bluuebunny/crossref_metadata_2025 huggingface dataset:
Prevalence and factors associated with intestinal parasitic infections among food handlers working at higher public University student’s cafeterias and public food establishments in Ethiopia: a systematic review and meta-analysis
Authors: Alemnew Birhan , Gedefaw Getnet , Alen Gedefaw Diress , Bizuneh Asmamaw Demis
Published: February 2020

Background

Intestinal infection is still an important public health problem in low-income countries. Food handlers may be infected by a wide range of enteropathogens and have been implicated in the transmission of many infections to the public. Therefore, the aim of this review was to produce the pooled prevalence and factors associated with intestinal parasitic infections among food handlers working at higher public University student’s cafeterias and public food establishments in Ethiopia.

Methods

Articles published in PubMed/Medline, Hinari, Web of Science, Science Direct, and Google Scholar were used using a search strategy. Observational studies (cross-sectional) revealing the prevalence and factors associated with intestinal parasitic infections at higher public University student’s cafeterias and public food establishments were incorporated. Meta-analysis was computed using STATA version 14 statistical software. Heterogeneity of the study was assessed using Cochrane Q test statistics and I2 test. The pooled prevalence of the intestinal parasitic infection and associated factors among food handlers was calculated by the random-effect model.

Results

Out of 138 reviewed studies, 18 studies were included to estimate the pooled prevalence of intestinal parasitic infections among food handlers in Ethiopia. All the eighteen articles were included in the analysis. This study revealed that the pooled prevalence of intestinal parasitic infections was 28.5% (95% CI: 27.4, 29.7). E. hystolitica /E. dispar complex 6.38 (95% Cl: 5.73, 7.04), A.lumbricodes 4.12 (95% Cl: 3.56, 4.67), and G. lamblia 3.12(95% Cl: 2.65, 3.60) were the most common intestinal parasitic infections in this study. Untrimmed fingernail 3.04 (95% CI: 2.19, 4.22), do not washing hands after defecation 2.71 (95% CI: 1.93, 3.82), do not washing hands after touching any body parts 2.41 (95% CI: 1.64, 3.56), do not made medical checkup 2.26 (95% CI: 1.57, 3.25), and do not receive food safety training 1.79 (95% CI: 1.30, 2.45) were factors significantly and positively associated with intestinal parasitic infections.

Conclusion

Parasitic infections among food handlers were significantly high. Untrimmed fingernail, do not washing hands after defecation, do not washing hands after touching any body parts, do not made regular medical checkup and do not receive food safety training were factors that increase the prevalence of intestinal parasitic infections.
Addressing ethnic disparity in antenatal care: a qualitative evaluation of midwives’ experiences with the MAMAACT intervention
Authors: Johnsen Helle , Ghavami Kivi Nazila , Morrison Cecilie H. , Juhl Mette , Christensen Ulla , Villadsen Sarah F.
Published: February 2020

Background

In Denmark, 13% of all children are born by non-Western immigrant women. The public antenatal care has not adapted to this increased diversity of women. Compared to women coming from Western countries, non-Western immigrant women have an increased prevalence of severe maternal morbidity and higher risks of maternal death, stillbirth and infant death. Suboptimal care is a contributing factor to these ethnic disparities, and thus the provision of appropriate antenatal care services is pivotal to reducing these disparities and challenges to public health. Yet, little is known about the targeted interventions which have been developed to reduce these inequities in reproductive health. The MAMAACT intervention, which included a training course for midwives, a leaflet and a mobile application, as well as additional visit time, was developed and tested at a maternity ward to increase responses to pregnancy warning signs among midwives and non-Western immigrant women. Aim: To explore the feasibility and acceptability of the MAMAACT intervention among midwives and identify factors affecting midwives’ delivery of the intervention.

Methods

Eight mini-group interviews with midwives (n = 18) were undertaken. Systematic text condensation was used to analyse data.

Results

Three main categories were identified, which were ‘Challenges of working with non-Western immigrant women’, ‘Attitudes towards and use of the leaflet and mobile application’, and ‘Organisational factors affecting the use of the MAMAACT intervention’.

Conclusions

The MAMAACT intervention was found to be feasible as well as acceptable among midwives. Women turning to relatives for pregnancy-related advice, time constraints during midwifery visits, incomplete clinical records and lack of professional interpreter assistance impacted midwives’ delivery of the MAMAACT intervention. Midwives displayed a readiness for the MAMAACT intervention; however, there is a need to further examine how contextual factors may impact the use of the intervention in antenatal care.

Trial registration

ClinicalTrials.gov, Retrospective Registration (07/2/2020), registration number NCT04261400.
Unrestricted prevalence of sedentary behaviors from early childhood
Authors: Azabdaftari Fariba , Jafarpour Parisa , Asghari-Jafarabadi Mohammad , Shokrvash Behjat , Reyhani Parvin
Published: February 2020

Background

Light and sedentary behaviors impose heavy challenges on societies. The objectives of this study are to identify child sedentary behaviors, and to examine the relationship between parent knowledge and behavioral style on children’s sedentary time in Iran.

Methods

This cross-sectional study was done among children and their parents selected randomly using multi-stage method, from 12 urban districts in Tabriz, Iran;2017. Data were collected through designing a multi-sectional questionnaire adopted from the Bjelland and previous studies to assess the time spent on sedentary behaviors among children/adolescents along with parent knowledge and behavioral style.

Results

From 480 children/adolescents and their parents 54.6% came from middle class families, and 55.62% were boys aged 2 to18. The percentage of time spent more than 120 min per day (min/d) on weekdays was for watching television (TV): (girls 24.4%, boys 21.0%), for playing computer and video games: (girls 38.7%, boys 54.7%), for electronic media communication (EMC): (girls 52.8%, boys 60.2%). The associated factors for watching TV: child age [12 years and above OR = 1.37; 95% CI = 0.53–3.54], parent knowledge [OR = 0.59, 95% CI = 0.35–0.99], and communicative styles [OR = 1.43, 95%CI = 1.11–1.86], and for playing computer and EMC: child age [5 years old and above OR = 4.83,95% CI =1.52–15.38, 12 years old and above OR = 13.76, 95% CI= 4.22–24.91], family socio-economic status [middle class OR = 2.52, 95% CI = 1.54–4.11, high class OR = 5.53, 95%CI = 1.80–15.89].

Conclusion

There is an urgent need to combat the unrestricted prevalence of sedentary behaviors among Iranian children/ adolescents who use computers and other electronic devices more than the recommended time every day from early childhood.

Parents should be provided with appropriate information about adverse effects of using electronic devices longer than recommended time by children. It is also essential to teach them beneficial communicative styles to monitor their children’s sedentary behaviors.
Testing for Mycobacterium tuberculosis infection using the QuantiFERON-TB GOLD assay in patients with comorbid conditions in a tertiary care endemic setting
Authors: Masood Kiran Iqbal , Jamil Bushra , Akber Alnoor , Hassan Maheen , Islam Muniba , Hasan Zahra
Published: February 2020

Introduction

There were 10 million new cases of tuberculosis (TB) in 2017. To eliminate TB, it is necessary to diagnose active TB and latent tuberculosis infection (LTBI). Diagnosis of paucibacillary disease and in extrapulmonary TB (EPTB) remains challenging; low mycobacterial load can be missed by microbiological or molecular based confirmation; EPTB, can be misdiagnosed due to absence of site specific specimens for testing. Interferon gamma release assays (IGRA) use T cell-based Interferon-gamma (IFN-γ) to identify infection with M. tuberculosis (MTB) but cannot discriminate between active and LTBI. We investigated how IGRA was being used in a high burden low resource setting.

Methods

We conducted a retrospective review of 149 consecutive cases received for QuantiFERON-TB Gold In-Tube Assay (QFT-GIT) testing in routine clinical service.

Results

Fifty-six cases were QFT-GIT positive and 93 were QFT-GIT negative. Thirty-six per cent of QFT-GIT tested cases had active TB. Of QFT-GIT positive cases, 59% patients had active TB; 10 with pulmonary and 23 with extra-pulmonary TB. The remaining 41% QFT-positive cases were LTBI. Of the QFT-GIT negative cases, 22% had active TB. Co-morbid conditions were present in 37% of QFT-GIT positive and 60% of QFT-GIT negative cases.

Conclusions

Our study shows that IGRA is being used as an adjunct test for active TB in this population. It highlights the complexity of interpreting QFT-GIT results particularly for QFT-GIT negative cases when ruling out MTB infection.
Single-tree influence of Tectona grandis Linn. f. on plant distribution and soil characteristics in a planted forest
Authors: Ikhajiagbe Beckley , Ogwu Matthew Chidozie , Lawrence Adebayo Emmanuel
Published: February 2020

Background

Little is known about the single-tree influence of Tectona grandis Linn. f. on plant distribution and soil characteristics in Benin City, Nigeria. We investigated the possible single-tree effect of T. grandis on understory plants in an 8-year-old teak plantation at the Moist Forest Research Station. An area of 36.57 m by 60.96 m was marked out and divided into 15 equal-sized subplots containing 10 trees per subplot. Marked distances from the base of a randomly selected tree per subplot were made (0–0.5 m, 0.5–1.0 m and 1.0–1.5 m).

Results

Single-tree influence of T. grandis was observed in the soil total organic carbon, total nitrogen and soluble phosphorus, where concentrations were higher with 1.5-m radius from the tree than beyond. Moreover, the pH of the topsoil within 1.5 m from the base of the tree was lower (pH 4.4) than beyond 1.5 m from the base of the tree (pH 5.4). Species-specific single-tree effect was also observed on the understory plant distribution likely due to diverse ecophysiological interactions. Within 1.5 m from the tree, plant species abundance, especially of Sida garckeana, Reisantia indica, Momordica charantia and Tridax procumbens were negatively affected. However, the distribution of Eleusine indica around the tree was not negatively influenced. Plant abundance was generally suppressed in Cynodon dactylon, Axonopus compressus, Andropogon gayanus, Commelina diffusa and Euphorbia hirta. Generally, there were more plant species beyond the canopy fringes than within the canopy, indicating inhibitory single-tree effects.

Conclusion

Not all plant species in close proximity to T. grandis are affected. This is important considering that plant-plant associations affect the quality of forest soils. Generally, more plant species were recorded outside the 1.5-m demarcation than within, an increase in soil organic matter may further enhance such plant species abundance. The impact of T. grandis in forest soil quality is possibly a factor of the outcome of its association with neighbouring plant species. Diverse mechanisms at play may be responsible for the observed effects on soil chemistry. However, a reduction in the soil organic matter and variations in other environmental factors also contributed to observed single-tree effect.
Planning of Food-Energy-Water-Waste (FEW2) nexus for sustainable development
Authors: Feng Bowen , van Dam Koen H. , Guo Miao , Shah Nilay , Passmore Stephen , Wang Xiaonan
Published: February 2020

It is critical for reliable infrastructure planning to address the Food-Energy-Water-Waste (FEW2) nexus at system level. This paper presents the applicability of resilience.io platform across water, energy and waste sectors (including food and agricultural waste) with focus on waste-to-energy pathway, aiming to establish the optimal FEW2 nexus based on economic and environmental indicators. A rich array of technology options, including water production facilities, clean energy technologies and waste-to-energy conversions are evaluated to meet the demand of water and energy (mainly gas and electricity), and the treatment requirement of waste and wastewater. A case study of Hunter Region, the largest region in Australia, is presented in this study, featuring the supply and demand context of developed countries. A full set of scenarios, including business-as-usual (BAU), water and wastewater, power plant decommission, waste-to-energy and policy intervention, is created to present FEW2 nexus from the perspective of individual nodes and the whole system. The results signal the benefits of biogas and syngas generation from anaerobic digestion and gasification for waste-to-energy pathway, alongside findings in water and energy sectors. The outcome of this analysis can then form the foundation of regional planning involving relevant stakeholders, with the modelling tools supporting scenario evaluation and collaborative learning to reach consensus in view of different performance indicators including financial and environmental metrics.
Awareness of analgesics complications in Saudi Arabia: a cross-sectional study
Authors: Siddig Amal I. , Alqahtani Abdulhadi M. , AlShalawi Alia , Turkistani Marwah , Binbaz Sarah , Altowairqi Amal
Published: February 2020

Background

All over the world, analgesics are considered one of the most widely used and abused medications. Painkillers such as paracetamol (acetaminophen), non-steroidal anti-inflammatory drugs (NSAIDs), and aspirin currently represent the principal means of pain management. Unfortunately, paracetamol and NSAIDs have dangerous side effects primarily when they are used improperly and without respect to safety rules. This study aims to assess the awareness of the indications, complications, and contraindications of commonly used analgesics.

Results

A total of 1554 participants responded to the survey, and the findings indicated that the main analgesic used is paracetamol. A proportion of 68.1% of the total number of respondents received their information about analgesic medications from a physician or pharmacist; 95.7% used analgesics when needed, and 70.9% mentioned that they would consult a physician or pharmacist if the pain was not relieved after the use of over-the-counter medications. Nearly 29% were not aware of the possibility of adverse effects of analgesic use.

Conclusion

The most commonly used analgesic is paracetamol, and most of the participants had a poor level of awareness regarding the complications and side effects of analgesics in general. Our recommendation is to conduct a continuous health education campaign about the use of analgesics.
Targeting NFE2L2/KEAP1 mutations in advanced NSCLC with the TORC1/2 inhibitor TAK-228.
Authors: Paik Paul K. , Ahn Linda Su Hyun , Ginsberg Michelle S. , Plodkowski Andrew J. , Kim Rachel , Doyle L. Austin , Rudin Charles M.
Published: February 2020

9085

Background: Despite efforts over the past decade, no targeted therapy options exist for SQCLC pts. We have identified a heretofore untargeted oncogene (NFE2L2)/tumor suppressor (KEAP1) pair, each mutated in ~20% of patients with SQCLC. NFE2L2 encodes Nrf2, a transcription factor involved in the oxidative stress response which is targeted for degradation by Keap1. NFE2L2 mutations occur exclusively in an exon 2 hotspot that encodes the Neh2 domain (aa.1-86), which is the binding site for Keap1. Mutations in this region disrupt Keap1 binding, leading to Nrf2 nuclear translocation and increased mTOR signaling through RagD (Shibata Cancer Res 2010). We report translational studies and results from an ongoing phase 2 trial of the oral TORC1/2 inhibitor TAK-228. Methods: Cytotoxicity, signaling, and xenograft experiments were performed using LK-2 SQCLC cells (NFE2L2 E79K mut) treated with TAK-228, everolimus, rapamycin, or deforolimus. Pts with stage IV SQCLC harboring NFE2L2 or KEAP1 mutations and NSCLC harboring KRAS + NFE2L2 or KEAP1 co-mutations are treated on an NCI CTEP phase 2 study of TAK228 3mg po qd (continuous 28 day cycles; NCT02417701). Primary endpoint: ORR. Secondary endpoints: PFS. The study utilizes a Simon 2-stage design for each cohort with H0 = 5% (N≥1/5 responses), HA = 40% (N≥2/10 responses). Results: TAK-228 exhibited increased anti-tumor activity over TORC1 rapalogs in LK-2 cells. TAK-228 alone was cytotoxic at sub-[μM] (IC50 68nM); all other rapalogs exhibited IC50s > 10μM. This was associated with marked decrease in pS6, pAKT, and pERK. Tumor response (-55%) was seen in an LK-2 xenograft treated with TAK228. No anti-tumor/growth inhibitory response was seen with any other rapalog. N = 15 evaluable pts have been treated on study (7 NFE2L2, 3 KEAP1, 5 KRAS + NFE2L2 or KEAP1). 2 related-SAEs (G3 hyperglycemia, G3 confusion) were seen; there were no unexpected AEs. Within SQCLC NFE2L2 pts ORR = 29% (2/7 PR) and DCR = 100%. Prolonged duration of response is present, with PFS = 10.5mo, 11.4mo (18.2mo tx beyond PD), 6mo (8mo tx beyond PD), 5.5mo+, 4.5mo, and 1.5mo+. Within SQCLC KEAP1 pts DCR = 66% (2SD, 1PD) with PFS = 7.4mo+, 3mo+, 1mo. Data for the KRAS + NFE2L2/KEAP1 arm will be presented. Conclusions: TAK228 is tolerable with evidence of pre-clinical activity, radiographic responses, and prolonged DOR in biomarker-selected NSCLC pts. Accrual is ongoing. Clinical trial information: NCT02417701.
Determination of the ability of a novel, long-acting subcutaneous GnRH antagonist, VERU-100, to castrate without a testosterone surge in a rat model.
Authors: Getzenberg Robert H. , Lin Jui-Chen , Cerro Andrew , Rhodes Christopher A. , Steiner Mitchell S.
Published: February 2020

128

Background: Androgen deprivation therapy (ADT) is the mainstay for the treatment of advanced prostate cancer. LHRH agonists are frequently used for ADT but these agents often result in initial surges in testosterone (T) levels. Although they do not result in initial T surges, current injectable GnRH antagonists are short term (1 month) subcutaneous (sc) depots that require a high volume loading dose followed by monthly maintenance dosing. VERU-100 is a novel GnRH decapeptide antagonist for long term suppression of T to castrate levels and is administered as a low volume sc injection without the requirement of a loading dose. Eight distinct formulations were evaluated in rats in order to select the best formulation, VERU-100. Methods: Male Sprague Dawley rats (n=3 per group) were injected sc through a 21G needle, with approximately 200 μl of each formulation at a dose level of 20 mg/kg. Eight groups consisting of the distinct test formulations were evaluated. Blood samples were drawn at weekly intervals until week 4 and then bi-weekly for pharmacokinetic (PK) (Integrated Analytical Solutions) and testosterone (T) level determinations (Cornell University Animal Health Diagnostic Center). Results: Within approximately 24 hours after administration of the GHRH antagonist formulations, testosterone levels in the rats went from a mean of 7.36 ng/ml to undetectable. The T levels resulting from a single injection of the lead formulation in these studies, VH-030-002, remained undetectable for greater than 26 weeks (6 months) as did the other formulations tested. The corresponding PK analysis demonstrated that the GnRH antagonist levels were detectable for greater than 26 weeks and remained above 1 ng/ml for almost all of the study points. The T levels correlated to the exposure from the formulations, and PKPD was as consistent for GnRH antagonists. Conclusions: VERU-100 is a novel GnRH antagonist formulation that in this rodent study, with a low injection volume, resulted in undetectable T for at least six months. No surge of T is observed after administration. An IND submission is anticipated in early 2020 for the dose finding Phase 2 trial in men with advanced prostate cancer.
Results of the ADRRAD Trial of pelvic IMRT plus radium-223 in men with mHSPC metastatic to bone.
Authors: O'Sullivan Joe , Turner Philip Geoffrey , Jain Suneil , Grey Arthur , Biggart Sandra , Hounsell Alan R. , Cole Aidan
Published: February 2020

136

Background: Radiotherapy to the Prostate in mHSPC improves overall survival (OS) and Progression free survival (PFS) for patients with low-volume-disease[1]. Radium-223 in metastatic castration resistant prostate cancer (mCRPC) improves OS [2]. We conducted a prospective phase 1/2 clinical trial in mHSPC, testing the combination of with LHRHa, concurrent pelvic radiotherapy and radium-223. Methods: Thirty patients were recruited with mHSPC; they had a minimum of 3 bone metastases (majority had > 20 bone mets), nil visceral metastases, PS0-1. Patients were encouraged to receive up front docetaxel. They were treated with ongoing LHRHa, pelvic radiotherapy aiming for 74Gy in 37 fractions to prostate PTV with 60Gy concomitantly delivered to pelvic nodal PTV. Concurrently, patients received radium-223, 55kBq/kg for 6 cycles q28 days; fraction 1 radiotherapy was synchronous with cycle 1 day 1 radium-223. Results: Median age was 63 years and 28 (93%) received at least 4 cycles of docetaxel. One patient received prostate only radiotherapy due to bowel constraints. Three patients had cycle 6 radium-223 omitted. At a median follow-up of 28 months, there have been 415 Adverse events, (3% Grade >3), and 6 serious adverse events (SAEs) ( 2 episodes of UTI, 1 each of cystitis non-infective, cardiac chest pain, pyrexia and AKI). Commonest AEs by number were: leucopenia, neutropenia, and diarrhoea. Ten SSE’s have occurred including 8 courses of palliative radiotherapy for bone pain, 1 course of radiotherapy for impending MSCC and 1 pathological fracture. At median follow up 28.0 months, median biochemical PFS is 17.9 months, median OS not yet reached. Conclusions: This trial shows clear tolerability and promising early efficacy data requiring further exploration in a randomised phase 3 trial. Clinical trial information: 2014-000273-39.
Cabozantinib (C) in combination with atezolizumab (A) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC): Results of Cohort 6 of the COSMIC-021 Study.
Authors: Agarwal Neeraj , Loriot Yohann , McGregor Bradley Alexander , Dreicer Robert , Dorff Tanya B. , Maughan Benjamin Louis , Kelly William Kevin , Pagliaro Lance C. , Srinivas Sandy , Squillante Christian Michael , Vaishampayan Ulka N. , Liu Yingjie , Curran Dominic , Choueiri Toni K. , Pal Sumanta K.
Published: February 2020

139

Background: C may enhance response to immune checkpoint inhibitors by promoting an immune-permissive microenvironment. COSMIC-021 (NCT03170960), a multinational phase 1b study, is evaluating the combination of C with A in various solid tumors. We report interim results from Cohort 6 in mCRPC. Methods: Eligible pts were required to have radiographic progression in soft tissue after enzalutamide and/or abiraterone, measurable disease, and an ECOG PS of 0 or 1. Prior chemotherapy for mCSPC was permitted. Pts received C 40 mg PO qd and A 1200 mg IV q3w. CT/MRI scans were performed q6w for 52w and q12w thereafter. Bone scans were performed q12w. The primary endpoint is ORR per RECIST 1.1. Other endpoints include safety, ORR per irRECIST, duration of response (DOR), PFS, and OS. Results: As of Oct 2019, 44 mCRPC pts were enrolled with a median follow-up of 10.6 mo (range 3.4+, 17.9). Median age was 70 y (range 49, 90), 50% had ECOG PS 1, 34% had visceral metastases, and 61% had extrapelvic lymph node metastases. 27% of pts had prior docetaxel and 52% had ≥2 prior novel hormonal therapies. The most common any grade TEAEs were fatigue (57%), nausea (48%), decreased appetite (45%), diarrhea (39%), PPE (32%), and vomiting (32%). One Grade 5 TRAE of dehydration was reported in a 90 y/o. Median duration of treatment was 5.3 mo. The ORR per RECIST 1.1 among all pts was 32% (2 CRs [4.5%] and 12 PRs [27%]); 21 (48%) pts had SD giving a disease control rate of 80% in all pts. One pt with initial PD per RECIST 1.1 had an irPR per irRECIST. ORR per RECIST 1.1 was 33% in 36 pts with high-risk clinical features (visceral and/or extrapelvic lymph node metastases). Median DOR for all pts with response per RECIST 1.1 was 8.3 mo (range 1.38+, 9.76+). In 12 responders with at least 1 post-baseline PSA evaluation, 8 (67%) had a PSA decline ≥50%. Conclusions: The combination of C+A had a tolerable safety profile and demonstrated clinically meaningful activity with durable responses in men with mCRPC. Given the encouraging activity in these pts, especially in those with visceral and/or extra pelvic lymph node metastases, further evaluation of C+A in men with mCRPC is being pursued. Clinical trial information: NCT03170960.
Comparative quality of life in patients randomized contemporaneously to docetaxel or abiraterone in the STAMPEDE trial.
Authors: Rush Hannah L. , Cook Adrian David , Brawley Christopher D. , Murphy Laura , Macnair Archie , Millman Robin , Attard Gerhardt , Clarke Noel , Morgans Alicia K. , Chowdhury Simon , Gilbert Duncan C. , Dearnaley David P. , Sydes Matthew R. , James Nicholas D. , Langley Ruth E. , Parmar Mahesh K. B. ,   STAMPEDE Investigators
Published: February 2020

14

Background: Docetaxel (DOC) and abiraterone (ABI) both improve overall survival (OS) in men with locally advanced or metastatic hormone-sensitive prostate cancer (HSPC) but no head to head trials compare the 2 agents. STAMPEDE, a multi-arm multi-stage platform trial, recruited patients (pts) to treatments including DOC or ABI between Nov-11 and Mar-13. There was no evidence OS differed between DOC or ABI, thus quality of life (QOL) may increasingly inform treatment options. Methods: QOL scores were analysed in pts contemporaneously randomised to receive DOC or ABI, in addition to standard of care treatment. Self-assessment QOL questionnaires EORTC QLQ C30 and PR25 were completed during treatment and follow-up. These analyses focus on average global QOL over the first 2 years after randomisation, using repeated measures analysis, plus cross-sectional analyses at 3, 6, 12 and 24 months. A score difference of ≥4 points was pre-defined as clinically meaningful. Results: 173 men randomised to DOC and 342 men randomised to ABI participated in the QOL sub-study and contributed to this analysis. Baseline characteristics and proportion of missing data were similar between groups. Baseline global QOL scores were similar (mean (sd): DOC 77.8 (20) and ABI 78.0 (19.3)). Average global QOL over 2 years was higher in pts randomised to ABI than DOC, although the difference was statistically significant it did not meet the pre-defined clinical parameter (+3.9, 95%CI 0.6 to 7.1, p=0.021). Cross-sectional analyses showed clinically meaningful superior QOL in the ABI group at 3 and 6 months (+6.6, 95%CI 2.6 to 10.7, p=0.001; +8.0, 95%CI 3.6 to 12.3, p<0.001), but not at 1 or 2 years (+1.3, 95%CI -3.0 to 5.6, p=0.545; +4.5, 95%CI -0.25 to 9.2, p=0.063). An exploratory analysis indicated average QOL for pts with metastatic disease (n=207) was better in the ABI group (+4.44, 95%CI 0.2 to 8.6, p=0.036). Conclusion: Global QOL was significantly higher in the first 2 years of treatment for the ABI group compared to the DOC group, though did not meet the pre-defined clinically meaningful threshold. The majority of difference was seen in the first year of treatment. This should be considered when discussing treatment options with pts. Clinical trial information: NCT00268476.
Luminal B subtype as a predictive biomarker of docetaxel benefit for newly diagnosed metastatic hormone sensitive prostate cancer (mHSPC): A correlative study of E3805 CHAARTED.
Authors: Hamid Anis , Wang Xin Victoria , Chen Yu-Hui , Feng Felix Y , Den Robert Benjamin , Attard Gerhardt , Van Allen Eliezer Mendel , Huang Huei-Chung , Karns Amy , Dittamore Ryan , Davicioni Elai , Liu Glenn , DiPaola Robert S. , Carducci Michael Anthony , Sweeney Christopher
Published: February 2020

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Background: Through gene expression profiling (GEP), the PAM50 classifier demonstrates prognostic value in localized prostate cancer (PCa). Pre-clinical drug response models predict increased taxane sensitivity in luminal subtypes compared to basal subtype. Men with mHSPC and high-risk features have greatest benefit from androgen deprivation therapy (ADT) plus docetaxel (D) vs ADT alone. We therefore sought to test the prognostic and predictive value of PAM50 in pre-ADT specimens from E3805 CHAARTED. Methods: Whole transcriptomic profiling of formalin-fixed, paraffin-embedded primary PCa biopsies from pts enrolled in the E3805 CHAARTED trial of ADT vs ADT+D was performed using the Human Exon 1.0 ST microarray platform (Decipher Biosciences). Normalized gene expression was used to classify subjects as luminal A, luminal B or basal subtype. Multivariable analyses (MVA) adjusted for ECOG status, de novo metastasis vs prior local therapy and volume of disease. The primary endpoint was overall survival (OS). Secondary endpoint was time to castration resistant PCa (TTCRPC). Results: Successful GEP was completed in 160 of 198 pts with available specimens. Eighty (50%), 77 (48%) and 3 (2%) pts were classified as luminal B, basal and luminal A, respectively. High volume disease was similarly present in luminal B (79%) and basal (78%) subtypes. In the ADT arm, luminal B subtype was associated with shorter OS vs basal (HR 1.75, p=0.05); consistent in MVA. Pts with luminal B subtype treated with ADT+D showed significant improvement in TTCRPC and OS (Table). By contrast, basal subtype showed no OS benefit from ADT+D even in pts with high volume disease. Conclusions: We demonstrate that GEP identifies tumor subtypes associated with differential benefit from chemohormonal therapy for mHSPC. Luminal B subtype is associated with poorer OS with ADT alone and benefits from addition of D. Basal subtype shows a lack of OS benefit from upfront ADT+D. We plan to validate these findings in independent trial cohorts.[Table: see text]
Targeting tumor-associated macrophage (TAM) mediated inhibition of T-cell migration in prostate cancer using epigenetic modifying agents.
Authors: Kosoff David , Ellis Leigh , Beebe David J. , Lang Joshua Michael
Published: February 2020

166

Background: Cytotoxic T lymphocytes (CTLs) perform vital anti-tumor functions and are critical to the efficacy of many anticancer therapies. In prostate cancer, the characteristic paucity of activated CTLs within the tumor microenvironment (TME) may be a key factor in disease progression and likely underlies the limited role for immune checkpoint inhibitors (ICIs) in prostate cancer treatment. In this study, we utilized novel microfluidic technologies to evaluate whether TAMs may be driving the exclusion of T cells from the prostate TME and whether the immunosuppressive functions of TAMs could be modified by epigenetic modifying agents. Methods: Primary macrophages and autologous T cells were derived from peripheral blood samples of prostate cancer patients at the University of Wisconsin. Mono-, co-, and tri-culture systems of macrophages, T cells, and 22RV1 cells (androgen-dependent prostate cancer cell line) were cultured in 2D and 3D in microfluidic cell culture platforms. Culture systems were treated with the EZH2 inhibitors (EZH2i) DZNep or EPZ-6438 or left untreated. Macrophages were also treated with M1 (IFN-g) and M2 (IL-4) polarizing cytokines. Systems were analyzed for T cell migration as well as mRNA and protein expression in each cell population. Results: Autologous macrophages inhibited activated T cell migration towards tumor cells in a multi-cellular microscale TME. T cell migration was restored through treatment with EZH2i. Gene expression analysis identified that EZH2i altered macrophage gene expression in the unpolarized and M1/M2 polarized states. In particular, there was increased expression of genes involved in T cell recruitment/chemotaxis, including CXCL10, CXCL11, CXCL12, following EZH2i treatment. Conclusions: We used novel microfluidic technologies to model and analyze multicellular TMEs using primary, patient-derived cells. We demonstrate that TAM-mediated suppression of T cell migration is mediated, in part, through epigenetic pathways, which can be targeted with EZH2i. Treatment with EZH2i, alone or in combination other therapies such as ICIs, may enhance cytotoxic T cell migration and activity in primary prostate cancer.
Association of very small nuclear circulating tumor cell (vsnCTC) with clinical outcomes in metastatic castration-resistant prostate cancer.
Authors: Wang Jasmine Jiemei , Teng Pai-Chi , Jan Yu Jen , Chen Jie-Fu , Cook-Wiens Galen , Yao Nu , Chu Gina Chia-Yi , Chen Pin-Jung , Ho Hao , Yang Yingying , Lee Yi-Te , Huang Jiaoti , Chung Leland WK , You Sungyong , Zhu Yazhen , Freeman Michael , Rogatko Andre , Yang Ju Dong , Tseng Hsian-Rong , Posadas Edwin M.
Published: February 2020

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Background: Circulating tumor cells (CTCs) have arisen as contemporary noninvasive prognostic biomarkers for prostate cancer (PC). Previously, a subgroup of PC CTCs, with particularly small nuclei (<8.5 μm), were found to be correlated with the presence of visceral metastases. This subgroup was named very-small-nuclear CTCs (vsnCTCs). We proposed vsnCTCs as a putative biomarker of a lethal subtype in metastatic castration resistant PC (mCRPC). Methods: In this study, 76 patients with mCRPC were recruited for overall survival (OS) analysis. Of the 76 patients, 47 had available pre-treatment blood specimens prior to the initiation of androgen receptor signaling inhibitor (ARSI, e.g. abiraterone and enzalutamide) or taxane therapy. Using the NanoVelcro CTC Assay, CTCs were captured and subjected to immunofluorescence staining. CTCs were identified as DAPI+/CK+/CD45- with a round or oval nucleus. Additionally, CTC nuclear size was measured and defined as the square root of the product of the long axis and the short axis. Kaplan-Meier analysis and Cox proportional hazards model were conducted. Results: Patients with vsnCTC (i.e., vsnCTC+) had a significantly shortened OS compared with patients without vsnCTC (i.e., vsnCTC-). The median OS was 34 (vsnCTC+, n=49) vs. 149 (vsnCTC-, n=27) weeks (log-rank HR=2.6 with 95% CI 1.5 to 4.5, p=0.0006). Progression free survival (PFS) analysis was performed for the 47 patients with pre-treatment blood samples. The median PFS was 14 (vsnCTC+, n=29) vs. 26 (vsnCTC-, n=18) weeks (log-rank HR=2.2 with 95% CI 1.2 to 3.9, p=0.0069). We also found that the hazard ratio of overall survival increased significantly as the CTC nuclear size decreased using the p spline plot. Conclusions: Our study showed that nuclear size reduction has importance in CTCs in a fashion similar to its utility in tissue. This study points toward the importance of the vsnCTC in patients with mCRPC, as vsnCTC+ patients represented a group at risk for faster clinical progression who are at the highest risk for morality. We posit that the vsnCTC represents a new hallmark of an aggressive subtype of mCRPC. This has potential importance in optimizing therapeutic choices.
Cyclin pathway genomic alterations across 5,356 prostate cancers.
Authors: Fontes Jardim Denis Leonardo , Millis Sherri Z. , Woo Michele Sue-Ann , Ross Jeffrey S. , Ali Siraj Mahamed , Kurzrock Razelle
Published: February 2020

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Background: The cyclin pathway is comprised of possible targetable alterations as well as resistant alterations that affect treatment, including hormonal agents. We describe the landscape of cyclin genomic alterations in prostate cancer. Methods: Consecutive samples were analyzed in a CLIA-certified laboratory using comprehensive genomic profiling (CGP) performed by next-generation sequencing (315 genes, >500X coverage). We describe alterations in activating genes (Table) and co-alterations in resistant genes ( RB1 and CCNE1) (related to cyclin inhibition) and androgen receptor ( AR). Results: Alterations in any cyclin pathway genes were found in 9.7% of the 5,356 tumors analyzed. Frequent alterations included CCND1 amplification (4.2%) and CDKN2A and B loss (2.4% each). Frequencies were substantially different according to prostate cancer histology (Table). The majority of alterations were copy number changes. Alterations in possible resistance genes, RB1 and CCNE1 were detected in 9.7% (up to 54.6% in neuroendocrine) and 1.2% of cases, respectively, while AR alterations were seen in 20.9% (up to 27.3% in anaplastic). Co-occurrence analysis demonstrated a lower likelihood of concomitant vs. isolated alterations in cyclin activating and resistance pathway (odds ratio (OR), 0.44, p<0.001). Conversely, we detected a higher likelihood of co-occurrence between AR and cyclin alterations (OR 1.79, p<0.001). Conclusions: Cyclin pathway genomic abnormalities were observed in about 10% of prostate cancer tumors, and are more frequently associated with concomitant AR alterations and absence of co-alterations associated with resistance to cyclin inhibition.[Table: see text]
Biomarker analysis of the phase III IPATential150 trial of first-line ipatasertib (Ipat) plus abiraterone (Abi) in metastatic castration-resistant prostate cancer (mCRPC).
Authors: Shi Zhen , Sweeney Christopher , Bracarda Sergio , Sternberg Cora N. , Chi Kim N. , Olmos David , Sandhu Shahneen Kaur , Massard Christophe , Matsubara Nobuaki , Harle-Yge Marie-Laurence , Nowicka Malgorzata , Wongchenko Matthew , De Bono Johann S.
Published: February 2020

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Background: IPATential150 is a randomized trial comparing Ipat + Abi vs placebo + Abi in patients (pts) with 1L mCRPC (NCT03072238). We evaluated the potential associations between PTEN loss, genomic alterations, and country of enrollment (East Asian [EAS] vs non-EAS). Methods: Before randomization, tumor samples (archival > 90%) were centrally tested for PTEN loss by VENTANA PTEN (SP218) immunohistochemistry (IHC) assay (N = 1101). Tumor genetic alterations were profiled by Foundation Medicine FoundationOne CDx (F1CDx) NGS assay (n = 735). Results: Of 1101 pts enrolled, 521 (47%) had PTEN loss by IHC. An overall 76% agreement was observed between PTEN IHC and F1CDx. TMPRSS2 fusion, alterations in TP53 and PTEN were most frequent (28%-32%). Alterations in PIK3CA, SPOP, APC, MYC, RAD21, and genes involved in DNA damage repair, including BRCA2, CDK12, ATM, had a 5%-8% prevalence. PTEN loss (IHC) tended to co-occur with genetic alterations in TP53 and TMPRSS2. The prevalence of PTEN loss in EAS vs non-EAS pts was 35% vs 50% by IHC and 15% vs 31% by F1CDx. Alterations in CDK12, BRCA2, SPOP, and MYC were more prevalent in EAS pts, whereas alterations in TMPRSS2, PTEN, and TP53 were more prevalent in non-EAS pts. Conclusions: This analysis reveals molecular heterogeneity in prostate cancer and association between potentially actionable targets. It also suggests that EAS pts with mCRPC have a genetic profile that may be at least quantitatively different from non-EAS pts. Clinical trial information: NCT03072238. [Table: see text]
High-exosomal AKR1C3 mRNA expression as a marker of poor efficacy of abiraterone in metastatic PCa patients.
Authors: Zhu Sha , Sun Guangxi , Zhang Xingming , Dai Jindong , Chen Junru , Zhu Xudong , Zhang Haoran , Ni Yuchao , Zhao Jinge , Wang Zhipeng , Shen Pengfei , Zeng Hao
Published: February 2020

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Background: Aldo-keto reductase family 1 member C3 (AKR1C3) has been proved to be an important part in the androgen biosynthesis process. Previous researches have showed that immunohistochemical (IHC) AKR1C3 expression is a prognosticator in prostate cancer (PCa) patients treated with abiraterone. This study is to find out the relationship between exosomal AKR1C3 mRNA expression and the efficacy of abiraterone in metastatic PCa patients. Methods: Blood samples of metastatic prostate cancer patients during different disease stages were collected. We isolated the exosomes and extracted the RNA for analysis of AKR1C3 by ddPCR. Absolute target mRNA concentration was measured by ddPCR as copies per milliliter (copies/20ul). Clinical data were collected for all patients. Primary study endpoint was progression-free survival (PFS). Statistical analyses were performed with SPSS 25.0. Results: Exosomal AKR1C3 mRNA expression was positive in 71.9% (41/57) patients, and high expression (defined as ≥ 20 copies/20μl) was found in 12.3% (7/57) patients. High exosomal AKR1C3 mRNA expression was not related to positive IHC AKR1C3 expression ( P=0.723). Patients with high exosomal AKR1C3 expression and negative IHC AKR1C3 expression harbored only 4.866 months’ median progression-free survival (PFS) compared with the whole cohort (9.37 months). High exosomal AKR1C3 expression is significantly associated with shorter PFS (median PFS 8.036 months, p<0.001). Multivariate Cox regression analysis revealed that high exosomal AKR1C3 expression was an independent prognosticator of abiraterone treatment efficacy (OR: 8.891, 95%CI: 1.309-61.631, P=0.026). In subsequently subgroup analyses, high exosomal AKR1C3 expression demonstrates particularly high hazard ratio in multiple subgroups (patients with baseline PSA >100 ng/mL, ALP >71 IU/L, HGB >120 g/L, and patients receiving abiraterone as first-line therapy in castration resistant prostate cancer). Conclusions: Exosomal AKR1C3 level is an independent adverse prognosticator in metastatic PCa patients receiving abiraterone treatment, especially when abiraterone was used as first-line therapy in castration resistant prostate cancer.
Comprehensive genomic profiling (CGP) of metastatic castrate-sensitive prostate cancer (mCSPC) to reveal potential biomarkers and therapeutic targets.
Authors: Jiang Di Maria , Wong Bryan , Hansen Aaron Richard , Fallah-Rad Nazanin , Sacher Adrian G. , Zhang Tong , Selvarajah Shamini , Stockley Tracy , Bedard Philippe L. , Sridhar Srikala S.
Published: February 2020

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Background: Docetaxel and androgen receptor (AR) targeted agents have become standard options for mCSPC. CGP data is limited in mCSPC, however has the potential to guide treatment selection. We aimed to establish the feasibility of using CGP to characterize genomic alterations (GAs) in mCSPC. Methods: Patients with mCSPC were prospectively recruited at the Princess Margaret Cancer Centre to the OCTANE trial (NCT02906943), which aims to establish a genomically-characterized and clinically-annotated patient base that can be enrolled into specific research initiatives. Archival tumour specimens (after clinical testing completed) were profiled using next-generation sequencing (NGS) with a custom hybridization capture DNA-based panel (555 genes) or a targeted DNA/RNA amplicon panel (Oncomine Comprehensive Assay v3, 161 driver gene panel). GAs were classified according to the 2017 AMP/ASCO/CAP consensus recommendation. Clinical data were extracted from electronic health records. Results: Since 2016, 17/31 (55%) mCSPC patients who enrolled had sufficient tissue (15 from primary, 1 lymph node, 1 bone) for CGP. All had adenocarcinoma histology, most had high volume (76%) or de novo (71%) mCSPC. Median presenting PSA was 56 µg/L (range 8.4 – 1394). Patients received docetaxel (88%) or abiraterone (12%). Tier I/II GAs consistent with possible benefit from approved or investigational targeted therapies were identified in 14/17 patients (82%). AR pathway GAs (in 29%) were present regardless of prior androgen deprivation therapy or disease volume. DNA damage repair GAs (in 65%) included BRCA2, ATM, PALB2, MLH1/3, CDK12, FANCA, ERCC4, and SPOP. Other GAs involved the cell cycle, mTOR, EGFR, wnt, hedgehog, notch, and epigenetic pathways. Conclusions: In this small cohort, CGP was feasible in the setting of mCSPC for half of the patients. Potentially actionable GAs were identified in over 80% of patients tested. Pending confirmation from larger cohorts, these data support CGP in mCSPC prior to systemic therapy initiation, and highlight its potential role in future biomarker development and trial design in mCSPC.
Androgen deprivation therapy and statin therapy in prostate cancer patients.
Authors: Lai Kin Chung , Turknett Toiya , Singh Parminder
Published: February 2020

205

Background: Metastatic prostate cancer (mPC) is treated with androgen deprivation therapy( ADT). Duration of response to ADT predicts patient’s survival. It has been shown in observational studies that concurrent statin use may prolong response to ADT. Studies in mice have shown negative interactions. We wanted to examine the effect of this interaction in patients being followed at Mayo Clinic Arizona (MCA). Methods: We examined 441 patients with mPC, who received ADT and were treated at MCA from year 2011 to 2017. . Our study evaluated the time to progression (TTP) and overall survival(OS) for patients with mPC on ADT with or without concurrent statin use. Among the patients who were evaluated, there was a subset of 156 patients taking abiraterone (ABI). Characteristics were compared between statin users and nonusers using Chi squared test and Wilcoxon rank-sum tests. The primary outcome was TTP defined as the duration from ADT initiation to disease progression. The association between statin use and TTP was analyzed by multivariable Cox regression to estimate hazard ratios (HRs) and 95% Conference Interval (CI), and adjusted for Gleason score, primary therapy type, prior ADT, metastatic status, and PSA at ADT initiation. Results: There was no significant difference in TTP when comparing patients with statin to those without a statin. The HR for statin use vs no statin use is 1.049 with CI (0.838, 1.314) and p-value is 0.677. There was no significant difference in overall survival when comparing statin vs no statin use. The HR for statin use vs no statin use was 0.928(CI 0.642, 1.342) with p-value at 0.693. In the ABI population, there was no significant difference in TTP for patients with statin vs no statin. HR was 1.00 CI (0.725, 1.377) with p-value at 0.998. For overall survival, there was no significant difference with HR at 0.852 (CI 0.502, 1.446) with p-value at 0.553. Conclusions: Despite retrospective studies showing benefit of use of statin in men with prostate cancer, our study observed no difference in long term outcomes. Possible explanations could be smaller sample size, inability to verify data as medication intake was not verified directly. Also, patient’s compliance with medications could be a confounding variable.