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Introduction Immune-checkpoint inhibitor immunotherapy and stereotactic body radiotherapy (SBRT) are powerful stand-alone cancer therapies and mechanistic studies support combination regimens (1). Numerous potential mechanisms of combined SBRT and immunotherapy efficacy [...], BACKGROUND. We previously demonstrated the safety of stereotactic body radiotherapy followed by pembrolizumab (SBRT+P) in patients with advanced solid tumors. This phase I clinical trial was expanded to study the safety of partial tumor irradiation (partial-Rx). We assessed irradiated local failure (LF) and clinical outcomes with correlations to biomarkers including [CD8.sup.+] T cell radiomics score (RS) and circulating cytokines. METHODS. Patients received SBRT to 2-4 metastases and pembrolizumab for up to 7 days after SBRT. Tumors measuring up to 65 cc received the full radiation dose (complete-Rx), whereas tumors measuring more than 65 cc received partial- Rx. Landmark analysis was used to assess the relationship between tumor response and overall survival (OS). Multivariable analysis was performed for RS and circulating cytokines. RESULTS. In the combined (expansion plus original) cohort, 97 patients (219 metastases) were analyzed and received SBRT+P. Forty-six (47%) patients received at least 1 partial-Rx treatment. There were 7 (7.2%) dose-limiting toxicities (DLTs). 1-year LF was 7.6% overall, and 13.3% and 5.4% for partial-Rx and complete-Rx tumors, respectively (HR 2.32, 95% CI 0.90- 5.97, P = 0.08). The overall, unirradiated, and irradiated objective response rates were 22%, 12%, and 34%, respectively. Irradiated tumor response to SBRT+P was associated with prolonged OS; 1-year OS was 71% (responders), 42% (mixed-responders), and 0% (nonresponders) (P < 0.01). High-RS was significantly associated with improved LF, progression-free survival (PFS), and OS. Elevated circulating IL-8 was independently associated with inferior PFS and OS. CONCLUSION. SBRT+P is safe in patients with large, advanced solid tumors. Additional studies are warranted to assess noninferiority of complete versus partial irradiation of tumors in the setting of immunotherapy. TRIAL REGISTRATION. Clinicaltrials.gov NCT02608385 FUNDING. Merck Investigator Studies Program; Hillman Fellows for Innovative Cancer Research Program; NIH grants UM1CA186690-06, P50CA254865-01A1, P30CA047904-32, and R01DE031729-01A1.

Introduction Cancers express antigens that are targets for specific CTLs (1), (2); however, tumor evasion by different mechanisms remains a significant obstacle to effective adoptive T cell therapy. Cancer cells [...], Tumors elicit antitumor immune responses, but over time they evolve and can escape immune control through various mechanisms, including the loss of the antigen to which the response is directed. The escape of antigen-loss variants (ALVs) is a major obstacle to T cell--based immunotherapy for cancer. However, cancers can be cured if both the number of CTLs and the expression of antigen are high enough to allow targeting of not only tumor cells, but also the tumor stroma. Here, we showed that IFN-γ and TNF produced by CTLs were crucial for the elimination of established mouse tumors, including ALVs. In addition, both BM-and non-BM--derived stromal cells were required to express TNF receptors and IFN-γ receptors for the elimination of ALVs. Although IFN-γ and TNF were not required by CTLs for perforin-mediated killing of antigen-expressing tumor cells, the strong inference is that tumor antigen--specific CTLs must secrete IFN-γ and TNF for destruction of tumor stroma. Therefore, bystander killing of ALVs may result from IFN-γ and TNF acting on tumor stroma.

Identification of the specific cytogenetic abnormality is one of the critical steps for classification of acute myeloblastic leukemia (AML) which influences the selection of appropriate therapy and provides information about disease prognosis. However at present, the genetic complexity of AML is only partially understood. To obtain a comprehensive, unbiased, quantitative measure, we performed serial analysis of gene expression (SAGE) on CD[15.sup.+] myeloid progenitor cells from 22 AML patients who had four of the most common translocations, namely t(8;21), t(15;17), t(9;11), and inv(16). The quantitative data provide clear evidence that the major change in all these translocation-carrying leukemias is a decrease in expression of the majority of transcripts compared with normal CD[15.sup.+] cells. From a total of 1,247,535 SAGE tags, we identified 2,604 transcripts whose expression was significantly altered in these leukemias compared with normal myeloid progenitor cells. The gene ontology of the 1,110 transcripts that matched known genes revealed that each translocation had a uniquely altered profile in various functional categories including regulation of transcription, cell cycle, protein synthesis, and apoptosis. Our global analysis of gene expression of common translocations in AML can focus attention on the function of the genes with altered expression for future biological studies as well as highlight genes/pathways for more specifically targeted therapy. hematopoietic cell differention | diagnostic microarray

Previous studies have shown that a single dose of methyl-naltrexone, a unique peripheral opioid antagonist, reverses opioid-induced gut hypomotility in humans. Because repeated drug doses are likely to be needed [...]

BCL6, a gene on chromosome 3, band q27, encodes a zinc finger transcriptional repressor that is needed for germinal center formation and has been implicated in the pathogenesis of some human lymphomas when it is mutated or involved in chromosomal rearrangements. To explore further the mechanisms of action of BCL6 in lymphomagenesis, we developed a transgenic mouse model mimicking a common translocation, the t(3, 14)(q27;q32), in human lymphomas. The transgenic mice develop normally and express the transgenic BCL6 protein constitutively in lymphocytes. A small fraction of the animals develop B and T cell lymphomas after a long latency period, but the incidence is dramatically enhanced following administration of N-ethyl-N-nitrosourea, a carcinogen that induces DNA mutations. The N-ethyl-N-nitrosourea-induced lymphomas spread widely, were exclusively T cell, expressed the BCL6 protein, and occurred only in the transgenic mice. Because BCL6 expression has been reported in a number of T cell tumors as well as in the more commonly occurring B cell lymphomas in humans, our transgenic mice provide a model for the study of human lymphomas.

Miller has studied the asymptotic efficiency of the nonparametric, Kaplan-Meier survival estimator relative to parametric estimates based on the exponential and Weibull distributions. He concluded that in certain cases, the asymptotic efficiency is low and recommended that analysts give more consideration to parametric estimators, particularly for estimation of small tail probabilities. In this article we revisit this issue and examine the performance of the nonparametric procedure for estimation not only of a point on the survival curve, but also of the mean (or restricted mean) lifetime. In addition to the exponential and Weibull families, we consider the performance of the Kaplan-Meier procedure relative to a more flexible parametric model proposed by Efron. We find that the reduction in efficiency of the Kaplan-Meier survival estimate becomes negligible fairly quickly as the number of parameters in the parametric model increases. Moreover, for estimation of the mean or restricted mean, the loss in efficiency, even relative to the exponential distribution, is small or nil. We conclude that a parametric estimate of the survival curve may be necessary in certain extreme situations, such as when the sample size is very small. In these cases, careful attention must be given to considering the degree of fit, although with sparse data, this must be assessed from outside sources. For certain functionals of the survival curve, such as the mean or restricted mean, the nonparametric approach is unbiased and entails little or no loss in efficiency, and therefore would generally be preferred over a parametric-based estimate. KEY WORDS: Efficiency; Kaplan-Meier estimator; Mean squared error; Parametric modeling; Restricted mean., 1. INTRODUCTION Twenty-three years ago, after the publication of 'Nonparametric Estimation from Incomplete Observations' by Kaplan and Meier (1958), Rupert Miller wrote a textbook titled Survival Analysis (Miller 1981), which [...]

The effects of thyroid hormone(TH) excess on fetuses carried by mothers with resistance to TH, who are euthyroid are studied. The result reveals that the lower birth weight and suppressed levels of TSH in unaffected infants born to affected mothers indicates that the high maternal TH levels produce fetal thyrotoxicosis.

Byline: Hedy L. Kindler (1), Anjali Avadhani (2), Kurombi Wade-Oliver (1), Theodore Karrison (3), Sridhar Mani (4), Everett E. Vokes (1) Keywords: 9-aminocamptothecin; gastric cancer; gastroesophageal junction; clinical trial Abstract: 9-Aminocamptothecin (9-AC) is a water-insoluble camptothecin derivative that demonstrated broad activity in pre-clinical studies. In vitro, greater anti-tumor efficacy can be achieved with prolonged administration. A minor response was observed in gastric cancer in a phase I study. We conducted a phase II study of 9-AC in 15 patients with previously untreated metastatic gastric cancer and adenocarcinoma of the gastroesophageal junction. 9-AC was administered at a dose of 25 ug/m.sup.2/h over 120 hours (3000 ug/m.sup.2 over 5 days) on two consecutive weeks every 21 days. Fourteen patients were evaluable for response. There were no objective responses. Three patients had stable disease lasting a median of 3.4 months (range 1.6--4.3 months). Median time to progression was 1.4 months; median survival was 5.2 months. Grade 3 neutropenia developed in 20% of patients, and anemia in 7%. Grade 3 nausea and fatigue each developed in 7% of patients. We conclude that 9-AC given by 120-hour continuous infusion demonstrates no clinical activity in patients with metastatic gastric cancer. Author Affiliation: (1) Section of Hematology/Oncology, University of Chicago, Chicago, IL (2) Department of Medicine, University of Chicago, Chicago, IL (3) Department of Health Studies, University of Chicago, Chicago, IL (4) Montefiore Medical Center, Bronx, NY, USA Article History: Registration Date: 21/10/2004

It is commonly held that 'the Coombs' test may be negative in ABO hemolytic disease,' (1) although much of the evidence for this opinion is based on older literature from [...], Objective. It is stated that the direct antiglobulin (Coombs') test (DAT) may be negative in ABO hemolytic disease of the newborn. Thus, significant jaundice in neonates who are A-B incompatible with their mothers but DAT test negative is often attributed to isoimmunization and another diagnosis is not sought. We wished to determine the rate of bilirubin production, as an objective measure of hemolysis, in 2 groups of DAT-negative neonates--ABO-compatible and ABO-incompatible--and in DAT-positive ABO-incompatible neonates. Methods. In consecutive, term, healthy newborns who were admitted to the general care nursery, we measured the level in parts per million (ppm) of end-tidal breath carbon monoxide (CO), corrected for inspired CO (ETCOc), an index of the rate of bilirubin production. We compared the levels in DAT-negative ABO-incompatible neonates with those in ABO-compatible neonates and with the levels in DAT-positive ABO-incompatible neonates. Statistical analysis was performed using 2-sample t and [chi square] tests. Results. There was no significant difference between the mean 12-hour ETCOc levels in DAT-negative ABO-incompatible neonates (n = 60, 2.2 ± 0.6 ppm) versus DAT-negative ABO-compatible neonates (n = 171, 2.1 ± 0.6 ppm), although there was a difference between the mean levels in DAT-positive ABO-incompatible neonates (n = 14, 3.4 ± 1.8 ppm) and the DAT-negative groups. Four DAT-negative ABO-incompatible neonates had elevated ETCOc levels; in 2, we diagnosed a specific hematologic abnormality, namely, glucose-6-phosphate dehydrogenase deficiency in 1 and elliptocytosis in the other. Conclusion. In DAT-negative newborns with significant jaundice or increased bilirubin production, even if ABO-incompatible, a cause other than isoimmunization should be sought. Pediatrics 2002;110:127-130; direct antiglobulin test, Coombs' test, end-tidal carbon monoxide, neonatal jaundice, ABO incompatibility.

Objectives. To determine population size, demographic characteristics, hospital utilization patterns, the specialties of physicians providing care, and costs for hospitalized adult sickle cell patients in Illinois. Methods. A statewide, administrative […]

The presence of the allele delta-F508 in patients with cystic fibrosis (CF) may not be a predictor for a severe disease course. CF is a hereditary disorder that affects the pancreas and exocrine glands. Delta-F508 is a common genetic mutation in CF. A total of 119 ethnically diverse patients with CF were studied for five months. Researchers evaluated genetic mutations, ethnicity and disease course. The patients were divided into three genotype groups: delta-F508/delta-F508, delta-F508/other and other/other. Delta-F508 was present in 56% of the patients. The groups were not different based on age, pancreatic disease and common complications associated with CF. In addition, measures of disease severity such as pulmonary disease were not different among the groups. Delta-F508 does not appear to indicate either a better or worse clinical prognosis. More research is needed to determine the implications of genetic mutations in CF., ABSTRACT. Objective. As part of a study to determine population-based frequencies of CFTR mutations in an ethnically diverse, midwestern cystic fibrosis (CF) population, clinical histories were studied in 119 CF patients. Methodology. We sought to examine the association between genotype as characterized by the [delta]F508 and 11 other commonly occurring mutations and clinical parameters including age at diagnosis, clinical presentation, sweat chloride level, chest roentgenogram score, clinical scores, pulmonary function test results, percent weight for height, and presence of associated CF complications. Results. Age at diagnosis of CF was significantly associated with homozygosity for [delta]F508 (mean age at diagnosis [+ or -] SE: 1.7 [+ or -] 0.3 years for [delta]F508/[delta]F508 vs 3.9 [+ or -] 0.9 years for [delta]F508/other and other/other; P = .03). No other age-adjusted clinical parameter was significantly associated with [delta]F508 or any other genotype. Conclusion. These data suggest that in this sample of CF patients, [delta]F508 genotype is not predictive of disease severity. The lack of association between disease severity and genotype in this ethnically diverse sample may reflect the presence of more severe undetected mutations in our sample, or the effects of modifying genes at other, non-CF loci. Pediatrics 1994;93:114-118; cystic fibrosis; [delta]F508 genotype.

The results of a national survey of population on age-based rationing of health care resources are presented. The majority of respondents are inclined to withhold life-prolonging medical care to terminally ill patients although this would specifically deny such care on the basis of age. The results indicate very little consensus on how to allocate scarce and expeensive health care resources and the ethical standards that should govern such strategies.

Background. Elderly patients treated with antidepressants for depression are at high risk for injury due to falling. The primary purpose of this study was to determine the effects of amitriptyline, desipramine, and paroxetine on the gait of healthy elderly subjects during unobstructed and obstructed (i.e., stepping over obstacles) gait. Psychomotor and mood tests were also performed. Methods. A randomized, crossover, four-period, double-blind, placebo-controlled laboratory trial was performed. Twelve healthy elderly subjects (average age, 67 years: range, 65-72 years) were tested. Subjects were assigned the three antidepressant drugs or a placebo in a random order. Single doses of amitriptyline 50 mg, desipramine 50 mg, paroxetine 20 mg, or placebo were given 4 hours prior to gait testing. Temporal-distance measures and kinematics of the lower trailing limb (i.e., limb going over obstacle last) were obtained. Results. Compared with placebo, amitriptyline significantly reduced gait velocity by as much as 8.0% (p = .028), cadence by as much as 4.9% (p = .012), angular velocity of hip flexion by as much as 10.0% (p = .004), and angular velocity of knee flexion by as much as 8.3% (p = .018) during the crossing strides when stepping over obstacles. Except for knee flexion angle, unobstructed gait was not affected. Amitriptyline affected integrative capacity of the central nervous system (CNS) and ability to concentrate as measured by psychomotor and mood tests. Conclusions. The results for amitriptyline suggest that the subjects slowed their obstacle crossing speeds as a result of reduced CNS integrative capacities. Neither paroxeline nor desipramine significantly affected gait, psychomotor function, or mood.

Objectives. This study assessed the quality of diabetes care in community health centers. Methods. In 55 midwestern community health centers, we reviewed the charts of 2865 diabetic adults for American Diabetes Association measures of quality. Results. On average. 70% of the patients in each community health center had measurements of glycosylated hemoglobin. 26% had dilated eye examinations, 66% had diet intervention. and 51% received foot care. The average glycosylated hemoglobin value per community health center was 8.6%. Practice guidelines were independently associated with higher quality of care. Conclusions. Rates of adherence to process measures of quality were relatively low among community health centers, compared with the targets established by the American Diabetes Association. (Am J Public Health. 2000;90: 431-434)

Low-dose methylnaltrexone can relieve constipation in patients taking opioids for pain. Constipation is the most common adverse effect of opioid pain medications. Researchers randomly assigned 22 people with opioid-induced constipation to receive a 9-minute intravenous dose of methylnaltrexone or placebo. Compared to those who received placebo, all 11 patients who received methylnaltrexone were able to have a bowel movement and food traveled from their mouth to their colon in about half the time.

Objective: To examine the effect of alcohol abuse on the subsequent health status of elderly patients seen in an emergency department (ED). Patients and methods: A sample of 966 patients aged 65 or older who presented to one urban academic ED between the hours of 8 A.M. and 12 midnight was followed for 1 year. A personal interview was administered during the ED visit. Current problem drinkers had a score of 1 or greater on the CAGE questionnaire at ED presentation and drank within the prior 6 months; former problem drinkers had a score of I or greater on the CAGE questionnaire at ED presentation and a last drink more than 6 months previously. We used 13 items from the Medical Outcomes Study short form adapted to the ED setting and 6 items from the Index of Activities of Daily Living (ADL) to measure health status. Results: In multivariate models for repeated-measures controlling for potential confounding factors, current problem drinkers had worse overall health (parameter estimate [Beta] -3.6; 95% CI -7.1 to -0.04), and former problem drinkers had worse mental health ([Beta] -3.6; CI -6.9 to -0.24) on follow-up. We could find no effect of problem drinking on physical health or social function. Conclusions: Current problem drinking is associated with worse self-perceived health among elderly patients in the year following presentation to an ED. The magnitude of decline in health perception may approximate the effect of having back pain, sciatica, or other musculoskeletal complaints. Elderly former problem drinkers suffer from more severe mental health problems over that same period. Key Words. Aging; Alcoholism; Alcohol abuse; Emergency services; Health status; Health-related quality of life, INTRODUCTION Alcohol problems are common among older people in medical settings. Active problem drinking is present in 4% to 15% of elderly outpatients (1, 2), 14% of older emergency department [...]

URL:www.pediatrics.org/cgi/doi/10.1542/peds.2005-1530 Nancy Roizen, MD, Kristen Kasza, MS, Theodore Karrison, PhD, Marilyn Mets, MD, A. Gwendolyn Noble, MD, PhD, Kenneth Boyer, MD, Charles Swisher, MD, Paul Meier, PhD, Jack Remington, MD, [...], OBJECTIVES. The purpose of this work was to determine whether visual impairment caused by toxoplasmic chorioretinitis is associated with impaired performance of specific tasks on standardized tests of cognitive function. If so, then we worked to determine whether there are patterns in these difficulties that provide a logical basis for development of measures of cognitive function independent of visual impairment and compensatory intervention strategies to facilitate learning for such children. METHODS. Sixty-four children with congenital toxoplasmosis with intelligence quotient scores ≥ 50 and visual acuity sufficient to cooperate with all of the intelligence quotient subscales had assessments of their vision, appearance of their retinas, and cognitive testing performed between 3.5 and 5 years of age. These evaluations took place between 1981 and 1998 as part of a longitudinal study to determine outcome of congenital toxoplasmosis. Children were evaluated at 3.5 or 5 (37 children) or both 3.5 and 5 (27 children) years of age. Cognitive function was measured using the Wechsler Preschool and Primary Scale of Intelligence-Revised. Wechsler Preschool and Primary Scale of Intelligence-Revised scale scores were compared for children grouped as those children who had normal visual acuity in their best eye (group 1 ), and those who had impaired vision in their best eye (acuity RESULTS. There were 48 children with normal visual acuity in their best eye (group 1) and 16 children with impaired vision because of macular involvement in their best eye (group 2). Ethnicity and socioeconomic scores were similar. There was a significantly greater proportion of males in group 2 compared with group 1 (81% vs 46%). There was no significant diminution in Wechsler Preschool and Primary Scale of Intelligence-Revised test scores between 3.5 and 5 years of age for the 27 children tested at both of these ages. Verbal intelligence quotient, performance intelligence quotient, full-scale intelligence quotient scores, and all of the scaled scores except arithmetic and block design were significantly lower for children in group 2 compared with group 1. The majority of the differences remained statistically significant or borderline significant after adjusting for gender. However, the difference in overall verbal scores does not remain statistically significant. Mean ± SD verbal (98 ± 20) and performance (95 ± 17) intelligence quotients were not significantly different for children in group 1. However, verbal (88 ± 13) and performance intelligence quotients (78 ± 17) were significantly different for children in group 2. For children in group 2, their lowest scale scores were in object assembly, geometric design, mazes, and picture completion, all timed tests that involved visual discrimination of linear forms with small intersecting lines. In the 2 scales scored that did not differ between groups 1 and 2, arithmetic and block design, timing and vision but not linear forms were components of the tasks. Children with monocular and binocular normal visual acuity did not differ in verbal, performance, or full-scale intelligence quotients or any of the subscale tests. Difficulty with sight or concomitant neurologic involvement also seemed to impact the ability to acquire information, comprehension skills, and vocabulary and performance in similarities testing. After controlling for gender, however, these differences were diminished, and there were no longer differences in overall verbal scores. As noted above, results were generally similar when all of the tests for 3.5-year-olds or 5-year-olds were analyzed separately. At the 3.5-year visit there were fewer significant differences between the 2 groups for the verbal components than at the 5-year visit. CONCLUSIONS. In children with congenital toxoplasmosis and bilateral macular disease (group 2) because of toxoplasmic chorioretinitis, scaled scores were lowest on timed tests that require discrimination of fine intersecting lines. Although the severity of ocular and neurologic involvement is often congruent in children with congenital toxoplasmosis, ophthalmologic involvement seems to account for certain specific limitations on tests of cognitive function. Children with such visual impairment compensate with higher verbal skills, but their verbal scores are still less than those of children with normal vision, and in some cases significantly so, indicating that vision impairment might affect other aspects of cognitive testing. Patterns of difficulties noted in the subscales indicate that certain compensatory intervention strategies to facilitate learning and performance may be particularly helpful for children with these impairments. These patterns also provide a basis for the development of measures of cognitive function independent of visual impairment. KEY WORDS. congenital toxoplasmosis, T gondii, visual impairment, cognitive function.