Phase 1 study of sirolimus in combination with oral cyclophosphamide and topotecan in children and young adults with relapsed and refractory solid tumors.

PURPOSE: To determine the maximum tolerated dose (MTD), toxicities, and pharmacodynamics effects of sirolimus combined with oral metronomic topotecan and cyclophosphamide in a pediatric population. MATERIALS AND METHODS: Patients who were 1 to 30 years of age with relapsed/refractory solid tumors (including CNS) were eligible. Patients received daily oral sirolimus and cyclophosphamide (25-50 mg/m2/dose) on days 1-21 and oral topotecan (0.8 mg/m2/dose) on days 1-14 in 28-day cycles. Sirolimus steady-state plasma trough concentrations of 3-7.9 ng/mL and 8-12.0 ng/mL were evaluated, with dose escalation based on a 3+3 phase 1 design. Biomarkers of angiogenesis were also evaluated. RESULTS: Twenty-one patients were treated (median age 18 years; range 9-30). Dose-limiting toxicities included myelosuppression, ALT elevation, stomatitis, and hypertriglyceridemia. The MTD was sirolimus with trough goal of 8-12.0 ng/mL; cyclophosphamide 25 mg/m2/dose; and topotecan 0.8 mg/m2/dose. No objective responses were observed. Four patients had prolonged stable disease > 4 cycles (range 4-12). Correlative biomarker analyses demonstrated reductions in thrombospondin-1 (p=0.043) and soluble vascular endothelial growth factor receptor-2 plasma concentrations at 21 days compared to baseline. CONCLUSIONS: The combination of oral sirolimus, topotecan, and cyclophosphamide was well tolerated and biomarker studies demonstrated modulation of angiogenic pathways with this regimen.

Transcript Analysis for Internal Biodosimetry Using Peripheral Blood from Neuroblastoma Patients Treated with (131)I-mIBG, a Targeted Radionuclide.

Calculating internal dose from therapeutic radionuclides currently relies on estimates made from multiple radiation exposure measurements, converted to absorbed dose in specific organs using the Medical Internal Radiation Dose (MIRD) schema. As an alternative biodosimetric approach, we utilized gene expression analysis of whole blood from patients receiving targeted radiotherapy. Collected blood from patients with relapsed or refractory neuroblastoma who received (131)I-labeled metaiodobenzylguanidine ((131)I-mIBG) at the University of California San Francisco (UCSF) was used to compare calculated internal dose with the modulation of chosen gene expression. A total of 40 patients, median age 9 years, had blood drawn at baseline, 72 and 96 h after (131)I-mIBG infusion. Whole-body absorbed dose was calculated for each patient based on the cumulated activity determined from injected mIBG activity and patient-specific time-activity curves combined with (131)I whole-body S factors. We then assessed transcripts that were the most significant for describing the mixed therapeutic treatments over time using real-time polymerase chain reaction (RT-PCR). Modulation was evaluated statistically using multiple regression analysis for data at 0, 72 and 96 h. A total of 10 genes were analyzed across 40 patients: CDKN1A; FDXR; GADD45A; BCLXL; STAT5B; BAX; BCL2; DDB2; XPC; and MDM2. Six genes were significantly modulated upon exposure to (131)I-mIBG at 72 h, as well as at 96 h. Four genes varied significantly with absorbed dose when controlling for time. A gene expression biodosimetry model was developed to predict absorbed dose based on modulation of gene transcripts within whole blood. Three transcripts explained over 98% of the variance in the modulation of gene expression over the 96 h (CDKN1A, BAX and DDB2). To our knowledge, this is a novel study, which uses whole blood collected from patients treated with a radiopharmaceutical, to characterize biomarkers that may be useful for biodosimetry. Our data indicate that transcripts, which have been previously identified as biomarkers of external exposures in ex vivo whole blood and in vivo radiotherapy patients, are also good early indicators of internal exposure. However, for internal sources of radiation, the biokinetics and physical decay of the radionuclide strongly influence the gene expression.

A pragmatic descriptive study of rewarming the newborn after the first bath.

OBJECTIVES: To evaluate two methods of rewarming newborns after the first bath: radiant rewarming and skin-to-skin maternal newborn contact. DESIGN: A nonrandomized clinical trial in which mothers chose the rewarming method, with 200 participants in the skin-to-skin rewarming group (experimental condition), and 200 in the radiant rewarming group (control). SETTING: A teaching hospital in the Southeast United States. PARTICIPANTS: Healthy, term infants after vaginal delivery. METHODS: Newborn temperatures were taken immediately prior to the bath (T1), and 30 minutes (T2) and 60 minutes (T3) after the bath. Descriptive statistics and t tests were used to determine differences between groups and between time points. Logistic regression was employed to assess risk factors for newborns with temperatures less than 36.4°C 30 minutes after the bath. RESULTS: Because 96 of the first 100 mothers chose skin-to-skin rewarming, we concluded the study early and analyzed the data. Of the 96 mothers who chose skin-to-skin, 91 infants were successfully rewarmed and five required rescue rewarming under the radiant warmer. Careful review of newborns requiring rescuing showed inadequate skin-to-skin contact or removal of the protective covering. In this sample, African American mothers were significantly younger, had smaller newborns, and their newborns had lower temperatures than non-African American newborns. CONCLUSIONS: Given a choice, mothers overwhelmingly preferred skin-to-skin rewarming. Newborns can safely rewarm skin-to-skin if staff pay special attention to how they are positioning the newborn and recheck mother and newborn frequently. The unexpected finding of racial differences in maternal and newborn characteristics will require further investigation.

Countertransference and self-injury: a cognitive behavioural cycle.

AIM: This paper discusses the emotional, cognitive and behavioural effects of self-injury on nurses as helpers, and shows the usefulness of a cycle that can affect care provision for this group of people. BACKGROUND: People self-injure for many different reasons, such as feeling angry, sad, guilty or frightened, and these emotions are often linked to feeling helpless, powerless or out of control. Self-injury has often been reported as a coping strategy to gain control. Psychoanalytic and cognitive behavioural concepts have been used to understand why people self-injure and also inform intervention strategies. Unfortunately, negative emotional responses in professionals may interfere with the effectiveness of any therapeutic relationship. DISCUSSION: Negative emotional responses from nurses can affect the way they think about and behave towards clients who self-injure. During clinical supervision or education, nurses' thoughts can be challenged to become less negative, so that their resulting behaviour can also become less punitive. Non-punitive or more positive behaviour can in turn challenge some of the negative self-beliefs of clients. CONCLUSIONS: Knowledge about countertransference when working with people who self-injure may reduce nurses' negative thoughts and behaviours, which may result in improved client care.