Publications by authors named "Markus Hecht"

60 Publications

PARP Inhibitors Talazoparib and Niraparib Sensitize Melanoma Cells to Ionizing Radiation.

Genes (Basel) 2021 May 31;12(6). Epub 2021 May 31.

Department of Radiation Oncology, University Hospital Erlangen, 91054 Erlangen, Germany.

(1) Background: Niraparib and Talazoparib are poly (ADP-ribose) polymerase (PARP) 1/2 inhibitors. It is assumed that combining PARP inhibitors with radiotherapy could be beneficial for cancer treatment. In this study, melanoma cells were treated with Niraparib and Talazoparib in combination with ionizing radiation (IR). (2) Methods: The effects of Talazoparib and Niraparib in combination with IR on cell death, clonogenicity and cell cycle arrest were studied in healthy primary fibroblasts and primary melanoma cells. (3) Results: The melanoma cells had a higher PARP1 and PARP2 content than the healthy fibroblasts, and further increased their PARP2 content after the combination therapy. PARP inhibitors both sensitized fibroblasts and melanoma cells to IR. A clear supra-additive effect of KI+IR treatment was detected in two melanoma cell lines analyzing the surviving fraction. The cell death rate increased in the healthy fibroblasts, but to a larger extent in melanoma cells after combined treatment. Finally, a lower percentage of cells in the radiosensitive G2/M phase is present in the healthy fibroblasts compared to the melanoma cells. (4) Conclusions: Both PARP inhibitors sensitize melanoma cells to IR. Healthy tissue seems to be less affected than melanoma cells. However, the great heterogeneity of the results suggests prior testing of the tumor cells in order to personalize the treatment.
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http://dx.doi.org/10.3390/genes12060849DOI Listing
May 2021

Salvage laryngectomy after primary radio- and radiochemotherapy : A retrospective study.

HNO 2021 May 21. Epub 2021 May 21.

Department of Otorhinolaryngology, Head and Neck Surgery, Friedrich Alexander University of Erlangen-Nuremberg, Waldstraße 1, 91054, Erlangen, Germany.

Background: Recurrent and residual laryngeal cancer after organ-preserving radio- or radiochemotherapy is associated with a poor prognosis. Salvage surgery is the most important therapeutic option in these cases.

Objective: The study assessed rates of recurrence and residual tumor as well as survival and complication rates after salvage laryngectomy at the authors' academic cancer center.

Materials And Methods: A retrospective examination of all patients receiving laryngectomy between 2001 and 2019 due to tumor residuals or recurrence after primary radio- and radiochemotherapy was conducted.

Results: A total of 33 salvage procedures were performed. Defect reconstruction was performed by free flap surgery in 30.3% (n = 10) and regional flap surgery in 15.2% (n = 5) . One patient received regional flap surgery and free flap surgery simultaneously. Overall survival after 1, 2, and 5 years was 68.7, 47.9, and 24.2%, and disease-free survival was 81.6, 47.8, and 24.2%, respectively, with 48.5% (n = 16) postoperative tumor recurrences overall. Disease-free survival was significantly shorter for tumor extension into or onto the hypopharynx (p = 0.041). Postoperatively, 72.7% of patients developed a pharyngocutaneous fistula, of which 24.2% required surgical treatment. The hospital stay was 28.0 ± 16.1 days.

Conclusion: Salvage laryngectomy is associated with a high rate of treatable complications and high morbidity. Nevertheless, considering the advanced tumor stages treated, it allows for respectable oncological results.
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http://dx.doi.org/10.1007/s00106-021-01030-3DOI Listing
May 2021

Radiotherapy and the immune system: More than just immune suppression.

Stem Cells 2021 May 7. Epub 2021 May 7.

Translational Radiobiology, Department of Radiation Oncology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.

Radiotherapy (RT) is still one of the standard cancer therapies with up to two third of all cancer patients with solid tumors being irradiated in the course of their disease. The aim of using ionizing radiation in fractionated treatment schedules was always to achieve local tumor control by inducing DNA damage which can be repaired by surrounding normal tissue but leads to cell death in tumor cells. Meanwhile, it is known that RT also has immunological effects reshaping the tumor microenvironment. Nevertheless, RT alone often fails to elicit potent antitumor immune responses as these effects can be immunostimulatory as well as immunosuppressive. Here, we discuss how immunotherapies can be exploited in combined therapies to boost RT-induced antitumor immune responses or to counteract preexisting and RT-mediated immunosuppression to improve local and systemic tumor control. Furthermore, we highlight some parameters of radioimmunotherapies (RITs) which are under investigation for potential optimizations and how RIT approaches are tested in first phases II and III trials. Finally, we discuss how RT might affect normal and cancer stem cells.
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http://dx.doi.org/10.1002/stem.3391DOI Listing
May 2021

Identification of 15 lncRNAs Signature for Predicting Survival Benefit of Advanced Melanoma Patients Treated with Anti-PD-1 Monotherapy.

Cells 2021 Apr 22;10(5). Epub 2021 Apr 22.

Department of Radiation Oncology, Universitätsklinikum Erlangen, 91054 Erlangen, Germany.

The blockade of programmed cell death protein 1 (PD-1) as monotherapy has been widely used in melanoma, but to identify melanoma patients with survival benefit from anti-PD-1 monotherapy is still a big challenge. There is an urgent need for prognostic signatures improving the prediction of immunotherapy responses of these patients. We analyzed transcriptomic data of pre-treatment tumor biopsies and clinical profiles in advanced melanoma patients receiving only anti-PD-1 monotherapy (nivolumab or pembrolizumab) from the PRJNA356761 and PRJEB23709 data sets as the training and validation cohort, respectively. Weighted gene co-expression network analysis was used to identify the key module, then least absolute shrinkage and selection operator was conducted to determine prognostic-related long noncoding RNAs (lncRNAs). Subsequently, the differentially expressed genes between different clusters were identified, and their function and pathway annotation were performed. In this investigation, 92 melanoma patients with complete survival information (51 from training cohort and 41 from validation cohort) were included in our analyses. We initiallyidentified the key module (skyblue) by weighted gene co-expression network analysis, and then identified a 15 predictive lncRNAs (AC010904.2, LINC01126, AC012360.1, AC024933.1, AL442128.2, AC022211.4, AC022211.2, AC127496.5, NARF-AS1, AP000919.3, AP005329.2, AC023983.1, AC023983.2, AC139100.1, and AC012615.4) signature in melanoma patients treated with anti-PD-1 monotherapy by least absolute shrinkage and selection operator in the training cohort. These results were then validated in the validation cohort. Finally, enrichment analysis showed that the functions of differentially expressed genes between two consensus clusters were mainly related to the immune process and treatment. In summary, the 15 lncRNAs signature is a novel effective predictor for prognosis in advanced melanoma patients treated with anti-PD-1 monotherapy.
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http://dx.doi.org/10.3390/cells10050977DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8143567PMC
April 2021

Implementation of Double Immune Checkpoint Blockade Increases Response Rate to Induction Chemotherapy in Head and Neck Cancer.

Cancers (Basel) 2021 Apr 19;13(8). Epub 2021 Apr 19.

Department of Radiation Oncology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, 91054 Bayern, Germany.

To determine whether a single dose of double immune checkpoint blockade (induction chemoimmunotherapy (ICIT)) adds benefit to induction single-cycle platinum doublet (induction chemotherapy (IC)) in locally advanced head and neck squamous cell carcinoma (HNSCC), patients treated with cisplatin 30 mg/m d1-3 and docetaxel 75 mg/m d1 combined with durvalumab 1500 mg fixed dose d5 and tremelimumab 75 mg fixed dose d5 (ICIT) within the CheckRad-CD8 trial were compared with a retrospective cohort receiving the same chemotherapy (IC) without immunotherapy. The endpoint of this analysis was the complete response rate (CR). A total of 53 patients were treated with ICIT and 104 patients with IC only. CR rates were 60.3% for ICIT and 40.3% for IC ( = 0.018). In the total population ( = 157), the most important predictor to achieve a CR was treatment type (OR: 2.21 for ICIT vs. IC; = 0.038, multivariate analysis). The most diverse effects in CR rates between ICIT and IC were observed in younger (age ≤ 60) patients with HPV-positive OPSCCs (82% vs. 33%, = 0.176), while there was no difference in older patients without HPV-positive OPSCCs (53% vs. 48%). The analysis provides initial evidence that ICIT could result in higher CR rates than IC. Young patients with HPV-positive OPSCCs may have the greatest benefit from additional immune checkpoint inhibitors.
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http://dx.doi.org/10.3390/cancers13081959DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8073509PMC
April 2021

Low- vs. high-dose radiotherapy in Graves' ophthalmopathy: a retrospective comparison of long-term results.

Strahlenther Onkol 2021 Apr 16. Epub 2021 Apr 16.

Department of Radiation Oncology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Universitaetsstraße 27, 91054, Erlangen, Germany.

Purpose: Radiotherapy represents an effective treatment option in Graves' ophthalmopathy (GO), leading to palliation of clinical symptoms. However, there are only a limited number of trials comparing the effectiveness of low- vs. high-dose radiotherapy.

Methods: We analyzed 127 patients treated with radiotherapy for stage 3/4 GO (NOSPECS classification). Patients were treated with single doses of 2.0 Gy (cumulative dose 20 Gy) until 2007, afterwards a single dose of 0.8 Gy (cumulative dose 4.8 Gy) was applied. With a median follow-up-time of 9.0 years, the treatment efficacy (overall improvement, sense of eye pressure, lid edema, ocular motility, exophthalmos, subjective vision, and diplopia) and adverse effects were analyzed by a standardized survey.

Results: Overall, 63.8% described improvement of symptoms after radiotherapy. No significant differences in overall treatment response and improvement of main outcome measures between low- or high-dose radiotherapy treatments are detectable, while low-dose radiotherapy leads significantly more often to retreatment (13.1% vs. 1.7%, p = 0.016). The main independent predictor of treatment response is the presence of lid edema (odds ratio, OR, 3.53; p = 0.006).

Conclusion: At long-term follow-up, the majority of patients reported palliation of symptoms with limited adverse effects, suggesting clinical effectiveness of radiotherapy for amelioration of GO symptoms independent of low- or high-dose radiotherapy.
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http://dx.doi.org/10.1007/s00066-021-01770-9DOI Listing
April 2021

[Salvage laryngectomy after primary radio- and radiochemotherapy : A retrospective study. German version].

HNO 2021 Apr 9. Epub 2021 Apr 9.

Hals-Nasen-Ohrenklinik, Kopf- und Hals-Chirurgie, Universitätskliniken Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Waldstraße 1, 91054, Erlangen, Deutschland.

Background: Recurrent and residual laryngeal cancer after organ-preserving radio- or radiochemotherapy is associated with a poor prognosis. Salvage surgery is the most important therapeutic option in these cases.

Objective: The study assessed rates of recurrence and residual tumor as well as survival and complication rates after salvage laryngectomy at the authors' academic cancer center.

Materials And Methods: A retrospective examination of all patients receiving laryngectomy between 2001 and 2019 due to tumor residuals or recurrence after primary radio- and radiochemotherapy was conducted.

Results: A total of 33 salvage procedures were performed. Defect reconstruction was performed by free flap surgery in 30.3% (n = 10) and regional flap surgery in 15.2% (n = 5) . One patient received regional flap surgery and free flap surgery simultaneously. Overall survival after 1, 2, and 5 years was 68.7, 47.9, and 24.2%, and disease-free survival was 81.6, 47.8, and 24.2%, respectively, with 48.5% (n = 16) postoperative tumor recurrences overall. Disease-free survival was significantly shorter for tumor extension into or onto the hypopharynx (p = 0.041). Postoperatively, 72.7% of patients developed a pharyngocutaneous fistula, of which 24.2% required surgical treatment. The hospital stay was 28.0 ± 16.1 days.

Conclusion: Salvage laryngectomy is associated with a high rate of treatable complications and high morbidity. Nevertheless, considering the advanced tumor stages treated, it allows for respectable oncological results.
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http://dx.doi.org/10.1007/s00106-021-01029-wDOI Listing
April 2021

Oligometastatic head and neck cancer: Which patients benefit from radical local treatment of all tumour sites?

Radiat Oncol 2021 Mar 31;16(1):62. Epub 2021 Mar 31.

Department of Radiotherapy, Friedrich-Alexander-Universität Erlangen-Nürnberg, Universitaetsstraße 27, 91054, Erlangen, Germany.

Background: There is a large lack of evidence for optimal treatment in oligometastatic head and neck cancer and it is especially unclear which patients benefit from radical local treatment of all tumour sites.

Methods: 40 patients with newly diagnosed oligometastatic head and neck cancer received radical local treatment of all tumour sites from 14.02.2008 to 24.08.2018. Primary endpoint was overall survival. Time to occurrence of new distant metastases and local control were evaluated as secondary endpoints as well as prognostic factors in univariate und multivariate Cox's regression analysis. To investigate the impact of total tumour volume on survival, all tumour sites were segmented on baseline imaging.

Results: Radical local treatment included radiotherapy in 90% of patients, surgery in 25% and radiofrequency ablation in 3%. Median overall survival from first diagnosis of oligometastatic disease was 23.0 months, 2-year survival was 48%, 3-year survival was 37%, 4-year survival was 24% and 5-year survival was 16%. Median time to occurrence of new distant metastases was 11.6 months with freedom from new metastases showing a tail pattern after 3 years of follow-up (22% at 3, 4- and 5-years post-treatment). In multivariate analysis, better ECOG status, absence of bone and brain metastases and lower total tumour volume were significantly associated with improved survival, whereas the number of metastases and involved organ sites was not.

Conclusions: Radical local treatment in oligometastatic head and neck cancer shows promising outcomes and needs to be further pursued. Patients with good performance status, absence of brain and bone metastases and low total tumour volume were identified as optimal candidates for radical local treatment in oligometastatic head and neck cancer and should be considered for selection in future prospective trials.
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http://dx.doi.org/10.1186/s13014-021-01790-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8011153PMC
March 2021

Questionnaire-based detection of immune-related adverse events in cancer patients treated with PD-1/PD-L1 immune checkpoint inhibitors.

BMC Cancer 2021 Mar 24;21(1):314. Epub 2021 Mar 24.

Department of Radiation Oncology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Universitätsstraße 27, 91054, Erlangen, Germany.

Background: Immune checkpoint inhibitors (ICI) have become standard treatment in different tumor entities. However, safe treatment with ICI targeting the PD-1/PD-L1 axis requires early detection of immune-related adverse events (irAE). There exist different questionnaires of drug manufacturers for the detection of irAE that have not been validated so far.

Methods: The prospective non-interventional ST-ICI trial studied treatment with PD-1/PD-L1 ICI alone or combined with radiotherapy. In the current analysis, the detection rate of self-reported irAE with a patient questionnaire containing 41 different questions was compared to clinician-reported irAE.

Results: Between April 2017 and August 2019, a total of 104 patients were prospectively enrolled. NSCLC (44%) and HNSCC (42%) were the most frequent tumor entities. A total of 784 questionnaires were collected. A total of 29 irAE were reported by clinicians. The most frequent irAE was hypothyroidism (9%), followed by skin reactions (5%), hepatitis (4%), diarrhea (3%), and pneumonitis (3%). Questions that became significantly more often positive at time points of clinician-reported irAE were "weight change", "difficulty to grip things", "bloody or mucous stool" and "insomnia". Self-reported organ-specific questions detected at least 50% of clinician-reported irAE of gastrointestinal, lung, endocrine, and skin irAE. It was not possible to detect hepatic irAE with the questionnaire.

Conclusion: Questionnaires can help to detect gastrointestinal, lung, endocrine, or skin irAE, but not hepatic irAE. Questions on "weight change" and "insomnia" may help to increase the detection rate of irAE, besides organ-specific questions. These results are a valuable contribution to the future development of a specific and practicable questionnaire for early self-reported detection of irAE during ICI therapy in cancer patients.

Trial Registration: ClinicalTrials.gov, NCT03453892 . Registered on 05 March 2018.
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http://dx.doi.org/10.1186/s12885-021-08006-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7992796PMC
March 2021

Polymorphism in Squaraine Dye Aggregates by Self-Assembly Pathway Differentiation: Panchromatic Tubular Dye Nanorods versus J-Aggregate Nanosheets.

Angew Chem Int Ed Engl 2021 May 2;60(21):11949-11958. Epub 2021 May 2.

Institut für Organische Chemie, Universität Würzburg, Am Hubland, 97074, Würzburg, Germany.

A bis(squaraine) dye equipped with alkyl and oligoethyleneglycol chains was synthesized by connecting two dicyanomethylene substituted squaraine dyes with a phenylene spacer unit. The aggregation behavior of this bis(squaraine) was investigated in non-polar toluene/tetrachloroethane (98:2) solvent mixture, which revealed competing cooperative self-assembly pathways into two supramolecular polymorphs with entirely different packing structures and UV/Vis/NIR absorption properties. The self-assembly pathway can be controlled by the cooling rate from a heated solution of the monomers. For both polymorphs, quasi-equilibrium conditions between monomers and the respective aggregates can be established to derive thermodynamic parameters and insights into the self-assembly mechanisms. AFM measurements revealed a nanosheet structure with a height of 2 nm for the thermodynamically more stable polymorph and a tubular nanorod structure with a helical pitch of 13 nm and a diameter of 5 nm for the kinetically favored polymorph. Together with wide angle X-ray scattering measurements, packing models were derived: the thermodynamic polymorph consists of brick-work type nanosheets that exhibit red-shifted absorption bands as typical for J-aggregates, while the nanorod polymorph consists of eight supramolecular polymer strands of the bis(squaraine) intertwined to form a chimney-type tubular structure. The absorption of this aggregate covers a large spectral range from 550 to 875 nm, which cannot be rationalized by the conventional exciton theory. By applying the Essential States Model and considering intermolecular charge transfer, the aggregate spectrum was adequately reproduced, revealing that the broad absorption spectrum is due to pronounced donor-acceptor overlap within the bis(squaraine) nanorods. The latter is also responsible for the pronounced bathochromic shift observed for the nanosheet structure as a result of the slip-stacked arranged squaraine chromophores.
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http://dx.doi.org/10.1002/anie.202102183DOI Listing
May 2021

Prospective development and validation of a liquid immune profile-based signature (LIPS) to predict response of patients with recurrent/metastatic cancer to immune checkpoint inhibitors.

J Immunother Cancer 2021 Feb;9(2)

Department of Radiation Oncology, Universitätsklinikum Erlangen, Erlangen, Germany.

Background: The predictive power of novel biological markers for treatment response to immune checkpoint inhibitors (ICI) is still not satisfactory for the majority of patients with cancer. One should identify valid predictive markers in the peripheral blood, as this is easily available before and during treatment. The current interim analysis of patients of the ST-ICI cohort therefore focuses on the development and validation of a liquid immune profile-based signature (LIPS) to predict response of patients with metastatic cancer to ICI targeting the programmed cell death protein 1 (PD-1)/programmed cell death-ligand 1 (PD-L1) axis.

Methods: A total of 104 patients were prospectively enrolled. 54 immune cell subsets were prospectively analyzed in patients' peripheral blood by multicolor flow cytometry before treatment with ICI (pre-ICI; n=89), and after the first application of ICI (n=65). Pre-ICI, patients were randomly allocated to a training (n=56) and a validation cohort (n=33). Univariate Cox proportional hazards regression analysis and least absolute shrinkage and selection operator Cox model were used to create a predictive immune signature, which was also checked after the first ICI, to consider the dynamics of changes in the immune status.

Results: Whole blood samples were provided by 89 patients pre-ICI and by 65 patients after the first ICI. We identified a LIPS which is based on five immune cell subtypes: CD14 monocytes, CD8+/PD-1 T cells, plasmacytoid dendritic cells, neutrophils, and CD3/CD56/CD16 natural killer (NK)T cells. The signature achieved a high accuracy (C-index 0.74 vs 0.71) for predicting overall survival (OS) benefit in both the training and the validation cohort. In both cohorts, the low-risk group had significantly longer OS than the high-risk group (HR 0.26, 95% CI 0.12 to 0.56, p=0.00025; HR 0.30, 95% CI 0.10 to 0.91, p=0.024, respectively). Regarding the whole cohort, LIPS also predicted progression-free survival (PFS). The identified LIPS was not affected by clinicopathological features with the exception of brain metastases. NKT cells and neutrophils of the LIPS can be used as dynamic predictive biomarkers for OS and PFS after first administration of the ICI.

Conclusion: Our study identified a predictive LIPS for survival of patients with cancer treated with PD-1/PD-L1 ICI, which is based on immune cell subsets in the peripheral whole blood.

Trial Registration Number: NCT03453892.
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http://dx.doi.org/10.1136/jitc-2020-001845DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7888377PMC
February 2021

Increase in non-professional phagocytosis during the progression of cell cycle.

PLoS One 2021 5;16(2):e0246402. Epub 2021 Feb 5.

Department of Radiation Oncology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.

Homotypic or heterotypic internalization of another, either living or necrotic cell is currently in the center of research interest. The active invasion of a living cell called entosis and cannibalism of cells by rapidly proliferating cancers are prominent examples. Additionally, normal healthy tissue cells are capable of non-professional phagocytosis. This project studied the relationship between non-professional phagocytosis, individual proliferation and cell cycle progression. Three mesenchymal and two epithelial normal tissue cell lines were studied for homotypic non-professional phagocytosis. Homotypic dead cells were co-incubated with adherent growing living cell layers. Living cells were synchronized by mitotic shake-off as well as Aphidicolin-treatment and phagocytotic activity was analyzed by immunostaining. Cell cycle phases were evaluated by flow cytometry. Mesenchymal and epithelial normal tissue cells were capable of internalizing dead cells. Epithelial cells had much higher non-professional phagocytotic rates than mesenchymal cells. Cells throughout the entire cell cycle were able to phagocytose. The phagocytotic rate significantly increased with progressing cell cycle phases. Mitotic cells regularly phagocytosed dead cells, this was verified by Nocodazole and Colcemid treatment. Taken together, our findings indicate the ability of human tissue cells to phagocytose necrotic neighboring cells in confluent cell layers. The origin of the cell line influences the rate of cell-in-cell structure formation. The higher cell-in-cell structure rates during cell cycle progression might be influenced by cytoskeletal reorganization during this period or indicate an evolutionary anchorage of the process. Recycling of nutrients during cell growth might also be an explanation.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0246402PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7864402PMC
February 2021

Differences in and Prognostic Value of Quality of Life Data in Rectal Cancer Patients with and without Distant Metastases.

Healthcare (Basel) 2020 Dec 22;9(1). Epub 2020 Dec 22.

Department of Radiation Oncology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität of Erlangen-Nürnberg (FAU), D-91054 Erlangen, Germany.

(1) Background: Individualization of treatment is a major challenge in oncology and requires a variety of predictive and prognostic parameters. In addition to tumor biology analyses, baseline health-related quality of life might be a valid tool to predict overall survival. This study was conducted to evaluate the prognostic relevance of baseline quality of life data in patients with rectal cancer. In this context, differences between patients with and without distant metastases were of particular interest. (2) Methods: Our cohort included 258 patients with rectal cancer treated in the radiotherapy department of the University Hospital Erlangen. Patients completed the European Organisation for Research and Treatment of Cancer (EORTC) core quality of life questionnaire (QLQ C30) and colorectal cancer questionnaire (CR38). Clinical and survival data were provided by the Gießener Tumor Documentation System (GTDS) of the Comprehensive Cancer Center Erlangen-EMN (CCC, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany). Statistical analyses were performed using Kaplan-Meier analyses and univariate and multivariate Cox regression. (3) Results: A cohort of 258 patients with rectal adenocarcinoma was analyzed including 50 patients (19.4%) with metastatic disease. No differences were observed between patients with and without distant metastases in most areas of quality of life studied, with the exception of physical function, loss of appetite, chemotherapy side effects and weight loss. Gender, baseline physical function, sexual function, diarrhea, and weight loss over time had a prognostic value in the entire cohort. Appetite loss was an additional prognostic parameter in patients with distant metastases. (4) Conclusions: The quality of life of patients with metastatic disease differed only slightly from non-metastatic patients. Health-related quality of life data provide prognostic information for patients with rectal cancer.
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http://dx.doi.org/10.3390/healthcare9010001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7821945PMC
December 2020

Peer review analysis in the field of radiation oncology: results from a web-based survey of the Young DEGRO working group.

Strahlenther Onkol 2020 Dec 18. Epub 2020 Dec 18.

Department of Radiation Oncology, University Hospital Jena, Jena, Germany.

Purpose: To evaluate the reviewing behaviour in the German-speaking countries in order to provide recommendations to increase the attractiveness of reviewing activity in the field of radiation oncology.

Methods: In November 2019, a survey was conducted by the Young DEGRO working group (jDEGRO) using the online platform "eSurveyCreator". The questionnaire consisted of 29 items examining a broad range of factors that influence reviewing motivation and performance.

Results: A total of 281 responses were received. Of these, 154 (55%) were completed and included in the evaluation. The most important factors for journal selection criteria and peer review performance in the field of radiation oncology are the scientific background of the manuscript (85%), reputation of the journal (59%) and a high impact factor (IF; 40%). Reasons for declining an invitation to review include the scientific background of the article (60%), assumed effort (55%) and a low IF (27%). A double-blind review process is preferred by 70% of respondents to a single-blind (16%) or an open review process (14%). If compensation was offered, 59% of participants would review articles more often. Only 12% of the participants have received compensation for their reviewing activities so far. As compensation for the effort of reviewing, 55% of the respondents would prefer free access to the journal's articles, 45% a discount for their own manuscripts, 40% reduced congress fees and 39% compensation for expenses.

Conclusion: The scientific content of the manuscript, reputation of the journal and a high IF determine the attractiveness for peer reviewing in the field of radiation oncology. The majority of participants prefer a double-blind peer review process and would conduct more reviews if compensation was available. Free access to journal articles, discounts for publication costs or congress fees, or an expense allowance were identified to increase attractiveness of the review process.
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http://dx.doi.org/10.1007/s00066-020-01729-2DOI Listing
December 2020

Dual mTOR/DNA-PK Inhibitor CC-115 Induces Cell Death in Melanoma Cells and Has Radiosensitizing Potential.

Int J Mol Sci 2020 Dec 7;21(23). Epub 2020 Dec 7.

Department of Radiation Oncology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Universitätsstr. 27, 91054 Erlangen, Germany.

CC-115 is a dual inhibitor of the mechanistic target of rapamycin (mTOR) kinase and the DNA-dependent protein kinase (DNA-PK) that is currently being studied in phase I/II clinical trials. DNA-PK is essential for the repair of DNA-double strand breaks (DSB). Radiotherapy is frequently used in the palliative treatment of metastatic melanoma patients and induces DSBs. Melanoma cell lines and healthy-donor skin fibroblast cell lines were treated with CC‑115 and ionizing irradiation (IR). Apoptosis, necrosis, and cell cycle distribution were analyzed. Colony forming assays were conducted to study radiosensitizing effects. Immunofluorescence microscopy was performed to determine the activity of homologous recombination (HR). In most of the malign cell lines, an increasing concentration of CC-115 resulted in increased cell death. Furthermore, strong cytotoxic effects were only observed in malignant cell lines. Regarding clonogenicity, all cell lines displayed decreased survival fractions during combined inhibitor and IR treatment and supra-additive effects of the combination were observable in 5 out of 9 melanoma cell lines. CC-115 showed radiosensitizing potential in 7 out of 9 melanoma cell lines, but not in healthy skin fibroblasts. Based on our data CC-115 treatment could be a promising approach for patients with metastatic melanoma, particularly in the combination with radiotherapy.
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http://dx.doi.org/10.3390/ijms21239321DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7730287PMC
December 2020

Supramolecularly Engineered J-Aggregates Based on Perylene Bisimide Dyes.

Acc Chem Res 2021 02 8;54(3):642-653. Epub 2020 Dec 8.

Institut für Organische Chemie, Center for Nanosystems Chemistry & Bavarian Polymer Institute, Universität Würzburg, Am Hubland, 97074 Würzburg, Germany.

The discovery of the self-assembly of cyanine dyes into J-aggregates had a major impact on the development of dye chemistry due to the emergence of new useful properties in the aggregated state. The unique optical features of these J-aggregates are narrowed, bathochromically shifted absorption bands with almost resonant fluorescence with an increased radiative rate that results from the coherently coupled molecular transition dipoles arranged in a slip-stacked fashion. Because of their desirable properties, J-aggregates gained popularity in the field of functional materials and enabled the efficient photosensitization of silver halide grains in color photography. However, despite a good theoretical understanding of structure-property relationships by the molecular exciton model, further examples of J-aggregates remained scarce for a long time as supramolecular designs to guide the formation of dye aggregates into the required slip-stacked arrangement were lacking.Drawing inspiration from the bacteriochlorophyll self-organization found in the chlorosomal light-harvesting antennas of green sulfur bacteria, we envisioned the use of nature's supramolecular blueprint to develop J-aggregates of perylene bisimides (PBIs). This class of materials is applied in high-performance color pigments and as n-type organic semiconductors in transistors and solar cells. Combining outstanding photochemical and thermal stability, high tinctorial strength and excellent fluorescence, PBIs are therefore an ideal model system for the preparation of J-aggregates with a wide range of potential applications.In this Account, we elucidate how a combination of steric constraints and hydrogen bonding receptor sites can guide the self-assembly of PBI dyes into slip-stacked packing motifs with J-type exciton coupling. We will discuss the supramolecular polymerization of multiple hydrogen-bonded PBI strands in organic and aqueous media and how minor structural modifications in monomeric PBI molecules can be used to obtain near-infrared absorbing J-aggregates, organogels, or thermoresponsive hydrogels. Pushing the boundaries of self-assembly into the bulk, engineering of the substituents' steric requirements by a dendron-wedge approach afforded adjustable numbers of helical strands of PBI J-aggregates in the columnar liquid-crystalline state and the preparation of lamellar phases. To fully explore their potential, we have studied PBI J-aggregates in collaborative work with spectroscopists, physicists, and theoreticians. In this way, exciton migration over distances of up to 180 nm was shown, and insights into the influence of static disorder on the transport of excitation energy in PBI J-aggregates were derived. Furthermore, the application of PBI J-aggregates as functional materials was demonstrated in photonic microcavities, thin-film transistors, and organic solar cells.
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http://dx.doi.org/10.1021/acs.accounts.0c00590DOI Listing
February 2021

Prospective Evaluation of All-lesion Versus Single-lesion Radiotherapy in Combination With PD-1/PD-L1 Immune Checkpoint Inhibitors.

Front Oncol 2020 29;10:576643. Epub 2020 Oct 29.

Department of Radiation Oncology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.

Background: Local ablative treatments improve survival in patients with oligometastatic disease in addition to chemotherapy. The application of immune checkpoint inhibitors prolonged patients' survival in different tumor entities. This raises the question if patients still benefit from intensified local treatments in combination with a more efficient systemic treatment with immune checkpoint inhibitors.

Methods: The prospective non-interventional ST-ICI trial investigates treatment with PD-1/PD-L1 (Programmed cell death protein 1/Programmed cell death 1 ligand 1) immune checkpoint inhibitors and radiotherapy in different tumor entities. Patients who started radiotherapy and immunotherapy concomitantly were included in this interim analysis. In this cohort patients with all-lesion radiotherapy (all tumor lesions irradiated, al-RT) were compared to patients with radiotherapy to only a single of their tumor lesions (single-lesion radiotherapy, sl-RT). Endpoints of the interim analysis were progression-free survival (PFS), overall survival (OS) and time to progression (TTP).

Results: A total of 104 patients were registered between April 2017 and August 2019. Fifty patients started immune checkpoint inhibitor treatment and radiotherapy concomitantly and were included. Most frequent tumor entities were non-small cell lung cancer (62%) followed by head and neck squamous cell cancer (26%). Most frequent location of radiotherapy was lung (34%) and central nervous system (20%). Median duration of follow-up was 8.6 months beginning with first administration of the immune-checkpoint-inhibitor. Median PFS was 9.2 months (95% CI, 5.8 - 12.6) in the al-RT group and 3.0 months (95% CI, 2.5 - 3.5) in the sl-RT group (p<0.001). Median OS was 11.6 months (95% CI, 8.1 - 15.1) in the al-RT group and 4.2 months (95% CI, 3.0 - 5.4) in the sl-RT group (p=0.007). Median TTP was not reached in the al-RT group compared to 4.6 months (95% CI, 1.1-8.0) in the sl-RT group (p=0.028). Univariate Cox regression analyses computed tumor entity, histology, central nervous system metastases, immunotherapy drug and al-RT as predictors of OS (with an effect p-value of ≤ 0.1). In the multivariable analysis only tumor entity and al-RT remained prognostic factors for OS.

Conclusion: Patients with PD-1/PD-L1 immune checkpoint inhibitor therapy benefit from local radiotherapy to all known lesions compared to single-lesion radiotherapy regarding PFS and OS.
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http://dx.doi.org/10.3389/fonc.2020.576643DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7673414PMC
October 2020

Radiomics to predict outcomes and abscopal response of patients with cancer treated with immunotherapy combined with radiotherapy using a validated signature of CD8 cells.

J Immunother Cancer 2020 11;8(2)

Department of Radiation Oncology, Gustave Roussy, Villejuif, Île-de-France, France

Background: Combining radiotherapy (RT) with immuno-oncology (IO) therapy (IORT) may enhance IO-induced antitumor response. Quantitative imaging biomarkers can be used to provide prognosis, predict tumor response in a non-invasive fashion and improve patient selection for IORT. A biologically inspired CD8 T-cells-associated radiomics signature has been developed on previous cohorts. We evaluated here whether this CD8 radiomic signature is associated with lesion response, whether it may help to assess disease spatial heterogeneity for predicting outcomes of patients treated with IORT. We also evaluated differences between irradiated and non-irradiated lesions.

Methods: Clinical data from patients with advanced solid tumors in six independent clinical studies of IORT were investigated. Immunotherapy consisted of 4 different drugs (antiprogrammed death-ligand 1 or anticytotoxic T-lymphocyte-associated protein 4 in monotherapy). Most patients received stereotactic RT to one lesion. Irradiated and non-irradiated lesions were delineated from baseline and the first evaluation CT scans. Radiomic features were extracted from contrast-enhanced CT images and the CD8 radiomics signature was applied. A responding lesion was defined by a decrease in lesion size of at least 30%. Dispersion metrices of the radiomics signature were estimated to evaluate the impact of tumor heterogeneity in patient's response.

Results: A total of 94 patients involving multiple lesions (100 irradiated and 189 non-irradiated lesions) were considered for a statistical interpretation. Lesions with high CD8 radiomics score at baseline were associated with significantly higher tumor response (area under the receiving operating characteristic curve (AUC)=0.63, p=0.0020). Entropy of the radiomics scores distribution on all lesions was shown to be associated with progression-free survival (HR=1.67, p=0.040), out-of-field abscopal response (AUC=0.70, p=0.014) and overall survival (HR=2.08, p=0.023), which remained significant in a multivariate analysis including clinical and biological variables.

Conclusions: These results enhance the predictive value of the biologically inspired CD8 radiomics score and suggests that tumor heterogeneity should be systematically considered in patients treated with IORT. This CD8 radiomics signature may help select patients who are most likely to benefit from IORT.
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http://dx.doi.org/10.1136/jitc-2020-001429DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7668366PMC
November 2020

Role of tumor cell senescence in non-professional phagocytosis and cell-in-cell structure formation.

BMC Mol Cell Biol 2020 Nov 7;21(1):79. Epub 2020 Nov 7.

Department of Radiation Oncology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, D-91054, Erlangen, Germany.

Background: Non-professional phagocytosis is usually triggered by stimuli such as necrotic cell death. In tumor therapy, the tumors often disappear slowly and only long time after the end of therapy. Here, tumor therapy inactivates the cells by inducing senescence. Therefore, study focused whether senescence is a stimulus for non-professional phagocytosis or whether senescent cells themselves phagocytize non-professionally.

Results: Senescence was induced in cell lines by camptothecin and a phagocytosis assay was performed. In tissue of a cohort of 192 rectal cancer patients senescence and non-professional phagocytosis was studied by anti-histone H3K9me3 and anti-E-cadherin staining. Senescent fibroblasts and pancreas carcinoma cells phagocytize necrotic cells but are not phagocytized. In the tissue of rectal carcinoma, senescent cells can phagocytize and can be phagocytized. A high number of senescent cells and, at the same time, high numbers of non-professional phagocytizing cells in the rectal carcinoma tissue lead to an extremely unfavorable prognosis regarding overall survival.

Conclusion: Senescent cells can be non-professionally phagocytized and at the same time they can non-professionally phagocytize in vivo. In vitro experiments indicate that it is unlikely that senescence is a strong trigger for non-professional phagocytosis. Combined high rates of non-professional phagocytosis and high rates of senescence are an extremely poor prognostic factor for overall survival.
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http://dx.doi.org/10.1186/s12860-020-00326-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7648987PMC
November 2020

Influence of p16 status on indication and outcome of salvage neck dissection in oropharyngeal cancer.

Acta Otolaryngol 2021 Feb 28;141(2):187-192. Epub 2020 Oct 28.

Department of Otorhinolaryngology, Head and Neck Surgery, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Erlangen, Germany.

Background: Human papillomavirus (HPV)+ and HPV- oropharyngeal squamous cell carcinomas (OPSCC) are separate tumor entities.

Aims/objectives: The aim of this study was to examine if the p16 status influences the need and outcome of a salvage neck dissection (SND) after primary radiochemotherapy (pRCT).

Material And Methods: Retrospective study of 164 patients ( = 108 p16-,  = 56 p16+) who underwent pRCT for OPSCC between 2009 and 2016. HPV status was defined p16 immunohistochemical staining. Clinical nodal status was assessed using ultrasound and computed tomography of the neck with contrast.

Results: Of the 56 p16+ patients, 17 (30.4%) patients were given an indication for a SND after pRCT with 4 (23.5%) patients showing persistent malignant nodes. Of the 108 p16- patients, 24 (22.2%) patients underwent a SND with 8 (33.3%) patients showing persistent malignant nodes. There was no significant association of the p16 status and neither the indication for SND (p(Chi(two-sided)-Test) = 0.25, ϕ = 0.34) nor the occurrence of positive nodes (p(Chi(two-sided)-Test) = 0.74, ϕ = 0.50). The probability for persistence of the ypN + nodal status independent of HPV-status was 29.2%(12/41).

Conclusions And Significance: There was neither a significant association between the p16 status and the indication for a SND nor for persistent malignant nodal disease after pRCT.
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http://dx.doi.org/10.1080/00016489.2020.1831697DOI Listing
February 2021

Unfolding multi-stranded perylene bisimide LC columns - a mesogen design for efficient nanoscale multilayer self-assembly.

Chem Commun (Camb) 2020 Nov;56(90):14015-14018

Institut für Organische Chemie, Am Hubland, 97074 Würzburg, Germany. and Center for Nanosystems Chemistry & Bavarian Polymer Institute, Universität Würzburg, Theodor-Boveri-Weg, 97074 Würzburg, Germany.

A mesogen tethered, twofold bay-substituted perylene bisimide (PBI) is found to generate a columnar phase, which unfolds and gradually transforms to a completely nanosegregated multilayer columnar-lamellar liquid crystal. The structure is based on the formation of bundles of H-bonded PBI strands in the central layer. This design opens the way to new complex multifunctional materials.
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http://dx.doi.org/10.1039/d0cc06458kDOI Listing
November 2020

Prospective evaluation of the prognostic value of immune-related adverse events in patients with non-melanoma solid tumour treated with PD-1/PD-L1 inhibitors alone and in combination with radiotherapy.

Eur J Cancer 2020 11 9;140:55-62. Epub 2020 Oct 9.

Department of Radiation Oncology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany; Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany.

Background: Prospective data about the prognostic value of immune-related adverse events (irAEs) in non-melanoma solid tumours are rare. The prognostic value of irAEs in patients treated with combined radiotherapy and immunotherapy is currently unknown.

Patients And Methods: The prospective non-interventional ST-ICI trial investigates treatment response of tumour patients to anti-programmed cell death-ligand 1 (PD-L1) immune checkpoint inhibitors alone and in combination with radiotherapy and possible predictive markers. Patients undergoing immunotherapy or immunoradiotherapy were surveyed for irAEs.

Results: A total of 104 patients were included of whom 29 patients (28%) developed irAEs. Additional radiotherapy was performed in 50 patients (48%). Main tumour entities within the entire cohort were non-small cell lung cancer (NSCLC) (44%) and head and neck squamous cell carcinoma (42%). The rate of irAEs did not differ in patients with and without radiotherapy (p = 0.668). Patients who developed irAEs had longer overall survival (OS) (median: 22.8 months versus 9.0 months without irAEs, p = 0.001) and progression-free survival (PFS) (median: 7.8 months versus 3.2 months without irAEs, p = 0.002). In the subgroup with combined radiotherapy, patients with irAEs also had longer OS (median: 22.8 months versus 7.1 months without irAEs, p = 0.005) and PFS (median: 8.8 months versus 3.0 months without irAEs, p = 0.005). On multivariate analysis only PD-L1 on tumour cells (p = 0.049) and irAEs (p = 0.001) remained independent predictors of OS.

Conclusion: The development of irAEs represents a favourable prognostic parameter in patients undergoing immunotherapy and immunoradiotherapy for solid tumours.
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http://dx.doi.org/10.1016/j.ejca.2020.09.001DOI Listing
November 2020

Safety and efficacy of single cycle induction treatment with cisplatin/docetaxel/ durvalumab/tremelimumab in locally advanced HNSCC: first results of CheckRad-CD8.

J Immunother Cancer 2020 10;8(2)

Department of Radiation Oncology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Bayern, Germany.

Background: To determine safety and efficacy of single cycle induction treatment with cisplatin/docetaxel and durvalumab/tremelimumab in stage III-IVB head and neck cancer.

Methods: Patients received a single cycle of cisplatin 30 mg/m² on days 1-3 and docetaxel 75 mg/m² on day 1 combined with durvalumab 1500 mg fix dose on day 5 and tremelimumab 75 mg fix dose on day 5. Patients with pathologic complete response (pCR) in the rebiopsy after induction treatment or at least 20% increase of intratumoral CD8+ cell density in the rebiopsy compared with baseline entered radioimmunotherapy with concomitant durvalumab/tremelimumab. The objective of this interim analysis was to analyze safety and efficacy of the chemoimmunotherapy-induction treatment before radioimmunotherapy.

Results: A total of 57 patients were enrolled, 56 were treated. Median pretreatment intratumoral CD8+ cell density was 342 cells/mm². After induction treatment, 27 patients (48%) had a pCR in the rebiopsy and further 25 patients (45%) had a relevant increase of intratumoral CD8+ cells (median increase by a factor of 3.0). Adverse event (AE) grade 3-4 appeared in 38 patients (68%) and mainly consisted of leukopenia (43%) and infections (29%). Six patients (11%) developed grade 3-4 immune-related AE. Univariate analysis computed p16 positivity, programmed death ligand 1 immune cell area and intratumoral CD8+ cell density as predictors of pCR. On multivariable analysis, intratumoral CD8+ cell density predicted pCR independently (OR 1.0012 per cell/mm², 95% CI 1.0001 to 1.0022, p=0.016). In peripheral blood CD8+ cells, the coexpression of programmed death protein 1 significantly increased especially in patients with pCR.

Conclusions: Single cycle induction treatment with cisplatin/docetaxel and durvalumab/tremelimumab is feasible and achieves a high biopsy-proven pCR rate.
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http://dx.doi.org/10.1136/jitc-2020-001378DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7539609PMC
October 2020

Treatment response lowers tumor symptom burden in recurrent and/or metastatic head and neck cancer.

BMC Cancer 2020 Sep 29;20(1):933. Epub 2020 Sep 29.

Department of Radiation Oncology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Universitätsstraße 27, 91054, Erlangen, Germany.

Background: Head and neck squamous cell cancer (HNSCC) frequently causes severe symptoms that may be reduced, when the tumor is successfully treated. The SOCCER trial studied the association of treatment response with patient reported tumor symptom burden in first line treatment of recurrent and/or metastatic HNSCC.

Methods: In this prospective, multi-center, non-interventional trial patients were treated either with platinum-based chemotherapy and cetuximab or radiotherapy and cetuximab. Tumor symptom burden was assessed every four weeks with a questionnaire containing ten visual analogue scales (VAS, range 0-100), which were summarized to the overall VAS score.

Results: Fourhundred seventy patients were registered in 97 German centers. A total of 315 patients with at least the baseline and one subsequent questionnaire were available for analysis. Changes in the VAS score were rated as absolute differences from baseline. Negative values indicate improvement of symptoms. The overall VAS score improved significantly at the first post-baseline assessment in responders (- 2.13 vs. non-responders + 1.15, p = 0.048), and even more for the best post-baseline assessment (- 7.82 vs. non-responders - 1.97, p = 0.0005). The VAS for pain (- 16.37 vs. non-responders - 8.89, p = 0.001) and swallowing of solid food (- 16.67 vs. non-responders - 5.06, p = 0.002) improved significantly more in responders (best post-baseline assessment). In the multivariable Cox regression analysis, worse overall VAS scores were associated with worse overall survival (hazard ratio for death 1.12 per 10 points increment on the overall VAS scale, 95% CI 1.05-1.20, p = 0.0009).

Conclusion: In unselected patients beyond randomized controlled trials, treatment response lowers tumor symptom burden in recurrent and/or metastatic HNSCC.

Trial Registration: ClinicalTrials.gov, NCT00122460 . Registered 22 Juli 2005.
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http://dx.doi.org/10.1186/s12885-020-07440-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7526421PMC
September 2020

Senescence Induction by Combined Ionizing Radiation and DNA Damage Response Inhibitors in Head and Neck Squamous Cell Carcinoma Cells.

Cells 2020 09 1;9(9). Epub 2020 Sep 1.

Department of Radiation Oncology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, D-91054 Erlangen, Germany.

DNA damage response inhibitors (DDRi) may selectively enhance the inactivation of tumor cells in combination with ionizing radiation (IR). The induction of senescence may be the key mechanism of tumor cell inactivation in this combinatorial treatment. In the current study the effect of combined IR with DDRi on the induction of senescence was studied in head and neck squamous cell carcinoma (HNSCC) cells with different human papilloma virus (HPV) status. The integrity of homologous recombination (HR) was assessed in two HPV positive, two HPV negative HNSCC, and two healthy fibroblast cell cultures. Cells were treated with the DDRi CC-115 (DNA-dependent protein kinase, DNA-pK; dual mammalian target of rapamycin, mTor), VE-822 (ATR; ataxia telangiectasia and Rad3-related kinase), and AZD0156 (ATM; ataxia telangiectasia mutated kinase) combined with IR. Effects on senescence, apoptosis, necrosis, and cell cycle were analyzed by flow cytometry. The fibroblast cell lines generally tolerated IR or combined treatment better than the tumor cell lines. The ATM and ATR inhibitors were effectively inducing senescence when combined with IR. The DNA-PK inhibitor was not an important inductor of senescence. HPV status and HR activity had a limited influence on the efficacy of DDRi. Induction of senescence and necrosis varied individually among the cell lines due to molecular heterogeneity and the involvement of DNA damage response pathways in senescence induction.
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http://dx.doi.org/10.3390/cells9092012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7563880PMC
September 2020

Deterioration of Health-Related Quality of Life Scores under Treatment Predicts Longer Survival.

Biomed Res Int 2020 17;2020:3565238. Epub 2020 Aug 17.

Department of Radiation Oncology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany.

Objectives: Baseline health-related quality of life (HRQoL) scores predict survival, which has already been demonstrated in various studies. However, we were interested in whether changes in baseline scores during treatment are also significant predictors of survival.

Methods And Materials: We analysed the data of 400 consecutive cancer patients receiving radiochemotherapy. Leading diagnoses were head and neck cancer (34.5%), rectal cancer (24.5%), and lung cancer (13%). HRQoL was studied at baseline, six weeks after therapy and after each completed year after the start of therapy until drop out of the study using the EORTC QLQ-C30 questionnaire. The change score was calculated as the baseline score subtracted from the score after therapy. Statistics included Kaplan-Meier estimates and Cox regression.

Results: High global health status ( = 0.005) and low pain scores ( = 0.040) at baseline were related to favourable overall survival. Change scores of role functioning ( = 0.027), global health status ( < 0.018), and pain ( < 0.001) were predictive of overall survival. Pain was the superior predictor of survival ( = 0.001) among all variables and QoL scores studied by multivariate analysis. A deterioration in pain was associated with a 2.8 times higher chance of survival (HR 0.36).

Conclusions: Deterioration of HRQoL baseline pain score by cancer treatment is a favourable and superior prognostic factor for survival.
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http://dx.doi.org/10.1155/2020/3565238DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7448240PMC
May 2021

PARP inhibitors combined with ionizing radiation induce different effects in melanoma cells and healthy fibroblasts.

BMC Cancer 2020 Aug 18;20(1):775. Epub 2020 Aug 18.

Department of Radiation Oncology, University Hospital Erlangen, Strahlenklinik, Universitätsstraße 27, 91054, Erlangen, Germany.

Background: PARP inhibitors niraparib and talazoparib are FDA approved for special cases of breast cancer. PARP is an interesting repair protein which is frequently affected in cancer cells. We studied the combined action of talazoparib or niraparib with ionizing radiation in melanoma cells and healthy fibroblasts.

Methods: Homologous recombination (HR) status in six different melanoma cell lines and healthy fibroblasts was assessed. Cell cultures were treated with PARP inhibitors talazoparib or niraparib and ionizing radiation (IR). Apoptosis, necrosis and cell cycle distribution was analyzed via flow cytometry. Cell migration was studied by scratch assays.

Results: Studied melanoma cell cultures are HR deficient. Studied healthy fibroblasts are HR proficient. Talazoparib and niraparib have congruent effects within the same cell cultures. In all cell cultures, combined treatment increases cell death and G2/M arrest compared to IR. Combined treatment in melanoma cells distinctly increases G2/M arrest. Healthy fibroblasts are less affected by G2/M arrest. Treatment predominantly decelerates or does not modify migration. In two cell cultures migration is enhanced under the inhibitors.

Conclusions: Although the two PARP inhibitors talazoparib and niraparib appear to be suitable for a combination treatment with ionizing radiation in our in vitro studies, a combination treatment cannot generally be recommended. There are clear interindividual differences in the effect of the inhibitors on different melanoma cells. Therefore, the effect on the cancer cells should be studied prior to a combination therapy. Since melanoma cells increase more strongly than fibroblasts in G2/M arrest, the fractional application of combined treatment should be further investigated.
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http://dx.doi.org/10.1186/s12885-020-07190-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7433076PMC
August 2020

Exciton Migration in Multistranded Perylene Bisimide J-Aggregates.

J Phys Chem Lett 2020 Aug 4;11(16):6612-6617. Epub 2020 Aug 4.

Institute for Physics and Department "Life, Light & Matter", University of Rostock, 18051 Rostock, Germany.

Exciton migration in self-assembled supramolecular ensembles of dye molecules is controlled by the electronic coupling between adjacent sites, the delocalization of the excitation and thereby by the packing arrangement. Here, we put emphasis on the packing structure and analyze the exciton migration in two perylene bisimide-based J-aggregates composed of almost identical molecular building blocks but forming double-strand versus quadruple-strand slip-stacked supramolecular architectures. Analyzing ultrafast transient absorption spectra in dependence on the exciton density by a kinetic model for exciton-exciton annihilation based on incoherent transfer demonstrates that the migration is quasi one-dimensional. The migration distance is enhanced by a beneficial geometrical structure. We find a factor of more than two between the diffusion lengths of 188 and 77 nm for the double- and quadruple-stranded system. The supramolecular design efficiently influences the exciton mobility and minor structural changes have a pronounced influence on functional properties of dye aggregates.
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http://dx.doi.org/10.1021/acs.jpclett.0c01669DOI Listing
August 2020

Self-Sorting Supramolecular Polymerization: Helical and Lamellar Aggregates of Tetra-Bay-Acyloxy Perylene Bisimide.

Angew Chem Int Ed Engl 2020 Sep 7;59(39):17084-17090. Epub 2020 Aug 7.

Institut für Organische Chemie, Am Hubland, 97074, Würzburg, Germany.

A new perylene bisimide (PBI), with a fluorescence quantum yield up to unity, self-assembles into two polymorphic supramolecular polymers. This PBI bears four solubilizing acyloxy substituents at the bay positions and is unsubstituted at the imide position, thereby allowing hydrogen-bond-directed self-assembly in nonpolar solvents. The formation of the polymorphs is controlled by the cooling rate of hot monomer solutions. They show distinctive absorption profiles and morphologies and can be isolated in different polymorphic liquid-crystalline states. The interchromophoric arrangement causing the spectral features was elucidated, revealing the formation of columnar and lamellar phases, which are formed by either homo- or heterochiral self-assembly, respectively, of the atropoenantiomeric PBIs. Kinetic studies reveal a narcissistic self-sorting process upon fast cooling, and that the transformation into the heterochiral (racemic) sheetlike self-assemblies proceeds by dissociation via the monomeric state.
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http://dx.doi.org/10.1002/anie.202006744DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7540443PMC
September 2020

Regulatory T cells and cytotoxic T cells close to the epithelial-stromal interface are associated with a favorable prognosis.

Oncoimmunology 2020 14;9(1):1746149. Epub 2020 Apr 14.

Department of Radiation Oncology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.

Cytotoxic T cells and regulatory T cells play a crucial role in the outcome of cancer patients. Besides the density of these cells, it was shown recently that the spatial distribution is equally important. Here, we specifically analyzed the spatial distribution of these T cell subtypes at the epithelial-stromal interface in a rectal cancer cohort and its relevance for prognosis. We studied a cohort of 191 patients with advanced rectal cancer treated by radiochemotherapy (RCT). Tissue microarrays were immunohistochemical double-stained by FoxP3+ and CD+. Cell densities were analyzed in the stromal and epithelial compartment. Additionally, an image analysis software calculated the distances of lymphocytes to the epithelial-stromal interface (ESI). CD8+ and FoxP3+ cell counts decreased clearly after RCT with the decrease of FoxP3+ being more pronounced than of CD8+ cells. In the invasive front, short distances of the ESI to CD8+ and to FoxP3+ cells were associated with improved overall survival. Cell counts in the stromal compartment had no influence on prognosis. No correlation between stromal and epithelial lymphocyte densities was observed. The distance of epithelial-stromal interface to CD8+ and FoxP3+ cells was more accurate in predicting prognosis in the stromal compartment of rectal cancer patients than mere cell counts and could thereby be means of better stratifying patients for therapy. This observation will have to be validated in future prospective studies with regard to other tumor entities and its implications for the responsiveness of tumors to new therapeutic modalities.
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http://dx.doi.org/10.1080/2162402X.2020.1746149DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7185207PMC
April 2020