Young oncologists' perspective on the role and future of the clinician-scientist in oncology

Jóvenes oncólogos; OncologíaJoves oncòlegs; OncologiaYoung oncologists; OncologyThe clinician-scientist, or more commonly known as physician-scientist in North America, covers a wide spectrum of roles, but is essentially an individual who holds a medical degree and usually a postgraduate scientific qualification (e.g. MS/MSc/MRes and PhD) and is primarily dedicated to pursuing their academic research interests, which can range from basic science to more translational or clinical research. Clinician-scientists are important players within the contemporary multidisciplinary and interprofessional teamscience approach to cancer research and cancer care. Clinical experience alongside rigorous training in research and scientific methodologies provides a strong foundation for clinician-scientists to conduct and lead research advancing the way we understand and treat patients with cancer.European Society for Medical Oncology (ESMO) (no grant number)

Direct image to subtype prediction for brain tumors using deep learning

Background: Deep Learning (DL) can predict molecular alterations of solid tumors directly from routine histopathology slides. Since the 2021 update of the World Health Organization (WHO) diagnostic criteria, the classification of brain tumors integrates both histopathological and molecular information. We hypothesize that DL can predict molecular alterations as well as WHO subtyping of brain tumors from hematoxylin and eosin-stained histopathology slides. // Methods: We used weakly supervised DL and applied it to three large cohorts of brain tumor samples, comprising N = 2845 patients. // Results: We found that the key molecular alterations for subtyping, IDH and ATRX, as well as 1p19q codeletion, were predictable from histology with an area under the receiver operating characteristic curve (AUROC) of 0.95, 0.90, and 0.80 in the training cohort, respectively. These findings were upheld in external validation cohorts with AUROCs of 0.90, 0.79, and 0.87 for prediction of IDH, ATRX, and 1p19q codeletion, respectively. // Conclusions: In the future, such DL-based implementations could ease diagnostic workflows, particularly for situations in which advanced molecular testing is not readily available

Sarcopenia in Neurological Patients: Standard Values for Temporal Muscle Thickness and Muscle Strength Evaluation.

Temporal muscle thickness (TMT) was investigated as a novel surrogate marker on MRI examinations of the brain, to detect patients who may be at risk for sarcopenia. TMT was analyzed in a retrospective, normal collective cohort (n = 624), to establish standard reference values. These reference values were correlated with grip strength measurements and body mass index (BMI) in 422 healthy volunteers and validated in a prospective cohort (n = 130) of patients with various neurological disorders. Pearson correlation revealed a strong association between TMT and grip strength (retrospective cohort, ρ = 0.746; p < 0.001; prospective cohort, ρ = 0.649; p < 0.001). A low or no association was found between TMT and age (retrospective cohort, R2 correlation coefficient 0.20; p < 0.001; prospective cohort, ρ = -0.199; p = 0.023), or BMI (retrospective cohort, ρ = 0.116; p = 0.042; prospective cohort, ρ = 0.227; p = 0.009), respectively. Male patients with temporal wasting and unintended weight loss, respectively, showed significantly lower TMT values (p = 0.04 and p = 0.015, unpaired t-test). TMT showed a high correlation with muscle strength in healthy individuals and in patients with various neurological disorders. Therefore, TMT should be integrated into the diagnostic workup of neurological patients, to prevent, delay, or treat sarcopenia

Programmed death ligand 1 expression and tumor-infiltrating lymphocytes in glioblastoma

Background Immune checkpoint inhibitors targeting programmed cell death 1 (PD1) or its ligand (PD-L1) showed activity in several cancer types. Methods We performed immunohistochemistry for CD3, CD8, CD20, HLA-DR, phosphatase and tensin homolog (PTEN), PD-1, and PD-L1 and pyrosequencing for assessment of the O6-methylguanine-methyltransferase (MGMT) promoter methylation status in 135 glioblastoma specimens (117 initial resection, 18 first local recurrence). PD-L1 gene expression was analyzed in 446 cases from The Cancer Genome Atlas. Results Diffuse/fibrillary PD-L1 expression of variable extent, with or without interspersed epithelioid tumor cells with membranous PD-L1 expression, was observed in 103 of 117 (88.0%) newly diagnosed and 13 of 18 (72.2%) recurrent glioblastoma specimens. Sparse-to-moderate density of tumor-infiltrating lymphocytes (TILs) was found in 85 of 117 (72.6%) specimens (CD3+ 78/117, 66.7%; CD8+ 52/117, 44.4%; CD20+ 27/117, 23.1%; PD1+ 34/117, 29.1%). PD1+ TIL density correlated positively with CD3+ (P < .001), CD8+ (P < .001), CD20+ TIL density (P < .001), and PTEN expression (P = .035). Enrichment of specimens with low PD-L1 gene expression levels was observed in the proneural and G-CIMP glioblastoma subtypes and in specimens with high PD-L1 gene expression in the mesenchymal subtype (P = 5.966e-10). No significant differences in PD-L1 expression or TIL density between initial and recurrent glioblastoma specimens or correlation of PD-L1 expression or TIL density with patient age or outcome were evident. Conclusion TILs and PD-L1 expression are detectable in the majority of glioblastoma samples but are not related to outcome. Because the target is present, a clinical study with specific immune checkpoint inhibitors seems to be warranted in glioblastom

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Microrna expression pattern modulates temozolomide response in gbm tumors with cancer stem cells

Temozolomide (TMZ) is widely used to treat glioblastoma multiforme (GBM). Although the MGMT gene methylation status is postulated to correlate with TMZ response, some patients with a methylated MGMT gene still do not benefit from TMZ therapy. Cancer stem cells (CSCs) may be one of the causes of therapeutic resistance, but the molecular mechanism underlying this resistance is unclear. microRNA (miRNA) deregulation has been recognized as another chemoresistance modulating mechanism. Thus, we aimed to evaluate the miRNA expression patterns associated with chemoresistance that is dependent on the CSC status in GBM tumors to identify therapeutic biomarkers. CSCs were identified in 5 of 20 patients' tumor tissues using magnetic separation. CSC (+) tumors displayed a significant induction of CpG island methylation in the MGMT gene promoter (p = 0.009). Using real-time reverse transcription polymerase chain reaction (qRT-PCR), 9 miRNAs related to GBM (mir-181b, miR-153, miR-137, miR-145, miR-10a, miR-10b, let-7d, miR-9, and miR-455-3p), which are associated with cell cycle and invasion was analyzed in tumor samples. Low miR-181b and high miR-455-3p expression levels were detected (p = 0.053, p = 0.004; respectively) in CSC (+) tumors. Analysis revealed a significant correlation between miR-455-3p expression and Smad2 protein levels as analyzed by immunohistochemistry in CSC (+) tumors (p = 0.002). Thus, miR-455-3p may be involved in TMZ resistance in MGMT methylated CSC (+) GBM patients. Further studies and evaluations are required, but this miRNA may provide novel therapeutic molecular targets for GBM treatment and new directions for the development of anticancer drugs

New Approaches with Precision Medicine in Adult Brain Tumors

Primary central nervous system (CNS) tumors represent a heterogenous group of tumors. The 2021 fifth edition of the WHO Classification of Tumors of the CNS emphasizes the advanced role of molecular diagnostics with routine implementation of molecular biomarkers in addition to histologic features in the classification of CNS tumors. Thus, novel diagnostic methods such as DNA methylome profiling are increasingly used to provide a more precise diagnostic work-up of CNS tumors. In addition to these diagnostic precision medicine advantages, molecular alterations are also addressed therapeutically with targeted therapies. Like in other tumor entities, precision medicine has therefore also arrived in the treatment of CNS malignancies as the application of targeted therapies has shown promising response rates. Nevertheless, large prospective studies are currently missing as most targeted therapies were evaluated in single arm, basket, or platform trials. In this review, we focus on the current evidence of precision medicine in the treatment of primary CNS tumors in adults. We outline the pathogenic background and prevalence of the most frequent targetable genetic alterations and summarize the existing evidence of precision medicine approaches for the treatment of primary CNS tumors

Focal Radiotherapy of Brain Metastases in Combination With Immunotherapy and Targeted Drug Therapy

Background: Advances in systemic treatment and in brain imaging have led to a higher incidence of diagnosed brain metastases. In the treatment of brain metastases, stereotactic radiotherapy and radiosurgery, systemic immunotherapy, and targeted drug therapy are important evidence-based options. In this review. we summarize the available evidence on the treatment of brain metastases of the three main types of cancer that give rise to them: non-small-cell lung cancer, breast cancer, and malignant melanoma. Methods: This narrative review is based on pertinent original articles. meta-analyses. and systematic reviews that were retrieved by a selective search in PubMed. These publications were evaluated and discussed by an expert panel including radiation oncologists. neurosurgeons. and oncologists. Results: There have not yet been any prospective randomized trials concerning the optimal combination of local stereotactic radiotherapy/radiosurgery and systemic immunotherapy or targeted therapy. Retrospective studies have consistently shown a benefit from early combined treatment with systemic therapy and (in particular) focal radiotherapy. compared to sequential treatment. Two meta-analyses of retrospective data from cohorts consisting mainly of patients with non-small-cell lung cancer and melanoma revealed longer overall survival after combined treatment with focal radiotherapy and checkpoint inhibitor therapy (rate of 12-month overall survival for combined versus non-combined treatment: 64.6% vs. 51.6%, p <0.001). In selected patients with small, asymptomatic brain metastases in non-critical locations. systemic therapy without focal radiotherapy can be considered, as long as follow-up with cranial magnetic resonance imaging can be performed at close intervals. Conclusion: Brain metastases should be treated by a multidisciplinary team, so that the optimal sequence of local and systemic therapies can be determined for each individual patient

EVI1 Promotes the Proliferation and Invasive Properties of Human Head and Neck Squamous Cell Carcinoma Cells

Head and neck squamous cell carcinoma (HNSCC) is a frequent malignancy with a poor prognosis. So far, the EGFR inhibitor cetuximab is the only approved targeted therapy. A deeper understanding of the molecular and genetic basis of HNSCC is needed to identify additional targets for rationally designed, personalized therapeutics. The transcription factor EVI1, the major product of the MECOM locus, is an oncoprotein with roles in both hematological and solid tumors. In HNSCC, high EVI1 expression was associated with an increased propensity to form lymph node metastases, but its effects in this tumor entity have not yet been determined experimentally. We therefore overexpressed or knocked down EVI1 in several HNSCC cell lines and determined the impact of these manipulations on parameters relevant to tumor growth and invasiveness, and on gene expression patterns. Our results revealed that EVI1 promoted the proliferation and migration of HNSCC cells. Furthermore, it augmented tumor spheroid formation and the ability of tumor spheroids to displace an endothelial cell layer. Finally, EVI1 altered the expression of numerous genes in HNSCC cells, which were enriched for Gene Ontology terms related to its cellular functions. In summary, EVI1 represents a novel oncogene in HNSCC that contributes to cellular proliferation and invasiveness