ERBB2 (HER2)-targeted therapy provides benefits in metastatic breast cancer (mBC) and gastric cancer, but additional treatments are needed to maximize efficacy and quality of life.
To determine ...maximum tolerated doses (MTDs) of trastuzumab emtansine (T-DM1) plus capecitabine in patients with previously treated ERBB2-positive mBC and locally advanced/metastatic gastric cancer (LA/mGC) (phase 1) and the efficacy and safety of this combination vs T-DM1 alone in patients with mBC (phase 2).
The MTD in phase 1 was assessed using a 3 + 3 design with capecitabine dose modification. Phase 2 was an open-label, randomized, international multicenter study of patients with mBC treated with T-DM1 plus capecitabine or T-DM1 alone. Eligible patients had previously treated ERBB2-positive mBC or LA/mGC with no prior chemotherapy treatment for advanced disease.
Patients in the phase 1 mBC cohort received capecitabine (750 mg/m2, 700 mg/m2, or 650 mg/m2 twice daily, days 1-14 of a 3-week cycle) plus T-DM1 3.6 mg/kg every 3 weeks. Patients with LA/mGC received capecitabine at the mBC phase 1 MTD, de-escalating as needed, plus T-DM1 2.4 mg/kg weekly. In phase 2, patients with mBC were randomized (1:1) to receive capecitabine (at the phase 1 MTD) plus T-DM1 or T-DM1 alone.
The phase 1 primary objective was to identify the MTD of capecitabine plus T-DM1. The phase 2 primary outcome was investigator-assessed overall response rate (ORR).
In phase 1, the median (range) age was 54.0 (37-71) and 57.5 (53-70) years for patients with mBC and patients with LA/mGC, respectively. The capecitabine MTD was identified as 700 mg/m2 in 11 patients with mBC and 6 patients with LA/mGC evaluable for dose-limiting toxic effects. In phase 2, between October 2014 and April 2016, patients with mBC (median range age, 52.0 28-80 years) were randomized to receive combination therapy (n = 81) or T-DM1 (n = 80). The ORR was 44% (36 of 81 patients) and 36% (29 of 80 patients) in the combination and T-DM1 groups, respectively (difference, 8.2%; 90% CI, -4.5 to 20.9; P = .34; clinical cutoff, May 31, 2017). Adverse events (AEs) were reported in 78 of 82 patients (95%) in the combination group, with 36 (44%) experiencing grade 3-4 AEs, and 69 of 78 patients (88%) in the T-DM1 group, with 32 (41%) experiencing grade 3-4 AEs. No grade 5 AEs were reported.
Adding capecitabine to T-DM1 did not statistically increase ORR associated with T-DM1 in patients with previously treated ERBB2-positive mBC. The combination group reported more AEs, but with no unexpected toxic effects.
ClinicalTrials.gov Identifier: NCT01702558.
Comprehensive environmental observation, eco-innovation and smartization are essential to ensure the delivery of the long-term data and information required to address the shift towards smart, green ...and integrated raw materials efficiency. For this reason we need the mine-wide digitalization and informatization base model, an advanced mine-wide decision support system and a smart supervision system to supervise and control the production, back to predefined short-term production targets with most likelihood and optimal approaches. There are three main steps to be taken: analysis, evaluation and determination of the shift requirements, development of the models as well as modeling of the scenarios and connection to the smart platform for the support of the decision makers. The paper aims to consider what would be required for a raw materials area to operate as a modern smart technology-supported business. It attempts to provide a vision of some future smart architectures scenarios.
The aim of this study was to retrospectively compare the incidence, risk factors, and outcome in patients seen over a 7-year period at the National Cancer Institute in the Slovak Republic, with ...vancomycin-sensitive or vancomycin-resistant enterococcal bacteremia. The total incidence of enterococcal bacteremia at the National Cancer Institute increased from 5.1% in 1991 to 11.1% in 1993 and then decreased to 4.3% in 1995. Analysis of the 77 episodes of enterococcal bacteremia from 66 patients showed that 69 episodes from 60 patients were due to vancomycin-sensitive Enterococcus faecalis (group 1) and 8 episodes from 8 patients were due to vancomycin-resistant Enterococcus faecium (group 2). The features most frequently associated with enterococcal bacteremia were the insertion of a central venous catheter, neutropenia lasting more than 10 days, previous therapy with cephalosporins or vancomycin, previous prophylaxis with quinolones, and the incidence of superinfections. There was no difference in the clinical course or outcome between the 2 study groups. Previous therapy with aminoglycosides, cephalosporins, vancomycin or imipenem, neutropenia less than 10 days in length, malignancies other than leukemia or solid tumors, and the incidence of breakthrough bacteremia significantly correlated with patients with vancomycin-resistant E. faecium rather than patients with vancomycin-sensitive E. faecalis. The overall mortality was similar in both groups and averaged 32.5% for all enterococcal bacteremic patients. In this study, the major risk factors associated with cancer patients for developing vancomycin-resistant enterococcal bacteremia were previous therapy with aminoglycosides, cephalosporins or vancomycin, superinfections with other organisms and the incidence of breakthrough bacteremia.
60 patients with 60 viridans streptococcal bacteraemic episodes (42 due to penicillin-sensitive and 18 due to penicillin-resistant viridans streptococci) were analysed in a population of 12,185 ...admissions and 1,380 bacteraemic episodes during a 7-year period in a National Cancer Institute. The incidence of viridans streptococci among bacteraemias decreased from 11.5% in 1989 to 2.5% in 1995 after penicillin was introduced for prophylaxis of febrile neutropenia in acute leukaemia in 1993. However, the proportion of penicillin-resistant viridans streptococcal bacteraemias increased from 0 in 1989 and 1990 before any prophylaxis was given, to 12.9-16.7% after quinolones were used for prophylaxis in 1991 and 1992, and to 44.4-81.8% in 1993-1995 after penicillin was added to the quinolones. Mortality rate was higher in the subgroup of penicillin-resistant viridans streptococcal bacteraemias (p < 0.05). Statistically significant risk factors in patients with penicillin-resistant (compared with penicillin-sensitive) viridans streptococcal bacteraemia were: acute leukaemia (p < 0.03), high doses of cytarabine (p < 0.05), mucocutaneous lesions (p < 0.004), breakthrough bacteraemia during prophylaxis with ofloxacine plus penicillin (p < 0.001). Multiple logistic regression analysis showed that only acute leukaemia (OR 2.05, CI 0.85-1.85, p < 0.0452) and penicillin-resistance (OR 0.71, CI 0.103-4.887, p < 0.0209) were significant independent predictors of inferior outcome. Breakthrough bacteraemia during empiric therapy with vancomycine occurred in 5 of 116 patients treated with vancomycine, and during therapy with ampicillin plus gentamicin in 6 patients of 18 treated.
Polybrominated diphenylethers (PBDEs) are persistent organic pollutants (POPs), they are considered endocrine disruptors and can bioaccumulate in nature, and in living tissue. Human exposure to and ...the presence of PBDEs in human samples is of concern due to their potential health risks. Young children are one of the most vulnerable populations to PBDE's potential health effects.
Ninety-one serum samples of 6-year-old children, residing in a contaminated location, due to former production of polychlorinated biphenyls (PCBs), were analysed to examine children's exposure to PBDEs in Slovakia. Median serum concentrations found for individual PBDE congeners BDE-28+33, −47, −99, −100, −153, −154 and −183 were 0.015, 0.184, 0.079, 0.046, 0.176, 0.014, and 0.097 ng g−1 lipid weight, respectively.
Children's preschool maturity was measured using the Wechsler Preschool and Primary Scale of Intelligence (WPPSI-III) test. In multivariate analyses BDE-153 serum concentrations were significantly inversely associated with WPPSI-III composite score (p = 0.011, β = −23.6), while adjusting for PCB-153 and sex. Significant negative associations were observed for BDE-153 serum concentrations (p = 0.002, β = −29.8) and WPPSI-III composite score, after controlling for PCB-118 and sex. Negative associations were also observed for BDE-47, BDE-100 and BDE-153, with different individual WPPSI subtest scores, after adjustment with PCB-153 and/or PCB-118 and sex. Serum concentrations of PCB-153 and PCB-118 were not statistically significantly associated with WPPSI-III composite score and individual subtest scores. These findings demonstrate adverse effects of PBDE serum exposure on preschool maturity of children, and PBDEs potentially negative impact on child neuropsychological development.
•PBDE serum concentrations in children from Slovakia.•BDE-47 and BDE-153 were the most abundant congeners.•Negative associations observed between PBDE serum concentrations and preschool maturity of children using the WPPSI test.•No associations between PCBs and preschool maturity tests.•Adverse effect of PBDEs on neuropsychological development of children.
Myeloid sarcoma is a rare presentation of acute leukemia as a solid tumor at various extramedullary sites. It may present concurrently, before or after the onset of systemic bone marrow leukemia. ...Unusual clinical localization may lead to misdiagnosis, or delayed diagnosis and treatment. We describe the first case, to our knowledge, of de novo myeloid sarcoma of the breast confirmed as acute promyelocytic leukemia. Immunohistochemical analysis, flow cytometry, fluorescent in situ hybridization analysis and molecular analysis using RQ-PCR of tissue samples should be routine in determining the correct diagnosis in this setting.
•clinical reports on ALL treatment from small countries are insufficient.•treatment according to adapted well designed protocols is standard approach.•retrospective study of biological ...characteristics and survival of 90 patients.
The results of treatment of acute lymphoblastic leukemia (ALL) from the low population countries are missing in the literature.
We retrospectively examined biological characteristics and survival of 90 patients with ALL.
At median follow-up 17 months, 52 men and 38 women were eligible for the analysis with median age 43 years (18–74). As for the risk stratification, 25.6% of patients were in standard risk, 46.7% in high risk and 27.8% in very high-risk group. Complete remission achieved 88.9% of patients. We observed 5.6% of induction deaths and 4.5% of resistant disease. 47.8% of the patients underwent allogeneic stem cell transplantation (alloSCT), 59% in the young adults (YA; < 40 years) and 40% in adult group (≥ 40 years). We noticed 32.6% relapses overall with median survival of relapsed patients 3.9 months. YA patients had longer survival than adults: 3-year overall survival (OS) 65.0% vs 30.2%; (HR = 0.36; 95% CI 0.2–0.64; P = .001) and event free survival (EFS) 51.5% vs 21.9%; (HR = 0.45; 95% CI 0.26–0.78; P = .005). There was significant difference in 3-year EFS between risk groups in YA patients 90.9%, 48.0%, 11.4%; (P = .001). OS after alloSCT individually for the YA was 62.6% and for adults 39.1%, hazard ratio (HR) = 0.49 (95% CI 0.20–1.21); (P = .095). We observed 14% early deaths, 25.6% late deaths and 3 relapses (7%) after allogeneic stem cell transplantation.
Our data proved that even in a low population country similar result can be achieved as in larger ones while using well designed adapted protocols from leukemic study groups.
The published reports on real life data on ALL treatment from low population countries are insufficient. They usually use protocols of well-known leukemic groups and try to achieve the results reported in the literature. It is necessary to know not only results from well-designed clinical trials but also results from real life treatment analyses, which can bring equally interesting information.
Cronobacter sp. is considered an opportunistic pathogen implicated in food-borne life-threatening infection, in particular in neonates and infants. Contaminated powdered infant formula was identified ...as the primary source of Cronobacter sp. at very low levels. Multiplication of survived cells of thermotolerant Cronobacter strains was often found a crucial factor for causing outbreaks. The aim of our work was to develop and evaluate a detection method for thermotolerant Cronobacter strains using triplex TaqMan real-time polymerase chain reaction (PCR) targeting a specific sequence for Cronobacter sp., a thermotolerance marker and an internal amplification control. The proposed method was evaluated on 48 strains, including 32 Cronobacter sp. and 16 related species of Enterobacteriaceae family. The results showed 100% inclusivity and exclusivity, and 100% correlation with the time required to kill 90% of cells exposed at 58 degreesC (D sub(58)-value). The developed real-time PCR method facilitated rapid and specific detection of thermotolerant Cronobacter strains isolated from powdered infant formula products or from the production chain.
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