EVITA-a double-blind, vehicle-controlled, randomized phase II trial of vitamin K1 cream as prophylaxis for cetuximab-induced skin toxicity.

Background: Acne-like skin rash is a frequently occurring adverse event associated with drugs against the epidermal growth factor receptor. This randomized vehicle-controlled study investigated the addition of vitamin K1 cream to doxycycline in patients with metastatic colorectal cancer treated with cetuximab. Patients and methods: Patients receiving first-line cetuximab + FOLFIRI were randomly assigned to prophylactic treatment with doxycylin and vitamin K1 cream or doxycycline and the vehicle. The primary end point of the study was the incidence of grade ≥ 2 skin rash (NCI CTCAE version 4.02) during 8 weeks of skin treatment. Secondary end points comprised skin rash according to a more thorough tripartite skin toxicity score (WoMo), quality of life, efficacy, and compliance. The study had 80% power to show a 20% reduction of the incidence of grade ≥ 2 skin rash. Results: A total of 126 patients were analyzed. The incidence of skin rash grade ≥ 2 was comparable between the arms. Likewise, no difference was seen in the WoMo score with respect to the percentage of skin affected. However, starting in week 5 and increasing over time patients treated with vitamin K1 cream had less severe rash and fewer fissures. Quality of life as well as efficacy and compliance with study medication and anticancer treatment was comparable in both arms. Conclusion: The primary end point of decreasing grade ≥ 2 skin rash was not met. However, using vitamin K1 cream as part of prophylactic treatment decreased the severity of acne-like skin rash according to WoMo, an alternative and more thorough skin toxicity scoring tool.

[Standards for diagnostics and therapy of gastric cancer]. / Standards der Diagnostik und Therapie des Magenkarzinoms.

Despite a decreasing frequency gastric cancer is the fifth or sixth most common cancer in Germany. Usually the cancer is discovered in an advanced stage. This article is based primarily on the current S3 guidelines for gastric cancer published 2011. General aspects of risk factors, diagnosis and therapy with the current classification system are the main topics in this article. Furthermore, this article focuses on treatment of local advanced disease. Especially in recent years, many studies have dealt with the concept of perioperative treatment. However, a worldwide standard of care could not be reached for this indication.

Hepatic vascular inflow occlusion is associated with reduced disease free survival following resection of colorectal liver metastases.

BACKGROUND: Hepatic vascular inflow occlusion (VIO) can be applied during resection of colorectal liver metastases (CRLM) to control intra-operative blood loss, but has been linked to accelerated growth of micrometastases in experimental models. This study aimed to investigate the effects of hepatic VIO on disease-free and overall survival (DFS and OS) in patients following resection for CRLM. METHODS: All patients who underwent liver resection for CRLM between January 2006 and September 2015 at our center were analyzed. Hepatic VIO was performed if deemed indicated by the operating surgeon and severe ischemia was defined as ≥20 min continuous or ≥45 min cumulative intermittent VIO. Cox regression analysis was performed to identify predictive factors for DFS and OS. RESULTS: A total of 208 patients underwent liver resection for CRLM. VIO was performed in 64 procedures (31%), and fulfilled the definition of severe ischemia in 40 patients. Patients with severe ischemia had inferior DFS (5-year DFS 32% vs. 11%, P < 0.01), and inferior OS (5-year OS 37% vs. 64%, P < 0.01). At multivariate analysis, a high clinical risk score (Hazard ratio (HR) 1.60 (1.08-2.36)) and severe ischemia (HR 1.89 (1.21-2.97)) were independent predictors of worse DFS. Severe ischemia was not an independent predictor of OS. CONCLUSION: The present cohort study suggests that prolonged hepatic VIO during liver resection for CRLM was associated with reduced DFS. A patient-tailored approach seems advisable although larger studies should confirm these findings.

Multiple mechanisms of resistance to cis-diamminedichloroplatinum(II) in murine leukemia L1210 cells.

As an experimental model for resistance to cis-diamminedichloroplatinum(II) (cis-DDP), murine leukemia L1210 cells have been exposed to a stepwise increase in cis-DDP concentration to produce a variety of resistant cell lines. Intraspecies hybrids of the sensitive and resistant cells were made to determine whether cis-DDP resistance is a dominant or recessive trait. Hybrid cells displayed a partial degree of resistance as compared to the parental cells. To determine whether this was due to a single codominant trait or contribution from a variety of resistance mechanisms, the cells and hybrids were investigated for alterations in the accumulation of drug, as well as alterations in glutathione levels which might inactivate the drug. The cis-DDP-resistant cells demonstrated both a 50% reduction in accumulation of drug and a 1.7-fold increase in intracellular glutathione. Reducing the glutathione levels in these cells with buthionine sulfoximine did not sensitize them to cis-DDP. The hybrid cells had the same accumulation and the same levels of glutathione as the cis-DDP-sensitive cells. Parallel studies were performed with cells resistant to 1,2-diaminocyclohexaneplatinum(II) analogues. These cells also demonstrated reduced drug accumulation but no increase in glutathione. Therefore, both a decrease in accumulation and increase in glutathione may mediate resistance. Both mechanisms represent recessive traits as demonstrated in the cell hybrids. These mechanisms can only account for a small part of the resistance in these cells. A major, dominant mechanism occurs after the DNA has been platinated, but it remains to be determined whether this involves DNA repair, postreplication repair, or some other as yet unidentified process.

The frequency of alpha 2-adrenoceptor restriction fragment length polymorphisms in normotensive and hypertensive humans.

OBJECTIVE: To examine the frequency of distribution of allelic polymorphisms of the alpha 2-adrenoceptor gene in normotensive and hypertensive humans. DESIGN: The frequency of alpha 2-adrenoceptor genotypes was compared in the two groups using the chi 2-test. SETTING: The Midwest Hypertension Research Center Outpatient Clinic of Creighton University School of Medicine. STUDY PARTICIPANTS: History was taken from and physical examination performed on each of the 60 hypertensive and 47 normotensive adults. METHODS: DNA was extracted from leukocytes from each participants. Twenty restriction endonucleases were used and one restriction fragment length polymorphism (RFLP) was found using a 950-bp restriction fragment from the coding region of the human platelet alpha 2-adrenoceptor gene (ADRA2R) and Bsu36I restriction endonuclease. This probe and Bsu36I restriction endonuclease, in addition to another restriction endonuclease (Dra I), were then used in the study. RESULTS: Three genotype patterns were found. Homozygotes for the Bsu36I RFLP have either a unique 12-kb or a unique 5.8-kb band. Heterozygotes have both bands. The frequency of this alpha 2-adrenoceptor RFLP was calculated. In hypertensives the frequencies of the 12- and 5.8-kb alleles were 0.52 and 0.48, compared with 0.45 and 0.55, respectively, in normotensive, a difference that was not statistically significant. CONCLUSIONS: The frequency of the Bsu36I RFLP involving an alpha 2-adrenoceptor gene in hypertensives did not differ significantly from that in normotensives. A genetic linkage study is now under way to test for an association of the Bsu36I RFLP of the alpha 2-adrenoceptor gene with essential hypertension in families.

8,9-Didehydrofluoranthenes as building blocks for the synthesis of extended polycyclic aromatic hydrocarbons (PAHs).

[reaction: see text] The synthesis of phenyl-substituted 8,9-dibromofluoranthene and p-dodecylphenyl-substituted 8,9-fluoranthene anthranilic acid is presented. Their synthetic potential as 8,9-didehydrofluoranthene precursors is demonstrated in combination with a new biscyclopentadienone by the synthesis of novel phenyl-substituted PAHs with up to 14 annulated rings. The crystal structure of 7,16-diphenylfluorantheno[8,9-k]fluoranthene is given.

Differing postneonatal mortality rates of Mexican-American infants with United-States-born and Mexico-born mothers in Chicago.

OBJECTIVES: This study sought to determine the relationship between maternal nativity and the postneonatal mortality rate of urban Mexican-American infants. DESIGN: This is a population-based study. METHODS: Stratified and logistic regression analyses were performed on a data set of 1992-1995 computerized birth-death records of all Mexican-American infants born to Chicago residents with appended 1990 United States Census income and 1995 Chicago Department of Public Health data. RESULTS: In Chicago, Mexican-American infants (N = 10,599) of US-born mothers had a postneonatal mortality rate of 3.2/1,000 compared to 2.1/1,000 for infants (40,813) of Mexico-born mothers; relative risk (95% confidence interval) equaled 1.5 (1.0-2.3). The adjusted odds ratio of postneonatal mortality was 1.4 (1.1-1.9) for Mexican-American infants of US-born mothers. The mortality rate due to preventable causes (sudden infant death syndrome, homicides, non-intentional injuries, and infections) for Mexican-American infants of US-born mothers was twice that of infants of Mexico-born mothers; relative risk (95% confidence interval) equaled 2.2 (1.3-3.8); this nativity differential persisted in non-impoverished communities. CONCLUSION: The postneonatal mortality rate of urban Mexican-American infants with US-born mothers exceeds that of infants with Mexico-born mothers. This nativity disparity is attributable to preventable causes.

Postterm delivery among African Americans, Mexican Americans and Whites in Chicago.

OBJECTIVES: The purpose of the present study was to examine the effect of individual-level and community-level risk factors on the postterm delivery rates of infants born to African-American, Mexican-American, and non-Latino White mothers; and to compare postterm delivery rates between these ethnic groups. DESIGN: This is a population-based study. METHODS: We performed stratified and multivariate logistic regression analyses on a linked dataset of 1992-1995 Illinois vital records, 1990 United States Census income data, and 1995 Chicago Department of Public Health information. Communities with one or more high-risk characteristics (low median family income or high rates of unemployment, homicide or lead poisoning) were classified as impoverished. RESULTS: In Chicago, African Americans (N = 85,978) had a postterm rate of 4.3/1,000 and Mexican Americans (N = 47,266) had a postterm rate of 3.6/1,000, compared to 2.3/1,000 for non-Latino Whites (N = 48,601); relative risk (ninety-five percent confidence interval) = 1.9 (1.5-2.3) and 1.6 (1.2-2.0), respectively. Maternal age, education, marital status, parity, and prenatal care usage were associated with ethnic group-specific postterm delivery rates. In a multivariate logistic regression model for non-impoverished mothers, the adjusted odds ratios of postterm delivery for African Americans and Mexican Americans were 1.0 (0.5-3.2) and 1.0 (0.6-1.7), respectively. CONCLUSIONS: We conclude that African Americans and Mexican Americans have greater postterm delivery rates than do Whites; however, commonly cited individual and community-level risk factors account for most of the disparity.

Differential effect of ecologic risk factors on the low birthweight components of African-American, Mexican-American, and non-Latino white infants in Chicago.

This study explored the relationship between ecologic risk factors and infant birthweight. A stratified analysis was performed on all African-American, Mexican-American, and white infants born in Chicago in 1990. One half of African-American mothers (n = 26,799) resided in communities with multiple ecologic risk factors, yet their very low birthweight rates were unaffected by the number of these factors. By contrast, only 5% of Mexican-American mothers (n = 9913) and 5% of white mothers (n = 13,596) lived in communities with multiple ecologic risk factors. Their very low birthweights were twice that of infants born to mothers who resided in communities with no ecologic risk factors. These results indicate that ecologic risk factors affect the very low birthweight rates of Mexican Americans and whites but not African Americans.

Enhanced DNA repair as a mechanism of resistance to cis-diamminedichloroplatinum(II).

Murine leukemia L1210 cells, either sensitive or resistant to the toxic action of the cancer chemotherapeutic agent cis-diamminedichloroplatinum(II), have been studied for potential differences in the formation and repair of drug-induced DNA damage. The sensitivity for these experiments was obtained by using the radiolabeled analogue [3H]-cis-dichloro(ethylenediamine)platinum(II). The resistant cells demonstrated a 40% reduction in drug accumulation but a qualitatively similar profile of DNA-bound adducts. These adducts resembled those previously characterized in pure DNA and represented intrastrand cross-links at GG, AG, and GNG (N is any nucleotide) sequences in DNA. Repair of these cross-links occurred in a biphasic manner: rapid for the first 6 h and then much slower. The resistant cells removed up to 4 times as many adducts during the rapid phase of repair. The extent of this repair did not directly correlate with the degree of resistance in that cells with 100-fold resistance were only slightly more effective at repair than cells with 20-fold resistance. Therefore, although enhanced DNA repair is thought to contribute markedly to drug resistance, other mechanisms for tolerance of DNA damage may also occur in these cells.

Starch degradation in chloroplasts isolated from C3 or CAM (crassulacean acid metabolism)-induced Mesembryanthemum crystallinum L.

C3 or crassulacean acid metabolism (CAM)-induced Mesembryanthemum crystallinum plants perform nocturnal starch degradation which is linear with time. To analyse the composition of metabolites released by isolated leaf chloroplasts during starch degradation we developed a protocol for the purification of starch-containing plastids. Isolated chloroplasts from C3 or CAM-induced M. crystallinum plants are also able to degrade starch. With respect to the endogenous starch content of isolated plastids the rate of starch degradation in intact leaves. The combined presence of Pi, ATP, and oxaloacetate is identified to be the most positive effector combination to induce starch mobilization. The metabolic flux through the oxidative pentose-phosphate pathway in chloroplasts isolated from CAM-induced M. crystallinum is less than 3.5% compared with other metabolic routes of starch degradation. Here we report that starch-degrading chloroplasts isolated from CAM-induced M. crystallinum plants use exogenously supplied oxaloacetate for the synthesis of malate. The main products of starch degradation exported into the incubation medium by these chloroplasts are glucose 6-phosphate, 3-phosphoglyceric acid, dihydroxyacetone phosphate and glucose. The identification of glucose 6-phosphate as an important metabolite released during starch degradation is in contrast to the observations made on all other types of plastids analysed so far, including chloroplasts isolated from M. crystallinum in the C3 state. Therefore, we analysed the transport properties of isolated chloroplasts from M. crystallinum. Surprisingly, both types of chloroplasts, isolated from either C3 or CAM-induced plants, are able to transport glucose 6-phosphate in counter exchange with endogenous Pi, indicating the presence of a glucose 6-phosphate translocator as recently demonstrated to occur in other types of plastids. The composition of metabolites released and the stimulatory effect of oxaloacetate on the rate of starch degradation are discussed with respect to the acidification observed for CAM leaves during the night.

Transcription factor activation and mitogenic synergism in airway smooth muscle cells.

Simultaneous treatment of human airway smooth muscle (HASM) cells with lysophosphatidic acid (LPA) and epidermal growth factor (EGF) leads to strikingly synergistic stimulation of mitogenesis. The purpose of this study was to explore potential sites for signal integration mediating synergism, focusing on extracellular signal-regulated kinase (ERK) and transcription factors involved in proliferation and inflammation as likely candidates. Activation of ERK was analysed by immunoblotting. Transcription factor activation was assessed using HASM cells transduced with luciferase reporter gene constructs. LPA and EGF both activated ERK but had no synergistic effect when combined. LPA and EGF both activated activator protein (AP)-1, cyclic adenosine monophosphate response element-binding protein, nuclear factor of activated T-cells and the serum response element; however, only AP-1 activation exhibited synergism. Activation of the inhibitory guanine nucleotide-binding protein and of ERK signalling pathways were required for most transcription factor responses to LPA. In contrast, nuclear factor (NF)-kappaB was activated by LPA but not EGF and NF-kappaB activation was completely blocked only when Rho was inhibited. Rapid activation of Rho was observed in response to LPA but not to EGF. Importantly, inhibition of Rho selectively blocked synergism in both AP-1 activation and mitogenesis. In summary, extracellular signal-regulated kinase activation is required for many transcription factor responses to lysophosphatidic acid and epidermal growth factor, however it is not synergistic. Activation of activator protein-1 is synergistic, and Rho activation by lysophosphatidic acid is required for synergism in both activator protein-1 activation and mitogenesis.

Mutation analysis for cystic fibrosis to determine carrier status in 167 sperm donors from the Nebraska Genetic Semen Bank.

Cystic fibrosis is the most common autosomal recessive disorder in Caucasian populations, with an approximate frequency of 1/2500 live births and a carrier frequency of 1/25. Due to the high rate of predicted carriers (> 63,000) in the Nebraska population (1990 U.S. Census = 1,578,358), we analyzed sperm DNA obtained from semen donors at the University of Nebraska Genetic Semen Bank for eight of the more common mutations to determine the frequency and diversity in our population. The subjects included 167 semen donors (31 normal healthy donors, 56 infertility patients, 21 prevasectomy patients, and 59 prechemotherapy or preradiation cancer patients). The mutations analyzed included delta F508, R117H, G542X, S549R/N, G551D, R553X, R560T, and W1282X. Analyses were performed using PCR amplified products that were analyzed using polyacrylamide gel electrophoresis, slot blot, and restriction endonuclease digestion. These results were correlated with results from the clinical semen analyses and selected clinical parameters. Results for the total donor population studied showed that the delta F508 mutation was present in 8/167 (4.8%) donors, the R117H mutation was present in 4/167 (2.4%) donors and the G542X mutation was present in 1/167 (0.6%) donors. The observed number of carriers from this population, 13/167 (7.8%), was significantly greater (P = 0.02) than that expected assuming a carrier frequency of 1/25. The excess of carriers was restricted to the subgroup of infertility patients. This suggests that CF carriers may be at higher risk for infertility than the general population.

Mutation analysis and haplotype correlation for 139 cystic fibrosis patients from the Nebraska Regional Cystic Fibrosis Center.

Cystic fibrosis (CF) is the most common autosomal recessive disorder in Caucasian populations with an approximate frequency of one in 2,500 live births and a carrier frequency of one in 25. We studied 400 individuals seen at The Nebraska Regional Cystic Fibrosis Center that included 139 CF patients, 206 parents, and 55 unaffected siblings to determine the frequency of the delta F508, R117H, G542X, S549R/N, G551D, R553X, R560T, and W1282X mutations. In addition, we determined haplotypes on each of these individual's chromosomes using four markers that included XV-2c, KM-19, pMP6d.9, and G2. Results from this study showed that the delta F508 mutation was present in 70% of CF chromosomes. Of the 139 CF patients 74 (53%) were homozygous for the delta F508 deletion, 47 (34%) were heterozygous for the delta F508 deletion and an unknown mutation, and 18 (13%) carried two unknown mutations. Four additional mutations were also found in our population and included G542X (6%), G551D (5%), R553X (4%), and R560T (1%). One patient was documented to be a compound heterozygote for G542X/G551D. A polymorphism, F508C, that has previously been reported in several families was also present in our study. The most common haplotype associated with the delta F508 deletion in our CF patients was the E haplotype (CF Consortium B) while other mutations were associated with a variety of haplotypes.

Analgesia after thoracotomy: effects of epidural fentanyl concentration/infusion rate.

After thoracotomy some patients have discomfort, primarily in the rostral portion of their incisions. In this prospective, randomized study in 66 patients after lateral thoracotomy we evaluated whether, for equal fentanyl dosage in micrograms per kilogram, epidural infusion (lumbar catheter) of fentanyl 5 micrograms/mL provided better segmental analgesia (including the rostral portion of the incision) than a 10-micrograms/mL concentration infused at a rate half that used in the 5-micrograms/mL group. Ketorolac was used as an analgesic adjunct for nonincisional pain. Postoperative epidural fentanyl infusion included a 1-microgram/kg initial dose and an initial infusion rate of 1 microgram.kg-1.h-1 in both the 5-micrograms/mL and 10-micrograms/mL groups. Patients were evaluated for comfort level and pain relief while resting, taking a deep breath, coughing, and ambulating at eight times over 3 days using two visual analog scales for overall comfort and a verbal rating score (VRS) for segmental analgesia. There were no significant differences in demographics, surgical procedure, intraoperative fentanyl dose, side effects, rates of epidural fentanyl infusion, or total epidural fentanyl doses at 12, 24, 36, 48, and 60 h postbolus. Analgesia was effective in both groups. Although overall comfort levels were lower (i.e., indicated greater comfort) in the 5-micrograms/mL group in 6 of 8 visual analog scores (VASs) for comfort level and 20 of 24 VRSs for comfort level scores, and mean VRSs for the rostral portion of the incision were lower (i.e., indicated greater comfort) in the 5-micrograms/mL group at 21 of 24 evaluation subsets (one statistically significant), statistical significance was achieved in only six evaluation subsets.(ABSTRACT TRUNCATED AT 250 WORDS)