Normative values for esophageal functional lumen imaging probe measurements: A meta-analysis.

BACKGROUND: The functional lumen imaging probe (Endoflip™) is increasingly used for evaluation of patients with esophageal symptoms. To improve the interpretation of Endoflip™ in clinical practice, normative values with appropriate cut-off values are required. METHODS: Original clinical studies describing Endoflip™ use for measurements of esophageal motility in healthy adults were considered. Meta-analysis was performed based on published values. RESULTS: A total of 17 articles were included in the systematic review, 15 of which were included in the meta-analysis, representing 154 unique subjects. At 40 ml distention, the 5th-95th and 10th-90th percentiles for esophagogastric junction distensibility index (EGJ-DI) were 1.96-10.95 mm2 /mmHg and 2.36-8.95 mm2 /mmHg, respectively. An EGJ-DI below 2 mm2 /mmHg was found in 5.4%, and below 3 mm2 /mmHg in 20.1% of healthy subjects. At 50 ml distention, the 5th-95th and 10th-90th percentiles for EGJ-DI are 2.86-10.66 mm2 /mmHg and 3.28-9.12 mm2 /mmHg, respectively (below 2 mm2 /mmHg: 0.6%, 3 mm2 /mmHg: 6.3%). The 5th-95th and 10th-90th percentiles for EGJ-DI at 60 ml distention were 3.06-8.14 mm2 /mmHg and 3.33-7.18 mm2 /mmHg, respectively (below 2 mm2 /mmHg: 0.0%, 3 mm2 /mmHg: 7%). A clear cut-off for lower values was identified while a large spread in values was observed for upper limits of normal for EGJ-DI for all filling volumes. CONCLUSIONS: Given these observations, we recommend using a cut-off of 2 mm2 /mmHg for clinical practice, values below can be considered abnormal. Given that 5.4% of the healthy subjects will have an EGJ-DI below 2 mm2 /mmHg at 40 ml, we recommend using the 50 and 60 ml distention volumes. The clinical use of an upper limit for normality of EGJ-DI seems questionable.

Cancer cell sensitization and improved treatment efficacy by combined sodium butyrate and paclitaxel formulations is cancer-type specific.

We queried whether cancer treatment by combinations of paclitaxel and butyrate - free or formulated in drug delivery systems - can improve therapeutic responses compared to each drug alone. Combination treatments were conducted with HT-29 and HeLa cells, as representatives of differentiation-induced and cell-death-induced cancer lines, respectively. Pre-treatment of the HT-29 cells with butyrate (at doses inducing differentiation), followed by butyrate+paclitaxel generated changes in cell cycle profile, increased the level of dead cells beyond that of each drug alone, and allowed reduction in paclitaxel doses. A similar combination treatment of HeLa cells was detrimental, indicating that whether the combination is beneficial or not is cancer-type specific. We hypothesize that while butyrate-treated HT-29 cells became sensitive to paclitaxel-induced Fas-mediated apoptosis, butyrate-adapted HeLa cells became apoptosis-resistant. We next tested the same drug combination on HT-29 cells, but each drug in a specific tumor-targeted carrier. The combination of drug carriers outperformed an equidose combination of the free drugs, showing potential to achieve high therapeutic responses (even in drug-resistant cells) at significantly lower and detergent-free paclitaxel doses, which should allow for reduction in adverse effects and risks of toxicity.

Novel steroid carbamates reverse multidrug-resistance in cancer therapy and show linkage among efficacy, loci of drug action and P-glycoprotein's cellular localization.

P-glycoprotein (Pgp) is a major ABC transporter responsible for multidrug-resistance (MDR) in cancer chemotherapy. Pre-clinical MDR modulation studies identified promising chemosensitizers, but none are in the clinic yet. Two novel progesterone-derived carbamates (11-carbamic acid N,N-dibenzyl progesterone ester and 11-carbamic acid N,N-dibutyl progesterone ester) were examined as potential chemosensitizers in the Pgp-expressing human colon cancer line HCT-15, applying the classical MDR-drugs paclitaxel and doxorubicin. The major findings were: (1) Pgp was expressed in the HCT-15 cells in both the cell and the nuclear membranes, (2) at the low dose range of 1-5 microM, each new candidate: (i) increased cytotoxicity of doxorubicin (15-fold) and (separately) of paclitaxel (40-fold), (ii) induced an increase in intracellular accumulation, 60% (4h) for doxorubicin and 300% (18h) for paclitaxel, (iii) reduced drug efflux from the cell, 2-fold and 4-fold for doxorubicin and for paclitaxel, respectively. Based on detailed kinetic analysis, using liposomes to model paclitaxel diffusion through cell membranes, efflux slowdown can be attributed to reduction in the rate constant of drug diffusion through Pgp, and not to Pgp blockage. Chemosensitization was consistently-better for paclitaxel (cytosol-operating) than for doxorubicin (nuclear-operating) implying linkage between P-glycoprotein localization and loci of drug action. Mapping intracellular locations of MDR-pumps may assist therapeutic strategies.

Treatment of resistant human colon cancer xenografts by a fluoxetine-doxorubicin combination enhances therapeutic responses comparable to an aggressive bevacizumab regimen.

Pre-clinical studies of multidrug resistance (MDR) usually address severe resistance, yet moderate MDR is already clinically-impeding. The purpose of this study was to characterize moderate drug resistance in human colon cancer, and it's modulation by fluoxetine. In vitro fluoxetine enhanced doxorubicin's cytotoxicity (10-fold), increased doxorubicin's intracellular accumulation (32%) and decreased efflux of intracellular doxorubicin (70%). In vivo, mild treatment with a doxorubicin-fluoxetine combination slowed-down tumor progression significantly (p<0.001 vs. doxorubicin alone), comparable to aggressive treatment with bevacizumab. Collectively, our results suggest that combinations of fluoxetine with chemotherapeutic drugs (P-glycoprotein substrates) are worthy of further pursuit for moderate MDR in the clinic.