Search

Simple Summary: In breast cancer patients in whom tumor cells overexpress the protein human epidermal growth factor receptor 2 (HER2), HER2-targeted therapy is the mainstay of neoadjuvant therapy (NAT). Two thirds of these patients respond so well to HER2-targeted therapy that during microscopic analysis of the surgically resected tissue, it becomes apparent there are no vital tumor cells left, classified as complete responders. These patients might not have needed surgery. However, with current imaging techniques such as MRI, it remains difficult to preoperatively assess whether there is residual tumor after NAT or not, so all patients still undergo surgery. This study investigated if a HER2-targeted PET/CT scan can reliably assess the response to NAT. In six patients, a HER2-targeted PET/CT scan was acquired before and after NAT. Two out of six patients had residual tumor at microscopic analysis. Visual assessment of the PET/CT scans correctly predicted the response in 66.7% of cases. When the PET/CT signal in both the scan before and after NAT was quantified and (percentual) changes were calculated, there was a difference in the change of signal between patients with and without residual tumor. This difference, although not statistically significant due to the limited patient number in this study, suggests that quantitative assessment of HER2-targeted PET/CT can be used for accurate response evaluation after NAT. Background: Approximately 20% of invasive ductal breast malignancies are human epidermal growth factor receptor 2 (HER2)-positive. These patients receive neoadjuvant systemic therapy (NAT) including HER2-targeting therapies. Up to 65% of patients achieve a pathological complete response (pCR). These patients might not have needed surgery. However, accurate preoperative identification of a pCR remains challenging. A radiologic complete response (rCR) on MRI corresponds to a pCR in only 73% of patients. The current feasibility study investigates if HER2-targeted PET/CT-imaging using Zirconium-89 (89Zr)-radiolabeled trastuzumab can be used for more accurate NAT response evaluation. Methods: HER2-positive breast cancer patients scheduled to undergo NAT and subsequent surgery received a 89Zr-trastuzumab PET/CT both before (PET/CT-1) and after (PET/CT-2) NAT. Qualitative and quantitative response evaluation was performed. Results: Six patients were enrolled. All primary tumors could be identified on PET/CT-1. Four patients had a pCR and two a pathological partial response (pPR) in the primary tumor. Qualitative assessment of PET/CT resulted in an accuracy of 66.7%, compared to 83.3% of the standard-of-care MRI. Quantitative assessment showed a difference between the SUVR on PET/CT-1 and PET/CT-2 (ΔSUVR) in patients with a pPR and pCR of −48% and −90% (p = 0.133), respectively. The difference in tumor-to-blood ratio on PET/CT-1 and PET/CT-2 (ΔTBR) in patients with pPR and pCR was −79% and −94% (p = 0.133), respectively. Three patients had metastatic lymph nodes at diagnosis that were all identified on PET/CT-1. All three patients achieved a nodal pCR. Qualitative assessment of the lymph nodes with PET/CT resulted in an accuracy of 66.7%, compared to 50% of the MRI. Conclusions: NAT response evaluation using 89Zr-trastuzumab PET/CT is feasible. In the current study, qualitative assessment of the PET/CT images is not superior to standard-of-care MRI. Our results suggest that quantitative assessment of 89Zr-trastuzumab PET/CT has potential for a more accurate response evaluation of the primary tumor after NAT in HER2-positive breast cancer. [ABSTRACT FROM AUTHOR]

Rationale and Objectives: The paravertebral muscles, characterized by their susceptibility to severe size loss and fat infiltration in old age, lack established reference values for age-related variations in muscle parameters. This study aims to fill this gap by establishing reference values for paravertebral muscles in a Chinese adult population., Materials and Methods: This cross-sectional study utilized the baseline data from the prospective cohort China Action on Spine and Hip (CASH). A total of 4305 community-dwelling participants aged 21-80 years in China were recruited between 2013 and 2017. Pregnant women, individuals with metal implants, limited mobility or diseases/conditions (spinal tumor, infection, etc.) affecting lumbar vertebra were excluded from the study. Psoas and paraspinal muscles were measured in quantitative computed tomography (QCT) images at the L3 and L5 levels using Osirix software. Age-related reference values for muscle area, density, and fat fraction were constructed as percentile charts using the lambda-mu-sigma (LMS) method., Results: The paravertebral muscles exhibited an age-related decline in muscle area and density, coupled with an increase in muscle fat fraction. Between the ages of 25 and 75, the reductions in psoas and paraspinal muscle cross-sectional area at the L3 level were - 0.47%/yr and - 0.53%/yr in men, and - 0.19%/yr and - 0.23%/yr in women, respectively. Notably, accelerated muscle loss was observed during menopause and postmenopause in women (45-75 years) and intermittently during middle and old age in men (35-55 and 60-75 years). Besides, the age-related decreases in PSMA, PMA, and PSMD and the increases in PSMFF were more pronounced in L5 than in L3 CONCLUSION: This study shows distinct patterns of accelerated muscle loss were identified in menopausal and postmenopausal women and in middle-aged and old men. The findings contribute valuable information for future investigations on paravertebral muscle loss and myosteatosis., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved.)

Background: Type 2 diabetes (T2D) is a heterogeneous and polygenic disease. Previous studies have leveraged the highly polygenic and pleiotropic nature of T2D variants to partition the heterogeneity of T2D, in order to stratify patient risk and gain mechanistic insight. We expanded on these approaches by performing colocalization across GWAS traits while assessing the causality and directionality of genetic associations., Methods: We applied colocalization between T2D and 20 related metabolic traits, across 243 loci, to obtain inferences of shared casual variants. Network-based unsupervised hierarchical clustering was performed on variant-trait associations. Partitioned polygenic risk scores (PRSs) were generated for each cluster using T2D summary statistics and validated in 21,742 individuals with T2D from 3 cohorts. Inferences of directionality and causality were obtained by applying Mendelian randomization Steiger's Z-test and further validated in a pediatric cohort without diabetes (aged 9-12 years old, n = 3866)., Results: We identified 146 T2D loci that colocalized with at least one metabolic trait locus. T2D variants within these loci were grouped into 5 clusters. The clusters corresponded to the following pathways: obesity, lipodystrophic insulin resistance, liver and lipid metabolism, hepatic glucose metabolism, and beta-cell dysfunction. We observed heterogeneity in associations between PRSs and metabolic measures across clusters. For instance, the lipodystrophic insulin resistance (Beta - 0.08 SD, 95% CI [- 0.10-0.07], p = 6.50 × 10 -32 ) and beta-cell dysfunction (Beta - 0.10 SD, 95% CI [- 0.12, - 0.08], p = 1.46 × 10 -47 ) PRSs were associated to lower BMI. Mendelian randomization Steiger analysis indicated that increased T2D risk in these pathways was causally associated to lower BMI. However, the obesity PRS was conversely associated with increased BMI (Beta 0.08 SD, 95% CI 0.06-0.10, p = 8.0 × 10 -33 ). Analyses within a pediatric cohort supported this finding. Additionally, the lipodystrophic insulin resistance PRS was associated with a higher odds of chronic kidney disease (OR 1.29, 95% CI 1.02-1.62, p = 0.03)., Conclusions: We successfully partitioned T2D genetic variants into phenotypic pathways using a colocalization first approach. Partitioned PRSs were associated to unique metabolic and clinical outcomes indicating successful partitioning of disease heterogeneity. Our work expands on previous approaches by providing stronger inferences of shared causal variants, causality, and directionality of GWAS variant-trait associations., (© 2024. The Author(s).)

Background and Objectives: Low bone mineral density (BMD) and dementia commonly co-occur in older individuals, with bone loss accelerating in patients with dementia due to physical inactivity and poor nutrition. However, uncertainty persists over the extent to which bone loss already exists before onset of dementia. Therefore, we investigated how dementia risk was affected by BMD at various skeletal regions in community-dwelling older adults., Methods: In a prospective population-based cohort study, BMD at the femoral neck, lumbar spine, and total body and the trabecular bone score (TBS) were obtained using dual-energy X-ray absorptiometry in 3,651 participants free from dementia between 2002 and 2005. Persons at risk of dementia were followed up until January 1, 2020. For analyses of the association between BMD at baseline and the risk of incident dementia, we used Cox proportional hazards regression analyses, adjusting for age, sex, educational attainment, physical activity, smoking status, body mass index, systolic and diastolic blood pressure, cholesterol level, high-density lipoprotein cholesterol, history of comorbidities (stroke and diabetes mellitus), and APOE genotype., Results: Among the 3,651 participants (median age 72.3 ± 10.0 years, 57.9% women), 688 (18.8%) developed incident dementia during a median of 11.1 years, of whom 528 (76.7%) developed Alzheimer disease (AD). During the whole follow-up period, participants with lower BMD at the femoral neck (per SD decrease) were more likely to develop all-cause dementia (hazard ratio [HR] total follow-up 1.12, 95% CI 1.02-1.23) and AD (HR total follow-up 1.14, 95% CI 1.02-1.28). Within the first 10 years after baseline, the risk of dementia was greatest for groups with the lowest tertile of BMD (femoral neck BMD, HR 0-10 years 2.03; 95% CI 1.39-2.96; total body BMD, HR 0-10 years 1.42; 95% CI 1.01-2.02; and TBS, HR 0-10 years 1.59; 95% CI 1.11-2.28)., Discussion: In conclusion, participants with low femoral neck and total body BMD and low TBS were more likely to develop dementia. Further studies should focus on the predictive ability of BMD for dementia., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

A synoptic overview of scientific methods applied in bone and associated research fields across species has yet to be published. Experts from the EU Cost Action GEMSTONE ("GEnomics of MusculoSkeletal Traits translational Network") Working Group 2 present an overview of the routine techniques as well as clinical and research approaches employed to characterize bone phenotypes in humans and selected animal models (mice and zebrafish) of health and disease. The goal is consolidation of knowledge and a map for future research. This expert paper provides a comprehensive overview of state-of-the-art technologies to investigate bone properties in humans and animals - including their strengths and weaknesses. New research methodologies are outlined and future strategies are discussed to combine phenotypic with rapidly developing -omics data in order to advance musculoskeletal research and move towards "personalised medicine"., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Foessl, Bassett, Bjørnerem, Busse, Calado, Chavassieux, Christou, Douni, Fiedler, Fonseca, Hassler, Högler, Kague, Karasik, Khashayar, Langdahl, Leitch, Lopes, Markozannes, McGuigan, Medina-Gomez, Ntzani, Oei, Ohlsson, Szulc, Tobias, Trajanoska, Tuzun, Valjevac, van Rietbergen, Williams, Zekic, Rivadeneira and Obermayer-Pietsch.)

Background: The combination treatment regimen of thermal ablation (TA) and transarterial chemoembolization (TACE) has gained a place in treatment of hepatocellular carcinoma (HCC) lesions > 3 cm unsuitable for surgery. Despite a high heterogeneity in the currently used treatment protocols, the pooled results of combined treatments seem to outperform those of TA or TACE alone. TACE preceding TA has been studied extensively, while results of the reverse treatment sequence are lacking. In this retrospective cohort study we compared the two treatment sequences., Patients and Methods: 38 patients (median age: 68.5 yrs (range 40-84), male: 34, liver cirrhosis: 33, early stage HCC: 21, intermediate stage HCC: 17) were included in two tertiary referral centers, of whom 27 were treated with TA and adjuvant TACE (TA + TACE). The other 11 patients received TA with neoadjuvant TACE (TACE + TA). Overall survival (OS), time to progression (TTP) and local tumor progression (LTP) free survival were determined for the entire cohort and compared between the two treatment sequences., Results: The median OS of all patients was 52.7 months and the median time to LTP was 11.5 months (censored for liver transplantation). No differences were found with respect to OS between the two treatment sequences. Median time to LTP for TACE + TA was 23.6 months and 8.1 months for TA + TACE (p = 0.19)., Discussion: No statistical differences were found for OS, TTP and time to LTP between patients treated with TA combined with neoadjuvant or adjuvant TACE., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)