Treatment of muscle-invasive and advanced bladder cancer in 2020.

Bladder cancer accounts for nearly 170,000 deaths worldwide annually. For over 4 decades, the systemic management of muscle-invasive and advanced bladder cancer has primarily consisted of platinum-based chemotherapy. Over the past 10 years, innovations in sequencing technologies have led to rapid genomic characterization of bladder cancer, deepening our understanding of bladder cancer pathogenesis and exposing potential therapeutic vulnerabilities. On the basis of its high mutational burden, immune checkpoint inhibitors were investigated in advanced bladder cancer, revealing durable responses in a subset of patients. These agents are now approved for several indications and highlight the changing treatment landscape of advanced bladder cancer. In addition, commonly expressed molecular targets were leveraged to develop targeted therapies, such as fibroblast growth factor receptor inhibitors and antibody-drug conjugates. The molecular characterization of bladder cancer and the development of novel therapies also have stimulated investigations into optimizing treatment approaches for muscle-invasive bladder cancer. Herein, the authors review the history of muscle-invasive and advanced bladder cancer management, highlight the important molecular characteristics of bladder cancer, describe the major advances in treatment, and offer future directions for therapeutic development.

Biomarker Development Trial of Satraplatin in Patients with Metastatic Castration-Resistant Prostate Cancer.

BACKGROUND: In the phase III SPARC trial, satraplatin, an oral platinum analogue, demonstrated anticancer activity in men with metastatic castration-resistant prostate cancer (mCRPC). Repeat biopsies are uncommon in mCRPC, limiting the feasibility of tissue-based biomarkers. This phase II study sought to evaluate the feasibility and utility of blood-based biomarkers to identify platinum-sensitive mCRPC. METHODS: Patients with mCRPC who had progressed on docetaxel were enrolled at a single center from 2011 to 2013. Subjects received satraplatin 80 mg/m2 by mouth daily on days 1-5 and prednisone 5 mg PO twice daily, on a 35-day cycle. Serial peripheral blood samples were collected for biomarker assessment. RESULTS: Thirteen docetaxel-refractory mCRPC patients were enrolled, with a median age of 69 years (range 54-77 years) and median PSA of 71.7 ng/mL (range 0.04-3057). Four of 13 patients (31%) responded to satraplatin (defined as a PSA decline of ≥30%). Responders demonstrated improved time to disease progression (206 vs. 35 days, HR 0.26, 95% CI, 0.02-0.24, P = .003). A 6-gene peripheral blood RNA signature and serum tissue inhibitor of metalloproteinase-1 (TIMP-1) levels were assessed as biomarkers, but neither was significantly associated with response to satraplatin. CONCLUSION: In this small series, one-third of mCRPC patients responded to platinum-based chemotherapy. Peripheral blood biomarker measurement is feasible in mCRPC, though the biomarkers we investigated were not associated with platinum response. Other biomarkers, such as DNA damage repair mutations, should be evaluated.

Antenatal Steroids, Prophylactic Indomethacin, and the Risk of Spontaneous Intestinal Perforation.

OBJECTIVE: To estimate if the odds of spontaneous intestinal perforation (SIP) are increased when antenatal steroids (ANS) given close to delivery are combined with indomethacin on day 1 after birth (Indo-D1). STUDY DESIGN: A retrospective cohort study using the Neonatal Research Network (NRN) database of inborn infants, gestational age 220-286 weeks or birth weight of 401-1000 g, born between January 1, 2016 and December 31, 2019, and surviving >12 hours. The primary outcome was SIP through 14 days. Time of last ANS dose prior to delivery was analyzed as a continuous variable (using 169 hours for durations >168 hours or no steroid exposure). Associations between ANS, Indo-D1, and SIP were obtained from a multilevel hierarchical generalized linear mixed model after covariate adjustment. This yielded aOR and 95% CI. RESULTS: Of 6851 infants, 243 had SIP (3.5%). ANS exposure occurred in 6393 infants (93.3%) and IndoD1 was given to 1863 infants (27.2%). The time (median, IQR) from last dose of ANS to delivery was 32.5 hours (6-81) vs 37.1 hours (7-110) for infants with or without SIP, respectively (P = .10). Indo-D1 was given to 51.9 vs 26.3% of infants with SIP vs no SIP, respectively (P < .0001). Adjusted analysis indicated no interaction between time of last ANS dose and Indo-D1 for SIP (P = .7). Indo-D1 but not ANS was associated with increased odds of SIP (aOR: 1.73, 1.21-2.48, P = .003). CONCLUSION: The odds of SIP were increased after receipt of Indo-D1. Exposure to ANS prior to Indo-D1 was not associated with an increase in SIP.

Fluid Intake in the First Week of Life and the Duration of Hemodynamically Significant Patent Ductus Arteriosus in Extremely Preterm Infants.

OBJECTIVE: This study aimed to determine the association between daily fluid intake and the duration of hemodynamically significant patent ductus arteriosus (hsPDA). STUDY DESIGN: This is a retrospective cohort study of extremely preterm infants (<29 weeks) admitted in the Neonatal Intensive Care Unit of the Advent Health for Children from January 2013 to March 2016, if hsPDA was diagnosed in first week of life and serial echocardiograms were available. Diagnosis of hsPDA was based on a scoring system and its duration was estimated from serial echocardiograms. Cohort was divided into two groups based on duration of hsPDA (<1week, group A and ≥1 week, group B). Daily fluid intake was categorized as prescribed and actual. Prescribed volume was ordered by clinicians based on birth weight, not including trophic feeds, intravenous (IV) boluses or transfusions, etc. Actual intake was calculated by the electronic medical records based on daily weights and included all enteral or parenteral fluids. Multivariate analysis was performed to determine an association between total daily fluid intake over the first week of life and the duration of hsPDA. Two groups were compared to observe the difference between prescribed and actual daily fluid intakes. RESULTS: We enrolled 50 infants in group A and 76 in group B. Infants in group B were of significantly lower gestation and required prolonged ventilation and hospitalization. An association between higher fluid intake in the first 2 days of life and prolonged duration of hsPDA was confirmed by multivariate analysis. Actual fluid intake was significantly higher than prescribed total fluid intake in first 4 days of life for infants in both groups. CONCLUSION: In extremely preterm infants, higher fluid intake in first 2 days of life is associated with prolonged duration of hsPDA. Actual daily fluid intake can be significantly higher than prescribed daily fluids due to daily weight changes and additional fluid administration. KEY POINTS: · In preterm infants, actual daily fluid intake may be higher than prescribed volume.. · Higher daily fluid intake in first week of life is associated with prolonged duration of PDA.. · PDA scoring system can be helpful for objective assessment of PDA in preterm infants..

Global DNA methylation of WTC prostate cancer tissues show signature differences compared to non-exposed cases.

There is increased incidence of prostate cancer (PC) among World Trade Center (WTC)-exposed responders and community members, with preliminary evidence suggestive of more aggressive disease. While previous research is supportive of differences in DNA methylation and gene expression as a consequence of WTC exposure, as measured in blood of healthy individuals, the epigenetics of WTC PC tissues has yet to be explored. Patients were recruited from the World Trade Center Health Program. Non-WTC PC samples were frequency matched on age, race/ethnicity and Gleason score. Bisulfite-treated DNA was extracted from tumor tissue blocks and used to assess global DNA methylation with the MethylationEPIC BeadChip. Differential and pathway enrichment analyses were conducted. RNA from the same tumor blocks was used for gene expression analysis to further support DNA methylation findings. Methylation data were generated for 28 samples (13 WTC and 15 non-WTC). Statistically significant differences in methylation were observed for 3,586 genes; on average WTC samples were statistically significantly more hypermethylated (P = 0.04131). Pathway enrichment analysis revealed hypermethylation in epithelial mesenchymal transition (EMT), hypoxia, mitotic spindle, TNFA signaling via NFKB, WNT signaling, and TGF beta signaling pathways in WTC compared to non-WTC samples. The androgen response, G2M and MYC target pathways were hypomethylated. These results correlated well with RNA gene expression. In conclusion, long-term epigenic changes associated with WTC dust exposure were observed in PC tissues. These occurred in genes of critical pathways, likely increasing prostate tumorigenesis potential. This warrants analysis of larger WTC groups and other cancer types.

Phase II Clinical and Translational Study of Everolimus ± Paclitaxel as First-Line Therapy in Cisplatin-Ineligible Advanced Urothelial Carcinoma.

BACKGROUND: Treatment options have been historically limited for cisplatin-ineligible patients with advanced urothelial carcinoma (UC). Given the need for alternatives to platinum-based chemotherapy, including non-chemotherapy regimens for patients with both impaired renal function and borderline functional status, in 2010 (prior to the immune checkpoint blockade era in metastatic UC), we initiated a phase II trial to test the activity of everolimus or everolimus plus paclitaxel in the cisplatin-ineligible setting. METHODS: This was an open-label phase II trial conducted within the US-based Hoosier Cancer Research Network (ClinicalTrials.gov number: NCT01215136). Patients who were cisplatin-ineligible with previously untreated advanced UC were enrolled. Patients with both impaired renal function and poor performance status were enrolled into cohort 1; patients with either were enrolled into cohort 2. Patients received everolimus 10 mg daily alone (cohort 1) or with paclitaxel 80 mg/m2 on days 1, 8, and 15 of each 28-day cycle (cohort 2). The primary outcome was clinical benefit at 4 months. Secondary outcomes were adverse events, progression-free survival (PFS), and 1-year overall survival (OS). Exploratory endpoints included genomic correlates of outcomes. The trial was not designed for comparison between cohorts. RESULTS: A total of 36 patients were enrolled from 2010 to 2018 (cohort 1, N = 7; cohort 2, N = 29); the trial was terminated due to slow accrual. Clinical benefit at 4 months was attained by 0 (0%, 95% confidence interval [CI] 0-41.0%) patients in cohort 1 and 11 patients (37.9%, 95% CI 20.7-57.7%) in cohort 2. Median PFS was 2.33 (95% CI 1.81-Inf) months in cohort 1 and 5.85 (95% CI 2.99-8.61) months in cohort 2. Treatment was discontinued due to adverse events for 2 patients (29%) in cohort 1 and 11 patients (38%) in cohort 2. Molecular alterations in microtubule associated genes may be associated with treatment benefit but this requires further testing. CONCLUSION: Everolimus plus paclitaxel demonstrates clinical activity in cisplatin-ineligible patients with metastatic UC, although the specific contribution of everolimus cannot be delineated. Patients with both impaired renal function and borderline functional status may be difficult to enroll to prospective trials. (ClinicalTrials.gov Identifier NCT01215136).

Targeted Next-Generation Sequencing Reveals Exceptionally High Rates of Molecular Driver Mutations in Never-Smokers With Lung Adenocarcinoma.

INTRODUCTION: Historically, high rates of actionable driver mutations have been reported in never-smokers with lung adenocarcinoma (ADC). In the era of modern, comprehensive cancer mutation sequencing, this relationship necessitates a more detailed analysis. METHODS: All Mount Sinai patients between January 1, 2015, and June 1, 2020, with a diagnosis of ADC of any stage with known smoking status who received genomic testing were included. Most patients were analyzed using the Sema4 hotspot panel or the Oncomine Comprehensive Assay version 3 next-generation sequencing (NGS) panel conducted at Sema4. Patients were considered fully genotyped if they were comprehensively analyzed for alterations in EGFR, KRAS, MET, ALK, RET, ROS1, BRAF, NTRK1-3, and ERBB2, otherwise they were considered partially genotyped. RESULTS: Two hundred and thirty-six never-smokers and 671 smokers met the above criteria. Of the never-smokers, 201 (85%) had a driver mutation with 167 (71%) considered actionable (ie, those with US Food and Drug Administration-approved agents). Among smokers, 439 (65%) had an identified driver mutation with 258 (38%) actionable (P < .0001). When comprehensively sequenced, 95% (70/74) of never-smokers had a driver mutation with 78% (58/74) actionable; whereas, for smokers, 75% (135/180) had a driver with only 47% (74/180) actionable (P < .0001). Within mutations groups, EGFR G719X and KRAS G12Cs were more common to smokers. For stage IV patients harboring EGFR-mutant tumors treated with EGFR-directed therapies, never-smokers had significantly improved OS compared to smokers (hazard ratio = 2.71; P = .025). In multivariable analysis, Asian ancestry and female sex remained significant predictors of (1) OS in stage IV patients and (2) likelihood of harboring a receptor of fusion-based driver. CONCLUSION: Comprehensive NGS revealed driver alterations in 95% of never-smokers, with the majority having an associated therapy available. All efforts should be exhausted to identify or rule out the presence of an actionable driver mutation in all metastatic lung ADC.

Impact of body mass index on the efficacy of aromatase inhibitors in patients with metastatic breast cancer.

PURPOSE: Higher levels of estrogen in obese patients may lead to incomplete inhibition by aromatase inhibitors (AIs). The aim of this study was to determine the impact of body mass index (BMI) on efficacy of AIs in patients with metastatic hormone receptor (HR)-positive breast cancer (BC). METHODS: We performed a retrospective chart review of all female patients with metastatic HR-positive BC on an AI in first- or second-line settings and seen at our academic institution between 2001 and 2020. The primary endpoint was progression-free survival (PFS), defined as the time from start of AI to disease progression or death from any cause. RESULTS: We identified 219 patients who had received an AI in the first- or second-line settings for metastatic HR-positive BC and with documented information on BMI. Of the 219 patients, 56% (123) had a low BMI (defined as < 27 kg/m2) and 44% (96) had a high BMI (≥ 27 kg/m2). The median PFS was 21.9 months (95% CI 14.5 to 28.4) in the low BMI group versus 20.2 months (95% CI 14.3 to 27.5) in the high BMI group (p = 0.73). CONCLUSION: While BMI influences efficacy of AIs in the adjuvant setting, our results suggest that in the metastatic setting, BMI may not impact the efficacy of AIs. This discrepancy could be due to other differences in disease characteristics that make complete aromatase inhibition more important in the adjuvant setting when disease burden is the lowest.

Consensus report: Definition and interpretation of remission in type 2 diabetes.

Improvement of glucose levels into the normal range can occur in some people living with diabetes, either spontaneously or after medical interventions, and in some cases can persist after withdrawal of glucose-lowering pharmacotherapy. Such sustained improvement may now be occurring more often due to newer forms of treatment. However, terminology for describing this process and objective measures for defining it are not well established, and the long-term risks versus benefits of its attainment are not well understood. To update prior discussions of this issue, an international expert group was convened by the American Diabetes Association to propose nomenclature and principles for data collection and analysis, with the goal of establishing a base of information to support future clinical guidance. This group proposed "remission" as the most appropriate descriptive term, and HbA1c <6.5% (48 mmol/mol) measured at least 3 months after cessation of glucose-lowering pharmacotherapy as the usual diagnostic criterion. The group also made suggestions for active observation of individuals experiencing a remission and discussed further questions and unmet needs regarding predictors and outcomes of remission.

Factors that guide selection among androgen receptor inhibitors in patients with nonmetastatic castration-resistant prostate cancer.

Prostate cancer is the most common cancer affecting men in the United States. A significant proportion of men have nonmetastatic castration-resistant prostate cancer (CRPC), in which biochemical progression is evidenced by rising levels of prostate-specific antigen without radiographic progression in the setting of castrate levels of testosterone. Historically, the preferred treatment for these patients has been observation and continued treatment with androgen deprivation therapy (ADT). The standard of care has recently evolved to include the addition of androgen receptor (AR) inhibitors to ADT. The US Food and Drug Administration has approved 3 next-generation AR inhibitors for nonmetastatic CRPC: apalutamide, enzalutamide, and darolutamide. These agents were approved based on data from phase 3 randomized trials. There is now a significant amount of data from these trials. All 3 agents improve metastasis-free survival and overall survival. Selection of treatment can be guided by factors such as the patient's overall health and frailty, potential drug-drug interactions, and the safety profile associated with each agent.

Maternal Body Mass Index and Risk of Bronchopulmonary Dysplasia in Extremely Preterm Infants.

OBJECTIVE: We evaluated the relationship between maternal body mass index (BMI) and death or bronchopulmonary dysplasia (BPD). We hypothesized that in extremely low birth weight (ELBW; BW < 1,000 g) infants, the risk of death or BPD would be greater if the maternal BMI deviated further from the ideal BMI of 24. STUDY DESIGN: ELBW infants admitted to AdventHealth Neonatal Intensive Care Unit (NICU) between calendar years 2012 and 2017 were included in this retrospective observational study. BPD was defined as continuous supplemental oxygen use at 36 weeks post-menstrual age. RESULT: There was no association between the deviation of maternal BMI from the ideal of 24 and the composite outcome of death or BPD (6.9 ± 6.7 vs. 7.06 ± 6.6, pp = 0.966). However, there was a lower risk of death with a higher maternal BMI (p = 0.024). BPD was also associated with a higher maternal BMI (p = 0.045). CONCLUSION: Maternal BMI was not associated with the composite variable of death or BPD in ELBW infants. The lack of association was due to the contrast between high BMI and a lower risk of death and a higher risk for BPD. KEY POINTS: · Maternal BMI was not associated with the composite outcome of death or BPD.. · Elevated BMI was associated with a higher risk of BPD.. · Elevated BMI was associated with a lower risk of death..

Consensus report: definition and interpretation of remission in type 2 diabetes.

Improvement of glucose levels into the normal range can occur in some people living with diabetes, either spontaneously or after medical interventions, and in some cases can persist after withdrawal of glucose-lowering pharmacotherapy. Such sustained improvement may now be occurring more often due to newer forms of treatment. However, terminology for describing this process and objective measures for defining it are not well established, and the long-term risks vs benefits of its attainment are not well understood. To update prior discussions of this issue, an international expert group was convened by the American Diabetes Association to propose nomenclature and principles for data collection and analysis, with the goal of establishing a base of information to support future clinical guidance. This group proposed 'remission' as the most appropriate descriptive term, and HbA1c <48 mmol/mol (6.5%) measured at least 3 months after cessation of glucose-lowering pharmacotherapy as the usual diagnostic criterion. The group also made suggestions for active observation of individuals experiencing a remission and discussed further questions and unmet needs regarding predictors and outcomes of remission.

Analysis of Real-World Data to Investigate the Impact of Race and Ethnicity on Response to Programmed Cell Death-1 and Programmed Cell Death-Ligand 1 Inhibitors in Advanced Non-Small Cell Lung Cancers.

BACKGROUND: Racial disparities among clinical trial participants present a challenge to assess whether trial results can be generalized into patients representing diverse races and ethnicities. The objective of this study was to evaluate the impact of race and ethnicity on treatment response in patients with advanced non-small cell lung cancer (aNSCLC) treated with programmed cell death-1 (PD-1) or programmed cell death-ligand 1 (PD-L1) inhibitors through analysis of real-world data (RWD). MATERIALS AND METHODS: A retrospective cohort study of 11,138 patients with lung cancer treated at hospitals within the Mount Sinai Health System was performed. Patients with confirmed aNSCLC who received anti-PD-1/PD-L1 treatment were analyzed for clinical outcomes. Our cohort included 249 patients with aNSCLC who began nivolumab, pembrolizumab, or atezolizumab treatment between November 2014 and December 2018. Time-to-treatment discontinuation (TTD) and overall survival (OS) were the analyzed clinical endpoints. RESULTS: After a median follow-up of 14.8 months, median TTD was 7.8 months (95% confidence interval, 5.4-not estimable [NE]) in 75 African American patients versus 4.6 (2.4-7.2) in 110 White patients (hazard ratio [HR], 0.63). Median OS was not reached (18.4-NE) in African American patients versus 11.6 months (9.7-NE) in White patients (HR, 0.58). Multivariable Cox regression conducted with potential confounders confirmed longer TTD (adjusted HR, 0.65) and OS (adjusted HR, 0.60) in African American versus White patients. Similar real-world response rate (42.6% vs. 43.5%) and disease control rate (59.6% vs. 56.5%) were observed in the African American and White patient populations. Further investigation revealed the African American patient group had lower incidence (14.7%) of putative hyperprogressive diseases (HPD) upon anti-PD-1/PD-L1 treatment than the White patient group (24.5%). CONCLUSION: Analysis of RWD showed longer TTD and OS in African American patients with aNSCLC treated with anti-PD-1/PD-L1 inhibitors. Lower incidence of putative HPD is a possible reason for the favorable outcomes in this patient population. IMPLICATIONS FOR PRACTICE: There is a significant underrepresentation of minority patients in randomized clinical trials, and this study demonstrates that real-world data can be used to investigate the impact of race and ethnicity on treatment response. In retrospective analysis of patients with advanced non-small cell lung cancer treated with programmed cell death-1 or programmed cell death-ligand 1 inhibitors, African American patients had significantly longer time-to-treatment discontinuation and longer overall survival. Analysis of real-world data can yield clinical insights and establish a more complete picture of medical interventions in routine clinical practice.

Advanced Prostate Cancer: AUA/ASTRO/SUO Guideline PART II.

PURPOSE: The summary presented herein represents Part II of the two-part series dedicated to Advanced Prostate Cancer: AUA/ASTRO/SUO Guideline discussing prognostic and treatment recommendations for patients with castration-resistant disease. Please refer to Part I for discussion of the management of patients with biochemical recurrence without metastatic disease after exhaustion of local treatment options as well as those with metastatic hormone-sensitive prostate cancer. RESULTS: The Advanced Prostate Cancer Panel created evidence- and consensus-based guideline statements to aid clinicians in the management of patients with advanced prostate cancer. Such statements are summarized in figure 1[Figure: see text] and detailed herein. MATERIALS AND METHODS: The systematic review utilized to inform this guideline was conducted by an independent methodological consultant. A research librarian conducted searches in Ovid MEDLINE (1998 to January Week 5 2019), Cochrane Central Register of Controlled Trials (through December 2018), and Cochrane Database of Systematic Reviews (2005 through February 6, 2019). An updated search was conducted prior to publication through January 20, 2020. The methodology team supplemented searches of electronic databases with the studies included in the prior AUA review and by reviewing reference lists of relevant articles. CONCLUSIONS: This guideline attempts to improve a clinician's ability to treat patients diagnosed with advanced prostate cancer. Continued research and publication of high-quality evidence from future trials will be essential to improve the level of care for these patients.

Advanced Prostate Cancer: AUA/ASTRO/SUO Guideline PART I.

PURPOSE: The summary presented herein represents Part I of the two-part series dedicated to Advanced Prostate Cancer: AUA/ASTRO/SUO Guideline discussing prognostic and treatment recommendations for patients with biochemical recurrence without metastatic disease after exhaustion of local treatment options as well as those with metastatic hormone-sensitive prostate cancer. Please refer to Part II for discussion of the management of castration-resistant disease. MATERIALS AND METHODS: The systematic review utilized to inform this guideline was conducted by an independent methodological consultant. A research librarian conducted searches in Ovid MEDLINE (1998 to January Week 5 2019), Cochrane Central Register of Controlled Trials (through December 2018), and Cochrane Database of Systematic Reviews (2005 through February 6, 2019). An updated search was conducted prior to publication through January 20, 2020. The methodology team supplemented searches of electronic databases with the studies included in the prior AUA review and by reviewing reference lists of relevant articles. RESULTS: The Advanced Prostate Cancer Panel created evidence- and consensus-based guideline statements to aid clinicians in the management of patients with advanced prostate cancer. Such statements are summarized in figure 1[Figure: see text] and detailed herein. CONCLUSIONS: This guideline attempts to improve a clinician's ability to treat patients diagnosed with advanced prostate cancer. Continued research and publication of high-quality evidence from future trials will be essential to improve the level of care for these patients.

Tracheomegaly among Extremely Preterm Infants on Prolonged Mechanical Ventilation.

By using phantom radiographs, the accuracy of tracheal measurements was established. Preterm infants (≤29 weeks) were enrolled in short (<7 days) and prolonged ventilation (≥28 days) groups. Both groups had 3 weight categories, namely, <1000 g, 1000-1999 g, and >2000 g. Tracheal sizes were measured on serial chest radiographs (CXR). We noted tracheomegaly in association with prolonged ventilation at ≥1000 g.

Unbound bilirubin levels in phototherapy-treated preterm infants receiving soy-based lipid emulsion.

BACKGROUND: Phototherapy is an effective treatment for neonatal jaundice. Treatment indication uses total serum bilirubin (TSB), although unbound bilirubin (Bf) more accurately predicts disability risk. The goals of this investigation were to examine the response of Bf and TSB to phototherapy in preterm infants, and we hypothesized that (i) TSB and Bf respond differently; (ii) the relationship between TSB and Bf is altered; and (iii) unexpected Bf elevations are found. METHODS: One hundred and seventeen preterm infants <2 kg at birth and receiving (IL) were enrolled; and measurements of TSB and Bf were obtained. TSB was measured by the diazo method and Bf with a fluorescent Bf sensor BL22P1B11-Rh. RESULTS: Initial mean (± SD) TSB and Bf levels (41.4 ± 6.9 h) were 8.0 ± 9.0 mg/dL and 16.9 ± 12.4 nmol/L (P < 0.05). The rates of rise (ROR) were 0.21 ± 0.10 mg/dL/h for TSB and 0.38 ± 0.33 nmol/L/h for Bf. Phototherapy reduced TSB from 8.0 ± 9.0 to 5.8 ± 9.4 mg/dL (P = 0.068) but Bf did not change (16.9 ± 12.4 to 14.1 ± 9.4 nmol/L P = n.s.). Bf levels were >11 nmol/L in 64, >17 nmol/L in 18, and >22 nmol/L in 7 infants. CONCLUSIONS: Bf and TSB responded differently. While TSB and Bf correlated well before phototherapy, they did not correlate during phototherapy. TSB showed a trend toward a reduction with treatment, Bf did not. While TSB ROR information is not helpful, ROR Bf data can be utilized to anticipate treatment. Potentially high Bf levels existed before and after phototherapy and the mean Bf level at phototherapy termination remained elevated in a significant proportion of infants.

Clinical development of novel therapeutics for castration-resistant prostate cancer: historic challenges and recent successes.

There have been more drugs approved by the US Food and Drug Administration for the treatment of castration-resistant prostate cancer in the past 3 years than in the prior 3 decades, with additional drugs on the verge of approval based on the results of recently reported randomized trials. While an improvement in the understanding of the pathogenesis of castration-resistant prostate cancer has undeniably accelerated the transition of novel approaches from "bench to bedside," the recent successes in the treatment of prostate cancer are also a result of the efforts of clinical investigators to redefine the framework in which drugs for castration-resistant disease are evaluated. This review will explore the shifting paradigm in drug development for castration-resistant prostate cancer over the past several decades, and highlight how new definitions, trial designs, and endpoints have facilitated the emergence of new therapies for this challenging disease.

Castration-Resistant Prostate Cancer: AUA Guideline Amendment 2018.

PURPOSE: The purpose of this amendment is to incorporate newly-published literature to provide a rational basis for the management of patients with non-metastatic castration-resistant prostate cancer (CRPC). MATERIALS AND METHODS: The original systematic review and meta-analysis of the published literature yielded 303 studies published from 1996 through 2013. This review informed the majority of the guideline statements from the 2013 guideline. Clinical Principles and Expert Opinions were used for guideline statements lacking sufficient evidence. The guideline was subsequently amended in April 2014 and March 2015. The current 2018 amendment search yielded 770 references with 47 studies eventually providing relevant data. The resulting amendment focuses on the incorporation of information relating to the treatment of patients with non-metastatic CRPC. RESULTS: Guideline statements based on six Index Patients developed to represent the most common scenarios encountered in clinical practice were amended appropriately. The additional literature provided the basis for an update of current supporting text as well as the incorporation of new guideline statements for asymptomatic non-metastatic CRPC. CONCLUSIONS: Given the rapidly evolving nature of this field, this guideline should be used in conjunction with recent systematic literature reviews and an understanding of individual patients' treatment goals. Shared decision-making incorporating patients' preferences and personal goals should be implemented when choosing management strategies. This guideline will be continually updated as new literature emerges.

Natural History of Postnatal Cardiopulmonary Adaptation in Infants Born Extremely Preterm and Risk for Death or Bronchopulmonary Dysplasia.

OBJECTIVE: To study the natural history of postnatal cardiopulmonary adaptation in infants born extremely preterm and establish its association with death or bronchopulmonary dysplasia (BPD). STUDY DESIGN: This was a prospective, observational, cohort study of infants born extremely preterm (<29 weeks). Initial echocardiogram was performed at <48 hours of life, followed by serial echocardiograms every 24-48 hours until 14 days of life. Resolution or no resolution of pulmonary hypertension (PH) at 72-96 hours was considered normal or delayed postnatal cardiopulmonary adaptation, respectively. PH between 96 hours and 14 days was defined as subsequent PH. Elevated pulmonary artery pressure throughout the 14 days of life was considered persistent PH. BPD was assessed at 36 weeks of postmenstrual age. RESULTS: Sixty infants were enrolled; 2 died before a sequential echocardiogram could be done at 72-96 hours. Normal and delayed cardiopulmonary adaptation were noted in 26 (45%) and 32 (55%) infants, respectively. Five patterns of postnatal cardiopulmonary adaptation were recognized: normal without subsequent PH (n = 20), normal with subsequent PH (n = 6), delayed adaptation without subsequent PH (n = 6), delayed adaptation with subsequent PH (n = 16), and persistent PH (n = 10). Infants with delayed cardiopulmonary adaptation were of lower gestation and birth weight and required prolonged ventilation and supplemental oxygen (P < .05). On multivariate analysis, the incidence of death or BPD was significantly greater among infants with delayed adaptation (P < .001). CONCLUSION: Infants born extremely preterm have normal or delayed postnatal cardiopulmonary adaptation that can be complicated by subsequent or persistent PH. Delayed cardiopulmonary adaptation is associated independently with death or BPD.