Alicia Y. Toledano

Spatial and temporal control of gene therapy using ionizing radiation

Activation of transcription of the Egr-1 gene by X-rays is regulated by the promoter region of this gene. We linked the radiation-inducible promoter region of the Egr-1 gene to the gene encoding the radiosensitizing and tumoricidal cytokine, tumour necrosis factor-α (TNF-α) and used a replication-deficient adenovirus to deliver the Egr-TNF construct to human tumours growing in nude mice. Combined treatment with Ad5.Egr-TNF and 5,000 cGy (rad) resulted in increased intratumoral TNF-α production and increased tumour control compared with treatment with Ad5.Egr-TNF alone or with radiation alone. The increase in tumour control was achieved without an increase in normal tissue damage when compared to tissue injury from radiation alone. Control of gene transcription by iohizing radiation in vivo represents a novel method of spatial and temporal regulation of gene-based medical treatments.

Methylnaltrexone prevents morphine-induced delay in oral-cecal transit time without affecting analgesia: a double-blind randomized placebo-controlled trial.

Methylnaltrexone is a quaternary opioid antagonist with limited ability to cross the blood‐brain barrier and the potential to antagonize the peripherally mediated effects of opioids. The effectiveness of methylnaltrexone in preventing morphine‐induced changes in gastrointestinal motility and transit without affecting analgesia was evaluated in humans. Twelve healthy volunteers were given intravenous placebo, placebo plus 0.05 mg/kg morphine, or 0.45 mg/kg methylnaltrexone plus 0.05 mg/kg morphine. Oral‐cecal transit time was assessed by the pulmonary hydrogen measurement technique, and analgesia was measured with use of the cold‐pressor test. Morphine significantly increased oral‐cecal transit time from 104.6 ± 31.1 minutes (mean ± SD) to 163.3 ± 39.8 minutes (p < 0.01). Methylnaltrexone prevented 97% of morphine‐induced increase in oral‐cecal transit time (106.3 ± 39.8 minutes; not significant compared with baseline; p < 0.01 compared with morphine alone). Methylnaltrexone did not affect the analgesic effect of morphine on both pain intensity and pain bothersomeness ratings. At a higher dose of morphine (0.1 mg/kg), our preliminary results indicated that 0.45 mg/kg methylnaltrexone also prevented the morphine‐induced delay in oral‐cecal transit time, with no effect on analgesia. Methylnaltrexone may be a useful adjunct to opioids for the relief of opioid‐induced constipation.

The safety and efficacy of oral methylnaltrexone in preventing morphine‐induced delay in oral‐cecal transit time

Methylnaltrexone is a quaternary opioid antagonist with limited ability to cross the blood‐brain barrier that has the potential to antagonize the peripherally mediated gastrointestinal effects of opioids. In recent trials in human volunteers, we demonstrated that intravenous methylnaltrexone prevented morphine‐induced changes in gastroin‐testinal motility and transit, without affecting analgesia. In this study, 14 healthy volunteers were first given three ascending oral doses of methylnaltrexone to obtain safety and tolerance data (phase A study). In phase B, these subjects were then given single‐blind oral placebo and intravenous placebo, followed by randomized, double‐blind oral placebo and intravenous morphine (0.05 mg/kg) or oral methylnaltrexone (19.2 mg/kg, an established highest and safe dose based on previous administrations of two smaller doses of 0.64 mg/kg and 6.4 mg/kg in phase A) and intravenous morphine (0.05 mg/kg). Oral‐cecal transit time was assessed by the pulmonary hydrogen measurement technique after lactulose ingestion. Morphine significantly increased oral‐cecal transit time from 114.6 ± 37.0 minutes (mean ± SD) to 158.6 ± 50.2 minutes (p < 0.001). Oral methylnaltrexone (19.2 mg/kg) completely prevented morphine‐induced increase in oral‐cecal transit time (110.4 ± 45.0 minutes; not significant compared with baseline; p < 0.005 compared with morphine alone). These sessions were then followed by single‐blind evaluations of descending doses of methylnaltrexone. We observed that 6.4 mg/kg oral methylnaltrexone significantly attenuated the morphine‐induced delay in oral‐cecal transit time (p < 0.005 compared with morphine alone), and a dose‐dependent response was obtained. There was no correlation between oral methylnaltrexone effects on the transit time and the drug plasma concentration, suggesting direct preferential luminal effects of oral methylnaltrexone. Oral methylnaltrexone may have a clinical value in the prevention and treatment of constipation induced by long‐term opioid use.

Computerized tomographic colonography: Performance evaluation in a retrospective multicenter setting

BACKGROUND & AIMS No multicenter study has been reported evaluating the performance and interobserver variability of computerized tomographic colonography. The aim of this study was to assess the accuracy of computerized tomographic colonography for detecting clinically important colorectal neoplasia (polyps >or=10 mm in diameter) in a multi-institutional study. METHODS A retrospective study was developed from 341 patients who had computerized tomographic colonography and colonoscopy among 8 medical centers. Colonoscopy and pathology reports provided the standard. A random sample of 117 patients, stratified by criterion standard, was requested. Ninety-three patients were included (47% with polyps >or=10 mm; mean age, 62 years; 56% men; 84% white; 40% reported colorectal symptoms; 74% at increased risk for colorectal cancer). Eighteen radiologists blinded to the criterion standard interpreted computerized tomography colonography examinations, each using 2 of 3 different software display platforms. RESULTS The average area under the receiver operating characteristic curve for identifying patients with at least 1 lesion >or=10 mm was 0.80 (95% lower confidence bound, 0.74). The average sensitivity and specificity were 75% (95% lower confidence bound, 68%) and 73% (95% lower confidence bound, 66%), respectively. Per-polyp sensitivity was 75%. A trend was observed for better performance with more observer experience. There was no difference in performance across software display platforms. CONCLUSIONS Computerized tomographic colonography performance compared favorably with reported performance of fecal occult blood testing, flexible sigmoidoscopy, and barium enema. A prospective study evaluating the performance of computerized tomography colonography in a screening population is indicated.

ORDINAL REGRESSION METHODOLOGY FOR ROC CURVES DERIVED FROM CORRELATED DATA

We present an approach for the analysis of correlated ROC data, using ordinal regression models in conjunction with generalized estimating equations. The approach applies to the analysis of degree-of-suspicion data derived from multiple interpretations of the same diagnostic study and from the examination of the same patients with multiple diagnostic modalities. The regression models make it possible to incorporate patient and reader characteristics into the analysis, without having to resort to stratification. We illustrate the potential of the approach with analysis of data from two studies in diagnostic oncology.

JOURNAL CLUB: Molecular Breast Imaging at Reduced Radiation Dose for Supplemental Screening in Mammographically Dense Breasts

OBJECTIVE. The purpose of this study was to assess the diagnostic performance of supplemental screening molecular breast imaging (MBI) in women with mammographically dense breasts after system modifications to permit radiation dose reduction. SUBJECTS AND METHODS. A total of 1651 asymptomatic women with mammographically dense breasts on prior mammography underwent screening mammography and adjunct MBI performed with 300-MBq (99m)Tc-sestamibi and a direct-conversion (cadmium zinc telluride) gamma camera, both interpreted independently. The cancer detection rate, sensitivity, specificity, and positive predictive value of biopsies performed (PPV3) were determined. RESULTS. In 1585 participants with a complete reference standard, 21 were diagnosed with cancer: two detected by mammography only, 14 by MBI only, three by both modalities, and two by neither. Of 14 participants with cancers detected only by MBI, 11 had invasive disease (median size, 0.9 cm; range, 0.5-4.1 cm). Nine of 11 (82%) were node negative, and two had bilateral cancers. With the addition of MBI to mammography, the overall cancer detection rate (per 1000 screened) increased from 3.2 to 12.0 (p < 0.001) (supplemental yield 8.8). The invasive cancer detection rate increased from 1.9 to 8.8 (p < 0.001) (supplemental yield 6.9), a relative increase of 363%, while the change in DCIS detection was not statistically significant (from 1.3 to 3.2, p =0.250). For mammography alone, sensitivity was 24%; specificity, 89%; and PPV3, 25%. For the combination, sensitivity was 91% (p < 0.001); specificity, 83% (p < 0.001); and PPV3, 28% (p = 0.70). The recall rate increased from 11.0% with mammography alone to 17.6% (p < 0.001) for the combination; the biopsy rate increased from 1.3% for mammography alone to 4.2% (p < 0.001). CONCLUSION. When added to screening mammography, MBI performed using a radiopharmaceutical activity acceptable for screening (effective dose 2.4 mSv) yielded a supplemental cancer detection rate of 8.8 per 1000 women with mammographically dense breasts.

Adenosine receptor blockade and nitric oxide synthase inhibition in the retina: Impact upon post-ischemic hyperemia and the electroretinogram

We preformed this study to determine the effect on ocular blood flow and the electroretinogram of either nitric oxide synthase (NOS) inhibition, adenosine receptor blockade or the combination of both after 1 hr of ocular ischemia. Thirty-seven cats under general anesthesia were subjected to 1 hr of complete ischemia in one eye by raising the intraocular pressure above systolic blood pressure. The other eye in each animal served as a non-ischemic control. Arterial blood gas tension, systemic arterial pressure, body temperature, hematocrit, and anesthetic level were controlled in each experiment. Cats were divided into four groups. Group 1 received normal saline injections [intravenous (i.v.) and intravitreal], Group 2 adenosine receptor blockade (0.1 ml of 0.01 M 8-sulfophenyltheophylline intravitreal) and saline i.v., Group 3 NOS inhibition (30 mg/kg l-NG-nitroarginine-methyl-ester i.v.) and saline intravitreal, and Group 4 intravitreal adenosine receptor blockade and NOS inhibition i.v. A subset of Group 3 received l-arginine to investigate the reversibility of NOS inhibition, after the blood flow measurements were completed. Five minutes after the end of ischemia, blood flows in retina and choroid were measured using injections of radioactively labeled microspheres. Electroretinographic (ERG) studies were carried out before treatment, before ischemia, during ischemia, and 1, 2, 3, and 4 hr after ischemia ended. NOS inhibition significantly reduced basal blood flow in the choroid, and in the retina when combined with adenosine receptor blockade. Adenosine receptor blockade completely attenuated post-ischemic hyperemia in the retina, but retinal hyperemia reappeared when adenosine receptor blockade and NOS inhibition were combined. Adenosine receptor blockade had no effect on ERG recovery after ischemia. NOS inhibition led to a reduction of ERG a- and b-wave amplitudes in control eyes, that could be reversed by l-arginine. Nitric oxide (NO) appears to be a significant factor in the regulation of basal blood flow in the choroid. Adenosine appears to be a major mediator of retinal hyperemia after 60 min of ischemia. Since NOS inhibition appeared to have direct effects on ERG wave amplitudes, short-term ERG studies may be of limited use in assessing the role of NO in postischemic recovery of the retina. Our observations correlate well with the emerging role of NO as a neurotransmitter in the retina.

Technology assessment and the "learning contamination" bias.

n an article in this issue, Wang et al. (1) conclude that there were no differences in outcome between I patients who received end-tidal anesthetic monitoring and those who did not. There are several reasons why this lack of difference could occur. First, there may not have been a sufficient number of patients per group for differences to be found if they existed. Second, the protocol specified antagonizing residual neuromuscular blockade and discontinuing anesthetic 3-5 min before the end of surgery. This protocol could preclude the anesthesiologist from judging appropriate anesthetic depth independently, thereby decreasing the value of end-tidal monitoring. Future studies may address these two issues by using more patients in each group and a protocol that more closely resembles actual clinical practice. We wish to focus, however, on a third possible reason that outcomes were not different between monitored and unmonitored patients. This reason has implications for technology assessment studies in general: technology teaches practitioners who use it for a small segment of patients, thereby improving outcome for all their patients. The design of the study by Wang et al. (1) involved six groups, based on three dose combinations crossed with two monitoring situations (monitored or unmonitored). In the monitored groups, physicians may have learned from the act of monitoring itself. The learning transfers to practice in the unmonitored groups, improving their outcomes as well. When outcomes in the monitored and unmonitored groups are compared, such a design biases toward a conclusion of no difference in outcome attributable to the technology. A danger in rejecting the technology as of no benefit is that the learning from it will no longer be reinforced. Outcomes could worsen in future patients because no patients would be monitored and no learning would occur.

Effective analgesia after bilateral tubal ligation.

Postpartum bilateral tubal ligation is a brief surgical procedure with minimal tissue injury, yet postoperative recovery times and analgesia requirements are often disproportionately large.To evaluate the analgesic efficacy of local anesthetic infiltration, 20 parturients scheduled for elective minilaparotomy and bilateral tubal ligation with either spinal or epidural anesthesia participated in this prospective, randomized, controlled, double-blind trial. All patients received IV metoclopramide 10 mg and ketorolac 60 mg intraoperatively, as well as preincisional infiltration of the infraumbilical skin incision with 0.5% bupivacaine. Infiltration of bilateral uterine tubes and mesosalpinx was performed with either 0.5% bupivacaine (n = 10) or isotonic sodium chloride solution (saline) (n = 10). IV meperidine (25 mg every 3 min as needed) was given to treat pain in the postanesthesia care unit (PACU). The total amount of meperidine administered in the PACU was significantly larger in the saline group than in the bupivacaine group. Pain scores at 30, 45, 60, 75, and 90 min postoperatively and on the seventh postoperative day were significantly lower in the bupivacaine group than in the saline group. During tubal ligation, infiltration of uterine tubes and mesosalpinx with 0.5% bupivacaine significantly enhanced analgesia both in the immediate postoperative setting and on the seventh postoperative day compared with infiltration with sodium chloride. Implications: During bilateral tubal ligation with either spinal or epidural anesthesia, preemptive analgesia using IV ketorolac, IV metoclopramide, and infiltration of the incised skin and uterine tubes with 0.5% bupivacaine allowed 9 of 10 patients to recover with no pain, nausea, vomiting, or cramping and to maintain good analgesia for 7 days postoperatively. (Anesth Analg 1998;87:619-23)

Can radiologist training and testing ensure high performance in CT colonography? Lessons from the national CT colonography trial

OBJECTIVE The objective of this article is to describe the experience of the National CT Colonography Trial with radiologist training and qualification testing at CT colonography (CTC) and to correlate this experience with subsequent performance in a prospective screening study. SUBJECTS AND METHODS Ten inexperienced radiologists participated in a 1-day educational course, during which partial CTC examinations of 27 cases with neoplasia and full CTC examinations of 15 cases were reviewed using primary 2D and 3D search. Subsequently 15 radiologists took a qualification examination composed of 20 CTC cases. Radiologists who did not pass the first qualification examination attended a second day of focused retraining of 30 cases, which was followed by a second qualification examination. The results of the initial and subsequent qualification tests were compared with reader performance in a large prospective screening trial. RESULTS All radiologists took and passed the qualification examinations. Seven radiologists passed the qualification examination the first time it was offered, and eight radiologists passed after focused retraining. Significantly better sensitivities were obtained on the second versus the first examination for the retrained radiologists (difference = 16%, p < 0.001). There was no significant difference in sensitivities between the groups who passed the qualification examination the first time versus those who passed the second time in the prospective study (88% vs 92%, respectively; p = 0.612). In the prospective study, the odds of correctly identifying diseased cases increased by 1.5 fold for every 50-case increase in reader experience or formal training (p < 0.025). CONCLUSION A significant difference in performance was observed among radiologists before formalized training, but testing and focused retraining improved radiologist performance, resulting in an overall high sensitivity across radiologists in a subsequent, prospective screening study.