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Biomedical subjects

John F Ward

Publications and source records attributed to John F Ward.

At least 19 recordsLinked to original sources
PubMed2006

Management of the patient with a rising PSA alone.

PSA-only recurrence after definitive RP or RT for PCA is an increasingly com-mon scenario. The very definition of advanced prostate cancer is changing. Multimodal therapy improves cancer-specific outcomes especially in men with high-risk disease. After RP, a detectable serum PSA has been considered suggestive of PCA recurrence. After RT, the ASTRO definition of BCR has been widely used to define BCR. Both of these definitions of BCR are subject to dispute. The kinetics of a rising PSA (PSA doubling time) appears to be the best surrogate marker for disease risk, clinical progression, and ultimately cancer-specific death. Therapeutic options include salvage RT after primary RP or systemic HT through surgical/chemical castration, antiandrogens, or nontraditional HT. Re-cent studies suggest that early HT can provide modest survival benefits, but at both an economic cost and decreased quality of life. The diminished side effects of an oral antiandrogen are appealing, and may be as efficacious as castration therapies in low-volume disease. More clinical trials are needed to determine the best treatments, alone and in combination. The potential opportunities for novel therapeutic agents with low associated morbidity are great.

Disease Management↗
PubMed2005

Rising prostate-specific antigen after primary prostate cancer therapy.

An estimated 20-40% of men experience a biochemical recurrence within 10 years of definitive prostate cancer treatment. No single prostate-specific antigen (PSA) value is invariably associated with clinical metastasis or cancer-specific survival; PSA kinetics might prove to be a more important predictor of eventual progression-free survival and cancer-specific survival than absolute PSA level alone. With only one-third of patients progressing from biochemical recurrence to clinical disease, therapeutic morbidity should not outpace risk of disease progression. Salvage radiation therapy following radical prostatectomy has widely variable long-term biochemical control rates (from 18 to 64% depending on the follow-up period). Early hormonal therapy delivered as castration or complete androgen blockade might delay clinical metastasis in patients with high-risk pathologic disease; however, the adverse effects and morbidity of long-term therapy must not be underestimated. Non-steroidal antiandrogens as monotherapy for early biochemical recurrence, particularly for younger men who wish to preserve their libido and sexual potency, have received considerable attention, but there are conflicting data on long-term outcomes. Because of their favorable adverse-effect profiles, non-traditional therapies that exert localized hormonal or cellular effects are receiving considerable attention for treatment of early, PSA-only recurrence. Data from animal models provide a rationale for the use of these therapies, but there is a lack of evidence to support prolongation of progression-free survival or cancer-specific survival.

Androgen Antagonists↗
PubMed2005

Salvage surgery for radiorecurrent prostate cancer: contemporary outcomes.

PURPOSE: We present a 30-year experience with performing salvage surgery in patients with persistent prostate cancer (PCA) after definitive radiotherapy. MATERIALS AND METHODS: Patients with biopsy proven PCA following definitive radiotherapy who underwent salvage surgery were identified retrospectively (1967 to 2000). Prostate specimens were evaluated by a single pathologist. Progression-free survival (PFS) and cancer specific survival (CSS) estimates were made with multivariate analysis of outcome predictors. Complications were reviewed. RESULTS: Sufficient information was available on 199 patients, including 138 with retropubic prostatectomy (RP) and 61 with cystoprostatectomies (CP). Median followup was 7.0 years. Rectal injury rates (5% for RP and 10% for CP) remained stable, while transfused units of blood decreased. Urinary extravasation (15% of cases) and bladder neck contracture (22%) were the most common complications. Urinary continence (0 pads) improved from 43% to 56% of patients (p = 0.17) with an additional 20% requiring 1 or fewer pad daily. Overall 10-year CSS in all patients undergoing salvage surgery was 65%. Patients undergoing RP fared better than those needing CP (10-year CSS 77% vs 38%, p <0.001 and median PFS 8.7 vs. 4.4 years, p <0.001). Tumor ploidy, percent 4/5 Gleason grade and pathological stage were strong predictors of outcome, while margin status and preoperative prostate specific antigen had minimal predictive strength. CONCLUSIONS: Significant PFS and CSS can be expected following salvage surgery for radioresistant PCA. Several pathological features of the removed prostate are predictive of survival. The surgical risks of salvage surgery are now defined. Morbidity rates, including continence, have moderately improved with time.

Aged↗
PubMed2005

Biochemical recurrence after definitive prostate cancer therapy. Part I: defining and localizing biochemical recurrence of prostate cancer.

PURPOSE OF REVIEW: The introduction of prostate-specific antigen into clinical practice heralded a dramatic shift in the epidemiology of prostate cancer. The diagnosis and treatment of lower stage disease in younger men with fewer competing co-morbidities has resulted in a longer period of post-treatment cancer surveillance and the potential for disease recurrence. Life-long periodic prostate-specific antigen testing for biochemical recurrence is standard of care; however, there is no single definition of biochemical recurrence that reliably predicts clinical recurrence. This review explores the complexities of biochemical recurrence, a thorough understanding of which is crucial to making appropriate treatment decisions after primary treatment. It also evaluates the array of diagnostic tests frequently employed when biochemical recurrence has occurred. RECENT FINDINGS: There is a disconnection between biochemical recurrence and progression to clinical disease. The definition of biochemical recurrence varies both by the prostate-specific antigen cut-point used and by the primary therapy employed. Furthermore, biochemical recurrence by itself appears not to be as reliable a predictor of eventual clinical recurrence as prostate-specific antigen doubling time. Current imaging modalities are rarely useful in localizing disease when biochemical recurrence is first detected. SUMMARY: The correct interpretation of biochemical recurrence is crucial to treatment decision-making. New data show that prostate-specific antigen doubling time during prostate-specific antigen recurrence may be a valid surrogate for death from the disease. The potential therefore exists for prostate-specific antigen doubling time to be accepted as a trial endpoint, which might accelerate drug approval by the United States Food and Drug Administration.

Antibodies, Monoclonal↗
PubMed2005

Biochemical recurrence after definitive prostate cancer therapy. Part II: treatment strategies for biochemical recurrence of prostate cancer.

PURPOSE OF REVIEW: Through the prostate-specific antigen era, the proportion of men less than 55 years old with newly diagnosed prostate cancer more than doubled to almost 15%. As increasing numbers of men are living longer with prostate cancer, larger proportions will eventually present to our collective practices with rising prostate-specific antigen levels. Such prostate-specific antigen relapses, conservatively estimated to affect approximately 50 000 men each year, have become the most common form of advanced prostate cancer in the current period. RECENT FINDINGS: Increasing evidence suggests that early hormonal therapy improves progression-free survival and may alter the cancer-specific survival. However, there is a cost to pay in side-effects when androgen deprivation is administered over prolonged periods. The non-steroidal anti-androgen bicalutamide may offer an equivalent progression-free survival to castration without the complications of androgen deprivation. Observational data seem to indicate that high-risk individuals (i.e. those with high-grade, high-stage disease or a prostate-specific antigen doubling time less than 12 months) may also receive benefit from early therapy. SUMMARY: The definition of advanced prostate cancer has changed. Multimodal therapy improves cancer-specific outcomes especially in men with high-risk disease. The potential opportunities for novel therapeutic agents with low associated morbidity are great.

Androgen Antagonists↗
PubMed2005

Radical prostatectomy for clinically advanced (cT3) prostate cancer since the advent of prostate-specific antigen testing: 15-year outcome.

UNLABELLED: In the first paper in this section, authors from the Mayo Clinic describe their experience and 15-year outcomes in the controversial subject of radical prostatectomy in patients with clinical T3 prostate cancer. The findings were interesting in many respects, but the authors concluded that radical prostatectomy as part of multimodal treatment for patients with clinical T3 disease offers cancer control and good survival rates. There follows a series of papers on both prostate cancer and bladder cancer, but the final paper in this section from the UK attempts to define the accuracy of urologists and oncologists in assessing patient life-expectancy. Using various methods they found that, rather disappointingly, doctors were poor at predicting 10-year survival, leading to the possible outcome that some patients may be denied treatment after a pessimistic assessment of life-expectancy. OBJECTIVE: To report a long-term experience with extirpative surgery in patients presenting with locally advanced (cT3) prostate cancer, as the best management of such patients remains a problem. PATIENTS AND METHODS: In a single-institution retrospective study identifying 5652 men who had radical prostatectomy (RP) for histologically confirmed prostate cancer since the advent of prostate-specific antigen (PSA) testing (1987-97), 15% (842) had RP for cT3 disease. The median follow-up of these men was 10.3 years. Cancer-specific, overall and disease-free survival was plotted and compared with those of patients having RP for cT2 disease during the same period. Perioperative morbidity, continence and erectile function rates were examined, with a multivariate analysis for risk factors of disease recurrence. RESULTS: Freedom from local or systemic disease at 5, 10, and 15 years after RP for cT3 disease was 85%, 73% and 67%; the respective cancer-specific survival rates were 95%, 90% and 79%. Significantly many men who did not receive neoadjuvant therapy (27%) were clinically over-staged (pT2) and most men with pT3 disease (78%) received adjuvant therapy. The mean time to adjuvant therapy after RP was not significantly different between men with cT3 and cT2 disease (4.0 and 4.3 years). Pathological grade (> or =7), positive surgical margins, and nondiploid chromatin were all independently associated with a significant risk for clinical disease recurrence, while preoperative PSA level had little effect on outcome. Complications and continence rates after RP in patients with cT3 mirrored those in patients with cT2 disease. CONCLUSIONS: Significantly many patients with cT3 prostate cancer are overstaged (pT2) in the PSA era. RP as part of a multimodal treatment strategy for patients with cT3 disease offers cancer control and survival rates approaching those achieved for cT2 disease. Pathological grade, ploidy and margin status are all significant predictors of outcome after RP. Complications and incontinence rates in patients with cT3 disease mirror those after RP for cT2 disease.

Aged↗
PubMed2005

Treating the biochemical recurrence of prostate cancer after definitive primary therapy.

As increasing numbers of men are living longer with prostate cancer, larger proportions will eventually present to our collective practices with increasing prostate-specific antigen (PSA) levels. Such PSA relapses, conservatively estimated to affect approximately 50,000 men each year, have become the most common form of advanced prostate cancer. Salvage radiation therapy and salvage prostatectomy have important roles in our therapeutic armamentarium and should be valid options for young, healthy men. Counseling patients regarding expectations for cancer control and treatment morbidity has become better because of reports from larger series of patients who have had salvage radiation therapy and surgery. Some patients may not be appropriate candidates for salvage local therapies. A growing body of evidence suggests early hormonal therapy improves progression-free survival (PFS) and could alter cancer-specific survival. This benefit seems to be greatest when hormonal therapy is initiated while PSA levels are low, before clinically measurable disease becomes apparent. However, there is a cost to be paid in side effects and health care dollars when androgen deprivation is administered over prolonged periods. The nonsteroidal antiandrogen agent bicalutamide could offer PFS equivalent to that seen with castration without the complications of androgen deprivation. Observational data seem to indicate that individuals at high risk could also receive benefit from therapy administered before PSA detection. The potential opportunities for novel therapeutic agents with low associated morbidity are great.

Androgen Antagonists↗
PubMed2004

Repair of oxidative guanine damage in plasmid DNA by indoles involves proton transfer between complementary bases.

We have used the single electron oxidizing agent (SCN)(2)(*)(-) (generated by gamma-irradiation of aqueous thiocyanate) to produce guanyl radicals in plasmid DNA. The stable product(s) formed from these radicals can be detected after conversion with a base excision repair endonuclease to single strand breaks. The yield of enzyme-induced breaks is decreased by the presence during irradiation of indole compounds. Rate constants for the reduction of DNA guanyl radicals by these indoles can be calculated from the concentration dependence of the attenuation in the yield of enzyme sensitive sites. Indoles bearing electron-donating groups (methoxy or methyl) appear to react at the diffusion-controlled rate, but those bearing electron-withdrawing groups (cyano or nitro) are significantly less reactive. At physiological pH values, the reduction of a DNA guanyl radical involves the transfer of a proton as well as an electron. Comparison of the kinetic results with literature thermodynamic data suggests that the source of this proton is the complementary base-paired cytosine.

Base Pairing↗
PubMed2004

Peptide repair of oxidative DNA damage.

Guanyl radical species are produced in DNA by electron removal caused by ionizing radiation, photoionization, oxidation, or photosensitization. DNA guanyl radicals can be reduced by electron donation from mild reducing agents. Important biologically relevant examples are the redox active amino acids cysteine, cystine, methionine, tryptophan, and tyrosine. We have quantified the reactivity of derivatives of these amino acids with guanyl radicals located in plasmid DNA. The radicals were produced by electron removal using the single electron oxidizing agent (SCN)(2)(*)(-). Disulfides (cystine) are unreactive. Thioethers (methionine), thiols (cysteine), and phenols (tyrosine) react with rate constants in the range 10(4)-10(6), 10(5)-10(6), and 10(5)-10(6) dm(3) mol(-1) s(-1), respectively. Indoles (tryptophan) are the most reactive with rate constants of 10(7)-10(8) dm(3) mol(-1) s(-1). Selenium analogues of amino acids are over an order of magnitude more reactive than their sulfur equivalents. Increasing positive charge is associated with a ca. 10-fold increase in reactivity. The results suggest that amino acid residues located close to DNA (for example, in DNA binding proteins such as histones) might participate in the repair of oxidative DNA damage.

Amino Acids↗
PubMed2004

Repair of guanyl radicals in plasmid DNA by electron transfer is coupled to proton transfer.

By using gamma-irradiation in the presence of thiocyanate ions, we have generated guanyl radicals in plasmid DNA. These can be detected by using an Escherichia coli base excision repair endonuclease to convert their stable end products to strand breaks. The yield of enzyme-sensitive sites is strongly attenuated by the presence of micromolar concentrations of one of a series of singly substituted phenols, and it is possible to derive bimolecular rate constants for the reduction of DNA guanyl radicals by these phenols. More strongly reducing phenols were found to react more rapidly. This electron-transfer reaction also involves a proton transfer. By comparing the expected energetics of the reaction with the observed rate constants, the electron transfer is found to be mechanistically coupled with the proton transfer.

DNA↗
PubMed2004

The impact of surgical approach (nerve bundle preservation versus wide local excision) on surgical margins and biochemical recurrence following radical prostatectomy.

PURPOSE: Surgical margin (SM) status is widely reported as a significant risk factor for prostate cancer recurrence following radical prostatectomy (RP). It has been presupposed that preserving the neurovascular bundle may compromise cancer control due to the limited surgical margin obtained with a resultant increase in treatment failure. We examined whether neurovascular bundle preservation during RP is a risk factor for positive SMs and progression-free survival after adjusting for disease severity. MATERIALS AND METHODS: Outcomes following RP in 7,268 men between 1990 and 2000 were examined retrospectively. Median followup in those last known to be alive is 6.4 years. RP was performed by a total of 21 surgeons in the same basic fashion with strict attention to anatomical detail. RESULTS: Overall a positive SM was identified in 38% of patients. The positive SM rate was higher for wide excision than for nerve sparing (NS) (42% vs 34%) (p </= 0.001). The OR for positive SMs in patients undergoing NS-RP was 0.86 (95% CI 0.76 to 0.97, p = 0.012) after incorporating age, clinical stage, biopsy grade, year of surgery and prostate specific antigen. Similarly NS-RP had no significant impact on biochemical progression rates after controlling for these variables (HR 0.98, 95% CI 0.88 to 1.08, p = 0.64). CONCLUSIONS: NS-RP is not an independent adverse risk factor for positive SMs or progression-free survival. Tumor biology appears set prior to technically skilled anatomical radical prostatectomy independent of wide excision of the neurovascular bundles. All patients with organ confined prostate cancer should be considered candidates for an NS operation.

Aged↗
PubMed2004

Prostate specific antigen doubling time subsequent to radical prostatectomy as a prognosticator of outcome following salvage radiotherapy.

PURPOSE: Therapy for men with detectable prostate specific antigen (PSA) following radical prostatectomy (RP) for prostate cancer remains controversial. Salvage radiotherapy (SRT) is commonly used because of its relatively low morbidity. We present a single institution retrospective review of patients treated with SRT. MATERIALS AND METHODS: A longitudinal cohort study (between April 1987 and April 2000) using the referral based Mayo Clinic Prostate Cancer Registry was conducted. A total of 211 patients were included in this study if detectable serum PSA was the sole indication for SRT and no hormonal therapy was administered. RESULTS: Median followup from surgery to death or last followup was 7.2 years, from RP to SRT was 1.7 years and from SRT to last contact was 4.2 years. Median PSA and prostate specific antigen doubling time (PSADT) at SRT initiation was 0.60 ng/ml and 7.32 months; respectively. Of the patients 90% had nadir PSA less than 0.4 ng/ml within 3 years of SRT. Biochemical disease-free rates at 5 years for PSADT less than 12 or 12 months or greater was 48% and 66%; respectively (p = 0.080). By 10 years there was no significant difference in biochemical disease-free rate (34% vs 35%). Clinical metastasis (10% and 29%) developed in patients with a PSADT less than 12 months at a significantly higher rate than in patients with a PSADT of 12 months or more (0% and 17%, p = 0.045) at 5 and 10 years, respectively. Multivariate analysis revealed pre-SRT PSADT (less than 12 months, H.R. 3.88, p = 0.032), seminal vesicle invasion (H.R. 3.22, p = 0.008), pathological grade (H.R. 1.58, p = 0.023) and PSA at SRT (H.R. 1.29 for a 2-fold increase, p = 0.044) to be significant independent predictors of clinical recurrence. The interval from RP to SRT did not add to the model (p = 0.22). CONCLUSIONS: A biochemical response can be expected in the majority of patients within 3 years of receiving SRT. Patients with a pre-SRT PSADT of 1 year or less have a less sustained biochemical response to SRT than patients with a PSADT greater than 1, yet the majority of patients appear to receive long-term benefit from this adjunctive therapy. PSADT is an independent predictor of biochemical and clinical disease recurrence following SRT.

Aged↗
PubMed2004

The effects of dietary factors on the androgen receptor and related cellular factors in prostate cancer.

It has been strongly suggested that androgens and the cognate receptor (AR) may play important roles in the development and progression of prostate cancer. The AR is a transcription factor consisting of three major domains, i.e., N-terminal transactivation, middle DNA binding, and C-terminal steroid binding domains. Molecular events of androgen induced activation of the AR include conformation change, phosphorylation, acetylation, genomic DNA binding, and co-regulator recruiting. Many of these events can be manipulated in certain prostate cancer cells in favor of their progression. Dietary compounds and certain herbs have recently drawn a great deal of attention because of their relevance to development of several cancers including prostate cancer. We discuss in depth the findings from our and other laboratories of effects of dietary factors or herbs on the function of the AR and potential mechanisms on expression of the AR and AR regulated genes. We further discuss the potential implication of these dietary chemicals on prevention of development and progression of prostate cancer.

Androgens↗
PubMed2003

Radical prostatectomy for the patient with locally advanced prostate cancer.

The proper management of patients with locally advanced adenocarcinoma of the prostate has been contentious and too frequently based on antiquated misconceptions. Non-extirpative treatments, even when combined with neoadjuvant hormonal therapy, are inferior to the surgical removal of the prostate for controlling local progression and distant dissemination of the cancer. Radical prostatectomy combined with early adjunctive hormonal therapy for patients with nodal metastasis is superior to all other forms of therapy and should be considered the standard of care. This approach provides survival rates comparable with patients with clinically organ-confined prostate cancer.

Adenocarcinoma↗
PubMed2003

The long-term clinical impact of biochemical recurrence of prostate cancer 5 or more years after radical prostatectomy.

PURPOSE: Information regarding the clinical impact of delayed (5 years or greater) biochemical failure (BF) after radical prostatectomy (RP) is lacking. We undertook an investigation to differentiate the innocuous recurrence of serum prostate specific antigen (PSA) from that which heralds an eventual clinical failure (CF), and to determine if there is a period following RP when a patient is cured of clinical disease. MATERIALS AND METHODS: Men with clinically localized prostate cancer (PCA) undergoing RP (1987 to 1995) were identified from our longitudinal PCA registry. Outcome measurements were based on the detection of post-RP serum PSA 0.4 ng/ml or greater, clinical identification of cancer recurrence and disease related death. RESULTS: Following RP in 3,903 eligible men, 33% had a detectable PSA (median followup 8.8 years). Of these BFs 27% occurred after 5 or more disease-free years. Currently, 29% of all men with BF have clinical evidence of PCA, with 8% dying of PCA (median actuarial survival time from CF to death 9.8 years). Progression from BF to CF was not significantly altered by the disease-free interval (p = 0.544). A PSA doubling time less than 12 months significantly increased the risk of CF regardless of the interval from surgery. Risk factors for BF were significant throughout the duration of followup. CONCLUSIONS: Patients are at prolonged risk for BF and CF following RP. Regardless of the timing of the initial PSA recurrence the PSA doubling time is the most powerful predictor of progression, stratifying patients with BF into high and low risk groups for CF.

Adult↗