TrueNTH Sexual Recovery Intervention for couples coping with prostate cancer: Randomized controlled trial results.

BACKGROUND: Despite significant sexual dysfunction and distress after localized prostate cancer treatment, patients typically receive only physiologic erectile dysfunction management. The authors performed a randomized controlled trial of an online intervention supporting couples' posttreatment recovery of sexual intimacy. METHODS: Patients treated with surgery, radiation, or combined radiation and androgen deprivation therapy who had partners were recruited and randomized to an online intervention or a control group. The intervention, tailored to treatment type and sexual orientation, comprised 6 modules addressing expectations for sexual and emotional sequelae of treatment, rehabilitation, and guidance toward sexual intimacy recovery. Couples, recruited from 6 sites nationally, completed validated measures at the baseline and 3 and 6 months after treatment. Primary outcome group differences were assessed with t tests for individual outcomes. RESULTS: Among 142 randomized couples, 105 patients (mostly surgery) and 87 partners completed the 6-month survey; this reflected challenges with recruitment and attrition. There were no differences between the intervention and control arms in Patient-Reported Outcomes Measurement Information System Global Satisfaction With Sex Life scores 6 months after treatment (the primary outcome). Three months after treatment, intervention patients and partners reported more engagement in penetrative and nonpenetrative sexual activities than controls. More than 73% of the intervention participants reported high or moderate satisfaction with module content; more than 85% would recommend the intervention to other couples. CONCLUSIONS: Online psychosexual support for couples can help couples to connect and experience sexual pleasure early after treatment despite patients' sexual dysfunction. Participants' high endorsement of the intervention reflects the importance of sexual health support to couples after prostate cancer treatment. LAY SUMMARY: This study tested a web-based program supporting couples' sexual recovery of sexual intimacy after prostate cancer treatment. One hundred forty-two couples were recruited and randomly assigned to the program (n = 60) or to a control group (n = 82). The program did not result in improvements in participants' satisfaction with their sex life 6 months after treatment, but couples in the intervention group engaged in sexual activity sooner after treatment than couples in the control group. Couples evaluated the program positively and would recommend it to others facing prostate cancer treatment.

Current role of neoadjuvant and adjuvant systemic therapy for high-risk localized prostate cancer.

PURPOSE OF REVIEW: Although most men are diagnosed with readily curable localized prostate cancer, those with high-risk features face a significant mortality risk. Androgen deprivation therapy (ADT) is a standard adjunct to radiotherapy for high-risk prostate cancer, but its role around prostatectomy has not been as clearly defined, and concerns over cardiovascular toxicity have led to decreasing use. The use of chemotherapy for localized disease remains experimental. We review the most recently published trials of neoadjuvant or adjuvant systemic therapy for prostate cancer. RECENT FINDINGS: The optimal duration of ADT with higher dose modern radiation techniques is under active investigation, but current data support the use of longer duration as standard. Prostate-specific antigen (PSA) and MRI changes may be useful in future studies optimizing duration of neoadjuvant ADT. Two years of combined ADT after prostatectomy is associated with a lower risk of disease recurrence and better prostate cancer specific mortality than predicted. Persistence of intraprostatic androgens during neoadjuvant ADT may contribute to resistance. SUMMARY: Androgen deprivation added to definitive radiation or surgery improves outcomes for high-risk prostate cancer, although the role of chemotherapy remains undefined. Molecular classification is needed to improve risk stratification.

A familial germline mutation in KIT associated with achalasia, mastocytosis and gastrointestinal stromal tumors shows response to kinase inhibitors.

BACKGROUND: Activating mutations of the tyrosine kinase receptor KIT have been described in both mastocytosis and gastrointestinal stromal tumors (GIST), but are usually found in separate domains and often respond differently to signal transduction inhibitors. We describe here a large family with both GIST, mastocytosis, and achalasia. Affected family members have a unique activating mutation in exon 9 of KIT which show promise to a novel signal transduction inhibitor. METHODS: Clinical data was collected from 15 family members, 7 of whom were variably affected with GIST, achalasia and mastocytosis. DNA was prepared from WBC of 12 subjects (6 affected and 6 unaffected) and exons 9, 11, 13 and 17 of KIT were amplified by PCR and directly sequenced. RESULTS: A unique activating single base pair mutation in the extracellular domain of KIT was found in all 6 affected subjects resulting in a K>I amino acid change at codon 509. CONCLUSIONS: In the family reported here, a unique mutation in the extracellular domain leads to receptor activation resulting in GIST and mastocytosis as well as achalasia. Initial data suggests that this activation can be suppressed by signal transduction inhibitors and these patients may benefit from such therapy.

Chemopreventive effects of silymarin and silibinin on N-butyl-N-(4-hydroxybutyl) nitrosamine induced urinary bladder carcinogenesis in male ICR mice.

Effective strategies are lacking for the management of urinary bladder cancer for which smoking is a potential risk factor. Herein, we evaluated chemoprevention of urinary bladder cancer by natural chemopreventive agents, silymarin and silibinin, in a preclinical animal (ICR mouse) model of bladder cancer induced by tobacco smoke carcinogen N-butyl-N-(4-hydroxybutyl) nitrosamine (OH-BBN). Mice were fed p.o. with saline or OH-BBN (0.05%, w/v) in drinking water for 6 weeks or with silymarin or silibinin (200 mg/kg body weight for both) starting 1 week before OH-BBN exposure for 51 weeks. Silymarin and silibinin strongly arrested OH-BBN-induced tumor progression at the stage of mucosal dysplasia with a striking reduction in papillary nodular dysplasia as well as invasive carcinoma. Some silymarin- or silibinin-treated mice developed no urothelial lesions in spite of OH-BBN exposure. Immunohistochemical analyses at study conclusion revealed that silymarin and silibinin decreased cell proliferation by 42% (P < 0.001) and 44% (P < 0.001) and increased apoptosis by 4-fold (P < 0.05) and 6-fold (P < 0.05) in OH-BBN-induced urothelium, respectively. Antiproliferative and apoptotic effects of silymarin and silibinin were associated with decreases in (a) cyclin D1 protein level and extracellular signal-regulated kinase-1/2 phosphorylation and in (b) protein levels of survivin and nuclear phospho-p65 (Ser(276) and Ser(536)), respectively. Together, these results suggest that silymarin and silibinin inhibit chemically induced urinary bladder tumor growth and progression possibly by inhibiting cell proliferation and enhancing apoptosis.

Phase II Trial of Acai Juice Product in Biochemically Recurrent Prostate Cancer.

BACKGROUND: Plant derivatives have been studied as therapies for prostate cancer based on their purported anti-inflammatory and antioxidant properties and low toxicities. The acai berry is an example of a plant rich in phytochemicals, which may slow the growth of prostate cancer. METHODS: This was a phase II, Simon 2-stage clinical trial in patients with biochemically recurrent prostate cancer with a primary endpoint of prostate-specific antigen (PSA) response. Patients were asymptomatic, with a rising PSA of at least 0.2 ng/mL, and were treated with twice daily intake of Acai Juice Product until PSA progression, with a primary endpoint of PSA response. RESULTS: Twenty-one patients were enrolled in the first stage of the trial. One of those patients had a PSA response within the study time period. The PSA doubling time was lengthened in 71% of patients (95% confidence interval = 48% to 89%) on the trial, and in a small number of responders, this was sustained over an extended time. CONCLUSIONS: This study did not meet its primary endpoint of 50% PSA response. Nevertheless, the overall tolerability and effects on PSA stabilization warrant further exploration in a biochemically recurrent population.

Phase III Intergroup Trial of Adjuvant Androgen Deprivation With or Without Mitoxantrone Plus Prednisone in Patients With High-Risk Prostate Cancer After Radical Prostatectomy: SWOG S9921.

Purpose Patients with high-risk prostate cancer after radical prostatectomy are at risk for death. Adjuvant androgen-deprivation therapy (ADT) may reduce this risk. We hypothesized that the addition of mitoxantrone and prednisone (MP) to adjuvant ADT could reduce mortality compared with adjuvant ADT alone. Methods Eligible patients had cT1-3N0 prostate cancer with one or more high-risk factors after radical prostatectomy (Gleason score [GS] ≥ 8; pT3b, pT4, or pN+ disease; GS 7 and positive margins; or preoperative prostate-specific antigen [PSA] > 15 ng/mL, biopsy GS score > 7, or PSA > 10 ng/mL plus biopsy GS > 6. Patients with PSA ≤ 0.2 ng/mL after radical prostatectomy were stratified by pT/N stage, GS, and adjuvant radiation plan and randomly assigned to ADT (bicalutamide and goserelin for 2 years) or ADT plus six cycles of MP. The primary end point was overall survival (OS). Median OS was projected to be 10 years in the ADT arm, requiring 680 patients per arm to detect a hazard ratio of 1.30 with 92% power and one-sided α = .05. Results Nine hundred sixty-one eligible intent-to-treat patients were randomly assigned to ADT or ADT + MP from October 1999 to January 2007, when the Data Safety Monitoring Committee recommended stopping accrual as a result of higher leukemia incidence with ADT + MP. Median follow-up was 11.2 years. The 10-year OS estimates were 87% with ADT (expected 50%) and 86% with ADT + MP (hazard ratio, 1.06; 95% CI, 0.79 to 1.43). The 10-year estimate for disease-free survival was 72% for both arms. Prostate cancer was the cause of death in 18% of patients in the ADT arm and 22% in the ADT + MP arm. More patients in the MP arm died of other cancers (36% v 18% in ADT alone arm). Conclusion MP did not improve OS and increased deaths from other malignancies. The DFS and 10-year OS in these patients treated with 2 years of ADT were encouraging compared with historical estimates, although a definitive conclusion regarding value of ADT may not be made without a nontreatment control arm.

Binding and cytotoxicity of conjugated and recombinant fusion proteins targeted to the gonadotropin-releasing hormone receptor.

Pokeweed antiviral protein (PAP) is a plant-derived, highly potent ribosome inactivating protein that causes inhibition of protein translation and rapid cell death. We and others have delivered this protein to various cell types, including cancer cells, using hormones to specifically target cells bearing the hormone receptor. Here, we compare binding and cytotoxicity of GnRH-PAP hormonotoxins prepared either by protein conjugation (GnRH-PAP conjugate) or through recombinant DNA technology (GnRH-PAP fusion). Although GnRH-PAP conjugate protein bound specifically to and caused cell death in cells bearing the gonadotropin-releasing hormone (GnRH) receptor, we could not detect binding or cytotoxicity using two different versions of the fusion protein in receptor-positive cells. We conclude that generation of an active GnRH-PAP fusion protein may not be feasible either because both ends of the GnRH molecule are required for receptor binding, but only the NH(2) terminus is free in the fusion protein and/or that more potent analogues of GnRH (inclusion of which is not feasible in the fusion protein) are needed for efficient targeting. In contrast, the GnRH-PAP conjugate shows promise as a novel anticancer agent, capable of targeting cancer cells expressing the GnRH receptor such as prostate, breast, ovarian, endometrial, and pancreatic cells. It may also be useful as a therapeutic agent to eliminate pituitary gonadotrophs, eliminating the need for chronic GnRH analogue administration to treat hormone-sensitive diseases.

Inhibition of Lipid Oxidation Increases Glucose Metabolism and Enhances 2-Deoxy-2-[(18)F]Fluoro-D-Glucose Uptake in Prostate Cancer Mouse Xenografts.

PURPOSE: Prostate cancer (PCa) is the second most common cause of cancer-related death among men in the United States. Due to the lipid-driven metabolic phenotype of PCa, imaging with 2-deoxy-2-[(18)F]fluoro-D-glucose ([(18)F]FDG) is suboptimal, since tumors tend to have low avidity for glucose. PROCEDURES: We have used the fat oxidation inhibitor etomoxir (2-[6-(4-chlorophenoxy)-hexyl]oxirane-2-carboxylate) that targets carnitine-palmitoyl-transferase-1 (CPT-1) to increase glucose uptake in PCa cell lines. Small hairpin RNA specific for CPT1A was used to confirm the glycolytic switch induced by etomoxir in vitro. Systemic etomoxir treatment was used to enhance [(18)F]FDG-positron emission tomography ([(18)F]FDG-PET) imaging in PCa xenograft mouse models in 24 h. RESULTS: PCa cells significantly oxidize more of circulating fatty acids than benign cells via CPT-1 enzyme, and blocking this lipid oxidation resulted in activation of the Warburg effect and enhanced [(18)F]FDG signal in PCa mouse models. CONCLUSIONS: Inhibition of lipid oxidation plays a major role in elevating glucose metabolism of PCa cells, with potential for imaging enhancement that could also be extended to other cancers.

Epidermal growth factor receptor mediates silibinin-induced cytotoxicity in a rat glioma cell line.

Silibinin, derived from milk thistle extract, has been shown to inhibit growth factor receptor-mediated mitogenic and cell survival signaling, and to alter cell cycle regulators. Alteration in pathways regulating cell growth likely account for silibinin's inhibition of tumor growth. Since the epidermal growth factor receptor (EGFR) is a key regulator in cell signaling pathways, in the present study we directly tested the hypothesis that the EGFR plays a key role in mediating silibinin cytotoxicity to cancer cells. We generated a cell line, 9L-EGFR, which stably expressed human EGFR; the parental rat glioma cell line, 9L, does not contain endogenous EGFR message or protein. Our results show that expression of EGFR was both necessary and sufficient for conferring toxicity in response to silibinin in 9L-EGFR cells. Addition of silibinin was shown to inhibit EGFR activation by EGF in 9L-EGFR cells. These studies support the hypothesis that silibinin toxicity to cancer cells involves the EGFR signaling pathway. The findings presented here provide a rationale for understanding the growth inhibition effect of silibinin in cancer cells, and warrant further investigation into the effect of silibinin on specific pathways of cell signaling mediated by the EGF receptor.

Prostate cancer on the internet: impact on patients and how technology helps physicians and researchers.

The Internet is a repository of information unparalleled in history. The abundance of published material about prostate cancer has never been greater. Couple this with burgeoning pharmaceutical public-relations budgets and the result is a bewildering maze of hundreds of thousands of prostate cancer-oriented Internet pages. Our purposes are to help practitioners understand the profound handicap that patients are faced with when they attempt to search the Internet for information about their newly diagnosed disease and to succinctly evaluate the presence or absence of key aspects of prostate cancer on some of the most easily accessible sites. Part two of this paper will then discuss 4 of the most valuable Web sites for the prostate cancer specialist. Surfing the World Wide Web can be frustrating and time-consuming, but it can also be rewarding and informative.

High Gleason scores and lower prostate-specific antigen levels in a single institution over the past decade.

Recent trends suggest that carcinoma of the prostate is being detected at earlier stages in its natural history; our objective is to determine if this trend is accompanied by changes in tumor characteristics. Two hundred ninety-three men from 1990-1993, 308 from 1994-1996, and 323 from 1998-2000 with newly diagnosed prostate cancer have been evaluated at the University of Colorado Health Sciences Center. We compared the Gleason score, mean age, and the mean prostate-specific antigen (PSA) among the 3 cohorts. The same pathologist reviewed all the pathology slides. A high Gleason prostate cancer score was defined as > or = 7. One hundred seventy-two patients (53.3%) were found to have a high Gleason score in 1998-2000 compared to 116 patients (39.5%) in 1990-1993; the difference was statistically significant (P = 0.0009, Yates-corrected chi2 test). From 1994-1996, 141 patients (45.7%) had a high Gleason score. The mean PSA in high Gleason score, localized prostate cancer was 7.52 ng/mL (range, 0.9-15.3 ng/mL) in the 1998-2000 group, 9.09 ng/mL (range, 1.7-20 ng/mL) in the 1994-1996 group, and 12.6 ng/mL (range, 3.9-25 ng/mL) in the 1990-1993 group. The difference between these groups was statistically significant (P = 0.000018, one-way analysis of variance test). The mean ages for patients in the 3 cohorts were 64.4, 64.5, and 65.2 years of age for the 1998-2000, 1994-1996, and 1990-1993 groups, respectively (P = 0.702). These data suggest a trend toward the diagnosis of more aggressive prostate cancer, with higher Gleason score, and lower PSA in newly diagnosed patients. Continued screening for prostate cancer is resulting in the diagnosis of more unfavorable cancers.

High-risk localized prostate cancer: primary surgery and adjuvant therapy.

High risk localized prostate cancer includes patients with palpable disease outside the capsule (clinical stage T3) as well as those with apparently localized disease but with adverse prognostic factors such as Gleason 8-10 tumors or very extensive disease on biopsy. The goals of therapy for these patients are to achieve both long-term local control and to remain free of metastatic disease. The ideal treatment to achieve these goals is unknown. We present a review of the outcome of contemporary reported series of such patients treated with primary radical prostatectomy, with or without neoadjuvant or adjuvant therapies. Over 80% of the patients overall achieved a 5-year disease-specific survival, though well under 50% have undetectable prostate specific antigen at that time point. We also review what is known about the choice and timing of adjuvant therapies, and describe current cooperative group studies underway to answer some of these questions.

Migration and invasion of human prostate cancer cells is related to expression of VEGF and its receptors.

BACKGROUND: Vascular endothelial growth factor (VEGF) and its receptors are becoming of increasing interest as major regulators of cancer cell growth and metastases. VEGF is expressed by many cancer cells including most prostatic carcinomas. Recently it has also been shown that the VEGF receptors are also expressed by prostate cancer cells and it has been suggested that there may be autocrine regulatory loops that are important in the development and progression of the disease. To date, however, there have only been descriptive studies of expression without correlation of the findings with possible pathophysiologic effects. The present studies were done to determine if there is a correlation between expression of VEGF receptors and the ability of human prostate cancer cells to invade and migrate in vitro. MATERIALS AND METHODS: Using RT-PCR we examined the expression of VEGF and its receptors, KDR, Flt-1, NP-1 and NP-2, in 8 human prostate cancer cell lines and then correlated the expression patterns with the ability of these cell lines to invade and migrate through membranes in a modified Boyden Chamber assay in the presence and absence of VEGF. RESULTS: Six of the 8 cell lines expressed VEGF. None expressed the Flt-1 receptor and only 2 expressed KDR. The most commonly expressed VEGF receptor was NP-1 (5 of 8 cell lines) and its expression was strongly, and negatively, correlated with the ability of these cell lines to invade and migrate in the assay system used. Cell lines expressing NP-1 had low levels of migration both with and without VEGF compared to those not expressing NP-1. CONCLUSION: These studies suggest that variable expression of VEGF receptors in prostate cancer, particularly NP-1, may have important consequences for cell growth, invasion and metastases in this disease.

Lipid catabolism via CPT1 as a therapeutic target for prostate cancer.

Prostate cancer is the most commonly diagnosed malignancy among Western men and accounts for the second leading cause of cancer-related deaths. Prostate cancer tends to grow slowly and recent studies suggest that it relies on lipid fuel more than on aerobic glycolysis. However, the biochemical mechanisms governing the relationships between lipid synthesis, lipid utilization, and cancer growth remain unknown. To address the role of lipid metabolism in prostate cancer, we have used etomoxir and orlistat, clinically safe drugs that block lipid oxidation and lipid synthesis/lipolysis, respectively. Etomoxir is an irreversible inhibitor of the carnitine palmitoyltransferase (CPT1) enzyme that decreases ß oxidation in the mitochondria. Combinatorial treatments using etomoxir and orlistat resulted in synergistic decreased viability in LNCaP, VCaP, and patient-derived benign and prostate cancer cells. These effects were associated with decreased androgen receptor expression, decreased mTOR signaling, and increased caspase-3 activation. Knockdown of CPT1A enzyme in LNCaP cells resulted in decreased palmitate oxidation but increased sensitivity to etomoxir, with inactivation of AKT kinase and activation of caspase-3. Systemic treatment with etomoxir in nude mice resulted in decreased xenograft growth over 21 days, underscoring the therapeutic potential of blocking lipid catabolism to decrease prostate cancer tumor growth.