Multicenter phase 1 trial of intraventricular immunochemotherapy in recurrent CNS lymphoma.

UNLABELLED: Recurrent CNS lymphoma continues to be associated with poor outcomes in the rituximab era. Although IV rituximab mediates superior disease control of systemic non-Hodgkin lymphoma (NHL), it fails to completely eliminate the risk of meningeal recurrence, likely due to minimal CNS penetration. Given that rituximab acts synergistically with chemotherapy, we conducted the first phase 1 study of intraventricular immunochemotherapy in patients with recurrent CNS NHL. Fourteen patients received 10 mg or 25 mg intraventricular rituximab twice weekly for 4 weeks, with rituximab administered as monotherapy during the first treatment each week and rituximab administered in combination with methotrexate (MTX) during the second treatment each week. More than 150 doses were administered without serious toxicity. In a population with high-refractory CNS NHL, 75% of patients achieved complete cytologic responses and 43% achieved an overall complete response in CSF and/or brain parenchyma. Two patients achieved a first complete response of CNS NHL with intraventricular rituximab/MTX, including 1 with CNS lymphoma refractory to high-dose systemic and intrathecal MTX plus IV rituximab. We conclude that intraventricular rituximab in combination with MTX is feasible and highly active in the treatment of drug-resistant CNS NHL that is refractory or unresponsive to IV rituximab. KEY POINTS: Phase I study showed that intraventricular rituximab plus methotrexate is feasible and active in the treatment of refractory CNS lymphoma.

Withdrawal in adolescent light smokers following 24-hour abstinence.

INTRODUCTION: Withdrawal is one of the most important symptoms of nicotine addiction. We examined the extent to which adolescent light smokers experienced withdrawal symptoms when deprived of nicotine for a 24-hr period. METHODS: A total of 20 adolescents aged 13-17 years who smoked 1-5 cigarettes/day (CPD) refrained from smoking for a 24-hr period. Withdrawal scales were administered, and heart rate was measured at baseline, 12, and 24 hr. Neuropsychological testing was performed at baseline and 24 hr. Participants were divided into two groups: very light smokers (1-3 CPD) and light smokers (4-5 CPD). RESULTS: At 12 hr, very light smokers experienced a decrease in withdrawal symptoms versus light smokers, who reported an increase in symptoms (-2.9 vs. 2.8, p = .02). Similarly, at 24 hr, very light smokers experienced a mean decrease in withdrawal score compared with a mean increase for the light smoker group (-2.2 vs. 5.8, p = .04). We did not find a significant change in heart rate or any differences in participants' scores on the memory or concentration tasks. DISCUSSION: Based on our findings in this controlled laboratory experiment, adolescent very light smokers did not appear to have significant withdrawal symptoms following abstinence from nicotine. Adolescent light smokers who smoke 4-5 CPD experienced subjective withdrawal symptoms but did not have objective signs of nicotine withdrawal. The stage of smoking in which adolescents are smoking 5 CPD or fewer appears to be a crucial time for studying development of nicotine addiction in teens as they may be transitioning from social smoking to early addiction.

Interruptions in Medicaid coverage and risk for hospitalization for ambulatory care-sensitive conditions.

BACKGROUND: Many low-income U.S. citizens experience interruptions in health insurance coverage. OBJECTIVE: To determine the rate of hospitalization for ambulatory care-sensitive conditions among Medicaid beneficiaries with interruptions in coverage. DESIGN: Retrospective cohort study. SETTING: California Medicaid population. PATIENTS: 4,735,797 adults in California age 18 to 64 years who received a minimum of 1 month of Medicaid coverage between 1998 to 2002. MEASUREMENT: Time to hospitalization for an ambulatory care-sensitive condition. RESULTS: Sixty-two percent of Medicaid beneficiaries experienced at least 1 interruption in coverage during the study period. The 3 most common ambulatory care-sensitive conditions resulting in a hospitalization were heart failure, diabetes, and chronic obstructive pulmonary disease. Interruptions in coverage were associated with a higher risk for hospitalization for an ambulatory care-sensitive condition (adjusted hazard ratio, 3.66 [95% CI, 3.59 to 3.72]; P < 0.001). In subgroup analyses, the association between interrupted coverage and hospitalization was stronger for beneficiaries eligible through the Temporary Aid to Needy Families program (adjusted hazard ratio, 8.56 [CI, 8.06 to 9.08]) than for beneficiaries eligible through the Supplemental Security Income program (adjusted hazard ratio, 1.72 [CI, 1.67 to 1.76]), who typically retain Medicare coverage even when their Medicaid coverage is interrupted. LIMITATION: The study lacked information on why interruptions occurred and whether beneficiaries with interruptions transitioned to other insurance coverage. CONCLUSION: Interruptions in Medicaid coverage are associated with a higher rate of hospitalization for ambulatory care-sensitive conditions. Policies that reduce the frequency of interruptions in Medicaid coverage might prevent some of the health events that trigger hospitalization and high-cost health care spending.

Medicaid re-enrollment policies and children's risk of hospitalizations for ambulatory care sensitive conditions.

BACKGROUND: Many poor children rotate through the Medicaid program with periods of being uninsured. OBJECTIVE: To determine health and cost consequences of a Medicaid policy change that extended the Medicaid eligibility redetermination period for children in California from 3 to 12 months. RESEARCH DESIGN: A pre/postevaluation with a comparison group of a natural experiment. SUBJECTS: All California children ages 1-17 years who received a minimum of 1 month of Medicaid coverage in 1999-2000 (3,288,171) and/or 2001-2002 (3,230,120). MEASURES: The percentage of children with continuous Medicaid coverage and the hospitalization rate and costs for ambulatory care sensitive conditions in each time period. RESULTS: In the 2 years before the policy change, 49% of children had continuous Medicaid coverage compared with 62% in the 2 years afterward (P < 0.0001). After adjusting for demographic and programmatic differences in the population of children in each time period, the relative hazard of a hospitalization for an ambulatory care sensitive condition for a child with at least 1 month of Medicaid coverage decreased to 0.74 (P < 0.0001) after the extension of the Medicaid enrollment period. There was dollars 17 million less in estimated hospitalization costs for ambulatory care sensitive conditions with less frequent eligibility redetermination that partially offset the estimated dollars 150 million in additional costs to Medicaid for providing more continuous coverage. CONCLUSIONS: Reducing the frequency of eligibility redetermination for children in Medicaid was associated with higher costs to the program but more continuity of insurance coverage, improvements in health, and lower hospital spending.

Phase I dose-escalation study of 5-day intermittent oral lapatinib therapy in patients with human epidermal growth factor receptor 2-overexpressing breast cancer.

PURPOSE: The highly effective treatment of human epidermal growth factor receptor (HER) 2-amplified breast cancer has proven challenging because of a signal buffering capacity inherent in the functionally relevant HER2-HER3 target. HER2-HER3 signaling can be inactivated by doses of lapatinib that fully inactivate the HER2 kinase. In mouse models, such doses are not tolerable in continuous administration, but they are tolerable and highly effective in intermittent dosing. We pursued the clinical translation of this treatment hypothesis. PATIENTS AND METHODS: We conducted a phase I dose-escalation study in women with advanced HER2-overexpressing breast cancer. Lapatinib was administered on days 1 through 5 of repeating 14-day cycles. Dose escalation was conducted using a 3+3 design with plasma lapatinib level monitoring. RESULTS: Forty patients were evaluable for toxicity, and 34 patients were evaluable for dose-limiting toxicity (DLT). Lapatinib dose was escalated to 7,000 mg per day in twice-daily dosing with no DLTs; however, plasma lapatinib concentrations plateaued in this dose range. Additional cohorts evaluated strategies to increase lapatinib exposure, including the food effect, CYP3A4 inhibition, and dose fractionation. Of these, only ketoconazole was able to increase lapatinib exposure, despite highly variable lapatinib bioavailability. Intolerable exposure levels were not encountered. Eight patients (20%) experienced grade 3 diarrhea. Six patients achieved a response, and dramatic responses were seen in three patients with lapatinib concentrations approaching 10,000 ng/mL. CONCLUSION: Lapatinib exposure can be safely and significantly increased through intermittent dosing but reaches a ceiling that currently impedes clinical translation of the treatment hypothesis. Preliminary efficacy data suggest that exposures approaching those seen in mouse models can result in highly significant tumor responses.

Health plan competition for Medicaid enrollees based on performance does not improve quality of care.

Incentives to improve the quality of care provided in Medicaid managed care plans are increasingly common and take many forms. One is a pay-for-performance program that automatically assigns new enrollees to better-performing Medicaid plans in California. Our qualitative and quantitative study of this program examined the expected and actual impacts of the performance incentive on all areas of care. We compared quality outcomes in plans included in the pay-for-performance, "auto-assignment" incentive and comparable outcomes in plans that were not included. We found that quality did not improve significantly faster in plans included in the incentive scheme. Combined with some evidence of negative impact on other areas of care, the findings raise questions about the usefulness of this program in California Medicaid, and about similar programs in other states.

A randomized trial of nicotine nasal spray in adolescent smokers.

OBJECTIVES: Nicotine nasal spray has been 1 of the most successful forms of nicotine-replacement therapy in adult populations. The nasal sprayer has not been studied in adolescent smokers. The objective of this pilot study was to determine the feasibility and utility of using nicotine nasal spray for adolescent smokers who wanted to quit smoking. METHODS: Forty adolescent smokers who were between 15 and 18 years of age and smoked >/=5 cigarettes daily for at least 6 months were recruited from several San Francisco Bay area schools from 2005 to 2007. Using a randomized, open-label, 12-week trial, adolescent smokers were assigned to receive either weekly counseling alone (control) for 8 weeks or 8 weeks of counseling along with 6 weeks of nicotine nasal spray. Self-reported smoking abstinence was verified by both expired-air carbon monoxide and salivary cotinine. RESULTS: There was no difference in cessation rates, the numbers of cigarettes smoked per day, or cotinine levels at 12 weeks. Fifty-seven percent of participants stopped using their spray after only 1 week. The most commonly reported adverse effect was nasal irritation and burning (34.8%) followed by complaints about the taste and smell (13%). CONCLUSIONS: The unpleasant adverse effects, poor adherence, and consequent lack of efficacy observed in our pilot study do not support the use of nicotine nasal spray as an adjunct to counseling for adolescent smokers who wish to quit.

Rate of nicotine metabolism and withdrawal symptoms in adolescent light smokers.

OBJECTIVES: The rate of nicotine metabolism may contribute to vulnerability in adolescents' transition from smoking initiation to addiction. The objectives of this study were to examine the associations between the rate of nicotine metabolism and cigarette consumption, addiction, and withdrawal symptoms in a sample of adolescent light smokers. PARTICIPANTS: Twenty adolescent smokers between 13 and 17 years old, who smoked between 1 and 6 cigarettes daily for >/=6 months, were recruited from several San Francisco Bay area schools and pediatric clinics from 2006 to 2007. METHODS: Participants underwent 24 hours of supervised tobacco abstinence. Serum was collected at baseline and at 24 hours for measurement of the nicotine metabolites cotinine and 3'-hydroxycotinine. Participants also completed self-report measures, which included smoking behavior, nicotine dependence, and withdrawal scales at baseline and 24 hours after baseline. The ratio of serum 3'-hydroxycotinine/cotinine (the nicotine metabolite ratio), a measure of the rate of nicotine metabolism, was computed by using measurements from the 24-hour serum samples. RESULTS: Participants were divided into 2 groups: faster metabolizers (3'-hydroxycotinine/cotinine ratio >/= 0.5; n = 5) and slower metabolizers (3'-hydroxycotinine/cotinine ratio < 0.5; n = 15). Faster metabolizers reported greater withdrawal symptoms after 24 hours of abstinence compared with slower metabolizers even after adjusting for the number of cigarettes smoked per day. The metabolite ratio was significantly correlated with self-described level of addiction. CONCLUSIONS: This is the first study to report a significant relationship between the rate of nicotine metabolism and withdrawal symptoms and self-reported addiction in adolescent light smokers. Given the association between withdrawal symptoms and nicotine addiction, adolescent smokers who are faster metabolizers of nicotine may be at greater risk for becoming addicted to nicotine compared with slower metabolizers.