Search

Vasculopathy associated with connective tissue diseases (CTD) has diverse clinical presentations and complex underlying pathology. Existing imaging techniques remain inadequate for assessing vasculopathy in CTD, particularly in earlier stages of pathogenesis. Novel imaging techniques, such as optical coherence tomography, near-infrared spectroscopy and superb microvascular imaging, demonstrate potential in monitoring disease progression at earlier stages prior to systemic complications.

Background: Infection is a leading cause of morbidity, mortality and hospital admission in systemic lupus erythematosus (SLE) patients. Aim of the work: To study infection in SLE patients regarding site of infection, pathogenic organism, hospitalization and/or intensive care unit (ICU) admission. Patients and methods: This study included 79 patients. SLE disease activity index (SLEDAI-2K) and damage index were evaluated. Detailed information about the site of infection and pathogens were reported. Results: 71 females and 8 male patients (F:M 8.9:1), with a mean age of 29 ± 9.6 years (17–55 years) and disease duration of 5.9 ± 5.7 years, 55 (69.6%) patients had infection at time of study while 24 (30.4%) did not. The SLEDAI-2 k and damage index were significantly higher in SLE patients with infection (14.2 ± 11.8 and 3.7 ± 3.7) compared to those without infection (5.9 ± 5.03 and 1.8 ± 1.3) (p = 0.03 and p = 0.045 respectively). Those with infection had a shorter disease duration (4.9 ± 5.2 vs 8.3 ± 6.2; p = 0.005), received more cyclophosphamide (56.4% vs 16.7%; p = 0.001), higher erythrocyte sedimentation rate (ESR) (75.5 ± 27.1 vs 35.8 ± 24.7 mm/1sthr) (p

[Purpose] To determine whether the development of levodopa-induced dyskinesia (LID) in Parkinson disease (PD) specifically relates to dopaminergic depletion in sensorimotor-related subregions of the striatum., [Methods] Our primary study sample consisted of 185 locally recruited PD patients, of which 73 (40%) developed LID. Retrospective 123I-FP-CIT SPECT data were used to quantify the specific dopamine transporter (DAT) binding ratio within distinct functionally defined striatal subregions related to limbic, executive, and sensorimotor systems. Regional DAT levels were contrasted between patients who developed LID (PD + LID) and those who did not (PD-LID) using analysis of covariance models controlled for demographic and clinical features. For validation of the findings and assessment of the evolution of LID-associated DAT changes from an early disease stage, we also studied serial 123I-FP-CIT SPECT data from 343 de novo PD patients enrolled in the Parkinson Progression Marker’s Initiative using mixed linear model analysis., [Results] Compared with PD-LID, DAT level reductions in PD + LID patients were most pronounced in the sensorimotor striatal subregion (F = 5.99, P = 0.016) and also significant in the executive-related subregion (F = 5.30, P = 0.023). In the Parkinson Progression Marker’s Initiative cohort, DAT levels in PD + LID (n = 161, 47%) were only significantly reduced compared with PD-LID in the sensorimotor striatal subregion (t = −2.05, P = 0.041), and this difference was already present at baseline and remained largely constant over time., [Conclusion] Measuring DAT depletion in functionally defined sensorimotor-related striatal regions of interest may provide a more sensitive tool to detect LID-associated dopaminergic changes at an early disease stage and could improve individual prognosis of this common clinical complication in PD.

Traditionally, the efficacy of novel cancer therapies has been confirmed in patients failing regular treatment before being tested in early disease. Improved understanding of the mechanisms guiding therapeutic efficacy may challenge this dogma, suggesting novel therapies to move into early evaluation based on biological rationales without late-stage efficacy evaluation.

POLE mutations, which lead to an ultramutated phenotype in colorectal cancer (CRC), have been reported as a promising marker in immunotherapy. We performed sequencing of CRC cases in Zhejiang University (ZJU) and extracted obtainable data from recently published results, including The Cancer Genome Atlas (TCGA), Japanese studies and clinical trials, to present clinical patterns of POLE driver‐mutated CRC and reveal its heterogeneity. The rate of somatic POLE driver mutations has been reported as 2.60% (ZJU cohort), 1.50% (TCGA cohort), 1.00% (Japan cohort), and 1.00% (Lancet cohort). POLE driver mutations show a clearly increased mutation burden (mean TMB: 217.98 mut/Mb in ZJU; 203.13 mut/Mb in TCGA). Based on pooled data, more than 70.00% of patients with POLE driver mutations were diagnosed before they were 55 years old and at an early disease stage (Stage 0–II >70.00%), and more than 70.00% were male. Among Asian patients, 68.40% developed POLE driver mutations in the left‐side colon, whereas 64.00% of non‐Asian patients developed them in the right‐side colon (p, POLE could be a promising marker for immunotherapy, and its heterogeneity should not be ignored. Here we present the clinical patterns and heterogeneity of POLE driver mutations so that investigators and physicians will be better equipped to design clinical trials and analyze their data.

Objective Clinically differentiating multiple system atrophy cerebellar type (MSA-C) and spinocerebellar ataxias (SCAs) is challenging, especially at early disease stages, because of their similarities in clinical manifestation and imaging results. The purpose of this study was to explore the value of external anal-sphincter electromyography (EAS-EMG) and urethral-sphincter electromyography (US-EMG) for distinguishing between MSA-C and SCAs. Methods A total of 51 subjects, including 33 MSA-C and 18 SCAs, were recruited. Average duration and amplitude of motor unit potentials (MUPs), percentage of polyphasic MUPs, amplitude during strong contraction and recruitment pattern during maximal voluntary contraction were recorded and analyzed to identify differential diagnostic results of EAS-EMG and US-EMG for MSA-C and SCAs. Results Significant differences in average MUP duration, percentage of polyphasic MUPs, and ratio of simple phase and simple-mix phase using EAS-EMG were noted between patients with MSA-C and SCAs. These same parameters also differed significantly between MSA-C and SCAs male patients using US-EMG. Conclusions EAS-EMG may serve as a potential method for early differential diagnosis between patients with MSA-C and SCAs. Furthermore, US-EMG could be a supplementary method for males when EAS-EMG is not available.

Hepatocellular carcinoma (HCC) is one of the most prevalent cancers globally. In contrast to the declining death rates observed for all other common cancers such as breast, lung, and prostate cancers, the death rates for HCC continue to increase by ~2–3% per year because HCC is frequently diagnosed late and there is no curative therapy for an advanced HCC. The early diagnosis of HCC is truly a big challenge. Over the past years, the early diagnosis of HCC has relied on surveillance with ultrasonography (US) and serological assessments of alpha-fetoprotein (AFP). However, the specificity and sensitivity of US/AFP is not satisfactory enough to detect early onset HCC. Recent technological advancements offer hope for early HCC diagnosis. Herein, we review the progress made in HCC diagnostics, with a focus on emerging imaging techniques and biomarkers for early disease diagnosis.

Purpose. To determine the anamnestic predictors of severe bronchial asthma in children. Material and methods. We analyzed risk factors of 335 patients with bronchial asthma. We statistically selected 287 patients and developed a prognostic model. Results. The predictors of severe bronchial asthma are combination of factors such as high incidence of ARVI in the first 3 years of life (odds ratio – OR 4.5; p

ObjectiveThis study aimed to define the minimal evidence of disease activity (MEDA) during treatment that can be tolerated without exposing patients with relapsing-remitting multiple sclerosis at risk of long-term disability.MethodsWe retrospectively collected data of patients followed up to 10 years after starting interferon beta or glatiramer acetate. Survival analyses explored the association between the long-term risk of reaching an Expanded Disability Status Scale≥6.0 and early clinical and MRI activity assessed after the first and second year of treatment. Early disease activity was classified by the so-called ‘MAGNIMS score’ (low: no relapses and medium: no relapses and ≥3 new T2 lesions or 1 relapse and 0–2 new T2 lesions; high: 1 relapse and ≥3 new T2 lesions or ≥2 relapses) and the absence or presence of contrast-enhancing lesions (CELs).ResultsAt follow-up, 148/1036 (14.3%) patients reached the outcome: 61/685 (8.9%) with low score (reference category), 57/241 (23.7%) with medium score (HR=1.94, p=0.002) and 30/110 (27.3%) with high score (HR=2.47, plow score subgroup, the risk was further reduced in the absence (49/607, 8.1%) than in the presence of CELs (12/78, 15.4%; HR=2.11, p=0.01). No evident disease activity and low score in the absence of CELs shared the same risk (p=0.54). Similar findings were obtained even after the second year of treatment.ConclusionsEarly marginal MRI activity of one to two new T2 lesions, in the absence of both relapses and CELs, is associated with a minor risk of future disability, thus representing a simple and valuable definition for MEDA.

Though ursodeoxycholic acid (UDCA) remains the baseline treatment for most cholestatic liver diseases, UDCA treatment leaves approximately one-third of patients with primary biliary cholangitis (PBC) and all patients with primary sclerosing cholangitis (PSC) at risk for disease progression. New anticholestatic agents, including nuclear receptor agonists, choleretics, and bile acid synthesis suppressors, will likely increase response rates to therapy in PBC and PSC. Strategies that target early immune-mediated injury have so far been disappointing, hampered by the lack of biomarkers to detect early disease states, which then could profit from immunomodulatory therapy. Future concepts need to personalize treatments according to disease stage, progression, and phase, and to combine multiple drugs to target different pathogenic pathways.

Objective Timely initiation of Alzheimer’s disease (AD)-specific treatment may postpone cognitive deterioration and preserve patient independence. We explored real-world physician behavior in the treatment of AD. Methods Online questionnaires and patient record forms (PRFs) were completed by participating physicians. The physicians included general practitioners, neurologists, geriatricians and psychiatrists, recruited from France, Germany, Japan, the UK and the USA. Physicians completed an online interview and two to three PRFs based on selected records of their patients with AD. Data on treatment algorithms and key drivers for therapy were captured. Results A total of 3346 PRFs were submitted and 1086 physicians interviewed. Overall, 44% of patients with mild cognitive impairment/prodromal AD, 71% of patients with mild disease and 76% of patients with moderate disease had already received therapy. The most common reasons for not prescribing therapy were patient refusal (35%) and early disease stage (26%). Except in the USA, the majority of physicians preferred to prescribe monotherapy. Almost 30% of patients at any stage of the disease did not receive AD-specific pharmacotherapy immediately after diagnosis. Conclusions Physicians’ attitudes toward AD treatment could be driven by limited awareness regarding the benefits of early intervention and the modest efficacy of currently available therapies. Efficacious therapies for AD, especially early AD, which could be used alone or in combination with current medications to maximize treatment benefit, are still needed. The availability of more efficacious therapies may improve time to treatment initiation, treatment rates and acceptance of treatment by patients, caregivers and physicians.

Introduction. Prompt successful control of disease activity in multiple sclerosis (MS) patients improves outcomes. Therefore, tools to aid drug selection and detect non-responders are urgently needed. Although several biochemical markers for predicting response to treatment have been proposed, clinical markers involving relapses, imaging activity and disability progression in the initial years of therapy remain competitive and appear cost-effective in a real-life setting. The aim of this study was to evaluate the prognostic value of select clinical scores in interferon beta-1b (IFNβ-1b) treated MS patients. Materials and methods. Eighty-eight relapsing-remitting MS (RRMS) patients initiating treatment with IFNβ-1b in a Polish outpatient clinic were followed for a median of 5.5 years. Rio, modified Rio and BREMSO scores, as well as two-year no evidence of disease activity (NEDA), were assessed as predictors of disease activity during the observation. Results. A Rio score of 1 had a Positive Predictive Value (PPV) of 83.3% and a Negative Predictive Value (NPV) of 71.4% for the occurrence of relapses in the first five years. A Rio and modified Rio score of 1 was associated with MRI activity after year 3. A loss of NEDA within the first two years was associated with a failure to maintain NEDA in the next three years. The BREMSO score was higher in patients with early relapse activity. Only baseline EDSS and total number of pre-treatment relapses were significantly associated with disability progression. Conclusions. Rio, modified Rio, early NEDA on treatment and BREMSO score are relatively specific, but insensitive, predictors of relapse activity in the first years of IFNβ-1b treatment. Higher pre-treatment EDSS and relapse activity is associated with disability progression, but not overall NEDA, in subsequent observation. While none of the markers is sufficiently sensitive or specific to make a certain prognosis, they may aid treatment decisions in patients with continued early disease activity.

Carotid artery disease is considered a major cause of strokes and there is a need for early disease detection and management. Although imaging techniques have been developed for the diagnosis of carotid artery disease and different imaging-based markers have been proposed for the characterization of atherosclerotic plaques, there is still need for a definition of high-risk plaques in asymptomatic patients who may benefit from surgical intervention. Measurement of circulating biomarkers is a promising method to assist in patient-specific disease management, but the lack of robust clinical evidence limits their use as a standard of care. The purpose of this review paper is to present circulating biomarkers related to carotid artery diagnosis and prognosis, which are mainly provided by statistical-based clinical studies. The result of our investigation showed that typical well-established inflammatory biomarkers and biomarkers related to patient lipid profiles are associated with carotid artery disease. In addition to this, more specialized types of biomarkers, such as endothelial and cell adhesion, matrix degrading, and metabolic biomarkers seem to be associated with different carotid artery disease outputs, assisting vascular specialists in selecting patients at high risk for stroke and in need of intervention.

Background The ML18174 study, which showed benefits of bevacizumab (BEV) continuation beyond progression (BBP) for metastatic colorectal cancer (mCRC), excluded patients with first-line progression-free survival (PFS) shorter than 3 months. The present study was conducted to evaluate the efficacy of second-line chemotherapy after early disease progression during first-line chemotherapy containing bevacizumab. Methods The subjects of this study were mCRC patients who experienced disease progression Results Sixty-one patients were identified as subjects of this study. Baseline characteristics were numerically different between BBP (n = 37) and non-BBP (n = 25) groups, such as performance status (0–1/> 2/unknown: 89/8/3 and 56/40/4%), RAS status (wild/mutant/unknown: 32/54/16 and 76/16/8%). Response rate was 8.6% in BBP group and 9.1% in non-BBP group (p = 1.00). Median PFS was 3.9 months in BBP group and 2.8 months in non-BBP group (HR [95%CI]: 0.79 [0.46–1.34], p = 0.373, adjusted HR: 0.87 [0.41–1.82], p = 0.707). Median overall survival was 8.5 months in BBP group and 5.4 months in non-BBP group (HR 0.66 [0.38–1.12], p = 0.125, adjusted HR 0.53 [0.27–1.07], p = 0.078). Conclusion In mCRC patients who experienced early progression in first-line chemotherapy, second-line chemotherapy showed poor clinical outcomes regardless use of anti-angiogenic agents.

Inflammation and autoimmunity related ischaemic and nonischemic complications can occur in Behcet’s syndrome and can cause coronary vasculitis, myocarditis, aortic regurgitation and root dilatation...

Simple Summary In this review we summarized the most relevant biological features concerning smoldering multiple myeloma (SMM). We outlined the genetic architecture of the disease and how it is entering in the SMM risk stratification. In particular, we pointed out how the identification of a high-risk setting, meaning the population with the risk of faster progression to the symptomatic phase, is crucial and, despite huge improvements in recent years, still represents an unmet clinical need. Indeed, the correct identification of these patients will drive to an early therapeutical intervention. Moreover, we also discussed the role of the microenvironment, which is highly relevant in the symptomatic disease but still understudied in the SMM setting. Finally, we debated the state-of-the-art current available therapies and ongoing clinical trials, and envisioned possible strategies to introduce a biological-based stratification approach within the daily clinical practice. Abstract Smoldering multiple myeloma (SMM) is an asymptomatic disorder of clonal bone marrow (BM) plasma cells (PCs) in between the premalignant condition known as monoclonal gammopathy of undetermined significance and overt multiple myeloma (MM). It is characterized by a deep biological heterogeneity that is reflected in a markedly variable progression risk among patients. Recently proposed risk stratification models mainly rely on indirect markers of disease burden and are unable to identify cases in whom clonal PCs have already undergone the “malignant switch” but major clonal expansion has not occurred yet. In the last years, the application of next-generation sequencing (NGS) techniques has led to profound advances in the understanding of the molecular bases of SMM progression, and in all likelihood, it will contribute to the needed improvement of SMM prognostication. In this Review, we describe the recent advances in characterizing the genomic landscape of SMM and intrinsic determinants of its progression, highlighting their implications in terms of understanding of tumor evolution and prognostication. We also review the main studies investigating the role of the microenvironment in this early disease stage. Finally, we mention the results of the first randomized clinical trials and discuss the potential clinical translability of the genomic insights.

While the incidence and mortality of gastric cancer (GC) have declined due to public health programs, it remains the third deadliest cancer worldwide. For patients with early disease, innovative endoscopic and complex surgical techniques have improved survival. However, for patients with advanced disease, there are limited treatment options and survival remains poor. Therefore, there is an urgent need for more effective therapies. Since novel therapies require extensive preclinical testing prior to human trials, it is important to identify methods to expedite this process. Traditional cancer models are restricted by the inability to accurately recapitulate the primary human tumor, exorbitant costs, and the requirement for extended periods of development time. An emerging in vitro model to study human disease is the patient-derived organoid, which is a three-dimensional system created from fresh surgical or biopsy tissues of a patient’s gastric tumor. Organoids are cultured in plastic wells and suspended in a gelatinous matrix, providing a substrate for extension and growth in all dimensions. They are rapid-growing and highly representative of the molecular landscape, histology, and morphology of the various subtypes of GC. Organoids uniquely model tumor initiation and growth, including steps taken by normal stomach cells to transform into invasive, intestinal-type tumor cells. Additionally, they provide ample material for biobanking and screening novel therapies. Lastly, organoids are a promising model for personalized therapy and warrant further investigation in drug sensitivity studies for GC patients.

Hypertension (HT), or high blood pressure (BP), is a chronic disease that is common among populations worldwide. The occurrence of HT is one of the leading causes of cardiovascular morbidity and mortality in adults. Although multiple studies have stressed the multifactorial and multigenic nature of HT, uncertainties about its etiology persist, and current diagnostic biomarkers can explain only a small part of the phenotypic variance of BP. Hence, the search for novel biomarkers that enable early disease prevention and guided therapy is warranted. Regulatory circRNAs have emerged as the newest player in HT-related gene networks and hold promise for improving the accuracy of diagnosis. These RNAs are genome products that are formed through back-splicing of specific regions of pre-mRNAs. Evidence suggests that these RNA species are involved in various metabolic diseases. Recent studies have revealed that aberrant expression of circRNAs is relevant to the occurrence and development of HT. Accordingly, circRNAs are proposed as a new generation of predictive biomarkers and potential therapeutic targets for different forms of HT, including pulmonary hypertension and preeclampsia. This paper presents an overview of the findings from current research focusing on the emerging role of circRNAs in the pathogenesis of hypertension. Furthermore, some of the challenges encountered by circRNA studies are highlighted, and perspectives are provided on the future of research in this area.

Metabolomics has developed as a powerful tool for investigating the complex pathophysiology underlying atherosclerosis and cardiovascular disease. Many epidemiological studies have applied this technique to accurately and comprehensively assess the effects of environmental factors on health outcomes, which used to be a perpetual challenge. Metabolites are defined as small molecules which are intermediate products of metabolic reactions catalyzed by numerous enzymes occurring within cells. Consequent to both genetic variation and environment, they allow us to explore the gene-environment interactions and to gain a better understanding of multifactorial diseases like cardiovascular disease. This review article highlights the findings of well-known prospective cohort studies around the world that have utilized metabolomics for a wide range of purposes, including biomarker discovery, improving cardiovascular risk prediction and early disease diagnosis, and exploring detailed mechanisms of disease onset and progression. However, technical challenges still exist in applying them clinically. One limitation is due to various analytical platforms that are used based on the judgment of each study; comparative assessments among different platforms need to be conducted in order to correctly interpret and validate each data externally. Secondly, metabolite levels obtained in most high-throughput metabolomics profiling studies are often semiquantitative rather than fully quantitative concentrations, which makes it difficult to compare and combine results among different studies and to determine the levels for practical use. In 2014, the Consortium of Metabolomics Studies was developed, which is expected to take the lead in overcoming these issues.

Aim of the work: This study aimed to assess long-term articular damage and function in rheumatoid arthritis (RA) patients in relation to the type of treatment. Early disease modifying anti-rheumatic drug (DMARD) therapy has not been evaluated in this study. Patients and methods: One hundred and fifty RA patients (141 females and 9 males) with disease duration more than five years and disease activity score-28 (DAS-28)

Urothelial cancer (UC) holds one of the leading positions amongst oncourological diseases. Rate of cancer is growing all around the world and according to experts the growth rate of cancer is estimated as alarming. Clinical implications of the early disease are so poor that they result in late detection of the decease. Understanding of tumor’s pathogenesis opened the door for development of new approaches for diagnosis of cancer, use of innovative methods and technologies. The modern UC diagnostics includes a variety of lab tests and special exams (invasive method and noninvasive methods). Considering low informative value and limited prospects of these methods, today there are researches in improvement of methods which are already being used and development of new methods for early diagnosis and forecasting of the decease being done. Detecting the most specific, vulnerable and informative markers or its combination of the UC is a pressing topic. In this article we consider questions of peculiarities of structure and site of the UC from all angles; we show directions of the UC phenotype research and results of molecular pan-cancer analysis; new tendencies in the UC classification based on study of genetic profile of the UC’s different forms; a short review of the researched molecular genetic markers of early detection of the UC and prognosticating its progression; prognostic value of somatic mutation in the UC; we evaluate the connection between gene expression, invasion, tumor’s prevalence and survivability in the UC patients; we give some data on our own researches in the UC diagnostics improvement, study of expression of cancer/testis antigen and detection of abnormalities in genetic code in the UC.

Biliary tract cancers, including gallbladder cancer, intrahepatic, perihilar, and distal cholangiocarcinomas, although anatomically contiguous, represent a heterogeneous group of cancers with extensive biologic and genetic diversity. With early disease, surgical resection is the preferred option for all subtypes; however, relapse rates remain high, and survival outcomes are poor. Data to guide the use of adjuvant therapy have been limited to retrospective series, population-based studies, and meta-analyses, all with their associated limitations. The number of prospective trials ongoing or completed is increasing, and these results will ultimately dictate optimal treatment of this group of diseases. This review summarizes the data for adjuvant therapy in biliary tract cancers.

BackgroundThe ML18174 study, which showed benefits of bevacizumab (BEV) continuation beyond progression (BBP) for metastatic colorectal cancer (mCRC), excluded patients with first-line progression-free survival (PFS) shorter than 3 months. The present study was conducted to evaluate the efficacy of second-line chemotherapy after early disease progression during first-line chemotherapy containing bevacizumab.MethodsThe subjects of this study were mCRC patients who experienced disease progression ResultsSixty-one patients were identified as subjects of this study. Baseline characteristics were numerically different between BBP (n = 36) and non-BBP (n = 25) groups, such as performance status (0-1/>2: 89/11 and 56/44%), RAS status (wild/mutant/unknown: 28/56/16 and 76/16/8%). Response rate was 5.9% in BBP group and 9.1% in non-BBP group (p = 0.642). Median PFS was 3.7 months in BBP group and 2.8 months in non-BBP group (HR [95%CI]: 0.83 [0.49–1.41], p = 0.489, adjusted HR: 0.97 [0.48–1.96], p = 0.932). Median overall survival was 7.6 months in BBP group and 5.4 months in non-BBP group (HR 0.70 [0.41–1.19], p = 0.191, adjusted HR 0.65 [0.34–1.25], p = 0.195).ConclusionIn patients experienced early progression in first-line chemotherapy, their outcomes of second-line chemotherapy were poor regardless of whether they were in BBP or non-BBP group.

Hepatocellular carcinoma (HCC) is a leading cause of cancer mortality. Operative management of early disease includes ablation, resection, and transplantation. We compared the operative management of early-stage HCC in patients stratified by race.We identified patients with cT1 HCC and Charlson-Deyo score 0-1 in the National Cancer Database (2004-2016). We compared operative/non-operative management by race, adjusting for clinicodemographic variables. We performed marginal standardization of logistic regression to ascertain adjusted probabilities of resection or transplantation in patients under 70 years of age with insurance.A total of 25,029 patients were included (White = 20,410; Black = 4619). After adjusting for clinico demographic variables, Black race was associated with a lower likelihood of undergoing operative intervention (OR 0.89,p = 0.009). Black patients were more likely to undergo resection (OR 1.23,p 0.001) and less likely to undergo transplantation (OR 0.60,p 0.001). Marginal standardization models demonstrated Black race was associated with increased probability of resection in patients50yrs, with private insurance/Medicare, and lower probability of transplantation regardless of age or insurance payor.Black race is associated with lower rates of hepatic transplantation and higher rates of hepatic resection for early HCC regardless of age or insurance payor. The etiology of these disparities is multifactorial and correcting the root causes represents a critical area for improvement.

To investigate the relationship of different subtypes of intracerebral hemorrhage (ICH) to early disease evolution and long-term prognosis in patients with acute cerebral infarction after intravenous recombinant tissue plasminogen activator(r-tPA). Seventy ischemic stroke patients treated with intravenous r-tPA who underwent computed tomography (CT) within 24 hours after thrombolysis were divided into 4 types (hemorrhagic infarction type 1 [HI-1], HI-2, parenchymal hemorrhage type 1 [PH-1], or PH-2 which according to the size of the hematoma and the presence or absence of space-occupying effect). Early evolution of the disease was observed by the change in the National Institutes of Health Stroke Scale (NIHSS) score within 24 hours after thrombolysis. The long-term prognosis was assessed by the modified Rankin Scale (mRS) score at the third month. There were 17 (24.3%) patients with ICH. Compared with patients in the non-ICH group, HI did not affect early neurological function or clinical outcome at the third month. PH-1 did not increase the risk of early neurological deterioration; however, PH-1 has a tendency to increase the risk of death at the third month (50% vs 11.3%, P = 0.090). PH-2 was significantly related to early neurological deterioration (66.7% vs 3.8%, P < 0.001) and mortality at the third month (50.0% vs 11.3%, P = 0.040). Patients with different subtypes of ICH after thrombolysis have different clinical outcomes. PH-2 is significantly associated with early neurological deterioration and increases mortality at the third month.

PURPOSE: Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, characterized by substantial risks of early disease recurrence and mortality. We constructed and validated clinical calculators for predicting recurrence-free survival (RFS) and overall survival (OS) for TNBC. METHODS: Data from 605 women with centrally confirmed TNBC who underwent primary breast cancer surgery at Mayo Clinic during 1985–2012 were used to train risk models. Variables included age, menopausal status, tumor size, nodal status, Nottingham grade, surgery type, adjuvant radiation therapy, adjuvant chemotherapy, Ki67, stromal tumor-infiltrating lymphocytes (sTIL) score, and neutrophil-to-lymphocyte ratio (NLR). Final models were internally validated for calibration and discrimination using ten-fold cross-validation and compared with their base-model counterparts which include only tumor size and nodal status. Independent external validation was performed using data from 478 patients diagnosed with stage II/III invasive TNBC during 1986–1992 in the British Columbia Breast Cancer Outcomes Unit database. RESULTS: Final RFS and OS models were well calibrated and associated with C-indices of 0.72 and 0.73, as compared with 0.64 and 0.62 of the base models (p < 0.001). In external validation, the discriminant ability of the final models was comparable to the base models (C-index: 0.59–0.61). The RFS model demonstrated greater accuracy than the base model both overall and within patient subgroups, but the advantages of the OS model were less profound. CONCLUSIONS: This TNBC clinical calculator can be used to predict patient outcomes and may aid physician’s communication with TNBC patients regarding their long-term disease outlook and planning treatment strategies.

Follicular lymphoma (FL) is an indolent yet challenging disease. Despite a generally favorable response to immunochemotherapy regimens, a fraction of patients does not respond or relapses early with unfavorable prognosis. For the vast majority of those who initially respond, relapses will repeatedly occur with increasing refractoriness to available treatments. Addressing the clinical challenges in FL warrants deep understanding of the nature of treatment-resistant FL cells seeding relapses, and of the biological basis of early disease progression. Great progress has been made in the last decade in the description and interrogation of the (epi)genomic landscape of FL cells, of their major dependency to the tumor microenvironment (TME), and of the stepwise lymphomagenesis process, from healthy to subclinical disease and to overt FL. A new picture is emerging, in which an ever-evolving tumor-TME duo sparks a complex and multilayered clonal and functional heterogeneity, blurring the discovery of prognostic biomarkers, patient stratification and reliable designs of risk-adapted treatments. Novel technological approaches allowing to decipher both tumor and TME heterogeneity at the single-cell level are beginning to unravel unsuspected cell dynamics and plasticity of FL cells. The upcoming drawing of a comprehensive functional picture of FL within its ecosystem holds great promise to address the unmet medical needs of this complex lymphoma.

Objective.To address the hypothesis that very early patients with systemic sclerosis (SSc) are a heterogeneous group with mild or early disease, we analyzed the extent of heterogeneity in clinical, epidemiological, and immunological characteristics of these patients.Methods.We performed an analysis of very early SSc patients from the Zurich cohort, who fulfilled neither the 2013 American College of Rheumatology (ACR)/European League Against Rheumatism nor the 1980 ACR classification criteria, but had a clinical expert diagnosis of SSc with Raynaud phenomenon (RP) and additional features of SSc (puffy fingers, SSc-specific antibodies, SSc pattern on nailfold capillaroscopy, or any organ involvement characteristic for SSc). Disease duration was defined from first RP symptom.Results.One hundred and two patients fulfilled the inclusion criteria and were analyzed. Their clinical presentation was heterogeneous with the large majority presenting with RP, antinuclear antibodies, and nailfold capillaroscopy changes, but with varying presentations of other features such as SSc-specific antibodies and early signs of organ involvement. While 54.1% (52/96) of patients had a disease duration of < 5 years, as many as 29.1% (28/96) of patients had a disease duration of > 10 years, indicating long-standing mild disease. Patients with very early, potentially progressive disease did not differ from patients with long-standing mild disease in terms of their clinical features at first presentation.Conclusion.This study showed that patients with very early SSc are a mixture with mild or early disease. This needs to be considered in clinical practice for risk stratification and for the study design of patients considered as early SSc.

Immuno- and targeted therapy improved survival in metastatic NSCLC, but before their implementation in early disease, several challenges need to be overcome. Adequate staging is important, and molecular testing must be incorporated in early disease.https://bit.ly/3heLe6W

Quantitative proteomic profiling is progressively emerging as a reliable strategy to achieve early diagnosis, and prognostic stratification in epithelial ovarian cancer (OC). In particular, specific proteomic profiles of tumor-derived circulating proteins involved in regulating apoptosis, epithelial-to-mesenchymal transition, and cellular motility seem to show promising performances in early disease identification and prognostic stratification. Furthermore, proteomic characterization of ascites and pleural effusions will significantly improve the accuracy of predicting outcomes and selecting OC patients to benefit from the current therapies. Cancer tissues, pleural effusions, and ascitic fluids should be considered as the best biological samples for proteomic profiling to achieve the optimal use of biomarkers. On the other hand, plasma circulating-free proteins, or tumor-derived extracellular vesicles-embedded proteins are considered as the most appropriate source of data for early disease identification in OC patients. In the next decade, proteomic profiling will certainly be introduced in the clinical algorithms of the management of OC.

BackgroundBlood-based amyloid biomarkers may provide a non-invasive, cost-effective and scalable manner for detecting cerebral amyloidosis in early disease stages.MethodsIn this prospective cross-sectional study, we quantified plasma Aβ1–42/Aβ1–40ratios with both routinely available ELISAs and novel SIMOA Amyblood assays, and provided a head-to-head comparison of their performances to detect cerebral amyloidosis in a nondemented elderly cohort (n = 199). Participants were stratified according to amyloid-PET status, and the performance of plasma Aβ1–42/Aβ1–40to detect cerebral amyloidosis was assessed using receiver operating characteristic analysis. We additionally investigated the correlations of plasma Aβ ratios with amyloid-PET and CSF Alzheimer’s disease biomarkers, as well as platform agreement using Passing-Bablok regression and Bland-Altman analysis for both Aβ isoforms.ResultsELISA and SIMOA plasma Aβ1–42/Aβ1–40detected cerebral amyloidosis with identical accuracy (ELISA: area under curve (AUC) 0.78, 95% CI 0.72–0.84; SIMOA: AUC 0.79, 95% CI 0.73–0.85), and both increased the performance of a basic demographic model including only age andAPOE-ε4genotype (p ≤ 0.02). ELISA and SIMOA had positive predictive values of respectively 41% and 36% in cognitively normal elderly and negative predictive values all exceeding 88%. Plasma Aβ1–42/Aβ1–40correlated similarly with amyloid-PET for both platforms (Spearmanρ = − 0.32,p 1–42/t-tau were stronger for ELISA (ρ = 0.41,p = 0.002) than for SIMOA (ρ = 0.29,p = 0.03). Plasma Aβ levels demonstrated poor agreement between ELISA and SIMOA with concentrations of both Aβ1–42and Aβ1–40measured by SIMOA consistently underestimating those measured by ELISA.ConclusionsELISA and SIMOA demonstrated equivalent performances in detecting cerebral amyloidosis through plasma Aβ1–42/Aβ1–40, both with high negative predictive values, making them equally suitable non-invasive prescreening tools for clinical trials by reducing the number of necessary PET scans for clinical trial recruitment.Trial registrationEudraCT 2009-014475-45 (registered on 23 Sept 2009) and EudraCT 2013-004671-12 (registered on 20 May 2014,https://www.clinicaltrialsregister.eu/ctr-search/trial/2013-004671-12/BE).

The artificial distinction between relapsing remitting multiple sclerosis (RRMS) and secondary progressive multiple sclerosis (SPMS) can lead to substantial difficulties in decisions on disease-modifying therapy (DMT) at this stage of multiple sclerosis (MS). There is not a simple transition between the two; patients may demonstrate background progression with superimposed relapses for many years. Progressive disease almost certainly starts some years before clinical acknowledgement; once it is identified, clinicians face a dilemma about the use of highly effective DMT. The influence of highly effective therapy on relapses and medium-term outcomes in early disease is well established; however, disentangling efficacy in terms of relapses and progression at this later stage is more complex.

We thank Ronnelid et al for their comments on our paper, ‘Performance of the 2019 EULAR/ACR classification criteria for systemic lupus erythematosus in early disease, across sexes, and ethnicities.’1 In 2019, the authors comparatively evaluated the ‘diagnostic accuracy’ of the 2019 European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) systemic lupus erythematosus (SLE) criteria2 3 against the 2012 Systemic Lupus International Collaborating Clinics (SLICC) criteria. In referring to their paper,4 we stated that it is inappropriate to evaluate the 2019 EULAR/ACR criteria as diagnostic criteria. Ronnelid et al now point out that diagnostic use of the criteria was not their intention. They make the point that they used the term diagnostic, as diagnostic sensitivity …

Background The impact of different disease stages and treatment for human epidermal growth factor 2 positive (HER2-positive) breast cancer (BC) on work productivity and health-related quality of life (HRQoL) is poorly understood. Methods This was a UK cross-sectional study of 299 adult patients with HER2-positive early or metastatic BC (NCT03099200). Productivity was assessed using the work productivity and activity impairment scale; HRQoL was measured using EuroQol-5 Dimensions-5 levels (EQ-5D-5L), and Functional Assessment of Cancer Therapy Breast (FACT-G and -B) instruments. Three balanced patient groups were recruited: (1) early BC on treatment post-surgery, (2) early BC after completion of adjuvant treatment, (3) during metastatic BC treatment. Between-group comparisons were performed using an analysis of variance. Results Group 1 comprised 89 patients, Group 2, 108 and Group 3, 102. Age, ethnicity and comorbidities were similar across groups. Patients in Group 3 reported more often being unable to work (significant Bonferroni adjusted p p = 0.002). Group 2 also had significantly lower levels of work absenteeism and overall work impairment compared with Group 1 (p p ≤ 0.002), moderate or worse problems in the EQ-5D-5L self-care and usual activity domains (p ≤ 0.001), and lower HRQoL as assessed by FACT summary scores (p p Conclusions Metastatic disease and treatment of HER2-positive BC adversely impacted on work productivity and HRQoL. The results of this study support the idea that being able to delay or prevent the metastatic recurrence of BC, for example by extending the time patients are in remission or at early stage of BC, has wider benefits in terms of patient productivity and HRQoL.

Hydroxychloroquine (HCQ) exerts antiviral effects through several mechanisms. Our initial experience suggests that HCQ could be used for prophylaxis of COVID-19 infection in health care workers (HCW) and could help to control the virus in the early disease stages. We suggest a prophylactic strategy with HCQ for autumn-winter-spring 2020-2021.

Funder: American College of Rheumatology Research and Education Foundation; FundRef: http://dx.doi.org/10.13039/100000960, Funder: National Institute of Arthritis and Musculoskeletal and Skin Diseases; FundRef: http://dx.doi.org/10.13039/100000069, Funder: European League Against Rheumatism; FundRef: http://dx.doi.org/10.13039/501100008741, OBJECTIVES: The European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) 2019 Classification Criteria for systemic lupus erythematosus (SLE) have been validated with high sensitivity and specificity. We evaluated the performance of the new criteria with regard to disease duration, sex and race/ethnicity, and compared its performance against the Systemic Lupus International Collaborating Clinics (SLICC) 2012 and ACR 1982/1997 criteria. METHODS: Twenty-one SLE centres from 16 countries submitted SLE cases and mimicking controls to form the validation cohort. The sensitivity and specificity of the EULAR/ACR 2019, SLICC 2012 and ACR 1982/1997 criteria were evaluated. RESULTS: The cohort consisted of female (n=1098), male (n=172), Asian (n=118), black (n=68), Hispanic (n=124) and white (n=941) patients; with an SLE duration of 1 to

Introduction Achievement of remission is a key treatment goal for patients with axial spondyloarthritis (axSpA). C-OPTIMISE assessed achievement of sustained clinical remission in patients with axSpA, including radiographic (r) and non-radiographic (nr) axSpA, during certolizumab pegol (CZP) treatment, and subsequent maintenance of remission following CZP dose continuation, dose reduction or withdrawal. Here, we report outcomes from the first 48 weeks (induction period) of C-OPTIMISE, during which patients received open-label CZP. Methods C-OPTIMISE (NCT02505542) was a two-part, multicenter, phase 3b study in adult patients with early axSpA (r-/nr-axSpA), including a 48-week open-label induction period followed by a 48-week maintenance period. Patients with active adult-onset axSpA

Quantitative MRI and MRS of muscle are increasingly being used to measure individual pathophysiological processes in Becker muscular dystrophy (BMD). In particular, muscle fat fraction was shown to be highly associated with functional tests in BMD. However, the muscle strength per unit of contractile cross‐sectional area is lower in patients with BMD compared with healthy controls. This suggests that the quality of the non‐fat‐replaced (NFR) muscle tissue is lower than in healthy controls. Consequently, a measure that reflects changes in muscle tissue itself is needed. Here, we explore the potential of water T 2 relaxation times, diffusion parameters and phosphorus metabolic indices as early disease markers in patients with BMD. For this purpose, we examined these measures in fat‐replaced (FR) and NFR lower leg muscles in patients with BMD and compared these values with those in healthy controls. Quantitative proton MRI (three‐point Dixon, multi‐spin‐echo and diffusion‐weighted spin‐echo echo planar imaging) and 2D chemical shift imaging 31P MRS data were acquired in 24 patients with BMD (age 18.8‐66.2 years) and 13 healthy controls (age 21.3‐63.6 years). Muscle fat fractions, phosphorus metabolic indices, and averages and standard deviations (SDs) of the water T 2 relaxation times and diffusion tensor imaging (DTI) parameters were assessed in six individual leg muscles. Phosphodiester levels were increased in the NFR and FR tibialis anterior, FR peroneus and FR gastrocnemius lateralis muscles. No clear pattern was visible for the other metabolic indices. Increased T 2 SD was found in the majority of FR muscles compared with NFR and healthy control muscles. No differences in average water T 2 relaxation times or DTI indices were found between groups. Overall, our results indicate that primarily muscles that are further along in the disease process showed increases in T 2 heterogeneity and changes in some metabolic indices. No clear differences were found for the DTI indices between groups., In this study, diffusion measures and the means and standard deviations of the water T 2 relaxation time and 31P metabolic indices were explored as early markers for muscle tissue changes in the lower leg muscles of patients with Becker muscular dystrophy. Primarily muscles that were further along in the disease process as defined by elevated fat fractions showed increased T 2 heterogeneity in the majority of lower leg muscles and some changes in 31P metabolic indices.

Background Heat shock protein (HSP)-90 promotes tumor growth and is overexpressed in many malignancies. HSP90 expression profile and its potential as a therapeutic target in primary and metastatic neuroendocrine tumors (NETs) are not known. Methods HSP90 cytoplasmic expression and Ki-67 index were re-reviewed and scored by a pathologist blinded to all other clinicopathologic variables for patients who underwent resection of primary and metastatic gastroenteropancreatic (GEP) neuroendocrine tumors at a single institution (2000–2013). Primary outcome was recurrence-free survival (RFS). Results Of 263 tumors reviewed, 73% (n = 191) were primary GEP NETs, and 12% (n = 31) were NET liver metastases. Of the primary GEP-NETs, mean age was 56 years, 42% were male; 53% (n = 103) were pancreatic and 23% (n = 44) were small bowel. HSP90 expression was high in 34% (n = 64) and low in 66% (n = 127). Compared to low expression, high HSP90 was associated with advanced T-stage (T3/T4) (47 vs 27%; p = 0.02). Among patients who underwent curative-intent resections for primary, non-metastatic NETs (n = 145), high HSP90 was independently associated with worse RFS (HR 5.09, 95% CI 1.65–15.74; p = 0.005), after accounting for positive margin, LN involvement, increased tumor size, site of primary tumor, and Ki-67. When assessing NET liver metastases, 13% (n = 4) had high HSP90 expression and 87% (n = 26) had low expression. Patients with liver metastases with high HSP90 tended to have worse 1- and 3-year progression-free survival (25%, 25%) compared to those with low HSP90 (69%, 49%; p = 0.059). Conclusion HSP90 exhibits differential expression in resected GEP-NETs and liver metastases. High cytoplasmic expression is associated with early disease recurrence, even after accounting for other adverse pathologic factors. HSP90 inhibition may be a potential therapeutic target for neuroendocrine tumors.

Understanding temporal dynamics of COVID-19 patient symptoms could provide fine-grained resolution to guide clinical decision-making. Here, we use deep neural networks over an institution-wide platform for the augmented curation of clinical notes from 77,167 patients subjected to COVID-19 PCR testing. By contrasting Electronic Health Record (EHR)-derived symptoms of COVID-19-positive (COVIDpos; n=2,317) versus COVID-19-negative (COVIDneg; n=74,850) patients for the week preceding the PCR testing date, we identify anosmia/dysgeusia (27.1-fold), fever/chills (2.6-fold), respiratory difficulty (2.2-fold), cough (2.2-fold), myalgia/arthralgia (2-fold), and diarrhea (1.4-fold) as significantly amplified in COVIDpos over COVIDneg patients. The combination of cough and fever/chills has 4.2-fold amplification in COVIDpos patients during the week prior to PCR testing, and along with anosmia/dysgeusia, constitutes the earliest EHR-derived signature of COVID-19. This study introduces an Augmented Intelligence platform for the real-time synthesis of institutional biomedical knowledge. The platform holds tremendous potential for scaling up curation throughput, thus enabling EHR-powered early disease diagnosis.

Cardiomyopathy is the leading cause of death in Duchenne muscular dystrophy (DMD). Elevated troponin levels are observed in DMD and may vary with disease progression. We studied troponin levels in DMD related to cardiac fibrosis and native T1 measures. This is a prospective, cross-sectional, observational study of 30 DMD subjects measuring native T1 levels and late gadolinium enhancement (LGE) on cardiac MR imaging (CMR) correlated with temporally associated serum troponin I levels. Non-parametric analyses including Spearman correlations and Kruskal–Wallis test were performed between groups. p values resulting from the pair-wise comparisons were adjusted for multiple comparisons using the Sidak method where appropriate. There were 15 DMD subjects with no LGE (age 12 ± 3 yo; EF% 60 ± 5) and troponin I level of 0.05 ± 0.08 ng/ml, of which three had an abnormal troponin level (over 0.04 ng/ml); 7 DMD subjects with mild LGE (age 17 ± 5 yo, EF% 52 ± 8) and troponin I level of 0.28 ± 0.36 ng/ml, of which five had an abnormal troponin level; and 8 DMD subjects with moderate-to-severe LGE (age 16 ± 6 yo; EF% 54 ± 8) and troponin I level of 0.11 ± 0.14 ng/ml, of which four had an abnormal troponin level. Troponin I levels in DMD subjects with mild LGE was significantly increased compared to subjects with no LGE (p = 0.02). There was a statistically significant positive correlation between troponin I levels and MOLLI septal native T1 values (r(2) = 0.173, p = 0.02). Overall, MOLLI lateral native T1 levels were increased with moderate–severe LGE compared to mild and none (p < 0.01). Serum biomarker troponin I levels were increased in DMD subjects with mild LGE and correlated with MOLLI septal native T1 values. Troponin I levels may be a useful minimally invasive outcome marker to monitor myocardial disease progression in DMD cardiomyopathy.

Head and neck cancer (HNC) accounts for more than 330,000 cancer deaths annually worldwide. Despite late diagnosis being a major factor contributing to HNC mortality, no satisfactory biomarkers exist for early disease detection. Cytoplasmic gelsolin (cGSN) was discovered to predict disease progression in HNC and other malignancies, and circulating plasma gelsolin (pGSN) levels are significantly correlated with infectious and inflammatory disease prognoses. Here, the plasma levels of five candidate biomarkers (circulating pGSN, squamous cell carcinoma antigen, cytokeratin 19 fragment, soluble Fas, and soluble Fas ligand (sFasL)) in 202 patients with HNC and 45 healthy controls were measured using enzyme-linked immunosorbent assay or Millipore cancer multiplex assay. The results demonstrated that circulating pGSN levels were significantly lower in patients with HNC than in healthy controls. Moreover, circulating pGSN outperformed other candidate biomarkers as an independent diagnostic biomarker of HNC in both sensitivity (82.7%) and specificity (95.6%). Receiver operating characteristic curves indicated that combined pGSN and sFasL levels further augmented this sensitivity (90.6%) for early disease detection. Moreover, higher pGSN levels predicted improved prognosis at both 5-year overall survival and progression-free survival. In conclusion, circulating pGSN could be an independent predictor of favorable clinical outcomes and a novel biomarker for the early HNC detection in combination with sFasL.

Purpose Endometrial cancer (EC) is the most common gynecological malignancy with high disease burden especially in advanced stages of the disease. Our study investigated the metabolomic profile of EC patient’s serum with the aim of identifying novel diagnostic biomarkers that could be used especially in early disease detection. Material and methods Using targeted metabolomic serum profiling based on HPLC-TQ/MS, women with EC (n ​= ​15) and controls (n ​= ​21) were examined for 232 endogenous metabolites. Results Top performing biomarkers included ceramides, acylcarnitines and 1-methyl adenosine. Top 4 biomarkers combined achieved 94% sensitivity with 75% specificity with AUC 92.5% (CI 90.5–94.5%). Individual markers also provided significant predictive values: C16-ceramide achieved sensitivity 73%, specificity 81%, AUC 0.83, C22-ceramide sensitivity 67%, specificity 81%, AUC 0.77, hydroxyhexadecenoylcarnitine sensitivity 60%, specificity 96%, AUC 0.76 and 1-methyladenosine sensitivity 67%, specificity 81%, AUC 0.75. The individual markers, however, did not reach the high sensitivity and specificity of the 4-biomarker combination. Conclusions Using mass spectrometry targeted metabolomic profiling, ceramides, acylcarnitines and 1-methyladenosine were identified as potential diagnostic biomarkers for EC. Additionally, these identified metabolites may provide additional insight into cancer cell metabolism.

Background Supported by both the ACR and EULAR, the EULAR/ACR 2019 Classification Criteria for SLE employ positive ANA (ever) as an entry criterion and use a weighted scheme with values ranging from 2 to 10, for a classification cut-off of 10. Criteria items are attributed to SLE only if there is no more likely alternative diagnosis in the individual patients. Items are organized in domains, and only the highest ranking item within a domain is counted. These criteria have been validated in a cohort of 696 SLE patients and 574 non-SLE patients from a total of 21 centers, reaching an overall sensitivity of 96.1% and a specificity of 93.4%. To at least estimate the performance in groups underrepresented in the validation cohort of this transatlantic project, we analyzed this cohort for patient subsets with regard to sex, ethnicity, and disease duration. Methods The full EULAR/ACR 2019 classification criteria validation cohort was analyzed for female (n=1,098) and male (n=172) patients, Asian (n=118), Black (n=68), Hispanic (n=124) and White (n=941) patients, and patients with an SLE duration of less than 1 year (n=34), one to less than 3 years (n=196), 3 to less than 5 years (n=157), and 5 or more years (n=879). Sensitivity and specificity were calculated for the EULAR/ACR 2019 criteria, the SLICC 2012 criteria and the ACR 1997 criteria each. Results As shown in table 1, most of the point estimates for sensitivity and specificity in subsets lay within the 95% confidence intervals of the sensitivity and specificity of the EULAR/ACR 2019 criteria validation. In particular, sensitivity and specificity for all ethnic groups were within the confidence intervals or even higher. Formally, the sensitivity was slightly lower for male patients, corresponding to a higher specificity, but the male 95% confidence intervals (0.86–0.98 for sensitivity, 0.90–0.99 for specificity) overlapped. While sensitivity appeared independent of disease duration from year 1 on, sensitivity was only 89% in the first year of disease, identical to the SLICC criteria (89%) and numerically higher than the ACR criteria (56%), but all confidence intervals overlapped. Conclusion While not all subgroups of SLE patients in the validation cohort are of adequate size to fully explore the sensitivity and specificity of the EULAR/ACR 2019 SLE classification criteria in the respective subsets, the point estimates of sensitivity and specificity suggest that the new criteria perform at least reasonably well in all ethnic groups, in men and in early disease. Nevertheless, sensitivity and specificity should be independently validated in larger groups of Asian, Black and Hispanic patients, male patients and in early disease.

We described a reduction of target of Myb1 (TOM1) protein levels by Western blot in the postmortem hippocampus of subjects with Alzheimer’s disease (AD) versus nondemented subjects (1), validating similar findings by an independent research group in a separate human cohort (2). Based on single-cell transcriptomic data (3), Peng and Zhao (4) conclude that TOM1 levels are, contrariwise to our findings, higher in AD. Although we do not disagree with their hypothesis that TOM1 expression could be up-regulated in AD, at least at early disease stages, precautions should be taken when comparing our findings to theirs. First, we determined the protein levels in the hippocampus whereas the RNAseq was performed in the prefrontal cortex. Discrepancies could therefore be related to … [↵][1]1To whom correspondence may be addressed. Email: d.baglietto{at}uci.edu, rodrigo.medeiros{at}neurula.org, or laferla{at}uci.edu. [1]: #xref-corresp-1-1

The Italian Association of Medical Oncology (AIOM) has developed clinical practice guidelines for the diagnosis and treatment of patients with early and locally advanced non-small cell lung cancer. In the current paper a panel of AIOM experts in the field of thoracic malignancies discussed these topics, analyzing available scientific evidences, with the final aim of providing a summary of clinical recommendations, which may guide physicians in their current practice.

Although colorectal cancer (CRC) is the second leading cause of death in developed countries, current diagnostic tests for early disease stages are suboptimal. We have performed a combination of UHPLC-MS metabolomics and 16S microbiome analyses on 224 feces samples in order to identify early biomarkers for both advanced adenomas (AD) and CRC. We report differences in fecal levels of cholesteryl esters and sphingolipids in CRC. We identified Fusobacterium, Parvimonas and Staphylococcus to be increased in CRC patients and Lachnospiraceae family to be reduced. We finally described Adlercreutzia to be more abundant in AD patients&rsquo, feces. Integration of metabolomics and microbiome data revealed tight interactions between bacteria and host and performed better than FOB test for CRC diagnosis. This study identifies potential early biomarkers that outperform current diagnostic tools and frame them into the stablished gut microbiota role in CRC pathogenesis.

Triple-negative breast cancer (TNBC) occurs in around one-sixth of all breast cancer (BC) patients, with the most aggressive behavior and worst prognosis of all BC subtypes. It is a heterogeneous disease, with specific molecular characteristics and natural dynamics of early recurrence and fast progression. Due to the lack of biomarkers or any valid treatment targets, it can only be treated with classic cytotoxic chemotherapy. We analyzed a cohort of 152 patients, median age 58 years, diagnosed with and treated for early stage TNBC at the University Hospital for Tumors, Sestre milosrdnice University Hospital Centre, Zagreb, Croatia, during the 2009-2012 period. Patients were treated with primary surgical approach, adjuvant chemotherapy and adjuvant irradiation. We observed a relatively large proportion of locally advanced TNBC at diagnosis, with large tumor size and nodal involvement, with high grade and high proliferation index Ki67. Patient age, tumor size and lymph node involvement, as expected, were significant and clinically most important prognostic factors for 5-year disease-free survival (67%; 95% CI 60%-75%) and overall absolute survival rate (74%; 95% CI 66%-81%)., Trostruko negativni rak dojke (TNRD) javlja se u oko šestine svih bolesnica s rakom dojke, s najagresivnijim ponašanjem i najgorom prognozom od svih podtipova raka dojke. To je heterogena bolest sa specifičnim molekularnim karakteristikama i prirodnom dinamikom ranog povrata i brze progresije bolesti. Zbog nedostatka biobiljega ili bilo kakvog uporabljivog terapijskog cilja temelj liječenja i dalje je klasična citotoksična kemoterapija. Analizirali smo kohortu od 152 bolesnice, medijan dobi 58 godina, dijagnosticirane i liječene od ranog TNRD u Klinici za tumore Kliničkoga bolničkog centra Sestre milosrdnice u Zagrebu, Hrvatska u razdoblju od 2009. do 2012. godine. Bolesnice su liječene primarno kirurškim pristupom, adjuvantnom kemoterapijom i adjuvantnim zračenjem. Zamijetili smo relativno velik udio lokalno uznapredovalog stadija TNRD pri dijagnozi, s velikom veličinom tumora i zahvaćanjem limfnih čvorova, visokim gradusom i visokim proliferacijskim indeksom Ki 67. Dob bolesnica, veličina tumora i zahvaćenost limfnih čvorova, očekivano, pokazali su se statistički značajnim i klinički najvažnijim prognostičkim čimbenicima petogodišnjeg preživljenja bez bolesti (67%; 95% CI 60-75%) i stope sveukupnog preživljenja (74%; 95% CI 66-81%).

Objectives According to the existence of subclinical organ involvement pre-scleroderma should be divided into two subsets: very early and early disease. Pre-scleroderma patients included in the Spanish Scleroderma Registry (RESCLE) Cohort were reclassified into subsets. Differences were evaluated and the risk of progression to definite systemic sclerosis was estimated. Methods The characteristics of very early and early SSc patients were compared. A logistic regression model was used to determine the risk factors of progression. Results 1632 patients were included, 36 (2.2%) in the very early subset and 111 (6.8%) in the early subset. There were no differences in sex, age at disease onset, duration of Raynaud's phenomenon, antinuclear antibodies or capillaroscopic findings. Three (8.3%) very early SSc patients evolved to definite SSc, 2 (5.6%) of them meeting the ACR/EULAR 2013 criteria, unlike 31 (28%) early SSc patients, 20 (24%) of them meeting the criteria ( p = 0.034). Digestive involvement was an independent risk factor of progression (OR 17; 95% CI, 6.1–47.2). Conclusions The classification of early forms of scleroderma identifies patients with different prognostic risk of progression. The evolution to definite SSc is more frequent in early than in very early SSc patients. Digestive involvement is a risk factor of progression. An active assessment of organ damage in preclinical stages allows a correct classification and risk stratification, with implications for monitoring and treatment.