High-Frequency Electroporation and Chemotherapy for the Treatment of Cutaneous Malignancies: Evaluation of Early Clinical Response.

High-frequency electroporation (HF-EP) with chemotherapy is a novel therapy proposed for both curative and palliative treatment of cutaneous malignancies. The use of high-frequency biphasic pulses is thought to reduce the painful muscle contractions associated with traditional electrochemotherapy (ECT), allowing treatment administration under local anaesthesia. This proof-of-concept study investigated the efficacy and tolerability of HF-EP protocols on a variety of cutaneous malignancies. A total of 97 lesions of five different histological subtypes were treated across 25 patients. At 12 weeks post-treatment, a 91.3% overall lesion response rate was observed (complete response: 79%; partial response: 12.3%), with excellent intraprocedural patient tolerability under local anaesthetic. HF-EP with chemotherapy shows promising results regarding tumour response rates for cutaneous malignancies of varying histological subtypes when compared to traditional ECT protocols. Improved patient tolerability is important, increasing the possibility of treatment delivery under local anaesthesia and potentially broadening the treatment envelope for patients with cutaneous malignancies.

Hollow silicon microneedles, fabricated using combined wet and dry etching techniques, for transdermal delivery and diagnostics.

Microneedle-based technologies are the subject of intense research and commercial interest for applications in transdermal delivery and diagnostics, primarily because of their minimally invasive and painless nature, which in turn could lead to increased patient compliance and self-administration. In this paper, a process for the fabrication of arrays of hollow silicon microneedles is described. This method uses just two bulk silicon etches - a front-side wet etch to define the 500 µm tall octagonal needle structure itself, and a rear-side dry etch to create a 50 µm diameter bore through the needle. This reduces the number of etches and process complexity over the approaches described elsewhere. Ex-vivo human skin and a customised applicator were used to demonstrate biomechanical reliability and the feasibility of using these microneedles for both transdermal delivery and diagnostics. Microneedle arrays show no damage even when applied to skin up to 40 times, are capable of delivering several mL of fluid at flowrates of 30 µL/min, and of withdrawing 1 µL of interstitial fluid using capillary action.

Towards Micropump- and Microneedle-based Drug Delivery using Micro Transdermal Interface Platforms (MicroTIPs).

Micro Transdermal Interface Platforms (MicroTIPs) will combine minimally invasive microneedle arrays with highly miniaturized sensors, actuators, control electronics, wireless communications and artificial intelligence. These patch-like devices will be capable of autonomous physiological monitoring and transdermal drug delivery, resulting in increased patient adherence and devolved healthcare. In this paper, we experimentally demonstrate the feasibility of controlled transdermal drug delivery using a combination of 500 µm tall silicon microneedles, a commercial micropump, pressure and flow sensors, and bespoke electronics. Using ex-vivo human skin samples and a customized application/retraction system, leak-free delivery of volumes ranging from 0.7-1.1 mL has been achieved in under one hour. Clinical Relevance - This work experimentally confirms the feasibility of combining micropumps with microneedle arrays for applications in transdermal drug delivery.

A Comparison of Flow- and Pressure-Controlled Infusion Strategies for Microneedle-based Transdermal Drug Delivery.

Microneedle-based transdermal drug delivery is considered an attractive alternative to conventional injections using hypodermic needles due to its minimally invasive and painless nature; this has the potential to improve patient adherence to medication regimens. Hollow microneedles (MNs) are sharp, sub-millimeter protrusions with a channel that serves as a fluidic interface with the skin. This technology could be coupled with micro-pumps, embedded sensors, actuators and electronics to create Micro Transdermal Interface Platforms - smart, wearable infusion systems capable of delivering precise microdoses over a prolonged period. Using 500 µm tall hollow microneedles, ex-vivo human skin and a customized application/retraction device, this work focuses on comparing two infusion control strategies, namely 'set pressure' (SP) and 'set flow' (SF) infusion. It was found that flow-controlled infusion was capable of delivering higher volumes than pressure-driven delivery, and a mean volume of 3.8 mL was delivered using a set flowrate of 50 µL/minute. This suggests that flow driven delivery is a better control strategy and confirms that MN array retraction is beneficial for transdermal MN infusion.

Combination of Pembrolizumab with Electrochemotherapy in Cutaneous Metastases from Melanoma: A Comparative Retrospective Study from the InspECT and Slovenian Cancer Registry.

Electrochemotherapy (ECT) is an effective locoregional therapy for cutaneous melanoma metastases and has been safely combined with immune checkpoint inhibitors in preliminary experiences. Since ECT is known to induce immunogenic cell death, its combination with immune checkpoint inhibitors might be beneficial. In this study, we aimed to investigate the effectiveness of ECT on cutaneous melanoma metastases in combination with pembrolizumab. We undertook a retrospective matched cohort analysis of stage IIIC-IV melanoma patients, included in the International Network for sharing practices of ECT (InspECT) and the Slovenian Cancer Registry. We compared the outcome of patients who received the following treatments: (a) pembrolizumab alone, (b) pembrolizumab plus ECT, and (c) ECT. The groups were matched for age, sex, performance status, and size of skin metastases. The local objective response rate (ORR) was higher in the pembrolizumab-ECT group than in the pembrolizumab group (78% and 39%, p < 0.001). The 1 year local progression-free survival (LPFS) rates were 86% and 51% (p < 0.001), and the 1 year systemic PFS rates were 64% and 39%, respectively (p = 0.034). The 1 year overall survival (OS) rates were 88% and 64%, respectively (p = 0.006). Our results suggest that skin-directed therapy with ECT improves superficial tumor control in melanoma patients treated with pembrolizumab. Interestingly, we observed longer PFS and OS in the pembrolizumab-ECT group than in the pembrolizumab group. These findings warrant prospective confirmation.

Electrochemotherapy and basal cell carcinomas: First-time appraisal of the efficacy of electrochemotherapy on survivorship using FACE-Q.

INTRODUCTION: The establishment and success of new treatments are significantly influenced by patient satisfaction. Post-operative scarring is an important outcome for patients, and subsequently influences overall satisfaction with treatment. The objective was to measure post-treatment scarring satisfaction using a novel scale, the FACE-Q Skin Cancer Module, to compare electrochemotherapy (ECT) to traditional surgical excision (SE) to demonstrate equivalence of ECT and SE regarding outcome and survivorship. METHODS AND MATERIALS: This was a multicentre first-time appraisal study of the efficacy of ECT. All patients with facial BCCs treated with either ECT or SE were deemed eligible and subsequently recruited from either a previous clinical trial or outpatient clinics, respectively. Of the 40 participants invited, 25 responses were received. Patient information recorded included age, gender, location and size of BCCs, and time since treatment. Patient outcomes were measured using the FACE-Q Skin Cancer Module. RESULTS: The ECT and SE groups consisted of 14 and 11 patients, respectively. Mean age was 68 years (M:F = 16:9), while mean time since treatment was 4.98 years (range 0.3-9.58 years). Appraisal of scars was significantly higher in the ECT cohort versus SE (p = 0.034). Cancer worry was equivalent across both cohorts (p = 0.804). According to treatment type, no correlation was detected between time since treatment and both appraisal of scars (ECT p = 0.466 and SE p = 0.214) and adverse effects (ECT p = 0.924 and SE p = 0.139). CONCLUSION: Based on this study, ECT has superior scar outcomes and overall equivalence to SE. This demonstrates high patient satisfaction for those treated with ECT without any additional cancer worry.

Outcomes of older adults aged 90 and over with cutaneous malignancies after electrochemotherapy with bleomycin: A matched cohort analysis from the InspECT registry.

BACKGROUND: With extending life expectancy, more people are diagnosed with cutaneous malignancies at advanced ages and are offered nonsurgical treatment. We assessed outcomes of the oldest-old adults after electrochemotherapy (ECT). METHODS: The International Network for Sharing Practices of ECT (InspECT) registry was queried for adults aged ≥90 years (ys) with skin cancers/cutaneous metastases of any histotype who underwent bleomycin-ECT (2006-2019). These were subanalysed with patients aged <90 ys after matching 1:2 for tumor location, number, size, histotype, and previous treatments. We assessed ECT modalities, toxicity (CTCAE), response (RECIST), and patient perception (EQ-5D). RESULTS: Sixty-one patients represented the study cohort (median 92 ys, range 92-104), 122 the control group (median 77 ys, range 23-89). Among the oldest-old, 44 patients (72%) had primary/recurrent skin cancers, 17 (28%) cutaneous metastases. Median tumour size was 15 mm (range, 5-450). The oldest-old adults underwent ECT mainly under local/regional anaesthesia (59% vs 39% p = .012). We observed no differences regarding dose and route of chemotherapy (intravenous vs intratumoral, p = .308), electrode geometry (linear vs hexagonal, p = .172) and procedural duration (18 vs 21 min, p = .378). Complete response (57.4 [95%-CI 44.1%-70.0%] vs 64.7% [95%-CI 55.6%-73.2%], p = .222) and 1-year local control (76.7% vs 81.7, p = .092) rates were comparable. Pain and skin hyperpigmentation were mild in both groups. Skin ulceration persisted longer in the oldest-old patients (4.4 vs 2.4 months, p = .008). CONCLUSIONS: The oldest-old adults with cutaneous malignancies undergo ECT most commonly under local/regional anaesthesia with safety profiles and clinical effectiveness similar to their younger counterparts, except in case of ulcerated tumors.

Differential association of CD68+ and CD163+ macrophages with macrophage enzymes, whole tumour gene expression and overall survival in advanced melanoma.

BACKGROUND: The density and phenotype of tumour-associated macrophages have been linked with prognosis in a range of solid tumours. While there is strong preclinical evidence that tumour-associated macrophages promote aspects of tumour progression, it can be challenging to infer clinical activity from surface markers and ex vivo behaviour. We investigated the association of macrophage infiltration with prognosis and functional changes in the tumour microenvironment in primary human melanoma. METHODS: Fifty-seven formalin-fixed, paraffin-embedded primary melanomas were analysed by immunohistochemical analysis of CD68, CD163, inducible nitric oxide synthase (iNOS) and arginase expression. RNA sequencing was performed on serial sections of 20 of the stained tumours to determine the influence of macrophage infiltration on gene expression. RESULTS: CD68+ cells are a functionally active subset of macrophages that are associated with increased iNOS and arginase staining and altered gene expression. In comparison, while there is a greater accumulation of CD163+ macrophages in larger tumours, these cells are comparatively inactive, with no association with the level of iNOS or arginase staining, and no effect on gene expression within the tumour. The infiltration of either subset of macrophages did not correlate to overall survival. CONCLUSIONS: Thus, melanomas contain distinct macrophage populations with diverse phenotypes, but with no observable prognostic role.

Updated standard operating procedures for electrochemotherapy of cutaneous tumours and skin metastases.

Electrochemotherapy is now in routine clinical use to treat cutaneous metastases of any histology, and is listed in national and international guidelines for cutaneous metastases and primary skin cancer. Electrochemotherapy is used by dermatologists, surgeons, and oncologists, and for different degrees and manifestations of metastases to skin and primary skin tumours not amenable to surgery. This treatment utilises electric pulses to permeabilize cell membranes in tumours, thus allowing a dramatic increase of the cytotoxicity of anti-cancer agents. Response rates, often after only one treatment, are very high across all tumour types. The most frequent indications are cutaneous metastases from malignant melanoma and breast cancer. In 2006, standard operating procedures (SOPs) were written for this novel technology, greatly facilitating introduction and dissemination of the therapy. Since then considerable experience has been obtained treating a wider range of tumour histologies and increasing size of tumours which was not originally thought possible. A pan-European expert panel drawn from a range of disciplines from dermatology, general surgery, head and neck surgery, plastic surgery, and oncology met to form a consensus opinion to update the SOPs based on the experience obtained. This paper contains these updated recommendations for indications for electrochemotherapy, pre-treatment information and evaluation, treatment choices, as well as follow-up.

Education in burns: Lessons from the past and objectives for the future.

Burns are devastating to the individual and society, representing a huge biomedical burden. Improved education in burns has however ignited a revolution in high-income countries-burn mortality is reducing. Education in burns is far-reaching. For the purpose of this concise review, we focus on four categories: education of both (1) emergency and (2) specialist physicians, and the general population, both at a (3) societal and (4) individual level. Tragically, the global burns picture is bleak with burns representing a neglected but solvable health crisis. Ninety-five percent of burns occur in low-income countries, causing enormous suffering, death and disability. Here, we examine the literature detailing burn education with a focus on past lessons, current trends and future objectives. We have identified key educational objectives to revolutionise burn care on a global perspective. Now is the time to build on promising educational strides to reduce the global burns burden.

Effective treatment of intractable cutaneous metastases of breast cancer with electrochemotherapy: Ten-year audit of single centre experience.

PURPOSE: Electrochemotherapy (ECT) is the application of electric pulses to tumour tissue to render the cell membranes permeable to usually impermeant hydrophilic anti-cancer drugs, thereby enhancing cytotoxic effects. We sought to ascertain whether ECT can be an effective palliative treatment for cutaneous metastases of breast cancer. METHODS: This work reports data from the European Standard Operating Procedures for Electrochemotherapy trial (EudraCT Number: 2004-002183-18). In combination with systemic and/or intratumoural bleomycin, optimised electric pulses were delivered to locally recurrent or metastatic cutaneous breast cancer lesions. Follow-up continued until December 2014. RESULTS: Between February 2004 and December 2014, twenty-four patients were treated. All patients had received prior multimodal therapy. In total, the patient cohort had, or developed, 242 lesions. Two hundred and 36 lesions were treated, with 34 lost to follow-up. An objective response was seen in 161 of 202 lesions (79.7%), with a complete response observed in 130 (64.3%). Thirty-nine lesions (19.3%) did not respond, while 2 (1%) progressed following ECT. 17 (73.9%) patients received two or fewer treatments. A minimum of a partial response was seen in at least 50% of treated lesions in 18 of the 24 (75%) patients. Smaller lesions were more likely to have an objective response (Chi-square test for trend, p < 0.001). CONCLUSIONS: Electrochemotherapy is an effective treatment for cutaneous breast cancer lesions that have proven refractory to standard therapies. As smaller lesions were found to be more responsive, we suggest that ECT should be considered as an early treatment modality, within multimodal treatment strategies.

Recommendations for improving the quality of reporting clinical electrochemotherapy studies based on qualitative systematic review.

BACKGROUND: Electrochemotherapy is becoming a well-established treatment for malignancies of skin and non-skin origin and its use is widening across Europe. The technique was developed and optimized from solid experimental and clinical evidence. A consensus document is now warranted to formalize reporting results, which should strengthen evidence-based practice recommendations. This consensus should be derived from high quality clinical data collection, clinical expertise and summarizing patient feedback. The first step, which is addressed in this paper, aims to critically analyze the quality of published studies and to provide the recommendations for reporting clinical trials on electrochemotherapy. METHODS: The quality of reporting in published studies on electrochemotherapy was analyzed in order to produce procedure specific reporting recommendations. A comprehensive literature search of studies published from 2006 to 2015 was performed followed by qualitative analysis of manuscripts assessing for 47 quality criteria grouped into four major clusters: (1) trial design, (2) description of patient population, (3) description of treatment delivery and patient outcome, (4) analysis of results and their interpretation. The summary measure during literature assessment was the proportion of studies fulfilling each manuscript quality criteria. RESULTS: A total of 56 studies were screened, from the period 2006 to 2015, of which 33 were included in the qualitative analysis, with a total of 1215 patients. Overall, the quality of reporting was highly variable. Twenty-four reports (73%) were single-center, non-comparative studies, and only 15 (45%) were prospective in nature (only 2 of them were entered into a clinical trials registry). Electrochemotherapy technique was consistently reported, with most studies (31/33) adhering closely to published standard operating procedures. The quality of reporting the patient population was variable among the analyzed studies, with only between 45% and 100% achieving dedicated quality criteria. Reporting of treatment delivery and patient outcome was also highly variable with studies only fulfilling between 3% and 100%. Finally, reporting study results critically varied, fulfilling from 27% to 100% of the quality criteria. Based on the critical issues emerging from this analysis, recommendations and minimal requirements for reporting clinical data on electrochemotherapy were prepared and summarized into a checklist. CONCLUSIONS: There is an increasing body of published clinical data on electrochemotherapy, but more high quality clinical data are needed. Published papers often lack accurate description of study population, treatment delivery as well as patient outcome. Our recommendations, provided in the form of a summary checklist, are intended to ameliorate data reporting in future studies on electrochemotherapy and help researchers to provide a solid evidence basis for clinical practice.

Local tumour ablative therapies: opportunities for maximising immune engagement and activation.

The relationship between cancer and the immune system is a complex one. The immune system can prevent tumour growth by eliminating cancer cells but this editing process ultimately results in poorly immunogenic cells remaining allowing for unchallenged tumour growth. In light of this, the focus of cancer treatment should be to maximise cancer elimination and the prevention of escape mechanisms. In this review we will examine current and emerging ablative treatment modalities that induce Immunogenic Cell Death (ICD), a special type of cell death that allows for immune cell involvement and the generation of an anti-tumour specific immune response. When paired with immune modulating agents, capable of potentiating the immune response and reversing the immune-suppressive environment created by tumours, we may be looking at the future of anti-cancer therapy.

Adhesive strip wound closure after thyroidectomy/parathyroidectomy: a prospective, randomized controlled trial.

BACKGROUND: Conventional collar incision closure in thyroid and parathyroid surgery involves the insertion of an epidermal layer of subcutaneous absorbable sutures that are reinforced by a deep layer of sutures. Adhesive strips offer an alternative method to close the epidermal layer. The aim of this study was to compare adhesive strip closure with absorbable sutures for collar incisions in a prospective, single-blinded, randomized controlled trial. METHODS: Eighty-two patients were randomized to wound closure using either adhesive strips or absorbable subcutaneous sutures (control). Operative time, complication rate, and postoperative pain at day 1 and 6 weeks postoperatively were recorded. Wound appearance was assessed using the Hollander Cosmesis and Likert scales at 6 weeks postoperatively by a single assessor and a plastic surgeon who was blinded to the study group. RESULTS: Forty-three patients were randomized to the control group and 39 patients to the adhesive strip group. No difference was seen in operation time (93 vs. 111 minutes; P = .341) and complication rate (2.5% vs. 6.9%; P = .323). There was a decrease in the postoperative pain score on day 1 in the adhesive strip group (2.0 vs. 2.6; P = .015) and improvement in the wound appearance at 6 weeks in the adhesive strip group using the Hollander Cosmesis (4.6 vs. 3.7; P = .012) and Likert scales (3.3 vs. 3.0; P = .046), as confirmed by independent assessment. CONCLUSION: Adhesive strips offer a safe and effective alternative approach to epidermal closure of surgical wounds in the neck. In addition, adhesive strips provide an equivalent if not better cosmetic benefit compared to traditional methods of epidermal closure.

Experience of an orthoplastic limb salvage team after the Haiti earthquake: analysis of caseload and early outcomes.

BACKGROUND: After the devastating earthquake in Haiti on January 12, 2010, a British orthoplastic limb salvage team was mobilized. The team operated in a suburb of Port-au-Prince from January 20, 2010. This analysis gives an overview of the caseload and early outcomes. METHODS: A retrospective analysis of operative data from the log book was performed from the opening of the facility on January 20, 2010, until March 12, 2010. RESULTS: In total, 348 operations were carried out on 158 patients, at an average of 47 cases per week. Seventy-three percent of the cases were soft-tissue cases and 25 percent were bony or combined soft-tissue and bony cases. The majority of bony procedures (n = 26; 16 percent) and flap procedures (n = 16; 10 percent) took place in the early weeks (weeks 1 through 4). Combined orthoplastic cases accounted for 37 percent of cases (16 of 44) in week 2 but only 7 percent (three of 43) in week 7. General anesthetic cases accounted for 89 percent of cases (39 of 44) in week 2 but only 40 percent (17 of 43) in week 7. Only six patients (4 percent) underwent amputation, but 36 operations (10 percent) dealt with the sequelae of amputation. Sixteen patients (10 percent) suffered complications, including two amputations for failed limb salvage. CONCLUSIONS: This article reports the outcomes of a limb salvage team in the acute response after an earthquake disaster with a favorable amputation rate and highlights the potential benefit of mobilizing this type of team. Detailing the changing caseload over time will allow for more efficient planning in case of a similar future disaster.