Summary Accurate pathological diagnosis is crucial for optimal management of cancer patients. For the ~100 known central nervous system (CNS) tumour entities, standardization of the diagnostic process has been shown to be particularly challenging - with substantial inter-observer variability in the histopathological diagnosis of many tumour types. We herein present the development of a comprehensive approach for DNA methylation-based CNS tumour classification across all entities and age groups, and demonstrate its application in a routine diagnostic setting. We show that availability of this method may have substantial impact on diagnostic precision compared with standard methods, resulting in a change of diagnosis in up to 12% of prospective cases. For broader accessibility we have designed a free online classifier tool (www.molecularneuropathology.org) requiring no additional onsite data processing. Our results provide a blueprint for the generation of machine learning-based tumour classifiers across other cancer entities, with the potential to fundamentally transform tumour pathology.
Olfactory neuroblastoma/esthesioneuroblastoma (ONB) is an uncommon neuroectodermal neoplasm thought to arise from the olfactory epithelium. Little is known about its molecular pathogenesis. For this study, a retrospective cohort of n = 66 tumor samples with the institutional diagnosis of ONB was analyzed by immunohistochemistry, genome-wide DNA methylation profiling, copy number analysis, and in a subset, next-generation panel sequencing of 560 tumor-associated genes. DNA methylation profiles were compared to those of relevant differential diagnoses of ONB. Unsupervised hierarchical clustering analysis of DNA methylation data revealed four subgroups among institutionally diagnosed ONB. The largest group (n = 42, 64%, Core ONB) presented with classical ONB histology and no overlap with other classes upon methylation profiling-based t-distributed stochastic neighbor embedding (t-SNE) analysis. A second DNA methylation group (n = 7, 11%) with CpG island methylator phenotype (CIMP) consisted of cases with strong expression of cytokeratin, no or scarce chromogranin A expression and IDH2 hotspot mutation in all cases. T-SNE analysis clustered these cases together with sinonasal carcinoma with IDH2 mutation. Four cases (6%) formed a small group characterized by an overall high level of DNA methylation, but without CIMP. The fourth group consisted of 13 cases that had heterogeneous DNA methylation profiles and strong cytokeratin expression in most cases. In t-SNE analysis, these cases mostly grouped among sinonasal adenocarcinoma, squamous cell carcinoma, and undifferentiated carcinoma. Copy number analysis indicated highly recurrent chromosomal changes among Core ONB with a high frequency of combined loss of chromosome 1-4, 8-10, and 12. NGS sequencing did not reveal highly recurrent mutations in ONB, with the only recurrently mutated genes being TP53 and DNMT3A. In conclusion, we demonstrate that institutionally diagnosed ONB are a heterogeneous group of tumors. Expression of cytokeratin, chromogranin A, the mutational status of IDH2 as well as DNA methylation patterns may greatly aid in the precise classification of ONB.
Summary: CD19- and B-cell maturation antigen (BCMA)–directed chimeric antigen receptor (CAR) T cells have enabled unprecedented responses in a subset of refractory patients with B-cell and plasma cell malignancies, leading to their approval by the FDA for the treatment of leukemia, lymphoma, and myeloma. These “living drugs” can become part of a synthetic immune system, persisting at least a decade in some patients. However, despite this tremendous impact, significant unmet treatment needs remain for patients with hematologic malignancies and solid cancers. In this perspective, we highlight recent innovations that advance the field toward production of a more potent and universal cellular immunotherapy of the future. Next-generation CAR T cells will incorporate advances in gene engineering and synthetic biology to enhance functionality and persistence, and reduce treatment-associated toxicities. The combination of autologous CAR T cells with various allogeneic cell treatment strategies designed to target the immunosuppressive tumor microenvironment will broaden the impact of future CAR T-cell therapies.
Unrecognized genome instability syndromes can potentially impede the rational treatment of cancer in rare patients. Identification of cancer patients with a hereditary condition is a compelling necessity for oncologists, giving varying hypersensitivities to various chemotherapeutic agents or radiation, depending on the underlying genetic cause. Omission of genetic testing in the setting of an overlooked hereditary syndrome may lead to unexpected and unbearable toxicity from oncological standard approaches. We present a case of a 33-year-old man with an early-onset stage IV intrahepatic cholangiocarcinoma, who experienced unusual bone marrow failure and neutropenic fever syndrome as a consequence of palliative chemotherapy containing cisplatin and gemcitabine, leading to a fatal outcome on day 25 of his first chemotherapeutic cycle. The constellation of bone marrow failure after exposure to the platinum-based agent cisplatin, the presence of an early-onset solid malignancy and the critical appraisal of further phenotypical features raised suspicion of a hereditary genome instability syndrome. Whole-exome sequencing from buccal swab DNA enabled the post mortem diagnosis of Fanconi anemia, most likely linked to the fatal outcome due to utilization of the DNA crosslinking agent cisplatin. The patient's phenotype was exceptional, as he never displayed significant hematologic abnormalities, which is the hallmark of Fanconi anemia. As such, this case stresses the importance to at least question the possibility of a hereditary basis in cases of relatively early-onset malignancy before defining an oncological treatment strategy.
Canonical Wnt signaling is known to promote proliferation of olfactory stem cells. In order to investigate the effects of a constitutive activation of Wnt signaling in Sox2-positive precursor cells of the olfactory epithelium, we used transgenic mice that allowed an inducible deletion of exon 3 of the Ctnnb1 gene, which is responsible for the phosphorylation and degradation of Ctnnb1 protein. After induction of aberrant Wnt activation by Ctnnb1 deletion at embryonic day 14, such mice developed tumor-like lesions in upper parts of the nasal cavity. We still observed areas of epithelial hyperplasia within the olfactory epithelium following early postnatal Wnt activation, but the olfactory epithelial architecture remained unaffected in most parts when Wnt was activated at postnatal day 21 or later. In summary, our results suggest an age-dependent tumorigenic potential of aberrant Wnt signaling in the olfactory epithelium of mice.
Isolated myeloid sarcoma (MS) is a rare malignancy in which myeloid blast forms tumors at various locations while the bone marrow (BM) remains cytomorphologically free from disease. We analyzed isolated MS from four patients and their BMs at initial diagnosis and follow-up, using a custom next-generation sequencing (NGS) panel. We observed possible clonal evolution and a clonal hematopoiesis of indeterminate potential (CHIP)-like finding in the BM of one of three cases with detectable mutations. Clinical presentation of one patient suggested extramedullary confined homing of blasts to distal sites in the relapse situation still sparing the BM. In summary, our findings shall motivate future work regarding signals of extramedullary blast trafficking and clonal evolution in MS.
Delayed methotrexate (MTX) elimination after treatment with high-dose (HD) MTX may result in lifethreatening toxicities as well as acute kidney injury (AKI). Treatment includes administration of glucarpidase, an enzyme that rapidly inactivates MTX. Dosing of glucarpidase is based on body weight; however, recommendations for dosage adjustments in obese patients are lacking. We describe three obese adult patients (body mass index [BMI] range 31-43 kg/m 2 ) who received HD-MTX following all precautions for its treatment. Although peak MTX concentrations were within the expected range (308-368 µmol/L), MTX concentrations after 24 hours or later were markedly increased (97, 52, and 19 µmol/L, respectively). Two patients experienced AKI. After a single intravenous dose of glucarpidase 4000 units (50 units/kg on the basis of ideal body weight [IBW]) was administered to each patient 38, 46, and 60 hours, respectively, after the start of MTX, MTX concentrations dropped quickly to 1.37, 0.07, and 0.03 µmol/L, respectively, and further decreased steadily. Over time, clinical status and renal function improved in all patients. Glucarpidase is a highly hydrophilic molecule with a volume of distribution of 3.6 L, representing the intravascular volume of an adult. Therefore, we used IBW for glucarpidase dose calculations, allowing us to reduce the dose that would have been determined by using total body weight. This approach resulted in a rapid decrease of MTX serum concentrations and may reduce treatment costs of this highly expensive drug. KEY WORDS glucarpidase, methotrexate, high dose, obesity. (Pharmacotherapy 2020;40(5):479-483)
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