A randomized, open-label study of the efficacy and safety of AZD4547 monotherapy versus paclitaxel for the treatment of advanced gastric adenocarcinoma with FGFR2 polysomy or gene amplification.

BACKGROUND: Approximately 5%-10% of gastric cancers have a fibroblast growth factor receptor-2 (FGFR2) gene amplification. AZD4547 is a selective FGFR-1, 2, 3 tyrosine kinase inhibitor with potent preclinical activity in FGFR2 amplified gastric adenocarcinoma SNU16 and SGC083 xenograft models. The randomized phase II SHINE study (NCT01457846) investigated whether AZD4547 improves clinical outcome versus paclitaxel as second-line treatment in patients with advanced gastric adenocarcinoma displaying FGFR2 polysomy or gene amplification detected by fluorescence in situ hybridization. PATIENTS AND METHODS: Patients were randomized 3:2 (FGFR2 gene amplification) or 1:1 (FGFR2 polysomy) to AZD4547 or paclitaxel. Patients received AZD4547 80 mg twice daily, orally, on a 2 weeks on/1 week off schedule of a 21-day cycle or intravenous paclitaxel 80 mg/m2 administered weekly on days 1, 8, and 15 of a 28-day cycle. The primary end point was progression-free survival (PFS). Safety outcomes were assessed and an exploratory biomarker analysis was undertaken. RESULTS: Of 71 patients randomized (AZD4547 n = 41, paclitaxel n = 30), 67 received study treatment (AZD4547 n = 40, paclitaxel n = 27). Among all randomized patients, median PFS was 1.8 months with AZD4547 and 3.5 months with paclitaxel (one-sided P = 0.9581); median follow-up duration for PFS was 1.77 and 2.12 months, respectively. The incidence of adverse events was similar in both treatment arms. Exploratory biomarker analyses revealed marked intratumor heterogeneity of FGFR2 amplification and poor concordance between amplification/polysomy and FGFR2 mRNA expression. CONCLUSIONS: AZD4547 did not significantly improve PFS versus paclitaxel in gastric cancer FGFR2 amplification/polysomy patients. Considerable intratumor heterogeneity for FGFR2 gene amplification and poor concordance between FGFR2 amplification/polysomy and FGFR2 expression indicates the need for alternative predictive biomarker testing. AZD4547 was generally well tolerated.

Results of the phase IIa RADICAL trial of the FGFR inhibitor AZD4547 in endocrine resistant breast cancer.

We conducted a phase IIa, multi-centre, open label, single arm study (RADICAL; NCT01791985) of AZD4547 (a potent and selective inhibitor of Fibroblast Growth Factor Receptor (FGFR)-1, 2 and 3 receptor tyrosine kinases) administered with anastrozole or letrozole in estrogen receptor positive metastatic breast cancer patients who had become resistant to aromatase inhibitors. After a safety run-in study to assess safety and tolerability, we recruited 52 patients. The primary endpoint was change in tumour size at 12 weeks, and secondary endpoints were to assess response at 6 weeks, 20 weeks and every 8 weeks thereafter and tolerability of the combined treatment. Two partial responses (PR) and 19 stable disease (SD) patients were observed at the 12-week time point. At 28 weeks, according to centrally reviewed Response Evaluation Criteria in Solid Tumours (RECIST) criteria, five PR and 8 SD patients were observed in 50 assessable cases. Overall, objective response rate (5 PR) was of 10%, meeting the pre-specified endpoint. Fourteen patients discontinued due to adverse events. Eleven patients had retinal pigment epithelial detachments which was asymptomatic and reversible in all but one patient. Exploratory ribonucleic acid sequencing (RNA-Seq) analysis was done on patients' samples: 6 differentially-expressed-genes could distinguish those who benefited from the addition of AZD4547.

An examination of serotonin and psychological variables in the relationship between exercise and mental health.

Research has revealed that exercise is effective for reducing symptoms of depression and anxiety. The mechanisms by which these reductions occur, however, have not been widely studied. To examine several potential theories, a prospective, randomized, 7-week exercise intervention was conducted. Untrained participants were randomly assigned to an aerobic exercise group or to a stretching-control group. Participants completed several questionnaires to assess psychological variables, including measures of depression and anxiety, and blood was drawn at pre- and post-test to measure serum serotonin levels. A mixed-design ANOVA revealed that the exercise group had lower levels of depression than the stretching-control group after the intervention. The exercise group also showed a larger percentage decrease in serotonin than the stretching-control group. This reduction in blood serotonin after exercise is similar to the effects of selective serotonin reuptake inhibitors. Additionally, percent change in serotonin was found to partially mediate the relationship between exercise and depression.

Organ weight and serum triglyceride responses of older (80 week) commercial laying hens fed an alfalfa meal molt diet.

Since one of the costs in the commercial egg industry is that of replacement pullets, commercial egg layer managers have opted to induce molt older hens in order to extend their productive life for additional egg laying cycles. Conventional molt induction involves the complete removal of feed for several days. However, this management practice can lead to deleterious physiological responses by the hen and subsequent susceptibility to infection by pathogens. Consequently less stressful molting regimens involving the feeding of low energy diets such as alfalfa have been developed. In this study, 80 week old laying hens that were deprived of feed or fed alfalfa meal during a nine day induced molt. Full fed hens were used as the control. On day 8 serum triglycerides were quantified and on day 9 hens were euthanized and the liver, spleen, heart, intestine, pancreas, ovary, and kidney were collected and weighed. Intestinal weight were highest in the non-molted hens, lower in the hens fed alfalfa, and lower still in the hens deprived of feed. Molted hens exhibited reduced weights of liver, heart, ovary, and pancreas compared to the non-molted hens. Serum triglycerides were highest in the non-molted hens, less in feed deprived hens, and the lowest in alfalfa fed hens. These results suggest that a comparable molt could be achieved with feeding alfalfa meal to 80 week hens compared to feed deprivation.

Immunological cell and serum metabolite response of 60-week-old commercial laying hens to an alfalfa meal molt diet.

The practice of induced molting involves the restriction of light, feed removal and optionally water for 5-14 days. However, there is growing concern regarding feed removal and animal welfare issues. With this in mind, alternative diets have been developed to produce similar molting effects as that of feed deprivation. Alfalfa, which largely consists of insoluble fiber, can be used as a molting diet. In this study, heterophil and lymphocyte counts, serum chemistry, and organ weight parameters were evaluated in hens that were deprived of feed or fed alfalfa during a nine day induced molt. Full-fed hens were used as the control. Blood serum parameters assessed included calcium, magnesium, glucose, total protein, ketone bodies, uric acid, and cholesterol. White blood cells were counted and categorized by cell type. On the ninth day of the trial, the hens were euthanized and the liver, spleen, heart, intestine, pancreas, ovary, oviduct, and kidney were collected and weighed. On day 8 birds molted with alfalfa or by feed deprivation had significantly higher (P<0.05) levels of ketone bodies and cholesterol and lower levels of calcium, and magnesium compared to the full-fed hens while birds molted by feed deprivation exhibited significantly lower levels of uric acid. Birds molted by both methods exhibited significant reductions in ovary, oviduct, liver and pancreas weights and increased spleen weights when compared to the non-molted hens. On days 0, 2, and 6 there were no significant differences (P>0.05) in either heterophil or lymphocyte percentages. However, heterophil percentages were higher in feed withdrawal birds than full-fed birds on day 4 but lymphocyte percentages were higher in full-fed birds compared to feed withdrawal birds. On day 8 of the induced molt lymphocyte percentages were higher from full-fed birds when compared to feed withdrawal birds but no significant differences were detectable for heterophil percentages. Based on reproductive organ weight loss and changes in serum and immunological responses of birds during molt, it appears that alfalfa meal can be an effective molt induction alternative.

Partitioning of vasoactive intestinal polypeptide into lipid bilayers.

Incubation of radiolabeled vasoactive intestinal polypeptide (VIP) with preformed lipid vesicles composed of phosphatidylcholine, phosphatidylglycerol and cholesterol resulted in reversible and saturable association of the peptide with the lipid bilayer. The pH-optimum for the reaction was in the physiological range. The vesicle-associated peptide displayed enhanced stability to proteolytic digestion, it was efficiently released into the supernatant by detergent-solubilization of the vesicles but remained vesicle-associated during treatment with agents that disrupt ionic interactions. Peptide binding by electrically neutral vesicles was lower than that by negative vesicles. Electron spin resonance studies with 5-doxylstearic acid or 16-doxylstearic acid labeled vesicles suggested that VIP decreased the fluidity close to the surface of the bilayer and increased the fluidity in its hydrophobic core. These observations suggest that VIP can bind and penetrate lipid bilayers.

Interleukin-6 secretion in vitro is up-regulated in ectopic and eutopic endometrial stromal cells from women with endometriosis.

An in vitro model developed to compare human endometrial and endometriosis stromal cells was used to examine basal and stimulated expression of interleukin (IL-6). Stromal cells isolated from normal endometrium (NE) exhibited the lowest level of IL-6 secretion (84 pg/10(6) cells-48 h), whereas those cells isolated from endometriosis implants (EI) secreted the highest concentration of this inflammatory cytokine (46,284 pg/10(5) cells-48 h; P < 0.01). Eutopic endometrial stromal cells from women with endometriosis (EE) expressed an intermediate concentration of IL-6 (831 pg/10(6) cells-48 h). Stimulation of the various cultures with IL-1 beta dramatically augmented stromal cell production of IL-6. The mean concentrations of stimulated IL-6 secretion were 16,257, 37,800, and 264,290 pg/10(5) cells-48 h for NE, EE, and EI cells, respectively (P < 0.03). Exposure of the cell cultures to 10 nmol/L estradiol had little direct effect on IL-6 production. The results indicate that endometrial stromal cells isolated from tissues of women with and without endometriosis express IL-6 under basal and cytokine-stimulated conditions. Differential responsiveness among the three cell sources indicates that NE, EE, and EI cells have intrinsic quantitative differences in cytokine regulation.

Microvascular destruction in renal transplant rejection.

In normal kidneys, peritubular and glomerular capillaries can be readily identified by their intense expression of HLA class I and class II compared to other cells within the graft. This high density of expression of MHC, plus their exposure to activated circulating lymphocytes, makes these cells the likely early and primary target of rejection responses. The fate of these capillaries during renal allograft rejection was examined using an indirect immunoperoxidase staining technique and monoclonal antibodies to class I and class II MHC antigens as well as other antigens on capillary endothelium including ICAM-1, LFA-3, and a novel antigen identified by E1.5. Expression of HLA-DR by peritubular capillaries was decreased during rejection, and this disappearance of peritubular capillaries with severe rejection was confirmed by loss of other markers of microvascular endothelium. These studies suggest peritubular capillaries may be the major target of the acute rejection response, and the techniques described allow assessment of degree of damage to these structures in renal allograft biopsies.

Sulbactam/ampicillin versus metronidazole/gentamicin in the treatment of severe pelvic infections.

The clinical efficacy and safety of sulbactam/ampicillin versus metronidazole/gentamicin were compared in 39 patients with severe pelvic infections. 30 patients had severe acute pelvic inflammatory disease with peritonitis, 3 tubo-ovarian abscesses, 4 endomyometritis, and 2 posthysterectomy pelvic cellulitis. Aerobic and anaerobic cultures from the sites of infection yielded 259 micro-organisms from 38 patients; an average of 6.8 bacteria per infection (3.9 anaerobes and 2.9 aerobes). The most frequent isolates were Bacteroides spp. (21), B. bivius (13), B. disiens (8), Fusobacterium spp. (9), Peptostreptococcus anaerobius (15), P. asaccharolyticus (8), anaerobic Gram-positive cocci (17), Gardnerella vaginalis (24), Neisseria gonorrhoeae (14), alpha-haemolytic streptococci (6) and Escherichia coli (3). Clinical cure was noted in 19 of 20 patients treated with sulbactam/ampicillin and 16 of 19 treated with metronidazole/gentamicin. The sulbactam/ampicillin failure was a patient with pelvic inflammatory disease with a positive Chlamydia trachomatis culture who required antichlamydial therapy. The metronidazole/gentamicin failures included a patient with a tubo-ovarian abscess requiring surgical drainage and 2 patients with pelvic inflammatory disease requiring antichlamydial treatment. No adverse haematological, renal, or hepatic effects were noted with either regimen.

Acute cholecystitis in pregnancy.

Thirty cases of acute cholecystitis in pregnancy were identified during a 12-year period. Twenty-one patients were successfully managed with medical therapy alone. Nine underwent surgical intervention, four after failing medical therapy and five as the initial approach to therapy. Surgical therapy was complicated by preterm labor and delivery in two patients undergoing surgery during the early third trimester. One patient underwent cholecystectomy during the first trimester and subsequently aborted. There were no serious complications in patients undergoing surgery during the second trimester. These data suggest that conservative medical management can be successfully used in most patients with acute cholecystitis in pregnancy.

Isolation of Chlamydia trachomatis from sexually abused female adolescents.

Cultures for Chlamydia trachomatis were obtained from 127 female adolescents (13-17 years of age) evaluated for reported sexual abuse. The rate of positive cultures for C trachomatis in this population was 14% (18 of 127). Neisseria gonorrhoeae was found in 12% (15 of 127) of these patients. All but two of the culture-positive patients admitted sexual activity before the abuse, and it is likely that most of the infections were acquired during this previous sexual activity. Concomitant infection with N gonorrhoeae was found in seven adolescents positive for C trachomatis. No adolescents in this study exhibited a positive VDRL. Victims of abuse should be tested for both gonococcal and chlamydial infection. These data show that if antibiotic prophylaxis is used for the sexually abused adolescent, it should be directed against both C trachomatis and N gonorrhoeae.

Pelvic inflammatory disease in human immunodeficiency virus-infected women.

OBJECTIVE: To determine whether the clinical course of pelvic inflammatory disease differs between women with human immunodeficiency virus (HIV) infection and seronegative controls. METHODS: All admissions for acute pelvic inflammatory disease from January 1, 1986 to December 31, 1992 at San Francisco General Hospital were reviewed, identifying 23 HIV-seropositive women. Their clinical course was compared with a control group of 108 seronegative women admitted for acute pelvic inflammatory disease. RESULTS: Human immunodeficiency virus-seropositive women with acute pelvic inflammatory disease had significantly lower abdominal tenderness scores (P < .05), lower admission and discharge white blood cell counts (WBC) (P < .01, P < .05), and fewer gonococcal infections (odds ratio 0.3, 95% confidence interval [CI] 0.1-0.9; P < .05) than the seronegative controls. There were no significant differences in duration of treatment, length of hospitalization, or incidence of tubo-ovarian abscess. Significantly more HIV-positive women with acute pelvic inflammatory disease required surgical intervention than seronegative women (odds ratio 5.5, 95% CI 1.0-29.3; P < .05). CONCLUSION: Human immunodeficiency virus-seropositive women with acute pelvic inflammatory disease may have an altered immune response, resulting in inadequate response to antimicrobial agents and the need for more surgical intervention. Future studies must include larger numbers of HIV-infected women, and the results must be stratified for CD4 counts, clinical HIV stage, and other measures of immunocompromise.

Amoxicillin therapy for Chlamydia trachomatis in pregnancy.

For treating Chlamydia trachomatis cervical infection in pregnancy, the Centers for Disease Control guidelines recommend either erythromycin base or erythromycin ethylsuccinate. There is no alternate therapy. Because of compliance problems with erythromycin regimens due to gastrointestinal side effects, such an alternative is needed. For this reason, we compared, in an open trial, the efficacy and patient compliance of amoxicillin (500 mg three times a day for 7 days) with those of erythromycin base (500 mg four times a day for 7 days) in treating C trachomatis cervical infections during pregnancy. In the amoxicillin group, 63 of 64 women (98.4%) had negative cervical cultures after treatment, compared with 55 of 58 women (94.8%) treated with erythromycin base. Vertical transmission to the infants was assessed by culture and/or persistent or rising immunoglobulin G antichlamydial antibody. In the amoxicillin group, 37 of 39 infants (94.9%) had no evidence of chlamydial infection, compared with 32 of 36 infants (88.8%) in the erythromycin group. These differences were not significant. The frequency of side effects was higher with erythromycin base than with amoxicillin (15 versus 8%), although not significantly so. However, the frequency of stopping medication because of side effects was significantly higher with erythromycin base than with amoxicillin (13 versus 2%; P less than .006). These results suggest that amoxicillin may be an acceptable alternative treatment for chlamydial infections in pregnancy.

Plasma cell endometritis in women with symptomatic bacterial vaginosis.

OBJECTIVE: To evaluate the endometrial microbiology and histopathology in women with symptomatic bacterial vaginosis but no signs or symptoms of upper genital tract disease or other vaginal or cervical infections. METHODS: Endometrial biopsies were performed on 41 women complaining of vaginal discharge or pelvic pain at a sexually transmitted disease clinic. These women had neither culture nor serologic evidence of Neisseria gonorrhoeae or Chlamydia trachomatis infection. Twenty-two women with bacterial vaginosis diagnosed by Gram stain examination of vaginal fluid, but with neither signs nor symptoms of upper genital tract infection, were compared with 19 women who had no evidence of bacterial vaginosis on vaginal fluid Gram stain. Endometrial biopsies were evaluated for histopathologic evidence of plasma cell endometritis and were cultured for N gonorrhoeae, C trachomatis, aerobic and anaerobic bacteria, Mycoplasma species, and Ureaplasma urealyticum. RESULTS: Ten of 22 women with bacterial vaginosis had plasma cell endometritis, compared with one of 19 controls (odds ratio [OR] 15, 95% confidence interval [CI] 2-686; P < .01). Bacterial vaginosis-associated organisms were cultured from the endometria of nine of 11 women with and eight of 30 women without plasma cell endometritis (OR 12.4, 95% CI 2-132; P = .002). CONCLUSION: Plasma cell endometritis was frequently present in women with bacterial vaginosis and without other vaginal or cervical infections. This suggests the possibility of an association between bacterial vaginosis and nonchlamydial, nongonococcal, upper genital tract infection.

Ischemic brain injury in vitro: protective effects of NMDA receptor antagonists and calmidazolium.

Excessive Ca2+ influx through NMDA receptor-coupled channels has been linked to neuronal cell death. Using an in vitro model of transient brain ischemia, we investigated possible protective effects of NMDA receptor antagonists ketamine or MK-801 and of calmidazolium, an inhibitor of intracellular Ca2(+)-activated proteins. Brain ischemia/recovery was simulated in isolated hippocampal slices and injury monitored by measurement of ATP levels. Omission of both glucose and oxygen (but not oxygen alone) for 20 min led to persistent ATP deficits after 4 h recovery. Addition of ketamine or MK-801 at 1 microM permitted ATP to recover within 1 h, as did addition of calmidazolium at 10 microM. Our findings are consistent with other reports that NMDA receptor antagonists can protect neuronal tissue from ischemic damage. The role of inappropriately activated Ca2(+)-mediated signaling processes in the mechanism(s) of such injury is suggested by the protection also seen with calmidazolium, an inhibitor of calmodulin and other structurally related proteins such as calpain(s) and protein kinase C. The inhibition of intracellular Ca2+ target proteins may be an alternative for protection of the brain against injury due to insults that activate NMDA receptors.

Interleukin-8 concentrations are elevated in peritoneal fluid of women with endometriosis.

OBJECTIVE: To investigate the presence of interleukin-8 (IL-8), a macrophage-derived angiogenic factor, in peritoneal fluid (PF) of women with and without endometriosis. DESIGN: Case-control study. SETTING: University hospital. PATIENTS: Eighteen women with laparoscopic findings of mild to severe endometriosis, and nine women with no visual evidence of pelvic pathology. MAIN OUTCOME MEASURES: Peritoneal fluid IL-8 levels were determined using an ELISA. Interleukin-8 concentrations were compared among women with and without endometriosis. Correlation between PF IL-8 concentration and endometriosis stage was investigated. RESULTS: Interleukin-8 was detectable in the PF of a majority of women (67%). Interleukin-8 concentrations were higher in the PF of women with endometriosis than in matched normal controls. A significant correlation between PF IL-8 concentration and endometriosis stage was noted. CONCLUSIONS: We hypothesize that IL-8 is an important angiogenic factor that contributes to the pathogenesis of endometriosis by promoting the neovascularization of ectopic endometrial implants.

Temporary keratoprosthesis for use during pars plana vitrectomy.

We have developed a series of temporary keratoprostheses that permit closed pars plana vitrectomy in eyes with abnormal corneas. These devices are placed into a trephined opening in the cornea, and provide a clear, stable view of the intraocular contents. Immediately after vitrectomy, the keratoprosthesis is replaced with a corneal graft. We have used this technique successfully in four eyes with opaque or severely traumatized corneas.

The effects of acute and chronic exercise on sleep. A meta-analytic review.

Studies attempting to ascertain the effects of acute and chronic exercise on measures of sleep have yielded conflicting results and interpretations. Methodological differences among studies may explain this lack of consensus; however, small sample sizes and subsequently low statistical power may also have contributed. In an attempt to resolve these issues, this review used meta-analytical techniques to: (a) re-examine the effects of exercise on sleep; and (b) examine possible moderators of these effects. Studies meeting the selection criteria were included in the analysis. Analyses of moderating factors were performed for stage 4 sleep and rapid eye movement (REM) sleep. The results indicated that acute and chronic exercise increased slow wave sleep (SWS) and total sleep time but decreased sleep onset latency and REM sleep. Moderating variables influencing the magnitude and direction of these effects were related to characteristics of the individual (e.g. sex, age, fitness level) and the exercise (e.g. time of day exercise was completed, type of exercise, exercise duration). Mechanisms which have been suggested to explain the relationship between exercise and sleep are discussed and directions for further research are provided.