Citations

Susceptibility tests using 7 antimicrobial agents (carbenicillin, chloramphenicol, clindamycin, penicillin, cephalothin, metronidazole, and tetracycline) were run against 35 anaerobes including Bacteroides fragilis (17), other gram-negative bacilli (7), clostridia (5), peptococci (4), and eubacteria (2). Results in triplicate obtained by the microbroth dilution method and the aerobic modification of the broth disk method were compared with those obtained with an agar dilution method using Wilkins-Chalgren agar. Media used in the microbroth dilution method included Wilkins-Chalgren broth, brain heart infusion broth, brucella broth, tryptic soy broth, thioglycolate broth, and Schaedler's broth. A result differing by more than one dilution from the Wilkins-Chalgren agar result was considered a discrepancy, and when there was a change in susceptibility status this was termed a significant discrepancy. The microbroth dilution method using Wilkins-Chalgren broth and thioglycolate broth produced the fewest total discrepancies (22 and 24, respectively), and Wilkins-Chalgren broth, thioglycolate, and Schaedler's broth had the fewest significant discrepancies (6, 5, and 5, respectively). With the broth disk method, there were 15 significant discrepancies, although half of these were with tetracycline, which was the antimicrobial agent associated with the highest number of significant discrepancies (33), considering all of the test methods and media.

Abstract Mesenchymal Stem Cells (MSCs) have the ability to migrate specifically to tumours in vivo, and coupled with their capacity to bypass immune surveillance, are potentially attractive vehicles for tumor-targeted delivery of therapeutic agents. The aim of this study was to determine the potential of MSC-mediated expression of the sodium iodide symporter (NIS) for in vivo imaging and therapy of breast tumours. Expression of NIS allows cells to concentrate radionuclides including technetium-99m (Tc-99m) and 131-Iodine (131-I). This could potentially support imaging of NIS-expressing MSCs following engraftment, and 131-I therapy of surrounding tumour tissue based on the bystander effect of the radionuclide. Methods: Tumor bearing animals (MDA-MB-231 flank) were given an intravenous or intratumoral injection of NIS expressing human MSCs (MSC-NIS), followed by imaging 3, 7, 10 or 14 days later. Imaging was performed using a Bazooka SPECT γ-camera, following intraperitoneal injection of 2mCi/74MBq Tc-99m. Following imaging, animals were sacrificed and organs harvested for analysis of hNIS expression by RQ-PCR. A second group of animals received an intraperitoneal injection of 1mCi/37MBq 131-I or saline (controls) 14 days following intratumoral or intravenous injection of MSC-NIS, and tumour volume was tracked for 8 weeks. Results: Bazooka SPECT imaging of animals revealed uptake of tracer (Tc-99m) in the mouse thyroid/salivary glands and stomach, representing native NIS expression. Following injection of MSC-NIS, an image of animal intestines was also observed at D3, with a weak image of the tumour also visible. By Day14, uptake of tracer was visible at the site of the tumour with no significant image of non-target tissue observed. Expression of hNIS in harvested organs supported the imaging data, with hNIS detected in the intestines, heart, lungs and tumour at early timepoints. While NIS expression depleted in non-target tissues by D7, gene expression persisted at the tumour site. Based on imaging/biodistribution data, animals were given a therapeutic dose of 131-I 14 days following MSC-NIS injection to avoid toxicity to non-target organs. No adverse effect of injection of MSC-NIS or radionuclide was observed. Tracking of tumour volume revealed a significant reduction in tumour growth in animals that had received an intravenous injection of 131-I 14days following MSC-NIS injection (Mean ± SEM, 236 ± 62mm3 versus 665 ± 204 mm3 in controls). Following intratumoral injection of MSC-NIS + 131-I, although tumour size was reduced compared to controls (472 ± 80 mm3), the difference in volume was not significant. Conclusion: The ability to non-invasively track MSC migration and transgene expression in real time prior to therapy is a major advantage to this strategy. This promising data supports the viability of this approach as a novel therapy for metastatic breast cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5392. doi:10.1158/1538-7445.AM2011-5392

Abstract Rare germline mutations in the breast and ovarian cancer predisposition genes BRCA1 and BRCA2 are present in roughly 5 percent of ovarian cancer patients. Both genes play key roles in DNA damage repair but appear to have distinct, although often complementary, functions. The risks of breast and ovarian cancer have been shown to differ between BRCA1 and BRCA2 carriers, and mutation-specific effects have also been suggested for both groups. Published reports comparing the survival of ovarian cancer patients with and without BRCA1/2 mutations generally show a survival advantage among mutation carriers. This is thought to be related to an improved response of carriers to platinum-based therapies. Since it is not known whether BRCA1 and BRCA2 carriers show similar survival patterns, we have performed a large, multicenter study to investigate the impact of germline BRCA1 and BRCA2 mutations on ovarian cancer survival. 3,531 invasive epithelial ovarian cancer cases (1,178 BRCA1, 367 BRCA2 and 1,986 BRCA-negative) with survival time data from twenty-four studies in the U.S.A, Europe, Israel and Asia were included. In our main analysis, we excluded patients who were known or who were likely to have not received platinum-based therapy. Compared to non-carriers, BRCA1 and BRCA2 carriers were more likely to present with advanced stage (BRCA1; p=2×10−4, BRCA2; p=4×10−6), high grade (BRCA1; p=4×10−9, BRCA2; p=1×10−4), serous disease (BRCA1; p=3×10−6, BRCA2; p=0.003). BRCA1 carriers were younger at diagnosis (p=2×10−9) and BRCA2 slightly older at diagnosis (p=0.002) than non-carriers. BRCA1 and BRCA2 carriers did not differ in terms of tumor stage, grade or histology but did show differences in the age at diagnosis (p=2×10−14). In an unadjusted analysis, neither BRCA1 nor BRCA2 carriers differed from non-carriers in overall survival (BRCA1: HR=1.02, p=0.77, BRCA2: HR=0.89, p=0.36). After adjusting for stage, grade, histology and age at diagnosis, BRCA1 carriers showed a modest, non-significant, survival advantage (HR=0.84, p=0.12) while BRCA2 carriers showed a marked improvement (HR=0.57, p=6×10−4) compared to non-carriers. This survival advantage was also seen when comparing BRCA2 carriers to BRCA1 carriers after adjustment for age at diagnosis (HR=0.69, p=5×10−4). Similar results were obtained when we restricted the analysis to high grade, advanced stage, serous cases. The survival differences we observed between BRCA1 and BRCA2 carriers could be related to differences in tumor biology or chemo-sensitivity. Additional analyses investigating the later will be presented in addition to mutation-specific effects within BRCA1 and BRCA2. In this study, we provide strong evidence for genetic heterogeneity of survival effects in ovarian cancer patients with BRCA mutations. This could be applied to both clinical prediction and to aid our understanding of the complex biology of BRCA mutations. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2752. doi:10.1158/1538-7445.AM2011-2752