Takanobu Utsumi

FOXA1 promotes tumor progression in prostate cancer via the insulin-like growth factor binding protein 3 pathway.

Fork-head box protein A1 (FOXA1) is a “pioneer factor” that is known to bind to the androgen receptor (AR) and regulate the transcription of AR-specific genes. However, the precise role of FOXA1 in prostate cancer (PC) remains unknown. In this study, we report that FOXA1 plays a critical role in PC cell proliferation. The expression of FOXA1 was higher in PC than in normal prostate tissues (P = 0.0002), and, using immunohistochemical analysis, we found that FOXA1 was localized in the nucleus. FOXA1 expression levels were significantly correlated with both PSA and Gleason scores (P = 0.016 and P = 0.031, respectively). Moreover, FOXA1 up-regulation was a significant factor in PSA failure (P = 0.011). Depletion of FOXA1 in a prostate cancer cell line (LNCaP) using small interfering RNA (siRNA) significantly inhibited AR activity, led to cell-growth suppression, and induced G0/G1 arrest. The anti-proliferative effect of FOXA1 siRNA was mediated through insulin-like growth factor binding protein 3 (IGFBP-3). An increase in IGFBP-3, mediated by depletion of FOXA1, inhibited phosphorylation of MAPK and Akt, and increased expression of the cell cycle regulators p21 and p27. We also found that the anti-proliferative effect of FOXA1 depletion was significantly reversed by simultaneous siRNA depletion of IGFBP-3. These findings provide direct physiological and molecular evidence for a role of FOXA1 in controlling cell proliferation through the regulation of IGFBP-3 expression in PC.

High predictive accuracy of Aldosteronoma Resolution Score in Japanese patients with aldosterone-producing adenoma.

BACKGROUND Primary aldosteronism caused by aldosterone-producing adenoma is the most common curable cause of secondary hypertension, but despite resection, many patients continue to require antihypertensive medications to control their blood pressure postoperatively. The Aldosteronoma Resolution Score is a preoperative 4-item predictive model for the complete postoperative resolution of hypertension. Our aim was to validate the accuracy of this model in predicting postoperative resolution of hypertension in Japanese patients. METHODS The records of 91 Japanese patients who underwent unilateral adrenalectomy for aldosterone-producing adenoma were surveyed retrospectively. Patients were distributed into 2 groups according to whether blood pressure was normal without antihypertensive medications at 6 months postoperatively. Clinical and biochemical data were evaluated at baseline and after the 6-month follow-up. RESULTS At 6 months, blood pressure had normalized in 45% of the patients without antihypertensive medications. Multivariate logistic regression analysis revealed that patients who had complete resolution of hypertension were significantly more likely to have been taking ≤2 antihypertensive medications preoperatively, have a duration of hypertension of <6 years, and be female. The predictive accuracy of the Aldosteronoma Resolution Score was assessed using the area under the curve of receiver operator characteristics analysis. The value of the area under the curve was 0.81. CONCLUSION Our external validation revealed that the Aldosteronoma Resolution Score developed using Western data can identify accurately Japanese individuals with aldosterone-producing adenoma who are likely to have complete resolution of hypertension after adrenalectomy.

Current topics and perspectives relating to hormone therapy for prostate cancer

Prostate cancer is androgen-dependent, and hormone therapy, mainly achieved by androgen deprivation, has been one of the main treatment modalities in the clinical management of prostate cancer patients for more than six decades. In the 1980s, luteinizing hormonereleasing hormone agonists, which reduce testosterone to castration levels, were introduced Also, after the 1980s, nonsteroidal antiandrogens were developed in addition to steroidal antiandrogens. Since then, so-called maximum androgen blockade (MAB)/combined androgen blockade (CAB), which is a combination of surgical or medical castration and oral antiandrogens, has been developed. More recently, novel treatment modalities have been developed, such as intermittent androgen suppression, nonsteroidal antiandrogen monotherapy, and alternative antiandrogen therapy after relapse from initial MAB/CAB, The present article focuses on these treatment modalities to review current topics and perspectives with respect to hormone therapy for prostate cancer.

Preoperative masked renal damage in Japanese patients with primary aldosteronism: identification of predictors for chronic kidney disease manifested after adrenalectomy.

Correct interpretation of renal function in patients with primary aldosteronism is difficult before adrenalectomy, because subtle kidney impairment is often masked by glomerular hyperfiltration peculiar to primary aldosteronism. The aim of this study was to investigate postoperative changes in renal function for patients with primary aldosteronism and to identify clinical predictors of chronic kidney disease manifested postoperatively in the patients without pre‐existing chronic kidney disease.

External Validation of a Nomogram Predicting the Probability of Prostate Cancer Gleason Sum Upgrading Between Biopsy and Radical Prostatectomy Pathology Among Japanese Patients

OBJECTIVES To explore the rate of upgrading in a contemporary cohort from 2 Japanese institutions, and evaluating the predictive accuracy of the nomogram when applied to patients, regardless of race. Previous reports have indicated that a maximum of 43% of men with prostate cancer will show an upgraded Gleason score from biopsy to radical prostatectomy (RP). A preparative nomogram was developed at the University of Hamburg to predict the probability of upgrading from biopsy to RP specimen. METHODS Clinical and pathologic data of 503 patients from 2 Japanese institutions were supplied for validation. Nomogram-predicted probabilities of upgrading from biopsy to RP specimen were compared with actual rate of upgrading. The area under the receiver operating characteristic curve (AUC) was calculated for all patients. Calibration of the nomogram was achieved by comparing the predicted upgrading rate with that of an ideal nomogram. RESULTS Gleason sum upgrading was recorded in 29.8% of patients at RP. Accuracy of the nomogram was 79.2% (confidence interval, 75.1%-83.2%). Overall AUC was 0.79 when applied to the validation dataset, with individual institutional AUCs ranging from 0.79-0.80. Nomogram predictions of upgrading were not within 10% of an ideal nomogram. CONCLUSIONS Gleason sum upgrading between biopsy and final pathology represents an important consideration in treatment decision-making, and nearly one third of patients with prostate cancer will be upgraded. The Hamburg nomogram seems to provide reasonably accurate predictions regardless of minor variations in pathologic assessment, but is not necessarily so accurate when applied to Japanese patient population.

External validation and head‐to‐head comparison of Japanese and Western prostate biopsy nomograms using Japanese data sets

The objective of this study was to perform external validation of a previously developed prostate biopsy nomogram (the CHIBA nomogram) and to compare it with previously published nomograms developed in Japanese and overseas populations. Two different cohorts of patients were used: one from the Chiba Cancer Center (n = 392) in which transperineal 16‐core biopsy was performed, and another from Chibaken Saiseikai Narashino Hospital (n = 269) in which transrectal 16‐core biopsy was carried out. All patients were Japanese men with serum prostate‐specific antigen levels less than 10 ng/mL. The predictive accuracy of our CHIBA nomogram and of four other published nomograms (Finnes sextant biopsy‐based logistic regression model, Karakiewiczs sextant biopsy‐based nomogram, Chuns 10‐core biopsy‐based nomogram and Kawakamis three‐dimensional biopsy‐based nomogram) was quantified based on area under the curve derived from receiver operating characteristic curves. Head‐to‐head comparison of area under the curve values demonstrated that our nomogram was significantly more accurate than all other models except Chuns (P = 0.012 vs Finnes, P = 0.000 vs Karakiewiczs, and P = 0.003 vs Kawakamis). Our nomogram appears to be more useful for the Japanese population than Western models. Moreover, external validation demonstrates that its predictive accuracy does not vary according to biopsy approach. This is the first report to demonstrate that the predictive accuracy of a nomogram is independent from the biopsy method.

Clinical predictors of prolonged postresection hypotension after laparoscopic adrenalectomy for pheochromocytoma

BACKGROUND Although the perioperative management of patients with pheochromocytoma has been improving recently, severe hypotensive episodes can occur that require postoperative catecholamine support and are challenging to manage. Our aim was to identify the clinical factors that predict prolonged postresection hypotension in patients after laparoscopic adrenalectomy for pheochromocytoma. METHODS The records of 73 Japanese patients who underwent unilateral laparoscopic adrenalectomy for pheochromocytoma were surveyed retrospectively. Patients were divided into 2 groups according to whether catecholamine support was needed after postoperatively. Clinical and biochemical data were evaluated at baseline and after operation. RESULTS Thirty-four of 73 patients (47%) required continuous infusion of catecholamine to maintain systolic blood pressure >90 mm Hg at the end of the operation. The median duration of postoperative catecholamine support was 17 hours (range, 3-130) in these 34 patients. On multivariate analysis, tumor size >60 mm, urinary epinephrine levels >200 μg/day, and urinary norepinephrine levels >600 μg/day were independent predictors of prolonged hypotension requiring postoperative catecholamine support. Tumor size and urinary norepinephrine levels were significantly correlated with the duration of postoperative catecholamine support. CONCLUSION Larger tumor size and greater values of urinary epinephrine and norepinephrine levels were significant predictors of prolonged hypotension requiring postoperative catecholamine support. Moreover, tumor size and urinary norepinephrine levels were positively correlated with the duration of postoperative catecholamine support. Clinicians can identify and manage patients more effectively with a greater risk of prolonged hypotension after tumor resection using these preoperative clinical variables.

Association between serum sex hormone levels and prostate cancer: effect of prostate cancer on serum testosterone levels

Androgens are essential for prostatic growth and development, but also play a significant role in the pathogenesis of prostate disease. The traditional view that higher testosterone levels represent a risk factor for prostate cancer (PCa) appears to have little evidentiary support. Some studies have described a relationship between lower testosterone levels and more advanced disease. Serum androgen levels, within a broad range, are thus suggested to show no association with PCa risk, whereas low rather than high serum testosterone levels have been found to be associated with advanced or high-grade disease at the time of PCa diagnosis. Dihydrotestosterone, the principal prostatic androgen, is transformed from testosterone by type 1 and type 2 5alpha-reductase, and therapeutic benefits may thus be potentially achieved through the inhibition of 5alpha-reductase.

Development and External Validation of a Nomogram Predicting the Probability of Significant Gleason Sum Upgrading among Japanese Patients with Localized Prostate Cancer

Objective. The aim of this study is to develop a prognostic model capable of predicting the probability of significant upgrading among Japanese patients. Methods. The study cohort comprised 508 men treated with RP, with available prostate-specific antigen levels, biopsy, and RP Gleason sum values. Clinical and pathological data from 258 patients were obtained from another Japanese institution for validation. Results. Significant Gleason sum upgrading was recorded in 92 patients (18.1%) at RP. The accuracy of the nomogram predicting the probability of significant Gleason sum upgrading between biopsy and RP specimens was 88.9%. Overall AUC was 0.872 when applied to the validation data set. Nomogram predictions of significant upgrading were within 7.5% of an ideal nomogram. Conclusions. Nearly one-fifth of Japanese patients with prostate cancer will be significantly upgraded. Our nomogram seems to provide considerably accurate predictions regardless of minor variations in pathological assessment when applied to Japanese patient populations.

Analysis of Preoperative Detection for Apex Prostate Cancer by Transrectal Biopsy

Background. The aim of this study was to determine concordance rates for prostatectomy specimens and transrectal needle biopsy samples in various areas of the prostate in order to assess diagnostic accuracy of the transrectal biopsy approach, especially for presurgical detection of cancer in the prostatic apex. Materials and Methods. From 2006 to 2011, 158 patients whose radical prostatectomy specimens had been evaluated were retrospectively enrolled in this study. Concordance rates for histopathology results of prostatectomy specimens and needle biopsy samples were evaluated in 8 prostatic sections (apex, middle, base, and transitional zones bilaterally) from 73 patients diagnosed at this institution, besides factors for detecting apex cancer in total 118 true positive and false negative apex cancers. Results. Prostate cancer was found most frequently (85%) in the apex of all patients. Of 584 histopathology sections, 153 (49%) from all areas were false negatives, as were 45% of apex biopsy samples. No readily available preoperative factors for detecting apex cancer were identified. Conclusions. In Japanese patients, the most frequent location of prostate cancer is in the apex. There is a high false negative rate for transrectal biopsy samples. To improve the detection rate, transperitoneal biopsy or more accurate imaging technology is needed.