Ionizing radiation potentiates the antitumor efficacy of oncolytic herpes simplex virus G207 by upregulating ribonucleotide reductase

BACKGROUND: Replication-competent herpes simplex virus-1 (HSV-1) mutants have an oncolytic effect on human and animal cancers. The aim of this study was to determine whether G207, an HSV-1 mutant, can be combined with ionizing radiation (IR) to increase antitumor activity while decreasing treatment-associated toxicity. METHODS: This study was performed by using G207, a replication-competent HSV-1 mutant deficient in viral ribonucleotide reductase (RR) and the gamma(1)34.5 neurovirulence protein. The antitumor activity of G207 or IR was tested against HCT-8 human colorectal cancer cells in vitro and in an in vivo mouse subcutaneous tumor model. RESULTS: We demonstrated that G207 has significant oncolytic effect on HCT-8 cells in vitro in a cytotoxicity assay and in vivo in a mouse flank tumor model and that these effects are improved with low-dose IR. We further illustrated that the increased tumoricidal effect is dependent on the up-regulation of cellular RR by IR measured by a functional bioassay for RR activity. Chemical inhibition of RR by hydroxyurea abrogates the enhanced effect. In contrast to G207, R3616, the parent virus of G207 that expresses functional RR, does not exhibit enhanced oncolysis when combined with IR. CONCLUSIONS: These data encourage clinical investigation of combination radiation therapy and HSV oncolytic therapy.     

Toward further expansion of the organ pool for adult liver recipients: splitting the cadaveric liver into right and left lobes

BACKGROUND: Current methods of living donor right lobe transplantation can be expanded for use in the cadaveric setting. The aim of this study is to discuss alternative methods for the management of large-for-size cadaveric livers and determine the feasibility of splitting these organs into left and right hemi-livers using similar techniques to those used in the living donor setting. METHODS: The indication for an in situ right-left split procedure was an offer of a large liver for a small recipient with a recipient-donor ratio of greater than 1.5. A total of three livers were split. Mean donor age was 33.3 (range, 22-40) years. Mean weight was 118 (range, 90-150) kg. All donors were without significant medical history and were hemodynamically stable, with normal liver function and short hospital stay. Mean duration of the procurement procedure was 235 (range, 210-270) min. Mean cold ischemia time was 8.5 hr. Mean recipient weight was 58.3 kg, and mean donor to recipient weight ratio was 2.0 (1.6-2.6). United Network for Organ Sharing statuses at the time of transplantation were 1 (n=1), 2A (n=1), and 2B (n=4). RESULTS: Immediate graft function was seen in five recipients. Delayed nonfunction was identified in one recipient of a left lobe, who did not undergo transplantation because of sepsis that resulted in death at 30 days. A second mortality occurred in a left lobe recipient, from a fungal brain abscess at 90 days. Complications related to the split included bile leaks in two patients, one necessitating operative revision. CONCLUSIONS: Splitting of livers from appropriate brain-dead donors into right and left lobes is technically and logistically feasible. The large-for-size organ provides a more substantial amount of liver tissue to each of the adult recipients, which may result in a greater graft to recipient weight ratio than the current standard that is used in the living donor grafting. The importance of this variable will need to be studied, because it may positively impact on the ability of the reduced-size graft to withstand donor-related organ system stress and injury, which is associated with brain death and the inevitable longer period of cold preservation.     

Differences in the effects in the newborn piglet of various nonsteroidal antiinflammatory drugs on cerebral blood flow but not on cerebrovascular prostaglandins

To characterize the role of prostaglandins (PG) in the regulation of basal cerebral blood flow (CBF) in the newborn, we determined the effects of four nonsteroidal antiinflammatory drugs, indomethacin (3 mg/kg, n = 8 and 10 mg/kg, n = 5), aspirin (65 mg/kg, n = 6), ibuprofen (30 mg/kg, n = 8), and naproxen (15 mg/kg, n = 6), on CBF, cerebral metabolism, and cerebrovascular PG in conscious 1- to 3-d-old piglets. Drugs and vehicle (n = 8) were injected i.v., and measurements were made 5 min before and 20 and 60 min after injections. Neither the vehicle nor any of the nonsteroidal antiinflammatory drugs exerted significant effects on mean arterial blood pressure and on blood gases and pH. All four drugs, with the exception of indomethacin at the lower dose (3 mg/kg), decreased PG to nearly undetectable levels within 20 min; the low dose of indomethacin caused a small decrease (18-32%) in PG at 60 min. However, the effects of these agents on CBF were diverse. CBF increased after the administration of aspirin, decreased to almost the same extent after both low and high doses of indomethacin, and did not change after the administration of ibuprofen and naproxen. Cerebral metabolic rate for oxygen was increased by aspirin but was unaltered by the other drugs. The data suggest that PG may not play a critical role in the regulation of basal CBF in the newborn animal and that certain nonsteroidal antiinflammatory drugs may have additional actions unrelated to the inhibition of PG synthesis.     

Cavoportal hemitransposition in liver transplantation

Over the last decade a large number of patients with portal vein thrombosis have undergone successful liver transplantation. In most of these patients, simple modifications in vascular reconstruction techniques are adequate. However, anastomosis of the donor portal vein may not be possible in the presence of extensive portal and superior mesenteric venous thrombosis and in the absence of any other large tributary of the portal venous system. Cavoportal hemitransposition has been described as a salvage technique under these circumstances. We report a 43-year-old patient who underwent such a procedure and remains well 1 year later. We review the literature and discuss the implications of cavoportal hemitransposition.     

Effects of protein-calorie malnutrition on transplacental kinetics of aminoisobutyric acid in rats.

In order to find out if inefficient transport of amino acids contributes to a decrease in fetal weight during maternal malnutrition, we injected [14C]- and [3H]-labelled aminoisobutyric acid (AIB), respectively, in the mother and its fetuses and determined its transplacental kinetics on day 20 of gestation in rats fed a 21 per cent (control) or a low (5 per cent) protein diet. Rats fed a low protein diet consumed significantly less food than did the rats fed a control diet and thus suffered from protein-calorie malnutrition. A low protein diet led to a significant (P less than 0.05) decrease in maternal and fetal volume of distribution of AIB, a decrease in the clearance of AIB from the mother to the fetus and an increase in the time required for the fetal plasma AIB concentration following maternal injection to exceed the maternal plasma AIB concentration. The clearance of AIB from the fetus into the mother or to outside (e.g. amniotic fluid) was not altered by protein deficiency. It is concluded that a decrease in the efficiency of the placenta to deliver amino acids to the fetus may be a contributing factor in fetal growth retardation during maternal protein malnutrition.     

Prolonged, pregnancy-related pure red cell aplasia; a case report.

We describe the clinical course of a patient with pregnancy-related, acquired, pure red cell aplasia (PRCA). The course of PRCA was prolonged and ultimately responded only to corticosteroids. It did not recurr over 4 years of observation despite another gestation, and no other cause for PRCA could be detected during this long period.     

The prevalence and characteristics of colorectal neoplasia in acromegaly

An increased prevalence of colorectal neoplasia has been reported in acromegalic patients, and recommendations have been made for early colonoscopic screening and regular surveillance. This assumption, however, is frequently drawn from studies using selected control populations. To clarify colonoscopic management in these patients, we undertook a 2-center prospective screening colonoscopy study in 122 acromegalics (age range, 25-82 yr). In the absence of ideal age-matched controls, we calculated prevalence rates of occult adenocarcinomas and adenomas in the general population using cumulative data in the published literature from 8 autopsy studies (model 1, n = 3,559) and 4 screening colonoscopy studies (model 2, n= 810), applying linear regression models. Of the 115 patients with complete examinations, adenocarcinomas were discovered in 3 (2.6%), and at least 1 adenoma was found in 11, giving an overall prevalence of neoplasia of 12% (14 of 115). Prevalence rates for age bands 30-40, 40-49, 50-59, 60-69, and 70+ yr were 0%, 8%, 12%, 20%, and 21%, respectively. Compared with the 2 control models, the prevalence of occult colorectal cancer was not significantly increased (acromegalics vs. models 1 and 2, 2.6% vs. 2.3% and 0.9%), nor was there an increase in the prevalence of adenomas in any age band. Pathological characteristics showed some differences, in that adenomas in acromegalics tended to be right sided (68% vs. 57% and 56%), larger (for > or =10 mm, 27% vs. 13% and 9%), and of advanced histology (for tubulovillous, 27% vs. 4% and 22%). No associations were found between the presence of colonic neoplasia and the duration of disease, total GH exposure, cure status, and serum insulin-like growth factor I. This study has failed to demonstrate an increased prevalence of neoplasia in acromegalic patients compared with the expected prevalence in the general population and questions the need for an aggressive colonoscopic screening policy.