Safety and dose modification for patients receiving niraparib.

Background: Niraparib is a poly(ADP-ribose) polymerase inhibitor approved in the USA and Europe for maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response to platinum-based chemotherapy. In the pivotal ENGOT-OV16/NOVA trial, the dose reduction rate due to treatment-emergent adverse event (TEAE) was 68.9%, and the discontinuation rate due to TEAE was 14.7%, including 3.3% due to thrombocytopenia. A retrospective analysis was carried out to identify clinical parameters that predict dose reductions. Patients and methods: All analyses were carried out on the safety population, comprising all patients who received at least one dose of study drug. Patients were analyzed according to the study drug consumed (i.e., as treated). A predictive modeling method (decision trees) was used to identify important variables for predicting the likelihood of developing grade ≥3 thrombocytopenia within 30 days after the first dose of niraparib and determine cut-off points for chosen variables. Results: Following dose modification, 200 mg was the most commonly administered dose in the ENGOT-OV16/NOVA trial. Baseline platelet count and baseline body weight were identified as risk factors for increased incidence of grade ≥3 thrombocytopenia. Patients with a baseline body weight <77 kg or a baseline platelet count <150 000/µl in effect received an average daily dose ∼200 mg (median = 207 mg) due to dose interruption and reduction. Progression-free survival in patients who were dose reduced to either 200 or 100 mg was consistent with that of patients who remained at the 300 mg starting dose. Conclusions: The analysis presented suggests that patients with baseline body weight of <77 kg or baseline platelets of <150 000/µl may benefit from a starting dose of 200 mg/day. ClinicalTrials.gov ID: NCT01847274.

Clinical outcomes in elderly patients with advanced non-small cell lung cancer: results from ARIES, a bevacizumab observational cohort study.

AIMS: Retrospective analyses from first-line clinical studies in advanced non-small cell lung cancer (NSCLC) have reported conflicting results on progression-free survival (PFS) and overall survival benefits with the addition of bevacizumab to chemotherapy in elderly patients. Here we report effectiveness and safety outcomes by age subgroup for patients with NSCLC in the ARIES observational cohort study. MATERIALS AND METHODS: ARIES enrolled patients with advanced non-squamous NSCLC who received first-line bevacizumab-containing treatment per physician's choice. Kaplan-Meier estimates were used to calculate medians and 95% confidence intervals for PFS and overall survival for patients aged <65, ≥65, <75 and ≥75 years. RESULTS: In total, 1967 patients receiving first-line treatment with bevacizumab and chemotherapy were enrolled. The median PFS and overall survival values were 6.4 (95% confidence interval = 6.0-6.8) and 14.2 (95% confidence interval = 12.7-15.2) months for patients aged <65 years, respectively, and 6.8 (95% confidence interval = 6.3-7.0) and 12.1 (95% confidence interval = 11.4-13.1) months for patients ≥65 years, respectively. For patients <75 years, the median PFS and overall survival values were 6.6 (95% confidence interval = 6.3-6.9) and 13.5 (95% confidence interval = 12.6-14.5) months, respectively, and 6.6 (95% confidence interval = 5.9-7.1) and 11.6 (95% confidence interval = 10.0-12.5) months, respectively, for patients ≥75 years. Incidence proportions of bevacizumab-associated adverse events were generally similar across all age groups. CONCLUSIONS: Data from the ARIES study suggest that treatment with bevacizumab in combination with chemotherapy is a viable first-line treatment option for elderly bevacizumab-eligible patients with advanced non-squamous NSCLC.

Correlation of complications of body contouring surgery with increasing body mass index.

BACKGROUND: There have been conflicting reports regarding the incidence of postoperative complications in body contouring procedures in obese and morbidly obese patients. Our subjective impression has been that the complication rate is significantly higher for these patients than it is for other weight groups. OBJECTIVE: The purpose of our study was to conduct a retrospective chart review to delineate our institution's complication rate in body contouring operations across all weight groups and to identify predictors of poor outcomes/complications that would help guide patient selection. METHODS: The records of 129 patients who underwent a single body contouring procedure at The Penn State Hershey Medical Center from 1993 to 2002 were reviewed. Patients were categorized based on their body mass index into the following weight groups: ideal, overweight, obese, morbidly obese, and severely morbidly obese. The complications were grouped into minor, major, or combined (minor or major). Patients who underwent combined procedures were excluded from the study. RESULTS: There was a statistically significant association between minor (P = .0006), major (P = .0098), and combined (P < .0001) complications and weight group. More specifically, the percentage of complications increased as weight category increased. The percentage of minor complications increased from 3.3% in the ideal weight group to 46.9% in the severely morbidly obese group. Similarly, the percentage of major complications increased from 6.6% in the ideal weight group to 43.7% in the severely morbidly obese group. Both major and minor complications saw the largest increase in complication rates between the morbidly obese and severely morbidly obese groups. Furthermore, those in the obese (odds ratio [OR] = 6.43; P = .0115), morbidly obese (OR = 5.54; P = .0237), and severely morbidly obese (OR = 19.80; P < .0001) weight groups were more likely to experience minor or major complications than those in the ideal weight group. CONCLUSIONS: This study demonstrates two points: (1) it confirms that there is a significant increase in the occurrence of complications among morbidly obese and severely morbidly obese patients undergoing a single body contouring procedure, and (2) it shows there is an increase in the occurrence of complications with worsening degree of obesity. The (post-weight loss) body mass index at the time of body contouring surgery is a predictor for postoperative complications.

Transforaminal lumbar interbody fusion: an independent assessment of outcomes in a difficult patient population.

BACKGROUND: Transforaminal lumbar interbody fusion is becoming increasingly popular for the surgical treatment of lumbar degenerative conditions. However, the outcomes following the procedure have only begun to be evaluated. MATERIAL/METHODS: The authors reviewed all patients previously treated by TLIF at our tertiary center with minimum two year follow-up. Between 1997 and 2001, twenty-seven patients underwent the procedure. They were evaluated clinically and radiographically at regular intervals for a minimum two years following surgery and longer term follow-up was carried out by telephone interview. Long-term follow-up was undertaken by an independent assessor (a spine surgeon not directly involved in the patient's care) and outcomes were assessed using the measure designed by Macnab/McCulloch/An. Follow-up averaged 30 months and ranged from 24 to 42 months. RESULTS: All but two patients obtained a solid radiographic arthrodesis and complications were few. However, only eleven patients obtained excellent or good clinical results, while 16 had fair or poor outcomes. CONCLUSIONS: TLIF is a technically demanding procedure which can be done with relatively few complications and offers excellent rates of arthrodesis. However, the outcomes of the procedure and indications for the procedure in difficult patient populations clearly require further study.

The immunoglobulin heavy chain locus of the duck. Genomic organization and expression of D, J, and C region genes.

The region of the duck IgH locus extending from upstream of the proximal diversity (D) segment to downstream of the constant gene cluster has been cloned and mapped. A sequence contig of 48,796 base pairs established that the organization of the genes is D-J(H)-mu-alpha-upsilon. No evidence for a functional homologue (or remnant) of a delta gene was found. The alpha gene is in inverted transcriptional orientation; class switch to IgA expression thus requires inversion of the approximately 27-kilobase pair region that includes both mu and alpha genes. The secreted forms of duck alpha and mu are each encoded by 4 constant region exons, and the hydrophobic C-terminal regions of the membrane receptor forms of alpha and mu are encoded by one and two transmembrane exons, respectively. Putative switch (S) regions were identified for duck mu and upsilon by comparison with chicken Smu and Supsilon sequences and for duck alpha by comparison with mouse Salpha. The duck IgH locus is rich in complex variable number tandem repeats, which occupy approximately 60% of the sequenced region, and occur at a much higher frequency in the IgH locus than in other sequenced regions of the duck genome.

Two genes that map to the STSL locus cause sitosterolemia: genomic structure and spectrum of mutations involving sterolin-1 and sterolin-2, encoded by ABCG5 and ABCG8, respectively.

Sitosterolemia is a rare autosomal recessive disorder characterized by (a) intestinal hyperabsorption of all sterols, including cholesterol and plant and shellfish sterols, and (b) impaired ability to excrete sterols into bile. Patients with this disease have expanded body pools of cholesterol and very elevated plasma plant-sterol species and frequently develop tendon and tuberous xanthomas, accelerated atherosclerosis, and premature coronary artery disease. In previous studies, we have mapped the STSL locus to human chromosome 2p21. Recently, we reported that a novel member of the ABC-transporter family, named "sterolin-1" and encoded by ABCG5, is mutated in 9 unrelated families with sitosterolemia; in the remaining 25 families, no mutations in sterolin-1 could be identified. We identified another ABC transporter, located <400 bp upstream of sterolin-1, in the opposite orientation. Mutational analyses revealed that this highly homologous protein, termed "sterolin-2" and encoded by ABCG8, is mutated in the remaining pedigrees. Thus, two highly homologous genes, located in a head-to-head configuration on chromosome 2p21, are involved as causes of sitosterolemia. These studies indicate that both sterolin-1 and sterolin-2 are indispensable for the regulation of sterol absorption and excretion. Identification of sterolin-1 and sterolin-2 as critical players in the regulation of dietary-sterol absorption and excretion identifies a new pathway of sterol transport.

Fine-mapping, mutation analyses, and structural mapping of cerebrotendinous xanthomatosis in U.S. pedigrees.

Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive disorder of bile acid biosynthesis. Clinically, CTX patients present with tendon xanthomas, juvenile cataracts, and progressive neurological dysfunction and can be diagnosed by the detection of elevated plasma cholestanol levels. CTX is caused by mutations affecting the sterol 27-hydroxylase gene (CYP27 ). CTX has been identified in a number of populations, but seems to have a higher prevalence in the Japanese, Sephardic Jewish, and Italian populations. We have assembled 12 previously unreported pedigrees from the United States. The CYP27 locus had been previously mapped to chromosome 2q33-qter. We performed linkage analyses and found no evidence of genetic heterogeneity. All CTX patients showed segregation with the CYP27 locus, and haplotype analysis and recombinant events allowed us to precisely map CYP27 to chromosome 2q35, between markers D2S1371 and D2S424. Twenty-three mutations were identified from 13 probands analyzed thus far; 11 were compound heterozygotes and 2 had homozygous mutations. Of these, five are novel mutations [Trp100Stop, Pro408Ser, Gln428Stop, a 10-base pair (bp) deletion in exon 1, and a 2-bp deletion in exon 6 of the CYP27 gene]. Three-dimensional structural modeling of sterol 27-hydroxylase showed that, while the majority of the missense mutations disrupt the heme-binding and adrenodoxin-binding domains critical for enzyme activity, two missense mutations (Arg94Trp/Gln and Lys226Arg) are clearly located outside these sites and may identify a potential substrate-binding or other protein contact site.

Identification of a gene, ABCG5, important in the regulation of dietary cholesterol absorption.

The molecular mechanisms regulating the amount of dietary cholesterol retained in the body, as well as the body's ability to exclude selectively other dietary sterols, are poorly understood. An average western diet will contain about 250-500 mg of dietary cholesterol and about 200-400 mg of non-cholesterol sterols. About 50-60% of the dietary cholesterol is absorbed and retained by the normal human body, but less than 1% of the non-cholesterol sterols are retained. Thus, there exists a subtle mechanism that allows the body to distinguish between cholesterol and non-cholesterol sterols. In sitosterolemia, a rare autosomal recessive disorder, affected individuals hyperabsorb not only cholesterol but also all other sterols, including plant and shellfish sterols from the intestine. The major plant sterol species is sitosterol; hence the name of the disorder. Consequently, patients with this disease have very high levels of plant sterols in the plasma and develop tendon and tuberous xanthomas, accelerated atherosclerosis, and premature coronary artery disease. We previously mapped the STSL locus to human chromosome 2p21 and further localized it to a region of less than 2 cM bounded by markers D2S2294 and D2S2291 (M.-H.L. et al., manuscript submitted). We now report that a new member of the ABC transporter family, ABCG5, is mutant in nine unrelated sitosterolemia patients.

Hyperoxic reperfusion exacerbates postischemic renal dysfunction.

BACKGROUND: Hyperoxic reperfusion from global ischemia worsens functional outcome because of oxygen radical-mediated injury. This study tested the hypothesis that hyperoxic reperfusion would exacerbate postischemic renal dysfunction. METHODS: Twenty-nine healthy, uninephrectomized, male mongrel rabbits (Oryctolagus cuniculus) in 3 groups were subjected to 30 minutes of complete normothermic renal ischemia followed by reperfusion under hyperoxic or normoxic conditions. The groups were: hyperoxically reperfused (n = 8), normoxically reperfused (n = 8), hyperoxic sham (no ischemia, n = 5), and allopurinol-pretreated (50 mg/kg, intravenously), hyperoxically reperfused animals (n = 8). Plasma concentrations of creatinine, urea nitrogen and electrolytes were measured at 0, 24, 48, and 72 hours after ischemia and served as functional outcome markers. Histopathologic analysis of kidneys for injury was performed by an expert who was blinded to the procedures. RESULTS: Plasma creatinine in hyperoxically reperfused rabbits was significantly elevated above normoxic (P =.02) and sham (P =.003) animals by 48 hours and remained elevated to 72 hours. Plasma urea nitrogen in hyperoxically reperfused rabbits was significantly elevated above the normoxic group (P = .01), the sham group (P = .02), and the allopurinol group (P = .04) by 72 hours. These coincided with a significantly elevated histopathologic injury score in hyperoxically reperfused rabbits compared with sham (P = .019), normoxic (P = .035), and allopurinol-pretreated hyperoxically reperfused animals (P = .037). CONCLUSIONS: Hyperoxic reperfusion exacerbates renal dysfunction after 30 minutes of complete normothermic ischemia. This dysfunction may be mediated by oxygen radical-related injury.

Stabilization of the GDP-bound conformation of Gialpha by a peptide derived from the G-protein regulatory motif of AGS3.

The G-protein regulatory (GPR) motif in AGS3 was recently identified as a region for protein binding to heterotrimeric G-protein alpha subunits. To define the properties of this approximately 20-amino acid motif, we designed a GPR consensus peptide and determined its influence on the activation state of G-protein and receptor coupling to G-protein. The GPR peptide sequence (28 amino acids) encompassed the consensus sequence defined by the four GPR motifs conserved in the family of AGS3 proteins. The GPR consensus peptide effectively prevented the binding of AGS3 to Gialpha1,2 in protein interaction assays, inhibited guanosine 5'-O-(3-thiotriphosphate) binding to Gialpha, and stabilized the GDP-bound conformation of Gialpha. The GPR peptide had little effect on nucleotide binding to Goalpha and brain G-protein indicating selective regulation of Gialpha. Thus, the GPR peptide functions as a guanine nucleotide dissociation inhibitor for Gialpha. The GPR consensus peptide also blocked receptor coupling to Gialphabetagamma indicating that although the AGS3-GPR peptide stabilized the GDP-bound conformation of Gialpha, this conformation of Gialpha(GDP) was not recognized by a G-protein coupled receptor. The AGS3-GPR motif presents an opportunity for selective control of Gialpha- and Gbetagamma-regulated effector systems, and the GPR motif allows for alternative modes of signal input to G-protein signaling systems.

Receptor-independent activators of heterotrimeric G-protein signaling pathways.

Heterotrimeric G-protein signaling systems are activated via cell surface receptors possessing the seven-membrane span motif. Several observations suggest the existence of other modes of stimulus input to heterotrimeric G-proteins. As part of an overall effort to identify such proteins we developed a functional screen based upon the pheromone response pathway in Saccharomyces cerevisiae. We identified two mammalian proteins, AGS2 and AGS3 (activators of G-protein signaling), that activated the pheromone response pathway at the level of heterotrimeric G-proteins in the absence of a typical receptor. beta-galactosidase reporter assays in yeast strains expressing different Galpha subunits (Gpa1, G(s)alpha, G(i)alpha(2(Gpa1(1-41))), G(i)alpha(3(Gpa1(1-41))), Galpha(16(Gpa1(1-41)))) indicated that AGS proteins selectively activated G-protein heterotrimers. AGS3 was only active in the G(i)alpha(2) and G(i)alpha(3) genetic backgrounds, whereas AGS2 was active in each of the genetic backgrounds except Gpa1. In protein interaction studies, AGS2 selectively associated with Gbetagamma, whereas AGS3 bound Galpha and exhibited a preference for GalphaGDP versus GalphaGTPgammaS. Subsequent studies indicated that the mechanisms of G-protein activation by AGS2 and AGS3 were distinct from that of a typical G-protein-coupled receptor. AGS proteins provide unexpected mechanisms for input to heterotrimeric G-protein signaling pathways. AGS2 and AGS3 may also serve as novel binding partners for Galpha and Gbetagamma that allow the subunits to subserve functions that do not require initial heterotrimer formation.

Developmental neurotoxicity to methamphetamines.

1. To investigate the long-term changes caused by amphetamines in the developing brain, we used both an in vivo and in vitro model of chronic fetal exposure to methamphetamine and related drugs. 2. Offspring of rats, treated with either saline, 2 mg/kg twice a day (b.i.d.) or 10 mg/kg b.i.d. methamphetamine throughout gestation, were examined at 30 days of age for changes in the monoamine system of their brains. 3. At the lower dose methamphetamine was neurotoxic to specific neuronal populations, mostly serotonergic. At the higher dose, methamphetamine retained its neurotoxic properties, but also stimulated the growth of axonal terminals in specific regions as evidenced by an increase in monoamine uptake sites. The neurochemical changes at the higher dose were correlated with deficits in adult behavioural measures. 4. Corresponding in vitro drug treatments of rat neuroblastomas cells also produced a dose-related effect on cellular growth and differentiation patterns. Neurotoxic as well as stimulatory effects of methamphetamine and some related compounds were seen in culture. 5. Our in vivo and in vitro observations demonstrate neurotoxic effects of amphetamines and the remodelling of synaptic morphology in response.

Outcome assessment in depressed hospitalized patient.

Psychiatric symptoms as well as work, social, and physical functioning were compared in two groups of psychiatric patients (36 depressed only and 34 depressed in conjunction with an eating disorder) and 77 controls. In both groups, Global Assessment of Functioning (GAF) scores significantly improved from hospital admission to discharge and remained improved at 1.5 years postdischarge. As outpatients, the GAF, Zung Depression, and anxiety scores of both groups were significantly lower than for controls. Ratings of social functioning for depressed only outpatients did not differ from controls on five out of six measures. Predictors of posthospital improvement included high satisfaction with hospital treatment, high GAF scores on admission to hospital, perceived effectiveness of outpatient therapy, younger age, and an historical absence of sexual abuse or prior psychiatric hospitalization.

In utero methamphetamine effects: I. Behavior and monoamine uptake sites in adult offspring.

Chronic in utero methamphetamine treatment, throughout gestation in rats, resulted in alterations in both behavior and brain monoamine function in the adult offspring. The higher dose of methamphetamine (10 mg/kg/b.i.d.) caused a significant decrease in square crossing and rearing in an open field, as well as a regional increase of serotonin and dopamine uptake sites. In contrast, the lower dose of in utero methamphetamine (2 mg/kg/b.i.d.) resulted in a significant decrease in regional densities of serotonin and dopamine uptake sites, and only decreased rearing behavior. Across treatment groups, there were significant correlations between open-field square crossing activity and the number of uptake sites in specific brain areas. Other measured behaviors, such as the neonate righting reflex and the adult Morris water maze performance, were unaffected by either in utero drug regimen. These results are discussed in terms of the known neurotoxicity of amphetamines and the ability of the immature nervous system to compensate for fetal exposure to methamphetamine.

Clinical and biochemical aspects of depressive disorders: III. Treatment and controversies.

The present document is the final of three parts of a review that focuses on recent data from clinical and animal research concerning the biochemical bases of depressive disorders, diagnosis, and treatment. Various treatments for depression, including psychotherapy, pharmacological, and somatic treatments, will be described in this third part. Also, some of the controversies in the field, as well as a summary of the most salient points of the review, will be discussed. Previous sections of this review dealt with the classification of depressive disorders and research techniques for studying the biochemical mechanisms of these disorders (Part I) and various transmitter/receptor theories of depressive disorder (Part II).

Clinical and biochemical aspects of depressive disorders: II. Transmitter/receptor theories.

The present document is the second of three parts in a review that focuses on recent data from clinical and animal research concerning the biochemical bases of depressive disorders, diagnosis, and treatment. Various receptor/transmitter theories of depressive disorders are discussed in this section. Specifically, data supporting noradrenergic, serotonergic, cholinergic, dopaminergic, GABAergic, and peptidergic theories, as well as interactions between noradrenergic and serotonergic, or cholinergic and catecholaminergic systems are presented. Problems with the data and future directions for research are also discussed. A previous publication, Part I of this review, dealt with the classification of depressive disorders and research techniques for studying the biochemical mechanisms of these disorders. A future publication, Part III of this review, discusses treatments for depression and some of the controversies in this field.

Clinical and biochemical aspects of depressive disorders: I. Introduction, classification, and research techniques.

The present review focuses on recent data from clinical and animal research concerning the biochemical bases of depressive disorders, diagnosis, and treatment. In addition to integrating these data, problems and future directions in this research are discussed. The review is presented in three parts. This study, Part I, describes diagnostic classification schemes for depressive disorders, some epidemiological and biological correlates of the classifications, and research techniques for investigating depressive disorders. Research techniques include animal models, human biochemical techniques, and Positron Emission Tomography. In a future issue, Part II will discuss various transmitter/receptor theories of depressive disorders, e.g., noradrenergic, serotonergic, cholinergic, and dopaminergic, GABAergic, and peptidergic theories. Also in a future issue, Part III will discuss treatments for depression and some of the controversies in the field.

Neurobiological evidence for epilepsy-induced interictal disturbances.

It is not in the best interest of persons with epilepsy to deny the possibility that seizures could cause enduring behavioral disturbances. Rather, it is essential to pursue clinical and animal investigations in order to identify any such changes that might occur and to elucidate their mechanisms. Many testable hypotheses can be developed from existing evidence. Antiepileptic medication may produce interictal behavioral disturbances in patients with epilepsy by indirect mechanisms. Some aberrant behaviors could be due to medication-induced systemic disorders, neuroendocrine dysfunction, or REM deficit, whereas depression following successful treatment with drugs, as well as with surgery, may be related more specifically to cessation of seizures. The underlying neuropathological process also induces neurological and mental deficits, but it is not always possible to differentiate those behavioral disturbances due to destructive effects of the lesion from those due to recurrent epileptic seizures. Behavioral disturbances are associated more frequently with epileptogenic lesions in limbic structures than with those elsewhere in the brain, but a relationship between hemispheric lateralization of the epileptogenic lesion and specific interictal behavioral symptoms remains controversial. When considering the effects of seizures per se on interictal behavior, it is important to realize that some "interictal" behavioral disturbances may actually be ictal events. Prolonged affective, autonomic, and psychic disturbances can occur in clear consciousness with unilateral limbic seizures that are not associated with scalp EEG changes. When epilepsy is acquired as a result of cerebral damage, the epileptogenic process takes time to develop before spontaneous seizures appear. It is more reasonable to assume that this progressive process continues than to postulate that it stops completely at the time the first seizure occurs. Epilepsy-induced protective homeostatic mechanisms that act to terminate ictal events, prevent ictal spread, and maintain the interictal state may also disrupt interictal function. Furthermore, seizures could indirectly influence interictal behavior as a result of their effects on neuroendocrine function and sleep. Because of confounding biological factors, it is difficult to document the association of any epilepsy disorder, by itself, with progressive behavioral disturbances in humans. Secondary epileptogenesis, protective homeostatic mechanisms, and epilepsy-induced disturbances in development can be readily demonstrated, however, in experimental animal models. In experimental animals, endogenous opoids are released during seizures and mediate some postictal behaviors. A physiological dependency on high levels of endogenous opioids released during seizures could produce depression as a withdrawal symptom interictally or when seizures no longer occur as a result of successful therapy. Experimental animal models of depression exist to test hypotheses concerning pro- and antidepressant effects of epileptogenesis.(ABSTRACT TRUNCATED AT 400 WORDS)