Ubiquitin-proteasomal regulation of chromatin remodeler INO80 in the nucleus accumbens mediates persistent cocaine craving.

Neuroadaptations in the nucleus accumbens (NAc) underlie cue-induced cocaine craving that intensifies ("incubates") during abstinence and is believed to contribute to persistent relapse vulnerability. Changes in gene expression often govern perpetual behavioral abnormalities, but epigenetic plasticity during prolonged abstinence from drug exposure is poorly understood. We examined how E3 ubiquitin ligase TRIM3 dysregulates chromatin remodeler INO80 to mediate cocaine craving during prolonged abstinence. We found that INO80 expression increased in the NAc on abstinence day 30 (AD30) but not on AD1 following cocaine self-administration. Furthermore, TRIM3, which mediates degradation of INO80, was reduced on AD30, along with TRIM3-INO80 interaction. Viral-mediated gene transfer of INO80 or TRIM3 governed cocaine craving during prolonged abstinence. Lastly, chromatin immunoprecipitation followed by massively parallel DNA sequencing identified INO80-mediated transcriptional regulation of predicted pathways associated with cocaine plasticity. Together, these results demonstrate a novel ubiquitin-proteasomal-epigenetic mechanism by which TRIM3-INO80 mediates cocaine craving during prolonged abstinence.

The dendritic spine morphogenic effects of repeated cocaine use occur through the regulation of serum response factor signaling.

The nucleus accumbens (NAc) is a primary brain reward region composed predominantly of medium spiny neurons (MSNs). In response to early withdrawal from repeated cocaine administration, de novo dendritic spine formation occurs in NAc MSNs. Much evidence indicates that this new spine formation facilitates the rewarding properties of cocaine. Early withdrawal from repeated cocaine also produces dramatic alterations in the transcriptome of NAc MSNs, but how such alterations influence cocaine's effects on dendritic spine formation remain unclear. Studies in non-neuronal cells indicate that actin cytoskeletal regulatory pathways in nuclei have a direct role in the regulation of gene transcription in part by controlling the access of co-activators to their transcription factor partners. In particular, actin state dictates the interaction between the serum response factor (SRF) transcription factor and one of its principal co-activators, MAL. Here we show that cocaine induces alterations in nuclear F-actin signaling pathways in the NAc with associated changes in the nuclear subcellular localization of SRF and MAL. Using in vivo optogenetics, the brain region-specific inputs to the NAc that mediate these nuclear changes are investigated. Finally, we demonstrate that regulated SRF expression, in turn, is critical for the effects of cocaine on dendritic spine formation and for cocaine-mediated behavioral sensitization. Collectively, these findings reveal a mechanism by which nuclear-based changes influence the structure of NAc MSNs in response to cocaine.

Cost-of-illness of patients with lymphoedema.

BACKGROUND: Chronic lymphoedema is characterized by a continuous need for medical treatment, many comorbidities and impaired quality of life. In Germany, about 4.5 million patients are affected by lymphoedema. Thus, lymphoedema causes high direct and indirect costs, even more in case of complications such as erysipelas and ulcers. OBJECTIVE: The aim of this study was to determine the costs of illness of community lymphoedema patients living in the metropolitan area of Hamburg, Germany. METHODS: An observational cross-sectional study in patients with lymphoedema and combined lipolymphoedema of any origin was performed analysing direct and indirect costs for the patients, the statutory health insurance and society. RESULTS: In total, 348 patients (90.8% female) were examined and interviewed. The mean age of the patients was 57.3 ± 14.5 years. On average, the total costs per patient and year were € 5784, of which € 4445 (76.9%) were direct costs and € 1338 indirect costs. Within the direct medical costs, € 3796 were accounted for the statutory health insurances and € 649 for the patient. The main cost drivers were costs for manual decongestive therapy and disability costs. CONCLUSION: Chronic lymphoedema is associated with high direct and indirect costs. This community-based study is the first cost analysis of chronic lymphoedema and combined lipolymphoedema giving insights to economic impact of lymphoedema treatment. There is a high need for structured disease management programs in order to diagnose and treat lymphoedema early and to avoid complications, thus limiting socio-economic burden.

Restorative proctocolectomy: an example of how surgery evolves in response to paradigm shifts in care.

AIM: Surgical technique constantly evolves in response to the pressure of progress. Ileal pouch anal anastomosis (IPAA) is a good example. We analysed the effect of changes in practice on the technique of IPAA and its outcomes. METHOD: Patients undergoing primary IPAA at this institution were divided into three groups by date of the IPAA: those operated from 1983 to 1993, from 1994 to 2004 and from 2005 to 2015. Demographics, patient comorbidity, surgical techniques, postoperative outcomes, pouch function and quality of life were analysed. RESULTS: In all, 4525 patients had a primary IPAA. With each decade, increasing numbers of surgeons were involved (decade I, 8; II, 16; III, 31), patients tended to be sicker (higher American Society of Anesthesiologists score) and three-staged pouches became more common. After an initial popularity of the S pouch, J pouches became dominant and a mucosectomy rate of 12% was standard. The laparoscopic technique blossomed in the last decade. 90-day postoperative morbidity by decade was 38.3% vs 50% vs 48% (P < 0.0001), but late morbidity decreased from 74.2% through 67.1% to 30% (P < 0.0001). Functional results improved, but quality of life scores did not. Pouch survival rate at 10 years was maintained (94% vs 95.2% vs 95.2%; P = 0.06). CONCLUSION: IPAA is still evolving. Despite new generations of surgeons, a more accurate diagnosis, appropriate staging and the laparoscopic technique have made IPAA a safer, more effective and enduring operation.

Intra-ventral tegmental area microinjections of urotensin II modulate the effects of cocaine.

Although the peptide urotensin II (UII) has well studied direct actions on the cardiovascular system, the UII receptor (UIIR) is expressed by neurons of the hindbrain. Specifically, the UIIR is expressed by the cholinergic neurons of the laterodorsal tegmentum (LDTg) and the pedunculopontine tegmentum (PPTg). These neurons send axons to the ventral tegmental area (VTA), for which the PPTg and LDTg are the sole source of acetylcholine. Therefore, it was hypothesized that UIIR activation within the VTA would modulate reward-related behaviors, such as cocaine-induced drug seeking. Intra-VTA microinjections of UII at high concentrations (1 nmole) established conditioned place preference (CPP), but also blocked cocaine-mediated CPP (10 mg/kg). When rats received systemic sub-effectual doses of cocaine (7.5 mg/kg) with intra-VTA injections of 1 or 10 pmole of UII CPP was formed. Furthermore, the second endogenous ligand for the UIIR, urotensin II-related peptide, had the same effect at the 10 pmole dose. The effects of low doses of UII were blocked by pretreatment with the UIIR antagonist SB657510. Furthermore, it was found that intra-VTA UII (10 pmole) further increased cocaine-mediated (7.5 mg/kg) rises in electrically evoked dopamine in the nucleus accumbens. Our study has found that activation of VTA-resident UIIR produces observable behavioral changes in rats, and that UIIR is able to modulate the effects of cocaine. In addition, it was found that UIIR activation within the VTA can potentiate cocaine-mediated neurochemical effects. Therefore, the coincident activation of the UII-system and cocaine administration may increase the liability for drug taking behavior.

Substrate-limited co-culture for efficient production of propionic acid from flour hydrolysate.

Propionic acid is presently mainly produced by chemical synthesis. For many applications, especially in feed and food industries, a fermentative production of propionic acid from cheap and renewable resources is of large interest. In this work, we investigated the use of a co-culture to convert household flour to propionic acid. Batch and fed-batch fermentations of hydrolyzed flour and a process of simultaneous saccharification and fermentation were examined and compared. Fed-batch culture with substrate limitation was found to be the most efficient process, reaching a propionic acid concentration of 30 g/L and a productivity of 0.33 g/L*h. This is the highest productivity so far achieved with free cells on media containing flour hydrolysate or glucose as carbon source. Batch culture and culture with controlled saccharification and fermentation delivered significantly lower propionic acid production (17-20 g/L) due to inhibition by the intermediate product lactate. It is concluded that co-culture fermentation of flour hydrolysate can be considered as an appealing bioprocess for the production of propionic acid.

Juvenile and adult rats differ in cocaine reward and expression of zif268 in the forebrain.

Adolescents are more likely to experiment with and become addicted to drugs of abuse. A number of studies indicate that the developmental forebrain may be responsible for making adolescents vulnerable to the addictive properties of such drugs. The aim of this study was to first compare behavioral responses to novelty and cocaine between juvenile and adult rats and then compare levels of the immediate-early gene zif268 activation in several forebrain areas via in situ hybridization. We found that juveniles demonstrated higher locomotion scores and required a higher dose of cocaine than adults to establish a conditioned place preference. Additionally, at this higher dose, juvenile rats exhibited higher levels of zif268 mRNA in the prefrontal cortex compared with adults. A developmental effect for increased zif268 mRNA was also observed in the striatum and nucleus accumbens, but there was no interaction with the cocaine dose. These findings hold interesting implications for the study of the molecular mechanisms underlying juvenile drug addiction.

Clinical implications of acellular mucin pools in resected rectal cancer with pathological complete response to neoadjuvant chemoradiation.

AIM: Approximately 20% of rectal cancers treated with neoadjuvant chemoradiation achieve a pathological complete response (pCR), which is associated with an improved oncological outcome. However, in a proportion of patients with a pCR, acellular pools of mucin are present in the surgical specimen. The aim of this study was to evaluate the clinical implications of acellular mucin pools in patients with rectal adenocarcinoma achieving a pCR after neoadjuvant chemoradiation followed by proctectomy. METHOD: A single-centre colorectal cancer database was searched for patients with clinical Stage II and Stage III rectal adenocarcinoma who achieved a pCR (i.e. ypT0N0M0) after neoadjuvant chemoradiation followed by proctectomy between 1997 and 2007. Patients were categorized according to the presence or absence of acellular mucin pools in the resected specimen, and groups were compared. Patient demographics, tumour and treatment characteristics, and oncological outcomes were recorded. Primary outcomes were 3-year local and distant recurrences, and disease-free and overall survivals. RESULTS: Two hundred and fifty-eight patients with clinical Stage II or Stage III rectal adenocarcinoma were treated by neoadjuvant chemoradiation. Fifty-eight of these patients had a 58 pCR. Eleven of the 58 patients with a pCR had acellular mucin pools in the surgical specimen. The median follow up was 40 months. The groups were statistically similar with respect to demographics, chemoradiation regimens, distance of tumour from the anal verge, clinical stage and surgical procedure. No patient had local recurrence. Patients with acellular mucin pools had increased distant recurrence (21%vs 5%), decreased disease-free survival (79%vs 95%) and decreased overall survival (83%vs 95%) rates, although none of these differences was statistically significant. CONCLUSION: The presence of acellular mucin pools in a proctectomy specimen with a pCR does not affect local recurrence, but may suggest a more aggressive tumour biology.

Molecular mechanisms of psychostimulant-induced structural plasticity.

Drug addiction is characterized by persistent behavioral and cellular plasticity throughout the brain's reward regions. Among the many neuroadaptations that occur following repeated drug administration are alterations in cell morphology including changes in dendritic spines. While this phenomenon has been well documented, the underlying molecular mechanisms are poorly understood. Here, within the context of drug abuse, we review and integrate several of the established pathways known to regulate synaptic remodeling, and discuss the contributions of neurotrophic and dopamine signaling in mediating this structural plasticity. Finally, we discuss how such upstream mechanisms could regulate actin dynamics, the common endpoint involved in structural remodeling in neurons.

Subtotal colectomy for toxic and fulminant colitis in the era of immunosuppressive therapy.

OBJECTIVE: Prolonged use of immunosuppressive medication to avoid surgery is becoming more common in patients with inflammatory bowel disease, with severe or fulminant colitis. The effect of immunosuppression on postoperative outcomes was reviewed. METHOD: Patients undergoing subtotal colectomy (STC) for fulminant or toxic colitis from 1992 to 2006 were studied to define the effect of immunosuppression (IS) on postoperative complications (POCs). Patient characteristics, diagnosis, operative indication, details of surgery, use of IS, and POC's were reviewed and univariate and multivariate analysis was performed. RESULTS: Eighty-nine patients were studied (55 males). Seventy-two (91%) patients had fulminant colitis and 17 (20%) had toxic colitis. The preoperative diagnosis was ulcerative colitis in 74, indeterminate in 10, and Crohn's disease in five patients. Eighty-two (92%) patients were on some form of immunosuppression, and 14 had a perforation at surgery. Thirty-nine (43.8%) patients experienced a POC. There was no operative mortality. Univariate analysis identified perforation (P = 0.048) and length of surgery (P = 0.002) as predictive of POCs, while multivariate analysis failed to identify a predictor of complications. CONCLUSION: There was no association between immunosuppression and postoperative complications. Complications in this setting are a result of the severity of the inflammatory bowel disease.

Predictors of disease-free survival in rectal cancer patients undergoing curative proctectomy.

OBJECTIVE: To identify the factors that affect the disease-free survival (DFS) of rectal cancer patients. METHOD: Patients from an IRB approved rectal cancer database were reviewed (1990-2000). All patients underwent either abdominoperineal resection or low anterior resection using total mesorectal excision with curative intent. Univariate and multivariate analyses were performed to analyse the factors that influenced DFS. RESULTS: A total of 304 patients were reviewed (mean age 64, 52% male). Seventy-seven per cent of patients received neoadjuvant therapy (28.6% short-course radiation therapy (RT), 35.5% long-course RT, 12.5% chemo-RT). The radial margin was involved with tumour in 5.2% of patients (final pathology). The overall survival rate was 85.2% with a mean follow-up time of 33 +/- 26 months. The mean time to death was 34.8 +/- 26.8 months. Local recurrence (+/- distant recurrence) occurred in 4%. Anastomotic leaks occurred in 3.6% of patients. Overall pathologic stage, pathologic T stage, nodal status, the use of adjuvant chemotherapy, tumour fixation, involvement of the radial margin, the presence of mucin, and lymphatic and perineural invasion (PNI) were predictors of DFS by univariate analysis. Of note, anastomotic leaks and obstructing cancers did not influence DFS. Using multivariate analysis with backward elimination, overall pathologic stage, radial margin status, adjuvant chemotherapy, and PNI predicted the DFS. CONCLUSION: Major predictors of DFS in rectal cancer are the overall pathologic stage, adjuvant chemotherapy, radial margin status and PNI. Radial margin status may be a marker of tumour aggressiveness and should be considered in deciding on adjuvant chemotherapy.

Repeated social defeat stress-induced sensitization to the locomotor activating effects of d-amphetamine: role of individual differences.

RATIONALE: In this study, we sought to examine individual differences in stress-induced behavioral sensitization to d-amphetamine after repeated social defeat stress. In an effort to understand what mechanisms underlie stress-induced sensitization to d-amphetamine, we examined striatal gene expression of the dopamine receptor D(2). Additionally, we investigated if repeated social defeat was associated with changes in dendritic spine density in the hippocampus, prefrontal cortex, and nucleus accumbens of rats that exhibit stress-induced sensitization. METHODS: Male rats were classified into high responders (HR) and low responders (LR) based on their locomotor response to a novel environment. Then, rats were either handled as a control or defeated on four occasions by aggressive rats. Two weeks after the last defeat, animals were challenged with one of three doses of d-amphetamine and their locomotor activity was recorded. RESULTS: Non-defeated HR rats exhibited higher locomotor activity in response to d-amphetamine when compared to LR non-defeated rats. Fourteen days from the last repeated social defeat, LR rats and HR rats were behaviorally identical in response to acute injections of amphetamine. Furthermore, HR non-defeated rats had less D(2) mRNA expression in the nucleus accumbens core and dorsal striatum than do LR non-defeated rats. However, after repeated social defeat, HR and LR rats had identical D(2) mRNA expression in both the core and dorsal striatum. Finally, there were no changes in dendritic spine density in any of the brain areas examined in LR rats. CONCLUSION: Repeated social defeat abolishes individual differences in behavioral responses to d-amphetamine which may be due to a down-regulation of striatal dopamine D(2) receptors in LR rats.

Strictureplasty for obstructing small-bowel lesions in diffuse radiation enteritis--successful outcome in five patients.

INTRODUCTION: Complications from chronic radiation enteritis can lead to resection or bypass of large segments of intestine, placing the patient at risk for short-bowel syndrome. We have operated on five patients with complications of chronic radiation enteritis in the setting of limited intestinal reserve. In each case, strictureplasty was used as an adjunct to resection or bypass to treat short, relatively isolated radiation strictures with the goal of preserving intestinal length and avoiding dependence on parenteral nutrition. METHODS: There were four females and 1 male, mean age 57 (range, 45-71) years. Complications developed from 1 to 30 years after radiation therapy and all patients had undergone at least one prior laparotomy for complications of radiation enteritis. Four patients had resultant short bowel syndrome and were dependent on parenteral nutrition preoperatively. Indications for the present operations were chronic small-bowel obstruction (3 patients), enterocutaneous fistula and bowel obstruction (1 patient), and chronic small-bowel obstruction along with a rectovaginal fistula (1 patient). Details of the operative procedure, postoperative complications, and eventual weaning from parenteral nutrition were determined by review of the medical records. RESULTS: Strictureplasty was performed either alone (1 patient) or was accompanied by resection or bypass (4 patients). Postoperative complications developed in 3 patients and were comprised of pancreatitis (1), acute renal failure (1), and wound infection (1). There were no anastomotic leaks, reoperations, or deaths. All four patients on preoperative parenteral nutrition were successfully weaned postoperatively and were maintained on enteral nutrition at last follow-up (mean 42, range, 18-120 months). One patient developed recurrent small-bowel obstruction requiring reoperation ten years after the strictureplasty surgery. CONCLUSIONS: Strictureplasty may be an effective and safe tool to conserve intestinal length in certain highly selected patients with chronic radiation enteritis and small-bowel strictures, namely those with limited intestinal reserve where strictures are located within long segments of diseased bowel which, if resected or bypassed, would have significant nutritional or metabolic consequences. Strictureplasty is not indicated for the treatment of perforation, hemorrhage, fistula, or short segments of disease in patients with adequate intestinal reserve.

Safety and longterm efficacy of strictureplasty in 314 patients with obstructing small bowel Crohn's disease.

BACKGROUND: Since its introduction in the early 1980s, strictureplasty (SXP) has become a viable option in the surgical management of obstructing small bowel Crohn's disease. Questions still remain regarding its safety and longterm durability in comparison to resection. Precise indications and contraindications to the procedure are also not well defined. STUDY DESIGN: A retrospective review of all patients undergoing SXP for obstructing small bowel Crohn's disease at the Cleveland Clinic between 1984 and 1999 was conducted. A total of 314 patients underwent a laparotomy that included the index SXP The total number of SXPs performed was 1,124, with a median of two (range 1 to 19) per patient. Sixty-six percent of patients underwent a synchronous bowel resection. Recurrence was defined as the need for reoperation. Followup information was determined by personal interviews, phone interviews, or both. RESULTS: The overall morbidity rate was 18%, with septic complications occurring in 5% of patients. Preoperative weight loss (p = 0.004) and older age (p = 0.008) were found to be significant predictors of morbidity. The surgical recurrence rate was 34%, with a median followup period of 7.5 years (range 1 to 16 years). Age was found to be a significant predictor of recurrence (p = 0.02), with younger patients having a shorter time to reoperation. CONCLUSIONS: This large series of patients with longterm followup confirms the safety and efficacy of strictureplasty in patients with obstructing small bowel Crohn's disease. The 18% morbidity and 34% operative recurrence rates compare favorably with reported results of resective surgery. Caution should be used in patients with preoperative weight loss, because they experienced higher complication rates. Although young patients seem to follow an accelerated course, SXP remains indicated as part of an overall strategy to conserve intestinal length.

Effect of rotational speed on the breakage of nickel-titanium rotary files.

Nickel-titanium 0.04-tapered rotary files were evaluated for breakage at different rotational speeds in semicircular bovine bone simulated root canals of identical size and radius for each file size group tested. The bovine bone canals had a radius of curvature of 5 mm and a canal width equivalent to the D1 diameter of the file plus 0.04 mm. Profile instrument #3, #4, and #5 were tested at 150, 250, and 350 rpm. A contra-angle electric handpiece was mounted on an Instron machine that was set to deliver a constant downward speed of 5 mm/min. The electric handpiece and Instron machine were activated until the files broke. The amount of file tip penetration into the semicircular bovine bone canal was measured in degrees with a protractor from a radiographic image taken of the file inside the bone model. Greater degrees of tip penetration indicated greater resistance to breakage. Statistical analysis was done and the results indicated that there was a significant difference for all file sizes in the extent of file tip penetration before breakage. In the rotation range between 150 and 350 rpm the greatest extent of penetration occurred at 150 rpm. This study concluded that 0.04 taper nickel-titanium rotary file breakage is less likely to occur if the files are rotated at lower speeds.

Hepatic tumor radioembolization in a rat model using radioactive rhenium (186Re/188Re) glass microspheres.

PURPOSE: The aim of this study was to fully characterize newly developed radioactive rhenium glass microspheres in vivo by determining their biodistribution, stability, antitumor effect, and toxicity after hepatic arterial injection in a syngeneic rat hepatoma model. The dose response of the tumors to increasing amounts of radioactive 186Re and 188Re microspheres was also determined. METHODS AND MATERIALS: Rhenium glass microspheres were made radioactive by neutron activation and then injected into the hepatic artery of Sprague-Dawley rats containing 1-week-old Novikoff hepatomas. The biodistribution of the radioactivity and tumor growth were determined 1 h and 14 days after injection. RESULTS: Examination of the biodistribution indicated a time-dependent, up to 7-fold increase in Novikoff hepatoma uptake as compared to healthy liver tissue uptake. After 14 days, the average T:L ratio was 1.97. Tumor growth in the rats receiving radioactive microspheres was significantly lower than in the group receiving nonradioactive microspheres (142% vs. 4824%, p = 0.048). Immediately after injection, 0.065% of the injected radioactivity was measured in the thyroid; it decreased to background levels within 24 h. CONCLUSION: Radioactive rhenium microspheres are effective in diminishing tumor growth without altering hepatic enzyme levels. The microspheres are safe with respect to their radiation dose to healthy tissue and radiation release in vivo and can be directly imaged in the body with a gamma camera. Furthermore, rhenium microspheres have an advantage over pure beta-emitting microspheres in terms of preparation and neutron-activation time. In sum, this novel radiopharmaceutical may provide an innovative and cost-effective approach for the treatment of nonresectable liver cancer.

Vasopressin selectively increases 5-fluorouracil uptake by colorectal liver metastases following hepatic artery bolus infusion.

BACKGROUND: Poor drug uptake secondary to the hypovascularity of colorectal liver metastases may partially explain their limited response to hepatic artery chemotherapy. Vasoconstrictors can increase tumor perfusion but their effect on drug uptake has not been well-characterized. The aim of this study was to determine whether vasopressin could selectively increase tumor uptake of 5-FU. MATERIALS AND METHODS: A syngeneic rat model of colorectal liver metastases was used. Control group rats underwent a 60-s hepatic artery infusion of 14C-5-FU (30 mCi/150 microL). Treatment group rats had vasopressin (60 mIU/kg, dose determined in pilot study) added to the 14C-5-FU infusion. Mean systemic arterial pressure was minimally affected. Tumor:liver (T/L UR) and tumor center:periphery (C/P UR) 5-FU uptake ratios were determined using quantitative autoradiography techniques. Differences in tumor size (< or > 4 mm) and location (superficial vs deep) were accounted for. Statistical analysis was by repeated measures ANOVA (P = 0.01 significant). RESULTS: A total of 161 tumors in 18 rats was analyzed. T/L URs were significantly higher in the treatment group compared to controls for tumors <4 mm (1.72 +/- 0.14 vs 0.70 +/- 0.16, P <0.001), tumors >4 mm (0.99 +/- 0.15 vs 0.45 +/- 0.16, P = 0.01), deep tumors (1.17 +/- 0.13 vs 0.68 +/- 0.15, P = 0.01), and superficial tumors (1.54 +/- 0. 15 vs 0.47 +/- 0.17, P <0.001). C/P URs did not differ significantly between the groups. CONCLUSIONS: The results of this study show that vasopressin selectively enhances the uptake of 5-FU by colorectal liver metastases in a rat model of hepatic artery infusion. This may represent a promising strategy for improving tumor response rates and patient survival.

Perfusion to colorectal cancer liver metastases is not uniform and depends on tumor location and feeding vessel.

Future effective therapies for hepatic metastases may depend on a better understanding of perfusion to these tumors. The purpose of this project was to define blood flow to colorectal cancer liver metastases using quantitative autoradiography (QAR). Liver tumors were established in F1 hybrids of WF x BN rats by intrasplenic injection of a DMH-induced rat colon adenocarcinoma. Rats underwent laparotomy 4-5 weeks later and [14C]iodoantipyrine (a radiotracer) was infused via the hepatic artery (HA) or portal vein (PV). Livers were harvested, frozen in liquid nitrogen, and sectioned at 20 microns through all tumors. QAR compared optical density of cross sections of tumors to surrounding normal liver tissue. Tumor:liver perfusion ratios (T/L PR) and tumor center:tumor periphery perfusion ratios (C/P PR) were calculated. All groups were analyzed with regard to tumor location and size. Seventy-seven tumors in 6 rats in the HA infusion group were analyzed; 74 tumors in 8 rats in the PV group were analyzed. Statistical analysis was by repeated measures analysis of variance. Mean HA T/L PR = 0.97 +/- 0.13, mean PV T/L PR = 0.25 +/- 0.11. Mean HA T/L PR for deep tumors was 1.38 +/- 0.17 and for superficial tumors was 0.57 +/- 0.15 (P < 0.01). Mean HA T/L PR for small tumors was 1.09 +/- 0.12 and for large tumors was 0.86 +/- 0.21 (P = 0.27). Mean PV T/L PR for deep tumors was 0.27 +/- 0.14 and for superficial tumors was 0.24 +/- 0.15 (P = 0.71). Mean PV T/L PR for small tumors was 0.31 +/- 0.15 and for large tumors was 0.20 +/- 0.14 (P = 0.54). Mean HA C/P PR = 1.15 +/- 0.15, mean PV C/P PR = 0.81 +/- 0.14 (P = 0.06). Mean HA C/P PR for small tumors was 1.37 +/- 0.16 and for large tumors was 0.92 +/- 0.17 (P = 0.01). Mean PV C/P PR for small tumors was 0.78 +/- 0.18 and for large tumors was 0.72 +/- 0.13 (P = 0.71). HA perfusion of tumors is significantly higher than PV perfusion compared to surrounding normal liver tissue. HA perfusion varies significantly depending on tumor location. There was a trend toward HA perfusion to the tumor center being slightly greater than to the periphery whereas the reverse was seen for PV perfusion. Tumor size did not affect overall perfusion but it did affect regional HA tumor perfusion.