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Biomedical subjects

J M Robertson

Publications and source records attributed to J M Robertson.

At least 73 records · Page 4Linked to original sources
PubMed1995

High-dose localized radiation therapy for treatment of hepatic malignant tumors: CT findings and their relation to radiation hepatitis.

OBJECTIVE: High-dose radiation therapy of the liver performed using overlapping portals defined by a three-dimensional treatment-planning system (conformal radiation therapy) is a new method of treating hepatic tumors. This study was performed to delineate the differences in the CT appearances of the liver after therapy compared with other methods of radiotherapy and to correlate imaging findings to clinical findings of radiation hepatitis. MATERIALS AND METHODS: Contrast-enhanced CT scans were obtained at 8- to 12-week intervals on 31 consecutive patients with primary or metastatic hepatic malignant tumors. All had undergone high-dose conformal radiation therapy and injection of fluorodeoxyuridine into the hepatic artery as part of the treatment for unresectable hepatic neoplasms. Tumor size, location, presence of changes within the target volume after therapy, presence of atrophy of the treated segments or hypertrophy of the untreated segments, ascites, and any changes in adjacent organs seen on serial CT scans obtained before and after treatment were recorded. Clinical records were reviewed for evidence of radiation hepatitis (nonmalignant ascites evident on physical examination and a twofold elevation of alkaline phosphatase in the anicteric patient). RESULTS: In 23 (74%) of the 31 patients, follow-up CT studies after treatment showed a low-attenuation area adjacent to the hepatic tumor in the target volume. In two patients with fatty infiltration of the liver, CT showed relative increased density in the treatment portal. A sharp, straight interface was rarely seen at the treatment margin. Maximal effect was seen 2-3 months after completion of therapy and persisted for up to 3 months. Atrophy in the treated segment or lobe was seen in four patients, hypertrophy of the untreated liver was seen in four patients, and both effects were seen in seven patients. Extrahepatic effects included segmental right renal atrophy in three patients and duodenal wall thickening in two patients. Only two patients (6%) in this series had clinical evidence of radiation hepatitis. CONCLUSION: High-dose localized radiotherapy of the liver results in reversible hypodense regions in the liver parenchyma within the target volume that do not have a sharp interface delineating the radiation portal. This appearance should not be confused with tumor progression or irreversible liver injury. The changes evident on CT scans after therapy are not predictive of radiation hepatitis.

Adult↗
PubMed1995

Current status of radiation sensitization by fluoropyrimidines.

Numerous clinical studies suggest that the combination of the fluoropyridimine fluorouracil and radiation is a more effective treatment for many cancers, especially gastrointestinal tumors, than is either modality alone. Also, the combination of fluorouracil and radiation has greatly expanded the possibilities for organ-preserving treatments, for example, in patients with bladder cancer. Another fluoropyridimine, floxuridine, administered via the hepatic artery, has been used in combination with irradiation in the treatment of patients with intrahepatic cancers and may prolong survival in patients with unresectable hepatobiliary malignancies. The beneficial effects of combining fluoropyrimidines and radiation are thought to be due to radiosensitization. More studies are needed to clarify the mechanism(s) of radiosensitization so as to optimize regimens in which the fluoropyrimidines are used.

Animals↗
PubMed1994

Adrenalectomy does not modify the suppressive effect of angiotensin II on voluntary ethanol drinking in rats.

Enhancement of activity in the renin-angiotensin system reduces voluntary ethanol consumption in rats. Because angiotensin II, which is a major bioactive component of the renin-angiotensin system, stimulates the release of aldosterone, aldosterone may play a role in the reduction of ethanol intake by angiotensin II. The present study examined ethanol drinking in a group of rats that was bilaterally adrenalectomized and incapable of producing aldosterone, and in a sham group that underwent similar surgery except that the adrenal glands were left intact. Rats were maintained on ad libitum food, water and 1.5% saline solution in their home cages. Access to ethanol (6% weight/volume) was restricted to a daily 40 min period and was always offered as a choice in conjunction with water. Adrenalectomy did not alter the effect of angiotensin II on ethanol intake as subcutaneous injections of angiotensin II (400 micrograms/kg) significantly reduced ethanol intake to the same degree in both the adrenalectomized and sham groups. In the next phase, daily subcutaneous injections of aldosterone (100 micrograms/kg) reduced the home cage intake of 1.5% saline in the adrenalectomized group indicating that this dose of aldosterone was biologically active. These aldosterone injections did not affect ethanol intake in either the adrenalectomized or sham groups. Under the present conditions of testing aldosterone does not appear to play a role in the angiotensin II-induced reduction of ethanol consumption.

Adrenalectomy↗
PubMed1994

Simplified method for three-dimensional evaluation of interstitial brachytherapy applications.

Although three-dimensional (3-D) treatment planning has primarily been used for external beam radiation therapy, the advantages of 3-D treatment planning can be realized for brachytherapy applications. As with teletherapy, the use of 3-D treatment planning for brachytherapy can provide both superior dose distribution as well as detailed evaluations of the relationship of dose and volume in critical structures and target tissues. Conventional 3-D treatment planning uses computed tomography (CT) scans to localize structures; however, localizing individual brachytherapy sources on each CT slice can be impractical for routine clinical use. In the transition from two-dimensional to 3-D localization and dose evaluation of interstitial perineal templates in particular, a practical method of seed localization on a postimplant CT dataset has been developed. This method does not utilize dummy sources and, as such, does not require individual seed locations to be identified. Instead, the position of the afterloading catheter is defined as a reference line by connecting its location as seen on the axial CT slices and seed locations defined along its length. Full volumetric calculations can then be performed, including dose-volume histograms (DVH) for critical organs and tumor volumes. Source localization and normal tissue doses were calculated using both orthogonal films and the 3-D method for a series of perineal template guided implants. Point dose calculations of the rectum and bladder were obtained from orthogonal films and were then compared to the corresponding DVHs for these organs.

Brachytherapy↗
PubMed1993

Duchenne/Becker muscular dystrophy carrier detection using quantitative PCR and fluorescence-based strategies.

Dystrophin gene deletions account for up to 68% of all Duchenne (DMD) and Becker (BMD) muscular dystrophy mutations. In affected males, these deletions can be detected easily using multiplex PCR tests which monitor for exon presence. In addition, quantitative dosage screening can discriminate female carriers. We previously analyzed multiplex PCR products by gel electrophoresis and quantitation of fluorescently labeled primers with the Gene Scanner in order to test carrier status. These multiplex PCR protocols detect DMD gene deletions adequately, but require up to 18 pairs of fluorochrome-labeled primers. We previously described two alternative fluorescent labeling strategies, each with approximately 1,000-fold greater sensitivity than ethidium bromide staining, which can be used to quantify the products of multiplex PCR. The first method uses the DNA intercalating thiazole orange dye TOTO-1 to stain PCR products after 20 cycles. In the second method, fluorescein-12,2'-dUTP is incorporated into products during PCR as a fluorescent tag for subsequent quantitative dosage studies. Both methods label all multiplexed exons including the 506 bp exon 48 fragment that is difficult to detect and quantify by standard ethidium bromide staining. Using this approach, we determined DMD/BMD carrier status in 24 unrelated families using a fluorescent fragment analyzer. Analysis of fluorochrome-labeled PCR products facilitates quantitative multiplex PCR for gene-dosage analysis.

Deoxyuracil Nucleotides↗
PubMed1993

Use of Veff and iso-NTCP in the implementation of dose escalation protocols.

PURPOSE: This report investigates the use of a normal tissue complication probability (NTCP) model, 3-D dose distributions, and a dose volume histogram reduction scheme in the design and implementation of dose escalation protocols for irradiation of sites that are primarily limited by the dose to a normal tissue which exhibits a strong volume effect (e.g., lung, liver). METHODS AND MATERIALS: Plots containing iso-NTCP contours are generated as a function of dose and partial volume using a parameterization of a NTCP description. Single step dose volume histograms are generated from 3-D dose distributions using the effective-volume (Veff) reduction scheme. In this scheme, the value of Veff for each dose volume histogram is independent of dose units (Gy, %). Thus, relative dose distributions (%) may be used to segregate patients by Veff into bins containing different ranges of Veff values before the assignment of prescription doses (Gy). The doses for each bin of Veff values can then be independently escalated between estimated complication levels (iso-NTCP contours). RESULTS AND CONCLUSION: Given that for the site under study, an investigator believes that the NTCP parameterization and the Veff methodology at least describe the general trend of clinical expectations, the concepts discussed allow the use of patient specific 3-D dose/volume information in the design and implementation of dose escalation studies. The result is a scheme with which useful prospective tolerance data may be systematically obtained for testing the different NTCP parameterizations and models.

Humans↗
PubMed1993

Bradykinin suppresses alcohol intake and plays a role in the suppression produced by an ACE inhibitor.

The possible role of the endogenous kinins in the control of alcohol intake was assessed in two experiments. In Experiment 1, naive rats, maintained on ad lib food and water, were given daily 40-min access to a 6% (w/v) alcohol solution and water. Daily intraperitoneal (IP) injections of captopril (20 mg/kg) significantly reduced alcohol intake, while pretreatment with subcutaneous (SC) injections of the bradykinin antagonist [D-Phe7]-bradykinin (100-300 micrograms/kg) attenuated the suppressive effect of captopril on alcohol intake. The saline vehicle or the bradykinin antagonist alone did not alter alcohol intake. In Experiment 2, bradykinin was administered daily at 100, 200, and 400 micrograms/kg doses SC either alone or in combination with captopril 10 mg/kg IP. Neither bradykinin nor captopril by themselves changed alcohol or water intake. Bradykinin combined with captopril stimulated water intake and reduced alcohol intake by up to 70%. This effect was not due to drug-induced changes in the pharmacokinetics of alcohol. The angiotensin II receptor antagonist [Sar1,Thr8]-angiotensin II at 250 and 500 micrograms/kg SC attenuated the stimulation of water intake but not the reduction in alcohol intake. It is suggested that by inhibiting kininase II, ACE inhibitors extend the duration of action of bradykinin and thereby unmask a potent inhibition of alcohol intake mediated by kinins--an effect that is dissociable from the accompanying stimulation of water intake. Taken together, these results point to an involvement of the kinin system in the regulation of alcohol intake and in particular to a role of bradykinin in the suppressive effect of ACE inhibitors on alcohol intake.

Alcohol Deterrents↗
PubMed1993

Captopril and hydrochlorothiazide (Capozide) combine to enhance the reduction in voluntary alcohol intake in rats.

The effect of Capozide, the combination of captopril with a hydrochlorothiazide diuretic, on voluntary alcohol intake was assessed in two experiments. In experiment 1 naive rats who were maintained on ad libitum food and water were given daily 40-min access to a 6% (w/v) alcohol solution and water. Daily intraperitoneal injections of captopril (10 mg/kg) reduced alcohol intake, but the combination of captopril (5 and 10 mg/kg) and hydrochlorothiazide (2.5, 5, and 10 mg/kg) enhanced the reduction in intake. In experiment 2, captopril alone, hydrochlorothiazide alone, and the combination of captopril and hydrochlorothiazide were again administered daily in the limited access procedure. Captopril (10 mg/kg) again reduced alcohol intake as did all three doses of hydrochlorothiazide (2.5, 5, and 10 mg/kg). Compared with the individual effects of captopril and hydrochlorothiazide, Capozide exerted a supra-additive reduction in alcohol intake. These effects were not due to drug-induced changes in the pharmacokinetics of alcohol. Taken together these results demonstrate an enhanced potency of Capozide in suppressing alcohol intake and invite their testing in a population of hypertensive alcoholics and alcohol abusers.

Alcohol Drinking↗
PubMed1993

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.

Actuarial Analysis↗
PubMed1993

Modeling mortality in the intensive care unit: comparing the performance of a back-propagation, associative-learning neural network with multivariate logistic regression.

The objective of this study was to compare and contrast two techniques of modeling mortality in a 30 bed multi-disciplinary ICU; neural networks and logistic regression. Fifteen physiological variables were recorded on day 3 for 422 consecutive patients whose duration of stay was over 72 hours. Two separate models were built using each technique. First, logistic and neural network models were constructed on the complete 422 patient dataset and discrimination was compared. Second, the database was randomly divided into a 284 patient developmental dataset and a 138 patient validation dataset. The developmental dataset was used to construct logistic and neural net models and the predictive power of these models was verified on the validation dataset. On the complete dataset, the neural network clearly outperformed the logistic model (sensitivity and specificity of 1 and .997 vs. .525 and .966, area under ROC curve .9993 vs. .9259), while both performed equally well on the validation dataset (area under ROC of .82). The excellent performance of the neural net on the complete dataset reveals that the problem is classifiable. Since our dataset only contained 40 mortality events, it is highly likely that the validation dataset was not representative of the developmental dataset, which led to a decreased predictive performance by both the neural net and the logistic regression models. Theoretically, given an extensive dataset, the neural network should be able to perform mortality prediction with a sensitivity and a specificity approaching 95%. Clinically, this would be an extremely important achievement.(ABSTRACT TRUNCATED AT 250 WORDS)

Hospital Mortality↗
PubMed1993

Conformal high-dose radiation plus intraarterial floxuridine for hepatic cancer.

The role of traditional whole liver irradiation in the treatment of unresectable intrahepatic cancers has been limited by low liver tolerance. The development of three-dimensional (3D) conformal radiation treatment planning offers the potential to treat tumor-bearing portions of the liver to a far higher dose than the entire liver could tolerate, while sparing uninvolved liver. This concept resembles that used by the surgeon, who determines resectability based on the function of the liver anticipated to remain after resection. We have treated patients with unresectable intrahepatic cancers by combining 3D conformal irradiation with intraarterial hepatic floxuridine, which our laboratory studies show is a radiation sensitizer. We have delivered more than 70 Gy to parts of the liver without producing significant radiation hepatitis. Furthermore, the median survivals of patients with primary hepatobiliary cancer (19 months) and colorectal cancer metastatic to the liver (22 months) approach those achieved by surgical excision in a more favorable group of patients.

Aged↗
PubMed1993

Inhibition of intra-abdominal adhesions: fibrin glue in a long term model.

Fibrin glue is being used more frequently to assist in the control of surgical bleeding in the abdominal and thoracic cavities. Prior investigation at this institution has indicated that fibrin glue actually inhibits adhesion formation in the peritoneal cavity of rats up to the first week postoperatively. To ascertain whether this protective effect is borne out in the long term, a randomized study was performed in 42 rats. As in the initial study, bilateral circular peritoneal-muscular defects were created to induce adhesion formation. The right-sided defects were closed linearly with interrupted sutures, thus closing the peritoneum, and the left-sided defects were closed with a continuous suture placed circumferentially, leaving the peritoneal defect open. The rats were randomized to two groups. In 21 animals, the abdomen was closed with no further treatment. In the other 21 animals the defects were covered with fibrin glue made from 0.2 mL of human fibrinogen (31.5 g/L) from cryoprecipitate and 0.2 mL of bovine thrombin and calcium. All rats were killed at 30 days, and adhesions were graded on a scale of 0 to 4 by a blinded observer. In the control group, 15 of 21 rats had high grade adhesions to the closed defect compared with 3 of 21 in the experimental (fibrin glue) group (P = 0.0003). For the left-sided lesions, 16 of 21 animals in the control group had high grade adhesions compared with 2 of 21 animals in the experimental group (P = 0.0004).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

The reinforcing and discriminative stimulus properties of para-ethoxy- and para-methoxyamphetamine.

The purpose of this study was two-fold: 1) to assess the degree to which para-methoxyamphetamine and para-ethoxyamphetamine maintain self-administration behavior, and 2) to determine the similarity or difference between these drugs and amphetamine in drug discrimination tests. Animals were trained to self-administer 0.3 mg/kg/infusion cocaine on a fixed-ratio 5 (FR5) schedule of reinforcement. Substitution of para-ethoxyamphetamine (PEA), para-methoxyamphetamine (PMA), or saline produced similar results; in all cases responding decreased substantially. A separate group of animals was trained to discriminate amphetamine (1 mg/kg) from saline in a fixed-ratio (FR10), food-reinforced paradigm. PEA and PMA produced only limited responding on the amphetamine-appropriate lever (maximum of approximately 30%). Both PMA and PEA had effects on response rate which were similar to those of amphetamine, although PMA had slightly greater rate-decreasing effects than the other two compounds. These data suggest that neither PMA nor PEA are reinforcing in rats, and do not possess amphetamine-like discriminative properties.

Amphetamines↗
PubMed1992

Discriminative stimulus properties of substituted amphetamine derivatives.

Animals were trained to discriminate amphetamine (1 mg/kg) from saline in a fixed-ratio (FR 10), food-reinforced paradigm. Amphetamine-appropriate responding was engendered by the training dose, and by 3 mg/kg, while at lower doses there was a progressive decrease in the extent of responding on the drug-appropriate lever. The following three novel amphetamine derivatives were tested for their ability to produce amphetamine-appropriate responding: 2,5-dimethoxy-4-ethoxy-amphetamine (DMEA); 2,5-dimethoxy-4-methylthio-amphetamine (DMMTA), and 2,4,5-trimethoxy-amphetamine (TMA). DMEA produced only minimal (< 20%) amphetamine-appropriate responding over a dose range of 0.1-10 mg/kg. Substantial decreases in response rate limited testing of the other amphetamines to a dose maximum of 3 mg/kg, but over the range of 0.1-3.0 mg/kg there was little evidence for generalization. At 3 mg/kg of either DMMTA or TMA, only 2 of 10 animals completed at least one uninterrupted FR 10 on either lever, and with either compound only 1 of these 2 animals responded more than 50% on the drug-appropriate lever. Of the three compounds tested, DMMTA had the greatest response rate-decreasing effect.

Amphetamines↗
PubMed1992

The clinical application of a non-axial treatment plan for pancreatic and biliary malignancies.

Standard radiation therapy for adenocarcinoma of the pancreas treats a substantial portion of the renal parenchyma. It was hypothesized that rotating the plane of treatment to a non-axial orientation, with the anterior field entering the patient from an inferior oblique direction, would decrease the renal dose of radiation without increasing the liver dose or compromising the target dose. To test this hypothesis, patients referred for radical radiation treatment for tumors of the pancreas or distal common bile duct were prospectively evaluated by performing treatment planning using axial and non-axial field arrangements. Treatment plans were compared using dose volume histograms (DVHs) of both kidneys and the liver. In all 15 cases analyzed, the non-axial plan was superior to the axial plan with respect to renal dose, without significantly increasing the hepatic dose and was used for treatment. Treatment was not significantly more complex nor was gastrointestinal toxicity increased. These findings show that non-axial field arrangements can be used on a routine basis to decrease the renal dose of radiation for the treatment of pancreatic and biliary malignancies. It is anticipated that in the future, a combination of DVH-guided treatment planning and sophisticated renal function studies will be necessary to permit a more accurate prediction of the probability of renal complications resulting from radiation therapy.

Aged↗