Targeting proprotein convertases in furin-rich lung cancer cells results in decreased in vitro and in vivo growth

ABSTRACT

Proprotein convertases (PCs) are serine proteases with an active role in the post-translational processing of numerous inactive proteins to active proteins including many substrates of paramount importance in cancer development and progression. Furin (PCSKC3), a well-studied member of this family, is overexpressed in numerous human and experimental malignancies. In the present communication we treated two furin-overexpressing non-small cell carcinoma (NSCLC) cell lines (Calu-6 andHOP-62) with the PC inhibitor CMK (Decanoyl-Arg-Val-Lys-Arg-chloromethylketone). This resulted in a diminished IGF-1R processing and a simultaneous decrease in cell proliferation of two NSCLC lines. Similarly, growth and proliferation of subcutaneous xenografts of both cell lines, were partially inhibited by an in vivo treatment with the same drug. These observations point to a potential role of PC inhibitors in cancer therapy. This article is protected by copyright. All rights reserved

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Protective effect of metformin in an aberrant crypt foci model induced by 1,2-dimethylhydrazine: Modulation of oxidative stress and inflammatory process

Abstract

Colorectal Cancer (CRC) is the third most frequent type of cancer worldwide. In the past few years, studies have revealed a protective effect of metformin (MET - an anti-hyperglycemic drug, used to treat type 2 diabetes), against CRC. The protective effect of MET has been associated with AMPK activation (and mTOR inhibition), resulting in suppressed protein synthesis, and reduced cell proliferation in malignant transformed cells. To elucidate new mechanisms for the protective effect of metformin, we evaluated the oxidative stress and inflammatory process modulation, since these processes are strictly involved in colorectal carcinogenesis. The present study evaluated the protective effect of MET in a CRC model induced by 1,2-dimethylhydrazine (DMH) in Balb/c female mice. The simultaneous/continuous treatment (administration of MET and DMH simultaneously), revealed protective activity of MET, preventing the formation of aberrant crypt foci (ACF) in 71.4% at distal colon sections, and was able to restore basal labeling of apoptosis. Treatment with MET also reduced the inflammatory process induced by DMH, resulting in of the reduction of oxidative stress and nitric oxide related parameters. This article is protected by copyright. All rights reserved

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Alternative lengthening of telomeres does exist in various canine sarcomas

Abstract

Alternative lengthening of telomeres (ALT) is a telomere maintenance mechanism (TMM) found in some human tumors such as sarcomas. Canine tumors are not characterized for ALT and the study aim was to identify if the ALT phenotype exists in canine sarcomas. Sixty-four canine sarcoma samples (20 snap-frozen, 44 FFPE) as well as six canine sarcoma cell lines were screened for ALT by C-circle assay. ALT was further evaluated by measuring telomere length via qPCR and telomere restriction-fragments including pulsed-field electrophoresis. ALT-associated proteins were validated by immunohistochemistry. Further, telomerase activity (TA) and gene expression were analyzed by TRAP and qPCR. DNA from 20 human neuroblastomas and 8 sarcoma cell lines served as comparative controls. ALT was detected in 9.4% (6/64) canine sarcomas including aggressive subtypes as hemangiosarcoma, osteosarcoma and histiocytic sarcoma. C-circle levels were comparable with human ALT-positive controls. All ALT tumors demonstrated loss of ATRX expression and 5/6 showed strong p53 expression. TA was detected in 93% (14/15) snap-frozen samples including a sarcoma with ALT activity. This tumor showed long heterogeneous telomeres, and a high level of colocalization of DAXX with telomeres. One sarcoma was ALT and TA negative. All canine and human sarcoma cell lines were ALT negative. In this study we demonstrated that canine sarcomas use ALT. As in humans, ALT was identified in aggressive sarcomas subtypes and coexisted with TA in one tumor. Overall, canine sarcomas seem to share many similarities with their human counterparts and appear an attractive model for comparative telomere research. This article is protected by copyright. All rights reserved

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The Effect of Zinc Supplementation on Insulin Resistance in Obese Subjects: a Systematic Review

Abstract

Obesity is a chronic disease characterized by excessive accumulation of body fat and the presence of metabolic disorders such as insulin resistance. In this sense, zinc is an important nutrient that stimulates insulin secretion and increases sensitivity to insulin. The aim of this study was to investigate the effect of zinc supplementation on insulin resistance in obese subjects through a systematic review of the available clinical trials. The search for articles was conducted using the PubMed, SciVerse Scopus, SciVerse ScienceDirect, and Cochrane databases, on May 25, 2016, by two authors independently. The recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) were followed in the conduct of this review. The Cochrane Collaboration tool was used to assess the risk of bias of the trials included in this review. After screening of the articles, six clinical trials were included in this systematic review. The scientific evidence presented in this systematic review shows that zinc supplementation improves insulin resistance in obese individuals of both sexes.

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Association of axitinib plasma exposure and genetic polymorphisms of ABC transporters with axitinib-induced toxicities in patients with renal cell carcinoma

Abstract

Purpose

Axitinib is a selective tyrosine kinase inhibitor of VEGF receptors, approved for advanced renal cell carcinoma (RCC). Associations between axitinib plasma exposure, genetic polymorphisms of ABC transporters and axitinib-induced toxicities have not been adequately explored.

Methods

Twenty RCC patients treated with axitinib were enrolled in this study. Blood samples were collected 0, 0.5, 1, 2, 4, and 6 h after administration of axitinib on day 1 and at steady state. Plasma concentrations of axitinib were analyzed by UPLC–MS/MS. The ABCG2 (421C>A) and ABCB1 (1236C>T, 2677G>T/A, 3435C>T) genetic polymorphisms were determined by real-time PCR.

Results

ABCB1 haplotype was associated with increased dose-adjusted area under the plasma concentration–time curve (AUC) of axitinib at steady state. The incidence of fatigue during therapy was associated with high AUC_0–6 of axitinib (P = 0.013). The treatment period without discontinuation or dose reduction due to adverse events in patients with high AUC_0–6 of axitinib was significantly shorter than for those with low AUC_0–6 (P = 0.024). No significant differences were found in the frequency of adverse events among the ABCG2 genotype and ABCB1 haplotype groups.

Conclusions

Our results have demonstrated that adverse events leading to discontinuation or dose reduction in axitinib were associated with increased axitinib plasma exposure, but not directly with genetic polymorphisms of ABC transporters. Therefore, measurement of steady state axitinib plasma concentrations may be useful in avoiding adverse events in axitinib therapy.

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Ionotropic glutamate receptor antagonists and cancer therapy: time to think out of the box?

Abstract

Glutamate has a trophic function in the development of the central nervous system, regulating the proliferation and migration of neuronal progenitors. The resemblance between neuronal embryonic and tumor cells has paved the way for the investigation of the effects of glutamate on tumor cells. Indeed, tumor cells derived from neuronal tissue express ionotropic glutamate receptor (iGluRs) subunits and iGluR antagonists decrease cell proliferation. Likewise, iGluRs subunits are expressed in several peripheral cancer cells and blockade of the N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) ionotropic glutamate receptor subtypes decreases their proliferation and migration. Although these mechanisms are still being investigated, the inhibition of the mitogen-activated protein kinase pathway was shown to play a key role in the antiproliferative activity of iGluR antagonists. Importantly, MK-801, a NMDAR channel blocker, was effective and well tolerated in animal models of melanoma, lung, and breast cancers, suggesting that the blockade of iGluR signaling may represent a new strategy for cancer treatment. In this review, we focus on the significance of NMDA and AMPA receptor expression in tumor cells, as well as possible therapeutic strategies targeting these receptors.

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A pilot study of concurrent chemoradiotherapy with gemcitabine and cisplatin in patients with locally advanced biliary tract cancer

Abstract

Purpose

Combination chemotherapy with gemcitabine and cisplatin is a standard treatment for patients with advanced biliary tract cancer. This study aimed to evaluate the efficacy and safety of gemcitabine- and cisplatin-based concurrent chemoradiotherapy in patients with unresectable biliary tract cancer.

Methods

Patients with pathologically proven, unresectable, non-metastatic biliary tract cancer were enrolled. Gemcitabine was administered intravenously at a dose of 1000 mg/m² on days 1, 8, and 15. Cisplatin was administered intravenously at a dose of 70 mg/m² on day 1. All the patients underwent concurrent radiotherapy with 45 Gy in 1.8-Gy daily fractions. After treatment completion, tumor response was evaluated by using computed tomography.

Results

Eighteen patients were enrolled between June 2007 and October 2011. Their median age was 61 years (range, 38–72 years). Eight patients (44.5 %) were diagnosed with gallbladder cancer, six (33.3 %) with Klatskin's tumor, and four (22.2 %) with distal common bile duct cancer. After treatment completion, partial response was achieved in five patients (27.8 %) and stable disease in 13 patients (72.2 %). The overall response rate was 27.8 %, and the disease stabilization rate was 100 %. No grade 4 adverse events or treatment-related deaths occurred. The most common grade 3 adverse events were thrombocytopenia (33.3 %) and anemia (11.1 %). The median progression-free and overall survival times were 6.8 months (range, 4.5–19.8 months) and 9.6 months (5.4–30.4 months), respectively.

Conclusions

This study shows that gemcitabine- and cisplatin-based concurrent chemoradiotherapy is feasible and tolerable in patients with unresectable and non-metastatic biliary tract cancer.

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Venetoclax does not prolong the QT interval in patients with hematological malignancies: an exposure–response analysis

Abstract

Purpose

Venetoclax (ABT-199/GDC-0199) is a selective first-in-class B cell lymphoma-2 inhibitor being developed for the treatment of hematological malignancies. The aim of this study was to determine the potential of venetoclax to prolong the corrected QT (QT_c) interval and to evaluate the relationship between systemic venetoclax concentration and QT_c interval.

Methods

The study population included 176 male and female patients with relapsed or refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (n = 105) or non-Hodgkin's lymphoma (n = 71) enrolled in a phase 1 safety, pharmacokinetic, and efficacy study. Electrocardiograms were collected in triplicate at time-matched points (2, 4, 6, and 8 h) prior to the first venetoclax administration and after repeated venetoclax administration to achieve steady state conditions. Venetoclax doses ranged from 100 to 1200 mg daily. Plasma venetoclax samples were collected after steady state electrocardiogram measurements.

Results

The mean and upper bound of the 2-sided 90 % confidence interval (CI) QT_c change from baseline were <5 and <10 ms, respectively, at all time points and doses (<400, 400, and >400 mg). Three subjects had single QT_c values >500 ms and/or ΔQT_c > 60 ms. The effect of venetoclax concentration on both ΔQT_c and QT_c was not statistically significant (P > 0.05). At the mean maximum concentrations achieved with therapeutic (400 mg) and supra-therapeutic (1200 mg) venetoclax doses, the estimated drug effects on QT_c were 0.137 (90 % CI [−1.01 to 1.28]) and 0.263 (90 % CI [–1.92 to 2.45]) ms, respectively.

Conclusion

Venetoclax does not prolong QT_c interval even at supra-therapeutic doses, and there is no relationship between venetoclax concentrations and QT_c interval.

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The role of Ly49E receptor expression on murine intraepithelial lymphocytes in intestinal cancer development and progression

Abstract

Ly49E is a member of the Ly49 family of NK receptors and is distinct from other members of this family on the basis of its structural properties, expression pattern and ligand recognition. Importantly, Ly49E receptor expression is high on small intestinal and colonic intraepithelial lymphocytes (IELs). Intestinal IELs are regulators of the mucosal immune system and contribute to front-line defense at the mucosal barrier, including anti-tumor immune response. Whereas most Ly49 receptors have MHC class-I ligands, we showed that Ly49E is instead triggered by urokinase plasminogen activator (uPA). uPA has been extensively implicated in tumor development, where increased uPA expression correlates with poor prognosis. As such, we investigated the role of Ly49E receptor expression on intestinal IELs in the anti-tumor immune response. For this purpose, we compared Ly49E wild-type mice to Ly49E knockout mice in two established tumor models: Apc^Min/+-mediated and azoxymethane-induced intestinal cancer. Our results indicate that Ly49E expression on IELs does not influence the development or progression of intestinal cancer.

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Thermal and mechanical high-intensity focused ultrasound: perspectives on tumor ablation, immune effects and combination strategies

Abstract

Tumor ablation technologies, such as radiofrequency-, cryo- or high-intensity focused ultrasound (HIFU) ablation will destroy tumor tissue in a minimally invasive manner. Ablation generates large volumes of tumor debris in situ, releasing multiple bio-molecules like tumor antigens and damage-associated molecular patterns. To initiate an adaptive antitumor immune response, antigen-presenting cells need to take up tumor antigens and, following activation, present them to immune effector cells. The impact of the type of tumor ablation on the precise nature, availability and suitability of the tumor debris for immune response induction, however, is poorly understood. In this review, we focus on immune effects after HIFU-mediated ablation and compare these to findings using other ablation technologies. HIFU can be used both for thermal and mechanical destruction of tissue, inducing coagulative necrosis or subcellular fragmentation, respectively. Preclinical and clinical results of HIFU tumor ablation show increased infiltration and activation of CD4⁺ and CD8⁺ T cells. As previously observed for other types of tumor ablation technologies, however, this ablation-induced enhanced infiltration alone appears insufficient to generate consistent protective antitumor immunity. Therapies combining ablation with immune stimulation are therefore expected to be key to boost HIFU-induced immune effects and to achieve systemic, long-lasting, antitumor immunity.

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Association between polymorphisms in xenobiotic detoxification-related genes with prognosis of epithelial ovarian cancer

Abstract

This study aimed to evaluate whether GSTM1 and GSTT1 (presents or nulls), GSTP1 c.313A>G and NQO2 c.-102A>C polymorphisms, involved in xenobiotic detoxification pathways, alter outcomes of epithelial ovarian cancer (EOC) patients. DNA from 84 EOC patients diagnosed at the University of Campinas Academic Hospital from January 1995 and July 2007 was analyzed by polymerase chain reaction and restriction fragment length polymorphism assays. The prognostic impact of genotypes of polymorphisms on progression-free survival and overall survival (OS) of EOC patients was examined using the Kaplan–Meier probability estimates and univariate and multivariate Cox proportional hazard ratio (HR) regression analyses. The significant results of Cox analyses were validated using a bootstrap resampling study (1000 replications). At 60 months of follow-up, lower OS was seen in patients with GSTT1 null genotype (50.0 vs. 76.7 %, P = 0.02) compared with the other genotype (Kaplan–Meier estimate). This outcome remained the same in univariate Cox analysis (HR 2.22, P = 0.02). After multivariate Cox analysis, patients with GSTT1 null (HR 2.11, P = 0.04, P _bootstrap = 0.04) and NQO2 AA (HR 2.13, P = 0.03, P _bootstrap = 0.04) genotypes were under greater risks of progressing to death when compared with those with others genotypes. Our data suggest, for the first time, that inherited abnormalities in xenobiotic detoxification pathway related to GSTT1 and NQO2 c.-102A>C polymorphisms act as independent prognostic factors for OS of EOC patients.

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Pioglitazone is equally effective for diabetes prevention in older versus younger adults with impaired glucose tolerance

Abstract

To determine the efficacy of pioglitazone to prevent type 2 diabetes in older compared to younger adults with pre-diabetes. Six hundred two participants with impaired glucose tolerance (IGT) were randomized in double blind fashion to placebo or pioglitazone for diabetes prevention in the ACT NOW study (NEJM 364:1104–1115, 2011). Cox proportional hazard regression was used to compare time to development of diabetes over a mean of 2 years between older (≥61 years) and younger participants. We compared effects of pioglitazone versus placebo on metabolic profiles, inflammatory markers, adipokines, β cell function (disposition index), insulin sensitivity (Matsuda index), and body composition by ANOVA. Diabetes incidence was reduced by 85 % in older and 69 % in younger subjects (p = 0.41). β cell function (disposition index) increased by 35.0 % in the older and 26.7 % in younger subjects (p = 0.83). Insulin sensitivity (Matsuda index) increased by 3.07 (5.2-fold) in older and by 2.54 (3.8-fold) in younger participants (p = 0.58). Pioglitazone more effectively increased adiponectin in older versus younger subjects (22.9 ± 3.2 μg/mL [2.7-fold] vs. 12.7 ± 1.4 μg/mL [2.2-fold], respectively; p = 0.04). Younger subjects tended to have a greater increase in whole body fat mass compared to older subjects (3.6 vs. 3.1 kg; p = 0.061). Younger and older subjects had similar decreases in bone mineral density (0.018 ± 0.0071 vs. 0.0138 ± 0.021 g/cm²). Younger and older pre-diabetic adults taking pioglitazone had similar reductions in conversion to diabetes and older adults had similar or greater improvements in metabolic risk factors, demonstrating that pioglitazone is useful in preventing diabetes in older adults.

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Association between rapid force production by the plantar flexors and balance performance in elderly men and women

Abstract

Plantar flexion strength and balance ability are considered to be crucial for avoiding falls. However, no clear relationship has been established between these two factors in elderly population. This study aimed to examine the association between plantar flexion strength and balance performance in elderly men and women. Forty-three men and 35 women aged over 65 years performed isometric plantar flexion as fast and hard as possible. From the time-torque curve, the rate of torque development in time intervals of 30, 50, 100, 150, and 200 ms from the onset of contraction was determined and normalized to peak torque. In addition, the center of pressure displacement during single-leg standing was calculated and normalized to height. When the data were collapsed over sexes, the normalized rate of torque development was negatively correlated with the normalized center of pressure displacement, except for the time interval of 200 ms. By sex, regardless of the time interval, there was a negative correlation between the normalized rate of torque development and the normalized center of pressure displacement in the elderly men but not in the elderly women. No correlation was seen between the peak torque and normalized center of pressure displacement in either pooled or separated data. The findings suggest that the capability of rapid force production rather than maximal force production of the plantar flexion is important for balance ability in elderly men, but this capability may not be relevant in elderly women.

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The role of Ly49E receptor expression on murine intraepithelial lymphocytes in intestinal cancer development and progression

Abstract

Ly49E is a member of the Ly49 family of NK receptors and is distinct from other members of this family on the basis of its structural properties, expression pattern and ligand recognition. Importantly, Ly49E receptor expression is high on small intestinal and colonic intraepithelial lymphocytes (IELs). Intestinal IELs are regulators of the mucosal immune system and contribute to front-line defense at the mucosal barrier, including anti-tumor immune response. Whereas most Ly49 receptors have MHC class-I ligands, we showed that Ly49E is instead triggered by urokinase plasminogen activator (uPA). uPA has been extensively implicated in tumor development, where increased uPA expression correlates with poor prognosis. As such, we investigated the role of Ly49E receptor expression on intestinal IELs in the anti-tumor immune response. For this purpose, we compared Ly49E wild-type mice to Ly49E knockout mice in two established tumor models: Apc^Min/+-mediated and azoxymethane-induced intestinal cancer. Our results indicate that Ly49E expression on IELs does not influence the development or progression of intestinal cancer.

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Thermal and mechanical high-intensity focused ultrasound: perspectives on tumor ablation, immune effects and combination strategies

Abstract

Tumor ablation technologies, such as radiofrequency-, cryo- or high-intensity focused ultrasound (HIFU) ablation will destroy tumor tissue in a minimally invasive manner. Ablation generates large volumes of tumor debris in situ, releasing multiple bio-molecules like tumor antigens and damage-associated molecular patterns. To initiate an adaptive antitumor immune response, antigen-presenting cells need to take up tumor antigens and, following activation, present them to immune effector cells. The impact of the type of tumor ablation on the precise nature, availability and suitability of the tumor debris for immune response induction, however, is poorly understood. In this review, we focus on immune effects after HIFU-mediated ablation and compare these to findings using other ablation technologies. HIFU can be used both for thermal and mechanical destruction of tissue, inducing coagulative necrosis or subcellular fragmentation, respectively. Preclinical and clinical results of HIFU tumor ablation show increased infiltration and activation of CD4⁺ and CD8⁺ T cells. As previously observed for other types of tumor ablation technologies, however, this ablation-induced enhanced infiltration alone appears insufficient to generate consistent protective antitumor immunity. Therapies combining ablation with immune stimulation are therefore expected to be key to boost HIFU-induced immune effects and to achieve systemic, long-lasting, antitumor immunity.

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Pediatric Radiology Continuing Medical Education Activity

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Comparative analysis of anterior and posterior contrast injection approaches for shoulder MR arthrograms in adolescents

Abstract

Background

There is no consensus in the literature concerning the optimal approach for performing a fluoroscopically guided shoulder arthrogram injection in a pediatric population.

Objective

To compare adequacy of capsular injection and radiation doses between fluoroscopically guided anterior and posterior glenohumeral joint contrast injections in adolescents.

Materials and methods

We evaluated imaging in 67 adolescents (39 boys, 28 girls; mean age 16.0 years; range 11.7–19.1 years) who underwent an anterior approach glenohumeral contrast injection with subsequent MR imaging, and 67 age- and gender-matched subjects (39 boys, 28 girls; mean age 16.0 years; range 11.1–19.2 years) who underwent a posterior approach injection during the period June 2010 to September 2015. Two pediatric radiologists independently evaluated all MR shoulder arthrograms to assess adequacy of capsular distention and degree of contrast extravasation. We recorded total fluoroscopic time, dose–area product (DAP) and cumulative air kerma (CAK).

Results

There were no significant differences in age, gender, height, weight or body mass index between the populations (P-values > 0.6). The amount of contrast extravasation between the groups was not significantly different (P = 0.27). Three anterior injections (4.5%) and one posterior (1.5%) were suboptimal (P = 0.62). Fluoroscopy time was not different: 1.1 min anterior and 1.3 min posterior (P = 0.14). There was a significant difference in CAK (0.7 mGy anterior and 1.1 mGy posterior; P = 0.007) and DAP (5.3 μGym² anterior and 9.4 μGym² posterior; P = 0.008). Inter-rater agreement was excellent (Cohen kappa >0.81).

Conclusion

Both techniques were technically successful. There was no difference in the fluoroscopy time for either approach. The radiation dose was higher with the posterior approach but this is of questionable clinical significance.

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Hermes

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Comparison of complications between pediatric peripherally inserted central catheter placement techniques

Abstract

Background

Peripherally inserted central catheter (PICC) is among the most common procedures performed in children in the hospital setting. PICC insertion can be simplified with the use of a sheathed needle as an alternative to the modified Seldinger technique.

Objective

To retrospectively evaluate PICC placement for the technique used and the incidence of complications at a large pediatric tertiary care center.

Materials and methods

We retrospectively reviewed all PICC placements at a single institution over a 4-year period. We reviewed patient records for demographic data, PICC placement technique, catheter size and number of lumens, and the incidence of complications (i.e. multiple attempted puncture sites, phlebitis and vessel thrombosis). We analyzed complication rates between two placement techniques using a chi-square test.

Results

We identified 8,816 successful PICC placements, 4,749 (53.9%) in males and 4,067 (46.1%) in females. The average age of the patients for which a line was placed was 5.6 years (range 1 day to 45 years). A direct sheathed needle puncture technique was used in 8,362 (94.9%) placements and a modified Seldinger technique was used in 454 (5.1%). Complications occurred in 312 (3.7%) of direct sheathed needle puncture placements versus 17 (3.7%) of modified Seldinger placements (P = 0.99). Multiple puncture sites were required in 175 (2.1%) attempted direct sheathed needle puncture placements compared with 8 (1.7%) attempted modified Seldinger placements (P = 0.63). Phlebitis occurred in 94 (1.1%) direct sheathed needle puncture lines versus 5 (1.1%) modified Seldinger placed lines (P = 0.96). Vessel thrombosis occurred in 43 (0.5%) direct sheathed needle puncture lines versus 4 (0.9%) modified Seldinger placed lines (P = 0.30).

Conclusion

The direct peel-away sheathed needle vessel puncture technique and the modified Seldinger technique used to place PICC lines in children have similar complication rates.

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Prospective detection of cortical dysplasia on clinical MRI in pediatric intractable epilepsy

Abstract

Background

Cortical dysplasia is the most common cause of pediatric refractory epilepsy. MRI detection of epileptogenic lesion is associated with good postsurgical outcome. Additional electrophysiological information is suggested to be helpful in localization of cortical dysplasia. Educational measures were taken to increase the awareness of cortical dysplasia at our institution in the context of a recent International League Against Epilepsy (ILAE 2011) classification of cortical dysplasia.

Objective

To determine changes in the rate of prospective identification of cortical dysplasia on an initial radiology report and also evaluate the benefit of MRI review as part of a multidisciplinary epilepsy conference in identifying previously overlooked MRI findings.

Materials and methods

We retrospectively evaluated surgically treated children with refractory epilepsy from 2007 to 2014 with cortical dysplasia on histopathology. We analyzed the initial radiology report, preoperative MRI interpretation at multidisciplinary epilepsy conference and subsequent retrospective MRI review with knowledge of the resection site. We recorded additional electrophysiological data and the presence of lobar concordance with the MRI findings.

Results

Of 78 children (44 MRI lesional) evaluated, 18 had initially overlooked MRI findings. Comparing 2007–2010 to 2011–2014, there was improvement in the rate of overlooked findings on the initial radiology report (54% vs. 13% of lesional cases, respectively; P = 0.008). The majority (72%) were identified at a multidisciplinary conference with lobar concordance of findings with at least one additional electrophysiological investigation in 89%.

Conclusion

Awareness of current classification schemes of cortical dysplasia and image review in the context of a multidisciplinary conference can lead to improved MRI detection of cortical dysplasia in children.

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Presentation to publication: proportion of abstracts published for ESPR, SPR and IPR

Abstract

Background

Advancement of knowledge requires presentation and publication of high-quality scientific research. Studies submitted for presentation undergo initial peer review before acceptance and the rate of subsequent publication may be taken as an indicator of access to publication for pediatric radiology studies.

Objectives

Evaluate the proportion of abstracts also published in journals for pediatric radiology conferences and identify factors associated with publication success.

Materials and methods

All Medline articles that originated from oral presentations at the European Society for Paediatric Radiology (ESPR), the Society for Pediatric Radiology (SPR) or the International Pediatric Radiology (IPR) conferences between 2010 – 2012 were evaluated. Descriptive statistics to evaluate published and unpublished groups were calculated overall and split by characteristics of the abstracts such as number of authors.

Results

Overall number of abstracts published was 300/715 (41.9%), with most articles published in radiology specific journals (181/300; 60.3%), with median impact factor 2.31 (interquartile range [IQR]: 1.65-3.14, range: 0-18.03). Those published after the conference (262/300, 87.6%) had a median time to publication of 18 months and for those published before, the median time was -11 months. Median sample size in published articles was 52 (IQR: 33-105, range: 1-6,351).

Conclusion

Of pediatric radiology oral abstracts, 41.9% achieve publication after a period of at least 3 years from presentation. Studies originating from certain countries and on certain subspecialty topics were more likely to get published.

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Size of testes, ovaries, uterus and breast buds by ultrasound in healthy full-term neonates ages 0–3 days

Abstract

Background

Hormonally sensitive organs in the neonate can change size within days of birth as circulating maternal estrogen wanes. Although several reports document the size of these organs through infancy, few focus attention on the near-birth period. Clinical and research evaluation of hormonal and genitourinary disorders would benefit from reference size standards.

Objective

We describe the size of the uterus, ovaries, testes and breast buds in healthy term neonates.

Materials and methods

As part of the Infant Feeding and Early Development (IFED) study, we sonographically measured the largest diameter of these organs in sagittal, transverse and anterior-posterior planes for 194 female and 204 male newborns up to 3 days old. We calculated mean, median and percentiles for longest axis length and for volume calculated from measured diameters. We evaluated size differences by laterality, gender and race and compared our observations against published values.

Results

Mean length and mean volume were as follows: uterus, 4.2 cm and 10.0 cm³; ovary, 1.0 cm and 0.2 cm³; testis, 1.1 cm and 0.3 cm³ (0.4 cm³ Lambert volume); female breast bud, 1.2 cm and 0.7 cm³; male breast bud, 1.1 cm and 0.6 cm³. Breast buds were larger in females than males. Laterality differences were typically below the precision of clinical measurement. No significant race differences were detected.

Conclusion

Using data from our large cohort together with published values, we provide guidelines for evaluating the size of reproductive organs within the first 3 days of age. Discrepancies between our results and published values are likely attributable to technique.

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Adoptive cell therapy and modulation of the tumour microenvironment: new insights from ASCO 2016

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Outcome of radical prostatectomy in primary circulating prostate cell negative prostate cancer

Nigel P Murray, Sócrates Aedo, Eduardo Reyes, Cynthia Fuentealba and Omar Jacob

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Maps and atlases of cancer mortality: a review of a useful tool to trigger new questions

Alberto d'Onofrio, Chiara Mazzetta, Chris Robertson, Michel Smans, Peter Boyle and Mathieu Boniol

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Effects of long-term androgen deprivation therapy on cognitive function over 36 months in men with prostate cancer

BACKGROUND

Many men with prostate cancer (PC) require long-term androgen deprivation therapy (ADT), but to the authors' knowledge, its effects on cognitive function beyond 1 year are not described.

METHODS

Three groups of men aged ≥50 years who were matched based on age and education were enrolled: 77 patients with nonmetastatic PC who initiated continuous ADT, 82 patients with PC who were not receiving ADT (PC controls), and 82 healthy controls. A battery of 14 neuropsychological tests, examining 8 cognitive domains, was administered on 5 occasions over 36 months. Changes in cognitive scores over time were analyzed using 3 approaches: linear mixed effects regression, the percentage of participants per group with declines in ≥1/2 cognitive tests, and a global summary of cognitive change.

RESULTS

The mean age of the study subjects was 68.9 years, with a median of 16 years of education. In mixed effects models adjusted for age and education, ADT use was not found to be associated with significant changes over time in any cognitive test compared with healthy controls. The percentage of participants declining by ≥1.5 standard deviations in ≥2 tests or ≥2 standard deviations in ≥1 tests was similar across groups. A global summary of cognitive change found no statistically significant worsening of cognitive function among ADT users compared with controls. Sensitivity analyses adjusting for duration of ADT and using multiple imputation for missing data did not materially alter the study findings.

CONCLUSIONS

The ongoing use of ADT for up to 36 months does not appear to be associated with cognitive decline. Cancer 2016. © 2016 American Cancer Society.

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Genetic Ancestry using Mitochondrial DNA in patients with Triple-negative breast cancer (GAMiT study)

BACKGROUND

Triple-negative breast cancer (TNBC) lacks estrogen, progesterone, and human epidermal growth factor receptor 2 (HER2)/neu receptors, and is aggressive and therapeutically challenging. Genetic ancestry testing is an emerging medical field. Mitochondrial DNA (mtDNA), which is distinct from nuclear DNA, is maternally inherited and allows for origin determination. Patients with TNBC tend to be younger and are more likely to be African American, making this an ideal disease for mtDNA exploration. To the authors' knowledge, the current study is the first to perform mtDNA for self-described African American, White, and Hispanic patients with TNBC to identify mtDNA patterns.

METHODS

Patients with TNBC who were at any stage of therapy/survivorship were included. Self-reported ethnicity was confirmed at the time of the prospective buccal swab. Haplogroup prediction was performed on sequencing of hypervariable region 1. Using sequence similarity scores and lineage databases, sequence patterns were determined. Data regarding presentation and treatment, tumor features, and outcomes was collected.

RESULTS

A total of 92 patients were included: 31 self-described African American, 31 White, and 30 Hispanic individuals. Hispanic patients were found to have the largest tumor size (4.5 cm; P = .01) and youngest age (41 years; P<.0001). Eight patients were BRCA1/2 mutation carriers. There were no differences noted among groups with regard to surgery, lymph node metastases, or survival. Analysis revealed Nigerian, Cameroon, or Sierra Leone ancestry and haplogroups A, U, H, or B to be the most common mtDNA patterns. Twelve discordances (13%) between mtDNA analysis and self-described ethnicity were identified among the 92 patients. The highest discordance (26%; 8 patients) was noted in self-described Hispanic patients: 3 had Nigerian ancestry, and 1 individual demonstrated haplogroup K mtDNA (Ashkenazi Jewish ancestry).

CONCLUSIONS

Discordance between self-reported ethnicity and mtDNA analysis was identified in 13% of patients with TNBC. The identification of mtDNA patterns with a predisposition toward TNBC may allow for risk stratification. Cancer 2016. © 2016 American Cancer Society.

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A randomized, double-blind, phase 2 trial of platinum therapy plus etoposide with or without concurrent vandetanib (ZD6474) in patients with previously untreated extensive-stage small cell lung cancer: Hoosier Cancer Research Network LUN06-113

BACKGROUND

This randomized, double-blind, phase 2 trial evaluated whether the addition of vandetanib to platinum plus etoposide for previously untreated extensive-stage small cell lung cancer (SCLC) prolonged the time to disease progression in comparison with chemotherapy alone.

METHODS

Patients with previously untreated extensive-stage SCLC received platinum (cisplatin or carboplatin) with etoposide in combination with vandetanib (100 mg daily) or a placebo for up to 4 total cycles (no maintenance therapy). An initial safety run-in phase was conducted with the first 6 patients enrolled; all these patients received vandetanib with cisplatin and etoposide. With an overall sample size of 68 patients, the study had 80% power to detect a 3-month difference in the time to progression (TTP) from 4 to 7 months (significance level,.10 [1-sided log-rank test]).

RESULTS

Seventy-four patients were enrolled between April 2008 and May 2013. Thirty-three patients were ultimately randomized to each arm. The baseline characteristics were well balanced, and the median number of treatment cycles was 4 for each arm. Thirty-one patients in each arm were evaluable for TTP; the median TTP was 5.62 months with vandetanib and 5.68 months with the placebo (P = .9518). The median overall survival was 13.24 months with vandetanib and 9.23 months with the placebo (P = .4577; 33 evaluable patients in each arm). Nonhematologic toxicity was increased with vandetanib versus the placebo. No correlation was seen between vascular endothelial growth factor polymorphisms and outcomes.

CONCLUSIONS

The addition of vandetanib to platinum and etoposide did not improve outcomes for patients with newly diagnosed extensive-stage SCLC. Toxicity was increased in comparison with chemotherapy alone. Cancer 2016. © 2016 American Cancer Society.

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NCCN News

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Ovarian Cancer, Version 1.2016, NCCN Clinical Practice Guidelines in Oncology

This selection from the NCCN Guidelines for Ovarian Cancer focuses on the less common ovarian histopathologies (LCOHs), because new algorithms were added for LCOHs and current algorithms were revised for the 2016 update. The new LCOHs algorithms include clear cell carcinomas, mucinous carcinomas, and grade 1 (low-grade) serous carcinomas/endometrioid epithelial carcinomas. The LCOHs also include carcinosarcomas (malignant mixed Müllerian tumors of the ovary), borderline epithelial tumors (also known as low malignant potential tumors), malignant sex cord-stromal tumors, and malignant germ cell tumors.

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Oncology Research Program

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The Population Benefit of Radiotherapy for Malignant Brain Tumors: Local Control and Survival Estimates for Guideline-Based Use

Objective: To estimate the population benefit of radiotherapy (RT) for primary malignant brain tumors if evidence-based guidelines were routinely followed. Methods: This study investigated 5-year local control (LC) and 2- and 5-year overall survival (OS) benefits. RT benefit was the absolute proportional benefit of RT alone over no RT for radical indications, and over surgery alone for adjuvant indications. Chemoradiotherapy (CRT) benefit was the absolute incremental benefit of concurrent chemotherapy and RT over RT alone. Decision tree models were adapted to define the incidence of each indication. Citation databases were systematically queried for the highest level of evidence defining indication benefits. Meta-analysis was performed if there were multiple sources of the same evidence level, and deterministic and probabilistic sensitivity analysis was also performed. Results: Among all patients with malignant brain tumors, 82% had indications for curative- or adjuvant-intent RT. The magnitude of benefit was based on level I or II evidence in 44% of all patients. A total of 25 relevant studies were used to quantify indication benefits. All RT benefit included in the model was irreplaceable. For malignant brain tumors, the estimated population benefit for RT alone was 9% for 5-year LC (95% CI, 7%–10%), 9% for 2-year OS (95% CI, 8%–11%), and 5% for 5-year OS (95% CI, 4%–5%). The incremental benefit of CRT was 1% for 5-year LC (95% CI, 0%–2%), 7% for 2-year OS (95% CI, 4%–11%), and 3% for 5-year OS (95% CI, 1%–5%). The model was robust in sensitivity analysis. Conclusions: When optimally used, RT provides an important benefit for many patients with malignant brain tumors. The model provided a robust means for estimating the magnitude of this benefit.

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Hillary and Donald, Our Patients Are Watching

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Principles of Treatment for Borderline, Micropapillary Serous, and Low-Grade Ovarian Cancer

Borderline ovarian tumors (BOTs) are less common than epithelial ovarian cancers (EOCs). Low-grade EOCs (LG-EOCs) occur even less frequently than BOTs. After primary therapy, recurrence rates of BOTs and LG-EOCs are significantly lower and the stage-adjusted survival is higher than for high-grade EOCs. Thus, determining the best management in terms of traditional ovarian cancer staging and debulking procedures is more challenging and has been recently brought to question. This article reviews the particulars of BOTs and LG-EOCs, their similarities and differences, and how they are best managed and treated, and emphasizes the major role of surgery and the controversial role of chemotherapy. Because these tumors disproportionately affect younger women, this review addresses ovarian preservation in circumstances when fertility or hormonal preservation is desired.

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Allogeneic Hematopoietic Cell Transplantation for AML--A Missed Opportunity!

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Current Status of Distress Screening in Designated Cancer Hospitals: A Cross-Sectional Nationwide Survey in Japan

Background: The purpose of this study was to investigate the current status of distress screening implementation in Japanese designated cancer hospitals. Subjects and Methods: This was a cross-sectional observational study. Palliative care team representatives in all designated cancer hospitals in Japan completed an ad hoc questionnaire. Demographic data in 2014 were obtained from the Ministry of Health, Labour and Welfare in Japan. Results: Of 422 institutions, 389 responded (92%) and data were obtained from 379 (90%). Approximately 90% of institutions had implemented a distress screening program at some level, and approximately 60% had just started screening. Among those institutions that screened, 77% provided individualized triage to specialized services within the institutions, whereas 60% did not routinely follow-up with patients who had positive screening results. The estimated median percentage of screened patients referred to palliative care teams was 0.4% in outpatient settings and 6.3% in inpatient settings. Although 68% of respondents perceived that screening was useful overall, they also reported difficulties when conducting screening with patients, reporting "no established effective treatment for problems screened" (66%), "patients complain it is difficult to express their distress using scales" (58%), and that it was "difficult to manage screened problems because of lack of time" (49%). Eight perceived barriers to implementing distress screening programs in hospitals were identified; a lack of human resources ranked highest. Conclusions: Implementation of distress screening in designated cancer hospitals in Japan has just begun. Policymakers should acknowledge that screening can be beneficial for patients when it is implemented with appropriate resources and established methods.

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Characterization of Prostate Cancer in a Functional Eunuch

Background: Eunuchs rarely, if ever, develop prostate cancer (CaP). This article reports on a 62-year-old functional eunuch from prepubertal mumps orchitis who developed clinically localized CaP. Methods: Serum and CaP and benign prostate tissue androgen levels were measured using a validated liquid chromatography-tandem mass spectrometry assay. The assay measures testosterone; dihydrotestosterone (DHT); the adrenal androgens, androstenedione and dehydroepiandrosterone; and the androgen metabolites, androsterone and androstanedione. Gene and protein expression levels of androgen metabolism enzymes, and androgen receptor and androgen-regulated genes were measured using quantitative reverse-transcription polymerase chain reaction and immunohistochemistry, respectively. Results: Intracrine androgen metabolism produced tissue DHT when serum and tissue testosterone levels were castrate and undetectable, respectively. Androgen receptor, androgen-regulated, and androgen metabolism enzyme genes were expressed but at lower levels in CaP than benign tissues. Conclusions: DHT was synthesized using the primary backdoor androgen metabolism pathway and not using androstenedione or dehydroepiandrosterone via the frontdoor or secondary backdoor pathways.

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Risk Factors for Early Death After Rituximab-Based Immunochemotherapy in Older Patients With Diffuse Large B-Cell Lymphoma

Background: Older patients with diffuse large B-cell lymphoma (DLBCL) are at risk of severe chemotherapy-related morbidity and mortality. Our objective was to quantify the risk and identify factors associated with death during the first cycle of immunochemotherapy in this population. Patients and Methods: Using Medicare claims linked to the population-based SEER registry (SEER-Medicare), we studied patients with DLBCL aged 65 years and older who received immunochemotherapy containing rituximab, cyclophosphamide, and vincristine, in combination with doxorubicin, mitoxantrone, or etoposide in 2003–2012. Risk factors for death and hospitalization within the first 30 days of treatment were studied in multivariable logistic regression models. Results: We identified 5,530 patients with a median age of 76 years, of whom 94% received doxorubicin-containing immunochemotherapy. Granulocyte colony-stimulating factor (G-CSF) was administered to 66% of patients during the first treatment cycle. Cumulative incidence of death at day 30 was 2.2%. The risk was significantly higher in patients aged 75 years and older and those who had B symptoms, chronic kidney disease, poor functional status, use of walking aids or wheelchairs, and prior hospitalization or upper endoscopy. The group with 0 to 1 risk factors (56% of patients) had a very low (0.6%) risk of early death, whereas the group with 4 or more risk factors (6% of patients) had a risk of 8.3%. Receipt of G-CSF was associated with a lower probability of early death in the high-risk group. The incidence of hospitalization within the first 30 days was 23.5%, peaking at day 8 of the cycle. Conclusions: Among older patients with DLBCL who receive contemporary immunochemotherapy, 1 in 45 die during the first month of treatment, and 1 in 4 are hospitalized. Factors identifiable from administrative/electronic records can stratify this risk and could be incorporated into decision support tools. Prophylactic G-CSF is not administered to more than one-third of patients, indicating an opportunity for improved preventive interventions.

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NCCN Guidelines Insights: Non-Hodgkin's Lymphomas, Version 3.2016

Peripheral T-cell lymphomas (PTCLs) represent a relatively uncommon heterogeneous group of non-Hodgkin's lymphomas (NHLs) with an aggressive clinical course and poor prognosis. Anthracycline-based multiagent chemotherapy with or without radiation therapy followed by first-line consolidation with high-dose therapy followed by autologous stem cell rescue (HDT/ASCR) is the standard approach to most of the patients with newly diagnosed PTCL. Relapsed or refractory disease is managed with second-line systemic therapy followed by HDT/ASCR or allogeneic stem cell transplant, based on the patient's eligibility for transplant. In recent years, several newer agents have shown significant activity in patients with relapsed or refractory disease across all 4 subtypes of PTCL. These NCCN Guideline Insights highlight the important updates to the NCCN Guidelines for NHL, specific to the management of patients with relapsed or refractory PTCL.

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Next-Generation Sequencing: Role in Gynecologic Cancers

Next-generation sequencing (NGS) has risen to the forefront of tumor analysis and has enabled unprecedented advances in the molecular profiling of solid tumors. Through massively parallel sequencing, previously unrecognized genomic alterations have been unveiled in many malignancies, including gynecologic cancers, thus expanding the potential repertoire for the use of targeted therapies. NGS has expanded the understanding of the genomic foundation of gynecologic malignancies and has allowed identification of germline and somatic mutations associated with cancer development, enabled tumor reclassification, and helped determine mechanisms of treatment resistance. NGS has also facilitated rationale therapeutic strategies based on actionable molecular aberrations. However, issues remain regarding cost and clinical utility. This review covers NGS analysis of and its impact thus far on gynecologic cancers, specifically ovarian, endometrial, cervical, and vulvar cancers.

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Predictors of Antiestrogen Recommendation in Women With Estrogen Receptor-Positive Ductal Carcinoma In Situ

Background: Antiestrogen (anti-e) use in estrogen receptor–positive (ER+) ductal carcinoma in situ (DCIS) has been shown to reduce the incidence of noninvasive and invasive breast cancer. Few studies have evaluated factors associated with anti-e recommendation in ER+ DCIS. Methods: The California Cancer Registry was queried for female patients diagnosed with ER+ DCIS and treated with lumpectomy or unilateral mastectomy from 2004 to 2011. Patient demographics, comorbidities, and clinical characteristics were analyzed for association with anti-e recommendation. Results: Of 5,527 patients identified, 76.4% patients underwent lumpectomy and 23.6% underwent unilateral mastectomy. Of the total cohort, 31.6% patients were recommended anti-e therapy, 60.4% were not, and the remaining 8.0% were recommended anti-e, but administration was not documented. Performance of lumpectomy predicted anti-e use compared with mastectomy (odds ratio [OR], 2.08; 95% CI, 1.77–2.43). Asian/Pacific Islanders were more often recommended anti-e therapy when compared with whites (OR, 1.28; 95% CI, 1.10–1.49). Patients younger than 70 years were more often recommended anti-e (age, 18–49 years: OR, 1.38; CI, 1.12–1.71; and age, 50–69 years: OR, 1.43; CI, 1.20–1.71). Conclusions: Despite current guidelines to consider the use of anti-e therapy, recommendation of anti-e after surgical treatment of DCIS is low, having been recommended to 40% of patients, and used by fewer than one-third. Significant predictors include lumpectomy compared with unilateral mastectomy, Asian/Pacific Islander race, younger age, and number of comorbidities. Further work is merited to understand patterns of anti-e therapy recommendation by providers in patients with DCIS.

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Transdisciplinary Approach to Managing Hepatitis C Virus Infection in Patients at a Tertiary Care Cancer Center

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Advanced Vulvar Cancers: What are the Best Options for Treatment?

Abstract

The treatment of patients with vulvar cancer remains challenging for gynecologic oncologists. Up to 30 % of the cases are diagnosed in a clinical condition of irresectability, and some kind of strategy has to be taken into account beyond surgery. In this regard, a common and standard definition is critical to maximize oncological results and minimize complications after treatments. Each patient treatment must be tailored individually according to their clinical and biological features and to the setting in which they are dealing with.

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Treatment of Metastatic Prostate Cancer in Older Adults

Abstract

The aging of the population, along with rising life expectancy, means that increasing numbers of older men will be diagnosed with prostate cancer, and a large proportion of these men will present with metastatic disease. In this paper, we discuss recent advances in prostate cancer treatment. In particular, we review management approaches for older patients with metastatic prostate cancer based on the decision tree developed by the International Society of Geriatric Oncology, which categorized older men as "fit," "vulnerable," and "frail" according to comprehensive geriatric assessment.

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Snus use, smoking and survival among prostate cancer patients

Abstract

Smoking is associated with prostate cancer mortality. The Scandinavian smokeless tobacco product snus is a source of nicotine but not the combustion products of smoke, and has not been studied with respect to prostate cancer survival. The study is nested among 9,582 men with incident prostate cancer within a prospective cohort of 336,381 Swedish construction workers. Information on tobacco use was collected at study entry between 1971 and 1992, and categorized into (1) never users of any tobacco, (2) exclusive snus: ever users of snus only, (3) exclusive smokers: ever smokers (cigarette, cigar, and/or pipe) only, and (4) ever users of both snus and smoking. Hazard ratios for prostate cancer-specific and total mortality for smoking and snus use based on Cox proportional hazards models adjusted for age, calendar period at diagnosis, and body mass index at baseline. During 36 years of follow-up, 4,758 patients died – 2,489 due to prostate cancer. Compared to never users of tobacco, exclusive smokers were at increased risk of prostate cancer mortality (HR 1.15, 95% CI: 1.05-1.27) and total mortality (HR 1.17, 95% CI: 1.09-1.26). Exclusive snus users also had increased risks for prostate cancer mortality (HR 1.24, 95% CI: 1.03-1.49) and total mortality (HR 1.19, 95% CI: 1.04-1.37). Among men diagnosed with non-metastatic disease, the HR for prostate cancer death among exclusive snus users was 3.17 (95% CI: 1.66-6.06). The study is limited by a single assessment of tobacco use prior to diagnosis. Snus use was associated with increased risks of prostate cancer and total mortality among prostate cancer patients. This suggests that tobacco-related components such as nicotine or tobacco-specific carcinogens may promote cancer progression independent of tobacco's combustion products. This article is protected by copyright. All rights reserved.

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Cancers, Vol. 8, Pages 82: Wnt Drug Discovery: Weaving Through the Screens, Patents and Clinical Trials

The Wnt signaling pathway is intricately involved in many aspects of development and is the root cause of an increasing number of diseases. For example, colorectal cancer is the second leading cause of death in the industrialized world and aberration of Wnt signaling within the colonic stem cell is the cause of more than 90% of these cancers. Despite our advances in successfully targeting other pathways, such as Human Epidermal Growth Factor Receptor 2 (HER2), there are no clinically relevant therapies available for Wnt-related diseases. Here, we investigated where research activities are focused with respect to Wnt signaling modulators by searching the United States Patent and Trade Office (USPTO) for patents and patent applications related to Wnt modulators and compared this to clinical trials focusing on Wnt modulation. We found that while the transition of intellectual property surrounding the Wnt ligand-receptor interface to clinical trials is robust, this is not true for specific inhibitors of β-catenin, which is constitutively active in many cancers. Considering the ubiquitous use of the synthetic T-cell Factor/Lymphoid Enhancer Factor (TCF/Lef) reporter system and its success in identifying novel modulators in vitro, we speculate that this model of drug discovery does not capture the complexity of in vivo Wnt signaling that may be required if we are to successfully target the Wnt pathway in the clinic. Notwithstanding, increasingly more complex models are being developed, which may not be high throughput, but more pragmatic in our pursuit to control Wnt signaling.

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The up-regulation of PD-L1 promotes the resistant response in non-small cell lung cancer patients with neo-adjuvant chemotherapy

Abstract

To assess the significance of programmed cell death ligand 1 (PD-L1) in non-small cell lung cancer (NSCLC) and its association with cisplatin-based neo-adjuvant chemotherapy (NAC) response. We investigated that PD-L1 was increased in chemo-resistant tumors compared with chemo-sensitive tumors according to RNA-Seq analysis, which was confirmed in the same cohort using IHC. In a cohort of 92 patients with NAC, the positive staining of PD-L1 was correlated with the TNM stage, lower sensitive-response rates and shorter overall survival rates. In another 30 paired tumor specimens pre- and post-chemotherapy, the patients with high PD-L1 expression of post-chemotherapy had a worse outcome and higher stable disease rate. CD8⁺ tumor infiltrating lymphocytes (TILs) was found to be related to chemosensitive response and better prognosis and negative PD-L1 expression. Furthermore, in two PDX models and cell lines A549 and PC-9, cisplatin up-regulated PD-L1 expression, and the enhancement of PD-L1 in cancer cell lines was in a drug dose dependent manner. Moreover, the depletion of PD-L1 significantly reduced the cisplatin resistance. When PI3K/AKT signaling was inhibited by corresponding inhibitors, PD-L1 expression was down-regulated and apoptosis was up-regulated in the cisplatin treated cancer cells. These results suggest that the up-regulation of PD-L1 promotes the resistant response in lung cancer cells that might be through activation of PI3K/AKT pathway and suppression of TILs. The high expression of PD-L1 after NAC could be the indication of therapeutic resistance and poor prognosis of NSCLC patients.

This article is protected by copyright. All rights reserved.

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FGFR gene alterations in lung squamous cell carcinoma are potential targets for the multikinase inhibitor nintedanib

Summary

Fibroblast growth factor receptor (FGFR) gene alterations are relatively frequent in lung squamous cell carcinoma (LSCC) and are a potential targets for therapy with FGFR inhibitors. However, little is known regarding the clinicopathologic features associated with FGFR alterations. The angiokinase inhibitor nintedanib has shown promising activity in clinical trials for non–small cell lung cancer. We have now applied next-generation sequencing (NGS) to characterize FGFR alterations in LSCC patients as well as examined the antitumor activity of nintedanib in LSCC cell lines positive for FGFR1 copy number gain (CNG). The effects of nintedanib on the proliferation of and FGFR signaling in LSCC cell lines were examined in vitro, and its effects on tumor formation were examined in vivo. A total of 75 clinical LSCC specimens were screened for FGFR alterations by NGS. Nintedanib inhibited the proliferation of FGFR1 CNG positive LSCC cell lines in association with attenuation of the FGFR1-ERK signaling pathway in vitro and in vivo. FGFR1 CNG (10.7%), FGFR1 mutation (2.7%), FGFR2 mutation (2.7%), FGFR4 mutation (5.3%), and FGFR3 fusion (1.3%) were detected in LSCC specimens by NGS. Clinicopathologic features did not differ between LSCC patients positive or negative for FGFR alterations. However, among the 36 patients with disease recurrence after surgery, prognosis was significantly worse for those harboring FGFR alterations. Screening for FGFR alterations by NGS warrants further study as a means to identify patients with LSCC recurrence after surgery who might benefit from nintedanib therapy.

This article is protected by copyright. All rights reserved.

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Irradiation normofractionnée des cancers du sein. Indications et bénéfices

Publication date: Available online 31 August 2016
Source:Cancer/Radiothérapie
Author(s): A. Fourquet, S.-L. Krhili, F. Campana, A. Chilles, Y.-M. Kirova
L'irradiation normofractionnée du sein après une chirurgie conservatrice est la référence de pratique. Elle consiste à délivrer une dose de 50Gy en 25 fractions de 2Gy dans le point de référence, et dans certains cas, une dose additionnelle de 16Gy en 8 fractions de 2Gy dans le lit tumoral. Plusieurs essais thérapeutiques et des méta-analyses, dans les cancers infiltrants comme dans les cancers intracanalaires, ont évalué les résultats et la toxicité à long terme de cette irradiation. Les taux de récidive intrammaire à 10ans sont en moyenne de 6 %, avec une toxicité cardiaque, pulmonaire et des tissus mous (fibrose) qui reste très limitée avec les techniques modernes. L'identification des facteurs de risque à long terme peut contribuer à définir de nouveaux schémas de fractionnement adaptés à la biologie tumorale. Les nouveaux schémas d'irradiation doivent être évalués rigoureusement sur le long terme dans le cadre d'essais thérapeutique, pour qu'ils puissent constituer de nouveaux standards.Whole-breast normofractionated irradiation following breast-conserving surgery is the reference treatment. It delivers a dose of 50Gy in 25 fractions of 2Gy to the reference point, and, in some patients, an additional dose of 16Gy in 8 fractions of 2Gy in the tumor bed. Long-term results and toxicity of this irradiation scheme was prospectively evaluated in several randomised trials and meta-analyses, in invasive cancers as well as in ductal carcinoma in situ. The average 10-year rate of in breast recurrences was 6 % in these trials, with limited cardiac and pulmonary toxicity and limited rate of severe fibrosis. Identification of risk factors of recurrences may help to design new irradiation schemes adapted to tumor biology. The new irradiation schemes must be rigorously evaluated in the long-term in the frame of prospective clinical trials, in order to validate them as new standards of treatment.



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Synchronisation respiratoire et radiothérapie mammaire

Publication date: Available online 31 August 2016
Source:Cancer/Radiothérapie
Author(s): A. Mège, A. Ziouèche-Mottet, V. Bodez, R. Garcia, A. Arnaud, G. de Rauglaudre, N. Pourel, B. Chauvet
La radiothérapie adjuvante des cancers du sein améliore les taux de contrôle locorégional et de survie globale, mais le bénéfice des techniques d'irradiation de haute précision, comme la modulation d'intensité, peut être compromis par les mouvements respiratoires. Ces mouvements pendant les fractions peuvent entraîner un sous- ou un surdosage des volumes cibles, ou à exposer les organes à risque de proximité. Cet article résume les mouvements respiratoires, leurs effets sur l'imagerie, la dosimétrie et la délivrance de dose lors de la radiothérapie des cancers du sein. Nous proposons une mise au point sur les méthodes de synchronisation respiratoires disponibles en radiothérapie mammaire, pour minimiser l'impact des mouvements respiratoires et épargner les organes de proximité, comme le cœur et les poumons.Adjuvant radiation therapy following breast cancer surgery continues to improve locoregional control and overall survival. But the success of highly targeted-conformal radiotherapy such as intensity-modulated techniques, can be compromised by respiratory motion. The intrafraction motion can potentially result in significant under- or overdose, and also expose organs at risk. This article summarizes the respiratory motion and its effects on imaging, dose calculation and dose delivery by radiotherapy for breast cancer. We will review the methods of respiratory synchronization available for breast radiotherapy to minimize the respiratory impact and to spare organs such as heart and lung.



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