Clinical efficacy of CDK4/6 inhibitor plus endocrine therapy in HR-positive/HER2-0 and HER2-low-positive metastatic breast cancer: a secondary analysis of PALOMA-2 and PALOMA-3 trials.

BACKGROUND: Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors in combination with traditional endocrine therapy (ET) are now the recommended first-line treatment for hormone receptor (HR)-positive and HER2-negative metastatic breast cancer (MBC). However, the benefits of adding CDK4/6 inhibitors to ET in HER2-low-positive and HER2-0 subgroups remain unclear. We aimed to assess the effectiveness of CDK4/6 inhibitors in combination with ET in patients with HR-positive, HER2-low-positive and HER2-0 MBC. METHODS: This secondary analysis assessed progression-free survival (PFS) among HER2-low-positive and HER2-0 patients enrolled in the double-blind, placebo-controlled randomised clinical trials PALOMA-2 and PALOMA-3. The study included 1186 HER2-negative, HR-positive female patients, with available immunohistochemistry (IHC) and/or in situ hybridization (ISH) results, across 17 countries enrolled between February 2013 and August 2014. HER2-low-positive status was defined by IHC 1+ or 2+ with negative ISH, and HER2-zero by IHC 0. Data analyses were conducted between March and May 2023. In the PALOMA-2 trial, patients were randomly assigned to receive either palbociclib or placebo, in combination with letrozole in the first-line treatment for HR-positive MBC. Patients in the PALOMA-3 study, who had progression or relapse during previous ET, were randomly allocated to receive either palbociclib plus fulvestrant or placebo plus fulvestrant. The primary endpoint was investigator-assessed PFS. Kaplan-Meier approach and Cox proportional hazards model were applied to estimate the association of treatment strategies with PFS among HER2-0 and HER2-low-positive populations. The two trials are registered with ClinicalTrials.gov, number NCT01740427 and NCT01942135. FINDINGS: Of the 666 patients with MBC from the PALOMA-2 study, there were 153 HER2-0 and 513 HER2-low-positive patients. In the HER2-0 population, no significant difference in PFS was observed between the palbociclib-letrozole and placebo-letrozole groups (hazard ratio = 0.79, 95% confidence interval [CI] 0.48-1.30, p = 0.34). In the HER2-low-positive population, palbociclib-letrozole demonstrated a significantly lower risk of PFS than placebo-letrozole group (hazard ratio = 0.52, 95% CI 0.41-0.66, p < 0.0001). The PALOMA-3 study analysed 520 patients with MBC. Within the 153 HER2-0 patients, the palbociclib-fulvestrant group showed a significantly longer PFS than the placebo-fulvestrant group (hazard ratio = 0.54, 95% CI 0.30-0.95, p = 0.034). Among the 367 HER2-low-positive patients, palbociclib-fulvestrant improved PFS (hazard ratio = 0.39, 95% CI 0.28-0.54, p < 0.0001). INTERPRETATION: The combination of a CDK4/6 inhibitor with ET significantly improved PFS in HER2-low-positive patients, while for HER2-0 patients, benefits were primarily observed in patients who had progressed on previous ET. Furthermore, HER2-0 patients may derive limited benefits from first-line CDK4/6 inhibitor treatment. Further work is needed to validate these findings and to delineate patient subsets that are most likely to benefit from the combination of CDK4/6 inhibitors and ET as first-line treatments. FUNDING: None.

Impact of HER2-low status for patients with early-stage breast cancer and non-pCR after neoadjuvant chemotherapy: a National Cancer Database Analysis.

PURPOSE: To investigate potential differences in pathological complete response (pCR) rates and overall survival (OS) between HER2-low and HER2-zero patients with early-stage hormone receptor (HR)-positive and triple-negative breast cancer (TNBC), in the neoadjuvant chemotherapy setting. METHODS: We identified early-stage invasive HER2-negative BC patients who received neoadjuvant chemotherapy diagnosed between 2010 and 2018 in the National Cancer Database. HER2-low was defined by immunohistochemistry (IHC) 1+ or 2+ with negative in situ hybridization, and HER2-zero by IHC0. All the methods were applied separately in the HR-positive and TNBC cohorts. Logistic regression was used to estimate the association of HER2 status with pCR (i.e. ypT0/Tis and ypN0). Kaplan-Meier method and Cox proportional hazards model were applied to estimate the association of HER2 status with OS. Inverse probability weighting and/or multivariable regression were applied to all analyses. RESULTS: For HR-positive patients, 70.9% (n = 17,934) were HER2-low, whereas 51.1% (n = 10,238) of TNBC patients were HER2-low. For both HR-positive and TNBC cohorts, HER2-low status was significantly associated with lower pCR rates [HR-positive: 5.0% vs. 6.7%; weighted odds ratio (OR) = 0.81 (95% CI: 0.72-0.91), p < 0.001; TNBC: 21.6% vs. 24.4%; weighted OR = 0.91 (95% CI: 0.85-0.98), p = 0.007] and improved OS [HR-positive: weighted hazard ratio = 0.85 (95% CI: 0.79-0.91), p < 0.001; TNBC: weighted hazard ratio = 0.91 (95% CI: 0.86-0.96), p < 0.001]. HER2-low status was associated with favorable OS among patients not achieving pCR [HR-positive: adjusted hazard ratio = 0.83 (95% CI: 0.77-0.89), p < 0.001; TNBC: adjusted hazard ratio = 0.88 (95% CI 0.83-0.94), p < 0.001], while no significant difference in OS was observed in patients who achieved pCR [HR-positive: adjusted hazard ratio = 1.00 (95% CI: 0.61-1.63), p > 0.99; TNBC: adjusted hazard ratio = 1.11 (95% CI: 0.85-1.45), p = 0.44]. CONCLUSION: In both early-stage HR-positive and TNBC patients, HER2-low status was associated with lower pCR rates. HER2-zero status might be considered an adverse prognostic factor for OS in patients not achieving pCR.

Novel Genetic Variants in TP37, PIK3R1, CALM1, and PLCG2 of the Neurotrophin Signaling Pathway Are Associated with the Progression from Mild Cognitive Impairment to Alzheimer's Disease.

BACKGROUND: Alzheimer's disease (AD) is a common neurodegenerative disease and mild cognitive impairment (MCI) is considered as the prodromal stage of AD. Previous studies showed that changes in the neurotrophin signaling pathway could lead to cognitive decline in AD. However, the association of single nucleotide polymorphisms (SNPs) in genes that are involved in this pathway with AD progression from MCI remains unclear. OBJECTIVE: We investigated the associations between SNPs involved in the neurotrophin signaling pathway with AD progression. METHODS: We performed single-locus analysis to identify neurotrophin-signaling-related SNPs associated with the AD progression using 767 patients from the Alzheimer's Disease Neuroimaging Initiative study and 1,373 patients from the National Alzheimer's Coordinating Center study. We constructed polygenic risk scores (PRSs) using the identified independent non-APOE SNPs and evaluated its prediction performance on AD progression. RESULTS: We identified 25 SNPs significantly associated with AD progression with Bayesian false-discovery probability ≤0.8. Based on the linkage disequilibrium clumping and expression quantitative trait loci analysis, we found 6 potentially functional SNPs that were associated with AD progression independently. The PRS analysis quantified the combined effects of these SNPs on longitudinal cognitive assessments and biomarkers from cerebrospinal fluid and neuroimaging. The addition of PRSs to the prediction model for 3-year progression to AD from MCI significantly increased the predictive accuracy. CONCLUSION: Genetic variants in the specific genes of the neurotrophin signaling pathway are predictors of AD progression. eQTL analysis supports that these SNPs regulate expression of key genes involved in the neurotrophin signaling pathway.

Ionic liquid functionalized injectable and conductive hyaluronic acid hydrogels for the efficient repair of diabetic wounds under electrical stimulation.

The treatment and care of diabetic wounds remains a global challenge due to the high rates of amputation, recurrence, and mortality. It has been proven that electrical stimulation has a positive effect on promoting diabetic wound healing. Hyaluronic acid is an acidic mucopolysaccharide that exhibits important physiological functions in the body. However, it is not an ideal electrical substrate because of its poor electrical conductivity. In this work, a series of novel ionic liquid functionalized injectable and conductive hydrogels was prepared based on hyaluronic acid. The obtained hydrogels exhibited excellent electrical conductivity, flexibility and mechanical properties, and conferred significant antibacterial effects without the need for additional antibiotics. These hydrogels coupled with exogenous electrical stimulation can significantly accelerate diabetic wound healing compared with the commercial Tegaderm™ film.

A visible and near-infrared light dual responsive "signal-off" and "signal-on" photoelectrochemical aptasensor for prostate-specific antigen.

A visible and near-infrared light dual responsive "signal-off" and "signal-on" photoelectrochemical aptasensor was constructed for determining prostate-specific antigen (PSA) based on MoS2 nanoflowers and gold nanobipyramids. The dual responsive photoelectrochemical aptasensor can provide accurate results for PSA determination. For the photoelectrochemical aptasensor fabrication, amino-group functionalized aptamers were immobilized on a MoS2 nanoflowers modified glassy carbon electrode surface for the specific recognition, and thus to achieve a "signal-off" aptasensor for PSA under visible light illumination. Subsequently, gold nanobipyramids integrated with thiol-functional aptamer were introduced to the "signal-off" aptasensing interface after PSA recognition. Under excitation with near-infrared light at 808 nm, the photocurrent response can be amplified significantly due to the excellent conductivity and local surface plasmon resonance effect of gold nanobipyramids, thus to producing a "signal-on" model for determining PSA. Under the optimized conditions, the dual-responsive photoelectrochemical aptasensor shows a linear response to the logarithm of PSA concentration in the range of 0.005-100 ng/mL. The detection limits for PSA determination with a "signal-off" or a "signal-on" mode are 1.75 pg mL-1 and 0.39 pg mL-1, respectively. The dual-responsive photoelectrochemical aptasensor was also employed for determining PSA in clinical serum samples with satisfactory selectivity and excellent accuracy.

Hidden Telltale Signs in Hyperacute Ischemic Stroke Caused by Aortic Dissection: A Case Report and Post Hoc Analysis.

INTRODUCTION: Rapid identification of hidden telltale signs in hyperacute ischemic stroke caused by aortic dissection (AD) is challenging, mainly owing to the narrow time window for bridging therapy. CASE REPORT: A 63-year-old man was referred for sudden right-side weakness accompanied by a decreased level of consciousness for almost 1 hour and 37 minutes. He had a history of hypertension. His skin was clammy, and on physical examination, there was involuntary chest thumping in the left upper limb. Hyperacute cerebral infarction was considered after no bleeding was observed on emergency head computed tomography, and intravenous thrombolysis with alteplase was administered immediately after. The patient was then taken to the catheter room, ready for endovascular thrombectomy. Stanford type A AD was found by cerebral angiography before endovascular thrombectomy. The infusion of alteplase was stopped immediately during cerebral angiography, but the patient's blood pressure, heart rate, and blood oxygen were still declining progressively, and the degree of consciousness disturbance deepened. The patient died after the combined but failed rescue attempts of multiple departments. CONCLUSION: Hyperacute ischemic stroke caused by AD often hides some telltale signs. Clinicians should master basic clinical skills to exclude AD by looking for these telltale signs hidden in hyperacute ischemic stroke to avoid the fatal consequences of intravenous thrombolysis and/or cerebral angiography within the narrow window of time.

Eu-MOF nanorods functionalized with large heterocyclic ionic liquid for photoelectrochemical immunoassay of α-fetoprotein.

An ionic liquid with a sizeable heterocyclic structure was successfully synthesized and used as a linker to coordinate with Eu3+ ions to provide metal-organic framework (Eu-MOF) nanorods. Gold nanoparticles-modified Eu-MOF nanocomposites (Eu-MOF@AuNPs) were synthesized by the in-situ reduction of chloroauric acid on the Eu-MOF nanorod surface. The outstanding conductivity and local surface plasmon resonance (LSPR) of Au-NPs and the distinct nature of MOFs worked together to enhance photoelectrochemical (PEC) performance by decreasing the recombination of photo-excited carriers and taking advantage of a broad absorption range for light harvesting. Under white light irradiation, the Eu-MOF@AuNPs nanocomposite had a better PEC performance than pure Eu-MOF. Therefore, a novel photoelectrochemical immunosensor was fabricated for alpha-fetoprotein (AFP) using Eu-MOF@AuNPs as the photoactive element. When the anti-AFP was attached to the Eu-MOF@AuNPs/GCE interface, the designed immunosensor exhibited a specific photocurrent response to AFP. The specific binding of AFP to anti-AFP can cause a significant steric hindrance, thus hinder the charge transfer and the separation of electron-hole pairs due to large molecular size and poor conductivity. As a result, the PEC immunosensing platform presented a decreasing trend on photocurrent intensity. Under the optimized conditions, the calibration plot showed a linearity with the logarithm of AFP concentration (0.002-15.0 ng mL-1), and a detection limit of 0.16 pg mL-1 was obtained (S/N = 3). Moreover, this immunosensor presented a brilliant selectivity, high reproducibility, and outstanding stability, which possesses remarkable potential applications in determining AFP in serum samples.

Near-infrared photoactive Yb-MOF functionalized with a large conjugate ionic liquid: synthesis and application for photoelectrochemical immunosensing of carcinoma embryonic antigen.

A novel near-infrared (NIR)-excited photoelectrochemical (PEC) immunosensor based on an ionic liquid functionalized metal organic framework (Yb-MOF) and gold nanoparticles (Au-NPs) was designed for the high-performance determination of carcinoembryonic antigen (CEA). The Yb-MOF was synthesized from the coordination of the Yb3+ metal ion with the 1,1'-(1,5-dihydropyrene-2,7-diyl)bis(3-(4-carboxybenzyl)-1H-imidazol-3-ium) bromide [DDPDBCBIm(Br)2] ionic liquid by a hydrothermal method. To improve the photoelectric conversion efficiency of the Yb-MOF in the NIR region, the surface of the Yb-MOF was integrated with gold nanoparticles (AuNPs) to fabricate a Yb-MOF@AuNP nanocomposite through an in situ reduction of chloroauric acid with sodium borohydride. The NIR photoelectrochemical response of the Yb-MOF@AuNPs at 808 nm was enhanced 4-fold over the pristine Yb-MOF. Subsequently, a photoelectrochemical platform based on the Yb-MOF@AuNPs was constructed for loading the CEA antibody (anti-CEA). After cross-linking with glutaraldehyde followed by blocking with bovine serum albumin, a photoelectrochemical sensor for assaying CEA was fabricated. Upon specifically interacting with CEA, CEA can block the photogenerated electron-hole pair transfer and the mass transfer of ascorbic acid to the sensing interface, thus leading to a decrease in photocurrent response. The photocurrent variation can be used for determining CEA quantitatively. After optimizing the experimental conditions, the photocurrent variations before and after incubation with CEA were linearly correlated with the CEA concentration over the range of 0.005-15 ng mL-1. The detection limit of CEA was calculated to be 0.25 pg mL-1 (S/N = 3). The immunosensor was employed for the measurement of free CEA in clinical serum samples, and the results were very consistent with the values obtained by clinical tests. The NIR PEC immunosensor also demonstrated excellent accuracy and recovery, which corroborates its potential as a practical technique in clinical diagnosis.