Synthesis and preclinical evaluation of novel 18F-vancomycin-based tracers for the detection of bacterial infections using positron emission tomography.

INTRODUCTION: Bacterial infections are a major problem in medicine, and the rapid and accurate detection of such infections is essential for optimal patient outcome. Bacterial infections can be diagnosed by nuclear imaging, but most currently available modalities are unable to discriminate infection from sterile inflammation. Bacteria-targeted positron emission tomography (PET) tracers have the potential to overcome this hurdle. In the present study, we compared three 18F-labelled PET tracers based on the clinically applied antibiotic vancomycin for targeted imaging of Gram-positive bacteria. METHODS: [18F]FB-NHS and [18F]BODIPY-FL-NHS were conjugated to vancomycin. The resulting conjugates, together with our previously developed [18F]PQ-VE1-vancomycin, were tested for stability, lipophilicity, selective binding to Gram-positive bacteria, antimicrobial activity and biodistribution. For the first time, the pharmacokinetic properties of all three tracers were compared in healthy animals to identify potential binding sites. RESULTS: [18F]FB-vancomycin, [18F]BODIPY-FL-vancomycin, and [18F]PQ-VE1-vancomycin were successfully synthesized with radiochemical yields of 11.7%, 2.6%, and 0.8%, respectively. [18F]FB-vancomycin exhibited poor in vitro and in vivo stability and, accordingly, no bacterial binding. In contrast, [18F]BODIPY-FL-vancomycin and [18F]PQ-VE1-vancomycin showed strong and specific binding to Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA), which was outcompeted by unlabeled vancomycin only at concentrations exceeding clinically relevant vancomycin blood levels. Biodistribution showed renal clearance of [18F]PQ-VE1-vancomycin and [18F]BODIPY-FL-vancomycin with low non-specific accumulation in muscles, fat and bones. CONCLUSION: Here we present the synthesis and first evaluation of the vancomycin-based PET tracers [18F]BODIPY-FL-vancomycin and [18F]PQ-VE1-vancomycin for image-guided detection of Gram-positive bacteria. Our study paves the way towards real-time bacteria-targeted diagnosis of soft tissue and implant-associated infections that are oftentimes caused by Gram-positive bacteria, even after prophylactic treatment with vancomycin.

Successful Implementation of a Multidisciplinary Chemotherapy Efficiency Initiative at a Community Hospital.

PURPOSE: Long wait times at chemotherapy infusion centers adversely affect patients' perception of quality of care and result in patient dissatisfaction. We conducted a quality improvement initiative at a busy community hospital to improve infusion center efficiency and reduce patient wait time, while maintaining patient safety and avoiding chemotherapy waste. METHODS: We used a coordinated and collaborative effort between providers, infusion center nurses, and pharmacists to ensure completion of orders, review of laboratory data, and prepreparation of chemotherapy 1 day ahead of each patient's scheduled infusion center appointment. Monthly Plan-Do-Study-Act cycles were conducted for 6 months beyond the pilot month to refine and sustain the intervention. RESULTS: The average patient cycle time, measured as time from patient check-in to check-out from the infusion chair, decreased from 252 minutes to 173 minutes in the last 4 months evaluated (30% decrease) after the intervention. Similarly, the average chemotherapy turnaround time, measured as time from chemotherapy request by nursing to pharmacy delivery, improved from 90 minutes to 27 minutes after the intervention (70% decrease). Infusion center capacity was unaffected by the intervention. The cost of wasted chemotherapy was minimal after the first postintervention month. Surveys revealed extremely high patient and employee satisfaction with the new system. CONCLUSION: A strategy involving prepreparation of chemotherapy on the day before the scheduled infusion is feasible to implement at a busy community hospital infusion center and is associated with significant improvement in infusion center efficiency as well as patient and employee satisfaction.

Stress hormones reduce the efficacy of paclitaxel in triple negative breast cancer through induction of DNA damage.

BACKGROUND: The mechanisms by which stress hormones impact triple-negative breast cancer (TNBC) etiology and treatment are unclear. We have previously shown that stress hormones, cortisol, and catecholamines induce rapid DNA damage and impact DNA repair in NIH 3T3 fibroblasts. This study investigates whether stress hormones increase DNA damage in breast cancer cells and if this impacts drug efficacy. METHODS: We first screened a panel of 39 breast cancer cell lines for expression of adrenergic and glucocorticoid receptors and examined if stress hormones induce DNA damage and alter cell cycle regulation in vitro. A TNBC xenograft model was used to assess the impact of restraint stress on tumour growth and chemosensitivity to paclitaxel. RESULTS: We found that stress hormones induced DNA damage, phosphorylation of ATR, which was accompanied by an up-regulation of the G1 cell kinase inhibitor p21 and a cell cycle halt of TNBCs in the G1 phase. p21 knockdown abrogated G1 arrest by stress hormones. We also demonstrated that stress significantly decreased efficacy of paclitaxel. CONCLUSION: We describe a novel mechanism through which stress hormones can induce drug resistance to paclitaxel, which may have profound implications for treating drug resistance in patients with TNBC.

Automated pain intervention for underserved minority women with breast cancer.

BACKGROUND: Minority patients with breast cancer are at risk for undertreatment of cancer-related pain. The authors evaluated the feasibility and efficacy of an automated pain intervention for improving pain and symptom management of underserved African American and Latina women with breast cancer. METHODS: Sixty low-income African American and Latina women with breast cancer and cancer-related pain were enrolled in a pilot study of an automated, telephone-based, interactive voice response (IVR) intervention. Women in the intervention group were called twice weekly by the IVR system and asked to rate the intensity of their pain and other symptoms. The patients' oncologists received e-mail alerts if the reported symptoms were moderate to severe. The patients also reported barriers to pain management and received education regarding any reported obstacles. RESULTS: The proportion of women in both groups reporting moderate to severe pain decreased during the study, but the decrease was significantly greater for the intervention group. The IVR intervention also was associated with improvements in other cancer-related symptoms, including sleep disturbance and drowsiness. Although patient adherence to the IVR call schedule was good, the oncologists who were treating the patients rated the intervention as only somewhat useful for improving symptom management. CONCLUSIONS: The IVR intervention reduced pain and symptom severity for underserved minority women with breast cancer. Additional research on technological approaches to symptom management is needed.

Breast mass or sternalis muscle?

This is the first description of the sternalis muscle being found among the cadavers used during the last two decades in the dissection laboratories of the San Juan Bautista School of Medicine.