Publications by authors named "Martin Stuschke"

134 Publications

Identification of a Prognostic Clinical Score for Patients With Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck Treated With Systemic Therapy Including Cetuximab.

Front Oncol 2021 13;11:635096. Epub 2021 May 13.

Department of Medical Oncology, West German Cancer Center, University Hospital Essen, Essen, Germany.

Cetuximab-based chemoimmunotherapy has been the standard of care for recurrent or metastatic squamous cell carcinoma of the head and neck (r/m SCCHN) for more than a decade. To date, no predictive or prognostic biomarkers have been established to further guide the systemic treatment with cetuximab-based chemoimmunotherapy in r/m SCCHN. Against this background, we retrospectively analyzed clinical and blood-based parameters from 218 r/m SCCHN patients treated with chemoimmunotherapy including cetuximab. Multivariate Cox-regression models were used to assess their prognostic or predictive value. Eastern Co-operative Oncology Group (ECOG) performance status (≥2), older age (≥61.8 years), anemia (hemoglobin <11.80), and increased neutrophil-to-lymphocyte ratio (NLR ≥5.73) were independently and strongly associated with inferior overall survival (OS). To group patients according to risk profiles we established a prognostic clinical score (PCS) that can easily be used in clinical practice. The PCS stratified the cohort into low, intermediate, poor or very poor risk subgroups with median OS times of 23.4, 12.1, 7.5, and 4.0 months, respectively. Patients with low risk PCS had a prolonged progression-free survival (PFS) and increased overall response rate (ORR) under first-line cetuximab-based therapy. Interestingly, only patients with low and intermediate risk benefitted from the more intensive first-line cisplatin/cetuximab combination compared to carboplatin/cetuximab therapy, whereas the intensity of first-line treatment had no impact in the poor and very poor risk subgroups. Following external validation, particularly in the context of newly established first-line options, the PCS may guide clinical decision making and serve for stratification of patients with r/m SCCHN in future clinical trials.
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http://dx.doi.org/10.3389/fonc.2021.635096DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8155676PMC
May 2021

PROGNOSTIC VALUE OF POST-INDUCTION CHEMOTHERAPY VOLUMETRIC PET/CT PARAMETERS FOR STAGE IIIA/B NON-SMALL CELL LUNG CANCER PATIENTS RECEIVING DEFINITIVE CHEMORADIOTHERAPY.

J Nucl Med 2021 May 20. Epub 2021 May 20.

1. Department for Radiotherapy, University Hospital Essen, West German Cancer Center, University Duisburg-Essen, Essen, Germany 2. German Cancer Consortium, Partner Site University Hospital Essen, Essen, Germany.

The aim of this follow-up analysis of the ESPATUE phase-3 trial was to explore the prognostic value of post-induction chemotherapy PET metrics in patients with stage III non-small cell lung cancer (NSCLC) who were assigned to receive definitive chemoradiotherapy. All eligible patients stage IIIA (cN2) and stage IIIB of the trial received induction chemotherapy consisting of 3 cycles of cisplatin/paclitaxel and chemoradiotherapy up to 45 Gy/1.5 Gy per fraction twice-a-day, followed by a radiation-boost with 2 Gy once per day with concurrent cisplatin/vinorelbine. The protocol definition prescribed a total dose of 65-71 Gy. F-FDG-PET/CT (PETpre) was performed at study entry and before concurrent chemoradiotherapy (interim-PET; PETpost). Interim PETpost metrics and known prognostic clinical parameters were correlated in uni- and multivariable survival analyses. Leave-one-out cross-validation was used to show internal validity. Ninety-two patients who underwent F-FDG-PET/CT after induction chemotherapy were enrolled. Median MTVpost value was 5.9 ml. Altogether 85 patients completed the whole chemoradiation with the planned total dose of 60-71 Gy. In univariable proportional hazard analysis, each of the parameters MTVpost, SUV(post) and TLGmax(post) was associated with overall survival ( < 0.05). Multivariable survival analysis, including clinical and post-induction PET parameters, found TLGmax(post) (hazard ratio: 1.032 (95%-CI: 1.013-1.052) per 100 ml increase) and total radiation dose (hazard ratio: 0.930 (0.902-0.959) per Gray increase) significantly related with overall survival in the whole group of patients, and also in patients receiving a total dose ≥ 60 Gy. The best leave-one-out cross-validated 2 parameter classifier contained TLGmax(post) and total radiation dose. TLGmax(post) was associated with time to distant metastases ( = 0.0018), and SUV(post) with time to loco-regional relapse ( = 0.039) in multivariable analysis of patients receiving a total dose ≥ 60 Gy. Post-induction chemotherapy PET parameters demonstrated prognostic significance. Therefore, an interim F-FDG-PET/CT is a promising diagnostic modality for guiding individualized treatment intensification.
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http://dx.doi.org/10.2967/jnumed.120.260646DOI Listing
May 2021

Phase 3 multicenter randomized trial of PSMA PET/CT prior to definitive radiation therapy for unfavorable intermediate-risk or high-risk prostate cancer [PSMA dRT]: study protocol.

BMC Cancer 2021 May 7;21(1):512. Epub 2021 May 7.

Department of Nuclear Medicine, University of Duisburg-Essen and German Cancer Consortium (DKTK)-University Hospital Essen, Hufelandstraße 55, 45131, Essen, Germany.

Background: Definitive radiation therapy (dRT) is an effective initial treatment of intermediate-risk (IR) and high-risk (HR) prostate cancer (PCa). PSMA PET/CT is superior to standard of care imaging (CT, MRI, bone scan) for detecting regional and distant metastatic PCa. PSMA PET/CT thus has the potential to guide patient selection and the planning for dRT and improve patient outcomes.

Methods: This is a multicenter randomized phase 3 trial (NCT04457245). We will randomize 312 patients to proceed with standard dRT (control Arm, n = 150), or undergo a PSMA PET/CT scan at the study site (both 18F-DCFPyL and 68Ga-PSMA-11 can be used) prior to dRT planning (intervention arm, n = 162). dRT will be performed at the treating radiation oncologist facility. In the control arm, dRT will be performed as routinely planned. In the intervention arm, the treating radiation oncologist can incorporate PSMA PET/CT findings into the RT planning. Androgen deprivation therapy (ADT) is administered per discretion of the treating radiation oncologist and may be modified as a result of the PSMA PET/CT results. We assume that approximately 8% of subjects randomized to the PSMA PET arm will be found to have M1 disease and thus will be more appropriate candidates for long-term systemic or multimodal therapy, rather than curative intent dRT. PET M1 patients will thus not be included in the primary endpoint analysis. The primary endpoint is the success rate of patients with unfavorable IR and HR PCa after standard dRT versus PSMA PET-based dRT. Secondary Endpoints (whole cohort) include progression free survival (PFS), metastasis-free survival after initiation of RT, overall survival (OS), % of change in initial treatment intent and Safety.

Discussion: This is the first randomized phase 3 prospective trial designed to determine whether PSMA PET/CT molecular imaging can improve outcomes in patients with PCa who receive dRT. In this trial the incorporation of PSMA PET/CT may improve the success rate of curative intent radiotherapy in two ways: to optimize patient selection as a biomarker and to personalizes the radiotherapy plan.

Clinical Trial Registration: UCLA IND#147591 ○ Submission: 02.27.2020 ○ Safe-to-proceed letter issued by FDA: 04.01.2020 UCLA IRB #20-000378 ClinicalTrials.gov Identifier NCT04457245 . Date of Registry: 07.07.2020. Essen EudraCT 2020-003526-23.
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http://dx.doi.org/10.1186/s12885-021-08026-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8103642PMC
May 2021

Case Report: Pseudomeningeosis and Demyelinating Metastasis-Like Lesions From Checkpoint Inhibitor Therapy in Malignant Melanoma.

Front Oncol 2021 15;11:637185. Epub 2021 Apr 15.

Department of Neurology, Division of Clinical Neurooncology, University Hospital Essen, Essen, Germany.

Immune checkpoint inhibitors (ICIs) have considerably expanded the effective treatment options for malignant melanoma. ICIs revert tumor-associated immunosuppression and potentiate T-cell mediated tumor clearance. Immune-related neurologic adverse events (irNAEs) manifest in the central (CNS) or peripheral nervous system (PNS) and most frequently present as encephalitis or myasthenia gravis respectively. We report on a 47-year old male patient with metastatic melanoma who developed signs of cerebellar disease five weeks after the start of ICI treatment (ipilimumab and nivolumab). Magnetic resonance imaging (MRI) of the brain and spine revealed multiple new contrast enhancements suggestive of parenchymal and leptomeningeal metastasis. Cerebral spinal fluid (CSF) evaluation showed a lymphomononuclear pleocytosis in the absence of tumor cells. Subsequent stereotactic brain biopsy confirmed demyelinating disease. High-dose corticosteroid treatment resulted in immediate improvement of the clinical symptoms. MRI scans and CSF re-evaluation were conducted six weeks later and showed a near-complete remission. The strong resemblance to neoplastic CNS dissemination and irNAEs is a particularly difficult diagnostic challenge. Treating physicians should be aware of irNAEs as those can be effectively treated with high-dose steroids.
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http://dx.doi.org/10.3389/fonc.2021.637185DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8081911PMC
April 2021

BRAF mutations and BRAF mutation functional class have no negative impact on the clinical outcome of advanced NSCLC and associate with susceptibility to immunotherapy.

Eur J Cancer 2021 May 16;149:211-221. Epub 2021 Apr 16.

Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Germany; Division of Thoracic Oncology, West German Cancer Center, University Medicine Essen - Ruhrlandklinik, University Duisburg-Essen, Germany; German Cancer Consortium (DKTK), Partner Site University Hospital Essen, Essen, Germany.

Objective: BRAF mutations have been subtyped in three functional classes with different oncogenic modes of action. The clinical impact of BRAF mutational subtypes in non-small-cell lung cancer (NSCLC) remains to be defined. So far, ambiguous results were reported from analyses of heterogeneous patient cohorts.

Methods: We studied patients with metastatic or recurrent NSCLC who were sequentially enrolled in precision oncology programs at two large German lung cancer centres from 2009 to 2019. The study period allowed evaluating the specific impact of BRAF V600E-targeting.

Results: In a cohort of 72 patients, BRAF mutation subtyping revealed p.V600E mutations in 31 cases (43%), whereas 41 cases (57%) harboured 18 different BRAF mutational subtypes of functional classes II/III. Functionally relevant comutations were observed in 6.4% of class I, and 24.4% of class II/III BRAF mutations. Most patients were treated with chemotherapy. Targeted therapy was administered in 11 patients with a response rate of 72.7%. PD-1/PD-L1-immunotherapy was given in 14 patients with a response rate of 28.6%. Overall survival of patients with BRAF-mutated NSCLC was inferior (HR 1.38, p = 0.048) as compared to patients with BRAF wild-type cancers. Median time-to-treatment-failure with BRAF-targeting agents was shorter as compared to approved targeted therapy of other oncogenic drivers (HR 1.97, p = 0.05). Survival outcomes were not impacted by BRAF mutation subtype functional class.

Conclusions: Patients with BRAF-mutated NSCLC have an inferior prognosis, which is not determined by BRAF mutation functional class. In contrast to NSCLC with other tractable driver mutations, BRAF-mutated NSCLC exhibit high susceptibility to immune checkpoint inhibitors.
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http://dx.doi.org/10.1016/j.ejca.2021.02.036DOI Listing
May 2021

Scleral necrosis after brachytherapy for uveal melanoma: Analysis of risk factors.

Clin Exp Ophthalmol 2021 Apr 17. Epub 2021 Apr 17.

Department of Ophthalmology, University Hospital of Essen, Essen, Germany.

Background: Radiation-induced scleral necrosis (RISN) is a rare, but a serious complication of brachytherapy for uveal melanoma. We aimed at analysing the incidence, timing and risk factors associated with development of RISN in a large institutional series.

Methods: All consecutive cases with brachytherapy for uveal melanoma treated by the Departments of Ophthalmology and Radiotherapy at University Hospital Essen between 1999 and 2016 were eligible. Development of RISN during the post-treatment follow-up was recorded. A 1:2 propensity score matched case-control study was performed for the evaluation of the prognostic value of different tumour- and treatment-associated parameters.

Results: RISN was documented in 115 (2.9%) of 3960 patients with uveal melanoma included in the final analysis, and occurred at the mean 30.3 months (range: 1.26-226 months) after brachytherapy. In the whole cohort, younger age (p = 0.042), plaque type (p = 0.001) and ciliary body involvement (p < 0.0001) were independently associated with the RISN occurrence. In the case-control study, multivariable weighted proportional hazard analysis discovered the association of the following additional tumour- and treatment-associated characteristics with RISN: posterior tumour margin anterior to equatorial region (p = 0.0003), extraocular tumour extension (p = <0.0001), scleral contact dose (p = <0.0001), conjunctival dehiscence after therapy (p = 0.0001), disinsertion of the superior rectus muscle (p = 0.001) and the glaucoma medication (p = 0.014).

Conclusions: Our study confirms RISN as a rare complication, which might occur even years later after the brachytherapy for uveal melanoma. Alongside with scleral dose five other tumour and therapy related factors predict the risk of RISN after brachytherapy for uveal melanoma were established.
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http://dx.doi.org/10.1111/ceo.13928DOI Listing
April 2021

Patterns of cervical lymph node metastasis in supraglottic laryngeal cancer and therapeutic implications of surgical staging of the neck.

Eur Arch Otorhinolaryngol 2021 Mar 27. Epub 2021 Mar 27.

Department of Otorhinolaryngology, Head and Neck Surgery, University Hospital Essen, University of Duisburg-Essen, Hufelandstraße 55, 45147, Essen, Germany.

Purpose: Accurate therapeutic management of the neck is a challenge in patients with supraglottic laryngeal cancer. Nodal metastasis is common at all disease stages, and treatment planning relies on clinical staging of the neck, for both surgical and non-surgical treatment. Here, we compared clinical and surgical staging results in supraglottic carcinoma patients treated with primary surgery to assess the accuracy of pre-therapeutic clinical staging and guide future treatment decisions.

Methods: Retrospective analysis of clinical, pathological, and oncologic outcome data of 70 patients treated with primary surgery and bilateral neck dissection for supraglottic laryngeal cancer. Patients where clinical and pathological neck staging results differed, were identified and analyzed in detail.

Results: On pathologic assessment, patients with early stage (pT1/2) primaries showed cervical lymph node metastases in 55% (n = 17/31) of cases, compared to 67% (n = 26/39) of patients with pT3/4 tumors. In 24% (n = 17/70) of all patients, cN status differed from pN status, resulting in an upstaging in 16% of cases (n = 11/70) and a downstaging in 9% (n = 6/70) of cases. 14% of patients with cN0 status had occult metastases (n = 5/30). As assessed by a retrospective tumor board, in case of a non-surgical treatment approach, the inaccurate clinical staging of the neck would have led to an over- or undertreatment of the neck in 20% (n = 14/70) of all patients.

Conclusion: Our data re-emphasize the high cervical metastasis rates of supraglottic laryngeal cancer across all stages. Inaccurate clinical staging of the neck is common and should be taken into consideration when planning treatment.
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http://dx.doi.org/10.1007/s00405-021-06753-1DOI Listing
March 2021

Acquired Resistance to BRAF/MEK Inhibitor Therapy in BRAF-V-mutated Squamous Cell Lung Cancer: Concurrent Evolvement of PTEN and MEK1 Mutations.

Clin Lung Cancer 2020 Dec 2. Epub 2020 Dec 2.

Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany.

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http://dx.doi.org/10.1016/j.cllc.2020.11.008DOI Listing
December 2020

Impact of EBUS-TBNA in addition to [F]FDG-PET/CT imaging on target volume definition for radiochemotherapy in stage III NSCLC.

Eur J Nucl Med Mol Imaging 2021 Feb 5. Epub 2021 Feb 5.

Department of Radiotherapy, University Hospital Essen, West German Cancer Center, University Duisburg-Essen, Essen, Germany.

PURPOSE/INTRODUCTION: [F]FDG-PET/CT is the standard imaging-technique for radiation treatment (RT) planning in locally advanced non-small cell lung cancer (NSCLC). The purpose of this study was to examine the additional value of endobronchial-ultrasound transbronchial needle aspiration (EBUS-TBNA) to standard PET/CT for mediastinal lymph-node (LN) staging and its impact on clinical target volume (CTV).

Materials And Methods: All consecutive patients with primary stage III NSCLC who underwent [F]FDG-PET/CT and EBUS-TBNA prior to RT were analyzed from 12/2011 to 06/2018. LN-stations were assessed by an expert-radiologist and a nuclear medicine-physician. CTV was evaluated by two independent radiation oncologists. LNs were grouped with increasing distance along the lymphatic chains from primary tumor into echelon-1 (ipsilateral hilum), echelon-2 (LN-station 7 and ipsilateral 4), and echelon-3 (remaining mediastinum and contralateral hilum).

Results: A total of 675 LN-stations of which 291 were positive for tumor-cells, were sampled by EBUS-TBNA in 180 patients. The rate of EBUS-positive LNs was 43% among all sampled LNs. EBUS-positivity in EBUS-probed LNs decreased from 85.8% in echelon-1 LNs to 42.4%/ 9.6% in echelon-2/ -3 LNs, respectively (p < 0.0001, Fisher's exact test). The false discovery rate of PET in comparison with EBUS results rose from 5.3% in echelon-1 to 32.9%/ 69.1% in echelon-2/ -3 LNs, respectively (p < 0.0001, Fisher's exact test). Sensitivity and specificity of FDG-PET/CT ranged from 85 to 99% and 67 to 80% for the different echelons. In 22.2% patients, EBUS-TBNA finding triggered changes of the treated CTV, compared with contouring algorithms based on FDG-avidity as the sole criterion for inclusion. CTV was enlarged in 6.7% patients due to EBUS-positivity in PET-negative LN-station and reduced in 15.5% by exclusion of an EBUS-negative but PET-positive LN-station.

Conclusion: The false discovery rate of [F]FDG-PET/CT increased markedly with distance from the primary tumor. Inclusion of systematic mediastinal LN mapping by EBUS-TBNA in addition to PET/CT has the potential to increase accuracy of target volume definition, particularly in echelon-3 LNs. EBUS-TBNA is recommended as integral part of staging for radiochemotherapy in stage III NSCLC.
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http://dx.doi.org/10.1007/s00259-021-05204-7DOI Listing
February 2021

Preoperative and early postoperative seizures in patients with glioblastoma-two sides of the same coin?

Neurooncol Adv 2021 Jan-Dec;3(1):vdaa158. Epub 2020 Nov 18.

Department of Neurosurgery and Spine Surgery, University Hospital Essen, Essen, Germany.

Background: Symptomatic epilepsy is a common symptom of glioblastoma, which may occur in different stages of disease. There are discrepant reports on association between early seizures and glioblastoma survival, even less is known about the background of these seizures. We aimed at analyzing the risk factors and clinical impact of perioperative seizures in glioblastoma.

Methods: All consecutive cases with de-novo glioblastoma treated at our institution between 01/2006 and 12/2018 were eligible for this study. Perioperative seizures were stratified into seizures at onset (SAO) and early postoperative seizures (EPS, ≤21days after surgery). Associations between patients characteristics and overall survival (OS) with SAO and EPS were addressed.

Results: In the final cohort ( = 867), SAO and EPS occurred in 236 (27.2%) and 67 (7.7%) patients, respectively. SAO were independently predicted by younger age ( = .009), higher KPS score ( = .002), tumor location (parietal lobe, = .001), GFAP expression (≥35%, = .045), and serum chloride at admission (>102 mmol/L, = .004). In turn, EPS were independently associated with tumor location (frontal or temporal lobe, = .013) and pathologic laboratory values at admission (hemoglobin < 12 g/dL, [ = .044], CRP > 1.0 mg/dL [ = 0.036], and GGT > 55 U/L [ = 0.025]). Finally, SAO were associated with gross-total resection ( = .006) and longer OS ( = .030), whereas EPS were related to incomplete resection ( = .005) and poorer OS ( = .009).

Conclusions: In glioblastoma patients, SAO and EPS seem to have quite different triggers and contrary impact on treatment success and OS. The clinical characteristics of SAO and EPS patients might contribute to the observed survival differences.
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http://dx.doi.org/10.1093/noajnl/vdaa158DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7813191PMC
November 2020

Machine learning-based differentiation between multiple sclerosis and glioma WHO II°-IV° using O-(2-[18F] fluoroethyl)-L-tyrosine positron emission tomography.

J Neurooncol 2021 Apr 27;152(2):325-332. Epub 2021 Jan 27.

Division of Clinical Neurooncology, Department of Neurology, University Hospital Essen, University Duisburg-Essen, Hufelandstrasse 55, 45147, Essen, Germany.

Introduction: This study aimed to test the diagnostic significance of FET-PET imaging combined with machine learning for the differentiation between multiple sclerosis (MS) and glioma II°-IV°.

Methods: Our database was screened for patients in whom FET-PET imaging was performed for the diagnostic workup of newly diagnosed lesions evident on MRI and suggestive of glioma. Among those, we identified patients with histologically confirmed glioma II°-IV°, and those who later turned out to have MS. For each group, tumor-to-brain ratio (TBR) derived features of FET were determined. A support vector machine (SVM) based machine learning algorithm was constructed to enhance classification ability, and Receiver Operating Characteristic (ROC) analysis with area under the curve (AUC) metric served to ascertain model performance.

Results: A total of 41 patients met selection criteria, including seven patients with MS and 34 patients with glioma. TBR values were significantly higher in the glioma group (TBRmax glioma vs. MS: p = 0.002; TBRmean glioma vs. MS: p = 0.014). In a subgroup analysis, TBR values significantly differentiated between MS and glioblastoma (TBRmax glioblastoma vs. MS: p = 0.0003, TBRmean glioblastoma vs. MS: p = 0.0003) and between MS and oligodendroglioma (ODG) (TBRmax ODG vs. MS: p = 0.003; TBRmean ODG vs. MS: p = 0.01). The ability to differentiate between MS and glioma II°-IV° increased from 0.79 using standard TBR analysis to 0.94 using a SVM based machine learning algorithm.

Conclusions: FET-PET imaging may help differentiate MS from glioma II°-IV° and SVM based machine learning approaches can enhance classification performance.
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http://dx.doi.org/10.1007/s11060-021-03701-1DOI Listing
April 2021

Dosimetric impact of the positioning variation of tumor treating field electrodes in the PriCoTTF-phase I/II trial.

J Appl Clin Med Phys 2021 Jan 3;22(1):242-250. Epub 2021 Jan 3.

Department of Radiotherapy, West German Cancer Center, University Hospital Essen, University of Duisburg, Essen, Germany.

Purpose: The aim of the present study based on the PriCoTTF-phase I/II trial is the quantification of skin-normal tissue complication probabilities of patients with newly diagnosed glioblastoma multiforme treated with Tumor Treating Field (TTField) electrodes, concurrent radiotherapy, and temozolomide. Furthermore, the skin-sparing effect by the clinically applied strategy of repetitive transducer array fixation around their center position shall be examined.

Material And Methods: Low-dose cone-beam computed tomography (CBCT) scans of all fractions of the first seven patients of the PriCoTTF-phase I/II trial, used for image guidance, were applied for the dosimetric analysis, for precise TTField transducer array positioning and contour delineation. Within this trial, array positioning was varied from fixation-to-fixation period with a standard deviation of 1.1 cm in the direction of the largest variation of positioning and 0.7 cm in the perpendicular direction. Physical TTField electrode composition was examined and a respective Hounsfield Unit attributed to the TTField electrodes. Dose distributions in the planning CT with TTField electrodes in place, as derived from prefraction CBCTs, were calculated and accumulated with the algorithm Acuros XB. Dose-volume histograms were obtained for the first and second 2 mm scalp layer with and without migrating electrodes and compared with those with fixed electrodes in an average position. Skin toxicity was quantified according to Lyman's model. Minimum doses in hot-spots of 0.05 cm and 25 cm ( D , D ) size in the superficial skin layers were analyzed.

Results: Normal tissue complication probabilities (NTCPs) for skin necrosis ranged from 0.005% to 1.474% (median 0.111%) for the different patients without electrodes. NTCP logarithms were significantly dependent on patient (P < 0.0001) and scenario (P < 0.0001) as classification variables. Fixed positioning of TTField arrays increased skin-NTCP by a factor of 5.50 (95%, CI: 3.66-8.27). The variation of array positioning increased skin-NTCP by a factor of only 3.54 (95%, CI: 2.36-5.32) (P < 0.0001, comparison to irradiation without electrodes; P = 0.036, comparison to irradiation with fixed electrodes). NTCP showed a significant rank correlation with D25cm over all patients and scenarios (r  = 0.76; P < 0.0001).

Conclusion: Skin-NTCP calculation uncovers significant interpatient heterogeneity and may be used to stratify patients into high- and low-risk groups of skin toxicity. Array position variation may mitigate about one-third of the increase in surface dose and skin-NTCP by the TTField electrodes.
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http://dx.doi.org/10.1002/acm2.13144DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7856507PMC
January 2021

Spatial and dosimetric evaluation of residual distortions of prostate and seminal vesicle bed after image-guided definitive and postoperative radiotherapy of prostate cancer with endorectal balloon.

J Appl Clin Med Phys 2021 Jan 30;22(1):226-241. Epub 2020 Dec 30.

Department of Radiotherapy, University Hospital Essen, Essen, Germany.

Purpose: To quantify daily residual deviations from the planned geometry after image-guided prostate radiotherapy with endorectal balloon and to evaluate their effect on the delivered dose distribution.

Methods: Daily kV-CBCT imaging was used for online setup-correction in six degrees of freedom (6-dof) for 24 patients receiving definitive (12 RT patients) or postoperative (12 RT patients) radiotherapy with endorectal balloon (overall 739 CBCTs). Residual deviations were evaluated using several spatial and dosimetric variables, including: (a) posterior Hausdorff distance HD (=maximum distance between planned and daily CTV contour), (b) point P with largest HD over all fractions, (c) equivalent uniform dose using a cell survival model (EUD ) and the generalized EUD concept (gEUD with parameter a = -7 and a = -20). EUD values were determined for planned ( ), daily ( ), and delivered dose distributions ( ) for plans with 6 mm (=clinical plans) and 2 mm CTV-to-PTV margin. Time series analyses of interfractional spatial and dosimetric deviations were conducted.

Results: Large HD values ≥ 12.5 mm (≥15 mm) were observed in 20/739 (5/739) fractions distributed across 7 (3) patients. Points P were predominantly located at the posterior CTV boundary in the seminal vesicle region (16/24 patients, 6/7 patients with HD  ≥ 12.5 mm). Time series analyses revealed a stationary white noise characteristic of HD and relative dose at P . The EUD difference between planned and accumulated dose distributions was < 5.4% for all 6-mm plans. Evaluating 2-mm plans, EUD deteriorated by < 10% (<5%) in 75% (58.5%) of the patients. was well described by the median value of the distribution. PTV margin calculation at P yielded 8.8 mm.

Conclusions: Accumulated dose distributions in prostate radiotherapy with endorectal balloon are forgiving of considerable residual distortions after 6-dof patient setup if they are observed in a minority of fractions and the median value of determined per fraction stays within 95% of prescribed dose. Common PTV margin calculations are overly conservative because after online correction of translational and rotational errors only residual deformations need to be included. These results provide guidelines regarding online navigation, margin optimization, and treatment adaptation strategies.
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http://dx.doi.org/10.1002/acm2.13138DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7856505PMC
January 2021

F-FDG PET/CT for Target Volume Contouring in Lung Cancer Radiotherapy.

J Nucl Med 2020 12;61(Suppl 2):178S-179S

Department of Radiotherapy, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.

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http://dx.doi.org/10.2967/jnumed.120.251660DOI Listing
December 2020

Host CD39 Deficiency Affects Radiation-Induced Tumor Growth Delay and Aggravates Radiation-Induced Normal Tissue Toxicity.

Front Oncol 2020 22;10:554883. Epub 2020 Oct 22.

Medical School, Institute of Cell Biology (Cancer Research), University of Duisburg-Essen, Essen, Germany.

The ectonucleoside triphosphate diphosphohydrolase (CD39)/5' ectonuclotidase (CD73)-dependent purinergic pathway emerges as promising cancer target. Yet, except for own previous work revealing a pathogenic role of CD73 and adenosine in radiation-induced lung fibrosis, the role of purinergic signaling for radiotherapy outcome remained elusive. Here we used C57BL/6 wild-type (WT), CD39 knockout (CD39), and CD73 knockout (CD73) mice and hind-leg tumors of syngeneic murine Lewis lung carcinoma cells (LLC1) to elucidate how host purinergic signaling shapes the growth of LLC1 tumors to a single high-dose irradiation with 10 Gy . In complementary experiments, we examined the radiation response of LLC1 cells in combination with exogenously added ATP or adenosine, the proinflammatory and anti-inflammatory arms of purinergic signaling. Finally, we analyzed the impact of genetic loss of CD39 on pathophysiologic lung changes associated with lung fibrosis induced by a single-dose whole-thorax irradiation (WTI) with 15 Gy. Loss of CD73 in the tumor host did neither significantly affect tumor growth nor the radiation response of the CD39/CD73-negative LLC1 tumors. In contrast, LLC1 tumors exhibited a tendency to grow faster in CD39 mice compared to WT mice. Even more important, tumors grown in the CD39-deficient background displayed a significantly reduced tumor growth delay upon irradiation when compared to irradiated tumors grown on WT mice. CD39 deficiency caused only subtle differences in the immune compartment of irradiated LLC1 tumors compared to WT mice. Instead, we could associate the tumor growth and radioresistance-promoting effects of host CD39 deficiency to alterations in the tumor endothelial compartment. Importantly, genetic deficiency of CD39 also augmented the expression level of fibrosis-associated osteopontin in irradiated normal lungs and exacerbated radiation-induced lung fibrosis at 25 weeks after irradiation. We conclude that genetic loss of host CD39 alters the tumor microenvironment, particularly the tumor microvasculature, and thereby promotes growth and radioresistance of murine LLC1 tumors. In the normal tissue loss of host, CD39 exacerbates radiation-induced adverse late effects. The suggested beneficial roles of host CD39 on the therapeutic ratio of radiotherapy suggest that therapeutic strategies targeting CD39 in combination with radiotherapy have to be considered with caution.
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http://dx.doi.org/10.3389/fonc.2020.554883DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7649817PMC
October 2020

Demographic, radiographic, molecular and clinical characteristics of primary gliosarcoma and differences to glioblastoma.

Clin Neurol Neurosurg 2021 01 1;200:106348. Epub 2020 Nov 1.

Department of Neurosurgery and Spine Surgery, University Hospital Essen, University of Duisburg-Essen, Essen, Germany; German Cancer Consortium, Partner Site University Hospital Essen, Essen, Germany.

Objective: Gliosarcoma (GSC) is a rare histological variant of glioblastoma (GBM). Due to limited evidence regarding clinical, genetic and radiographic characteristics of GSC, this study aimed to analyze independent outcome predictors of GSC, and to address the differences between GSC and GBM concerning the baseline characteristics and patients' survival.

Methods: Patients treated between 2001 and 2018 for the diagnosis of GBM and GSC were included in this study. Patients' records were reviewed for demographic, clinical, genetic and radiographic characteristics. Univariate, multivariate and propensity score matched analyses were performed.

Results: In the GSC sub-cohort (N = 56), patients' age, preoperative clinical status, midline tumor location and tumor size were found to be independently associated with overall survival. As compared to GBM individuals (N = 1249), a temporal location (p = 0.002), presence of eccentric tumor cysts (p < 0.001), a higher ratio of TP53 staining (p = 0.002) and a lower ratio of GFAP staining (p = 0.005) were characteristic for GSC. The diagnosis of GSC was associated with a poorer survival (p = 0.002) independently of the patients' age, sex, clinical status and extent of resection, However, this association was no more significant, when enhancing the multivariate analysis with molecular-genetic characteristics (IDH1 mutation and MGMT promotor methylation status).

Discussion: Certain radiographic and molecular-genetic patterns present the distinct characteristics of GSC. There is an association between the diagnosis of GSC and a poorer outcome. This difference might be linked to different genetic alterations in GBM and GSC. Prospective studies are needed to further elucidate the characteristics of GSC and develop targeted treatment approaches for this rare variant.
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http://dx.doi.org/10.1016/j.clineuro.2020.106348DOI Listing
January 2021

Machine learning reveals a PD-L1-independent prediction of response to immunotherapy of non-small cell lung cancer by gene expression context.

Eur J Cancer 2020 11 12;140:76-85. Epub 2020 Oct 12.

Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Hufelandstrasse 55, 45122 Essen, Germany; Division of Thoracic Oncology, University Medicine Essen - Ruhrlandklinik, University Duisburg-Essen, Tüschener Weg 40, 45239 Essen, Germany; German Cancer Consortium (DKTK), Partner Site University Hospital Essen, Hufelandstrasse 55, 45122 Essen, Germany. Electronic address:

Objective: Current predictive biomarkers for PD-1 (programmed cell death protein 1)/PD-L1 (programmed death-ligand 1)-directed immunotherapy in non-small cell lung cancer (NSCLC) mostly focus on features of tumour cells. However, the tumour microenvironment and immune context are expected to play major roles in governing therapy response. Against this background, we set out to apply context-sensitive feature selection and machine learning approaches on expression profiles of immune-related genes in diagnostic biopsies of patients with stage IV NSCLC.

Methods: RNA expression levels were determined using the NanoString nCounter platform in formalin-fixed paraffin-embedded tumour biopsies obtained during the diagnostic workup of stage IV NSCLC from two thoracic oncology centres. A 770-gene panel covering immune-related genes and control genes was used. We applied supervised machine learning methods for feature selection and generation of predictive models.

Results: Feature selection and model creation were based on a training cohort of 55 patients with recurrent NSCLC treated with PD-1/PD-L1 antibody therapy. Resulting models identified patients with superior outcomes to immunotherapy, as validated in two subsequently recruited, separate patient cohorts (n = 67, hazard ratio = 0.46, p = 0.035). The predictive information obtained from these models was orthogonal to PD-L1 expression as per immunohistochemistry: Selecting by PD-L1 positivity at immunohistochemistry plus model prediction identified patients with highly favourable outcomes. Independence of PD-L1 positivity and model predictions were confirmed in multivariate analysis. Visualisation of the models revealed the predictive superiority of the entire 7-gene context over any single gene.

Conclusion: Using context-sensitive assays and bioinformatics capturing the tumour immune context allows precise prediction of response to PD-1/PD-L1-directed immunotherapy in NSCLC.
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http://dx.doi.org/10.1016/j.ejca.2020.09.015DOI Listing
November 2020

ERK phosphorylation as a marker of RAS activity and its prognostic value in non-small cell lung cancer.

Lung Cancer 2020 11 10;149:10-16. Epub 2020 Sep 10.

Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany; Division of Thoracic Oncology, West German Cancer Center, Ruhrlandklinik, University Hospital Essen, University Duisburg-Essen, Essen, Germany. Electronic address:

Background: Deregulated signal transduction pathways play a key role in development, progression and therapeutic resistance of non-small cell lung cancers (NSCLC). The purpose of this study is to assess the downstream markers of two well-characterized pathways and to correlate them with clinical outcome.

Design: 670 patients with metastatic NSCLC were prospectively enrolled in a comprehensive biomarker profiling program at a single center from 2012 to 2016. Phosphorylation of extracellular signal-regulated kinase (p-ERK), and protein kinase B (p-AKT) was assessed by standardized immunohistochemistry. Product of scores for quantity and quality of staining were calculated (immunoreactive score, 0-9). Somatic mutations of Kirsten rat sarcoma viral oncogene homolog [KRAS], epithelial growth factor receptor [EGFR], v-Raf murine sarcoma viral oncogene homolog B [BRAF] and phosphatidylinositol 3-kinase [PIK3CA]) were detected by Sanger (2012-03/2015) and amplicon NGS (04/2015-02/2016). Patients enrolled during the first year (2012) were used as discovery cohort. Patients enrolled from 2013 to 02/2016 were used as validation cohort. Clinical data were retrieved from the electronic medical records and were analyzed retrospectively.

Results: Using a discovery cohort, we identified an immunoreactive score of p-ERK ≥3 to be prognostically relevant. The validation cohort confirmed that higher levels of p-ERK correlated with worse overall survival (OS) and higher proportion of RAS mutations. Multivariate analysis including established risk factors such EGFR, ALK or ROS mutations and metastatic disease showed a trend of a detrimental effect of high p-ERK on OS (HR 1.23, CI 0.94-1.59, p = 0.131 for p-ERK immunoreactive score ≥3) and time to treatment failure after first-line therapy in the validation cohort. Phosphorylated AKT did not correlate with clinical outcome.

Conclusion: While serving as a prognosticator in univariate analysis, highly phosphorylated ERK does not convey a significant prognostic effect for OS in the presence of other prognostic factors. Phosphorylated ERK indicates a higher activity of RAS in advanced NSCLC.
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http://dx.doi.org/10.1016/j.lungcan.2020.09.005DOI Listing
November 2020

Measures of infection prevention and incidence of SARS-CoV-2 infections in cancer patients undergoing radiotherapy in Germany, Austria and Switzerland.

Strahlenther Onkol 2020 12 10;196(12):1068-1079. Epub 2020 Sep 10.

Medical Faculty, Department of Radiation Oncology, Heinrich Heine University, Duesseldorf, Germany.

Purpose: COVID-19 infection has manifested as a major threat to both patients and healthcare providers around the world. Radiation oncology institutions (ROI) deliver a major component of cancer treatment, with protocols that might span over several weeks, with the result of increasing susceptibility to COVID-19 infection and presenting with a more severe clinical course when compared with the general population. The aim of this manuscript is to investigate the impact of ROI protocols and performance on daily practice in the high-risk cancer patients during this pandemic.

Methods: We addressed the incidence of positive COVID-19 cases in both patients and health care workers (HCW), in addition to the protective measures adopted in ROIs in Germany, Austria and Switzerland using a specific questionnaire.

Results: The results of the questionnaire showed that a noteworthy number of ROIs were able to complete treatment in SARS-CoV‑2 positive cancer patients, with only a short interruption. The ROIs reported a significant decrease in patient volume that was not impacted by the circumambient disease incidence, the type of ROI or the occurrence of positive cases. Of the ROIs 16.5% also reported infected HCWs. About half of the ROIs (50.5%) adopted a screening program for patients whereas only 23.3% also screened their HCWs. The range of protective measures included the creation of working groups, instituting home office work and protection with face masks. Regarding the therapeutic options offered, curative procedures were performed with either unchanged or moderately decreased schedules, whereas palliative or benign radiotherapy procedures were more often shortened. Most ROIs postponed or cancelled radiation treatment for benign indications (88.1%). The occurrence of SARS-CoV‑2 infections did not affect the treatment options for curative procedures. Non-university-based ROIs seemed to be more willing to change their treatment options for curative and palliative cases than university-based ROIs.

Conclusion: Most ROIs reported a deep impact of SARS-CoV‑2 infections on their work routine. Modification and prioritization of treatment regimens and the application of protective measures preserved a well-functioning radiation oncology service and patient care.
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http://dx.doi.org/10.1007/s00066-020-01681-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7483062PMC
December 2020

Comparison of early tumour-associated versus late deaths in patients with central or >7 cm T4 N0/1 M0 non-small-cell lung-cancer undergoing trimodal treatment: Only few risks left to improve.

Eur J Cancer 2020 10 2;138:156-168. Epub 2020 Sep 2.

Department of Oncology, West German Cancer Center, University Hospital Essen, Germany; Division of Thoracic Oncology, University Medicine Essen - Ruhrlandklinik, Essen, Germany.

Background: The optimal treatment for patients with locally advanced non-small-cell lung-cancer (NSCLC) cT4 cN0/1 cM0 is still under debate. The purpose of this study was to examine the long-term survival of cT4 cN0/1 cM0 NSCLC patients undergoing induction chemotherapy and concurrent radiochemotherapy before surgery.

Methods: All consecutive patients with confirmed NSCLC (cT4 cN0/1 cM0) treated with neoadjuvant chemotherapy, concurrent radiochemotherapy (RT/CTx) (45-46 Gy) and surgical resection between 2000 and 2015 were included. According to the UICC guidelines (8th edition), T4 stage was reanalysed by an expert radiologist. The mediastinal staging was performed by systematic EBUS-TBNA or mediastinoscopy. The primary end-point was overall-survival (OS). The power to detect an increase of early tumour-associated mortality (hazard ratio > 3.5) within the first 5 years after treatment in comparison to late deaths beyond 96 months was >80%.

Results: Overall, 67 patients were treated with concurrent RT/CTx. T4 criteria were fulfilled by all patients, and multiple T4 criteria by 53 patients. Seventy percent of patients had an initial PET/CT staging. The median follow-up period was 134 months. OS rates at 2, 5, 10 and 15 years were 83.6 ± 4.5%, 65.4 ± 5.9%, 53.3 ± 6.3% and 36.6 ± 6.8%, respectively. A total of 44.8% of patients achieved a pathologic complete response. In multivariable analysis, ypT category was the most predictive factor. OS at 5 years for ypT0 (n = 31) was 80.5%, and ypT1 (n = 11) was 62.5%. Main sites of failure were brain and pulmonary metastases in seven and three patients, respectively. The intercurrent annual death rate was estimated from the survival curve beyond 96 months and was found to be 4.75% (95% CI 2.40-9.27%). No significant increased mortality was observed during the first 5 years (annual death rate: 8.31% [95% CI 5.60-12.24%], hazard-ratio = 1.72 [95% CI 0.81-3.65]).

Conclusions: The effectiveness of this trimodality schedule is high in patients with cT4 cN0/1 cM0 NSCLC with excellent local control rates. Considering the annual death rate beyond 8 years of survival as an intercurrent death rate due to comorbidity, this treatment schedule reduces annual mortality to background even in the first 5 years after therapy.
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http://dx.doi.org/10.1016/j.ejca.2020.07.025DOI Listing
October 2020

Estimation of radiation exposure of children undergoing superselective intra-arterial chemotherapy for retinoblastoma treatment: assessment of local diagnostic reference levels as a function of age, sex, and interventional success.

Neuroradiology 2021 Mar 29;63(3):391-398. Epub 2020 Aug 29.

Department of Diagnostic and Interventional Radiology and Neuroradiology, University Hospital Essen, Hufelandstrasse 55, 45147, Essen, Germany.

Purpose: This study aims to determine local diagnostic reference levels (LDRLs) of intra-arterial chemotherapy (IAC) procedures of pediatric patients with retinoblastoma (RB) to provide data for establishing diagnostic reference levels (DRLs) in pediatric interventional radiology (IR).

Methods: In a retrospective study design, LDRLs and achievable dose (AD) were assessed for children undergoing superselective IAC for RB treatment. All procedures were performed at the flat-panel angiography systems (I) ArtisQ biplane (Siemens Healthineers) and (II) Allura Xper (Philips Healthcare). Patients were differentiated according to age (A1: 1-3 months; A2: 4-12 months; A3: 13-72 months; A4: 73 months-10 years; A5: > 10 years), sex, conducted or not-conducted chemotherapy.

Results: 248 neurointerventional procedures of 130 pediatric patients (median age 14.5 months, range 5-127 months) with RB (68 unilateral, 62 bilateral) could be included between January 2010 and March 2020. The following diagnostic reference values, AD, and mean values could be determined: (A2) DRL 3.9 Gy cm, AD 2.9 Gy cm, mean 3.5 Gy cm; (A3) DRL 7.0 Gy cm, AD 4.3 Gy cm, mean 6.0 Gy cm; (A4) DRL 14.5 Gy cm, AD 10.7 Gy cm, mean 10.8 Gy cm; (A5) AD 8.8 Gy cm, mean 8.8 Gy cm. Kruskal-Wallis-test confirmed a significant dose difference between the examined age groups (A2-A5) (p < 0.001). There was no statistical difference considering sex (p = 0.076) and conducted or not-conducted chemotherapy (p = 0.627). A successful procedure was achieved in 207/248 cases.

Conclusion: We report on radiation exposure during superselective IAC of a pediatric cohort at the German Retinoblastoma Referral Centre. Although an IAC formally represents a therapeutic procedure, our results confirm that radiation exposure lies within the exposure of a diagnostic interventional procedure. DRLs for superselective IAC are substantially lower compared with DRLs of more complex endovascular interventions.
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http://dx.doi.org/10.1007/s00234-020-02540-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7880957PMC
March 2021

Practice Recommendations for Lung Cancer Radiotherapy During the COVID-19 Pandemic: An ESTRO-ASTRO Consensus Statement.

Int J Radiat Oncol Biol Phys 2020 07;107(4):631-640

Department of Radiation Oncology, Comprehensive Cancer Center, Medical University of Vienna, Austria.

Background: The COVID-19 pandemic has caused radiotherapy resource pressures and led to increased risks for lung cancer patients and healthcare staff. An international group of experts in lung cancer radiotherapy established this practice recommendation pertaining to whether and how to adapt radiotherapy for lung cancer in the COVID-19 pandemic.

Methods: For this ESTRO & ASTRO endorsed project, 32 experts in lung cancer radiotherapy contributed to a modified Delphi consensus process. We assessed potential adaptations of radiotherapy in two pandemic scenarios. The first, an early pandemic scenario of risk mitigation, is characterized by an altered risk-benefit ratio of radiotherapy for lung cancer patients due to their increased susceptibility for severe COVID-19 infection, and minimization of patient travelling and exposure of radiotherapy staff. The second, a later pandemic scenario, is characterized by reduced radiotherapy resources requiring patient triage. Six common lung cancer cases were assessed for both scenarios: peripherally located stage I NSCLC, locally advanced NSCLC, postoperative radiotherapy after resection of pN2 NSCLC, thoracic radiotherapy and prophylactic cranial irradiation for limited stage SCLC and palliative thoracic radiotherapy for stage IV NSCLC.

Results: In a risk-mitigation pandemic scenario, efforts should be made not to compromise the prognosis of lung cancer patients by departing from guideline-recommended radiotherapy practice. In that same scenario, postponement or interruption of radiotherapy treatment of COVID-19 positive patients is generally recommended to avoid exposure of cancer patients and staff to an increased risk of COVID-19 infection. In a severe pandemic scenario characterized by reduced resources, if patients must be triaged, important factors for triage include potential for cure, relative benefit of radiation, life expectancy, and performance status. Case-specific consensus recommendations regarding multimodality treatment strategies and fractionation of radiotherapy are provided.

Conclusion: This joint ESTRO-ASTRO practice recommendation established pragmatic and balanced consensus recommendations in common clinical scenarios of radiotherapy for lung cancer in order to address the challenges of the COVID-19 pandemic.
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http://dx.doi.org/10.1016/j.ijrobp.2020.05.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7836268PMC
July 2020

Superior Vena Cava Syndrome Induced Collateral Circulation on 99mTc-Macroaggregated Albumin Lung Perfusion Scintigraphy.

Clin Nucl Med 2020 Oct;45(10):e435-e438

From the Departments of Nuclear Medicine.

Perfusion lung scintigraphy using SPECT/CT is one mainstay in diagnosing pulmonary embolism. Although typically almost all tracer will be accumulated in the lung capillaries, occasionally abnormal uptake can be detected. As superior vena cava syndrome leads to aberrant blood flow, tracer injected to an arm vein might partly circumvent the pulmonary capillary bed and accumulate in well-perfused anatomical structures. In this case, next to the commonly described liver enhancement, more prominent pseudo-uptake of various thoracic vertebrae was observable. However, a time-related FDG PET/CT demonstrated only the hepatic pseudo-uptake. Taken together, careful assessment of superior vena cava syndrome patient studies is highly recommended.
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http://dx.doi.org/10.1097/RLU.0000000000003127DOI Listing
October 2020

ERCC2 gene single-nucleotide polymorphism as a prognostic factor for locally advanced head and neck carcinomas after definitive cisplatin-based radiochemotherapy.

Pharmacogenomics J 2021 02 16;21(1):37-46. Epub 2020 Jun 16.

Department of Radiotherapy, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.

Identifying patients with locally advanced head and neck carcinoma on high risk of recurrence after definitive concurrent radiochemotherapy is of key importance for the selection for consolidation therapy and for individualized treatment intensification. In this multicenter study we analyzed recurrence-associated single-nucleotide polymorphisms (SNPs) in DNA repair genes in tumor DNA from 132 patients with locally advanced head and neck carcinoma (LadHnSCC). Patients were treated with definitive radiotherapy and simultaneous cisplatin-based chemotherapy at six partner sites of the German Cancer Consortium (DKTK) Radiation Oncology Group from 2005 to 2011. For validation, a group of 20 patients was available. Score selection method using proportional hazard analysis and leave-one-out cross-validation were performed to identify markers associated with outcome. The SNPs rs1799793 and rs13181 were associated with survival and the same SNPs and in addition rs17655 with freedom from loco-regional relapse (ffLRR) in the trainings datasets from all patients. The homozygote major rs1799793 genotype at the ERCC2 gene was associated with better (Hazard ratio (HR): 0.418 (0.234-0.744), p = 0.003) and the homozygote minor rs13181 genotype at ERCC2 with worse survival (HR: 2.074, 95% CI (1.177-3.658), p = 0.017) in comparison to the other genotypes. At the ffLRR endpoint, rs1799793 and rs13181 had comparable prognostic value. The rs1799793 and rs13181 genotypes passed the leave-one-out cross-validation procedure and associated with survival and ffLRR in patients with LadHnSCC treated with definitive radiochemotherapy. While findings were confirmed in a small validation dataset, further validation is underway within a prospective biomarker study of the DKTK.
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http://dx.doi.org/10.1038/s41397-020-0174-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7840506PMC
February 2021

RADIANCE - Radiochemotherapy with or without Durvalumab in the treatment of anal squamous cell carcinoma: A randomized multicenter phase II trial.

Clin Transl Radiat Oncol 2020 Jul 1;23:43-49. Epub 2020 May 1.

Department of Radiotherapy and Oncology, University of Frankfurt, Germany.

Purpose: Anal squamous cell carcinomas (ASCC) are increasing in frequency across the developed world. The 3-year disease-free survival (DFS) in patients with locally-advanced disease is approximately 60% after primary radiochemotherapy (RCT). There is a strong rationale for combining immunotherapy with RCT in patients with ASCC due to its association with human papilloma virus (HPV) infection.

Methods/design: RADIANCE is an investigator initiated, prospective, multicenter, randomized phase II trial testing the addition of Durvalumab, a PD-L1 immune checkpoint inhibitor, to standard RCT in 178 patients with locally advanced ASCC (T2 ≥ 4 cm Nany, cT3-4 and/or cN+). In the control arm, patients will be treated with standard mitomycin C (MMC)/5-fluorouracil (5-FU)-based RCT. Intensity-modulated radiotherapy (IMRT) will be applied as follows: PTV_A (primary tumor) T1-T2 < 4 cm N+: 28 × 1.9 Gy = 53.2 Gy; T2 ≥ 4 cm, T3-4 Nany: 31 × 1.9 Gy = 58.9 Gy; PTV_N (involved node): 28 × 1.8 Gy = 50.4 Gy ; and PTV_Elec (elective node): 28 × 1.43 Gy = 40.0 Gy over a period of 5,5-6 weeks. Concomitant chemotherapy will be administered using MMC with 5-FU during weeks 1 and 5 of radiotherapy (MMC 12 mg/m, day 1 [maximum single dose 20 mg]; 5-FU 1000 mg/m days 1-4 and 29-32). In the experimental arm, Durvalmab (1500 mg absolute dose, intravenously) will be combined with the same RCT as in the control arm. Immunotherapy with Durvalumab will start 14 days before initiation of standard RCT, administered every four weeks (q4w) thereafter for a total of twelve doses. The primary endpoint is disease-free survival (DFS) after 3 years.

Discussion: As ASCC is considered an immunogenically "hot" tumor due to its association with HPV infection, the combination of RCT with Durvalumab may improve tumor control and long-term clinical outcome in this patient collective compared to RCT alone.
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http://dx.doi.org/10.1016/j.ctro.2020.04.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7218223PMC
July 2020

Practice recommendations for lung cancer radiotherapy during the COVID-19 pandemic: An ESTRO-ASTRO consensus statement.

Radiother Oncol 2020 05 6;146:223-229. Epub 2020 Apr 6.

Department of Radiation Oncology, Comprehensive Cancer Center, Medical University of Vienna, Austria.

Background: The COVID-19 pandemic has caused radiotherapy resource pressures and led to increased risks for lung cancer patients and healthcare staff. An international group of experts in lung cancer radiotherapy established this practice recommendation pertaining to whether and how to adapt radiotherapy for lung cancer in the COVID-19 pandemic.

Methods: For this ESTRO & ASTRO endorsed project, 32 experts in lung cancer radiotherapy contributed to a modified Delphi consensus process. We assessed potential adaptations of radiotherapy in two pandemic scenarios. The first, an early pandemic scenario of risk mitigation, is characterized by an altered risk-benefit ratio of radiotherapy for lung cancer patients due to their increased susceptibility for severe COVID-19 infection, and minimization of patient travelling and exposure of radiotherapy staff. The second, a later pandemic scenario, is characterized by reduced radiotherapy resources requiring patient triage. Six common lung cancer cases were assessed for both scenarios: peripherally located stage I NSCLC, locally advanced NSCLC, postoperative radiotherapy after resection of pN2 NSCLC, thoracic radiotherapy and prophylactic cranial irradiation for limited stage SCLC and palliative thoracic radiotherapy for stage IV NSCLC.

Results: In a risk-mitigation pandemic scenario, efforts should be made not to compromise the prognosis of lung cancer patients by departing from guideline-recommended radiotherapy practice. In that same scenario, postponement or interruption of radiotherapy treatment of COVID-19 positive patients is generally recommended to avoid exposure of cancer patients and staff to an increased risk of COVID-19 infection. In a severe pandemic scenario characterized by reduced resources, if patients must be triaged, important factors for triage include potential for cure, relative benefit of radiation, life expectancy, and performance status. Case-specific consensus recommendations regarding multimodality treatment strategies and fractionation of radiotherapy are provided.

Conclusion: This joint ESTRO-ASTRO practice recommendation established pragmatic and balanced consensus recommendations in common clinical scenarios of radiotherapy for lung cancer in order to address the challenges of the COVID-19 pandemic.
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http://dx.doi.org/10.1016/j.radonc.2020.04.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7252074PMC
May 2020

Identifying Genetic Lesions in Ocular Adnexal Extranodal Marginal Zone Lymphomas of the MALT Subtype by Whole Genome, Whole Exome and Targeted Sequencing.

Cancers (Basel) 2020 Apr 17;12(4). Epub 2020 Apr 17.

Institute of Cell Biology (Cancer Research), Medical Faculty, University of Duisburg-Essen, 45147 Essen, Germany.

The pathogenesis of ocular adnexal marginal zone lymphomas of mucosa-associated lymphatic tissue-type (OAML) is not fully understood. We performed whole genome sequencing (WGS) and/or whole exome sequencing (WES) for 13 cases of OAML and sequenced 38 genes selected from this analysis in a large cohort of 82 OAML. Besides confirmation of frequent mutations in the genes transducin beta like 1 X-linked receptor 1 () and cAMP response element binding protein (), we newly identifed as a frequently mutated gene in OAML (11% of cases). In our retrospective cohort, mutant cases had a shorter progression-free survival compared with unmutated cases. Other newly identified genes recurrently mutated in 5-10% of cases included members of the collagen family (collagen type XII alpha 1/2 (, )) and . Evaluation of the WGS data of six OAML did not reveal translocations or a current infection of the lymphoma cells by viruses. Evaluation of the WGS data for copy number aberrations confirmed frequent loss of , and revealed recurrent gains of the NOTCH target , and of members of the CEBP transcription factor family. Overall, we identified several novel genes recurrently affected by point mutations or copy number alterations, but our study also indicated that the landscape of frequently (>10% of cases) mutated protein-coding genes in OAML is now largely known.
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http://dx.doi.org/10.3390/cancers12040986DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7225979PMC
April 2020

Comparison of GeneChip, nCounter, and Real-Time PCR-Based Gene Expressions Predicting Locoregional Tumor Control after Primary and Postoperative Radiochemotherapy in Head and Neck Squamous Cell Carcinoma.

J Mol Diagn 2020 06 2;22(6):801-810. Epub 2020 Apr 2.

German Cancer Consortium (DKTK) partner site Dresden, Dresden, Germany; German Cancer Research Center (DKFZ), Heidelberg; the OncoRay-National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Helmholtz-Zentrum Dresden-Rossendorf, Dresden, Germany; Department of Radiotherapy and Radiation Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; National Center for Tumor Diseases (NCT), Partner Site Dresden, Germany: German Cancer Research Center (DKFZ), Heidelberg, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, and Helmholtz Association/Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Dresden, Germany.

This article compares the expression and applicability of biomarkers, from single genes and gene signatures, identified in patients with locally advanced head and neck squamous cell carcinoma using the GeneChip Human Transcriptome Array 2.0, nCounter, and real-time PCR analyses. Two multicenter, retrospective cohorts of patients with head and neck squamous cell carcinoma from the German Cancer Consortium Radiation Oncology Group who received postoperative radiochemotherapy or primary radiochemotherapy were considered. Real-time PCR was performed for a limited number of 38 genes of the cohort who received postoperative radiochemotherapy only. Correlations between the methods were evaluated by the Spearman rank correlation coefficient. Patients were stratified based on the expression of putative cancer stem cell markers, hypoxia-associated gene signatures, and a previously developed seven-gene signature. Locoregional tumor control was compared between these patient subgroups using log-rank tests. Gene expressions obtained from nCounter analyses were moderately correlated to GeneChip analyses (median ρ = approximately 0.68). A higher correlation was obtained between nCounter analyses and real-time PCR (median ρ = 0.84). Significant associations with locoregional tumor control were observed for most of the considered biomarkers evaluated by GeneChip and nCounter analyses. In general, all applied biomarkers (single genes and gene signatures) classified approximately 70% to 85% of the patients similarly. Overall, gene signatures seem to be more robust and had a better transferability among different measurement methods.
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http://dx.doi.org/10.1016/j.jmoldx.2020.03.005DOI Listing
June 2020

Mapping Patient Data to Colorectal Cancer Clinical Algorithms for Personalized Guideline-Based Treatment.

Appl Clin Inform 2020 03 18;11(2):200-209. Epub 2020 Mar 18.

West German Cancer Center, University Hospital Essen, Essen, Germany.

Background: Colorectal cancer is the most commonly occurring cancer in Germany, and the second and third most commonly diagnosed cancer in women and men, respectively. In this context, evidence-based guidelines positively impact the quality of treatment processes for cancer patients. However, evidence of their impact on real-world patient care remains unclear. To ensure the success of clinical guidelines, a fast and clear provision of knowledge at the point of care is essential.

Objectives: The objectives of this study are to model machine-readable clinical algorithms for colon carcinoma and rectal carcinoma annotated by Unified Medical Language System (UMLS) based on clinical guidelines and the development of an open-source workflow system for mapping clinical algorithms with patient-specific information to identify patient's position on the treatment algorithm for guideline-based therapy recommendations.

Methods: This study qualitatively assesses the therapy decision of clinical algorithms as part of a clinical pathway. The solution uses rule-based clinical algorithms, which were developed based on the corresponding guidelines. These algorithms are executed on a newly developed open-source workflow system and are visualized at the point of care. The aim of this approach is to create clinical algorithms based on an established business process standard, the Business Process Model and Notation (BPMN), which is annotated by UMLS terminologies. The gold standard for the validation process was set by manual extraction of clinical datasets from 86 rectal cancer patients and 89 colon cancer patients.

Results: Using this approach, the algorithm achieved a precision value of 87.64% for colon cancer and 84.70% for rectal cancer with recall values of 87.64 and 83.72%, respectively.

Conclusion: The results indicate that the automatic positioning of a patient on the decision pathway is possible with tumor stages that have a less complex clinical algorithm with fewer decision points reaching a higher accuracy than complex stages.
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http://dx.doi.org/10.1055/s-0040-1705105DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7080556PMC
March 2020