Long-term survivors with pN2 non-small cell lung cancer after a complete resection with a systematic mediastinal node dissection

OBJECTIVE: To determine the distribution and significance of microcalcifications in histologic sections of the prostate. DESIGN: Retrospective review of all histologic slides of completely embedded prostates from surgical specimens. MATERIALS: Randomly selected material included 266 radical prostatectomy and 10 cystoprostatectomy prostates without prostate cancer. Nonrandomly selected specimens included 26 radical prostatectomy specimens with a Gleason pattern 5 component, 24 cases with collagenous micronodules, and 8 cases previously noted to have microcalcifications within foci of prostate cancer. RESULTS: Four patterns of microcalcifications were noted in association with prostate cancer: (1) dystrophic calcification in the comedo-type necrosis of Gleason pattern 5, (2) intraluminal calcification in cribriform-type Gleason pattern 3 prostate cancer, (3) intraluminal calcification in small acinar adenocarcinoma, and (4) stromal calcification within collagenous micronodules associated with prostate cancer. Microcalcifications were noted in 32% of prostates without cancer; 1.9% of randomly selected prostates demonstrated microcalcifications associated with prostate cancer. CONCLUSIONS: Microcalcifications are less common in association with prostate cancer than with benign prostatic ducts and acini. However, intraluminal microcalcifications associated with an atypical small glandular proliferation should not be taken as unequivocal evidence of a benign process.     

Triiodothyronine restricts myofibrillar growth and enhances beating frequency in cultured adult rat cardiomyocytes

Epidemiological and laboratory data support a role for vitamin D in the growth and differentiation of human prostatic cells. These findings prompted us to ask whether prostatic cells could convert 25-hydroxyvitamin D3 (25-OH-D3), the major circulating metabolite of vitamin D3, to 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], the hormonally active metabolite, in a manner similar to cultured human keratinocytes. Therefore, we investigated three well-characterized human prostate cancer cell lines, LNCaP, DU 145, and PC-3; two primary cultures of cells derived from noncancerous human prostates (one normal and one benign prostatic hyperplasia); and primary cultures of normal human keratinocytes for their ability to synthesize 1,25(OH)2D3. Assays were performed in the presence of 25-OH-D3 as the enzyme substrate and 1,2-dianilinoethane, an antioxidant and free radical scavenger, and in the presence and absence of clotrimazole, a cytochrome P450 inhibitor. DU 145 and PC-3 cells produced 0.31 +/- 0.06 and 0.07 +/- 0.01 pmol of 1,25(OH)2D3/mg protein/h, respectively. No measurable 1,25(OH)2D3 was detected in LNCaP cells. The normal and benign prostatic hyperplasia primary cultures and keratinocyte cultures produced 3.08 +/- 1.56, 1.05 +/- 0.31, and 2.1 +/- 0.1 pmol of 1,25(OH)2D3/mg protein/h, respectively, using a calf thymus receptor binding assay to measure 1,25(OH)2D3 in the presence of 1,2-dianilinoethane. The identity of the analyte as 1,25(OH)2D3 was supported by high performance liquid chromatography using [3H]25-OH-D3 as the enzyme substrate and a solvent system that is specific for 1,25(OH)2D3. The production of 1,25(OH)2D3 in the prostate cancer cell lines and in the primary cultures was completely inhibited in the presence of clotrimazole. This report demonstrates that two of three human prostate cancer cell lines, as well as primary cultures of noncancerous prostatic cells, possess 1alpha-hydroxylase activity and can synthesize 1,25(OH)2D3 from 25-OH-D3. Together with recent data indicating that 1,25(OH)2D3 inhibits the invasiveness of human prostate cancer cells (G. G. Schwartz et al., Cancer Epidemiol. Biomark. Prev., 6: 727-732, 1997), these data suggest a potential role for 25-OH-D3 in the chemoprevention of invasive prostate cancer.     

Differential expression of telomerase activity in human cervical cancer and cervical intraepithelial neoplasia lesions

PURPOSE: Telomeres are tandem arrays of repeated DNA sequences located at the ends of eukaryotic chromosomes, and are synthesized by the enzyme telomerase. Loss of telomeric DNA may play an important role in the development of human cancers. However, very little is known about the status of telomerase during human cervical cancer development. PATIENTS AND METHODS: Telomerase activity was measured by telomere repeat amplification protocol (TRAP) assay in 24 cervical cancers, one carcinoma in situ (CIS), and 20 cervical intraepithelial neoplasia (CIN) lesions. Adjacent nontumor cervical tissue from the same 24 cervical cancer patients and normal cervical tissues from 11 control individuals also were examined for the presence of telomerase activity. RESULTS: Twenty two of the 24 (91.7%) cervical cancer specimens and the single CIS tissue were strongly positive for telomerase activity. Relatively weak but distinctive telomerase activity also was detectable in one of four CIN-I (25%), two of eight CIN-II (25%), and two of eight CIN-III (25%), respectively. However, telomerase activity was not found in the 24 corresponding nontumor cervical tissues from the same cervical cancer patients and the 11 normal cervical tissues from control individuals. CONCLUSION: The majority of cervical cancers contain strong telomerase activity. Significant proportions of noncancerous CIN tissues also contain telomerase activity, although weaker than that in cervical cancer. It seems that there is a progressive increase of telomerase activity in association with an increased degree of cervical malignancy. These results seem to suggest that the expression of telomerase may play a crucial role in cervical cancer carcinogenesis.     

Surgical significance of telomerase activity in noncancerous liver tissue from patients with hepatocellular carcinoma

Telomerase activity has been detected in tissue from noncancerous liver of patients with chronic liver disease, but its functional significance remains to be elucidated. We therefore evaluated the telomerase activity in surgically obtained noncancerous liver tissue from 20 hepatocellular carcinoma (HCC) patients. Two samples of noncancerous liver tissue were obtained from each patient: one from the parenchyma adjacent to the HCC nodules of the resected specimen; the other from the parenchyma distant from the HCC nodules of the remnant liver. Telomerase activity was assayed by a non-radioisotope quantitative system based on "TRAP-eze." Five samples from the noncancerous liver tissue adjacent to the HCC nodules (25.0%) were telomerase-positive; all such cases showed high-grade malignant potential, such as intrahepatic metastasis and/or portal vascular invasion and infiltration of the fibrous capsule in the corresponding HCC nodules, and telomerase positivity showed neither a relationship with the histological activity index scores nor a correlation with liver function. Interestingly, no telomerase activity was detected in any of the 20 samples obtained from the parenchyma of the remnant liver. These results indicate that telomerase in noncancerous liver tissue is associated not with the hepatic condition accompanying HCC, but with the biological characteristics of the tumor itself, and may derive from infiltrating cancer cells. Determination of telomerase status may aid in designing more effective surgical procedures.     

One core positive prostate biopsy is a poor predictor of cancer volume in the radical prostatectomy specimen

PURPOSE: In view of the recent increase in patients presenting with only 1 core positive for prostate carcinoma, we examined the correlation in tumor volume between the biopsy and the subsequent radical prostatectomy specimen. MATERIALS AND METHODS: We studied a total of 169 consecutive prostate biopsies with matched radical prostatectomy specimens and selected 48 patients with only 1 positive core. RESULTS: Cancers found in the biopsy regardless of their size were associated with a wide range of cancer volume in the radical prostatectomy specimens, and the amount of cancer in the biopsy was a poor predictor of the volume of cancer in the prostatectomy specimen. Even with a cancer of 3 mm. or less in the biopsy, 57% of patients had cancer of clinically significant volume (greater than 0.5 ml.). Other modalities for the evaluation of prostate cancer such as Gleason score and clinical stage were not helpful in segregating patients with clinically significant from those with insignificant volume of cancer. However, when combined with a preoperative serum prostate-specific antigen higher than 10 ng./ml., 1 core positive biopsy could reliably predict the presence of cancer of significant volume. CONCLUSIONS: One core only positive prostate biopsy, when accompanied by an elevated serum prostate specific antigen value (greater than 10 ng./ml.), strongly suggests the presence of clinically significant cancer.     

Numerical chromosomal anomalies in latent adenocarcinomas of the prostate

BACKGROUND: Even the high incidence of clinically diagnosed prostate cancer is exceeded by the frequency of tumors detected at autopsy. However, there is some debate concerning the malignant potential of these so-called "latent prostate cancers." In this study, prostate cancers detected at autopsy were investigated for the presence of numerical aberrations of chromosomes 7, 10, 17, X, and Y. METHODS: Prostates from 57 autopsies, performed on male patients aged 45 years or older, were histologically investigated for the presence of cancer. Interphase cytogenetics, an in situ hybridization method with chromosome-specific probes, was performed on paraffin sections. RESULTS: Of the 57 specimens investigated, 23 contained foci of prostate cancer. Three prostates contained more than one tumor focus. Interphase cytogenetics could be performed successfully in 19 specimens. Of the 22 tumor foci investigated, 14 were disomic and 8 were nondisomic for the five chromosomes tested. Ploidy correlated significantly with the presence of a Gleason score of 7 or higher (P = 0.0109), but not with a tumor volume larger than 0.5 cm3, or with patient age over 75 years. CONCLUSIONS: Some latent prostate cancers display a nondisomic chromosomal status and a low histologic differentiation in spite of a small tumor volume, suggesting a more aggressive potential in a subset of these tumors.     

Distinguishing clinically important from unimportant prostate cancers before treatment: value of systematic biopsies

PURPOSE: We assessed the ability of diagnostic tests to distinguish clinically unimportant cancers. MATERIALS AND METHODS: We correlated T stage (based on digital examination and ultrasound), prostate specific antigen (PSA), PSA density and pathological features of cancer in systematic biopsy specimens with features of cancer in 170 radical prostatectomy specimens. Clinically unimportant cancers were defined as small (0.5 cm.3 or less), well or moderately differentiated and confined to the prostate. RESULTS: Of the patients 10% had an unimportant cancer. On logistic regression analysis the 2 significant predictors were maximum length of cancer in any core and PSA density. Of 12 patients with maximum cancer length 2 mm. or less and PSA density less than 0.1., 75% had an unimportant cancer compared to 5% of the remaining 158 (p < 0.0005). CONCLUSIONS: Quantitative analysis of systematic biopsy specimens combined with PSA density provides valuable staging information and helps to identify cancers of low biological potential.     

Differential nuclear matrix protein expression in prostate cancers: correlation with pathologic stage

PURPOSE: Nuclear Matrix Proteins (NMP) have been shown to be tissue and cell-type specific. Several unique NMPs have been investigated in various cancerous tissues, including prostate, bladder and kidney, and some are presently utilized as tumor markers. This study was aimed at characterizing the differential NMP expression in the pathologically more aggressive prostate cancers. METHODS: High resolution two-dimensional gel electrophoresis and silver staining was used to elucidate the NMP distribution of fresh prostate cancer nuclei, obtained from 39 radical prostatectomy specimens, surgically removed from men with clinically localized prostate cancer. Based on the final pathological grading, specimens were grouped according to predicted prognosis: poor--with seminal vesicle (SV) or lymph node (LN) involvement or established capsular penetration (ECP) with gleason score >7; intermediate--organ confined (OC) or focal capsular penetration (FCP) with gleason score 7 or ECP with gleason score 6; and good--with OC or FCP and gleason score <7. RESULTS: A specific charged protein (YL-1) of molecular weight 76 kD and isoelectric range 6.0-6.6 was found to be consistently present in 19 of 19 aggressive cancers. It was present only in 1 of 10 in the group with good prognosis and weakly positive in 9 of 10 in the intermediate group. CONCLUSIONS: Within this preliminary study, the expression of YL-1 appears to be related to aggressive prostate cancer, suggesting a potential marker of poor prognosis for clinically localized prostate cancer. Further characterization of the identity and function of this NMP is needed to fully ascertain its clinical potential.     

Correlation between bone metabolic markers and bone scan in prostatic cancer

PURPOSE: We examined the correlation between bone metabolic markers and bone scintigraphy in prostatic cancer. MATERIALS AND METHODS: Osteoblastic and osteoclastic markers, prostate specific antigen (PSA) and bone scans were investigated in 83 specimens from 70 patients with prostatic cancer, including 32 with and 38 without bone metastasis. RESULTS: All markers except for osteocalcin were significantly greater in patients with than without bone metastasis. Pyridinoline cross-linked carboxyterminal telopeptide, an osteoclastic marker, reflected the extent of bone metastasis more accurately than PSA and other bone markers. CONCLUSIONS: Pyridinoline cross-linked carboxyterminal telopeptide might assist PSA and bone scintigraphy in monitoring metastatic bone activity of prostatic cancer.     

Epidural anaesthesia for caesarean section in an achondroplastic dwarf

Telomerase is a ribonucleoprotein that synthesizes telomeric DNA on chromosomal ends. Telomerase activation has been seen in many immortal cell lines and cancers. Telomerase activity was analyzed in prostate carcinoma; in coexistent prostatic intraepithelial neoplasia (PIN), benign prostatic hyperplasia (BPH), atrophy and normal tissue; and in benign prostate glands. Telomerase activity was detected in 80 of 87 (92%) prostate cancers. Forty-one matched samples (from a total of 32 cases) were available for comparative analysis. The presence of telomerase activity in adjacent PIN, BPH, and normal tissue was correlated with telomerase activity in the malignant epithelium. In these adjacent tissues, telomerase activity was found in 11 of 15 (73%) PINs, 13 of 26 (50%) BPHs, and 1 of 6 (16%) atrophy and 4 of 11 (36%) normal tissues. In contrast to the BPH tissue from cancer-bearing glands, all 16 BPH specimens from patients only diagnosed with BPH were telomerase activity negative. In cancer samples, there was no correlation between telomerase activity and Gleason grade or preoperation prostate-specific antigen level. Our data indicate that telomerase activity is present in most prostate cancers. The high rate of telomerase activity in the benign-appearing areas of these glands may be attributed either to the presence of occult cancer cells or to early molecular alterations of cancer that were histologically inapparent.     

The effect of prostate volume, age, total prostate specific antigen level and acute inflammation on the percentage of free serum prostate specific antigen levels in men without clinically detectable prostate cancer

PURPOSE: We determine the influence of age, prostate volume, total serum prostate specific antigen (PSA) level and histological evidence of acute inflammation in biopsy specimens on the percent free serum PSA level in men without clinically detectable prostate cancer. MATERIALS AND METHODS: We studied 70 men with total PSA levels of 2.6 to 9.9 ng./ml. who had undergone at least 3 sets of prostate biopsies that were negative for cancer as part of our PSA based prostate cancer screening program. Total and free PSA levels were measured using Hybritech immunoassays. Prostate volume and the presence of acute inflammation were determined from the most recent transrectal ultrasonography and prostate needle biopsy. RESULTS: Percent free PSA levels correlated significantly with age (r = 0.48, p = 0.0001) and prostate volume (r = 0.44, p = 0.0002) but not with total PSA (r = 0.04, p = 0.7). The mean percent free PSA did not differ for those with or without acute inflammation. Multivariate regression models demonstrated that age and prostate volume were significant predictors of percent free PSA. CONCLUSIONS: Among men without detectable prostate cancer and a total PSA level between 2.6 and 9.9 ng./ml. percent free serum PSA was higher in older men and in men with a larger prostate gland but was not influenced by total PSA level or the presence of acute inflammation in the prostatic biopsy specimen.     

Ratio of free-to-total prostate specific antigen in serum cannot distinguish patients with prostate cancer from those with chronic inflammation of the prostate

PURPOSE: We demonstrate the effect of chronic inflammation of the prostate on the ratio of free-to-total prostate specific antigen (PSA) in serum calculated as a percentage of free PSA and, therefore, that percentage of free PSA is an unspecific means to distinguish among prostate cancer, chronic prostatitis and benign prostatic hyperplasia (BPH). MATERIALS AND METHODS: Total, free and percentage of free PSA was measured in 66 men with prostate cancer, 119 with BPH and 17 with asymptomatic chronic prostatitis. In all patients the diagnosis was histopathologically confirmed by microscopic examination of prostatic specimens after sextant biopsy, transurethral prostatic resection or prostatectomy. RESULTS: The median values of total, free and percentage of free PSA were 4.11 microg./l., 0.75 microg./l. and 20.4% in patients with BPH, 10.0 microg./l., 0.84 microg./l. and 8.5% in those with prostate cancer, and 7.60 microg./l., 1.23 microg./l. and 10.6% in those with chronic prostatitis. Patients with prostate cancer and chronic prostatitis had a significantly lower percentage of free PSA than those with BPH. Receiver operating characteristics curve analysis showed that percentage of free PSA as a discriminator between prostate cancer and BPH was not suitable for differentiating between prostate cancer and chronic prostatitis. CONCLUSIONS: Chronic prostatitis is not characterized by elevated total PSA concentrations alone but also by a decreased percentage of free PSA, a tendency similar to that in prostate cancer. This unspecific change in percentage of free PSA must be considered to interpret the percentage of free PSA correctly.     

Sex steroid-binding globulin in serum of children with psoriasis

Intraluminal prostatic crystalloids (IPC) are more common in prostate cancer acini than in benign acini. This study was undertaken to evaluate the hypothesis that crystalloids seen in a benign biopsy may indicate an increased risk of a concomitant prostatic carcinoma. A total of 600 patients underwent more than one prostate biopsy. For 394 patients the results of the biopsy were either negative or positive for prostate cancer. After exclusion of patients whose biopsy results were considered negative but coded as high-grade prostatic intraepithelial neoplasia or were suspicious for cancer or whose slides were unavailable for review, 331 patients remained. Biopsy results for these patients were evaluated for the presence of IPC. Also, 18 completely-embedded benign prostates from cystoprostatectomy specimens from patients with bladder cancer were evaluated for the presence of IPC. Seven hundred twenty-five biopsy specimens were reviewed; 51 (7%) contained crystalloids. Thirty-two of 634 (5%) benign biopsy specimens and 19 of 91 (21%) prostatic carcinoma biopsy specimens contained crystalloids. Sixteen of 331 patients (5%) had crystalloids in the initial benign biopsy specimen; 6 patients subsequently were determined to have carcinoma (38%), and 10 continued to have negative results (62%). Three hundred fifteen initial benign biopsies did not show crystalloids; 83 (26%) patients were subsequently diagnosed as having prostatic carcinoma (p = 0.238, Fisher's Exact Test, chi-square test). The IPC were found in 5 of 18 cystoprostatectomy prostates (28%). In this study, the presence of IPC on the initial biopsy specimens was not a significant risk factor for a subsequent diagnosis of prostate cancer. The IPC were not uncommon in prostates without cancer.     

Presence of Streptococcus anginosus DNA in esophageal cancer, dysplasia of esophagus, and gastric cancer

We recently reported cloning of Streptococcus anginosus (S. anginosus) DNA fragments containing the 16S ribosomal gene from DNA samples of surgical specimens of gastric cancers. To investigate the specificity of S. anginosus infection, Southern blot analysis with S. anginosus 16S ribosomal DNA probe and PCR analysis with S. anginosus-specific primers were performed in DNA samples prepared from 15 esophageal cancers, 43 gastric cancers, 16 lung cancers, 10 cervical cancers, 14 renal cell carcinomas, 10 colorectal cancers, and 19 bladder cancers. We frequently found S. anginosus DNA sequences in DNA samples from esophageal cancer and gastric cancer tissues, as well as in those from dysplasia of the esophagus of esophageal cancer patients. No S. anginosus DNA bands were detected by Southern blot analysis on DNAs from the noncancerous portions of the esophagus or the stomach. By PCR analysis with 35 cycles, only 7% of the noncancerous portion of the esophagus was shown to contain S. anginosus sequences. No S. anginosus sequences were found in DNAs from cancers in lung, cervix, and kidney, but they were found in 1 of 10 colon cancers.     

Immuno-hemolytic transfusion reactions. II Physiopathologic basis and diagnosis

Prostatic intraepthelial neoplasia (PIN) is a putative premalignant change that bears a morphological similarity to prostatic cancer and shows increased frequency, severity, and extent in patients with prostate cancer. This article discusses the evidence for PIN as a premalignant lesion, reviews the morphology, terminology, appropriate grading system, and diagnostic significance of PIN, as well as describes management recommendations for further evaluation when PIN is diagnosed in prostate resection and biopsy specimens. Clinical management of high-grade PIN found in transurethral resection of the prostate (TURP) or prostate biopsy specimens should include repeat transrectal ultrasound (TRUS) and prostate biopsy for early detection of prevalent coexistent prostate cancer. In cases of high-grade PIN, increased surveillance methods have the potential to decrease morbidity and mortality by early cancer diagnosis.     

Intracellular levels of SGP-2 (Clusterin) correlate with tumor grade in prostate cancer

Our previous observations in LNCaP cells in vitro demonstrated an association between apoptotic cell death resistance and SGP-2 (Clusterin) overexpression. Accordingly, we hypothesized that high levels of cellular SGP-2 would aid in identifying biologically aggressive prostate cancer cells with unique survival advantages. To test this hypothesis, 40 archival radical prostatectomy and/or biopsy specimens of varying grades of prostate cancer were subjected to immunohistochemical SGP-2 staining. The resulting epithelial stains were quantified subjectively on a scale of 1-3 by four independent observers. Benign prostatic epithelial cells from young donors served as controls and showed a consistently weak staining intensity. In contrast, prostate cancer specimens showed varying degrees of staining intensity that correlated with a Gleason pattern (P = 0.006). This correlation supports the hypothesis that protection from apoptotic death may account, in part, for biologically aggressive tumor behavior.