Itsuhiro Takizawa

Androgen deprivation promotes intratumoral synthesis of dihydrotestosterone from androgen metabolites in prostate cancer

Intratumoral synthesis of dihydrotestosterone (DHT) from precursors cannot completely explain the castration resistance of prostate cancer. We showed that DHT was intratumorally synthesized from the inactive androgen metabolites 5α-androstane-3α/β,17β-diol (3α/β-diol) in prostate cancer cells via different pathways in a concentration-dependent manner. Additionally, long-term culture in androgen-deprived media increased transcriptomic expression of 17β-hydroxysteroid dehydrogenase type 6 (HSD17B6), a key enzyme of oxidative 3α-HSD that catalyzes the conversion of 3α-diol to DHT in prostate cancer cells. Correspondingly, the score for HSD17B6 in tissues of 42 prostate cancer patients undergoing androgen deprivation therapy (ADT) was about 2-fold higher than that in tissues of 100 untreated individuals. In men receiving ADT, patients showing biochemical progression had a higher HSD17B6 score than those without progression. These results suggested that 3α/β-diol also represent potential precursors of DHT, and the back conversion of DHT from androgen derivatives can be a promising target for combination hormone therapy.

Primary solitary fibrous tumor (SFT) in the retroperitoneum

BACKGROUND Solitary fibrous tumor (SFT) is an infrequent but distinct neoplasm, which generally arises from submesothelial connective tissue in the pleura. SFT is rarely recognized in extrathoracic sites, and histologically identical conditions have also been reported in the retroperitoneum, although their pathophysiology has not been extensively investigated. METHODS We present four cases of primary SFT in the retroperitoneum, and review 37 similar cases in the previous literature. RESULTS About 40% of patients were asymptomatic, and 19.2% and 15.4% presented with an abdominal mass and urinary symptoms, respectively. The tumor size ranged between 2 and 26 (mean 9.1) cm. Sixty-three percent of tumors showed nonspecific development with haphazard distribution of bland short spindle or polygonal cells with or without collagenous bundles and stromal hyalinization. In 22.0%, hemangiopericytomatous appearance was seen. About 15% of cases showed histologically malignant characteristics. The tumor cells were immunoreactive for vimentin in all cases, CD34 in 91% and Bcl-2 in 86%. All tumors were excised, and in 85.4% of cases, tumors did not recur postoperatively for 6 to 48 months. No significant difference was found between the recurrence rate of histologically benign and malignant cases. Cases positive for both CD34 and Bcl-2 had no recurrence. CONCLUSIONS The identification of SFT in the retroperitoneum is of importance because histopathological indicators of malignancy are not necessarily associated with clinical malignant potential in many cases of retroperitoneal SFT. Retroperitoneal SFT showing typical pathological features with expression of CD34 and Bcl-2 is associated with a favorable outcome following excision.

Serum prostate-specific antigen levels reflect the androgen milieu in patients with localized prostate cancer receiving androgen deprivation therapy: Tumor malignant potential and androgen milieu†‡

Although androgen deprivation therapy (ADT) has a marked impact on the androgen milieu in vivo and outcomes of prostate cancer (PCa), it remains unclear which parameters reflect the androgen milieu during ADT or whether the milieu is associated with PCa aggressiveness.

Decline of the Red Blood Cell Count in Patients Receiving Androgen Deprivation Therapy for Localized Prostate Cancer: Impact of ADT on Insulin-like Growth Factor-1 and Erythropoiesis

OBJECTIVES To elucidate the mechanism of blood hemoglobin loss in patients with prostate cancer during androgen deprivation therapy (ADT), and to examine the activity of the growth hormone (GH)/insulin-like growth factor-1 (IGF-1) axis during ADT, which plays an important role in hematopoiesis. METHODS A total of 83 patients with localized prostate cancer, who received ADT, were prospectively studied on the basis of their blood samples at the baseline and after ADT for 6 months. RESULTS Before ADT, the IGF-1 level was correlated with the red blood cell (RBC) count (Spearmans rank correlation coefficient analysis [rs]=0.315, P=.011), hemoglobin (rs=0.278, P=.018), and mean corpuscular volume (rs=0.266, P=.020), but such relationships disappeared after ADT. After ADT, the serum IGF-1 level increased compared with that at the baseline (21+/-6 vs 18+/-5 nmol/L, respectively, P<.001), but no change was observed in the serum GH level (P=.691). There was no difference between erythropoietin and interleukin-6 concentrations before and after ADT (P=.852 and P=.208, respectively). The hemoglobin concentration and RBC count declined after ADT compared with those before treatment (P<.001 for each). Although the mean corpuscular volume declined after ADT (P=.002), the mean cell hemoglobin was comparable between before and after ADT (P=.676). CONCLUSIONS Despite the unaffected GH, erythropoietin, and interleukin-6 levels, the serum IGF-1 concentration was elevated by ADT. Even with the increased IGF-1 level, the RBC count and hemoglobin concentration declined after ADT. IGF-1 in the bone marrow erythroid progenitor cells might be functionally inactivated during ADT.

Oncological results, functional outcomes and health-related quality-of-life in men who received a radical prostatectomy or external beam radiation therapy for localized prostate cancer: a study on long-term patient outcome with risk stratification

Health-related quality-of-life (HRQOL) after a radical prostatectomy (RP) or external beam radiation therapy (EBRT) has not been studied in conjunction with oncological outcomes in relation to disease risk stratification. Moreover, the long-term outcomes of these treatment approaches have not been studied. We retrospectively analyzed oncological outcomes between consecutive patients receiving RP (n=86) and EBRT (n=76) for localized prostate cancer. HRQOL and functional outcomes could be assessed in 62 RP (79%) and 54 EBRT (79%) patients over a 3-year follow-up period (median: 41 months) using the Medical Outcomes Study Short Form-36 (SF-36) and the University of California Los Angeles Prostate Cancer Index (UCLA PCI). The 5-year biochemical progression-free survival did not differ between the RP and EBRT groups for low-risk (74.6% vs. 75.0%, P=0.931) and intermediate-risk (61.3% vs. 71.1%, P=0.691) patients. For high-risk patients, progression-free survival was lower in the RP group (45.1%) than in the EBRT group (79.7%) (P=0.002). The general HRQOL was comparable between the two groups. Regarding functional outcomes, the RP group reported lower scores on urinary function and less urinary bother and sexual bother than the EBRT group (P<0.001, P<0.05 and P<0.001, respectively). With risk stratification, the low- and intermediate-risk patients in the RP group reported poorer urinary function than patients in the EBRT group (P<0.001 for each). The sexual function of the high-risk patients in the EBRT group was better than that of the same risk RP patients (P<0.001). Biochemical recurrence was not associated with the UCLA PCI score in either group. In conclusion, low- to intermediate-risk patients treated with an RP may report relatively decreased urinary function during long-term follow-up. The patients HRQOL after treatment did not depend on biochemical recurrence.

Bone metabolic disorder in patients with prostate cancer receiving androgen deprivation therapy (ADT): impact of ADT on the growth hormone/insulin‐like growth factor‐1/parathyroid hormone axis

Although androgen deprivation therapy (ADT) has been associated with bone loss in patients with prostate cancer, its mechanism remains unclear. The growth hormone (GH)/insulin‐like growth factor‐1 (IGF‐1)/parathyroid hormone (PTH) axis plays a critical role in bone synthesis, but its activity during ADT is also unknown.

Prediction of pathological and oncological outcomes based on extended prostate biopsy results in patients with prostate cancer receiving radical prostatectomy: a single institution study

BackgroundThe prediction of pathological outcomes prior to surgery remains a challenging problem for the appropriate surgical indication of prostate cancer. This study was performed to identify preoperative values predictive of pathological and oncological outcomes based on standardized extended prostate biopsies with core histological results diagrammed/mapped in patients receiving radical prostatectomy for prostate cancer clinically diagnosed as localized or locally advanced disease.MethodsIn 124 patients with clinically localized or locally advanced prostate cancer (cT1c–cT3a) without prior treatment, pathological outcomes on the surgical specimen including seminal vesicle involvement (SVI), positive surgical margin (PSM), and perineural invasion (PNI) were studied in comparison with clinical parameters based on the results of 14-core prostate biopsies comprising sextant, laterally-directed sextant, and bilateral transition zone (TZ) sampling.ResultsConcerning the association of pathological outcomes with oncological outcomes, patients with PSM and PNI on surgical specimens had poorer biochemical-progression-free survival than those without PSM (logrank p = 0.002) and PNI (p = 0.003); it was also poorer concerning SVI, although the difference was not significant (p = 0.120). Concerning the impact of clinical parameters on these pathological outcomes, positive TZ and multiple positive biopsy cores in the prostatic middle were independent values predictive of SVI with multivariate analyses (p = 0.020 and p = 0.025, respectively); both positive TZ and multiple positive prostatic middle biopsies were associated with larger tumor volume (p < 0.001 in both). The percentage of positive biopsy cores (%positive cores) and biopsy Gleason score were independent values predictive of PSM (p = 0.001) and PNI (p = 0.001), respectively. Multiple positive cores in the prostatic base were associated with proximal/bladder-side PSM (p < 0.001), and also linked to poorer biochemical-progression-free survival (p = 0.004). Clinical T stage had no association with these pathological outcomes.Conclusions%positive cores and Gleason score in extended biopsies were independent values predictive of PSM and PNI in prostate cancer clinically diagnosed as localized or locally advanced disease, respectively, which were associated with poorer oncological outcomes. When diagramming biopsy-core results, extended biopsy may provide additional information for predicting oncological and pathological outcomes including SVI in patients clinically diagnosed as having localized or locally advanced disease.Virtual slidesThe virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/8790262771042628

Insulin-like growth factor-1 is associated with regulation of the luteinizing hormone production in men receiving androgen deprivation therapy with gonadotropin-releasing hormone analogues for localized prostate cancer.

BACKGROUND Luteinizing hormone (LH) during androgen-deprivation therapy (ADT) with gonadotropin-releasing hormone analogues (GnRHa) has been thought to be biologically inactive, and the regulation of LH during ADT with GnRHa is thus unknown. Insulin-like growth factor-1 (IGF-1) is involved in the regulation of cell proliferation and differentiation, and IGF-1 production in the liver is dependent on growth hormone (GH) secretion from the anterior pituitary. Despite the presence of IGF-1 receptors in the gonadotroph, associations between the GH/IGF-1 and pituitary-gonadal axes, e.g., whether IGF-1 elicits the LH secretion, remain unclear. METHODS Seventy-one patients with localized prostate cancer, who received ADT with GnRHa, were prospectively studied based on their blood samples before treatment and after ADT for 6 months. We employed highly sensitive assays for measurement of serum testosterone (electrochemiluminescence immunoassay), GH/IGF-1 (radioimmunoassay), adrenocorticotropic hormone (ACTH: immunoradiometric assay), LH (chemiluminescent immunoassay), and dehydroepiandrosterone sulfate (DHEA-S: chemiluminescent enzyme immunoassay). RESULTS No correlation was noted between the pretreatment LH and IGF-1 levels; after ADT, the serum LH level was closely correlated with the IGF-1 concentration [Spearmans correlation coefficient (rs) = 0.370, P = 0.001]. The serum levels of androgens and gonadotropins reduced following ADT (P < 0.001 in all). The serum IGF-1 level increased (22 ± 6 nmol/L) compared with that at the baseline (19 ± 5 nmol/L) (P < 0.001), but no change was observed in the serum GH concentration between before and after ADT (1.4 ± 2.3 vs. 0.9 ± 0.9 μg/L, respectively, P = 0.691). The serum testosterone level was not correlated with the LH level either before or after ADT. The testosterone and DHEA-S levels after ADT were correlated with ACTH concentration (rs = 0.367, P = 0.002 and rs = 0.354, P = 0.002, respectively). We did not identify any correlations between the serum IGF-1 concentration and Gleason score, PSA value, or androgen levels. CONCLUSIONS During ADT with GnRHa, IGF-1 possibly promotes LH production, although its role is unclear. Associations among pituitary-gonadal, pituitary-adrenal, and GH/IGF-1 axes represented by IGF-1-mediated LH secretion and ACTH-mediated androgen synthesis are of interest, since both prostate epithelium proliferation and male anabolic activity are involved in these 3 axes. Assessment of oncologic outcomes is warranted for their significance in patients with prostate cancer.

Trilostane, an inhibitor of 3β-hydroxysteroid dehydrogenase, has an agonistic activity on androgen receptor in human prostate cancer cells

The intracellular androgen metabolism and cell activity in prostate cancer cells with mutated (LNCaP-FGC) or wild-type (VCaP) androgen receptors in the presence of trilostane, an inhibitor of 3β-hydroxysteroid dehydrogenase, were examined. Trilostane suppressed the intracellular production of androstenedione, testosterone, and dihydrotestosterone from dehydroepiandrosterone in LNCaP-FGC cells. In both LNCaP-FGC and VCaP cell types, the prostate-specific antigen (PSA) levels in media were increased by trilostane alone in a concentration-dependent manner. Both cells pretreated with trilostane showed a dose-dependent decrease in PSA production with bicalutamide (P<0.001). Trilostane should be used with particular concern when treating prostate cancer.

Primary gastrointestinal stromal tumor in the retroperitoneum

Abstract  Gastrointestinal stromal tumor (GIST) is the most frequent non‐epithelial neoplasm in the gastrointestinal tract. GIST has received much attention both for its clinical significance and biological nature, while the retroperitoneal condition identical to GIST has been rarely described. Presented herein is a case of GIST arising from the retroperitoneum in a 67‐year‐old man. The solid tumor measuring 4 cm was uncovered in the retroperitoneum, between the abdominal aorta and inferior vena cava, on computed tomography. The patient underwent surgical excision of the tumor. Histological examination showed proliferating spindle cells in the clearly demarcated tumor; immunoreactivity for Kit and CD34 in tumor cells confirmed the diagnosis of GIST. The histological origin of GIST is suggested to be gastrointestinal pacemaker cells, because they share specific immunoreactivity for CD117/Kit, which is also relevant to pathogenesis of GIST. The present case was a rare primary GIST in the retroperitoneum with typical immunopathological features.