Publications by authors named "Thomas Muley"

177 Publications

Comprehensive Dissection of Treatment Patterns and Outcome for Patients With Metastatic Large-Cell Neuroendocrine Lung Carcinoma.

Front Oncol 2021 8;11:673901. Epub 2021 Jul 8.

Department of Thoracic Oncology, Thoraxklinik and National Center for Tumor diseases (NCT), Heidelberg University Hospital, Heidelberg, Germany.

Background: Large-cell neuroendocrine lung carcinoma (LCNEC) is a rare pulmonary neoplasm with poor prognosis and limited therapeutic options.

Methods: We retrospectively analyzed all patients with metastatic LCNEC in the records of a large German academic center since 2010.

Results: 191 patients were identified with a predominance of male (68%) smokers (92%) and a median age of 65 years. The single most important factor associated with outcome was the type of systemic treatment, with a median overall survival (OS) of 26.4 months in case of immune checkpoint inhibitor administration (n=13), 9.0 months for other patients receiving first-line platinum doublets (n=129), and 4.0 months with non-platinum chemotherapies (n=17, p<0.01). Other patient characteristics independently associated with longer OS were a lower baseline serum LDH (hazard ratio [HR] 0.54, p=0.008) and fewer initial metastatic sites (HR 0.52, p=0.006), while the platinum drug type (cisplatin carboplatin) and cytotoxic partner (etoposide paclitaxel), patients' smoking status and baseline levels of tumor markers (NSE, CYFRA 21-1, CEA) did not matter. 12% (23/191) of patients forewent systemic treatment, mainly due to tumor-related clinical deterioration (n=13), while patient refusal of therapy (n=5) and severe concomitant illness (n=5) were less frequent. The attrition between successive treatment lines was approximately 50% and similar for platinum-based other therapies, but higher in case of a worse initial ECOG status or higher serum LDH (p<0.05). 19% (36/191) of patients had secondary stage IV disease and showed fewer metastatic sites, better ECOG status and longer OS (median 12.6 8.7 months, p=0.030). Among the 111 deceased patients with palliative systemic treatment and complete follow-up, after exclusion of oligometastatic cases (n=8), administration of local therapies (n=63 or 57%) was associated with a longer OS (HR 0.58, p=0.008), but this association did not persist with multivariable testing.

Conclusions: Highly active systemic therapies, especially immunotherapy and platinum doublets, are essential for improved outcome in LCNEC and influence OS stronger than clinical disease parameters, laboratory results and other patient characteristics. The attrition between chemotherapy lines is approximately 50%, similar to other NSCLC. Patients with secondary metastatic disease have a more favorable clinical phenotype and longer survival.
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http://dx.doi.org/10.3389/fonc.2021.673901DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8295750PMC
July 2021

Therapeutic and Prognostic Implications of Immune-Related Adverse Events in Advanced Non-Small-Cell Lung Cancer.

Front Oncol 2021 29;11:703893. Epub 2021 Jun 29.

Department of Thoracic Oncology, Thoraxklinik and National Center for Tumor Diseases (NCT) at Heidelberg University Hospital, Heidelberg, Germany.

Introduction: PD-(L)1 inhibitors have improved prognosis of non-small-cell lung cancer (NSCLC), but can also cause immune-related adverse events (irAEs) that complicate management.

Methods: We analyzed NSCLC patients receiving PD-(L)1 inhibitors from 2012 to 2020 in a German academic center.

Results: IrAE showed comparable frequencies in stage IV (198/894 or 22%) III (14/45 or 31%, p = 0.15), after anti-PD-(L)1 monotherapy chemoimmunotherapy (139/483 58/213, p = 0.75), and across treatment lines. In stage IV, irAE occurred after 3.1 months in median, affected multiple organs (median 2) in 27/894 patients and were associated with PD-L1 positivity (25 14%, p = 0.003), lower neutrophil-to-lymphocyte ratios (29 17%, p < 0.001 for NLR dichotomized at 5), better ECOG status (26 18% for 0 1, p = 0.004), but not related to age, sex, smoking and palliative radiotherapy. Two hundred thirty two irAEs occurred mostly in endocrine glands (4.9%), lungs (4.4%), the musculoskeletal system (4.2%), colon (4.1%), liver (3.7%), and skin (2.6%), while pneumonitis was most frequent with durvalumab following definitive chemoradiation (16% or 7/45, p < 0.01). IrAE severity was grade 1 in 11%, 2 in 41%, 3 in 36%, and 4 in 11% events, while two were lethal (<1%, myocarditis and pneumonitis). Therapy was suspended in 72%, while steroids were initiated in 66% and complemented by other immunosuppressants in 6%, with longest treatment duration for rheumatic events (mean >3 months), and average cumulative prednisone doses >700 mg for all organs, except for skin. Patients developing irAE had longer progression-free (PFS) and overall survival (OS) in multivariable 12/14-week landmark analyses including ECOG status, treatment line, treatment type, PD-L1 TPS, and NLR (median PFS 17 10 months, HR = 0.68, p = 0.009; median OS 37 15 months, HR = 0.40, p < 0.001), regardless of grade. OS was longest with skin (95% at 2 years) and shortest with pneumonitis, hepatitis, neurologic, and cardiologic irAE (38, 37, 28, and 0% at 2 years, p < 0.001).

Conclusions: Approximately one-fourth of immunotherapy-treated NSCLC patients develop irAEs, most of which necessitate treatment suspension and steroids. Despite more frequent occurrence with PD-L1 positive tumors, lower NLR, and better ECOG PS, irAEs are independently associated with longer survival, especially when affecting the skin. Lethality is below 1%.
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http://dx.doi.org/10.3389/fonc.2021.703893DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8277237PMC
June 2021

Deciphering the immunosuppressive tumor microenvironment in ALK- and EGFR-positive lung adenocarcinoma.

Cancer Immunol Immunother 2021 Jun 14. Epub 2021 Jun 14.

Institute of Pathology, Heidelberg University Hospital, Im Neuenheimer Feld 224, Heidelberg, Germany.

Introduction: The advent of immune checkpoint blockade (ICB) has led to significantly improved disease outcome in lung adenocarcinoma (ADC), but response of ALK/EGFR-positive tumors to immune therapy is limited. The underlying immune biology is incompletely understood.

Methods: We performed comparative mRNA expression profiling of 31 ALK-positive, 40 EGFR-positive and 43 ALK/EGFR-negative lung ADC focused on immune gene expression. The presence and levels of tumor infiltration lymphocytes (TILs) as well as fourteen specific immune cell populations were estimated from the gene expression profiles.

Results: While total TILs were not lower in ALK-positive and EGFR-positive tumors compared to ALK/EGFR-negative tumors, specific immunosuppressive characteristics were detected in both subgroups: In ALK-positive tumors, regulatory T cells were significantly higher compared to EGFR-positive (fold change: FC = 1.9, p = 0.0013) and ALK/EGFR-negative tumors (FC = 2.1, p = 0.00047). In EGFR-positive tumors, cytotoxic cells were significantly lower compared to ALK-positive (FC =  - 1.7, p = 0.016) and to ALK/EGFR-negative tumors (FC =  - 2.1, p = 2.0E-05). A total number of 289 genes, 40 part of cytokine-cytokine receptor signaling, were differentially expressed between the three subgroups. Among the latter, five genes were differently expressed in both ALK-positive and EGFR-positive tumors, while twelve genes showed differential expression solely in ALK-positive tumors and eleven genes solely in EGFR-positive tumors.

Conclusion: Targeted gene expression profiling is a promising tool to read out tumor microenvironment characteristics from routine diagnostic lung cancer biopsies. Significant immune reactivity including specific immunosuppressive characteristics in ALK- and EGFR-positive lung ADC, but not a total absence of immune infiltration supports further clinical evaluation of immune-modulators as partners of ICB in such tumors.
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http://dx.doi.org/10.1007/s00262-021-02981-wDOI Listing
June 2021

Conventional and semi-automatic histopathological analysis of tumor cell content for multigene sequencing of lung adenocarcinoma.

Transl Lung Cancer Res 2021 Apr;10(4):1666-1678

Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.

Background: Targeted genetic profiling of tissue samples is paramount to detect druggable genetic aberrations in patients with non-squamous non-small cell lung cancer (NSCLC). Accurate upfront estimation of tumor cell content (TCC) is a crucial pre-analytical step for reliable testing and to avoid false-negative results. As of now, TCC is usually estimated on hematoxylin-eosin (H&E) stained tissue sections by a pathologist, a methodology that may be prone to substantial intra- and interobserver variability. Here we the investigate suitability of digital pathology for TCC estimation in a clinical setting by evaluating the concordance between semi-automatic and conventional TCC quantification.

Methods: TCC was analyzed in 120 H&E and thyroid transcription factor 1 (TTF-1) stained high-resolution images by 19 participants with different levels of pathological expertise as well as by applying two semi-automatic digital pathology image analysis tools (HALO and QuPath).

Results: Agreement of TCC estimations [intra-class correlation coefficients (ICC)] between the two software tools (H&E: 0.87; TTF-1: 0.93) was higher compared to that between conventional observers (0.48; 0.47). Digital TCC estimations were in good agreement with the average of human TCC estimations (0.78; 0.96). Conventional TCC estimators tended to overestimate TCC, especially in H&E stainings, in tumors with solid patterns and in tumors with an actual TCC close to 50%.

Conclusions: Our results determine factors that influence TCC estimation. Computer-assisted analysis can improve the accuracy of TCC estimates prior to molecular diagnostic workflows. In addition, we provide a free web application to support self-training and quality improvement initiatives at other institutions.
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http://dx.doi.org/10.21037/tlcr-20-1168DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8107748PMC
April 2021

Role of Synaptophysin, Chromogranin and CD56 in adenocarcinoma and squamous cell carcinoma of the lung lacking morphological features of neuroendocrine differentiation: a retrospective large-scale study on 1170 tissue samples.

BMC Cancer 2021 May 1;21(1):486. Epub 2021 May 1.

Institute of Pathology, University Hospital Heidelberg, Im Neuenheimer Feld 224, Heidelberg, Germany.

Background: Synaptophysin, chromogranin and CD56 are recommended markers to identify pulmonary tumors with neuroendocrine differentiation. Whether the expression of these markers in pulmonary adenocarcinoma and pulmonary squamous cell carcinoma is a prognostic factor has been a matter of debate. Therefore, we investigated retrospectively a large cohort to expand the data on the role of synaptophysin, chromogranin and CD56 in non-small cell lung cancer lacking morphological features of neuroendocrine differentiation.

Methods: A cohort of 627 pulmonary adenocarcinomas (ADC) and 543 squamous cell carcinomas (SqCC) lacking morphological features of neuroendocrine differentiation was assembled and a tissue microarray was constructed. All cases were stained with synaptophysin, chromogranin and CD56. Positivity was defined as > 1% positive tumor cells. Data was correlated with clinico-pathological features including overall and disease free survival.

Results: 110 (18%) ADC and 80 (15%) SqCC were positive for either synaptophysin, chromogranin, CD56 or a combination. The most commonly positive single marker was synaptophysin. The least common positive marker was chromogranin. A combination of ≤2 neuroendocrine markers was positive in 2-3% of ADC and 0-1% of SqCC. There was no significant difference in overall survival in tumors with positivity for neuroendocrine markers neither in ADC (univariate: P = 0.4; hazard ratio [HR] = 0.867; multivariate: P = 0.5; HR = 0.876) nor in SqCC (univariate: P = 0.1; HR = 0.694; multivariate: P = 0.1, HR = 0.697). Likewise, there was no significant difference in disease free survival.

Conclusions: We report on a cohort of 1170 cases that synaptophysin, chromogranin and CD56 are commonly expressed in ADC and SqCC and that their expression has no impact on survival, supporting the current best practice guidelines.
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http://dx.doi.org/10.1186/s12885-021-08140-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8088012PMC
May 2021

Prognostic Impact of PD-L1 Expression in pN1 NSCLC: A Retrospective Single-Center Analysis.

Cancers (Basel) 2021 Apr 23;13(9). Epub 2021 Apr 23.

Department of Thoracic Surgery, Thoraxklinik, Heidelberg University, 69117 Heidelberg, Germany.

The programmed death-ligand 1 (PD-L1) plays a crucial role in immunomodulatory treatment concepts for end-stage non-small cell lung cancer (NSCLC). To date, its prognostic significance in patients with curative surgical treatment but regional nodal metastases, reflecting tumor spread beyond the primary site, is unclear. We evaluated the prognostic impact of PD-L1 expression in a surgical cohort of 277 consecutive patients with pN1 NSCLC on a tissue microarray. Patients with PD-L1 staining (clone SP263) on >1% of tumor cells were defined as PD-L1 positive. Tumor-specific survival (TSS) of the entire cohort was 64% at five years. Low tumor stage ( < 0.0001) and adjuvant therapy ( = 0.036) were identified as independent positive prognostic factors in multivariate analysis for TSS. PD-L1 negative patients had a significantly better survival following adjuvant chemotherapy than PD-L1 positive patients. The benefit of adjuvant therapy diminished in patients with PD-L1 expression in more than 10% of tumor cells. Stratification towards histologic subtype identified PD-L1 as a significant positive predictive factor for TSS after adjuvant therapy in patients with adenocarcinoma, but not squamous cell carcinoma. Routine PD-L1 assessment in curative intent treatment may help to identify patients with a better prognosis. Further research is needed to elucidate the predictive value of PD-L1 in an adjuvant setting.
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http://dx.doi.org/10.3390/cancers13092046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8122862PMC
April 2021

Validation of the T Descriptor (TNM-8) in T3N0 Non-Small-Cell Lung Cancer Patients; a Bicentric Cohort Analysis with Arguments for Redefinition.

Cancers (Basel) 2021 Apr 10;13(8). Epub 2021 Apr 10.

Department of Thoracic Surgery, Thoraxklinik, Heidelberg University Hospital, Roentgenstrasse 1, 69126 Heidelberg, Germany.

The current pT3N0 category represents a heterogeneous subgroup involving tumor size, separate tumor nodes in one lobe, and locoregional growth pattern. We aim to validate outcomes according to the eighth edition of the TNM staging classification. A total of 281 patients who had undergone curative lung cancer surgery staged with TNM-7 in two German centers were retrospectively analyzed. The subtypes tumor size >7 cm and multiple nodules were grouped as T3a, and the subtypes parietal pleura invasion and mixed were grouped as T3b. We stratified survival by subtype and investigated the relative benefit of adjuvant chemotherapy according to subtype. The 5-year overall survival (OS) rates differed between the different subtypes tumor diameter >7 cm (71.5%), multiple nodules in one lobe (71.0%) (grouped as T3a), parietal pleura invasion (59.%), and mixed subtype (5-year OS 50.3%) (grouped as T3b), respectively. The cohort as a whole did not gain significant OS benefit from adjuvant chemotherapy. In contrast, adjuvant chemotherapy significantly improved OS in the T3b subgroup (logrank = 0.03). This multicenter cohort analysis of pT3N0 patients identifies a new prognostic mixed subtype. Tumors >7 cm should not be moved to pT4. Patients with T3b tumors have significantly worse survival than patients with T3a tumors.
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http://dx.doi.org/10.3390/cancers13081812DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8068959PMC
April 2021

Versus Secondary Metastatic -Mutated Non-Small-Cell Lung Cancer.

Front Oncol 2021 9;11:640048. Epub 2021 Apr 9.

Department of Thoracic Oncology, Thoraxklinik at Heidelberg University Hospital, Heidelberg, Germany.

Background: Metastatic epidermal growth factor receptor-mutated (EGFR) non-small-cell lung cancer (NSCLC) can present or following previous nonmetastatic disease (secondary). Potential differences between these two patient subsets are unclear at present.

Methods: We retrospectively analyzed characteristics of tyrosine kinase inhibitor (TKI)-treated patients with vs. secondary metastatic EGFR NSCLC until December 2019 (n = 401).

Results: metastatic disease was 4× more frequent than secondary (n = 83/401), but no significant differences were noted regarding age (median 66 vs. 70 years), sex (65% vs. 65% females), smoking history (67% vs. 62% never/light-smokers), and histology (both >95% adenocarcinoma). Patients with secondary metastatic disease showed a better ECOG performance status (PS 0-1 67%-32% vs. 46%-52%, p = 0.003), fewer metastatic sites (mean 1.3 vs. 2.0, p < 0.001), and less frequent brain involvement (16% vs. 28%, p = 0.022) at the time of stage IV diagnosis. Progression-free survival (PFS) under TKI (median 17 for secondary vs. 12 months for , p = 0.26) and overall survival (OS, 29 vs. 25 months, respectively, p = 0.47) were comparable. alterations (55% vs. 60% exon 19 deletions), mutation rate at baseline (47% vs. 43%, n = 262), and T790M positivity at the time of TKI failure (51% vs. 56%, n = 193) were also similar. OS according to differing characteristics, e.g., presence or absence of brain metastases (19-20 or 30-31 months, respectively, p = 0.001), and ECOG PS 0 or 1 or 2 (32-34 or 20-23 or 5-7 months, respectively, p < 0.001), were almost identical for and secondary metastatic disease.

Conclusions: Despite the survival advantage reported in the pre-TKI era for relapsed NSCLC, molecular features and outcome of TKI-treated metastatic EGFR tumors are currently independent of preceding nonmetastatic disease. This simplifies design of outcome studies and can assist prognostic considerations in everyday management of patients with secondary metastatic EGFR tumors.
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http://dx.doi.org/10.3389/fonc.2021.640048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8063726PMC
April 2021

Versatile workflow for cell type-resolved transcriptional and epigenetic profiles from cryopreserved human lung.

JCI Insight 2021 Mar 22;6(6). Epub 2021 Mar 22.

BioMed X Institute, Heidelberg, Germany.

Complexity of lung microenvironment and changes in cellular composition during disease make it exceptionally hard to understand molecular mechanisms driving development of chronic lung diseases. Although recent advances in cell type-resolved approaches hold great promise for studying complex diseases, their implementation relies on local access to fresh tissue, as traditional tissue storage methods do not allow viable cell isolation. To overcome these hurdles, we developed a versatile workflow that allows storage of lung tissue with high viability, permits thorough sample quality check before cell isolation, and befits sequencing-based profiling. We demonstrate that cryopreservation enables isolation of multiple cell types from both healthy and diseased lungs. Basal cells from cryopreserved airways retain their differentiation ability, indicating that cellular identity is not altered by cryopreservation. Importantly, using RNA sequencing and EPIC Array, we show that gene expression and DNA methylation signatures are preserved upon cryopreservation, emphasizing the suitability of our workflow for omics profiling of lung cells. Moreover, we obtained high-quality single-cell RNA-sequencing data of cells from cryopreserved human lungs, demonstrating that cryopreservation empowers single-cell approaches. Overall, thanks to its simplicity, our workflow is well suited for prospective tissue collection by academic collaborators and biobanks, opening worldwide access to viable human tissue.
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http://dx.doi.org/10.1172/jci.insight.140443DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8026197PMC
March 2021

DNA methylation profiles of bronchoscopic biopsies for the diagnosis of lung cancer.

Clin Epigenetics 2021 02 17;13(1):38. Epub 2021 Feb 17.

Institute of Human Genetics, University Medical Center Ulm, Albert-Einstein-Allee 11, 89081, Ulm, Germany.

Background: Lung cancer is the leading cause of cancer-related death in most western countries in both, males and females, accounting for roughly 20-25% of all cancer deaths. For choosing the most appropriate therapy regimen a definite diagnosis is a prerequisite. However, histological characterization of bronchoscopic biopsies particularly with low tumor cell content is often challenging. Therefore, this study aims at (a) determining the value of DNA methylation analysis applied to specimens obtained by bronchoscopic biopsy for the diagnosis of lung cancer and (b) at comparing aberrantly CpG loci identified in bronchoscopic biopsy with those identified by analyzing surgical specimens.

Results: We report the HumanMethylation450-based DNA methylation analysis of paired samples of bronchoscopic biopsy specimens either from the tumor side or from the contralateral tumor-free bronchus in 37 patients with definite lung cancer diagnosis and 18 patients with suspicious diagnosis. A differential DNA methylation analysis between both biopsy sites of patients with definite diagnosis identified 1303 loci. Even those samples were separated by the set of 1303 loci in which histopathological analysis could not unambiguously define the dignity. Further differential DNA methylation analyses distinguished between SCLC and NSCLC. We validated our results in an independent cohort of 40 primary lung cancers obtained by open surgical resection and their corresponding controls from the same patient as well as in publically available DNA methylation data from a TCGA cohort which could also be classified with high accuracy.

Conclusions: Considering that the prognosis correlates with tumor stage at time of diagnosis, early detection of lung cancer is vital and DNA methylation analysis might add valuable information to reliably characterize lung cancer even in histologically ambiguous sample material.
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http://dx.doi.org/10.1186/s13148-021-01024-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7890863PMC
February 2021

Differentially methylated regions within lung cancer risk loci are enriched in deregulated enhancers.

Epigenetics 2021 Feb 17:1-16. Epub 2021 Feb 17.

Division of Cancer Epigenomics, German Cancer Research Center (DKFZ), Heidelberg, Germany.

Genome-wide association studies (GWAS) have identified SNPs linked with lung cancer risk. Our aim was to discover the genes, non-coding RNAs, and regulatory elements within GWAS-identified risk regions that are deregulated in non-small cell lung carcinoma (NSCLC) to identify novel, clinically targetable genes and mechanisms in carcinogenesis. A targeted bisulphite-sequencing approach was used to comprehensively investigate DNA methylation changes occurring within lung cancer risk regions in 17 NSCLC and adjacent normal tissue pairs. We report differences in differentially methylated regions between adenocarcinoma and squamous cell carcinoma. Among the minimal regions found to be differentially methylated in at least 50% of the patients, 7 candidates were replicated in 2 independent cohorts (n = 27 and n = 87) and the potential of 6 as methylation-dependent regulatory elements was confirmed by functional assays. This study contributes to understanding the pathways implicated in lung cancer initiation and progression, and provides new potential targets for cancer treatment.
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http://dx.doi.org/10.1080/15592294.2021.1878723DOI Listing
February 2021

Neoadjuvant anti-programmed death-1 immunotherapy by pembrolizumab in resectable non-small cell lung cancer: First clinical experience.

Lung Cancer 2021 03 21;153:150-157. Epub 2021 Jan 21.

Department of Thoracic Surgery, Thoraxklinik, University Hospital Heidelberg, Heidelberg, Germany; Translational Lung Research Center (TLRC) Heidelberg, Member of the German Center for Lung Research (DZL), Germany. Electronic address:

Objectives: A phase II trial investigating the therapeutic effect of neoadjuvant programmed cell death 1 (PD-1) inhibitor pembrolizumab (MK-3475, KEYTRUDA®) administered prior to surgery for the treatment of non-small cell lung cancer (NSCLC) has been conducted (NCT03197467). We report the first clinical results of a planned interim safety analysis after 15 patients were enrolled.

Material And Methods: Patients with resectable NSCLC stage II/IIIA were included. Two cycles of pembrolizumab (200 mg intravenously once every 3 weeks) were administered prior to surgery. The primary objectives were to assess the feasibility and safety of neoadjuvant pembrolizumab therapy and to evaluate antitumor activity. We analyzed the clinical parameters as well as pathological and radiological tumor response data.

Results: The NSCLC histology was adenocarcinoma for 13 patients and squamous cell carcinoma for 2 patients. All patients but two underwent 2 cycles of pembrolizumab prior to surgery. Four patients (27 %) presented a major pathologic response. Significant tumor target response in positron emission tomography computed tomography (PET-CT) was detected in all 4 pathologic responders. Nevertheless, the PET findings mismatched the tumor load in some patients. A PD-L1 expression ≥10 % in the pretreatment biopsy was associated with at least major pathologic response. Five patients (33 %) presented grade 2-3 treatment related adverse events (TRAE), the overall postoperative morbidity was 7 % and 30-day mortality was 0 %.

Conclusion: Neoadjuvant pembrolizumab is a feasible therapy in surgical lung cancer patients. It was associated with tolerable toxicity and did not compromise tumor resection.
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http://dx.doi.org/10.1016/j.lungcan.2021.01.018DOI Listing
March 2021

A gene expression signature associated with B cells predicts benefit from immune checkpoint blockade in lung adenocarcinoma.

Oncoimmunology 2021 01 11;10(1):1860586. Epub 2021 Jan 11.

Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany.

Immune checkpoint blockade (ICB) expands the therapeutic options for metastatic lung cancer nowadays representing a standard frontline strategy as monotherapy or combination therapy, as well as an option in oncogene-addicted NSCLC after exhaustion of targeted therapies. Predictive markers are urgently needed, since only a minority of patients benefits from ICB, while serious adverse effects of immunotoxicity may occur. The study cohort included 43 ICB-treated metastatic lung adenocarcinoma showing long-term response (n = 16), rapid progression (n = 21) or intermediate patterns of response (n = 6). Lung biopsies acquired before initiation of ICB were analyzed by targeted mRNA expression profiling of 770 genes. Level and proportions of 14 immune cell types were estimated using characteristic gene expression signatures. Abundance of B cells (HR = 0.66, = .00074), CD45+ cells (HR = 0.61, = .01) and total TILs (HR = 0.62, = .025) was associated with prolonged progression-free survival after ICB treatment. In a ROC analysis, B cells (AUC = 0.77, = .0055) and CD45+ cells (AUC = 0.73, = .019) predicted benefit of ICB, which was not the case for PD-L1 mRNA (AUC = 0.54, = .72) and PD-L1 protein expression (AUC = 0.68, = .082). Clustering of 79 candidate predictive markers identified among 770 investigated genes revealed two distinct predictive clusters which included cytotoxic cell or macrophage markers, respectively. In summary, targeted gene expression profiling was feasible using routine diagnostics biopsies. This study proposes B cells and total TILs as complementary predictors of ICB benefit in NSCLC. While further preferably prospective validation is required, gene expression profiling could be integrated in the routine diagnostic work-up complementing existing NGS protocols.
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http://dx.doi.org/10.1080/2162402X.2020.1860586DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7808386PMC
January 2021

Interferon Regulatory Factor 9 Promotes Lung Cancer Progression via Regulation of Versican.

Cancers (Basel) 2021 Jan 8;13(2). Epub 2021 Jan 8.

Max Planck Institute for Heart and Lung Research, Member of the German Center for Lung Research (DZL), Member of the Cardio-Pulmonary Institute (CPI), 61231 Bad Nauheim, Germany.

Transcription factors can serve as links between tumor microenvironment signaling and oncogenesis. Interferon regulatory factor 9 (IRF9) is recruited and expressed upon interferon stimulation and is dependent on cofactors that exert in tumor-suppressing or oncogenic functions via the JAK-STAT pathway. IRF9 is frequently overexpressed in human lung cancer and is associated with decreased patient survival; however, the underlying mechanisms remain to be elucidated. Here, we used stably transduced lung adenocarcinoma cell lines (A549 and A427) to overexpress or knockdown . Overexpression led to increased oncogenic behavior in vitro, including enhanced proliferation and migration, whereas knockdown reduced these effects. These findings were confirmed in vivo using lung tumor xenografts in nude mice, and effects on both tumor growth and tumor mass were observed. Using RNA sequencing, we identified versican () as a novel downstream target of IRF9. Indeed, and expression levels were found to be correlated. We showed for the first time that IRF9 binds at a newly identified response element in the promoter region of to regulate its transcription. Using an siRNA approach, VCAN was found to enable the oncogenic properties (proliferation and migration) of IRF9 transduced cells, perhaps with involvement. The targeted inhibition of IRF9 in lung cancer could therefore be used as a new treatment option without multimodal interference in microenvironment JAK-STAT signaling.
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http://dx.doi.org/10.3390/cancers13020208DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7827113PMC
January 2021

An integrated multiomic and quantitative label-free microscopy-based approach to study pro-fibrotic signalling in human precision-cut lung slices.

Eur Respir J 2021 Jul 1;58(1). Epub 2021 Jul 1.

European Molecular Biology Laboratory, Heidelberg, Germany

Fibrosis can affect any organ, resulting in the loss of tissue architecture and function with often life-threatening consequences. Pathologically, fibrosis is characterised by the expansion of connective tissue due to excessive deposition of extracellular matrix (ECM) proteins, including the fibrillar forms of collagen. A significant limitation for discovering cures for fibrosis is the availability of suitable human models and techniques to quantify mature fibrillar collagen deposition as close as possible to human physiological conditions.Here we have extensively characterised an cultured human lung tissue-derived, precision-cut lung slices (hPCLS) model using label-free second harmonic generation (SHG) light microscopy to quantify fibrillar collagen deposition and mass spectrometry-based techniques to obtain a proteomic and metabolomic fingerprint of hPCLS in culture.We demonstrate that hPCLS are viable and metabolically active, with mesenchymal, epithelial, endothelial and immune cell types surviving for at least 2 weeks in culture. Analysis of hPCLS-conditioned supernatants showed a strong induction of pulmonary fibrosis-related ECM proteins upon transforming growth factor-β1 (TGF-β1) stimulation. This upregulation of ECM proteins was not translated into an increased deposition of fibrillar collagen. In support of this observation, we revealed the presence of a pro-ECM degradation activity in our cultures of hPCLS, inhibition of which by a metalloproteinase inhibitor resulted in increased collagen deposition in response to TGF-β1 stimulation.Together the data show that an integrated approach of measuring soluble pro-fibrotic markers alongside quantitative SHG-based analysis of fibrillar collagen is a valuable tool for studying pro-fibrotic signalling and testing anti-fibrotic agents.
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http://dx.doi.org/10.1183/13993003.00221-2020DOI Listing
July 2021

Germline Genetic Variants of the Renin-Angiotensin System, Hypoxia and Angiogenesis in Non-Small Cell Lung Cancer Progression: Discovery and Validation Studies.

Cancers (Basel) 2020 Dec 18;12(12). Epub 2020 Dec 18.

i3S-Institute for Research & Innovation in Health, University of Porto, 4200-135 Porto, Portugal.

Introduction: The renin-angiotensin system (RAS) is involved in cell proliferation, immunoinflammatory response, hypoxia and angiogenesis, which are critical biological processes in lung cancer. Our aim was to study the association of putatively functional genetic polymorphisms in genes coding for proteins involved in RAS, hypoxia and angiogenesis with non-small cell lung cancer (NSCLC) prognosis.

Methods: Genotyping of 52 germline variants from genes of the RAS and hypoxic/angiogenic factors/receptors was performed using MassARRAY iPLEX Gold in a retrospective cohort ( = 167) of advanced NSCLC patients. Validation of the resulting genetic markers was conducted in an independent group ( = 190), matched by clinicopathological characteristics.

Results: Multivariate analysis on the discovery set revealed that rs701109 C carriers were protected from disease progression in comparison with homozygous T (hazard ratio (HR) = 0.5, 95% confidence interval (CI) = 0.2-0.8, = 0.010). Homozygous A and T genotypes for rs1870377 were at increased risk for disease progression and death compared to heterozygous (HR = 1.7, 95% CI = 1.2-2.5, = 0.005 and HR = 2.1, 95% CI = 1.2-3.4, = 0.006, respectively). Carriers of homozygous genotypes for rs908004 presented increased risk for disease progression, only in the subgroup of patients without tumour actionable driver mutations (HR = 2.9, 95% CI = 1.3-6.3, = 0.010). Importantly, the association of homozygous genotypes in rs701109 with risk for disease progression was confirmed after multivariate analysis in the validation set.

Conclusion: This study provides evidence that polymorphism, which encodes neprilysin, may modulate progression-free survival in advanced NSCLC. Present genetic variation findings will foster basic, translational, and clinical research on their role in NSCLC.
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http://dx.doi.org/10.3390/cancers12123834DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7766842PMC
December 2020

Consolidation Immunotherapy After Platinum-Based Chemoradiotherapy in Patients With Unresectable Stage III Non-Small Cell Lung Cancer-Cross-Sectional Study of Eligibility and Administration Rates.

Front Oncol 2020 1;10:586449. Epub 2020 Dec 1.

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

Introduction: The PACIFC trial demonstrated a significant benefit of durvalumab consolidation immunotherapy (CIT) after definitive platinum-based chemoradiotherapy (P-CRT) for survival in stage III non-small cell lung cancer (NSCLC). It is unknown how many patients are eligible in clinical practice to receive CIT according to PACIFIC criteria compared to real administration rates and what influencing factors are.

Patients And Methods: We analyzed 442 patients with unresectable stage III NSCLC who received P-CRT between 2009 and 2019 regarding CIT eligibility rates according to PACIFIC criteria and administration rates since drug approval.

Results: Sixty-four percent of 437 patients were male, median age was 63 years [interquartile range (IQR): 57-69]. The most common histologic subtypes were adenocarcinoma (42.8%) and squamous cell carcinoma (41.1%), most tumors were in stage IIIB (56.8%). Mean PD-L1 tumor proportion score (TPS) was 29.8% (IQR: 1-60). The median total RT dose was 60 Gy (IQR: 60-66). Platinum component of P-CRT was evenly distributed between cisplatin (51.4%) and carboplatin (48.6%). 50.3% of patients were eligible for CIT according to PACIFIC criteria. Observed contraindications were progressive disease according to RECIST (32.4%), followed by a PD-L1 TPS < 1% (22.3%), pneumonitis CTCAE ≥ 2 (12.6%) and others (4.9%). One year after drug approval, 85.6% of patients who were eligible according to PACIFIC criteria actually received CIT. Time interval between chemotherapy start and radiation therapy start (OR 0.9, 95% CI: [0.9; 1.0] p = 0.009) and probably cisplatin as platinum-component of P-CRT (OR 1.5, 95% CI: [1.0; 2.4] p < 0.061) influence CIT eligibility. Highly positive PD-L1 TPS (≥50%; (OR 2.4, 95% CI: [1.3; 4.5] p = 0.004) was associated to a better chance for CIT eligibility.

Conclusion: Eighty-five percent of potentially eligible patients received CIT one year after drug approval. Fifty percent of patients did not meet PACIFIC criteria for durvalumab eligibility, this was mainly caused by disease progression during platinum-based CRT, followed by therapy-related pneumonitis and PD-L1 TPS < 1% (in view of the EMA drug approval).
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http://dx.doi.org/10.3389/fonc.2020.586449DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7736629PMC
December 2020

Epigenetic Inactivation of the Tumor Suppressor Occurs Frequently in Lung Adenocarcinoma and Its Silencing Is Associated with Impaired Prognosis.

Cancers (Basel) 2020 Nov 26;12(12). Epub 2020 Nov 26.

Faculty of Biology, Institute for Genetics, Justus-Liebig-University Giessen, 35392 Giessen, Germany.

(IRX) encodes members of homeodomain containing genes which are involved in development and differentiation. Since it has been reported that the gene is localized in a lung cancer susceptibility locus, the epigenetic regulation and function of IRX1 was investigated in lung carcinogenesis. We observed frequent hypermethylation of the promoter in non-small cell lung cancer (NSCLC) compared to small cell lung cancer (SCLC). Aberrant methylation was significantly correlated with reduced expression. In normal lung samples, the promoter showed lower median DNA methylation levels (<10%) compared to primary adenocarcinoma (ADC, 22%) and squamous cell carcinoma (SQCC, 14%). A significant hypermethylation and downregulation of was detected in ADC and SQCC compared to matching normal lung samples ( < 0.0001). Low expression was significantly correlated with impaired prognosis of ADC patients ( = 0.001). Reduced survival probability was also associated with higher promoter methylation ( = 0.02). Inhibition of DNA methyltransferase (DNMT) activity reactivated expression in human lung cancer cell lines. Induced DNMT3A and EZH2 expression was correlated with downregulation of . On the cellular level, IRX1 exhibits nuclear localization and expression of IRX1 induced fragmented nuclei in cancer cells. Localization of IRX1 and induction of aberrant nuclei were dependent on the presence of the homeobox of IRX1. By data mining, we showed that is negatively correlated with oncogenic pathways and expression induces the proapoptotic regulator . In conclusion, we report that expression is significantly associated with improved survival probability of ADC patients. hypermethylation may serve as molecular biomarker for ADC diagnosis and prognosis. Our data suggest that acts as an epigenetically regulated tumor suppressor in the pathogenesis of lung cancer.
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http://dx.doi.org/10.3390/cancers12123528DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7760495PMC
November 2020

Circulating Interleukin-4 Is Associated with a Systemic T Cell Response against Tumor-Associated Antigens in Treatment-Naïve Patients with Resectable Non-Small-Cell Lung Cancer.

Cancers (Basel) 2020 Nov 24;12(12). Epub 2020 Nov 24.

Regensburg Center for Interventional Immunology and Regensburg University Hospital, Franz-Josef-Strauss-Allee 11, 93053 Regensburg, Germany.

Spontaneous T cell responses to tumor-associated antigens (TAs) in the peripheral blood of patients with non-small-cell lung cancer (NSCLC) may be relevant for postoperative survival. However, the conditions underlying these T cell responses remain unclear. We quantified the levels of 27 cytokines in the peripheral blood and tumor tissues from treatment-naïve patients with NSCLC ( = 36) and analyzed associations between local and systemic cytokine profiles and both TA-specific T cell responses and clinical parameters. We defined T cell responders as patients with circulating T cells that were reactive to TAs and T cell nonresponders as patients without detectable TA-specific T cells. TA-specific T cell responses were correlated with serum cytokine levels, particularly the levels of interleukin(IL)-4 and granulocyte colony-stimulating factor (G-CSF), but poorly correlated with the cytokine levels in tumor tissues. Nonresponders showed significantly higher serum IL-4 levels than responders ( = 0.03); the predicted probability of being a responder was higher for individuals with low serum IL-4 levels. In multivariable Cox regression analyses, in addition to IL-4 (hazard ratio (HR) 2.8 (95% confidence interval (CI): 0.78-9.9); = 0.116), the age-adjusted IL-8 level (HR 3.9 (95% CI: 1.05-14.5); = 0.042) predicted tumor recurrence. However, this study included data for many cytokines without adjustment for multiple testing; thus, the observed differences in IL-4 or IL-8 levels might be incidental findings. Therefore, additional studies are necessary to confirm these results.
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http://dx.doi.org/10.3390/cancers12123496DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7761081PMC
November 2020

Longitudinal therapy monitoring of ALK-positive lung cancer by combined copy number and targeted mutation profiling of cell-free DNA.

EBioMedicine 2020 Dec 9;62:103103. Epub 2020 Nov 9.

Division of Cancer Genome Research, German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), and National Center for Tumor Diseases (NCT), Heidelberg, Germany; German Center for Lung Research (DZL), Translational Lung Research Center Heidelberg, Germany. Electronic address:

Background: Targeted therapies (TKI) have improved the prognosis of ALK-rearranged lung cancer (ALK NSCLC), but clinical courses vary widely. Early identification and molecular characterisation of treatment failure have key importance for subsequent therapies. We performed copy number variation (CNV) profiling and targeted panel sequencing from cell-free DNA (cfDNA) to monitor ALK NSCLC.

Methods: 271 longitudinal plasma DNA samples from 73 patients with TKI-treated metastatic ALK NSCLC were analysed by capture-based targeted (average coverage 4,100x), and shallow whole genome sequencing (sWGS, 0.5x). Mutations were called using standard algorithms. CNVs were quantified using the trimmed median absolute deviation from copy number neutrality (t-MAD).

Findings: cfDNA mutations were identified in 58% of patients. They included several potentially actionable alterations, e.g. in the genes BRAF, ERBB2, and KIT. sWGS detected CNVs in 18% of samples, compared to 6% using targeted sequencing. Several of the CNVs included potentially druggable targets, such as regions harboring EGFR, ERBB2, and MET. Circulating tumour DNA (ctDNA) mutations and t-MAD scores increased during treatment, correlated with markers of higher molecular risk, such as the EML4-ALK variant 3 and/or TP53 mutations, and were associated with shorter patient survival. Importantly, t-MAD scores reflected the tumour remission status in serial samples similar to mutant ctDNA allele frequencies, and increased with disease progression in 79% (34/43) of cases, including those without detectable single nucleotide variant (SNV).

Interpretation: Combined copy number and targeted mutation profiling could improve monitoring of ALK NSCLC. Potential advantages include the identification of treatment failure, in particular for patients without detectable mutations, and broader detection of genomic changes acquired during therapy, especially in later treatment lines and in high-risk patients.

Funding: This work was supported by the German Center for Lung Research (DZL), by the German Cancer Consortium (DKTK), by the Heidelberg Center for Personalized Oncology at the German Cancer Research Center (DKFZ-HIPO), and by Roche Sequencing Solutions (Pleasanton, CA, USA).
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http://dx.doi.org/10.1016/j.ebiom.2020.103103DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7670098PMC
December 2020

Mass Spectrometry Imaging for Reliable and Fast Classification of Non-Small Cell Lung Cancer Subtypes.

Cancers (Basel) 2020 Sep 21;12(9). Epub 2020 Sep 21.

Department of Hematology, Oncology and Rheumatology, University of Heidelberg, 69120 Heidelberg, Germany.

Subtyping of non-small cell lung cancer (NSCLC) is paramount for therapy stratification. In this study, we analyzed the largest NSCLC cohort by mass spectrometry imaging (MSI) to date. We sought to test different classification algorithms and to validate results obtained in smaller patient cohorts. Tissue microarrays (TMAs) from including adenocarcinoma (ADC, = 499) and squamous cell carcinoma (SqCC, = 440), were analyzed. Linear discriminant analysis, support vector machine, and random forest (RF) were applied using samples randomly assigned for training (66%) and validation (33%). The species most relevant for the classification were identified by on-tissue tandem mass spectrometry and validated by immunohistochemistry (IHC). Measurements from multiple TMAs were comparable using standardized protocols. RF yielded the best classification results. The classification accuracy decreased after including less than six of the most relevant species. The sensitivity and specificity of MSI in the validation cohort were 92.9% and 89.3%, comparable to IHC. The most important protein for the discrimination of both tumors was cytokeratin 5. We investigated the largest NSCLC cohort by MSI to date and found that the classification of NSCLC into ADC and SqCC is possible with high accuracy using a limited set of species.
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http://dx.doi.org/10.3390/cancers12092704DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7564257PMC
September 2020

A continuous responder algorithm to optimize clinical management of small-cell lung cancer with progastrin-releasing peptide as a simple blood test.

Tumour Biol 2020 Sep;42(9):1010428320958603

Thoraxklinik at University Hospital of Heidelberg, Heidelberg, Germany.

This study aimed to investigate whether changes in progastrin-releasing peptide (ProGRP) levels correlate with treatment response and can be used to optimize clinical management of patients with small-cell lung cancer. Patients with small-cell lung cancer (any stage) receiving chemotherapy were eligible. ProGRP was measured in serum/plasma at baseline and after each chemotherapy cycle using the Elecsys ProGRP assay (Roche Diagnostics). Treatment response was assessed by computed tomography scan. The primary objective was to examine whether changes in ProGRP levels correlated with computed tomography scan results after two cycles of chemotherapy. The prognostic value of ProGRP among patients receiving first-line chemotherapy was also assessed. Overall, 261 patients from six centers were eligible. Among patients with elevated baseline ProGRP (>100 pg/mL), a ProGRP decline after Cycle 2 was associated with nonprogression (area under the curve: 84%; 95% confidence interval: 72.8-95.1; n = 141). ProGRP changes from baseline to end of Cycle 1 were predictive of response, as determined by computed tomography scan 3 weeks later (area under the curve: 87%; 95% confidence interval: 74.1-99.2; n = 137). This was enhanced by repeat measurements, with a 92% area under the curve (95% confidence interval: 85.3-97.8) among patients with ProGRP data after both Cycles 1 and 2 (n = 123); if a patient experienced a ≥25% decline in ProGRP after Cycle 1, and ProGRP remained stable or decreased after Cycle 2, the probability of finding progression on the interim computed tomography scan at the end of Cycle 2 was almost zero (sensitivity: 100%, specificity: 71%). Both ProGRP levels at baseline and at the end of first-line chemotherapy were prognostic; the latter provided a moderately improved hazard ratio of 2.43 (95% confidence interval: 1.33-4.46; n = 110) versus 1.87 (95% confidence interval: 1.04-3.37; n = 216). In summary, for patients with small-cell lung cancer and elevated baseline ProGRP levels, ProGRP may be a simple, reliable, and repeatable tool for monitoring response to chemotherapy and provide valuable prognostic information.
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http://dx.doi.org/10.1177/1010428320958603DOI Listing
September 2020

Comprehensive serial biobanking in advanced NSCLC: feasibility, challenges and perspectives.

Transl Lung Cancer Res 2020 Aug;9(4):1000-1014

Translational Lung Research Center Heidelberg (TLRC), German Center for Lung Research (DZL), Heidelberg, Germany.

Background: Availability of tumor material at baseline and disease progression is increasingly important for patient management in non-small-cell lung cancer (NSCLC), especially for the application of targeted therapies like tyrosine kinase inhibitors and for immune checkpoint inhibitor treatment. Here we report the experience of prospective biomaterial acquisition in advanced NSCLC from a pilot project.

Methods: Main objective was the longitudinal collection of high-quality, cryoconserved biopsies in addition to formalin-fixed paraffin-embedded (FFPE) biopsies required for routine diagnostics, along with blood samples and detailed clinical annotation using standardized questionnaires.

Results: Over five years, 205 patients were enrolled for the project, yielding 387 cryoconserved biopsies and 1,098 serum, plasma and buffy-coat samples. The feasibility of obtaining the cryoconserved biopsies in addition to the FFPE biopsies was 89% for newly diagnosed cases, but dropped down to 56% and 47% at first and second disease progression, respectively. While forceps biopsy was the preferred procedure for tissue acquisition, the highest tissue amounts were received using the cryobiopsy method. Biopsies had a median tumor cellularity of 34% and yielded in median 13.6 µg DNA and 12 µg RNA (median RIN =8). During the five-year project, a maximum of 38 follow-up blood samples per patient were assembled in up to four therapy lines.

Conclusions: Despite the poor condition and limited prognosis of most NSCLC patients, this serial biomaterial acquisition including routine collection of cryoconserved biopsies is feasible to support individualized management. The standardized collection of high-quality material has enabled and enriched several translational research studies that can advance therapeutic options.
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http://dx.doi.org/10.21037/tlcr-20-137DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7481602PMC
August 2020

MCL-1 gains occur with high frequency in lung adenocarcinoma and can be targeted therapeutically.

Nat Commun 2020 09 10;11(1):4527. Epub 2020 Sep 10.

Department of Medicine III, Klinikum rechts der Isar, TUM School of Medicine, Technical University of Munich, Munich, Germany.

Evasion of programmed cell death represents a critical form of oncogene addiction in cancer cells. Understanding the molecular mechanisms underpinning cancer cell survival despite the oncogenic stress could provide a molecular basis for potential therapeutic interventions. Here we explore the role of pro-survival genes in cancer cell integrity during clonal evolution in non-small cell lung cancer (NSCLC). We identify gains of MCL-1 at high frequency in multiple independent NSCLC cohorts, occurring both clonally and subclonally. Clonal loss of functional TP53 is significantly associated with subclonal gains of MCL-1. In mice, tumour progression is delayed upon pharmacologic or genetic inhibition of MCL-1. These findings reveal that MCL-1 gains occur with high frequency in lung adenocarcinoma and can be targeted therapeutically.
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http://dx.doi.org/10.1038/s41467-020-18372-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7484793PMC
September 2020

Fibroblast Growth Factor-14 Acts as Tumor Suppressor in Lung Adenocarcinomas.

Cells 2020 07 22;9(8). Epub 2020 Jul 22.

Max Planck Institute for Heart and Lung Research, 61231 Bad Nauheim, Germany.

Investigation of the molecular dynamics in lung cancer is crucial for the development of new treatment strategies. Fibroblast growth factor (FGF) 14 belongs to the FGF family, which might play a crucial role in cancer progression. We analyzed lung adenocarcinoma (LUAC) patients samples and found that FGF14 was downregulated, correlating with reduced survival and oncogenic mutation status. FGF14 overexpression in lung cancer cell lines resulted in decreased proliferation, colony formation, and migration, as well as increased expression of epithelial markers and a decreased expression of mesenchymal markers, indicating a mesenchymal to epithelial transition in vitro. We verified these findings using small interfering RNA against FGF14 and further confirmed the suppressive effect of FGF14 in a .- Il2rg/ immunodeficient xenograft tumor model. Moreover, FGF14 overexpressing tumor cell RNA sequencing data suggests that genes affected by FGF14 were related to the extracellular matrix, playing a role in proliferation and migration. Notably, newly identified FGF14 target genes, adenosine deaminase RNA specific B1 (), collagen and calcium-binding epidermal growth factor domain-containing protein 1 (), α1 chain of collagen XI (), and mucin 16 () expression was negatively correlated with overall survival when was downregulated in LUAC. These findings led us to suggest that FGF14 regulates proliferation and migration in LUAC.
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http://dx.doi.org/10.3390/cells9081755DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7466013PMC
July 2020

Immunohistological expression of oestrogen receptor, progesterone receptor, mammaglobin, human epidermal growth factor receptor 2 and GATA-binding protein 3 in non-small-cell lung cancer.

Histopathology 2020 Dec 11;77(6):900-914. Epub 2020 Oct 11.

Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.

Aims: Non-small-cell lung cancer (NSCLC) and breast cancer are common entities. Staining for oestrogen receptor (ER), progesterone receptor (PgR), mammaglobin (MAMG) and GATA-binding protein 3 (GATA3) is frequently performed to confirm a mammary origin in the appropriate diagnostic setting. However, comprehensive data on the immunohistological expression of these markers in NSCLC are limited. Therefore, the aim of this study was to analyse a large cohort of NSCLCs and correlate the staining results with clinicopathological variables.

Methods And Results: A tissue microarray was stained for ER, PgR, MAMG, human epidermal growth factor receptor 2 (HER2), and GATA3, and included 636 adenocarcinomas (ADCs), 536 squamous cell carcinomas (SqCCs), 65 large-cell-carcinomas, 34 pleomorphic carcinomas, and 20 large-cell neuroendocrine carcinomas. HER2 status was determined for immunohistochemically positive cases with chromogenic in-situ hybridisation. Markers with a proportion of ≥5% positive cases in ADC and SqCC were considered for survival analysis. Among ADCs, 62 (10%), 17 (3%), one (<1%), seven (1%), and 49 (8%) cases were positive for ER, PgR, MAMG, HER2, and GATA3, respectively. Among SqCCs, 10 (2%), 14 (3%), two (<1%) and 109 (20%) cases were positive for ER, PgR, HER2, and GATA3, but none of the samples showed positivity for MAMG. ER positivity was associated with ADC, female sex, smaller tumour size, and lower clinical stage. None of the markers had an impact on survival.

Conclusion: We report on ER, PgR, MAMG, HER2 and GATA3 expression in a large cohort of NSCLCs. Interpretation of these markers in the differential diagnostic setting should be based on a multimarker panel.
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http://dx.doi.org/10.1111/his.14203DOI Listing
December 2020

Deep Learning for the Classification of Small-Cell and Non-Small-Cell Lung Cancer.

Cancers (Basel) 2020 06 17;12(6). Epub 2020 Jun 17.

Department Hematology, Oncology and Rheumatology, Heidelberg University, 69120 Heidelberg, Germany.

Reliable entity subtyping is paramount for therapy stratification in lung cancer. Morphological evaluation remains the basis for entity subtyping and directs the application of additional methods such as immunohistochemistry (IHC). The decision of whether to perform IHC for subtyping is subjective, and access to IHC is not available worldwide. Thus, the application of additional methods to support morphological entity subtyping is desirable. Therefore, the ability of convolutional neuronal networks (CNNs) to classify the most common lung cancer subtypes, pulmonary adenocarcinoma (ADC), pulmonary squamous cell carcinoma (SqCC), and small-cell lung cancer (SCLC), was evaluated. A cohort of 80 ADC, 80 SqCC, 80 SCLC, and 30 skeletal muscle specimens was assembled; slides were scanned; tumor areas were annotated; image patches were extracted; and cases were randomly assigned to a training, validation or test set. Multiple CNN architectures (VGG16, InceptionV3, and InceptionResNetV2) were trained and optimized to classify the four entities. A quality control (QC) metric was established. An optimized InceptionV3 CNN architecture yielded the highest classification accuracy and was used for the classification of the test set. Image patch and patient-based CNN classification results were 95% and 100% in the test set after the application of strict QC. Misclassified cases mainly included ADC and SqCC. The QC metric identified cases that needed further IHC for definite entity subtyping. The study highlights the potential and limitations of CNN image classification models for tumor differentiation.
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http://dx.doi.org/10.3390/cancers12061604DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352768PMC
June 2020

Reduction of Liver Metastasis Stiffness Improves Response to Bevacizumab in Metastatic Colorectal Cancer.

Cancer Cell 2020 06;37(6):800-817.e7

Department of General, Visceral and Transplantation Surgery, University Hospital Heidelberg, University Heidelberg, Im Neuenheimer Feld 110, 69120 Heidelberg, Germany. Electronic address:

Tumors are influenced by the mechanical properties of their microenvironment. Using patient samples and atomic force microscopy, we found that tissue stiffness is higher in liver metastases than in primary colorectal tumors. Highly activated metastasis-associated fibroblasts increase tissue stiffness, which enhances angiogenesis and anti-angiogenic therapy resistance. Drugs targeting the renin-angiotensin system, normally prescribed to treat hypertension, inhibit fibroblast contraction and extracellular matrix deposition, thereby reducing liver metastases stiffening and increasing the anti-angiogenic effects of bevacizumab. Patients treated with bevacizumab showed prolonged survival when concomitantly treated with renin-angiotensin inhibitors, highlighting the importance of modulating the mechanical microenvironment for therapeutic regimens.
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http://dx.doi.org/10.1016/j.ccell.2020.05.005DOI Listing
June 2020

Protein-altering germline mutations implicate novel genes related to lung cancer development.

Nat Commun 2020 05 11;11(1):2220. Epub 2020 May 11.

Radboud University Medical Center, Radboud Institute for Health Sciences, Nijmegen, The Netherlands.

Few germline mutations are known to affect lung cancer risk. We performed analyses of rare variants from 39,146 individuals of European ancestry and investigated gene expression levels in 7,773 samples. We find a large-effect association with an ATM L2307F (rs56009889) mutation in adenocarcinoma for discovery (adjusted Odds Ratio = 8.82, P = 1.18 × 10) and replication (adjusted OR = 2.93, P = 2.22 × 10) that is more pronounced in females (adjusted OR = 6.81 and 3.19 and for discovery and replication). We observe an excess loss of heterozygosity in lung tumors among ATM L2307F allele carriers. L2307F is more frequent (4%) among Ashkenazi Jewish populations. We also observe an association in discovery (adjusted OR = 2.61, P = 7.98 × 10) and replication datasets (adjusted OR = 1.55, P = 0.06) with a loss-of-function mutation, Q4X (rs150665432) of an uncharacterized gene, KIAA0930. Our findings implicate germline genetic variants in ATM with lung cancer susceptibility and suggest KIAA0930 as a novel candidate gene for lung cancer risk.
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http://dx.doi.org/10.1038/s41467-020-15905-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7214407PMC
May 2020
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