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DNA/RNA-based classification of bladder cancer (BC) supports the existence of multiple molecular subtypes, while investigations at the protein level are scarce. Here, we aimed to investigate if Nonmuscle Invasive Bladder Cancer (NMIBC) can be stratified to biologically meaningful groups based on the proteome. Tissue specimens from 117 patients at primary diagnosis (98 with NMIBC and 19 with MIBC), were processed for high-resolution proteomics analysis by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The proteomics output was subjected to unsupervised consensus clustering, principal component analysis (PCA) and investigation of subtype-specific features, pathways, and gene sets. NMIBC patients were optimally stratified to three NMIBC proteomic subtypes (NPS), differing in size, clinicopathologic and molecular backgrounds: NPS1 (mostly high stage/grade/risk samples) was the smallest in size (17/98) and overexpressed proteins reflective of an immune/inflammatory phenotype, involved in cell proliferation, unfolded protein response and DNA damage response, whereas NPS2 (mixed stage/grade/risk composition) presented with an infiltrated/mesenchymal profile. NPS3 was rich in luminal/differentiation markers, in line with its pathological composition (mostly low stage/grade/risk samples). PCA revealed a close proximity of NPS1 and conversely, remoteness of NPS3 to the proteome of MIBC. Proteins distinguishing these two extreme subtypes were also found to consistently differ at the mRNA levels between high and low-risk subtypes of the UROMOL and LUND cohorts. Collectively, our study identifies three proteomic NMIBC subtypes and following a cross-omics validation in two independent cohorts, shortlists molecular features meriting further investigation for their biomarker or potentially therapeutic value.

Metaplastic breast carcinoma (MBC) is a rare subtype of invasive breast cancer consisting of various combinations of malignant epithelial and mesenchymal cells. Its aggressive growth pattern combined with its histological heterogeneity account for MBC's characteristic resistance to systemic therapies, which subsequently leads to increased risk of recurrence and breast cancer mortality compared with other invasive mammary carcinomas. The aim of this review is to discuss the current therapeutic approaches, both in loco-regional as well as in systemic management of MBC. With the accumulation of knowledge from histopathologic assessment and the increasing identification of underlying molecular aberrations, emerging, novel targeted therapies will enable physicians to implement a more individualized and efficacious therapeutic strategy, leading hopefully to an improvement in the poor prognosis of MBC.

Tyrosine kinase inhibitors that target the BCR/ABL mutation have been used as therapies of BCR/ABL positive acute lymphoblastic leukemia (ALL) with significant results. Dasatinib is a multitargeted tyrosine kinase inhibitor with significant activity in Philadephia positive ALL which is resistant to imatinib, as well as in treatment-naïve patients. We present a case of an elderly patient with Philadelphia chromosome-positive ALL, who presented with acute hypoxic respiratory failure in the setting of active immunotherapy with dasatinib.

Thyrotoxic periodic paralysis (TPP) is characterized by a classic triad of muscle paralysis, hypokalemia, and hyperthyroidism. The underlying thyroid disorder is often very subtle making it challenging to recognize TPP. It is a completely reversible condition if diagnosed early; however, it is associated with fatal outcomes if delayed.

Immunoglobulin A vasculitis (IgA vasculitis) is a small-vessel vasculitis usually triggered by bacterial or viral infections, antibiotics, and vaccinations. Although it is a disease of the pediatric population, it can occur in adults as well. We present a case of IgA vasculitis that was triggered by underlying infective endocarditis (IE). IE is a rare and fatal cause of the vasculitis that requires timely diagnosis and management to prevent catastrophic outcomes. Our patient was treated with antibiotics for IE, which led to the resolution of vasculitis.

Pulmonary fibrosis is a chronic progressive interstitial lung disease characterized by repetitive cycles of epithelial cell injury and dysregulated repair. Although most cases of pulmonary fibrosis are idiopathic, a detailed history that includes medications, comorbidities, tobacco use, environmental exposures, and family history should be taken to rule out secondary etiology. We present a case of flavocoxid-induced pulmonary toxicity which progressed from hypersensitivity pneumonitis to pulmonary fibrosis even after discontinuation of the offending drug.

Paraneoplastic manifestations are frequently seen in patients with small cell lung carcinoma (SCLC) and can present as diverse clinical entities ranging from endocrinopathies to neurological conditions. Anti-Hu encephalitis is a rare paraneoplastic manifestation most commonly seen in patients with SCLC. This case highlights an SCLC patient who presented with behavioral changes, cognitive deficits, and memory issues, and was found to have anti-Hu encephalitis. The subacute course of this clinical entity should be kept in mind and prompt further investigation in SCLC patients with these symptoms, especially when the laboratory workup of the major culprits is negative or inconclusive.

Background: Glioma is a heterogeneous, highly complicated central nervous system (CNS) tumor with uncertain mechanism of initiation and progression, resulting in an unfavorable outcome. An extended network of cytokines is recognized as a major regulator of glioma pathogenesis, either promoting or inhibiting glioma progression based on their type and specificity. Interleukin-8 (IL-8) has been revealed as a critical regulator of CNS function and development with participation in many CNS disorders including gliomas. Objective: The aim of the present review is to address the role of IL-8 in glioma pathogenesis focusing on the implicated molecular pathways as well as on its potential targeting for glioma therapy. Methods and Results: PubMed-Medline, SCOPUS, and Google Scholar databases were searched for pre-clinical and clinical studies related to IL-8 implication in gliomagenesis and IL-8 targeting strategies for gliomas. Literature data indicate that IL-8 participates in glioma angiogenesis and cell migration and it can serve as a potential biomarker, for early diagnosis, follow-up and response to therapy. Conclusion: Several promising approaches that target directly or indirectly IL-8 effects in gliomas are currently in progress while more-in-depth studies are needed to validate its biomarker role and elucidate the underlying molecular mechanisms.

6569 Background: Lung cancer (ca) screening has shown to reduce mortality by up to 20%.Despite this, only 4% of eligible patients in the US undergo screening. Our initial analysis revealed that 18.3% of patients who met screening criteria had an appropriately ordered LDCT scan, with an 8.7% completion rate. The aim of this study was to improve lung ca screening compliance following the USPSTF guidelines among residents from the University of Connecticut Internal Medicine (IM) residency program at a Clinic in Hartford, Connecticut. Methods: Care provided to patients by an IM resident at the Gengras Clinic were included. After initial data was gathered, we implemented an intervention to improve screening compliance between October 2019 and March 2020, when SARS-CoV-2 pandemic occurred and routine services were interrupted. USPSTF screening guidelines were emailed monthly to residents and attendings; they were reminded of the importance of lung ca screening; updating the pack-year smoking history; as well as instructions on correctly ordering LDCT and documenting shared decision making, which is needed for insurance approval. In-person reminders also occurred at the clinic. Results: Post-intervention, 601 charts were reviewed. 168/601 (27%) patients met screening criteria. 433 patients were excluded due to unclear pack-year, did not meet screening criteria, were deceased or last seen at the clinic prior to the intervention. 63/168 (37.5%) met the criteria and had an appropriately ordered LDCT; 51/168 (30.35%) had a completed LDCT in chart. The remaining 12/168 (7.14%) with an appropriately ordered LDCT, had it scheduled at the time of data collection or it had been cancelled for unclear reasons. 20 patients’ LDCT was ordered by their pulmonologist. 94 (62.5%) who met screening criteria did not have a LDCT ordered. 11 patients with a smoking history, who did not meet screening criteria had a LDCT ordered because of clinical suspicion for cancer. Lastly, 4/168 (2.4%) had a diagnosis of personal history of lung ca. Conclusions: After our educational intervention, patients who qualified had an increase of LDCT being ordered (37.5% from 18.3%) and completed (30.3% from 8.7%). This is, to our knowledge, the first study of its kind. We identified areas of improvement that were key to achieving higher screening rates: educating all residents and attendings on lung ca screening guidelines; educating patients on the importance of undergoing screening tests; creating a best practice advisory in the electronic medical record system that reminds provider to input pack-year smoking history and if the criteria for screening is met, a pop-up prompting the provider to order LDCT; obtaining insurance approval; and lastly, stressing the importance on screening and overall outcomes.

Background: Infections are among the most serious complications in patients with aNCA-associated vasculitides (AAV) and contribute significantly in overall mortality. Objectives: To describe the incidence and risk factors for serious infections, as well as the patterns of cotrimoxazole prophylaxis in aAV patients (GPA and MPA). Methods: Retrospective, descriptive study of aAV patients followed in a tertiary referral center (Clinical Immunology-Rheumatology Unit and Nephrology department). Patient and disease characteristics treatments and serious infections were recorded. Results: 56 aAV patients were included (women: 50%, mean age at diagnosis: 59.8 years, mean disease duration: 5.1 years, GPA: 68%, generalized disease: 82%). Most frequent organ involvement was renal (71%), lung (68%), nervous (20%), skin (18%) and mucous membranes/eyes (14%). 21 serious infections were recorded in 16 patients (incidence: 7.2 per 100 patient-years), with respiratory tract infections (43%) and herpes zoster (19%) being the most frequent. Incidence was 6.2-times higher in patients with severe combined lung-kidney involvement compared to those without (20 vs 3.2 per 100 patient-years, p 60 years (62% vs 35%) and treatment with cyclophosphamide (CYC)/rituximab (RTX) combination (38% vs 3%, p=0.001) were more common among those who developed a serious infection. Lung-kidney involvement and combined CYC/RTX treatment remained statistically significant in multivariate logistic regression analysis. Cotrimoxazole prophylaxis was given in 70% of patients treated with CYC and/or RTX (n=46). Patients with combined lung-kidney involvement were more likely to receive prophylaxis (82% vs 58%, p=0.08). No case of pneumocystis pneumonia was diagnosed during follow-up. Conclusion: In this real-life cohort, more than one out of four aAV patients experienced a serious infection during follow-up, with pneumonia and herpes zoster being the most frequent. Patients with combined lung and kidney involvement had a ∼6 times higher risk for developing a serious infections and were more likely to receive appropriate cotrimoxazole prophylaxis. Disclosure of interests: None declared

Coronary artery disease remains the leading cause of mortality in adult diabetic population with however, a high predominance also in non-diabetic subjects. In search of common molecular mechanisms and metabolic by-products with potential pathogenic role, increased advanced glycation end products (AGEs) present a critical biomarker for CAD development in both cases. Interaction of AGEs with their transmembrane cell receptor, RAGE in endothelial and smooth muscle cells as well as in platelets, activates intracellular signaling that leads to endothelial injury, modulation of vascular smooth muscle cell function and altered platelet activity. Furthermore, tissue accumulation of AGEs affects current treatment approaches being involved in stent restenosis. The present review provides an update of AGE-induced molecular mechanisms involved in CAD pathophysiology while it discusses emerging therapeutic interventions targeting AGE reduction and AGE-RAGE signaling with beneficial clinical outcome.

INTRODUCTION: Lyme disease can cause significant cardiovascular complications such as channelopathies, cardiomyopathy, or peri-myocarditis (PM) We present a case of PM in a young patient who was managed with timely initiation of antibiotics METHODS: A 21-year-old male with no significant medical or family history presented to the hospital with chest pain He was in his usual state of health when he developed a sudden onset of dull, substernal chest pain, radiating to the bilateral upper extremities On presentation, his physical examination was unremarkable Electrocardiogram demonstrated diffuse ST-segment elevations in the precordial leads Laboratory investigations were notable for a troponin elevation of 12 ng/ml Echocardiogram was unremarkable The patient was admitted to the hospital for possible PM and was initiated on colchicine therapy He underwent cardiac magnetic resonance imaging, which revealed a patchy intramural myocardial enhancement consistent with myocarditis Workup included testing for COVID-19, Epstein-Barr virus, Coxsackie virus, which was negative, and rheumatologic workup was negative Upon further investigation, it was revealed that the patient had a tick bite a few weeks ago Subsequently, he had a positive serological test for Lyme disease with positive IgM antibodies which were confirmed on the immunoblot test PM was thereby attributed to Lyme disease, and the patient was treated with doxycycline for 21 days with complete resolution RESULTS: PM is characterized by varying disease manifestations and may rapidly deteriorate into a lifethreatening condition leading to catastrophic outcomes such as arrhythmias, cardiac arrest, or cardiogenic shock The etiology of PM is broad and can be due to a variety of insults Lyme carditis occurs when the bacteria disseminate and affect the cardiac muscle and the conduction system Although the predominant abnormality is heart block, PM is a rare manifestation of Lyme carditis Physicians should have a high degree of clinical suspicion to diagnose this condition to prevent catastrophic cardiovascular outcomes Timely introduction of antibiotic therapy is essential to prevent fatal outcomes

e19187 Background: Lung cancer remains the leading cause of morbidity and mortality, with an estimated 2.1 million newly diagnosed cases each year. A large percentage of cases are detected at an advanced stage, making treatment recalcitrant. Only about 15% are diagnosed at an early stage, highlighting the significance of timely screening. USPSTF recommends annual screening with low-dose computed tomography (LDCT) in adults aged 55-80, who have a 30 pack-year smoking history and are current smokers, or former smokers who have quit within the last 15 years. The National Comprehensive Cancer Network (NCCN) guidelines, as well as the National Lung Screening Trial (NLST), recommend annual screening with LDCT until a person is no longer a candidate for definitive treatment. This study aimed to evaluate the compliance with annual LDCT based on USPSTF guidelines among internal medicine residents from the University of Connecticut residency program at a Clinic in Hartford, Connecticut, USA. Methods: Patients who were under the care of internal medicine residents and who had undergone an initial LDCT for lung cancer screening were included. A total of 61 medical charts were reviewed. Three patients were diagnosed with lung cancer and nineteen patients had their initial LDCT in 2019, and therefore excluded. Results: Out of the 39 patients, 10 patients (25.64%) had a follow-up annual LDCT performed, 2 patients before the annual mark due to various clinical concerns, and 9 patients (23%) in the following 24-48 months. 6 patients (15.38%) had a repeat LDCT ordered but was not done or it was canceled. 12 patients (30.77%) had no repeat LDCT ordered at 12 months. Overall, 69.23% had no follow-up CT at 12 months, and 46.15% with no follow up CT at all at the time of chart review. Conclusions: Based on our analysis, follow-up annual LDCT scans for lung cancer screening on patients under the care of residents-in-training are not being ordered frequently enough. The failure to order annual LDCT could be due to a false sense of relief with a normal initial LDCT, the lack of provider’s awareness of USPSTF guidelines, or insurance issues. Educating primary care providers on the importance of follow-up annual LDCT will ensure early detection and decrease mortality from lung cancer in high risk patient population.