Evaluation of the Indications for Sentinel Node Biopsy in Early-Stage Melanoma with the Advent of Adjuvant Systemic Therapy: An International, Multicenter Study.

BACKGROUND: Patients presenting with early-stage melanoma (AJCC pT1b-pT2a) reportedly have a relatively low risk of a positive SNB (~5-10%). Those patients are usually found to have low-volume metastatic disease after SNB, typically reclassified to AJCC stage IIIA, with an excellent prognosis of ~90% 5-year survival. Currently, adjuvant systemic therapy is not routinely recommended for most patients with AJCC stage IIIA melanoma. The purpose was to assess the SN-positivity rate in early-stage melanoma and to identify primary tumor characteristics associated with high-risk nodal disease eligible for adjuvant systemic therapy METHODS: An international, multicenter retrospective cohort study from 7 large-volume cancer centers identified 3,610 patients with early primary cutaneous melanomas 0.8-2.0 mm in Breslow thickness (pT1b-pT2a; AJCC 8th edition). Patient demographics, primary tumor characteristics, and SNB status/details were analyzed. RESULTS: The overall SNB-positivity rate was 11.4% (412/3610). Virtually all SNB-positive patients (409/412; 99.3%) were reclassified to AJCC stage IIIA. Multivariate analysis identified age, T-stage, mitotic rate, primary site and subtype, and lymphovascular invasion as independent predictors of sentinel node status. A mitotic rate of >1/mm2 was associated with a significantly increased SN-positivity rate and was the only significant independent predictor of high-risk SNB metastases (>1 mm maximum diameter). CONCLUSIONS: The new treatment paradigm brings into question the role of SNB for patients with early-stage melanoma. The results of this large international cohort study suggest that a reevaluation of the indications for SNB for some patients with early-stage melanoma is required.

Prospektive Kohortenstudie von InspECT zur Sicherheit und Wirksamkeit der Elektrochemotherapie bei Hauttumoren und Metastasen in Abhängigkeit von Ulzeration.

HINTERGRUND: Elektrochemotherapie (ECT) ist eine wirksame lokale Behandlung von Hauttumoren. Ziel dieser Studie war es, die Wirksamkeit der ECT bei ulzerierten gegenüber nichtulzerierten Tumoren zu vergleichen und den Effekt auf tumorassoziierte Symptome zu untersuchen. METHODIK: 20 Krebszentren des International Network for Sharing Practices on Electrochemotherapy (InspECT) sammelten prospektiv Daten. Die ECT wurde nach dem ESOPE-Protokoll durchgeführt. Das Therapieansprechen wurde anhand der Entwicklung der Läsionsgröße bewertet. Zusätzlich wurden Schmerzen, Symptome, Leistungsstatus (ECOG-Index) und Gesundheitszustand (EQ-5D-Fragebogen) untersucht. ERGEBNISSE: 716 Patienten mit ulzerierten (n = 302) und nichtulzerierten (n = 414) Hauttumoren und Metastasen wurden eingeschlossen (Mindest-Nachsorge 45 Tage). Nicht-ulzerierte Läsionen sprachen besser auf die ECT an als ulzerierte Läsionen (vollständiges Ansprechen: 65 % gegenüber 51 %, p = 0,0061). Nur 38 % (115/302) der Patienten mit ulzerierten Läsionen vor der ECT wiesen bei der letzten Nachuntersuchung ulzerierte Läsionen auf. Patienten mit ulzerierten Läsionen berichteten über stärkere Schmerzen und schwerere Symptome im Vergleich zu Patienten mit nichtulzerierten Läsionen, die sich nach der ECT signifikant und kontinuierlich besserten. Bei Patienten mit nichtulzerierten Läsionen hingegen nahmen die Schmerzen während der Behandlung vorübergehend zu. Es wurden keine schwerwiegenden Nebenwirkungen beobachtet. SCHLUSSFOLGERUNGEN: Die ECT ist eine sichere und wirksame lokale Behandlung von Hauttumoren. Während die ECT die Symptome insbesondere bei Patienten mit ulzerierten Läsionen verbessert, sollte auf Basis der Daten die Implementation eines perioperativen Schmerzmanagements besonders bei nichtulzerierten Läsionen während der ECT erwogen werden.

Prospective cohort study by InspECT on safety and efficacy of electrochemotherapy for cutaneous tumors and metastases depending on ulceration.

BACKGROUND: Electrochemotherapy (ECT) is an effective local treatment for cutaneous tumors. The aim of this study was to compare the effectiveness of ECT in ulcerated vs. non-ulcerated tumors and investigate the effect on tumor-associated symptoms. METHODS: Twenty cancer centers in the International Network for Sharing Practices on Electrochemotherapy (InspECT) prospectively collected data. ECT was performed following ESOPE protocol. Response was evaluated by lesion size development. Pain, symptoms, performance status (ECOG-Index) and health status (EQ-5D questionnaire) were evaluated. RESULTS: 716 patients with ulcerated (n = 302) and non-ulcerated (n = 414) cutaneous tumors and metastases were included (minimum follow-up of 45 days). Non-ulcerated lesions responded to ECT better than ulcerated lesions (complete response 65 % vs. 51 %, p = 0.0061). Only 38 % (115/302) with ulcerated lesions before ECT presented with ulcerated lesions at final follow-up. Patients with ulcerated lesions reported higher pain and more severe symptoms compared to non-ulcerated lesions, which significantly and continuously improved following ECT. In non-ulcerated lesions however, pain spiked during the treatment. No serious adverse events were reported. CONCLUSIONS: ECT is a safe and effective local treatment for cutaneous tumors. While ECT improves symptoms especially in patients with ulcerated lesions, data suggest the implementation of a perioperative pain management in non-ulcerated lesions during ECT.

Correction to: 1 Versus 2-cm Excision Margins for pT2-pT4 Primary Cutaneous Melanoma (MelMarT): A Feasibility Study.

In the original article John F. Thompson was inadvertently omitted as an author. The author list is updated as shown in this correction.

1 Versus 2-cm Excision Margins for pT2-pT4 Primary Cutaneous Melanoma (MelMarT): A Feasibility Study.

BACKGROUND: There is a lack of consensus regarding optimal surgical excision margins for primary cutaneous melanoma > 1 mm in Breslow thickness (BT). A narrower surgical margin is expected to be associated with lower morbidity, improved quality of life (QoL), and reduced cost. We report the results of a pilot international study (MelMarT) comparing a 1 versus 2-cm surgical margin for patients with primary melanoma > 1 mm in BT. METHODS: This phase III, multicentre trial [NCT02385214] administered by the Australia & New Zealand Medical Trials Group (ANZMTG 03.12) randomised patients with a primary cutaneous melanoma > 1 mm in BT to a 1 versus 2-cm wide excision margin to be performed with sentinel lymph node biopsy. Surgical closure technique was at the discretion of the treating surgeon. Patients' QoL was measured (FACT-M questionnaire) at baseline, 3, 6, and 12 months after randomisation. RESULTS: Between January 2015 and June 2016, 400 patients were randomised from 17 centres in 5 countries. A total of 377 patients were available for analysis. Primary melanomas were located on the trunk (56.9%), extremities (35.6%), and head and neck (7.4%). More patients in the 2-cm margin group required reconstruction (34.9 vs. 13.6%; p < 0.0001). There was an increased wound necrosis rate in the 2-cm arm (0.5 vs. 3.6%; p = 0.036). After 12 months' follow-up, no differences were noted in QoL between groups. DISCUSSION: This pilot study demonstrates the feasibility of a large international RCT to provide a definitive answer to the optimal excision margin for patients with intermediate- to high-risk primary cutaneous melanoma.

The Mersey Burns App: evolving a model of validation.

INTRODUCTION: 'Mersey Burns App' is a smartphone/tablet application that aids in the assessment of total burn surface area (TBSA) and calculation of fluid resuscitation protocols in burns. This paper presents two studies assessing the speed and accuracy of calculations using Mersey Burns (App) in comparison with a Lund and Browder chart (paper) when a burn is assessed by medical students and clinicians. METHODS: The first study compared the speed and accuracy of TBSA and resuscitation calculation for a photograph of a burn with App and paper using burns and plastics and emergency medicine trainees and consultants. Developing on some of the feedback and results of that study, a second study was then carried out using burns-naive medical students assessing a fully simulated burn with both modalities. Preference and ease of use of each modality were assessed anonymously. RESULTS: The clinician study showed a lower variance in TBSA and fluid calculations using the App (p<0.05). The student study showed no difference in mean TBSA estimations (p=0.7). Mean time to completion of calculations was faster and calculations were more likely to be correct with the App (p<0.001). Students favoured the App in the following categories: preference in emergency setting, confidence in output, accuracy, speed, ease of calculation, overall use and shading (p<0.0001). CONCLUSIONS: Mersey Burns App can facilitate quicker and more accurate calculations than Lund and Browder charts. Students also preferred the App. This suggests a useful role for the App in the care of patients with burns by inexperienced staff.

Quantifying postoperative recovery using wearable activity monitors following abdominal wall surgery: The AbTech trial.

PURPOSE: This work aimed to investigate the validity of wearable activity monitors (WAMs) as an objective tool to measure the return toward normal functional mobility following abdominal wall surgery. This was achieved by quantifying and comparing pre- and postoperative physical activity (PA). METHODS: A multicenter, prospective, observational cohort study was designed. Patients undergoing abdominal wall surgery were assessed for eligibility and consent for study participation was obtained. Participants were asked to wear a WAM (AX3, Axivity) on the wrist of their dominant hand at least 48 hours pre-operatively, for up to 2 weeks postop, and again after 6 months postop for 48 hours. RESULTS: A cohort of 20 patients were recruited in this validation study with a mean age of 47.3 ± 13.0 years. Postoperation, the percentage median PA (±IQR) dropped to 32.6% (20.1), whereas on day 14, PA had reached 64.6% (22.7) of the preoperative value providing construct validity. Activity levels at >6 months postop increased by 16.4% on an average when compared to baseline preoperative PA (p = 0.046). CONCLUSION: This study demonstrates that WAMs are valid markers of postoperative recovery following abdominal wall surgery. This was achieved by quantifying the reduction in PA postoperation, which has not been previously shown. In addition, this study suggests that abdominal wall surgery may improve the patient's quality of life via increased functional mobility at 6 months postop. In the future, this technology could be used to identify the patient and surgical factors that are predictors of outcome following abdominal wall surgery.

Accuracy of a tool to prioritise patients awaiting elective surgery: an implementation report.

STUDY OBJECTIVE: The objective of this study was to evaluate the accuracy of a new elective surgery clinical decision support system, the 'Patient Tacking List' (PTL) tool (C2-Ai(c)) through receiver operating characteristic (ROC) analysis. METHODS: We constructed ROC curves based on risk predictions produced by the tool and compared these with actual patient outcomes on a retrospective cohort of patients awaiting elective surgery. RESULTS: A total of 11 837 patients were included across three National Health Service (NHS) hospitals in England. ROC analysis revealed an area under the curve of 0.95 (95% CI 0.92 to 0.98) for mortality and 0.8 (95% CI 0.78 to 0.82) for complications. DISCUSSION: The PTL tool was successfully integrated into existing data infrastructures, allowing real-time clinical decision support and a low barrier to implementation. ROC analysis demonstrated a high level of accuracy to predict the risk of mortality and complications after elective surgery. As such, it may be a valuable adjunct in prioritising patients on surgical waiting lists.Health systems, such as the NHS in England, must look at innovative methods to prioritise patients awaiting surgery in order to best use limited resources. Clinical decision support tools, such as the PTL tool, can improve prioritisation and thus positively impact clinical care and patient outcomes. CONCLUSIONS: The high level of accuracy for predicating mortality and complications after elective surgery using the PTL tool indicates the potential for clinical decision support tools to help tackle rising waiting lists and improve surgical planning.

Efficacy of Electrochemotherapy in Breast Cancer Patients of Different Receptor Status: The INSPECT Experience.

Electrochemotherapy has been proven to be an efficient treatment for cutaneous metastases of various cancers. Data on breast cancer (BC) patients with cutaneous metastases were retrieved from the INSPECT database. Patients were divided by their receptor status: HER2+, HR+ (ER/PgR+), and TN (triple negative). Groups were similar for histological subtype and location of the nodules. Most patients were previously treated with surgery/systemic therapy/radiotherapy. We found no differences in the three groups in terms of response ratio (OR per patient 86% HER2+, 80% HR+, 76% TN, p = 0.8664). The only factor positively affecting the complete response rate in all groups was small tumor size (<3 cm, p = 0.0105, p = 0.0001, p = 0.0266, respectively). Local progression-free survival was positively impacted by the achievement of complete response in HER2+ (p = 0.0297) and HR+ (p = 0.0094), while overall survival was affected by time to local progression in all groups (p = 0.0065 in HER2+, p < 0.0001 in HR+, p = 0.0363 in TN). ECT treatment is equally effective among groups, despite different receptor status. Response and local tumor control seem to be better in multiple small lesions than in big armor-like lesions, suggesting that treating smaller, even multiple, lesions at the time of occurrence is more effective than treating bigger long-lasting armor-like cutaneous lesions.

Clinical Outcomes and Risk Stratification of Early-Stage Melanoma Micrometastases From an International Multicenter Study: Implications for the Management of American Joint Committee on Cancer IIIA Disease.

PURPOSE: Indications for offering adjuvant systemic therapy for patients with early-stage melanomas with low disease burden sentinel node (SN) micrometastases, namely, American Joint Committee on Cancer (AJCC; eighth edition) stage IIIA disease, are presently controversial. The current study sought to identify high-risk SN-positive AJCC stage IIIA patients who are more likely to derive benefit from adjuvant systemic therapy. METHODS: Patients were recruited from an intercontinental (Australia/Europe/North America) consortium of nine high-volume cancer centers. All were adult patients with pathologic stage pT1b/pT2a primary cutaneous melanomas who underwent SN biopsy between 2005 and 2020. Patient data, primary tumor and SN characteristics, and survival outcomes were analyzed. RESULTS: Three thousand six hundred seven patients were included. The median follow-up was 34 months. Pairwise disease comparison demonstrated no significant survival difference between N1a and N2a subgroups. Survival analysis identified a SN tumor deposit maximum dimension of 0.3 mm as the optimal cut point for stratifying survival. Five-year disease-specific survival rates were 80.3% and 94.1% for patients with SN metastatic tumor deposits ≥ 0.3 mm and < 0.3 mm, respectively (hazard ratio, 1.26 [1.11 to 1.44]; P < .0001). Similar findings were seen for overall disease-free and distant metastasis-free survival. There were no survival differences between the AJCC IB patients and low-risk (< 0.3 mm) AJCC IIIA patients. The newly identified high-risk (≥ 0.3 mm) subgroup comprised 271 (66.4%) of the AJCC IIIA cohort, whereas only 142 (34.8%) patients had SN tumor deposits > 1 mm in maximum dimension. CONCLUSION: Patients with AJCC IIIA melanoma with SN tumor deposits ≥ 0.3 mm in maximum dimension are at higher risk of disease progression and may benefit from adjuvant systemic therapy or enrollment into a clinical trial. Patients with SN deposits < 0.3 mm in maximum dimension can be managed similar to their SN-negative, AJCC IB counterparts, thereby avoiding regular radiological surveillance and more intensive follow-up.

Electrochemotherapy for the treatment of cutaneous squamous cell carcinoma: The INSPECT experience (2008-2020).

Introduction: Cutaneous squamous cell carcinoma (cSCC) is a frequent skin cancer with a high risk of recurrence characterized by tumor infiltration and, in advanced cases, a poor prognosis. ECT (electrochemotherapy) is an alternative treatment option for locally advanced or recurrent cSCC that is unsuitable for surgical resection. In this study, we aimed to evaluate the data in the InspECT (International Network for Sharing Practice on ECT) registry of the referral centers and to clarify the indications for the use of ECT as a treatment modality for cSCC. Materials and methods: Patients with primary, recurrent or locally advanced cSCC from 18 European centers were included. They underwent at least one ECT session with bleomycin between February 2008 and November 2020, which was performed following the European Standard Operating Procedures. Results: The analysis included 162 patients (mean age of 80 years; median, 1 lesion/patient). Side effects were mainly local and mild (hyperpigmentation, 11%; ulceration, 11%; suppuration, 4%). The response to treatment per patient was 62% complete and 21% partial. In the multivariate model, intravenous drug administration and small tumor size showed a significant association with a positive outcome (objective response). One-year local progression-free survival was significantly better (p<0.001) in patients with primary tumors (80% (95% C.I. 70%-90%) than in patients with locally advanced disease (49% (95% C.I. 30%-68%). Conclusion: In the present study, ECT showed antitumor activity and a favorable safety profile in patients with complex cSCC for whom there was no widely accepted standard of care. Better results were obtained in primary and small tumors (<3 cm) using intravenous bleomycin administration.

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.

Cranberry capsules are not superior to placebo capsules in managing acute non-haemorrhagic radiation cystitis in prostate cancer patients: A phase III double blinded randomised placebo controlled clinical trial.

PURPOSE: Acute radiation cystitis affects the quality of life of many prostate cancer patients. A previous pilot study suggested that cranberry capsules may decrease some of the symptoms of acute radiation cystitis. Here we further test their effectiveness in a multicentre double blinded placebo-controlled clinical trial. MATERIAL AND METHODS: A total of 108 prostate cancer patients were recruited at three New Zealand hospitals between September 2016 and January 2019. Out of this cohort, 101 patients provided datasets for analysis (51 men on cranberry capsules and 50 men on beetroot-containing placebo capsules). Patients took two capsules each morning during RT and for 2 weeks after completion of RT. Three measures were used to assess cystitis severity: modified RTOG, O'Leary interstitial cystitis scale and a sensitive novel radiation induced cystitis assessment scale (RICAS). Cystitis severity was scored at baseline and weekly thereafter during RT and for two weeks after completion of RT. Radiation protocols were stratified to conventional fractionation or hypo-fractionated radiation therapy (CHHiP) to the prostate or radiation to the prostate bed. RESULTS: Cranberry capsules performed significantly worse than placebo capsules with respect to day time frequency and bladder control, using the more sensitive RICAS scale. No significant difference in cystitis severity was seen between patients receiving hypofractionation and those receiving conventional fractionation to the prostate gland. CONCLUSION: Cranberry capsules were not superior to beetroot-containing placebo capsules in managing radiation cystitis in our prostate patient cohort. RICAS may be a useful tool for measuring radiation cystitis in future studies.

VEGF165b, an inhibitory vascular endothelial growth factor splice variant: mechanism of action, in vivo effect on angiogenesis and endogenous protein expression.

Growth of new blood vessels (angiogenesis), required for all tumor growth, is stimulated by the expression of vascular endothelial growth factor (VEGF). VEGF is up-regulated in all known solid tumors but also in atherosclerosis, diabetic retinopathy, arthritis, and many other conditions. Conventional VEGF isoforms have been universally described as proangiogenic cytokines. Here, we show that an endogenous splice variant, VEGF(165)b, is expressed as protein in normal cells and tissues and is circulating in human plasma. We also present evidence for a sister family of presumably inhibitory splice variants. Moreover, these isoforms are down-regulated in prostate cancer. We also show that VEGF(165)b binds VEGF receptor 2 with the same affinity as VEGF(165) but does not activate it or stimulate downstream signaling pathways. Moreover, it prevents VEGF(165)-mediated VEGF receptor 2 phosphorylation and signaling in cultured cells. Furthermore, we show, with two different in vivo angiogenesis models, that VEGF(165)b is not angiogenic and that it inhibits VEGF(165)-mediated angiogenesis in rabbit cornea and rat mesentery. Finally, we show that VEGF(165)b expressing tumors grow significantly more slowly than VEGF(165)-expressing tumors, indicating that a switch in splicing from VEGF(165) to VEGF(165)b can inhibit tumor growth. These results suggest that regulation of VEGF splicing may be a critical switch from an antiangiogenic to a proangiogenic phenotype.

Relative expression of vascular endothelial growth factor isoforms in squamous cell carcinoma of the head and neck.

BACKGROUND: Alternative splicing of the vascular endothelial growth factor (VEGF) gene results in a family of antiangiogenic isoforms (VEGFxxx b), not yet investigated in squamous cell carcinoma of the head and neck (SCCHN). We examined, therefore, the prognostic value of the relative expression of VEGF isoforms in SCCHN. METHODS: A tissue microarray comprising 187 SCCHNs was studied by immunohistochemistry with total VEGF (panVEGF) and VEGFxxx b-specific antibodies, and scored by 2 assessors for intensity and proportion. Scores were combined and expression ratios calculated. RESULTS: No meaningful significant differences were observed between panVEGF, VEGFxxx b, or expression ratio, and presence of lymphatic metastasis, or overall survival. This held true when tumor subsites were analyzed independently and when human papillomavirus (HPV) was accounted for in the oropharyngeal subgroup. CONCLUSION: Differential VEGF isoform expression is not a reliable prognostic biomarker for either the clinically node negative/pathologically node-positive neck or overall survival in pharyngeal and laryngeal SCCHNs.

The role of vascular endothelial growth factor in wound healing.

Revascularization of damaged tissue is a necessary part of wound healing. With unregulated or insufficient vessel growth, healing is delayed or pathological. Angiogenesis is regulated by expression of a variety of vascular growth factors and modulators, the most widely expressed and critical of which is vascular endothelial growth factor (VEGF). This protein is secreted by tissues in response to ischemic and inflammatory stimuli and results in endothelial migration, proliferation, and increased vascular permeability. The regulation of VEGF expression during wound healing is of considerable importance since angiogenesis appears to be disturbed in abnormally healing wounds. This paper describes the current state of knowledge of VEGF expression in wounds, regulation of expression, control of isoform specificity, and the effects of VEGF expression on blood vessels as they grow in wound healing, as understood from many different pathological paradigms.