The cyclin-dependent kinase inhibitor UCN-01 plus cisplatin in advanced solid tumors: a California cancer consortium phase I pharmacokinetic and molecular correlative trial.

BACKGROUND: UCN-01 (7-hydroxy-staurosporine) is a novel antineoplastic agent targeting cyclin-dependent kinases, which shows potent in vitro and in vivo activity against a broad range of tumor types. Our group has previously shown that UCN-01 potentiates the apoptotic response of agents such as cisplatin in vitro by preventing sequence-specific abrogation of G2 arrest caused by DNA-damaging chemotherapies. PATIENTS AND METHODS: This National Cancer Institute-sponsored phase I trial was designed to determine the safety, maximum tolerated dose, and pharmacokinetics of escalating doses of cisplatin in combination with UCN-01 in patients with advanced malignant solid tumors, as well as to do molecular correlative studies on tumor specimens. Cisplatin was infused over 1 hour before UCN-01 (45 mg/m2/d) given as a 72-hour continuous infusion. Escalation of cisplatin was planned through five dose levels at 20, 30, 45, 60, and 75 mg/m2. RESULTS: Ten patients were accrued. Accrual was halted at dose level 2 (cisplatin, 30 mg/m2) due to dose-limiting toxicities consisting of grade 5 sepsis with respiratory failure associated with grade 3 creatinine (one patient) and grade 3 atrial fibrillation (one patient). Plasma and salivary pharmacokinetics of UCN-01 were unaffected by cisplatin. Pretreatment and posttreatment tumor biopsies showed that UCN-01 was active against a key molecular target, the checkpoint kinase Chk1.CONCLUSIONS: This phase I trial failed to achieve targeted therapeutic dose levels of cisplatin when combined with prolonged infusion UCN-01. However, because preclinical data indicate that UCN-01 potentiates response to platinum, further studies with alternative dose schedules of the combination, or with other platinum analogues, are warranted.     

Parent and physician perspectives on quality of care at the end of life in children with cancer.

PURPOSE: To ascertain parents' and physicians' assessments of quality of end-of-life care for children with cancer and to determine factors associated with high-quality care as perceived by parents and physicians. METHODS: A survey was conducted between 1997 and 2001 of 144 parents of children who received treatment at the Dana-Farber Cancer Institute and Children's Hospital (Boston, MA) or Children's Hospitals and Clinics of St Paul and Minneapolis, MN, between 1990 and 1999 (65% of those located and eligible) and 52 pediatric oncologists. RESULTS: In multivariable models, higher parent ratings of physician care were associated with physicians giving clear information about what to expect in the end-of-life period (odds ratio [OR] = 19.90, P = .02), communicating with care and sensitivity (OR = 7.67, P < .01), communicating directly with the child when appropriate (OR = 11.18, P < .01), and preparing the parent for circumstances surrounding the child's death (OR = 4.84, P = .03). Parent reports of the child's pain and suffering were not significant correlates of parental ratings of care (P = .93 and .35, respectively). Oncologists' ratings of care were inversely associated with the parent's report of the child's experience of pain (OR = 0.15, P = .01) and more than 10 hospital days in the last month of life (OR = 0.24, P < .01). Parent-rated communication factors were not correlates of oncologist-rated care. No association was found between parent and physician care ratings (P = .88). CONCLUSION: For parents of children who die of cancer, doctor-patient communication is the principal determinant of high-quality physician care. In contrast, physicians' care ratings depend on biomedical rather than relational aspects of care.     

Clinical Outcomes and Resource Use for Infants With Hypoplastic Left Heart Syndrome During Bidirectional Glenn: Summary From the Joint Council for Congenital Heart Disease National Pediatric Cardiology Quality Improvement Collaborative Registry

The National Pediatric Cardiology Quality Improvement Collaborative (NPC-QIC) registry captures information on interstage management of infants with hypoplastic left heart syndrome (HLHS). The purpose of this study was to identify interstage risk factors for increased resource use and adverse outcomes during bidirectional Glenn (BDG) hospitalization. All infants in the NPC-QIC registry (31 United States hospitals) undergoing BDG surgery were included (December 2009 to August 2010). Patient demographics, interstage variables, operative procedures, and complications were recorded. Days of hospitalization, ventilation, inotrope use, and complications were surrogates of resource use. Logistic regression analysis determined the associations between predictor variables and resource use. Of 162 infants, 105 (65 %) were males. At BDG, the median age was 155 days (range 78–128), mean weight-for-age z-score was ?1.6 ± 1.1, mean length-for-age z-score was ?1.5 ± 1.7, and mean preoperative oxygen saturation was 78 % ± 7 %. Caloric recommendations were met in 60 % of patients, and 85 % of patients participated in a home-surveillance program. Median days of intubation, inotrope use, and hospitalization were 1, 2, and 7, respectively. There were 4 post-BDG deaths and 55 complications. In multivariate analysis, lower weight-for-age z-score, female sex, and aortic atresia with mitral stenosis were associated with a higher risk of BDG complications. Meeting caloric recommendations before BDG was associated with fewer hospitalization days. Lower weight-for-age z-score was an independent and potentially modifiable risk factor for BDG complications. HLHS infants who met caloric recommendations before BDG had a lower duration of hospitalization at BDG. These data justify targeting nutrition in interstage strategies to improve outcomes and decrease costs for patients with HLHS.     

Effect of antipyrine on prostaglandin levels and uterine and umbilical blood flow

Antipyrine and 4-aminoantipyrine have been used for approximately 20 years to measure uterine and umbilical blood flow. Fetal infusion of 4-aminoantipyrine has been shown to decrease myometrial activity and to significantly lower prostaglandin F2 alpha metabolite levels. Since prostaglandins are thought to be important in regulating uterine and umbilical blood flow, their decrease could cause significant changes in blood flow. The purpose of the present study was to evaluate the effects of antipyrine on uterine and umbilical blood flow as measured with electromagnetic flow probes and to determine whether antipyrine causes significant changes in levels of prostaglandin E2, prostaglandin F2 alpha metabolite, and prostaglandin I2 measured as 6-keto-prostaglandin F1 alpha. Antipyrine infusion produced significant reductions in the uterine venous levels of prostaglandin E2 and prostaglandin F2 alpha metabolite (p less than 0.05). These reductions in prostaglandin levels were not associated with any significant changes in maternal blood pressure, heart rate, uterine blood flow, or oxygen content. Although fetal prostaglandin levels tended to decrease during the antipyrine infusion, these changes were not significant. Fetal blood pressure, heart rate, umbilical blood flow, PaO2, and oxygen content were not significantly altered. These data suggest that the antipyrine method does not affect basal blood flow in the uterine or umbilical circulation even though uterine prostaglandin levels are significantly decreased.     

New guidelines for maternal and neonatal resuscitation

New evidence has prompted changes in our national cardiopulmonary resuscitation guidelines for both neonates and adult patients. The purpose of this article is to provide an overview of the changes recommended by the American Heart Association, Academy of American Pediatrics, and the American College of Obstetrics and Gynecology. In addition, a strategy for implementing these guidelines into practice is suggested.     

Health-enhancing physical activity,psychological needs satisfaction,and well-being: Is it how often,how long,or how much effort that matters?

The objective of this study was to examine the role of basic psychological need satisfaction as a potential mediator of the relationship between health-enhancing physical activity (HEPA) and well-being. Participants (N = 201) were young adults who recalled their HEPA behavior, experiences of psychological need satisfaction, and levels of well-being across multiple indicators using a cross-sectional design targeting the previous day. Results from path analysis demonstrated that effort put forth in HEPA activities, as opposed to frequency or duration of HEPA, predicted well-being. Further, psychological needs satisfaction mediated between 10% and 44% of the HEPA-Effort – well-being relationship. Overall, these findings lend credence to the notion that effortful investment is associated with well-being when engaged in HEPA, and that the satisfaction of basic psychological needs may act as a salient explanatory mechanism partially accounting for that relationship.