Nodal positivity in patients with clinically and radiologically node-negative breast cancer treated with neoadjuvant chemotherapy: multicentre collaborative study.

BACKGROUND: The necessity of performing a sentinel lymph node biopsy in patients with clinically and radiologically node-negative breast cancer after neoadjuvant chemotherapy has been questioned. The aim of this study was to determine the rate of nodal positivity in these patients and to identify clinicopathological features associated with lymph node metastasis after neoadjuvant chemotherapy (ypN+). METHODS: A retrospective multicentre study was performed. Patients with cT1-3 cN0 breast cancer who underwent sentinel lymph node biopsy after neoadjuvant chemotherapy between 2016 and 2021 were included. Negative nodal status was defined as the absence of palpable lymph nodes, and the absence of suspicious nodes on axillary ultrasonography, or the absence of tumour cells on axillary nodal fine needle aspiration or core biopsy. RESULTS: A total of 371 patients were analysed. Overall, 47 patients (12.7%) had a positive sentinel lymph node biopsy. Nodal positivity was identified in 22 patients (29.0%) with hormone receptor+/human epidermal growth factor receptor 2- tumours, 12 patients (13.8%) with hormone receptor+/human epidermal growth factor receptor 2+ tumours, 3 patients (5.6%) with hormone receptor-/human epidermal growth factor receptor 2+ tumours, and 10 patients (6.5%) with triple-negative breast cancer. Multivariable logistic regression analysis showed that multicentric disease was associated with a higher likelihood of ypN+ (OR 2.66, 95% c.i. 1.18 to 6.01; P = 0.018), whilst a radiological complete response in the breast was associated with a reduced likelihood of ypN+ (OR 0.10, 95% c.i. 0.02 to 0.42; P = 0.002), regardless of molecular subtype. Only 3% of patients who had a radiological complete response in the breast were ypN+. The majority of patients (85%) with a positive sentinel node proceeded to axillary lymph node dissection and 93% had N1 disease. CONCLUSION: The rate of sentinel lymph node positivity in patients who achieve a radiological complete response in the breast is exceptionally low for all molecular subtypes.

Evaluation of the clinical impact of repeat application of hydrogel-forming microneedle array patches.

Hydrogel-forming microneedle array patches (MAPs) have been proposed as viable clinical tools for patient monitoring purposes, providing an alternative to traditional methods of sample acquisition, such as venepuncture and intradermal sampling. They are also undergoing investigation in the management of non-melanoma skin cancers. In contrast to drug or vaccine delivery, when only a small number of MAP applications would be required, hydrogel MAPs utilised for sampling purposes or for tumour eradication would necessitate regular, repeat applications. Therefore, the current study was designed to address one of the key translational aspects of MAP development, namely patient safety. We demonstrate, for the first time in human volunteers, that repeat MAP application and wear does not lead to prolonged skin reactions or prolonged disruption of skin barrier function. Importantly, concentrations of specific systemic biomarkers of inflammation (C-reactive protein (CRP); tumour necrosis factor-α (TNF-α)); infection (interleukin-1ß (IL-1ß); allergy (immunoglobulin E (IgE)) and immunity (immunoglobulin G (IgG)) were all recorded over the course of this fixed study period. No biomarker concentrations above the normal, documented adult ranges were recorded over the course of the study, indicating that no systemic reactions had been initiated in volunteers. Building upon the results of this study, which serve to highlight the safety of our hydrogel MAP, we are actively working towards CE marking of our MAP technology as a medical device.

In vivo studies investigating biodistribution of nanoparticle-encapsulated rhodamine B delivered via dissolving microneedles.

Nanoparticles (NPs) have undergone extensive investigation as drug delivery and targeting vehicles. NP delivery is often via the parenteral route, reliant on administration using hypodermic needles, which can be associated with patient compliance issues and safety concerns. In the recent past, the intradermal delivery of NPs, via novel dissolving microneedle (MN) arrays has garnered interest in the pharmaceutical community. However, published studies using this combinatorial approach have been limited, in that they have focussed on the use of in vitro and ex vivo models only. The current study was designed to answer the fundamental question of how such NPs are distributed in an in vivo murine model, following MN-mediated delivery. Rhodamine B (RhB) was employed as a model tracer dye to facilitate study of biodistribution. Following MN application, RhB was detected in the livers, kidneys, spleens and superficial parotid lymph nodes of the mice. Uptake into the lymphatics was of particular note, as it points towards the potential for utilisation of a minimally-invasive MN delivery strategy in controlled targeting of active drug substances and vaccines to the lymphatics. The use of such a delivery system could, following further development, have far-reaching benefits in enhancement of immunomodulatory and anti-cancer therapies. As a consequence, further investigation of MN/NP combinatorial delivery strategies is warranted.

Punishment Attacks in Post-Ceasefire Northern Ireland: An Emergency Department Perspective.

Northern Ireland (NI) has been in a post-conflict state for over twenty years. However, injuries sustained during paramilitary Punishment Attacks (PA) remain a common hospital presentation. The aim of this study was to compare the current province-wide frequency and cost with data collected from the same unit in 1994, the end of the so called, "Troubles". A ten month retrospective emergency chart analysis from all assault and gunshot wound (GSW) attendances to the Emergency Department, Royal Victoria Hospital Belfast (RVH) in 2012 was carried out. Age, sex, injury type, treatment outcome and associated cost of PA was documented. During the study period we recorded a total of thirty two PAs. Twenty seven were the result of gunshot wounds (GSWs), while five were assaults (punishment beatings). Seventeen required admission for definitive management. Nine cases required orthopaedic intervention, two required plastic surgery, two required maxillofacial input and one case required vascular surgery. All but two of those involved were male. Mean age of individuals admitted was 27.47. Total cost of patients both admitted and managed in the Emergency Department (ED) amounted to £91,362. On comparison with 1994, there are more PA presentations. Due to changing wound characteristics and evolving management overall cost is however less.

Potential of microneedles in enhancing delivery of photosensitising agents for photodynamic therapy.

Photodynamic therapy can be used in the treatment of pre-malignant and malignant diseases. It offers advantages over other therapies currently used in the treatment of skin lesions including avoidance of damage to surrounding tissue and minimal or no scarring. Unfortunately, systemic delivery of photosensitising agents can result in adverse effects, such as prolonged cutaneous photosensitivity; while topical administration lacks efficacy in the clearance of deeper skin lesions and those with a thick overlying keratotic layer. Therefore, enhancement of conventional photosensitiser delivery is desired. However, the physicochemical properties of photosensitising agents, such as extreme hydrophilicity or lipophilicity and large molecular weights make this challenging. This paper reviews the potential of microneedles as a viable method to overcome these delivery-limiting physicochemical characteristics and discusses the current benefits and limitations of solid, dissolving and hydrogel-forming microneedles. Clinical studies in which microneedles have successfully improved photodynamic therapy are also discussed, along with benefits which microneedles offer, such as precise photosensitiser localisation, painless application and reduction in waiting times between photosensitiser administration and irradiation highlighted.

In vitro testing of chitosan in gentamicin-loaded bone cement: no antimicrobial effect and reduced mechanical performance.

BACKGROUND AND PURPOSE: Efforts to prevent infection of arthroplasties, including the use of antibiotic-loaded bone cement, are not always successful. We investigated whether the incorporation of chitosan in gentamicin-loaded bone cement increases antibiotic release, and prevents bacterial adherence and biofilm formation by clinical isolates of Staphylococcus spp. In addition, we performed mechanical and degradation tests. METHODS: Different amounts of chitosan were added to the powder of the gentamicin-loaded bone cement. Gentamicin release was determined using high-per-formance liquid chromatography mass spectrometry. Bacterial adherence and bacterial biofilm formation were determined using clinical isolates cultured from implants retrieved at revision hip surgery. The mechanical properties were determined as a function of degradation in accordance with ISO and ASTM standards for PMMA bone cement. RESULTS: The addition of chitosan to bone cement loaded with gentamicin reduced gentamicin release and did not increase the efficacy of the bone cement in preventing bacterial colonization and biofilm formation. Moreover, the mechanical performance of cement containing chitosan was reduced after 28 days of degradation. The compressive and bending strengths were not in compliance with the minimum ISO and ASTM requirements. INTERPRETATION: Clinically, incorporation of chitosan into gentamicin-loaded bone cement for use in joint replacement surgery has no antimicrobial benefit and the detrimental effect on mechanical properties may have an adverse effect on the longevity of the prosthetic joint.

In vitro activity of tea-tree oil against clinical skin isolates of meticillin-resistant and -sensitive Staphylococcus aureus and coagulase-negative staphylococci growing planktonically and as biofilms.

The susceptibility of Staphylococcus aureus [meticillin-resistant (MRSA) and meticillin-sensitive (MSSA)] and coagulase-negative staphylococci (CoNS), which respectively form part of the transient and commensal skin flora, to tea-tree oil (TTO) was compared using broth microdilution and quantitative in vitro time-kill test methods. MRSA and MSSA isolates were significantly less susceptible than CoNS isolates, as measured by both MIC and minimum bactericidal concentration. A significant decrease in the mean viable count of all isolates in comparison with the control was seen at each time interval in time-kill assays. However, the only significant difference in the overall mean log10 reduction in viable count between the groups of isolates was between CoNS and MSSA at 3 h, with CoNS isolates demonstrating a significantly lower mean reduction. To provide a better simulation of in vivo conditions on the skin, where bacteria are reported to grow as microcolonies encased in glycocalyx, the bactericidal activity of TTO against isolates grown as biofilms was also compared. Biofilms formed by MSSA and MRSA isolates were completely eradicated following exposure to 5 % TTO for 1 h. In contrast, of the biofilms formed by the nine CoNS isolates tested, only five were completely killed, although a reduction in viable count was apparent for the other four isolates. These results suggest that TTO exerts a greater bactericidal activity against biofilm-grown MRSA and MSSA isolates than against some biofilm-grown CoNS isolates.