High-Dose Chemotherapy With Hematopoietic Stem Cell Transplant in Patients With High-Risk Breast Cancer and 4 or More Involved Axillary Lymph Nodes 20-Year Follow-up of a Phase 3 Randomized Clinical Trial:20-Year Follow-up of a Phase 3 Randomized Clinical Trial

Importance: Trials of adjuvant high-dose chemotherapy (HDCT) have failed to show a survival benefit in unselected patients with breast cancer, but long-term follow-up is lacking. Objective: To determine 20-year efficacy and safety outcomes of a large trial of adjuvant HDCT vs conventional-dose chemotherapy (CDCT) for patients with stage III breast cancer. Design, Setting, and Participants: This secondary analysis used data from a randomized phase 3 multicenter clinical trial of 885 women younger than 56 years with breast cancer and 4 or more involved axillary lymph nodes conducted from August 1, 1993, to July 31, 1999. Additional follow-up data were collected between June 1, 2016, and December 31, 2017, from medical records, general practitioners, the Dutch national statistical office, and nationwide cancer registries. Analysis was performed on an intention-to-treat basis. Statistical analysis was performed from February 1, 2018, to October 14, 2019. Interventions: Participants were randomized 1:1 to receive 5 cycles of CDCT consisting of fluorouracil, 500 mg/m 2, epirubicin, 90 mg/m 2, and cyclophosphamide, 500 mg/m 2, or HDCT in which the first 4 cycles were identical to CDCT and the fifth cycle was replaced by cyclophosphamide, 6000 mg/m 2, thiotepa, 480 mg/m 2, and carboplatin, 1600 mg/m 2, followed by hematopoietic stem cell transplant. Main Outcomes and Measures: Main end points were overall survival and safety and cumulative incidence risk of a second malignant neoplasm or cardiovascular events. Results: Of the 885 women in the study (mean [SD] age, 44.5 [6.6] years), 442 were randomized to receive HDCT, and 443 were randomized to receive CDCT. With 20.4 years median follow-up (interquartile range, 19.2-22.0 years), the 20-year overall survival was 45.3% with HDCT and 41.5% with CDCT (hazard ratio, 0.89; 95% CI, 0.75-1.06). The absolute improvement in 20-year overall survival was 14.6% (hazard ratio, 0.72; 95% CI, 0.54-0.95) for patients with 10 or more invoved axillary lymph nodes and 15.4% (hazard ratio, 0.67; 95% CI, 0.42-1.05) for patients with triple-negative breast cancer. The cumulative incidence risk of a second malignant neoplasm at 20 years or major cardiovascular events was similar in both treatment groups (20-year cumulative incidence risk for second malignant neoplasm was 12.1% in the HDCT group vs 16.2% in the CDCT group, P =.10), although patients in the HDCT group more often had hypertension (21.7% vs 14.3%, P =.02), hypercholesterolemia (15.7% vs 10.6%, P =.04), and dysrhythmias (8.6% vs 4.6%, P =.005). Conclusions and Relevance: High-dose chemotherapy provided no long-term survival benefit in unselected patients with stage III breast cancer but did provide improved overall survival in very high-risk patients (ie, with ≥10 involved axillary lymph nodes). High-dose chemotherapy did not affect long-term risk of a second malignant neoplasm or major cardiovascular events. Trial Registration: ClinicalTrials.gov Identifier: NCT03087409

Immunogenicity and reactogenicity of SARS-CoV-2 vaccines in people living with HIV in the Netherlands: a nationwide prospective cohort study

Background: Vaccines can be less immunogenic in people living with HIV (PLWH), but for SARS-CoV-2 vaccinations this is unknown. In this study we set out to investigate, for the vaccines currently approved in the Netherlands, the immunogenicity and reactogenicity of SARS-CoV-2 vaccinations in PLWH. Methods and findings: We conducted a prospective cohort study to examine the immunogenicity of BNT162b2, mRNA-1273, ChAdOx1-S, and Ad26.COV2.S vaccines in adult PLWH without prior COVID-19, and compared to HIV-negative controls. The primary endpoint was the anti-spike SARS-CoV-2 IgG response after mRNA vaccination. Secondary endpoints included the serological response after vector vaccination, anti-SARS-CoV-2 T-cell response, and reactogenicity. Between 14 February and 7 September 2021, 1,154 PLWH (median age 53 [IQR 44-60] years, 85.5% male) and 440 controls (median age 43 [IQR 33-53] years, 28.6% male) were included in the final analysis. Of the PLWH, 884 received BNT162b2, 100 received mRNA-1273, 150 received ChAdOx1-S, and 20 received Ad26.COV2.S. In the group of PLWH, 99% were on antiretroviral therapy, 97.7% were virally suppressed, and the median CD4+ T-cell count was 710 cells/mu L (IQR 520-913). Of the controls, 247 received mRNA-1273, 94 received BNT162b2, 26 received ChAdOx1-S, and 73 received Ad26.COV2.S. After mRNA vaccination, geometric mean antibody concentration was 1,418 BAU/mL in PLWH (95% CI 1322-1523), and after adjustment for age, sex, and vaccine type, HIV status remained associated with a decreased response (0.607, 95% CI 0.5080.725, p 300 BAU/mL, whilst in PLWH this response rate was 93.6%. In PLWH vaccinated with mRNA-based vaccines, higher antibody responses were predicted by CD4+ Tcell count 250-500 cells/mu L (2.845, 95% CI 1.876-4.314, p 500 cells/mu L (2.936, 95% CI 1.961-4.394, p 50 copies/mL was associated with a reduced response (0.454, 95% CI 0.286-0.720, p = 0.001). Increased IFN-gamma, CD4+ T-cell, and CD8+ T-cell responses were observed after stimulation with SARS-CoV-2 spike peptides in ELISpot and activation-induced marker assays, comparable to controls. Reactogenicity was generally mild, without vaccine-related serious adverse events. Due to the control of vaccine provision by the Dutch National Institute for Public Health and the Environment, there were some differences between vaccine groups in the age, sex, and CD4+ Tcell counts of recipients.Conclusions: After vaccination with BNT162b2 or mRNA-1273, anti-spike SARS-CoV-2 antibody levels were reduced in PLWH compared to HIV-negative controls. To reach and maintain the same serological responses as HIV-negative controls, additional vaccinations are probably required. Author summary: Why was this study done? The efficacy of SARS-CoV-2 vaccines in people living with HIV (PLWH) is not well characterised.HIV has been repeatedly associated with lower immune responses to other vaccines, and this diminished response is strongly correlated with CD4+ T-cell count.The SARS-CoV-2 vaccines BNT162b2, mRNA-1273, ChAdOx1-S, and Ad26.COV2.S showed good protection against severe COVID-19 and hospitalisation in phase III registration trials; however, the number of PLWH in these trials was very limited. What did the researchers do and find?We initiated a nationwide prospective study including 1,154 PLWH and 440 HIV-negative controls.We show that lower antibody levels are seen in PLWH compared to controls after completion of the vaccination schedule, regardless of the vaccine received.All controls receiving an mRNA vaccine had an adequate response, defined as >300 BAU/mL, whilst in PLWH this response rate was 93.6%. In multivariable analyses, having HIV had the largest negative effect on antibody responses following vaccination, more than both age and sex. Following mRNA vaccination, the antibody response was higher in PLWH with CD4+ T-cell counts between 250 and 500 cells/mu L or higher than 500 cells/mu L (both p Immunogenetics and cellular immunology of bacterial infectious disease

Adding semantics to image-region annotations with the Name-It-Game

In this paper we present the Name-It-Game, an interactive multimedia game fostering the swift creation of a large data set of region-based image annotations. Compared to existing annotation games, we consider an added semantic structure, by means of the WordNet ontology, the main innovation of the Name-It-Game. Using an ontology-powered game, instead of the more traditional annotation tools, potentially makes region-based image labeling more fun and accessible for every type of user. However, the current games often present the players with hard-to-guess objects. To prevent this from happening in the Name-It-Game, we successfully identify WordNet categories which filter out hard-to-guess objects. To verify the speed of the annotation process, we compare the online Name-It-Game with a desktop tool with similar features. Results show that the Name-It-Game outperforms this tool for semantic region-based image labeling. Lastly, we measure the accuracy of the produced segmentations and compare them with carefully created LabelMe segmentations. Judging from the quantitative and qualitative results, we believe the segmentations are competitive to those of LabelMe, especially when averaged over multiple games. By adding semantics to region-based image annotations, using the Name-It-Game, we have opened up an efficient means to provide precious labels in a playful manner

Verantwoording over risicobeheersing

De Nederlandse code-Tabaksblat kent concrete bepalingen met betrekking tot de verantwoording over risicobeheersing en de ‘in control’-verklaring die in het jaarrapport moet worden opgenomen. Ondanks de aanvullende aanbevelingen die de Monitoring Commissie sinds 2005 ter verduidelijking en aanscherping jaarlijks uitvaardigt, blijkt naleving van deze bepalingen nog niet 100 procent te zijn. In de discussie over het nut van de in-controlverklaring hebben wij verschillende stakeholders bij de onderneming, namelijk aandeelhouders, banken en centrale ondernemingsraden, in een serie interviews gevraagd naar hun informatiebehoefte. De informatie verstrekking over risicobeheersing blijkt nog niet toereikend om een rol te spelen in besluitvormingsprocessen. Uit het onderzoek komen ook suggesties naar voren ten aanzien van de inhoud van de in-controlverklaring en de wijze van handhaving van de naleving van de bepalingen in de code-Tabaksblat

Verantwoording over risicobeheersing

De Nederlandse code-Tabaksblat kent concrete bepalingen met betrekking tot de verantwoording over risicobeheersing en de ‘in control’-verklaring die in het jaarrapport moet worden opgenomen. Ondanks de aanvullende aanbevelingen die de Monitoring Commissie sinds 2005 ter verduidelijking en aanscherping jaarlijks uitvaardigt, blijkt naleving van deze bepalingen nog niet 100 procent te zijn. In de discussie over het nut van de in-controlverklaring hebben wij verschillende stakeholders bij de onderneming, namelijk aandeelhouders, banken en centrale ondernemingsraden, in een serie interviews gevraagd naar hun informatiebehoefte. De informatie verstrekking over risicobeheersing blijkt nog niet toereikend om een rol te spelen in besluitvormingsprocessen. Uit het onderzoek komen ook suggesties naar voren ten aanzien van de inhoud van de in-controlverklaring en de wijze van handhaving van de naleving van de bepalingen in de code-Tabaksblat