Efficacy and safety of delafloxacin compared with vancomycin plus aztreonam for acute bacterial skin and skin structure infections : A Phase 3, double-blind, randomized study

Funding Information: This work was funded by Melinta Therapeutics. In addition the editorial assistance (see below) was funded by Melinta Therapeutics. Publisher Copyright: © The Author 2017.Background: Delafloxacin is an investigational anionic fluoroquinolone in development for oral or intravenous administration for the treatment of infections caused by Gram-positive (including MRSA), Gram-negative, atypical and anaerobic organisms. Objectives: To establish the non-inferiority of delafloxacin compared with vancomycin plus aztreonam for the treatment of acute bacterial skin and skin structure infections and to compare the safety of the two antimicrobials. Patients and methods: A Phase 3, multicentre, randomized, double-blind, active-controlled study with 660 patients compared delafloxacin 300mg or vancomycin 15 mg/kg plus aztreonam2 g each administered twice daily intravenously for 5-14 days. Non-inferiority was evaluated by objective response ( ≥ 20% erythema reduction) at 48-72 h after initiation of study drug, investigator subjective assessment of outcome and microbiological responses. Clinical Trials Registration: NCT01811732. EudraCT number: 2012-001767-71. Results: In the ITT analysis set, the objective response was 78.2% in the delafloxacin arm and 80.9% in the vancomycin/aztreonam arm (mean treatment difference, -2.6%; 95% CI, -8.78% to 3.57%). Investigatorassessed cure was similar between the two groups at follow-up (52.0% versus 50.5%) and late follow-up (70.4% versus 66.6%). Bacterial eradication of MRSA was 100% and 98.5% in the delafloxacin group and the vancomycin/ aztreonamgroup, respectively. Frequency of treatment-emergent adverse events in the delafloxacin and vancomycin/aztreonam groups was similar. Treatment-emergent adverse events leading to study drug discontinuation were higher in the vancomycin/aztreonam group compared with the delafloxacin group (4.3% versus 0.9%). Conclusions: Delafloxacin, an anionic fluoroquinolone, was statistically non-inferior to vancomycin/aztreonam at 48-72 h following the start of therapy and was well tolerated as monotherapy in the treatment of acute bacterial skin and skin structure infections.publishersversionPeer reviewe

Evaluation of family histories and analysis of BRCA1 founder mutations in a population-based series of breast and ovarian cancer cases in Latvia

publishersversionPeer reviewe

Fibrinolytic system changes in liver surgery : A pilot observational study

Publisher Copyright: © 2018 Ozolina, Nemme, Ozolins, Bjertnæs, Vanags, Gardovskis, Viksna and Krumina.Introduction: Bleeding occurs frequently in liver surgery. Unbalance between tissue plasminogen activator (t-PA) and plasminogen activator inhibitor-1 (PAI-1) concentrations might increase bleeding. Our aim was to analyze perioperative fibrinolytic changes during liver surgery. Materials and Methods: We evaluated 15 patients for inclusion into a prospective pilot study of liver surgery. We assessed fibrinolysis by plasma PAI-1 and t-PA: before surgery (T1), before Pringle maneuver (PM;T2), at the end of surgery (T3) and 24 h postoperatively (T4), and registered demographic and laboratory data, extent and duration of surgery, hemodynamic parameters, blood loss, and transfused volumes of blood products. Data presented as mean ± SD. Significance at P < 0.05. Results: After exclusion of six patients only undergoing biopsies, we included six women and three men aged 49.1 ± 19.6 years; two patients with liver metastases of colorectal cancer and hepatocellular carcinoma, respectively, two with focal nodular hyperplasia, two with hepatic hemangioma, and one with angiomyolipoma. Six patients underwent PM. PAI-1 plasma concentration (n = 9) rose from 6.25 ± 2.25 at T1 through 17.30 ± 14.59 ng/ml at T2 and 28.74 ± 20.4 (p = 0.007) and 22.5 ± 16.0 ng/ml (p = 0.04), respectively, at T3 and T4. Correspondingly, t-PA plasma concentration (n = 9) increased from 4.76 ± 3.08 ng/ml at T1 through 8.00 ± 5.10 ng/ml (p = 0.012) at T2 and decreased to 4.25 ± 2.29 ng/ml and 3.04 ± 3.09 at T3 and T4, respectively. Plasma t-PA level at T2 was significantly different from those at T1, T3, and T4 (p < 0.004). In PM patients, t-PA levels increased from T1, peaked at T2 (p = 0.001), and subsequently decreased at T3 and T4 (p = 0.011 and p = 0.037), respectively. Mean blood loss was 1,377.7 ± 1,062.8 ml; seven patients received blood products. Patients with higher PAI-1 levels at T3 received more fresh frozen plasma (r = 0.79; p = 0.01) and red blood cells (r = 0.88; p = 0.002). Conclusions: During liver surgery, fibrinolysis increased, as evidenced by rises in plasma PAI-1and t-PA, especially after start of surgery and following PM. Transfused volumes of blood products correlated with higher plasma concentrations of PAI-1. Confirming this tendency requires a larger cohort of patients.publishersversionPeer reviewe

Novel germline MLH1 and MSH2 mutations in latvian Lynch syndrome families

Background/Aims: Hereditary non-polyposis colorectal cancer or Lynch syndrome is an autosomal dominantly inherited disease with high penetrance, mostly due to mutations in the MLH1 and MSH2 genes. The aim of this study is to investigate the mutation spectrum of the MLH1 and MSH2 genes. Methodology: High risk colorectal cancer families were selected from overall 1053 consecutive patients. Screening of germline mutations in the MLH1 and MSH2 was performed by direct sequencing and multiplex ligation-dependent probe amplification. Results: Ten patients fulfilled the Amsterdam I/II criteria and Bethesda guidelines of the Lynch syndrome. Three novel mutations were identified in MLH1 and MSH2 genes, as well as two known mutations in the MLH1 gene. Large rearrangements in the MLH1 gene were found in two patients. Conclusions: The mutations in the MLH1 and MSH2 genes in Latvian high-risk families are highly heterogeneous. Combination of direct sequencing and MLPA is the most appropriate molecular method of detecting hereditary nonpolyposis colorectal cancer patients and family members at risk

BRCA1/2 mutation screening in high-risk breast/ovarian cancer families and sporadic cancer patient surveilling for hidden high-risk families

Background: The estimated ratio of hereditary breast/ovarian cancer (HBOC) based on family history is 1.5% in Latvia. This is significantly lower than the European average of 5-10%. Molecular markers like mutations and SNPs can help distinguish HBOC patients in the sporadic breast and ovarian cancer group.Methods: 50 patients diagnosed with HBOC in the Latvian Cancer Registry from January 2005 to December 2008 were screened for BRCA1 founder mutation-negatives and subjected to targeted resequencing of BRCA1 and BRCA2 genes. The newly found mutations were screened for in the breast and ovarian cancer group of 1075 patients by Real Time-PCR/HRM analysis and RFLP.Results: Four BRCA2 mutations including three novel BRCA2 frameshift mutations and one previously known BRCA2 frameshift mutation and one BRCA1 splicing mutation were identified. Two of the BRCA2 mutations were found in a group of consecutive breast cancer patients with a frequency of 0.51% and 0.38%.Conclusions: Molecular screening of sequential cancer patients is an important tool to identify HBOC families.publishersversionPeer reviewe

Role of percutaneous needle biopsy of axillary lymph nodes to evaluate node positive breast cancer after neoadjuvant chemotherapy

publishersversionPeer reviewe

Genotype-phenotype correlations among BRCA1 4153delA and 5382insC mutation carriers from Latvia

<p>Abstract</p> <p>Background</p> <p>Mutations in the high penetrance breast and ovarian cancer susceptibility gene <it>BRCA1 </it>account for a significant percentage of hereditary breast and ovarian cancer cases. Genotype-phenotype correlations of <it>BRCA1 </it>mutations located in different parts of the <it>BRCA1 </it>gene have been described previously; however, phenotypic differences of specific <it>BRCA1 </it>mutations have not yet been fully investigated. In our study, based on the analysis of a population-based series of unselected breast and ovarian cancer cases in Latvia, we show some aspects of the genotype-phenotype correlation among the <it>BRCA1 </it>c.4034delA (4153delA) and c.5266dupC (5382insC) founder mutation carriers.</p> <p>Methods</p> <p>We investigated the prevalence of the <it>BRCA1 </it>founder mutations c.4034delA and c.5266dupC in a population-based series of unselected breast (n = 2546) and ovarian (n = 795) cancer cases. Among the <it>BRCA1 </it>mutation carriers identified in this analysis we compared the overall survival, age at diagnosis and family histories of breast and ovarian cancers.</p> <p>Results</p> <p>We have found that the prevalence of breast and ovarian cancer cases (breast: ovarian cancer ratio) differs significantly among the carriers of the c.5266dupC and c.4034delA founder mutations (OR = 2.98, 95%CI = 1.58 to 5.62, P < 0.001). We have also found a difference in the prevalence of breast and ovarian cancer cases among the 1^stand 2^nddegree relatives of the c.4034delA and c.5266dupC mutation carriers. In addition, among the breast cancer cases the c.4034delA mutation has been associated with a later age of onset and worse clinical outcomes in comparison with the c.5266dupC mutation.</p> <p>Conclusions</p> <p>Our data suggest that the carriers of the c.4034delA and c.5266dupC founder mutations have different risks of breast and ovarian cancer development, different age of onset and prognosis of breast cancer.</p

Impact of KRAS variant rs61764370 on breast cancer morbidity

Low-penetrance gene variants and their combinations are topical study objects in breast cancer pathogenesis. Single nucleotide polymorphism rs61764370, localized in 3՛ UTR of KRAS gene, plays an important role in the development and progression of seve­ral cancers. The aim of our study was to determine the KRAS variant impact on breast cancer morbidity. Patients and Methods: 2214 patients diagnosed with breast cancer and 861 healthy controls were screened for KRAS variant by RFLP method. Available clinical data were collected and processed using statistical analysis methods. Results of present study suggest the KRAS variant impact on breast cancer development risk in premenopausal women, but it has no effect on breast cancer prognosis. We did not observe any KRAS variant effect on breast cancer patient 10-year disease-specific survival rates. Key Words: breast cancer, rs61764370, KRAS variant, predisposing factor

Survival rates of familial and sporadic prostate cancer patients

Aim: To compare cancer-specific survival rates for familial and sporadic prostate cancer patients. Materials and Methods: Gleason score and age at diagnosis of familial group and sporadic group were compared by χ² and t-test. Cancer-specific survival rates were analyzed by the Kaplan — Meier method and compared by log-rank test. Statistically significant level was set at p < 0.05. Results: Among 1175 prostate cancer patients, familial group consisted of 215 (18.3%) patients, the sporadic group consisted of 960 (81.7%) patients. The familial group patient’s mean age at diagnosis (58.9 years old, 95% confidence interval (CI) 57.8–60.1) was significantly younger than that of sporadic group patients (67.2 years old, 95% CI 66.7–67.6) (p < 0.0001). Comparing Gleason score between familial group and sporadic group revealed no statistically significant difference. The analysis showed that 92% (95% CI 0.88–0.97) of familial group patients had a 10-year cancer-specific survival rates, which was a significantly better outcome than that of sporadic group with 69% (95% CI 0.60–0.78) 10-year cancer-specific survival rates (p = 0.0237). Conclusion: The study data demonstrate statistically significant difference between familial group and sporadic group concerning age and cancer-specific survival rates, but not Gleason score. Key Words: prostate cancer, hereditary, familial, survival rates

52. Development of network of cancer family syndrome registries in eastern Europe

It has been proven that organizing the registries of families affected by CFS is very helpful in research leading to: 1. Identification of new genes of CFS, 2. Better knowledge of correlations in CFS, 3. Identification of external factors having impact on mutated genes, 4. Description of mutation characteristic for particular populations.Thus, development of CFS registries is very important for increasing pre-clinical and clinical research facilities. Direct positive consequence will also be the improvement of quality of life by better management of patients affected by CFS. Without registries these patients are very often not identified and deprived of appropriate recommendations concerning prophylactics, surveillance and treatment. Development of CFS registries leads also to further improvement of quality of life by progress in management in families with these tumours which can be achieved by better organizing of research on CFS. Better management in CFS families decreases also health-care costs by lowering the number of cancers and increasing the number of tumours detected at their earliest clinical stage when the treatment is less expensive.The scientific objectives of the project include:-elaboration of standards for a model cancer family syndrome registries in Eastern Europe-registration of ∼ 2000 families with different types of CFS in populations of East European countries (Czech, Hungary, Latvia, Lithuania, Poland)-initiation of European collaborative studies with the use of material collected by East European CFS registries