Objective: To assess the clinical features and treatment outcomes in patients with primary ovarian squamous cell carcinoma (POSCC). Methods: Fifteen patients with primary ovarian squamous cell carcinoma diagnosed from January 2009 to December 2018 in Cancer Hospital of the University of Chinese Academy of Sciences were collected. The expression of p16, hMLH1, hMSH2, hMSH6 and PMS2 in POSCC was detected by immunohistochemistry, and the status of high-risk human papillomavirus (HPV) by RNAscope test. Results: Squamous cell carcinoma with different degrees of differentiation was found in 15 cases, including three cases with high differentiation and 12 cases with medium to low differentiation. There were four cases with in situ squamous cell carcinoma, four cases with teratoma, one case with endometrial carcinoma/atypical hyperplasia, and one case with endometriosis. p16 was expressed in five cases (5/15), indicating coexisting high-risk HPV infection. There was no high-risk HPV infection in the remaining 10 cases, and p16 staining was negative. There was no deficient mismatch repair protein in all cases. The overall survival time (P=0.038) and progression free survival (P=0.045) of patients with high-risk HPV infection were longer than those without HPV infection. Conclusions: POSCC is more commonly noted in postmenopausal women and often occurs unilaterally. Elevated serological indexes CA125 and SCC are the most common finding. Morphologically, the tumors show variable degrees of differentiation, but the current data suggest that the degree of differentiation cannot be used as an independent prognostic index. High-risk HPV infection may be associated with the occurrence of POSCC, and that the prognosis of POSCC patients with HPV infection is better than that of patients without infection.
Carcinoma, Squamous Cell/pathology* ; Cyclin-Dependent Kinase Inhibitor p16/analysis* ; Female ; Humans ; Immunohistochemistry ; Papillomavirus Infections/diagnosis* ; Prognosis

PURPOSE: Hypermethylation of the CpG island of p16(INK4a) occurs in a significant proportion of colorectal cancer (CRC). We aimed to investigate its predictive role in CRC patients treated with 5-fluorouracil, leucovorin, irinotecan (FOLFIRI), and cetuximab. MATERIALS AND METHODS: Pyrosequencing was used to identify KRAS mutation and hypermethylation of 6 CpG island loci (p16, p14, MINT1, MINT2, MINT31, and hMLH1) in DNA extracted from formalin-fixed paraffin-embedded specimens. Logistic regression and Cox regression were performed for analysis of the relation between methylation status of CpG island methylator phenotype (CIMP) markers including p16 and clinical outcome. RESULTS: Hypermethylation of the p16 gene was detected in 14 of 49 patients (28.6%) and showed significant association with KRAS mutation (Fisher exact, p=0.01) and CIMP positivity (Fisher exact, p=0.002). Patients with p16-unmethylated tumors had significantly longer time to progression (TTP; median, 9.0 months vs. 3.5 months; log-rank, p=0.001) and overall survival (median, 44.9 months vs. 16.4 months; log-rank, p=0.008) than those with p16-methylated tumors. Patients with both KRAS and p16 aberrancy (n=6) had markedly shortened TTP (median, 2.8 months) compared to those with either KRAS or p16 aberrancy (n=11; median, 8.6 months; p=0.021) or those with neither (n=32; median, 9.0 months; p < 0.0001). In multivariate analysis, KRAS mutation and p16 methylation showed independent association with shorter TTP (KRAS mutation: hazard ratio [HR], 3.21; p=0.017; p16 methylation: HR, 2.97; p=0.027). CONCLUSION: Hypermethylation of p16 was predictive of clinical outcome in metastatic CRC patients treated with cetuximab and FOLFIRI, irrespective of KRAS mutation.
Colorectal Neoplasms* ; CpG Islands ; Cyclin-Dependent Kinase Inhibitor p16 ; DNA ; Drug Therapy* ; Fluorouracil ; Genes, p16 ; Humans ; Leucovorin ; Logistic Models ; Methylation ; Multivariate Analysis ; Phenotype

We report three patients with normal karyotype (NK) ALL, who showed genetic aberrations as determined by high-resolution single nucleotide polymorphism array (SNP-A) analysis at both diagnosis and relapse. We evaluated the clinical relevance of the SNP-A assay for the detection of subtle changes in the size of affected genetic lesions at relapse as well as the prognostic value of the assay. In our patients, application of the SNP-A assay enabled sensitive detection of cryptic changes affecting clinically important genes in NK ALL. Therefore, this assay seems to be more advantageous compared to other conventional methods such as FISH assay, HemaVision (DNA Technology, Denmark), and conventional karyotyping for the detection of an "unstable genotype" at relapse, which may be associated with microscopic clonal evolution and poor prognosis. Further comprehensive studies are required to confirm the issues presented by our case patients in this report.
Adult ; Cyclin-Dependent Kinase Inhibitor p16/genetics ; Female ; Genotype ; Humans ; In Situ Hybridization, Fluorescence ; Karyotype ; Karyotyping ; Loss of Heterozygosity ; Male ; Middle Aged ; Oligonucleotide Array Sequence Analysis ; Polymorphism, Single Nucleotide ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/*diagnosis/genetics ; Recurrence ; Retinoblastoma Protein/genetics

OBJECTIVETo detect the infection of human papillomavirus (HPV) 6/11, 16/18, 31/33 in patients with head and neck squamous cell carcinoma and explore the relationship between HPV infection and expression of p16 and EGFR in the tumor tissue and their clinical significance.

METHODSThe infection of HPV6/11, 16/18, 31/33 was detected by in situ hybridization (ISH), and expression of p16 and EGFR was assessed by immunohistochemistry in biopsy or surgical specimens of 43 cases of head and neck squamous cell carcinoma, and analyzed its impact on the prognosis. Spearman rank correlation method was used for analysis of the relationship. Overall survival rate of the patients was estimated by Kaplan-Meier analysis. Cox regression model was used for multivariate analysis.

RESULTSHPV6/11, 16/18, 31/33 were detected in 25.6% (11/43) of this group of patients, among them, HPV16/18 accounted for 63.6%, HPV31/33 accounted for 27.3%, and HPV6/11 accounted for 0. EGFR was expressed in 69.8% and p16 was expressed in 53.5% of the patients. The difference was statistically significant between the HPV-positive and HPV-negative groups in ethnicity, smoking, alcohol consumption (P = 0.045, 0.040, 0.011, respectively). HPV infection was found to be positively correlated with p16 expression and inversely correlated with EGFR expression (P = 0.029, P = 0.009). The expression of p16 protein was negatively correlated with EGFR protein expression (r = -0.447, P = 0.003). The 3-year overall survival rate was 60.0% in the HPV-positive group and 59.7% in the negative group (P = 0.789); 72.2% in the p16-positive patients and 43.9% in the p16-negative patients (P = 0.012); 48.8% in the EGFR-positive patients and 81.8% in the EGFR-negative patients (P = 0.037).

CONCLUSIONSThe results of our study suggest that the HPV infection rate, HPV subtypes and clinicopathological features of HPV-positive SCCHN are in accordance with those reported in Western literatures. There may be differences between the HPV infections in Uygur and Han nationalities. HPV infection is positively correlated with p16 and negatively correlated with EGFR expressions. The prognosis of p16-positive patients is significantly better than that of negative cases, and p16 is an independent prognostic factor for head and neck squamous cell carcinoma.

Carcinoma, Squamous Cell ; mortality ; virology ; Cyclin-Dependent Kinase Inhibitor p16 ; metabolism ; Head and Neck Neoplasms ; mortality ; virology ; Human papillomavirus 16 ; Humans ; Papillomavirus Infections ; metabolism ; Prognosis ; Receptor, Epidermal Growth Factor ; metabolism ; Survival Analysis

BACKGROUND: This study investigates the prevalence of human papillomavirus (HPV) 52 and 58 genotypes among women residing in Busan, and the expression of p16 and p53 proteins in cervical neoplasia with HPV 52 and 58 infections. METHODS: A total of three hundred fifteen cases were analyzed using the HPV DNA chip test for HPV genotypes, and of these, we retrospectively examined p16 and p53 expression in 62 cases of cervical tissues infected with HPV 52 and 58 using immunohistochemistry. RESULTS: HPV 52 and 58 genotypes were identified in 62 (54.9%) out of 113 high-risk, HPV-infected cases. Of the cases examined, there were 19 single HPV 52 infections (16.8%), 23 single HPV 58 infections (20.4%), 4 multiple HPV 52 infections (3.5%), and 16 multiple HPV-58 infections (14.2%). Immunoreactivity of p16 and p53 was observed in 41 (66.1%) and 23 (37.1%) of the 62 cases of cervical neoplasia infected with HPV 52 and 58 genotypes, respectively. CONCLUSIONS: This study demonstrates a high prevalence of HPV 52 and 58 genotypes, in addition to HPV 16, among high-risk strains of cervical neoplasia in Korea. These findings suggest that development of more vaccines would be beneficial for the prevention of the various HPV genotypes.
Busan ; Cyclin-Dependent Kinase Inhibitor p16 ; Female ; Genotype* ; Human papillomavirus 16 ; Humans* ; Immunohistochemistry ; Korea ; Oligonucleotide Array Sequence Analysis ; Prevalence ; Retrospective Studies ; Tumor Suppressor Protein p53 ; Vaccines

BACKGROUND: The primary purpose of this study was to investigate the prevalence and characteristics of p16 methylation and determine the prognostic implications of the clinical data, hematologic data, and p16 methylation changes in plasma cell myeloma (PCM). METHODS: We reviewed clinical characteristics and results of laboratory tests and investigated the response to combination chemotherapy and survival time. DNA methylation of the p16 gene was tested by methylation-specific PCR. Clinical significance was evaluated. RESULTS: A total of 103 patients were enrolled in this study. The median patient age was 59.0 yr at diagnosis and the male to female ratio was 1.15:1. According to the International Staging System (ISS), patients were diagnosed as stage: I (N=17, 16.5%), II (N=41, 39.8%), III (N=39, 37.9%), or not classified (N=6). Forty-five (43.7%) patients and 36 (35.0%) patients showed abnormal karyotype and complex karyotype, respectively, on the chromosome study. The p16 methylation was observed in 39 (37.9%) of 103 patients, but there was no significant association between p16 methylation status and other clinical or laboratory factors and survival outcome. Male gender, albumin, and complex karyotype were independent prognostic factors for overall survival according to multivariate analysis (P<0.05). CONCLUSIONS: The male gender, low serum albumin level, and complex karyotype were independent poor prognostic factors for PCM. p16 methylation was relatively common in PCM, but did not influence the survival outcome.
Adult ; Aged ; Aged, 80 and over ; Antineoplastic Agents/therapeutic use ; Cyclin-Dependent Kinase Inhibitor p16/*genetics ; *DNA Methylation ; Female ; Humans ; Karyotyping ; Male ; Middle Aged ; Multiple Myeloma/drug therapy/*genetics/mortality ; Neoplasm Staging ; Polymerase Chain Reaction ; Prognosis ; Republic of Korea ; Serum Albumin/analysis ; Sex Factors ; Survival Rate

OBJECTIVETo determine whether testosterone modulates markers of cardiomyocytes aging via its classic androgen receptor (AR)-dependent pathway or conversion to estradiol.

METHODSMale littermates and testicular feminized (Tfm) mice were randomly separated into 4 experimental groups littermate controls (n=8), Tfm mice (n=7), testosterone-treated Tfm mice (n=8), and Tfm mice treated with testosterone in combination with the aromatase inhibitor anastrazole (n=7). Cardiomyocytes were isolated from mouse left ventricles, the activity of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), and the amount of malondialdehyde (MDA) were measured using colorimetry method, and expression of p16(INK4α) and retinoblastoma (Rb) proteins were detected by Western blotting.

RESULTSThe SOD and GSH-Px enzyme activities of cardiomyocytes were decreased, and the MDA levels and the expression of p16(INK4α) and Rb proteins were increased in Tfm mice compared with control mice. An increase was observed in the activities of SOD and GSH-Px enzyme as well as a decrease in MDA levels and the expression of p16(INK4α) and Rb proteins in the testosterone-treated Tfm mice. After co-treatment with anastrazole in Tfm mice, these improvement were partly inhibited.

CONCLUSIONPhysiological testosterone replacement can delay cardiomyocyte aging in Tfm mice, an effect that is independent of the AR pathway and in part conversion to estradiol.

Androgen-Insensitivity Syndrome ; metabolism ; Animals ; Cellular Senescence ; Cyclin-Dependent Kinase Inhibitor p16 ; analysis ; Female ; Glutathione Peroxidase ; metabolism ; Male ; Mice ; Myocytes, Cardiac ; physiology ; Receptors, Androgen ; physiology ; Superoxide Dismutase ; metabolism ; Testosterone ; physiology

Acid Anhydride Hydrolases ; genetics ; metabolism ; Animals ; Antimetabolites, Antineoplastic ; pharmacology ; Azacitidine ; analogs & derivatives ; pharmacology ; Biomarkers, Tumor ; analysis ; Carcinoma, Squamous Cell ; diagnosis ; genetics ; metabolism ; pathology ; Cyclin-Dependent Kinase Inhibitor p16 ; genetics ; metabolism ; DNA Methylation ; drug effects ; Genes, p16 ; Humans ; Laryngeal Neoplasms ; diagnosis ; genetics ; metabolism ; pathology ; Neoplasm Proteins ; genetics ; metabolism ; Tumor Suppressor Proteins ; genetics ; metabolism

OBJECTIVETo evaluate the value of the detection of a 4-marker (ER, VIM, CEA and p16) panel in the differential diagnosis of primary endocervical and endometrial adenocarcinomas.

METHODSImmunohistochemical EnVison method was used to detect the expressions of ER, VIM, CEA and p16 in paraffin-embedded tissues from 31 cases of primary endocervical adenocarcinomas and 30 cases of endometrial adenocarcinomas. The specificity, sensitivity, predictive value and accuracy were compared between the 4-marker and 3-marker (ER, VIM and CEA) panels.

RESULTSThe positivity rates of ER, VIM, CEA and p16 in endocervical adenocarcinomas were 35.5%, 19.4%, 77.4% and 67.7%, respectively; those in endometrial adenocarcinomas were 70%, 73.3%, 40% and 13.3%, respectively, showing significant frequency differences (P<0.05) between primary endocervical and endometrial adenocarcinomas. The specificity, sensitivity, positive predictive value and accuracy of the 4-marker panel in endocervical adenocarcinomas were significantly higher than those of the 3-marker panel (96.3% vs 90.2%, 65.1% vs 57.6%, 94.9% vs 89.4%, and 85.8% vs 80.6%, respectively). These values were almost similar for both panels in endometrial carcinoma except for better negative predictive value and accuracy value with the 4-marker panel (58.7% vs 51.9% and 75.4% vs 68.6%, respectively).

CONCLUSIONAdding the p16 marker to the traditional 3-marker panel may have significant clinical importance in the differential diagnosis of primary endocervical and endometrial adenocarcinomas to improve the diagnostic accuracy, although there is only a slight increase in the diagnostic sensitivity.

Adenocarcinoma ; diagnosis ; metabolism ; Adult ; Aged ; Biomarkers, Tumor ; analysis ; Carcinoembryonic Antigen ; analysis ; Cyclin-Dependent Kinase Inhibitor p16 ; Diagnosis, Differential ; Endometrial Neoplasms ; diagnosis ; metabolism ; Female ; Humans ; Middle Aged ; Neoplasm Proteins ; analysis ; Predictive Value of Tests ; Receptors, Estrogen ; analysis ; Sensitivity and Specificity ; Uterine Cervical Neoplasms ; diagnosis ; metabolism ; Vimentin ; analysis

The aim of this study was to assess immunohistochemical expression of p53, pRb, p16, and cyclin D1, alone or in combination, as prognostic indicators and to investigate their correlation with clinocopathologic features of urothelial carcinoma. Immunohistochemical staining for p53, pRb, p16, and cyclin D1 was performed on a tissue microarray from 103 patients with urothelial carcinoma who underwent radical cystectomy. Of the patient samples analyzed, 36 (35%), 61 (59%), 47 (46%) and 30 (29%) had altered expression of p53, pRb, p16, and cyclin D1, respectively. Abnormal expression of p53 and pRb correlated with depth of invasion (P=0.040 and P=0.044, respectively). Cyclin D1 expression was associated with tumor stage and recurrence (P=0.017 and P=0.036, respectively). Altered pRb was significantly correlated with overall survival (P=0.040). According to the expression pattern of pRb and p53, p53/pRb (altered/normal) had worse survival than p53/pRb (normal/altered) (P=0.022). Alteration of all markers had worse survival than all normal (P=0.029). As determined by multivariate analysis, tumor stage, lymph node metastasis and the combined expression of p53 and pRb are independent prognostic factors. In conclusion, immunohistochemical evaluation of cell cycle regulators, especially the p53/pRb combination, might be useful in planning appropriate treatment strategies.
Adult ; Aged ; Aged, 80 and over ; Carcinoma, Transitional Cell/*metabolism/mortality/pathology ; Cyclin D1/*metabolism ; Cyclin-Dependent Kinase Inhibitor p16/*metabolism ; Female ; Humans ; Immunohistochemistry ; Lymphatic Metastasis ; Male ; Middle Aged ; Multivariate Analysis ; Neoplasm Staging ; Prognosis ; Recurrence ; Retinoblastoma Protein/*metabolism ; Survival Rate ; Tumor Suppressor Protein p53/*metabolism ; Urinary Bladder Neoplasms/*metabolism/mortality/pathology