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Thanks to their unique optical and physicochemical properties, gold nanoparticles have gained increased interest as radiosensitizing, photothermal therapy and optical imaging agents to enhance the effectiveness of cancer detection and therapy. Furthermore, their ability to carry multiple medically relevant radionuclides broadens their use to nuclear medicine SPECT and PET imaging as well as targeted radionuclide therapy. In this review, we discuss the radiolabeling process of gold nanoparticles and their use in (multimodal) nuclear medicine imaging to better understand their specific distribution, uptake and retention in different in vivo cancer models. In addition, radiolabeled gold nanoparticles enable image-guided therapy is reviewed as well as the enhancement of targeted radionuclide therapy and nanobrachytherapy through an increased dose deposition and radiosensitization, as demonstrated by multiple Monte Carlo studies and experimental in vitro and in vivo studies. ispartof: NUCLEAR MEDICINE AND BIOLOGY vol:100 pages:61-90 ispartof: location:United States status: published

OBJECTIVES: Internal organ dosimetry is an important procedure to demonstrate the reliable application of 177Lu-trastuzumab radioimmunotherapy for human epidermal growth factor receptor-positive metastatic breast cancers. We are reporting the first human dosimetry study for 177Lu-trastuzumab. Another objective of our study was to calculate and compare the absorbed doses for normal organs and tumor lesions in patients before radioimmunotherapy with 177Lu-trastuzumab using two different imaging scenarios.METHODS: Eleven patients (48.27 ± 8.95 years) with a history of metastatic breast cancer were included in the study. Postadministration of 177Lu-trastuzumab (351.09 ± 23.89 MBq/2 mg), acquisition was performed using planar and hybrid imaging scenarios at 4, 24, 72 and 168 h. Single-photon emission computed tomography/computed tomography imaging was performed at 72 h postinjection. Acquired images were processed using Dosimetry Toolkit software for the estimation of normalized cumulated activity in organs and tumor lesions. OLINDA/EXM 2.0 software was used for absorbed dose calculation in both scenarios.RESULTS: Significant difference in normalized cumulated activity and the absorbed dose is noted between two imaging scenarios for the organs and tumor lesions (P CONCLUSIONS: On the basis of our dosimetric evaluation, we concluded that radioimmunotherapy with 177Lu-trastuzumab is well tolerated to be implemented in routine clinical practice against HER2 positive metastatic breast cancer. Liver is the main critical organ at risk. Hybrid scenario demonstrated significantly lower absorbed doses in organs and tumors compared to the multiplanar method.

PURPOSE To analyze the prevalence of homologous recombination deficiency (HRD) in patients with pancreatic ductal adenocarcinoma (PDAC). MATERIALS AND METHODS We conducted a systematic review and meta-analysis of the prevalence of HRD in PDAC from PubMed, Scopus, and Cochrane Library databases, and online cancer genomic data sets. The main outcome was pooled prevalence of somatic and germline mutations in the better characterized HRD genes ( BRCA1, BRCA2, PALB2, ATM, ATR, CHEK2, RAD51, and the FANC genes). The secondary outcomes were prevalence of germline mutations overall, and in sporadic and familial cases; prevalence of germline BRCA1/2 mutations in Ashkenazi Jewish (AJ); and prevalence of HRD based on other definitions (ie, alterations in other genes, genomic scars, and mutational signatures). Random-effects modeling with the Freeman-Tukey transformation was used for the analyses. PROSPERO registration number: (CRD42020190813). RESULTS Sixty studies with 21,842 participants were included in the systematic review and 57 in the meta-analysis. Prevalence of germline and somatic mutations was BRCA1: 0.9%, BRCA2: 3.5%, PALB2: 0.2%, ATM: 2.2%, CHEK2: 0.3%, FANC: 0.5%, RAD51: 0.0%, and ATR: 0.1%. Prevalence of germline mutations was BRCA1: 0.9% (2.4% in AJ), BRCA2: 3.8% (8.2% in AJ), PALB2: 0.2%, ATM: 2%, CHEK2: 0.3%, and FANC: 0.4%. No significant differences between sporadic and familial cases were identified. HRD prevalence ranged between 14.5%-16.5% through targeted next-generation sequencing and 24%-44% through whole-genome or whole-exome sequencing allowing complementary genomic analysis, including genomic scars and other signatures (surrogate markers of HRD). CONCLUSION Surrogate readouts of HRD identify a greater proportion of patients with HRD than analyses limited to gene-level approaches. There is a clear need to harmonize HRD definitions and to validate the optimal biomarker for treatment selection. Universal HRD screening including integrated somatic and germline analysis should be offered to all patients with PDAC.

Item does not contain fulltext IMPORTANCE: Most women with a BRCA1/2 pathogenic variant undergo premature menopause with potential short- and long-term morbidity due to the current method of ovarian carcinoma prevention: risk-reducing salpingo-oophorectomy (RRSO). Because the fallopian tubes play a key role in ovarian cancer pathogenesis, salpingectomy with delayed oophorectomy may be a novel risk-reducing strategy with benefits of delaying menopause. OBJECTIVE: To compare menopause-related quality of life after risk-reducing salpingectomy (RRS) with delayed oophorectomy with RRSO in carriers of the BRCA1/2 pathogenic variant. DESIGN, SETTING, AND PARTICIPANTS: A multicenter nonrandomized controlled preference trial (TUBA study), with patient recruitment between January 16, 2015, and November 7, 2019, and follow-up at 3 and 12 months after surgery was conducted in all Dutch university hospitals and a few large general hospitals. In the Netherlands, RRSO is predominantly performed in these hospitals. Patients at the clinical genetics or gynecology department between the ages of 25 and 40 years (BRCA1) or 25 to 45 years (BRCA2) who were premenopausal, had completed childbearing, and were undergoing no current treatment for cancer were eligible. INTERVENTIONS: Risk-reducing salpingo-oophorectomy at currently recommended age or RRS after completed childbearing with delayed oophorectomy. After RRSO was performed, hormone replacement therapy was recommended for women without contraindications. MAIN OUTCOMES AND MEASURES: Menopause-related quality of life as assessed by the Greene Climacteric Scale, with a higher scale sum (range, 0-63) representing more climacteric symptoms. Secondary outcomes were health-related quality of life, sexual functioning and distress, cancer worry, decisional regret, and surgical outcomes. RESULTS: A total of 577 women (mean [SD] age, 37.2 [3.5] years) were enrolled: 297 (51.5%) were pathogenic BRCA1 variant carriers and 280 (48.5%) were BRCA2 pathogenic variant carriers. At the time of analysis, 394 patients had undergone RRS and 154 had undergone RRSO. Without hormone replacement therapy, the adjusted mean increase from the baseline score on the Greene Climacteric Scale was 6.7 (95% CI, 5.0-8.4; P

Previous studies indicate that bilberry with high amounts of phenolic compounds can inhibit carcinogenic processes of colorectal cancer in vitro and in vivo. However, no studies have focused on the effects of bilberry on oral cancer. In this study, we aimed to examine the effects of bilberry powder on oral squamous cell carcinoma (OSCC) cells using both in vitro and in vivo assays. The effects of 0, 1, 10, and 25 mg/mL of whole bilberry powder on the viability, proliferation, migration, and invasion of OSCC (HSC-3) cells were examined and compared with 0.01 mg/mL of cetuximab. Two oral keratinocyte cell lines served as controls. Tumor area was analyzed in zebrafish microinjected with HSC-3 cells and treated with 2.5, 10, or 25 µg/mL of bilberry powder. Metastases in the head or tail areas were counted. Bilberry powder inhibited the viability, proliferation, migration, and invasion of HSC-3 cells (p &lt, 0.05), which was more pronounced with higher concentrations. Cetuximab had no effect on HSC-3 cell migration or invasion. Compared to controls, the tumor area in zebrafish treated with bilberry powder (10 and 25 µg/mL) was reduced significantly (p = 0.038 and p = 0.021, respectively), but the number of fish with metastases did not differ between groups. Based on our in vitro and in vivo experiments, we conclude that whole bilberry powder has anti-tumor effects on OSCC cells.

Purpose: To investigate the longitudinal associations between demographic, clinical and lifestyle factors, and changes in patient-reported outcomes (PROs) in cancer survivors 6–9 years post-diagnosis in Western Australia. Methods: A total of 290 individuals participated in this study. Three-quarters of participants were female, and 55%, 31%, and 14% were survivors of breast cancer, colon cancer, and non-Hodgkin lymphoma (NHL), respectively. PROs (fatigue, depression, and health-related quality of life (HRQOL)) were reported at two time points (2012–13 and 2017). Descriptive statistics were used to assess the overall changes over time and linear mixed models were used to identify factors associated with changes over time, after adjusting for confounders. Results: No significant changes were observed in PROs between time point 1 and follow-up at the population level, yet a notable proportion of participants (23% for fatigue, 10% for depression, and 39% for HRQOL) reported a negative minimal clinically important difference (MCID). Being non-Caucasian and having had NHL were associated with negative changes over time. Being obese and having had radiotherapy were related to improved outcomes. Conclusion: Cancer survivors whose levels of fatigue, depression, and quality of life are compromised during cancer treatment may require intervention even 6–9 years post-treatment. Our results suggest particular attention should be paid to those who are non-Caucasian and who have had NHL. This is crucial for providing appropriate care and to support those who are at increased risk of deteriorating naturally over time. Refereed/Peer-reviewed

Background: Cancer-related cognitive impairment (CRCI) is a prevalent source of comprised quality of life in cancer survivors. This study evaluated the efficacy of Emotional Freedom Techniques (EFT) on self-reported CRCI (sr-CRCI). Methods: In this prospective multicentre randomised wait-list controlled study (ClinicalTrials.gov Identifier: NCT02771028), eligible cancer survivors had completed curative treatment, were 18 years or older and screened positive for sr-CRCI with > 43 on the Cognitive Failures Questionnaire (CFQ). Participants were randomised to the immediate treatment group (ITG) or wait-list control (WLC) group, based on age (< or > 65 years), gender, treatment (chemotherapy or not), and centre. The ITG started to apply EFT after inclusion and performed this for 16 weeks. The WLC group could only start the application of EFT after 8 weeks of waiting. Evaluations took place at baseline (T0), 8 weeks (T1) and 16 weeks (T2). The primary outcome was the proportion of patients with sr-CRCI according to the CFQ score. Findings: Between October 2016 and March 2020, 121 patients were recruited with CFQ > 43 indicating sr-CRCI. At T1, the number of patients scoring positive on the CFQ was significantly reduced in the ITG compared to the WLC group (40.8% vs. 87.3% respectively; p

The C-X-C chemokine receptor 4 (CXCR4) is G protein-coupled receptor that upon binding to its cognate ligand, can lead to tumor progression. Several CXCR4-targeted therapies are currently under investigation, and with it comes the need for imaging agents capable of accurate depiction of CXCR4 for therapeutic stratification and monitoring. PET agents enjoy the most success, but more cost-effective and radiation-free approaches such as ultrasound (US) imaging could represent an attractive alternative. In this work, we developed a targeted microbubble (MB) for imaging of vascular CXCR4 expression in cancer. A CXCR4-targeted MB was developed through incorporation of the T140 peptide into the MB shell. Binding properties of the T140-MB and control, non-targeted MB (NT-MB) were evaluated in MDA-MB-231 cells where CXCR4 expression was knocked-down (via shRNA) through optical imaging, and in the lymphoma tumor models U2932 and SuDHL8 (high and low CXCR4 expression, respectively) by US imaging. PET imaging of [18F]MCFB, a tumor-penetrating CXCR4-targeted small molecule, was used to provide whole-tumor CXCR4 readouts. CXCR4 expression and microvessel density were performed by immunohistochemistry analysis and western blot. T140-MB were formed with similar properties to NT-MB and accumulated sensitively and specifically in cells according to their CXCR4 expression. In NOD SCID mice, T140-MB persisted longer in tumors than NT-MB, indicative of target interaction, but showed no difference between U2932 and SuDHL8. In contrast, PET imaging with [18F]MCFB showed a marked difference in tumor uptake at 40–60 min post-injection between the two tumor models (pEx vivo analysis revealed that the large differences in CXCR4 expression between the two models are not reflected in the vascular compartment, where the MB are restricted; in fact, microvessel density and CXCR4 expression in the vasculature was comparable between U2932 and SuDHL8 tumors. In conclusion, we successfully developed a T140-MB that can be used for imaging CXCR4 expression in the tumor vasculature.

Standardization of tumor assessment lays the foundation for validation of grading systems, permits reproducibility of oncologic studies among investigators, and increases confidence in the significance of study results. Currently, there is minimal methodological standardization for assessing tumors in veterinary medicine, with few attempts to validate published protocols and grading schemes. The current article attempts to address these shortcomings by providing standard guidelines for tumor assessment parameters and protocols for evaluating specific tumor types. More detailed information is available in the Supplemental Files, the intention of which is 2-fold: publication as part of this commentary, but more importantly, these will be available as “living documents” on a website (www.vetcancerprotocols.org), which will be updated as new information is presented in the peer-reviewed literature. Our hope is that veterinary pathologists will agree that this initiative is needed, and will contribute to and utilize this information for routine diagnostic work and oncologic studies. Journal editors and reviewers can utilize checklists to ensure publications include sufficient detail and standardized methods of tumor assessment. To maintain the relevance of the guidelines and protocols, it is critical that the information is periodically updated and revised as new studies are published and validated with the intent of providing a repository of this information. Our hope is that this initiative (a continuation of efforts published in this journal in 2011) will facilitate collaboration and reproducibility between pathologists and institutions, increase case numbers, and strengthen clinical research findings, thus ensuring continued progress in veterinary oncologic pathology and improving patient care. Accepted version

Purpose: Radiation-induced cardiac toxicity is a potential lethal complication. The aim of this study was to assess whether there is a dose-dependent relationship between radiation dose and myocardial fibrosis in patients who received neoadjuvant chemoradiation (nCRT) for esophageal cancer (EC).Methods and Materials: Forty patients with EC treated with a transthoracic esophagectomy with (n = 20) or without (n = 20) nCRT (CROSS study regimen) were included. Cardiovascular magnetic resonance imaging (1.5 Tesla) for left ventricular (LV) function, late gadolinium enhancement, and T1 mapping were performed. Extracellular volume (ECV), as a surrogate for collagen burden, was measured for all LV segments separately. The dose-response relationship between ECV and mean radiation dose per LV myocardial segment was evaluated using a mixed-model analysis.Results: Seventeen nCRT and 16 control patients were suitable for analysis. The mean time after treatment was 67.6 +/- 8.1 (nCRT) and 122 +/- 35 (controls) months (P = .02). In nCRT patients, we found a significantly higher mean global ECV of 28.2% compared with 24.0% in the controls (P < .001). After nCRT, LV myocardial segments with elevated ECV had received significantly higher radiation doses. In addition, a linear dose-effect relation was found with a 0.136% point increase of ECV for each Gy (P < .001). There were no differences in LV function measures and late gadolinium enhancement between both groups.Conclusions: Myocardial ECV was significantly higher in long-term EC survivors after nCRT compared with surgery only. Moreover, this ECV increase was linear with the radiation dose per LV segment, indicating radiation-induced myocardial fibrosis. (C) 2021 The Author(s). Published by Elsevier Inc.

Objective The majority of cancer patients with depressive symptoms does not perceive a need for psychological care. Reasons for this are still unclear. We examined the mediating role of cancer patients' perceptions of depressive symptoms in the relationship between depressive symptoms and perceived need for psychological care. Methods For this cross-sectional study, we recruited 127 Dutch cancer patients with moderate to severe levels of depressive symptoms (Patient Health Questionnaire [PHQ]-9 >= 10) who did not receive professional psychological care. Depressive symptoms were measured with the PHQ-9 questionnaire, by using three different depression score operationalizations. We used mediation analyses to test the mediating role of patients' illness perceptions (measured with subscales of the Brief Illness Perception Questionnaire) in the relation between depressive symptoms and need for care. Results Whilst results did not show significant direct associations between depressive symptoms and perceived need for psychological care, we found positive indirect effects of severity (B = 0.07, SE = 0.04, p < 0.02), meeting the DSM-5 diagnosis (B = 0.45, SE = 0.26, p < 0.02) and having relatively more affective symptoms (B = 2.37, SE = 1.10, p < 0.02) on need for care through the identity perception. Conclusions Including assessments of patients' recognition of depressive symptoms and their perceptions of depression treatment efficacy might improve depression screening in cancer patients by more accurately identifying those with a need for psychological care. Moreover, improving patients' knowledge and recognition of symptoms as being depressive symptoms might be a possible target point in increasing care needs and hereby optimizing the uptake of psychological care in cancer patients with depressive symptoms.

The prediction by classification of side effects incidence in a given medical treatment is a common challenge in medical research. Machine Learning (ML) methods are widely used in the areas of risk prediction and classification. The primary objective of such algorithms is to use several features to predict dichotomous responses (e.g., disease positive/negative). Similar to statistical inference modelling, ML modelling is subject to the class imbalance problem and is affected by the majority class, increasing the false-negative rate. In this study, seventynine ML models were built and evaluated to classify approximately 2000 participants from 26 hospitals in eight different countries into two groups of radiotherapy (RT) side effects incidence based on recorded observations\ud from the international study of RT related toxicity “REQUITE”. We also examined the effect of sampling techniques and cost-sensitive learning methods on the models when dealing with class imbalance. The combinations of such techniques used had a significant impact on the classification. They resulted in an improvement in incidence status prediction by shifting classifiers’ attention to the minority group. The best classification model for RT acute toxicity prediction was identified based on domain experts' success criteria. The Area Under Receiver Operator Characteristic curve of the models tested with an isolated dataset ranged between 0.50 and 0.77. The scale of improved results is promising and will guide further development of models to predict RT acute toxicities. One model was optimised and found to be beneficial to identify patients who are at risk of developing acute RT early-stage toxicities as a result of undergoing breast RT ensuring relevant treatment interventions can be appropriately targeted. The design of the approach presented in this paper resulted in\ud producing a preclinical-valid prediction model. The study was developed by a multi-disciplinary collaboration of data scientists, medical physicists, oncologists and surgeons in the UK Radiotherapy Machine Learning Network.

Despite widespread adoption of electronic health records (EHRs), most hospitals are not ready to implement data science research in the clinical pipelines. Here, we develop MEDomics, a continuously learning infrastructure through which multimodal health data are systematically organized and data quality is assessed with the goal of applying artificial intelligence for individual prognosis. Using this framework, currently composed of thousands of individuals with cancer and millions of data points over a decade of data recording, we demonstrate prognostic utility of this framework in oncology. As proof of concept, we report an analysis using this infrastructure, which identified the Framingham risk score to be robustly associated with mortality among individuals with early-stage and advanced-stage cancer, a potentially actionable finding from a real-world cohort of individuals with cancer. Finally, we show how natural language processing (NLP) of medical notes could be used to continuously update estimates of prognosis as a given individual’s disease course unfolds. Morin and colleagues develop a data-integration framework capable of performing continuous learning from electronic health records on clinical, social and demographic data collected over a decade to estimate pan-cancer survival prognosis.

Purpose Musculoskeletal diagnoses (MSD) are one of the largest diagnostic groups for disability pensions (DP). This study investigated the associations between life events and DP due to MSD, considering sociodemographic, health, and familial factors. Methods The study sample included 18,530 Finnish twins, 24–64 years old at baseline, who responded to a questionnaire in 1981 including a 21-item life event inventory. Information on DP with diagnosis codes (ICD codes: M00–M99) were obtained from the official national pension registers. Life events were divided into family- and work-related events. “Positive change in life” was analyzed separately. Cox proportional hazards models were used to calculate hazard ratios (HR) with 95% confidence intervals (CI). Results During the follow-up of 23 years, 1273 (7%) individuals were granted DP due to MSD. In discordant pair analysis, family-related events (≥ 4 events) increased (HR 1.63, 95% CI 1.31, 2.03) and the absence of such events decreased (HR 0.68, 95% CI 0.48, 0.95) the risk of DP due to MSD. For work-related events (≥ 3 events), the risk estimates were non-significant when controlling for familial factors. Having had a positive change in life decreased the risk of DP due to MSD (HR 0.79, 95% CI 0.65, 0.96) while controlling for familial confounding, but were non-significant in the full model controlling for various covariates (HR 0.91, 95% CI 0.75, 1.12). Conclusions The associations between life events and the risk of DP due to MSD are complex and potentially affected by familial and other confounding factors including sociodemographics and health.

Summary Cancer cell stemness (CCS) plays critical roles in both malignancy maintenance and metastasis, yet the underlying molecular mechanisms are far from complete. Although the importance of SOX2 in cancer development and CCS are well recognized, the role of MTA3 in these processes is unknown. In this study, we used esophageal squamous cell carcinoma (ESCC) as a model system to demonstrate that MTA3 can repress both CCS and metastasis in vitro and in vivo. Mechanistically, by forming a repressive complex with GATA3, MTA3 downregulates SOX2OT, subsequently suppresses the SOX2OT/SOX2 axis, and ultimately represses CCS and metastasis. More importantly, MTA3low/SOX2high is associated with poor prognosis and could serve as an independent prognostic factor. These findings altogether indicate that MTA3/SOX2OT/SOX2 axis plays an indispensable role in CCS. Therefore, this axis could be potentially used in cancer stratification and serves as a therapeutic target., Graphical Abstract, Highlights • MTA3 is recruited by GATA3 to repress SOX2OT transcription • The MTA3/GATA3 complex dampens SOX2 signaling by inhibiting SOX2OT transcription • MTA3 can repress both cancer stemness and metastasis of squamous esophageal cancer • Low MTA3 and high SOX2 expression predicts poor prognosis in esophageal cancer, Biological Sciences; Molecular Biology; Cell Biology; Stem Cells Research; Cancer

Introduction To provide optimal care for patients with cancer, timely and efficient communication between healthcare providers is essential. In this study, we aimed to achieve consensus regarding the desired content of communication between general practitioners (GPs) and oncology specialists before and during the initial treatment of cancer. Methods In a two-round Delphi procedure, three expert panels reviewed items recommended for inclusion on referral and specialist letters. Results The three panels comprised 39 GPs (42%), 42 oncology specialists (41%) (i.e. oncologists, radiotherapists, urologists and surgeons) and 18 patients or patient representatives (69%). Final agreement was by consensus, with 12 and 35 items included in the GP referral and the specialist letters, respectively. The key requirements of GP referral letters were that they should be limited to medical facts, a short summary of symptoms and abnormal findings, and the reason for referral. There was a similar requirement for letters from specialists to include these same medical facts, but detailed information was also required about the diagnosis, treatment options and chosen treatment. After two rounds, the overall content validity index (CVI) for both letters was 71%, indicating that a third round was not necessary. Discussion This is the first study to differentiate between essential and redundant information in GP referral and specialist letters, and the findings could be used to improve communication between primary and secondary care. Electronic supplementary material The online version of this article (10.1007/s00520-019-04712-5) contains supplementary material, which is available to authorized users.

The CDK7 inhibitors (CDK7i) ICEC0942 and THZ1, are promising new cancer therapeutics. Resistance to targeted drugs frequently compromises cancer treatment. We sought to identify mechanisms by which cancer cells may become resistant to CDK7i. Resistant lines were established through continuous drug selection. ABC-transporter copy number, expression and activity were examined using real-time PCR, immunoblotting and flow cytometry. Drug responses were measured using growth assays. ABCB1 was upregulated in ICEC0942-resistant cells and there was cross-resistance to THZ1. THZ1-resistant cells upregulated ABCG2 but remained sensitive to ICEC0942. Drug resistance in both cell lines was reversible upon inhibition of ABC-transporters. CDK7i response was altered in adriamycin- and mitoxantrone-resistant cell lines demonstrating ABC-transporter upregulation. ABCB1 expression correlated with ICEC0942 and THZ1 response, and ABCG2 expression with THZ2 response, in a panel of cancer cell lines. We have identified ABCB1 upregulation as a common mechanism of resistance to ICEC0942 and THZ1, and confirmed that ABCG2 upregulation is a mechanism of resistance to THZ1. The identification of potential mechanisms of CDK7i resistance and differences in susceptibility of ICEC0942 and THZ1 to ABC-transporters, may help guide their future clinical use.

Resistant tumours are thought to arise from the action of Darwinian selection on genetically heterogenous cancer cell populations. However, simple clonal selection is inadequate to describe the late relapses often characterising luminal breast cancers treated with endocrine therapy (ET), suggesting a more complex interplay between genetic and non-genetic factors. Here, we dissect the contributions of clonal genetic diversity and transcriptional plasticity during the early and late phases of ET at single-cell resolution. Using single-cell RNA-sequencing and imaging we disentangle the transcriptional variability of plastic cells and define a rare subpopulation of pre-adapted (PA) cells which undergoes further transcriptomic reprogramming and copy number changes to acquire full resistance. We find evidence for sub-clonal expression of a PA signature in primary tumours and for dominant expression in clustered circulating tumour cells. We propose a multi-step model for ET resistance development and advocate the use of stage-specific biomarkers., The development of resistance to endocrine therapy is a significant, clinical problem in breast cancer. Here, the authors identify a rare subpopulation of cells that drive resistance following transcriptional reprogramming.

Several ongoing international prostate cancer (PC) clinical trials are exploring therapies that target the DNA damage response (DDR) pathway. This systematic review summarizes the prevalence of DDR mutation carriers in the unselected (general) PC and familial PC populations. A total of 11 electronic databases, 10 conference proceedings, and grey literature sources were searched from their inception to December 2017. Studies reporting the prevalence of somatic and/or germline DDR mutations were summarized. Metastatic PC (mPC), castration-resistant PC (CRPC) and metastatic CRPC (mCRPC) subgroups were included. A total of 11,648 records were retrieved, and 80 studies (103 records) across all PC populations were included; 59 records were of unselected PC and 13 records of familial PC. Most data were available for DDR panels (n=12 studies), ataxia telangiectasia mutated (ATM; n=13), breast cancer susceptibility gene (BRCA)1 (n=14) and BRCA2 (n=20). ATM, BRCA2 and partner and localizer of BRCA2 (PALB2) had the highest mutation rates (>= 4%). Median prevalence rates for DDR germline mutations were 18.6% in PC (range, 17.2-19%; three studies, n=1,712), 11.6% in mPC (range, 11.4-11.8%; two studies, n=1,261) and 8.3% in mCRPC (range, 7.5-9.1%; two studies, n=738). Median prevalence rates for DDR somatic mutations were 10.7% in PC (range, 4.9-22%; three studies, n=680), 13.2% in mPC (range, 10-16.4%; two studies, n=105) and not reported (NR) in mCRPC. The prevalence of DDR germline and/or somatic mutations was 27% in PC (one study, n=221), 22.67% in mCRPC (one study, n=150) and NR in mPC. In familial PC, median mutation prevalence was 12.1% (range, 7.3-16.9%) for germline DDR (two studies, n=315) and 3.7% (range, 1.3-7.9%) for BRCA2 (six studies, n=945). In total, 88% of studies were at a high risk of bias. The prevalence of DDR gene mutations in PC varied widely within somatic subgroups depending on study size, genetic screening techniques, DDR mutation definition and PC diagnosis; somatic and/or germline DDR mutation prevalence was in the range of 23-27% in PC. These findings support DDR mutation testing for all patients with PC (including those with mCRPC). With the advent of the latest clinical practice PC guidelines highlighting the importance of DDR mutation screening, and ongoing mCRPC clinical trials evaluating DDR mutation-targeted drugs, future larger epidemiological studies are warranted to further quantify the international burden of DDR mutations in PC.

Background: Lymphedema is a chronic, progressive disease consisting of tissue swelling resulting from excessive retention of lymphatic fluid. Measuring upper limb volume is crucial in patients to detect disease progression and to study the effects of treatment. The aim is to assess the validity and reliability of a newly developed system, Peracutus Aqua Meth, for measuring the upper limb volume compared with the gold standard water volumetry device. (In this study, the Bravometer was used). Methods and Results: Healthy volunteers were recruited in October 2017. Three measurements were performed per device. The obtained data were recorded per measurement, device, and researcher. Primary outcome was to determine the validity and reliability of the Peracutus Aqua Meth. Secondary outcomes were intra- and interrater reliability, measurement time, self-reported participant satisfaction, and influence of body mass index (BMI). Thirty-nine healthy volunteers were included. Mean differences in the validity in the Peracutus Aqua Meth and Bravometer were 47.26 and 78.16 mL, respectively (p = 0.04), with a Pearson's r of 0.99. Intra- and interrater reliability of the Peracutus Aqua Meth were both 0.99, in the Bravometer 0.96 and 0.97, respectively (p

Several ongoing international prostate cancer (PC) clinical trials are exploring therapies that target the DNA damage response (DDR) pathway. This systematic review summarizes the prevalence of DDR mutation carriers in the unselected (general) PC and familial PC populations. A total of 11 electronic databases, 10 conference proceedings, and grey literature sources were searched from their inception to December 2017. Studies reporting the prevalence of somatic and/or germline DDR mutations were summarized. Metastatic PC (mPC), castration-resistant PC (CRPC) and metastatic CRPC (mCRPC) subgroups were included. A total of 11,648 records were retrieved, and 80 studies (103 records) across all PC populations were included; 59 records were of unselected PC and 13 records of familial PC. Most data were available for DDR panels (n=12 studies), ataxia telangiectasia mutated (ATM; n=13), breast cancer susceptibility gene (BRCA)1 (n=14) and BRCA2 (n=20). ATM, BRCA2 and partner and localizer of BRCA2 (PALB2) had the highest mutation rates (>= 4%). Median prevalence rates for DDR germline mutations were 18.6% in PC (range, 17.2-19%; three studies, n=1,712), 11.6% in mPC (range, 11.4-11.8%; two studies, n=1,261) and 8.3% in mCRPC (range, 7.5-9.1%; two studies, n=738). Median prevalence rates for DDR somatic mutations were 10.7% in PC (range, 4.9-22%; three studies, n=680), 13.2% in mPC (range, 10-16.4%; two studies, n=105) and not reported (NR) in mCRPC. The prevalence of DDR germline and/or somatic mutations was 27% in PC (one study, n=221), 22.67% in mCRPC (one study, n=150) and NR in mPC. In familial PC, median mutation prevalence was 12.1% (range, 7.3-16.9%) for germline DDR (two studies, n=315) and 3.7% (range, 1.3-7.9%) for BRCA2 (six studies, n=945). In total, 88% of studies were at a high risk of bias. The prevalence of DDR gene mutations in PC varied widely within somatic subgroups depending on study size, genetic screening techniques, DDR mutation definition and PC diagnosis; somatic and/or germline DDR mutation prevalence was in the range of 23-27% in PC. These findings support DDR mutation testing for all patients with PC (including those with mCRPC). With the advent of the latest clinical practice PC guidelines highlighting the importance of DDR mutation screening, and ongoing mCRPC clinical trials evaluating DDR mutation-targeted drugs, future larger epidemiological studies are warranted to further quantify the international burden of DDR mutations in PC.

Background Mediterranean diet (MD) adherence has been associated with reduced risks of esophageal and gastric cancer (subtypes) in a limited number of studies. We prospectively investigated associations between MD adherence and risks of esophageal squamous cell carcinoma (ESCC), esophageal adenocarcinoma (EAC), gastric cardia adenocarcinoma (GCA), and gastric non-cardia adenocarcinoma (GNCA) in a Dutch cohort. Methods Analyses were conducted using data from the 120852 participants of the Netherlands Cohort Study (NLCS), who were aged between 55 and 69 years at enrollment. Various MD scores, with and without alcohol, were calculated to estimate MD adherence. Using 20.3 years of follow-up, 133 ESCC, 200 EAC, 191 GCA, and 586 GNCA cases could be included in multivariable Cox regression analyses. Results Of the investigated scores, the alternate Mediterranean diet score without alcohol (aMEDr) performed best. aMEDr was inversely associated with risks of GCA and GNCA in men and women. However, statistical significance was only reached in men [ptrend: 0.019 (GCA), 0.016 (GNCA)]. Furthermore, higher aMEDr values were significantly associated with a reduced ESCC risk in men [HRper two−point increment (95% CI) = 0.57 (0.41–0.80), ptrend = 0.013], but not in women (pheterogeneity = 0.008). There was no evidence of an association between aMEDr and EAC risk. Educational level was a significant effect modifier for the association between aMEDr and GNCA risk (pheterogeneity = 0.0073). Conclusions Higher MD adherence was associated with reduced risks of ESCC, GCA, and GNCA in the NLCS. However, the decreased ESCC risk might be limited to men. Electronic supplementary material The online version of this article (10.1007/s10120-019-00927-x) contains supplementary material, which is available to authorized users.

PubMed: 31209238, The effectiveness of most cancer targeted therapies is short-lived. Tumors often develop resistance that might be overcome with drug combinations. However, the number of possible combinations is vast, necessitating data-driven approaches to find optimal patient-specific treatments. Here we report AstraZeneca’s large drug combination dataset, consisting of 11,576 experiments from 910 combinations across 85 molecularly characterized cancer cell lines, and results of a DREAM Challenge to evaluate computational strategies for predicting synergistic drug pairs and biomarkers. 160 teams participated to provide a comprehensive methodological development and benchmarking. Winning methods incorporate prior knowledge of drug-target interactions. Synergy is predicted with an accuracy matching biological replicates for >60% of combinations. However, 20% of drug combinations are poorly predicted by all methods. Genomic rationale for synergy predictions are identified, including ADAM17 inhibitor antagonism when combined with PIK3CB/D inhibition contrasting to synergy when combined with other PI3K-pathway inhibitors in PIK3CA mutant cells. © 2019, The Author(s)., National Institute for Health Research, NIHR Wellcome Trust, WT: 102696, 206194 Magyar Tudományos Akadémia, MTA Bayer 668858 PrECISE AstraZeneca, We thank the Genomics of Drug Sensitivity in Cancer and COSMIC teams at the Wellcome Trust Sanger Institute for help with the preparation of the molecular data, Denes Turei for help with Omnipath, and Katjusa Koler for help with matching drug names across combination screens. We thank AstraZeneca for funding and provision of data to the DREAM Consortium to run the challenge, and funding from the European Union Horizon 2020 research (under grant agreement No 668858 PrECISE to J.S.R.), the Joint Research Center for Computational Biomedicine (which is partially funded by Bayer AG) to J.S.R., National Institute for Health Research (NIHR) Sheffield Biomedical Research Center, Premium Postdoctoral Fellowship Program of the Hungarian Academy of Sciences. M.G lab is supported by Wellcome Trust (102696 and 206194)., Competing interests: K.C.B., Z.G., G.Y.D., E.K.Y.T., S.F., and J.R.D. are AstraZeneca employees. K.C.B., Z.G., E.K.Y.T., S.F., and J.R.D. are AstraZeneca shareholders. Y.G. receives personal compensation from Eli Lilly and Company, is a shareholder of Cleerly, Inc., and Ann Arbor Algorithms, Inc. M.G. receives research funding from AstraZeneca and has performed consultancy for Sanofi. The remaining authors declare no competing interests.

Purpose Employers are important stakeholders in the return to work (RTW) of employees with cancer. However, it is unclear what employer actions are most important to that process. The objective, therefore, was to reach consensus on what employer actions are considered most important for the RTW of employees with cancer, by employers and employees separately. Methods A two-round online Delphi study was conducted with two expert panels: one with 23 employers and one with 29 employees with cancer. The results from each panel were analysed separately. Out of 24 suggested employer actions, participants selected the 10 they considered most important for RTW in each of the following RTW phases: (1) disclosure, (2) treatment, (3) RTW plan, and (4) actual RTW. The consensus threshold was set at ≥ 80% during the second round. Results The employer and employee expert panels both reached consensus on the importance of 'emotional support', 'practical support', 'allow sufficient sick leave', 'plan return to work', 'adjust expectations', 'assess work ability', and 'show appreciation'. Employers also reached consensus on 'communicate' and 'treat normally', and employees on 'handle unpredictability'. All these employer actions were considered to be specific for one to three RTW phases. Conclusions Employers reached consensus on the importance of nine employer actions, employees on eight. Both stakeholder perspectives showed great similarities, but did vary regarding important employer actions during the employee's treatment. We recommend developing interventions targeting the employer, meeting both employer and employee needs in each RTW phase, to enhance RTW support for employees with cancer.

Bone metastasis is a disastrous manifestation of most malignancies, especially in breast, prostate and lung cancers. Since asymptomatic bone metastases are not uncommon, early detection, precise assessment, and localization of them are very important. Various imaging modalities have been employed in the setting of diagnosis of bone metastasis, from plain radiography and bone scintigraphy to SPECT, SPECT/CT, PET/CT, MRI. However, each modality showed its own limitation providing accurate diagnostic performance. In this regard, various tumor-targeted radiotracers have been introduced for molecular imaging of bone metastases using modern hybrid modalities. In this article we review the strength of different cancer-specific radiopharmaceuticals in the detection of bone metastases. As shown in the literature, among various tumor-targeted tracers, Ga-68 DOTA-conjugated-peptides, Ga-68 PSMA, F-18 DOPA, F-18 galacto-RGD integrin, F-18 FDG, C-11/F-18 acetate, C-11/F-18 choline, In-111 octreotide, I-123/131 MIBG, Tc-99m MIBI, and Tl-201 have acceptable capabilities in detecting bone metastases depending on the cancer type. However, different study designs and gold standards among reviewed articles should be taken into consideration.

Introduction Adrenocortical carcinoma (ACC) is a rare cancer that commonly spreads to the liver, lungs and lymph nodes. Bone metastases are infrequent. Objective The aim of this report was to describe the clinical characteristics, survival perspective, prognostic factors and frequency of adverse skeletal-related events (SREs) in patients with ACC who developed bone metastasis. Methods This is a retrospective, observational, multicenter, multinational study of patients diagnosed with bone metastases from ACC who were treated and followed up in three European countries (France, Italy and The Netherlands) and one center in the United States. Results Data of 156 patients were captured. The median overall survival was 11 months. SREs occurred in 47% of patients: 17% bone fractures, 17% spinal cord compression, 1% hypercalcemia, 12% developed more than one SRE. In multivariate analysis, cortisol hypersecretion was the only prognostic factor significantly associated with a higher mortality risk (hazard ratio (HR) 2.24, 95% confidence interval (CI): 1.19–4.23, P = 0.013) and with the development of a SREs (of border line significance). The administration of antiresorptive therapies (bisphosphonates and denosumab) was associated with a lower risk of death, even if not significant, and their survival benefit appeared confined in patients attaining serum mitotane levels within the therapeutic range. Conclusion Bone metastases in ACC patients are associated with poor prognosis and high risk of SREs. Cortisol hypersecretion was the only prognostic factor suggesting a potential benefit from antisecretory medications. The therapeutic role of bisphosphonates and denosumab to improve patient outcome deserves to be tested in a prospective clinical trial.

Cardiovascular (CV) disease and cancer are the leading causes of death.1,2 Over the last decades, it has been appreciated that both CV disease and cancer are more common in individuals in whom risk factors for disease development accumulate, and preventative measures have been extremely important in driving down the incidence of disease.3–6 In general, the field of epidemiology, risk reduction, and preventative trials is divided into health care professionals who have an interest in either CV disease or cancer. As a result, the medical literature and medical practice has largely focused on the one disease, or the other. However, human individuals do not behave according to this dogma. Emerging data clearly suggest that identical risk factors may lead to CV disease in the one individual, but may cause cancer in another, or even both diseases in the same individual. This overlap exists between risk factors that are historically classified as ‘CV risk factors’ as these factors do equally strong predict cancer development. Therefore, we propose that a holistic approach might better estimate actual risks for CV disease and cancer. In this review, we summarize current insights in common behavioural risk factors for heart failure, being the most progressed and lethal form of CV disease, and cancer.

Cardiovascular (CV) disease and cancer are the leading causes of death.(1,2) Over the last decades, it has been appreciated that both CV disease and cancer are more common in individuals in whom risk factors for disease development accumulate, and preventative measures have been extremely important in driving down the incidence of disease.(3-6) In general, the field of epidemiology, risk reduction, and preventative trials is divided into health care professionals who have an interest in either CV disease or cancer. As a result, the medical literature and medical practice has largely focused on the one disease, or the other. However, human individuals do not behave according to this dogma. Emerging data clearly suggest that identical risk factors may lead to CV disease in the one individual, but may cause cancer in another, or even both diseases in the same individual. This overlap exists between risk factors that are historically classified as CV risk factors' as these factors do equally strong predict cancer development. Therefore, we propose that a holistic approach might better estimate actual risks for CV disease and cancer. In this review, we summarize current insights in common behavioural risk factors for heart failure, being the most progressed and lethal form of CV disease, and cancer.

BACKGROUND: Research has been mainly focused on how to elicit patient preferences, with less attention on why patients form certain preferences.OBJECTIVES: To assess which psychological instruments are currently used and which psychological constructs are known to have an impact on patients' preferences and health-related decisions including the formation of preferences and preference heterogeneity.METHODS: A systematic database search was undertaken to identify relevant studies. From the selected studies, the following information was extracted: study objectives, study population, design, psychological dimensions investigated, and instruments used to measure psychological variables.RESULTS: Thirty-three studies were identified that described the association between a psychological construct, measured using a validated instrument, and patients' preferences or health-related decisions. We identified 33 psychological instruments and 18 constructs, and categorized the instruments into 5 groups, namely, motivational factors, cognitive factors, individual differences, emotion and mood, and health beliefs.CONCLUSIONS: This review provides an overview of the psychological factors and related instruments in the context of patients' preferences and decisions in healthcare settings. Our results indicate that measures of health literacy, numeracy, and locus of control have an impact on health-related preferences and decisions. Within the category of constructs that could explain preference and decision heterogeneity, health locus of control is a strong predictor of decisions in several healthcare contexts and is useful to consider when designing a patient preference study. Future research should continue to explore the association of psychological constructs with preference formation and heterogeneity to build on these initial recommendations.

BACKGROUND: Older adults with cancer experience negative long-term functional effects of both cancer and treatments. Exercise may minimize their age-related and cancer-related functional decline. METHODS: We conducted a multicentre open-label 12month randomized clinical trial with two parallel arms including participants aged ≥70years with lymphoma or carcinoma requiring curative treatment. The study started at the beginning of any phase of cancer treatment (surgery, chemotherapy, or radiotherapy). The usual care group (UCG) received the current national recommendations in physical activity (a guideline without specific counselling). The intervention group (IG) received 1year phoned physical activity advice individually adapted to physical assessment (twice a month during the first 6months and then monthly). The primary outcome was the proportion of subjects with a 1year decreased short physical performance battery (SPPB) score of 1 point or more. Physical, cognitive, and clinical secondary outcomes were also investigated. RESULTS: We allocated 301 participants (age 76.7±5.0, female 60.6%) to each group. At baseline, the median SPPB was 10/12 in both groups. Breast was the most frequent tumour site (35.7%). After 1year, 14.0% of participants in the UCG and 18.7% in the IG had a decrease in SPPB score of 1 point or more (P=0.772). At 2years, there was no difference in SPPB, gait speed, International Physical Activity Questionnaire score, and verbal fluency. Subgroup analyses after 2years showed a decline in SPPB for 29.8% of UCG and 5.0% of IG breast cancer participants (P=0.006), in 21.7% of UCG and 6.2% of IG female participants (P=0.019), and in 24.5% of UCG and 11.1% of IG normal nutritional status participants (P=0.009). Falls, hospitalization, institutionalization, and death rates were similar in both groups. CONCLUSIONS: Personalized phoned physical activity advice had not reduced functional decline at 1year but provided preliminary evidence that may prevent physical performance decline at 2years in older adults with breast cancer. © 2019 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of the Society on Sarcopenia, Cachexia and Wasting Disorders. This work was funded by the National Hospital Program of Clinical Research (Programme Hospitalier de Recherche Clinique 2010) and sponsored by the University Hospital of Bordeaux (CHU Bordeaux). Haritz Arrieta was supported by a fellowship from University of the Basque Country (UPV/EHU).

BACKGROUND: Adjuvant therapy improves the prognosis of stage II & III colon cancer patients. Unfortunately, most patients do not benefit from this treatment. PePITA (NCT00994864) is a prospective, multicenter, non-randomized study whose primary objective is to predict the outcome of adjuvant therapy in colon cancer. METHODS: The primary objective was to determine the prognostic and predictive value of circulating tumor cell (CTC) detection before therapy and after one course of preoperative FOLFOX. RESULTS: Out of the 58 first patients accrued in PePiTA trial, 36 patients participated in the CTC companion study, of whom 32 had at least one evaluable sample. Only 5 patients (14, 95% CI = 5-30%) had ≥1 CTC/22.5 ml blood in at least one of the two timepoints with 2 patients having ≥1 CTC/22.5 ml at baseline (6, 95% CI: 1-19%). The detection rate of patients with CTCs at baseline being lower than expected, the inclusion of patients in the PePiTA CTC substudy was stopped. The limited sample size did not allow us to investigate the prognostic and predictive value of CTCs in locally advanced colon cancer. CONCLUSIONS: Our data illustrate the need for further standardized studies in order to find the most reliable prognostic/predictive biomarker in early-stage colon cancer. TRIAL REGISTRATION: This trial was prospectively registered at Jules Bordet institute ( NCT00994864 ) on the October 14, 2009. ispartof: BMC CANCER vol:19 issue:1 ispartof: location:England status: published

To inform novel personalized medicine approaches for race and socioeconomic disparities in head and neck cancer, we examined germline and somatic mutations, immune signatures, and epigenetic alterations linked to neighborhood determinants of health in Black and non-Latino White (NLW) patients with head and neck cancer. Cox proportional hazards revealed that Black patients with squamous cell carcinoma of head and neck (HNSCC) with PAX5 (P = 0.06) and PAX1 (P = 0.017) promoter methylation had worse survival than NLW patients, after controlling for education, zipcode, and tumor–node–metastasis stage (n = 118). We also found that promoter methylation of PAX1 and PAX5 (n = 78), was correlated with neighborhood characteristics at the zip-code level (P < 0.05). Analyses also showed differences in the frequency of TP53 mutations (n = 32) and tumor-infiltrating lymphocyte (TIL) counts (n = 24), and the presence of a specific C → A germline mutation in JAK3, chr19:17954215 (protein P132T), in Black patients with HNSCC (n = 73; P < 0.05), when compared with NLW (n = 37) patients. TIL counts are associated (P = 0.035) with long-term (>5 years), when compared with short-term survival (

BACKGROUND: Research has been mainly focused on how to elicit patient preferences, with less attention on why patients form certain preferences. OBJECTIVES: To assess which psychological instruments are currently used and which psychological constructs are known to have an impact on patients' preferences and health-related decisions including the formation of preferences and preference heterogeneity. METHODS: A systematic database search was undertaken to identify relevant studies. From the selected studies, the following information was extracted: study objectives, study population, design, psychological dimensions investigated, and instruments used to measure psychological variables. RESULTS: Thirty-three studies were identified that described the association between a psychological construct, measured using a validated instrument, and patients' preferences or health-related decisions. We identified 33 psychological instruments and 18 constructs, and categorized the instruments into 5 groups, namely, motivational factors, cognitive factors, individual differences, emotion and mood, and health beliefs. CONCLUSIONS: This review provides an overview of the psychological factors and related instruments in the context of patients' preferences and decisions in healthcare settings. Our results indicate that measures of health literacy, numeracy, and locus of control have an impact on health-related preferences and decisions. Within the category of constructs that could explain preference and decision heterogeneity, health locus of control is a strong predictor of decisions in several healthcare contexts and is useful to consider when designing a patient preference study. Future research should continue to explore the association of psychological constructs with preference formation and heterogeneity to build on these initial recommendations. ispartof: VALUE IN HEALTH vol:22 issue:4 pages:491-501 ispartof: location:United States status: Published online

PEREIRA, JULIANA/0000-0002-0655-2821; ZINZANI, PIER LUIGI/0000-0002-2112-2651; Trotman, Judith/0000-0001-8009-4593 WOS: 000462407900001 PubMed: 30707661 PURPOSEThe aim of this open-label, first-in-setting, randomized phase III trial was to evaluate the efficacy of alisertib, an investigational Aurora A kinase inhibitor, in patients with relapsed/refractory peripheral T-cell lymphoma (PTCL).PATIENTS AND METHODSAdult patients with relapsed/refractory PTCLone or more prior therapywere randomly assigned 1:1 to receive oral alisertib 50 mg two times per day (days 1 to 7; 21-day cycle) or investigator-selected single-agent comparator, including intravenous pralatrexate 30 mg/m(2) (once per week for 6 weeks; 7-week cycle), or intravenous gemcitabine 1,000 mg/m(2) or intravenous romidepsin 14 mg/m(2) (days 1, 8, and 15; 28-day cycle). Tumor tissue (disease subtype) and imaging were assessed by independent central review. Primary outcomes were overall response rate and progression-free survival (PFS). Two interim analyses and one final analysis were planned.RESULTSBetween May 2012 and October 2014, 271 patients were randomly assigned (alisertib, n = 138; comparator, n = 133). Enrollment was stopped early on the recommendation of the independent data monitoring committee as a result of the low probability of alisertib achieving PFS superiority with full enrollment. Centrally assessed overall response rate was 33% for alisertib and 45% for the comparator arm (odds ratio, 0.60; 95% CI, 0.33 to 1.08). Median PFS was 115 days for alisertib and 104 days for the comparator arm (hazard ratio, 0.87; 95% CI, 0.637 to 1.178). The most common adverse events were anemia (53% of alisertib-treated patients v 34% of comparator-treated patients) and neutropenia (47% v 31%, respectively). A lower percentage of patients who received alisertib (9%) compared with the comparator (14%) experienced events that led to study drug discontinuation. Of 26 on-study deaths, five were considered treatment related (alisertib, n = 3 of 11; comparator, n = 2 of 15). Two-year overall survival was 35% for each arm.CONCLUSIONIn patients with relapsed/refractory PTCL, alisertib was not statistically significantly superior to the comparator arm. Millennium Pharmaceuticals, Cambridge, MA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited Funded by Millennium Pharmaceuticals, Cambridge, MA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited.

BACKGROUND: Cancer and cancer treatments may impact the brain through several pathways leading to cognitive impairment. Neuroimaging evidence has begun to elucidate the neurobiological underpinnings of cancer-related cognitive impairment. The aim of this paper was to systematically review available literature on structural brain alterations following adult non-central nervous system (CNS) cancers and associated treatments.METHODS: This review followed PRISMA guidelines and was registered in PROSPERO (ID#107387). Comprehensive searches were conducted in June 2018 using PubMed and Web of Science. Inclusion criteria were English peer-reviewed journal articles of formal, controlled studies that examined structural neuroimaging outcomes in adult non-CNS cancer patients and survivors. Selected articles were assessed for quality and risk of bias using the National Institutes of Health Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies.RESULTS: Thirty-six publications of prospective and cross-sectional studies met inclusion criteria and were included. Structural brain alterations following cancer and its treatment were reported in a majority of the publications as evidenced by reduced global and local gray matter volumes, impaired white matter microstructural integrity, and brain network alterations. Structural alterations were most often evident when cancer-treated groups were compared with healthy controls, and more subtle when compared with cancer controls. Regarding the existence of pretreatment impairments, the evidence was equivocal. There was significant between-study heterogeneity in imaging analytical approaches and use of statistical adjustments. Over half reported associations with cognitive outcomes, though regions and associated cognitive domains were heterogeneous.CONCLUSIONS: Structural brain alterations following cancer and cancer treatments were reported in a majority of the reviewed studies. However, the extent of observed alterations depended on the choice of comparison groups. Methodological issues exist that will need to be addressed systematically to ensure the validity of findings. Large-scale prospective studies with extended assessment points are warranted to replicate and build upon initial findings.

Population ageing has substantially contributed to the rising number of new cancer cases worldwide. We document cancer incidence patterns in 2012 among older adults globally, and examine the changing magnitude of cancer in this age group over the next decades. Using GLOBOCAN 2012 data, we presented the number and proportion of new cancer cases, and the truncated age-standardised incidence rates among adults aged 65 years and older for all cancer sites combined and for the five most common cancer sites by world region. We calculated the incidence in 2035 by applying population projections, assuming no changes in rates. In 2012, 6.7 million new cancer cases (47.5% of all cancers) were diagnosed among older adults worldwide, with marked regional disparities. Nearly 48% of these cases occurred in less developed regions. Lung, colorectal, prostate, stomach and breast cancers represented 55% of the global incidence, yet distinct regional patterns were observed. We predict 14 million new cancer cases by 2035, representing almost 60% of the global cancer incidence. The largest relative increase in incidence is predicted in the Middle East and Northern Africa (+157%), and in China (+155%). Less developed regions will see an increase of new cases by 144%, compared to 54% in more developed regions. The expected increase in cancer incidence at older ages will have substantial economic and social impacts globally, posing considerable and unique challenge to healthcare systems in every world region, especially in those with limited resources and weaker health systems.

PurposeIn the Netherlands, online patient reporting of side effects is a new phenomenon. The aim of this study was to gain insight into patients' user experiences and the benefits of the web application BijKanker ('AlongsideCancer').MethodsPatients in seven hospitals were asked to make entries in BijKanker at least once a week. On logging in to the application for the first time (T1), patients were asked to complete a questionnaire on information needs and Internet use. Four months after starting their treatment (T2), they were asked to complete a second questionnaire on their experiences with BijKanker and its four functions: information; reporting side effects; communication with oncology nurses and clinicians; and data feedback.ResultsNinety-nine patients logged in to BijKanker, 60 patients (61%) had completed the first questionnaire (T1) and 40 (40%) had also completed the second questionnaire (T2). In total, 1661 side effects were reported. Generally, patients experienced BijKanker as user-friendly and patients appreciated the attention given to their side effects.Conclusions The user-centred design gives ample insight into user experiences and usability. The results provide useful starting points for improvements to the online application. We recommend to put much effort into supporting oncology nurses in the implementation of the application.

ObjectiveAlopecia is a frequently occurring side effect of chemotherapy and has high impact on many patients. Currently, scalp cooling is the only method to prevent this chemotherapy-induced alopecia (CIA) and it is effective in about half of the patients. Since determinants of the success are largely unknown, all patients should be prepared for potential hair loss. The objective was to provide up-to-date online information about CIA and scalp cooling to support patients in coping with CIA and in their choice regarding scalp cooling. MethodsEssential aspects of delivering information and lack of information were identified during focus groups, interviews, and a questionnaire survey among cancer patients, and in discussions with nurses. ResultsThe obtained information was used to develop a website (www.scalpcooling.org) and a web-based tool. It combines scientific evidence and practical advice about CIA and regrowth of hair, scalp-cooling tolerance, efficacy and safety, as well as an overview of possible advantages and disadvantages. The web-based tool provides tailored information about the probability of CIA with and without scalp cooling in particular chemotherapy regimens. Besides, the tool offers patients' support in decision-making by allowing them to reflect and consider their values and opinions about scalp cooling. ConclusionsThis comprehensive information is useful during nursing consultations.

Endometriosis is a gynecological disorder affecting about 10% of women and can lead to invalidating painful symptoms and infertility. Since there is no current definitive cure for this disease, new therapeutic options are necessary. 17β-Hydroxysteroid dehydrogenase type 1 (17β-HSD1) is involved in the production of estradiol (E2), the most potent estrogen in women, and of 5-androstene-3β,17β-diol (5-diol), a weaker estrogen than E2, but whose importance increases after menopause. 17β-HSD1 is therefore a pharmacological target of choice for the treatment of estrogen-dependent diseases such as endometriosis. We developed a targeted-covalent (irreversible) and non-estrogenic inhibitor of 17β-HSD1, a molecule named PBRM, and herein evaluated its efficiency for the treatment of endometriosis. In a cell-free assay containing estrone (E1), the natural substrate of 17β-HSD1, PBRM was able to block the formation of E2 in a collection of 50 human endometriosis lesions from a different clinical feature type, location, and phase. When given orally by gavage at 15 mg/kg to baboons, the resulting plasmatic concentration of PBRM was found to be sufficiently high (up to 125 ng/mL) for an efficacy study in a non-human primate (baboon) endometriosis model. After 2 months of treatment, the number of lesions/adhesions decreased in 60% of animals (3/5) in the PBRM-treated group, compared to the placebo group which showed an increase in the number of lesion/adhesions in 60% (3/5) of animals. Indeed, the total number of lesions/adhesions decreased in treated group (-6.5 or -19% when excluding one animal) while it increased in the control group receiving a placebo (+11%). Analysis of specific endometriotic lesions revealed that PBRM decreased the number of red lesions (-67%; 8/12) and white lesions (-35%; 11/31), but not of blue-black lesions. Similarly, PBRM decreased the surface area of dense adhesions and filmy adhesions, as compared to placebo. Also, PBRM treatment did not significantly affect the number of menstrual days. Finally, this targeted covalent inhibitor showed no adverse effects and no apparent toxicity for the duration of the treatment. These data indicate that 17β-HSD1 inhibitor PBRM is a promising candidate for therapy targeting endometriosis and supports the need of additional efforts toward clinical trials.

Extensive literature addresses the correlates of communication behaviors within couples in the specific stressful context of oncology. This literature focused mainly on the concepts of disclosure, concealment, holding back and protective buffering to gain more insight into the potential benefits of open communication on the psychological and relational wellbeing of the patient, the spouse and the dyad. The current systematic review aims to present this literature, summarize research findings and suggest empirical, theoretical and clinical implications. Methods: The search method applied in this review was in line with the PRISMA guidelines. Key words related to couples' communication and oncology were used to identify relevant studies according to title and abstract fields from 1.1.2000 until 31.1.22. Results: Out of 3277 papers, a total of 55 articles were identified as relevant for this review. These quantitative studies used cross-sectional and longitudinal designs. Overall, integrating findings from different studies showed that while avoiding communication is negatively associated with psychological and relational wellbeing, the benefits of disclosure seems to be dependent on different factors including the partner's responsiveness, contextual factors and personal characteristics. The existing literature is limited in providing data regarding the nature of adequate or helpful partner responses, the best timing, and the specific topics that are recommended to be disclosed such as specific fears. Most importantly, it is limited in heteroge-neity of constructs of communication that were studied, scales that were used and diverse mediators and moderators that were examined. Accordingly, an effort to reach consensus of definition and assessment of communicative behavior is recommended for future studies, and addressing responsiveness to communicative initiations seems to be important for clinical practice.

Background The prevalence of the group of workers that had a cancer diagnosis in the past is growing. These workers may still be confronted with late effects of cancer (treatment) possibly affecting their work ability. As little is known about the guidance of this group, the aim of this study was to explore the experiences and ideas of managers and professionals about the guidance of these workers in the case of late effects of cancer (treatment). Given the positive associations with work ability of the job resources autonomy, social support by colleagues and an open organisational culture found in several quantitative studies, these job resources were also discussed. Further ideas about the influences of other factors and points of attention in the guidance of this group of workers were explored. Methods Semi-structured interviews were conducted with managers (n = 11) and professionals (n = 47). Data-collection was from November 2019 to June 2020. The data were coded and analysed using directed content analyses. Results The late effects of cancer or cancer treatment discussed were physical problems, fatigue, cognitive problems, anxiety for cancer recurrence, and a different view of life. The self-employed have less options for guidance but may struggle with late effects affecting work ability in the same way as the salaried. Late effects may affect work ability and various approaches have been described. Autonomy, social support of colleagues and an open organisational culture were regarded as beneficial. It was indicated that interventions need to be tailor-made and created in dialogue with the worker. Conclusions Especially with respect to cognitive problems and fatigue, guidance sometimes turned out to be complicated. In general, the importance of psychological safety to be open about late effects that affect work ability was emphasized. Moreover, it is important to take the perspective of the worker as the starting point and explore the possibilities together with the worker. Autonomy is an important factor in general, and a factor that must always be monitored when adjustments in work are considered. There is a lot of experience, but there are still gaps in knowledge and opportunities for more knowledge sharing.

Simple Summary The tumor microenvironment is characterized by increased tissue stiffness, low (acidic) pH, and elevated temperature, all of which contribute to the development of cancer. Improving our in vitro models of cancer, therefore, requires the development of cell culture platforms that can mimic these microenvironmental properties. Here, we study a new biomaterial composed of short amino acid chains that self-assemble into a fibrous hydrogel network. This material enables simultaneous and independent tuning of substrate rigidity, extracellular pH, and temperature, allowing us to mimic both healthy tissues and the tumor microenvironment. We used this platform to study the effect of these conditions on pancreatic cancer cells and found that high substrate rigidity and low pH promote proliferation and survival of cancer cells and activate important signaling pathways associated with cancer progression. Abstract The tumor microenvironment plays a critical role in modulating cancer cell migration, metabolism, and malignancy, thus, highlighting the need to develop in vitro culture systems that can recapitulate its abnormal properties. While a variety of stiffness-tunable biomaterials, reviewed here, have been developed to mimic the rigidity of the tumor extracellular matrix, culture systems that can recapitulate the broader extracellular context of the tumor microenvironment (including pH and temperature) remain comparably unexplored, partially due to the difficulty in independently tuning these parameters. Here, we investigate a self-assembled polypeptide network hydrogel as a cell culture platform and demonstrate that the culture parameters, including the substrate stiffness, extracellular pH and temperature, can be independently controlled. We then use this biomaterial as a cell culture substrate to assess the effect of stiffness, pH and temperature on Suit2 cells, a pancreatic cancer cell line, and demonstrate that these microenvironmental factors can regulate two critical transcription factors in cancer: yes-associated protein 1 (YAP) and hypoxia inducible factor (HIF-1A).

BackgroundThe possibility to monitor patient's serum proteome during treatment can provide deepened understanding of the biology associated with response to specific drugs. Non-invasive serum sampling provides an opportunity for sustainable repetitive sampling of patients, which allows for more frequent evaluation of the biological response and enhanced flexibility in treatment selection in contrast to tissue biopsies.AimTo pin-point biologically relevant changes in pre- and on-treatment serum proteome samples in relapsed mantle cell lymphoma (MCL) patients, leading to insight into mechanisms behind response to treatment in sub-groups of patients.MethodsPre- and on-treatment serum samples from relapsed MCL patients treated with a triple combination therapy of rituximab, ibrutinib and lenalidomide were available for the study, together with detailed clinicopathological information. A microarray technology targeting 158 serum proteins using 371 antibody-fragments was used to compare the serum proteome at the two time-points.ResultsProteins modulated by the treatment were shown to be associated to a MCL sub-group with ATM/TP53 alterations, which emphasizes the importance of treatment stratification. Absolute values of serum protein levels in on-treatment samples were highly variable and showed no correlation to outcome. To circumvent the challenge of variability in absolute serum protein levels, the velocity of change of individual serum proteins was used to identify proteins associated with clinical response. Increased values of TGF-β1, CD40 and complement component 4 comparing pre- and on-treatment samples were associated with remaining minimal residual disease (MRD) and increased BTK was associated with short progression-free survival (PFS).ConclusionWe show that the genetic sub-type of MCL affects the biological response to treatment in serum and that the change in defined serum proteins reveals the biology associated with clinical response.

Post-transcriptional modifications of RNA constitute an emerging regulatory layer of gene expression. The demethylase fat mass- and obesity-associated protein (FTO), an eraser of N-6-methyladenosine (m(6)A), has been shown to play a role in cancer, but its contribution to tumor progression and the underlying mechanisms remain unclear. Here, we report widespread FTO downregulation in epithelial cancers associated with increased invasion, metastasis and worse clinical outcome. Both in vitro and in vivo, FTO silencing promotes cancer growth, cell motility and invasion. In human-derived tumor xenografts (PDXs), FTO pharmacological inhibition favors tumorigenesis. Mechanistically, we demonstrate that FTO depletion elicits an epithelial-to-mesenchymal transition (EMT) program through increased m(6)A and altered 3-end processing of key mRNAs along the Wnt signaling cascade. Accordingly, FTO knockdown acts via EMT to sensitize mouse xenografts to Wnt inhibition. We thus identify FTO as a key regulator, across epithelial cancers, of Wnt-triggered EMT and tumor progression and reveal a therapeutically exploitable vulnerability of FTO-low tumors.Fuks and colleagues report that downregulation of the FTO m(6)A RNA demethylase activates the Wnt pathway, promoting EMT-mediated progression of epithelial tumors and conferring sensitivity to Wnt inhibitors.

Introduction: We previously reported the prognostic impact of circulating tumor cells (CTCs) in a multicenter study on minimal residual disease in primary ovarian cancer. With additional follow-up data, we evaluated the combined CTC approach (CTCscombo), in particular for the patients who had survived more than five years. Material and Methods: Blood samples taken at baseline and six months after adjuvant treatment (follow-up) were assessed by quantitative PCR (qPCR) measuring PPIC transcripts and immunofluorescent staining (IF). A positive result with either IF or qPCR was classified as CTCcombo-positive. Further, PPIC was assessed in the primary tumor tissue. Results: The concordance of IF and qPCR was 65% at baseline and 83% after treatment. Results showed that 50.5% of the baseline and 29.5% of the follow-up samples were CTCcombo-positive. CTCscombo after treatment were associated with increased mortality after adjusting for FIGO stage (HR 2.574, 95% CI: 1.227–5.398, p = 0.012), a higher risk of recurrence after adjusting for peritoneal carcinosis (HR 4.068, 95% CI: 1.948–8.498, p &lt, 0.001), and increased mortality after five survived years. Discussion: The two-sided analytical approach revealed CTC subpopulations associated with ovarian cancer progression and may illuminate a potential treatment-related shift in molecular phenotypes. That approach can identify patients who have elevated risk of recurrence and death due to ovarian cancer and who may require risk-adapted treatment strategies.

Cancer is a complex disease where cancer cells express epigenetic and transcriptomic mechanisms to promote tumor initiation, progression, and survival. To extract relevant features from the 2019 Cancer Cell Line Encyclopedia (CCLE), a multi-layer nonnegative matrix factorization approach is used. We used relevant feature genes and DNA promoter regions to construct genomic interaction network to study gene–gene and gene—DNA promoter methylation relationships. Here, we identified a set of gene transcripts and methylated DNA promoter regions for different clusters, including one homogeneous lymphoid neoplasms cluster. In this cluster, we found different methylated transcription factors that affect transcriptional activation of EGFR and downstream interactions. Furthermore, the hippo-signaling pathway might not function properly because of DNA hypermethylation and low gene expression of both LATS2 and YAP1. Finally, we could identify a potential dysregulation of the CD28-CD86-CTLA4 axis. Characterizing the interaction of the epigenome and the transcriptome is vital for our understanding of cancer cell line behavior, not only for deepening insights into cancer-related processes but also for future disease treatment and drug development. Here we have identified potential candidates that characterize cancer cell lines, which give insight into the development and progression of cancers.

Simple SummaryAdolescents and young adults (AYA), aged 18-39 years at first cancer diagnosis, are recognized as a distinct population within the oncology community due to the unique challenges they encounter including recognition, diagnosis, treatment, and monitoring of their disease. It is imperative for advances in the field of AYA oncology to pool data sources (patient-reported outcomes, clinical, treatment, genetic, and biological data) across institutions and countries and create large cohorts that include the full range of AYA ages and diagnoses to be able to address the many pressing questions that remain unanswered in this vulnerable population. The Dutch COMPRAYA study aims to examine the incidence, risk factors, and mechanisms of impaired health outcomes (short- and long-term medical and psychosocial effects) over time among AYA cancer patients. The overarching aim is to provide a research infrastructure for (future) data analyses and observational retrospective/prospective ancillary studies and to expand data collection to other countries.Adolescent and young adult (AYA) cancer patients suffer from delay in diagnosis, and lack of centralized cancer care, age-adjusted expertise, and follow-up care. This group presents with a unique spectrum of cancers, distinct tumor biology, cancer risk factors, developmental challenges, and treatment regimens that differ from children and older adults. It is imperative for advances in the field of AYA oncology to pool data sources across institutions and create large cohorts to address the many pressing questions that remain unanswered in this vulnerable population. We will create a nationwide infrastructure (COMPRAYA) for research into the incidence, predictive/prognostic markers, and underlying mechanisms of medical and psychosocial outcomes for AYA between 18-39 years diagnosed with cancer. A prospective, observational cohort of (n = 4000), will be established. Patients will be asked to (1) complete patient-reported outcome measures; (2) donate a blood, hair, and stool samples (to obtain biochemical, hormonal, and inflammation parameters, and germline DNA); (3) give consent for use of routinely archived tumor tissue and clinical data extraction from medical records and registries; (4) have a clinic visit to assess vital parameters. Systematic and comprehensive collection of patient and tumor characteristics of AYA will support the development of evidence-based AYA care programs and guidelines.

Background The mechanisms underlying the obesity-cancer relationship are incompletely understood. This study aimed to characterise metabolic signatures of greater body size and to investigate their association with two obesity-related malignancies, endometrial and colorectal cancers, and with weight loss within the context of an intervention study. Methods Targeted mass spectrometry metabolomics data from 4326 participants enrolled in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort and 17 individuals from a single-arm pilot weight loss intervention (Intercept) were used in this analysis. Metabolic signatures of body size were first determined in discovery (N = 3029) and replication (N = 1297) sets among EPIC participants by testing the associations between 129 metabolites and body mass index (BMI), waist circumference (WC), and waist-to-hip ratio (WHR) using linear regression models followed by partial least squares analyses. Conditional logistic regression models assessed the associations between the metabolic signatures with endometrial (N = 635 cases and 648 controls) and colorectal (N = 423 cases and 423 controls) cancer risk using nested case-control studies in EPIC. Pearson correlation between changes in the metabolic signatures and weight loss was tested among Intercept participants. Results After adjustment for multiple comparisons, greater BMI, WC, and WHR were associated with higher levels of valine, isoleucine, glutamate, PC aa C38:3, and PC aa C38:4 and with lower levels of asparagine, glutamine, glycine, serine, lysoPC C17:0, lysoPC C18:1, lysoPC C18:2, PC aa C42:0, PC ae C34:3, PC ae C40:5, and PC ae C42:5. The metabolic signature of BMI (OR1-sd 1.50, 95% CI 1.30–1.74), WC (OR1-sd 1.46, 95% CI 1.27–1.69), and WHR (OR1-sd 1.54, 95% CI 1.33–1.79) were each associated with endometrial cancer risk. Risk of colorectal cancer was positively associated with the metabolic signature of WHR (OR1-sd: 1.26, 95% CI 1.07–1.49). In the Intercept study, a positive correlation was observed between weight loss and changes in the metabolic signatures of BMI (r = 0.5, 95% CI 0.06–0.94, p = 0.03), WC (r = 0.5, 95% CI 0.05–0.94, p = 0.03), and WHR (r = 0.6, 95% CI 0.32–0.87, p = 0.01). Conclusions Obesity is associated with a distinct metabolic signature comprising changes in levels of specific amino acids and lipids which is positively associated with both colorectal and endometrial cancer and is potentially reversible following weight loss.