Progression Of Lesions Research Articles

Temporal changes in FFR in initially deferred vessels in symptomatic patients

Abstract Background A sizeable proportion of deferred patients based on non ischemic FFR, continue to experience symptoms. Evaluation of serial temporal changes in FFR may help guide follow up and management in such patients. Methods Consecutive patients undergoing FFR evaluation in whom PCI was deferred were followed. Patients who had repeat angiographic evaluation for recurrent symptoms and who had FFR re-measured in the same artery were analyzed. In patients who had progression to ischemic FFR, we performed multivariate analysis to identify the factors most associated with accelerated progression. Results 796 non-ischemic lesions in 559 patients, by FFR were deferred for medical management. Among them 48 patients with 56 lesions underwent repeat FFR evaluation at a mean follow up of 686 ± 418 days (range 30 to 1649) for persistent or recurrent symptoms. FFR value significantly changed from initial mean of 0.85 ± 0.04 to 0.82 ± 0.07 with a mean difference of 0.032 ± 0.01 (P = 0.003) (Figure 1a). 51 lesions were initially non ischemic with FFR > 0.80. Among these 22 (41%) lesions progressed to develop ischemia (FFR < 0.80) from an initial mean FFR of 0.85 ± 0.037 to 0.75 ± 0.051 with a mean difference of 0.1 ± 0.054 ( P <0.001) (Figure 1 b). Among the remaining 30 patients there was no significant change in FFR (0.87 ± 0.048 vs 0.87 ± 0.041; mean difference 0.006 ± 0.05; P = 0.54). Differences in baseline characteristics were as follows (lesion progression vs. none): Age (61±5 vs 63±5;p=0.12), stenosis (58±12 vs 52±10;p=0.07) FFR (0.84±0.04 vs 0.86±0.05;p=0.2); DM (29% ± 58%; p=0.07) smoking 43 ± 48%) prior MI/revascularization (90% vs. 79%; p=0.34) CKD 5% vs. 15%; p=0.24) ACS (38% vs. 38%) and LAD (38% vs. 36%). Conclusion Among lesions, initially deferred PCI based on non ischemic FFR, recurrence of symptoms should prompt re-evaluation of ischemia as a large proportion (~40%) of these lesions may demonstrate progression to ischemia (FFR<0.80).Factors associated with progressive decline in FFR warrant further study.Repeat FFR value changesRepeat FFR with ischemia development

Enhancing computational fluid dynamics simulation for coronary artery disease analysis through spatial iterative modeling

Abstract Background Endothelial shear stress (ESS) critically influences the pathogenesis of coronary artery disease (CAD) by modulating the formation and progression of atherosclerotic lesions. Despite the use of 3D modeling in computational fluid dynamics (CFD) simulations to calculate ESS, the precision of these models significantly depends on the method of reconstruction. Spatial Iterative Method (SIM) extends the iterative approach in computer science to spatial data, using recurring algorithms to refine 3D models and analyses. Iterative approach executes a sequence of instructions repeatedly until a certain condition is met, enabling progressive problem-solving. Purpose In this study, we investigated the application of the SIM to estimate ESS in coronary arteries and explored Atherosclerotic Plaque Areas (APA) in patients with CAD. Methods We analyzed fifteen patients (9 males, mean age of 63 ± 10.56 years) with atherosclerotic plaque on coronary arteries. The eighteen images captured from an anterior viewpoint in 10-degree increments of the coronary artery obtained from Coronary Computed Tomography Angiography at the best diastolic phase for each patient were used. We implemented the SIM for 3D model reconstruction, facilitating ninety comparisons across all iterations to evaluate ESS estimations accurately. (Figure 1.) Results In our study, we evaluated ESS contours from CFD simulations for a total of 282 APA (200 calcified and 82 soft plaques) across ninety spatial iterations. We categorized ESS into three groups: low (162 APA cases with ESS of less than 1 Pascal (Pa)), medium (67 APA cases with ESS between 1 and 2 Pa), and high (53 APA cases with ESS greater than 2 Pa). There was a significant association between ESS categories and plaque types (p < 0.0001, Figure 2.). The calcified plaques were formed in areas with low ESS (%80 of calcified plaques) and soft plaques in areas with medium and high ESS (%97 percent of soft plaques). Conclusion The significant association between ESS categories and plaque types shows the potential of SIM in hemodynamic analysis. This finding highlights the potential of SIM in enhancing the understanding of hemodynamic influences on plaque formation, offering a promising direction for future cardiovascular research.Figure 1.Sample Iteration of the SIMFigure 2.Heatmap of ESS vs. APA

A novel methylation-detection panel for HPV associated high-grade squamous intraepithelial lesion and cervical cancer screening

Cervical cancer (CC) was considered to be the most common gynaecological cancer, with an estimated 342,000 deaths worldwide each year, as the majority of patients were diagnosed at an advanced stage of the disease. The purpose of this study was to evaluate the predictive value of multi-locus methylation assay for the early detection of CC. The cervical exfoliated cell samples from 492 HPV-positive females with cervical lesions were collected and subjected to methylation detection of gene FAM19A4, EPB41L3 and PAX1 after bisulfite conversion. The levels of gene methylation in patients with different severity of cervical lesions were evaluated and compared. The receiver-operating characteristic (ROC) curve was established and efficacy indexes such as sensitivity, specificity and area under the curve (AUC) were calculated to assess the diagnostic value of DNA methylation detection at multiple gene loci for CC. The methylation levels of FAM19A4, EPB41L3 and PAX1 were significantly increased with the grade of cervical squamous intraepithelial lesions. The sensitivities of FAM19A4, EPB41L3 and PAX1 alone for high-grade squamous intraepithelial lesion (HSIL) and CC diagnosis were 84.6%, 86.3% and 88.0%, respectively; when three markers were combined by a logistic regression model, the sensitivity was 88.0%, with a high specificity of 97.7% and AUC of 0.957 (95% CI 0.937–0.977). Methylation status of FAM19A4, EPB41L3 and PAX1 were highly specific and effective for monitoring the progression of cervical lesions and the tri-gene methylation assay could be used as a triage tool for CC early screening.

Patients with coronary atherosclerosis had an altered ratio of monocyte subpopulations in the blood, which was associated with an inflammatory cell response

Coronary artery disease (CAD) is one of the leading causes of death in developed countries. Experimental data confirm the role of monocytes in the development of CAD. Three main subpopulations of circulating blood monocytes are known: classical CD14++CD16- (~80%), intermediate CD14+CD16+ (~5%) and non-classical CD14+CD16++(~15%). It is believed that each of the subpopulations of monocytes performs different functions. There are studies that demonstrate that classical monocytes respond more to the bacterial presence, whereas non-classical ones respond to the viral one. However, the functions of monocyte subpopulations have not been fully studied. Previously, we demonstrated that circulating monocytes of the blood of patients with atherosclerosis had increased proinflammatory activity. We decided to find out how the ratio of monocyte subpopulations in the blood is related to the inflammatory response of cells in atherosclerosis. The aim of our work was to investigate the relationship of the inflammatory response of primary monocytes with the distribution of monocyte subpopulations relative to the total pool of monocytes in healthy and sick CAD. The study included 20 men aged 46 to 70 years, 10 of them without CAD and 10 patients with CAD. A coronary angiography was performed, according to the results of which the patients were divided into patients with coronary atherosclerosis with detected stenosis in 2 or more arteries (CAD) and healthy ones without stenosis in the arteries. Next, blood was taken to study circulating monocytes. Monocyte subpopulations were detected by flow cytometry from the leukocyte fraction using antibodies against CD14- FITC and CD16-PB450-A. Immediately after isolation, monocytes were stimulated with LPS with a final concentration of 1 ug/mL, and a supernatant was selected 24 hours later for further enzyme immunoassay. The inflammatory response was assessed by the secretion of cytokines TNFα, IL-1β, IL-6, IL-8, IL-10, and CCL2 using ELISA. The monocytes of CAD patients had an altered inflammatory response in response to LPS stimulation compared to patients without CAD. This was manifested in increased secretion of IL-1β and TNF, and decreased secretion of CCL2 and IL-6. An increase in the number of intermediate and non-classical monocytes in patients with CAD was associated with changes in the inflammatory response of cells to the secretion of cytokines IL-1β and CCL2. It can be assumed that pathological changes in the representation of monocyte subpopulations in the bloodstream may be one of the causes of chronic inflammation in the walls of the arteries, contributing to the progression of atherosclerotic lesions.

Very early symptomatic metastasis pseudoprogression after stereotactic brain radiosurgery in a melanoma patient treated with BRAF/MEK inhibitors: a case report and review of the literature

IntroductionSignificant therapeutic changes have recently occurred in the management of melanoma brain metastases (BMs), both in the field of local treatments, with the rise of stereotactic radiotherapy (RT), as well as in systemic ones, with the advent of immunotherapy and targeted therapies (TT). These advances have brought about new challenges, particularly regarding the potential interactions between new TT (notably BRAF/MEK inhibitors) and irradiation. Through a clinical case, we will discuss a side effect not previously described in the literature: ultra-early pseudoprogression (PP) following brain stereotactic radiosurgery (SRS), in a patient treated with dabrafenib-trametinib.Case presentationA 61-year-old patient with BRAFV600E-mutated melanoma, receiving second-line dabrafenib-trametinib therapy, was referred for SRS on three progressing meningeal implants, without evidence of systemic progression. Four days after the first RT session (1x6 Gy on a fronto-orbital lesion prescribed 5x6 Gy, and 1x20 Gy single fraction on the other lesions), the patient presented with an epileptic seizure. An MRI, compared to the planning MRI ten days earlier, revealed significant progression of the irradiated lesions. The patient’s condition improved with dexamethasone and levetiracetam, and RT was halted out of caution. A follow-up MRI at one month demonstrated a size reduction of all treated lesions. Subsequent imaging at five months revealed further shrinking of the two lesions treated with an ablative dose of 20 Gy, while the under-treated fronto-orbital lesion progressed. These dynamics suggest an initial PP in the three irradiated lesions, followed by good response in the ablatively treated lesions and progression in the partially treated lesion.ConclusionTo our knowledge, this represents the first documented case of ultra-early PP following brain SRS in a patient receiving concomitant dabrafenib-trametinib. It highlights the need for particular vigilance when using tyrosine kinase inhibitors (TKIs) with SRS, and warrants further research into potential treatment interactions between RT and novel systemic agents, as well as the optimal treatment sequence of melanoma BMs.

Histomorphometric analysis of excisional cutaneous wounds with different diameters in an animal model.

The skin wound model in rats is a fundamental stage in preclinical trials, but there is a lack of standardization in these trials regarding the initial wound area, making analysis and comparison between studies difficult. Therefore, this study evaluates the healing progression of excisional skin lesions of varying diameters in Wistar rats, aiming to identify the optimal wound size for monitoring treatment effects on wound healing. Excisions of 0.8, 1.5, 2.0 and 3.0 cm in diameter were made on the back of the animals. Thirty animals were used per treatment and evaluated on days 3, 7, 10, 14 and 21 after surgery. The lesions were cleaned daily with saline solution until they were completely closed. The 0.8 cm group showed complete repair on D14, while in the other groups, the wounds persisted until day 21, with a reddened surface and no complete epidermal coverage, but with greater keratinization and presence of appendages in the 1.5 cm lesions. Therefore, as a standardization model for creating skin wounds, we suggest using 1.5 or 2.0 cm excisions, considering that 0.8 cm wounds close very early and 3.0 cm wounds, although behaving similarly to 2.0 cm wounds, are more invasive for the animals. The 1.5 cm model proved to be suitable for closure within 21 days. When evaluating a product intended to accelerate wound healing, 2.0 cm lesions are recommended to assess the effectiveness of the treatment.

"Atherosclerotic" phenotype of rheumatoid arthritis. What do we know about it?

Several studies have shown that systemic rheumatoid inflammation may cause induction and accelerated progression of atherosclerotic vascular lesions, which in turn may lead to more frequent development of cardiovascular diseases (CVD) in patients with rheumatoid arthritis (RA) compared to the general population.Objective. To evaluate the presence, nature and role of conventional and RA-specific risk factors for the development of CVD in patients with active RA in real-life clinical practice.Material and methods. Data from 967 patients with confirmed active RA were analyzed. Biologic disease-modifying antirheumatic drugs (DMARDs) or targeted DMARDs were prescribed/switched due to the ineffectiveness of previous therapy. Patients were divided into two groups: with and without CVD. In addition, comparable age subgroups of elderly (60–74 years) and middle-aged (45–59 years) patients were formed in each group. In all patients, clinical and laboratory parameters of RA activity, presence of extra-articular manifestations, the severity and progression of RA and characteristics of pharmacotherapy were analyzed. In addition, concomitant diseases and several traditional risk factors for the development of CVD were analyzed in all RA patients.Results and discussion. In patients with similar RA activity and duration, there is a parallel, tatistically significant accumulation of traditional CVD risk factors with increasing age-related CVD. The incidence of arterial hypertension, diabetes mellitus, chronic kidney disease, chronic obstructive pulmonary disease, thyroid pathology, anemic syndrome, dyslipidemia, hyperuricemia and obesity was significantly higher in the group of elderly RA patients with CVD than in the group of middle-aged patients.Conclusion. It seems appropriate to identify a specific variant of RA that is closely associated with atherosclerosis.

Punctate inner choroiditis and choroidal neovascular membrane formation following vitreoretinal surgery: A case report.

To report a case of punctate inner choroiditis (PIC) and subsequent choroidal neovascular membrane (CNVM) development in a young, high myope following vitreoretinal surgery for rhegmatogenous retinal detachment. A 44-year-old male with high myopia underwent pars plana vitrectomy for subtotal retinal detachment in the left eye, followed by cataract extraction and silicone oil removal. Three years postoperatively, he presented with blurred vision, and fundus examination revealed PIC lesions at the posterior pole. Spectral-domain optical coherence tomography (SD-OCT) showed characteristic features of PIC, including hyperreflective nodule-like elevations, disrupted ellipsoid and interdigitation zones, retinal pigment epithelium (RPE) elevations and increased choroidal hyper transmission signals. Initially, no treatment was initiated, and the patient was monitored. Three years later, the patient experienced further vision loss, and fundus examination showed progression of PIC lesions and new CNVM formation in the left eye. The patient was treated with systemic corticosteroids and an intravitreal anti-VEGF injection (Razumab® 0.5 mg/0.05 ml). Three weeks after the intervention, SD-OCT showed regression of the CNVM, and the patient's visual symptoms improved. This case underscores the importance of long-term follow-up and timely intervention in managing PIC, especially in high myopes post-retinal surgery. Early identification and treatment with systemic corticosteroids and anti-VEGF therapy are crucial to preserving visual function and preventing severe complications like CNVM.

Assessment of Different Castration Resistance Definitions and Staging Modalities in Metastatic Castration-Resistant Prostate Cancer.

Background/Objectives: Progression to metastatic castration-resistant prostate cancer (mCRPC) is defined either biochemically, radiographically or both. Moreover, staging for mCRPC can be performed either conventionally or with molecular imaging such as prostate-specific membrane antigen computer tomography (PSMA-PET/CT). Methods: We relied on the Frankfurt Metastatic Cancer Database of the Prostate (FRAMCAP) database to compare progression-free (PFS) and overall survival (OS) outcomes regarding the cause of castration resistance and the staging modality used. Results: Overall, 35% progressed to mCRPC biochemically vs. 23% radiographically vs. 42% biochemically + radiographically. The PSA nadir in mHSPC (1.4 vs. 0.4 vs. 0.8 ng/mL) and PSA level at mCRPC progression (15 vs. 2 vs. 21 ng/mL, both p ≤ 0.01) were significantly higher for biochemical vs. radiographic vs. both progressed patients. In PFS and OS analyses, no significant differences were observed among all three compared groups. In the comparison of the staging used for progression to mCRPC, 67% received conventional vs. 33% PSMA-PET/CT, with higher metastatic burden in mHSPC and osseous lesions in mCRPC for conventionally staged patients (both p < 0.01). In PFS (15.3 vs. 10.1 months, hazard ratio [HR]: 0.75) and OS analyses (52.6 vs. 34.3 months, HR: 0.61, both p < 0.05), PSMA-PET/CT harbored better prognosis; however, this did not hold after multivariable adjustment. Similar results were observed for further analyses in second- and third-line mCRPC or patients with a PSA level of ≥2 ng/mL. Conclusions: The cause of progression to mCRPC seems not to influence cancer-control outcomes, despite important baseline tumor characteristic differences. The PSMA-PET/CT staging modality might be associated with better PFS and OS outcomes, possibly due to its more sensitive detection of progression or new metastatic lesions.

Field Trial with Vaccine Candidates Against Bovine Tuberculosis Among Likely Infected Cattle in a Natural Transmission Setting.

Background/Objectives: Vaccines may improve the control and eradication of bovine tuberculosis. However, the evaluation of experimental candidates requires the assessment of the protection, excretion, transmission and biosafety. A natural transmission trial among likely infected animals was conducted. Methods: Seventy-four male heifers were randomly distributed (five groups) and vaccinated subcutaneously with attenuated strains (M. bovis Δmce2 or M. bovis Δmce2-phoP), a recombinant M. bovis BCG Pasteur (BCGr) or M. bovis BCG Pasteur. Then, they cohoused with a naturally infected bTB cohort under field conditions exposed to the infection. Results: A 23% of transmission of wild-type strains was confirmed (non-vaccinated group). Strikingly, first vaccination did not induce immune response (caudal fold test and IFN-gamma release assay). However, after 74 days of exposure to bTB, animals were re-vaccinated. Although their sensitization increased throughout the trial, the vaccines did not confer significant protection, when compared to the non-vaccinated group, as demonstrated by pathology progression of lesions and confirmatory tools. Besides, the likelihood of acquiring the infection was similar in all groups compared to the non-vaccinated group (p > 0.076). Respiratory and digestive excretion of viable vaccine candidates was undetectable. To note, the group vaccinated with M. bovis Δmce2-phoP exhibited the highest proportion of animals without macroscopic lesions, compared to the one vaccinated with BCG, although this was not statistically supported. Conclusions: This highlights that further evaluation of these vaccines would not guarantee better protection. The limitations detected during the trial are discussed regarding the transmission rate of M. bovis wild-type, the imperfect test for studying sensitization, the need for a DIVA diagnosis and management conditions of the trials performed under routine husbandry conditions. Re-vaccination of likely infected bovines did not highlight a conclusive result, even suggesting a detrimental effect on those vaccinated with M. bovis BCG.

Investigation on clinical risk factors of bladder lesion by machine learning based interpretable model

Bladder lesion commonly occurs in patients with benign prostatic hyperplasia (BPH), and the routine screening of bladder lesion is vital for its timely detection and treatment, in which the risk of bladder lesion progression can be effectively alleviated. However, current clinical methods are inconvenient for routine screening. In this study, we proposed a convenient routine screening method to diagnose bladder lesions based on several clinical risk factors, which can be obtained through non-invasive, easy-to-operate, and low-cost examinations. The contribution of each clinical risk factor was further quantitatively analyzed to understand their impact on diagnostic decision-making. Based on a cohort study of 253 BPH patients with or without bladder lesions, the proposed diagnostic model achieved high accuracy using these clinical risk factors. Bladder compliance, maximum flow rate (Qmax), prostate specific antigen (PSA), and postvoid residual (PVR) were identified as the four most important clinical risk factors. To the best of our knowledge, this is the innovative research to predict bladder lesions based on the risk factors and quantitatively reveal their contributions to diagnostic decision-making. The proposed model has the potential to serve as an effective routine screening tool for bladder lesions in BPH patients, enabling early intervention to prevent lesion progression and improve the quality of life.

Liraglutide Therapy in Obese Patients Alters Macrophage Phenotype and Decreases Their Tumor Necrosis Factor Alpha Release and Oxidative Stress Markers-A Pilot Study.

Introduction: Obesity is one of the major healthcare challenges. It affects one in eight people around the world and leads to several comorbidities, including type 2 diabetes, hyperlipidemia, and arterial hypertension. GLP-1 analogs have become major players in the therapy of obesity, leading to significant weight loss in patients. However, benefits resulting from their usage seem to be greater than simple appetite reduction and glucose-lowering potential. Recent data show better cardiovascular outcomes, which are connected with the improvements in the course of atherosclerosis. Macrophages are crucial cells in the forming and progression of atherosclerotic lesions. Previously, it was shown that in vitro treatment with GLP-1 analogs can affect macrophage phenotype, but there is a paucity of in vivo data. Objective: To evaluate the influence of in vivo treatment with liraglutide on basic phenotypic and functional markers of macrophages. Methods: Basic phenotypic features were assessed (including inducible nitric oxide synthase, arginase 1 and mannose receptors), proinflammatory cytokine (IL-1β, TNFα) release, and oxidative stress markers (reactive oxygen species, malondialdehyde) in macrophages obtained prior and after 3-month therapy with liraglutide in patients with obesity. Results: Three-month treatment with subcutaneous liraglutide resulted in the alteration of macrophage phenotype toward alternative activation (M2) with accompanying reduction in the TNFα release and diminished oxidative stress markers. Conclusions: Our results show that macrophages in patients treated with GLP-1 can alter their phenotype and function. Those findings may at least partly explain the pleiotropic beneficial cardiovascular effects seen in subjects treated with GLP-1 analogs.

HPV16 E6-induced M2 macrophage polarization in the cervical microenvironment via exosomal miR-204-5p

The persistent infection of high-risk human papillomavirus (HPV) and the progression of cervical cancer necessitate the involvement of microenvironmental immunity. As cervical lesions advance, there is an observed increase in the infiltration of type 2 (M2) macrophages. However, the precise mechanism driving this increased infiltration of M2 macrophages remains unclear. In this study, we investigated the role of exosomes in polarising M2 macrophages in cervical lesions associated with HPV E6. Through the analysis of bioinformatics data and clinical specimens, we discovered a positive correlation between HPV E6/E7 mRNA copy number and the level of M2 macrophage infiltration. Exosomes derived from HPV E6 overexpressed (HPV E6+) cervical squamous cell carcinoma (CESC) cells were found to induce the polarisation of macrophages towards M2 type. Specifically, miR-204-5p, enriched in HPV E6 + CESC exosomes, was transported into macrophages and triggered M2 macrophage polarisation by inhibiting JAK2. The clinical relevance of exosomal miR-204-5p in the progression of cervical lesions was validated through serum samples from 35 cases. Exosomal miR-204-5p emerges as a critical factor influencing M2 macrophage polarisation and is correlated with the severity of cervical lesions. Consequently, miR-204-5p could be used as a potential treatment and a candidate biomarker for cervical lesions.

Bovine tuberculosis in Central Ethiopian slaughterhouses and the identification of causative mycobacteria by multiplex real-time PCR

BackgroundBovine tuberculosis (bTB) is a chronic disease caused by members of the Mycobacterium tuberculosis complex (MTBC) that ultimately leads to the development of progressive granulomatous lesions. Although the disease is widespread, especially in crossbred cattle in Ethiopia, routine investigations and surveillance are lacking. Thus, the aim of this study was to determine the prevalence, associated risk factors, and species of mycobacteria causing bTB in slaughtered cattle at four slaughterhouses in Central Ethiopia.MethodsPostmortem examination of 7,640 cattle was conducted using a cross-sectional slaughterhouse survey. A total of 388 tuberculous-like lesions (TBLs) were collected from 173 animals and cultured. Six target genes were used to differentiate mycobacterial species using multiplex real-time PCR (mRT-PCR). Multivariate logistic regression analyses and related odds ratios (ORs) were used to gauge the strength of the associations between risk factors, TBL incidence and culture growth.ResultsThe prevalence of TBL was 2.3% (95% CI = 2.0-2.6). Logistic regression analysis indicated an increased risk of TBL in crossbred cattle (OR = 11.8, 95% CI: 6.4, 21.2, p < 0.001). Animals slaughtered at Adama (OR = 3.2, 95% CI: 1.2, 7.3, p = 0.009) or Burayu (OR = 5.8, 95% CI: 3.9, 8.9, p < 0.001) had a greater risk of TBL than those slaughtered at Sululta. There were significantly more TBL-positive lesions in the lungs and lymph nodes related to the lung (OR = 7.1; 95% CI: 2.7, 24.5, p < 0.001) and the head lymph node (OR = 5.6; 95% CI: 1.8, 21.7; p = 0.006) compared to gut associated lymph nodes. Among the 173 TBL-positive animals, 36% (95% CI = 28.8, 43.2), and among the 388 TBL-positive tissues, 24.2% (95% CI = 20, 29) were culture and mRT-PCR positive. All the culture-generated isolates were positive for M. bovis in mRT-PCR. Among them, two animals had mixed infections including one zebu cattle tested positive for both M. caprae and M. bovis, and a crossbred cow tested positive for both M. tuberculosis and M. bovis in mRT-PCR. This suggests persistent transmission within the cattle population, posing a substantial public health threat.ConclusionThis study revealed an eleven-fold greater risk of bTB-related lesions in crossbred cattle compared to local zebu cattle. This finding highlights the necessity for targeted interventions, continuous vigilance, and thorough carcass inspection to mitigate public health risks.

Diagnostic imaging findings in lame Warmblood horses with bone injuries of the medial proximal phalanx glenoid cavity.

This retrospective study aims to describe baseline and follow-up imaging findings in subchondral and trabecular bone damage occurring outside of the sagittal groove in the proximal phalanx (P1) glenoid in a case series of lame Warmblood horses. Thirteen lame horses (16 forelimbs) with standing magnetic resonance imaging (sMRI) evidence of nonsagittal groove glenoid subchondral and trabecular bone injury of P1 as the main lesion were included. All injuries were located at the medial aspect of the P1 glenoid. At sMRI, changes included subchondral bone plate thickening and trabecular sclerosis, bone marrow edema-like signal, subchondral bone resorption (11/16), and new bone production (8/16). Subchondral bone resorption in the transverse plane was linear (8/11), round (2/11), or ill-defined (1/11). Sclerosis, bone resorption, and new bone production were seen radiographically in 10, 4, and 5 limbs, respectively. All limbs had concurrent metacarpal condyle sMRI imaging abnormalities, osteophytosis, and joint effusion. Follow-up sMRIs were obtained in 8 of 16 limbs, five of which showing progression of the resorptive lesion. One horse encountered a comminuted fracture of the affected P1 18 months after the follow-up sMRI examination. The imaging appearance of the medial glenoid bone injuries of P1 in this case series is consistent with chronic bone overload. The linear configuration of bone resorption seen in eight lesions suggests short, incomplete stress fractures, which is supported by the ultimate catastrophic fracture occurring in one case.

Dynamics of CD4+ and CD8+ Lymphocytic Inflammatory Infiltrates in Lupus Nephritis.

Lupus nephritis (LN) is a common clinical manifestation of systemic lupus erythematosus (SLE). Our study aims to quantitatively analyze CD4+ and CD8+ lymphocytes in different areas and LN classes and describe a specific distribution pattern that is correlated with the severity of LN-specific lesions. In total, 53 LN renal biopsies were immunohistochemically investigated using anti-CD4 and anti-CD8 antibodies. T lymphocytes were counted in 3 areas, including intraglomerular, periglomerular, and interstitial regions. The severity of glomerular and tubulo-interstitial lesions was assessed using an original semi-quantitative algorithm based on the renal corpuscle score (RC_S) and the tubulo-interstitial score (TI_S). The number of CD8+ T lymphocytes was higher than that of CD4+ T lymphocytes in each of the three areas and in each LN class, showing statistically significant differences. ANOVA analysis of all LN classes showed significant differences between periglomerular and interstitial CD4+ and CD8+ T lymphocytes, respectively. Irrespective of location, the number of CD8+ T lymphocytes statistically correlates with the RC_S and the TI_S; no significant correlations were found between the number of CD4+ T lymphocytes and the RC_S and the TI_S for all three considered areas. Our data provide strong evidence supporting the major role of CD8+ lymphocytes in LN lesion progression, with CD4+ lymphocytes playing a limited role.

12325 Adrenocortical Carcinoma Masquerading As Pheochromocytoma In A Patient With Congenital Adrenal Hyperplasia

Abstract Disclosure: E.M. Niedzialkowska: None. A.A. Banka: None. Introduction: The development of adrenocortical carcinoma (ACC) in patients with congenital adrenal hyperplasia (CAH) is rare. The patients with CAH are at increased risk of adrenal tumors which is attributed to ACTH stimulation of adrenal gland if the disease is not appropriately treated. ACC cases mistaken for pheochromocytomas have been reported in the literature and are attributed to the variety of immunohistochemical markers expressed by the tumors. Case description:59 y.o female with salt-wasting CAH diagnosed at the age of 2 (21-hydroxylase deficiency) on hydrocortisone supplementation reported to the hospital due to episodes of sweating, tachycardia and hypertension. Work up revealed mildly elevated plasma normetanephrine 1 nmol/l (N &amp;lt;0.9), urine normetanephrine 1762 mcg (N&amp;lt;899), VMA 11.2 mcg/24hr (N 3.3-7.2). MRI of the abdomen revealed 2 left adrenal masses of 3.7 and 2.4 cm, right adrenal gland hyperplasia and low T1 and T2 enhancement. I-123 MIBG revealed increased activity and thickness of the right adrenal gland and no significant uptake on the left with nodular masses. The patient underwent left adrenalectomy with pathological report consistent with pheochromocytoma due to positive chromogranin and synaptophysin staining and moderate Ki activity. A year later follow up imaging showed an enhancing mass up to 7 cm at the suprarenal fossa invading the left kidney that was positive for nodular adrenocortical hyperplasia per pathology report. The patient continued to have elevated 17-OH- progesterone (2740 ng/l, N &amp;lt;51) despite compliance with her steroid therapy and suppressed ACTH. She underwent mass resection along with nephrectomy, splenectomy, partial colectomy and partial pancreatectomy. Pathology report was positive for adrenocortical carcinoma (positive chromogranin, synaptophysin, CAM 5.2, polycystic cytokeratin, Ki positive in greater than 10% of the tumor cells) with renal and regional lymph node invasion and colonic metastases. The patient was started on mitotane therapy but a year later PET scan was positive for liver and omental metastases and was subsequently started on carboplatin/etoposide followed by streptozocin/adriamycin with initial good response, however repeat PET a year afterwards showed progression of the liver lesions, metastases to omentum and metastatic lesion to calvarium and the patient expired soon afterwards. Discussion: CAH predisposes patients to adrenal tumors which is attributed to increased ACTH stimulation of the adrenal gland but ACC in this population is extremely rare. In very rare cases ACC can present clinically as pheochromocytoma with elevated catecholamine levels and positive synaptophysin and chromogranin staining which poses a clinical challenge. Both CAH and ACC can lead to increased androgen levels and ACTH levels can help to differentiate the origin of the hyperandrogenemia. Presentation: 6/2/2024

12214 Metastatic Functional Thyroid Carcinoma As An Unusual Cause Of Hyperthyroidism

Abstract Disclosure: S. Jimenez Salazar: None. N. Aristizabal Henao: None. C. Aguilar Londoño: None. N. Buitrago Gómez: None. S. Saldarriaga Betancur: None. D.L. Beltran: None. J.L. Torres: None. Background: Differentiated thyroid carcinoma (DTC) represents the most prevalent endocrine neoplasm. Less than 10% present distant metastases, with the lung (50%), and skeleton (25%) being the most frequently affected sites. The location of bone metastases predominates in the spine and pelvis; usually as osteolytic lesions, being more frequent in follicular thyroid cancer (FTC) (7-28%) than in patients with papillary thyroid cancer (PTC) (1.4-7%). In rare cases this metastasis can be functional and trigger a thyrotoxicosis syndrome with or without recombinant human TSH injections prior to therapy with 131-I. Clinical case: 59-year-old woman with a history of bone metastatic follicular thyroid cancer (FTC) presented with 1 month of palpitations, 4 kg weight loss, non-dysenteric diarrhea and progressive dyspnea. Her FTC had been diagnosed 8 years prior her consultation. In that time iodine refractoriness was considered due to the progression of bone lesions, and Sorafenib 800 mg per day was initiated, which was not tolerated due to severe dermatological manifestations, and the patient decided not to continue with TKI therapy. Since then, she has been treated with zoledronic acid and local radiotherapy as part of palliative care. On physical examination, she was tachycardic (150 bpm), and hypertensive (BP 160/100 mmHg). A suppressed TSH (&amp;lt;0.01 uUI/mL, n: 0.4-4 uUI/mL) with elevation of thyroid hormones (free T4 3.99 ng/dL, n: 0.8-2 ng/dL and total T3 480 ng/dL, n: 45-140 ng/dL) was documented, associated with a patient who had required a dose adjustment of levothyroxine from 700 mcg to 350 mcg weekly 2 months prior to admission. Additionally, she had a significantly elevated thyroglobulin (&amp;gt;5000 ng/mL, n: 0.1-64.1 ng/mL) with undetectable antithyroglobulin antibodies (1.09 UI/mL, n: 0-4.11 UI/mL). Considering the history of total thyroidectomy and the high tumor burden, secondary thyrotoxicosis due to functioning bone metastases of DTC was considered. Levothyroxine was discontinued, and propranolol was initiated for the control of adrenergic symptoms, along with methimazole, cholestyramine, and systemic steroids to control thyroid hormone production. 3 days after therapy adjustment dyspnea, palpitations, and thyroid function tests improved significantly (free T4 1.43 ng/dL, n: 0.8-2 ng/dL and total T3 178 ng/dL, n: 45-140 ng/dL). A new administration of therapy with 131-I 200 mCi was indicated. Antithyroid therapy and beta-blockers were continued with sustained biochemical control. Conclusion: Functional bone metastases of FTC can lead to high morbidity and mortality. Treatment consists of surgical cytoreduction of any large accessible metastatic lesion, therapy with 131-I, and high-dose antithyroid drugs to control hyperthyroidism. It is important to avoid the use of recombinant human TSH due to the risk of secondary thyrotoxicosis following its administration. Presentation: 6/2/2024

12459 Exceptional Response To A Single Dose Of Pembrolizumab As Salvage Therapy In A Patient With Metastatic Adrenocortical Carcinoma (ACC)

Abstract Disclosure: L. Branchaud-Croisetière: None. J. Castilloux: None. E. Turcotte: None. A. Bégin: None. M. St-Jean: Advisory Board Member; Self; GlaxoSmithKline, HRA Pharmaceuticals. Research Investigator; Self; AstraZeneca, Novo Nordisk, Spruce Biosciences. Speaker; Self; GlaxoSmithKline, Recordati Rare Diseases. In advanced ACC, limited effective treatment options are available beyond mitotane and cytotoxic chemotherapy. PD-L1 blockade has shown promising results in small numbers of advanced ACC. In ACC, the reported partial response rate to pembrolizumab is around 25%.[1] Only one case of a significant partial response to a single dose of Pembrolizumab as salvage therapy for metastatic ACC was previously published.[1] In April 2023, a 19-year-old woman presented with severe hypertension, hypokalemia and clinical signs of Cushing syndrome (CS). Thoraco-abdominal scan revealed a left-sided cluster of confluent adrenal masses (7.3 x 14.4 x 11.4 cm), a left cortical renal lesion (2.8x2x2.1cm), a right ovarian teratoma (7.9 x 7.8x7.9 cm) and at least 25 pulmonary micronodules. FDG-PET SCAN revealed a significant hypermetabolism of the left adrenal lesions (SUV 18.6), ovarian teratoma (SUV 5.5) and pulmonary micronodules (SUV 1.1-2). Cortisol and androgens secretion was confirmed biochemically. Initially, she was not candidate for a debulking surgery because the tumor was surrounding the aorta, and mesenteric arteries. Hypertension and hypokalemia were treated with spironolactone, amlodipine, amiloride and irbesartan. Cushing syndrome was treated with metyrapone. In April 2023, Etoposide-Doxorubicine-Cisplatin (EDP) was administered in combination with Mitotane (max: 8g/day). After 6 cycles of EDP-M the disease regressed slightly but was considered stable based on RECIST criteria. After 8 cycles, the follow-up imaging showed a progression of the adrenal lesion (9.2x18.2cm) but stable pulmonary micronodules. A biopsy of the adrenal lesion, for therapeutic purpose, revealed microsatellite stability (MSS). The patient refused germinal genetic testing. It was decided in multidisciplinary tumor board to try Pembrolizumab. In December 2023, she received one cycle of Pembrolizumab (140mg), but the treatment was complicated by grade 4 immune-mediated hepatitis. A few weeks following Pembrolizumab she completely normalized her blood pressure and hypokalemia despite cessation of all her anti-hypertensive drugs. Pembrolizumab and Mitotane were stopped and hepatitis completely resolved after two months of Mycophenolate Mofetil and ongoing decreasing dose of prednisone. In March 2024, CT scan showed a 60% regression of the adrenal mass (4.1 x 7.2 cm), stability of the renal lesion and ovarian teratoma and complete resolution of the pulmonary micronodules. We suspect an ongoing effect of immunotherapy and Mitotane, since Mitotane levels were still in the therapeutic range (15.1 mg/L) six weeks following cessation. Mitotane was resumed in March 2024. The patient will potentially have a resection of the left adrenal lesion in the next month. This is second published case of a significant response to Pembrolizumab as second-line therapy for advanced ACC. [1] Raj Net al. J Clin Oncol. 2020 Presentation: 6/1/2024

Integrating generative AI with ABCDE rule analysis for enhanced skin cancer diagnosis, dermatologist training and patient education.

The early detection and accurate monitoring of suspicious skin lesions are critical for effective dermatological diagnosis and treatment, particularly for reliable identification of the progression of nevi to melanoma. The traditional diagnostic framework, the ABCDE rule, provides a foundation for evaluating lesion characteristics by visual examination using dermoscopes. Simulations of skin lesion progression could improve the understanding of melanoma growth patterns. This study aims to enhance lesion analysis and understanding of lesion progression by providing a simulated potential progression of nevi into melanomas. The study generates a dataset of simulated lesion progressions, from nevi to simulated melanoma, based on a Cycle-Consistent Adversarial Network (Cycle-GAN) and frame interpolation. We apply an optical flow analysis to the generated dermoscopic image sequences, enabling the quantification of lesion transformation. In parallel, we evaluate changes in ABCDE rule metrics as example to assess the simulated evolution. We present the first simulation of nevi progressing into simulated melanoma counterparts, consisting of 152 detailed steps. The ABCDE rule metrics correlate with the simulation in a natural manner. For the seven samples studied, the asymmetry metric increased by an average of 19%, the border gradient metric increased by an average of 63%, the convexity metric decreased by an average of 3%, the diameter increased by an average of 2%, and the color dispersion metric increased by an average of 45%. The diagnostic value of the ABCDE rule is enhanced through the addition of insights based on optical flow. The outward expansion of lesions, as captured by optical flow vectors, correlates strongly with the expected increase in diameter, confirming the simulation's fidelity to known lesion growth patterns. The heatmap visualizations further illustrate the degree of change within lesions, offering an intuitive visual proxy for lesion evolution. The achieved simulations of potential lesion progressions could facilitate improved early detection and understanding of how lesions evolve. By combining the optical flow analysis with the established criteria of the ABCDE rule, this study presents a significant advancement in dermatoscopic diagnostics and patient education. Future research will focus on applying this integrated approach to real patient data, with the aim of enhancing the understanding of lesion progression and the personalization of dermatological care.