Plain language summary of the CheckMate 76K study results: nivolumab given after stage 2B/2C melanoma is removed by surgery.

WHAT IS THIS SUMMARY ABOUT?: In this article, we summarize results from the ongoing phase 3 CheckMate 76K clinical study published online in Nature Medicine in October 2023. The study goal was to learn whether nivolumab works as an adjuvant therapy (that is, helps to keep cancer from coming back when it is given after surgery) for stage 2 melanoma (skin cancer) that has not spread to other parts of the body. Nivolumab is an immunotherapy that activates a person's immune system so it can destroy cancer cells. In melanoma, staging describes the severity of the cancer. Melanoma staging ranges from 0 (very thin and confined to the upper layer of the skin) to 4 (spread to distant parts of the body), with earlier stages removed by surgery. The people in this study had stage 2 melanoma that had not spread to the lymph nodes or other organs in the body. HOW WAS THE STUDY DESIGNED?: People 12 years and older with stage 2 melanoma that had not spread and had been removed by surgery were included in CheckMate 76K. People were randomly assigned to receive either nivolumab (526 patients) or placebo (264 patients). A placebo resembles the test medicine but does not contain any active medicines. The researchers assessed whether people who received nivolumab lived longer without their cancer returning and/or spreading to other parts of their bodies (compared with placebo) and if nivolumab was well tolerated. WHAT WERE THE RESULTS?: Researchers found that people who received nivolumab were 58% less likely to have their cancer return and 53% less likely of having their cancer spread to distant parts of their body, compared with placebo. These reductions in risk with nivolumab were seen in different subgroups of people with a range of characteristics, and regardless of how deep the melanoma had gone into the skin. People taking nivolumab had more side effects than those taking placebo, but most were mild to moderate and manageable. WHAT DO THE RESULTS MEAN?: Results from CheckMate 76K support the benefit of using nivolumab as a treatment option for people with stage 2 melanoma post-surgery.

Long-term outcomes of patients with active melanoma brain metastases treated with combination nivolumab plus ipilimumab (CheckMate 204): final results of an open-label, multicentre, phase 2 study.

BACKGROUND: Combination nivolumab plus ipilimumab was efficacious in patients with asymptomatic melanoma brain metastases (MBM) in CheckMate 204, but showed low efficacy in patients with symptomatic MBM. Here, we provide final 3-year follow-up data from the trial. METHODS: This open-label, multicentre, phase 2 study (CheckMate 204) included adults (aged ≥18 years) with measurable MBM (0·5-3·0 cm in diameter). Asymptomatic patients (cohort A) had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 and no neurological symptoms or baseline corticosteroid use; symptomatic patients (cohort B) had an ECOG performance status of 0-2 with stable neurological symptoms and could be receiving low-dose dexamethasone. Nivolumab 1 mg/kg plus ipilimumab 3 mg/kg was given intravenously every 3 weeks for four doses, followed by nivolumab 3 mg/kg every 2 weeks for up to 2 years, until disease progression or unacceptable toxicity. The primary endpoint was intracranial clinical benefit rate (complete responses, partial responses, or stable disease lasting ≥6 months) assessed in all treated patients. Intracranial progression-free survival and overall survival were key secondary endpoints. This study is registered with ClinicalTrials.gov, NCT02320058. FINDINGS: Between Feb 19, 2015, and Nov 1, 2017, 119 (72%) of 165 screened patients were enrolled and treated: 101 patients were asymptomatic (cohort A; median follow-up 34·3 months [IQR 14·7-36·4]) and 18 were symptomatic (cohort B; median follow-up 7·5 months [1·2-35·2]). Investigator-assessed intracranial clinical benefit was observed in 58 (57·4% [95% CI 47·2-67·2]) of 101 patients in cohort A and three (16·7% [3·6-41·4]) of 18 patients in cohort B; investigator-assessed objective response was observed in 54 (53·5% [43·3-63·5]) patients in cohort A and three (16·7% [3·6-41·4]) patients in cohort B. 33 (33%) patients in cohort A and three (17%) patients in cohort B had an investigator-assessed intracranial complete response. For patients in cohort A, 36-month intracranial progression-free survival was 54·1% (95% CI 42·7-64·1) and overall survival was 71·9% (61·8-79·8). For patients in cohort B, 36-month intracranial progression-free survival was 18·9% (95% CI 4·6-40·5) and overall survival was 36·6% (14·0-59·8). The most common grade 3-4 treatment-related adverse events (TRAEs) were increased alanine aminotransferase and aspartate aminotransferase (15 [15%] of 101 patients each) in cohort A; no grade 3 TRAEs occurred in more than one patient each in cohort B, and no grade 4 events occurred. The most common serious TRAEs were colitis, diarrhoea, hypophysitis, and increased alanine aminotransferase (five [5%] of each among the 101 patients in cohort A); no serious TRAE occurred in more than one patient each in cohort B. There was one treatment-related death (myocarditis in cohort A). INTERPRETATION: The durable 3-year response, overall survival, and progression-free survival rates for asymptomatic patients support first-line use of nivolumab plus ipilimumab. Symptomatic disease in patients with MBM remains difficult to treat, but some patients achieve a long-term response with the combination. FUNDING: Bristol Myers Squibb.

Triple-layer midface lifting: long-term follow-up of an effective approach to aesthetic surgery of the lower eyelid and the midface.

BACKGROUND: It is becoming more and more accepted that better aesthetic results can be obtained when the lower eyelid is considered as part of the midface when contemplating surgical rejuvenation. Descent of the orbicularis muscle and midface tissue causes malar bags, loss of volume over the tear-trough, apparent vertical lengthening of the lower eyelid, and an accentuation of the orbit-cheek junction. METHODS: We describe a triple-layer technique that effectively corrects these problems, performed under local anesthesia and via a standard subciliary incision, to separately reposition the postseptal fat, suborbicularis oculi fat, and the musculocutaneous layer of skin and orbicularis oculi. We present a detailed analysis of the complications arising from a series of over 500 patients, in which this technique has been performed by the senior author. RESULTS: The average patient age at the time of surgery was 51 years old (± 7.9), with a median follow-up of 7 months (range 3-121). Complications were observed in 77 of 512 cases. In total, 44 of these cases required surgical reintervention under local anesthesia (rated as major complications and all reinterventions lasted <30 min) and 33 cases were treated conservatively (minor complications). CONCLUSION: The triple-layer midface lift is an effective way to reverse the combination of ptosis and changes in volume of the aging midface. It yields long-lasting results with a minimal risk for complications, particularly when a tarsal tuck is performed simultaneously in patients at high risk for the development of scleral show. LEVEL OF EVIDENCE V: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Adjuvant nivolumab in resected stage IIB/C melanoma: primary results from the randomized, phase 3 CheckMate 76K trial.

Patients with resected stage IIB/C melanoma have high recurrence risk, similar to those with resected stage IIIA/B disease. The phase 3, double-blind CheckMate 76K trial assessed 790 patients with resected stage IIB/C melanoma randomized 2:1 (stratified by tumor category) to nivolumab 480 mg or placebo every 4 weeks for 12 months. The primary endpoint was investigator-assessed recurrence-free survival (RFS). Secondary endpoints included distant metastasis-free survival (DMFS) and safety. At 7.8 months of minimum follow-up, nivolumab significantly improved RFS versus placebo (hazard ratio (HR) = 0.42; 95% confidence interval (CI): 0.30-0.59; P < 0.0001), with 12-month RFS of 89.0% versus 79.4% and benefit observed across subgroups; DMFS was also improved (HR = 0.47; 95% CI: 0.30-0.72). Treatment-related grade 3/4 adverse events occurred in 10.3% (nivolumab) and 2.3% (placebo) of patients. One treatment-related death (0.2%) occurred with nivolumab. Nivolumab is an effective and generally well-tolerated adjuvant treatment in patients with resected stage IIB/C melanoma. ClinicalTrials.gov identifier: NCT04099251 .

Prophylactic administration of avotermin for improvement of skin scarring: three double-blind, placebo-controlled, phase I/II studies.

BACKGROUND: Research into mechanisms of skin scarring identified transforming growth factor beta3 (TGFbeta3) as a potential antiscarring therapy. We assessed scar improvement with avotermin (recombinant, active, human TGFbeta3). METHODS: In three double-blind, placebo-controlled studies, intradermal avotermin (concentrations ranging from 0.25 to 500 ng/100 microL per linear cm wound margin) was administered to both margins of 1 cm, full-thickness skin incisions, before wounding and 24 h later, in healthy men and women. Treatments (avotermin and placebo or standard wound care) were randomly allocated to wound sites by a computer generated randomisation scheme, and within-participant controls compared avotermin versus placebo or standard wound care alone. Primary endpoints were visual assessment of scar formation at 6 months and 12 months after wounding in two studies, and from week 6 to month 7 after wounding in the third. Investigators, participants, and scar assessors were blinded to treatment. Efficacy analyses were intention to treat. These studies are registered with ClinicalTrials.gov, numbers NCT00847925, NCT00847795, and NCT00629811. RESULTS: In two studies, avotermin 50 ng/100 microL per linear cm significantly improved median score on a 100 mm visual analogue scale (VAS) by 5 mm (range -2 to 14; p=0.001) at month 6 and 8 mm (-29 to 18; p=0.0230) at month 12. In the third, avotermin significantly improved total scar scores at all concentrations versus placebo (mean improvement: from 14.84 mm [95 % CI 5.5-24.2] at 5 ng/100 microL per linear cm to 64.25 mm [49.4-79.1] at 500 ng/100 microL per linear cm). Nine [60%] scars treated with avotermin 50 ng/100 microL per linear cm showed 25% or less abnormal orientation of collagen fibres in the reticular dermis versus five [33%] placebo scars. After only 6 weeks from wounding, avotermin 500 ng/100 microL per linear cm improved VAS score by 16.12 mm (95% CI 10.61-21.63). Adverse events at wound sites were similar for avotermin and controls. Erythema and oedema were more frequent with avotermin than with placebo, but were transient and deemed to be consistent with normal wound healing. INTERPRETATION: Avotermin has potential to provide an accelerated and permanent improvement in scarring.

Enhanced Morbidity and Mortality Meeting and Patient Safety Education for Specialty Trainees.

INTRODUCTION: Mortality and morbidity (M&M) meetings present a forum to discuss and review in-hospital deaths and complications to improve patient care. However, it remains an untapped resource to improve the exposure of the trainees to the principles of patient safety METHODS: We modified the departmental M&M meetings to enhance the delivery of patient safety education. The meeting started with a 5-minute overview of general patient safety principles, followed by a trainee-led discussion of a recent patient safety incident where opinions were sought about key learning points and ways to prevent the incident from happening in future. The discussion concluded with a patient safety presentation summarizing the salient points that were mapped to the WHO Patient Safety Curriculum. The suggestions from the meeting were noted, and the changes were instituted in the department over the next month and were reported back in the next meeting. RESULTS: From January to August 2012, seven enhanced M&M meetings were organized and attended by orthopaedic specialty trainees in a postgraduate Deanery. We explored the early impact of these monthly discussions by using the Junior Doctors' Patient Safety Attitudes and Climate Questionnaire as an assessment tool. The questionnaire reports an early impact on patient safety knowledge, awareness, and attitudes to patient safety; however, more work is needed to improve the workplace safety climate. CONCLUSIONS: We recommend immediate introduction of the enhanced M&M meetings focusing on patient safety in the other disciplines and postgraduate deaneries.

Avotermin: a novel antiscarring agent.

Published literature shows that both physicians and their patients are highly concerned about scarring, even relatively minor scars and those that can be concealed by clothing. Furthermore, both patients and their physicians value any opportunities to improve or minimize scarring. While a range of treatment paradigms have been evaluated, no single therapy has been adopted as a universally accepted standard of care and, currently, there are no marketed pharmaceuticals for the prophylactic reduction of scarring. Many of the available treatments are used empirically and most have not been evaluated in robust prospective, randomized, controlled clinical trials. To address this unmet medical need, translational research into the molecular mechanisms of scarring has led to the discovery and commercial development of a new class of prophylactic medicines that promote the regeneration of normal skin and improve scar appearance. Avotermin, the first agent identified in this class, is the clinical application of human recombinant transforming growth factor beta3 (TGFbeta3), a key protein involved in scar-free healing observed in embryos. Controlled, double-blind, randomized phase I/II clinical studies have shown that avotermin, administered as an intradermal injection at the time of surgery, leads to both short-term and longer-term (at >or=12 months) improvements in the appearance of scars compared with placebo and standard wound care.

Povidone-iodine: use in hand disinfection, skin preparation and antiseptic irrigation.

Iodine and its antibacterial properties have been used for the prevention or management of wound infections for over 150 years. However, the use of solutions (tincture) of iodine has been replaced by the widespread use of povidone-iodine, a water-soluble compound, which is a combination of molecular iodine and polyvinylpyrrolidone. The resultant broad spectrum of antimicrobial activity is well documented and its efficacy, particularly in relation to resistant micro-organisms such as methicillin-resistant Staphylococcus aureus, has been shown. In the clinical environment, there is no general agreement regarding the 'best' antiseptic and the practice varies widely. This article reviews the studies that have assessed the efficacy of povidone-iodine in hand disinfection and skin preparation and its use as an antiseptic irrigant. Although there is a distinct lack of well-designed, randomised controlled trials evaluating antiseptic efficacy, selection should be based on the next best available evidence. This evidence suggests that the use of povidone-iodine as an agent of choice is dependent on the clinical need but is also likely to be influenced by personal preference.

Topical antimicrobial therapy of chronic wounds healing by secondary intention using iodine products.

All open wounds healing by secondary intention are contaminated by bacteria and in chronic wounds this can progress through colonisation to invasive infection. Iodine products reduce bacterial load and are active against most species of micro-organisms, and certainly those encountered in chronic wound care. This review evaluates the use of iodine products in chronic wound care including povidone-iodine solutions and cadexomer iodine. Antiseptics containing iodine are relatively cheap, resistance is unknown and concerns about systemic toxicity are probably overstated. More widespread use of these agents as topical anti-microbials in chronic wound care should be considered to reduce the need for systemic antibiotics when colonisation has progressed to invasive infection with systemic signs.

Google searches do not correlate with melanoma incidence in majority English speaking countries.

Recent reports have suggested that internet search behaviour may be a valuable tool to estimate melanoma incidence and mortality. Previous studies have used incorrect statistical methods, were focussed on the United States and/or did not use non-cancer control search terms to provide a context for interpreting the effects seen with the cancer-related terms. Using more robust statistical methods we found that no cancer search terms were significantly, or strongly correlated with melanoma incidence in 6 countries.

Junior doctors and patient safety: evaluating knowledge, attitudes and perception of safety climate.

INTRODUCTION: Engagement of junior doctors in patient safety initiatives is high on the national agenda, but there is a lack of studies evaluating patient safety attitudes among junior doctors. METHODS: The Junior Doctor-Patient Safety Attitudes and Climate Questionnaire is a multidimensional scale created using items from already-validated scales and inclusion of new items based on further review. It consists of three subscales: 'knowledge and training' (10 items), 'attitudes to patient safety' (15 items) and 'perception of workplace safety climate' (15 items). This was disseminated to foundation trainees, general practice trainees and hospital core and speciality trainees via the Deanery distribution lists and responses were collected anonymously. RESULTS: A total of 527 complete responses were collected; although self-declared knowledge in patient safety concepts was high, there was less declared understanding of a 'high reliability organisation' (74% no/unsure) and the concept of active failures/latent conditions (60% no/unsure). The greatest agreement was demonstrated for the statement 'Even the most experienced and competent doctors make errors' (p<0.01). However, more senior trainees and surgical trainees (vs medical trainees) demonstrated greater agreement with 'Medical error is a sign of incompetence' (p<0.01). More junior trainees demonstrated greater agreement with 'Management is more interested in meeting performance targets than focusing on patient safety issues' (p<0.01). CONCLUSIONS: This study demonstrates subtle differences in attitudes to patient safety among junior doctors of different grades and specialities. These should be taken into account when designing interventions to improve patient safety education and culture among junior doctors.

Avotermin for scar improvement following scar revision surgery: a randomized, double-blind, within-patient, placebo-controlled, phase II clinical trial.

BACKGROUND: Skin scarring is associated with psychosocial distress and has a negative effect on quality of life. The transforming growth factor (TGF)-ß family of cytokines plays a key role in scarring. TGF-ß3 improves scar appearance in a range of mammalian species. This study was performed to assess the efficacy of intradermal avotermin (TGF-ß3) for the improvement of scar appearance following scar revision surgery. METHODS: Sixty patients (35 men and 25 women; age, 19 to 78 years; 53 Caucasians; scar length, 5 to 21 cm) received intradermal avotermin (200 ng/100 µl/linear cm wound margin) and placebo to outer wound segments immediately after, and again 24 hours after, complete (group 1) or staged (group 2) scar revision surgery. A within-patient design was chosen to control for interindividual factors that affect scarring. The primary efficacy variable was a total scar score derived from a visual analogue scale, scored by a lay panel from standardized photographs from months 1 through 7 following treatment. RESULTS: : Primary endpoint data from the combined surgical groups showed that avotermin significantly improved scar appearance compared with placebo (total scar score difference, 21.93 mm; p = 0.04). Profilometry showed a greater reduction in scar surface area from baseline with avotermin treatment compared with placebo, significant in group 2 at months 7 and 12 (difference, 41.99 mm and 25.85 mm, respectively; p = 0.03 for both comparisons). Histologic analysis from group 2 showed that, compared with placebo treatment, collagen organization in avotermin-treated scars more closely resembled normal skin in 14 of 19 cases. Avotermin was well tolerated. CONCLUSION: Avotermin administration following scar revision surgery is well tolerated and significantly improves scar appearance compared with placebo. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, I.(Figure is included in full-text article.).

Scar-improving efficacy of avotermin administered into the wound margins of skin incisions as evaluated by a randomized, double-blind, placebo-controlled, phase II clinical trial.

BACKGROUND: The authors report on a prospective, randomized, placebo-controlled phase II trial to investigate avotermin (transforming growth factor beta-3) for reducing scarring resulting from acute incised skin wounds. METHODS: Seventy-one healthy male subjects (18 to 45 years) received avotermin at 50 or 200 ng/100 µl/linear centimeter of wound margin. Subjects received three standardized 1-cm incisional wounds on the inner aspect of each upper arm. Wounds were randomized to receive (into each margin): no injection (standard wound care only), one intradermal injection of avotermin or placebo (immediately before surgery), or two injections of avotermin or placebo (immediately before surgery and 24 hours later). The primary efficacy variable was a 10-cm visual analog scale score, which assessed how closely scars resembled normal skin, administered at month 12 by an independent external scar assessment panel (a panel of lay public individuals). RESULTS: Avotermin at 200 ng/100 µl/linear centimeter, administered once or twice, achieved significant improvements in scar appearance compared with controls (p<0.02 for all comparisons). The 50-ng dose, administered twice, achieved significant improvements in scar appearance versus placebo (p=0.043). Treatment was well tolerated. CONCLUSION: These results confirm that avotermin is the first of a new class of regenerative medicines that reduce scarring when administered once or twice to the approximated margins of acute skin incisions.

The Patient Scar Assessment Questionnaire: a reliable and valid patient-reported outcomes measure for linear scars.

BACKGROUND: There is a lack of rigorously validated patient-based outcomes measures of scarring. The aim of this study was to construct such a scale and demonstrate reliability and validity by applying the scale in a wide range of scarring samples. METHODS: The Patient Scar Assessment Questionnaire with five subscales (i.e., Appearance, Symptoms, Consciousness, Satisfaction with Appearance, and Satisfaction with Symptoms) was constructed using multiple categorical response items. The Patient Scar Assessment Questionnaire was applied to various surgical samples (total scar assessments n = 667) at months 3, 6, and 12 after surgery (and preoperatively in the scar revision group) and tested for internal consistency, test-retest reliability, convergent validity, known group differences, and sensitivity, against widely accepted criteria from psychometric measurement science. RESULTS: Subscales showed high internal consistency (Cronbach alpha, 0.73 to 0.93), except the Symptoms subscale. Test-retest reliability was high across all subscales (intraclass correlation coefficient, 0.74 to 0.87) across all groups except the scar revision group. Change in Patient Scar Assessment Questionnaire scores was significant between months 3 and 6 postoperatively (p < 0.001) and subscales demonstrated known group differences (p < 0.001). Convergent validity was demonstrated by significant moderate correlations with various measures of similar constructs (r = 0.26 to 0.61, p < 0.001). CONCLUSIONS: The Patient Scar Assessment Questionnaire is a reliable and valid measure of the patient's perception of scarring, although the Symptoms subscale requires further refinement. Subscales can be used independently of each other to allow assessment of scar change in specific domains.

Current scales for assessing human scarring: a review.

Patients can have wide-ranging problems related to scars, in terms of cosmesis, function, symptoms, psychological problems and overall quality of life issues. A range of treatments have been recommended for problematic scarring, however it has been acknowledged that the evidence base for most of the recommendations for scar therapy is limited, with few studies using validated measures of scar assessment in generating data. This review critically evaluates the subjective scar assessment scales developed to date and provides an insight into developments required in this area for the future. The principles of psychometric theory are discussed as a means of developing reliable and valid outcome measures and these are also applicable for measuring outcomes in other fields of plastic surgery research.

Duplicate publications: redundancy in plastic surgery literature.

The practice of duplicate publication has been condemned widely in the scientific community and several studies have been conducted to establish the level of the problem in various surgical fields. A retrospective review of original articles from the British Journal of Plastic Surgery and Plastic and Reconstructive Surgery during 2000 was conducted, using Medline (PubMed). A total of 431 abstracts were screened, from which 27 index articles related to 33 'suspected redundant' publications. Further evaluation was carried out by comparing the full text versions of these articles and assigning a grade of non-dual, dual, potentially dual and 'salami-slicing'. Only four suspect articles were confirmed as having some degree of redundancy, and these related to three index articles (3/431, <1%). The incidence of duplication in plastic surgery literature seems to be much lower compared to other surgical specialties, providing reassurance for reviewers, editors and readers of these journals.