[177Lu]Lu-PSMA-617 plus enzalutamide in patients with metastatic castration-resistant prostate cancer (ENZA-p): an open-label, multicentre, randomised, phase 2 trial.

BACKGROUND: Enzalutamide and lutetium-177 [177Lu]Lu-prostate-specific membrane antigen (PSMA)-617 both improve overall survival in patients with metastatic castration-resistant prostate cancer. Androgen and PSMA receptors have a close intracellular relationship, with data suggesting complementary benefit if targeted concurrently. In this study, we assessed the activity and safety of enzalutamide plus adaptive-dosed [177Lu]Lu-PSMA-617 versus enzalutamide alone as first-line treatment for metastatic castration-resistant prostate cancer. METHODS: ENZA-p was an open-label, randomised, controlled phase 2 trial done at 15 hospitals in Australia. Participants were men aged 18 years or older with metastatic castration-resistant prostate cancer not previously treated with docetaxel or androgen receptor pathway inhibitors for metastatic castration-resistant prostate cancer, gallium-68 [68Ga]Ga-PSMA-PET-CT (PSMA-PET-CT) positive disease, Eastern Cooperative Oncology Group performance status of 0-2, and at least two risk factors for early progression on enzalutamide. Participants were randomly assigned (1:1) by a centralised, web-based system using minimisation with a random component to stratify for study site, disease burden, use of early docetaxel, and previous treatment with abiraterone acetate. Patients were either given oral enzalutamide 160 mg daily alone or with adaptive-dosed (two or four doses) intravenous 7·5 GBq [177Lu]Lu-PSMA-617 every 6-8 weeks dependent on an interim PSMA-PET-CT (week 12). The primary endpoint was prostate-specific antigen (PSA) progression-free survival, defined as the interval from the date of randomisation to the date of first evidence of PSA progression, commencement of non-protocol anticancer therapy, or death. The analysis was done in the intention-to-treat population, using stratified Cox proportional hazards regression. This trial is registered with ClinicalTrials.gov, NCT04419402, and participant follow-up is ongoing. FINDINGS: 162 participants were randomly assigned between Aug 17, 2020, and July 26, 2022. 83 men were assigned to the enzalutamide plus [177Lu]Lu-PSMA-617 group, and 79 were assigned to the enzalutamide group. Median follow-up in this interim analysis was 20 months (IQR 18-21), with 32 (39%) of 83 patients in the enzalutamide plus [177Lu]Lu-PSMA-617 group and 16 (20%) of 79 patients in the enzalutamide group remaining on treatment at the data cutoff date. Median age was 71 years (IQR 64-76). Median PSA progression-free survival was 13·0 months (95% CI 11·0-17·0) in the enzalutamide plus [177Lu]Lu-PSMA-617 group and 7·8 months (95% CI 4·3-11·0) in the enzalutamide group (hazard ratio 0·43, 95% CI 0·29-0·63, p<0·0001). The most common adverse events (all grades) were fatigue (61 [75%] of 81 patients), nausea (38 [47%]), and dry mouth (32 [40%]) in the enzalutamide plus [177Lu]Lu-PSMA-617 group and fatigue (55 [70%] of 79), nausea (21 [27%]), and constipation (18 [23%]) in the enzalutamide group. Grade 3-5 adverse events occurred in 32 (40%) of 81 patients in the enzalutamide plus [177Lu]Lu-PSMA-617 group and 32 (41%) of 79 patients in the enzalutamide group. Grade 3 events that occurred only in the enzalutamide plus [177Lu]Lu-PSMA-617 group included anaemia (three [4%] of 81 participants) and decreased platelet count (one [1%] participant). No grade 4 or 5 events were attributed to treatment on central review in either group. INTERPRETATION: The addition of [177Lu]Lu-PSMA-617 to enzalutamide improved PSA progression-free survival providing evidence of enhanced anticancer activity in patients with metastatic castration-resistant prostate cancer with risk factors for early progression on enzalutamide and warrants further evaluation of the combination more broadly in metastatic prostate cancer. FUNDING: Prostate Cancer Research Alliance (Movember and Australian Federal Government), St Vincent's Clinic Foundation, GenesisCare, Roy Morgan Research, and Endocyte (a Novartis company).

Executive summary of the KDIGO 2024 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease: known knowns and known unknowns.

The Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease (CKD) updates the KDIGO 2012 guideline and has been developed with patient partners, clinicians, and researchers around the world, using robust methodology. This update, based on a substantially broader base of evidence than has previously been available, reflects an exciting time in nephrology. New therapies and strategies have been tested in large and diverse populations that help to inform care; however, this guideline is not intended for people receiving dialysis nor those who have a kidney transplant. The document is sensitive to international considerations, CKD across the lifespan, and discusses special considerations in implementation. The scope includes chapters dedicated to the evaluation and risk assessment of people with CKD, management to delay CKD progression and its complications, medication management and drug stewardship in CKD, and optimal models of CKD care. Treatment approaches and actionable guideline recommendations are based on systematic reviews of relevant studies and appraisal of the quality of the evidence and the strength of recommendations which followed the "Grading of Recommendations Assessment, Development, and Evaluation" (GRADE) approach. The limitations of the evidence are discussed. The guideline also provides practice points, which serve to direct clinical care or activities for which a systematic review was not conducted, and it includes useful infographics and describes an important research agenda for the future. It targets a broad audience of people with CKD and their healthcare, while being mindful of implications for policy and payment.

Inpp5d haplodeficiency alleviates tau pathology in the PS19 mouse model of Tauopathy.

INTRODUCTION: A noncoding variant (rs35349669) within INPP5D, a lipid and protein phosphatase restricted to microglia in the brain, is linked to increased susceptibility to Alzheimer's disease (AD). While Inpp5d is well-studied in amyloid pathology, its role in tau pathology remains unclear. METHODS: PS19 Tauopathy mice were crossed with Inpp5d-haplodeficient (Inpp5d+/-) mice to examine the impact of Inpp5d in tau pathology. RESULTS: Increased INPP5D expression correlated positively with phospho-Tau AT8 in PS19 mice. Inpp5d haplodeficiency mitigated hyperphosphorylated tau levels (AT8, AT180, AT100, and PHF1) and motor deficits in PS19 mice. Transcriptomic analysis revealed an up-regulation of genes associated with immune response and cell migration. DISCUSSION: Our findings define an association between INPP5D expression and tau pathology in PS19 mice. Alleviation in hyperphosphorylated tau, motor deficits, and transcriptomics changes in haplodeficient-Inpp5d PS19 mice indicate that modulation in INPP5D expression may provide therapeutic potential for mitigating tau pathology and improving motor deficits. HIGHLIGHTS: The impact of Inpp5d in the context of tau pathology was studied in the PS19 mouse model. INPP5D expression is associated with tau pathology. Reduced Inpp5d expression in PS19 mice improved motor functions and decreased total and phospho-Tau levels. Inpp5d haplodeficiency in PS19 mice modulates gene expression patterns linked to immune response and cell migration. These data suggest that inhibition of Inpp5d may be a therapeutic approach in tauopathies.

Assessment of neurovascular uncoupling: APOE status is a key driver of early metabolic and vascular dysfunction.

BACKGROUND: Alzheimer's disease (AD) is the most common cause of dementia worldwide, with apolipoprotein Eε4 (APOEε4) being the strongest genetic risk factor. Current clinical diagnostic imaging focuses on amyloid and tau; however, new methods are needed for earlier detection. METHODS: PET imaging was used to assess metabolism-perfusion in both sexes of aging C57BL/6J, and hAPOE mice, and were verified by transcriptomics, and immunopathology. RESULTS: All hAPOE strains showed AD phenotype progression by 8 months, with females exhibiting the regional changes, which correlated with GO-term enrichments for glucose metabolism, perfusion, and immunity. Uncoupling analysis revealed APOEε4/ε4 exhibited significant Type-1 uncoupling (↓ glucose uptake, ↑ perfusion) at 8 and 12 months, while APOEε3/ε4 demonstrated Type-2 uncoupling (↑ glucose uptake, ↓ perfusion), while immunopathology confirmed cell specific contributions. DISCUSSION: This work highlights APOEε4 status in AD progression manifests as neurovascular uncoupling driven by immunological activation, and may serve as an early diagnostic biomarker. HIGHLIGHTS: We developed a novel analytical method to analyze PET imaging of 18F-FDG and 64Cu-PTSM data in both sexes of aging C57BL/6J, and hAPOEε3/ε3, hAPOEε4/ε4, and hAPOEε3/ε4 mice to assess metabolism-perfusion profiles termed neurovascular uncoupling. This analysis revealed APOEε4/ε4 exhibited significant Type-1 uncoupling (decreased glucose uptake, increased perfusion) at 8 and 12 months, while APOEε3/ε4 demonstrated significant Type-2 uncoupling (increased glucose uptake, decreased perfusion) by 8 months which aligns with immunopathology and transcriptomic signatures. This work highlights that there may be different mechanisms underlying age related changes in APOEε4/ε4 compared with APOEε3/ε4. We predict that these changes may be driven by immunological activation and response, and may serve as an early diagnostic biomarker.

In vivo validation of late-onset Alzheimer's disease genetic risk factors.

INTRODUCTION: Genome-wide association studies have identified over 70 genetic loci associated with late-onset Alzheimer's disease (LOAD), but few candidate polymorphisms have been functionally assessed for disease relevance and mechanism of action. METHODS: Candidate genetic risk variants were informatically prioritized and individually engineered into a LOAD-sensitized mouse model that carries the AD risk variants APOE ε4/ε4 and Trem2*R47H. The potential disease relevance of each model was assessed by comparing brain transcriptomes measured with the Nanostring Mouse AD Panel at 4 and 12 months of age with human study cohorts. RESULTS: We created new models for 11 coding and loss-of-function risk variants. Transcriptomic effects from multiple genetic variants recapitulated a variety of human gene expression patterns observed in LOAD study cohorts. Specific models matched to emerging molecular LOAD subtypes. DISCUSSION: These results provide an initial functionalization of 11 candidate risk variants and identify potential preclinical models for testing targeted therapeutics. HIGHLIGHTS: A novel approach to validate genetic risk factors for late-onset AD (LOAD) is presented. LOAD risk variants were knocked in to conserved mouse loci. Variant effects were assayed by transcriptional analysis. Risk variants in Abca7, Mthfr, Plcg2, and Sorl1 loci modeled molecular signatures of clinical disease. This approach should generate more translationally relevant animal models.

The Creation of LIFE-M: The Longitudinal, Intergenerational Family Electronic Micro-Database Project.

This paper describes the creation of the Longitudinal, Intergenerational Family Electronic Micro-Database (LIFE-M), a new data resource linking vital records and decennial censuses for millions of individuals and families living in the late 19th and 20th centuries in the United States. This combination of records provides a life-course and intergenerational perspective on the evolution of health and economic outcomes. Vital records also enable the linkage of women, because they contain a crosswalk between women's birth (i.e., "maiden") and married names. We describe (1) the data sources, coverage, and linking sequence; (2) the process and supervised machine-learning methods to linking records longitudinally and across generations; and (3) the resulting linked samples, including linking rates, representativeness, and weights.

Breaking down barriers to COPD management in primary care: applying the updated 2023 Canadian Thoracic Society guideline for pharmacotherapy.

Chronic obstructive pulmonary disease (COPD) is a highly prevalent yet under-recognized and sub-optimally managed disease that is associated with substantial morbidity and mortality. Primary care providers (PCPs) are at the frontlines of COPD management, and they play a critical role across the full spectrum of the COPD patient journey from initial recognition and diagnosis to treatment optimization and referral to specialty care. The Canadian Thoracic Society (CTS) recently updated their guideline on pharmacotherapy in patients with stable COPD, and there are several key changes that have a direct impact on COPD management in the primary care setting. Notably, it is the first guideline to formally make recommendations on mortality reduction in COPD, which elevates this disease to the same league as other chronic diseases that are commonly managed in primary care and where optimized pharmacotherapy can reduce all-cause mortality. It also recommends earlier and more aggressive initial maintenance inhaler therapy across all severities of COPD, and preferentially favors the use of single inhaler therapies over multiple inhaler regimens. This review summarizes some of the key guideline changes and offers practical tips on how to implement the new recommendations in primary care. It also addresses other barriers to optimal COPD management in the primary care setting that are not addressed by the guideline update and suggests strategies on how they could be overcome.

Current state of theranostics in metastatic castrate-resistant prostate cancer.

Prostate cancer remains one of the leading causes of cancer-related death in the world. There have been significant advances in chemotherapy, hormonal therapy and targeted therapy options for patients with castrate-resistant disease. However, these systemic treatments are often associated with unwanted toxicities. Targeted therapy with radiopharmaceuticals has become of key interest to limit systemic toxicity and provides a more precision oncology approach to treatment. Strontium-89, Samarium-153 EDTMP and Radium-223 have been trialled with mixed results. Strontium-89 and Samarium-153 EDTMP have shown benefits in palliating metastatic bone pain but with no impact on survival outcomes. Early therapeutic radiopharmaceuticals targeting PSMA that were developed were beta-emitting agents, but recently alpha-emitting agents are being investigated as potentially superior options. Radium-223 is the first alpha-particle emitter therapeutic agent approved by the FDA, with phase III trial evidence showing benefits in overall survival and delay in symptomatic skeletal events for patients. Recently, 177-Lutetium-PSMA-617 has demonstrated significant survival advantages in pre-treated metastatic castrate-resistant cancer patients in a number of phase II and III studies. Furthermore, 225-Actinium-PSMA-617 also showed promise even in patients pre-treated with 177-Lutetium-PSMA-617. Hence, there has been an explosion of radiopharmaceutical treatment options for patients with prostate cancer. This review explores past and current theranostic capacities in the radiopharmaceutical treatment of metastatic castrate-resistant prostate cancer.

The Presence of Small-Size Circulating Tumor Cells Predicts Worse Prognosis in Non-Small Cell Lung Cancer Patients.

CONTEXT.­: Most patients with non-small cell lung cancers (NSCLC) are diagnosed at advanced stages. The 5-year survival rate of patients with advanced lung cancer is less than 20%, which makes lung cancer the leading cause of cancer-related deaths worldwide. OBJECTIVE.­: To identify indicators that can predict the prognosis of lung cancer patients. DESIGN.­: To determine the correlation between circulating tumor cells (CTCs), circulating tumor-derived endothelial cells (CTECs), and their subtypes and the prognosis of patients with NSCLC, 80 patients with lung cancer were recruited and 48 patients who met the enrollment criteria were selected in this study. Peripheral blood was collected from the enrolled patients before any treatment and analyzed by the subtraction enrichment and immunostaining-fluorescence in situ hybridization technique to determine the correlation between CTCs and CTECs and lung cancer disease progression and to identify prognostic indicators. RESULTS.­: In all patients, the positive rate of CTCs was 100% and the positive rate of CTECs was 81.3%. The CTEC positivity rate was higher in late-stage patients than in early-stage patients (P = .03). Patients with advanced or lymph node metastases had a higher rate of small-size CTC positivity than those with early or no lymph node metastases. Large-size CTEC positivity was higher in patients with advanced NSCLC than in early-stage patients. Patients with ≥1 small-size CTC had shorter progression-free survival, and it was an independent prognostic factor. CONCLUSIONS.­: Small-size CTCs are a reliable prognostic indicator and a probable predictor of the severity of disease in NSCLC patients.

12th Tuscany Retreat on Cancer Research and Apoptosis: Genetic profiling, resistance mechanisms and novel treatment concepts in cancer and neurodegeneration.

The 12th Tuscany Retreat on Cancer Research and Apoptosis was held on August 19-26, 2023. The biennial retreat aims to bring together scientists who advance research in cancer, cell death, and neurodegenerative diseases. Topics covered ranged from drug resistance in cancer to insights into novel molecular cell signaling mechanisms and targets, all related to the pathways and molecules that regulate programmed cell death and the diseases that result from the dysregulation of programmed cell death. In this meeting review, we summarize the content of the most recent retreat.

Usability and Tolerability of Virtual Reality-Based Cognitive Stimulation in Healthy Elderly Volunteers-A Feasibility Clinical Trial.

Background: The aim of the current pilot study was to evaluate the usability, acceptability, and tolerability of virtual reality (VR)-based cognitive stimulation exercises (CSEs) in healthy young versus old populations before health care integration. A secondary aim was to assess the accuracy of VR games as a proxy for cognitive stimulation, specifically for attention. VR-based CSEs promise to improve attention and brain function through varied learning systems. Methods: This is a Phase 1 feasibility clinical trial at a single center. It involves 30 healthy volunteers randomly selected using the American Society of Anesthesiologists (ASA) physical status classification system. Participants fall into ASA 1 (age >18-35 years, n = 15) or ASA 2 (age >60 years, n = 15) categories. All participants tested the ReCognitionVR-based CSEs. Feasibility criterion: Participants in each group were monitored for completion of 20 minutes of VR-based CSEs. Acceptability criterion: Proportion of participants with system usability scale (SUS) >35 or SUS score of 87.5. Safety (tolerability) monitoring: Sessions were monitored for neurological, cardiovascular, or pulmonary adverse events (AEs). Safety criterion: No more than 10% of sessions stopped due to neurological, cardiovascular, or pulmonary AEs. Results: The primary outcome (feasibility) of ReCognitionVR-based CSEs was 100%. For the secondary outcome (acceptability), there was no group difference in SUS scores (ASA 1 = 88.17 ± 12.83 vs. ASA 2 = 88.39 ± 10.22, P = 0.81). For the tertiary outcome (safety), mild transient uneasiness was reported by two (13.4%) ASA 1 participants (resolved in 2 minutes), and one (6.67%) ASA 1 participant experienced a temporary >20% increase in blood pressure from baseline. No ASA 2 participants had AEs. Conclusion: The feasibility, acceptability, and safety of ReCognitionVR-based CSEs in healthy elderly volunteers are acceptable, indicating that the evaluation of the ReCognitionVR-based CSEs in hospitalized patients is reasonable.

Therapeutic targeting of immunometabolism reveals a critical reliance on hexokinase 2 dosage for microglial activation and Alzheimer's progression.

Neuroinflammation is a prominent feature of Alzheimer's disease (AD). Activated microglia undergo a reprogramming of cellular metabolism necessary to power their cellular activities during disease. Thus, selective targeting of microglial immunometabolism might be of therapeutic benefit for treating AD. In the AD brain, the levels of microglial hexokinase 2 (HK2), an enzyme that supports inflammatory responses by promoting glycolysis, are significantly increased. In addition, HK2 displays non-metabolic activities that extend its inflammatory role beyond glycolysis. The antagonism of HK2 affects microglial phenotypes and disease progression in a gene-dose-dependent manner. HK2 complete loss fails to improve pathology by exacerbating inflammation, while its haploinsufficiency reduces pathology in 5xFAD mice. We propose that the partial antagonism of HK2 is effective in slowing disease progression by modulating NF-κB signaling through its cytosolic target, IKBα. The complete loss of HK2 affects additional inflammatory mechanisms related to mitochondrial dysfunction.

Biphasic co-detection of melanoma aneuploid tumor cells and tumor endothelial cells in guidance of specifying the field cancerized surgical excision margin and administering immunotherapy.

An optimum safety excision margin (EM) delineated by precise demarcation of field cancerization along with reliable biomarkers that enable predicting and timely evaluating patients' response to immunotherapy significantly impact effective management of melanoma. In this study, optimized biphasic "immunofluorescence staining integrated with fluorescence insitu hybridization" (iFISH) was conducted along the diagnosis-metastasis-treatment-cellular MRD axis to longitudinally co-detect a full spectrum of intact CD31- aneuploid tumor cells (TCs), CD31+ aneuploid tumor endothelial cells (TECs), viable and necrotic circulating TCs (CTCs) and circulating TECs (CTECs) expressing PD-L1, Ki67, p16 and Vimentin in unsliced specimens of the resected primary tumor, EM, dissected sentinel lymph nodes (SLNs) and peripheral blood in an early-stage melanoma patient. Numerous PD-L1+ aneuploid TCs and TECs were detected at the conventional safety EM (2 cm), quantitatively indicating the existence of a field cancerized EM for the first time. Contrary to highly heterogeneous PD-L1 expression and degrees of Chr8 aneuploidy in TCs and TECs in the primary lesions as well as CTCs and CTECs in peripheral blood, almost all TCs and TECs in SLNs and EM were homogeneously PD-L1+ haploid cells. Dynamic monitoring and cellular MRD assessment revealed that, in contrast to PD-L1+ CTCs being responsive to the immune checkpoint inhibitor (ICI-anti-PD-1), multiploid (≥pentasomy 8) PD-L1+ and Ki67+ CTECs were respectively resistant to ICI-sensitized T cells. In therapeutically stressed lymphatic and hematogenous metastatic cascades, stratified phenotypic and karyotypic profiling of iFISH tissue and liquid biopsied TCs, TECs, CTCs and CTECs in future large-cohort studies will enable appropriate re-specification of the optimal safety EM and distribution mapping of in-depth characterized, subcategorized target cells to help illustrate their metastatic relevance, ultimately improving risk stratification and clinical intervention of tumor progression, metastases, therapy resistance and cancer relapse.

Assessment of Neurovascular Uncoupling: APOE Status is a Key Driver of Early Metabolic and Vascular Dysfunction.

BACKGROUND: Alzheimer's disease (AD) is the most common cause of dementia worldwide, with apolipoprotein ε4 (APOEε4) being the strongest genetic risk factor. Current clinical diagnostic imaging focuses on amyloid and tau; however, new methods are needed for earlier detection. METHODS: PET imaging was used to assess metabolism-perfusion in both sexes of aging C57BL/6J, and hAPOE mice, and were verified by transcriptomics, and immunopathology. RESULTS: All hAPOE strains showed AD phenotype progression by 8 mo, with females exhibiting the regional changes, which correlated with GO-term enrichments for glucose metabolism, perfusion, and immunity. Uncoupling analysis revealed APOEε4/ε4 exhibited significant Type-1 uncoupling (↓ glucose uptake, ↑ perfusion) at 8 and 12 mo, while APOEε3/ε4 demonstrated Type-2 uncoupling (↑ glucose uptake, ↓ perfusion), while immunopathology confirmed cell specific contributions. DISCUSSION: This work highlights APOEε4 status in AD progression manifest as neurovascular uncoupling driven by immunological activation, and may serve as an early diagnostic biomarker.

In vivo validation of late-onset Alzheimer's disease genetic risk factors.

Introduction: Genome-wide association studies have identified over 70 genetic loci associated with late-onset Alzheimer's disease (LOAD), but few candidate polymorphisms have been functionally assessed for disease relevance and mechanism of action. Methods: Candidate genetic risk variants were informatically prioritized and individually engineered into a LOAD-sensitized mouse model that carries the AD risk variants APOE4 and Trem2*R47H. Potential disease relevance of each model was assessed by comparing brain transcriptomes measured with the Nanostring Mouse AD Panel at 4 and 12 months of age with human study cohorts. Results: We created new models for 11 coding and loss-of-function risk variants. Transcriptomic effects from multiple genetic variants recapitulated a variety of human gene expression patterns observed in LOAD study cohorts. Specific models matched to emerging molecular LOAD subtypes. Discussion: These results provide an initial functionalization of 11 candidate risk variants and identify potential preclinical models for testing targeted therapeutics.

In situ reconstruction with cryopreserved arterial allograft in mycotic aneurysms or aortoiliac prosthetic grafts infection: a multi-institucional experience

Objective: Aortic prosthetic graft infection remains a highly fatal surgical complication. Recent studies with cryopreserved allografts inthe treatment of vascular graft infection suggest improved clinical outcomes. The purpose of this study was to evaluate the efficacy of cryopreserved aortic allografts in the treatment of infected prosthetic grafts or mycotic aneurysms. Methods: Clinical data of all patients who underwent in situ aortic reconstruction with cryopreserved allografts for either infected aortic prosthetic graft mycotic aneurysms from 1999 to 2003 were reviewed...