P = 0.883). A significant difference in survival was seen comparing groups with or without vascular invasion (DFS P < 0.001). A correlation between vascular invasion and stroma-high was seen (χ2-test P = 0.043).
The TSR confirmed to be a strong prognosticator for disease-free survival in a selected high-risk patient population. No benefit was found in response to treatment with bevacizumab when stratified for TSR. TSR showed to have an additional prognostic value in patients with vascular invasion present in the primary tumor.
The risk of recurrence after resection of non-metastatic gastro-entero-pancreatic neuroendocrine tumors (GEP-NET) is poorly defined. We developed/validated a nomogram to predict risk of recurrence after curative-intent resection.
A training set to develop the nomogram and test set for validation were identified. The predictive ability of the nomogram was assessed using c-indices.
Among 1477 patients, 673 (46%) were included in the training set and 804 (54%) in y the test set. On multivariable analysis, Ki-67, tumor size, nodal status, and invasion of adjacent organs were independent predictors of DFS. The risk of death increased by 8% for each percentage increase in the Ki-67 index (HR 1.08, 95% CI, 1.05-1.10; P < 0.001). GEP-NET invading adjacent organs had a HR of 1.65 (95% CI, 1.03-2.65; P = 0.038), similar to tumors ≥3 cm (HR 1.67, 95% CI, 1.11-2.51; P = 0.014). Patients with 1-3 positive nodes and patients with >3 positive nodes had a HR of 1.81 (95% CI, 1.12-2.87; P = 0.014) and 2.51 (95% CI, 1.50-4.24; P < 0.001), respectively. The nomogram demonstrated good ability to predict risk of recurrence (c-index: training set, 0.739; test set, 0.718).
The nomogram was able to predict the risk of recurrence and can be easily applied in the clinical setting.
Histomorphological features have been described as prognostic factors after resection of colorectal liver metastases (CLM). The objectives of this study were to assess the prognostic significance of tumor budding (TB) and poorly differentiated clusters (PDC) among CLM, and their association with other prognostic factors.
We evaluated 229 patients who underwent a first resection of CLM. Slides stained by HE were assessed for TB, PDC, tumor border pattern, peritumoral pseudocapsule, peritumoral, and intratumoral inflammatory infiltrate. Lymphatic and portal invasion were evaluated through D2-40 and CD34 antibody.
Factors independently associated with poor overall survival were nodules>4 (P = 0.002), presence of PDC G3 (P = 0.007), portal invasion (P = 0.005), and absence of tumor pseudocapsule (P = 0.006). Factors independently associated with disease-free survival included number of nodules>4 (P < 0.001), presence of PDC G3 (P = 0.005), infiltrative border (P = 0.031), portal invasion (P = 0.006), and absent/mild peritumoral inflammatory infiltrate (P = 0.002). PDC and TB were also associated with histological factors, as portal invasion (TB), peritumoral inflammatory infiltration (PDC), infiltrative border, and absence of tumor pseudocapsule (TB and PDC).
This is the first study demonstrating PDC as a prognostic factor in CLM. TB was also a prognostic factor, but it was not an independent predictor of survival.
To compare outcomes in patients receiving neoadjuvant stereotactic body radiation therapy (SBRT) with those receiving intensity-modulated radiation therapy (IMRT) for pancreatic adenocarcinoma.
We analyzed patients receiving neoadjuvant SBRT for borderline resectable (BRPC) and locally advanced pancreatic cancer (LAPC) (2012-2016). Differences in baseline characteristics, perioperative outcomes, progression-free survival (PFS), and overall survival (OS) were compared.
Seventy-five (82.4%) patients received SBRT and 16 (17.6%) received IMRT. There were no differences in surgical resection rates in the SBRT (n = 38, 50.7%) and IMRT (n = 11, 68.8%) groups (P = 0.188). Among resected patients, there was no difference in postoperative outcomes or pathologic outcomes including lymph node status, margin status, lymphovascular and perineural invasion, or pathologic response to neoadjuvant treatment (P > 0.05). Among all patients, median PFS and OS were 9.9 and 23.5 months in the SBRT group, respectively, and 15.3 and 21.8 months in the IMRT group, respectively (P > 0.05). Similarly, there was no difference in PFS or OS between groups when stratified by BRPC, LAPC, and surgically resected patients (P > 0.05).
In the neoadjuvant setting, SBRT and IMRT appear to have similar rates of resection, perioperative outcomes, and survival outcomes, but additional studies with increased sample size and longer follow up are needed.
The role of surgical resection in the treatment of patients with metastatic/recurrent gastrointestinal stromal tumors (GIST) is unclear. The aim of this study was to identify preoperative factors associated with oncologic outcomes for recurrent/metastatic GIST after tyrosine kinase inhibitor (TKI) therapy.
We identified 107 patients with metastatic or recurrent GIST treated with TKIs and surgical resection (2002-2012). Patients that underwent palliative or incomplete resection were excluded. Complete resection was achieved in 87 patients which comprise the analytic cohort. Univariate and multivariate analyses were conducted to identify risk factors for GIST-specific survival (DSS) and time-to-recurrence (TTR).
At a median follow-up of 51 months (91 months for survivors), median DSS was 74 months and TTR was 21 months. By univariate analysis, unifocal disease, duration of TKI < 365 days, and no evidence of radiographic progression were associated with improved TTR and DSS. Multivariate Cox regression demonstrated that evidence of radiographic progression was associated with shorter DSS (HR 2.53, 95%CI = 1.27-5.06, P = 0.008) and increased risk of recurrence (HR 3.33, 95%CI = 1.91-5.82, P < 0.001).
Patients with unifocal disease and radiographic evidence of response to TKI therapy may achieve improved oncologic outcomes when complete surgical resection is achieved following treatment with TKI.
Selective internal radiotherapy (SIRT) has emerged as an effective therapy for patients with liver malignancies. Here, we report our analysis of histopathological changes in tumors and healthy liver tissue after SIRT and liver resection. Our main intent was to determine if specific histopathological changes occur in tumor and normal liver tissues.
We identified 17 patients in whom SIRT was applied to achieve liver resectability. Samples were taken from the resected liver tissue. The tumor, tumor peripheries, and tumor-free tissue were examined microscopically.
Microspheres were identified in the vascular tumor bed, tumor-free liver, and portal tract. More microspheres were detected in the tumor than in the healthy liver tissue. When the effects of SIRT were analyzed, most patients showed a partial pathological response. Specific histopathological changes could not be described. We did not find any typical signs of radiation-induced hepatitis in healthy liver tissue.
Our findings support the clinical experience of effective tumor control after SIRT together with minimal impairment of healthy liver tissue. The observed histopathological changes suggest that SIRT might play a role in preoperative downsizing of liver malignancies.
Approximately 30-50% of patients with colorectal cancer develop liver metastasis for which liver resection is the only hope for potential cure. However, hepatic resection is associated with considerable morbidity. The aim was to detect early complications by utilising the neutrophil: lymphocyte ratio (NLR).
We performed a retrospective cohort study of patients undergoing hepatic resection at a single institution between 2008 and 2016. Baseline demographics and complications within 30 days following surgery were recorded, with blood tests measured until day 7. Statistical analysis was performed using Mann Whitney and ROC analysis.
One hundred eighty-eight operations were included. 47.3% had an associated complication, of which 31.46% were major. The median NLR was 6.31 across the cohort, 5.44 for uncomplicated procedures, 7.0 for complications and 10.65 in major complications. Median NLR was the best parameter for detecting major complications versus minor complications (AUC 0.74) as opposed to lymphocytes (AUC 0.65), neutrophils (AUC 0.60), and CRP (AUC 0.60). The diagnostic ability of NLR increased further when predicting major complications versus an uncomplicated recovery (AUC 0.78), and it was the only significant parameter in the early post-operative period on days 2, 3, and 4 (AUC 0.70, 0.72, and 0.75).
The NLR may have a role in predicting complications following hepatic resection for CLM, and with earlier detection, potentially improving outcomes.
To analyze our experience in retroperitoneal laparoscopic adrenalectomy (RLA) with transient renal artery occlusion for large adrenal tumors (≥8 cm) and to explore the safety and feasibility of this surgical procedure.
A retrospective cohort study was conducted with a surgical data review of 18 patients with large adrenal tumors who underwent RLA with transient renal artery occlusion in our hospital.
Eighteen patients were treated by RLA with transient occlusion of the renal artery, and none were converted to open adrenalectomy. The renal artery occlusion time, operative time, estimated blood loss, perirenal drainage time, postoperative hospital stay, and postoperative drainage were 7.6 ± 1.0 min, 176.3 ± 49.7 min, 247.2 ± 274.1 mL, 4.1 ± 1.02 days, 6.3 ± 1.4 days, and 73.6 ± 47.9 mL, respectively. No severe complications occurred, with the exception of hemodynamic instability in one patient with a pheochromocytoma and one transfusion during the operation. Only one case of adrenal crisis occurred postoperatively. Pathological examination revealed 9 cases of pheochromocytoma, 6 cases of adrenal myelolipoma, 1 case of adrenal ganglioneuroma, 1 case of hygromata, and 1 case of adrenal teratoma. No recurrence or evidence of metastasis was observed during the 7-to-30-month follow-up period.
RLA with transient renal artery occlusion is a feasible, effective, and safe treatment for large adrenal tumors (≥8 cm).
Deregulation of methionine adenosyltransferase (MAT) is involved in hepatocarcinogenesis. This study aimed to investigate the prognostic implications of the level of histological MAT1A and MAT2A in patients with resected hepatocellular carcinoma (HCC).
A total of 210 patients with HCC who underwent curative resection between 2004 and 2011 were included. The levels of MAT proteins were immunohistochemically measured.
MAT1A and MAT2A were over-expressed in 134 (63.8%) and 124 (59.1%) of the 210 tumor tissues, respectively. Up-regulation of tumoral MAT1A was independently associated with male gender, and inversely related to tumors >5 cm (adjusted odds ratios [OR] 2.59, P = 0.008, and OR 0.44, P = 0.012, respectively). Enhanced MAT2A expression was significantly related to age ≥60 years and serum AFP >200 ng/mL (OR 0.51, P = 0.030; and OR 2.65, P = 0.003; respectively). Tumoral MAT2A over-expression independently predicted an increased rate of recurrence within 1 year after hepatectomy (adjusted hazard ratio [HR] 2.45, P = 0.012), but that was not the case for MAT1A expression (HR 0.90, P = 0.744). High MAT2A was also an independent predictor of early recurrence (HR 2.54, P = 0.034) in the subset of patients without microvascular invasion (n = 155).
Over-expression of MAT2A in HCC may be a useful biomarker for predicting and monitoring tumor recurrence, especially early after hepatic resection.
Evaluation of mandibular reconstructions with free fibula flaps. Identification of factors associated with major recipient site complications, that is, necessitating surgical intervention under general anaesthesia.
Seventy-nine reconstructions were included. The following factors were analyzed: fixation type, number of osteotomies, site of defect (bilateral/unilateral), surgeon, sex, ASA classification, continuous smoking, pathological N-stage, age, defect size, flap ischemic time, and postoperative radiotherapy. Proportional hazards regression was used to test the effect on the time between reconstruction and intervention.
Sixty-nine (87%) of the 79 fibula flaps were successful at the last follow-up. Forty-eight major recipient site complications occurred in 41 reconstructions. Nineteen complications required surgical intervention within six weeks and were mostly vascular problems, necessitating immediate intervention. These early complications were associated with defects crossing the midline, with an estimated relative risk of 5.3 (CI 1.1-20, P = 0.01). Twenty-nine complications required surgical intervention more than 6 weeks after the reconstruction. These late complications generally occurred after months or years, and were associated with smoking, with an estimated relative risk of 2.8 (CI 1.0-8.3, P = 0.05).
Fibula flaps crossing the midline have a higher risk of early major recipient site complications than unilateral reconstructions. Smoking increases the risk of late complications.
The prognostic performance of the albumin-bilirubin (ALBI) grade in hepatocellular carcinoma (HCC) as an objective method of assessing liver function was investigated.
Data from 2099 patients with HCC in Korea were collected and analyzed retrospectively. The discriminative performance of ALBI grade was compared with Child-Pugh (C-P) grade for different stages or treatments.
The median follow up duration was 16.2 months (range: 1.0-124.9). The median survival times were 49.7 months for C-P grade A (65.8%), 12.4 months for C-P grade B (25.5%), and 4.2 months for C-P grade C (8.6%) (P < 0.001). The median survival times were 84.2 months for ALBI grade 1 (32.8%), 25.5 months for ALBI grade 2 (53.5%), and 7.7 months for ALBI grade 3 (13.7%) (P < 0.001). In early UICC stages, ALBI grade showed better discriminative performance than C-P grade. In curative treatments, ALBI grade also showed better discriminative performance than C-P grade (Harrell's C: 0.624 (C-P grade) vs 0.667 [ALBI grade]).
ALBI grade provided better prognostic performance in survival analysis and better distribution of the grades than C-P grade in HCC, suggesting that ALBI grade could be a good alternative grading system for liver function in patients with HCC.
AbstractBackground.Sarcomas comprise over 50 subtypes of mesenchymal cancers. For the majority of sarcomas, the driver mutations remain unknown. In this article, we describe our experience with a targeted next‐generation sequencing (NGS) platform in clinic patients.Materials and Methods.We retrospectively analyzed results of NGS using 133 tumor samples from patients diagnosed with a variety of sarcomas that were analyzed with targeted NGS covering over 400 cancer‐related genes (405 DNA, 265 RNA) on a commercially available platform.Results.An average of two gene alterations were identified per tumor sample (range 0–14), and a total of 342 DNA mutations were detected. Eight‐eight percent of samples had at least one detected mutation. The most common mutations were in the cell cycle, including TP53 (n = 35), CDKN2A/B (n = 23), and RB1 (n = 19). Twenty‐seven PI3‐kinase pathway alterations were observed, including PTEN (n = 14), PIK3Ca (n = 4), TSC1 (n = 1), TSC2 (n = 3), STK11 (n = 1), mTOR (n = 3), and RICTOR (n = 2). There were 75 mutations in genes that are targetable with existing drugs (excluding KIT in gastrointestinal stromal tumor) that would allow enrollment onto clinical trials. In general, the estimated tumor mutation burden was low, in particular for those with disease‐defining gene fusions or genetic alterations. Microsatellite instability (MSI) data were available for 50 patients, and all were MSI stable.Conclusion.Our study describes a single‐center experience with targeted NGS for patients with sarcoma. Mutations were readily detected and 75 (representing 40% of patients) were testable for therapeutic effect using existing drugs within the confines of a clinical trial. These data indicate that targeted NGS is a useful tool in potentially routing patients to mutation‐specific clinical trials. Further study will be required to determine if these mutations are clinically meaningful drug targets in sarcoma.Implications for Practice.The sarcomas are a heterogenous family of over 50 different mesenchymal tumors. Current practice for metastatic disease involves systemic chemotherapy or nonspecific kinase inhibitors such as pazopanib. Sarcomas typically lack the classic kinase alterations seen in many carcinomas. The role of next‐generation sequencing in sarcoma clinical practice remains undefined.
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AbstractBackground.Data on the development and outcomes of effective interventions to address aberrant opioid‐related behavior (AB) in patients with cancer are lacking. Our outpatient supportive care clinic developed and implemented a specialized interdisciplinary team approach to manage patients with AB. The purpose of this study was to report clinical outcomes of this novel intervention.Materials and Methods.The medical records of 30 consecutive patients with evidence of AB who received the intervention and a random control group of 70 patients without evidence of AB between January 1, 2015, and August 31, 2016, were reviewed.Results.At baseline, pain intensity (p = .002) and opioid dose (p = .001) were significantly higher among patients with AB. During the course of the study, the median number of ABs per month significantly decreased from three preintervention to 0.4 postintervention (p < .0001). The median morphine equivalent daily dose decreased from 165 mg/day at the first intervention visit to 112 mg/day at the last follow‐up (p = .018), although pain intensity did not significantly change (p = .984). "Request for opioid medication refills in the clinic earlier than the expected time" was the AB with the highest frequency prior to the intervention and the greatest improvement during the study period. Younger age (p < .0001) and higher Edmonton Symptom Assessment System anxiety score (p = .005) were independent predictors of the presence of AB.Conclusion.The intervention was associated with a reduction in the frequency of AB and opioid utilization among patients with cancer receiving chronic opioid therapy. More research is needed to further characterize the clinical effectiveness of this intervention.Implications for Practice.There are currently no well‐defined and evidence‐based strategies to manage cancer patients on chronic opioid therapy who demonstrate aberrant opioid‐related behavior. The findings of this study offer a promising starting point for the creation of a standardized strategy for clinicians and provides valuable information to guide their practice regarding these patients. The study results will also help clinicians to better understand the types and frequencies of the most common aberrant behaviors observed among patients with cancer who are receiving chronic opioid therapy. This will enhance the process of timely patient identification, management, or referral to the appropriate specialist teams.
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AbstractAdult survivors of childhood cancers are more prone to developing poor reproductive and obstetrical outcomes than their siblings and the general population as a result of previous exposure to chemotherapy and radiation during childhood. Chemotherapy drugs exert cytotoxic effects systemically and therefore can damage the ovaries, leading to infertility, premature ovarian failure, and, to a lesser extent, spontaneous abortions. They have very limited or no deleterious effects on the uterus that can be recognized clinically. By contrast, radiation is detrimental to both the ovaries and the uterus, thereby causing a greater magnitude of adverse effects on the female reproductive function. These include infertility, premature ovarian failure, miscarriage, fetal growth restrictions, perinatal deaths, preterm births, delivery of small‐for‐gestational‐age infants, preeclampsia, and abnormal placentation. Regrettably, the majority of these adverse outcomes arise from radiation‐induced uterine injury and are reported at higher incidence in the adult survivors of childhood cancers who were exposed to uterine radiation during childhood in the form of pelvic, spinal, or total‐body irradiation. Recent findings of long‐term follow‐up studies evaluating reproductive performance of female survivors provided some reassurance to female cancer survivors by documenting that pregnancy and live birth rates were not significantly compromised in survivors, including those who had been treated with alkylating agents and had not received pelvic, cranial, and total‐body irradiation. We aimed in this narrative review article to provide an update on the impact of chemotherapy and radiation on the ovarian and uterine function in female survivors of childhood cancer.Implications for Practice.Adult survivors of childhood cancers are more prone to developing a number of poor reproductive and obstetrical outcomes than their siblings and the general population as a result of previous exposure to chemotherapy and radiation during childhood. The impact of radiation therapy on the female genital system is greater than chemotherapy regimens because radiation is detrimental to both the uterus and the ovaries, whereas toxic effects of chemotherapy drugs are confined to the ovaries. Therefore, radiation‐induced uterine damage accounts for most poor obstetrical outcomes in the survivors. These include infertility, miscarriages, stillbirths, fetal growth restrictions, preeclampsia, and preterm deliveries.
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AbstractWe previously reported on a family with hereditary lung cancer, in which a germline mutation in the transmembrane domain (G660D) of avian erythroblastic leukemia viral oncogene homolog 2 (erb‐b2 receptor tyrosine kinase 2) (ERBB2; human epidermal growth factor receptor 2 [HER2]) seemed to be responsible for the cancer predisposition. Although few data are available on treatment, anti‐ERBB2 therapeutic agents may be effective for ERBB2‐mutant cancers. The familial lung cancer patient in one of the authors' institutes developed bone metastasis with enlarging lung tumors and was treated with the ERBB2 inhibitor afatinib. We also encountered a patient with ampullary adenocarcinoma with ERBB2 G660D and S310F comutations in another institute of the authors', revealed by comprehensive genomic profiling. This patient was then treated with afatinib and also achieved transitory response. We also searched for ERBB2 transmembrane mutations in various types of cancers in PubMed, The Cancer Genome Atlas (TCGA), and the Memorial Sloan Kettering‐Integrated Mutation Profiling of Actionable Cancer Targets (MSK‐IMPACT) database. Besides our two cases, two patients with V659E mutations were found via PubMed. Three potential patients were found in TCGA. In addition, MSK‐IMPACT allowed identification of three additional urothelial carcinomas with G660D mutations and two lung adenocarcinomas with V659E mutations. Our experience suggests that establishing a database of integrated information regarding the clinical genome and therapeutic outcome of patients with recurrent but less common mutations is essential to implement precision oncology.Key Points. Rare but targetable mutations such as avian erythroblastic leukemia viral oncogene homolog 2 (erb‐b2 receptor tyrosine kinase 2) (ERBB2; human epidermal growth factor receptor 2 [HER2]) transmembrane domain (TMD) mutations can be detected by comprehensive genomic profiling.Afatinib may be effective for patients with cancer with ERBB2 (HER2) TMD mutations.In order to implement precision oncology, it is important to establish a database of integrated information regarding the clinical genomes and therapeutic outcomes of patients with recurrent but less common mutations.
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