Effects of the WRITE Symptoms Interventions on Symptoms and Quality of Life Among Patients With Recurrent Ovarian Cancers: An NRG Oncology/GOG Study (GOG-0259).

PURPOSE: GOG-259 was a 3-arm randomized controlled trial of two web-based symptom management interventions for patients with recurrent ovarian cancer. Primary aims were to compare the efficacy of the nurse-guided (Nurse-WRITE) and self-directed (SD-WRITE) interventions to Enhanced Usual Care (EUC) in improving symptoms (burden and controllability) and quality of life (QOL). METHODS: Patients with recurrent or persistent ovarian, fallopian, or primary peritoneal cancer with 3+ symptoms were eligible for the study. Participants completed baseline (BL) surveys (symptom burden and controllability and QOL) before random assignment. WRITE interventions lasted 8 weeks to develop symptom management plans for three target symptoms. All women received EUC: monthly online symptom assessment with provider reports; online resources; and every 2-week e-mails. Outcomes were evaluated at 8 and 12 weeks after BL. Repeated-measures modeling with linear contrasts evaluated group by time effects on symptom burden, controllability, and QOL, controlling for key covariates. RESULTS: Participants (N = 497) reported mean age of 59.3 ± 9.2 years. At BL, 84% were receiving chemotherapy and reported a mean of 14.2 ± 4.9 concurrent symptoms, most commonly fatigue, constipation, and peripheral neuropathy. Symptom burden and QOL improved significantly over time (P < .001) for all three groups. A group by time interaction (P < .001) for symptom controllability was noted whereby both WRITE intervention groups had similar improvements from BL to 8 and 12 weeks, whereas EUC did not improve over time. CONCLUSION: Both WRITE Intervention groups showed significantly greater improvements in symptom controllability from BL to 8 and BL to 12 weeks compared with EUC. There were no significant differences between Nurse-WRITE and SD-WRITE. SD-WRITE has potential as a scalable intervention for a future implementation study.

A Novel Splice Variant of HYAL-4 Drives Malignant Transformation and Predicts Outcome in Patients with Bladder Cancer.

PURPOSE: Poor prognosis of patients with muscle-invasive bladder cancer that often metastasizes drives the need for discovery of molecular determinants of bladder cancer progression. Chondroitin sulfate proteoglycans, including CD44, regulate cancer progression; however, the identity of a chondroitinase (Chase) that cleaves chondroitin sulfate from proteoglycans is unknown. HYAL-4 is an understudied gene suspected to encode a Chase, with no known biological function. We evaluated HYAL-4 expression and its role in bladder cancer. EXPERIMENTAL DESIGN: In clinical specimens, HYAL-4 wild-type (Wt) and V1 expression was evaluated by RT-qPCR, IHC, and/or immunoblotting; a novel assay measured Chase activity. Wt and V1 were stably expressed or silenced in normal urothelial and three bladder cancer cell lines. Transfectants were analyzed for stem cell phenotype, invasive signature and tumorigenesis, and metastasis in four xenograft models, including orthotopic bladder. RESULTS: HYAL-4 expression, specifically a novel splice variant (V1), was elevated in bladder tumors; Wt expression was barely detectable. V1 encoded a truncated 349 amino acid protein that was secreted. In bladder cancer tissues, V1 levels associated with metastasis and cancer-specific survival with high efficacy and encoded Chase activity. V1 cleaved chondroitin-6-sulfate from CD44, increasing CD44 secretion. V1 induced stem cell phenotype, motility/invasion, and an invasive signature. CD44 knockdown abrogated these phenotypes. V1-expressing urothelial cells developed angiogenic, muscle-invasive tumors. V1-expressing bladder cancer cells formed tumors at low density and formed metastatic bladder tumors when implanted orthotopically. CONCLUSIONS: Our study discovered the first naturally-occurring eukaryotic/human Chase and connected it to disease pathology, specifically cancer. V1-Chase is a driver of malignant bladder cancer and potential predictor of outcome in patients with bladder cancer.

Web-based symptom management for women with recurrent ovarian cancer: a pilot randomized controlled trial of the WRITE Symptoms intervention.

CONTEXT: Little research has focused on symptom management among women with ovarian cancer. Written Representational Intervention To Ease Symptoms (WRITE Symptoms) is an educational intervention delivered through asynchronous web-based message boards between a study participant and a nurse. OBJECTIVES: We evaluated WRITE Symptoms for 1) feasibility of conducting the study via message boards, 2) system usability, 3) participant satisfaction, and 4) initial efficacy. METHODS: Participants were 65 women (mean age, 56.5; SD = 9.23) with recurrent ovarian cancer randomized using minimization with race/ethnicity (non-Hispanic white vs. minority) as the stratification factor. Measures were obtained at baseline and two and six weeks after intervention. Outcomes were feasibility of conducting the study, system usability, participant satisfaction, and efficacy (symptom severity, distress, consequences, and controllability). RESULTS: Fifty-six (87.5%) participants were retained, and the mean usability score (range 1-7) was 6.18 (SD = 1.29). All satisfaction items were scored at 5 (of 7) or higher. There were significant between-group effects at T2 for symptom distress, with those in the WRITE Symptoms group reporting lower distress than those in the control group [t(88.4) = -2.57; P = 0.012], with a similar trend for symptom severity [t(40.4) = -1.95; P = 0.058]. Repeated measures analysis also supported a group effect, with those in the WRITE Symptoms group reporting lower symptom distress than those in the control condition [F(1, 56.7) = 4.59; P = 0.037]. CONCLUSION: Participants found the intervention and assessment system easy to use and had high levels of satisfaction. Initial efficacy was supported by decreases in symptom severity and distress.

Altered expression of farnesyl pyrophosphate synthase in prostate cancer: evidence for a role of the mevalonate pathway in disease progression?

BACKGROUND: Preclinical studies demonstrated effects of drugs inhibiting the mevalonate pathway including nitrogen-containing bisphosphonates (N-BPs) and statins on tumor growth and progression. The exact role of this pathway in prostate cancer (PC) has not been identified yet. Herein, we evaluate the expression of farnesyl pyrophosphate synthase (FPPS), the key enzyme of the mevalonate pathway, in PC. PATIENTS AND METHODS: Prostate cancer (PC) and benign prostate tissue of 114 men who underwent radical prostatectomy were constructed to a tissue microarray. Immunohistochemical staining of FPPS was quantified by the Remmele/Stegner immunoreactivity-score. Patients' clinical follow-up was assessed. IRS was correlated to pathological and clinical data. The impact of FPPS expression on clinical course was assessed univariate and multivariate. RESULTS: Mean IRS in PC and benign tissue was 5.7 (95% CI 5.0-6.5) and 2.6 (2.1-3.0, p < 0.0001). Mean IRS in PC tissue of patients with organ-confined and locally advanced disease (pT ≥ 3) was 5.09 (4.22-5.96) and 6.87 (5.57-8.17, p = 0.035). IRS of PC tissue significantly correlated with Gleason score (p = 0.03). Patients with PC tissue IRS >3 showed shorter recurrence-free survival compared to the remaining (p = 0.01). Increased FPPS expression is an independent risk factor for early biochemical recurrence (p = 0.032). CONCLUSIONS: This is the first study on FPPS in PC specimens. The association of FPPS with established histopathological risk parameters and biochemical recurrence implicates a contribution of the mevalonate pathway to PC progression. Further functional analysis is required to explore the role of this pathway in PC and to investigate whether FPPS expression affects the response of PC cells to N-BPs.

Galectin-3 expression in prostate cancer and benign prostate tissues: correlation with biochemical recurrence.

BACKGROUND: Galactin-3 is a cell adhesion molecule involved in tumor progression. Our aim was to examine Gal-3 expression in tumor, benign tissue adjacent to the tumor (adjacent-benign) and benign prostate specimens and correlated it with biochemical recurrence. MATERIALS AND METHODS: Tissue microarrays were prepared from 83 tumor, 78 adjacent-benign and 75 benign tissues obtained from 83 patients undergoing prostatectomy for clinically localized prostate cancer. Tissues were stained using a Gal-3 antibody and immunohistochemistry. The staining was graded between 0 and 300 depending upon staining intensity and the area of staining. In 37 patients on whom there was follow-up (Mean: 57.8 months; Median: 68 months), staining intensity was correlated with biochemical recurrence. RESULTS: Gal-3 showed both nuclear and cytoplasmic localization in benign, adjacent-benign and tumor tissues. Median Gal-3 staining scores significantly decreased from benign (192.5) to adjacent-benign (148.8 p = 0.007) and to tumor (108.8; p < 0.0001) tissues. In univariate analysis, age (p = 0.028), Gleason sum (p = 0.007), T stage (p = 0.011), seminal vesicle invasion (p = 0.009), pre-operative prostate-specific antigen (p = 0.045) and Gal-3 staining in tumor tissues (0.018) significantly correlated with biochemical recurrence. In multivariate analysis, Gal-3 expression in tumor (p = 0.04), adjacent-benign (p = 0.037) and benign (p = 0.005) tissues significantly correlated with biochemical recurrence. Gal-3 staining in tumor tissues had 91.7 % sensitivity, 64 % specificity and 73 % accuracy in predicting biochemical recurrence. CONCLUSIONS: This is the first study that showed a decreasing gradient of Gal-3 expression in benign, adjacent-benign and tumor tissues. Gal-3 expression may be useful in predicting biochemical recurrence.

C-X-C chemokine receptor 7: a functionally associated molecular marker for bladder cancer.

BACKGROUND: C-X-C chemokine receptor 4 (CXCR4) and CXCR7 are 7-transmembrane chemokine receptors of the stroma-derived factor (SDF-1). CXCR4, but not CXCR7, has been examined in bladder cancer (BCa). This study examined the functional and clinical significance of CXCR7 in BCa. METHODS: CXCR4 and CXCR7 levels were measured in BCa cell lines, tissues (normal = 25; BCa = 44), and urine specimens (n = 186) by quantitative polymerase chain reaction and/or immunohistochemistry. CXCR7 function in BCa cells were examined by transient transfections using a CXCR7 expression vector or small interfering RNA. RESULTS: In BCa cell lines, CXCR7 messenger RNA levels were 5- to 37-fold higher than those for CXCR4. Transient overexpression of CXCR7 in BCa cell lines promoted growth and chemotactic motility. CXCR7 colocalized and formed a functional complex with epidermal growth factor receptor, phosphoinositide 3-kinase/Akt, Erk, and src and induced their phosphorylation. CXCR7 also induced up-regulation of cyclin-D1 and bcl-2. Suppression of CXCR7 expression reversed these effects and induced apoptosis. CXCR7 messenger RNA levels and CXCR7 staining scores were significantly (5- to 10-fold) higher in BCa tissues than in normal tissues (P < .001). CXCR7 expression independently associated with metastasis (P = .019) and disease-specific mortality (P = .03). CXCR7 was highly expressed in endothelial cells in high-grade BCa tissues when compared to low-grade BCa and normal bladder. CXCR7 levels were elevated in exfoliated urothelial cells from high-grade BCa patients (P = .0001; 90% sensitivity; 75% specificity); CXCR4 levels were unaltered. CONCLUSIONS: CXCR7 promotes BCa cell proliferation and motility plausibly through epidermal growth factor receptor receptor and Akt signaling. CXCR7 expression is elevated in BCa tissues and exfoliated cells and is associated with high-grade and metastasis.

XPA-210: a new proliferation marker determines locally advanced prostate cancer and is a predictor of biochemical recurrence.

PURPOSE: XPA-210 is a proliferation marker derived from Thymidine kinase-1. It is of clinical significance in kidney, breast, and bladder cancer. There are no data available for XPA-210 in prostate cancer (PC). Herein, we aim to determine the clinical usefulness of XPA-210 in PC. MATERIALS AND METHODS: In a retrospective study, cancer and benign tissue samples of 103 patients (median age 65 years, median PSA 9.04 ng/ml, median Gleason score 6) who underwent prostatectomy were constructed to a tissue micro array and stained for XPA-210. Semi-quantitative results were correlated with pathological and clinical data by Wilcoxon-Kruskall-Wallis and linear regression analysis. Expression levels in PC were correlated between the time of biochemical recurrence and the time to development of metastasis by the Kaplan-Meier method. Multivariate analysis was done to correlate those with the resection status. RESULTS: Mean staining score was 0.51-0.14 for tumor and benign tissue (P < 0.0001). Tumor staining score was significantly associated with Gleason score <6/≥6 (P < 0.0001) and T2/T >2 (P = 0.0007). When dividing the tumor score by the mean value, higher expression of XPA-210 was associated with a shorter time to biochemical recurrence (P = 0.003) and time to development of metastasis (P = 0.0061). Tumor staining (P = 0.0371) was an independent prognostic factor for biochemical relapse regardless of resection status. CONCLUSIONS: XPA-210 is a new tissue-based prognostic marker for prostate cancer histopathology. It reliably differentiates tumor and normal prostatic tissue predicting biochemical relapse and onset of metastatic disease. XPA-210 might be clinically useful for individual decision-making in PC-treatment.

Altered expression of Akt signaling pathway parameters in prostate needle biopsies derived from benign, adjacent and cancerous tissue.

PTEN, p-Akt and p27kip1 are known to be altered in prostate cancer. The aim of the present study was to determine the addition of molecular markers to a classical histopathological approach to enhance the sensitivity in detection of malignant or premalignant lesions within prostatic biopsies. Forty-two fine needle biopsies from malignant, tumor adjacent and benign areas were obtained from 14 patients scheduled for a prostatic biopsy. Biomarker expression was determined by immunohistochemistry and correlated to different localizations. We observed a reduction of Akt signaling proteins in cancer tissue compared to benign controls with significantly lower expression of p27kip1 (P=0.0024), PTEN (P=0.0045) and p-Akt (P=0.028). A pathologist histopathologically classified the tumor adjacent tissue obtained from areas distinctly apart from the primary tumor as benign in all cases. In these regions we observed an intermediate expression of Akt signaling proteins without significant difference in relation to the findings in the malignant samples. The expression of Akt signaling proteins is reduced in prostate cancer compared to normal prostate tissue. The intermediate expression of these proteins in tumor adjacent tissue warrants further investigations into the role of Akt signaling in the carcinogenesis and early detection of prostate cancer. There seems to be a marked difference between the molecular and histopathological characterization of prostate tissue. Molecular markers might further augment the histopathological diagnosis suggesting the need for earlier repeated prostate biopsy in case of microscopic malignancy.

HYAL-1 hyaluronidase: a potential prognostic indicator for progression to muscle invasion and recurrence in bladder cancer.

BACKGROUND: For bladder cancer (BCa) patients undergoing bladder-sparing treatments, molecular markers may aid in accurately predicting progression to muscle invasion and recurrence. Hyaluronic acid (HA) is a glycosaminoglycan that promotes tumor metastasis. Hyaluronoglucosaminidase 1 (HYAL-1)-type hyaluronidase (HAase) promotes tumor growth, invasion, and angiogenesis. Urinary HA and HAase levels are diagnostic markers for BCa. OBJECTIVE: We evaluated whether HA and HYAL-1 can predict progression to muscle invasion and recurrence among patients with non-muscle-invasive BCa. DESIGN, SETTING, AND PARTICIPANTS: : Based on tissue availability, tissue microarrays were prepared from a cohort of 178 BCa specimens (144 non-muscle invasive, 34 muscle invasive). Follow-up information was available on 111 patients with non-muscle-invasive BCa (mean follow-up: 69.5 mo); 58 patients recurred and 25 progressed to muscle invasion (mean time to progress: 22.3 mo). MEASUREMENTS: HA and HYAL-1 expression was evaluated by immunohistochemistry and graded for intensity and area of staining. Association of HA and HYAL-1 staining with BCa recurrence and muscle invasion was evaluated by univariate and multivariate models. RESULTS AND LIMITATIONS: HA and HYAL-1 expression correlated with tumor grade, stage, and multifocality (p<0.05). In non-muscle-invasive BCa specimens, HYAL-1 staining was higher (234.3+/-52.2; 200.6+/-61.4) if patients experienced progression to muscle invasion or recurrence when compared with no progression or recurrence (164.1+/-48.2; 172.1+/-57; p<0.001). HA staining correlated with muscle invasion (p<0.001). In univariate analysis, age (p=0.014), multifocality (p=0.023), and HYAL-1 staining (p<0.001) correlated with muscle invasion, whereas only HYAL-1 correlated with recurrence (p=0.013). In multivariate analysis, HYAL-1 significantly associated with muscle invasion (p<0.001; 76.8% accuracy) and recurrence (p=0.01; 67.8% accuracy). CONCLUSIONS: HYAL-1 is a potential prognostic marker for predicting progression to muscle invasion and recurrence.

Hyaluronic acid and HYAL-1 in prostate biopsy specimens: predictors of biochemical recurrence.

PURPOSE: Molecular markers could aid prostate specific antigen, biopsy Gleason sum and clinical stage to provide accurate information on prostate cancer progression. HYAL-1 hyaluronidase and hyaluronic acid staining in prostatectomy specimens predicts biochemical recurrence. We examined whether hyaluronic acid and HYAL-1 staining in biopsy specimens predicts biochemical recurrence and correlates with staining in matched prostatectomy specimens. MATERIALS AND METHODS: Biopsy and prostatectomy specimens were obtained from 61 patients with clinically localized prostate cancer from multiple centers, including 23 with (group 1) and 38 without (group 2) biochemical recurrence. Mean followup was 103.1 months. Biotinylated hyaluronic acid binding protein and anti-HYAL-1 antibody were used for hyaluronic acid and HYAL-1 staining, respectively. Staining was graded between 0 and 300 depending on staining intensity and area. RESULTS: HYAL-1 and hyaluronic acid were expressed in tumor cells and stroma, respectively. In biopsy specimens HYAL-1 and hyaluronic acid expression was higher in group 1 than in group 2 (203.9 and 182.1 vs 48.8 and 87.0, respectively, p <0.0001). On univariate analysis hyaluronic acid, HYAL-1, biopsy Gleason and prostate specific antigen significantly predicted biochemical recurrence (p <0.001). On multivariate analysis only HYAL-1 staining independently predicted recurrence with an accuracy of 81.8% (p <0.001). In prostatectomy specimens only HYAL-1 staining correlated with staining in biopsy specimens (Spearman rho = 0.72, p = 0.0002) and predicted biochemical recurrence. CONCLUSIONS: To our knowledge this is the first report that HYAL-1 staining in biopsy specimens is an independent predictor of biochemical recurrence. This may be useful when selecting treatment.

Epigenetic regulation of HYAL-1 hyaluronidase expression. identification of HYAL-1 promoter.

HYAL-1 (hyaluronoglucosaminidase-1) belongs to the hyaluronidase family of enzymes that degrade hyaluronic acid. HYAL-1 is a marker for cancer diagnosis and a molecular determinant of tumor growth, invasion, and angiogenesis. The regulation of HYAL-1 expression is unknown. Real time reverse transcription-PCR using 11 bladder and prostate cancer cells and 69 bladder tissues showed that HYAL-1 mRNA levels are elevated 10-30-fold in cells/tissues that express high hyaluronidase activity. Although multiple transcription start sites (TSS) for HYAL-1 mRNA were detected in various tissues, the major TSS in many tissues, including bladder and prostate, was at nucleotide 27274 in the cosmid clone LUCA13 (AC002455). By analyzing the 1532 base sequence 5' to this TSS, using cloning and luciferase reporter assays, we identified a TACAAA sequence at position -31 and the minimal promoter region between nucleotides -93 and -38. Mutational analysis identified that nucleotides -73 to -50 (which include overlapping binding consensus sites for SP1, Egr-1, and AP-2), bases C(-71) and C(-59), and an NFkappaB-binding site (at position -15) are necessary for promoter activity. The chromatin immunoprecipitation assay identified that Egr-1, AP-2, and NFkappaB bind to the promoter in HYAL-1-expressing cells, whereas SP1 binds to the promoter in non-HYAL-1-expressing cells. 5-Aza-2'-deoxycytidine treatment, bisulfite DNA sequencing, and methylation-specific PCR revealed that HYAL-1 expression is regulated by methylation at C(-71) and C(-59); both Cs are part of the SP1/Egr-1-binding sites. Thus, HYAL-1 expression is epigenetically regulated by the binding of different transcription factors to the methylated and unmethylated HYAL-1 promoter.

Involvement of decreased Galectin-3 expression in the pathogenesis and progression of prostate cancer.

BACKGROUND: Altered expression or loss of function of Galectin-3 (Gal-3) was suggested to be involved in the pathogenesis and progression of various human cancer entities. The aim of the present study is to determine the expression of Gal-3 in prostate tissue emerging from a benign to a malignant, in the beginning hormone-sensitive and finally hormone-refractory status to further elucidate the role of this carbohydrate-binding protein for the pathogenesis and/or progression of malignant prostatic disease. MATERIALS AND METHODS: Five hundred and eighty three tissue samples from malignant, tumor adjacent benign, and histologically benign intra-prostatic areas, retrieved out of 25 whole mounted prostate cancer (CaP) specimens and additional 95 samples of hormone-refractory CaP, were processed to tissue microarrays. Immunohistochemical Gal-3 expression was correlated with clinicopathological parameters among the different tissue entities. RESULTS: Gal-3 expression was significantly decreased in the hormone-sensitive CaP specimens when compared with the respective benign tissue either localized far distant from the malignant lesion (P < 0.0001, Wilcoxon test) or directly neighboring the primary tumor (P < 0.0001). The staining reaction in the benign tissue areas directly neighboring the primary cancerous lesions differed significantly from the benign glands localized distant from the primary tumors (P < 0.001). A statistically highly significant, almost complete loss of Gal-3 was observed in the hormone-refractory when compared with the hormone-sensitive tumors (P < 0.0001; mean staining score: 27.7% vs. 8.5%). CONCLUSIONS: The present investigation clearly indicates decreased expression of Gal-3 to be substantially involved in the pathogenesis and further progression of CaP from benign prostate glands to a finally hormone-refractory malignant disease.