BACKGROUND Immune checkpoint inhibitors and targeted therapies have dramatically improved outcomes in patients with advanced melanoma, but approximately half these patients will not have a durable... Show moreBACKGROUND Immune checkpoint inhibitors and targeted therapies have dramatically improved outcomes in patients with advanced melanoma, but approximately half these patients will not have a durable benefit. Phase 1-2 trials of adoptive cell therapy with tumor-infiltrating lymphocytes (TILs) have shown promising responses, but data from phase 3 trials are lacking to determine the role of TILs in treating advanced melanoma. METHODS In this phase 3, multicenter, open-label trial, we randomly assigned patients with unresectable stage IIIC or IV melanoma in a 1:1 ratio to receive TIL or anti-cytotoxic T-lymphocyte antigen 4 therapy (ipilimumab at 3 mg per kilogram of body weight). Infusion of at least 5x10(9) TILs was preceded by nonmyeloablative, lymphodepleting chemotherapy (cyclophosphamide plus fludarabine) and followed by high-dose interleukin-2. The primary end point was progression-free survival. RESULTS A total of 168 patients (86% with disease refractory to anti-programmed death 1 treatment) were assigned to receive TILs (84 patients) or ipilimumab (84 patients). In the intention-to-treat population, median progression-free survival was 7.2 months (95% confidence interval [CI], 4.2 to 13.1) in the TIL group and 3.1 months (95% CI, 3.0 to 4.3) in the ipilimumab group (hazard ratio for progression or death, 0.50; 95% CI, 0.35 to 0.72; P < 0.001); 49% (95% CI, 38 to 60) and 21% (95% CI, 13 to 32) of the patients, respectively, had an objective response. Median overall survival was 25.8 months (95% CI, 18.2 to not reached) in the TIL group and 18.9 months (95% CI, 13.8 to 32.6) in the ipilimumab group. Treatment-related adverse events of grade 3 or higher occurred in all patients who received TILs and in 57% of those who received ipilimumab; in the TIL group, these events were mainly chemotherapy-related myelosuppression. CONCLUSIONS In patients with advanced melanoma, progression-free survival was significantly longer among those who received TIL therapy than among those who received ipilimumab. Show less
Hansen, M.; Armour, C.; McGlinchey, E.; Ross, J.; Ravn, S.L.; Andersen, T.E.; ... ; Fried, E. 2022
Objective: Posttraumatic stress disorder (PTSD) has long been debated with a recent focus on the consequences of having two different diagnostic descriptions of PTSD (i.e., the Diagnostic and... Show moreObjective: Posttraumatic stress disorder (PTSD) has long been debated with a recent focus on the consequences of having two different diagnostic descriptions of PTSD (i.e., the Diagnostic and Statistical Manual of Mental Disorders-Fifth Edition [DSM-5] and the International Classification of Diseases-11th Edition [ICD-11]). Research has modeled PTSD as a network of interacting symptoms according to both diagnostic systems, but the relations between the two systems remain unclear regarding which symptoms are more central or interconnected. To answer this question, the present study is the first study to investigate the combined network structure of PTSD symptoms according to both systems using validated measurements (i.e., the International Trauma Questionnaire [ITQ] and the Posttraumatic Stress Disorder Checklist 5 [PCL-5] across two distinct trauma samples [a community sample, N = 2,367], and a military sample, N = 657). Method: We estimated two Gaussian Graphical Models of the combined ICD-11 and DSM-5 PTSD symptoms across the two samples. Results: Five of the six most central symptoms were the same across both samples. Conclusions: The results underline that a combination of five symptoms representing both diagnostic systems may hold central positions and potentially be important for treatment. However, the implications depend on if the different diagnostic descriptions can be reconciled in an indexical rather than constitutive perspective.Clinical Impact Statement Five identical posttraumatic stress disorder (PTSD) symptoms representing both diagnostic systems were identified across two distinct trauma exposed samples using network analysis. These symptoms may hold important positions compared with the remaining symptoms of the network and potentially be central for treatment. However, the implications depend on whether the results can be reconciled by viewing the two diagnostic descriptions of PTSD as indexical. Show less
Aims Failure of right ventricular (RV) function worsens outcome in pulmonary hypertension (PH). The adaptation of RV contractility to afterload, the RV-pulmonary artery (PA) coupling, is defined by... Show moreAims Failure of right ventricular (RV) function worsens outcome in pulmonary hypertension (PH). The adaptation of RV contractility to afterload, the RV-pulmonary artery (PA) coupling, is defined by the ratio of RV end-systolic to PA elastances (Ees/Ea). Using pressure-volume loop (PV-L) technique we aimed to identify an Ees/Ea cut-off predictive for overall survival and to assess hemodynamic and morphologic conditions for adapted RV function in secondary PH due to heart failure with reduced ejection fraction (HFREF).Methods and results This post hoc analysis is based on 112 patients of the prospective Magdeburger Resynchronization Responder Trial. All patients underwent right and left heart echocardiography and a baseline PV-L and RV catheter measurement. A subgroup of patients (n = 50) without a pre-implanted cardiac device underwent magnetic resonance imaging at baseline. The analysis revealed that 0.68 is an optimal Ees/Ea cut-off (area under the curve: 0.697, P < 0.001) predictive for overall survival (median follow up = 4.7 years, Ees/Ea >= 0.68 vs. <0.68, log-rank 8.9, P = 0.003). In patients with PH (n = 76, 68%) multivariate Cox regression demonstrated the independent prognostic value of RV-Ees/Ea in PH patients (hazard ratio 0.2, P < 0.038). Patients without PH (n = 36, 32%) and those with PH but RV-Ees/Ea >= 0.68 showed comparable RV-Ees/Ea ratios (0.88 vs. 0.9, P = 0.39), RV size/function, and survival. In contrast, secondary PH with RV-PA coupling ratio Ees/Ea < 0.68 corresponded extremely close to cut-off values that define RV dilatation/remodelling (RV end-diastolic volume >160 mL, RV-mass/volume-ratio <= 0.37 g/mL) and dysfunction (right ventricular ejection fraction <38%, tricuspid annular plane systolic excursion <16 mm, fractional area change <42%, and stroke-volume/end-systolic volume ratio <0.59) and is associated with a dramatically increased short and medium-term all-cause mortality. Independent predictors of prognostically unfavourable RV-PA coupling (Ees/Ea < 0.68) in secondary PH were a pre-existent dilated RV [end-diastolic volume >171 mL, odds ratio (OR) 0.96, P = 0.021], high pulsatile load (PA compliance <2.3 mL/mmHg, OR 8.6, P = 0.003), and advanced systolic left heart failure (left ventricular ejection fraction <30%, OR 1.23, P = 0.028).Conclusions The RV-PA coupling ratio Ees/Ea predicts overall survival in PH due to HFREF and is mainly affected by pulsatile load, RV remodelling, and left ventricular dysfunction. Prognostically favourable coupling (RV-Ees/Ea >= 0.68) in PH was associated with preserved RV size/function and mid-term survival, comparable with HFREF without PH. Show less
Background: The posttraumatic stress disorder (PTSD) diagnosis has been widely debated since it was introduced into the diagnostic nomenclature four decades ago. Recently, the debate has focused on... Show moreBackground: The posttraumatic stress disorder (PTSD) diagnosis has been widely debated since it was introduced into the diagnostic nomenclature four decades ago. Recently, the debate has focused on consequences of having two different descriptions of PTSD: 20 symptoms belonging to four symptom clusters in the Diagnostic and Statistical Manual of Mental Disorders 5(th) edition (DSM-5), and three symptoms clusters in the 11(th) edition of the International Classification of Diseases (ICD-11) most often operationalized by six symptoms in the International Trauma Questionnaire (ITQ) (2017) and Hansen, Hyland, Armour, Shevlin, & Elklit (2015). Research has provided support for both models of PTSD, but at the same time indicates differences in estimated prevalence rates of PTSD (Hansen et al., 2015, 2017). A growing body of research has modelled PTSD both theoretically and statistically as a network of interacting symptoms (Birkeland, Greene, & Spiller, 2020), yet it remains more unclear how the two diagnostic systems perform regarding which symptoms are more central/interconnected.Objectives and methods: We estimated two 23-item Gaussian Graphical Models to investigate whether ICD-11 or DSM-5 PTSD symptoms are more central in two trauma-exposed samples: a community sample (N = 2,367) and a military veteran sample (N = 657). PTSD DSM-5 was measured with the PTSD checklist-5 (PCL-5) and the PTSD ICD-11 was measure by the ITQ PTSD subscale.Results: Five of the six most central symptoms estimated via the expected influence centrality metric across the two samples were identical and represented symptoms from both diagnostic systems operationalized by the PCL-5 and the ITQ.Conclusions: The results of the present study underline that symptoms from both diagnostic systems hold central positions. The implications of the results are discussed from the perspectives of an indexical (i.e. the diagnostic systems reflect both shared and different aspects of PTSD) and a constitutive view (i.e., the diagnostic systems represent different disorders and the results cannot be reconciled per se) of mental health diagnoses (Kendler, 2017). Show less
Aims The aim of this study was to validate the tricuspid annular plane systolic excursion/systolic pulmonary artery (PA) pressure (TAPSE/PASP) ratio with the invasive pressure-volume (PV) loop... Show moreAims The aim of this study was to validate the tricuspid annular plane systolic excursion/systolic pulmonary artery (PA) pressure (TAPSE/PASP) ratio with the invasive pressure-volume (PV) loop-derived end-systolic right ventricular (RV) elastance/PA elastance (Ees/Ea) ratio in patients with heart failure with reduced ejection fraction (HFREF) and secondary pulmonary hypertension (PH).Methods and results The relationship of TAPSE and TAPSE/PASP with RV-PV loop (single-beat)-derived contractility Ees, afterload Ea, and Ees/Ea was assessed in 110 patients with HFREF with and without secondary PH. The results were compared with other surrogate parameters such as the fractional area change/PASP ratio. The association of the surrogates with all-cause mortality was evaluated. In patients with PH (n=74, 67%), TAPSE significantly correlated with Ees (r = 0.356), inverse with Ea (r = -0.514) but was most closely associated with Ees/Ea (r = 0.77). Placing TAPSE in a ratio with PASP slightly reduced the relationship to Ees/Ea (r = 0.71) but was more closely related to the parameters of PA vascular Load, diastolic RV function, and RV energetics. The area under the curve of TAPSE/PASP and TAPSE for discriminating overall survival in receiver operating characteristic analysis was not different (P = 0.78. Prognostic relevant cut-offs were 17mm for TAPSE and 0.38 mmimmHg for TAPSE/PASP. Both parameters in multivariate cox regression remained independently prognostically relevant.Conclusion TAPSE is an easily and reliably obtainable and valid surrogate parameter for RV-PA coupling in PH due to HFREF. Putting TAPSE into a ratio with PASP did not further improve the coupling information or prognostic assessment. Show less
