Cynthia Kuk

Human tissue kallikrein expression in the stratum corneum and serum of atopic dermatitis patients.

Abstract:  Human tissue kallikreins are a family of 15 trypsin‐ or chymotrypsin‐like secreted serine proteases (KLK1–KLK15). Many KLKs have been identified in normal stratum corneum (SC) and sweat, and are candidate desquamation‐related proteases.

Prevalence of Prostate Cancer on Autopsy: Cross-Sectional Study on Unscreened Caucasian and Asian Men

BACKGROUND Substantial geographical differences in prostate cancer (PCa) incidence and mortality exist, being lower among Asian (ASI) men compared with Caucasian (CAU) men. We prospectively compared PCa prevalence in CAU and ASI men from specific populations with low penetrance of prostate-specific antigen screening. METHODS Prostate glands were prospectively obtained during autopsy from men who died from causes other than PCa in Moscow, Russia (CAU), and Tokyo, Japan (ASI). Prostates were removed en-block and analyzed in toto. We compared across the 2 populations PCa prevalence, number and Gleason score (GS) of tumour foci, pathological stage, spatial location, and tumor volume using χ(2), Mann-Whitney-Wilcoxon tests, and multiple logistic regression. All statistical tests were two-sided. RESULTS Three hundred twenty prostates were collected, 220 from CAU men and 100 from ASI mean. The mean age was 62.5 in CAU men and 68.5 years in ASI men (P < .001). PCa prevalences of 37.3% in CAU men and 35.0% in ASI men were observed (P = .70). Average tumor volume was 0.303cm(3). In men aged greater than 60 years, PCa was observed in more than 40% of prostates, reaching nearly 60% in men aged greater than 80 years. GS 7 or greater cancers accounted for 23.1% and 51.4% of all PCa in CAU and ASI men, respectively, (P = .003). When adjusted for age and prostate weight, ASI men still had a greater probability of having GS 7 or greater PCa (P = .03). CONCLUSIONS PCa is found on autopsy in a similar proportion of Russian and Japanese men. More than 50% of cancers in ASI and nearly 25% of cancers in CAU men have a GS of 7 or greater. Our results suggest that the definition of clinically insignificant PCa might be worth re-examining.

Mining the Ovarian Cancer Ascites Proteome for Potential Ovarian Cancer Biomarkers

Current ovarian cancer biomarkers are inadequate because of their relatively low diagnostic sensitivity and specificity. There is a need to discover and validate novel ovarian cancer biomarkers that are suitable for early diagnosis, monitoring, and prediction of therapeutic response. We performed an in-depth proteomics analysis of ovarian cancer ascites fluid. Size exclusion chromatography and ultrafiltration were used to remove high abundance proteins with molecular mass ≥30 kDa. After trypsin digestion, the subproteome (≤30 kDa) of ascites fluid was determined by two-dimensional liquid chromatography-tandem mass spectrometry. Filtering criteria were used to select potential ovarian cancer biomarker candidates. By combining data from different size exclusion and ultrafiltration fractionation protocols, we identified 445 proteins from the soluble ascites fraction using a two-dimensional linear ion trap mass spectrometer. Among these were 25 proteins previously identified as ovarian cancer biomarkers. After applying a set of filtering criteria to reduce the number of potential biomarker candidates, we identified 52 proteins for which further clinical validation is warranted. Our proteomics approach for discovering novel ovarian cancer biomarkers appears to be highly efficient because it was able to identify 25 known biomarkers and 52 new candidate biomarkers that warrant further validation.

Comprehensive Analysis of Conditioned Media from Ovarian Cancer Cell Lines Identifies Novel Candidate Markers of Epithelial Ovarian Cancer

Ovarian cancer remains a deadly threat to women as the disease is often diagnosed in the late stages when the chance of survival is low. There are no good biomarkers available for early detection and only a few markers have shown clinical utility for prognosis, response to therapy and disease recurrence. We mined conditioned media of four ovarian cancer cell lines (HTB75, TOV-112D, TOV-21G and RMUG-S) by two-dimensional liquid chromatography-mass spectrometry. Each cell line represented one of the major histological types of epithelial ovarian cancer. We identified 2039 proteins from which 228 were extracellular and 192 were plasma membrane proteins. Within the latter list, we identified several known markers of ovarian cancer including three that are well established, namely, CA-125, HE4, and KLK6. The list of 420 extracellular and membrane proteins was cross-referenced with the proteome of ascites fluid to generate a shorter list of 51 potential biomarker candidates. According to Ingenuity Pathway Analysis, two of the top 10 diseases associated with the list of 51 proteins were cancer and reproductive diseases. We selected nine proteins for preliminary validation using 20 serum samples from healthy women and 10 from women with ovarian cancer. Of the nine proteins, clusterin (increase) and IGFBP6 (decrease) showed significant differences between women with or without ovarian cancer. We conclude that in-depth proteomic analysis of cell culture supernatants of ovarian cancer cell lines can identify potential ovarian cancer biomarkers that are worth further clinical validation.

Aberrant human tissue kallikrein levels in the stratum corneum and serum of patients with psoriasis: dependence on phenotype, severity and therapy

Background  Human tissue kallikreins (KLKs) are a family of 15 trypsin‐like or chymotrypsin‐like secreted serine proteases (KLK1–KLK15). Multiple KLKs have been quantitatively identified in normal stratum corneum (SC) and sweat as candidate desquamation‐related proteases.

Upstaging of urothelial cancer at the time of radical cystectomy: factors associated with upstaging and its effect on outcome

Study Type – Therapy (case series)

Patients with Lynch syndrome mismatch repair gene mutations are at higher risk for not only upper tract urothelial cancer but also bladder cancer.

BACKGROUND Lynch syndrome (LS), or hereditary nonpolyposis colorectal cancer, is caused by mutations in mismatch repair (MMR) genes. An increased risk for upper tract urothelial carcinoma (UTUC) has been described in this population; however, data regarding the risk for bladder cancer (BCa) are sparse. OBJECTIVE To assess the risk of BCa in MMR mutation carriers and suggest screening and management recommendations. DESIGN, SETTING, AND PARTICIPANTS Cancer data from 1980 to 2007 were obtained from the Familial Gastrointestinal Cancer Registry in Toronto for 321 persons with known MMR mutations: mutL homolog 1, colon cancer, nonpolyposis type 2 (E. coli) (MLH1); mutS homolog 2, colon cancer, nonpolyposis type 1 (E. coli) (MSH2); mutS homolog 6 (E. coli) (MSH6); and PMS2 postmeiotic segregation increased 2 (S. cerevisiae) (PMS2). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Standardized incidence ratios from the Ontario Cancer Registry, using the Surveillance Epidemiology and End Results public database, were used to compare cancer risk in patients with MMR mutations with the Canadian population. Microsatellite instability analysis and immunohistochemistry (IHC) of the MMR proteins were also performed and the results compared with matched sporadic bladder tumors. RESULTS AND LIMITATIONS Eleven of 177 patients with MSH2 mutations (6.21%, p<0.001 compared with the Canadian population) were found to have BCa, compared with 3 of 129 patients with MLH1 mutations (2.32%, p>0.05). Of these 11 tumors, 81.8% lacked expression of MSH2 on IHC, compared with the matched sporadic cases, which all displayed normal expression of MSH2 and MLH1. The incidence of UTUC among MSH2 carriers was 3.95% (p<0.001), and all tumors were found to be deficient in MSH2 expression on IHC. Mutations in the intron 5 splice site and exon 7 of the MSH2 gene increased the risk of urothelial cancer. Limitations include possible inflated risk estimates due to ascertainment bias. CONCLUSIONS LS patients with MSH2 mutations are at an increased risk for not only UTUC but also BCa and could be offered appropriate screening.

Propensity score analysis of radical cystectomy versus bladder-sparing trimodal therapy in the setting of a multidisciplinary bladder cancer clinic

Purpose Multidisciplinary management improves complex treatment decision making in cancer care, but its impact for bladder cancer (BC) has not been documented. Although radical cystectomy (RC) currently is viewed as the standard of care for muscle-invasive bladder cancer (MIBC), radiotherapy-based, bladder-sparing trimodal therapy (TMT) that combines transurethral resection of bladder tumor, chemotherapy for radiation sensitization, and external beam radiotherapy has emerged as a valid treatment option. In the absence of randomized studies, this study compared the oncologic outcomes between patients treated with RC or TMT by using a propensity score matched-cohort analysis. Methods Data from patients treated in a multidisciplinary bladder cancer clinic (MDBCC) from 2008 to 2013 were reviewed retrospectively. Those who received TMT for MIBC were identified and matched (for sex, cT and cN stage, Eastern Cooperative Oncology Group status, Charlson comorbidity score, treatment date, age, carcinoma in situ status, and hydronephrosis) with propensity scores to patients who underwent RC. Overall survival and disease-specific survival (DSS) were assessed with Cox proportional hazards modeling and a competing risk analysis, respectively. Results A total of 112 patients with MIBC were included after matching (56 who had been treated with TMT, and 56 who underwent RC). The median age was 68.0 years, and 29.5% had stage cT3/cT4 disease. At a median follow-up of 4.51 years, there were 20 deaths (35.7%) in the RC group (13 as a result of BC) and 22 deaths (39.3%) in the TMT group (13 as a result of BC). The 5-year DSS rate was 73.2% and 76.6% in the RC and TMT groups, respectively ( P = .49). Salvage cystectomy was performed in 6 (10.7%) of 56 patients who received TMT. Conclusion In the setting of a MDBCC, TMT yielded survival outcomes similar to those of matched patients who underwent RC. Appropriately selected patients with MIBC should be offered the opportunity to discuss various treatment options, including organ-sparing TMT.

Long-term follow-up of T1 high-grade bladder cancer after intravesical bacille Calmette-Guérin treatment

Study Type – Therapy (cohort) Level of Evidence 2b

Nidogen-2: A new serum biomarker for ovarian cancer

OBJECTIVES New ovarian cancer biomarkers suitable for early disease diagnosis, prognosis or monitoring could improve patient management and outcomes. DESIGN AND METHODS Nidogen-2 was measured by immunoassay in serum of 100 healthy women, 100 women with benign gynecological conditions and 100 women with ovarian carcinoma. RESULTS Serum nidogen-2 concentration between normal and benign disease patients was not different (median, 13.2 and 12.1 mg/L, respectively). However, nidogen-2 concentration in serum of ovarian cancer patients was elevated (median, 18.6 mg/L; p<0.0001). Both nidogen-2 and CA125 were elevated more in serous histotypes of ovarian cancer and late state disease. Nidogen-2 and CA125 concentrations were strongly correlated. ROC curve analysis for nidogen-2 had an area under the curve (AUC) ranging from 0.73 to 0.83 but CA125 was superior (AUC ranging from 0.87 to 0.99). There was no complementarity between the two markers. CONCLUSIONS Nidogen-2 is a new biomarker for ovarian cancer which correlates closely with CA125.