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Background: Soft tissue myoepithelial carcinomas (STMC) are a rare, malignant subgroup of myoepithelial tumors that arise typically in glandular or ductal tissues, but also in the bone and soft and cutaneous tissues. Due to its rarity, there is no consensus regarding the treatment of STMC, including chemotherapy or other systemic agents for metastatic STMC. Case Report: A chemotherapy- and regorafenibrefractory STMC, harboring an AGK-BRAF fusion, was successfully treated using MEK-inhibition with cobimetinib in monotherapy. MEK-inhibition with cobimetinib effectively silenced paradoxical MAP kinase/ERK-signaling pathway activation after regorafenib monotherapy, and resulted in a significant and durable clinical response. Conclusion: This effect of MEK-inhibition in STMC harboring an AGK-BRAF fusion has not been previously reported and contributes to the existing, yet limited, knowledge on the treatment of BRAF fusion-driven tumors. Also, our case highlights the importance of next generation sequencing in driving further rational therapeutic choices to provide disease control and palliation.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal diseases, characterized by a treatment-resistant and invasive nature. In-line with these inherent aggressive characteristics, only a subset of patients show a clinical response to the standard of care therapies, thereby highlighting the need for a more personalized treatment approach. In this study, we comprehensively unraveled the intra-patient response heterogeneity and intrinsic aggressive nature of PDAC on bulk and single-organoid resolution. We leveraged a fully characterized PDAC organoid panel (N=8) and matched our artificial intelligence-driven, live-cell organoid image analysis with retrospective clinical patient response. In-line with the clinical outcomes, we identified patient-specific sensitivities to the standard of care therapies (gemcitabine-paclitaxel and FOLFIRINOX) using a growth rate-based and normalized drug response metric. Moreover, the single-organoid analysis was able to detect resistant as well as invasive PDAC organoid clones, which was orchestrates on a patient, therapy, drug, concentration and time-specific level. Furthermore, ourin vitroorganoid analysis indicated a strong correlation with the matched patient progression-free survival (PFS) compared to the current, conventional drug response readouts. This work not only provides valuable insights on the response complexity in PDAC, but it also highlights the potential applications (extendable to other tumor types) and clinical translatability of our approach in drug discovery and the emerging era of personalized medicine.

Upper gastrointestinal tract tumors historically have a poor prognosis. The decision to treat esophageal or gastric cancers by surgery, radiotherapy, systemic therapy, or a combination of these treatment modalities should always be discussed multidisciplinary. The introduction of immunotherapy has drastically transformed the treatment landscape of multiple solid malignancies. Emerging data from early and late phase clinical trials suggests that the use of immunother-apies that target immune checkpoint proteins such as PD-1/PD-L1 result in superior overall survival in advanced, metastatic, or recurrent esophageal and gastric cancer, whether or not with specific molecular characteristics such as PD-L1 expression level or microsatellite instability. This review offers an overview of the most recent advances in the field of immunotherapy treatment in esophageal and gastric cancer.

Simple Summary The tumor microenvironment (TME) is increasingly believed to be involved in therapy resistance and disease progression of different cancer types. Cancer-associated fibroblasts (CAFs) are prominent components and a central player in creating this TME. In particular, lung and pancreatic cancer, two solid tumor types associated with therapy resistance and poor long-term prognosis have clear evidence of CAFs. In order to provide a more holistic approach of therapy resistance, we highlight different mechanisms of CAF contribution to tumor progression and provide a comprehensive review on how CAFs affect their response to clinical therapy and prognosis, and present an overview of novel therapies and future perspectives involving CAF-targeting agents for both cancer types. Abstract Cancer arises from mutations accruing within cancer cells, but the tumor microenvironment (TME) is believed to be a major, often neglected, factor involved in therapy resistance and disease progression. Cancer-associated fibroblasts (CAFs) are prominent and key components of the TME in most types of solid tumors. Extensive research over the past decade revealed their ability to modulate cancer metastasis, angiogenesis, tumor mechanics, immunosuppression, and drug access through synthesis and remodeling of the extracellular matrix and production of growth factors. Thus, they are considered to impede the response to current clinical cancer therapies. Therefore, targeting CAFs to counteract these protumorigenic effects, and overcome the resistance to current therapeutic options, is an appealing and emerging strategy. In this review, we discuss how CAFs affect prognosis and response to clinical therapy and provide an overview of novel therapies involving CAF-targeting agents in lung and pancreatic cancer.

Aim: The purpose of this manuscript is to study the potential characteristics of acquired nutlin-3 resistant non-small cell lung cancer cells (NSCLC). Nutlin-3 is an inhibitor of the murine-double minute 2 protein, the main negative regulator of wild type p53, of which several derivatives are currently in clinical development. Methods: A549 NSCLC cells were exposed to increasing concentrations of nutlin-3 for a period of 18 weeks. Monoclonal derivates were cultured, and the most resistance subclone was selected for whole transcriptome analysis. Gene set enrichment analysis was performed on differentially expressed genes between A549 nutlin-3 resistant cancer cells and the parental A549 p53 wild type cancer cells. Relevant findings were validated at the gene, protein and/or functional level. Results: All nutlin-3 resistant subclones acquired mutations in the TP53 gene, resulting in overexpression of the mutant p53 protein. The most resistant subclone was enriched for genes related to epithelial to mesenchymal transition (EMT), resulting in increased migratory and invasive potential. Furthermore, these cells were enriched in genes related to inflammation, tissue remodelling, and angiogenesis. Importantly, expression of several immune checkpoints, including PD-L1 and PD-L2, was significantly upregulated, and cisplatin-induced cell death was reduced. Conclusion: Transcriptome analysis of a highly nutlin-3 resistant A549 subclone shows the relevance of studying (1) resistance to standard of care chemotherapy; (2) secretion of immunomodulating chemo- and cytokines; (3) immune checkpoint expression; and (4) EMT and invasion in nutlin-3 resistant cancer cells in addition to acquired mutations in the TP53 gene.

Simple Summary Soft tissue and bone sarcomas is a very heterogeneous group of tumors that has an aggressive course, especially in the metastatic setting. In this group the therapeutic options are rather limited. Immunotherapy is nowadays used successfully for the treatment of various tumor types. However in sarcomas this is still not the case. In this review article we aim to present all the available published information from clinical trials about the results of using immune checkpoint blockade as a therapeutic agent in sarcomas. Moreover, we try to unravel the possible prognostic biomarkers that may play here an important role. Soft tissue and bone sarcomas are a very heterogeneous group of tumors with many subtypes for which diagnosis and treatment remains a very challenging task. On top of that, the treatment choices are limited, and the prognosis of aggressive sarcomas remains poor. Immune checkpoint inhibitors (ICIs) have drawn a lot of attention last years because of their promising response rates and their durable effects. ICIs are currently widely used in the daily routine practice for the treatment of a different malignancies, such as melanoma, Hodgkin lymphoma, and non-small cell lung carcinoma. Still, ICIs are not included in the standard treatment protocols of the different sarcoma types. However, a plethora of clinical trials investigates the clinical benefit of ICIs in sarcomas. There is clear need to develop predictive biomarkers to determine which sarcoma patients are most likely to benefit from immune checkpoint blockade. This review will focus on (i) the clinical trial results on the use of ICIs in different sarcoma types; and on (ii) possible biomarkers predictive for the effectiveness of these drugs in sarcomas.

The optimal treatment of malignant pleural mesothelioma (MPM) has not yet been established and is still under investigation. Surgery is one of the pillars in the multimodality approach with the purpose of removing as much as visible tumor as possible and to relieve symptoms. To date, two major surgical procedures are available for removal or debulking of MPM that is considered to be resectable: [extended (e)] pleurectomy/decortication (P/D) and extrapleural pneumonectomy (EPP). Historically, EPP was regarded as the only way to achieve a macroscopic complete resection. However, in the last years, there is a shift in literature towards (e) P/D as the preferred surgical procedure whenever possible as several retrospective studies and meta-analyses showed a similar or lower long-term survival and higher perioperative mortality and postoperative morbidity in patients who been treated with EPP. On the other hand, no randomized-controlled trials regarding surgical treatment with (e) P/D or EPP exist and therefore level A evidence favoring one surgical procedure is lacking. In this review we provide a nuanced and well-considered answer to the question whether EPP is still indicated in the surgical treatment of MPM.

Purpose Laparoscopic primary or incisional abdominal hernia repair with intraperitoneal mesh placement is a well-accepted and safe technique. Evidence for complications however remains inconclusive, and little is known about the occurrence of postoperative ileus secondary to postoperative intra-abdominal adhesions with different types of IPOM meshes used. Therefore, we retrospectively compared the occurrence of postoperative ileus between two of the different meshes used in our center. Methods Three hundred seventy-five patients who underwent ventral hernia repair with intraperitoneal mesh placement, either with a DynaMesh (R)-IPOM (FEG Textiltechnik mbH, Aachen, Nordrhein-Westfalen, Germany) or a Parietex (TM) Composite mesh (Medtronic, Minneapolis, MN, USA), at the Heilig-Hart Hospital in Lier (Antwerp, Belgium) between 2012 and 2017 were retrospectively compared with regard to the occurrence of postoperative ileus until 6 weeks postoperatively. Baseline demographics and clinical data up to 6 weeks postoperatively of the patients in the two mesh groups are provided. Results The DynaMesh (R)-IPOM mesh group was associated with a significantly higher incidence of postoperative ileus compared with the Parietex (TM) Composite mesh group with a cutoff limit at postoperative day 1 (n = 17, 6.8% vs. n = 0, 0.0%; P = 0.003) and postoperative day 4 (n = 13, 5.2% vs. n = 0, 0.0%, P = 0.006), even with a mesh surface area of

Polo-like kinase 1 (Plk1), a master regulator of mitotic cell division, is highly expressed in non-small cell lung cancer (NSCLC) making it an interesting drug target. We examined the in vitro therapeutic effects of volasertib, a Plk1 inhibitor, in combination with irradiation in a panel of NSCLC cell lines with different p53 backgrounds. Pretreatment with volasertib efficiently sensitized p53 wild type cells to irradiation. Flow cytometric analysis revealed that significantly more cells were arrested in the G2/M phase of the cell cycle after the combination therapy compared to either treatment alone (p < 0.005). No significant synergistic induction of apoptotic cell death was observed, but, importantly, significantly more senescent cells were detected when cells were pretreated with volasertib before irradiation compared to both monotherapies alone (p < 0.001), especially in cells with functional p53. Consequently, while most cells with functional p53 showed permanent growth arrest, more p53 knockdown/mutant cells could re-enter the cell cycle, resulting in colony formation and cell survival. Our findings assign functional p53 as a determining factor for the observed radiosensitizing effect of volasertib in combination with radiotherapy for the treatment of NSCLC.

Background: Malignant pleural mesothelioma (MPM) is a rare but aggressive neoplasm that typically originates from the mesothelial surfaces of the pleural cavity. Exposure to asbestos is the principal etiological agent of MPM. The disease is characterized by difficult stage classification and limited consensus on therapeutic approach. We have evaluated the experience with MPM in the Antwerp University Hospital over the past 15 years. Methods: A database was created with all patients diagnosed with or treated for a MPM between 2001 and 2015. A total of 101 patients were included on which different survival analyses were performed combined with a reproduction of demographic, clinical, histologic and therapeutic data, and these were compared to literature data. Results: Vast majority of our 101 patients were male (80%) with a median age of 66 years at diagnosis with predominantly epitheloid histology (81%). Overall median survival was 18.3 months and overall 1-, 2- and 5-year survival rates were 68%, 37% and 7%, respectively. Kaplan-Meier analysis showed a non-significant difference in survival between the several best (b) TNM-stages (p = .356). A significant difference in survival was observed in patients undergoing surgery versus no surgery (p = .008), between the different histological types (p < .0001) and treatment with chemotherapy alone versus chemotherapy with surgery (p < .0001). Smoking at diagnosis and epitheloid histology have been identified as significant prognostic factors in the multivariate Cox regression model (HR 3.13 and 0.53, respectively). Conclusion: Descriptive and survival analysis of our patient database confirmed the limitations of the current staging system and were concordant with literature regarding MPM.

Background : Malignant pleural mesothelioma (MPM) is a rare but aggressive thoracic malignancy with a poor prognosis. In this regard, a well-defined staging system is of utmost importance in order to correctly diagnose-and assign an appropriate treatment to the patient. Methods : The current TNM-staging system (7th edition) enables to either clinically or pathologically stage the severity of the disease according to extension of the tumor (T), number of nodes (N) and presence of metastases (M). Patients with stage I-III are considered for surgery, while palliative treatment is indicated for stage IV patients according to the current classification. Results : Despite its widespread use, the validity of this staging system is questioned due to the low prevalence, histological variety and retrospective nature of the previous study design. In addition, the role of specific treatment modalities including surgery, has yet to be determined, especially for treatment of early-stage disease. In this regard, the International Association for the Study of Lung Cancer (IASLC) initiated the multi-centre, prospective "Mesothelioma Staging Project" in order to address limitations of the 7th edition and to optimize the staging system in accordance to current needs. Conclusions : An improved staging system will contribute to the design of prospective multi-institutional clinical trials investigating novel treatment strategies for mesothelioma. In this way comparison of outcome between different medical centres also becomes feasible.

Aim/Purpose of the Study: Activation of the renin-angiotensin system leading to increased angiotensin-(1–7) (Ang-(1–7)) and decreased angiotensin 2 (Ang 2) levels may be a new therapeutic approach to reduce acute lung injury. Prolylcarboxypeptidase (PRCP) and prolyloligopeptidase (PREP) are capable of hydrolyzing Ang 2 into Ang-(1–7). However, their relation with circulating Ang 2 levels after lung ischemia–reperfusion injury (LIRI) has never been explored. This study determines whether the activity and expression of PRCP and PREP in plasma and lung tissue is related to circulating Ang 2 levels in a murine model of LIRI. Materials and Methods: LIRI in Swiss mice (6 animals per group) was induced by temporary left lung hilar clamping (1 h) followed by 0, 1 or 24 h of reperfusion. Animals in the sham group received thoracotomy only. PRCP activity was measured via RP-HPLC, PREP activity using a fluorogenic substrate and plasma Ang 2 levels via ELISA. Western blotting was used to determine the PRCP and PREP protein expression profiles in left lung tissue. Results: Plasma Ang 2 levels significantly rise after lung ischemia and remain increased after 1 h and 24 h of reperfusion compared to the sham group. While a significant decrease in plasma PREP activity was found after 24 h of reperfusion, a transient increase in plasma PRCP activity was observed after ischemia. However, no correlation with plasma Ang 2 levels could be demonstrated. The activity profiles of PRCP and PREP and the protein expression of PRCP in the lung tissues remained unchanged after LIRI. Conclusions: LIRI causes a dysregulation of circulating Ang 2 levels and plasma PREP activity, although no direct link between both phenomena could be shown. The activity profile of pulmonary PRCP and PREP was not significantly changed after LIRI, which implies a minor role for local PRCP and PREP in the ischemic lung itself.

The prognosis of patients with malignant pleural mesothelioma remains poor and although it is clear that multimodal therapy is necessary to improve long-term results, precise treatment schemes have not yet been unequivocally established. Single-modality therapy does not have a major impact on long-term survival and combined-modality therapies are being further evaluated. However, the relative contributions of chemotherapy, radiotherapy and surgery have not been clearly determined at the present time. Moreover, the extent of resection and precise surgical procedure remain a highly debated topic. To better compare and combine results from different institutions and trials, uniform definitions of surgical procedures including extrapleural pneumonectomy and different forms of pleurectomy have recently been introduced. Due to the relatively higher morbidity and mortality of extrapleural pneumonectomy, there is currently a shift towards pleurectomy/decortication when a macroscopic complete resection of all tumour can be obtained by this procedure. In most recent trials, induction chemotherapy was administered to improve surgical resection rates but pathological complete responses are infrequently observed. The role of post-operative radiotherapy has to be further elucidated. Further treatment options that are currently explored include hyperthermic intrapleural chemotherapy, immunotherapy, gene therapy and photodynamic therapy. However, no randomised comparisons are available yet.

Les cellules cancéreuses ne fonctionnent pas de manière autonome, mais interagissent et sont influencées par leur environnement, à savoir le microenvironnement tumoral. Cet écosystème complexe se compose d’une matrice extracellulaire, de cellules endothéliales, de cellules immunitaires infiltrantes des systèmes immunitaires inné et adaptatif, ainsi que de fibroblastes activés. Dans des conditions physiologiques, les fibroblastes sont dans un état de repos et agissent de manière à soutenir l’homéostasie tissulaire normale. En revanche, dans le tissu tumoral, ces fibroblastes sont activés de manière chronique et irréversible, raison pour laquelle ils sont appelés «fibroblastes associés au cancer» (FAC). La recherche sur les FAC a montré qu’ils jouent non seulement un rôle important dans la progression et le caractère malin de la tumeur, mais aussi un rôle central en tant que médiateurs de la résistance à la thérapie dans les cancers du poumon et du pancréas.

Kankercellen fungeren niet autonoom, maar interageren en worden beïnvloed door het milieu waar ze zich in bevinden, namelijk de tumormicro-omgeving. Dit complex ecosysteem bestaat uit extracellulaire matrix, endotheelcellen, infiltrerende immuuncellen van zowel het aangeboren als adaptief immuunsysteem en geactiveerde fibroblasten. In fysiologische condities bevinden fibroblasten zich in een rusttoestand en functioneren ze ter ondersteuning van de normale weefselhomeostase. In het tumorweefsel echter, worden deze fibroblasten chronisch en irreversibel geactiveerd, en daardoor kankergeassocieerde fibroblasten (KAFs) genoemd. Onderzoek naar KAFs heeft aangetoond dat deze niet enkel een belangrijke rol spelen in de progressie en het kwaadaardig karakter van de tumor, maar ook een centrale rol vervullen als mediatoren van therapieresistentie in long- en pancreaskanker.