Long-term results of multicatheter interstitial high-dose-rate brachytherapy for accelerated partial-breast irradiation.

PURPOSE: The purpose of this study was to report the long-term results of women treated in one center with accelerated partial-breast irradiation (APBI) with interstitial high-dose-rate (HDR) brachytherapy. MATERIALS AND METHODS: We analyzed data from women treated in one center with adjuvant interstitial HDR brachytherapy for early-stage breast cancer. Treatment regimen was homogeneous for all women with treatment dose 32Gy in 8 fractions twice daily given to the tumor bed with interstitial HDR brachytherapy. RESULTS: About 364 women were treated with interstitial HDR brachytherapy as APBI from March 2000 to March 2014. Mean age at diagnosis was 62 years. Stage distribution was as follows: T1a = 12%, T1b = 33%, T1c = 40%, T2 = 14%, and Tis = 1%. 97% of patients were N0. 88% had invasive ductal carcinoma. 86% had positive hormone receptor status. 14 ipsilateral breast tumor recurrences were identified with 12 deemed local recurrences and 2 deemed to be second ipsilateral primaries. Actuarial 5-year and 10-year overall survival rates were 95.1% and 92.2%, respectively. Actuarial 5-year and 10-year local relapse-free survival rates were 96.2% and 88.8%, respectively. CONCLUSIONS: The results of this previously unreported series of women treated with a homogeneous APBI method exclusively with interstitial HDR brachytherapy present further data justifying that in appropriately selected women, APBI with interstitial brachytherapy provides rates of local control and survival comparable with whole-breast irradiation.

An approved in vitro approach to preclinical safety and efficacy evaluation of engineered T cell receptor anti-CD3 bispecific (ImmTAC) molecules.

Robust preclinical testing is essential to predict clinical safety and efficacy and provide data to determine safe dose for first-in-man studies. There are a growing number of examples where the preclinical development of drugs failed to adequately predict clinical adverse events in part due to their assessment with inappropriate preclinical models. Preclinical investigations of T cell receptor (TCR)-based immunotherapies prove particularly challenging as these biologics are human-specific and thus the conventional testing in animal models is inadequate. As these molecules harness the full force of the immune system, and demonstrate tremendous potency, we set out to design a preclinical package that would ensure adequate evaluation of these therapeutics. Immune Mobilising Monoclonal TCR Against Cancer (ImmTAC) molecules are bi-specific biologics formed of an affinity-enhanced TCR fused to an anti-CD3 effector function. ImmTAC molecules are designed to activate human T lymphocytes and target peptides within the context of a human leukocyte antigen (HLA), thus require an intact human immune system and peptidome for suitable preclinical screening. Here we draw upon the preclinical testing of four ImmTAC molecules, including IMCgp100, the first ImmTAC molecule to reach the clinic, to present our comprehensive, informative and robust approach to in vitro preclinical efficacy and safety screening. This package comprises a broad range of cellular and molecular assays using human tissues and cultured cells to test efficacy, safety and specificity, and hence predict human responses in clinical trials. We propose that this entirely in vitro package offers a potential model to be applied to screening other TCR-based biologics.

Early toxicity and health-related quality of life results of high-dose-rate brachytherapy as monotherapy for low and intermediate-risk prostate cancer.

PURPOSE: To determine the acute toxicity and effect on health-related quality of life of a two-fraction regimen of high-dose-rate (HDR) prostate brachytherapy. METHODS AND MATERIALS: Patients with low- or intermediate-risk prostate cancer were treated with HDR brachytherapy as monotherapy in two implants of 13.5 Gy spaced 7-14 days apart. Patients completed International Prostate Symptom Score (IPSS) and Expanded Prostate Index Composite (EPIC) questionnaires at 1, 3, 6, 9, 12, 16, 20, and 24 months after brachytherapy. Proportion of patients in each IPSS category (mild = 0-7, moderate = 8-18, severe = 19+) was evaluated at each of the intervals above. Paired t tests with baseline values were done for IPSS and EPIC scores. RESULTS: Thirty patients were accrued to the study. Median prostate-specific antigen was 8,7 (range 4.1-17.5). T stages were T1c = 65%, T2a = 21%, and T2b = 14%. Twenty-seven percent of patients had a Gleason score of 6 and 73% had a Gleason score of 7. IPSS categories at baseline, 1, 3, 6, 12, and 24 months were mild (81%, 43%, 58%, 62%, 76%, 64%), moderate (19%, 32%, 29%, 30%, 20%, 29%), and severe (0%, 25%, 13%, 7%, 4%, 6%), respectively. There was a significant decrease in EPIC sexual summary scores at 1, 3, 6, and 12 months of 0 points (p < 0.001), 17 points (p = 0.01), 18 points (p = 0.02), and 17 points (p = 0.01), respectively. CONCLUSIONS: This is the first report of this cohort of patients treated with two-fraction HDR monotherapy. This regimen shows rates of toxicity and health-related quality of life that appear acceptable as compared to other treatment modalities. These results are also comparable with other reports with similar treatment regimens.

Safe handling of oral chemotherapeutic agents in clinical practice: recommendations from an international pharmacy panel.

Although there has been a significant increase in the availability and use of oral chemotherapeutic agents, the guidelines around their safe handling are still evolving. Although oral chemotherapy is associated with ease of administration, it has the same exposure risks to health care practitioners, patients, and their caregivers as intravenous formulations, and because it is administered in the home, to the families of patients. However, the general misconception appears to be that exposure risk is low and therefore oral chemotherapeutic agents present little risk and are safer to handle. In a series of three roundtable meetings, a team of international pharmacists from North America and Europe reviewed existing guidelines and identified gaps in recommendations that we believe are important for safe handling. The present article is a compilation of these gaps, especially applicable to manufacturers and distributors, storage and handling, and patient education regarding safe handling. These recommendations, on the basis of our experience and of best practices, provide an international perspective and can be adapted by institutions and practices for development of standardized procedures specific to their needs for the safe handling of oral chemotherapeutic agents.

Antibody limits in vivo murid herpesvirus-4 replication by IgG Fc receptor-dependent functions.

Antibody is an important antiviral defence. However, it is considered to do little against human gamma-herpesviruses, which establish predominantly latent infections regulated by T cells. One limitation on analysing these infections has been that latency is already well-established at clinical presentation; early infection may still be accessible to antibody. Here, using murid herpesvirus-4 (MuHV-4), we tested the impact of adoptively transferred antibody on early gamma-herpesvirus infection. Immune sera and neutralizing and non-neutralizing monoclonal antibodies (mAbs) all reduced acute lytic MuHV-4 replication. The reductions, even by neutralizing mAbs, were largely or completely dependent on host IgG Fc receptors. Therefore, passive antibody can blunt acute gamma-herpesvirus lytic infection, and does this principally by IgG Fc-dependent functions rather than by neutralization.

Murid herpesvirus-4 lacking thymidine kinase reveals route-dependent requirements for host colonization.

Gammaherpesviruses infect at least 90 % of the world's population. Infection control is difficult, in part because some fundamental features of host colonization remain unknown, for example whether normal latency establishment requires viral lytic functions. Since human gammaherpesviruses have narrow species tropisms, answering such questions requires animal models. Murid herpesvirus-4 (MuHV-4) provides one of the most tractable. MuHV-4 genomes delivered to the lung or peritoneum persist without lytic replication. However, they fail to disseminate systemically, suggesting that the outcome is inoculation route-dependent. After upper respiratory tract inoculation, MuHV-4 infects mice without involving the lungs or peritoneum. We examined whether host entry by this less invasive route requires the viral thymidine kinase (TK), a gene classically essential for lytic replication in terminally differentiated cells. MuHV-4 TK knockouts delivered to the lung or peritoneum were attenuated but still reached lymphoid tissue. In contrast, TK knockouts delivered to the upper respiratory tract largely failed to establish a detectable infection. Therefore TK, and by implication lytic replication, is required for MuHV-4 to establish a significant infection by a non-invasive route.

Prevention and control of infection in non-acute healthcare settings.

This article discusses the main principles of infection prevention and control in non-acute healthcare settings. It explores the use of a set of ten tools developed by the Infection Control Nurses Association (ICNA) to audit infection prevention and control, using the standard statements and criteria within the tools as a checklist. The results of the audit of facilities, commodities and practice using the ICNA audit tools will help staff to identify areas of best practice and areas where improvements are needed to enhance patient care.

Unusual water flux in the extracellular polysaccharide of the cyanobacterium Nostoc commune.

The speed of water uptake by desiccated Nostoc commune was found to depend upon the duration of desiccation. The rehydration of desiccated colonies led to marked, time-dependent changes in structure and ultrastructure and fluctuations in the composition of the transcriptome. Physical evaporative water loss is an active process that was influenced by inhibitors of transcription and translation.