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MET exon 14 ( MET ex14) skipping mutations occur in 3% to 4% of non-small cell lung cancer (NSCLC) cases. Currently, four oral MET tyrosine kinase inhibitors (TKIs) are in use for the treatment of patients with MET ex14 skipping NSCLC (tepotinib, capmatinib, savolitinib, and crizotinib). To support optimal management of MET ex14 skipping NSCLC in this typically older patient population, the safety profiles of these treatment options are reviewed here. Published safety data from prospective clinical trials with MET TKIs in patients with MET ex14 skipping NSCLC were reviewed. Treatmentrelated adverse events (TRAEs) occurring in > 10% of patients were reported where feasible. Guidance on clinical monitoring and management of key MET TKI TRAEs and dr ug-dr ug interactions is provided. Across the clinical trials, safety data for MET TKIs were reported for 442 patients with MET ex14 skipping. Peripheral edema was the most reported TRAE (50%-63% of patients; grade > 3: 1%-11%), followed by nausea (26%-46% of patients; grade > 3: 0%1%). TRAEs led to dose reductions in 33% to 38% of patients and to discontinuation in 7% to 14% of patients, across the MET TKIs. Considerations on interpreting available safety data are provided, along with insights into monitoring and managing specific MET TKI TRAEs of interest and dr ug-dr ug interactions. Overall, MET TKIs are tolerable treatment options for patients with MET ex14 skipping NSCLC, an older population for whom chemo- or immuno-therapy may not be an effective nor tolerable option. More data regarding the effectiveness of safety interventions and management strategies are needed.

A 59-year-old man presented with exertional dyspnoea and pretibial oedema that had lasted 6 months. He was referred to our hospital with suspected constrictive pericarditis (CP). Several examinations, including CT, echocardiography and cardiac catheterisation, indicated heart failure associated with CP that had been induced by trauma 13 years prior. The CP and heart failure were unresponsive to medical treatment, therefore, a surgical pericardiectomy was performed, which is considered the only definitive treatment. Pathological examination of the resected pericardium revealed a fatty texture and dense fibrous connective tissues, which are associated with old haemorrhage and focal calcification. The patient’s symptoms were improved to New York Heart Association Class I, and his peripheral oedema disappeared 6 months after leaving hospital.

Актуальність теми. Інфузійна терапія є невід’ємною частиною інтенсивної терапії постраждалих з тяжкою черепно-мозковою травмою (ЧМТ), однак ефективність інфузійно-трансфузійної терапії багато в чому залежить від цілеспрямованого обґрунтування її програми, характеристик інфузійних розчинів, їх фармакологічних властивостей і фармакокінетики. На даному етапі інтенсивної терапії вибір розчину для проведення волемічної підтримки у постраждалих із тяжкою черепно-мозковою травмою залишається дискутабельним. Мета дослідження: оптимізувати методику проведення волемічної підтримки у постраждалих із тяжкою черепно-мозковою травмою з метою зменшення вираженості набрякового синдрому. Матеріали та методи. Обстежено 60 постраждалих із тяжкою ЧМТ віком від 18 до 65 років, з рівнем свідомості 5–11 балів за шкалою коми Глазго при надходженні та через 12 годин після проведення первинної ресусцитації та тяжкістю стану за шкалою APACHE II 21,0 ± 2,7 бала, які були поділені на дві групи: контроль та дослідження. Постраждалим у групі контролю волемічна підтримка проводилась розчином NaCl 0,9% за загальноприйнятою методикою. У групі дослідження волемічна підтримка проводилась збалансованим кристалоїдним розчином. В обох групах моніторувались показники збільшення товщини масиву тканин у фронтальній ділянці, на тилі стопи та окружності над променево-зап’ястковим суглобом. Результати. За даними нашого дослідження, у постраждалих, волемічна підтримка яким здійснювалась збалансованим кристалоїдним розчином, набряковий синдром був менш вираженим, також у групі дослідження спостерігається регресування набрякового синдрому на 8–9-й добі лікування, на той час як у групі контролю набряки зберігаються впродовж усіх 10 діб лікування. Висновки. Встановлено, що застосування для волемічної підтримки збалансованого кристалоїдного розчину суттєво зменшило вираженість набрякового синдрому у постраждалих із тяжкою черепно-мозковою травмою впродовж перших 10 діб лікування, дозволило ліквідувати набряковий синдром до 9–10-ї доби лікування, що, у свою чергу, дозволяє покращити параметри зовнішнього дихання, зменшити кількість ускладнень з боку дихальної системи, тривалість проведення штучної вентиляції легень, а відповідно і перебування у відділенні інтенсивної терапії та термінів лікування.

Dysphonia has been reported with anti-angiogenic chemotherapy agents. Dysphonia in patients with cancer receiving chemotherapy tends to be overlooked in clinical practice since it is non-life-threatening. However, it reduces quality of life. Although inhibition of vascular endothelial growth factor receptor is the reported mechanism of dysphonia, it has not been elucidated. We report 6 cases of patients with dysphonia suspected to be due to panitumumab and nivolumab that have not been reported previously. Peripheral edema, a factor in dysphonia, can be seen with aflibercept, bevacizumab, panitumumab, and nivolumab. Therefore, chemotherapy drugs with peripheral edema may be related to dysphonia.

The deficits in sensory pathways caused by peripheral edema, pain, and inflammation of the damaged ligaments may induce maladaptive changes within the central nervous system. The purpose of this study was to determine whether patients with lateral ankle instability (LAI) exhibit morphological differences of brain grey matter when compared with healthy controls, and then assess the relationships between the observed differences and the characteristics of patients.Cross-sectional.Thirty patients with LAI and 32 healthy controls without LAI underwent MRI scans using anatomical T1 sequences. A voxel-wise general linear model was used to compare the grey matter volume throughout the whole brain between patients and controls. Linear regression analyses were performed for the grey matter volume within the significant clusters to assess their relationship with age, sex, the existence of acute injury, pain level, sports activity level, and the duration of LAI within the patient group.The grey matter volume of a cluster within the cerebellar vermis (Vermis_4_5 in automated anatomical labeling template) was significantly reduced in patients with LAI (Gaussian Random Field corrections with two-tailed p-cluster 0.05 and p-voxel 0.001). Multivariate linear regression analysis revealed that the duration of LAI tended to be passively associated with the grey matter volume of this LAI-related vermal cluster (p = 0.092).Participants with LAI exhibited a reduced grey matter volume of a cluster within the cerebellar vermis compared with participants without LAI, and the degree of volume reduction tended to be positively associated with the duration of LAI.

Background Constrictive pericarditis (CP) is characterized by scarring and loss of elasticity of the pericardium. This case demonstrates that mixed martial arts (MMA) is a previously unrecognized risk factor for CP, diagnosis of which is supported by cardiac imaging, right and left heart catheterization, and histological findings of dense fibrous tissue without chronic inflammation. Case presentation A 47-year-old Caucasian male former mixed martial arts (MMA) fighter from the Western United States presented to liver clinic for elevated liver injury tests (LIT) and a 35-pound weight loss with associated diarrhea, lower extremity edema, dyspnea on exertion, and worsening fatigue over a period of 6 months. Past medical history includes concussion, right bundle branch block, migraine headache, hypertension, chronic pain related to musculoskeletal injuries and fractures secondary to MMA competition. Involvement in MMA was extensive with an 8-year history of professional MMA competition and 13-year history of MMA fighting with recurrent trauma to the chest wall. The patient also reported a 20-year history of performance enhancing drugs including testosterone. Physical exam was notable for elevated jugular venous pressure, hepatomegaly, and trace peripheral edema. An extensive workup was performed including laboratory studies, abdominal computerized tomography, liver biopsy, echocardiogram, and cardiac magnetic resonance imaging. Finally, right and left heart catheterization—the gold standard—confirmed discordance of the right ventricle-left ventricle, consistent with constrictive physiology. Pericardiectomy was performed with histologic evidence of chronic pericarditis. The patient’s hospital course was uncomplicated and he returned to NYHA functional class I. Conclusions CP can be a sequela of recurrent pericarditis or hemorrhagic effusions and may have a delayed presentation. In cases of recurrent trauma, CP may be managed with pericardiectomy with apparent good outcome. Further studies are warranted to analyze the occurrence of CP in MMA so as to better define the risk in such adults.

BACKGROUND Aggressive intravenous fluid hydration, by administering 3500 mL of lactated Ringer's solution (LRS) in 9 h with a peri-procedural bolus, reduces post-ERCP pancreatitis (PEP) incidence. A concern of this strategy is adverse events related to volume overload; however, the impact of fluid hydration over an extended period without a bolus on PEP is unknown. AIM To assess the effect of continuous infusion of high-volume fluid at a constant rate over 24 h on PEP incidence and severity. METHODS Two-hundred patients were randomly assigned (1:1) to receive either 3600 mL of LRS in 24 h starting 2 h before the ERCP (high-volume group) or maintenance fluid hydration calculated by the Holliday-Segar method (control group). RESULTS The mean age of the patients was 50.6 ± 11.6 years. The predominant indications were choledocholithiasis (48%) and malignancies (32%). Patient demographics and PEP risk factors were similar in both groups. Patients in the high-volume group received significantly more fluid than the control group (3600 vs. 2413 ml, P

Hereditary angioedema is a rare (orphan) disease associated with the development of angioedema of various localization caused by the action of bradykinin. The main symptoms of the disease are peripheral angioedema, abdominal attacks (accompanied by severe pain syndrome), edema of the upper respiratory tract, which may lead to asphyxia and death of the patient. Peripheral edema disrupts social and professional activity, the occurrence of facial edema complicates social adaptation, the unpredictability and potential threat to life of edema in the larynx, as well as the lack of effect from standard (systemic glucocorticoid and antihistamines) therapy regimens lead to a low quality of life of patients, a large number of days of disability, hospitalizations, in some cases, premature death of patients. According to international studies, on-demand therapy does not reduce the burden of the disease, and therefore international guidelines emphasize the importance of timely and individualized selection of long-term prevention for patients with hereditary angioedema. Taking into account the appearance of a new drug for long-term prevention in Russia, an Expert Council was held to assess the burden of the disease in Russian patients, determine the proportion of patients who need long-term prevention, criteria for choosing a medication for prophylaxis and the place of Lanadelumab in it.

Risperidone is the first line of treatment for bipolar disorder, atypical depression, and Schizophrenia. We present a 55-year-old male with a history of schizoaffective disorder with bipolar type I presented with aggressive behavior and suicidal ideation. Our patient was treated with low-dose Risperidone; after that, he gradually developed leg pain and edema. His leg pain hampers his ambulation, which is clinically improved after a week of medication discontinuation; however, his leg edema did not resolve completely. In addition, we evaluated our patient's compliance with an empathic verbal interview that shows edema and leg pain hampers his quality of life. We have found that not informing edema as one of the possible side effects increases medication non-compliance in our case. There are several case reports about the side effect of Risperidone (such as leg edema) in combination with other medications, but there is no recommendation about patient counseling of forthcoming leg edema and mobility issues.

Masho Tigabe,1 Abaynesh Fentahun,1 Solomon Getawa,2 Kassahun Alemu Gelaye,3 Eyob Alemayehu Gebreyohannes1,4 1Department of Clinical Pharmacy, School of Pharmacy, College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia; 2Department of Hematology and Immunohematology, School of Biomedical and Laboratory Sciences, College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia; 3Department of Epidemiology and Biostatistics, Institute of Public Health, College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia; 4Division of Pharmacy, School of Allied Health, University of Western Australia, Nedlands, AustraliaCorrespondence: Solomon GetawaDepartment of Hematology and Immunohematology, School of Biomedical and Laboratory Sciences, College of Medicine and Health Sciences, University of Gondar, P.O. Box 196, Gondar, EthiopiaTel +251 914-665-736Email solomon2525geta@gmail.comBackground: Despite the growing burden of heart failure in developing countries, data describing the clinical characteristics and in-hospital outcomes of acute heart failures are limited. Therefore, this study aimed at describing the clinical characteristics and in-hospital outcomes of acute heart failure patients admitted to the medical ward of University of Gondar Comprehensive Specialized Hospital, Northwest Ethiopia.Methods: A prospective observational hospital-based cross-sectional study was conducted on 226 patients with acute heart failure at the University of Gondar Comprehensive Specialized Hospital from November 2019 to October 2020. Data were collected by using a pretested data abstraction format and analyzed with Statistical Package for Social Sciences version 21. Bivariable and multivariable binary logistic regression model were fitted to identify factors associated with in-hospital outcome and reported with 95% confidence interval (CI). P-value < 0.05 was considered as statistically significant.Results: The mean (± standard deviation) age of the study participant was 51.17± 19.03 years and 59.3% were females. Majority, 60.6% of patients were admitted with new onset heart failure. Dyspnea (88.05%) and peripheral edema (80.5%) were the most frequent clinical findings. The in-hospital mortality was 10.6% (95% CI: 7.1– 14.7). Atrial fibrillation (AOR=9.46; 95% CI: 1.49– 60.29), concurrent ischemic heart disease (AOR=8.23; 95% CI: 1.15– 58.89), being admitted with reduced left ventricular ejection fraction (AOR=5.36; 95% CI: 2.81– 35.52), presence of orthopnea (AOR=6.63; 95% CI: 2.94– 46.76), and using intranasal oxygen therapy (AOR=9.41; 95% CI: 1.35– 65.82) were significantly associated with in-hospital mortality in patients with acute heart failure.Conclusion: The in-hospital mortality of acute heart failure patients was relatively higher in the study area. Therefore, specific preventative and therapeutic strategies focusing on heart failure patients with reduced left ventricular ejection fraction, atrial fibrillation, ischemic heart disease, orthopnea, and intranasal oxygen therapy are required to reduce the mortality rate.Keywords: heart failure, clinical characteristics, in-hospital mortality, Ethiopia

Introduction Rovalpituzumab tesirine (Rova-T) is an antibody-drug conjugate targeting DLL3, a Notch pathway ligand highly expressed on SCLC cells. Rova-T was evaluated alone or in combination with platinum-based chemotherapy (cisplatin or carboplatin combined with etoposide [CE]) in frontline treatment of extensive-stage SCLC. Methods One cycle of CE pre-enrollment was permitted (later mandated). The following four cohorts were enrolled: Rova-T monotherapy (0.3 mg/kg, every 6 [q6] wk × 2; cohort 1; n = 4); Rova-T induction (0.3 mg/kg, q6 wk × 2) followed by CE every 21 days (q21) × 4 (cohort 2; n = 5); Rova-T (0.1 or 0.2 mg/kg, q6 wk × 2) overlapping with CE q21 × 4 (cohort 3; n = 14); and Rova-T maintenance (0.3 mg/kg, q6 wk × 2) after CE q21 × 4 (cohort 4; n = 3). Results A total of 26 patients were dosed (cohort 3: 14; cohorts 1, 2, and 4 combined: 12). Median age was 66 years, and 73% had Eastern Cooperative Oncology Group performance status of 1. In cohort 3, seven patients (50%) had confirmed objective responses, with a median progression-free survival of 5.2 months and median overall survival of 10.3 months. Compared with cohorts 1, 2, and 4 combined, cohort 3 had lower frequency of some Rova-T–related adverse events of special interest, such as pleural effusion (0 versus 33%), pericardial effusion (0 versus 17%), ascites (0 versus 8%), peripheral edema (36% versus 42%), generalized edema (0 versus 8%), pneumonia (7% versus 25%), and hypoalbuminemia (0 versus 17%). Conclusions Lower Rova-T doses may be associated with lower incidence of some Rova-T–related adverse events of special interest. Rova-T 0.2 mg/kg plus CE (cohort 3) was tolerable; however, there was no clear efficacy benefit of adding Rova-T to CE.

A 57-year-old man had presented with a 6-month history of worsening dyspnea, renal failure, hypertension, pancytopenia, and a continuous machinery murmur. Imaging studies revealed pleuropericardial effusions that recurred despite aspiration and suprarenal mid-thoracic aortic occlusion (AO) with extensive collateral vessels to the chest wall, rectus sheath, and diaphragm. A right axillofemoral bypass transformed his clinical course. The murmurs, renal failure, pleuropericardial drainage, and pancytopenia resolved, and his hypertension had markedly improved. The association of chronic AO with pleuropericardial effusions without peripheral edema or ascites was most likely due to increased supradiaphragmatic interstitial pressure, and the bone marrow hypoperfusion likely explains the pancytopenia. In addition to posing diagnostic challenges, chronic AO reveals unique insights into the pathogenesis of pleuropericardial effusions and pancytopenia.

In October 2016, we received reports of five deaths among prisoners with leg swelling of unknown etiology in southwestern Ethiopia. A descriptive cross-sectional study was conducted to investigate the outbreak. A suspected case was defined as a prisoner with leg swelling of unknown etiology noted between May 15, 2016 and November 29, 2016. A total of 118 suspected cases were identified with unilateral or bilateral leg swelling without an identifiable cause from a total of 2,790 prisoners. Eight of the suspected cases were thoroughly examined, and seven of these suspected cases had clinical findings consistent with scurvy. Three of the clinical cases had undetectable vitamin C levels in the serum. The attack rate for the prison was 4.2% (118/2,790), and 11 deaths were identified, making the case fatality rate 9.3% (11/118). Clinical cases of scurvy had symptoms of fatigue, myalgia, arthralgia, and signs of follicular hyperkeratosis, petechiae, peripheral edema, and oral lesions. All clinical cases had severe anemia with hemoglobin < 6.0 g/dL. The diet provided by the prison excluded fruits and vegetables. Scurvy was determined to be the cause of the outbreak, and vitamin C supplementation was promptly initiated. All symptomatic prisoners improved, and no further cases were identified in a 4-week follow-up period of active surveillance.

Capillary blood pressure (CBP) is the primary driving force for fluid exchange across microvessels. Subclinical systemic venous congestion prior to overt peripheral edema can directly result in elevated peripheral CBP. Therefore, CBP measurements can enable timely edema control in a variety of clinical cases including venous insufficiency, heart failure and so on. However, currently CBP measurements can be only done invasively and with a complicated experimental setup. In this work, we proposed an opto-mechanical system to achieve non-invasive and automatic CBP measurements through modifying the widely implemented oscillometric technique in home-use arterial blood pressure monitors. The proposed CBP system is featured with a blue light photoplethysmography sensor embedded in finger/toe cuffs to probe skin capillary pulsations. The experimental results demonstrated the proposed CBP system can track local CBP changes induced by different levels of venous congestion. Leveraging the decision tree technique, we demonstrate the use of a multi-site CBP measurement at fingertips and toes to classify four categories of subjects (total N = 40) including patients with peripheral arterial disease, varicose veins and heart failure. Our work demonstrates the promising non-invasive CBP measurement as well as its great potential in realizing point-of-care systems for the management of cardiovascular diseases.

Nephrotic syndrome (NS) was first described in 1827 as the presence of proteinuria of ≥ 3.5 g/24 h, hypoalbuminemia < 3.0 g/dl, peripheral edema, hyperlipidemia, lipiduria, and increased thrombotic risk. Nephrotic syndrome has an incidence of three cases per 100,000 each year in adults. Nephrotic syndrome also has serious complications due to hypercoagulable state in both various venous and arteries which could lead thromboembolic events. The pathophysiology of hypercoagulability in the nephrotic syndrome is due to an imbalance of prothrombotic and antithrombotic factors, as well as impaired thrombolytic activities.Here, we will present a 19-year-old woman who presented to the emergency department complaining of chest pain and shortness of breath for 3 days. The patient was quickly diagnosed with pulmonary embolism and inferior vena cava thrombosis as a complication of nephrotic syndrome, allowing prompt initiation of anticoagulant therapy. After 2 weeks of admission, the patient’s condition resolved, her laboratory results returned to almost normal and the patient was discharged with oral prednisolone, coumadin, atorvastatin, and ramipril. We aim to determine which is the likely cause of pulmonary embolism in patients with nephrotic syndrome.

A 68-year-old female patient with metastatic breast cancer presented 12 weeks after starting chemotherapy with abemaciclib and fulvestrant with breathlessness, peripheral edema, and weight gain. Brain natriuretic peptide (BNP) and troponin I levels were raised above normal, and chest radiography revealed an increase in the cardiothoracic ratio from 47% before chemotherapy to 55%. The transthoracic echocardiogram showed a reduction in left ventricular ejection fraction from 76% before chemotherapy to 68%. Contrast-enhanced cardiac magnetic resonance imaging (MRI) revealed delayed accumulation in the interventricular septum. Under the diagnosis of abemaciclib-induced myocardial dysfunction and heart failure, abemaciclib was discontinued, and enalapril and furosemide were started. Two months later, imaging revealed a cardiothoracic ratio of 47% with a left ventricular ejection fraction of 73%. A cardiac MRI after three months was normal. This case report demonstrates that cardiac dysfunction caused by abemaciclib is reversible if detected early and treated appropriately.

Immunomodulatory properties of histone deacetylase inhibitors represent a reasonable approach for acute graft-versus-host disease (aGVHD) prevention. We report a phase 2 trial evaluating panobinostat (PANO) administered over 26 weeks, starting on day −5 (5 mg orally 3 times a week) with tacrolimus initiated on day −3 plus sirolimus on day −1, with a median patient age of 58 years (range, 19-72 years) (n = 38). Donor source consisted of HLA 8/8–matched donors, related (n = 13) or unrelated (n = 25), using granulocyte colony-stimulating factor–stimulated peripheral blood stem cells. Myeloablative (n = 18) or reduced-intensity (n = 20) conditioning regimens were used for patients with acute myeloid leukemia (n = 17), myelodysplastic syndrome (n = 13), or other malignancies (n = 8). The cumulative incidence of aGVHD II-IV by day 100 was 18.4% (90% confidence interval [CI], 9.4% to 29.9%). Cumulative incidence of chronic GVHD at 1 year was 31.6% (90% CI, 19.5% to 44.3%). Adverse events related to PANO were thrombocytopenia (n = 5), leukopenia (n = 6), gastrointestinal toxicity (n = 3), rash (n = 4), renal failure/peripheral edema (n = 1), and periorbital edema (n = 1). At 1 year, overall survival was 89.5% (90% CI, 81.6% to 98.0%), relapse-free survival was 78.9% (90% CI, 68.8% to 90.6%), nonrelapse mortality was 2.6% (90% CI, 0.3% to 9.9%), and GVHD relapse-free survival was 60.5% (90% CI, 48.8% to 75.1%). PANO hits histone 3 as early as day 15 in CD8, CD4 and T regs. In conclusion, PANO combination met the primary study end point for aGVHD prevention and warrants further testing. This trial was registered at www.clinicaltrials.gov as #NCT02588339.

Background Activation of the mTOR pathway has been implicated in the development of several malignancies and alterations in TSC1, TSC2, STK11 and NF1, can lead to the dysregulation of this pathway. Furthermore, mutations in TSC1 and NF2 are known to confer sensitivity to everolimus-an mTOR inhibitor. Based on these data, a single-arm, open label, single-institution phase II basket study was designed to assess the activity of everolimus in patients with solid malignancies whose tumors harbored mutations in TSC1, TSC2, NF1, NF2, or STK11. Methods A total of 12 patients with histologically confirmed diagnosis of advanced solid tumors (metastatic, recurrent, or unresectable) with mutations in TSC1, TSC2, NF1, NF2 or STK11 genes, who had failed at least one line of standard of care systemic therapy, were enrolled to this open label, single-arm study. Presence of mutations in TSC1, TSC2, NF1, NF2 or STK11 genes was assessed using targeted-next generation sequencing (NGS). All eligible patients were treated with everolimus at an initial dose of 10 mg orally once daily in cycles of 28 days. The primary endpoint of this study was overall response rate (ORR). Results Of 12 patients enrolled, 8 were evaluable for response at the end of 2 cycles. One complete response (CR) was observed (12.5%) and one patient (12.5%) had stable disease (SD), while six (75%) patients showed disease progression. Everolimus was overall well tolerated with anemia, decreased neutrophil and lymphocyte counts, peripheral edema and hyperglycemia representing the most common adverse events. One patient discontinued treatment due to a treatment related grade 4 pericardial effusion. Both patients with CR or SD had a diagnosis of lung adenocarcinoma with NF1 or STK11 mutations, respectively. Conclusions Although this study failed to meet its prespecified ORR threshold for success of 30% or higher, exploratory analyses suggest potential activity for everolimus in a subset of patients with lung adenocarcinomas with STK11 or NF1 mutations. Further studies are necessary to systematically explore the clinical activity of everolimus, potentially as a combination therapy, in these patients.

We report on the development of minimal change disease (MCD) with nephrotic syndrome and acute kidney injury (AKI), shortly after first injection of the BNT162b2 COVID-19 vaccine (Pfizer-BioNTech). A 50-year-old previously healthy man was admitted to our hospital following the appearance of peripheral edema. Ten days earlier, he had received the first injection of the vaccine. Four days after injection, he developed lower leg edema, which rapidly progressed to anasarca. On admission, serum creatinine was 2.31 mg/dL and 24-hour urinary protein excretion was 6.9 grams. As kidney function continued to decline over the next days, empirical treatment was initiated with prednisone 80 mg/d. A kidney biopsy was performed and the findings were consistent with MCD. Ten days later, kidney function began to improve, gradually returning to normal. The clinical triad of MCD, nephrotic syndrome, and AKI has been previously described under a variety of circumstances, but not following the Pfizer-BioNTech COVID-19 vaccine. The association between the vaccination and MCD is at this time temporal and by exclusion, and by no means firmly established. We await further reports of similar cases to evaluate the true incidence of this possible vaccine side effect.

BACKGROUND: In 2018, a new form of hereditary angioedema without C1-inhibitor deficiency hereditary angioedema with a mutation in the plasminogen gene was identified. The world scientific literature describes a small number of patients with this form of the disease and, therefore, new research is relevant. AIMS: To identify the sociodemographic and clinical features of patients with hereditary angioedema with plasminogen gene mutation; to evaluate the treatment efficacy; to conduct a comparative analysis in a group of patients with hereditary angioedema type I/II. MATERIAL AND METHODS: 14 patients (1 male and 13 females, mean age 51.6413.55 years) with hereditary angioedema with c.988AG mutation in the plasminogen gene (p.Lys330Glu; K330E) were enrolled in a retrospective study. The comparison group included 194 patients with hereditary angioedema type I/II (56 males and 138 females, mean age 37.0316.23 years). RESULTS: The average age at disease onset in patients with hereditary angioedema with a mutation in the plasminogen gene is 25.0710.46 years, which is significantly higher than in patients with hereditary angioedema type I/II 11.588.92 years (p 0.001). Peripheral angioedema was reported in 21.4% of patients with hereditary angioedema with a mutation in the plasminogen gene, abdominal attacks in 28.6%, which is less common than in patients with hereditary angioedema type I/II (peripheral edema 97.4%, p 0.001; abdominal attacks 86.6%, p 0.001). Face and neck angioedema was observed in all patients with hereditary angioedema with a mutation in the plasminogen gene (100%) and in 72.2% of patients in the group of hereditary angioedema type I/II (p=0.023). 85.7% of patients with hereditary angioedema with a mutation in the plasminogen gene had edema of the tongue. A decrease in the severity and duration of 28 out of 29 attacks by an average of 71.4% was reported by 4/5 of patients who used icatibant (Firazyr); 3/4 of patients reported a decrease in the frequency of attacks during treatment with tranexamic acid. CONCLUSIONS: The diseases manifestation in adulthood, the predominance of face and tongue angioedema are common features of hereditary angioedema with a mutation in the plasminogen gene. The efficacy of tranexamic acid and icatibant was demonstrated in the observed cohort of patients.

A thirty-year-old pregnant woman was admitted to hospital with headache and gastrointestinal discomfort. She developed peripheral oedema and had an emergency caesarean section following an episode of tonic-clonic seizures. Her delivery was further complicated by postpartum haemorrhage and she was admitted to the Intensive Care Unit (ICU) for further resuscitation and seizure control which required infusions of magnesium and multiple anticonvulsants. Despite haemodynamic optimisation she developed an acute kidney injury with evidence of liver damage, thrombocytopenia and haemolysis. Haemolysis, Elevated Liver enzymes and Low Platelets (HELLP) syndrome, a multisystem disease of advanced pregnancy which overlaps with pre-eclampsia, was diagnosed. HELLP syndrome is associated with a range of complications which may require critical care support, including placental abruption and foetal loss, acute kidney injury, microangiopathic haemolytic anaemia, acute liver failure and liver capsule rupture. Definitive treatment of HELLP is delivery of the fetus and in its most severe forms requires admission to the ICU for multiorgan support. Therapeutic strategies in ICU are mainly supportive and include blood pressure control, meticulous fluid balance and possibly escalation to renal replacement therapy, mechanical ventilation, neuroprotection, seizure control, and management of liver failure-related complications. Multidisciplinary input is essential for optimal treatment.

Background: CD6 is a co-stimulatory receptor predominantly expressed on T cells. CD6high CD4+ T cells were recently shown to drive Th1/Th17 immune responses in inflammatory bowel disease and may have a similar role in acute graft-versus-host disease (aGHVD). The CD6 ligand, activated leukocyte cell adhesion molecule (ALCAM), is expressed on antigen presenting cells, as well as epithelial and endothelial cells of aGVHDtarget organs (e.g. skin, GI tract). Previous studies in patients receiving allogeneic hematopoietic cell transplants showed that ex vivo depletion of donor CD6+ T cells lowered the incidence of aGVHD, providing a rationale for therapeutically targeting CD6 in aGVHD. Itolizumab is a humanized IgG1 monoclonal antibody that binds CD6 and blocks interaction with ALCAM to inhibit T cell activity and trafficking that is being evaluated as treatment for aGVHD. Methods: Here we present interim study results from EQUATE (as of 2020 Nov 13), an ongoing US-based Phase 1b/2 study of itolizumab in combination with steroids for newly diagnosed severe aGVHD (Grade III-IV). Phase 1b involves an open-label, dose-escalation study evaluating doses from 0.4 to 2.4 mg/kg (IV Q2 weeks through Day 57). Results: Ten subjects have completed treatment through Day 57: 0.4 mg/kg (n=4), 0.8 mg/kg (n=3), and 1.6 mg/kg (n=3). All subjects received corticosteroids at an initial dose of 1-2 mg/kg/day. Baseline characteristics include mean age of 48, 90% male, 90% white, 80% with peripheral blood graft source, 80% with HLA matched donor, mean time to GVHD onset of 43 days, and 100% with GI involvement. Across dosing cohorts, all subjects experienced at least 1 adverse event (AE), with hypomagnesemia (n = 3) and peripheral edema (n = 3) being the most common. Most AEs were mild to moderate in severity. One mild infusion reaction AE was noted. Serious AEs that are not unexpected for severe aGVHD on systemic immune suppression were noted in 5 subjects, including recurrent GVHD (n = 1), sepsis (n = 2;1 was considered a DLT) and fever (n = 1). COVID-19 (n = 1) and disseminated nocardia (n = 1) were also reported. Across cohorts, the overall response rate (ORR;complete response [CR] + partial response [PR] + very good partial response [VGPR]) was 80% at Day 29, with 70% of subjects experiencing CR and 10% experiencing VGPR. ORR was sustained through Day 57. At Day 57, 7 subjects had tapered steroids by ≥80% (Fig 1B). Immunologically, itolizumab dose-dependently decreased CD6 levels on T cells within 24 h of first dose, which was maintained throughout the treatment period, particularly at 0.8 and 1.6 mg/kg (Fig 1C). Conclusions: In summary, the preliminary safety and high response rates of itolizumab with steroid therapy in newly diagnosed severe aGVHD is encouraging. Its early risk-benefit profile supports continued study and evaluation in future randomized controlled trials.

Background Carbohydrate antigen 125 (CA125) and B-type natriuretic peptides are surrogate markers of congestion in patients with acute heart failure (AHF). The aim of the study was to assess the association between CA125 and NT-proBNP and congestion parameters in patients with AHF. Methods and results Prospective multicentre observational study that included 191 patients hospitalised for AHF. We recorded the presence of pleural effusion, peripheral oedema and inferior vena cava (IVC) diameter during the first 24–48 h after admission and evaluated their independent association with CA125 concentrations and the amino-terminal fraction of pro-B-type natriuretic peptide (NT-proBNP). The mean age was 73.4 ± 12 years, 79 (41.4%) were women, and 127 (66.5%) had left ventricular ejection fraction ≥50%. The median of CA125, NT-proBNP and IVC diameter was 58 (22.7–129) U/mL, 3,985 (1,905–9,775) pg/mL and 21 (17–25) mm, respectively. Multivariate analysis showed that CA125 was positively and independently associated with the presence of peripheral oedema, pleural effusion and elevated IVC levels. NT-proBNP was associated with pleural effusion and IVC diameter but not with oedema. The addition of CA125 increased the discriminatory capacity of the baseline model to identify peripheral oedema and pleural effusion, but not NT-proBNP. The most important predictor of ICV dilation was CA125 (R2 = 48.3%). Conclusion In patients with AHF, serum CA125 levels are associated more significantly than NT-proBNP with a state of congestion.

Background MET exon 14 skipping is an oncogenic driver occurring in 3–4% of non-small cell lung cancer (NSCLC). The MET inhibitor tepotinib has demonstrated clinical efficacy in patients with MET exon 14 skipping NSCLC. Here, we present data from Japanese patients in the Phase II VISION study, evaluating the efficacy and safety of tepotinib. Methods In the open-label, single-arm, Phase II VISION study, patients with advanced/metastatic NSCLC with MET exon 14 skipping received oral tepotinib 500 mg once daily. The primary endpoint was objective response by independent review. Subgroup analyses of Japanese patients were preplanned. Results As of 1 January 2020, 19 Japanese patients received tepotinib and were evaluated for safety, 15 of whom had ≥9 months’ follow-up and were also analysed for efficacy. By independent review, objective response rate (ORR) was 60.0% (95% confidence interval [CI]: 32.3, 83.7), median duration of response was not reached (95% CI: 6.9, not estimable [ne]), and progression-free survival was 11.0 months (95% CI: 1.4, ne). ORR in patients with MET exon 14 skipping identified by liquid biopsy (n = 8) was 87.5% (95% CI: 47.3, 99.7), and by tissue biopsy (n = 12) was 50.0% (95% CI: 21.1, 78.9). Patients’ quality of life was maintained with tepotinib treatment. Among patients evaluated for safety, the most common treatment-related adverse events (any grade) were blood creatinine increase and peripheral oedema (12 and nine patients, respectively). Conclusions Tepotinib demonstrated robust and durable clinical efficacy in Japanese patients with advanced NSCLC harbouring MET exon 14 skipping, identified by either liquid or tissue biopsy. The main adverse events, blood creatinine increase and peripheral oedema, were manageable., In VISION, tepotinib demonstrated robust efficacy in Japanese patients with MET exon 14 skipping NSCLC. The safety profile was tolerable, with mostly mild–moderate adverse events and few treatment discontinuations.

Aims This study aimed to assess the ability of a voice analysis application to discriminate between wet and dry states in chronic heart failure (CHF) patients undergoing regular scheduled haemodialysis treatment due to volume overload as a result of their chronic renal failure. Methods and results In this single‐centre, observational study, five patients with CHF, peripheral oedema of ≥2, and pulmonary congestion‐related dyspnoea, undergoing haemodialysis three times per week, recorded five sentences into a standard smartphone/tablet before and after haemodialysis. Recordings were provided that same noon/early evening and the next morning and evening. Patient weight was measured at the hospital before and after each haemodialysis session. Recordings were analysed by a smartphone application (app) algorithm, to compare speech measures (SMs) of utterances collected over time. On average, patients provided recordings throughout 25.8 ± 3.9 dialysis treatment cycles, resulting in a total of 472 recordings. Weight changes of 1.95 ± 0.64 kg were documented during cycles. Median baseline SM prior to dialysis was 0.87 ± 0.17, and rose to 1.07 ± 0.15 following the end of the dialysis session, at noon (P = 0.0355), and remained at a similar level until the following morning (P = 0.007). By the evening of the day following dialysis, SMs returned to baseline levels (0.88 ± 0.19). Changes in patient weight immediately after dialysis positively correlated with SM changes, with the strongest correlation measured the evening of the dialysis day [slope: −0.40 ± 0.15 (95% confidence interval: −0.71 to −0.10), P = 0.0096]. Conclusions The fluid‐controlled haemodialysis model demonstrated the ability of the app algorithm to identify cyclic changes in SMs, which reflected bodily fluid levels. The voice analysis platform bears considerable potential as a harbinger of impending fluid overload in a range of clinical scenarios, which will enhance monitoring and triage efforts, ultimately optimizing remote CHF management.

In May 2020 and February 2021, capmatinib and tepotinib, respectively were approved by the Food and Drug Administration (FDA) for the treatment of metastatic non‐small cell lung carcinoma harboring mesenchymal‐epithelial transition (MET) exon 14 skipping alterations. Herein, we present a case of intolerable peripheral edema caused by tepotinib, in which MET inhibitor could be continued by switching to capmatinib. Peripheral edema has been identified as one of the most common adverse events in capmatinib and tepotinib; however, there is no unified management for this adverse event. This is the first report that two MET inhibitors have different effects on the development of peripheral edema, and that the MET inhibitors can be continued by switching these drugs., Peripheral edema has been identified as one of the most common adverse events in capmatinib and tepotinib; however, there is no unified management for this side effect. This is the first report that two MET inhibitors have different effects on the development of peripheral edema, and that the MET inhibitors can be continued by switching these drugs.

Oriane Chausiaux,1 Gareth Williams,1 Michał Nieznański,1 Adem Bagdu,2 Philip Downer,1 Melanie Keyser,1 Shamus Husheer1 1Heartfelt Technologies Ltd, Cambridge, UK; 2Warwick Medical School, University of Warwick, Coventry, UKCorrespondence: Oriane Chausiaux Email oriane@hftech.orgBackground and Objectives: Peripheral edema, change in foot volume, is a marker of congestion which is regularly assessed in routine clinical care. A novel video and Artificial Intelligence (AI)-based solution used to measure anatomical parameters, including volume and foot length, Heartfelt HF-1, is compared to the laboratory gold standard (water displacement) and a medical disposable measuring tape.Design, Setting, Participants, and Measurements: 58 healthy volunteers were measured with the Heartfelt device; 22 were also measured with the water displacement method and 19 with the medical tape. Bland–Altman analysis was performed for both volumes and foot lengths. Left/right foot differences provided covariance-corrected standard error of measurement (ccSEM) and minimum detectable difference (MDD) for each measurement method.Results: Heartfelt device measured volumes displayed excellent correlation to the gold standard (water displacement), with Bland–Altman bias of +32mL ± 81mL (1 std.dev). Clinically important change in foot volume is approximately 13%. Water displacement yielded ccSEM of ± 32.1mL and MDD of 90mL (6.7% of average foot volume), while the Heartfelt device measurements yielded ccSEM of ± 12.6mL and MDD of 35.3mL (2.6% of average foot volume). The majority of differences were attributable to manual positioning of the patient foot in the waterbath.Conclusion: This study finds that in clinical and non-clinical settings, the Heartfelt device measures foot volume and length more precisely than either the water displacement technique or manual foot length measurements using a medical disposable tape, while having an excellent agreement with these methods.Keywords: AI, peripheral edema, congestion, -medical device, heart failure, lymphedema, renal disease

Background Inflammatory diseases can interfere with adequate nutrition and even lead to a malnourished state. Nutritional deficiency manifestations may be similar to rheumatologic manifestations. Aim of the work To assess whether malnutrition is an associated feature of rheumatic diseases (RDs). Patients and methods A multicenter study included Egyptian patients with different RDs; nutrition measurements and common features of deficiency were assessed; general appearance, skin, hair/nail changes, spooning of nails, night blindness, mouth problems, edema, tetany, dysphagia, diarrhea, thyromegaly, loss of appetite and weight loss. Results The study included 284 patients with various RDs: rheumatoid arthritis (RA) (n = 128), systemic lupus erythematosus (n = 120), Behcet’s disease (n = 17), spondyloarthritis (n = 6), systemic sclerosis (n = 5), dermatomyositis (n = 2), relapsing polychondritis (n = 2), and one patient each with familial Mediterranean fever, Gout, Still's disease and undifferentiated connective tissue disease. Muscle wasting was present in 44(15.5%) patients, spooning of nails in 26(9.2%), night blindness in 38(13.4%), glossitis in 48(16.9%), tetany in 32(11.3%) and loss of appetite in 51(18%). Although there was significant differences among RDs in some nutritional deficiency signs, the type and their durations did not significantly affect symptoms or signs of nutritional deficiency, while age was associated with peripheral edema (p = 0.014) and tetany (p = 0.009); azathioprine was associated with hair/nail changes (p = 0.04); methotrexate with peripheral edema and hair/nail changes (p = 0.002, p = 0.01 respectively); and hydroxychloroquine was negatively associated with skin rash, wasting and hair/nail changes (p = 0.011, p = 0.001 and p Conclusion Nutritional deficiency is common among RD patients especially elderly and should be monitored frequently regardless type and onset.

Bullous pemphigoid (BP) is an autoimmune blistering disease resulting from autoantibodies directed against BP180 and/or BP230 proteins. BP is traditionally diagnosed based on clinical features, histologic assessment of cutaneous biopsies, direct (DIF) and indirect immunofluorescence (IIF) studies, and/or enzyme-linked immunoassay (ELISA) analysis. We here report, 6 elderly patients who presented with multiple tense bullae, clinically mimicking BP in the absence of detectable autoantibodies by DIF, IIF, and ELISA for BP-180, BP-230, and type VII collagen autoantibodies. All patients in this case series had histological overlap between BP and eczema, potentially representing a unique form of bullous eczema. Patient demographics are listed in Table I along with clinical images (Fig 1). Patients were evaluated in the Autoimmune Blistering Disease Clinic at Emory University. All patients had at least 2 negative DIFs on 2 separate occasions. Only 1 patient was subject to systemic immune suppression at the time of biopsy, and no history of diabetes, peripheral edema, or arthropod assault was noted. Table I Clinical summary of patients 1 to 6

Central nervous system tuberculoma is rare and challenging situation. Clinical records of patients with pathologically proven tuberculoma were retrospectively reviewed. Clinical presentation, lesion location, radiological characteristics, perioperative and surgical management, and outcome is summarized and analyzed. Eight patients were included and there was one girl. Age ranged from 3 to 14 years with mean age 9.8 years. Clinical duration ranged from 20 days to 2 years, and 3 patients had previous lung tuberculosis with anti-TB treatment. The lesion was in cerebellum in 6 cases, including 1 involving basal ganglia and 1 involving thalamus. The lesion was in basal ganglia, thalamus, and third ventricle in 1 case, and in T12-L1 spinal cord in another. Cerebellar lesion was resected via paramedian suboccipital approach in 5 patients, basal ganglia lesion via trans-cortical frontal horn approach in 2 patients, and intra-spinal lesion via trans-laminar approach in 1 patient. Follow-up ranged from 10 to 24 months. Of the 8 patients, 6 returned to normal life. One patient had cerebellar lesion resected and the thalamic lesion reduced in size after anti-TB treatment. One patient died from TB spreading. Our data showed that most patients can be successfully treated by resection of the lesion. Low T2 signal, ring shaped enhancement and peripheral edema strongly suggest tuberculoma. Empirical anti-TB treatment should be initiated perioperatively.

Objective We aimed to describe the typical clinical and laboratory features and treatment of children diagnosed with multisystem inflammatory syndrome in children (MIS-C) and to understand the differences as compared to severe/critical pediatric cases with COVID-19 in an eastern Mediterranean country. Methods Children (aged

Hao Liang,1,2,* Xinru Zhang,3,* Zhuo Ma,4,* Yan Sun,1,2 Chang Shu,1 Yihua Zhu,5,6 Yanwei Zhang,6 Songnian Hu,1,2 Xiujuan Fu,3 Lihong Liu4 1State Key Laboratory of Microbial Resources, Institute of Microbiology, Chinese Academy of Sciences, Beijing, People’s Republic of China; 2University of Chinese Academy of Sciences, Beijing, People’s Republic of China; 3Department of Pharmacy, The Second Hospital of Jilin University, Changchun, Jilin Province, People’s Republic of China; 4Department of Pharmacy, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, People’s Republic of China; 5College of Information Science and Technology, Nanjing Agricultural University, Nanjing, Jiangsu Province, People’s Republic of China; 6E-Seq Medical Technology Co. Ltd., Beijing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Songnian HuState Key Laboratory of Microbial Resources, Institute of Microbiology, Chinese Academy of Sciences, Beijing, People’s Republic of ChinaTel +86-1064806939Email husn@im.ac.cnLihong LiuDepartment of Pharmacy, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, People’s Republic of ChinaTel +86-1085231000Email liulihong@bjcyh.comBackground: Amlodipine is one of the most used members of calcium channel blockers (CCB), available to treat hypertension. It is mainly metabolized by the Cytochrome P450 3A4/5 (CYP3A4/5) in the liver. Peripheral edema emerges as the major adverse drug reaction to amlodipine and is the primary reason for discontinuation of amlodipine therapy. However, genetic changes in CYP3A5 may lead to changes in the tolerability of amlodipine.Purpose: In this study, we were interested whether variants in CYP3A5 have a role to play in amlodipine-induced peripheral edema.Methods: A total number of 240 Chinese Han patients that have experienced hypertension were included in the study. Sixty-four patients had experienced amlodipine-induced peripheral edema, while the remaining 176 patients with no history of edema formed the control group. Twenty-four single-nucleotide polymorphisms (SNPs) of CYP3A5 gene were sequenced by targeted region sequencing method. The relationship of these genetic variants with amlodipine-induced peripheral edema risk was assessed using logistic regression.Results: The allele frequencies of CYP3A5*1D (rs15524), CYP3A5*1E (rs4646453) and CYP3A5*3 (rs776746) were significantly different between cases and controls (P< 0.05). The CYP3A5 *3/*3 (CC) or CYP3A5 *1D/*1D (AA) carriers showed an increased risk of amlodipine-induced peripheral edema in dominant model. Meanwhile, patients carrying CYP3A5 *1E (AC/AA) showed a reduced risk of peripheral edema. Furthermore, we found a strong linkage disequilibrium among rs15524, rs4646453 and rs776746.Conclusion: Our study reveals for the first time that CYP3A5 *1D, *1E and *3 were associated with amlodipine-induced peripheral edema in Chinese Han patients with hypertension. However, further studies comprising larger number of samples, more related genes and other factors are wanted.Keywords: pharmacogenomics, amlodipine, edema, CYP3A5, SNP

This systematic review investigates complications and recurrence of Dupuytren’s contracture in metacarpophalangeal joints (MCPJs) and/or proximal interphalangeal joints (PIPJs) of fingers treated with collagenase clostridium histolyticum (CCH). A review of the literature on Dupuytren’s disease was performed using PRISMA guidelines. Included publications described complications and/or recurrences for contractures ≥20° in MCPJs and/or PIPJs treated with CCH. Successful treatments reduced contractures to ≤5° immediately. Treatment-related adverse events (AEs) were classified as minor, major surgical, and major nonsurgical. Contracture recurrence involved return of fixed-flexion contracture ≥20° in a successfully treated finger in patients with ≥12 months of follow-up. Of 2675 patients (3753 joints), 94% experienced ≥1 treatment-related AE, most commonly peripheral edema (64%), pain in extremity (53%), and contusion (51%). Major surgical complications occurred in 9 patients (1.0%). Major nonsurgical complications occurred in 2 patients, specifically nonrupture tendon injury and anaphylaxis. Of 1488 patients (2069 joints), recurrences were reported in 23% of successfully treated joints (n = 466; 20% MCPJs, 28% PIPJs), on average 12 to 24 months after treatment. MCPJs achieved greater success than PIPJs in initial contracture reduction (77% versus 36%). CCH is a safe, effective treatment to improve hand function in Dupuytren’s contracture. Most AEs are minor and self-resolving, although the risk of major AEs still exists. Following treatment, 23% of successfully treated joints experience recurrence, typically within 12 to 24 months but sometimes as early as 6 months. Surgeons are encouraged to discuss these risks with patients for shared decision-making regarding optimal treatment modalities.

Background: Obesity may cause right ventricular (RV) remodeling due to volume overload. However, obesity is also associated with better prognosis compared with normal weight in patients with various cardiac diseases. The aim of this study was to assess the impact of obesity on RV remodeling and long-term prognosis in patients with significant (moderate and severe) tricuspid regurgitation (TR).Methods: A total of 951 patients with significant TR (median age, 70 years; interquartile range, 61-77 years; 50% men) were divided into three groups according to body mass index (BMI): normal weight (BMI 18.5-24.9 kg/m(2)), overweight (BMI 25-29.9 kg/m(2)), and obese (BMI >= 30 kg/m(2)). Patients with congenital heart disease, peripheral edema, active endocarditis, and BMI < 18.5 kg/m(2) were excluded. RV size and function for each group were measured using transthoracic echocardiography and compared with reference values of healthy study populations. The primary end point was all-cause mortality. Event rates were compared across the three BMI categories.Results: Four hundred seventy-six patients (50%) with significant TR had normal weight, 356 (37%) were over-weight, and 119 (13%) were obese. RV end-diastolic and end-systolic areas were larger in overweight and obese patients compared with normal-weight patients. However, no differences in RV systolic function were observed. During a median follow-up period of 5 years, 358 patients (38%) died. Five-year survival rates were significantly better in overweight and obese patients compared with patients with normal weight (65% and 67% vs 58%, respectively, P < .001 and P = .005). In multivariate analysis, overweight and obesity were independently associated with lower rates of all-cause mortality compared with normal weight (hazard ratios, 0.628 [95% CI, 0.493-0.800] and 0.573 [95% CI, 0.387-0.848], respectively).Conclusions: In patients with significant TR, overweight and obese patients demonstrated more RV remodeling compared with patients with normal weight. Nevertheless, a higher BMI was independently associated with better long-term survival, confirming the obesity paradox in this context.

Aims Capmatinib, an orally bioavailable, highly potent and selective MET inhibitor, was recently approved to treat adult patients with metastatic nonsmall cell lung cancer with METex14 skipping mutations. The study investigated the effect of capmatinib on the pharmacokinetics of a single oral dose of digoxin and rosuvastatin in patients with MET-dysregulated advanced solid tumours. Methods This was a multicentre, open-label, single-sequence study. An oral drug cocktail containing 0.25 mg digoxin and 10 mg rosuvastatin was administered to adult patients with MET-dysregulated advanced solid tumours on Day 1, and then on Day 22 with capmatinib. Between Days 11 and 32, capmatinib 400 mg was administered twice daily to ensure the attainment of steady state for drug-drug interaction assessment. Pharmacokinetics of cocktail drugs and safety of capmatinib were evaluated. Results Thirty-two patients were enrolled. Compared to digoxin alone, the geometric mean ratios (90% confidence interval) of area under the concentration-time curve from time zero to infinity and maximum concentration for digoxin plus capmatinib were 1.47 (1.28, 1.68) and 1.74 (1.43, 2.13), respectively. Compared to rosuvastatin alone, the geometric mean ratios (90% confidence interval) of area under the curve to infinity and maximum concentration for rosuvastatin plus capmatinib were 2.08 (1.56, 2.76) and 3.04 (2.36, 3.92), respectively. Most frequent adverse events (≥25% for all grades) were nausea, asthenia, constipation, vomiting, peripheral oedema and pyrexia. Most frequent Grade 3/4 adverse events (≥5%) were anaemia, pulmonary embolism, asthenia, dyspnoea, nausea and vomiting. Conclusion This study demonstrated that capmatinib is an inhibitor of P-gp and BCRP transporters, with clinically relevant drug-drug interaction potential. Capmatinib was well-tolerated and no unexpected safety concerns were observed.

Background Cardiac myxomas are considered the most common benign heart tumours. The clinical manifestations mainly depend on the size of the tumour. They usually vary from asymptomatic, mild non-specific symptoms, to severe obstructive cardiac and systemic findings. We describe herein a significantly large left atrial myxoma in a patient misdiagnosed with respiratory asthma. Case summary A 54-year-old lady, was diagnosed previously with asthma, presented with a history of dyspnoea on exertion, palpitations, and mild peripheral oedema. Chest X-ray suggested pulmonary congestion. Due to high suspicion of cardiac issues, transthoracic echocardiography was done revealing giant left atrial mass. Consequently, the mass was approached and excised surgically through the inverted T biatrial incision. Grossly, the mass measured 10 × 8 × 6 cm, and it had a smooth surface and was filled with gelatinous material. The histopathology confirmed benign myxoma without malignant features. Discussion Our article mainly focuses on the diagnostic challenges of a patient with atrial myxoma. The major discrepancy between the tumour size and the severity of the patient’s symptoms should draw physicians’ attention to consider atrial myxoma over a long list of differentials, in order to take immediate action to reduce the mortality and improve the overall prognosis.

The Ras/Raf/mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (Ras/Raf/MEK/ERK) signaling cascade is frequently constitutively activated in human cancers. Pimasertib is a selective and potent adenosine triphosphate non-competitive MEK1/2 inhibitor. Our objectives were to describe the results of a phase I, first-in-human, dose-escalation trial of pimasertib that investigated the maximum tolerated dose, recommended phase II dose, and safety, as well as other endpoints. Four dosing schedules of pimasertib (once daily [qd], 5 days on, 2 days off; qd, 15 days on, 6 days off; continuous qd; continuous twice daily [bid]) were evaluated in patients with advanced solid tumors. Each treatment cycle lasted 21 days. The primary objective was to determine the maximum tolerated dose based on dose-limiting toxicities (DLTs) evaluated during cycle 1, and the recommended phase II dose (RP2D). Secondary objectives included safety, pharmacokinetics, pharmacodynamics, and antitumor activity. Overall, 180 patients received pimasertib (dose range 1–255 mg/day). DLTs were mainly observed at doses ≥ 120 mg/day and included skin rash/acneiform dermatitis and ocular events, such as serous retinal detachment. The most common drug-related adverse events were consistent with class effects, including diarrhea, skin disorders, ocular disorders, asthenia/fatigue, and peripheral edema. The median time to maximum pimasertib concentration was 1.5 h across dosing schedules, and the apparent terminal half-life was 5 h across qd dosing schedules. Pimasertib decreased ERK phosphorylation within 2 h of administration, which was maintained for up to 8 h at higher doses and prolonged with bid dosing. Based on the safety profile and efficacy signals, a continuous bid regimen was the preferred dosing schedule and the RP2D was defined as 60 mg bid. ClinicalTrials.gov, NCT00982865.

Summary Background B-lines have been associated with adverse clinical outcomes in patients with heart failure (HF) when found at hospital discharge or during outpatient visits. Whether lung ultrasound (LUS) assessed B-lines may predict in-hospital mortality in patients with acute HF is still undetermined. Aim To evaluate the association between B-lines on admission and in-hospital mortality among patients admitted with acute HF. Methods Hand-held LUS was used to examine patients with acute HF. LUS was performed in eight chest zones with a pocket ultrasound device and analyzed offline. The association between B-lines and in-hospital mortality was assessed using Cox regression models. Results We included 62 patients with median age 56 years, 69.4% men, and median left ventricle ejection fraction 25%. The sum of B-lines ranged from 0 to 53 (median 6.5). An optimal receiver operating characteristic-determined cut-off of ≥19 B-lines demonstrated a sensitivity of 57% and a specificity of 86% (area under the curve 0.788) for in-hospital mortality. The incremental prognostic value of LUS when compared with lung crackles or peripheral edema by integrated discrimination improvement was 12.96% (95% CI: 7.0–18.8, P = 0.02). Patients with ≥19 B-lines had a 4-fold higher risk of in-hospital mortality (HR 4.38; 95% CI: 1.37–13.95, P Conclusion In patients admitted with acute HF, point-of-care LUS measurements of pulmonary congestion (B-lines) are associated with in-hospital mortality.

Background The whole-body bioelectrical phase-angle (PhA) is emerging as a new tool in stratifying prognosis in patients with both acute (AHF) and chronic heart failure (CHF). Objective To evaluate the determinants of PhA in HF patients. Methods We analyzed data from 900 patients with AHF or CHF (mean age: 76±10 years, 54% AHF). Clinical, serum biochemical, echocardiographic and bioelectrical measurements were collected from all of patients. PhA was quantified in degrees. Congestion was assessed by a multiparametric approach, including the presence of peripheral edema, brain natriuretic peptides (BNP) plasma levels, blood urea nitrogen to creatinine ratio (BUN/Cr), and relative plasma volume status (PVS) calculated by Kaplan-Hakim's formula. Geriatric Nutritional Risk Index (GNRI) was adopted as indicator for nutritional status. Results At univariate analysis, PhA was significantly lower in females, in patients with peripheral edema, and AHF. PhA significantly correlates age, BNP, PVS, BUN/Cr, and GNRI. At multivariate analysis, congestion biomarkers emerged as the major determinant of PhA as they explained the 34% of data variability, while age, GNRI, and gender only explained 6%, 0.5%, and 0.5%, respectively (adjusted R2 = 0.41). In particular, PVS (regression of coefficient B=−0.17) explained the 20% of PhA variability, while peripheral congestion (B=−0.27) and BNP (B=−0.15) contributed to 10% and 2%, respectively. Conclusions The main determinant of bioelectrical PhA in patients with HF is congestion and PVS in particular, while nutritional status has marginal impact.

Pharmacological openers of ATP-sensitive potassium (KATP) channels are effective antihypertensive agents, but off-target effects, including severe peripheral edema, limit their clinical usefulness. It is presumed that the arterial dilation induced by KATP channel openers (KCOs) increases capillary pressure to promote filtration edema. However, KATP channels also are expressed by lymphatic muscle cells (LMCs), raising the possibility that KCOs also attenuate lymph flow to increase interstitial fluid. The present study explored the effect of KCOs on lymphatic contractile function and lymph flow. In isolated rat mesenteric lymph vessels (LVs), the prototypic KATP channel opener cromakalim (0.01-3 µmol/l) progressively inhibited rhythmic contractions and calculated intraluminal flow. Minoxidil sulfate and diazoxide (0.01-100 µmol/l) had similar effects at clinically relevant plasma concentrations. High-speed in vivo imaging of the rat mesenteric lymphatic circulation revealed that superfusion of LVs with cromakalim and minoxidil sulfate (0.01-10 µmol/l) maximally decreased lymph flow in vivo by 38.4% and 27.4%, respectively. Real-time polymerase chain reaction and flow cytometry identified the abundant KATP channel subunits in LMCs as the pore-forming Kir6.1/6.2 and regulatory sulfonylurea receptor 2 subunits. Patch-clamp studies detected cromakalim-elicited unitary K+ currents in cell-attached patches of LMCs with a single-channel conductance of 46.4 pS, which is a property consistent with Kir6.1/6.2 tetrameric channels. Addition of minoxidil sulfate and diazoxide elicited unitary currents of similar amplitude. Collectively, our findings indicate that KCOs attenuate lymph flow at clinically relevant plasma concentrations as a potential contributing mechanism to peripheral edema. SIGNIFICANCE STATEMENT: ATP-sensitive potassium (KATP) channel openers (KCOs) are potent antihypertensive medications, but off-target effects, including severe peripheral edema, limit their clinical use. Here, we demonstrate that KCOs impair the rhythmic contractions of lymph vessels and attenuate lymph flow, which may promote edema formation. Our finding that the KATP channels in lymphatic muscle cells may be unique from their counterparts in arterial muscle implies that designing arterial-selective KCOs may avoid activation of lymphatic KATP channels and peripheral edema.

Background Hyperkalemia is associated with many chronic diseases and renin-angiotensin-aldosterone system inhibitor therapy. Sodium zirconium cyclosilicate (SZC), an oral, highly selective cation-exchanger, is approved for the treatment of hyperkalemia. Methods This phase 3, multicenter, open-label, single-arm, flexible-dose study assessed the safety and efficacy of SZC in Japanese patients with hyperkalemia during a correction phase of up to 3 days and long-term (1 year) maintenance phase (NCT03172702). Results Overall, 150 patients received treatment during both study phases; the study population was generally representative of hyperkalemic Japanese patients in clinical practice. Most patients (78.7%) had three doses of SZC during the correction phase. All but one patient received SZC for ≤ 48 h before transitioning to the maintenance phase. In the maintenance phase, mean (standard deviation; SD) exposure to the study drug was 319.4 (98.1) days and mean (SD) dose was 7.38 (2.85) g/day. Adverse events (AEs) were reported in 131 patients (87.3%); most were mild. The most common treatment-related AEs as evaluated by investigators were constipation (6.7%), peripheral edema (4.0%), and hypertension (2.7%). In the correction phase, 78.7% of patients were normokalemic at 24 h and 98.7% within 48 h; ≥ 65.5% maintained normokalemia throughout the maintenance phase. Conclusion After a year of exposure, SZC treatment was well tolerated by Japanese patients and potassium levels were well controlled.

A 51-year-old female patient was admitted to our clinic with numbness and anesthesia in the left upper extremity. There was widespread peripheral edema above and below the left elbow. Symptoms of the patient were associated with axillary lymphatic nodular dissection during previous the mastectomy operation. The patient was successfully treated using the supermicrosurgery technique via lymphaticovenular anastomosis.

Background Matrix metalloproteinase 9 (MMP9) expression in the tumor microenvironment is implicated in multiple protumorigenic processes. Andecaliximab (GS-5745), a monoclonal antibody targeting MMP9 with high affinity and selectivity, was evaluated in combination with gemcitabine and nab-paclitaxel in patients with advanced pancreatic adenocarcinoma. Patients and Methods This phase I study was completed in two parts: part A was a dose-finding, monotherapy phase that enrolled patients with advanced solid tumors, and part B examined andecaliximab in combination with chemotherapy in specific patient cohorts. In the cohort of patients with pancreatic adenocarcinoma (n = 36), andecaliximab 800 mg every 2 weeks was administered in combination with gemcitabine and nab-paclitaxel. Patients were treated until unacceptable toxicity, withdrawal of consent, disease progression, or death. Efficacy, safety, and biomarker assessments were performed. Results Andecaliximab combined with gemcitabine and nab-paclitaxel appeared to be well tolerated and did not demonstrate any unusual toxicities in patients with pancreatic adenocarcinoma. The most common treatment-emergent adverse events were fatigue (75.0%), alopecia (55.6%), peripheral edema (55.6%), and nausea (50.0%). Median progression-free survival was 7.8 months (90% confidence interval, 6.9−11.0) with an objective response rate of 44.4% and median duration of response of 7.6 months. Maximal andecaliximab target binding, defined as undetectable, andecaliximab-free MMP9 in plasma, was observed. Conclusion Andecaliximab in combination with gemcitabine and nab-paclitaxel demonstrates a favorable safety profile and clinical activity in patients with advanced pancreatic adenocarcinoma. Implications for Practice The combination of andecaliximab, a novel, first-in-class inhibitor of matrix metalloproteinase 9, with gemcitabine and nab-paclitaxel in patients with advanced pancreatic adenocarcinoma provided a median progression-free survival of 7.8 months and objective response rate of 44.4%. The majority of systemic biomarkers related to matrix metalloproteinase 9 activity and immune suppression increased at 2 months, whereas biomarkers related to tumor burden decreased. Although this study demonstrates promising results with andecaliximab plus chemotherapy in patients with advanced pancreatic adenocarcinoma, andecaliximab was not associated with a survival benefit in a phase III study in patients with advanced gastric/gastroesophageal junction carcinoma.

Cardiovascular diseases are the leading cause of death both in the world and in the Russian Federation. The most significant contributors to the increase in mortality are arterial hypertension (AH) and ischemic heart disease (IHD). Dihydropyridine calcium channel blockers (CCBs) are the first line of treatment for these conditions. This is noted in the clinical guidelines for the diagnosis and treatment of AH and in the guidelines for the management of patients with chronic coronary syndromes. CCBs are a heterogeneous group of drugs that have both general and individual pharmacokinetic and pharmacodynamic properties. They are used in patients with AH and/or IHD, including those with concomitant diseases (diabetes mellitus, chronic kidney disease, bronchial asthma, chronic obstructive pulmonary disease, peripheral arterial disease). Felodipine is one of the CCBs. It has a combination of clinical effects, allowing the drug to be prescribed as a first-line therapy for AH, IHD and a combination of these diseases. This is noted in the registered indications for its use. This CCB has a sufficient evidence base of clinical trials demonstrating not only good antihypertensive and antianginal potential of the drug, but also the nephroprotection and cerebroprotection properties. The nephroprotective effect of felodipine is associated with a slowdown in the progression of chronic kidney disease, and the cerebroprotective effect is associated with a decrease in the risk of stroke and an improvement in cognitive functioning. The safety profile of felodipine is favorable: peripheral edema develops much less frequently. This is confirmed by the results of comparative studies. Felodipine is recommended for a wide range of patients with AH, IHD and their combination due to such clinical and pharmacological properties.

Objective Epithelial ovarian carcinoma (EOC) is diagnosed at advanced stage in the majority of women and, despite being initially chemosensitive, eventually recurs and develops resistance to known therapies. SC-003 is a pyrrolobenzodiazepine-based antibody-drug conjugate targeting dipeptidase 3 (DPEP3), a membrane-bound dipeptidase associated with tumor-initiating cells in patient-derived EOC xenograft models. This first-in-human phase 1a/1b study evaluated the safety/tolerability, pharmacokinetics, and preliminary antitumor activity of SC-003 alone or in combination with budigalimab (formerly ABBV-181), an antibody targeting PD-1, in patients with platinum-resistant/refractory EOC ( NCT02539719 ). Methods Patients received SC-003 at 1 of 6 dose levels (0.025–0.4 mg/kg) every 3 weeks (Q3W), utilizing a standard 3 + 3 design (dose-limiting toxicity [DLT] period: 21 days). Patients with DPEP3-positive tumors were enrolled in the dose-expansion phase of the study and treated with SC-003 monotherapy or in combination with budigalimab. Results Seventy-four patients (n = 29, dose escalation; n = 45, dose expansion; n = 3 budigalimab combination) were enrolled and received ≥ 1 dose of study drug. One DLT occurred (grade 3 ileus) but was considered unrelated to study drug. The MTD for the Q3W schedule was 0.3 mg/kg and the SC-003 doses selected for the dose-expansion phase of the study were 0.3 mg/kg and 0.2 mg/kg. The most common treatment-emergent adverse events were fatigue, nausea, decreased appetite, pleural effusion, abdominal pain, and peripheral edema. The overall response rate was low (4%), and responses were not durable. Post-hoc examination of antitumor activity suggested a higher response rate in patients with higher DPEP3 expression. Conclusions SC-003 lacked the requisite safety profile and antitumor activity to warrant further development.

Primary cardiac lymphoma is a rare condition with a poor prognosis, and patients are at risk for sudden cardiac death. A prompt diagnosis and early treatment are therefore essential. A 68-year-old woman was admitted for shortness of breath and peripheral edema. Echocardiograms showed massive pericardial effusion and a mass on the free wall of the right atrium and ventricle. Subsequent pericardial effusion cytology revealed diffuse large B-cell lymphoma. We started chemotherapy with rituximab and achieved a good clinical course. This case is made unique by the use of pericardial effusion cytology, which allowed us to diagnose primary cardiac lymphoma promptly and safely.

Antipsikotikler, şizofreni ve bipolar bozukluk gibi çeşitli psikiyatrik bozuklukların tedavisinde uzun yıllardır kullanılmaktadır. Distoni, tardif diskinezi, akatizi, sedasyon, kilo artışı, aritmi antipsikotiklerin bazı yan etkilerindendir. Periferik ödem antipsikotiklerin bir diğer önemli yan etkisidir. İnterstisyel alanda normalde bulunması gerekenden daha fazla sıvı bulunması olarak tanımlanabilecek periferik ödemin hem birinci kuşak antipsikotikler hem de ikinci kuşak antipsikotiklerle ilişkisi bildirilmiştir. Bu yan etkinin olası mekanizmalarını açıklamak için aşırı duyarlılık ve vazodilatasyon, doz-cevap ilişkisi, doz artırım hızı ve alerjik reaksiyon modelleri oluşturulmuştur. Hasta konforunu bozan bu yan etkinin ayırıcı tanısı ve olası risk faktörlerinin belirlenmesi önem arz etmektedir. Bu hastalar, multidisipliner bir yaklaşımla ele alınmalı ve müdahalede geç kalınmamalıdır. Hasta ve yakınlarının bu yan etkiye karşı uyarılması gerekmektedir.

Gabapentin binds to the alpha-2-delta subunit of presynaptic voltage-gated calcium channels and is used for a wide variety of on- and off-label indications. Gabapentin is dosed at total daily doses ranging from 300 to 3600 mg/d, which is generally divided into 3 doses. Although gabapentin is generally well tolerated, 1 potential reported adverse effect is peripheral edema. However, due to the extensive number of etiologies of peripheral edema, medication causes may be overlooked on an inpatient psychiatric unit. This is a case of delayed identification of a probable adverse drug reaction to gabapentin (Naranjo score of 5) consisting of painful, 4+ pitting bilateral edema and a clear dose relationship in a patient with pervasive developmental disorder and schizoaffective disorder.

Introduction Preterm neonates often depend on peripheral intravenous administration of nutrition and medication. Since their skin is not fully developed and very vulnerable, extravasation injury is a risk. Medical-grade honey (MGH) possesses antimicrobial activity and stimulates wound healing; although its use in neonatal patients is limited. Clinical findings We present a case series of 7 preterm neonates (28-36 weeks of gestation) with extravasation injuries secondary to peripheral intravenous administration of total parental nutrition and medication. Primary diagnosis Extravasation injury following the unintentional leakage of total parenteral nutrition, and medication into the surrounding tissue. Signs of extravasation include local pain, erythema, burning, pruritus, and/or swelling. Interventions All extravasation injuries were treated with daily cleaning and application of MGH. Some of the cases needed additional surgical intervention or assisted debridement. Outcomes After treatment, all extravasation injury wounds presented with granulation tissue formation progressed to normal epithelialization and closed in 7 to 67 days (median: 32 days). Upon initial application, peripheral edema and inflammation decreased. When present, necrotic tissue was effectively debrided, slough was removed, and no signs of infection were detected, irrespective of initial wound presentations. Cicatrization was minimal, and the full range of motion was preserved in all cases. Practice recommendations Continuous and thorough assessment of peripheral intravenous line placement for malposition, leaking, and signs of extravasation is needed for fast discovery and prevention of further damage. Conclusion Medical-grade honey possesses antimicrobial, anti-inflammatory, and antioxidative activity, enhancing wound healing. Medical-grade honey was safe and effective for treating extravasation-induced injuries, independent of location and severity. We recommend MGH for treating extravasation wounds and consideration for other types of wounds.