Overall Survival with Ribociclib plus Fulvestrant in Advanced Breast Cancer.

BACKGROUND: In an earlier analysis of this phase 3 trial, ribociclib plus fulvestrant showed a greater benefit with regard to progression-free survival than fulvestrant alone in postmenopausal patients with hormone-receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer. Here we report the results of a protocol-specified second interim analysis of overall survival. METHODS: Patients were randomly assigned in a 2:1 ratio to receive either ribociclib or placebo in addition to fulvestrant as first-line or second-line treatment. Survival was evaluated by means of a stratified log-rank test and summarized with the use of Kaplan-Meier methods. RESULTS: This analysis was based on 275 deaths: 167 among 484 patients (34.5%) receiving ribociclib and 108 among 242 (44.6%) receiving placebo. Ribociclib plus fulvestrant showed a significant overall survival benefit over placebo plus fulvestrant. The estimated overall survival at 42 months was 57.8% (95% confidence interval [CI], 52.0 to 63.2) in the ribociclib group and 45.9% (95% CI, 36.9 to 54.5) in the placebo group, for a 28% difference in the relative risk of death (hazard ratio, 0.72; 95% CI, 0.57 to 0.92; P = 0.00455). The benefit was consistent across most subgroups. In a descriptive update, median progression-free survival among patients receiving first-line treatment was 33.6 months (95% CI, 27.1 to 41.3) in the ribociclib group and 19.2 months (95% CI, 14.9 to 23.6) in the placebo group. No new safety signals were observed. CONCLUSIONS: Ribociclib plus fulvestrant showed a significant overall survival benefit over placebo plus fulvestrant in patients with hormone-receptor-positive, HER2-negative advanced breast cancer. (Funded by Novartis; MONALEESA-3 ClinicalTrials.gov number, NCT02422615.).

Impact of Anti-HER2 Therapy Alone and With Weekly Paclitaxel on the Ovarian Reserve of Young Women With HER2-Positive Breast Cancer.

BACKGROUND: The potential gonadotoxicity of anti-HER2 agents remains largely unknown, and limited, conflicting evidence exists for taxanes. Antimüllerian hormone (AMH) is an established biomarker of ovarian reserve that may aid in quantifying anticancer treatment-induced gonadotoxicity. PATIENTS AND METHODS: The present biomarker analysis of the randomized phase III neoadjuvant NeoALTTO trial included premenopausal women aged ≤45 years at diagnosis of HER2-positive early breast cancer with available frozen serum samples at baseline (ie, before anticancer treatments), at week 2 (ie, the "biological window" of anti-HER2 therapy alone), and/or at the time of surgery (ie, after completing paclitaxel + anti-HER2 therapy, before starting adjuvant chemotherapy). RESULTS: The present analysis included 130 patients with a median age of 38 years (interquartile ratio [IQR], age 33-42 years). AMH values at the 3 time points differed significantly (P<.001). At baseline, median AMH levels were 1.29 ng/mL (IQR, 0.56-2.62 ng/mL). At week 2, a small but significant reduction in AMH levels was observed (median, 1.10 ng/mL; IQR, 0.45-2.09 ng/mL; P<.001). At surgery, a larger significant decline in AMH levels was observed (median, 0.01 ng/mL; IQR, 0.01-0.03 ng/mL; P<.001). Although the type of anti-HER2 treatment (trastuzumab and/or lapatinib) did not seem to impact the results, age and pretreatment ovarian reserve had a major influence on treatment-induced gonadotoxicity risk. CONCLUSIONS: This NeoALTTO biomarker analysis showed that anti-HER2 therapies alone had limited gonadotoxicity but that the addition of weekly paclitaxel resulted in marked AMH decline with possible negative implications for subsequent ovarian function and fertility.

Porous MOF Featuring 2D Intersecting Channels Based on a Pentanuclear Mn5(COO)10CO3 Cluster with Upgrading of Pipeline Natural Gas.

Natural gas plays a crucial role in daily and industrial production, but the impurities contained in natural gas limit its further use. It is very important to develop adsorbents that can separate CH4 from multicomponent mixtures, but there are still many challenges and problems. Herein, a novel porous MOF {[Mn5(pbdia)2(CO3)(H2O)2] ↔ 5H2O ↔ 2DMF}n (pbdia = 2,2'-(5-carboxy-1,3-phenylene)bis(oxy) diterephthalic acid) was successfully synthesized based on a flexible pentacarboxylic acid ligand and a unique pentanuclear Mn5(COO)10CO3 cluster. The MOF reveals a 3D porous structure with 2D intersecting channels, which shows high C3H8, C2H6, and CO2 adsorption capacities and affinities over CH4. Moreover, the ideal adsorption solution theory selectivities of C3H8/CH4, C2H6/CH4, and CO2/CH4 can reach 263.0, 27.0, and 7.7, respectively, suggesting a potential for removing the low content of C3H8, C2H6, and CO2 from pipeline natural gas, which was further confirmed by breakthrough curves and GCMC simulations.

Giant muscle hydatid in lower extremity: a rare case with neurological symptoms as the first manifestation.

BACKGROUND: Human hydatid disease typically occurs in organs such as the liver and kidney. Primary solitary intramuscular hydatid disease, however, is rare. CASE PRESENTATION: We report a case of a giant muscle hydatid in the lower extremity, with neurological symptoms as the first manifestation. The symptoms specifically manifested as intermittent pain in the right lower extremity and numbness in the sole of the right foot. However, there were no obvious abnormalities detected in electromyography and lumbar MRI. Subsequent ultrasonography and calf MRI showed that the patient had cystic lesions in the calf. The patient was initially diagnosed with a muscle hydatid cyst. Treatment involved complete surgical excision of the lesion, and the diagnosis of a hydatid cyst was confirmed through macroscopic and microscopic histopathological examination after the mass was excised. The patient was given oral albendazole, and no recurrence was observed during the 12 months of follow-up. CONCLUSIONS: This case underscores the need to consider hydatid disease when diagnosing soft tissue masses in muscles, particularly in endemic areas. Patients may initially present with atypical symptoms like peripheral nerve issues.

Outcomes of patients with small and node-negative HER2-positive early breast cancer treated with adjuvant chemotherapy and anti-HER2 therapy-a sub-analysis of the ALTTO study.

BACKGROUND: Patients with small node-negative HER2-positive breast cancer are commonly treated with paclitaxel and 1 year of adjuvant trastuzumab. We performed a sub-analysis of the ALTTO trial to explore the long-term outcomes of patients with small node-negative tumours. METHODS: The ALTTO trial randomised 8381 patients with early HER2-positive BC treated with adjuvant chemotherapy (anthracycline/taxane- or taxane/carboplatin-based), to trastuzumab (T), lapatinib (L), their sequence (T → L) or their combination (L + T). Patients with tumours ≤3 cm and node-negative were included in this sub-analysis. RESULTS: A total of 2821 patients were analysed (median follow-up of 7 years). The median age was 52 years, and most patients had tumours ≤2 cm (64.3%). The 7-year disease-free survival (DFS) was 88.1% (95% CI: 86.7-89.3%). DFS was similar for arms T, T + L and T⟶L and significantly lower for arm L (stratified log-rank P = 0.031). The 7-year overall survival rate was 95.9% (95% CI: [95.0-96.6%) and the 7-year time-to-distant recurrence was 93.4% (95% CI: 92.3-94.4%). CONCLUSION: With most patients treated with anthracycline-based regimens, ALTTO shows that patients with small tumours treated with trastuzumab and concomitant chemotherapy have excellent long-term outcomes, similar to those of the APT trial. TRIAL REGISTRATION: Clinicaltrials.gov identifier NCT00490139.

A new attempt to treat coronal plane fractures of the elbow joint with salvage via an anterior approach.

BACKGROUND: Existing approaches for treating elbow fractures include lateral, medial, anterior and posterior approaches, though the anterior approach is often not chosen by surgeons to avoid damage to important nerves and blood vessels. However, the anterior approach has unique advantages. The purpose of this study was to report outcomes of 38 patients with coronal plane elbow fractures treated through the anterior approach. METHODS: We retrospectively analyzed 38 cases of coronal plane elbow fracture treated through an anterior approach at our institution between March 2015 and July 2019. The length of the surgical incision, operation time, and postoperative complications were recorded. The range of flexion, extension, and rotation of the affected elbow and the healthy elbow were collected at follow-up. Functional outcomes were evaluated using the Mayo Elbow Function Score (MEPS). RESULTS: All 38 patients were followed up for a mean of 21.26 months (range 12-36 months). Intraoperatively, the mean surgical incision length was 8 ± 2 cm and the mean operative time was 123 ± 59 min. At the final follow-up, solid osseous union was confirmed for all coronal plane elbow fractures. The mean elbow flexion arc was 129 ± 7°, and the extension arc was 9 ± 6°. The mean pronation arc was 83 ± 3°, and the supination arc was 80 ± 3°. The mean MEPS was 90 ± 8 points, with 18 excellent cases and 20 cases of excellent and good results, respectively. In 31 cases, there was no significant difference in elbow extension, flexion, or pronation between the single-fracture and healthy elbows (P > 0.05), though the arc of supination was slightly worse than that of the healthy elbow (P < 0.05). VAS pain scores before the operation, at three months after the operation, and during follow-up were compared, and pain was significantly reduced after treatment (P < 0.05). Two patients experienced transient postoperative median nerve paralysis, from which they recovered within three months. One patient had mild heterotopic ossification and was not treated because it did not affect the function of the elbow joint. All patients returned to work and were satisfied with the treatment. CONCLUSION: The anterior approach has the benefits of simplicity, safety, minimal invasiveness, excellent exposure, and satisfactory prognosis for coronal plane elbow fracture.

Nine-year-long complex humeral nonunion salvaged by distraction osteogenesis technique: a case report and review of the literature.

BACKGROUND: Humeral nonunion with significant bone loss or shortening is uncommon and poses a complex clinical problem. We present a case of humeral nonunion with a large segmental bone defect treated with the distraction osteogenesis technique and remedy the radial nerve palsy produced during distraction osteogenesis by forearm tendon transfers. The reconstruction of upper limb function was achieved with satisfactory results. This case provides a referenceable alternative method for repairing large segmental bone defects due to complex nonunion of the upper extremity, as well as a remedy in the unfortunate event of radial nerve palsy, providing a reference and lessons learned for the treatment of similar cases and the management of possible complications. CASE PRESENTATION: A 31-year-old male patient experienced 9 years of hypertrophic nonunion due to an unreliable internal fixation. The radiographs showed the absence of bone bridging between the two fragments, loosening of the screws, and extensive osteolysis around the internal screws. The patient was treated with distraction osteogenesis. At the end of the distraction period, the patient unfortunately developed right radial nerve paresis, which was salvaged by forearm tendon transplantation, and finally reconstructed hand function and achieved bone union of the humerus. CONCLUSION: Distraction osteogenesis, although not a panacea for all humeral nonunions with significant segmental bone loss, does offer a viable salvage procedure in this unusual and often complex clinical problem. When irreversible radial nerve palsy occurs during distraction, forearm tendon transfers can have a good clinical effect.

Biomimetic-Inspired One-Step Strategy for Improvement of Interfacial Interactions in Cellulose Nanofibers by Modification of the Surface of Nitramine Explosives.

Recently, a burgeoning category of biocompatible botanically derived nanomaterial cellulose nanofibers (CNFs) has captured tremendous attention on account of its entangled nanostructured network, natural abundance, and outstanding mechanical properties. Biomimetically inspired by the superior properties of CNFs, this paper examined them as the coating material to cover cyclotrimethylenetrinitramine (RDX), cyclotetramethylenetetranitramine (HMX), and hexanitrohexaazaisowurtzitane (CL-20) via a facile water suspension method and the ultrasonic technology. The core-shell structure and the composition of energetic crystal@CNF were examined through scanning electron microscopy, X-ray diffraction, Fourier transform infrared spectroscopy, Raman spectroscopy, and X-ray photoelectron spectroscopy analyses. The obtained outcomes demonstrated that the dispersibility of the CNF enhanced favorably upon covering the surface of explosive crystals; the interfacial contact ability between CNFs and energetic crystals was also manifested to be increased, which could be ascribed to the interfacial interaction of hydrogen bonds and the electrostatic force of self-assembly. In addition, the stable crystalloid construction of ß-HMX and ε-CL-20 has been preserved positively in the preparation process. In comparison with raw explosives, the thermal stability and sensitivity performances of the core-shell structure composites were outstanding. Accordingly, this work demonstrated the rewarding application of coating CNFs uniformly on the surface of energetic crystals, ulteriorly offering a potential fabrication strategy for the embellishment of high-explosive crystals.

Using ecological propensity score to adjust for missing confounders in small area studies.

Small area ecological studies are commonly used in epidemiology to assess the impact of area level risk factors on health outcomes when data are only available in an aggregated form. However, the resulting estimates are often biased due to unmeasured confounders, which typically are not available from the standard administrative registries used for these studies. Extra information on confounders can be provided through external data sets such as surveys or cohorts, where the data are available at the individual level rather than at the area level; however, such data typically lack the geographical coverage of administrative registries. We develop a framework of analysis which combines ecological and individual level data from different sources to provide an adjusted estimate of area level risk factors which is less biased. Our method (i) summarizes all available individual level confounders into an area level scalar variable, which we call ecological propensity score (EPS), (ii) implements a hierarchical structured approach to impute the values of EPS whenever they are missing, and (iii) includes the estimated and imputed EPS into the ecological regression linking the risk factors to the health outcome. Through a simulation study, we show that integrating individual level data into small area analyses via EPS is a promising method to reduce the bias intrinsic in ecological studies due to unmeasured confounders; we also apply the method to a real case study to evaluate the effect of air pollution on coronary heart disease hospital admissions in Greater London.

Antenatal corticosteroid therapy (ACT) and size at birth: A population-based analysis using the Finnish Medical Birth Register.

BACKGROUND: Antenatal corticosteroid therapy (ACT) is used clinically to prepare the fetal lung for impending preterm birth, but animal and human studies link corticosteroids to smaller birth size. Whether ACT is associated with birth size is debated; therefore, we assessed differences in birth size in treated versus untreated pregnancies. METHODS AND FINDINGS: This observational register-based study used data from the Finnish Medical Birth Register (FMBR) covering all births in Finland (January 1, 2006-December 31, 2010). We used unadjusted and adjusted regression analyses as well as propensity score matching (PSM) to analyze whether birth size differed by ACT exposure. PSM provides a stringent comparison, as subsamples were created matched on baseline and medical characteristics between treated and untreated women. All analyses were stratified by timing of birth. The primary study outcome was birth size: birth weight (BWT), birth length (BL), ponderal index (PI), and head circumference (HC) measured immediately after birth and recorded in the FMBR. Additional analyses explored indicators of neonatal health in relation to ACT exposure and birth size. A total of 278,508 live-born singleton births with ≥24 gestational completed weeks were registered in the FMBR during the 5-year study period. Over 4% of infants were born preterm, and 4,887 women were treated with ACT (1.75%). More than 44% of the exposed infants (n = 2,173) were born at term. First, results of unadjusted regression analyses using the entire sample showed the greatest reductions in BWT as compared to the other analytic methods: very preterm -61.26 g (±SE 24.12, P < 0.01), preterm -232.90 g (±SE 17.24, P < .001), near term -171.50 g (±SE 17.52, P < .001), and at term -101.95 g (±SE 10.89, P < .001). Second, using the entire sample, regression analyses adjusted for baseline and medical conditions showed significant differences in BWT between exposed and unexposed infants: very preterm -61.54 g (±SE 28.62, P < .03), preterm -222.78 g (±SE 19.64, P < .001), near term -159.25 g (±SE 19.14, P < .001), and at term -91.62 g (±SE 11.86, P < .03). Third, using the stringent PSM analyses based on matched subsamples, infants exposed to ACT weighed less at birth: -220.18 g (±SE 21.43, P < .001), -140.68 g (±SE 23.09, P < .001), and -89.38 g (±SE 14.16, P < .001), born preterm, near term, and at term, respectively. Similarly, significant reductions in BL and HC were also observed using the three analytic methods. There were no differences among postterm infants regardless of analytic method. Likewise, we observed no differences with respect to PI. Additional analyses showed that exposed and unexposed infants had generally similar Apgar scores at birth, yet the ACT-treated infants received greater medical care during the first 7 days of life and beyond. Our study is mainly limited by lack of data in FMBR specifying the interval between treatment and birth as well as other potential confounders that could not be tested. CONCLUSIONS: In this study, ACT was consistently associated with reduction in birth size for infants born preterm, near term, or at term. Further investigation is warranted alongside reevaluation of guidelines. Efforts need to be made to correctly identify and target patients who will deliver preterm. Reduced growth should be considered when deliberating early care decisions.

A Mussel-Inspired Persistent ROS-Scavenging, Electroactive, and Osteoinductive Scaffold Based on Electrochemical-Driven In Situ Nanoassembly.

Conductive polymers are promising for bone regeneration because they can regulate cell behavior through electrical stimulation; moreover, they are antioxidative agents that can be used to protect cells and tissues from damage originating from reactive oxygen species (ROS). However, conductive polymers lack affinity to cells and osteoinductivity, which limits their application in tissue engineering. Herein, an electroactive, cell affinitive, persistent ROS-scavenging, and osteoinductive porous Ti scaffold is prepared by the on-surface in situ assembly of a polypyrrole-polydopamine-hydroxyapatite (PPy-PDA-HA) film through a layer-by-layer pulse electrodeposition (LBL-PED) method. During LBL-PED, the PPy-PDA nanoparticles (NPs) and HA NPs are in situ synthesized and uniformly coated on a porous scaffold from inside to outside. PDA is entangled with and doped into PPy to enhance the ROS scavenging rate of the scaffold and realize repeatable, efficient ROS scavenging over a long period of time. HA and electrical stimulation synergistically promote osteogenic cell differentiation on PPy-PDA-HA films. Ultimately, the PPy-PDA-HA porous scaffold provides excellent bone regeneration through the synergistic effects of electroactivity, cell affinity, and antioxidative activity of the PPy-PDA NPs and the osteoinductivity of HA NPs. This study provides a new strategy for functionalizing porous scaffolds that show great promise as implants for tissue regeneration.

Combining Non-Uniform Time Slice and Finite Difference to Improve 3D Ghost Imaging.

Three-dimensional ghost imaging (3DGI) using a detector is widely used in many applications. The performance of 3DGI based on a uniform time slice is difficult to improve because obtaining an accurate time-slice position remains a challenge. This paper reports a novel structure based on non-uniform time slice combined with finite difference. In this approach, finite difference is beneficial to improving sensitivity of zero crossing to accurately obtain the position of the target in the field of view. Simultaneously, non-uniform time slice is used to quickly obtain 3DGI on an interesting target. Results show that better performances of 3DGI are obtained by our proposed method compared to the traditional method. Moreover, the relation between time slice and the signal-noise-ratio of 3DGI is discussed, and the optimal differential distance is obtained, thus motivating the development of a high-performance 3DGI.

Fabrication of Gelatin-Based Electrospun Composite Fibers for Anti-Bacterial Properties and Protein Adsorption.

A major goal of biomimetics is the development of chemical compositions and structures that simulate the extracellular matrix. In this study, gelatin-based electrospun composite fibrous membranes were prepared by electrospinning to generate bone scaffold materials. The gelatin-based multicomponent composite fibers were fabricated using co-electrospinning, and the composite fibers of chitosan (CS), gelatin (Gel), hydroxyapatite (HA), and graphene oxide (GO) were successfully fabricated for multi-function characteristics of biomimetic scaffolds. The effect of component concentration on composite fiber morphology, antibacterial properties, and protein adsorption were investigated. Composite fibers exhibited effective antibacterial activity against Staphylococcus aureus and Escherichia coli. The study observed that the composite fibers have higher adsorption capacities of bovine serum albumin (BSA) at pH 5.32-6.00 than at pH 3.90-4.50 or 7.35. The protein adsorption on the surface of the composite fiber increased as the initial BSA concentration increased. The surface of the composite reached adsorption equilibrium at 20 min. These results have specific applications for the development of bone scaffold materials, and broad implications in the field of tissue engineering.

Association between serum neuron-specific enolase at admission and the risk of delayed neuropsychiatric sequelae in adults with carbon monoxide poisoning: A meta-analysis.

Delayed neuropsychiatric sequelae (DNS) significantly impact the quality of life in patients following acute carbon monoxide poisoning (COP). This systematic review and meta-analysis aimed to assess the relationship between serum neuron-specific enolase (NSE) levels at admission and the risk of DNS in adults after acute COP. Relevant observational studies with longitudinal follow-up were identified through searches in PubMed, Embase, Web of Science, Wanfang, and China National Knowledge Infrastructure databases. The random-effects model was used to aggregate results, accounting for potential heterogeneity. Nine cohort studies, including 1501 patients, were analyzed, with 254 (16.9%) developing DNS during follow-up. The pooled data indicated that elevated serum NSE in the early phase was linked to a higher risk of subsequent DNS (odds ratio per 1 ng/mL increase in NSE: 1.10, 95% confidence interval: 1.06 to 1.15, P < 0.001). Moderate heterogeneity (I2 = 46%) among the studies was entirely attributed to one study with the longest follow-up duration (22.3 months; I2 = 0% after excluding this study). Subgroup analyses based on country, study design, sample size, age, sex, admission carboxyhemoglobin levels, DNS incidence, follow-up duration, and quality score yielded consistent results (P for subgroup differences all > 0.05). In summary, high serum NSE levels in the early phase of acute COP are associated with an increased risk of developing DNS during follow-up.

In Situ Photoactivated Antibacterial and Antioxidant Composite Materials to Promote Bone Repair.

Trauma and tumor removal usually cause bone defects; in addition, the related postoperative infection also shall be carefully considered clinically. In this study, polylactic acid (PLLA) composite fibers containing Cerium oxide (CeO2) are first prepared by electrospinning technology. Then, the PLLA/CeO2@PDA/Ag composite materials are successfully prepared by reducing silver ion (Ag+) to nano-silver (AgNPs)  coating in situ and binding AgNPs to the materials surface by mussel structure liked polydopamine (PDA). In the materials, Ag+ can be slowly released in simulated body fluids. Based on the photothermal performance of AgNPs, the photothermal conversion efficiency of the materials is 21%, under NIR 808 nm illumination. The effective photothermal conversion can help materials fighting with E. coli and S. aureus in 3 h, with an antibacterial rate of 100%. Additionally, the sustained Ag+ release contributes to the antibacterial in long term. Meanwhile, the materials can mimic the bio-behavior of superoxide dismutase and catalase in decreasing the singlet oxygen level and removing the excess reactive oxygen species. Furthermore, the materials are beneficial for cell proliferation and osteogenic differentiation in vitro. In this study, a promising bone-regenerated material with high photothermal conversion efficiency and antibacterial and anti-oxidation properties, is successfully constructed.

Local Gate Enhanced Correlated Phases in Twisted Monolayer-Bilayer Graphene.

Manipulating the flat band degeneracy and thus getting the correlated insulating phases has been an ideal thread for realizing the exotic quantum phenomenon in the moiré system. To achieve this goal, the delicately tuned twist angle and a substantial displacement field (D) are rigorously requested. Here, we report our scanning tunneling microscope (STM) work on reaching these correlated insulating states in twisted monolayer-bilayer graphene through a decorated tip. It acts as a local top gate, leading to an enhanced local D, and enables us to fully lift the 8-fold degeneracy of the flat bands. With the aid of this technique, we further expand the correlated insulating states into a more tolerant twist angle that is down to 0.92°. Moreover, the correlated insulating phases in the hole-doping regime are realized. Our tip decoration method allows us to integrate the STM study with the high displacement field for the correlated phases in the twisted moiré systems.

Advancing skeletal health and disease research with single-cell RNA sequencing.

Orthopedic conditions have emerged as global health concerns, impacting approximately 1.7 billion individuals worldwide. However, the limited understanding of the underlying pathological processes at the cellular and molecular level has hindered the development of comprehensive treatment options for these disorders. The advent of single-cell RNA sequencing (scRNA-seq) technology has revolutionized biomedical research by enabling detailed examination of cellular and molecular diversity. Nevertheless, investigating mechanisms at the single-cell level in highly mineralized skeletal tissue poses technical challenges. In this comprehensive review, we present a streamlined approach to obtaining high-quality single cells from skeletal tissue and provide an overview of existing scRNA-seq technologies employed in skeletal studies along with practical bioinformatic analysis pipelines. By utilizing these methodologies, crucial insights into the developmental dynamics, maintenance of homeostasis, and pathological processes involved in spine, joint, bone, muscle, and tendon disorders have been uncovered. Specifically focusing on the joint diseases of degenerative disc disease, osteoarthritis, and rheumatoid arthritis using scRNA-seq has provided novel insights and a more nuanced comprehension. These findings have paved the way for discovering novel therapeutic targets that offer potential benefits to patients suffering from diverse skeletal disorders.

Subaxial Cervical Pedicular Screw Insertion via the Nonanatomic Axis: Technical Notes and Preliminary Clinical Report.

STUDY DESIGN: Retrospective study. OBJECTIVE: To report the technical details of subaxial cervical pedicular screw insertion via the nonanatomic axis (nAA-CPS) and evaluate its clinical safety and accuracy. METHODS: The nAA-CPS technique was performed in 21 patients. Preoperative and intraoperative management-related details are described, and a manipulation protocol is presented. Clinical outcomes were used to assess the safety and accuracy of screws was evaluated using postoperative computed tomography (CT) according to the pedicle perforation grading system, and the nonanatomic pedicle transverse angle (nPTA) and nonanatomic pedicle axis length (nPAL) were assessed based on pre- and postoperative CT images. RESULTS: According to "one constant entry point (EP) and two perpendicular trajectory angles" protocol, nAA-CPS was performed without much interference from the muscles. No intraoperative or postoperative neurovascular complications related to the technique were observed. Of the 112 inserted screws, 78 (69.64%) were assessed as grade 0, 24 (21.43%) as grade 1, 4 (3.57%) as grade 2 and 6 (5.36%) as grade 3. The overall rate of correct position (grades 0 and 1) was 91.07% (102/112), and the rate of malposition was 8.93% (10/112), including five screws implanted medially and the other five laterally. The nPTA was highly consistent on pre- and postoperative CT (P < .05), while postoperative nPAL was significantly shorter than preoperative nPAL (P > .05). CONCLUSIONS: Clinically, the accuracy and safety of nAA-CPS was similar to the traditional CPS technique. The protocol, derived from previous radiological studies and workshops, greatly helped standardize clinical manipulation; thus, nAA-CPS is a promising alternative to the traditional CPS.

Justifying Ribociclib Dose in Patients with Advanced Breast Cancer with Renal Impairment Based on PK, Safety, and Efficacy Data: An Innovative Approach Integrating Data from a Dedicated Renal Impairment Study and Oncology Clinical Trials.

BACKGROUND AND OBJECTIVE: Renal impairment is common in patients with cancer and can alter the PK and thus the safety and efficacy of drugs. We assessed the impact of renal impairment during treatment with ribociclib, a cyclin-dependent kinase 4/6 inhibitor, and determined dose recommendations for patients with advanced breast cancer with renal impairment. METHODS: A comprehensive assessment integrating pharmacokinetic, safety, and efficacy data from a phase I dedicated renal impairment study in non-cancer subjects and six phase I-III trials in patients with cancer was performed. RESULTS: Ribociclib showed higher pharmacokinetic exposure in subjects with renal impairment than those with normal renal function following a single 400-mg dose in the dedicated renal impairment study. However, in patient trials, both single-dose and steady­state ribociclib exposure was comparable between patients with cancer with mild/moderate renal impairment and those with normal renal function following the recommended starting dose of 600 mg. Model-predicted steady­state exposure in patients with advanced breast cancer was also similar across the renal function groups. Progression-free survival was similar and safety profiles were generally consistent across the renal cohorts (normal/mild/moderate) in patients with advanced breast cancer, with low-grade and manageable adverse events, demonstrating a positive benefit-risk profile. CONCLUSIONS: From the collective evidence and considering a real-world clinical setting, no dose adjustment is recommended for patients with mild/moderate renal impairment, whereas a reduced dose is recommended for patients with severe renal impairment. This report presented a holistic and innovative strategy to determine dose in patients with renal impairment and demonstrated the effectiveness of integrating the data of both a clinical pharmacology study and patient trials to justify doses in patients with renal impairment. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov identifiers: NCT02431481, NCT01958021, NCT02422615, NCT02278120, NCT01237236, NCT01898845, NCT01872260.

Subaxial Cervical Pedicular Screw Insertion via the Nonanatomic Axis: Identification of Entry Point and Trajectory Based on a Radiographic Study and Workshop.

STUDY DESIGN: A radiological study and workshop. OBJECTIVE: To propose a novel technique for subaxial cervical pedicle screw (CPS) insertion via the nonanatomic axis (nAA) and identify a new entry point (EP) and trajectory based on a radiological study. METHODS: The new EP was determined to be the center of the upper half of the lateral mass, and the nAA was defined as the line connecting the EP and center of the pedicle. CT images of 493 subaxial cervical pedicles from 51 adults were utilized. The pedicle axis length (PAL/nPAL), pedicle transverse angle (PTA/nPTA), sagittal and transverse pedicle screw depth ratio (S-DO, T-DO), and sagittal and transverse angles (S-angle, T-angle) were measured in the anatomical axis (AA) and nAA. nAA-CPS insertions were conducted on dry specimens, and the positions of the screws were graded. RESULTS: The nPTA (22.35° ± 1.57°), nPAL (23.75 ± 2.07 mm), T-DO (45.61% ± 3.10%), and S-DO (70.46% ± 4.44%) of the nAA-CPS were significantly different from the PTA (41.86° ± 2.77°), PAL (31.98 ± 2.40 mm), T-DO and S-DO of the AA-CPS (both 100% in ideal conditions), respectively (P < .05). The T-angle and S-angle were 92.78° ± 3.07° and 92.18° ± 3.78°, respectively. A constant EP and consistent trajectory of the nAA-CPS identified by 2 perpendicular angles were summarized and utilized as the manipulation protocols of the workshop, and a perfect position was achieved in 80.00% (24/30) of screws. CONCLUSION: The nAA-CPS is a novel alternative to the classic CPS technique. A constant entry point and 2 perpendicular angles in the sagittal and transverse planes for identifying the trajectory of the nAA-CPS should be taken into account in the establishment of a manipulation protocol.