Gene expression profile alone is inadequate in predicting complete response in multiple myeloma.

With advent of several treatment options in multiple myeloma (MM), a selection of effective regimen has become an important issue. Use of gene expression profile (GEP) is considered an important tool in predicting outcome; however, it is unclear whether such genomic analysis alone can adequately predict therapeutic response. We evaluated the ability of GEP to predict complete response (CR) in MM. GEP from pretreatment MM cells from 136 uniformly treated MM patients with response data on an IFM, France led study were analyzed. To evaluate variability in predictive power due to microarray platform or treatment types, additional data sets from three different studies (n=511) were analyzed using same methods. We used several machine learning methods to derive a prediction model using training and test subsets of the original four data sets. Among all methods employed for GEP-based CR predictive capability, we got accuracy range of 56-78% in test data sets and no significant difference with regard to GEP platforms, treatment regimens or in newly diagnosed or relapsed patients. Importantly, permuted P-value showed no statistically significant CR predictive information in GEP data. This analysis suggests that GEP-based signature has limited power to predict CR in MM, highlighting the need to develop comprehensive predictive model using integrated genomics approach.

Transcription factor-pathway coexpression analysis reveals cooperation between SP1 and ESR1 on dysregulating cell cycle arrest in non-hyperdiploid multiple myeloma.

Multiple myeloma is a hematological cancer of plasma B cells and remains incurable. Two major subtypes of myeloma, hyperdiploid MM (HMM) and non-hyperdiploid MM (NHMM), have distinct chromosomal alterations and different survival outcomes. Transcription factors (TrFs) have been implicated in myeloma oncogenesis, but their dysregulation in myeloma subtypes are less studied. Here, we developed a TrF-pathway coexpression analysis to identify altered coexpression between two sample types. We apply the method to the two myeloma subtypes and the cell cycle arrest pathway, which is significantly differentially expressed between the two subtypes. We find that TrFs MYC, nuclear factor-κB and HOXA9 have significantly lower coexpression with cell cycle arrest in HMM, co-occurring with their overactivation in HMM. In contrast, TrFs ESR1 (estrogen receptor 1), SP1 and E2F1 have significantly lower coexpression with cell cycle arrest in NHMM. SP1 chromatin immunoprecipitation targets are enriched by cell cycle arrest genes. These results motivate a cooperation model of ESR1 and SP1 in regulating cell cycle arrest, and a hypothesis that their overactivation in NHMM disrupts proper regulation of cell cycle arrest. Cotargeting ESR1 and SP1 shows a synergistic effect on inhibiting myeloma proliferation in NHMM cell lines. Therefore, studying TrF-pathway coexpression dysregulation in human cancers facilitates forming novel hypotheses toward clinical utility.

Unbound bilirubin predicts abnormal automated auditory brainstem response in a diverse newborn population.

OBJECTIVE: The objective of this study was to determine if plasma unbound or 'free' bilirubin concentration (B(f)) measured during the first 30 days of life is associated with subsequent abnormal hearing screening testing by automated auditory brainstem response (AABR) in a diverse population of newborns. STUDY DESIGN: An observational study of newborns receiving AABR, plasma total bilirubin concentration (TBC) and B(f) measurements and without underlying conditions known to affect hearing was conducted. Logistic regression was used to determine associations between abnormal AABR and B(f) or TBC. The impacts of a variety of clinical factors on the regression model were also assessed. RESULT: A total of 191 patients with birth weights and gestations ranging from 406 to 4727 g and 24 to 42 weeks, respectively, were studied. Among them, 175 (92%) had normal (bilateral PASS) AABR and 16 had abnormal AABR (6 had unilateral REFER AABR, and 10 had bilateral REFER AABR). Mean TBC was not significantly different in babies with normal or abnormal AABR, but mean B(f) was greater in the latter group (1.76 versus 0.93 microg per 100 ml, respectively, P=0.012). B(f), but not TBC, was associated with an abnormal AABR (B(f) adjusted odds ratio 3.3, 95% CI 1.8 to 6.1). Comparing receiver-operating characteristics curves, the B(f)/TBC ratio was a better predictor of an abnormal AABR than B(f) alone. Intraventricular hemorrhage was the only confounding clinical variable. CONCLUSION: An abnormal AABR is associated with an elevated B(f) or B(f)/TBC ratio, but not the TBC alone. The prevalence of bilirubin neurotoxicity as a cause of audiological dysfunction may be underestimated if the TBC alone is used to assess the severity of newborn jaundice.

Indomethacin use for the management of patent ductus arteriosus in preterms: a web-based survey of practice attitudes among neonatal fellowship program directors in the United States.

The objective of this study was to determine whether neonatal-perinatal fellowship programs (NFTPs) in the United States vary in indomethacin use for the management of patent ductus arteriosus (PDA) in < or =28 week gestational age infants at birth. A 53-item web-based survey was sent to 84 NFTP directors who received prenotification, followed 2 weeks later by a reminder letter. A total of 56 NFTP directors responded (67% maximum response rate). Wide variation exists in the maximum number of indomethacin courses used to close ductus, use of indomethacin for reopened PDA beyond 14 days, ductal closure definition, contraindications before consideration of indomethacin, interventions for contraindications, and reported ductal closer rate after each indomethacin course. Indomethacin therapy for symptomatic PDA and short course of indomethacin are common practices. Indomethacin use for the management of PDA in premature infants varies among NFTP directors. Practice attitudes may explain variations in ductal closure and ligation rates. Because practice variations may have implications for long-term outcome of vulnerable premature infants, studies relevant to the management of PDA in premature infants are needed.

Bilirubin and serial auditory brainstem responses in premature infants.

OBJECTIVES: To determine the usefulness of the bilirubin-albumin (B:A) molar ratio (MR) and unbound bilirubin (UB) as compared with serum total bilirubin (TB) in predicting bilirubin encephalopathy as assessed by auditory brainstem responses (ABR) in infants of 28 to 32 weeks' gestational age. STUDY DESIGN: During a 2-year period, serial ABRs were obtained on 143 infants of 28 to 32 weeks' gestational age during the first postnatal week. Waveforms were categorized on the basis of response replicability and the presence of waves III and V. Wave V latencies were also serially analyzed when measurable for individual infants. Maturation of the ABR was defined as abnormal when the waveform category worsened and/or latency increased during the study interval. Serum albumin was analyzed at 48 to 72 hours of age in all patients. Serum TB was analyzed as clinically indicated. Aliquots of the same samples were also analyzed for UB in a subset of infants. RESULTS: The mean peak TB concentration (10.1 +/- 1.7 mg/dL) for the 71 infants with normal ABR maturation was not significantly different from the mean peak TB (10.2 +/- 2.1 mg/dL) in the 24-hour period preceding the ABR's first showing abnormal maturation in the other 55 infants. However, in infants with UB analyzed, the mean peak UB (0.62 +/- 0.20 vs 0.40 +/- 0.15 microg/dL) was significantly higher in the infants with abnormal maturation (n = 25) than in infants with normal maturation (n = 20). The B:A MR results were equivocal. In the entire study population, there was no difference in B:A MR between infants with normal versus abnormal ABR maturation. However, in the subset of infants in whom UB was measured, although TB was not different, there was a significant difference in B:A MR. Based on receiver-operating characteristic curves, a UB level of 0.5 microg/dL was the best discriminator with a sensitivity of 70% and a specificity of 75%. The proportion of infants who had UB >0.5 microg/dL and UB 0.5 microg/dL compared with UB

Brainstem maturation in premature infants as a function of enteral feeding type.

OBJECTIVE: To determine whether brainstem maturation as measured by brainstem auditory-evoked responses (BAERs) in preterm infants is a function of dietary intake. STUDY DESIGN: We obtained serial BAERs on infants 28 to 32 weeks' gestation at birth, cared for in the neonatal intensive care unit of a regional referral center in Upstate New York. Waveforms were analyzed for replicability and for the presence of waves III and V. Absolute and interwave latencies were measured. Baseline and follow-up BAER measurements were compared, and the rates of change were calculated. Patient charts were reviewed for type of enteral feeding during the interval between BAERs. Student's t test was used to analyze continuous variables and chi(2) analysis was used to analyze categorical variables. RESULTS: Data from 37 study infants (17 fed breast milk and 20 fed commercial premature formula) revealed that there was no difference in absolute latencies of waves III and V at baseline; however, the rates of decrease of absolute latencies over the study interval were significantly greater in infants receiving human milk. CONCLUSIONS: Infants fed breast milk have faster brainstem maturation, compared with infants fed formula, based on the rate of maturation of BAERs. This effect may be attributable to the constituent composition of breast milk, compared with synthetic formulas.

Expression of vascular endothelial growth factor and Flk-1 in developing and glucocorticoid-treated mouse lung.

Although the endothelial cell is the most abundant cell type in the differentiated lung, little is known about regulation of lung developmental vasculogenesis. Vascular endothelial growth factor (VEGF) is an endothelial cell mitogen and angiogenic factor that has putative roles in vascular development. Mitogenic actions of VEGF are mediated by the tyrosine kinase receptor KDR/murine homologue fetal liver kinase Flk-1. HLF (hypoxia-inducible factor-like factor) is a transcription factor that increases VEGF gene transcription. Dexamethasone augments lung maturation in fetal and postnatal animals. However, in vitro studies suggest that dexamethasone blocks induction of VEGF. The objectives for the current study were to measure VEGF mRNA and Flk-1 mRNA in developing mouse lung and to measure the effects of dexamethasone treatment in vivo on VEGF and Flk-1 in newborn mouse lung. Our results show that VEGF and Flk-1 messages increase in parallel during normal lung development (d 13 embryonic to adult) and that the distal epithelium expresses VEGF mRNA at all ages examined. Dexamethasone (0.1-5.0 mg x kg(-1) x d(-1)) treatment of 6-d-old mice resulted in significantly increased VEGF, HLF, and Flk-1 mRNA. Dexamethasone did not affect cell-specific expression of VEGF, VEGF protein, or proportions of VEGF mRNA splice variants. These data suggest that the developing alveolar epithelium has an important role in regulating alveolar capillary development. In addition, unlike effects on cultured cells, dexamethasone, even in relatively high doses, did not adversely affect VEGF expression in vivo. The relatively high levels of VEGF and Flk-1 mRNA in adult lung imply a role for pulmonary VEGF in endothelial cell maintenance or capillary permeability.

Morphological changes in serial auditory brain stem responses in 24 to 32 weeks' gestational age infants during the first week of life.

OBJECTIVE: The purpose of this investigation was to describe and quantify the sequential morphological changes in the auditory brain stem response (ABR) during the first postnatal week of life in very premature infants < or = 32 wk gestational age. These normative data could be useful in predicting neurological outcome in infants with perinatal risk factors. DESIGN: Sequential ABRs were recorded on a total of 135 infants on 5 out of the first 7 days of life. For analysis, data were grouped by gestational age in 2 wk intervals. In addition, a unique system was devised to categorize waveform response types in premature infants: type 1, a response with normal morphology and replicable waves III and V; type 2, a replicable response with either a wave III or wave V; type 3, a replicable response with neither a wave III or wave V; type 4, a response with no replicable waveform. RESULTS: The frequency of detection of waves improves over the first week of life with the detectability of waves III and V being more frequent than wave I at all gestational ages. There was a gradual improvement in response types in infants > 26 wk with the greatest improvement occurring during the 28 to 29 wk gestation. ABRs were predominantly types 3 and 4 at 24 to 25 wk, type 3 at 26 to 27 wk, type 2 at 28 to 29 wk, and types 1 and 2 at 30 to 31 wk. Absolute wave latencies and interwave latencies also progressively decreased during the first postnatal week. In some infants there was a transient increase in latencies or worsening of response type on the second to third test day. CONCLUSIONS: There is progressive improvement in frequency of detection of waves I, III, and V with increasing gestational age. Response types gradually mature over the first postnatal week, particularly in premature infants 28 to 32 wk gestational age.

Lipid intolerance in neonates receiving dexamethasone for bronchopulmonary dysplasia.

BACKGROUND: We hypothesized that dexamethasone induces hypertriglyceridemia (triglyceride levels >2.82 mmol/L [250 mg/dL]) and increases free fatty acid (FFA) levels and that steroid-induced hypertriglyceridemia is associated with hyperinsulinemia and elevated FFA levels. OBJECTIVE: To study the effect of dexamethasone sodium phosphate on lipid metabolism in neonates receiving intravenous lipids. DESIGN: A prospective cohort study with patients serving as their own controls. SETTING: Neonatal Intensive Care Unit, Children's Hospital at Strong, Rochester, NY. METHODS: All neonates younger than 29 weeks' gestational age at birth receiving 3 g/kg per day of intravenous lipids who were to start dexamethasone therapy for bronchopulmonary dysplasia were eligible. Exclusion criteria included neonates with active infection, prior hypertriglyceridemia, bleeding manifestations, recent surgery, thyroid medication, and human recombinant insulin intravenous infusion therapy. Ten neonates were studied. Blood was drawn for triglyceride, FFA, and insulin assays before initiating and at 1, 2, 3, and 5 days after starting dexamethasone therapy. On day 3, dexamethasone dosage was decreased as per protocol. Intravenous lipid intake was kept constant. Statistical analysis was done using a paired t test. RESULTS: Six of 10 neonates reached a state of hypertriglyceridemia (95% confidence interval, 26.2%-87.8%). The mean average increase in triglycerides, insulin, and FFA levels in neonates receiving 3 g/kg per day of intravenous lipids after initiation of dexamethasone therapy was 0.75 mmol/L (66.6 mg/dL) (P=.007), 127 pmol/L (P = .006), and 47.5 micromol/L (P = .65), respectively. Six neonates who developed hypertriglyceridemia had significantly elevated mean peak FFA levels (918.3 micromol/L) prior to developing hypertriglyceridemia compared with 4 neonates (mean peak FFA levels, 380.2 micromol/L) who had triglyceride levels lower than 2.82 mmol/L (250 mg/dL) (P = .002). CONCLUSION: We conclude that dexamethasone induces hypertriglyceridemia in the presence of hyperinsulinemia and increased FFA levels.

Absidia corymbifera infections in neonates.

We report the first two documented cases of neonatal zygomycosis caused by Absidia corymbifera. A premature infant developed disseminated disease from a cutaneous site with pulmonary, gastrointestinal, and cerebral involvement. The infant died despite amphotericin B therapy and surgical debridement. The second case occurred in a full-term infant with congenital heart disease and fungal pneumonitis. Zygomycosis was not suspected because of underlying cardiac disease and a complicated postoperative course, and this infant also died. Absidia joins a growing list of opportunistic fungal pathogens of the compromised neonate.