Jeffrey R. Gingrich

Radical Prostatectomy versus Observation for Localized Prostate Cancer

BACKGROUND The effectiveness of surgery versus observation for men with localized prostate cancer detected by means of prostate-specific antigen (PSA) testing is not known. METHODS From November 1994 through January 2002, we randomly assigned 731 men with localized prostate cancer (mean age, 67 years; median PSA value, 7.8 ng per milliliter) to radical prostatectomy or observation and followed them through January 2010. The primary outcome was all-cause mortality; the secondary outcome was prostate-cancer mortality. RESULTS During the median follow-up of 10.0 years, 171 of 364 men (47.0%) assigned to radical prostatectomy died, as compared with 183 of 367 (49.9%) assigned to observation (hazard ratio, 0.88; 95% confidence interval [CI], 0.71 to 1.08; P=0.22; absolute risk reduction, 2.9 percentage points). Among men assigned to radical prostatectomy, 21 (5.8%) died from prostate cancer or treatment, as compared with 31 men (8.4%) assigned to observation (hazard ratio, 0.63; 95% CI, 0.36 to 1.09; P=0.09; absolute risk reduction, 2.6 percentage points). The effect of treatment on all-cause and prostate-cancer mortality did not differ according to age, race, coexisting conditions, self-reported performance status, or histologic features of the tumor. Radical prostatectomy was associated with reduced all-cause mortality among men with a PSA value greater than 10 ng per milliliter (P=0.04 for interaction) and possibly among those with intermediate-risk or high-risk tumors (P=0.07 for interaction). Adverse events within 30 days after surgery occurred in 21.4% of men, including one death. CONCLUSIONS Among men with localized prostate cancer detected during the early era of PSA testing, radical prostatectomy did not significantly reduce all-cause or prostate-cancer mortality, as compared with observation, through at least 12 years of follow-up. Absolute differences were less than 3 percentage points. (Funded by the Department of Veterans Affairs Cooperative Studies Program and others; PIVOT ClinicalTrials.gov number, NCT00007644.).

Pathologic progression of autochthonous prostate cancer in the TRAMP model

The ability to manipulate gene expression in specific cell types at specific times utilizing transgenic technology has allowed the development of novel mouse model systems that can mimic human disease. We have previously established the Transgenic Adenocarcinoma of Mouse Prostate (TRAMP) model for prostate cancer using the rat probasin promoter to direct expression of the SV40 early genes to prostate epithelium. Male TRAMP mice exhibit consistent prostate-specific patterns of expression and develop prostatic intraepithelial neoplasia that will become invasive and metastasize primarily to the lymph nodes and lungs. In this paper we report our continued experience with this model and present a standardized histologic grading system to designate low and high grade prostatic intraepithelial neoplasia and well, moderate, and poorly differentiated prostate adenocarcinoma. In addition, we demonstrate the persistence of androgen receptor expression during pathologic progression and characterize heterogeneous cytokeratin expression in localized and metastatic prostate cancer. Finally, we report on our observations that phenotypic variability in tumor and pathologic progression in TRAMP occurs as a function of genetic background.

Phase II Randomized, Double-Blind, Placebo-Controlled Study of Tasquinimod in Men With Minimally Symptomatic Metastatic Castrate-Resistant Prostate Cancer

PURPOSE The activity of the novel antitumor agent tasquinimod (TASQ) with S100A9 as a molecular target was investigated in men with metastatic castration-resistant prostate cancer (CRPC) and minimal symptoms. PATIENTS AND METHODS We conducted a randomized, double-blind, placebo-controlled phase II trial in men assigned (at a ratio of two to one) to either oral once-daily TASQ 0.25 mg/d escalating to 1.0 mg/d over 4 weeks or placebo. The primary end point was the proportion of patients without disease progression at 6 months, defined by Response Evaluation Criteria in Solid Tumors Group, Prostate Cancer Working Group (PCWG2), or pain criteria, excluding prostate-specific antigen. RESULTS Two hundred one men (134 assigned to TASQ; 67 to placebo) were evaluable, and baseline characteristics were well balanced. Six-month progression-free proportions for TASQ and placebo groups were 69% and 37%, respectively (P < .001), and median progression-free survival (PFS) was 7.6 versus 3.3 months (P = .0042). In PCWG2 CRPC clinical subgroups, PFS in months was as follows: nodal metastases, 6.1 versus 3.1; bone metastases, 8.8 versus 3.4; and visceral metastases, 6.0 versus 3.0 for patients receiving TASQ versus placebo, respectively. Bone alkaline phosphatase levels were stabilized in the TASQ group, whereas the impact on PSA kinetics was less pronounced. Adverse events (AEs) occurring more frequently in the TASQ arm included GI disorders, fatigue, musculoskeletal pains, and elevations of pancreatic and inflammatory biomarkers. Grade 3 to 4 AEs, including asymptomatic elevations of laboratory parameters, were reported in 40% of patients receiving TASQ versus 10% receiving placebo; deep vein thrombosis (4% v 0%) was more common in the TASQ arm. CONCLUSION TASQ significantly slowed progression and improved PFS in patients with metastatic CRPC with an acceptable AE profile.

The Prostate cancer Intervention Versus Observation Trial:VA/NCI/AHRQ Cooperative Studies Program #407 (PIVOT): Design and baseline results of a randomized controlled trial comparing radical prostatectomy to watchful waiting for men with clinically localized prostate cancer ☆

BACKGROUND Prostate cancer is the most common noncutaneous malignancy and the second leading cause of cancer death in men. Ninety percent of men with prostate cancer are over aged 60 years, diagnosed by early detection with the prostate specific antigen (PSA) blood test and have disease believed confined to the prostate gland (clinically localized). Common treatments for clinically localized prostate cancer include watchful waiting surgery to remove the prostate gland (radical prostatectomy), external beam radiation therapy and interstitial radiation therapy (brachytherapy) and androgen deprivation. Little is known about the relative effectiveness and harms of treatments due to the paucity of randomized controlled trials. The VA/NCI/AHRQ Cooperative Studies Program Study #407: Prostate cancer Intervention Versus Observation Trial (PIVOT), initiated in 1994, is a multicenter randomized controlled trial comparing radical prostatectomy to watchful waiting in men with clinically localized prostate cancer. METHODS We describe the study rationale, design, recruitment methods and baseline characteristics of PIVOT enrollees. We provide comparisons with eligible men declining enrollment and men participating in another recently reported randomized trial of radical prostatectomy versus watchful waiting conducted in Scandinavia. RESULTS We screened 13,022 men with prostate cancer at 52 United States medical centers for potential enrollment. From these, 5023 met initial age, comorbidity and disease eligibility criteria and a total of 731 men agreed to participate and were randomized. The mean age of enrollees was 67 years. Nearly one-third were African-American. Approximately 85% reported they were fully active. The median prostate specific antigen (PSA) was 7.8 ng/mL (mean 10.2 ng/mL). In three-fourths of men the primary reason for biopsy leading to a diagnosis of prostate cancer was a PSA elevation or rise. Using previously developed tumor risk categorizations incorporating PSA levels, Gleason histologic grade and tumor stage, approximately 43% had low risk, 36% had medium risk and 20% had high-risk prostate cancer. Comparison to our national sample of eligible men declining PIVOT participation as well as to men enrolled in the Scandinavian trial indicated that PIVOT enrollees are representative of men being diagnosed and treated in the U.S. and quite different from men in the Scandinavian trial. CONCLUSIONS PIVOT enrolled an ethnically diverse population representative of men diagnosed with prostate cancer in the United States. Results will yield important information regarding the relative effectiveness and harms of surgery compared to watchful waiting for men with predominately PSA detected clinically localized prostate cancer.

Src in synaptic transmission and plasticity

In the central nervous system (CNS), Src and other Src family kinases are widely expressed and are abundant in neurons. Src has been implicated in proliferation and differentiation during the development of the CNS. But Src is highly expressed in fully differentiated neurons in the developed CNS, implying additional functions of this kinase. Over the past decade, a large body of evidence has accumulated showing that a main function of Src is to upregulate the activity of N-methyl-D-aspartate (NMDA) receptors and other ion channels. NMDA receptors (NMDARs) are a principal subtype of glutamate receptors, which mediate fast excitatory transmission at most central synapses. In this review, we focus on Src as a regulator of NMDARs and on the role of Src in NMDAR-dependent synaptic plasticity. We also describe recent studies that give insights into the regulation of Src itself at glutamatergic synapses. By upregulating the function of NMDARs, Src gates the production of NMDAR-dependent synaptic potentiation and plasticity. Thus, Src may be critical for processes underlying physiological plasticity, including learning and memory, and pathological plasticity, such as pain and epilepsy.

A transgenic mouse prostate cancer model

Adenocarcinoma of the prostate is the most common cancer in American men. It is estimated that in 1996 prostate cancer will account for over 40,000 deaths and 200,000 new cases will be reported. Despite the magnitude of the problem, our understanding of the molecular mechanisms involved in the initiation, progression, and metastasis of prostate cancer has been slow, largely due to the scarcity of adequate animal model systems that reproduce the spectrum of human prostatic disease. Therefore, we have undertaken the task of developing a transgenic mouse prostate cancer model to facilitate prostate cancer research.

Effect of flaxseed supplementation on prostatic carcinoma in transgenic mice

OBJECTIVES To investigate the effects of flaxseed supplementation on prostatic neoplasia in the transgenic adenocarcinoma mouse prostate (TRAMP) model. METHODS A total of 135 male TRAMP mice 5 to 6 weeks old were randomized to a control group (AIN-76A diet) or an experimental group (AIN-76A diet plus 5% flaxseed by weight). One half of the mice in each group were treated for 20 weeks and the remainder for 30 weeks. At autopsy, urogenital tissues (four prostatic lobes, seminal vesicles, and emptied bladder), lungs, lymph nodes, and grossly abnormal tissues were collected for histologic evaluation. RESULTS Of the control mice, 100% developed prostate cancer versus 97% of the mice in the flaxseed group. The tumor/urogenital weight was 3.6 +/- 0.4 g in the controls versus 1.9 +/- 0.2 g in the flaxseed-treated mice (P = 0.0005). At 20 weeks, no significant difference in tumor grade was seen between the two groups; however, at 30 weeks, the flaxseed-treated mice had significantly less aggressive tumors than did the controls (P = 0.01). The prevalence of lung and lymph node metastases was 13% and 16%, respectively, in the control mice versus 5% and 12%, respectively, in the experimental group (difference not significant). After 20 weeks of treatment, cellular proliferation (Ki-67) differed significantly between the control and experimental groups (38.1 +/- 2.03 versus 26.2 +/- 2.03; P <0.0001), and the apoptotic index (deoxynucleotidyl transferase-mediated dUTP-digoxigenin nick end labeling) was 1.45 +/- 0.14 versus 3.3 +/- 0.31 (P <0.0001). Similar differences were seen after 30 weeks of treatment. CONCLUSIONS A diet supplemented with 5% flaxseed inhibits the growth and development of prostate cancer in the TRAMP model.

Hemorrhagic Cystitis after Allogeneic Bone Marrow Transplantation in Children: Clinical Characteristics and Outcome

Hemorrhagic cystitis (HC) is a well-documented adverse event experienced by patients undergoing hematopoietic stem cell transplantation. When severe, HC causes significant morbidity, leads to renal complications, prolongs hospitalization, increases health-care costs, and occasionally contributes to death. We retrospectively studied the medical records of 245 children undergoing an initial allogeneic bone marrow transplantation for malignant disease at St. Jude Childrens Research Hospital between 1992 and 1999 to describe the clinical course of HC in all patients and to identify the risk factors for HC in this cohort. Conditioning regimens included cyclophosphamide, cytarabine, and total body irradiation. Grafts from unrelated or mismatched related donors were depleted of T lymphocytes, whereas matched sibling grafts were unmanipulated. All patients received cyclosporine as prophylaxis for graft-versus-host disease. Recipients of grafts from matched siblings also received pentoxifylline or short-course methotrexate. Severe HC developed in 27 patients (11.0%). The median duration of HC was 73 days (range, 5-619 days); 12 patients had ongoing HC at the time of death. In univariate analyses, patients were at increased risk of severe HC if they were male (P =.021) or had received T cell-depleted grafts (P =.017), grafts from unrelated donors (P =.021), a lower total nucleated cell dose (P =.032), or antithymocyte globulin (P =.0446). Multiple regression analysis revealed male sex (beta =.97; P =.027) and unrelated donor graft recipients (beta =.83; P =.039) to be significant factors.

Importance of Delayed Imaging for Blunt Renal Trauma

The advent of noninvasive computed tomography of the abdomen and pelvis for evaluation of blunt renal trauma has led to the practice of expectant management for hemodynamically stable patients. Although expectant management of higher grade injuries (American Association for the Surgery of Trauma Renal Injury Scale) would intuitively result in an increased frequency of urologic complications, this has not been previously examined in a large series of patients utilizing contemporary radiologic imaging techniques. A retrospective review of patients from a single institution within a recent 4-year period revealed 4 grade I, 13 grade II, 21 grade III, 7 grade IV, and 4 grade V injuries. None of grade I, 15% of grade II, 38% of grade III, 43% of grade IV, and 100% of grade V injuries had one or more (15 major and 11 minor) urologic complications. The incidence of urinary complications correlated significantly with increasing grade (0%, 15%, 38%, 43%, and 100% for grades I to V, respectively; r = 0.94, p = 0.0158). Of the delayed urologic complications, 50% were diagnosed on follow-up imaging studies and 33% of them required intervention. Therefore we advocate repeat imaging 2 to 4 days after trauma resulting in grade III to V blunt renal lacerations to identify delayed complications that may require intervention.

GENE THERAPY FOR PROSTATE CANCER: WHERE ARE WE NOW?

PURPOSE The ability to recombine specifically and alter DNA sequences followed by techniques to transfer these sequences or even whole genes into normal and diseased cells has revolutionized medical research and ushered the clinicians of today into the age of gene therapy. We provide urologists a review of relevant background information, outline current treatment strategies and clinical trials, and delineate current challenges facing the field of gene therapy for advanced prostate cancer. MATERIALS AND METHODS We comprehensively reviewed the literature, including PubMed and recent abstract proceedings from national meetings, relevant to gene therapy and advanced prostate cancer. We selected for review literature representative of the principal scientific background for current gene therapy strategies and National Institutes of Health Recombinant DNA Advisory Committee approved clinical trials. RESULTS Current prostate cancer gene therapy strategies include correcting aberrant gene expression, exploiting programmed cell death pathways, targeting critical cell biological functions, introducing toxic or cell lytic suicide genes, enhancing the immune system antitumor response and combining treatment with conventional cytotoxic chemotherapy or radiation therapy. CONCLUSIONS Many challenges lie ahead for gene therapy, including improving DNA transfer efficiency to cells locally and at distant sites, enhancing levels of gene expression and overcoming immune responses that limit the time that genes are expressed. Nevertheless, despite these current challenges it is almost certain that gene therapy will be part of the urological armamentarium against prostate cancer in this century.