Malignant Melanotic Nerve Sheath Tumor.

Malignant melanotic nerve sheath tumors are uncommon pigmented tumors of Schwann cell origin, most often found along the spinal nerves. Although well-described in the literature, the tumors are quite rare, making up <1% of nerve sheath tumors. Physicians are, therefore, often unfamiliar with both the appearance and the optimal treatment of such tumors. Morphologically, many imaging features overlap with schwannomas and neurofibromas. Nevertheless, the malignant melanotic nerve sheath tumors are crucial to identify. They can be extremely aggressive, and the management of these tumors is considerably different from their benign counterparts. In this radiology-pathology review, we will highlight the imaging appearance, histologic features, surgical resection, and subsequent therapeutic strategies in a patient with a lumbar malignant melanotic nerve sheath tumor.

Macrophage migration inhibitory factor downregulation: a novel mechanism of resistance to anti-angiogenic therapy.

Anti-angiogenic therapies for cancer such as VEGF neutralizing antibody bevacizumab have limited durability. While mechanisms of resistance remain undefined, it is likely that acquired resistance to anti-angiogenic therapy will involve alterations of the tumor microenvironment. We confirmed increased tumor-associated macrophages in bevacizumab-resistant glioblastoma patient specimens and two novel glioblastoma xenograft models of bevacizumab resistance. Microarray analysis suggested downregulated macrophage migration inhibitory factor (MIF) to be the most pertinent mediator of increased macrophages. Bevacizumab-resistant patient glioblastomas and both novel xenograft models of resistance had less MIF than bevacizumab-naive tumors, and harbored more M2/protumoral macrophages that specifically localized to the tumor edge. Xenografts expressing MIF-shRNA grew more rapidly with greater angiogenesis and had macrophages localizing to the tumor edge which were more prevalent and proliferative, and displayed M2 polarization, whereas bevacizumab-resistant xenografts transduced to upregulate MIF exhibited the opposite changes. Bone marrow-derived macrophage were polarized to an M2 phenotype in the presence of condition-media derived from bevacizumab-resistant xenograft-derived cells, while recombinant MIF drove M1 polarization. Media from macrophages exposed to bevacizumab-resistant tumor cell conditioned media increased glioma cell proliferation compared with media from macrophages exposed to bevacizumab-responsive tumor cell media, suggesting that macrophage polarization in bevacizumab-resistant xenografts is the source of their aggressive biology and results from a secreted factor. Two mechanisms of bevacizumab-induced MIF reduction were identified: (1) bevacizumab bound MIF and blocked MIF-induced M1 polarization of macrophages; and (2) VEGF increased glioma MIF production in a VEGFR2-dependent manner, suggesting that bevacizumab-induced VEGF depletion would downregulate MIF. Site-directed biopsies revealed enriched MIF and VEGF at the enhancing edge in bevacizumab-naive patients. This MIF enrichment was lost in bevacizumab-resistant glioblastomas, driving a tumor edge M1-to-M2 transition. Thus, bevacizumab resistance is driven by reduced MIF at the tumor edge causing proliferative expansion of M2 macrophages, which in turn promotes tumor growth.

Autogenous vein graft repair of injured extremity arteries: early and late results with 134 consecutive patients.

Autogenous vein tissue is recognized as the preferred material for extremity revascularizations that require the use of a conduit. However, the results after vascular repair of injured extremity arteries with autogenous vein interposition or bypass grafts have not been well defined. This study was done to determine both the early and late patency and limb salvage rates as well as the graft infection rate of autogenous vein repairs of injured extremity arteries. The records of 134 consecutive patients with acute extremity arterial injuries requiring repair with a reversed autogenous vein graft over a recent 5-year period were reviewed. Follow-up graft patency was defined by the presence of a palpable pulse and an extremity Doppler-derived pressure index of greater than or equal to 0.9 distal to the arterial repair. Cumulative patency was assessed by the life-table method. Acute graft thrombosis occurred in two patients, one of whom underwent successful graft thrombectomy. Four patients (3%) required extremity amputation: one patient with a thrombosed vein graft and three patients with patent vein grafts but nonsalvageable limbs as a result of myonecrosis (2) or osteomyelitis (1). No perioperative graft infections occurred. One hundred twenty-eight patients (97%) had an intact extremity and a patent vein graft at the time of hospital discharge. One hundred three patients (80%) were examined at 30 days, and all grafts were patent. Seventy-three patients (57%) were available for follow-up at intervals exceeding 6 months, and 40 patients (31%) were followed-up for periods exceeding 24 months.(ABSTRACT TRUNCATED AT 250 WORDS)

Circumvention of pleiotropic drug resistance in subcutaneous tumours in vivo with verapamil and clomipramine.

The development of pleiotropic drug resistance (PDR) in vivo in solid tumour models suggests that a similar process may occur in the clinic. A subline of the Ridgway osteogenic sarcoma (ROS)--a murine subcutaneously-growing solid tumour--with moderate resistance (1.5 fold) to actinomycin D was selected by repeated suboptimal treatment with this drug in vivo. This subline (ROS/ADX/G2) showed cross-resistance to vincristine (3.5 fold) and etoposide (over 5.1 fold) but not to doxorubicin. The resistance could in all cases be partly or completely overcome by treatment with non-cytotoxic doses of verapamil or clomipramine. Resistance to actinomycin in this model was associated with lower (up to 3.2 fold) drug accumulation into tumours which could be increased (up to 2.8 fold) by treatment with 25 micrograms/g verapamil. These data support clinical trials of the use of membrane-active agents to overcome PDR.

Microvascular disease and limited joint mobility in diabetes. A comparison of fibrinolysis and prostacyclin in diabetes and systemic sclerosis.

The pathogenesis of Limited Joint Mobility (LJM) in diabetes is unknown, but the abnormality is said to be associated with an increased incidence of microangiopathy. To examine the possibility that LJM may be a manifestation of microvascular disease, fibrinolysis and blood prostacyclin metabolites were measured in diabetic patients with and without LJM, and compared with patients who have systemic sclerosis (PSS). The concentrations of plasma fibrinogen (p less than 0.01) and Plasminogen Activator Activity (PAA) (p less than 0.02) were increased in both diabetic groups, compared with non-diabetic controls, and were of similar magnitude to the changes observed in PSS. Antithrombin III (AT III) activity was significantly lower in diabetic patients with LJM than in those without LJM, but not significantly different from controls. Prostacyclin concentrations were raised in PSS patients compared to controls (p less than 0.02) but were not raised in diabetic subjects. Thus abnormal fibrinolysis was demonstrated in diabetic patients compared to non-diabetic controls, and prostacyclin concentrations in diabetics were lower than in PSS patients. The diabetic patients with LJM had lower AT III activity than diabetics without LJM, but overall a convincing difference between the two groups of diabetics was not proven. No sure inferences could be drawn on the vascular aetiology of LJM, while the impaired prostacyclin activity might contribute to the development of diabetic microangiopathy.

Crush syndrome due to limb compression.

Four patients with the crush syndrome due to prolonged limb compression were treated at Cook County Hospital, Chicago. Limb injury was caused when the obtunded patient fell asleep lying on the involved extremity. Prolonged limb compression may cause an acute compartment syndrome with ischemic muscle injury. Continued muscle ischemia may lead to myonecrosis resulting in shock or renal failure. A history of prolonged limb compression with a swollen limb should suggest the diagnosis of crush syndrome. Prompt therapy, including rapid correction of volume and metabolic derangements, extensive open fasciotomy, and dialysis for severe acute renal failure should provide good functional results in the majority of patients.

Peripheral vascular trauma from close-range shotgun injuries.

This report summarizes an eight-year experience (1976 to 1983) with 49 close-range shotgun blasts with associated major vascular injuries seen in a large urban hospital. Injuries to the upper extremity (40%), lower extremity (56%), and neck (4%) were seen. A high frequency of associated deep venous injury (82%), nerve injury (37%), fracture (33%), massive soft-tissue loss (43%), and compartmental hypertension (39%) was observed. There were no deaths in this series, and the limb salvage rate was 96%. Neither patient with multiple carotid artery injuries suffered a neurologic deficit. We attribute our success in the management of these complex injuries to rapid fracture immobilization, early and aggressive use of fasciotomy, adequate débridement of devitalized tissue, repair of deep venous injuries, arterial repair with autogenous tissue, and extra-anatomic bypass grafting in selected cases.

Indirect assessment of carotid occlusive disease by ocular pneumoplethysmography. 500 mm Hg vacuum pressure measurements and ocular pulse timing.

The interpretation and diagnostic value of the ophthalmic artery pressure measurement and ocular pulse timing modes of the 500 mm Hg vacuum OPG-Gee ocular pneumoplethysmograph were evaluated in 65 patients who underwent aortic arch and cerebral arteriography. Data analysis revealed the OPG-Gee differential tracing which electronically compares and amplifies differences between the right and left eye pulse waveforms to be of little value. In predicting the presence of a greater than or equal to 50 percent diameter unilateral stenosis, an eye-eye pulse interval of greater than 15 msec was 82 percent accurate, a greater than or equal to 5 mm Hg ophthalmic artery pressure difference was 77 percent accurate and when combined these two criteria were 84 percent accurate. Neither of the criteria intended to detect bilateral carotid lesions, eye-ear pulse interval nor ophthalmic/brachial pressure index, were reliable. Ocular pulse timing was found to be highly specific but insensitive to hemodynamically significant carotid disease. OPG-Gee pressure determinations were more sensitive but lacked specificity. In combination, these criteria allowed identification of unilateral hemodynamically significant lesions with a sensitivity of 83 percent and a specificity of 86 percent. If used to detect more severe degrees of arteriographic stenosis, 60 and 70 percent diameter reduction, the overall diagnostic accuracy of these techniques was not improved. These results do not justify the use of the OPG-Gee instrument as a single noninvasive test for carotid arterial disease.

Cardiovascular lymphoscintigraphy.

The technique of lymphoscintigraphy when applied to the heart and blood vessels correlates well with results of anatomic investigations of arterial and cardiac lymphatic vessels reported in the literature. Five dogs and eight rabbits underwent lymphoscintigraphy of the heart and aorta, as well as the iliac, femoral, and tibial arteries. After surgical exposure, approximately 500 microCi of 99mTc-labelled antimony sulfide was injected into the myocardium or the adventitial-medial plane of an artery. The colloid particle size of 4 to 12 m mu causes resorption and transport only via the lymphatic vessels. Twenty-one preparations were imaged from 2 to 48 hours after administration. This method provides a functional demonstration that the tibial and femoral arteries of both species are invested with lymphatics. The first echelon of lymph nodes which drain muscular arteries are imaged within 2 hours. Regional lymph nodes could not be seen to drain the aorta or iliac arteries. Anterior left ventricular myocardial injection in the dog showed a single cardiac lymph node. This drainage pattern has been described previously by other investigators. In the rabbit a similarly placed injection visualized a group of regional cardiac nodes. Ligation of the collecting ducts afferent to the cardiac node in the dog prevented removal of the isotope from the heart at 3, 6, and 9 hours. At 24 hours the liver and spleen were imaged, the radiocolloid gaining entrance to the blood vascular system presumably via myocardial lymphaticovenous anastomoses. Lymphoscintigraphy reflects physiologic processes such as lymph transport, filtration, and reticuloendothelial function. It defines regional patterns of cardiac and arterial lymph drainage. It can confirm experimentally produced impairment of lymph drainage from a defined area of tissue. Lymphoscintigraphy should be useful in the investigation of the significance of lymph drainage to diseases of the heart and blood vessels.

Anatomic and hemodynamic evaluation of percutaneous transluminal angioplasty.

Of 34 balloon angioplasties of the lower extremity performed during a two year period, 29 were observed for three to 21 months. Hemodynamic measurements were performed preangioplasty, immediately postangioplasty and at three month intervals thereafter. Immediately, postangioplasty arteriograms were performed upon all patients. Late follow-up arteriograms were obtained for selected patients. Immediate anatomic success was achieved in 93 per cent of procedures, but early hemodynamic improvement occurred in only 62 per cent of the angioplasty procedures. At a mean follow-up time of nine months, continued success was noted in only 48 per cent of the procedures. Late failure with iliac artery procedures was demonstrated in only 18 per cent of the patients, while, in femoropopliteal angioplasty, late failure occurred in 50 per cent of the procedures. The results of this study and of others indicate that femoropopliteal balloon angioplasty in not a durable procedure. The durability of iliac artery angioplasty requires further evaluation.

Neonatal abdominal aortic thrombosis.

Thromboembolism of abdominal aorta and its branches after umbilical artery catheterization has been previously reported. In the past, total occlusion of the abdominal aorta and its major branches was associated with high mortality. Successful aortic thrombectomy in the neonatal period has been reported only once in English literature. The successful management of 2 infants described here shows the need for early diagnosis and aggressive approach, including surgical thrombectomy when indicated. Thromboembolism of abdominal aorta and iliac arteries can be diagnosed by noninvasive methods, such as 2-dimensional echoaortography and Doppler blood flow measurement.

Rational approach to the differentiation of vascular and neurogenic claudication.

Lower extremity pain caused by exercise but relieved by rest is usually a reliable symptom of chronic arterial insufficiency. However, similar discomfort often occurs in patients with neurospinal compression. Furthermore, arterial occlusive disease and demonstrable spinal stenosis may be present simultaneously. Fifty-two patients with symptoms suggesting intermittent claudication comprised the study group. All were proven to have a nonarterial cause of their complaint. The study consists of a retrospective analysis of the diagnostic methods used in confirming the proper diagnosis. Conclusions reached suggest a rational approach to solution of individual patient problems. The nonvascular origin of the symptoms was suggested initially by clinical evaluation in 19 patients, and by noninvasive arterial evaluation in an additional 22. The neurospinal origin of symptoms was obscured in 11 patients because of the presence of significant arterial occlusive disease, as demonstrated by nominvasive arterial testing. Seven of the 11 patients underwent arterial reconstruction, which failed to relieve their symptoms. Subsequently, the neurospinal origin of these symptoms was proven by appropriate treatment. This experience has shown that the errors in diagnosis and treatment could have been avoided by using a combined diagnostic approach, correlating results of an accurate clinical evaluation with noninvasive arterial testing as well as the findings shown on lumbosacral spine films.

Chronic upper extremity arterial insufficiency. Etiology, manifestations, and operative management.

Forty-eight arterial reconstructions were performed for chronic upper extremity ischemia in 43 patients, aged 31 to 81 years. Diagnostic arterial catheterization was the most frequent cause of symptomatic occlusion, followed by proximal arteriosclerotic lesions and noniatrogenic trauma. Doppler ultrasound evaluation provided important diagnostic and prognostic data that complemented information derived from arteriography. Indications for operation included disabling claudication (39 cases) or digital gangrene (four cases). Restoration of normal extremity function can be anticipated except in instances where poor forearm runoff exists. Autogenous saphenous and basilic interposition vein grafts have proved excellent for axillary-brachial revascularizations. Axillary-axillary bypass procedures for innominate-subclavian artery occlusions appear hemodynamically sound and technically simple. Follow-up, averaging 48 months, extended to 144 months. Late vein graft failure or progressive distal occlusive disease was not encountered.

Impaired tissue oxygenation in cyanate-treated animals.

Carbamylation of red cells with sodium cyanate has been suggested as a potential treatment for sickle cell disease. Because carbamylation of red cells increases their oxygen affinity, the present study was done to determine whether cyanate administration caused impaired tissue oxygenation. Rats given i.p. (250 mg/kg/wk) or oral (625 mg/kg/wk) cyanate were found to have significantly reduced skin bubble oxygen tensions compared to controls. These reduced oxygen tensions were associated with significantly increased blood oxygen affinity. Treated animals developed greater red cell masses than controls, but these increases were not sufficient to compensate for increased blood oxygen affinity. These findings need to be considered when cyanate is used for treatment of sickle cell disease.

Biliary cysts.

This review brings the total number of biliary cysts reported in the world literature to 955. Eighty-one per cent of patients are females and 61% were discovered before age ten. The classical triad of right upper quadrant pain, right upper quandrant mass, and juandice is present in 38% of cases. The duration of symptoms prior to diagnosis ranged from less than one week to more than 40 years. The etiology is multifaceted and evidence of the existence of both acquired and congenital cysts is presented. The most useful diagnostic tool is fiberoptic endoscopy with retrograde contrast injection of the common bile duct and pancreatic duct. The incidence of biliary carcinoma in patients with biliary cysts is found to be 2.5%; 24 cases have been reported. Considerable controversy has existed concerning the best operative procedure for biliary cysts; no treatment or medical treatment yielding a 97% mortality rate. In an analysis of 235 patients presented since 1968 with an average followup of 5.2 years, the best procedure appears to be excision with either choledochocholedocostomy or Roux-en-Y hepaticojejunostomy. The operative mortality for all procedures is now 3 to 4%.

Enhancement of filterability of sickle cells by cyanate: an effect independent of oxygen saturation.

Filterability and morphology of cyanate-treated sickle cells were compared to those of untreated cells at equal oxygen saturations to determine whether carbamylation inhibited sickling by an effect other than by its alteration of the oxygen dissociation curve. Morphology of treated and untreated cells was not significantly different at all levels of oxygen saturation examined. Filterability, on the other hand, was improved significantly by carbamylation. This latter finding indicates that carbamylation enhances deformability of sickle cells by a mechanism(s) in addition to its effect on red cell oxygen saturation. This mechanism(s) may account for the clinical benefit of cyanate therapy with doses which do not significantly affect the oxygen dissociation curve.