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1. ECTIL: Label-efficient Computational Tumour Infiltrating Lymphocyte (TIL) assessment in breast cancer: Multicentre validation in 2,340 patients with breast cancer

Author

Schirris, Yoni, Voorthuis, Rosie, Opdam, Mark, Liefaard, Marte, Sonke, Gabe S, Dackus, Gwen, de Jong, Vincent, Wang, Yuwei, Van Rossum, Annelot, Steenbruggen, Tessa G, Steggink, Lars C, de Vries, Liesbeth G. E., van de Vijver, Marc, Salgado, Roberto, Gavves, Efstratios, van Diest, Paul J, Linn, Sabine C, Teuwen, Jonas, Menezes, Renee, Kok, Marleen, and Horlings, Hugo

Subjects
Electrical Engineering and Systems Science - Image and Video Processing, Computer Science - Artificial Intelligence, Computer Science - Computer Vision and Pattern Recognition
Abstract

The level of tumour-infiltrating lymphocytes (TILs) is a prognostic factor for patients with (triple-negative) breast cancer (BC). Computational TIL assessment (CTA) has the potential to assist pathologists in this labour-intensive task, but current CTA models rely heavily on many detailed annotations. We propose and validate a fundamentally simpler deep learning based CTA that can be trained in only ten minutes on hundredfold fewer pathologist annotations. We collected whole slide images (WSIs) with TILs scores and clinical data of 2,340 patients with BC from six cohorts including three randomised clinical trials. Morphological features were extracted from whole slide images (WSIs) using a pathology foundation model. Our label-efficient Computational stromal TIL assessment model (ECTIL) directly regresses the TILs score from these features. ECTIL trained on only a few hundred samples (ECTIL-TCGA) showed concordance with the pathologist over five heterogeneous external cohorts (r=0.54-0.74, AUROC=0.80-0.94). Training on all slides of five cohorts (ECTIL-combined) improved results on a held-out test set (r=0.69, AUROC=0.85). Multivariable Cox regression analyses indicated that every 10% increase of ECTIL scores was associated with improved overall survival independent of clinicopathological variables (HR 0.86, p<0.01), similar to the pathologist score (HR 0.87, p<0.001). We demonstrate that ECTIL is highly concordant with an expert pathologist and obtains a similar hazard ratio. ECTIL has a fundamentally simpler design than existing methods and can be trained on orders of magnitude fewer annotations. Such a CTA may be used to pre-screen patients for, e.g., immunotherapy clinical trial inclusion, or as a tool to assist clinicians in the diagnostic work-up of patients with BC. Our model is available under an open source licence (https://github.com/nki-ai/ectil)., Comment: Under review. 54 pages including supplementary materials, 2 main tables, 3 main figures, 14 supplementary figures, 4 supplementary tables

Published
2025

5. Vascular aging in long-term survivors of testicular cancer more than 20 years after treatment with cisplatin-based chemotherapy

Author

Stelwagen, Johannes, Lubberts, Sjoukje, Steggink, Lars C., Steursma, Gerrie, Kruyt, Lara M., Donkerbroek, Jan Willem, van Roon, Arie M., van Gessel, Anne I., van de Zande, Saskia C., Meijer, Coby, Gräfin zu Eulenburg, Christine H., Oosting, Sjoukje F., Nuver, Janine, Walenkamp, Annemiek M. E., Jan de Jong, Igle, Lefrandt, Joop D., and Gietema, Jourik A.

Published
2020
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7. Physical Activity and Cardiac Function in Long-Term Breast Cancer Survivors: A Cross-Sectional Study

Author

Epi Kanker Team B, Cancer, Externen Med. Onco, Epi Kanker, JC onderzoeksprogramma Cancer, Naaktgeboren, Willeke R, Groen, Wim G, Jacobse, Judy N, Steggink, Lars C, Walenkamp, Annemiek M E, van Harten, Wim H, Stuiver, Martijn M, Aaronson, Neil K, Aleman, Berthe M P, van der Meer, Peter, Schaapveld, Michael, Sonke, Gabe S, Gietema, Jourik A, van Leeuwen, Flora E, May, Anne M, Epi Kanker Team B, Cancer, Externen Med. Onco, Epi Kanker, JC onderzoeksprogramma Cancer, Naaktgeboren, Willeke R, Groen, Wim G, Jacobse, Judy N, Steggink, Lars C, Walenkamp, Annemiek M E, van Harten, Wim H, Stuiver, Martijn M, Aaronson, Neil K, Aleman, Berthe M P, van der Meer, Peter, Schaapveld, Michael, Sonke, Gabe S, Gietema, Jourik A, van Leeuwen, Flora E, and May, Anne M

Published
2022

8. Predictive value of ectopic HORMAD1 tumor expression for high-dose platinum-based chemotherapy benefit in patients with high-risk HER2-negative breast cancer.

Author

De Boo, Leonora, primary, Quist, Jelmar, additional, Opdam, Mark, additional, Jozwiak, Katarzyna, additional, Gazinska, Patrycja, additional, Peters, Dennis, additional, Horlings, Hugo M., additional, Steenbruggen, Tessa Gerjanne, additional, Steggink, Lars C., additional, De Vries, Elisabeth, additional, Sonke, Gabe S., additional, Gietema, Jourik A., additional, Tutt, Andrew, additional, Kok, Marleen, additional, Grigoriadis, Anita, additional, and Linn, Sabine C., additional

Published
2022
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10. 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

Author

Steenbruggen, Tessa G, Steggink, Lars C, Seynaeve, Caroline M, van der Hoeven, Jacobus J M, Hooning, Maartje J, Jager, Agnes, Konings, Inge R, Kroep, Judith R, Smit, Wim M, Tjan-Heijnen, Vivianne C G, van der Wall, Elsken, Bins, Adriaan D, Linn, Sabine C, Schaapveld, Michael, Jacobse, Judy N, van Leeuwen, Flora E, Schröder, Carolien P, van Tinteren, Harm, de Vries, Elisabeth G E, Sonke, Gabe S, Gietema, Jourik A, Guided Treatment in Optimal Selected Cancer Patients (GUTS), and Damage and Repair in Cancer Development and Cancer Treatment (DARE)

Subjects
SUPPORT, CYCLOPHOSPHAMIDE, CONVENTIONAL ADJUVANT CHEMOTHERAPY, EPIRUBICIN, WOMEN, BENEFIT, RECURRENCE, EFFICACY, THERAPY
Abstract

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/m2, epirubicin, 90 mg/m2, and cyclophosphamide, 500 mg/m2, or HDCT in which the first 4 cycles were identical to CDCT and the fifth cycle was replaced by cyclophosphamide, 6000 mg/m2, thiotepa, 480 mg/m2, and carboplatin, 1600 mg/m2, 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.

Published
2020

13. 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

Author

Steenbruggen, Tessa G., Steggink, Lars C., Seynaeve, Caroline M., Hoeven, J.J.M. van der, Hooning, Maartje J., Jager, Agnes, Sonke, Gabe S., Gietema, Jourik A., Steenbruggen, Tessa G., Steggink, Lars C., Seynaeve, Caroline M., Hoeven, J.J.M. van der, Hooning, Maartje J., Jager, Agnes, Sonke, Gabe S., and Gietema, Jourik A.

Abstract

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Published
2020

14. 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

Author

Speerpunt Cancer, Cancer, Steenbruggen, Tessa G., Steggink, Lars C., Seynaeve, Caroline M., Van Der Hoeven, Jacobus J.M., Hooning, Maartje J., Jager, Agnes, Konings, Inge R., Kroep, Judith R., Smit, Wim M., Tjan-Heijnen, Vivianne C.G., Van Der Wall, Elsken, Bins, Adriaan D., Linn, Sabine C., Schaapveld, Michael, Jacobse, Judy N., Van Leeuwen, Flora E., Schröder, Carolien P., Van Tinteren, Harm, De Vries, Elisabeth G.E., Sonke, Gabe S., Gietema, Jourik A., Speerpunt Cancer, Cancer, Steenbruggen, Tessa G., Steggink, Lars C., Seynaeve, Caroline M., Van Der Hoeven, Jacobus J.M., Hooning, Maartje J., Jager, Agnes, Konings, Inge R., Kroep, Judith R., Smit, Wim M., Tjan-Heijnen, Vivianne C.G., Van Der Wall, Elsken, Bins, Adriaan D., Linn, Sabine C., Schaapveld, Michael, Jacobse, Judy N., Van Leeuwen, Flora E., Schröder, Carolien P., Van Tinteren, Harm, De Vries, Elisabeth G.E., Sonke, Gabe S., and Gietema, Jourik A.

Published
2020

15. Myocardial dysfunction in long‐term breast cancer survivors treated at ages 40–50 years

Author

Jacobse, Judy N., primary, Steggink, Lars C., additional, Sonke, Gabe S., additional, Schaapveld, Michael, additional, Hummel, Yoran M., additional, Steenbruggen, Tessa G., additional, Lefrandt, Joop D., additional, Nuver, Janine, additional, Crijns, Anne P.G., additional, Aleman, Berthe M.P., additional, Meer, Peter, additional, Gietema, Jourik A., additional, and Leeuwen, Flora E., additional

Published
2020
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16. Cardiac Function After Radiation Therapy for Breast Cancer

Author

van den Bogaard, Veerle A.B., primary, van Luijk, Peter, additional, Hummel, Yoran M., additional, van der Meer, Peter, additional, Schuit, Ewoud, additional, Boerman, Liselotte M., additional, Maass, Saskia W.M.C., additional, Nauta, Jan F., additional, Steggink, Lars C., additional, Gietema, Jourik A., additional, de Bock, Geertruida H., additional, Berendsen, Annette J., additional, Smit, Wilma G.J.M., additional, Sijtsema, Nanna M., additional, Kierkels, Roel G.J., additional, Langendijk, Johannes A., additional, Crijns, Anne P.G., additional, and Maduro, John H., additional

Published
2019
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17. Cardiac Function After Radiation Therapy for Breast Cancer

Author

van den Bogaard, Veerle A B, van Luijk, Peter, Hummel, Yoran M, van der Meer, Peter, Schuit, E, Boerman, Liselotte M, Maass, Saskia W M C, Nauta, Jan F, Steggink, Lars C, Gietema, Jourik A, de Bock, Geertruida H, Berendsen, Annette J, Smit, Wilma G J M, Sijtsema, Nanna M, Kierkels, Roel G J, Langendijk, Johannes A, Crijns, Anne P G, Maduro, John H, van den Bogaard, Veerle A B, van Luijk, Peter, Hummel, Yoran M, van der Meer, Peter, Schuit, E, Boerman, Liselotte M, Maass, Saskia W M C, Nauta, Jan F, Steggink, Lars C, Gietema, Jourik A, de Bock, Geertruida H, Berendsen, Annette J, Smit, Wilma G J M, Sijtsema, Nanna M, Kierkels, Roel G J, Langendijk, Johannes A, Crijns, Anne P G, and Maduro, John H

Published
2019

18. Cardiac Function After Radiation Therapy for Breast Cancer

Author

Epi Methoden Team 4, JC onderzoeksprogramma Methodologie, Externen Med. Onco, PMC Medisch specialisten, van den Bogaard, Veerle A B, van Luijk, Peter, Hummel, Yoran M, van der Meer, Peter, Schuit, E, Boerman, Liselotte M, Maass, Saskia W M C, Nauta, Jan F, Steggink, Lars C, Gietema, Jourik A, de Bock, Geertruida H, Berendsen, Annette J, Smit, Wilma G J M, Sijtsema, Nanna M, Kierkels, Roel G J, Langendijk, Johannes A, Crijns, Anne P G, Maduro, John H, Epi Methoden Team 4, JC onderzoeksprogramma Methodologie, Externen Med. Onco, PMC Medisch specialisten, van den Bogaard, Veerle A B, van Luijk, Peter, Hummel, Yoran M, van der Meer, Peter, Schuit, E, Boerman, Liselotte M, Maass, Saskia W M C, Nauta, Jan F, Steggink, Lars C, Gietema, Jourik A, de Bock, Geertruida H, Berendsen, Annette J, Smit, Wilma G J M, Sijtsema, Nanna M, Kierkels, Roel G J, Langendijk, Johannes A, Crijns, Anne P G, and Maduro, John H

Published
2019

19. Een vrouw met huidafwijkingen en spierzwakte: Een vrouw met huidafwijkingen en spierzwakte

Author

Steggink, Lars C., Hettema, Martha E., Delsing, Corine E., and Medical Oncology

Abstract

A 54-year-old woman presented to the emergency department with progressive proximal muscle weakness and a symmetric skin rash. Physical examination demonstrated a heliotrope rash, Gottron lesions, mechanic's hands and symmetrical erythema of the face, neck and upper legs. The diagnosis 'dermatomyositis' was established. Subsequently, the patient was successfully treated with prednisolone 1 mg/kg.

Published
2013

20. 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.

Author

Steenbruggen TG, Steggink LC, Seynaeve CM, van der Hoeven JJM, Hooning MJ, Jager A, Konings IR, Kroep JR, Smit WM, Tjan-Heijnen VCG, van der Wall E, Bins AD, Linn SC, Schaapveld M, Jacobse JN, van Leeuwen FE, Schröder CP, van Tinteren H, de Vries EGE, Sonke GS, and Gietema JA

Subjects
Adult, Axilla pathology, Breast drug effects, Breast pathology, Breast Neoplasms epidemiology, Breast Neoplasms pathology, Cardiovascular Abnormalities chemically induced, Cardiovascular Abnormalities pathology, Child, Cyclophosphamide administration & dosage, Cyclophosphamide adverse effects, Disease-Free Survival, Dose-Response Relationship, Drug, Epirubicin administration & dosage, Epirubicin adverse effects, Female, Fluorouracil administration & dosage, Fluorouracil adverse effects, Hematopoietic Stem Cell Transplantation adverse effects, Humans, Lymph Nodes drug effects, Lymph Nodes pathology, Lymphatic Metastasis, Middle Aged, Breast Neoplasms therapy, Cardiovascular Abnormalities epidemiology, Hematopoietic Stem Cell Transplantation methods
Abstract

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/m2, epirubicin, 90 mg/m2, and cyclophosphamide, 500 mg/m2, or HDCT in which the first 4 cycles were identical to CDCT and the fifth cycle was replaced by cyclophosphamide, 6000 mg/m2, thiotepa, 480 mg/m2, and carboplatin, 1600 mg/m2, 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.

Published
2020
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21. [A woman with skin abnormalities and muscle weakness].

Author

Steggink LC, Hettema ME, and Delsing CE

Subjects
Dermatomyositis complications, Dermatomyositis drug therapy, Dermatomyositis pathology, Female, Humans, Middle Aged, Muscle Weakness diagnosis, Muscle Weakness drug therapy, Muscle Weakness etiology, Paresis diagnosis, Paresis drug therapy, Paresis etiology, Treatment Outcome, Anti-Inflammatory Agents therapeutic use, Dermatomyositis diagnosis, Prednisolone therapeutic use
Abstract

A 54-year-old woman presented to the emergency department with progressive proximal muscle weakness and a symmetric skin rash. Physical examination demonstrated a heliotrope rash, Gottron lesions, mechanic's hands and symmetrical erythema of the face, neck and upper legs. The diagnosis 'dermatomyositis' was established. Subsequently, the patient was successfully treated with prednisolone 1 mg/kg.

Published
2013

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