Influence of BRAF and PIK3CA mutations on the efficacy of FOLFIRI plus bevacizumab or cetuximab as first-line therapy in patients with RAS wild-type metastatic colorectal carcinoma and <3 baseline circulating tumour cells: the randomised phase II VISNÚ-2 study.

BACKGROUND: We explored the influence of BRAF and PIK3CA mutational status on the efficacy of bevacizumab or cetuximab plus 5-fluorouracil/leucovorin and irinotecan (FOLFIRI) as first-line therapy in patients with RAS wild-type metastatic colorectal cancer (mCRC). PATIENTS AND METHODS: VISNÚ-2 was a multicentre, randomised, phase II study. Patients with RAS wild-type mCRC and <3 circulating tumour cells/7.5 ml blood were stratified by BRAF/PIK3CA status (wild-type versus mutated) and number of affected organs (1 versus >1), and allocated to bevacizumab (5 mg/kg every 2 weeks) or cetuximab (400 mg/m2 then 250 mg/m2 weekly) plus FOLFIRI [irinotecan 180 mg/m2, leucovorin 400 mg/m2, 5-fluorouracil 400 mg/m2 (bolus) then 2400 mg/m2 (46-h continuous infusion) every 2 weeks]. The primary endpoint was progression-free survival (PFS). All analyses were exploratory. RESULTS: Two hundred and forty patients with BRAF/PIK3CA wild-type (n = 196) or BRAF- and/or PIK3CA-mutated tumours (n = 44) were enrolled. Median PFS was 12.7 and 8.8 months in patients with BRAF/PIK3CA wild-type and BRAF/PIK3CA-mutated tumours, respectively [hazard ratio (HR) = 1.22; 95% confidence interval (CI) 0.80-1.85; P = 0.3602]. In the BRAF- and/or PIK3CA-mutated cohort, median PFS was 2.8, 8.8 and 15.0 months in patients with BRAF/PI3KCA-mutated (n = 8), BRAF-mutated/PI3KCA wild-type (n = 16) and BRAF wild-type/PI3KCA-mutated (n = 20) tumours, respectively (P = 0.0002). PFS was similar with bevacizumab plus FOLFIRI versus cetuximab plus FOLFIRI in BRAF/PIK3CA wild-type (HR = 0.99; 95% CI 0.67-1.45; P = 0.9486) and BRAF/PIK3CA-mutated tumours (HR = 1.11; 95% CI 0.53-2.35; P = 0.7820). The most common grade 3/4 treatment-related adverse events were neutropenia, diarrhoea and asthenia in both treatment groups. CONCLUSIONS: BRAF/PIK3CA status influences outcomes in patients with RAS wild-type mCRC but does not appear to assist with the selection of first-line targeted therapy.

Fractura del olécranon por cizallamiento / Fracture of olecranon in children: a case report

Pese a que las fracturas metafisarias del olécranon son relativamente raras, cuando se presentan lesiones complejas que involucran mecanismos de cizallamiento es necesario considerar la posibilidad de reducción abierta. Se presenta el caso de una paciente de 5 años con luxo-fractura de codo, con un aparente deslizamiento epifisario Tipo I de Salter de la cúpula radial

Fetal fibronectin detection as a predictor of preterm birth in actual clinical practice.

OBJECTIVE: This study was undertaken to determine whether fetal fibronectin determination is more useful for predicting preterm delivery in clinical practice than it has appeared to be in prospective blinded studies. STUDY DESIGN: Charts of 151 patients with fetal fibronectin tests performed during 2 years were reviewed. Patients were included if they had symptoms of preterm labor, a singleton pregnancy at 24 to 35 weeks' gestation, intact membranes, and cervical dilatation < or =3 cm. RESULTS: Complete data were available for 85 tests. For delivery within 7 days after specimen collection the sensitivity, specificity, positive predictive value, and negative predictive value were 89%, 84%, 40%, and 98%, respectively. The positive predictive value was greater (P <.002) than those reported in three prospective studies evaluating delivery within 7 days in patients with symptoms. Gestational age at delivery and birth weight were lower for patients with positive results (P <. 0001 and P <.006, respectively). Patients with positive results were also treated more with tocolysis, corticosteroid use, and hospitalization than were patients with negative results. For direct comparison with studies of patients with cervical dilatation <3 cm, only 4 patients with cervical dilatation of 3 cm were enrolled. All 4 had negative results of fetal fibronectin testing, and their outcomes therefore did not affect the positive predictive value. CONCLUSION: The positive predictive value of fetal fibronectin measured in actual clinical practice was significantly greater for delivery within 7 days than has been reported in blinded prospective studies.

Assessment of azinphosmethyl exposure in California peach harvest workers.

We compared measurements of urinary alkylphosphate metabolites and oxime-induced reactivation of plasma cholinesterase (P-ChE) and erythrocyte acetylcholinesterase (RBC-AChE) with measurements of foliar residues, skin and clothing contamination, and P-ChE and RBC-AChE activities among 20 Northern California peach orchard workers exposed to the organophosphate agent azinphosmethyl (Guthion). Subjects entered orchards treated 30 d previously with azinphosmethyl and worked 21 d in treated fields during the ensuing 6 wk. Dislodgeable foliar residues ranged from 0.32-0.96 micrograms/cm2. Median reduction in RBC-AChE activity was 7% (p < .001) over the initial 3-d period of exposure and 19% (p < .01) over the 6-wk season. Urinary metabolites were the most sensitive indicator of recent exposure and correlated moderately with dermal and clothing levels (rs = +0.31-(+)0.55); urinary metabolites correlated well with RBC-AChE drawn 3 d after exposure began (rs = -0.77). No significant oxime-induced reactivation was found.

Asthma mortality in California, 1960-1989. Demographic patterns and occupational associations.

We analyzed asthma mortality rates in California during the years 1960 to 1989. Sex- and race-specific rates were stratified by age group (0 to 4, 5 to 34, 35 to 64, and 65+ yr) and for all ages directly standardized to the 1970 U.S. age distribution. Observed and expected asthma deaths were also calculated by occupation for the period 1979 to 1981 among persons aged 16 to 64 yr using data from the California Occupational Mortality Study. Asthma mortality rates were strongly associated with increasing age, but no consistent differences were observed between men and women. Mortality rates among blacks under age 65 yr were two to four times the corresponding rate among whites between 1960 and 1989, but this difference was not observed for those over age 65. Asthma mortality rates were calculated for Hispanics and Asians from 1985 to 1989. In this time period the asthma mortality rate ratios for Hispanics were 0.4 to 0.8 compared with the age-stratified rates among whites, 0.1 to 0.2 times the black rates in age categories under 65, and 0.5 times the rate for blacks ages 65 and above. Asthma mortality rates among Asians under 65 yr of age were similar to rates for whites, but for Asians 65 yr of age and over the rate ratios for males and females compared with whites were 1.8 and 1.1, respectively. A decrease of approximately 50% in asthma mortality occurred from 1960 to 1970, and a marked increase occurred between 1975 and 1989.(ABSTRACT TRUNCATED AT 250 WORDS)

Inhibition of the myeloperoxidase-H2O2-Cl- system of neutrophils by indomethacin and other non-steroidal anti-inflammatory drugs.

The results presented herein demonstrate that the non-steroidal anti-inflammatory drug (NSAID) indomethacin is a strong inhibitor of the formation of HOCl by murine neutrophils (50% inhibition at 15 microM). Addition of 40 microM indomethacin to activated neutrophils caused 80% inhibition of HOCl formation throughout a 60-min time course while slightly increasing the levels of O2- and H2O2 produced. Comparable degrees of inhibition were achieved when the cells were stimulated with phorbol myristate acetate and with opsonized zymosan. Control experiments indicated that the drug did not act by scavenging HOCl. Direct inhibition of the chlorinating activity of myeloperoxidase (MPO) was confirmed using highly purified human enzyme in vitro. Kinetic analysis of the mechanism of inhibition showed that the drug was competitive with respect to Cl- and uncompetitive with respect to H2O2, showing a Ki of 37 microM. In contrast to its inhibition of the oxidation of Cl- by MPO, indomethacin had no effect on the peroxidative activity of the enzyme (oxidation of 4-aminoantipyrene), nor did it inhibit the activity of several other enzymes involved in H2O2 metabolism, including horseradish peroxidase, catalase, xanthine oxidase, and superoxide dismutase. Finally, it was found that inhibition of HOCl formation was a shared but non-uniform property of many NSAIDs; piroxicam, salicylate, sulindac, ibuprofen, and aspirin were all inhibitory but at widely different concentrations [Ki(app) values of 0.05, 0.18, 0.18, greater than 1, and 3 mM respectively] that correlated only partially with their therapeutic dose range. The results encourage further studies into the possibility that inhibition of HOCl formation may constitute an additional mechanism whereby NSAIDs reduce tissue destruction in chronically inflamed tissues.

DNA damage induced by phorbol ester-stimulated neutrophils is augmented by extracellular cofactors. Role of histidine and metals.

Activated neutrophils cause extensive DNA damage in neighboring nonphagocytic cells. To determine whether compounds in the extracellular milieu participate in the DNA damage process, murine neutrophils were cocultivated with target tumor cells in media of varying composition. Using the alkaline elution assay, it was found that the level of strand breaks induced was significantly higher (2.8-fold) in complex cell culture media than in minimal phosphate-buffered saline. Addition of amino acids in general and of histidine in particular increased the level of damage nearly to that observed in complete media (2.7- and 2.1-fold, respectively). The histidine stimulation was concentration-dependent and reached a maximum at 100-400 microM. The mechanism whereby this occurred is not proven but probably derived from chelation of metals and participation in a site-specific Fenton reaction. Addition of the cell-impermeable chelator EDTA dramatically inhibited induction of strand breaks by neutrophils in complete media and prevented the enhancement of damage induced by histidine in phosphate-buffered saline. None of the effects on neutrophil-induced damage could be attributed to modulation of the oxidative burst activity of the cells (O2- and H2O2 production). Histidine also enhanced induction of strand breaks by reagent H2O2. However, EDTA had no effect or actually increased the level of damage induced by both a bolus of H2O2 and a flux of H2O2 generated by glucose oxidase. The cell-permeable chelator o-phenanthroline inhibited both neutrophil- and H2O2-induced damage. The results indicate that secondary reactions involving extracellular amino acids and metals contribute significantly to neutrophil-induced DNA damage to neighboring cells. Moreover, the data show that the mechanism whereby neutrophils induce this damage cannot be attributed solely to secretion of H2O2.

Malignant struma ovarii. A case report and literature review.

A woman developed papillary adenocarcinoma in a struma ovarii. The focus of malignancy was within a benign struma found at laparotomy for a pelvic mass. The patient had a previous history of bilateral cystic teratomas. The tumor was composed of papillae of crowded, pleomorphic cells with minimal cytoplasm but a wide range of chromatin patterns. Immunoperoxidase staining for thyroglobulin revealed positive regions in both the benign and malignant areas of tumor. A 15-year review of cystic teratomas in the state of Colorado revealed a frequency of 0.3% for malignant struma ovarii.