Risk factors for overweight and obesity in children aged 2–6 years

Journal Name: Journal of Pediatric Endocrinology and Metabolism
Issue: Ahead of print


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Anonymity and Electronics

Publication date: Available online 18 March 2017
Source:Academic Radiology
Author(s): Teresa Chapman, Janet R. Reid, Erin E. O'Conner
Rationale and ObjectivesDiagnostic radiology resident assessment has evolved from a traditional oral examination to computerized testing. Teaching faculty struggle to reconcile the differences between traditional teaching methods and residents' new preferences for computerized testing models generated by new examination styles. We aim to summarize the collective experiences of senior residents at three different teaching hospitals who participated in case review sessions using a computer-based, interactive, anonymous teaching tool, rather than the Socratic method.Materials and MethodsFeedback was collected from radiology residents following participation in a senior resident case review session using Nearpod, which allows residents to anonymously respond to the teaching material.ResultsSubjective resident feedback was uniformly enthusiastic. Ninety percent of residents favor a case-based board review incorporating multiple-choice questions, and 94% favor an anonymous response system.ConclusionsNearpod allows for inclusion of multiple-choice questions while also providing direct feedback to the teaching faculty, helping to direct the instruction and clarify residents' gaps in knowledge before the Core Examination.



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The rationale of indoleamine 2,3-dioxygenase inhibition for cancer therapy

Publication date: May 2017
Source:European Journal of Cancer, Volume 76
Author(s): Lieve Brochez, Ines Chevolet, Vibeke Kruse
Indoleamine 2,3-dioxygenase (IDO, also referred to as IDO1) has been demonstrated to be a normal endogenous mechanism of acquired peripheral immune tolerance in vivo.In the field of oncology, IDO expression and/or activity has been observed in several cancer types and has usually been associated with negative prognostic factors and worse outcome measures.This manuscript reviews current available data on the role of IDO in cancer and the current results obtained with IDO inhibition, both in animal models and in phase 1 and 2 clinical trials in humans. Preliminary results with IDO inhibitors, usually combined with other anti-cancer drugs, seem encouraging. Further studies are needed to clarify the conditions in which IDO inhibitors can be of value as an anti-cancer strategy. In addition, further research should address whether the expression of IDO in tissue or blood can be a marker to select patients who can benefit most from IDO inhibition.



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Biological mechanisms of immune escape and implications for immunotherapy in head and neck squamous cell carcinoma

Publication date: May 2017
Source:European Journal of Cancer, Volume 76
Author(s): Jennifer D. Moy, Jessica M. Moskovitz, Robert L. Ferris
Head and neck squamous cell carcinoma (HNSCC) is an aggressive malignancy with high morbidity and mortality. Despite advances in cytotoxic therapies and surgical techniques, overall survival (OS) has not improved over the past few decades. This emphasises the need for intense investigation into novel therapies with good tumour control and minimal toxicity. Cancer immunotherapy has led this endeavour, attempting to improve tumour recognition and expand immune responses against tumour cells. While various forms of HNSCC immunotherapy are in preclinical trials, the most promising direction thus far has been with monoclonal antibodies (mAbs), targeting growth factor and immune checkpoint receptors. Preclinical and early phase trials have shown unprecedented efficacy with minimal adverse effects. This article will review biological mechanisms of immune escape and implications for immunotherapy in HNSCC.



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Impaired quality of life in patients with treated acromegaly despite long-term biochemically stable disease: results from a 5-year prospective study

Abstract

Objective

Patients with acromegaly demonstrate impaired quality of life (QoL), but data on long-term QoL changes in treated acromegaly are limited. This study evaluates and identifies factors that influence QoL in patients with long-term biochemical remission.

Design

The study consists of a cross-sectional arm comparing QoL between patients with treated and controlled acromegaly and healthy controls; and a longitudinal arm assessing QoL changes in patients with biochemically stable disease during 5.7±0.6yrs of follow-up.

Patients

58 patients and 116 matched controls were recruited for the cross-sectional arm; 28 patients completed the longitudinal arm.

Measurements

Three generic questionnaires [Psychological General Well-Being Schedule (PGWBS), 36-item Short-Form (SF-36), EuroQoL (EQ-5D)] and the disease-specific acromegaly QoL questionnaire (AcroQoL) were applied.

Results

QoL assessment was performed 11.6±8.2yrs following diagnosis and treatment of acromegaly. Patients with treated acromegaly had lower QoL scores compared with controls in all questionnaires with the exception of the PGWBS "Anxiety" subscale. The AcroQoL "Appearance" subscale and the "physical function" subscales of the remaining questionnaires were the most underscored domains. No difference in the total and subscale scores of all questionnaires was observed between baseline and follow-up, with the exception of the SF-36 "Physical Function", where a decline was found (58.5±24.7% vs. 43.1±31.1%; p=0.002). However, after adjusting for covariates, no significant change in any of the QoL scores was seen. Duration of IGF-1/GH control was positively correlated with QoL scores in most questionnaires at baseline, whereas use of GH lowering therapy at the time of QoL assessment was a negative predictive factor of QoL.

Conclusions

Patients with biochemically controlled acromegaly demonstrate impaired QoL, which persists despite long-term disease control. This primarily consists of impaired physical function and secondly of impaired psycho-social well-being. Duration of biochemical disease control and current use of GH lowering therapy were the predominant factors determining patients' QoL.

This article is protected by copyright. All rights reserved.

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The effects of DASH diet on weight loss, anti-Müllerian hormone and metabolic profiles in women with polycystic ovary syndrome: a randomized clinical trial

Summary

Objective

This study was designed to evaluate the effects of the Dietary Approaches to Stop Hypertension (DASH diet) on weight loss, anti-Müllerian hormone (AMH) and metabolic profiles in women with polycystic ovary syndrome (PCOS).

Design, Patients and Measurements

A randomized controlled clinical trial was conducted among 60 overweight or obese patients with PCOS. Patients were randomly assigned to receive either low-calorie DASH (N=30) or control diet (N=30) for 12 weeks. The DASH and control diets were consisted of 52-55% carbohydrates, 16-18% proteins and 30% total fats; however, the DASH diet was designed to be rich in fruits, vegetables, whole grains, low-fat dairy products, cholesterol and refined grains. Both diets were equicaloric.

Results

Adherence to the DASH diet, compared to the control diet, resulted in a significant decrease in BMI (-1.6±0.5 vs. -1.2±0.7 kg/m², P=0.02). Significant decreases in AMH (-1.1±3.1 vs. +0.3±0.7 ng/mL, P=0.01), insulin (-25.2±51.0 vs. -1.2±28.8 pmol/L, P=0.02), homeostasis model of assessment-estimated insulin resistance (-0.9±2.0 vs. -0.1±1.0, P=0.02), free androgen index (FAI) (-0.03±0.09 vs. +0.06±0.21, P=0.02) and malondialdehyde (MDA) levels (-0.5±0.4 vs. +0.2±0.3 μmol/L, P<0.001), and significant increases in quantitative insulin sensitivity check index (+0.01±0.03 vs. -0.004±0.01, P=0.02), sex hormone-binding globulin (SHBG) (+3.7±8.5 vs. -1.5±7.2 nmol/L, P=0.01) and nitric oxide (NO) (+9.0±4.9 vs. +0.6±2.3 μmol/L, P<0.001) were also seen in the DASH group compared with the control group .

Conclusions

Adherence to the DASH diet for 12 weeks among PCOS women had beneficial effects on BMI, AMH, insulin metabolism, SHBG, FAI, NO and MDA levels.

This article is protected by copyright. All rights reserved.

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Biological predictors of radiosensitivity in head and neck squamous cell carcinoma

Abstract

Objectives

The aim of this study is to investigate the influence of prognostic biomarkers on radiosensitivity and survival of advanced head and neck squamous cell carcinomas treated by primary (chemo)radiation.

Material and methods

The clinicopathological data and immunohistochemical staining of p16, c-Met, survivin, PD-1, and PD-L1 of 82 primarily (chemo)irradiated patients with head and neck squamous cell carcinoma were analyzed. Associations with local and locoregional radiation response, overall survival (OS), disease-free (DFS), and disease-specific survival (DSS) were assessed.

Results

Complete tumor response was associated with increased patient age (p = 0.007), N0-status (p = 0.022), M0-status (p = 0.007), and p16-positivity (p = 0.022). High PD-L1 was associated with M0-status (p = 0.026) and indicated tumor response to irradiation (p = 0.057); survivin expression showed higher rates of response failure (p = 0.073). Low PD-1 was associated with increased T-stage (p = 0.029) and local recurrence (p = 0.014). High PD-1 was strongly correlated with PD-L1-positive tumor infiltrating lymphocytes (p < 0.001). Low PD-L1 showed a significant correlation with high c-Met expression (p = 0.01). Significant predictors for unfavorable univariate survival were incomplete tumor response (DSS, p < 0.001), single radiotherapy (DSS, p = 0.002), M1-status (DSS, p < 0.001), decreased radiation dose (DSS, p = 0.014), high survivin (DSS, p = 0.045), and high c-Met (OS, p < 0.05). Survivin and c-Met also showed prognostic significance in multivariate survival analysis.

Conclusions

P16 and PD-L1 indicate radiosensitivity, whereas survivin and c-Met implicate radioresistance in primarily (chemo)irradiated head and neck squamous cell carcinomas. The role of the PD-1/PD-L1 immune checkpoints in radiation response and survival merits further investigation.

Clinical relevance

The findings may improve patient-specific therapy according to individual tumor characteristics.

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Exogenous application of plant growth regulators (PGRs) induces chilling tolerance in short-duration hybrid maize

Abstract

Chilling stress hampers the optimal performance of maize under field conditions precipitously by inducing oxidative stress. To confer the damaging effects of chilling stress, the present study aimed to investigate the effects of some natural and synthetic plant growth regulators, i.e., salicylic acid (SA), thiourea (TU), sorghum water extract (SWE), and moringa leaf extract (MLE) on chilling stress tolerance in autumn maize hybrid. Foliar application of growth regulators at low concentrations was carried out at six leaf (V6) and tasseling stages. An increase in crop growth rate (CGR), leaf area index (LAI), leaf area duration (LAD), plant height (PH), grain yield (GY), and total dry matter accumulation (TDM) was observed in exogenously applied plants as compared to control. In addition, improved physio-biochemical, phenological, and grain nutritional quality attributes were noticed in foliar-treated maize plots as compared to non-treated ones. SA-treated plants reduced 20% electrolyte leakage in cell membrane against control. MLE and SA were proved best in improving total phenolic, relative water (19–23%), and chlorophyll contents among other applications. A similar trend was found for photosynthetic and transpiration rates, whereas MLE and SWE were found better in improving CGR, LAI, LAD, TDM, PH, GY, grains per cob, 1000 grain weight, and biological yield among all treatments including control. TU and MLE have significantly reduced the duration in phenological events of crop at the reproductive stage. MLE, TU, and SA also improved the grain protein, oil, and starch contents as compared to control. Enhanced crop water productivity was also observed in MLE-treated plants. Economic analysis suggested that MLE and SA applications were more economical in inducing chilling stress tolerance under field conditions. Although eliciting behavior of all growth regulators improved morpho-physiological attributes against suboptimal temperature stress conditions, MLE and SA acted as leading agents which proved to be better stress alleviators by improving plant physio-biochemical attributes and maize growth.

http://ift.tt/2mGLL3g

Toxic elements and bio-metals in Cantharellus mushrooms from Poland and China

Abstract

Data on multi-trace element composition and content relationships have been obtained for Cantharellus cibarius, C. tubaeformis, and C. minor mushrooms from Poland and China by inductive coupled plasma–dynamic reaction cell–mass spectroscopy. There is no previous data published on As, Li, V, Tl, and U in chanterelles from Poland and on Ba, Co, Cr, Ni, Rb, and Sr in chanterelles from China. The results implied a role of the soil background geochemistry at the collection site with the occurrence of Ag, As, Ba, Cr, Cs, Li, Mn, Pb, Rb, Sr, U, and V in the fruiting bodies. Both geogenic Cd and anthropogenic Cd can contribute in load of this element in chanterelles from the Świetokrzyskie Mts. region in Poland, while geogenic source can be highly dominant in the background areas of Yunnan. An essentiality of Cu and Zn and effort by mushroom to maintain their physiological regulation could be reflected by data for Cantharellus mushrooms from both regions of the world, but its geogenic source (and possibly anthropogenic) can matter also in the region of the Świetokrzyskie Mountains in Poland. The elements Co, Ni, and Tl were at the same order of magnitude in contents in C. cibarius in Poland and Yunnan, China. C. tubaeformis differed from C. cibarius by a lower content of correlated Co, Ni, and Zn. Soil which is polymetallic and highly weathered in Yunnan can be suggested as a natural geogenic source of greater concentrations of As, Ba, Cr, Li, Pb, Sr, U, and V in the chanterelles there while lower of Mn and Rb, when related to chanterelles in Poland. A difference in Cs content between the sites can be attributed as an effect of the ¹³⁷Cs release from the Chernobyl accident, in which Poland was much more affected than Yunnan, where deposition was negligible.

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Biodegradation of 2,2′,4,4′-tetrabromodiphenyl ether (BDE-47) by Phanerochaete chrysosporium in the presence of Cd 2+

Abstract

Aerobic biodegradation of 2,2′,4,4′-tetrabrominated diphenyl ether (BDE-47) by Phanerochaete chrysosporium in the presence of Cd²⁺ was investigated in this study. The results showed that P. chrysosporium could effectively degrade BDE-47, and its extracellular enzyme played an important role in the process of decomposition. BDE-47 biodegradation by fungi was more tolerant than extracellular enzyme in the presence of Cd²⁺. Also, both of the activity of two typical enzymes, MnP and LiP, descended with ascended Cd²⁺ concentration. Based on the four mono-hydroxylated PBDEs (5-OH-BDE-47, 4′-OH-BDE-17, 6-OH-BDE-47, and 2′-OH-BDE-28) and two bromophenols (2,4-DBP, 4-BP) detected, three possible degradation pathways were proposed, inferring that BDE-47 was more easily to transform via hydroxylation. With addition of Cd²⁺, the types of degradation products did not change, merely a variation of the content of these products observed. Meanwhile, the major metabolites of BDE-47, bromophenol compounds, have been found to be transformed or even mineralized by P. chrysosporium quickly, which also helped better explain why the amounts of BDE-47 decomposed did not match with that of the metabolites detected.

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Changes and relations of photosynthesis and iron cycling in anoxic paddy soil amended with high concentrations of sulfate

Abstract

Sulfate contamination is an increasingly serious environmental problem related to microbial reduction processes in anoxic paddy soil. This study revealed the changes and interrelations of ferric iron [Fe(III)] reduction, ferrous iron [Fe(II)] oxidation, and oxygenic photosynthesis in an anoxic paddy soil (Fe-accumuli-Stagnic Anthrosols) amended with a range of high sulfate concentrations. Soil slurries mixed with 0 (control), 50, 100, 200, and 400 mmol kg⁻¹ Na₂SO₄ were incubated anaerobically under dark and light conditions. The changes in chlorophyll a (Chl a), Fe(II), pH levels, and the chlorophyll absorption spectrum were determined over a 42-day period. Fe(II) concentrations increased with the addition of sulfate under dark conditions, while Fe(III) reduction potential was enhanced by increasing sulfate addition. The effect of light on Fe(II) concentration was observed after 16 days of incubation, when Fe(II) started to decrease markedly in the control. The decrease in Fe(II) slowed with increasing sulfate addition. The concentrations of Chl a increased in all treatments after 16 days of incubation under light conditions. There was a reduction in Chl a accumulation with increasing sulfate at the same incubation time. The absorption peaks of chlorophyll remained shorter than the 700-nm wavelength throughout the incubation period. The pH of all treatments decreased in the first week and then increased thereafter. The pH increased with sulfate addition and light conditions. In conclusion, contamination with high concentrations of sulfate could accelerate Fe(III) reduction while inhibiting oxygenic photosynthesis, which correspondingly slows chemical Fe(II) oxidation in an anoxic paddy soil.

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Nitrogen removal and microbial community shift in an aerobic denitrification reactor bioaugmented with a Pseudomonas strain for coal-based ethylene glycol industry wastewater treatment

Abstract

An aerobic denitrification system, initially bioaugmented with Pseudomonas strain T13, was established to treat coal-based ethylene glycol industry wastewater, which contained 3219 ± 86 mg/L total nitrogen (TN) and 1978 ± 14 mg/L NO₃⁻-N. In the current study, a stable denitrification efficiency of 53.7 ± 4.7% and nitrite removal efficiency of 40.1 ± 2.7% were achieved at different diluted influent concentrations. Toxicity evaluation showed that a lower toxicity of effluent was achieved when industry wastewater was treated by stuffing biofilm communities compared to suspended communities. Relatively high TN removal (~50%) and chemical oxygen demand removal percentages (>65%) were obtained when the influent concentration was controlled at below 50% of the raw industry wastewater. However, a further increased concentration led to a 20–30% decrease in nitrate and nitrite removal. Microbial network evaluation showed that a reduction in Pseudomonas abundance was induced during the succession of the microbial community. The napA gene analysis indicated that the decrease in nitrate and nitrite removal happened when abundance of Pseudomonas was reduced to less than 10% of the overall stuffing biofilm communities. Meanwhile, other denitrifying bacteria, such as Paracoccus, Brevundimonas, and Brucella, were subsequently enriched through symbiosis in the whole microbial network.

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Treatment of municipal wastewater in full-scale on-site sand filter reduces BOD efficiently but does not reach requirements for nitrogen and phosphorus removal

Abstract

A traditional sand filter for treatment of household wastewater was constructed in the fall of 2012 at Biolinja 12, Turku, Finland. Construction work was led and monitored by an authorized wastewater treatment consultant. The filter was placed on a field bordered by open ditches from all sides in order to collect excess rain and snowmelt waters. The filter was constructed and insulated from the environment so that all outflowing water was accounted for. Untreated, mainly municipal, wastewater from Varissuo suburb was pumped from a sewer separately via three septic tanks (volume = 1 m³ each) into the filters. Normally, wastewater was distributed to ground filters automatically according to pre-programmed schedule. Initially, the daily flow was 1200 L day⁻¹ to reflect the average organic load of a household of five persons (load: ca 237 g day⁻¹ BOD; 73 g day⁻¹ total N; and 10.4 g day⁻¹ total P). Later in the test, the flow rate was decreased first to 900 and then to 600 L day⁻¹ to better reflect the average volume produced by five persons. Volumes of inlet wastewater as well as treated water were monitored by magnetic flow meters. Samples were withdrawn from the inlet water, from the water entering the filters after the third septic tank, and from the outflowing water. After an initial adaption time, the reductions in BOD and chemical oxygen demand were constantly between 92 and 98%, showing that the biological degradation process in the filters functioned optimally and clearly comply with the national and EU standards. The reduction in total nitrogen and total phosphorus, however, reached required levels only during the first months of testing, apparently when buildup of microbial biomass was still ongoing. After this initial period of 3 months showing satisfactory reduction levels, the reduction of total nitrogen varied between 5 and 25% and total phosphorus mostly between 50 and 65%. Nitrification was efficient in the filter, but as indicated by high nitrate levels and poor nitrogen reductions, denitrification was inefficient or absent. During the winter period, the temperature in the filter dropped to near freezing, but at all time points, the flow of water was unaffected by freezing. During snowmelt and heavy rain, occasional flooding was observed. Such situations may lead to dilution rather than purification of the wastewater. In conclusion, the sand filter tested worked well for reduction of the organic load in municipal wastewater but failed to sufficiently reduce nitrogen and phosphorus levels.

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The influence of TNF-α and Ang II on the proliferation, migration and invasion of HepG2 cells by regulating the expression of GRK2

Abstract

Purpose

Hepatocellular carcinoma (HCC) is a common digestive system malignancy that is associated with a poor prognosis. This study researched the interaction of tumor necrosis factor-α (TNF-α) and angiotensin II (Ang II) in HCC cells proliferation, migration and invasion and examined their influence on the expression of G protein-coupled receptor kinase 2 (GRK2) and relevant receptors.

Methods

Cell Counting Kit-8 and Transwell assays were performed to evaluate the effects of TNF-α and Ang II on HepG2 cells proliferation, migration and invasion. Flow cytometry was used to investigate the expression of tumor necrosis factor receptor 1 (TNFR1), angiotensin II type 1 (AT1R) and type 2 receptors (AT2R) on the surface of HepG2 cells. Additionally, Western blot was performed to assess the modulation of GRK2 expression by TNF-α and Ang II in HepG2 cells. Meanwhile, GRK2 siRNA-transfected HepG2 cells were used to confirm the effects of GRK2, TNF-α and Ang II on the proliferation, migration and invasion of GRK2-knockdown HCC cells. Finally, the expression of TNF-α, Ang II, TNFR1, AT1R, AT2R and GRK2 proteins in HCC, tumor-adjacent and normal liver tissues were tested by immunohistochemistry.

Results

The data demonstrated that TNF-α and Ang II can enhance the proliferation, migration and invasion of HepG2 cells through suppressing GRK2 expression but that the two reagents combined did not have synergistic effects. Moreover,overexpression of TNFR1 and AT1R perhaps promoted the formation and progression of HCC, while high AT2R expression had the opposite effect.

Conclusions

This study provides new ideas for the prevention and treatment of HCC by researching the interaction and probable mechanism of different bioactive factors associated with HCC.

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Inhibition of GOT1 sensitizes colorectal cancer cells to 5-fluorouracil

Abstract

Purpose

Almost all colorectal cancer (CRC) cell lines are known to overexpress aspartate aminotransferase (GOT1), which potentially regulates the intracellular levels of reactive oxygen species (ROS) via the production of NADPH, and supports tumor growth. In our study, the role of GOT1 in the anticancer efficacy of 5-fluorouracil (5-FU) was examined.

Methods

HCT116, SW480, and HT-29 cells were transfected with lentiviral vectors expressing short hairpin RNA (shRNA) against GOT1. Following 5-FU treatment, cellular proliferation was evaluated, the NADP⁺/NADPH ratio was monitored, ROS was measured, and intracellular levels of glutamine (Gln), Aspartate (Asp), oxaloacetate (OAA), malate, and pyruvate were investigated using liquid chromatography–mass spectrometry (LC-MS). A CRC subcutaneous tumor model was performed to determine the impact of GOT1 inhibition on 5-FU efficacy in vivo.

Results

In response to 5-FU administration, CRC cells undergo metabolic adaptation, resulting in increased glutamine flux for the synthesis of aspartate. GOT1 is responsible for the conversion of glutamine-derived aspartate into OAA, which subsequently can be converted into malate and pyruvate. The GOT1-mediated metabolic process is able to maintain the NADP⁺/NADPH ratio, which counteracts 5-FU-induced oxidative stress. Inhibition of GOT1 impaired the defense against 5-FU-induced ROS, thereby sensitizing cells to 5-FU. The importance of GOT1 in supporting tumor growth during 5-FU treatment was also indicated in an in vivo tumor model of CRC.

Conclusion

These findings show that GOT1 could serve as a promising target for increasing the anticancer efficacy of the conventional therapy in patients with CRC.

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XPG genetic polymorphisms and clinical outcome of patients with advanced non-small cell lung cancer under platinum-based treatment: a meta-analysis of 12 studies

Abstract

Purpose

A number of studies on the relationship between xeroderma pigmentosum group G (XPG) polymorphisms and clinical outcomes in non-small cell cancer (NSCLC) have led to inconclusive results. This meta-analysis evaluates the predictive value of XPG polymorphisms on the treatment response rate and overall survival of patients with NSCLC.

Methods

To measure the correlative strength of the relationship between XPG polymorphisms and outcomes of patients with NSCLC, we searched electronic databases, including PubMed and China National Knowledge Infrastructure, to retrieve studies up to August 2016. We also employed pooled odds ratios (ORs) and hazard ratios (HRs) corresponding to 95% confidence intervals (95% CIs).

Results

Twelve studies involving 2877 patients with NSCLC were included: 8 studies involving 1473 patients examined the correlation between XPG polymorphisms and tumor response rate and 7 studies involving 2329 patients reported on the correlation of XPG polymorphisms with overall survival. None of the XPG His1104Asp(C>G)/His46His(C>T) polymorphisms exhibited a correlation with treatment response rate or overall survival. However, in a further stratified analysis by ethnicity, carriers of the 1104G allele were associated with good response among Asians in the homozygote model (GG vs. CC: OR = 1.57, 95% CI: 1.05–2.34, P = 0.027). Meanwhile, further stratified by ethnicity, His46His polymorphism was not associated with RR and OS in any genetic models.

Conclusions

No strong evidence was found to support the use of XPG polymorphisms as tumor response and prognostic factors of patients with NSCLC receiving a platinum-based treatment regimen, which is attributed to marginal association. Studies with large-scale and multiple ethnicities need to be conducted to verify the conclusion.

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An apparent clinical pharmacokinetic drug–drug interaction between bevacizumab and the anti-placental growth factor monoclonal antibody RO5323441 via a target-trapping mechanism

Abstract

Purpose

RO5323441 is a humanized anti-placental growth factor (PlGF) monoclonal antibody that has shown preclinical activity in several cancer models. The objective of this analysis is to examine the pharmacokinetic (PK) results from four Phase I studies that have been conducted with RO5323441 (n = 61) and to report an apparent drug–drug interaction observed when RO5323441 was administered in combination with bevacizumab.

Methods

The four Phase I studies were a multiple-ascending dose study in 23 patients with solid tumors (Study 1), an open-label study in seven patients with colorectal/ovarian cancer (Study 2), a sorafenib combination study in nine patients with hepatocellular carcinoma (Study 3), and a bevacizumab combination study in 22 patients with recurrent glioblastoma (Study 4). A two-compartment linear population PK model was developed from these four studies to characterize the PK of RO5323441 in patients with cancer.

Results

The PK properties of RO5323441 were similar in the first three studies. However, substantially higher RO5323441 exposures were observed in Study 4 when RO5323441 was administered in combination with bevacizumab. A linear two-compartmental population PK model indicated that the co-administration of bevacizumab would decrease the clearance of RO5323441 by 53%. Clinical data suggested that the decrease in RO5323441 clearance was inversely associated with bevacizumab exposure.

Conclusions

The exact reason for the increase in RO5323441 exposure following bevacizumab co-administration is not currently known. One possibility is a drug–drug interaction via a target-trapping mechanism that is mediated by the vascular endothelial growth factor receptor-1 (VEGFR-1).

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Prognostic impact of normalization of serum tumor markers following neoadjuvant chemotherapy in patients with borderline resectable pancreatic carcinoma with arterial contact

Abstract

Purpose

The survival benefit of neoadjuvant therapy for patients with borderline resectable pancreatic carcinoma has been reported recently. However, prognostic factors for this strategy have not been clearly elucidated. The aim of this study was to clarify prognostic factors for patients with borderline resectable pancreatic carcinoma who received neoadjuvant chemotherapy.

Methods

Medical records of 66 patients with pancreatic carcinoma with arterial contact who intended to undergo tumor resection following neoadjuvant chemotherapy were analyzed retrospectively. Prognostic factors were investigated by analyzing the clinicopathological factors with univariate and multivariate survival analyses.

Results

Gemcitabine plus S-1 was generally used as neoadjuvant chemotherapy. The objective response rate was 24%, and normalization of serum tumor markers following neoadjuvant chemotherapy was achieved in 29 patients (44%). Of the 66 patients, 60 patients underwent tumor resection and the remaining six patients did not due to distant metastases following neoadjuvant chemotherapy. For all 66 patients, overall 1-, 2-, and 5-year survival rates were 87.8, 54.5, and 20.5%, respectively (median survival time, 27.1 months) and multivariate analysis revealed that normalization of serum tumor markers was found to be an independent prognostic factor of better overall survival (P = 0.023). Moreover, for 60 patients who undergo tumor resection, normalization of serum tumor markers (P = 0.005) was independently associated with better overall survival by multivariate analysis.

Conclusions

Patients with pancreatic carcinoma with arterial contact who undergo neoadjuvant chemotherapy and experience normalization of serum tumor markers thereafter may be good candidates for tumor resection.

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Uncommon distant metastasis of pleural mesothelioma detected by whole-body 18F-FDG PET/CT

Publication date: Available online 18 March 2017
Source:Revista Española de Medicina Nuclear e Imagen Molecular
Author(s): C. Rapicetta, S. Taddei, M. Casali, R. Valli, F. Lococo, G. Treglia, M. Paci




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Unusual case of tumor of unknown origin found by 18F-FDG PET/CT: Metastatic clear cell carcinoma of the thyroid gland

Publication date: Available online 18 March 2017
Source:Revista Española de Medicina Nuclear e Imagen Molecular
Author(s): G. Treglia, P. Trimboli, V. Zilioli, F. Fulciniti, L. Giovanella




http://ift.tt/2mUOC9L