Patient Preferences Regarding Chemotherapy in Metastatic Breast Cancer—A Conjoint Analysis for Common Taxanes

Background: The purpose of this investigation was to explore patient perception regarding the importance of efficacy, toxicity, and logistics in the choice of regimen of taxane-based chemotherapy (CHT) for patients with metastatic breast cancer (MBC).Methods: This dual-center study analyzed data of 100 women diagnosed with MBC, who were asked for their preferences regarding chemotherapy by means of conjoint analysis. Included attributes were progression free survival (PFS), application form, time and frequency, need of premedication, risk of alopecia, fatigue, febrile neutropenia, and neuropathy. Furthermore, participants completed a questionnaire about their personal and medical history. Regression analyses were performed to identify factors that influence patient preference in terms of specific treatment choice.Results: Of 8 attributes, severe neutropenia was top priority for the majority of patients, followed by alopecia, neuropathy and PFS. When combining these patient preferences and the results of the questionnaire, patients' age as, well as, relationship status had significant impact on the importance of PFS. Moreover, longer travel time to the treatment center was significantly associated with preferences regarding PFS. Ranking by combination of respective part-worth values demonstrated nab-paclitaxel to be favored over paclitaxel and docetaxel.Conclusion: Side effects of CHT and PFS prove to be critical factors for patients affecting choice of treatment in MBC with severe neutropenia being top priority, followed by alopecia, neuropathy, and PFS. Age, commute time, and relationship status were identified as significant determinants of patient preference. Total utility calculation by combination of part-worth values ranked nab-paclitaxel as the most preferable taxane

The SyBil-AA real-time fMRI neurofeedback study: protocol of a single-blind randomized controlled trial in alcohol use disorder

Background: Alcohol Use Disorder is a highly prevalent mental disorder which puts a severe burden on individuals, families, and society. The treatment of Alcohol Use Disorder is challenging and novel and innovative treatment approaches are needed to expand treatment options. A promising neuroscience-based intervention method that allows targeting cortical as well as subcortical brain processes is real-time functional magnetic resonance imaging neurofeedback. However, the efficacy of this technique as an add-on treatment of Alcohol Use Disorder in a clinical setting is hitherto unclear and will be assessed in the Systems Biology of Alcohol Addiction (SyBil-AA) neurofeedback study. Methods: N = 100 patients with Alcohol Use Disorder will be randomized to 5 parallel groups in a single-blind fashion and receive real-time functional magnetic resonance imaging neurofeedback while they are presented pictures of alcoholic beverages. The groups will either downregulate the ventral striatum, upregulate the right inferior frontal gyrus, negatively modulate the connectivity between these regions, upregulate, or downregulate the auditory cortex as a control region. After receiving 3 sessions of neurofeedback training within a maximum of 2 weeks, participants will be followed up monthly for a period of 3 months and relapse rates will be assessed as the primary outcome measure. Discussion: The results of this study will provide insights into the efficacy of real-time functional magnetic resonance imaging neurofeedback training in the treatment of Alcohol Use Disorder as well as in the involved brain systems. This might help to identify predictors of successful neurofeedback treatment which could potentially be useful in developing personalized treatment approaches. Trial registration: The study was retrospectively registered in the German Clinical Trials Register (trial identifier: DRKS00010253 ; WHO Universal Trial Number (UTN): U1111–1181-4218) on May 10th, 2016

Does Physical Activity Improve Quality of Life in Cancer Patients Undergoing Chemotherapy?

Background: Improved cancer treatments have resulted in prolonged survival. Nevertheless, tumor symptoms and side effects still compromise physical activity and quality of life (QoL). Patients and Methods: We conducted an anonymous survey among cancer patients undergoing chemotherapy using standardized questionnaires: the ‘Freiburger Fragebogen zur körperlichen Aktivität’ (Freiburg Questionnaire on Physical Activity) and European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30. Two main questions were addressed: were there differences (1) in physical activity and QoL between patients who do not believe that sport could improve their QoL and those who believe it could (group A vs. B); and (2) in QoL between patients with a total activity (TA) < 18 metabolic equivalent of task (MET) h/week and those with a TA of ˰ 18 MET h/week (group C vs. D)? Results: 276 of 400 questionnaires were completed. Groups A and B were balanced in terms of baseline characteristics. Group A suffered significantly more from fatigue and pain; group B reported higher levels of global health status (GHS) and TA. Groups C and D differed in gender distribution, age, and educational background. Group D had significantly higher levels of GHS, group C suffered more from fatigue, pain, and appetite loss. Conclusion: Physical activity correlates with a better QoL of cancer patients undergoing chemotherapy

Subcellular analysis of starch metabolism in developing barley seeds using a non-aqueous fractionation method

Compartmentation of metabolism in developing seeds is poorly understood due to the lack of data on metabolite distributions at the subcellular level. In this report, a non-aqueous fractionation method is described that allows subcellular concentrations of metabolites in developing barley endosperm to be calculated. (i) Analysis of subcellular volumes in developing endosperm using micrographs shows that plastids and cytosol occupy 50.5% and 49.9% of the total cell volume, respectively, while vacuoles and mitochondria can be neglected. (ii) By using non-aqueous fractionation, subcellular distribution between the cytosol and plastid of the levels of metabolites involved in sucrose degradation, starch synthesis, and respiration were determined. With the exception of ADP and AMP which were mainly located in the plastid, most other metabolites of carbon and energy metabolism were mainly located outside the plastid in the cytosolic compartment. (iii) In developing barley endosperm, the ultimate precursor of starch, ADPglucose (ADPGlc), was mainly located in the cytosol (80–90%), which was opposite to the situation in growing potato tubers where ADPGlc was almost exclusively located in the plastid (98%). This reflects the different subcellular distribution of ADPGlc pyrophosphorylase (AGPase) in these tissues. (iv) Cytosolic concentrations of ADPGlc were found to be close to the published Km values of AGPase and the ADPGlc/ADP transporter at the plastid envelope. Also the concentrations of the reaction partners glucose-1-phosphate, ATP, and inorganic pyrophosphate were close to the respective Km values of AGPase. (v) Knock-out of cytosolic AGPase in Riso16 mutants led to a strong decrease in ADPGlc level, in both the cytosol and plastid, whereas knock-down of the ADPGlc/ADP transporter led to a large shift in the intracellular distribution of ADPGlc. (v) The thermodynamic structure of the pathway of sucrose to starch was determined by calculating the mass–action ratios of all the steps in the pathway. The data show that AGPase is close to equilibrium, in both the cytosol and plastid, whereas the ADPGlc/ADP transporter is strongly displaced from equilibrium in vivo. This is in contrast to most other tissues, including leaves and potato tubers. (vi) Results indicate transport rather than synthesis of ADPGlc to be the major regulatory site of starch synthesis in barley endosperm. The reversibility of AGPase in the plastid has important implications for the regulation of carbon partitioning between different biosynthetic pathways

Assessment of the safety of glucocorticoid regimens in combination with abiraterone acetate for metastatic castration-resistant prostate cancer:a randomized, open-label phase 2 study

Importance: Abiraterone acetate is combined with prednisone, 5 mg, twice daily for metastatic castration-resistant prostate cancer (mCRPC) and with prednisone, 5 mg, once daily for newly diagnosed, high-risk, metastatic castration-sensitive prostate cancer. Understanding the physiological effects of these and other regimens is important. Objective: To evaluate the safety of abiraterone acetate with 4 glucocorticoid regimens. Design, Setting, and Participants: Open-label, randomized clinical trial (1:1:1:1) of 164 men with mCRPC from 22 hospitals in 5 countries who were randomly assigned to 1 of 4 intervention groups between June 2013 and October 2014. Analyses were conducted from August 2017 to June 2018. Interventions: Abiraterone acetate, 1000 mg, once daily with prednisone, 5 mg, twice daily (n = 41), 5 mg once daily (n = 41), 2.5 mg twice daily (n = 40), or dexamethasone, 0.5 mg, once daily (n = 42). Main Outcomes and Measures: Primary end point was no mineralocorticoid excess (grade ≥1 hypokalemia or grade ≥2 hypertension) through 24 weeks (6 cycles) from treatment. Results: Of 164 men (median [range] age, 70 [50-90] years) randomized to receive abiraterone acetate, 1000 mg, daily with prednisone, 5 mg, twice daily, once daily, or 2.5 mg twice daily, or dexamethasone, 0.5 mg, once daily, 24 (70.6%) of 34 patients (95% CI, 53.8%-83.2%), 14 (36.8%) of 38 patients (95% CI, 23.4%-52.7%), 21 (60.0%) of 35 patients (95% CI, 43.6%-74.4%), and 26 (70.3%) of 37 patients (95% CI, 54.2%-82.5%), respectively, had no mineralocorticoid excess. Plasma adrenocorticotrophic hormone and urinary mineralocorticoid metabolites after 8 weeks were higher with prednisone, 2.5 mg, twice daily and 5 mg once daily than with 5 mg twice daily or dexamethasone, 0.5 mg, once daily. The level of urinary glucocorticoid metabolites appeared higher in patients who did not meet the primary end point, regardless of glucocorticoid regimen. Total lean body mass decreased in the prednisone groups and total body fat increased in the prednisone, 5 mg, twice daily and dexamethasone groups. In the dexamethasone group, there was an increase in serum insulin and homeostatic model assessment of insulin resistance, while total bone mineral density decreased. In the prednisone, 5 mg, twice daily, 5 mg once daily, 2.5 mg twice daily, and dexamethasone groups, median radiographic progression-free survival was 18.5, 15.3, 12.8, and 26.6 months, respectively. Conclusions and Relevance: Abiraterone acetate with prednisone, 5 mg, twice daily or dexamethasone, 0.5 mg, once daily met the prespecified threshold for the primary end point (95% CI excluded 50% mineralocorticoid excess); abiraterone acetate with prednisone, 5 mg, once daily or 2.5 mg twice daily did not meet the threshold. Abiraterone acetate in combination with dexamethasone appeared to be particularly active but may be associated with adverse metabolic consequences

Integrin signalling regulates YAP and TAZ to control skin homeostasis

The skin is a squamous epithelium that is continuously renewed by a population of basal layer stem/progenitor cells and can heal wounds. Here, we show that the transcription regulators YAP and TAZ localise to the nucleus in the basal layer of skin and are elevated upon wound healing. Skin-specific deletion of both YAP and TAZ in adult mice slows proliferation of basal layer cells, leads to hair loss and impairs regeneration after wounding. Contact with the basal extracellular matrix and consequent integrin-Src signalling is a key determinant of the nuclear localisation of YAP/TAZ in basal layer cells and in skin tumours. Contact with the basement membrane is lost in differentiating daughter cells, where YAP and TAZ become mostly cytoplasmic. In other types of squamous epithelia and squamous cell carcinomas, a similar control mechanism is present. By contrast, columnar epithelia differentiate an apical domain that recruits CRB3, Merlin (also known as NF2), KIBRA (also known as WWC1) and SAV1 to induce Hippo signalling and retain YAP/TAZ in the cytoplasm despite contact with the basal layer extracellular matrix. When columnar epithelial tumours lose their apical domain and become invasive, YAP/TAZ becomes nuclear and tumour growth becomes sensitive to the Src inhibitor Dasatinib

Management of patients with advanced prostate cancer : the report of the Advanced Prostate Cancer Consensus Conference APCCC 2017

BACKGROUND: In advanced prostate cancer (APC), successful drug development as well as advances in imaging and molecular characterisation have resulted in multiple areas where there is lack of evidence or low level of evidence. The Advanced Prostate Cancer Consensus Conference (APCCC) 2017 addressed some of these topics. OBJECTIVE: To present the report of APCCC 2017. DESIGN, SETTING, AND PARTICIPANTS: Ten important areas of controversy in APC management were identified: high-risk localised and locally advanced prostate cancer; "oligometastatic" prostate cancer; castration-naïve and castration-resistant prostate cancer; the role of imaging in APC; osteoclast-targeted therapy; molecular characterisation of blood and tissue; genetic counselling/testing; side effects of systemic treatment(s); global access to prostate cancer drugs. A panel of 60 international prostate cancer experts developed the program and the consensus questions. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The panel voted publicly but anonymously on 150 predefined questions, which have been developed following a modified Delphi process. RESULTS AND LIMITATIONS: Voting is based on panellist opinion, and thus is not based on a standard literature review or meta-analysis. The outcomes of the voting had varying degrees of support, as reflected in the wording of this article, as well as in the detailed voting results recorded in Supplementary data. CONCLUSIONS: The presented expert voting results can be used for support in areas of management of men with APC where there is no high-level evidence, but individualised treatment decisions should as always be based on all of the data available, including disease extent and location, prior therapies regardless of type, host factors including comorbidities, as well as patient preferences, current and emerging evidence, and logistical and economic constraints. Inclusion of men with APC in clinical trials should be strongly encouraged. Importantly, APCCC 2017 again identified important areas in need of trials specifically designed to address them. PATIENT SUMMARY: The second Advanced Prostate Cancer Consensus Conference APCCC 2017 did provide a forum for discussion and debates on current treatment options for men with advanced prostate cancer. The aim of the conference is to bring the expertise of world experts to care givers around the world who see less patients with prostate cancer. The conference concluded with a discussion and voting of the expert panel on predefined consensus questions, targeting areas of primary clinical relevance. The results of these expert opinion votes are embedded in the clinical context of current treatment of men with advanced prostate cancer and provide a practical guide to clinicians to assist in the discussions with men with prostate cancer as part of a shared and multidisciplinary decision-making process

Management of patients with advanced prostate cancer—metastatic and/or castration-resistant prostate cancer: report of the Advanced Prostate Cancer Consensus Conference (APCCC) 2022

Background: Innovations in imaging and molecular characterisation together with novel treatment options have improved outcomes in advanced prostate cancer. However, we still lack high-level evidence in many areas relevant to making management decisions in daily clinical practise. The 2022 Advanced Prostate Cancer Consensus Conference (APCCC 2022) addressed some questions in these areas to supplement guidelines that mostly are based on level 1 evidence. Objective: To present the voting results of the APCCC 2022. Design, setting, and participants: The experts voted on controversial questions where high- level evidence is mostly lacking: locally advanced prostate cancer; biochemical recurrence after local treatment; metastatic hormone-sensitive, non-metastatic, and metastatic castration- resistant prostate cancer; oligometastatic prostate cancer; and managing side effects of hormonal therapy. A panel of 105 international prostate cancer experts voted on the consensus questions. Outcome measurements and statistical analysis: The panel voted on 198 pre-defined questions, which were developed by 117 voting and non-voting panel members prior to the conference following a modified Delphi process. A total of 116 questions on metastatic and/or castration- resistant prostate cancer are discussed in this manuscript. In 2022, the voting was done by a web-based survey because of COVID-19 restrictions. Results and limitations: The voting reflects the expert opinion of these panellists and did not incorporate a standard literature review or formal meta-analysis. The answer options for the consensus questions received varying degrees of support from panellists, as reflected in this article and the detailed voting results are reported in the supplementary material. We report here on topics in metastatic, hormone-sensitive prostate cancer (mHSPC), non-metastatic, castration-resistant prostate cancer (nmCRPC), metastatic castration-resistant prostate cancer (mCRPC), and oligometastatic and oligoprogressive prostate cancer. Conclusions: These voting results in four specific areas from a panel of experts in advanced prostate cancer can help clinicians and patients navigate controversial areas of management for which high-level evidence is scant or conflicting and can help research funders and policy makers identify information gaps and consider what areas to explore further. However, diagnostic and treatment decisions always have to be individualised based on patient characteristics, including the extent and location of disease, prior treatment(s), co-morbidities, patient preferences, and treatment recommendations and should also incorporate current and emerging clinical evidence and logistic and economic factors. Enrolment in clinical trials is strongly encouraged. Importantly, APCCC 2022 once again identified important gaps where there is non-consensus and that merit evaluation in specifically designed trials. Patient summary: The Advanced Prostate Cancer Consensus Conference (APCCC) provides a forum to discuss and debate current diagnostic and treatment options for patients with advanced prostate cancer. The conference aims to share the knowledge of international experts in prostate cancer with healthcare providers worldwide. At each APCCC, an expert panel votes on pre-defined questions that target the most clinically relevant areas of advanced prostate cancer treatment for which there are gaps in knowledge. The results of the voting provide a practical guide to help clinicians discuss therapeutic options with patients and their relatives as part of shared and multidisciplinary decision-making. This report focuses on the advanced setting, covering metastatic hormone-sensitive prostate cancer and both non-metastatic and metastatic castration-resistant prostate cancer. Twitter summary: Report of the results of APCCC 2022 for the following topics: mHSPC, nmCRPC, mCRPC, and oligometastatic prostate cancer. Take-home message: At APCCC 2022, clinically important questions in the management of advanced prostate cancer management were identified and discussed, and experts voted on pre-defined consensus questions. The report of the results for metastatic and/or castration- resistant prostate cancer is summarised here

TXS 0506+056 with Updated IceCube Data

Past results from the IceCube Collaboration have suggested that the blazar TXS 0506+056 is a potential source of astrophysical neutrinos. However, in the years since there have been numerous updates to event processing and reconstruction, as well as improvements to the statistical methods used to search for astrophysical neutrino sources. These improvements in combination with additional years of data have resulted in the identification of NGC 1068 as a second neutrino source candidate. This talk will re-examine time-dependent neutrino emission from TXS 0506+056 using the most recent northern-sky data sample that was used in the analysis of NGC 1068. The results of using this updated data sample to obtain a significance and flux fit for the 2014 TXS 0506+056 "untriggered" neutrino flare are reported