Feasibility of targeted therapies in the adjuvant setting of early breast cancer in men: real-world data from a population-based registry.

BACKGROUND: Following the positive iDFS and OS results of the phase III clinical trials monarchE, NATALEE and OlympiA, new oral anticancer agents (the CDK4/6 inhibitors abemaciclib, ribociclib as well as the PARP inhibitor olaparib) have recently been introduced into the treatment of high-risk early breast cancer (eBC). However, only few male patients were included in these trials (0.4%, 0.6% and 0.3%, respectively). The objective of this real-world analysis was to determine the proportion of male patients with eBC fulfilling the clinical high-risk criteria of above-mentioned trials. PATIENTS AND METHODS: We conducted a data inquiry and analysis with the Cancer Registry of Baden-Württemberg of men with breast cancer diagnosed between January 1, 2015 and December 31, 2021. Men with eBC were identified and the number of patients at clinical high-risk according to the inclusion criteria of monarchE, NATALEE and OlympiA was assessed. RESULTS: Of 397 men with eBC, 354 (89.1%) had a HR + /Her2- and 4 (1.0%) a triple-negative subtype. 84 patients (21.2%) met the clinical high-risk criteria according to the monarchE, 189 (47.6%) those according to the NATALEE and 50 (12.6%) those according to the OlympiA trial. CONCLUSION: In a large real-world sample, more men with eBC are at clinical high risk according to the inclusion criteria of monarchE, NATALEE and OlympiA than would be expected in women. This is most likely due to more advanced stages at initial diagnosis in men. To evaluate whether CDK4/6 and PARP inhibitors improve prognosis also in men should be the topic of future real- world analyses.

Association between genetic variants in key vitamin-D-pathway genes and external apical root resorption linked to orthodontic treatment.

This study evaluated the association between single-nucleotide polymorphisms (SNPs) in vitamin-D-related genes and the amount of external apical root resorption linked to orthodontic treatment. One hundred and forty-three individuals were assessed. The amount of external apical root resorption of upper central incisors (EARRinc ) and lower first molars (EARRmol ) were evaluated in radiographs. Seven SNPs were genotyped across four genes including the vitamin D receptor [VDR], group-specific component [GC], cytochrome P450 family 27 subfamily B member 1 [CYP27B1], and cytochrome P450 family 24 subfamily A member 1 [CYP24A1]. Linear regressions were implemented to determine allele-effects on external apical root resorption. Individuals carrying the AA genotype in VDR rs2228570 had a 21% higher EARRmol than those having AG and GG genotypes (95% CI: 1.03,1.40). EARRmol in heterozygous rs2228570, was 12% lower than for homozygotes (95%CI: 0.78,0.99). Participants with the CCG haplotype (rs1544410-rs7975232-rs731236) in VDR had an EARRmol 16% lower than those who did not carry this haplotype. Regarding CYP27B1 rs4646536, EARRinc in participants who had at least one G allele was 42% lower than for homozygotes AA (95%CI: 0.37,0.93). Although these results did not remain significant after multiple testing adjustment, potential associations may still be suggested. Further replication studies are needed to confirm or refute these findings.

Translational imaging of the fibroblast activation protein (FAP) using the new ligand [68Ga]Ga-OncoFAP-DOTAGA.

PURPOSE: The fibroblast activation protein (FAP) is an emerging target for molecular imaging and therapy in cancer. OncoFAP is a novel small organic ligand for FAP with very high affinity. In this translational study, we establish [68Ga]Ga-OncoFAP-DOTAGA (68Ga-OncoFAP) radiolabeling, benchmark its properties in preclinical imaging, and evaluate its application in clinical PET scanning. METHODS: 68Ga-OncoFAP was synthesized in a cassette-based fully automated labeling module. Lipophilicity, affinity, and serum stability of 68Ga-OncoFAP were assessed by determining logD7.4, IC50 values, and radiochemical purity. 68Ga-OncoFAP tumor uptake and imaging properties were assessed in preclinical dynamic PET/MRI in murine subcutaneous tumor models. Finally, biodistribution and uptake in a variety of tumor types were analyzed in 12 patients based on individual clinical indications that received 163 ± 50 MBq 68Ga-OncoFAP combined with PET/CT and PET/MRI. RESULTS: 68Ga-OncoFAP radiosynthesis was accomplished with high radiochemical yields. Affinity for FAP, lipophilicity, and stability of 68Ga-OncoFAP measured are ideally suited for PET imaging. PET and gamma counting-based biodistribution demonstrated beneficial tracer kinetics and high uptake in murine FAP-expressing tumor models with high tumor-to-blood ratios of 8.6 ± 5.1 at 1 h and 38.1 ± 33.1 at 3 h p.i. Clinical 68Ga-OncoFAP-PET/CT and PET/MRI demonstrated favorable biodistribution and kinetics with high and reliable uptake in primary cancers (SUVmax 12.3 ± 2.3), lymph nodes (SUVmax 9.7 ± 8.3), and distant metastases (SUVmax up to 20.0). CONCLUSION: Favorable radiochemical properties, rapid clearance from organs and soft tissues, and intense tumor uptake validate 68Ga-OncoFAP as a powerful alternative to currently available FAP tracers.

Linearly Polarized Electroluminescence from MoS2 Monolayers Deposited on Metal Nanoparticles: Toward Tunable Room-Temperature Single-Photon Sources.

Break junctions in noble-metal films can exhibit electroluminescence (EL) through inelastic electron tunneling. The EL spectrum can be tuned by depositing a single-layer crystal of a transition-metal dichalcogenide (TMDC) on top. Whereas the emission from the gaps between silver or gold nanoparticles formed in the break junction is spectrally broad, the hybrid metal/TMDC structure shows distinct luminescence from the TMDC material. The EL from individual hotspots is found to be linearly polarized, with a polarization axis apparently oriented randomly. Surprisingly, the degree of polarization is retained in the EL from the TMDC monolayer at room temperature. In analogy to polarized photoluminescence experiments, such polarized EL can be interpreted as a signature of valley-selective transitions, suggesting that spin-flip transitions and dephasing for excitons in the K valleys are of limited importance. However, polarized EL may also originate from the metal nanoparticles formed under electromigration which constitute optical antenna structures. Such antennae can apparently change over time since jumps in the polarization are observed in bare silver-nanoparticle films. Remarkably, photon-correlation spectroscopy reveals that gold-nanoparticle films exhibit signatures of deterministic single-photon emission in the EL, suggesting a route to designing room-temperature polarized single-photon sources with tunable photon energy through the choice of TMDC overlayer.

Clonidine Effect on Pain After Cesarean Delivery: A Randomized Controlled Trial of Different Routes of Administration.

BACKGROUND: Intrathecal clonidine prolongs spinal anesthesia. We evaluated the effects of the addition of intrathecal or intravenous clonidine (75 µg) to standard cesarean delivery spinal anesthesia on postoperative pain and neonatal outcomes. METHODS: In a randomized, placebo-controlled, double-blind trial, 64 women scheduled for elective cesarean delivery under spinal anesthesia were randomly allocated and compared among 3 groups: intrathecal clonidine 75 µg, intravenous clonidine 75 µg, and placebo. The primary outcome was acute postoperative pain. A sample size of 26 individuals per group (N = 78) was planned. RESULTS: From April 2015 to April 2016, 64 women were analyzed (14 excluded). No differences in postoperative pain scores were found (Numerical Verbal Scale for pain at movement at 24 hours of postcesarean delivery: 4.53 ± 3.0 vs 4.45 ± 2.73 vs 3.93 ± 3.07 for control, intrathecal, and intravenous, respectively, P = .771). Intrathecal and intravenous clonidine led to more sedation, in comparison to the control group, during the intraoperative period (Richmond Agitation and Sedation Scale: -0.3 ± 0.47 vs -1 ± 0.53 vs -0.73 ± 0.45 for control, intrathecal, and intravenous, respectively, overall P < .001; Dunn correction: P < .001 for intrathecal versus control; P = .021 for intravenous versus control; and P = .208 for intrathecal versus intravenous). CONCLUSIONS: Intrathecal or intravenous clonidine had no effect on postoperative pain after cesarean delivery. Both intrathecal and intravenous clonidine caused more sedation.

Treatment with the HIV protease inhibitor nelfinavir triggers the unfolded protein response and may overcome proteasome inhibitor resistance of multiple myeloma in combination with bortezomib: a phase I trial (SAKK 65/08).

Downregulation of the unfolded protein response mediates proteasome inhibitor resistance in multiple myeloma. The Human Immunodeficieny Virus protease inhibitor nelfinavir activates the unfolded protein response in vitro. We determined dose-limiting toxicity and recommended dose for phase II of nelfinavir in combination with the proteasome inhibitor bortezomib. Twelve patients with advanced hematologic malignancies were treated with nelfinavir (2500-5000 mg/day p.o., days 1-14, 3+3 dose escalation) and bortezomib (1.3 mg/m(2), days 1, 4, 8, 11; 21-day cycles). A run in phase with nelfinavir monotherapy allowed pharmakokinetic/pharmakodynamic assessment of nelfinavir in the presence or absence of concomittant bortezomib. End points included dose-limiting toxicity, activation of the unfolded protein response, proteasome activity, toxicity and response to trial treatment. Nelfinavir 2×2500 mg was the recommended phase II dose identified. Nelfinavir alone significantly up-regulated expression of proteins related to the unfolded protein response in peripheral blood mononuclear cells and inhibited proteasome activity. Of 10 evaluable patients in the dose escalation cohort, 3 achieved a partial response, 4 stable disease for 2 cycles or more, while 3 had progressive disease as best response. In an exploratory extension cohort with 6 relapsed, bortezomib-refractory, lenalidomide-resistant myeloma patients treated at the recommended phase II dose, 3 reached a partial response, 2 a minor response, and one progressive disease. The combination of nelfinavir with bortezomib is safe and shows promising activity in advanced, bortezomib-refractory multiple myeloma. Induction of the unfolded protein response by nelfinavir may overcome the biological features of proteasome inhibitor resistance. (clinicaltrials.gov identifier: 01164709).

Administration of ivermectin to peridomestic cattle: a promising approach to target the residual transmission of human malaria.

BACKGROUND: The success of current control tools in combatting malaria vectors is well established. However, sustained residual transmission of Plasmodium parasites persists. Mass drug administration (MDA) to humans of the endectocide ivermectin for vector control is receiving increasing attention. However, vectors feeding upon animals escape this promising approach. Zoophagy of mosquitoes sustains both the vector population and endemic population of vector-borne pathogens. Therefore, only a strategy that will combine ivermectin MDAs targeted at humans and their peridomestic animals could be successful at controlling residual malaria transmission. METHODS: Burkinabé cattle have been treated with injectable therapeutic dose of ivermectin (0.2 mg/kg of body weight) to render blood meals toxic to field representative populations of Anopheles coluzzii carrying the kdr mutation. Direct skin-feeding assays were performed from 2 to 28 days after injection (DAI) and mosquitoes were followed for their survival, ability to become gravid and fecundity. Membrane feeding assays were further performed to test if an ivermectin blood meal taken at 28 DAI impacts gametocyte establishment and development in females fed with infectious blood. RESULTS: The mosquitocidal effect of ivermectin is complete for 2 weeks after injection, whether 12 days cumulative mortalities were of 75 and 45 % the third and fourth weeks, respectively. The third week, a second ivermectin blood meal at sub-lethal concentrations further increased mortality to 100 %. Sub-lethal concentrations of ivermectin also significantly decreased egg production by surviving females, increasing further the detrimental effect of the drug on vector densities. Although females fitness was impaired by sub-lethal ivermectin blood meals, these did not diminish nor increase their susceptibility to infection. CONCLUSION: This study demonstrates the potential of integrated MDA of ivermectin to both human and peridomestic cattle to target vector reservoirs of residual malaria transmission. Such integration lies in 'One-Health' efforts being implemented around the globe, and would be especially relevant in rural communities in Africa where humans are also at risk of common zoonotic diseases.

[Influence of migration background on child development at school-enrolment - a multivariate model]. / Migrationshintergrund als Einflussfaktor auf die kindliche Entwicklung im Einschulungsalter - ein multivariates Modell.

BACKGROUND AND AIM: There is an increasing awareness for the role of a migration background regarding health over the past years in Germany. Descriptive data show that children from families with a migration background score significantly lower in developmental screening tests at school-enrolment compared to their peers of German origin. The analyses presented here examine the impact of a migration background on child development in the context of additional factors of influence. METHODS: Data are from the routine examina-tion at school-enrolment in Berlin in 2010 and 2011 (N=54 818). Because of the multicollinearity of migration background and the German language skills of the child and its parents these variables are combined to one variable. Multiple regression models are conducted with 'poor performance in 2 or more developmental domains' as the dependent variable and the migration variables as the independent variable controlled for sociodemographic and other relevant predictor variables. RESULT: The strongest predictor variable is the socioeconomic status of the family (OR 5.8). A migration background is only a predictor in combination with insufficient German language skills of child or parent (OR 1.6) and insufficient German language skills of child and parent (OR 5.3) respectively. Furthermore, very low birth weight children (birth weight < 1 500 g) are at risk for poor performance in 2 or more developmental domains (OR 4.2). Having spent not more than 2 years in day care (OR 1.6), living with a single parent and missing the preventive health check-up at the age of 4 (so called U8) have only a weak significant impact (OR 1.2 each). Electronic media exposure (television, computer) is no significant risk factor in our analyses. CONCLUSION: The analyses show that migration background is not a risk factor for poor performance in developmental tests per se, but is attributed to the higher proportion of families with a low socioeconomic status in this group and with insufficient German language skills. This emphasizes the importance of support for socially disadvantaged children in general and for comprehensive promotion of German language skills for children and their parents from foreign origin.

Non-eligibility for pivotal HFpEF/HFmrEF outcome trials and mortality in a contemporary heart failure cohort.

Pivotal outcome trials targeting heart failure with preserved (HFpEF) and mildly-reduced ejection fraction (HFmrEF) may have excluded patients at highest risk of poor outcomes. We aimed to assess eligibility for HFpEF/HFmrEF outcome trials in an unselected heart failure cohort and its association with all-cause mortality. Among 32.028 patients presenting to a tertiary care center emergency unit for any reason between August 2018 and July 2019, we identified 407 admissions with evident HFpEF and HFmrEF. Eligibility criteria for pivotal trials CHARM-Preserved, I-PRESERVE, TOPCAT, PARAGON-HF, EMPEROR-Preserved and DELIVER were assessed by chart review. The proportions of admissions fulfilling HFpEF/HFmrEF trial eligibility criteria were 88% for CHARM-Preserved, 40% for I-PRESERVE, 35% for TOPCAT, 28% for PARAGON-HF, 51% for EMPEROR-Preserved, and 49% for DELIVER. During a median follow-up of 1.9 years, death-from-any-cause occurred in 121 cases (30%). Twenty-four-month overall survival estimates for non-eligible and eligible admissions were 53% vs. 76% for CHARM-Preserved (HR=2.32, 95% CI: 1.47-3.67, p<0.001), 62% vs. 87% for I-PRESERVE (HR=2.97, 1.85-4.77, p<0.001), 67% vs. 84% for TOPCAT (HR=2.04, 1.29-3.24, p = 0.002), 68% vs. 85% for PARAGONHF (HR=2.28, 1.33-3.90, p = 0.003), 64% vs. 81% for EMPEROR-Preserved (HR=1.90, 1.27-2.84, p = 0.002), and 65% vs. 80% for DELIVER (HR=1.71, 1.14-2.57, p = 0.010). Exclusion criteria independently predicting death were eGFR <20 ml/min/1.73 m2, COPD with home oxygen therapy, and severe valvular heart disease. Conclusively, in a contemporary HFpEF/HFmrEF cohort, non-eligibility for outcome trials predicted for strongly increased mortality. HFpEF/HFmrEF patients at highest mortality risk were likely underrepresented in previous outcome trials and their treatment remains an unmet medical need.

Decreased levels of nucleotide pyrophosphatase phosphodiesterase 1 are associated with cartilage calcification in osteoarthritis and trigger osteoarthritic changes in mice.

OBJECTIVE: To analyse the function of nucleotide pyrophosphatase phosphodiesterase (NPP1), a member of the pyrophosphate pathway, in osteoarthritis (OA). METHODS: mRNA expression of NPP1, ANK ankylosing protein and tissue non-specific alkaline phosphatase was assessed by quantitative PCR. NPP1 protein levels were analysed in mouse and human cartilage samples. Bone metabolism was analysed by F18-positron emission tomography-scanning and µCT in ttw/ttw mice. Ttw/ttw mice are mice carrying a loss-of-function mutation in NPP1. Calcification of articular cartilage was assessed using von Kossa staining and OA severity using the Mankin score. Cartilage remodelling was investigated by type X collagen immunohistochemistry. RESULTS: Expression of NPP1, but not the other members of this pathway, inversely correlated with cartilage calcification and OA severity in mouse and humans. Proinflammatory cytokines downregulated the expression of NPP1, demonstrating an influence of inflammation on matrix calcification. Ttw/ttw mutant mice, carrying a loss-of-function mutation in NPP1, exhibit increased bone formation process in joints compared with wild types. Ttw/ttw mice also developed spontaneous OA-like changes, evaluated by histological analysis and in vivo imaging. Ectopic calcifications were associated with increased expression of collagen X in the cartilage. CONCLUSION: The authors conclude that OA is characterised by the reactivation of molecular signalling cascades involving proinflammatory cytokines, thereby regulating the pyrophosphate pathway which consequently leads to cartilage ossification, at least in part resembling endochondral ossification.

Monitoring of patients with rheumatoid arthritis by indocyanine green (ICG)-enhanced fluorescence optical imaging treated with anti-TNFα therapy.

BACKGROUND: Fluorescence optical imaging (FOI) enables visualisation of inflammation in both hands in rheumatoid arthritis (RA). OBJECTIVE: To investigate the usefulness of FOI in treatment monitoring under anti-TNFα therapy with certolizumab pegol (CZP) in patients with RA in comparison to clinical and laboratory outcome parameters. METHODS: CZP-naïve patients with RA were eligible for this open-label study with an observational period of 52 weeks. Disease activity was monitored by the clinical score DAS28, tender/swollen joint count (TJC-28/SJC-28) and laboratory outcomes for systemic inflammation (CRP and ESR). FOI results were analysed in three different phases (P1-3) and PrimaVistaMode (PVM) by the FOI activity score (FOIAS). RESULTS: Twenty-eight RA patients (median age 52.5 years, 26 females, thirteen with a history of other biologic therapy) were included. DAS28 (CRP) decreased from moderate disease activity at baseline (median 4.6, IQR 1.8) to low disease activity at week (w)52 (median 2.7, IQR 2.1; p < 0.001). Statistically significant decreases could also be demonstrated for SJC-28 and TJC-28. CRP/ESR were reduced numerically from baseline to w52. FOIAS in P1 (early phase) showed a continuous decrease of enhancement during the course of treatment period: from baseline (median 1.5, IQR 9.3) over w6 (median 1.0, IQR 3.0; p = 0.069), w12 (median 0.5, IQR 3.0; p = 0.171), w24 (n = 27, median 0.0, IQR 3.0; p = 0.004), until w52 (n = 18, median 0.0, IQR 2.8; p = 0.091), which could not be presented for FOIAS in P2, P3 and PVM. CONCLUSION: FOI in P1 appears to be a valuable tool for fast and easy monitoring of treatment response to certolizumab in a clinical setting.

Eating out, weight and weight gain. A cross-sectional and prospective analysis in the context of the EPIC-PANACEA study.

OBJECTIVE: The aim of this study was to examine the association of body mass index (BMI) and weight gain with eating at restaurants and similar establishments or eating at work among 10 European countries of the European Prospective Investigation into Cancer and Nutrition (EPIC) study. SUBJECTS: This study included a representative sample of 24,310 randomly selected EPIC participants. METHODS: Single 24-h dietary recalls with information on the place of consumption were collected using standardized procedures between 1995 and 2000. Eating at restaurants was defined to include all eating and drinking occasions at restaurants, cafeterias, bars and fast food outlets. Eating at work included all eating and drinking occasions at the workplace. Associations between eating at restaurants or eating at work and BMI or annual weight changes were assessed using sex-specific linear mixed-effects models, controlling for potential confounders. RESULTS: In southern Europe energy intake at restaurants was higher than intake at work, whereas in northern Europe eating at work appeared to contribute more to the mean daily intake than eating at restaurants. Cross-sectionally, eating at restaurants was found to be positively associated with BMI only among men (ß=+0.24, P=0.003). Essentially no association was found between BMI and eating at work among both genders. In a prospective analysis among men, eating at restaurants was found to be positively, albeit nonsignificantly, associated with weight gain (ß=+0.05, P=0.368). No association was detected between energy intake at restaurants and weight changes, controlling for total energy intake. CONCLUSION: Among men, eating at restaurants and similar establishments was associated with higher BMI and possibly weight gain.