ctDNA guiding adjuvant immunotherapy in urothelial carcinoma.

Minimally invasive approaches to detect residual disease after surgery are needed to identify patients with cancer who are at risk for metastatic relapse. Circulating tumour DNA (ctDNA) holds promise as a biomarker for molecular residual disease and relapse1. We evaluated outcomes in 581 patients who had undergone surgery and were evaluable for ctDNA from a randomized phase III trial of adjuvant atezolizumab versus observation in operable urothelial cancer. This trial did not reach its efficacy end point in the intention-to-treat population. Here we show that ctDNA testing at the start of therapy (cycle 1 day 1) identified 214 (37%) patients who were positive for ctDNA and who had poor prognosis (observation arm hazard ratio = 6.3 (95% confidence interval: 4.45-8.92); P < 0.0001). Notably, patients who were positive for ctDNA had improved disease-free survival and overall survival in the atezolizumab arm versus the observation arm (disease-free survival hazard ratio = 0.58 (95% confidence interval: 0.43-0.79); P = 0.0024, overall survival hazard ratio = 0.59 (95% confidence interval: 0.41-0.86)). No difference in disease-free survival or overall survival between treatment arms was noted for patients who were negative for ctDNA. The rate of ctDNA clearance at week 6 was higher in the atezolizumab arm (18%) than in the observation arm (4%) (P = 0.0204). Transcriptomic analysis of tumours from patients who were positive for ctDNA revealed higher expression levels of cell-cycle and keratin genes. For patients who were positive for ctDNA and who were treated with atezolizumab, non-relapse was associated with immune response signatures and basal-squamous gene features, whereas relapse was associated with angiogenesis and fibroblast TGFß signatures. These data suggest that adjuvant atezolizumab may be associated with improved outcomes compared with observation in patients who are positive for ctDNA and who are at a high risk of relapse. These findings, if validated in other settings, would shift approaches to postoperative cancer care.

Impact of individualized treatment on recovery from fatigue and return to work in survivors of advanced-stage Hodgkin's lymphoma: results from the randomized international GHSG HD18 trial.

BACKGROUND: Persisting cancer-related fatigue impairs health-related quality of life (HRQoL) and social reintegration in patients with Hodgkin's lymphoma (HL). The GHSG HD18 trial established treatment de-escalation for advanced-stage HL guided by positron emission tomography after two cycles (PET-2) as new standard. Here, we investigate the impact of treatment de-escalation on long-term HRQoL, time to recovery from fatigue (TTR-F), and time to return to work (TTR-W). PATIENTS AND METHODS: Patients received European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30) and life situation questionnaires at baseline, interim, end of treatment, and yearly follow-up. TTR-F was defined as time from the end of chemotherapy until the first fatigue score <30. TTR-W was analyzed in previously working or studying patients and measured from the end of treatment until the first documented work or education. We compared duration of treatment on TTR-F and TTR-W using Cox proportional hazards regression adjusted for confounding variables. RESULTS: HRQoL questionnaires at baseline were available in 1632 (83.9%) of all randomized patients. Overall, higher baseline fatigue and age were significantly associated with longer TTR-F and TTR-W and male sex with shorter TTR-W. Treatment reduction from eight to four chemotherapy cycles led to a significantly shorter TTR-F [hazard ratio (HR) 1.41, P = 0.008] and descriptively shorter TTR-W (HR 1.24, P = 0.084) in PET-2-negative patients. Reduction from six to four cycles led to non-significant but plausible intermediate accelerations. The addition of rituximab caused significantly slower TTR-F (HR 0.70, P = 0.0163) and TTR-W (HR 0.64, P = 0.0017) in PET-2-positive patients. HRQoL at baseline and age were the main determinants of 2-year HRQoL. CONCLUSIONS: Individualized first-line treatment in patients with advanced-stage HL considerably shortens TTR-F and TTR-W in PET-2-negative patients. Our results support the use of response-adapted shortened treatment duration for patients with HL.

Molecular classification of hormone-sensitive and castration-resistant prostate cancer, using nonnegative matrix factorization molecular subtyping of primary and metastatic specimens.

BACKGROUND: Despite the rapidly evolving therapeutic landscape, immunotherapy has demonstrated limited activity in prostate cancer. A greater understanding of the molecular landscape, particularly the expression of immune-related pathways, will inform future immunotherapeutic strategies. Consensus nonnegative matrix factorization (cNMF) is a novel model of molecular classification analyzing gene expression data, focusing on biological interpretation of metagenes and selecting meaningful clusters. OBJECTIVE: We aimed to identify molecular subtypes of prostate cancer using cNMF and correlate these with existing biomarkers to inform future immunotherapeutic strategies. METHODS: A cohort of archival tumor specimens from hormone-sensitive and castration-resistant disease was studied. Whole transcriptomic profiles were generated using TruSeq RNA Access technology and subjected to cNMF. Comprehensive genomic profiling was performed with the FoundationOne assay. NMF subtypes were characterized by gene expression pathways, genomic alterations and correlated with clinical data, then applied to The Cancer Genome Atlas data set. RESULTS: We studied 164 specimens, including 52 castration-resistant and 13 paired primary/metastatic specimens. cNMF identified four distinct subtypes. NMF1 (19%) is enriched for immune-related and stromal-related pathways with transforming growth factor ß (TGFß) signature. NMF2 (36%) is associated with FOXO-mediated transcription signature and AKT signaling, NMF3 (26%) is enriched for ribosomal RNA processing, while NMF4 (19%) is enriched for cell cycle and DNA-repair pathways. The most common gene alterations included TMPRSS22 (42%), TP53 (23%), and DNA-repair genes (19%), occurring across all subtypes. NMF4 is significantly enriched for MYC and Wnt-signaling gene alterations. TMB, CD8 density, and PD-L1 expression were low overall. NMF1 and NMF4 were NMF2 was associated with superior overall survival. CONCLUSIONS: Using cNMF, we identified four molecularly distinct subtypes which may inform treatment selection. NMF1 demonstrates the most inflammatory signature with asuppressive TGFß signature, suggesting potential benefit with immunotherapy combination strategies targeting TGFß and PD-(L)1. Prospective studies are required to evaluate the use of this novel model to molecularly stratify patients for optimal treatment selection.

Taking cohesin and condensin in context.

Structural maintenance of chromosome (SMC) protein complexes, including cohesin and condensin, are increasingly being recognized for their important role in cancer and development, making it critical that we understand how these evolutionarily conserved multi-subunit protein complexes associate with and organize the genome. We review adaptor proteins for SMC complexes and how these adaptors may capture SMC complexes following loop extrusion to provide a framework for chromosome organization.

Value of bone marrow biopsy in Hodgkin lymphoma patients staged by FDG PET: results from the German Hodgkin Study Group trials HD16, HD17, and HD18.

Background: Bone marrow (BM) involvement defines advanced-stage Hodgkin lymphoma and thus has impact on the assignment to treatment. Our aim was to evaluate whether the established BM biopsy may be omitted in patients if 18F-fluorodeoxyglucose positron emission tomography (PET) scanning is carried out during staging. Patients and methods: Our analysis set consisted of 832 Hodgkin lymphoma patients from the German Hodgkin Study Group trials HD16, HD17, and HD18 who underwent both PET scanning and BM biopsy before treatment. All PET studies were centrally reviewed and BM was categorized as showing focal involvement or not. Results: Taking BM biopsy as reference standard, baseline PET showed a negative predictive value of 99.9% [95% confidence interval (CI) 99.2% to 100%] with true-negative results in 702 of 703 cases. The sensitivity of PET for detecting BM involvement was 95.0% (95% CI 75.1% to 99.9%) as it could identify 19 out of 20 patients with positive BM biopsy. Moreover, PET found 110 additional subjects with focal BM lesions who would have been considered negative by biopsy. Conclusions: When compared with BM biopsy, PET was able to detect focal BM lesions in a large number of additional patients. This indicates that conventional BM biopsy may substantially underestimate the actual incidence of BM involvement. Given the high negative predictive value, baseline PET scanning can safely be used to exclude BM involvement in Hodgkin lymphoma. BM biopsy should be considered only in such patients in whom PET-detected lesions lead to a change of treatment protocol. Registered trials: The trials included in this analysis were registered at ClinicalTrials.gov: HD16-NCT00736320, HD17-NCT01356680, and HD18-NCT00515554.

Mef2c-F10N enhancer driven ß-galactosidase (LacZ) and Cre recombinase mice facilitate analyses of gene function and lineage fate in neural crest cells.

Neural crest cells (NCC) comprise a multipotent, migratory stem cell and progenitor population that gives rise to numerous cell and tissue types within a developing embryo, including craniofacial bone and cartilage, neurons and glia of the peripheral nervous system, and melanocytes within the skin. Here we describe two novel stable transgenic mouse lines suitable for lineage tracing and analysis of gene function in NCC. Firstly, using the F10N enhancer of the Mef2c gene (Mef2c-F10N) linked to LacZ, we generated transgenic mice (Mef2c-F10N-LacZ) that express LacZ in the majority, if not all migrating NCC that delaminate from the neural tube. Mef2c-F10N-LacZ then continues to be expressed primarily in neurogenic, gliogenic and melanocytic NCC and their derivatives, but not in ectomesenchymal derivatives. Secondly, we used the same Mef2c-F10N enhancer together with Cre recombinase to generate transgenic mice (Mef2c-F10N-Cre) that can be used to indelibly label, or alter gene function in, migrating NCC and their derivatives. At early stages of development, Mef2c-F10N-LacZ and Mef2c-F10N-Cre label NCC in a pattern similar to Wnt1-Cre mice, with the exception that Mef2c-F10N-LacZ and Mef2c-F10N-Cre specifically label NCC that have delaminated from the neural plate, while premigratory NCC are not labeled. Thus, our Mef2c-F10N-LacZ and Mef2c-F10N-Cre transgenic mice provide new resources for tracing migratory NCC and analyzing gene function in migrating and differentiating NCC independently of NCC formation.

A lab-based comparison of differential ratings of perceived exertion between a run and jump protocol involving low or high impacts on the lower extremities.

The rating of perceived exertion method (RPE) allows to describe training intensity in a single value. To better understand the underlying components, the separate rating of perceived breathlessness (RPE-B) and leg-muscle exertion (RPE-L) has been proposed. Here we hypothesised that the separation between the two components may (partly) be determined by the impacts on the lower extremities. In this study, we aimed to experimentally evaluate the differential effect of high versus low impact running and jumping on RPE-B and RPE-L in team sport activities by manipulating the movement strategy (heel strike and passive landing pattern versus forefoot strike and active landing pattern). Eighteen recreational team sport players participated in two submaximal tests consisting of a sequence of running and jumping bouts, whilst ground reaction forces (GRF) were collected. RPE-B and RPE-L data were collected after each bout using the CR100 scale. Paired-samples t-tests were used to analyse between-session differences in these variables. GRF analysis showed that absorption mechanics differed considerably between the two sessions. RPE-L was on average 6.50 AU higher in the low impact session (p = 0.006). However, RPE-B was also increased by 4.96 AU with low impact (p = 0.009). We conclude that the extent to which the lower extremities are being exposed to high or low impacts does not explain a possible separation between the two RPE types.HighlightsThe separate rating of the different underlying components of RPE (e.g. variables related to the cardiorespiratory and the muscular system) may provide more insight in the relationship between training load and training outcomes, which likely differs between these components.The findings of this study do not support the idea that the separation in rating between perceived breathlessness (RPE-B, cardiorespiratory) and leg-muscle exertion (RPE-L, muscular) is also rooted in the extent to which musculoskeletal structures in the lower extremities are being exposed to high or low impacts.

Large mediastinal tumor mass as a prognostic factor in Hodgkin's lymphoma. Is the definition on the basis of a chest radiograph in the era of CT obsolete?

PURPOSE: The risk factor "large mediastinal tumor mass" is an internationally accepted unfavorable prognostic factor in the staging of Hodgkin's lymphoma (HL). The definition of this risk factor varies considerably between large cooperative study groups. The purpose of the present analysis was to determine to which degree data obtained from chest radiograph (CRX) give the same results as those from CT scans (CT). METHODS: A total of 145 de novo HL patients in early unfavorable and advanced stages were included in this study. A total of 94 patients had a large mediastinal tumor mass according to the guidelines of the German Hodgkin Study Group (GHSG), while 51 had mediastinal lymph node involvement only. The size of mediastinal involvement and the thoracic diameter were measured on CRX and CT. Agreement between CRX and CT was determined by sensitivity and specificity analysis as well as descriptive statistics and correlations. RESULTS: The correlation of the diameters on CRX with those of CT was 0.95 for the tumor size and 0.77 for the thoracic diameter. The diagnostic decision-large mediastinal mass or not-correlated with 0.81 between CRX and CT and was identical in 90.3% of cases. The sensitivity was 0.87 and the specificity 0.96 for CRX, which is considered the current standard. CONCLUSION: The results show that there is a high agreement between the measurements of CRX and CT. Diagnosis of a large mediastinal mass disagreed in 10% of patients. Since the correct diagnosis of this risk factor is decisive for the adequate multimodal treatment choice, CRX should not be omitted.

Differential Ratings of Perceived Exertion: Relationships With External Intensity and Load in Elite Men's Football.

PURPOSE: To examine the utility of differential ratings of perceived exertion (dRPE) for monitoring internal intensity and load in association football. METHODS: Data were collected from 2 elite senior male football teams during 1 season (N = 55). External intensity and load data (duration × intensity) were collected during each training and match session using electronic performance and tracking systems. After each session, players rated their perceived breathlessness and leg-muscle exertion. Descriptive statistics were calculated to quantify how often players rated the 2 types of rating of perceived exertion differently (dRPEDIFF). In addition, the association between dRPEDIFF and external intensity and load was examined. First, the associations between single external variables and dRPEDIFF were analyzed using a mixed-effects logistic regression model. Second, the link between dRPEDIFF and session types with distinctive external profiles was examined using the Pearson chi-square test of independence. RESULTS: On average, players rated their session perceived breathlessness and leg-muscle exertion differently in 22% of the sessions (range: 0%-64%). Confidence limits for the effect of single external variables on dRPEDIFF spanned across largely positive and negative values for all variables, indicating no conclusive findings. The analysis based on session type indicated that players differentiated more often in matches and intense training sessions, but there was no pattern in the direction of differentiation. CONCLUSIONS: The findings of this study provide no evidence supporting the utility of dRPE for monitoring internal intensity and load in football.

Monitoring Elite Youth Football Players' Physiological State Using a Small-Sided Game: Associations With a Submaximal Running Test.

PURPOSE: To examine the utility of a standardized small-sided game (SSG) for monitoring within-player changes in mean exercise heart rate (HRex) when compared with a submaximal interval shuttle-run test (ISRT). METHODS: Thirty-six elite youth football players (17 [1] y) took part in 6 test sessions across an in-season period (every 4 wk). Sessions consisted of the ISRT (20-m shuttles, 30″:15″ work:rest ratio, 70% maximal ISRT) followed by an SSG (7v7, 80 × 56 m, 6 min). HRex was collected during both protocols, with SSG external load measured as high-speed running distance (>19.8 km·h-1) and acceleration distance (>2 m·s-2). Data were analyzed using linear mixed-effect models. RESULTS: Controlling for SSG external load improved the model fit describing the SSG-ISRT HRex relationship (χ2 = 12.6, P = .002). When SSG high-speed running distance and SSG acceleration distance were held constant, a 1% point change in SSG HRex was associated with a 0.5% point change in ISRT HRex (90% CI: 0.4 to 0.6). Inversely, when SSG HRex was held constant, the effects of a 100-m change in SSG high-speed running distance and a 21-m change in SSG acceleration distance on ISRT HRex were -1.0% (-1.5 to -0.4) and -0.6% points (-1.1 to 0.0), respectively. CONCLUSIONS: An SSG can be used to track within-player changes in HRex for monitoring physiological state. Given the uncertainty in estimates, we advise to only give meaning to changes in SSG HRex >2% points. Additionally, we highlight the importance of considering external load when monitoring SSG HRex.

Atezolizumab with enzalutamide versus enzalutamide alone in metastatic castration-resistant prostate cancer: a randomized phase 3 trial.

Early clinical data indicate that some patients with castration-resistant prostate cancer may benefit from program death ligand-1 (PD-L1) inhibition, especially with enzalutamide. The IMbassador250 trial (no. NCT03016312) enrolled 759 men with metastatic castration-resistant prostate cancer whose disease progressed on abiraterone. The addition of atezolizumab to enzalutamide in an open-label randomized trial did not meet the primary endpoint of improved overall survival in unselected patients (stratified hazard ratio 1.12, 95% confidence interval (0.91, 1.37), P = 0.28), despite an acceptable safety profile. In archival tumor samples, prostate tumors showed comparatively low expression of key immune biomarkers. DNA damage-response alterations, phosphatase and tensin homolog status and PD-L1 expression levels were similar between hormone-sensitive and castration-resistant prostate cancers. In planned biomarker analysis, longer progression-free survival was seen with atezolizumab in patients with high PD-L1 IC2/3, CD8 expression and established immune gene signatures. Exploratory analysis linked progression-free survival in the atezolizumab arm with immune genes such as CXCL9 and TAP1, together with other potentially relevant biomarkers including phosphatase and tensin homolog alterations. Together these data indicate that the expected biology associated with response to immune checkpoint inhibitors is present in prostate cancer, albeit in fewer patients. Careful patient selection may be required for immune checkpoint inhibitors to identify subgroups of patients who may benefit from this treatment approach.

Evaluation of interim PET response criteria in paediatric Hodgkin's lymphoma--results for dedicated assessment criteria in a blinded dual-centre read.

BACKGROUND: The aim of this study was to evaluate the use and reliability of the new positron emission tomography (PET)-based response criteria for interim positron emission tomography (iPET) in patients with paediatric Hodgkin's lymphoma (pHL). Particular emphasis was put on interobserver variability and on identification of a visual cut-off defining patients with very low risk for relapse. PATIENTS AND METHODS: The iPET scans of 39 pHL patients were evaluated in two independent centres by two PET-experienced specialists in nuclear medicine (blinded read, centre consensus) each. The iPET scans were interpreted using a 5-point scale and were compared with the outcome. Cohen's kappa-test (κ) was used to analyse the interobserver agreement. RESULTS: Concordant ratings were assessed in 19 patients with iPET-negative findings, in 11 patients with iPET-positive findings and in 2 patients with inconclusive ratings. A 'substantial agreement' between attended centres was achieved (κ = 0.748). All patients suffering relapse were concordantly identified, taking mediastinal blood pool structures (MBPS) as visual cut-off between PET-positive and PET-negative findings, respectively. All pHL patients with uptake lower than or equal to MBPS remained in complete remission. CONCLUSION(S): The iPET interpretation assured low interobserver variability. High sensitivity for identification of pHL patients suffering relapse is achieved if [18F]-fluorodeoxyglucose uptake above the MBPS value is rated as a PET-positive finding.

Managing the Training Process in Elite Sports: From Descriptive to Prescriptive Data Analytics.

Elite sport practitioners increasingly use data to support training process decisions related to athletes' health and performance. A careful application of data analytics is essential to gain valuable insights and recommendations that can guide decision making. In business organizations, data analytics are developed based on conceptual data analytics frameworks. The translation of such a framework to elite sport may benefit the use of data to support training process decisions. Purpose: The authors aim to present and discuss a conceptual data analytics framework, based on a taxonomy used in business analytics literature to help develop data analytics within elite sport organizations. Conclusions: The presented framework consists of 4 analytical steps structured by value and difficulty/complexity. While descriptive (step 1) and diagnostic analytics (step 2) focus on understanding the past training process, predictive (step 3) and prescriptive analytics (step 4) provide more guidance in planning the future. Although descriptive, diagnostic, and predictive analytics generate insights to inform decisions, prescriptive analytics can be used to drive decisions. However, the application of this type of advanced analytics is still challenging in elite sport. Thus, the current use of data in elite sport is more focused on informing decisions rather than driving them. The presented conceptual framework may help practitioners develop their analytical reasoning by providing new insights and guidance and may stimulate future collaborations between practitioners, researchers, and analytics experts.

Load Monitoring Practice in European Elite Football and the Impact of Club Culture and Financial Resources.

Load monitoring is considered important to manage the physical training process in team sports such as Association Football. Previous studies have described the load monitoring practices of elite English football clubs and clubs with an established sports-science department. An examination of a broader international sample is currently not available. In addition, previous research has suggested factors that may improve the implementation of load monitoring practices, such as a strong club belief on the benefit of evidence-based practice (EBP) and high club financial resources. However, no study has examined yet the actual impact of these factors on the monitoring practices. Therefore, this study aims (1) to provide an overview of load monitoring practices in European elite football and (2) to provide insight into the differences in implementation between clubs by examining the impact of the club beliefs on the benefit of EBP and the club financial resources. An online survey, consisting of multiple choice and Likert scale questions, was distributed among sports-science and sports-medicine staff (n = 99, 50% response rate). Information was asked about the types of data collected, collection purposes, analysis methods, and staff involvement. The results indicated that external load data (e.g., global navigation satellite system, accelerometer…) was collected the most whilst respondents also indicated to collect internal load (e.g., heart rate, rating of perceived exertion…) and training outcome data (e.g., aerobic fitness, neuromuscular fatigue…) for multiple purposes. Considerable diversity in data analysis was observed suggesting that analysis is often limited to reporting the gathered data. Sports-science staff were responsible for data collection and analysis. Other staff were involved in data discussion to share decision-making. These practices were positively impacted by a stronger club belief on the benefit of EBP and greater financial resources. Creating an organizational culture, characterized by a strong belief on the benefit of EBP, is important to increase the impact of load monitoring. However, the actual potential may still be largely determined by financial resources. High-level clubs could therefore play a leading role in generating and sharing knowledge to improve training practices and player health.

Load Monitoring Practice in Elite Women Association Football.

The description of current load monitoring practices may serve to highlight developmental needs for both the training ground, academia and related industries. While previous studies described these practices in elite men's football, no study has provided an overview of load monitoring practices in elite women's football. Given the clear organizational differences (i.e., professionalization and infrastructure) between men's and women's clubs, making inferences based on men's data is not appropriate. Therefore, this study aims to provide a first overview of the current load monitoring practices in elite women's football. Twenty-two elite European women's football clubs participated in a closed online survey (40% response rate). The survey consisted of 33 questions using multiple choice or Likert scales. The questions covered three topics; type of data collected and collection purpose, analysis methods, and staff member involvement. All 22 clubs collected data related to different load monitoring purposes, with 18 (82%), 21 (95%), and 22 (100%) clubs collecting external load, internal load, and training outcome data, respectively. Most respondents indicated that their club use training models and take into account multiple indicators to analyse and interpret the data. While sports-science staff members were most involved in the monitoring process, coaching, and sports-medicine staff members also contributed to the discussion of the data. Overall, the results of this study show that most elite women's clubs apply load monitoring practices extensively. Despite the organizational challenges compared to men's football, these observations indicate that women's clubs have a vested interest in load monitoring. We hope these findings encourage future developments within women's football.

External load differences between elite youth and professional football players: ready for take-off?

This study examines differences in weekly load between the first (FT) and the under 19 team (U19) within a professional football setting. Data were collected in 11 FT and 9 U19 players (2016-2017 season). FT data was divided into weeks with (FT-M1) or without (FT-M0) a mid-week match. Indicators were total distance (TD) and TD at 12-15, 15-20, 20-25 and >25 km‧h-1 and were analysed as external load (m), intensity (m‧min-1) and load monotony (a.u.). TD-based load was higher for U19 compared to FT-M0 (very likely moderate) and FT-M1 (likely large). Differences at higher velocities were substantially less (trivial to possibly small), with TD >25 km‧h-1 being lower than FT-M0 (very likely moderate) and FT-M1 (likely small). All intensity indicators were lower for U19 (likely small to almost certainly large). Load monotony was higher compared to FT-M1 (possibly small to almost certainly very large). Compared to FT-M0, monotony was higher for TD (possibly very large) and TD >25 km‧h­1 (possibly moderate) but lower for TD 12-15 (possibly small) and 15-20 km‧h­1 (likely moderate). So, despite higher weekly external loads at low velocity for elite youth players, external intensity and load variation increases when these players may transition to professional football.

A Phase Ib Study of Atezolizumab with Radium-223 Dichloride in Men with Metastatic Castration-Resistant Prostate Cancer.

PURPOSE: Men with metastatic castration-resistant prostate cancer (mCRPC) have limited treatment options after progressing on hormonal therapy and chemotherapy. Here, we evaluate the safety and efficacy of atezolizumab (anti-PD-L1) + radium-223 dichloride (radium-223) in men with mCRPC. PATIENTS AND METHODS: This phase Ib study evaluated atezolizumab + radium-223 in men with mCRPC and bone and lymph node and/or visceral metastases that progressed after androgen pathway inhibitor treatment. Following safety assessment of concurrent dosing, 45 men were randomized 1:1:1 to concurrent or one of two staggered dosing schedules with either agent introduced one cycle before the other. This was followed by a safety-efficacy expansion cohort (randomized 1:1:1). The primary endpoints were safety and objective response rate (ORR) by RECIST 1.1. Secondary endpoints included radiographic progression-free survival (rPFS), PSA responses, and overall survival (OS). RESULTS: As of October 4, 2019, 44 of 45 men were evaluable. All 44 had ≥1 all-cause adverse event (AE); 23 (52.3%) had a grade 3/4 AE. Fifteen (34.1%) grade 3/4 and 3 (6.8%) grade 5 AEs were related to atezolizumab; none were related to radium-223. Confirmed ORR was 6.8% [95% confidence interval (CI), 1.4-18.7], median rPFS was 3.0 months (95% CI, 2.8-4.6), median PSA progression was 3.0 months (95% CI, 2.8-3.3), and median OS was 16.3 months (95% CI, 10.9-22.3). CONCLUSIONS: This phase Ib study demonstrated that atezolizumab + radium-223, regardless of administration schedule, had greater toxicity than either drug alone, with no clear evidence of additional clinical benefit for patients with mCRPC and bone and lymph node and/or visceral metastases.

Genome Sequences of Akoni, Ashton, and Truong, Podoviridae Bacteriophages Isolated from Microbacterium foliorum.

Cluster EK2 Akoni, Ashton, and Truong are lytic Podoviridae actinobacteriophages that were isolated from soil in Florida using Microbacterium foliorum NRRL B-24224 as the host. The genomes are 54,307 bp, 54,560 bp, and 54,309 bp, respectively, and are 60% GC rich. Each genome contains a novel 13,464-bp gene that encompasses 25% of the genome.

Recombinant human TSH versus hypothyroidism. Cost-minimization-analysis in the follow-up care of differentiated thyroid carcinoma.

UNLABELLED: The primary aim of this study was to compare pharmacoeconomic effects of hypothyroidism secondary to hormone withdrawal (THW) and recombinant human TSH (rhTSH) for follow-up WBS in patients with differentiated thyroid cancer (DTC). The second aim was to determine patients' preference for one procedure or the other. PATIENTS, METHODS: This retrospective survey included 327 patients with DTC who underwent at least one in-hospital WBS with rhTSH between 1999 and 2006. They had also undergone THW for WBS. Patients received a two-page questionnaire via mail addressing five symptoms and ten items regarding managing their daily life which was answered by 61.6%. The responder group did not differ from the entire group. The medical and societal cost of both procedures for diagnostic WBS was calculated including direct and all ascertainable indirect cost for the reference year 2005. A sensitivity analysis included the German DRG system of 2007 and 2010. RESULTS: After THW, 94% of patients reported hypothyroid symptoms. Using rhTSH, symptoms occurred significantly less. As a result, 97% of patients favored rhTSH over THW. Mean absence from salaried work was 12.3 days after THW compared to 4 days with rhTSH. Family members of salaried employees missed 3 and 0.7 workdays after THW and rhTSH, respectively. Almost twice as often, medical attention was sought after THW (36%) compared to rhTSH (19 %). Undergoing THW, 48% of patients still used their car while hypothyroid. Our cost calculation revealed a slight benefit of about 89.00 Euro in favour of rhTSH stimulation. CONCLUSION: Hypothyroidism after THW causes significant morbidity and safety risks. The clinical and societal benefits associated with rhTSH are roughly gained at equivalent overall cost to that of THW.