Therapy For Disease Research Articles

The Effectiveness of Risankizumab as Induction Therapy for Crohn's Disease: Data From the Sicilian Network for Inflammatory Bowel Diseases.

Lay Summary This multicentre cohort study showed that Risankizumab is an effective induction therapy in patients with Crohn’s disease, and that the best results are obtained when Risankizumab is used as second-line therapy following a previous failure with a TNF inhibitor.

Uncovering ASO-Targetable Deep Intronic AIRE Variants: Insights and Therapeutic Implications.

High-throughput DNA sequencing has accelerated the discovery of disease-causing genetic variants, yet only in 10-40% of cases yield a genetic diagnosis. Increased implementation of genome sequencing has enabled a deeper exploration of the noncoding genome and recognition of noncoding variants as major contributors to disease. In a recent study, we identified a deep intronic variant in the AutoImmune REgulator (AIRE) gene (c.1504-818 G>A) as the cause of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), a life-threatening monogenic autoimmune disorder most often caused by biallelic AIRE defects. This deep intronic variant disrupts normal splicing AIRE , causing pseudoexon inclusion and altered protein function. By developing an antisense oligonucleotide (ASO) targeting the pseudoexon sequence, we restored normal AIRE transcript in vitro, thereby revealing a potential genotype-specific candidate treatment. Our study illustrates key aspects of intronic variant detection, validation, and candidate ASO development. Herein, we briefly highlight the growing potential of ASO-based therapies for deep intronic variants, addressing the unmet need of personalized, genotype-specific therapies in diseases lacking curative options.

Engineering supramolecular peptide nanofibers for in vivo platelet-hitchhiking beyond ligand-receptor recognition.

Ex vivo or in vivo cell-hitchhiking has emerged as a potential means for efficient drug delivery and various disease therapies. However, many challenges remain, such as the complicated engineering process and dependence on ligand-receptor interaction. Here, we present a simple in vivo platelet-hitchhiking strategy based on self-assembling peptides without ligand modification. The engineered peptide nanofibers can hitchhike ultrafast (<5 s) and efficiently on both resting and activated platelets in a receptor-independent and species-independent manner. Mechanistic studies showed that unique secondary structure of nanofibers, which lead to surface exposure of hydrophobic and hydrogen bond-forming groups, might primarily contribute to the selective and efficient platelet-hitchhiking behavior. After intravenous injection, these peptide nanofibers hitchhiked in situ on circulating platelets and achieved almost 20-fold lung accumulation. Our study provides not only a different paradigm of in vivo platelet-hitchhiking beyond ligand-receptor recognition but also a potential strategy for lung-targeted drug delivery and pulmonary disease therapy.

Ibrutinib for therapy of steroid-refractory chronic graft vs. host disease: A multicenter real-world analysis

To examine activity of ibrutinib in steroid-refractory chronic GVHD (SR-cGVHD) after FDA approval, we conducted a multicenter retrospective study. Data were standardly collected (N=270 from 19 centers). Involved organs included skin (75%), eye (61%), mouth (54%), joint/fascia (47%), GI (26%), lung (27%), liver (19%), genital (7%), other (4.4%). NIH severity was mild in 5.7%, moderate 42%, severe 53%. 39% had overlap subtype. KPS was ≥ 80% in 72%. Median prednisone (mg/kg) was 0.21 (0-2.27). Ibrutinib was started at median of 18.2 months after cGVHD onset and in earlier lines of therapy (2nd line: 26%, 3rd: 30%, 4th: 21%, 5th: 9.6%, 6th: 10%, 7th or higher: 1.2%)). Among evaluable subjects, the 6 month NIH overall response rate (CR/PR) was 45% (PR 42%, CR 3%). Median duration of response was 15 months (range 1-46). Liver involvement had association with 6 month ORR (multivariate (MVA) OR 5.49 (95% CI 2.3-14.2, p <0.001). Best overall response was 56%, with most (86%) achieving by 1-3 months. With median follow up for survivors of 30.5 months, FFS was 59% (53-65%) at 6 months and 41% (36-48%) at 12 months. On MVA, increased age (HR 1.01, 95% CI 1.0-1.02, p=0.033), higher baseline prednisone (HR 1.92, 1.09-3.38, p=0.032), and lung involvement (HR 1.58, 1.1-2.28, p=0.016) had worse FFS. Ibrutinib discontinuation was most commonly due to progressive cGVHD (44%) or toxicity (42%). These data support that ibrutinib has activity in SR-cGVHD, provide new insight into factors associated with response and FFS, and demonstrate the toxicity profile associated with discontinuation.

Primary Bone Tumors and Breast Cancer-Induced Bone Metastases: In Vivo Animal Models and New Alternative Approaches

Bone is the preferential site of metastasis for the most common tumors, including breast cancer. On the other hand, osteosarcoma is the primary bone cancer that most commonly occurs and causes bone cancer-related deaths in children. Several treatment strategies have been developed so far, with little or no efficacy for patient survival and with the development of side effects. Therefore, there is an urgent need to develop more effective therapies for bone primary tumors and bone metastatic disease. This almost necessarily requires the use of in vivo animal models that better mimic human pathology and at the same time follow the ethical principles for the humane use of animal testing. In this review we aim to illustrate the main and more suitable in vivo strategies employed to model bone metastases and osteosarcoma. We will also take a look at the recent technologies implemented for a partial replacement of animal testing.

The regulatory T cell-selective interleukin-2 receptor agonist rezpegaldesleukin in the treatment of inflammatory skin diseases: two randomized, double-blind, placebo-controlled phase 1b trials

Regulatory T cell (Treg) impairment is implicated in the pathogenesis of chronic inflammatory diseases, but relatively little is known about the therapeutic potential of Treg restoration. Here we present clinical evidence for the Treg-selective interleukin-2 receptor agonist rezpegaldesleukin (REZPEG) in two randomized, double-blind, placebo-controlled Phase 1b trials in patients with moderate-to-severe atopic dermatitis (AD) (NCT04081350) or chronic plaque psoriasis (PsO) (NCT04119557). Key inclusion criteria for AD included an Eczema Area and Severity Index (EASI) score ≥ 16 and a validated Investigator Global Assessment for Atopic Dermatitis (vIGA-AD) ≥ 3, and for PsO included a Psoriasis Area and Severity Index (PASI) score of ≥ 12 and a static Physician’s Global Assessment (sPGA) score of ≥ 3. REZPEG is safe and well-tolerated and demonstrates consistent pharmacokinetics in participants receiving subcutaneous doses of 10 to 12 µg/kg or 24 µg/kg once every 2 weeks for 12 weeks, meeting the primary and secondary objectives, respectively. AD patients receiving the higher dose demonstrate an 83% improvement in EASI score after 12 weeks of treatment. EASI improvement of ≥ 75% (EASI-75) and vIGA-AD responses are maintained for 36 weeks after treatment discontinuation in 71% and 80% of week 12 responders, respectively. These exploratory clinical improvements are accompanied by sustained increases in CD25bright Tregs. REZPEG thus represents a homeostatic approach to cutaneous disease therapy and holds clinical potential in providing long-term, treatment-free disease control.

Photocleavable Guide RNA for Photocontrolable CRISPR/Cas9 System

The development of gene editing systems on the base of CRISPR/Cas having higher efficacy, specificity, and possibility of their activity regulation by light irradiation is actually problem. Modification of CRISPR/Cas components, in particular guide RNA, by introduction of photocleavable linkers is the prospective approach for the solution of this problem. We developed the approach for the synthesis of photocleavable guide sgRNA for the CRISPR/Cas9 system containing the linkers on the base of 1-(2-nitrophenyl)-1,2-ethanediol. Such photomodified guide RNAs degrade upon UV-irradiation and CRISPR/Cas9 system is inactivated. We obtained three variants of photomodified sgRNA with different photolinker positions. It was demonstrated that sgRNA variant with photolinker introduced in the Cas9 protein binding and hairpins formation region is able to effectively guide Cas9 nuclease for DNA-target cleavage before UV-irradiation and lose its activity after irradiation. The conditions of controllable 40%-cleavage of model DNA-target were chosen. Developed approach provide specific inactivation of CRISPR/Cas9 gene editing system in specific time moment in definite place. Photoregulation of gene editing system permits not only reduce the undesirable off-target effects, but also becomes the basis of genetic disease therapy.

A cocktail of Cu2+- and Zn2+-peptoid-based chelators can stop ROS formation for Alzheimer's disease therapy.

The formation of reactive oxygen species (ROS) in the brain is a major cause of neuropathologic degradation associated with Alzheimer's Disease (AD). It has been suggested that the copper (Cu)-amyloid-β (Aβ) peptide complex can lead to ROS formation in the brain. An external chelator for Cu that can extract Cu from the CuAβ complex should inhibit the formation of ROS, making Cu chelation an excellent therapeutic approach for AD. Such a chelator should possess high selectivity for Cu over zinc (Zn), which is also present within the synaptic cleft. However, such selectivity is generally hard to achieve in one molecule due to the similarities in the binding preferences of these two metal ions. As an alternative to monotherapy (where Cu extraction is performed using a single chelator), herein we describe a variation of combination therapy - a novel cocktail approach, which is based on the co-administration of two structurally different peptidomimetic chelators, aiming to target both Cu2+ and Zn2+ ions simultaneously but independently from each other. Based on rigorous spectroscopic experiments, we demonstrate that our peptidomimetic cocktail allows, for the first time, the complete and immediate inhibition of ROS production by the CuAβ complex in the presence of Zn2+. In addition, we further demonstrate the high stability of the cocktail under simulated physiological conditions and its resistance to proteolytic degradation by trypsin and report the water/n-octanol partition coefficient, initially assessing the blood-brain barrier (BBB) permeability potential of the chelators.

Thrombosis-inflammation: a novel target for antithrombotic therapy in coronary heart disease

Thrombosis-inflammation: a novel target for antithrombotic therapy in coronary heart disease

Augmented cortisol and antiglucocorticoid therapy in mood disorders: the hippocampus as a potential drug target

The pathophysiology of many mood disorders is closely related to abnormal stress response associated with the dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis and cortisol overproduction. The hippocampus, a key structure of the limbic system responsible for both cognitive and emotional spheres, is selectively vulnerable to excess of glucocorticoids (GCs) inducing neuroinflammation and neurodegeneration. The antiGC therapy of psychiatric diseases, in particular depressive disorders, may be a useful additional treatment. Among other approaches, targeting glucocorticoid receptors, abounded in the hippocampus, is regarded as highly promising. However, though the preclinical data provide fairly firm evidence to the concept of antiGC therapy for stress-related diseases, clinical studies still are at the proof-of-concept stage. Noteworthy, chronic GC excess is associated not only with mood diseases, but also with cognitive decline, metabolic disorders, diabetes. Potentially, antiGC (HPA axis modifying) therapy may alleviate affective symptoms, cognitive disturbances, GC and insulin resistance and adverse side effects of conventional drugs through beneficial effects on the hippocampus mitigating its dysfunction and neurodegeneration, neuroinflammation, and impairment of neurogenesis. Since stress/GC-associated neuroinflammation-mediated pathology of the limbic system and, specifically, the hippocampus, is a general feature typical for many brain diseases, the concept of antiGC therapy may be extended, tested and validated in a wider spectrum of cerebral pathologies.

Personalized COPD Care: The Future of Precision-Based Therapies.

Chronic obstructive pulmonary disease (COPD) is a progressive respiratory illness characterized by long-standing respiratory symptoms and airflow limitation. It is a major contributor to respiratory disease-related deaths and currently ranked as the sixth leading cause of mortality in the United States. Approved pharmacological therapies for the stable disease primarily consist of inhaled short and long-acting bronchodilators, inhaled corticosteroids, azithromycin, and roflumilast. In recent years, significant progress has been made in the management of COPD through the identification of different COPD phenotypes and endotypes, which allows for a more personalized treatment approach. While earlier studies investigating targeted therapies were less promising, recent data on drugs targeting type 2 inflammatory pathways have shown promising results in carefully selected patients. In this article, we will review the available data on targeted therapies as well as the ongoing clinical studies of novel targeted therapies for COPD. Understanding and implementing these advancements hold promise for improving outcomes and quality of life for individuals living with COPD.

CellSAM: Advancing Pathologic Image Cell Segmentation via Asymmetric Large-Scale Vision Model Feature Distillation Aggregation Network.

Segment anything model (SAM) has attracted extensive interest as a potent large-scale image segmentation model, with prior efforts adapting it for use in medical imaging. However, the precise segmentation of cell nucleus instances remains a formidable challenge in computational pathology, given substantial morphological variations and the dense clustering of nuclei with unclear boundaries. This study presents an innovative cell segmentation algorithm named CellSAM. CellSAM has the potential to improve the effectiveness and precision of disease identification and therapy planning. As a variant of SAM, CellSAM integrates dual-image encoders and employs techniques such as knowledge distillation and mask fusion. This innovative model exhibits promising capabilities in capturing intricate cell structures and ensuring adaptability in resource-constrained scenarios. The experimental results indicate that this structure effectively enhances the quality and precision of cell segmentation. Remarkably, CellSAM demonstrates outstanding results even with minimal training data. In the evaluation of particular cell segmentation tasks, extensive comparative analyzes show that CellSAM outperforms both general fundamental models and state-of-the-art (SOTA) task-specific models. Comprehensive evaluation metrics yield scores of 0.884, 0.876, and 0.768 for mean accuracy, recall, and precision respectively. Extensive experiments show that CellSAM excels in capturing subtle details and complex structures and is capable of segmenting cells in images accurately. Additionally, CellSAM demonstrates excellent performance on clinical data, indicating its potential for robust applications in treatment planning and disease diagnosis, thereby further improving the efficiency of computer-aided medicine.

The Well-Forgotten Old: Platelet-Rich Plasma in Modern Anti-Aging Therapy.

Currently, approaches to personalized medicine are actively developing. For example, the use of platelet-rich plasma (PRP) is actively growing every year. As a result of activation, platelets release a wide range of growth factors, cytokines, chemokines, and angiogenic factors, after which these molecules regulate chemotaxis, inflammation, and vasomotor function and play a crucial role in restoring the integrity of damaged vascular walls, angiogenesis, and tissue regeneration. Due to these characteristics, PRP has a wide potential in regenerative medicine and gerontology. PRP products are actively used not only in esthetic medicine but also to stimulate tissue regeneration and relieve chronic inflammation. PRP therapy has a number of advantages, but the controversial results of clinical studies, a lack of standardization of the sample preparation of the material, and insufficient objective data on the evaluation of efficacy do not allow us to unambiguously look at the use of PRP for therapeutic purposes. In this review, we will examine the current clinical efficacy of PRP-based products and analyze the contribution of PRP in the therapy of diseases associated with aging.

Progress on Carbon Dots with Intrinsic Bioactivities for Multimodal Theranostics.

Carbon dots (CDs) with intrinsic bioactivities are candidates for bioimaging and disease therapy due to their diverse bioactivities, high biocompatibility, and multiple functionalities in multimodal theranostics. It is a multidisciplinary research hotspot that includes biology, physics, materials science, and chemistry. This progress report discusses the CDs with intrinsic bioactivities and their applications in multimodal theranostics. The relationship between the synthesis and structure of CDs is summarized and analyzed from a material and chemical perspective. The bioactivities of CDs including anti-tumor, antibacterial, anti-inflammatory etc. are discussed from biological points of view. Subsequently, the optical and electronic properties of CDs that can be applied in the biomedical field are summarized from a physical perspective. Based on the functional review of CDs, their applications in the biomedical field are reviewed, including optical diagnosis and treatment, biological activity, etc. Unlike previous reviews, this review combines multiple disciplines to gain a more comprehensive understanding of the mechanisms, functions, and applications of CDs with intrinsic bioactivities.

Identification of Structure-Linked Activity on Bioactive Peptides from Sea Cucumber (Stichopus japonicus): A Compressive In Silico/In Vitro Study.

A sea cucumber (Stichopus japonicus) is an invertebrate rich in high-quality protein peptides that inhabits the coastal seas around East Asian countries. Such bioactive peptides can be utilized in targeted disease therapies and practical applications in the nutraceutical industry. Bioactive peptides were isolated from Stichopus japonicus through ultrafiltration and Sephadex G-10 size exclusion chromatography. The low-molecular-weight fraction (ACSH-III) showed the highest hydroxyl radical scavenging and angiotensin-converting enzyme (ACE) inhibitory activities. Subsequent purification of ACSH-III resulted in four fractions, of which ACSH-III-F3 and ACSH-III-F4 exhibited significant bioactivity. Peptides identified in these fractions, including Phenylalanine-Proline-Threonine-Tyrosine (FPTY) and Tyrosine-Proline-Serine-Tyrosine-Proline-Serine (YPSYPS), were characterized using high-performance liquid chromatography (HPLC) and quadrupole time-of-flight mass spectrometry (QTOF-MS). FPTY demonstrated the most potent antioxidant and antihypertensive activities among these peptides, with IC50 values of 0.11 ± 0.01 mg/mL for hydroxyl radicals and 0.03 ± 0.01 mg/mL for ACE inhibition. Docking simulations revealed strong binding affinities of these peptides to the active site of the ACE, with FPTY displaying interactions similar to those of the synthetic inhibitor lisinopril. These findings suggest that the identified peptides, particularly FPTY, have potential applications as natural antioxidants and functional foods.

Mechanisms of Action of Exclusive Enteral Nutrition and Other Nutritional Therapies in Crohn's Disease.

Crohn's disease (CD) is an inflammatory bowel disease (IBD) characterized by transmural inflammation and intestinal fibrosis involving mostly the small intestine and colon. The pathogenic mechanisms of CD remain incompletely understood and cures are unavailable. Current medical therapies are aimed at inducing prolonged remission. Most of the medical therapies such as corticosteroids have substantial adverse effects. Consequently, many dietary therapies have been explored for the management of CD. Up to now, exclusive enteral nutrition (EEN) has been considered the only established dietary treatment for IBD, especially CD. In this article, we aim to give a concise review about the current therapeutic options and challenges in the management of CD and aim to compare the efficacy of EEN with other dietary therapies and update on the possible mechanisms of the benefits of EEN and other nutritional therapies. We searched the literature up to August 2024 through PubMed, Web of Science, and other sources using search terms such as EEN, nutritional therapy, IBD, Crohn's disease, ulcerative colitis. Clinical studies in patients and preclinical studies in rodent models of IBD were included in the summary of the therapeutic benefits. EEN involves oral or nasogastric tube feeding of a complete liquid diet with exclusion of normal foods for a defined period (usually 6 to 8 weeks). EEN treatment is demonstrated to have anti-inflammatory and healing effects in CD through various potential pathways, including altering gut bacteria and their metabolites, restoring the barrier function, direct anti-inflammatory action, and indirect anti-inflammatory action by eliminating mechanical stress in the bowel. However, efficacy of other nutritional therapies is not well established in CD, and mechanisms of action are largely unknown.

Ketogenic diet and intermittent fasting - impact on body weight and various diseases

Introduction and purpose: Obesity affects every age group and is associated with many negative health effects. Various diets are used to remove excess body weight. Recently, popular became two diets - intermittent fasting and ketogenic diet. Material and Method: This paper reviews various types of research documents published since 2018. Its main aim is to summarize the latest knowledge of ketogenic diet and intermittent fasting, including contraindications, side effects, impact on body weight and many diseases. It is also aimed to highlight the need for future research of the effects of both diets on various diseases and body weight reduction. Results: Both diets may be effective in weight loss and show other health benefits. Both ketogenic diet and intermittent fasting have proven to be effective in weight reduction. In the case of intermittent fasting the biggest impact on weight loss is calorie restriction. Ketogenic diet is effective as a result of calorie restriction, increased gluconeogenesis and loss of free water through increased diuresis. They can be used in the prevention and treatment of many diseases, including cardiovascular disorders, neurological disorders or potentially cancer. However, they cannot be administered by everyone and may cause dangerous side effects. Conclusion: Ketogenic diet and intermittent fasting are successful strategies for body weight reduction. Moreover, both of them may be used as an additional therapy for various diseases. However, patients should be under supervision.

Genetics in nephrology - any news?

While genetic kidney diseases were long regarded as a rare cause of kidney failure, it has been shown in recent years that they account for a relevant proportion of cases. In cohorts of kidney transplant recipients, a monogenic cause is found in up to 30% of cases. Identifying the genetic cause of kidney disease has become much easier thanks to technological advances in DNA sequencing. The focus has now shifted to understanding the significance of the findings and identifying diagnostic gaps. It is still not possible to clarify all CKD cases of unclear aetiology. Besides very effective generic treatments for monogenic kidney disease (e.g., ACE-inhibitor use in Alport Syndrome), increasing knowledge of the pathophysiology of genetic kidney diseases has led to a growing number of targeted therapies. These include the treatment of ADPKD with Tolvaptan, which has now been in use for 10 years. Recently, exciting, and completely new approaches have been added, such as the first siRNA therapies in nephrology for primary hyperoxaluria type 1, the targeted treatment of hyperphagia in Bardet-Biedl syndrome, the therapy of APOL1-associated kidney disease or the use of the HIF-2 antagonist Belzutifan for renal cell carcinoma associated with Von-Hippel-Lindau syndrome. The new possibilities in the treatment of patients with genetic kidney diseases have also clearly revealed deficits in current patient care. Centers of excellence with extensive experience in this area therefore play an important role in improving care. This also applies to the further training of colleagues in the field. In Germany, the National Action Alliance for People with Rare Diseases (NAMSE) and the nationwide establishment of - to date - 36 centers for rare diseases play an important role in this regard.

Use of long-acting triple therapy for chronic obstructive pulmonary disease (COPD) in practice: The ELETHON physicians' survey

Gaps in optimal COPD management have been identified in clinical practice, with discrepancies between guideline recommendations and routine care. The reasons for such discrepancies are incompletely understood. The ELETHON survey aimed to identify physicians' attitudes towards general concepts of COPD management and, in particular, initiation of inhaled triple therapies. ELETHON was a nationwide cross-sectional survey with general practitioners (GP) and pulmonary specialists (PS) working in the ambulatory outpatient setting in Germany, using a structured 17-item questionnaire (single or multiple choice questions) addressing the topics of secondary prevention, exacerbation detection, strategies for therapy escalation, choice of inhaled triple therapies and evaluation of treatment benefits. Questionnaires filled by n=2028 GPs and n=371 PS were analyzed. In both groups, secondary prevention was deemed important in COPD care (GP/PS 76.4%/90.6%), with inhalation technique, vaccination status, and appropriate inhaled pharmacotherapy as key components. Activity/rehabilitation was rarely mentioned by GPs (48.3% vs. 84.5%). Exacerbations and symptomatic worsening were the main triggers for therapy escalation, but were not recorded in a structured way. "Hospitalization" and "≥2 ambulatory exacerbations" were mentioned most frequently as thresholds. Neither GPs nor PS measured eosinophils in the majority of patients. Fixed triple combinations were preferred, with availability of different treatment steps in the same device as important decision aid. Treatment success was evaluated by exacerbations, quality of life, symptoms, lung function and rescue medication use, while COPD Assessment Test (CAT) score was rarely used by GPs and PS. The ELETHON survey identified gaps in COPD management in Germany. While secondary prevention is deemed important, escalation of inhaled therapy is undertaken rather late, the reported importance of vaccinations does not match current quota in German COPD patients, and non-pharmacological measures are often unused. Exacerbation and symptom documentation is rather subjective, validated questionnaires and blood eosinophils are of minor relevance. These results provide evidence of barriers and hidden potentials towards optimization of routine ambulatory care for COPD patients in Germany.

Phase 2 Study of Palbociclib in Patients with Tumors with CDK4 or CDK6 Amplification: Results from the NCI-MATCH ECOG-ACRIN Trial (EAY131) Sub-protocol Z1C.

Amplification of CDK4 and CDK6 is a feature of a variety of malignancies, and preclinical evidence suggests inhibition of CDK4/6 is a plausible treatment strategy in these tumors. Subprotocol Z1C of the NCI-MATCH trial was designed to evaluate the CDK4/6 inhibitor palbociclib in CDK4- or CDK6-amplified tumors. Patients had a solid malignancy with progression on at least one systemic therapy for advanced disease. Tumors with ≥ 7 copies of CDK4 or CDK6 were considered amplified and molecularly eligible. Enrolled patients were treated with palbociclib 125 mg daily on days 1-21 of a 28-day cycle. The primary endpoint was ORR. Forty-three patients were enrolled on subprotocol Z1C, and 38 patients were deemed eligible, treated, and included in analyses; 25 patients were eligible, treated, and centrally confirmed to have CDK4 or CDK6 amplification and comprised the primary analysis cohort for ORR endpoint. Among the 25 patients in the primary cohort, one patient had a PR, 4 patients had SD, and 16 patients had PD as best response. Four patients were not evaluable due to lack of follow-up scans. Among the 38 evaluable patients, one patient had a PR, 10 patients had SD, and 21 patients had PD as best response. Partial response and stable disease were only seen in patients with CDK4 amplification. Median progression-free survival was 2.0 months, and median overall survival was 8.8 months. Palbociclib showed limited activity in histology-agnostic CDK4- or CDK6-amplified tumors, though CNS tumors may be worthy of future investigation.