CLPTM1L antibodies for pancreatic and lung cancer therapy

We and others have recently shown Cisplatin Resistance-Related Protein 9 (CRR9)/Cleft Lip and Palate Transmembrane 1-Like (CLPTM1L) to affect survival and proliferation in lung and pancreatic tumor cells. Our research has indicated that CLPTM1L affects multiple survival signaling pathways in tumor cells under oncogenic, genotoxic, and microenvironmental stress. We have confirmed the association of CLPTM1L with pancreatic cancer by demonstrating overexpression of CLPTM1L in pancreatic tumors and poor survival in patients with high tumor expression of CLPTM1L. Predicting a transmembrane structure, we determined that CLPTM1L could be targeted at the plasma membrane. Herein, we describe the development of monoclonal antibodies targeting CLPTM1L. Lead antibodies inhibited surface accumulation of CLPTM1L, Akt phosphorylation, anchorage-independent growth, and chemotherapeutic resistance in lung and pancreatic tumor cells. Gemcitabine promoted a physical interaction between CLPTM1L and p110α in pancreatic tumor cells, which was inhibited by anti-CLPTM1L. In-vivo treatment with anti-CLPTM1L robustly inhibited the growth of both lung and pancreatic adenocarcinoma xenografts. The efficacy of anti-CLPTM1L correlated with specific epitopes representing important targets in human cancers, particularly those driven by KRas, for which effective targeted therapies have been elusive. This study is the first to report cell-surface exposure of the tumor survival protein CLPTM1L and inhibition of the function of surface CLPTM1L with novel, systematically developed inhibitory monoclonal antibodies establishing proof of concept of clinically practical agents inhibiting this compelling new tumor survival target in cancer.

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Predictive biomarkers of venetoclax efficacy in myeloma

BCL-2 family proteins dictate survival of human multiple myeloma (MM) cells making them attractive drug targets. Indeed, MM cells are sensitive to antagonists that selectively target pro-survival proteins such as BCL-2/BCL-X_L (ABT-737 and ABT-263/navitoclax) or BCL-2 only (ABT-199/GDC-0199/venetoclax). Resistance to these three drugs is mediated by expression of MCL-1. However, given the selectivity profile of venetoclax it is unclear whether co-expression of BCL-X_L also affects anti-tumor responses to venetoclax in MM. In MM cell lines (n=21) BCL-2 is expressed but sensitivity to venetoclax correlated with high BCL-2 and low BCL-X_L or MCL-1 expression. MM cells that co-express BCL-2 and BCL-X_L were resistant to venetoclax but sensitive to a BCL-X_L selective inhibitor (A-1155463). MM xenograft models that co-expressed BCL-X_L or MCL-1 with BCL-2 were also resistant to venetoclax. Resistance to venetoclax was mitigated by co-treatment with bortezomib in xenografts that co-expressed BCL-2 and MCL-1 due to upregulation of NOXA, a pro-apoptotic factor that neutralizes MCL-1. In contrast, xenografts that expressed BCL-X_L, MCL-1 and BCL-2 were more sensitive to the combination of bortezomib with a BCL-X_Lselective inhibitor (A-1331852) but not with venetoclax co-treatment when compared to monotherapies. Immunohistochemistry of MM patient bone marrow biopsies and aspirates (n=95) revealed high levels of BCL-2 and BCL-X_L in 62% and 43% of evaluable samples, respectively, while 34% were characterized as BCL-2^High/BCL-X_L^Low. In addition to MCL-1, our data suggests that BCL-X_L may also be a potential resistance factor to venetoclax monotherapy and in combination with bortezomib.

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Protein kinase inhibitor H89 enhances immunotoxin activity

HA22 (Moxetumomab pasudotox) is a recombinant immunotoxin (RIT), composed of an anti-CD22 Fv fused to a truncated portion of Pseudomonas exotoxin A. HA22 is in clinical trials to treat patients with hairy cell leukemia and acute lymphoblastic leukemia (ALL). LMB-11 is an improved variant of HA22 with reduced immunogenicity, has a longer half-life in the blood and high activity in vitro and in a Burkitt lymphoma model in vivo. Searching for RIT enhancing combination therapies, we found the protein kinase A inhibitor H89 to enhance LMB-11 and HA22 activity 5- to 10-fold on ALL cell lines and on patient-derived ALL samples. In addition, H89 increased the activity of mesothelin-targeting RITs SS1P (38-fold) and RG7787 (7-fold) against the cervical cancer cell line KB31. Unexpectedly we found that the enhancement by H89 was not due to inhibition of protein kinase A; it was partially recapitulated by inhibition of S6K1, which led to inactivation of its down-stream targets rpS6 and GSK3β, resulting in a fall in MCL1 levels. H89 increased the rate of ADP-ribosylation of eukaryotic elongation factor 2, enhancing the arrest of protein synthesis and the reduction of MCL1 in synergy with the RIT. In summary, H89 increased RIT activity by enhancing the two key events: ADP-ribosylation of eEF2 and reduction of MCL1 levels. Significant enhancement was seen with both CD22- and mesothelin-targeting RITs, indicating that H89 might be a potent addition to RIT treatment of CD22-positive ALL and mesothelin-expressing solid tumors.

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Preclinical Characterization of Entrectinib

Activated ALK and ROS1 tyrosine kinases, resulting from chromosomal rearrangements, occur in a subset of non-small cell lung cancers (NSCLC) as well as other tumor types and their oncogenic relevance as actionable targets has been demonstrated by the efficacy of selective kinase inhibitors such as crizotinib, ceritinib and alectinib. More recently, low frequency rearrangements of TRK kinases have been described in NSCLC, colorectal carcinoma (CRC), glioblastoma and Spitzoid melanoma. Entrectinib, whose discovery and preclinical characterization are reported herein, is a novel, potent inhibitor of ALK, ROS1 and importantly, of TRK family kinases which shows promise for therapy of tumors bearing oncogenic forms of these proteins. Proliferation profiling against over 200 human tumor cell lines revealed that entrectinib is exquisitely potent in vitro against lines that are dependent on the drug's pharmacological targets. Oral administration of entrectinib to tumor-bearing mice induced regression in relevant human xenograft tumors, including the TRKA-dependent colorectal carcinoma KM12, ROS1-driven tumors and several ALK-dependent models of different tissue origins including a model of brain-localized lung cancer metastasis. Entrectinib is currently showing great promise in Phase I/II clinical trials, including the first documented objective responses to a TRK inhibitor in CRC and in NSCLC. The drug is thus potentially suited to the therapy of several molecularly defined cancer settings, especially that of TRK-dependent tumors, for which no approved drugs are currently available.

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BRD4 regulates EZH2 transcription in bladder cancer

People who develop bladder cancer frequently succumb to the intractable disease. Current treatment strategies are limited presumably due to the underlying molecular complexity and insufficient comprehension. Therefore, exploration of new therapeutic targets in bladder cancer remains necessary. Here, we identify that bromodomain-4 protein (BRD4), an important epigenome reader of bromodomain and extraterminal domain (BET) family member, is a key upstream regulator of enhancer of zeste homologue 2 (EZH2), and represents a novel therapeutic target in bladder cancer. We found that BRD4 was significantly overexpressed in bladder cancer cells and tissues. Inhibition of BRD4 decreased bladder cancer cell proliferation concomitantly with the accumulation of cell apoptosis in vitro and suppressed tumor growth in vivo. We further found that suppression of BRD4 decreased the mRNA and protein levels of EZH2, which was reversed by ectopic expression of C-MYC. In particular, individual silencing of BRD4 using shRNA or the BET inhibitor JQ1 strikingly diminished the recruitment of C-MYC to EZH2 promoter in bladder cancer. Briefly, our research reveals that BRD4 positively regulate EZH2 transcription through upregulation of C-MYC, and is a novel promising target for pharmacological treatment in transcriptional program intervention against this intractable disease.

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AR compromises cytotoxicity of NK cells against HCC

Gender disparity has long been considered as a key to fully understand hepatocellular carcinoma development. At the same time, immunotherapy related to interleukin-12 still need more investigation before applied in clinical settings. The aim of this study is to investigate the influence of androgen receptor (AR) on natural killer (NK) cells related innate immune surveillance in liver cancer, and provide a novel therapeutic approach to suppress hepatocellular carcinoma (HCC) via altering IL-12A. By using in vitro cell cytotoxicity test and in vivo liver orthotopic xenograft mice model, we identified the role of AR in modulating NK cells cytotoxicity. Luciferase report assay and chromatin immunoprecipitation assay were applied for mechanism dissection. Immunohistochemistry is performed for sample staining. Our results showed AR could suppress IL-12A expression at the transcriptional level via direct binding to the IL-12A promoter region that resulted in repressing efficacy of NK cell cytotoxicity against HCC, and sorafenib treatment could enhance IL-12A signals via suppressing AR signals. These results not only help to explain the AR roles in the gender disparity of HCC but also provide a potential new therapy to better suppress HCC via combining sorafenib with NK cells related immunotherapy.

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Elevated eIF4E is therapeutic target in Myeloma

eIF4E is the key regulator of protein translation and critical for translation. The oncogenic potential of tumorigenesis which is highly contingent on cap-dependent eIF4E also arises from the critical role in the nuclear export and cytosolic translation of oncogenic transcripts. Inhibition of Exportin1 (XPO1) which is the major nuclear export protein for eIF4E-bound oncoprotein-mRNAs results in decreased tumor cell growth in vitro and vivo suggesting that eIF4E is critical in multiple myeloma (MM). Indeed we found that eIF4E is overexpressed in myeloma cell lines and primary myeloma cells compared to normal plasma cells. While stable overexpression of eIF4E in MM cells significantly increases tumorigenesis, knockdown of eIF4E impairs MM tumor progression in human xenograft mice model. Using a tet-on inducible eIF4E-knockdown system, eIF4E-downregulation, blocks MM tumor growth in vivo correlating with decreased eIF4E expression. Further overexpression and knockdown of eIF4E revealed that eIF4E regulates translation of mRNAs with highly complex 5'-untranslated regions such as c-MYC and C/EBPβ and subsequently proliferation in MM cells, but not in non-malignant bone marrow stromal cells. Since many transcription factors that are critical for MM proliferation exhibit a higher dependency on protein translation, eIF4E is an ideal and selective tool to target MM cell growth.

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GRP78 Increases PDAC Chemoresistance

The prognosis for patients with pancreatic ductal adenocarcinoma (PDAC) is dismal. While gemcitabine (GEM) is the standard chemotherapeutic agent for adjuvant therapy of resectable PDAC, recurrent disease is observed in an alarming number of GEM-treated patients. Regardless of the adjuvant therapy, the vast majority of patients treated with chemotherapy after surgical resection show tumor recurrence. A better understanding of the molecular mechanisms that contribute to chemoresistance woul¬¬¬d aid the development of more effective treatment strategies. GRP78 is an endoplasmic reticulum (ER) chaperone protein that primarily resides in the lumen of the ER and is the master regulator of the unfolded protein response (UPR). Here, we report that expression of GRP78 is significantly higher in GEM-resistant PDAC compared to GEM-sensitive PDAC patient samples. We show that GRP78 induces chemoresistance in PDAC cells. Our results also show that knockdown of GRP78 reduces chemoresistance in PDAC. Finally, we found that IT-139, a ruthenium-based anticancer drug, can overcome GRP78 mediated chemoresistance. In vitro, IT-139 restores sensitivity to cytotoxic drugs in drug resistant PDAC cells and induces twice as much cell death in combination treatment compared with GEM alone. In vivo, a single weekly IT-139 treatment in combination with GEM caused a 35% increase in median survival and a 25% increase in overall survival compared to GEM alone. Collectively, our data show that GRP78 expression promotes chemoresistance in PDAC and therapeutic strategies blocking the activity of GRP78 increase the efficacy of currently available therapies.

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Effects of r-AtHSP70 on breast cancer cells

The chaperone HSP70 protein is widely present in many different tumors and its expression correlates with an increased cell survival, low differentiation and poor therapeutic outcome in human breast cancer. The intracellular protein has prevalently a cytoprotective function, while the extracellular HSP70 mediates immunological responses. Evolutionarily, HSPs are well conserved from prokaryotes to eukaryotes, and human HSP70 shows a strong similarity to that of plant origin. In the present paper, we have tested the potential effect of recombinant HSP70, from Arabidopsis thaliana, on cell survival and metastatic properties of breast cancer cells. Our data show that HSP70 sustains cell viability in MCF-7 and MDA-MB-231 breast tumoral cells and increases Cyclin D1 and Survivin expression. The extracellular HSP70 triggers cell migration and the activation of MMPs particularly in MDA-MB-231 cells. Furthermore, under UV-induced stress condition, the low levels of phospho-AKT were increased by exogenous HSP70, together with the up-regulation of Cyclin D1 particularly in the tumoral cell phenotype. On the other hand, UV increased TP53 expression and the co-incubation of HSP70 lowers the TP53 levels similar to the control. These findings correlate with the cytoprotective and anti-apoptotic role of HSPs, as reported in different cellular contexts. This is the first study on mammary cells that highlights how the heterologous HSP70 from Arabidopsis thaliana sustains cell survival prevalently in breast cancer cell types, thus maintaining their metastatic potential. Therefore, targeting HSP70 would be of clinical importance since HSP70 blocking selectively targets tumor cells, in which it supports cell growth and survival.

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Polymer therapeutics overcome chemotherapy resistance

The success of chemotherapy is limited by poor selectivity of active drugs combined with occurrence of tumor resistance. New star-like structured N-(2-hydroxypropyl) methacrylamide (HPMA) copolymer-based drug delivery systems containing Doxorubicin (Dox) attached via a pH-sensitive hydrazone bond were designed and investigated for their ability to overcome chemotherapy resistance. These conjugates combine two strategies to achieve a high drug concentration selectively at the tumor site: (I) high accumulation by passive tumor targeting based on enhanced permeability and retention (EPR) - effect and (II) pH-sensitive site-specific drug release due to an acidic tumor microenvironment. Mice bearing Dox resistant xenograft tumors were treated with Dox, PBS, pHPMA precursor or pHPMA-Dox conjugate at different equivalent doses of 5mg/kg bodyweight Dox up to a 7-fold total dose using different treatment schedules. Intratumoral drug accumulation was analyzed by fluorescence imaging utilizing intrinsic fluorescence of Dox. Free Dox induced significant toxicity but hardly any tumor inhibiting effects. Administering of at least 3-fold dose of pHPMA-Dox conjugate was necessary to induce a transient response whereas doses of about 5- to 6-fold induced strong regressions. Tumors completely disappeared in some cases. The onset of response was differential delayed depending on the tumor model which could be ascribed to distinct characteristics of the microenvironment. Further fluorescence imaging based analyses regarding underlying mechanisms of the delayed response revealed a related switch to a more supporting intratumoral microenvironment for effective drug release. In conclusion, the present study demonstrates that the concept of tumor site-restricted high-dose chemotherapy is able to overcome therapy resistance.

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Occurrence and significance of tumor-associated neutrophils in patients with colorectal cancer

Abstract

Inflammatory cells are an essential component of the tumor microenvironment. Neutrophils have emerged as important players in the orchestration and effector phase of innate and adaptive immunity. The significance of tumor-associated neutrophils (TAN) in colorectal cancer (CRC) has been the subject of conflicting reports and the present study was designed to set up a reliable methodology to assess TAN infiltration in CRC and to evaluate their clinical significance. CD66b and myeloperoxidase (MPO) were assessed as candidate neutrophil markers in CRC using immunohistochemistry. CD66b was found to be a reliable marker to identify TAN in CRC tissues, whereas MPO also identified a subset of CD68⁺ macrophages. CRC patients (n=271) (stage I to stage IV) were investigated retrospectively by computer-assisted imaging on whole tumor sections. TAN density dramatically decreases in stage IV patients compared to stage I-III. At Cox analysis, higher TAN density was associated with better prognosis. Importantly, multivariate analysis showed that prognostic significance of TAN can be influenced by clinical stage and 5-fluorouracil(5-FU)-based chemotherapy. On separate analysis of stage III patients (n=178), TAN density had a dual clinical significance depending on the use of 5-FU-based chemotherapy. Unexpectedly, higher TAN density was associated with better response to 5-FU-based chemotherapy. Thus, TAN are an important component of the immune cell infiltrate in CRC and assessment of TAN infiltration may help identify patients likely to benefit from 5-FU-based chemotherapy. These results call for a reassessment of the role of neutrophils in cancer using rigorous quantitative methodology. This article is protected by copyright. All rights reserved.

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Sex hormones and the risk of keratinocyte cancers among women in the United States: A population-based case-control study

Abstract

Men are at a higher risk of developing both squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) than women, but there is emerging evidence that women may be experiencing greater increases in the incidence rates of these malignancies than men. One possible explanation is the expanding use of sex steroids among women, although only a few studies have examined this hypothesis. As part of a population-based, case-control study of women in New Hampshire, USA, we sought to evaluate the risk of SCC, BCC, and early-onset BCC in relation to exogenous and endogenous sex hormones. We found that oral contraceptive (OC) use was associated with an increased risk of SCC (OR = 1.4, 95% CI = 1.1-1.8) and BCC (OR = 1.4, 95% CI = 1.0-1.8), particularly high estrogen dose (>50mg) OC use. Hormone replacement therapy (HRT) use also related to SCC, with an elevated OR largely for progestin use (OR = 1.4, 95% CI = 1.1-1.8). Additionally, both OC use and combination HRT use were associated with more aggressive BCC subtypes. In contrast, menstrual and reproductive history did not appear to influence keratinocyte cancer risk in our data. Our findings provide evidence that use of sex steroids may enhance risk of KC. This article is protected by copyright. All rights reserved.

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Mitochondrial DNA sensing by STING signaling participates in inflammation, cancer and beyond

ABSTRACT

Recent studies have revealed the diverse pathophysiological functions of mitochondria beyond traditional energetic metabolism in cells. Mitochondria-released DAMPs (damage-associated molecular patterns), particularly mitochondrial deoxyribonucleic acid (mtDNA), play a central role in host immune defenses against foreign pathogens. Newly discovered cGAS-STING signaling is responsible for microbial DNA recognition, and potentially participates in mitochondrial DNA sensing. Inappropriate inflammatory signaling mediated by mtDNA is implicated in various human diseases, especially infectious/inflammatory disease and cancer. In addition, mtDNA horizontal transfer between tumor cells and surrounding somatic cells has been recently observed and been associated with tumorigenesis and cancer progression. In this review, we will summarize the molecular signaling of mtDNA recognition (especially STING signaling), and discuss the underlying mechanism by which mtDNA transfer triggers cancer progression in human. Besides, we will highlight the central role of mtDNA in host immunity, with particular emphasis on mtDNA-induced NETs (neutrophil extracellular traps) formation, apoptosis and autophagy. This article is protected by copyright. All rights reserved.

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Nuclear expression of Y-box binding protein-1 is associated with poor prognosis in patients with pancreatic cancer and its knockdown inhibits tumor growth and metastasis in mice tumor models

Abstract

The objective of this study was to examine the implication of Y-box-binding protein-1 (YB-1) for the aggressive phenotypes, prognosis and therapeutic target in pancreatic ductal adenocarcinoma (PDAC). YB-1 expression in PDAC, pancreatic intraepithelial neoplasia (PanIN) and normal pancreas specimens was evaluated by immunohistochemistry, and its correlation with clinicopathological features was assessed in PDAC patients. The effects of YB-1 on proliferation, invasion and expressions of cell cycle-related proteins and matrix metalloproteinases (MMPs) were analyzed by WST-8, cell cycle and Matrigel invasion assays, western blotting and quantitative RT-PCR in PDAC cells transfected with YB-1-siRNAs. To verify the significance of YB-1 for tumor progression in vivo, the growth and metastasis were monitored after intrasplenic implantation of ex vivo YB-1 siRNA-transfected PDAC cells, and YB-1-targeting antisense oligonucleotides were intravenously administered in nude mice harboring subcutaneous tumor. The intensity of YB-1 expression and positivity of nuclear YB-1 expression were higher in PDAC than PanIN and normal pancreatic tissues. Nuclear YB-1 expression was significantly associated with dedifferentiation, lymphatic/venous invasion and unfavorable prognosis. YB-1 knockdown inhibited cell proliferation via cell cycle arrest by S-phase kinase-associated protein 2 downregulation and consequent p27 accumulation, and decreased the invasion due to downregulated membranous-type 2 MMP expression in PDAC cells. Tumor growth and liver metastasis formation were significantly suppressed in nude mice after implantation of YB-1-silenced PDAC cells, and the YB-1 targeting antisense oligonucleotide significantly inhibited the growth of subcutaneous tumors. In conclusion, YB-1 may be involved in aggressive natures of PDAC and a promising therapeutic target. This article is protected by copyright. All rights reserved.

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Quantification of the increase in thyroid cancer prevalence in Fukushima after the nuclear disaster in 2011--a potential overdiagnosis?

A thyroid ultrasound examination programme has been conducted in Fukushima Prefecture, Japan, after the nuclear disaster in 2011. Although remarkably high prevalence of thyroid cancer was observed, no relevant quantitative evaluation was conducted. We calculated the observed/expected (O/E) ratio of thyroid cancer prevalence for the residents aged ≤20 years. Observed prevalence was the number of thyroid cancer cases detected by the programme through the end of April 2015. Expected prevalence was calculated as cumulative incidence by a life-table method using the national estimates of thyroid cancer incidence rate in 2001–10 (prior to the disaster) and the population of Fukushima Prefecture. The underlying assumption was that there was neither nuclear accident nor screening intervention. The observed and estimated prevalence of thyroid cancer among residents aged ≤20 years was 160.1 and 5.2, respectively, giving an O/E ratio of 30.8 [95% confidence interval (CI): 26.2, 35.9]. When the recent increasing trend in thyroid cancer was considered, the overall O/E ratio was 22.2 (95% CI: 18.9, 25.9). The cumulative number of thyroid cancer deaths in Fukushima Prefecture, estimated with the same method (annual average in 2009–13), was 0.6 under age 40. Combined with the existing knowledge about radiation effect on thyroid cancer, our descriptive analysis suggests the possibility of overdiagnosis. Evaluation including individual-level analysis is required to further clarify the contribution of underlying factors.

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The validity and reliability of the Korean version of the Cancer-chemotherapy Concerns Rating Scale

Objective

The Cancer-chemotherapy Concerns Rating Scale was developed in Japan for outpatients undergoing chemotherapy, and its validity and reliability have been reported. The purpose of the study was to test the reliability and validity of the Korean version of the Cancer-chemotherapy Concerns Rating Scale.

Methods

The questionnaire was filled out by 199 cancer patients, who were currently undergoing outpatient chemotherapy. The data were analyzed using exploratory factor analysis with Promax Rotation to determine the factor construct validity. The reliability of the Cancer-chemotherapy Concerns Rating Scale was investigated by Cronbach's alpha and the Spearman Brown coefficient.

Results

Four factors were obtained and the overall structure was similar to that of the Japanese version; reorganization of daily life, self-existence, disease progress, and social and economic concerns. Cronbach's alpha for the total scale was 0.91 and the Spearman Brown coefficient was 0.85.

Conclusions

We found that the Korean version of the Cancer-chemotherapy Concerns Rating Scale could be clinically useful. It could provide health-care providers with information useful to understand the psychological state of patients undergoing outpatient chemotherapy.

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Current status of immunotherapy

The successful use of immune checkpoint inhibitors has been big breakthrough in the development of cancer immunotherapy. Anti-CTLA-4 monoclonal antibody, ipilimumab, is the first-approved immune checkpoint inhibitor and has shown durable objective responses for advanced melanoma beyond the effect of dacarbazine. Anti-PD-1 monoclonal antibodies, nivolumab and pembrolizumab, are other immune checkpoint inhibitors that have demonstrated more effective results than conventional drugs in clinical trials for a variety of advanced solid tumors including melanoma, non-small cell lung carcinoma and renal carcinoma. These studies have indicated that the enhancement of anti-cancer immunity by controlling the immune suppressive environment in cancer tissues is an important issue for the development of cancer immune-therapy. Accordingly, in recent years, the enthusiasm for research of cancer immunology has shifted to studies regarding the formation of the immune suppressive environment, immune suppression mechanisms in cancer tissues and the molecules and cells involved in these pathways. Novel findings from these studies might lead to the development of cancer immunotherapy based on control of the immune suppressive environment.

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IN THIS ISSUE

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Trousseau's syndrome: cancer-associated thrombosis

Trousseau's syndrome (cancer-associated thrombosis) is the second leading cause of death in cancer patients, after death from cancer itself. The risk of a venous thromboembolism is 4- to 7-fold higher in patients with cancer than in those without cancer. The causes of this impaired coagulation are associated with general patient-related risk factors, and other factors that are specific to the particular cancer or treatment. It is important to assess the risk of thrombotic events in cancer patients and administer effective prophylaxis and treatment. Effective prophylaxis and treatment of venous thromboembolism reduces morbidity and mortality, and improves patients' quality of life. Low molecular weight heparin is the first-line treatment for venous thromboembolism, as an effective and safe means for prophylaxis and treatment, according to guidelines released by international scientific societies. Oral anticoagulation therapy with warfarin is preferable to no therapy. However, warfarin has low efficacy and is associated with high rates of recurrence. If low molecular weight heparin is unavailable, some guidelines recommend the use of vitamin K antagonists that have a target international normalized ratio in the range of 2–3, as acceptable alternatives. Novel oral anticoagulants that directly inhibit factor Xa or thrombin are promising for the prophylaxis of high-risk cancer patients and in the long-term treatment of venous thromboembolism. However, to date, there is insufficient evidence to support the use of these new anticoagulants.

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Nivolumab-induced organizing pneumonia in a melanoma patient

We report the case of a 70-year-old woman with vaginal melanoma and multiple metastases in the lung. After the third dose of nivolumab, decreased room-air resting arterial oxygen saturation with bilateral basal fine crackles on auscultation developed despite the absence of respiratory symptoms. Computed tomography showed ground-glass opacities with airspace consolidations scattered with a peculiar distribution, and most were observed around the existing metastatic tumors in the lung. From the 42nd day to the 56th day after the last administration of nivolumab, she received dexamethasone 1–2 mg/body for the prevention of adverse events after stereotactic radiation for brain metastasis. At 3 months after the last administration of nivolumab, a computed tomography scan revealed improvement of the pneumonia and a decreased size and number of metastatic lesions in the lung, although some lesions showed enlargement. Further examination is needed to clarify the relationship between the pattern of pneumonia after Nivo therapy and clinical effects.

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Forkhead box protein k1 recruits TET1 to act as a tumor suppressor and is associated with MRI detection

Objective

Today, more and more evidence suggests that Foxk proteins (Foxk1 and Foxk2) work as transcriptional repressors in different kinds of cancer, but whether Foxk1 has a role in mediating tumorigenesis in breast cancer, the evidence is rare.

Methods

MCF-7 cells transfected with shFoxk1 displayed a mesenchymal morphology and reduced the expression of E-cadherin, and increased the expression of N-cadherin. Transwell invasion assay and living imaging assay show that the overexpression of Foxk1 could inhibit metastasis in vitro and in vivo. Ribonucleic acid sequencing revealed that the knockdown of Foxk1 resulted in the up-regulation of different oncogenes, which was implicated in metastasis and tumor angiopoiesis. Quantitative chromatin immunoprecipitation, chromatin immunoprecipitation and Luciferase reporter assays suggested that Foxk1 could bind to the promoter of epithelial–mesenchymal transition inducer Twist and vascular endothelial growth factor, VEGF. Mass Spectrometry, co-immunoprecipitation assays and glutathione-S-transferase pull-down assay detected that Foxk1 was physically associated with Ten-eleven translocation 1, TET1, in vivo and in vitro.

Results

We reported that the mean expression level of Foxk1 in breast cancer was significantly lower than the adjacent noncarcinoma tissue. The higher Foxk1 expression was associated with better prognosis. Endothelial tube formation assays indicated that Foxk1 might regulate breast cancer angiogenesis through transcriptional repression of vascular endothelial growth factor. Furthermore, in vivo magnetic resonance imaging revealed the overexpression of Foxk1 could enhance the detection of the tumors. Further, a strong negative correlation was observed between Foxk1 and Twsit or between Foxk1 and vascular endothelial growth factor, and the higher Foxk1 expression is correlated with better over all survivals and better relapse-free survivals.

Conclusions

Together, our data indicated the function of Foxk1 as a tumor suppressor in facilitating angiogenesis and metastasis in breast cancer.

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A case of aneurysmal lymphoma of the small intestine

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ATAD2 overexpression is associated with progression and prognosis in colorectal cancer

Objectives

ATPase family AAA domain-containing 2 plays an important role in tumor progression including cell cycle, proliferation, apoptosis and chemoresistance. However, the expression of ATPase family AAA domain-containing 2 in colorectal cancer and its significance are still unclear. The aim of this study was to examine the expression of ATPase family AAA domain-containing 2 in colorectal cancer.

Methods

Immunohistochemistry was used to determine the expression of ATPase family AAA domain-containing 2 in 155 colorectal cancer and 30 matched adjacent noncancerous tissues. The correlation of ATPase family AAA domain-containing 2 expression with clinicopathological variables was assessed using chi-square test. Patient survival was analyzed using the Kaplan–Meier and log-rank tests. Cox regression was performed for the multivariate analysis of prognostic factors.

Results

High expression of ATPase family AAA domain-containing 2 was detected in 58.1% of the colorectal cancers and was significantly associated with advanced tumor-node-metastasis stage (P = 0.044), poor differentiation (P = 0.028), deep infiltration (P < 0.001), lymphovascular invasion (P = 0.006), lymph node metastasis (P = 0.024) and recurrence (P = 0.022). Patients with high ATPase family AAA domain-containing 2 expression had significantly poorer overall survival and disease-free survival (both P < 0.001) when compared with patients with low expression of ATPase family AAA domain-containing 2. The multivariate analysis showed that ATPase family AAA domain-containing 2 was an independent factor for both overall survival (P = 0.003; hazard ratio (HR): 2.356; 95% confidence interval (CI): 1.335–4.158) and disease-free survival (P = 0.001; HR: 2.643; 95% CI: 1.489–4.693).

Conclusions

These results showed that ATPase family AAA domain-containing 2 overexpression was associated with progression and prognosis of colorectal cancer.

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Study on the psychosocial aspects of risk-reducing salpingo-oophorectomy (RRSO) in BRCA1/2 mutation carriers in Japan: a preliminary report

Objective

This study investigated the psychosocial aspects of risk-reducing salpingo-oophorectomy in Japan.

Methods

The subjects were 16 patients who underwent risk-reducing salpingo-oophorectomy at the Cancer Institute Hospital. Worry about cancer, emotional state and cancer-specific distress level were evaluated using a four-point Likert scale, the Profile of Mood States-Short Form and the Impact of Event Scale-Revised, respectively, before and 1 year after the surgery. In addition, the subjects were interviewed regarding their expectation for the risk-reducing surgery, the effects of the surgery, and the recovery from surgery, before the surgery and at 1, 6 and 12 months after the surgery. A t-test or Wilcoxon rank-sum test was used for the analysis, and literal analects were prepared for the interview and the answers were organized per question item using NVIVO10.

Results

The results revealed that the total score for worry about breast cancer and ovarian cancer (P = 0.021) as well as the Impact of Event Scale-Revised (P = 0.021) were significantly lower 1 year after surgery, compared with the values before the surgery. Regarding the preoperative expectations for the surgery, the expectation for reducing the cancer risk was the highest. The reported effects of risk-reducing salpingo-oophorectomy on life included the appearance of menopausal symptoms, a loss of motivation and poor concentration; more effects were reported at 1 year after surgery than at 6 months after surgery.

Conclusions

These results suggest that risk-reducing salpingo-oophorectomy can be effective for reducing worry about breast cancer and ovarian cancer and cancer-specific distress as well as contributing to a reduction in mortality from fallopian tube and ovarian related cancer.

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A short interval between bevacizumab and anti-epithelial growth factor receptor therapy interferes with efficacy of subsequent anti-EGFR therapy for refractory colorectal cancer

Background

Both bevacizumab and anti-epithelial growth factor receptor (EGFR) agents (e.g. cetuximab and panitumumab) are sequentially used for metastatic colorectal cancer (mCRC). Their co-administration as a first-line treatment does not improve outcome, indicating that there are negative interactions between these agents. A long-term pharmacokinetics study demonstrated serum persistence of bevacizumab following termination of bevacizumab 6 months after the last administration. This prompted us to investigate the impact of short intervals between bevacizumab and anti-EGFR antibody on the efficacy of subsequent anti-EGFR therapy.

Methods

We retrospectively reviewed consecutive patients with KRAS exon 2 wild-type mCRC who underwent anti-EGFR therapy after the failure of fluoropyrimidines, oxaliplatin and irinotecan. We divided patients into two groups (Group A: the interval between bevacizumab and anti-EGFR agent< 6 months; Group B: the interval >6 months).

Results

Of the 114 included patients (median age, 63 years), 78 (68%) were male. Most patients (88%) were treated with cetuximab plus irinotecan. Groups A and B consisted of 74 and 40 patients, respectively. There were no significant differences in patient characteristics. Group B patients had significantly longer progression-free survival (4.2 vs. 6.6 months; HR, 0.65; 95% CI, 0.43–0.98; P = 0.038) and longer overall survival (11.6 vs. 14.3 months; HR, 0.63; 95% CI, 0.41–0.98, P = 0.039). The response rate was 24.3% in Group A and 47.5% in Group B (P = 0.012).

Conclusion

A short interval between bevacizumab and anti-EGFR antibody treatment may interfere with the efficacy of subsequent anti-EGFR therapy.

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Prognostic implications of diffusion-weighted magnetic resonance imaging in patients with superior sulcus tumors receiving induction chemoradiation therapy

Objective

The aim of this study was to evaluate a diffusion-weighted magnetic resonance imaging to represent therapeutic response of induction chemoradiation and outcome in patients with non-small cell lung cancer of the superior sulcus.

Methods

Seventeen patients with non-small cell lung cancer of the superior sulcus (median age, 57 years; range, 44–70 years) received induction chemoradiation, followed by surgery. Diffusion-weighted magnetic resonance imaging of the lesion using b values of 0 and 800 s/mm² was acquired before treatment and after induction chemoradiation. Changes in tumoral apparent diffusion coefficient were compared with clinical and histopathological response. Cumulative disease-free survival and proportion of surviving were estimated by the Kaplan–Meier method. Survival of diffusion responders and non-responders were compared by log-rank test.

Results

A significant correlation was observed between changes of diffusion response after induction chemoradiation and overall survival. Using a defined threshold of percent increase in mean apparent diffusion coefficient, nine out of 17 patients (53%) were classified as diffusion responders and had a mean increase in mean apparent diffusion coefficient of 40.7 ± 11.2%, while eight diffusion non-responding patients (47%) had a mean increase of 11.0 ± 15.5% (P < 0.0001). Significant difference was found in overall survival between diffusion responders and diffusion non-responders (88.9 months versus 20.3 months, P = 0.002).

Conclusions

Diffusion-weighted magnetic resonance imaging represented therapeutic effect and prognosis after induction chemoradiation in patients with non-small cell lung cancer of the superior sulcus.

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Bevacizumab safety in Japanese patients with colorectal cancer

Background

Bevacizumab (Avastin^®) was approved in Japan in April 2007 for patients with advanced or metastatic colorectal cancer. To address the limited clinical experience in Japanese patients, a post-approval surveillance study was undertaken in bevacizumab-treated patients in Japan.

Methods

Bevacizumab (5 or 10 mg/kg every 2 weeks) was administered with chemotherapy; patients were observed for 26 weeks from initiation of treatment. The primary objective was to investigate the incidence of adverse drug reactions, particularly those of interest for bevacizumab. Univariate and multivariate analyses were performed to identify potential risk factors for adverse drug reactions.

Results

In total, 2712 patients were registered and 2696 patients were included in the safety analysis. Hypertension (13.1%), hemorrhage (10.5%) and proteinuria (4.5%) were the most common adverse drug reaction. The incidences of serious adverse drug reactions were low: gastrointestinal perforation occurred in 0.9% of patients, hemorrhage in 1.3%, arterial thromboembolic events in 0.3%, venous thromboembolic events in 1.3% and wound-healing complications in 0.4%. The incidence of bevacizumab-specific adverse drug reactions was not influenced by the bevacizumab dose. Multivariate analyses identified risk factors for the following adverse drug reactions: hypertension (prior/concurrent hypertension); tumor-associated bleeding (performance status, prior/concomitant anticoagulant or nonsteroidal anti-inflammatory drug use); proteinuria (sex, performance status, prior/concurrent diabetes and proteinuria); gastrointestinal perforation (primary tumor in situ, concurrent nonsteroidal anti-inflammatory drug use); venous thromboembolic event (treatment stage, port insertion).

Conclusions

The safety profile of bevacizumab-containing regimens in this Japanese population was comparable with studies performed in Western countries. Bevacizumab is generally well tolerated in Japanese patients with advanced or metastatic colorectal cancer.

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Cigarette smoking and bladder cancer risk: an evaluation based on a systematic review of epidemiologic evidence in the Japanese population

Objective

Although several epidemiological studies have demonstrated that cigarette smoking is an important risk factor for bladder cancer, no systematic review in the Japanese population has yet been performed. Accurate evaluation of bladder cancer risk in relation to smoking for Japanese populations can provide necessary information for Japanese policy-makers and doctors to enlighten the importance of smoking cessation. We reviewed epidemiologic data to estimate the strength of the association between cigarette smoking and bladder cancer in the Japanese population.

Methods

We identified previous cohort and case-control studies, extracting data from databases in the MEDLINE (PubMed) and Ichushi. The magnitude of association and strength of evidence were evaluated in each study, and a meta-analysis was conducted to obtain summary estimates for the overall magnitude of association.

Results

Three cohort and eight case–control studies were identified. Except for one case–control study, all studies showed a strong positive association between cigarette smoking and bladder cancer. The summary relative risk for ever smokers relative to never smokers was 2.14 (95% confidence interval 1.87–2.44) in a fixed-effect model.

Conclusions

We conclude that cigarette smoking is a convincing risk factor for bladder cancer among Japanese.

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Long-term survival of nasopharyngeal carcinoma patients with Stage II in intensity-modulated radiation therapy era

Objectives

To evaluate the long-term survival and the role of chemotherapy in nasopharyngeal carcinoma (NPC) patients in Stage II treated by intensity-modulated radiation therapy (IMRT).

Methods

Three hundred and eleven NPC patients in Stage II were reviewed. All were treated with IMRT with or without chemotherapy, with 191, 20 and 100 patients being defined as T1N1M0, T2N0M0 and T2N1M0 stage, respectively.

Results

At a median follow-up of 57 months, the 5-year overall survival, disease-specific survival, distant metastasis-free survival, loco-regional relapse-free survival (LRRFS) and progression-free survival were 91.1, 93.5, 90.6, 95.9 and 87.6%, respectively. T2N1 patients had significant poorer survival outcomes than T1N1 patients, with T2N0 patients in between. Further analysis showed that the addition of chemotherapy could only improve LRRFS [hazard ratio (HR) 0.263, 95% confidence interval (CI) 0.083–0.839, P = 0.024], especially for T1N1 patients (HR 0.209, 95% CI 0.046–0.954, P = 0.043). For those in the T2N1M0 group, chemotherapy, as used in our series, added no benefit to any endpoint.

Conclusions

IMRT in NPC patients in Stage II was quite therapeutic; however, different subgroups have distinct survival outcomes. Distant metastasis was the main failure pattern, especially for those with T2N1 disease, and the chemotherapy currently in use failed to treat subclinical metastatic foci effectively. Further prospective study is warranted to find out the role and the optimal schedule of chemotherapy in this subgroup of patients.

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Brachytherapy in Gynecologic Cancers: Why Is It Underused?

Abstract

Despite its established efficacy, brachytherapy is underused in the management of cervical and vaginal cancers in some parts of the world. Possible reasons for the underutilization of brachytherapy include the adoption of less invasive techniques, such as intensity-modulated radiotherapy; reimbursement policies favoring these techniques over brachytherapy; poor physician or patient access to brachytherapy; inadequate maintenance of brachytherapy skills among practicing radiation oncologists; transitioning to high-dose-rate (HDR) brachytherapy with increased time requirements; and insufficient training of radiation oncology residents.

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Adaptation of vacuum-assisted mouthpiece head immobilization system for precision infant brain radiation therapy

Publication date: Available online 3 March 2016
Source:Practical Radiation Oncology
Author(s): Kenneth Wong, Justine Cheng, Kristine Bowlin, Arthur Olch
PurposeTo describe an adaptation of a commercially available mouthpiece for vacuum-assisted mouthpiece immobilization for radiation therapy in infants.Methods and materialsAn infant diagnosed with a brain tumor required radiation therapy. After reviewing dental literature about obturators, we designed a modification for the smallest commercially available mouthpiece tray.ResultsThe patient was simulated with the adapted mouthpiece tray. We achieved excellent immobilization and had small daily image-guided treatment position shifts. Our patient tolerated treatment well without injury to oral cavity or mucosa.ConclusionsHead immobilization with a vacuum-assisted modified mouthpiece has not been described in infants. Our modification is a novel and safe, and permits effective and accurate immobilization for infants for radiation therapy. New manufacturing technologies may allow creation of individualized mouthpieces.



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Evaluation of polymorphisms in angiogenesis-related genes as predictive and prognostic markers for sunitinib-treated metastatic renal cell carcinoma patients

Abstract

Purpose

Single nucleotide polymorphisms (SNPs) in angiogenesis-associated genes might play an important role in activity of the tyrosine kinase inhibitor sunitinib and could affect survival of cancer patients treated with this drug. The aim of this retrospective study was to elucidate the role of 10 known SNPs in VEGFA, VEGFR1, VEGFR2 and VEGFR3 as potential prognostic and predictive markers in an independent cohort of patients with metastatic renal cell carcinoma (mRCC).

Methods

DNA from 121 mRCC patients treated with sunitinib was used to analyze SNPs by TaqMan genotyping assays. Disease control rate was evaluated according to RECIST. Adverse effects of sunitinib were registered from medical records. The results of Cox and logistic regression were verified by correction for multiple testing.

Results

Kaplan–Meier analysis revealed a reduced progression-free survival in patients with the wild-type (WT) allele of the VEGFA SNP rs699947 compared to variant alleles. Patients with the AA/AC-alleles of the VEGFR1 SNP rs9582036 had an improved median overall survival compared to those with the CC–WT allele what could be confirmed by multivariable Cox proportional hazard regression analyses. No statistically significant associations between the analyzed SNPs and higher risk for adverse effects were observed.

Conclusions

The results of this study suggest that most of the selected SNPs in angiogenesis-related genes are not associated with survival of mRCC patients after sunitinib therapy or with adverse effects. Only the VEGFR1 SNP rs9582036 showed a statistically significant association with overall survival. The potential of SNPs as prognostic and predictive markers for sunitinib-treated mRCC patients should be finally assessed by prospective studies.

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Early-stage prostate cancer, PSA screening rates decline

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Issue Information – TOC - Masthead

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Randomized phase II study of axitinib versus physicians best alternative choice of therapy in patients with recurrent glioblastoma

Abstract

We conducted a randomized, non-comparative, multi center, phase II clinical trial in order to investigate the efficacy of axitinib, an oral small molecule tyrosine kinase inhibitor with high affinity and specificity for the vascular endothelial growth factor receptors, in patients with recurrent glioblastoma following prior treatment with radiation and temozolomide. Forty-four patients were randomly assigned to receive treatment with axitinib (5 mg BID starting dose; N = 22) or "physicians best alternative choice of therapy" that consisted of bevacizumab (N = 20) or lomustine (N = 2). Six-month progression-free survival served as the primary endpoint. The estimated 6-month progression-free survival rate was 34 % (95 % CI 14–54) for patients treated with axitinib and 28 % (95 % CI 8–48) with best alternative treatment; median overall survival was 29 and 17 weeks, respectively. Objective responses according to RANO criteria were documented in 28 % of patients treated with axitinib and 23 % of patients treated with best alternative therapy. A decrease in maximal uptake of 18F-fluoro-ethyl-tyrosine (18F-FET) by the glioblastoma on PET imaging was documented in 85 % of patients at the time of response on axitinib. Corticosteroid treatment could be stopped in four and tapered in seven out of the 15 patients who were treated with steroids at baseline in the axitinib cohort. Most frequent axitinib related grade ≥3 adverse events consisted of fatigue (9 %), diarrhea (9 %), and oral hyperesthesia (4.5 %). We conclude that axitinib has single-agent clinical activity and a manageable toxicity profile in patients with recurrent glioblastoma.

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Cilengitide with metronomic temozolomide, procarbazine, and standard radiotherapy in patients with glioblastoma and unmethylated MGMT gene promoter in ExCentric, an open-label phase II trial

Abstract

Newly diagnosed glioblastoma multiforme with unmethylated MGMT promoter has a poor prognosis, with a median survival of 12 months. This phase II study investigated the efficacy and safety of combining the selective integrin inhibitor cilengitide with a combination of metronomic temozolomide and procarbazine for these patients. Eligible patients (newly diagnosed, histologically confirmed supratentorial glioblastoma with unmethylated MGMT promoter) were entered into this multicentre study. Cilengitide (2000 mg IV twice weekly) was commenced 1 week prior to radiotherapy combined with daily temozolomide (60 mg/m²) and procarbazine (50 or 100 mg) and, after 4 weeks' break, followed by six adjuvant cycles of temozolomide (50–60 mg/m²) and procarbazine (50 or 100 mg) on days 1–20, every 28 days. Cilengitide was continued for up to 12 months or until disease progression or unacceptable toxicity. The primary endpoint for efficacy was a 12-month overall survival rate of 65 %. Twenty-nine patients completed study treatment. Sixteen patients survived for 12 months or more, an overall survival rate of 55 %. The median overall survival was 14.5 months (95 % CI 11.1–19.6) and the median progression-free survival was 7.4 months (95 % CI 6.1–8). Cilengitide combined with metronomic temozolomide and procarbazine in MGMT-promoter unmethylated glioblastoma did not improve survival compared with historical data and does not warrant further investigation.

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Impact of MR-safe headphones on PET attenuation in combined PET/MRI scans

Abstract

Background

MR headphones are attenuation sources affecting PET quantification in hybrid PET/MRI. Despite potentially better patient communication, usage in PET/MRI scans is not approved by the vendor. This study aims to determine the impact of headphones on PET by means of phantom and patient scans. Additionally, the perceived benefit of using headphones was evaluated.

Findings

A cylinder phantom was scanned without and with dedicated MR headphones in a PET/CT scanner. Headphone attenuation was additionally assessed in a clinical setup in 10 patients on a PET/MR scanner using F-18-fluoro-deoxy-glucose. The difference in tracer uptake with and without headset was determined for the various brain regions. Additionally, the patients were asked for differences in noise levels, patient comfort, communication quality, and preference. CT data revealed headphone attenuation values of 350–500 HU. Neglecting headphone attenuation leads to a decrease in PET values between the earcups of about 11 % when compared to the correctly reconstructed data. Regions further away from the headphones were less affected. Patient images demonstrated a decrease of 11 % on average in the cerebellum and temporal lobes, while other regions were less affected. No visual artefacts in the images were noticed. On average, no advantage in terms of noise and patient comfort and only slightly better quality of communication were imparted by the patients.

Conclusions

Using headphones during PET/MR acquisition leads to a negative bias in brain uptake values without introducing obvious image artefacts. Since they lack benefits for the patients, they should be avoided if PET quantification of the brain is needed.

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St. Jude Cancer Education for Children Program: The Impact of a Teacher-Led Intervention on Student Knowledge Gains

Abstract

In 2006, St. Jude Children's Research Hospital (Memphis, Tennessee) began developing a school-based outreach program known as the St. Jude Cancer Education for Children Program (SJCECP). The aim of this program is to teach Memphis-area children about cells, cancer, and healthy habits that can prevent the development of cancer in adulthood. Initial plans for delivery of the program was for St. Jude staff to present the program at local schools. This plan for disseminating instruction was not feasible due to the limited availability of St. Jude staff. As a next step, during the 2012–2014 academic years, we conducted a study entitled SJCECP2, utilizing the SJCECP curriculum, with the objective of evaluating the impact of the educational intervention on knowledge acquisition and retention among fourth-grade students participating in a modified, teacher-led version of the program. Eighteen teachers and 426 students from 10 local schools in the greater Memphis area participated in the program evaluation. This study used a single-group, pre-test/post-test design to determine the impact of the SJCECP intervention on changes in knowledge scores among fourth-grade students. Testing was on cells, cancer, and healthy living. The mean scores increased from 6.45 to 8.12, 5.99 to 7.65, and 5.92 to 7.96 on cell, cancer, and health behaviors units, respectively (all p values <.001). Preliminary evidence suggests that the SJCECP2 intervention is a useful tool for teachers to improve student knowledge of knowledge of cells, cancer, and healthy living concepts at the fourth-grade level.

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Erratum to: Postpartum pathology in Yankasa ewes experimentally infected with Trypanosoma evansi during pregnancy

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Metabolomics of papillary thyroid carcinoma tissues: potential biomarkers for diagnosis and promising targets for therapy

Abstract

Papillary thyroid carcinoma (PTC) is the most common pathological type of thyroid cancer. Our study was to construct a tissue-targeted metabolomics analysis method based on untargeted and targeted metabolic multi-platforms to identify a comprehensive PTC metabolic network in clinical samples. We applied untargeted gas chromatography-time-of-flight mass spectrometry (GC-TOF-MS) for preliminary screening of potential biomarkers. With diagnostic models constructed using principal component analysis (PCA), partial least squares discriminant analysis (PLS-DA) and orthogonal partial least squares discriminant analysis (OPLS-DA), 45 differentially abundant metabolites with a variable importance in the projection (VIP) value greater than 1 and a P value less than 0.05 were identified, and we show that our approach was able to discriminate PTC tissues from healthy tissues. We then performed validation experiments based on targeted GC-TOF-MS combined with ultra-high-performance liquid chromatography-triple-quadrupole mass spectrometry (UHPLC-QqQ-MS) through constructing linear standard curves of analytes. Ultimately, galactinol, melibiose, and melatonin were validated as significantly altered metabolites (p < 0.05). These three metabolites were defined as a combinatorial biomarker to assist needle biopsy for PTC diagnosis as demonstrated by receiver operating characteristic (ROC) curve analysis, which revealed an area under the ROC curve (AUC) value of 0.96. Based on the metabolite enrichment analysis results, the galactose metabolism pathway was regarded as an important factor influencing PTC development by affecting energy metabolism. Alpha-galactosidase (GLA) was considered to be a potential target for PTC therapy.

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miRNA-204 suppresses human non-small cell lung cancer by targeting ATF2

Abstract

MicroRNAs (miRNAs) play a critical role in cancer development and progression. Deregulated expression of miR-204 has been reported in several cancers, but the mechanism through which miR-204 modulates human non-small cell lung cancer (NSCLC) is largely unknown. In this study, we investigate the expression and functional role of miR-204 in human NSCLC tissues and cell lines. RNA isolation, qRT-PCR, MTT, colony formation assay, cell cycle assay, cell apoptosis assay, cell migration assay, and Western blot were performed. Statistical analysis was performed using SPSS 18.0 software and statistical significance was accepted at p value <0.05. miR-204 level was significantly reduced in NSCLC tissues as compared to that of non-neoplastic tissues. Transient over-expression of miR-204 by transfecting with miR-204 mimics suppressed NSCLC cell proliferation, migration, and induced apoptosis and G1 arrest, whereas inhibition of miR-204 showed the converse effects. Additionally, activating transcription factor 2 (ATF2), an important transcription factor, was demonstrated as a potential target gene of miR-204. Subsequent investigations found a negative correlation between miR-204 level and ATF2 expression in NSCLC tissue samples. Moreover, we observed that miR-204 expression inversely affected endogenous ATF2 expression at both mRNA and protein levels in vitro. Taken together, miR-204 may act as a tumor suppressor by directly targeting ATF2 in NSCLC.

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Hepatic resection provided long-term survival for patients with intermediate and advanced-stage resectable hepatocellular carcinoma

Abstract

Background

Hepatic resection has the highest local controllability that results in long-term survival for hepatocellular carcinoma (HCC). This study aimed to investigate the role of hepatic resection in selected patients of intermediate and advanced stage.

Methods

Clinical, pathological, and outcome data of 542 consecutive patients were retrospectively analyzed from a single center. The Kaplan-Meier method was used to estimate survival. Postoperative prognostic factors were evaluated using univariate and multivariate analyses.

Results

The 1-, 3-, and 5-year overall survival rates were 89.0, 64.3, and 53.0 %, respectively. The 1-, 3-, and 5-year disease-free survival rates were 72.2, 44.5, and 34.2 %, respectively. Preoperative α-fetoprotein level >400 ng/mL, macroscopic vascular invasion, microscopic portal vein thrombosis, multiple tumor nodules, and the largest tumor size >5 cm were significantly correlated with overall survival. When these clinical risk factors were used in a postoperative staging system, assigning one point for each factor, the total score was precisely predictive of long-term survival. For patients with surgery plus adjuvant TACE (transarterial chemoembolization), the median overall survival was 56 months (range 1–110 months) and the 5-year OS rate was 48.5 %.

Conclusions

Hepatic resection is efficient and safe for HCC patients of intermediate and advanced stage. The adjuvant TACE should be recommended for HCC patients with poor risk factors.

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Récidive tumorale osseuse locale après cimentoplastie : à propos d’un cas ; discussion de l’intérêt de la radiothérapie après cimentoplastie

Publication date: Available online 2 March 2016
Source:Cancer/Radiothérapie
Author(s): Y. Brahimi, D. Antoni, X. Buy, A. Gangi, G. Noël
Les techniques de radiologie interventionnelle antalgiques et de consolidation osseuse, cimentoplastie, vertébroplastie et kyphoplastie, font partie de l'arsenal thérapeutique en cancérologie. Elles ne sont toutefois pas antitumorales par elles-mêmes. L'association d'un traitement antitumoral doit être préconisée. Nous présentons le cas d'un patient atteint d'une métastase lombaire qui a bénéficié d'une cimentoplastie sans traitement complémentaire antitumoral. Les suites ont été marquées par un développement tumoral autour du ciment. Ce cas illustre l'évolution potentielle d'une métastase osseuse dont les douleurs sont bien contrôlées à l'inverse de la cinétique tumorale. Nous avons repris les études associant ces techniques de consolidation avec des traitements locaux antitumoraux. Si de nombreuses associations ont été publiées, aucun essai thérapeutique ne permet de classer ces associations dans des recommandations solides.Interventional radiology techniques – vertebroplasty, kyphoplasty and vertebroplasty – are part of the therapeutic arsenal in oncology. They are not, however, antitumoural by themselves. A combination of these techniques with an antitumoral treatment is thus required. We present the case of a patient with a spinal metastasis who received antitumor vertebroplasty without additional treatment. The follow-up has found a tumour development around the cement. This case illustrates the need for a complementary antitumor treatment following a consolidative procedure. Many combinations of treatment and techniques have been published; however, no study reached a sufficient proof of efficiency for any combination to be recommended. Prospective trials are needed to guide clinicians.



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Cancers, Vol. 8, Pages 31: Differentially Expressed MicroRNAs in Meningiomas Grades I and II Suggest Shared Biomarkers with Malignant Tumors

Meningiomas represent the most common primary tumors of the central nervous system, but few microRNA (miRNA) profiling studies have been reported so far. Deep sequencing of small RNA libraries generated from two human meningioma biopsies WHO grades I (benign) and II (atypical) were compared to excess dura controls. Nineteen differentially expressed miRNAs were validated by RT-qPCR using tumor RNA from 15 patients and 5 meninges controls. Tumor suppressor miR-218 and miR-34a were upregulated relative to normal controls, however, miR-143, miR-193b, miR-451 and oncogenic miR-21 were all downregulated. From 10 selected putative mRNA targets tested by RT-qPCR only four were differentially expressed relative to normal controls. PTEN and E-cadherin (CDH1) were upregulated, but RUNX1T1 was downregulated. Proliferation biomarker p63 was upregulated with nuclear localization, but not detected in most normal arachnoid tissues. Immunoreactivity of E-cadherin was detected in the outermost layer of normal arachnoids, but was expressed throughout the tumors. Nuclear Cyclin D1 expression was positive in all studied meningiomas, while its expression in arachnoid was limited to a few trabecular cells. Meningiomas of grades I and II appear to share biomarkers with malignant tumors, but with some additional tumor suppressor biomarkers expression. Validation in more patients is of importance.

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