Backbone gouty tophus showing as an epidural mass sore An incident statement

PURPOSE The histone-methyl transferase EZH2, catalytic subunit of the PRC2 complex involved in transcriptional regulation is mutated in approximately 25% of germinal center B-cell lymphomas. Aberrant proliferative dependency on EZH2 activity can be targeted by the orally available EZH2 inhibitor tazemetostat (EPZ-6438). We report the results of the phase Ib tazemetostat plus R-CHOP combination (NCT02889523), in patients 60-80 years with newly diagnosed diffuse large B cell lymphoma. EXPERIMENTAL DESIGN The primary objective of this dose escalation study was to evaluate the safety of the combination and to determine the recommended phase 2 dose (RP2D) of tazemetostat. RESULTS 17 patients were enrolled. During C1 and C2, 2 dose limiting toxicities were observed one grade 3 constipation at 400 mg and one grade 5 pulmonary infection at 800 mg. Grade 3 or more toxicities observed in more than 10% of the patients were constipation (24%), nausea (12%) and hypokalemia (12%). Grade 3 to 4 hematologic AE were recorded in 8 patients (47%) neutropenia (47%), leukopenia (29%), anemia (18%) and thrombocytopenia (12%). The tazemetostat RP2D was 800 mg. No organ-oriented toxicity increased with tazemetostat dosage escalation (severity and incidence). At 800 mg, AUC and Cmax of tazemetostat were similar compared to the single agent study (E7438-G000-101). CONCLUSIONS The RP2D of tazemetostat combined with R-CHOP is 800 mg BID. The association presents safety and PK comparable to R-CHOP alone. Preliminary efficacy data are encouraging and further investigations in phase 2 trial are warranted. Copyright ©2020, American Association for Cancer Research.PURPOSE Several aggressive pediatric cancers harbor alterations in SMARCB1, including rhabdoid tumors, epithelioid sarcoma and chordoma. As tumor profiling has become more routine in clinical care, we investigated the relationship between SMARCB1 genetic variants identified by next-generation sequencing (NGS) and INI1 protein expression. Therapeutic approaches for INI1-deficient tumors are limited. selleck chemicals llc Early reports suggest a potential role for immune checkpoint inhibition in these patients. Thus, we also investigated PD-L1 and CD8 expression in INI1-negative pediatric brain and solid tumors. EXPERIMENTAL DESIGN We performed immunohistochemistry (IHC) for INI1 and immune markers (PD-L1, CD8, and CD163) and NGS on tumor samples from 43 pediatric patients who had tumors with INI1 loss on previous IHC or SMARCB1 genomic alterations on prior somatic sequencing. RESULTS SMARCB1 two-copy deletions and inactivating mutations on NGS were associated with loss of INI1 protein expression. Single-copy deletion of SMARCB1 was not predictive of INI1 loss in tumor histologies not known to be INI1-deficient. In the 27 cases with INI1 loss and successful tumor sequencing, 24 (89%) had a SMARCB1 alteration detected. Additionally, 47% (14/30) of the patients with INI1-negative tumors had a tumor specimen that was PD-L1 positive and 60% (18/30) had positive or rare CD8 staining. We report on 3 patients with INI1-negative tumors with evidence of disease control on immune checkpoint inhibitors. CONCLUSIONS A significant proportion of the INI1-negative tumors express PD-L1, and PD-L1 positivity was associated with extracranial tumor site. These results suggest that clinical trials of immune checkpoint inhibitors are warranted in INI1-negative pediatric cancers. Copyright ©2020, American Association for Cancer Research.Circulating cell-free DNA (cfDNA) is rapidly transitioning from discovery research to an important tool in clinical decision making. However, the lack of harmonization of preanalytical practices across institutions may compromise the reproducibility of cfDNA-derived data and hamper advancements in cfDNA testing in the clinic. Differences in cellular genomic contamination, cfDNA yield, integrity, and fragment length have been attributed to different collection tube types and anticoagulants, processing delays and temperatures, tube agitation, centrifugation protocols and speeds, plasma storage duration and temperature, the number of freeze-thaw events, and cfDNA extraction and quantification methods, all of which can also ultimately impact subsequent downstream analysis. Thus, there is a pressing need for widely applicable standards tailored for cfDNA analysis that include all preanalytical steps from blood draw to analysis. The National Cancer Institute's (NCI) Biorepositories and Biospecimen Research Branch (BBRB) has developed cfDNA-specific guidelines that are based upon published evidence and have been vetted by a panel of internationally recognized experts in the field. The guidelines include optimal procedures as well as acceptable alternatives to facilitate the generation of evidence-based protocols by individual laboratories and institutions. The aim of the document, which is entitled "Biospecimen Evidence-based Best Practice for Cell-free DNA Biospecimen Collection and Processing", is to improve the accuracy of cfDNA analysis in both basic research and the clinic by improving and harmonizing practices across institutions. Copyright ©2020, American Association for Cancer Research.PURPOSE Cytarabine is an effective treatment for AML with associated toxicities including treatment related mortality (TRM). The purpose is to determine the clinical relevance of single-nucleotide polymorphisms (SNPs) identified through the use of HapMap lymphoblastoid cell-based models, in predicting cytarabine response and toxicity in AML. EXPERIMENTAL DESIGN We tested clinical significance of SNPs associated with cytarabine sensitivity in children with AML treated on Children's Oncology Group regimens (CCG 2941/2961). Endpoints included overall survival (OS), event free survival (EFS) and TRM. Patients who received bone marrow transplant were excluded. We tested 124 SNPs associated with cytarabine sensitivity in HapMap cell lines in 348 children to determine if any associated with treatment outcomes. In addition, we tested five SNPs previously associated with TRM in children with AML in our independent data set of 385 children. RESULTS Homozygous variant genotypes of rs2025501 and rs6661575 had increased in vitro cellular sensitivity to cytarabine and were associated with increased TRM.