Cancer incidence in patients with hereditary hemorrhagic telangiectasia

Abstract

Purpose

Hereditary hemorrhagic telangiectasia (HHT) is a genetic disorder characterized by deficiency in endoglin, an angiogenic protein. We previously showed that HHT, in which systemic endoglin expression is reduced, was associated with better survival outcomes in cancer patients (Duarte et al. in Cancer Epidemiol Biomarkers Prev 23:117–125, 2014). Here, we evaluated whether HHT was associated with reduced cancer incidence.

Methods

A matched case–control analysis using SEER Medicare was conducted to evaluate the effect of HHT on diagnosis with breast, colorectal, lung, or prostate cancer between 2000 and 2007 (n = 633,162). Cancer and non-cancer patients were matched on age, sex, SEER registry region, and length of the ascertainment period for HHT. We assessed crude association using a McNemar's test and then adjusted for demographic variables, cancer type, cancer stage, comorbidities, and ascertainment period with a conditional logistic regression model for cancer incidence.

Results

The McNemar's test showed no significant association between HHT and cancer incidence (p = 0.74). Adjusting for covariates with the conditional logistic regression model did not change the result [HHT odds ratio 0.978; 95 % CI (0.795, 1.204)]. The lack of association between HHT and cancer incidence is unexpected given the previously discovered significant association between HHT and improved survival outcomes (Duarte et al. in Cancer Epidemiol Biomarkers Prev 23:117–125, 2014).

Conclusions

We conclude that the protective effect of reduced systemic endoglin expression in cancer is specific to cancer progression through its effect on vascularization and other stromal effects but does not extend to cancer initiation.

from Cancer via ola Kala on Inoreader http://ift.tt/2cVWe6m
via IFTTT

CCAT1: an oncogenic long noncoding RNA in human cancers

Abstract

Purpose

Long noncoding RNAs (lncRNAs) are a new class of noncoding RNAs that participate in a variety of biological processes such as cell proliferation, cell cycle, differentiation and apoptosis, mainly by regulation of gene expression at various levels, including chromatin, splicing, transcriptional and post-transcriptional levels. CCAT1 is a recently identified oncogenic lncRNA, which has been reported to be consistently upregulated in multiple cancer tissues and closely correlated with initiation and progression of cancers. The aim of this paper is to provide an overview of various roles of CCAT1 in human cancers.

Methods and results

We searched studies in electronic databases. Studies have shown the high expression pattern and oncogenic role of CCAT1 in different types of cancer, and aberrant expression of CCAT1 is involved in several processes correlated with carcinogenesis such as cell proliferation, apoptosis, migration and invasion by regulating different target genes and pathways.

Conclusion

LncRNA CCAT1 promises to be a novel diagnostic biomarker, therapeutic target, as well as prognostic biomarker in human cancers.

from Cancer via ola Kala on Inoreader http://ift.tt/2cNg5HU
via IFTTT

Transarterial embolization combined with RNA interference targeting hypoxia-inducible factor-1α for hepatocellular carcinoma: a preliminary study of rat model

Abstract

Purpose

To study whether transarterial embolization (TAE) with RNA interference (RNAi) targeting hypoxia-inducible factor-1α (HIF-1α) can improve efficacy of TAE in treating hepatocellular carcinoma (HCC).

Materials and methods

CBRH-7919 rat hepatoma cell line was used and HCC models of rats were constructed. The siRNA transfection compound was made by mixing specific siRNA and Lipofectamine 2000™. Delivery and transfection of siRNA were administered by injecting iodized oil emulsion (diluted lipiodol and siRNA) via hepatic artery. The expression levels of mRNA and protein were detected using the real-time reverse transcription polymerase chain reaction (RT-PCR), immunohistochemistry and western blotting assays, respectively.

Results

In vitro experiment, the specific HIF-1α-siRNA was proved to inhibit expression levels of HIF-1α and vascular endothelial growth factor (VEGF) effectively. In animal study, real-time RT-PCR assay showed the average relative mRNA expressions of HIF-1α were 0.31 ± 0.01, 0.65 ± 0.03, 0.46 ± 0.005, and 1.00 ± 0.00 in TAE + siRNA, siRNA, TAE, and control groups, respectively. Western blotting assay showed the average relative protein expressions of HIF-1α were 0.13 ± 0.02, 0.87 ± 0.02, 0.39 ± 0.02, and 1.02 ± 0.01 in TAE + siRNA, siRNA, TAE, and control groups, respectively. Compared with control, TAE, and siRNA groups, TAE + siRNA can significantly inhibit protein expressions of HIF-1α and VEGF (P _HIF-1α < 0.001; P _VEGF < 0.001). Overall survival of rats underwent TAE + siRNA was significantly longer than that of rats treated with TAE monotherapy (P = 0.001).

Conclusion

This animal study showed TAE combined with HIF-1α-RNAi could significantly improve efficacy of TAE in treating HCC by inhibiting expressions of HIF-1α and VEGF after TAE treatment.

from Cancer via ola Kala on Inoreader http://ift.tt/2cEjdVR
via IFTTT

Urinary metabolic profiling by 1 H NMR spectroscopy in patients with cirrhosis may discriminate overt but not covert hepatic encephalopathy

Abstract

To date urinary metabolic profiling has been applied to define a specific metabolic fingerprint of hepatocellular carcinoma on a background of cirrhosis. Its utility for the stratification of other complications of cirrhosis, such as hepatic encephalopathy (HE), remains to be established. Urinary proton nuclear magnetic resonance (¹H-NMR) spectra were acquired and NMR data from 52 patients with cirrhosis (35 male; 17 female, median (range) age [60 (18–81) years]) and 17 controls were compared. A sub-set of 45 patients (33 male; 12 female, [60 (18–90) years, median model for end stage liver disease (MELD) score 11 (7–27)]) were fully characterised by West-Haven criteria, Psychometric Hepatic Encephalopathy Score (PHES) and electroencephalogram (EEG), and defined as overt HE (OHE, n = 21), covert HE (cHE, n = 7) or no HE (n = 17). Urinary proton nuclear magnetic resonance (¹H-NMR) spectra were analysed by partial-least-squares discriminant analysis (PLS-DA). The results showed good discrimination between patients with cirrhosis (n = 52) and healthy controls (n = 17) (R2X = 0.66, R2Y = 0.47, Q2Y = 0.31, sensitivity-60 %, specificity-100 %) as the cirrhosis group had higher 1-methylnicotinamide with lower hippurate, acetate, phenylacetylglycine and N-methyl nicotinic acid levels. While patients with OHE could be discriminated from those with no HE, with higher histidine, citrate and creatinine levels, the best models lack robust validity (R2X = 0.65, R2Y = 0.48, Q2Y = 0.12, sensitivity-100 %, specificity-64 %) with the sample size used. Urinary ¹H-NMR metabolic profiling did not discriminate patients with cHE from those without HE, nor discriminate subjects on the basis of PHES/EEG result or MELD score. In conclusion, patients with cirrhosis showed different urinary ¹H-NMR metabolic profiles compared to healthy controls and those with OHE may be distinguished from those with no HE although larger studies are required. However, urinary ¹H-NMR metabolic profiling did not discriminate patients with differing grades of HE or according to severity of underlying liver disease.

from Cancer via ola Kala on Inoreader http://ift.tt/2d5hDuz
via IFTTT

Current state of knowledge of hepatic encephalopathy (part III): non-absorbable disaccharides

Abstract

Nonabsorbable disaccharides have been the mainstay of treatment for hepatic encephalopathy since introduced into clinical practice in 1966. Their beneficial effects reflect their ability to reduce the intestinal production/absorption of ammonia. A recent Cochrane review confirmed the efficacy and safety of nonabsorbable disaccharides for the treatment and prevention of hepatic encephalopathy in patients with cirrhosis. The findings were robust and support the use of nonabsorbable disaccharides as a first line treatment for hepatic encephalopathy, in this patient population, and for its prevention.

from Cancer via ola Kala on Inoreader http://ift.tt/2cEjoki
via IFTTT

Genomic Heterogeneity of Cancer

In this issue of Cancer Research, Almassalha and colleagues have proposed a new concept of the development of malignancy, that of the greater genomic landscape. They propose a stressor-related exploration of intracellular genomic sites as a response mechanism. This process can express sites with beneficial or deleterious effects, among them those that promote cell proliferation. They point out that their conception is broader, although certainly inclusive, of the process of gene induction. The authors view the physical process of chromatin reorganization as central to the exploration of the genomic landscape. Accordingly, they advocate the development of agents to limit chromatin structural modification as a chemotherapeutic approach in cancer. We found their theory relevant to understand the phenotypic heterogeneity of malignancy, particularly in familial cancer syndromes. For example, the familial atypical multiple mole melanoma (FAMMM) syndrome, related to a gene mutation, is characterized by a diversity of melanocytic lesions, only some of which become malignant melanoma. This new conceptualization can do much to increase understanding of the diversity of malignancy in families with hereditary cancer. Cancer Res; 76(19); 1–3. ©2016 AACR.

from Cancer via ola Kala on Inoreader http://ift.tt/2d5gD9L
via IFTTT

Evaluating patients for psychosocial distress and supportive care needs based on health-related quality of life in primary brain tumors: a prospective multicenter analysis of patients with gliomas in an outpatient setting

Abstract

The association between health-related quality of life (HRQoL), psychosocial distress, and supportive care is in the focus of patient-centered neuro-oncology. We investigated the relationship between the aforementioned in glioma-patients to evaluate the association of these instruments and determine cut-off values for suitable HRQoL scales indicating a potential need for intervention. In an observational multi-center study, outpatients completed the Distress Thermometer (DT), EORTC Quality of Life Questionnaire (EORTC-QLQ-C30/BN20, HRQoL), and Supportive-Care-Needs-Survey-SF34-G (SCNS). Based on nine EORTC-function and selected -symptom scales items of the questionnaires were matched. Convergent validity of related single items and scores across the instruments was estimated. EORTC cut-off values were calculated. Data of 167 patients were analyzed. The strongest correlation of EORTC-QLQ-C30 and DT was found for cognitive function (cogf), global health status (GHS), emotional (emof), role function (rolef), future uncertainty (FU), fatigue, and between EORTC-QLQ-C30 and SCNS for FU, emof, rolef (r = |0.4–0.7|; p < 0.01). EORTC cut-off values of <54.2 (GHS/QoL) and <62.5 (emof) predicted a DT ≥ 6 (AUC 0.79, 0.85, p < 0.01). EORTC cut-off values of <70.8 (emof) and <52.8 (FU) predicted the need for supportive care (AUC 0.78, 0.85; p < 0.01). Worse EORTC-C30 scores correlate with higher DT and SCNS scores. With this exploratory assessment, cut-off values for EORTC-C30 subscores to predict distress and pathological SCNS-scores could be determined, which could influence patients' referral to further treatment. However, further prospective clinical trials are needed to confirm the clinical relevance of these cut-off values.

from Cancer via ola Kala on Inoreader http://ift.tt/2cNbvcx
via IFTTT

MiR-377 inhibits the proliferation of pancreatic cancer by targeting Pim-3

Abstract

MicroRNAs (miRNAs) play important roles in the regulation of various tumor biological processes including proliferation and apoptosis. MiR-377 has been implicated in many types of cancer, whereas its expressional feature and potential biological function in pancreatic ductal adenocarcinoma (PDAC) remains unclear. In this study, we scanned the global miRNA expression profiles in PDAC from The Cancer Genome Atlas (TCGA) and found miR-377 was down-regulated significantly in PDAC. Then, its expression was measured in both pancreatic cancer tissues and cells; the data showed that miR-377 was de-regulated and inversely correlated with pathologic parameters of tumor growth or metastasis. We generated PDAC cell lines with stable overexpression or inhibition of miR-377, and our results indicated that miR-377 up-regulation significantly promoted cell viability, proliferation, and migration in PDAC cells, and also induced cell apoptosis and cell cycle arrest simultaneously. Binding-site predictions by bioinformatics showed that Pim-3 might be a potential target of miR-377. Luciferase reporter assay ulteriorly identified that miR-377 suppressed Pim-3 expression by binding the 3′-UTR. In tumor tissues, we also showed that the Pim-3 expression was inversely correlated with that of miR-377. Furthermore, stable ectopic miR-377 expression in pancreatic cancer cell lines suppressed Pim-3 expression, leading to the attenuation of Bad phosphorylation level at its Ser¹¹² and promoting cell apoptosis. Overall, these results reveal that miR-377 may have tumor growth suppression function by down-regulating Pim-3 kinase expression to inhibit both pancreatic tumor growth and migration, and induce cell apoptosis. Hence, miR-377 may be a potential diagnostic marker and therapeutic target.

from Cancer via ola Kala on Inoreader http://ift.tt/2cwbGLo
via IFTTT

Alkylating agent induced NRF2 controls ER stress via GSH

Alkylating agents are a commonly used cytotoxic class of anticancer drugs. Understanding the mechanisms whereby cells respond to these drugs is key to identify means to improve therapy while reducing toxicity. By integrating genome-wide gene expression profiling, protein analysis and functional cell validation, we herein demonstrated a direct relationship between NRF2 and Endoplasmic Reticulum (ER) stress pathways in response to alkylating agents, which is coordinated by the availability of glutathione (GSH) pools. GSH is essential for both drug detoxification and protein thiol homeostasis within the ER, thus inhibiting ER stress induction and promoting survival; an effect independent of its antioxidant role. NRF2 accumulation induced by alkylating agents resulted in increased GSH synthesis via GCLC/GCLM enzyme, and interfering with this NRF2 response by either NRF2 knockdown or GCLC/GCLM inhibition with buthionine sulfoximine (BSO) caused accumulation of damaged proteins within the ER, leading to PERK-dependent apoptosis. Conversely, upregulation of NRF2, through KEAP1 depletion or NRF2-myc overexpression, or increasing GSH levels with N-acetylcysteine (NAC) or glutathione-ethyl-ester (GSH-E), decreased ER stress and abrogated alkylating agents-induced cell death. Based on these results, we identified a subset of lung and head-and-neck carcinomas with mutations in either KEAP1 or NRF2/NFE2L2 genes that correlate with NRF2 targets overexpression and poor survival. In KEAP1 mutant cancer cells, NRF2 knockdown and GSH depletion increased cell sensitivity via ER stress induction in a mechanism specific to alkylating drugs. Overall, we show that the NRF2-GSH influence on ER homeostasis implicates defects in NRF2-GSH or ER stress machineries as affecting alkylating therapy toxicity.

from Cancer via ola Kala on Inoreader http://ift.tt/2cEaOC6
via IFTTT

Synergistic antitumor activity of XL184 with CT-707

Hepatocellular carcinoma (HCC) is among the leading causes of cancer-related death worldwide, and the development of new treatment regimens is urgently needed to improve therapeutic approach. In our study, we found that the combination of a Met inhibitor, cabozantinib, and a novel FAK inhibitor, CT-707, exerted synergistic anti-tumor effects against HCC in vitro and in vivo. Interestingly, further studies showed that therapeutic concentrations of cabozantinib increased the phosphorylation of FAK, which might attenuate the anti-tumor activity of cabozantinib. The simultaneous exposure to CT-707 effectively inhibited the activation of FAK that was induced by cabozantinib, which contributes to the synergistic effect of the combination. Furthermore, cabozantinib increased the mRNA and protein levels of integrin α5, which is a canonical upstream of FAK, and the introduction of cilengitide to block integrin function could abrogate FAK activation by cabozantinib, indicating that cabozantinib up-regulated the phosphorylation of FAK in an integrin-dependent manner. Similar synergy was also observed on PHA-665752, another selective MET inhibitor, indicating that this observation might be a common characteristic of MET-targeting strategies. Our findings not only favor the development of the novel FAK inhibitor, CT-707, as a therapeutic agent against HCC but also provide a new strategy of combining MET and FAK inhibitors to potentiate the anticancer activities of these two types of agents for treating HCC patients.

from Cancer via ola Kala on Inoreader http://ift.tt/2d5a0UM
via IFTTT

ATM predicts drug sensitivity in gastric cancer

Identification of synthetically lethal cellular targets and synergistic drug combinations are important in cancer chemotherapy as they help to overcome treatment resistance and increase efficacy. The Ataxia Telangiectasia Mutated (ATM) kinase is a nuclear protein that plays a major role in the initiation of DNA repair signalling and cell cycle check points during DNA damage. Although ATM was shown to be associated with poor prognosis in gastric cancer, its implications as a predictive biomarker for cancer chemotherapy remains unexplored. The present study evaluated ATM-induced synthetic lethality and its role in sensitization of gastric cancer cells to PARP and TOP1 inhibitors, veliparib (ABT-888) and irinotecna (CPT-11) respectively. ATM expression was detected in a panel of gastric cell lines and the IC50 against each inhibitors was determined. The combinatorial effect of ABT-888 and CPT-11 in gastric cancer cells was also determined both in vitro and in vivo. ATM deficiency was found to be associated with enhanced sensitivity to ABT-888 and CPT-11 monotherapy, hence suggesting a mechanism of synthetic lethality. Cells with high ATM expression showed reduced sensitivity to monotherapy, however showed a higher therapeutic effect with ABT-888 and CPT-11 combinatorial therapy. Furthermore, ATM expression was shown to play a major role in cellular homeostasis by regulating cell cycle progression and apoptosis in a P53-independent manner. The present study highlights the clinical utility of ATM expression as a predictive marker for sensitivity of gastric cancer cells to PARP and TOP1 inhibition and provides a deeper mechanistic insight into ATM-dependent regulation of cellular processes.

from Cancer via ola Kala on Inoreader http://ift.tt/2cEaLWK
via IFTTT

Aspirin-PC plus anti-angiogenic drugs in ovarian cancer

To determine the efficacy of a novel and safer (for gastrointestinal tract) aspirin (aspirin-PC) in preclinical models of ovarian cancer, in vitro dose-response studies were performed to compare the growth-inhibitory effect of aspirin-PC vs. aspirin on 3 human (A2780, SKOV3ip1, HeyA8), and a mouse (ID8) ovarian cancer cell line over an 8-day culture period. In the in vivo studies, the aspirin test drugs were studied alone and in the presence of a VEGF-A inhibitor (bevacizumab or B20), due to an emerging role for platelets in tumor growth following anti-angiogenic therapy, and we examined their underlying mechanisms. Aspirin-PC was more potent (vs. aspirin) in blocking the growth of both human and mouse ovarian cancer cells in monolayer culture. Using in vivo model systems of ovarian cancer, we found that aspirin-PC significantly reduced ovarian cancer growth by 50-90% (depending on the ovarian cell line/density). The efficacy was further enhanced in combination with Bevacizumab or B20. The growth-inhibitory effect on ovarian tumor mass and number of tumor nodules was evident, but less pronounced for aspirin and the VEGF inhibitors alone. There was no detectable gastrointestinal toxicity. Both aspirin and aspirin-PC also inhibited cell proliferation, angiogenesis and increased apoptosis of ovarian cancer cells. In conclusion, PC-associated aspirin markedly inhibits the growth of ovarian cancer cells, which exceeds that of the parent drug, in both cell culture and in mouse model systems. We also found that both aspirin-PC and aspirin have robust anti-neoplastic action in the presence of VEGF blocking drugs.

from Cancer via ola Kala on Inoreader http://ift.tt/2d5bPRF
via IFTTT

Translational PKPD modeling to differentiate compounds

We quantitatively compare the efficacy of two approved EGFR tyrosine kinase inhibitors, erlotinib and gefitinib based on in vivo and in vitro data and show how a modeling approach can be used to scale from animal to humans. Gefitinib shows a higher tumor uptake in cancer patients and we explored the potential impact on pharmacological and anti-tumor activity in in vitro and in xenograft mice. Tumor growth inhibition was monitored and the pharmacokinetics (PK) in plasma and tumor, as well as temporal changes of phospho-Erk (pErk) signals were examined in patient-derived tumor xenograft mice. These data were integrated in a translational PKPD model, allowing us to project an efficacious human dose which we retrospectively compared to prescribed doses for cancer patients. In vitro experiments showed that cell cycle arrest was similar for erlotinib and gefitinib. Similar pERK biomarker responses were obtained despite 6.6-fold higher total tumor exposure for gefitinib. The PKPD model revealed a 3.7-fold higher in vivo potency for gefitinib which did not translate into a lower anticipated efficacious dose in humans. The model-based dose prediction matched the recommended clinical doses well. These results suggest that despite having lower total tumor to plasma ratios, active drug exposure at target site is higher for erlotinib. Considering the pharmacokinetic properties, this translates in a 50% lower recommended daily dose of erlotinib in cancer patients. In summary, total exposure at target site is not suitable to rank compounds, and an integrated modeling and experimental approach can assess efficacy more accurately.

from Cancer via ola Kala on Inoreader http://ift.tt/2cEaC5x
via IFTTT

Resistance to FAK-kinase Inhibitors by RTKs

Focal adhesion kinase (FAK) is a major drug target in cancer and current inhibitors targeted to the ATP-binding pocket of the kinase domain have entered clinical trials. However, preliminary results have shown limited single-agent efficacy in patients. Despite these unfavorable data, the molecular mechanisms which drive intrinsic and acquired resistance to FAK-kinase inhibitors are largely unknown. We have demonstrated that receptor tyrosine kinases (RTKs) can directly bypass FAK-kinase inhibition in cancer cells through phosphorylation of FAK's critical tyrosine 397 (Y397). We also showed that HER2 forms a direct protein-protein interaction with the FAK-FERM-F1 lobe, promoting direct phosphorylation of Y397. Additionally, FAK-kinase inhibition induced two forms of compensatory RTK reprogramming: 1) the rapid phosphorylation and activation of RTK signaling pathways in RTKHigh cells and 2) the long-term acquisition of RTKs novel to the parental cell line in RTKLow cells. Finally, HER2+ cancer cells displayed resistance to FAK-kinase inhibition in 3D-growth assays using a HER2 isogenic system and HER2+ cancer cell lines. Our data indicate a novel drug resistance mechanism to FAK-kinase inhibitors whereby HER2 and other RTKs can rescue and maintain FAK activation (pY397) even in the presence of FAK-kinase inhibition. These data may have important ramifications for existing clinical trials of FAK inhibitors and suggest that individual tumor stratification by RTK expression would be important to predict patient response to FAK-kinase inhibitors.

from Cancer via ola Kala on Inoreader http://ift.tt/2d5aF8Q
via IFTTT

SFVmiRT for treatment of glioblastoma and neuroblastoma

Purpose:: Glioblastoma multiforme (GBM) and high–risk neuroblastoma are cancers with poor outcome. Immunotherapy in the form of neurotropic oncolytic viruses is a promising therapeutic strategy for these malignancies. Here we evaluate the oncolytic potential of the neurovirulent and partly interferon (IFN)–β–resistant Semliki Forest virus (SFV)–4 in GBMs and neuroblastomas. To reduce neurovirulence we constructed SFV4miRT, which is attenuated in normal CNS cells through insertion of microRNA target sequences for miR124, miR125, miR134 Experimental Design:Oncolytic activity of SFV4miRT was examined in mouse neuroblastoma and GBM cell lines and in patient–derived human glioblastoma cell cultures (HGCC). In vivo neurovirulence and therapeutic efficacy was evaluated in two syngeneic orthotopic glioma models (CT–2A, GL261) and syngeneic subcutaneous neuroblastoma model (NXS2). The role of IFN–β in inhibiting therapeutic efficacy was investigated. Results:The introduction of microRNA target sequences reduced neurovirulence of SFV4 in terms of attenuated replication in mouse CNS cells and ability to cause encephalitis when administered intravenously. A single intravenous injection of SFV4miRT prolonged survival and cured 4 of 8 mice (50%) with NXS2 and 3 of 11 mice (27%) with CT–2A, but not for GL261 tumor bearing mice. In vivo therapeutic efficacy in different tumor models inversely correlated to secretion of IFN–β by respective cells upon SFV4 infection in vitro. Similarly, killing efficacy of HGCC lines inversely correlated to IFN–β response and interferon–α/β receptor (IFNAR)–1 expression. Conclusions:SFV4miRT has reduced neurovirulence, while retaining its oncolytic potential. SFV4miRT is an excellent candidate for treatment of GBMs and neuroblastomas with low IFN–β secretion.

from Cancer via ola Kala on Inoreader http://ift.tt/2cQBRvo
via IFTTT

Daratumumab in CLL

Purpose: To establish a proof-of-concept for the efficacy of the anti-CD38 antibody daratumumab in the poor prognosis CD38+ CLL subtype. Experimental design: The mechanism of action of daratumumab was assessed in CLL primary cells and cell lines using peripheral blood mononuclear cells to analyze antibody-dependent cell cytotoxicity (ADCC), murine and human macrophages to study antibody-dependent cell phagocytosis (ADCP) or human serum to analyze complement-dependent cytotoxicity (CDC). The effect of daratumumab on CLL cell migration and adhesion to extracellular matrix was characterized. Daratumumab activity was validated in two in vivo models. Results: Daratumumab demonstrated efficient lysis of patient-derived CLL cells and cell lines by ADCC in vitro and ADCP both in vitro and in vivo, while exhibited negligible CDC in these cells. To demonstrate the therapeutic effect of daratumumab in CLL, we generated a disseminated CLL mouse model with the CD38+ MEC2 cell line and CLL patient derived xenografts (CLL-PDX). Daratumumab significantly prolonged overall survival of MEC2 mice, completely eliminated cells from the infiltrated organs and significantly reduced disease burden in the spleen of CLL-PDX. The effect of daratumumab on patient-derived CLL cell dissemination was demonstrated in vitro by its effect on CXCL12-induced migration and in vivo by interfering with CLL cell homing to spleen in NSG mice. Daratumumab also reduced adhesion of CLL cells to VCAM-1, accompanied by down-regulation of the matrix metalloproteinase MMP9. Conclusions: These unique and substantial effects of daratumumab on CLL viability and dissemination support the investigation of its use in a clinical setting of CLL.

from Cancer via ola Kala on Inoreader http://ift.tt/2cDLgDa
via IFTTT

TGF{beta} and TP53 cooperation in PDA metastasis

Purpose: TP53 and the TGFβ pathway are major mediators of pancreatic cancer metastasis. The mechanisms by which they cause hematogenous metastasis have not been fully explored. Experimental Design: KPC (LSL-KRASG12D/+;LSL-Trp53R172H/+; Ptf1aCre/+) mice were generated and the frequency and morphology of organ-specific hematogenous metastases compared to that seen in KPTC and KTC littermates (Tgfbr2+/-). Key findings were validated in primary cells from each genotype and samples of human pancreatic cancer liver metastases. Results: The frequency of hematogenous metastasis in KPTC mice was significantly lower than for KPC mice (41% vs 68%, p<0.05), largely due to a reduction in liver metastases. No differences were found between KPC and KPTC lung metastases whereas liver metastases in KPTC mice showed a profound extravasation deficiency characterized by sinusoidal growth and lack of desmoplastic stroma. Analogous findings were confirmed in liver samples from patients indicating their clinical relevance. Portal vein colonization as a direct mode of access to the liver was observed in both mice and humans. Secretome analyses of KPC cells revealed an abundance of secreted prometastatic mediators including Col6A1 and Lcn2 that promoted early steps of metastatic colonization. These mediators were overexpressed in primary tumors but not metastases suggesting the ability to colonize is in part developed within the primary site, a phenomenon we refer to as the "Cinderella effect". Conclusions: These findings establish a novel paradigm for understanding pancreatic cancer metastasis and the observed clinical latencies of liver versus lung metastases specifically.

from Cancer via ola Kala on Inoreader http://ift.tt/2cQC2qN
via IFTTT

Histone H3 lysine 23 acetylation is associated with oncogene TRIM24 expression and a poor prognosis in breast cancer

Abstract

Acetylated H3 lysine 23 (H3K23ac) is a specific histone post-translational modification recognized by oncoprotein TRIM24. However, it is not clear whether H3K23ac levels are correlated with TRIM24 expression and what role H3K23ac may have in cancer. In this study, we collected breast carcinoma samples from 121 patients and conducted immunohistochemistry to determine the levels of TRIM24 and H3K23ac in breast cancer. Our results demonstrated that TRIM24 expression is positively correlated with H3K23ac levels, and high levels of both TRIM24 and H3K23ac predict shorter overall survival of breast cancer patients. We also showed that both TRIM24 and H3K23ac are higher in HER2-positive patients, and their levels were positively correlated with HER2 levels in breast cancer. Moreover, TRIM24 expression is associated with estrogen receptor (ER) and progesterone receptor (PR) statuses in both our cohort and The Cancer Genome Atlas (TCGA) breast carcinoma. In summary, our results revealed an important role of TRIM24 and H3K23ac in breast cancer and provided further evidence that TRIM24 small-molecule inhibitors may benefit ER- and PR-negative or HER2-positive breast cancer patients.

from Cancer via ola Kala on Inoreader http://ift.tt/2cws2Aa
via IFTTT

Meeting Patients Where They Are: Liberating Clinical Trials Data Under the Cancer Moonshot

Cancer clinical trials are a critically important step on the pathway for new or improved treatments to make their way to patients in clinics and hospitals in towns and cities across the country.

Patients and their loved ones are relying on these rigorous studies to determine whether promising new therapies and approaches might extend how long they live or improve their quality of life.

from Cancer via ola Kala on Inoreader http://ift.tt/2d5KSQN
via IFTTT

Cytomorphology of clear cell papillary renal cell carcinoma

BACKGROUND

Clear cell papillary renal cell carcinoma (CCPRCC) shares some morphologic and immunohistochemical markers with clear cell RCC and papillary RCC. To the author's knowledge, its cytomorphology on fine-needle aspiration (FNA) or touch preparations (TPs) of core needle biopsy specimens has not been well delineated in the English language literature.

METHODS

The FNA/TP cytomorphology of 7 retrieved cases was studied.

RESULTS

The tumor cells were arranged in small nests (100%), 3-dimensional clusters (71%), papillary/tubular/acinar arrays (43%), and as single cells (57%). The tumor cells were columnar (100%) and polygonal (57%) in shape, with eccentric, small, round-to-oval nuclei. The nuclei contained evenly distributed, fine granular chromatin and demonstrated a smooth nuclear membrane (100%) (Fuhrman grade 1 to 2). The tumor cells had a moderate amount of delicate or clear cytoplasm containing small vacuoles (100%) and ill-defined cytoplasmic borders (100%). Scattered macrophages (57%) and necrosis (29%) were identified in the background. Vessels were noted within the papillary cores, transversing or surrounding nests of tumors. Immunochemical studies demonstrated expression of cytokeratin 7 (CK7) (100%), carbonic anhydrase IX (CA 9) (100% in a cup-shaped membranous pattern), α-methylacyl-CoA racemase (AMACR) (50%), and CD10 (43%). The tumor cells were negative for CD117.

CONCLUSIONS

CCPRCC was found to demonstrate cytologic features that when taken together are helpful in diagnosing CCPRCC on FNA smears and TPs. If core needle biopsy specimens or cell blocks are available, an immunohistochemical panel including CK7, CA IX, CD10, and AMACR may help in excluding congeners. This subtype of RCC requires differentiation from clear cell RCC and papillary RCC due to its low-grade indolent behavior. Cancer Cytopathol 2016. © 2016 American Cancer Society.

from Cancer via ola Kala on Inoreader http://ift.tt/2d3Ekz8
via IFTTT

Diagnosis of trichomoniasis in men by urine cytology

BACKGROUND

Trichomonas vaginalis is a rare finding in urine cytology specimens, especially those from men; only 2 case reports have been described in the literature. The authors of the current report sought to determine the incidence and clinical significance of this finding in urine cytology in males.

METHODS

The authors' cytopathology archives were queried for urine cytology specimens that contained Trichomonas over a 30-year period. Clinical information from men with Trichomonas-positive urines was reviewed retrospectively. Slides were reviewed, and the morphologic characteristics of the organisms were recorded.

RESULTS

Trichomonas was detected in 73 of 60,000 urine cytology specimens (0.1%). The patients included 45 women and 28 men. Men with Trichomonas in their urine ranged in age from 28 to 87 years (mean age, 67 years; median, 71 years). Trichomonas organisms were round to oval, with eccentric nuclei and cytoplasmic granules. Acute inflammation was observed in 6 of 7 cases. Clinical history was available in 13 of 28 men. Lower urinary tract symptoms were reported in 10 of 13 men, most commonly hematuria; and urethral strictures were identified by cystoscopy in 3 of 13 men. Clinical follow-up was available for 10 of 13 patients; of these, 8 (80%) had received treatment with metronidazole based on urine cytology results.

CONCLUSIONS

This study is the largest series of Trichomonas infection in men diagnosed by urine cytology in the literature. Most men had no prior diagnosis of trichomoniasis and received specific antibiotic therapy based on their urine cytology results. Urine cytology may represent the initial diagnostic test for Trichomonas in men, and accurate cytologic diagnosis may prevent undesired adverse outcomes for them and their partners. Cancer Cytopathol 2016. © 2016 American Cancer Society.

from Cancer via ola Kala on Inoreader http://ift.tt/2cCBe7e
via IFTTT

Cytology smears as excellent starting material for next-generation sequencing-based molecular testing of patients with adenocarcinoma of the lung

BACKGROUND

Molecular testing of lung adenocarcinomas (ADCs) is crucial for therapy stratification of patients. Because of the often limited diagnostic material, the authors aimed to explore the suitability of cytology smears for next-generation sequencing (NGS) and compared the results with concurrent histological specimens or cell blocks.

METHODS

A total of 16 formalin-fixed paraffin-embedded (FFPE) ADCs with known genetic alterations were used as the first cohort for targeted DNA and RNA sequencing. In the second cohort of 8 cases, 8 cytological smears were compared with matching histological specimens or cell blocks for the study. For NGS library amplification, commercially available panels for DNA and RNA sequencing were applied. The Ion Torrent Personal Genome Machine and the Ion Reporter workflow (version 5.0) were used for sequencing.

RESULTS

All DNA libraries derived from FFPE and non-formalin-fixed cytological smear samples produced acceptable quality metrics, thereby enabling successful targeted DNA sequencing (100% performance). Targeted RNA sequencing failed in 1 FFPE case and 1 cytology probe by not reaching enough mapped fusion reads (92% performance rate). All previously detected mutations and gene rearrangements could be confirmed (sensitivity of 100%), whereas specificity of the DNA-based NGS assay reached 96%.

CONCLUSIONS

The results of the current study demonstrated the suitability of non-formalin cytology specimens for the simultaneous NGS testing of lung ADCs using amplicon resequencing panels. These assays allowed for the input of cytological smears equal to concurrent histology or cell blocks and proved to be accurate in the detection of therapeutically actionable somatic mutations and gene rearrangements. Cancer Cytopathol 2016. © 2016 American Cancer Society.

from Cancer via ola Kala on Inoreader http://ift.tt/2d3DhiA
via IFTTT

2016 publication schedule

from Cancer via ola Kala on Inoreader http://ift.tt/2cCAhMe
via IFTTT

Test anxiety

from Cancer via ola Kala on Inoreader http://ift.tt/2d3DHWe
via IFTTT

Issue Information

from Cancer via ola Kala on Inoreader http://ift.tt/2cCB7sg
via IFTTT

Reduced expression of CXCR4, a novel renal cancer stem cell marker, is associated with high-grade renal cell carcinoma

Abstract

Purpose

Cancer stem cells (CSCs) represent a population with tumour-initiating, self-renewal, and differentiation potential. This study aimed to evaluate the expression patterns and clinical significance of chemokine receptor type 4 (CXCR4) as a novel CSC marker in renal cell carcinoma (RCC).

Methods

The expression of CXCR4 was examined in 173 well-defined renal tumour tissues, including 106 (61.5 %) clear cell renal cell carcinomas (ccRCCs), 35 (20 %) papillary renal cell carcinomas (pRCCs), and 32 (18.5 %) chromophobe renal cell carcinomas (ChRCCs), by immunohistochemistry on a tissue microarray. The association between expression of this marker and clinicopathologic parameters was then analysed.

Results

There was a significant difference in the expression levels of CXCR4 in the ccRCC samples compared to the ChRCC and pRCC samples (P < 0.001). Increased expression of CXCR4 was significantly correlated with higher-grade tumours (P < 0.001) and worse stage (P = 0.001). A significant association was also found between expression of CXCR4 and microvascular invasion (P = 0.018). Among RCC subtypes, comparison of the differences between CXCR4 expression in low- and high-grade tumours demonstrated that pRCC tumours had a significantly higher expression of CXCR4 (P < 0.001) than ccRCC tumours (P = 0.01).

Conclusion

Significantly higher expression levels of CXCR4 were found in pRCC and ccRCC samples. Increased CXCR4 expression was associated with more aggressive tumour behaviour in RCC patients, especially in pRCC and ccRCC subtypes due to their more metastatic behaviour. These findings suggest that CXCR4 can be considered as a novel diagnostic and therapeutic marker for targeted therapy of renal carcinoma.

from Cancer via ola Kala on Inoreader http://ift.tt/2cCmzc0
via IFTTT

Synergistic effect of fenretinide and curcumin for treatment of non-small cell lung cancer.

Synergistic effect of fenretinide and curcumin for treatment of non-small cell lung cancer.

Cancer Biol Ther. 2016 Aug 11;:1-8

Authors: Chen H, Chen L, Wang L, Zhou X, Chan JY, Li J, Cui G, Lee SM

Abstract
Curcumin and fenretinide are 2 well-known and promising chemotherapeutic compounds via various molecular mechanisms. However, the anticancer capacity of either curcumin or fenretinide is limited. This prompted us to examine the combined anticancer effects of curcumin and fenretinide. Our results demonstrate for the first time that there is synergistic anticancer effect of combined treatment with these 2 agents, leading to enhanced cytotoxicity and enhanced expression level of pro-apoptotic protein cleaved PARP in non-small cell lung cancer (NSCLC) cells while showed little toxicity to rat cardiomyoblast normal cells. The combination treatment was also demonstrated to inhibit lung carcinoma growth in vivo. Furthermore, we show that fenretinide or the ER stress inhibitor 4-PBA decreased curcumin-induced Glucose-regulated protein 78 (GRP78) upregulation, and produced a similar enhanced cytotoxic effect. In addition, GRP78 knockdown by siRNA also enhanced the cytotoxic effect of curcumin in A549 and H1299 cells. Our findings suggest that the 2 small molecules, when used in combination, can potentially be effective therapeutic agents for treating NSCLC, at least in part, by regulating endoplasmic reticulum (ER) chaperone protein GRP78.

PMID: 27628049 [PubMed - as supplied by publisher]

from Cancer via ola Kala on Inoreader http://ift.tt/2d5dEkv
via IFTTT

Synergistic effect of fenretinide and curcumin for treatment of non-small cell lung cancer.

Synergistic effect of fenretinide and curcumin for treatment of non-small cell lung cancer.

Cancer Biol Ther. 2016 Aug 11;:1-8

Authors: Chen H, Chen L, Wang L, Zhou X, Chan JY, Li J, Cui G, Lee SM

Abstract
Curcumin and fenretinide are 2 well-known and promising chemotherapeutic compounds via various molecular mechanisms. However, the anticancer capacity of either curcumin or fenretinide is limited. This prompted us to examine the combined anticancer effects of curcumin and fenretinide. Our results demonstrate for the first time that there is synergistic anticancer effect of combined treatment with these 2 agents, leading to enhanced cytotoxicity and enhanced expression level of pro-apoptotic protein cleaved PARP in non-small cell lung cancer (NSCLC) cells while showed little toxicity to rat cardiomyoblast normal cells. The combination treatment was also demonstrated to inhibit lung carcinoma growth in vivo. Furthermore, we show that fenretinide or the ER stress inhibitor 4-PBA decreased curcumin-induced Glucose-regulated protein 78 (GRP78) upregulation, and produced a similar enhanced cytotoxic effect. In addition, GRP78 knockdown by siRNA also enhanced the cytotoxic effect of curcumin in A549 and H1299 cells. Our findings suggest that the 2 small molecules, when used in combination, can potentially be effective therapeutic agents for treating NSCLC, at least in part, by regulating endoplasmic reticulum (ER) chaperone protein GRP78.

PMID: 27628049 [PubMed - as supplied by publisher]

from Cancer via ola Kala on Inoreader http://ift.tt/2d5dEkv
via IFTTT

Why did Danish women’s life expectancy stagnate? The influence of interwar generations’ smoking behaviour

Abstract

The general health status of a population changes over time, generally in a positive direction. Some generations experience more unfavourable conditions than others. The health of Danish women in the interwar generations is an example of such a phenomenon. The stagnation in their life expectancy between 1977 and 1995 is thought to be related to their smoking behaviour. So far, no study has measured the absolute effect of smoking on the mortality of the interwar generations of Danish women and thus the stagnation in Danish women's life expectancy. We applied a method to estimate age-specific smoking-attributable number of deaths to examine the effect of smoking on the trends in partial life expectancy of Danish women between age 50 and 85 from 1950 to 2012. We compared these trends to those for women in Sweden, where there was no similar stagnation in life expectancy. When smoking-attributable mortality was excluded, the gap in partial life expectancy at age 50 between Swedish and Danish women diminished substantially. The effect was most pronounced in the interwar generations. The major reason for the stagnation in Danish women's partial life expectancy at age 50 was found to be smoking-related mortality in the interwar generations.

from Cancer via ola Kala on Inoreader http://ift.tt/2cCdyQa
via IFTTT

Synergistic effect of fenretinide and curcumin for treatment of non-small cell lung cancer.

Synergistic effect of fenretinide and curcumin for treatment of non-small cell lung cancer.

Cancer Biol Ther. 2016 Aug 11;:1-8

Authors: Chen H, Chen L, Wang L, Zhou X, Chan JY, Li J, Cui G, Lee SM

Abstract
Curcumin and fenretinide are 2 well-known and promising chemotherapeutic compounds via various molecular mechanisms. However, the anticancer capacity of either curcumin or fenretinide is limited. This prompted us to examine the combined anticancer effects of curcumin and fenretinide. Our results demonstrate for the first time that there is synergistic anticancer effect of combined treatment with these 2 agents, leading to enhanced cytotoxicity and enhanced expression level of pro-apoptotic protein cleaved PARP in non-small cell lung cancer (NSCLC) cells while showed little toxicity to rat cardiomyoblast normal cells. The combination treatment was also demonstrated to inhibit lung carcinoma growth in vivo. Furthermore, we show that fenretinide or the ER stress inhibitor 4-PBA decreased curcumin-induced Glucose-regulated protein 78 (GRP78) upregulation, and produced a similar enhanced cytotoxic effect. In addition, GRP78 knockdown by siRNA also enhanced the cytotoxic effect of curcumin in A549 and H1299 cells. Our findings suggest that the 2 small molecules, when used in combination, can potentially be effective therapeutic agents for treating NSCLC, at least in part, by regulating endoplasmic reticulum (ER) chaperone protein GRP78.

PMID: 27628049 [PubMed - as supplied by publisher]

from Cancer via ola Kala on Inoreader http://ift.tt/2d5dEkv
via IFTTT

Recent Progress in Mutation-driven Therapy, Immunotherapy and Combination Therapy for the Treatment of Melanoma.

Recent Progress in Mutation-driven Therapy, Immunotherapy and Combination Therapy for the Treatment of Melanoma.

Curr Cancer Drug Targets. 2016 Jul 19;

Authors: Assi HI, Assi R

Abstract
With increases in our understanding of the human genome and immune system, the treatment armamentarium for melanoma has benefitted from the development and approval of BRAF inhibitors, MEK inhibitors, immune checkpoint modulators via cytotoxic T-lymphocyte antigen-4 blockade, and PD-1 and PD-L1 inhibitors. These advances, however, have raised questions about combination therapy, the optimal sequential use of these agents, the limited assessment of response using traditional metrics, and the optimal selection of the population to be treated. In this review we summarize recent breakthroughs and then itemize the development of newer agents, potential prognostic and predictive biomarkers, resistance mechanisms, and strategies of combination therapy. We also emphasize the multifaceted attributes of immunotherapy in terms of durable responses and long-term survival that paradoxically necessitate further research into the underlying mechanisms and longer patient follow-up.

PMID: 27628745 [PubMed - as supplied by publisher]

from Cancer via ola Kala on Inoreader http://ift.tt/2cBjaZe
via IFTTT

LRIGs: A Prognostically Significant Family with Emerging Therapeutic Competence against Cancers.

LRIGs: A Prognostically Significant Family with Emerging Therapeutic Competence against Cancers.

Curr Cancer Drug Targets. 2016 Sep 7;

Authors: Malik U, Javed A

Abstract
The human leucine-rich repeats and immunoglobulin like domains (LRIG) are evolutionary conserved family of single-pass transmembrane proteins. LRIG gene family includes three members, LRIG1 (formerly LIG1), LRIG2 and LRIG3, all of which are differentially expressed in human tissues and have long been proposed to be tumor suppressors. However, recently accumulated evidence on LRIG protein expression in human cancer appears to be inconsistent with this belief, as LRIG proteins have been found to be upregulated in certain tumors. Moreover, LRIG3 has been shown to act in an opposite manner to LRIG1 and LRIG1, in turn, has been shown to attenuate LRIG3 activity by its proteolytic degradation. These remarkable observations underline and reveal the previously unappreciated complexity of LRIG family dynamics. In the current review, the role of LRIG proteins in various human cancers is summarized and their differential regulation and expression is brought to light in order to understand how these proteins are involved in the genesis and progression of human cancers. Moreover, this is the first compilation that highlights the therapeutic potential of LRIG1 and suggests the same to be undertaken for LRIG2 and LRIG3. By virtue of their potential in prognosis of several cancer types, as well as their role as probable therapeutic proteins or in enhancing the receptiveness of the cancer cells to anti-tumor agents, it is strongly proposed that LRIG analysis should be undertaken and consequently be employed as a part of potential cancer treatment strategies.

PMID: 27628597 [PubMed - as supplied by publisher]

from Cancer via ola Kala on Inoreader http://ift.tt/2cOvEAd
via IFTTT

Optimization of hybrid iterative reconstruction level and evaluation of image quality and radiation dose for pediatric cardiac computed tomography angiography

Abstract

Background

Hybrid iterative reconstruction can reduce image noise and produce better image quality compared with filtered back-projection (FBP), but few reports describe optimization of the iteration level.

Objective

We optimized the iteration level of iDose⁴ and evaluated image quality for pediatric cardiac CT angiography.

Materials and methods

Children (n = 160) with congenital heart disease were enrolled and divided into full-dose (n = 84) and half-dose (n = 76) groups. Four series were reconstructed using FBP, and iDose⁴ levels 2, 4 and 6; we evaluated subjective quality of the series using a 5-grade scale and compared the series using a Kruskal-Wallis H test. For FBP and iDose⁴-optimal images, we compared contrast-to-noise ratios (CNR) and size-specific dose estimates (SSDE) using a Student's t-test. We also compared diagnostic-accuracy of each group using a Kruskal-Wallis H test.

Results

Mean scores for iDose⁴ level 4 were the best in both dose groups (all P < 0.05). CNR was improved in both groups with iDose⁴ level 4 as compared with FBP. Mean decrease in SSDE was 53% in the half-dose group. Diagnostic accuracy for the four datasets were in the range 92.6–96.2% (no statistical difference).

Conclusion

iDose⁴ level 4 was optimal for both the full- and half-dose groups. Protocols with iDose⁴ level 4 allowed 53% reduction in SSDE without significantly affecting image quality and diagnostic accuracy.

from Cancer via ola Kala on Inoreader http://ift.tt/2cB6sda
via IFTTT

Apoptotic effect of the selective PPARβ/δ agonist GW501516 in invasive bladder cancer cells

Abstract

GW501516 is a selective and high-affinity synthetic agonist of peroxisome proliferator-activated receptor β/δ (PPARβ/δ). This molecule promoted the inhibition of proliferation and apoptosis in few cancer cell lines, but its anticancer action has never been investigated in bladder tumor cells. Thus, this study was undertaken to determine whether GW501516 had antiproliferative and/or apoptotic effects on RT4 and T24 urothelial cancer cells and to explore the molecular mechanisms involved. Our results indicated that, in RT4 cells (derived from a low-grade papillary tumor), GW501516 did not induce cell death. On the other hand, in T24 cells (derived from an undifferentiated high-grade carcinoma), this PPARβ/δ agonist induced cytotoxic effects including cell morphological changes, a decrease of cell viability, a G2/M cell cycle arrest, and the cell death as evidenced by the increase of the sub-G1 cell population. Furthermore, GW501516 triggered T24 cell apoptosis in a caspase-dependent manner including both extrinsic and intrinsic apoptotic pathways through Bid cleavage. In addition, the drug led to an increase of the Bax/Bcl-2 ratio, a mitochondrial dysfunction associated with the dissipation of ΔΨm, and the release of cytochrome c from the mitochondria to the cytosol. GW501516 induced also ROS generation which was not responsible for T24 cell death since NAC did not rescue cells upon PPARβ/δ agonist exposure. For the first time, our data highlight the capacity of GW501516 to induce apoptosis in invasive bladder cancer cells. This molecule could be relevant as a therapeutic drug for high-grade urothelial cancers.

from Cancer via ola Kala on Inoreader http://ift.tt/2ciMchm
via IFTTT

Starving cancer from the outside and inside: separate and combined effects of calorie restriction and autophagy inhibition on Ras-driven tumors

Abstract

Background

Calorie restriction (CR) prevents obesity and exerts anticancer effects in many preclinical models. CR is also increasingly being used in cancer patients as a sensitizing strategy prior to chemotherapy regimens. While the beneficial effects of CR are widely accepted, the mechanisms through which CR affects tumor growth are incompletely understood. In many cell types, CR and other nutrient stressors can induce autophagy, which provides energy and metabolic substrates critical for cancer cell survival. We hypothesized that limiting extracellular and intracellular substrate availability by combining CR with autophagy inhibition would reduce tumor growth more effectively than either treatment alone.

Results

A 30 % CR diet, relative to control diet, in nude mice resulted in significant decreases in body fat, blood glucose, and serum insulin, insulin-like growth factor-1, and leptin levels concurrent with increased adiponectin levels. In a xenograft model in nude mice involving H-Ras^G12V-transformed immortal baby mouse kidney epithelial cells with (Atg5 ^+/+ ) and without (Atg5 ^−/−) autophagic capacity, the CR diet (relative to control diet) genetically induced autophagy inhibition and their combination, each reduced tumor development and growth. Final tumor volume was greatest for Atg5 ^+/+ tumors in control-fed mice, intermediate for Atg5 ^+/+ tumors in CR-fed mice and Atg5 ^−/− tumors in control-fed mice, and lowest for Atg5 ^−/− tumors in CR mice. In Atg5 ^+/+ tumors, autophagic flux was increased in CR-fed relative to control-fed mice, suggesting that the prosurvival effects of autophagy induction may mitigate the tumor suppressive effects of CR. Metabolomic analyses of CR-fed, relative to control-fed, nude mice showed significant decreases in circulating glucose and amino acids and significant increases in ketones, indicating CR induced negative energy balance. Combining glucose deprivation with autophagy deficiency in Atg5 ^−/− cells resulted in significantly reduced in vitro colony formation relative to glucose deprivation or autophagy deficiency alone.

Conclusions

Combined restriction of extracellular (via CR in vivo or glucose deprivation in vitro) and intracellular (via autophagy inhibition) sources of energy and nutrients suppresses Ras-driven tumor growth more effectively than either CR or autophagy deficiency alone. Interventions targeting both systemic energy balance and tumor-cell intrinsic autophagy may represent a novel and effective anticancer strategy.

from Cancer via ola Kala on Inoreader http://ift.tt/2cvC58Q
via IFTTT

Preoperative radiation therapy combined with radical surgical resection is associated with a lower rate of local recurrence when treating unifocal, primary retroperitoneal liposarcoma

Background and Objectives

Local recurrence (LR) is the primary cause of death in patients with retroperitoneal liposarcoma (RP-LPS). The purpose of this study was to evaluate if the addition of preoperative radiation therapy (XRT) to radical resection for RP-LPS at a single institution was associated with improved LR.

Methods

This retrospective analysis included patients with unifocal, primary RP-LPS who underwent complete R0/R1 resection at a single institution between 1991 and 2013. Multiple patient, tumor, and surgeon characteristics were tested to evaluate their association to LR (recurrence in the retroperitoneal space). We used competing risk hazards regression to evaluate the effect of preoperative XRT on the probability of LR.

Results

There were 41 patients with liposarcoma histology whose tumors included entirely well-differentiated (N = 13), de-differentiated components (n = 26), myxoid (n = 1), and NOS (n = 1). Preoperative XRT was significantly associated with a lower probability of LR (HR 0.11, 95%CI 0.01–0.91, P = 0.04) and a higher 5-year local recurrence-free survival (95.6%, 95%CI 72.4–99.4%, vs. 75.0%, 95%CI 40.8–91.2%; P = 0.0213), but not with 5-year distant recurrence-free survival or disease-specific survival.

Conclusions

Preoperative XRT combined with complete R0/R1 resection for unifocal, primary RP-LPS was associated with improved LR and it should be considered in the multimodality treatment of RP-LPS. J. Surg. Oncol. © 2016 Wiley Periodicals, Inc.

from Cancer via ola Kala on Inoreader http://ift.tt/2ciwG5b
via IFTTT

Anterior approach to improve the long-term outcome in patients with large-size hepatocellular carcinoma having liver resection

Background and Objective

A prospective study was conducted to investigate the effect of anterior approach for hepatectomy on long-term outcome of HCC patients with different tumor size.

Methods

Long-term outcomes were investigated between patients with different tumor size underwent liver resection by either anterior or conventional approach (i.e., AA or CA group).

Results

The recurrence rate in AA group was much lower than that in CA group (52.4% vs.73.1%, P = 0.001). The survival rate in AA group was much higher than that in CA group (60.0% vs. 38.0%, P < 0.001). Furthermore, the differences in recurrence and survival rates in patients with large-size tumor (>5 cm) between AA and CA groups were significant (80.0% vs. 54.7%, P = 0.002; 25.0% vs. 54.2%, P = 0.001, respectively), whereas the differences in tumor recurrence and survival rates in patients with small-size tumor between the two groups (≤5 cm) were not significant (64.6% vs. 50.0%, P = 0.141; 56.3% vs. 65.4%, P = 0.349, respectively). Multivariate analysis found that convention approach for hepatectomy was one of the independent risk factors for HCC recurrence and poor survival.

Conclusions

Prognosis of patients with large-size HCC tumor with the anterior approach was superior to that with the conventional approach. Large-size tumor (>5 cm) could be the clinical indicator for anterior approach for hepatectomy. J. Surg. Oncol. © 2016 Wiley Periodicals, Inc.

from Cancer via ola Kala on Inoreader http://ift.tt/2cD8hoq
via IFTTT

Association between age and overall survival of patients with hepatocellular carcinoma after hepatic resection

Aim

The suitability of hepatic resection for older patients remains controversial. This study aimed to investigate whether age influences overall survival of patients with hepatocellular carcinoma (HCC) after resection.

Methods

Records of 1,132 patients with HCC after hepatic resection were retrospectively reviewed. Overall survival (OS) was compared between younger and older patients based on five cut-off ages (30, 40, 50, 60, and 70 years).

Results

Across all patients, OS was 89.7% at 1 year, 67.7% at 3 years, and 47.7% at 5 years. OS was similar between younger and older patients at all cut-off ages (all P > 0.1), but OS was marginally lower among patients >70 years old than those ≤70 (P = 0.090). Multivariate analyses identified several risk factors for lower OS: preoperative serum albumin <35 g/L, alanine aminotransferase >80 U/L, α-fetoprotein ≥400 ng/ml, presence of esophagogastric varices or macrovascular invasion, incomplete/absent tumor capsule, tumor size >10 cm, tumor number ≥3, and major hepatectomy.

Conclusion

Age does not influence the prognosis of patients with HCC after hepatic resection. Older patients should be considered for curative resection if remnant liver volume and liver function are adequate. J. Surg. Oncol. © 2016 Wiley Periodicals, Inc.

from Cancer via ola Kala on Inoreader http://ift.tt/2civw9K
via IFTTT

Actual 10-year survivors following resection of adrenocortical carcinoma

Background

Adrenocortical carcinoma (ACC) is a rare and aggressive malignancy with limited therapeutic options beyond surgical resection. The characteristics of actual long-term survivors following surgical resection for ACC have not been previously reported.

Method

Patients who underwent resection for ACC at one of 13 academic institutions participating in the US Adrenocortical Carcinoma Group from 1993 to 2014 were analyzed. Patients were stratified into four groups: early mortality (died within 2 years), late mortality (died within 2–5 years), actual 5-year survivor (survived at least 5 years), and actual 10-year survivor (survived at least 10 years). Patients with less than 5 years of follow-up were excluded.

Results

Among the 180 patients available for analysis, there were 49 actual 5-year survivors (27%) and 12 actual 10-year survivors (7%). Patients who experienced early mortality had higher rates of cortisol-secreting tumors, nodal metastasis, synchronous distant metastasis, and R1 or R2 resections (all P < 0.05). The need for multi-visceral resection, perioperative blood transfusion, and adjuvant therapy correlated with early mortality. However, nodal involvement, distant metastasis, and R1 resection did not preclude patients from becoming actual 10-year survivors. Ten of twelve actual 10-year survivors were women, and of the seven 10-year survivors who experienced disease recurrence, five had undergone repeat surgery to resect the recurrence.

Conclusion

Surgery for ACC can offer a 1 in 4 chance of actual 5-year survival and a 1 in 15 chance of actual 10-year survival. Long-term survival was often achieved with repeat resection for local or distant recurrence, further underscoring the important role of surgery in managing patients with ACC. J. Surg. Oncol. © 2016 Wiley Periodicals, Inc.

from Cancer via ola Kala on Inoreader http://ift.tt/2cD8yrl
via IFTTT

Pulmonary fissure development is a prognostic factor for patients with resected stage I lung adenocarcinoma

Background

Pulmonary fissure differs among patients, but the relationship between pulmonary fissure development and survival in patients with resected lung adenocarcinoma has not been evaluated. In this study, we analyzed the effect of fissure development on prognosis in patients with stage I lung adenocarcinoma.

Methods

From January 2009 to December 2012, data, including pulmonary fissure development, were collected prospectively for all lung cancer, and this was a retrospective study of prospectively collected data. In total, 297 patients who had undergone a lobectomy and had pathologic stage I adenocarcinoma were analyzed. Patients were categorized into two groups based on fissure sum average (FSA) fissure development scores. Group A patients ranged from complete to 30% incomplete (0 ≤ FSA ≤ 1) while in Group B patients development was more than 30% incomplete (1 < FSA ≤ 3).

Results

In univariate analysis, Group B had poorer overall 5 year survival than did Group A (83.1% vs. 96.5%, P = 0.015). Multivariate analysis revealed that the level of fissure development was a significant prognostic factor for overall survival (HR = 3.905, CI = 1.168–13.057, P = 0.027).

Conclusions

The overall survival of patients with resected stage I adenocarcinoma was adversely affected by incomplete fissure development. J. Surg. Oncol. © 2016 Wiley Periodicals, Inc.

from Cancer via ola Kala on Inoreader http://ift.tt/2ciwmTU
via IFTTT

Frozen section analysis of SLNs in trunk and extremity melanoma has a high false negative rate but can spare some patients a second operation

Objectives

The purpose of this study was to evaluate the accuracy of frozen section (FS) analysis of sentinel lymph nodes (SLN) in melanoma.

Methods

Five hundred seventy-one patients underwent FS analysis of SLN between 1/2000 and12/2010. Surgical and pathological characteristics, recurrence, and survival were analyzed. Comparisons were made using χ² and Fisher's exact t-test.

Results

One hundred thirty-three (23%) patients were SLN positive of which 63 (47.4%) were identified on FS. 16/70 SLN metastases not identified on FS (23%) were seen only on immunohistochemistry. FS analysis detected 84% of SLN metastasis >2 mm. SLN FS false negative rate was 53%, positive predictive value 100%, negative predictive value 88%, and overall accuracy 89%. Among patients with a FS positive SLN, 17/63 (27%) had additional positive nodes on CLND, versus 1 of 70 (1.4%) with a positive SLN identified only on permanent section pathology (P < 0.0001). The nodal recurrence rate following a negative SLN biopsy was 5%.

Conclusions

FS analysis for SLNs spared approximately half of patients a second operation. Patients with a positive SLN detected on FS were more likely to have further nodal involvement. In our experience intraoperative pathologic analysis of melanoma SLNs does not impair our ability to detect SLN metastasis or lead to a high rate of false positive results or nodal recurrences. J. Surg. Oncol. © 2016 Wiley Periodicals, Inc.

from Cancer via ola Kala on Inoreader http://ift.tt/2cD7Zhn
via IFTTT

Advantages of day-before lymphoscintigraphy and undiluted methylene blue dye injections for sentinel lymph node biopsies for melanoma

Background and Objectives

Lymphatic mapping (LM) and blue dye injections are essential to identification of sentinel lymph nodes (SLN) for melanoma. LM is performed the day before (DB) or the same day (SD) of surgery, but the optimal timing is unknown. Similarly, methylene blue (MB), used during SLN biopsy (SLNB), is administered diluted (dMB) or undiluted (uMB), but the relative efficacies are unknown.

Methods

Patients who underwent SLNB for melanoma from 2009 to 2013 at our institution were evaluated. Outcomes included operative correlation with LM, SLN identification, and postoperative complications.

Results

One hundred seventy-one patients underwent SLNB. Sixty-seven (39%) had DB LM. Sixty-seven (39%) received uMB. Operative findings correlated with both LM groups, though the DB patients had lower background count (P = 0.018) and lower highest SLN radioactive signal count (P = 0.046). More uMB patients had blue SLNs (90% vs. 68%, P = 0.001). There was no difference in the total number of SLNs or complication rates in the LM and MB groups.

Conclusions

This is the first study to compare the use of DB LM with SD LM and the efficacy of uMB versus dMB. DB LM and uMB offer advantageous alternatives for patients and their surgeons without loss of accuracy or increased morbidity. J. Surg. Oncol. © 2016 Wiley Periodicals, Inc.

from Cancer via ola Kala on Inoreader http://ift.tt/2ciw7IK
via IFTTT

The impact of bowel preparation on the severity of anastomotic leak in colon cancer patients

Background and Objectives

The routine use of preoperative bowel preparation (BP) is heavily debated in the colorectal surgery literature. To date, no study has investigated the effect preoperative BP has on patients with an established anastomotic leak. We therefore seek to compare the severity of patient morbidity and mortality in patients with a known anastomotic leak based on type of preoperative BP using the Targeted Colectomy American College of Surgeons National Surgery Quality Improvement Program (ACS-NSQIP).

Methods

All elective colon cancer operations performed with primary anastomosis were identified within the targeted colectomy database from 2012 to 2013. Patients who experienced a postoperative anastomotic leak were identified and stratified based on preoperative BP. Variables that had an association with mechanical BP at P < 0.10 were included in a multivariate logistic regression model to determine if BP was independently associated with postoperative morbidity and mortality.

Results

A total of 6,297 patients underwent elective colon resection with primary anastomosis for colon cancer. Two hundred and nineteen (3.5%) patients experienced an anastomotic leak. Thirty-day wound morbidity and mortality was not worse in patients who underwent preoperative BP.

Conclusions

BP is not associated with worse patients outcomes in those patients with an established anastomotic leak following elective colon research with primary anastomosis. J. Surg. Oncol. © 2016 Wiley Periodicals, Inc.

from Cancer via ola Kala on Inoreader http://ift.tt/2cD858y
via IFTTT

A nomogram predicting contralateral central neck lymph node metastasis for papillary thyroid carcinoma

Background and Objectives

Central compartment neck dissection (CCND) is recommended for patients with papillary thyroid carcinoma (PTC). However, whether to perform contralateral CCND remains unclear. An individualized estimation of the contralateral central neck metastasis (CNM) risk would assist in the tailoring of treatment for PTC patients.

Methods

Consecutive patients who underwent bilateral CCND for unilateral PTC between 2012 and 2014 in a tertiary center were identified. The clinicopathological data of 142 patients were analyzed retrospectively. The variables that had clinical significance in the final multivariate logistic regression model were built into a nomogram to assess the risk of metastasis of the contralateral central compartment. This model was internally validated using bootstrap resampling.

Results

This nomogram demonstrated good calibration and discrimination, with a concordance index of 0.834 (bootstrap corrected, 0.824). The variables with the greatest influence on the risk of contralateral CNM in this model included tumor size, the number of positive lymph nodes, and extranodal extension in the ipsilateral central neck.

Conclusions

This nomogram integrates three variables to estimate an individualized risk of contralateral CNM in unilateral PTC patients. This model may assist in individual decision-making regarding contralateral CCND and help avoid the over- and under-treatment of PTC. J. Surg. Oncol. © 2016 Wiley Periodicals, Inc.

from Cancer via ola Kala on Inoreader http://ift.tt/2csM4yV
via IFTTT

Health-related quality of life following treatment for extremity soft tissue sarcoma

Background and Objectives

The primary objective of this study was to estimate the change in health-related quality of life (HRQL) 1 year following treatment for extremity soft tissue sarcoma (STS), measured by the EQ-5D. Secondary objectives included determining clinical variables associated with HRQL at 1 year, estimating the proportion with a clinically important difference (CID) in HRQL, and evaluating variability within EQ-5D domains.

Methods

Patients over the age of 16 years, treated for a localized extremity STS, were included. The EQ-5D change score from pre-treatment to 1-year follow-up was determined. The association of clinical variables with EQ-5D scores was estimated using a linear regression model. The proportion of patients with a CID in HRQL score was determined. A vector analysis of the EQ-5D domains was undertaken.

Results

The mean EQ-5D change score was 0.02. Age, sex, disease status, and initial EQ-5D score were associated with EQ-5D score at 1 year. There was a CID improvement in 32% and a deterioration in 24%. The anxiety and depression domain demonstrated the most change between baseline and 1 year after treatment.

Conclusion

Most patients maintain a high level of HRQL following treatment for extremity STS. J. Surg. Oncol. © 2016 Wiley Periodicals, Inc.

from Cancer via ola Kala on Inoreader http://ift.tt/2civCyk
via IFTTT