Genetic tests in lymphatic vascular malformations and lymphedema.

Syndromes with lymphatic malformations show phenotypic variability within the same entity, clinical features that overlap between different conditions and allelic as well as locus heterogeneity. The aim of this review is to provide a comprehensive clinical genetic description of lymphatic malformations and the techniques used for their diagnosis, and to propose a flowchart for genetic testing. Literature and database searches were performed to find conditions characterised by lymphatic malformations or the predisposition to lymphedema after surgery, to identify the associated genes and to find the guidelines and genetic tests currently used for the molecular diagnosis of these disorders. This search allowed us to identify several syndromes with lymphatic malformations that are characterised by a great heterogeneity of phenotypes, alleles and loci, and a high frequency of sporadic cases, which may be associated with somatic mutations. For these disorders, we found many diagnostic tests, an absence of harmonic guidelines for molecular diagnosis and well-established clinical guidelines. Targeted sequencing is the preferred method for the molecular diagnosis of lymphatic malformations. These techniques are easy to implement and have a good diagnostic success rates. In addition, they are relatively inexpensive and permit parallel analysis of all known disease-associated genes. The targeted sequencing approach has improved the diagnostic process, giving patients access to better treatment and, potentially, to therapy personalised to their genetic profiles. These new techniques will also facilitate the prenatal and early postnatal diagnosis of congenital lymphatic conditions and the possibility of early intervention.

Comparison Between Duplex Ultrasound and Multigate Quality Doppler Profile Software in the Assessment of Lower Limb Perforating Vein Direction.

OBJECTIVES: The aim was to assess more accurately the net flow of the lower limb perforating veins (PVs). MATERIAL AND METHODS: This was an observational prospective study. Two hundred and twenty one limbs with chronic venous disease (C1-6EpAs,pPr) of 193 patients underwent a duplex ultrasound (DUS). All identified PVs were scanned also by means of quality Doppler profile (QDP) multigate analysis in order to determine their net inward and outward flow direction. A comparison between the traditional pulsed wave Doppler analysis and QDP was performed to detect potential discrepancy between the traditional definition of PV incompetence and a net outward flow. RESULTS: The DUS investigation identified 774 PVs. Only 7.7% of the PVs showed an outward flow lasting more than 500 ms. Among the PVs showing a longer than 500 ms outward flow, QDP assessment revealed net outward flow in only 84% of the PVs along the thigh and in 28.6% along the lower leg. Among the PVs showing a shorter than 500 ms outward flow, QDP assessment reported a net outward flow in 2.4% of the PVs along the thigh and in 47.3% of those along the lower leg. The sensitivity of an outward flow lasting more than 500 ms in detecting an actual net outward flow was 13.9% (9-20.1%). The specificity of an outward flow lasting less than 500 ms in detecting a net inward flow was 96.4% (93.2-98.3%). CONCLUSIONS: A lack of overlap exists between the finding of a PV outward flow lasting more than 500 ms and the net outward flow of the same vessel. The traditional definition of PV incompetence is challenged by the reported data and further investigations are required to identify a gold standard assessment.

Hepatic vena cava syndrome: New concept of pathogenesis.

Hepatic vena cava syndrome, also known as membranous obstruction of inferior vena cava (IVC), was considered a rare congenital disease and classified under Budd-Chiari syndrome. It is now recognized as a bacterial infection-induced disease related to poor hygiene. Localized thrombophlebitis of the IVC at the site close to hepatic vein outlets is the initial lesion which converts on resolution into stenosis or complete obstruction, the circulatory equilibrium being maintained by development of cavo-caval collateral anastomosis. These changes persist for the rest of the patient's life. The patient remains asymptomatic for a variable period until acute exacerbations occur, precipitated by bacterial infection, resulting in deposition of thrombi at the site of the lesion and endophlebitis in intrahepatic veins. Large thrombus close to hepatic vein outlets results in ascites from hepatic venous outflow obstruction, which is followed by development of venocentric cirrhosis. Endophlebitis of intrahepatic veins results in ischemic liver damage and development of segmental stenosis or membrane. Acute exacerbations are recognized clinically as intermittent jaundice and/or elevation of aminotransferase or ascites associated with neutrophil leukocytosis and elevation of C-reactive protein; sonologically, they are recognized as the presence of thrombi of different ages in IVC and thrombosis of intrahepatic veins. Development of liver cirrhosis and hepatocellular carcinoma is related to severity or frequency of acute exacerbations and not to duration or type of caval obstruction. Hepatic vena cava syndrome is a common co-morbid condition with other liver diseases in developing countries and it should be considered in differential diagnosis in patient with intermittent elevation serum bilirubin and or aminotransferase or development of ascites and cirrhosis.

Fake-news-free evidence-based communication for proper vein-lymphatic disease management.

Published scientific evidence demonstrate the current spread of healthcare misinformation in the most popular social networks and unofficial communication channels. Up to 40% of the medical websites were identified reporting inappropriate information, moreover being shared more than 450,000 times in a 5-year-time frame. The phenomenon is particularly spread in infective diseases medicine, oncology and cardiovascular medicine. The present document is the result of a scientific and educational endeavor by a worldwide group of top experts who selected and analyzed the major issues and related evidence-based facts on vein and lymphatic management. A section of this work is entirely dedicated to the patients and therefore written in layman terms, with the aim of improving public vein-lymphatic awareness. The part dedicated to the medical professionals includes a revision of the current literature, summing up the statements that are fully evidence-based in venous and lymphatic disease management, and suggesting future lines of research to fulfill the still unmet needs. The document has been written following an intense digital interaction among dedicated working groups, leading to an institutional project presentation during the Universal Expo in Dubai, in the occasion of the v-WINter 2022 meeting.

Predictive factors for response of peripheral arteriovenous malformations to embolization therapy: analysis of clinical data and imaging findings.

PURPOSE: To find a significant predictive factor for the efficacy of endovascular treatment of peripheral arteriovenous malformations (AVMs). MATERIALS AND METHODS: One hundred seventy-six patients (73 male patients and 103 female patients; mean age, 29.4 y) who underwent treatment for AVMs in the body or extremities were included. Per Schobinger classification, lesions in 31 patients (18%) were stage II, those in 136 (77%) were stage III, and those in nine (5%) were stage IV. AVMs were located in the extremities in 130 patients (74%) and in the trunk in 46 patients (26%). AVMs were angiographically classified as type I (n = 1), type II (n = 36), type IIIa (n = 6), type IIIb (n = 9 1), or complex type (n = 42). Demographic factors, clinical data, and imaging data were analyzed to determine a statistically significant relationship with overall clinical outcomes. RESULTS: Overall, 68 patients (39%) were cured, 91 patients (52%) showed a partial response, nine patients (5%) showed no response, treatment failed in seven patients (4%), and treatment aggravated the condition in one patient (1%). The overall complication rate was 45% (79 of 176 patients). Minor complications developed in 62 patients (35%) and major complications developed in 17 (10%). Statistically, the extent of AVMs (odds ratio, 0.199) and angiographic classification (odds ratio, 0.162) were significant predictive factors for overall clinical outcome. CONCLUSIONS: Endovascular treatment of peripheral AVMs, planned with consideration of anatomic extent and angiographic subtypes, is likely to yield good clinical results with low complication rates.

Treatment of arteriovenous malformations involving the hand.

BACKGROUND: Hand arteriovenous malformations (AVMs) are difficult to treat because of the necessity to maintain function and the high complication rate of treatment. The purpose of this study was to review the treatment of hand AVMs with embolo/sclerotherapy and the surgical procedures at a single institute. MATERIAL AND METHODS: We retrospectively reviewed the medical records and identified the patients who were referred to the vascular division owing to hand AVMs between 1995 and 2009. The lesions were classified according to their affected areas. The treatments used at the clinic included conservative treatment, amputation, and embolo/sclerotherapy. We investigated the clinical data and assessed the treatment results. RESULTS: Sixty-four patients were involved in this study. The median follow-up duration was 26.9 months (range: 3.5-141.8 months). The median age of the patients was 31.5 years (range: 0.3-75.0 years). All of the lesions were of the extratruncal (ET) form, and 37 cases (57.8%) were of the infiltrating type. Sixteen patients were treated conservatively. Primary amputation was performed in seven cases with previous complications such as ulcer, bleeding, or functional limitations. Embolo/sclerotherapy with ethanol was performed in 41 patients. Sixteen (39.0%) of them showed clinical improvement. The treatment of 20 (48.8%) of the 41 patients was interrupted owing to a variety of complications, and 2 (4.9%) of these patients failed with embolo/sclerotherapy. Skin necrosis was the major complication, and this occurred in 17 patients treated with embolo/sclerotherapy--14 of these cases were small and the skin necrosis healed with conservative treatment; 1 patient had autoamputation owing to necrosis; and 2 patients underwent amputation surgery owing to gangrene. The risk for skin necrosis was higher for the AVMs that involved the subcutaneous layer and the AVMs that extended diffusely (P = 0.021, P = 0.011). Seven neuropathic complications developed after embolo/sclerotherapy, and all of them were transient. CONCLUSIONS: The symptoms and characteristics of the lesions are important factors in devising a treatment plan for AVMs. AVM treatment, and especially embolo/sclerotherapy, is a long-term prospect, and it carries a potential risk for serious complications. After every treatment, the lesions must be reevaluated and new treatment plans must be made by the members of a multidisciplinary team.

The results of surgical treatment for patients with venous malformations.

BACKGROUND: The objective of this study was to estimate the outcomes of surgical treatment for patients with venous malformations (VMs). METHODS: We retrospectively reviewed the data of 48 patients who underwent surgical management for VMs from 1994 to 2009 at our institute. The 1-year responses to surgeries were classified into three groups based on the results: "remission," "improvement," and "no change." RESULTS: The indications of surgeries were mass or swelling in 48 patients (100%), intractable pain in 11 (23%), limb length discrepancy in seven (15%), bleeding in three (6%), and limitation of the range of motion in one (2%). The locations of the VMs were head and neck in 17 patients (35%), abdomen and pelvis in one (2%), perineum and genitalia in three (6%), upper extremities in 12 (25%), and lower extremities or buttocks in 15 (31%). Of the 48 surgeries for radical excision and debulking, 25 (52%) resulted in remission, 11 (23%) in improvement, and 12 (25%) in no change. During follow-up (mean: 44.8 ± 36.6 months, range: 0-111 months), recurrence after radical excision occurred in 10% (3 of 31) of the patients, and size increase after debulking surgery in 24% (4 of 17) of the patients. CONCLUSIONS: Surgical treatment can be an option in patients with VMs, especially with symptoms that cannot be managed with conservative therapy or sclerotherapy. After excisional or debulking surgery in patient with VMs, remission or improvement can be observed in 75%.

Predictors of response to percutaneous ethanol sclerotherapy (PES) in patients with venous malformations: analysis of patient self-assessment and imaging.

BACKGROUND: Percutaneous ethanol sclerotherapy (PES) is the primary tool in the treatment of venous malformations (VM). However, PES has known serious complications. This study is aimed at identifying predictors of good response to PES in patients with VM to improve patient selection. METHODS: We performed a retrospective, cross-sectional study of 158 VM patients (mean age, 14.3 years, male 42%) who underwent ethanol sclerotherapy at a specialized vascular malformation center. For clinical result assessment, patients or parents in pediatric patients answered questions on symptomatic, functional, and cosmetic improvement after PES. In each category, the possible choices were markedly improved, moderately improved, no change, moderately worse, or markedly worse compared with pretreatment status. A "good response" was defined as one or more areas of marked improvement on the self-assessment in conjunction with marked improvement on post-treatment images (> or =30% decrease in maximal diameter of VM on magnetic resonance imaging [MRI] or > or =50% decrease in abnormal blood pool ratio on whole body blood pool scintigraphy [WBBPS] compared with pretreatment images). To determine predictors of a good response to PES, uni- and multivariate analysis were conducted on demographics (age, gender), clinical features of VM (location, size, depth of involved tissue, presence of associated lymphatic malformation, MRI findings; well-defined vs ill-defined margin, characteristics of venous drainage during PES) and treatment variables (number of PES sessions, maximal concentration and dosage of ethanol used in PES, adjuvant therapy). RESULTS: Symptomatic, functional, and cosmetic improvement was 28%, 27%, and 34%, respectively, based on patient questionnaires. Based on imaging studies, 42 patients (27%) had markedly improvement. Composite outcome combining questionnaire results and imaging study showed that 16% of patients had a "good response". On multivariate analysis, female gender (odds ratio [OR]: 4.49, 95% confidence interval [CI]: 1.24-16.28), no or delayed visualization of drainage vein (OR: 9.22, 95% CI: 1.79-47.51), and a well-defined margin on MRI (OR: 13.38, 95% CI: 2.84-63.12) were independent predictors of "good response" to PES. CONCLUSIONS: PES should be performed in selected patients in order to obtain the best outcomes and minimize complications. No or delayed visualization of drainage vein on initial direct puncture venogram, a well-defined margin on MRI, and female gender were statistically significant predictors of a "good response" to PES and may be useful in selecting patients.

Vascular anomalies: molecular bases, genetic testing and therapeutic approaches.

INTRODUCTION: Vascular anomalies encompass an extremely heterogeneous group of congenital abnormalities of the vascular system. They include vascular tumors and malformations and have a prevalence of 4.5%. Vascular anomalies are frequently sporadic and associated with somatic mutations and/or a double-hit mechanism and are characterized by considerable phenotypic and genetic heterogeneity. The aim of this review was to provide a genetic description of vascular anomalies, the sequencing technologies used for their diagnosis and the drugs that may potentially be used for their treatment. EVIDENCE ACQUISITION: PubMed, OMIM, Orphanet, Genetic Testing Registry and ClinicalTrials.gov were searched for monogenic vascular anomalies in order to evaluate the genetic tests (based on sequencing) currently used for their diagnosis, and for any drugs that could be useful to treat them. EVIDENCE SYNTHESIS: From the search of the clinical synopsis section of OMIM and PubMed for vascular anomalies we selected 19 disorders with a known molecular etiology. From the search for pharmacological trials and therapies in the ClinicalTrials.gov and PubMed databases we selected 87 drugs. CONCLUSIONS: Most genetic tests with validated clinical utility are based on a next generation sequencing (NGS) approach. Targeted NGS is indeed the best approach for the analysis of disorders with complex phenotypes and genetics and involvement of somatic mutations. Genetic diagnosis provides data for determine genotype-phenotype correlations, segregation and recurrence risk in families, and new targets for gene- or mutation-specific pharmacological therapies. Improvement of diagnostic techniques is needed to offer patients appropriate care, more focused follow-up, and hopefully drugs to treat their disorders.

Expression of heat shock protein 27 in human atherosclerotic plaques and increased plasma level of heat shock protein 27 in patients with acute coronary syndrome.

BACKGROUND: We intended to identify proteins that are differentially expressed in human atherosclerotic plaques. METHODS AND RESULTS: Comparative 2-dimensional electrophoretic analysis on carotid atherosclerotic endarterectomy specimens (n = 10) revealed that heat shock protein 27 (Hsp27) expression was significantly increased in the nearby normal-appearing area compared with the plaque core area from the same vessel specimen, which was further confirmed by Western blot analysis. The Hsp27 expression in the adjacent normal-appearing vessel areas was much higher than that in nonatherosclerotic reference arteries. The phosphorylation of Hsp27 showed a gradation in the degree of phosphorylation: greatest in the reference arteries, intermediate in the adjacent normal-appearing area, and lowest in plaque core area. Immunohistochemical analysis showed that the phosphorylation of Hsp27 of smooth muscle cells in the carotid endarterectomy specimens was decreased compared with that in the reference artery specimen. The mean plasma level of Hsp27 was significantly higher in patients with acute coronary syndrome (ACS) (n = 27; 106.1 +/- 74.1 ng/mL) than in the normal reference subjects (n = 29; 45.8 +/- 29.5 ng/mL; P < 0.005). The plasma levels of Hsp27 were significantly correlated with those of heat shock protein 70 (Hsp70) (r = 0.422, P < 0.0005), with adjustment for ACS/reference status. CONCLUSIONS: In the atherosclerotic lesion, Hsp27 expression is increased in the normal-appearing vessel adjacent to atherosclerotic plaque, whereas levels in the plaque itself are significantly decreased. Both plaque and adjacent artery show decreased Hsp27 phosphorylation compared with reference vessel. In ACS, plasma Hsp27 and Hsp70 are increased, and levels of Hsp27 correlate with Hsp70, C-reactive protein, and CD40L levels.

Lymphedema : A Concise Compendium of Theory and Practice

Lymphedema: A Concise Compendium of Theory andPractice brings into one volume the most important sources ofinformation to guide the evaluation and treatment of patients withlymphedema. The management of chronic lymphedema continues tochallenge both patients and treating physicians worldwide. In thepast decades, however, substantial progress has been achieved forboth diagnosis and therapy of these disabling conditions. Withincreasing attention to the quality of life, this debilitatinglife-long disease is receiving more attention not only bylymphedema specialists, but also by clinicians across the spectrumof health care delivery. Lymphedema: A Concise Compendium of Theoryand Practice provides clear, concise background and recommendationsin an easy-to-use format. It is a valuable reference tool forclinical practitioners (physicians/nurse practioners/technicians)who wish to deliver state-of-the-art health care to their patientswith lymphatic and venous disorders.

Angiosarcoma after excisional surgery for chronic lymphedema.

Angiosarcoma is a rare soft tissue sarcoma of endothelial cell origin. It can arise from the endothelium of lymphatics (lymphangiosarcoma) or blood vessels (hemangiosarcoma). Chronic lymphedema of any origin is associated with its development. Few cases have been reported after surgical procedures for lymphedema. Here, we report one case of angiosarcoma that developed 15 months after excisional surgery for lymphedema. In spite of radical surgery and adjuvant chemoradiotherapy, the patient died of multiple lung metastases and pleural effusion 13 months later.