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Showing papers in "Clinical & Translational Oncology in 2019"


Journal ArticleDOI
TL;DR: New treatments mean that the authors must reconsider what should be done in oligometastatic disease where local treatment attains greater value, and it is important to evaluate each treatment alternative in accordance with scientific evidence.
Abstract: Non-small cell lung cancer (NSCLC) accounts for up to 85% of all lung cancers. The last few years have seen the development of a new staging system, diagnostic procedures such as liquid biopsy, treatments like immunotherapy, as well as deeper molecular knowledge; so, more options can be offered to patients with driver mutations. Groups with specific treatments account for around 25% and demonstrate significant increases in overall survival, and in some subgroups, it is important to evaluate each treatment alternative in accordance with scientific evidence, and even more so with immunotherapy. New treatments similarly mean that we must reconsider what should be done in oligometastatic disease where local treatment attains greater value.

105 citations


Journal ArticleDOI
TL;DR: The molecular mechanisms for radioprotection and radiosensitizer effects of melatonin are described and some other proposed mechanisms that may be involved are presented.
Abstract: It is estimated that more than half of cancer patients undergo radiotherapy during the course of their treatment. Despite its beneficial therapeutic effects on tumor cells, exposure to high doses of ionizing radiation (IR) is associated with several side effects. Although improvements in radiotherapy techniques and instruments could reduce these side effects, there are still important concerns for cancer patients. For several years, scientists have been trying to modulate tumor and normal tissue responses to IR, leading to an increase in therapeutic ratio. So far, several types of radioprotectors and radiosensitizers have been investigated in experimental studies. However, high toxicity of chemical sensitizers or possible tumor protection by radioprotectors creates a doubt for their clinical applications. On the other hand, the protective effects of these radioprotectors or sensitizer effects of radiosensitizers may limit some type of cancers. Hence, the development of some radioprotectors without any protective effect on tumor cells or low toxic radiosensitizers can help improve therapeutic ratio with less side effects. Melatonin as a natural body hormone is a potent antioxidant and anti-inflammatory agent that shows some anti-cancer properties. It is able to neutralize different types of free radicals produced by IR or pro-oxidant enzymes which are activated following exposure to IR and plays a key role in the protection of normal tissues. In addition, melatonin has shown the ability to inhibit long-term changes in inflammatory responses at different levels, thereby ameliorating late side effects of radiotherapy. Fortunately, in contrast to classic antioxidants, some in vitro studies have revealed that melatonin has a potent anti-tumor activity when used alongside irradiation. However, the mechanisms of its radiosensitive effect remain to be elucidated. Studies suggested that the activation of pro-apoptosis gene, such as p53, changes in the metabolism of tumor cells, suppression of DNA repair responses as well as changes in biosynthesis of estrogen in breast cancer cells are involved in this process. In this review, we describe the molecular mechanisms for radioprotection and radiosensitizer effects of melatonin. Furthermore, some other proposed mechanisms that may be involved are presented.

87 citations


Journal ArticleDOI
Jian Gao1, Hao-Ran Li1, Chun Jin1, Jia-Hao Jiang1, Ding Jianyong1 
TL;DR: The next-generation EGFR TKI and immunotherapy represent two novel directions for overcoming acquired resistance and have achieved promising efficacy.
Abstract: Epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI) represents a paradigm shift in the treatment of non-small cell lung cancer (NSCLC) patients and has been the first-line therapy in clinical practice. While erlotinib, gefitinib and afatinib have achieved superior efficacy in terms of progression-free survival and overall survival compared with conventional chemotherapy in NSCLC patients, most people inevitably develop acquired resistance to them, which presents another challenge in the treatment of NSCLC. The mechanisms of acquired resistance can be classified as three types: target gene mutation, bypass signaling pathway activation and histological transformation. And the most common mechanism is T790M which accounts for approximately 50% of all subtypes. Many strategies have been explored to overcome the acquired resistance to EGFR TKI. Continuation of EGFR TKI beyond progressive disease is confined to patients in asymptomatic stage when the EGFR addiction is still preserved in some subclones. While the combination of EGFR TKI and chemotherapy or other targeted agents has improved the survival benefit in EGFR TKI resistant patients, there are controversies within them. The next-generation EGFR TKI and immunotherapy represent two novel directions for overcoming acquired resistance and have achieved promising efficacy. Liquid biopsy provides surveillance of the EGFR mutation by disclosing the entire genetic landscape but tissue biopsy is still indispensable because of the considerable rate of false-negative plasma.

75 citations


Journal ArticleDOI
TL;DR: The rationale and clinical evidence of immunotherapy in SCLC, the conflictive clinical results of novel immunotherapeutic agents and combinatorial therapies under evaluation in SclC patients, and the use of cytokines, cancer vaccines, antiganglioside therapies, TLR9 inhibition, anti-Notch signaling, and anti-CD47 are discussed.
Abstract: Despite decades of research, prognosis for SCLC patients remains poor, and treatment options limited. SCLC is an immunogenic tumor with high somatic mutation rates due to tobacco exposure resulting in potential neo-antigens, the presence of suppressed immune responses, and occurrence of paraneoplastic disorders. The use of T cell immune-checkpoint inhibitors (anti-PD1: nivolumab, pembrolizumab; anti-PD-L1: atezolizumab, durvalumab; anti-CTLA-4: ipilimumab, tremelimumab) have shown promising antitumor activity with the potential to prolong survival in SCLC patients. In fact, atezolizumab when combined with chemotherapy has achieved the milestone of being the first drug to improve survival in patients with newly diagnosed extensive-stage SCLC. Other immunotherapeutic approaches evaluated in clinical trials for SCLC include the use of cytokines, cancer vaccines, antiganglioside therapies, TLR9 inhibition, anti-Notch signaling, and anti-CD47. This review discusses the rationale and clinical evidence of immunotherapy in SCLC, the conflictive clinical results of novel immunotherapeutic agents and combinatorial therapies under evaluation in SCLC patients.

74 citations


Journal ArticleDOI
TL;DR: Reported MS relapses after ICI are rare, but the adverse events described include rapid neurologic progression and death, and larger and prospective studies are warranted to assess disability and long-term outcomes and outweigh the risks of starting immunotherapy in patients with MS.
Abstract: Neurological immune-related adverse events are a rare but potentially deadly complication after immune checkpoint inhibitor (ICI) treatment. As multiple sclerosis (MS) is an immune-mediated disease, it is unknown how ICI treatment may affect outcomes. We analyzed the United States Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database for pembrolizumab, atezolizumab, nivolumab, ipilimumab, avelumab, and durvalumab 2 years prior their FDA approval until December 31, 2017, to include all cases with confirmed diagnosis/relapse of MS. We also included cases reported in the literature and a patient from our institution. We identified 14 cases of MS with median age of presentation of 52 years. Indications for ICI included melanoma in 7 (36.36%) cases, non-small cell lung carcinoma in 2 (18.18%) cases, 1 case (9.09%) each of pleural mesothelioma, renal cell carcinoma, and colorectal cancer, and unreported in 2 (18.18%) cases. History of MS was confirmed in 8 (57.1%) cases. Median time to beginning of symptoms was 29 days with rapid disease progression; two patients died due to their relapse. Median time for symptom resolution was 8 weeks. Outcomes did not vary by comparing CTLA-4 and PD-1/PD-L1 inhibitors. Reported MS relapses after ICI are rare, but the adverse events described include rapid neurologic progression and death. Larger and prospective studies are warranted to assess disability and long-term outcomes and outweigh the risks of starting immunotherapy in patients with MS.

66 citations


Journal ArticleDOI
TL;DR: The combination of hydroxytyrosol, omega-3 fatty acids, and curcumin reduced inflammation as indicated by a reduction in CRP and reduced pain in patients with aromatase-induced musculoskeletal symptoms.
Abstract: Breast cancer patients receiving hormonal therapies face risks of relapse, increased rates of cardiovascular events, and toxicities of therapy such as aromatase inhibitor (AI)-associated musculoskeletal symptoms (AIMSS). C-reactive protein (CRP), a marker for inflammation, is associated with breast cancer outcomes. We evaluated whether the olive-derived polyphenol hydroxytyrosol combined with omega-3 fatty acids and curcumin would reduce CRP and musculoskeletal symptoms in breast cancer patients receiving adjuvant hormonal therapies. This prospective, multicenter, open-label, single arm, clinical trial enrolled post-menopausal breast cancer patients (n = 45) with elevated C-reactive protein (CRP) taking predominantly aromatase inhibitors to receive a combination of hydroxytyrosol, omega-3 fatty acids, and curcumin for 1 month. CRP, other inflammation-associated cytokines, and pain scores on the Brief Pain Inventory were measured before therapy, at the end of therapy and 1 month after completion of therapy. CRP levels declined during the therapy [from 8.2 ± 6.4 mg/L at baseline to 5.3 ± 3.2 mg/L (p = 0.014) at 30 days of treatment], and remained decreased during the additional 1 month off therapy. Subjects with the highest baseline CRP levels had the greatest decrease with the therapy. Pain scores also decreased during the therapy. There were no significant adverse events. The combination of hydroxytyrosol, omega-3 fatty acids, and curcumin reduced inflammation as indicated by a reduction in CRP and reduced pain in patients with aromatase-induced musculoskeletal symptoms. Longer studies comparing this combination to other anti-inflammatories in larger groups of patients with clinical outcome endpoints are warranted.

60 citations


Journal ArticleDOI
TL;DR: The indications of nutritional interventions as well as artificial nutrition in general and according to the type of treatment (radiotherapy, surgery, or systemic therapy), or palliative care, and pharmacological agents and pharmaconutrients will be reviewed in addition to the role of regular physical activity are reviewed.
Abstract: Nutritional deficiency is a common medical problem that affects 15–40% of cancer patients. It negatively impacts their quality of life and can compromise treatment completion. Oncological therapies, such as surgery, radiation therapy, and drug therapies are improving survival rates. However, all these treatments can play a role in the development of malnutrition and/or metabolic alterations in cancer patients, induced by the tumor or by its treatment. Nutritional assessment of cancer patients is necessary at the time of diagnosis and throughout treatment, so as to detect nutritional deficiencies. The Patient-Generated Subjective Global Assessment method is the most widely used tool that also evaluates nutritional requirements. In this guideline, we will review the indications of nutritional interventions as well as artificial nutrition in general and according to the type of treatment (radiotherapy, surgery, or systemic therapy), or palliative care. Likewise, pharmacological agents and pharmaconutrients will be reviewed in addition to the role of regular physical activity.

60 citations


Journal ArticleDOI
TL;DR: This review has highlighted the most consistently reported dysregulated miRNAs in prostate cancer from the existing literature and discussed the currently available data on their role in regulating the hallmarks of prostate cancer.
Abstract: MicroRNAs (miRNAs) are short, non-coding, conserved, oligonucleotides that are regulatory in nature and are often dysregulated in many cancers including prostate cancer. Depending on the level of complementarity between the miRNA and mRNA target, they can either inhibit translation or degrade the target mRNA. MiRNAs expression is specific to the type of cancer, its stage and level of metastasis, making miRNAs potential stage-specific biomarkers of cancer. Recent research has shown that these miRNAs have the potential to be a diagnostic and prognostic non-invasive biomarker for various cancers including prostate cancer. Various miRNAs have been reported as novel biomarkers for prostate cancer therapy. However, there is inconsistency in the data reported and no overlapping expression pattern could be found. In this review, we have highlighted the most consistently reported dysregulated miRNAs in prostate cancer from the existing literature and discussed the currently available data on their role in regulating the hallmarks of prostate cancer. These four most consistently reported dysregulated miRNAs viz. miRNA-141, miRNA-375, miRNA-221 and miRNA-21 need to be further validated in terms of their regulatory potential in regulating various pathways important for prostate cancer management.

58 citations


Journal ArticleDOI
TL;DR: It is indicated that PCGEM1 is a hypoxia-responsive lncRNA, and contributes to the invasion and metastasis of GC, and the potential mechanism is attributed to the regulation of EMT by PCG EM1 and its influence on the expression of SNAI1.
Abstract: Hypoxia is an indispensable factor in the progression of metastasis. Hypoxia inducible factor-1α (HIF-1α), the core element in generating the hypoxia response, induces invasion and metastasis by promoting epithelial–mesenchymal transition (EMT). This study explored the underlying mechanism of hypoxia associated with the invasion and metastasis of gastric cancer (GC). Six methods were employed to assess the function of the long noncoding RNA (lncRNA) prostate cancer gene expression marker 1 (PCGEM1) including gene silencing, RT-PCR, the separation of nuclear and cytoplasmic fractions, scrape motility assay, transwell migration assay, and Western-blot. LncRNA PCGEM1 was overexpressed in GC cells and tissues, and was induced by hypoxia in GC cells. Additional experiments confirmed that the knockdown of PCGEM1 significantly repressed the invasion and metastasis of GC cells. SNAI1, a key transcription factor of EMT, was regulated by PCGEM1. Overexpression of SNAI1 rescued the inhibition of PCGEM1-knockdown during the invasion and metastasis of GC cells. In addition, PCGEM1 and SNAI1 jointly affected the biomarkers of EMT. Our findings indicated that PCGEM1 is a hypoxia-responsive lncRNA, and contributes to the invasion and metastasis of GC. The potential mechanism is attributed to the regulation of EMT by PCGEM1 and its influence on the expression of SNAI1.

55 citations


Journal ArticleDOI
TL;DR: The finding that ALC at baseline and at 6 weeks on treatment is positively correlated with the OS provides an easily obtained predictive marker and supports that the combination of radiation therapy with immunotherapy should be carefully applied and potentially peripheral blood counts can be utilized to stratify patients for this approach.
Abstract: The neutrophil-to-lymphocyte (ANC/ALC) ratio is associated with worse prognosis in patients with NSCLC on immunotherapies, but the role of ALC remains unclear. The previous radiation therapy causes lymphopenia, and given approaches of combining radiation with immunotherapies, it is critical to better understand the impact of peripheral lymphocytes. We evaluated retrospectively 22 patients with advanced NSCLC treated with nivolumab at Boston Medical Center from January 2014 to September 2016 and correlated the peripheral blood counts with the overall survival (OS) and overall time on treatment. We assessed the effect of the previous radiation on peripheral blood counts and clinical outcomes. Baseline ALC and ANC/ALC ratios are positively and negatively correlated, respectively, with the OS on nivolumab. The ALC and ALC/WBC ratios at 6 weeks on treatment are positively associated with the OS. Kaplan–Meier analysis at baseline and at 6 weeks showed significantly increased OS in the group of patients with the highest ALC. The previous radiation therapy was positively correlated with the ANC and negatively correlated with the ALC/WBC ratio at 8 weeks after the initiation of nivolumab. Our finding that ALC at baseline and at 6 weeks on treatment is positively correlated with the OS provides an easily obtained predictive marker. Our result that the previous radiation is associated with higher ANC and lower ALC during treatment supports that the combination of radiation therapy with immunotherapy should be carefully applied and potentially peripheral blood counts can be utilized to stratify patients for this approach.

54 citations


Journal ArticleDOI
TL;DR: The optimal treatment strategy for patients with metastatic CRC should be discussed in a multidisciplinary expert team to select the most appropriate treatment, and integrate systemic treatment and other options depending on the characteristics of the tumour, the patient and the location of the disease and metastases.
Abstract: Colorectal cancer (CRC) is the second cause of cancer death in Spain, the objective of this guide published by the Spanish Society of Medical Oncology is to develop a consensus for the diagnosis and management of metastatic disease. The optimal treatment strategy for patients with metastatic CRC should be discussed in a multidisciplinary expert team to select the most appropriate treatment, and integrate systemic treatment and other options such as surgery and ablative techniques depending on the characteristics of the tumour, the patient and the location of the disease and metastases.

Journal ArticleDOI
TL;DR: For patients with pre-operative risk factors of LNM, an accurate preoperative evaluation of central compartment or lateral compartment is needed to find suspicious lymph nodes and prophylactic lymph node dissection should be performed in patients with high risk of CLNM.
Abstract: Central lymph node metastasis (LNM) in papillary thyroid carcinoma (PTC) is common. But the association between primary tumor characteristics and specific features of metastatic lymph nodes in PTC has not been fully identified. Determining risk factors for LNM may help surgeons determine rational extent of lymph node dissection. Data from 432 patients who underwent thyroidectomy with cervical lymph node dissection for PTC were retrospectively analyzed. The relationships between LNM to central compartment or lateral compartment and clinicopathologic factors were analyzed. Cox regression model was used to determine the risk factors for recurrence-free survival (RFS). Central lymph node metastasis (CLNM) and lateral lymph node metastasis (LLNM) were found in 216 (50.0%) and 65 (15.0%) patients, respectively. In the multivariate analysis for CLNM, patients < 45 years of age (OR 2.037, 95% CI 1.388–2.988, P < 0.001), extrathyroidal invasion (OR: 2.144, 95% CI 0.824–5.457, P = 0.011), vascular invasion (OR 13.817, 95% CI 1.694–112.693, P = 0.014), LLNM (OR 2.851, 95% CI 1.196–6.797, P = 0.014) and TNM Stage III–IV (OR 465.307, 95% CI 113.903–1900.826, P < 0.001) were independent predictors for high prevalence of CLNM. In the multivariate analysis for LLNM, tumor size more than 1cm (OR 3.474, 95% CI 1.728–6.985, P < 0.001) and CLNM (OR 5.532, 95% CI 2.679–11.425, P < 0.001) were independent predictors for high prevalence of LLNM. Moreover, tumor with T3–T4 stage, extrathyroidal invasion and CLNM were the significant factors related to the RFS. For patients with pre-operative risk factors of LNM, an accurate preoperative evaluation of central compartment or lateral compartment is needed to find suspicious lymph nodes. And prophylactic lymph node dissection should be performed in patients with high risk of CLNM. Moreover, we suggest performing close follow-up for patients with high risk of RFS.

Journal ArticleDOI
TL;DR: The combination of p53MVA vaccine with pembrolizumab is feasible, safe, and may offer clinical benefit in select group of patients that should be identified through further studies.
Abstract: Vaccination of cancer patients with p53-expressing modified vaccinia Ankara virus (p53MVA) has shown in our previous studies to activate p53-reactive T cells in peripheral blood but without immediate clinical benefit. We hypothesized that the immunological responses to p53MVA vaccine may require additional immune checkpoint blockade to achieve clinically beneficial levels. We therefore conducted a phase I trial evaluating the combination of p53MVA and pembrolizumab (anti-PD-1) in patients with advanced solid tumors. Eleven patients with advanced breast, pancreatic, hepatocellular, or head and neck cancer received up to 3 triweekly vaccines in combination with pembrolizumab given concurrently and thereafter, alone at 3-week intervals until disease progression. The patients were assessed for toxicity and clinical response. Correlative studies analyzed p53-reactive T cells and profile of immune function gene expression. We observed clinical responses in 3/11 patients who remained with stable disease for 30, 32, and 49 weeks. Two of these patients showed increased frequencies and persistence of p53-reactive CD8+ T cells and elevation of expression of multiple immune response genes. Borderline or undetectable p53-specific T cell responses in 7/11 patients were related to no immediate clinical benefit. The first study patient had a grade 5 fatal myocarditis. After the study was amended for enhanced cardiac monitoring, no additional cardiac toxicities were noted. We have shown that the combination of p53MVA vaccine with pembrolizumab is feasible, safe, and may offer clinical benefit in select group of patients that should be identified through further studies.

Journal ArticleDOI
TL;DR: A better knowledge of this disease is improving the ability to select the most appropriate therapy for each patient with a recent diagnosis of an early stage breast cancer, minimizing unnecessary toxicities and improving long-term efficacy.
Abstract: Breast cancer is the most common cancer in women in our country and it is usually diagnosed in the early and potentially curable stages. Nevertheless, around 20–30% of patients will relapse despite appropriate locoregional and systemic therapies. A better knowledge of this disease is improving our ability to select the most appropriate therapy for each patient with a recent diagnosis of an early stage breast cancer, minimizing unnecessary toxicities and improving long-term efficacy.

Journal ArticleDOI
TL;DR: It was concluded on numerous studies that the rational combination of administration and encapsulation of ATO have promising potentials in increasing drug efficacy and decreasing adverse drug effects.
Abstract: Arsenic trioxide (ATO), a highly effective drug in treating acute promyelocytic leukemia with low toxicity, demonstrates a significant effect on lung cancer. The anti-cancer mechanisms of ATO include inhibition of cancer stem-like cells, induction of apoptosis, anti-angiogenesis, sensitization of chemotherapy and radiotherapy, anti-cancer effects of hypoxia, and immunoregulation properties. In addition, some studies have reported that different lung cancers respond differently to ATO. It was concluded on numerous studies that the rational combination of administration and encapsulation of ATO have promising potentials in increasing drug efficacy and decreasing adverse drug effects. We reviewed the efficacy of ATO in the treatment of lung cancer in recent years to provide some views for further study.

Journal ArticleDOI
TL;DR: An association between low PLR and longer DFS in elderly breast cancer patients is found that is in line with findings in patients with a wider range of ages, indicating a potential differential effect in elderly patients.
Abstract: Several studies have found an association between peripheral inflammatory cells and outcome. However, no study has explored their impact specifically in elderly patients. We have retrospectively examined pretreatment peripheral neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR), lymphocyte/monocyte ratio (LMR), and neutrophil/monocyte ratio (NMR) in 113 elderly breast cancer patients and correlated our findings with disease-free survival (DFS) and overall survival (OS). All patients ≥ 65 years diagnosed from 2004 to 2018 with locally advanced breast cancer were included and classified as high vs low NLR, PLR, LMR, and NMR based on previously identified cutoffs. Estimated 1-, 3-, and 5-year DFS and OS were compared by Chi square analysis. Among 104 evaluable patients, only PLR was significantly associated with estimated 3-year DFS (85.1% vs 63.6%; P = 0.04) and OS (89.3% vs 68.1%; P = 0.03). Among 69 patients with three or more years of follow-up, PLR (P = 0.05), absolute lymphocyte count (ALC) (P = 0.01), polychemotherapy (P = 0.04), number of comorbidities (P = 0.02), polypharmacy (P = 0.005), and clinical stage (P = 0.03) were associated with 3-year DFS. Polypharmacy (OR 4.9; P = 0.02) and ALC (OR 4.6; P = 0.04) retained their significance in the multivariate analysis. We have found an association between low PLR and longer DFS in elderly breast cancer patients that is in line with findings in patients with a wider range of ages. Our findings on NLR contrast with those of other studies, indicating a potential differential effect in elderly patients. In addition, the effect of polypharmacy on outcome in elderly patients warrants further investigation.

Journal ArticleDOI
X. Jin1, L. Zhu, Z. Cui, J. Tang, M. Xie, G. Ren1 
TL;DR: It is suggested that GNAS promoted breast cancer cell proliferation and migration (EMT) through the PI3K/AKT/Snail1/E-cadherin signaling pathway and can serve as a potential prognostic indicator and novel therapeutic target in breast cancer.
Abstract: Although it has been well established that G protein plays pivotal roles in physiologic or pathologic conditions, including cancer formation, its role in breast cancer, especially specific subunits, remains largely unknown. Our work aimed to evaluate the correlation of the G protein alpha subunit (GNAS) with breast cancer and to investigate the underlying molecular mechanism. The expression of GNAS was determined by breast tumor tissue microarray of 150 patients with complete follow-up information. The correlation between GNAS expression and clinical features was assessed. CCK8, EdU incorporation, flow cytometry, wound healing, transwell, western blot and tumor formation assays were carried out in nude mice to study the biological function of GNAS and the underlying molecular mechanism in breast cancer by silencing GNAS using a specific siRNA. High GNAS expression showed a close correlation with a reduced overall survival (p = 0.021), frequent distal metastasis (p = 0.026), advanced clinical stage (p = 0.001), stronger cell proliferation (ki67+ positive cell rate, p = 0.0351) and enhanced cancer cell migration, which was further confirmed by in vitro and in vivo assays and might be dependent on the PI3K/AKT/Snail1/E-cadherin axis. The data suggested that GNAS promoted breast cancer cell proliferation and migration (EMT) through the PI3K/AKT/Snail1/E-cadherin signaling pathway. These findings also indicate that GNAS can serve as a potential prognostic indicator and novel therapeutic target in breast cancer.

Journal ArticleDOI
TL;DR: The prognostic role of PD-1/PD-L1 as a bio-marker in various clinical scenarios is discussed and the strengths and limits in both prognosis and therapy of HCC will be highlighted.
Abstract: Hepatocellular carcinoma (HCC) is the most common primary neoplasia of the liver. There have been tremendous efforts in the development of therapeutic strategies in the last decades. As opposed to other cancer entities immunotherapy has just recently gained popularity in HCC. Among various immunotherapy approaches, programmed cell death protein-1 (PD-1), and its ligand programmed death receptor ligand-1 (PD-L1) axis became one of the most promising pathway of the decade. The scientific interest in PD-1/PD-L1 axis is definitely justified due to: ability to detect PD-L1 expression in patients that underwent resection for HCC with prognostic values; the role of serum PD-L1 as a tool to identify early recurrences and to monitor treatment outcome; PD-1/PDL1 is a highly targetable pathway, with possible predictive markers, and with high clinical applicability that might help us in selecting a subgroup of HCC patients who are most likely to benefit from PD-1/PD-L1 inhibitors. In this review we will first discuss the prognostic role of PD-1/PD-L1 as a bio-marker in various clinical scenarios. Afterwards we will critically analyse the recently published trials with PD-1/PD-L1 inhibitors in HCC either alone or in combination with other treatment modalities. The higher focus will be on clinical rather than preclinical studies. Nevertheless, the strengths and limits of PD-1/PD-L1 axis in both prognosis and therapy of HCC will be highlighted.

Journal ArticleDOI
TL;DR: CEP55 expression was significantly correlated with poor outcome including neoplasm disease stage, histologic grade and TNM status, as well as survival status of patients and showed that CEP55 could promote EMT through PI3K/AKT/mTOR pathway and might be an effective prognostic marker in RCC.
Abstract: To study the detailed mechanisms of tumorigenesis and clinical outcomes of centrosomal protein 55 (CEP55) overexpression in renal cell carcinoma. Microarray analysis was performed to explore differentially expressed genes in five pairs of RCC tissues. Data of CEP55 expression and corresponding clinical information for 532 RCC patients of TCGA database were downloaded from cBioPortal. The expression of CEP55 in RCC tissues and cells was determined by real-time quantitative reverse transcription PCR (qRT-PCR), Western blot analysis and immunohistochemistry (IHC). Cells were transfected with siRNAs or lentivirus to regulate the expression of CEP55. The effects of CEP55 on proliferation, migration, invasion and epithelial-to-mesenchymal transition (EMT) of RCC cells were determined by MTS, migration and invasion assay and Western blot analysis. CEP55, one of the most upregulated genes in microarray analysis, was overexpressed in RCC tissues and cells. CEP55 expression was significantly correlated with poor outcome including neoplasm disease stage, histologic grade and TNM status, as well as survival status of patients. In vitro experiments showed that downregulation of CEP55 could dramatically inhibit RCC cell proliferation, migration and invasion, while overexpression of CEP55 could promote these biological behaviors. We further demonstrated that CEP55 knockdown suppressed epithelial–mesenchymal transition (EMT), which was mediated via upregulation of E-cadherin and downregulation of N-cadherin and ZEB1, through PI3K/AKT/mTOR pathway. In contrast, overexpression of CEP55 could promote EMT in RCC cells via the activation of PI3K/AKT/mTOR pathway. Importantly, inhibition of PI3K/AKT/mTOR pathway reduced the effects of CEP55 on the migration, invasion and EMT of RCC cells. Our study showed that CEP55 could promote EMT through PI3K/AKT/mTOR pathway and might be an effective prognostic marker in RCC.

Journal ArticleDOI
Lihua Tang1, Wenxi Yu1, Yungying Wang1, Hui Li1, Zhoujun Shen1 
TL;DR: Anlotinib might suppress proliferation of SS through a novel downstream GINS1-regulated network which plays a vital function in SS proliferation and also demonstrated that targeting the GINS 1-regulated signal pathway could be a potential strategy for management of SS.
Abstract: Synovial sarcoma (SS) is an aggressive soft-tissue sarcoma with a poor prognosis owing to its resistance to radiation and chemotherapy. Thus, novel therapeutic strategies for SS are urgently required. Anlotinib, a new oral tyrosine kinase inhibitor, is designed to primarily inhibit multi-targets in vasculogenesis and angiogenesis. This study was designed to characterize its antitumor efficacy and possible mechanism in patients with advanced refractory synovial sarcoma. Anlotinib’s antitumor effect was evaluated in vivo and vitro. Downstream targets of anlotinib in treating synovial sarcoma were analyzed through microarray assay. Cell proliferation and apoptosis analyses were performed to evaluate the impact of candidate downstream gene depletion in synovial sarcoma cells. Microarray assay were carried out to investigate potential signal network related with candidate downstream gene. Anlotinib significantly suppresses synovial sarcoma proliferation in PDTX model and cell lines. Additionally, GINS1 (also named as PSF1, Partner of SLD Five 1), rather than other conventional gene target, was demonstrated to be a vital target of anlotinib’s antitumor effect in synovial sarcoma through microarray assay. Expression of GINS1 was remarkably higher in synovial sarcoma tumor samples and related with poor outcome. Knockdown of GINS1 expression could remarkably inhibit proliferation and promote apoptosis in vitro. Meanwhile, through microarray assay, CITED2, EGR1, SGK1 and SPP1 were identified and further validated by qPCR/WB as downstream targets of GINS1. Anlotinib might suppress proliferation of SS through a novel downstream GINS1-regulated network which plays a vital function in SS proliferation and also demonstrated that targeting the GINS1-regulated signal pathway could be a potential strategy for management of SS.

Journal ArticleDOI
TL;DR: An encouraging efficacy of nintedanib/docetaxel in patients with adenocarcinoma NSCLC pretreated with platinum‐based doublet chemotherapy and immunotherapy is suggested, reinforcing the importance of an optimal therapeutic sequence for managing advanced lung adenOCarcinomas.
Abstract: Both nintedanib/docetaxel and anti‐PD‐1/PD‐L1 immunotherapies have demonstrated efficacy as second‐line treatment of patients with advanced lung adenocarcinoma. This is the first report on the efficacy of the nintedanib/docetaxel combination following first‐line platinum‐based chemotherapy and subsequent immunotherapy in a real-world setting. From May 2014 to December 2015, 390 patients in 108 Spanish centres enrolled in the nintedanib named patient use program. Inclusion criteria were advanced lung adenocarcinoma with progressive disease following at least one line of platinum‐based doublet chemotherapy. The objective was to evaluate the efficacy of the nintedanib/docetaxel combination in patients who also received immunotherapy. Eleven patients met the inclusion criteria; with a median age of 67 years. PD‐L1 expression was positive in six patients. Median progression‐free survival (PFS) of first‐line platinum‐based chemotherapy was 3.3 months (95% CI 1.9–4.6). Second‐line immunotherapy was pembrolizumab (36.5%), atezolizumab (36.5%) or nivolumab (27%). Median PFS of second‐line immunotherapy was 2.3 months (95% CI 0–6.1). The overall response rate (ORR) to second‐line immunotherapy was 18% with a disease‐control rate (DCR) of 45%. Median PFS of nintedanib/docetaxel was 3.2 months (95% CI 1.9–4.5). Best response was partial response in four patients (36%), stable disease in five patients (46%), and progressive disease in two patients (18%), for an ORR of 36% and a DCR of 82%. Our experience suggests an encouraging efficacy of nintedanib/docetaxel in patients with adenocarcinoma NSCLC pretreated with platinum‐based doublet chemotherapy and immunotherapy, reinforcing the importance of an optimal therapeutic sequence for managing advanced lung adenocarcinoma.

Journal ArticleDOI
TL;DR: DC-CIK combined with chemotherapy administration resulted in numerically superior PFS and OS compared with monotherapy in advanced NSCLC.
Abstract: Advanced non-small cell lung cancer (NSCLC) has remained challenging to treat effectively. This study aimed to investigate the clinical effects and safety of immunotherapy with dendritic cells and cytokine-induced killer cells (DC-CIK) administered with chemotherapy (CT) in this malignancy. We have developed a new clinical trial design termed as the prospective patient’s preference-based study (PPPS). Consecutive patients (n = 135) with advanced NSCLC were treated with DC-CIK administered with CT or mono-therapy (CT or DC-CIK alone). For all the patients, the median PFS was 5.7 months and the median OS was 17.5 months. The 1-year PFS and OS rates were 29.4% and 58.2%, respectively. The 1-year PFS and OS rates for DC-CIK plus CT were significantly higher than that in the group of patients who received DC-CIK alone and CT alone (P < 0.05). The number of adoptively infused DC-CIK cells was associated with clinical efficacy. After adjusting for competing risk factors, DC-CIK combined with CT and infused number of CIKs remained independent predictors of PFS and OS. Phenotypic analysis of peripheral blood mononuclear cells showed that CD8+CD28+, and CD8+CD28− T cells, changed significantly in all groups (P < 0.01). The CD3+ T cells increased in the chemotherapy plus immunotherapy and the immunotherapy alone group (P < 0.01), while CD3−CD16+CD56 T cells decreased in the chemotherapy plus immunotherapy and the immunotherapy alone group (P < 0.01). DC-CIK combined with chemotherapy administration resulted in numerically superior PFS and OS compared with monotherapy in advanced NSCLC.

Journal ArticleDOI
TL;DR: DEB-TACE treatment was equally efficient and tolerated in liver cancer patients with different times of previous conventional transarterial chemoembolization (cTACE) treatments.
Abstract: To assess the efficacy and safety of drug-eluting beads transarterial chemoembolization (DEB-TACE) in liver cancer patients with different times of previous conventional transarterial chemoembolization (cTACE) treatments. 367 liver cancer patients about to receive DEB-TACE treatment were enrolled in this prospective cohort study. All patients were divided into no previous cTACE group (NPC group), 1–2 times previous cTACE group (PC group) and triple or above previous cTACE group (TPC group) according to the times of previous cTACE treatments. There was no difference in complete response (CR) (P = 0.671) and objective response rate (ORR) (P = 0.062) among three groups. Additionally, no difference in overall survival (OS) among groups (P = 0.899) was found. As to liver function, most liver function indexes were deteriorative at 1 week after DEB-TACE operation, but returned to baseline at 1–3 months after DEB-TACE operation in all three groups, while percentage of abnormal total bile acid (TBA) patients was higher in TPC group than NPC and PC groups at 1–3 month post-DEB-TACE (P = 0.018). As for safety profiles, the incidence of pain during DEB-TACE operation was lower in TPC group compared to NPC and PC groups (P = 0.005), while no difference of other adverse events was found during and 1 month post-DEB-TACE treatment among three groups. DEB-TACE treatment was equally efficient and tolerated in liver cancer patients with different times of previous cTACE treatments.

Journal ArticleDOI
Lian Hui1, H. Wu1, T.-W. Wang, N. Yang1, X. Guo1, X.-J. Jang1 
TL;DR: Hydrogen peroxide upregulated the expression of FUNDC1 through the activation of ERK1/2 signal to trigger a mitophagic response, giving laryngeal cancer cells a befit for survival, suggesting that FUNDC 1 might be a potential target for the treatment of larynGEal cancer accompanied with high lipid peroxidation status.
Abstract: The purpose of our study was to investigate an underlying mechanism that hydrogen peroxide-induced mitophagy contributed to laryngeal cancer cells survivals under oxidative stress condition. Tumor tissue and serum samples were collected from patients with laryngeal cancer. The Hep2 cell, a human laryngeal carcinoma cell, was used in in vitro experiments. The levels of lipid peroxidation were analyzed by ELISA. Knockdown of FUNDC1 was performed by RNAi. The changes of target proteins were determined by qRT-PCR and western blot. The cells were analyzed for changes in proliferation using cell counting kit-8 and mitophagy by the mitochondrial membrane potential assay and transmission electron microscopy. FUNDC1 in laryngeal cancer tissues were relative to the levels of lipid peroxidation in laryngeal cancer patients, which suggested that FUNDC1 was associated with the status of oxidative stress in the laryngeal cancer patients. Hydrogen peroxide significantly induced the elevation of FUNDC1, a mitophagic factor, in a time- and dose-dependent manner in laryngeal cancer cells, which was dependent on ERK signal activation. Knockdown of FUNDC1 by the siRNA attenuated the survival of laryngeal cancer cells under hydrogen peroxide stimulation. Moreover, the elevated FUNDC1 was required for the occurrence of mitophagy under hydrogen peroxide stimulation, which was identified by transmission electron microscopy, the alterations of mitochondrial permeability transition and the specific mitochondrial protein, hsp60. Inhibition of mitophagy with cyclosporine A could also effectively attenuate the laryngeal cancer cells survival under hydrogen peroxide stimulation. Hydrogen peroxide upregulated the expression of FUNDC1 through the activation of ERK1/2 signal to trigger a mitophagic response, giving laryngeal cancer cells a befit for survival. These findings suggested that FUNDC1 might be a potential target for the treatment of laryngeal cancer accompanied with high lipid peroxidation status.

Journal ArticleDOI
TL;DR: Patients’ diagnoses were identified using the Surveillance, Epidemiology, and End Result database between 2006 and 2015 and it was demonstrated that the prognoses of Patients with left-sided cancers were better than those of patients with right- sided cancers regardless of stage.
Abstract: Emerging data have shown that patients with left-sided cancers have better survival than patients with right-sided cancers in terms of metastatic colorectal cancer. However, the available information and findings remain limited and contradictory in localized colorectal cancer. This study aimed to evaluate the clinical characteristics and prognosis of primary tumor location (PTL) in colorectal cancer. Patients’ diagnoses were identified using the Surveillance, Epidemiology, and End Result database between 2006 and 2015. The analyses were further stipulated to patients with primary cancer site, histology, and stage information. The correlations between PTL and overall survival (OS) were assessed. Compared with left-sided tumors, right-sided tumors were more likely to develop into T3 cancers (50.0% vs. 44.8%), T4 cancers (15.8% vs. 12.3%), mucinous or mucin-producing adenocarcinoma (10.8% vs. 5.0%), and signet ring cell carcinoma (1.4% vs. 0.7%), P < 0.01, respectively. Patients with right-sided tumors showed inferior OS (56.1% vs. 60.2%), and the hazard ratio was 1.224 (95% CI, 1.208–1.241, P < 0.001) in all stages. Stage-specific Cox regression analysis revealed that patients with right-sided tumors also showed inferior OS in every stage (respectively, P < 0.05) than left-sided tumors. This study demonstrated that the prognoses of patients with left-sided cancers were better than those of patients with right-sided cancers regardless of stage. PTL can be a prognosis factor in colorectal cancer. We encourage developing clinical and translational studies to elucidate the causative relationship between PTL and prognosis.

Journal ArticleDOI
Puyuan Xing1, Yuxin Mu1, Xuezhi Hao1, Yuanshu Wang1, Jian-Rui Li1 
TL;DR: Osimertinib indeed demonstrated clinically meaningful efficacy against CNS metastases in Chinese patients with advanced NSCLC and the safety profile was acceptable and no new unexpected findings were found.
Abstract: Central nervous system (CNS) metastases are very common in patients with non-small-cell lung cancer (NSCLC). We aimed to explore the clinical impact of osimertinib, a third-generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI), on CNS metastases in patients with advanced NSCLC in real-world setting. Patients with advanced NSCLC who received osimertinib after progression of early-generation EGFR-TKIs and CNS metastases on baseline brain scan were retrospectively collected. Primary outcomes were disease control rate (DCR) and progression-free survival (PFS), and secondary objectives were objective response rate (ORR), time to tumor response, median best percentage change from baseline in CNS target lesion (TL) size and safety. Between Apr 1, 2017, and Dec 30, 2017, 22 patients met selection criteria, 15 with ≥ 1 measurable CNS lesion (RECIST 1.1) were included in CNS evaluable for response (cEFR) set. Among the 22 patients, ORR and DCR were 40.9% and 86.4%, respectively, with median PFS of 8.5 months (95% CI 4.1, 13.0). Median intracranial PFS was not reached. Of 15 patients in cEFR set, CNS DCR was 80.0% with complete response reported in 3 patients (20.0%). Median best percentage change from baseline in CNS TL size was − 40% (range − 100 to + 60%) and median time to CNS tumor response was 1.3 months. CNS ORR was 53.3%. The safety profile was acceptable and no new unexpected findings were found. This real-world analysis further confirmed that osimertinib indeed demonstrated clinically meaningful efficacy against CNS metastases in Chinese patients with advanced NSCLC.

Journal ArticleDOI
TL;DR: Age of less than 65 years, female patients, married status and receiving surgery were all the beneficial factors for prognosis of GIST patients with liver metastasis, and multivariate analysis showed Liver metastasis might have no relationship with bone or lung metastasis and liver might play a more dominant role than the other two sites in the prognosis.
Abstract: This SEER-based study aimed to explore and analyze the relationship of metastasis of liver, lung and bone of GIST patients and their prognosis. The data of GIST patients were from Surveillance, Epidemiology, and End Results (SEER) database from 2010 to 2015 and all the statistical analyses were conducted by statistical software package SPSS (Version 22.0). A total of 4224 GIST patients were identified, of which 388 (9.19%) patients with liver metastasis, 20 (0.47%) patients with bone metastasis and 32 (0.76%) patients with lung metastasis. There was no significant difference of risk of bone or lung metastasis between patients with and without liver metastasis (P = 0.935). The median overall survival of patients with liver, bone, or lung metastasis was, respectively, 49 months, 18 months, and 20 months, which were all shorter than that of patients without metastasis. The overall survival of patients with both liver and bone metastasis and those with metastasis of all three sites was not significantly different from that of patients with only liver metastasis. The multivariate analysis showed age of less than 65 years, female patients, married status and receiving surgery were all the beneficial factors for prognosis of GIST patients with liver metastasis. Patients with metastasis had a poorer prognosis than those without. Liver metastasis might have no relationship with bone or lung metastasis and liver might play a more dominant role than the other two sites in the prognosis of GIST patients with metastasis. So, more attention should be paid to liver status in diagnosis and treatment of GIST patients.

Journal ArticleDOI
H. Tuerxun1, Jiuwei Cui1
TL;DR: This extensive review attempts to comprehensively understand the effects of morphine and summarize both its positive and negative influences on various aspects of tumors, including tumor growth, angiogenesis, metastasis, inflammation, and immunomodulation.
Abstract: Morphine is a classic opioid drug used for reducing pain and is commonly prescribed as an effective drug to control cancer pain. Morphine has a direct role in the central nervous system to relieve pain, but because of its peripheral functions, morphine also has some side effects, such as nausea, constipation, and addiction (Gupta et al. in Sci World J 2015:10, 2015). In addition to its analgesic effect, the role of morphine in tumor development is an important question that has been investigated for many years with conflicting results. Numerous studies suggest that morphine has a role in both promoting and inhibiting tumor growth. In this extensive review, we attempt to comprehensively understand the effects of morphine and summarize both its positive and negative influences on various aspects of tumors, including tumor growth, angiogenesis, metastasis, inflammation, and immunomodulation.

Journal ArticleDOI
TL;DR: The role of RANK/RANKL in tumourigenesis is reviewed, including effects on tumour initiation, progression and metastasis and the impact of Ranks/RanksL on tumours immunology and immune evasion is considered.
Abstract: Drug repurposing offers advantages over traditional drug development in terms of cost, speed and improved patient outcomes. The receptor activator of nuclear factor kappa B (RANK) ligand (RANKL) inhibitor denosumab is approved for the prevention of skeletal-related events in patients with advanced malignancies involving bone, including solid tumours and multiple myeloma. Following improved understanding of the role of RANK/RANKL in cancer biology, denosumab has already been repurposed as a treatment for giant cell tumour of bone. Here, we review the role of RANK/RANKL in tumourigenesis, including effects on tumour initiation, progression and metastasis and consider the impact of RANK/RANKL on tumour immunology and immune evasion. Finally, we look briefly at ongoing trials and future opportunities for therapeutic synergy when combining denosumab with anti-cancer agents such as immune checkpoint inhibitors.

Journal ArticleDOI
Guihai Zhang1, Qiuyue Zhong1, Xiaoxia Gou1, Erxi Fan1, Yu Shuai1, Mingna Wu1, Guojun Yue1 
TL;DR: A novel seven-gene signature in patients with glioma is identified, which could be used as a predictor for the prognosis of patients withglioma in the future.
Abstract: Glioma is a common malignant tumor of the central nervous system, which is characterized by a low cure rate, high morbidity, and high recurrence rate. Consequently, it is imperative to explore some indicators for prognostic prediction in glioma. We obtained glioma data from The Cancer Genome Atlas (TCGA). Differentially expressed genes (DEGs) were obtained by R software from TCGA data sets. Through Cox regression analysis, risk scores were obtained to assess the weighted gene-expression levels, which could predict the prognosis of patients with glioma. The validity and the prognostic value of this model in glioma were confirmed by the manifestation of receiver-operating characteristic (ROC) curves, area under the curve (AUC), and 5-year overall survival (OS). In total, 920 DEGs of transcriptome genes in glioma were extracted from the TCGA database. We identified a novel seven-gene signature associated with glioma. Among them, AL118505.1 and SMOC1 were positively related to the 5-year OS of patients with glioma, showing a better prognosis for glioma; however, RAB42, SHOX2, IGFBP2, HIST1H3G, and IGF2BP3 were negatively related to 5-year OS, displaying a worse prognosis. In addition, according to risk scores, AL118505.1 was also a protective factor, while others were risk factors. Furthermore, the expression levels of SHOX2, IGFBP2, and IGF2BP3 were significantly positively correlated with glioma grades. Receiver-operating characteristic (ROC) curve assessed the accuracy and sensitivity of the gene signature. Each of the seven genes for patients with the distribution of the risk score was presented in the heat map. We identified a novel seven-gene signature in patients with glioma, which could be used as a predictor for the prognosis of patients with glioma in the future.