cancersfakianakis1

[cancersfakianakis1]

Congruence of Reproductive Goals and Fertility-Related Attitudes of Adolescent and Young Adult Males and Their Parents After Cancer Treatment

Journal of Adolescent and Young Adult Oncology, Ahead of Print. https://ift.tt/2XvBl9x

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[cancersfakianakis1]

The Impact of Financial Toxicity on Psychological Well-Being, Coping Self-Efficacy, and Cost-Coping Behaviors in Young Adults with Cancer

Journal of Adolescent and Young Adult Oncology, Ahead of Print. https://ift.tt/2Szk77k

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[cancersfakianakis1]

INSIGHT MM: a large, global, prospective, non-interventional, real-world study of patients with multiple myeloma

Future Oncology, Ahead of Print. https://ift.tt/2H8qEnt

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[cancersfakianakis1]

5th Symposium on Primary Breast Cancer in Older Women

Future Oncology, Ahead of Print. https://ift.tt/2tHS3EO

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[cancersfakianakis1]

Cancers, Vol. 11, Pages 286: The Novel Role of SOX2 as an Early Predictor of Cancer Risk in Patients with Laryngeal Precancerous Lesions

Cancers, Vol. 11, Pages 286: The Novel Role of SOX2 as an Early Predictor of Cancer Risk in Patients with Laryngeal Precancerous Lesions

Cancers doi: 10.3390/cancers11030286

Authors: Rocío Granda-Díaz Sofía T. Menéndez Daniel Pedregal Mallo Francisco Hermida-Prado René Rodríguez Laura Suárez-Fernández Aitana Vallina Mario Sánchez-Canteli Aida Rodríguez M. Soledad Fernández-García Juan P. Rodrigo Juana M. García-Pedrero

The SOX2 gene located at 3q26 is frequently amplified and overexpressed in multiple cancers, including head and neck squamous cell carcinomas (HNSCC). The tumor-promoting activity and involvement of SOX2 in tumor progression has been extensively demonstrated, thereby emerging as a promising therapeutic target. However, the role of SOX2 in early stages of tumorigenesis and its possible contribution to malignant transformation remain unexplored. This study investigates for the first time SOX2 protein expression by immunohistochemistry and gene amplification by real-time PCR using a large series of 94 laryngeal precancerous lesions. Correlations with the histopathological classification and the risk of progression to invasive carcinoma were established. Nuclear SOX2 expression was frequently detected in 38 (40%) laryngeal dysplasias, whereas stromal cells and normal adjacent epithelia showed negative expression. SOX2 gene amplification was detected in 18 (33%) of 55 laryngeal dysplasias. Univariate Cox analysis showed that SOX2 gene amplification (p = 0.046) and protein expression (p < 0.001) but not histological grading (p = 0.432) were significantly associated with laryngeal cancer risk. In multivariate stepwise analysis including age, tobacco, histology, SOX2 gene amplification and SOX2 expression, SOX2 expression (HR = 3.531, 95% CI 1.144 to 10.904; p = 0.028) was the only significant independent predictor of laryngeal cancer development. These findings underscore the relevant role of SOX2 in early tumorigenesis and a novel clinical application of SOX2 expression as independent predictor of laryngeal cancer risk in patients with precancerous lesions beyond current WHO histological grading. Therefore, targeting SOX2 could lead to effective strategies for both cancer prevention and treatment.

https://ift.tt/2SzktLt

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[cancersfakianakis1]

A functional landscape of resistance to MEK1/2 and CDK4/6 inhibition in NRAS mutant melanoma

Combinatorial inhibition of MEK1/2 and CDK4/6 is currently undergoing clinical investigation in NRAS-mutant melanoma. To prospectively map the landscape of resistance to this investigational regimen, we utilized a series of gain- and loss-of-function forward genetic screens to identify modulators of resistance to clinical inhibitors of MEK1/2 and CDK4/6 alone and in combination. First, we identified NRAS-mutant melanoma cell lines that were dependent on NRAS for proliferation and sensitive to MEK1/2 and CDK4/6 combination treatment. We then employed a genome-scale ORF overexpression screen and a CRISPR knockout screen to identify modulators of resistance to each inhibitor alone or in combination. These orthogonal screening approaches revealed concordant means of achieving resistance to this therapeutic modality, including tyrosine kinases, RAF, RAS, AKT, and PIK3CA signaling. Activated KRAS was sufficient to cause resistance to combined MEK/CDK inhibition and to replace genetic depletion of oncogenic NRAS. In summary, our comprehensive functional genetic screening approach revealed modulation of resistance to the inhibition of MEK1/2, CDK4/6 or their combination in NRAS-mutant melanoma. https://ift.tt/2EDQvSK

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[cancersfakianakis1]

Label-free Raman spectroscopy reveals signatures of radiation resistance in the tumor microenvironment

Delay in the assessment of tumor response to radiation therapy continues to pose a major challenge to quality of life for patients with non-responsive tumors. Here we exploited label-free Raman spectroscopic mapping to elucidate radiation-induced biomolecular changes in tumors and uncovered latent microenvironmental differences between treatment-resistant and -sensitive tumors. We used isogenic radiation-resistant and -sensitive A549 human lung cancer cells human head and neck squamous cell carcinoma (HNSCC) cell lines (UM-SCC-47 and UM-SCC-22B, respectively) to grow tumor xenografts in athymic nude mice and demonstrated the molecular specificity and quantitative nature of Raman spectroscopic tissue assessments. Raman spectra obtained from untreated and treated tumors were subjected to chemometric analysis using multivariate curve resolution-alternating least squares (MCR-ALS) and support vector machine (SVM) to quantify biomolecular differences in the tumor microenvironment. The Raman measurements revealed significant and reliable differences in lipid and collagen content post-radiation in the tumor microenvironment, with consistently greater changes observed in the radiation-sensitive tumors. In addition to accurately evaluating tumor response to therapy, the combination of Raman spectral markers potentially offers a route to predicting response in untreated tumors prior to commencing treatment. Combined with its non-invasive nature, our findings provide a rationale for in vivo studies using Raman spectroscopy, with the ultimate goal of clinical translation for patient stratification and guiding adaptation of radiotherapy during the course of treatment. https://ift.tt/2VnsAMI

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[cancersfakianakis1]

Sleep, emotional distress, and physical health in survivors of childhood cancer: A report from the Childhood Cancer Survivor Study

Abstract

Objective

Sleep disorders are associated with psychological and physical health, though reports in long‐term survivors of childhood cancer are limited. We characterized the prevalence and risk factors for behaviors consistent with sleep disorders in survivors and examined longitudinal associations with emotional distress and physical health outcomes.

Methods

Survivors (n=1933; median [IQR] age=35 [30, 41]) and siblings (n=380; age=33 [27, 40]) from the Childhood Cancer Survivor Study completed measures of sleep quality, fatigue, and sleepiness. Emotional distress and physical health outcomes were assessed approximately five years before and after the sleep survey. Multivariable logistic or modified Poisson regression models examined associations with cancer diagnosis, treatment exposures, and emotional and physical health outcomes.

Results

Survivors were more likely to report poor sleep efficiency (30.8% vs. 24.7%; prevalence ratio [PR]=1.26, 95% confidence interval [1.04‐1.53]), daytime sleepiness (18.7% vs. 14.2%; PR=1.31[1.01‐1.71]), and sleep supplement use (13.5% vs. 8.3%; PR=1.56[1.09‐2.22]) than siblings. Survivors who developed emotional distress were more likely to report poor sleep efficiency (PR=1.70[1.40‐2.07]), restricted sleep time (PR=1.35[1.12‐1.62]), fatigue (PR=2.11[1.92‐2.32]), daytime sleepiness (PR=2.19[1.71‐2.82]), snoring (PR=1.85[1.08‐3.16]), and more sleep medication (PR=2.86[2.00‐4.09]) and supplement use (PR=1.89[1.33‐2.69]). Survivors reporting symptoms of insomnia (PR=1.46[1.02‐2.08]), fatigue (PR=1.31[1.01‐1.72]), and using sleep medications (PR=2.16[1.13‐4.12]) were more likely to develop migraines/headaches.

Conclusions

Survivors report more sleep difficulties and efforts to manage sleep than siblings. These sleep behaviors are related to worsening or persistently elevated emotional distress and may result in increased risk for migraines. Behavioral interventions targeting sleep may be important for improving health outcomes.

https://ift.tt/2SB94e2

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[cancersfakianakis1]

Identifying Distinct Trajectories of Change in Young Breast Cancer Survivors’ Sexual Functioning

Abstract

Objectives

To identify and characterize distinct trajectories of change in young women's sexual functioning over five years following breast cancer diagnosis.

Methods

Group‐based trajectory modeling was applied to the sexual functioning of 896 women diagnosed with stage I‐IV breast cancer at age ≤40 years. The Cancer Rehabilitation Evaluation System was used to evaluate women's symptoms of sexual dysfunction annually for five years.

Results

Five distinct trajectories of sexual functioning were identified: one asymptomatic, one minimally symptomatic, two moderately symptomatic, and one severely symptomatic trajectory. 12% of women were asymptomatic throughout follow‐up. The plurality of women experienced stable mild symptoms (42%). Amongst those with moderate symptoms, some experienced improvement over time (22%) while others experienced deterioration (13%). 11% experienced stable severe symptoms that did not remit over time. Independent predictors of experiencing a symptomatic rather than asymptomatic trajectory (p<0.05, two‐sided) included diagnosis with stage 2 versus 1 disease, ER+ disease treated with oophorectomy or ovarian suppression, being partnered, having anxiety, poorer body image, and greater musculoskeletal pain.

Conclusions

We identified distinct trajectories that describe the reported sexual symptoms in this cohort of young breast cancer survivors. The majority of women reported various degrees of sexual dysfunction that remained stable over the study period. There is, however, potential for improvement of moderate and severe symptoms of sexual dysfunction in early survivorship.

https://ift.tt/2XwXKU6

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[cancersfakianakis1]

A novel approach to modelling transcriptional heterogeneity identifies the oncogene candidate <i>CBX2</i> in invasive breast carcinoma

A novel approach to modelling transcriptional heterogeneity identifies the oncogene candidate CBX2 in invasive breast carcinoma

A novel approach to modelling transcriptional heterogeneity identifies the oncogene candidate <i>CBX2</i> in invasive breast carcinoma, Published online: 01 March 2019; doi:10.1038/s41416-019-0387-8

A novel approach to modelling transcriptional heterogeneity identifies the oncogene candidate CBX2 in invasive breast carcinoma https://ift.tt/2IJA0Zz

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[cancersfakianakis1]

Phase 1 Open-Label, Multicenter Study of First-in-Class ROR{gamma} Agonist LYC-55716: Safety, Tolerability, and Preliminary Evidence of Antitumor Activity

Purpose:Transcription factor retinoic acid receptor-related orphan receptor g (RORg) regulates type 17 effector T cell differentiation and function and is key to immune cell regulation. Synthetic RORg agonists modulate immune cell gene expression to increase effector T cell activity and decrease immune suppression. A Phase 1 study evaluated the safety and tolerability of LYC-55716, a first-in-class, oral, small-molecule RORg agonist in adults with relapsed/refractory metastatic cancer. Experimental Design: Patients received 28-day treatment cycles of oral LYC-55716; dose and dosing regimen were determined according to pharmacokinetic profile and safety. Primary endpoints were safety and tolerability. Secondary endpoints included pharmacokinetics and objective tumor response rate. Results: No dose-limiting toxicities occurred among the 32 enrolled patients who received LYC-55716 150 mg BID to 450 mg BID. Treatment-related adverse events (AEs) were primarily Grade 1-2 and included diarrhea (n=11), fatigue (n=7), anemia (n=4), decreased appetite (n=4), nausea (n=4). Grade 3 AEs were anemia (n=2), elevated gamma-glutamyl transferase (n=1), and hypophosphatemia (n=1). Pharmacokinetic concentrations achieved levels expected for target gene regulation. Pharmacodynamic results indicated RORg pathway engagement. Two patients (NSCLC and sarcomatoid breast cancer) had confirmed partial responses; 11 had disease stabilization for 2-12 months (6 received >4 months of treatment). Conclusions: These data support the safety and tolerability of LYC-55716 and selection of 450 mg BID dose for a Phase 2a study assessing LYC-55716 clinical activity, safety, and biomarkers in patients with NSCLC, head and neck, gastroesophageal, renal cell, urothelial, and ovarian cancers.

https://ift.tt/2EE4XKm

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[cancersfakianakis1]

Radionuclide Treatment Yields Responses in mCRPC [News in Brief]

Lutetium-177 PSMA-617 provides targeted delivery of radiation to metastatic castration-resistant prostate cancer.

https://ift.tt/2Vnr4Kw

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[cancersfakianakis1]

MicroRNA-1297 inhibits proliferation and promotes apoptosis in gastric cancer cells by downregulating CDC6 expression

Gastric cancer (GC), one of the most common malignant tumors and the second most common leading cause of cancer-related death worldwide, is a biologically heterogeneous disease accompanied by various genetic and epigenetic alterations. However, the molecular mechanisms underlying this disease are complex and not completely understood. Increasing studies have shown that aberrant microRNA (miRNA) expression is associated with GC tumorigenesis and growth. MiR-1297 has been confirmed to be a cancer suppressor in diverse tumors in humans. However, to date, the function and mechanism of miR-1297 in GC have not been determined. Here, we found that the expression of miR-1297 was significantly reduced in GC tissues or GC cell lines compared with paracarcinoma normal tissue or normal cell lines. Exogenic overexpression of miR-1297 in GC cell lines can inhibit cell proliferation and colony formation and induce apoptosis, and inhibition of miR-1297 in GC cell lines can promote cell proliferation and colony formation, and reduce apoptosis in vitro. We further confirmed that miR-1297 acted as a tumor suppressor through targeting cell division control protein 6 (CDC6) in GC. Moreover, the inverse relationship between miR-1297 and CDC6 was verified in GC cell lines. Our results indicated that miR-1297 is a potent tumor suppressor in GC, and its antiproliferative and gene-regulatory effects are, in part, mediated through its downstream target gene, CDC6. These findings implied that miR-1297 might be used as a novel therapeutic target of GC. Correspondence to Chen Huang, PhD, School of Basic Medical Sciences, Xi’an Jiaotong University Health Science Center, 76# Yanta West Road, Xi’an, Shaanxi Province 710049, China Tel/fax: [phone]; e-mail: [email protected] Received October 29, 2018 Accepted February 11, 2019 Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved. https://ift.tt/2XvQqYx

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[cancersfakianakis1]

Evaluation of the antileukemic effects of neurokinin-1 receptor antagonists, aprepitant, and L-733,060, in chronic and acute myeloid leukemic cells

Neurokinin-1 receptor (NK1R) antagonists are known for their anxiolytic, antiemetic, anticancer, and anti-inflammatory effects. Aprepitant is used in vomiting and nausea, which are the most common side-effects of patients undergoing chemotherapy for cancer. L-733,060 has been shown to have anxiolytic and antidepressant effects in animal studies and anticancer effect in in-vitro studies. Previous anticancer activity studies with NK1R antagonists have reported that NK-1 antagonists have an antitumoral activity on gastric carcinoma, larynx carcinoma, retinoblastoma, hepatocarcinoma, glioma, neuroblastoma, and osteoblastoma cells. In this study, we have aimed to show and compare the antileukemic effects of aprepitant and L-733,060 on acute and chronic myeloid leukemic cells by using in-vitro experiments, such as WST-1, cell imaging, annexin-V binding, soft agar colony formation, and Hoescht staining. As a result, we have determined that both aprepitant and L-733,060 had strong antiproliferative effects on K562 and HL-60 cells. Moreover, the two drugs caused significant apoptosis and decreased colony forming depending on concentration increase. These findings suggested that NK1R antagonists exhibited antileukemic activities and may be considered to have a novel therapeutic potential for acute and chronic myeloid leukemia. Correspondence to Miriş Dikmen, PhD, Department of Pharmacology, Faculty of Pharmacy, Anadolu Universty, Eskisehir, Centrum TR-26470, Turkey Tel: [phone] x3748; fax: [phone]; e-mail: [email protected] Received October 7, 2018 Accepted January 29, 2019 Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved. https://ift.tt/2SCPrm0

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[cancersfakianakis1]

Andrographolide sensitizes Hep-2 human laryngeal cancer cells to carboplatin-induced apoptosis by increasing reactive oxygen species levels

Andrographolide is a natural diterpenoid from Andrographis paniculata that has been proposed as an anticancer agent as well as a chemosensitizer for use in combination with anticancer drugs. Carboplatin is the first-line chemotherapeutic agent for advanced laryngeal carcinoma. However, the clinical efficacy of carboplatin is limited by drug resistance and side effects. The aim of this study was to investigate whether andrographolide has a synergistic antitumor effect with carboplatin on human laryngeal cancer cells. Hep-2 cells were exposed to andrographolide with or without carboplatin. The effects of indicated therapies were examined using the Cell Counting Kit-8 assay, the colony-forming assay, the Hoechst 33342/PI double staining, and flow cytometry analysis. The molecular mechanism was assessed by reactive oxygen species (ROS) detection and western blot. At the sublethal concentration, andrographolide increased carboplatin sensitivity of Hep-2 cells by increasing carboplatin-induced apoptosis and inhibiting cell viability. Moreover, we found that andrographolide sensitized carboplatin mainly through the induction of ROS generation and apoptotic signaling. Taken together, these results indicate that andrographolide, along with carboplatin, synergistically inhibited cell proliferation and induced mitochondrial apoptosis of Hep-2 cells by increasing the intracellular ROS, regulating the mitogen-activated protein kinase and phosphatidylinositol 3-kinase (PI3K/AKT) pathways, altering the BCL2/BAX ratio, and ultimately activating the cleavage of Caspase-3 and PARP. These results suggest that andrographolide sensitizes human laryngeal cancer cells to carboplatin-induced apoptosis by increasing ROS levels. *Wenjing Mao and Peijie He contributed equally to the writing of this article. Correspondence to Chunsheng Wei, PhD, Department of Otolaryngology-Head and Neck Surgery, Shanghai Key Clinical Disciplines of Otorhinolaryngology, Affiliated Eye, Ear, Nose and Throat Hospital, Fudan University, No. 83, Fenyang Road, Shanghai 200031, China Tel/fax: [phone]; e-mail: [email protected] Received October 2, 2018 Accepted February 7, 2019 Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved. https://ift.tt/2Xvto4j

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A randomized phase II study to determine the efficacy and tolerability of two doses of eribulin plus lapatinib in trastuzumab-pretreated patients with HER-2-positive metastatic breast cancer (E-VITA)

The E-VITA study evaluated the efficacy and tolerability of two schedules of eribulin and lapatinib in patients with trastuzumab-pretreated HER-2-positive metastatic breast cancer. This multicenter, open-label phase II trial, randomly assigned patients with trastuzumab-pretreated HER-2-positive metastatic breast cancer to lapatinib 1000 mg daily with eribulin 1.23 mg/m2 (equivalent to 1.4 mg/m2 eribulin mesylate) days 1+8 every 21 days (split-dose arm) or eribulin 1.76 mg/m2 (equivalent to 2.0 mg/m2 eribulin mesylate) day 1 every 21 days (3-weekly arm). Time to progression and tolerability were defined as primary end points; no sample size calculation for formal comparison of efficacy data has been performed. Secondary end points included objective response rate, clinical benefit rate, and overall survival. Overall, 43 patients of a planned number of 80 patients were recruited. At a median follow-up of 28.7 months, the median time to progression was 8.1 months [95% confidence interval (CI): 4.8–9.4] in the split-dose arm and 6.5 months (95% CI: 4.6–13.4) in the 3-weekly arm. Objective response rate was 52.4% (95% CI: 31.0–73.7) in the split-dose arm and 45.0% (95% CI: 23.2–66.8) in the 3-weekly arm, and clinical benefit rate was 71.4% (95% CI: 52.1–90.8) and 75.0% (95% CI: 56.0–94.0), respectively. Overall survival was also similar in both arms. The most frequent grade 3–4 adverse events were neutropenia (58.5%) and leukopenia (39.0%). The combination of eribulin and lapatinib showed an acceptable safety profile with less toxicity observed in the eribulin 1.23 mg/m2 day 1+8 group. This might be an alternative regimen when other treatment options are exhausted. Therefore, further clinical studies are warranted. Presented in part at the 2016 ESMO meeting, Copenhagen, 7–11 October 2016. Correspondence to Sibylle Loibl, MD, German Breast Group, Martin-Behaim-Strasse 12, 63263 Neu-Isenburg, Germany Tel: [phone]; fax: [phone]; e-mail: [email protected] Received April 17, 2018 Accepted November 3, 2018 Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved. https://ift.tt/2SCPo9O

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Talazoparib has no clinically relevant effect on QTc interval in patients with advanced solid tumors

The aims of this study were (i) to evaluate the effect of talazoparib (1 mg once daily) on cardiac repolarization in patients with advanced solid tumors by assessing corrected QT interval (QTc) and (ii) to examine the relationship between plasma talazoparib concentration and QTc. In this open-label phase 1 study, patients had continuous 12-lead ECG recordings at baseline followed by time-matched continuous ECG recordings and collection of talazoparib plasma pharmacokinetic samples predose and at 1, 2, 4, and 6 h postdose on treatment days 1 and 22 and before talazoparib administration on day 2. ECG recordings were submitted for independent central review where triplicate 10-s ECGs, extracted up to 15 min before pharmacokinetic samples, were assessed for RR, PR, QRS, and QT intervals and ECG morphology. QT interval was corrected for heart rate using Fridericia’s (QTcF) and Bazett’s (QTcB) formulae. Linear mixed-effects modeling was used to examine the relationship between QTc and RR interval change from baseline and plasma talazoparib concentration. Thirty-seven patients received talazoparib. Mean change in QTcF from time-matched baseline ranged from −3.5 to 6.9 ms, with the greatest change 1 h postdose on day 22. No clinically relevant changes in PR, QRS, QTcB, QTcF, or RR intervals, heart rate, or ECG morphology were observed. No concentration-dependent effect on heart rate or QTc was observed. No deaths, permanent treatment discontinuations due to adverse events were reported. Talazoparib (1 mg once daily) had no clinically relevant effects on cardiac repolarization. * Justin Hoffman and Jayeta Chakrabarti contributed equally to the writing of this article. Correspondence to Diane Wang, PhD, 10555 Science Center Drive, San Diego, CA 92130, USA Tel: [phone]; fax: [phone]; e-mail: [email protected] Received December 13, 2018 Accepted February 2, 2019 Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved. https://ift.tt/2Xvtlp9

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