Citations

Background The US Food and Drug Administration issued a black box warning regarding the use of droperidol and the potential for torsade de pointes (TdP). Methods The primary objective of this retrospective study was to determine whether low-dose droperidol administration increased the incidence of TdP in the general surgical population during a 3-yr time period before and after the Food and Drug Administration black box warning. A random sample of 150 surgical patients during each time interval was selected to estimate the droperidol use for each time period. Results During the time period before the black box warning (July 1, 1998 to June 30, 2001), 2,321/139,932 patients (1.66%) had QT prolongation, TdP, or death within 48 h after surgery. We could identify no patients who clearly developed TdP before the black box warning. There was one patient for whom the cause of death could not positively be ruled out as due to TdP. In the time period after the black box warning (July 1, 2002 to June 30, 2005), 2,207 patients (1.46%) had documented QT prolongation, TdP, or death within 48 h after surgery, including only two cases (<0.1%) of TdP. The incidence of droperidol exposure was approximately 12% (exact 95% confidence interval, 7.3-18.3%) before the black box warning and 0% after placement of the black box warning on droperidol. Therefore, we estimate that approximately 16,791 patients (95% confidence interval, 10,173-25,607) were exposed to droperidol, none of whom experienced documented TdP. Conclusions This indicates that the Food and Drug Administration black box warning for low dose droperidol is excessive and unnecessary.

Increases in reactive oxygen species (ROS) have been implicated in age-related diseases, including cancer. The serine/threonine kinase protein kinase D1 (PKD1) is a stress-responsive kinase and sensor for reactive oxygen species, which can initiate cell survival through NF-κB signaling. We have previously shown that in response to ROS, PKD1 is activated at the mitochondria. However, the initial signaling events leading to localization of PKD1 to the mitochondria are unknown. Here, we show that formation of mitochondrial diacylglycerol (DAG) and its binding to PKD1 is the means by which PKD1 is localized to the mitochondria in response to ROS. Interestingly, DAG to which PKD1 is recruited in this pathway is formed downstream of phospholipase D1 (PLD1) and a lipase-inactive PLD1 or inhibition of PLD1 by pharmacological inhibitors blocked PKD1 activation under oxidative stress. To date it has been viewed that monosaturated and saturated DAG formed via PLD1 have no signaling function. However, our data describe a role for PLD1-induced DAG as a competent second messenger at the mitochondria that relays ROS to PKD1-mediated mitochondria-to-nucleus signaling.

Involuntary apnea during sleep elicits sustained arterial hypertension through sympathetic activation; however, little is known about voluntary apnea, particularly in elite athletes. Their physiological adjustments are largely unknown. We measured blood pressure, heart rate, hemoglobin oxygen saturation, muscle sympathetic nerve activity, and vascular resistance before and during maximal end-inspiratory breath holds in 20 elite divers and in 15 matched control subjects. At baseline, arterial pressure and heart rate were similar in both groups. Maximal apnea time was longer in divers (1.7±0.4 versus 3.9±1.1 minutes; P <0.0001), and it was accompanied by marked oxygen desaturation (97.6±0.7% versus 77.6±13.9%; P <0.0001). At the end of apnea, divers showed a >5-fold greater muscle sympathetic nerve activity increase ( P <0.01) with a massively increased pressor response compared with control subjects (9±5 versus 32±15 mm Hg; P <0.001). Vascular resistance increased in both groups, but more so in divers (79±46% versus 140±82%; P <0.01). Heart rate did not change in either group. The rise in muscle sympathetic nerve activity correlated with oxygen desaturation ( r 2 =0.26; P <0.01) and with the increase in mean arterial pressure ( r 2 =0.40; P <0.0001). In elite divers, breath holds for several minutes result in an excessive chemoreflex activation of sympathetic vasoconstrictor activity. Extensive sympathetically mediated peripheral vasoconstriction may help to maintain adequate oxygen supply to vital organs under asphyxic conditions that untrained subjects are not able to tolerate voluntarily. Our results are relevant to conditions featuring periodic apnea.

PurposePerformance status (PS) is a prognostic factor in patients with metastatic colorectal cancer. Clinical trials typically enroll less than 10% of patients with a PS of 2 (PS2); thus, the benefit of systemic chemotherapy in PS2 patients is uncertain.Patients and MethodsIndividual data from 6,286 patients (509 PS2 patients) from nine clinical trials were used to compare treatment efficacy by PS. Progression-free survival (PFS), grade ≥ 3 adverse events, 60-day all-cause mortality, overall survival (OS), and response rate (RR) were explored in the full set of nine trials and in the five trials comparing first-line monotherapy with combination therapy.ResultsCompared with patients with PS of 0 or 1, PS2 patients had significantly higher rates of grade ≥ 3 nausea (8.5% v 16.4%, respectively; P < .0001) and vomiting (7.6% v 11.9%, respectively; P = .006) and 60-day all-cause mortality (2.8% v 12.0%, respectively; P < .0001). PS2 was prognostic for PFS (hazard ratio [HR] = 1.52; P < .0001; median PFS, 7.6 months for PS 0 or 1 v 4.9 months for PS2), OS (HR = 2.18; P < .0001; median OS, 17.3 months for PS 0 or 1 v 8.5 months for PS2), and RR (odds ratio = 0.61; P < .0001; 43.8% for PS 0 or 1 v 32.0% for PS2). The relative benefit and toxicity of experimental versus control treatment and monotherapy versus combination therapy were not different in PS 0 or 1 patients versus PS2 patients.ConclusionIn clinical trials, PS2 patients derive similar benefit from superior treatment as patients with PS of 0 to 1 but with an increased risk of toxicities and 12% 60-day mortality. Although current treatment provides benefit, new approaches are required to approach 1-year median survival for PS2 patients.

Purpose To determine the maximum-tolerated radiation-absorbed dose (RAD) to critical organs delivered by yttrium-90 (90Y) ibritumomab tiuxetan in combination with high-dose carmustine, etoposide, cytarabine, and melphalan (BEAM) chemotherapy with autologous transplantation. Patients and Methods Eligible patients had relapsed or refractory CD20+ non-Hodgkin's lymphoma (NHL). Individualized 90Y activities were based on dosimetry and were calculated to deliver cohort-defined RAD (1 to 17 Gy) to critical organs with three to six patients per cohort. The therapeutic dose of 90Y ibritumomab tiuxetan was followed by high-dose BEAM and autologous transplantation. Results Forty-four patients were treated. Thirty percent of patients had achieved less than a partial remission to their most recent therapy and would not have been eligible for autologous transplantation at most centers. The toxicity profile was similar to that associated with high-dose BEAM chemotherapy. Two dose-limiting toxicities occurred at the 17 Gy dose level, which made 15 Gy the recommended maximum-tolerated RAD. Although eight patients received at least twice the conventional dose of 0.4 mCi/kg, a weight-based strategy at 0.8 mCi/kg would have resulted in a wide range of RAD; nearly 25% of patient cases would have received 17 Gy or more, and many would have received less than 10 Gy. With a median follow-up of 33 months for all patients, the estimated 3-year progression-free and overall survivals were 43% and 60%, respectively. Conclusion Dose-escalated 90Y ibritumomab tiuxetan may be safely combined with high-dose BEAM with autologous transplantation and has the potential to be more effective than standard-dose radioimmunotherapy. Careful dosimetry is required to avoid toxicity and undertreatment.