We report a phase II study of 50 advanced non-small cell lung cancer (NSCLC) patients with point mutations or insertions in EGFR exon 20 treated with poziotinib (NCT03066206). The study achieved its ...primary endpoint, with confirmed objective response rates (ORRs) of 32% and 31% by investigator and blinded independent review, respectively, with a median progression-free survival of 5.5 months. Using preclinical studies, in silico modeling, and molecular dynamics simulations, we found that poziotinib sensitivity was highly dependent on the insertion location, with near-loop insertions (amino acids A767 to P772) being more sensitive than far-loop insertions, an observation confirmed clinically with ORRs of 46% and 0% observed in near versus far-loop, respectively (p = 0.0015). Putative mechanisms of acquired resistance included EGFR T790M, MET amplifications, and epithelial-to-mesenchymal transition (EMT). Our data demonstrate that poziotinib is active in EGFR exon 20-mutant NSCLC, although this activity is influenced by insertion location.
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•Poziotinib yields a 32% response rate in EGFR exon 20-mutant NSCLC•Poziotinib sensitivity is highly dependent on insertion location•Near-loop exon 20 insertions are more sensitive to poziotinib than far-loop insertions•Mechanisms of acquired poziotinib resistance include EGFR T790M and MET amplifications
Elamin et al. show that poziotinib is active in EGFR exon 20-mutant non-small cell lung cancer. The activity of poziotinib is influenced by insertion location in exon 20, with near-loop insertion being more sensitive than far-loop insertion. Poziotinib acquired resistance is mediated via EGFR-dependent and -independent mechanisms.
This study explored the biologic response of chondrocytes and mesenchymal stem cells (MSCs) to a dynamic mechanical loading regime. We developed a time-efficient methodology for monitoring regional ...changes in extracellular matrix gene transcription using reporter promoter constructs. Specifically, transfected cells were homogenously distributed throughout agarose hydrogel constructs, and spatial and temporal gene expression and the ability to form functional ECM were analyzed in response to dynamic mechanical stimuli. Theoretical analyses were used to predict the physical signals generated within the gel in response to these loading regimes. Using a custom compression bioreactor system, changes in aggrecan and type II collagen promoter activity in transfected chondrocyte-laden cylindrical constructs were evaluated in response to a range of loading frequencies and durations. In general, aggrecan promoter activity increased with increasing duration of loading, particularly in the outer annulus region. Interestingly, type II collagen promoter activity decreased in this annular region under identical loading conditions. In addition, we explored the role of mechanical compression in directing chondrogenic differentiation of MSCs by monitoring short-term aggrecan promoter activity. As an example of long-term utility, a specific loading protocol was applied to MSC-laden constructs for 5 days, and the resultant changes in glycosaminoglycan (GAG) production were evaluated over a 4-week period. This dynamic loading regime increased not only short-term aggrecan transcriptional activity but also GAG deposition in long-term culture. These results demonstrate the utility of a new reporter promoter system for optimizing loading protocols to improve the outcome of engineered chondrocyte- and MSC-laden cartilaginous constructs.
Aliment Pharmacol Ther 2011; 33: 194–202
Summary
Background Andrographis paniculata is an herbal mixture used to treat inflammatory diseases. An extract of the herb, HMPL‐004, inhibits TNF‐α and ...IL‐1β, and prevents colitis in animal models.
Aim To determine the efficacy and safety of HMPL‐004 in patients with mild‐to‐moderate ulcerative colitis.
Methods A randomised, double‐blind, multicentre, 8‐week parallel group study was conducted using HMPL‐004 1200 mg/day compared with 4500 mg/day of slow release mesalazine (mesalamine) granules in patients with mild‐to‐moderately active ulcerative colitis. Disease activity was assessed at baseline and every 2 weeks for clinical response, and at baseline and 8 weeks by colonoscopy.
Results One hundred and twenty patients at five centres in China were randomised and dosed. Clinical remission and response were seen in 21% and 76% of HMPL‐004‐treated patients, and 16% and 82% of mesalazine‐treated patients. By colonoscopy, remission and response were seen in 28% and 74% of HMPL‐004‐treated patients and 24% and 71% of mesalazine‐treated patients, respectively. There was no significant difference between the two treatment groups.
Conclusion HMPL‐004 may be an efficacious alternative to mesalazine in ulcerative colitis.
Background & Aims:
Colonoscopic polypectomy is considered effective for preventing colorectal cancer (CRC), but the incidence of cancer in patients under colonoscopic surveillance has rarely been ...investigated. We determined the incidence of CRC in patients under colonoscopic surveillance and examined the circumstances and risk factors for CRC and adenoma with high-grade dysplasia.
Methods:
Patients were drawn from 3 adenoma chemoprevention trials. All underwent baseline colonoscopy with removal of at least one adenoma and were deemed free of remaining lesions. We identified patients subsequently diagnosed with invasive cancer or adenoma with high-grade dysplasia. The timing, location, and outcome of all cases of cancer and high-grade dysplasia identified are described and risks associated with their development explored.
Results:
CRC was diagnosed in 19 of the 2915 patients over a mean follow-up of 3.7 years (incidence, 1.74 cancers/1000 person-years). The cancers were located in all regions of the colon; 10 were at or proximal to the hepatic flexure. Although most of the cancers (84%) were of early stage, 2 participants died of CRC. Seven patients were diagnosed with adenoma with high-grade dysplasia during follow-up. Older patients and those with a history of more adenomas were at higher risk of being diagnosed with invasive cancer or adenoma with high-grade dysplasia.
Conclusions:
CRC is diagnosed in a clinically important proportion of patients following complete colonoscopy and polypectomy. More precise and representative estimates of CRC incidence and death among patients undergoing surveillance examinations are needed.
Laboratory and epidemiological data suggest that folic acid may have an antineoplastic effect in the large intestine.
To assess the safety and efficacy of folic acid supplementation for preventing ...colorectal adenomas.
A double-blind, placebo-controlled, 2-factor, phase 3, randomized clinical trial conducted at 9 clinical centers between July 6, 1994, and October 1, 2004. Participants included 1021 men and women with a recent history of colorectal adenomas and no previous invasive large intestine carcinoma.
Participants were randomly assigned in a 1:1 ratio to receive 1 mg/d of folic acid (n = 516) or placebo (n = 505), and were separately randomized to receive aspirin (81 or 325 mg/d) or placebo. Follow-up consisted of 2 colonoscopic surveillance cycles (the first interval was at 3 years and the second at 3 or 5 years later).
The primary outcome measure was occurrence of at least 1 colorectal adenoma. Secondary outcomes were the occurrence of advanced lesions (> or =25% villous features, high-grade dysplasia, size > or =1 cm, or invasive cancer) and adenoma multiplicity (0, 1-2, or > or =3 adenomas).
During the first 3 years, 987 participants (96.7%) underwent colonoscopic follow-up, and the incidence of at least 1 colorectal adenoma was 44.1% for folic acid (n = 221) and 42.4% for placebo (n = 206) (unadjusted risk ratio RR, 1.04; 95% confidence interval CI, 0.90-1.20; P = .58). Incidence of at least 1 advanced lesion was 11.4% for folic acid (n = 57) and 8.6% for placebo (n = 42) (unadjusted RR, 1.32; 95% CI, 0.90-1.92; P = .15). A total of 607 participants (59.5%) underwent a second follow-up, and the incidence of at least 1 colorectal adenoma was 41.9% for folic acid (n = 127) and 37.2% for placebo (n = 113) (unadjusted RR, 1.13; 95% CI, 0.93-1.37; P = .23); and incidence of at least 1 advanced lesion was 11.6% for folic acid (n = 35) and 6.9% for placebo (n = 21) (unadjusted RR, 1.67; 95% CI, 1.00-2.80; P = .05). Folic acid was associated with higher risks of having 3 or more adenomas and of noncolorectal cancers. There was no significant effect modification by sex, age, smoking, alcohol use, body mass index, baseline plasma folate, or aspirin allocation.
Folic acid at 1 mg/d does not reduce colorectal adenoma risk. Further research is needed to investigate the possibility that folic acid supplementation might increase the risk of colorectal neoplasia.
clinicaltrials.gov Identifier: NCT00272324.
The prompt gamma activation analysis (PGAA) facility at the Nuclear Engineering Teaching Laboratory at The University of Texas at Austin was utilized to quantify boron concentrations in boron carbide ...semiconductor films deposited on silicon substrates. Calibration was complicated by the unique and varying sample geometries analyzed. In addition, there was a dearth of solid materials available with quantified boron concentrations having comparable or readily modifiable dimensions to exploit for calibration purposes. Therefore, a novel hybrid comparator method was developed for the quantification of boron utilizing aluminum as an inexpensive and easily machinable reference material. Aluminum samples were manufactured with high tolerances to match the geometry of each sample of interest. Each boron carbide film sample and its congruent aluminum sample were measured in the PGAA system. The measured aluminum responses and relevant nuclear parameters were used to standardize the measurements. A boron standard was created using a procedure derived from a similar approach used by the National Institute of Standards and Technology. Quality control measurements using this standard show that the method provided accuracy to within 5% for boron quantification.
BACKGROUND: Persistent hyperglycemia is common in alpacas and typically requires insulin administration for resolution; however, little is known about alpacas’ response to different insulin ...formulations. OBJECTIVES: To evaluate the effects of 3 insulin formulations on blood glucose concentrations and the use of a continuous glucose monitoring (CGM) system in alpacas. ANIMALS: Six healthy alpacas. METHODS: The CGM was installed in the left paralumbar fossa at the start of this crossover study and recorded data every 5 minutes. Regular insulin, NPH insulin, insulin glargine, and dextrose were administered to each alpaca over a 2‐week period. Blood samples were collected for glucose testing at 0, 1, 2, 4, 6, 8, and 12 hours, and then every 6 hours after each administration of insulin or dextrose. Data were compared by using method comparison techniques, error grid plots, and ANOVA. RESULTS: Blood glucose concentrations decreased most rapidly after regular insulin administration when administered IV or SC as compared to the other formulations. The NPH insulin produced the longest suppression of blood glucose. The mean CGM interstitial compartment glucose concentrations were typically lower than the intravascular compartment glucose concentrations. The alpacas had no adverse reactions to the different insulin formulations. CONCLUSIONS AND CLINICAL IMPORTANCE: The NPH insulin might be more appropriate for long‐term use in hyperglycemic alpacas because of its extended duration of action. A CGM is useful in monitoring glucose trends and reducing blood collection events, but it should not be the sole method for determining treatment protocols.
Background
Infection control is critical to providing high‐quality patient care. Many veterinary teaching hospitals (VTHs) utilize footbaths or footmats at entrances and key control points throughout ...the facility to decrease trafficking of pathogenic microorganism on contaminated footwear.
Hypothesis/Objectives
To compare efficacy of 4 disinfectants used in footmats for decreasing bacterial contamination of footwear in a large animal hospital.
Animals
A single adult dairy cow was housed in a stall for 4 days to facilitate stall contamination with fecal material.
Methods
Overboots were experimentally contaminated with organic material in a standardized manner. Each boot was randomly assigned to 1 of 5 treatments (no treatment, or exposure to 1 of 4 disinfectants: an accelerated peroxygen AHP, a peroxygen VIRKON, a quaternary ammonium QUAT, and a phenolic disinfectant PHENOLIC) by stepping on a soaked footmat and collecting samples from boot soles. Generalized linear modeling was used to analyze differences in bacterial counts.
Results
Reductions in colony‐forming units (CFUs) on treated boots ranged from no detectable reduction to 0.45 log10 and varied by disinfectant. Percentage reductions in total bacterial counts generally were larger (albeit still modest) for AHP and QUAT disinfectants (range 37–45%) and smallest for the PHENOLIC (no detectable reduction).
Conclusions and Clinical Importance
In general, use of disinfectant footmats was associated with significant reductions in viable bacteria on overboots—albeit with variable efficacy. Footmats may be useful adjuncts to cleaning and disinfection programs for decreasing trafficking of microorganisms throughout VTHs but should not be considered as a sole prevention method.
Less sensitive (LS) HIV-1 enzyme immunoassays (EIAs) have significantly improved the quantity and quality of HIV surveillance data. The first LS-HIV-1 EIA, the Abbott 3A11-LS, provided reliable ...incidence data, but the assay required specialized equipment, and the lack of available reagents made testing difficult. This study evaluated the use of an alternate assay, a modified version of the Vironostika HIV-1 EIA (Vironostika-LS), to be used for LS testing. The Vironostika-LS has similar performance characteristics to the Abbott 3A11-LS with additional advantages. This 96-well formatted assay is commonly found in public health laboratories for routine HIV-1 testing and can be used with both serum and dried blood spot specimens. The estimated mean time from seroconversion (defined using a standardized optical density cutoff of 1.0) with the Vironostika-LS was 170 days (95% CI, 145-200 days). When the Vironostika-LS was applied to a matched serum set previously tested with the Abbott 3A11-LS, the Vironostika-LS accurately identified 97% of specimens with recent or long-standing HIV infection. The paper also reports Vironostika-LS quality control guidelines and the results from 3 rounds of proficiency testing.
To assess the efficacy of the analgesic technique and the incidence of complications, we prospectively evaluated patients who received intrathecal opioid analgesia (ITOA) to manage postsurgical pain. ...Daily quality assurance data were collected on the first postoperative day and tabulated for 5969 adult patients who had received ITOA for major urologic, orthopedic, general/ vascular, thoracic, and nonobstetrical gynecologic surgery. A scale of 1-10 was used to quantify each patient's satisfaction with analgesia. The incidence of side effects, complications, and naloxone usage was also recorded and tabulated. The mean satisfaction score using a 10-point numeric rating scale was 8.51, with a score of 1 connoting "complete dissatisfaction" and 10 connoting "complete satisfaction." Side effects were minor and easily managed. Pruritus was the most common (37%). Respiratory depression was the least common (3%), easily detected by nursing observation, never life-threatening, and always responsive to treatment with naloxone. There were no deaths, nerve injuries, central nervous system infections, or naloxone-related complications. Postdural puncture headaches were rare (0.54%), as was the need for epidural blood patch (0.37%).
Over a 7-yr period, intrathecal opioid analgesia was used to control acute postoperative pain on nearly 6000 patients, resulting in a high degree of patient satisfaction and a low incidence of side effects and complications.
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