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BACKGROUND: To evaluate the safety, tolerability, pharmacokinetics, and maximum tolerated dose (MTD) of copanlisib, a phosphatidylinositol 3-kinase inhibitor, in patients with advanced solid tumors or non-Hodgkin's lymphoma (NHL). PATIENTS AND METHODS: Phase I dose-escalation study including patients with advanced solid tumors or NHL, and a cohort of patients with type 2 diabetes mellitus. Patients received three weekly intravenous infusions of copanlisib per 28-day cycle over the dose range 0.1-1.2 mg/kg. Plasma copanlisib levels were analyzed for pharmacokinetics. Biomarker analysis included PIK3CA, KRAS, BRAF, and PTEN mutational status and PTEN immunohistochemistry. Whole-body [(18)F]-fluorodeoxyglucose positron emission tomography ((18)FDG-PET) was carried out at baseline and following the first dose to assess early pharmacodynamic effects. Plasma glucose and insulin levels were evaluated serially. RESULTS: Fifty-seven patients received treatment. The MTD was 0.8 mg/kg copanlisib. The most frequent treatment-related adverse events were nausea and transient hyperglycemia. Copanlisib exposure was dose-proportional with no accumulation; peak exposure positively correlated with transient hyperglycemia post-infusion. Sixteen of 20 patients treated at the MTD had reduced (18)FDG-PET uptake; 7 (33%) had a reduction >25%. One patient achieved a complete response (CR; endometrial carcinoma exhibiting both PIK3CA and PTEN mutations and complete PTEN loss) and two had a partial response (PR; both metastatic breast cancer). Among the nine NHL patients, all six with follicular lymphoma (FL) responded (one CR and five PRs) and one patient with diffuse large B-cell lymphoma had a PR by investigator assessment; two patients with FL who achieved CR (per post hoc independent radiologic review) were on treatment >3 years. CONCLUSION: Copanlisib, dosed intermittently on days 1, 8, and 15 of a 28-day cycle, was well tolerated and the MTD was determined to be 0.8 mg/kg. Copanlisib exhibited dose-proportional pharmacokinetics and promising anti-tumor activity, particularly in patients with NHL. CLINICALTRIALSGOV: NCT00962611; https://clinicaltrials.gov/ct2/show/NCT00962611.

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PURPOSES: The objective of this study was to develop a mechanism-based population pharmacokinetic/pharmacodynamic (PK/PD) model in describing troxacitabine-induced neutropenia in patients with cancer. METHODS: A total of 727 PK/PD samples from 31 patients with cancer were included in the analysis. A mechanism-based population PD model was developed to describe neutropenia and the final model consisted of (1) a drug-sensitive uncommitted progenitor cell compartment (2) three transit compartments, and (3) a circulating neutrophil compartment with feedback mechanism. The troxacitabine affected the proliferation of sensitive progenitor cells through an inhibitory E (max) model. The model parameters were estimated using the MCPEM algorithm that was implemented in a parallel computing platform consisting of a single computer equipped with a quad-core INTEL central processor unit. RESULTS AND CONCLUSIONS: The mechanism-based PK/PD model developed using parallelized MCPEM method adequately describes the complex relationship between the exposure and absolute neutrophil counts in troxacitabine-treated patients with cancer. The simulation results suggested that the less frequent dosing schedule of troxacitabine used currently in clinical studies was associated with less incidence of neutropenia compared to more frequent dosing schedule.

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BACKGROUND: Resistance to endocrine therapy is a major impediment in breast cancer therapeutics. The Phosphatidylinositol-3-OH kinase (PI3K)/Protein kinase B (Akt/PKB) kinase signaling pathway has been implicated in altering breast cancer response to multiple therapies. How Akt modulates response is an area of significant clinical relevance. METHODS: We have used an in vitro model to discern the effects of robust Akt activity on breast cancer cellular response to endocrine therapies. RESULTS: High levels of Akt activity confer resistance to the aromatase inhibitor Letrozole (Let) and the selective estrogen receptor (ER) down-regulator Fulvestrant (ICI). Akt-induced resistance is not due to failure of these endocrine agents to inhibit estrogen receptor alpha activity. Instead, resistance is characterized by altered cell cycle and apoptotic response. Cotreatment with low concentrations of the mTOR inhibitor RAD-001 and either Let or ICI restores response of the resistant cells to levels observed in the responsive cells treated with either Let or ICI as a single agent. CONCLUSIONS: Our preliminary findings in experiments with RAD-001 indicate that cotreatment with mTOR inhibitors and either Let or ICI reverses the Akt-mediated resistance and restores responsiveness to antiestrogens. Concurrent ER and mTOR inhibition is therefore an effective strategy to overcome growth factor-induced resistance and bears significant implications for optimal clinical development of these agents in breast cancer treatment.

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The purposes of this study are (1) to evaluate the practice of red blood cell transfusions in very low birth weight (VLBW) infants (between 501 to 1500 g) during the postsurfactant era of the 1990s; and (2) to evaluate if there is a decreasing trend in red cell transfusions in the 1990s. Database and medical records of VLBW infants admitted to the neonatal intensive care unit (NICU) between January 1990 and December 1995 at Scott & White Clinic, Temple, Texas, were reviewed. Five hundred twenty-seven infants were admitted to the NICU, excluding 5 infants that were transferred out for possible cardiac surgery or for other reasons. Fifty one (9.7%) of these infants died prior to discharge. Hence, data from 476 survivors were reviewed for red blood cell (RBC) transfusions. Transfusions were given at the discretion of the attending neonatologist. None of the infants received erythropoietin. Of the 476 infants, 289 (61%) received RBC transfusions during the hospital stay, with 2.7+/-3.6 transfusions per infant with a volume of 40.5+/-50.4 mL/kg. Smaller infants required significantly more transfusions compared to larger infants when divided into 250-g subgroups. No statistically significant difference was noted in the number of RBC transfusions per infant or number of infants transfused during the 6-year period from year to year. We conclude that VLBW infants in the 1990s postsurfactant era required 2.7 RBC transfusions per infant, on average, with the smallest infants requiring the most transfusions. These data will be helpful to counsel mothers in preterm labor regarding the need of transfusions for each birth weight category. Red cell transfusion practice has not changed over this 6-year period in the 1990s. Additional measures such as erythropoietin or even stricter transfusion criteria may be necessary to decrease transfusions further. However, safety of such measures should be carefully evaluated.

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Hypothyroxinemia is a common finding in premature infants, presumably resulting from an immature hypothalamic-pituitary-thyroid axis. Because dynamic studies of thyroid function in premature infants are normal and the condition resolves spontaneously, HOP has been considered physiologic rather than pathologic. Thus, thyroid hormone supplementation has been assumed to be not required in premature infants. True hypothyroidism of hypothalamic pituitary or thyroid origin, however, does occur in premature as well as in term infants and should be investigated aggressively and treated appropriately. Current studies in premature infants with hypothyroxinemia suggest the following: infants with more than 27 weeks of gestation do not appear to benefit and may, in fact, be harmed by thyroid hormone supplementation; and short-term thyroid hormone supplementation in infants born before 27 weeks of gestation may be important to diminish morbidity and to improve neurodevelopmental outcome.

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The gustatory-vagal hypothesis proposes that gustatory stimulation elicits a coordinated vagal response manifested as an increase in ingestive behaviors (e.g., sucking) and a decrease in nucleus ambiguus vagal tone measured by decreases in the amplitude of respiratory sinus arrhythmia (RSA). The current study tested the gustatory-vagal hypothesis in a bottle feeding paradigm with 29 clinically stable, high-risk, low-birthweight neonates. The amplitude of respiratory sinus arrhythmia (RSA) was collected before, during, and after bottle feeding. Consistent with the gustatory-vagal hypothesis, RSA decreased during bottle feeding. In a longitudinal subsample of subjects, the pattern of RSA changes during the feeding paradigm was stable across two test sessions.

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Methylxanthine use in the treatment of apnea of prematurity is well documented. This drug is avoided in patients with aberrant pathways of conduction such as Wolff-Parkinson-White syndrome. In theory, methylxanthines enhance precipitation and exacerbation of tachyarrhythmias to which these patients are predisposed. This article reports a case of Wolff-Parkinson-White syndrome in a preterm neonate with severe apneic episodes in which methylxanthines were used. However, no adverse effects on cardiac rate or rhythm were encountered.

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OBJECTIVE: To evaluate the usefulness of lumbar puncture (LP) in the initial evaluation of symptom-free infants for congenital syphilis. STUDY DESIGN: We retrospectively studied infants who had successful LPs and were born to untreated or inadequately treated seropositive women between 1990 and 1993 in two hospitals in Washington, D.C. We identified 329 such symptom-free infants (syphilis group). The cerebrospinal fluid (CSF) VDRL was reactive in two (0.6%) infants. The CSF leukocyte and protein concentrations of these infants were compared with those in 84 symptom-free control infants who were born to seronegative women and who had LPs performed in 1993 to rule out sepsis because of associated risk factors. Control infants had negative results for bacterial cultures (CSF and blood) and bacterial antigen tests (CSF and urine). RESULTS: Thirty control subjects and 67 infants in the syphilis group had traumatic taps (CSF erythrocytes > 500 x 10(6)/L), and hence were excluded from the analysis of cell count and proteins. Birth weights and gestational ages were similar in both groups. The CSF leukocyte and protein values were similar in the syphilis group and in control infants: mean CSF leukocytes 7.7 x 10(6)/L (mean 7.7/mm3, range 0 to 57/mm3, SD 8.8) versus 6.9 x 10(6)/L (mean 6.9/mm3, range 0 to 31/mm3, SD 7), p = 0.5, and mean protein concentration 981 mg/L (range 270 to 2280 mg/L, SD 376) versus 936 mg/L (range 360 to 1750 mg/L, SD 368), p = 0.96, respectively. The combination of CSF leukocyte values > 5 x 10(6)/L (> 5/mm3) or protein values > 400 mg/L (> 40 mg/dl) was found in 97.8% of the infants in the syphilis group, compared with 95.3% of the control group. CONCLUSION: Because of the low yield of reactive CSF VDRL and the similar CSF leukocyte and protein values in the syphilis group and the control infants, the role of routine LP in the initial evaluation of symptom-free infants for congenital syphilis should be reconsidered.

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The incidence of congenital syphilis has recently reached epidemic proportions. With the resurgence of this important clinical entity, currently recommended screening procedures may be inadequate. We describe three cases that highlight the limitations of these screening procedures. All these infants had associated maternal risk factors for congenital syphilis, such as poor prenatal care and illicit drug use. All the infants and mothers were seronegative for syphilis at the time of birth but the infants became seropositive at 2 months of age. These cases support the need to reexamine current screening policies. In addition to prenatal and at-delivery screenings for congenital syphilis, it may be appropriate to screen infants born to high-risk mothers at 4 to 8 weeks of age.

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Recently, a number of infants have been born at home, in an ambulance, car, etc., before arrival at the District of Columbia General Hospital. Many of these infants had poor outcome. To evaluate the prevalence and outcome of these infants, we reviewed medical records of all infants born before arrival at the hospital (out-born infants) and compared them with in-hospital deliveries from July 1988 to June 1992. Data were analyzed using Fisher's Exact Test and chi-square test. There were 151 (1.8%) out-born infants and 8,169 (98.2%) in-born infants during this 4-year period. Infants in both groups were predominantly black (85%). The following were significant differences (P < 0.001) between out-born and in-hospital deliveries, respectively: illicit drug exposure 35% vs 21%; low-birth-weight (< 2,500 g) infants 39% vs 16%; intensive care unit admissions 29% vs 15%; and neonatal deaths per 1,000 live births 80 vs 7. We conclude that there is a twofold increase in the morbidity (required intensive care) and an 11-fold increase in the mortality among out-born infants compared with infants delivered in-hospital. Even though out-born infants were < 2% of the total deliveries, they accounted for 17% of total neonatal mortality.

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To evaluate the effect of intrauterine cocaine exposure on lung maturity of very low birthweight infants, the medical records of all infants with birthweight < 1500 g born between January 1989 and December 1990 at DC General Hospital were reviewed. Infants with conditions known to cause lung maturity, severe congenital anomalies, proven early sepsis, and birthweight > or = 500 g were excluded. A total of 69 infants were included in the study. Chest roentgenograms of these infants were evaluated by a pediatric radiologist, who was unaware of the infant's medical course, for evidence of respiratory distress syndrome (RDS), and radiological findings were correlated with clinical signs. Forty infants were exposed to cocaine in utero (cocaine group) and 29 were not exposed (noncocaine group). African-American ethnicity, pregnancy-induced hypertension, prolonged rupture of membranes, and alcohol use were similar in both groups. Tobacco use among cocaine group mothers was higher (42.5% versus 13.8%; P = .01). Gestational age (28.3 +/- 2.8 versus 28.3 +/- 3 weeks), birthweight (966 +/- 282 versus 1059 +/- 295 g), male gender, and Apgar scores were similar in both groups. Thirty (75%) infants in the cocaine group developed RDS compared with 19 (66%) in the noncocaine group (P > .05). Using multiple logistic regression analysis and controlling for smoking, alcohol use, and prolonged rupture of membranes (24 to 72 hours), the incidence of RDS between the groups remained statistically insignificant. We conclude that intrauterine cocaine exposure does not alter the incidence of RDS in very low birthweight infants.

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The occurrence of craniosynostosis (premature closure of cranial sutures) has been reported to be 3 to 5 per 10,000 live births. The incidence is even lower among African-American infants. The District of Columbia General Hospital serves primarily the African-American population with approximately 2000 deliveries a year. In the last 10 years, three neonates with craniosynostosis have been born at DC General Hospital; all three infants were African Americans. These infants were exposed to cocaine and tobacco in utero, which suggests a possible association between intrauterine cocaine and tobacco exposure and premature closure of cranial sutures. Possible pathogenesis of craniosynostosis in association with cocaine and tobacco use is discussed.

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To evaluate the effect of saline instillation prior to tracheal suction on lung mechanics in mechanically ventilated newborn infants, we studied pulmonary mechanics in nine infants with respiratory distress syndrome (RDS) and nine infants with meconium-aspiration syndrome (MAS) at a mean postnatal age of 3 days. Pulmonary mechanics were measured at 10 minutes prior to, and at 10, 20, and 30 minutes after tracheal suction with saline instillation. Suction and study protocol were repeated within 12 hours without saline instillation. The sequence of the study with and without saline instillation was randomly assigned. In infants with RDS, tracheal suction had no effect on pulmonary compliance or airway resistance with and without saline instillation. In infants with MAS, there was no change in compliance after tracheal suction with and without saline instillation. Airway resistance decreased by 35% after tracheal suction with saline instillation in infants with MAS; tracheal suction without saline instillation had no effect on airway resistance. We conclude that saline instillation into trachea as commonly done during tracheal suction has no deleterious effects on lung mechanics in newborn infants.

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