Development of Response Classifier for Vascular Endothelial Growth Factor Receptor (VEGFR)-Tyrosine Kinase Inhibitor (TKI) in Metastatic Renal Cell Carcinoma.

Vascular endothelial growth factor receptor (VEGFR)-targeted therapy improved the outcome of metastatic renal cell carcinoma (mRCC) patients. However, a prediction of the response to VEGFR-tyrosine kinase inhibitor (TKI) remains to be elucidated. We aimed to develop a classifier for VEGFR-TKI responsiveness in mRCC patients. Among 101 mRCC patients, ones with complete response, partial response, or ≥24 weeks stable disease in response to VEGFR-TKI treatment were defined as clinical benefit group, whereas patients with <24 weeks stable disease or progressive disease were classified as clinical non-benefit group. Clinicolaboratory-histopathological data, 41 gene mutations, 20 protein expression levels and 1733 miRNA expression levels were compared between clinical benefit and non-benefit groups. The classifier was built using support vector machine (SVM). Seventy-three patients were clinical benefit group, and 28 patients were clinical non-benefit group. Significantly different features between the groups were as follows: age, time from diagnosis to TKI initiation, thrombocytosis, tumor size, pT stage, ISUP grade, sarcomatoid change, necrosis, lymph node metastasis and expression of pAKT, PD-L1, PD-L2, FGFR2, pS6, PDGFRß, HIF-1α, IL-8, CA9 and miR-421 (all, P < 0.05). A classifier including necrosis, sarcomatoid component and HIF-1α was built with 0.87 accuracy using SVM. When the classifier was checked against all patients, the apparent accuracy was 0.875 (95% CI, 0.782-0.938). The classifier can be presented as a simple decision tree for clinical use. We developed a VEGFR-TKI response classifier based on comprehensive inclusion of clinicolaboratory-histopathological, immunohistochemical, mutation and miRNA features that may help to guide appropriate treatment in mRCC patients.

AZGP-1 immunohistochemical marker in prostate cancer: potential predictive marker of biochemical recurrence in post radical prostatectomy specimens.

One of the major challenges in prostate cancer research is to identify prognostic/predictive factors to distinguish aggressive disease from indolent one. To select prognostic/predictive markers of postoperative biochemical recurrence (BCR) that could be easily performed in daily pathology practice, the expression of 6 immunohistochemical markers including zinc-α-2-glycoprotein (AZGP-1), hCAP-D3, mucin 1, vimentin, E-cadherin, and ERG was assessed in a tissue microarray of 400 radical prostatectomy specimens. The expression levels were correlated with clinicopathologic factors and BCR. During the median follow-up period of 55 months, BCR occurred in 70 cases (17.5%). Low expression of AZGP-1 was noted in 76 cases (19.0%), whereas high expression of hCAP-D3, mucin 1, vimentin, and ERG was observed in 205 (51.3%), 81 (20.3%), 33 (8.3%), and 58 (14.5%) cases, respectively. Aberrant E-cadherin expression was noted in 29 cases (7.3%). By univariate analysis, BCR was associated with low expression of AZGP-1, high expression of hCAP-D3, and aberrant expression of E-cadherin. By multivariate analysis, only AZGP-1 remained an independent immunohistochemical factor, in addition to age, preoperative serum prostate-specific antigen level, Gleason score, tumor stage, and resection margin status. These results show that AZGP-1, hCAP-D3, and E-cadherin are potentially useful immunohistochemical markers to predict BCR, and that AZGP-1 can be used as an independent prognostic marker of aggressive prostate cancer.

Low production of reactive oxygen species and high DNA repair: mechanism of radioresistance of prostate cancer stem cells.

BACKGROUND: Cancer stem cells (CSCs) are resistant to radiotherapy and are responsible for tumor recurrence of various malignant tumors, including prostate cancer. MATERIALS AND METHODS: In order to define the radioresistance mechanism of prostate CSCs, their proliferative activity, cell cycle distribution, expression of CD133 stem cell marker, reactive oxygen species (ROS) production, and DNA repair efficiency were examined using prostatospheres and adherent LNCaP cells as a model of prostate CSC and bulk model of differentiated cells, respectively. RESULTS: Compared to adherent cells, prostatospheres exhibited greater number of low-to-intermediate ROS-producing cells and CD133-positive cells. Prostatospheres showed higher expression of DNA repair proteins after ionizing radiation (IR). CONCLUSION: Low vulnerability to ROS-induced cellular damage and the efficient repair of IR-induced DNA injury may explain the radioresistance of prostate CSCs. Therefore, increasing ROS-induced cytotoxicity and inhibition of DNA repair in prostate CSCs may help achieve complete eradication of prostate CSCs by radiotherapy.

Long-term recovery of irradiated prostate cancer increases cancer stem cells.

BACKGROUND: Despite improvements in treatment, prostate cancer (PC) remains the second-leading cause of cancer death in men. Radiotherapy is among the first-line treatments for PC, but a significant number of patients relapse. Recent evidence supports the idea that PC is initiated by a subset of cells, termed cancer stem cells (CSCs). CSCs have also been implicated in radioresistance in various malignancies, but their role in PC has not yet been investigated. METHODS: We compared the relative radiosensitivity of isolated CSCs to the total population of their corresponding cell lines, and examined the relative numbers of CSCs in irradiated cell lines following long-term recovery and in recurrent human PC. RESULTS: Here, we show that while irradiation does not immediately favor increased survival of CSCs, irradiated PC cell lines showed an increase in CSC properties with long-term recovery. These data suggest that, although CSCs are initially damaged by radiation, they possess a greater capacity for recovery and regrowth. CONCLUSIONS: The combination of radiotherapy with a CSC-targeted therapeutic strategy may prevent tumor recurrence.

Single nucleotide polymorphism of Wilms' tumor 1 gene rs16754 in Korean patients with cytogenetically normal acute myeloid leukemia.

A recent study from Germany showed that WT1 single nucleotide polymorphism (SNP) rs16754 was an independent prognostic factor in cytogenetically normal acute myeloid leukemia (CN-AML). We analyzed clinical impact of the WT1 rs16754 genotype on disease characteristics and outcomes in Korean patients with CN-AML. A total of 73 patients with CN-AML were included in the study. All patients received standard induction chemotherapy and their bone marrow or peripheral blood samples were cryopreserved at the time of diagnosis. WT1 exons 7 and 9 were amplified using polymerase chain reaction and directly sequenced. The genotype frequency for WT1 rs16754 was 6.8% for AA, 39.7% for GA, and 53.4% for GG. G was a minor allele in German population, whereas it was a major allele in Korean (13.7% vs. 73.3%, P < 0.001). Complete remission was induced in 85.3% of patients with GA/AA and 84.6% of those with GG (P = 0.936). Survival rates were also similar between patients with GG and those with GA/AA. Asian and Western populations exhibited significant differences in allele and genotype frequencies of WT1 rs16754. In Korean patients with CN-AML, WT1 SNP rs16754 had no significant impact on clinical outcomes and further investigations are needed to define prognostic implication of WT1 SNP rs16754 in CN-AML.

Histology and distribution of prostatic tissue on prostatic urethral margins: evaluation of radical prostatectomy specimens and implications on frozen section analysis.

The identification of prostate-specific antigen (PSA)-producing glands in prostatic urethral margins is often challenging, especially when examined as intraoperative frozen sections. To assess the histology of periurethral prostatic urethral glands and their expression of PSA and cytokeratins 7 and 20, we examined prostatic urethras of frozen and permanent sections of radical prostatectomy specimens. We observed 3 types of prostatic urethral glands: urethral mucosal, prostatic acinar, and mixed. The urethral mucosal type consisted of a single layer of surface cuboidal to columnar cells with densely eosinophilic luminal cytoplasm and underlying urothelial cells. The prostatic acinar type was lined by prostatic-type secretory cells and basal cells. The mixed type showed luminal secretory cells and underlying urothelial cells. The gland types were correctly assigned in most frozen section slides. The proximal segment of the prostatic urethra and the bladder neck consisted mostly of the urethral mucosal type, whereas the distal segment and apical margins consisted mostly of the prostatic acinar type. Prostate-specific antigen was expressed in secretory cells in prostatic acinar and mixed types, whereas cytokeratin 7 was expressed by urothelial cells and surface cells of the urethral mucosal type. Cytokeratin 20 was not expressed in any of these cells. These results indicate that PSA-expressing cells are abundant in the distal segment of the prostatic urethra and apical margin and share histologic features of prostatic secretory cells. These PSA-expressing prostatic acinar and mixed-type glands should be reported as a potential source of PSA-secreting benign glands.

Clinical significance of GSTM1 and GSTT1 polymorphisms in younger patients with acute myeloid leukemia of intermediate-risk cytogenetics.

We investigated the association between GSTM1 or GSTT1 polymorphisms and clinical outcomes in 133 younger patients with AML of intermediate-risk cytogenetics. Clinical outcomes were not significantly different among the GSTM1 polymorphism genotypes, whereas cumulative incidence of relapse (CIR) was significantly lower and event-free survival (EFS) was significantly higher in patients with the GSTT1-present genotype compared with those with the GSTT1-null genotype (CIR at 5 year, 28.9% vs. 44.6%, P=0.018; EFS at 5 year, 51.4% vs. 34.1%, P=0.029). Our results suggest that GSTT1 gene polymorphism has significant clinical implications in younger patients with AML of intermediate-risk cytogenetics.

C3435T polymorphism of the MDR1 gene is not associated with P-glycoprotein function of leukemic blasts and clinical outcome in patients with acute myeloid leukemia.

We investigated the association between the MDR1 C3435T polymorphism and P-glycoprotein function of leukemic blasts as well as clinical outcomes in 200 patients with AML, excluding the M3 subtype. The CC, CT and TT genotype frequencies of the C3435T polymorphism among patients were 71, 93 and 36, respectively. The C3435T polymorphism genotypes did not have influence on the P-glycoprotein function of leukemic blasts. Complete remission rates and overall, relapse-free and event-free survival rates were not significantly different among the C3435T polymorphism genotypes. In conclusion, the MDR1 C3435T polymorphism does not appear to have significant clinical implications in AML.