Risk of Heart Disease in Patients With Amputation: A Nationwide Cohort Study in South Korea.

BACKGROUND: Amputation confers disabilities upon patients and is linked to substantial morbidity and death attributed to heart disease. While some studies have focused on traumatic amputees in veterans, few studies have focused on traumatic amputees within the general population. Therefore, the present study aimed to assess the risk of heart disease in patients with traumatic amputation with disability within the general population using a large-scale nationwide population-based cohort. METHODS AND RESULTS: We used data from the Korean National Health Insurance System. A total of 22 950 participants with amputation were selected with 1:3 age, sex-matched controls between 2010 and 2018. We used Cox proportional hazard models to calculate the risk of myocardial infarction, heart failure, and atrial fibrillation among amputees. Participants with amputation had a higher risk of myocardial infarction (adjusted hazard ratio [aHR], 1.30 [95% CI, 1.14-1.47]), heart failure (aHR, 1.27 [95% CI, 1.17-1.38]), and atrial fibrillation (aHR, 1.17 [95% CI, 1.03-1.33]). The risks of myocardial infarction and heart failure were further increased by the presence of disability (aHR, 1.43 [95% CI, 1.04-1.95]; and aHR, 1.38 [95% CI, 1.13-1.67], respectively). CONCLUSIONS: We demonstrate an increased risk of myocardial infarction, heart failure, and atrial fibrillation among individuals with amputation, and the risk further increased in those with disabilities. Clinicians should pay attention to the increased risk for heart disease in patients with amputation.

Gene therapy in pediatrics - Clinical studies and approved drugs (as of 2023).

Gene therapy in pediatrics represents a cutting-edge therapeutic strategy for treating a range of genetic disorders that manifest in childhood. Gene therapy involves the modification or correction of a mutated gene or the introduction of a functional gene into a patient's cells. In general, it is implemented through two main modalities namely ex vivo gene therapy and in vivo gene therapy. Currently, a noteworthy array of gene therapy products has received valid market authorization, with several others in various stages of the approval process. Additionally, a multitude of clinical trials are actively underway, underscoring the dynamic progress within this field. Pediatric genetic disorders in the fields of hematology, oncology, vision and hearing loss, immunodeficiencies, neurological, and metabolic disorders are areas for gene therapy interventions. This review provides a comprehensive overview of the evolution and current progress of gene therapy-based treatments in the clinic for pediatric patients. It navigates the historical milestones of gene therapies, currently approved gene therapy products by the U.S. Food and Drug Administration (FDA) and/or European Medicines Agency (EMA) for children, and the promising future for genetic disorders. By providing a thorough compilation of approved gene therapy drugs and published results of completed or ongoing clinical trials, this review serves as a guide for pediatric clinicians to get a quick overview of the situation of clinical studies and approved gene therapy products as of 2023.

Utilizing a High-Performance Piezoelectric Nanocomposite as a Self-Activating Component in Piezotronic Artificial Mechanoreceptors.

Challenges such as poor dispersion and insufficient polarization of BaTiO3 (BTO) nanoparticles (NPs) within poly(vinylidene fluoride-co-trifluoroethylene) (P(VDF-TrFE)) composites have hindered their piezoelectricity, limiting their uses in pressure sensors, nanogenerators, and artificial sensory synapses. Here, we introduce a high-performance piezoelectric nanocomposite material consisting of P(VDF-TrFE)/modified-BTO (mBTO) NPs for use as a self-activating component in a piezotronic artificial mechanoreceptor. To generate high-performance piezoelectric nanocomposite materials, the surface of BTO is hydroxylated, followed by the covalent attachment of (3-aminopropyl)triethoxysilane to improve the dispersibility of mBTO NPs within the P(VDF-TrFE) matrix. We also aim to enhance the crystallization degree of P(VDF-TrFE), the efficiency characteristics of mBTO, and the poling efficiency, even when incorporating small amounts of mBTO NPs. The piezoelectric potential mechanically induced from the P(VDF-TrFE)/mBTO NPs nanocomposite was three times greater than that from P(VDF-TrFE) and twice as high as that from the P(VDF-TrFE)/BTO NPs nanocomposite. The piezoelectric potential generated by mechanical stimuli on the piezoelectric nanocomposite was utilized to activate the synaptic ionogel-gated field-effect transistor for the development of self-powered piezotronics artificial mechanoreceptors on a polyimide substrate. The device successfully emulated fast-adapting (FA) functions found in biological FA mechanoreceptors. This approach has great potential for applications to future intelligent tactile perception technology.

Timoshenko-Ehrenfest Beam-Based Reconfigurable Elastic Metasurfaces for Multifunctional Wave Manipulation.

Herein, a Timoshenko-Ehrenfest beam-based reconfigurable elastic metasurface is introduced that can perform multifunctional wave phenomena within a single substrate, featuring high transmission in the ultrabroadband frequency range. Conventional elastic metasurfaces are typically limited to specific purposes and frequencies, thereby imposing significant constraints on their practical application. The approach involves assembly-components with various geometries on a substrate for reconfigurability, enabling to easily control and implement multifunctional wave phenomena, including anomalous-refraction, focusing, self-acceleration, and total-reflection. This is the first study on elastic metasurfaces to theoretically analyze the dispersion relation based on the Timoshenko-Ehrenfest beam theory, which considers shear deformations and rotational inertia. The analytical model is validated by demonstrating an excellent agreement with numerical and experimental results. The findings include full-wave harmonic simulations and experimentally visualized fields for measuring various wave modulations. Furthermore, the practicality of the system is verified by significantly enhancing the piezoelectric energy harvesting performance within the focusing configuration. It is believed that the reconfigurable elastic metasurface and analytical model based on the Timoshenko-Ehrenfest beam theory have vast applications such as structural health monitoring, wireless sensing, and Internet of Things.

Increased Risk of Myocardial Infarction, Heart Failure, and Atrial Fibrillation After Spinal Cord Injury.

BACKGROUND: Heart diseases are a growing concern for the spinal cord injury (SCI) population. OBJECTIVES: This study aims to compare the incidence of heart diseases between SCI survivors and the general non-SCI population. METHODS: We identified 5,083 SCI survivors and 1:3 age- and sex-matched non-SCI controls. Study outcomes were myocardial infarction (MI), heart failure (HF), and atrial fibrillation (AF). The cohort was followed up from the index date (diagnosis date for SCI or corresponding date for matched controls) until 2019. RESULTS: SCI survivors showed a higher risk for MI (adjusted HR [aHR]: 2.41; 95% CI: 1.93-3.00), HF (aHR: 2.24; 95% CI: 1.95-2.56), and AF (aHR: 1.84; 95% CI: 1.49-2.28) compared to controls. The risks were further increased for those who were registered in the National Disability Registry within 1 year from the index date (SCI survivors with disability): SCI survivors with severe disability had the highest risks of MI (aHR: 3.74; 95% CI: 2.43-5.76), HF (aHR: 3.96; 95% CI: 3.05-5.14), and AF (aHR: 3.32; 95% CI: 2.18-5.05). Cervical and lumbar SCI survivors had an increased risk of heart disease regardless of disability compared to matched controls; these risks were slightly higher in those with disability. Thoracic SCI survivors with disability had significantly increased risk of heart disease compared to matched controls. CONCLUSIONS: SCI survivors at all levels were at significantly greater risk for heart disease than non-SCI controls, particularly those with severe disability. Clinicians must be aware of the importance of heart disease in SCI survivors.

Lenvatinib Plus Pembrolizumab Versus Sunitinib in First-Line Treatment of Advanced Renal Cell Carcinoma: Final Prespecified Overall Survival Analysis of CLEAR, a Phase III Study.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical trial updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.We present the final prespecified overall survival (OS) analysis of the open-label, phase III CLEAR study in treatment-naïve patients with advanced renal cell carcinoma (aRCC). With an additional follow-up of 23 months from the primary analysis, we report results from the lenvatinib plus pembrolizumab versus sunitinib comparison of CLEAR. Treatment-naïve patients with aRCC were randomly assigned to receive lenvatinib (20 mg orally once daily in 21-day cycles) plus pembrolizumab (200 mg intravenously once every 3 weeks) or sunitinib (50 mg orally once daily [4 weeks on/2 weeks off]). At this data cutoff date (July 31, 2022), the OS hazard ratio (HR) was 0.79 (95% CI, 0.63 to 0.99). The median OS (95% CI) was 53.7 months (95% CI, 48.7 to not estimable [NE]) with lenvatinib plus pembrolizumab versus 54.3 months (95% CI, 40.9 to NE) with sunitinib; 36-month OS rates (95% CI) were 66.4% (95% CI, 61.1 to 71.2) and 60.2% (95% CI, 54.6 to 65.2), respectively. The median progression-free survival (95% CI) was 23.9 months (95% CI, 20.8 to 27.7) with lenvatinib plus pembrolizumab and 9.2 months (95% CI, 6.0 to 11.0) with sunitinib (HR, 0.47 [95% CI, 0.38 to 0.57]). Objective response rate also favored the combination over sunitinib (71.3% v 36.7%; relative risk 1.94 [95% CI, 1.67 to 2.26]). Treatment-emergent adverse events occurred in >90% of patients who received either treatment. In conclusion, lenvatinib plus pembrolizumab achieved consistent, durable benefit with a manageable safety profile in treatment-naïve patients with aRCC.

Analytical and Clinical Validation of a Highly Sensitive NGS-Based ctDNA Assay with Real-World Concordance in NSCLC.

Purpose: There have been needs to improve the sensitivity of liquid biopsy. This report aims to report the analytical and clinical validation of a next generation sequencing (NGS)-based circulating tumor DNA (ctDNA) assay. Materials and Methods: Analytical validation was conducted in vitro by evaluating the limit of detection (LOD), precision, and specificity for various genomic aberrations. The real-world performance in non-small cell lung cancer (NSCLC) was assessed by comparing the results of AlphaLiquid®100 to the tissue-based results. Results: The LODs with 30 ng input DNA were 0.11%, 0.11%, 0.06%, 0.21%, and 2.13 copies for detecting SNVs, insertions, deletions, fusions, and copy number alterations (CNA), respectively. Quantitatively, SNV/INDELs, fusions, and CNAs showed a good correlation (R2=0.91, 0.40, and 0.65; y=0.95, 1.06, and 1.19) to the manufacturer's values, and per-base specificities for all types of variants were near 100%. In real-world NSCLC (n=122), key actionable mutations in NSCLC were detected in 60.7% (74/122) with the ctDNA assay. Comparative analysis against the NGS-based tissue results for all key mutations showed positive percent agreement (PPA) of 85.3%. For individual genes, the PPA was as high as 95.7% for EGFR mutations and 83.3% for ALK translocations. AlphaLiquid 100 detected drug-sensitive EGFR mutation at a variant allele frequency as low as 0.02% and also identified an EGFR mutation in a case where tissue sample missed. Blood samples collected post-targeted therapies revealed additional acquired mutations. Conclusion: The AlphaLiquid®100 ctDNA assay demonstrates robust analytical validity, offering clinically important information for NSCLC patients.

Case Series of Soft Tissue Sarcoma Patients with Brain Metastasis with Implications from Genomic and Transcriptomic Analysis.

PURPOSE: Brain metastasis rarely occurs in soft tissue sarcoma (STS). Here, we present five cases of STS with brain metastases with genetic profiles. MATERIALS AND METHODS: We included five patients from Seoul National University Hospital who were diagnosed with STS with metastasis to the brain. Tissue from the brain metastasis along with that from the primary site or other metastases were used for DNA and RNA sequencing to identify genetic profiles. Gene expression profiles were compared with sarcoma samples from The Cancer Genome Atlas. RESULTS: The overall survival after diagnosis of brain metastasis ranged from 2.2 to 34.3 months. Comparison of mutational profiles between brain metastases and matched primary or other metastatic samples showed similar profiles. In two patients, copy number variation profiles between brain metastasis and other tumors showed several differences including MYCL, JUN, MYC, and DDR2 amplification. Gene ontology analysis showed that the group of genes significantly highly expressed in the brain metastasis samples was enriched in the G-protein coupled receptor activity, structural constituent of chromatin, protein heterodimerization activity, and binding of DNA, RNA, and protein. Gene set enrichment analysis showed enrichment in the pathway of neuroactive ligand-receptor interaction and systemic lupus erythematosus. CONCLUSION: The five patients had variable ranges of clinical courses and outcomes. Genomic and transcriptomic analysis of STS with brain metastasis implicates possible involvement of complex expression modification and epigenetic changes rather than the addition of single driver gene alteration.

Xaluritamig, a STEAP1 × CD3 XmAb 2+1 Immune Therapy for Metastatic Castration-Resistant Prostate Cancer: Results from Dose Exploration in a First-in-Human Study.

Xaluritamig (AMG 509) is a six-transmembrane epithelial antigen of the prostate 1 (STEAP1)-targeted T-cell engager designed to facilitate lysis of STEAP1-expressing cancer cells, such as those in advanced prostate cancer. This first-in-human study reports monotherapy dose exploration for patients with metastatic castration-resistant prostate cancer (mCRPC), primarily taxane pretreated. Ninety-seven patients received ≥1 intravenous dose ranging from 0.001 to 2.0 mg weekly or every 2 weeks. MTD was identified as 1.5 mg i.v. weekly via a 3-step dose. The most common treatment-related adverse events were cytokine release syndrome (CRS; 72%), fatigue (45%), and myalgia (34%). CRS occurred primarily during cycle 1 and improved with premedication and step dosing. Prostate-specific antigen (PSA) and RECIST responses across cohorts were encouraging [49% PSA50; 24% objective response rate (ORR)], with greater frequency at target doses ≥0.75 mg (59% PSA50; 41% ORR). Xaluritamig is a novel immunotherapy for prostate cancer that has shown encouraging results supporting further development. SIGNIFICANCE: Xaluritamig demonstrated encouraging responses (PSA and RECIST) compared with historical established treatments for patients with late-line mCRPC. This study provides proof of concept for T-cell engagers as a potential treatment for prostate cancer, validates STEAP1 as a target, and supports further clinical investigation of xaluritamig in prostate cancer. See related commentary by Hage Chehade et al., p. 20. See related article by Nolan-Stevaux et al., p. 90. This article is featured in Selected Articles from This Issue, p. 5.

Clinical Practice Recommendations for the Use of Next-Generation Sequencing in Patients with Solid Cancer: A Joint Report from KSMO and KSP.

In recent years, next-generation sequencing (NGS)-based genetic testing has become crucial in cancer care. While its primary objective is to identify actionable genetic alterations to guide treatment decisions, its scope has broadened to encompass aiding in pathological diagnosis and exploring resistance mechanisms. With the ongoing expansion in NGS application and reliance, a compelling necessity arises for expert consensus on its application in solid cancers. To address this demand, the forthcoming recommendations not only provide pragmatic guidance for the clinical use of NGS but also systematically classify actionable genes based on specific cancer types. Additionally, these recommendations will incorporate expert perspectives on crucial biomarkers, ensuring informed decisions regarding circulating tumor DNA panel testing.

CRISPR-Cas9-Based Gene Knockout of Immune Checkpoints in Expanded NK Cells.

Natural killer (NK) cell immunotherapy has emerged as a novel treatment modality for various cancer types, including leukemia. The modulation of inhibitory signaling pathways in T cells and NK cells has been the subject of extensive investigation in both preclinical and clinical settings in recent years. Nonetheless, further research is imperative to optimize antileukemic activities, especially regarding NK-cell-based immunotherapies. The central scientific question of this study pertains to the potential for boosting cytotoxicity in expanded and activated NK cells through the inhibition of inhibitory receptors. To address this question, we employed the CRISPR-Cas9 system to target three distinct inhibitory signaling pathways in NK cells. Specifically, we examined the roles of A2AR within the metabolic purinergic signaling pathway, CBLB as an intracellular regulator in NK cells, and the surface receptors NKG2A and CD96 in enhancing the antileukemic efficacy of NK cells. Following the successful expansion of NK cells, they were transfected with Cas9+sgRNA RNP to knockout A2AR, CBLB, NKG2A, and CD96. The analysis of indel frequencies for all four targets revealed good knockout efficiencies in expanded NK cells, resulting in diminished protein expression as confirmed by flow cytometry and Western blot analysis. Our in vitro killing assays demonstrated that NKG2A and CBLB knockout led to only a marginal improvement in the cytotoxicity of NK cells against AML and B-ALL cells. Furthermore, the antileukemic activity of CD96 knockout NK cells did not yield significant enhancements, and the blockade of A2AR did not result in significant improvement in killing efficiency. In conclusion, our findings suggest that CRISPR-Cas9-based knockout strategies for immune checkpoints might not be sufficient to efficiently boost the antileukemic functions of expanded (and activated) NK cells and, at the same time, point to the need for strong cellular activating signals, as this can be achieved, for example, via transgenic chimeric antigen receptor expression.

Ultrasonic barrier-through imaging by Fabry-Perot resonance-tailoring panel.

Imaging technologies that provide detailed information on intricate shapes and states of an object play critical roles in nanoscale dynamics, bio-organ and cell studies, medical diagnostics, and underwater detection. However, ultrasonic imaging of an object hidden by a nearly impenetrable metal barrier remains intractable. Here, we present the experimental results of ultrasonic imaging of an object in water behind a metal barrier of a high impedance mismatch. In comparison to direct ultrasonic images, our method yields sufficient object information on the shapes and locations with minimal errors. While our imaging principle is based on the Fabry-Perot (FP) resonance, our strategy for reducing attenuation in our experiments focuses on customising the resonance at any desired frequency. To tailor the resonance frequency, we placed an elaborately engineered panel of a specific material and thickness, called the FP resonance-tailoring panel (RTP), and installed the panel in front of a barrier at a controlled distance. Since our RTP-based imaging technique is readily compatible with conventional ultrasound devices, it can realise underwater barrier-through imaging and communication and enhance skull-through ultrasonic brain imaging.

Prognostic utility of body composition parameters based on computed tomography analysis of advanced non-small cell lung cancer treated with immune checkpoint inhibitors.

OBJECTIVE: The purpose of this study was to evaluate the prognostic impact of body composition parameters based on computed tomography (CT) in patients with non-small cell lung cancer (NSCLC) who received ICI treatment. METHODS: This retrospective study analyzed the data from advanced NSCLC patients treated with ICI therapy between 2013 and 2019. We included patients with NSCLC who underwent baseline CT scans. The exclusion criteria included patients who received three or more lines of chemotherapy, those with insufficient clinical information, or those without treatment response evaluation. RESULTS: A total of 136 patients were enrolled. Among the volumetric body composition parameters, patients in the highest quartiles (Q2-4) of the visceral fat index (VFI) exhibited a higher response rate to ICI therapy than those in the lowest quartile (Q1) of VFI (Q1 vs. Q2-4: 18.2% vs. 43.1%, p = 0.012). Patients with a VFI in Q2-4 had significantly prolonged progression-free survival (PFS) and overall survival (OS) (PFS, Q1 vs. Q2-4: 3.0 months vs. 6.4 months, p = 0.043; OS, Q1 vs. Q2-4: 5.6 months vs. 16.3 months, p = 0.004). Kaplan-Meier analysis based on the VFI and visceral fat Hounsfield unit (HU) revealed that patients with VFI in Q1 and HU in Q2-4 had the worst prognosis. CONCLUSIONS: Visceral fat volume is significantly associated with treatment outcomes in ICI-treated patients with NSCLC. Moreover, fat quality may impact the treatment outcomes. This finding underscores the potential significance of both fat compartments and fat quality as prognostic indicators. CRITICAL RELEVANCE STATEMENT: Visceral fat volume is significantly associated with treatment outcomes in ICI-treated patients with non-small cell lung cancer. Moreover, fat quality may impact the treatment outcomes. This finding underscores the potential significance of both fat compartments and fat quality as prognostic indicators. KEY POINTS: • We found that visceral fat volume positively correlated with treatment response and survival in patients with non-small cell lung cancer receiving immune checkpoint inhibitors. • Additionally, a trend toward a negative correlation between visceral fat attenuation and survival was observed. • The findings highlight the prognostic utility of fat compartments and fat quality.

A phase II study on the efficacy of regorafenib in treating patients with c-KIT-mutated metastatic malignant melanoma that progressed after previous treatment (KCSG-UN-14-13).

BACKGROUND: c-KIT mutations are found in approximately 15% of patients with malignant melanoma in the Asian population. Regorafenib, an oral multikinase inhibitor, acts against both wild-type and mutant KIT. OBJECTIVE: This multi-institutional, phase II, single-arm study aimed to evaluate the efficacy of regorafenib against metastatic malignant melanoma harbouring c-KIT mutations. METHODS: Patients with metastatic melanoma positive for c-KIT mutations, upon progression after at least one line of systemic treatment, were enroled. Patients received oral regorafenib 160 mg once daily for 3 weeks (4-week cycle). The primary endpoint was disease control rate (DCR), and secondary endpoints were safety, overall response rate (ORR), progression-free survival (PFS), and overall survival (OS). RESULTS: In total, 23 patients were enrolled. c-KIT mutations were frequently reported in exon 11 (14/23, 60.9%), followed by exons 13, 17, and 9 in 5 (21.7%), 5 (21.7%), and 2 (8.7%) patients, respectively. DCR at 8 weeks was 73.9%, with 2 patients (8.7%) achieving complete response, 5 (21.7%) achieving partial response, and 10 (43.5%) showing stable disease. ORR was 30.4% (7/23). The median follow-up period was 15.7 months (95% confidence interval [CI], 9.6-21.3), and median OS and PFS were 21.5 months (95% CI, 15.1-27.9) and 7.1 months (95% CI, 5.0-9.2), respectively. Circulating tumour DNA analysis in selected patients showed high c-KIT correlation (85.7%) with tissue-based tumour mutational profiles. The most common adverse events (AEs) were skin reactions, including palmar-plantar erythrodysesthesia (52.2%), and grade 3 AEs were reported in 39.1% (9/23) of the patients. CONCLUSION: Regorafenib in second- or later-line settings demonstrated significant activity in patients with metastatic melanoma harbouring c-KIT mutations.

Artificial intelligence-powered spatial analysis of tumor-infiltrating lymphocytes as a biomarker in locally advanced unresectable thymic epithelial neoplasm: A single-center, retrospective, longitudinal cohort study.

BACKGROUND: Thymic epithelial tumors (TET) are rare malignancies and lack well-defined biomarkers for neoadjuvant therapy. This study aimed to evaluate the clinical utility of artificial intelligence (AI)-powered tumor-infiltrating lymphocyte (TIL) analysis in TET. METHODS: Patients initially diagnosed with unresectable thymoma or thymic carcinoma who underwent neoadjuvant therapy between January 2004 and December 2021 formed our study population. Hematoxylin and eosin-stained sections from the initial biopsy and surgery were analyzed using an AI-powered spatial TIL analyzer. Intratumoral TIL (iTIL) and stromal TIL (sTIL) were quantified and their immune phenotype (IP) was identified. RESULTS: Thirty-five patients were included in this study. The proportion of patients with partial response to neoadjuvant therapy was higher in the group with nondesert IP in preneoadjuvant biopsy (63.6% vs. 17.6%, p = 0.038). A significant increase in both iTIL (median 22.18/mm2 vs. 340.69/mm2 , p < 0.001) and sTIL (median 175.19/mm2 vs. 531.02/mm2 , p = 0.004) was observed after neoadjuvant therapy. Patients with higher iTIL (>147/mm2 ) exhibited longer disease-free survival (median, 29 months vs. 12 months, p = 0.009) and overall survival (OS) (median, 62 months vs. 45 months, p = 0.002). Patients with higher sTIL (>232.1/mm2 ) exhibited longer OS (median 62 months vs. 30 months, p = 0.021). CONCLUSIONS: Nondesert IP in initial biopsy was associated with a better response to neoadjuvant therapy. Increased infiltration of both iTIL and sTIL in surgical specimens were associated with longer OS in patients with TET who underwent resection followed by neoadjuvant therapy.

Longitudinal multi-omics study of palbociclib resistance in HR-positive/HER2-negative metastatic breast cancer.

BACKGROUND: Cyclin-dependent kinase 4/6 inhibitor (CDK4/6) therapy plus endocrine therapy (ET) is an effective treatment for patients with hormone receptor-positive/human epidermal receptor 2-negative metastatic breast cancer (HR+/HER2- MBC); however, resistance is common and poorly understood. A comprehensive genomic and transcriptomic analysis of pretreatment and post-treatment tumors from patients receiving palbociclib plus ET was performed to delineate molecular mechanisms of drug resistance. METHODS: Tissue was collected from 89 patients with HR+/HER2- MBC, including those with recurrent and/or metastatic disease, receiving palbociclib plus an aromatase inhibitor or fulvestrant at Samsung Medical Center and Seoul National University Hospital from 2017 to 2020. Tumor biopsy and blood samples obtained at pretreatment, on-treatment (6 weeks and/or 12 weeks), and post-progression underwent RNA sequencing and whole-exome sequencing. Cox regression analysis was performed to identify the clinical and genomic variables associated with progression-free survival. RESULTS: Novel markers associated with poor prognosis, including genomic scar features caused by homologous repair deficiency (HRD), estrogen response signatures, and four prognostic clusters with distinct molecular features were identified. Tumors with TP53 mutations co-occurring with a unique HRD-high cluster responded poorly to palbociclib plus ET. Comparisons of paired pre- and post-treatment samples revealed that tumors became enriched in APOBEC mutation signatures, and many switched to aggressive molecular subtypes with estrogen-independent characteristics. We identified frequent genomic alterations upon disease progression in RB1, ESR1, PTEN, and KMT2C. CONCLUSIONS: We identified novel molecular features associated with poor prognosis and molecular mechanisms that could be targeted to overcome resistance to CKD4/6 plus ET. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03401359. The trial was posted on 18 January 2018 and registered prospectively.

Treatment outcomes of advanced/metastatic extramammary Paget's disease in Korean patients: KCSG-RC20-06.

BACKGROUND: Extramammary Paget's disease (EMPD) is rare. There are no standard treatments due to its rarity and few clinical trials. METHODS: The objective of this multicenter study was to investigate treatment outcomes of Korean patients with advanced/metastatic EMPD. Data were collected retrospectively from 14 institutions participating in Korean Cancer Study Group (KCSG) Rare Cancer Committee. RESULTS: A total of 37 patients were identified. Of these 37 patients, 6 received locoregional therapy as a first-line treatment. In 31 patients who received systemic chemotherapy as a first-line treatment, platinum-based chemotherapy (n = 22) achieved an objective response rate (ORR) of 45.5% and a median progression-free survival (PFS) of 7.89 months. Taxane-based chemotherapy (n = 8) achieved an objective response rate of 62.5% and median PFS of 9.73 months. In second-line chemotherapy, platinum-based chemotherapy (n = 4) had a disease control rate (DCR) of 75.0% and median PFS of 3.45 months. Taxane-based chemotherapy (n = 8) had a DCR of 75.0% and a median PFS of 8.67 months. Six patients received anti-human epidermal growth factor receptor 2 (HER2) antibody during first- and second-line chemotherapy. Overall, systemic chemotherapy combined with anti-HER2 antibody had an ORR of 100% and a median PFS of 13.31 months. The ORR and PFS with systemic chemotherapy combined with trastuzumab was better than platinum- and taxane-based chemotherapy only. CONCLUSIONS: Due to its rarity, advanced or metastatic EMPD still has no established standard treatment. Results of our study indicate that the combination of trastuzumab with taxane has longer survival than trastuzumab monotherapy or conventional platinum- or taxane-based chemotherapy.

Assessment of Disability and Depression Following Amputation Among Adults in Korea.

This nationwide, population-based, retrospective cohort study assesses the risk of depression following amputation among adults in Korea.

A Phase Ib, Open-label Study Evaluating the Safety and Efficacy of Ipatasertib plus Rucaparib in Patients with Metastatic Castration-resistant Prostate Cancer.

PURPOSE: To report the safety and efficacy of ipatasertib (AKT inhibitor) combined with rucaparib (PARP inhibitor) in patients with metastatic castration-resistant prostate cancer (mCRPC) previously treated with second-generation androgen receptor inhibitors. PATIENTS AND METHODS: In this two-part phase Ib trial (NCT03840200), patients with advanced prostate, breast, or ovarian cancer received ipatasertib (300 or 400 mg daily) plus rucaparib (400 or 600 mg twice daily) to assess safety and identify a recommended phase II dose (RP2D). A part 1 dose-escalation phase was followed by a part 2 dose-expansion phase in which only patients with mCRPC received the RP2D. The primary efficacy endpoint was prostate-specific antigen (PSA) response (≥50% reduction) in patients with mCRPC. Patients were not selected on the basis of tumor mutational status. RESULTS: Fifty-one patients were enrolled (part 1 = 21; part 2 = 30). Ipatasertib 400 mg daily plus rucaparib 400 mg twice daily was the selected RP2D, received by 37 patients with mCRPC. Grade 3/4 adverse events occurred in 46% (17/37) of patients, with one grade 4 adverse event (anemia, deemed related to rucaparib) and no deaths. Adverse events leading to treatment modification occurred in 70% (26/37). The PSA response rate was 26% (9/35), and the objective response rate per Response Criteria in Solid Tumors (RECIST) 1.1 was 10% (2/21). Median radiographic progression-free survival per Prostate Cancer Working Group 3 criteria was 5.8 months [95% confidence interval (CI), 4.0-8.1], and median overall survival was 13.3 months (95% CI, 10.9-not evaluable). CONCLUSIONS: Ipatasertib plus rucaparib was manageable with dose modification but did not demonstrate synergistic or additive antitumor activity in previously treated patients with mCRPC.

Targeting CD73 to Overcomes Resistance to First-Generation EGFR Tyrosine Kinase Inhibitors in Non-Small Cell Lung Cancer.

PURPOSE: In patients with epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC), EGFR tyrosine kinase inhibitors (TKIs) improve response rate and survival. However, most patients eventually develop resistance. This study aimed to identify the role of CD73 in EGFR-mutant NSCLC and explore whether CD73 inhibition may serve as a therapeutic strategy in NSCLC patients with acquired resistance to EGFR-TKIs. MATERIALS AND METHODS: We evaluated the prognostic role of CD73 expression in EGFR-mutant NSCLC using tumor samples from a single institution. We silenced CD73 in EGFR-TKI-resistant cell lines using short hairpin RNA (shRNA) targeting CD73 and also transfected a vector alone as a negative control. Using these cell lines, cell proliferation and viability assays, immunoblot assays, cell cycle analysis, colony-forming assays, flow cytometry, and apoptosis analysis were performed. RESULTS: High expression of CD73 was associated with shorter survival in patients with metastatic EGFR-mutant NSCLC treated with first-generation EGFR-TKI. CD73 inhibition synergistically inhibited cell viability with first-generation EGFR-TKI treatment compared with the negative control. When CD73 inhibition and EGFR-TKI treatment were combined, G0/G1 cell cycle arrest was induced through the regulation of p21 and cyclin D1. In addition, the apoptosis rate was increased in CD73 shRNA-transfected cells treated with EGFR-TKI. CONCLUSION: High expression of CD73 adversely affects the survival of patients with EGFR-mutant NSCLC. The study demonstrated that inhibiting CD73 in EGFR-TKI-resistant cell lines resulted in increased apoptosis and cell cycle arrest, which overcame the acquired resistance to first-generation EGFR-TKIs. Further research is needed to determine whether blocking CD73 plays a therapeutic role in EGFR-TKI-resistant patients with EGFR-mutant NSCLC.