Prostate-specific antigen adjusted for total prostatic tumor volume as a predictor for outcome after radical prostatectomy.

The aim of this study was to investigate the potential prognostic value of preoperative serum prostate-specific antigen levels adjusted for total tumor volume (PSA-TTV density) for outcome following radical prostatectomy for prostate cancer by retrospective review in 268 patients. Lower PSA-TTV density was not only associated with a significantly higher risk for biological failure (bF), systemic failure and cancer death but also an independent predictor for bF (hazard ratio, 6.3). Therefore, these data suggest that there are subsets of prostate cancer with lower PSA secretion levels, and this phenotype is associated with a higher risk of failure after surgery.

Impact of biochemical failure on long-term clinical outcome after radical prostatectomy for prostate cancer in Japan.

Detailed information is needed to understand the impact of biochemical failure (bF) on long-term outcome after definitive therapy for prostate cancer. In all, 223 consecutive men treated with radical retropubic prostatectomy were followed and long-term clinical outcome was investigated. Pathological examination revealed more locally advanced tumors in this study compared with the typical cohorts seen in the Western series. The Cox proportional hazards model indicates pretreatment prostate-specific antigen levels and risk group stratification to be a significant predictors for bF (P<0.05), but not for overall survival. Seminal vesicle involvement was a significant predictor of systemic progression, cancer death and overall survival (P<0.05). Positive surgical margin and bF were also found to be independent predictors of overall survival (P<0.05). In contrast to reports from Western countries, this study found a significant correlation between bF after radical prostatectomy and overall survival. This may reflect years-later detection of prostate cancer in Japan compared with Western series. Biochemical failure may ultimately be translated into decreased overall survival after sufficient follow-up.

Probability of prostate cancer at various levels of per cent free prostate specific antigen in Japanese men with total PSA of 4.1-10.0 ng/ml.

Estimates for the likelihood of prostate cancer at different levels of per cent free prostate specific antigen (PSA) were derived from experience with consecutive Japanese male patients with intermediate total PSA values who underwent ultrasound-guided biopsies and/or transurethral resection of the prostate. Receiver operating characteristic (ROC) curve analysis showed that in patients with a total PSA of 4.1-10.0 ng/ml, per cent free PSA identified those with prostate cancer better than did total PSA; per cent free PSA also proved superior in the subgroup whose glands appeared benign on palpation. The probabilities of prostate cancer at per cent free PSA values of 10-15, >15-20, >20-26 and >26% were 58.3, 40.8, 25.3, 14.3 and 7.6%, respectively, when analyzed without regard to findings on palpation. In patients with palpably benign glands, the corresponding values were 55.3, 35.4, 19.6, 9.7, and 4.6%, respectively. These probabilities are lower than those reported in Western countries, probably reflecting both different patterns of practice and racial differences. Race-specific assessment is recommended before applying a clinical test.

Co-expression of N-cadherin and alpha-fetoprotein in stomach cancer.

Although N-cadherin is necessary for organ formation originating in the endoderm, the expression of N-cadherin in gastric carcinoma and its role has not yet been reported. The present study was conducted to determine the pattern of immunohistochemical expression of E-cadherin and N-cadherin, using formalin-fixed, paraffin-embedded tissues from 97 primary gastric carcinomas, including 17 which were producing alpha-fetoprotein (AFP). Samples were subdivided into 50 tubular adenocarcinomas and 47 poorly differentiated adenocarcinomas. Results showed that E-cadherin was expressed in varying degrees in areas of cell adhesion between tumor cells, in 94 out of 97 cases studied. Three cases which showed no expression of E-cadherin were diagnosed as AFP-producing tumors by immunohistochemistry. Expression of N-cadherin was observed in varying degrees in the intercellular spaces between tumor cells in 11 tubular adenocarcinomas and in six poorly differentiated adenocarcinomas, including E-cadherin-negative cases, all of which were AFP positive. The present findings suggest a possible role for N-cadherin in gastric carcinoma.

Thrombotic thrombocytopenic purpura in autoimmune hepatitis.

A 19-year-old woman presented with clinical manifestations of sudden, fulminant thrombotic thrombocytopenic purpura associated with autoimmune hepatitis and autoimmune thrombocytopenic purpura. Although thrombotic thrombocytopenic purpura may, rarely, be associated with systemic lupus erythematosus and other autoimmune diseases, to our knowledge, the syndrome has never been described in association with autoimmune hepatitis. In this patient, too, the etiology of thrombotic thrombocytopenic purpura associated with autoimmune disease remains elusive. The patient was treated with corticosteroid, which brought about no improvement in her condition, and she died of multiorgan failure. Diagnosis is challenging, but prompt diagnosis is necessary because thrombotic thrombocytopenic purpura is a life-threatening syndrome whose prognosis has been improved significantly by early plasmapheresis treatment.

Treatment outcome by risk group after radical prostatectomy in Japanese men.

BACKGROUND: North American investigators have suggested the usefulness of risk-group stratification based on prostate-specific antigen (PSA), clinical stage and biopsy Gleason score for predicting the biochemical outcome of prostate cancer after radical prostatectomy. There have been no reports of the application of this stratification to early biochemical outcome after radical surgery in Japanese men. METHODS: The study population consisted of 178 men treated with radical retropubic prostatectomy and bilateral pelvic lymph node dissection at Kitasato University Hospital (n = 110) and Kurashiki Central Hospital (n = 68) between October 1992 and May 1999. Pathologic and biochemical outcomes after radical prostatectomy were analyzed based on risk-group stratification. Risk groups were further analyzed according to detailed pathologic findings at biopsy. RESULTS: The median follow-up period for the 178 patients after radical surgery was 41.5 months (range, 2.0--82.0 months; mean, 40.9 months). Fifty-eight patients experienced PSA failure at a median of 8.0 months following surgery (range, 0.0--58.0). Risk-group stratification distinctly defined groups of pathologic findings in the radical prostatectomy specimens. The proportion of patients with PSA failure for low, intermediate and high-risk groups were 9.5%, 23.9% and 56.9%, respectively (P < 0.0001). Use of the number of cores with cancer and maximum cancer length in biopsy cores failed to improve risk stratification for PSA outcome in all risk groups. CONCLUSIONS: Risk-group stratification based on preoperative variables may significantly improve a physician's ability to counsel patients about PSA outcome after radical prostatectomy. Further improvement in risk stratification may call for use of variables other than the pathologic information in biopsy cores.

A study of pretreatment nomograms to predict pathological stage and biochemical recurrence after radical prostatectomy for clinically resectable prostate cancer in Japanese men.

BACKGROUND: Accurate pretreatment identification of the risks that prostate cancer has extended beyond the gland and that it will recur would significantly influence practice patterns. Preoperative nomograms to predict such risks have not been developed for the oriental male population. METHODS: Construction of nomograms to predict preoperatively pathological outcome and early biochemical failure following radical prostatectomy in Japanese males was based on logistic regression analysis, with predicted probabilities and 95% confidence intervals for the final model being obtained by repeating the analysis on 1000 bootstrap samples from the original cohort. RESULTS: Prostate-specific antigen level, clinical stage and biopsy Gleason score contributed significantly to the prediction of pathological stage and of biochemical failure in the univariate analysis (p < 0.001). Combined use of these three variables predicted these treatment outcomes better than any single variable (p < 0.001). Nomograms combining these three variables to predict final pathological findings and early biochemical failure were then developed. The medians and 95% confidence intervals of the predicted probabilities are presented in the nomograms. CONCLUSIONS: This information enables clinicians to use their nomograms when counseling Japanese patients, leading to more informed treatment decisions and helping to identify those with a high risk of early biochemical failure. The nomograms may also be used to assure comparability of different treatment modalities in investigational trials.

Volume-weighted mean nuclear volume predicts tumor biology of clinically organ-confined prostate cancer.

BACKGROUND: Estimates of volume-weighted mean nuclear volume (MNV) are the only means by which unbiased estimates of three-dimensional parameters can be obtained from a single two-dimensional section, with stereological methods. The present study was conducted to elucidate the role of MNV in predicting tumor biology for patients treated with radical prostatectomy. METHODS: A retrospective prognostic study of 71 patients with T1/T2 disease, treated with radical prostatectomy alone, was performed. MNV was estimated using biopsy specimens based on a stereological method, and was compared with other preoperative clinical variables. For patients with prostate-specific antigen (PSA) failure, we determined the correlation of MNV with PSA doubling time (PSA DT) which was calculated using PSA values obtained with an ultrasensitive assay. RESULTS: Mean MNVs for pathologically organ-confined and non-organ-confined tumors were 198.9 and 236.3 microm3, respectively; this difference was significant (P = 0.0364). Univariate analysis showed that PSA, MNV, and Gleason score were significant predictors of prognosis (P = 0.0126, 0.0148, and 0.0375, respectively). Multivariate analysis revealed that MNV and preoperative PSA were powerful independent predictors of prognosis (P = 0.0160 and P = 0.0147, respectively), but the Gleason score was not correlated with prognosis (P = 0.4120). For patients with PSA failure, PSA DT was significantly correlated with MNV (r = -0.597, P = 0.0099). When these patients were classified using median PSA DT at 6 months into two groups, MNV was significantly greater in PSA rapid-riser group than in the slow-riser group (P = 0.0008), but no differences were observed between these groups in PSA, the Gleason score, or cancer volume. CONCLUSIONS: The findings of the present study suggest that MNV is a powerful predictor of PSA failure for patients with clinically organ-confined disease treated with radical prostatectomy. More importantly, they suggest that MNV can be a useful new parameter for prediction of tumor biology for patients with PSA failure after radical prostatectomy.

The role of volume-weighted mean nuclear volume in predicting tumour biology and clinical behaviour in patients with prostate cancer undergoing watchful waiting.

OBJECTIVE: To investigate whether the volume-weighted mean nuclear volume (MNV, the only means by which unbiased estimates of three-dimensional variables can be obtained from a two-dimensional section by stereological methods) at diagnosis correlates with tumour biology and clinical behaviour in patients with prostate cancer treated by watchful waiting. PATIENTS AND METHODS: In a prognostic study, 64 patients with clinically localized prostate cancer were followed prospectively with initial expectant management. The median (mean, range) follow-up was 22 (27, 6.0-68) months. The prostate specific antigen (PSA) doubling time (PSADT) was calculated by linear regression. The MNV was estimated using biopsy specimens, based on a stereological method, and compared with PSADT and traditional clinicopathological variables. RESULTS: PSADT was significantly associated with MNV, but not with other clinicopathological variables. The PSA 'rapid-riser' subset (PSADTor=median value) and PSA-stable subsets (P = 0.0017 and 0.004, respectively). On multivariate analysis using a stepwise Cox proportional hazards regression, only MNV remained independently significant as a predictor of clinical progression among the clinicopathological variables (P < 0.001). CONCLUSIONS: These findings suggest that cancer cell nuclear volume is significantly associated with tumour biology and behaviour in patients with prostate cancer. Although further study with a larger patient population is needed to confirm the findings, estimates of MNV may be an important prognostic indicator in men treated with watchful waiting.

Toxicity and health-related quality of life during and after high dose rate brachytherapy followed by external beam radiotherapy for prostate cancer.

BACKGROUND: The optimal protocol for combining high dose rate brachytherapy and external beam irradiation as treatment for localized prostate cancer is unknown. Toxicity rates and clinical and biochemical outcomes should be evaluated to validate the current treatment protocol. METHODS: Fifty-eight patients were treated for prostate cancer with high dose rate brachytherapy followed by 30 Gy of external beam radiation therapy. Toxicity during treatment and for 12-18 months thereafter, and treatment-related morbidity, were evaluated. Physician-assessed treatment-related toxicity was graded at the time of occurrence using the Radiation Therapy Oncology Group morbidity criteria. Four separate self-administered questionnaires were used to collect longitudinally demographic data and general and prostate disease-related measures of quality of life. RESULTS: Various degrees of rectal bleeding due to radiation proctitis were experienced by 13 patients (22%) at a median time of 11 months. Two of these patients needed hospitalization to undergo laser coagulation of the rectal mucosa. Study patients had statistically significant decreases in five SF-36 domains during the first month of treatment. All measures recovered by 12 months. Sexual function was not affected by irradiation. Lower urinary tract symptoms assessed by IPSS/QOL scores worsened significantly during the first month of treatment but later recovered to baseline levels. Physician-assessed RTOG scores failed to detect these changes. CONCLUSIONS: Morbidity associated with combined radiation therapy was greatest during the first month of treatment and affected quality of life significantly. Most measures recovered to baseline levels by 12 months following radiation therapy. Although the current protocol appears acceptable, measures should be taken to decrease treatment-related morbidity further.

Mixed carcinoid-adenocarcinoma of the liver.

A 61-year-old man with a mixed carcinoid-adenocarcinoma of the liver is described. Microscopic examination of the lesion showed a differentiated adenocarcinoma with distinct carcinoid components that stained positively for argyrophil. The tumor cells contained serotonin granules on immunohistochemical studies. Detailed examination disclosed no primary tumor in the gastrointestinal tract or in any other organ. Resection was considered impractical because there were multiple tumors. The patient received chemotherapy six times (cisplatin 60 mg/m2, epirubicin 40 mg/ m2 per month). The multiple tumors gradually shrank. At the time of this writing, the patient is still alive. To our knowledge, this is the first reported case of mixed carcinoid-adenocarcinoma of the liver.

Three-dimensional reconstruction of colorectal tumors from serial tissue sections by computer graphics: a preliminary study.

BACKGROUND/AIMS: We present herein the three-dimensional reconstruction of colorectal tumors, with particular reference to growth pattern into each layer of the colorectal wall, and measurement of tumor volume and surface area. METHODOLOGY: Conventional tissue section images of colorectal tumors were analyzed using a computer graphics analysis program. The two-dimensional extent of invasion by each tumor into each layer of intestinal wall were determined from the images of each section. Based on data from multiple sections, tumor and surrounding normal tissue layers were reconstructed three-dimensionally, and volume and surface area of the tumors were determined. RESULTS: Using this technique, three-dimensional morphology of tumor and tumor progression into colorectal wall could be determined. Volume and surface area of the colon tumor were 4871 mm3 and 1741 mm2, respectively. Volume and surface area of the rectal tumor were 1090 mm3 and 877 mm2, respectively. CONCLUSIONS: This technique may provide a new approach for pathological analysis of colorectal carcinoma.

Infrequent involvement of the anterior base in low-risk patients with clinically localized prostate cancer and its possible significance in definitive radiation therapy.

BACKGROUND: The zonal distribution and location of tumors in different subgroups of Japanese patients with clinically localized prostate cancer have not been fully described. The appropriate radiation treatment volume thus remains unclear. METHODS: Radical prostatectomy specimens of 141 consecutive patients with clinically localized prostate cancer were examined by the whole organ step-section technique. The zonal distribution and location of tumors at different levels of the gland were investigated after stratification into patient subgroups based on preoperative clinicopathological findings and risk group assessment. RESULTS: The median tumor volume was 2.8 cm3; 72 patients (51.1%) had pathologically organ-confined disease (pT2). Higher risk groups showed a statistically significant increase in tumor volume and a decrease in the rate of pathologically confirmed organ confinement. Involvement of the anterior base was found infrequently in certain patient subgroups: in only one of 20 patients (5%) with preoperative PSA <4.0 ng/ml, in three of 19 patients (15.8%) with specimen Gleason scores of 2-4 and in two of 32 patients (6.3%) identified as low-risk. CONCLUSIONS: Infrequent involvement of the anterior base in low-risk patients may be an intrinsic feature of clinically localized prostate cancer. Treatment volume modifications in these patients that reduce the radiation dose to the anterior base may be justified to avoid acute and late genitourinary toxicities.

[Malignant mesothelioma presenting as a perineal and pelvic mass--a trial of high dose intra-arterial methotrexate injection and irradiation].

A 50-year-old male with the complaints of lumbago and voiding disturbance was diagnosed to have malignant mesothelioma. Serum CA-125 was found to be elevated. The tumor was stained positive immunohistochemically only for CA-125 and epithelial membrane antigen. Magnetic resonance imaging of the pelvic demonstrated a large mass extending from the right external obturator muscle to the perineum. He was treated by two courses of methotrexate given intra-arterially (2,000 mg) followed by external beam irradiation at a total dose of 60 Gy. Disease progression was not apparent 15 months after treatment.

A pilot study of intermittent androgen ablation in advanced prostate cancer in Japanese men.

BACKGROUND: Permanent androgen ablation has been the mainstay of treatment for advanced prostate cancer. However, the favorable outcome seen in recent pilot studies of intermittent androgen ablation raises the possibility of overtreatment. METHODS: This study included 35 Japanese men with advanced prostate cancer. Initial androgen ablation continued for 2 months after PSA levels decreased to <4.0 ng/ml, then was withdrawn. Androgen ablation was reinstituted 2 months after PSA reached levels >10 ng/ml, when indicated clinically or on patient request. Cycling continued until androgen independence was reached. RESULTS: Mean follow-up was 21.0 months, representing an average of 2.5 cycles. Nine patients developed androgen independence at an average of 16.0 months following androgen ablation; three of these have died. Six of the nine patients with early biochemical progression had elevated alkaline phosphatase levels at entry; five of these exhibited a flare in alkaline phosphatase activity after initiation of androgen ablation. Mean bone mineral density (BMD) in the lumbar spines of 17 patients was 81.5 mg/cm3 at 23 months following therapy. The BMD of 10 of these patients was normal for their age. Four patients suffered bone fractures, none pathological. CONCLUSIONS: Intermittent androgen ablation may be an option for patients with advanced prostate cancer and may be especially beneficial for those with initially low BMD levels. Patients with elevated alkaline phosphatase levels at entry or a flare in its activity may not be ideal candidates. Whether prolonging time to androgen independence will provide benefit remains to be investigated in a randomized, prospective study.

Measuring the tumor volume of gastric carcinoma by computer image analysis: clinical significance.

The tumor diameter of gastric carcinoma, measured by gross or histologic examination, is a rough indicator of actual tumor size. Therefore we investigated the utility of three-dimensional reconstruction of tumors in gastric carcinoma. Altogether 105 primary gastric carcinoma lesions, consisting of 16 advanced and 89 early carcinomas, were analyzed. A total of 942 lesion tissue sections, comprising 2 to 37 sections per lesion (mean 9 sections), were examined histologically. Surface rendering using a computer graphics analysis program was then performed from serial sections to create a three-dimensional reconstruction of tumor morphology from which to measure tumor volume. For the 105 lesions the tumor diameter ranged between 4 and 106 mm (average +/- SE: 32.4 +/- 2.0 mm), and tumor volume ranged between 4 and 5853 mm3 (average +/- SE: 773.0 +/- 104.6 mm3). A significant correlation was found between tumor diameter and the log of the tumor volume (r = 0.733, p < 0.0001). Although the logs of tumor volume for advanced carcinomas were all > 2.5, in 11 of these 16 patients (66%) the tumor diameter was < 4 cm, and in one patient < 2 cm. In addition, tumor diameter did not differ significantly between the 16 advanced and the 89 early gastric carcinomas (p = 0.114), whereas the log of the tumor volume did (p < 0.0001). In conclusion, conventional measurements of tumor diameter as a rough indicator of tumor size can predict the actual tumor size of a gastric carcinoma. Three-dimensional reconstruction using computer graphics provides a better estimation of true tumor size and extent of progression than tumor diameter.

Cardiac dendritic cells and acute myocarditis in the human heart.

Cardiac dendritic cells are considered to play an important role in the immunoresponse of the heart. However, it is unclear whether these cells occur in human myocarditis and whether they function in similar ways to those in rats. Cardiac samples were obtained from 22 autopsied patients with myocarditis, and compared with 20 age-and sex-matched controls. Formalin-fixed hearts were immunostained by the LSAB method. Cardiac dendritic cells were detectable even in the control hearts (1.5 cells/high power field (HPF)). In the acute phase of myocarditis, the number of cardiac dendritic cells increased up to 12.6 cells/HPF (p<0.001). In the subacute phase of myocarditis, T cells (36.6 cells/HPF) and HLA-DR+ cells (10.2 cells/HPF) continued to infiltrate the periphery of the inflammatory lesions, but they had no expression without inflammation. In this study, cardiac dendritic cells were reactive for HLA-DR, but negative for CD68, and were characteristically large monocytes with long, slender, dendritic processes. Accordingly, they were clearly distinguishable from macrophages. In the human heart, cardiac dendritic cells may be recruited in the acute phase of myocarditis, and seem to play an important role in the succeeding immunoresponse.

Use of pretreatment prostate-specific antigen doubling time to predict outcome after radical prostatectomy.

The objective of this study was to better understand the implications of the rate of prostate-specific antigen (PSA) changes in prostate carcinoma. We retrospectively calculated PSA doubling times prior to surgery in 62 patients with prostate carcinoma. The calculated values were compared with final pathologic findings and with rates of PSA failure after surgery. PSA values increased during the period of observation in 82.3% of the patients, whereas 17.7% had levels that remained stable. The median calculated PSA doubling time in those with increasing levels was 25.8 months, with doubling times 36 months (P=0.02). Biochemical failure was more common in patients with rapid PSA doubling times (P<0.01). The calculated PSA doubling time prior to radical surgery is significantly associated with the final pathologic findings. Early PSA failure is more common in patients with rapid PSA doubling times prior to radical surgery. Prostate Cancer and Prostatic Diseases (2000) 3, 269-274