Coexistence Case of Papillary Fibroelastoma and Lambl's Excrescence of the Left Heart, Which Is Occasionally Associated with Significant Stroke.

Papillary fibroelastoma (PFE) is a benign tumor that arises mostly from left-sided valves. PFE can cause stroke, and surgical resection may be needed. Lambl's excrescence (LE) is a filiform valvular lesion and is considered a possible cause of stroke. A 79-year-old man with light-headedness and left-sided hemiparesis was diagnosed with stroke. Transesophageal echocardiography (TEE) revealed a round-shaped mobile mass in the left ventricular outflow tract (LVOT), which was considered the cause of the stroke. Surgical resection was performed transaortically, and during surgery, a mass was incidentally detected on the noncoronary cusp (NCC), which was also resected followed by aortic valve replacement. Pathology confirmed that the mass in the LVOT was a PFE and that the filiform mass on the NCC was LE. We herein report a rare case of PFE in the LVOT and coexisting LE on the NCC. A careful examination via TEE helps to identify other possible causes of stroke hidden behind the obvious cause.

Filter paper-assisted cell transfer (FaCT) technique: A novel cell-sampling technique for intraoperative diagnosis of central nervous system tumors.

BACKGROUND: Intraoperative diagnosis of central nervous system (CNS) tumors provides critical guidance to surgeons in the determination of surgical resection margins and treatment. The techniques and preparations used for the intraoperative diagnosis of CNS tumors include frozen sectioning and cytologic methods (squash smear and touch imprint). Cytologic specimens, which do not have freezing artifacts, are important as an adjuvant tool to frozen sections. However, if the amount of submitted tissue samples is limited, then it is difficult to prepare both frozen sections and squash smears or touch imprint specimens from a single sample at the same time. Therefore, the objective of this study was to derive cells directly from filter paper on which tumor samples are placed. METHODS: The authors established the filter paper-assisted cell transfer (FaCT) smear technique, in which tumor cells are transferred onto a glass slide directly from the filter paper sample spot after the biopsy is removed. RESULTS: Cell yields and diagnostic accuracy of the FaCT smears were assessed in 40 CNS tumors. FaCT smears had ample cell numbers and well preserved cell morphology sufficient for cytologic diagnosis, even if the submitted tissues were minimal. The overall diagnostic concordance rates between frozen sections and FaCT smears were 90% and 87.5%, respectively (no significant differences). When combining FaCT smears with frozen sections, the diagnostic concordance rate rose to 92.5%. CONCLUSIONS: The current results suggest that the FaCT smear technique is a simple and effective processing method that has significant value for intraoperative diagnosis of CNS tumors. Cancer Cytopathol 2017;125:277-282. © 2016 American Cancer Society.

Immunohistochemical expression profiles of solute carrier transporters in alpha-fetoprotein-producing gastric cancer.

AIMS: Alpha-fetoprotein (AFP)-producing gastric cancer (GC) is an aggressive tumour with high rates of liver metastasis and poor prognosis, and for which a validated chemotherapy regimen has not been established. Drug uptake by solute carrier (SLC) transporters is proposed as one of the mechanisms involved in sensitivity to chemotherapy. In this study, we aimed to develop important insights into effective chemotherapeutic regimens for AFP-producing GC. METHODS AND RESULTS: We evaluated immunohistochemically the expression levels of a panel of SLC transporters in 20 AFP-producing GCs and 130 conventional GCs. SLC transporters examined were human equilibrative nucleoside transporter 1 (hENT1), organic anion transporter 2 (OAT2), organic cation transporter (OCT) 2, OCT6 and organic anion-transporting polypeptide 1B3 (OATP1B3). The rates of high expression levels of hENT1 (hENT1high ) and OAT2 (OAT2high ) were statistically higher in AFP-producing GC, compared with conventional GC. When analysing hENT1 and OAT2 in combination, hENT1high /OAT2high was the most particular expression profile for AFP-producing GC, with a greater significance than hENT1 or OAT2 alone. However, no significant differences in OCT2, OCT6 or OATP1B3 levels were detected between AFP-producing and conventional GCs. However, immunoreactivity for hENT1, OAT2 and OCT6 tended to be increased in GC tissues compared with non-neoplastic epithelia. CONCLUSIONS: Because hENT1 and OAT2 are crucial for the uptake of gemcitabine and 5-fluorouracil, respectively, our results suggest that patients with AFP-producing GC could potentially benefit from gemcitabine/fluoropyrimidine combination chemotherapy. Increased expression of hENT1, OAT2 and OCT6 may also be associated with the progression of GC.

Rapid immunocytochemistry with simple heat-induced antigen retrieval technique for improvement in the quality of cytological diagnosis.

Rapid immunocytochemistry (ICC) can improve the accuracy of intraoperative cytological diagnoses; however, it is usually applied without heat-induced antigen retrieval (HIAR). We established a HIAR method for rapid ICC and evaluated its efficacy and reliability. Rapidly fixed smear samples were immunostained using 35 antibodies. We compared the results of HIAR by boiling in a pot or heating in an electric kettle. The smears were incubated for 3 min with each primary antibody and immuno-enzyme polymer reagent, and for 1 min with diaminobenzidine solution. HIAR for 1 min using the kettle method yielded the best cellular integrity. For 32 out of the 35 antibodies, results achieved using rapid ICC within 11 min were comparable to that achieved using standard ICC. HIAR was essential for 13 antibodies. For two of the antibodies, HIAR was not required when standard ICC was applied, but consistent staining with rapid ICC was obtained only with HIAR. In conclusion, we established a rapid ICC procedure using a simple HIAR method, which allowed efficient immunostaining of a panel of antigens, including nuclear antigens, within only 11 min. The combined use of this rapid ICC technique with other staining techniques could be useful for improving intraoperative cytological diagnoses.

Differential diagnosis of reactive mesothelial cells and malignant mesothelioma cells using the cell proliferation markers minichromosome maintenance protein 7, geminin, topoisomerase II alpha and Ki-67.

OBJECTIVE: The aim of this study was to evaluate whether the immunocytochemical expression of cell proliferation markers, such as minichromosome maintenance protein 7 (MCM 7), geminin, topoisomerase II alpha (topo IIα) and Ki-67, which are different types of cell proliferation markers, could be useful for their differential diagnosis in reactive mesothelial cells and malignant mesothelioma cells obtained from body cavity fluids. STUDY DESIGN: Samples diagnosed and later histologically confirmed as reactive mesothelial cells (39 cases) or malignant mesothelioma (32 cases) in body cavity fluids were examined. Immunocytochemical staining of MCM 7, geminin, topo IIα and Ki-67 was performed with the immunoperoxidase polymer method. RESULTS: Labeling indices (LIs) of MCM 7 (cutoff value 20.0%; sensitivity 100%; specificity 100%), geminin (cutoff value 4.5%; sensitivity 88.0%; specificity 70.0%), topo IIα (cutoff value 11.0%; sensitivity 88.0%; specificity 92.0%) and Ki-67 (cutoff value 15.3%; sensitivity 78.0%; specificity 79.0%) of malignant mesothelioma cells were significantly higher than those of reactive mesothelial cells. CONCLUSION: LIs of MCM 7, geminin and topo IIα can be reliable tools for the differential diagnosis of reactive mesothelial cells and malignant mesothelioma cells.

Overexpression of the miR-34 family suppresses invasive growth of malignant melanoma with the wild-type p53 gene.

Malignant melanoma is the most aggressive neoplasm, with severe metastatic potential. microRNAs represent a class of endogenously expressed, small non-coding RNAs that regulate gene expression. As a consequence, the translation of these mRNAs is inhibited or they are destabilized resulting in downregulation of the encoded protein. The microRNA-34 (miR-34) family, which comprises three processed microRNAs (miR-34a/b/c) was identified as the mediator of tumor suppression by p53. Many reports suggest that the miR-34s contribute to the inhibition of invasion or metastasis in various tumor types. In this study, we evaluated the expression of the miR-34 family in four human melanoma cell lines (A375, G361, C32TG and SK-MEL-24) which have the wild-type p53 gene using real-time reverse transcription PCR. We also examined their generative and invasive characteristics using the cell proliferation assay and the invasion/migration assay, respectively. All four melanoma cell lines showed significant expression of miR-34s - A375: miR-34a 0.6176, miR-34b 0.7625, miR-34c 0.7877; G361: 7.6424, 16.4127, 22.0332; C32TG: 2.1630, 2.1091, 8.4425; SK-MEL-24: 0.3621, 2.5659, 8.5907. The cell doubling times of these cell lines in h:min were as follows: A375 23:23, G361 68:24, C32TG 47:22 and SK-MEL-24 67:03. The in vitro generation times of G361 and SK-MEL-24, which showed increased expression of miR-34c, were significantly shorter than A375 with decreased expression of miR-34c (p=0.0063, ANOVA). Invasion (%) of the four cell lines was as follows: A375 44.0%, G361 22.4%, C32TG 13.8% and SK-MEL-24 45.0%. In vitro invasiveness of G361 and C32TG, which showed increased expression of miR-34a, was significantly suppressed (p= 0.005, ANOVA). These results suggest that overexpression of miR-34a and c suppresses invasive and generative potentials, respectively, in human malignant melanoma.

Optimal antigen retrieval for ethanol-fixed cytologic smears.

BACKGROUND: Antigen retrieval, a crucial technique for immunostaining, is often carried out on formalin-fixed, paraffin-embedded (FFPE) tissue sections. The role of antigen retrieval in immunostaining of ethanol-fixed smears remains unclear. The authors evaluated the effects of 2 common antigen retrieval procedures, heat-induced antigen retrieval and protease-induced antigen retrieval, for immunostaining using a broad panel of antibodies. METHODS: Papanicolaou-stained ethanol-fixed smears from 36 surgical specimens were immunostained with 43 antibodies. Three widely used heat-induced antigen retrieval solutions, namely, citrate buffer (pH 6.0 and pH 7.0) and ethylenediaminetetraacetic acid solution (pH 8.0) for heat-induced antigen retrieval, and pronase were used. The staining results were compared between the ethanol-fixed smears and the corresponding FFPE tissue sections. RESULTS: Heat-induced antigen retrieval was essential for all the 9 antibodies examined against nuclear antigens, and for 7 of 26 antibodies against cytoplasmic and cell membrane antigens. Superior results were obtained using lower-pH heat-induced antigen retrieval solutions for ethanol-fixed smears than was the case for FFPE tissue sections; use of citrate buffer (pH 6.0) was optimal for most antibodies. For 17 antibodies against cytoplasmic/cell membrane antigens, satisfactory results were obtained even without antigen retrieval on the ethanol-fixed smears, whereas antigen retrieval was necessary for detection on the FFPE tissue sections. Protease-induced antigen retrieval frequently exerted deleterious effects on ethanol-fixed smears. Despite antigen retrieval, detection of 2 lymphocytic markers failed on ethanol-fixed smears. This limitation was overcome by heat-induced antigen retrieval on formalin vapor-fixed smears. CONCLUSIONS: In ethanol-fixed smears, most of the antibodies can be immunostained successfully without antigen retrieval treatment or mild heat-induced antigen retrieval using citrate buffer (pH 6.0). The optimal antigen retrieval condition for each antibody must be individually determined.

Pyothorax-associated lymphoma diagnosed by preoperative pleural effusion aspiration cytology: a case report.

BACKGROUND: Pyothorax-associated lymphoma (PAL) is a comparatively rare tumor, and it is difficult to definitively diagnose it preoperatively, especially in patients with only pleural thickening without mass formation. Pleural effusion aspiration cytology is a useful and easy diagnostic method for a large number of chest diseases. However, the cytologic findings of PAL have been rarely described. Here we report on the cytologic findings in a patient with PAL, manifested by pleural thickening without mass formation, and which was diagnosed preoperatively by pleural effusion aspiration cytology. CASE: A 64-year-old man was admitted to our hospital because of pleural thickening involving an empyema sac located in the left thorax and rapidly increasing pleural effusion. He had a 30-year history of chronic empyema and a 10-year history of diabetes mellitus. Left pleural effusion aspiration cytology showed malignant lymphoma. The patient was admitted to our hospital for PAL treatment. Because of poor respiratory function, he only underwent decortication with complete resection of the thickening pleural peel. However, he was well, without recurrence, 5 years after the operation. The histologic examination revealed that lymphoma cells were located only in the thickening pleural peel. CONCLUSION: This is a very rare case of PAL diagnosed by preoperative aspiration cytology for an increasing pleural effusion. This report demonstrates that pleural effusion aspiration cytology can be valuable for the diagnosis of PAL.

Significance of cell proliferation markers (Minichromosome maintenance protein 7, topoisomerase IIalpha and Ki-67) in cavital fluid cytology: can we differentiate reactive mesothelial cells from malignant cells?

The aim of this study was to evaluate whether immunocytochemical expressions of proliferation markers, such as minichromosome maintenance protein 7 (MCM 7), topoisomerase IIalpha (topo IIalpha), and Ki-67, in reactive mesothelial cells and malignant cells obtained from cavital fluids could be useful for their differential diagnosis. Samples diagnosed as reactive mesothelial cells (14 cases) or malignant tumors (28 cases) in cavital fluids were examined. Immunocytochemical staining of MCM 7, topo IIalpha, and Ki-67 was performed with the universal immunoperoxidase polymer method. In reactive mesothelial cells, MCM 7 was stained in a fine granular pattern and its distribution was uniform in the nuclei. Topo IIalpha and Ki-67 were stained in a coarse granular pattern and the distributions were the same as MCM 7. In contrast, in malignant cells, MCM 7 was stained in an irregular and fine granular pattern, and topo IIalpha and Ki-67 were stained in a uniform and coarse granular pattern. Labeling indices of MCM 7 (cut-off value; 30%, sensitivity; 100%, and specificity; 100%), topo IIalpha (cut-off value; 15%, sensitivity; 89.3%, and specificity; 92.9%) and Ki-67 (cut-off value; 30%, sensitivity; 64.3%, and specificity; 92.9%) of malignant cells were significantly higher than those of reactive mesothelial cells. MCM 7, topo IIalpha, and Ki-67 are different types of cell proliferation markers. MCM 7 and topo IIalpha, in particular, could be reliable tools for differential diagnosis between reactive mesothelial cells and malignant cells.

[Histopathological characteristics of radical prostatectomy specimen and long-term PSA changes in men with PSA levels of 4.0 ng/ml or less].

Out of 132 prostate cancer (Pca) patients who underwent radical prostatectomy 31 (mean age 65 +/- 5 years) had prostate specific antigen (PSA) levels of 4.0 ng/ml or less (low PSA group). The average PSA level was 3.3 +/- 0.5 ng/ml in the low PSA group and 8.5 +/- 5.5 ng/ml in patients with a higher PSA (high PSA group). The pT2 ratio of the radical prostatectomy specimens was 74% (23/31) in the low PSA group and 55% (55/101) in the high PSA group, pT3a was 16% (5/31) and 31% (31/101), pT3b was 10% (3/31) and 10% (10/101), pN1 was 0% and 5% (5/101), respectively. The digital rectal examination (DRE) gave a positive result significantly (p = 0.026) less frequently in the low PSA group (6/31 : 20%), than in the high PSA group (44/101 : 44%). However all three pT3b patients with a low PSA were positive in DRE. This suggests the importance of DRE to detect significant Pca with PSA < or = 4.0. PSA was measured at least three times for more than one year in 19 of the 31 patients with a low PSA level before diagnosis. In 14 of these 19 cases (74%), PSA velocity was more than 0.5 ng/ml/ year and PSA doubling time was less than 4 years. Some patients with significant Pca can not be detected with a PSA cutoff level at 4.0 ng/ml. We recommend that individuals have their own PSA levels, and that long-term changes of PSA are sometimes very important to detect cases of Pca with lower PSA.

Loss expression of uroplakin III is associated with clinicopathologic features of aggressive bladder cancer.

OBJECTIVES: Tissue-specific expression is of key importance in gene therapy and can be achieved by using tissue-specific promoters to drive therapeutic gene expression. The uroplakin (UP) promoter is a powerful tool for bladder cancer gene therapy, but the role of UP protein in the bladder remains unknown. This study aimed to detect UP III expression in transitional cell carcinoma (TCC) of the bladder and to determine whether the role of UP III heterogeneity is associated with predicting disease recurrence and patient survival. METHODS: Immunohistochemical staining for UP III was carried out in 92 archival radical cystectomy and 38 normal specimens and correlated with pathologic features and clinical outcomes. RESULTS: UP III expression was significantly decreased in bladder cancer tissues compared with normal controls (P <0.0001). Loss of UP III expression was associated with high-grade, muscle-invasive cancer, lymphovascular invasion (P <0.01), and decreased cancer-specific survival at a median follow-up of 25.3 months (P = 0.04). When adjusted for the effects of standard pathologic features, only lymph node metastases were associated with bladder cancer progression (P = 0.01) and mortality (P = 0.04). CONCLUSIONS: Loss of UP III expression is associated with established markers of biologically aggressive bladder cancer such as lymphovascular invasion, pathologic stage, and grade. UP III expression has limited prognostic value in patients with bladder TCC, but gene therapy viral vectors driven by the UP promoter would drive therapeutic gene expression in high-UP-expressing TCC cells, but not in aggressive low-UP-expressing TCC cells.

The maximum tumour length in biopsy cores as a predictor of outcome after radical prostatectomy.

OBJECTIVES: To evaluate maximum tumour length (MTL) in biopsy cores as a predictor of prostate-specific antigen (PSA)-failure, systemic failure, and death from prostate cancer after radical prostatectomy (RP). PATIENTS AND METHODS: We assessed 209 men with clinically localized prostate cancer treated with RP; preoperative variables were correlated with unfavourable pathological characteristics in the RP specimens and with outcome after surgery, using univariate and multivariate analysis. RESULTS: The median (range) MTL was 4 (0.2-19) mm and correlated with adverse pathological findings, including specimen Gleason score (P = 0.003), pT3 (P < 0.001), seminal vesicle invasion (P < 0.001) and lymph node involvement (P = 0.019) in multivariate analysis. Preoperative PSA (P < 0.001), biopsy Gleason score (P = 0.002), and MTL (P = 0.045) were independent predictors of PSA failure, whereas only MTL remained a predictor of systemic-failure (P < 0.001) and death from prostate cancer (P = 0.004). The median (range) follow-up after surgery was 90 (17-152) months, during which 83 patients had PSA failure, 20 developed systemic failure and 15 died from prostate cancer. CONCLUSIONS: The MTL correlates well with adverse pathological findings and appears to be an independent predictor of outcome after RP. Patients with a greater MTL might have cancer with an aggressive phenotype and therefore be candidates for more aggressive therapies.

Expression of chemoresistance-related proteins in alpha-fetoprotein-producing adenocarcinoma of the digestive organs.

alpha-fetoprotein-producing adenocarcinoma of the digestive organs (APAD) is known to show a poor prognosis. To clarify the characteristics of chemoresistance in APAD, three proteins of fluoropyrimidine chemotherapy association [dihydropyrimidine dehydrogenase (DPD), thymidine phosphorylase (TP) and thymidylate synthase (TS)] and one protein of cisplatin association [metallothionein (MT)] were immunohistochemically evaluated. Tissue samples were taken from 12 AFP-positive gastric cancers and 94 AFP-negative gastric cancers. Four AFP-positive cancer xenografts (one colonic, two pancreatic, and one biliary tract) and 17 AFP-negative cancer xenografts were also examined. In gastric cancers, high expression of TP was observed in 30% of AFP-negative tumors but in none of AFP-positive tumors (p=0.03). High expression of MT was found in 30% of AFP-negative tumors but in only one of the AFP-positive tumors. The TP-low and MT-low phenotype was noted in 92% of AFP-positive tumors and in 46% of AFP-negative tumors (p=0.004). None of the AFP-positive cancer xenografts revealed high TP expression and only one showed high MT expression. In the cellular level, TP and MT were scarcely co-expressed with AFP in either gastric cancer or xenograft series, using double immunostaining and serial sectioning techniques. There were no significant differences in the expression of DPD and TS between AFP-positive group and -negative group. However, DPD was frequently co-expressed with AFP in poorly differentiated medullary areas of the AFP-positive gastric cancers. The data presented herein suggest that APAD should be sensitive to cisplatin, but resistant to capecitabine and 5'-deoxyfluorouridine, fluoropyrimidines which are converted to 5-fluorouracil by TP. S-1, a fluoropyrimidine containing a strong DPD inhibitor, may be effective for AFP-positive gastric cancers with poorly differentiated medullary growth pattern.

Efficacy and morbidity of transrectal ultrasound-guided 12-core biopsy for detection of prostate cancer in Japanese men.

BACKGROUND: The objectives of the present study were to determine whether an extensive biopsy scheme contributes to enhanced detection of prostate cancer in Japanese men and to assess the associated pain and morbidity. METHODS: A total of 147 patients were included in this analysis, with 12 biopsy cores being obtained from each patient. Standard systematic sextant biopsy at the apex, mid-prostate and base of the prostate gland was carried out under local anesthesia and this was followed by the acquisition of additional sextant cores at the same levels from the far lateral peripheral zone. Each patient answered a self-administered questionnaire on pain and morbidity during the 5 days following biopsy. RESULTS: Overall, 39 patients (26.5%) received a diagnosis of prostate cancer. Nine patients (23.1%) were positive only at the standard sextant sites, three patients (7.7%) were positive exclusively at the far lateral sites and the remaining 27 patients (69.2%) were positive at both sites. Cancer was found most frequently in cores obtained from the apex (P = 0.009), with this trend being more evident in patients with abnormal rectal findings, positive sonographic findings, gland volume < 40 cm(3) and prostate-specific antigen density > 0.15 ng/mL/cm(3) (P < 0.03). These findings were also true for those with a prostate-specific antigen range from 4.1 to 20.0 ng/mL. A gradual decrease in incidence and grade of pain, hematuria and rectal bleeding was observed during the first 5 days after biopsy (P < 0.0001). CONCLUSIONS: Using this 12-core biopsy scheme, we found cancer most frequently in cores taken at the level of the apex. While the extensive procedure only marginally enhanced overall detection of prostate cancer, it was well tolerated with gradually decreasing pain and morbidity over a brief postbiopsy period. Further efforts to optimize biopsy schemes are warranted.

RM2 antigen (beta1,4-GalNAc-disialyl-Lc4) as a new marker for prostate cancer.

Although prostate-specific antigen (PSA) has been widely used for early detection of prostate cancer, PSA has problems with specificity and prediction of pathological stage. Therefore, a new marker for prostate cancer is urgently required. We examined expression of a novel carbohydrate antigen, beta1,4-GalNAc-disialyl-Lc(4), defined by the monoclonal antibody RM2, in prostate cancer using 75 cases of radical prostatectomy specimens. RM2 immunoreactivity was negative to weak in all benign glands, and weak to moderate in high-grade prostatic intraepithelial neoplasia. In prostatic adenocarcinoma, RM2 immunoreactivity was negative to weak (lower expression) in 20 cases, and moderate to strong (higher expression) in 55 cases. A clear difference of RM2 expression level was observed between Gleason patterns 3 and >/=4. Higher expression of RM2 antigen was significantly associated with primary Gleason pattern >/=4, high Gleason score (>/=8), larger tumor volume and advanced tumor stage. Furthermore, 5-year PSA failure-free survival was significantly lower in the higher expression group. However, no significant relationship was observed between RM2 expression level and preoperative serum PSA. Western blot analysis in prostate cancer cell lines PC3 and LNCap revealed that major 49-kDa and minor 39-kDa glycoproteins were common to both cells, but there was an increase of 59- and 125-kDa glycoproteins unique to LNCap and an increase of 88- and 98-kDa glycoproteins unique to PC3. RM2 antigen is a new histological marker for prostate cancer that may reflect the Gleason grading system. Identification of the glycoproteins carrying the RM2 antigen will provide new insights into the properties of prostate cancer.

Recurrent fulminant viral myocarditis with a short clinical course.

A 75-year-old man recovered from an episode of acute influenza. A myocarditis with a normalized level of serum cardiac troponin T, but less than 2 weeks after recovery, he rapidly fell into cardiogenic shock and died of fulminant myocarditis. The autopsied heart showed marked inflammatory cell infiltration that mainly consisted of mononuclear cells positive for CD8, suggesting that the second bout of myocarditis was caused by viral re-infection.

Caveolin-1 expression is a predictor of recurrence-free survival in pT2N0 prostate carcinoma diagnosed in Japanese patients.

BACKGROUND: The authors previously identified elevated caveolin-1 expression in human prostate carcinoma and determined that caveolin-1 levels as detected by immunohistochemistry of radical prostatectomy specimens offered novel prognostic information. A higher incidence of caveolin-1 expression also was reported in African-American men compared with white men in the U.S. To explore these ethnic/racial differences in caveolin-1 expression further, the authors evaluated caveolin-1 expression as a predictive marker in Japanese men with prostate carcinoma. METHODS: Immunohistochemical staining with a caveolin-1 specific antibody was performed on routinely processed paraffin sections from 152 consecutively collected radical prostatectomy specimens. The mean patient age was 64.3 years (range, 49-74 years; median, 64.5 years) and the mean follow-up period was 49.5 months (range, 1.3-103.3 months; median, 48.2 months). Caveolin-1 immunoreactivity was evaluated in association with patient's age; preoperative prostate specific antigen level; clinical stage; and pathologic features including Gleason score, extraprostatic extension, status of surgical margins, seminal vesicle involvement, lymph node involvement, and time to disease progression after surgery. RESULTS: Positive caveolin-1 immunostaining was detected in 46 of the 152 tumors (30.3%) and was found to be associated significantly with a positive surgical margin (P = 0.022). A higher incidence of caveolin-1 expression tended to be found in patients with poorly differentiated tumors (Gleason score > 7, 6-7, and < 6, 35.0% vs. 34.9% vs. 20.4%, respectively) or in patients with extraprostatic extension versus those without extraprostatic extension (35.4% vs. 24.7%) or patients with lymph node involvement compared with those without lymph node involvement (50% vs. 29.5%), although these differences did not reach statistical significance (P = 0.100, P = 0.150, and P = 0.178, respectively, by the Spearman correlation test). Kaplan-Meier analysis revealed that increased caveolin-1 expression was associated with an increased risk of disease progression at 5 years (P = 0.0122 by the log-rank test). In patients with organ-confined (pT2N0) disease, univariate Cox proportional hazards regression analysis revealed that positive caveolin-1 expression was the only significant predictor of disease recurrence after radical prostatectomy (P = 0.011; hazards ratio = 4.75; and 95% confidence interval, 1.43-15.76). CONCLUSIONS: The results of the current study confirm that positive caveolin-1 expression is associated with clinical markers of disease progression and is predictive of poor clinical outcome after surgery in Japanese patients with pT2N0 prostate carcinoma.

Anterior distribution of Stage T1c nonpalpable tumors in radical prostatectomy specimens.

OBJECTIVES: To determine the anatomic patterns of tumor distribution in radical prostatectomy specimens from nonpalpable prostate cancer. METHODS: Tumor maps directly traced from histologic slides of 62 radical prostatectomy specimens were superimposed by a computer-assisted imaging technique to create an idealized prostate gland at three levels: apex, mid-prostate, and base. To investigate specific patterns of tumor distribution, the sites of tumor in each quadrant were compared according to risk group stratification. The tumor extent was compared with the patterns of positivity in routine sextant biopsies. RESULTS: Among all patients, the tumor frequency was 85.5% in the mid-gland, 82.3% in the apex, and 48.4% in the base. Analysis by quadrant showed that tumors were significantly denser in the apex to mid-prostate. The primary extent of these tumors appeared to lie predominantly in the anterior half of the gland. Biopsy yields at the apex and mid-prostate appeared low compared with the frequency of cancers at these levels. No patterns specific to the different risk groups were found, but no tumors within the anterior base were found in the low-risk group. CONCLUSIONS: The primary extent of nonpalpable tumors appeared to lie predominantly in the anterior half of the gland at the apex to mid-prostate levels. Additional biopsy cores taken from more anterior regions of the gland may enhance the detection of nonpalpable cancers further.

The dynamics of prostate specific antigen during watchful waiting of prostate carcinoma: a study of 94 Japanese men.

BACKGROUND: For the moment, there is uncertainty about the usefulness of early treatment of localized prostate carcinoma, uncertainty about whether some patients with early cancer can be managed expectantly, and uncertainty about how such patients might be recognized. METHODS: The authors studied serial values of prostate specific antigen (PSA) in 94 Japanese men with diagnosed prostate carcinoma and who were managed by watchful waiting. Their median follow-up duration was 32 months (range, 1.6-118). The authors used a log-linear model to fit the values of PSA over time, and then they used the Cox survival model to relate the intercept (PSA amplitude) and slope (relative velocity) to observed local or systemic outcomes that were independent of PSA. RESULTS: The authors found that the log-linear model fit the serial values of PSA during watchful waiting very well. Prostate specific antigen amplitude related significantly to T classification (P = 0.0006), but not to grade (P > 0.2), and the relative velocity related significantly to both T classification (P = 0.009) and to grade (P = 0.02). Although the T classification, histologic grade, and log(PSA) at diagnosis were associated significantly with time to outcome, the combination of amplitude and relative velocity provided more information. These 2 PSA parameters resulted in a higher model likelihood ratio, and their individual P values in the Cox model were 0.0005 and 0.005, respectively. With these two in the Cox model, T classification, grade, log(PSA), and PSA doubling time provided no further significant information. CONCLUSIONS: A log-linear model seems to fit serial measurements of PSA during watchful waiting, and preliminary results suggest that both the amplitude and the relative velocity relate closely to clinical outcomes.

Artificial neural network analysis for predicting pathological stage of clinically localized prostate cancer in the Japanese population.

BACKGROUND: Although prostate cancer has been prevalent in Japan, there has been no particular model for predicting the pathological stage in the Japanese population. We examined whether artificial neural network analysis (ANNA), which is a relatively new diagnostic tool in prostate cancer, can be one of the predictive methods for predicting organ confinement, compared with the traditional logistic regression model, in the Japanese population for the first time. METHODS: The study population comprised 178 men who underwent radical prostatectomy at our institutions between October 1992 and May 1999. As additional pretreatment parameters to the preoperative serum PSA level, clinical TNM classification and biopsy Gleason score, the percentage of number of cores exhibiting traces of tumor, maximum tumor length in biopsy cores, PSA density and patient age were used. The predictive ability of ANNA with several parameters for a set of 36 randomly selected test data was compared with those of logistic regression analysis and 'Partin Tables' by area under the receiver operating characteristics (ROC) curve analysis. RESULTS: Of 178 patients, 97 (54.5%) had organ-confined disease but 81 (45.5%) had locally advanced disease. With three parameters, the area under the ROC curve of ANNA (0.825 +/- 0.071) was larger than those for logistic regression (0.782 +/- 0.079) and Partin Tables (0.756 +/- 0.087), but not to a significant extent (P = 0.690 and 0.541). Although the expansion of the parameters did not increase the difference in area under the ROC curve between the best ANNA and logistic regression (0.899 +/- 0.053 and 0.873 +/- 0.065, respectively), the difference between the best ANNA and Partin Tables did not reach but approached statistical significance (P = 0.157). CONCLUSION: Although more modeling optimization is necessary to improve the predictive accuracy and generalizability of ANNA, we suggest that there is the possibility for this new predictive method to evolve in the analysis of clinical staging of prostate cancer.