Optimal patient stratification is of utmost importance in the era of personalized medicine. Prediction of individual treatment responses by functional ex vivo assays requires model systems derived from viable tumor samples, which should closely resemble in vivo tumor characteristics and microenvironment. This review discusses a broad spectrum of model systems, ranging from classic 2D monolayer culture techniques to more experimental 'cancer-on-chip' procedures. We mainly focus on organotypic tumor slices that take tumor heterogeneity and tumor-stromal interactions into account. These 3D model systems can be exploited for patient selection as well as for fundamental research. Selection of the right model system for each specific research endeavor is crucial and requires careful balancing of the pros and cons of each technology.

Ex vivo tumor culture systems for functional drug testing and therapy response prediction.

https://pure.rug.nl/ws/files/74680084/1_s2.0_S1044579X18300464_main.pdf

Patient-derived tumor organoids for prediction of cancer treatment response.

Cancer treatment is challenged by the heterogeneous nature of cancer, where prognosis depends on tumor type and disease stage, as well as previous treatments. Optimal patient stratification is critical for the development and validation of effective treatments, yet pre-clinical model systems are lacking in the delivery of effective individualized platforms that reflect distinct patient-specific clinical situations. Advances in cancer cell biology, biofabrication, and microengineering technologies have led to the development of more complex in vitro three-dimensional (3D) models to act as drug testing platforms and to elucidate novel cancer mechanisms. Mostly, these strategies have enabled researchers to account for the tumor microenvironment context including tumor-stroma interactions, a key factor of heterogeneity that affects both progression and therapeutic resistance. This is aided by state-of-the-art biomaterials and tissue engineering technologies, coupled with reproducible and high-throughput platforms that enable modeling of relevant physical and chemical factors. Yet, the translation of these models and technologies has been impaired by neglecting to incorporate patient-derived cells or tissues, and largely focusing on immortalized cell lines instead, contributing to drug failure rates. While this is a necessary step to establish and validate new models, a paradigm shift is needed to enable the systematic inclusion of patient-derived materials in the design and use of such models. In this review, we first present an overview of the components responsible for heterogeneity in different tumor microenvironments. Next, we introduce the state-of-the-art of current in vitro 3D cancer models employing patient-derived materials in traditional scaffold-free approaches, followed by novel bioengineered scaffold-based approaches, and further supported by dynamic systems such as bioreactors, microfluidics, and tumor-on-a-chip devices. We critically discuss the challenges and clinical prospects of models that have succeeded in providing clinical relevance and impact, and present emerging concepts of novel cancer model systems that are addressing patient specificity, the next frontier to be tackled by the field.

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Addressing Patient Specificity in the Engineering of Tumor Models.

Helicobacter pylori Infection Modulates Host Cell Metabolism through VacA-Dependent Inhibition of mTORC1

Choosing wisely - Preclinical test models in the era of precision medicine.

Gastric and esophagogastric junction cancers are heterogeneous and aggressive tumors with an unpredictable response to cytotoxic treatment. New methods allowing for the analysis of drug resistance are needed. Here, we describe a novel technique by which human tumor specimens can be cultured ex vivo, preserving parts of the natural cancer microenvironment. Using a tissue chopper, fresh surgical tissue samples were cut in 400 μm slices and cultivated in 6-well plates for up to 6 days. The slices were processed for routine histopathology and immunohistochemistry. Cytokeratin stains (CK8, AE1/3) were applied for determining tumor cellularity, Ki-67 for proliferation, and cleaved caspase-3 staining for apoptosis. The slices were analyzed under naive conditions and following 2-4 days in vitro exposure to 5-FU and cisplatin. The slice culture technology allowed for a good preservation of tissue morphology and tumor cell integrity during the culture period. After chemotherapy exposure, a loss of tumor cellularity and an increase in apoptosis were observed. Drug sensitivity of the tumors could be assessed. Organotypic slice cultures of gastric and esophagogastric junction cancers were successfully established. Cytotoxic drug effects could be monitored. They may be used to examine mechanisms of drug resistance in human tissue and may provide a unique and powerful ex vivo platform for the prediction of treatment response.

Organotypic slice cultures of human gastric and esophagogastric junction cancer.

Chirurgische Fachdisziplinen kampfen mit einem kritischen und sich zuspitzenden Nachwuchsproblem. Potenzielle Berufsanfanger zahlen zur Generation Y, die Chefarzte und Personalabteilungen regelmasig vor grose Herausforderungen stellt. Ziel dieser Arbeit ist die Analyse verschiedener Masnahmen der Personalakquise unter Berucksichtigung erhobener Motivationsfaktoren junger Medizinstudenten. Umfrage unter Medizinstudenten des 1. und 9. Fachsemesters (FS) einer medizinischen Fakultat zu individuellen Motivationsfaktoren, der angestrebten Facharztweiterbildung und der gesammelten Berufserfahrung in der Chirurgie. Ergebnisse von 179 der 269 befragten Medizinstudenten (66,5 %) konnten ausgewertet werden. Das Interesse an einer chirurgischen Facharztweiterbildung ist im 1. FS hoch (21 %) – fallt jedoch bis zum 9. FS deutlich ab (13 %; p = 0,23). Medizinstudenten, die im 9. FS „Aufstieg und Anerkennung“ gegenuber „flexible Arbeitszeiten“ praferieren, zeigen ein signifikant hoheres Interesse an einer chirurgischen Weiterbildung (p = 0,022). Erworbene chirurgische Berufserfahrung wird mit einer durchschnittlichen Schulnote von 2+ bewertet. Das hohe Grundinteresse an einer chirurgischen Facharztweiterbildung zu Studienbeginn ist ein Wettbewerbsvorteil der Chirurgie. Die vielfaltigen Rekrutierungsanstrengungen setzen jedoch oft erst gegen Ende des Studiums an. Zur langfristigen Nachwuchsbindung haben sich insbesondere fruhzeitige Programme mit „Hands-on“-Charakter im chirurgischen Kernarbeitsbereich – dem Operationssaal – als erfolgreich erwiesen.

/pdf/generation-y-in-der-chirurgie-der-konkurrenzkampf-um-talente-3y3mrxm9rv.pdf

Generation Y in der Chirurgie – der Konkurrenzkampf um Talente in Zeiten des Nachwuchsmangels

Background and objectives Texture analysis derived from morphological magnetic resonance (MR) images might be associated with histopathology in tumors. The present study sought to elucidate possible associations between texture features derived from T1-and T2-weighted images with proliferation index Ki67 in soft tissue sarcomas. Methods Overall, 29 patients (n = 13, 44.8% female) with a median age of 52 years were included into this retrospective study. Several soft tissue sarcomas were investigated. Texture analysis was performed on pre-contrast T1-weighted and T2-weighted images using the free available Mazda software. Results The best correlation coefficients with Ki67 index were identified for the following parameters: T1-weighted images “45dgr_RLNonUni (p = 0.50, P = 0.006), T2-weighted images “S (4,0)SumAverg” (p = −0.45, P = 0.02). A ROC analysis was performed for Ki67-index with a threshold of 10%. The highest area under the curve (AUC) was found for the parameter “T1_WavEnHL_s-7” with an AUC of 0.90. For the threshold of Ki67 = 20% the highest AUC was identified for the parameter „T2_S (1,1)Entropy” with an AUC of 0.77. Conclusion Several texture features derived from T1-and T2-weighted images correlated with proliferation index Ki67 and might be used as valuable novel biomarkers in soft tissue sarcomas.

Texture analysis parameters derived from T1-and T2-weighted magnetic resonance images can reflect Ki67 index in soft tissue sarcoma

Regulator of Chromatin Condensation 1 (RCC1) is the only known guanine nucleotide exchange factor that acts on the Ras-like G protein Ran and plays a key role in cell cycle regulation. Although there is growing evidence to support the relationship between RCC1 and cancer, detailed pancancer analyses have not yet been performed. In this genome database study, based on The Cancer Genome Atlas, Genotype-Tissue Expression and Gene Expression Omnibus databases, the potential role of RCC1 in 33 tumors’ entities was explored. The results show that RCC1 is highly expressed in most human malignant neoplasms in contrast to healthy tissues. RCC1 expression is closely related to the prognosis of a broad variety of tumor patients. Enrichment analysis showed that some tumor-related pathways such as “cell cycle” and “RNA transport” were involved in the functional mechanism of RCC1. In particular, the conducted analysis reveals the relation of RCC1 to multiple immune checkpoint genes and suggests that the regulation of RCC1 is closely related to tumor infiltration of cancer-associated fibroblasts and CD8+ T cells. Coherent data demonstrate the association of RCC1 with the tumor mutation burden and microsatellite instability in various tumors. These findings provide new insights into the role of RCC1 in oncogenesis and tumor immunology in various tumors and indicate its potential as marker for therapy prognosis and targeted treatment strategies.

Integrative and Comprehensive Pancancer Analysis of Regulator of Chromatin Condensation 1 (RCC1).

Lower-grade glioma (LGG) is a group of tumors arising from the cells of the central nervous system. Although various therapy interventions are used, the prognosis remains different. Novel biomarkers are needed for the prognosis of disease and novel therapeutic strategies in LGG. The procollagen-lysine, 2-oxoglutarate 5-dioxygenase (PLOD) family contains three members and is related to multiple cancers, yet it was not investigated in LGG. Data from the Chinese Glioma Genome Atlas (CGGA) and The Cancer Genome Atlas (TCGA) cohorts were used to analyze the role of PLOD in LGG. As the PLOD family is involved in processes, such as tumor formation and cancer metastasis, we focused on its relationship to the tumor microenvironment (TME) in LGG. A high expression of the PLOD family relates to poor prognosis and high infiltration of immune cells within the TME. The expression level of the PLOD family might become a novel biomarker for prognosis and is a potential target for individual treatment decisions in LGG.

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Nikolas Schopow

Papers

Organotypic slice cultures of human gastric and esophagogastric junction cancer.

Generation Y in der Chirurgie – der Konkurrenzkampf um Talente in Zeiten des Nachwuchsmangels

Texture analysis parameters derived from T1-and T2-weighted magnetic resonance images can reflect Ki67 index in soft tissue sarcoma

Integrative and Comprehensive Pancancer Analysis of Regulator of Chromatin Condensation 1 (RCC1).

Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase Family: Novel Prognostic Biomarkers and Tumor Microenvironment Regulators for Lower-Grade Glioma