Effects of monoclonal antibody therapy in patients with chronic lymphocytic leukemia

A phase I clinical trial was initiated to treat patients with stage IV B-derived chronic lymphocytic leukemia (CLL) with the IgG2a murine monoclonal antibody T101. This antibody binds to a 65,000-mol wt (T65) antigen found on normal T lymphocytes, malignant T lymphocytes, and B- derived CLL cells. All of the patients had a histologically confirmed diagnosis of advanced B-derived CLL and were refractory to standard therapy, and more than 50% of their leukemia cells reacted with the T101 antibody in vitro. The patients received T101 antibody two times per week, over two to 50 hours by intravenous administration in 100 mL of normal saline containing 5% human albumin. Twelve patients were treated with a fixed dosage of 1, 10, 50, or 100 mg, and one patient was treated with 140 mg of antibody. It was demonstrated that patients given two-hour infusions of 50 mg developed pulmonary toxicity, with shortness of breath and chest tightness. This toxicity was eliminated when infusions of 50 or 100 mg of T101 were prolonged to 50 hours. All dose levels caused a rapid but transient decrease in circulating leukemia cell counts. In vivo binding to circulating and bone marrow leukemia cells was demonstrated at all dose levels with increased binding at higher dosages. Antimurine antibody responses were not demonstrated in any patients at any time during treatment. Circulating free murine antibody was demonstrated in the serum of only the two patients treated with 100 mg of antibody as a 50-hour infusion and the patient treated with 140 mg of antibody over 30 hours. Antigenic modulation was demonstrated in patients treated at all dose levels but was particularly apparent in patients treated with prolonged infusions of 50 and 100 mg of antibody. We were also able to demonstrate antigenic modulation in lymph node cells, which strongly suggests in vivo labeling of these cells. Overall, T101 antibody alone appears to have a very limited therapeutic value for patients with CLL. The observations of in vivo labeling of tumor cells, antigenic modulation, antibody pharmacokinetics, toxicity, and antimurine antibody formation may be used in the future for more effective therapy when drugs or toxins are conjugated to the antibody.     

Taking a Better History for Behavioral Issues Pre‐ and Post‐Deep Brain Stimulation: Issues Missed by Standardized Scales

Objectives: To screen for potentially underreported behavioral changes in patients with idiopathic Parkinson's disease (PD) pre‐ and post‐deep brain stimulation (DBS), a retrospective data base review was performed. Methods: In total, 113 patients who underwent unilateral or bilateral DBS at the University of Florida in either subthalamic nucleus or globus pallidus internus for PD were screened for behavioral issues by asking about the presence or absence of seven neuropsychiatric symptoms (panic, fear, paranoia, anger, suicidal flashes, crying, and laughing). Results: There was a high prevalence of fear (16.3%), panic (14.0%), and anger (11.6%) at baseline in this cohort. In the first six months following DBS implantation, anger (32.6%), fear (26.7%), and uncontrollable crying (26.7%) were the most frequent symptoms reported. Those symptoms also were present following six months of DBS surgery (30.2%, 29.1%, and 19.8%, respectively). New uncontrollable crying occurred more in the acute postoperative stage (less than or equal to six months) (p= 0.033), while new anger occurred more in the chronic postoperative stage (greater than six months) (p= 0.017). The frequency of uncontrollable laughing significantly increased with bilateral DBS (p= 0.033). Conclusions: Many of the neuropsychiatric issues were identified at preoperative baseline and their overall occurrence was more than expected. There was a potential for worsening of these issues post‐DBS. There were subtle differences in time course, and in unilateral vs. bilateral implantations. Clinicians should be aware of these potential behavioral issues that may emerge following DBS therapy, and should consider including screening questions in preoperative and postoperative interviews. Standardized scales may miss the presence or absence of these clinically relevant issues.     

Choice of Vein‐Harvest Technique for Coronary Artery Bypass Grafting: Rationale and Design of the REGROUP Trial

The Randomized Endo‐vein Graft Prospective (REGROUP) trial ( ClinicalTrials.gov  NCT01850082) is a randomized, intent‐to‐treat, 2‐arm, parallel‐design, multicenter study funded by the Cooperative Studies Program (CSP No. 588) of the US Department of Veterans Affairs. Cardiac surgeons at 16 Veterans Affairs (VA) medical centers with technical expertise in performing both endoscopic vein harvesting (EVH) and open vein harvesting (OVH) were recruited as the REGROUP surgeon participants. Subjects requiring elective or urgent coronary artery bypass grafting using cardiopulmonary bypass with use of ≥1 saphenous vein graft will be screened for enrollment using pre‐established inclusion/exclusion criteria. Enrolled subjects (planned N = 1150) will be randomized to 1 of the 2 arms (EVH or OVH) after an experienced vein harvester has been assigned. The primary outcomes measure is the rate of major adverse cardiac events (MACE), including death, myocardial infarction, or revascularization. Subject assessments will be performed at multiple times, including at baseline, intraoperatively, postoperatively, and at discharge (or 30 days after surgery, if still hospitalized). Assessment of leg‐wound complications will be completed at 6 weeks after surgery. Telephone follow‐ups will occur at 3‐month intervals after surgery until the participating sites are decommissioned after the trial's completion (approximately 4.5 years after the full study startup). To assess long‐term outcomes, centralized follow‐up of MACE for 2 additional years will be centrally performed using VA and non‐VA clinical and administrative databases. The primary MACE outcome will be compared between the 2 arms, EVH and OVH, at the end of the trial duration.