Myelodysplastic syndromes with ring sideroblasts.

Myelodysplastic syndromes (MDS) are acquired bone marrow malignant disorders characterized by ineffective hematopoiesis, resulting from a complex interaction between genetic and epigenetic mutations, alterations of the marrow microenvironment, and the immune system. In 2001, the World Health Organization (WHO) proposed a classification that integrates morphologic and genetic information, considering the MDS with ring sideroblasts (MDS-RS) as a distinct entity. Considering the strong association between MDS-RS and SF3B1 mutation and its importance in the development of MDS, the last WHO classification replaced the prior entity of MDS-RS with MDS with SF3B1 mutation. Several studies were performed to explore this genotype-phenotype correlation. Mutant SF3B1 protein deregulates the expression of genes implicated in developing hematopoietic stem and progenitor cells. Of paramount importance are PPOX and ABCB7 involved in iron metabolism. Another essential role in hemopoiesis is played by the transforming growth factor-beta (TGF-ß) receptor. This gene exerts its effects on SMAD pathways, regulating hematopoiesis through effects on balancing proliferation and apoptosis cell inactivity, differentiation, and migration. Luspatercept (ACE-536) is a soluble fusion protein that inhibits molecules in the TGF-ß superfamily. Since its structure resembles the TGF-ß family receptor, it catches TGF-ß superfamily ligands before binding to the receptor, resulting in reduced activation of SMAD signaling, thus enabling erythroid maturation. Luspatercept was investigated in the phase III trial MEDALIST, showing promising efficacy in treating anemia compared to placebo. Nowadays, further studies are needed to explore the real potential of luspatercept, investigating the biological features likely associated with treatment response, the potential use in combination treatments, and its role in the treatment of naïve MDS.

Iron chelation therapy.

Iron overload is a pathological condition resulting from a congenital impairment of its regulation, increased intestinal iron absorption secondary to bone marrow erythroid hyperplasia, or a chronic transfusional regimen. In normal conditions, intracellular and systemic mechanisms contribute to maintaining iron balance. When this complex homeostatic mechanism fails, an iron overload could be present. Detecting an iron overload is not easy. The gold standard remains the liver biopsy, even if it is invasive and dangerous. Identifying iron using noninvasive techniques allowed a better understanding of the rate of iron overload in different organs, with a low risk for the patient. Estimating serum ferritin (mg/L) is the easiest and, consequently, the most employed diagnostic tool for assessing body iron stores, even if it could be a not specific method. The most common hematological causes of iron overload are myelodysplastic syndromes, sickle cell disease, and thalassemia. In all of these conditions, three drugs have been approved for the treatment of iron overload: deferiprone, deferoxamine, and deferasirox. These chelators have been demonstrated to help lower tissue iron levels and prevent iron overload complications, improving event-free survival (EFS). Nowadays, the decision to start chelation and which chelator to choose remains the joint decision of the clinician and patient.

Prevalence of Pulmonary Embolism among Patients Hospitalized for Syncope.

BACKGROUND: The prevalence of pulmonary embolism among patients hospitalized for syncope is not well documented, and current guidelines pay little attention to a diagnostic workup for pulmonary embolism in these patients. METHODS: We performed a systematic workup for pulmonary embolism in patients admitted to 11 hospitals in Italy for a first episode of syncope, regardless of whether there were alternative explanations for the syncope. The diagnosis of pulmonary embolism was ruled out in patients who had a low pretest clinical probability, which was defined according to the Wells score, in combination with a negative d-dimer assay. In all other patients, computed tomographic pulmonary angiography or ventilation-perfusion lung scanning was performed. RESULTS: A total of 560 patients (mean age, 76 years) were included in the study. A diagnosis of pulmonary embolism was ruled out in 330 of the 560 patients (58.9%) on the basis of the combination of a low pretest clinical probability of pulmonary embolism and negative d-dimer assay. Among the remaining 230 patients, pulmonary embolism was identified in 97 (42.2%). In the entire cohort, the prevalence of pulmonary embolism was 17.3% (95% confidence interval, 14.2 to 20.5). Evidence of an embolus in a main pulmonary or lobar artery or evidence of perfusion defects larger than 25% of the total area of both lungs was found in 61 patients. Pulmonary embolism was identified in 45 of the 355 patients (12.7%) who had an alternative explanation for syncope and in 52 of the 205 patients (25.4%) who did not. CONCLUSIONS: Pulmonary embolism was identified in nearly one of every six patients hospitalized for a first episode of syncope. (Funded by the University of Padua; PESIT ClinicalTrials.gov number, NCT01797289 .).

Impact of residual pulmonary obstruction on the long-term outcome of patients with pulmonary embolism.

The impact of residual pulmonary obstruction on the outcome of patients with pulmonary embolism is uncertain.We recruited 647 consecutive symptomatic patients with a first episode of pulmonary embolism, with or without concomitant deep venous thrombosis. They received conventional anticoagulation, were assessed for residual pulmonary obstruction through perfusion lung scanning after 6 months and then were followed up for up to 3 years. Recurrent venous thromboembolism and chronic thromboembolic pulmonary hypertension were assessed according to widely accepted criteria.Residual pulmonary obstruction was detected in 324 patients (50.1%, 95% CI 46.2-54.0%). Patients with residual pulmonary obstruction were more likely to be older and to have an unprovoked episode. After a 3-year follow-up, recurrent venous thromboembolism and/or chronic thromboembolic pulmonary hypertension developed in 34 out of the 324 patients (10.5%) with residual pulmonary obstruction and in 15 out of the 323 patients (4.6%) without residual pulmonary obstruction, leading to an adjusted hazard ratio of 2.26 (95% CI 1.23-4.16).Residual pulmonary obstruction, as detected with perfusion lung scanning at 6 months after a first episode of pulmonary embolism, is an independent predictor of recurrent venous thromboembolism and/or chronic thromboembolic pulmonary hypertension.

General Practitioner-Performed Compression Ultrasonography for Diagnosis of Deep Vein Thrombosis of the Leg: A Multicenter, Prospective Cohort Study.

BACKGROUND: Patients with suspected deep vein thrombosis (DVT) of the lower limb represent a diagnostic dilemma for general practitioners. Compression ultrasonography (US) is universally recognized as the best test of choice. We assessed the diagnostic accuracy of compression US performed by general practitioners given short training in the management of symptomatic proximal DVT. METHODS: From May 2014 to May 2016, we evaluated in a multicenter, prospective cohort study all consecutive outpatients with suspected DVT; bilateral proximal lower limb compression US was performed by general practitioners and by physicians expert in vascular US, each group blinded to the other's findings. In all examinations with a negative or nondiagnostic result, compression US was repeated by the same operator after 5 to 7 days. Inter-observer agreement and accuracy were calculated. RESULTS: We enrolled a total of 1,107 patients. The expert physicians diagnosed DVT in 200 patients, corresponding to an overall prevalence of 18.1% (95% CI, 15.8%-20.3%). The agreement between the trained general practitioners and the experts was excellent (Cohen κ = 0.86; 95% CI, 0.84-0.88). Compression US performed by general practitioners had a sensitivity of 90.0% (95% CI, 88.2%-91.8%) and a specificity of 97.1% (95% CI, 96.2%-98.1%) with a diagnostic accuracy for DVT of 95.8% (95% CI, 94.7%-97.0%). CONCLUSIONS: Our results suggest that, even in hands of physicians not expert in vascular US, compression US can be a reliable tool in the diagnosis of DVT. We found that the sensitivity achieved by general practitioners appeared suboptimal, however, so future studies should evaluate the implementation of proper training strategies to maximize skill.

Extensive Computed Tomography versus Limited Screening for Detection of Occult Cancer in Unprovoked Venous Thromboembolism: A Multicenter, Controlled, Randomized Clinical Trial.

Patients with unprovoked venous thromboembolism (VTE) may harbor occult cancer. Whether an extensive diagnostic work-up for cancer has additional value over a more limited screening for detection of underlying malignancy in these patients is controversial. We performed a randomized multicenter trial to assess if in patients with unprovoked VTE, a computed tomography (CT)-based diagnostic strategy including thoracic, abdominal, and pelvic CT in combination with fecal occult blood test yields a higher cancer detection rate than a nonstandardized testing approach based on physicians' clinical judgment and patients' preferences. Cancer-free patients were followed up for up to 24 months. Of the 195 consecutive patients with unprovoked VTE who were eligible for this investigation, an occult cancer was identified in 10 of the 98 patients (10.2%) randomized to the CT-based strategy, and in 8 of the 97 (8.2%) allocated to the personalized strategy (absolute difference, 2.0%; 95% confidence interval, -7.2-11.1; p = 0.81). During follow-up, cancer was identified in an additional 2 patients in each group. Overall, 7 (7.1%) patients of the CT-based strategy died, as compared with 11 (11.3%) of the personalized strategy, with 2 and 4, respectively, due to cancer. In conclusion, a CT-based strategy in combination with fecal occult blood test does not provide a clinically significant benefit over more limited cancer screening for detecting occult cancer in patients with unprovoked VTE. (ClinicalTrials.gov number, NCT00361647).

Identification of intermediate-risk patients with acute symptomatic pulmonary embolism.

The identification of normotensive patients with acute pulmonary embolism (PE) at high risk of adverse PE-related clinical events (i.e. intermediate-risk group) is a major challenge. We combined individual patient data from six studies involving 2874 normotensive patients with PE. We developed a prognostic model for intermediate-risk PE based on the clinical presentation and the assessment of right ventricular dysfunction and myocardial injury. We used a composite of PE-related death, haemodynamic collapse or recurrent PE within 30 days of follow-up as the main outcome measure. The primary outcome occurred in 198 (6.9%) patients. Predictors of complications included systolic blood pressure 90-100 mmHg (adjusted odds ratio (aOR) 2.45, 95% CI 1.50-3.99), heart rate ≥ 110 beats per min (aOR 1.87, 95% CI 1.31-2.69), elevated cardiac troponin (aOR 2.49, 95% CI 1.71-3.69) and right ventricular dysfunction (aOR 2.28, 95% CI 1.58-3.29). We used these variables to construct a multidimensional seven-point risk index; the odds ratio for complications per one-point increase in the score was 1.55 (95% CI 1.43-1.68; p<0.001). The model identified three stages (I, II and III) with 30-day PE-related complication rates of 4.2%, 10.8% and 29.2%, respectively. In conclusion, a simple grading system may assist clinicians in identifying intermediate-risk PE.

Thigh-length versus below-knee compression elastic stockings for prevention of the postthrombotic syndrome in patients with proximal-venous thrombosis: a randomized trial.

Although below-knee compression elastic stockings (CES) are effective for the prevention of the postthrombotic syndrome (PTS), a substantial number of patients with deep venous thrombosis still develop PTS. In the present open-label, randomized clinical trial, we compared thigh-length with below-knee CES for the prevention of PTS. A total of 267 patients with the first episode of proximal deep venous thrombosis were randomized to wear either thigh-length or below-knee CES for 2 years. After 3, 6, 12, 18, 24, and 36 months, they were assessed for PTS manifestations according to the Villalta scale. PTS developed in 44 (32.6%) of the 135 patients randomized to thigh-length CES and in 47 (35.6%) of the 132 allocated to below-knee CES, for an adjusted hazard ratio of 0.93 (95% confidence interval, 0.62-1.41). Severe PTS developed in 3 patients in each group. CES-related side effects developed in 55 (40.7%) of the 135 patients allocated to thigh-length CES and in 36 (27.3%) of those randomized to the below-knee group (P = .017), and led to premature discontinuation of their use in 29 (21.5%) and 18 (13.6%) patients, respectively. We conclude that thigh-length CES do not offer a better protection against PTS than below-knee CES and are less well tolerated.

Budd-Chiari syndrome mimicking autoimmune hepatitis.

Budd-Chiari syndrome is a rare disorder characterized by obstruction of hepatic venous outflow involving either the hepatic veins or the inferior vena cava. Risk factors include thrombophilia and myeloproliferative disorders, and symptoms are often unspecific. We present a case of a 60-year-old woman admitted to our medical unit for ascites and abdominal pain. Although her medical history significant for a mixed connective tissue disease and a mild increase of the transaminases had raised the suspicion of autoimmune hepatitis, the demonstration on computed tomography of the absence of outflow in the terminal tract of the supra-hepatic veins allowed a correct diagnosis. The contribution of radiological imaging is fundamental in the diagnosis of this rare and elusive pathology.

Safety and efficacy of caplacizumab in a case of thrombotic thrombocytopenic purpura in the postpartum period.

Thrombotic thrombocytopenic purpura (TTP) is a rare and life-threatening disease for which pregnancy and the postpartum period represent risk factors. Here, we present the case of a 39-year-old woman at the 31st week of gestation, who presented with cutaneous haemorrhagic symptoms. The complete blood count showed anaemia, thrombocytopenia, increase in haemolysis indices and undetectable ADAMTS13 activity. Acquired TTP was diagnosed, and she started daily plasma exchange (PEX) and methylprednisolone. After 5 days, an emergency caesarean section was performed with success because of pathologic cardiotocographic findings. After 7 days of PEX, the patient showed an initial laboratoristic improvement; unfortunately, 3 days later, she had a recurrence of disease and started daily PEX, caplacizumab and steroid, obtaining a haematological improvement. No literature data about caplacizumab use in pregnant or breastfeeding patients are available. In the present study, we describe that caplacizumab in the postpartum period could be well tolerated and effective.

Prevalence of pulmonary embolism among patients with recent onset of dyspnea on exertion. A cross-sectional study.

BACKGROUND: Exertional dyspnea is a frequently encountered complaint in clinical practice. However, the prevalence of pulmonary embolism (PE) among patients with dyspnea on exertion has not been reported. OBJECTIVE: The objective of this study was to assess the prevalence of objectively confirmed PE among consecutive patients visiting an emergency department because of recent onset of exertional dyspnea. METHODS: Patients aged ≤75 years with recent (<1 month) marked exertional dyspnea had a systematic workup for PE, irrespective of concomitant signs or symptoms of venous thromboembolism and alternative explanations for dyspnea. PE was excluded on the basis of a low pretest clinical probability and normal age-adjusted D-dimer. All other patients had computed tomography pulmonary angiography. An interim analysis after inclusion of 400 patients would stop recruitment if the 95% confidence interval (CI) of the PE prevalence had a lower limit exceeding 20%. RESULTS: The study was prematurely terminated after the inclusion of 417 patients. In 134 patients (32.1%), PE was excluded based on low clinical probability and normal D-dimer. PE was found in 134 (47.3%) of the remaining 283 patients, for an overall prevalence of 32.1% (95% CI, 27.8-36.8). PE was present in 40 of 204 (19.6%) patients without other findings suspicious for PE and in 94 of 213 patients (44.1%) with such findings. PE involved a main pulmonary artery in 37% and multiple lobes in 87% of the patients. CONCLUSION: The angiographic demonstration of PE is common in patients presenting with recent onset of marked exertional dyspnea, including 20% without other findings suggesting pulmonary embolism.

Rupture of pseudoaneurysm of a digiunal artery in the pancreatic duct.

Visceral arterial pseudoaneurysms are uncommon vascular abnormalities affecting renal or splanchnic arteries. They can be complications of chronic pancreatitis, blunt or penetrating abdominal trauma, or surgical, endoscopic and interventional radiological procedures. Visceral arterial pseudoaneurysms can be life-threatening because of hemorrhagic shock secondary to rupture and massive bleeding. We report an unusual case of rupture of a pseudoaneurysm of a digiunal artery in the pancreatic duct.

Multisystem Inflammatory Syndrome after Ad26.COV2.S vaccination.

BACKGROUND: The multisystem inflammatory syndrome (MIS) is a rare and sometime life-threatening post-infectious complication of coronavirus disease 2019 (Covid-19) in children and adults. To date, only a very few reports have associated such systemic reaction with SARS-CoV-2 vaccination. CASE REPORT: we describe a case that resembled MIS, in a 46-year-old White man, 12 days after vaccination with Ad26. COV2. S vaccine (Johnson &Johnson/Janssen), a recombinant adenovirus serotype 26 vector encoding the SARS-CoV-2 spike glycoprotein. The patient experienced high grade fever, cutaneous rash, severe weakness, pericardial effusion and raised inflammatory markers, which met the criteria for definition of MIS. The symptoms improved with steroidal therapy. CONCLUSIONS: Our case suggests that MIS could occur after SARS-CoV-2 vaccination.

A challenging case of anemia, respiratory failure and seizures.

BACKGROUND: Hemorrhagic Hereditary Telangiectasia (HHT), or  Rendu-Osler-Weber syndrome,  is a rare genetic disorder characterized by mucocutaneous telangiectasias and visceral arteriovenous malformations. AIM AND METHODS: We describe the case of a 64-year old woman  in which radiology was useful to interpret an apparently unexplained constellation of symptoms. RESULTS: Brain MRI showing ischemic stroke, pulmonary angiography demonstrating arteriovenous malformations, and capsule endoscopy detecting telangiectasias in the jejunum, along with a clinical history of recurrent epistaxis, allowed us to diagnose HHT. CONCLUSIONS: HHT is rare and difficult to diagnose. Radiology can aid the clinical suspicion. www.actabiomedica.it.

Pulmonary embolism and renal artery thrombosis in a patient with patent foramen ovale.

BACKGROUND AND AIM: Paradoxical embolism is a rare condition in which a thrombus migrates from the venous system to the arterial circulation, usually through a patent foramen ovale (PFO). Pulmonary embolism (PE) and isolated occlusion of one renal artery has been seldom reported. METHODS: We describe a case of a 47-year old white man with a one-month history of exertional dyspnea who was admitted to our hospital for  severe pain in the right lumbar region. RESULTS: A computed tomography showed  PE and a thrombotic occlusion of the right renal artery. A trans-thoracic echocardiogram documented a PFO with right to left shunt. Magnetic resonance imaging of the brain and venous compression ultrasonography of the lower extremities were normal. Therapeutic anticoagulation was started. CONCLUSIONS: Pulmonary embolism and thrombotic occlusion of one renal artery is a rare manifestation of paradoxical embolism. Exertional dyspnea is an atypical manifestation of PE and can delay the diagnosis.

Transit time flow measurement guiding the surgical treatment for anomalous origin of the right coronary artery: A case report.

Anomalous origin of a coronary artery from the opposite sinus of Valsalva (ACAOS) in symptomatic patients is a rare but serious finding whose treatment consists of a surgical correction. The surgical treatment has a level of complexity that could vary from unroofing and ostioplasty to coronary artery bypass grafting. We present our management of a 59-year-old woman presenting with chest pain and dyspnea for right ACAOS with an interarterial route. The right coronary artery (RCA) was bypassed with the right internal thoracic artery. An intraoperative transit time flowmetry (TTFM) showed a competitive flow from the native RCA. RCA proximal ligation site was identified intraoperatively, considering the best mean graft flow (MGF) and the absence of ischemic events. The patient was discharged after a week without adverse events. The 1-year follow-up was uneventful. The intraoperative use of TTFM could guide the surgeon's hand making straightforward the surgical treatment for ACAOS.

Serial 2-point ultrasonography plus D-dimer vs whole-leg color-coded Doppler ultrasonography for diagnosing suspected symptomatic deep vein thrombosis: a randomized controlled trial.

CONTEXT: Patients with suspected deep vein thrombosis (DVT) of the lower extremities are usually investigated with ultrasonography either by the proximal veins (2-point ultrasonography) or the entire deep vein system (whole-leg ultrasonography). The latter approach is thought to be better based on its ability to detect isolated calf vein thrombosis; however, it requires skilled operators and is mainly available only during working hours. No randomized comparisons are yet available evaluating the relative values of these 2 strategies. OBJECTIVE: To assess if the 2 diagnostic strategies are equivalent for the management of symptomatic outpatients with suspected DVT of the lower extremities. DESIGN, SETTING, AND PATIENTS: A prospective, randomized, multicenter study of consecutive symptomatic outpatients (n = 2465) with a first episode of suspected DVT of the lower extremities who were randomized to undergo 2-point or whole-leg ultrasonography. Data were taken from ultrasound laboratories of 14 Italian universities or civic hospitals between January 1, 2003, and December 21, 2006. Patients with normal ultrasound findings were followed up for 3 months, with study completion on March 20, 2007. MAIN OUTCOME MEASURE: Objectively confirmed 3-month incidence of symptomatic venous thromboembolism in patients with an initially normal diagnostic workup. RESULTS: Of 2465 eligible patients, 345 met 1 or more exclusion criteria and 22 refused to participate; therefore, 2098 patients were randomized to either 2-point (n = 1045) or whole-leg (n = 1053) ultrasonography. Symptomatic venous thromboembolism occurred in 7 of 801 patients (incidence, 0.9%; 95% confidence interval [CI], 0.3%-1.8%) in the 2-point strategy group and in 9 of 763 patients (incidence, 1.2%; 95% CI, 0.5%-2.2%) in the whole-leg strategy group. This met the established equivalence criterion (observed difference, 0.3%;95% CI, -1.4% to 0.8%). CONCLUSION: The 2 diagnostic strategies are equivalent when used for the management of symptomatic outpatients with suspected DVT of the lower extremities. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00353093.

A prospective validation of the Bova score in normotensive patients with acute pulmonary embolism.

BACKGROUND: The Bova score has shown usefulness in the identification of intermediate-high risk patients with acute pulmonary embolism (PE), but lacks prospective validation. The aim of this study was to prospectively validate the Bova score in different settings from the original derivation cohort. METHODS: Consecutive, normotensive patients with acute PE recruited at 13 academic or general hospitals were stratified, using their baseline data, into the three Bova risk stages (I-III). The primary outcome was the 30-day composite of PE-related mortality, hemodynamic collapse and non-fatal PE recurrences in the three risk categories. RESULTS: In the study period, 639 patients were enrolled. The primary end point occurred in 45 patients (7.0%; 95% Confidence Intervals, 5.2%-9.3%). Risk stage correlated with the PE-related complication rate (stage I, 2.9%; stage II, 17%; stage III, 27%). Patients classified as stage III by the Bova score had a 6.5-fold increased risk for adverse outcomes (3.1-13.5, p < 0.001) compared with stages I and II combined. Rescue thrombolysis increased from stage I to stage III (0.6%, 12% and 15% respectively). All-cause mortality (5.3%) did not substantially differ among the stages. CONCLUSIONS: The Bova score accurately stratifies normotensive patients with acute PE into stages of increasing risk of 30-day PE-related complications.