Regional trends in prostate cancer incidence, treatment with curative intent and mortality in Norway 1980-2007.

OBJECTIVES: To compare the trends in prostate cancer incidence, treatment with curative intent and mortality across regions and counties in Norway, and to consider changes in incidence (an indicator for early diagnosis) and treatment with curative intent as explanatory factors for the decreasing prostate cancer mortality rates. PATIENTS AND METHODS: Prostate cancer incidence and mortality data (1980-2007) alongside treatment data (1987-2005) were obtained from the national, population-based Cancer Registry of Norway. Joinpoint regression models were fitted to age-adjusted incidence, treatment and mortality rates to identify linear changes in the trends. RESULTS: Both age-adjusted incidence rates and rates of curative treatment of prostate cancer increased significantly in all five regions of Norway since the early 1990s. There was a strong positive correlation between increasing incidence and increasing use of curative treatment. The frequency of curative treatment in Western Norway was almost threefold that in the Northern and Central regions around year 2000. Subsequently, the regional trends converged and only minor differences in prostate cancer incidence and use of curative treatment were observed by 2005. The declines in mortality were observed earliest in the regions with the highest incidence and the most frequent use of curative treatment, while the largest decreases in mortality were found in counties where the largest increases in curative treatment were observed. CONCLUSIONS: The elucidation of the prostate cancer mortality trends is hindered by an inability to tease out the potential effects of early treatment from the more general impact of improved and more active treatment. However, it is likely that both sets of intervention have contributed to the decline in prostate cancer mortality in Norway since 1996.

Neonatal lethal dwarfism with distinct skeletal malformations--a separate entity?

We describe a case of neonatal lethal dwarfism characterised by short trunk, short, stick-like tubular bones, deficient ossification of the axial skeleton and broad, sclerotic horizontal ribs. Two similar cases have previously been reported as examples of the Neu-Laxova syndrome. However, the radiological findings of the Neu-Laxova syndrome, as reported in 16 out of 40 documented cases, show a heterogeneous pattern of minor features, which differ distinctively from those found in the previous two cases and by us. A literature research did not reveal similar cases, and we therefore suggest that our case, together with the two previous cases, may represent a new distinctive form of neonatal lethal dwarfism.

Maximum Ki-67 staining in prostate cancer provides independent prognostic information after radical prostatectomy.

BACKGROUND: We have evaluated the prognostic value of Ki-67 growth fraction after radical prostatectomy, especially focusing on intermediate grade carcinomas. MATERIALS AND METHODS: 104 patients treated by radical prostatectomy for clinically localized prostate cancer were studied. The area of highest tumour grade was selected from the prostatectomy specimens and used for Ki-67 immunostaining The fraction of Ki-67 positive tumour nuclei in the area of most intense proliferation ("hot spot") was estimated, and related to biochemical failure. RESULTS: Ki-67 expression (median 6.7%, range 1.2-42.6%) was significantly associated with WHO histological grade. In univariate analysis of all 104 carcinomas, Ki-67 expression was associated with time to biochemical failure as were age, tumour dimension, WHO histological grade, pathological stage, positive surgical margins and pre-operative s-PSA. In multivariate Cox' analysis, Ki-67 expression, pathological stage and pre-operative s-PSA remained as independent predictors of time to biochemical failure. Ki-67 expression (HR 4.8, p < 0.001) was also found to be an independent predictor among moderately-differentiated carcinomas. CONCLUSION: Estimates of Ki-67 growth fraction in areas of highest tumour grade may prove to be a useful prognostic biomarker after radical prostatectomy.

Prognostic significance of p16 and CDK4 proteins in localized prostate carcinoma.

BACKGROUND: In prostate carcinoma, a very low frequency of point mutations of the tumor suppressor gene CDKN2/MTS1 (p16(INK4) ) has been reported, but deletions of 9p21 and inactivation by promoter methylation are observed more frequently. In the current study the authors evaluated the expression of p16 and CDK4 proteins and their prognostic significance in patients with clinically localized prostate carcinoma. METHODS: The levels of p16 and CDK4 proteins were quantitated by immunofluorescence flow cytometry, using paraffin embedded material, in 104 adenocarcinomas of the prostate after radical prostatectomy. These levels then were compared with 25 cases of benign prostate hyperplasia (BPH). RESULTS: In prostatic carcinoma specimens, p16 protein was elevated significantly compared with BPH, with a median fluorescence index (FI) of 15.4 versus 10.7, respectively (P = 0.010). This was not the case for CDK4 protein, although p16 protein expression correlated significantly with CDK4 protein expression in BPH (Spearman rank correlation [R(S)] = 0.63) and carcinoma (R(S) = 0.78). In univariate survival analysis of the first 5 years, high levels of p16 protein expression (FI > 11.7) (P = 0.005), tumor greatest dimension, World Health Organization (WHO) histologic grade, capsular penetration, seminal vesicle invasion, positive surgical margins, lymph node involvement, and preoperative serum prostate specific antigen > 20 ng/mL all were significant predictors of biochemical failure. In multivariate survival analysis, high p16 protein expression (P = 0.015), age, WHO histologic grade, capsular penetration, and seminal vesicle involvement remained as independent predictors of biochemical failure. CONCLUSIONS: These data suggest that increased expression of p16 protein, but not CDK4 protein, may be involved in the development of prostate carcinoma and may represent an independent predictor of biochemical failure after radical prostatectomy.

Independent prognostic importance of microvessel density in clinically localized prostate cancer.

BACKGROUND: Previous studies have reported a possible prognostic importance of microvessel density (MVD) in prostate cancer, although the significance after radical prostatectomy is not clear. The purpose of this study was to assess the prognostic value of MVD in clinically localized prostatic adenocarcinomas, focusing on moderately-differentiated tumours. MATERIALS AND METHODS: We examined a series of 104 patients treated for presumed organ-confined cancer in the period 1988-94. The area of highest tumour grade was selected from the prostatectomy specimens and vessels were high-lighted by staining for factor-VIII-related antigen. MVD was quantitated in the "hot spot" area and related to biochemical failure and clinical recurrence. RESULTS: In moderately differentiated tumours (WHO grade) (n = 66), MVD was associated with preoperative s-PSA and positive surgical margins. In univariate 5-year analysis, microvessel density (MVDmean > 122 mm-2, median) (p = 0.0074), s-PSA, tumour dimension, capsular penetration, seminal vesicle invasion and positive surgical margins were all significant predictors of biochemical failure, while MVDmean (p = 0.0084) was the only statistically significant predictor of clinical recurrence. In multivariate Cox' analysis, MVDmean (p = 0.0003), capsular penetration and tumour dimension remained as independent predictors of biochemical failure. CONCLUSION: Assessment of MVD in moderately differentiated prostatic adenocarcinomas may improve the prognostic stratification of patients after radical prostatectomy.

Cushing's syndrome in prostate cancer. An aggressive course of prostatic malignancy.

We report a case with an initial diagnosis of adenocarcinoma of the prostate in whom Cushing's syndrome developed. The disease did not respond to estrogen treatment and the patient died of severe septicemia. Histopathologic examination of the autopsy specimens revealed a small cell carcinoma intermingled with a moderately differentiated adenocarcinoma in the prostate and widespread metastases of small cell carcinoma. Immunoreactivity for neuroendocrine differentiation was found only in the small cell carcinoma. Determination of different tumor markers in plasma samples showed markedly elevated levels of prostate-specific antigen as well as carcinoembryonic antigen prior to treatment, with no significant changes after treatment. The concentration of the neuroendocrine marker chromogranin A was initially within the normal range, but increased during estrogen treatment, whilst neuron-specific enolase was moderately elevated throughout the observation period.

Use of pelvic surface coil MR imaging for assessment of clinically localized prostate cancer with histopathological correlation.

We evaluated the ability of magnetic resonance imaging (MRI) operating at 1.0 Tesla with a Helmholz pelvic surface coil to predict the pathological stage of prostate carcinoma. Radiological diagnosis was based on fast spin-echo axial T2-weighted images with and without frequency selective fat-suppression and fast spin-echo coronal T2-weighted images. Thirty-one consecutive patients (mean age 61 years, range 49 to 71 years) underwent pelvic MRI before radical prostatectomy. Correlation with whole-mount step-sections of the surgical specimens showed that the tumours were correctly localized in all but one prostate gland in which the tumour could not be seen on pelvic MRI. The transverse diameter of the visible tumour at pelvic MRI appeared to represent an approximate estimate of the true tumour dimension. Based on histopathologic whole-mount step-sections of the surgical specimens, 22 of 31 patients (71%) had tumours extending beyond the confines of the prostatic capsule. The specificity for MRI to predict capsular penetration and seminal vesicle invasion was relatively high (0.80 and 0.86, respectively). The sensitivity was acceptable for capsular penetration (0.62) but poor for seminal vesicle invasion (0.30).

MRI with an endorectal coil for staging of clinically localised prostate cancer prior to radical prostatectomy.

The purpose of this study was to evaluate the ability of MR imaging with an endorectal coil (erMRI) to predict the local pathological stage of prostatic carcinoma prior to radical prostatectomy. Thirty-one consecutive patients (median age 61 years, range 40-71 years) with clinically localised prostate cancer were assessed preoperatively by endorectal MRI (at 1.0 T). The pulse sequences consisted of fast spin-echo axial and coronal T2-weighted images and inversion recovery with two echoes for axial fat-suppressed images. The assessment of tumour stage and measurement of tumour dimension by erMRI were compared with the corresponding findings on whole-mount step sections of the surgical specimens. Postoperatively, 14 of the 31 patients (45 %) were found to have extracapsular extension, 7 with capsular penetration (CP) only, and 7 had a combination of CP and seminal vesicle invasion (SVI). Capsular penetration was detected by erMRI with a sensitivity of 0.71 and specificity of 0.47, whereas the sensitivity for SVI detection was 0.71 and the specificity 0.83. Endorectal MRI for staging clinically localised prostatic carcinoma gives a good prediction of invasion of the seminal vesicles but is unreliable in predicting capsular penetration.

Lymphangiography combined with biopsy and computer tomography to detect lymph node metastases in localized prostate cancer.

To evaluate the efficacy of lymphangiography combined with fine needle aspiration biopsy and computer tomography (CT) for lymph node staging in clinically localized prostate cancer. Prospective evaluation of nodal involvement was carried out using standard bipedal lymphangiography combined with fine needle aspiration biopsy (FNAB) in 70 patients (aged 47 to 75 years, mean age 63 years) with apparently locally confined prostate cancer before intended radical prostatectomy. Sixty-four patients also underwent computer tomography. Seventeen withdrew the decision to undergo a radical prostatectomy, leaving 53 patients with pathologic examination of the lymph nodes eligible for analysis. Lymph node metastases were diagnosed in 8 patients (8/53 = 15.1%). Three were diagnosed preoperatively by FNAB, 3 peroperatively by lymph node dissection and frozen section biopsy and an additional 2 at the final pathologic assessment. The sensitivity, specificity, positive and negative predictive values for lymphangiography and lymphangiography combined with FNAB in predicting nodal disease, based on the analysis of the 53 patients with known pathologic results, were 0.63, 0.76, 0.31, 0.92 and 0.38, 1.00, 1.00, 0.90, respectively. The corresponding values for CT staging were 0.25, 0.98, 0.67 and 0.87, respectively. The efficacy of bipedal lymphangiography alone or combined with FNAB or CT alone for assessment of nodal metastases is too low to be worthwhile for lymph node staging in localized prostate cancer patients with expected low or intermediate probability of nodal disease.

Tumour size measured by transrectal ultrasonography in the staging of prostate cancer before radical prostatectomy.

OBJECTIVE: To assess the diagnostic accuracy of transrectal ultrasonography (TRUS) in predicting the local extent of prostate cancer before radical prostatectomy. PATIENTS AND METHODS: From April 1990 to April 1993, 59 consecutive patients (mean age 63 years, range 49-71) with clinically localized prostate cancer were examined using TRUS before radical prostatectomy. Primary tumours were clinically categorized according to the TNM classification and biopsies graded histologically. Tumour size was measured as length on a longitudinal and height and width on a transverse ultrasonogram. The results from TRUS were compared with those from the histopathological examination of whole-mount step sections of the surgical specimens. RESULTS: In 50 patients, TRUS using standard criteria achieved sensitivity, specificity, positive- and negative predictive values (PPV, NPV) of 0.47, 0.63, 0.73 and 0.36, respectively, in predicting pathological stage. Dimensions were obtained from 45 patients with hypoechoic tumours; in a multivariate linear discriminant analysis the TRUS estimate of width was the best predictor of pathological stage. The sensitivity, specificity, PPV and NPV for tumour width from TRUS, using a threshold of 19 mm, were 0.42, 0.93, 0.93 and 0.43, respectively. CONCLUSION: Tumour width measured by TRUS may improve the assessment of the local extent of prostate cancer.

When is bone scintigraphy necessary in the assessment of newly diagnosed, untreated prostate cancer?

OBJECTIVE: To evaluate the utility of bone scintigraphy in the assessment of newly diagnosed, untreated prostate cancer. PATIENTS AND METHODS: The probability of a positive bone scan for metastases was analysed for different threshold values of pre-treatment concentrations of prostate specific antigen (PSA), clinical stage, tumour grade based on biopsy, and age in 128 men (mean age 69 years, range 50-90) with newly diagnosed, untreated prostate cancer. The overall survival probabilities estimated from PSA level, extent of bone metastases, tumour grade, clinical stage, and age were calculated using the product-limit method. RESULTS: The positive predictive values of PSA level for bone metastases at thresholds of 10 and 20 ng/mL were poor (27.5 and 47.5%, respectively) whereas similar threshold levels of PSA gave negative predictive values of 100 and 94%, respectively, for a positive bone scan. In a univariate analysis, the overall survival was significantly affected by the extent of bone scan pathology (P < 0.001), the pre-treatment level of PSA (P < 0.001) and tumour grade (P = 0.01), whereas a multivariate analysis identified, in order of significance, tumour grade (P = 0.003), bone scan findings (P = 0.007) and PSA levels (P = 0.03) as independent prognostic factors. CONCLUSIONS: Bone scintigraphy seems to be unnecessary in the evaluation of newly diagnosed, untreated prostate cancer in patients with no clinical signs of bone pathology and serum PSA levels of < or = 10 ng/mL. However, the bone scan accurately assesses bone metastases and the prognostic significance of bone scan findings is superior to that of serum PSA level.

Transcutaneous abdominal ultrasonography in the staging of lung cancer.

BACKGROUND: There is limited information available regarding the relationship between clinical indicators of widespread disease in patients with lung cancer and the findings of transcutaneous ultrasonography. METHODS: A retrospective survey was made of 279 consecutive patients with lung cancer. By reviewing the patients' records the clinical findings were divided into symptoms, signs, and laboratory tests indicative of metastatic disease. All patients had been examined by abdominal ultrasonography. RESULTS: The patients included 19% with small cell carcinoma. The frequency of abdominal metastases by ultrasonography in those with small cell carcinoma was 40%, in the other patients it was 8%. Regardless of histological group, all the 40 patients with abdominal metastases by ultrasonography had at least one clinical category indicative of widespread disease and 38 (95%) had two or all three clinical categories positive. Fifty nine patients had no clinical indicators of metastases and none of these had abdominal metastases by ultrasonography. CONCLUSIONS: The results of this study indicate that abdominal metastases are found in lung cancer patients with clinical findings indicative of widespread disease. No abdominal metastases were found in patients with a negative clinical evaluation. The results indicate that transcutaneous ultrasonography of the abdomen is not necessary in the initial staging if the clinical evaluation is unremarkable.

Expression of p 16 protein in prostatic adenocarcinomas, intraepithelial neoplasia, and benign/hyperplastic glands.

The tumor suppressor gene CDKN2/MTSI(p16(INK4)) may be inactivated by point mutations, deletions, or methylation in many tumor types. In prostate cancer, a very low frequency of point mutations has been reported, but deletions of 9p21 and inactivation by methylation are observed more frequently. The purpose of this study was to assess the expression pattern of the CDKN2 protein product p 16 in a series of 104 prostatic adenocarcinomas treated by radical prostatectomy, using immunohistochemical detection on archival, paraffin-embedded material. Nuclear staining was completely absent in 13 (13%) of 104 cases, whereas cytoplasmic staining was found in 99 (95%) of 104 carcinomas. Significant differences were found when comparing the staining intensity of carcinomas and coexisting prostatic intraepithelial neoplasia (PIN) with benign/hyperplastic glands. In 86 (95%) of 91 cases the overall staining intensity of carcinomas was stronger than the reactivity in benign/hyperplastic glands, which were most often weakly stained. In 71 (95%) of 75 cases the staining intensity of PIN was stronger than in benign/hyperplastic glands, a contrast also observed within single glands. However, p16 immunostaining in carcinomas was not prognostically important and it was not associated with standard clinicopathologic parameters. Our results support that CDKN2/plb is inactivated in only a small proportion of localized prostate cancers. The increased p16 staining of carcinomas/PIN in comparison with benign/hyperplastic glands suggests that p 16 protein may be involved in early stages of prostate tumorigenesis by mechanisms other than CDKN2/p16 gene inactivation, and the possibility of using p(16) immunostaining as a marker for PIN is discussed.

Transrectal ultrasonography to assess local extent of prostatic cancer before radical prostatectomy.

OBJECTIVE: To evaluate transrectal ultrasonography (TRUS) with a 7 mHz rotating probe as a staging procedure in 33 patients with localized prostatic carcinoma. PATIENTS AND METHODS: The ultrasound scans were compared to histopathological whole-mount step sections of the surgical specimens. Twenty-five of the patients had tumours with pathological stage T3 (pT3) and eight had tumours with stage pT2 giving a prevalence of extracapsular growth of 0.76. RESULTS: The overall sensitivity, specificity, positive and negative predictive values for detection of extracapsular tumour growth by TRUS of prostatic cancer were found to be 0.68, 0.63, 0.85 and 0.38, respectively. Six tumours showed solely microscopic foci of extracapsular tumour growth. CONCLUSION: This technique gives a high percentage of both understaging (32%) and overstaging (37%) and therefore TRUS is an unreliable tool in the staging protocol prior to radical prostatectomy.

Prognostic significance of p53 protein expression and DNA ploidy in surgically treated non-small cell lung carcinomas.

A series of 112 patients operated for non-small cell lung cancer was analyzed retrospectively. Nuclear suspensions were prepared from formalin-fixed, paraffin-embedded biopsies, and DNA content was measured simultaneously with p53 expression using flow cytometry. The expression of p53 protein was determined by the monoclonal antibody PAb 1801, which recognizes both wild-type (normal) and mutated forms of p53. By the level of p53 expression, four patient groups were statistically defined. Patients in the two groups with no detectable and extremely high p53 expression had a significantly better prognosis than patients in the two groups with moderately increased p53 expression. By logistic regression, p53 expression was found to be the single best predictor of 5 year survival. Patient age and tumor stage were less important prognostic factors. No difference in 5 year survival was observed between diploid and aneuploid tumors. We conclude that p53 is a useful prognostic predictor in low stage non-small cell lung carcinoma using the monoclonal antibody PAb 1801. The applicability of this antibody to archival material in flow cytometric analysis should allow a broad range of tumor types to be analyzed with respect to the prognostic significance of p53 overexpression.

Inability of refined CT to assess local extent of prostatic cancer.

A refined procedure for CT was evaluated as a staging procedure in 19 patients with localized prostatic carcinoma. The CT images were compared to histopathologic whole-mount step sections of the surgical specimens. Fourteen of the patients had pathologic stage T3 (pT3) and 5 had stage pT2 giving a prevalence of extracapsular growth of 0.74. The CT images were read by 2 radiologists independently with a diagnostic accuracy of 0.37 for both observers. This is no better than in previous studies using a routine CT procedure. We conclude that CT is of little value in the staging protocol for the local extent of prostatic carcinoma before radical prostatectomy.

Quantitation of biological tumor markers (p53, c-myc, Ki-67 and DNA ploidy) by multiparameter flow cytometry in non-small-cell lung cancer.

Fifteen primary non-small-cell lung carcinomas (8 adenocarcinomas and 7 squamous-cell carcinomas) were analyzed by multiparameter flow cytometry for their expression of p53 and c-myc proteins. In addition, the fraction of cells staining with the proliferation-associated antibody Ki-67 and DNA ploidy was determined. These 4 biological markers were analyzed in parallel samples from a single-cell suspension made from fresh, frozen biopsies. Thus, the internal relationship between these markers within each tumor-cell population was established. Three different anti-p53 antibodies were used: PAb 421, PAb 1801 and PAb 240. All 15 tumors were p53-positive with the antibodies PAb 1801 and PAb 240, whereas only 9 were positive as judged by the antibody PAb 421. This indicates that the choice of p53 antibody is not irrelevant. Ten tumors were c-myc-positive; 7 of these were adenocarcinomas. The c-myc-positive tumors had a significantly higher level of p53 expression, judged by PAb 1801 and PAb 240, than c-myc-negative tumors. For PAb 421, there was no difference. We did not find any correlation between Ki-67 staining and expression of p53 and c-myc proteins, either with DNA ploidy, S-phase fraction or histological type. Our study indicates that there might be an association between accumulation of p53 protein and c-myc over-expression in non-small-cell lung cancer, and that this in particular might apply to adenocarcinomas. Furthermore, we show that multiparameter flow cytometry is a powerful tool in the study of the relationship between different markers in a cell population.

Radical retropubic prostatectomy: our experience with the first 54 patients.

Complications were analysed in a contemporary series of the first 54 retropubic radical prostatectomies performed for carcinoma of the prostate at our Institution. The postoperative morbidity was notable; three life threatening and ten minor complications occurred within the first 30 postoperative days. Thus, more than 1 year after the operations 7 patients had severe stress incontinence and 17 noticed minor degree of incontinence. Twenty-six per cent of the patients who claimed to be potent before surgery maintained potency. The operative time averaged 195 min and the demand for transfusions averaged 2.98 units per patient. Our experience in this early series of radical prostatectomy is that the operation cannot be done without notable postoperative morbidity.

Transrectal ultrasonography in the staging of localized prostatic carcinoma. A pilot study.

Transrectal ultrasonography (TRUS) was evaluated as a staging procedure in ten patients with localized prostatic carcinoma. The ultrasound images were correlated to histopathological whole-mount step sections of the surgical specimens after radical prostatectomy. Nine of the patients had pathological stage T3 (pT3) and only one was pT2. TRUS gave a diagnostic accuracy of 60% compared to 10% both for digital rectal examination (DRE) and computer tomography (CT) in detecting extracapsular tumor spread. We conclude so far that TRUS is superior to DRE and CT in detecting extracapsular tumor spread. Further we state that whole-mount step section of the surgical specimens is mandatory in order to achieve a correct pathological staging (pT-stage).

Effect of misoprostol and antacids on gastric and duodenal mucosal enzyme activities in duodenal ulcer patients.

The activities of 11 marker enzymes from the gastric and duodenal mucosa were determined in 15 patients with active duodenal ulcer disease before therapy, after 4 weeks of therapy with the prostaglandin E1 analogue misoprostol, 400 micrograms twice daily, and after another 4 weeks without any therapy. Another 15 patients were given a high-dose liquid antacid regimen. The activities were measured in homogenized material obtained with forceps through an endoscope. The healing rates of the two groups at 4 weeks were 53% and 80%, respectively. No changes in mucosal inflammation were noted during therapy. During treatment with misoprostol the activities in the descending duodenum of the membrane enzymes alkaline phosphatase, leucyl-beta-naphthylamidase, gamma-glutamyltransferase, and 5'-nucleotidase increased towards the values seen in normal controls. Despite a higher healing rate, no changes in the enzyme activities occurred in the group given high-dose antacid therapy. Four weeks after cessation of therapy the enzyme activities in the misoprostol group were not significantly different from the pretreatment values. In the biopsy specimens from the duodenal bulb the activities of monoamine oxidase fell during treatment with misoprostol and were restored to the pretreatment activity when therapy was stopped. In the stomach mucosa the enzyme activities were largely unchanged during treatment with both misoprostol and antacids. These results indicate that misoprostol and antacids have different mechanisms of action but may also suggest that the demonstrated enzymic changes are unrelated to the healing process.