Dual Inhibition of mTORC1/2 Reduces Migration of Cholangiocarcinoma Cells by Regulation of Matrixmetalloproteinases

Cholangiocarcinoma (CCA) is a rare but highly aggressive tumor entity for which systemic therapies only showed limited efficacy so far. As OSI-027—a dual kinase inhibitor targeting both mTOR complexes, mTORC1 and mTORC2 - showed improved anti-cancer effects, we sought to evaluate its impact on the migratory and metastatic capacity of CCA cells in vitro. We found that treatment with OSI-027 leads to reduced cell mobility and migration as well as a reduced surviving fraction in colony-forming ability. While neither cell viability nor proliferation rate was affected, OSI-027 decreased the expression of MMP2 and MMP9. Moreover, survival as well as anti-apoptotic signaling was impaired upon the use of OSI-027 as determined by AKT and MAPK blotting. Dual targeting of mTORC1/2 might therefore be a viable option for anti-neoplastic therapy in CCA.

Influence of the First Wave of the COVID-19 Pandemic on Cancer Care in a German Comprehensive Cancer Center

Introduction: During the first wave of the COVID-19 pandemic in 2020, the German government implemented legal restrictions to avoid the overloading of intensive care units by patients with COVID-19. The influence of these effects on diagnosis and treatment of cancer in Germany is largely unknown.Methods: To evaluate the effect of the first wave of the COVID-19 pandemic on tumor board presentations in a high-volume tertiary referral center (the German Comprehensive Cancer Center NCT/UCC Dresden), we compared the number of presentations of gastrointestinal tumors stratified by tumor entity, tumor stage, and treatment intention during the pandemic to the respective data from previous years.Results: The number of presentations decreased by 3.2% (95% CI −8.8, 2.7) during the COVID year 2020 compared with the pre-COVID year 2019. During the first shutdown, March–May 2020, the total number of presentations was 9.4% (−18.7, 1) less than during March–May 2019. This decrease was significant for curable cases of esophageal cancer [N = 37, 25.5% (−41.8, −4.4)] and colon cancer [N = 36, 17.5% (−32.6, 1.1)] as well as for all cases of biliary tract cancer [N = 26, 50% (−69.9, −15)] during the first shutdown from March 2020 to May 2020.Conclusion: The impact of the COVID-19 pandemic on the presentation of oncological patients in a CCC in Germany was considerable and should be taken into account when making decisions regarding future pandemics.

Sprouty3, but Not Sprouty1, Expression Is Beneficial for the Malignant Potential of Osteosarcoma Cells

Sprouty proteins are widely accepted modulators of receptor tyrosine kinase-associated pathways and fulfill diversified roles in cancerogenesis dependent on the originating cells. In this study we detected a high expression of Sprouty3 in osteosarcoma-derived cells and addressed the question of whether Sprouty3 and Sprouty1 influence the malignant phenotype of this bone tumor entity. By using adenoviruses, the Sprouty proteins were expressed in two different cell lines and their influence on cellular behavior was assessed. Growth curve analyses and Scratch assays revealed that Sprouty3 accelerates cell proliferation and migration. Additionally, more colonies were grown in Soft agar if the cells express Sprouty3. In parallel, Sprouty1 had no significant effect on the measured endpoints of the study in osteosarcoma-derived cells. The promotion of the tumorigenic capacities in the presence of Sprouty3 coincided with an increased activation of signaling as measured by evaluating the phosphorylation of extracellular signal-regulated kinases (ERKs). Ectopic expression of a mutated Sprouty3 protein, in which the tyrosine necessary for its activation was substituted, resulted in inhibited migration of the treated cells. Our findings identify Sprouty3 as a candidate for a tumor promoter in osteosarcoma.

PATH-44. RAMAN SPECTROSCOPY AS A DIAGNOSTIC TOOL IN NEUROPATHOLOGY

BACKGROUND Although microscopic assessment is still the diagnostic gold standard in pathology, non-light microscopic methods such as new imaging methods and molecular pathology have considerably contributed to more precise diagnostics. As an upcoming method, Raman spectroscopy (RS) offers a "molecular fingerprint" which could be used to differentiate tissue heterogeneity or diagnostic entities. RS has so far been successfully applied on fresh and frozen tissue, however more aggressively, chemically treated tissue such as formalin-fixed, paraffin-embedded (FFPE) samples are challenging for RS. METHODS To address this issue, we examined FFPE samples of a broad range of intracranial tumors (e.g. glioblastoma and primary CNS lymphoma) and also different areas of morphologically highly heterogeneous glioblastoma tumor tissue. The latter in order to classify not only the tumor entity but also histologically defined GBM areas according to their spectral properties. We applied linear and nonlinear machine learning algorithms (Logistic Regression, Random Forest, Support Vector Machine) on our spectroscopic data and compared statistical performance of resulting classifiers. RESULTS We found that Random Forest classification distinguished between glioblastoma and primary CNS lymphoma with a balanced accuracy of 94%, only using Raman measurements on FFPE tissue. Furthermore, our established support vector machine-based classifier identified distinct histological areas in glioblastoma such as tumor core and necroses with an overall accuracy of 70.5% and showed a clear separation between the areas of necrosis and peritumoral zone. CONCLUSIONS This relatively cheap and easy-to-apply tool may serve useful to complement histopathological and molecular diagnostics. It provides an unbiased approach to tumor diagnostics with very little requirements (e.g. histopathological feature completeness of the tumor entity) to the sample. As a conclusion, we propose RS as a potential future additional method in the (neuro)-pathological toolbox for tumor diagnostics.

Clinical Implications of Malnutrition in the Management of Patients with Pancreatic Cancer: Introducing the Concept of the Nutritional Oncology Board

Pancreatic cancer represents a very challenging disease, with an increasing incidence and an extremely poor prognosis. Peculiar features of this tumor entity are represented by pancreatic exocrine insufficiency and an early and intense nutritional imbalance, leading to the highly prevalent and multifactorial syndrome known as cancer cachexia. Recently, also the concept of sarcopenic obesity has emerged, making the concept of pancreatic cancer malnutrition even more multifaceted and complex. Overall, these nutritional derangements play a pivotal role in contributing to the dismal course of this malignancy. However, their relevance is often underrated and their assessment is rarely applied in clinical daily practice with relevant negative impact for patients’ outcome in neoadjuvant, surgical, and metastatic settings. The proper detection and management of pancreatic cancer-related malnutrition syndromes are of primary importance and deserve a specific and multidisciplinary (clinical nutrition, oncology, etc.) approach to improve survival, but also the quality of life. In this context, the introduction of a “Nutritional Oncology Board” in routine daily practice, aimed at assessing an early systematic screening of patients and at implementing nutritional support from the time of disease diagnosis onward seems to be the right path to take.

Best of ASCO 2021: new data from triple-negative breast cancer

SummaryThis year’s ASCO Annual Meeting has been a showcase for the overwhelming success of novel, targeted therapies, particularly in a tumor entity that has – until recently – been felt to be only treatable with chemotherapy. New data are extremely encouraging, but also highlight the need for target identification beyond the classical clinicopathological factors. Both, the Olympia and the Neotala study have been performed in BRCA-mutated tumors, and their results clearly point to the necessity to offer germline testing to HER2-negative high risk early breast cancer. In addition, GeparNuevo once more highlights the fact that immunotherapy is here to stay, not only in the advanced breast cancer setting, but also in early stage breast cancer. The side effect profile is acceptable, and long-term outcome a real improvement to conventional chemotherapy.

Human Papillomavirus-Related Multiphenotypic Sinonasal Carcinoma—An Even Broader Tumor Entity?

Human papillomavirus (HPV)-related multiphenotypic sinonasal carcinoma (HMSC) is a recently defined tumor subtype with apparent favorable clinical outcome despite aggressive histomorphology. However, in recent years, additional numbers of cases, with more variable features and at locations outside the sinonasal region, have complicated the definition of HMSC. Here, we have performed a systematic review of all cases described so far in order to accumulate more knowledge. We identified 127 articles published between 2013 and 2021, of which 21 presented unique cases. In total, 79 unique patient cases were identified and their clinical and micromorphological nature are herein summarized. In our opinion, better clinical follow-up data and a more detailed tumor characterization are preferably needed before HMSC can finally be justified as its own tumor entity.

Comparative Analysis of the Antitumor Activity of Cis- and Trans-Resveratrol in Human Cancer Cells with Different p53 Status

Resveratrol, a natural plant phytoalexin, is produced in response to fungal infection or− UV irradiation. It exists as an isomeric pair with cis- and trans-conformation. Whereas multiple physiological effects of the trans-form, including a pronounced anti-tumoral activity, are nowadays elucidated, much less knowledge exists concerning the cis-isomer. In our work, we analyzed the antiproliferative and cytotoxic properties of cis-resveratrol in four different human tumor entities in direct comparison to trans-resveratrol. We used human cell lines as tumor models for hepatocellular carcinoma (HCC; HepG2, Hep3B), colon carcinoma (HCT-116, HCT-116/p53(−/−)), pancreatic carcinoma (Capan-2, MiaPaCa-2), and renal cell carcinoma (A498, SN12C). Increased cytotoxicity in all investigated tumor cells was observed for the trans-isomer. To verify possible effects of the tumor suppressor p53 on resveratrol-induced cell death, we used wild type and p53-deleted or -mutated cell lines for every tested tumor entity. Applying viability and cytotoxicity assays, we demonstrated a differential, dose-dependent sensitivity towards cis- or trans-resveratrol among the respective tumor types.

Anaplastic Sarcoma of the Kidney With Heterologous Ganglioneuroblastic Differentiation: Another DICER1-Associated Tumor

Anaplastic sarcoma of the kidney (ASK) is a rare renal tumor for which less than thirty cases have been described in the literature to date. Diagnosis of ASK is primarily based on histology, which features solid spindle cell neoplastic islands arranged in a fascicular pattern, prominent anaplastic nuclear morphology, brisk mitoses, and multiple multiloculated cysts lined by hobnail epithelium reminiscent of cystic nephroma. Chondroid or rhabdomyocytic differentiation is often present within the sarcoma. It has been recently suggested that this tumor entity belongs to the DICER1 syndrome tumors based on identification of DICER1 mutations. We report on a case of this rare tumor found in a twenty-month-old female. In addition to the typical histologic findings of ASK, this case also displayed heterologous neuroblastic-gangliocytic differentiation, which has not been previously described in the literature. TP53 and BRAF v600E had aberrant immunostaining. Chromosomal microarray and genomic sequencing revealed loss of chromosome 10 p15.3-p11.2 and both somatic and germline DICER1 mutations, consistent with recent research and further supporting the classification of this tumor within the DICER1 syndrome associated tumors.