Assessment of the Non-Technical Skills for Surgeons (NOTSS) framework in the USA.

BACKGROUND: Surgeons' non-technical skills are important for patient safety. The Non-Technical Skills for Surgeons assessment tool was developed in the UK and recently adapted to the US surgical context (NOTSS-US). The aim of this study was to evaluate the reliability and distribution of non-technical skill ratings given by attending (consultant) surgeons who underwent brief online training. METHODS: Attending surgeons across six specialties at a large US academic medical centre underwent a 10-min online training, then rated 60-s standardized videos of simulated operations. Intraclass correlation coefficient (ICC), and mean(s.d.) values for NOTSS-US ratings were determined for each non-technical skill category (score range 1-5, where 1 indicates poor, 3 average and 5 excellent) and for total NOTSS-US score (range 4-20; sum of 4 category scores). Outcomes were adjusted for rater characteristics including sex, specialty and clinical experience. RESULTS: A total of 8889 ratings were submitted by 81 surgeon raters on 30 simulated intraoperative videos. The mean(s.d.) total NOTSS-US score for all videos was 9·5(4·8) of 20. The within-video ICC for total NOTSS-US score was 0·64 (95 per cent c.i. 0·57 to 0·70). For individual non-technical skill categories, the ICC was highest for social skills (communication/teamwork: 0·63, 95 per cent c.i. 0·56 to 0·71; leadership: 0·64, 0·55 to 0·72) and lowest for cognitive skills (situation awareness: 0·54, 0·45 to 0·62; decision-making: 0·50, 0·41 to 0·59). Women gave higher total NOTSS-US scores than men (adjusted mean difference 0·93, 95 per cent c.i. 0·44 to 1·43; P = 0·001). CONCLUSION: After brief online training, the inter-rater reliability of the NOTSS-US assessment tool achieved moderate strength among trained surgeons rating simulated intraoperative videos.

ANTECEDENTES: Las habilidades no técnicas de los cirujanos (Non-Technical Skills for Surgeons, NOTSS) son importantes para la seguridad del paciente. La herramienta de evaluación de habilidades no técnicas para cirujanos se desarrolló en el Reino Unido y se adaptó recientemente al contexto quirúrgico de los Estados Unidos (NOTSS-US.). El objetivo de este estudio fue evaluar la fiabilidad y distribución de las calificaciones de habilidades no técnicas obtenidas por cirujanos adjuntos de cirugía (consultores) que recibieron una breve formación online. MÉTODOS: Cirujanos adjuntos de 6 especialidades en un gran centro universitario de Estados Unidos recibieron una formación online de 10 minutos de duración y seguidamente puntuaron vídeos estandarizados de operaciones simuladas de 60 minutos de duración. Se calcularon el coeficiente de correlación intraclase (intraclass correlation coefficient, ICC), la media y la desviación estándar (standard deviation, SD) para la puntuación de cada categoría de habilidad no técnica del NOTSS-US (rango 1-5, siendo 1 = pobre, 3 = promedio, 5 = excelente) y para la puntuación global de NOTSS-US (rango 4-20, suma de las puntuaciones de las cuatro categorías). Los resultados se ajustaron de acuerdo con las características del evaluador, incluyendo sexo, especialidad, experiencia clínica. RESULTADOS: En 30 videos intraoperatorios simulados, 81 cirujanos evaluadores proporcionaron 8.889 puntaciones. La puntuación media global de NOTSS-US para todos los vídeos fue de 9,5 sobre 20 (SD 4,8). El ICC de los vídeos para la puntuación global de NOTSS-US fue 0,64 (i.c. del 95% 0,57-0,70). Para las categorías individuales de habilidades no técnicas, el ICC más alto fue para las habilidades sociales (comunicación / trabajo en equipo: 0,63, (i.c. del 95% 0,56-0,71); liderazgo, 0,64 (i.c. del 95% 0,55-0,72)) y el más bajo para las habilidades cognitivas (conciencia de la situación 0,54 (i.c. del 95% 0,45-0,62); toma de decisiones 0,50 (i.c. del 95% 0,41-0,59)). Las evaluadoras femeninas presentaron puntuaciones globales de NOTSS-US más altas que los evaluadores masculinos (diferencia 0,93, i.c. del 95% 0,44-1,43; P = 0,001)). CONCLUSIÓN: Después de una breve formación online, la fiabilidad de la herramienta de evaluación NOTSS-US mostró una correlación moderada entre los cirujanos que puntuaron vídeos de simulaciones de intervenciones quirúrgicas.

Variation in global uptake of the Surgical Safety Checklist.

BACKGROUND: The Surgical Safety Checklist (SSC) is a patient safety tool shown to reduce mortality and to improve teamwork and adherence with perioperative safety practices. The results of the original pilot work were published 10 years ago. This study aimed to determine the contemporary prevalence and predictors of SSC use globally. METHODS: Pooled data from the GlobalSurg and Surgical Outcomes studies were analysed to describe SSC use in 2014-2016. The primary exposure was the Human Development Index (HDI) of the reporting country, and the primary outcome was reported SSC use. A generalized estimating equation, clustering by facility, was used to determine differences in SSC use by patient, facility and national characteristics. RESULTS: A total of 85 957 patients from 1464 facilities in 94 countries were included. On average, facilities used the SSC in 75·4 per cent of operations. Compared with very high HDI, SSC use was less in low HDI countries (odds ratio (OR) 0·08, 95 per cent c.i. 0·05 to 0·12). The SSC was used less in urgent compared with elective operations in low HDI countries (OR 0·68, 0·53 to 0·86), but used equally for urgent and elective operations in very high HDI countries (OR 0·96, 0·87 to 1·06). SSC use was lower for obstetrics and gynaecology versus abdominal surgery (OR 0·91, 0·85 to 0·98) and where the common or official language was not one of the WHO official languages (OR 0·30, 0·23 to 0·39). CONCLUSION: Worldwide, SSC use is generally high, but significant variability exists. Implementation and dissemination strategies must be developed to address this variability.

ANTECEDENTES: Se ha demostrado que la utilización de la lista de verificación de seguridad quirúrgica (Surgical Safety Checklist, SSC) reduce la mortalidad y mejora el trabajo en equipo, así como el cumplimiento de las prácticas de seguridad perioperatorias. Los resultados de un trabajo piloto original se publicaron hace 10 años. El objetivo de este estudio fue determinar la prevalencia actual y los predictores de uso de la SSC a nivel mundial. MÉTODOS: Se analizaron los datos agrupados de los estudios GlobalSurg y Surgical Outcomes para describir la utilización de la SSC entre 2014-2016. La principal variable de exposición fue el índice de desarrollo humano (Human Development Index, HDI) del país informante y la principal variable de resultado, la tasa de utilización de la SCC. Para determinar las diferencias en la utilización de la SSC por paciente, centro y características nacionales se utilizó una ecuación de estimación generalizada con conglomerados por centros. RESULTADOS: Se incluyeron 85.957 pacientes de 1.464 centros en 94 países. La tasa media de utilización de la SSC fue del 75,4% de las operaciones. Al compararlos con países de HDI muy alto, la utilización de la SCC fue menor en los países con HDI bajo (razón de oportunidades, odds ratio, OR 0,08, i.c. del 95% 0,05-0,12). En países con HDI bajo, la SSC se utilizó menos en operaciones urgentes en comparación con operaciones electivas (OR 0,68, i.c. del 95% 0,53- 0,86) a diferencia de los países con HDI elevado, en los que se utilizó por igual en ambas situaciones (OR 0,96, i.c. del 95% 0,87-1,06). La utilización de la SSC fue menor en operaciones de obstetricia y ginecología que en cirugía abdominal (OR 0,91, i.c. del 95% 0,85 a 0,98) y en aquellos países en los que el idioma habitual u oficial era diferente a los idiomas oficiales de la OMS (OR 0,30, i.c. del 95% 0,23 a 0,39). CONCLUSIÓN: A nivel mundial, el uso de SSC en general es alto, pero existe una variabilidad significativa. Se deben desarrollar estrategias de implementación y difusión para resolver esta variabilidad.

Reducing surgical mortality in Scotland by use of the WHO Surgical Safety Checklist.

BACKGROUND: The WHO Surgical Safety Checklist has been implemented widely since its launch in 2008. It was introduced in Scotland as part of the Scottish Patient Safety Programme (SPSP) between 2008 and 2010, and is now integral to surgical practice. Its influence on outcomes, when analysed at a population level, remains unclear. METHODS: This was a population cohort study. All admissions to any acute hospital in Scotland between 2000 and 2014 were included. Standardized differences were used to estimate the balance of demographics over time, after which interrupted time-series (segmented regression) analyses were performed. Data were obtained from the Information Services Division, Scotland. RESULTS: There were 12 667 926 hospital admissions, of which 6 839 736 had a surgical procedure. Amongst the surgical cohort, the inpatient mortality rate in 2000 was 0·76 (95 per cent c.i. 0·68 to 0·84) per cent, and in 2014 it was 0·46 (0·42 to 0·50) per cent. The checklist was associated with a 36·6 (95 per cent c.i. -55·2 to -17·9) per cent relative reduction in mortality (P < 0·001). Mortality rates before implementation were decreasing by 0·003 (95 per cent c.i. -0·017 to +0·012) per cent per year; annual decreases of 0·069 (-0·092 to -0·046) per cent were seen during, and 0·019 (-0·038 to +0·001) per cent after, implementation. No such improvement trends were seen in the non-surgical cohort over this time frame. CONCLUSION: Since the implementation of the checklist, as part of an overall national safety strategy, there has been a reduction in perioperative mortality.

Variation in expenditure for common, high cost surgical procedures in a working age population: implications for reimbursement reform.

BACKGROUND: In the move toward value-based care, bundled payments are believed to reduce waste and improve coordination. Some commercial insurers have addressed this through the use of bundled payment, the provision of one fee for all care associated with a given index procedure. This system was pioneered by Medicare, using a population generally over 65 years of age, and despite its adoption by mainstream insurers, little is known of bundled payments' ability to reduce variation or cost in a working-age population. This study uses a universally-insured, nationally-representative population of adults aged 18-65 to examine the effect of bundled payments for five high-cost surgical procedures which are known to vary widely in Medicare reimbursement: hip replacement, knee replacement, coronary artery bypass grafting (CABG), lumbar spinal fusion, and colectomy. METHODS: Five procedures conducted on adults aged 18-65 were identified from the TRICARE database from 2011 to 2014. A 90-day period from index procedure was used to determine episodes of associated post-acute care. Data was sorted by Zip code into hospital referral regions (HRR). Payments were determined from TRICARE reimbursement records, they were subsequently price standardized and adjusted for patient and surgical characteristics. Variation was assessed by stratifying the HRR into quintiles by spending for each index procedure. RESULTS: After adjusting for case mix, significant inter-quintile variation was observed for all procedures, with knee replacement showing the greatest variation in both index surgery (107%) and total cost of care (75%). Readmission was a driver of variation for colectomy and CABG, with absolute cost variation of $17,257 and $13,289 respectively. Other post-acute care spending was low overall (≤$1606, for CABG). CONCLUSIONS: This study demonstrates significant regional variation in total spending for these procedures, but much lower spending for post-acute care than previously demonstrated by similar procedures in Medicare. Targeting post-acute care spending, a common approach taken by providers in bundled payment arrangements with Medicare, may be less fruitful in working aged populations.

Minimally invasive surgery and its impact on 30-day postoperative complications, unplanned readmissions and mortality.

BACKGROUND: A critical appraisal of the benefits of minimally invasive surgery (MIS) is needed, but is lacking. This study examined the associations between MIS and 30-day postoperative outcomes including complications graded according to the Clavien-Dindo classification, unplanned readmissions, hospital stay and mortality for five common surgical procedures. METHODS: Patients undergoing appendicectomy, colectomy, inguinal hernia repair, hysterectomy and prostatectomy were identified in the American College of Surgeons National Surgical Quality Improvement Program database. Non-parsimonious propensity score methods were used to construct procedure-specific matched-pair cohorts that reduced baseline differences between patients who underwent MIS and those who did not. Bonferroni correction for multiple comparisons was applied and P < 0·006 was considered significant. RESULTS: Of the 532 287 patients identified, 53·8 per cent underwent MIS. Propensity score matching yielded an overall sample of 327 736 patients (appendicectomy 46 688, colectomy 152 114, inguinal hernia repair 59 066, hysterectomy 59 066, prostatectomy 10 802). Within the procedure-specific matched pairs, MIS was associated with significantly lower odds of Clavien-Dindo grade I-II, III and IV complications (P ≤ 0·004), unplanned readmissions (P < 0·001) and reduced hospital stay (P < 0·001) in four of the five procedures studied, with the exception of inguinal hernia repair. The odds of death were lower in patients undergoing MIS colectomy (P < 0·001), hysterectomy (P = 0·002) and appendicectomy (P = 0·002). CONCLUSION: MIS was associated with significantly fewer 30-day postoperative complications, unplanned readmissions and deaths, as well as shorter hospital stay, in patients undergoing colectomy, prostatectomy, hysterectomy or appendicectomy. No benefits were noted for inguinal hernia repair.

Using extended reality (XR) for medical training and real-time clinical support during deep space missions.

Medical events can affect space crew health and compromise the success of deep space missions. To successfully manage such events, crew members must be sufficiently prepared to manage certain medical conditions for which they are not technically trained. Extended Reality (XR) can provide an immersive, realistic user experience that, when integrated with augmented clinical tools (ACT), can improve training outcomes and provide real-time guidance during non-routine tasks, diagnostic, and therapeutic procedures. The goal of this study was to develop a framework to guide XR platform development using astronaut medical training and guidance as the domain for illustration. We conducted a mixed-methods study-using video conference meetings (45 subject-matter experts), Delphi panel surveys, and a web-based card sorting application-to develop a standard taxonomy of essential XR capabilities. We augmented this by identifying additional models and taxonomies from related fields. Together, this "taxonomy of taxonomies," and the essential XR capabilities identified, serve as an initial framework to structure the development of XR-based medical training and guidance for use during deep space exploration missions. We provide a schematic approach, illustrated with a use case, for how this framework and materials generated through this study might be employed.

Utilizing hospital discharge data (HD) to compare fatal and non-fatal work-related injuries among Hispanic workers in New Jersey.

BACKGROUND: This study explores the utilization of Hospital Discharge (HD) data to obtain estimates of work-related non-fatal injuries rates in NJ to determine if Hispanics workers have an increased risk of specific work-related injuries. In addition, HD data are used to compare the rate ratios between fatal and non-fatal injuries in this population to demonstrate the effectiveness of using HD as a surveillance tool for monitoring injury trends and performing evaluations. METHODS: Several types of fatal and non-fatal injuries were modeled using Poisson regression with the following predictor variables: gender, ethnicity, and year. The estimated number of workers by ethnicity employed in NJ each year was obtained from the U.S. Census Bureau, DataFerrett, Current Population Survey, November 2006, a data mining tool which accesses CPS data. RESULTS: These analyses, utilizing estimates of working population at-risk, indicate that Hispanic workers have an increased risk of four particular work-related injuries compared with non-Hispanics, and Hispanics were injured at a younger age than non-Hispanics. In addition the rankings of the rate ratios from the comparison between non-fatal and fatal risk estimates were similar; indicating that occupational surveillance of non-fatal injuries is a viable component to be considered. CONCLUSIONS: HD data are effective for monitoring trends over time across ethnic groups and injury types. Therefore, non-fatal injury surveillance should be considered for targeting specific worker populations for interventions to reduce exposure to workplace hazards, and can be a valuable surveillance tool in efforts to reduce occupational injuries.

Phase II trial of preoperative radiation therapy and chemotherapy for patients with localized, resectable adenocarcinoma of the pancreas: an Eastern Cooperative Oncology Group Study.

PURPOSE: A prospective, multiinstitutional trial was initiated in 1991 to examine the tolerance to and efficacy of a program of preoperative chemoradiotherapy (CTRT) and surgical resection for patients with localized adenocarcinoma of the pancreas. PATIENTS AND METHODS: Fifty-three patients were assessable for analysis, with a median follow-up of 52 months for survivors. Radiation therapy (RT) totaling 5,040 cGy in 180 cGy fractions with mitomycin 10 mg/m2 day 2 and fluorouracil (5-FU) 1,000 mg/m2/d continuous infusion days 2 through 5 and 29 through 32 were given as preoperative adjuvant therapy. Twelve patients did not proceed to surgery (one death, one toxicity, three local progression, six distant metastases, one intercurrent illness), whereas 41 patients underwent surgery. Of these, 17 patients did not have resection (11, hepatic and/or peritoneal metastases and six local extension that precluded resection). Twenty-four patients had tumor resection (19 Whipple, four total pancreatectomy, one distal pancreatectomy). RESULTS: Treatment toxicity was primarily hematologic, although a comparable number suffered biliary tract complications, either from obstruction or cholangitis as a result of an occluded stent or the primary tumor. There was one postoperative death. Median survival for the entire group and for the 24 patients with resection was 9.7 and 15.7 months. This survival rate reflected the advanced state of most resected cancers (positive peritoneal cytology, three patients; margins within 2 mm, 13 patients; involved lymph nodes, four patients; and need for superior mesenteric vein (SMV) resection, four patients). Tumor progression was most frequent at metastatic sites. CONCLUSION: This preoperative CTRT protocol was feasible and safe in a cooperative group setting. Entry of patients with advanced tumors probably accounted for the suboptimal resectability and survival results.

Relationship between cumulative anthracycline dose and late cardiotoxicity in childhood acute lymphoblastic leukemia.

PURPOSE: Late anthrocycline cardiotoxicity after treatment for childhood cancer is common and often progressive. A safe anthracycline dose that will not result in late cardiac abnormalities has not been established due to the limited dose ranges used in existing studies. PATIENTS AND METHODS: To determine the relationship between cumulative anthracycline dose and late cardiotoxicity, we performed echocardiograms on 189 survivors of childhood acute lymphoblastic leukemia a median of 8.1 years (range, 2.0 to 23.4) after completion of anthracycline therapy. Patients were treated according to protocols that used widely varying cumulative anthracycline doses, but comparable nonanthracycline chemotherapy. Patients were divided into four groups based on the city of treatment and cumulative anthracycline dose: Copenhagen, 0 to 23 mg/m2 (n = 32); Boston, 45 mg/m2 (n = 17); Copenhagen, 73 to 301 mg/m2 (n = 53); and Boston, 244 to 550 mg/m2 (n = 87). Left ventricular dimension and fractional shortening were adjusted for sex and age or body-surface area through use of a control population (n = 296), and then compared among the four groups. RESULTS: Mean left ventricular dimension was significantly increased in the high-dose Boston group (observed:predicted value, 4.57 cm:4.45 cm; P = .002) and significantly higher than in the two Copenhagen groups. In the three lower-dose groups, there was no significant increase in mean left ventricular dimension, and the groups were not significantly different from each other. Similarly, the mean left ventricular fractional shortening was significantly depressed in the high-dose Boston group (observed:predicted value, 29.0%:33.8%; P = .0001) and significantly lower than in the three lower-dose groups. CONCLUSION: Depressed left ventricular fractional shortening and left ventricular dilatation were uncommon years after treatment of childhood leukemia when cumulative anthracycline doses were < or = 300 mg/m2.

Testing for bias in weighted estimating equations.

It is very common in regression analysis to encounter incompletely observed covariate information. A recent approach to analyse such data is weighted estimating equations (Robins, J. M., Rotnitzky, A. and Zhao, L. P. (1994), JASA, 89, 846-866, and Zhao, L. P., Lipsitz, S. R. and Lew, D. (1996), Biometrics, 52, 1165-1182). With weighted estimating equations, the contribution to the estimating equation from a complete observation is weighted by the inverse of the probability of being observed. We propose a test statistic to assess if the weighted estimating equations produce biased estimates. Our test statistic is similar to the test statistic proposed by DuMouchel and Duncan (1983) for weighted least squares estimates for sample survey data. The method is illustrated using data from a randomized clinical trial on chemotherapy for multiple myeloma.

Modeling kappa for measuring dependent categorical agreement data.

A method for analysing dependent agreement data with categorical responses is proposed. A generalized estimating equation approach is developed with two sets of equations. The first set models the marginal distribution of categorical ratings, and the second set models the pairwise association of ratings with the kappa coefficient (kappa) as a metric. Covariates can be incorporated into both sets of equations. This approach is compared with a latent variable model that assumes an underlying multivariate normal distribution in which the intraclass correlation coefficient is used as a measure of association. Examples are from a cervical ectopy study and the National Heart, Lung, and Blood Institute Veteran Twin Study.

Physician Perceptions and Beliefs about Generating and Providing a Clinical Summary of the Office Visit.

BACKGROUND: A core measure of the meaningful use of EHR incentive program is the generation and provision of the clinical summary of the office visit, or the after visit summary (AVS), to patients. However, little research has been conducted on physician perceptions and beliefs about the AVS. OBJECTIVES: Evaluate physician perceptions and beliefs about the AVS and the effect of the AVS on workload, patient outcomes, and the care the physician delivers. METHODS: A cross-sectional online survey of physicians at two academic medical centers (AMCs) in the northeast who are participating in the meaningful use EHR incentive program. RESULTS: Of the 1 795 physicians at both AMCs participating in the incentive program, 853 completed the survey for a response rate of 47.5%. Eighty percent of the respondents reported that the AVS was easy (very easy or quite easy or somewhat easy) to generate and provide to patients. Nonetheless, more than three-fourths of the respondents reported a negative effect of generating and providing the AVS on workload of office staff (78%) and workload of physicians (76%). Primary care physicians had more positive beliefs about the effect of the AVS on patient outcomes than specialists (p<0.001) and also had more positive beliefs about the effect of the AVS on the care they delivered than specialists (p<0.001). CONCLUSIONS: Achieving the core meaningful use measure of generating and providing the AVS was easy for physicians but it did not necessarily translate into positive beliefs about the effect of the AVS on patient outcomes or the care the physician delivered. Physicians also had negative beliefs about the effect of the AVS on workload. To promote positive beliefs among physicians around the AVS, organizations should obtain physician input into the design and implementation of the AVS and develop strategies to mitigate its negative impacts on workload.

Vitamin A supplementation and dietary vitamin A in relation to the risk of xerophthalmia.

We examined the effect of 60-mg (200,000-IU) supplements of vitamin A administered every 6 mo on the incidence of xerophthalmia among preschool children who were free of eye symptoms and signs of vitamin A deficiency. We also prospectively studied the relationship of dietary vitamin A intake with the same endpoint. After 18 mo of follow-up, 400 children developed xerophthalmia during 80,104 child-periods of follow-up. Vitamin A supplementation only modestly reduced the risk of xerophthalmia (relative risk 0.88, 95% confidence interval 0.72-1.07, P = 0.19). On the other hand, total dietary vitamin A intake was strongly associated with reduced risk of xerophthalmia; the multivariate relative risk when children in extreme quintiles were compared was 0.38 (95% confidence interval 0.19-0.74; P for trend over quintiles = 0.002). These results emphasize the need for further data on factors that modify the bioavailability of large-dose vitamin A supplements. Increased consumption of inexpensive vegetables and fruits is highly likely to reduce significantly the risks of vitamin A deficiency, including nutritional blindness in developing countries.

Dietary vitamin A intake and the risk of mortality among children.

Increased consumption of dietary vitamin A is advocated as a long-term solution to vitamin A deficiency. We prospectively examined the relationship of dietary vitamin A intake and child mortality among 28,753 Sudanese children aged 6 mo to 6 y, who participated in a trial of vitamin A supplementation. After 18 mo of follow-up, 232 children died. Total dietary vitamin A intake was strongly and inversely associated with risk of mortality. The age- and sex-adjusted relative risk (RR) of mortality for a comparison of children in extreme quintiles was 0.35 (95% CIs 0.21-0.60; P for trend over quintiles < 0.0001). Even after possible confounding by socioeconomic variables was adjusted for, vitamin A intake was significantly protective (multi-variate relative risk 0.53). Dietary vitamin A intake was especially protective among children who were wasted and stunted or who had diarrhea or cough. These prospective data support an important role of dietary vitamin A in reducing childhood mortality in developing countries.

Initial results of a phase II trial of high dose radiation therapy, 5-fluorouracil, and cisplatin for patients with anal cancer (E4292): an Eastern Cooperative Oncology Group study.

PURPOSE: A prospective clinical trial was performed to assess the response and toxicity associated with the use of high dose radiation therapy, 5-fluorouracil, and cisplatin in patients with anal cancer. METHODS AND MATERIALS: Patients with anal cancer without distant metastasis were eligible for this study. Radiation therapy consisted of 59.4 Gy in 33 fractions; a 2 week break in treatment was taken after 36 Gy had been given. A treatment of 5-fluorouracil, 1,000 mg/m2 per day intravenously, was given for the first 4 days of radiation therapy, and cisplatin, 75 mg/m2 intravenously, was given on day 1 of radiation therapy. A second course of 5-fluorouracil and cisplatin was given after 36 Gy of radiation, when the radiation therapy was resumed. RESULTS: Nineteen patients entered this study and received treatment. Thirteen (68%) had a complete response, 5 (26%) had a partial response, and 1 (5%) had stable disease. The patient with stable disease and one of the patients with a partial response had complete disappearance of tumor more than 8 weeks after completion of radiation therapy. Fifteen patients had toxicity of Grade 3 or higher: the worst toxicity was Grade 3 in eight patients, Grade 4 in six patients, and Grade 5 in one patient. The most common form of toxicity of Grade 3 or higher was hematologic. The one lethal toxicity was due to pseudomembranous colitis, which was a complication of antibiotic therapy for a urinary tract infection. CONCLUSION: Radiation therapy, cisplatin, and 5-fluorouracil resulted in an overall response rate of 95%. Significant toxicity occurred, an indication that this regimen is near the maximal tolerated dose. A Phase III clinical trial is planned in which radiation therapy, cisplatin, and 5-fluorouracil will be used as an experimental arm.

Non-invasive assessment of rejection in pediatric transplant patients: serologic and echocardiographic prediction of biopsy-proven myocardial rejection.

BACKGROUND: Cardiac allograft rejection is a multifocal immune process that is currently assessed using biopsy-guided histologic classification systems (International Society for Heart and Lung Transplantation). Cardiac troponin T and I are established serologic markers of global myocyte damage. The use of load-independent measures of contractility have also been shown to accurately assess the presence of ventricular dysfunction. Little is known about their utility in accurately predicting rejection in the pediatric age group. We undertook the present study to compare rejection grade with echocardiographic and serologic estimates of transplant rejection-related myocardial damage. METHODS: We compared histologic rejection grades (0 to 4) with patient characteristics, echocardiographic measurements, catheterization measurements, and biochemical markers for 86 evaluations in 37 transplant recipients at Children's Hospital. RESULTS: In univariate analyses, biopsy scores correlated (p < 0.05) inversely with left ventricular systolic function (shortening fraction) and contractility (stress velocity index, SVI), and directly with mitral E-wave amplitude. In multivariate analyses, lower contractility and higher mitral E-wave amplitude remained significantly (p < or = 0.01) associated with rejection (SVI, p = 0.002, odds ratio = 0.393; E wave, p = 0.0002, odds ratio = 228). Most rejection episodes were associated with elevation of biochemical markers of myocardial injury. Although troponin I was weakly associated with differences between rejection grades (p = 0.034), troponin T, creatine kinase-MB fraction, and C-reactive protein did not differ with biopsy-rejection scores. Serum markers had a poor predictive capacity for biopsy-detected rejection. Troponin T and I did correlate with increased left ventricular wall thickness and mass. CONCLUSION: Progressively depressed left ventricular contractility and diastolic function are found with worsening pediatric heart transplant rejection-biopsy score; however, sensitive and specific serum markers do not correspond to the degree of active myocardial injury. The use of echocardiographic measures of contractility is associated with a specificity of 91.8% but low sensitivity of 66.7%. Overall we found poor concordance between serum markers and grade of rejection. It is unclear whether myocardial injury as assessed by serum markers, echocardiography, or histologic scoring is more important for assessment of acute rejection or long-term outcome, but it does not appear that serum and tissue markers of rejection can be used interchangeably.

Analysis of dichotomous outcome data for community intervention studies.

Community intervention trials are becoming increasingly popular as a tool for evaluating the effectiveness of health education and intervention strategies. Typically, units such as households, schools, towns, counties, are randomized to receive either intervention or control, then outcomes are measured on individuals within each of the units of randomization. It is well recognized that the design and analysis of such studies must account for the clustering of subjects within the units of randomization. Furthermore, there are usually both subject level and cluster level covariates that must be considered in the modelling process. While suitable methods are available for continuous outcomes, data analysis is more complicated when dichotomous outcomes are measured on each subject. This paper will compare and contrast several of the available methods that can be applied in such settings, including random effects models, generalized estimating equations and methods based on the calculation of 'design effects', as implemented in the computer package SUDAAN. For completeness, the paper will also compare these methods of analysis with more simplistic approaches based on the summary statistics. All the methods will be applied to a case study based on an adolescent anti-smoking intervention in Australia. The paper concludes with some general discussion and recommendations for routine design and analysis.

Hepatocellular carcinoma. An ECOG randomized phase II study of beta-interferon and menogaril.

This study was undertaken to investigate the response rate, time to treatment failure and survival time of patients with hepatocellular cancer (HCC) treated with beta-interferon or menogaril. Sixty-nine patients with histologically confirmed, advanced, measurable hepatocellular carcinoma were randomized to receive beta-interferon or menogaril. Eligibility criteria included an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, 2, or 3, as well as adequate kidney and liver function and hematologic reserve. The number of patients with lethal, life-threatening, and severe toxicities on beta-interferon were 1, 3, and 12 and on menogaril 2, 5, and 10, respectively. No objective responses were documented among the 61 patients who had HCC, histologically reviewed and confirmed. The time to treatment failure was 6.7 weeks on beta-interferon and 8.6 weeks on menogaril. The median survival time was 11.1 weeks on beta-interferon and 23.1 weeks on menogaril (South African patients 10.1 weeks). The difference is not significant. Poor prognostic factors were jaundice, age, and associated hepatitis. After controlling for other covariates, beta-interferon appears to increase the relative risk of dying by 2.7. This trial reconfirms the importance, previously reported by ECOG of jaundice and age in the prognosis of patients with HCC. It shows that further trials with neither beta-interferon nor menogaril are warranted.

Treatment of squamous cell esophageal cancer with topotecan: an Eastern Cooperative Oncology Group Study (E2293).

Seventeen patients with enhanced measurable squamous cell carcinoma of the esophagus were treated with topotecan 1.5 mg/m2 daily for 5 days repeated every 21 days. Toxicity was severe, with 1 death from myelotoxicity and 10 patients with life-threatening myelotoxicity. Severe gastrointestinal toxicity consisting of vomiting was also seen in three patients. No response was seen in any of the patients in the study. Topotecan given in this manner has no activity in squamous cell carcinoma of the esophagus.

Phase II trial of prolonged continuous infusion of 5-fluorouracil and interferon-alpha in patients with advanced pancreatic cancer. Eastern Cooperative Oncology Group Protocol 3292.

Evidence suggests that interferon-alpha (IFN-alpha) augments the antineoplastic activity of 5-fluorouracil (5-FU) in human adenocarcinoma cell lines in vitro and may enhance the efficacy of 5-FU in patients with advanced colorectal carcinoma. In addition, 5-FU may be more effective when given as a prolonged, continuous i.v. infusion (PCI). The Eastern Cooperative Oncology Group performed a Phase II trial of PCI 5-FU plus IFN-alpha in patients with advanced pancreatic carcinoma. Twenty-six patients with advanced, surgically incurable adenocarcinoma of the pancreas received PCI 5-FU (250 mg/m2 daily for 28 days) in combination with IFN-alpha (5 x 10(6) IU/m2 s.c. thrice weekly). Treatment cycles were repeated 14 days or longer after completion of the previous cycle. Treatment was interrupted prior to day 28 if intolerable toxicity developed, and the dose of 5-FU was reduced in subsequent cycles. Partial response occurred in two of 24 evaluable patients (8%; 95% confidence interval, 0-19%). The majority of the study group (88%) had liver metastases. Patients whose serum lactate dehydrogenase (LDH) was more than twofold elevated developed 5-FU-related toxicity significantly sooner than patients with smaller elevations in serum LDH (9 vs. 22 days; p = 0.003). A similar trend was observed for patients with a more than twofold elevation in serum glutamic-oxaloacetic transaminase (SGOT; 9 vs. 15 days; p = 0.07). In conclusion, PCI 5-FU plus IFN-alpha has minimal activity in patients with advanced pancreatic carcinoma, and elevated serum LDH and/or SGOT may be useful for predicting greater toxicity from 5-FU-based therapy in patients with liver metastases.