Prox1-GFP/Flt1-DsRed transgenic mice: an animal model for simultaneous live imaging of angiogenesis and lymphangiogenesis

Abstract

The roles of angiogenesis in development, health, and disease have been studied extensively; however, the studies related to lymphatic system are limited due to the difficulty in observing colorless lymphatic vessels. But recently, with the improved technique, the relative importance of the lymphatic system is just being revealed. We bred transgenic mice in which lymphatic endothelial cells express GFP (Prox1-GFP) with mice in which vascular endothelial cells express DsRed (Flt1-DsRed) to generate Prox1-GFP/Flt1-DsRed (PGFD) mice. The inherent fluorescence of blood and lymphatic vessels allows for direct visualization of blood and lymphatic vessels in various organs via confocal and two-photon microscopy and the formation, branching, and regression of both vessel types in the same live mouse cornea throughout an experimental time course. PGFD mice were bred with CDh5CreERT2 and VEGFR2lox knockout mice to examine specific knockouts. These studies showed a novel role for vascular endothelial cell VEGFR2 in regulating VEGFC-induced corneal lymphangiogenesis. Conditional deletion of vascular endothelial VEGFR2 abolished VEGFA- and VEGFC-induced corneal lymphangiogenesis. These results demonstrate the potential use of the PGFD mouse as a powerful animal model for studying angiogenesis and lymphangiogenesis.

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Issue Information

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Cost-effectiveness analysis of potentially curative and combination treatments for hepatocellular carcinoma with person-level data in a Canadian setting

Abstract

Patients with early-stage hepatocellular carcinoma (HCC) are potential candidates for curative treatments such as radiofrequency ablation (RFA), surgical resection (SR), or liver transplantation (LT), which have demonstrated a significant survival benefit. We aimed to estimate the cost-effectiveness of curative and combination treatment strategies among patients diagnosed with HCC during 2002–2010. This study used Ontario Cancer Registry-linked administrative data to estimate effectiveness and costs (2013 USD) of the treatment strategies from the healthcare payer's perspective. Multiple imputation by logistic regression was used to handle missing data. A net benefit regression approach of baseline important covariates and propensity score adjustment were used to calculate incremental net benefit to generate incremental cost-effectiveness ratio (ICER) and uncertainty measures. Among 2,222 patients diagnosed with HCC, 10.5%, 14.1%, and 10.3% received RFA, SR, and LT monotherapy, respectively; 0.5–3.1% dual treatments; and 0.5% triple treatments. Compared with no treatment (53.2%), transarterial chemoembolization (TACE) + RFA (average $2,465, 95% CI: −$20,000–$36,600/quality-adjusted life years [QALY]) or RFA monotherapy ($15,553, 95% CI: $3,500–$28,500/QALY) appears to be the most cost-effective modality with lowest ICER value. The cost-effectiveness acceptability curve showed that if the relevant threshold was $50,000/QALY, RFA monotherapy and TACE+ RFA would have a cost-effectiveness probability of 100%. Strategies using LT delivered the most additional QALYs and became cost-effective at a threshold of $77,000/QALY. Our findings found that TACE+ RFA dual treatment or RFA monotherapy appears to be the most cost-effective curative treatment for patients with potential early stage of HCC in Ontario. These findings highlight the importance of identifying and measuring differential benefits, costs, and cost-effectiveness of alternative HCC curative treatments in order to evaluate whether they are providing good value for money in the real world.

The aim of this article was to estimate the cost-effectiveness of mutually exclusive potentially curative monotherapies such as radiofrequency ablation (RFA), surgical resection (SR), or liver transplantation (LT) and combination therapies with palliative treatment (transarterial chemoembolization, TACE) among patients diagnosed with hepatocellular carcinoma (HCC) during 2002–2010. Compared with no treatment, TACE plus RFA (average $2,465, 95% CI: −$20,000–$36,600/quality-adjusted life years [QALY]) or RFA monotherapy ($15,553, 95% CI: $3,500–$28,500/QALY) appears to be the most cost-effective modality with lowest incremental cost-effectiveness ratio (ICER) value. Our findings found that TACE plus RFA dual treatment or RFA monotherapy appears to be the most cost-effective curative treatment for patients with potential early stage of HCC in Ontario, which may potentially provide good value for money in the real world within the context of an organized healthcare system.

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Health-Related Quality of Life in Individuals with Down Syndrome: Results from a Non-Interventional Longitudinal Multi-National Study

Abstract

Introduction

To date, there is little research on health-related quality of life (HRQoL) in Down syndrome (DS), and existing research is variable with regard to reported HRQoL in DS. There are also no HRQoL measures developed specifically to be used with individuals with Down syndrome.

Methods

A multi-national, longitudinal, 24-week non-interventional study was conducted in adolescents and adults with DS. HRQoL was assessed (n = 90) using the parent-report KIDSCREEN-27 questionnaire.

Results

HRQoL domain scores were found to be similar to those in the KIDSCREEN-27 European normative group data set on the Physical Well-being, Psychological Well-being, Autonomy and Parent Relations domains. Compared with the normative data set, the adolescent participants with DS in the current study were found to have lower scores on the Social Support and Peers domain and higher scores than the normative group on the School Environment domain. The test-retest reliability of the KIDSCREEN-27 was also examined using the intraclass correlation coefficient (ICC) in a subgroup of stable participants. The KIDSCREEN-27 demonstrated poor-to-moderate test-retest reliability; however, test-retest reliability was assessed using a long time interval between assessment time points.

Conclusion

The findings of this study underline that further research is needed to better understand the nature of HRQoL in DS. Further research using a shorter time interval between assessment time points to examine test-retest reliability is also required.

Funding

F. Hoffmann-La Roche Ltd.

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The Patterns of Non-vitamin K Antagonist Oral Anticoagulants (NOACs) Use in Patients with Atrial Fibrillation in Seven Balkan Countries: a Report from the BALKAN-AF Survey

Abstract

Introduction

Data on management of atrial fibrillation (AF) in the Balkan Region are scarce. To capture the patterns in AF management in contemporary clinical practice in the Balkan countries a prospective survey was conducted between December 2014 and February 2015, and we report results pertinent to the use of non-vitamin K antagonist oral anticoagulants (NOACs).

Methods

A 14-week prospective, multicenter survey of consecutive AF patients seen by cardiologists or internal medicine specialists was conducted in Albania, Bosnia and Herzegovina, Bulgaria, Croatia, Montenegro, Romania, and Serbia (a total of about 50 million inhabitants).

Results

Of 2712 enrolled patients, 2663 (98.2%) had complete data relevant to oral anticoagulant (OAC) use (mean age 69.1 ± 10.9 years, female 44.6%). Overall, OAC was used in 1960 patients (73.6%) of whom 338 (17.2%) received NOACs. Malignancy [odds ratio (OR), 95% confidence interval (CI) 2.06, 1.20–3.56], rhythm control (OR 1.64, 1.25–2.16), and treatment by cardiologists were independent predictors of NOAC use (OR 2.32, 1.51–3.54) [all p < 0.01)], whilst heart failure and valvular disease were negatively associated with NOAC use (both p < 0.01). Individual stroke and bleeding risk were not significantly associated with NOAC use on multivariate analysis.

Conclusions

NOACs are increasingly used in AF patients in the Balkan Region, but NOAC use is predominantly guided by factors other than evidence-based decision-making (e.g., drug availability on the market or reimbursement policy). Efforts are needed to establish an evidence-based approach to OAC selection and to facilitate the optimal use of OAC, thus improving the outcomes in AF patients in this large region.

http://ift.tt/2vlb5kv

Prognostic Implications of miR-302a/b/c/d in Human Gastric Cancer

Abstract

Background: The microRNA (miR)-302 family consisting four members, miR-302a, miR-302b, miR-302c and miR-302d, plays an important role in diverse biological processes, and regulates many pathological changes, including cancer. However, the involvement of the miR-302 family into human gastric cancer (GC) remains unclear. The aim of this study was to investigate the expression patterns of miR-302a/b/c/d and determine their clinical significance in GC. Materials and methods: Expression levels of miR-302a/b/c/d in 160 pairs of human GC and matched normal mucosa tissues were detected by quantitative real-time polymerase chain reaction. Then, the associations of miR-302a/b/c/d expression with various clinicopathological characteristics and patients' prognosis were statistically evaluated. Results: The expression levels of miR-302a, miR-302b and miR-302c in GC tissues were all significantly lower than those in matched normal mucosa (all P < 0.001), but miR-302d expression had no significant differences between cancer and normal groups. Additionally, GC patients with low miR-302a, miR-302b and miR-302c expression more frequently had positive lymph node metastasis (all P < 0.05), advanced TNM stage (all P < 0.05) and great depth of invasion (all P < 0.05). More importantly, low miR-302a, miR-302b and miR-302c expression in GC tissues were significantly associated with shorter disease-free and overall survivals of GC patients (all P < 0.05). Further multivariate analysis identified miR-302a, miR-302b and miR-302c as independent prognostic markers for GC patients. Conclusions: GC patients with the decreased expression of miR-302a, miR-302b and miR-302c may had aggressive cancer progression and unfavorable prognosis. Further rigorous validation based on a large cohort of clinical cases should be performed.

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Protein Intake in Chronic Kidney Disease

Abstract

Purpose of Review

The purpose of this review is to better understand the protein needs in patients with chronic kidney disease (CKD) not on dialysis. Protein energy wasting is common in patients with chronic kidney disease, and the incidence increases as the kidney function declines. Typically, protein intake in patients with CKD is lower than the daily-recommended allowance for healthy adults, and that poor nutritional status has been associated with increase in morbidity and mortality. It is of interest to note that the current guidelines for protein intake vary in terms of both quantity as well as the quality, thus making it confusing for the practicing nephrologist.

Recent Findings

Recent studies show that very low protein intake when supplemented by keto-analogues of essential amino acid could be helpful in slowing the progression of chronic kidney disease. However, it is important to understand that recommending low protein intake could be harmful in CKD patients especially those with poor nutritional status or during an acute illness.

Summary

In summary, it is important for the physician to understand that patients with chronic kidney disease have very complex nutritional requirements, and that recommendations for protein intake should be based on the individual patient needs.

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The course of quality of life and neurocognition in newly diagnosed patients with glioblastoma

The importance of QoL and neurocognitive functions in patients with glioblastoma (GB) is above controversy by now. We followed newly diagnosed GB patients treated with radio-chemotherapy during their course of disease by continuously evaluating their quality of life (QoL) and cognitive functions.

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Papillary fibroelastoma diagnosed through multimodality cardiac imaging: a rare tumour in an uncommon location with review of literature

We describe the case of a woman presenting with transient ischaemic attack, who was found to have a papillary fibroelastoma arising from the aortic wall, an extremely rare location. We describe the multimodality imaging techniques used in diagnosing this patient and review the most recent literature on evaluation and management of patients with cardiac papillary fibroelastomas.

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Complementary value of contralateral parenchymal enhancement on DCE-MRI to prognostic models and molecular assays in high-risk ER+HER2- breast cancer

Purpose: To determine whether markers of healthy breast stroma are able to select a subgroup of patients at low risk of death or metastasis from patients considered at high risk according to routine markers of the tumor. <p>Experimental Design: Patients with ER-positive/HER2-negative breast cancer were consecutively included for retrospective analysis. The contralateral parenchyma was segmented automatically on dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), whereupon the average of the top-10% late enhancement was calculated. This contralateral parenchymal enhancement (CPE) was analyzed with respect to routine prognostic models and molecular assays (Nottingham Prognostic Index, Dutch clinical chemotherapy-selection guidelines, 70-gene signature, and 21-gene recurrence score). CPE was split in tertiles and tested for overall and distant disease-free survival. CPE was adjusted for patient and tumor characteristics, as well as systemic therapy, using inverse probability weighting (IPW). Subanalyses were performed in patients at high risk according to prognostic models and molecular assays.</p> <p>Results: Four-hundred-and-fifteen patients were included, constituting the same group in which the association between CPE and survival was discovered. Median follow-up was 85 months, 34/415(8%) patients succumbed. After IPW-adjustment for patient and tumor characteristics, patients with high CPE had significantly better overall survival than those with low CPE in groups at high risk according to the Nottingham Prognostic Index (HR(95%CI):0.08(0.00-0.40),P<.001); Dutch clinical guidelines (HR(95%CI):0.22(0.00-0.81),P=.021); and 21-gene recurrence score (HR(95%CI):0.14(0.00-0.84),P=.030). One group showed a trend (70-gene signature:HR(95%CI):0.25(0.00-1.02),P=.054).</p> Conclusions: In patients at high risk based on the tumor, subgroups at relatively low risk were identified using pretreatment enhancement of the stroma on breast DCE-MRI.

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ANTI-CD137 AND PD-1/PD-L1 ANTIBODIES IN ROUTE TOWARDS CLINICAL SYNERGY.

T-cell co-stimulation and co-inhibition can be exploited  by blocking and agonist monoclonal antibodies (mAbs) respectively. Both strategies can be synergistically combined in mouse models. Early clinical results from combinations of anti-PD-1 mAbs in conjunction with agonist anti-CD137 (4-1BB) mAbs show excellent safety and promising efficacy.

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In Vivo Validation of PAPSS1 (3'-phosphoadenosine 5'-phosphosulfate synthase 1) as a Cisplatin-Sensitizing Therapeutic Target

Introduction: Our previous screening efforts found that inhibition of PAPSS1 increases the potency of DNA damaging agents in non-small cell lung cancer (NSCLC) cell lines. Here, we explored the clinical relevance of PAPSS1 and further investigated it as a therapeutic target in pre-clinical model systems. Methods: PAPSS1 expression and cisplatin IC₅₀ values were assessed in 52 lung adenocarcinoma (LAC) cell lines. Effects of PAPSS1 inhibition on A549 cisplatin sensitivity under hypoxic and starvation conditions, in 3D spheroids, as well as in zebrafish and mouse xenografts, were evaluated. Finally, the association between PAPSS1 expression levels and survival in patients treated with standard chemotherapy was assessed. Results: Our results show a positive correlation between low PAPSS1 expression and increased cisplatin sensitivity in LAC. In vitro, the potentiation effect was greatest when A549 cells were serum-starved under hypoxic conditions. When treated with low-dose cisplatin, PAPSS1-deficient A549 spheroids showed a 58% reduction in size compared to control cells. In vivo, PAPSS1 suppression and low-dose cisplatin treatment inhibited proliferation of lung tumor cells in zebrafish xenografts and significantly delayed development of subcutaneous tumors in mice. Clinical data suggest that NSCLC and ovarian cancer patients with low PAPSS1 expression survive longer following platinum-based chemotherapy. Conclusions: These results suggest that PAPSS1 inhibition enhances cisplatin activity in multiple pre-clinical model systems and that low PAPSS1 expression may serve as a biomarker for platin sensitivity in cancer patients. Developing strategies to target PAPSS1 activity in conjunction with platinum-based chemotherapy may offer an approach to improving treatment outcomes.

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Burden and profile of somatic mutation in duodenal adenomas from patients with familial adenomatous- and MUTYH-associated polyposis

Purpose: Duodenal polyposis and cancer are important causes of morbidity and mortality in familial adenomatous polyposis (FAP) and MUTYH-associated polyposis (MAP). This study aimed to comprehensively characterize somatic genetic changes in FAP and MAP duodenal adenomas to better understand duodenal tumorigenesis in these disorders.<br /><br />Experimental Design: Sixty-nine adenomas were biopsied during endoscopy in 16 FAP and 10 MAP patients with duodenal polyposis. Ten FAP and 10 MAP adenomas and matched blood DNA samples were exome sequenced, 42 further adenomas underwent targeted sequencing and 47 were studied by array comparative genomic hybridization. Findings in FAP and MAP duodenal adenomas were compared to each other and to the reported mutational landscape in FAP and MAP colorectal adenomas.<br /><br />Results: MAP duodenal adenomas had significantly more protein-changing somatic mutations (P = 0.018), truncating mutations (P = 0.006) and copy number variants (P = 0.005) than FAP duodenal adenomas, even though MAP patients had lower Spigelman stage duodenal polyposis. Fifteen genes were significantly recurrently mutated. Targeted sequencing of APC, KRAS, PTCHD2 and PLCL1 identified further mutations in each of these genes in additional duodenal adenomas. In contrast to MAP and FAP colorectal adenomas, neither exome nor targeted sequencing identified WTX mutations (P=0.0017).<br /><br />Conclusions: The mutational landscapes in FAP and MAP duodenal adenomas overlapped with, but had significant differences to those reported in colorectal adenomas. The significantly higher burden of somatic mutations in MAP than FAP duodenal adenomas despite lower Spigelman stage disease could increase cancer risk in the context of apparently less severe benign disease.

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MSH2 Loss in Primary Prostate Cancer

Purpose: Inactivation of mismatch repair (MMR) genes may predict sensitivity to immunotherapy in metastatic prostate cancers. We studied primary prostate tumors with MMR defects. Experimental Design: 1133 primary prostatic adenocarcinomas and 43 prostatic small cell carcinomas (NEPC) were screened by MSH2 immunohistochemistry with confirmation by next-generation sequencing (NGS). Microsatellite instability (MSI) was assessed by PCR and NGS (mSINGS). Results: Of primary adenocarcinomas and NEPC, 1.2% (14/1176) had MSH2 loss. Overall, 8% (7/91) of adenocarcinomas with primary Gleason pattern 5 (Gleason score 9-10) had MSH2 loss compared to 0.4% (5/1042) of tumors with any other scores (p<0.05). 5% (2/43) of NEPC had MSH2 loss. MSH2 was generally homogenously lost, suggesting it was an early/clonal event. NGS confirmed MSH2 loss-of-function alterations in all (12/12) samples, with bi-allelic inactivation in 83% (10/12) and hypermutation in 83% (10/12). Overall, 61% (8/13) and 58% (7/12) of patients had definite MSI by PCR and mSINGS, respectively. Three patients (25%) had germline mutations in MSH2. Tumors with MSH2 loss had a higher density of infiltrating CD8+ lymphocytes compared to grade-matched controls without MSH2 loss (390 vs. 76 cells/mm²; p=0.008), and CD8+ density was correlated with mutation burden among cases with MSH2 loss (r=0.72, p=0.005). T-cell receptor sequencing on a subset revealed a trend towards higher clonality in cases versus controls. Conclusion: Loss of MSH2 protein is correlated with MSH2 inactivation, hypermutation and higher tumor-infiltrating lymphocyte density, and appears most common among very high-grade primary tumors, where routine screening may be warranted if validated in additional cohorts.

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Neurotensin receptor 1 antagonist SR48692 improves response to carboplatin by enhancing apoptosis and inhibiting drug efflux in ovarian cancer

Purpose: The high affinity receptor 1 (NTSR1) and its agonist, neurotensin (NTS), is correlated with tumor cell aggressiveness in most solid tumors. As chemo-resistance and tumor aggressiveness are often related; we decided to study the role of the NTSR1 complex within platinum-based chemotherapy responses. In an ovarian model, we studied carboplatin because it is the main standard of care for ovarian cancer (OC).Experimental Design: Experimental tumors and in vitro studied were performed using SKOV3 and A2780 cells treated with carboplatin, with or without a very specific NTSR1 antagonist, SR48692. We measured the effects of these treatments on cell apoptosis and apoptosis related proteins, platinum accumulation in the cell and nucleus, and the expression and localization of platinum transporters. NTS and NTSR1 labelling was measured in patients with ovarian cancer. Results: SR48692 enhanced the response to carboplatin in OC cells and experimental tumors. When SR48692 is combined to carboplatin, we noted a major improvement of platinum induced DNA damage and cell death, as well as a decrease in tumor growth. The relationship of these results to clinic studies was made by the detection of NTS and NTSR1 in 72% and 74% of OC, respectively. Furthermore, in a large series of high grade OC, NTSR1 mRNA was shown to correlate with higher stages and platinum resistance. Conclusions: This study strongly suggests that the addition of NTSR1 inhibitor in combination with platinum salt-based therapy will improve the response to the drug.

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Amiloride, an old diuretic drug, is a potential therapeutic agent for multiple myeloma

Purpose: <br />The search for new drugs that control the continuous relapses of multiple myeloma is still required. Here, we report for the first time the potent anti-myeloma activity of amiloride, an old potassium-sparing diuretic approved for the treatment of hypertension and edema due to heart failure.<br /><br />Experimental Design:  <p>Myeloma cell lines and primary samples were used to evaluate cytotoxicity of amiloride. In vivo studies were carried out in a xenograft mouse model. The mechanisms of action were investigated using RNA-Seq, qRT-PCR, immunoblotting and immunofluorescence assays.</p> Results: <p>Amiloride-induced apoptosis was observed in a broad panel of MM cell lines and in a xenograft mouse model. Moreover, amiloride also had a synergistic effect when combined with dexamethasone, melphalan, lenalidomide and pomalidomide. RNA-Seq experiments showed that amiloride not only significantly altered the level of transcript isoforms and alternative splicing events, but also deregulated the spliceosomal machinery. Additionally, disruption of the splicing machinery in immunofluorescence studies was associated with the inhibition of myeloma cell viability after amiloride exposure. Although amiloride was able to induce apoptosis in myeloma cells lacking p53 expression, activation of p53 signaling was observed in wild-type and mutated TP53 cells after amiloride exposure. On the other hand, we did not find a significant systemic toxicity in mice treated with amiloride. </p> <br />Conclusions: <p>Overall, our results demonstrate the anti-myeloma activity of amiloride and provide a mechanistic rationale for its use as an alternative treatment option for relapsed MM patients, especially those with 17p deletion or TP53 mutations that are resistant to current therapies.

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Differential toxicity in patients with and without DNA repair mutations: Phase I Study of Carboplatin and Talazoparib in advanced solid tumors

<p>Purpose: The PARP inhibitor, talazoparib, may potentiate activity of chemotherapy in cells vulnerable to DNA damage. Experimental Design: This phase 1 study evaluated the safety, tolerability, pharmacokinetics (PK), and efficacy of talazoparib and carboplatin. Pharmacokinetic-modeling explored associations between dosing and hematological toxicity. Results: 24 patients with solid tumors were enrolled in 4 cohorts at 0.75mg and 1mg daily talazoparib and weekly carboplatin (AUC 1 and 1.5, Q2W or Q3W). Dose-limiting toxicities included grade 3 fatigue and grade 4 thrombocytopenia; the maximum tolerated dose was not reached. Grade 3/4 toxicities included fatigue (13%), neutropenia (63%), thrombocytopenia (29%), and anemia (38%). Post-cycle 2 dose modifications were required in all patients. One complete and two partial responses occurred in germline BRCA1/2 (gBRCA1/2) patients. Four patients showed stable disease beyond four months, three of which had mutations in DNA repair pathways. Pharmacokinetic-toxicity modeling showed that after 3 cycles of carboplatin AUC 1.5 Q3W and talazoparib 1mg daily, neutrophil counts decreased 78% (CI: 87 to 68%) from baseline in gBRCA carriers and 63% (CI: 72 to 55%) in non-carriers (p<0.001). This modeling suggests an intermittent, pulse dosing schedule of PARP inhibition, differentiated by gBRCA mutation status may improve tolerance of combination therapy. Conclusions: In order to optimize efficacy and minimize toxicity, we feel that the combination of carboplatin and talazoparib is likely best pursued using differentiated dosing schedules for patients with somatic DNA repair mutations vs. gBRCA mutations.

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Replication stress leading to apoptosis within the S-phase contributes to synergism between vorinostat and AZD1775 in HNSCC harboring high risk TP53 mutation

Purpose: The cure rate for patients with advanced head and neck squamous cell carcinoma (HNSCC) remains poor due to resistance to standard therapy primarily consisting of chemoradiation. Since mutation of TP53 in HNSCC occurs in 60-80% of non-HPV associated cases and is in turn associated with resistance to these treatments, more effective therapies are needed. In this study, we evaluated the efficacy of a regimen combining vorinostat and AZD1775 in HNSCC cells with a variety of p53 mutations. <p>Experimental Design: Clonogenic survival assays and an orthotopic mouse model of oral cancer were used to examine the in vitro and in vivo sensitivity of high-risk mutant p53 HNSCC cell lines to vorinostat in combination with AZD1775. Cell cycle, replication stress, homologous recombination (HR), live cell imaging, RNA-sequencing, and apoptosis analyses were performed to dissect molecular mechanisms.</p> <p>Results: We found that vorinostat synergizes with AZD1775 in vitro to inhibit growth of HNSCC cells harboring high-risk mutp53. These drugs interact synergistically to induce DNA damage, replication stress associated with impaired Rad51-mediated homologous recombination through activation of CDK1 and inhibition of Chk1 phosphorylation, culminating in an early apoptotic cell death during the S-phase of the cell cycle. The combination of vorinostat and AZD1775 inhibits tumor growth and angiogenesis in vivo in an orthotopic mouse model of oral cancer and prolongs animal survival.</p> <p>Conclusions: Vorinostat synergizes with AZD1775 in HNSCC cells with mutant p53 in vitro and in vivo. A strategy combining HDAC and WEE1 inhibition deserves further clinical investigation in patients with advanced HNSCC.

http://ift.tt/2vNoSDE

Cyclophilin A Maintains Glioma-Initiating Cell Stemness by Regulating Wnt/{beta}-catenin Signaling

Purpose: Glioma-initiating cells (GICs) are glioma stem-like cells that contribute to glioblastoma (GBM) development, recurrence, and resistance to chemotherapy and radiotherapy. They have recently become the focus of novel treatment strategies. Cyclophilin A (CypA) is a cytosolic protein that belongs to the peptidyl-prolyl isomerase (PPIase) family and the major intracellular target of the immunosuppressive drug cyclosporin A (CsA). In this study, we investigate the functions of CypA and its mechanism of action in GICs' development. Experimental Design: We analyzed differences in CypA expression between primary tumors and neurospheres from the GDS database, both before and after GIC differentiation. A series of experiments was conducted to investigate the role of CypA in GIC stemness, self-renewal, proliferation, radiotherapy resistance, and mechanism. We then designed glutathione S-transferase (GST) pull-down and co-immunoprecipitation assays to detect signaling activity. Results: In this study, we demonstrated that CypA promotes GIC stemness, self-renewal, proliferation, and radiotherapy resistance. Mechanistically, we found that CypA binds β-catenin and is recruited to Wnt target gene promoters. By increasing the interaction between β-catenin and TCF4, CypA enhances transcriptional activity. Conclusions: Our results demonstrate that CypA enhances GIC stemness, self-renewal, and radio-resistance through Wnt/β-catenin signaling. Due to its promotive effects on GICs, CypA is a potential target for future glioma therapy.

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Prospective Validation of Molecular Prognostic Markers in Cutaneous Melanoma: A Correlative Analysis of E1690

Purpose: To validate the prognostic impact of combined expression levels of three markers (SPP1, RGS1, and NCOA3) in melanoma specimens from patients enrolled in the E1690 clinical trial of high-dose or low-dose interferon alpha-2b (IFN) versus observation. <p>Experimental Design: Tissue was available from 248 patients. Marker expression was determined by digital imaging of immunohistochemically stained slides. The prognostic impact of each marker was first assessed by recording its expression value relative to the median. A multi-marker index was then developed to combine marker expression levels by counting for each patient the number of markers with high expression. The impact of the multi-marker index on relapse-free survival (RFS) and overall survival (OS) was assessed using Kaplan-Meier analysis, and both univariate and multivariate Cox regression analyses.</p> <p>Results: By Kaplan-Meier analysis, high multi-marker expression scores were significantly predictive of RFS (P<0.001) and OS (P<0.001). Stepwise multivariate Cox regression analysis with backward elimination that included routine clinical and histological prognostic factors revealed high multi-marker expression scores and tumor thickness as the only factors significantly and independently predicting RFS and OS. Stepwise multivariate Cox regression analyses that also included treatment type and number of positive lymph nodes generated identical results for both RFS and OS. In the molecularly defined low-risk subgroup, patients treated with high-dose IFN had a significantly improved RFS compared with patients in the other two subgroups (P<0.05).</p> <p> </p> Conclusions: These results validate the independent impact of combined expression levels of SPP1, RGS1, and NCOA3 on survival of melanoma in a prospectively collected cohort.

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Targeted proteomics identifies proteomic signatures in liquid-biopsies of the endometrium to diagnose endometrial cancer and assist in the prediction of the optimal surgical treatment

Purpose: Endometrial cancer (EC) diagnosis relies on the observation of tumor cells in endometrial biopsies obtained by aspiration i.e., uterine aspirates), but it is associated with 22% undiagnosed patients and up to 50% of incorrectly assigned EC histotype and grade. We aimed to identify biomarker signatures in the fluid fraction of these biopsies to overcome these limitations. Experimental Design: The levels of 52 proteins were measured in the fluid fraction of uterine aspirates from 116 patients by LC-PRM, the latest generation of targeted mass-spectrometry acquisition. A logistic regression model was used to assess the power of protein panels to differentiate between EC and non-EC patients and between EC histological subtypes. The robustness of the panels was assessed by the "leave-one-out" cross-validation procedure performed within the same cohort of patients and an independent cohort of 38 patients. Results: The levels of 28 proteins were significantly higher in EC patients (n=69) compared to controls (n=47). The combination of MMP9 and KPYM exhibited 94% sensitivity and 87% specificity for detecting EC cases. This panel perfectly complemented the standard diagnosis, achieving 100% of correct diagnosis in this dataset. Nine proteins were significantly increased in endometrioid EC (n=49) compared to serous EC (n=20). The combination of CTNB1, XPO2 and CAPG achieved 95% sensitivity and 96% specificity for the discrimination of these subtypes. Conclusions: We developed two uterine aspirate-based signatures to diagnose EC and classify tumors in the most prevalent histological subtypes. This will improve diagnosis and assist in the prediction of the optimal surgical treatment.

http://ift.tt/2vio3RL

GSK 3 inhibition drives maturation of NK cells and enhances their antitumor activity

Maturation of human natural killer cells (NK cells) as defined by accumulation of cell surface expression of CD57 is associated with increased cytotoxic character and TNF and IFN-γ production upon target cell recognition. Notably, multiple studies point to a unique role for CD57+ NK cells in cancer immunosurveillance, yet there is scant information about how they mature. In this study, we show that pharmacological inhibition of GSK3 kinase in peripheral blood NK cells expanded ex vivo with IL-15 greatly enhances CD57 upregulation and late-stage maturation. GSK3 inhibition elevated the expression of several transcription factors associated with late-stage NK cell maturation including T-BET, ZEB2 and BLIMP-1 without affecting viability or proliferation. When exposed to human cancer cells, NK cell expanded ex vivo in the presence of a GSK3 inhibitor exhibited significantly higher production of TNF and IFN-γ, elevated natural cytotoxicity, and increased antibody-dependent cellular cytotoxicity (ADCC). In an established mouse xenograft model of ovarian cancer, adoptive transfer of NK cells conditioned in the same way also displayed more robust and durable tumor control. Our findings show how GSK3 kinase inhibition can greatly enhance the mature character of NK cells most desired for effective cancer immunotherapy.

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ATM deficiency generating genomic instability sensitizes pancreatic ductal adenocarcinoma cells to therapy-induced DNA damage

Pancreatic adenocarcinomas (PDAC) harbour recurrent functional mutations of the master DNA damage response kinase ATM which has been shown to accelerate tumorigenesis and epithelial-mesenchymal transition. To study how ATM deficiency affects genome integrity in this setting, we evaluated the molecular and functional effects of conditional Atm deletion in a mouse model of PDAC. ATM deficiency was associated with increased mitotic defects, recurrent genomic rearrangements and deregulated DNA integrity checkpoints, reminiscent of human PDAC. We hypothesized that altered genome integrity might allow synthetic lethality-based options for targeted therapeutic intervention. Supporting this possibility, we found that the PARP inhibitor olaparib or ATR inhibitors reduced the viability of PDAC cells in vitro and in vivo associated with a genotype-selective increase in apoptosis. Overall, our results offered a preclinical mechanistic rationale for the use of PARP and ATR inhibitors to improve treatment of ATM-mutant PDAC.

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Clinical study of genomic drivers in pancreatic ductal adenocarcinoma

http://ift.tt/2wFV6Nl

Comparative frequency of four different types of pregnancy-associated thyrotoxicosis in a single thyroid centre

Abstract

Background

Pregnancy and delivery markedly influence thyroid function. However, the comparative prevalence of gestational thyrotoxicosis (GT), new onset of Graves' disease during pregnancy (GD during pregnancy), postpartum destructive thyrotoxicosis (PPT), and postpartum Graves' thyrotoxicosis (PPGD) has not yet been determined.

Methods

We prospectively registered and performed a review of 4127 consecutive non treated female patients with thyrotoxicosis, seen between August 2008 and December 2013 in our outpatient clinic of Kuma Hospital. 187 out of the 4127 women had new diagnosis of thyrotoxicosis during pregnancy or in the postpartum period. We investigated the prevalence of new diagnosis of GT, GD during pregnancy, PPT and PPGD and compared the characteristics of these types of thyrotoxicosis. The postpartum period is defined as twelve months after delivery.

Results

Out of 187 pregnant or postpartum women, we identified 30 (16.0%) with GT, 13 (7.0%) with GD during pregnancy, 42 (22.5%) with PPT, and 102 (54.5%) with PPGD. The onset time of thyrotoxicosis during pregnancy, i.e., both GT and GD during pregnancy, was delayed by a couple of weeks when hCG peaked at 10 gestational weeks. Seventy-six percent of patients with PPT developed thyrotoxicosis between delivery and 4 months postpartum; on the other hand, 83.3% of patients with PPGD developed thyrotoxicosis at 6 months postpartum or later.

Conclusions

We named gestational thyrotoxicosis, new onset of Graves' disease during pregnancy, postpartum destructive thyrotoxicosis, and postpartum Graves' thyrotoxicosis as pregnancy-associated thyrotoxicosis. A clinically significant number of women developed Graves' disease in the postpartum period in a single thyroid centre.

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Non-invasive prediction of recurrence in bladder cancer by detecting somatic TERT promoter mutations in urine

http://ift.tt/2vNdOWP

Detection of phosphatidylserine-positive exosomes for the diagnosis of early-stage malignancies

http://ift.tt/2wFMjet

Lifestyle predictors for non-participation and outcome in the second round of faecal immunochemical test in colorectal cancer screening

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MiR-646 inhibited cell proliferation and EMT-induced metastasis by targeting FOXK1 in gastric cancer

http://ift.tt/2wFSord

Geriatric assessment is superior to oncologists’ clinical judgement in identifying frailty

http://ift.tt/2vMLSmh

LIM kinase 1 interacts with myosin-9 and alpha-actinin-4 and promotes colorectal cancer progression

http://ift.tt/2wG2NmU

Integrating cytokines and angiogenic factors and tumour bulk with selected clinical criteria improves determination of prognosis in advanced renal cell carcinoma

http://ift.tt/2vN88wi

HYPE or HOPE: the prognostic value of infiltrating immune cells in cancer

http://ift.tt/2wFZf3O

Harmonisation of biobanking standards in endometrial cancer research

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UV radiation promotes melanoma dissemination mediated by the sequential reaction axis of cathepsins–TGF-β1–FAP-α

http://ift.tt/2wG7Ao2

Kinase-driven metabolic signalling as a predictor of response to carboplatin–paclitaxel adjuvant treatment in advanced ovarian cancers

http://ift.tt/2vN4kuI

KIBRA attains oncogenic activity by repressing RASSF1A

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TOPK modulates tumour-specific radiosensitivity and correlates with recurrence after prostate radiotherapy

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Modulating cancer cell survival by targeting intracellular cholesterol transport

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Pre-diagnostic statin use, lymph node status and mortality in women with stages I–III breast cancer

http://ift.tt/2wGgdzk

Role of Plasma D-Dimer Levels in Breast Cancer Patients and Its Correlation with Clinical and Histopathological Stage

Abstract

Breast cancer, the most common female malignancy, represents a heterogeneous group of tumors, which presen both varied behaviors and response to therapy. This study was done with an attempt to evaluate the role of D-dimer in patients of carcinoma breast, in predicting lymph node metastasis in carcinoma patients and to look for relationship of these markers with histopathologic parameters. Clinical data was obtained from clinical examination of patients admitted in the Department of Surgery with history of breast lump and confirmed with fine needle aspiration cytology (FNAC). Clinical staging was done using TNM staging. D-dimer level was measured prior to commencement of treatment, i.e., modified radical mastectomy (MRM) or neoadjuvant chemotherapy and finally 6 months after surgery or completion of 6 cycles of chemotherapy. The characteristics of the study population Out of 60 study cases minimum age of the patient being 30 years and maximum being 74 years. Of all histopathologic variables examined, D-dimer levels directly correlated with extent of lymph node involvement and lymphovascular invasion, D-dimer levels correlated strongest with the number of positive lymph nodes, but not with tumor size, estrogen receptor status, and progesterone receptor status. This study clearly shows that plasma D-Dimer levels are elevated in carcinoma breast patients. Increased D-Dimer levels are an important marker of clinical stage, lymphovascular invasion, lymph node involvement, and tumor metastasis.

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Insomnia, postpartum depression and estradiol in women after delivery

Abstract

After childbirth, women may develop symptoms of depression with the associated sleep disturbances. This study assessed the relationship between insomnia and both depression symptoms and blood estradiol levels in women during the early postpartum period. 84 patients were assessed 24–48 h after labor. The main assessment methods were the following psychometric scales: Beck Depression Inventory (BDI), Edinburgh Postnatal Depression Scale (EPDS) and Athens Insomnia Scale (AIS). Serum estradiol levels were measured using ELISA assay. Women who developed postpartum insomnia significantly more often reported insomnia during pregnancy (P = 0.001), were more likely to have suffered from depression in the past (P = 0.007) and had significantly higher BDI (P = 0.002) and EPDS (P = 0.048) scores. Our study demonstrated no significant association between Restless Legs Syndrome (RLS) during pregnancy and postpartum insomnia. The groups of women with and without postpartum RLS showed no significant differences in the incidence of postpartum insomnia. No significant differences in estradiol levels were observed in women with and without postpartum insomnia. The study showed the following factors to play a major role in development of postpartum insomnia: an increase in Beck Depression Inventory score, a history of depression and a history of insomnia during pregnancy.

http://ift.tt/2vLt06b

Metabolic Tumor Volume of Primary Tumor Predicts Survival Better than T Classification in the Larynx Preservation Approach

Abstract

We aimed to determine whether pretreatment metabolic tumor volume of the primary tumor (T-MTV) or T classification would be a better predictor of laryngectomy-free survival (LFS) and overall survival (OS) after chemoradiotherapy in patients with locally advanced laryngeal or hypopharyngeal cancer requiring total laryngectomy. We analyzed 85 patients using a Cox proportional hazards model and evaluated its usefulness by Akaike's information criterion. A T-MTV cutoff value was determined by time-dependent receiver operating characteristic curve analysis. Interobserver reliability for measuring T-MTV was estimated by the intraclass correlation coefficient (ICC). After adjustment for covariables, T-MTV, irrespective of whether a continuous or dichotomized variable, and T classification remained independent predictors of LFS and OS. Large T-MTV (>28.7 ml) was associated with inferior LFS [hazard ratio (HR), 4.16; 95% confidence interval (CI), 1.97–8.70; P = 0.0003] and inferior OS (HR, 3.18; 95% CI, 1.47–6.69; P = 0.004) compared with small T-MTV (≤28.7 ml). The T-MTV model outperformed the T classification model in predicting LFS and OS (P = 0.007 and 0.01, respectively). The 3-year LFS and OS rates for patients with small versus large T-MTV were 68% versus 9% (P < 0.0001) and 77% versus 25% (P < 0.0001), respectively, while those for patients with T2-T3 versus T4a were 61% versus 31% (P = 0.003) and 71% versus 48% (P = 0.10), respectively. The ICC was 0.99 (95% lower confidence bound, 0.99). Given the excellent interobserver reliability, T-MTV would serve better than T classification to identify patients who benefit from the larynx preservation approach.

This article is protected by copyright. All rights reserved.

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A combination of anti-CD4 antibody treatment and DLI ameliorates GVHD while preserving GVT effects in murine allo-HSCT

Abstract

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is not only a well-established immunotherapy for hematologic malignancies, but is potentially useful for treating solid tumors refractory to available therapies. However, application of allo-HSCT to solid tumors is limited, despite the beneficial anti-tumor effects, by the risk of graft-versus-host disease (GVHD). CD4⁺ T cells have been implicated in several aspects of GVHD, and suppress anti-tumor CD8⁺ T cell responses. In the present study, we investigated clinically applicable allo-HSCT protocols designed to maximize anti-tumor effects while reducing the risk of GVHD. We used a mouse model of allo-HSCT with subcutaneous tumors. We found that myeloablative conditioning was associated with better inhibition of tumor growth but with severe acute GVHD. Early administration of anti-CD4 mAb substantially ameliorated GVHD, while preserving anti-tumor effects, leading to improved survival in myeloablative allo-HSCT. Late administration of anti-CD4 mAb also ameliorated GVHD to some extent. Donor lymphocyte infusion (DLI) in GVHD mice treated with anti-CD4 mAb further suppressed tumor growth without exacerbating GVHD. Collectively, our results suggest that myeloablative allo-HSCT followed by anti-CD4 mAb treatment and DLI may be a potent and safe immunotherapy for patients with cancers refractory to available therapies.

This article is protected by copyright. All rights reserved.

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ICG-fluorescence imaging for detection of peritoneal metastases and residual tumoral scars in locally advanced ovarian cancer: A pilot study

Background and Objectives

No intraoperative imaging techniques exist for detecting tumor nodules or tumor scar tissues in patients treated with upfront or interval cytoreductive surgery (CS) after neoadjuvant chemotherapy (NAC). The aims of this study were to evaluate the role of indocyanine green (ICG) fluorescence imaging (FI) for the detection of peritoneal metastases (PM) and evaluate whether it can be used to detect remnant tumor cells in scar tissue.

Methods

Patients with PM from ovarian cancer admitted for CS were included. ICG, at 0.25 mg per kg of patient weight, was injected intraoperatively after explorative laparotomy before CS.

Results

A total of 108 peritoneal lesions, including 25 scars, were imaged in 20 patients. Seventy-three were malignant (67.6%) and 35 benign (32.4%). The mean Tumor to Background Ratio (ex vivo) was 1.8 (SD 1.3) in malignant and 1.0 (SD 0.79) in benign nodules (P = 0.007). Of 25 post-NAC scars, the mean Tumor to Background Ratio (TBR) (in vivo) was 2.06 (SD 1.15) in malignant and 1.21 (SD 0.50) in benign nodules (P = 0.26). The positive predictive value of ICG-FI to detect tumor cells in scars was 57.1%.

Conclusions

ICG-FI is accurate to demonstrate PM in ovarian cancer but unable to discriminate between benign and malignant post-NAC.

http://ift.tt/2vC8chH

Impact of lympho-vascular space invasion on tumor characteristics and survival outcome of women with low-grade serous ovarian carcinoma

Background and Objectives

To examine association of lympho-vascular space invasion (LVSI) with clinico-pathological factors and to evaluate survival of women with low-grade serous ovarian carcinoma containing areas of LVSI.

Methods

This is a multicenter retrospective study examining consecutive cases of surgically treated stage I-IV low-grade serous ovarian carcinoma (n = 178). Archived histopathology slides for the ovarian tumors were reviewed, and LVSI was scored as present or absent. LVSI status was correlated to clinico-pathological findings and survival outcome.

Results

LVSI was seen in 79 cases (44.4%, 95% confidence interval [CI] 37.1-51.7). LVSI was associated with increased risk of omental metastasis (87.0% vs 64.9%, odds ratio [OR] 3.62, P = 0.001), high pelvic lymph node ratio (median 12.9% vs 0%, P = 0.012), and malignant ascites (49.3% vs 32.6%, OR 2.01, P = 0.035). On multivariable analysis, controlling for age, stage, and cytoreductive status, presence of LVSI in the ovarian tumor remained an independent predictor for decreased progression-free survival (5-year rates 21.0% vs 35.7%, adjusted-hazard ratio 1.57, 95%CI 1.06-2.34, P = 0.026). LVSI was significantly associated with increased risk of recurrence in lymph nodes (OR 2.62, 95%CI 1.08-6.35, P = 0.047).

Conclusion

LVSI in the ovarian tumor is associated with adverse clinico-pathological characteristics and decreased progression-free survival in women with low-grade serous ovarian carcinoma.

http://ift.tt/2vjCinR

ICG-fluorescence imaging for detection of peritoneal metastases and residual tumoral scars in locally advanced ovarian cancer: A pilot study

Background and Objectives

No intraoperative imaging techniques exist for detecting tumor nodules or tumor scar tissues in patients treated with upfront or interval cytoreductive surgery (CS) after neoadjuvant chemotherapy (NAC). The aims of this study were to evaluate the role of indocyanine green (ICG) fluorescence imaging (FI) for the detection of peritoneal metastases (PM) and evaluate whether it can be used to detect remnant tumor cells in scar tissue.

Methods

Patients with PM from ovarian cancer admitted for CS were included. ICG, at 0.25 mg per kg of patient weight, was injected intraoperatively after explorative laparotomy before CS.

Results

A total of 108 peritoneal lesions, including 25 scars, were imaged in 20 patients. Seventy-three were malignant (67.6%) and 35 benign (32.4%). The mean Tumor to Background Ratio (ex vivo) was 1.8 (SD 1.3) in malignant and 1.0 (SD 0.79) in benign nodules (P = 0.007). Of 25 post-NAC scars, the mean Tumor to Background Ratio (TBR) (in vivo) was 2.06 (SD 1.15) in malignant and 1.21 (SD 0.50) in benign nodules (P = 0.26). The positive predictive value of ICG-FI to detect tumor cells in scars was 57.1%.

Conclusions

ICG-FI is accurate to demonstrate PM in ovarian cancer but unable to discriminate between benign and malignant post-NAC.

http://ift.tt/2vC8chH

Impact of lympho-vascular space invasion on tumor characteristics and survival outcome of women with low-grade serous ovarian carcinoma

Background and Objectives

To examine association of lympho-vascular space invasion (LVSI) with clinico-pathological factors and to evaluate survival of women with low-grade serous ovarian carcinoma containing areas of LVSI.

Methods

This is a multicenter retrospective study examining consecutive cases of surgically treated stage I-IV low-grade serous ovarian carcinoma (n = 178). Archived histopathology slides for the ovarian tumors were reviewed, and LVSI was scored as present or absent. LVSI status was correlated to clinico-pathological findings and survival outcome.

Results

LVSI was seen in 79 cases (44.4%, 95% confidence interval [CI] 37.1-51.7). LVSI was associated with increased risk of omental metastasis (87.0% vs 64.9%, odds ratio [OR] 3.62, P = 0.001), high pelvic lymph node ratio (median 12.9% vs 0%, P = 0.012), and malignant ascites (49.3% vs 32.6%, OR 2.01, P = 0.035). On multivariable analysis, controlling for age, stage, and cytoreductive status, presence of LVSI in the ovarian tumor remained an independent predictor for decreased progression-free survival (5-year rates 21.0% vs 35.7%, adjusted-hazard ratio 1.57, 95%CI 1.06-2.34, P = 0.026). LVSI was significantly associated with increased risk of recurrence in lymph nodes (OR 2.62, 95%CI 1.08-6.35, P = 0.047).

Conclusion

LVSI in the ovarian tumor is associated with adverse clinico-pathological characteristics and decreased progression-free survival in women with low-grade serous ovarian carcinoma.

http://ift.tt/2vjCinR

Identification of a novel mutation in PEX10 in a patient with attenuated Zellweger spectrum disorder: a case report

The peroxisome biogenesis disorders, which are caused by mutations in any of 13 different PEX genes, include the Zellweger spectrum disorders. Severe defects in one of these PEX genes result in the absence of fun...

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Long-term daily temozolomide with dose-dependent efficacy in MGMT promotor methylation negative recurrent high-grade astrocytoma

Abstract

Temozolomide (TMZ) for malignant gliomas is traditionally dosed in 5 out of a 28-day cycle, however alternative regimens exist, including dose-dense. Continuous daily dosing is available, but the acceptable dose and duration of therapy is unknown. We document a 40-year-old male with recurrent anaplastic astrocytoma, IDH mutant and MGMT promotor methylation negative, who has well-tolerated continuous daily TMZ for 20 months at 100 mg per day for nearly the length of this period. A trial at 80 mg per day demonstrated disease progression with response upon return to 100 mg per day. Prior to the daily TMZ, the patient underwent three surgical resections, radiation therapy with concurrent TMZ according to the EORTC-NCIC protocol, and subsequently bevacizumab in combination with use of the Optune device. Long-term survival of patients with recurrent malignant gliomas is uncommon, and currently no standard treatment strategies exist for these patients. We present this case to demonstrate the tolerability and dose dependency of prolonged daily TMZ dosing as a therapeutic option for recurrent anaplastic astrocytomas.

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Feasibility of dose-dense epirubicin and cyclophosphamide with subcutaneous pegfilgrastim 3.6 mg support: a single-center prospective study in Japan

Abstract

Background

Dose-dense chemotherapy consisting of a combination of epirubicin and cyclophosphamide (EC) improves the survival of patients with breast cancer. Although pegfilgrastim was used at a subcutaneous dose of 6.0 mg in a pivotal study of dose-dense EC treatment, pegfilgrastim at a dose of 3.6 mg has been approved in Japan. We have assessed the feasibility of dose-dense EC treatment supported with a 3.6 mg dose of pegfilgrastim by evaluating the relative dose intensity (RDI) and safety of the treatment, together with measuring the pegfilgrastim concentrations remaining on the day of starting the next cycle of chemotherapy.

Methods

Patients with primary breast cancer received a total of 4 cycles of dose-dense EC treatment every 2 weeks, together with a subcutaneous injection of 3.6 mg pegfilgrastim on the day after chemotherapy. The serum granulocyte colony-stimulating factor (G-CSF) concentrations were measured on the 15th day of every chemotherapy cycle.

Results

From March 2015 through to July 2016, a total of 51 patients (median age 51 years; range 33–73 years) were studied. The mean RDI was 95.2% (range 60.0–100%). Although most adverse events were consistent with those reported in previous studies, pneumocystis pneumonia developed in two patients during the following course of docetaxel treatment. The median serum G-CSF concentration was 92.5 (range 30.4–440) pg/ml.

Conclusions

With support provided by pegfilgrastim injection at a dose of 3.6 mg, dose-dense EC is feasible and associated with maintenance of a high RDI. There was no clinically significant accumulation of serum G-CSF concentrations associated with the use of a 3.6 mg dose of pegfilgrastim at 2-week intervals.

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Contrasting effects of cyclophosphamide on anti-CTLA-4 blockade therapy in two mouse tumor models

Summary

Immune checkpoint blockade is a promising anti-cancer therapy, but must be used in combination with other anti-cancer therapies to increase therapeutic efficacy. Cyclophosphamide (CP) is a chemotherapeutic drug that exhibits immune-modulating effects. In this study, we examined the effect of CP on anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) blockade therapy in two mouse tumor models. Drastic tumor regression was observed in the CT26 colon carcinoma model after intraperitoneal (i.p.) injection of CP (100 mg/kg) followed by anti-CTLA-4 antibody. However, administration in the reverse order increased apoptosis in tumor-specific CD8⁺ T cells. In the RENCA renal carcinoma model, the anti-tumor effect of combination therapy was marginal and the tumor-bearing state reduced body weight with an increased serum level of interleukin (IL)-6. Interestingly, although CP monotherapy increased myeloid-derived suppressor cells (MDSCs) in the spleens of both models, subsequent anti-CTLA-4 therapy increased MDSCs only in RENCA-bearing mice. Additionally, the serum levels of chemokine ligand 2 (CCL2) and C-X-C motif chemokine 10 (CXCL10) were increased by the combination therapy only in RENCA-bearing mice and in vivo depletion of Gr-1⁺ cells augmented the anti-tumor effect to some degree. These results reveal a contrasting effect of CP on anti-CTLA-4 therapy between the two mouse tumor models. CP augments the anti-tumor effect of anti-CTLA-4 therapy in CT26-bearing hosts, whereas CP after anti-CTLA-4 therapy attenuates this effect via induction of apoptosis in tumor-reactive T cells. Alternatively, CP-induced MDSCs can be increased by anti-CTLA-4 therapy only in RENCA-bearing hosts with an elevated level of IL-6.

This article is protected by copyright. All rights reserved.

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The cost-effectiveness of active surveillance compared to watchful waiting and radical prostatectomy for low risk localised prostate cancer

Abstract

Background

Radical prostatectomy is the most common treatment for localised prostate cancer in New Zealand. Active surveillance was introduced to prevent overtreatment and reduce costs while preserving the option of radical prostatectomy. This study aims to evaluate the cost-effectiveness of active surveillance compared to watchful waiting and radical prostatectomy.

Methods

Markov models were constructed to estimate the life-time cost-effectiveness of active surveillance compared to watchful waiting and radical prostatectomy for low risk localised prostate cancer patients aged 45–70 years, using national datasets in New Zealand and published studies including the SPCG-4 study. This study was from the perspective of the Ministry of Health in New Zealand.

Results

Radical prostatectomy is less costly than active surveillance in men aged 45–55 years with low risk localised prostate cancer, but more costly for men aged 60–70 years. Scenario analyses demonstrated significant uncertainty as to the most cost-effective option in all age groups because of the unavailability of good quality of life data for men under active surveillance. Uncertainties around the likelihood of having radical prostatectomy when managed with active surveillance also affect the cost-effectiveness of active surveillance against radical prostatectomy.

Conclusions

Active surveillance is less likely to be cost-effective compared to radical prostatectomy for younger men diagnosed with low risk localised prostate cancer. The cost-effectiveness of active surveillance compared to radical prostatectomy is critically dependent on the 'trigger' for radical prostatectomy and the quality of life in men on active surveillance. Research on the latter would be beneficial.

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Potential circulating miRNA signature for early detection of NSCLC

Publication date: Available online 7 August 2017
Source:Cancer Genetics
Author(s): Ayda Arab, Morteza Karimipoor, Shiva Irani, Arda Kiani, Sirous Zeinali, Elham Tafsiri, Kambiz Sheikhy
Circulating microRNAs (c-miRNAs) are promising biomarkers for screening, early detection and prognosis of cancer. The purpose of this investigation was to identify a panel of c-miRNAs in plasma that could contribute to early detection of non-small cell lung cancer (NSCLC). We profiled the expression of 44 unique plasma miRNAs in training set of 34 NSCLC patients and 20 matched healthy individuals by miRCURY LNA™ Universal RT microRNA PCR Panel and calculated dysregulation fold changes using the 2-ΔΔCt equation. Selected plasma miRNAs were then validated by SYBR green q-RT PCR using an independent validation set of plasma samples from NSCLC patients (n: 72) and NC (n: 50). In the validation set, the receiver operating characteristic (ROC) curves were generated for four miRNAs. In the training set, 17 miRNAs were significantly up-regulated and nine were down-regulated in the plasma from NSCLC patients versus matched normal controls. Four miRNAs (miR-21, miR-328, miR-375 and miR-141) were selected for validating their diagnostic value in the testing set. ROC plot analysis showed that a high specificity (98%) and sensitivity (82.7%) in miR-141 in comparing early NSCLC patient and controls. So among these four plasma miRNAs only miR-141 could be promising biomarkers for early detection of NSCLC. In addition to, we found a significant positive correlation between stage and miR-21 expression level (95% CI: 0.687-0.863; p-value<0.0001). Considering the accessibility and stability of circulating miRNAs, plasma miR-141 is a useful biomarker early detection of NSCLC as a supplement in future screening studies.



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Pivotal regulators of tissue homeostasis and cancer: macrophages

Abstract

Macrophages are an essential component of innate immunity and play a vital role in inflammation and host defense. Based on immunological responses, the macrophages are classified into "activated" macrophage (M1 macrophages) participating in the responses of type I helper T (Th1) cells to pathogens and "alternatively activated" macrophages (M2 macrophages) in response to interleukin (IL)-4 and IL-13. In this review, we discuss the origin, classification and function of macrophages. We also discuss the mechanisms underlying polarization of different macrophage subtypes, including transcriptional, epigenetic and post-transcriptional regulation.

http://ift.tt/2wEVL1J

Advances in the diagnosis of hereditary kidney cancer: Initial results of a multigene panel test

BACKGROUND

Panel testing has been recently introduced to evaluate hereditary cancer; however, limited information is available regarding its use in kidney cancer.

METHODS

The authors retrospectively reviewed test results and clinical data from patients who underwent targeted multigene panel testing of up to 19 genes associated with hereditary kidney cancer from 2013 to 2016. The frequency of positive (mutation/variant likely pathogenic), inconclusive (variant of unknown significance), and negative results was evaluated. A logistic regression analysis evaluated predictive factors for a positive test.

RESULTS

Patients (n = 1235) had a median age at diagnosis of 46 years, which was significantly younger than the US population of individuals with kidney cancer (P < .0001). Overall, 6.1%, 75.5%, and 18.4% of individuals had positive, negative, and inconclusive results, respectively. The most commonly altered genes included folliculin (FLCN) and fumarate hydratase (FH), which were altered in 1.8% and 1.3% of patients, respectively. Tuberous Sclerosis Complex 2 (TSC2), mesenchymal epithelial transition factor proto-oncogene (MET), and PMS1 homolog 2 (PMS2) had the highest rates of variants of unknown significance, which were identified in 2.7%, 2.2%, and 1.7% of patients, respectively. Early age of onset was the only factor that was identified as predictive of a positive test on multivariate analysis (odds ratio, 0.975; P = .0052) and may be the only identifying characteristic of low-penetrant syndromes, such as those associated with MITF (melanogenesis-associated transcription factor) mutations, which do not have singular histology or a family history of kidney cancer.

CONCLUSIONS

Panel tests may be particularly useful for patients who lack distinguishing clinical characteristics of known hereditary kidney cancer syndromes. The current results support the use of early age of onset for genetic counseling and/or testing. Cancer 2017. © 2017 American Cancer Society.

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Comparison of efficacy, safety, and quality of life between sorafenib and sunitinib as first-line therapy for Chinese patients with metastatic renal cell carcinoma

Sorafenib and sunitinib are widely used as first-line targeted therapy for metastatic renal cell carcinoma (mRCC) in China. This study aimed to compare the efficacy, safety, and quality of life (QoL) in Chines...

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Selective targeting of melanoma using N -(2-diethylaminoethyl) 4-[ 18 F]fluoroethoxy benzamide (4-[ 18 F]FEBZA): a novel PET imaging probe

Abstract

Background

The purpose of this study was to develop a positron emission tomography (PET) imaging probe that is easy to synthesize and selectively targets melanoma in vivo. Herein, we report the synthesis and preclinical evaluation of N-(2-diethylaminoethyl) 4-[¹⁸F]Fluoroethoxy benzamide (4-[¹⁸F]FEBZA).

A one-step synthesis was developed to prepare 4-[¹⁸F]FEBZA in high radiochemical yields and specific activity. The binding affinity, the in vitro binding, and internalization studies were performed using B16F1 melanoma cell line. The biodistribution studies were performed in C57BL/6 normal mice, C57BL/6 mice bearing B16F1 melanoma tumor xenografts, and nu/nu athymic mice bearing HT-29 human adenocarcinoma tumor and C-32 amelanotic melanoma tumor xenografts. MicroPET studies were performed in mice bearing B16F1 and HT-29 tumor xenografts.

Results

4-[¹⁸F]FEBZA was prepared in 53 ± 14% radiochemical yields and a specific activity of 8.7 ± 1.1 Ci/μmol. The overall synthesis time for 4-[¹⁸F]FEBZA was 54 ± 7 min. The in vitro binding to B16F1 cells was 60.03 ± 0.48% after 1 h incubation at 37 °C. The in vivo biodistribution studies show a rapid and high uptake of F-18 in B16F1 tumor with 8.66 ± 1.02%IA/g in this tumor at 1 h. In contrast, the uptake at 1 h in HT-29 colorectal adenocarcinoma and C-32 amelanotic melanoma tumors was significantly lower with 3.68 ± 0.47%IA/g and 3.91 ± 0.23%IA/g in HT-29 and C-32 tumors, respectively. On microPET images, the melanoma tumor was clearly visible by 10 min post-injection and the intensity in the tumor continued to increase with time. In contrast, the HT-29 tumor was not visible on the microPET scans.

Conclusions

A rapid and facile synthesis of 4-[¹⁸F]FEBZA is developed. This method offers a reliable production of 4-[¹⁸F]FEBZA in high radiochemical yields and specific activity. A high binding affinity to melanoma cells and high uptake in tumor was noted. The microPET scan clearly delineates the melanoma tumor by 10 min post-injection. The results from these preclinical studies support the potential of 4-[¹⁸F]FEBZA as an effective probe to image melanoma.

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Hedgehog inhibitor sonidegib potentiates 177 Lu-octreotate therapy of GOT1 human small intestine neuroendocrine tumors in nude mice

Abstract

Background

¹⁷⁷Lu-octreotate can be used to treat somatostatin receptor expressing neuroendocrine tumors. It is highly effective in animal models, but clinical studies have so far only demonstrated low cure rates. Hedgehog inhibitors have shown therapeutic effect as monotherapy in neuroendocrine tumor model systems and might be one option to enhance the efficacy of ¹⁷⁷Lu-octreotate therapy. The aim of this study was to determine the therapeutic effect of combination therapy using ¹⁷⁷Lu-octreotate and the Hedgehog signaling pathway inhibitor sonidegib.

Methods

GOT1-bearing BALB/c nude mice were treated with either sonidegib (80 mg/kg twice a week via oral gavage), a single injection of 30 MBq ¹⁷⁷Lu-octreotate i.v., or a combination of both. Untreated animals served as controls. Tumor size was measured twice-weekly using calipers. The animals were killed 41 d after injection followed by excision of the tumors. Total RNA was extracted from each tumor sample and then subjected to gene expression analysis. Gene expression patterns were compared with those of untreated controls using Nexus Expression 3.0, IPA and Gene Ontology terms. Western blot was carried out on total protein extracted from the tumor samples to analyze activation-states of the Hh and PI3K/AKT/mTOR pathways.

Results

Sonidegib monotherapy resulted in inhibition of tumor growth, while a significant reduction in mean tumor volume was observed after ¹⁷⁷Lu-octreotate monotherapy and combination therapy. Time to progression was prolonged in the combination therapy group compared with ¹⁷⁷Lu-octreotate monotherapy. Gene expression analysis revealed a more pronounced response following combination therapy compared with both monotherapies, regarding the number of regulated genes and biological processes. Several cancer-related signaling pathways (i.e. Wnt/β-catenin, PI3K/AKT/mTOR, G-protein coupled receptor, and Notch) were affected by the combination therapy, but not by either monotherapy. Protein expression analysis revealed an activation of the Hh- and PI3K/AKT/mTOR pathways in tumors exposed to ¹⁷⁷Lu-octreotate monotherapy and combination therapy.

Conclusions

A comparative analysis of the different treatment groups showed that combination therapy using sonidegib and ¹⁷⁷Lu-octreotate could be beneficial to patients with neuroendocrine tumors. Gene expression analysis revealed a functional interaction between sonidegib and ¹⁷⁷Lu-octreotate, i.e. several cancer-related signaling pathways were modulated that were not affected by either monotherapy. Protein expression analysis indicated a possible PI3K/AKT/mTOR-dependent activation of the Hh pathway, independent of SMO.

http://ift.tt/2vfoZWS

Two different protein expression profiles of oral squamous cell carcinoma analyzed by immunoprecipitation high-performance liquid chromatography

Abstract

Background

Oral squamous cell carcinoma (OSCC) is one of the most dangerous cancers in the body, producing serious complications with individual behaviors. Many different pathogenetic factors are involved in the carcinogenesis of OSCC. Cancer cells derived from oral keratinocytes can produce different carcinogenic signaling pathways through differences in protein expression, but their protein expression profiles cannot be easily explored with ordinary detection methods.

Methods

The present study compared the protein expression profiles between two different types of OSCCs, which were analyzed through immunoprecipitation high-performance liquid chromatography (IP-HPLC).

Results

Two types of squamous cell carcinoma (SCC) occurred in a mandibular (SCC-1) and maxillary gingiva (SCC-2), but their clinical features and progression were quite different from each other. SCC-1 showed a large gingival ulceration with severe halitosis and extensive bony destruction, while SCC-2 showed a relatively small papillary gingival swelling but rapidly grew to form a large submucosal mass, followed by early cervical lymph node metastasis. In the histological observation, SCC-1 was relatively well differentiated with a severe inflammatory reaction, while SCC-2 showed severely infiltrative growth of each cancer islets accompanied with a mild inflammatory reaction. IP-HPLC analysis revealed contrary protein expression profiles analyzed by 72 different oncogenic proteins. SCC-1 showed more cellular apoptosis and invasive growth than SCC-2 through increased expression of caspases, MMPs, p53 signaling, FAS signaling, TGF-β1 signaling, and angiogenesis factors, while SCC-2 showed more cellular growth and survival than SCC-1 through the increased expression of proliferating factors, RAS signaling, eIF5A signaling, WNT signaling, and survivin.

Conclusions

The increased trends of cellular apoptosis and invasiveness in the protein expression profiles of SCC-1 were implicative of its extensive gingival ulceration and bony destruction, while the increased trends of cellular proliferation and survival in the protein profile of SCC-2 were implicative of its rapid growing tumor mass and early lymph node metastasis. These analyses of the essential oncogenic protein expression profiles in OSCC provide important information for genetic counseling or customized gene therapy in cancer treatment. Therefore, protein expression profile analysis through IP-HPLC is helpful not only for the molecular genetic diagnosis of cancer but also in identifying target molecules for customized gene therapy in near future.

http://ift.tt/2vB6oWx

Twisted intra-abdominal cyst in a neonate: a surprise revelation

We, herein, present a male neonate with an antenatally detected intra-abdominal cyst who presented at 18 days of life at which time, the ultrasound revealed a 5x4 cm cyst. Since he was asymptomatic, we planned to repeat the ultrasound a month later and operate if the cyst showed no regression. However, a week later, he presented with an acute abdomen, irritable cry and a repeat ultrasound showing a larger (8x6 cm) cystic mass with debris within. He was taken up for an emergency laparotomy. Intraoperatively, the cyst was found arising from the left lateral abdominal wall free from all structures with a twisted pedicle. Histopathology surprisingly revealed seminiferous tubules within the cyst wall with the vas deferens, thus confirming the diagnosis of a torsion of intra-abdominal testis. Hence, we emphasise the importance of examining for an undescended testis when dealing with a male neonate presenting with a cystic intra-abdominal mass.

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Staged retroperitoneal mesenteric revascularisation and aortobifemoral bypass after endovascular rescue for acute mesenteric ischaemia

Visceral artery revascularisation through a retroperitoneal approach provides an infrequent yet viable, alternative means of managing mesenteric ischaemia in patients with previous abdominal operations. We present a unique case implementing this surgical approach in a 55-year-old man in which we performed a retroperitoneal aortobifemoral bypass with concomitant retrograde jump graft from the aortic prosthesis to the superior mesenteric artery (SMA) for bilateral lower extremity rest pain and chronic mesenteric ischaemia. Three months previously, the patient had presented with acute mesenteric ischaemia and colonic perforation. He underwent emergent celiac artery stenting followed by an exploratory laparotomy with total abdominal colectomy and diverting loop ileostomy. Given the patient's hostile abdomen, a retroperitoneal approach to SMA revascularisation was elected over a transabdominal approach during concomitant lower extremity revascularisation for critical limb ischaemia. We achieved an excellent technical result with resolution of limb ischaemia and abdominal symptoms.

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High prevalence of co-infection between human papillomavirus (HPV) 51 and 52 in Mexican population

Abstract

Background

Human papillomavirus (HPV) is associated with the genesis of cervical carcinoma. The co-infection among HPV genotypes is frequent, but the clinical significance is controversial; in Mexico, the prevalence and pattern of co-infection differ depending on the geographic area of study. We analyzed the mono- and co-infection prevalence of multiple HPV genotypes, as well as preferential interactions among them in a Mexico City sample population.

Methods

This study was designed as a retrospective cohort study. Cervical cytology samples from 1163 women and 166 urethral scraping samples of men were analyzed between 2010 and 2012. The detection of HPV infection was performed using the hybrid capture and the genotyping was by PCR (HPV 6, 11, 16, 18, 30, 31, 33, 35, 45, 51, and 52).

Results

36% of women were HPV-positive and the most prevalent genotypes were HPV 51, 52, 16, and 33 (42, 38, 37, and 34%, respectively). The prevalence of co-infection was higher (75.37%) than mono-infection in women HPV positives. All genotypes were co-infected with HPV 16, but the co-infection with 51–52 genotypes was the most frequent combination in all cases.

Conclusion

The co-infection was very common; each HPV genotype showed different preferences for co-infection with other genotypes, HPV 51–52 co-infection was the most frequent. The HPV 16, 33, 51 and 52 were the most prevalent and are a public health concern to the Mexican population.

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Squamous differentiation in patients with superficial bladder urothelial carcinoma is associated with high risk of recurrence and poor survival

Abstract

Background

The independent prognostic role of squamous differentiation in pT1 bladder urothelial carcinoma has not been reported in previous studies. This article describes the impact of squamous differentiation on tumor recurrence and survival, and whether this histologic variant could indeed alter definitive treatment, based on single center-based retrospective data.

Methods

Totally, we retrieved (1)1449 histologically confirmed pT1 bladder urothelial carcinoma patients without histologic variants; (2)227 pT1 bladder urothelial carcinoma patients with squamous differentiation in our institution, from May 2004 to Oct 2015. The total amount of high/low grade urothelial carcinoma patients was 991/685 respectively. Transurethral resection of bladder tumor (TURBT) and intravesical chemotherapy were performed as initial treatments for all the patients. The clinical and pathological characteristics, treatment and survival outcomes were compared between squamous differentiation-positive and squamous differentiation-negative patients.

Results

In our study, 14% urothelial carcinoma patients were detected with squamous differentiation. The mean age of all the patients examined was 66.4, of whom 82% were males. The 5-year cancer specific survival rates were 69% for squamous differentiation-positive patients and 91% for squamous differentiation-negative patients (p < 0.001). Recurrence proved to be more common in squamous differentiation-positive patients than in negative patients. In the results of the univariate and multivariate Cox proportional hazard analysis, tumor size, lymphovascular invasion, recurrence and squamous differentiation were confirmed to be the prognostic factors associated with patients' survival.

Conclusions

Squamous differentiation in pT1 bladder urothelial carcinoma is correlated to high risk of recurrence and poor prognosis as an independent prognostic factor. Radical cystectomy is essential for recurred high grade pT1 bladder urothelial carcinoma with squamous differentiation accompanied by lymphovascular invasion.

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Comparison of efficacy, safety, and quality of life between sorafenib and sunitinib as first-line therapy for Chinese patients with metastatic renal cell carcinoma

Abstract

Background

Sorafenib and sunitinib are widely used as first-line targeted therapy for metastatic renal cell carcinoma (mRCC) in China. This study aimed to compare the efficacy, safety, and quality of life (QoL) in Chinese mRCC patients treated with sorafenib and sunitinib as first-line therapy.

Methods

Clinical data of patients with mRCC who received sorafenib (400 mg twice daily; 4 weeks) or sunitinib (50 mg twice daily; on a schedule of 4 weeks on treatment followed by 2 weeks off) were retrieved. Primary outcomes were overall survival (OS), progression-free survival (PFS), adverse events (AEs), and QoL (SF-36 scores), and secondary outcomes were associations of clinical characteristics with QoL.

Results

Medical records of 184 patients (110 in the sorafenib group and 74 in the sunitinib group) were reviewed. PFS and OS were comparable between the sorafenib and sunitinib groups (both P > 0.05). The occurrence rates of leukocytopenia, thrombocytopenia, and hypothyroidism were higher in the sunitinib group (36.5% vs. 10.9%, P < 0.001; 40.5% vs. 10.9%, P < 0.001; 17.6% vs. 3.6%, P = 0.001), and that of diarrhea was higher in the sorafenib group (62.7% vs. 35.2%, P < 0.001). There was no significant difference in SF-36 scores between the two groups. Multivariate analysis indicated that role-physical and bodily pain scores were associated with the occurrence rate of grade 3 or 4 AEs (P = 0.017 and 0.005).

Conclusions

Sorafenib has comparable efficacy and lower toxicity profile than sunitinib as first-line therapy for mRCC. Both agents showed no significant impact on QoL of patients.

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ZAR1 knockdown promotes the differentiation of human neuroblastoma cells by suppression of MYCN expression

Abstract

Although DNA hypermethylation at non-promoter region of the Zygote arrest 1 (ZAR1) gene has been observed in many types of tumor, including neuroblastoma (NB), the role of this gene in tumor development and/or progression is unclear. One reason is that knowledge about the function of ZAR1 protein is limited. Although it has been reported that ZAR1 plays a crucial role in early embryogenesis and may act as a transcriptional repressor for some transcripts, the detailed mechanism is still elusive. In the present study, we analyzed public data of NB patients and found that higher expression levels of ZAR1 were significantly associated with a shorter survival period. Consistent with this result, ZAR1-depleted NB cells showed well-differentiated phenotypes with elongated neurites and upregulated expression of TRKA and RET, which are markers for differentiated NB. Moreover, the expression level of MYCN protein was markedly suppressed in ZAR1-depleted NB cells. MYCN-depleted cells showed similar phenotypes to ZAR1-depleted cells. The present findings indicate that ZAR1 has oncogenic effects in NB by suppressing cell differentiation via regulation of MYCN expression.

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Predictive factors of prolonged mechanical ventilation, overall survival, and quality of life in patients with post-thymectomy myasthenic crisis

Abstract

Background

Thymectomy is the primary approach for the treatment of myasthenia gravis (MG). This retrospective study aimed to identify the clinical and demographical features that may impact the duration of mechanical ventilation (DMV), the long-term survival, and the quality of life (QOL) in patients with post-thymectomy myasthenic crisis (PTMC).

Methods

We reviewed the patients who suffered from PTMC from June 2008 to November 2015. Cox proportional hazard regression analysis was used to identify potential prognostic factors that may impact DMV and long-term survival. Spearman bivariate correlation analysis was used to analyze the relationship between DMV and QOL. Statistical powers were calculated.

Results

In total, 70 patients with PTMC were enrolled. Alcohol abuse, high scores of Myasthenia Gravis Foundation of America (MGFA) classification and Clavien-Dindo classification were critical factors that remarkably delayed early extubation. High scores of Osserman's classification, MGFA classification, and Clavien-Dindo classification predicted a poor prognosis in PTMC patients. Occupational skills and job status were observed to be negatively affected in PTMC patients.

Conclusions

To decrease the duration of mechanical ventilation, we suggest alcohol abstinence before the operation, appropriate preoperative treatment to decrease MGFA classification, and greater attention to the treatment of postoperative complications.

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Genetic association of telomere length with hepatocellular carcinoma risk: A Mendelian randomization analysis

Publication date: October 2017
Source:Cancer Epidemiology, Volume 50, Part A
Author(s): Yue Cheng, Chengxiao Yu, Mingtao Huang, Fangzhi Du, Ci Song, Zijian Ma, Xiangjun Zhai, Yuan Yang, Jibin Liu, Jin-Xin Bei, Weihua Jia, Guangfu Jin, Shengping Li, Weiping Zhou, Jianjun Liu, Juncheng Dai, Zhibin Hu
BackgroundObservational studies show an association between telomere length and Hepatocellular carcinoma (HCC) risk, but the relationship is controversial. Particularly, it remains unclear whether the association is due to confounding or biases inherent in conventional epidemiological studies. Here, we applied Mendelian randomization approach to evaluate whether telomere length is causally associated with HCC risk.MethodsIndividual-level data were from HBV-related HCC Genome-wide association studies (1,538 HBV positive HCC patients and 1,465 HBV positive controls). Genetic risk score, as proxy for actual measured telomere length, derived from nine telomere length-associated genetic variants was used to evaluate the effect of telomere length on HCC risk.ResultsWe observed a significant risk signal between genetically increased telomere length and HBV-related HCC risk (OR=2.09, 95% CI 1.32–3.31, P=0.002). Furthermore, a U-shaped curve was fitted by the restricted cubic spline curve, which indicated that either short or long telomere length would increase HCC risk (P=0.0022 for non-linearity test). Subgroup analysis did not reveal significant heterogeneity between different age, gender, smoking status and drinking status groups.ConclusionsOur results indicated that a genetic background that favors longer or shorter telomere length may increase HBV-related HCC risk—a U-shaped association.



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Anaphylaxis after disinfection with 2% chlorhexidine wand applicator

A 54-year-old man with end-stage renal failure attended for dialysis. Within seconds of applying 2% w/v chlorhexidine (ChloraPrep 3 mL Wand Applicator) to the skin surrounding the insertion point of his dialysis catheter (Tesio catheter), he developed pruritus, urticaria, shortness of breath, hypotension and reduced responsiveness. Treatment for anaphylaxis was initiated with rapid improvement of his symptoms, and he made a full recovery. Allergy to chlorhexidine was confirmed with skin testing, and the patient was warned against all future exposure to chlorhexidine. Subsequent dialysis without chlorhexidine was uneventful.

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Cor triatriatum and stroke

Cor triatriatum sinistrum (CTS) is a congenital anomaly where the left atrium is divided into two compartments by a fibromuscular membrane. This report aims to add to the literature on a rare cardiac condition that can cause neurological morbidity. We report a case of a 19-year-old female with an infarct in the right middle cerebral artery (MCA) territory initially maintained on aspirin. Eighteen months later, she had recurrence of weakness, for which repeat transthoracic echocardiography (TTE) and re-evaluation of the first TTE demonstrated a hyperechoic membrane spanning the width of the left atrium, clinching the diagnosis of CTS. Despite anticoagulation with apixaban, she was admitted for a third stroke where she succumbed to hospital-acquired pneumonia. Among cases of CTS associated with stroke, anticoagulation and surgery were the main modes of treatment. This case has the longest follow-up and the first to demonstrate failure of antiplatelet therapy and anticoagulation.

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Severe aortic complications in a patient with variant Shone's complex and bicuspid aortic valve

Description

A 47-year-old man presented with new onset exertional dyspnoea. He received a surgical repair of coarctation of the aorta (COA) at the age of 21 years and aortic root grafting with mechanical aortic valve replacement for type A aortic dissection and bicuspid aortic valve (BAV) at the age of 28 years. He had been otherwise healthy and did not follow-up with a cardiologist or surgeon after his last surgery. An echocardiogram (Echo) revealed normal left ventricular size and wall thickness, with an ejection fraction of 45%–50%. There was a parachute mitral valve (MV) (figure 1), with only one severely underdeveloped lateral papillary muscle. The mechanical aortic valve was functioning normally. There was a massively dilated distal aortic arch and proximal descending aorta with maximum dimension of up to 65 mm (figure 2). There was no Doppler evidence of recurrent COA. The CT angiogram confirmed the giant aneurysm,...

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Kaposi's sarcoma of the tonsils

Description

A 19-year-old HIV-positive man was referred to the ENT (ear, nose and throat) team with dysphagia and intermittent hearing loss. He had a CD4 count of 70 cells/mm³ (9%) and was receiving antiretroviral treatment (Raltegravir and Truvada). He had known Kaposi's sarcoma (KS) skin lesions on the neck and arms, and a left-sided level 5 neck node biopsy was positive for KS.

He gave a 2-week history of dysphagia at the level of the hyoid bone, as well as intermittent episodes of haemoptysis and haematemesis. He also described bilateral intermittent hearing loss over 2 weeks.

On examination there were large, irregular lesions on both tonsils, which clinically appeared to be KS (figure 1). There were several firm lymph nodes in the posterior triangle of the neck bilaterally and in the left supraclavicular fossa. Both tympanic membranes were dull and retracted. Flexible nasoendoscopy revealed a large adenoid...

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Will Availability of SMOF Lipid Emulsions for Parenteral Nutrition Change Surgical Nutrition Practice?

Abstract

Purpose of Review

Parenteral nutrition (PN) is a widely accepted form of nutrition administration in patients in whom enteral feeding is contraindicated or insufficient. This is true in surgical patient populations, as well. As a component of PN, intravenous fat emulsions (IVFEs) are essential for the administration of essential fatty acids (EFAs) and adequate energy intake. The oils that make up standard IVFE formulations have evolved over time.

Recent Findings

A newer formulation, known as SMOF, contains a combination of soybean oil, medium chain triglycerides, olive oil, and fish oil and is gaining popularity for its purported beneficial effects on liver function, inflammation, and anti-oxidant status.

Summary

This literature review examines the current data regarding the effects of SMOF in the patient receiving PN and examines the role SMOF may play in the future management of nutrition in the surgical population.

http://ift.tt/2wDBdX7

Long Standing Esophageal Perforation due to Foreign Body Impaction in Children: A Therapeutic Challenge in a Resource Limited Setting

Late presentation of foreign body impaction in the esophagus, complicated by perforation in children, has rarely been reported in the literature. Esophageal surgery is very difficult and challenging in Cameroon (a resource limited setting). We are reporting herein 2 cases of esophageal perforation in children seen very late (12 days and 40 days) after foreign body impaction, complicated with severe sepsis, who were successfully operated upon with very good results.

http://ift.tt/2vi3hjq

Cardiac Imaging: Multimodality Advances and Surveillance Strategies in Detection of Cardiotoxicity

Abstract

Contemporary cancer management has increased the overall number of cancer survivors, but cardiotoxicity remains a subject of concern, which is a major cause of noncancer mortality among survivors. Among the potential cardiovascular complications, left ventricular (LV) systolic dysfunction is a poor prognostic factor. The importance of its early detection is based on the principle that the likelihood of response to heart failure (HF) treatment is temporally related to the initiation of HF treatment. For these reasons, cardiac monitoring is commonly applied in general practice, based on serial measurements of LV ejection fraction (LVEF); transthoracic echocardiography (TTE) is generally used. However, the LVEF, as a diagnostic and predictive parameter, has significant limitations, which calls for more effective multimodality imaging strategies. This approach requires further study, but there is increasing available data in the literature, encouraging the combination of multimodality imaging parameters and techniques for early cancer therapeutic-related cardiac dysfunction (CTRCD) detection.

http://ift.tt/2uBHEJ9

Cancers, Vol. 9, Pages 103: Secondary Intracranial Tumors Following Radiotherapy for Pituitary Adenomas: A Systematic Review

Cancers, Vol. 9, Pages 103: Secondary Intracranial Tumors Following Radiotherapy for Pituitary Adenomas: A Systematic Review

Cancers doi: 10.3390/cancers9080103

Authors: Ryuya Yamanaka Eisuke Abe Toshiteru Sato Azusa Hayano Yasuo Takashima

Pituitary adenomas are often treated with radiotherapy for the management of tumor progression or recurrence. Despite the improvement in cure rates, patients treated by radiotherapy are at risk of development of secondary malignancies. We conducted a comprehensive literature review of the secondary intracranial tumors that occurred following radiotherapy to pituitary adenomas to obtain clinicopathological characteristics. The analysis included 48 neuroepithelial tumors, 37 meningiomas, and 52 sarcomas which were published between 1959–2017, although data is missing regarding overall survival and type of irradiation in a significant proportion of the reports. The average onset age for the pituitary adenoma was 37.2 ± 14.4 years and the average latency period before the diagnosis of the secondary tumor was 15.2 ± 8.7 years. Radiotherapy was administered in pituitary adenomas at an average dose of 52.0 ± 19.5 Gy. The distribution of pituitary adenomas according to their function was prolactinoma in 10 (7.2%) cases, acromegaly in 37 (27.0%) cases, Cushing disease in 4 (2.9%) cases, PRL+GH in 1 (0.7%) case, non-functioning adenoma in 57 (41.6%) cases. Irradiation technique delivered was lateral opposing field in 23 (16.7%) cases, 3 or 4 field technique in 27 (19.6%) cases, rotation technique in 10 (7.2%) cases, radio surgery in 6 (4.3%) cases. Most of the glioma or sarcoma had been generated after lateral opposing field or 3/4 field technique. Fibrosarcomas were predominant before 1979 (p &lt; 0.0001). The median overall survival time for all neuroepithelial tumors was 11 months (95% confidence intervals (CI), 3–14). Patients with gliomas treated with radiotherapy exhibited a non-significant positive trend with longer overall survival. The median overall survival time for sarcoma cases was 6 months (95% CI, 1.5–9). The median survival time in patients with radiation and/or chemotherapy for sarcomas exhibited a non-significant positive trend with longer overall survival. In patients treated with radiotherapy for pituitary adenomas, the risk of secondary tumor incidence warrants a longer follow up period. Moreover, radiation and/or chemotherapy should be considered in cases of secondary glioma or sarcoma following radiotherapy to the pituitary adenomas.

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Laser-Induced Choroidal Neovascularizations: Clinical Study of 3 Cases

Background: We report 3 patients with laser-induced choroidal neovascularization (CNV). Method: Retrospective, observational case series. Medical charts and photographs were reviewed. Results: Two patients with central serous chorioretinopathy who developed iatrogenic CNV after focal laser photocoagulation were treated with intravitreal ranibizumab injections. One patient with CNV secondary to thermal laser photocoagulation for diabetic macular edema was treated with photodynamic therapy (PDT). Visual improvement has been demonstrated in the patients treated with intravitreal ranibizumab injections, and their successful visual outcome was stable for more than 2 years. Stable visual acuity was also observed in the patient treated with PDT, no visual improvement was observed possibly due to the macular scar and macular ischemia. No systemic or ocular complications were detected among the 3 cases. Conclusion: To prevent a laser-induced CNV, it is critical to avoid heavy small-spot laser burns and repeated application. Patients should be monitored carefully for CNV after laser treatment. In our cases, PDT and intravitreal ranibizumab injections were effective for the treatment of laser-induced CNV.
Case Rep Ophthalmol 2017;8:429–435

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Electroencephalographic effect of age-adjusted 1 MAC desflurane and sevoflurane in young, middle-aged, and elderly patients

Abstract

Purpose

We examined the hypothesis that 1 minimum alveolar concentration (MAC) of desflurane and sevoflurane provides different depth of anesthesia.

Methods

One hundred and twenty young (20–30 years), middle-aged (31–65 years), and elderly (66–80 years) patients were randomly allocated to receive either desflurane or sevoflurane (n = 20, each group). General anesthesia was induced with propofol 2 mg/kg bolus and remifentanil 0.25 µg/kg/min, which was stopped after tracheal intubation. Maintenance of anesthesia was started with an end-tidal concentration of desflurane or sevoflurane at age-adjusted 1 MAC and maintained for 10 min, followed by 1-min assessment of bispectral index (BIS), 95% spectral edge frequency (SEF95), and amplitude of the electroencephalogram taken at 10-s intervals.

Results

BIS and SEF95 in patients receiving 1 MAC desflurane were significantly lower than those receiving 1 MAC sevoflurane including all age groups [35 (29, 39) vs. 41 (38, 49); 12.53 (10.99, 13.95) Hz vs. 14.42 (12.99, 17.17) Hz median (25, 75 percentile), respectively, P < 0.001 for both]. Both BIS and SEF95 in young patients were lower than in middle-aged and elderly patients receiving either desflurane or sevoflurane (P < 0.001 for both). There were no differences in amplitude between patients receiving desflurane and sevoflurane.

Conclusions

BIS as well as SEF95 were lower in patients receiving 1 MAC desflurane than those receiving 1 MAC sevoflurane, suggesting that desflurane provides higher depth of anesthesia than sevoflurane at 1 MAC.

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Breast density and impacts on health

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Prognosis of cancer in persons with infrequent consultations in general practice: A population-based cohort study

Abstract

Cancer survival rates are lower in Denmark than in comparable European countries. This may partly be attributable to subgroups of cancer patients who seek medical attention at late disease stages. It is unknown if differences in usual (i.e. customary) consultation frequency in general practice are associated with cancer prognosis.

We aimed to estimate the cancer prognosis of cancer patients stratified by their usual consultation frequency in general practice.

We performed a population-based cohort study including 123,943 incident cancer patients aged 50-89 years diagnosed in Denmark in 2009-2013. We estimated associations between the patient's usual general practitioner (GP) consultation frequency 19-36 months before the cancer diagnosis and all-cause mortality by using hazard ratios (HR), estimated by Cox proportional hazards regression. We also estimated the associations between the patient's usual GP consultation frequency and tumour stage, by using logistic regression estimates of odds ratios (ORs).

Patients who usually did not see their GP (non-consulters) had higher all-cause mortality (HR=1.39 (95% CI: 1.33-1.44)) compared to patients who usually saw their GP three to five times during an 18 months period (average consulters). Non-consulters had higher odds of having distant tumour stage (OR=1.46 (95% CI: 1.38-1.57)) than average consulters. Similar, yet less strong, patterns were seen among patients with low usual GP consultation frequency, yet not statistically significant for all cancer types.

In conclusion, the association between usual GP non-consultation and cancer prognosis is a combination of at least two things: a mechanism through more advanced tumour stage and other independent factors. This article is protected by copyright. All rights reserved.

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Low preoperative serum cholesterol level is associated with aggressive pathologic features and poor cancer-specific survival in patients with surgically treated renal cell carcinoma

Abstract

Background

The prognostic implications of preoperative serum total cholesterol (TC) level in patients with renal cell carcinoma (RCC) remain poorly understood. We investigated the prognostic role of preoperative serum TC in patients with surgically treated RCC from a large, multi-institutional Korean collaboration.

Patients and methods

A database of 3064 patients with RCC who underwent radical or partial nephrectomy between 1999 and 2011 at eight academic centers was analyzed. Preoperative serum TC levels were measured in fasting blood samples.

Results

Low preoperative serum TC level was associated with aggressive tumor characteristics, including large tumor size, advanced stage, high nuclear grade, lymph node involvement, and sarcomatous differentiation (all P < 0.001). Low TC level was associated with poor recurrence-free or cancer-specific survival (CSS) in the entire cohort, whereas the significance of the association changed after stratification by disease stage and histologic subtype. Multivariate Cox regression analysis showed that preoperative TC, as a continuous or categorical variable, was an independent predictor of CSS.

Conclusions

Preoperative low serum TC level was associated with aggressive tumor characteristics and poor CSS in patients with surgically treated RCC. Preoperative TC may provide additional guidance regarding the choice of therapeutic strategies to improve prognosis.

http://ift.tt/2hFb081

Impact of Imatinib on the Fertility of Male Patients with Chronic Myelogenous Leukaemia in the Chronic Phase

Abstract

Background

Imatinib is a first-line tyrosine kinase inhibitor for treating chronic myelogenous leukaemia (CML) and has greatly improved the prognosis of this disease. An increasing number of CML patients of reproductive age are diagnosed each year, and the impact of imatinib on fertility is a major concern. Providing useful advice to these patients regarding the choice of their therapeutic treatment is very important.

Objective

This study examined the impact of imatinib on the fertility of male patients with CML in the chronic phase.

Patients and Methods

We performed a study of 48 adult male CML patients in the chronic phase (CML-CP), 50 healthy control subjects, and 10 male patients with infertility. Imatinib levels in semen and plasma were measured using high-performance liquid chromatography/mass spectrometry. We examined the effects of imatinib on sperm parameters and the male reproductive system using a computer-assisted sperm assay and ultrasound, respectively. We analysed sex hormone levels in the sera of CML-CP patients using an enzyme-linked immunosorbent assay.

Results

Imatinib levels in semen were comparable to plasma levels in CML-CP patients. CML-CP patients treated with imatinib exhibited reduced sperm density, counts, survival rates, and activity. Ultrasound demonstrated that the shape and size of the testis and epididymis in CML-CP patients undergoing imatinib treatment were normal. However, 19 of these patients exhibited a hydrocele in their tunica vaginalis, with a large dark area of effusion (0.7–2.9 cm in width). Sex hormone levels in the sera of the CML-CP patients were normal.

Conclusions

These results suggest that imatinib crosses the blood-testis barrier and reduces sperm density, sperm count, survival rates, and activity in CML-CP patients. However, imatinib did not affect the structure of reproductive organs or sex hormone levels.

http://ift.tt/2vIdVCu