NKTR-102 Efficacy versus irinotecan in a mouse model of brain metastases of breast cancer

Background: Brain metastases are an increasing problem in women with invasive breast cancer. Strategies designed to treat brain metastases of breast cancer, particularly chemotherapeutics such as irinotecan, demonstrate limited efficacy. Conventional irinotecan distributes poorly to brain metastases; therefore, NKTR-102, a PEGylated irinotecan conjugate should enhance irinotecan and its active metabolite SN38 exposure in brain metastases leading to brain tumor cytotoxicity. Methods: Female nude mice were intracranially or intracardially implanted with human brain seeking breast cancer cells (MDA-MB-231Br) and dosed with irinotecan or NKTR-102 to determine plasma and tumor pharmacokinetics of irinotecan and SN38. Tumor burden and survival were evaluated in mice treated with vehicle, irinotecan (50 mg/kg), or NKTR-102 low and high doses (10 mg/kg, 50 mg/kg respectively). Results: NKTR-102 penetrates the blood-tumor barrier and distributes to brain metastases. NKTR-102 increased and prolonged SN38 exposure (\u3e20 ng/g for 168 h) versus conventional irinotecan (\u3e1 ng/g for 4 h). Treatment with NKTR-102 extended survival time (from 35 days to 74 days) and increased overall survival for NKTR-102 low dose (30 % mice) and NKTR-102 high dose (50 % mice). Tumor burden decreased (37 % with 10 mg/kg NKTR-102 and 96 % with 50 mg/kg) and lesion sizes decreased (33 % with 10 mg/kg NKTR-102 and 83 % with 50 mg/kg NKTR-102) compared to conventional irinotecan treated animals. Conclusions: Elevated and prolonged tumor SN38 exposure after NKTR-102 administration appears responsible for increased survival in this model of breast cancer brain metastasis. Further, SN38 concentrations observed in this study are clinically achieved with 145 mg/m2 NKTR-102, such as those used in the BEACON trial, underlining translational relevance of these results

New combined parameter of liver and splenic stiffness as determined by elastography in healthy volunteers

Background: The diagnosis of chronic liver disease (CLD) leading to fibrosis, cirrhosis, and portal hypertension had witnessed dramatic changes after the introduction of noninvasive figure accessible tools over the past few years. Imaging techniques that are based on evaluation of the liver stiffness was particularly useful in this respect. Acoustic radiation force impulse (ARFI) emerged as an interesting figure tool with reliable repute and high precision. Aims: To evaluate liver stiffness measurement (LSM) and splenic stiffness measurement (SSM) in healthy volunteers as concluded by the ARFI technique and to out a numeric calculated ratio that may reflect their correlation in the otherwise healthy liver. Patients and Methods: A ratio (splenic stiffness/liver stiffness in kPa) was determined in 207 consenting healthy subjects and was investigated with respect to age, gender, ethnic origin, body mass index (BMI), liver and spleen sizes healthy volunteers, alanine aminotransferase (ALT), aspartate aminotransferase (AST), platelet count (PLT), APRI, and FIB-4 scores. Results: Data from this work led to computing an index of 4.72 (3.42–7.33) in healthy persons on an average. Females had a higher index than males 6.37 vs 4.92, P=0.002. There was not any significant difference of the ratio in different age groups; ethnic origins; any correlation between SSM/LSM ratio and BMI; liver and spleen sizes; or ALT, AST, PLT, APRI, and FIB-4 scores. Conclusions: A quantifiable numeric relationship between splenic and liver stiffness in the healthy subjects could be computed to a parameter expressed as SSM/LSM ratio. We believe that this ratio can be a useful reference tool for further researches in CLD

Do probiotics improve eradication response to Helicobacter pylori on standard triple or sequential therapy?

Background: The standard triple therapy for the eradication of Helicobacter pylori consists of a combination of a proton pump inhibitor at a standard dose together with two antibiotics (amoxicillin 1000 mg plus either clarithromycin 500 mg or metronidazole 400 mg) all given twice daily for a period of 7-14 days. Recent reports have shown a dramatic decline in the rate of H. pylori eradication utilizing standard triple therapy from 95% down to 70-80%. Aims: Our study was designed to evaluate the effect of adding a probiotic as an adjuvant to common regimens used for H. pylori eradication. Materials and Methods: An open label randomized observational clinical study was designed to test three different regimens of H. pylori eradication treatment: Standard triple therapy with a concomitant probiotic added at the same time (n = 100), starting the probiotic for 2 weeks before initiating standard triple therapy along with the probiotic (n = 95), and the third regimen consists of the probiotic given concomitantly to sequential treatment (n = 76). The three arms were compared to a control group of patients treated with the traditional standard triple therapy (n = 106). Results: The eradication rate for the traditional standard therapy was 68.9%, and adding the probiotic "Bifidus infantis" to triple therapy, led to a successful rate of eradication of 83% (P < 0.001). Pre-treatment with 2 weeks of B. infantis before adding it to standard triple therapy increased the success rate of eradication to 90.5%. Similar improvement in eradication rate was noted when B. infantis was added as an adjuvant to the sequential therapy leading to an eradication rate of 90.8%. Conclusion: Adding B. infantis as an adjuvant to several therapeutic regimens commonly used for the eradication of H. pylori infection significantly improves the cure rates