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  • 1
    Abstract: BACKGROUND: Increased incidence of brain metastases (BM) in non-small cell lung cancer (NSCLC) with ALK translocations was postulated, however, ALK gene aberrations in NSCLC-BM have not been investigated so far. METHODS: We investigated ALK and EML4 gene aberrations (amplifications, translocations, inversions) by fluorescent in situ hybridization (FISH) (n=175) and ALK and EML4 protein expression by immunohistochemistry (n=221) in NSCLC BM and corresponding primary tumors. RESULTS: ALK translocations were found in 4/151 (2.6%; 3 of them involving EML4) of BM of adenocarcinomas (AC), 1/9 (11.1%) of adenosquamous carcinomas (ASC), 0/5 of squamous cell carcinomas (SCC) and 0/10 of large cell carcinomas (LCC). Rearrangement of ALK without involvement of EML4 was seen in 1 AC-BM and rearrangement of EML4 without involvement of ALK in 3 AC-BM, 1 ASC-BM and 1 LCC. ALK amplifications without gene rearrangements were found in BM of 16/151 (10.6%) AC, 2/5 (40%) SCC, 0/9 ASC and one LCC. ALK translocation status was constant between BM and primary tumors in 16 evaluable cases including two cases with ALK-EML4 translocations Among these 16 cases ALK amplification was seen in two BM and none of the primary tumors. All cases with translocations but not with amplifications of ALK showed protein expression. We found no association of ALK gene status with patient age, gender or overall survival time. CONCLUSIONS: ALK translocations and amplifications are found in approximately 3% and 11% of NSCLC-BM, respectively. While ALK translocations appear to be constant between primary tumors and BM, amplifications seem to be more prevalent in BM. ALK translocation, but not ALK amplification is associated with ALK protein overexpression. Further studies are needed to determine whether NSCLC-BM patients with ALK gene aberrations may benefit from specific inhibitor therapy.
    Type of Publication: Journal article published
    PubMed ID: 23453647
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  • 2
    Abstract: 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 glioblastoma.
    Type of Publication: Journal article published
    PubMed ID: 25355681
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  • 3
    Abstract: Background: We aimed to investigate the potential of standard hematologic and serum biochemical parameters to provide an independent and substantial contribution to the prediction of survival in patients with newly diagnosed brain metastases (BM). Methods: Hemoglobin, white blood cell count, platelet count, serum albumin, creatinine, lactate dehydrogenase (LDH), and C-reactive protein (CRP) were assessed at diagnosis of BM in a discovery cohort of 1200 cancer patients. A multivariable Cox regression model was used to derive the LabBM score. The LabBM score was externally validated in an independent cohort consisting of 366 patients. Results: Hemoglobin below lower limit of normal (〈LLN; hazard ratio [HR] 1.28; P = .001), platelet count 〈LLN (HR: 1.36; P = .013), albumin 〈LLN (HR: 1.19; P = .038), LDH above upper limit of normal (〉ULN; HR: 1.51; P 〈 .001), and CRP 〉ULN (HR: 1.52; P 〈 .001) were associated with survival in a multivariable Cox regression model and were included in the calculation of the LabBM score. Multivariable analysis including the LabBM score and graded prognostic assessment class revealed an independent and significant association of the LabBM score with overall survival (OS) (HR: 1.42; 95% CI: 1.29-1.57; P 〈 .001). The strong and independent association of LabBM score (HR: 1.93; 95% CI: 1.54-2.42) with OS prognosis was confirmed in the validation cohort. Conclusion: Standard clinical blood parameters, combined in the easy-to-calculate LabBM score, provide strong and independent prognostic information in patients with BM. The LabBM score is an objective, inexpensive, and reproducible tool to plan clinical management strategies in BM patients and to improve patient selection and stratification for clinical trials.
    Type of Publication: Journal article published
    PubMed ID: 28096493
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