Comparison of three analgesic regimens in women undergoing cervical brachytherapy.

PURPOSE: Effective periprocedural analgesia is an important aspect of cervical brachytherapy delivery, with implications for patient comfort and attendance for subsequent fractions. We compared the efficacy and safety of three analgesic modalities: intravenous patient-controlled analgesia (IV-PCA), continuous epidural infusion (CEI) and programmed-intermittent epidural bolus with patient-controlled epidural analgesia (PIEB-PCEA). METHODS AND MATERIALS: Ninety-seven brachytherapy episodes involving 36 patients between July 2016 and June 2019 in a single tertiary center were retrospectively reviewed. Episodes were divided into two key phases: Phase 1 (while applicator remained in situ) and Phase 2 (following applicator removal until discharge or 4 h). For the primary endpoint, pain scores were retrieved and analyzed by analgesic modality with respect to median score and an internally defined "unacceptable" pain experience (>20% of scores being ≥4/10; i.e., moderate or greater). Total nonepidural oral morphine equivalent dose (OMED) and toxicity/complication events were reported as secondary endpoints. RESULTS: In Phase 1, there was a significantly higher median pain score (p < 0.001) and more episodes with unacceptable pain scores (46%) in the IV-PCA group compared with either epidural modality (6-14%; p < 0.001). In Phase 2, we observed a greater median pain score (p = 0.007) and higher proportion of patient episodes with unacceptable pain scores (38%) in the CEI group compared with both the IV-PCA (13%) and PIEB-PCEA (14%) groups (p = 0.001). There was a significant difference in median OMED used throughout all phases across the PIEB-PCEA (0 mg), IV-PCA (70 mg), and CEI (15 mg) groups (p < 0.001). CONCLUSIONS: PIEB-PCEA is safe and offers superior analgesia compared to IV-PCA or CEI for pain control after applicator placement in cervical brachytherapy.

A Clinician's Guide to Cancer-Derived Exosomes: Immune Interactions and Therapeutic Implications.

Understanding of the role of immunity in the regulation of cancer growth continues to rapidly increase. This is fuelled by the impressive results yielded in recent years by immune checkpoint inhibitors, which block regulatory pathways to increase immune-mediated cancer destruction. Exosomes are cell-secreted membranous nanoscale vesicles that play important roles in regulating physiological and pathophysiological processes. Cancer-derived exosomes (CDEXs) and their biologically-active cargos have been proven to have varied effects in malignant progression, including the promotion of angiogenesis, metastasis, and favorable microenvironment modification. More recently, there is an increasing appreciation of their role in immune evasion. In addition to CDEXs, there are immune-derived exosomes that facilitate communication between immune cells in the non-malignant setting. Investigation of cancer-mediated mechanisms behind interruption or modification of these normal exosomal pathways may provide further understanding of how malignant immune evasion is accomplished. Accumulating evidence indicates that immune-active CDEXs also have the potential to impact clinical oncological management. Whilst immune checkpoint inhibitors have well-established pharmacologically-targeted pathways involving the immune system, other widely used treatments such as radiation and cytotoxic chemotherapies do not. Thus, investigating exosomes in immunotherapy is important for the development of next-generation combination therapies. In this article, we review the ways in which CDEXs impact individual immune cell types and how this contributes to the development of immune evasion. We discuss the relevance of lymphocytes and myeloid-lineage cells in the control of malignancy. In addition, we highlight the ways that CDEXs and their immune effects can impact current cancer therapies and the resulting clinical implications.

Endobronchial brachytherapy in the management of lung malignancies: 20 years of experience in an Australian center.

OBJECTIVES: Management of end-stage lung cancers focuses on symptom control, requiring multimodality management. Endobronchial brachytherapy (EBB) is an evidence-based approach allowing safe delivery of clinically meaningful radiation doses. We provide a summary of treatment characteristics and clinical outcomes of EBB in a single center. METHODS AND MATERIALS: Our retrospective study examined all EBB procedures performed at St George Hospital, NSW, Australia, between 1997 and 2016. Patients received single-fraction brachytherapy treatment under procedural sedation, using either the pulsed-dose-rate or high dose-rate modality. Symptomatic response was noted at the 4- to 6-week followup consultation. RESULTS: Ninety-two EBB procedures were identified in 83 patients, with 75 patients treated with pulsed-dose-rate and 17 with high-dose-rate. Clinical and/or radiological airway obstruction in a prior high-dose irradiated volume was the most common indication for treatment (85%). Sixty (72%) patients had a partial or complete response of symptoms. Patients with hemoptysis were more likely to respond than those with airway obstruction (92% vs. 70%; p = 0.036). There was no difference in clinical response between pulsed-dose-rate and high-dose-rate patients (p = 0.24). Median overall survival was 8 months, with a statistically significant difference in those with clinical response (4 vs. 9 months; p = 0.0101). No Grade >2 toxicities were recorded. CONCLUSIONS: We present the largest Australian series of EBB to date. We continue to demonstrate that despite a variety of symptomatic presentations and histologies, EBB is an effective approach to the palliation of malignant lung lesions. Given its low risk of toxicity, EBB is recommended as an option in the palliative treatment of endobronchial malignancies.

Qualitative investigation of the reasons behind opposition to water fluoridation in regional NSW, Australia.

OBJECTIVES: To investigate reasons behind strong opposition to water fluoridation in regional New South Wales, Australia, and to make recommendations to improve community engagement. IMPORTANCE: Few studies have used qualitative methodologies to understand the reasons for strong antifluoridation views. An understanding of these reasons could be useful when designing public campaigns to combat the strong antifluoridation message. METHODS: The qualitative study used semistructured interviewing and thematic analysis. Ten participants were recruited using purposive and snowball sampling methods until data saturation was reached. Thematic analysis and graphical representation of themes assisted in analysing the data for logical connections and relationships. RESULTS: Six dominant themes and numerous subthemes were identified. Five of the major themes were reasons for opposition: scepticism, health effects, ethics, environmental impacts and economics. Each of these was inextricably linked to a sixth major theme: alternatives to fluoridation. CONCLUSIONS: All participants had strongly held antifluoridation views, and provided a unique insight into their perceptions and reasons for opposing water fluoridation. Concerns about 'fraudulent research' and the influence of industry on government bodies were novel themes. The concerns raised could be used to inform future population health campaigns, research, public education and resource-allocation decisions. Open community consultation may be able to address the issues raised in a nonjudgemental and collaborative manner.

Educational Antimicrobial Stewardship Intervention Ineffective in Changing Surgical Prophylactic Antibiotic Prescribing.

BACKGROUND: High rates of inappropriate use of prophylactic antibiotics in surgery continue to be reported in the literature, with many institutions designing interventions aimed at improving prescription. This study evaluates the surgical arm of a clinician-focused educational antimicrobial stewardship program implemented in February 2014 at Blacktown Hospital, Australia. METHODS: A before-after analysis of the surgical antibiotic prophylaxis intervention was conducted at Blacktown Hospital, New South Wales, Australia. Two hundred abdominal general surgical patients were selected via simple random sampling and categorized into pre-intervention (n = 100) and post-intervention (n = 100) groups. Antibiotic prophylaxis regimens were compared with the Australian guideline, Therapeutic Guidelines: Antibiotic (v14) with respect to drug choice, dosage, timing of administration, and duration of administration. RESULTS: Overall adherence rates in the pre- and post-intervention periods were 18% and 15% respectively, demonstrating no substantial change (p = 0.568). No patients in either group were administered antibiotics without an appropriate indication. There were no substantial decreases in error rates across any category, including drug choice, dosage, timing of administration, duration of administration, or re-dosing. The apparent decrease in the rate of inappropriate broad-spectrum cephalosporin usage was not statistically significant (29.3% vs. 18.8%; p = 0.16). CONCLUSIONS: The educational intervention studied demonstrated no substantial change to overall adherence. Given the frequent failure of such interventions, stronger and more directly mandated adoption of prescribing guidelines is recommended for surgical services. Future consideration should be given to focused computer-based solutions, integrated with electronic medical records where possible.

Adherence to Surgical Antibiotic Prophylaxis Guidelines in New South Wales, Australia: Identifying Deficiencies and Regression Analysis of Contributing Factors.

BACKGROUND: Surgical antibiotic prophylaxis is frequently reported in the literature to be suboptimal, a finding having both clinical and public health implications. This study aimed to calculate rates and patterns of adherence to guidelines at two sites and identify extrinsic contributing factors. METHODS: A retrospective analysis was conducted over two 12-mo periods during 2013-2014 at the metropolitan Blacktown Hospital and regional Lismore Base Hospital, New South Wales, Australia. A group of 400 patients undergoing abdominal general surgery was selected via simple random sampling (n = 200 per site). Medical records were reviewed, and prophylactic antibiotic regimens were compared with the Australian guideline, Therapeutic Guidelines: Antibiotic (v. 14) with respect to drug choice, dosage, timing of administration, and duration of administration. RESULTS: The overall rate of adherence to the guidelines was 16.5% at Blacktown Hospital and 19.5% at Lismore Base Hospital. At each site, prophylaxis was administered to more than 95% of patients and was inappropriately withheld in 4%. Drug choice was the most frequent error type, specifically involving inappropriate omission of metronidazole and use of newer-generation cephalosporins. Errors in the timing of administration also were frequent, with prophylaxis typically occurring excessively early. Logistic regression identified emergency surgery as independently associated with prophylactic errors in both the Blacktown Hospital (p < 0.001) and the Lismore Base Hospital cohorts (p = 0.020). CONCLUSIONS: Adherence to antibiotic prophylactic guidelines was poor at both the metropolitan and regional sites. Choice of antibiotic and timing of administration were identified as major error types. Consideration should be given to multidisciplinary involvement of anesthetists, implementation of focused interventions with an emphasis on emergency settings, and further research correlating antibiotic use with clinical significance.

TGFbeta is responsible for skin tumour infiltration by macrophages enabling the tumours to escape immune destruction.

Infiltration of skin tumours by macrophages is an important step in tumour progression, although the mechanisms of macrophage recruitment to the tumour mass and the subsequent effects on tumour growth are poorly understood. Transfecting a murine regressing skin tumour with the gene for transforming growth factor (TGF)beta enabled the tumours to grow progressively in vivo thus allowing us to study the role of this cytokine in tumour growth. Flow cytometry was used to show that TGFbeta-mediated tumour progression was accompanied by an increase in tumour-associated macrophages (TAM) and a decrease in tumour-infiltrating dendritic cells (DCs). TAM in TGFbeta-secreting tumours expressed lower levels of major histocompatibility complex II and CD86 compared to DC in control tumours and had a high phagocytic capacity as measured by uptake of latex beads in vivo. Indeed, TGFbeta was directly responsible not only for the enhanced macrophage phagocytosis but also altering the ratio of antigen-presenting cells to favour macrophages over DC. Our results demonstrate that TGFbeta recruitment and retention of macrophages at the tumour site enable effective tumour evasion of the host immune system and reinforces the need to target TGFbeta in human cancer immunotherapy trials.