A strain of Enterococcusfaecalis (A256) was isolated from the urine of a patient with urinary sepsis and was found to exhibit susceptibilities (micrograms per milliliter) to various glycopeptides as follows: vancomycin, 256; teicoplanin, 16; 62208, 512; 62211, 4; and 62476, 16. As judged by growth rates before and after exposure to sub-MICs of glycopeptides, vancomycin and 62476 induced self-resistance, 62208 and 62211 induced slight self-resistance, and teicoplanin did not induce self-resistance. Vancomycin induced cross-resistance to all other glycopeptides tested, as judged both in growth experiments and by direct measurement of inhibition of peptidoglycan synthesis in cells exposed to sub-MICs of vancomycin. Thus, the spectra of activity of the glycopeptides were not correlated with their patterns of induction. There was a correlation between the increased synthesis of a 39-kilodalton (kDa) protein located in the cytoplasmic membrane and the induction of resistance. Protoplasts of A256 were susceptible to inhibition of peptidoglycan synthesis by vancomycin at levels similar to those for susceptible strains. Vancomycin resistance was transferable on filters from the parent strain to E. faecalis JH2-2 at a frequency of about 10-7, and the 39-kDa protein was also inducible by glycopeptides in these transconjugants. We conclude that A256 is resistant to glycopeptides by virtue of the synthesis of a 39-kDa cytoplasmic membrane protein, that this protein is probably involved in preventing access of the glycopeptides to their peptidoglycan targets, and that this resistance is transferable, probably by conjugation.Enterococcus faecalis and E. faecium are common causes of infection in humans (6, 19). These infections can be difficult to treat because of the degree of antibiotic resistance normally conferred to these strains by chromosomal or plasmid-borne determinants (12,16). This appears to be especially true for E. faecium, which tends to be more resistant to aminoglycoside-beta-lactam synergy than E. faecalis (16). For strains with high levels of beta-lactam resistance or when beta-lactams are poorly tolerated by the patient, glycopeptide antibiotics, mainly vancomycin, have been used in treatment with favorable results. A new glycopeptide, teicoplanin, is in clinical trials in the United States and Europe (14). Recently, reports of glycopeptide-resistant enterococcal strains have appeared in the literature (11,13,22). Two such strains of E. faecium with transferable, plasmid-mediated, glycopeptide resistance have been described (13). In the latter study, for Streptococcuis sanquis strains carrying the plasmids but not for the enterococcal parent strains, glycopeptide MICs were shown to be increased after preexposure to low concentrations of glycopeptides, suggesting inducible resistance. We here present data regarding the mechanism of resistance in a glycopeptide-resistant strain of E. faecalis, A256. MATERIALS AND METHODSBacterial strains. A256 is an E. faecalis strain isolated from the urine of a patient wit...

Background Previous studies have shown modest impact of tyrosine kinase inhibitors on primary renal tumors. These studies were mostly retrospective and heterogeneous in their eligibility criteria with regards to histology, disease stage, duration of therapy, and time off therapy prior to surgery. Objective To prospectively investigate the safety and efficacy of axitinib in downsizing tumors in patients with non-metastatic biopsy-proven clear cell renal cell carcinoma (ccRCC). Design, Setting, and Participants This is a single-institutional, single-arm phase 2 clinical trial. Patients with locally-advanced non-metastatic biopsy-proven ccRCC were eligible. This trial was registered with clinicaltrials.gov(NCT01263769). Intervention Patients received axitinib 5mg for up to 12 weeks. Axitinib was continued until 36 hours prior to surgery. Patient underwent partial or radical nephrectomy after axitinib therapy. Outcome Measurements and Statistical Analysis The primary outcome was objective response rate prior to surgery. Secondary outcomes included safety, tolerability, and quality of life. A dedicated radiologist independently reviewed all CT scans to evaluate for response using RECIST. Results and Limitations Twenty-four patients were treated. 22 patients continued axitinib for 12 weeks, while 1 patient continued axitinib for 11 weeks, and underwent surgery as planned. One patient stopped treatment at 7 weeks due to adverse events. Median reduction of primary renal tumor diameter was 28.3%. Eleven patients experienced a partial response by RECIST; 13 had stable disease. There was no progression of disease while on axitinib. The most common AEs were hypertension, fatigue, oral mucositis, hypothyroidism, and hand-foot syndrome. Postoperatively, 2 grade 3 and 13 grade 2 complications were noted. No grade 4 or 5 complications occurred. FKSI (Functional Assessment of Cancer Therapy-Kidney Specific Index-15) changed over time, with quality of life worsening while on therapy, but by week 19, it was not statistically different from screening. Limitations include single-arm design and small patient numbers. Conclusions Axitinib was clinically active and reasonably well tolerated in the neoadjuvant setting in patients with locally-advanced non-metastatic ccRCC.

Other targeted agents are effective salvage treatments after sorafenib failure, despite similar mechanisms of action, and should be offered to patients who are able to receive salvage therapy.

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Although vulvar cancer is diagnosed clinically, cross-sectional imaging plays an important complimentary role in staging of the tumor, assessing extent of disease, and selecting operable versus inoperable candidates to ultimately help in decreasing morbidity and increasing survival in these patients.