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.

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.

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.

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.

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.

Insect taxonomy can be difficult: a noctuid moth (Agaristinae: Aletopus imperialis) and a geometrid moth (Sterrhinae: Cartaletis dargei) combined into a cryptic species complex in eastern Africa (Lepidoptera).

The systematic position of a large and strikingly coloured reddish-black moth, Cartaletis dargei Herbulot, 2003 (Geometridae: Sterrhinae) from Tanzania, has remained questionable since its description. Here we present molecular and morphological evidence showing that Cartaletis dargei only superficially resembles true Cartaletis Warren, 1894 (the relative name currently considered a junior synonym of Aletis Hübner, 1820), which are unpalatable diurnal moths superficially resembling butterflies, and that it is misplaced in the family Geometridae. We transfer it to Noctuidae: Agaristinae, and combine it with the genus Aletopus Jordan, 1926, from Tanzania, as Aletopus dargei (Herbulot, 2003) (new combination). We revise the genus Aletopus to contain three species, but find that it is a cryptic species complex that needs to be revised with more extensive taxon sampling. Our results demonstrate the difficulties in interpreting and classifying biological diversity. We discuss the problems in species delimitation and the potential drivers of evolution in eastern Africa that led to phenotypic similarity in unrelated lepidopteran lineages.

Breastfeeding positions and techniques used by Canadians with physical disabilities.

BACKGROUND: Breastfeeding is recommended by both the World Health Organization and the Canadian Pediatric Society due to the numerous maternal and infant benefits. Current literature examining breastfeeding among people with physical disabilities is limited to the United States with limited information about the Canadian context. OBJECTIVE: The primary aim of this study was to identify breastfeeding positions and techniques used by people with physical disabilities and explore their perceptions of effectiveness in a Canadian context where individuals had universal access to a lactation consultant. METHODS: A cross-sectional interview-based study was undertaken. Individuals were eligible for the study if they breastfed within the last 10 years and a) used a mobility device or b) experienced dysmobility, weakness or pain due to a medical condition while breastfeeding. Interviews were semi-structured to allow in-depth exploration of breastfeeding techniques and perceptions of effectiveness. The interviews were audiotaped, professionally transcribed, and assessed for content surrounding the use and effectiveness of breastfeeding positions and techniques. RESULTS: Eleven people participated in our study. Participants in our sample mentioned a variety of techniques used to breastfeed including a) accessories, b) assistance from others, c) breastfeeding positions, and d) location of feeding. CONCLUSIONS: People with physical disabilities use a variety of breastfeeding techniques to overcome physical limitations. This practical advice may improve guidance for healthcare professionals, including lactation consultants, to better support people with physical disabilities meet their breastfeeding goals.

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.

Inhibition of the Proteasome ß2 Site Sensitizes Triple-Negative Breast Cancer Cells to ß5 Inhibitors and Suppresses Nrf1 Activation.

The proteasome inhibitors carfilzomib (Cfz) and bortezomib (Btz) are used successfully to treat multiple myeloma, but have not shown clinical efficacy in solid tumors. Here we show that clinically achievable inhibition of the ß5 site of the proteasome by Cfz and Btz does not result in loss of viability of triple-negative breast cancer cell lines. We use site-specific inhibitors and CRISPR-mediated genetic inactivation of ß1 and ß2 to demonstrate that inhibiting a second site of the proteasome, particularly the ß2 site, sensitizes cell lines to Btz and Cfz in vitro and in vivo. Inhibiting both ß5 and ß2 suppresses production of the soluble, active form of the transcription factor Nrf1 and prevents the recovery of proteasome activity through induction of new proteasomes. These findings provide a strong rationale for the development of dual ß5 and ß2 inhibitors for the treatment of solid tumors.

Complexity of gap junctions between horizontal cells of the carp retina.

In the vertebrate retina, horizontal cells (HCs) reveal homologous coupling by gap junctions (gj), which are thought to consist of different connexins (Cx). However, recent studies in mouse, rabbit and zebrafish retina indicate that individual HCs express more than one connexin. To provide further insights into the composition of gj connecting HCs and to determine whether HCs express multiple connexins, we examined the molecular identity and distribution of gj between HCs of the carp retina. We have cloned four carp connexins designated Cx49.5, Cx55.5, Cx52.6 and Cx53.8 with a close relationship to connexins previously reported in HCs of mouse, rabbit and zebrafish, respectively. Using in situ hybridization, Cx49.5 expression was detected in different subpopulations of retinal neurons including HCs, whereas the Cx52.6 transcript was localized exclusively in HCs. Using specific antibodies, Cx55.5 and Cx53.8 were detected on dendrites of all four HC subtypes and axon terminals. Immunoelectron microscopy confirmed the presence of Cx55.5 and Cx53.8 in gap junctions between these processes and Cx55.5 was additionally observed in HC dendrites invaginating cone pedicles, suggesting its participation in the modulation of photoreceptor output in the carp retina. Furthermore, using single-cell RT-PCR, all four connexins were detected in different subtypes of HCs, suggesting overlapping expression patterns. Thus, the composition of gj mediating homologous coupling between subtypes of carp HCs appears to be more complex than expected. Moreover, BLAST searches of the preliminary carp genome, using novel sequences as query, suggest that most of the analyzed connexin genes are duplicated in carp.