Insulin Resistance in Macrophages Alters Their Metabolism and Promotes an M2-Like Phenotype.

Obesity and insulin resistance influences metabolic processes, but whether it affects macrophage metabolism is not known. In this study, we demonstrate that chronic exposure of macrophages to insulin either in culture or in vivo in diet-induced, glucose-intolerant mice rendered them resistant to insulin signals marked by failure to induce Akt2 phosphorylation. Similarly, macrophages lacking Akt2 or IGF1 receptor were also resistant to insulin signals. Insulin-resistant macrophages had increased basal mTORC1 activity, possessed an M2-like phenotype, and reduced LPS responses. Moreover, they exhibited increased glycolysis and increased expression of key glycolytic enzymes. Inhibition of mTORC1 reversed the M2-like phenotype and suppressed glycolysis in insulin-resistant macrophages. In the context of polymicrobial sepsis, mice harboring insulin-resistant macrophages exhibited reduced sepsis-induced lung injury. Thus, macrophages obtain resistance to insulin characterized by increased glycolysis and a unique M2-like phenotype, termed M-insulin resistant, which accounts for obesity-related changes in macrophage responses and a state of trained immunity.

Hybrid autofluorescence and photoacoustic label-free microscopy for the investigation and identification of malignancies in ocular biopsies.

We demonstrate the development and application of a prototype hybrid microscopy system integrating autofluorescence (AF) and photoacoustic (PA) label-free contrast modes, for the differentiation of ocular tumors in human surgical biopsies. Hybrid imaging was performed in conjunctival nevi and uveal melanomas tissue sections to acquire quantified data for each molecular background. The AF and PA signals were spatially correlated to establish a novel malignancy indicator that could detect melanomas with high accuracy (t-test; p<0.01). The proposed methodology has the potential to simplify relevant diagnostic procedures and paves the way for the development of novel ophthalmoscopes aiming to the early diagnosis of ocular malignancies in a clinical setting.

The prognostic value of JUNB-positive CTCs in metastatic breast cancer: from bioinformatics to phenotypic characterization.

BACKGROUND: Circulating tumor cells (CTCs) are important for metastatic dissemination of cancer. They can provide useful information, regarding biological features and tumor heterogeneity; however, their detection and characterization are difficult due to their limited number in the bloodstream and their mesenchymal characteristics. Therefore, new biomarkers are needed to address these questions. METHODS: Bioinformatics functional enrichment analysis revealed a subgroup of 24 genes, potentially overexpressed in CTCs. Among these genes, the chemokine receptor CXCR4 plays a central role. After prioritization according to the CXCR4 corresponding pathways, five molecules (JUNB, YWHAB, TYROBP, NFYA, and PRDX1) were selected for further analysis in biological samples. The SKBR3, MDA-MB231, and MCF7 cell lines, as well as PBMCs from normal (n = 10) blood donors, were used as controls to define the expression pattern of all the examined molecules. Consequently, 100 previously untreated metastatic breast cancer (mBC) patients (n = 100) were analyzed using the following combinations of antibodies: CK (cytokeratin)/CXCR4/JUNB, CK/NFYA/ΥWHΑΒ (14-3-3), and CK/TYROBP/PRDX1. A threshold value for every molecule was considered the mean expression in normal PBMCs. RESULTS: Quantification of CXCR4 revealed overexpression of the receptor in SKBR3 and in CTCs, following the subsequent scale (SKBR3>CTCs>Hela>MCF7>MDA-MB231). JUNB was also overexpressed in CTCs (SKBR3>CTCs>MCF7>MDA-MB231>Hela). According to the defined threshold for each molecule, CXCR4-positive CTCs were identified in 90% of the patients with detectable tumor cells in their blood. In addition, 65%, 75%, 14.3%, and 12.5% of the patients harbored JUNB-, TYROBP-, NFYA-, and PRDX-positive CTCs, respectively. Conversely, none of the patients revealed YWHAB-positive CTCs. Interestingly, JUNB expression in CTCs was phenotypically and statistically enhanced compared to patients' blood cells (p = 0.002) providing a possible new biomarker for CTCs. Furthermore, the detection of JUNB-positive CTCs in patients was associated with poorer PFS (p = 0.015) and OS (p = 0.002). Moreover, JUNB staining of 11 primary and 4 metastatic tumors from the same cohort of patients revealed a dramatic increase of JUNB expression in metastasis. CONCLUSIONS: CXCR4, JUNB, and TYROBP were overexpressed in CTCs, but only the expression of JUNB was associated with poor prognosis, providing a new biomarker and a potential therapeutic target for the elimination of CTCs.

Upregulation of citrullination pathway: From Autoimmune to Idiopathic Lung Fibrosis.

BACKGROUND: Increased protein citrullination and peptidylarginine deiminases (PADIs), which catalyze the citrullination process, are central in Rheumatoid arthritis pathogenesis and probably involved in the initial steps towards autoimmunity. Approximately, 10% of RA patients develop clinically significantly ILD. A possible shared role of protein citrullination in rheumatoid arthritis associated interstitial lung disease (RA-ILD), and idiopathic pulmonary fibrosis (IPF) pathogenesis remains unclear. METHODS: We evaluated PADI2 and PADI4 mRNA expression in bronchoalveolar lavage fluid (BALF) cells of 59 patients with IPF, 27 patients RA-ILD and 10 healthy controls. PADI 2 and 4 expression was analyzed by western blot and immunohistochemistry. Citrullinated protein levels were also quantified. RESULTS: PADI4 mRNA and protein levels were higher in RA-ILD and IPF than controls. Furthermore, PADI4 mRNA levels showed an increase among smokers in RA-ILD. PADI4 expression was detected in granulocytes and macrophages in all groups, with the strongest cytoplasmic expression observed in granulocytes in RA-ILD and IPF. PADI2 mRNA and immunostaining of BAL cells, were similar in all groups among smokers. Overall, stronger staining was observed in current smokers. Citrullinated peptides were significantly increased in IPF compared to RA-ILD and controls. In RA-ILD, protein citrullination strongly correlated with PADI4 expression and anti-citrullinated protein antibodies (ACPAs). CONCLUSIONS: These results suggest that the citrullination pathway is upregulated in IPF and in RA-ILD.

Akt2 deficiency protects from acute lung injury via alternative macrophage activation and miR-146a induction in mice.

Acute respiratory distress syndrome (ARDS) is a major cause of respiratory failure, with limited effective treatments available. Alveolar macrophages participate in the pathogenesis of ARDS. To investigate the role of macrophage activation in aseptic lung injury and identify molecular mediators with therapeutic potential, lung injury was induced in wild-type (WT) and Akt2(-/-) mice by hydrochloric acid aspiration. Acid-induced lung injury in WT mice was characterized by decreased lung compliance and increased protein and cytokine concentration in bronchoalveolar lavage fluid. Alveolar macrophages acquired a classical activation (M1) phenotype. Acid-induced lung injury was less severe in Akt2(-/-) mice compared with WT mice. Alveolar macrophages from acid-injured Akt2(-/-) mice demonstrated the alternative activation phenotype (M2). Although M2 polarization suppressed aseptic lung injury, it resulted in increased lung bacterial load when Akt2(-/-) mice were infected with Pseudomonas aeruginosa. miR-146a, an anti-inflammatory microRNA targeting TLR4 signaling, was induced during the late phase of lung injury in WT mice, whereas it was increased early in Akt2(-/-) mice. Indeed, miR-146a overexpression in WT macrophages suppressed LPS-induced inducible NO synthase (iNOS) and promoted M2 polarization, whereas miR-146a inhibition in Akt2(-/-) macrophages restored iNOS expression. Furthermore, miR-146a delivery or Akt2 silencing in WT mice exposed to acid resulted in suppression of iNOS in alveolar macrophages. In conclusion, Akt2 suppression and miR-146a induction promote the M2 macrophage phenotype, resulting in amelioration of acid-induced lung injury. In vivo modulation of macrophage phenotype through Akt2 or miR-146a could provide a potential therapeutic approach for aseptic ARDS; however, it may be deleterious in septic ARDS because of impaired bacterial clearance.

Akt1 and Akt2 protein kinases differentially contribute to macrophage polarization.

Activated macrophages are described as classically activated or M1 type and alternatively activated or M2 type, depending on their response to proinflammatory stimuli and the expression of genetic markers including iNOS, arginase1, Ym1, and Fizz1. Here we report that Akt kinases differentially contribute to macrophage polarization, with Akt1 ablation giving rise to an M1 and Akt2 ablation resulting in an M2 phenotype. Accordingly, Akt2(-/-) mice were more resistant to LPS-induced endotoxin shock and to dextran sulfate sodium (DSS)-induced colitis than wild-type mice, whereas Akt1(-/-) mice were more sensitive. Cell depletion and reconstitution experiments in a DSS-induced colitis model confirmed that the effect was macrophage-dependent. Gene-silencing studies showed that the M2 phenotype of Akt2(-/-) macrophages was cell autonomous. The microRNA miR-155, whose expression was repressed in naive and in LPS-stimulated Akt2(-/-) macrophages, and its target C/EBPß appear to play a key role in this process. C/EBPß, a hallmark of M2 macrophages that regulates Arg1, was up-regulated upon Akt2 ablation or silencing. Overexpression or silencing of miR-155 confirmed its central role in Akt isoform-dependent M1/M2 polarization of macrophages.

Detection and genotype analysis of human papillomavirus in non-small cell lung cancer patients.

Although the role of human papillomavirus (HPV) in the development of uterine cervical cancer is well established, the role of HPV in lung carcinogenesis remains controversial. The detection rates of HPV DNA are subject to a wide variation from 0 to 100%. This is partly influenced by the detection techniques employed. To elucidate the impact of HPV infection on lung parenchyma, we analyzed 100 non-small cell lung cancer (NSCLC) specimens (39 squamous cell carcinomas, 50 adenocarcinomas, 5 samples with characteristics of both squamous cell and adenocarcinoma, 5 undifferentiated and 1 large cell carcinoma) from the region of Crete, Greece. Sixteen non-cancerous samples served as the negative controls. DNA was extracted from 100 paraffin-embedded tissue sections obtained from NSCLC patients. The specimens were examined for the detection of HPV DNA by Real-Time PCR using GP5+/GP6+ primers. Furthermore, the HPV-positive samples were subjected to genotyping. In contrast to the absence of viral genomes in the control samples, HPV DNA was detected in 19 NSCLC specimens (19%). In particular, 4 squamous cell carcinomas, 12 adenocarcinomas, 1 sample with characteristics of both squamous cell and adenocarcinoma, and 2 undifferentiated samples were HPV-positive. The distribution of HPV genotypes was as follows: HPV 16: eight cases (42.1%); HPV 11: three cases (15.8%); HPV 6: one case (5.2%); HPV 59: one case (5.2%); HPV 33: two cases (10.5%); HPV 31: two cases (10.5%) and HPV 18: two cases (10.5%). The presence of HPV in the tumor samples provides evidence of the potential role of HPV in NSCLC and strongly argues for additional research on this issue.

LKB1 Loss Correlates with STING Loss and, in Cooperation with ß-Catenin Membranous Loss, Indicates Poor Prognosis in Patients with Operable Non-Small Cell Lung Cancer.

To investigate the incidence and prognostically significant correlations and cooperations of LKB1 loss of expression in non-small cell lung cancer (NSCLC), surgical specimens from 188 metastatic and 60 non-metastatic operable stage I-IIIA NSCLC patients were analyzed to evaluate their expression of LKB1 and pAMPK proteins in relation to various processes. The investigated factors included antitumor immunity response regulators STING and PD-L1; pro-angiogenic, EMT and cell cycle targets, as well as metastasis-related (VEGFC, PDGFRα, PDGFRß, p53, p16, Cyclin D1, ZEB1, CD24) targets; and cell adhesion (ß-catenin) molecules. The protein expression levels were evaluated via immunohistochemistry; the RNA levels of LKB1 and NEDD9 were evaluated via PCR, while KRAS exon 2 and BRAFV600E mutations were evaluated by Sanger sequencing. Overall, loss of LKB1 protein expression was observed in 21% (51/248) patients and correlated significantly with histotype (p < 0.001), KRAS mutations (p < 0.001), KC status (concomitant KRAS mutation and p16 downregulation) (p < 0.001), STING loss (p < 0.001), and high CD24 expression (p < 0.001). STING loss also correlated significantly with loss of LKB1 expression in the metastatic setting both overall (p = 0.014) and in lung adenocarcinomas (LUACs) (p = 0.005). Additionally, LKB1 loss correlated significantly with a lack of or low ß-catenin membranous expression exclusively in LUACs, both independently of the metastatic status (p = 0.019) and in the metastatic setting (p = 0.007). Patients with tumors yielding LKB1 loss and concomitant nonexistent or low ß-catenin membrane expression experienced significantly inferior median overall survival of 20.50 vs. 52.99 months; p < 0.001 as well as significantly greater risk of death (HR: 3.32, 95% c.i.: 1.71-6.43; p <0.001). Our findings underscore the impact of the synergy of LKB1 with STING and ß-catenin in NSCLC, in prognosis.

Retroperitoneal Hemorrhage Due to Spontaneous Renal Rupture as the First Presentation of Antiphospholipid Syndrome: A Case Report.

Spontaneous renal rupture (SRR) with retroperitoneal hemorrhage is an extremely rare medical emergency and is rather challenging for the surgical team. Management of SRR often requires surgical intervention and nephrectomy as it is life-threatening. Antiphospholipid syndrome (APLS) is an autoimmune disease that affects several organs, including kidneys, causing significant abnormalities. Current data suggest that APLS can result in renal artery stenosis, renal vein thrombosis, arterial hypertension, thrombotic microangiopathy, and antiphospholipid syndrome nephropathy where there is renal involvement. Here, we report the case of a 49-year-old man who presented to the Emergency Department with sudden-onset abdominal pain in the context of retroperitoneal bleeding due to SRR. The patient developed hemodynamic instability and underwent a total nephrectomy. The surgical specimen revealed APLS-related lesions. Serological tests confirmed the diagnosis of APLS, which was managed with acenocoumarol and hydroxychloroquine. Since then, he has not experienced any thromboembolic or hemorrhagic episodes. This article aims to present for the first time a case of SRR as the first presentation of APLS as well as to analyze the possible associated mechanisms.

Retroperitoneal Soft Tissue Sarcoma: Emerging Therapeutic Strategies.

Retroperitoneal soft tissue sarcoma (RPS) is a rare and heterogenous disease for which surgery is the cornerstone of treatment. However, the local recurrence rate is much higher than in soft tissue sarcoma of the extremities since wide resection is usually unfeasible in RPS due to its large size, indistinct tumour borders, anatomical constraints and the thinness of the overlying peritoneum. Local recurrence is the leading cause of death for low-grade RPS, whereas high-grade tumours are prone to distant metastases. In recent decades, the role of emerging therapeutic strategies, such as more extended surgery and (neo)adjuvant treatments to improve oncological outcome in primary localised RPS, has been extensively investigated. In this review, the recent data on the evolving multidisciplinary management of primary localised RPS are comprehensively discussed. The heterogeneity of RPS, with their different histological subtypes and biological behaviour, renders a standard therapeutic 'one-size-fits-all' approach inappropriate, and treatment should be modified according to histological type and malignancy grade. There is sufficient evidence that frontline extended surgery with compartmental resection including all ipsilateral retroperitoneal fat and liberal en bloc resection of adjacent organs and structures, even if they are not macroscopically involved, increases local tumour control in low-grade sarcoma and liposarcoma, but not in leiomyosarcoma for which complete macroscopic resection seems sufficient. Additionally, preoperative radiotherapy is not indicated for all RPSs, but seems to be beneficial in well-differentiated liposarcoma and grade I/II dedifferentiated liposarcoma, and probably in solitary fibrous tumour. Whether neoadjuvant chemotherapy is of benefit in high-grade RPS remains unclear from retrospective data and is subject of the ongoing randomised STRASS 2 trial, from which the results are eagerly awaited. Personalised, histology-tailored multimodality treatment is promising and will likely further evolve as our understanding of the molecular and genetic characteristics within RPS improves.

Pulmonary microRNA profiling in a mouse model of ventilator-induced lung injury.

The aim of this study was to investigate the changes induced by high tidal volume ventilation (HVTV) in pulmonary expression of micro-RNAs (miRNAs) and identify potential target genes and corresponding miRNA-gene networks. Using a real-time RT-PCR-based array in RNA samples from lungs of mice subjected to HVTV for 1 or 4 h and control mice, we identified 65 miRNAs whose expression changed more than twofold upon HVTV. An inflammatory and a TGF-ß-signaling miRNA-gene network were identified by in silico pathway analysis being at highest statistical significance (P = 10(-43) and P = 10(-28), respectively). In the inflammatory network, IL-6 and SOCS-1, regulated by miRNAs let-7 and miR-155, respectively, appeared as central nodes. In TGF-ß-signaling network, SMAD-4, regulated by miR-146, appeared as a central node. The contribution of miRNAs to the development of lung injury was evaluated in mice subjected to HVTV treated with a precursor or antagonist of miR-21, a miRNA highly upregulated by HVTV. Lung compliance was preserved only in mice treated with anti-miR-21 but not in mice treated with pre-miR-21 or negative-control miRNA. Both alveolar-arterial oxygen difference and protein levels in bronchoalveolar lavage were lower in mice treated with anti-miR-21 than in mice treated with pre-miR-21 or negative-control miRNA (D(A-a): 66 ± 27 vs. 131 ± 22, 144 ± 10 mmHg, respectively, P < 0.001; protein concentration: 1.1 ± 0.2 vs. 2.3 ± 1, 2.1 ± 0.4 mg/ml, respectively, P < 0.01). Our results show that HVTV induces changes in miRNA expression in mouse lungs. Modulation of miRNA expression can affect the development of HVTV-induced lung injury.

Clinical Controversy Surrounding the Differential Diagnosis of Branchiogenic Carcinoma.

Clinical evaluation, differential diagnosis, and management of a neck mass constitute commonly encountered problems for the head and neck surgeon. An asymptomatic neck mass in adults may be the only clinical sign of head and neck cancer. A 50-year-old female patient presented with a painless, slowly enlarging, left lateral neck lump. Ultrasonography described a possible lymph node with cystic degeneration, and fine needle aspiration biopsy only detected atypical cells of squamous epithelium. An open biopsy under general anesthesia was performed. Histopathological findings suggested the diagnosis of lymph node infiltration by squamous cell carcinoma of an unknown primary site, but differential diagnosis also included branchiogenic carcinoma arising in a branchial cleft cyst. A diagnostic algorithm for metastatic squamous cell carcinoma of an unknown primary site was followed, including positron emission tomography with computed tomography. The patient underwent panendoscopy and bilateral tonsillectomy, and an ipsilateral p16 positive tonsillar squamous cell carcinoma was detected. Further appropriate management followed. The existence of true branchiogenic carcinoma is controversial. When such a diagnosis is contemplated, every effort should be made to detect a possible primary site. Branchiogenic carcinoma, if exists at all, remains a diagnosis of exclusion.

Novel oligomeric proanthocyanidin derivatives interact with membrane androgen sites and induce regression of hormone-independent prostate cancer.

Prostate cancer is the most common malignancy among men in Western societies, and current therapeutic approaches are evolving to manage growth, recurrence, and mortality neoplasia. Membrane androgen receptors (mARs) have been characterized in human prostate cancer, being preferentially expressed in tumor rather than benign gland areas. Furthermore, mAR agonists (protein-conjugated testosterone) decrease in vitro prostate cancer cell growth and induce apoptosis, whereas in vivo they regress growth of tumor xenografts alone or in combination with taxane drugs. In this respect, targeting mARs might be a novel therapeutic approach in prostate cancer. In our search for new small-molecule ligands of mAR, we report that flavanol dimers B1-B4 (oligomeric procyanidins) decrease in vitro growth of the androgen-sensitive (LnCaP) and androgen-resistant (DU145) human prostate cancer cell lines in the following order: B3 = B4 > B2 ≫ B1 (LnCaP) and B2 ≫ B3 = B4 ≫ B1 (DU145). Some of these analogs were previously shown to trigger signaling cascades similar to testosterone-bovine serum albumin (BSA) conjugate. Galloylation does not confer an additional advantage; however, oleylation increases the dimers' antiproliferative potency by a factor of 100. In addition, we report that B2, oleylated or not, displaces testosterone from mARs with an IC(50) value at the nanomolar range and induces DU145 tumor xenograft regression by 50% (testosterone-BSA 40%). In this respect, oleylated B2 is a potent small-molecule agonist of mAR and could be a novel therapeutic agent for advanced prostate cancer, especially when taking into account the absence of androgenic actions and (liver) toxicity.

Differentiating low from high-grade soft tissue sarcomas using post-processed imaging parameters derived from multiple DWI models.

PURPOSE: To investigate and histopathologically validate the role of model selection in the design of novel parametric meta-maps towards the discrimination of low from high-grade soft tissue sarcomas (STSs) using multiple Diffusion Weighted Imaging (DWI) models. METHODS: DWI data of 28 patients were quantified using the mono-exponential, bi-exponential, stretched-exponential and the diffusion kurtosis model. Akaike Weights (AW) were calculated from the corrected Akaike Information Criteria (AICc) to select the most suitable model for every pixel within the tumor volume. Pseudo-colorized classification maps were then generated to depict model suitability, hypothesizing that every single model underpins different tissue properties and cannot solely characterize the whole tumor. Single model parametric maps were turned into meta-maps using the classification map and a histological validation of the model suitability results was conducted on several subregions of different tumors. Several histogram metrics were calculated from all derived maps before and after model selection, statistical analysis was conducted using the Mann-Whitney U test, p-values were adjusted for multiple comparisons and performance of all statistically significant metrics was evaluated using the Receiver Operator Characteristic (ROC) analysis. RESULTS: The histologic analysis on several tumor subregions confirmed model suitability results on these areas. Only 3 histogram metrics, all derived from the meta-maps, were found to be statistically significant in differentiating low from high-grade STSs with an AUC higher than 89 %. CONCLUSION: Embedding model selection in the design of the diffusion parametric maps yields to histogram metrics of high discriminatory power in grading STSs.

Apocrine and eccrine hidrocystomas: a clinicopathological study.

INTRODUCTION: Eccrine and apocrine hidrocystomas are uncommon, benign, cystic proliferations of the sweat glands usually located on the head and neck area. OBJECTIVES: To describe the key clinical and histopathological characteristics of a large series of hidrocystomas in Greece to improve diagnostic accuracy, and to perform a historical review of the medical term hidrocystoma. METHODS: A case series of 22 hidrocystomas from 20 consecutive patients treated with surgery at University Hospital of Heraklion in Crete, Greece, from January 1, 1998 to January 1, 2020 was performed along with a comprehensive historical literature review of the term hidrocystoma and its corresponding term hydatis from ancient Greek literature to the present. Data were obtained from medical records. All patients had a histopathologically confirmed diagnosis of hidrocystoma. Formalin-fixed paraffin-embedded (FFPE) sections of 22 tumors of the 20 consecutive patients were retrieved from the pathology laboratory archive and stained for SMA, p63, and GCDFP-15 with immunochemistry and periodic acid-Schiff (PAS) histochemical stain. RESULTS: Overall, 22 hidrocystomas (11 apocrine and 11 eccrine hidrocystomas) surgically excised from 20 patients were included in this study. Of the 20 patients, 10 (50%) were male and 10 (50%) were female, with a mean age of 56 ± 15 years. Hidrocystomas commonly occurred on the eyelids (73%), inner canthus (9%), eyebrow (4.5%), neck (4.5%), nose (4.5%), and ear (4.5%). All apocrine hidrocystomas stained positive for SMA, GCDFP-15, CAM 5.2, PAS, and PAS-D. No recurrence was observed. CONCLUSIONS: Here we have presented the clinicopathological characteristics of the largest case series of hidrocystomas in Europe and the Mediterranean region. Only apocrine hidrocystomas stained positive for SMA, GCDFP-15, CAM 5.2, PAS, and PAS-D.

Factors Associated with Healthcare Workers' (HCWs) Acceptance of COVID-19 Vaccinations and Indications of a Role Model towards Population Vaccinations from a Cross-Sectional Survey in Greece, May 2021.

A Knowledge, Attitudes and Practices (KAP) study was conducted at the end of May 2021 engaging 1456 healthcare workers (HCWs) from 20 hospitals throughout Greece. Acceptance of vaccination against coronavirus disease 2019 (COVID-19) was estimated at 77.7%, with lower vaccine acceptance identified in nurses compared to physicians. Fears related to vaccine safety, lack of information and general knowledge about vaccinations, influenza vaccine acceptance, education level and years of practice were among the factors independently associated with vaccine acceptance. A strong association was identified between vaccination of HCWs in each health region and the population coverage, indicating that HCWs may be role models for the general population. Information campaigns should continue despite decisions taken regarding mandatory vaccinations.

Palmoplantar Pustulosis-like Eruption Induced by Baricitinib for Treatment of Rheumatoid Arthritis.

OBJECTIVES: Baricitinib is an orally active Janus kinase (JAK) inhibitor used in the treatment of moderate to severe rheumatoid arthritis (RA). MATERIALS AND METHODS: Here, we report the case of a 56-year-old Caucasian male diagnosed with RA who developed palmoplantar pustulosis (PPP) while being treated with baricitinib. RESULTS: The patient's PPP resolved after discontinuation of baricitinib and recurred when this was restarted. Based on causality assessment, it was considered a drug-induced PPP. CONCLUSION: To the authors' knowledge, this is the first case of baricitinib-induced PPP. LEARNING POINTS: Baricitinib is a small, orally active molecule that inhibits JAK-1 and JAK-2, which is used in the treatment of rheumatoid arthritis.Baricitinib has been also used in the treatment of psoriasis, alopecia areata and atopic dermatitis.Palmoplantar pustulosis is a rare cutaneous side effect of baricitinib.

Pyoderma gangrenosum associated with chronic refractory pouchitis: a case successfully treated with infliximab.

Pouchitis-associated pyoderma gangrenosum (PG) is rare, with only a few cases reported in the literature. Here we report a rare case of chronic refractory pouchitis-associated PG successfully treated with infliximab (IFX). A 43-year-old Caucasian male, with a past medical history of chronic refractory pouchitis after proctocolectomy and ileal pouch-anal anastomosis for severe ulcerative colitis, developed PG on his right lower leg. This subsided after treatment with intravenous IFX at a dose of 5 mg/kg at weeks 0, 2, 6 and then every 8 weeks. Pouchitis-associated PG is rare. Clinicians should be aware of the risk of PG in patients who suffer from pouchitis and develop rapidly extensive painful ulcers. Furthermore, the therapeutic choice should take into consideration the effectiveness of IFX on the inflammatory background, which sustains both intestinal and skin disease in these types of patients.

Multiexponential T2 relaxometry of benign and malignant adipocytic tumours.

BACKGROUND: We investigated a recently proposed multiexponential (Mexp) fitting method applied to T2 relaxometry magnetic resonance imaging (MRI) data of benign and malignant adipocytic tumours and healthy subcutaneous fat. We studied the T2 distributions of the different tissue types and calculated statistical metrics to differentiate benign and malignant tumours. METHODS: Twenty-four patients with primary benign and malignant adipocytic tumours prospectively underwent 1.5-T MRI with a single-slice T2 relaxometry (Carr-Purcell-Meiboom-Gill sequence, 25 echoes) prior to surgical excision and histopathological assessment. The proposed method adaptively chooses a monoexponential or biexponential model on a voxel basis based on the adjusted R2 goodness of fit criterion. Linear regression was applied on the statistical metrics derived from the T2 distributions for the classification. RESULTS: Healthy subcutaneous fat and benign lipoma were better described by biexponential fitting with a monoexponential and biexponential prevalence of 0.0/100% and 0.2/99.8% respectively. Well-differentiated liposarcomas exhibit 17.6% monoexponential and 82.4% biexponential behaviour, while more aggressive liposarcomas show larger degree of monoexponential behaviour. The monoexponential/biexponential prevalence was 47.6/52.4% for myxoid tumours, 52.8/47.2% for poorly differentiated parts of dedifferentiated liposarcomas, and 24.9/75.1% pleomorphic liposarcomas. The percentage monoexponential or biexponential model prevalence per patient was the best classifier distinguishing between malignant and benign adipocytic tumours with a 0.81 sensitivity and a 1.00 specificity. CONCLUSIONS: Healthy adipose tissue and benign lipomas showed a pure biexponential behaviour with similar T2 distributions, while decreased adipocytic cell differentiation characterising aggressive neoplasms was associated with an increased rate of monoexponential decay curves, opening a perspective adipocytic tumour classification.