Lymphovascular invasion is significantly associated with biochemical relapse after radical prostatectomy even in patients with pT2N0 negative resection margin.

BACKGROUND: The significance of lymphovascular invasion (LVI) remains controversial, and the association of LVI with biochemical relapse was investigated in men treated with radical prostatectomy according to pathological results. METHODS: Data from 1268 patients undergoing radical prostatectomy between 2000 and 2009 were retrospectively reviewed. Clinicopathological variables were compared between LVI-negative and LVI-positive patients. Multivariate analyses by Cox proportional hazard model and Kaplan-Meier method were performed to identify risk factors for biochemical relapse in all patients, patients with pT2N0 and pT2N0 negative resection margin (RM). RESULTS: LVI information was available in 1160 cases, and LVI was seen in 121 cases (10.4%). Clinicopathological variables were significantly worse in LVI-positive patients than in LVI-negative patients. On multivariate analyses, PSA⩾10 ng ml(-1), pathological Gleason score ⩾8, pathological T stage ⩾3, lymph node metastasis, positive RM and LVI were independent predictors for biochemical relapse in all patients. In patients with pT2N0, PSA⩾10 ng ml(-1), pathological Gleason score ⩾8, positive RM and LVI were independent predictors for biochemical relapse. In patients with pT2N0 negative RM, LVI and pathological Gleason score ⩾8 were independent predictors for biochemical relapse (LVI; hazard ratio 3.809, 95% confidence interval 1.900-7.635, P-value<0.001, Gleason score ⩾8; hazard ratio 2.189, 95% confidence interval 1.199-3.999, P-value=0.011). With a median follow-up of 50 months, 5-year biochemical relapse-free survival in patients with pT2N0 negative RM was 95.7% in those with negative LVI in comparison to 85.3% in those with positive LVI (P<0.001, log rank). CONCLUSIONS: LVI was consistently a significant predictor for biochemical relapse after radical prostatectomy in not only all patients but also in patients with pT2N0 and pT2N0 negative RM. These results strongly support the significance of LVI as a predictor for biochemical relapse.

Impact of body mass index on clinicopathological outcome and biochemical recurrence after radical prostatectomy.

BACKGROUND: Accumulating evidence suggests that obesity is associated with tumor progression in prostate cancer (PCa) patients after radical prostatectomy (RP). We conducted a retrospective multicenter study to determine the effect of body mass index (BMI) on the clinicopathological characteristics and biochemical recurrence of PCa in Japanese men who underwent RP. METHODS: The medical records of 1257 men with PCa treated by RP without neoadjuvant therapy at four medical institutes between 2001 and 2009 were retrospectively reviewed. Patients were categorized into four groups using the World Health Organization (WHO) BMI classification and BMI quartiles. Associations of the various BMI categories with clinicopathological characteristics and biochemical recurrences were statistically evaluated. Biochemical recurrence was defined as a PSA level of >0.2 ng ml(-1). RESULTS: Of the 1257 patients, 230 (18.3%) experienced biochemical recurrence during the median follow-up period of 49 months. The median BMI was 23.8 kg m(-2), and 1.4% patients were underweight, 65.4% were of normal weight, 30.9% were overweight and 2.4% were obese (WHO classification). Preoperative PSA levels and PSA density (PSAD) tended to decrease as BMI increased. Pathological characteristics did not differ significantly among BMI categories. As per the WHO classification and quartile categories, biochemical recurrence rate was comparable among the BMI groups. After adjusting for other pre- and postoperative covariables, multivariate Cox proportional hazards analysis revealed that a high BMI did not have an independent impact on biochemical recurrence-free survival. CONCLUSIONS: Underweight Japanese PCa patients treated by RP had higher preoperative PSA levels and PSAD. High BMI was not associated with adverse pathological findings or increased biochemical recurrence rate in Japanese PCa patients treated with RP. Racial differences may exist in the relationship between obesity and outcomes of RP in PCa patients.

Plasma membrane-associated sialidase (NEU3) regulates progression of prostate cancer to androgen-independent growth through modulation of androgen receptor signaling.

Prostate cancers generally become androgen-independent and resistant to hormone therapy with progression. To understand the underlying mechanisms and facilitate the development of novel treatments for androgen-independent prostate cancer, we have investigated plasma membrane-associated sialidase (NEU3), the key enzyme for ganglioside hydrolysis participating in transmembrane signaling. We have discovered NEU3 to be upregulated in human prostate cancer compared with non-cancerous tissue, correlating with the Gleason score. NEU3 silencing with siRNA in prostate cancer PC-3 and LNCaP cells resulted in increased expression of differentiation markers and in cell apoptosis, but decrease in Bcl-2 as well as a progression-related transcription factor, early growth response gene (EGR-1). In androgen-sensitive LNCaP cells, forced overexpression of NEU3 significantly induced expression of EGR-1, androgen receptor (AR) and PSA both with and without androgen, the cells becoming sensitive to androgen. The NEU3-mediated induction was abrogated by inhibitors for PI-3 kinase and MAP kinase and more specifically by their silencing in the absence of androgen, being confirmed by increased phosphorylation of AKT and ERK1/2 in NEU3 overexpressing cells. NEU3 siRNA introduction caused reduction of cell growth of an androgen-independent PC-3 cells in culture and of transplanted tumors in nude mice. These data suggest that NEU3 regulates tumor progression through AR signaling, and thus be a potential tool for diagnosis and therapy of androgen-independent prostate cancer.

Sexual function following radical prostatectomy: a prospective longitudinal study of cultural differences between Japanese and American men.

We conducted a cross-cultural comparison of the recovery of sexual function and bother during the first 2 years after radical prostatectomy (RP) between American and Japanese men. A total of 275 Japanese and 283 American men who underwent RP alone were prospectively enrolled into longitudinal cohort studies of health-related quality of life outcomes. Sexual function and bother (distress) were estimated with English and validated Japanese versions of the UCLA Prostate Cancer Index before RP and 1, 2-3, 4-6, 12, 18 and 24 months after RP. Each subject served as his own control. Japanese men reported lower sexual function scores at baseline, even after adjusted for age, prostate-specific antigen (PSA) and comorbidity (38 vs 61, P<0.001). The two groups had similar baseline sexual bother (70 vs 69, P=0.84). Japanese men had a smaller improvement in sexual function (beta=0.8 vs beta=5.3) and bother (beta=0.2 vs beta=2.9) over time than did the American men postoperatively, after adjusting for baseline score, age, baseline PSA and nerve-sparing. American men were more likely than Japanese men to regain their baseline sexual function by 24 months after surgery (hazard ratio (HR)=1.60; 95% confidence interval (CI)=1.06-2.42). In contrast, American men were less likely than Japanese men to return to baseline sexual bother (HR=0.57; 95% CI=0.44-0.75). This study demonstrates that Japanese and American men experience different patterns of recovery of their sexual function and bother after RP. Ethnicity may be a contributing factor.

[Retrospective evaluation of PSA density for selection of biopsy candidates with prostate specific antigen in the gray zone].

PURPOSE: We examined the usefulness of prostate specific antigen density (PSAD) for selection of biopsy candidate with prostate specific antigen levels between 4.1 and 10.0 ng./ml. in prostate cancer screening retrospectively. MATERIALS AND METHODS: The screening was conducted on male candidates in Natori city, aged 55 years or older, for 6 years from 1994 through 1999. We could analyze serum PSA levels and PSA density in 118 men with PSA levels between 4.1 and 10.0 ng./ml. All of 118 men underwent ultrasound guided systematic prostate biopsy regardless of findings of digital rectal examination and transrectal ultrasound. Prostate volume was estimated by transrectal ultrasound measurements using the prolate ellipse formula (pi/6 x length x width x height). PSAD was calculated by dividing serum PSA level by prostate volume. Serum PSA levels were determined by Tandem-R assay. RESULTS: In 118 men, twenty-five men had prostate cancer. There was no significant difference in mean PSA between those with prostate cancer and those without prostate cancer, but the difference was significant in the mean PSA density (mean 0.26 and 0.16, respectively, p < 0.0001). Receiver operating characteristic curves for PSA and PSAD demonstrated superior benefit for PSAD in 118 men. A sensitivity, a specificity, a positive predictive value and a negative predictive value of PSAD cut-off of 0.15 were 88%, 52.7%, 33.3% and 94.2%. PSAD cut-off of 0.18 showed the highest sum of sensitivity and specificity, which gave a sensitivity of 80%, a specificity of 72%, a positive predictive value of 43.5% and a negative predictive value of 93.1%. PSAD cut-off of 0.15 would seem to be preferable to cut-off of 0.18 because of less cancer missing. CONCLUSIONS: Although further studies are needed to determine optimal cut-off value to be used in clinical practice, PASD seems to be useful for the selection of biopsy candidates with PSA levels of 4.1 to 10.0 ng./ml. in the prostate cancer screening.

Intrascrotal epidermoid cyst: report of two cases.

A 70-year-old man and a 52-year-old man each presented with a painless extratesticular, intrascrotal mass. Magnetic resonance imaging revealed a cystic mass and was the most useful modality for the diagnosis. Complete excisions were performed, and the lesions were histologically diagnosed as epidermoid cysts. Intrascrotal, extratesticular epidermoid cysts are uncommon lesions believed to be teratomas or the result of abnormal embryological closure of the median raphe. However, it is difficult to explain the etiology of some masses by either of these mechanisms.

Immediate-type allergy related to okra (Hibiscus esculentus Linn) picking and packing.

Two workers (cases A and B) engaged in picking and packing okra who had complaints of work-related allergic symptoms showed distinct positive intradermal reactions to two brands of okra extracts only with thresholds of 1 x 10(-8) w/v for Case A and 1 x 10(-6) w/v for Case B. Both also showed positive reactions to okra extracts in the Prausnitz-Küstner test and in the provocative nasal test. The radioallergosorbent test scores to the okra extract were determined to be 2 (defined as clear positive) for Case A and 1 (border line) for Case B. These findings indicated that the allergic conditions of these cases were from an IgE-mediated immediate-type allergy induced by handling okra. To confirm the etiology of the two cases 14 farmers engaged in picking and packing okra were examined. Among them, 8 subjects (57%) showed positive intradermal reactions to okra extracts. A close association between intradermal reactions to okra extracts and complaints of work-related allergic symptoms was seen in these subjects. These results confirm that the okra may be capable of inducing IgE-mediated immediate-type allergy to workers handling okra.

Immediate type of allergy in statis growers.

Three statis growers complaining of immediate allergic symptoms induced by harvesting statis in a plastic greenhouse were examined to clarify their allergic conditions. Distinct positive reactions in the intradermal test and nasal and eye provocation test to the statis extracts were shown in all three cases. High score of radioallergosorbent test (RAST) IgE and remarkable RAST inhibitory effects to the statis extracts were seen in these cases. The immunologic cross-reactivity between statis and chrysanthemum was absent in the RAST inhibition in the patient labeled case C who had complained of the same allergic symptoms when handling chrysanthemums in the off-season for harvesting statis. Those results indicated that the allergic conditions of the present cases were from an immediate type of allergy mediated by a specific IgE antibody to the statis extract.

[Case report of Farmer's lung disease in siblings in Kagoshima Prefecture].

Two cases of farmer's lung disease in siblings are reported. A 54-year-old male farmer, who had been engaged in stock work for 20 years, presented to our clinic for the second episode of fever, productive cough and shortness of breath. Chest roentgenogram revealed diffuse micronodular pattern, and mild hypoxemia was recognized on arterial blood gas analysis. Cytology obtained from BALF showed lymphocytosis, with especially increased OKT3, OKT4 positive cells and OKT4/8 ratio. The diagnosis was confirmed by highly positive reaction of precipitins to Thermoactinomyces vulgaris and granulomatous interstitial pneumonitis on histopathological examination. The second case was a 51-year-old female patient, the sister of the first case, who also worked as a stock farmer of another farm for 20 years. She presented with an episode of similar symptoms to the first case, one and a half years after the onset of her brother's symptoms. The findings of roentgenogram, BALF analysis, precipitins to T. Vulgaris and pathology were similar to those of the first case. The finding of high OKT4/8 ratio on BALF analysis in both cases is characteristic of formers lung disease, in contrast to the summer-type hypersensitivity pneumonitis which usually shows low OKT4/8 ratio in BALF. To our knowledge, this is the first report of farmer's lung disease in an area other than the northern part of Japan. Thus we conclude that farmer's lung disease may occur in Japan under any environmental conditions, and that some genetic factor may take part in the onset of this disease.

[Percutaneous transabdominal whole layer core needle biopsy for staging the urinary bladder cancer].

Accurate staging is one of the most important determinants necessary in planning an effective treatment for bladder cancer, but at the present time, staging by the conventional clinical methods are not completely reliable. Accordingly, we have newly developed a percutaneous transabdominal core needle biopsy technique capable of obtaining good cylindrical specimens of the entire layer. In order to obtain the core specimen of the bladder wall, which is a vesico-elastic material, the biopsy needle must penetrate the bladder wall at an extremely high speed. We have developed an original automatic biopsy instrument and modified the head of needle for this purpose. With this method, we could obtain good core specimens for pathological staging in about 90% cases. The correlation between the pathological stagings of core specimens and those of cystectomy specimens were in good agreement. This technique is accurate not only for preoperative pathological staging, but also monitoring histopathologically the responsiveness of multi-disciplinary treatment for invasive bladder cancer. This method allows us to determine the optimal therapeutic modality for managing individual patient with invasive bladder cancer.

[Whole layer needle biopsy for evaluation of neoadjuvant therapy to invasive bladder cancer].

The most important information for treatment of bladder cancer is to know its exact staging. A whole layer needle biopsy technique has been developed for this purpose. Recently, neoadjuvant therapy has been used for invasive bladder cancer. Although down staging of bladder cancer after neoadjuvant therapy are evaluated by CT or ultrasound, these imaging are not reliable. We examined 11 invasive bladder cancer patients by whole layer needle biopsy pre and post neoadjuvant therapy. All cases were pT3-4 by pretreatment biopsy. After neoadjuvant therapy 4 were changed to pT0 by needle biopsy, other cases were no change or minimal change. In 4 changed to pT0, 3 were done total or partial cyctectomy and the results of pathological diagnosis of cystectomized specimens were also pT0. Another one case changed to pT0 is selected as candidate for bladder sparing and the patient is now in close surveillance. All 4 cases changed to pT0 were done combined treatment by chemo (internal iliac artery infusion) and radiotherapy. In remaining 7 cases, pathological staging of surgical or autopsy specimen agreed with that of whole layer needle biopsy. Whole layer needle biopsy showed no severe complication, except minor bleeding from the bladder wall. Tumor seeding into the needle tract was not observed up to present time. In conclusion, this biopsy system is useful for evaluation of the change of stage with chemotherapy and/or radiation therapy. By using this technique we can select the cases for candidate of bladder sparing.

[Evaluation of bone metastases from renal cell carcinoma].

Twenty-nine cases of bone metastases from renal cell carcinoma were examined. Eight had metastatic bone pain as the initial symptom and were diagnosed that the primary lesion was in a kidney. In eight cases bone metastases appeared after treatment of the primary site. Seven had only bone metastases and another 22 cases had multiple metastases in organs such as the lung and lymph node when the bone metastasis was found. Curable surgical treatment was performed in only 2 cases. The survival curve of these patients were: 1 year; 41 per cent, 2 year; 30 per cent and 3 year; 15 per cent. Bone scan used for detection of bone metastases of carcinoma frequently ends with false positive results. CT scan and angiography are available for differential diagnosis of bone metastasis. We examined 6 cases (9 lesions) of bone metastases from renal cell carcinoma (3 pelvic bones, 2 lumbar bones, 2 femurs and 2 humerus). All lesions were hypervascular by angiography and were easily diagnosed as bone metastases. For early detection of bone metastases from renal cell carcinoma, angiography is useful because hypervascularity and tumor stain are easily detected even in such small lesions as 2 cm. Angiography was also useful for chemoembolization.

[Aspiration biopsy of regional lymph node in bladder cancer].

Percutaneous transabdominal fine needle aspiration biopsy (FNAB) of the pelvic and retroperitoneal lymph nodes was performed in 116 patients with bladder cancer. Metastasis to the regional lymph nodes was determined by this method in 21 patients. FNAB was positive in 10 of 12 patients having unequivocally positive or highly suspicious lymphogram, and in 11 of 104 patients (11%) having normal lymphogram. The results of FNAB were compared to the finding of lymph node dissection (LND) in 51 patients. FNAB and LND were negative in 43 patients and positive in 5. Two patients were FNAB negative but LND positive, and the remaining one case was FNAB positive but LND negative. The correlation between cytological diagnosis of FNAB and histological diagnosis of LND was 94 per cent. The survival rate of the cases of FNAB positive and lymphography negative was significantly higher than that of lymphography positive (p less than 0.01). The metastatic site of 5 cases with bladder cancer who are alive now without disease after more than 3 years was under the common iliac node and the number of the involved nodes was within 3.

[Prostate specific monoclonal antibody gained by glycolipid immunization].

Extraction of glycolipid component from hypertrophic and cancerous prostatic tissue were performed using chloroform-methanol solution and isopropanol-hexan-solution. The extract was separated into the "upper phase" and "lower phase" by Folchs fractionation technic. Each fraction was conjugated with acid treated salmonella minesota and than it was injected subcutaneously, intra-peritoneally and finally intravenously to BALB/c mice. Spleen cells from immunized mice were fused with P3X63, and antibody APG1 was obtained. APG1 shows a preferential reactivity towards prostatic tissue by the immunohistochemical analysis. Furthermore, the immunohistochemical analysis using enzyme and acid treated tissue and TLC immunostaining indicate that this monoclonal antibody specifically recognizes the sialylglycochain expressed in the prostatic tissue.

[Two cases of ectopic prostatic tissue in the prostatic urethra].

Two cases of ectopic prostatic tissue or adenomatous polyps with prostatic type epithelium in the prostatic urethra were reported. They were 30-and 33-year-old males suffering from gross-hematuria and from urethral pain on urination with terminal gross-hematuria. Endoscopic examination revealed papillary lesions from the dilated orifice of the prostatic utricle. Biopsied pathology demonstrated a tissue similar to that of the prostatic gland. PSA (prostatic specific antigen) stain using immunohistochemical methods was positive. Histogenesis and the importance of this lesion particularly as a cause of hematuria in the young male adult were discussed.

[Partial remission of pulmonary metastasis of malignant gonadal stromal tumor by salvage chemotherapy].

Fourteen malignant cases of gonadal stromal tumor were found among the cases reported in literature, but the roles of chemotherapy and radiotherapy have not been defined. We treated a malignant case and achieved 98.9 per-cent remission of lung metastases by salvage chemotherapy (cis-platinum + VP-16). A 34 year-old desk-worker, underwent left orchiectomy for testicular tumor on March 20, 1984. Histologic examination showed a malignant gonadal stromal tumor invading into the epididymis. Three course of adjuvant chemotherapy with cis-platinum, vinblastine, and peplomycin (PVP) were performed. However, chest X-ray films 13 months later revealed multiple lung metastases. Although 3 courses of combination chemotherapy with cyclophosphamide, adriamycin, vincristine, and prednisolone (CHOP) were given, no remission was obtained. However following 4 courses of combination chemotherapy with cis-platinum and VP-16, 98.9 per-cent remission of lung metastases was achieved. Subsequent bilateral residual lung tumors were resected. However, lung metastases recurred 3 months later, and the patient died on February 29, 1988. The autopsy revealed extensive lung, liver and pancreas metastases, but no lymph node metastases.

Hypersensitivity pneumonitis due to mushroom (Pholiota nameko) spores.

Hypersensitivity pneumonitis due to the inhalation of spores from the edible mushroom Pholiota nameko was demonstrated. A 52-year-old mushroom worker noticed cough, exertional dyspnea, and high fever several hours after work in the mushroom-cultivating room. His examination revealed bilateral basilar crepitations, fine granular shadows in both lung fields of chest x-ray film, and slight decrease in diffusion capacity. Precipitin and macrophage migration inhibition factor were found against the mushroom spore extract and not other contaminants and molds. Histologic finding by transbronchial lung biopsy showed granulomatous alveolitis. Manifest increase of lymphocytes was found in his bronchoalveolar lavage fluid. Provocative inhalation test with the extract revealed similar symptoms and signs in his workplace eight hours after inhalation. It seems to be the first case of hypersensitivity pneumonitis to the Pholiota nameko mushroom spores.

[Platinum concentrations in human tissue after administration of cisplatin].

Using flameless atomic absorption spectrophotometry, platinum concentrations in tissue samples were determined to clarify the distribution and accumulation of platinum in the human tissue after administration of cisplatin. Tissue samples were obtained at the time of autopsies or operation from 14 patients who were given cisplatin 0.7-20.1 mg/kg. Platinum concentrations were highest in the liver and testicle, high in the kidney, lung, heart and spleen, and lowest in the brain. In most organs except the brain, the tissue platinum concentrations increased exponentially according to the total dose of cisplatin. Platinum concentrations in metastatic tumors were generally somewhat lower than those in the normal parts of the organs, with the exception of cerebral metastasis. However, some of the metastatic tumors in the lung and brain showed higher concentrations than those in normal parts of the lung and brain, respectively.