Purpose: Completeness of cytoreductive surgery is a key prognostic factor for survival in patients with ovarian cancer. The ability to differentiate clearly between malignant and healthy tissue is essential for achieving complete cytoreduction. Using current approaches, this differentiation is often difficult and can lead to incomplete tumor removal. Near-infrared fluorescence imaging has the potential to improve the detection of malignant tissue during surgery, significantly improving outcome. Here, we report the use of OTL38, a near-infrared (796 nm) fluorescent agent, that binds folate receptor alpha, which is expressed in >90% of epithelial ovarian cancers.Experimental Design: We first performed a randomized, placebo-controlled study in 30 healthy volunteers. Four single increasing doses of OTL38 were delivered intravenously. At fixed times following drug delivery, tolerability and blood/skin pharmacokinetics were assessed. Next, using the results of the first study, three doses were selected and administered to 12 patients who had epithelial ovarian cancer and were scheduled for cytoreductive surgery. We measured tolerability and blood pharmacokinetics, as well as the ability to detect the tumor using intraoperative fluorescence imaging.Results: Intravenous infusion of OTL38 in 30 healthy volunteers yielded an optimal dosage range and time window for intraoperative imaging. In 12 patients with ovarian cancer, OTL38 accumulated in folate receptor alpha-positive tumors and metastases, enabling the surgeon to resect an additional 29% of malignant lesions that were not identified previously using inspection and/or palpation.Conclusions: This study demonstrates that performing realtime intraoperative near-infrared fluorescence imaging using a tumor-specific agent is feasible and potentially clinically beneficial.

These results provide further evidence that use of ecstasy may be associated with impairment of memory and of serotonergic function. These findings are compatible with neurotoxicity of ecstasy as shown in animals.

Summary:Purpose: This study was designed to assess whether sleep disturbance is more frequent among patients with partial seizures and what impact on quality of life (QoL) sleep disturbance may have on patients with partial seizures.Methods: Questionnaire booklets were mailed to 1,183 patients from four Dutch clinics. Each patient was asked to find two age-and gender-matched controls to complete the same set of questionnaires [Sleep Diagnosis List (SDL), Medical Outcomes Study (MOS)-Sleep Scale, Groningen Sleep Questionnaire, Epworth Sleepiness Scale, and the SF-36 Health Survey]. The prevalence of sleep disturbance, based on the SDL, was compared between those with partial epilepsy and controls. Mean scores on sleep and the SF-36 Physical (PCS) and Mental (MCS) Component Summary scales were compared.Results: Responses from 486 patients and 492 controls were analyzed. Respondents with partial epilepsy had a highly significant, twofold higher prevalence of sleep disturbance compared with controls (38.6 vs. 18.0%; p < 0.0001). Most sleep-disorder subscales showed significant abnormalities in respondents with epilepsy, compared with controls. Mean SF-36 MCS and PCS scores were significantly lower in respondents with epilepsy compared with controls in both the strata with sleep disturbance and without (all p values <0.05). The presence of a sleep disturbance in respondents with epilepsy was associated with the greatest impairment in QoL.Conclusions: Sleep disturbance is more than twice as prevalent in persons with partial epilepsy compared with controls, and most domains of sleep are significantly disturbed. Persons with partial epilepsy have significant QoL impairment, and sleep disturbance further compounds this.

Therapeutic vaccination with human papillomavirus type 16 synthetic long peptides (HPV16-SLPs) results in T cell-mediated regression of HPV16-induced premalignant lesions but fails to install clinically effective immunity in patients with HPV16-positive cervical cancer. We explored whether HPV16-SLP vaccination can be combined with standard carboplatin and paclitaxel chemotherapy to improve immunity and which time point would be optimal for vaccination. This was studied in the HPV16 E6/E7-positive TC-1 mouse tumor model and in patients with advanced cervical cancer. In mice and patients, the presence of a progressing tumor was associated with abnormal frequencies of circulating myeloid cells. Treatment of TC-1-bearing mice with chemotherapy and therapeutic vaccination resulted in superior survival and was directly related to a chemotherapy-mediated altered composition of the myeloid cell population in the blood and tumor. Chemotherapy had no effect on tumor-specific T cell responses. In advanced cervical cancer patients, carboplatin-paclitaxel also normalized the abnormal numbers of circulating myeloid cells, and this was associated with increased T cell reactivity to recall antigens. The effect was most pronounced starting 2 weeks after the second cycle of chemotherapy, providing an optimal immunological window for vaccination. This was validated with a single dose of HPV16-SLP vaccine given in this time window. The resulting proliferative HPV16-specific T cell responses were unusually strong and were retained after all cycles of chemotherapy. In conclusion, carboplatin-paclitaxel therapy fosters vigorous vaccine-induced T cell responses when vaccination is given after chemotherapy and has reset the tumor-induced abnormal myeloid cell composition to normal values.

The pharmacokinetics of lamotrigine, a new anticonvulsant, were studied in three studies in normal volunteers. In the first study, five subjects received oral doses of lamotrigine up to 240 mg. A linear relationship was observed between dose administration and both peak drug concentration and AUC. In a second study 10 subjects received 120 mg lamotrigine and the mean (+/- SD) of the elimination half-life (t1/2) was 24.1 +/- 5.7 hours and of volume of distribution/bioavailability 1.2 +/- 0.12 L/kg. Saliva concentrations were 46% of the plasma concentration. Total urinary recovery of drug over 144 hours was 70.5% of the oral dose. A glucuronide conjugate accounted for 89.4% of the urinary recovery. In a third study the kinetics of repeated administration were studied. Fifteen subjects were randomized to lamotrigine (n = 10) or placebo (n = 5) and received multiple doses over 7 days. The overall plasma elimination t1/2 calculated from data during the 7 days was 25.5 +/- 10.2 hours. Observed pharmacokinetics on multiple administration obeyed closely those predicted from the single-dose experiment, suggesting the absence of autoinduction of metabolism. No clinically important side effects or changes in central nervous system or cardiovascular system variables, hematology, biochemistry, or urinalysis occurred during the 7 days.