S-H Lee

Final results from the large sunitinib global expanded-access trial in metastatic renal cell carcinoma

Background:We report final results with extended follow-up from a global, expanded-access trial that pre-regulatory approval provided sunitinib to metastatic renal cell carcinoma (mRCC) patients, ineligible for registration-directed trials.Methods:Patients ⩾18 years received oral sunitinib 50 mg per day on a 4-weeks-on–2-weeks-off schedule. Safety was assessed regularly. Tumour measurements were scheduled per local practice.Results:A total of 4543 patients received sunitinib. Median treatment duration and follow-up were 7.5 and 13.6 months. Objective response rate was 16% (95% confidence interval (CI): 15–17). Median progression-free survival (PFS) and overall survival (OS) were 9.4 months (95% CI: 8.8–10.0) and 18.7 months (95% CI: 17.5–19.5). Median PFS in subgroups of interest: aged ⩾65 years (33%), 10.1 months; Eastern Cooperative Oncology Group performance status ⩾2 (14%), 3.5 months; non-clear cell histology (12%), 6.0 months; and brain metastases (7%), 5.3 months. OS was strongly associated with the International Metastatic Renal-Cell Carcinoma Database Consortium prognostic model (n=4065). The most common grade 3/4 treatment-related adverse events were thrombocytopenia (10%), fatigue (9%), and asthenia, neutropenia, and hand–foot syndrome (each 7%).Conclusion:Final analysis of the sunitinib expanded-access trial provided a good opportunity to evaluate the long-term side effects of a tyrosine kinase inhibitor used worldwide in mRCC. Efficacy and safety findings were consistent with previous results.

Methylator phenotype of malignant germ cell tumours in children identifies strong candidates for chemotherapy resistance

Background:Yolk sac tumours (YSTs) and germinomas are the two major pure histological subtypes of germ cell tumours. To date, the role of DNA methylation in the aetiology of this class of tumour has only been analysed in adult testicular forms and with respect to only a few genes.Methods:A bank of paediatric tumours was analysed for global methylation of LINE-1 repeat elements and global methylation of regulatory elements using GoldenGate methylation arrays.Results:Both germinomas and YSTs exhibited significant global hypomethylation of LINE-1 elements. However, in germinomas, methylation of gene regulatory regions differed little from control samples, whereas YSTs exhibited increased methylation at a large proportion of the loci tested, showing a ‘methylator’ phenotype, including silencing of genes associated with Caspase-8-dependent apoptosis. Furthermore, we found that the methylator phenotype of YSTs was coincident with higher levels of expression of the DNA methyltransferase, DNA (cytosine-5)-methyltransferase 3B, suggesting a mechanism underlying the phenotype.Conclusion:Epigenetic silencing of a large number of potential tumour suppressor genes in YSTs might explain why they exhibit a more aggressive natural history than germinomas and silencing of genes associated with Caspase-8-dependent cell death might explain the relative resistance of YSTs to conventional therapy.

Oligomeric and functional properties of a debranching enzyme (TreX) from the archaeon Sulfolobus solfataricus P2

A gene, treX, encoding a debranching enzyme previously cloned from the trehalose biosynthesis gene cluster of Sulfolobus solfataricus P2 was expressed in Escherichia coli as a His-tagged protein and the biochemical properties were studied. The specific activity of the S. solfataricus debranching enzyme (TreX) was highest at 75°C and pH 5.5. The enzyme exhibited hydrolysing activity toward α-1,6-glycosidic linkages of amylopectin, glycogen, pullulan, and other branched substrates, and glycogen was the preferred substrate. TreX has a high specificity for hydrolysis of maltohexaosyl α-1,6-β-cyclodextrin, indicating the high preference for side chains consisting of 6 glucose residues or more. The enzyme also exhibited 4-α-sulfoxide-glucan transferase activity, catalysing transfer of α-1,4-glucan oligosaccharides from one chain to another. Dimethyl sulfoxide (10%, v/v) increased the hydrolytic activity of TreX. Gel permeation chromatography and sedimentation equilibrium analytical ultracentrifugation revealed that the enzyme exists mostly as a dimer at pH 7.0, and as a mixture of dimers and tetramers at pH 5.5. Interestingly, TreX existed as a tetramer in the presence of DMSO at pH 5.5–6.5. The tetramer showed a 4-fold higher catalytic efficiency than the dimer. The enzyme catalysed not only intermolecular trans-glycosylation of malto-oligosaccharides (disproportionation) to produce linear α-1,4-glucans, but also intramolecular trans-glycosylation of glycogen. The results presented in this study indicated that TreX may be associated with glycogen metabolism by selective cleavage of the outer side chain.

ESRP1 is overexpressed in ovarian cancer and promotes switching from mesenchymal to epithelial phenotype in ovarian cancer cells

Epithelial splicing regulatory protein 1 (ESRP1) and 2 (ESRP2), epithelial cell-specific regulators of alternative splicing, are downregulated during the epithelial–mesenchymal transition (EMT). These factors have roles in tumor progression and metastasis in some cancers; however, their expression and function in ovarian cancer (OC) remain unclear. We found that ESRP1 and ESRP2 mRNAs were expressed at higher levels in OC cells than in immortalized ovarian surface epithelial (IOSE) cells, and confirmed their overexpression in OC tissues at the protein level. The Cancer Genome Atlas (TCGA) data analysis revealed frequent gene amplification of ESRP1 in OC tissues; however, we detected no significant correlation between ESRP1 gene copy number and gene expression in OC cells. Importantly, expression of ESRP1 and ESRP2 was inversely correlated with DNA methylation in OC cells, and ESRP2 overexpression in OC tissues was significantly associated with DNA hypomethylation. Notably, survival analysis using TCGA data from 541 OC tissues revealed that high ESRP1 expression was significantly associated with shorter 5-year survival of patients. Ectopic ESRP1 expression in mesenchymal OC cells promoted cell proliferation but suppressed cell migration. Furthermore, we found that ESRP1 drives a switch from mesenchymal to epithelial phenotype characterized by reduced cell migration in association with induction of epithelial cell-specific variant of CD44 and ENAH. Taken together, our findings suggest that an epigenetic mechanism is involved in ESRP1 overexpression, and that ESRP1 has a role in OC progression.

Dental implications in Hajdu-Cheney syndrome: A novel case report and review of the literature

OBJECTIVE To identify the molecular genetic etiology of an individual with a dysmorphic face, unusual teeth mobility, and root resorption. SUBJECTS AND METHODS DNA samples were collected from a trio of family members, and whole-exome sequencing was performed. RESULTS Mutational analysis revealed a de novo mutation (c.6787C>T) in the last exon of the NOTCH2 gene. This mutation would introduce a premature stop codon [p.(Gln2263*)] and generate a truncated protein without C-terminus, escaping from the nonsense-mediated decay system. Sanger sequencing confirmed that this mutation was generated spontaneously. CONCLUSIONS In this study, we identified a novel nonsense mutation in the last exon of the NOTCH2 gene causing Hajdu-Cheney syndrome. We described the genotype and phenotype correlation and the related dental complications. These results will advance the understanding of the NOTCH2 signaling in periodontitis and root resorption.

Abstract P1-05-15: Multi-omics and immuno-oncology profiling reveal distinct molecular signatures of young Asian breast cancers

Breast cancers (BC) in younger, premenopausal patients (YBC) tend to be more aggressive with worse prognosis, higher chance of relapse and poorer response to endocrine therapies compared to breast cancers in older patients. The proportion of YBC (age ≤ 40) among BC in East Asia is estimated to be 16-32%, significantly higher than the 7% reported in Western countries. To characterize the molecular bases of Asian YBC, we have performed whole-exome sequencing (WES) and whole-transcriptome sequencing (WTS) on tumor and matched normal samples from 134 Korean BC patients consisting of 74 YBC cases (age ≤ 40) and 60 OBC cases (age > 40). We then performed comparison analyses and integrative analyses with the TCGA BC cohort consisting of 1,116 tumors from primarily Caucasian patients, also grouped by age into YBC (age ≤ 40), IBC (40 60). Somatic mutation prevalence analysis identified 7 significantly mutated genes and the same top three genes – TP53, GATA3 and PIK3CA – were reported by the TCGA BC study. To identify differentially expressed (DE) genes and pathways in YBCs vs. OBCs, we performed logistic regression analyses while controlling for the confounding effects of tumor purity and stage. We were surprised to see a significant overlap in DE pathways between a comparison of adjacent normal tissues in younger vs. older TCGA cohorts and a comparison of YBC vs. OBC tumors, indicating that normal tissue compartment could contribute to observed differences between bulk tumors. To separately examine molecular signatures from tumor, stroma and normal compartments, we used non-negative matrix factorization (NMF) analyses to virtually dissect bulk tumor expression data and identified 14 factors including 3 factors associated with normal tissues, 1 factor associated with stroma and 1 factor associated with tumor infiltrating lymphocytes (TIL). Integrative analyses of tumor associated factors and DE pathways revealed that estrogen response, endocrine therapy resistance, and oxidative phosphorylation pathways are up-regulated in YBCs compared to OBCs while cell cycle and proliferation pathways are up-regulated in Asian OBCs. Interestingly, many immune and inflammation pathways correlated with the TIL factor were significantly upregulated in OBCs vs. YBCs. Using gene expression signatures representing distinct immune cell types, we classified our cohort into four subtypes of varying TIL activities and observed significant enrichment of the TIL-high subtype in OBCs compared to YBCs. These observations were confirmed by IHC analyses of four TIL markers (CD45, CD4, CD8 and CD163) in 120 tumors. To our knowledge, this is the first large-scale multi-omics study of Asian breast cancer and would significantly contribute to the compendium of molecular data available for studying young breast cancers. The major landmarks in the molecular landscape looked similar across BCs of different ethnicities and ages, however, we have identified a number of distinguishing molecular characteristics associated with Asian YBC. The sources for some signatures were further traced to non-tumor intrinsic compartments, indicating that tumor microenvironment may play potentially important roles in driving the carcinogenesis of young breast cancers. Citation Format: Kan Z, Ding Y, Cho S, Lee S-H, Powell E, Jung HH, Chung W, Deng S, Choi Y-l, Kim J, Park W-Y, Vizcarra P, Fernandez-Banet J, Nichols T, Ram S, Lee SK, Kim SW, Lee JE, Ching KA, Kim J-Y, Ahn JS, Im Y-H, Nam SJ, Park YH. Multi-omics and immuno-oncology profiling reveal distinct molecular signatures of young Asian breast cancers [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P1-05-15.

Predictors of Revisit and Admission after Discharge from an Emergency Department in Acute Pyelonephritis

Introduction The aim of this study is to construct clinical prediction models to predict emergency department (ED) return visit following initial discharge for acute pyelonephritis (APN) and the need for hospital re-admission upon ED return visits. Method A retrospective analysis included 1250 discharged women with APN. Independent risk factors for revisit and subsequent admission after revisit were determined by multivariate analysis, and a prediction model for revisit and subsequent admission after revisit was constructed. Results Independent risk factors for revisit were nausea (2 points), age ≥ 65 years (2 points), C-reactive protein >20 mg/dL (2 points), serum albumin <3.3 g/dL (3 points) and urine white blood cell count ≥ 30/high power field (2 points). Re-visit risk scores were categorised to five groups and the re-visit rate was 5.4%, 8.6%, 12.2%, 19.1% and 43.8%, respectively, showing an area under curve (AUC) of 0.62. Risk factors for subsequent admission after revisit were vomiting (1 point), hypertension (2 points), serum creatinine <1.5 mg/dL (2 points), C-reactive protein >20 mg/dL (2 points) and serum albumin <3.3 g/dL (4 points). The subsequent admission after revisit risk scores were classified to three groups and subsequent admission after revisit rate was 3.5%, 15.0%, and 38.2%, respectively. Conclusion The developed model can identify a group of patients at high risk for a return visit and for requiring subsequent hospital admission, and might be used to improve initial disposition decision and discharge instructions. (Hong Kong j.emerg. med. 2015;22:154-162)

Abstract P2-09-36: Role of ABCB1 Polymorphisms as Predictive Markers in Patients with HER-2 FISH Positive Metastatic Breast Cancer Who Were Treated with Taxane Plus Trastuzumab First Line Chemotherapy

Background: ABCB1 polymorphisms could predict treatment results of taxane therapy in several malignancies. FCGR2A and FCGR3A polymorphisms were associated with clinical outcomes in several diseases after treatment with monoclonal antibody drugs which had antibody-dependent cell-mediated cytotoxicity activity. These polymorphisms could be possible predictive markers after taxane plus trastuzumab (TH) chemotherapy in patients with HER-2-positive metastatic breast cancer (MBC). Methods: Fifty-seven patients with HER-2 FISH positive MBC who received TH chemotherapy as the 1st-line treatment were enrolled. We analyzed 5 polymorphisms using DNA from peripheral blood mononuclear cells: ABCB1 1236C>T (rs1128503), ABCB1 2677G>T/A (rs2032582), ABCB1 3435C>T (rs1045642), FCGR2A 131H/R (rs1801274), and FCGR3A 158V/F (rs396991), then correlated them to treatment results of patients. Results: Among 57 patients, 22 patients (38.6%) received weekly paclitaxel plus trastuzumab, 26 patients (45.6%) tri-weekly paclitaxel plus trastuzumab, and 9 patients (15.8%) tri-weekly docetaxel plus trastuzumab. After a median follow-up of 30.6 (range, 0.6-75.9) months, median progression-free survival (PFS) was 15.1 (95% confidence interval (CI), 10.3-19.8) months. ABCB1 2677T allele carriers had longer PFS than the others (42.1 (95% CI, 12.7-71.4) months vs. 13.0 (95% CI, 10.6-15.4) months; p=0.037) along with a tendency toward higher response rate (RR) (86.4% vs. 76.0%; p=0.470) and longer overall survival (OS) (54.7 (95% CI, 43.0-66.4) months vs. 38.9 (95% CI, 18.1-59.7) months; p=0.057). In addition, ABCB1 3435CC genotype carriers had shorter PFS than the others (13.0 (95% CI, 10.8-15.2) months vs. 19.1 (95% CI, 0.0-38.5) months; p=0.039) along with a tendency toward lower RR (78.6% vs. 100%; p=0.567) and shorter OS (38.9 (95% CI, 19.7-58.1) months vs. 54.7 (95% CI, 43.0-66.4) months; p=0.093). ABCB1 1236C>T, FCGR2A 131H/R, and FCGR3A 158V/F were not significantly associated with RR, PFS, and OS. None of these polymorphisms were associated with any grades of hematologic or cardiac toxicities. Conclusions: Our results support that ABCB1 2677G>T/A and 3435C>T may have predictive roles after the 1st-line TH chemotherapy in patients with HER-2-positive MBC. In contrast, ABCB1 1236C>T, FCGR2A 131H/R, and FCGR3A 158V/F could not predict response after TH treatment. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P2-09-36.