Association of Venous Disorders with Leg Symptoms: Results from the Bonn Vein Study 1.

OBJECTIVES: The aim was to study the association between venous disorders and leg symptoms in the population based cross sectional Bonn Vein Study 1 (BVS1). METHODS: A total of 1,350 men and 1,722 women aged 18-79 years were enrolled into BVS1. Chronic venous insufficiency (CVI), varicose veins (VVs), and clinical classes (C-classes/CEAP [Clinical, Etiological, Anatomical, and Pathophysiological]) were determined by clinical and duplex investigation. Leg symptoms (heaviness, tightness, swelling, pain after standing or sitting, pain while walking, muscle cramps, itching, and restless legs) were assessed in a standardized interview. For 2,624 subjects (48.7% male) with complete information on venous disorders, relevant characteristics and information on at least one leg symptom, multivariate logistic regression analysis was performed. RESULTS: More women (929/63.0%) reported at least one leg symptom within the last 4 weeks than men (560/48.7%). Prevalence of reported symptoms increased with age (45.4% of the 18-29 year olds, 73.9% of the 70-79 year olds). Leg symptoms were more frequent in obese and underweight subjects. As confirmed by clinical and duplex examination 22.6% had VV and 15.8% had CVI. VV (OR: 1.4; CI: 1.1-1.7) and CVI (OR: 1.8; CI: 1.3-2.3) were significantly associated with reporting at least one leg symptom. In particular, there was a positive association of VV and CVI with itching, feeling of heaviness, tightness, swelling, and pain after standing or sitting. C2-C6 showed a statistically significant association with feeling of heaviness, tightness, swelling, and itching, while for pain on walking and muscle cramps this was shifted towards C classes C3-C6 and C3-C4, respectively. CONCLUSIONS: Venous disorders show significant associations with several leg symptoms. Itching, feeling of heaviness, or tightness seem to be more closely related than other symptoms. The associations between C classes and symptoms seem to be restricted to classes C2 or higher.

[Endovenous thermal ablation of saphenous varicosis]. / Endovenöse Thermoablation der Stammvarikose.

Endoluminal catheter-based procedures enable venous reflex in varicose saphenous veins to be eliminated. The catheter tip is positioned in the sapheno femoral or popliteal junction under ultrasound guidance. The energy necessary to ablate the vein is generated as heat by high-frequency current (radiofrequency) by laser light or by steam. Advantages of this procedure include low invasiveness, subcutaneous infusion anesthesia (SIA), low perioperative morbidity and rapid restoration of mobility of patients.

Immune checkpoint analysis in lip cancer.

The aim of this study was to establish whether PD-L1, PD-1, and markers of the tumor microenvironment (CD4, CD8, FOXP3) could have a prognostic value in squamous cell carcinoma of the lip (LSCC). In patients with histologically proven LSCC, tumor specimens were stained using immunohistochemistry (for PD-1, PD-L1, CD4, CD8, and FOXP3) on paraffin-embedded tissues. Patients with (N+) and without (N-) nodal metastasis were stratified and matched to each other according to prognostically relevant clinicopathological parameters. 58 patients (29 N+ and 29 N-) were included. PD-L1 expression was positive (>1%) in 56.1% (n = 33) of all LSCC cases, but its expression did not differ significantly between metastasis groups (65.5% in N+ versus 48.3% in N-; p = 0.144). Nodal disseminated LSCC showed a tendency for higher PD-L1 expression. None of the analyzed markers showed significant correlation with the risk for nodal disease, or revealed significant prognostic value. Due to their significant expression, PD-L1 and PD-1 are potential targets for checkpoint inhibitor therapy in LSCC. Their expression should be analyzed in advanced and metastasized LSCC cases.

Efficacy and safety of great saphenous vein sclerotherapy using standardised polidocanol foam (ESAF): a randomised controlled multicentre clinical trial.

AIM: To assess the safety and efficacy of sclerotherapy of the great saphenous vein (GSV) comparing standardised polidocanol foam to liquid polidocanol in a randomised controlled trial (RCT). METHODS: A multicentre randomised controlled clinical trial was carried out in which saphenous trunks were treated by sclerotherapy. 106 patients with primary varicose veins due to an incompetent GSV were treated with either standardised 3% polidocanol foam or 3% liquid polidocanol. The primary efficacy criterion was elimination of reflux (<0.5 sec) measured 3 cm below the sapheno-femoral junction (SFJ) by duplex ultrasonography 3 months after the last injection. RESULTS: A significantly greater number of patients were successfully treated by foam sclerotherapy resulting in 69% elimination of reflux compared to 27% patients treated with liquid sclerosant. The secondary endpoints of vein occlusion, reflux time, refilling time and patient satisfaction also improved significantly more in the foam group. The mean number of treatment sessions was 1.3 in the foam group compared to 1.6 in the liquid group. Differences between study centres occurred with a mean of 96% reflux elimination in 6 centres versus 39% in 4 other centres. Centres with a high response rate injected a higher mean volume (4.3 vs. 3.6 ml) in the first session in a vein with a smaller diameter (7.5 mm vs. 8.4 mm). No difference in adverse drug reactions was observed between treatment groups. CONCLUSIONS: Standardised 3% polidocanol foam is more efficient and equally safe compared to 3% liquid polidocanol for treatment of GSV. In comparison to other studies a relatively small volume was injected into relatively large veins.

Guidelines for clinical studies with compression devices in patients with venous disorders of the lower limb.

OBJECTIVES: The scientific quality of published clinical trials is generally poor in studies where compression devices have been assessed in the management of venous disease. The authors' aim was to establish a set of guidelines which could be used in the design of future clinical trials of compression treatments for venous diseases. DESIGN: Consensus conference leading to a consensus statement. METHODS: The authors form a expert consensus group known as the International Compression Club (ICC). This group obtained published medical literature in the field of compression treatment in venous disease by searching medical literature databases. The literature was studied by the group which attended a consensus meeting. A draft document was circulated to ICC members and revised until agreement between contributors was reached. RESULTS: The authors have prepared a set of guidelines which should be given consideration when conducting studies to assess the efficacy of compression in venous disease. CONCLUSIONS: The form of compression therapy including the comparators used in the clinical study must be clearly characterised. In future studies the characteristics of the material provided by the manufacturer should be described including in vivo data on pressure and stiffness of the final compression system. The pressure exerted on the distal lower leg should be stated in mmHg and the method of pressure determination must be quoted.

Mid-term results following endovenous laser ablation (EVLA) of saphenous veins with a 980 nm diode laser.

AIM: To assess the mid-term results after endovenous laser ablation (EVLA) of saphenous veins by a standardized duplex and clinical protocol. METHODS: A non-randomized prospective trial was performed. We included a total of 67 unselected legs of 65 patients with incompetent great or small saphenous veins (GSV and SSV), confirmed by duplex ultrasound. EVLA was carried out with a 980 nm diode laser in pulsed mode and using tumescent local anaesthesia. All patients were given heparin prophylaxis and compression therapy. Patients underwent standard clinical and duplex follow-up examinations with an average of 2.2 years (0.5-3.5 years) after EVLA. RESULTS: Reflux was eliminated in 59 (88.1%) of the 67 treated veins after 2.2 (SD 0.9) years with an average energy density of 48 J/cm vein (19.8-96.1, SD 13.2). 11.9% of the cases demonstrated antegrade flow without reflux. In 8 of 67 treated legs (11.9%) reflux >0.5 s was still present. In these patients the initial vein diameter was significantly (P=0.01) higher than in the successfully treated limbs. Without reflux, the majority of treated veins, 41 of 59 (69.5%), were no longer detectable by ultrasound. In all groups with still visible veins, there was a diameter reduction of about 50%. Clinical classification (CEAP) and pitting edema similarly improved in all groups, and patient satisfaction was very high across the board. Recurrent varicose veins were significantly more frequent in the reflux group. Severe complications such as deep vein thrombosis or pulmonary embolism did not occur in any of the 67 treated cases. CONCLUSIONS: EVLA of the GSV and SSV is a minimally invasive, safe and efficient treatment option with a high mid-term success rate. Not only standardized duplex, but also clinical criteria should be used in assessing the results.

Endovenous laser therapy and radiofrequency ablation of saphenous varicose veins.

Radiofrequency ablation (RFA) and endovenous laser treatment (EVLT) are minimal invasive methods to treat saphenous varicose veins. The short- and mid-term results are excellent with an occlusion rate for RFA of almost 90% after 5 years and about 95% for EVLT after 2 years. Severe side effects are rare in both cases. Prospective randomised comparative studies are available for RFA and surgery showing comparable short-term results and superiority of RFA concerning short-term quality of life outcome. For laser treatment no prospective randomised comparative studies are available. Endovenous treatment is only a part of the complex treatment concept of varicose veins. Insufficient tributaries have to be treated in addition. The fact that the insufficient saphenous vein is treated without high ligation seems not to influence the short-term and mid-term recurrence rates. More prospective randomised comparative studies comparing endovenous treatment and surgery or foam sclerotherapy are necessary to decide which method is the best for which patient.

Embolization is not essential in the treatment of leg varices due to pelvic venous insufficiency.

AIM: To consider if it is essential to perform embolization in the treatment of leg varices due to pelvic venous insufficiency. METHODS: Review of the current literature concerning treatment options of leg varicose veins of pelvic origin. RESULTS: Pelvic venous insufficiency, vulvar and pudendal varicose veins as well as pelvic congestive syndrome are under diagnosed entities. Embolization of ovarian and pelvic veins is well established in patients with pelvic congestive syndrome. In varicose veins of pelvic origin but without pelvic congestive syndrome, comparative studies comparing the outcome of embolization or treatment of varicose veins by sclerotherapy or phlebectomy alone are missing. Foam sclerotherapy or phlebectomy shows good results in patients with varicose veins of pelvic origin. CONCLUSIONS: Embolization is not essential in the treatment of leg varices of pelvic origin without pelvic congestive syndrome. Foam sclerotherapy or phlebectomy shows good results in patients with vulvar or pudendal varicose veins. Randomized comparative studies using embolization of incompetent pelvic veins or sclerotherapy of varicose veins with pelvic origin should be performed.

Progression in venous pathology.

AIM: To review epidemiologic data on progression of venous pathology in varicose veins and from varicose veins towards chronic venous insufficiency. METHODS: We searched Medline and PubMed for epidemiologic studies concerning progression of venous pathology. RESULTS: The data suggest that reflux progression may develop from segmental to multisegmental superficial reflux. In younger age, reflux in tributaries and non-saphenous veins is more frequent. In older age, more saphenous reflux develops and more proximal sites seem to be affected. A high proportion of uncomplicated varicose vein (C2) develops skin changes and chronic venous insufficiency (C3-C6). Significant risk factors for the progression of varicose vein towards venous leg ulcers are skin changes, corona phlebectatica, higher body mass index and popliteal vein reflux. During a 13.4-year follow-up period, 57.8% (4.3%/year) of all chronic venous disease patients showed progression of the disease. SUMMARY: Studies on the progression of venous pathology show a high progression rate of chronic venous disease. More follow-up studies are still needed to get better information about the risk of varicose vein patients for progression to venous leg ulcers and to answer the question which patients may benefit from early varicose vein interventions.

High-performance liquid chromatographic-inductively coupled plasma mass spectrometric evidence for Se-"alliins" in garlic and onion grown in Se-rich soil.

Garlic and onion, are well known for their medical value, especially in against cancer and anticardiovacular diseases. "Alliins" (S-alk(en)yl-L-cysteine sulphoxides) are sources of major active compounds in Allium plants. Se incorporation into garlic significantly increases activities of garlic in cancer prevention and inhibition. Selenomethionine, selenocysteine and Se-methylselenocysteine have been identified in garlic and onion. Previously we identified gamma-glutamyl-Se-methyl-L-selenocysteine, in extracts of garlic cultivated in Se-rich soil [Med. Res. Rev. 16 (1) (1996) 111], suggesting the possible existence of Se-alk(en)yl-L-cysteine selenoxides (Se-"alliins") in garlic. Several comparative experiments were carried out to demonstrate the existence of Se-"alliins" in Se-enriched garlic and onion. We found that there was one similar time-dependent Se signal in HPLC-inductively coupled plasma MS chromatograms of cold-water extracts of freeze-dried garlic powder and fresh garlic. This signal was lost when the extracts of garlic powder and fresh garlic were stored for 1 day at >4 degrees C, but remained in fresh onion extract at the same storage conditions. These phenomena and possible mechanisms are discussed. An additional experiment showed that Allium species cultivated in Se-rich soil might contain two different Se-"alliins".

Indications, contraindications and performance: European Guidelines for Sclerotherapy in Chronic Venous Disorders.

AIM: Sclerotherapy is the targeted chemical ablation of varicose veins by intravenous injection of a liquid or foamed sclerosing drug. The treated veins may be intradermal, subcutaneous, and/or transfascial as well as superficial and deep in venous malformations. The aim of this guideline is to give evidence-based recommendations for liquid and foam sclerotherapy. METHODS: This guideline was drafted on behalf of 23 European Phlebological Societies during a Guideline Conference on 7th - 10th May 2012 in Mainz. The conference was organized by the German Society of Phlebology. RESULTS: This guideline focuses on the two sclerosing drugs which are licensed in the majority of the European countries, Polidocanol (POL) and Sodium tetradecyl sulphate (STS). Other sclerosants are not discussed in detail. In this paper the recommendations concerning indications, contraindications, concentrations, volumes and technique of liquid and foam sclerotherapy of varicose veins and venous malformations are reviewed.

Results from RCTs in Sclerotherapy: European Guidelines for Sclerotherapy in Chronic Venous Disorders*

AIM: Sclerotherapy is the targeted chemical ablation of varicose veins by intravenous injection of a liquid or foamed sclerosing drug. The treated veins may be intradermal, subcutaneous, and/or transfascial as well as superficial and deep in venous malformations. The aim of this guideline is to give evidence-based recommendations for liquid and foam sclerotherapy. METHODS: This guideline was drafted on behalf of 23 European Phlebological Societies during a Guideline Conference on 7th-10th May 2012 in Mainz. The conference was organized by the German Society of Phlebology. RESULTS: This guideline focuses on the two sclerosing drugs which are licensed in the majority of the European countries, Polidocanol (POL) and Sodium tetradecyl sulphate (STS). Other sclerosants are not discussed in detail. In this paper the results from recent RCTs in sclerotherapy are reviewed.

European guidelines for sclerotherapy in chronic venous disorders.

AIM: Sclerotherapy is the targeted chemical ablation of varicose veins by intravenous injection of a liquid or foamed sclerosing drug. The treated veins may be intradermal, subcutaneous, and/or transfascial as well as superficial and deep in venous malformations. The aim of this guideline is to give evidence-based recommendations for liquid and foam sclerotherapy. METHODS: This guideline was drafted on behalf of 23 European Phlebological Societies during a Guideline Conference on 7-10 May 2012 in Mainz. The conference was organized by the German Society of Phlebology. These guidelines review the present state of knowledge as reflected in published medical literature. The regulatory situation of sclerosant drugs differs from country to country but this has not been considered in this document. The recommendations of this guideline are graded according to the American College of Chest Physicians Task Force recommendations on Grading Strength of Recommendations and Quality of Evidence in Clinical Guidelines. RESULTS: This guideline focuses on the two sclerosing drugs which are licensed in the majority of the European countries, polidocanol and sodium tetradecyl sulphate. Other sclerosants are not discussed in detail. The guideline gives recommendations concerning indications, contraindications, side-effects, concentrations, volumes, technique and efficacy of liquid and foam sclerotherapy of varicose veins and venous malformations.

Differential diagnosis of leg ulcers.

Leg and foot ulcers are symptoms of very different diseases. The aim of this paper is to demonstrate the differential diagnosis of leg ulcers. The majority of leg ulcers occur in the lower leg or foot. In non-venous ulcers the localization in the foot area is more frequent. The most frequent underlying disease is chronic venous disease. In 354 leg ulcers, Koerber found 75.25% venous leg ulcers, 3.66% arterial leg ulcers, 14.66% ulcers of mixed venous and arterial origin and 13.5% vasculitic ulcers. In the Swedish population of Skaraborg, Nelzen found a venous origin in 54% of the ulcer patients. Each leg ulcer needs a clinical and anamnestic evaluation. Duplex ultrasound is the basic diagnostic tool to exclude vascular anomalies especially chronic venous and arterial occlusive disease. Skin biopsies help to find a correct diagnosis in unclear or non-healing cases. In conclusion, chronic venous disease is the most frequent cause of leg ulcerations. Because 25% of the population have varicose veins or other chronic venous disease the coincidence of pathological venous findings and ulceration is very frequent even in non-venous ulcerations. Leg ulcers without the symptoms of chronic venous disease should be considered as non-venous.

Sclerotherapy in venous malformation.

Venous malformations are the result of an arrested development of the venous system during the embryogenesis. In the treatment of venous malformations the standard of care is a multidisciplinary approach including the use of traditional surgical therapy if applicable and endovascular treatment. Endovascular techniques include embolization therapy for instance with coils but also sclerotherapy with liquid or foamed sclerosants. The aim of this paper is to give an overview of foam sclerotherapy in venous malformations. Sclerotherapy of venous malformations has been performed in superficial and intramuscular malformations. In many cases ethanol has been used for the treatment. Since more than 10 years, less aggressive sclerosants like polidocanol and sodiumtetradecyl sulphate have been used to treat venous malformations. These substances can be used without anaesthesia and the rate of side-effects is much lower. Yamaki and Cabrera are the first who used foam sclerotherapy for the treatment of symptomatic venous malformations. Compared with liquid sclerotherapy foam sclerotherapy has the advantage of a better and longer lasting contact of the sclerosing agent with the vessel wall which leads to a more effective treatment and to a reduction of concentrations needed. In a recent European Guideline on Sclerotherapy foam sclerotherapy is recommended over liquid therapy for the treatment of venous malformations. Foam sclerotherapy is an effective treatment option for low flow extratruncular and truncular venous malformations. Foam is significantly more effective than liquid sclerotherapy and side-effects with polidocanol or sodiumtetradecyl sulphate foam are less compared with sclerotherapy with ethanol. With foam sclerotherapy a significant reduction of pain and volume of the venous malformations can be reached.