Synovial effusion and synovial fluid biomarkers in psoriatic arthritis to assess intraarticular tumor necrosis factor-α blockade in the knee joint

Introduction: Evaluation of synovial effusion (SE), synovial fluid (SF) and synovial tissue (ST) biomarkers in relation to disease activity indexes to assess the response to intraarticular (IA) tumor necrosis factor (TNF)-\u3b1 blockers in psoriatic arthritis (PsA). Methods: Systemic and local disease activity indexes (disease activity score [DAS]; the Ritchie articular index [mRAI], erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP); Thompson articular [THOMP] and joint articular [KJAI]-Index ) and ST samples were assessed at baseline, throughout treatment, and during the follow-up in 14 patients affected with PsA who underwent IA injections (0.5 ml - 12.5 mg) in the knee joint of etanercept (E) or placebo (P) once every two weeks for a ten week period. Total SF white blood cell (WBC) counts (WBC/ \u3bcl) and SF cytokine/chemokine (CK/CCK) levels were measured before IA-E at baseline, after IA-E, and as long as there were adequate amounts of SF for knee aspiration (post). Characterization of synovial mononuclear cell infiltration and synovial vessels was carried out in 8/14 knees by staining serial sections of synovial tissue biopsies for CD45, CD3, CD68, CD31 and CD105. Results: At baseline, CRP and/or ESR were significantly correlated with SF-CK (IL-1\u3b2, IL-1Ra, IL-6, IL-8) and CCK (CCL2, CCL3 and CCL4). Post-IA injections, there was a decrease in SE in the knees in which aspiration following IA-E injection was possible as well as a significant reduction in SF WBC/\u3bcl and in SF-CK (TNF-\u3b1, IL- 1\u3b2, IL-1Ra, IL-6 and IL-22). Pre- and post- IAE injections, there were significant correlations between ST markers and SF-CK (IL-1\u3b2 with CD45; IL-1\u3b2 and IL-6 with CD31) and between SF-CCK (CCL4 and CCL3 with CD3). At the end of the study, there was a significant reduction in disease activity indexes (CRP, DAS, RAI, THOMP, KJAI) as well as in the ST markers (CD45; CD3)

Domino Effect: mechanic factors role

The rapid onset of the Domino Effect following the first Vertebral Compression Fracture is a direct consequence of the mechanical variations that affect the spine when physiological curves are modified. The degree of kyphosis influences the intensity of the Flexor Moment; this is greater on vertebrae D7, D8 and on vertebrae D12, L1 when the spine flexes. Fractures of D7, D8, D12 and L1 are, by far, the most frequent and also the main cause of the mechanical alterations that can trigger the Domino Effect. For these considerations vertebrae D7, D8, D12 and L1 have to be taken in consideration as “critical". In the case of critical clinical vertebral fractures it is useful to provide an indication for minimally invasive surgical reduction or intrasomatic stabilization. When occurs a fracture of a “critical vertebra”, prompt restoration of the heights leads to a reduction in the Kyphosis Index and therefore in the Flexor Moment, not only of the fractured vertebra but also, in turn, of all the other metameres which, even if morphologically still intact, are structurally fragile; so, through the restoration of the mechanical vertebral proprieties, we can reduce the risk of the Domino Effect. At the same time the prompt implementation of osteoinductive therapy is indispensable in order to achieve rapid and intense reconstruction of the trabecular bone, the strength of which increases significantly in a short period of time. Clinical studies are necessary to confirm the reduction of the domino effect following a fragility fracture of "critical vertebrae" with the restoration of the mechanical properties together with anabolic therapy

An asbestos-exposed family with multiple cases of pleural malignant mesothelioma without inheritance of a predisposing BAP1 mutation

We report a family with domestic exposure to asbestos and diagnosis of multiple cancers, including eight pleural malignant mesotheliomas and several other lung or pleural tumors. DNA sequence analysis revealed no evidence for an inherited mutation of BAP1. Sequence analysis of other potentially relevant genes, including TP53, CDKN2A, and BARD1, also revealed no mutation. DNA microarray analysis of tissue from two mesotheliomas revealed multiple genomic imbalances, including consistent losses of overlapping segments in 2q, 6q, 9p, 14q, 15q, and 22q, but no losses of chromosome 3 harboring the BAP1 locus. However, the results of immunohistochemical analysis demonstrated loss of nuclear BAP1 staining in three of six mesotheliomas tested, suggesting that somatic alterations of BAP1 occurred in a subset of tumors from this family. Since mesothelioma could be confirmed in only a single generation, domestic exposure to asbestos may be the predominant cause of mesothelioma in this family. Given the existence of unspecified malignant pleural tumors and lung cancers in a prior generation, we discuss the possibility that some other tumor susceptibility or modifier gene(s) may contribute to the high incidence of mesothelioma in this family. Because the incidence of mesothelioma in this family is higher than that expected even in workers heavily exposed to asbestos, we conclude that both asbestos exposure and genetic factors have played a role in the high rate of mesothelioma and potentially other pleural or lung cancers seen in this family.

Mesothelioma families without inheritance of a BAP1 predisposing mutation

Familial malignant mesothelioma clusters are ideal candidates to explore BAP1 genomic status as a predisposing risk factor. We report data on BAP1 analysis in four families with multiple mesothelioma cases to investigate possible BAP1 alterations associated with an inherited cancer syndrome. We also recorded family history of cancer and assessed asbestos exposure. By genomic direct sequencing, we found no evidence of a BAP1 germline mutation in tumor DNA samples (one mesothelioma per family: n = 3 epithelioid; n = 1 biphasic). On the other hand, we identified a novel BAP1 somatic alteration (c.329_335delinsTC) in exon 5 (n = 1 biphasic), and we hypothesized the occurrence of somatic inactivating events not identifiable by sequencing in the other cases (n = 3 epithelioid), as demonstrated by the loss of nuclear BAP1 immunostaining. History of other cancers was in sites not typical of the BAP1 cancer syndrome. Asbestos exposure was occupational (n = 2 clusters), household (n = 1), and unknown (n = 1). These family units without inheritance of a BAP1 predisposing mutation expand the number of unmutated germline BAP1 families with multiple mesothelioma cases. This suggests that besides the exposure to asbestos other currently unknown genetic or epigenetic factors may be responsible for the high incidence of mesothelioma in BAP1-unmutated families

Blockade of intra-articular TNF in peripheral spondyloarthritis: Its relevance to clinical scores, quantitative imaging and synovial fluid and synovial tissue biomarkers

OBJECTIVES: This open-label study is based on a translational approach with the aim of detecting changes in the clinical condition as well as in imaging and synovial biological markers in both synovial fluid (SF) and synovial tissue (ST) in peripheral spondyloarthritis (SpA) patients following intra-articular (IA) blockade of TNF-α by serial etanercept injections. METHODS: Twenty-seven SpA patients with resistant knee synovitis underwent four biweekly IA injections of etanercept (E) (12.5mg). The primary outcome of Thompson's Knee Index (THOMP), and secondary outcomes of Knee Joint Articular Index (KJAI), C-reactive protein (CRP), HAQ-Disability Index (HAQ-DI), maximal synovial thickness (MST) according to ultrasonography (US) and contrast-enhanced magnetic resonance (C+MR) imaging, ST-CD45+ mononuclear cells (MNC) and ST-CD31+ vessels, IL-1β, IL-1Ra and IL-6 levels in SF were assessed at baseline and at the end of the study. RESULTS: At the study end, clinical and imaging outcomes as well as ST and SF biological markers were significantly reduced compared to baseline. There were significant correlations between clinical, imaging and biological markers (CRP with either THOMP, or KJAI, or HAQ-DI or SF-IL-1Ra; US-MST with KJAI, ST-CD45+ with either THOMP, or KJAI, or ST-CD31+, or SF-IL-1β; SF-IL-6 with either THOMP, or KJAI, or SF-IL-1β, or IL-1Ra). CONCLUSIONS: The proof of concept study revealed early improvement either in local and systemic clinical scores, in synovial thickness measures by C+MR and US, or expression of synovial biological markers. CD45+, CD31+ in ST and IL-6 and IL-1β in SF may be considered potential biomarkers of the peripheral SpA response to IA TNF-α blocking

Synovial biomarkers in psoriatic arthritis

To find candidate biomarkers of psoriatic arthritis (PsA). A panel of synovial fluid (SF) and synovial tissue (ST) biomarkers was analyzed in patients with resistant peripheral PsA, in relation to clinical and imaging outcomes of synovitis response following serial intraarticular (IA) etanercept injections (12.5 mg)

Vascular perfusion kinetics by contrast-enhanced ultrasound are related to synovial microvascularity in the joints of psoriatic arthritis.

The purpose of the study was to assess the relationship of the continuous mode contrast-enhanced harmonic ultrasound (CEUS) imaging with the histopathological and immunohistochemical (IHC) quantitative estimation of microvascular proliferation on synovial samples of patients affected by sustained psoriatic arthritis (PsA). A dedicated linear transducer was used in conjunction with a specific continuous mode contrast enhanced harmonic imaging technology with a second-generation sulfur hexafluoride-filled microbubbles C-agent. The examination was carried out within 1 week before arthroscopic biopsies in 32 active joints. Perfusional parameters were analyzed including regional blood flow (RBF); peak (PEAK) of the C-signal intensity, proportional to the regional blood volume (RBV); beta (\u3b2) perfusion frequency; slope (S), representing the inclination of the tangent in the origin; and the refilling time (RT), the reverse of beta. Arthroscopic synovial biopsies were targeted in the hypervascularity areas, as in the same knee recesses assessed by CEUS; the synovial cell infiltrate and vascularity (vessel density) was evaluated by IHC staining of CD45 (mononuclear cell) and CD31, CD105 (endothelial cell) markers, measured by computer-assisted morphometric analysis. In the CEUS area examined, the corresponding time-intensity curves demonstrated a slow rise time. Synovial histology showed slight increased layer lining thickness, perivascular lymphomonocyte cell infiltration, and microvascular remodeling, with marked vessel wall thickening with reduction of the vascular lumen. A significant correlation was found between RT and CD31+ as PEAK and CD105+ vessel density; RT was inversely correlated to RBF, PEAK, S, and \u3b2. The study demonstrated the association of the CEUS perfusion kinetics with the histopathological quantitative and morphologic estimation of synovial microvascular proliferation, suggesting that a CEUS imaging represents a reliable tool for the estimate of the synovial hypervascularity in PsA

Comparing accuracy of tomosynthesis plus digital mammography or synthetic 2D mammography in breast cancer screening: baseline results of the MAITA RCT consortium

Aim: The analyses here reported aim to compare the screening performance of digital tomosynthesis (DBT) versus mammography (DM). Methods: MAITA is a consortium of four Italian trials, REtomo, Proteus, Impeto, and MAITA trial. The trials adopted a two-arm randomised design comparing DBT plus DM (REtomo and Proteus) or synthetic-2D (Impeto and MAITA trial) versus DM; multiple vendors were included. Women aged 45 to 69 years were individually randomised to one round of DBT or DM. Findings: From March 2014 to February 2022, 50,856 and 63,295 women were randomised to the DBT and DM arm, respectively. In the DBT arm, 6656 women were screened with DBT plus synthetic-2D. Recall was higher in the DBT arm (5·84% versus 4·96%), with differences between centres. With DBT, 0·8/1000 (95% CI 0·3 to 1·3) more women received surgical treatment for a benign lesion. The detection rate was 51% higher with DBT, ie. 2·6/1000 (95% CI 1·7 to 3·6) more cancers detected, with a similar relative increase for invasive cancers and ductal carcinoma in situ. The results were similar below and over the age of 50, at first and subsequent rounds, and with DBT plus DM and DBT plus synthetic-2D. No learning curve was appreciable. Detection of cancers >= 20 mm, with 2 or more positive lymph nodes, grade III, HER2-positive, or triple-negative was similar in the two arms. Interpretation: Results from MAITA confirm that DBT is superior to DM for the detection of cancers, with a possible increase in recall rate. DBT performance in screening should be assessed locally while waiting for long-term follow-up results on the impact of advanced cancer incidence