J. Kay Dunn

The Pathological Features and Prognosis of Prostate Cancer Detectable With Current Diagnostic Tests

The discrepancy between the high prevalence of prostate cancer found at autopsy and the low incidence of clinical cancer prompted a study to determine whether the new diagnostic tests, that is ultrasonography and serum prostatic specific antigen (PSA) levels, detect prostate cancer at an earlier stage than the traditional test, digital rectal examination, without detecting a larger proportion of clinically unimportant cancer. Clinically detected cancer treated by radical prostatectomy (306 cases) and incidental cancer found in cystoprostatectomy specimens (90) were categorized into 3 groups by the volume, grade, extent of the cancer and outcome of treatment: clinically unimportant tumor (0.5 cm.3 or less, Gleason grades 1 to 3 and confined to the prostate), clinically important curable cancer (more than 0.5 cm.3 or grade 4 or 5 and confined, or with microscopic extracapsular extension) or advanced disease (extensive extracapsular extension, seminal vesicle invasion or lymph node metastases). Of 306 clinically detected tumors 9% were unimportant and 29% were advanced. In contrast, incidental cystoprostatectomy disease was either unimportant (78%) or curable (22%) and no tumor was advanced (p < 0.0005). Cancer detectable by digital rectal examination, ultrasonography or PSA was distributed similarly among the 3 groups. Impalpable cancer detected by PSA was less likely to be advanced (11%) than cancer detected by digital rectal examination (34%, p = 0.01) but no more likely to be unimportant (13% versus 8%). Of 29 tumors detected only by systematic biopsies because of an elevated PSA level only 4% were advanced, while 17% were unimportant. Cancer detectable with each of the available diagnostic tests was similar and differed distinctly from that found incidentally in cystoprostatectomy specimens. The detection of impalpable cancer by PSA or ultrasound decreased the proportion of advanced tumor detected without increasing significantly the detection of unimportant disease.

A Comparison of the Morphological Features of Cancer Arising in the Transition Zone and in the Peripheral Zone of the Prostate

To determine the characteristics of transition zone and peripheral zone prostate cancer, we examined a series of 42 stage A and 54 stage B radical prostatectomy specimens with particular attention to the number of separate foci of cancer, zone of origin, volume and grade of each focus, and presence of severe intraductal dysplasia (high grade prostatic intraepithelial neoplasia), extra-capsular extension and seminal vesicle invasion associated with cancer in each zone. We found that there were fundamental differences between transition zone and peripheral zone cancers, and that the features that characterize these tumors were apparent in stages A and B disease. Although the total tumor burden was similar in stages A (3.98 cc) and B (4.56 cc) disease, stage A cancer tended to be multifocal (3.1 tumors per prostate) and more diffuse. While 81% of stage A prostate specimens contained a tumor of transition zone origin and 93% had cancer of peripheral zone origin, transurethral resection of the prostate sampled a transition zone cancer in 77% and a peripheral zone cancer in 31% (8% had both types). Stage B cancer tended to be more focal (2.3 cancers per prostate). All stage B prostate specimens contained a peripheral zone cancer and 43% had a transition zone cancer as well. In only 1 stage B cancer patient was the transition zone tumor the palpable or index cancer. In stages A and B disease, peripheral zone tumors were less well differentiated (median Gleason sum 6 and 7) than transition zone tumors (5 and 5, respectively) and more likely to extend through the capsule (44% versus 11%). Seminal vesicle invasion arose from 19% of the peripheral zone but none of the transition zone cancers. Peripheral zone tumors were almost always (93%) associated with high grade prostatic intraepithelial neoplasia, while none of the transition zone cancers was so associated. For peripheral zone disease there was a moderate correlation between volume and grade (tau = 0.46, p less than 0.001) so that the larger the tumor the higher the Gleason sum but within transition zone disease this correlation was poor (tau = 0.23) and not statistically significant (p greater than 0.05). Extracapsular extension occurred at a smaller volume with peripheral zone cancer (mean 3.86, minimum 0.06 cc) than transition zone cancer (mean 4.98, minimum 0.39 cc). Cancer that arises in the transition zone appears to have a different histogenesis, is associated with more favorable pathological features and may have less malignant potential than tumors that arise in the peripheral zone.

Influence of Low HDL on Progression of Coronary Artery Disease and Response to Fluvastatin Therapy

BACKGROUND--Patients with coronary artery disease (CAD) commonly have low HDL cholesterol (HDL-C) and mildly elevated LDL cholesterol (LDL-C), leading to uncertainty as to whether the appropriate goal of therapy should be lowering LDL-C or raising HDL-C. METHODS AND RESULTS--Patients in the Lipoprotein and Coronary Atherosclerosis Study (LCAS) had mildly to moderately elevated LDL-C; many also had low HDL-C, providing an opportunity to compare angiographic progression and the benefits of the HMG-CoA reductase inhibitor fluvastatin in patients with low versus patients with higher HDL-C. Of the 339 patients with biochemical and angiographic data, 68 had baseline HDL-C <0.91 mmol/L (35 mg/dL), mean 0.82+/-0.06 mmol/L (31. 7+/-2.2 mg/dL), versus 1.23+/-0.29 mmol/L (47.4+/-11.2 mg/dL) in patients with baseline HDL-C >/=0.91 mmol/L. Among patients on placebo, those with low HDL-C had significantly more angiographic progression than those with higher HDL-C. Fluvastatin significantly reduced progression among low-HDL-C patients: 0.065+/-0.036 mm versus 0.274+/-0.045 mm in placebo patients (P=0.0004); respective minimum lumen diameter decreases among higher-HDL-C patients were 0. 036+/-0.021 mm and 0.083+/-0.019 mm (P=0.09). The treatment effect of fluvastatin on minimum lumen diameter change was significantly greater among low-HDL-C patients than among higher-HDL-C patients (P=0.01); among low-HDL-C patients, fluvastatin patients had improved event-free survival compared with placebo patients. CONCLUSIONS--Although the predominant lipid-modifying effect of fluvastatin is to decrease LDL-C, patients with low HDL-C received the greatest angiographic and clinical benefit.

Cigarette smoking and othervascular risk factors in vasculogenic impotence

A total of 132 consecutive patients with erectile impotence underwent extensive evaluation, including vascular evaluation with intracavernous injection of papaverine and penile duplex ultrasonography, to determine the etiology of impotence. Three vascular risk factors, smoking, diabetes mellitus and hypertension, were investigated for their impact on vasculogenic impotence. The patients were divided into four groups: one with no risk factors, one with one vascular risk factor, one with two vascular risk factors, and one with all three risk factors. The results of penile vascular evaluation in these patient groups were compared. The incidence of penile vascular impairment was found to be higher in patients with one vascular risk factor than in those with none. The proportion of abnormal penile vascular findings significantly increased as the number of risk factors increased. These data confirm the important role of vascular risk factors, smoking, diabetes mellitus, and hypertension, in the pathogenesis of organic impotence.

Nonsurgical Septal Reduction Therapy for Hypertrophic Obstructive Cardiomyopathy: One-Year Follow-up

OBJECTIVE The objective of this study is to evaluate the one-year outcome of the first 50 patients who underwent nonsurgical septal reduction for symptomatic hypertrophic obstructive cardiomyopathy at our institution. BACKGROUND Left ventricular outflow tract obstruction is an important determinant of clinical symptoms in patients with hypertrophic obstructive cardiomyopathy. Nonsurgical septal reduction is a new therapy that has been shown to result in left ventricular outflow tract gradient reduction and resolution of symptoms immediately after the procedure and on midterm follow-up. METHODS Fifty patients with hypertrophic obstructive cardiomyopathy who underwent nonsurgical septal reduction at our institution and completed 1-year follow-up are described. Complete history, physical examination, two-dimensional echocardiography with Doppler and exercise treadmill testing have been analyzed. RESULTS The mean age of the study group was 53 +/- 17 years. All patients had refractory symptoms before enrollment. Ninety-four percent had class III or IV New York Heart Association class symptoms at baseline compared to none at 1 year (p < 0.001). The exercise duration increased by 136 s at 1 year (p < 0.021). Only 20% of patients were either receiving beta-blockers or calcium-channel blockers on follow-up. The resting left ventricular outflow tract gradient decreased from 74 +/- 23 mm Hg to 6 +/- 18 mm Hg (p < 0.01) and from 84 +/- 28 mm Hg to 30 +/- 33 mm Hg (p < 0.01) in patients with dobutamine-provoked gradient at one year. These changes are associated with decreased septal thickness and preserved systolic function. CONCLUSION Nonsurgical septal reduction therapy is an effective therapy for symptomatic patients with hypertrophic obstructive cardiomyopathy with persistence of the favorable outcome up to one year after the procedure.

Frequency of apoptotic bodies positively correlates with Gleason grade in prostate cancer

Tissue samples from patients with carcinoma of the prostate of various Gleason grades were examined for the frequency of apoptotic bodies. Apoptotic bodies were scored by morphometric methods using hematoxylin-eosin (HE)-stained sections from surgical specimens of prostate cancer. Non-neoplastic prostate tissue adjacent to foci of cancer showed a very low frequency of apoptotic bodies. Significantly larger numbers of apoptotic bodies were observed in the areas of carcinoma than in the non-neoplastic control tissues, regardless of Gleason grade. Interestingly, a positive correlation was noted between apoptotic bodies and increasing Gleason grade. The positive correlation suggests that increased programmed cell death is a feature of the increasing malignant potential that is associated with higher Gleason grade in prostate cancer.

Electrocardiographic findings in Rett syndrome : an explanation for sudden death ?

Girls with Rett syndrome had significantly longer corrected QT intervals (p < 0.001) and more T-wave abnormalities (p < 0.001) than were found in age-matched healthy girls. With advancing stages of the syndrome, the proportion of corrected QT interval prolongations and T-wave changes increased. The findings suggest a possible cardiac basis for sudden, unexpected death in Rett syndrome.

Apolipoprotein E genotypes and response of plasma lipids and progression–regression of coronary atherosclerosis to lipid-lowering drug therapy ☆

OBJECTIVES We sought to examine the association of apolipoprotein (apo) E genotypes with baseline plasma lipid levels and severity of coronary artery disease (CAD), as well as the response to treatment with fluvastatin in the Lipoprotein and Coronary Atherosclerosis Study (LCAS). BACKGROUND Apo E genotypes have been associated with plasma lipid levels and CAD. However, the influence of apo E genotypes on the response of plasma lipids and CAD progression or regression to statin treatment in patients with mildly to moderately elevated cholesterol remains unknown. METHODS Apo E genotypes were determined by polymerase chain reaction and restriction mapping. Plasma lipids were measured at baseline and 12 weeks after therapy with fluvastatin or placebo in 320 subjects. In 287 subjects, quantitative coronary angiography was performed at baseline and after 2.5 years of treatment. RESULTS Subjects with the 3/3 genotype had greater reductions in total cholesterol (20.4% vs. 15.4%, p = 0.01) and low density lipoprotein (LDL) cholesterol (28.8% vs. 22.7%, p = 0.03) than did the subjects with the 3/4 or 4/4 genotype. In contrast, subjects with the 2/3 genotype (n = 10) had a greater increase in high density lipoprotein cholesterol (19.1%) than did the subjects with the 3/3 genotype (4.3%, p = 0.002) and those with the 3/4 or 4/4 genotype (7.0%, p = 0.02). Subjects with the 3/4 or 4/4 genotype had an increased frequency of previous angioplasty, but other measures of baseline CAD severity and baseline lipids did not differ significantly among the genotypes, nor did CAD progression or clinical events. CONCLUSIONS Although subjects with the epsilon4 allele had less reduction in LDL cholesterol with fluvastatin, they had similar benefit in terms of CAD progression.

Interactions between angiotensin-I converting enzyme insertion/deletion polymorphism and response of plasma lipids and coronary atherosclerosis to treatment with fluvastatin: the lipoprotein and coronary atherosclerosis study.

OBJECTIVES Our objectives were to determine whether angiotensin-1 converting enzyme (ACE) insertion/deletion (I/D) polymorphism was associated with the severity of coronary artery disease (CAD) and its progression/regression in response to fluvastatin therapy in the Lipoprotein and Coronary Atherosclerosis Study (LCAS) population. BACKGROUND Genetic factors are involved in susceptibility to CAD. Angiotensin-1 converting enzyme I/D polymorphism, which accounts for half of the variance of plasma and tissue levels of ACE, has been implicated in susceptibility to CAD and myocardial infarction (MI). METHODS Angiotensin-1 converting enzyme genotypes were determined by polymerase chain reaction (PCR). Fasting plasma lipids were measured and quantitative coronary angiograms were obtained at baseline and 2.5 years following randomization to fluvastatin or placebo. RESULTS Ninety-one subjects had DD, 198 ID and 75 II genotypes. The mean blood pressure, minimum lumen diameter (MLD), number of coronary lesions and total occlusions were not significantly different at baseline or follow-up among the genotypes. There was a significant genotype-by-treatment interaction for total cholesterol (p = 0.018), low-density lipoprotein cholesterol (LDL-C) (p = 0.005) and apolipoprotein (apo) B (p = 0.045). In response to fluvastatin therapy, subjects with DD, compared with those with ID and II genotypes, had a greater reduction in total cholesterol (19% vs. 15% vs. 13%), LDL-C (31% vs. 25% vs. 21%) and apo B (23% vs. 15% vs. 12%). Definite progression was less (14%) and regression was more common (24%) in DD as compared with those with ID (32% and 17%) and II (33% and 3%) genotypes (p = 0.023). Changes in the mean MLD and lesion-specific MLD also followed the same trend. CONCLUSIONS Angiotensin-1 converting enzyme I/D polymorphism is associated with the response of plasma lipids and coronary atherosclerosis to treatment with fluvastatin. Subjects with DD genotype had a greater reduction in LDL-C, a higher rate of regression and a lower rate of progression of CAD.

Semen Quality and Endocrine Parameters after Acute Testicular Torsion

Of 16 postpubertal patients evaluated following testicular torsion 9 were treated with detorsion and bilateral orchiopexy (detorsion group), and 7 were treated with ipsilateral orchiectomy and contralateral orchiopexy (orchiectomy group). Each patient was evaluated with regard to semen quality, endocrine parameters (follicle-stimulating hormone, luteinizing hormone and testosterone) and the presence or absence of semen antisperm antibodies. These data were compared to similar data from a group of proved fertile semen donors. The semen quality in the detorsion group did not differ significantly from that of controls (p = 0.25) but follicle-stimulating hormone was significantly elevated compared with that of controls before and after stimulation with gonadotropin-releasing hormone. The orchiectomy group, which had been subjected to prolonged torsion (mean 69 hours), demonstrated a significant decrease in semen quality compared with semen quality in controls (p = 0.001), with average sperm density of only 29.0 million per ml. Baseline and post-stimulation levels of follicle-stimulating hormone in the orchiectomy group were also significantly abnormal when compared with those in controls and in the detorsion group. Our study demonstrates that testicular damage (changes in semen quality and/or endocrine parameters) occurs in the ipsilateral and contralateral testis following torsion, regardless of treatment modality. However, with early intervention by detorsion and testicular salvage, subsequent semen quality is likely to remain within normal limits. Late surgical intervention, even with removal of the nonviable testes, may result in significant impairment of semen quality.