Systematic evaluation of pembrolizumab dosing in patients with advanced non-small cell lung cancer

International audienceBACKGROUND: In the phase I KEYNOTE-001 study, pembrolizumab demonstrated durable antitumor activity in patients with advanced non-small cell lung cancer (NSCLC). We sought to characterize the relationship between pembrolizumab dose, exposure, and response to define an effective dose for these patients. METHODS: Patients received pembrolizumab 2 mg/kg every 3 weeks (Q3W) (n=55), 10 mg/kg Q3W (n=238), or 10 mg/kg Q2W (n=156). Response (RECIST v1.1) was assessed every 9 weeks. The relationship between the estimated pembrolizumab area under the concentration-time curve at steady-state over 6 weeks (AUCss-6weeks) and the longitudinal change in tumor size (sum of longest diameters) was analyzed by regression and nonlinear mixed effects modeling. This model was simultaneously fit to all tumor size data, then used to simulate response rates, normalizing the trial data across dose for prognostic covariates (tumor PD-L1 expression and EGFR mutation status). The exposure-safety relationship was assessed by logistic regression of pembrolizumab AUCss-6weeks versus occurrence of adverse events of interest based on their immune etiology. RESULTS: Overall response rates were 15% (95% confidence interval [CI] 7%-28%) at 2 Q3W, 25% (18%-33%) at 10 Q3W, and 21% (95% CI 14% to 30%) at 10 Q2W. Regression analyses of percentage change from baseline in tumor size versus AUCss-6week indicated a flat relationship (regression slope P\textgreater0.05). Simulations showed the exposure-response relationship to be similarly flat, thus indicating that the lowest evaluated dose of 2 mg/kg Q3W to likely be at or near the efficacy plateau. Exposure-safety analysis showed the adverse event incidence to be similar among the clinically tested doses. CONCLUSIONS: No significant exposure dependency on efficacy or safety was identified for pembrolizumab across doses of 2 mg/kg to 10 mg/kg. These results support the use of a 2-mg/kg Q3W dosage in patients with previously treated, advanced NSCLC.ClinicalTrials.gov registry: NCT0129582

Compare the quality fish paste production of Kilka (Clupeonella cultriventris) and Silver carp (Hypophthalmichthys molitrix)

Qualitative changes in the fish spread a mixture of minced meat, fish Kilka (Clupeonella cultiventris) and silver carp (Hypophthalmichthys molitrix) in pasteurized. Fish spread of fish products ready for consumption with soft tissue, such as butter is very good in the world market, ready to use paste of fish production due to the variety, taste good, able to use for all ages in the community a special place in the fisheries industry countries are active in the field of fisheries products. The valuable features of this product, it is possible to produce fish midget, cheap, circumstantial fished, farmed fish, waste and waste from the fish processing factories are notably food production of fish protein sources that have the flavor is very suitable for all age groups was the research goals, in order to process the cream edible fillets and minced meat (minced fish) cultured fish silver carp (Hypophthalmichthys molitrix) and fish in the Caspian Sea Kilka (Clupeonella cultriventris) are treated as a combination of four: 1. Silver carp minced meat 100% +30% filler +1% spice, thickeners, improved color, taste 2. Kilka minced meat 100% +30% filler +1% spice, thickeners, improved color, taste 3. Kilka and Silver carp minced meat 50+50 % +30% filler +1% spice, thickeners, improved color, taste 4. Silver carp and Kilka minced meat 75+25 % +30% filler +1% spice, thickeners, improved color, taste 5. Silver carp and Kilka minced meat 25+75 % +30% filler +1% spice, thickeners, improved color, taste. After the initial blanching minced meat (80oc temperature for 3 min) were processed, heat resistant glass samples processed at the full weight of 50 g were, after a hot air steam, capping has been pasteurized for 60 minutes at 80oc, after a hot air steam, capping has been pasteurized for 60 minutes at 80oc and the results show, treatment 100% Silver carp minced fish +30% filler +1% spice, thickeners, improved color, taste better than other treatments and data was significant (P<0.05)

Study of process and quality assessment on hot smoked fish kilka production, determining its shelf life in vacuum and modified atmosphere and conventional packaging

In this study shelflife of whole hot smocked common kilka (Clupeonella cultriventris) fish packed in usual, vacuum and MAP packages and stored 6 weeks at refrigerator and or frozen temperatures was studied. Samples were analysed for TVBN, PV, pH, TBA, and total count, coliforms, clostridia, psychrophile, mold and sensory attributes weekly and monthly respectively. The ratio of Co2, N2 and O2 in the MAP package was 5: 55: 40%. Results indicated that the mixture gases could decline microbial growth and chemical changes during storage. Microbial and chemical changes in control samples were greater than that found for other samples. No significant microbial and chemical changes was observed in frozen samples during 6 weeks storage except for PV . Samples had the same sensory attributes just after production but were changed during storage significantly. Shelflife of samples packed in usual and MAP packages and stored at referigeratore was 21 and 35 days respectively; while it was 3 and 5 months for frozen samples packed in usual and vacuum packages. The conclusion is that packing hot smocked Kilka fish in vacuum and MAP packages can increase shelflife and decrease economical loss due to fish spoilage

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Molecular analysis of pbp2b in Streptococcus pneumonia isolated from clinical and normal flora samples

Streptococcus pneumoniae is an important bacterial pathogen responsible for respiratory infections, bacteraemia, and meningitis remains an important cause of disease and mortality in infants and younger children around the world, with penicillin being considered the drug of choice for the treatment of infections. However, penicillin-resistant S. pneumonia is now becoming endemic worldwide. In this study, a total of 80 pneumococcal isolates were collected from different clinical sources as well as normal flora. These isolates were subjected to antimicrobial susceptibility testing and MIC determination. The penicillin-binding proteins, pbp2b, were amplified by PCR, and they were sequenced. The genetic relationship of the penicillin-resistant isolates was performed by BOX PCR. Overall, 36 pneumococcal (45 ) isolates were found to be resistant to penicillin with different MICs. The majority of them (80 ) were intermediately resistant with MIC of 0.12�1 µg/ml, whereas 20 of isolates were penicillin resistant with MICs of >2 µg/ml. The results identified seven groups which were based on the amino acid substitutions of pbp2b. Sequencing analysis revealed that the most prevalent mutation was the substitution of Adenine for Thymine at the position 445 which is next to the second PBP2b-conserved motif (SSN). This study indicates that resistance to penicillin appears to be dependent on specific mutations in pbp2b, and the substitution in S620 � T near to the third PBP2b-conserved motif appears to be important in developing highly antibiotic-resistant isolates. Moreover, there was a positive correlation between the mutations in pbp2b gene and MIC. © 2014, Springer Science+Business Media New York

Assessment of Risk Factors and Management Associated with Preterm Deliveries and their Outcomes in Tertiary Care Teaching Hospital

Background: Preterm is a major obstetrical challenge of health care. It is the top most cause of perinatal morbidity and mortality of neonatal deaths. The births of these neonates are at a greater risk of developmental disabilities, health and growth problems than neonates of full term. Aim and objective: To assess the risk factors and management associated with preterm deliveries and their outcomes. Materials &amp; Methods: “A prospective observational cohort study” was conducted over a period of 6 months on 80 Preterm subjects, who were enrolled based on inclusion and exclusion criteria. A detailed questionnaire was used to record socio-demographic, clinical profile and prescribing management. Statistical analysis was performed by percentage method using parameters like mean, standard deviation. Results: The impact of incidence range in the present study was 31.52%. Maximum preterm deliveries were observed in the age group of 18-23 years (44%). Multiparous woman was at more risk for preterm i.e., about 51%. The commonest risk factor for preterm was Anemia (45%) followed by Pre-eclampsia (24%). The treatment prescribed for preterm was Betamethasone, Tidilon, Magnesium sulphate, Progesterone. The commonest neonatal outcome was found to be low birth weight with KMC and supplements of vitamins, iron, calcium as a therapy for their better recovery. Conclusion: The study suggests an urgent need for strengthening effective guidelines and appropriate counselling for prevention of preterm. Maintenance of good hygiene, adequate&nbsp;&nbsp; bed rest and proper antenatal care visits for the better outcomes.&nbsp; Keywords: preterm, multiparous, risk factors, neonatal outcomes, antenatal care, cohort