bluuebunny/crossref_metadata_2025 huggingface dataset:
Preventing Juvenile Transitions to Adult Crime: A Pilot Study of Probation Interventions for Older, High-Risk Juvenile Delinquents
Authors: Ashford Jose B. , Gallagher John M.
Published: March 2019

This pilot study compared the recidivism risks of older, high-risk juvenile probationers exposed or unexposed to an experimental case-management intervention to further the development of a supportive community intervention. The experimental intervention targeted unmet basic needs before and after the exposed group aged out of the juvenile justice system to prevent transition to adult crime. A prospective-cohort design compared the recidivism risks of the intervention group ( n = 29) with a randomly selected comparison group ( n = 114) stratified by gender, race, and risks/needs. We followed both groups for 3 years after members turned 18. The results of this pilot study showed no effects on recidivism risks, but statistically significant effects on the timing to recidivism for the group exposed to an innovative intervention. The study also revealed that the intervention was able to recruit and maintain the probationers and members of their family for the duration of the intervention.
Decision Support System to Develop Evidence-based Policies for Inequity Reduction in Maternal and Child Health Care
Authors: Saha Partha
Published: March 2019

To reduce inequity in maternal and child health care indicators among socio-economically different regions, strategic location-specific policies should be designed. In this research work, a knowledge-discovery-based interactive decision support system has been developed on a web platform which would assist health care policymakers to design evidence-based decisions. Two modules have been prepared under this system to find out key influential Maternal and Child Healthcare (MCH) interventions for socio-economically different regions which had high impact on health care indicators. Data of 284 districts of nine high-focus states of India have been provided into the system to find out the efficiency of the system. Those data have been collected from district- level household survey part three (DLHS-3). The first module of the system has segregated all 284 districts into three segments based on their educational, social and economic conditions, and the second module has found out key influential health care interventions for all three segments separately which had high impact on health care indicators. It has been observed that adolescent health care intervention like female sterilization and childhood health care interventions such as DPT (diphtheria, pertussis, and tetanus) vaccine and measles vaccine were key influential health care interventions. The improvement of coverage of these interventions would help to reduce inequity and improve health care indicators of regions. Further research should be done to understand how the coverage of these interventions can be improved, especially in socio-economically poor regions.
Service Tyre and Tube Division: Strategic Capabilities for Business Growth
Authors: Chatha Kamran A.
Published: March 2019

The case describes the growth challenges faced by Service Industries Limited (SIL) in the year 2014. There were a number of strategic growth options available to the firm, some related to product diversification and some related to product extension, and SIL had to devise the best plan in order to tap into these strategic growth options.

Since 2011, SIL was continuously on the growth path where its domestic and international sales had increased. This had been made possible through improving virtually every aspect of its value chain as well as activities in the market and product development sides. However, recently, the domestic sector which gave the lion’s share of its sales was undergoing a stagnation, and thus SIL was exploring new avenues of growth in both the domestic and the international markets. These avenues included venturing into tractor tyres and tubes business, auto spare parts business (in which SIL had already embarked) and export business. Each of these growth options had its own peculiarities and implications on various sections of its value chain. This might disturb the very recipe of its internal systems that had given SIL significant growth since 2011 in the first place. Arif Saeed, Managing Director of SIL Tyre and Tube Division had to take steps in a careful and cautious manner in order to further grow.
Integrative Research Syntheses as Sites of Disruption in Literacy Teacher Education
Authors: Lysaker Judith T. , Handsfield Lara J.
Published: March 2019

In this Insight article, we look across the syntheses in this issue to consider how they help readers notice dominant flows and identify sites for disruption within the field of literacy teacher preparation. We first consider the meaning of disruption with respect to the metaphor of flow. We then identify and discuss possible sites of disruption authors of research syntheses create, providing examples from the literature. Finally, we suggest how research syntheses might be framed and crafted for purposes of disrupting the flows of dominant discourses and power structures in the field of literacy teacher preparation.
Multimodal imaging in an idiopathic spontaneously absorbed cataractous lens: A rare case report
Authors: Deshmukh Saurabh , Gupta Krati , Bhattacharjee Harsha
Published: March 2019

Purpose:

To report an unusual and rare case of idiopathic spontaneous absorption of the cataractous lens and its multimodal imaging features.

Methods:

A 56-year-old female presented with a complaint of diminution of vision in both eyes (OU). Slit lamp examination of the right eye (OD) revealed Morgagnian cataract with a normal anterior segment. Slit lamp examination of the left eye (OS) revealed absorbed cataractous lens with intact lens capsule with clear visual axis. Fundus examination OS was unremarkable. No history of trauma, past ocular surgery or any ocular or systemic disease. Ultrasonography B-scan OU was unremarkable. Her blood examination was normal. Anterior segment optical coherence tomography showed increased anterior chamber depth OS. It also showed Morgagnian cataractous lens with nucleus in the bag OD and absorbed cataractous lens with thin adhered capsular bag OS. Scheimpflug imaging also showed decreased densitometry OS. She underwent successful phacoemulsification in OD with in-the-bag placement of intraocular lens. For OS with absorbed lens, she underwent phacoemulsification with anterior circular curvilinear capsulorhexis using a capsulotomy forceps. The cortical matter in the bag area was aspirated with implantation of intraocular lens in the ciliary sulcus over the intact capsule rim.

Results:

The patient underwent phacoemulsification with anterior continuous curvilinear capsulorhexis with intraocular lens placement in the ciliary sulcus OS.

Conclusions:

This case is first of its kind in the literature. The role of ultrasound B-scan, anterior segment optical coherence tomography, and Scheimpflug imaging in the preoperative evaluation of capsulolenticular status and subsequent successful management is discussed.
Towards a neoliberal education system in Queensland: Preliminary notes on senior secondary schooling reforms
Authors: Rodgers Gibson Morgan
Published: March 2019

Neoliberalism is often understood as being both an epoch of capitalism and a zealous ideological commitment to the primacy of private property and free markets. In practice, it has tended towards mobilising state power in the interests of capital, remaking societies and individuals in this process. Perhaps inevitably, education systems, the world over, have been reformed in light of neoliberalism’s overarching imperatives. It is in this light that we can best understand and make sense of recent reforms to Queensland’s senior secondary schooling system. While some details continue to be ironed out, the reformed system will revolve around three main planks: (a) an assessment model combining school-based and common external assessment, (b) a process that quantifies and standardises school-based assessment through external review processes and (c) a transition away from the Overall Position (OP) rank towards an Australian Tertiary Admission Rank (ATAR). These changes to assessment and tertiary admission represent a pivot away from Queensland’s historical commitments to school-based assessment and teacher and curriculum flexibility towards a standardised national system of curriculum and external assessment. Ultimately, the reforms embody the ideological commitments of neoliberalism, perpetuating schools as producers of human capital. Hence, Queensland’s senior secondary schooling reforms ought to be understood through two different frames: firstly, as embodying the dominant ideological imperatives of neoliberalism and, secondly, that education is, within this context, being reconstituted to meet the perceived needs of capital.
Pharmacological inhibition of Bax-induced cell death: Bax-inhibiting peptides and small compounds inhibiting Bax
Authors: Jensen Kelsey , WuWong David Jasen , Wong Sean , Matsuyama Mieko , Matsuyama Shigemi
Published: March 2019

Bax is an essential mediator of mitochondria-dependent programed cell death. Bax belongs to the Bcl-2 family of proteins and its activities are regulated through interaction with other member proteins in the Bcl-2 family. To date, several apoptosis-inducing drugs activating Bax have been developed, and some of them are already in the market as therapeutics against cancer. However, at present, there are no clinically effective pharmacological Bax inhibitors protecting essential cells. Previously, we developed Bax-Inhibiting Peptides (BIPs) that belong to the peptide group of Cell-Penetrating Peptides (CPPs). CPPs have the ability to deliver cargo molecules into the cell. In this review, we will describe the mechanism of action of BIPs together with the recent applications of BIPs in disease models in vitro and in vivo. However, BIPs have several limitations in their use to treat human diseases, and other types of Bax inhibitors need to be developed for future therapeutics. Recently, several groups reported the successful development of novel small compounds inhibiting Bax. We will review these Bax inhibitors to discuss current strategies to develop pharmacological Bax inhibitors.

Impact statement

Bax induces mitochondria-dependent programed cell death. While cytotoxic drugs activating Bax have been developed for cancer treatment, clinically effective therapeutics suppressing Bax-induced cell death rescuing essential cells have not been developed. This mini-review will summarize previously reported Bax inhibitors including peptides, small compounds, and antibodies. We will discuss potential applications and the future direction of these Bax inhibitors.
Big Data, precision medicine and private insurance: A delicate balancing act
Authors: Blasimme Alessandro , Vayena Effy , Van Hoyweghen Ine
Published: March 2019

In this paper, we discuss how access to health-related data by private insurers, other than affecting the interests of prospective policy-holders, can also influence their propensity to make personal data available for research purposes. We take the case of national precision medicine initiatives as an illustrative example of this possible tendency. Precision medicine pools together unprecedented amounts of genetic as well as phenotypic data. The possibility that private insurers could claim access to such rapidly accumulating biomedical Big Data or to health-related information derived from it would discourage people from enrolling in precision medicine studies. Should that be the case, the economic value of personal data for the insurance industry would end up affecting the public value of data as a scientific resource. In what follows we articulate three principles – trustworthiness, openness and evidence – to address this problem and tame its potentially harmful effects on the development of precision medicine and, more generally, on the advancement of medical science.
Surgery for scar revision and reduction: from primary closure to flap surgery
Authors: Ogawa Rei
Published: March 2019

Scars are the final result of the four processes that constitute cutaneous wound healing, namely, coagulation, inflammation, proliferation, and remodeling. Permanent scars are produced if the wounds reach the reticular dermis. The nature of these scars depends on the four wound healing processes. If the remodeling process is excessive, collagen degradation exceeds collagen synthesis and atrophic scars are produced. If the inflammation phase is prolonged and/or more potent for some reason, inflammatory/pathological scars such as keloids or hypertrophic scars can arise. If these pathological scars are located on joints or mobile regions, scar contractures can develop. When used with the appropriate timing and when selected on the basis of individual factors, surgical techniques can improve mature scars. This review paper focuses on the surgical techniques that are used to improve mature scars, burn scars, and scar contractures. Those methods include z-plasties, w-plasties, split-thickness skin grafting, full-thickness skin grafting, local flaps (including the square flap method and the propeller flap), and expanded flaps, distant flaps, regional flaps, and free flaps.
Headaches in Moria: a reflection on mental healthcare in the refugee camp population of Lesbos
Authors: Nutting Tom
Published: March 2019

Having returned from a period of volunteering with a healthcare charity working with the refugee camp population of Lesbos in Greece, a junior doctor reflects on the common presentations he saw and the current state of mental healthcare for these patients. The placement of already-traumatised people in an overcrowded and under-resourced camp environment creates a perfect storm for the emergence of post-traumatic stress disorder, depression and anxiety. With extremely limited psychiatric care in place, he considers the simple interventions he could use to help his patients with their distressing symptoms. This prompts exploration of the importance of giving time to listen as well as encouraging small but significant lifestyle changes. After exploring the ethics of psychiatric diagnosis in this setting, the author concludes that while we must acknowledge the political origins of some of the symptomatology in this population, we must continue to strive to treat psychiatric illness with all the appropriate interventions available to us in order to help those in this patient group recover and move forward.
Racial disparities in late-stage prostate cancer: A SEER database analysis 2005–2015.
Authors: Lin Jianqing , Rodriguez Stephanie , Zhou Hanbing , Sparks Andrew D , Simmens Samuel J. , Amdur Richard
Published: March 2019

115

Background: Incidence of metastatic prostate cancer in U.S. males has increased over the past ten years, but it is unknown how this trend varies over time within different racial and ethnic populations. Methods: We identified all men first diagnosed with prostate cancer from 2005-2015 in the Surveillance, Epidemiology, and End Results (SEER) program of the National Cancer Institute, which monitors 18 population-based cancer registries. Yearly cancer diagnosis frequency from 2005 to 2015 was categorized and analyzed by stage (in situ/localized, regional, and distant), race/ethnicity [White, Asian American/Pacific Islander (AAPI), Black], and age group (45-54, 55-69, 70-75). Chi-square tests, multivariable logistic regression models were used for data analysis with p < 0.05 considered significant. Results: In the 10-year study period, the proportion of regional-stage prostate cancer increased from 14.2% to 16.6% of cases (p < .0001) and distant-stage increased from 3.3% to 5.8% (p < .0001). The odds of being diagnosed with regional-stage prostate cancer in 2013-2015 compared to 2005-2008 were 1.3 times higher for Black men (95% CI: 1.2-1.5), 1.3 times higher for AAPI men (95% CI: 1.1-1.5), and 1.2 times higher for White men (95% CI: 1.2-1.3). The odds of being diagnosed with distant-stage prostate cancer in 2013-2015 compared to 2005-2008 were 1.6 times higher for Black men (95% CI: 1.4-1.9), 1.8 times higher for AAPI men (95% CI: 1.5-2.3), and 2.1 times higher for White men (95% CI: 1.9-2.2). Conclusions: The incidence of late-stage prostate cancer has increased significantly in all US male despite race and ethnicity. However, reginal-stage prostate cancer increased the most over time in AAPI and Black men, while newly-diagnosed distant prostate cancer increased the most over time in White men.
Impact of the USPSTF recommendations on prostate cancer stage migration and de-novo metastatic prostate cancer.
Authors: Chen Yu-Wei , Gupta Ruby , Ornstein Moshe Chaim , Rini Brian I. , Gilligan Timothy D. , Garcia Jorge A.
Published: March 2019

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Background: The US Preventive Services Task Force (USPSTF) recommended against prostate specific antigen (PSA) screening for men aged≥75 in 2008 and all men in 2012 in an effort to reduce overdiagnosis and overtreatment of men with prostate cancer (PCa). This recommendation may delay diagnosis of clinically significant PCa. Methods: The Surveillance, Epidemiology and End Results Program (SEER) was used to identify men diagnosed with PCa between 2004-2015. PCa stage was categorized as localized (N0M0), nodal (N1M0) and metastatic (NxM1). Trend analysis was stratified on age group (PSA screening eligible was defined as age 55-69 according to the 2018 updated USPSTF recommendation). Multivariable logistic regression was used to identify predictors for nodal and metastatic disease. Results: Between 2004-2015, there were 603,323 men with PCa identified. Metastatic disease accounted for 2.8% of PCa in 2004-2008, 3.7% in 2009-2012, and 6.1% in 2013-2015. In men eligible for PCa screening, metastatic disease increased from 1.9% in 2004-2008, to 2.6% in 2009-2012, to 4.2% in 2013-2015; nodal disease increased from 1.4% to 1.6% to 2.6%, respectively (both p-value for trend< 0.0001). This stage migration was also observed in non-screening eligible groups (age >70 and <55). Compared with PCa diagnosed in 2009-2012, PCa diagnosed in 2013-2015 had higher odds of metastatic disease (AOR: 1.70, p-value<0.0001) or nodal disease (AOR: 1.71, p-value<0.0001). Conclusions: Men diagnosed with PCa in 2013-2015 were more likely to have metastatic or nodal disease, suggesting PCa stage migration since PSA screening was recommended to be discontinued in 2012. Although the impact of PSA screening on PCa mortality remains debatable, the reduced quality of life with advanced Pca should not be overlooked. Future population studies are warranted to investigate the influence of the updated 2018 USPSTF recommendation. [Table: see text]
Genomic determinants of sensitivity to bipolar androgen therapy (BAT) in castrate-resistant prostate cancer (CRPC).
Authors: Schweizer Michael Thomas , Antonarakis Emmanuel S. , Eisenberger Mario A. , Nelson Peter , Luo Jun , Pritchard Colin , Denmeade Samuel R.
Published: March 2019

200

Background: BAT is a promising treatment for CRPC and preclinical work has shown that its effects may be mediated by inducing DNA damage or cell cycle arrest. We sought to evaluate if mutations in DNA damage repair (DDR) genes or cell cycle regulators were associated with improved outcomes. Methods: Biospecimens from CRPC patients enrolled to studies testing BAT underwent germline or somatic next-generation sequencing (NGS). Samples tested included plasma (i.e. cell-free DNA) (N = 79), tumor tissue (N = 21) and saliva (N = 10). A variety of clinical grade NGS platforms were generally used. Given the concern for false negatives, we excluded cases if plasma NGS did not reveal a somatic alteration. Absence of a germline alteration was not assumed to indicate absence of somatic alterations. Comparative analyses to assess candidate biomarkers of BAT efficacy were performed. Results: Most patients received BAT following one or more next generation hormonal therapy, while 6 received BAT as first-line CRPC therapy. Of 65 cases where a germline or somatic pathogenic alteration in any gene was detected, 30 (46%) had evidence of homologous recombination deficiency (HRD), with mutations found in BRCA2 (N = 10), ATM (N = 8), CHEK2 (N = 5), PALB2 (N = 4), CDK12 (N = 3), CHD1 (N = 2), FANCA (N = 1), FANCD2 (N = 1) and BRCA1 (N = 1). TP53 alterations were also common (27/65; 42%). HRD mutations associated with increased PSA50 responses, with a trend toward improved PSA50 responses in TP53 mutated cases too (Table). In a combined analysis, men with HRD and/or TP53 mutations had improved PSA50 responses and near-significant improvement in progression free survival (PFS). Conclusions: These preliminary data suggest that BAT may be most efficacious in cancers harboring mutations in genes involved in DDR and/or cell cycle regulation. These results require prospective confirmation. [Table: see text]
Impact of new systemic therapies on outcomes of patients with non-metastatic castration resistant prostate cancer (nmCRPC).
Authors: Vicier Cecile , Xie Wanling , Hamid Anis , Evan Carolyn , Sweeney Christopher
Published: March 2019

244

Background: Treatments and outcomes of men with nmCRPC in routine care are poorly described. We assessed the cumulative impact of new therapies in men who transition through nmCRPC using a single-institution database. Methods: We conducted a retrospective study of consecutive nmCRPC pts enrolled into a hospital-based registry at Dana-Farber Cancer Institute. Pts were analyzed by era of diagnosis of nmCRPC: 2000-2009 (when docetaxel was the only life prolonging metastatic CRPC therapy) (cohort A) and 2010-2018 (when new systemic therapies were approved for mCRPC or in trials for nmCRPC) (cohort B). We collected pt, treatment, metastasis-free survival (MFS) and overall survival (OS) data. Results: 230 men were included: 148 in cohort A and 62 in cohort B. Despite only 39% of cohort B pts receiving new hormonal therapies for nmCRPC, there was no difference in median MFS between both eras: 2.7 yrs (2.1-3.2) in cohort A and 2.2 yrs (1.4-3.3) in cohort B. 30% of pts in cohort A and 53% of pts in cohort B had two or more life prolonging mCRPC therapies at any time (Table). No difference in 3-year OS was seen but 4-year OS was numerically higher in cohort B, with a trend towards improved OS in the new era. Conclusions: In an era with access to more than one life prolonging therapy for mCRPC, greater use of these agents in pts who transition through nmCRPC to mCRPC did not improve 3-year OS but may impact longer term OS. [Table: see text]
Neutrophil-to-lymphocyte ratio as a prognostic biomarker for overall survival in men with advanced prostate cancer treated with platinum chemotherapy.
Authors: Vlachostergios Panagiotis J. , Lee Aileen , Thomas Charlene , Hackett Amy , Molina Ana M. , Nanus David M. , Beltran Himisha , Tagawa Scott T.
Published: March 2019

266

Background: Platinum compounds are active in pts with metNEPC/CRPC. The neutrophil-to-lymphocyte ratio (NLR) is a simple clinical metric of systemic inflammation with prognostic and predictive value in advanced PC treated with FDA-approved therapies (doc, abi, enza, cabaz, mitox). We hypothesized that pretreatment NLR may be associated with clinical outcomes of platinum-treated pts. Methods: Records were reviewed from NEPC/CRPC platinum-treated pts with available information to enable pretreatment NLR calculation. Kaplan Meier curves, Cox regression analyses were used to predict PSA-PFS, radiographic PFS and OS after platinum initiation. For NLR, a cutoff of ≤5 was used as previously described (Leibowitz-Amit et al. 2014). Results: 108 men, median age 64 yrs (range 46-80), were studied. 28 pts (26%) were NEPC based on histological features. 54 had visceral mets (39 liver, 31 lung, 8 brain). 100 received carboplatin, 17 received cisplatin (9 received both sequentially, with initial platinum used for this analysis). Most received platinum in combination with other drugs, most commonly paclitaxel (N = 71) and etoposide (N = 20). 51 (47.2%) had low NLR ≤5 and 57 (52.7%) had high NLR > 5. Median PSA-PFS was 5 months in the low NLR group versus 3 months in the high NLR group (log-rank P = 0.07). Median rPFS did not differ between the two NLR groups (log-rank P = 0.36). Median OS of pts with NLR ≤5 was 15 months vs only 9 months in the high NLR ( > 5) subgroup (log-rank P = 0.06). There was no significant difference in NLR or OS status between NEPC and CRPC pts. On multivariate analysis (adjusted for age at platinum, Gleason, PSA, ALP, LDH, Hb, measurable disease, visceral mets, ECOG PS, use of opioids), NLR emerged as an independent prognostic factor for OS (HR 5.39, 95% CI 1.25-23.33, P = 0.02), together with PSA (P = 0.03) and visceral mets (P = 0.02). Conclusions: NLR is associated with shorter OS in men with advanced PC who receive platinum-based chemotherapy. It may serve as a useful clinical indicator of systemic inflammatory response and is more prognostic than standard NEPC vs adenocarcinoma histology. Prospective validation studies in such pts are needed to confirm these findings.
Racial disparities in radium-223 treatment in a large real-world population.
Authors: Zhao Hanson Hanqing , Howard Lauren , de Hoedt Amanda , Terris Martha K , Amling Christopher L. , Kane Christopher J. , Cooperberg Matthew R. , Aronson William J. , Polascik Thomas , Freedland Stephen J.
Published: March 2019

268

Background: Black men with prostate cancer are more likely to have unfavorable tumor characteristics and are at greater risk of prostate cancer mortality. Radium-223 is a FDA approved treatment for metastatic castration-resistant prostate cancer (mCRPC) that showed a survival benefit in the ALSYMPCA trial, where 94% of the participants were Caucasian. We aim to examine treatment patterns and outcomes of radium-223 in a large, heterogeneous population in the real world. Methods: We reviewed charts of all men with diagnosed with mCRPC in the entire Veterans Affairs (VA) system alive as of January 1st, 2013 who received radium-223. We compared common treatment patterns and characteristics between black and nonblack men. We analyzed predictors of time from radium-223 start to overall survival and time to skeletal related event (SRE) with Cox models. Results: 318 patients with bone mCRPC who received radium-223 were identified. 27% (87/318) were black. Black men were younger (67 vs 70 years, p = 0.001) and had higher PSA and alkaline phosphatase (ALP) levels at radium start (p = 0.014 and 0.017, respectively). There were no significant differences in biopsy Gleason, number of bone metastasis, primary localized treatment (yes/no), PSA doubling time, bone pain, or number of radium injections. Black men had lower mortality risk (HR 0.75; 95% CI 0.57 to 0.98; P = 0.038) on multivariable analysis. Comparison of common treatment patterns between black and nonblack men revealed that black men were more likely to receive other therapies prior to radium, including chemotherapy. Conclusions: Using a large, heterogeneous, real world cohort, we describe differences in treatment patterns and outcomes with radium-223 between black and nonblack men with mCRPC. While black men had a lower risk of mortality in this cohort, they had higher PSA and ALP levels when receiving radium-223. They were also more likely to receive other therapies prior to radium-223, indicating a possible delay in radium use in black men.
SelectMDx versus Prostate Health Index in the identification of high-grade prostate cancer.
Authors: Hoyer Gretchen , Crawford E. David , Arangua Paul , Stanton Whitney , La Rosa Francisco G. , Poage Wendy , Lucia M. Scott , van Bokhoven Adrie , Werahera Priya N.
Published: March 2019

30

Background: A major clinical challenge is to identify patients at increased risk of high-grade prostate cancer (PCa) (Gleason scores ≥ 7) before biopsy. Thus, we evaluated the clinical utility of SelectMDx and Prostate Health Index (phi) tests for diagnosis of high-grade PCa as compared with transperineal mapping biopsy (TMB) results, where an average of 80 prostate needle biopsies are taken every 5 mm for a diagnostic accuracy of 98%. Methods: 70 patients were selected who had TMB. They were evaluated with both SelectMDx and phi tests from before or after TMB; all had serum and post-digital rectal examination urine samples collected prior to treatment, stored in our biorepository. phi was evaluated using proPSA, free PSA and total PSA in serum. SelectMDx test measured mRNA levels of the HOXC6 and DLX1 in post-DRE urine. Published data shows that phi <27 and SelectMDx score = 0% correlate with patients free of HG PCa. Test results were compared against TMB histopathology data. Multivariate logistic regression (MLS) analyses and receiver operating characteristic (ROC) curves were used to determine diagnostic accuracy. DeLong test was used to determine statistical significance of ROC curves. All analyses were done for diagnosis of any PCa and high-grade PCa. Results: TMB histopathology showed 17/70 patients with no PCa and 22/53 with high-grade PCa. The sensitivity, specificity, positive (PPV) and negative (NPV) predictive values of each test are shown in the table below. Pairwise ROC comparison showed no statistically significant difference in the area under the curve of diagnosing PCa (0.75 vs 0.65) and high-grade PCa (0.71 vs 0.81) by phi and SelectMDx tests respectively. MLS analyses showed phi was significantly better than SelectMDx for diagnosing PCa (β = 0.054; p=0.005) and SelectMDx was significantly better than phi for diagnosing high-grade PCa (β = 8.45; p=0.0002). Conclusions: With high sensitivity and NPV, SelectMDx test is more useful than phi for screening patients at risk of high-grade PCa prior to biopsy. [Table: see text]
Impact of compliance on outcomes for patients on active surveillance for prostate cancer.
Authors: Detsky Jay , Fotouhi Ghiam Alireza , Mamedov Alexandre , Commisso Kristina , Commisso Angela , Klotz Laurence , Liu Stanley K. , Loblaw Andrew , Vesprini Danny
Published: March 2019

36

Background: Active surveillance (AS) is the standard of care for low-risk prostate cancer to reduce the risk of overtreatment. However, the impact of compliance to AS on outcomes has not been well described. We hypothesized that compliance to an AS protocol and to the recommendation for active treatment would affect subsequent treatment failure. Methods: A prospective, single-arm cohort study was initiated in 1995 to assess an AS program. Triggers for intervention included a PSA doubling time of less than three years and histologic upgrade. The AS protocol was defined as PSA measurements every three months for two years and then twice annually, as well as a confirmatory biopsy within 12 months and then every three years. Compliance to the AS protocol was defined as four PSA tests and a confirmatory biopsy by 1.5 years after enrollment. Compliance to treatment was defined as the initiation of any active therapy within 12 months from the time of any trigger described above. Treatment failure was defined as a PSA > 0.2 after surgery, PSA > nadir + 2 for other treatments, or the development of metastases. Statistics were performed using logistic regression analysis and the Fisher exact test. Results: A total of 1282 patients were included in the final analysis, of which 460 received treatment. Median follow up was 7.1 years. The actuarial rate of biochemical control at five and 10 years amongst treated patients was 78% and 59% respectively. The rates of compliance to biopsy at years one, four and seven were 71%, 36% and 13%. The treatment failure rate was lower for patients compliant to the AS protocol (crude rate 28%) than those non-compliant (crude rate 38%) with an odds ratio of 0.64 (95% CI 0.43-0.94, p = 0.03). Patients compliant to the protocol were also less likely to develop metastases (OR 0.42, 95% CI 0.21-0.88, p = 0.02). There was no impact on treatment failure by adherence to active therapy within 12 months (p = 0.25) after reaching a trigger to come off AS. Conclusions: Non-compliance to an AS protocol leads to a higher risk of subsequent treatment failure and development of metastases. Physicians and patients need to work together diligently to ensure enrollment on an AS program is followed by adherence to regular PSA checks and repeat biopsies.
The role of adjuvant chemotherapy for pT2-4 upper urinary tract urothelial cancer: Exploratory analysis of large multi-institutional study (JCOG1110A).
Authors: Inokuchi Junichi , Kuroiwa Kentaro , Nishiyama Hiroyuki , Kojima Takahiro , Kakehi Yoshiyuki , Sugimoto Mikio , Tanikawa Toshiki , Fujimoto Hiroyuki , Gotoh Momokazu , Masumori Naoya , Ogawa Osamu , Eto Masatoshi , Ohyama Chikara , Yamaguchi Akito , Matsuyama Hideyasu , Ichikawa Tomohiko , Ito Keiichi , Mizusawa Junki , Eba Junko , Naito Seiji ,   The Urologic Oncology Study Group of Japan Clinical Oncology Group (JCOG)
Published: March 2019

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Background: Recently, it was presented that adjuvant chemotherapy (AC) after radical nephroureterectomy (RNU) improved metastasis-free survival in pT2-4 upper urinary tract urothelial cancer (UTUC) with a median follow-up of 17.6 months (POUT study). However, the impact of AC on other outcomes remains unclear, especially for pT2 disease. Methods: The large case-series study, JCOG1110A, included 2,744 patients with non-metastatic UTUC who underwent RNU in 30 institutions in Japan between 1995 and 2009. In this analysis, patients with prior history or synchronous bladder cancer, patients who received neoadjuvant chemotherapy were excluded. Patients who received AC except for GC (gemcitabine, cisplatin) or MVAC (methotrexate, vinblastine, doxorubicin, cisplatin) were also excluded. We extracted pT2-4 patients as study subjects from remaining patients, and identified 950 patients. The impact of AC on overall survival (OS) and extravesical recurrence-free survival (RFS) were examined by the multivariable Cox regression model in all patient and pT2, pT3-4 subgroups. Results: Of 244 pT2 and 706 pT3-4 patients with a median follow-up of 41.1 months, AC were performed in 34 (13.9%) and 183 (25.9%). In AC (+) group, high frequency of pT3-4 disease, high grade tumor, pathological node metastasis, lymphovascular invasion, and younger age were seen compared to AC (-) group. The 5-year survival of the AC (+) and AC (-) were 66.0% and 67.4% for OS, 58.0% and 57.8% for RFS, respectively. Multivariable analysis showed the improved outcome in AC (+) group on both OS and RFS in all patients (OS: HR 0.60, 95% CI 0.41-0.89, RFS: HR 0.71, 95% CI 0.51-1.00). Although AC had a great impact on OS in pT3-4 patients (HR 0.56, 95% CI 0.36-0.87), there was no clear impact on either OS or RFS in pT2 patients (OS: HR 0.81, 95% CI 0.32-2.07, RFS: HR 0.69, 95% CI 0.29-1.62). Conclusions: AC after RNU had the significant impacts on OS and RFS in pT2-4 UTUC patients. This tendency was seen strongly in pT3-4 patients, but not in only pT2 patients. The randomized trial is necessary to determine the utility of AC in UTUC patients, especially in pT2 patients. Clinical trial information: NCT01993979.
Effect of concurrent beta-blocker (BB) use in patients receiving immune checkpoint inhibitors for metastatic urothelial (mUC) and renal cell carcinomas (mRCC).
Authors: Patel Vaibhav G. , Oh William K. , Galsky Matt D. , Liaw Bobby Chi-Hung , Tsao Che-Kai
Published: March 2019

467

Background: Stress-induced adrenergic signaling suppresses the immune system. A pre-clinical mouse model has shown that pharmacologic beta-blockade can stimulate CD8+ T-cell activity, and as a result improve efficacy of checkpoint inhibitors (CPI) to inhibit growth in solid tumors. Herein, we investigate the effect of BB on outcomes of patients receiving immunotherapy in mUC and mRCC. Methods: Using the Mount Sinai Genitourinary (GU) Cancer Biorepository, an IRB approved database containing all consented GU cancer patients seen between 2010-2018, we identified patients with either UC or RCC that have received CTLA-4 and/or PD-1/PD-L1 blockade. Patients who received only 1 dose of CPI were excluded from this analysis. A descriptive analysis was performed to assess clinical characteristics and treatment response. Overall Survival (OS) was calculated with Kaplan-Meier curves and cox proportional hazard models. Results: We identified 34 evaluable patients with mUC and 14 with mRCC that received CPI (Table). The median age at initiation was 69 years (39–91 years) and 81.2% (39/48) received prior chemotherapy and/or molecular targeted therapies. The mean duration of therapy was longer in the BB group compared to non-BB group (10.6 vs. 4.0 mo). For patients with mUC, the overall response rate (ORR) was 62.5% vs. 12.5% in favor of the BB group. For the patients with mRCC, the ORR was 40.0% vs. 10.0% in favor of the BB group. There were more outstanding responders (>1 year) in the BB group when compared with the non-BB group (41.2% vs. 6.5%). Patients with BB use had significantly improved median OS (NR vs. 11.6 mo, p = 0.004) when compared to those who did not receive BB. Conclusions: In this single-center cohort, the concurrent use of BB receiving CPI therapy is associated with an improved ORR, duration of therapy, and OS. Although this is hypothesis generating, the addition of BB is a promising strategy to improve response of immunotherapy, and prospective validation of this approach will be needed. [Table: see text]
CB-839, a glutaminase inhibitor, in combination with cabozantinib in patients with clear cell and papillary metastatic renal cell cancer (mRCC): Results of a phase I study.
Authors: Meric-Bernstam Funda , Lee Richard J. , Carthon Bradley Curtis , Iliopoulos Othon , Mier James Walter , Patel Manish R. , Tannir Nizar M. , Owonikoko Taofeek Kunle , Haas Naomi B. , Voss Martin Henner , Harding James J. , Srinivasan Ramaprasad , Shapiro Geoffrey , Telli Melinda L. , Munster Pamela N. , Carvajal Richard D. , Jenkins Yonchu , Whiting Sam H. , Bendell Johanna C. , Bauer Todd Michael
Published: March 2019

549

Background: Glutaminase (GLS) is a key enzyme that controls glutamine utilization, a metabolic pathway upregulated in RCC and important for tumor proliferation and survival. CB-839 is a first-in-clinic, small molecule, reversible, oral GLS inhibitor that synergizes with cabozantinib (Cabo), a VEGFR2/MET/AXL inhibitor, in preclinical RCC models to inhibit metabolic pathways and enhance anti-tumor activity. Cabo monotherapy is associated with a 17% overall response rate (ORR) for clear cell (cc) mRCC (Choueiri et al. Lancet Oncol. 2016). Here we present findings from a Phase 1 study cohort evaluating the safety, efficacy, and recommended Phase 2 dose (RP2D) of CB-839 + Cabo in patients (pts) with mRCC as 2L+ therapy. Methods: Eligible pts had mRCC with cc or papillary histology, ECOG 0-1, RECIST measurable disease, and, for cc pts, treatment with ≥1 prior anti-VEGF therapy. Escalating doses of CB-839 (600-800 mg PO BID) plus Cabo (60 mg PO QD) were evaluated using a 3+3 design. Tumor response was assessed per RECIST 1.1 every 8 wks. Results: The CB-Cabo cohort enrolled 13 pts with a median 3 (range, 0-7) prior lines of therapy. No maximum tolerated dose was reached; 800 mg was selected as the CB-839 RP2D. The most common treatment-related AEs (occurring in >25% of pts) were diarrhea (62%), decreased appetite (46%), ALT increased (39%), fatigue (39%), AST increased (31%), nausea (31%), and rash (31%); Gr ≥3 treatment-related AEs included diarrhea, hypertension, platelet count decreased, and hallucination (n=1 each). Among 12 evaluable pts, ORR was 42% and disease control rate (DCR = complete response + partial response [PR] + stable disease [SD]) was 100%: 42% (5/12) PR, 58% (7/12) SD. Among 10 evaluable cc mRCC pts, 50% (5/10) had PRs, 50% (5/10) SDs. As of Sept 24, 2018, 5 pts received >12 months treatment; 4 remain on study. Conclusions: CB-839 plus Cabo showed encouraging clinical activity and tolerability in heavily pretreated mRCC pts, with response rates for cc mRCC (50% ORR, 100% DCR) comparing favorably to historical Cabo monotherapy. A randomized Phase 2 study of CB-839 + Cabo vs. Cabo + placebo in cc mRCC is ongoing. (CANTATA; NCT0342821) Clinical trial information: NCT02071862.
Impact of treatment and insurance on socioeconomic disparities on the survival of renal cancer patients in Thailand.
Authors: Chansriwong Phichai , Srikaew Piyaporn , Worawichawong Suchin
Published: March 2019

576

Background: Access to care is an important aspect of high-quality cancer care. Patients' health insurance status is a factor influencing an individual's ability to access high-quality cancer care. The increased costs of cancer care are negatively impacting patients. 75% of Thai people use the Thailand’s Universal Coverage Scheme (UCS), about 15% use the Civil Servant Medical Benefit Scheme (CSMBS) or the Social Security Scheme (SSS). Only CSMBS can reimburse cost of the targeted therapy. Multiple new therapies have emerged for the treatment of metastatic renal cell carcinoma (mRCC) that showed OS increased in following introduction of targeted therapies and immunotherapy. However, many patients lack access to affordable, high-quality cancer care. Aim: To determine the relationship between treatment affordability, insurance status and RCC cancer survival. Methods: Retrospectively reviewed 281 medical records of RCC patients at the Ramathibodi hospital between January 2009 and December 2017. We searched the Surveillance, Epidemiology, and End Results dataset. Kaplan–Meier methods and multivariable Cox regression models were used to analyze survival outcomes and risk factors. Results: 281 RCC patients, and 127 metastasis were identified. Median age was 59.1 years, and 74.7% were male gender. There were clear cell carcinoma (77.9%), and non-clear cell was 17.1%. IMDC prognostic model categorized as favorable/intermediate/poor risk group as 14.2%/51.2%/29.1%. 41.7% has health insurance status as CSMBS, 7% in SSS and 50.9% in UCS. Only 50% of SSS and UCS paid out of their pocket of mRCC treatment. First line treatment for mRCC were targeted therapy with VEGFR TKI 73.9%, but 26.8% received only supportive care. Median OS was 24 months in the treatment group and only 4.1 months in the best supportive care group (p <0.05). Health insurance status and medication affordability was confirmed as an independent prognostic factor for mRCC patients. Conclusions: Insurance status and medication affordability are important predictive factors for mRCC, and improving access to affordable targeted therapies is likely to improve outcomes in mRCC.
Evaluation of tumor microenvironment and biomarkers of immune checkpoint inhibitor (ICI) response in metastatic renal cell carcinoma (mRCC).
Authors: Zhu Jason , Pabla Sarabjot , Labriola Matthew , Gupta Rajan T. , McCall Shannon , George Daniel J. , Dressman Devin , Glenn Sean , Nesline Mary , George Saby , Morrison Carl , Zhang Tian
Published: March 2019

607

Background: ICIs are now standard of care for mRCC; however, there are few biomarkers to predict ICI response. Recent data from atezolizumab/bevacizumab trials in mRCC suggest tumors with high Teffhigh/PD-L1+ are more likely to respond to ICI. Here, we use this Teff gene panel as well as other markers of inflammation in the tumor microenvironment to correlate with ICI responses. Methods: This multicenter study evaluated 69 pts with mRCC treated with ICIs. FFPE tumor samples were evaluated by RNA sequencing to measure transcript levels of genes related Teff status. Teff status was defined as the mRNA expression of 17 genes (CD8, CD27, IFNG, GZMA, GZMB, PRF1, EOMES, CXCL9, CXCL10, CXCL11, CD274, CTLA4, FOXP3, TIGIT, IDO1, PSMB9, TAP1), with Teffhigh/low separated at the median. PD-L1 positivity was defined as ≥1% TPS based on Dako 22C3 IHC assay, and TMB high as > 10 mutations per megabase. Inflamed tumors were defined as CD8 expression in the top 75th percentile compared to a large reference population of multiple tumor types. Best responses to ICI was determined by an expert radiologist using RECIST 1.1 criteria. Inflamed tumor status, Teff gene expression, PD-L1 positive, and TMB were associated with disease control (DC, defined as CR, PR, or stable disease). DC comparisons were tested using a chi-squared test with Yates’s continuity correction. Results: DC was 63% (5/8) amongst PD-L1 positive pts and 52% (31/60) in PD-L1 negative patients (p = 0.84). Only 2 pts were TMB high. The majority of mRCC tumors (97%, 67/69) were TMB low. 6-month DC in TMB high tumors was 50% (1/2) and 49.3% (33/67) in TMB low tumors (p = 1.0). 36 pts were classified as Teffhigh and 33 patients were classified as Tefflow. 6-month DC was 61% (22/36) in the Teffhigh cohort and 36% (12/33) in the Tefflow cohort (p = 0.069). 6-month DC was 64% of inflamed tumors (16/25) vs 41% of non-inflamed tumors (18/44) (p = 0.111). Conclusions: TMB high and PD-L1 expression do not reliably predict for DC in pts with mRCC. Utilizing a gene signature score may better predict ICI response.
A phase III trial of docetaxel versus docetaxel and radium-223 (Ra-223) in patients with metastatic castration-resistant prostate cancer (mCRPC): DORA.
Authors: Morris Michael J. , De Wit Ronald , Vogelzang Nicholas J. , Tagawa Scott T. , Higano Celestia S. ,   On behalf of DORA Trial Investigators
Published: March 2019

TPS348

Background: Ra-223, a bone-targeted alpha therapy, is a well-tolerated treatment option that prolongs survival in patients (pts) with symptomatic mCRPC to bone. Docetaxel targets microtubule trafficking improving survival in the mCRPC and metastatic hormone-sensitive settings. We hypothesized that simultaneously targeting the tumor and bone compartment yields superior outcomes than targeting either alone. We previously determined the dose and schedule of co-administering Ra-223 + docetaxel in a randomized phase I/IIa trial. The combination appeared to have superior declines in prostate specific antigen (PSA) and bone markers, delayed PSA progression, and was better tolerated (with adjusted dose/schedule) relative to standard docetaxel alone. We are now conducting a phase III study. Methods: DORA is an open-label investigator-initiated phase III study sponsored by Memorial Sloan Kettering Cancer Center and managed by the Prostate Cancer Clinical Trials Consortium. Pts with mCRPC are randomized (1:1) to docetaxel or docetaxel + Ra-223. Pts with ≥2 bone lesions and progression by Prostate Cancer Working Group 3 criteria are eligible. Other key inclusion criteria are an Eastern Cooperative Oncology Group performance status of 0–1 and normal organ function. Key exclusion criteria are: use of anticancer therapy ≤4 weeks (wks) before randomization and use of bone-seeking radiopharmaceuticals or chemotherapy in the castration-resistant setting, and bulky visceral metastases (≥3 lung and/or liver or a lesion ≥2 cm in the previous 8 wks). Pts will receive docetaxel 75 mg/m2 IV q3w for 10 doses with oral prednisone 5 mg b.i.d. or docetaxel 60 mg/m2 IV q3w for 10 doses with oral prednisone 5 mg b.i.d. + Ra-223 55 kBq/kg IV q6w for 6 injections. The primary endpoint is overall survival. Secondary and exploratory endpoints include: radiographic progression-free survival, symptomatic skeletal event-free survival, safety, markers of bone metabolism, alterations in circulating tumor cells and DNA, detection of androgen-receptor splice variant 7 and changes in automated bone scan index. Enrollment of 738 pts is expected. The study is conducted in the US and Netherlands. Clinical trial information: NCT03574571.