IL-2 in combination with IFN-αand 5-FU versus tamoxifen in metastatic renal cell carcinoma: long-term results of a controlled randomized clinical trial

We conducted a prospectively randomized clinical trial to compare the efficacy and safety of subcutaneous interferon-α2a, subcutaneous interleukin-2 and intravenous 5-fluorouracil as home therapy against oral tamoxifen in 78 patients with progressive metastatic renal cell carcinoma. Treatment courses consisted of interferon-α2a 5 × 106 IU m−2day 1 weeks 1 + 4; days 1, 3, 5 weeks 2 + 3; 10 × 106 IU m−2days 1, 3, 5 weeks 5–8; interleukin-2 10 × 106 IU m−2twice daily days 3–5 weeks 1 + 4; 5 × 106 IU m−2days 1, 3, 5 weeks 2 + 3; and 5-fluorouracil 1000 mg m−2day 1 weeks 5–8. The tamoxifen group received tamoxifen 80 mg twice daily over 8 weeks. Among 41 patients treated with interleukin-2, interferon-α2a and 5-fluorouracil there were 7 complete (17.1%) and 9 partial responders (21.9%), with an overall objective response rate of 39.1% (95% CI, 24.2–55.5). An additional 15 patients (36.6%) were stable throughout therapy. The overall survival was 24 months (range 5–76+). In 37 patients receiving tamoxifen no objective remissions occurred. 13 patients (35.1%) had stable disease and 24 patients (64.9%) showed continued disease progression. The overall survival was 13 months (range 3–73+). In summary, this home-based therapy regimen of interferon-α2a, interleukin-2 and 5-fluorouracil demonstrated significant therapeutic efficacy in patients with progressive renal cell carcinoma when compared to hormonal therapy. © 2001 Cancer Research Campaign  http://www.bjcancer.co

DNA methylation, transcriptome and genetic copy number signatures of diffuse cerebral WHO grade II/III gliomas resolve cancer heterogeneity and development

Background: Diffuse lower WHO grade II and III gliomas (LGG) are slowly progressing brain tumors, many of which eventually transform into a more aggressive type. LGG is characterized by widespread genetic and transcriptional heterogeneity, yet little is known about the heterogeneity of the DNA methylome, its function in tumor biology, coupling with the transcriptome and tumor microenvironment and its possible impact for tumor development. Methods: We here present novel DNA methylation data of an LGG-cohort collected in the German Glioma Network containing about 85% isocitrate dehydrogenase (IDH) mutated tumors and performed a combined bioinformatics analysis using patient-matched genome and transcriptome data. Results: Stratification of LGG based on gene expression and DNA-methylation provided four consensus subtypes. We characterized them in terms of genetic alterations, functional context, cellular composition, tumor microenvironment and their possible impact for treatment resistance and prognosis. Glioma with astrocytoma-resembling phenotypes constitute the largest fraction of nearly 60%. They revealed largest diversity and were divided into four expression and three methylation groups which only partly match each other thus reflecting largely decoupled expression and methylation patterns. We identified a novel G-protein coupled receptor and a cancer-related ‘keratinization’ methylation signature in in addition to the glioma-CpG island methylator phenotype (G-CIMP) signature. These different signatures overlap and combine in various ways giving rise to diverse methylation and expression patterns that shape the glioma phenotypes. The decrease of global methylation in astrocytoma-like LGG associates with higher WHO grade, age at diagnosis and inferior prognosis. We found analogies between astrocytoma-like LGG with grade IV IDH-wild type tumors regarding possible worsening of treatment resistance along a proneural-to-mesenchymal axis. Using gene signature-based inference we elucidated the impact of cellular composition of the tumors including immune cell bystanders such as macrophages. Conclusions: Genomic, epigenomic and transcriptomic factors act in concert but partly also in a decoupled fashion what underpins the need for integrative, multidimensional stratification of LGG by combining these data on gene and cellular levels to delineate mechanisms of gene (de-)regulation and to enable better patient stratification and individualization of treatment

Anaplastic astrocytoma with piloid features, a novel molecular class of IDH wildtype glioma with recurrent MAPK pathway, CDKN2A/B and ATRX alterations

Tumors with histological features of pilocytic astrocytoma (PA), but with increased mitotic activity and additional high-grade features (particularly microvascular proliferation and palisading necrosis) have often been designated anaplastic pilocytic astrocytomas. The status of these tumors as a separate entity has not yet been conclusively demonstrated and molecular features have only been partially characterized. We performed DNA methylation profiling of 102 histologically defined anaplastic pilocytic astrocytomas. T-distributed stochastic neighbor-embedding (t-SNE) and hierarchical clustering analysis of these 102 cases against 158 reference cases from 12 glioma reference classes revealed that a subset of 83 of these tumors share a common DNA methylation profile that is distinct from the reference classes. These 83 tumors were thus denominated DNA methylation class anaplastic astrocytoma with piloid features (MC AAP). The 19 remaining tumors were distributed amongst the reference classes, with additional testing confirming the molecular diagnosis in most cases. Median age of patients with MC AAP was 41.5 years. The most frequent localization was the posterior fossa (74%). Deletions of CDKN2A/B (66/83, 80%), MAPK pathway gene alterations (49/65, 75%, most frequently affecting NF1, followed by BRAF and FGFR1) and mutations of ATRX or loss of ATRX expression (33/74, 45%) were the most common molecular alterations. All tumors were IDH1/2 wildtype. The MGMT promoter was methylated in 38/83 tumors (45%). Outcome analysis confirmed an unfavorable clinical course in comparison to PA, but better than IDH wildtype glioblastoma. In conclusion, we show that a subset of histologically defined anaplastic pilocytic astrocytomas forms a separate DNA methylation cluster, harbors recurrent alterations in MAPK pathway genes in combination with alterations of CDKN2A/B and ATRX, affects patients who are on average older than those diagnosed with PA and has an intermediate clinical outcome

Early T cell differentiated chronic myeloid leukemia blast crisis with rearrangement of the breakpoint cluster region but not of the T cell receptor beta chain genes

Abstract Early T cell differentiation is described in a case of Philadelphia chromosome-positive chronic myeloid leukemia (CML) in blast crisis, supporting multi-lineage differentiation potential of CML precursor cells. In the absence of myeloid markers, strong positivity for terminal deoxynucleotidyl transferase (TdT) and reactivity with T cell antibody 3A1, but lack of more mature T cell antigens, provided evidence for immature T cell differentiation. Molecular analysis of the breakpoint cluster region (bcr) in chromosome 22 revealed a rearrangement and thus confirmed the CML origin of the early T cell blasts. T cell receptor beta chain sequences were found in germline configuration and therefore suggest a very immature stage of T cell differentiation in the CML blasts.</jats:p