Neoadjuvant Nivolumab and Ipilimumab in Resectable Stage III Melanoma.

BACKGROUND: Phase 1-2 trials involving patients with resectable, macroscopic stage III melanoma have shown that neoadjuvant immunotherapy is more efficacious than adjuvant immunotherapy. METHODS: In this phase 3 trial, we randomly assigned patients with resectable, macroscopic stage III melanoma, in a 1:1 ratio, to receive two cycles of neoadjuvant ipilimumab plus nivolumab and then undergo surgery or to undergo surgery and then receive 12 cycles of adjuvant nivolumab. Only the patients in the neoadjuvant group who had a partial response or nonresponse received subsequent adjuvant treatment. The primary end point was event-free survival. RESULTS: A total of 423 patients underwent randomization. At a median follow-up of 9.9 months, the estimated 12-month event-free survival was 83.7% (99.9% confidence interval [CI], 73.8 to 94.8) in the neoadjuvant group and 57.2% (99.9% CI, 45.1 to 72.7) in the adjuvant group. The difference in restricted mean survival time was 8.00 months (99.9% CI, 4.94 to 11.05; P<0.001; hazard ratio for progression, recurrence, or death, 0.32; 99.9% CI, 0.15 to 0.66). In the neoadjuvant group, 59.0% of the patients had a major pathological response, 8.0% had a partial response, 26.4% had a nonresponse (>50% residual viable tumor), and 2.4% had progression; in 4.2%, surgery had not yet been performed or was omitted. The estimated 12-month recurrence-free survival was 95.1% among patients in the neoadjuvant group who had a major pathological response, 76.1% among those who had a partial response, and 57.0% among those who had a nonresponse. Adverse events of grade 3 or higher that were related to systemic treatment occurred in 29.7% of the patients in the neoadjuvant group and in 14.7% in the adjuvant group. CONCLUSIONS: Among patients with resectable, macroscopic stage III melanoma, neoadjuvant ipilimumab plus nivolumab followed by surgery and response-driven adjuvant therapy resulted in longer event-free survival than surgery followed by adjuvant nivolumab. (Funded by Bristol Myers Squibb and others; NADINA ClinicalTrials.gov number, NCT04949113.).

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.

First clinical results of 1-year follow-up of the femoral neck system for internal fixation of femoral neck fractures.

BACKGROUND: Closed reduction and internal fixation (CRIF) is the preferred treatment to retain the native joint and maintain optimal functionality in femoral neck fractures. Sliding hip screw (SHS) and cannulated hip screws (CHS) are established CRIF options. SHS offer high biomechanical stability, whereas CHS are minimally invasive. These established systems have a 17-21% failure rate. The Femoral neck system (FNS) was recently developed to combine the advantages of both predecessors. The aim of this study was to describe the first clinical experience with this novel implant with special emphasis on the safety and efficacy. METHODS: During a 1-year period all patients in our level-2 trauma centre with a FNF indicated for CRIF were treated using the FNS and evaluated at 2, 6, 12 weeks, 6 months and 1 year postoperatively using patient and fracture characteristics, surgical notes and radiographic imaging. RESULTS: Thirty-four patients were included, mean age was 63 years (SD 8), 58.2% was female. Fractures were classified as Pauwels I (n = 10), Pauwels II (n = 15), Pauwels III (n = 9), Garden I (n = 1), Garden II (n = 17), Garden III (n = 12) and Garden IV (n = 4). Eight reoperations were reported after 1-year follow-up; osteosyntheses failed in 6 patients due to avascular necrosis (n = 4) and cut-out (n = 2). In two patients the implant was removed due to inexplicable pain. Age (< 65 years) was related to lower risk for failure. There was a trend for females having more failures. CONCLUSION: This study indicates that the FNS is a potential safe and effective CRIF modality. Age (< 65 years) is an important factor to keep in mind when selecting patients for CRIF as it is related to lower risk for failure. Future long-term follow-up studies with larger populations should indicate if functional results and risk factors for failure are comparable to SHS or CHS.

Effective Distance between Aortic Valve and Conduction System Is an Independent Predictor of Persistent Left Bundle Branch Block during Transcatheter Aortic Valve Implantation.

Background and objectives: Persistent left bundle branch block (P-LBBB) has been associated with poor clinical outcomes of transcatheter aortic valve implantation (TAVI) procedures. We hypothesized that the distance from the aortic valve to the proximal conduction system, expressed as the effective distance between the aortic valve and conduction system (EDACS), can predict the occurrence of P-LBBB in patients undergoing a TAVI procedure. Materials and methods: In a retrospective study, data from 269 patients were analyzed. EDACS was determined using two longitudinal CT sections. Results: Sixty-four of the patients developed P-LBBB. EDACS ranged between -3 and +18 mm. EDACS was significantly smaller in P-LBBB than in non-P-LBBB patients (4.6 (2.2-7.1) vs. 8.0 (5.8-10.2) mm, median values (interquartile range); p < 0.05). Receiver operating characteristic analysis showed an area under the curve of 0.78 for predicting P-LBBB based on EDACS. In patients with EDACS of ≤3 mm and >10 mm, the chance of developing P-LBBB was ≥50% and <10%, respectively. Conclusions: A small EDACS increases the risk for the development of P-LBBB during TAVI by a factor of >25. As EDACS can be measured pre-procedurally, it may be a valuable additional factor to weigh the risks of transcatheter and surgical aortic valve replacement.

Clinical evaluation of the clinicopathologic and gene expression profile (CP-GEP) in patients with melanoma eligible for sentinel lymph node biopsy: A multicenter prospective Dutch study.

Sentinel lymph node biopsy (SLNB) is recommended for patients with >pT1b cutaneous melanoma, and should be considered and discussed with patients diagnosed with pT1b cutaneous melanoma for the purpose of staging, prognostication and determining eligibility for adjuvant therapy. Previously, the clinicopathologic and gene expression profile (CP-GEP, Merlin Assay®) model was developed to identify patients who can forgo SLNB because of a low risk for sentinel node metastasis. The aim of this study was to evaluate the clinical use and implementation of the CP-GEP model in a prospective multicenter study in the Netherlands. Both test performance and feasibility for clinical implementation were assessed in 260 patients with T1-T4 melanoma. The CP-GEP model demonstrated an overall negative predictive value of 96.7% and positive predictive value of 23.7%, with a potential SLNB reduction rate of 42.2% in patients with T1-T3 melanoma. With a median time of 16 days from initiation to return of test results, there was sufficient time left before the SLNB was performed. Based on these outcomes, the model may support clinical decision-making to identify patients who can forgo SLNB in clinical practice.

COVID outcome prediction in the emergency department (COPE): using retrospective Dutch hospital data to develop simple and valid models for predicting mortality and need for intensive care unit admission in patients who present at the emergency department with suspected COVID-19.

OBJECTIVES: Develop simple and valid models for predicting mortality and need for intensive care unit (ICU) admission in patients who present at the emergency department (ED) with suspected COVID-19. DESIGN: Retrospective. SETTING: Secondary care in four large Dutch hospitals. PARTICIPANTS: Patients who presented at the ED and were admitted to hospital with suspected COVID-19. We used 5831 first-wave patients who presented between March and August 2020 for model development and 3252 second-wave patients who presented between September and December 2020 for model validation. OUTCOME MEASURES: We developed separate logistic regression models for in-hospital death and for need for ICU admission, both within 28 days after hospital admission. Based on prior literature, we considered quickly and objectively obtainable patient characteristics, vital parameters and blood test values as predictors. We assessed model performance by the area under the receiver operating characteristic curve (AUC) and by calibration plots. RESULTS: Of 5831 first-wave patients, 629 (10.8%) died within 28 days after admission. ICU admission was fully recorded for 2633 first-wave patients in 2 hospitals, with 214 (8.1%) ICU admissions within 28 days. A simple model-COVID outcome prediction in the emergency department (COPE)-with age, respiratory rate, C reactive protein, lactate dehydrogenase, albumin and urea captured most of the ability to predict death. COPE was well calibrated and showed good discrimination for mortality in second-wave patients (AUC in four hospitals: 0.82 (95% CI 0.78 to 0.86); 0.82 (95% CI 0.74 to 0.90); 0.79 (95% CI 0.70 to 0.88); 0.83 (95% CI 0.79 to 0.86)). COPE was also able to identify patients at high risk of needing ICU admission in second-wave patients (AUC in two hospitals: 0.84 (95% CI 0.78 to 0.90); 0.81 (95% CI 0.66 to 0.95)). CONCLUSIONS: COPE is a simple tool that is well able to predict mortality and need for ICU admission in patients who present to the ED with suspected COVID-19 and may help patients and doctors in decision making.

[Clinical course of COVID-19 in the Netherlands: an overview of 2607 patients in hospital during the first wave]. / Klinisch beloop van covid-19 in Nederland.

OBJECTIVE: To systematically collect clinical data from patients with a proven COVID-19 infection in the Netherlands. DESIGN: Data from 2579 patients with COVID-19 admitted to 10 Dutch centers in the period February to July 2020 are described. The clinical data are based on the WHO COVID case record form (CRF) and supplemented with patient characteristics of which recently an association disease severity has been reported. METHODS: Survival analyses were performed as primary statistical analysis. These Kaplan-Meier curves for time to (early) death (3 weeks) have been determined for pre-morbid patient characteristics and clinical, radiological and laboratory data at hospital admission. RESULTS: Total in-hospital mortality after 3 weeks was 22.2% (95% CI: 20.7% - 23.9%), hospital mortality within 21 days was significantly higher for elderly patients (> 70 years; 35, 0% (95% CI: 32.4% - 37.8%) and patients who died during the 21 days and were admitted to the intensive care (36.5% (95% CI: 32.1% - 41.3%)). Apart from that, in this Dutch population we also see a risk of early death in patients with co-morbidities (such as chronic neurological, nephrological and cardiac disorders and hypertension), and in patients with more home medication and / or with increased urea and creatinine levels. CONCLUSION: Early death due to a COVID-19 infection in the Netherlands appears to be associated with demographic variables (e.g. age), comorbidity (e.g. cardiovascular disease) but also disease char-acteristics at admission.

High Prevalence of Sarcopenia in Older Trauma Patients: A Pilot Study.

Sarcopenia is related to adverse outcomes in various populations. However, little is known about the prevalence of sarcopenia in polytrauma patients. Identifying the number of patients at risk of adverse outcome will increase awareness to prevent further loss of muscle mass. We utilized data from a regional prospective trauma registry of all polytrauma patients presented between 2015 and 2019 at a single level-I trauma center. Subjects were screened for availability of computed tomography (CT)-abdomen and height in order to calculate skeletal mass index, which was used to estimate sarcopenia. Additional parameters regarding clinical outcome were assessed. Univariate analysis was performed to identify parameters related adverse outcome and, if identified, entered in a multivariate regression analysis. Prevalence of sarcopenia was 33.5% in the total population but was even higher in older age groups (range 60-79 years), reaching 82 % in patients over 80 years old. Sarcopenia was related to 30-day or in-hospital mortality (p = 0.032), as well as age (p < 0.0001), injury severity score (p = 0.026), and Charlson comorbidity index (p = 0.001). Log rank analysis identified sarcopenia as an independent predictor of 30-day mortality (p = 0.032). In conclusion, we observed a high prevalence of sarcopenia among polytrauma patients, further increasing in older patients. In addition, sarcopenia was identified as a predictor for 30-day mortality, underlining the clinical significance of identification of low muscle mass on a CT scan that is already routinely obtained in most trauma patients.