Five-year analysis of neoadjuvant dabrafenib and trametinib for stage III melanoma.

BACKGROUND: Neoadjuvant dabrafenib plus trametinib has a high pathological response rate and impressive short-term survival in patients with resectable stage III melanoma. We report five-year outcomes from the phase II NeoCombi trial. METHODS: NeoCombi (NCT01972347) was a single-arm, open-label, single-centre, phase II trial. Eligible patients were adults (aged ≥18) with histologically-confirmed, resectable, RECIST-measurable AJCC 7th ed. clinical stage IIIB-C BRAF V600E/K-mutant melanoma and Eastern Co-operative Oncology Group performance status ≤1. Patients received 52 weeks of treatment with 150 mg dabrafenib (orally twice per day) plus 2 mg trametinib (orally once per day), with complete resection of the pre-therapy tumour bed at Week 12. RESULTS: Between August 20, 2014, and April 19, 2017, 35 patients were enrolled. At data cut-off (August 17, 2021), the median follow-up was 60 months (95% CI 56-72). Overall, 21 of 35 (60%) patients recurred, including twelve (57%) with first recurrence in locoregional sites (followed by later distant recurrence in six) and nine (43%) with first recurrence in distant sites, including three in the brain. Most recurrences occurred within two years, with no recurrences beyond three years. At five years, recurrence-free survival was 40% (95% CI 27-60), distant metastasis-free survival was 57% [95% CI 42-76%], and overall survival was 80% (95% CI 67-94). Five-year survival outcomes were stratified by pathological response: recurrence-free survival was 53% with pCR versus 28% with non-pCR (p=0.087), distant metastasis-free survival was 59% versus 55% (p=0.647), and overall survival was 88% versus 71% (p=0.205), respectively. CONCLUSIONS: Neoadjuvant dabrafenib plus trametinib has high pathological response rates in clinical stage III melanoma, but low rates of recurrence-free survival, similar to those achieved with adjuvant targeted therapy alone. Patients with a pCR to dabrafenib plus trametinib still had a high risk of recurrence, unlike that seen with immunotherapy where recurrences are rare.

The Effect of Neoadjuvant Systemic Therapy on Surgical Outcomes After Lymph Node Dissections for Stage III Melanoma; An Australian Cohort.

BACKGROUND: Neoadjuvant systemic therapy (NAST) for patients with stage III melanoma achieves high major pathologic response rates and high recurrence-free survival rates. This study aimed to determine how NAST with targeted therapies (TTs) and immune checkpoint inhibitors (ICIs) influences surgical outcomes after lymph node dissection in terms of complications, morbidity, and textbook outcomes. METHODS: Patients who underwent a lymph node dissection after either NAST in a clinical trial or upfront surgery for stage III melanoma between 2014 and 2022 were identified from an institutional research database. RESULTS: The study included 89 NAST-treated patients and 79 upfront surgery-treated patients. The rate of postoperative complications did not differ between the NAST- and upfront surgery-treated patients (55% vs. 51%; p = 0.643), and steroid treatment for drug toxicity did not influence the complication rate (odds ratio [OR], 1.1; 95% confidence interval [CI], 0.4-3; p = 0.826). No significant differences in postoperative morbidity were observed in terms of seroma (23% vs. 11%; p = 0.570) or lymphedema (36% vs. 51%; p = 0.550). The rate of achieving a textbook outcome was comparable for the two groups (61% vs. 57%; p = 0.641). CONCLUSIONS: The surgical outcomes after lymph node dissections were comparable between the patients who received NAST and those who had upfront surgery, indicating that surgery can be safely performed after NAST with TT or ICI for stage III melanoma.

Impact of an Online Risk Calculator for Sentinel Node Positivity on Management of Patients with T1 and T2 Melanomas.

BACKGROUND: Predicting which patients with American Joint Committee on Cancer (AJCC) T1-T2 melanomas will have a positive sentinel lymph node (SLN) is challenging. Melanoma Institute Australia (MIA) developed an internationally validated SLN metastatic risk calculator. This study evaluated the nomogram's impact on T1-T2 melanoma patient management at MIA. METHODS: SLN biopsy (SLNB) rates were compared for the pre- and post-nomogram periods of 1 July 2018-30 June 2019 and 1 August 2020-31 July 2021, respectively. RESULTS: Overall, 850 patients were identified (pre-nomogram, 383; post-nomogram, 467). SLNB was performed in 29.0% of patients in the pre-nomogram group and 34.5% in the post-nomogram group (p = 0.091). The overall positivity rate was 16.2% in the pre-nomogram group and 14.9% in the post-nomogram group (p = 0.223). SLNB was performed less frequently in T1a melanoma patients in the pre-nomogram group (1.1%, n = 2/177) than in the post-nomogram group (8.6%, n = 17/198) [p ≤ 0.001]. This increase was particularly for melanomas with a risk score ≥ 5%, with an SLN positivity rate of 11.8% in the post-nomogram group (p = 0.004) compared with zero. For T1b melanomas with a risk score of > 10%, the SLNB rate was 40.0% (8/20) pre-nomogram and 75.0% (12/16) post-nomogram (p = 0.049). CONCLUSIONS: In this specialized center, the SLN risk calculator appears to influence practice for melanomas previously considered low risk for metastasis, with increased use of SLNB for T1a and higher-risk T1b melanomas. Further evaluation is required across broader practice settings. Melanoma management guidelines could be updated to incorporate the availability of nomograms to better select patients for SLNB than previous criteria.

The impact of CREBRF rs373863828 Pacific-variant on infant body composition.

In Maori and Pacific adults, the CREBRF rs373863828 minor (A) allele is associated with increased body mass index (BMI) but reduced incidence of type-2 and gestational diabetes mellitus. In this prospective cohort study of Maori and Pacific infants, nested within a nutritional intervention trial for pregnant women with obesity and without pregestational diabetes, we investigated whether the rs373863828 A allele is associated with differences in growth and body composition from birth to 12-18 months' corrected age. Infants with and without the variant allele were compared using generalised linear models adjusted for potential confounding by gestation length, sex, ethnicity and parity, and in a secondary analysis, additionally adjusted for gestational diabetes. Carriage of the rs373863828 A allele was not associated with altered growth and body composition from birth to 6 months. At 12-18 months, infants with the rs373863828 A allele had lower whole-body fat mass [FM 1.4 (0.7) vs. 1.7 (0.7) kg, aMD -0.4, 95% CI -0.7, 0.0, P = 0.05; FM index 2.2 (1.1) vs. 2.6 (1.0) kg/m2 aMD -0.6, 95% CI -1.2,0.0, P = 0.04]. However, this association was not significant after adjustment for gestational diabetes, suggesting that it may be mediated, at least in part, by the beneficial effect of CREBRF rs373863828 A allele on maternal glycemic status.

Refining the predictive value of preoperative apparent diffusion coefficient (ADC) by whole-tumor analysis for facial nerve outcomes in vestibular schwannomas.

BACKGROUND: Apparent diffusion coefficient (ADC) in MRI has been shown to correlate with postoperative House-Brackmann (HB) scores in patients with vestibular schwannoma despite limited methodology. To rectify limitations of single region of interest (ROI) sampling, we hypothesize that whole-tumor ADC histogram analysis will refine the predictive value of this preoperative biomarker related to postoperative facial nerve function. METHODS: Of 155 patients who underwent resection of vestibular schwannoma (2014-2020), 125 patients were included with requisite clinical and radiographic data. After volumetric analysis and whole-tumor ADC histogram, regression tree analysis identified ADC cutoff for significant differences in HB grade. Outcomes were extent of resection, facial nerve function, hospital length of stay (LOS), and complications. RESULTS: Regression tree analysis defined three quantitative ADC groups (× 10-6 mm2/s) as high (> 2248.77; HB 1.7), mid (1468.44-2248.77; HB 3.1), and low (< 1468.44; HB 2.3) range (p 0.04). The mid-range ADC group had significantly worse postoperative HB scores and longer hospital LOS. Large tumor volume was independently predictive of lower rates of gross total resection (p <0.0001), higher postoperative HB score (p 0.002), higher rate of complications (p 0.04), and longer LOS (p 0.003). CONCLUSIONS: Whole-tumor histogram yielded a robust regression tree analysis that defined three ADC groups with significantly different facial nerve outcomes. This likely reflects tumor heterogeneity better than solid-tumor ROI sampling. Whole-tumor ADC warrants further study as a useful radiographic biomarker in patients with vestibular schwannoma who are considering surgical resection.

Development and validation of a novel model to predict recurrence-free survival and melanoma-specific survival after sentinel lymph node biopsy in patients with melanoma: an international, retrospective, multicentre analysis.

BACKGROUND: The introduction of adjuvant systemic treatment for patients with high-risk melanomas necessitates accurate staging of disease. However, inconsistencies in outcomes exist between disease stages as defined by the American Joint Committee on Cancer (8th edition). We aimed to develop a tool to predict patient-specific outcomes in people with melanoma rather than grouping patients according to disease stage. METHODS: Patients older than 13 years with confirmed primary melanoma who underwent sentinel lymph node biopsy (SLNB) between Oct 29, 1997, and Nov 11, 2013, at four European melanoma centres (based in Berlin, Germany; Amsterdam and Rotterdam, the Netherlands; and Warsaw, Poland) were included in the development cohort. Potential predictors of recurrence-free and melanoma-specific survival assessed were sex, age, presence of ulceration, primary tumour location, histological subtype, Breslow thickness, sentinel node status, number of sentinel nodes removed, maximum diameter of the largest sentinel node metastasis, and Dewar classification. A prognostic model and nomogram were developed to predict 5-year recurrence-free survival on a continuous scale in patients with stage pT1b or higher melanomas. This model was also calibrated to predict melanoma-specific survival. Model performance was assessed by discrimination (area under the time-dependent receiver operating characteristics curve [AUC]) and calibration. External validation was done in a cohort of patients with primary melanomas who underwent SLNB between Jan 30, 1997, and Dec 12, 2013, at the Melanoma Institute Australia (Sydney, NSW, Australia). FINDINGS: The development cohort consisted of 4071 patients, of whom 2075 (51%) were female and 1996 (49%) were male. 889 (22%) had sentinel node-positive disease and 3182 (78%) had sentinel node-negative disease. The validation cohort comprised 4822 patients, of whom 1965 (41%) were female and 2857 (59%) were male. 891 (18%) had sentinel node-positive disease and 3931 (82%) had sentinel node-negative disease. Median follow-up was 4·8 years (IQR 2·3-7·8) in the development cohort and 5·0 years (2·2-8·9) in the validation cohort. In the development cohort, 5-year recurrence-free survival was 73·5% (95% CI 72·0-75·1) and 5-year melanoma-specific survival was 86·5% (85·3-87·8). In the validation cohort, the corresponding estimates were 66·1% (64·6-67·7) and 83·3% (82·0-84·6), respectively. The final model contained six prognostic factors: sentinel node status, Breslow thickness, presence of ulceration, age at SLNB, primary tumour location, and maximum diameter of the largest sentinel node metastasis. In the development cohort, for the model's prediction of recurrence-free survival, the AUC was 0·80 (95% CI 0·78-0·81); for prediction of melanoma-specific survival, the AUC was 0·81 (0·79-0·84). External validation showed good calibration for both outcomes, with AUCs of 0·73 (0·71-0·75) and 0·76 (0·74-0·78), respectively. INTERPRETATION: Our prediction model and nomogram accurately predicted patient-specific risk probabilities for 5-year recurrence-free and melanoma-specific survival. These tools could have important implications for clinical decision making when considering adjuvant treatments in patients with high-risk melanomas. FUNDING: Erasmus Medical Centre Cancer Institute.

The Cost-Effectiveness of Smoking Cessation Programs for Prevention of Wound Complications Following Total Ankle Arthroplasty: A Break-Even Analysis.

Background: Tobacco use significantly increases the rate of wound complications in patients undergoing total ankle arthroplasty (TAA). Preoperative optimization through smoking cessation programs significantly minimizes the rate of infection and improves wound healing in arthroplasty procedures. Despite its utility, minimal research has examined the cost-effectiveness of preoperative smoking cessation programs to reduce the need for extracapsular irrigation and debridement (I&D) due to wound complications following TAA. Methods: The cost of an I&D procedure was obtained from our institution's purchasing records. Baseline wound complication rates among tobacco users who have undergone TAA and smoking cessation program cost were obtained from literature. A break-even economic analysis was performed to determine the absolute risk reduction (ARR) to economically justify the implementation of preoperative smoking cessation programs. Different smoking cessation program and I&D costs were tested to account for variations in each factor. ARR was then used to calculate the number needed to treat (NNT) to prevent a single I&D while remaining cost-effective. Results: Smoking cessation programs were determined to be economically justified if it prevents 1 I&D surgery out of 8 TAAs among tobacco users (ARR = 12.66%) in the early postoperative period (<30 days). ARR was the same at the literature high (27.3%) and weighted literature average (13.3%) complication rates when using the cost of I&D surgery at our institution ($1757.13) and the literature value for a smoking cessation program ($222.45). Cost-effectiveness was maintained with higher I&D surgery costs and lower costs of smoking cessation treatment. Conclusion: Our model's input data suggest that the routine use of smoking cessation programs among tobacco users undergoing TAA is cost-effective for risk reduction of I&D surgery in the early postoperative period. This intervention was also found to be economically warranted with higher I&D costs and lower smoking cessation program costs than those found in the literature and at our institution.Level of Evidence: Level III, economic and decision analysis.

Outcomes of Pars Plana Vitrectomy With Membrane Peel for Lamellar Macular Holes and Related Conditions Using a New Optical Coherence Tomography Consensus Definition.

Purpose: To characterize the change in visual acuity (VA) in eyes treated with vitrectomy using the 2020 international consensus-based optical coherence tomography (OCT) definition of lamellar macular hole (LMH), macular pseudohole (MPH), and epiretinal membrane with foveoschisis (ERMF). Methods: A retrospective chart review was performed from 2000 to 2022 of patients who had vitrectomy for symptomatic decreased VA from LMH, MPH, or ERMF performed by the same surgeon at a community hospital. Preoperative spectral domain (SD-OCT) was reviewed to classify patients using the consensus guidelines. Primary outcomes were the mean change in best-corrected VA at 3 months, 1 year, and the final postoperative examination. Results: Fifty-one patients were included, 30 with LMH, 14 with MPH, and 7 with ERMF. The VA was 20/63 at baseline, 20/62 (P = .79) 3 months postoperatively, 20/40 (P = .003) at 1 year, and 20/52 (P = .10) at the final examination for LMH; 20/64, 20/50 (P = .16), 20/40 (P = .040), and 20/40 (P = .02), respectively, for MPH; and 20/53, 20/50 (P = .42), 20/30 (P = .03), and 20/38 (P = .04), respectively, for ERMF. Subgroup analysis showed that eyes with LMH without ellipsoid zone (EZ) disruption on SD-OCT improved from 20/57 at baseline to 20/39 (P = .01) at the final examination. Conclusions: There was no significant improvement in VA at the final postvitrectomy examination in eyes with LMH, while there was significant improvement in eyes with MPH and ERMF. This supports surgery in selected eyes with MPH and ERMF but possibly not in eyes with LMH, unless OCT shows no EZ disruption.

Predicting Recurrence-Free and Overall Survival for Patients With Stage II Melanoma: The MIA Calculator.

PURPOSE: Improvements in recurrence-free survival (RFS) were demonstrated in two recent randomized trials for patients with sentinel node (SN)-negative stage IIB or IIC melanoma receiving adjuvant systemic therapy (pembrolizumab/nivolumab). However, adverse events also occurred. Accurate individualized prognostic estimates of RFS and overall survival (OS) would allow patients to more accurately weigh the risks and benefits of adjuvant therapy. Since the current American Joint Committee on Cancer eighth edition (AJCC-8) melanoma staging system focuses on melanoma-specific survival, we developed a multivariable risk prediction calculator that provides estimates of 5- and 10-year RFS and OS for these patients. METHODS: Data were extracted from the Melanoma Institute Australia (MIA) database for patients diagnosed with stage II (clinical or pathological) melanoma (n = 3,220). Survival prediction models were developed using multivariable Cox regression analyses (MIA models) and externally validated twice using data sets from the United States and the Netherlands. Each model's performance was assessed using C-statistics and calibration plots and compared with Cox models on the basis of AJCC-8 staging (stage models). RESULTS: The 5-year and 10-year RFS C-statistics were 0.70 and 0.73 (MIA-model) versus 0.61 and 0.60 (stage-model), respectively. For OS, the 5-year and 10-year C-statistics were 0.71 and 0.75 (MIA-model) compared with 0.62 and 0.61 (stage-model), respectively. The MIA models were well calibrated and externally validated. CONCLUSION: The MIA models offer accurate and personalized estimates of both RFS and OS in patients with stage II melanoma even in the absence of pathological staging with SN biopsy. These models were robust on external validations and may be used in everyday practice both with (ideally) and without performing SN biopsy to identify high-risk patients for further management strategies. An online tool will be available at the MIA website (Risk Prediction Tools).

Transmission and Non-transmission of Melanoma From Deceased Solid Organ Donors to Transplant Recipients: Risks and Missed Opportunities.

BACKGROUND: Biovigilance concerns are in tension with the need to increase organ donation. Cancer transmission risk from donor to recipient may be overestimated, as non-transmission events are rarely reported. We sought to estimate melanoma transmission risk in deceased organ donation and identify missed opportunities for donation in an Australian cohort with high melanoma prevalence. METHODS: We used a population-based approach and linked deceased organ donors, transplant recipients, and potential donors forgone, 2010-2018, with the Central Cancer Registry (CCR), 1976-2018. We identified melanomas using ICD-O-3 classification, assessed the probability of transmission, and compared suspected melanoma history in potential donors forgone with melanoma notifications in the CCR. RESULTS: There were 9 of 993 donors with melanoma in CCR; 4 in situ low-risk and 5 invasive high-to-unacceptable risk. Four were unrecognized before donation. Of 16 transplant recipients at risk, we found 0 of 14 transmission events (2 recipients had insufficient follow-up). Of 35 of 3588 potential donors forgone for melanoma risk alone, 17 were otherwise suitable for donation; 6 of 35 had no melanoma in CCR, 2 of 35 had in situ melanomas and 9 of 35 had thin invasive melanomas (localized, ≤0.8 mm thickness). CONCLUSIONS: Our findings contribute to current evidence that suggests donors with melanomas of low metastatic potential may provide an opportunity to safely increase organ donation and so access to transplantation.

Smoking Status and Survival in Patients With Early-Stage Primary Cutaneous Melanoma.

Importance: While smoking is associated with a decreased incidence of cutaneous melanoma, the association of smoking with melanoma progression and death is not well defined. Objective: To determine the association of smoking with survival in patients with early-stage primary cutaneous melanoma. Design, Setting, and Participants: This cohort study performed a post hoc analysis of data derived from the randomized, multinational first and second Multicenter Selective Lymphadenectomy Trials (MSLT-I and MSLT-II). Participants were accrued for MSLT-I from January 20, 1994, to March 29, 2002; MSLT-II, from December 21, 2004, to March 31, 2014. Median follow-up was 110.0 (IQR, 53.4-120.0) months for MSLT-I and 67.6 (IQR, 25.8-110.2) months for MSLT-II. Patients aged 18 to 75 years with clinical stages I or II melanoma with a Breslow thickness of 1.00 mm or greater or Clark level IV to V and available standard prognostic and smoking data were included. Analyses were performed from October 4, 2022, to March 31, 2023. Exposure: Current, former, and never smoking. Main Outcomes and Measures: Melanoma-specific survival of patients with current, former, and never smoking status was assessed for the entire cohort and for nodal observation and among subgroups with sentinel lymph node biopsy (SLNB)-negative and SLNB-positive findings. Results: Of 6279 included patients, 3635 (57.9%) were men, and mean (SD) age was 52.7 (13.4) years. The most common tumor location was an extremity (2743 [43.7%]), and mean (SD) Breslow thickness was 2.44 (2.06) mm. Smoking status included 1077 (17.2%) current, 1694 (27.0%) former, and 3508 (55.9%) never. Median follow-up was 78.4 (IQR, 30.5-119.6) months. Current smoking was associated with male sex, younger age, trunk site, thicker tumors, tumor ulceration, and SLNB positivity. Current smoking was associated with a greater risk of melanoma-associated death by multivariable analysis for the entire study (hazard ratio [HR], 1.48 [95% CI, 1.26-1.75]; P < .001). Former smoking was not. The increased risk of melanoma-specific mortality associated with current smoking was greatest for patients with SLNB-negative melanoma (HR, 1.85 [95% CI, 1.35-2.52]; P < .001), but also present for patients with SLNB-positive melanoma (HR, 1.29 [95% CI, 1.04-1.59]; P = .02) and nodal observation (HR, 1.68 [95% CI, 1.09-2.61]; P = .02). Smoking at least 20 cigarettes/d doubled the risk of death due to melanoma for patients with SLNB-negative disease (HR, 2.06 [95% CI, 1.36-3.13]; P < .001). Conclusions and Relevance: The findings of this cohort study suggest that patients with clinical stage I and II melanoma who smoked had a significantly increased risk of death due to melanoma. Smoking status should be assessed at time of melanoma diagnosis and may be considered a risk factor for disease progression.

Brain Shift during Staged Deep Brain Stimulation for Movement Disorders.

INTRODUCTION: Deep brain stimulation (DBS) is a routine neurosurgical procedure utilized to treat various movement disorders including Parkinson's disease (PD), essential tremor (ET), and dystonia. Treatment efficacy is dependent on stereotactic accuracy of lead placement into the deep brain target of interest. However, brain shift attributed to pneumocephalus can introduce unpredictable inaccuracies during DBS lead placement. This study aimed to determine whether intracranial air is associated with brain shift in patients undergoing staged DBS surgery. METHODS: We retrospectively evaluated 46 patients who underwent staged DBS surgery for PD, ET, and dystonia. Due to the staged nature of DBS surgery at our institution, the first electrode placement is used as a concrete fiducial marker for movement in the target location. Postoperative computed tomography (CT) images after the first electrode implantation, as well as preoperative, and postoperative CT images after the second electrode implantation were collected. Images were analyzed in stereotactic targeting software (BrainLab); intracranial air was manually segmented, and electrode shift was measured in the x, y, and z plane, as well as a Euclidian distance on each set of merged CT scans. A Pearson correlation analysis was used to determine the relationship between intracranial air and brain shift, and student's t test was used to compare means between patients with and without radiographic evidence of intracranial air. RESULTS: Thirty-six patients had pneumocephalus after the first electrode implantation, while 35 had pneumocephalus after the second electrode implantation. Accumulation of intracranial air following the first electrode implantation (4.49 ± 6.05 cm3) was significantly correlated with brain shift along the y axis (0.04 ± 0.35 mm; r (34) = 0.36; p = 0.03), as well as the Euclidean distance of deviation (0.57 ± 0.33 mm; r (34) = 0.33; p = 0.05) indicating statistically significant shift on the ipsilateral side. However, there was no significant correlation between intracranial air and brain shift following the second electrode implantation, suggesting contralateral shift is minimal. Furthermore, there was no significant difference in brain shift between patients with and without radiographic evidence of intracranial air following both electrode implantation surgeries. CONCLUSION: Despite observing volumes as high as 22.0 cm3 in patients with radiographic evidence of pneumocephalus, there was no significant difference in brain shift when compared to patients without pneumocephalus. Furthermore, the mean magnitude of brain shift was <1.0 mm regardless of whether pneumocephalus was presenting, suggesting that intracranial air accumulation may not produce clinical significant brain shift in our patients.

Population-Based Validation of the MIA and MSKCC Tools for Predicting Sentinel Lymph Node Status.

Importance: Patients with melanoma are selected for sentinel lymph node biopsy (SLNB) based on their risk of a positive SLN. To improve selection, the Memorial Sloan Kettering Cancer Center (MSKCC) and Melanoma Institute Australia (MIA) developed predictive models, but the utility of these models remains to be tested. Objective: To determine the clinical utility of the MIA and MSKCC models. Design, Setting, and Participants: This was a population-based comparative effectiveness research study including 10 089 consecutive patients with cutaneous melanoma undergoing SLNB from the Swedish Melanoma Registry from January 2007 to December 2021. Data were analyzed from May to August 2023. Main Outcomes and Measures,: The predicted probability of SLN positivity was calculated using the MSKCC model and a limited MIA model (using mitotic rate as absent/present instead of count/mm2 and excluding the optional variable lymphovascular invasion) for each patient. The operating characteristics of the models were assessed and compared. The clinical utility of each model was assessed using decision curve analysis and compared with a strategy of performing SLNB on all patients. Results: Among 10 089 included patients, the median (IQR) age was 64.0 (52.0-73.0) years, and 5340 (52.9%) were male. The median Breslow thickness was 1.8 mm, and 1802 patients (17.9%) had a positive SLN. Both models were well calibrated across the full range of predicted probabilities and had similar external area under the receiver operating characteristic curves (AUC; MSKCC: 70.8%; 95% CI, 69.5-72.1 and limited MIA: 69.7%; 95% CI, 68.4-71.1). At a risk threshold of 5%, decision curve analysis indicated no added net benefit for either model compared to performing SLNB for all patients. At risk thresholds of 10% or higher, both models added net benefit compared to SLNB for all patients. The greatest benefit was observed in patients with T2 melanomas using a threshold of 10%; in that setting, the use of the nomograms led to a net reduction of 8 avoidable SLNBs per 100 patients for the MSKCC nomogram and 7 per 100 patients for the limited MIA nomogram compared to a strategy of SLNB for all. Conclusions and Relevance: This study confirmed the statistical performance of both the MSKCC and limited MIA models in a large, nationally representative data set. However, decision curve analysis demonstrated that using the models only improved selection for SLNB compared to biopsy in all patients when a risk threshold of at least 7% was used, with the greatest benefit seen for T2 melanomas at a threshold of 10%. Care should be taken when using these nomograms to guide selection for SLNB at the lowest thresholds.

Role of Concurrent Ultrasound Surveillance of Sentinel Node-Positive Node Fields in Melanoma Patients Having Routine Cross-Sectional Imaging.

PURPOSE: In sentinel node-positive (SN+ve) melanoma patients, active surveillance with regular ultrasound examination of the node field has become standard, rather than completion lymph node dissection (CLND). A proportion of these patients now receive adjuvant systemic therapy and have routine cross-sectional imaging (computed tomography [CT] or positron emission tomography [PET]/CT). The role of concurrent ultrasound (US) surveillance in these patients is unclear. The purpose of our study was to describe the modality of detection of nodal recurrence in SN+ve node fields. METHODS: SN+ve melanoma patients who did not undergo CLND treated at a single institution from January 1, 2016 to December 31, 2020 were included. RESULTS: A total of 225 SN+ve patients with a median follow-up of 23 months were included. Of these, 119 (53%) received adjuvant systemic therapy. Eighty (36%) developed a recurrence at any site; 24 (11%) recurred first in the SN+ve field, of which 12 (5%) were confirmed node field recurrence only at 2 months follow-up. The nodal recurrences were first detected by ultrasound in seven (3%), CT in seven (3%), and PET/CT in seven (3%) patients. All nodal recurrences evident on US were also evident on PET/CT and vice versa. CONCLUSIONS: The high rate of recurrences outside the node field and the identification of all US-detected nodal recurrences on concurrent cross-sectional imaging modalities suggest that routine concurrent ultrasound surveillance of the node-positive field may be unnecessary for SN+ve melanoma patients having routine cross-sectional imaging.

Assessment of the association between ambient air pollution and stillbirth in the UK: Results from a secondary analysis of the MiNESS case-control study.

OBJECTIVE: We examined whether the risk of stillbirth was related to ambient air pollution in a UK population. DESIGN: Prospective case-control study. SETTING: Forty-one maternity units in the UK. POPULATION: Women who had a stillbirth ≥28 weeks' gestation (n = 238) and women with an ongoing pregnancy at the time of interview (n = 597). METHODS: Secondary analysis of data from the Midlands and North of England Stillbirth case-control study only including participants domiciled within 20 km of fixed air pollution monitoring stations. Pollution exposure was calculated using pollution climate modelling data for NO2 , NOx and PM2.5 . The association between air pollution exposure and stillbirth risk was assessed using multivariable logistic regression adjusting for household income, maternal body mass index (BMI), maternal smoking, Index of Multiple Deprivation quintile and household smoking and parity. MAIN OUTCOME MEASURE: Stillbirth. RESULTS: There was no association with whole pregnancy ambient air pollution exposure and stillbirth risk, but there was an association with preconceptual NO2 exposure (adjusted odds ratio [aOR] 1.06, 95% CI 1.01-1.08 per microg/m3 ). Risk of stillbirth was associated with maternal smoking (aOR 2.54, 95% CI 1.38-4.71), nulliparity (aOR 2.16, 95% CI 1.55-3.00), maternal BMI (aOR 1.05, 95% CI 1.01-1.08) and placental abnormalities (aOR 4.07, 95% CI 2.57-6.43). CONCLUSIONS: Levels of ambient air pollution exposure during pregnancy in the UK, all of were beneath recommended thresholds, are not associated with an increased risk of stillbirth. Periconceptual exposure to NO2 may be associated with increased risk but further work is required to investigate this association.