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D Robert Siemens

Publications and source records attributed to D Robert Siemens.

16 recordsLinked to original sources
PubMed2007

Atrial natriuretic peptide attenuates hypoxia induced chemoresistance in prostate cancer cells.

PURPOSE: Low tumor oxygenation (hypoxia) correlates with resistance to chemotherapeutic agents. We recently reported that in vitro hypoxia induced resistance to various anti-cancer drugs can be attenuated by nitric oxide mimetic agents. Natriuretic peptides are molecules that mediate their cellular effects by activating a signaling pathway similar to that activated by nitric oxide. In the current study we determined whether atrial natriuretic peptide is able to inhibit hypoxia induced chemoresistance in prostate carcinoma cells. MATERIALS AND METHODS: Reverse transcriptase-polymerase chain reaction and atrial natriuretic peptide binding studies were used to determine the presence and function of natriuretic peptide receptors on a panel of human cell lines as well as in tissue samples. Drug sensitivity assays of cell lines exposed to hypoxic or standard conditions were performed in the presence of various concentrations of atrial natriuretic peptide. RESULTS: These studies revealed the presence of the 3 known natriuretic peptide receptors A, B and C in PC-3 and DU-145 human prostate carcinoma cells (American Type Culture Collection, Manassas, Virginia) as well as in tissue samples of human prostate cancer. Atrial natriuretic peptide binding to these cells was unaffected by culture in 0.5% vs 20% O(2). Clonogenic assays revealed that incubation of these cells in 0.5% O(2) for 24 hours resulted in a subsequent 4 to 10-fold increase in their survival following 1-hour exposure to doxorubicin (Sigma) (12.5 microM) (p <0.001). While small concentrations of atrial natriuretic peptide (10(-7) to 10(-13) M) did not affect sensitivity to doxorubicin in cells incubated in 20% O(2), similar concentrations of atrial natriuretic peptide inhibited the survival of these cells incubated in 0.5% O(2) by up to 50% (p <0.006). Using the cyclic guanosine monophosphate dependent protein kinase G inhibitor KT5823 (15 microM) the chemosensitizing effect of atrial natriuretic peptide was abrogated. CONCLUSIONS: These results indicate the potential use of natriuretic peptides as adjuvants to chemotherapy for prostate cancer.

Adenocarcinoma↗
PubMed2006

Induction of protective immunity to RM-1 prostate cancer cells with ALVAC-IL-2/IL-12/TNF-alpha combination therapy.

Human prostate cancers characteristically express low levels of major histocompatibility complex (MHC) Class I, which makes it challenging to induce protective antitumor responses involving T cells. Here we demonstrate that a whole cell tumor vaccine can induce protective T cell immunity to a low MHC Class I-expressing mouse prostate cancer cell line, RM-1. ALVAC recombinant canarypox viruses encoding interleukin-2, interleukin-12 and tumor necrosis factor-alpha were used to create therapeutic vaccines in 2 different ways. The RM-1 cells were pre-infected in vitro with the viruses prior to injection (pre-infection vaccine) or the RM-1 cells were injected alone, followed by the viruses (separate injection vaccine). The vaccines were each tested subcutaneously or intradermally. The pre-infection vaccine resulted in 100% clearance of primary tumors, whereas intradermal delivery of the separate injection vaccine cleared 40-60% of primary tumors. Despite the highly efficient primary tumor clearance by the pre-infection vaccine, only the separate injection vaccine generated protection upon rechallenge. Tumor-free survival induced by the separate injection vaccine required natural killer (NK) cells, CD4(+), and CD8(+) T cells. None of these cells alone were sufficient to induce tumor-free survival to the primary challenge, demonstrating an important cooperativity between NK cells and T cells. Secondary clearance of tumors also required NK and CD8(+) T cells, but not CD4(+) T cells. We report for the first time the generation of T cell immunity to the RM-1 prostate cancer cell line, demonstrating that it is possible to generate protective T cell immunity to a MHC I-low expressing tumor.

Animals↗
PubMed2006

Multifocal penile epithelioid hemangioendothelioma masquerading as superficial penile vein thrombosis.

A 42-year-old man presented with a progressively painful mass of the penile shaft that clinically resembled superficial penile vein thrombosis. The patient's symptoms were refractory to conservative therapy, and surgical excision revealed multifocal penile epithelioid hemangioendothelioma. He had no evidence of metastatic disease and was well 1 year after excision. Vascular neoplasms should be included in the differential diagnosis of painful penile masses and penile thrombophlebitis. To our knowledge, this is only the second reported case of multifocal penile epithelioid hemangioendothelioma.

Adult↗
PubMed2006

Predictive validity of five comorbidity indices in prostate carcinoma patients treated with curative intent.

BACKGROUND: Comorbidity is important to consider in clinical research on curative prostate carcinoma because of the role of competing risks. Five chart-based comorbidity indices were assessed for their ability to predict survival. METHODS: This was a case-cohort study of prostate carcinoma patient cohort treated with curative intent in Toronto and Southeast Cancer Care Ontario regions between 1990 and 1996; the subcohort was drawn from these men, whereas cases were cohort members who died from causes other than prostate carcinoma. Comorbidity data were obtained from medical charts (269 subjects). Vital status, age, area of residence, and socioeconomic status information were available. Predictive validity was quantified by the percent variance explained (PVE) over and above age using proportional hazards modeling. RESULTS: The Chronic Disease Score (CDS) (PVE = 11.3%; 95% confidence interval [95% CI], 3.5-22.8%), Index of Coexistent Disease (ICED) (PVE = 9.0%; 95% CI, 2.9-17.9%), Cumulative Illness Rating Scale (CIRS) (PVE = 7.2%; 95% CI, 1.4-17.1%), Kaplan-Feinstein Index (PVE = 4.9%; 95% CI, 0.6-12.8%), and Charlson Index (PVE = 3.8%; 95% CI, 0.3-10.9%) each explained some outcome variability beyond age. PVE differences among indices were not statistically significant. A comorbidity identified at the time of cancer diagnosis was the cause of death in 59.2% of cases (75% for cardiac or vascular causes). CONCLUSIONS: The better-performing, more comprehensive indices (CDS, ICED, and CIRS) would be useful in measuring and controlling for comorbidity in this setting. The CDS was easiest to apply and explained the most outcome variability.

Aged↗
PubMed2006

Stimulation of human breast carcinoma cell invasiveness and urokinase plasminogen activator activity by glucose deprivation.

Glucose deprivation has been shown to increase the invasive and metastatic potential of tumour cells. In the present study, we determined whether the enhanced tumour cell invasiveness resulting from glucose deprivation is linked to increased activity of enzymes required for extracellular matrix degradation. Results of in vitro invasion assays revealed that the invasiveness of human MDA-MB-231 and MCF-7 breast carcinoma cells and MCF-10A1 normal breast cells was, respectively, 3.9-, 2.9-, and 2.1-fold higher when they were incubated under glucose-deprivation (0.2 mM glucose) than when incubated under physiological blood glucose levels (5 mM). This effect of glucose deprivation on invasion correlated with increased urokinase plasminogen activator (uPA) and plasmin activity. Glucose deprivation did not increase the levels of gelatinase and plasminogen activator inhibitor-1 secretion, or the expression of cell-associated uPA receptor. To determine whether the increased invasiveness resulting from glucose deprivation is causally linked to increased uPA activity, invasion assays were conducted using MDA-MB-231 cells incubated in 0.2 mM or 5 mM glucose in the presence of a neutralising anti-uPA antibody. Results revealed that the anti-uPA antibody significantly inhibited invasion in a dose-dependent manner and to a much greater extent in cells incubated in 0.2 mM glucose than in cells incubated in 5 mM glucose. These results suggest that low glucose levels in malignant cancers increase tumour cell invasiveness by stimulating uPA and plasmin activity.

Breast Neoplasms↗
PubMed2006

Parameters affecting urologic complications after major joint replacement surgery.

INTRODUCTION AND OBJECTIVES: Peri-operative bladder management after major arthroplasty procedures remains controversial. The purpose of this study was to assess the risk of urological complications in those patients undergoing hip or knee joint replacement. As well, we identified those factors that may affect the likelihood of developing complications. METHODS: Two hundred and twenty-one consecutive patients receiving a total knee or hip arthroplasty were reviewed. The outcomes measured were prolonged urinary retention, as well as urinary tract infections and the development of a septic prosthesis. Statistical significance of any predisposing factors identified was determined using a two-tailed Fisher exact test. RESULTS: Urological complications in the cohort were common at 47%, with patients having hip arthroplasty being at higher risk (p < 0.03). Despite this there was a low incidence of documented infections. Increased rates of urinary retention were identified in those who received intrathecal narcotics (p < 0.02), as well as those who suffered from hypertension (p < 0.05). Gender and anesthetic techniques (general or regional) did not affect the rate of complications. There was a decrease in urological complications when bladder management included peri-operative catheterization rather than expectant management. CONCLUSIONS: Bladder management is a significant problem for patients after hip and knee arthroplasty as urinary retention was identified in almost half of the patients. Parameters that may identify those with higher risks include patients with hypertension and those who receive intrathecal narcotics. In high-risk patients, the practice of utilizing a catheter peri-operatively may decrease the risk of multiple post-operative catheterizations without increasing the rate of infections.

Arthroplasty, Replacement, Hip↗
PubMed2005

A population-based study of the waiting times for prostatectomy in Ontario.

INTRODUCTION AND OBJECTIVE: Despite the high incidence of prostate cancer in Canada, there is currently limited information describing how these patients are being managed. The aim of this study was to review the surgical waiting times for radical prostatectomy in Ontario, utilizing existing population-based cancer databases, and to describe factors associated with prolonged waiting times. METHODS: This is a retrospective, population-based, observational study of men diagnosed with prostate cancer in Ontario between 1980 and 2000. The sources of data include the Ontario Cancer Registry linked to hospital discharge data, as well as census data from Statistics Canada. Study variables include age, county of residence, teaching hospital status, hospital surgical volume, area-level median household income and cause-specific survival. Waiting times were compared across study variables using univariate and graphical methods. Survival was compared across geographic regions with differing average wait times. RESULTS: We identified 9524 men treated with radical prostatectomy in Ontario over the study period and found the percentage of all patients with the disease who were treated surgically increasing from 3% to 20% over the last 2 decades. The overall time to prostatectomy has almost doubled with a median waiting time of 55 days in earlier eras to 91 days in 1996-2000. A few counties had significantly different wait times, whereas age and socio-economic factors were not associated with wait times across most eras. In the most recent eras, acute care hospitals and hospitals with higher surgical volumes had significantly higher waiting times (up to 20 days longer in 1996-2000, p<0.0001). Patients living in regions with the shortest wait times had statistically significant worse survival (p=0.02), implying that triaging has a greater impact than the potential effect of prolonged waits. CONCLUSIONS: The observed increases in waiting times for radical prostatectomy from this study are similar to the known increases in waiting times for radiotherapy. This increased time to treatment is an illustration of the stress on the health care system in Ontario.

Aged↗
PubMed2004

Growth characteristics of renal cortical tumors in patients managed by watchful waiting.

OBJECTIVE: To characterize tumor growth of patients managed conservatively for renal cell carcinoma. METHODS: Patients electing conservative management of radiographically determined renal cell carcinomas were referred to a surveillance database. Exclusion criteria consisted of locally advanced disease (>T2) and those with metastatic disease. Clinical follow-up included renal imaging with ultrasound or computed tomography at least every 6 months. RESULTS: Twenty-two patients were originally managed conservatively, two of whom subsequently underwent nephrectomy because of rapid tumor growth. Mean follow-up was 26 months. Mean tumor volume and diameter at presentation was 62.4 cc and 4.08 cm respectively. Overall tumor growth was 24 cc/year by volume or .86 cm/year diameter. CONCLUSIONS: Given the stage migration of incidentally detected renal masses, the natural history of these tumors remains incomplete. Overall tumor growth in selected populations appear to be slow even in those diagnosed with larger masses. These data may be useful in counseling patients and directing further trials on conservative therapy for renal cell carcinoma.

Aged↗
PubMed2003

Treatment of phimosis with topical steroids in 194 children.

PURPOSE: Topical steroids have been advocated as an effective economical alternative to circumcision in boys with phimosis. We evaluated the effectiveness of topical steroid therapy as primary treatment in 194 patients with phimosis. METHODS: Between January 1996 and November 2000, 228 boys 16 years old or younger were referred for consideration of circumcision. When intervention was determined to be necessary, a 6-week course of topical steroids was used as primary treatment. Efficacy of treatment was evaluated at 3 months from initiation of therapy. RESULTS: Of the 228 patients 15 had such a mild degree of phimosis that no intervention was believed to be necessary, 19 were scheduled directly for circumcision due to cosmetic reasons, parent wishes, or severe phimosis with associated voiding problems and the remaining 194 received topical steroids as primary treatment. Of these 194 patients 25 had coexisting balanitis and 4 had a history of urinary tract infection. Conservative treatment was successful in 87%, 88% and 75% of patients with phimosis alone, coexisting balanitis and history of urinary tract infection, respectively. Overall, circumcision was avoided in 87% of patients treated with topical steroids. CONCLUSION: Topical steroids are becoming the standard conservative measure for treating phimosis. Our study supports this trend, with an overall efficacy of 87%.

Administration, Topical↗
PubMed2003

Comparison of viral vectors: gene transfer efficiency and tissue specificity in a bladder cancer model.

PURPOSE: Gene transfer efficiency and specific cell targeting of vectors is a major obstacle in preclinical studies of gene therapy for malignant disease. Previous attempts at gene transfer in bladder cancer models have resulted in variable urothelial and tumor transgene expression after intravesical administration of recombinant viral vectors. In the current study we compared the gene transfer efficiencies of different viral vectors. MATERIALS AND METHODS: We compared the gene transfer efficiencies of the viral vectors replication-deficient adenovirus, attenuated vaccinia virus (NYVAC) and canarypox virus (ALVAC) in vitro and in an orthotopic murine bladder cancer model. We used beta-galactosidase and firefly luciferase reporter gene expression to compare gene transfer efficiency. RESULTS: Significantly higher transgene expression was observed in vitro when these cells were infected with NYVAC or ALVAC compared with adenovirus vectors. Similarly the efficiency of adenovirus vectors to transfer genetic material into bladder urothelium and orthotopic bladder tumors was inferior to that of ALVAC and NYVAC vectors, which interestingly appeared to have a predilection to infect the orthotopic tumor. Analysis of the expression of coxsackie-adenovirus receptor using reverse transcriptase-polymerase chain reaction revealed the bladder tumor cell lines were lacking this adenovirus receptor. While adenovirus transferred genes poorly to normal bladder, coxsackie-adenovirus receptor expression was high in bladder tissue. CONCLUSIONS: The viral vectors examined in these experiments resulted in significantly different gene transfer in the orthotopic bladder cancer model, underscoring the importance of vector selection in gene therapy protocols.

Adenoviridae↗
PubMed2003

Hypoxia induced resistance to doxorubicin in prostate cancer cells is inhibited by low concentrations of glyceryl trinitrate.

PURPOSE: Tumor hypoxia has been correlated with metastasis and resistance to chemotherapy. Hypoxia is also associated with human prostate cancers, which are highly resistant to chemotherapy. We hypothesized that hypoxia contributes to chemoresistance in prostate cancer cells and this hypoxia induced chemoresistance can be inhibited by low concentrations of nitric oxide (NO) mimetics. MATERIALS AND METHODS: Human PC-3 and mouse TRAMP-C2 prostatic adenocarcinoma cells were incubated in 20% or 0.5% O(2) for 12 hours with or without glyceryl trinitrate (GTN) (0.1 nM). This treatment was followed by a 1-hour incubation with doxorubicin and survival was assessed by clonogenic assays. Western blot analysis was used to measure NO synthase levels. The effect of hypoxia and GTN on cell cycle distribution was determined by flow cytometry. RESULTS: Hypoxic pre-incubation of the 2 cell lines resulted in increased survival following exposure to doxorubicin. Co-incubation of PC-3 and TRAMP-C2 cells with GTN (0.1 nM) inhibited the hypoxia induced resistance to doxorubicin. Each cell line expressed all 3 NO synthase isoforms at levels that were not significantly affected by O(2) concentrations. Cell cycle analysis revealed that there was no significant difference in the distribution of PC-3 cells at each stage of the cycle. However, incubation under hypoxia resulted in a small decrease in the number of TRAMP-C2 cells in S-phase. CONCLUSIONS: These findings indicate that NO may have an important role in the regulation of chemosensitivity in prostate cancer cells. Furthermore, the results suggest that GTN administration may represent a means of chemosensitizing prostatic carcinomas.

Adenocarcinoma↗
PubMed2003

A comparative analysis of rapid urine tests for the diagnosis of upper urinary tract malignancy.

OBJECTIVES: To compare the effectiveness of two rapid urine tests fibrinogen/fibrin degradation products FDP (Aura Tek FDP, PerImmune Inc., Rockville, Maryland, USA) and bladder tumor antigen BTA (Bard BTA, Bard Canada Inc., Mississauga, Ontario, Canada) to urinary cytology in establishing the diagnosis of transitional cell carcinoma (TCC) in patients with suspected upper tract malignancy. MATERIALS AND METHODS: In a prospective study, urine samples were collected from 29 patients with abnormalities of the upper tracts highly suspicious for malignancy. Sensitivity and specificity of the BTA and FDP tests were determined and compared to those of cytology. All persons interpreting the individual tests were blinded to the other test results. RESULTS: Of the 29 patients evaluated, 14 were found to have upper tract TCC. The overall sensitivity of FDP, BTA and urinary cytology was found to be 100%, 50% and 29%, respectively. The accuracy of the FDP test was 83% as compared to 62% for BTA and 59% for cytology. CONCLUSION: Urinary cytology lacks sensitivity in the diagnosis of upper tract TCC. This preliminary study suggests that the point-of-care test, FDP, has better test characteristics than urinary cytology. Further evaluation of these tests is warranted for their potential to improve and facilitate the diagnosis of upper tract tumors.

Antigens, Neoplasm↗
PubMed2002

The patient with chronic epididymitis: characterization of an enigmatic syndrome.

PURPOSE: We provide a baseline description of men diagnosed with chronic epididymitis, explore relevant associations that may be important etiological factors and suggest a classification system and specific symptom assessment tool. MATERIALS AND METHODS: Men diagnosed with chronic epididymitis, described as symptoms of discomfort or pain at least 3 months in duration in the scrotum, testicle or epididymis localized to 1 or each epididymis on clinical examination, completed an extensive specific clinical inventory questionnaire. Evaluation included demographics, preceding and concurrent clinical history, duration since diagnosis, associated and previous clinical associations, frequency and severity of prostatitis, voiding and sexual symptoms, specific and general quality of life, and history of investigation and/or treatment for the condition. Volunteers with no past or concurrent history of chronic epididymitis completed similar clinical inventory questionnaires. RESULTS: A total of 50 consecutive men 21 to 83 years old (average age 46) diagnosed with chronic epididymitis who had an average symptom duration of 4.9 years (range 0.25 to 29) were enrolled in the study. The average pain score plus or minus standard deviation was 4.7 +/- 2.1 (range 0 to 10). Of the men 16% were reasonably satisfied with their quality of life. Although 66% of the patients thought about the symptoms some or a lot, in only 30% did symptoms keep them from doing the kinds of things that they would usually do. The most common previous therapies recollected by the patients were antibiotics (74%) and anti-inflammatory agents (36%). At the time of the survey 26% of the men were on some type of pain medication. There were no significant epidemiological, sexual, medical or associated factors that differentiated patients with chronic epididymitis from the 20 controls. A chronic epididymitis classification system (inflammatory, obstructive and epididymalgia) and a symptom assessment index based on assessing pain and quality of life-impact was developed. CONCLUSIONS: This comprehensive clinical survey of men diagnosed with chronic epididymitis is the first step for defining and characterizing this particular population. Development of a classification system and symptom assessment index may direct further studies in the etiology, epidemiology and management of chronic epididymitis.

Adult↗