Two different mutational types of familial gastrointestinal stromal tumors: Two case reports.

BACKGROUND: Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal (GI) tract, and cases of GISTs tend to be of the disseminated type, with a global incidence of 10 to 15 cases/million each year. The rarer familial GISTs, which often represent a population, differ in screening, diagnosis, and treatment. Familial GISTs include primary familial GISTs with predominantly KIT/PDGFRA mutations and wild-type GISTs. However, whether the same genetic family has different phenotypes has not been reported. CASE SUMMARY: We report two cases of rare GISTs in the same family: A male patient with the V561D mutation in exon 12 of the PDGFRA gene, who has been taking the targeted drug imatinib since undergoing surgery, and a female patient diagnosed with wild-type GIST, who has been taking imatinib for 3 years since undergoing surgery. The favorable prognosis of these patients during the 7-year follow-up period validates the accuracy of our treatment strategy, and we have refined the entire process of diagnosis and treatment of familial GISTs in order to better manage this rare familial disease. CONCLUSION: Different mutation types of familial GISTs in the same family are very rare, thus it is very important to make the correct diagnosis and treatment strategies according to the results of molecular detection for the management of familial GISTs.

N-Acetyl-L-Cysteine (NAC) Blunts Axitinib-Related Adverse Effects in Preclinical Models of Glioblastoma.

OBJECTIVE: Axitinib is a tyrosine kinase inhibitor characterized by a strong affinity for Vascular Endothelial Growth Factor Receptors (VEGFRs). It was approved in 2012 by Food and Drug Administration and European Medicines Agency as a second line treatment for advanced renal cell carcinoma and is currently under evaluation in clinical trial for the treatment of other cancers. Glioblastoma IDH-wild type (GBM) is a highly malignant brain tumor characterized by diffusely infiltrative growth pattern and by a prominent neo-angiogenesis. In GBM, axitinib has demonstrated a limited effectiveness as a monotherapy, while it was recently shown to significantly improve its efficacy in combination treatments. In preclinical models, axitinib has been reported to trigger cellular senescence both in tumor as well as in normal cells, through a mechanism involving intracellular reactive oxygen species (ROS) accumulation and activation of Ataxia Telangiectasia Mutated kinase (ATM). Limiting axitinib-dependent ROS increase by antioxidants prevents senescence specifically in normal cells, without affecting tumor cells. METHODS: We used brain tumor xenografts obtained by engrafting Glioma Stem Cells (GSCs) into the brain of immunocompromised mice, to investigate the hypothesis that the antioxidant molecule N-Acetyl-L-Cysteine (NAC) might be used to reduce senescence-associated adverse effects of axitinib treatment without altering its anti-tumor activity. RESULTS: We demonstrate that the use of the antioxidant molecule N-Acetyl-Cysteine (NAC) in combination with axitinib stabilizes tumor microvessels in GBM tumor orthotopic xenografts, eventually resulting in vessel normalization, and protects liver vasculature from axitinib-dependent toxicity. CONCLUSION: Overall, we found that NAC co-treatment allows vessel normalization in brain tumor vessels and exerts a protective effect on liver vasculature, therefore minimizing axitinib-dependent toxicity.

Prospective Multicenter Screening With High-Sensitivity Cardiac Troponin T for Wild-Type Transthyretin Cardiac Amyloidosis in Outpatient and Community-Based Settings.

BACKGROUND: High-sensitivity cardiac troponin T (hs-cTnT) was proposed as a simple and useful diagnostic tool for cardiac amyloidosis (CA). We performed exploratory systemic screening using hs-cTnT to detect wild-type transthyretin CA (ATTRwt-CA) in outpatient and community-based settings. METHODS AND RESULTS: This study was a prospective multicenter study including 8 internal medicine clinics in Kochi Prefecture, Japan. Consecutive individuals aged ≥70 years who visited those clinics as outpatients were enrolled. Patients with a prior diagnosis of CA or a history of heart failure hospitalization were excluded. We measured hs-cTnT levels in the enrolled individuals at each clinic, and those with elevated hs-cTnT levels (≥0.03ng/mL) received further detailed examination, including remeasurement of hs-cTnT. The diagnosis of ATTRwt-CA was confirmed by biopsy-proven transthyretin. Of 1,141 individuals enrolled in the study, 55 (4.8%) had elevated hs-cTnT levels. Of the 33 patients who underwent further examination, 22 had elevated hs-cTnT levels at remeasurement. Finally, 2 men were diagnosed with ATTRwt-CA. The prevalence of ATTRwt-CA was 9.1% (2/22) among patients with elevated hs-cTnT levels at two examinations, and at least 0.18% (2/1,141) in the whole study population. CONCLUSIONS: Measurement of hs-cTnT will help to screen for patients with undiagnosed ATTRwt-CA in primary care practice.

Genotype of Varicella-zoster virus isolated in Jiangsu, China.

OBJECTIVE: To analyze the genotypes of VZV in Jiangsu province to identify vaccine strains and wild strains, providing a molecular biological background for the effective prevention and control of varicella. METHOD: Stratified sampling was used to collect herpes fluid or throat swab from patients diagnosed with varicella. ORF22 was carried out, and the restriction enzyme site of ORF38, ORF54 and ORF62 were detected. RESULTS: All 207 virus strains were Clade 2 type by sequencing the PCR products of ORF22. The sequencing results showed that five SNP sites changed compared to the Dumas reference strain(Clade 1). From A to G at 37,902, from T to c at 38,055, from A to C at 38,081, and from G to A at 38,177, from G to A at 39,394. The prevalent VZV genotypes in Jiangsu is consistent with the P-Oka. The restriction enzyme site analysis of PCR amplification products from ORF38 (PstI), ORF54 (BglI), ORF62 (SmaI) showed that all 207 virus strains were wild-type. There were two different types of the wild strains, and 183 strains (88.4%) were PstI (+), BglI (+), SmaI (-). The wild strains between different regions showed no significant differences (χ2 = 0.05, P = 0.982). CONCLUSIONS: The prevalent VZV genotypes are Clade 2 and the prevalent virus strains are wild strains in Jiangsu Province, the primary wild strain observed is mainly PstI (+), BglI (+), SmaI (-).

A multicenter study of clinical predictors of positive pyrophosphate scintigraphy findings in the diagnosis of transthyretin amyloidosis.

BACKGROUND: The prevalence of wild-type transthyretin (ATTR) amyloidosis is increasing with advancements in diagnostic techniques and growing awareness of the disease worldwide. 99mTc-labeled pyrophosphate (99mTc-PYP) scintigraphy exhibits high performance in diagnosing ATTR cardiac amyloidosis. This study aimed to validate the characteristics of patients with positive 99mTc-PYP scintigraphy results in a multicenter setting to provide more accurate case selection criteria. METHODS AND RESULTS: In total, 180 patients with suspected ATTR amyloidosis underwent 99mTc-PYP scintigraphy in participating institutions in Japan between January 2018 and July 2022. Of 135 patients included in the analysis, 62 were 99mTc-PYP-positive. Logistic regression analysis was performed, and the following five factors were adopted to create a scoring system, with each weighted according to its odds ratio value; 1 point was scored for the absence of hypertension, existence of peripheral entrapment neuropathy (carpal tunnel syndrome or spinal canal stenosis), conduction disturbance (the presence of QRS complex ≥120 ms, first-degree atrioventricular block, higher degree of atrioventricular block, or presence of pacemaker implantation), and left ventricular hypertrophy and 2 points for troponin I/T ≥ 0.06 ng/mL. 99mTc-PYP scintigraphy positivity rate in the 0-point group was 0 %, whereas that in the 6-point group was 100 %. The area under the curve of the criteria was 0.820 (95 % confidence interval, 0.752-0.888; P < 0.001). CONCLUSIONS: The combination of clinical information, which is easily available in local clinics, can provide accurate pretest prediction of positive 99mTc-PYP scintigraphy results. This will help clinicians to make an early diagnosis of ATTR amyloidosis.

Health-Related Quality of Life and Treatment Satisfaction of Patients with Malignant IDH Wild-Type Gliomas and Their Caregivers.

(1) Background: Clinical aspects like sex, age, Karnofsky Performance Scale (KPS) and psychosocial distress can affect the health-related quality of life (HR-QoL) and treatment satisfaction of patients with malignant isocitrate dehydrogenase wild-type (IDHwt) gliomas and caregivers. (2) Methods: We prospectively investigated the HR-QoL and patient/caregiver treatment satisfaction in a cross-sectional study with univariable and multiple regression analyses. Questionnaires were applied to investigate the HR-QoL (EORTC QLQ-C30, QLQ-BN20) and treatment satisfaction (EORTC PATSAT-C33). (3) Results: A cohort of 61 patients was investigated. A higher KPS was significantly associated with a better HR-QoL regarding the functional scales of the EORTC QLQ-C30 (p < 0.004) and a lower symptom burden regarding the EORTC QLQ-BN20 (p < 0.001). The patient treatment satisfaction was significantly poorer in the patients older than 60 years in the domain of family involvement (p = 0.010). None of the investigated aspects showed a significant impact on the treatment satisfaction of caregivers. (4) Conclusions: We demonstrated that in patients with IDHwt gliomas, the KPS was the most important predictor for a better HR-QoL in functional domains. Data on the HR-QoL and treatment satisfaction in patients with IDHwt gliomas and their caregivers are rare; therefore, further efforts should be made to improve supportive care in this highly distressed cohort.

Unveiling the Potential of CuO and Cu2O Nanoparticles against Novel Copper-Resistant Pseudomonas Strains: An In-Depth Comparison.

Four novel Pseudomonas strains with record resistance to copper (Cu2+) previously isolated from ecologically diverse samples (P. lactis UKR1, P. panacis UKR2, P. veronii UKR3, and P. veronii UKR4) were tested against sonochemically synthesised copper-oxide (I) (Cu2O) and copper-oxide (II) (CuO) nanoparticles (NPs). Nanomaterials characterisation by X-ray diffractometry (XRD), X-ray photoelectron spectroscopy (XPS), Fourier transform infrared spectroscopy (FTIR), and High-Resolution Transmission Electron Microscopy (HRTEM) confirmed the synthesis of CuO and Cu2O NPs. CuO NPs exhibited better performance in inhibiting bacterial growth due to their heightened capacity to induce oxidative stress. The greater stability and geometrical shape of CuO NPs were disclosed as important features associated with bacterial cell toxicity. SEM and TEM images confirmed that both NPs caused membrane disruption, altered cell morphology, and pronounced membrane vesiculation, a distinctive feature of bacteria dealing with stressor factors. Finally, Cu2O and CuO NPs effectively decreased the biofilm-forming ability of the Cu2+-resistant UKR strains as well as degraded pre-established biofilm, matching NPs' antimicrobial performance. Despite the similarities in the mechanisms of action revealed by both NPs, distinctive behaviours were also detected for the different species of wild-type Pseudomonas analysed. In summary, these findings underscore the efficacy of nanotechnology-driven strategies for combating metal tolerance in bacteria.

Association of preoperative seizures with reduced expression of soluble CD163, an M2 macrophage marker, in the cerebrospinal fluid in isocitrate dehydrogenase wild-type glioblastoma.

PURPOSE: To investigate the relationship between the tumor microenvironment (TME), tumor-related seizures (TRS), and cerebrospinal fluid (CSF) markers that predict preoperative seizures in patients with glioblastoma. METHODS: In total, 47 patients with isocitrate dehydrogenase (IDH) wild-type glioblastoma who underwent preoperative CSF examination, 3-T magnetic resonance spectroscopy (MRS), and neurological surgery between January 2017 and December 2023 were included. We measured the concentrations of soluble CD163 (sCD163), a soluble form of the M2 macrophage marker, in the CSF, the metabolite concentration on MRS, and the number of CD163-positive M2 macrophages in the tumor tissue. Factors associated with preoperative seizures were examined. RESULTS: Twelve patients (25.5%) had preoperative seizures. sCD163 levels in the CSF were positively correlated with the number of CD163-positive M2 macrophages in the tumor tissue, and both were significantly lower in the preoperative seizure group than in the non-preoperative seizure group (p = 0.0124 and p < 0.0001, respectively). MRS indicated that only glutathione (GSH) concentrations were higher in the preoperative seizure group than in the non-preoperative seizure group (2.55 mM and 1.87 mM, respectively; p = 0.0171). CD163-positive M2 macrophages were inversely correlated with GSH levels. sCD163 in the CSF had a high predictive accuracy (sensitivity, 91.7%; specificity, 54.3%; and area under the receiver operator curve, 0.745) for preoperative seizures. CONCLUSIONS: The CSF level of sCD163 is useful for predicting the TME and preoperative seizures in IDH wild-type glioblastoma.

Successful cetuximab rechallenge in metastatic colorectal cancer: A case report.

BACKGROUND: Metastatic colorectal cancer (mCRC) treatment has been evolving and increasingly driven by tumor biology and gene expression analysis. Rechallenge with epidermal growth factor receptor (EGFR) inhibitors (anti-EGFR) represents a promising strategy for patients with RAS wild-type (RAS-wt) mCRC and circulating tumor DNA has emerged as a potential selection strategy. Herein, we report the case of a RAS-wt mCRC patient who had a successful response to cetuximab rechallenge. CASE SUMMARY: Our patient was diagnosed with stage IV RAS-wt, microsatellite-stable rectosigmoid junction adenocarcinoma. He was started on first-line treatment with FOLFIRI and cetuximab and achieved partial response, allowing for a left hepatectomy (R0), followed by post-operative chemotherapy and an anterior resection; progression-free survival (PFS) of 16 months was obtained. Due to hepatic and nodal relapse, second-line treatment with FOLFOX and bevacizumab was started with partial response; metastasectomy was performed (R0), achieving a PFS of 11 months. After a 15 months anti-EGFR-free interval, FOLFIRI and cetuximab were reintroduced upon disease progression, again with partial response and a PFS of 16 months. Following extensive hepatic relapse, cetuximab was reintroduced and a marked clinical and analytical improvement was seen, after only one cycle. RAS-wt status was confirmed on circulating tumor DNA. The patient's overall survival exceeded 5 years. CONCLUSION: Our case provides real-world data to support cetuximab rechallenge in later lines of RAS-wt mCRC treatment.

Discovery of dual-targeted molecules based on Olaparib and Rigosertib for triple-negative breast cancer with wild-type BRCA.

PARP inhibitors (PARPis) demonstrate significant potential efficacy in the clinical treatment of BRCA-mutated triple-negative breast cancer (TNBC). However, a majority of patients with TNBC do not possess BRCA mutations, and therefore cannot benefit from PARPis. Previous studies on multi-targeted molecules derived from PARPis or disruptors of RAF-RAF pathway have offered an alternative approach to develop novel anti-TNBC agents. Hence, to broaden the application of PARP inhibitors for TNBC patients with wild-type BRCA, a series of dual-targeted molecules were constructed via integrating the key pharmacophores of Olaparib (Ola) and Rigosertib into a single entity. Subsequent studies exhibited that the resulting compounds 13a-14c obtained potential anti-proliferative activity against BRCA-defected or wild-type TNBC cells. Among them, an optimal compound 13b showed good inhibitory activity toward PARP-1, displayed approximately 34-fold higher inhibitory activity than that of Ola in MDA-MB-231 cells, and exerted multi-functional mechanisms to induce apoptosis. Moreover, 13b displayed superior antitumor efficacy (TGI, 61.3 %) than the single administration of Ola (TGI, 38.5 %), 11b (TGI, 51.8 %) or even their combined administration (TGI, 56.7 %), but did not show significant systematic toxicity. These findings suggest that 13b may serve as a potential candidate for BRCA wild-type TNBC.

[Clinical aspects of systemic amyloidosis in 2024]. / Aspects cliniques des amyloses systémiques en 2024.

The three most common varieties of systemic amyloidosis are transthyretin amyloidosis (ATTR), immunoglobulin amyloidosis (AL) and inflammatory amyloidosis (AA). There are two forms of transthyretin amyloidosis: the wild type, the most common, represents approximately 15% of heart diseases and the genetic, or "mutated" form, which is a rare disease and manifests mainly by peripheral neuropathy and heart disease. Major therapeutic advances have been made in recent years thanks to molecules that stabilize transthyretin and/or prevent its translation by destroying messenger RNA. Immunoglobulin amyloidosis (AL) is a hematological disease whose severity is due to the toxicity of immunoglobulin light chains forming amyloid deposits that are toxic to tissues, particularly the heart and kidneys. Treatments for immunoglobulin amyloidosis are increasingly effective, and target the plasma cell, leading to an overall improvement in the prognosis, with cardiac involvement being the most worrying condition. Inflammatory amyloidosis (AA) complicates chronic inflammatory diseases less often due to the effectiveness of anti-inflammatory biotherapies in inflammatory rheumatism, chronic inflammatory bowel diseases and genetic auto-inflammatory diseases. The causes of inflammatory amyloidosis are now more diverse with an increase in cases of unknown cause associated or not with obesity.

[PET/CT with 11C-methionine as a predictor of disease-free survival in patients with IDH1 wild type diffuse glioma]. / Pozitronno-emissionnaya tomografiya, sovmeshchennaya s komp'yuternoi tomografiei, s 11S-metioninom kak nezavisimyi prediktor bezretsidivnoi vyzhivaemosti u bol'nykh s diffuznymi gliomami bez mutatsii v gene IDH1.

Prognosis of IDH (IDHwt) wild-type gliomas is worse compared to IDH-mutant tumors regardless of histological criteria for glioblastoma. However, there is still uncertainty regarding favorable course of disease and predictors of long-term survival in IDHwt gliomas. OBJECTIVE: To study the metabolic characteristics of IDH1wt diffuse astrocytomas using 11C-methionine PET/CT and prognostic significance of PET-associated parameters for disease-free survival. MATERIAL AND METHODS: We analyzed 79 adults with IDH1wt diffuse gliomas. Quantitative analysis consisted of 11C-methionine accumulation index and metabolic tumor volume. Kaplan-Meier and Cox analyses were used to determine prognostic significance of histological findings and PET parameters. RESULTS: Glioblastoma and astrocytoma grade 2 or 3 were diagnosed in 41% and 59% of patients, respectively. Accumulation index significantly differed between astrocytomas grade 2 and 3 (p=0.03). Significant predictors of disease-free survival were age, histological type of astrocytoma and tumor grade, contrast enhancement, PET-associated biomarkers (accumulation index and metabolic tumor volume) and compliance of metabolic pattern with glioblastoma syndrome (p<0.05). Disease-free survival >24 months was established for age <41 years, maximum accumulation index <1.64, tumor accumulation index <1.39 and metabolic tumor volume <13.44 cm3. In multivariate Cox analysis, independent predictors of disease-free survival were age and PET syndrome of glioblastoma. CONCLUSION: Diffuse IDH1wt gliomas are a heterogeneous group differing in metabolic characteristics and prognosis. PET/CT with 11C-methionine may be effective for stratifying patients into groups with unfavorable and favorable prognosis, as well as assessment of advisability of in-depth searching for IDH1/IDH2 mutation.

First-Line Therapy in Metastatic, RAS Wild-Type, Left-Sided Colorectal Cancer: Should Everyone Receive Anti-EGFR Therapy?

PURPOSE OF REVIEW: This narrative review explores the efficacy and applicability of anti-EGFR therapy as the first-line treatment for patients with RAS wild-type (WT) left-sided metastatic colorectal cancer (mCRC). It critically examines current guidelines, along with recent evidence in the literature, to assess whether it should be universally applied. RECENT FINDINGS: Recent evidences highlight the variability of the response to anti-EGFR therapies due to molecular diversity and several clinical factors, such as RAS mutational status and primary tumor location. Anti-EGFR plus chemotherapy is the standard first-line treatment for most patients with MSS, RAS-WT, left-sided mCRC. Whether this combination is the best treatment for these patients remains an open question. This review delves into the role of EGFR inhibition in mCRC, focusing on clinical factors and the knowledge of biology, molecular targets, and biomarkers. It underscores the crucial role of a personalized approach, empowering healthcare providers and equipping them with the confidence to make informed decisions.

Non-Zoonotic Transmission of Sporotrichosis: A Translational Study of Forty-Three Cases in a Zoonotic Hyperendemic Area.

Over the past two decades, zoonotic sporotrichosis transmitted by naturally infected cats has become hyperendemic in Rio de Janeiro, Brazil. Sporothrix brasiliensis is the main agent involved. However, there are other forms of transmission of sporotrichosis. The aim of this study was to evaluate and associate the epidemiological, clinical and therapeutic data and the susceptibility of Sporothrix spp. to antifungal drugs in 43 non-zoonotic sporotrichosis cases. Forty-three clinical strains of Sporothrix were identified by partial sequencing of the calmodulin gene. An antifungal susceptibility test of amphotericin B, terbinafine, itraconazole, posaconazole and isavuconazole was performed according to the broth microdilution method. Most patients were male (55.8%). Regarding the source of infection, 21 patients (48.8%) reported trauma involving plants and/or contact with soil. Sporothrix brasiliensis was the predominant species (n = 39), followed by S. globosa (n = 3) and S. schenckii (n = 1). Sporothrix brasiliensis was associated with all the sources of infection, reinforcing previous data showing the presence of this species in environmental sources, as well as with all the clinical forms, including severe cases. One clinical strain of Sporothrix brasiliensis was classified as a non-wild-type strain for amphotericin B and another for itraconazole. S. schenckii was classified as non-WT for all the antifungals tested. In this context, it is important to emphasize that non-zoonotic sporotrichosis still occurs in the state of Rio de Janeiro, with S. brasiliensis as the main etiological agent, primarily associated with infections acquired after traumatic inoculation with plants and/or soil contact, followed by S. globosa and S. schenckii. In addition, non-WT strains were found, indicating the need to monitor the antifungal susceptibility profile of these species. It is crucial to investigate other natural sources of S. brasiliensis to better understand this fungal pathogen and its environment and host cycle.

Use and Reuse of Animal Behavioral, Molecular, and Biochemical Data in Alzheimer's Disease Research: Focus on 3Rs and Saving People's Tax Dollars.

Several decades of research on cell and animal models contributed tremendously to understanding human diseases. Particularly, research on rodents and non-human primates revealed that animal research is a major and important component in biomedical research in learning complex pathophysiological processes. Further, animal research helped us to understand human diseases, such as Alzheimer's disease. In addition, animal research has also helped us to test hundreds of drugs and develop treatments for human use. Researchers can gain a better understanding of key biological and physiological processes in humans by comparing them to laboratory animals. Based on their relevance and resemblance to people, or even usual living conditions, scientists rationalize the use of particular animal models in their studies. It is suggested that in the National Institutes of Health and other agencies-funded research, animal models should be carefully selected to study the biology and pathophysiology of human health and diseases such as Alzheimer's disease and other dementias. However, it is critical to use a minimum number of animals for human research. Further, it is also noted that the use and reuse of behavioral,  molecular, and biochemical data from wild-type (WT) control mice with mutant lines of disease models, as long as the genetic background is the same in both WT and disease mice. On the other hand, anonymous readers have challenged the use and reuse of WT mice data for comparison. In the current article, we discuss the minimum utility of animals, covering the 3Rs, Replacement, Reduction, and Refinement, and also discuss the use and reuse of behavioral, molecular, and biochemical data.

Establishment and Application of Mismatch Amplification Mutation Assay-PCR for Rapid Detection and Differentiation of Duck Hepatitis A Virus-1 Attenuated Vaccine and Wild Strains.

Duck hepatitis A virus type 1 (DHAV-1) is the main pathogen causing viral hepatitis in ducks, marked by high contagion and acute mortality. Live attenuated DHAV-1 vaccines are widely used to control the disease. This study aims to develop a mismatch amplification mutation assay (MAMA)-PCR for the rapid detection and differentiation of Korean DHAV-1 wild-type strains from vaccine strains. A MAMA primer was designed to target a single nucleotide polymorphism (SNPs) at position 2276 within the VP1 gene, allowing differentiation in a single PCR reaction. The MAMA-PCR accurately identified both strains, with detection limits of 100.5 ELD50/mL and 102.3 ELD50/mL, respectively. The MAMA-PCR demonstrated specificity, showing no cross-reactivity with 12 other viral and bacterial pathogens. The MAMA-PCR was applied to 89 farms, yielding results consistent with nested-PCR and sequence determination, identifying four positive farms for DHAV-1 vaccine strains. In conclusion, this study is the first to employ the MAMA-PCR method to distinguish between DHAV-1 wild-type and vaccine strains. The developed method is rapid, simple, specific, and sensitive, thereby serving as an effective tool for clinical diagnostics in identifying and differentiating between Korean DHAV-1 wild-type and vaccine strains.

Early diagnosis, disease stage and prognosis in wild-type transthyretin amyloid cardiomyopathy: The DIAMOND study.

AIMS: Disease staging and prognostic scoring in wild-type transthyretin-related cardiac amyloidosis (ATTRwt-CA) can be captured by two systems (NAC and Columbia scores). However, uncertainty remains as epidemiology of the disease is evolving rapidly. We evaluated features associated with staging systems across ATTRwt-CA patients from different diagnostic pathways, and their association with prognosis. METHODS: We performed an analysis on DIAMOND patients with available data to evaluate NAC and Columbia score. DIAMOND was a retrospective study from 17 Italian referral centres for CA, enrolling 1281 patients diagnosed between 2016 and 2021, and aimed at describing characteristics of pathways leading to ATTRwt-CA diagnosis. Of the original cohort, 811 patients were included in this analysis. Each patient had NAC and Columbia score calculated. Patients were grouped according to NAC and Columbia scoring classes. We described characteristics of patients according to staging classes and diagnostic pathways at diagnosis. Prevalence of early diagnoses, defined as NAC Ia, NYHA class I, no use of diuretics, no history of heart failure (HF) hospitalizations nor of atrial fibrillation prior to diagnosis, was investigated. Finally, prognostic variables were tested alone and grouped as NAC or Columbia scores in Cox univariate and multivariate regression analyses. Prognosis was investigated as all-cause mortality, in the whole population and dividing patients in HF versus other diagnostic pathways. RESULTS: Only 1% of the study population had an early ATTRwt-CA diagnosis. Distribution of prognostic variables and of NAC and Columbia classes was heterogeneous across diagnostic pathways. The prevalence of NAC III and Columbia III was higher in the HF diagnostic pathway, but all NAC and Columbia classes were present in all pathways. Both NAC and Columbia scores were associated with all-cause mortality at univariate Cox regression analysis in the whole population, in patients from the HF diagnostic pathway and in those from other pathways. At multivariate analysis, Columbia score remained significantly associated with the outcome, together with age at diagnosis, left ventricular ejection fraction and maximal wall thickness. CONCLUSIONS: In this contemporary nationwide cohort, an ATTRwt-CA early diagnosis was very rare. Disease staging with NAC and Columbia scoring systems determined classes of patients with heterogeneous features. Both scores were significantly associated with mortality, but other variables also had prognostic significance.

Circulating ECM proteins decorin and alpha-L-iduronidase differentiate ATTRwt-CM from ATTRwt-negative HFpEF/HFmrEF.

AIMS: Wild-type transthyretin cardiac amyloidosis (ATTRwt-CM) is an under-recognized aetiology of heart failure (HF), necessitating early detection for timely treatment. Our study aimed to differentiate patients with ATTRwt-CM from ATTRwt-negative HFpEF/HFmrEF patients by identifying and validating circulating protein biomarkers. In addition, we measured the same biomarkers in patients with cardiomyopathy due to light chain amyloidosis (AL)-CM to gain disease-specific insights. METHODS AND RESULTS: In this observational study, serum concentrations of 363 protein biomarkers were measured in a discovery cohort consisting of 73 ATTRwt-CM, 55 AL-CM, and 59 ATTRwt-negative HFpEF/HFmrEF patients, using multiplex proximity extension assays. Sparse partial least squares analyses showed overlapping ATTRwt-CM and AL-CM biomarker profiles with clear visual differentiation from ATTRwt-negative patients. Pathway analyses with g:Profiler revealed significantly up-regulated proteoglycans (PG) and cell adhesion pathways in both ATTRwt-CM and AL-CM. Penalized regression analysis revealed that the proteoglycan decorin (DCN), lysosomal hydrolase alpha-L-iduronidase (IDUA) and glycosyl hydrolase galactosidase ß-1 (GLB-1) most effectively distinguished ATTRwt-CM from ATTRwt-negative patients (R2 = 0.71). In a prospective validation cohort of 35 ATTRwt-CM patients and 25 ATTRwt-negative patients, DCN and IDUA significantly predicted ATTRwt-CM in the initial analysis (DCN: OR 3.3, IDUA: OR 0.4). While DCN remained significant after correcting for echocardiographic parameters, IDUA did not. DCN showed moderate discriminative ability (AUC, 0.74; 95% CI, 0.61-0.87; sensitivity, 0.91; specificity, 0.52) as did IDUA (AUC, 0.78; 95% CI, 0.65-0.91; sensitivity, 0.91; specificity, 0.61). A model combining clinical factors (AUC 0.92) outperformed DCN but not IDUA, a combination of the biomarkers was not significantly better. Neither DCN nor IDUA correlated with established disease markers. CONCLUSION: ATTRwt-CM has a distinctly different biomarker profile compared with HFpEF/HFmrEF, while ATTRwt-CM patients share a similar biomarker profile with AL-CM patients characterized by up-regulation of proteoglycans and cell-adhesion pathways. The biomarkers DCN and IDUA show the potential to serve as an initial screening tool for ATTTRwt-CM. Further research is needed to determine the clinical usefulness of these and other extracellular matrix components in identifying ATTRwt-CM.

Right Ventricular Free Wall Strain Predicts ATTR Prognosis as Well as Biomarker- Based Staging Systems.

AIMS: The diagnosis of transthyretin amyloidosis (ATTR) significantly impacts the management and prognosis of patients initially presenting with heart failure (HF). Despite recent advances in treatment, prognosticating ATTR remains challenging. We aimed to assess echocardiographic parameters associated with mid-term prognosis in patients with wild-type ATTR using a biomarker staging system as a reference point. METHODS AND RESULTS: We studied 182 consecutive patients with wild-type ATTR (91% male, median age 82 years) who were referred to our center between 2016 and 2022. Using NT- proBNP and eGFR cutoffs, we divided patients into stage I (101 patients, 55.5%), stage II (53, 29.0%), and stage III disease (28, 15.5%). We then compared traditional echocardiographic indices and markers of subclinical ventricular dysfunction (LV global longitudinal strain, RV free wall strain, and LA strain) among groups. Over a fixed follow-up of 18 months, which included treatment with tafamidis 61 mg daily, 48 patients (26.4%) experienced the composite outcome of death or HF hospitalization. When compared with stage I ATTR, the hazard ratio for death or hospitalization was 1.55 (95% CI 0.62-3.86) for stage II ATTR and 4.53 (95% CI 1.66-12.4, p = 0.0116) for stage III ATTR. Among echocardiographic parameters, reduced RV FWS was independently associated with all-cause mortality or HF hospitalization after adjustment for the staging system (HR 2.03, 95% CI 1.07-3.85, p < 0.05). CONCLUSION: RV FWS should be routinely assessed for all patients with ATTR. It is an independent predictor of poor prognosis and provides additional value beyond biomarker staging systems.

Frailty in heart failure according to the presence or absence of wild-type transthyretin cardiac amyloidosis.

AIMS: Wild-type transthyretin cardiac amyloidosis (ATTRwt CA) is a common, underdiagnosed cause of heart failure (HF) in the elderly. Concurrent extracardiac amyloid infiltration might be responsible for a specific frailty phenotype. This study aims to compare the prevalence and characteristics of frailty parameters in HF patients, with or without ATTRwt CA. METHODS: In a comparative cross-sectional study, we prospectively included consecutive HF patients with or without ATTRwt CA (the HF + ATTRwt+ and HF + ATTRwt- groups, respectively) between April 2018 and April 2021. Logistic regression models were used to compare the groups with regard to frailty as assessed using multidimensional geriatric tools. RESULTS: We included 123 patients (68 HF + ATTRwt+ and 55 HF + ATTRwt-). The mean age was 80.9 (standard deviation 6.3) years, 87% were male, 34% had left ventricular systolic dysfunction and 34% were New York Heart Association (NYHA) III. Relative to the HF + ATTRwt- group, patients in the HF + ATTRwt+ group were more likely to have shrinking [odds ratios = 2.9 (95% confidence interval, 1.1 to 1.7), P = 0.03], balance disorders [1.8 (1.1 to 2.8), P = 0.02], memory complaints [2.5, (1.0 to 5.9), P = 0.05] and overactive bladder [1.5 (1.1 to 2.2), P = 0.03], independently of age, sex, NYHA class and diabetes status. The proportion of very frail patients was higher (albeit not significantly) in the HF + ATTRwt+ group than in the HF + ATTRwt- group [2.4 (0.9 to 6.9), P = 0.10]. CONCLUSIONS: ATTRwt CA is associated with a specific frailty phenotype. Patients with ATTRwt CA should be screened for frailty and managed collaboratively by cardiologists and geriatricians, with a view to improving quality of life.