Clinical effectiveness and safety of olaparib in BRCA-mutated, HER2-negative metastatic breast cancer in a real-world setting: final analysis of LUCY.

PURPOSE: The interim analysis of the phase IIIb LUCY trial demonstrated the clinical effectiveness of olaparib in patients with germline BRCA-mutated (gBRCAm), human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (mBC), with median progression-free survival (PFS) of 8.11 months, which was similar to that in the olaparib arm of the phase III OlympiAD trial (7.03 months). This prespecified analysis provides final overall survival (OS) and safety data. METHODS: The open-label, single-arm LUCY trial of olaparib (300 mg, twice daily) enrolled adults with gBRCAm or somatic BRCA-mutated (sBRCAm), HER2-negative mBC. Patients had previously received a taxane or anthracycline for neoadjuvant/adjuvant or metastatic disease and up to two lines of chemotherapy for mBC. RESULTS: Of 563 patients screened, 256 (gBRCAm, n = 253; sBRCAm, n = 3) were enrolled. In the gBRCAm cohort, median investigator-assessed PFS (primary endpoint) was 8.18 months and median OS was 24.94 months. Olaparib was clinically effective in all prespecified subgroups: hormone receptor status, previous chemotherapy for mBC, previous platinum-based chemotherapy (including by line of therapy), and previous cyclin-dependent kinase 4/6 inhibitor use. The most frequent treatment-emergent adverse events (TEAEs) were nausea (55.3%) and anemia (39.2%). Few patients (6.3%) discontinued olaparib owing to a TEAE. No deaths associated with AEs occurred during the study treatment or 30-day follow-up. CONCLUSION: The LUCY patient population reflects a real-world population in line with the licensed indication of olaparib in mBC. These findings support the clinical effectiveness and safety of olaparib in patients with gBRCAm, HER2-negative mBC. CLINICAL TRIAL REGISTRATION: Clinical trials registration number: NCT03286842.

The moderating role of dispositional mindfulness in the associations of morningness-eveningness with depressive and anxiety symptoms.

Several studies have shown that eveningness is positively related to both depressive and anxiety symptoms. However, little is known about factors that may play a protective role against the undesirable emotional consequences of evening preference. Thus, in the present study, we explored the moderating effects of dispositional mindfulness on the relationship between morningness-eveningness and the presence of depressive symptoms, as well as between morningness-eveningness and the presence of anxiety symptoms. The study was conducted on a group of 1107 individuals (559 women and 548 men) aged 18-55 years (M = 36.26, SD = 9.89). Consistent with previous findings, eveningness was positively related to the presence of both depressive and anxiety symptoms. The magnitude of these effects decreased with higher dispositional mindfulness. The latter result remained significant when the analogical moderating effects of personality, established in earlier studies, were controlled for in the regression models. This leads to the conclusion that dispositional mindfulness may act as a protective factor against the elevated depressive and anxiety symptoms reported by evening-oriented individuals.

The Influence of Air Humidity on the Output Signal from an Ionization Smoke Detector in the Presence of Soot Nanoparticles.

In 2019, the European Committee for Standardization (CEN) initiated work on the preparation of a strategy for air quality monitoring at workplaces. The aim was to determine the concentrations of nano-objects and their aggregates and agglomerates (NOAA) by means of direct measurements using low-cost sensors. There is a growing need for low-cost devices that can continuously monitor the concentrations of nanoparticles, and that can be installed where nanoparticles are used or created spontaneously. In search of such a device, in this study, a smoke detector with an ionization sensor was tested. The aim of the research was to investigate the response of the analog output signal with respect to changes in environmental parameters such as the relative humidity of air. The research was conducted in controlled laboratory conditions, and the results confirmed that an ionization detector could be used to measure the concentrations of nanoaerosols. The modified smoke detector detected soot particles smaller than 100 nm. The linear regression line was calculated for the relative humidity dataset and had a slope coefficient of -1.214 × 10-4; thus, the value of the output signal was constant during the experiment. The dependence on air temperature was approximated by a second-degree curve, with a slope coefficient of -8.113 × 10-2. Air humidity affected aerosol concentrations, which may be related to surface modification of nanoparticles.

Therapeutic relationship and professional burnout in psychotherapists: A structural equation model approach.

Previous studies on the therapists' burnout have focused on individual and environmental risk factors. This study aimed to analyse whether variables reflecting therapeutic relationship-the therapist experience of relational depth and quality of the therapeutic relationship-can be related to psychotherapist burnout. Four alternative path models were examined. A total of 101 humanistic-experiential psychotherapists, aged between 29 and 86 years, participated in the research. The Relational Depth Frequency Scale, the Scale to Assess the Therapeutic Relationship, the Psychological Well-Being Scale and the Link Burnout Questionnaire were applied to the research. The results showed that relational depth and therapeutic quality correlated negatively with psychotherapist burnout. Relational depth is the main predictor of psychological well-being and psychotherapist burnout through its effect on therapeutic quality. The experiences of relational depth, primarily of person-centred therapists, have positive psychological potential in predicting lower professional burnout.

Relational depth from the perspective of the psychotherapy dyad: Psychometric properties of the Relational Depth Frequency Scale.

Objective: The Relational Depth Frequency Scale (RDFS) is a 6-item measure to assess the impact of relational depth experiences on psychotherapeutic outcomes. To date, the RDFS has only been validated in online samples of clinical and non-clinical individuals. This study aimed to examine the psychometric properties of the RDFS in clinical dyads of clients and psychotherapists.Method: A total of 86 psychotherapy dyads-86 psychotherapists (18 male, 68 female, mean age = 44.34) and 86 clients (17 male, 69 female, mean age = 34.22)-completed the RDFS, and the Scale to Assess the Psychotherapeutic Relationship (STAR), mid-psychotherapy.Results: CFA showed acceptable fit statistics for a one-factor model. The partial measurement invariance across both partners of the psychotherapeutic dyad was positively verified. The RDFS had good internal consistency for psychotherapists and clients (α = .90 and .81, respectively). Actor-partner interdependence model confirmed moderate to high levels of convergent validity against the STAR. Relational depth in both partners was predicted by their own perceptions of the quality of the psychotherapeutic relationship. Psychotherapist frequency of relational depth was also related to client perceptions of the psychotherapeutic relationship.Conclusion: The RDFS is a promising tool measuring relational depth both from psychotherapist and client perspectives.

Genomic prediction of avian influenza infection outcome in layer chickens.

Avian influenza (AI) is a devastating poultry disease that currently can be controlled only by liquidation of affected flocks. In spite of typically very high mortality rates, a group of survivors was identified and genotyped on a 600K single nucleotide polymorphism (SNP) chip to identify genetic differences between survivors, and age- and genetics-matched controls from unaffected flocks. In a previous analysis of this dataset, a heritable component was identified and several regions that are associated with outcome of the infection were localized but none with a large effect. For complex traits that are determined by many genes, genomic prediction models using all SNPs across the genome simultaneously are expected to optimally exploit genomic information. In this study, we evaluated the diagnostic value of genomic estimated breeding values for predicting AI infection outcome within and across two highly pathogenic avian influenza viral strains and two genetic lines of layer chickens using receiver operating curves. We show that genomic prediction based on the 600K SNP chip has the potential to predict disease outcome especially within the same strain of virus (area under receiver operating curve above 0.7), but did not predict well across genetic varieties (area under receiver operating curve of 0.43).

Metacognitive model of mindfulness.

Mindfulness training has proven to be an efficacious therapeutic tool for a variety of clinical and nonclinical health problems and a booster of well-being. In this paper we propose a multi-level metacognitive model of mindfulness. We postulate and discuss following hypothesis: (1) mindfulness is related to the highest level of metacognition; (2) mindfulness depends on dynamic cooperation of three main components of the metacognition (metacognitive knowledge, metacognitive experiences and metacognitive skills); (3) a mindful meta-level is always conscious while the other meta-cognitive processes can occur implicitly; (4) intentionally practiced mindfulness decreases dissociations between awareness and meta-awareness; (5) components of mindful meta-level develop and change during continuous practice. The current model is discussed in the light of empirical data and other theoretical approaches to mindfulness concept. We believe that presented model provides some helpful avenues for future research and theoretical investigations into mindfulness and the mechanisms of its actions.

The Significance of Keratinized Mucosa in Implant Therapy: Narrative Literature Review and Case Report Presentation.

Background/Objectives: Implant treatment in patients who require teeth extraction due to periodontitis presents a significant challenge. The consideration of peri-implantitis is crucial when planning the placement of dental implants. The predictability of implant treatment relies on the suitability of both hard and soft tissue quality. The aim of this article is to present a case report demonstrating a secure treatment protocol for implant procedures in patients with periodontitis requiring the extraction of all teeth, soft tissue management targeted at increasing the keratinized mucosa zone, and the provision of a reliable prosthetic solution. The secondary objective is to review the relevant literature regarding the significance of keratinized mucosa surrounding dental implants and its association with the occurrence of peri-implantitis. Case presentation: A 65-year-old female with generalized periodontitis, stage IV grade C and very poor oral hygiene came for treatment and rehabilitation of the lower jaw. CBCT revealed periodontal lesions and labio-lingual ridge dimensions in the region of teeth 34-44 from 8.0 to 10.2 mm. The first surgery included teeth extraction and periodontal lesions enucleation with simultaneous placement of four implants in the positions of teeth 32, 34, 42, 44. The second-stage surgery involved increasing the keratinized mucosa using two free gingival grafts. Conclusions: The present case report described the treatment process of the patient with periodontitis, including immediate implantation in the infected region, soft tissue augmentation using free gingival grafts and the ultimate placement of a bar-retained overdenture for final restoration. After two years of observation, despite questionable hygiene, no symptoms of gingival inflammation were detected. Furthermore, there is limited information in the literature regarding the correlation between inadequate keratinized gingiva and the occurrence of peri-implantitis.

[Risk assessment and toxicity effects of materials used during additive manufacturing with FDM technology]. / Ocena zagrozen i dzialanie toksyczne materialów stosowanych podczas drukowania przestrzennego w technologii FDM.

This paper discusses the potential of additive printing, the risks it poses to users' health (including 3D printer operators) and the effects of chemical substances released during the printing based on the available in vitro and in vivo studies. It was shown that substances emitted during printing with the commonly used acrylonitrile butadiene styrene filament in additive manufacturing might have carcinogenic, hepatotoxic and teratogenic effects, as well as toxic effect on the respiratory system. The latest research on the mechanism of formation of particles and volatile organic compounds during 3D printing, the parameters affecting their potential emission, and trends in reducing these hazards are indicated. The need for the design of more environmentally friendly and less emissive printing materials, as well as strategies for prevention and individual and collective protection measures are emphasized. Users of 3D printers should be familiar with all possible aspects of the threats associated with the printing process. Insufficient data on direct exposure to chemicals and particles released during the use of filaments makes it difficult to build awareness of safe working practices. Of particular concern is the health impact of emitted chemicals and particles from thermally treated materials in one of the most popular technologies for 3D printing, i.e., fused deposition modelling. Exposure of the users to, e.g., plasticizers added to filaments occurs through a variety of routes, by absorption through the skin, by inhalation or ingestion. Available epidemiological data, as well as current experimental works, indicate that such exposure is a high risk of cardiovascular diseases, atherosclerosis in adults, and cardiac problems and metabolic disorders in children. This review, by identifying potential risk factors, may contribute to reducing the health loss of printer users and improving working conditions and safety, especially in enterprises where additive manufacturing technology is used. Med Pr Work Health Saf. 2024;75(2):159-171.

Skeletal facial asymmetry: reliability of manual and artificial intelligence-driven analysis.

OBJECTIVES: To compare artificial intelligence (AI)-driven web-based platform and manual measurements for analysing facial asymmetry in craniofacial CT examinations. METHODS: The study included 95 craniofacial CT scans from patients aged 18-30 years. The degree of asymmetry was measured based on AI platform-predefined anatomical landmarks: sella (S), condylion (Co), anterior nasal spine (ANS), and menton (Me). The concordance between the results of automatic asymmetry reports and manual linear 3D measurements was calculated. The asymmetry rate (AR) indicator was determined for both automatic and manual measurements, and the concordance between them was calculated. The repeatability of manual measurements in 20 randomly selected subjects was assessed. The concordance of measurements of quantitative variables was assessed with interclass correlation coefficient (ICC) according to the Shrout and Fleiss classification. RESULTS: Erroneous AI tracings were found in 16.8% of cases, reducing the analysed cases to 79. The agreement between automatic and manual asymmetry measurements was very low (ICC < 0.3). A lack of agreement between AI and manual AR analysis (ICC type 3 = 0) was found. The repeatability of manual measurements and AR calculations showed excellent correlation (ICC type 2 > 0.947). CONCLUSIONS: The results indicate that the rate of tracing errors and lack of agreement with manual AR analysis make it impossible to use the tested AI platform to assess the degree of facial asymmetry.

Pembrolizumab-combination therapy for NSCLC- effectiveness and predictive factors in real-world practice.

Introduction: Pembrolizumab combined with chemotherapy has become the standard of care for patients with non-small-cell lung cancer (NSCLC) and the expression of programmed death ligand 1 (PD-L1) in <50% of tumour cells (TC). Methods: We evaluated the efficacy of the treatment in real-world practice, paying attention to the predictive factors, with a special focus on low level of PD-L1 expression. This study is a multicenter retrospective analysis of patients with stage IV NSCLC. Results: A group of 339 consecutive patients was analysed, among them 51% patients with low PD-L1 expression. In the overall population, the ORR was 40.6%, median PFS and OS were 13 months (95% CI 11.4-15) and 16.8 months (95% CI 13.3-20.3), respectively. In multivariate analysis for the entire study population, performance status - ECOG 1 vs. 0 (HR 2.2, 95%CI 1.1-4.6; p=0.02), neutrophil to lymphocyte ratio (NLR)>3 (HR 2.3, 95%CI 1.3-4.2; p=0.04), presence of liver (HR 2.0, 95%CI 1-3.7; p=0. 03) and bone metastases (HR 1.3, 95%CI 1-3; p=0.04), weight loss (HR 1.8, 95%CI 1.1-2.8; p=0.01) and sum of measurable lesions diameters >110 mm (HR 1.7, 95%CI 1-2.9, p=0.049) had a negative impact on OS. Conclusions: In the real world, patients can clinically benefit from immunochemotherapy, regardless of the expression of PD-L1 and the histological type. Other clinicopathological factors such as performance status, extent, and location of secondary lesions have prognostic significance.

Genome-wide association study for Marek's disease mortality in layer chickens.

A genome-wide association study (GWAS) using Bayesian variable selection was performed to determine genomic regions associated with mortality due to Marek's disease virus (MDV) infection in layers. Mortality (%) under experimental disease challenge (500 plaque-forming units of a very virulent plus MDV strain) was recorded for progeny groups (average 15.5 birds; range 3 to 30) of 253 genotyped sires from four generations of a brown-egg layer line. An additional generation of 43 sires with progeny data was used to validate results. Sires were genotyped with a 42K Illumina single-nucleotide polymorphism (SNP) chip. Methods BayesB (pi = 0.995) and BayesCpi, with or without weighting residuals by the size of progeny groups were applied. The proportion of genetic variance contributed by SNPs within each 1-megabase (Mb) genomic region was quantified. Average mortality was 33% but differed significantly between generations. Genetic markers explained about 11% of phenotypic variation in mortality. Correlations between genomic estimated breeding values and percentage of progeny mortality for the validation generation (sons of individuals in training) were 0.12, 0.17, 0.02, and 0.16 for BayesB, weighted BayesB, BayesCpi, and weighted BayesCpi, respectively, when using the whole genome, and 0.03, 0.20, -0.06, and 0.14, when using only SNP from the 10, 1-Mb regions, explaining the largest proportion of genetic variance according to each method. Results suggest that regions on chromosomes 2, 3, 4, 9, 15, 18, and 21 are associated with Marek's disease resistance and can be used for selection and that accounting for the size of progeny groups has a large impact on correct localization of such genomic regions.

Pedigree and genomic analyses of feed consumption and residual feed intake in laying hens.

Efficiency of production is increasingly important with the current escalation of feed costs and demands to minimize the environmental footprint. The objectives of this study were 1) to estimate heritabilities for daily feed consumption and residual feed intake and their genetic correlations with production and egg-quality traits; 2) to evaluate accuracies of estimated breeding values from pedigree- and marker-based prediction models; and 3) to localize genomic regions associated with feed efficiency in a brown egg layer line. Individual feed intake data collected over 2-wk trial periods were available for approximately 6,000 birds from 8 generations. Genetic parameters were estimated with a multitrait animal model; methods BayesB and BayesCπ were used to estimate marker effects and find genomic regions associated with feed efficiency. Using pedigree information, feed efficiency was found to be moderately heritable (h(2) = 0.46 for daily feed consumption and 0.47 for residual feed intake). Hens that consumed more feed and had greater residual feed intake (lower efficiency) had a genetic tendency to lay slightly more eggs with greater yolk weights and albumen heights. Regions on chromosomes 1, 2, 4, 7, 13, and Z were found to be associated with feed intake and efficiency. The accuracy from genomic prediction was higher and more persistent (better maintained across generations) than that from pedigree-based prediction. These results indicate that genomic selection can be used to improve feed efficiency in layers.

A cognitive perspective on mindfulness.

Mindfulness, the core teaching of the Buddhist tradition, has been receiving serious attention from the West in recent decades as evidence of the efficacy of mindfulness-based interventions for emotional distress have become available. Although traditional Buddhist texts have described the mechanisms of mindfulness and the way to cultivate it in great detail, much is still not known from the perspective of Western science. In particular, there is no general agreement on the conceptualization and operationalization of mindfulness. Several conceptual models of mindfulness (referred to as "state" or "trait") have been put forward to elucidate different aspects of this phenomenon, but none has gained sufficient empirical validation. This article proposes a new cognitive model of mindfulness. It has been our goal to describe and interrelate a relatively comprehensive group of determinants of a state of mindfulness, the consequences of its regular practicing, the mechanisms responsible for its beneficial effects, and the feedback mechanisms operating between the various constituents of the model. Within this model, the primary emphasis has been placed on understanding the cognitive processes shaping a state of mindfulness (i.e., the links between consciousness, meta-awareness and the unconscious), and on their determinants (i.e., the executive functions of attention and the components of working memory). A metacognitive system promoting mindfulness, as well as the general capability of the central executive system, is suggested as a factor explaining individual differences in mindfulness, whereas decentering, self-compassion, and reduction of self-focused attention are proposed as mechanisms mediating beneficial changes. We hope that the model presented will encourage further discussion and orient future studies in the area of mindfulness.

Pressure Drop Dynamics during Filtration of Mixture Aerosol Containing Water, Oil, and Soot Particles on Nonwoven Filters.

The pressure drop dynamics during the filtration of three-component mixture aerosols are investigated and compared with two and single-component aerosols. The main area of interest is the effect of the addition of a small quantity of liquid (oil) and solid (soot) particles during the filtration of aerosol containing water mist. In addition, calculations of the change in filter mass during oil aerosol filtration have been carried out and compared with the experimental results. The new, improved filtration efficiency model takes into account a better coefficient fitting in the filtration mechanism equations. The limitations in the change in fibre diameter and packing density resulting from the filter loading have been implemented in the model. Additionally, the calculation model employs the fibre size distribution representation via multiple average fibre diameters. The changes in fibre diameter are dependent on each fibre's calculated filtration efficiency. The improved filtration model has been utilised to predict the mass change of the filters during the filtration of pure and mixture aerosols. The pressure drop calculation model based on changes in filter mass has been formulated. The model is then utilised to calculate pressure drop changes resulting from the filtration of the oil aerosol and water and oil mixture aerosol.

The value of metal artifact reduction and iterative algorithms in dual energy CT angiography in patients after complex endovascular aortic aneurysm repair.

Rationale and objectives: Evaluation of the diagnostic value of linearly blended (LB) and virtual monoenergetic images (VMI) reconstruction techniques with and without metal artifacts reduction (MAR) and of adaptive statistical iterative reconstructions (ASIR) in the assessment of target vessels after branched/fenestrated endovascular aortic repair (f/brEVAR) procedures. Materials and methods: CT scans of 28 patients were used in this study. Arterial phase of examination was obtained using a dual-energy fast-kVp switching scanner. CT numbers in the aorta, celiac trunk, superior mesenteric artery, and renal arteries were measured in the following reconstructions: LB, VMI 60 keV, VMI MAR 60 keV, VMI ASIR 60 % 60 keV. Contrast-to-noise ratio (CNR) and signal-to-noise ratio (SNR) were calculated for each reconstruction. Luminal diameters (measurements at 2 levels of stent) and subjective image quality (5-point Likert scale) were assessed (2 readers, blinded to the type of reconstruction). Results: The highest mean values of CNR and SNR in vascular structures were obtained in VMI MAR 60 keV (CNR 12.526 ± 2.46, SNR 17.398 ± 2.52), lower in VMI 60 keV (CNR 11.508 ± 2.01, SNR 16.524 ± 2.07) and VMI ASIR (CNR 11.086 ± 1.78, SNR 15.928 ± 1.82), and the lowest in LB (CNR 6.808 ± 0.79, SNR 11.492 ± 0.79) reconstructions. There were no statistically significant differences in the measurements of the stent width between reconstructions (p > 0.05). The highest subjective image quality was obtained in the ASIR VMI (4.25 ± 0.44) and the lowest in the MAR VMI (1.57 ± 0.5) reconstruction. Conclusion: Despite obtaining the highest values of SNR and CNR in the MAR VMI reconstruction, the subjective diagnostic value was the lowest for this technique due to significant artifacts. The type of reconstruction did not significantly affect vessel diameter measurements (p > 0.05). Iterative reconstructions raised both objective and subjective image quality.

Self-concept clarity and processing self-relevant information: An event-related potential study.

Self-concept clarity (SCC) refers to the extent to which self-beliefs are clearly and confidently defined, internally consistent, and stable. While there is an abundance of research showing an association between SCC, well-being, and effective self-regulation, there is little knowledge about how SCC relates to basic cognitive processes such as attention and memory. Drawing on the attentional function theory of cognitive control, we hypothesized that low SCC is associated with greater attentional control during a trait assessment task. We also expected that low SCC individuals retrieve self-related information from semantic memory less efficiently compared to high SCC individuals. Fifty participants took part in the ERP study. The P300 and N400 components were measured as electrophysiological indices of attentional and semantic processing. The results showed that individuals with low SCC had larger P300 amplitude in response to positive versus negative words, and marginally larger P300 amplitude in response to positive words compared to high SCC individuals. These results suggest greater attentional involvement in the processing of positive self-related information in people with low SCC. There were no significant differences between groups in N400 amplitude. The results are discussed in the context of the relationship of SCC to self-esteem and self-motive theory.

Improved Detection of Endoleaks in Virtual Monoenergetic Images in Dual-Energy CT Angiography Following EVAR.

OBJECTIVES: The objective of this prospective study was to evaluate the virtual monoenergetic images (VMI) and virtual noncontrast (VNC) phase in the detection of endoleaks after endovascular abdominal aortic repair (EVAR). The potential dose reduction of abbreviated examination protocols was calculated. MATERIALS AND METHODS: Ninety-seven patients after the EVAR procedure were enrolled in this study. An initial single-source noncontrast acquisition was followed by two dual-energy acquisitions (arterial and 60 s delayed). Fast-kVp switching scanner was used. VNC images were reconstructed from the delayed phase. First examination session (reference) included a full triphasic study protocol consisting of true noncontrast (TNC) images and two postcontrast phases, the latter ones presented as classical polyenergetic reconstructions. Reading sessions II and III were performed by two independent and blinded readers evaluating VMIs in abbreviated protocols-biphasic (VNC + arterial, delayed phase), monophasic (VNC + delayed phase). The diagnostic accuracy of sessions II and III was calculated. RESULTS: The calculated sensitivity of the biphasic protocol with the use of VMIs in endoleak detection was 100%, with a statistically significant increase in the number of endoleaks detected in comparison with the reference study. The monophasic protocol showed 83.33% sensitivity. The use of abbreviated examination protocols led to a decrease in the mean effective dose (ED) of 23.28% (biphasic protocol) and 61.37% (monophasic protocol). CONCLUSION: The use of VMIs increases the number of endoleaks diagnosed with a possible radiation reduction by up to » (biphasic protocol). Further reduction to a monophasic protocol leads to over 60% dose reduction but with a decrease in diagnostic accuracy.

Efficacy and Safety of Lenabasum, a Cannabinoid Type 2 Receptor Agonist, in a Phase 3 Randomized Trial in Diffuse Cutaneous Systemic Sclerosis.

OBJECTIVE: This phase 3 study was undertaken to investigate the efficacy and safety of lenabasum, a cannabinoid type 2 receptor agonist, in patients with diffuse cutaneous systemic sclerosis (dcSSc). METHODS: A multinational double-blind study was conducted in 365 dcSSc patients who were randomized and dosed 1:1:1 with lenabasum 20 mg, lenabasum 5 mg, or placebo, each twice daily and added to background treatments, including immunosuppressive therapies (IST). RESULTS: The primary end point, the American College of Rheumatology combined response index in dcSSc (CRISS) at week 52 for lenabasum 20 mg twice a day versus placebo, was not met, with CRISS score of 0.888 versus 0.887 (P = 0.4972, using mixed models repeated measures [MMRM]). The change in the modified Rodnan skin thickness score (MRSS) at week 52 for lenabasum 20 mg twice a day versus placebo was -6.7 versus -8.1 (P = 0.1183, using MMRM). Prespecified analyses showed higher CRISS scores, greater improvement in MRSS, and lower decline in forced vital capacity in patients on background mycophenolate and those who were taking IST for ≤1 year. No deaths or excess in serious or severe adverse events related to lenabasum were observed. CONCLUSION: A benefit of lenabasum in dcSSc was not demonstrated. Most patients were treated with background IST, and treatment with mycophenolate mofetil in particular was associated with better outcomes. These findings support the use of IST in the treatment of dcSSc and highlight the challenge of demonstrating a treatment effect when investigational treatment is added to standard of care IST. These findings have relevance to trial design in SSc, as well as to clinical care.

Correlation between quantitative HER-2 protein expression and risk for brain metastases in HER-2+ advanced breast cancer patients receiving trastuzumab-containing therapy.

BACKGROUND: Patients with human epidermal growth factor receptor (HER)-2+ breast cancer are at particularly high risk for brain metastases; however, the biological basis is not fully understood. Using a novel HER-2 assay, we investigated the correlation between quantitative HER-2 expression in primary breast cancers and the time to brain metastasis (TTBM) in HER-2+ advanced breast cancer patients treated with trastuzumab. METHODS: The study group included 142 consecutive patients who were administered trastuzumab-based therapy for HER-2+ metastatic breast cancer. HER-2/neu gene copy number was quantified as the HER-2/centromeric probe for chromosome 17 (CEP17) ratio by central laboratory fluorescence in situ hybridization (FISH). HER-2 protein was quantified as total HER-2 protein expression (H2T) by the HERmark® assay (Monogram Biosciences, Inc., South San Francisco, CA) in formalin-fixed, paraffin-embedded tumor samples. HER-2 variables were correlated with clinical features and TTBM was measured from the initiation of trastuzumab-containing therapy. RESULTS: A higher H2T level (continuous variable) was correlated with shorter TTBM, whereas HER-2 amplification by FISH and a continuous HER-2/CEP17 ratio were not predictive (p = .013, .28, and .25, respectively). In the subset of patients that was centrally determined by FISH to be HER-2+, an above-the-median H2T level was significantly associated with a shorter TTBM (hazard ratio, [HR], 2.4; p = .005), whereas this was not true for the median HER-2/CEP17 ratio by FISH (p = .4). Correlation between a continuous H2T level and TTBM was confirmed on multivariate analysis (HR, 3.3; p = .024). CONCLUSIONS: These data reveal a strong relationship between the quantitative HER-2 protein expression level and the risk for brain relapse in HER-2+ advanced breast cancer patients. Consequently, quantitative assessment of HER-2 protein expression may inform and facilitate refinements in therapeutic treatment strategies for selected subpopulations of patients in this group.