bluuebunny/crossref_metadata_2025 huggingface dataset:
The Video intervention to Inspire Treatment Adherence for Life (VITAL Start): protocol for a multisite randomized controlled trial of a brief video-based intervention to improve antiretroviral adherence and retention among HIV-infected pregnant women in Malawi
Authors: Kim Maria H. , Tembo Tapiwa A. , Mazenga Alick , Yu Xiaoying , Myer Landon , Sabelli Rachael , Flick Robert , Hartig Miriam , Wetzel Elizabeth , Simon Katie , Ahmed Saeed , Nyirenda Rose , Kazembe Peter N. , Mphande Mtisunge , Mkandawire Angella , Chitani Mike J. , Markham Christine , Ciaranello Andrea , Abrams Elaine J.
Published: February 2020

Background

Improving maternal antiretroviral therapy (ART) retention and adherence is a critical challenge facing prevention of mother-to-child transmission (PMTCT) of HIV programs. There is an urgent need for evidence-based, cost-effective, and scalable interventions to improve maternal adherence and retention that can be feasibly implemented in overburdened health systems. Brief video-based interventions are a promising but underutilized approach to this crisis. We describe a trial protocol to evaluate the effectiveness and implementation of a standardized educational video-based intervention targeting HIV-infected pregnant women that seeks to optimize their ART retention and adherence by providing a VITAL Start (Video intervention to Inspire Treatment Adherence for Life) before committing to lifelong ART.

Methods

This study is a multisite parallel group, randomized controlled trial assessing the effectiveness of a brief facility-based video intervention to optimize retention and adherence to ART among pregnant women living with HIV in Malawi. A total of 892 pregnant women living with HIV and not yet on ART will be randomized to standard-of-care pre-ART counseling or VITAL Start. The primary outcome is a composite of retention and adherence (viral load < 1000 copies/ml) 12 months after starting ART. Secondary outcomes include assessments of behavioral adherence (self-reported adherence, pharmacy refill, and tenofovir diphosphate concentration), psychosocial impact, and resource utilization. We will also examine the implementation of VITAL Start via surveys and qualitative interviews with patients, partners, and health care workers and conduct cost-effectiveness analyses.

Discussion

This is a robust evaluation of an innovative facility-based video intervention for pregnant women living with HIV, with the potential to improve maternal and infant outcomes.

Trial registration

ClinicalTrials.gov,NCT03654898. Registered on 31 August 2018.
Effect of polymorphisms in porcine guanylate-binding proteins on host resistance to PRRSV infection in experimentally challenged pigs
Authors: Khatun Amina , Nazki Salik , Jeong Chang-Gi , Gu Suna , Mattoo Sameer ul Salam , Lee Sim-In , Yang Myun-Sik , Lim Byeonghwi , Kim Kwan-Suk , Kim Bumseok , Lee Kyoung-Tae , Park Choi-Kyu , Lee Sang-Myeong , Kim Won-Il
Published: February 2020

Guanylate-binding proteins (GBP1 and GBP5) are known to be important for host resistance against porcine reproductive and respiratory syndrome virus (PRRSV) infection. In this study, the effects of polymorphisms in GBP1 (GBP1E2 and WUR) and GBP5 on host immune responses against PRRSV were investigated to elucidate the mechanisms governing increased resistance to this disease. Seventy-one pigs [pre-genotyped based on three SNP markers (GBP1E2, WUR, and GBP5)] were assigned to homozygous (n = 36) and heterozygous (n = 35) groups and challenged with the JA142 PRRSV strain. Another group of nineteen pigs was kept separately as a negative control group. Serum and peripheral blood mononuclear cells (PBMCs) were collected at 0, 3, 7, 14, 21 and 28 days post-challenge (dpc). Viremia and weight gain were measured in all pigs at each time point, and a flow cytometry analysis of PBMCs was performed to evaluate T cell activation. In addition, 15 pigs (5 pigs per homozygous, heterozygous and negative groups) were sacrificed at 3, 14 and 28 dpc, and the local T cell responses were evaluated in the lungs, bronchoalveolar lavage cells (BALc), lymph nodes and tonsils. The heterozygous pigs showed lower viral loads in the serum and lungs and higher weight gains than the homozygous pigs based on the area under the curve calculation. Consistently, compared with the homozygous pigs, the heterozygous pigs exhibited significantly higher levels of IFN-α in the serum, proliferation of various T cells (γδT, Th1, and Th17) in PBMCs and tissues, and cytotoxic T cells in the lungs and BALc. These results indicate that the higher resistance in the pigs heterozygous for the GBP1E2, WUR and GBP5 markers could be mediated by increased antiviral cytokine (IFN-α) production and T cell activation.
The challenges of estimating the distribution of flight heights from telemetry or altimetry data
Authors: Péron Guillaume , Calabrese Justin M. , Duriez Olivier , Fleming Christen H. , García-Jiménez Ruth , Johnston Alison , Lambertucci Sergio A. , Safi Kamran , Shepard Emily L. C.
Published: February 2020

Background

Global positioning systems (GPS) and altimeters are increasingly used to monitor vertical space use by aerial species, a key aspect of their ecological niche, that we need to know to manage our own use of the airspace, and to protect those species. However, there are various sources of error in flight height data (“height” above ground, as opposed to “altitude” above a reference like the sea level). First the altitude is measured with a vertical error from the devices themselves. Then there is error in the ground elevation below the tracked animals, which translates into error in flight height computed as the difference between altitude and ground elevation. Finally, there is error in the horizontal position of the animals, which translates into error in the predicted ground elevation below the animals. We used controlled field trials, simulations, and the reanalysis of raptor case studies with state-space models to illustrate the effect of improper error management.

Results

Errors of a magnitude of 20 m appear in benign conditions for barometric altimeters and GPS vertical positioning (expected to be larger in more challenging context). These errors distort the shape of the distribution of flight heights, inflate the variance in flight height, bias behavioural state assignments, correlations with environmental covariates, and airspace management recommendations. Improper data filters such as removing all negative flight height records introduce several biases in the remaining dataset, and preclude the opportunity to leverage unambiguous errors to help with model fitting. Analyses that ignore the variance around the mean flight height, e.g., those based on linear models of flight height, and those that ignore the variance inflation caused by telemetry errors, lead to incorrect inferences.

Conclusion

The state-space modelling framework, now in widespread use by ecologists and increasingly often automatically implemented within on-board GPS data processing algorithms, makes it possible to fit flight models directly to the output of GPS devices, with minimal data pre-selection, and to analyse the full distribution of flight heights, not just the mean. In addition to basic research about aerial niches, behaviour quantification, and environmental interactions, we highlight the applied relevance of our recommendations for airspace management and the conservation of aerial wildlife.
Design of a bio-conditioner prototype for the treatment of degraded soils: biomass production and lignite formulation for Microbacterium sp. CSB3
Authors: Pantoja-Guerra Manuel , Valero-Valero Nelson
Published: February 2020

Background

A new prototype of bio-conditioner useful in rehabilitation of degraded soils was performed. In order to obtain this aim two stages were established: production of biomass of Microbacterium sp. CSB3 and formulation of this inoculum in a sediment supplemented with low-rank coal (LRC).

Materials and methods

The effect of agitation and pH on microbial growth was determined. As response variables, the final production of biomass (Xf) and yield (Yx/s) were determined. Growth dynamics of CSB3 in a 2-L reactor was also evaluated through Xf, Yx/s and the determination of kinetic parameters (specific growth rate [μ] and duplication time [Dt]). The formulation of CSB3 was evaluated; mixtures of several LRC proportions with a sediment from a municipal aqueduct were made. During 90 days, the viability of CSB3 was monitored by counting CFU.

Results

The optimal pH and agitation for Xf and Yx/x were 7.5 and 232 rpm, respectively; the values of Xf, Yx/s, μ and Dt in 2-L reactor were: 1.5 gL−1, 0.28 g/g, 0.0208 h−1, 33.3 h, respectively. Regarding the formulation, the most suitable combination to conserve the viability of CSB3 was LRC 25%–sediment 75%; the heavy metals content of LRC allow to infer that the prototype of bio-conditioner does not represent a pollution risk for environment soil.

Conclusions

It was possible to optimize the growth of CSB3 under laboratory conditions. The viability of CSB3 could be maintained by a formulation in a sediment supplemented with lignite; this formulation constitutes a new prototype of soil bio-conditioner.
Acceleration mechanism of radiation belt electrons through interaction with multi-subpacket chorus waves
Authors: Hiraga Ryoko , Omura Yoshiharu
Published: February 2020

We conduct test particle simulations to examine the acceleration mechanism of relativistic electrons through interaction with multi-subpacket chorus waves. As the analysis of recent observations reveals, amplitude of a rising tone element of chorus wave consists of many short wave packets. We call this single rising tone chorus element with the collective structure of multiple short wave packets as a multi-subpacket chorus wave. In this simulation, we develop the wave model with rapidly fluctuating amplitude and phase discontinuities across each subpacket, in order to examine how these features of multi-subpacket chorus wave influence the nonlinear trapping processes in efficient acceleration of relativistic electrons such as relativistic turning acceleration (RTA) and ultra-relativistic acceleration (URA). To conduct comprehensive examinations, we test more than nine million particles with various initial conditions covering the energy range from 100 to 6 MeV, and the equatorial pitch angles from 10° to 89°. The test particles interact with a single rising tone element of multi-subpacket chorus wave set up with the maximum amplitude of about 2 nT and the frequency rise from about 1.3 kHz to 3.8 kHz over 0.25 s. Relativistic electrons are accelerated by about 160 keV under preferable conditions. The energy increase verifies the high efficiency of acceleration by the wave–particle interactions, based on the fact that it is achieved by a short time interaction less than 1 s with a single element of chorus wave. By analyzing the detailed behavior of the accelerated electrons, we find successive trapping of the resonant electrons resulting in the efficient accelerations from the consecutive multiple subpackets of a chorus wave element.
Should we transfer poor quality embryos?
Authors: Kirillova Anastasia , Lysenkov Sergey , Farmakovskaya Maria , Kiseleva Yulia , Martazanova Bella , Mishieva Nona , Abubakirov Aydar , Sukhikh Gennady
Published: February 2020

Background

To evaluate if it is safe and effective to transfer poor quality embryos.

Methods

It was a retrospective analysis using individual patient data with positive controls. All patients undergoing embryo transfers of poor quality embryos on day 3 or on day 5 as part of fresh In Vitro Fertilization (IVF) cycles performed between 2012 and 2016. This study assessed a total of 738 poor quality embryos from 488 IVF programs. 261 embryo transfers were performed on day 3 (402 embryos were transferred) and 227 on day 5 (336 embryos were transferred). Control group consisted of 9893 fair and good quality embryos from 5994 IVF programs. Outcome rates were compared with two-tailed Fisher exact test using fisher.test function in R software. 95% confidence intervals for proportions were calculated using the Clopper-Pearson method with binom.test function in R. The groups of patients with poor vs. good and fair quality embryos were compared by age, body mass index(BMI), number of oocytes, female and male main diagnosis, cycle type, controlled ovarian stimulation (COS) protocol, the starting day of gonadotropin administration, the starting dose of gonadotropins, the total dose of gonadotropins, the total number of days of gonadotropins administration, the starting day of gonadotropin-releasing hormone (GnRH) agonist administration, the total number of ampoules of GnRH-agonist used, day of the trigger of ovulation administration and the type of the trigger of ovulation using the Student’s t-test for interval variables and with the chi-square test for nominal variables.

Results

No significant differences in the implantation rate, clinical pregnancy rate, miscarriage rate, live births, and the number of children born were found between the groups of poor quality embryos transferred on day 3 and day 5. Though the implantation rate was lower for the group of poor quality embryos, than for the control (13.9% vs 37.2%), statistically significant differences between the proportion of implanted embryos which resulted in clinical pregnancies and live births in both groups were not observed (72% vs 78.2 and 55.8% vs 62.0% respectively).

Conclusion

Transfer of poor quality embryos at either day 3 or day 5 have a low potential for implantation, though those embryos which successfully implanted have the same potential for live birth as the embryos of fair and good quality. This study supports that it is safe to transfer poor quality embryos when they are the only option for fresh embryo transfer (ET).
Can electrophysiological tests be used as screening tools in detection of cognitive impairment in obstructive sleep apnea hypopnea syndrome?
Authors: Nada Mona M. , Maher Eman A. , Basheer Mye A. , El-Mekkawy Leqaa A.
Published: February 2020

Background

One of the most prevalent sleep disorders is obstructive sleep apnea (OSA). Patients with OSA have increased risk of car and work place accidents which may be attributed to cognitive impairment due to poor sleep quality. Thus, there is an increasing need to implement simple, reliable and rapid screening for cognitive impairment in OSA patients.

Objectives

To assess auditory event-related potentials (ERPs) and quantitative electroencephalography (QEEG) as screening tools for detection of cognitive impairment in OSA patients taking circadian effects into consideration.

Subjects and methods

Twenty OSA patients as well as 20 gender- and age-matched volunteers were subjected to trail making test (TMT), auditory ERPs and QEEG before and after at least 6 h polysomnographic recording. Correlating electrophysiological tools with TMT and clinical parameters was done as well

Results

Statistically significant changes in P300 latency and reaction time, in addition to occipital alpha power were noted in cases; however, TMT failed to detect such changes. Electrophysiological results were not constantly correlated to clinical parameters.

Conclusion

Auditory ERPs and QEEG before and after polysomnography can be of benefit as cognitive screening test for suspected cognitive impairment in OSA patients.
Single level anterior cervical discectomy and fusion versus dynamic cervical implant: clinical and radiological outcome
Authors: Ahmed Omar El Farouk , Galal Ahmed
Published: February 2020

Background

Although anterior cervical discectomy and fusion (ACDF) is considered a gold standard approach for surgical management of cervical disc herniation syndromes, the use of dynamic cervical implant (DCI) provided a novel technique that aims at reconstruction of the anterior column while facilitating controlled neck motion and reducing stress across the facet joints.

Aim of the work

The objective of this study is to evaluate the clinical and radiological outcome of the DCI surgery in comparison to that achieved with ACDF using a conventional polyethylethylketone (PEEK) cage.

Materials and methods

This is a retrospective comparative study of 30 patients, with single level cervical degenerative disc disease (DDD), managed by the authors, either by DCI (n = 15) or ACDF (n = 15). Clinical and radiologic outcomes were assessed at 1, 3, and 12 months postoperatively. Clinical scoring systems included the Visual Analog Scale for Neck (VAS-N) and Arm (VAS-A), the Neck Disability Index score (NDI), as well as the evaluation of incidence of complications and neurological deterioration postoperatively. Radiographic evaluation included the assessment of postoperative cervical implant fusion, as well as evaluating the incidence of implant migration. Study duration was for two years from October 2016 to October 2018.

Results

Both the ACDF and DCI groups showed significant clinical improvement at 12 months postoperatively regarding the clinical outcome including VAS-A, VAS-N, and NDI values (P = 0.001), while there was no significant difference on comparing between the two groups as regard the VAS-N, the VAS-A, and the NDI at 1,3 and 12 months after surgery. The ACDF group however showed better rate of implant fusion at 12 months postoperatively in contrast to the DCI group (80% and 26,7%, respectively) also, the ACDF group showed a lower rate of implant subsidence at 12 months after surgery (P = 0.002). Besides, the incidence of implant migration was relatively high in the DCI group (20%).

Conclusion

The clinical results for DCI arthroplasty for the management of single-level cervical DDD are equivalent to those for ACDF; however, though providing an immediate dynamic stability, DCI is associated with a low fusion rate, higher rates of implant subsidence, and relatively high implant migration rate. Larger series and further studies should be considered with longer follow-up periods giving special attention to these issues.
Olaparib Versus Nonplatinum Chemotherapy in Patients With Platinum-Sensitive Relapsed Ovarian Cancer and a Germline BRCA1/2 Mutation (SOLO3): A Randomized Phase III Trial
Authors: Penson Richard T. , Valencia Ricardo Villalobos , Cibula David , Colombo Nicoletta , Leath Charles A. , Bidziński Mariusz , Kim Jae-Weon , Nam Joo Hyun , Madry Radoslaw , Hernández Carlos , Mora Paulo A.R. , Ryu Sang Young , Milenkova Tsveta , Lowe Elizabeth S. , Barker Laura , Scambia Giovanni
Published: February 2020

PURPOSE

A phase II study (ClinicalTrials.gov identifier: NCT00628251 ) showed activity of olaparib capsules versus pegylated liposomal doxorubicin in patients with germline BRCA-mutated platinum-resistant or partially platinum-sensitive relapsed ovarian cancer. We conducted a phase III trial (SOLO3) of olaparib tablets versus nonplatinum chemotherapy in patients with germline BRCA-mutated platinum-sensitive relapsed ovarian cancer who had received at least 2 prior lines of platinum-based chemotherapy.

PATIENTS AND METHODS

In this randomized, open-label trial, patients were randomly assigned 2:1 to olaparib 300 mg twice a day or physician’s choice single-agent nonplatinum chemotherapy (pegylated liposomal doxorubicin, paclitaxel, gemcitabine, or topotecan). The primary end point was objective response rate (ORR) in the measurable disease analysis set assessed by blinded independent central review (BICR). The key secondary end point was progression-free survival (PFS) assessed by BICR in the intent-to-treat population.

RESULTS

Of 266 randomly assigned patients, 178 were assigned to olaparib and 88 to chemotherapy. In patients with measurable disease (olaparib, n = 151; chemotherapy, n = 72), the BICR-assessed ORR was significantly higher with olaparib than with chemotherapy (72.2% v 51.4%; odds ratio [OR], 2.53 [95% CI, 1.40 to 4.58]; P = .002). In the subgroup who had received 2 prior lines of treatment, the ORR was 84.6% with olaparib and 61.5% with chemotherapy (OR, 3.44 [95% CI, 1.42 to 8.54]). BICR-assessed PFS also significantly favored olaparib versus chemotherapy (hazard ratio, 0.62 [95% CI, 0.43 to 0.91]; P = .013; median, 13.4 v 9.2 months). Adverse events were consistent with the established safety profiles of olaparib and chemotherapy.

CONCLUSION

Olaparib resulted in statistically significant and clinically relevant improvements in ORR and PFS compared with nonplatinum chemotherapy in patients with germline BRCA-mutated platinum-sensitive relapsed ovarian cancer who had received at least 2 prior lines of platinum-based chemotherapy.
Results of a phase I/II prospective dose-escalation trial evaluating safety and efficacy of combination 177LuPSMA-617 and NOX66 in men with mCRPC post androgen signalling inhibition and two lines of taxane chemotherapy (LuPIN trial).
Authors: Emmett Louise , Pathmanandavel Sarennya , Nguyen Andrew , Crumbaker Megan , Yam Andrew On Wah , Chan Wai Ling , Fullard Karen , Ho Bao , Azad Arun , Joshua Anthony M.
Published: February 2020

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Background: Despite treatment advances, metastatic castrate resistant prostate cancer (mCRPC) remains a lethal disease. Trials in 177LuPSMA-617 have demonstrated good efficacy and safety, but synergistic combinations may further improve treatment responses. NOX66 inhibits external NADH oxidase type 2 with downstream pro-apoptotic actions including radio-sensitization. We present results of a prospective open label single arm phase 1/2 dose escalation/expansion trial of 177LuPSMA-617 and NOX66 in mCRPC. Methods: Men with progressive mCRPC post androgen signalling inhibition (ASI) and taxane chemotherapy were eligible. Inclusion criteria included PSMA PET/CT intensity > SUV max 15, with no discordant disease on FDG PET/CT, Hb > 100 g/L, Platelets > 90 x 106/L and GFR > 40 mL/min. Protocol allowed up to 6 doses of 177 Lu-PSMA 617 (7.5Gbq) on day 1 with NOX66 (suppository) given day 1-10 at 6-weekly intervals; the first 8 men received 400mg NOX66. After safety review, dose was escalated to 800mg. Data regarding safety, efficacy, pain scores, and QOL were collected. Results: 32/43 (26% imaging screen failures) screened men were enrolled (November 2017 – June 2019), of whom 100% had prior docetaxel and ASI, and 94% (30/32) cabazitaxel. All men received ≥ 2 cycles, with 12/32 completing 6 cycles, and 16/32 2 - 5 cycles, while 4/32 remain on treatment. Any PSA response was seen in 84% (27/32), with a PSA response > 50% in 62.5% (20/32). Median PSA PFS was 6.5 months (95%CI 3.54-9.3). To date, 72% (23/32) of patients have progressed. 34% (11/32) men have died with median OS not reached. 50% (12/24) of men with baseline pain scores ≥3 (24/32) had significant reduction in pain. Adverse events are summarized below. Conclusions: Combination 177LuPSMA-617 with NOX66 appears safe and efficacious in men with heavily pre-treated mCRPC. Clinical trial information: ACTRN12618001073291. [Table: see text]
The effect of AKR1C3 on the switch from prednisone to dexamethasone in metastatic castration-resistant prostate cancer patients receiving abiraterone.
Authors: Ni Yuchao , Zhao Jinge , Chen Junru , Sun Guangxi , Zhu Sha , Zhang Xingming , Dai Jindong , Wang Zhipeng , Zhang Haoran , Zhu Xudong , Chen Ni , Shen Pengfei , Zeng Hao
Published: February 2020

133

Background: Abiraterone is the first-line treatment for men with metastatic castration-resistant prostate cancer (mCRPC) and is recommended to be used with prednisone. Previous studies had demonstrated that the switch from prednisone to dexamethasone in some mCRPC patients can reverse abiraterone-resistance. However, it remains uncertain which group of patients will benefit from such switching. AKR1C3 is a critical enzyme contributing to the drug-resistance of abiraterone. Here, we aim to explore the significance of AKR1C3 in predicting the therapeutic efficacy of the corticosteroid switching in mCRPC patients receiving abiraterone. Methods: In total, 43 PCa patients treated with abiraterone after mCRPC between 2016 and 2018 in our institution were included. After biochemical progression in abiraterone plus prednisone, all cases received a corticosteroid switch to abiraterone plus dexamethasone. The expression of AKR1C3 was detected by immunohistochemical staining from re-biopsy (re‐Bx) of primary prostate lesions at the time of mCRPC. Kaplan‐Meier curves were used to analyze the association between AKR1C3 and treatment outcomes. Results: Totally, AKR1C3 was positive in 19 of 43 (44.19%) cases. In the corticosteroid switch treatment, 30% PSA decline was confirmed in 18/43 (41.86%) patients, while the median PSA progression‐free survival (PSA-PFS) and overall survival (OS) was 4.93 Mo and 31.57 Mo, respectively in the whole cohort. AKR1C3 expression was associated with statistically shorter median PSA-PFS (4.50 Mo vs 7.73 Mo; p =0.010) and numerically lower median OS (25.43 Mo vs 39.37 Mo, p =0.274). While the 30% PSA decline rate was numerically comparable between those with and without AKR1C3 expression (31.6% vs 50.0%, p =0.224). Conclusions: This study showed AKR1C3 detection in tissues from prostate re‐Bx at mCRPC was associated with poor PSA-PFS in the corticosteroid switch from abiraterone plus prednisone to abiraterone plus dexamethasone. These results would be helpful in making optimal personalized treatment decisions for patients with mCRPC, facilitating physicians predicting the effectiveness of corticosteroid switch treatment.
Clinical investigation of neuroendocrine differentiation in prostate cancer.
Authors: Shimomura Tatsuya , Kurauchi Takashi , Sakanaka Keigo , Kimura Takahiro , Egawa Shin
Published: February 2020

138

Background: Neuroendocrine prostate cancer (NEPC) is a lethal disease subset with median overall survival of less than 1 year from time of detection. The treatment strategy against NEPC is not yet established and some clinical trials are ongoing now. Recently, clinical trial (RADIIANT4) showed that treatment with everolimus was associated with significant improvement in survival in patients with progressive lung or gastrointestinal neuroendocrine tumors. In this study we evaluated the neuroendocrine differentiation of prostate cancer and we tried to introduce everolimus against pathologically proven NEPC and investigated the clinical outcomes of this agent. Methods: Total of 193 prostate cancer cases were included in this study. We tested serum neuroendocrine markers, including (NSE and pro-GRP). And we evaluated positive rate of these markers. Eleven cases were pathologically proven neuroendocrine prostate cancer (NEPC) in this cohort. Seven out of eleven NEPC cases were introduced everolimus 10mg daily. We investigated the change of serum neuroendocrine markers (NSE and pro-GRP), radiologic examination and survival. Results: The positive rate of serum neuroendocrine markers (at least one of the markers increasing above normal limit) were 23.5% in hormone sensitive prostate cancer (HSPC), 59.5% in castration resistant prostate cancer (CRPC), and 100% in neuroendocrine prostate cancer (NEPC). There were significant differences in each other (HSPC vs. CRPC: p=0.0001, CRPC vs. NEPC: p=0.0109). We introduced everolimus in seven cases out of eleven NEPC cases. The median follow up period was 18 months. Neuroendocrine markers decreased in five of seven (71.4%) cases after introduction of everolimus. Median decreasing rate were 67.1% in NSE and 65.5% in pro GRP. 24M progression free survival rate was 57.1% and 24M overall survival rate was 57.1%. Conclusions: There is a possibility that the incidence of NEPC is higher than expected, and treatment against prostate adenocarcinoma accelerate neuroendocrine differentiation. Everolimus showed efficacy against NEPC. Although this study was retrospective and number of cases was limited, everolimus would be a one of the treatment options against NEPC.
IND candidate EPI-7386 as an N-terminal domain androgen receptor inhibitor in development for the treatment of prostate cancer.
Authors: Le Moigne Ronan , Banuelos C. Adriana , Mawji Nasrin R. , Tam Teresa , Wang Jun , Jian Kunzhong , Andersen Raymond J. , Cesano Alessandra , Sadar Marianne , Zhou Han-Jie , Virsik Peter
Published: February 2020

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Background: The androgen receptor (AR) pathway drives most metastatic castration-resistant prostate cancers (mCRPC) even in late stages of the disease. Anti-androgen resistance mechanisms include AR gene amplification, C-terminal ligand-binding domain (LBD) mutations and expression of constitutively active AR splice variants lacking the LBD (e.g. AR-V7). Selective inhibition of the N-terminal domain (NTD) of the AR can inhibit its’ transcriptional activity even in the presence of LBD-driven resistance. In a phase I trial, the first-generation AR NTD inhibitor (aniten) EPI-002, demonstrated minor PSA declines in mCRPC patients. The efficacy and safety profile of second generation aniten IND-candidate EPI-7386 will be presented. Methods: Novel aniten chemical structures were developed to increase molecule potency using a wide variety of CRPC models. Similarly, the stability and selectivity of the molecule were characterized with screening and functional assays. IND-enabling studies further support the compounds’ safety profile. Results: EPI-7386 demonstrated a 20-fold improvement in AR-driven cellular potency compared to EPI-002, while being highly stable in human hepatocytes and across animal species. In vitro proliferation assays demonstrated on-target activity across a panel of prostate cancer cell lines, with activity in AR-V7-driven cellular models. EPI-7386 was able to induce tumor regression in CRPC xenografts and show superiority to enzalutamide (ENZ) in ENZ resistant models. In addition, the combination of ENZ with EPI-7386 demonstrated a more robust antitumor response. IND-enabling studies demonstrate a safe and well-tolerated profile supporting an IND filing in 1Q 2020. Pharmacodynamic markers specific to anitens will be presented, in addition to early clinical development plans. Conclusions: The next generation aniten compound EPI-7386 is more active and metabolically stable than EPI-002. It demonstrated potential as a single agent in overcoming anti-androgen clinical resistance as well as in combination therapy in earlier stages of the disease. The clinical strategy supporting the development of this new generation of aniten will be discussed.
Role of metastases-directed therapy (MDT) in the management of solitary metastatic prostate cancer.
Authors: Ahmed Mohamed E. , Jimbo Masaya , Haloi Rimki , Andrews Jack R. , Motterle Giovanni , Joshi Vidhu B. , Kendi Ayse T. , Stish Brad J. , Park Sean Sunghun , Karnes Jeffrey , Kwon Eugene D.
Published: February 2020

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Background: Systemic treatment in the management of metastatic prostate cancer is inevitable. However, there is a growing interest in metastases-directed therapy (MDT). We sought to investigate the efficacy of MDT in treating patients with solitary metastatic prostate cancer and hence, delaying initiation of systemic treatment (i.e., Androgen deprivation therapy or chemotherapy). Methods: We retrospectively identified 61 patients treated with targeted therapy in the form of surgery (n = 30), stereotactic body radiation therapy (SBRT) (n = 25), or cryotherapy (n = 7) for their solitary metastases prostate cancer. Complete response was defined by achieving a PSA value of ≤0.2 ng/ml plus resolution of the solitary metastatic lesion on C-11 choline PET choline scan, while incomplete response was defined by a residual PSA of > 0.2 ng/ml and/or radiographic evidence of disease following metastases-targeted therapy. Results: Mean (±SD) age was 68.4 (±7.8) yrs., median (IQR) primary Gleason Score was 7 (7-9) and median (IQR) pre-MDT PSA was 2 (1.3-3.8) ng/ml. Median (IQR) time from primary treatment of the prostate to MDT was 5.1 (2.7-10.1) years. None of the patients were on hormone therapy at the time of presentation with solitary metastases prostate cancer. 30 patients had bone metastases, 29 patients had lymph node metastases, 1 patient had soft tissue metastasis (pelvic metastatic mass), and another patient had visceral metastasis (to the lung). 42% of the patients (n = 26) achieved complete response to targeted therapy. Median time to initiation of 2nd line systemic treatment following MDT was 17.8 months for the complete responders versus 9.3 months for incomplete responders. 11% of the patients (n = 7) did not require 2nd line therapy after their MDT for a mean (±SD) time of 56.9 (±22.5) months. Conclusions: The use of targeted therapy in the management of patients with solitary metastatic disease or low-volume metastatic disease can provide comparable outcomes to those of systemic treatment. Further studies are warranted.
A prospective study of the relationship between clinical outcomes of enzalutamide and serum androgen levels measured by LC-MS/MS in patients with CRPC.
Authors: Miyazawa Yoshiyuki , Miyao Takeshi , Nakamura Toshiyuki , Takezawa Yutaka , Shimizu Nobuaki , Matsuo Yasushige , Ogura Haruyuki , Takei Tomoyuki , Oka Daisuke , Arai Seiji , Sekine Yoshitaka , Koike Hidekazu , Matsui Hiroshi , Shibata Yasuhiro , Suzuki Kazuhiro
Published: February 2020

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Background: Enzalutamide (ENZ) is commonly used to treat patients with castration resistant prostate cancer (CRPC). However, the kinetics of serum androgen levels before and after ENZ treatment are unknown. We elucidated the kinetics of serum androgens and explored the possibility of identifying a useful marker for predicting the effects of ENZ. Methods: We conducted a prospective study from 2014 to 2018 at Gunma University Hospital and related facilities. 104 CRPC patients treated with ENZ were analyzed. We investigated the PSA reduction rate (50%, 90%), PSA-progression-free survival (PFS), and overall survival (OS) after administration. To measure levels of androgens accurately we measured serum androgen levels using LC-MS/MS. OS and PSA-PFS were assessed according to the PCWG 2 criteria. This study was approved by the Institutional Review Board of Gunma University Hospital (No. 1177). Results: The 50% and 90% PSA decline rates were 62.5% and 25.0%, respectively. Median serum testosterone (T), dihydrotestosterone (DHT), androstenedione (A-dione), and dehydroepiandrosterone-sulfate levels were 49.0, 5.8, 222.2, and 326.3 pg/ml, respectively. Mean serum levels of T, DHT, and A-dione increased significantly 12 and 24 weeks after compared to before treatment (p < 0.05). We performed a multivariate analysis using a Cox regression to predict OS and PSA-PFS. ECOG PS (0 vs. 1–2), hemoglobin (Hb ≥ 12.5 vs. < 12.5 g/dL), albumin (≥ 3.9 vs. < 3.9 g/dL), visceral metastasis (no vs. yes), EOD (0–2 vs. 3–4), docetaxel treatment (no vs. yes), and DHT level (≥11.25 vs. < 11.25 pg/mL, 11.25 was third quartile) were significant predictors of OS (p < 0.05). Hb (≥12.5 vs. < 12.5 g/dL), docetaxel treatment (no vs. yes), and level of DHT (≥ 5.9 vs. < 5.9 pg/mL) were significant predictors of PSA-PFS (p < 0.05). As a result of the binomial logistic analysis of the predictors of fatigue and decreased appetite, the presence of visceral metastasis (yes) and low DHT (<5.9 pg/mL) were significant predictors of expression. Conclusions: These results suggest that serum androgen levels before ENZ treatment may be useful for predicting efficacy, prognosis, and the incidence of adverse events.
Identification of genomic alterations in signaling pathways associated with poor survival in newly diagnosed metastatic prostate cancer (mCSPC) using artificial intelligence (AI).
Authors: Lin Edwin , Wesolowski Sergiusz , Nussenzveig Roberto , McFarland Taylor Ryan , Swami Umang , Maughan Benjamin Louis , Yandell Mark , Agarwal Neeraj
Published: February 2020

169

Background: Although the survival outcomes for patients with mCSPC has improved over the last 5 years, disease remains universally fatal even with improved therapies. Currently, genomic information from the tumor is not taken into account for treatment selection and prognostication. AI is increasingly being used in clinical cancer genomics research. Probabilistic Graphical Models (PGMs) are AI algorithms that capture multivariate, multi-level dependencies in complex patterns in large datasets while retaining human interpretability. We hypothesize that PGMs can establish correlation of baseline somatic genomic alteration with poor survival outcomes in mCSPC. Methods: Eligible men had new mCSPC starting systemic therapy and had tumor genomic profiling done through a CLIA certified lab. Gene alterations with known pathogenicity were grouped into canonical pathways. Multilevel associations between survival, clinical variables (including baseline PSA, Gleason ≥ 8, and visceral metastasis), and genomic signatures (PI3K/AKT/mTOR, HRR, G1/S Cell Cycle, SPOP, TP53, WNT, and MYC) were assessed using a Bayesian Network (BN), and confidence intervals were estimated by bootstrapping. A Kaplan-Meier (KM) survival analysis was performed independently to support the results generated by the BN. Results: Among all variables, only genomic alterations in TP53 and the G1/S pathway were significantly associated with poor overall survival by BN analysis. KM analysis showed concordant results for TP53 (median OS, altered 50 mos vswild-type 84 mos; HR=2.79, 95% CI 1.63 – 4.80; P=0.0002) and G1/S (median OS altered 23 mos vswild-type 73 mos; HR=8.21, 95% CI 3.40 – 19.86; P<0.0001). Conclusions: These hypothesis-generating data reveal genomic signatures associated with poor survival in mCSPC patients. Our results, after external validation, may aid with counseling and treatment selection, as well as patient stratification in future trials in mCSPC.
The effect of abiraterone acetate treatment on CREB and the development of abiraterone acetate resistance in prostate cancer cells.
Authors: Pan Wenting , Zhang Zhouwei , Kimball Hannah , Qiu Fangfang , Lee Gwo-Shu Mary , Choueiri Toni K. , Kantoff Philip W.
Published: February 2020

177

Background: The androgen receptor (AR) remains an essential target in castration resistant prostate cancer (CRPC). Abiraterone acetate (AA), an inhibitor of CYP17A1, is an FDA approved drug for metastatic CRPC. AA can also be converted to the more active metabolite 4-abiraterone in vivo, which blocks multiple steroidogenic enzymes and antagonizes AR. However, not all patients respond to AA and AA resistance ultimately develops in those patients who initially respond. Methods: We established several AA resistant prostate cancer cell lines and performed a comprehensive study of mechanisms involved in the development of AA resistance. The AA-resistant cell lines are phenotypically stable with aggressive invasive features. By RNA-seq and phospho-kinase array screening, we found that the cAMP response element-CRE binding protein 1 (CREB1) is activated in AA resistant cell lines. Results: Over-expression of the wild type CREB1 or treatment with Forskolin desensitizes the cellular response to AA, while over-expressing the mutated CREB1 (S133A, an essential kinase site) did not significantly affect cell sensitivity to AA. Blocking pCREB1 with the CREB inhibitor increased the sensitivity of AA resistant cell lines to AA. The activation of pCREB1 in AA resistant cell lines may potentially activate the CBP/p300 complex. Our data demonstrated that treatment with a low dose of AA strongly synergistic the efficacy of CBP/p300 inhibitors in prostate cancer cell lines. Taken together, we found that AA treatment activates CREB1 and pCREB1 may interact with the CBP/p300 complex, leading to global gene expression alterations, which subsequently result in the development of drug resistance. Conclusions: Our study indicates that AR-targeted treatment potentially fosters de novo genetic and epigenetic alterations associated with progression. A more effective AR-targeted treatment for CRPC may be developed by considering low doses of multiple targets involved in the development of resistance pathways.
Impact of initial treatment selection on clinical outcomes after biochemical failure in radiorecurrent high-risk prostate cancer.
Authors: Levin-Epstein Rebecca , Romero Tahmineh , Wong Jessica Karen , Cook Kiri , Dess Robert Timothy , Spratt Daniel Eidelberg , Moran Brian Joseph , Merrick Gregory Stephen , Tran Phuoc T. , Demanes David Jeffrey , Stish Brad J. , Krauss Daniel J. , Wedde Trude Baastad , Lilleby Wolfgang , Stock Richard , Tward Jonathan David , Steinberg Michael L. , Horwitz Eric M. , Tendulkar Rahul D. , Kishan Amar Upadhyaya
Published: February 2020

208

Background: Treatment of high risk prostate cancer (HRPCa) with external beam radiotherapy (EBRT) plus brachytherapy (BT) boost (EBRT+BT) has been prospectively associated with lower rates of BCR, albeit potentially with increased toxicity, and retrospectively linked to decreased distant metastasis (DM) and PCa-specific mortality (PCSM) compared to EBRT alone. However, it is unclear whether patients who develop BCR following either approach have similar downstream oncologic outcomes. Methods: We identified 706 out of 3820 men with HRPCa treated at 13 institutions from 1998-2015 with EBRT (n=468/2134) or EBRT+BT (n=238/1686) who developed BCR. We compared rates of DM, PCSM, and all-cause mortality (ACM) after BCR between treatment groups using Fine-Gray competing risk regression. Models were adjusted for age, Gleason grade group, initial PSA (iPSA), clinical T stage, time-dependent use of systemic salvage, and interval to BCR using inverse probability of treatment weighting. Results: Median follow-up was 9.9 years from RT and 4.8 years from BCR. Groups were similar in age, iPSA, presence of ≥2 HR features, and median interval to BCR (3.3 years). Most men received neoadjuvant/concurrent androgen deprivation therapy (ADT), 92.5% and 91.0% for EBRT and EBRT+BT, respectively, though for a longer duration with EBRT (median 14.7 vs. 9.0 months, p=0.0012). Local and systemic salvage rates were 2.3% and 36.3% after EBRT, and 2.6% and 43.6% after EBRT+BT, respectively. Initial EBRT+BT was associated with significantly lower rates of DM after BCR (HR 0.48, 95% CI 0.36-0.64, p<0.001). Rates of PCSM and ACM did not significantly differ (HR 0.93, 95% CI 0.67-1.30, p=0.93, and HR 0.8, 95% CI 0.6-1.1, p=0.11, respectively). Conclusions: In this large retrospective series of radiorecurrent HRPCa, initial treatment with EBRT+BT was associated with significantly lower rates of DM after BCR compared with EBRT, despite shorter ADT use and a similar median interval to BCR. Local salvage was widely underutilized in both groups. In the absence of salvage for local failure after EBRT, upfront treatment intensification with BT may reduce DM, though not PCSM or ACM, even after development of BCR.
Preliminary outcomes of a prospective observational study of combinatorial abiraterone acetate/enzalutamide (AA/Enz) and radical radiotherapy (RT) in nonmetastatic node-positive (N+M0) prostate cancer (PCa).
Authors: Tan Mark Ting Le , Woo Wai Yee , Tuan Jeffrey , Tan Terence Wee Kiat , Wang Michael Lian Chek , Chua Eu Tiong , Looi Wen Shen , Li Youquan , Nei Wen Long , Wang Hai-Tao , Chimmiri Anusha , Sim Yen Ling Adelene , Ong Enya Hui Wen , Khor Li Yan , Yeong Joe Poh Sheng , Tan Chien sheng , Tay Kae-Jack , Lee Lui Shiong , Kanesvaran Ravindran , Chua Melvin Lee Kiang
Published: February 2020

227

Background: Treatment paradigm for N+M0 PCa has evolved, with the advent of multiple options for upfront AA/Enz or RT in combination with conventional hormonal therapy (HT). However, the optimal treatment protocol remains undefined. We therefore conducted a prospective observational study of combination AA/Enz+RT in N+M0 PCa patients. Methods: Patients with biopsy-proven adenocarcinoma of the prostate and N+M0 by imaging (68Ga-PSMA-PET or whole body MRI) were included. Exclusion criteria were 1) ECOG ≥2; 2) severe comorbidities; 3) cardiac event of <6 mo interval. Treatment protocol involved 18 mo of AA (1000 mg with 5 mg prednisolone once daily)/Enz (160 mg once daily)+HT (LHRH agonist/antagonist) in combination with RT to pelvis (54 Gy with simultaneous boost of 60-66 Gy in 27 fr) and prostate (78 Gy/39 fr); RT commenced 1-3 mo upon initiation of AA/Enz. Primary endpoint of this analysis was PSA of ≤0.1 ng/ml at 12 mo. Results: From Jun 2017-Sep 2019, 13 men were recruited; median follow-up duration was 14.0 mo (range 3.0-28.0 mo). Median age of the cohort was 67.0 y (IQR 61.0 – 69.0 y); 84.0% of men had GS8-10 disease, and median number of cN+ nodes was 2 (range 1-5 nodes). 11 received AA, and 2 received Enz. 53.8% (N = 7) and 69.2% (N = 9) of patients achieved a PSA nadir of ≤0.1 ng/ml at 6.0 and 12.0 mo, respectively; this contrasts against a propensity-matched cohort (N = 27) treated by HT+RT alone (33.3% and 51.9%, respectively). No biochemical recurrence was recorded at the time of analysis. 3 and 2 acute ≥G2 GU and GI toxicities were reported during RT. Late ≥G2 GU toxicities were observed in 2 men (G2 frequency). 2 patients experienced G2 fatigue and one with G2 transaminitis secondary to AA, with dose reduction. Germline genetic profiling with whole exome sequencing revealed two patients (15.4%) with BRCA2 frameshift mutations; interestingly, GU/GI RT toxicities were not observed in these patients. Conclusions: Our preliminary results suggest that combinatorial AA/Enz and high dose RT is tolerated and can induce a pronounced PSA response in low volume N+M0 PCa.
Characterization of metastatic spinal cord compression from prostate cancer.
Authors: Wang Jianbo
Published: February 2020

248

Background: Spinal cord compression (SCC) is one of the most debilitating conditions in metastatic prostate cancer patients (pts). A comprehensive analysis of pts could shed lights on predisposing factors and help with devising new ways for early detection and prompt treatment. Methods: 52 pts with magnetic resonance imaging-confirmed metastatic SCC from prostate cancer were identified at MD Anderson Cancer Center. Characteristics including age, anatomical site, Gleason score, overall survival(OS), time to diagnosis of SCC, underlying gene mutations, numbers of bone metastasis, number of lines of treatment and clinical outcome were analyzed. Results: 96.15% of SCC occurred in thoracic spine in comparison to 74% as reported previously. At the time of diagnosis of SCC, median age is 70 years, median OS is 1537 days, median time to development of SCC is 1222.5 days, median lines of systemic treatment is 4, median PSA value is 66.4, 100% of pts have a Gleason score above 7, 94% of pts have >4 bone metastasis, roughly 20% of pts had visceral metastases. 55% of 9 evaluable pts harbored P53 gene mutation. About 80% of pts received radiation treatment; 17% of pts received surgery; 49% of pts had fair clinical outcome after treatment (Table). Conclusions: The observed predominance of SCC in thoracic spine (96.15%) suggests an underlying mechanism governing development of SCC in preferential sites. Further research to define this mechanism will help with prevention, detection and treatment of SCC. Additionally, characterized potential predictive factors (Gleason score≥7, >4 bone mets, presence of P53 mutation) could be used to develop an algorithm to improve the management of SCC.[Table: see text]