The broad-spectrum antiemetic effects ETI-385 result from stimulation of 5-HT1A and 5-HT1D receptors.

In the present study, we describe how a nonstoichiometric ratio of the isomers of 8-hydroxy-2-(di-n-propylamino)tetralin (DPAT) produce a broad-spectrum of antiemetic effects in cats and shrews. Determination of the receptor profile of the isomers and testing them separately in cats revealed superior antiemetic effects but severe defensive behavior with the R isomer compared with the S isomer. Differing ratios yielded the best results with the 1:8 (R-S) ratio producing a drug more potent than DPAT and with negligible defensive behavior side effects. Studies with selective 5-HT1D ligands led to the conclusion that this site contributes antiemetic efficacy but is not related to defensive behavior, which is most likely a consequence of 5-HT7 receptor activation. ETI-385 was effective in preventing emetic responses to provocative motion, drugs acting at the chemical trigger zone and cisplatin in both cats and shrews. The results support a clinical trial of this drug for antiemetic effects.

Quantitative metrics for assessing plan quality.

Despite many studies over the last 3 decades that have attempted to explicitly quantify the decision-making process for radiotherapy treatment plan evaluation, judgments of an individual plan's degree of quality are still largely subjective and can show inter- and intra-practitioner variability even if the clinical treatment goals are the same. Several factors conspire to confound the full quantification of treatment plan quality, including uncertainties in dose response of cancerous and normal tissue, the rapid pace of new technology adoption, and the human component of treatment planning. However, new developments in clinical informatics and automation are lowering the bar for developing and implementing quantitative metrics into the treatment planning process. This review discusses general strategies for using quantitative metrics in the treatment planning process and presents a case study in intensity-modulated radiation therapy planning whereby control was established on a variable system via such techniques.

Experience-based quality control of clinical intensity-modulated radiotherapy planning.

PURPOSE: To incorporate a quality control tool, according to previous planning experience and patient-specific anatomic information, into the intensity-modulated radiotherapy (IMRT) plan generation process and to determine whether the tool improved treatment plan quality. METHODS AND MATERIALS: A retrospective study of 42 IMRT plans demonstrated a correlation between the fraction of organs at risk (OARs) overlapping the planning target volume and the mean dose. This yielded a model, predicted dose = prescription dose (0.2 + 0.8 [1 - exp(-3 overlapping planning target volume/volume of OAR)]), that predicted the achievable mean doses according to the planning target volume overlap/volume of OAR and the prescription dose. The model was incorporated into the planning process by way of a user-executable script that reported the predicted dose for any OAR. The script was introduced to clinicians engaged in IMRT planning and deployed thereafter. The script's effect was evaluated by tracking δ = (mean dose-predicted dose)/predicted dose, the fraction by which the mean dose exceeded the model. RESULTS: All OARs under investigation (rectum and bladder in prostate cancer; parotid glands, esophagus, and larynx in head-and-neck cancer) exhibited both smaller δ and reduced variability after script implementation. These effects were substantial for the parotid glands, for which the previous δ = 0.28 ± 0.24 was reduced to δ = 0.13 ± 0.10. The clinical relevance was most evident in the subset of cases in which the parotid glands were potentially salvageable (predicted dose <30 Gy). Before script implementation, an average of 30.1 Gy was delivered to the salvageable cases, with an average predicted dose of 20.3 Gy. After implementation, an average of 18.7 Gy was delivered to salvageable cases, with an average predicted dose of 17.2 Gy. In the prostate cases, the rectum model excess was reduced from δ = 0.28 ± 0.20 to δ = 0.07 ± 0.15. On surveying dosimetrists at the end of the study, most reported that the script both improved their IMRT planning (8 of 10) and increased their efficiency (6 of 10). CONCLUSIONS: This tool proved successful in increasing normal tissue sparing and reducing interclinician variability, providing effective quality control of the IMRT plan development process.

Event (error and near-miss) reporting and learning system for process improvement in radiation oncology.

PURPOSE: The value of near-miss and error reporting processes in many industries is well appreciated and typically can be supported with data that have been collected over time. While it is generally accepted that such processes are important in the radiation therapy (RT) setting, studies analyzing the effects of organized reporting and process improvement systems on operation and patient safety in individual clinics remain scarce. The purpose of this work is to report on the design and long-term use of an electronic reporting system in a RT department and compare it to the paper-based reporting system it replaced. METHODS: A specifically designed web-based system was designed for reporting of individual events in RT and clinically implemented in 2007. An event was defined as any occurrence that could have, or had, resulted in a deviation in the delivery of patient care. The aim of the system was to support process improvement in patient care and safety. The reporting tool was designed so individual events could be quickly and easily reported without disrupting clinical work. This was very important because the system use was voluntary. The spectrum of reported deviations extended from minor workflow issues (e.g., scheduling) to errors in treatment delivery. Reports were categorized based on functional area, type, and severity of an event. The events were processed and analyzed by a formal process improvement group that used the data and the statistics collected through the web-based tool for guidance in reengineering clinical processes. The reporting trends for the first 24 months with the electronic system were compared to the events that were reported in the same clinic with a paper-based system over a seven-year period. RESULTS: The reporting system and the process improvement structure resulted in increased event reporting, improved event communication, and improved identification of clinical areas which needed process and safety improvements. The reported data were also useful for the evaluation of corrective measures and recognition of ineffective measures and efforts. The electronic system was relatively well accepted by personnel and resulted in minimal disruption of clinical work. Event reporting in the quarters with the fewest number of reported events, though voluntary, was almost four times greater than the most events reported in any one quarter with the paper-based system and remained consistent from the inception of the process through the date of this report. However, the acceptance was not universal, validating the need for improved education regarding reporting processes and systematic approaches to reporting culture development. CONCLUSIONS: Specially designed electronic event reporting systems in a radiotherapy setting can provide valuable data for process and patient safety improvement and are more effective reporting mechanisms than paper-based systems. Additional work is needed to develop methods that can more effectively utilize reported data for process improvement, including the development of standardized event taxonomy and a classification system for RT.

Criticality accident dosimetry by chromosomal analysis.

The technique of measuring the frequency of dicentric chromosomal aberrations in blood lymphocytes was used to estimate doses in a simulated criticality accident. The simulation consisted of three exposures; approximately 5 Gy with a bare source and 1 and 2 Gy with a lead-shielded source. Three laboratories made separate estimates of the doses. These were made by the iterative method of apportioning the observed dicentric frequencies between the gamma and neutron components, taking account of a given gamma/neutron dose ratio, and referring the separated dicentric frequencies to dose-response calibration curves. An alternative method, based on Bayesian ideas, was employed. This was developed for interpreting dicentric frequencies in situations where the gamma/neutron ratio is uncertain. Both methods gave very similar results. One laboratory produced dose estimates close to the eventual exercise reference doses and the other laboratories estimated slightly higher values. The main reason for the higher values was the calibration relationships for fission neutrons.

Bayesian methods for chromosome dosimetry following a criticality accident.

Radiation doses received during a criticality accident will be from a combination of fission spectrum neutrons and gamma rays. It is desirable to estimate the total dose, as well as the neutron and gamma doses. Present methods for dose estimation with chromosome aberrations after a criticality accident use point estimates of the neutron to gamma dose ratio obtained from personnel dosemeters and/or accident reconstruction calculations. In this paper a Bayesian approach to dose estimation with chromosome aberrations is developed which allows the uncertainty of the dose ratio to be considered. Posterior probability densities for the total and the neutron and gamma doses were derived.

Bayesian analysis of overdispersed chromosome aberration data with the negative binomial model.

The usual assumption of a Poisson model for the number of chromosome aberrations in controlled calibration experiments implies variance equal to the mean. However, it is known that chromosome aberration data from experiments involving high linear energy transfer radiations can be overdispersed, i.e. the variance is greater than the mean. Present methods for dealing with overdispersed chromosome data rely on frequentist statistical techniques. In this paper. the problem of overdispersion is considered from a Bayesian standpoint. The Bayes Factor is used to compare Poisson and negative binomial models for two previously published calibration data sets describing the induction of dicentric chromosome aberrations by high doses of neutrons. Posterior densities for the model parameters, which characterise dose response and overdispersion are calculated and graphed. Calibrative densities are derived for unknown neutron doses from hypothetical radiation accident data to deterimine the impact of different model assumptions on dose estimates. The main conclusion is that an initial assumption of a negative binomial model is the conservative approach to chromosome dosimetry for high LET radiations.

Supracervical hysterectomy: back to the future?

Supracervical hysterectomy, commonly performed in the earlier decades of this century, is rarely performed in contemporary practice. The desire to prevent future cervical cancer initially underlay the advocacy of total hysterectomy. Cervical cytologic screening and effective outpatient treatment of preinvasive cervical disease are commonly available. Cancer of the cervical stump is an uncommon and largely preventable occurrence. Removal of the normal cervix reportedly may have adverse effects on bladder, bowel, and sexual function. Reduced operating time and a shorter recovery period may be associated with a supracervical procedure. The risk of subsequent cervical cancer may not outweigh the benefits of supracervical hysterectomy, which should be offered as an option to selected patients. Supracervical hysterectomy by minilaparotomy is within the capability of practicing gynecologists and may be adaptable to outpatient short-stay surgery, offering a cost-effective alternative for a variety of gynecologic conditions.

Selected use of midline episiotomy: effect on perineal trauma.

A prospective, nonrandomized controlled study was performed to determine the effect of using midline episiotomy only for mothers who experienced fetal distress and/or operative vaginal delivery. Such a policy resulted in a significant decline in third- and fourth-degree lacerations in nulliparous women. This reduction was most pronounced in nulliparous women delivering infants larger than 3400 g. No third- or fourth-degree laceration occurred without antecedent episiotomy in any woman. A policy of using episiotomy selectively appears to lower the incidence of perineal trauma.

Comparison of pharyngeal aspirate and amniotic fluid surfactant composition.

Amniotic fluid and oropharyngeal aspirate lung maturity profiles obtained simultaneously at delivery in 16 patients are compared. The lecithin/sphingomyelin ratio was greater in oropharyngeal aspirates than in amniotic fluid (p less than 0.02). The percent phosphatidylinositol was greater in oropharyngeal aspirates than in amniotic fluid (p less than 0.03). The mean differences between percent phosphatidylglycerol were not significant. These findings were uninfluenced by the time interval between amniotic fluid and oropharyngeal sampling, gestational age, or neonatal weight. These data could explain the lack of sensitivity of the amniotic fluid lung maturity profile.

Preeclampsia associated with hemolysis, elevated liver enzymes, and low platelets--an obstetric emergency?

A study was undertaken of 27 patients with severe preeclampsia who had hemolysis, liver enzyme elevation, and thrombocytopenia as described by Weinstein. In addition to this triad, all patients exhibited the symptoms and signs of pregnancy-induced hypertension by which the diagnosis is usually established. These patients were admitted to the hospital for strict bed rest. Patients who showed evidence of rapid maternal or fetal deterioration were delivered promptly. The remainder were managed without immediate delivery and with the institution of magnesium sulfate to prevent eclamptic seizures. Patients were monitored closely, and amniocentesis was performed to ascertain fetal lung status. If the lungs were mature, the infant was delivered. Attempting to delay delivery until a lecithin: sphingomyelin (L:S) ratio was mature resulted in only two infants developing respiratory distress syndrome (RDS); both had L:S ratios of less than 1.5 and were delivered for maternal indications. Maternal condition rapidly improved within 72 hours of delivery, and there was no persistence of thrombocytopenia or elevation of liver enzymes. Immediate delivery of preeclamptic patients who have thrombocytopenia and elevated liver enzymes may not be warranted. These findings suggest that the syndrome of hemolysis, elevated liver enzymes, and low platelets is not a separate entity, but merely a cluster of signs seen in some patients with hypertensive disorders in pregnancy.

Vaginal pool phospholipids in the management of premature rupture of membranes.

Clinical utility of vaginal pool amniotic fluid assessment in premature rupture of the membranes was prospectively studied in 214 patients between July 1, 1978, and June 30, 1981. We used a policy of nonintervention in patients with premature rupture of the membranes prior to 36 weeks' gestation. Vaginal samples collected on admission and daily thereafter were analyzed for phospholipids. Patients underwent delivery for any one of these conditions: (1) presence of phosphatidylglycerol, (2) spontaneous labor, or (3) sepsis. One hundred sixty-seven patients had no phosphatidylglycerol initially. Thirty-six of these acquired phosphatidylglycerol, and none had respiratory distress syndrome. Eight patients underwent delivery because of signs of sepsis in the mother, but all infants of septic mothers survived. The newborn infants of 49 patients developed the respiratory distress syndrome, and among these there were six deaths, with no maternal deaths. We believe that these results confirm the value of phosphatidylglycerol in patients with premature rupture of the membranes, and that delay in patients from premature rupture of the membranes results in few infections and a significant decrease in the respiratory distress syndrome.

Comparison of amniotic fluid lung maturity profiles in paired vaginal and amniocentesis specimens.

Amniotic fluid was obtained by transvaginal amniocentesis from 27 pregnant women in the third trimester. Subsequent to amniocentesis, membranes were ruptured and vaginal pool amniotic fluid was taken by bulb aspiration. The samples were analyzed for lung maturity profile, consisting of the lecithin/sphingomyelin (L/S) ratio and the percentages of phosphatidylinositol and phosphatidylglycerol. The L/S ratio was higher in the vaginal pool than in the amniotic sac in 22% of the paired samples. Similarly, the percentage of phosphatidylinositol was greater in the vaginal pool than in the amniotic sac in 48%. Phosphatidylglycerol, however, is invariably present in the amniotic sac when it is detected in the vaginal pool. The possible usefulness of these results in the management of patients with premature rupture of membranes is discussed.

Clinical utility of fetal lung maturity profile.

The usefulness of the lung maturity profile in predicting the absence of respiratory distress syndrome (RDS) in the newborn was assessed in 356 patients with an obstetric indication for amniocentesis. Newborn infants delivered of mothers with a lecithin:sphingomyelin (L:S) ratio greater than 2.0, phosphatidylinositol at a level indicating maturity, and phosphatidylglycerol greater than 2% experienced no RDS. Twenty-six of 40 patients with studies indicating immaturity, in contrast, experienced RDS. Similarly, 20 infants who were predicted to be mature by L:S ratio but in whom no phosphatidylglycerol was present experienced a 40% incidence of RDS. In a small number of patients in whom the L:S ratio suggested that the fetal lung was immature, but in whom the phosphatidylglycerol level was greater than 2%, no RDS occurred. These results suggest that a mature lung profile is more valuable in predicting absence of RDS in the newborn than the L:S ratio alone. Certain conditions known to be associated with development of RDS in the newborn may be more accurately assessed by the presence or absence of phosphatidylglycerol in amniotic fluid. Although the series is small, it appears that the presence of phosphatidylglycerol even with an immature L:S ratio predicts that the newborn will be free of RDS.

Residency education in the 1980's.

It appears that great changes in residency education will be made in the 1980's. These changes not only portend excitement and improvement, but also predicate troublesome and trying times. Medical schools must take a more active part in residency training and may ultimately take full responsibility. Educational institutions will be asked to guarantee the intellectual and technical competence of their postgraduate trainees by tightly structuring the educational effort, and this obligation rightfully inures to the medical school rather than the hospital. Training programs must develop methods of using all private populations for postgraduate education that will reach at least the level of that achieved with nonprivate patients. Training programs must utilize community hospitals, and the desirable components of academia must be introduced into these institutions. As difficult to achieve as it is simple to state, new sources of funding must be found for postgraduate education. Finally, there eventually may be a need to devise entirely new concepts of training based on career goals, and the 1980's will provide fertile ground for those faculties that wish to be imaginative and innovative.