Great saphenous vein diameter at the saphenofemoral junction and proximal thigh as parameters of venous disease class.

BACKGROUND: Great saphenous vein (GSV) incompetence is involved in the majority of cases of varicose disease. Standardised pre-interventional assessment is required to analyse the relative merit of treatment modalities. We weighed GSV diameter measurement at the sapheno-femoral junction (SFJ) against measurement at the proximal thigh 15 cm distal to the groin (PT), established a conversion factor and applied it to selected literature data. METHODS: Legs with untreated isolated GSV reflux and varices limited to its territory and control legs were studied clinically, with duplex ultrasound and photoplethysmography. GSV diameters were measured at both the SFJ and the PT. A conversion factor was calculated and used to compare published data. RESULTS: Of 182 legs, 60 had no GSV reflux (controls; group I), 51 had above-knee GSV reflux only (group II) and 71 had GSV reflux above and below knee (group III). GSV diameters in group I measured 7.5 mm (± 1.8) at the SFJ and 3.7 mm (± 0.9) at the PT. In groups II and III, they measured 10.9 mm (± 3.9) at the SFJ and 6.3 mm (± 1.9) at the PT (p < 0.001 each). Measurement at the PT revealed higher sensitivity and specificity to predict reflux and clinical class. Good correlation between sites of measurement (r = 0.77) allowed a conversion factor (SFJ = 1.767 * PT, PT = 0.566*SFJ) to be applied to pre-interventional data of published studies. CONCLUSIONS: GSV diameter correlates with clinical class, measurement at the PT being more sensitive and more specific than measurement at the SFJ. Applying the conversion factor to published data suggests that some studies included patients with minor disease.

Leg symptoms of somatic, psychic, and unexplained origin in the population-based Bonn vein study.

OBJECTIVE: To assess the somatic and psychic components of venous-type leg symptoms. METHODS: The psychic versus somatic venous disease questionnaire (PsySoVDQ) was applied to 1,800 participants of the Bonn Vein Study (BVS) II. RESULTS: Factor analysis of the PsySoVDQ made it possible to distinguish a psychic component (PC; 5 items, Cronbach's alpha = 0.73) separate from a somatic component (SC; 4 items, Cronbach's alpha = 0.67). The PC reflected anxiety and inhibition, was prevalent in 39.8% and explained 7.3% of the BVS findings. Higher PC scores were typically found in younger, slim women of higher social status, with feelings of leg heaviness and tension, and reduced psychic quality of life. The SC prevailed in 37.4% and explained 16.5% of BVS findings. Typical SC scorers were older, overweight women with lower social status, more symptoms (including swelling), signs of chronic venous insufficiency, ultrasound-documented venous abnormalities, and reduced multidimensional quality of life. The SC's predictive accuracy for CEAP 2 and 3 (classification according to clinical findings, etiology, anatomy, pathophysiology) was equal to that of the BVS assessment. CONCLUSION: The PsySoVDQ identified somatic and psychic components of the widespread and frequently reported leg symptoms in the general population. Nevertheless, in the majority of subjects symptoms remained unexplained. A neuropsychological and neurobiological hypothesis is advanced.

Compression therapy for occupational leg symptoms and chronic venous disorders - a meta-analysis of randomised controlled trials.

OBJECTIVE: Leg discomfort and oedema are commonly attributed to a venous disorder (CVD) or chronic venous insufficiency (CVI) and treated with compression hosiery. The pressure needed to achieve clinical benefit is a matter of debate. DESIGN: We performed a meta-analysis of randomised controlled trials (RCT) that compared stockings exerting an ankle pressure of 10-20mmHg with placebo or no treatment and with stockings exerting a pressure of more than 20mmHg. METHODS: RCT were retrieved and analysed with the tools of the Cochrane Collaboration. Each study was reviewed independently. Subjective dichotomous and continuous factors and objective findings were pooled for statistical treatment. RESULTS: Eleven RCT fulfilled the predefined criteria. They included 1453 randomised subjects, 794 healthy people exposed to various forms of stress, 552 patients with a chronic venous disorder or chronic venous insufficiency and 141 patients after varicose vein surgery. Over all, compression with 10-20mmHg had a clear effect on oedema and symptoms as compared with <10mmHg pressure, placebo stockings, or no treatment (p<.0001). No study showed a difference between 10-20 and >20mmHg stockings. CONCLUSIONS: Despite important methodological heterogeneity and sometimes sub-standard reporting the meta-analysis suggests that leg compression with 10-15mmHg is an effective treatment for CVD. Less pressure is ineffective and higher pressure may be of no additional benefit.

Superficial vein thrombophlebitis--serious concern or much ado about little?

Superficial vein thrombophlebitis (SVTP) appears in two distinct forms: varicose vein thrombophlebitis (TP) represents the principal cause. It is characterized by a large thrombus in a varicose vein and a modest inflammatory process localized in the vessel surrounding but not in its wall. Rarely, SVTP affects a non-varicose vein. Abundant intima proliferation and media fibrosis with non-important thrombosis are the hallmark of this form which may be associated with a systemic disease. Although SVTP is perceived as trivial and benign coexistence of (mostly distal) deep venous thrombosis (DVT), propagation to popliteal or femoral DVT, and even pulmonary embolism (PE) have been reported. Data for prevalence vary greatly: 6-53% for coexistence, 2.6-15% for propagation, and 0-33% for (asymptomatic) PE. Risk factors for these complications are those known for DVT. SVTP is diagnosed in a clinical setting but ultrasonography is useful to check for concomitant DVT. Anticoagulant treatment is mandatory if DVT is present and thrombectomy should be considered in cases of thrombus propagation into the deep veins. Historical therapy of uncomplicated SVTP consists of compression with bandages or stockings and local or systemic anti-inflammatory agents. Low-molecular-weight heparin (LMWH) has been given in high-prophylactic doses and found equally effective when compared with anti-inflammatory agents and full-therapeutic dose LMWH. Prophylactic saphenous vein ligation alone was found less effective than conservative therapy. Ligation combined with stripping proved the potential of eliminating at once all problems associated with SVTP but was associated with a complication rate of 10% or higher. Careful patient selection and saphenous vein thrombectomy prior to stripping may be the clue for better results.

Requirements for the construction of antibody heterodimers for the direction of lysis of tumors by human T cells.

We constructed a series of MAb heterodimers consisting of the J5 (anti-common acute lymphoblastic leukemia antigen [CALLA]) antibody and antibodies to a variety of structures present on the surface of activated human T cells, including CD3 antigen (T cell receptor-associated glycoproteins), CD2 antigen (T11/E-rosette receptor), CD25 antigen (IL-2 receptor), and the transferrin receptor. We tested the ability of these heterodimers to direct a CD2 + CD3 + CD8 + CD4 - CD25 + transferrin receptor + MHC-restricted human cytolytic T lymphocyte (CTL) clone to lyse a CALLA + human tumor in vitro. Only heterodimers containing an anti-CD3 antibody or activating antibodies to CD2 could direct the clone to lyse these human tumor targets, even when the clone was additionally activated with anti-CD3 or anti-CD2 antibodies. Our findings may have implications in the design of strategies for the use of such reagents in the treatment of human neoplasia.

Identification of domains of the insulin-like growth factor I receptor that are required for protection from apoptosis.

Using a series of insulin-like growth factor I (IGF-I) receptor mutants, we have attempted to define domains required for transmitting the antiapoptotic signal from the receptor and to compare these domains with those required for mitogenesis or transformation. In FL5.12 cells transfected with wild-type IGF-I receptors, IGF-I affords protection from interleukin 3 withdrawal but is not mitogenic. An IGF-I receptor lacking a functional ATP binding site provided no protection from apoptosis. However, receptors mutated at tyrosine residue 950 or in the tyrosine cluster (1131, 1135, and 1136) within the kinase domain remained capable of suppressing apoptosis, although such mutations are known to inactivate transforming and mitogenic functions. In the C terminus of the IGF-I receptor, two mutations, one at tyrosine 1251 and one which replaced residues histidine 1293 and lysine 1294, abolished the antiapoptotic function, whereas mutation of the four serines at 1280 to 1283 did not. Interestingly, receptors truncated at the C terminus had enhanced antiapoptotic function. In Rat-1/ c-MycER fibroblasts, the Y950F mutant and the tyrosine cluster mutant could still provide protection from c-Myc-induced apoptosis, whereas mutant Y1250/1251F could not. These studies demonstrate that the domains of the IGF-I receptor required for its antiapoptotic function are distinct from those required for its proliferation or transformation functions and suggest that domains of the receptor required for inhibition of apoptosis are necessary but not sufficient for transformation.

An immunotoxin prepared with blocked ricin: a natural plant toxin adapted for therapeutic use.

Ricin, the cytotoxic protein isolated from castor beans, is composed of two subunits, A-chain and B-chain. Ricin intoxicates cells by binding through its B-chain to galactose-terminated oligosaccharides found on the surface of all eukaryotic cells and then transferring its A-chain to the cytosol where it disrupts protein synthesis by inactivating ribosomes. In addition to binding, the B-chain plays an important, but not yet understood, role in the translocation of the A-chain through a cellular membrane to the cytosol. Blocking the two galactose-binding sites of native ricin by chemical modification with affinity ligands created an altered toxin, called blocked ricin, that has at least a 3500-fold lower binding affinity and is more than 1000-fold less cytotoxic than native ricin for Namalwa cells (a Burkitt's lymphoma line) but that has maintained the translocation function of the B-chain and the catalytic activity of the A-chain. Conjugation of blocked ricin to monoclonal antibodies that bind to cell surface antigens creates new cytotoxins that approach the potency of native ricin. These cytotoxins incorporate the three essential functions of natural toxins, i.e., binding to cells, transport through a membrane, and catalytic inactivation of an essential cellular process; but in addition they possess a defined cellular target specificity. Such potent immunotoxins may play an important therapeutic role in cancer treatment. Clinical trials with an anti-CD19-blocked ricin and an anti-CD33-blocked ricin conjugate against B-cell cancers and acute myeloblastic leukemia have begun.

Correlation between in vivo toxicity and preclinical in vitro parameters for the immunotoxin anti-B4-blocked ricin.

Anti-B4-blocked ricin (Anti-B4-bR) is an immunotoxin comprised of the anti-B4 monoclonal antibody and the protein toxin, "blocked ricin." In blocked ricin, the galactose-binding sites of the ricin B-chain which mediate nonspecific binding to cells are blocked by covalently linked affinity ligands prepared from N-linked oligosaccharides of fetuin. Blocked ricin consists of two species, one with two covalently attached ligands and one with three covalently attached ligands. In a Phase I dose escalation clinical trial, Anti-B4-bR was administered to patients with relapsed and refractory B-cell neoplasms by 7-day continuous infusion. Although several different lots of Anti-B4-bR had similar IC37 values as determined by in vitro cytotoxicity testing on cultured human cell lines, these lots differed in their in vivo toxicity when administered to patients. Thus, IC37 values alone were not sufficient to predict in vivo toxicity. We report that the degree of cell kill at concentrations of drug that saturate the B4 antigen and murine 50% lethal dose values provide additional parameters that may be predictive of in vivo cytotoxicity. Furthermore, we performed detailed cytotoxicity studies of the ricin species containing two and three covalently attached ligands, respectively. In vitro cytotoxicity testing using these samples revealed that Anti-B4-bR made with blocked ricin containing two covalently attached ligands is capable of depleting five logs of target cells in an in vitro cytotoxicity assay, while Anti-B4-bR comprised of blocked ricin with three ligands can deplete only one log of cells. Log cell kill at antigen saturating concentration, murine 50% lethal dose and biochemical analysis of the composition of blocked ricin are therefore important considerations for establishing the potential efficacy and safety of Anti-B4-bR.

Immunoconjugates containing novel maytansinoids: promising anticancer drugs.

The potential of immunoconjugates of cytotoxic drugs for the treatment of cancer has not yet been realized owing to the difficulty of delivering therapeutic concentrations of these drugs to the target cells. In an effort to overcome this problem we have synthesized maytansinoids that have 100- to 1000-fold higher cytotoxic potency than clinically used anticancer drugs. These maytansinoids are linked to antibodies via disulfide bonds, which ensures the release of fully active drug inside the cells. The conjugates show high antigen-specific cytotoxicity for cultured human cancer cells (50% inhibiting concentration, 10 to 40 pM), low systemic toxicity in mice, and good pharmacokinetic behavior.

Anti-B4-blocked ricin immunotoxin shows therapeutic efficacy in four different SCID mouse tumor models.

Anti-CD19 monoclonal antibody anti-B4 (IgG1) conjugated to the novel toxin-blocked ricin forms a potent immunotoxin, anti-B4-blocked ricin, that kills greater than 4.5 logs of CD19-positive cells in vitro after a 24-h exposure to a conjugate concentration of 5 x 10(-9) M (1.11 micrograms/ml). The efficacy of anti-B4-blocked ricin in vivo was assessed in survival models of SCID mice bearing either a human B-cell lymphoma (Namalwa), a human non-T and non-B acute lymphoblastic leukemia (Nalm-6), or a murine B-cell lymphoma transfected with the human CD19 gene (300B4). In one model, 5 x 10(7) tumor cells were injected i.p., and 1 h later the mice were treated with i.v. bolus injections of anti-B4-blocked ricin at 100 micrograms/kg/day for 5 days. Controls included similar treatment with anti-B4 antibody (72 micrograms/kg/day or 2 mg/kg/day for 5 days) alone or with the isotype-matched nonspecific immunotoxin, N901-blocked ricin (100 micrograms/kg/day). In a second model, 4 x 10(6) tumor cells were injected i.v., and 7 days later mice were treated i.v. as above. Anti-B4-blocked ricin showed efficacy by killing in vivo up to 3 logs of tumor cells, which was manifested in significant prolongation of the life of the treated animals. Only very limited or no effects were observed in animals treated with either anti-B4 antibody alone or N901-blocked ricin control conjugate. The concentration of anti-B4-blocked ricin in the blood of animals was 150 ng/ml after the first i.v. injection and about 800 ng/ml following the fifth injection of conjugate. This increase may be due to damage to the reticuloendothelial system by anti-B4-blocked ricin, since the rate of clearance of carbon from blood also decreased 5-fold after five injections as compared to the rate after only one injection. These studies indicate that anti-B4-blocked ricin has the potential to increase survival times of hosts with malignant disease.

Enhancement of the selectivity and antitumor efficacy of a CC-1065 analogue through immunoconjugate formation.

Bis-indolyl-(seco)-1,2,9a-tetrahydrocyclopropa[c]benz[e]indol-4-on e compounds are synthetic analogues of CC-1065 that are highly cytotoxic toward a broad spectrum of tumor cell lines. One of these compounds, called DC1, was conjugated to antibodies via novel cleavable disulfide linkers. Conjugates of DC1 with murine mAbs anti-B4 and N901 directed against tumor-associated antigens CD19 and CD56, respectively, proved to be extremely potent and antigen selective in killing target cells in culture. DC1 conjugates with humanized versions of anti-B4 and N901 antibodies were also constructed and demonstrated to be as cytotoxic and selective as the respective murine antibody conjugates. The anti-B4-DC1 conjugate showed antitumor efficacy in an aggressive metastatic human B-cell lymphoma survival model in SCID mice and completely cured animals hearing large tumors. Anti-B4-DC1 was considerably more effective in this tumor model than doxorubicin, cyclophosphamide, etoposide, or vincristine at their maximum tolerated doses.

Anti-B4-blocked ricin: a phase I trial of 7-day continuous infusion in patients with B-cell neoplasms.

PURPOSE: This phase I trial was undertaken to determine the maximum-tolerated dose (MTD) and dose-limiting toxicities (DLTs) of the B-cell-restricted immunotoxin anti-B4-blocked ricin (anti-B4-bR) when it is administered by 7-day continuous infusion. PATIENTS AND METHODS: Thirty-four patients with relapsed and refractory B-cell neoplasms (26 non-Hodgkin's lymphoma [NHL], four chronic lymphocytic leukemia [CLL], four acute lymphoblastic leukemia [ALL]) received 7-day continuous infusion anti-B4-bR. Successive cohorts of at least three patients were treated at doses of 10 to 70 micrograms/kg/d for 7 days with the dose increased by 10 micrograms/kg/d for each cohort. The initial three cohorts of patients (10, 20, and 30 micrograms/kg/d x 7 days) also received a bolus infusion of 20 micrograms/kg before beginning the continuous infusion. RESULTS: The MTD was reached at 50 micrograms/kg/d x 7 days. The DLTs were National Cancer Institute Common Toxicity Criteria (NCI CTC) grade IV reversible increases in AST and ALT, and grade IV decreases in platelet counts. Adverse reactions included fevers, nausea, headaches, myalgias, hypoalbuminemia, dyspnea, edema, and capillary leak syndrome. Potentially therapeutic serum levels of anti-B4-bR could be sustained for 4 days in patients treated at the MTD. Two complete responses (CRs), three partial responses (PRs), and 11 transient responses (TRs) were observed. CONCLUSION: Anti-B4-bR can be administered safely by 7-day continuous infusion with tolerable, reversible toxicities to patients with relapsed B-cell neoplasms. Although occasional responses were seen, future trials will use anti-B4-bR in patients with lower tumor burdens to circumvent the obstacle of immunotoxin delivery to bulk disease.

Immunotoxin therapy of small-cell lung cancer: a phase I study of N901-blocked ricin.

PURPOSE: Immunotoxins could improve outcome in small-cell lung cancer (SCLC) by targeting tumor cells that are resistant to chemotherapy and radiation. N901 is a murine monoclonal antibody that binds to the CD56 (neural cell adhesion molecule [NCAM]) antigen found on cells of neuroendocrine origin, including SCLC. N901-bR is an immunoconjugate of N901 antibody with blocked ricin (bR) as the cytotoxic effector moiety. N901-bR has more than 700-fold greater selectivity in vitro for killing the CD56+ SCLC cell line SW-2 than for an antigen-negative lymphoma cell line. Preclinical studies suggested the potential for clinically significant cardiac and neurologic toxicity. We present a phase I study of N901-bR in relapsed SCLC. PATIENTS AND METHODS: Twenty-one patients (18 relapsed, three primary refractory) with SCLC were entered onto this study. Successive cohorts of at least three patients were treated at doses from 5 to 40 microg/kg/d for 7 days. The initial three cohorts received the first day's dose (one seventh of planned dose) as a bolus infusion before they began the continuous infusion on the second day to observe acute toxicity and determine bolus pharmacokinetics. Toxicity assessment included nerve-conduction studies (NCS) and radionuclide assessment of left ventricular ejection fraction (LVEF) before and after N901-bR administration to fully assess potential neurologic and cardiac toxicity. RESULTS: The dose-limiting toxicity (DLT) of N901-bR given by 7-day continuous infusion is capillary leak syndrome, which occurred in two of three patients at the dose of 40 microg/kg (lean body weight [LBW])/d. Detectable serum drug levels equivalent to effective in vitro drug levels were achieved at the 20-, 30-, and 40-microg/kg(LBW)/d dose levels. Specific binding of the immunotoxin to tumor cells in bone marrow, liver, and lung was observed. Cardiac function remained normal in 15 of 16 patients. No patient developed clinically significant neuropathy. However, a trend was noted for amplitude decline in serial NCS of both sensory and motor neurons. One patient with refractory SCLC achieved a partial response. CONCLUSION: N901-bR is an immunotoxin with potential clinical activity in SCLC. N901-bR is well tolerated when given by 7-day continuous infusion at the dose of 30 microg/kg(LBW)/d. Neurologic and cardiac toxicity were acceptable when given to patients with refractory SCLC. A second study to evaluate this agent after induction chemoradiotherapy in both limited- and extensive-stage disease was started following completion of this study.

Effects of anti-CD33 blocked ricin immunotoxin on the capacity of CD34+ human marrow cells to establish in vitro hematopoiesis in long-term marrow cultures.

Human marrow cells that express the CD34 antigen but lack CD33 are able to initiate sustained, multilineage in vitro hematopoiesis in long-term Dexter cultures and are believed to include the primitive stem cells responsible for effecting long-term hematopoietic reconstitution in vivo following marrow transplantation. In studies described in this report we investigated the effects of a novel anti-CD33 immunotoxin on the clonogenic potential of normal human CD34+ marrow cells and on the ability of these cells to initiate hematopoiesis in two-stage Dexter cultures (long-term marrow cultures, LTMC). This immunotoxin (anti-CD33-bR), shown previously to kill both clonogenic myelogenous leukemia cells and normal mature myeloid progenitor cells (granulocyte-macrophage colony-forming units, CFU-GM), consists of an anti-CD33 monoclonal antibody conjugated to purified ricin that has been modified by blocking the carbohydrate binding domains of the ricin B-chain to eliminate nonspecific binding. For our studies, normal CD34+ human marrow cells were isolated from the light-density (less than 1.070 g/ml) cells of aspirated marrow by positive selection with immunomagnetic beads linked to the monoclonal antibody K6.1. These cell isolates were highly enriched with both multipotential and lineage-restricted clonogenic, hematopoietic progenitors (mixed lineage colony-forming units, CFU-Mix; CFU-GM; and erythroid burst-forming units, BFU-E) which constituted greater than or equal to 20% of the cells. Recovery of clonogenic progenitors from these CD34+ cell preparations, following treatment with anti-CD33-bR (10 nM), was reduced by greater than or equal to 85% for CFU-GM and 20%-40% for CFU-Mix and BFU-E. However, the capacity of these cells to initiate hematopoietic LTMC was preserved. Indeed, the production of high proliferative potential (HPP) CFU-GM, BFU-E, and CFU-Mix in cultures seeded with 10(5) anti-CD33-bR-treated CD34+ marrow cells was substantially greater than that observed in LTMC seeded with equivalent numbers of untreated CD34+ cells. Moreover, concentrations of long-term culture initiating cells in CD34+ cell isolates, quantified by a limiting dilution technique, were found to be increased following anti-CD33-bR treatment. These findings support the potential usefulness of anti-CD33-bR for in vitro marrow purging or in vivo treatment to eliminate CD33+ leukemic clones, while sparing normal CD34+/CD33- stem cells that support normal hematopoiesis and hematopoietic reconstitution in vivo.

Purification and biochemical characterization of immunotoxins.

Written on a plastic bottle of liquid soap in one of our bathrooms (JML) is the phrase 'Absolute cleanliness is next to Godliness!'. Perhaps absolute purity for ITs does not rank so highly, but the availability of purified ITs that contain no nonconjugated antibody or toxin, and no material of very high Mr (aggregates) is essential for a proper comparison of the biological activities of the component proteins with their nonconjugated counterparts. Purified and biochemically well-defined ITs make it possible to perform quantitative binding assays, to evaluate receptor-mediated endocytosis and to do cytotoxicity tests in vitro and efficacy studies in vivo, without fear that competition by nonconjugated antibody is affecting the experimental result. This chapter illustrates some of the methods that in combination can be used to purify ITs, including affinity chromatography, gel filtration, and ion-exchange chromatography with buffers of carefully defined composition, using examples from our laboratory to illustrate the procedures. For further details concerning these methods, we would refer the reader to the excellent book by Scopes [40], Purification of Proteins: Principles and Practice, which contains much useful information of both a technical and a practical nature regarding methods for purification of proteins.

Immunotoxins containing single-chain ribosome-inactivating proteins.

We have summarized what is currently known about the distribution, biological role, and the mechanism of action of the single chain ribosome-inactivating proteins and described the purification of one of them, gelonin, as an example. ITs have been made with several of these proteins and, depending upon the antibody used for conjugation, these immunoconjugates can show specific in vitro cytotoxicity which is similar to that shown by equivalent ITs prepared with ricin A chain. The most potent of these conjugates have shown antitumor efficacy in a variety of animal tumor models, including both syngeneic rodent tumors and xenografts in nude or immunosuppressed mice. An important point needs to be addressed, however, before concluding that ITs containing single chain toxins will be clinically useful. A major problem with this approach is that it is likely that both the antibody and the toxin components of these conjugates will be immunogenic. Both antitoxin and antixenogenic immunoglobulin responses have been shown to occur in animals after infusion of IT, although it has not yet been clearly demonstrated that such antibody responses adversely effect the pharmacokinetics or the efficacy of immunoconjugates. Thus, preliminary enthusiasm over the efficacy of these new reagents must be tempered with the knowledge that their use in the clinic may be limited by the host immune responses or other as yet undefined factors. The fact that there are many immunologically distinct single chain ribosome-inactivating proteins does suggest one way of evading the antitoxin response, by a sequential treatment with a panel of immunoconjugates, each containing a different single chain toxin.

Leg compression and ambulation is better than bed rest for the treatment of acute deep venous thrombosis.

AIM: Treatment of acute deep venous thrombosis (DVT) with low-molecular-weight heparin and vitamin K-antagonists reduces the risk of thrombus progression and pulmonary embolism but has no immediate effect on signs and symptoms. We addressed the question whether adding compression and walking would lead to a more rapid clinical improvement than bed rest. METHODS: Fifty-three symptomatic outpatients with proximal DVT were randomly treated, in addition to dalteparin and phenprocoumon, with either firm inelastic bandages (n=18), elastic compression stockings (n=18), both combined with immediate deliberate ambulation, or bed rest without any compression (n=17). We assessed daily walking distance, well-being, quality of life, pain, swelling and clinical scores over a period of 9 days. Lung scans and ultrasound of the leg were performed on days 0 and 9. RESULTS: In the compression groups the walking distance increased with time to 4 km/day on average. Improvement of well-being and DVT-related quality of life was significantly faster and more pronounced with compression than with bed rest (p<0.05 for stockings, p<0.001 for bandages). Pain monitored by visual analogue scale decreased with time in a linear pattern in all groups (p<0.001). There was a significant difference between the groups (p<0.01), the best effect being achieved with bandages. Pain assessed by a provocation test was reduced by half on day 3 with bed rest but remained constantly present over the subsequent 6 days. With compression it was reduced to near baseline on day 3. Swelling was almost completely removed with compression and clinical scores also improved more than with bed rest (p<0.001). Thrombus progression, as studied with ultrasound, was less frequent and less pronounced in the compression groups than with bed rest. There was no difference of new pulmonary embolism on repeat lung scans. CONCLUSION: Leg compression combined with walking is the better alternative to bed rest for the treatment of symptomatic outpatients with proximal DVT.

Ambulatory care for ambulant patients with deep vein thrombosis.

A follow-up study is reported on 49 patients with acute deep vein thrombosis (DVT) treated on an ambulatory basis. Venography had shown crural DVT in 27 % and proximal extension in 73 %. The initial treatment consisted of heparin (7,500 U iv, 40,000 U sc), ethylbiscoumacetate (900 mg), phenprocoumon (9 mg), and a ready made compression stocking for the calf. The patients were advised to undertake frequent strolls, the first when leaving the office. Pain, swelling and incapacity for walking vanished within two days. The partial thromboplastintime was prolonged 2.4-times on the first day and the thromboplastintime was in the therapeutic range on the second day already. Until follow-up 4 patients died of other diseases. There was no clinical pulmonary embolism, no secondary hospitalisation and only one new DVT. Of 844 months of patients at risk of recurrence 50 % passed under anticoagulants and 70 % with compression therapy. At an average of 19 months, 82 % of patients were asymptomatic and 45 % showed mild chronic venous insufficiency. In contrast, impaired drainage function (by lightreflectionrheography) was found in 79 % overall and in 100 % after DVT of the proximal veins. The discrepancy is explained by the compliance with compression therapy.

Therapeutic concept for acute leg and pelvic venous thrombosis.

Combination treatment in acute deep venous thrombosis essentially consists of a highly dosed locoregional thrombolysis of the valve-carrying crurofemoral axis and a mechanical thrombectomy of the valveless pelvic axis by Fogarty catheter. The success of this method is due to the fact that it largely eliminates the disadvantages of systemic thrombolysis, as well as those at conventional surgical thrombectomy, whilst retaining the advantages. Using combination treatment in acute leg and pelvic venous thrombosis within the first 7 days can result in restitutio ad integrum, i.e. complete desobliteration with maintained valve function in more than 80% of the cases.

[Practical proposals for overcoming problems with phlebography]. / Praktische Vorschläge zur Uberwindung des Malaises um die Phlebographie.

Venography is considered the gold standard in the diagnosis of venous disease. In the everyday practice, however, it is not used according to this attribute. The article scrutinizes the reasons for the discrepancy, emphasizes the possibilities wrongly renounced to and gives advice to a better indication for and execution of venography. Arguments not to use venography regularly to diagnose or exclude deep venous thrombosis, include claims that it would be superfluous, not readily available, invasive and expensive. Such considerations do not take into account that the clinical diagnosis it not better than tossing a coin. Real difficulties may occur in the evaluation of complicated superficial disease and the postthrombotic syndrome. The problems are minimized by using a methodology based on pathophysiologic knowledge and strictly aimed to solve specific therapeutic questions. The article stresses the need for a proper prevenographic work-up and for a technique tailored to the clinical situation of each individual patient.