Phase I trial and pharmacokinetic study of raltitrexed in children with recurrent or refractory leukemia: a pediatric oncology group study.

PURPOSE: To evaluate the toxicity, antileukemic activity, and pharmacology of raltitrexed administered weekly for 3 weeks to patients with refractory or recurrent leukemia. EXPERIMENTAL DESIGN: Raltitrexed was administered as a 15-minute infusion for 3 consecutive weeks every 5 weeks, at doses ranging from 1.3 to 2.8 mg/m(2). The first course was used to determine the dose-limiting toxicities and maximum tolerated dose. Correlative studies included an assessment of raltitrexed pharmacokinetics and measurement of plasma 2'-deoxyuridine concentrations, a surrogate measure of thymidylate synthase inhibition. RESULTS: Twenty-one children (18 evaluable) with refractory leukemia received 25 courses of raltitrexed. The dose-limiting toxicity was reversible elevation in liver transaminases at the 2.8-mg/m(2) dose level and the maximum tolerated dose was 2.1 mg/m(2) per dose. Pharmacokinetics were best characterized by a two-compartment model with a clearance of 139 mL/min/m(2) (8.3 L/h/m(2)), a 2.4-L volume of distribution, an initial half-life (t(1/2alpha)) of 6 minutes, and a terminal half-life (t(1/2beta)) of 45 minutes. There were three objective responses. CONCLUSIONS: Raltitrexed was well tolerated when administered as a single agent to children with recurrent or refractory leukemia. We observed preliminary evidence of antileukemia activity using this weekly dosing schedule and these observations support further evaluation of raltitrexed in this population.     

Rabies virus vaccines: Is there a need for a pan-lyssavirus vaccine?

All members of the lyssavirus genus are capable of causing disease that invariably results in death following the development of clinical symptoms. The recent detection of several novel lyssavirus species across the globe, in different animal species, has demonstrated that the lyssavirus genus contains a greater degree of genetic and antigenic variation than previously suspected. The divergence of species within the genus has led to a differentiation of lyssavirus isolates based on both antigenic and genetic data into two, and potentially a third phylogroup. Critically, from both a human and animal health perspective, current rabies vaccines appear able to protect against lyssaviruses classified within phylogroup I. However no protection is afforded against phylogroup II viruses or other more divergent viruses. Here we review current knowledge regarding the diversity and antigenicity of the lyssavirus glycoprotein. We review the degree of cross protection afforded by rabies vaccines, the genetic and antigenic divergence of the lyssaviruses and potential mechanisms for the development of novel lyssavirus vaccines for use in areas where divergent lyssaviruses are known to circulate, as well as for use by those at occupational risk from these pathogens.     

Inhalation of Tetramethyllead and Tetraethyllead

In a study of the specificity of the iodine-azide reaction in carbon disulfide (CS₂) exposure, iodine-azide reaction and dithiocarb (sodium diethyidithiocarbamate) in the urine of alcoholics treated with disulfiram (tetraethylthiuram disulfide) were determined.

After application of disulfiram, the iodine-azide reaction was negative 40% of the time, but some dithiocarb is always present in urine. Therefore, dithiocarb determination could be used to measure the patient’s discipline.

The great dispersion of dithiocarb results is discussed as a possible influence of pathologic condition and compared with other drugs, especially, meprobamate.

The application of meprobamate increased the percentage of positive iodine-azide reaction in disulfiram, treated alcoholics, but dispersion of dithiocarb results was the same as in alcoholics not using meprobamate.

The iodine-azide test (IAT) does not provide a satisfactory index of exposure in individuals taking disulfiram for alcoholism.     

Demystifying buprenorphine misuse: Has fear of diversion gotten in the way of addressing the opioid crisis?

Buprenorphine is considered one of the most effective treatments for opioid use disorder and significantly reduces risk of overdose death. However, concerns about its diversion and misuse have often taken center stage in public discourse and in the design of practices and policies regarding its use. This has been to the detriment of many vulnerable patient populations, especially those involved in the criminal justice system. Policies that restrict access to buprenorphine in criminal justice and other settings due to concerns of diversion do not accurately reflect the relative risks and safety profile associated with it, creating unnecessary barriers that drive an illicit market of this much-needed medication. Although proper regulation of all controlled medications should be a priority, in most instances the benefits of buprenorphine highly outweigh its risks. In the midst of a national crisis, efforts should be focused on expanding, and not restricting, access to this lifesaving treatment.     

Influenza in patients with hematological malignancies: Experience at two comprehensive cancer centers

The burden of influenza infections in patients with hematological malignancies (HMs) is not well defined. We describe the clinical presentation and associated outcomes of influenza at two comprehensive cancer centers (center 1 in the United States and center 2 in Mexico). Clinical and laboratory data on patients with HMs and influenza infection diagnosed from April 2009 to May 2014 at the two centers were reviewed retrospectively. A total of 190 patients were included, the majority were male (63%) with a median age of 49 years (range, 1‐88 years), and had active or refractory HMs (76%). Compared to center 1, patients in center 2 were significantly sicker (active cancer, decreased albumin levels, elevated creatinine levels, or hypoxia at influenza diagnosis) and experienced higher lower respiratory tract infection (LRI) rate (42% vs 7%; P < 0.001). In multivariable logistic regression analysis (odds ratio, 95% confidence interval), leukemia, (3.09, 1.23‐7.70), decreased albumin level (3.78, 1.55‐9.20), hypoxia at diagnosis (14.98, 3.30‐67.90), respiratory co‐infection (5.87, 1.65‐20.86), and corticosteroid use (2.71, 1.03‐7.15) were significantly associated with LRI; and elevated creatinine level (3.33, 1.05‐10.56), hypoxia at diagnosis (5.87, 1.12‐30.77), and respiratory co‐infection (6.30, 1.55‐25.67) were significantly associated with 60 day mortality in both centers. HM patients with influenza are at high risk for serious complications such as LRI and death, especially if they are immunosuppressed. Patients with respiratory symptoms should seek prompt medical care during influenza season.     

Da Vinci© Skills Simulator™: is an early selection of talented console surgeons possible?

To investigate whether the learning curve of robotic surgery simulator training depends on the probands’ characteristics, such as age and prior experience, we conducted a study of six distinct proband groups, using the da Vinci Skills Simulator: experienced urological robotic surgeons, surgeons with experience as da Vinci tableside assistants, urological surgeons with laparoscopic experience, urological surgeons without laparoscopic experience, and complete novices aged 25 and younger and 40 and older. The results showed that all experienced robotic surgeons reached expert level (>90 %, as defined previously in the literature) within the first three repetitions and remained on a high level of performance. All other groups performed worse. Tableside assistants, laparoscopically experienced surgeons, and younger novices showed a better performance in all exercises than surgeons without laparoscopic experience and older novices. A linear mixed-effects model analysis demonstrated no significant difference in learning curves between proband groups in all exercises except the RW1 exercise for the younger proband group. In summary, we found that performance in robotic surgery, measured by performance scores in three virtual simulator modules using the EndoWrist techniques, was dependent on age and prior experience with robotic and laparoscopic surgery. However, and most importantly, the learning curve was not significantly affected by these factors. This suggests that the da Vinci Skills Simulator? is a useful practice tool for everyone learning or performing robotic surgery, and that early selection of talented surgeons is neither possible nor necessary.