Diagnosis and Treatment of Venous Malformations. Consensus Document of the International Union of Phlebology (IUP): updated 2013.

Venous malformations (VMs) are the most common vascular developmental anomalies (birth defects) . These defects are caused by developmental arrest of the venous system during various stages of embryogenesis. VMs remain a difficult diagnostic and therapeutic challenge due to the wide range of clinical presentations, unpredictable clinical course, erratic response to the treatment with high recurrence/ persistence rates, high morbidity following non-specific conventional treatment, and confusing terminology. The Consensus Panel reviewed the recent scientific literature up to the year 2013 to update a previous IUP Consensus (2009) on the same subject. ISSVA Classification with special merits for the differentiation between the congenital vascular malformation (CVM) and vascular tumors was reinforced with an additional review on syndrome-based classification. A "modified" Hamburg classification was adopted to emphasize the importance of extratruncular vs. truncular sub-types of VMs. This incorporated the embryological ongm, morphological differences, unique characteristics, prognosis and recurrence rates of VMs based on this embryological classification. The definition and classification of VMs were strengthened with the addition of angiographic data that determines the hemodynamic characteristics, the anatomical pattern of draining veins and hence the risk of complication following sclerotherapy. The hemolymphatic malformations, a combined condition incorporating LMs and other CVMs, were illustrated as a separate topic to differentiate from isolated VMs and to rectify the existing confusion with name-based eponyms such as Klippei-Trenaunay syndrome. Contemporary concepts on VMs were updated with new data including genetic findings linked to the etiology of CVMs and chronic cerebrospinal venous insufficiency. Besides, newly established information on coagulopathy including the role of D-Dimer was thoroughly reviewed to provide guidelines on investigations and anticoagulation therapy in the management of VMs. Congenital vascular bone syndrome resulting in angio-osteo-hyper/hypotrophy and (lateral) marginal vein was separately reviewed. Background data on arterio-venous malformations was included to differentiate this anomaly from syndromebased VMs. For the treatment, a new section on laser therapy and also a practical guideline for follow up assessment were added to strengthen the management principle of the multidisciplinary approach. All other therapeutic modalities were thoroughly updated to accommodate a changing concept through the years.

Guideline. Diagnosis and treatment of venous malformations. consensus document of the international union of phlebology (iup): updated-2013.

Venous malformations (VMs) are the most common vascular developmental anomalies (birth defects). These defects are caused by developmental arrest of the venous system during various stages of embryogenesis. VMs remain a difficult diagnostic and therapeutic challenge due to the wide range of clinical presentations, unpredictable clinical course, erratic response to the treatment with high recurrence/persistence rates, high morbidity following nonspecific conventional treatment, and confusing terminology. The Consensus Panel reviewed the recent scientific literature up to the year 2013 to update a previous IUP Consensus (2009) on the same subject. ISSVA Classification with special merits for the differentiation between the congenital vascular malformation (CVM) and vascular tumors was reinforced with an additional review on syndrome-based classification. A "modified" Hamburg classification was adopted to emphasize the importance of extratruncular vs. truncular subtypes of VMs. This incorporated the embryological origin, morphological differences, unique characteristics, prognosis and recurrence rates of VMs based on this embryological classification. The definition and classification of VMs were strengthened with the addition of angiographic data that determines the hemodynamic characteristics, the anatomical pattern of draining veins and hence the risk of complication following sclerotherapy. The hemolymphatic malformations, a combined condition incorporating LMs and other CVMs, were illustratedas a separate topic to differentiate from isolated VMs and to rectify the existing confusion with namebased eponyms such as Klippel-Trenaunay syndrome. Contemporary concepts on VMs were updated with new data including genetic findings linked to the etiology of CVMs and chronic cerebrospinal venous insufficiency. Besides, newly established information on coagulopathy including the role of D-Dimer was thoroughly reviewed to provide guidelines on investigations and anticoagulation therapy in the management of VMs. Congenital vascular bone syndrome resulting in angio-osteo-hyper/hypotrophy and (lateral) marginal vein was separately reviewed. Background data on arterio-venous malformations was included to differentiate this anomaly from syndrome-based VMs. For the treatment, a new section on laser therapy and also a practical guideline for follow up assessment were added to strengthen the management principle of the multidisciplinary approach. All other therapeutic modalities were thoroughly updated to accommodate a changing concept through the years.

Consensus Document of the International Union of Angiology (IUA)-2013. Current concept on the management of arterio-venous management.

Arterio-venous malformations (AVMs) are congenital vascular malformations (CVMs) that result from birth defects involving the vessels of both arterial and venous origins, resulting in direct communications between the different size vessels or a meshwork of primitive reticular networks of dysplastic minute vessels which have failed to mature to become 'capillary' vessels termed "nidus". These lesions are defined by shunting of high velocity, low resistance flow from the arterial vasculature into the venous system in a variety of fistulous conditions. A systematic classification system developed by various groups of experts (Hamburg classification, ISSVA classification, Schobinger classification, angiographic classification of AVMs,) has resulted in a better understanding of the biology and natural history of these lesions and improved management of CVMs and AVMs. The Hamburg classification, based on the embryological differentiation between extratruncular and truncular type of lesions, allows the determination of the potential of progression and recurrence of these lesions. The majority of all AVMs are extra-truncular lesions with persistent proliferative potential, whereas truncular AVM lesions are exceedingly rare. Regardless of the type, AV shunting may ultimately result in significant anatomical, pathophysiological and hemodynamic consequences. Therefore, despite their relative rarity (10-20% of all CVMs), AVMs remain the most challenging and potentially limb or life-threatening form of vascular anomalies. The initial diagnosis and assessment may be facilitated by non- to minimally invasive investigations such as duplex ultrasound, magnetic resonance imaging (MRI), MR angiography (MRA), computerized tomography (CT) and CT angiography (CTA). Arteriography remains the diagnostic gold standard, and is required for planning subsequent treatment. A multidisciplinary team approach should be utilized to integrate surgical and non-surgical interventions for optimum care. Currently available treatments are associated with significant risk of complications and morbidity. However, an early aggressive approach to elimiate the nidus (if present) may be undertaken if the benefits exceed the risks. Trans-arterial coil embolization or ligation of feeding arteries where the nidus is left intact, are incorrect approaches and may result in proliferation of the lesion. Furthermore, such procedures would prevent future endovascular access to the lesions via the arterial route. Surgically inaccessible, infiltrating, extra-truncular AVMs can be treated with endovascular therapy as an independent modality. Among various embolo-sclerotherapy agents, ethanol sclerotherapy produces the best long term outcomes with minimum recurrence. However, this procedure requires extensive training and sufficient experience to minimize complications and associated morbidity. For the surgically accessible lesions, surgical resection may be the treatment of choice with a chance of optimal control. Preoperative sclerotherapy or embolization may supplement the subsequent surgical excision by reducing the morbidity (e.g. operative bleeding) and defining the lesion borders. Such a combined approach may provide an excellent potential for a curative result. Conclusion. AVMs are high flow congenital vascular malformations that may occur in any part of the body. The clinical presentation depends on the extent and size of the lesion and can range from an asymptomatic birthmark to congestive heart failure. Detailed investigations including duplex ultrasound, MRI/MRA and CT/CTA are required to develop an appropriate treatment plan. Appropriate management is best achieved via a multi-disciplinary approach and interventions should be undertaken by appropriately trained physicians.

[Congenital vascular malformations (Hauert disease)]. / Angiodysplastische Arthropathie ("Hauert disease").

Patients with congenital vascular malformations often suffer from arthralgia, especially of the lower limbs. This orthopaedic disease pattern is defined as destructive, angiodysplatic arthritis or Hauert disease and leads to very early destruction of the joints. By presenting diagnostic and therapeutic algorithms, Hauert disease is emphasized as a possible differential diagnosis in order to minimize the risk of an incorrect diagnosis which might lead to under-, over-, or even incorrect treatment. A minimally invasive transathroscopic therapy in the early stages can lead to significant improvement of symptoms and prevention of progressive joint destruction.

Etiological diagnosis in the hearing impaired newborn: proposal of a flow chart.

OBJECTIVE: Most industrialized countries have introduced some form of universal newborn hearing screening program. Both identification and rehabilitation of hearing loss in newborns have evolved to an acceptable standard and the need for a standardized etiological protocol is emerging. METHODS: Extensive literature search to determine which investigations can help identifying the cause of congenital hearing loss and how to limit extensive testing in these children by taking into account the most prevalent causes. FINDINGS: A stepwise approach to detect the cause of hearing loss in children with congenital sensorineural hearing loss was developed. CONCLUSION: In general it is advised to first rule out Cx26/Cx30 and infectious causes (cytomegalovirus and, if indicated, toxoplasmosis and rubella), and to preserve more extensive investigations for those children in whom these causes do not explain the hearing loss.

Bile acid transport in hypercholesterolemic resistant rabbits.

We examined bile acid transport and expression of the apical sodium-dependent bile acid transporter (ASBT) in ileal preparations to determine if alterations in bile acid excretion contributed to a hypercholesterolemia-resistant phenotype in rabbits (CRT/mlo). Taurocholate transport was not different between normal (NR) and CRT/mlo rabbits fed regular diet. However, feeding cholesterol-enriched diet reduced taurocholate transport significantly in CRT/mlo rabbits (0.53 + or - 0.06 pmol/microg protein) compared to regular diet (0.95 + or - 0.14 pmol/microg protein), but had no effect in NR rabbits. Cholesterol-enriched diet increased ASBT mRNA in CRT/mlo (2.6 + or - 0.7 to 5.4 + or - 0.1); no significant changes occurred in NR. Some CRT/mlo rabbits carry a polymorphism in ASBT at amino acid 333 (P333L). In transfected HEK293 cells, TC transport of P333L allele was significantly lower (0.08 + or - 0.01 vs 0.13 + or - 0.01 pmol/microg protein/15 sec, P< 0.05). This allele was not found in NR rabbits. The data suggest that the phenotype of the CRT/mlo rabbit is due to changes in bile acid transport as well as bile acid metabolism.

DNA methylation inhibits p53-mediated survivin repression.

The molecular progression of endometrial cancer is poorly understood, and both genetic and epigenetic factors play a role. Survivin is a member of the inhibitor of apoptosis (IAP) gene family and contains a canonical CpG island that has been described as epigenetically regulated. As survivin is overexpressed in endometrial tumors, we hypothesized that hypomethylation could explain this expression pattern. Surprisingly, methylation-specific PCR and pyrosequencing showed that survivin was hypermethylated in endometrial tumors and correlated with increased survivin expression. We speculated that methylation could inhibit the binding of p53, a repressor of survivin expression. Our data indicates that demethylation of the survivin promoter by decitabine results in p53-dependent survivin repression and that p53 binding can be inhibited by DNA methylation. We are the first to report survivin de-repression by DNA methylation. We also present microarray data, which suggest that de-repression by methylation is a general mechanism of p53 regulation. Demethylation induced by decitabine is traditionally thought to be active in tumors by allowing the re-expression of tumor suppressor genes. However, our results indicate that an additional important mechanism is to decrease the expression of oncogenes.

99mTc-HYNIC Annexin-V imaging of tumors and its relationship to response to radiotherapy and/or chemotherapy.

AIM: The aim of this study was to report on the relationship between preradiotherapy and prechemotherapy 99mTc-HYNIC Annexin-V tumor uptake values, reflecting ongoing apoptosis, and outcome to radiotherapy and/or chemotherapy. METHODS: Twenty-three cancer patients underwent staging examinations and a 99mTc-HYNIC Annexin-V scintigraphy and subsequent radiotherapy and/or chemotherapy. Tumor-to-background ratios derived from tomographic 99mTc-HYNIC Annexin-V images were related to treatment outcome as assessed by RECIST criteria. RESULTS: Six patients underwent radiotherapy or radiochemotherapy: 4 exhibited response to treatment, 1 had stable, and 1 progressive disease. Corresponding tumor-to-background ratio's were respectively >or=2.3 (in responders), 1.2 in the patient presenting with stable disease and 1 in the patient presenting with progressive disease. Seventeen patients were treated by chemotherapy alone: 8 were progressive, 1 patient presented with stable disease and 8 responded to treatment. In 1/8 progressive patients a tumor-to-background ratio of 1.4 was found, the others showed no uptake. In the patient presenting with stable disease a ratio of 0.1 was found. In the 8 responders, 7 patients had a tumor-to-background ratio >or=1.3 whereas in 1 patient a ratio of 0.3 was found. Tumor-to-background ratios in responders (complete plus partial) (median 2.5, range: 0.3-4.2) were significantly higher when compared to those obtained in non-responders (stable plus progressive disease) (median 1, range: 0.1-1.4) (P<0.001). CONCLUSION: The findings presented suggest that 99mTc-HYNIC Annexin-V pretreatment uptake may be useful to predict response to chemo- and radiotherapy.

Surgical management of venous malformations.

OBJECTIVES: Among vascular malformations, the predominantly venous malformations represent the majority of cases. They form a clinical entity and therefore need clear concepts concerning diagnosis and treatment. This paper presents an overview of contemporary classification as well as tactics and techniques of treatment. According to the Hamburg Classification, predominantly venous malformations are categorized into truncular and extratruncular forms, with truncular forms distinguished as obstructions and dilations, and extratruncular forms as limited or infiltrating. METHODS: The tactics of treatment represent surgical and non-surgical methods or combined techniques. Surgical approaches utilize different tactics and techniques that are adopted based on the pathologic form and type of the malformation: (I) operation to reduce the haemodynamic activity of the malformation; (II) operation to eliminate the malformation; and (III) reconstructive operation. As for (I), a type of a tactic is the operation to derive the venous flow. In (II), the total or partial removal of the venous malformation is demonstrated subdivided into three different techniques. In this way, the infiltrating as well as the limited forms can be treated. An additional technique is dedicated to the treatment of a marginal vein. Approach (III) involves the treatment of venous aneurysms, where a variety of techniques have been successful. RESULTS: Long-term follow-up demonstrates positive results in 91% of the cases. CONCLUSION: Congenital predominantly venous malformations should be treated according to the principles developed during the past decades in vascular surgery, interventional treatment and multidisciplinary treatment. The days of predominantly conservative treatment should be relegated to the past. Special skills and experiences are necessary to carry out appropriate surgical strategy, and the required operative techniques should be dictated by the location and type of malformation and associated findings.

Quantitative tumor apoptosis imaging using technetium-99m-HYNIC annexin V single photon emission computed tomography.

PURPOSE: Radiolabeled annexin V may allow for repetitive and selective in vivo identification of apoptotic cell death without the need for invasive biopsy. This study reports on the relationship between quantitative technetium-99m- (99mTc-) 6-hydrazinonicotinic (HYNIC) radiolabeled annexin V tumor uptake, and the number of tumor apoptotic cells derived from histologic analysis. PATIENTS AND METHODS: Twenty patients (18 men, two women) suspected of primary (n = 19) or recurrent (n = 1) head and neck carcinoma were included. All patients underwent a spiral computed tomography (CT) scan, 99mTc-HYNIC annexin V tomography, and subsequent surgical resection of the suspected primary or recurrent tumor. Quantitative 99mTc-HYNIC annexin V uptake in tumor lesions divided by the tumor volume, derived from CT, was related to the number of apoptotic cells per tumor high-power field derived from terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick end-labeling (TUNEL) assays performed on sectioned tumor slices. RESULTS: Diagnosis was primary head and neck tumor in 18 patients, lymph node involvement of a cancer of unknown primary origin in one patient, and the absence of recurrence in one patient. Mean percentage absolute tumor uptake of the injected dose per cubic centimeter tumor volume derived from tomographic images was 0.0003% (standard deviation [SD], 0.0004%) at 1 hour postinjection (PI) and 0.0001% (SD, 0.0000%) at 5 to 6 hours PI (P =.012). Quantitative 99mTc-HYNIC annexin V tumor uptake correlated well with the number of apoptotic cells if only tumor samples with no or minimal amounts of necrosis were considered. CONCLUSION: In the absence of necrosis, absolute 99mTc-HYNIC annexin V tumor uptake values correlate well with the number of apoptotic cells derived from TUNEL assays.

[Surgical correction of vascular malformations of the lower extremity]. / Operative Korrekturen vaskulärer Malformationen an der unteren Extremität.

On the basis of the Hamburg Classification from 1988 six different therapeutic tactics and surgical techniques have been proved in the treatment of vascular malformations. These are: 1) reconstructive surgery, 2) surgery to reduce the hemodynamic activity of the vascular defect, 3) surgery to extirpate the malformed vessels, 4) combined therapy, 5) unconventional therapy, 6) multidisciplinary treatment. More than 2500 cases had been worked out. In this survey the marginal vein and the embryonal vein respectively are of special interest. These veins are classified by morphologic radiologic criteria. The following types could be worked out: peripheral type, thigh type and pelvic type. Referring to these experiences the indications for vascular surgical treatment have to be distinguished precisely. In a retrospective European study the long follow-up results of all six therapeutic tactics had been registered and proved. 1378 cases were included. In 15% of the patients the results were excellent in 42% good, and in 34% an improvement could be observed. In 5% a relapse was stated and in 1.5% no change was registered.

Low-dose iloprost infusions compared to the standard dose in patients with peripheral arterial occlusive disease Fontaine stage IV. DAWID Study Group.

BACKGROUND: Intravenous iloprost, titrated from 0.5 up to 2.0 ng/kg/min has been shown in patients with PAOD III/IV to significantly improve healing of trophic lesions, relief of rest pain, and reduce the rate of major amputation or death at 6 months as compared to placebo. The effect is considered related to improvement of the microcirculation. The aim of the present trial was to identify an optimum dose regarding treatment response and tolerability, by studying 4 doses of 25, 50, 75 and 100 micrograms iloprost daily. PATIENTS AND METHODS: 302 patients with PAOD IV were randomised via a double-blind fashion to one of the 4 doses. The primary endpoint was the responder rate at end of treatment. Responders were defined as patients with very good or good global efficacy, as judged by lesion healing and pain relief. Side effects were documented and a pre-defined benefit/risk index was calculated. RESULTS: No dose-dependency of iloprost regarding primary or secondary endpoints was observed. The rate of responders ranged between 48.7-53.5%. Side effects, mainly related to vasodilation, increased dose-dependently (p < 0.001, chi 2-test), with a significant decrease of the benefit/risk index from 2.19 +/- 1.19 to 1.64 +/- 0.97 (p = 0.012, ANOVA). Responders had a better outcome at 6 months than non-responders (2.6 fold higher rate of major amputation or death; life table analysis). CONCLUSIONS: It is concluded that iloprost should be titrated to the optimum rather than maximum tolerated dose, since a higher incidence of side effects not associated with an increased treatment response was observed at higher doses.

Pathophysiological and clinical aspects of the CO2 pneumoperitoneum (CO2-PP).

Experimental studies demonstrated a severe cardiac load of the CO2 pneumoperitoneum caused by an accelerated after- and a decreased preload. Patients displaying cardiovascular risks are therefore often rejected from laparoscopic surgery. Hence, the pathophysiological changes and the intraoperative risk of the CO2 pneumoperitoneum in high-risk cardiopulmonary patients (NYHA II-III, n = 15) undergoing laparoscopic cholecystectomy are described. The changes in cardiac after- and preload seem to be due to the elevated intraabdominal pressure rather than transperitoneally resorbed CO2 and are reversible by desufflation. In one patient conversion to open operation had to be performed because of a severe drop in cardiac output and right ventricle ejection fraction. Mixed oxygen saturation was predicting intraoperative worsening in this case. The described pathophysiological changes may seem to be well tolerated even in high-risk cardiac patients. Monitoring of hemodynamics should include an arterial catheter line and blood gas analyses. Pharmacologic interventions or pressureless laparoscopic procedures might not be necessary as long as laparoscopic cholecystectomy is performed.

Combined treatment of congenital vascular defects: indications and tactics.

Congenital AV shunting defects are not as rare as sometimes presumed, and they are four times more frequent in girls than in boys. Inadequate treatment can aggravate the patient's complaints by increasing the circulatory disturbance in the affected region. As a result, ischemic ulceration may develop. Special, usually interdisciplinary, treatment of such findings is mandatory. When AV communications are present, the combined treatment of surgical and nonsurgical techniques must be considered. Location and pathoanatomic type influence this choice. Clinical, functional, and hemodynamic parameters must also be evaluated in order to decide the optimal combination of therapeutic measures. Usually several phases of treatment are necessary.

[Venous aneurysms]. / Venöse Aneurysmen.

Incidence, etiology, diagnostic procedures and therapy of venous aneurysms, basing on 152 own cases, are discussed. The main procedure for diagnosis is phlebography. It must be distinguished between aneurysms of epi- and subfascial veins. The localization determines the surgical procedure which represents the only successful therapy. Without proper treatment, venous aneurysms may be responsible for complications such as thrombophlebitis, thrombosis with pulmonary embolism, aneurysm rupture and compression of adjacent structures. The results of surgical treatment are excellent.