Publications by authors named "Hans-Ulrich Schildhaus"

125 Publications

Clinical and molecular characteristics associated with response to therapeutic PD-1/PD-L1 inhibition in advanced Merkel cell carcinoma.

J Immunother Cancer 2022 Jan;10(1)

Translational Skin Cancer Research, Deutsches Konsortium für Translationale Krebsforschung, Essen, Germany

Background: Based on its viral-associated or UV-associated carcinogenesis, Merkel cell carcinoma (MCC) is a highly immunogenic skin cancer. Thus, clinically evident MCC occurs either in immuno-compromised patients or based on tumor-intrinsic immune escape mechanisms. This notion may explain that although advanced MCC can be effectively restrained by treatment with PD-1/PD-L1 immune checkpoint inhibitors (ICIs), a considerable percentage of patients does not benefit from ICI therapy. Biomarkers predicting ICI treatment response are currently not available.

Methods: The present multicenter retrospective study investigated clinical and molecular characteristics in 114 patients with unresectable MCC at baseline before treatment with ICI for their association with therapy response (best overall response, BOR). In a subset of 21 patients, pretreatment tumor tissue was analyzed for activation, differentiation and spatial distribution of tumor infiltrating lymphocytes (TIL).

Results: Of the 114 patients, n=74 (65%) achieved disease control (BOR=complete response/partial response/stable disease) on ICI. A Bayesian cumulative ordinal regression model revealed absence of immunosuppression and a limited number of tumor-involved organ systems was highly associated with a favorable therapy response. Unimpaired overall performance status, high age, normal serum lactate dehydrogenase and normal serum C reactive protein were moderately associated with disease control. While neither tumor Merkel cell polyomavirus nor tumor PD-L1 status showed a correlation with therapy response, treatment with anti-PD-1 antibodies was associated with a higher probability of disease control than treatment with anti-PD-L1 antibodies. Multiplexed immunohistochemistry demonstrated the predominance of CD8 effector and central memory T cells (T) in close proximity to tumor cells in patients with a favorable therapy response.

Conclusions: Our findings indicate the absence of immunosuppression, a limited number of tumor-affected organs, and a predominance of CD8 T among TIL, as baseline parameters associated with a favorable response to PD-1/PD-L1 ICI therapy of advanced MCC. These factors should be considered when making treatment decisions in MCC patients.
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http://dx.doi.org/10.1136/jitc-2021-003198DOI Listing
January 2022

Combined multimodal ctDNA analysis and radiological imaging for tumor surveillance in Non-small cell lung cancer.

Transl Oncol 2022 Jan 17;15(1):101279. Epub 2021 Nov 17.

German Cancer Consortium (DKTK), Partner site University Hospital Essen, Hufelandstrasse 55, Essen 45122, Germany; Institute for Developmental Cancer Therapeutics, West German Cancer Center, University Hospital Essen, Essen 45122, Germany; Division of Solid Tumor Translational Oncology, German Cancer Consortium (DKTK, partner site Essen) and German Cancer Research Center, DKFZ, Heidelberg, Germany. Electronic address:

Background: Radiology is the current standard for monitoring treatment responses in lung cancer. Limited sensitivity, exposure to ionizing radiations and related sequelae constitute some of its major limitation. Non-invasive and highly sensitive methods for early detection of treatment failures and resistance-associated disease progression would have additional clinical utility.

Methods: We analyzed serially collected plasma and paired tumor samples from lung cancer patients (61 with stage IV, 48 with stages I-III disease) and 61 healthy samples by means of next-generation sequencing, radiological imaging and droplet digital polymerase chain reaction (ddPCR) mutation and methylation assays.

Results: A 62% variant concordance between tumor-reported and circulating-free DNA (cfDNA) sequencing was observed between baseline liquid and tissue biopsies in stage IV patients. Interestingly, ctDNA sequencing allowed for the identification of resistance-mediating p.T790M mutations in baseline plasma samples for which no such mutation was observed in the corresponding tissue. Serial circulating tumor DNA (ctDNA) mutation analysis by means of ddPCR revealed a general decrease in ctDNA loads between baseline and first reassessment. Additionally, serial ctDNA analyses only recapitulated computed tomography (CT) -monitored tumor dynamics of some, but not all lesions within the same patient. To complement ctDNA variant analysis we devised a ctDNA methylation assay (cfDNA) based on methylation-sensitive restriction enzymes. cfDNA methylation showed and area under the curve (AUC) of > 0.90 in early and late stage cases. A decrease in cfDNA between baseline and first reassessment was reflected by a decrease in CT-derive tumor surface area, irrespective of tumor mutational status.

Conclusion: Taken together, our data support the use of cfDNA sequencing for unbiased characterization of the molecular tumor architecture, highlights the impact of tumor architectural heterogeneity on ctDNA-based tumor surveillance and the added value of complementary approaches such as cfDNA methylation for early detection and monitoring.
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http://dx.doi.org/10.1016/j.tranon.2021.101279DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8605355PMC
January 2022

HER2 mediates clinical resistance to the KRAS inhibitor sotorasib, which is overcome by co-targeting SHP2.

Eur J Cancer 2021 12 26;159:16-23. Epub 2021 Oct 26.

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

Introduction: Mutant RAS guanosine triphosphate hydrolases (GTPases) are key oncogenic drivers in many cancers. The KRAS variant has recently become targetable by a new drug class specifically locking KRAS in its inactive guanosine diphosphate (GDP)-bound state. Clinical activity was demonstrated in patients with advanced lung cancers harbouring KRAS mutations but was limited by the development of resistance.

Methods: A biopsy from progressing lung cancer of a patient treated with the KRAS inhibitor sotorasib was obtained, and the underlying resistance factors were analysed. Mechanistic studies were performed in vitro and in vivo to uncover strategies to overcome resistance to KRAS inhibition.

Results: We demonstrated acquisition of HER2 copy number gain and KRAS mutation retention in the post-progression biopsy. To explore HER2 gain as the relevant resistance mechanism, we generated KRAS lung cancer models overexpressing HER2. MAPK pathway signalling remained active despite KRAS inhibitor treatment. Combined pharmacological inhibition of KRAS and SHP2 synergistically overcame HER2-mediated resistance in vitro and in vivo.

Conclusions: These findings establish HER2 copy number gain as a clinically relevant mechanism of resistance to pharmacological KRAS inhibition that can be overcome by co-targeting SHP2.
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http://dx.doi.org/10.1016/j.ejca.2021.10.003DOI Listing
December 2021

Polyclonal on- and off-target resistance mutations in an positive non-small cell lung cancer patient under ALK inhibition.

Oncotarget 2021 Sep 14;12(19):1946-1952. Epub 2021 Sep 14.

Department of Medicine A, Hematology, Oncology, and Pneumology, University Hospital Muenster, 48149 Muenster, Germany.

Treatment of advanced stage () positive non-small cell lung cancer (NSCLC) with ALK tyrosine kinase inhibitors (TKIs) has been shown to be superior to standard platinum-based chemotherapy. However, secondary progress of disease frequently occurs under ALK inhibitor treatment. The clinical impact of re-biopsies for treatment decisions beyond secondary progress is, however, still under debate. Here, we report on two novel subsequent polyclonal on- and off-target resistance mutations in a patient with -fused NSCLC under ALK inhibitor treatment. A 63-year-old male patient with an advanced stage fused pulmonary adenocarcinoma was initially successfully treated with the second-generation ALK inhibitor alectinib and upon progressions subsequently with brigatinib, lorlatinib and chemoimmunotherapy (CIT). Progress to alectinib was associated with a so far undescribed mutation (p.A1200_G1201delinsW) which was, however, tractable by brigatinib. An off-target -mutation (p.Q61K) occurred in association with subsequent progression under second-line TKI treatment. Third-line lorlatinib showed limited efficacy but chemoimmunotherapy resulted in disappearance of the mutant clone and clinical tumor control for another eight months. In conclusion, we suggest molecular profiling of progressive tumor disease also for -positive NSCLC to personalize treatment in a subgroup of -positive patients.
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http://dx.doi.org/10.18632/oncotarget.28062DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8448518PMC
September 2021

Localized Angiosarcoma, Not One Disease: A Retrospective Single-Center Study on Prognosis Depending on the Primary Site and Etiology.

Sarcoma 2021 10;2021:9960085. Epub 2021 Sep 10.

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

Background: Angiosarcomas are rare and heterogeneous tumors with poor prognosis. The clinical subtypes are classified depending on the primary site and etiology.

Methods: We conducted a retrospective, monocentric study of 136 patients with localized AS between May 1985 and November 2018. Overall survival (OS), local recurrence-free survival (LRFS), and metastasis-free survival (MFS) were estimated using the Kaplan-Meier method. To identify prognostic factors, univariate and multivariate analyses were performed based on Cox regressions.

Results: The median age was 67 years (19-72.8 years). Primary sites were cutaneous (27.2%), breast (38.2%), and deep soft tissue (34.6%). The majority was primary angiosarcomas (55.9%) followed by postradiation (40.4%) and chronic lymphedema angiosarcomas (2.9%). Prognosis significantly differed depending on the primary site and etiology. Shortest median OS and MFS were observed in deep soft tissue angiosarcomas, whereas cutaneous angiosarcomas, angiosarcomas of the breast, and radiation-associated angiosarcomas displayed worse median LRFS. Univariate analyses showed better OS for tumor size <10 cm ( = 0.009), negative surgical margins ( = 0.021), and negative lymph node status ( = 0.007). LRFS and MFS were longer for tumor size <10 cm ( = 0.012 and  = 0.013). In multivariate analyses, age <70 years was the only independent positive prognostic factor for OS in all subgroups. For LRFS, secondary AS of the breast was a negative prognostic factor (HR: 2.35;  = 0.035).

Conclusions: Different behaviors and prognoses depending on the primary site and etiology should be considered for the treatment of this heterogeneous disease. In cutaneous angiosarcomas of the head/neck and postradiation angiosarcomas of the breast, local recurrence seems to have a crucial impact on OS. Therefore, improved local therapies and local tumor staging may have to be implemented. However, in deep soft tissue angiosarcomas, distant recurrence seems to have a major influence on prognosis, which indicates a benefit of additional perioperative chemotherapy.
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http://dx.doi.org/10.1155/2021/9960085DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8449723PMC
September 2021

MSI testing : What's new? What should be considered?

Pathologe 2021 Nov 3;42(Suppl 1):110-118. Epub 2021 Sep 3.

Institute of Pathology, University Hospital Cologne, Kerpener Str. 62, 50937, Köln, Germany.

Based on new trial data regarding immune checkpoint inhibitors (ICIs), the detection of high-grade microsatellite instability (MSI-H) or underlying deficient mismatch repair protein (dMMR) is now becoming increasingly important for predicting treatment response. For the first time, a PD‑1 ICI (pembrolizumab) has been approved by the European Medicines Agency (EMA) for first-line treatment of advanced (stage IV) dMMR/MSI‑H colorectal cancer (CRC). Further indications, such as dMMR/MSI‑H endometrial carcinoma (EC), have already succeeded (Dostarlimab, 2nd line treatment) and others are expected to follow before the end of 2021. The question of optimal testing in routine diagnostics should therefore be re-evaluated. Based on a consideration of the strengths and weaknesses of the widely available methods (immunohistochemistry and PCR), a test algorithm is proposed that allows quality assured, reliable, and cost-effective dMMR/MSI‑H testing. For CRC and EC, testing is therefore already possible at the primary diagnosis stage, in line with international recommendations (NICE, NCCN). The clinician is therefore enabled from the outset to consider not only the predictive but also the prognostic and predispositional implications of such a test when counseling patients and formulating treatment recommendations. As a basis for quality assurance, participation in interlaboratory comparisons and continuous documentation of results (e.g., QuIP Monitor) are strongly recommended.
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http://dx.doi.org/10.1007/s00292-021-00948-3DOI Listing
November 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

Frequency of actionable molecular drivers in lung cancer patients with precocious brain metastases.

Clin Neurol Neurosurg 2021 Sep 24;208:106841. Epub 2021 Jul 24.

Department of Neuropathology, Otto-von-Guericke University Magdeburg, Germany. Electronic address:

Brain metastases frequently occur during the course of disease in patients suffering from lung cancer. Occasionally, neurological symptoms caused by brain metastases (BM) might represent the first sign of systemic tumor disease (so called precocious metastases), leading to the detection of the primary lung tumor. The biological basis of precocious BM is largely unknown, and treatment options are not well established for this subgroup of patients. Therefore, we retrospectively analyzed 33 patients (24 non-small cell lung cancer (NSCLC)), 9 small cell lung cancer (SCLC)) presenting with precocious BM focusing on molecular alterations potentially relevant for the tumor's biology and treatment. We found five FGFR1 amplifications (4 adenocarcinoma, 1 SCLC) among 31 analyzed patients (16.1%), eight MET amplifications among 30 analyzed tumors (7 NSCLC, 1 SCLC; 26.7%), three EGFR mutations within 33 patients (all adenocarcinomas, 9.1%), and five KRAS mutations among 32 patients (all adenocarcinomas; 15.6%). No ALK, ROS1 or RET gene rearrangements were detected. Our findings suggest that patients with precocious BM of lung cancer harbor EGFR mutations, MET amplifications or FGFR1 amplifications as potential targeted treatment options.
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http://dx.doi.org/10.1016/j.clineuro.2021.106841DOI Listing
September 2021

An unusual lymphoid lesion mimicking meningioma.

Brain Pathol 2021 09 13;31(5):e12995. Epub 2021 Jul 13.

Department of Neurosurgery, University Medical Center Göttingen, Göttingen, Germany.

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http://dx.doi.org/10.1111/bpa.12995DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8412078PMC
September 2021

Context-dependent modulation of aggressiveness of pediatric tumors by individual oncogenic RAS isoforms.

Oncogene 2021 08 25;40(31):4955-4966. Epub 2021 Jun 25.

Department of Human Genetics, University Medical Center Goettingen, Goettingen, Germany.

A prototypic pediatric cancer that frequently shows activation of RAS signaling is embryonal rhabdomyosarcoma (ERMS). ERMS also show aberrant Hedgehog (HH)/GLI signaling activity and can be driven by germline mutations in this pathway. We show, that in ERMS cell lines derived from sporadic tumors i.e. from tumors not caused by an inherited genetic variant, HH/GLI signaling plays a subordinate role, because oncogenic mutations in HRAS, KRAS, or NRAS (collectively named oncRAS) inhibit the main HH target GLI1 via the MEK/ERK-axis, but simultaneously increase proliferation and tumorigenicity. oncRAS also modulate expression of stem cell markers in an isoform- and context-dependent manner. In Hh-driven murine ERMS that are caused by a Patched mutation, oncHRAS and mainly oncKRAS accelerate tumor development, whereas oncNRAS induces a more differentiated phenotype. These features occur when the oncRAS mutations are induced at the ERMS precursor stage, but not when induced in already established tumors. Moreover, in contrast to what is seen in human cell lines, oncRAS mutations do not alter Hh signaling activity and marginally affect expression of stem cell markers. Together, all three oncRAS mutations seem to be advantageous for ERMS cell lines despite inhibition of HH signaling and isoform-specific modulation of stem cell markers. In contrast, oncRAS mutations do not inhibit Hh-signaling in Hh-driven ERMS. In this model, oncRAS mutations seem to be advantageous for specific ERMS populations that occur within a specific time window during ERMS development. In addition, this window may be different for individual oncRAS isoforms, at least in the mouse.
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http://dx.doi.org/10.1038/s41388-021-01904-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8342309PMC
August 2021

[MSI testing : What is new? What should be considered? German version].

Pathologe 2021 Jul 27;42(4):414-423. Epub 2021 May 27.

Institut für Pathologie, Universitätsklinikum Köln, Kerpener Str. 62, 50937, Köln, Deutschland.

Based on new trial data regarding immune checkpoint inhibitors (ICIs), the detection of high-grade microsatellite instability (MSI-H) or underlying deficient mismatch repair protein (dMMR) is now becoming increasingly important for predicting treatment response. For the first time, a PD‑1 ICI (pembrolizumab) has been approved by the European Medicines Agency (EMA) for first-line treatment of advanced (stage IV) dMMR/MSI‑H colorectal cancer (CRC). Further indications, such as dMMR/MSI‑H endometrial carcinoma (EC), have already succeeded (Dostarlimab, 2nd line treatment) and others are expected to follow before the end of 2021. The question of optimal testing in routine diagnostics should therefore be re-evaluated. Based on a consideration of the strengths and weaknesses of the widely available methods (immunohistochemistry and PCR), a test algorithm is proposed that allows quality assured, reliable, and cost-effective dMMR/MSI‑H testing. For CRC and EC, testing is therefore already possible at the primary diagnosis stage, in line with international recommendations (NICE, NCCN). The clinician is therefore enabled from the outset to consider not only the predictive but also the prognostic and predispositional implications of such a test when counseling patients and formulating treatment recommendations. As a basis for quality assurance, participation in interlaboratory comparisons and continuous documentation of results (e.g., QuIP Monitor) are strongly recommended.
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http://dx.doi.org/10.1007/s00292-021-00944-7DOI Listing
July 2021

Tropomyosin receptor kinases in sarcomas - of joy and despair.

Curr Opin Oncol 2021 07;33(4):336-344

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

Purpose Of Review: The relatively recent discovery of neurotrophic tropomyosin receptor kinase (NTRK) gene arrangements as pan-tumor predictive biomarkers has led to impressive novel treatments for patients with TRK fusions. Although the number of patients who qualify for treatment is vanishingly small for cancer patients in general, a few histological subsets of sarcomas exhibit NTRK fusions more commonly leading to large expectations within the sarcoma community.

Recent Findings: Larotrectenib and entrectenib have recently been approved based on durable responses in TRK positive cancers with nonresectable or metastatic disease, including many sarcomas. Identification of resistance mutations to TRKi has led to the development of novel salvage therapies which may soon further expand the armamentarium of treatments. The greatest barrier and frustration to date is the actual identification of patients who harbor the fusion. The dimension of rarity in sarcomas remains difficult to comprehend for both patients and caregivers. Diagnosis of NTRK fusions is complex, particularly in the context of sarcomas and can involve immunohistochemistry as a screening tool but frequently requires fluorescence-in-situ hybridization or next-generation sequencing (NGS) to confirm the diagnosis.

Summary: The growing evidence on subtype-specific incidence of NTRK fusions will help to improve strategic prioritization or exclusion of subtypes to reduce the burden of negative testing. Next-generation inhibitors provide potential salvage treatment options for patients failing first-line therapy.
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http://dx.doi.org/10.1097/CCO.0000000000000752DOI Listing
July 2021

[Predictive diagnostics for checkpoint inhibitors].

Pathologe 2021 Jul 6;42(4):380-390. Epub 2021 May 6.

Institut für Pathologie, Technische Universität München, München, Deutschland.

Checkpoint inhibitors have revolutionized oncological treatment in many cancers and added a new immuno-oncological treatment pillar to the medicinal arsenal of conventional and molecularly targeted therapies. In monotherapy and in combination therapies, however, not all patients respond equally well, even in generally responsive tumor entities. Therefore, since the introduction of these therapies, a major focus has been the research on and implementation of predictive markers for patient selection. The first established biomarker, the expression of the target molecule PD-L1, has found its way into routine diagnostics in a large number of unfortunately very divergent diagnostic constellations in multiple entities. In addition, some molecular predictors, including the measurement of microsatellite instability and tumor mutational burden, have also been suggested and in some cases are already implemented into routine diagnostics. Additional molecular parameters have been proposed but most of them have not yet found their way into routine patient care. This review article discusses the current status and recent developments in the field of diagnostic response predictors in the context of an immune checkpoint blockade.
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http://dx.doi.org/10.1007/s00292-021-00939-4DOI Listing
July 2021

Ga-FAPI as a Diagnostic Tool in Sarcoma: Data from the Ga-FAPI PET Prospective Observational Trial.

J Nucl Med 2022 Jan 30;63(1):89-95. Epub 2021 Apr 30.

German Cancer Consortium, Partner Site University Hospital Essen, and German Cancer Research Center, Essen, Germany.

Bone and soft-tissue sarcomas express fibroblast activation protein (FAP) on tumor cells and associated fibroblasts. Therefore, FAP is a promising therapeutic and diagnostic target. Novel radiolabeled FAP inhibitors (e.g., Ga-FAPI-46) have shown high tumor uptake on PET in sarcoma patients. Here, we report the endpoints of the Ga-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 Ga-FAPI PET observational trial. Of these patients, 43 also underwent F-FDG PET. The primary study endpoint was the association between Ga-FAPI PET uptake intensity and histopathologic FAP expression analyzed with Spearman correlation. Secondary endpoints were detection rate, positive predictive value (PPV), interreader reproducibility, and change in management. Datasets were interpreted by 2 masked readers. The primary endpoint was met, and the association between Ga-FAPI PET uptake intensity and histopathologic FAP expression was significant (Spearman  = 0.43;  = 0.03). By histopathologic 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 Ga-FAPI and F-FDG PET was 76.6% and 81.4%, respectively. In 8 (18.6%) patients, Ga-FAPI PET resulted in an upstaging compared with F-FDG PET. Ga-FAPI PET readers showed substantial to almost perfect agreement for the defined regions (Fleiss κ: 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 Ga-FAPI PET. We confirm an association between tumoral Ga-FAPI PET uptake intensity and histopathologic FAP expression in sarcoma patients. Further, with masked readings and independent histopathologic validation, Ga-FAPI PET had a high PPV and sensitivity for sarcoma staging.
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http://dx.doi.org/10.2967/jnumed.121.262096DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8717183PMC
January 2022

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

Number of metastases and their response to chemotherapy impact survival of patients with isolated lung metastases from bone-derived sarcoma.

BMC Cancer 2021 Apr 7;21(1):375. Epub 2021 Apr 7.

Department of Thoracic Surgery, Ruhrlandklinik, University of Duisburg-Essen, Ruhrlandklinik, Tüschener Weg 40, 45239, Essen, Germany.

Background: Pulmonary metastasectomy (PM) is an established treatment for selected patients with metastatic sarcomas. The aim of this study was to examine our institutional experience and evaluate factors predicting outcome.

Methods: We retrospectively reviewed all patients undergoing PM for bone sarcoma in our center from 2001 to 2019. Survival was calculated from the date of PM. Impact on survival of clinical parameters was assessed.

Results: Thirty-eight patients (27 males, 71%) were included. Histology was osteosarcoma (n = 20, 53%), Ewing sarcoma (n = 13, 34%) and chondrosarcoma (n = 5, 13%). Twelve patients (31.5%) had synchronous metastases, all received chemotherapy before PM. Median number of metastases was 3 (1 to 29). Twenty (53%) patients had mediastinal lymph node sampling. One patient had positive lymph nodes. Ninety-day mortality was 0%. Three and 5-year PFS were 24.5 and 21%, respectively. Three and 5-year OS were 64.5 and 38.5%, respectively. More than three metastases and progression under chemotherapy were significant independent predictors for OS.

Conclusion: PM is a safe procedure and encouraging long-term outcome can be achieved. Patients with progression of pulmonary metastases under chemotherapy as well as patients with more than three metastases had significantly worse OS.
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http://dx.doi.org/10.1186/s12885-021-08073-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8028220PMC
April 2021

Tumor DNA methylation profiles correlate with response to anti-PD-1 immune checkpoint inhibitor monotherapy in sarcoma patients.

J Immunother Cancer 2021 03;9(3)

Division of Oncology, Department of Medicine I, Medical University of Vienna, Vienna, Austria.

Background: Some sarcomas respond to immune checkpoint inhibition, but predictive biomarkers are unknown. We analyzed tumor DNA methylation profiles in relation to immunological parameters and response to anti-programmed cell death 1 (anti-PD-1) immune checkpoint inhibitor (ICI) therapy in patients with sarcoma.

Patients And Methods: We retrospectively identified adult patients who had received anti-PD-1 ICI therapy for recurrent sarcoma in two independent centers. We performed (1) blinded radiological response evaluation according to immune response evaluation criteria in solid tumors (iRECIST) ; (2) tumor DNA methylation profiling of >850,000 probes using Infinium MethylationEPIC microarrays; (3) analysis of tumor-infiltrating immune cell subsets (CD3, CD8, CD45RO, FOXP3) and intratumoral expression of immune checkpoint molecules (PD-L1, PD-1, LAG-3) using immunohistochemistry; and (4) evaluation of blood-based systemic inflammation scores (neutrophil-to-lymphocyte ratio, leucocyte-to-lymphocyte ratio, monocyte-to-lymphocyte ratio, platelet-to-lymphocyte ratio). Response to anti-PD-1 ICI therapy was bioinformatically and statistically correlated with DNA methylation profiles and immunological data.

Results: 35 patients (median age of 50 (23-81) years; 18 females, 17 males; 27 soft tissue sarcomas; 8 osteosarcomas) were included in this study. The objective response rate to anti-PD-1 ICI therapy was 22.9% with complete responses in 3 out of 35 and partial responses in 5 out of 35 patients. Adjustment of DNA methylation data for tumor-infiltrating immune cells resulted in identification of methylation differences between responders and non-responders to anti-PD-1 ICI. 2453 differentially methylated CpG sites (DMPs; 2043 with decreased and 410 with increased methylation) were identified. Clustering of sarcoma samples based on these DMPs revealed two main clusters: methylation cluster 1 (MC1) consisted of 73% responders and methylation cluster 2 (MC2) contained only non-responders to anti-PD-1 ICI. Median progression-free survival from anti-PD-1 therapy start of MC1 and MC2 patients was 16.5 and 1.9 months, respectively (p=0.001). Median overall survival of these patients was 34.4 and 8.0 months, respectively (p=0.029). The most prominent DNA methylation differences were found in pathways implicated in Rap1 signaling, focal adhesion, adherens junction Phosphoinositide 3-kinase (PI3K)-Akt signaling and extracellular matrix (ECM)-receptor interaction.

Conclusions: Our data demonstrate that tumor DNA methylation profiles may serve as a predictive marker for response to anti-PD-1 ICI therapy in sarcoma.
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http://dx.doi.org/10.1136/jitc-2020-001458DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7993298PMC
March 2021

Surgical Treatment for Primary Chest Wall Sarcoma: A Single-Institution Study.

J Surg Res 2021 04 16;260:149-154. Epub 2020 Dec 16.

Department of Thoracic Surgery, Ruhrlandklinik, University of Duisburg-Essen, Essen, Germany; German Cancer Consortium (DKTK), Center Essen, Essen, Germany. Electronic address:

Background: Primary sarcomas of the chest wall are rare aggressive tumors. Surgery is part of the multimodal treatment. We describe our institutional patient cohort and evaluate prognostic factors.

Methods: All patients who had curative intent surgery for primary chest wall sarcoma from 2004 to 2019 were retrospectively reviewed. Impact on survival-calculated from the date of surgery until last follow-up- was assessed for the following variables: age, gender, type of resection, size, grading, stage, completeness of resection, and neoadjuvant and adjuvant therapy.

Results: Twenty-three patients (15 males, 65%) with a median age of 54 y (4 to 82) were included. Most common histology was chondrosarcoma (n = 5, 22%). Seven patients (30%) received neoadjuvant and 13 patients (57%) received adjuvant treatment. R0 resection was achieved in 83%. Extended chest wall resection was performed in 14 patients (61%), including lung (n = 13, 57%), diaphragm (n = 2, 9%) and pericardium (n = 1, 4%). Morbidity and 90-day mortality were 23% and 0%, respectively. Three- and 5-year overall survival was 53% and 35%, respectively. R0 resection was predictor of overall survival (P = 0.029). Tumor grade and extended resections were predictors for recurrence (P = 0.034 and P = 0.018, respectively).

Conclusions: Surgical resection of primary chest wall sarcoma is a safe procedure even when extended resection is required.
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http://dx.doi.org/10.1016/j.jss.2020.11.078DOI Listing
April 2021

[In situ hybridization in molecular pathological diagnostics].

Pathologe 2020 11;41(6):561-562

Institut für Pathologie, Universitätsklinikum Essen, Hufelandstraße 55, 45147, Essen, Deutschland.

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http://dx.doi.org/10.1007/s00292-020-00846-0DOI Listing
November 2020

KRAS mutation status concordance between the primary tumor and the corresponding metastasis in patients with rectal cancer.

PLoS One 2020 1;15(10):e0239806. Epub 2020 Oct 1.

Department of General, Visceral and Pediatric Surgery, University Medical Center Goettingen, Goettingen, Germany.

Introduction: Oncogenic mutation within the KRAS gene represents a negative predictor for treatment response to anti-epidermal growth factor receptor (EGFR) in patients with colorectal cancer. Recently, we have shown no relevant heterogeneity for KRAS mutation status within and between pre- and posttherapeutic samples from the primary tumor in patients with locally advanced rectal cancer. The aim of this study was to evaluate the intertumoral heterogeneity of KRAS mutation status between the primary tumor and the corresponding metastasis or local recurrence in the similar cohort and to evaluate the ideal representative tissue for KRAS mutation testing.

Materials And Methods: KRAS mutation status was analyzed from 47 patients with locally advanced rectal cancer, which were enrolled in the CAO/ARO/AIO-94 or CAO/ARO/AIO-04 trial. Mutations in KRAS codons 12, 13, and 61 were analyzed by using the KRAS RGQ PCR Kit (therascreen® KRAS test). Six patients needed to be excluded due to incomplete follow up data. 11 patients showed a relapse of the disease during the follow up presented by distant metastases or local recurrence. DNA from representative areas of metastatic tissue was obtained from formalin-fixed paraffin-embedded specimens.

Results: The mean patient age was 64.13 ± 10.64 years. In total, 19 patients showed a KRAS mutation (46.34%) in the primary tumor. Of the eleven patients with a metastatic disease or local recurrence, five patients showed a KRAS mutation whereas six patients had a KRAS wildtype status. Metastatic localizations included the liver (n = 2), lung (n = 4), local recurrence (n = 1), liver + lung (n = 3), lung + local recurrence (n = 1). For these eleven patients with paired data available for the primary tumor and metastatic tissue, a significant KRAS mutation status concordance was detected in 81.18% (9/11) of the patients (p = 0.03271). Only two patients showed intertumoral heterogeneity, which harbored in one patient a KRAS G12C mutation status in the primary tumor, but a G12V KRAS mutation status in the corresponding lung lesion, and in the other patient a G12A mutation in the primary lesion and a WT in the lung metastasis.

Conclusions: We show a significant concordance of the KRAS mutation status between tumor samples obtained from the primary tumor and the corresponding metastasis and/ or local recurrence in patients with rectal cancer indicating no relevant intertumoral heterogeneity. Our data suggest that sampling either the primary (pre- or posttherapeutical tumor tissue) or metastatic lesion may be valid for the initial evaluation of KRAS mutation status predicting the response to anti-EGFR treatment and guiding clinical decisions.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0239806PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7529221PMC
November 2020

Resistance to Avapritinib in PDGFRA-Driven GIST Is Caused by Secondary Mutations in the PDGFRA Kinase Domain.

Cancer Discov 2021 01 24;11(1):108-125. Epub 2020 Sep 24.

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

Gastrointestinal stromal tumors (GIST) harboring activating mutations of respond to imatinib, with the notable exception of the most common mutation, D842V. Avapritinib is a novel, potent KIT/PDGFRA inhibitor with substantial clinical activity in patients with the D842V genotype. To date, only a minority of -mutant patients treated with avapritinib have developed secondary resistance. Tumor and plasma biopsies in 6 of 7 patients with primary mutations who progressed on avapritinib or imatinib had secondary resistance mutations within exons 13, 14, and 15 that interfere with avapritinib binding. Secondary mutations causing V658A, N659K, Y676C, and G680R substitutions were found in 2 or more patients each, representing recurrent mechanisms of PDGFRA GIST drug resistance. Notably, most PDGFRA-mutant GISTs refractory to avapritinib remain dependent on the PDGFRA oncogenic signal. Inhibitors that target PDGFRA protein stability or inhibition of PDGFRA-dependent signaling pathways may overcome avapritinib resistance. SIGNIFICANCE: Here, we provide the first description of avapritinib resistance mechanisms in PDGFRA-mutant GIST..
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http://dx.doi.org/10.1158/2159-8290.CD-20-0487DOI Listing
January 2021

[Fluorescence in situ hybridization for the diagnosis of soft-tissue and bone tumors].

Pathologe 2020 Nov;41(6):589-605

Institut für Pathologie, Universitätsklinikum Essen, Hufelandstraße 55, 45147, Essen, Deutschland.

Mesenchymal tumors, especially high-grade sarcomas, frequently harbor chaotic genotypes. Few tumors arise in association with genetic tumor predisposition syndromes with germline mutations in tumor suppressor genes. An increasing number of soft-tissue and bone tumors are characterized by recurrent genomic alterations, which can be utilized for diagnostic purposes. These include translocations and amplifications and less frequently deletions. These alterations can be detected by fluorescence in situ hybridization among other techniques. The rising number of whole genome sequencing of soft-tissue and bone tumors leads to an improved understanding of tumor genetics. On this basis, fluorescence in situ hybridization has gained relevance as a diagnostic tool. This review covers relevant genetic alterations in lipomatous tumors, soft-tissue tumors with spindle-cell and epithelioid morphology, vascular tumors, small-blue-round-cell tumors, and bone tumors that are detectable by fluorescence in situ hybridization.
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http://dx.doi.org/10.1007/s00292-020-00838-0DOI 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

A noninterventional, multinational study to assess PD-L1 expression in cytological and histological lung cancer specimens.

Cancer Cytopathol 2020 12 28;128(12):928-938. Epub 2020 Jul 28.

Department of Pathology, University of Aberdeen, Aberdeen, United Kingdom.

Background: The diagnosis of advanced lung cancer is made with minimally invasive procedures. This often results in the availability of cytological material only for subtype determination and companion diagnostic testing, with the latter being technically and clinically validated on histological material only. Thus, the primary objective of the MO29978 clinical study was to assess programmed death ligand 1 (PD-L1) protein expression on cytology samples as surrogates for histology samples in patients with lung cancer.

Methods: Formalin-fixed, paraffin-embedded histological samples and cytological cell blocks from 190 patients were analyzed with immunohistochemical assays using the rabbit monoclonal anti-PD-L1 antibody clones SP142 and SP263. PD-L1 expression was quantified on both tumor cells (TC) and tumor-infiltrating immune cells (IC). Overall concordance, sensitivity, specificity, and accuracy, with a 1% cutoff used for both assays, were assessed for PD-L1 expression on TC and IC.

Results: In non-small cell lung cancer histology and cytology samples measured with the PD-L1 (SP142) antibody (n = 173), the intraclass correlation coefficients were 0.40 and 0.06 on TC and IC, respectively. With SP142 and SP263, accuracies of 74.1% for TC and 51.9% for IC and accuracies of 75.2% for TC and 61.2% for IC, respectively, were reported.

Conclusions: Overall, this study has demonstrated that PD-L1 analysis on TC is feasible in cytological material, but quantification is challenging. Tumor tissue should be preferred over cell block cytology for PD-L1 immunohistochemical analysis unless laboratories have validated their cytology preanalytical approaches and demonstrated the comparability of histology and cytology for TC PD-L1 results.
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http://dx.doi.org/10.1002/cncy.22324DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7754298PMC
December 2020

Bone metastasis of retinoblastoma five years after primary treatment.

Am J Ophthalmol Case Rep 2020 Sep 17;19:100834. Epub 2020 Jul 17.

Institute of Pathology, University Hospital Essen, University of Duisburg, Essen, Germany.

Purpose: Histopathological, immunohistochemistry- and molecular pathology-based diagnostics to distinguish metastasis of retinoblastoma from subsequent primary malignancy in patients with heritable retinoblastoma.

Observations: An eight year-old girl presented with tibial pain and bone lesion five years after multimodal treatment of bilateral retinoblastoma, initially clinically suspicious of osteomyelitis. Histopathological examination of bone biopsy specimen revealed a highly proliferative small blue round cell tumor mimicking Ewing's sarcoma of bone. Immunohistochemistry confirmed the diagnosis of a distant metastasis of the previous retinoblastoma. Other subsequent primary malignancies presenting as small blue round cell tumors, such as sarcomas or leukemia, were excluded by immunohistochemistry and molecular methods.

Conclusions And Importance: In countries with early diagnosis of retinoblastoma, distant metastases of retinoblastoma are extremely rare, whereas subsequent primary malignancies are common in survivors of heritable retinoblastoma. Immunohistochemistry and molecular pathology are essential components of diagnostic pathway. In retinoblastoma patients, distant metastases including osseous lesions should be included in the differential diagnosis of small blue round cell tumors.
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http://dx.doi.org/10.1016/j.ajoc.2020.100834DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7374179PMC
September 2020

Top-level gene copy number gain defines a subtype of poorly differentiated pulmonary adenocarcinomas with poor prognosis.

Transl Lung Cancer Res 2020 Jun;9(3):603-616

Institute of Pathology, University Medical Center Göttingen, Göttingen, Germany.

Background: amplifications occur in human tumors, including non-small cell lung cancer (NSCLC). MET inhibitors have demonstrated some clinical activity in amplified NSCLC, presumably with a gene dose effect. However, the definition of MET positivity or amplification as a potential oncogenic driver is still under debate. In this study, we aimed to establish the molecular subgroup of NSCLC with the highest unequivocal MET amplification level and to describe the prevalence, and histologic and clinical phenotype of this subgroup.

Methods: A total of 373 unselected patients with NSCLC were consecutively tested for gene copy number (GCN) by FISH. Mean GCN, /CEN7 ratio and other FISH parameters were identified and correlated with morphological and molecular pathological characteristics of the tumors as well as with clinical data.

Results: Based on the variability of obtained data a top-level category of amplification was newly defined (>90th percentile of average GCN; ≥10 gene copies per tumor cell). This criterion was fulfilled in 2% of analyzed tumors. These tumors were exclusively poorly differentiated adenocarcinomas with a predominant solid subtype and pleomorphic features. Rarely, co-alterations were detected ( mutation or exon 14 skipping mutation). In this top-level group, there were no mutations or or alterations. The most important clinical feature was a significantly shortened overall survival (HR 3.61; median OS 8.2 23.6 months). Worse prognosis did not depend on initial stage or treatment.

Conclusions: The newly defined top-level category of amplification in NSCLC defines a specific subgroup of pulmonary adenocarcinoma with adverse prognosis and characteristic morphological features. Lower levels of gene copy number seem to have probably no specific value as a prognostic or predictive biomarker.
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http://dx.doi.org/10.21037/tlcr-19-339DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7354108PMC
June 2020

Influence of Biopsy Technique on Molecular Genetic Tumor Characterization in Non-Small Cell Lung Cancer-The Prospective, Randomized, Single-Blinded, Multicenter PROFILER Study Protocol.

Diagnostics (Basel) 2020 Jul 6;10(7). Epub 2020 Jul 6.

Department of Medical Oncology and Pneumology, Eberhard Karls University, 72076 Tübingen, Germany.

The detection of molecular alterations is crucial for the individualized treatment of advanced non-small cell lung cancer (NSCLC). Missing targetable alterations may have a major impact on patient's progression free and overall survival. Although laboratory testing for molecular alterations has continued to improve; little is known about how biopsy technique affects the detection rate of different mutations. In the retrospective study detection rate of epidermal growth factor (EGFR) mutations in tissue extracted by bronchoscopic cryobiopsy (CB was significantly higher compared to other standard biopsy techniques. This prospective, randomized, multicenter, single blinded study evaluates the accuracy of molecular genetic characterization of NSCLC for different cell sampling techniques. Key inclusion criteria are suspected lung cancer or the suspected relapse of known NSCLC that is bronchoscopically visible. Patients will be randomized, either to have a CB or a bronchoscopic forceps biopsy (FB). If indicated, a transbronchial needle aspiration (TBNA) of suspect lymph nodes will be performed. Blood liquid biopsy will be taken before tissue biopsy. The primary endpoint is the detection rate of molecular genetic alterations in NSCLC, using CB and FB. Secondary endpoints are differences in the combined detection of molecular genetic alterations between FB and CB, TBNA and liquid biopsy. This trial plans to recruit 540 patients, with 178 evaluable patients per study cohort. A histopathological and molecular genetic evaluation will be performed by the affiliated pathology departments of the national network for genomic medicine in lung cancer (nNGM), Germany. We will compare the diagnostic value of solid tumor tissue, lymph node cells and liquid biopsy for the molecular genetic characterization of NSCLC. This reflects a real world clinical setting, with potential direct impact on both treatment and survival.
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http://dx.doi.org/10.3390/diagnostics10070459DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7400559PMC
July 2020

Multimodality treatment including surgery for primary pulmonary sarcoma: Size does matter.

J Surg Oncol 2020 Sep 14;122(3):506-514. Epub 2020 May 14.

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

Background And Objectives: Primary pulmonary sarcoma (PPS) accounts for less than 1.1% of all pulmonary tumors. Few outcome data are reported. We evaluated outcome and prognostic factors in our series.

Methods: We retrospectively reviewed all patients who underwent resection for PPS in our center from 2002 to 2018. Survival was calculated from the date of surgery until last follow-up. Impact on survival of gender, type of lung resection, completeness of resection, grade, size, and TNM staging for lung cancer and soft tissue sarcoma (STS) was assessed.

Results: Thirteen patients were included. Eight (61.5%) patients received neoadjuvant treatment. Median tumor size at diagnosis was 11.5 cm (1-30 cm). Type of lung resection was wedge (n = 2, 15%), lobectomy (n = 4, 31%), intrapericardial (n = 3, 23%), and extrapleural pneumonectomies (n = 4, 31%). In-hospital mortality was 8%. Overall 5-year survival was 60%. Median disease-free survival was 17 months. Tumor size was a predictor for survival (P = .02) and recurrence (P = .05). Gender (P = .04) and type of lung resection (P = .04) were predictors of survival. T stage for STS of trunk and extremity, and TNM stage for lung cancer were predictors for recurrence (P = .03 and P = .04, respectively).

Conclusion: Surgical resection within a multimodality therapy concept in highly selected patients can offer good long-term outcome.
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http://dx.doi.org/10.1002/jso.25979DOI Listing
September 2020

Pleuropulmonary Blastoma Misinterpreted as Spontaneous Pneumothorax in an Infant.

Ann Thorac Surg 2020 07 17;110(1):e79. Epub 2020 Apr 17.

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

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http://dx.doi.org/10.1016/j.athoracsur.2020.03.033DOI Listing
July 2020
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