Localized dispersal and recruitment in great barrier reef corals: the helix experiment.

To examine the problem of how far coral larvae disperse from their natal reef, coral recruitment densities were experimentally determined at distances up to 5 kilometers from a small, relatively isolated platform reef, Helix Reef, on the central Great Barrier Reef for 7 months. High concentrations of recruits, accounting for up to 40 percent of all recruitment, were found downstream of the reef in areas of high water residence time, suggesting that near-field(proximal) circulation has a profound influence on dispersal and recruitment of coral larvae. Coral recruitment declined logarithmically with distance from the reef, decreasing by an order of magnitude at radial distances of only 600 to 1200 meters. On an ecological time scale, advective dispersal of semipassive marine larvae with relatively short planktonic lives(minimally days) may be extensive, but success of recruitment is highly limited. Through evolutionary time, sufficient dispersal occurs to ensure gene flow to reef tracts hundreds or possibly thousands of kilometers apart. In the short term, however, coral reefs appear to be primarily self-seeded with respect to coral larvae.

Clinical pharmacology of hepatic arterial infusions of 5-bromo-2'-deoxyuridine.

This investigation was undertaken to determine the pharmacokinetic parameters relevant to hepatic arterial (HA) infusion of 5-bromo-2'-deoxyuridine (BrdUrd) and to ascertain the maximum tolerated dose and related toxicities of BrdUrd administered as a 14-day HA infusion. In the pharmacokinetic study, 6 patients received a 2-h i.v. infusion (to steady-state) of BrdUrd at each of 5 escalating dose rates (10 to 160 mg/kg/day) with simultaneous blood sampling for BrdUrd levels from HA and hepatic venous catheters. Dose dependent HA and hepatic venous drug levels, total body clearance, hepatic extraction, and estimated regional exposure advantage were determined. The total body clearance of BrdUrd was high and dose rate dependent, falling from 3340 ml/min with a 10-mg/kg/day infusion to 2180 ml/min at a 160-mg/kg/day dose rate. Hepatic extraction was high and dose rate dependent as well, declining from 80% extraction at 10 mg/kg/day to 68% at 160 mg/kg/day. The calculated estimate for the exposure advantage achievable with HA as compared with i.v. infusion reflects the dose rate dependence of total body clearance and hepatic extraction and decreases from a 70-fold advantage at 10 mg/kg/day to a 30-fold advantage at 160 mg/kg/day. In the Phase I study aimed at determining the maximum tolerated dose, successive groups of 3 patients were administered continuous HA infusions for 14 days at escalated BrdUrd dose rates (5, 10, 15, 25, and 35 mg/kg/day) in order to ascertain dose-limiting toxicity. The maximum tolerated dose of BrdUrd for a 14-day continuous HA infusion was found to be 35 mg/kg/day with reversible thrombocytopenia as the sole dose-limiting toxicity. Skin and other toxicities were infrequent, minor, reversible, and non-dose dependent. No hepatic toxicity was detected despite direct drug infusion into the liver. The high total body clearance and hepatic extraction of BrdUrd substantiate its administration via the hepatic artery as a means to achieve higher exposure with intrahepatic tumors than can be obtained by systemic administration. Despite higher hepatic exposures, no hepatic toxicity was noted, and readily reversible systemic toxicity (thrombocytopenia) was dose limiting for the 14-day continuous HA infusion. Thus, HA infusion of the potent radiosensitizer BrdUrd is both pharmacokinetically rational and well tolerated.

Effects of hepatic arterial yttrium-90 microsphere administration alone and combined with regional bromodeoxyuridine infusion in dogs.

Brachytherapy by embolization with radiotherapeutic microspheres following intraarterial infusion of a radiosensitizer represents an attempt to combine several selective modalities into a more potent, focused attack on regionally confined tumors. In pursuit of this goal, we examined the ability of foxhounds with surgically implanted hepatic arterial (HA) delivery systems to tolerate a clinically relevant dosage of HA yttrium-90 (Y-90) by microsphere administration either alone or preceded by a 28-day constant HA infusion of either 5-bromo-2'-deoxyuridine (BUDR) or a control solution. Five dogs received BUDR (10 mg/kg/day) and five a control buffer infusion for 28 days immediately prior to the administration of Y-90-coated 15 micron resin microspheres (equivalent of 5000 rads to the entire liver) to each dog on day 31. In all animals, blood counts, bilirubin, amylase, appetite, weight, and behavior remained unchanged. Dogs receiving the microspheres after buffer infusion alone exhibited no hepatic enzyme alanine aminotransferase or alkaline phosphatase elevation. Alanine aminotransferase and alkaline phosphatase levels both rose during the third week of BUDR infusion, and while subsequent microsphere administration further increased enzyme levels, these levels had largely normalized by necropsy on day 82. At necropsy, the type and degree of hepatic toxicity among the animals receiving radioactive microspheres was comparable to that previously described in patients receiving external beam hepatic irradiation at conventional doses (2000-3000 rads). Also noted was a radiation-induced cholecystitis (due in large part to the gallbladder's total reliance on the hepatic artery for blood supply). One resin microsphere dog exhibited a small quantity of microspheres in the lungs causing focal radiation-induced granulomas suggesting the need to assess shunting of microspheres through the liver in clinical studies. Thus, HA Y-90 microspheres with BUDR can produce acceptable, nonlethal, and tolerable toxicities in this dog model suggesting that clinical studies of this combination are not likely to be contraindicated by synergistic toxicity. Although HA BUDR did not contribute significantly to the toxicity of the Y-90 microspheres, HA BUDR by itself administered uninterrupted for 4 weeks may, like HA FUDR (clinically), cause chemical hepatitis/cholangitis. The unexpected fragmentation of the resin spheres (albeit without myelosuppression) has led us to begin studies with a recently developed nondisruptible glass microsphere (ThereSphere) in which the Y-90 is part of the glass matrix and cannot leach.(ABSTRACT TRUNCATED AT 400 WORDS)

Treatment of primary hepatobiliary cancers with conformal radiation therapy and regional chemotherapy.

PURPOSE: To develop more effective regional therapy for patients with unresectable primary hepatobiliary cancer using concurrent conformal radiation therapy and intraarterial hepatic (IAH) fluorodeoxyuridine (FdUrd). PATIENTS AND METHODS: Twenty-six patients with unresectable, nonmetastatic primary hepatobiliary cancer were treated with concurrent IAH FdUrd (0.2 mg/kg/d) and conformal hepatic radiation therapy (1.5 to 1.65 Gy per fraction twice per day). The total dose of radiation administered to the tumor depended on the fraction of normal liver excluded from the high-dose volume. All patients were assessed for toxicity, hepatobiliary relapse, and survival; 17 patients were assessable for response (eight had cholangiocarcinoma not assessable by computed tomographic [CT] scan and one progressed distantly during treatment). The median potential follow-up duration was 27 months. RESULTS: Whole-liver radiation was administered to six patients with diffuse hepatocellular carcinoma (HCC). Eleven patients with localized HCC and nine with cholangiocarcinoma received focal radiation to a dose of 48 to 72.6 Gy. An objective response for assessable patients was observed in 11 of 11 patients treated with focal radiation, but only one of six patients treated with whole-liver radiation. Whole-liver radiation accounted for five of seven patients with > or = grade 3 toxicity and four of six local treatment failures. Two patients had nonfatal radiation hepatitis. The median survival duration for patients with localized hepatobiliary cancer was 19 months, while patients with diffuse HCC had a median survival duration of 4 months. The rate of actuarial freedom from hepatobiliary progression in patients with localized disease was 72% at 24 months. CONCLUSION: These findings suggest that three-dimensional planned focal liver radiation and IAH FdUrd can produce a high, durable response rate and an encouraging median survival duration in patients with nondiffuse, unresectable primary hepatobiliary cancer.

Agglutination of single catalyst particles during fluid catalytic cracking as observed by X-ray nanotomography.

Metal accumulation at the catalyst particle surface plays a role in particle agglutination during fluid catalytic cracking.

Noninsulinoma pancreatogenous hypoglycemia: a novel syndrome of hyperinsulinemic hypoglycemia in adults independent of mutations in Kir6.2 and SUR1 genes.

In adults, endogenous hyperinsulinemic hypoglycemia is almost invariably due to insulinoma. In these patients with insulinoma, neuroglycopenic episodes exclusively after meal ingestion and negative 72-h fasts are extraordinarily rare. We describe five adults with neuroglycopenic episodes from hyperinsulinemic hypoglycemia within 4 h of meal ingestion and negative 72-h fasts. Each had negative transabdominal ultrasonography, spiral computed tomographic scanning, and celiac axis angiography of the pancreas. However, all showed positive selective arterial calcium stimulation tests indicative of pancreatic beta-cell hyperfunction. At pancreatic exploration, no insulinoma was detected by intraoperative ultrasonography and complete mobilization and palpation of the pancreas. Moreover, the resected pancreata showed islet hypertrophy and nesidioblastosis, but no insulinoma. No definite disease-causing mutation was detected in Kir6.2 and SUR1 genes, which encode the subunits of the pancreatic ATP-sensitive potassium channel responsible for glucose-induced insulin secretion. Four patients who underwent gradient-guided partial pancreatectomy have been free of hypoglycemic symptoms for up to 3 yr follow-up; the other, who underwent a limited distal pancreatectomy, has had brief recurrence of symptoms. The unique clinical features and responses to dynamic testing in these adults with hyperinsulinemic hypoglycemia in the absence of insulinoma may constitute a new syndrome of postprandial hypoglycemia from diffuse beta-cell hyperfunction.

Early predictors of survival in symptomatic HIV-infected persons treated with high-dose zidovudine.

The survival times of 246 patients treated with high-dose zidovudine beginning in 1986 were obtained through November 1988. We analyzed clinical and laboratory predictors of survival as measured before initiation of therapy and during the first 32 weeks of therapy. In a multivariate proportional-hazards model, we found significant independent predictive abilities for four pretherapy measurements (AIDS versus ARC diagnosis, Karnofsky performance score, age, and hemoglobin) and four measurements made during therapy (change in log CD4 lymphocyte count from pretherapy to week 24, CD8 lymphocyte count at week 24, rate of decline of hemoglobin over the first 3 months of therapy, and rate of decline in white blood count over the first 6 months of therapy). The presence of three predictors measured during therapy that are statistically significant when controlled for changes in CD4 count suggests that the use of other measures in addition to CD4 counts may substantially improve the prediction of long-term survival based on early response of surrogate markers to therapy.

Zidovudine resistance, syncytium-inducing phenotype, and HIV disease progression in a case-control study. The VA Cooperative Study Group.

A case-control study of patients with progressive (cases) or nonprogressive (controls) disease was designed to determine the association among disease progression, zidovudine sensitivity, and syncytium-inducing phenotype. Viral isolates were screened for sensitivity to zidovudine using a peripheral blood mononuclear cell-based assay and for syncytium-inducing (SI) phenotype in MT2 cell culture. Thirty-four patients, whose disease progressed to AIDS or whose CD4 cell numbers fell < 200 cells/mm3, were matched with 34 patients whose conditions had not progressed or whose CD4 cell numbers remained > 200 cells/mm3. Virus was successfully cultured from both the progressor and the nonprogressor in 17 of these 34 matched case-control pairs. In six of the 17 pairs, virus isolated from the progressor had an IC50 (50% inhibitory concentration) for zidovudine > 1 microM and at least threefold greater than the IC50 of virus isolated from the matched nonprogressor (p = 0.04). In 16 of these 17 pairs the virus isolated from the progressor had the SI phenotype, indicative of high cytopathogenicity, while the virus from the matched nonprogressor had a non-syncytium-inducing phenotype (p < 0.0001). Zidovudine therapy did not appear to select for the SI phenotype in this patient population. A statistically significant association between high-level zidovudine resistance and clinical disease progression was demonstrated. A statistically significant association between the SI phenotype and disease progression was demonstrated. The results suggest that disease progression while being treated with zidovudine therapy may be more closely associated with the SI phenotype than with zidovudine resistance.

Pelvic radiation therapy combined with hepatic artery chemotherapy for resected rectal carcinoma with liver metastases.

PURPOSE: Patients with hepatic metastases from rectal cancer treated with hepatic artery (HA) chemotherapy have a life expectancy great enough to be at risk for pelvic failure. Therefore, a treatment plan was developed for patients with resected rectal cancer and unresectable hepatic metastases, when the pathologic features of transmural invasion and perirectal lymph node metastases were present. Treatment consisted of concurrent pelvic radiation therapy (RT) and HA 5-fluorouracil (FUra), as systemic levels of FUra are achievable with HA administration, followed by HA fluorodeoxyuridine (FdUrd). METHODS AND MATERIALS: Fifteen patients were offered combined pelvic RT and HA FUra. Radiation was given to an initial dose of 45 Gy to the pelvis, followed by boost treatment for an additional 5.4-10.8 Gy. Concurrent HA chemotherapy was given using FUra or FUra/leucovorin administered in two cycles of 14 days for each cycle. If HA chemotherapy could not be done, then intravenous FUra was given during RT. Following completion of RT and HA FUra, patients were evaluated for treatment with HA FdUrd. RESULTS: Eleven patients received concurrent HA FUra or FUra/leucovorin and pelvic RT. Of these, six continued to receive HA FdUrd after completion of RT, as five patients were found to have progressive hepatic disease. Four patients could not have therapy as outlined, but did receive pelvic RT with concurrent intravenous FUra (two patients), FUra/leucovorin (one patient), or sequential HA FUra (one patient). There were four pelvic recurrences at 1, 4, 14, and 17 months after RT. One was the first site of progression, two occurred simultaneously with other failure, and one occurred after hepatic progression. The liver was the most frequent site of first progression (alone in seven patients; as a component of progression in four patients). Treatment was well tolerated with three Grade > or = 3 toxicities. The median survival was 14 months. CONCLUSIONS: These data support the hypothesis that patients with metastatic rectal cancer are also at risk for pelvic recurrence. The frequency of hepatic progression supports continued aggressive therapy directed to this site. As systemic and regional therapy of metastatic rectal cancer improves, we anticipate that more patients will be at risk for a pelvic recurrence, making it increasingly important to explore the role of pelvic radiation therapy despite the presence of metastatic disease.

Long-term results of hepatic artery fluorodeoxyuridine and conformal radiation therapy for primary hepatobiliary cancers.

PURPOSE: We have previously shown that conformal radiation therapy (RT) combined with hepatic artery (HA) fluorodeoxyuridine (FdUrd) had encouraging hepatic control and survival rates for patients with nondiffuse primary hepatobiliary malignancies. With longer follow-up, we were particularly interested if long-term hepatic control and disease-free survival could be achieved, and if late hepatic complications due to radiation therapy were observed. METHODS AND MATERIALS: Patients with unresectable primary hepatobiliary cancer were treated with concurrent HA FdUrd (0.2 mg/kg/day) and conformal RT (1.5-1.65 Gy per fraction, twice a day), directed only to the liver abnormalities. Three-dimensional treatment planning was used to define both the target and normal liver volumes. The total dose of radiation (48 or 66 Gy) was determined by the fractional volume of normal liver excluded from the high dose volume. Patients were followed routinely for response, patterns of failure, long-term toxicity, and survival. The median potential follow-up was 54 months. RESULTS: A total of 22 patients (11 with hepatocellular carcinoma and 11 with cholangiocarcinoma) were treated. There were 10 objective responses in the 11 evaluable patients. The overall freedom from hepatic progression at more than 2 years was about 50%. The median survival was 16 months with an actuarial 4-year survival of about 20%. Gastrointestinal bleeding was the most common long-term toxicity. Late hepatic toxicity was not observed; in fact, hypertrophy of the untreated liver was seen. CONCLUSIONS: Combined conformal RT and HA FdUrd can produce long-term freedom from hepatic progression and survival in patients with unresectable, nondiffuse primary hepatobiliary malignancies. There were no long-term liver complications observed.

The treatment of colorectal liver metastases with conformal radiation therapy and regional chemotherapy.

PURPOSE: Whole-liver radiation, with or without chemotherapy, has been of modest benefit in the treatment of unresectable hepatic metastases from colorectal cancer. A Phase I/II study combining escalating doses of conformally planned radiation therapy (RT) with intraarterial hepatic (IAH) fluorodeoxyuridine (FdUrd) was performed. METHODS AND MATERIALS: Twenty-two patients with unresectable hepatic metastases from colorectal cancer, 14 of whom had progressed after previous chemotherapy (2 with prior IAH FdUrd), were treated with concurrent IAH FdUrd (0.2 mg/kg/day) and conformal hepatic radiation therapy (1.5-1.65 Gy/fraction twice a day). The total dose of radiation given to the tumor (48-72.6 Gy) depended on the fraction of normal liver excluded from the high-dose volume. All patients were assessed for response, toxicity, hepatobiliary relapse, and survival. Median potential follow-up was 42 months. RESULTS: Eleven of 22 patients demonstrated an objective response, with the remainder showing stable disease. Actuarial freedom from hepatic progression was 25% at 1 years. The most common acute toxicity was mild to moderate nausea and transient liver function test abnormalities. There were three patients with gastrointestinal bleeding (none requiring surgical intervention) after the completion of treatment. Overall median survival was 20 months. The presence of extrahepatic disease was associated with decreased survival (p < 0.01). CONCLUSIONS: Combined conformal radiation therapy and IAH FdUrd can produce an objective response in 50% of patients with hepatic metastases from colorectal cancer. However, response was not durable, and hepatic progression was frequent. Improvements in hepatic tumor control for patients with metastatic colorectal cancer may require higher doses of conformal radiation and/or improved radiosensitization. In an effort to increase radiosensitization, we have recently initiated a clinical trial combining IAH bromode-oxyuridine, a thymidine analog radiosensitizer, with conformal high dose radiation therapy.

The use of 3-D dose volume analysis to predict radiation hepatitis.

Although it is well known that the tolerance of the liver to external beam irradiation depends on the volume of liver irradiated, few data exist which quantify this dependence. Therefore, a review was carried out of our clinical trial for the treatment of intrahepatic malignancies in which the dose of radiation delivered depended on the volume of normal liver treated. Three dimensional treatment planning using dose-volume histogram analysis of the normal liver was used for all patients. Nine of the 79 patients treated developed clinical radiation hepatitis. None of the patient related variables assessed were associated with radiation hepatitis. All patients who developed radiation hepatitis received whole liver irradiation, as all or part of their treatment, which produced a mean dose greater than or equal to 37 Gy. Dose volume histograms were used to calculate normal tissue complication probabilities based on parameters derived from the literature. The risk of complication was greatly overestimated among patients receiving a high dose of radiation to part of the liver without whole liver treatment. An estimation of model parameters based on the clinical results indicated a larger magnitude for the "volume effect parameter" than the literature estimate (n = 0.69 +/- 0.05 vs 0.32; p less than 0.001). Computation of the normal tissue complication probabilities using the larger value of n produced a good description of the observed risk of radiation hepatitis. These findings suggest that dose volume histogram analysis can be used to quantify the tolerance of the liver to radiation. The predictive value of this parameterization of the normal tissue complication probability model will need to be tested with liver tolerance and dose volume histogram data from an independent clinical trial.

Treatment of cancers involving the liver and porta hepatis with external beam irradiation and intraarterial hepatic fluorodeoxyuridine.

A Phase I/II clinical trial was designed for patients with malignancies of the liver and porta hepatis. This protocol employed three concepts: a) boost treatment to gross tumor within the liver for selected patients, determined by the dose-volume histogram (DVH) of the normal liver that would be irradiated by boost treatment; b) concurrent use of intraarterial hepatic 5-fluorodeoxyuridine (FdUrd) as a radiosensitizer; and c) hyperfractionation (1.5 Gy fractions given bid greater than 4 hr apart). This report describes the results of treatment of the first 33 patients entered onto this study, with a minimum follow-up of 1 year. Twenty patients received only whole liver irradiation (33 Gy). Thirteen patients were treated with whole liver irradiation (30 Gy) plus a 15 Gy (6 patients) or 30 Gy (7 patients) boost (total 45 Gy and 60 Gy to the tumor, respectively). Forty-eight percent of the evaluable patients (14/29) had an objective response, based on CT scan. The median duration of response was 8 months. The chief toxicities were fatigue, nausea, gastritis, and diarrhea, which were less than or equal to grade 2 in severity. Two patients developed mild radiation hepatitis which was treated successfully with diuretics. These data suggest that the treatment of intrahepatic malignancies can be guided by the concept of DVH analysis of the normal liver to allow the safe administration of doses of radiation that are potentially tumoricidal and are well above those that would be predicted to be tolerable for the whole liver.

Morphologic evidence of accelerated closure of the ductus arteriosus in preterm infants.

In preterm infants, closure of the ductus arteriosus (DA) is often delayed, especially in those with respiratory distress syndrome (RDS). However, it has been suggested that functional closure of the DA may occur as early as 24 hours of age in some preterm infants exposed to intrauterine stress, and this is usually associated with decreased incidence of RDS. This suggests that accelerated maturation of the DA as well as of the lungs occurs in utero. Accordingly, histologic evidence of accelerated maturation of the DA was sought in a prospective autopsy study of 55 preterm infants ranging in gestational age from 19 to 32 weeks. There were four infants with clinically closed DA which showed histologic evidence of closure. The birth weight of these four infants ranged from 750--1,100 gm, the gestational age ranged from 24--32 weeks, and age of death was 39 hours to 6 days. The immediate causes of death were intracerebral hemorrhage or intrapulmonary hemorrhage, or both. Obstetric complications included chronic second trimester vaginal bleeding, abruptio placenta, malnutrition, diabetes, pulmonic stenosis of moderate degree, and chronic hypertension. These findings support the hypothesis that in some preterm infants exposed to chronic intrauterine stress, maturation of the DA is accelerated. This may result clinically in effective postnatal closure of the DA.

Hepatic radioembolization with yttrium-90 containing glass microspheres: preliminary results and clinical follow-up.

UNLABELLED: The treatment of hepatic tumors remains unsatisfactory. These lesions receive most of their blood supply from the hepatic artery, therefore the hepatic artery administration of beta-emitting particulate radiopharmaceuticals is an attractive approach to deliver therapeutic irradiation to the liver and differentially to tumors within the liver. METHODS: A Phase I dose escalation study of the hepatic tolerance to radiation delivered by 90Y containing glass microspheres was carried out in 24 patients with hepatic malignancy. Doses of 90Y microspheres to achieve an estimated whole-liver nominal absorbed radiation dose of 5000 cGy (two patients), 7500 cGy (six patients), 10,000 cGy (seven patients), 12,500 cGy (six patients), and 15,000 cGy (three patients) were administered via the hepatic artery. The administered nominal absorbed radiation dose (NARD) was estimated based on liver volume determined from CT scans and the assumption of uniform distribution of microspheres throughout the liver. RESULTS: No hematologic, hepatic or pulmonary toxicity was encountered in the dose range examined during a mean follow-up period of up to 53 mo. Reversible gastritis or duodenitis was encountered in four patients without imaging or biopsy evidence for extrahepatic deposition of microspheres. Response data, based on CT scans obtained 16 wk after treatment, showed progressive disease in eight patients, stable disease in seven patients, minimal response in four patients and partial response in five patients. Subsequent follow-up revealed three long-term survivors at 204, 216 and 228 wk. CONCLUSIONS: These preliminary data demonstrate that in the examined dose range, radiation may be safely delivered to liver tumors by means of 90Y glass microspheres with encouraging response data.

Percutaneous transcatheter embolization of coronary arteriovenous fistulas.

Coronary artery fistulas are infrequently encountered vascular communications that are either congenital or due to cardiac trauma. Most patients with these anomalies are asymptomatic, but late complications can occur and include congestive heart failure, myocardial ischemia, arrhythmias, and endocarditis. Therefore, many investigators have recommended surgical repair, even for asymptomatic patients. Although coronary arteriovenous fistulas pose many challenges to interventional cardiologists, early experiences suggest that these abnormal vessels can be successfully obliterated percutaneously; thus, the patient is spared the risks and morbidity associated with cardiac surgical intervention. Herein we present two cases that illustrate many of the technical issues involved in successful transcatheter embolization of coronary artery fistulas.

Endovascular repair of abdominal aortic aneurysms: where do we stand?

Endovascular repair of abdominal aortic aneurysms has evolved dramatically within the past few years. In light of the potential to reduce morbidity and mortality associated with open surgical repair, endoluminal grafting offers therapeutic options to patients who are not surgical candidates because of comorbidities. With the development of bifurcated devices, more complex aneurysms may be treated by endovascular grafting. Although successful placement of endovascular grafts requires a pronounced learning curve, including appropriate patient selection, midterm results seem consistent with those of traditional open repair of aneurysms. This review describes the current indications, minimal requirements, different devices and associated techniques, and potential complications of endoluminal repair of abdominal aortic aneurysms. Future aspects of endoluminal grafting are also discussed.

A simple method for long-term biliary access in large animals.

A simple method to obtain long-term access to the biliary tree in dogs and pigs is presented. In ten dogs and four pigs, a cholecystectomy was performed, the cystic duct isolated, and a catheter inserted into the cut end of the cystic duct. The catheter was connected to a subcutaneous infusion port, producing a closed, internal system to allow long-term access. The catheter placement was successful in three of the pigs and all of the dogs. Thirty-five cholangiograms were obtained in the 13 subjects by accessing the port with a 20 gauge Huber needle and injecting small amounts (4-10 mL) of contrast under fluoroscopic control. Cholangiograms were obtained up to four months after catheter placement without evidence for catheter failure or surgically induced changes in the biliary tree. This model provides a simple, reliable means to obtain serial cholangiograms in a research setting.

Floxuridine-associated sclerosing cholangitis. A dog model.

The authors developed a dog model for the biliary sclerosis that occurs as a severe complication of protracted hepatic arterial floxuridine (FUDR) infusions (using implanted drug delivery systems) in patients with hepatic cancers. Infusaid pumps attached to hepatic arterial catheters were used for protracted infusions in ten mixed breed hounds. To allow repeated cholangiograms, the animals' gallbladders were removed and catheters connected to subcutaneous infusion ports were positioned in the cystic ducts. Five treated dogs received FUDR 0.3 mg/kg/day through the pump for a total of 30 days. Five control dogs received only saline through the pump. Cholangiograms were obtained before and after treatment in all animals. In the control group, serum liver function test results and the cholangiographic appearance of the biliary tree remained within normal limits. By contrast, in the FUDR-treated group, serum glutamic-pyruvic transaminase and alkaline phosphatase progressively rose above normal, starting 2-3 weeks into FUDR infusion, followed by hyperbilirubinemia (7-28 mg/dl peak levels) beginning 4 to 6 weeks after initiation of the drug infusion. Cholangiograms revealed focal strictures involving the central bile ducts (five dogs) and diffuse attenuation of the intrahepatic ducts (four dogs). Thus, the liver function abnormalities and the cholangiographic findings in this dog model mimic the hepatobiliary toxicity in sensitive patients receiving similar treatment.

Local thrombolytic therapy for hepatic artery thrombosis following chemotherapy infusion catheter placement.

Nine patients with hepatic artery thrombosis subsequent to catheter placement (four surgical and five percutaneous) for hepatic arterial infusion chemotherapy were treated with local thrombolytic therapy. The thromboses were located in the common hepatic, proper hepatic and hepatic arteries. Thrombolytic therapy was instituted within seven days of catheter placement, at a rate of 5,000 to 20,000 units/hour (streptokinase) or 5,000 to 15,000 units/hour (urokinase) for 15 to 64 hours. All patients had repeat angiography and 99mTc-MAA hepatic artery perfusion scintigraphy after the infusion. In eight of the patients, thrombolytic therapy resulted in dissolution of the thrombus and recanalization of the hepatic artery. In three of these patients, rethrombosis occurred within a few days, and was attributed to underlying arterial abnormalities. The other five had documented continued hepatic arterial patency allowing completion of the chemotherapy course. The patient who did not respond to the lytic therapy had developed extensive collateral flow through the gastroduodenal artery to the liver.