A phase II/III randomized study to compare the efficacy and safety of rigosertib plus gemcitabine versus gemcitabine alone in patients with previously untreated metastatic pancreatic cancer.

BACKGROUND: Rigosertib (ON 01910.Na), a first-in-class Ras mimetic and small-molecule inhibitor of multiple signaling pathways including polo-like kinase 1 (PLK1) and phosphoinositide 3-kinase (PI3K), has shown efficacy in preclinical pancreatic cancer models. In this study, rigosertib was assessed in combination with gemcitabine in patients with treatment-naïve metastatic pancreatic adenocarcinoma. MATERIALS AND METHODS: Patients with metastatic pancreatic adenocarcinoma were randomized in a 2:1 fashion to gemcitabine 1000 mg/m(2) weekly for 3 weeks of a 4-week cycle plus rigosertib 1800 mg/m(2) via 2-h continuous IV infusions given twice weekly for 3 weeks of a 4-week cycle (RIG + GEM) versus gemcitabine 1000 mg/m(2) weekly for 3 weeks in a 4-week cycle (GEM). RESULTS: A total of 160 patients were enrolled globally and randomly assigned to RIG + GEM (106 patients) or GEM (54). The most common grade 3 or higher adverse events were neutropenia (8% in the RIG + GEM group versus 6% in the GEM group), hyponatremia (17% versus 4%), and anemia (8% versus 4%). The median overall survival was 6.1 months for RIG + GEM versus 6.4 months for GEM [hazard ratio (HR), 1.24; 95% confidence interval (CI) 0.85-1.81]. The median progression-free survival was 3.4 months for both groups (HR = 0.96; 95% CI 0.68-1.36). The partial response rate was 19% versus 13% for RIG + GEM versus GEM, respectively. Of 64 tumor samples sent for molecular analysis, 47 were adequate for multiplex genetic testing and 41 were positive for mutations. The majority of cases had KRAS gene mutations (40 cases). Other mutations detected included TP53 (13 cases) and PIK3CA (1 case). No correlation between mutational status and efficacy was detected. CONCLUSIONS: The combination of RIG + GEM failed to demonstrate an improvement in survival or response compared with GEM in patients with metastatic pancreatic adenocarcinoma. Rigosertib showed a similar safety profile to that seen in previous trials using the IV formulation.

Tracheal extubation of adult surgical patients while deeply anesthetized: a survey of United States anesthesiologists.

STUDY OBJECTIVE: To examine current practice regarding the performance of tracheal extubation of adult surgical patients while deeply anesthetized (deep extubation). DESIGN AND SETTING: Survey comprised of an anonymous written questionnaire mailed to 1,000 randomly selected active American Society of Anesthesiologists members. MEASUREMENTS AND MAIN RESULTS: Questionnaires were mailed between February and April 1998. Five hundred eighty-three completed forms were returned, 538 of which were suitable for data analysis. Responses from anesthesiologists who infrequently or never administer general anesthetics to adult surgical patients were excluded. The overall frequency of deep extubation of adults was "never" for 106 respondents (19.7%), "rarely" for 87 (16.2%), and "more frequently" for 345 (64.1%). The most common reasons for never performing deep extubations were lack of necessity and concern regarding potential laryngospasm and aspiration. The most frequent indications for deep extubations were unclipped intracranial aneurysm, reactive airway disease, and open-globe eye surgery. The most frequent contraindications to deep extubations for those who otherwise perform the technique were difficult airway, aspiration risk, and obesity. After performing a deep extubation, 44.0% of respondents remain with the patient in the operating room until he or she is awake. Deep extubations were perceived to have no consistent effect on operating room turnover time by 61.6% of anesthesiologists who perform them. CONCLUSIONS: Most anesthesiologists in this survey perform deep extubations in adult surgical patients. Lack of necessity and potential respiratory complications were the main reasons cited by those who do not use the technique. Future investigations are necessary to examine the risk-to-benefit ratio of the technique in adults. Our results may be used to determine which potential indications should be examined in such studies and to help delineate the standard of care followed in this country.

Anesthetic considerations in damage control surgery.

The damage control patient is a special subset of the acute trauma population that presents unique challenges for every clinician involved. Communication between team members is critical, but the knowledge of and respect for each other's role lead to prompt, cost-efficient, high-quality care. The anesthesiologist's early goal is control of the airway and prevention of airway catastrophes by early recognition of the difficult airway. The introduction of airway adjuncts such as the laryngeal mask airway and esophageal Combitube has given trauma teams additional options in an airway crisis. Recent insights into the physiologic effects of the intra-abdominal compartment syndrome have improved anesthetic care as well. Ongoing developments in pain management help to improve patient comfort and outcome. By using available therapeutic modalities, as well as serving as a team manager and communications expert, the anesthesiologist provides added value to clinical care during damage control surgery.

Invasive pressure monitoring of patients during magnetic resonance imaging.

The purpose of this paper is to describe a system for monitoring patients who require general anaesthesia, profound sedation or intensive care while undergoing high field (> or = 1.5 T) magnetic resonance (MR) imaging. Continuous evaluation of invasive and noninvasive pressures, inspired and end-tidal respiratory gas concentrations, body temperature, heart rate, ECG and pulse oximetry were measured successfully during the MR examination. Diagnostic quality MR images were acquired on all 15 monitored patients. The calculated signal-to-noise ratios were not different between the control and monitored patients. Commonly encountered technical problems and their solutions are described. This study demonstrates that invasive monitoring can be safely performed in critically ill patients who are undergoing high field MR examinations.

Postobstruction pulmonary edema.

Several occurrences of pulmonary edema following relief of acute upper airway obstruction have been reported. The edema is associated with normal cardiac filling pressures and responds promptly to conservative therapy. Its origin may be attributed to the cardiopulmonary effects of the vigorous inspiratory effort that the spontaneously breathing patient generates to overcome respiratory obstruction (the Müller maneuver). A patient with postobstruction pulmonary edema complicated by hypovolemia and myocardial infarction is described. Prompt invasive hemodynamic monitoring in selected high-risk patients is suggested.