Primary metastatic osteosarcoma: presentation and outcome of patients treated on neoadjuvant Cooperative Osteosarcoma Study Group protocols.

PURPOSE: To determine demographic data and define prognostic factors for long-term outcome in patients presenting with high-grade osteosarcoma of bone with clinically detectable metastases at initial presentation. PATIENTS AND METHODS: Of 1,765 patients with newly diagnosed, previously untreated high-grade osteosarcomas of bone registered in the neoadjuvant Cooperative Osteosarcoma Study Group studies before 1999, 202 patients (11.4%) had proven metastases at diagnosis and therefore were enrolled onto an analysis of demographic-, tumor-, and treatment-related variables, response, and survival. The intended therapeutic strategy included pre- and postoperative multiagent chemotherapy as well as aggressive surgery of all resectable lesions. RESULTS: With a median follow-up of 1.9 years (5.5 years for survivors), 60 patients were alive, 37 of whom were in continuously complete surgical remission. Actuarial overall survival rates at 5 and 10 (same value for 15) years were 29% (SE = 3%) and 24% (SE = 4%), respectively. In univariate analysis, survival was significantly correlated with patient age, site of the primary tumor, number and location of metastases, number of involved organ systems, histologic response of the primary tumor to preoperative chemotherapy, and completeness and time point of surgical resection of all tumor sites. However, after multivariate Cox regression analysis, only multiple metastases at diagnosis (relative hazard rate [RHR] = 2.3) and macroscopically incomplete surgical resection (RHR = 2.4) remained significantly associated with inferior outcomes. CONCLUSION: The number of metastases at diagnosis and the completeness of surgical resection of all clinically detected tumor sites are of independent prognostic value in patients with proven primary metastatic osteosarcoma.     

Antibody-directed enzyme prodrug therapy: pharmacokinetics and plasma levels of prodrug and drug in a phase I clinical trial

Antibody-directed enzyme prodrug therapy (ADEPT) was administered to ten patients in a phase I clinical trial. The aim was to measure plasma levels of the prodrug 4-[(2-chloroethyl)(2-mesyloxyethyl) amino] benzoyl-l-glutamic acid (CMDA) and the bifunctional alkylating drug (CJS11) released from it by the action of tumour-localised carboxypeptidase G2 (CPG2) enzyme. New techniques were developed to extract the prodrug and drug from plasma by solid-phase adsorbtion and elution and to measure CPG2 activity in plasma and tissue. All extracts were analysed by high-performance liquid chromatography (HPLC) and liquid chromatography-mass spectrometry (LC-MS). CPG2 activity was found in metastatic tumour biopsies but not in normal tissue, indicating that localisation had been successful. The clearing agent SB43-gal, given at 46.5 mg/m², achieved the aim of clearing non-tumour-localised enzyme in the circulation, indicating that conversion of prodrug to drug could take place only at the site of localised conjugate. Plasma prodrug did not always remain above its required threshold of 3 μM for the “therapeutic window” of 120 min after dosing, but the presence of residual prodrug after the first administration of each day indicated that this could be achieved during the remaining four doses over the following 8 h. Despite considerable inter-patient prodrug plasma concentration variability, the elimination half-life of the prodrug was remarkably reproducible at 18 ± 8 min. Rapid appearance of the drug in plasma indicated that successful conversion from the prodrug had taken place, but also undesirable leakback from the site of localisation into the bloodstream. However, drug plasma levels fell rapidly by at least 50% at between 10 and 60 min with a half-life of 36 ± 14 min. Analysis of the plasma extracts by LC/MS indicated that this technique might be used to confirm qualitatively the presence of prodrug, drug and their metabolites. Received: 21 July 1996 / Accepted: 20 January 1997     

Infantile hypertrophic pyloric stenosis in a regional centre

Background  

It has been suggested that only specialist paediatric surgeons should manage infantile hypertrophic pyloric stenosis (IMPS).     

Prenatal disruption of neocortical development alters prefrontal cortical neuron responses to dopamine in adult rats.

A growing body of evidence suggests that structural changes in the cortex may disrupt dopaminergic transmission in circuits involving the prefrontal cortex (PFC) and may contribute to the etiology of schizophrenia. In this study, we utilize a rodent model of neonatal disruption of cortical development using prenatal administration of the mitotoxin methylazoxymethanol acetate (MAM). Using intracellular recordings in vivo, we compare the physiology of prefrontal cortical neurons and their responses to topical administration of dopamine (DA) in intact animals and adult rats treated prenatally with MAM. Topical administration of DA hyperpolarized the membrane potential (MP) and decreased the firing rate of neurons recorded in deep layers of the PFC in intact animals. Furthermore, electrical stimulation of the VTA evoked fast onset epsps or long-lasting depolarizations in PFC neurons. In comparison, PFC neurons recorded in MAM-treated animals had significantly faster baseline firing rates. Moreover, topical administration of DA did not affect the MP or firing rate of the neurons in MAM-treated animals. However, MAM-treated animals exhibited an increase in the percentage of neurons responding with long-lasting depolarizations to stimulation of the VTA. The results of this study indicate that PFC neurons in the MAM-treated rats are not responsive to DA administered superficially, while at the same time exhibit greater responsiveness to VTA stimulation. These results are consistent with a rewiring of the corticolimbic system in response to neurodevelopmental insults.     

Morphine-induced suppression of saccharin intake is correlated with elevated corticosterone levels

Rats suppress intake of a saccharin conditioned stimulus (CS) when paired with a drug of abuse. This phenomenon, however, is not uniform across all subjects and is greater following exposure to stress and in animals that more readily self-administer drugs of abuse. The present study was designed to examine these individual differences in intake suppression following seven saccharin-morphine pairings. Plasma corticosterone also was evaluated both before and after conditioning in order to determine whether the magnitude of CS suppression is, or is not, related to circulating corticosterone levels. The findings indicated that, while all rats were exposed to the same number of saccharin-morphine pairings, only half of these animals actually suppressed intake of the saccharin CS. Moreover, the results showed that greater suppression of CS intake was associated with higher corticosterone levels at test (r=-0.84, P<0.0001). Taken together, the results demonstrate that individual differences affect not only the reduction in CS intake following taste-drug pairings, but also the associated cue-induced elevation in circulating corticosterone.     

Satisfaction with provider communication among Spanish-speaking Medicaid enrollees.

OBJECTIVE: To determine if differences between English- and Spanish-speaking parents in ratings of their children's health care can be explained by need for interpretive services. METHODS: Using the Consumer Assessment of Health Plans Survey-Child-Survey (CAHPS), reports about provider communication were compared among 3 groups of parents enrolled in a Medicaid managed care health plan: 1) English speakers, 2) Spanish speakers with no self-reported need for interpretive services, and 3) Spanish speakers with self-reported need for interpretive services. Parents were asked to report how well their providers 1) listened carefully to what was being said, 2) explained things in a way that could be understood, 3) respected their comments and concerns, and 4) spent enough time during medical encounters. Multivariate logistic regression was used to compare the ratings of each of the 3 groups while controlling for child's gender, parent's gender, parent's educational attainment, child's health status, and survey year. RESULTS: Spanish-speaking parents in need of interpretive services were less likely to report that providers spent enough time with their children (odds ratio = 0.34, 95% confidence interval = 0.17-0.68) compared to English-speaking parents. There was no statistically significant difference found between Spanish-speaking parents with no need of interpretive services and English-speaking parents. CONCLUSIONS: Among Spanish- versus English-speaking parents, differences in ratings of whether providers spent enough time with children during medical encounters appear to be explained, in part, by need for interpretive services. No other differences in ratings of provider communication were found.     

Psychometric evaluation of the Taiwan version of the Disability of the Arm, Shoulder, and Hand (DASH) questionnaire.

BACKGROUND AND PURPOSE: To adapt the Taiwan version of the Disability of the Arm, Shoulder, and Hand (DASH) questionnaire and evaluate its psychometric properties. METHODS: The DASH questionnaire was adapted through the process of translation, back-translation, and expert review. Eighty two subjects with upper extremity disorders were recruited in a medical center and 46 of these patients could be followed up to assess retest reliability in less than 10 days. Cronbach alpha and intraclass correlation coefficient were used to evaluate the internal consistency and test-retest reliability. Principal axis factor analysis was performed to assess the factor-construct validity, while concurrent validity was tested with the Medical Outcomes Study Short Form-36 (SF-36) Taiwan version questionnaire. RESULTS: The internal consistency of the Taiwan version of the DASH questionnaire was high (Cronbach alpha = 0.96) and the test-retest reliability was satisfactory (intraclass correlation coefficient = 0.9). Principal axis factor analysis confirmed the 1-factor model. The Pearson correlation coefficients of the DASH questionnaire to the SF-36 showed a correlation with physical component summary scores rather than mental component summary scores. Bodily pain, physical function and role-physical scores among the SF-36 subscales were most significantly correlated with DASH disability/symptom scores. CONCLUSION: The Taiwan version of the DASH questionnaire is a valid and reliable measure of health status for patients with upper-extremity disorders.     

Detection of alkaline sphingomyelinase activity in human stool: proposed role as a new diagnostic and prognostic marker of colorectal cancer.

OBJECTIVES: Intestinal alkaline sphingomyelinase, by exerting a major role in dietary sphingomyelin digestion, is responsible for the generation of messengers able to trigger the rapid turnover and apoptosis in intestinal epithelial cells. Markedly reduced mucosal alkaline sphingomyelinase activity has been associated with human colorectal neoplasms. The aim of this study was to analyze the alkaline sphingomyelinase activity in feces from healthy subjects and colorectal adenocarcinoma patients and to correlate it with the enzyme activity in intestinal tissues. MATERIALS AND METHODS: The enzyme activity was measured both in the intestinal samples from 12 healthy controls and 51 patients with colorectal adenocarcinoma (tumoral and paratumoral tissue) and in the fecal samples of 34 healthy subjects and 29 patients with adenocarcinoma. The relation between sphingomyelinase activity and Dukes' stage, cell differentiation degree, age, and gender was also analyzed. RESULTS: Alkaline sphingomyelinase was significantly decreased (P < 0.001; mean reduction >90%) in tumoral intestinal mucosa of patients compared with controls independently of Dukes' stage and tumor differentiation grade. Interestingly, the enzyme activity in histologically normal paratumoral tissues was statistically lower than control samples (P < 0.001). As occurs in neoplastic tissues, a relevant mean reduction (P < 0.0001; almost 90%) of alkaline sphingomyelinase was revealed in stool samples from tumor patients when compared with controls. CONCLUSION: These findings may have implications for cancer biology and perhaps also for the design of clinical test, thus suggesting that the fecal sphingomyelinase activity could really reflect the human intestinal mucosa enzyme level and could represent a new marker for human colorectal adenocarcinoma, mainly taking into account its early appearance in intestinal neoplasms.     

Drop‐offs in the isoniazid preventive therapy cascade among children living with HIV in western Kenya, 2015–2019

IntroductionIsoniazid preventive therapy (IPT) can reduce the risk of tuberculosis (TB) in children living with HIV (CLHIV), but data on the outcomes of the IPT cascade in CLHIV are limited.MethodsWe evaluated the IPT cascade among CLHIV aged <15 years and newly enrolled in HIV care in eight HIV clinics in western Kenya. Medical record data were abstracted from September 2015 through July 2019. We assessed the proportion of CLHIV completing TB symptom screening, IPT eligibility assessment, IPT initiation and completion. TB incidence rate was calculated stratified by IPT initiation and completion status. Risk factors for IPT non‐initiation and non‐completion were assessed using Poisson regression with generalized linear models.ResultsOverall, 856 CLHIV were newly enrolled in HIV care, of whom 98% ([95% CI 97–99]; n = 841) underwent screening for TB symptoms and IPT eligibility. Of these, 13 (2%; 95% CI 1–3) were ineligible due to active TB and 828 (98%; 95% CI 97–99) were eligible. Five hundred and fifty‐nine (68%; 95% CI 64–71) of eligible CLHIV initiated IPT; median time to IPT initiation was 3.6 months (interquartile range [IQR] 0.5–10.2). Overall, 434 (78%; 95% CI 74–81) IPT initiators completed. Attending high‐volume HIV clinics (aRR = 2.82; 95% CI 1.20–6.62) was independently associated with IPT non‐initiation. IPT non‐initiation had a trend of being higher among those enrolled in the period 2017–2019 versus 2015–2016 (aRR = 1.91; 0.98–3.73) and those who were HIV virally non‐suppressed (aRR = 1.90; 95% CI 0.98–3.71). Being enrolled in 2017–2019 versus 2015–2016 (aRR = 1.40; 1.01–1.96) was independently associated with IPT non‐completion. By 24 months after IPT screening, TB incidence was four‐fold higher among eligible CLHIV who never initiated (8.1 per 1000 person years [PY]) compared to CLHIV who completed IPT (2.1 per 1000 PY; rate ratio [RR] = 3.85; 95% CI 1.08–17.15), with a similar trend among CLHIV who initiated but did not complete IPT (8.2/1000 PY; RR = 4.39; 95% CI 0.82–23.56).ConclusionsDespite high screening for eligibility, timely IPT initiation and completion were suboptimal among eligible CLHIV in this programmatic cohort. Targeted programmatic interventions are needed to address these drop‐offs from the IPT cascade by ensuring timely IPT initiation after ruling out active TB and enhancing completion of the 6‐month course to reduce TB in CLHIV.     

Systematic Evidence Map for Over One Hundred and Fifty Per- and Polyfluoroalkyl Substances (PFAS)

Background: Per- and polyfluoroalkyl substances (PFAS) are a large class of synthetic (man-made) chemicals widely used in consumer products and industrial processes. Thousands of distinct PFAS exist in commerce. The 2019 U.S. Environmental Protection Agency (U.S. EPA) Per- and Polyfluoroalkyl Substances (PFAS) Action Plan outlines a multiprogram national research plan to address the challenge of PFAS. One component of this strategy involves the use of systematic evidence map (SEM) approaches to characterize the evidence base for hundreds of PFAS.Objective: SEM methods were used to summarize available epidemiological and animal bioassay evidence for a set of ∼150 PFAS that were prioritized in 2019 by the U.S. EPA’s Center for Computational Toxicology and Exposure (CCTE) for in vitro toxicity and toxicokinetic assay testing.Methods: Systematic review methods were used to identify and screen literature using manual review and machine-learning software. The Populations, Exposures, Comparators, and Outcomes (PECO) criteria were kept broad to identify mammalian animal bioassay and epidemiological studies that could inform human hazard identification. A variety of supplemental content was also tracked, including information on in vitro model systems; exposure measurement–only studies in humans; and absorption, distribution, metabolism, and excretion (ADME). Animal bioassay and epidemiology studies meeting PECO criteria were summarized with respect to study design, and health system(s) were assessed. Because animal bioassay studies with ≥21-d exposure duration (or reproductive/developmental study design) were most useful to CCTE analyses, these studies underwent study evaluation and detailed data extraction. All data extraction is publicly available online as interactive visuals with downloadable metadata.Results: More than 40,000 studies were identified from scientific databases. Screening processes identified 44 animal and 148 epidemiology studies from the peer-reviewed literature and 95 animal and 50 epidemiology studies from gray literature that met PECO criteria. Epidemiological evidence (available for 15 PFAS) mostly assessed the reproductive, endocrine, developmental, metabolic, cardiovascular, and immune systems. Animal evidence (available for 40 PFAS) commonly assessed effects in the reproductive, developmental, urinary, immunological, and hepatic systems. Overall, 45 PFAS had evidence across animal and epidemiology data streams.Discussion: Many of the ∼150 PFAS were data poor. Epidemiological and animal evidence were lacking for most of the PFAS included in our search. By disseminating this information, we hope to facilitate additional assessment work by providing the initial scoping literature survey and identifying key research needs. Future research on data-poor PFAS will help support a more complete understanding of the potential health effects from PFAS exposures. https://doi.org/10.1289/EHP10343