Publications by authors named "Tobias Engler"

7 Publications

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Measuring the Time to Deterioration for Health-Related Quality of Life in Patients With Metastatic Breast Cancer Using a Web-Based Monitoring Application: Longitudinal Cohort Study.

JMIR Cancer 2021 Oct 12;7(4):e25776. Epub 2021 Oct 12.

Department of Gynecology and Obstetrics, University Hospital Heidelberg, Heidelberg, Germany.

Background: Health-related quality of life (HRQoL) is used to evaluate the treatment of metastatic breast cancer. In a long-term therapy setting, HRQoL can be used as an important benchmark for treatment success. With the help of digital apps, HRQoL monitoring can be extended to more remote areas and be administered on a more frequent basis.

Objective: This study aims to evaluate 3 common HRQoL questionnaires in metastasized breast cancer in terms of TTD in a digital, web-based setting. We further aim to examine the development of the HRQoL in different systemic treatment groups in each of these evaluation instruments.

Methods: A total of 192 patients with metastatic breast cancer were analyzed in this bicentric prospective online cohort study at two German university hospitals. Patients completed questionnaires on HRQoL (EuroQol Visual Analog Scale [EQ-VAS], EuroQol 5 Dimension 5 Level [EQ-5D-5L], European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 item [EORTC QLQ-C30]) via an online platform over a 6-month period. Treatment schedules and medical history were retrieved from medical records. Unadjusted Cox regression analysis on treatment-related factors was performed. We conducted subgroup analyses in regard to TTD events between different treatments.

Results: The EQ-VAS showed a higher rate of deterioration after 8 weeks (84/179, 46.9%) than the EQ-5D-5L (47/163, 28.8%) and EORTC QLQ-C30 (65/176, 36.9%). Unadjusted Cox regression revealed significant connections between known metastases in the liver (P=.03, HR 1.64, 95% CI 1.06-2.52) and pleura (P=.04, HR 0.42, 95% CI 0.18-0.96) in the EQ-VAS. Significant relations between EQ-VAS events and single EQ-5D-5L items and the EQ-5D-5L summary score were demonstrated. All treatment groups significantly differed from the CDK4/6 inhibition subgroup in the EQ-VAS.

Conclusions: Compared to the EQ-5D-5L and QLQ-C30, the EQ-VAS showed a higher rate of deterioration after 8 weeks. Significant connections to certain metastatic locations were only detected in the EQ-VAS. The EQ-VAS is capable of reflecting the distinctive HRQoL profiles of different systemic treatments as well as the different aspects of HRQoL presented in the EQ-5D-5L. TTD with the EQ-VAS is an adequate mean of examining longitudinal development of HRQoL among breast cancer patients.
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http://dx.doi.org/10.2196/25776DOI Listing
October 2021

HLA Ligand Atlas: a benign reference of HLA-presented peptides to improve T-cell-based cancer immunotherapy.

J Immunother Cancer 2021 04;9(4)

Clinical Neuroscience Center and Department of Neurosurgery, University Hospital and University of Zurich, Zurich, Switzerland.

Background: The human leucocyte antigen (HLA) complex controls adaptive immunity by presenting defined fractions of the intracellular and extracellular protein content to immune cells. Understanding the benign HLA ligand repertoire is a prerequisite to define safe T-cell-based immunotherapies against cancer. Due to the poor availability of benign tissues, if available, normal tissue adjacent to the tumor has been used as a benign surrogate when defining tumor-associated antigens. However, this comparison has proven to be insufficient and even resulted in lethal outcomes. In order to match the tumor immunopeptidome with an equivalent counterpart, we created the HLA Ligand Atlas, the first extensive collection of paired HLA-I and HLA-II immunopeptidomes from 227 benign human tissue samples. This dataset facilitates a balanced comparison between tumor and benign tissues on HLA ligand level.

Methods: Human tissue samples were obtained from 16 subjects at autopsy, five thymus samples and two ovary samples originating from living donors. HLA ligands were isolated via immunoaffinity purification and analyzed in over 1200 liquid chromatography mass spectrometry runs. Experimentally and computationally reproducible protocols were employed for data acquisition and processing.

Results: The initial release covers 51 HLA-I and 86 HLA-II allotypes presenting 90,428 HLA-I- and 142,625 HLA-II ligands. The HLA allotypes are representative for the world population. We observe that immunopeptidomes differ considerably between tissues and individuals on source protein and HLA-ligand level. Moreover, we discover 1407 HLA-I ligands from non-canonical genomic regions. Such peptides were previously described in tumors, peripheral blood mononuclear cells (PBMCs), healthy lung tissues and cell lines. In a case study in glioblastoma, we show that potential on-target off-tumor adverse events in immunotherapy can be avoided by comparing tumor immunopeptidomes to the provided multi-tissue reference.

Conclusion: Given that T-cell-based immunotherapies, such as CAR-T cells, affinity-enhanced T cell transfer, cancer vaccines and immune checkpoint inhibition, have significant side effects, the HLA Ligand Atlas is the first step toward defining tumor-associated targets with an improved safety profile. The resource provides insights into basic and applied immune-associated questions in the context of cancer immunotherapy, infection, transplantation, allergy and autoimmunity. It is publicly available and can be browsed in an easy-to-use web interface at .
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http://dx.doi.org/10.1136/jitc-2020-002071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8054196PMC
April 2021

Platelet-expressed immune checkpoint regulator GITRL in breast cancer.

Cancer Immunol Immunother 2021 Sep 4;70(9):2483-2496. Epub 2021 Feb 4.

Cluster of Excellence iFIT (EXC 2180) "Image-Guided and Functionally Instructed Tumor Therapies", University of Tuebingen, Tuebingen, Germany.

Owing to their key role in several diseases including cancer, activating and inhibitory immune checkpoint molecules are increasingly exploited as targets for immunotherapy. Recently, we demonstrated that platelets, which largely influence tumor progression and immune evasion, functionally express the ligand of the checkpoint molecule GITR. This immunoreceptor modulates effector functions of T cells and NK cells with its function varying dependent on cellular context and activation state. Here, we provide a comparative analysis of platelet-derived GITRL (pGITRL) in breast cancer patients and healthy volunteers. The levels of pGITRL were found to be higher on platelets derived from cancer patients and appeared to be specifically regulated during tumor progression as exemplified by several clinical parameters including tumor stage/grade, the occurrence of metastases and tumor proliferation (Ki67) index. In addition, we report that pGITRL is upregulated during platelet maturation and particularly induced upon exposure to tumor-derived soluble factors. Our data indicate that platelets modulate the GITR/GITRL immune checkpoint in the context of malignant disease and provide a rationale to further study the GITR/GITRL axis for exploitation for immunotherapeutic intervention in cancer patients.
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http://dx.doi.org/10.1007/s00262-021-02866-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8360840PMC
September 2021

A Modern Approach to Endometrial Carcinoma: Will Molecular Classification Improve Precision Medicine in the Future?

Cancers (Basel) 2020 Sep 10;12(9). Epub 2020 Sep 10.

Department of Women's health, University Hospital Tuebingen, 72076 Tuebingen, Germany.

Endometrial cancer has been histologically classified as either an estrogen-dependent cancer with a favorable outcome or an estrogen-independent cancer with a worse prognosis. These parameters, along with the clinical attributions, have been the basis for risk stratification. Recent molecular and histopathological findings have suggested a more complex approach to risk stratification. Findings from the Cancer Genome Atlas Research Network established four distinctive genomic groups: ultramutated, hypermutated, copy-number low and copy-number high prognostic subtypes. Subsequently, more molecular and histopathologic classifiers were evaluated for their prognostic and predictive value. The impact of molecular classification is evident and will be recognized by the upcoming WHO classification. Further research is needed to give rise to a new era of molecular-based endometrial carcinoma patient care.
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http://dx.doi.org/10.3390/cancers12092577DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7564776PMC
September 2020

Ovarian cyst removal influences ovarian reserve dependent on histology, size and type of operation.

Womens Health (Lond) 2018 Jan-Dec;14:1745506518778992

1 Department of Gynecology and Obstetrics, University Hospital Tübingen, Tübingen, Germany.

Previous publications suggest a reduction in the ovarian reserve following ovarian surgery. The influence of the underlying disease, histology, size of the ovarian cyst and type of procedure remains unclear. The aim of this study was to investigate the influence of an ovarian operation on the ovarian reserve, based on the anti-Müllerian hormone levels. The anti-Müllerian hormone values were determined by means of a standardized enzyme-linked immunosorbent assay. In total, 52 patients with one or more ovarian cysts of different histologic entities treated at the Department of Women's Health at the Women's University Hospital in Tübingen were included in the study. Anti-Müllerian hormone was determined before and after surgery. The patients were 28 (range = 18-40) years old on average. There was a statistically significant decrease in anti-Müllerian hormone from 3.94 ± 3.18 to 3.14 ± 2.57 ng/mL (p = 0.001). In 80.8%, the cysts were unilateral, and in over 90.4%, a complete cyst extirpation was performed. A statistically significant reduction was seen in follicular cysts (4.72 ± 3.84 to 3.76 ± 2.91 ng/mL; p = 0.039) and endometriosis cysts (2.55 ± 1.87 to 1.72 ± 1.39 ng/mL; p = 0.024). Also, the size of the cysts had an influence on the ovarian reserve, only larger ovarian cysts with a diameter of 5 cm or more showed a statistically significant reduction in anti-Müllerian hormone. Our data showed a significant decrease in anti-Müllerian hormone levels after surgery on the ovaries. If this results in a long-term reduced ovarian reserve or is merely a short-term reaction to the procedure needs to be clarified. However, concerning young women, the indication of surgery should be given cautiously as-at least temporarily-a reduction in the ovarian reserve can occur.
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http://dx.doi.org/10.1177/1745506518778992DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5974568PMC
January 2019

The immunopeptidomic landscape of ovarian carcinomas.

Proc Natl Acad Sci U S A 2017 11 1;114(46):E9942-E9951. Epub 2017 Nov 1.

Department of Immunology, Institute of Cell Biology, University of Tübingen, 72076 Tübingen, Germany.

Immunotherapies, particularly checkpoint inhibitors, have set off a revolution in cancer therapy by releasing the power of the immune system. However, only little is known about the antigens that are essentially presented on cancer cells, capable of exposing them to immune cells. Large-scale HLA ligandome analysis has enabled us to exhaustively characterize the immunopeptidomic landscape of epithelial ovarian cancers (EOCs). Additional comparative profiling with the immunopeptidome of a variety of benign sources has unveiled a multitude of ovarian cancer antigens (MUC16, MSLN, LGALS1, IDO1, KLK10) to be presented by HLA class I and class II molecules exclusively on ovarian cancer cells. Most strikingly, ligands derived from mucin 16 and mesothelin, a molecular axis of prognostic importance in EOC, are prominent in a majority of patients. Differential gene-expression analysis has allowed us to confirm the relevance of these targets for EOC and further provided important insights into the relationship between gene transcript levels and HLA ligand presentation.
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http://dx.doi.org/10.1073/pnas.1707658114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5699044PMC
November 2017

Heart rate variability during treatment of breakthrough pain in patients with advanced cancer: a pilot study.

J Pain Res 2016 12;9:1215-1220. Epub 2016 Dec 12.

Clinical Division of Palliative Care, Department of Internal Medicine I, Medical University of Vienna, Vienna, Austria.

Background: Decisions on the intensity of analgesic therapy and judgments regarding its efficacy are difficult at the end of life, when many patients are not fully conscious and pain is a very common symptom. In healthy individuals and in postoperative settings, nociception and subsequent pain relief have been shown to induce changes in the autonomic nervous system (ANS), which can be detected by measuring heart rate variability (HRV).

Objectives: The changes in the ANS were studied by measuring HRV during opioid therapy for cancer breakthrough pain (CBTP) in palliative-care patients with cancer and compared these changes with patient-reported pain levels on a numeric rating scale (NRS).

Patients And Methods: The study included ten patients with advanced cancer and baseline opioid therapy. In each patient, a 24-hour peak-to-peak HRV measurement with a sampling rate of 4,000 Hz was performed. High frequency (HF), low frequency (LF), total power, pNN50 (indicating parasympathetic activity), and log LF/HF were obtained in two intervals prior to therapy and in four intervals thereafter. Intensity of CBTP was recorded using a patient-reported NRS prior to therapy and 30 minutes afterward.

Results: CBTP occurred in seven patients (three males and four females; mean age: 62 ± 5.2 years) and was treated with opioids. A highly significant positive correlation was found between opioid-induced reduction in patient-reported pain intensity based on NRS and changes in log LF/HF ( > 0.700; < 0.05). Log LF/HF decreased in patients who had a reduction in pain of >2 points on the NRS but remained unchanged in the other patients.

Conclusion: Our data suggest that log LF/HF may be a useful surrogate marker for alleviation of CBTP in patients with advanced cancer and might allow detection of pain without active contribution from patients.
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http://dx.doi.org/10.2147/JPR.S120343DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5161332PMC
December 2016
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