Diagnostic accuracy and tumor-targeting kinetics of complete versus fragmented 99mTc-labeled anti-carcinoembryonic antigen antibodies: an intraindividual comparison.

The goal of this study was to intraindividually compare a complete versus a fragmented, directly 99mTc-labeled, monoclonal anti-carcinoembryonic antigen (CEA) antibody, with respect to their antigen-targeting kinetics, sensitivity, and diagnostic accuracy in patients with CEA-expressing tumors. Twenty-five patients were investigated with the 99mTc-labeled anti-CEA IgG1 BW 431/26 and the F(ab')2/Fab' fragment mixture F023C5 within 7 days. For quantitative analysis, the region of interest technique was applied to planar scans, whole-body scans, and single photon emission computed tomography slices 10 min to 48 h postinjection (PI). Final correlations were performed according to the histopathology after surgery or biopsy. Earliest tumor detection was possible with complete IgG1 4 h PI (52% of finally positive lesions). Twenty-four- or even 48-h scans were necessary in 48% of finally positive lesions; tumor detection with fragments was possible in 17% at 1 h PI and in 94% at 4 h PI. With both monoclonal antibodies, in 35%, single photon emission computed tomography was necessary for tumor detection. Absolute antibody uptake in tumor lesions was higher with complete monoclonal antibodies than with fragments. The sensitivity of fragments was higher in detecting primary tumors, local recurrences, and lymph node metastases. For detection of liver metastases, sensitivity was also higher for fragments than for IgG (87 versus 73%), but in scintigraphically positive lesions, tumor:background ratios were significantly lower with fragments (1.26 +/- 0.12 versus 1.70 +/- 0.32; P < 0.01). Therefore, fragments seem to be more suitable for earlier detection of lesions known for their good vascularization, vascular permeability, and antigen accessibility, such as local recurrences, lymph node metastases, and peritoneal carcinomatoses. In liver metastases (high interstitial pressure, low vascular leakage), sensitivity of fragments is higher, but their rapid serum and whole-body clearance lead to a lower absolute antibody uptake, with the consequence of significantly lower tumor:background ratios than with IgG.

Reduction of the renal uptake of radiolabeled monoclonal antibody fragments by cationic amino acids and their derivatives.

The renal uptake of radiolabeled antibody fragments and peptides is a problem in radioimmunodetection and radioimmunotherapy, especially with intracellular retained radiometals. The aim of this study was to develop suitable methods to reduce this kidney uptake. BALB/c mice or nude mice bearing the human GW-39 colon carcinoma xenograft were given i.p. injections of basic amino acids or a range of different basic amino acid derivatives, amino sugars, as well as cationic peptides. The effect of these agents on the biodistribution of Fab' and F(ab')2 fragments of different mAbs radiolabeled with 99mTc, 188Re, 111In, 88Y, or 125I was studied. Tumor and organ uptake was determined and compared to untreated mice. The kidney uptake of Fab' fragments was reduced 5-6-fold in a dose-dependent manner as compared to untreated controls. The uptake in all other organs, as well as the tumor, was unaffected. A similar reduction in renal retention was seen for all other intracellularly retained isotopes, as well as for F(ab')2 fragments. D- and L-isomers of lysine were equally effective whether given i.p. or p.o. D-glucosamine was effective, but its N-acetyl derivative was not. Basic polypeptides (e.g., poly-L-lysine) were also effective; their potency increased with increasing molecular weight. HPLC of the urine taken from treated animals showed the excretion of intact Fab', in contrast to mostly low-molecular-weight metabolites in the control group. These studies indicate that a variety of basic compounds is capable of inhibiting the tubular reabsorption of peptides and proteins, thus lowering the kidney uptake of antibody fragments significantly. On a molecular basis, the effect seems to essentially rely on the presence of a positively charged amino group. By reducing renal retention of antibody fragments, their role as imaging and therapeutic agents may be expanded.

Reduction of renal uptake of monoclonal antibody fragments by amino acid infusion.

UNLABELLED: The renal uptake of radiolabeled antibody fragments and peptides presents a problem in radioimmunodetection and therapy, compromising lesion sensitivity, especially with intracellularly-retained isotopes. Previously, we showed that cationic amino acids and their derivatives are capable of significantly reducing kidney uptake in animals. We report our initial clinical results of successful renal uptake reduction in five patients who underwent cancer radioimmunodetection with 99mTc-anti-CEA Fab' fragments. METHODS: The patients were infused with two liters of a commercially-available nutritive amino acid solution (containing approximately 2.25 g/liter lysine-glutamate and 2.50 g/liter arginine), whereas 75 control patients received the same volume of saline (quantification of organ and tumor kinetics from conjugate whole-body views by ROI technique). RESULTS: The renal uptake in the amino acid group was significantly lower (p<0.05) than in the control group (11.1 +/- 2.0% injected dose versus 17.7 +/- 7.0% injected dose at 24 hr postinjection), whereas the uptake of all other organs remained unaffected. Gel filtration chromatography of the urine taken from amino-acid-treated patients showed that a significantly higher amount of excreted activity was bound to intact Fab' (53% of excreted activity) in contrast to only less than 10% in the control group. CONCLUSION: The renal uptake of monoclonal antibody fragments in patients can be reduced significantly by amino acid infusion, even at considerably lower doses than those that were safe and effective in animals. As was found in animals, the mechanism seems to rely on an inhibition of the re-absorption of tubularly-filtered proteins by the proximal tubule cells. These results encourage further clinical trials to lower the renal uptake experienced in radioimmunodetection, as well as in therapeutic trials with antibody fragments and peptides.

Comparison of complete versus fragmented technetium-99m-labeled anti-CEA monoclonal antibodies for immunoscintigraphy in colorectal cancer.

UNLABELLED: The goal of this study was to intraindividually compare complete versus fragmented directly labeled 99mTc monoclonal anti-CEA antibody with respect to antigen targeting and tumor uptake kinetics, sensitivity and diagnostic accuracy in colorectal cancer patients. METHODS: Twenty-five patients were investigated with 99mTc-labeled anti-CEA IgG1 BW 431/26 and the F(ab')2/Fab' fragment mixture F023C5 within 7 days. For quantitative analysis, an ROI technique was applied to planar scans, whole-body scans and SPECT slices 10 min to 48 hr postinjection. Final correlations were performed according to histology after surgery or biopsy. RESULTS: Earliest tumor detection with complete IgG1 was possible 4 hr postinjection (52% of finally positive lesions); imaging at 24 hr or even 48 hr was necessary in 48%. Tumor detection with fragments was possible in 17% at 1 hr postinjection and in 94% at 4 hr postinjection. In 35%, SPECT was necessary for tumor detection with both MAbs. Absolute antibody uptake in tumor lesions was higher with complete MAbs than with fragments. CONCLUSIONS: Lesions known for their good vascularization, vascular permeability and antigen accessibility were detected earlier and with higher sensitivity with fragments than with complete MAbs due to faster background clearance despite lower absolute antibody uptake.

Nonoperative management of adult blunt splenic trauma: a 15-year experience.

From January 1989 to December 1993, 40 consecutive adult patients with ruptured spleen from blunt trauma were examined. Fourteen patients (35%) were taken to the operating room initially because of hemodynamic instability and generalized peritoneal signs. Twenty-six patients (65%) were hemodynamically stabilized at admission and treated by nonoperative management, which included strict bed rest, intensive care unit monitoring, frequent physical examinations, and serial hematocrits. Four patients failed nonsurgical management and required a splenectomy, three because of clinical deterioration within 1 to 3 days of admission; the fourth patient had recurrent bleeding 7 days after injury. The patients in the operative group had a greater severity of injury with a mean injury severity score of 26.6, four deaths, and mean transfusion requirements of 3.7 to 4.0 units of blood, compared to a mean injury severity score of 14.6, one late death from cardiac causes, and average blood requirement of 0.4 to 0.7 units. Splenic injury grading averaged 3.2 in the surgical group (grade 1, one patient; grade 2, four patients; grade 3, eight patients; grade 4, no patients; and grade 5, one patient) and differed significantly from that of the nonoperative group (mean = 2.4; grade 1, 12 patients; grade 2, seven patients; grade 3, six patients; grade 4, two patients; and grade 5, no patients). Recent ultrasound analysis of select grades I to IV has shown excellent resolution or repair of these injuries. This report extends our series from 1978 to 1993 and includes 144 adult patients sustaining blunt splenic ruptures. Seventy-nine (55%) of these patients were treated nonsurgically. Seven patients (of 80) failed nonoperative management and required interval laparotomy, representing a 91 per cent success rate. Follow-up on more than 90 per cent of the patients has shown no sequelae from their splenic injuries. We conclude that adult patients with splenic injuries from blunt trauma who are hemodynamically stable and are without abdominal findings requiring celiotomy can be safely managed by a nonoperative approach.

Hypothermia-induced coagulopathy during hemorrhagic shock.

A porcine model of hemorrhagic shock was used to study the effect of hypothermia on hemodynamic, metabolic, and coagulation parameters. The model was designed to simulate the events of severe blunt injury with hemorrhage occurring initially, to a systolic blood pressure of 30 mm Hg, followed by simultaneous hemorrhage and crystalloid volume replacement, followed by cessation of hemorrhage and blood replacement. Half of the animals were rendered hypothermic by external application of ice, and half remained normothermic. There was seven pigs in each group. Two deaths occurred in each during the hemorrhage phase. The hypothermic pigs demonstrated larger reduction in cardiac output than normothermic pigs. Volume replacement in the normothermic group restored cardiac output to baseline values. In the hypothermic group, cardiac output remained depressed despite volume replacement. Prothrombin times and partial thromboplastin times showed significantly more prolongation in the hypothermic group. Furthermore, this was not corrected by replacement of shed blood in the hypothermic group, as was seen in the normothermic group. We conclude that when shock and hypothermia occur together, their deleterious effect on hemodynamic and coagulation parameters are additive. The effects of hypothermia persist despite the arrest of hemorrhage and volume replacement. Thus, it is necessary to aggressively address both shock and hypothermia when they occur simultaneously.

Nonoperative management of blunt splenic injury in adults 55 years and older: a twenty-year experience.

The nonoperative management of splenic injury secondary to blunt trauma in older patients remains controversial. We have reviewed our experience from January 1978 to December 1997 with selective nonoperative management of blunt splenic injury in adults 55 years and older. Criteria for nonoperative management included hemodynamic stability with any transient hypotension corrected using less than 2,000 cm3 crystalloid infusion, a negative abdominal physical examination ruling out associated injuries, and a blood transfusion requirement of no more than 2 units attributable to the splenic injury. During the study period, 18 patients over age 55 with radiographic confirmation of a splenic injury met the above criteria for nonoperative management. Their mean age was 72 years (range 56-86), and 13 of the 18 were female (72%). The mean Injury Severity Score was 15 (range 4-29), with the mechanism of injury equally divided between automobile crashes (9) and falls (9). During a similar time period, 15 patients 55 years or older with splenic injury composed an operative group; these patients did not differ with respect to age (mean 68 years), sex (60% female), or mechanism of injury. CT scans of 8 patients managed nonoperatively were available and graded using the American Association for the Surgery of Trauma classification, with a mean score of 2.3 (range 2-3). Eight of the 18 nonsurgical patients received blood transfusions. None of the 18 patients who met the criteria for nonoperative management "failed" the protocol, and none were taken to the operating room for abdominal exploration. Two patients (11%) died of associated thoracic injuries after lengthy hospital stays, one at 10 days and one at 24 days. We conclude from our data that nonoperative management of blunt splenic injury in patients age 55 years and older is indicated provided they are hemodynamically stable, do not require significant blood transfusion, and have no other associated abdominal injuries.

99mTc-labelled anti NCA-95 antibodies in prosthetic heart valve endocarditis.

A 54-y old women with earlier replacement of the mitral and aortic valves and clinical signs of localized endocarditis was studied with 99mTc-labelled anti NCA-95 antibody. Whereas echocardiographic findings were negative, increased radionuclide uptake was observed left parasternal over the mitral valve as a sign of prosthetic valve endocarditis. This result could be confirmed by a similar study with leukocytes labelled in vitro with 111In-oxine.

99mTc-trimethyl-BrIDA scintigraphy in HIV-related cholangiopathy.

A HIV-infected 37-year-old man with diffuse mid-abdominal pain and elevated liver enzymes was sequentially studied by sonography, computed tomography (CT), 99mTc-trimethyl-BrIDA scintigraphy and endoscopic retrograde cholangiopancreatography (ERCP). CT and sonography did not lead to a final diagnosis. Cholescintigraphy showed signs of cholecystitis and sclerosing cholangitis with intra- and extrahepatic bile duct dilatation. These findings could be confirmed by ERCP, rendering HIV-associated cholepathy probable. Cytomegalovirus infection was demonstrated by polymerase chain reaction from bile fluid and the presence of cryptosporidia infection in a histology specimen isolated by ERCP. Therefore, biliary scintigraphy seems promising for screening for HIV-associated cholangio- and cholecystopathy, being less invasive and less bothering for the patient than ERCP.

Tc-99m DTPA perfusion scintigraphy and color coded duplex sonography in the evaluation of minimal renal allograft perfusion.

AIM: The clinical impact of perfusion scintigraphy versus color coded Duplex sonography was evaluated, with respect to their potential in assessing minimal allograft perfusion in vitally threatened kidney transplants, i.e. oligoanuric allografts suspected to have either severe rejection or thrombosis of the renal vein or artery. METHODS: From July 1990 to August 1994 the grafts of 15 out of a total of 315 patients were vitally threatened. Technetium-99m DTPA scintigraphy and color coded Duplex sonography were performed in all patients. For scintigraphic evaluation of transplant perfusion analog scans up to 60 min postinjection, and time-activity curves over the first 60 sec after injection of 370-440 MBq Tc-99m diethylenetriaminepentaacetate acid (DTPA) were used and classified by a perfusion score, the time between renal and iliac artery peaks (TDiff) and the washout of the renogram curve. Additionally, evaluation of excretion function and assessment of vascular or urinary leaks were performed. By color coded Duplex sonography the perfusion in all sections of the graft as well as the vascular anastomoses were examined and the maximal blood flow velocity (Vmax) and the resistive index (RI) in the renal artery were determined by means of the pulsed Doppler device. Pathologic-anatomical diagnosis was achieved by either biopsy or post-explant histology in all grafts. RESULTS: Scintigraphy and color coded Duplex sonography could reliably differentiate minimal (8/15) and not perfused (7/15) renal allografts. The results were confirmed either by angiography in digital subtraction technique (DSA) or the clinical follow up. CONCLUSION: In summary, perfusion scintigraphy and color coded Duplex sonography are comparable modalities to assess kidney graft perfusion. In clinical practice scintigraphy and color-coded Doppler sonography can replace digital subtraction angiography in the evaluation of minimal allograft perfusion.

Positive I-123-MIBG-scintigraphy in osteosarcoma.

I-123-MIBG scintigraphy has become a standard imaging technique in the detection of neuroendocrine or neurocrest derived tumors, especially neuroblastoma and pheochromocytoma. We report on a positive I-123-MIBG uptake in a pediatric osteosarcoma patient and demonstrate, that unusual results still occur with this established imaging method.

Ascaridoid nematodes and associated lesions in stomachs of subadult male northern fur seals (Callorhinus ursinus) on St. Paul Island, Alaska: (1987-1999).

Stomachs from subadult male northern fur seals (SAMs) (Callorhinus ursinus) (n = 5,950) from St. Paul Island, Alaska, were examined from 1987 to 1999 for lesions and parasites. On gross examination of these stomachs, parasite nodules were evident in 92% of the stomachs and active and healing ulcers were found in 14% and 10%, respectively. Prevalence of nematodes from 1987 to 1997 was 88% for 5,700 SAMs for which numbers of parasites were estimated but not identified to the genus level. All nematodes recovered from 250 SAMs examined in 1998 (n = 124; 99% infected) and in 1999 (n = 126; 91% infected) were identified and counted. Prevalences in 1998 and 1999 were 5% and 0% for Anisakis spp., 52% and 18% for Contracaecum spp., and 96% and 89% for Pseudoterranova spp., respectively.

Prevalence of selected species of internal parasites in equids at necropsy in central Kentucky (1995-1999).

A survey to determine current prevalence of several species of endoparasites in equids (n=350) at necropsy was conducted at the Livestock Disease Diagnostic Center in central Kentucky (1995-1999). Thelazia lacrymalis were found in 42% of the 1- to 4-year olds (n=132), which was the only age group examined for these parasites. Five- to 30-year olds (n=157), examined for Onchocerca spp. worms/lesions, had a prevalence of 24%. In > or =1-year olds (n=324), the infection rate for Gasterophilus intestinalis was 12% for second instars and 14% for third instars and for Gasterophilus nasalis was 2% for second instars and 2% for third instars. For Anoplocephala perfoliata (n=268 equids), prevalence was 52%. Data were compiled for the equids according to breed, age, sex, month of necropsy, and number of parasites. Arterial lesions caused by migrating Strongylus vulgaris larvae were observed in a low number (3 of 52) of equids. Specific examination for Parascaris equorum revealed that 46% of 13 weanlings and 10% of 20 older horses were infected. Anoplocephala magna were found in one of the weanlings. Compared to previous studies (about 15-25 years ago) in Kentucky, the present survey indicated the genera Onchocerca and Gasterophilus greatly declined but Thelazia, Anoplocephala, and Parascaris did not.

Antimicrobial resistance in zoonotic enteric pathogens.

Antimicrobial resistance is a zoonotic health threat. As in humans, the use of antimicrobial agents in animals results in the emergence and spread of resistant bacteria. Resistant bacteria from animals may be passed to humans via the food chain or direct animal contact, and may result in resistant infections. Increasing prevalence of resistance to antimicrobial agents such as fluoroquinolones and third-generation cephalosporins, which are important for the treatment of infections caused by enteric pathogens, has significant public health implications. Controlling the spread of resistance requires the collaboration of several partners, including the farming, veterinary, medical, and public health communities.

Tension pneumopericardium during laparoscopy for trauma.

A case involving a patient with multiple stab wounds to the thoracoabdomen is reviewed. Laparoscopy was employed to determine peritoneal penetration. Hemodynamic collapse occurred secondary to tension pneumopericardium, which resulted from a 15 mm Hg pneumoperitoneum. The relevant literature is reviewed.

Is there still a need for Tc-99m DMSA renal imaging?

Scintigraphy with Tc-99m MAG3 is, to date, the most commonly used technique for evaluating separate renal function (SRF). In this study, the performance of this technique is compared to Tc-99m DMSA. A total of 37 patients with various kidney disorders (12 children and 25 adults) underwent both Tc-99m DMSA and Tc-99m MAG 3 scintigraphy. In children and adults of normal weight the correlation coefficient between the two methods was 0.99 (P < 0.001), whereas in individuals who were more than 10% overweight according to Broca, or who had abnormal anatomical positions of the kidneys, the correlation coefficient was 0.82 (P < 0.05). Scintigraphy with Tc-99m DMSA was more accurate in renal parenchyma lesions. These results indicate that Tc-99m DMSA scintigraphy is preferable for the evaluation of SRF in patients who are more than 10% overweight, or have abnormal positions of the kidneys.