Population-based study of disease trajectory after radical treatment for high-risk prostate cancer.

OBJECTIVES: To investigate long-term disease trajectories among men with high-risk localized or locally advanced prostate cancer (HRLPC) treated with radical radiotherapy (RT) or radical prostatectomy (RP). MATERIAL AND METHODS: Men diagnosed with HRLPC in 2006-2020, who received primary RT or RP, were identified from the Prostate Cancer data Base Sweden (PCBaSe) 5.0. Follow-up ended on 30 June 2021. Treatment trajectories and risk of death from prostate cancer (PCa) or other causes were assessed by competing risk analyses using cumulative incidence for each event. RESULTS: In total, 8317 men received RT and 4923 men underwent RP. The median (interquartile range) follow-up was 6.2 (3.6-9.5) years. After RT, the 10-year risk of PCa-related death was 0.13 (95% confidence interval [CI] 0.12-0.14) and the risk of death from all causes was 0.32 (95% CI 0.31-0.34). After RP, the 10-year risk of PCa-related death was 0.09 (95% CI 0.08-0.10) and the risk of death from all causes was 0.19 (95% CI 0.18-0.21). The 10-year risks of androgen deprivation therapy (ADT) as secondary treatment were 0.42 (95% CI 0.41-0.44) and 0.21 (95% CI 0.20-0.23) after RT and RP, respectively. Among men who received ADT as secondary treatment, the risk of PCa-related death at 10 years after initiation of ADT was 0.33 (95% CI 030-0.36) after RT and 0.27 (95% CI 0.24-0.30) after RP. CONCLUSION: Approximately one in 10 men with HRLPC who received primary RT or RP had died from PCa 10 years after diagnosis. Approximately one in three men who received secondary ADT, an indication of PCa progression, died from PCa 10 years after the start of ADT. Early identification and aggressive treatment of men with high risk of progression after radical treatment are warranted.

A US real-world study of treatment patterns and outcomes in localized or locally advanced prostate cancer patients.

PURPOSE: Men with localized or locally advanced prostate cancer (LPC/LAPC) are at risk of progression after radiotherapy (RT) or radical prostatectomy (RP). Using real-world data, we evaluated patient characteristics, treatment patterns, and outcomes in LPC/LAPC. METHODS: Optum claims and electronic health records (EHR) data from January 2010 to December 2021 were queried for men with LPC/LAPC who received primary RT, RP, or androgen deprivation therapy alone within 180 days after diagnosis. Survival outcomes were analyzed using descriptive statistics and Kaplan-Meier curves. Real-world overall survival (rwOS) was compared in patients with and without evidence of disease (i.e., disease recurrence, metastasis, diagnosis of castration-resistant PC) at defined time points. RESULTS: 61,772 and 62,361 men in claims and EHR cohorts met the inclusion criteria. Median follow-up was 719 and 901 days, respectively. Most men received primary RT (51.0% claims, 35.0% EHR) or RP (39.4% claims, 53.8% EHR). Survival was greatest among men treated with RP, followed by RT. Adjusted for age and comorbidity, rwOS was shorter among men with evidence of disease within 1, 3, 4, and 5 years after primary treatment than those without at the same time points. CONCLUSION: Real-world claims and EHR data show that survival among men with LPC/LAPC differs by primary treatment and time point of disease recurrence thereafter. Poor outcomes in men with LPC/LAPC who progress early indicate an unmet medical need for more effective primary treatment. If validated for surrogacy, no evidence of disease at specific time points could represent an intermediate efficacy endpoint in future trials.

Ustekinumab in the Management of Hidradenitis Suppurativa: A Retrospective Study.

Hidradenitis suppurativa (HS) is a chronic, inflammatory skin disease characterized by the formation of recurrent abscesses in apocrine-bearing areas. In advanced stages, chronic inflammation leads to sinus tract formation and cicatrization.

Quality-of-life changes following three-dimensional printing of prosthesis for large nasal septal perforations-Our experience of 13 patients.

Nasal septal perforations can be caused by a number of aetiology including intra-nasal drug abuse, trauma and iatrogenic causes.

A new look at the developmental profile of visual endogenous orienting.

There is a long-standing assumption that covert measurement of orienting, the shifting of the "mind's eye" independent of a saccade to a location in space, is a more "pure" measure of underlying attention than overt measurement of orienting. Testing attention covertly often relies on target detection tasks, which depend on making a decision about when and where a target has appeared and what is the appropriate action, all of which are potential confounds in measuring attention in children. This study cross-sectionally examined developmental profiles at ages 6-12  years of endogenous visual orienting. We used two tasks: one that measured orienting with a traditional covert attention button press response and one that measured orienting with eye tracking to measure overt saccades. The results obtained from the two orienting tasks demonstrate that each task measures distinct underlying processes with clear developmental profiles. Orienting, when measured by overt saccades, may be mature by 6 years of age, whereas the more complex manual response selection skills required in manual reaction time covert attention tasks continue to develop through middle childhood.

Pre-diagnostic blood immune markers, incidence and progression of B-cell lymphoma and multiple myeloma: Univariate and functionally informed multivariate analyses.

Recent prospective studies have shown that dysregulation of the immune system may precede the development of B-cell lymphomas (BCL) in immunocompetent individuals. However, to date, the studies were restricted to a few immune markers, which were considered separately. Using a nested case-control study within two European prospective cohorts, we measured plasma levels of 28 immune markers in samples collected a median of 6 years before diagnosis (range 2.01-15.97) in 268 incident cases of BCL (including multiple myeloma [MM]) and matched controls. Linear mixed models and partial least square analyses were used to analyze the association between levels of immune marker and the incidence of BCL and its main histological subtypes and to investigate potential biomarkers predictive of the time to diagnosis. Linear mixed model analyses identified associations linking lower levels of fibroblast growth factor-2 (FGF-2 p = 7.2 × 10-4 ) and transforming growth factor alpha (TGF-α, p = 6.5 × 10-5 ) and BCL incidence. Analyses stratified by histological subtypes identified inverse associations for MM subtype including FGF-2 (p = 7.8 × 10-7 ), TGF-α (p = 4.08 × 10-5 ), fractalkine (p = 1.12 × 10-3 ), monocyte chemotactic protein-3 (p = 1.36 × 10-4 ), macrophage inflammatory protein 1-alpha (p = 4.6 × 10-4 ) and vascular endothelial growth factor (p = 4.23 × 10-5 ). Our results also provided marginal support for already reported associations between chemokines and diffuse large BCL (DLBCL) and cytokines and chronic lymphocytic leukemia (CLL). Case-only analyses showed that Granulocyte-macrophage colony stimulating factor levels were consistently higher closer to diagnosis, which provides further evidence of its role in tumor progression. In conclusion, our study suggests a role of growth-factors in the incidence of MM and of chemokine and cytokine regulation in DLBCL and CLL.

Results of an early access treatment protocol of daratumumab in United States patients with relapsed or refractory multiple myeloma.

BACKGROUND: Daratumumab is a human CD38-directed monoclonal antibody indicated for the treatment of relapsed and refractory multiple myeloma (MM). METHODS: A multicenter, open-label treatment protocol provided early access to daratumumab for patients who had progressive MM after they received ≥3 prior lines of therapy that included a proteasome inhibitor and an immunomodulatory agent or if they were refractory to both a proteasome inhibitor and an immunomodulatory agent. Patients received daratumumab 16 mg/kg weekly for 8 weeks, every other week for 16 weeks, and monthly until they developed disease progression, unacceptable toxicity, or 60 days after the drug gained US approval. Treatment-emergent grade ≥3 adverse events (AEs), serious AEs, and AEs of special interest were collected. RESULTS: Three hundred forty-eight patients were enrolled at 39 US sites between June and December 2015. Patients received study therapy for a median of 1.9 months (range, 0.03-6.0 months). Fifty-two percent of patients transitioned to commercially-available daratumumab and 37% discontinued because of progressive disease. Grade ≥3 AEs occurred in 50% of patients, including thrombocytopenia (15%) and anemia (14%). Serious AEs occurred in 35% of patients (12% were drug-related), including infections (11%). Infusion reactions occurred in 56%, 2%, and 2% of patients during the first, second, and all subsequent infusions, respectively; respiratory symptoms (cough, dyspnea, throat irritation, nasal congestion) were common. The infusion reaction rate for the first infusion was 38% in 50 patients at 2 sites who received montelukast as premedication for their first infusion and 59% in patients who did not receive montelukast. CONCLUSIONS: The current findings are consistent with previously reported trials and confirm the safety profile of daratumumab in heavily pretreated US patients who have relapsed or refractory MM. Cancer 2018;124:000-000.

The INTEROCC case-control study: risk of meningioma and occupational exposure to selected combustion products, dusts and other chemical agents.

BACKGROUND: Little is known about occupational risk factors for meningioma. OBJECTIVES: To study whether risk of meningioma is associated with several occupational exposures, including selected combustion products, dusts and other chemical agents. METHODS: The INTEROCC study was an international case-control study of brain cancer conducted in seven countries. Data collection by interview included lifetime occupational histories. A job exposure matrix was used to derive estimates of exposure for the 12 agents. ORs for ever versus never exposed and for exposure-response using duration of exposure and cumulative exposure were derived using conditional logistic regression stratified by sex, age group, country/region, adjusted for education. RESULTS: These analyses included 1906 cases and 5565 controls. For 11 of the 12 agents, no excess risk was found for ever exposed. For ever exposure to oil mists, an elevated OR of 1.57 (95% CI 1.10 to 2.22, 51 exposed cases) was found. Statistically significant exposure-response relationships were observed with cumulative exposure (p=0.01) and duration of exposure (p=0.04). Among women, there were also significant trends for cumulative and duration of exposure to asbestos and excesses in the highest exposure categories for formaldehyde. CONCLUSIONS: Most agents examined did not provoke excess risks of meningioma. The main finding from this study is that it is the first study to identify a statistical association between exposure to oil mists and meningioma. This may be a chance finding or could be due to confounding with iron exposure and further research is required to understand whether the relationship is causal.

Changing place of death in children who died after discharge from paediatric intensive care units: A national, data linkage study.

BACKGROUND: Although child mortality is decreasing, more than half of all deaths in childhood occur in children with a life-limiting condition whose death may be expected. AIM: To assess trends in place of death and identify characteristics of children who died in the community after discharge from paediatric intensive care unit. DESIGN: National data linkage study. SETTING/PARTICIPANTS: All children resident in England and Wales when admitted to a paediatric intensive care unit in the United Kingdom (1 January 2004 and 31 December 2014) were identified in the Paediatric Intensive Care Audit Network dataset. Linkage to death certificate data was available up to the end of 2014. Place of death was categorised as hospital (hospital or paediatric intensive care unit) or community (hospice, home or other) for multivariable logistic modelling. RESULTS: The cohort consisted of 110,328 individuals. In all, 7709 deaths occurred after first discharge from paediatric intensive care unit. Among children dying, the percentage in-hospital at the time of death decreased from 83.8% in 2004 to 68.1% in 2014; 852 (0.8%) of children were discharged to palliative care. Children discharged to palliative care were eight times more likely to die in the community than children who died and had not been discharged to palliative care (odds ratio = 8.06 (95% confidence interval = 6.50-10.01)). CONCLUSIONS: The proportion of children dying in hospital is decreasing, but a large proportion of children dying after discharge from paediatric intensive care unit continue to die in hospital. The involvement of palliative care at the point of discharge has the potential to offer choice around place of care and death for these children and families.

Renal Replacement Therapy in the Critically Ill Child.

OBJECTIVES: Although renal replacement therapy is widely used in critically ill children, there have been few comprehensive population-based studies of its use. This article describes renal replacement therapy use, and associated outcomes, in critically ill children across the United Kingdom in the largest cohort study of this patient group. DESIGN: A retrospective observational study using prospectively collected data. SETTING: Data from the Pediatric Intensive Care Audit Network database which collects data on all children admitted to U.K. PICUs. PATIENTS: Children (< 16 yr) in PICU who received renal replacement therapy between January 1, 2005, and December 31, 2012, were identified. INTERVENTIONS: Individual-level data including age, underlying diagnosis, modality (peritoneal dialysis and continuous extracorporeal techniques [continuous renal replacement therapy]), duration of renal replacement therapy, PICU length of stay, and survival were extracted. MEASUREMENTS AND MAIN RESULTS: Three-thousand eight-hundred twenty-five of 129,809 PICU admissions (2.9%) received renal replacement therapy in 30 of 33 centers. Volumes of renal replacement therapy varied considerably from 0% to 8.6% of PICU admissions per unit, but volume was not associated with patient survival. Overall survival to PICU discharge (73.8%) was higher than previous reports. Mortality risk was related to age, with lower risk in older children compared with neonates (odds ratio, 0.6; 95% CI, 0.5-0.8) although mortality did not increase over the age of 1 year; mode of renal replacement therapy, with lower risk in peritoneal dialysis than continuous renal replacement therapy methodologies (odds ratio, 0.7; 0.5-0.9); duration of renal replacement therapy (odds ratio, 1.02/d; 95% CI, 1.01-1.04); and primary diagnosis, with the lowest survival in liver disease patients (53.9%). CONCLUSIONS: This study describes current renal replacement therapy use across the United Kingdom and associated outcomes. We describe a number of factors associated with outcome, including age, underlying diagnosis, and renal replacement therapy modality which will need to be factored into future trial design.

Occupational solvent exposure and risk of glioma in the INTEROCC study.

BACKGROUND: The aetiology of glioma remains largely unknown. Occupational solvent exposure has been suggested as a putative cause of glioma, but past studies have been inconsistent. We examined the association between a range of solvents and glioma risk within the INTEROCC project, a study of brain tumours and occupational exposures based on data from seven national case-control studies conducted in the framework of the INTERPHONE study. We also investigated associations according to tumour grade. METHODS: Data from the seven countries were standardised and then combined into one aggregate data set. Pooled odds ratios (ORs) were estimated for adjusted models that included sex, age, country-region of residence and level of educational attainment. Exposures to any solvent or 11 specific solvents or subgroups were assessed using a modified version of the FINJEM job exposure matrix (JEM) specifically developed for the study, called INTEROCC-JEM. RESULTS: Analysis included 2000 glioma cases and 5565 controls. For glioma and ever/never exposure to any solvent, the OR was 0.91 (95% confidence interval: 0.74-1.11). All ORs were <1.0 for specific solvents/subgroups. There were no increases in risk according to high or low grade of tumour. CONCLUSIONS: The results of this study show no consistent associations for any solvent exposures overall or by grade of tumour.

Outcomes for Children Receiving Noninvasive Ventilation as the First-Line Mode of Mechanical Ventilation at Intensive Care Admission: A Propensity Score-Matched Cohort Study.

OBJECTIVES: To compare outcomes of children receiving noninvasive ventilation with those receiving invasive ventilation as first-line mode of mechanical ventilation following unplanned intensive care admission. DESIGN: Propensity score-matched cohort study analyzing data prospectively collected by the Pediatric Intensive Care Audit Network over 8 years (2007-2014). SETTING: Thirty-one PICUs in the United Kingdom and Ireland; twenty-one of whom submitted Pediatric Critical Care Minimum Dataset data for the entire study period. PATIENTS: Children consecutively admitted to study PICUs. Planned admissions following surgery, unplanned admissions from other hospitals, those on chronic ventilation, and those who did not receive mechanical ventilation on the day of PICU admission were excluded. INTERVENTIONS: Use of noninvasive ventilation, rather than invasive ventilation, as the first-line mode of mechanical ventilation. MEASUREMENTS AND MAIN RESULTS: PICU mortality, length of ventilation, length of PICU stay, and ventilator-free days at day 28. During the study period, there were 151,128 PICU admissions. A total of 15,144 admissions (10%) were eligible for analysis once predefined exclusion criteria were applied: 4,804 (31.7%) received "noninvasive ventilation first," whereas 10,221 (67.5%) received "invasive ventilation first"; 119 (0.8%) admissions could not be classified. Admitting PICU site explained 6.5% of the variation in first-line mechanical ventilation group (95% CI, 2.0-19.0%). In propensity score-matched analyses, receiving noninvasive ventilation first was associated with a significant reduction in mortality by 3.1% (95% CI, 1.7-4.6%), length of ventilation by 1.6 days (95% CI, 1.0-2.3), and length of PICU stay by 2.1 days (95% CI, 1.3-3.0), as well as an increase in ventilator-free days at day 28 by 3.7 days (95% CI, 3.1-4.3). CONCLUSIONS: Use of noninvasive ventilation as first-line mode of mechanical ventilation in critically ill children admitted to PICU in an unplanned fashion may be associated with significant clinical benefits. Further high-quality evidence regarding optimal patient selection and timing of initiation of noninvasive ventilation could lead to less variability in clinical care between institutions and improved patient outcomes.