Rate of PSA rise predicts metastatic versus local recurrence after definitive radiotherapy

: A rising prostate specific antigen (PSA) following treatment for adenocarcinoma of the prostate indicates eventual clinical failure, but the rate of rise can be quite different from patient to patient, as can the pattern of clinical failure. We sought to determine whether the rate of PSA rise could differentiate future local versus metastatistic failure.

: Two thousand six hundred sixty-seven PSA values from 400 patients treated with radiotherapy for localized adenocarcinoma of the prostate were analyzed with respect to PSA patterns and clinical outcome. Patients had received no hormonal therapy or prostate surgey and had ?4 PSA values post-treatment PSA rate of rise, determined by the slope of the natural log, was classified as gradual (< 0.69 log (ng/ml)/year, or doubling time (DT) > 1 year), moderate (0.69-1.4 log (ng/ml)/year, or DT 6 months-1 year), or rapid [>1.4 log (ng/ml)/year, or DT < 6 months].

: SIxty-one percent of patients had non-rising PSA following treatment; 25% of patients with rising PSA developed clinical failure, and 93% of patients with clinical failure had rising PSA. The rate of rise discerned different clinical failure patterns. Local failure occurred in 23% of patients with moderate rate of rise versus 7% with gradual rise (p = 0.0001). Metastatic disease developed in 46% of those with rapid versus 8% with moderate rise (p < 0.0001). By multivariate analysis, in addition to rate of rise, PSA nadir and rate of decline predicted local failure; those with post-treatment nadir of 1–4 ng/ml were five times more likely to experience local failure than nadir < 1 ng/ml (p = 0.0002). Rapid rate of rise was the most significant independent predictor of metastastic failure.

: The rate of PSA rise following definitive radiotherapy can predict clinical failure patterns, with a rapidly rising PSA indicating metastatic recurrence and moderately rising PSA local recurrence. This information could potentially dirent therapy; if the rise predicts metastatic failure hormonal therapy could be cosidereed, while aggressive salvage therapy may benefit subclinical local recurrence identified by a moderate rate of PSA rise.     

Enduring effects of prenatal cocaine exposure on selective attention and reactivity to errors: evidence from an animal model

Adult Long-Evans rats, exposed prenatally to 1 of 4 doses of cocaine (0.0,0.5,1.0, or 3.0 mg/kg iv), were tested on a 3-choice visual attention task with an olfactory distractor presented unpredictably on one third of the trials. The performance of all 3 cocaine-exposed groups was significantly more disrupted than that of controls by the presentation of distractors. Results demonstrate that prenatal cocaine exposure increases susceptibility to distractors, using a task specifically designed to measure this function. In addition, the present study revealed that individuals exposed to cocaine in utero exhibit greater performance disruption after an error than controls, in certain types of tasks. Both areas of dysfunction, impaired selective attention and impaired arousal regulation, have important functional consequences in humans, possibly affecting the school performance and social development of cocaine-exposed children.     

Recent strategies for the development of oral medicines for the treatment of visceral leishmaniasis

Considered prevalent in many countries on five continents, especially in low-income regions, leishmaniasis is a neglected tropical disease classified by World Health Organization as one of the diseases for which the development of new treatments is a priority. It is an infectious disease caused by protozoa of the genus Leishmania, whose species may cause different clinical manifestations, such as cutaneous and visceral leishmaniasis (VL). Treatment is exclusively by drug therapy, as it has not been possible to develop vaccines yet. Currently available drugs are not fully effective in all cases; they have parenteral administration and exhibit a number of serious and very common adverse effects. The only oral drug available is expensive and it is not available in many endemic countries. Injectable administration is the main problem of treatments, since it requires patients to go to health centers, hospitalization and professional administration, which are conditions that are not adapted to the reality of the poverty conditions of patients with the disease. In this context, the development of an oral medicine has become a focus as it may solve many of these issues. Based on this scenario, this review aimed to investigate which therapeutic alternatives have been studied for the development of oral drugs directed to the treatment of human VL.     

Use of proton pump inhibitors during pregnancy and rates of major malformations: a meta-analysis

Proton pump inhibitors are used to treat gastroesophageal reflux, a symptom common in pregnancy. The aim of this study was to systematically analyze the available data on the risk for malformations following use of these agents in the first trimester of pregnancy. Medline, EMBASE, published abstracts, and reference lists were searched for articles reporting on proton pump inhibitor use in pregnancy. Summary relative risks and 95% confidence intervals (95% CI) were calculated using the Mantel-Haenszel method. Five cohort studies met the inclusion criteria for this meta-analysis. With almost 600 exposed pregnancies, the overall relative risk was 1.18 with a 95%CI of 0.72–1.94. In conclusion, proton pump inhibitors do not present a major teratogenic risk when used in recommend doses. These data are reassuring for the countless patients who have used these agents in the early part of their pregnancies.     

Tissue microarray sampling strategy for prostate cancer biomarker analysis

High-density tissue microarrays (TMA) are useful for profiling protein expression in a large number of samples but their use for clinical biomarker studies may be limited in heterogeneous tumors like prostate cancer. In this study, the optimization and validation of a tumor sampling strategy for a prostate cancer outcomes TMA is performed. Prostate cancer proliferation determined by Ki-67 immunohistochemistry was tested. Ten replicate measurements of proliferation using digital image analysis (CAS200, Bacus Labs, Lombard, IL, USA) were made on 10 regions of prostate cancer from a standard glass slide. Five matching tissue microarray sample cores (0.6 mm diameter) were sampled from each of the 10 regions in the parallel study. A bootstrap resampling analysis was used to statistically simulate all possible permutations of TMA sample number per region or sample. Statistical analysis compared TMA samples with Ki-67 expression in standard pathology immunohistochemistry slides. The optimal sampling for TMA cores was reached at 3 as fewer TMA samples significantly increased Ki-67 variability and a larger number did not significantly improve accuracy. To validate these results, a prostate cancer outcomes tissue microarray containing 10 replicate tumor samples from 88 cases was constructed. Similar to the initial study, 1 to 10 randomly selected cores were used to evaluate the Ki-67 expression for each case, computing the 90th percentile of the expression from all samples used in each model. Using this value, a Cox proportional hazards analysis was performed to determine predictors of time until prostate-specific antigen (PSA) recurrence after radical prostatectomy for clinically localized prostate cancer. Examination of multiple models demonstrated that 4 cores was optimal. Using a model with 4 cores, a Cox regression model demonstrated that Ki-67 expression, preoperative PSA, and surgical margin status predicted time to PSA recurrence with hazard ratios of 1.49 (95% confidence interval [CI] 1.01-2.20, p = 0.047), 2.36 (95% CI 1.15-4.85, p = 0.020), and 9.04 (95% CI 2.42-33.81, p = 0.001), respectively. Models with 3 cores to determine Ki-67 expression were also found to predict outcome. In summary, 3 cores were required to optimally represent Ki-67 expression with respect to the standard tumor slide. Three to 4 cores gave the optimal predictive value in a prostate cancer outcomes array. Sampling strategies with fewer than 3 cores may not accurately represent tumor protein expression. Conversely, more than 4 cores will not add significant information. This prostate cancer outcomes array should be useful in evaluating other putative prostate cancer biomarkers.     

Maternal hyperthermia and the risk for neural tube defects in offspring: systematic review and meta-analysis

BACKGROUND: In animals, excessive core body temperatures have been documented to cause malformations; neural tube defects (NTDs) are among the most frequently reported. In humans, data are inconclusive and often conflicting. The objective of our report is to determine the risk for neural tube defects associated with maternal hyperthermia in early pregnancy. METHODS: We conducted a systematic review and meta-analysis to evaluate available evidence on this topic in humans. MEDLINE, EMBASE, references from published reports, and biologic abstracts from meetings were searched for relevant studies. Reviewers evaluated all the retrieved articles and extracted the relevant data. Individual and summary odds ratios and relative risks were calculated using the Mantel-Haenszel method. RESULTS: Fifteen studies, reporting on 1,719 cases and 37,898 noncases, were included in the meta-analysis. The overall odds ratio for neural tube defects associated with maternal hyperthermia was 1.92 (95% confidence interval = 1.61-2.29). When analyzed separately, the 9 case-control studies had an odds ratio of 1.93 (1.53-2.42). The summary relative risk for the 6 cohort studies was 1.95 (1.30-2.92). CONCLUSIONS: Maternal hyperthermia in early pregnancy is associated with increased risk for neural tube defects and may be a human teratogen.     

Pneumothorax in cystic fibrosis

BACKGROUND: Spontaneous pneumothorax is a complication that is commonly reported in patients with cystic fibrosis (CF). An understanding of the pathophysiology of this complication and its consequences is important for the management of patients with CF. OBJECTIVE: To identify risk factors associated with pneumothorax and to determine the prognosis of CF patients following an episode of pneumothorax. DESIGN: A retrospective observational cohort study of the National Cystic Fibrosis Patient Registry between the years 1990 and 1999. PATIENTS: The registry contained data on 28,858 patients with CF who had been followed up over those 10 years at CF centers across the United States. RESULTS: Pneumothorax occurred with an average annual incidence of 0.64% and in 3.4% of patients overall. There was no increased occurrence by sex, but CF was more prevalent in older patients (mean [+/- SD] age, 21.9 +/- 9.1 years) with more severe pulmonary impairment (nearly 75% of patients with FEV1 of < 40% predicted). The principal risks associated with an increased occurrence of pneumothorax included the presence of Pseudomonas aeruginosa (odds ratio [OR], 2.3), Burkholderia cepacia (OR, 1.8), or Aspergillus (OR, 1.3) in sputum cultures, FEV1 < 30% predicted (OR, 1.5), enteral feeding (OR, 1.7), Medicaid insurance (OR, 1.1), pancreatic insufficiency (OR, 1.4), allergic bronchopulmonary aspergillosis (OR, 1.5), and massive hemoptysis (OR, 1.4). There is an increased morbidity (eg, increased number of hospitalizations and number of days spent in the hospital) and an increased 2-year mortality rate following pneumothorax. CONCLUSION: Pneumothorax is a serious complication in CF patients, occurring more commonly in older patients with more advanced lung disease. Nearly 1 in 167 patients will experience this complication each year. There is an attributable mortality to the complication and considerable morbidity, resulting in increased health-care utilization and a measurable decline in lung function.     

Inner-City Child Mental Health Service Use: The Real Question Is Why Youth and Families Do Not Use Services

OBJECTIVE: This study examines pathways to urban child mental health care as well as explores reasons why care was not received. METHODS: A single group longitudinal design was used to study initial attendance rates at an outpatient child mental health clinic and identify factors associated with initial service use for urban children and their families. RESULTS: Approximately one-third of families (n = 82) do not follow up with care despite their child being referred and an initial appointment scheduled. Yet, three-quarters of those who did not attend a first session still wanted services when interviewed. Factors most significantly related to service use were social support and parental skill efficacy. Miscommunication between adult caregiver and provider was the most often cited reason for non-attendance. CONCLUSIONS: There is a significant unmet need for care along with identification of significant barriers to access. Empirical findings can serve as the basis for modifying urban child mental health service delivery systems.