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Biomedical subjects

J A Knol

Publications and source records attributed to J A Knol.

At least 19 recordsLinked to original sources
PubMed1991

Biochemical modulation of 5-bromo-2'-deoxyuridine and 5-iodo-2'-deoxyuridine incorporation into DNA in VX2 tumor-bearing rabbits.

The thymidine analogues 5-bromo-2'-deoxyuridine (Brd-Urd) and 5-iodo-2'-deoxyuridine (IdUrd) compete with thymidine for incorporation into the DNA of replicating cells. This incorporation results in radiosensitizing effects which are directly related to the degree of analogue substitution. In vitro and in vivo evidence suggests that preadministration or coadministration of the thymidylate synthetase inhibitors fluorouracil and 5-fluoro-2'-deoxyuridine (FdUrd) can modulate analogue incorporation into DNA. We have evaluated in the rabbit VX2 tumor model the effects of thymidylate synthetase inhibitor (fluorouracil or FdUrd) coadministration (as 24-hour, intravenous infusions) on the incorporation of BrdUrd or IdUrd into the DNA of relevant normal tissues (bone marrow, gut mucosa) and intrahepatic VX2 tumor. Tissues were harvested and processed for gas chromatography-mass spectrometry analysis of the thymine, 5-bromouracil, and 5-iodouracil contents in hydrolyzed DNA. Coadministration of FdUrd resulted in statistically significant (P less than .01) enhancement of IdUrd incorporation into the DNA of intrahepatic VX2 tumor and normal (bone marrow and duodenal mucosa) rabbit tissues. Coadministered fluorouracil, on the other hand, significantly enhanced IdUrd incorporation only into DNA of intrahepatic VX2 tumor. Statistically significant enhancement of BrdUrd incorporation was achieved only with FdUrd coadministration and then only into the DNA of intrahepatic VX2 tumor. The percent of thymine replaced by analogue (I) is related to the steady-state arterial plasma drug concentration (C) by the Michaelis-Menten equation: I = I(MAX.) C/(C50 + C). The primary effect of FdUrd coadministration on BrdUrd incorporation into VX2 tumor DNA was a reduction of the C50 parameter (plasma BrdUrd concentration eliciting I = I(MAX)/2) from 8.17 microM to 1.78 microM. On the other hand, the I(MAX) parameter (I as C approaches infinity) was only slightly affected (29.7% to 25.2%). Thus, the degree to which the modulator enhanced analogue incorporation varied inversely with the analogue's steady-state plasma concentration. These results, which describe potential tissue specificity of modulator efficacy and characterize the effects of thymidylate synthetase inhibitor modulation on thymidine analogue incorporation pharmacodynamics, should provide guidance as to dose scheduling of BrdUrd and IdUrd in clinical trials for improved tumor specificity of uptake.

Animals↗
PubMed1991

Extracorporeal lithotripsy. An important adjunct in the nonoperative management of retained or recurrent bile duct stones.

Retained or recurrent bile duct stones can be successfully removed in up to 80% to 85% of patients with the use of percutaneous or endoscopic techniques. However, problems related to difficult biliary access, large stones, and biliary strictures may decrease the success rate of this approach. We evaluated the safety and efficacy of extracorporeal shock-wave lithotripsy (ESWL) in 16 patients with complicated biliary stones treated prospectively over a 24-month period. Successful stone fragmentation was achieved in 15 patients (94%) using a Dornier HM3 lithotripter (average of 2290 shocks at 22 kV). Three patients (19%) required a second ESWL treatment. Biliary clearance of stone fragments was spontaneous in seven (43%) of the patients and required additional treatment in eight (57%) of the patients. Complications from ESWL were minor and included transient hematuria and ecchymoses at the skin entry site. Extracorporeal shock-wave lithotripsy failed in one patient (6%) with a biliary stricture and surgery was required. At hospital discharge, all patients were asymptomatic and stone free. Treatment with ESWL appears to be a safe and effective adjunct for selected patients with complex biliary stone disease.

Adult↗
PubMed1991

Current concepts in the pathophysiology and treatment of portal hypertension and variceal hemorrhage.

Recent studies have demonstrated that increased resistance to portal inflow is not solely responsible for the development of portal hypertension. Increased splanchnic flow has been attributed to a combination of factors, including elevated circulating levels of vasodilators and diminished sensitivity of the splanchnic vasculature to endogenous vasoconstrictors. In selected animal models of portal hypertension, increased splanchnic flow accounts for approximately 40% of the observed elevations in total portal venous pressure. Improved understanding of the pathophysiologic factors responsible for the development of portal hypertension has led to pharmacologic efforts to decrease portal pressure. Current limitations include lack of drug selectivity and specificity and inability to predict and monitor patient responses. Primary treatment options include selective portosystemic shunts, endoscopic sclerotherapy (ES), and orthotopic liver transplantation. ES is more effective in preventing recurrent variceal hemorrhage than medical treatment but is less effective than shunt surgery. In selected studies, ES better maintains hepatic function and may prolong survival compared to primary shunt surgery. ES failures occur in nearly 33% of patients, but "salvage shunts" in these patients appear to be reasonably safe and quite effective in preventing recurrent hemorrhage. Selective shunts are favored because they appear to confer a better quality of life (but not improved longevity) than conventional shunts. Liver transplantation is preferred for patients with end-stage liver disease in whom the predicted mortality of conventional surgery outweighs the survival benefit.

Esophageal and Gastric Varices↗
PubMed1991

Injection sclerotherapy-induced esophageal strictures. Risk factors and prognosis.

Injection sclerotherapy (IS) has become an effective modality for the treatment of bleeding esophageal varices. Despite improvements in equipment, sclerosant solutions and operator technique, injection sclerotherapy-induced esophageal strictures (ISES) remain a significant cause of patient morbidity. To analyze the risk factors and prognosis of ISES, the records of 117 patients who underwent IS over a 6-year period at a single teaching institute were reviewed. The predictive value of multiple risk factors including the patient's age, Child's risk classification, previous bleeding episodes, etiology of varices, cumulative amount of sclerosant used, and the number of IS treatments were determined using ANOVA. A P value of less than 0.05 was considered significant. In all cases, a free-hand injection technique, flexible endoscopes and sodium morrhuate were used. During a mean follow-up period of 228 days (1-1,469 days), 41 patients (35%) died and 24 patients (20.5%) developed symptomatic strictures. The cumulative amount of sclerosant used (81.4 +/- 9.5 ml) and the number of IS treatments (6.5 +/- 0.7) required in the stricture group was significantly greater than in the nonstricture group (49.1 +/- 2.7 and 4.0 +/- 0.3, respectively). The risk of stricture formation did not correlate with the volume of sclerosant injected per treatment, cause of varices, number of previous bleeds, or Child's hepatic risk class. A mean of 3.6 +/- 4.5 dilations was required for treatment of established strictures and 18 patients (75%) required r 4 dilations. One esophageal perforation occurred following dilation. Mortality correlated with hepatic risk class as 30/41 (73%) of deaths occurred in Child's C patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Esophageal Stenosis↗
PubMed1989

5-Bromo-2'-deoxyuridine incorporation into DNA in hepatic VX2 tumor-bearing rabbits.

The halogenated pyrimidine 5-bromo-2'-deoxyuridine (BrdUrd) possesses both radiosensitizing and antimetabolite effects through its incorporation as a thymidine analog in replicating DNA. To evaluate the regional advantage for treatment of hepatic malignancy by hepatic arterial infusion, BrdUrd was infused into either the hepatic artery (HA) or a central vein (iv) in 26 rabbits with intrahepatic VX2 tumor. After a 24-hr constant rate infusion of 10, 20, or 40 mg/kg/24 hr, the percentage BrdUrd incorporation into the DNA of bone marrow, duodenal mucosa, liver, and hepatic VX2 tumor was measured by gas chromatography/mass spectrometry methods. VX2 tumor BrdUrd incorporation was greater by HA than by iv routes (P less than 0.001). At doses of 10 and 20 mg/kg/day, HA to iv BrdUrd incorporation ratios for VX2 tumor significantly exceeded those for bone marrow and duodenum (P less than 0.05). At appropriate dose rates, hepatic arterial administration of BrdUrd provides a regional advantage for DNA BrdUrd incorporation in the rabbit intrahepatic VX2 tumor.

Animals↗
PubMed1989

Steady-state arterial and hepatic venous plasma concentrations of 5-bromo-2'-deoxyuridine and 5-iodo-2'-deoxyuridine in animals--drugs which are subject to both splanchnic and extra-splanchnic elimination.

We have previously shown that 5-fluorouracil (FUra) in humans obeys Michaelis-Menten elimination kinetics. In this article we show that the related bromine and iodine-containing analogs in animals obey similar kinetics. Steady-state arterial (CssA) and hepatic venous plasma (CssV) concentrations of 5-bromo-2'-deoxyuridine (BrdUrd) are reported for 7 rabbits given 5 different infusion rates of BrdUrd and 5 dogs given 4 or 5 different infusion rates of BrdUrd. Steady-state arterial and hepatic venous plasma concentrations of 5-iodo-2'-deoxyuridine (IdUrd) are reported for 5 rabbits and 2 dogs given 5 different infusion rates of IdUrd. Each set of data could be fitted by a nonlinear least squares method to the equation: (equation; see text) where Vm/Q is the maximum difference, (CssA) - (CssV), and Km is the Michaelis constant. The estimated parameter Vm/Q and Km are compared for the two drugs and different species and also with the same parameters derived in the same manner from previously published data on fluorouracil in 8 cancer patients. The infusion rate needed to saturate the splanchnic elimination system (Rs in mumol/kg/min) was also estimated. For BrdUrd the mean value of Rs in the rabbit, namely 1.23, and in the dog, namely 1.25 mumol/kg/min are essentially the same.

Animals↗
PubMed1989

Combination chemo-radiation therapy for jaundice due to focal malignant obstruction of the major bile ducts.

Twenty patients with focal malignant obstruction of the major bile ducts (6 cholangiocarcinoma, 8 colorectal, 3 hepatoma, 2 unknown primary, and 1 gastric cancer) were treated on a protocol examining the toxicity and efficacy in relieving jaundice of external beam radiation therapy (4500 cGy in 300 cGy fractions) combined with continuous hepatic arterial (15 patients) or peripheral venous (5 patients) fluorouracil infusion. Toxicity of this regimen consisted of anorexia with mild nausea and vomiting in 55% of patients and gastric ulceration (responsive to medical management) in 15% of patients. One patient exhibited transient grade 2 hepatic toxicity and one had asymptomatic grade 4 leukopenia. Of 14 patients treated without prior biliary drainage, 8 exhibited a decrease in bilirubin levels from a mean of 14.5 mg/dl to 1.5 mg/dl. Four of six patients with biliary drainage catheters at the start of treatment were able to have them removed without reobstruction. For the 8 responding patients among those who did not have cholangiocarcinomas, the median response duration was 5 months with a median survival from treatment of 6.5 months. For the 4 responding patients with cholangiocarcinoma, the median response duration was 16 months with a median survival from treatment of 20 months. All responders did not have a return of jaundice due to reobstruction of the major ducts (until death or to the present). All responders who have died did so due to tumor progression outside of the treated field except for one who died of unrelated causes. The mean number of proven or presumed episodes of cholangitis per patient was virtually identical in those without (1.8) and those with stents/tubes (1.4, p = 0.561). This regionally focused combined modality cytotoxic therapy was able to relieve obstruction in the majority of patients without excess morbidity (including a lack of any detectable increase in sepsis). Thus, it appears feasible to consider randomized studies of this cytotoxic approach versus standard mechanical drainage procedures to define the relative risks and benefits of each.

Adult↗
PubMed1989

Unsatisfactory hepatic perfusion after placement of an implanted pump and catheter system: angiographic correlation.

Thirty-five patients with scintigrams showing unsatisfactory hepatic artery perfusion after surgical placement of an implanted pump and catheter system were examined with selective angiography (33 cases) or digital subtraction angiography (DSA) during which the contrast material was injected through the side port of the pump (six cases). In 34 of 35 cases, the cause of the unsatisfactory (either extrahepatic or incomplete) hepatic perfusion was defined. DSA was definitive in only two cases, in which extrahepatic flow through collateral vessels was demonstrated. The cause of the perfusion defect was hepatic artery thrombosis in 14 cases, extrahepatic flow through collateral vessels in 14 cases, a misplaced catheter in four cases, and a short proper hepatic artery without adequate length for mixing in two cases. Although hepatic artery perfusion scintigraphy is the primary tool for evaluation of hepatic perfusion after catheter placement, angiography plays an important role in treating the subset of patients with unsatisfactory hepatic perfusion.

Antineoplastic Agents↗
PubMed1989

Operative timing and patient survival following distal splenorenal shunt.

The importance of "operative timing" in cirrhotic patients with variceal hemorrhage is often underemphasized. To evaluate the effects of immediate versus delayed selective portasystemic decompression on hepatic function, operative mortality, and long-term patient survival, we reviewed the records of 77 patients who underwent distal splenorenal shunts (DSRS) over a 14-year period. A hepatic risk status score was calculated at the time of the index bleed (HRS1) or presentation and again just prior to operation (HRS2). Variables analyzed included age, sex, prior bleeding episodes, time from index bleed to operation, transfusion requirements, and etiology of cirrhosis. Operative mortality rates for immediate versus delayed DSRS were 46.2 per cent and 17 per cent, respectively. HRS improved significantly in elective DSRS patients from 1.46 to 1.30. Predictors of HRS2 included HRS1 and time in days from the index bleed to operation. The most important predictor of early survival for all patients after elective DSRS was the HRS2; however, for patients who underwent elective DSRS and survived, HRS1 was a better predictor of length of survival than HRS2. No other variable analyzed accurately predicted survival. We conclude that HRS can be expected to improve with supportive inhospital therapy; improved HRS at the time of operation is associated with decreased operative mortality; and the extent of liver disease as determined by HRS1 appears to be the chief determinant of long-term patient survival.

Female↗
PubMed1989

A prospective study of clinically and endoscopically documented colonic ischemia in 100 patients undergoing aortic reconstructive surgery with aggressive colonic and direct pelvic revascularization, compared with historic controls.

Clinically and endoscopically proved ischemia of the colon complicates elective aortic reconstruction in 1% to 2% and 6% to 7% of cases, respectively. Operative mortality exceeds 60% when transmural infarction occurs. A prospective study of colonic ischemia was undertaken in 100 male patients (mean age, 62.4 +/- 7.9 years) undergoing operation for aortic aneurysms (58) or aortoiliac occlusive disease (42). Conventional aortic surgery was undertaken in 88 patients, and in 12 patients adjunctive procedures to enhance colonic perfusion were performed 14 times, including IMA reimplantation (8), direct bypass to the internal iliac artery (4), and anastomosis of an aortofemoral bypass limb to adjacent common iliac artery (2). Colonoscopy was performed within 24 to 48 hours of aortic reconstruction. Three patients had endoscopic evidence of colonic ischemia. Transmural infarction did not develop in any patient, and bowel resections or diverting colostomies were not necessary. Three patients died, none manifesting colonic ischemia. The 12% utilization of adjunctive procedures to enhance blood flow in the colon was substantially greater than the 4% frequency of an earlier experience from our institution in which nearly half of the 5.7% operative mortality was attributed to colonic infarction. Attention to factors contributing to ischemia of the colon, and more frequent adjunctive revascularization of the colon, may lessen this complication of aortic reconstructive surgery.

Angiography↗
PubMed1988

Tissue-specific pharmacodynamics of 5-bromo-2'-deoxyuridine incorporation into DNA in VX2 tumor-bearing rabbits.

The thymidine analog 5-bromo-2'-deoxyuridine (BrdUrd) is felt to exert its cytotoxic effects primarily through incorporation into DNA. We have evaluated the incorporation of BrdUrd into the DNA of relevant normal tissues (bone marrow, gut mucosa, and liver) and tumor in rabbits with the VX2 tumor growing intrahepatically. Using constant i.v. infusions, steady state plasma drug concentrations ranging from 0.4 to 65.4 microM were maintained for 24 h and tissues were harvested and processed so that a sensitive gas chromatography/mass spectrometry (GC/MS) method could be used to analyze the thymine and 5-bromouracil content of hydrolyzed DNA. In all tissues, DNA incorporation showed saturating effects as plasma BrdUrd concentration was increased and, BrdUrd incorporation as a function of plasma concentration could be fitted to a Langmuir-like equation generating tissue-specific pharmacodynamic parameters: Imax for percentage thymine replacement at infinite plasma BrdUrd concentrations, and C50 for the arterial BrdUrd concentration generating incorporation that is Imax/2. At all plasma concentrations of BrdUrd the incorporation into DNA of bone marrow was greater than that observed in VX2 tumor. However, BrdUrd labeling index (with a BrdUrd monoclonal antibody) was greater in tumor than bone marrow. Thus, pharmacodynamic differences in incorporation do not result solely from cytokinetic differences between tissues. This model may prove useful in evaluating the pharmacodynamics of incorporation in studies using hepatic arterial infusion and biochemical modulation to improve selectivity.

Animals↗
PubMed1988

Malignancy and concomitant primary hyperparathyroidism.

Hypercalcemia is associated with a few primary malignant neoplasms and with a variety of tumors that have spread by metastases. Hyperparathyroidism is a diagnosis that is usually not considered in these patients. At our institution, 18 patients with malignant tumors presented over a 6-year period with hypercalcemia caused by hyperparathyroidism. There were five men and 13 women with a mean age of 48 years (range 24-87 years). Primary tumors in these patients included colon carcinoma (four cases), breast carcinoma (four cases), lymphoma (four cases), thyroid carcinoma (four cases), Paget's disease (one case), and lung carcinoma (one case). Metastases of the primary tumor occurred in seven patients, and in 11 patients the tumor was not metastatic or recurrent. Serum levels of calcium, phosphate, and chloride averaged 11.8 mg/dl, and 100 mEq/liter, respectively. C-terminal parathyroid hormone (PTH) levels ranged from 300 to 1,900 pg/ml with an average of 1,150 pg/ml (normal 50-340 pg/ml). At operation, a single parathyroid adenoma was discovered in 15 patients, and four-gland hyperplasia was noted in three patients. In all cases, serum levels of calcium returned to normal after operation. We conclude that patients with malignant tumors and concomitant hypercalcemia should be evaluated for the possibility of hyperparathyroidism. In cases of primary hyperparathyroidism, elevated C-terminal PTH level should be diagnostic. If hyperparathyroidism is determined to be the cause of hypercalcemia, neck exploration and parathyroidectomy are indicated.

Adenocarcinoma↗
PubMed1988

Completion gastrectomy for postsurgical gastroparesis syndrome. Preliminary results with 15 patients.

Postsurgical gastroparesis syndrome (PGS) is a complex disorder characterized by postprandial nausea, vomiting, and gastric atony without evidence of mechanical gastric outlet obstruction. These symptoms can be disabling and are frequently unresponsive to drug therapy. Fifteen patients with documented PGS, including 13 women and two men, were recently treated by completion gastrectomy (CG) over a 5-year period. Gastric emptying study (GES) was markedly prolonged in 12 of the patients studied, and improved partially in only one patient (8%) with the administration of metoclopramide alone or combined with other gastrokinetic drugs. Patients were evaluated both before and after surgery, using a modified Visick rating system and a severity of symptoms (SS) score based on seven gastrointestinal (G.I.) and five systemic variables. All 15 patients underwent CG and reconstruction with a 50 cm Roux-en-Y limb. There were no operative deaths or complications related to the esophagojejunal anastomosis. Mean postoperative follow-up was 13.9 months, with a range of 2-65 months. After CG, the Visick rating and overall SS score improved significantly. The improvement in SS score was primarily due to a significant decrease in G.I. symptoms with little or no change in systemic symptoms. Overall, 86% of patients reported a satisfactory clinical result. CG, while seemingly radical, can be performed with low risk, and for properly selected patients with PGS, may be the treatment of choice.

Adult↗
PubMed1988

Therapeutic dilemmas in patients with symptomatic polycystic liver disease.

Most reports of the operative treatment of symptomatic polycystic liver disease (PCLD) are anecdotal or consist of only a small subset of patients in an institution's overall experience treating hepatic cysts. We have reviewed our experience with nine consecutive patients with symptomatic PCLD undergoing operative treatment from 1981 to 1987. Indications for operation include chronic abdominal pain (4 patients), cyst infection (2 patients), biliary obstruction (2 patients), inferior vena cava obstruction (2 patients), and symptomatic abdominal distention (2 patients). The average duration of symptoms leading to operation was 7.8 months. Three types of cystic disease were identified based on gross morphology: dominant cystic disease (3 patients), diffuse cystic disease (4 patients), and mixed cystic disease (2 patients). Operations to treat symptomatic PCLD included unroofing and external drainage of infected cysts (2 operations), simple unroofing (1 operation), cyst fenestration alone (4 operations) and fenestration combined with resection (3 operations). Treatment directed at principally dominant cysts (five patients) was associated with resolution of symptoms and low morbidity and mortality. Treatment directed at diffusely cystic disease (four patients) resulted in significant morbidity and mortality including three deaths. Successful surgical treatment of symptomatic patients with PCLD depends on accurate preoperative identification of patients with symptoms related to one or more dominant cysts. In this setting fenestration or simple unroofing of the dominant cyst is safe and effective treatment. By comparison, extensive fenestration with or without hepatic resection in patients with symptoms attributed to a diffusely cystic liver may be associated with unacceptable morbidity and mortality.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1988

Duodenal exclusion for management of lateral duodenal fistulas.

The first clinical application of pyloric occlusion with gastrojejunostomy (duodenal exclusion) for management of lateral duodenal fistulas was reported by Berg in 1907. More recently Berne et al. applied this procedure to treat patients with complex pancreaticoduodenal trauma and modified it to include antrectomy with Billroth II reconstruction and tube duodenostomy. Over time the indications for duodenal exclusion have gradually been expanded to include management of actual or anticipated duodenal fistulas arising from operative injury or as a complication of inflammatory or neoplastic diseases. Our recent success using duodenal exclusion and/or diverticularization to manage one patient with duodenal trauma and two patients with nontraumatic forms of duodenal injury resulting in lateral duodenal fistulas caused us to reevaluate the efficacy of this procedure and forms the basis for this report.

Aged↗
PubMed1987

Critical appraisal of horizontal gastroplasty.

We evaluated 77 consecutive patients who had undergone horizontal gastroplasty over a 2 year period. Mean follow-up was 26 months (88 percent of patients) and ranged from 15 to 45 months. There were no operative deaths. Early complications were common. Stomal dilatation resulting in cessation of weight loss or in weight regain occurred in 19 patients (25 percent). Stomal stenosis occurred in four patients. Among patients with an intact gastroplasty, the percentage excess weight decreased from a preoperative mean of 142 +/- 46 percent to 80 +/- 38 percent at 1 year, 68 +/- 30 percent at 2 years, and 83 +/- 45 percent at 3 years. Fewer than 25 percent of the patients weighed less than 50 percent above ideal body weight at 2 or 3 years. In our experience, horizontal gastroplasty was associated with an unacceptably high mechanical failure rate. Using strict criteria, weight loss was generally inadequate at 2 years and not sustained, even in patients with intact gastroplasty.

Adolescent↗
PubMed1987

Blood flow and distribution in the canine pancreas.

Because of a tripartite arterial inflow, accurate determination of canine pancreatic blood flow (QP) in experimental studies remains problematic. Assessment of blood flow using a single electromagnetic flow probe on the anterior pancreaticoduodenal artery (APDA) was compared to the radiolabeled microsphere method. Distribution of QP was based on microsphere density. QP determined simultaneously with the flow probe technique and the microsphere method were 86 +/- 17 and 23 +/- 8 ml/min, respectively, (P less than 0.05). Following occlusion of the splenic artery (SA) and the posterior pancreaticoduodenal artery (PPDA), QP measured by the flow probe increased to 94 +/- 27 ml/min (NS) and decreased to 19 +/- 4 ml/min (NS) using microspheres. Intrapancreatic distribution of QP was not significantly altered by occlusion of the SA and PPDA. Intrapancreatic arterial collateral is adequate to maintain blood flow to the entire pancreas even when arterial inflow is restricted to the APDA. Flow probe determinations of QP are artifactually high because they include flow to the duodenum and may also be subject to methodologic error.

Animals↗