Dual EGFR inhibition in combination with anti-VEGF treatment: a phase I clinical trial in non-small cell lung cancer.

BackgroundPreclinical data indicate EGFR signals through both kinase-dependent and independent pathways and that combining a small-molecule EGFR inhibitor, EGFR antibody, and/or anti-angiogenic agent is synergistic in animal models.MethodsWe conducted a dose-escalation, phase I study combining erlotinib, cetuximab, and bevacizumab. The subset of patients with non-small cell lung cancer (NSCLC) was analyzed for safety and response.ResultsThirty-four patients with NSCLC (median four prior therapies) received treatment on a range of dose levels. The most common treatment-related grade ≥2 adverse events were rash (n=14, 41%), hypomagnesemia (n=9, 27%), and fatigue (n=5, 15%). Seven patients (21%) achieved stable disease (SD) ≥6 months, two achieved a partial response (PR) (6%), and two achieved an unconfirmed partial response (uPR) (6%) (total=32%). We observed SD≥6 months/PR/uPR in patients who had received prior erlotinib and/or bevacizumab, those with brain metastases, smokers, and patients treated at lower dose levels. Five of 16 patients (31%) with wild-type EGFR experienced SD≥6 months or uPR. Correlation between grade of rash and rate of SD≥6 months/PR was observed (p less than 0.01).ConclusionThe combination of erlotinib, cetuximab, and bevacizumab was well-tolerated and demonstrated antitumor activity in heavily pretreated patients with NSCLC

Contributions of the Combined Effects of Topoisomerase Mutations toward Fluoroquinolone Resistance in Escherichia coli▿

In defined, isogenic strains, at least three mutations, two of which must be in gyrA, were required to exceed the CLSI breakpoint for fluoroquinolone resistance. Strains with double mutations in both gyrA and parC had even higher MICs of fluoroquinolones than strains with totals of three mutations

Attitudes of patients with cutaneous melanoma toward prognostic testing using the 31‐gene expression profile test

Abstract Objective Although most patients diagnosed with early‐stage cutaneous melanoma (CM) have excellent outcomes, because of the large number diagnosed each year, many will experience recurrence or death. Prognostic testing for CM using the 31‐gene expression profile (31‐GEP) test can benefit patients by helping guide risk‐appropriate treatment and surveillance plans. We sought to evaluate patients' attitudes toward prognostic testing with the 31‐GEP and assess whether patients experience decision regret about having 31‐GEP testing. Methods A 43‐question survey was distributed by the Melanoma Research Foundation in June–August 2021 to CM patients enrolled in their database. Patients were asked questions regarding their decision to undergo 31‐GEP testing and the extent to which they experienced decision regret using a validated set of Decision Regret Scale questions. Results We analyzed responses from patients diagnosed in 2014 or later (n  = 120). Of these, 28 had received 31‐GEP testing. Most respondents (n  = 108, 90%) desired prognostic information when diagnosed. Of those who received 31‐GEP testing, most felt the results were useful (n  = 22 out of 24) and had regret scores significantly less than neutral regret, regardless of their test results (Class 1: p  < 0.001; Class 2: p  = 0.036). Further, decision regret scores were not significantly different between patients who received a Class 1 31‐GEP result and those who received a Class 2 result (mean Class 1 = 1.39 and mean Class 2 = 1.90, p  = 0.058). Conclusions Most newly diagnosed CM patients desired prognostic information about their tumors. Patients who received 31‐GEP testing felt it was useful and did not regret their decision to undergo 31‐GEP testing

Relationships among Ciprofloxacin, Gatifloxacin, Levofloxacin, and Norfloxacin MICs for Fluoroquinolone-Resistant Escherichia coli Clinical Isolates▿

Fluoroquinolones are some of the most prescribed antibiotics in the United States. Previously, we and others showed that the fluoroquinolones exhibit a class effect with regard to the CLSI-established breakpoints for resistance, such that decreased susceptibility (i.e., an increased MIC) to one fluoroquinolone means a simultaneously decreased susceptibility to all. For defined strains, however, clear differences exist in the pharmacodynamic properties of each fluoroquinolone and the extent to which resistance-associated genotypes affect the MICs of each fluoroquinolone. In a pilot study of 920 clinical Escherichia coli isolates, we uncovered tremendous variation in norfloxacin MICs. The MICs for all of the fluoroquinolone-resistant isolates exceeded the resistance breakpoint, reaching 1,000 μg/ml. Approximately 25% of the isolates (n = 214), representing the full range of resistant norfloxacin MICs, were selected for the simultaneous determinations of ciprofloxacin, gatifloxacin, levofloxacin, and norfloxacin MICs. We found that (i) great MIC variation existed for all four fluoroquinolones, (ii) the ciprofloxacin and levofloxacin MICs of >90% of the fluoroquinolone-resistant isolates were higher than the resistance breakpoints, (iii) ciprofloxacin and levofloxacin MICs were distributed into two distinct groups, (iv) the MICs of two drug pairs (ciprofloxacin and norfloxacin by Kendall's Tau-b test and gatifloxacin and levofloxacin by paired t test) were similar with statistical significance but were different from each other, and (v) ∼2% of isolates had unprecedented fluoroquinolone MIC relationships. Thus, although the fluoroquinolones can be considered equivalent with regard to clinical susceptibility or resistance, fluoroquinolone MICs differ dramatically for fluoroquinolone-resistant clinical isolates, likely because of differences in drug structure