Higher-Order Inter-chromosomal Hubs Shape 3D Genome Organization in the Nucleus.

Eukaryotic genomes are packaged into a 3-dimensional structure in the nucleus. Current methods for studying genome-wide structure are based on proximity ligation. However, this approach can fail to detect known structures, such as interactions with nuclear bodies, because these DNA regions can be too far apart to directly ligate. Accordingly, our overall understanding of genome organization remains incomplete. Here, we develop split-pool recognition of interactions by tag extension (SPRITE), a method that enables genome-wide detection of higher-order interactions within the nucleus. Using SPRITE, we recapitulate known structures identified by proximity ligation and identify additional interactions occurring across larger distances, including two hubs of inter-chromosomal interactions that are arranged around the nucleolus and nuclear speckles. We show that a substantial fraction of the genome exhibits preferential organization relative to these nuclear bodies. Our results generate a global model whereby nuclear bodies act as inter-chromosomal hubs that shape the overall packaging of DNA in the nucleus.

Dopamine activity in the nigrostriatal pathway alters cue-induced risky choice patterns in female rats.

Deficits in cost/benefit decision making is a critical risk factor for gambling disorder. Reward-paired cues may play an important role, as these stimuli can enhance risk preference in rats. Despite extensive research implicating the dorsal striatum in the compulsive aspects of addiction, the role of nigrostriatal dopaminergic activity in cue-induced risk preference remains unclear, particularly in females. Accordingly, we examined the effects of manipulating the dopaminergic nigrostriatal pathway on cue-induced risky choice in female rats. TH:Cre rats were trained on the cued version of the rat Gambling Task. This task was designed such that maximal reward is attained by avoiding the high-risk, high-reward options and instead favouring the options associated with lower per-trial gains, as they feature less frequent and shorter time-out penalties. Adding reward-paired audiovisual cues to the task leads to greater risky choice on average. To assess the role of the nigrostriatal pathway, a viral vector carrying either Cre-dependent inhibitory or excitatory DREADD was infused into the substantia nigra. Rats then received clozapine-N-oxide either during task acquisition or after a stable performance baseline was reached. Inhibition of this pathway accelerated the development of risk preference in early sessions and increased risky choice during performance, but long-term inhibition actually improved decision making. Activation of this pathway had minimal effects. These results provide evidence for the involvement of the dopaminergic nigrostriatal pathway in cue-induced risk preference in females, therefore shedding light on its role in cost/benefit decision-making deficits and expanding our knowledge of the female dopaminergic system.

Validation of the Revised Illness Perception Questionnaire of Obstructive Sleep Apnea among Elderly Chinese in the General Population.

PURPOSE: The prevalence of under-diagnosis among individuals with obstructive sleep apnea (OSA) is alarming, and may be associated with perceptions regarding OSA. To facilitate future studies on OSA, this study validated the revised version of the Illness Perception Questionnaire (IPQ-R) for OSA in a general population. METHODS: A random anonymous population-based telephone survey interviewed 580 adults aged ≥ 50 years in Hong Kong, who self-reported not having been told by doctors as having OSA, from February 5 to March 19, 2021. RESULTS: The confirmatory factor analysis identified a modified 7-factor model (i.e., timeline chronic, consequence, personal control, treatment control, illness coherence, timeline cyclical, and emotional representation) that showed satisfactory model fit index and internal consistency. Nine items were removed from the original version because of low factor loadings. No floor and ceiling effects were observed. Convergent validity was supported by the positive associations between the consequence subscale with perceived negative outcomes of OSA and between the illness coherence subscale and perceived understanding of OSA symptoms. The participants tended to endorse the items of timeline chronic, treatment control, and illness coherence but not with those of emotional representations. The mean scores of the IPQ-R subscales differed by age and education level. CONCLUSION: The modified IPQ-R of OSA showed acceptable psychometric properties. It is applicable to assessing illness perceptions of OSA in the Chinese general population aged ≥ 50 years not having received OSA diagnosis. The validated tool would support future studies and health practices related to OSA.

The Acute Effect of High-Intensity Resistance Training on Subsequent Firefighter Performance.

ABSTRACT: Mason, MR, Heebner, NR, Abt, JP, Bergstrom, HC, Shapiro, R, Langford, EL, and Abel, MG. The acute effect of high-intensity resistance training on subsequent firefighter performance. J Strength Cond Res 37(7): 1507-1514, 2023-High-intensity resistance training (HIRT) is commonly performed by structural firefighters on duty to enhance occupational readiness. However, exercise-induced fatigue may negatively impact subsequent occupational performance. Therefore, the purpose of this study was to assess the acute effect of HIRT on subsequent occupational physical ability in structural firefighters and to determine the time course of recovery. Seven resistance-trained male firefighters performed a timed maximal effort simulated fireground test (SFGT) in 3 randomized conditions: baseline (SFGT baseline ), 10 minutes post HIRT (SFGT 10min ), and 60 minutes post HIRT (SFGT 60min ). Work efficiency and air depletion were assessed during the SFGT. The timed HIRT session consisted of a standardized set of exercises using absolute training loads. Repeated measures analysis of variance and minimal difference (MD) analysis assessed group and individual effects between the conditions, respectively. The level of significance was set at p < 0.05. SFGT 10min completion time was greater than SFGT baseline (430 ± 137 vs. 297 ± 69 seconds, p < 0.01), with no difference between SFGT baseline and SFGT 60min (297 ± 69 vs. 326 ± 89 seconds, p = 0.08). The MD analysis indicated that all firefighters' SFGT 10min times exceeded the MD (±26.4 seconds) compared with SFGT baseline . However, 43% of firefighters still exceeded the MD at SFGT 60min . Air depletion during SFGT 10min was greater than that during SFGT baseline (2,786 ± 488 vs. 2,186 ± 276 lb·in -2 , p = 0.02), with no difference between SFGT baseline and SFGT 60min ( p = 0.25). Work efficiency during SFGT 10min was 40% lower than that during SFGT baseline ( p < 0.01), with no difference between SFGT baseline and SFGT 60min ( p = 0.25). These findings indicate that an acute bout of HIRT decreases multiple descriptors of firefighters' occupational performance 10 minutes post exercise with varied responses at 60 minutes post exercise.

Development and validation of the conservation of resources scale for COVID-19 in the Chinese adult general population.

Globally, the coronavirus disease 2019 (COVID-19) pandemic has caused severe and multi-dimensional resource losses among individuals. The Conservation of Resource (COR) theory postulates that resource loss generates related stress responses. It can suitably be applied to understand the pandemic's encompassing adverse consequences. Yet, no assessment tool exists. This study hence developed and validated the COR Scale for COVID-19 (CORS-COVID-19) to facilitate relevant research. The five hypothesized domains included losses in financial resource, family resource, future control, fun, and social resource. A population-based random telephone survey interviewed 300 Chinese adults in the general population in Hong Kong, China during April 3-10, 2020. The levels of different types of resource losses were high (especially for loss in fun). The 5-factor structure identified by factor analysis matches with the five hypothesized dimensions. Its psychometric properties are acceptable, including good internal consistency, content validity (the correlations between the items and their respective subscales were stronger than that between the items and the other four subscales), concurrent validity (significant correlations between the scale/subscale scores and both emotional distress due to COVID-19 and satisfaction with living in Hong Kong), and convergent validity (significant correlations between specific subscales and corresponding external variables). Relatively high floor effects were detected in some subscales. The scale, which is the first of the types to assess resource losses during a pandemic, can provide theory-based understandings/assessment about the negative impacts of COVID-19. It also facilitates warranted comparisons across countries and time periods in future studies. Supplementary Information: The online version contains supplementary material available at 10.1007/s12144-021-01933-y.

Sustained Coinfections with Staphylococcus aureus and Pseudomonas aeruginosa in Cystic Fibrosis.

Rationale: Staphylococcus aureus and Pseudomonas aeruginosa often infect the airways in cystic fibrosis (CF). Because registry studies show higher prevalence of P. aeruginosa versus S. aureus in older patients with CF, a common assumption is that P. aeruginosa replaces S. aureus over time. In vitro, P. aeruginosa can outgrow and kill S. aureus. However, it is unknown how rapidly P. aeruginosa replaces S. aureus in patients with CF.Methods: We studied a longitudinal cohort of children and adults with CF who had quantitative sputum cultures. We determined the abundance of P. aeruginosa and S. aureus in cfu/ml. We determined the duration and persistence of infections and measured longitudinal changes in culture positivity and abundance for each organism.Measurements and Main Results: Between 2004 and 2017, 134 patients had ≥10 quantitative cultures, with median observation time of 10.15 years. One hundred twenty-four patients had at least one positive culture for P. aeruginosa, and 123 had at least one positive culture for S. aureus. Both species had median abundance of >106 cfu/ml. Culture abundance was stable over time for both organisms. There was an increase in the prevalence of S. aureus/P. aeruginosa coinfection but no decrease in S. aureus prevalence within individuals over time.Conclusions: S. aureus and P. aeruginosa are abundant in CF sputum cultures. Contrary to common assumption, we found no pattern of replacement of S. aureus by P. aeruginosa. Many patients with CF have durable long-term coinfection with these organisms. New strategies are needed to prevent and treat these infections.

Working from home and positive/negative experiences due to social distancing as interacting factors of depressive symptoms during the COVID-19 pandemic in a Chinese general population.

PURPOSE: This study investigated the associations between some factors related to working from home status (WFHS) and positive/negative experiences due to social distancing and their interactions effects on depressive symptoms during the COVID-19 pandemic. METHODS: A random population-based telephone survey interviewed income-earning adults in the Hong Kong general population during April 21-28, 2020 (n = 200). RESULTS: Mild to severe depression (according to PHQ-9) was reported by 12% of the participants. The prevalence of WFHS categories was 14% for 3-7 days and 13% for ≥ 8 days (past 2 weeks). The multivariable regression analysis showed that, social isolation (ß = 0.36; p < 0.001), relaxation feeling in daily life (ß = - 0.22; p = 0.002), and WFHS ≥ 8 days (ß = 0.15; p = 0.027), but not perceived huge inconvenience and improved family relationship, were associated with depressive symptoms. Statistically significant interaction effects were found. Some positive experiences buffered the potential harms of some negative experiences of social distancing on depressive symptoms; WFHS ≥ 8 days significantly moderated the risk/protective effects of social isolation, improved family relationship, and relaxation feeling on depressive symptoms. CONCLUSIONS: Social distancing is double-edged. Positive experiences should be maximized while negative experiences be minimized, as both were directly and interactively associated with depression. Intensive but not mild to moderate (< 80%) WFHS may impact depressive symptoms negatively via its direct association with depression; it also moderated the associations between positive/negative experiences due to social distancing and depression. Further research is required to discern the inter-relationships among WFHS, positive/negative experiences of social distancing, and depression to better cope with the stressful pandemic.

Changes in physical activity during the initial stages of the COVID-19 pandemic.

INTRODUCTION: The COVID-19 pandemic response limited access to many traditional forms of physical activity (PA). Purpose:To assess changes in objectively measured PAofUniversity staff during the initial stageofthe COVID-19 pandemic. METHODS: We implemented a repeated measures natural experiment design. PA data (walking distance, steps∙d#x2D;1, and Moderate#x2D;to#x2D;Vigorous PA (MVPA) time) from commercial grade triaxial accelerometers were collected from employees (N#x3D;625) of a large, public university in the southeast United States during the months of Jan#x2D;May in calendar years 2019 and 2020. RESULTS: Walking distance (6#x2D;9#x25;, p#x3C;0.001) and steps∙d#x2D;1(7#x2D;11#x25;, p#x3C;0.001) were lower during April and May 2020 compared to 2019. However, MVPA time was not significantly different among calendar years for the months of March#x2D;May. Steps∙d#x2D;1significantly decreased after WHO's worldwide pandemic declaration (10,348#xB1;171 v. 9551#xB1;156 steps∙d#x2D;1, p#x3C;0.001) and campus closure (10,100#xB1;160 v. 9,186#xB1;167 steps∙d#x2D;1, p#x3C;0.001). Conversely, steps∙d#x2D;1significantly increased after implementation of the state's "Healthy at Home" order (9,693#xB1;177 vs. 10,156#xB1;185 steps∙d#x2D;1, p#x3C;0.001). CONCLUSION: A decrease in daily steps, but not MVPA, suggests increased sedentary behavior, not reduced participation in exercise, during the early stages of the COVID#x2D;19 pandemic. Specific pandemic response policies may positively or negatively affect PA and sedentary behavior.

Potential joint effects of perceptions related to COVID-19 and future social development on depressive symptoms: a Chinese population-based study.

BACKGROUND: The COVID-19 pandemic has caused significant negative socio-political, economic, and psychological consequences. AIMS: To investigate the impact of individual-level (illness representations of COVID-19) and structurally derived (anticipated social-political development in the economy, security, and social harmony in the next year) factors, and their potential moderation effects on depressive symptoms. METHODS: An anonymous population-based telephone survey was conducted among the general public of Hong Kong, China during 3-10 April 2020 (n = 300, response rate 56%). Depressive symptoms were assessed by the validated Chinese version of the Patient Health Questionnaire-9. RESULTS: Of the participants, 8.7% showed probable moderate-to-severe depression. Hierarchical linear regression models showed that illness representations of personal/treatment control and emotional responses and anticipated deterioration in social harmony were independently and significantly associated with depressive symptoms. Anticipated deterioration in security significantly moderated the associations between perceived consequence/treatment control of COVID-19 and depressive symptoms, such that the associations were stronger among people who anticipated a strong deterioration in security. CONCLUSIONS: The findings suggested that perceptions of COVID-19 and future social-political development jointly and interactively contributed to depressive symptoms during the COVID-19 pandemic. Mental health professionals and promotions should take the multiple-level mental health determinants into account.

Evaluation of cognitive effort in rats is not critically dependent on ventrolateral orbitofrontal cortex.

Organisms must frequently evaluate the amount of effort to invest in pursuing future rewards. Despite explicit awareness of the potential benefits of cognitive work, individuals vary in their willingness to attempt cognitively demanding tasks, regardless of intellectual ability. Such differences may suggest that the degree to which cognitive effort degrades perceived outcome value is a subjective, rather than objective, process, similar to risk and delay discounting. Although numerous studies suggest the orbitofrontal cortex (OFC) is important for allowing subjective value estimates to be updated and/or used in cost/benefit decision-making, the causal role of the OFC in valuations of mental effort has received scant investigation. We therefore trained 24 female Long-Evans rats on the rodent cognitive effort task (rCET) and assessed performance following temporary bilateral inactivation of the ventrolateral OFC (vlOFC). In the rCET, rats decide at trial outset whether to perform an easy or hard attentional challenge, namely to localize a brief visual stimulus to one of five possible locations. The difficulty of the challenge is determined by the stimulus duration (1.0 vs. 0.2s for easy vs. hard trials respectively), and success on hard trials results in double the sugar pellet rewards. Somewhat surprisingly, inactivations of the vlOFC did not affect rats' willingness or ability to exert cognitive effort for larger rewards, despite increasing omissions and motor impulsivity on-task. When considered with previous work, it appears the vlOFC plays a minimal role in cognitive effort allocation specifically, and in valuations of effort more generally.

Men's experiences of radiotherapy treatment for localized prostate cancer and its long-term treatment side effects: a longitudinal qualitative study.

PURPOSE: To investigate men's experiences of receiving external-beam radiotherapy (EBRT) with neoadjuvant Androgen Deprivation Therapy (ADT) for localized prostate cancer (LPCa) in the ProtecT trial. METHODS: A longitudinal qualitative interview study was embedded in the ProtecT RCT. Sixteen men with clinically LPCa who underwent EBRT in ProtecT were purposively sampled to include a range of socio-demographic and clinical characteristics. They participated in serial in-depth qualitative interviews for up to 8 years post-treatment, exploring experiences of treatment and its side effects over time. RESULTS: Men experienced bowel, sexual, and urinary side effects, mostly in the short term but some persisted and were bothersome. Most men downplayed the impacts, voicing expectations of age-related decline, and normalizing these changes. There was some reticence to seek help, with men prioritizing their relationships and overall health and well-being over returning to pretreatment levels of function. Some unmet needs with regard to information about treatment schedules and side effects were reported, particularly among men with continuing functional symptoms. CONCLUSIONS: These findings reinforce the importance of providing universal clear, concise, and timely information and supportive resources in the short term, and more targeted and detailed information and care in the longer term to maintain and improve treatment experiences for men undergoing EBRT.

Safety of Baricitinib 4 mg for the Treatment of Moderate to Severe Rheumatoid Arthritis.

OBJECTIVE: We evaluated the safety of baricitinib 4 mg at 24 weeks for the treatment of moderate to severe rheumatoid arthritis (RA). METHODS: Multiple databases were searched from inception up to November 26, 2019 for randomized controlled trials comparing baricitinib 4 mg with placebo for the treatment of moderate to severe RA. The safety outcomes of interest were the incidence of serious adverse events, adverse events leading to study discontinuation, all infections, and serious infections. Adjusted risk ratios (RRs) with 95% confidence intervals (CIs) were pooled for safety outcomes. The Cochrane tool was used to assess the risk of bias. RESULTS: This analysis included four randomized controlled trials with 3106 patients. For serious adverse events, the pooled RR (95% CI) was 1.09 (0.76-1.57). For adverse events leading to study discontinuation, the pooled RR (95% CI) was 1.41 (0.94-2.11). For all reported infections, the pooled RR (95% CI) was 1.24 (1.10-1.40), For serious infections, pooled RR (95% CI) was 0.97 (0.51-2.57). CONCLUSIONS: Patients with RA taking 4 mg baricitinib daily did have an increased risk of infections; however, the incidence of serious adverse events, adverse events leading to study discontinuation, or serious infections were not significantly different in patients treated with baricitinib 4 mg compared with placebo.

Subfamily-specific quantification of endogenous mouse L1 retrotransposons by droplet digital PCR.

Long interspersed element type 1 (LINE-1; L1) mobilizes during early embryogenesis, neurogenesis, and germ cell development, accounting for 25% of disease-causing heritable insertions and 98% of somatic insertions in cancer. To better understand the regulation and impact of L1 mobilization in the genome, reliable methods for measuring L1 copy number variation (CNV) are needed. Here we present a comprehensive analysis of a droplet digital PCR (ddPCR) based method for quantifying endogenous mouse L1. We provide experimental evidence that ddPCR assays can be designed to target specific L1 subfamilies using diagnostic single nucleotide polymorphisms (SNPs). The target and off-target L1 subfamilies form distinct droplet clusters, which were experimentally verified using both synthetic gene fragments and endogenous L1 derived plasmid clones. We further provide a roadmap for in silico assay design and evaluation of target specificity, ddPCR testing, and optimization for L1 CNV quantification. The assay can achieve a sensitivity of 5% CNV with 8 technical replicates. With 24 technical replicates, it can detect 2% CNV because of the increased precision. The same approach will serve as a guide for the development of ddPCR based assays for quantifying human L1 copy number and any other high copy genomic target sequences.

An easy-to-perform, culture-free Campylobacter point-of-management assay for processing plant applications.

AIMS: Current culture-based methods for detection and determination of Campylobacter levels on processed chickens takes at least 2 days. Here we sought to develop a new complete, low-cost and rapid (approximately 2·5 h) detection system requiring minimal operator input. METHODS AND RESULTS: We observed a strong correlation between culture-based cell counts and our ability to detect either Campylobacter jejuni or Campylobacter coli by loop-mediated isothermal amplification from the same samples. This knowledge was used to develop a rapid and simple five-step assay to quantify Campylobacter, which was subsequently assessed for its specificity, reproducibility and accuracy in quantifying Campylobacter levels from processed chickens. The assay was found to be highly specific for C. jejuni and C. coli and was capable of distinguishing between samples that are either within or exceeding the industry set target of 6000 Campylobacter colony forming units (CFU) per carcass (equivalent to 12 CFU per ml of chicken rinse) with >90% accuracy relative to culture-based methods. CONCLUSIONS: Our method can reliably quantify Campylobacter counts of processed chickens with an accuracy comparable to culture-based assays but provides results within hours as opposed to days. SIGNIFICANCE AND IMPACT OF THE STUDY: The research presented here will help improve food safety by providing fast Campylobacter detection that will enable the implementation of real-time risk management strategies in poultry processing plants to rapidly test processed chickens and identify effective intervention strategies. This technology is a powerful tool that can be easily adapted for other organisms and thus could be highly beneficial for a broad range of industries.

The National Psoriasis Foundation psoriasis treatment targets in real-world patients: prevalence and association with patient-reported outcomes in the Corrona Psoriasis Registry.

INTRODUCTION: The National Psoriasis Foundation (NPF) published treat-to-target guidelines for psoriasis, yet their applicability in clinical practice remains unknown. OBJECTIVES: To estimate the proportion of psoriasis patients meeting the NPF's body surface area (BSA) 'target' (≤1%) and 'acceptable' (≤3%) response criteria and the cross-sectional associations of these criteria with patient-reported outcomes (PROs) in the Corrona Psoriasis Registry. METHODS: Separately for three independent cross-sectional cohorts of patients at the (i) enrolment, (ii) 6-month and (iii) 12-month visits, we calculated the proportion of patients with BSA ≤1% and ≤3%. Furthermore, we calculated odds ratios estimating the risk of PROs associated with not meeting criteria in the 6-month cohort. RESULTS: The enrolment, 6- and 12-month cohorts included 2794, 1310 and 629 patients, respectively. At enrolment, 24% of patients had a BSA ≤ 1% and 41% a BSA ≤ 3%. In the 6-month cohort, 43%/64% had a BSA ≤ 1%/BSA ≤ 3%. In the 12-month cohort, 46%/69% of patients had a BSA ≤ 1%/BSA ≤ 3%. Patients not at target/acceptable criteria had higher odds for worse quality of life compared with those who were. CONCLUSION: While most patients at 6- and 12-month visits were at the 'acceptable' response, less than half were at the 'target' response despite systemic therapy. There remain unmet needs to optimize psoriasis therapy and further validate current treat-to-target guidelines.

Psychometric properties and normative data of the 10-item Connor-Davidson Resilience Scale among Chinese adolescent students in Hong Kong.

This study aimed to assess the psychometric properties of the 10-item Connor-Davidson Resilience Scale (CD-RISC10) and generate normative data for Chinese adolescents. A total of 24,499 participants (male 52.1%, mean age 13.3 years) were enrolled in the school-based survey among 132 secondary schools in Hong Kong during 2017. The CD-RISC10 showed high reliability and confirmatory factor analysis supported a unidimensional structure. Metric invariance across the gender, age, and grade subgroups was demonstrated. CD-RISC10 scores were positively correlated with psychological well-being and negatively correlated with mental distress. Male and younger students had higher resilience scores. There were significant interaction effects of gender and age/grade, with CD-RISC10 scores decreasing with age/grade in females while similar trends were not observed in males. Overall, the findings suggest that CD-RISC10 is appropriate for use in Chinese adolescents. The availability of normative data will facilitate the interpretation and comparison of research results in future studies.

Patient-Reported Outcomes after Monitoring, Surgery, or Radiotherapy for Prostate Cancer.

BACKGROUND: Robust data on patient-reported outcome measures comparing treatments for clinically localized prostate cancer are lacking. We investigated the effects of active monitoring, radical prostatectomy, and radical radiotherapy with hormones on patient-reported outcomes. METHODS: We compared patient-reported outcomes among 1643 men in the Prostate Testing for Cancer and Treatment (ProtecT) trial who completed questionnaires before diagnosis, at 6 and 12 months after randomization, and annually thereafter. Patients completed validated measures that assessed urinary, bowel, and sexual function and specific effects on quality of life, anxiety and depression, and general health. Cancer-related quality of life was assessed at 5 years. Complete 6-year data were analyzed according to the intention-to-treat principle. RESULTS: The rate of questionnaire completion during follow-up was higher than 85% for most measures. Of the three treatments, prostatectomy had the greatest negative effect on sexual function and urinary continence, and although there was some recovery, these outcomes remained worse in the prostatectomy group than in the other groups throughout the trial. The negative effect of radiotherapy on sexual function was greatest at 6 months, but sexual function then recovered somewhat and was stable thereafter; radiotherapy had little effect on urinary continence. Sexual and urinary function declined gradually in the active-monitoring group. Bowel function was worse in the radiotherapy group at 6 months than in the other groups but then recovered somewhat, except for the increasing frequency of bloody stools; bowel function was unchanged in the other groups. Urinary voiding and nocturia were worse in the radiotherapy group at 6 months but then mostly recovered and were similar to the other groups after 12 months. Effects on quality of life mirrored the reported changes in function. No significant differences were observed among the groups in measures of anxiety, depression, or general health-related or cancer-related quality of life. CONCLUSIONS: In this analysis of patient-reported outcomes after treatment for localized prostate cancer, patterns of severity, recovery, and decline in urinary, bowel, and sexual function and associated quality of life differed among the three groups. (Funded by the U.K. National Institute for Health Research Health Technology Assessment Program; ProtecT Current Controlled Trials number, ISRCTN20141297 ; ClinicalTrials.gov number, NCT02044172 .).

Relative contribution of clinicopathological variables, genomic markers, transcriptomic subtyping and microenvironment features for outcome prediction in stage II/III colorectal cancer.

BACKGROUND: It remains unknown to what extent consensus molecular subtype (CMS) groups and immune-stromal infiltration patterns improve our ability to predict outcomes over tumor-node-metastasis (TNM) staging and microsatellite instability (MSI) status in early-stage colorectal cancer (CRC). PATIENTS AND METHODS: We carried out a comprehensive retrospective biomarker analysis of prognostic markers in adjuvant chemotherapy-untreated (N = 1656) and treated (N = 980), stage II (N = 1799) and III (N = 837) CRCs. We defined CMS scores and estimated CD8+ cytotoxic lymphocytes (CytoLym) and cancer-associated fibroblasts (CAF) infiltration scores from bulk tumor tissue transcriptomes (CMSclassifier and MCPcounter R packages); constructed a stratified multivariable Cox model for disease-free survival (DFS); and calculated the relative proportion of explained variation by each marker (clinicopathological [ClinPath], genomics [Gen: MSI, BRAF and KRAS mutations], CMS scores [CMS] and microenvironment cells [MicroCells: CytoLym+CAF]). RESULTS: In multivariable models, only ClinPath and MicroCells remained significant prognostic factors, with both CytoLym and CAF infiltration scores improving survival prediction beyond other markers. The explained variation for DFS models of ClinPath, MicroCells, Gen markers and CMS4 scores was 77%, 14%, 5.3% and 3.7%, respectively, in stage II; and 55.9%, 35.1%, 4.1% and 0.9%, respectively, in stage III. Patients whose tumors were CytoLym high/CAF low had better DFS than other strata [HR=0.71 (0.6-0.9); P = 0.004]. Microsatellite stable tumors had the strongest signal for improved outcomes with CytoLym high scores (interaction P = 0.04) and the poor prognosis linked to high CAF scores was limited to stage III disease (interaction P = 0.04). CONCLUSIONS: Our results confirm that tumor microenvironment infiltration patterns represent potent determinants of the risk for distant dissemination in early-stage CRC. Multivariable models suggest that the prognostic value of MSI and CMS groups is largely explained by CytoLym and CAF infiltration patterns.

Addition of docetaxel to hormonal therapy in low- and high-burden metastatic hormone sensitive prostate cancer: long-term survival results from the STAMPEDE trial.

BACKGROUND: STAMPEDE has previously reported that the use of upfront docetaxel improved overall survival (OS) for metastatic hormone naïve prostate cancer patients starting long-term androgen deprivation therapy. We report on long-term outcomes stratified by metastatic burden for M1 patients. METHODS: We randomly allocated patients in 2 : 1 ratio to standard-of-care (SOC; control group) or SOC + docetaxel. Metastatic disease burden was categorised using retrospectively-collected baseline staging scans where available. Analysis used Cox regression models, adjusted for stratification factors, with emphasis on restricted mean survival time where hazards were non-proportional. RESULTS: Between 05 October 2005 and 31 March 2013, 1086 M1 patients were randomised to receive SOC (n = 724) or SOC + docetaxel (n = 362). Metastatic burden was assessable for 830/1086 (76%) patients; 362 (44%) had low and 468 (56%) high metastatic burden. Median follow-up was 78.2 months. There were 494 deaths on SOC (41% more than the previous report). There was good evidence of benefit of docetaxel over SOC on OS (HR = 0.81, 95% CI 0.69-0.95, P = 0.009) with no evidence of heterogeneity of docetaxel effect between metastatic burden sub-groups (interaction P = 0.827). Analysis of other outcomes found evidence of benefit for docetaxel over SOC in failure-free survival (HR = 0.66, 95% CI 0.57-0.76, P < 0.001) and progression-free survival (HR = 0.69, 95% CI 0.59-0.81, P < 0.001) with no evidence of heterogeneity of docetaxel effect between metastatic burden sub-groups (interaction P > 0.5 in each case). There was no evidence that docetaxel resulted in late toxicity compared with SOC: after 1 year, G3-5 toxicity was reported for 28% SOC and 27% docetaxel (in patients still on follow-up at 1 year without prior progression). CONCLUSIONS: The clinically significant benefit in survival for upfront docetaxel persists at longer follow-up, with no evidence that benefit differed by metastatic burden. We advocate that upfront docetaxel is considered for metastatic hormone naïve prostate cancer patients regardless of metastatic burden.

What is the optimal systemic treatment of men with metastatic, hormone-naive prostate cancer? A STOPCAP systematic review and network meta-analysis.

Background: Our prior Systemic Treatment Options for Cancer of the Prostate systematic reviews showed improved survival for men with metastatic hormone-naive prostate cancer when abiraterone acetate plus prednisolone/prednisone (AAP) or docetaxel (Doc), but not zoledronic acid (ZA), were added to androgen-deprivation therapy (ADT). Trial evidence also suggests a benefit of combining celecoxib (Cel) with ZA and ADT. To establish the optimal treatments, a network meta-analysis (NMA) was carried out based on aggregate data (AD) from all available studies. Methods: Overall survival (OS) and failure-free survival data from completed Systemic Treatment Options for Cancer of the Prostate reviews of Doc, ZA and AAP and from recent trials of ZA and Cel contributed to this comprehensive AD-NMA. The primary outcome was OS. Correlations between treatment comparisons within one multi-arm, multi-stage trial were estimated from control-arm event counts. Network consistency and a common heterogeneity variance were assumed. Results: We identified 10 completed trials which had closed to recruitment, and one trial in which recruitment was ongoing, as eligible for inclusion. Results are based on six trials including 6204 men (97% of men randomised in all completed trials). Network estimates of effects on OS were consistent with reported comparisons with ADT alone for AAP [hazard ration (HR) = 0.61, 95% confidence interval (CI) 0.53-0.71], Doc (HR = 0.77, 95% CI 0.68-0.87), ZA + Cel (HR = 0.78, 95% CI 0.62-0.97), ZA + Doc (HR = 0.79, 95% CI 0.66-0.94), Cel (HR = 0.94 95% CI 0.75-1.17) and ZA (HR = 0.90 95% CI 0.79-1.03). The effect of ZA + Cel is consistent with the additive effects of the individual treatments. Results suggest that AAP has the highest probability of being the most effective treatment both for OS (94% probability) and failure-free survival (100% probability). Doc was the second-best treatment of OS (35% probability). Conclusions: Uniquely, we have included all available results and appropriately accounted for inclusion of multi-arm, multi-stage trials in this AD-NMA. Our results support the use of AAP or Doc with ADT in men with metastatic hormone-naive prostate cancer. AAP appears to be the most effective treatment, but it is not clear to what extent and whether this is due to a true increased benefit with AAP or the variable features of the individual trials. To fully account for patient variability across trials, changes in prognosis or treatment effects over time and the potential impact of treatment on progression, a network meta-analysis based on individual participant data is in development.