Mitogen-activated protein kinases and apoptosis in PIN.

Mitogen-activated protein (MAP) kinases are key elements of the signalling systems needed to transduce different extracellular messages into cellular responses. At least three parallel MAP kinase pathways have been identified: one, stimulated by serum and growth factors to activate extracellular signal-regulated protein kinases (ERKs) by dual tyrosine and threonine phosphorylation, triggers cell proliferation or differentiation; the other two, induced by a variety of cellular stresses to activate c-jun N-terminal kinases (JNKs) and reactivating kinase (p38/RK), result in growth arrest and induction of apoptosis. Mitogen-activated protein kinase phosphatases (MKPs) inactivate MAP kinases through dephosphorylation and, thus, can modulate the MAP kinase pathways. Expression of JNK-1, ERK-1, p38/RK and MKP-1 proteins was investigated by immunohistochemistry and expression of MKP-1 mRNA by in situ hybridisation in 50 cases of high-grade prostatic intraepithelial neoplasia (PIN), thought to represent the precursor of prostate cancer. The frequency of apoptotic cells was also determined in these cases. Overexpression of the three MAP kinases and MKP-1 mRNA was found in all cases of high-grade PIN compared with normal prostate. Immunoreactivity for MKP-1 protein was found to be as intense as in normal glands in 30% and weaker in 56% of the PIN cases. Fourteen per cent of PIN cases did not stain with MKP-1 antibody. The proportion of apoptosis was significantly higher (P < 0.008) in PIN lesions that did not express MKP-1 protein than in those that did. These results are consistent with our previous demonstration of preferential inhibition of the apoptosis-related kinases by MKP-1 and further support the contention that MKP-1, even in PIN, may shift the balance existing between cell proliferation and death. When expressed, it may inhibiting those pathways that lead to apoptosis.

Patient-reported symptoms after primary therapy for early prostate cancer: results of a prospective cohort study.

PURPOSE: To assess complications of therapy for early (nonmetastatic) prostate cancer. PATIENTS AND METHODS: A prospective study of a cohort of 279 men who sought treatment advice and completed required pretreatment forms. The measures were self-reported patient symptoms and other measures of quality of life before therapy and at 3 and 12 months afterward. RESULTS: Bowel and bladder symptoms were uncommon pretreatment. Patients frequently reported irritative bowel and bladder symptoms at 3 months after radiotherapy, although these subsided somewhat at 12 months. Substantial ("a lot") urinary incontinence and wearing of absorptive pads were reported by 11% and 35% at 12 months after surgery and varied little by age. Incontinence occurred after radiotherapy infrequently, and only in men more than 65 years old. Inadequate erections, present in one third of men pretreatment, were nearly universal at 3 months after surgery, although some improvement, primarily in men under 65 years of age, was evident at 12 months. Sexual dysfunction after radiotherapy increased less but continually through 12 months, suggesting that observed treatment-related differences would decline with further follow-up. CONCLUSION: External-beam radiotherapy of early prostate cancer is followed by bowel and bladder irritability, by increasingly severe sexual dysfunction and, in men aged more than 65 years, occasional urinary incontinence. Greater sexual dysfunction and urinary incontinence occur in the year following radical prostatectomy. These postsurgical complication rates from patient questionnaires are greater than have been reported in other treatment series and confirm the results of two retrospective studies of patient-reported complications.

The epidemic of prostate cancer and the medical literature: a causal association?

The diagnosis of prostate cancer has undergone an unprecedented recent increase, while mortality has increased much more slowly. We examined new prostate cancer diagnoses from 1987-1992 in a nationwide prospective cohort study of 51 529 men enrolled in the Health Professionals Follow-up Study, a population likely to be medically sophisticated and thus early to adopt medical innovations. The age-adjusted incidence of prostate cancer rose approximately 2(1/2) fold during the study period. Nearly all of the increase occurred among organ-confined tumors, with a smaller increase for regionally-advanced tumors and none for metastatic tumors. Using a Poisson regression model of newly-diagnosed cancers, we found organ-confined cancers rose abruptly by 86% (95% CI: 36-256%; P=0.0001) and regionally-advanced tumors by 73% (95% CI:12-267%; P=0.01) after March, 1991, when a study advocating screening using the prostate specific antigen (PSA) was published in the New England Journal of Medicine. The recent increase in the incidence of prostate cancer is probably due to the increased PSA screening of asymptomatic men, resulting in the diagnosis of large numbers of men with early-stage disease from 1990 onward. Despite ongoing debate over the value of PSA screening, the rate of diagnosis accelerated sharply after the publication of a well-publicized but inconclusive study advocating screening. In a context of growing disease awareness, well-publicized research reports may result in unexpectedly amplified acceptance into medical practice.

Patient-reported impotence and incontinence after nerve-sparing radical prostatectomy.

BACKGROUND: The age-adjusted rate of radical prostatectomy, the most common treatment of early (nonmetastatic) prostate cancer, increased almost sixfold between 1984 and 1990. This increase was due in part to reported improvements in postoperative sexual potency after the use of newly developed "nerve-sparing" procedures. However, published estimates from physicians of impotence following various types of radical prostatectomy may be low, since not all patients may report treatment-related complications accurately and completely to their doctors. In contrast, direct surveys of patients indicate much higher rates of postoperative sexual and urinary dysfunction. One problem with most physician and patient surveys is that they have been performed retrospectively, and pretreatment impotence and incontinence prevalent in older men cannot be assessed accurately in retrospective studies. PURPOSE: This study was initiated in a cohort of men before they underwent radical prostatectomy to assess treatment-related effects on impotence and incontinence. METHODS: The study population consisted of 94 men enrolled in a cohort study of treatment for early prostate cancer. The patients completed questionnaires about sexual and urinary functions before surgery and at 3 and 12 months after surgery and had adequate information to assess the type of surgical technique used (non-nerve-sparing, unilateral nerve-sparing, or bilateral nerve-sparing). Because items assessing sexual function were inadvertently omitted from the questionnaire in the initial months of the study, information on sexual function for all time periods was available for only 49 men. RESULTS: Compared with men who had not been treated with a nerve-sparing procedure, men who underwent nerve-sparing radical prostatectomy, particularly of the bilateral type, were younger and had better prognostic features, indicating less advanced cancers. Before surgery, nine (75%) of 12 men not treated with a nerve-sparing procedure reported erections that were usually inadequate for sexual intercourse compared with six (33%) of 18 men and one (5%) of 19 men who underwent unilateral and bilateral nerve-sparing prostatectomies, respectively. At 12 months after surgery, most men reported inadequate erections, including 15 (79%) of the 19 men who had bilateral nerve-sparing surgery; unilateral nerve preservation provided no apparent benefit. In general, nerve-sparing surgery was associated with more use of absorbent pads at 3 and 12 months following treatment, and this approach was associated with substantial urinary incontinence at 3 months but not at 12 months following surgery. CONCLUSIONS: Nerve-sparing prostatectomy, particularly when performed unilaterally, improves postoperative sexual function to a lesser extent than previously reported. Because men with preoperative impotence and more advanced cancers receive nerve-sparing surgery less often, some of the previously reported benefit of nerve preservation may be the result of patient selection and not of the technique per se.

Mitogen-activated protein kinase phosphatase 1 is overexpressed in prostate cancers and is inversely related to apoptosis.

Several oncogenes involved in prostate carcinogenesis activate mitogen-activated protein (MAP) kinases, which can relay both proliferative (via extracellular regulated kinases (ERK)) and apoptotic signals (via jun N-terminal protein kinases (JNK)) to the nucleus. Mitogen-activated protein kinase phosphatase 1 (MKP-1) is induced by several oncogenes in the ras-dependent pathway and can inactivate both MAP kinase pathways. The role of MKP-1 in proliferation and apoptosis is, however, still controversial. A series of 51 prostate cancers, including a subset (n = 13) that had been previously treated by androgen ablation, was used to examine whether MKP-1 mRNA and protein expression correlated with that of ERK-1, JNK-1, bcl-2, which confers resistance to apoptosis, and apoptotic index measured by in situ end-labeling of fragmented DNA. In a subset of tumors, MKP-1 expression was assessed by semiquantitative RT-PCR and was compared with both ERK-1 and JNK-1 enzymatic activity. In cases not treated by androgen ablation, MKP-1 was overexpressed in the preinvasive stage of prostate cancer, but its expression decreased with higher histologic grade and advanced disease stage. There was coexpression of MKP-1, ERK-1, and JNK-1 proteins. In addition, MKP-1 expression was inversely correlated to JNK-1 but not to ERK-1 enzymatic activity. Finally, MKP-1 and bcl-2 were inversely related to apoptotic indices. In cases treated by total androgen ablation, MKP-1 and bcl-2 were both down-regulated, whereas JNK-1 was up-regulated. Subpopulations of cells that did not undergo apoptosis maintained expression of both MKP-1 and bcl-2. These results suggest that MKP-1 overexpression is associated with the early phases of neoplastic transformation in prostate tissue. The enzymatic data on MKP-1 kinase substrates and the inverse correlation between MKP-1 and parameters of programmed cell death support the hypothesis that MKP-1 inhibits apoptosis in human prostate tumors, perhaps through the JNK pathway.

Epididymo-orchitis developing as a late manifestation of intravesical bacillus Calmette-Guerin therapy and masquerading as a primary testicular malignancy: a report of 2 cases.

In 2 cases epididymo-orchitis, indistinguishable from a testicular tumor, developed as a late (15 and 34 months, respectively) complication following use of Tice strain bacillus Calmette-Guerin for treatment of superficial bladder carcinoma. In each instance the lesion was asymptomatic and ultrasonography demonstrated a complex scrotal mass. Inguinal orchiectomy was performed for diagnosis and therapy. The importance of obtaining a mycobacterial culture for further therapy planning is stressed.

Extended resection for locally advanced colorectal carcinoma.

We reviewed the medical records of 101 patients who underwent extended resection for locally advanced colorectal carcinoma between 1965 and 1989. Preoperative symptoms related to the genitourinary system were present in 46 patients. Malignant invasion of genitourinary structures by colorectal carcinoma was found in 43 of these 46 patients (93%). In contrast, 51% of the patients without such symptoms had malignant invasion of contiguous structures. Preoperative intravenous pyelography, computerized tomographic scans, and cystoscopy correctly predicted the presence or absence of malignant invasion in 89%, 83%, and 87% of patients, respectively. Tumor-positive resection margins had a negative impact on survival (mean survival: 11.4 months). The 5-year actuarial survival rate for the patients who underwent a curative extended resection (margins tumor negative) was 54%. A thorough preoperative evaluation can identify a significant number of patients with colorectal cancer extending into adjacent organs and structures. Such evaluation is vital for operative planning and patient preparation, since an appropriate extended resection can produce long-term local control and patient survival.

Stage B (P2/3A/N0) transitional cell carcinoma of bladder highly curable by radical cystectomy.

Seventy-one patients with pathologic Stage B (P2/3a/N0) transitional cell carcinoma (TCC) of the bladder underwent radical cystectomy alone without preoperative radiotherapy or perioperative chemotherapy between 1983 and 1987 and have been followed a median of fifty months. The five-year actuarial survival and disease-free survival rates were 82 percent and 77 percent, respectively, and only 13 patients (18%) have relapsed. Histologic parameters were evaluated as to prognostic impact; none correlated with disease-free survival rates although the presence of vessel involvement portended a worse disease-free survival rate (68% versus 80%). During this same period, an additional 15 patients underwent radical cystectomy for pathologic Stage B disease but received adjuvant chemotherapy on the basis of vessel invasion. Their disease-free survival rate at five years was 80 percent, comparable to the disease-free survival rate for patients with vessel invasion treated by surgery alone (68%). Although the role of systemic chemotherapy in the management of invasive bladder cancer remains under investigation, it would appear that patients with Stage B TCC are best treated with radical cystectomy alone. Continued analysis of modern surgical results grouped by current pathologic staging criteria is needed to identify patients who have a relatively low risk of relapse and thus little need for additional therapeutic intervention. These results demonstrate that Stage P2/3a/N0 TCC of the bladder is highly curable by surgery.

Will Rogers and the results of radical cystectomy for invasive bladder cancer.

Disease-free survival rates for patients with muscle-invasive bladder cancer treated by radical cystectomy with bilateral pelvic lymphadenectomy with or without adjuvant chemotherapy are 75% to 80% in stage B disease, 60% in stage C disease, and approximately 50% in stage D disease. Vascular invasion is an important prognostic factor in meticulously staged patients. Powerful selection factors, including more accurate clinical and pathologic staging and improved surgery, as well as unspecified selection factors, may contribute to the improved results. In order to evaluate the impact of adjuvant chemotherapy, a randomized, controlled study is necessary.

Medical lasers and safety.

Urologists will want to be familiar with the numerous lasers now available, the new delivery systems, and the safety considerations for their appropriate use. In the next decade and certainly in the next century, lasers will no doubt become an essential urologic therapy.

Laser denudation as treatment for diffuse epithelial dysplasia of the glans penis.

We describe a new technique using the neodymium: YAG laser to denude the entire epithelium of the glans penis as a treatment for diffuse dysplasia of the glans. Epithelial regrowth originated from the healthy epithelium at the margins of the denudation. Six months after surgery the glans was covered by an entirely new epithelium, which was normal by histopathologic evaluation. Laser denudation was performed at a single outpatient session with minimal postoperative morbidity and produced excellent functional and cosmetic results. We believe this technique is an attractive alternative to partial penectomy for appropriate patients.

Squamous cell carcinoma antigen (TA-4) in penile carcinoma.

TA-4 antigen, originally isolated from women with squamous cell carcinoma of the cervix, is elevated in the sera of patients with squamous cell carcinomas of several sites, including esophagus, lungs, and head and neck. In this study, we compared the serum levels of TA-4 in normal volunteers, patients with resected penile squamous cell carcinoma, and patients with metastatic penile squamous cell carcinoma. TA-4 values were elevated in 5 of 11 patients (45%) who had metastatic disease. In 2, TA-4 was normal the first time metastasis was clinically detected but rose as the disease progressed. Moreover, in 3 patients in whom serial determinations were made, serum TA-4 values correlated well with disease progression and response to treatment. We conclude that TA-4 values are elevated in some patients with metastatic squamous cell carcinoma of the penis and may become a useful marker for monitoring response to therapy.

Sutureless end-to-end bowel anastomosis using an argon laser and water-soluble intraluminal stent.

Sutureless end-to-end intestinal anastomoses were constructed in New Zealand white rabbits using an argon laser to weld the tissue edges, which were temporarily held together by a biodegradable, water-soluble, intraluminal stent. Various power settings ranging from 1.5 to 5 W were used with and without an exogenous chromophore (India ink). Delivering 4 W of power without using an exogenous chromophore but applying a continuous saline drip to the anastomotic seam during lasing proved most successful. We conclude that argon laser energy can be used to construct successful sutureless end-to-end intestinal anastomoses.

Indications for urethrectomy in an era of continent urinary diversion.

Interest in performing a continent urinary diversion and in preserving sexual potency after radical cystectomy for transitional cell carcinoma of the bladder has emphasized the need to identify accurately those men who are at high risk for urethral recurrences. We reviewed the records of 200 men who underwent radical cystectomy between 1969 and 1976. In 76 men urethrectomy and cystectomy were combined. Of these patients 6 had known urethral tumors and the incidence of unsuspected urethral malignancy was 2.9%. A total of 124 men had initial cystectomy only and were monitored up to 16 years (mean 67 months). Of these patients 6 (4.8%) underwent subsequent urethrectomy for malignant disease 6 to 40 months (median 23.5 months) after cystoprostatectomy. This group included 1 of 69 patients (1.5%) who presented with a solitary tumor not encroaching on the bladder neck, 1 of 22 (4.5%) with either carcinoma in situ or multifocal tumors not involving the prostate and none of the 9 with tumor at the bladder neck alone, which suggests that these patients may be satisfactory candidates for continent urinary diversion and may avoid the added risk to potency associated with urethrectomy. However, urethral recurrences were found in 4 of 24 patients (17%) who presented with disease extending into the prostate, including 3 of 10 (30%) with stromal invasion. These results emphasize the importance of assessing the prostatic urethra and ducts carefully before deciding to eliminate urethrectomy.

Mucinous adenocarcinoma of the prostate: histochemical and immunohistochemical studies.

Twelve patients with primary mucinous adenocarcinoma of the prostate were included in a clinicopathologic study; criteria included a total tumor volume more than 25% mucinous and single or clustered tumor cells floating in mucin lakes. Patient ages were 57 to 81 years; tumor stages were C (three), D (five), and unknown (four). Bone was the most frequent metastatic site (usually osteoblastic), followed by lymph nodes and lungs. Serum levels of prostatic acid phosphatase and prostate-specific antigen were frequently elevated (five of 10 and three of three measured, respectively). All mucinous adenocarcinomas also contained other histologic patterns: microglandular (four), cribriform (three), comedo (two), solid (two), and hypernephroid (one). Mucinous components composed less than 50% of three tumors, 50% and 75% of six, and more than 75% of three. No tumor contained signet-ring cells. Immunoperoxidase staining was positive for prostatic acid phosphatase and prostate-specific antigen and negative for carcinoembryonic antigen. Treatment was radiation, estrogen, orchiectomy, or a combination. In two of four patients, serum prostatic acid phosphatase levels normalized after therapy. Seven patients died of disease (mean follow-up, 56 months), and five patients are alive with disease (mean, 32.2 months). The proportion of mucinous component did not affect prognosis.

Prompt orchiectomy reduces morbidity and mortality from testicular carcinoma.

The records of 154 patients with non-seminomatous germ cell testicular tumours were reviewed to determine the potential effect of prompt diagnosis and orchiectomy on morbidity and mortality from this disease. Orchiectomy was performed 30 days or less after the onset of testicular symptoms on 65 patients (Group 1) and more than 30 days after the onset of symptoms on 89 patients (Group 2). The initial clinical stages of Group 1 patients were: I, 40 (62%); II, 14 (22%); III, 5 (8%); marker only, 6 (9%). The initial clinical stages for Group 2 patients were: I, 25 (28%); II, 15 (17%); III, 35 (39%); marker only, 14 (16%). The difference between the percentages of Group 1 and Group 2 patients with stage I disease was statistically significant, as was the difference between the percentages of Group 1 and Group 2 patients with stage III disease. One of the Group 1 patients died, whereas 11 of the Group 2 patients died. In 5 of the Group 2 patients who died, orchiectomy had been performed more than 120 days after the onset of testicular symptoms. This study suggests that orchiectomy performed promptly after the onset of testicular symptoms not only helps to reduce mortality from testicular cancer but also has a major effect on its morbidity by reducing the need for systemic chemotherapy or major surgery.

Long-term serum creatinine values after radical nephrectomy.

Both pre- and postnephrectomy levels of serum creatinine were measured in 52 consecutive patients who underwent radical nephrectomy for localized renal cell carcinoma between 1971 and 1976. At the time of follow-up, 17 patients were alive and 35 had died, 14 of renal cell carcinoma and 21 of other causes. Follow-up lasted a minimum of 115.5 months (mean 151.1 months, median 141.1, range 115.5-211.3 months) for 16 of the 17 patients who were alive. In this group only 2 patients had elevations in the serum creatinine level above 1.6 mg/dL-1.9 mg/dL and 2.4 mg/dL, respectively. The patient whose value was 2.4 mg/dL was a diabetic who required insulin. No serious renal failure, renal disease, or tumors in the contralateral kidney occurred among the total group of 52 patients. These data indicate that renal function remains adequate in patients who have a normal contralateral kidney and are treated by radical nephrectomy.