A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer.

PURPOSE: Three agents with differing mechanisms of action are available for treatment of advanced colorectal cancer: fluorouracil, irinotecan, and oxaliplatin. In this study, we compared the activity and toxicity of three different two-drug combinations in patients with metastatic colorectal cancer who had not been treated previously for advanced disease. PATIENTS AND METHODS: Patients were concurrently randomly assigned to receive irinotecan and bolus fluorouracil plus leucovorin (IFL, control combination), oxaliplatin and infused fluorouracil plus leucovorin (FOLFOX), or irinotecan and oxaliplatin (IROX). The primary end point was time to progression, with secondary end points of response rate, survival time, and toxicity. RESULTS: A total of 795 patients were randomly assigned between May 1999 and April 2001. A median time to progression of 8.7 months, response rate of 45%, and median survival time of 19.5 months were observed for FOLFOX. These results were significantly superior to those observed for IFL for all end points (6.9 months, 31%, and 15.0 months, respectively) or for IROX (6.5 months, 35%, and 17.4 months, respectively) for time to progression and response. The FOLFOX regimen had significantly lower rates of severe nausea, vomiting, diarrhea, febrile neutropenia, and dehydration. Sensory neuropathy and neutropenia were more common with the regimens containing oxaliplatin. CONCLUSION: The FOLFOX regimen of oxaliplatin and infused fluorouracil plus leucovorin was active and comparatively safe. It should be considered as a standard therapy for patients with advanced colorectal cancer.     

Comparative mouse skin tumorigenicity and induction of Ha-ras mutations by bay region diol epoxides of 5-methylchrysene and 5,6- dimethylchrysene

We compared the tumor-initiating activities toward mouse skin of two structurally related polycyclic aromatic hydrocarbon diol epoxides: racemic anti-1,2,3,4-tetrahydro-5,6-dimethylchrysene-1,2-diol-3,4- epoxide (5,6-diMeCDE) and racemic anti-1,2,3,4-tetrahydro-5- methylchrysene-1,2-diol-3,4-epoxide (5-MeCDE). Tumors induced by these diol epoxides were analysed for mutations in the Ha-ras gene. 5,6- diMeCDE is derived from the non-planar parent compound 5,6- dimethylchrysene, and reacts to approximately equal extents with dA and dG in DNA, whereas 5-MeCDE is derived from a nearly planar parent compound, 5-methylchrysene, and reacts mainly with dG in DNA. 5,6- diMeCDE, at initiating doses of 33, 100 or 400 nmol per mouse, induced 1.2, 2.2 and 6.2 skin tumors per mouse, respectively. It was significantly less tumorigenic than 5-MeCDE which induced 3.1, 7.5 and 9.1 skin tumors per mouse at the same doses. Tumors induced by 5,6- diMeCDE had a large number of CAA-->CTA mutations in codon 61 of the Ha- ras gene: 50, 55 and 75% of the tumors analysed had this mutation at the 33, 100 and 400 nmol doses. No mutations were found in codons 12 and 13 in the tumors induced by 5,6-diMeCDE. In contrast, CAA-->CTA mutations in codon 61 were rarely seen in tumors induced by 5-MeCDE. At the highest dose of 5-MeCDE, 20% of the tumors analysed had mutations at G of codons 12 and 13. The results of this comparative study support the hypothesis that mutations in the Ha-ras gene in mouse skin tumors induced by PAH diol epoxides occur as a result of their direct reaction with the gene. However, pathways other than the commonly observed Ha- ras codon 61 mutations are clearly important in mouse skin tumorigenesis by these diol epoxides.      

An epidemiological study on patients undergoing dacryocystorhinostomy

Dacryocystorhinostomy is performed in patients with naso-lacrimal duct obstruction to bypass the site of obstruction so as to relieve the patient of the irritating and socially embarrassing symptoms of epiphora. We discuss the various epidemiological aspects especially the vast difference by which the females out-number the males in patients undergoing DCR and the likely explanations for this difference in our study on 74 patients which underwent DCR in our institute.     

Effects of nortriptyline and paroxetine on QT variability in patients with panic disorder

This study investigated beat-to-beat QT variability in patients with panic disorder before and after treatment with nortriptyline (n = 13) and paroxetine (n = 16), using an automated algorithm to compute QT intervals. An increase in QT variability appears to be associated with symptomatic patients with dilated cardiomyopathy and also with an increased risk for sudden cardiac death. QTvi (QT variability index: a log ratio of QT variance normalized for mean QT over heart rate variability normalized for mean heart rate) was significantly higher in supine posture in patients with panic disorder treated with nortriptyline (P = 0.006) but not paroxetine. Thus paroxetine may be a better drug of choice especially in patients with coexisting cardiac disease. These findings are important especially in view of the recent reports of increased risk for cardiovascular mortality and sudden death in patients with anxiety and depression. QTvi can be a valuable noninvasive measure of temporal repolarization lability, especially to study the side effects of medications which affect cardiac autonomic function.     

Assessment of oral bioavailability and preclinical pharmacokinetics of DRF-6196, a novel oxazolidinone analogue, in comparison to linezolid.

The aim of this study was to determine the bioavailability of a novel oxazolidinone, DRF-6196, in mice and rats following intravenous (i.v) and oral dosing and to compare the pharmacokinetics with those obtained following linezolid dosing. Blood samples were drawn at predetermined intervals up to 24 h post-dose after either DRF-6196 or linezolid administration. The concentrations of DRF-6196 and linezolid in various plasma samples were determined by a HPLC method. Following oral administration maximum concentrations of DRF-6196 were achieved within 0.5 h irrespective of the species. While the doses increased in the ratio of 1 : 3 : 10, mean Cmax and AUC(0-infinity) values in mice for DRF-6196 increased in the ratio of 1 : 3.87 : 8.53 and 1 : 2.51 : 9.24, respectively. Both the Cmax and AUC(0-infinity) values increased almost proportional to the dose administered in mice. Following i.v administration, the concentration of DRF-6196 declined in a bi-exponential fashion with terminal elimination half-life of 1.5 h irrespective of the species. The systemic clearance and volume of distribution of DRF-6196 in mice were 1.14 L/h/kg and 0.66 L/kg, respectively after i.v administration, while the respective values in rats were 0.61 L/h/kg and 0.41L/kg, respectively. Elimination half-life ranged between 0.8-1.5 h. Absolute oral bioavailability of DRF-6196 was found to be 80-96% across the test dose range. Although plasma levels of DRF-6196 were lesser compared to linezolid in the initial hours, it may not have any consequences on the clinical effectiveness of the molecule.     

Randomized phase II trial of the clinical and biological effects of two dose levels of gefitinib in patients with recurrent colorectal adenocarcinoma.

PURPOSE: The clinical objective of this trial was to evaluate gefitinib in patients with metastatic colorectal cancer that had progressed despite prior treatment. Serial tumor biopsies were performed when possible and analyzed for activation of the epidermal growth factor receptor (EGFR) signaling pathway. Serial serum samples were measured for amphiregulin and transforming growth factor-alpha (TGFalpha). PATIENTS AND METHODS: One hundred fifteen patients were randomly assigned to receive gefitinib 250 or 500 mg orally once a day. One hundred ten patients were assessable for clinical efficacy. Biologic evaluation was performed on paired tumor samples from 28 patients and correlated with clinical outcome. RESULTS: Median progression-free survival was 1.9 months (95% CI, 1.8 to 2.1 months) and 4-month progression-free survival rate was 13% +/- 5%. One patient achieved a radiographic partial response (RR = 1%; 95% CI, 0.01% to 5%). Median survival was 6.3 months (95% CI, 5.1 to 8.2 months). The most common adverse events were skin rash, diarrhea, and fatigue. In the biopsy cohort, expression of total or activated EGFR, activated Akt, activated MAP-kinase, or Ki67 did not decrease following 1 week of gefitinib. However, a trend toward decreased post-treatment levels of activated Akt and Ki67 was observed in patients with a PFS higher than the median, although these did not reach the .05 level of significance. CONCLUSION: Gefitinib is inactive as a single agent in patients with previously treated colorectal cancer. In tumor samples, gefitinib did not inhibit activation of its proximal target, EGFR. Trends were observed for inhibition of downstream regulators of cellular survival and proliferation in patients achieving longer progression-free survival.     

Enhanced oral paclitaxel absorption with vitamin E-TPGS: Effect on solubility and permeability in vitro, in situ and in vivo

Solubility and permeability being important determinants of oral drug absorption, this study was aimed to investigate the effect of d--tocopheryl polyethylene glycol 1000 succinate (TPGS) on the solubility and intestinal permeability of paclitaxel in vitro, in situ and in vivo, in order to estimate the absorption enhancement ability of TPGS. Aqueous solubility of paclitaxel is significantly enhanced by TPGS, where a linear increase was demonstrated above a TPGS concentration of 0.1 mg/ml. Paclitaxel demonstrated asymmetric transport across rat ileum with significantly greater (26-fold) basolateral-to-apical (B–A) permeability than that in apical-to-basolateral (A–B) direction. Presence of P-glycoprotein (P-gp) inhibitor, verapamil (200 μM), diminished asymmetric transport of paclitaxel suggesting the role of P-gp-mediated efflux. TPGS showed a concentration-dependent increase in A–B permeability and decreased B–A permeability. The maximum efflux inhibition activity was found at a minimum TPGS concentration of 0.1 mg/ml, however, further increase in TPGS concentration resulted in decreased A–B permeability with no change in B–A permeability. Thus, the maximum paclitaxel permeability attained with 0.1 mg/ml TPGS was attributed to the interplay between TPGS concentration dependent P-gp inhibition activity and miceller formation. In situ permeability studies in rats also demonstrated the role of efflux in limiting permeability of paclitaxel and inhibitory efficiency of TPGS. The plasma concentration of [¹⁴C]paclitaxel following oral administration (25 mg/kg) was significantly increased by coadministration of TPGS at a dose of 50 mg/kg in rats. Bioavailability is enhanced about 4.2- and 6.3-fold when [¹⁴C]paclitaxel was administrated with verapamil (25 mg/kg) and TPGS, respectively, as compared to [¹⁴C]paclitaxel administered alone. The effect of verapamil on oral bioavailability of [¹⁴C]paclitaxel was limited relative to the TPGS, consistent with the in vitro solubility and permeability enhancement ability of TPGS. In conclusion, the current data suggests that the coadministration of TPGS may improve the bioavailability of BCS class II–IV drugs with low solubility and/or less permeable as a result of significant P-gp-mediated efflux.     

Decoding glaucoma module premium edition

Background:Traditional methods for neuroretinal rim width measurement in spectral domain optical coherence tomography (SD-OCT) employs the Bruch‘s membrane opening (BMO) as the anatomical border of the rim, referenced to a BMO horizontal reference plane, termed as “Bruch’s Membrane Opening-Horizontal Rim Width” (BMO-HRW). BMO-HRW is defined as the distance between BMO and internal limiting membrane (ILM) on the horizontal plane. In contrast, the Spectralis OCT (Heidelberg Engineering, Germany) employs a new parameter called “Bruch’s Membrane Opening–Minimum Rim Width” (BMO-MRW) with Glaucoma Module Premium Edition (GMPE). GMPE provides a novel objective method of optic nerve head (ONH) analysis using BMO, but the neuroretinal rim assessment is performed from the BMO to the nearest point on the ILM, rather than on the horizontal reference plane. It is the BMO-MRW and is defined as the minimum distance between the BMO and ILM in the ONH.Purpose:In this video, anatomy of the ONH and GMPE is decoded from a neophyte user’s point of view, as to why BMO-MRW is more important than the traditional BMO-HRW for glaucoma evaluation.Synopsis:The GMPE concepts are depicted in a novel dynamic (Clinical vs OCT Vs Histology) screenplay, detailing the below focal points with 2D & 3D animations: True Margin of ONH, Bruch’s Membrane (BM), Histology Vs OCT, BMO, Bruch’s Membrane Opening-Minimum Rim Width, Bruch’s Membrane Opening-Minimum Rim Width Versus Bruch’s Membrane Opening-Horizontal Rim Width, Alpha, Beta, Gamma Zone of ONH in OCT, Anatomic Positioning System, Impact of Fovea Bruch’s Membrane Opening Centre Axis.Highlights:This video also highlights, how with the advent of Anatomic Positioning System, scans were able to align relative to the individual’s Fovea-to-BMO-center (FoBMOC) axis at every follow-up, for accurately detecting changes, as small as 1 micron in BMO-MRW, thus creating a new world in diagnosing glaucoma and detecting glaucomatous progression with precision.Video link: https://youtu.be/6RqF5guAziw     

Thymoquinone Alterations of the Apoptotic Gene Expressions and Cell Cycle Arrest in Genetically Distinct Triple-Negative Breast Cancer Cells

Breast cancer (BC) is the most common cancer in women worldwide, and it is one of the leading causes of cancer death in women. triple-negative breast Cancer (TNBC), a subtype of BC, is typically associated with the highest pathogenic grade and incidence in premenopausal and young African American (AA) women. Chemotherapy, the most common treatment for TNBC today, can lead to acquired resistance and ineffective treatment. Therefore, novel therapeutic approaches are needed to combat medication resistance and ineffectiveness in TNBC patients. Thymoquinone (TQ) is shown to have a cytotoxic effect on human cancer cells in vitro. However, TQ’s mode of action and precise mechanism in TNBC disease in vitro have not been adequately investigated. Therefore, TQ’s effects on the genetically different MDA-MB-468 and MDA-MB-231 human breast cancer cell lines were assessed. The data obtained show that TQ displayed cytotoxic effects on MDA-MB-468 and MDA-MB-231 cells in a time- and concentration-dependent manner after 24 h, with IC₅₀ values of 25.37 µM and 27.39 µM, respectively. Moreover, MDA-MB-231 and MDA-MB-468 cells in a scratched wound-healing assay displayed poor wound closure, inhibiting invasion and migration via cell cycle blocking after 24 h. TQ arrested the cell cycle phase in MDA-MB-231 and MDA-MB-468 cells. The three cell cycle stages in MDA-MB-468 cells were significantly affected at 15 and 20 µM for G0/G1 and S phases, as well as all TQ concentrations for G2/M phases. In MDA-MB-468 cells, there was a significant decrease in G0/G1 phases with a substantial increase in the S phase and G2/M phases. In contrast, MDA-MB-231 showed a significant effect only during the two cell cycle stages (S and G2/M), at concentrations of 15 and 20 µM for S phases and all TQ values for G2/M phases. The TQ effect on the apoptotic gene profiles indicated that TQ upregulated 15 apoptotic genes in MDA-MB-231 TNBC cells, including caspases, GADD45A, TP53, DFFA, DIABLO, BNIP3, TRAF2/3, and TNFRSF10A. In MDA-MB-468 cells, 16 apoptotic genes were upregulated, including TNFRSF10A, TNF, TNFRSF11B, FADD TNFRSF10B, CASP2, and TRAF2, all of which are important for the apoptotic pathway andsuppress the expression of one anti-apoptotic gene, BIRC5, in MDA-MB-231 cells. Compared to MDA-MB-231 cells, elevated levels of TNF and their receptor proteins may contribute to their increased sensitivity to TQ-induced apoptosis. It was concluded from this study that TQ targets the MDA-MB-231 and MDA-MB-468 cells differently. Additionally, due to the aggressive nature of TNBC and the lack of specific therapies in chemoresistant TNBC, our findings related to the identified apoptotic gene profile may point to TQ as a potential agent for TNBC therapy.