Estimating the magnitude of clinical benefit of local therapy in patients with DCIS.

DCIS represents a heterogeneous disease with a wide range of outcomes according to biology. Without treatment, it is estimated that only 20-30% of DCIS will progress to invasive cancer. Long-term outcomes following treatment are at least as favorable as those for some other early stage cancer types such as prostate cancer, for which active surveillance is routinely offered as a standard of care option. However, active surveillance has not yet been tested in relation to DCIS. Worldwide, there are three international trials (LORIS, COMET, LORD) which are evaluating whether DCIS with favorable biologic features may be managed with close monitoring, with treatment only undertaken upon disease progression. These trials will determine whether there may be some women with low-risk DCIS who do not substantially benefit from treatment and who could thus be safely managed with close surveillance. If active monitoring for DCIS is deemed to be safe and feasible, additional work must be done to optimally implement this approach, involving effective communication between patients and their physicians about the risks and benefits of treatment versus surveillance. Importantly, these treatment decisions must take into account patient factors such as risk tolerance, age, and competing causes of mortality. Tailoring treatment to biology for early screen-detected cancers such as DCIS is an important goal of ongoing research. An improved understanding of the biology and clinical implications of this heterogeneous disease will improve the overall health and quality of life for hundreds of thousands of future women who will be diagnosed with DCIS.

Analysis of the challenges in implementing guidelines to prevent the spread of multidrug-resistant gram-negatives in Europe.

OBJECTIVE: The main objective of the study was to investigate major differences among European countries in implementing infection prevention and control (IPC) measures and reasons for reduced compliance. DESIGN: An online survey including experts in IPC and a gap analysis were conducted to identify major limitations in implementing IPC guidelines. SETTING: Europe. MAIN OUTCOME MEASURES: Four areas were targeted: (1) healthcare structure, (2) finances, (3) culture and (4) education and awareness. Perceived compliance to IPC measures was classified as low (<50%), medium (50% to 80%) and high (>80%). Countries were classified in three regions: North-Western Europe (NWE), Eastern Europe (EE) and Southern Europe (SE). RESULTS: In total, 482 respondents from 34 out of 44 (77.3%) European countries participated. Respondents reported availability of national guidelines to control multidrug-resistant Gram-negatives (MDR-GN) in 20 countries (58.0%). According to participants, compliance with IPC measures ranged from 17.8% (screening at discharge) to 96.0% (contact precautions). Overall, three areas were identified as critical for the compliance rate: (1) number of infection control staff, (2) IPC dedicated educational programmes and (3) number of clinical staff. Analysis of reasons for low compliance showed high heterogeneity among countries: participants from NWE and SE deemed the lack of educational programmes as the most important, while those from EE considered structural reasons, such as insufficient single bed rooms or lacking materials for isolation, as main contributors to the low compliance. CONCLUSIONS: Although national guidelines to reduce the spread of MDR-GN are reported in the majority of the European countries, low compliance with IPC measures was commonly reported. Reasons for the low compliance are multifactorial and vary from region to region. Cross-country actions to reduce the spread of MDR-GN have to consider structural and cultural differences in countries. Locally calibrated interventions may be fruitful in the future.

Treating urinary tract infections due to MDR E. coli with Isothiocyanates - a phytotherapeutic alternative to antibiotics?

BACKGROUND: Multidrug-resistant (MDR) bacteria are increasingly causing urinary tract infections (UTI), which has been linked to frequent use of antibiotics. Alternative treatment regimens are urgently needed and natural isothiocyanates (ITC) may represent one. ITCs are natural plant products found in nasturtium (Tropaeoli majoris herba) and horseradish (Armoraciae rusticanae radix). PURPOSE: The objectives were to (1) assess the antimicrobial effects of nature-identical ITCs for UTI treatment caused by uropathogenic E. coli (UPEC), (2) to evaluate a potential influence of antimicrobial resistance on ITC susceptibility, and (3) to test whether ITCs affect UPEC penetration into human uroepithelial cells. METHODS: We tested 217 clinical UPEC isolates, 54.5% of which were classified as MDR, for susceptibility against ITCs. ITC susceptibility testing was performed by broth dilution using a mixture of three synthetic ITCs. Internalization was tested using human T-24 bladder carcinoma cells in an internalization assay co-incubated with UPEC (n = 5) and ITCs. RESULTS: The mean minimal inhibitory concentration (MIC) 90 was 0.17 mg/ml, showing very high susceptibility against ITCs. Interestingly, MDR E. coli were significantly less susceptible than non-MDR strains (p = .01). Internalization of UPEC was decreased by 31.9% in the mean when treated with ITCs. Overall, ITCs exerted a strong antimicrobial activity against clinical UPEC isolates and reduced internalization into uroepithelial cells. CONCLUSION: ITCs might present a promising treatment alternative for UTIs, expressing both high antimicrobial activity as well as blocking the pathogenic process of human cell penetration by UPEC. Clinical studies, however, are needed to confirm activity of ITCs in UTIs in vivo.

Outcomes after hand and upper extremity transplantation.

Hand and upper extremity transplantation (HUET) has emerged as the most frequently performed reconstructive procedure in the burgeoning field of vascularized composite allotransplantation (VCA). VCA refers to a form of transplant with multiple tissue types that represents a viable treatment option for devastating injuries where conventional reconstruction would be unable to restore form and function. As hand transplantation becomes increasingly more common, discussions on advantages and disadvantages of the procedure seem to intensify. Despite encouraging functional outcomes, current immunosuppressive regimens with their deleterious side-effect profile remain a major concern for a life-changing but not life-saving type of transplant. In addition, a growing number of recipients with progressively longer follow-up prompt the need to investigate potential long-term sequelae, such as chronic rejection. This review will discuss the current state of HUET, summarizing outcome data on graft survival, motor and sensory function, as well as immunosuppressive treatment. The implications of these findings for VCA in terms of achievements and challenges ahead will then be discussed.

Split Tolerance in a Murine Model of Heterotopic En Bloc Chest Wall Transplantation.

BACKGROUND: Congenital and acquired chest wall deformities represent a significant challenge to functional reconstruction and may impact feasibility of heart transplantation for patients with end-stage organ failure. In the recent past, the concept of replacing like-with-like tissue by using vascularized composite allografts (VCA) has been enthusiastically employed for reconstruction of complex tissue defects. METHODS: In this study, we introduce a novel murine model for en bloc chest wall, heart, and thymus transplantation and thereby the use of complex tissue allografts for reconstruction of both chest wall defects and also end-stage organ failure. Additionally, this model allows us to study the features of combined vascularized bone marrow (VBM), thymus, and heart transplantation on allograft survival and function. Heterotopic chest wall, thymus, and heart transplants were performed in untreated syngeneic and allogeneic combinations and in allogeneic combinations treated with costimulation blockade (CTLA4-Ig and MR-1). RESULTS: Indefinite (ie, 150 d, N = 3) graft survival was observed in syngeneic controls. In untreated recipients of allogeneic grafts, the skin component was rejected after 10 (±1) days, whereas rejection of the heart occurred after 13 (± 1) days (N = 3). Costimulation blockade treatment prolonged survival of the heart and chest wall component (130 d, N = 3) as well as the VBM niche as evidenced by donor-specific chimerism (average: 2.35 ± 1.44%), whereas interestingly, the skin component was rejected after 13 (±1) days. CONCLUSION: Thus, this novel microsurgical model of VCA combined with solid organ transplantation is technically feasible and results in split tolerance when treated with costimulatory blockade.

Comparison of livestock-associated and health care-associated MRSA-genes, virulence, and resistance.

Livestock-associated methicillin-resistant Staphylococcus aureus (LA-MRSA) may colonize and infect humans with close contact to pigs. We compared phenotypic and genotypic differences in resistance and virulence of LA-MRSA isolates from farms and farmers with hospital-acquired methicillin-resistant S. aureus (HA-MRSA) and assessed carriage rates. Samples from pigs (n=330), occupationally exposed personnel (n=63), the farm environment (n=134), and hospital patients (n=220) were obtained. Approximately 50% (166/330) of pigs were MRSA positive. All LA-MRSA were resistant to tetracycline, compared to only 8% of HA-MRSA (P<0.001). In contrast, HA-MRSA isolates showed significantly higher resistance rates to quinolones (81% versus 7%; P<0.001). All strains isolated from occupationally exposed personnel (61.9%; 39/63) belonged to CC398. HA-MRSA isolates were diversely distributed, with predominance of CC5 (62.7%). Human strains carried significantly more virulence genes than porcine strains, especially exotoxins (P<0.001) and immune-evasion cluster genes (P<0.001). There were significant differences in resistance patterns and recognized genotypic virulence loci between LA-MRSA and HA-MRSA.