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D G McLeod

Publications and source records attributed to D G McLeod.

At least 19 recordsLinked to original sources
PubMed1996

Defining the role of antiandrogens in the treatment of prostate cancer.

OBJECTIVES: Although antiandrogens have been used as monotherapy and in combination with other treatment modalities for management of metastatic prostate cancer, their major role to date has been one in which they are used in conjunction with surgical or medical castration for treatment of Stage D (T4/Nx/M1) carcinoma of the prostate. The widespread use of prostate-specific antigen (PSA) is increasing the number of men who are diagnosed with earlier stages of this disease, thus resulting in a greater number of definitive therapeutic procedures. Also, PSA has become the primary modality for following these patients after definitive treatment. Because the use of PSA results in the discovery of lower volume of disease and in discerning earlier recurrence of disease, the question arises as to whether an antiandrogen alone could be an adequate treatment in both neoadjuvant and adjuvant settings. METHODS: As data accumulate that point to the efficacy of combined androgen blockade in metastatic disease, a protocol has been developed to test the hypothesis of intermittent combined treatment in patients who present with minimal disease and good performance status. In this study, the antiandrogen bicalutamide will be used in combination with the luteinizing hormone-releasing hormone (LHRH) analogue goserelin acetate. Also, short-term combined androgen ablation continues to be investigated prior to both radiation therapy and radical prostatectomy for localized disease. RESULTS: Two groups of patients are ideal candidates for the use of antiandrogen monotherapy following radical prostatectomy: those whose PSA values do not fall to undetectable levels and the far larger group of men who have capsular penetration or positive surgical margins with nondetectable PSA levels. Protocols have been developed to assess the clinical potential of bicalutamide as the sole adjuvant therapy in these postprostatectomy patients, based in no small part on the relative paucity of side effects of this antiandrogen. CONCLUSIONS: Antiandrogens in general, and bicalutamide in particular, are poised to play an increasing role in the treatment of all stages of adenocarcinoma of the prostate. The safety profile of bicalutamide, combined with its long half-life, resulting in once-a-day dosing, makes it an ideal choice for clinical trials evaluating an antiandrogen, either alone or combined with reversible medical castration, in earlier stages of prostate cancer as well as in various combination regimens in metastatic disease.

Androgen Antagonists↗
PubMed1995

Prostate-specific antigen values at the time of prostate cancer diagnosis in African-American men.

OBJECTIVE: To determine if African-American men with newly diagnosed prostate cancer (PC) have higher pretreatment serum prostate-specific antigen (PSA) values after adjustment for clinical stage, age, and tumor grade, and to determine if any difference detected is related to tumor volume difference. DESIGN: Consecutive case series of newly diagnosed PC patients between January 1990 and September 1994 and cohort analytic study of PC patients treated by radical prostatectomy (RP) and who had whole-mount pathologic tumor volume assessment between May 1993 December 1994. SETTING: Tertiary care military medical center. PATIENTS: A total of 541 evaluable newly diagnosed PC patients (408 white and 133 black) having pretreatment PSA assessment at one laboratory; 91 patients undergoing RP had whole-mount tumor volume analysis. INTERVENTIONS: Medical record review for pretreatment PSA value, race, tumor grade, clinical stage, and age, as well as whole-mount pathologic assessment of RP specimen and measurement of tumor volume. MAIN OUTCOME MEASURES: The PSA differences between black and white PC patients with adjustments for age, biopsy tumor grade (Gleason score), and clinical stage (TNM stage); PSA differences between black and white PC patients undergoing RP with adjustment for age, RP grade, clinical stage, and tumor volume. RESULTS: The mean (geometric) PSA value for 133 black men was 14.00 ng/mL compared with 8.29 ng/mL for 408 white men (P < .001). The black patients had higher PSA values across all stage, grade, and age categories. The racial difference in PSA levels remained statistically significant when stage, grade, and age were simultaneously controlled for (P < .001). Multivariable odds ratio testing revealed that even after adjustment for stage, grade, and age, black patients were 2.2 times as likely as white patients to have a PSA value greater than 10.0 ng/mL (95% confidence interval, 1.3 to 3.6). Tumor volume (geometric mean) was 5.42 cm3 and 2.10 cm3 for black and white RP patients, respectively (P = .002). Across all clinical stages (T1a to T3), black men had tumor volumes 1.3 to 2.5 times greater than those of white men. Multivariable analysis of covariance revealed that tumor volume and stage of disease were important predictors of PSA level, but race, grade, and age were not. (The percentage of white and black patients whose cancer was detected by screening [75.4% vs 70.4%] or who had symptoms [37.7% vs 29.6%] was not significantly different.) CONCLUSIONS: As a group, African-American men with newly diagnosed PC have higher PSA values at initial diagnosis than white men. This PSA difference appears to be due to larger tumor volumes within clinical (TNM) stage categories among black patients. Elevated PSA value was a surrogate for larger tumor volume in this cohort of black men. This stage-for-stage tumor volume disparity even in an equal-access health care environment should prompt further study of screening behavior and/or biological differences of PC in the black population.

Age Distribution↗
PubMed1995

Effect of exogenous testosterone replacement on prostate-specific antigen and prostate-specific membrane antigen levels in hypogonadal men.

Previous studies have suggested that serum prostate-specific antigen (PSA) levels are under androgenic influence, especially in patients with adenocarcinoma of the prostate. PSMA (prostate-specific membrane antigen) is thought to reflect hormonal or clonal resistance or an independence with respect to testosterone regulation. The influence of testosterone on serum PSA expression in normal men is not clear. We studied the effect of exogenous testosterone administration on the serum levels of PSA and PSMA in hypogonadal men. Serial serum PSA, serum PSMA by Western blot, and serum total testosterone levels were obtained at intervals of every 2-4 weeks in 10 hypogonadal men undergoing treatment with exogenous testosterone, delivered as testosterone enanthate injection or by testosterone patch. Linear and quadratic orthogonal polynomial scores were calculated for PSMA, PSA, and testosterone. A 2-tailed, paired t-test failed to demonstrate a significant correlation between serum PSA (linear P = 0.432, quadratic P = 0.290) or PSMA (linear P = 0.162, quadratic P = 0.973) and serum testosterone levels. This study suggests that in hypogonadal men, neither PSMA nor PSA expression is testosterone-dependent.

Adult↗
PubMed1995

Prostate cancer.

Explore the source record for details and available documents.

Humans↗
PubMed1995

Postoperative myocardial infarction after radical cystoprostatectomy masked by patient-controlled analgesia.

We present a case report where improper patient use of patient-controlled analgesia (PCA) in the postoperative period resulted in a significant delay in diagnosis of a postoperative myocardial infarction. Despite its excellent safety record and documented efficacy in controlling pain, PCA does have its limitations and can present a danger to the patient if operator error, patient error, or mechanical errors occur. Although the latter is rarely of concern, the two former possibilities exist. Other reported complications of PCA are discussed. We recommended that physicians, when considering use of patient-controlled anesthesia, discuss the qualitative and quantitative aspects of pain associated with the particular type of surgery performed to avoid missed postoperative complications.

Adenocarcinoma↗
PubMed1995

Estimating the cost effectiveness of total androgen blockade with flutamide in M1 prostate cancer.

OBJECTIVES: Although combined androgen blockade with flutamide plus medical or surgical castration is effective in metastatic prostate cancer, debate exists over whether it is cost effective. METHODS: Decision analysis model of hypothetical cohorts of 70-year-old men presenting with metastatic prostate cancer, using a societal perspective, calculated anticipated survival and incremental cost per life-year gained. Time to progression and survival rate were from the Intergroup 0036 trial. Costs were based on Medicare data and wholesale drug pricing. Flutamide was estimated to reduce the relative risk of progressive disease by 25% (range, 0 to 50%). Costs and survival benefits were discounted at a 5% annual rate. RESULTS: In our model for minimal disease, median survival increased from 42.3 to 49.4 months with flutamide and average survival by 5.2 months at an incremental cost of $25,300 per life-year gained. If the efficacy were as high as 50%, the benefit would be 12 months at a cost of $13,700 per life-year gained. At a 10% efficacy, the benefit would be 1.9 months at a cost of $60,900 per life-year gained. For severe disease, the model estimated the median survival increased from 29.5 to 34.3 months with flutamide and average survival by 4.0 months at an incremental cost of $20,000 per life-year gained. At worst-case 10% efficacy, the benefit decreased to 1.5 months at an incremental cost of $47,500 per life-year gained. Total costs for patients treated with an orchiectomy and flutamide compared to leuprolide alone were similar if severe disease was present and actually lowered costs if there was minimal disease. CONCLUSIONS: Flutamide has an incremental cost effectiveness more favorable than most accepted therapies. If drug costs are covered under health care reform, flutamide should be initiated and covered for all good performance status patients.

Aged↗
PubMed1995

Recombinant adenovirus vector expressing wild-type p53 is a potent inhibitor of prostate cancer cell proliferation.

OBJECTIVES: A recombinant adenovirus vector (AdWTp53) expressing wild-type p53 was evaluated for its cell growth inhibitory effects on metastatic human prostate cancer cells. METHODS: Human prostate cancer cells LNCaP, DU145, PC3, 1LN, and DUPro-1 were infected with AdWTp53 vector and expression of exogenous p53 in these cells was analyzed by immunoprecipitation and western blot assays. The cell growth inhibitory effects of AdWTp53 were determined by counting cell number on a hemocytometer or by crystal violet staining of cells after infection with AdWTp53. The p53-regulated gene WAF1 and DNA fragmentation were also analyzed in prostate cancer cells infected with AdWTp53. RESULTS: High levels of the AdWTp53 vector-derived p53 protein were present in metastatic prostate cancer cells, and the p53-regulated gene WAF1 was induced in these cells. Infection of these tumor cell lines with AdWTp53 vector resulted in severe growth inhibition and cell death in comparison to untreated or control adenovirus vector-infected cells. Furthermore, fragmentation of genomic DNA, a property associated with apoptosis, was also observed in prostate cancer cells infected with AdWTp53. CONCLUSIONS: AdWTp53 vector exhibited a potent inhibitory effect on the growth of all of human metastatic prostate cancer cells, and both cytostatic and cytotoxic effects of AdWTp53 were observed. The induction of p53-regulated gene WAF1 in AdWTp53-infected prostate cancer cells suggests the involvement of cellular p53 pathway in the cell growth inhibition. These results provide a molecular basis for further evaluation of antitumorigenic effects of AdWTp53 vector in animal models of prostate cancer.

Adenoviruses, Human↗
PubMed1995

Intravesical recombinant tumor necrosis factor in the treatment of superficial bladder cancer: an Eastern Cooperative Oncology Group study.

We tested and proved the safety of recombinant human tumor necrosis factor given intravesically weekly for 11 weeks (dwell time 2 hours) for the treatment of superficial bladder cancer in 8 men and 1 woman 46 to 87 years old (mean age 69 years). Cohorts of 3 patients received 200, 400 and 1,000 micrograms. recombinant human tumor necrosis factor. The maximal tolerated dose was not achieved. There were 9 episodes of urological symptoms, 8 of flu-like symptoms, 4 of headache and 3 of chest tightness. Hematological and gastrointestinal toxicities were minor, and no renal toxicity was encountered. Recombinant human tumor necrosis factor was safe to administer at doses up to 1,000 micrograms. We hope that recombinant human tumor necrosis factor in conjunction with other antitumor agents will lead to a new, effective treatment for superficial bladder cancer.

Administration, Intravesical↗
PubMed1995

Controversies in the treatment of prostate cancer with maximal androgen deprivation.

The concept of maximal androgen deprivation (MAD) has become the accepted therapy for metastatic prostate cancer. MAD is also under investigation as neoadjuvant therapy prior to radical prostatectomy and radiation therapy. Innovative new approaches, such as intermittent androgen deprivation and new combination therapies, will emerge over the next decade.

Androgen Antagonists↗
PubMed1994

Frequent detection of codon 877 mutation in the androgen receptor gene in advanced prostate cancers.

Prostatic tissue specimens derived from transurethral resections of patients with metastatic prostate cancer were analyzed for genetic alterations in the hormone-binding domain of the androgen receptor (AR) gene. Direct sequencing of the polymerase chain reaction-derived DNAs of 6 of 24 specimens revealed a codon 877 mutation (ACT-->GCT, Thr-->Ala) in the hormone-binding domain of the AR gene. This same AR mutation has been reported previously in a metastatic prostate cancer cell line, LNCaP, where this mutation confers upon the AR an altered ligand-binding specificity which is stimulated by estrogens, progestagens, and antiandrogens. It is possible that analogous to an activated/altered growth factor receptor oncogene, codon 877 mutant AR with altered ligand binding may provide a selective growth advantage in the genesis of a subset of advanced prostate cancer. Although estrogens are used infrequently, antiandrogens are used increasingly in hormonal therapy for patients with advanced prostate cancer. The stimulatory effect of these therapeutic agents on the codon 877 mutant AR further suggests that this frequently observed AR mutation may contribute to the treatment refractory disease.

Codon↗
PubMed1994

Thymic hyperplasia in newly diagnosed testicular germ cell tumors.

Thymic hyperplasia has been reported as a rebound phenomenon in children and young people, most commonly following chemotherapy for cancer. Although thymic hyperplasia has been documented in testis cancer patients after chemotherapy, to our knowledge it has not previously been reported in newly diagnosed cases before systemic therapy. A retrospective review of 362 testicular germ cell tumor patients treated at a single tertiary care center between January 1, 1980 and August 1, 1993 was performed, with special review of 221 who underwent computerized tomography staging of the chest. Thymic hyperplasia was detected in 4 of the 221 patients (1.8%) including 3 of 100 (3.0%) with seminoma and 1 of 121 (0.8%) with nonseminoma. All 4 patients had low stage (I or IIa) disease with a delay in diagnosis (5 to 24 weeks) and thymic hyperplasia was discovered at staging evaluation 18 to 37 days after orchiectomy but before other cancer therapy was administered. Of the 4 patients 2 underwent thymectomy, revealing histological thymic rebound hyperplasia. All 4 patients had no evidence of recurrence at 1 to 54 months after treatment. In addition to the well known post-chemotherapy phenomenon, thymic hyperplasia may also occur in nonsystemically treated, newly diagnosed testicular cancer patients. An anterior mediastinal mass in an otherwise low stage newly diagnosed testicular cancer patient may represent thymic hyperplasia and not necessarily metastatic disease.

Adult↗
PubMed1994

Clinically detected carcinoma of the prostate treated by radical prostatectomy in a 29-year-old man.

Prostate cancer is rare in young adults and when clinically detected it has been invariably locally or distantly advanced, undifferentiated and exhibiting aggressive behavior. To our knowledge no previous report documents clinically detected and localized disease amenable to curative surgery in a young adult. We report on a 29-year-old man with clinically detected, moderately differentiated adenocarcinoma of the prostate who was treated by nerve sparing radical retropubic prostatectomy. The patient was disease-free and morbidity-free 30 months after treatment.

Adenocarcinoma↗
PubMed1994

Retroperitoneal imaging with third and fourth generation computed axial tomography in clinical stage I nonseminomatous germ cell tumors.

OBJECTIVES: To examine the accuracy rate of abdominal staging using third and fourth generation computed tomography (CT) scanning in clinical Stage I testicular nonseminoma patients. METHODS: Between January 1985 and August 1993, 57 patients presented to our center with clinical Stage I testicular nonseminoma. Retroperitoneal computed tomographic staging studies were interpreted to be normal preoperatively in the entire group. In addition, tumor marker values were normal or returned to normal postorchiectomy within the appropriate half-life intervals. All patients were subjected to radical or modified retroperitoneal lymph node dissection (19% and 72%, respectively). Original abdominal CT scans (preretroperitoneal lymph node dissection) were available for blinded retrospective re-review in 16 cases (7 pathologic Stage II, 9 pathologic Stage I). RESULTS: Nineteen of 57 (33%) patients were upstaged at surgery including 6 patients (11%) who demonstrated II B volume disease. Third and fourth generation CT scanning of the retroperitoneum yielded a 66% accuracy rate in this population. Six out of 7 pathologic Stage II pre-lymph node dissection abdominal CT scans that were available for blinded re-review revealed nonpathologic nodes by size criteria in the primary landing zone for the corresponding original tumor. CONCLUSIONS: Our data suggests that for clinical Stage I nonseminoma in the 1985 to 1993 era, undue reliance was placed on a less than ideal staging test. The 33% false-negative rate reported showed no improvement over earlier reports and reaffirms concern for relying solely on third or fourth generation CT imaging of the retroperitoneum in the staging of clinical Stage I nonseminomatous germ cell tumor (NSGCT) patients. The presence of any number of lymph nodes in the expected primary landing zone, regardless of size, should raise serious suspicion for occult nodal disease.

False Negative Reactions↗
PubMed1994

Efficacy of radiographic chest imaging in patients with testicular cancer.

OBJECTIVE: To determine the efficacy of computed tomography of the chest (CTC) and plain radiograph (CXR) in the initial staging process of testicular germ cell tumors. METHODS: The medical records of 362 patients with testicular germ cell tumor treated at our center between January 1980 and August 1993 were reviewed with particular attention to initial chest screening studies. Two hundred one patients had both CXR and CTC, 24 CXR alone, and 20 CTC alone during initial staging. One hundred seventeen patients were excluded from analyses because of undergoing whole lung tomography (92), unknown staging (19), or inadequate follow-up (6). Analysis included findings based on abdominal staging results using computed tomography of the abdomen (CTA). RESULTS: Of the 201 patients who had both CTC and CXR, 117 (58.2%) had nonseminomas (NSGCT) and 84 (41.8%) had seminomas (SEM). Among the patients with NSGCT, 21 (17.9%) had chest metastasis, 16 (76.2%) of which were detected by CXR. The 5 that were missed on CXR had significant retroperitoneal disease documented by CTA and the knowledge of chest metastases potentially altered therapy in 2 patients. Only 2 of 84 (2.4%) patients with SEM had metastatic chest disease and both were identified by CXR. False-positive CTC following negative CXR resulted in costly and sometimes invasive additional procedures in 10 patients with NSGCT and 6 with SEM. None of the CXR-only patients had adverse consequences from the solitary study (at least 1 year follow-up). The CTC-only patients could have undergone CXR only and had similar outcome. CONCLUSIONS: CXR alone is preferable for initial chest staging in all patients with SEM and in patients with NSGCT with negative findings on CTA. CTC remains of slight benefit for patients with clinical Stage II and greater NSGCT and to evaluate further suspicious CXR findings in any patient, although it appears not to be necessary in patients who have clinical Stage I disease determined by CTA. These findings have important cost-saving implications.

False Negative Reactions↗
PubMed1994

Immunohistologic detection of prostate cancer pelvic lymph node micrometastases: correlation to preoperative serum prostate-specific antigen.

OBJECTIVE: To test the hypothesis that prostate cancer lymph node (LN) micrometastases, undetected by standard histology, might be found using sensitive immunohistologic methods and may correlate to preoperative prostate-specific antigen (PSA) levels. METHOD: Archival paraffin blocks of pelvic lymphadenectomy specimens from radical prostatectomy were blindly submitted for immunostaining using pan-cytokeratin monoclonal antibody SB-3, as well as antibodies directed against PSA. Automated immunostaining was performed on a Ventana Medical Systems 320 immunostainer. As a positive control, 7 cases with known nodal metastases by standard histology were blindly analyzed and all has detectable micrometastases by this methodology. RESULTS: For 13 patients with PSA < 10.1 (8%) had LN micrometastases detected. For 10 patients with PSA between 10 and 20 and for 9 patients with PSA > 20, no occult metastases were detected. We did find previously undetected prostate cancer (CaP) LN micrometastases in 1 of 32 (3%) clinically localized prostate cancer patients who had undergone radical prostatectomy. In many LNs, cytokeratin stains cross-reacted and stained individual plasma cells, whereas in the positive metastatic case, a cluster/nest of CaP cells were reactive. To the unfamiliar observer, the pitfall of false-positive results because of nonspecific cytokeratin staining must be considered. These results are in exact agreement with another recent study which also found only a 3 percent incidence of unsuspected pelvic lymph node micrometastases in clinically localized CaP utilizing similar methods. CONCLUSIONS: Our hypothesis was not substantiated: LN micrometastases were uncommon and did not correlate to serum PSA. Unlike studies with breast cancer, occult micrometastatic nodal disease not appreciated by standard methods appears to be uncommon in clinically localized prostatic carcinoma.

Humans↗