The efficacy of sacituzumab govitecan and trastuzumab deruxtecan on stable and active brain metastases in metastatic breast cancer patients-a multicenter real-world analysis.

BACKGROUND: Fifteen to thirty percent of all patients with metastatic breast cancer (MBC) develop brain metastases (BCBMs). Recently, the antibody-drug conjugates (ADCs) sacituzumab govitecan (SG) and trastuzumab deruxtecan (T-DXd) have shown to be highly effective in the treatment of MBC. However, there are only limited data whether these macromolecules are also effective in patients with BCBMs. We therefore aimed to examine the efficacy of SG and T-DXd in patients with stable and active BCBMs in a multicenter real-world analysis. PATIENTS AND METHODS: Female patients with stable or active BCBMs who were treated with either SG or T-DXd at three breast centers in Germany before 30 June 2023 were included. As per local clinical praxis, chemotherapy efficacy was evaluated by whole-body computed tomography and cranial magnetic resonance imaging at baseline and at least every 3 months according to local standards. Growth dynamics of BCBMs were assessed by board-certified neuroradiologists. RESULTS: Of 26 patients, with a median of 2.5 prior therapy lines in the metastatic setting (range 2-15), 12 (43%) and 16 (57%) patients received SG and T-DXd, respectively. Out of the 12 patients who received SG, 2 (17%) were subsequently treated with T-DXd. Five out of 12 (42%) and 5 out of 16 (31%) patients treated with SG and T-DXd, respectively, had active BCBMs at treatment initiation. The intracranial disease control rate was 42% [95% confidence interval (CI) 13% to 71%] for patients treated with SG and 88% (95% CI 72% to 100%) for patients treated with T-DXd. After a median follow-up of 12.7 months, median intracranial progression-free survival was 2.7 months (95% CI 1.6-10.5 months) for SG and 11.2 months (95% CI 7.5-23.7 months) for T-DXd. CONCLUSIONS: SG and T-DXd showed promising clinical activity in both stable and active BCBMs. Further prospective clinical studies designed to investigate the efficacy of modern ADCs on active and stable BCBMs are urgently needed.

Investigation of the cleaning performance of commercial orthodontic cleaning tablets regarding biofilm removal on PMMA test specimens : An ex vivo study.

PURPOSE: The purpose of this ex vivo study was to compare the cleaning performance of three commercially available orthodontic cleaners on polymethyl methacrylate (PMMA) test specimens covered with biofilm. METHODS: Twenty subjects wore an individually manufactured vacuum-formed maxillary splint with four integrated PMMA test specimens for 7 days. The four test specimens were located on the buccal surfaces of the maxillary molars. After a 7-day wearing period, the PMMA test specimens colonized by biofilm were divided into two halves. One half was placed in 150 ml of tap water or in 150 ml of cleaning solution of the cleaners Retainer Brite® (Dentsply International Raintree Essix, Sarasota, FL, USA), Kukis® Xpress (Reckitt Benckiser, Heidelberg, Germany) or Dontodent (Propack, Heidelberg, Germany) while the other half remained uncleaned. The modified o­phthaldialdehyde (OPA) method was used to determine the amount of protein on both halves of the test specimens. The difference was tested for significance as a measure of the cleaning effect using a paired sample t­test. RESULTS: The cleaning performance of the three orthodontic cleaners was higher than the cleaning performance of tap water (mean 25.9 ± 6.5%). While Retainer Brite® (mean 54.5 ± 7.1%) removed significantly more biofilm than Dontodent (mean 41.5 ± 9.2%, p < 0.001) and Kukis® Xpress (mean 39.9 ± 11.5%, p < 0.001), there was no significant difference in the cleaning performance between Kukis® Xpress and Dontodent (p = 1). CONCLUSION: Seven-day-old biofilm is only removed partially by the investigated orthodontic cleaners, so that they are not suitable as the only measure for removing established biofilms.

Richter transformation in chronic lymphocytic leukemia (CLL)-a pooled analysis of German CLL Study Group (GCLLSG) front line treatment trials.

Richter transformation (RT) is defined as development of aggressive lymphoma in patients (pts) with CLL. The incidence rates of RT among pts with CLL range from 2 to 10%. The aim of this analysis is to report the frequency, characteristics and outcomes of pts with RT enrolled in trials of the GCLLSG. A total of 2975 pts with advanced CLL were reviewed for incidence of RT. Clinical, laboratory, and genetic data were pooled. Time-to-event data, starting from time of CLL diagnosis, of first-line therapy or of RT diagnosis, were analyzed by Kaplan-Meier methodology. One hundred and three pts developed RT (3%): 95 pts diffuse large B-cell lymphoma (92%) and eight pts Hodgkin lymphoma (8%). Median observation time was 53 months (interquartile range 38.1-69.5). Median OS from initial CLL diagnosis for pts without RT was 167 months vs 71 months for pts with RT (HR 2.64, CI 2.09-3.33). Median OS after diagnosis of RT was 9 months. Forty-seven pts (46%) received CHOP-like regimens for RT treatment. Three pts subsequently underwent allogeneic and two pts autologous stem cell transplantation. Our findings show that within a large cohort of GCLLSG trial participants, 3% of the pts developed RT after receiving first-line chemo- or chemoimmunotherapy. This dataset confirms the ongoing poor prognosis and high mortality associated with RT.

Lower cognitive reappraisal capacity is related to impairments in attachment and personality structure in poly-drug use: an fMRI study.

Insecure attachment, impaired personality structure and impaired emotion regulation figure prominently in substance use disorders. While negative emotions can trigger drug-use and relapse, cognitive reappraisal may reduce emotional strain by promoting changes in perspective. In the present study, we explored behavioral and neural correlates of cognitive reappraisal in poly-drug use disorder by testing individuals' capability to generate cognitive reappraisals for aversive events (Reappraisal Inventiveness Test). 18 inpatients with poly-drug use disorder and 16 controls completed the Adult Attachment Scale, the Emotion Regulation Questionnaire, the Brief Symptom Inventory, the Wonderlic Personnel Test, and the Operationalized Psychodynamic Diagnosis Structure Questionnaire, as well as two versions of the Reappraisal Inventiveness Test (during fMRI and outside the lab). Compared to controls, polydrug inpatients reported impaired personality structure, attachment and emotion regulation abilities. In the Reappraisal Inventiveness Test, poly-drug inpatients were less flexible and fluent in generating reappraisals for anger-eliciting situations. Corresponding to previous brain imaging evidence, cognitive reappraisal efforts of both groups were reflected in activation of left frontal regions, particularly left superior and middle frontal gyri and left supplemental motor areas. However, no group differences in neural activation patterns emerged. This suggests that despite cognitive reappraisal impairments on a behavioral level, neural reflections of these deficits in poly-drug use disorder might be more complex.

Short-term application of ibuprofen before ovulation.

AIM OF THE STUDY: The aim was to analyse if ibuprofen, as a non-selective cyclooxygenase (COX) inhibitor, has any negative effect on oocyte competence and embryo quality. COX- inhibitors are popular over-the-counter analgesics. Whereas selective COX inhibitors have been shown to impair female fertility, data on non-selective COX inhibitors are poor. Hence, they have not been recommended for women trying to conceive. METHODS: This is an observational study comparing ibuprofen exposed and unexposed women from 18 to 42 years of age, using the model of natural cycle in vitro fertilisation (IVF) to determine oocyte and embryo quality. Follicular growth was monitored and if the follicle was mature (≥ 15mm size and estimated oestradiol level of ≥ 800pmol/l), ovulation was triggered. Women with luteinising hormone (LH) surge received 400mg ibuprofen every 8 hours to postpone ovulation, whereas women without LH surge received none (controls). Oocyte retrieval rate, oocyte maturity, fertilization rate, embryo development and embryo quality as well as implantation rate were analysed. RESULTS: Of the 111 women included, 63 received ibuprofen, and 48 did not. Rates of mature oocytes and implantation rate did not differ. Logistic regression showed no significant association of ibuprofen intake, LH- level or reason for infertility on embryo quality. CONCLUSION: Based on our results, we suggest that, particularly within natural cycle IVF, ibuprofen does no harm around ovulation as analgesic treatment.

Follicular flushing leads to higher oocyte yield in monofollicular IVF: a randomized controlled trial.

STUDY QUESTION: Does follicular flushing increase the number of mature oocytes in monofollicular IVF? SUMMARY ANSWER: Follicular flushing increases the number of mature oocytes in monofollicular IVF. WHAT IS KNOWN ALREADY: Flushing increases neither the oocyte yield nor the pregnancy rate in polyfollicular IVF or in poor responder patients. In monofollicular IVF, the effect of flushing has so far been addressed by two studies: (i) a prospective study with minimal stimulation IVF demonstrated an increased oocyte yield, and (ii) a retrospective study with natural cycle (NC)-IVF showed an increased oocyte yield and an increased transfer rate. STUDY DESIGN, SIZE, DURATION: Randomized controlled trial including 164 women who were randomized for either aspiration with or without flushing from 2016 to 2019. PARTICIPANTS/MATERIALS, SETTING, METHODS: Infertile women 18-42 years of age with an indication for IVF treatment at a university-based infertility unit. Women undergoing monofollicular IVF were randomized to either follicular aspiration only or follicular aspiration directly followed by five follicular flushes at a 1:1 ratio. The intervention was done without anaesthesia, using a gauge 19 single-lumen needle. Flushing volume was calculated (sphere formula) based on the size of the follicle. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 164 women were included; 81 were allocated to 'aspiration only' and 83 to additional 'flushing'. Primary analysis was based on the intention-to-treat: oocyte yield, defined as the collected mature oocyte rate, was higher (n = 64/83, 77.1%) in the flushing group compared to the aspiration only group (n = 48/81, 59.3%, adjusted risk difference (RD): 18.2% (95% CI 3.9-31.7%), P-value = 0.02). In the flushing group, most oocytes were retrieved within the first three flushes (63/83, 75.8%). Fertilization rate was higher in the flushing group (n = 53/83, 63.9% vs n = 38/81, 46.9%; adjusted RD: 16.8% (96% CI 1.5-31.4%), P = 0.045). Transfer rate was also higher in the flushing group (n = 52/83, 62.7% vs n = 38/81, 46.9%; RD: 15.71 (95% CI 0.3-30.3%)), but the difference was not significant (P = 0.06). The clinical pregnancy rate n = 9/83 versus n = 9/81 (RD: -0.3% (95% CI -9.9% to 9.5%)) and live birth rate n = 7/83 versus n = 8/81 (RD: -1.5% (95% CI -10.4% to 7.1%)) were not significantly different between the flushing and the aspiration group. The median duration of the intervention was significantly longer with flushing (2.38 min; quartiles 2.0, 2.7) versus aspiration only (0.43 min; quartiles 0.3, 0.5) (P < 0.01). There was no significant difference in the mean (±SD) visual analogue scales pain score between the follicular flushing (3.4 ± 1.8) and the aspiration group (3.1 ± 1.89). LIMITATIONS, REASONS FOR CAUTION: Blinding of the procedure was not possible. WIDER IMPLICATIONS OF THE FINDINGS: Our study proved that flushing of single follicles in NC-IVF increases the oocyte yield. In contrast to polyfollicular IVF flushing seems to be beneficial in a monofollicular setting if the technique used in our study (single-lumen needle, 5 flushings with flushing volume adaptation) is applied. STUDY FUNDING/COMPETING INTEREST(S): The study was funded by the financial sources of the division and in part by a research grant provided by NMS Biomedical SA, Switzerland. The company did not have any roles in design or conduct of the study or in the preparation of the manuscript. The authors have no other conflicts of interest. TRIAL REGISTRATION NUMBER: Clinicaltrials.gov NCT02641808. TRIAL REGISTRATION DATE: 29 December 2015. DATE OF FIRST PATIENT'S ENROLMENT: 22 August 2016.

The temporal association between incident late-life depression and incident dementia.

OBJECTIVE: There is an established association between depression and subsequent dementia. The present study examined temporal associations between incident late-life depression and subsequent dementia, also considering age and sex. METHODS: We used longitudinal health claims data from the largest German health insurance provider ('Allgemeine Ortskrankenkasse') considering up to 9 follow-up years in piecewise exponential models. ICD-10 codes were used to define incident depression and dementia in individuals ≥65 years (n = 97 110). RESULTS: Incident depression was associated with a higher risk of subsequent dementia (incidence rate ratios (IRR) adjusted for age and sex: IRR = 1.58, 95% CI = 1.51-1.64). The strongest association was found for the shortest interval of 1 quarter (IRR = 2.04, 95% CI = 1.88-2.21), with significant associations up to an interval of roughly 3 years. The association was more pronounced and lasted for more quarters in the younger portion of this study group (ages from 65-74: IRR = 2.00, 95% CI = 1.83-2.18; 75-84: IRR = 1.64, 95% CI = 1.55-1.73; ≥85: IRR = 1.19, 95% CI = 1.08-1.31). It was stronger among men than women (men: IRR = 1.98, 95% CI = 1.84-2.14; women: IRR = 1.44, 95% CI = 1.37-1.51) with no sex-specific temporal association. CONCLUSION: This large claims data study confirmed that incident late-life depression is associated with a higher risk of dementia within the 3 years following diagnosis. Hence, incident late-life depression should prompt further cognitive examinations and referrals to specialists. This might apply especially to younger seniors and men.

Pinpointing Neural Correlates of Attachment in Poly-Drug Use: A Diffusion Tensor Imaging Study.

An increasing amount of evidence indicates the significance of attachment in the etiology of poly-drug use disorder (PUD). The aim of this study was to investigate associations between PUD and adult attachment in particular, with a focus on white matter (WM) fiber tract integrity. For this purpose, we selected several regions-of-interest based on previous findings which were examined for their role in PUD and estimated whole-brain associations between adult attachment and WM integrity. A total sample of 144 right-handed males were investigated (Age: M = 27; SD = 4.66). This included a group of patients diagnosed with PUD (n = 70) and a group of healthy controls (HC; n = 74). The Adult Attachment Scales (AAS) was applied to assess attachment attitudes in participants. Diffusion Tensor Imaging was used to investigate differences in WM integrity. The findings suggest substantially less attachment security in PUD patients compared to HC. Furthermore, PUD patients exhibited reduced integrity in WM fiber tracts, most pronounced in the bilateral corticospinal tract, the fronto-occipital fasciculus, and the right inferior longitudinal fasciculus. However, these results were not controlled for comorbid depressiveness. With regard to associations between adult attachment and WM integrity, the results for PUD patients indicate a negative relationship between "Comfort with Closeness" and the structural integrity of a cluster comprising parts of the right anterior thalamic radiation, the inferior fronto-occipital fasciculus and the uncinate fasciculus. Despite being limited by the cross-sectional design of this study, the results emphasize the significance of attachment in PUD etiology, both at a behavioral and a neurological level. Largely in line with previous research, the findings revealed tentative links between adult attachment and WM fiber tracts related to cognitive and affective functions in PUD patients.

Septopreoptic holoprosencephaly in intracranial abnormalities: an under-diagnosed midline finding.

BACKGROUND: Septopreoptic holoprosencephaly is a mild form of holoprosencephaly in which the midline non-separation is restricted to the septal or preoptic regions. This entity has only been described in a small case series in which associated intracranial abnormalities were limited to the midline structures. OBJECTIVE: To describe the radiologic findings of septopreoptic holoprosencephaly and highlight that it can be associated with a variety of intracranial abnormalities, not merely with abnormalities restricted to midline structures as previously reported. MATERIALS AND METHODS: We retrospectively identified 22 children whose MRIs were confirmed to have non-separation restricted to the septal and preoptic region, fulfilling the criteria for septopreoptic holoprosencephaly. We then categorized MRIs as having, in addition, either intracranial abnormalities limited to the midline structures or major abnormalities not limited to the midline structures. RESULTS: Five children had intracranial abnormalities limited to the midline structures. Seventeen children had major intracranial abnormalities not limited to the midline structures. The major abnormalities included: patterning defects of the midbrain-hindbrain (elongated midbrain, shortened pons, shortened/elongated medulla, partial rhombencephalosynapsis), bilateral perisylvian polymicrogyria, microcephaly, megalencephaly and a spheno-ethmoidal encephalocele. Recognized syndromes/chromosomal abnormalities were also observed in this patient group. CONCLUSION: Our results suggest that septopreoptic holoprosencephaly has been under-recognized and under-reported to date. We propose that searching for this anomaly should be part of the complete assessment of the midline in all children undergoing brain MRI for intracranial malformations.

Macrocerebellum in Achondroplasia: A Further CNS Manifestation of FGFR3 Mutations?

Achondroplasia is the result of a mutation in the fibroblast growth factor receptor 3 gene (FGFR3). Appearances suggestive of macrocerebellum have not been described in this patient group. We retrospectively reviewed MR imaging studies of the brain in 23 children with achondroplasia. A constellation of imaging findings that are recognized in macrocerebellum was observed, including cerebellar hemisphere enlargement (inferior and superior extension, wrapping around the brainstem); an effaced retro- and infravermian cerebellar subarachnoid CSF space; a shortened midbrain; distortion of the tectal plate; and mass effect on the brainstem. All MR imaging studies exhibited some of these findings. Quantitative analysis confirmed an increased cerebellar volume compared with age- and sex-matched controls. We hypothesized that this may be due to direct effects of the FGFR3 mutation on cerebellar morphogenesis.

Leveraging proteomics to compare submerged versus air-liquid interface carbon nanotube exposure to a 3D lung cell model.

With the emerging concern over the potential toxicity associated with carbon nanotube inhalation exposure, several in vitro methods have been developed to evaluate cellular responses. Since the major concern for adverse effects by carbon nanotubes is inhalation, various lung cell culture models have been established for toxicity testing, thus creating a wide variation of methodology. Limited studies have conducted side-by-side comparisons of common methods used for carbon nanotube hazard testing. The aim of this work was to use proteomics to evaluate global cellular response, including pro-inflammatory and pro-fibrotic mediators, of a 3D lung model composed of macrophages, epithelial cells, and fibroblasts which mimics the human alveolar epithelial tissue barrier. The cells were exposed to Mitsui 7 (M-7) multi-walled carbon nanotubes (MWCNT) under submerged and air-liquid interface (ALI) conditions and discovery proteomics identified 3500 proteins. The M-7 ALI exposure compared to control was found to increase expression in proteins related to oxidative stress that were not found to be enriched in submerged exposure. Comparison of MWCNT exposure methods, M-7 ALI exposure versus M-7 submerged exposure, yielded protein enrichment in pathways known to be associated with carbon nanotube exposure stress response, such as acute phase response signaling and NRF2-mediated oxidative stress response. This study demonstrates a comparison of commonly deployed carbon nanotube exposure methods. These data should be considered by the nanotoxicology community when interpreting or cross comparing in vitro exposure results.

A novel sample holder for 4D live cell imaging to study cellular dynamics in complex 3D tissue cultures.

Three dimensional (3D) co-cultures to mimic cellular dynamics have brought significant impacts in tissue engineering approaches for biomedical research. Herein, we present a novel sample holder combined with time-lapse fluorescence imaging technique, referred as 4D live cell imaging, allowing direct visualization of various cells up to 24 hours. We further extended our approach to monitor kinetics and dynamics of particle uptake by cells and translocation across tissue membranes.

Activation of a novel p70 S6 kinase 1-dependent intracellular cascade in the basolateral nucleus of the amygdala is required for the acquisition of extinction memory.

Repeated presentations of a previously conditioned stimulus lead to a new form of learning known as extinction, which temporarily alters the response to the original stimulus. Previous studies have shown that the consolidation of extinction memory requires de novo protein synthesis. However, the role of specific nodes of translational control in extinction is unknown. Using auditory threat conditioning in mice, we investigated the role of mechanistic target of rapamycin complex 1 (mTORC1) and its effector p70 S6 kinase 1 (S6K1) in the extinction of auditory threat conditioning. We found that rapamycin attenuated the consolidation of extinction memory. In contrast, genetic deletion and pharmacological inhibition of S6K1, a downstream effector of mTORC1, blocked within-session extinction, indicating a role for S6K1 independent of protein synthesis. Indeed, the activation of S6K1 during extinction required extracellular signal-regulated kinase (ERK) activation in the basolateral nucleus of the amygdala (BLA) and was necessary for increased phosphorylation of the GluA1 (Thr840) subunit of the AMPA receptor following extinction training. Mice exposed to brief uncontrollable stress showed impaired within-session extinction as well as a downregulation of ERK and S6K1 signaling in the amygdala. Finally, using fiber photometry we were able to record calcium signals in vivo, and we found that inhibition of S6K1 reduces extinction-induced changes in neuronal activity of the BLA. These results implicate a novel ERK-S6K1-GluA1 signaling cascade critically involved in extinction.

Temporal Lobe Malformations in Achondroplasia: Expanding the Brain Imaging Phenotype Associated with FGFR3-Related Skeletal Dysplasias.

Thanatophoric dysplasia, achondroplasia, and hypochondroplasia belong to the fibroblast growth factor receptor 3 (FGFR3) group of genetic skeletal disorders. Temporal lobe abnormalities have been documented in thanatophoric dysplasia and hypochondroplasia, and in 1 case of achondroplasia. We retrospectively identified 13 children with achondroplasia who underwent MR imaging of the brain between 2002 and 2015. All children demonstrated a deep transverse temporal sulcus on MR imaging. Further common neuroimaging findings were incomplete hippocampal rotation (12 children), oversulcation of the mesial temporal lobe (11 children), loss of gray-white matter differentiation of the mesial temporal lobe (5 children), and a triangular shape of the temporal horn (6 children). These appearances are very similar to those described in hypochondroplasia, strengthening the association of temporal lobe malformations in FGFR3-associated skeletal dysplasias.

Parkinson's disease in Germany: prevalence and incidence based on health claims data.

BACKGROUND: In Germany, epidemiological information on Parkinson's disease (PD) is rare and outdated. Considering aging populations, current prevalences and incidence rates about this age-related disease would be important for adequate public health planning. METHODS: We used newly available health claims data sets from the largest German health insurer dating 2004-2007 and 2007-2010 with an analysis population in the base years of 491 038 persons aged 50 and older. Quarter-specific information about ICD-10 diagnoses and PD drug prescriptions from the inpatient and outpatient sectors was used to validate PD cases. Estimations were presented for two validation strategies relying on repeated PD diagnoses (SIa) and on one PD diagnosis followed by at least one PD drug prescription (SIb). RESULTS: The standardized prevalence was 797 (SIb) to 961/100 000 persons (SIa), showing an age-specific increase up to category 85-89 and a decline thereafter. The standardized incidence rate was 192 to 229/100 000 person-years with a similar age-specific shape. Prevalences and incidences rates were higher for men compared to women in regard to age. CONCLUSIONS: Health claims data are found to be suitable for PD assessment using the repeated diagnoses or PD drug prescriptions as necessary criteria.