A phase II study of temozolomide vs. procarbazine in patients with glioblastoma multiforme at first relapse.

A randomized, multicentre, open-label, phase II study compared temozolomide (TMZ), an oral second-generation alkylating agent, and procarbazine (PCB) in 225 patients with glioblastoma multiforme at first relapse. Primary objectives were to determine progression-free survival (PFS) at 6 months and safety for TMZ and PCB in adult patients who failed conventional treatment. Secondary objectives were to assess overall survival and health-related quality of life (HRQL). TMZ was given orally at 200 mg/m(2)/day or 150 mg/m(2)/day (prior chemotherapy) for 5 days, repeated every 28 days. PCB was given orally at 150 mg/m(2)/day or 125 mg/m(2)/day (prior chemotherapy) for 28 days, repeated every 56 days. HRQL was assessed using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30 [+3]) and the Brain Cancer Module 20 (BCM20). The 6-month PFS rate for patients who received TMZ was 21%, which met the protocol objective. The 6-month PFS rate for those who received PCB was 8% (P = 0.008, for the comparison). Overall PFS significantly improved with TMZ, with a median PFS of 12.4 weeks in the TMZ group and 8.32 weeks in the PCB group (P = 0.0063). The 6-month overall survival rate for TMZ patients was 60% vs. 44% for PCB patients (P = 0.019). Freedom from disease progression was associated with maintenance of HRQL, regardless of treatment received. TMZ had an acceptable safety profile; most adverse events were mild or moderate in severity.

Venous valve station changes in "primary" and postthrombotic reflux: an analysis of 149 cases.

The purpose of this study was to analyze valve station changes noted during venous valve reconstruction and the associated outcome. One hundred and forty-nine valve reconstructions were available for analysis at the time of surgical exploration; the venous valve was graded according to valve station changes (VS grades) from zero through six. Ascending venography was analyzed by a similar grading system and the two methods were compared. The results of this analysis showed that valve station wall changes are frequently present in patients with deep venous reflux and pose technical challenges during valve reconstruction; the outcome, however, appears unaffected. Grade 0 to 1 valve station changes are predominantly due to "primary" reflux, with an occasional instance of postthrombotic etiology. Grade 2 or 3 valve station changes are roughly evenly divided between phlebosclerosis of primary reflux and postthrombotic etiologies. The mechanism of onset of reflux with preservation of valve cusps in the latter group of postthrombotic cases is probably different from currently accepted theories of evolution of postthrombotic changes. Postthrombotic valve damage is variable, and the valve station anatomy may be sufficiently preserved in some patients to allow direct valve repair.

Studies in calf venous pump function utilizing a two-valve experimental model.

OBJECTIVES: to explore the hydrodynamic mechanisms involved in the regulation of ambulatory venous pressure. DESIGN: an experimental model of calf venous pump was constructed with collapsible tubes and valves. MATERIAL: the model consisted of a conduit and a pump with an intervening competent valve. Another valve that could allow reflux into the pump was mounted above the pump. METHODS: conduit pressure and recovery times were monitored under conditions of different degrees of ejection fraction and reflux into the pump. Model variables included using poorly compliant tubes for the pump, the conduit and for both the pump and conduit. RESULTS: the latex tube exhibited a non-linear volume-pressure relationship and a bi-modal regimen of compliance. This bestowed pressure-buffering properties. Ambulatory venous hypertension resulted when reflux beyond buffering capacity occurred. Substituting less compliant PTFE for latex at the pump had a relatively minor effect on post-ejection pressure and recovery times. Using PTFE at the conduit had a profound but divergent effect on both of these parameters. Conduit capacitance reduction had a similar effect. CONCLUSION: conduit elastance plays a significant role in the regulation of ambulatory venous pressure in this experimental model. The hydrodynamic principles illustrated by the model may enhance our understanding of the human calf venous pump.

Saphenectomy in the presence of chronic venous obstruction.

BACKGROUND: The results of saphenectomy in patients with morphologic and functional obstruction were compared with those in patients without obstruction. Excision of secondary saphenous varices associated with deep venous obstruction has long been considered contraindicated for fear of compromising its collateral contribution. Recent advances in accurate functional assessment of venous obstruction make it possible to test this concept. METHODS: Saphenectomy was carried out in 51 limbs without morphologic or functional obstruction and 64 limbs with varying grades of venous obstruction. Significant deep venous obstruction on ascending venography was present in the latter group. Functional assessment of obstruction was based on the arm/foot venous pressure differential technique, outflow fraction measurements, and outflow resistance calculations. Valve reconstruction was carried out in conjunction with saphenectomy in 81% of cases. RESULTS: Saphenectomy was clinically well tolerated in both groups, and there was no difference in outcome as measured by objective tests for obstruction; improvement in reflux and calf venous pump function was largely similar. Among seven limbs with severe preoperative venous obstruction (grade III or IV), five (70%) had significantly improved obstructive grading, presumably as a result of elimination of reflux flow. CONCLUSIONS: The traditional admonition against removal of secondary varices should be reexamined. Saphenectomy may be indicated in postthrombotic syndrome with mixed obstruction/reflux. The procedure is clinically well tolerated and without malsequelae. Improvement in reflux parameters without significant worsening of objective measures of obstruction is documented in this group.

Tube collapse and valve closure in ambulatory venous pressure regulation: studies with a mechanical model.

PURPOSE: To determine the role of valve closure and column segmentation in ambulatory venous pressure regulation. METHODS: Using a mechanical model consisting of a graduated adjustable valve and a collapsible tube, we studied the differential effects of valve closure and tube collapse on venous pressure regulation. By utilizing materials with differing wall properties for the infravalvular tube, the influence of wall property changes on tube function and pressure regulation was explored. RESULTS: Valve closure, per se, does not cause venous pressure reduction. Collapse of the tube below the valve is the primary pressure regulatory mechanism. The nonlinear volume-pressure relationship that exists in infravalvular tubes confers significant buffering properties to the collapsible tube, which tends to retain a near-constant pressure for a wide range of ejection fractions, residual tube volumes, and valve leaks. Changes in tube wall property affect this buffering action, at both the low and high ends of the physiological venous pressure range. CONCLUSIONS: The valve and the infravalvular venous segment should be considered together in venous pressure regulation. Tube collapse of the segment below the valve is the primary pressure regulatory mechanism. An understanding of the hydrodynamic principles involved in pressure regulation derived from this model will provide the basis for construction of more complex models to explore clinical physiology and dysfunction.

Intrathecal 131I-labeled antitenascin monoclonal antibody 81C6 treatment of patients with leptomeningeal neoplasms or primary brain tumor resection cavities with subarachnoid communication: phase I trial results.

We aimed to determine the maximum tolerated dose (MTD) of 131I-labeled 81C6 in patients with leptomeningeal neoplasms or brain tumor resection cavities with subarachnoid communication and to identify any objective responses. 81C6 is a murine IgG monoclonal antibody that reacts with tenascin in gliomas/carcinomas but does not react with normal adult brain. 131I-labeled 81C6 delivers intrathecal (IT) radiation to these neoplasms. This study was a Phase I trial in which patients were treated with a single IT dose of 131I-labeled 81C6. Cohorts of three to six patients were treated with escalating doses of 131I (starting dose, 40 mCi; 20 mCi escalations) on 10 mg 81C6. MTD is defined as the highest dose resulting in serious toxicity in no more than two of six patients. Serious toxicity is defined as grade III/IV nonhematological toxicity or major hematological toxicity. We treated 31 patients (8 pediatric and 23 adult). Eighteen had glioblastoma multiforme. Patients were treated with 131I doses from 40 to 100 mCi. Hematological toxicity was dose limiting and correlated with the administered 131I dose. No grade III/IV nonhematological toxicities were encountered. A partial response occurred in 1 patient and disease stabilization occurred in 13 (42%) of 31 patients. Twelve patients are alive (median follow-up, > 320 days); five are progression free >409 days median posttreatment. The MTD of a single IT administration of 131I-labeled 81C6 in adults is 80 mCi 131I-labeled 81C6. The MTD in pediatric patients was not reached at 131I doses up to 40 mCi normalized for body surface area.

Durability of venous valve reconstruction techniques for "primary" and postthrombotic reflux.

PURPOSE: The durability of the variety of valve reconstruction techniques in "primary" reflux and postthrombotic reflux was studied. METHODS: A total of 423 valve repairs in 235 patients with a follow-up period ranging from 1 to 12 years were analyzed. End points for assessment consisted of ulcer recurrence and Doppler competence in serial duplex examination. Multivariate analysis with Cox proportional hazards model was used. RESULTS: Ulcer-free survival curves were similar for "primary" and postthrombotic reflux. No significant difference in ulcer recurrence was seen regardless of the technique used. Different results were obtained when valve competence instead of ulcer recurrence was used for assessment of durability. Reconstructions in "primary" reflux were more durable than those in postthrombotic reflux. Durability differences were also noted among different techniques. A cohort of posterior tibial repairs proved extraordinarily durable (0 failures in 23 repairs). CONCLUSION: Valve reconstruction in postthrombotic reflux can yield clinical results similar to those in "primary" reflux. Although any of the several described techniques can produce similar clinical results, Doppler competence suggests the following order for choice of procedures: (1) internal valvuloplasty, (2) prosthetic sleeve in situ, (3) external valvuloplasty, and (4) axillary vein transfer.

Observations on the calf venous pump mechanism: determinants of postexercise pressure.

PURPOSE: We investigated the factors determining postexercise pressure and the relationship of venous valve closure and venous column segmentation to ambulatory venous pressure changes. METHODS: Valve closure and venous segmentation were observed during dynamic ascending phlebography in 40 nonrefluxive limbs and by duplex imaging in 25 normal limbs in healthy volunteers. Simultaneous volume (air plethysmography) and pressure studies during calf exercise were also carried out. Some studies used a simple mechanical model comprised of a collapsible latex tube ("calf pump") and a graduated "popliteal" valve. RESULTS: The femoropopliteal venous column above the popliteal valve remains unsegmented and continuous during ambulatory venous pressure changes in response to calf muscle contraction. Therefore ambulatory venous pressure changes cannot be explained purely on the basis of hydrostatic column pressure changes. Postexercise pressure appears to be determined by a complex set of factors: (1) physical segmentation of the venous column below the popliteal valve (i.e., tibial valve closure); (2) tube collapse below the closed valve, which further aids in the breakup of the hydrostatic column pressure and dampens the effect of any reflux through or around the closed valve; (3) ejection fraction, which influences the degree of tube collapse; and (4) the interaction of the resultant pressure forces with the wall properties of the venous pump. CONCLUSIONS: The mechanism of ambulatory venous pressure reduction is complex and multifactorial. The importance of venous wall characteristics as a determinant of postexercise pressure has not been previously appreciated. Changes in venous wall property after a thrombotic process, for example, could conceivably influence ambulatory venous pressure and recovery time in the absence of reflux.

Cerebral vasculitis associated with cocaine abuse.

BACKGROUND: Earlier reports of cocaine-associated cerebral vasculitis have been based primarily on angiographic findings without pathological verification. CASE DESCRIPTION: We present a case of acute encephalopathy following intravenous and intranasal administration of cocaine. Brain biopsy revealed vascular changes involving primarily small arteries. Findings included lymphocytic infiltration, endothelial thickening, and deposition of proteinaceous amorphous material within and around vessel walls. CONCLUSIONS: These abnormalities are consistent with pathological features of arteritis previously reported in association with amphetamine and multiple-drug abuse. Vasospasm-induced changes are an alternative explanation for the vascular picture seen in this case. The patient made modest improvement with high-dose intravenous steroids.

Venous obstruction: an analysis of one hundred thirty-seven cases with hemodynamic, venographic, and clinical correlations.

One hundred thirty-seven limbs with venous obstruction were analyzed. The arm/foot venous pressure differential and reactive hyperemia tests were found to be useful techniques to diagnose and grade venous obstruction. Traditional techniques including venography and ambulatory venous pressure are inferior in this regard. The newer techniques have provided newer insights in venous obstruction which are detailed herein. The hand-held Doppler was surprisingly very sensitive in grade I as well as in more severe forms of obstruction. Neither anatomic locale of obstruction nor its extent determined hemodynamic severity. Extensive proximal lesions could be hemodynamically mild, and conversely distal crural obstructions and single segment lesions could be hemodynamically severe. Phlebographic appearance was a poor index of collateralization. The paradoxical venous pressure response to the reactive hyperemia test in grade IV obstruction was found to be due to suppression or delay of the reactive hyperemia response itself in the presence of severe venous obstruction. The pain of venous claudication may be related to this phenomenon. Skin ulceration in the presence of venous obstruction was related to the associated reflux rather than the hemodynamic severity of the obstruction itself. The Linton procedure was found to be useful in treating such skin ulcerations. After perforator disruption, obstruction did not become hemodynamically worse, but reflux as measured by the Valsalva test improved with ulcer healing. The improvement in reflux related to Valsalva offers for the first time a hemodynamic rationale for the Linton procedure.

Hemodynamic basis of stasis ulceration--a hypothesis.

Approximately 25% of patients with stasis ulceration have normal or below normal ambulatory venous pressures. A reflux index was calculated by multiplying postexercise pressures by Valsalva-induced foot venous pressure elevation. In patients with stasis ulceration, reflux index was found to have an excellent negative predictive value with a clear discriminant line between normal limbs and those with ulcers. Increasing incidence of stasis ulceration was demonstrated with increasing reflux index value. Even when ambulatory venous pressure was within the normal range, the index was found to be abnormal in ulcerated limbs because Valsalva-induced foot venous pressure was elevated in these limbs. Conversely, some patients with stasis ulceration and normal Valsalva foot venous pressure elevation were found to have abnormal ambulatory venous pressure values, yielding an elevated reflux index. Preliminary analysis indicates that reflux index may be a better predictor of surgical outcome after valve reconstruction procedures than either ambulatory venous pressure or Valsalva-induced foot venous pressure elevation. The concept of reflux index is a hypothesis that attempts to explain inconsistencies observed in implicating ambulatory venous hypertension as the sole determinant of venous reflux.

Angiotropic intravascular large-cell lymphoma (malignant angioendotheliomatosis): report of a case and review of the literature.

We present a case of angiotropic large-cell lymphoma and review the literature in order to define the neurologic features of this rare disorder. This is the first report of gadolinium-DTPA imaging in angiotropic large-cell lymphoma that demonstrates infarcts of multiple ages, as well as striking meningeal enhancement. Angiotropic large-cell lymphoma should be suspected in patients with clinical evidence of small and large cerebral vessel disease and diagnosis requires skin, liver, renal, meningeal, or brain biopsy. Single modality treatment, using either radiation therapy or steroids, has been ineffective, and new findings of a lymphomatous origin of this neoplasm suggest that combination chemotherapy may be indicated.

Evaluation of methods for detecting venous reflux. Perspectives in venous insufficiency.

Using 793 limbs with nonobstructive venous reflux, we evaluated a number of techniques used for the assessment of venous reflux. The venous Doppler examination was found to be a reliable screening tool with excellent sensitivity and good specificity. Photoplethysmography was 97% sensitive in patients with ambulatory venous hypertension; however, in milder forms of reflux, it was less sensitive. The major drawback of photoplethysmography was the large number of false-positive results obtained. Ambulatory venous pressure measurement and another pressure-based technique, Valsalva-induced foot venous pressure measurement, defined overlapping but different normal and abnormal limbs. Descending venography, when performed as described by Kistner et al, was found to be a reliable tool to assess reflux with more than a 90% sensitivity. The horizontal technique of performing descending venography and nucleotide descending venographies had unacceptably low sensitivity and were abandoned. Features of venous reflux as outlined by these modern technical tools are described.

Implications of the angiographic string sign in carotid atherosclerosis.

We identified 60 patients (42 men and 18 women with an average age of 62.6 years) with angiographically documented carotid stenoses of greater than or equal to 95%; a string sign was demonstrated in 28. Twenty of the 60 patients (33%) were asymptomatic on presentation, 26 (43%) had hemispheric transient ischemic attacks, 21 (35%) had amaurosis fugax, and nine (15%) had previous ipsilateral infarctions. Demographics, mode of presentation, and prevalence of atherosclerotic risk factors were not significantly different between patients with and without a string sign. Doppler frequencies recorded in patients with a string sign were less than 6 or greater than 16 KHz. Real-time ultrasonography imaged a patent lumen in all but three cases with a string sign. Surgery was performed in 26 patients with a string sign and in 21 patients without a string sign. The rate of major perioperative complications was not influenced by the presence of a string sign, contralateral extracranial stenosis, or ipsilateral siphon stenosis. Average lumen size of the endarterectomy specimens was 0.94 mm in those with and 1.7 mm in those without a string sign. We conclude that combined noninvasive testing has a sensitivity of 83% for demonstrating a residual lumen in patients with greater than or equal to 95% carotid stenosis and that the angiographic string sign does not affect the mode of presentation or surgical outcome of these patients.

Gadolinium-enhanced MRI: a superior technique for the diagnosis of intraspinal metastases.

Intraspinal medullary metastases are difficult to demonstrate radiographically. We describe the value of gadolinium-DTPA-enhanced magnetic resonance imaging in the diagnosis of intraspinal medullary metastases. This safe, sensitive procedure should be a requisite study in myelogram-negative patients with symptomatology indicative of a cord lesion.

Valve reconstruction procedures for nonobstructive venous insufficiency: rationale, techniques, and results in 107 procedures with two- to eight-year follow-up.

Among 211 limbs with nonobstructive chronic venous insufficiency, valve reflux of the deep system was the predominant (more than 70%) pathologic condition. Superficial venous or perforator incompetence when present invariably occurred in combination with valve reflux of the deep veins, suggesting that the latter is a common denominator for symptom production. Single level-single system reflux was only occasionally symptomatic (10%), whereas the incidence of single level-multisystem reflux (25%) and multilevel-multisystem reflux (65%) in symptomatic limbs was much higher. Our experience with 107 venous valve reconstructions with a 2- to 8-year follow-up is described. Different techniques of valve reconstruction employed are detailed. The most common pathologic feature is a redundant valve with malcoaptation probably of nonthrombotic origin. Valsalva foot venous pressure elevation is a useful hemodynamic technique for assessing surgical results. Valvuloplasty may be superior to other reconstruction techniques in relieving symptoms of stasis, including stasis ulceration.

Carotid siphon stenosis.

Seventy-one cases of carotid siphon stenosis were analyzed for symptom presentation, non-invasive diagnosis, angiographic and CT scan features, and outcome. Our experience indicates that carotid siphon stenosis is a dangerous lesion with serious neurological sequelae, including a high stroke rate. Indirect evidence is presented to suggest that distal embolization is a significant feature of carotid siphon lesion.

Late hemodynamic sequelae of deep venous thrombosis.

Twenty-nine limbs in 19 patients who had deep venous thrombosis documented by phlebography were studied by hemodynamic techniques 2 to 13 years later (mean, 7 years). Two limbs were found to be "normal." Nine limbs were hemodynamically obstructed; the remaining 18 limbs had developed reflux abnormality. All of the nine limbs with obstruction demonstrated symptoms of severe swelling or ulceration. In contrast, limbs with valve reflux were either asymptomatic or had only mild to moderately severe symptoms. Correspondingly, the reflux hemodynamic derangement was also mild, with reflux confined to a single level (commonly the popliteal valve). The implications of the differences in clinical presentation and hemodynamic profile between this group with post-thrombotic valve reflux and the typical patient with stasis caused by chronic venous insufficiency are explored. The natural history of stasis sequelae of deep venous thrombosis has apparently changed somewhat since the introduction of anticoagulation therapy.

Bone resorption and humoral hypercalcemia of malignancy: stimulation of bone resorption in vitro by tumor extracts is inhibited by prostaglandin synthesis inhibitors.

Extracts of tumors from patients with humoral hypercalcemia of malignancy (HHM) were tested using an in vitro bone resorption assay in order to investigate the pathogenesis of the hypercalcemia. Bone resorption was assessed by comparing the percent release of previously incorporated 45Ca from paired halves of newborn mouse calvaria. Saline extracts of three out of five tumors from HHM patients caused a significant increase in 45Ca release relative to controls. Extracts of liver and non-HHM tumor did not cause significant resorption. Tumor-stimulated bone resorption was blocked by indomethacin and eicosatetraynoic acid, inhibitors of the synthesis of prostaglandins (PGs) and related metabolites of arachidonic acid, whereas resorption stimulated by parathyroid hormone (PTH), PGE2, or 1,25-(OH)2D3 was not. Furthermore, levels of immunoreactive PTH or PGE2 in tumor extracts were not sufficient to account for the degree of resorption observed. These observations indicate that PTH or PGE2 are not responsible for the bone resorption caused by extracts of tumors from these patients with HHM. Furthermore, they suggest that hypercalcemia in these patients may result from bone resorption stimulated by the local production in bone of PGs or related metabolites of arachidonic acid in response to a humoral factor elaborated by the tumor.