bluuebunny/crossref_metadata_2025 huggingface dataset:
Current status of periodontal disease in adults in Takahagi, Japan: a cross-sectional study
Authors: Sekino Satoshi , Takahashi Ryoichi , Numabe Yukihiro , Okamoto Hiroshi
Published: February 2020

Background

To date, a few studies have documented the detailed periodontal conditions of a Japanese population. It is important to know if the awareness of Japanese nationals and dentists regarding oral hygiene and prevention of periodontal disease have improved when compared with the past in Japan for the development of future scenarios regarding prevention. The aim of this study was to investigate the severity, prevalence, and extent of periodontal disease in the adult population of the city of Takahagi, Japan. Results were also compared with those of an epidemiological study performed in Japan in the 1980s.

Methods

A total of 582 (aged 20 to 89 years) randomly sampled Takahagi residents answered a comprehensive questionnaire and participated in clinical examinations.

Results

The mean percentages of tooth surfaces harboring plaque and exhibiting BOP were 59.5 ± 20.9% and 31.1 ± 21.1%, respectively. The mean PPD and CAL were 2.5 ± 0.5 mm and 2.9 ± 1.0 mm, respectively. Compared with results of the 1980s survey, the mean percentages of plaque and bleeding on probing were lower in the current population. The mean CAL and prevalence of attachment loss of ≥5 mm in some age groups were higher in the present study than in the 1980s study. There were no statistically significant differences with respect to mean probing depth between the 1980s and current age groups.

Conclusions

Periodontal disease was still prevalent in the current Japanese population, even though some improvement occurred. Proper public health programs therefore need to be established.
Development in Danish medical students’ empathy: study protocol of a cross-sectional and longitudinal mixed-methods study
Authors: Assing Hvidt E. , Søndergaard J. , Hvidt N. C. , Wehberg S. , Büssing A. , Andersen C. M.
Published: February 2020

Background

Clinical empathy has been associated with positive outcomes for both physicians and patients such as: more accurate diagnosis and treatment, increased patient satisfaction and compliance, and lower levels of burnout and stress among physicians. International studies show mixed results regarding the development of empathy among future physicians associating medical education with decline, stability or increase in empathy levels. These mixed results are due to several study limitations. In Denmark, no investigation of Danish medical students’ empathy trajectory has yet been conducted wherefore such a study is needed that optimizes the study design of earlier studies.

Methods

The aim of the study is to examine and analyze empathy levels and empathy changes among Danish medical students from the four medical faculties in Denmark, employing a cross-sectional and longitudinal mixed-methods design including a control group of non-medical students. By supplementing cross-sectional and longitudinal questionnaire studies with a focus group interview study it is the aim to identify and analyze factors (including educational) that are perceived by medical students to influence the development of empathy and its expression in clinical care.

Discussion

The results of the study will provide insight into the trajectory of medical students’ empathy and in undergraduate and graduate students’ experiences with and perceptions of empathy development. In addition, the study will provide evidence to support further research on how targeted educational programmes can best be designed to educate empathic and patient-centered physicians.
Identification, molecular characterization and expression of aminopeptidase N-1 (APN-1) from Anopheles stephensi in SF9 cell line as a candidate molecule for developing a vaccine that interrupt malaria transmission
Authors: Dadgar Pakdel Javad , Zakeri Sedigheh , Raz Abbasali , Dinparast Djadid Navid
Published: February 2020

Background

According to the World Health Organization reports, billions of people around the world are at risk for malaria disease and it is important to consider the preventive strategies for protecting the people that are living in high risk areas. One of the main reasons of disease survival is diversity of vectors and parasites in different malaria regions that have their specific features, behaviour and biology. Therefore, specific regional strategies are necessary for successful control of malaria. One of the tools that needs to be developed for elimination and prevention of reintroduction of malaria is a vaccine that interrupt malaria transmission (VIMTs). VIMT is a broad concept that should be adjusted to the biological characteristics of the disease in each region. One type of VIMT is a vector-based vaccine that affects the sexual stage of Plasmodium life cycle. According to recent studies, the aminopeptidase N-1 of Anopheles gambiae (AgAPN-1) is as a potent vector-based VIMT with considerable inhibition activity against the sexual stage of Plasmodium parasite.

Methods

Systems for rapid amplification of cDNA ends (3ʹ-RACE) and genome walking methods were used for sequence determination of apn-1 gene from Anopheles stephensi and distinct bioinformatics software were used for structural analysis. AsAPN-1 was expressed in Spodoptera frugiperda (Sf9) insect cell line using the baculovirus expression system. Recombinant AsAPN-1 was purified under the hybrid condition and its biological activity was assayed.

Results

Asapn-1 gene and its coded protein from An. stephensi were characterized for the first time in this study. Subsequently, the structural features and immunological properties of its coded protein were evaluated by in silico approaches. Enzymatic activity of the recombinant AsAPN-1, which was expressed in Sf9 insect cell line, was equal to 6 unit/μl.

Conclusions

Results of this study revealed that AsAPN-1 is very similar to its counterpart in An. gambiae. In silico evaluation and fundamental data which are necessary for its evaluation as a VIMT-based vaccine in the next steps were acquired in this study and those could be useful for research groups that study on malaria vaccine for countries that An. stephensi is the main malaria vector there.
Group plus “mini” individual pre-test genetic counselling sessions for hereditary cancer shorten provider time and improve patient satisfaction
Authors: Hynes Jaclyn , MacMillan Andrée , Fernandez Sara , Jacob Karen , Carter Shannon , Predham Sarah , Etchegary Holly , Dawson Lesa
Published: February 2020

Background

Genetic counselling (GC) is an integral component in the care of individuals at risk for hereditary cancer predisposition syndromes (CPS). In many jurisdictions, access to timely counselling and testing is limited by financial constraints, by the shortage of genetics professionals and by labor-intensive traditional models of individual pre and post-test counselling. There is a need for further research regarding alternate methods of GC service delivery and implementation. This quality improvement project was initiated to determine if pretest group GC followed immediately by a ‘mini’ individual session, would be acceptable to patients at risk for hereditary breast and colon cancer.

Methods

Patients on waitlists for GC at the Provincial Medical Genetics Program in St. John’s, NL, Canada (n = 112), were contacted by telephone and offered the option of a group counselling session (GGC), followed by a “mini” individual session, versus (TGC) traditional private appointments. GGC sessions consisted of a cancer genetics information session given to groups of 6–20 followed by brief 20 min “mini” individual sessions with the patient and genetic specialist. TGC individual appointments provided the same cancer genetics information and counselling to one patient at a time in the classic model. All but 2 participants selected group+mini session. A de-identified confidential 12-item, Likert scale survey was distributed at the conclusion of mini-sessions to measure perceptions of GGC and satisfaction with this counselling model.

Results

Sixty participants completed questionnaires. The majority of participants strongly agreed that they were comfortable with the group session (58/60); the explanation of cancer genetics was clear (54/59); they understood their cancer risks (50/60); and they would recommend such a session to others (56/59). 38/53 respondents disagreed or strongly disagreed that they would prefer to wait for a traditional private appointment. All 5 participating genetic counselors reported a preference for this model. At the end of the pilot project, the waitlist for counselling/testing was reduced by 12 months.

Conclusions

Group pre-test genetic counselling combined with immediate “mini” individual session is strongly supported by patients and reduces wait times. Additional formal investigation of this approach in larger numbers of patients is warranted.
Low dose of extracellular vesicles identified that promote recovery after ischemic stroke
Authors: Otero-Ortega Laura , Laso-García Fernando , Frutos Mari Carmen Gómez-de , Diekhorst Luke , Martínez-Arroyo Arturo , Alonso-López Elisa , García-Bermejo María Laura , Rodríguez-Serrano Macarena , Arrúe-Gonzalo Mercedes , Díez-Tejedor Exuperio , Fuentes Blanca , Gutiérrez-Fernández María
Published: February 2020

Background

Mesenchymal stem cell-derived extracellular vesicles (EVs) are one of the most promising therapeutics in protective and/or regenerative therapy in animal models of stroke using a dose of 100 μg. However, whether EVs dose is related to outcomes is not known. This study aimed to identify the optimal effective dose of EVs from adipose tissue-derived mesenchymal stem cells that promote functional recovery in subcortical stroke.

Materials and methods

For this purpose, various doses of EVs were tested in an in vitro oxygen-glucose deprivation (OGD) model of oligodendrocytes and neuronal ischemia. At least 50 μg of EVs were necessary to induce proliferation and differentiation of oligodendrocyte and neurons in OGD conditions. For in vivo study, rats were subjected to subcortical stroke and various doses (50 μg, 100 μg, or 200 μg) of EVs were intravenously administered after 24 h.

Results

All the animals in the EV groups showed significant improvement in functional tests, with an increase in tract connectivity and brain repair-associated markers, and a decrease in cell death and in astrocyte-marker expression. Cell proliferation was increased in the groups receiving 50 μg and 100 μg doses. Only the 50-μg dose was associated with significant increases in brain-derived neurotrophic factor expression.

Conclusion

In conclusion, 50 μg of EVs appears to be the minimal effective dose to enhance protection, brain repair, and recovery in subcortical ischemic stroke.
Ecological perspectives on variable retention forestry
Authors: Martínez Pastur Guillermo J. , Vanha-Majamaa Ilkka , Franklin Jerry F.
Published: February 2020

Forest management globally affects the ecosystem services, especially those related to ecosystem functioning and biodiversity conservation, by altering forest structure and composition. The degree of alteration was related to the intensity and type of harvesting; therefore, the major silvicultural challenge is to develop alternatives to mitigate climate change and maintain forest functions and biodiversity while also providing acceptable levels of timber production. Variable retention forestry (VRF) is a highly flexible concept, with continuity of forest cover, structure, function, and species composition, thereby supporting multiple economic, environmental, and cultural goals. This special issue provides an overview of the concepts and applications related to VRF implementation around the world. It shows that VRF has been applied globally for several decades, with varying levels and retention types, depending on local conditions and the economic importance of forestry. The challenges of VRF seem to differ to some extent on different continents, yet the general aims have been accepted in most of the continents. VRF has been successful in mitigating many effects of intensive harvesting, though in some forests of the world, the retention levels are too low to maintain acceptable levels of biodiversity and ecosystem functions. We conclude that an active collaboration between scientists and forest practitioners is needed to realize all of the opportunities provided by VRF in solving global forestry-related issues.
A text message intervention for quitting cigarette smoking among young adults experiencing homelessness: study protocol for a pilot randomized controlled trial
Authors: Tucker Joan S. , Pedersen Eric R. , Linnemayr Sebastian , Shadel William G. , DeYoreo Maria , Zutshi Rushil
Published: February 2020

Background

Cigarette smoking is much more prevalent among young people experiencing homelessness than in the general population of adolescents and young adults. Although many young homeless smokers are motivated to quit, there are no empirically-evaluated smoking cessation programs for this population. It is important that any such program address the factors known to be associated with quitting-related outcomes among homeless young people, to provide ongoing support in a way that accommodates the mobility of this population, and does not rely on scarce service provider resources for its delivery. The objective of this project is to develop and pilot test a text messaging-based intervention (TMI), as an adjunct to brief cessation counseling and provision of nicotine patches, to help homeless young people who want to quit smoking.

Methods/design

This pilot study will utilize a cluster cross-over randomized controlled design with up to 80 current smokers who desire to quit and are recruited from three drop-in centers serving young people experiencing homelessness in the Los Angeles area. All participants will be provided with a minimum standard of care: a 30-min group-based smoking cessation counseling session and free nicotine replacement. Half of these smokers will then also receive the TMI, as an adjunct to this standard care, which will provide 6 weeks of ongoing support for quitting. This support includes continued and more intensive education regarding nicotine dependence, quitting smoking, and relapse; does not require additional agency resources; can be available “on demand” to users; and includes features to personalize the quitting experience. This study will investigate whether receiving the TMI adjunct to standard smoking cessation care results in greater reductions in cigarette smoking compared to standard care alone over a 3-month period.

Discussion

This study has the potential to address an important gap in the clinical research literature on cigarette smoking cessation and provide empirical support for using a TMI to provide ongoing assistance and support for quitting among young smokers experiencing homelessness.

Trial registration ClinicalTrials.gov Identifier NCT03874585. Registered March 14, 2019, https://clinicaltrials.gov/ct2/show/record/NCT03874585.
Effects of dietary valine supplementation during late gestation on the reproductive performance and mammary gland development of gilts
Authors: Che Long , Xu Mengmeng , Gao Kaiguo , Wang Li , Yang Xuefen , Wen Xiaolu , Xiao Hao , Jiang Zongyong
Published: February 2020

Background

Mammary gland development during late gestation in gilts is a major factor that alters the composition of colostrum and growth performance of piglets. Plasma valine is taken up and metabolized extensively by the mammary gland; however, the effects of valine on mammary gland development during late gestation are still unclear. Thirty primiparous gilts were divided into three treatment groups (n = 10) and received one of the three diets starting on day 75 of gestation until the day of farrowing. The total dietary valine to lysine ratio of the three diets was 0.63 (LV), 0.73 (MV), and 0.93 (HV), respectively.

Results

Dietary valine supplementation during late gestation did not affect (P > 0.05) the litter size and weight at farrowing; however, the piglet weight and average daily gain at weaning were linearly increased (P < 0.05) as the dietary valine increased. The highest piglet weight at weaning was observed when the gilts were provided the HV diet. Dietary valine supplementation linearly elevated (P < 0.05) protein, fat and solids-not-fat and some free amino acids content in colostrum. The concentration of prolactin in plasma of gilts was linearly increased in response to valine supplementation at days 1 and 10 of lactation (P < 0.05). Furthermore, with increasing dietary valine allowance, a linear increase (P < 0.05) was observed in the area of the lumen of alveolus and the content of DNA, RNA, and total protein in the mammary tissues at day 1 of lactation. Moreover, the protein expression of cyclin D1, p-mTOR, p-S6, and p-4EBP1 was also linearly increased (P < 0.05) in the mammary tissue at day 1 of lactation. However, no difference (P > 0.05) was observed in the indices related to mammary development and the mTOR signaling pathway at day 21 of lactation.

Conclusion

The results revealed that increasing the total dietary valine to lysine ratio to 0.93 during late gestation significantly enhances the piglet weight and average daily gain at weaning probably due to improved development of mammary gland.
Improving collapsibility robustness of an EPS-CD by means of simulation and six sigma
Authors: Costas Muñoz Didac , Majzel Michał
Published: February 2020

Steering columns for column assist Electric Steering are one of the main elements of the passive safety restraint system in a passenger vehicle. It is designed to collapse applying an optimized ride down force to reduce chest and head injuries of the driver during a frontal crash event, making this requirement one of the most important ones for its development. The system crash response is generated by several elements and interfaces due to the fact of many other different product requirements that a steering column must fulfill. This could lead into a complex validation process throughout the development, as it is needed to integrate the product into the vehicle in order to meet the passive safety requirements. As part of ZF lean Validation approach a new method has been developed to improve the system robustness in ZF Active safety division by means of virtual simulation and six sigma disciplines. This resultant method is also applicable for a model based development process and also contributes to improve frontloading development techniques. An analysis of variance has been done using a correlated virtual model for crash simulation, where the main parameters of the system are known (normally the case when same product generation is reused in a new vehicle). Obtaining as a result of the analysis the regression equation of the system response. This equation defines and quantifies the importance of each factor, and consequently is defining the component contribution and how to develop a column from bottom to top. Moreover, as a second step, a Monte Carlo analysis has been applied using the equation obtained generating statistical results for a number of cases (based in the design tolerances) not manageable from the hardware testing perspective neither from the finite elements methods. In that project Monte Carlo analysis has been applied for 100,000 cases generating response confident intervals instead of the classic FEM deterministic response where only the nominal case is considered.
Survival outcomes and risk group validation from SWOG S0925, a randomized phase II study of androgen deprivation (AD) +/- cixutumumab, in new metastatic hormone-sensitive prostate cancer (mHSPC).
Authors: Wong Risa Liang , Duong Mai T. , Tangen Catherine , Agarwal Neeraj , Cheng Heather H. , Vogelzang Nicholas J. , Hussain Maha H. A. , Thompson Ian Murchie , Quinn David I. , Yu Evan Y.
Published: February 2020

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Background: Cixutumumab, a monoclonal antibody targeting insulin-like growth factor I receptor, did not improve rate of undetectable PSA at 28 weeks when combined with AD in the randomized phase II SWOG S0925 trial for patients with new mHSPC. We now present mature radiographic progression-free survival (rPFS) and overall survival (OS) analyses, along with pre-specified secondary and exploratory endpoints. Methods: We used Kaplan-Meier curves to analyze OS, rPFS, and castration resistance-free survival by treatment arm, disease volume (as per CHAARTED), and risk (as per LATITUDE). We explored differences in survival by treatment arm via covariate-adjusted Cox proportional hazard models adjusted for disease volume and risk. Results: The trial enrolled 210 patients, 105 per treatment arm. Median follow-up was 5.3 years. No difference was seen between treatment arms in OS (HR 1.01 [0.70-1.45]; p=0.97), rPFS (HR 1.17 [0.85-1.60]; p=0.35), or castration resistance-free survival (HR 1.02 [0.75-1.41]; p=0.88). At baseline, 105/198 (53.0%) patients had high risk and 119/210 (56.7%) had high volume disease. 17.3% of high volume patients were classified as low risk and 15.9% of low volume patients were classified as high risk; together, 16.7% of patients had discordant classification of high or low category for risk and volume. Adjusting for risk or volume yielded no differences in OS between arms. Inferior survival was observed in high risk (HR 1.89 [1.29-2.80]; p=0.001) and high volume (HR 2.75 [1.84-4.10]; p<0.0001) disease. Disease volume was a better fit to survival data than risk (AIC 878.3 vs. 889.2). Compared to patients achieving undetectable PSA at 28 weeks, inferior survival was observed in patients whose PSA was >0.2 to ≤4.0 ng/mL (HR 3.72 [1.99-6.95]; p<0.0001) or >4.0 ng/mL (HR 7.13 [4.24-11.9]; p<0.0001). Conclusions: In new mHSPC, adding cixutumumab to AD did not improve survival measures. Baseline risk and disease volume carried prognostic value for this distinct trial population, though disease volume was a better predictor of survival. PSA treatment response was a strong intermediate endpoint for survival. Clinical trial information: NCT01120236.
Randomized phase II study of olaparib with or without cediranib in men with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Kim Joseph W. , McKay Rana R. , Taplin Mary-Ellen , Davis Nancy B. , Monk Paul , Appleman Leonard Joseph , Lara Primo , Vaishampayan Ulka N. , Zhang Jingsong , Paul Asit K. , Bubley Glenn , Van Allen Eliezer Mendel , Huang Ying , Zhang Zhenwei , Loda Massimo , Shapiro Geoffrey , LoRusso Patricia , Ivy S. Percy , Petrylak Daniel Peter
Published: February 2020

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Background: Cediranib, a vascular endothelial growth factor receptor tyrosine kinase inhibitor, suppresses expression of BRCA1, BRCA2, and RAD51 and increases sensitivity of tumors to poly (ADP-ribose) polymerase (PARP) inhibitors in vitro. Olaparib, a PARP inhibitor, demonstrates clinical efficacy in men with DNA repair deficient, mCRPC. We therefore performed a randomized phase 2 trial comparing olaparib with or without cediranib in men with mCRPC. Methods: Men with a minimum of one prior line of systemic therapy for mCRPC were randomized 1:1 to receive cediranib 30mg po daily plus olaparib 200mg po BID (Arm A) or olaparib 300mg BID alone (Arm B). At radiographic progression, patients (pts) in Arm B could crossover to Arm A. The primary endpoint was radiographic progression-free survival (rPFS). Secondary endpoints were objective response rate (ORR) and PSA50 decline rate (PSA50). Tumor biopsy specimens were obtained for biomarker analyses pre- and on-treatment. Results: Baseline characteristics of the 90 pts enrolled are summarized below. The median rPFS was 11.1 versus 4.0 months in Arm A and Arm B, respectively (Hazard Ratio 0.54, 95% CI 0.317, 0.928, p=0.026). Trends toward a higher ORR (19% and 12%), Disease Control Rate (Stable Disease + Partial Response) (77% and 64%,) and PSA50 (29% and 17%) were observed in Arm A compared to Arm B, respectively. Thirteen pts in Arm B crossed over to Arm A. One pt had a PR after crossover. Grade 3/4 adverse events (G3/4 AEs), irrespective of attribution, occurred in 77% and 58% of Arm A and Arm B pts, respectively. G3/4 AEs occurring in >10% of pts were hypertension (32%), fatigue (23%) and diarrhea (11%) in Arm A, and anemia (16%) and lymphopenia (11%) in Arm B. Conclusions: The cediranib/olaparib combination significantly improves rPFS in unselected, mCRPC pts. AEs were manageable. Analyses of mutation status in homologous recombination DNA repair genes are pending and will be key in interpreting the data. Clinical trial information: NCT02893917. [Table: see text]
A pilot study of docetaxel and carboplatin for treatment of patients with mCRPC containing biallelic inactivation of genes in the BRCA1/2 pathway.
Authors: Cheng Heather H. , DeJong Makayla , Yu Evan Y. , Gulati Roman , Rettig Matthew , Higano Celestia S. , Nelson Peter , Pritchard Colin C. , Montgomery Robert B.
Published: February 2020

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Background: Despite new treatments, metastatic castration resistant prostate cancer (mCRPC) remains ultimately lethal. Upwards of 25% of mCRPC tumors have alterations in homologous recombination DNA repair (HRD) genes, most frequently BRCA2. Retrospective data suggest addition of the DNA damaging agent carboplatin to standard docetaxel for patients with mCRPC whose tumors have biallelic inactivation of BRCA2 may be effective. Methods: In this prospective, pilot single-arm phase 2 study, we assess response to the combination of docetaxel 60mg/m2 and carboplatin AUC 5 IV q21 days in patients with mCRPC whose tumors have evidence of biallelic inactivation of BRCA1, BRCA2 or ATM and have progressed after any prior treatment, including prior docetaxel and/or PARP inhibitor (PARPi). The primary endpoint is rate of ≥50% PSA decline from baseline (PSA50). With H0 of PSA50 of 26%, 14 patients will provide 80% power to conclude H1 of PSA50 of 60% based on Simon's 2-stage design with 1-sided α = 5%. Secondary endpoints include PSA30, response duration, time to progression and correlative studies. Biallelic inactivation of other HRD-related genes were included at investigators’ discretion. Results: The study opened in Jan 2016 and has enrolled 8/14 (57%) of patients plus 5 patients with other HRD-related genes. 6/13 (46%) treated pts had grade 3 expected AEs, and no grade 4-5 AEs were observed. To date, 7/8 (88%) of pts with biallelic inactivation of BRCA1, BRCA2 and ATM (Table) and 10/13 (77%) of all pts achieved a PSA50 (other HRD-related genes include CDK12, CHD1, MRE11A and PALB2). Updated results will be reported at final presentation. Conclusions: Addition of carboplatin to docetaxel appears to be well-tolerated and effective for patients with mCRPC whose tumors have biallelic inactivation in selected HRD genes such as BRCA2, including those with prior treatment with PARP inhibitor. Clinical trial information: NCT02598895. [Table: see text]
Assessing different sequencing regimens of atezolizumab (atezo) and sipuleucel-T (sipT) in patients who have asymptomatic or minimally symptomatic metastatic castrate-resistant prostate cancer.
Authors: Dorff Tanya B. , Acoba Jared David , Pal Sumanta K. , Scholz Mark C. , Tamura David Jon , Huang Jeffrey , Rosser Charles Joel
Published: February 2020

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Background: Combining an immune checkpoint inhibitor with a vaccine may leverage complementary mechanisms of action for treatment of mCRPC. We present a randomized study evaluating atezo (anti PD-L1) + sipT in patients (pts) with mCRPC. Methods: Pts who met standard criteria for sipT were randomized to receive (Arm1): atezo 1200 mg IV every 3 weeks for 2 doses then SipT every 2 weeks for a total of 3 infusions (induction) followed by maintenance atezo every 3 weeks until toxicity or loss of clinical benefit or (Arm2) sipT every 2 weeks for a total of 3 infusions followed by atezo 1200 mg IV every 3 weeks for 2 doses (induction) followed by maintenance atezo every 3 weeks until same. The primary endpoint was safety (CTCAE v4.0); secondary endpoints were PFS by PCWG2, objective response (modified RECIST1.1) and systemic immune responses after induction. Results: 37 pts, median age 75 [range 53–86] enrolled; median prior treatments was 4 [range 1-8] and 76% had ECOG PS = 0. Three patients did not complete induction (1 withdrew consent, 1 due to toxicity, and 1 progressed). There were no delays in induction dosing for Arm1 but 9 delays (1 week) for Arm2 (collection failure=6, holiday=2 and other=1). There were no grade 5 toxicities attributed to study drugs. 1 grade 4 toxicity was noted in each arm (Arm 1 bronchitis, Arm 2 hypotension). Eight grade 3 toxicities were noted in arm 1 (hyponatremia, pulmonary embolus x3, bone pain, hypophosphatemia, shock, fall with tooth fracture), while 4 grade 3 toxicities were noted in arm 2 (anemia, hypertension x 2, pneumonia). None of the grade 3 or 4 AEs were immune related. AEs led to discontinuation in 5 patients in Arm1 and 1 patient in Arm2. In Arm1 11 patients were RECIST evaluable at 6 months, with 1 PR (5.8%), 4 SD (23.5%) and 6 PD. In Arm2 13 patients were evaluable, with 1 PR (5.8%), 6 SD (32%) and 6 PD. 10/24 evaluable patients (41.7%) had stable disease at 6 months. Conclusions: The combination of atezo with sipT was safe, AEs consistent with the agents as monotherapy, with no immune related AEs. 2 pts had RECIST PR and 10 had stable disease at 6 months, more than expected with monotherapy. Clinical trial information: 03024216.
Checkpoint kinase inhibition in prostate cancer cells resistant to poly ADP-ribose polymerase inhibitors.
Authors: Atiq Mohammad Omar , Chakraborty Goutam , Nandakumar Subhiksha , Mazzu Ying Zhang , Stopsack Konrad H. , Yoshikawa Yuki , Lee Gwo-Shu Mary , Kantoff Philip W.
Published: February 2020

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Background: Poly ADP-ribose polymerase inhibitors (PARPi) have shown promise in the treatment of metastatic castration-resistant prostate cancer patients with DNA damage response defects . The phase 3 PROfound trial showed olaparib delayed the time to radiographic progression or death as compared with abiraterone or enzalutamide. In addition to olaparib, three other PARPi are in Phase 3 trials in prostate cancer (PC): rucaparib, talazoparib, and niraparib. Despite responses, resistance is common and treatment options for PARPi-resistant patients are limited. In this study, we observed de novo activation of checkpoint kinases (CHEK) in talazoparib-resistant (TR) PC cells. Therefore, we hypothesized that targeting CHEK may mitigate resistance to PARPi in PC. Methods: We developed TR human prostate cancer PC3 (low BRCA2 protein due to heterozygous deletion of BRCA2) cells. We performed phosphoproteomic analysis to identify possible mechanisms of talazoparib resistance in PC3 cells and validated the results with Western blot. Results: TR-PC3 cells proliferated slower and had a significant increase in the phosphorylation of CHEK2 compared to parental (p) PC3. Treatment with a CHEK2-selective inhibitor, CCT241533, did not affect cell growth in TR-PC3 cells. Conversely, treatment with a CHEK 1/2 inhibitor, prexasertib, led to significant cell growth inhibition in TR-PC3 at a much lower IG 50% concentration compared to pPC3. RNAi-mediated knockdown validated the superior efficacy of combined CHEK1 and CHEK2 inhibition since this combination produced the greatest cell growth inhibition seen in both TR-PC3 and de novo PARPi-resistant p22RV1. Treatment of pPC-3 and p22RV1 with combinations of talazoparib and prexasertib showed greater cell growth inhibition compared to either drug alone. Conclusions: Resistance to PARPi in PC cells with deletion of BRCA2 may potentially be overcome with CHEK inhibition. Moreover, our preliminary data suggested that the effect of PARPi and CHEK inhibitors on PARPi/CHEK inhibitor-naïve PC cells was greatest when used together, indicating that patients with PC may experience greatest anti-tumor activity of the two drugs when they are used in combination.
Multiregion expression profiling of prostate cancer from men randomized in the STAMPEDE trial: Stage I results of a multistage biomarker analysis.
Authors: Grist Emily , Parry Marina , Mendes Larissa , Lall Sharanpreet , Kudahetti Sakunthala C. , Santos Vidal Sara , Atako Nafisah B. , Anjum Mazna , Ishaq Sofeya , Todorovic Tamara , Huang Huei-Chung , Waugh David , Sweeney Christopher , Clarke Noel , James Nicholas D. , Berney Daniel , Parmar Mahesh K. B. , Davicioni Elai , Brown Louise C. , Attard Gerhardt
Published: February 2020

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Background: The PAM50 gene expression classifier stratifies localized prostate cancer into luminal A/B and basal subtypes: luminal A have superior prognosis compared to luminal B and basal. Drug response scores built using the NCI-60 cell lines predict luminal subtypes are more taxane sensitive compared to basal; luminal B is hypothesized to be the most proliferative and hormone responsive compared to the basal subtype. The STAMPEDE trial provides a framework to validate prognostic and predictive associations of the PAM50 test in tumors from men randomized to androgen deprivation therapy (ADT) alone or with docetaxel or abiraterone. We here present multi-region whole-transcriptome expression array data at completion of Stage I designed to confirm the feasibility of molecular subtyping STAMPEDE tumor blocks. Methods: In collaboration with Decipher Biosciences we generated clinical-grade whole-transcriptome expression array data (Human Exon 1.0 ST GeneChip) performed to CLIA standards on mRNA (from three 10 micron slides) from cancer-enriched areas and applied the PAM50 classifier. Results: As of January 2019, we retrieved blocks from 2012 men from an ITT population of 3879. For Stage I feasibility assessment, we sectioned diagnostic trans-rectal biopsies of the prostate from 50 randomly selected men treated with ADT. We extracted mRNA from 109 cores; > 92% cores (101) from > 94% patients (47/50) passed quality control. The prevalence of PAM50 subtypes was: 31 basal cases (62%), 18 luminal B (36%) and 1 luminal A (2%). 26 cases (52%) were identified as ETS-related gene (ERG) positive. More than one core was interrogated from 35/50 cases (range: 1-6 cores). ERG positive cores were homogeneous across cores from the same patient but PAM50 subtyping identified intra-patient variability across cores from the same case. Conclusions: We confirm the feasibility of expression profiling STAMPEDE tumor blocks and identify a low prevalence of luminal A subtype. Whereas ERG status is consistent across multiple cores, basal and luminal subtypes co-exist in the same prostate. Multi-region analysis will enable further refinement for individual patient classification.
AR-V7 and prediction of benefit with taxane therapy: Final analysis of PROPHECY.
Authors: Armstrong Andrew J. , Luo Jun , Anand Monika , Antonarakis Emmanuel S. , Nanus David M. , Giannakakou Paraskevi , Szmulewitz Russell Zelig , Danila Daniel Costin , Healy Patrick , Berry William R. , Wenstrup Rick , Scher Howard I. , Tagawa Scott T. , George Daniel J. , Halabi Susan
Published: February 2020

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Background: We previously found that men with AR-V7 (+) poor risk mCRPC have a low chance of benefit with abiraterone or enzalutamide. The benefits of subsequent taxane chemotherapy based on AR-V7 status may help inform treatment decisions. Methods: We conducted a multicenter prospective study of men with poor risk mCRPC (PROPHECY, NCT02269982) starting Abi or Enza and subsequent taxane chemotherapy. AR-V7 status from CTCs was assessed before abi/enza and again before taxane chemotherapy using the Epic nuclear protein assay or the Johns Hopkins Adnatest assay. The primary endpoint was to test the association of AR-V7 with radiographic/ clinical progression free survival (PFS) and OS with taxane chemotherapy, using the proportional hazards model, adjusting for Cell Search enumeration and clinical risk score. Results: We enrolled 118 men with mCRPC starting Abi/Enza; of these, 51 were evaluable with CTC AR-V7 testing and received subsequent taxane chemotherapy. With 50 PFS events, see table for final results. While AR-V7 positivity was associated with worse outcomes overall, AR-V7 (+) patients had similar PFS, OS, and confirmed >50% PSA declines adjusting for CTC enumeration and clinical prognostic factors. Concordance between the two AR-V7 assays pre-taxane was 0.78 (kappa 0.46). AR-V7 positivity increased at progression on abi/enza, but not following taxane chemotherapy. Conclusions: Men with AR-V7 positive mCRPC have poor outcomes, but may benefit from taxane chemotherapy after progression on abi/enza. AR-V7 may provide a helpful predictive biomarker to guide treatment with a second AR inhibitor or a taxane. Clinical trial information: NCT02269982. [Table: see text]
Prognostic value of novel inflammation index for patients with metastatic castration-resistant prostate cancer.
Authors: Yamada Yasutaka , Sakamoto Shinichi , Rii Junryo , Yamamoto Satoshi , Kamada Shuhei , Imamura Yusuke , Nakamura Kazuyoshi , Komiya Akira , Nakatsu Hiroomi , Ichikawa Tomohiko
Published: February 2020

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Background: Inflammation process has been reported to be involved in the development of several types of cancer. Recently, a lung immune prognostic index (LIPI) combining with derived neutrophils/ (leukocytes minus neutrophils) ratio (dNLR) and lactate dehydrogenase (LDH) level was proposed as an useful prognostic marker for advanced non-small cell lung cancer. However, the prognostic value of this index has not been evaluated and we aimed to validate its prognostic ability in metastatic castration resistant prostate cancer (mCRPC). Methods: Clinical data of 248 mCRPC patients were retrospectively collected from multi-institutions. We obtained the clinical factors including age, PSA, Gleason score (GS), tumor stage, white blood cell (WBC) count, dNLR, hemoglobin (Hb), LDH, alkaline phosphatase (ALP) and C-reactive protein (CRP) levels. The prognostic index was defined as poor (high dNLR and LDH), intermediate (high dNLR or LDH) and good (low dNLR and LDH) groups. We analyzed the overall survival (OS) after CRPC using Cox proportional hazard models and the Kaplan-Meier methods. Results: The median age at CRPC and baseline PSA level were 75 years and 458.39 ng/ml, respectively. The median OS after CRPC were 31.7 months. In multivariate analysis, dNLR (≥1.48, HR=1.75, P=0.0096), LDH (≥upper limits of normal, HR=1.94, P=0.0015) and ALP (≥310U/l, HR=2.37, P<0.0001) were independent prognostic factors for OS. The good prognostic index group showed significantly longer OS after CRPC compared with the intermediate and poor groups with the median survival of 46.2, 28.9 and 16.6 months, respectively (shown in Table). Conclusions: Novel inflammation index combined with dNLR and LDH was an useful prognostic marker for mCRPC. Further study with a large scale and treatment specific analysis will be required.[Table: see text]
Evaluation of bone metastasis and prognosis of prostate cancer with bone metastasis during standard hormonal therapy and chemotherapy: A report of PROSTAT-BSI multicenter registry in Japan.
Authors: Mizokami Atsushi , Takahashi Satoru , Matsuyama Hideyasu , Kaneko Gou , Shiina Hiroaki , Ichikawa Tomohiko , Horikoshi Hiroyuki , Hashine Katsuyoshi , Sugiyama Yutaka , Miyao Takeshi , Kamiyama Manabu , Harada Kenichi , Ito Akito , Nakajima Kenichi ,   The PROSTAT-BSI Investigators
Published: February 2020

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Background: Quantitative evaluation of the change of bone metastasis (bMet) has not been clearly defined during treatments in prostate cancer (PCa). As therapeutic effects of bMet have become quantified with scintigraphic bone scan index (BSI), we performed a nation-wide observational prospective study in patients who were treated by hormonal therapy (HTx) or chemotherapy (CTx). Methods: A total of 237 patients were recruited at 30 hospitals in Japan, and this report summarized baseline demographics and prognosis of 203 patients. All had bMet and underwent either standard HTx (group H) or docetaxel CTx (group C). Bone scans were performed with 99mTc-MDP. Patients were followed up for 3 years, and changes in biochemical and tumor markers during HTx and CTx were recorded in addition to skeletal-related events, recurrence, and death. Results: The basic characteristics of the patients (n=203) at the time of registration during December 2016 were as follows: mean age 71 ± 8 years; median BSI calculated on-site 3.0 ± 3.2% and median PSA was 265 ng/mL (22-2923 ng/mL) and 33 (3-537 ng/mL), for Group H and C (p=0.0014), respectively. BSI was comparable (H: 3.0 ± 3.4 vs C: 3.0 ± 2.8%, p=n.s.) between the two groups. A total of 54 patients (24%) died from PCa. BSI flare defined as increase at 3 months and decrease at 6 months was 13% and 31% (p<0.0069) for Groups H and C, respectively. When patients were classified into three groups with BSI <0.9 (low), 0.9-3.3 (intermediate), and >3.3% (high). Kaplan-Meier Survival analysis showed that mortality at 1100 days was 8%, 16%, and 35% for Group H (p=0.0097), and 50%, 55%, and 65% for Group C (p=ns) for the low, intermediate and high BSI group, respectively. In addition, patients who showed BSI decline >20% until 6 months showed better prognosis than those who did not (p<0.0001 and p= 0.038 and for Group H and C, respectively). Conclusions: The data of PROSTAT-BSI showed that BSI could be a good biomarker for prognosis in both Groups H and C, in particular for prognostic stratification of patients indicated for HTx. Six-month response of BSI by >20% indicated better prognosis in both groups. Clinical trial information: UMIN000007858.
Safety and effectiveness of radium-223 dichloride (Ra-223) in patients with mCRPC in real-world setting: A Japanese post-marketing study (PMS).
Authors: Takahashi Shunji , Kakehi Yoshiyuki , Masumori Naoya , Hosono Makoto , Kinuya Seigo , Okayama Yutaka , Sunaya Toshiyuki , Okumura Masafumi , Uemura Hirotsugu
Published: February 2020

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Background: In order to assess safety and effectiveness of Ra-223 in real-world setting, a PMS has been conducted under Japanese regulation for Good Post-marketing Study Practice. Methods: This was a prospective, single-arm, observational study of patients (pts) with mCRPC. The planned sample size was 300. In this primary analysis, clinical outcomes during the 6 month observational period up to 1 month after the last injection of Ra-223 were assessed. An exploratory subgroup analysis was performed according to symptom status at baseline (asymptomatic (AS) or symptomatic (S): WHO's cancer pain ladder 0 or >1). Results: A total of 334 pts were enrolled from Jun 2016 to Nov 2017. As of May 2019, data for 273 pts were available (table). The incidence of drug-related any treatment-emergent adverse events (TEAEs), hematologic TEAEs, and skeletal-related events were 27%, 18%, and 3%, respectively. Fractures were reported in 3 pts, but all were judged not related to Ra-223 by investigators. At the subgroup analysis, baseline characteristics for AS-group seemed more favorable than those in S-group (table). More pts in AS-group completed 6 cycles of Ra-223, and incidence of drug-related TEAEs appeared lower in AS-group compared with S-group. More than 90% of pts did not experience pain progression during 24 weeks, regardless of their symptoms status. Conclusions: During the 6 month observational period, no new safety concerns related to Ra-223 treatment were reported. Asymptomatic patients were more likely to complete treatment and experience fewer TEAEs, possibly reflecting less advanced disease. A follow-up observation up to 3 years is on-going.[Table: see text]
The effect of treatment sequence on overall survival for men with metastatic castration-resistant prostate cancer: A multicenter retrospective study.
Authors: Hatakeyama Shingo , Okita Kazutaka , Yamamoto Hayato , Yoneyama Takahiro , Hashimoto Yasuhiro , Ohyama Chikara
Published: February 2020

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Background: We aimed to evaluate the treatment sequence for patients with metastatic castration-resistant prostate cancer (mCRPC) in real-world practice and compare overall survival in each sequential therapy. Methods: We retrospectively evaluated 146 patients with mCRPC who were initially treated with androgen deprivation therapy as metastatic hormone-naïve prostate cancer in 14 hospitals between January 2010 and March 2019. The agents for the sequential therapy included new androgen receptor-targeted agents (ART: abiraterone acetate or enzalutamide), docetaxel, and/or cabazitaxel. We evaluated the treatment sequence for mCRPC and the effect of sequence patterns on overall survival. Results: The median age was 71 years. A total of 35 patients received ART-ART, 33 received ART-docetaxel, 68 received docetaxel-ART, and 10 received docetaxel-cabazitaxel sequences. The most prescribed treatment sequence was docetaxel-ART (47%), followed by ART-ART (24%). Overall survival calculated from the initial diagnosis reached 83, 57, 79, 37 months in the ART-ART, ART-docetaxel, docetaxel-ART, and docetaxel-cabazitaxel, respectively. Multivariate Cox regression analyses showed no significant difference in overall survival between the first-line ART (n = 68) and first-line docetaxel (n = 78) therapies (hazard ratio: HR 0.84, P = 0.530), between the ART-ART (n = 35) and docetaxel-mixed (n = 111) sequences (HR 0.82, P = 0.650), and between the first-line abiraterone (n = 32) and first-line enzalutamide (n = 36) sequences (HR 1.58, P = 0.384). Conclusions: The most prescribed treatment sequence was docetaxel followed by ART. No significant difference was observed in overall survival among the treatment sequences in real-world practice.
Real-world management of advanced prostate cancer: A Canadian comparison of academic specialists and community-based prostate cancer physicians.
Authors: Hotte Sebastien J. , Finelli Antonio , Chi Kim N. , Canil Christina M. , Fleshner Neil , Kapoor Anil , Kolinsky Michael Paul , Malone Shawn , Morash Chris , Niazi Tamim , Noonan Krista , Ong Michael , Pouliot Frederic , Shayegan Bobby , So Alan , Sorabji Delna , Hew Huong , Park-Wyllie Laura , Saad Fred
Published: February 2020

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Background: The Canadian GU Research Consortium recently conducted a consensus development conference with 27 academic prostate cancer (PC) specialists leading to 31 consensus recommendations. We conducted a survey to compare community-based practice with the consensus recommendations on the management of metastatic castration sensitive prostate cancer (mCSPC), metastatic castration resistant prostate cancer (mCRPC) and non-metastatic castration resistant prostate cancer (nmCRPC). Methods: An 87-item online questionnaire was sent to 600 Canadian community urologists, medical oncologists, radiation oncologists, and general practitioner oncologists involved in the treatment of PC. Results: Seventy-two physicians responded to the questionnaire (12% response). A discordance of >25% was observed in 15 of 31 recommendations (48%). Among the areas of discordance were treatment approach for patients with nmCRPC and PSADT < 10 months who are negative for metastases on conventional imaging but metastatic on PET-based imaging. Of the academic physicians, 89% indicated treating with agents approved for nmCRPC compared to 50% of community physicians (p=0.0005). Important discrepancies were also observed across academic and community physicians for radiation to the prostate for low-volume mCSPC which was 74% vs 27%, (p<0.0001) respectively; criteria for stopping therapy in mCRPC in which 78% of academic physicians favored continuation of therapy in the event of PSA progression only, compared to 24% of community physicians. Sequencing of therapy after prior apalutamide for nmCRPC using subsequent docetaxel treatment was observed in 81% of academic physicians vs 35% of community physicians, (p<0.0001), and use of genetic testing was favored by 74% of academics vs 36% of community physicians, (p<0.0001) for newly diagnosed metastatic prostate cancer. Conclusions: The areas of discordance between a national sample of community-based PC physicians and academic consensus recommendations represent potential areas for education, practice tools and future research.