The influence of prior total body irradiation on the tissue distribution of mouse lymphoma/leukemia.

The effect of a single dose of 10 Gy X rays on the distribution of subsequently injected mouse lymphoma/leukemia cells was studied. The organ distribution of an acute myeloid leukemia (A46) was not affected by prior (90 days) administration of 10 Gy X rays. A T-cell lymphoblastic lymphoma/leukemia (A55) and a B-cell lymphoblastic lymphoma/leukemia (A31) produced enhanced infiltration of the lung when 10 Gy of total body irradiation (TBI) was given 90 days before the tumor cells. The infiltration was predominantly in the peribronchiolar and perivascular spaces. Enhancement was not seen in any tissues other than lung. The possibility is raised that in those acute lymphoblastic leukemia patients whose treatment includes TBI, residual circulating cells may be encouraged to infiltrate the lung.

Autoradiographic study of tritium-labeled misonidazole in the mouse.

The localization of tritiated misonidazole metabolites in a number of normal tissues in the mouse is reported from autoradiography. The labeled misonidazole was injected at 750 or 75 mg/kg body weight (Rel. Sp. Act. 74 and 740 MBq/mg respectively). The grain count ratio, parenchyma:stroma, for selected tissues was: liver (centrilobular zone) 13; meibomian gland (acini) 68, (duct) 116; esophagus (keratinized layer) 61; enamel organ 17. It is concluded that there are a number of tissues which will accumulate MISO metabolites although they may not all be hypoxic.

Tissue distribution of 14C- and 3H-labelled misonidazole in the tumor-bearing mouse.

The retention of labelled misonidazole (MISO) was measured in a range of normal tissues in the mouse 24 hr after the intravenous injection of [14C]MISO (ring labelled) and [3H]-MISO (side-arm labelled). For [14C]MISO the 24 hr tissue retention, in order of the highest to the lowest levels (excluding pathways of excretion), was esophageal epithelium, liver, foot pad, eyelid, lung, subcutaneous lung tumor (A110), esophageal wall, uterus, eye ball, blood, salivary gland, spleen, voluntary muscle, pancreas, inguinal fat. It was assumed that the 14C represented MISO metabolite(s) bound to macromolecules. An approximately similar pattern was observed for [3H]MISO, but a higher percentage of the injected activity per gram of tissue was retained, probably due to the presence of tritiated water in the tissues. It has generally been assumed that significant levels of MISO binding are restricted to hypoxic tissues, for example tumors, but the present results show that significant levels of binding can also occur in apparently normoxic tissues. The explanation is put forward that this binding may be due to local high levels of nitroreductase capacity.

Retention of misonidazole in normal and malignant tissues: interplay of hypoxia and reductases.

Tritiated misonidazole (MISO) was injected intravenously (iv) into mice bearing five different tumors. At 24 hr the tumors were removed for analysis of bound MISO, and at the same time three normal tissues were removed (liver, labial gland, and esophagus). The labial gland and esophagus were selected as representatives of sebaceous and stratified squamous tissues, respectively, tissues that in many parts of the body retain high levels of MISO. The tumors used were early transplant generations of spontaneous mouse tumors of mammary gland, lung, and liver. The levels (mean +/- SEM) of MISO at 24 hr for the five tumors and three normal tissues, expressed as percentage of the injected dose per gram of tissue were: A110 (0.03 +/- 0.007), A114 (0.103 +/- 0.04), A150 (0.09 +/- 0.005), A167 (0.037 +/- 0.012), A168 (0.122 +/- 0.0016), esophagus (0.507 +/- 0.09), labial gland (0.125 +/- 0.013), liver (0.11 +/- 0.004). Histochemical examination of the normal tissues showed reductase activity in all three. In the esophagus and labial gland, inhibition of the reaction by dicumarol indicated the likely presence of the reductase DT-diaphorase which, by 2-electron transfer, can be expected to reduce MISO to a reactive, locally-binding metabolite, even in the presence of oxygen.

Nonuniformity of tumor dose in radioimmunotherapy.

The conventional approach to calculating tumor radiation dose from internally administered radioisotopes is by the MIRD schema. The raw input data for such dose calculations is obtained by immunoscintigraphic methods, PLANAR or SPECT imaging. Limitations in the spatial resolution of these techniques can lead to a considerable underestimate of the gross variation in tumor dose. The use of radiolabeled monoclonal antibodies for therapy can result in large nonuniformities in tumor dose. This paper discusses how antibody distribution can influence the energy deposition in the nuclei of target cells. Heterogeneity of antibody binding will lead to an expected decrease in the effectiveness of the radiation delivered. However, enhanced cell killing is possible if the radiolabeled Ab binds to the cell surface membrane and may be further enhanced if the Ab is internalized. Calculations are presented for two cases: (a) a three-dimensional random packing arrangement of cells as a model of the astructural nondifferentiated form seen in some tumors, and (b) differentiated carcinoma of the colon with the cells in tubules. Results for the magnitude of the mean energy deposition to individual cell nuclei from: (a) cell membrane bound 211At, 199Au, 131I, and 90Y-labeled Abs, and (b) a uniform distribution of these sources, as a function of internuclear distance for the two histologies are presented. Energy deposition in tumor cell nuclei from membrane bound radiolabeled antibody may be several times greater than estimated with the assumption of a uniform source distribution.

Internal dosimetry using data derived from autoradiographs.

Cancer therapies based on administered radionuclides require accurate information on tumor dose. One of the major factors influencing the distribution of absorbed-dose characteristics is the uniformity of the radiolabel distribution in tissue. To study the effect of nonuniformities, we used image analysis techniques to measure automatically the coordinates of autoradiographic grains (sources) and cell nuclei in cut sections from three different tumors, following treatment with radiolabeled antibodies. The spatial distribution data of sources and cell nuclei from these tumor sections were assessed and the pattern of energy deposition in the cell nuclei calculated, assuming that each autoradiograph grain corresponded to a source of the alpha emitter astatine-211 (211At) or the beta emitter yttrium-90 (90Y). The distribution of deposited energy obtained for the real grain distributions was compared to the distribution assuming a locally uniform source distribution, i.e., simulating grain count averaging as produced by a microdensitometric method within a 100 x 100 microns 2 frame size (frame averaging), and a uniform distribution across the entire section (section averaging). The results show first that when the grain distribution is uniform, the average dose within the section is an adequate estimate of the dose to the cell nuclei. Second, when the grain distribution is nonuniform, the distribution of doses to the cell nuclei is significantly less when calculations use the measured grain coordinates, or frame averaging, than when section averaging is used. Third, when the sources are located on or in the cells, both frame and section averaging produce underestimates of the dose to the cell nuclei.

Treatment of the murine lymphoma A31 with intravenous, sterilized, 114mIn-loaded A31 cells.

The effect on a mouse B-cell lymphoma (A31) of intravenously (i.v.) injected, sterilized, A31 lymphoma cells loaded with [114mIn]oxine was examined. The treatment of the B-cell lymphoma was started 14 days after the i.v. injection of 10(2) viable cells. The [114mIn]oxine-bearing gamma-ray sterilized A31 cells were injected at two dose levels either with 37 kBq on days 15, 22 and 27 (total dose 110 kBq) or 74 kBq on days 15, 16, 17, 22 and 27 (total dose 370 kBq). The smaller amount (110 kBq) of 114mIn activity did not extend the survival of mice when compared with non-treatment controls but the greater amount (370 kBq) produced a significant extension in survival. This survival time was longer than that produced by 370 kBq [114mIn]oxine without carrier cells, lethal total body irradiation (with bone marrow rescue), splenectomy at day 14 or a single injection on day 14 of a maximum tolerated dose of vincristine sulphate. The increase in survival time was thought to arise mainly from 114mIn held by spleen macrophages. The accumulated spleen dose by 7 days after the fifth of the five injections of 74 kBq was 167 Gy. At this dose level the spleen was hypoplastic and the red cells, white cells and platelets in the peripheral blood were severely, though not permanently, suppressed.

Relative concentration of astatine-211 and iodine-125 by human fetal thyroid and carcinoma of the thyroid in nude mice.

The concentrations of 211At and 125I were measured in various tissues in nude mice bearing xenografts of human thyroid tissue (fetal and malignant). The relative concentration of the two halogens was obtained at 4 and 24 h after injection. Samples were taken of the host blood, muscle and thyroid gland and the grafted tissues. The mouse thyroid concentrated 125I more efficiently than 211At but the human grafts concentrated both halogens about equally.

Distribution of injected monoclonal antibody in lymphoma-infiltrated spleen.

Specific and non-specific antibody was injected into mice with lymphoma-infiltrated spleens in order to assess the distribution with both time and with extent of tumour infiltration. The specific antibody (MRC OX7) bound to the Thy 1.1 antigen on the lymphoma cells (A120). There was evidence that the diffusion of MRC OX7 deeply into the tumour was hindered by competitive binding to the tumour cells immediately surrounding the supplying blood vessels. In some circumstances this situation persisted to 24 h, after which time the antibodies were being cleared from the host in significant amounts.

Aggressive fluid resuscitation following intestinal ischemia-reperfusion in immature rats prevents metabolic derangements and down regulates interleukin-6 release.

We have recently shown improved survival following intestinal ischemia-reperfusion in a model that utilized aggressive crystalloid resuscitation sufficient to eliminate reperfusion-induced cardiovascular instability. The aims of this study were to determine whether the salutary effects associated with this regimen were due to: 1) prevention of systemic metabolic derangements; 2) attenuation of secondary organ injury; or 3) modulation of the systemic immune response. Under anesthesia, 4-week-old (65-85 g) male Sprague-Dawley rats (N = 63) received crystalloids at either 15 or 65 ml.kg-1.h-1 intravenously and were subjected to 90 min of superior mesenteric artery occlusion followed by 90 min of reperfusion (IR15, IR65) or time-matched sham (SH) operation (SH15, SH65). Results indicate that inadequate fluid resuscitation following intestinal IR was associated with significant serum hyperkalemia and hyperphosphatemia, acute renal insufficiency, and enhanced serum interleukin-6 levels. Maintenance of cardiovascular stability with aggressive fluid resuscitation was associated with an attenuation of these alterations. Therefore, the prevention of circulatory shock and the attenuation of distant organ injury and inflammatory response are associated with improved survival when an aggressive crystalloid resuscitation regimen is applied after intestinal ischemiareperfusion in immature rats.

Effects of continuous inhalation exposure of rats to radon and its progeny at various levels of dose and dose rate: interim results.

Studies of rats at Harwell and CEA [Monchaux et al., Radiat. Res. 152 (Suppl.), S137-S140, 1999] are currently in progress to determine the factors affecting the risk of induction of lung tumors after exposure to radon and radon progeny. Knowledge of the effect of dose, dose rate and characteristics of the aerosol on lung tumor induction in rats may be used to improve estimates of risk from domestic exposure. At Harwell, three studies are in progress, studying the effect of dose, dose rate, and dose rate at low total exposures. Approximately 2000 adult male rats have been exposed. A small number of rats were taken to determine deposition in the respiratory tract and the early effects of exposure on cell proliferation and nuclear aberrations. The remaining animals have been held for their life span. To date 65% of the animals in the first study have been examined. Current results (for 421 rats) suggest that exposure to radon and radon progeny causes elevated incidences of both benign and malignant lung tumors. These findings are based on incomplete tumor incidences. Competing causes of death may affect the results, and full statistical analysis is required before firm conclusions can be drawn about the effect of dose and dose rate.

Effects of chronic inhalation of dimethyl ether in the rat.

Dimethyl ether (DME) is a colourless gas with an ethereal odour. It is used mainly as a liquid refrigerant and an aerosol dispersant. Little or no data exist on the toxicology of this material. In the present study, groups of male and female rats were exposed to 0.02%, 0.2% and 2% v/v of DME in air, 6 h/day, 5 days/week for 30 weeks. At the end of the study the high-dose level male rats showed a significant reduction on liver weight compared with the control group; this was accompanied by raising SGPT levels. In high-dose female rats there was no significant effect on liver weight but the SGPT levels were raised above control values. No histological abnormalities were observed in the liver or in any other organ.

Further experiments to study whether localised fission fragment irradiation of rat lung causes tumours.

Male albino rats inhaled an aerosol of 235UO2 (mass median aerodynamic diameter = 2.8 micrometers and geometric standard deviation = 1.6). Approximately 20 h or 7 d post-inhalation the rats were exposed briefly to 10(12) slow neutrons cm-2 in a nuclear reactor, causing the retained 235UO2 particles of approximate mass 40 or 400 micrograms to emit fission fragments which irradiated the lungs. The mean absorbed doses from the fission fragments were either 80 ot 800 cGy approximately and in addition the lungs were exposed to a background of alpha-rays throughout the rats' life-time from the retained 235UO2 which gave mean doses of about half that from the fission fragments. The animals were kept for their life-time and killed when they became moribund. Malignant tumours were found in the lungs (squamous cell carcinoma and adenocarcinoma) which were probably induced by the alpha-rays rather than the fission fragments. Because of insufficient numbers of animals in the experimental groups, however, some statistical uncertainty exists as to whether the fission fragments were in fact less effective than the alpha-rays per unit absorbed dose in causing malignant tumours of the lung.

Early postoperative nutritional support using the serosal tunnel jejunostomy.

A silicone rubber serosal tunnel jejunostomy for postoperative nutritional therapy was placed in 38 patients who had major operations. A dilute, chemically defined diet was begun within 48 hours of surgery and an attempt made to advance it slowly to full strength by the fifth day. No catheter-related complications occurred. Intravenous fluid therapy was shortened to less than three days in 11 (29%) patients. Only 17 (45%) patients tolerated full-strength feedings within the protocol time. Three (8%) patients depended on their tube feedings for over 30 days and the need for parenteral nutrition was avoided. Of six septic patients, four had complete intolerance of the diet; two of these developed massive gastric hypersecretion. Serum albumin was a statistically significant indicator of whether a patient could tolerate tube feedings. No patient with an albumin less than 3 g/dl tolerated full-strength feedings and the pded. Of six septic patients, four had complete intolerance of the diet; two of these developed massive gastric hypersecretion. Serum albumin was a statistically significant indicator of whether a patient could tolerate tube feedings. No patient with an albumin less than 3 g/dl tolerated full-strength feedings and the patients with albumin greater than 4 g/dl had no problems. Postoperative feeding utilizing the serosal tunnel jejunostomy is technically safe, but feeding difficulties can be anticipated in those patients who are septic or severely malnourished; these are the patients whose nutritional needs are the greatest. The greatest benefits accrue to those patients who are in need of long-term nutritional support. We recommend routine placement of these catheters in major operations.

Spinal anesthesia reduces the hazard of apnea in high-risk infants.

General anesthesia in premature babies is associated with a significant risk of life-threatening apnea. Spinal anesthesia in the high-risk infant is simple, safe, and effective, but the incidence of apnea with its use has not been previously determined. The total absence of apnea in 84 high-risk infants suggests that surgery below the umbilicus under spinal anesthesia can safely be performed on an outpatient basis in preterm infants or babies with a history of apnea. Ketamine as an adjunctive agent adds no apparent risk. The technique is relatively easy, surgery is not compromised, and parental acceptance is high.

Latissimus-sparing thoracotomy in the pediatric patient: a valuable asset for thoracic reconstruction.

The traditional posterolateral thoracotomy involves division of the latissimus dorsi muscle (LD). While the division results in no functional disability, it does negate the potential for possible future thoracic reconstruction if required in individual cases (eg, bronchopleural fistula, empyema, etc). A latissimus-sparing thoracotomy (LST) mobilizes the muscle dorsad and does not compromise the operation. Thus, the ipsilateral LD can be used when chest wall reconstruction is required. This option has been used frequently for adults; however, its use in children has not been extensively documented. Microvascular anastomoses for a contralateral LD free-flap may be tenuous in the small vessels of the child; thus, reconstruction using the ipsilateral LD could be beneficial and safer. The feasibility of LST has not been established with regard to the chest of the child. The authors present three pediatric thoracic cases that illustrate the value of this procedure, and discuss different situations in which latissimus-sparing thoracotomy is advantageous.

Surgical management of infantile (ectopic) ureteroceles: report of a modified approach.

Since 1970, our experience in managing 22 patients (24 renal units) with infantile (ectopic) ureteroceles suggests that no single procedure is universally applicable. Certain general principles, however, guide management strategy. First, preservation of the upper pole moiety is successful if there is functioning renal parenchyma on IVP (9 cases with one failure). Second, when extirpation is required, total ureterectomy-ureterocelectomy is unnecessary (13 cases with no reoperations specifically for stump extirpation). Third, urinary tract infections are fairly common in the first postoperative year (4 of 16 patients), being more common in children with common sheath ("double barrel") reimplantations. This review of our experience often showed the primary procedure to be long and difficult with significant blood loss. Although it did not occur in this series, devascularization of the lower pole ureter remains a danger. Therefore, a two-stage procedure was developed to obviate these problems. In the last 4 patients (5 renal units) in this series, the ureteroceles were first incised endoscopically. Six weeks later, reimplantation or upper pole nephrectomy-partial ureterectomy was performed. Adequate early decompression of the ureterocele resulted in less operative time and blood loss (average 27.5 cc for upper pole nephrectomy) at the subsequent procedure. We now prefer this method, especially in very young or compromised patients, although the follow-up time is inadequate to recommend it generally.

Silastic catheterization of the axillary vein in neonates: an alternative to the internal jugular vein.

The axillary vein is a suitable alternative to the jugular venous system for tunnelled silastic catheterization in neonates, and should be included in the armamentarium of the surgeon who treats neonates. It is technically easy and is comparable to the internal jugular vein in terms of complications. Proper positioning of the catheter tip can sometimes be problematic, but without a resultant increase in morbidity or mortality.

Obstructive jaundice associated with polysplenia syndrome in an older child.

Polysplenia syndrome includes malrotation and various forms of heterotaxy. Associated with this and malrotation are extrahepatic biliary anomalies. Actual obstruction, other than in associated biliary atresia, is extremely rare, and rarer still in older children. An 11-year-old girl presented with obstructive jaundice, malrotation, and heterotaxy, which were found in association with common bile duct anomalies and intermittent common bile duct obstruction. This case illustrates that the differential diagnosis of obstructive jaundice, even in older children, should include congenital anomalies, and that biliary anomalies should be considered in cases of malrotation and heterotaxy.

Care-giver evaluation of anti-gastroesophageal reflux procedures in neurologically impaired children: what is the real-life outcome?

Although the pediatric surgical literature is replete with reports of the success of operations for gastroesophageal reflux, postoperative complications are being reported with increasing frequency for the neurologically impaired subpopulation. Because a large portion of a care-giver's life is involved in attending to a neurologically impaired child, parental satisfaction with the outcome of these operations should be an important consideration when the use of such procedures is contemplated. The purpose of the present study was to assess the impact of antireflux operations with respect to care-giver opinions regarding the procedure. The authors retrospectively reviewed 25 charts (of 13 girls and 12 boys; age range, 3 months to 18 years) and documented (through survey results) perceived child well-being, objective care requirements, and overall care-giver satisfaction with the procedure. Results indicate there was significant improvement in feeding indexes, care-giver perception of the child's comfort, and quality of life postoperatively. Moreover, there was significant improvement in the care-givers' attitudes regarding their child, including the level of frustration in caring for the child, and the parents' overall quality of life. Care-givers also believed that the operation's result was about or better than what they had expected. In conclusion, the study documents care-giver satisfaction with antireflux procedures. Postoperatively, child care is easier and the quality of time spent with the child is better. The impression of better quality of life postoperatively for a neurologically impaired child may be the greatest success in this sometimes frustrating endeavor.