EBV-positive diffuse large B-cell lymphoma in young adults: is this a distinct disease entity?

BACKGROUND: Epstein-Barr virus (EBV)-positive diffuse large B-cell lymphoma (DLBCL) of the elderly is defined only in adults older than 50 years. However, EBV-positive DLBCL can affect younger patients. We investigated the prevalence, clinical characteristics and survival outcomes of EBV-positive DLBCL in young adults. PATIENTS AND METHODS: We analyzed patients with de novo DLBCL who were registered in the Samsung Medical Center (SMC) retrospective lymphoma cohort and prospective SMC Lymphoma Cohort Study I (ClinicalTrials.gov: NCT00822731). RESULTS: A total of 571 cases were included in the analysis. The prevalence of EBV positivity was 6.7% (13/195) and 9.3% (35/376) in the young group (≤50 years) and in the elderly group (>50 years), respectively. EBV status was closely associated with unique unfavorable clinical characteristics [older age, more advanced stage, two or more sites of extranodal involvement, higher International Prognostic Index (IPI), and age-adjusted IPI risk] only in the elderly group. Poor prognostic impact of EBV positivity on overall survival was observed only in the elderly group [hazard ratio (HR) 2.86; 95% confidence interval (CI) 1.83-4.47; P < 0.001], but not in the young group (HR 1.17; 95% CI 0.35-3.89; P = 0.801). CONCLUSION: A substantial proportion of EBV-positive DLBCL of the elderly can occur in young adults. EBV positivity of DLBCL in young adults was not associated with unfavorable clinical characteristics or worse outcomes. We suggest that EBV-positive DLBCL should not be confined only in the elderly and 'EBV-positive DLBCL in young adults' needs to be considered as a clinically distinct disease entity. ClinicalTrials.gov: NCT02060435.

Role of HER3 expression and PTEN loss in patients with HER2-overexpressing metastatic breast cancer (MBC) who received taxane plus trastuzumab treatment.

BACKGROUND: The aim of this study was to investigate the role of human epidermal growth factor receptor (HER3) and PTEN expression in patients with HER2-overexpressing metastatic breast cancer (MBC). METHODS: One hundred twenty-five MBC patients who were treated with taxane plus trastuzumab chemotherapy as first-line therapy were included in this analysis. Immunohistochemical (IHC) staining with HER3 and PTEN antibodies were conducted retrospectively. RESULTS: Patients who had negative HER3 staining (62.4%) had a better progression-free survival (PFS) than did those who had positive HER3 staining (P=0.001; median PFS, 21 vs 11 months). Patients who had a PTEN score >20 (78.1%) showed longer PFS than did those with a PTEN score ≤20 (P=0.006; median PFS, 13 vs 9 months). Patients who had a PTEN score >20 exhibited a longer overall survival (OS) than did those with a PTEN score ≤20 (P=0.005; median OS, 48 vs 25 months). HER3 negativity and PTEN loss were identified as independent risk factors for PFS. PTEN loss was identified as an independent risk factor for OS. CONCLUSION: HER3 and PTEN expressions may be predictive markers, and PTEN expression may be a predictive and prognostic biomarker for trastuzumab treatment in HER2-positive MBCs.

The impact of activated p-AKT expression on clinical outcomes in diffuse large B-cell lymphoma: a clinicopathological study of 262 cases.

BACKGROUND: Oncogenic phosphatidylinositol-3-kinase/serine-threonine kinase (PI3K/AKT) pathway plays a critical role in cell proliferation and growth. Phosphorylated AKT (p-AKT) has been reported to be abnormally overexpressed and to have poor prognostic impact in solid tumors. PATIENTS AND METHODS: To define the clinical implications of p-AKT expression in diffuse large B-cell lymphoma (DLBCL), we calculated arbitrary units (AUs) by multiplying the intensity and the proportion of p-AKT expression and investigated the impact of p-AKT expression on clinical outcomes. We assessed 262 patients with DLBCL. Based on a cutoff value of the upper limit of the third quartile of AUs, 56 patients were classified as high p-AKT and the remaining 206 patients were classified as low p-AKT. RESULTS: The high p-AKT group was closely associated with more advanced stage (stage III-IV, P = 0.02), two or more extranodal involvement (P = 0.03), lactic dehydrogenase elevation (P = 0.03), higher International Prognostic Index risk groups (high intermediate/high, P = 0.02), and the presence of B-symptoms (P = 0.01). The high p-AKT group showed substantially worse overall survival (OS) (median OS, 115.0 months versus not reached, P = 0.004) and progression-free survival (PFS) (median PFS, 25.5 versus 105.8 months, P = 0.019) compared with the low p-AKT group. Multivariate analysis revealed that high p-AKT expression retained its significant poor prognostic impact for OS (hazard ratio 1.7; 95% confidence interval, 1.0-2.7; P = 0.031). The subgroup with high p-AKT expression and concurrent Epstein-Barr virus positivity showed worst prognosis with the median OS and PFS of 15.2 and 7.4 months. CONCLUSION: DLBCL patients with high p-AKT expression showed distinct clinical features and followed a more rapidly deteriorating clinical course with worse OS and PFS. Thus, a more effective treatment option should be developed for this subset of DLBCL patients, and targeting PI3K/AKT pathway may be a promising therapeutic strategy.

A phase-1b study of everolimus plus paclitaxel in patients with small-cell lung cancer.

BACKGROUND: The mammalian target of rapamycin (mTOR) pathway is dysregulated in small-cell lung cancer (SCLC) and everolimus is an oral mTOR inhibitor. METHODS: This phase-1b study assessed everolimus safety at the levels of 2.5, 5, or 10 mg once daily in combination with paclitaxel (175 mg m(-2)) once every 3 weeks in previously treated SCLC patients. The primary end point was to determine the maximum tolerated dose of everolimus. RESULTS: Among 21 enrolled patients, common drug-related adverse events were anaemia, neutropenia, thrombocytopenia, pain, hyperglycemia, and stomatitis. Out of 11 evaluable patients treated with everolimus at the level of 5 mg, 1 patient experienced dose-limiting toxicity (DLT) of grade 4 febrile neutropenia and grade 3 thrombocytopenia. The other two DLTs (grade 4 thrombocytopenia and grade 3 hyperglycemia) occurred in two out of three patients receiving everolimus 10 mg. The overall objective response rate was 28%. CONCLUSION: Everolimus showed an acceptable safety profile and preliminary antitumour activity at the dose of 5 mg once daily when combined with 3-weekly paclitaxel 175 mg m(-2) in patients with SCLC.

A phase II study of combination chemotherapy with capecitabine and cisplatin in patients with metastatic or recurrent squamous cell carcinoma of the head and neck.

BACKGROUND: The purpose of this study was to assess the efficacy and toxicity of capecitabine and cisplatin (XP) combination chemotherapy in patients with metastatic or recurrent squamous cell carcinoma of the head and neck (SCCHN). PATIENTS AND METHODS: The chemotherapy regimen consisted of capecitabine 1250 mg/m(2) orally twice a day on day 1 to day 14 and cisplatin 60 mg/m(2) i.v. on day 1. Each cycle was repeated every 3 weeks up to a maximum of six cycles. RESULTS: By intent-to-treat analysis, the overall response rate was 50% [complete response, 0/36; partial response, 18/36; 95% confidence interval (CI) 32% to 67%]. The median progression-free survival was 3.7 months (95% CI 2.1-5.3 months), and the median response duration was 4.9 months. The median overall survival and 1-year survival rate were 10.3 months (95% CI 8.5-12.1 months) and 43.3%, respectively. The common grade 3 or 4 nonhematologic adverse events were anorexia (8.8%), fatigue (4.4%), diarrhea (4.4%), stomatitis (3.6%), and the hand-foot syndrome (1.5%). The most common grade 3 or 4 hematologic adverse event was neutropenia (14.6%), followed by anemia (1.5%). There was no treatment-related death. CONCLUSION: The XP combination regimen has antitumor activity and acceptable safety profile in patients with metastatic or recurrent SCCHN.

The NanoString-based multigene assay as a novel platform to screen EGFR, HER2, and MET in patients with advanced gastric cancer.

INTRODUCTION: Molecular targets are emerging rapidly and the development of clinical tests that simultaneously screen for multiple targets has become especially important. We assessed the gene expression levels of three known targets in advanced gastric cancer, epidermal growth factor receptor (EGFR), human epidermal growth factor 2 (HER2), and N-methyl-N-nitrosoguanidine human osteosarcoma transforming gene (MET), using the nCounter® assay (NanoString Technologies, Seattle, WA, USA) and compared these results with protein overexpression, detected by immunohistochemistry, to evaluate the performance of this new technology. METHODS: We investigated 42 formalin-fixed, paraffin-embedded tumor samples from patients with gastric cancer. A NanoString-based assay containing a 522 kinase gene panel was investigated. We analyzed the correlations between immunohistochemical findings and kinase gene expression levels of EGFR, HER2 and MET to validate this assay. RESULTS: EGFR, HER2, and MET overexpression were observed in 7 (16.6 %), 5 (11.9 %), and 3 (7.1 %) cases, respectively. For EGFR, HER2, and MET, the concordance rates between the NanoString-based assay results and the immunohistochemistry methods were 83.3, 97.6, and 100 %, respectively. Relative to immunohistochemistry findings, the NanoString-based assay sensitivities and specificities were 85.7 and 82.8 % for EGFR, 100 and 97.2 % for HER2, and 100 and 100 % for MET, respectively. CONCLUSIONS: We found a high concordance between immunohistochemistry- and nCounter-based assessments of EGFR, HER2, and MET in advanced gastric cancer. Judged against immunohistochemistry results, the NanoString assay had high sensitivities and high specificities. These results suggest that the nCounter assay provides a reliable, high-throughput assay to simultaneously screen for the overexpression of several target proteins.