Boolean network modeling and its integration with experimental read-outs : An interdisciplinary presentation using a leukemia model.

The limited availability of suitable animal models and cell lines often impedes experimental cancer research. Wet-laboratory experiments are also time-consuming and cost-intensive. In this review, we present an in silico modeling strategy, namely, Boolean network (BN) models, and demonstrate how it could be applied to streamline experimental design and to focus the effort of experimental read-outs.

Desmoplastic Small Round Cell Tumors: Clinical Presentation, Molecular Characterization, and Therapeutic Approach of Seven Patients.

Desmoplastic small round blue cell tumor (DSRCT) is a highly aggressive fatal sarcoma without evidence-based therapeutic guidelines. We present here seven patients with DSRCT including immunohistochemistry combined with fluorescence in situ hybridization (FISH), next generation sequencing (NGS,  = 6) as well as OncoScan array ( = 3) analyses and show consecutive therapeutic approaches. All seven DSRCT patients presented with an extended abdominal mass; median age at diagnosis was 24.

Impact of CDK Inhibitors on Expression in Chordoma Cell Lines Including the First Stable Cell Line of a High-Grade Chordoma.

Chordomas are very rare malignant neoplasms of the bone occurring almost exclusively along the spine. As the tumours are thought to arise from notochordal remnants, the vast majority of chordomas express the gene, resulting in detectable nuclear amounts of its gene product brachyury. This T-Box transcription factor is commonly recognised as being essential in chordoma cells, and limiting expression is thought to be the key factor in controlling this tumour.

Development, testing and validation of a targeted NGS-panel for the detection of actionable mutations in lung cancer (NSCLC) using anchored multiplex PCR technology in a multicentric setting.

Lung cancer is a paradigm for a genetically driven tumor. A variety of drugs were developed targeting specific biomarkers requiring testing for tumor genetic alterations in relevant biomarkers. Different next-generation sequencing technologies are available for library generation: 1) anchored multiplex-, 2) amplicon based- and 3) hybrid capture-based-PCR.

Molecular heterogeneity in histomorphologic subtypes of lung adeno carcinoma represents a challenge for treatment decision.

Lung cancer is the leading cause in cancer related death, with non-small cell lung cancer (NSCLC) being the most frequent subtype. The importance of NSCLC is reflected by the various targeted therapy options especially for NSCLC adenocarcinomas (lung adeno carcinoma (LUAD)) as well as a set of options for immune therapies. However, despite these therapy advances, the majority of patients do not show a long-term response to either targeted therapy or immune checkpoint inhibition.

Multicentric pilot study to standardize clinical whole exome sequencing (WES) for cancer patients.

A growing number of druggable targets and national initiatives for precision oncology necessitate broad genomic profiling for many cancer patients. Whole exome sequencing (WES) offers unbiased analysis of the entire coding sequence, segmentation-based detection of copy number alterations (CNAs), and accurate determination of complex biomarkers including tumor mutational burden (TMB), homologous recombination repair deficiency (HRD), and microsatellite instability (MSI). To assess the inter-institution variability of clinical WES, we performed a comparative pilot study between German Centers of Personalized Medicine (ZPMs) from five participating institutions.

AMBAR - Interactive Alteration annotations for molecular tumor boards.

Motivation: Personalized decision-making for cancer therapy relies on molecular profiling from sequencing data in combination with database evidence and expert knowledge. Molecular tumor boards (MTBs) bring together clinicians and scientists with diverse expertise and are increasingly established in the clinical routine for therapeutic interventions. However, the analysis and documentation of patients data are still time-consuming and difficult to manage for MTBs, especially as few tools are available for the amount of information required.

Heterogeneous expression of predictive biomarkers PD-L1 and TIGIT in non-mucinous lung adenocarcinoma and corresponding lymph node metastasis: A challenge for clinical biomarker testing.

The use of immune checkpoint inhibitors (ICI) targeting the PD-L1:PD1 interaction revolutionized tumor treatment by re-activating the anti-tumoral capacity of the immune system. Assessment of tumor mutational burden, microsatellite instability, or expression of the surface marker PD-L1 have been used to predict individual response to ICI therapy. However, the predicted response does not always correspond to the actual therapy outcome.

Targetable alterations in primary extranodal diffuse large B-cell lymphoma.

Primary extranodal diffuse large B-cell lymphoma (PE-DLBCL) is a heterogeneous subgroup of DLBCL. We investigated the prevalence and prognostic value of surface expression of PD-L1, PD1, and CD30, copy number of 9p24.1 (PD-L1 region), and mutations in , , , and in a cohort of 116 patients, localized in the mediastinum (PMBL,  = 12), ear, nose and throat (ENT,  = 28), central nervous system ( = 29), testis ( = 7), breast ( = 4), stomach ( = 10), bone ( = 8), spleen ( = 2), and skin ( = 16).

Epigenetic lockdown of CDKN1A (p21) and CDKN2A (p16) characterises the neoplastic spindle cell component of giant cell tumours of bone.

Giant cell tumour of bone (GCTB) comprises the eponymous osteoclastic multinucleated giant cells eliciting bone lysis, an H3F3A-mutated neoplastic mononucleated fibroblast-like cell population, and H3F3A wild-type mononucleated stromal cells. In this study, we characterised four new cell lines from GCTB. Furthermore, we compared the genome-wide DNA methylation profile of 13 such tumours and three further cell lines with giant cell-rich lesions comprising three H3F3B-mutated chondroblastomas, three USP6-rearranged aneurysmal bone cysts, three non-ossifying fibromas, two hyperparathyroidism-associated brown tumours as well as mesenchymal stem cells, osteoblasts, and osteoclasts.

CARD9 Forms an Alternative CBM Complex in Richter Syndrome.

Richter syndrome (RS) is defined as the transformation of chronic lymphocytic leukemia (CLL) into an aggressive lymphoma, mostly diffuse large B-cell lymphoma (DLBCL). Despite intensive therapy, patients with RS have an unfavorable clinical outcome. The detailed pathobiology of Richter transformation still needs to be elucidated.

CCND3 is indispensable for the maintenance of B-cell acute lymphoblastic leukemia.

The D-type cyclins (CCND1, CCND2, and CCND3) in association with CDK4/6 are known drivers of cell cycle progression. We reported previously that inactivation of FOXO1 confers growth arrest and apoptosis in B-ALL, partially mediated by subsequent depletion of CCND3. Given that previously the canonical MYC target CCND2 has been considered to play the major role in B-ALL proliferation, further investigation of the role of FOXO1 in CCND3 transcription and the role of CCND3 in B-ALL is warranted.

Combination of two monoclonal antibodies with SOCS1 N- and C-terminal binding sites to address SOCS1 status in B cells and B-cell lymphoma.

Introduction: Accumulating studies show that the tumour suppressor SOCS1 is one of the most frequently mutated genes in lymphomas, often affecting the coding sequence of SOCS1 protein. Depending on the type of mutation and lymphoma concerned, SOCS1 mutations have different impacts on progression-free and overall survival. Two antibodies binding the N and C terminals of SOCS1 would be a suitable 'test pair' to identify truncated versions of SOCS1.

Efficacy of Immune Checkpoint Inhibitors Alone or in Combination With Chemotherapy in NSCLC Harboring ERBB2 Mutations.

Introduction: In contrast to other driver mutations, no targeted therapies have yet been approved in ERBB2-mutated NSCLC (HER2mu NSCLC). Nevertheless, several compounds have revealed promising early efficacy data, which need to be evaluated in the context of current standard approaches. Although data on the efficacy of immune checkpoint inhibitors (ICIs) in second or subsequent lines of treatment remain limited and conflicting, there are virtually no data on patient outcome under ICI/platinum-doublet combinations in the first-line setting.

Spatial distribution of immune checkpoint proteins in histological subtypes of lung adenocarcinoma.

The most prevalent histological type of non-small cell lung cancer (NSCLC) is adenocarcinoma. The WHO classifies this tumor into subtypes according to the predominant growth pattern such as lepidic, acinar, papillary, solid or micropapillary, each harboring specific molecular features. NSCLC adenocarcinoma heterogeneity is discussed to be a reason for therapy failure using targeted therapy or immune checkpoint inhibitors.

Age-related activity of Poly (ADP-Ribose) Polymerase (PARP) in men with localized prostate cancer.

Mutations in DNA repair genes have been connected with familial prostate cancer and sensitivity to targeted drugs like PARP-inhibitors. Clinical use of this information is limited by the small fraction of prostate cancer risk gene carriers, variants of unknown pathogenicity and the focus on monogenic disease mechanisms. Functional assays capturing mono- and polygenic defects were shown to detect breast and ovarian cancer risk in blood-derived cells.

A new reliable and highly specific monoclonal antibody to detect the C-terminal region of silencer of cytokine signaling 1.

Introduction: SOCS1, a negative regulator of JAK/STAT signaling, is among the most frequently mutated genes in DLBCL and classical Hodgkin lymphoma. The C-terminal SOCS box domain, mediating the degradation of phospho-JAK2, is often affected or even lacking. The analysis of such variants is hampered by the lack of a SOCS1-specific monoclonal antibody recognizing the C-terminus of SOCS1.

Profiling of three H3F3A-mutated and denosumab-treated giant cell tumors of bone points to diverging pathways during progression and malignant transformation.

Giant cell tumor of bone (GCTB) is a locally aggressive lesion of intermediate malignancy. Malignant transformation of GCTB is a rare event. In 2013, the humanized monoclonal antibody against receptor activator of nuclear factor-κb-Ligand (RANKL) denosumab was approved for treatment of advanced GCTB.

Increasing Mean Age of Head and Neck Cancer Patients at a German Tertiary Referral Center.

Background: The impact of demographic change on the age at diagnosis in German head and neck cancer (HNC) patients is unclear. Here we present an evaluation of aging trends in HNC at a tertiary referral center.

Methods: Retrospective cohort study on aging trends at the initial diagnosis of newly diagnosed patients with HNC between 2004 and 2018 at the head and neck cancer center Ulm in relation to demographic data of the catchment area.

The PTP1B mutant PTP1B∆2-4 is a positive regulator of the JAK/STAT signalling pathway in Hodgkin lymphoma.

The neoplastic Hodgkin/Reed-Sternberg (HRS) cells of classical Hodgkin lymphoma (cHL) depend on chronic activation of the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signalling pathways to maintain survival and proliferation. Accumulating reports highlight the importance of the inactivation or reduced expression of negative JAK/STAT regulators such as the protein-tyrosine phosphatase 1B (PTP1B/PTPN1) in this process. Various PTPN1 mRNA variants as well as truncated PTP1B proteins were identified in cHL cell lines and primary cHL tumour samples.

Rescue of Non-Informative Circulating Tumor DNA to Monitor the Mutational Landscape in NSCLC.

In non-small cell lung cancer (NSCLC) the usage of plasma-derived circulating tumor DNA (ctDNA) have come into focus to obtain a comprehensive genetic profile of a given lung cancer. Despite the usage of specific sampling tubes, archived plasma samples as well as inappropriately treated blood samples still cause a loss of information due to cell lysis and contamination with cellular DNA. Our aim was to establish a reliable protocol to rescue ctDNA from such non-informative samples to monitor the mutational landscape in NSCLC.

Pancreatic cancer-derived organoids - a disease modeling tool to predict drug response.

Background: Organotypic cultures derived from pancreatic ductal adenocarcinoma (PDAC) termed pancreatic ductal cancer organoids (PDOs) recapitulate the primary cancer and can be derived from primary or metastatic biopsies. Although isolation and culture of patient-derived pancreatic organoids were established several years ago, pros and cons for individualized medicine have not been comprehensively investigated to date.

Methods: We conducted a feasibility study, systematically comparing head-to-head patient-derived xenograft tumor (PDX) and PDX-derived organoids by rigorous immunohistochemical and molecular characterization.