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.

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.

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.

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.

Treatment of chronic venous disease with flavonoids: recommendations for treatment and further studies.

OBJECTIVES: A variety of studies have suggested that flavonoids are effective for the treatment of CVD. However, many questions remain about their mechanism of action and when, how, and for what signs and symptoms they should be used. METHOD: A panel of experts in CVD met in Budapest, Hungary in December 2011 to discuss the current state of knowledge of CVD and the role of flavonoids in its treatment. The discussion was based on a literature search in the current databases. The goals of this paper are recommendations for further studies on the use of flavonoids in the treatment of CVD. RESULTS: There is good evidence to recommend the use of flavonoids in the treatment of CVD. However, because of the poor quality of some older clinical trials, inadequate reporting, and insufficient information, much work is still needed to firmly establish their clinical efficacy and to determine when and how they should be employed. In particular, long-term randomized, placebo-controlled, double-blind studies are needed to establish the efficacy and safety of flavonoids. Additional studies are also needed to establish their mechanism of action, pharmacokinetics, toxicity, and cost-effectiveness. CONCLUSIONS: Aside from good evidence for the use of flavonoids in CVD further studies are indicated to establish long term treatment in this indication.

[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.

The relevance of the natural history of varicose veins and refunded care.

Chronic venous disease (CVD) is one of the most common diseases in our population. Aside from venous symptoms like heaviness and pain, which are present in about 50% of the general population, signs of CVD include varicose veins (VVs), oedema, eczema, venous eczema, hyperpigmentation, white atrophy, lipodermatosclerosis and venous ulcers. The aim of this paper is to review current literature for the relevance of natural history of VVs in refunded care. Available papers on VVs, progression of the disease and complications were reviewed. Prevalence of VVs is high with more than 20% in the general population. Information on progression of uncomplicated VV to chronic venous insufficiency (CVI) is rare. However, most venous ulcers have a primary venous origin. The progression rate of VV to higher clinical stages reaches 4% per year. Among the risk factors are obesity and higher age. Quality of life (QOL) is also reduced in uncomplicated VV in C2 patients. In conclusion, there is evidence from the literature that a high proportion of patients with uncomplicated VVs in the clinical, aetiological, anatomical and pathophysiological classification (CEAP Clinical Class 2) will progress to CVI if untreated. VVs have a negative impact on QOL and clinical symptoms. VV patients with CVI (C3-C6) as well as those C2 patients with severe clinical symptoms and impaired QOL due to CVD should be treated with ablation of the VVs in a refunded care system.

Clinical, aetiological, anatomical and pathological classification (CEAP): gold standard and limits.

The first CEAP (clinical, aetiological, anatomical and pathological elements) consensus document was published after a consensus conference of the American Venous Forum, held at the sixth annual meeting of the AVF in February 1994 in Maui, Hawaii. In the following years the CEAP classification was published in many international journals and books which has led to widespread international use of the CEAP classification since 1995. The aim of this paper is to review the benefits and limits of CEAP from the available literature. In an actual Medline analysis with the keywords 'CEAP' and 'venous insufficiency', 266 publications using the CEAP classification in venous diseases are available. The CEAP classification was accepted in the venous community and used in scientific publications, but in most of the cases only the clinical classification was used. Limitations of the first version including a lack of clear definition of clinical signs led to a revised version. The CEAP classification is the gold standard of classification of chronic venous disorders today. Nevertheless for proper use some facts have to be taken into account: the CEAP classification is not a severity classification, C2 summarizes all kinds of varicose veins, in C3 it may be difficult to separate venous and other reasons for oedema, and corona phlebectatica is not included in the classification. Further revisions of the CEAP classification may help to overcome the still-existing deficits.

Calcium dobesilate in patients suffering from chronic venous insufficiency: a double-blind, placebo-controlled, clinical trial.

OBJECTIVE: To test the efficacy of calcium dobesilate (CaD) in chronic venous insufficiency (CVI). METHOD: Double-blind, parallel groups, placebo-controlled, multicentre trial in adult patients with symptomatic CVI and pitting oedema. Wearing of compression stockings Class II was admitted. During treatment period of eight weeks, the patients received CaD 3 × 500 mg/day or placebo. The leg volume calculation was based on a truncated cone model. RESULTS: A total of 256 patients was randomized to treatment (dobesilate: n = 132, placebo: n = 124); the demographic and anamnestic data at admission were comparable in the two therapeutic groups. The volume of the lower calf diminished in the dobesilate group at the end of the active treatment period by -64.72 ± 111.93 cm³ (mean ± SD), independent of the concomitant usage of compression stockings versus placebo +0.8 ± 152.98 cm³ (P = 0.0002). The symptoms of pain, discomfort, heavy legs, tired legs, tingling, itching and cramps, as well as the global assessments by investigators and patients, also improved significantly (P < 0.05) better in the dobesilate group at the end of the treatment. The observed adverse events correspond to the known profile. CONCLUSION: Dobesilate reduces leg oedema and improves the symptoms of objectively diagnosed CVI, independent of the concomitant usage of compression stockings.