Intracranial hematolymphoid malignancies: A case series with molecular characterization.

OBJECTIVE: Central nervous system (CNS) manifestations of hematologic malignancies are uncommon and often have a poor prognosis. As hematologic neoplasms are typically chemotherapy- and radiotherapy-sensitive, surgical resection is usually not indicated; thus, opportunities for in-depth characterization of CNS hematologic tumors are limited. Here, we report four cases of rare intracranial hematologic tumors requiring surgical intervention, allowing for histopathologic and genomic characterization. METHODS: The clinical course, genetic perturbations, and histopathological features are described for a case of 1) primary marginal zone B-cell lymphoma of the dura as well as cases of brain metastases of 2) cutaneous T-cell lymphoma, 3) acute myeloid leukemia/myeloid sarcoma, and 4) multiple myeloma. Targeted DNA sequencing, fluorescence in situ hybridization, cytogenetic analysis, flow cytometry and immunohistochemical staining were used to assess the lesions. RESULT: Molecular and histopathological characterizations of four unusual presentations of hematolymphoid diseases involving the CNS are presented. Genetic abnormalities were identified in each lesion, including chromosomal aberrations and single nucleotide variants resulting in missense or nonsense mutations in oncogenes. CONCLUSIONS: Our case series provides insight into unique pathological phenotypes of hematologic neoplasms with atypical CNS involvement. We offer targets for future studies by identifying potentially pathogenic genetic variants in these lesions, as the full implications of the novel molecular abnormalities described remain unclear.

Ventricular fibrillation during right coronary arteriography with ioxaglate, iohexol and iopamidol in dogs.

Radiograph contrast media (CM) are known to produce myocardial disturbances during cardiac angiography. The most severe electrical disturbance is ventricular fibrillation (VF). Previous studies using prolonged right coronary exposures have demonstrated a higher incidence of VF with dilute low sodium CM than with dilute CM containing more physiologic levels of sodium. In this study the incidence of VF was examined for more conventional concentrations of iopamidol, iohexol and ioxaglate and for sodium supplemented iohexol. The incidence of VF was determined during 25-second injections of contrast media into the canine right coronary artery at a rate of 0.4 mL/sec. Injections of iohexol and iopamidol at concentrations of 160, 240 and 320 mgI/mL produced significantly more VF (P less than .005, Fisher Exact Test) than meglumine/sodium ioxaglate or iohexol supplemented with 20 mM sodium chloride. The time required to produce a 50% incidence of VF with iohexol and iopamidol was significantly related to sodium concentration (r = .92, P less than .01).

The cardiovascular effects of iodinated contrast media injections.

Intravascular iodinated contrast media are used in high doses and high concentrations to achieve the necessary x-ray attenuation. These solutions have densities, viscosities, and osmolalities considerably higher than body fluids. The properties of the solutions are responsible for many of the dose-dependent side effects of intravascular injection. There are significant differences among the media available today; however, all will produce some side effects.

The importance of sodium concentration on the incidence of fibrillation during coronary arteriography in dogs.

Coronary arteriography is known to produce electrical disturbances including conduction disturbances, arrhythmias, and ventricular fibrillation. A canine model for studying ventricular fibrillation has been developed that uses relatively long injections in the right coronary artery. In experiments in 49 dogs over a five-year period, the authors have consistently observed that with low osmolality contrast media, the incidence of ventricular fibrillation becomes quite high when the formulation contains less than 3.2 mmol/L sodium. This effect seems independent of the concentration of the contrast media molecules. High concentrations of the ionic monomer diatrizoate cause fibrillation despite high sodium concentrations.

The physiologic effects of nonionic contrast media on the heart.

OBJECTIVES: This article briefly reviews the potential physiologic effects of ionic versus nonionic contrast media on the myocardium. METHODS: Selection criteria for articles included the use of quantitative measurement techniques, controlled contrast-media doses, and a focus on cardiac mechanical or electrical function. Two important reviews also were used. Most of the data considered represent the results of animal experiments. RESULTS/CONCLUSIONS: Nonionic monomer contrast media are associated with markedly less physiologic effect on the heart, compared with ionic agents. For instance, cardiac depression is minimal, and the incidence of arrhythmia and fibrillation is reduced with nonionic agents during coronary arteriography. Nonionic dimer agents with electrolyte supplementation produce even less mechanical and electrical disturbances.

Cardiovascular radiology. Possible factors in intravascular contrast media toxicity.

(I.) Toxicity of ionic coronary arteriography contrast media has been shown to depend on their cationic and anionic composition and their osmolality. Using a right coronary injection technique in the dog, the authors have shown a relationship between toxicity as manifested by occurrence of ventricular fibrillation and the presence of calcium binders in the contrast media. Sodium citrate and EDTA have been identified as the specific agents in certain contrast media that significantly increase the incidence of fibrillation in laboratory experiments. (II.) A deleterious synergism between water-soluble angiographic and urographic media and digitalis compounds has now been demonstrated, based on mortality studies (LD50) using bolus intravenous injections in white mice. The testing of a number of other classes of drugs for a similar effect has shown thus far that only the digitalis class exhibits this synergism. Surprisingly, the nonionic contrast medium, metrizamide, has been shown to have a greater synergistic effect with digitalis drugs than diatrizoate ionic media. (III.) In dog experiments under Nembutal anesthesia in which aortic flow, pulmonary artery and vein pressures, systemic arterial pressure, and EKG were monitored, left atrial pressure increases as soon as or before pulmonary artery pressure rises, even at low doses of ionic contrast media administered intravenously. This may indicate 1) flow to the left heart increases dramatically, or 2) there is a very early myocardial depression. The significance of the above findings and application to clinical practice will be discussed.

Incidence of fibrillation with dilute contrast media for intra-arterial coronary digital subtraction angiography.

State-of-the-art imaging technology such as digital subtraction angiography can produce coronary artery opacification with contrast media formulations that contain less than 170 mgI/ml. We examined the effect of electrolyte composition in such formulations on the incidence of fibrillation. Right coronary injections of contrast were made for 25 seconds in anesthetized dogs. This injection is longer than clinical injections, but the model approximates the worst condition of a wedged catheter preventing media washout. Formulations of several mixtures of meglumine and sodium diatrizoate (173 to 141 mgI/ml) and sodium diatrizoate alone (143 mgI/ml) produced fibrillation in only 10 to 20% of the injections. Meglumine diatrizoate (141 mgI/ml) and full strength meglumine/sodium diatrizoate (Angiovist 370) produced fibrillation in 100% and 50% of the injections, respectively. These animal studies demonstrate that dilute contrast media containing few or no sodium ions are more likely to induce fibrillation than Angiovist 370, whereas dilute contrast media containing sodium are the least likely to induce fibrillation.

An in vitro study of the hemodynamic effects of catheter injections.

The injection jet from a catheter has been shown to elevate distal pressure and flow. These disturbances in flow present a problem for the application of digital arteriography to measure physiologic flow. The authors used an in vitro model to determine the primary factors responsible for the increases in distal flow with the goal that these disturbances might be estimated and minimized. Experiments were performed to evaluate the importance of the cross-sectional area of the catheter and vessel, the importance of absolute vessel flow, and the importance of distal resistance. A lumped resistance model predicted the flow changes to within 3% of the preinjection vessel flow. In the model system the elevation of distal flow in percent was equal to (the injection rate divided by the tube flow rate) multiplied by (the proximal resistance divided by the total resistance) multiplied by 100. Because the resistance ratio generally is small, injections at physiologic flow rates should produce acceptably small increases in distal flow. The use of a large diameter catheter or the presence of a proximal stenotic lesion would increase the ratio.

Trapped plasma vs. osmolality in canine microcapillary hematocrits.

The trapped plasma in the packed red cell portion of the microcapillary hematocrit of hypertonic canine blood was measured with I-125 labelled albumin. Blood osmolalities were raised by the addition of sodium chloride and meglumine/sodium diatrizoate. The trapped plasma was 1.12 +/- 0.15%, 1.75 +/- 0.27% and 1.77 +/- 0.22% at 300, 580, and 723 mOsm/kg, respectively, for sodium chloride solutions. At 924 mOsm/kg some of the blood plus sodium chloride samples hemolyzed. In the group without hemolysis the trapped plasma was 5.84 +/- 1.35% while in the group with hemolysis it measured 12.43 +/- 1.90%. The trapped plasma with diatrizoate solutions was 1.41 +/- 0.11, 2.15 +/- 0.18 and 5.32 +/- 0.56 at 458, 531 and 602 mOsm/kg, respectively. Above an osmolality of 458 mOsm/kg the trapped plasma was significantly greater for the diatrizoate solutions than for the sodium chloride solutions. At osmolalities below 458 mOsm/kg only a small correction is needed for trapped plasma with either sodium chloride or meglumine/sodium diatrizoate solutions.

A comparison of the cardiovascular responses to carotid injections of ionic and nonionic contrast media.

Selective injection of contrast media into the canine common carotid artery results in alterations in carotid flow, heart rate, and systemic arterial pressure. In this study the responses to injections of the nonionic agents metrizamide and iopamidol were compared to the responses to the ionic agents meglumine iothalamate, meglumine sodium diatrizoate, mannitol, and saline solution. Heart rate and pressure responses were smallest for metrizamide, greater for iopamidol, and greater still for the hypertonic ionic agents: responses were roughly correlated to agent osmolality. Carotid flow increased with all agents and was roughly proportional to the agent's osmolality. The exception was metrizamide which despite its lowest osmolality, produced a large increase in flow which was maintained much longer than for other agents. The total response to the nonionic agents was judged less severe than to the ionic agents; however, the responses to all agents were transient and not life threatening.

A comparison of the systemic responses to rapid intravenous injections of ioxilan, iohexol, and diatrizoate in rabbits.

Rapid intravenous injections of contrast media are used for angiocardiography, intravenous digital subtraction angiography (DSA), and rapid scan computed tomography procedures. These rapid intravenous injections have been shown to produce significant hemodynamic changes that appear related to contrast media osmolality. In this study the systemic responses to 2-second injections at a dose of 1.5 mL/kg were compared for a new nonionic agent, ioxilan (350 mgI/mL), and for iohexol (350 mgI/mL), meglumine/sodium diatrizoate (370 mgI/mL), and saline. Ioxilan has a lower osmolality and viscosity than iohexol and is formulated with a 3 mM sodium citrate as a buffer and anticoagulant. All of the test solutions produced statistically significant changes in arterial pressure and respiratory rate (P less than .05, Student's t-test). The decrease in arterial pressure seen with diatrizoate (20.1%) was significantly greater than the decrease seen with either ioxilan (10.2%) or iohexol (10.2%). All of the responses observed were transient and would not be of clinical concern in a healthy patient. Ioxilan, which contains the calcium binding agent, sodium citrate, and iohexol appear to cause less systemic effects then diatrizoate.

Cardiovascular responses to the intravertebral artery injection of hypertonic contrast media in the dog.

Central nervous system-mediated cardiovascular responses to contrast medium (CM) are believed the result of a vagal or of a sympatholytic response; these effects may be enhanced in the setting of dehydration. The purpose of this investigation was to evaluate neurally mediated effects of intravertebral artery CM injections on blood pressure (BP), heart rate (HR) and regional vascular resistances in euvolemic and dehydrated dogs. Animal preparation consisted of food and water ad libitum (n = 7) vs. 2.0 ml/kg i.m. furosemide and 48 hours thirsting (n = 7). During pentobarbital anesthesia BP, HR and renal and femoral blood flows were continuously monitored and meglumine iothalamate 60% (1 ml/kg) injected via a left vertebral artery catheter at 3 ml/sec; matched volume injections of normal saline served as control. Decreases in BP, HR and femoral and renal vascular resistances post CM injection were observed in the first 10 seconds before the CM had reached the systemic circulation. Significant decreases in both BP (-10.6 +/- 1.7%) and HR (-11.5 +/- 1.6%) post CM injection were noted with dehydration (n = 7). In the euvolemic dogs (n = 7) the decrease in HR (-7.3 +/- 2.0%) was significant but the decrease in BP (-3.9 +/- 2.4%) was not. The decrease in femoral vascular resistance was -22.7 +/- 9.0% in euvolemic dogs and -21.9 +/- 8.8% in dehydrated dogs. No significant changes were noted with the intravertebral artery injections of normal saline in control euvolemic and dehydrated animals. The early cardiovascular responses to CM suggest a direct action on the vasomotor center of the medulla. The effects on BP and HR are more severe in the dehydrated than in the euvolemic state.

The effects of gadolinium-DTPA and -DOTA on neural tissue metabolism.

Gadolinium DTPA and DOTA are being used extensively for imaging blood-brain barrier lesions. This study was performed to determine clinically relevant blood, cerebrospinal fluid (CSF), and neural tissue concentrations of these agents, and to determine if they alter neural tissue glucose metabolism. Bolus injections of 0.2 mmol Gd-DTPA/kg were made in rabbits, and blood, CSF, and neural tissue Gd concentrations were measured using atomic emission. Rat hippocampus slices were incubated for 6 hours in solutions of Gd-DTPA and Gd-DOTA, and effects on the production of carbon-14-labeled CO2 from glucose determined. Plasma concentrations reached a peak of 2.46 mmol at 1 minute postinjection, and dropped to 50% of peak in 6 minutes. The highest CSF concentration observed was approximately 0.1 mmol, and the mean lumbar cord concentration was approximately 8.5 mumol/g. Gd-DTPA and Gd-DOTA concentrations greater than 1.0 mmol caused significant increases in CO2 production. In areas of blood-brain barrier lesions, Gd-DTPA and Gd-DOTA may cause changes in tissue metabolism; however, in other areas it is much less likely.

Effects of radiopaque contrast media on calcium uptake and phosphatidylinositol metabolism in rat brain synaptosomes.

Radiographic contrast media (RCM) used in the subarachnoid space are associated with occasional adverse reactions. This study examines the possibility that RCM reactions are caused by interactions with the plasma membrane phosphatidylinositol (PI) second messenger system. Isolated nerve endings, known as synaptosomes, were produced from rat brain homogenates. The synaptosomes were then incubated with RCM to determine if 32Pi labeling of the PIs or the uptake of 45Ca were influenced in a manner consistent with known mechanisms. The RCM metrizamide, iopamidol, iodixanol, and iotrol (but not iohexol) increased the 32Pi labeling. Hyperosmolality produced large increases in phosphatidylinositol-4-phosphate (PIP) and phosphatidylinositol-4, 5,-bisphosphate (PIP2) labeling. In the non-depolarized state iodixanol, but not metrizamide or iohexol, caused a time-dependent increase in 45Ca uptake. Iodixanol, iohexol, and metrizamide also augmented the veratrine-stimulated uptake of calcium, but none of the RCM affected the uptake of Ca resulting from potassium depolarization. The increased 32Pi labeling of the PIs caused by RCM is not directly related to Ca uptake, because the direction of change is wrong. RCM perturbations of the plasma membrane may cause an inhibition of other membrane components and systems. Hyperosmolality also may cause inhibition of membrane components. It is not known if these effects are important in clinically observed RCM toxicity.

Iopamidol and neural tissue metabolism. A comparative in vitro study.

Metrizamide was the first water-soluble contrast medium with a neurotoxicity low enough to allow it to be used routinely in the entire subarachnoid space. However, neurologic complications are still observed in some patients following the use of metrizamide. The cause of this toxicity has not been established, but existing evidence suggests an interference with glucose metabolism. In previous studies, a depression in CO2 production in neural tissue slices was demonstrated when isotonic metrizamide was added but not isotonic iohexol. In addition to iohexol, there is another new, nonionic, monomeric, water-soluble CM, iopamidol, soon to be released for clinical use in the United States. Iopamidol, like iohexol, has shown fewer adverse reactions and seems to be safer for myelography than metrizamide. Direct comparative studies of iopamidol and iohexol are sparse and the cause of their toxicity is not yet understood. This study was performed to determine the effect of iopamidol on neural tissue glucose metabolism as compared with the effects of iohexol and metrizamide. Metrizamide decreased CO2 production in neural tissue slices by 23%. Iopamidol and iohexol did not produce significant depression. Moreover, this model could not demonstrate any significant difference between iopamidol and iohexol in direct comparisons. The new monomeric contrast media, iopamidol and iohexol, thus do not appear to interfere with glucose metabolism. Adverse reactions to these new media are most likely caused by other mechanisms.

Cerebral water content, blood flow and EEG changes after cardiac arrest in the dog.

Changes of cerebral water content, blood flow and cortical EEG following cardiac arrest (8-14 minutes) were studied in 14 mongrel dogs. With five hours of maintenance, changes in the water content both in grey and white matter were found to be insignificant. (Grey matter: control 78.68 +/- 2.62%; arrest 79.91 +/- 1.76%. White matter: control 66.66 +/- 4.10%; arrest 67.76 +/- 1.88%). Blood flow was measured using 15 micron microspheres labeled with Sr, 85 Ce141 and Yb.169 Flow in grey matter was decreased to 47% at 3 hours and 53% at 5 hours; while in white matter it was 67% at 3 hours and 75% at 5 hours from baseline. Deterioration of the cortical electrical activity was observed in all animals having an arrest of more than 8 minutes. In aminals having arrest of longer than 12 minutes there is either no return (isoelectric) or marked slowing of cortical electrical activity. From this and previous studies, it is concluded that with more than 8 minutes of cardiac arrest and up to 5 hours of maintenance there is impairment of cortical perfusion which is not associated with a significant increase in total water content. The lack of increase in total water content, however, does not mean there is no local swelling or edema such as in endothelial cells.

Tissue fluid shifts during renal arteriography with conventional and low osmolality agents.

The osmotic effects caused by conventional and low osmolality radiopaque agents have been studied in the isolated perfused canine kidney. Changes in vein flow, hematocrit, osmolality, and iodine content were measured at injection doses of 0.25 and 0.5 ml/kg (300 mgI/ml). Increases in osmolality and decreases in hematocrit were significantly greater with the conventional ionic monomer meglumine/sodium diatrizoate than with the low osmolality agents iohexol, iopamidol, and ioxaglate. The standard renal vein flow response for all agents was an increase (loss of renal water) followed by a decrease (gain of renal water). Diatrizoate produced the greatest increase in outflow at 0.25 ml/kg, but the differences between agents were not statistically significant. At the 0.5 ml/kg dose the differences in peak renal vein flow between agents were negligible. Renal vein iodine was highest with the dimer, ioxaglate and lowest with the diatrizoate. The nonionics iohexol and iopamidol produced essentially the same renal vein iodine levels and clearance. The new low osmolality agents have significantly less effect on osmolality and hematocrit and produce higher venous iodine levels than a conventional ionic monomer. The only difference between the low osmolality agents was the higher venous iodine seen with the dimer ioxaglate.

Calcium binding by radiopaque media.

This study quantified the binding of ionic calcium by contrast media with disodium edetate and trisodium citrate versus those with only calcium disodium edetate. First, calcium binding by sodium diatrizoate with calcium disodium edetate was measured using an ion-selective electrode at ionic strengths of .08, .16, and .80 molal. Significant binding of calcium was observed, and the probable reaction product is calcium chloride diatrizoate. Second, solutions were mixed containing Renografin 76 (or Hypaque 76) and NaCl at a physiologic ionic strength. The Renografin, which contains disodium edetate and trisodium citrate, caused significantly more binding than did the Hypaque. However, 60% of the drop in ionic calcium was observed with Hypaque and is related to the diatrizoate anion. The nonionic agent iopamidol produced no decrease in ionic calcium. Significant reductions in ionic calcium are produced by both the diatrizoate anion and by edetate and citrate additives.

The effects of media viscosity on hemodynamics in selective arteriography.

Radiographic contrast media used for arteriography are generally more viscous than plasma or blood; however, little consideration is given to the hemodynamic effects of contrast media viscosity. In this study, in vivo and in vitro injection of isotonic solutions of saline and polyvinylpyrrolidone, having viscosities from 0.8 to 26 centipoise, have been made. The results demonstrate that, when the viscous saline reaches the microcirculation, the resistance to flow increases. The viscous saline thus significantly decreases flow immediately after the injection. At that time the pressure in the artery equals aortic pressure, but the local vascular resistance is elevated because of the viscous material present in the arterioles. Viscous contrast media would cause similar hemodynamic changes during and immediately following an injection. The effects of contrast media hypertonicity, however, modify the viscosity-related changes shortly after the contrast media reaches the capillaries.

A comparison of the hemodynamic responses to metrizamide and meglumine/sodium diatrizoate in canine renal angiography.

Selective renal angiography causes a biphasic change in renal blood flow and vascular resistance. In this study, 5 ml of meglumine/sodium diatrizoate (288 mg I/ml, 1455 mosm/kg), metrizamide (290 mg I/ml, 593 mosm/kg), isontonic saline (287 mosm/kg) and hypertonic saline (1500 mosm/kg) were injected into the renal arteries of seven adult mongrel dogs to determine whether the minimum flow (or maximum resistance) was related to the osmolality of the injected agent. The maximum resistance response was significantly smaller for metrizamide (20 +/- 4%) and isotonic saline (19 +/- 2%) than for diatrizoate (36 +/- 6%) or hypertonic saline (50 +/- 7%). Hypertonic saline produced two distinct types of responses: the typical biphasic response or a severe immediate drop in flow. Thus the maximum resistance response was related to agent osmolality. The "injection artifact," or flow changes occurring during the injection, were different for the four agents, and these differences appeared correlated to agent viscosity. Although both contrast media caused relatively small changes in renal hemodynamics, metrizamide caused significantly smaller changes than meglumine/sodium diatrizoate.