Publications by authors named "Martin Schuler"

190 Publications

Patterns of nodal spread in stage III NSCLC: importance of EBUS-TBNA and F-FDG PET/CT for radiotherapy target volume definition.

Radiat Oncol 2021 Sep 15;16(1):176. Epub 2021 Sep 15.

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

Purpose: The aim of this study was to compare the pattern of intra-patient spread of lymph-node (LN)-metastases within the mediastinum as assessed by F-FDG PET/CT and systematic endobronchial ultrasound-guided transbronchial-needle aspiration (EBUS-TBNA) for precise target volume definition in stage III NSCLC.

Methods: This is a single-center study based on our preceding investigation, including all consecutive patients with initial diagnosis of stage IIIA-C NSCLC, receiving concurrent radiochemotherapy (12/2011-06/2018). Inclusion criteria were curative treatment intent, F-FDG PET/CT and EBUS-TBNA prior to start of treatment. The lymphatic drainage was classified into echelon-1 (ipsilateral hilum), echelon-2 (ipsilateral LN-stations 4 and 7) and echelon-3 (rest of the mediastinum, contralateral hilum). The pattern of spread was classified according to all permutations of echelon-1, echelon-2, and echelon-3 EBUS-TBNA findings.

Results: In total, 180 patients were enrolled. Various patterns of LN-spread could be identified. Skip lesions with an involved echelon distal from an uninvolved one were detected in less than 10% of patients by both EBUS-TBNA and PET. The pattern with largest asymmetry was detected in cases with EBUS-TBNA- or PET-positivity at all three echelons (p < 0.0001, exact symmetry test). In a multivariable logistic model for EBUS-positivity at echelon-3, prognostic factors were PET-positivity at echelon-3 (Hazard ratio (HR) = 12.1; 95%-CI: 3.2-46.5), EBUS-TBNA positivity at echelon-2 (HR = 6.7; 95%-CI: 1.31-31.2) and left-sided tumor location (HR = 4.0; 95%-CI: 1.24-13.2). There were significantly less combined ipsilateral upper (LN-stations 2 and 4) and lower (LN-station 7) mediastinal involvements (16.8% of patients) with EBUS-TBNA than with PET (38.9%, p < 0.0001, exact symmetry test). EBUS-TBNA detected a lobe specific heterogeneity between the odds ratios of LN-positivity in the upper versus lower mediastinum (p = 0.0021, Breslow-Day test), while PET did not (p = 0.19).

Conclusion: Frequent patterns of LN-metastatic spread could be defined by EBUS-TBNA and PET and discrepancies in the pattern were seen between both methods. EBUS-TBNA showed more lobe and tumor laterality specific patterns of LN-metastases than PET and skipped lymph node stations were rare. These systematic relations offer the opportunity to further refine multi-parameter risk of LN-involvement models for target volume delineation based on pattern of spread by EBUS-TBNA and PET.
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http://dx.doi.org/10.1186/s13014-021-01904-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8442338PMC
September 2021

Antitumor immune response is associated with favorable survival in GEP-NEN G3.

Endocr Relat Cancer 2021 Sep 2;28(10):683-693. Epub 2021 Sep 2.

Bridge Institute of Experimental Tumor Therapy, West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.

The tumor immune microenvironment (TME) represents a key determinant for responses to cancer treatment. However, the immune phenotype of highly proliferative gastroenteropancreatic neuroendocrine neoplasms (GEP-NEN) is still largely elusive. In this retrospective study, we characterized the TME of high-grade (G3, Ki-67 > 20%) GEP-NEN. We analyzed formalin-fixed paraffin-embedded samples from 37 patients with GEP-NEN G3 by immunohistochemistry and multiplex immunofluorescence to address the abundance and spatial interaction of relevant immune subsets. We focused on the expression of immune checkpoint molecules PD-1 and PD-L1, the cytotoxic T-cell marker CD8, and the tumor-associated macrophage marker CD206. Findings were correlated with overall survival (OS) from the date of a cancer diagnosis. Patients with PD-L1-positive tumors (CPS ≥ 1) and intense PD-1+CD8+ immune cell infiltration showed the most favorable median OS. Multiplex immunofluorescence staining of ten representative tissue samples illustrated intratumoral heterogeneity of PD-L1 expression. Dense PD-1+CD8+ immune cell infiltrates were observed in PD-L1-positive tumor regions but not in PD-L1-negative regions. Proximity analysis revealed a spatial interaction between PD-1+CD8+ cells and PD-L1-positive cells. Our data suggest a pre-existing antitumor immune response in the TME in a subgroup of GEP-NEN G3. This supports a targeted clinical exploration of immunotherapeutic approaches.
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http://dx.doi.org/10.1530/ERC-21-0223DOI Listing
September 2021

Lung Cancer Surgery after Neoadjuvant Immunotherapy.

Cancers (Basel) 2021 Aug 10;13(16). Epub 2021 Aug 10.

Department of Thoracic Surgery, University Medicine Essen-Ruhrlandklinik, Tueschener Weg 40, 45239 Essen, Germany.

In early-stage lung cancer, recurrences are observed even after curative resection. Neoadjuvant immunotherapy might be a promising approach to eliminate micrometastasis and to potentially reduce recurrence rates and improve survival. Early trials have shown encouraging rates of pathologic response to neoadjuvant therapy and have demonstrated that surgery can be safely performed after neoadjuvant immunotherapy with various agents and in combination with chemo-(radio)therapy. However, whether these response rates translate into improved disease-free survival rates and overall survival rates remains to be determined by ongoing phase III studies.
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http://dx.doi.org/10.3390/cancers13164033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8393473PMC
August 2021

Initial clinical experience with Y-FAPI-46 radioligand therapy for advanced stage solid tumors: a case series of nine patients.

J Nucl Med 2021 Aug 12. Epub 2021 Aug 12.

Department of Medical Oncology, University Hospital Essen, Germany, Germany.

Fibroblast activation protein (FAP) is overexpressed in several solid tumors and therefore represents an attractive target for radiotheranostic applications. Recent investigations demonstrated rapid and high uptake of small-molecule inhibitors of FAP (Ga-FAPI-46) for PET imaging. Here, we report our initial experience in terms of feasibility and safety of Y-labelled FAPI-46 (Y-FAPI-46) for radioligand therapy (RLT) of extensively pretreated patients with solid tumors. Patients were considered for Y-FAPI-46 therapy in case of (a) exhaustion of all approved therapies based on multidisciplinary tumor board decision and (b) high FAP expression, defined as SUV ≥ 10 in more than 50% of all lesions. If tolerated, post-therapeutic Y-FAPI-46 bremsstrahlung scintigraphy was performed to visually confirm systemic distribution and focal tumor uptake, and Y-FAPI-46 PET scans at multiple time-points were performed to determine absorbed dose. Blood-based dosimetry was used to determine bone-marrow absorbed dose. Adverse Events were graded using CTCAE v.5.0. Nine patients with either metastatic soft tissue or bone sarcoma ( = 6) and pancreatic cancer ( = 3) were treated between June 2020 and March 2021. Patients received a median of 3.8 (IQR 3.25-5.40) GBq for the first cycle and three patients received subsequent cycles with a median of 7.4 (IQR 7.3-7-5) GBq. Post-therapy Y-FAPI-46 bremsstrahlung scintigraphy demonstrated sufficient Y-FAPI-46 uptake in tumor lesions in 7 of 9 patients (78%). Mean absorbed dose was 0.52 Gy/GBq (IQR 0.41-0.65) in kidney, 0.04 Gy/GBq (IQR 0.03-0.06) in bone marrow and below 0.26 Gy/GBq in the lung and liver. Measured tumor lesions received up to 2.28 Gy/GBq (median 1.28 Gy/GBq). Hematologic G3/G4 toxicities were noted in four patients (44%), of which thrombocytopenia was most prevalent ( = 6; 67%), whereas other G3/G4 laboratory-based adverse events were N ≤ 2. No acute toxicities attributed to Y-FAPI-46 were noted. Radiographic disease control was noted in three patients (33 %). FAP-targeted RLT with Y-FAPI-46 was well tolerated with a low rate of attributable adverse events. Low radiation doses to organs at risk suggest feasibility of repeat cycles of Y-FAPI-46. We observe signs of clinical activity, but further studies are warranted to determine efficacy and toxicity profile in a larger cohort.
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http://dx.doi.org/10.2967/jnumed.121.262468DOI Listing
August 2021

Long-term Normothermic Machine Preservation of Partial Livers: First Experience With 21 Human Hemi-livers.

Ann Surg 2021 11;274(5):836-842

Wyss Zurich, ETH Zurich/University of Zurich, Switzerland.

Objective: The aim of this study was to maintain long-term full function and viability of partial livers perfused ex situ for sufficient duration to enable ex situ treatment, repair, and regeneration.

Background: Organ shortage remains the single most important factor limiting the success of transplantation. Autotransplantation in patients with nonresectable liver tumors is rarely feasible due to insufficient tumor-free remnant tissue. This limitation could be solved by the availability of long-term preservation of partial livers that enables functional regeneration and subsequent transplantation.

Methods: Partial swine livers were perfused with autologous blood after being procured from healthy pigs following 70% in-vivo resection, leaving only the right lateral lobe. Partial human livers were recovered from patients undergoing anatomic right or left hepatectomies and perfused with a blood based perfusate together with various medical additives. Assessment of physiologic function during perfusion was based on markers of hepatocyte, cholangiocyte, vascular and immune compartments, as well as histology.

Results: Following the development phase with partial swine livers, 21 partial human livers (14 right and 7 left hemi-livers) were perfused, eventually reaching the targeted perfusion duration of 1 week with the final protocol. These partial livers disclosed a stable perfusion with normal hepatic function including bile production (5-10 mL/h), lactate clearance, and maintenance of energy exhibited by normal of adenosine triphosphate (ATP) and glycogen levels, and preserved liver architecture for up to 1 week.

Conclusion: This pioneering research presents the inaugural evidence for long-term machine perfusion of partial livers and provides a pathway for innovative and relevant clinical applications to increase the availability of organs and provide novel approaches in hepatic oncology.
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http://dx.doi.org/10.1097/SLA.0000000000005102DOI Listing
November 2021

N-staging in large cell neuroendocrine carcinoma of the lung: diagnostic value of [F]FDG PET/CT compared to the histopathology reference standard.

EJNMMI Res 2021 Jul 22;11(1):68. Epub 2021 Jul 22.

Department of Thoracic Surgery and Endoscopy, West German Lung Center, Ruhrlandklinik - University Hospital Essen, University Duisburg-Essen, Essen, Germany.

Background: Large cell neuroendocrine carcinoma of the lung (LCNEC) is a rare entity occurring in less than 4% of all lung cancers. Due to its low differentiation and high glucose transporter 1 (GLUT1) expression, LCNEC demonstrates an increased glucose turnover. Thus, PET/CT with 2-[F]-fluoro-deoxyglucose ([F]FDG) is suitable for LCNEC staging. Surgery with curative intent is the treatment of choice in early stage LCNEC. Prerequisite for this is correct lymph node staging. This study aimed at evaluating the diagnostic performance of [F]FDG PET/CT validated by histopathology following surgical resection or mediastinoscopy. N-staging interrater-reliability was assessed to test for robustness of the [F]FDG PET/CT findings.

Methods: Between 03/2014 and 12/2020, 46 patients with LCNEC were included in this single center retrospective analysis. All underwent [F]FDG PET/CT for pre-operative staging and subsequently either surgery (n = 38) or mediastinoscopy (n = 8). Regarding the lymph node involvement, sensitivity, specificity, accuracy, positive predictive value (PPV) and negative predictive value (NPV) were calculated for [F]FDG PET/CT using the final histopathological N-staging (pN0 to pN3) as reference.

Results: Per patient 14 ± 7 (range 4-32) lymph nodes were resected and histologically processed. 31/46 patients had no LCNEC spread into the lymph nodes. In 8/46 patients, the final stage was pN1, in 5/46 pN2 and in 2/46 pN3. [F]FDG PET/CT diagnosed lymph node metastasis of LCNEC with a sensitivity of 93%, a specificity of 87%, an accuracy of 89%, a PPV of 78% and a NPV of 96%. In the four false positive cases, the [F]FDG uptake of the lymph nodes was 33 to 67% less in comparison with that of the respective LCNEC primary. Interrater-reliability was high with a strong level of agreement (κ = 0.82).

Conclusions: In LCNEC N-staging with [F]FDG PET/CT demonstrates both high sensitivity and specificity, an excellent NPV but a slightly reduced PPV. Accordingly, preoperative invasive mediastinal staging may be omitted in cases with cN0 disease by [F]FDG PET/CT. In [F]FDG PET/CT cN1-cN3 stages histological confirmation is warranted, particularly in case of only moderate [F]FDG uptake as compared to the LCNEC primary.
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http://dx.doi.org/10.1186/s13550-021-00811-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8298649PMC
July 2021

Synthesis of coagulation factors during long-term ex situ liver perfusion.

Artif Organs 2021 Jul 20. Epub 2021 Jul 20.

Department of Surgery, Swiss Hepato-Pancreato-Biliary and Transplantation Center, University Hospital Zurich, Zurich, Switzerland.

Robust viability assessment of grafts during normothermic liver perfusion is a prerequisite for organ use. Coagulation parameters are used commonly for liver assessment in patients. However, they are not yet included in viability assessment during ex situ perfusion. In this study, we analysed coagulation parameters during one week ex situ perfusion at 34℃. Eight discarded human livers were perfused with blood-based, heparinised perfusate for one week; perfusions in a further four livers were terminated on day 4 due to massive ongoing cell death. Coagulation parameters were well below the physiologic range at perfusion start. Physiologic levels were achieved within the first two perfusion days for factor V (68.5 ± 35.5%), factor VII (83.5 ± 26.2%), fibrinogen (2.1 ± 0.4 g/L) and antithrombin (107 ± 26.5%) in the livers perfused for one week. Despite the increased production of coagulation factors, INR was detectable only at 24h of perfusion (2.1 ± 0.3) and prolonged thereafter (INR > 9). The prolongation of INR was related to the high heparin level in the perfusate (anti-FXa > 3 U/mL). Intriguingly, livers with ongoing massive cell death also disclosed synthesis of factor V and improved INR. In summary, perfused livers were able to produce coagulation factors at a physiological level ex situ. We propose that single coagulation factor analysis is more reliable for assessing the synthetic function of perfused livers as compared to INR when using a heparinised perfusate.
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http://dx.doi.org/10.1111/aor.14041DOI Listing
July 2021

Potential Prognostic Value of Preoperative Leukocyte Count, Lactate Dehydrogenase and C-Reactive Protein in Thymic Epithelial Tumors.

Pathol Oncol Res 2021 21;27:629993. Epub 2021 Apr 21.

Department of Thoracic Surgery, University Medicine Essen-Ruhrlandklinik, University Duisburg-Essen, Essen, Germany.

Thymic epithelial tumors are the most common mediastinal tumors. Surgery is the mainstay of treatment and complete resection provides the best survival rate. However, advanced tumors often require multimodality treatment and thus we analyzed the prognostic potential of routine circulating biomarkers that might help to risk-stratify patients beyond tumor stage and histology. Preoperative values for white blood cell count (WBC), C-reactive protein (CRP) and lactate dehydrogenase (LDH) were analyzed in 220 thymic epithelial tumor patients operated between 1999 and 2018. Increased CRP levels (>1 mg/dl) were significantly more often measured in thymic carcinoma and neuroendocrine tumors when compared to thymoma. LDH serum activity was higher in thymic neuroendocrine tumors when compared to thymoma or thymic carcinoma. The median disease specific survival was significantly longer in thymoma cases than in thymic carcinoma and neuroendocrine tumors. Increased preoperative LDH level (>240 U/L) associated with shorter survival in thymus carcinoma (HR 4.76, = 0.0299). In summary, higher CRP associated with carcinoma and neuroendocrine tumors, while LDH increased primarily in neuroendocrine tumors suggesting that biomarker analysis should be performed in a histology specific manner. Importantly, preoperative serum LDH might be a prognosticator in thymic carcinoma and may help to risk stratify surgically treated patients in multimodal treatment regimens.
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http://dx.doi.org/10.3389/pore.2021.629993DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8262211PMC
April 2021

Pralsetinib for patients with advanced or metastatic RET-altered thyroid cancer (ARROW): a multi-cohort, open-label, registrational, phase 1/2 study.

Lancet Diabetes Endocrinol 2021 08 9;9(8):491-501. Epub 2021 Jun 9.

Earle A Chiles Research Institute, Providence Portland Medical Center, Portland, OR, USA.

Background: Oncogenic alterations in RET represent important therapeutic targets in thyroid cancer. We aimed to assess the safety and antitumour activity of pralsetinib, a highly potent, selective RET inhibitor, in patients with RET-altered thyroid cancers.

Methods: ARROW, a phase 1/2, open-label study done in 13 countries across 71 sites in community and hospital settings, enrolled patients 18 years or older with RET-altered locally advanced or metastatic solid tumours, including RET-mutant medullary thyroid and RET fusion-positive thyroid cancers, and an Eastern Co-operative Oncology Group performance status of 0-2 (later limited to 0-1 in a protocol amendment). Phase 2 primary endpoints assessed for patients who received 400 mg once-daily oral pralsetinib until disease progression, intolerance, withdrawal of consent, or investigator decision, were overall response rate (Response Evaluation Criteria in Solid Tumours version 1.1; masked independent central review) and safety. Tumour response was assessed for patients with RET-mutant medullary thyroid cancer who had received previous cabozantinib or vandetanib, or both, or were ineligible for standard therapy and patients with previously treated RET fusion-positive thyroid cancer; safety was assessed for all patients with RET-altered thyroid cancer. This ongoing study is registered with clinicaltrials.gov, NCT03037385, and enrolment of patients with RET fusion-positive thyroid cancer was ongoing at the time of this interim analysis.

Findings: Between Mar 17, 2017, and May 22, 2020, 122 patients with RET-mutant medullary and 20 with RET fusion-positive thyroid cancers were enrolled. Among patients with baseline measurable disease who received pralsetinib by July 11, 2019 (enrolment cutoff for efficacy analysis), overall response rates were 15 (71%) of 21 (95% CI 48-89) in patients with treatment-naive RET-mutant medullary thyroid cancer and 33 (60%) of 55 (95% CI 46-73) in patients who had previously received cabozantinib or vandetanib, or both, and eight (89%) of nine (95% CI 52-100) in patients with RET fusion-positive thyroid cancer (all responses confirmed for each group). Common (≥10%) grade 3 and above treatment-related adverse events among patients with RET-altered thyroid cancer enrolled by May 22, 2020, were hypertension (24 patients [17%] of 142), neutropenia (19 [13%]), lymphopenia (17 [12%]), and anaemia (14 [10%]). Serious treatment-related adverse events were reported in 21 patients (15%), the most frequent (≥2%) of which was pneumonitis (five patients [4%]). Five patients [4%] discontinued owing to treatment-related events. One (1%) patient died owing to a treatment-related adverse event.

Interpretation: Pralsetinib is a new, well-tolerated, potent once-daily oral treatment option for patients with RET-altered thyroid cancer.

Funding: Blueprint Medicines.
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http://dx.doi.org/10.1016/S2213-8587(21)00120-0DOI Listing
August 2021

A randomized, multicenter phase II study comparing efficacy, safety and tolerability of two dosing regimens of cisplatin and pemetrexed in patients with advanced or metastatic non-small-cell lung cancer.

Ther Adv Med Oncol 2021 9;13:1758835921996506. Epub 2021 Mar 9.

Department of Medical Oncology, West German Cancer Center, University Hospital Essen, Hufelandstraße 55, Essen, Nordrhein-Westfalen, 45147, Germany.

Background: Pemetrexed and cisplatin is a first-line standard in non-squamous non-small-cell lung cancer without targetable mutations. It became the backbone of checkpoint-inhibitor-chemotherapy combinations. Single high doses of cisplatin pose toxicity risks and require hyperhydration, potentially prolonging outpatient application. The aim of this study was to compare efficacy, safety and tolerability of split-dose cisplatin with the standard schedule.

Methods: Patients with metastatic non-squamous non-small-cell lung cancer were randomly assigned to up to six 21-day cycles of pemetrexed 500 mg/m and cisplatin 75 mg/m on day 1 (arm A), or pemetrexed 500 mg/m (day 1) and cisplatin 40 mg/m (day 1 + 8, arm B), followed by pemetrexed maintenance. Primary endpoint was objective response rate. Secondary objectives were overall survival, progression-free survival, time to progression, treatment compliance, toxicity profile, and quality of life.

Results: We enrolled 130 patients (129 evaluable). Median cycle numbers in A and B were six (1-6) and five (1-6). Dose intensities were comparable between arms. More patients in A received pemetrexed maintenance (24.2% 11.1%). With 16 (24.2%) in A and 19 (30.2%) patients in B achieving objective responses [odds ratio 0.74 (0.34-1.62),  = 0.55] the primary endpoint was met. Overall survival was not different between arms (median 14.4 14.9 months); [HR = 1.07; (0.68-1.68),  = 0.78]. Median progression-free survival was 7.0 months in A and 6.2 months in B [HR = 1.63; (1.17-2.38);  = 0.01]. Adverse events of CTCAE grade ⩾3, particularly hematological, were more frequent in B. No difference in grade 4 and 5 infections between arms was noted. Treatment-related asthenia and nausea/vomiting of any grade were more frequent in A. Global health status, fatigue and constipation measured on day 1 of cycle 4 demonstrated superior scores in B.

Conclusion: Pemetrexed and split-dose cisplatin is safe and effective. Advantages of split-dose cisplatin with regard to specific toxicities allow personalization of this important chemotherapy backbone.

Trial Registration: European Clinical Trials Database (EudraCT) number 2011-001963-37.
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http://dx.doi.org/10.1177/1758835921996506DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8164550PMC
March 2021

Sotorasib for Lung Cancers with p.G12C Mutation.

N Engl J Med 2021 06 4;384(25):2371-2381. Epub 2021 Jun 4.

From the University of Texas M.D. Anderson Cancer Center, Houston (F.S.), and U.S. Oncology Research, the Woodlands (A. Spira) - both in Texas; Memorial Sloan Kettering Cancer Center and Weill Cornell Medicine (B.T.L.) and Thoracic Medical Oncology, Perlmutter Cancer Center, New York University (V.V.), New York, and Roswell Park Cancer Institute, Buffalo (G.K.D.) - all in New York; the Queen Elizabeth Hospital and University of Adelaide, Woodville, SA, Australia (T.J.P.); Sarah Cannon Research Institute at HealthONE, Denver (G.S.F.); Department I of Internal Medicine, Center for Integrated Oncology, University Hospital Cologne, Cologne (J.W.), the West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen (M.S.), and the German Cancer Consortium, Heidelberg (M.S.) - all in Germany; the Early Phase Trials and Sarcoma Units, Bergonie Cancer Institute, Bordeaux (A.I.), and Gustave Roussy Institute, Villejuif (F.B., B.B.) - both in France; Fox Chase Cancer Center, Philadelphia (H.B.); Kanagawa Cancer Center, Yokohama (T.K.), and the Division of Thoracic Oncology, Shizuoka Cancer Center, Shizuoka (T.T.) - both in Japan; the Department of Medical Oncology and Hematology, University Hospital Zurich, Zurich, Switzerland (A.C.-F.); Princess Margaret Cancer Centre, University Health Network, Toronto (A. Sacher); Virginia Cancer Specialists, Fairfax (A. Spira); Johns Hopkins School of Medicine, Johns Hopkins University, Baltimore (A. Spira); Winship Cancer Institute of Emory University, Atlanta (S.S.R.); Amgen, Thousand Oaks, CA (A. Anderson, A. Ang, Q.T., O.M., H.H., G.N., G.F.); and the Alvin J. Siteman Cancer Center, Washington University School of Medicine, St. Louis (R.G.).

Background: Sotorasib showed anticancer activity in patients with p.G12C-mutated advanced solid tumors in a phase 1 study, and particularly promising anticancer activity was observed in a subgroup of patients with non-small-cell lung cancer (NSCLC).

Methods: In a single-group, phase 2 trial, we investigated the activity of sotorasib, administered orally at a dose of 960 mg once daily, in patients with p.G12C-mutated advanced NSCLC previously treated with standard therapies. The primary end point was objective response (complete or partial response) according to independent central review. Key secondary end points included duration of response, disease control (defined as complete response, partial response, or stable disease), progression-free survival, overall survival, and safety. Exploratory biomarkers were evaluated for their association with response to sotorasib therapy.

Results: Among the 126 enrolled patients, the majority (81.0%) had previously received both platinum-based chemotherapy and inhibitors of programmed death 1 (PD-1) or programmed death ligand 1 (PD-L1). According to central review, 124 patients had measurable disease at baseline and were evaluated for response. An objective response was observed in 46 patients (37.1%; 95% confidence interval [CI], 28.6 to 46.2), including in 4 (3.2%) who had a complete response and in 42 (33.9%) who had a partial response. The median duration of response was 11.1 months (95% CI, 6.9 to could not be evaluated). Disease control occurred in 100 patients (80.6%; 95% CI, 72.6 to 87.2). The median progression-free survival was 6.8 months (95% CI, 5.1 to 8.2), and the median overall survival was 12.5 months (95% CI, 10.0 to could not be evaluated). Treatment-related adverse events occurred in 88 of 126 patients (69.8%), including grade 3 events in 25 patients (19.8%) and a grade 4 event in 1 (0.8%). Responses were observed in subgroups defined according to PD-L1 expression, tumor mutational burden, and co-occurring mutations in , , or .

Conclusions: In this phase 2 trial, sotorasib therapy led to a durable clinical benefit without new safety signals in patients with previously treated p.G12C-mutated NSCLC. (Funded by Amgen and the National Institutes of Health; CodeBreaK100 ClinicalTrials.gov number, NCT03600883.).
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http://dx.doi.org/10.1056/NEJMoa2103695DOI Listing
June 2021

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

Ga-68-FAPI as diagnostic tool in sarcoma: Data from the FAPI-PET prospective observational trial.

J Nucl Med 2021 Apr 30. Epub 2021 Apr 30.

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

Bone and soft tissue sarcomas express fibroblast activation protein (FAP) on tumor cells and associated fibroblast. Therefore, FAP is a promising therapeutic and diagnostic target. Novel radio-labelled FAP-Inhibitors (e.g. Ga-FAPI46) have shown high tumor uptake in positron emission tomography (PET) in sarcoma patients. Here we report endpoints of the FAPI-PET prospective observational trial. Forty-seven patients with bone or soft tissue sarcomas undergoing clinical Ga-FAPI-PET were eligible for enrollment into the FAPI-PET observational trial. Of these patients, 43 patients also underwent F-Fluordesoxyglucose PET (FDG). The primary study endpoint was the association of Ga-FAPI-PET uptake intensity and histopathological FAP-expression analyzed with Spearman's r correlation. Secondary endpoints were detection rate, positive predictive value (PPV), interreader reproducibility, and change in management. Datasets were interpreted by two blinded readers. Primary endpoint was met and the association between FAPI-PET uptake intensity and histopathological FAP-expression was significant (Spearman's r = 0.43; = 0.03). By histopathological validation PPV was 1.00 (95% CI, 0.87-1.00) on a per-patient and 0.97 (95% CI, 0.84-1.00) on a per-region basis. In cases with histopathologic validation, 27 of 28 (96%) confirmed patients and 32 of 34 (94%) confirmed regions were PET positive resulting in an SE of 0.96 (95%CI, 0.82-1.00) on a per-patient and 0.94 (95%CI, 0.80-0.99) on a per-region basis. The detection rate on a per-patient basis in FAPI- and FDG-PET was 76.6% and 81.4%, respectively. In 8 (18.6%) patients FAPI-PET resulted in an upstaging compared to FDG-PET. FAPI-PET readers showed substantial to almost perfect agreement for the defined regions (Fleiss kappa: primary κ = 0.78; local nodal κ = 0.54; distant nodal κ = 0.91; lung κ = 0.86; bone κ = 0.69 and other κ = 0.65). Clinical management changed in 13 (30%) patients after FAPI-PET. We confirm an association of tumoral FAPI-PET uptake intensity and histopathological FAP expression in sarcoma patients. Further, using blinded reads and independent histopathological validation we report high PPV and sensitivity of FAPI-PET for sarcoma staging.
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http://dx.doi.org/10.2967/jnumed.121.262096DOI Listing
April 2021

Sources and prevention of graft infection during long-term ex situ liver perfusion.

Transpl Infect Dis 2021 Aug 22;23(4):e13623. Epub 2021 Jun 22.

Department of Surgery, Swiss Hepatopancreatobiliary and Transplantation Center, University Hospital Zurich, Zurich, Switzerland.

Introduction: The use of normothermic liver machine perfusion to repair injured grafts ex situ is an emerging topic of clinical importance. However, a major concern is the possibility of microbial contamination in the absence of a fully functional immune system. Here, we report a standardized approach to maintain sterility during normothermic liver machine perfusion of porcine livers for one week.

Methods: Porcine livers (n = 42) were procured and perfused with blood at 34°C following aseptic technique and standard operating procedures. The antimicrobial prophylaxis was adapted and improved in a step-wise manner taking into account the pathogens that were detected during the development phase. Piperacillin-Tazobactam was applied as a single dose initially and modified to continuous application in the final protocol. In addition, the perfusion machine was improved to recapitulate partially the host's defense system. The final protocol was tested for infection prevention during one week of perfusion.

Results: During the development phase, microbial contamination occurred in 27 out of 39 (69%) livers with a mean occurrence of growth on 4 ± 1.6 perfusion days. The recovered microorganisms suggested an exogenous source of microbial contamination. The antimicrobial agents (piperacillin/tazobactam) could be maintained above the targeted minimal inhibitory concentration (8-16 mg/L) only with continuous application. In addition to continuous application of piperacillin/tazobactam, partial recapitulation of the host immune system ex situ accompanied by strict preventive measures for contact and air contamination maintained sterility during one week of perfusion.

Conclusion: The work demonstrates feasibility of sterility maintenance for one week during ex situ normothermic liver perfusion.
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http://dx.doi.org/10.1111/tid.13623DOI Listing
August 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 05 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

FDG-PET/CT: novel method for viability assessment of livers perfused ex vivo.

Nucl Med Commun 2021 Jul;42(7):826-832

Department of Nuclear Medicine, University Hospital of Zurich, University of Zurich.

Purpose: Ex vivo liver machine perfusion is a promising option to rescue marginal liver grafts mitigating the donated organ shortage. Recently, a novel liver perfusion machine that can keep injured liver grafts alive for 1 week ex vivo was developed and reported in Nature Biotechnology. However, liver viability assessment ex vivo is an unsolved issue and the value of 18F-fluorodeoxyglucose (FDG)-PET/CT for such purpose was explored.

Materials And Methods: Discarded two human and six porcine liver grafts underwent FDG-PET/CT for viability assessment after 1 week of ex vivo perfusion. PET parameters [standardized uptake value (SUV)max, SUVmean, SUVpeak and total lesion glycolysis] were compared between hepatic lobes and between porcine and human livers. The prevalence of FDG-negative organ parts was recorded. The estimated effective radiation dose for PET/CT was calculated.

Results: All organs were viable with essentially homogeneous FDG uptake. Of note, viability was preserved in contact areas disclosing the absence of pressure necrosis. Four porcine and two human organs had small superficial FDG-negative areas confirmed as biopsy sites. Total lesion glycolysis was significantly higher in the right hepatic lobe (P = 0.012), while there was no significant difference of SUVmax, SUVmean and SUVpeak between hepatic lobes. There was no significant difference in FDG uptake parameters between porcine and human organs. The estimated effective radiation dose was 1.99 ± 1.67 mSv per organ.

Conclusion: This study demonstrates the feasibility of FDG-PET/CT for viability assessment of ex vivo perfused liver grafts after 1 week.
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http://dx.doi.org/10.1097/MNM.0000000000001399DOI Listing
July 2021

GPR15 Facilitates Recruitment of Regulatory T Cells to Promote Colorectal Cancer.

Cancer Res 2021 06 16;81(11):2970-2982. Epub 2021 Mar 16.

Infection Immunology, Institute of Medical Microbiology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.

Colorectal cancer is one of the most frequent malignancies worldwide. Despite considerable progress in early detection and treatment, there is still an unmet need for novel antitumor therapies, particularly in advanced colorectal cancer. Regulatory T cells (Treg) are increased in the peripheral blood and tumor tissue of patients with colorectal cancer. Recently, transient ablation of tumor-associated Tregs was shown to foster CD8 T-cell-mediated antitumoral immunity in murine colorectal cancer models. However, before considering therapies on targeting Tregs in patients with cancer, detailed knowledge of the phenotype and features of tumor-associated Tregs is indispensable. Here, we demonstrate in a murine model of inflammation-induced colorectal cancer that tumor-associated Tregs are mainly of thymic origin and equipped with a specific set of molecules strongly associated with enhanced migratory properties. Particularly, a dense infiltration of Tregs in mouse and human colorectal cancer lesions correlated with increased expression of the orphan chemoattractant receptor GPR15 on these cells. Comprehensive gene expression analysis revealed that tumor-associated GPR15 Tregs have a Th17-like phenotype, thereby producing IL17 and TNFα. Gpr15 deficiency repressed Treg infiltration in colorectal cancer, which paved the way for enhanced antitumoral CD8 T-cell immunity and reduced tumorigenesis. In conclusion, GPR15 represents a promising novel target for modifying T-cell-mediated antitumoral immunity in colorectal cancer. SIGNIFICANCE: The G protein-coupled receptor 15, an unconventional chemokine receptor, directs Tregs into the colon, thereby modifying the tumor microenvironment and promoting intestinal tumorigenesis..
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http://dx.doi.org/10.1158/0008-5472.CAN-20-2133DOI Listing
June 2021

Phase I Assessment of Safety and Therapeutic Activity of BAY1436032 in Patients with IDH1-Mutant Solid Tumors.

Clin Cancer Res 2021 May 23;27(10):2723-2733. Epub 2021 Feb 23.

Pharmaceuticals Division, Bayer HealthCare Pharmaceuticals, Inc., Whippany, New Jersey.

Purpose: BAY1436032, an inhibitor of mutant isocitrate dehydrogenase 1 (mIDH1), was active against multiple IDH1-R132X solid tumors in preclinical models. This first-in-human study was designed to determine the safety and pharmacokinetics of BAY1436032, and to evaluate its potential pharmacodynamics and antitumor effects.

Patients And Methods: The study comprised of dose escalation and dose expansion cohorts. BAY1436032 tablets were orally administered twice daily on a continuous basis in subjects with m solid tumors.

Results: In dose escalation, 29 subjects with various tumor types were administered BAY1436032 across five doses (150-1,500 mg twice daily). BAY1432032 exhibited a relatively short half-life. Most evaluable subjects experienced target inhibition as indicated by a median maximal reduction of plasma R-2-hydroxyglutarate levels of 76%. BAY1436032 was well tolerated and an MTD was not identified. A dose of 1,500 mg twice daily was selected for dose expansion, where 52 subjects were treated in cohorts representing four different tumor types [lower grade glioma (LGG), glioblastoma, intrahepatic cholangiocarcinoma, and a basket cohort of other tumor types]. The best clinical outcomes were in subjects with LGG ( = 35), with an objective response rate of 11% (one complete response and three partial responses) and stable disease in 43%. As of August 2020, four of these subjects were in treatment for >2 years and still ongoing. Objective responses were observed only in LGG.

Conclusions: BAY1436032 was well tolerated and showed evidence of target inhibition and durable objective responses in a small subset of subjects with LGG.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-4256DOI Listing
May 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 2021 Sep 2;22(5):e668-e672. 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
September 2021

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 08 5;48(9):2894-2903. 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
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8263445PMC
August 2021

Bile formation in long-term ex situ perfused livers.

Surgery 2021 04 6;169(4):894-902. Epub 2021 Jan 6.

Department of Surgery, Swiss Hepatopancreatobiliary and Transplantation Center, University Hospital Zurich, Switzerland. Electronic address:

Background: Long-term ex situ liver perfusion may rescue injured grafts. Little is known about bile flow during long-term perfusion. We report the development of a bile stimulation protocol and motivate bile flow as a viability marker during long-term ex situ liver perfusion.

Methods: Porcine and human livers were perfused with blood at close to physiologic conditions. Our perfusion protocol was established during phase 1 with porcine livers (n = 23). Taurocholic acid was applied to stimulate bile flow. The addition of piperacillin-tazobactam (tazobac) and methylprednisolone was modified from daily bolus to controlled continuous application. We adapted the protocol to human livers (n = 12) during phase 2. Taurocholic acid was replaced with medical grade ursodeoxycholic acid.

Results: Phase 2: Despite administering taurocholic acid, bile flow declined from 29.3 ± 6.5 to 9.3 ± 1.4 mL/h (P < .001). Shortly after bolus of tazobac/methylprednisolone, bile flow recovered to 39.0 ± 9.7 mL/h with a decrease of solid bile components. This implied bile salt independent bile flow stimulation by tazobac/methylprednisolone. Phase 2: Ursodeoxycholic acid was shown to stimulate bile flow ex situ in human livers. Eight livers were perfused successfully for 1 week with continuous bile flow. The other 4 livers demonstrated progressive cell death, of which only 1 exhibited bile flow.

Conclusion: A lack of bile flow stimulation leads to a decline in bile flow and is not necessarily a sign of deterioration in liver function. Proper administration of stimulators can induce constant bile flow during ex situ liver perfusion for up to 1 week. Medical grade ursodeoxycholic acid is a suitable replacement for nonmedical grade taurocholic acid. The presence of bile flow alone is not sufficient to assess liver viability.
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http://dx.doi.org/10.1016/j.surg.2020.11.042DOI Listing
April 2021

Shall we use steroids when treating patients with lung cancer with checkpoint inhibitors?

Eur J Cancer 2021 03 5;145:255-257. Epub 2021 Jan 5.

West German Cancer Center Essen, Department of Medical Oncology, University Duisburg-Essen, 45122, Essen, Germany; German Cancer Consortium (DKTK), Partner Site University Hospital Essen, 45122, Essen, Germany.

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http://dx.doi.org/10.1016/j.ejca.2020.12.013DOI Listing
March 2021

Label-free vibrational imaging of different Aβ plaque types in Alzheimer's disease reveals sequential events in plaque development.

Acta Neuropathol Commun 2020 12 11;8(1):222. Epub 2020 Dec 11.

Division of Biospectroscopy, Center for Protein Diagnostics (PRODI), Ruhr University Bochum, Bochum, Germany.

The neuropathology of Alzheimer's disease (AD) is characterized by hyperphosphorylated tau neurofibrillary tangles (NFTs) and amyloid-beta (Aβ) plaques. Aβ plaques are hypothesized to follow a development sequence starting with diffuse plaques, which evolve into more compact plaques and finally mature into the classic cored plaque type. A better molecular understanding of Aβ pathology is crucial, as the role of Aβ plaques in AD pathogenesis is under debate. Here, we studied the deposition and fibrillation of Aβ in different plaque types with label-free infrared and Raman imaging. Fourier-transform infrared (FTIR) and Raman imaging was performed on native snap-frozen brain tissue sections from AD cases and non-demented control cases. Subsequently, the scanned tissue was stained against Aβ and annotated for the different plaque types by an AD neuropathology expert. In total, 160 plaques (68 diffuse, 32 compact, and 60 classic cored plaques) were imaged with FTIR and the results of selected plaques were verified with Raman imaging. In diffuse plaques, we detect evidence of short antiparallel β-sheets, suggesting the presence of Aβ oligomers. Aβ fibrillation significantly increases alongside the proposed plaque development sequence. In classic cored plaques, we spatially resolve cores containing predominantly large parallel β-sheets, indicating Aβ fibrils. Combining label-free vibrational imaging and immunohistochemistry on brain tissue samples of AD and non-demented cases provides novel insight into the spatial distribution of the Aβ conformations in different plaque types. This way, we reconstruct the development process of Aβ plaques in human brain tissue, provide insight into Aβ fibrillation in the brain, and support the plaque development hypothesis.
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http://dx.doi.org/10.1186/s40478-020-01091-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7733282PMC
December 2020

Hyperoxia in portal vein causes enhanced vasoconstriction in arterial vascular bed.

Sci Rep 2020 12 1;10(1):20966. Epub 2020 Dec 1.

Department of Surgery, Swiss Hepato-Pancreato-Biliary and Transplantation Center, University Hospital Zurich, Zurich, Switzerland.

Long-term perfusion of liver grafts outside of the body may enable repair of poor-quality livers that are currently declined for transplantation, mitigating the global shortage of donor livers. In current ex vivo liver perfusion protocols, hyperoxic blood (arterial blood) is commonly delivered in the portal vein (PV). We perfused porcine livers for one week and investigated the effect of and mechanisms behind hyperoxia in the PV on hepatic arterial resistance. Applying PV hyperoxia in porcine livers (n = 5, arterial PV group), we observed an increased need for vasodilator Nitroprussiat (285 ± 162 ml/week) to maintain the reference hepatic artery flow of 0.25 l/min during ex vivo perfusion. With physiologic oxygenation (venous blood) in the PV the need for vasodilator could be reduced to 41 ± 34 ml/week (p = 0.011; n = 5, venous PV group). This phenomenon has not been reported previously, owing to the fact that such experiments are not feasible practically in vivo. We investigated the mechanism of the variation in HA resistance in response to blood oxygen saturation with a focus on the release of vasoactive substances, such as Endothelin 1 (ET-1) and nitric oxide (NO), at the protein and mRNA levels. However, no difference was found between groups for ET-1 and NO release. We propose direct oxygen sensing of endothelial cells and/or increased NO break down rate with hyperoxia as possible explanations for enhanced HA resistance.
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http://dx.doi.org/10.1038/s41598-020-77915-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7708838PMC
December 2020

Functional screening identifies aryl hydrocarbon receptor as suppressor of lung cancer metastasis.

Oncogenesis 2020 Nov 19;9(11):102. Epub 2020 Nov 19.

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

Lung cancer mortality largely results from metastasis. Despite curative surgery many patients with early-stage non-small cell lung cancer ultimately succumb to metastatic relapse. Current risk reduction strategies based on cytotoxic chemotherapy and radiation have only modest activity. Against this background, we functionally screened for novel metastasis modulators using a barcoded shRNA library and an orthotopic lung cancer model. We identified aryl hydrocarbon receptor (AHR), a sensor of xenobiotic chemicals and transcription factor, as suppressor of lung cancer metastasis. Knockdown of endogenous AHR induces epithelial-mesenchymal transition signatures, increases invasiveness of lung cancer cells in vitro and metastasis formation in vivo. Low intratumoral AHR expression associates with inferior outcome of patients with resected lung adenocarcinomas. Mechanistically, AHR triggers ATF4 signaling and represses matrix metalloproteinase activity, both counteracting metastatic programs. These findings link the xenobiotic defense system with control of lung cancer progression. AHR-regulated pathways are promising targets for innovative anti-metastatic strategies.
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http://dx.doi.org/10.1038/s41389-020-00286-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7677369PMC
November 2020

The quest for efficient trial designs in precision oncology.

Authors:
Martin Schuler

Lancet Oncol 2020 12 27;21(12):1539-1541. Epub 2020 Oct 27.

West German Cancer Center, Department of Medical Oncology, University Duisburg-Essen, 45122 Essen, Germany; German Cancer Consortium (DKTK); Partner Site University Hospital Essen, Essen, Germany. Electronic address:

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http://dx.doi.org/10.1016/S1470-2045(20)30553-2DOI Listing
December 2020

Reply to: Lactate measurements in an integrated perfusion machine for human livers.

Nat Biotechnol 2020 11 26;38(11):1263-1264. Epub 2020 Oct 26.

Department of Surgery and Transplantation, Swiss Hepato-Pancreato-Biliary (HPB) Center, University Hospital Zurich, Zurich, Switzerland.

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http://dx.doi.org/10.1038/s41587-020-0627-8DOI Listing
November 2020

Automated Insulin Delivery - Continuous Blood Glucose Control During Ex Situ Liver Perfusion.

IEEE Trans Biomed Eng 2021 04 18;68(4):1399-1408. Epub 2021 Mar 18.

Objective: With the growing demand for livers in the field of transplantation, interest in normothermic ex situ machine perfusion (NMP) has increased in recent years. This may open the door for novel therapeutic interventions such as repair of suboptimal grafts. For successful long-term NMP of livers, blood glucose (BG) levels need to be maintained in a close to physiological range.

Methods: We present an "automated insulin delivery" (AID) system integrated into an NMP system, which automatically adjusts insulin infusion rates based on continuous BG measurements in a closed loop manner during ex situ pig and human liver perfusion. An online glucose sensor for continuous glucose monitoring was integrated and evaluated in blood. A model based and a proportional controller were implemented and compared in their ability to maintain BG within the physiological range.

Results: The continuous glucose sensor is capable of measuring BG directly in human and pig blood for multiple days with an average error of 0.6 mmol/L. There was no significant difference in the performance of the two controllers in terms of their ability to keep BG in the physiological range. With the integrated AID, BG was controlled within the physiological range on average in 80% and 76% of the perfusion time for human and pig livers, respectively.

Conclusion: The presented work offers a method and shows the feasibility to maintain BG in the physiological range for multiple (up to ten) days during ex situ liver perfusion with the help of an automated AID.

Significance: Maintaining BG within the physiological range is required to enable long-term ex situ liver perfusion.
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http://dx.doi.org/10.1109/TBME.2020.3033663DOI Listing
April 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
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