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Treatment of HBV infection with nucleic acid polymers and pegIFN is accompanied by transaminase elevations in 95% of participants. HBV viral rebound, partial cure (HBV DNA 2000 IU/mL, normal ALT) or functional cure (HBV DNA target not detected, HBsAgLLOQ, normal ALT) occurred in 27%, 38% and 35% of participants. Correlations between ALT, AST and GGT elevations, virologic baseline, response during therapy and HBV therapeutic outcome were investigated. A retrospective analysis of all 40 participants in the REP 401 study (NCT02565719) included maxima and area under the curve for ALT, AST and GGT, baseline virology, HBsAg and anti-HBs response and HBV therapeutic outcomes. ALT, AST and GGT elevations were asymptomatic, independent of baseline virologic status and anti-HBs response but correlated with HBsAg reduction ≥3 log

Hepatitis D virus (HDV) requires hepatitis B surface antigen (HBsAg) for its assembly and release. Current HBV treatments are only marginally effective against HDV because they fail to inhibit HBsAg production/secretion. However, monotherapy with the nucleic acid polymer REP 2139-Ca is accompanied by rapid declines in both HBsAg and HDV RNA. We used mathematical modeling to estimate HDV-HBsAg-host parameters and to elucidate the mode of action and efficacy of REP 2139-Ca against HDV in 12 treatment-naive HBV/HDV co-infected patients. The model accurately reproduced the observed decline of HBsAg and HDV, which was simultaneous. Median serum HBsAg half-life (t1/2) was estimated as 1.3 [0.9–1.8] days corresponding to a pretreatment production and clearance of ~108 [107.7–108.3] IU/day. The HDV-infected cell loss was estimated to be 0.052 [0.035–0.074] days−1 corresponding to an infected cell t1/2 = 13.3 days. The efficacy of blocking HBsAg and HDV production were 98.2 [94.5–99.9]% and 99.7 [96.0–99.8]%, respectively. In conclusion, both HBsAg production and HDV replication are effectively inhibited by REP 2139-Ca. Modeling HBsAg kinetics during REP 2139-Ca monotherapy indicates a short HBsAg half-life (1.3 days) suggesting a rapid turnover of HBsAg in HBV/HDV co-infection.

Chronic HBV infection results in various clinical manifestations due to different levels of immune response. In recent years, hepatitis B treatment has improved by long-term administration of nucleos(t)ide analogues (NUCs) and peg-interferon. Nucleic acid polymers (NAPs; REP 2139-Ca and REP 2139-Mg) are new antiviral drugs that block the assembly of subviral particles, thus preventing the release of HBsAg and allowing its clearance and restoration of functional control of infection when combined with various immunotherapies. In the REP 102 study (NCT02646189), 9 of 12 patients showed substantial reduction of HBsAg and seroconversion to anti-HBs in response to REP 2139-Ca, whereas 3 of 12 patients did not show responses (>1 log reduction of HBsAg and HBV DNA from baseline). We characterized the dynamic changes of HBV quasispecies (QS) within the major hydrophilic region (MHR) of the 'pre-S/S' open reading frame including the 'a' determinant in responders and nonresponders of the REP 102 study and four untreated matched controls. HBV QS complexity at baseline varied slightly between responders and nonresponders (P = .28). However, these responders showed significant decline in viral complexity (P = .001) as REP 2139-Ca therapy progressed but no significant change in complexity was observed among the nonresponders (P = .99). The MHR mutations were more frequently observed in responders than in nonresponders and matched controls. No mutations were observed in 'a' determinant of major QS population which may interfere with the detection of HBsAg by diagnostic assays. No specific mutations were found within the MHR which could explain patients' poor HBsAg response during REP 2139-Ca therapy.

Finite therapy of HBV/HDV co‐infection with REP 2139‐Ca and pegIFN has good long term safety and is accompanied by high rates of functional cure of HDV, normalization of liver function and additional functional cure of HBV. HBV functional cure is accompanied inactivation / clearance of cccDNA and clearance of integrated HBV DNA., The nucleic acid polymer REP 2139 inhibits assembly/secretion of hepatitis B virus (HBV) subviral particles. Previously, REP 2139‐Ca and pegylated interferon (pegIFN) in HBV/hepatitis delta virus (HDV) coinfection achieved high rates of HDV RNA and hepatitis B surface antigen (HBsAg) loss/seroconversion in the REP 301 study (NCT02233075). The REP 301‐LTF study (NCT02876419) examined safety and efficacy during 3.5 years of follow‐up. In the current study, participants completing therapy in the REP 301 study were followed for 3.5 years. Primary outcomes were safety and tolerability, and secondary outcomes were HDV functional cure (HDV RNA target not detected [TND], normal alanine aminotransferase [ALT]), HBV virologic control (HBV DNA ≤2,000 IU/mL, normal ALT), HBV functional cure (HBV DNA TND; HBsAg

The treatment of patients suffering from HBeAg-positive chronic hepatitis B with REP 2139-Ca resulted in potent reductions in HBsAg and HBV DNA, seroconversion to anti-HBs and the establishment of functional control of infection. In this cohort of 12 patients, we investigated whether differences between HBsAg sequences might explain the lack of response to REP 2139-Ca observed in 3 of 12 patients. We also assessed if the reduction or complete loss of HBsAg in serum observed during therapy were caused by mutations in the "a" determinant preventing the detection of HBsAg by standard diagnostic assays. The complete pre-S/S open reading frame (ORF) was sequenced and pre-S1, pre-S2 and S amino acid sequences were analysed. We found no major differences between pre-S1, pre-S2 and S sequences in responders and nonresponders correlated with low reduction in HBsAg. In addition, we found no mutations in the "a" determinant that would significantly affect the reactivity of HBsAg in diagnostic assays. These results demonstrate that the amino acid sequence of complete pre-S/S ORF has no direct influence on response to REP 2139-Ca therapy.

REP 2139 clears circulating hepatitis B virus (HBV) surface antigen (HBsAg), enhancing the restoration of functional control of HBV infection by immunotherapy. We assessed the safety and efficacy of REP 2139 and pegylated interferon alfa-2a in patients with chronic HBV and hepatitis D virus (HDV) co-infection.In this open-label, non-randomised, phase 2 trial, patients aged 18-55 years, who were treatment naive, hepatitis B e antigen [HBeAg] negative, anti-hepatitis D antigen [HDAg] positive, and HDV RNA positive, with serum HBsAg concentrations of more than 1000 IU/mL, and a history of HDV infection for 6 months or more before treatment, were recruited at Toma Ciorbă Hospital of Infectious Diseases in Chișinău, Moldova. Patients were excluded if they had HDV superinfection, liver infections other than HBV and HDV, or liver cirrhosis. Patients received 500 mg intravenous REP 2139 once per week for 15 weeks, followed by combined therapy with 250 mg intravenous REP 2139 and 180 μg subcutaneous pegylated interferon alfa-2a once per week for 15 weeks, then monotherapy with 180 μg pegylated interferon alfa-2a once per week for 33 weeks. The primary endpoints assessed at the end of treatment were the safety and tolerability of the treatment regimen, analysed in the intention-to-treat population. Secondary outcomes included the proportion of patients with serum HBsAg less than 50 IU/mL, the proportion of patients with suppressed HBV DNA, and the proportion of patients who maintained these responses through follow-up. The REP 301 trial is registered with ClinicalTrials.gov, number NCT02233075. We also did an additional follow-up at 1 year after the end of treatment, as an interim analysis of the REP 301-LTF trial (planned duration 3 years), registered with ClinicalTrials.gov, number NCT02876419, which is ongoing but not recruiting patients.Between Sept 8, 2014, and Jan 27, 2015, we enrolled 12 patients into the REP 301 study. All 12 patients experienced at least one adverse event during treatment: two (17%) patients experienced anaemia, eight (67%) neutropenia, and ten (83%) thrombocytopenia. Five (42%) patients had raised alanine aminotransferase levels, four (33%) had raised aspartate aminotransferase levels, and two (17%) had increased bilirubin concentrations. Four (33%) patients had a serious adverse event, and 12 (100%) patients had treatment-emergent lab abnormalities. Six patients had HBsAg levels less than 50 IU/mL by the end of treatment (all0·05 IU/mL); five maintained this level of suppression at the end of 1 year follow-up. Six patients had hepatitis B surface antibody (anti-HBs) titres above 10 mIU/mL at the end of treatment (five had maximum anti-HBs concentrations of 7681-86 532 mIU/mL during treatment), which were maintained at the end of 1 year follow-up in these five patients. Elevated alanine and aspartate aminotransferase concentrations and profound elevations of anti-HBs titres were restricted to patients who had HBsAg levels of less than1 IU/mL before the introduction of pegylated interferon alfa-2a. Nine patients had suppressed HBV DNA (10 IU/mL]) at the end of treatment, which was maintained by seven patients and newly established in an eighth patient at the end of 1 year follow-up. 11 patients became HDV RNA negative during treatment, with nine remaining HDV RNA negative at the end of treatment; seven of these patients remained HDV RNA negative by the end of 1 year follow-up. By the end of 1 year follow-up, normalisation of serum aminotransferases occurred in nine of 12 patients.Combined REP 2139 and pegylated interferon alfa-2a therapy is safe, well tolerated, and establishes functional control of HBV and HDV co-infection and normalisation of serum aminotransferases in a high proportion of patients 1 year after therapy. This combination therapy approach might provide a new treatment option for patients with HBV and HDV co-infection.Replicor.

Poster-Abstract

UNLABELLED:Previous in vivo studies have suggested that nucleic acid polymers (NAPs) may reduce circulating levels of HBsAg in the blood by blocking its release from infected hepatocytes and that this effect may have clinical benefit. NAP treatment, was evaluated in two clinical studies in patients with HBeAg positive chronic HBV infection. The REP 101 study examined REP 2055 monotherapy in 8 patients and the REP 102 study examined REP 2139-Ca, in monotherapy in 12 patients, 9 of which transitioned to short term combined treatment with pegylated interferon alpha 2a or thymosin alpha 1. In both studies NAP monotherapy was accompanied by 2-7 log reductions of serum HBsAg, 3-9 log reductions in serum HBV DNA and the appearance of serum anti-HBsAg antibodies (10-1712 mIU / ml). Eight of the 9 patients transitioning to combined treatment with immunotherapy (pegylated interferon or thymosin alpha 1) in the REP 102 study experienced HBsAg loss and all 9 patients experienced substantial increases in serum anti-HBsAg antibody titers before withdrawal of therapy. For 52 weeks after removal of REP 2055 therapy, rebound of serum viremia (HBV DNA > 1000 copies / ml, HBsAg > 1IU / ml) was not observed in 3 / 8 patients. Suppression of serum virema was further maintained for 290 and 231 weeks in 2 of these patients. After withdrawal of all therapy in the 9 patients that transitioned to combination therapy in the REP 102 study, 8 patients achieved HBV DNA < 116 copies / ml after treatment withdrawal. Viral rebound occurred over a period of 12 to 123 weeks in 7 patients but was still absent in two patients at 135 and 137 weeks of follow-up. Administration tolerability issues observed with REP 2055 were rare with REP 2139-Ca but REP 2139-Ca therapy was accompanied by hair loss, dysphagia and dysgeusia which were considered related to heavy metal exposure endemic at the trial site. These preliminary studies suggest that NAP can elicit important antiviral responses during treatment which may improve the effect of immunotherapy. NAPs may be a potentially useful component of future combination therapies for the treatment of chronic hepatitis B. TRIAL REGISTRATION:ClinicalTrials.gov NCT02646163 and NCT02646189.

Objectives. To assess the 30-day mortality rate and overall survival after radical retropubic prostatectomy (RRP). Methods. Identification of all RRPs performed in the Province of Quebec between January 5, 1988 and January 16, 1996 was accomplished through the Quebec Healthcare Plan Database. Results. Four thousand nine hundred ninety-seven RRPs were performed by 104 urologists. Overall, 451 deaths were recorded: 32 occurred during the first 30 days (0.6% 30-day mortality rate). A significant decrease in the 30-day mortality rate, from 2.45% to 0.5%, was recorded during the span of the study. The year of surgery, patient age, and hospital type were statistically significant short-term mortality variables (life table analysis). Patient age and year of surgery determined the cumulative survival probability (univariate and multivariate Cox analysis). Cumulative survival at 31 months of follow-up increased from 88.2% in 1988 to 98.1% in 1995. Men 75 years old and older were at a clear disadvantage with regard to survival probability compared with their younger counterparts. Conclusions. In this population-based analysis of RRP outcomes, we demonstrated a significant improvement in short- and long-term outcomes, as evidenced by a decrease in the 30-day mortality rate and an improved cumulative survival, recorded over the span of the study. The recorded outcome trends may be explained by improved patient selection and optimal management. Although we are unable to determine cancer-specific outcomes, the results of this analysis should prove valuable to urologists and patients until there are results from randomized trials.

Objectives To assess potency rate and patient attitudes regarding erectile dysfunction. Methods A multiple choice, self-administered questionnaire distributed to 750 men undergoing testing for early detection of prostate cancer was used. Results Overall, 33.9% of patients reported either partial or complete lack of erections and 31.1% were not sexually active or active less than once per month. Furthermore, 55.4% would be affected or very affected by lack of erections and 73.6% chose definitive treatment despite a 50% chance of erectile dysfunction. Finally, 47.4% found such treatment-induced erectile dysfunction to be an important or very important problem. When asked to ascribe a quantity of life or period of time that they would be willing to sacrifice to preserve sexual function following treatment, only 15.2% of patients were able to do so, but no consensus could be reached regarding its value. Conclusions Reported differences in quality-adjusted life expectancy when screening was compared to no screening and definitive therapy was compared to expectant management are marginal. Therefore, close attention to seemingly minor variables such as existing impotence rate, attitude regarding erectile dysfunction, and willingness to undergo therapy despite its inherent morbidity may substantially reduce or even reverse this reported disadvantage.

BACKGROUND. The objective of this study was to characterize the calcium mobilizing activity of bombesin-related neuropeptides in PC-3 cells. METHODS. Intracellular free Ca 2+ concentration ([Ca 2+ ] i ) was measured following the administration of bombesin-related neuropeptides using spectrofluorometric monitoring of PC-3 cells loaded with Fura2/AM. RESULTS. Individual neuropeptides induced a rapid rise in [Ca2+] i immediately after stimulation in similar fashion. When two different peptides were administered simultaneously, the [Ca2+] i changes were similar to that produced by each peptide alone. However, simultaneous addition of tyr 4 -bombesin 100 nM and 2% serum resulted in [Ca 2 + ] i increase greater than either alone. Sequential stimulation by same or different peptides, was not able to induce another response. However, 6 hrs after the first stimulus, a second stimulus was able to induce a similar response. CONCLUSIONS. The data indicate that all members of the bombesin-related family of neuropeptides are capable of triggering calcium mobilization in PC-3 cells via a similar signalling pathway. PC-3 cells become acutely desensitized to additional stimulation of neuropeptide. This desensitization is selective and reversible, requiring approximately 6 hrs for recovery.

Objectives To assess the potential difference in positive biopsy rates between four-sector and six-sector biopsy methods. Methods This computer-assisted analysis is based on the records of 156 consecutive patients previously diagnosed with T1c cancer on systematic sextant biopsy of the peripheral zone. For each patient the computer randomly deleted one biopsy result from the left and right prostatic lobes. The deletion process was repeated 1000 times. Based on four randomly chosen biopsy cores, we determined the number of undetected cancers initially diagnosed with sextant biopsy. Results Based on four-sector biopsy cores of the peripheral zone, between 6 and 30 (3.8% to 19.2% of cases) nonpalpable, isoechoic prostate cancers that were detected with sextant biopsy would have remained undiagnosed. Conclusions Our results suggest that the number of biopsy cores used in the early detection of nonpalpable, isoechoic prostate cancer may substantially affect the rate of positive findings.

Our goal was to develop an animal model of cavernous nerve injury similar to that encountered among patients having undergone a successful nerve sparing radical prostatectomy and to compare patterns of nicotinamide adenine dinucleotide phosphate (NADPH)-diaphorase staining to quality of erections using the newly developed model. We studied 50 mature Sprague Dawley rats, which were divided into five equal groups. Animals were either observed (sham), underwent an exploratory laparotomy, underwent moderate or severe percussive injury to both cavernous nerves, or underwent ablation of both cavernous nerves. Between 28 and 30 days later, all animals underwent electrostimulation and simultaneous recording of intracavernosal pressure. After sacrifice, penes were harvested and penile tissue NADPH-diaphorase staining pattern was assessed. Severity of cavernous nerve percussive injury and NADPH-diaphorase staining patterns correlated with the quality of recorded erections. This model is a useful experimental tool for research in the field of erectile dysfunction such as is encountered following a successful nerve sparing radical prostatectomy. Penile biopsy assessing NADPH-diaphorase staining may potentially prove to be a useful minimally-invasive diagnostic modality quantifying neurogenic erectile function among patients following radical prostatectomy.

The main objectives of this study were to reassess complications associated with transrectal ultrasound-guided biopsies (TRUSBx) of the peripheral zone (PZ) and to compare morbidity of exclusive PZ biopsy to morbidity associated with two additional transition zone (TZ) biopsies. We distributed a self-administered questionnaire assessing TRUSBx complications to 883 consecutive patients who underwent two systematic TZ TRUSBx in addition to systematic sextant PZ TRUSBx, and to 383 consecutive patients who underwent exclusive PZ TRUSBx. Of 316 (35.8%) patients subjects to TZ and PZ TRUSBx, 71% experienced hematuria, 63% hematospermia, 39% rectal bleeding, and 2.2% temperature elevation greater than 38°C. Of 137 (35.8%) patients who exclusively underwent PZ TRUSBx, 57%, 62%, 36%, and 1.4% reported these complications, respectively. Symptom duration and severity were similar in both groups. Although we report a substantially higher incidence of biopsy complications than previously published, these complications are self limited and require no intervention. Furthermore there appears to be no significant difference between complication rates associated with exclusive PZ biopsy compared with those associated with two additional biopsies of the TZ.

Objectives To explore the impact of cross-cultural differences on University of California, Los Angeles, Prostate Cancer Index (PCI) reliability and validity, which is unknown. The PCI represents the most widely used prostate cancer-specific health-related quality-of-life assessment tool. Methods The PCI sexual and urinary scales, the RAND SF-36 survey, and the Prostate Outcomes Research Team (PORT) prostate cancer treatment complication profile were self-administered. The principal sample consisted of 2415 men (anglophone 256, francophone 2159) treated with radical prostatectomy in Quebec between 1988 and 1996. An additional 35 men (anglophone 17, francophone 18) formed the retest sample. Results The PCI demonstrated excellent internal consistency and test-retest reliability in tests based on the entire cohort and in tests addressing the two linguistically different groups. The instrument showed a lack of convergence with the SF-36 scales, confirming the distinctness of the generic and prostate cancer-specific constructs. The PCI sexual scales converged with the aggregate PORT sexual items ( r = 0.8), and the PCI urinary scales were strongly related to the aggregate PORT urinary items ( r = 0.7). Convergence between PCI urinary bother and function was strong ( r = 0.8), but only moderate convergence was noted between PCI sexual bother and function ( r = 0.4). The relation between bother and function in both urinary and sexual domains was weaker in anglophone participants relative to their francophone counterparts. Conclusions The PCI is reliable and, at best, only modestly affected by cultural differences when administered to culturally distinct English-speaking men or when translated into French.

Objectives. To assess the relationship between tumor volume, gland volume, number of sectors submitted to biopsy, and prostatic biopsy detection rate. Methods. Using a three-dimensional mathematical model of the prostate, we assessed detection rates achieved with 4-, 6-, 8-, 10-, and 12-sector biopsies for glands ranging from 20 to 100 cc and peripheral zone tumors ranging from 0.3 to 1.4 cc. Results. Quadrant and sextant biopsy approaches only yielded from 6.2% to 13.4% and 8.6% to 18.3%, respectively, of lesions in a 40-cc gland. Conversely, 10- and 12-sector approaches yielded, respectively, from 19.8% to 48.8% and 25.4% to 62% of lesions for the same gland size. When assessed according to the density of sampling, one biopsy core used for every 1.5 to 3.5 cc of prostatic tissue detected 42.5% of 0.5-cc lesions. For the same lesion size, the density of sampling per biopsy core was then decreased to intervals extending from 3.6 to 7.5 cc, 7.6 to 12.5 cc, and 12.6 to 25 cc. These sampling density intervals yielded, respectively, 25.0%, 15.8%, and 9.8% detection rates. Conclusions. On the basis of our results, a gland volume-based biopsy algorithm is likely to result in improved detection of clinically significant prostate cancer.

Objectives. To examine the use of radical retropubic prostatectomy (RRP) in a large population-based study. Methods. Identification of all RRPs performed in the province of Quebec between the years 1988 and 1993 was accomplished by relying on the Quebec Healthcare Plan Database. Results. Overall, 2861 RRPs have been performed during the study period. On average, 80% of surgeries have been performed by urologists using this surgery 12 times or less annually. Of all surgeries, 420 (15%) RRPs have been performed in individuals 71 years of age or older. Conclusions. Each year, most RRPs (80%) in this population-based study were performed by urologists performing this procedure 12 times or less annually. A substantial proportion (15%) of RRPs have been performed in men 71 years of age or older, in whom the detriments of radical surgery may outweigh its benefits. These findings could potentially contribute to suboptimal outcomes when radical prostatectomy is compared with alternative treatment modalities.

Objectives Neoadjuvant androgen ablation (NAAA) causes significant cytoarchitectural changes in both benign and malignant prostatic epithelial cells that may contribute to underdetection of prostate cancer capsular involvement and positive surgical margins. Methods The aim of this study is to determine the ability of cytokeratin immunohistochemistry to enhance the determination of pathologic stage of prostate cancer following NAAA. Results Cytokeratin AE1/AE3 immunohistochemistry identified 6 (27.3%), 15 (68.2%), 5 (22.7%), and 5 (22.7%) cases of organ-confined disease, capsule penetration, positive surgical margin, and seminal vesicle involvement, respectively, as compared with 10 (45.5%), 10 (45.5%), 3 (13.6%), and 5 (22.7%) cases by hematoxylin-eosin (H&E) staining, respectively. Two cases without detectable tumor by H&E staining had demonstrable residual tumor by cytokeratin immunohistochemical staining. Conclusions Cytokeratin immunohistochemistry revealed more extensive intracapsular, capsular, and extracapsular tumor involvement and higher rate of positive surgical margin than did conventional H&E staining. Therefore, the beneficial pathologic effects of NAAA observed may, in part, be attributable to the artifact of observation.

OBJECTIVE: The objective of this study was to determine the benefit of repeat transrectal ultrasound-guided prostatic biopsy (TRUSBx) among men with prior benign histology on digitally guided biopsy despite suspicious digital rectal examination (DRE) findings. PATIENTS AND METHODS: From January 1, 1990 to May 30, 1993, we evaluated 130 consecutive men, referred to us with benign pathology on digitally-guided biopsy and DRE suspicious of cancer. All patients underwent systematic and directed TRUSBx. RESULTS: TRUSBx detected previously undiagnosed malignancy in 67 cases (51%). CONCLUSION: It is mandatory to reevaluate by TRUSBx, all patients with a palpable abnormality on DRE and a prior benign pathology on digitally-guided biopsy, as the likelihood of finding cancer is elevated.

To reassess positive rate of sextant biopsy according to gland size.We evaluated 1974 consecutive men with systematic sextant biopsy, among whom we examined biopsy yield according to gland-volume intervals of 10 cc.Decreasing yield of sextant biopsy is strongly associated with increasing gland volume (P0.001). Highest biopsy rate (39.6%) was recorded among men with prostates smaller than 20 cc. The lowest biopsy rate (10.1%) was recorded among men with prostates between 80 and 89.9 cc. Among men with biopsy-proven cancer, age, serum prostate-specific antigen, and Gleason grade were comparable (P0.05) throughout the range of gland-volume intervals.Our findings suggest that gland size represents an important determinant contributing to the yield of sextant biopsy in men at risk of harboring a nonpalpable, isoechoic cancer. Consequently, an individualized sector biopsy approach, based on prostate volume, may warrant consideration because it may ensure superior detection of clinically significant disease among all men at risk, regardless of prostate size.

OBJECTIVE: To reassess PSA density (PSAD) in the detection of non-palpable, isoechoic prostate cancer and to analyze the effect of potentially inaccurate non-planimetric transrectal ultrasound volume estimates on the diagnostic performance of this diagnostic tool. METHODS: We prospectively evaluated 343 consecutive men with non-suspicious digital rectal examination and transrectal ultrasound findings and with serum PSA in the intermediate range (4.1-10 ng/mL). All men underwent systematic sextant biopsies of the peripheral zone. We performed a two-fold analysis of PSAD performance first using measured gland volume and then using modified gland volumes ranging from a 25% underestimation to a 25% overestimation, in 5% stepwise increments. RESULTS: With a 0.15 PSAD cut-off, we would have missed 14, 34 and 48% of cancers, if we had respectively used a volume underestimate of 25%, the measured volume and a volume overestimate of 25%. CONCLUSIONS: Potential gland volume under- or overestimation may substantially affect the diagnostic performance of PSAD. Although PSAD may represent a useful adjunct in the early detection of prostate cancer, it may compromise cancer detection in a substantial proportion of cases, if used as the only indicator for biopsy.

Objectives To assess the accuracy and reproducibility of nonplanimetric transrectal ultrasound (TRUS) volume estimates because inaccurate volume estimates may potentially undermine the value of serum prostatespecific antigen density (PSAD) in early prostate cancer detection. Methods We prospectively evaluated 535 consecutive male patients with two consecutive volume determinations performed by the same ultrasonographer at the time of the same visit. Results Pearson correlation coefficients between two consecutive gland volume estimates ranged from 0.82 to 0.85 depending on the formula used; however, these correlation coefficients corresponded to an average 25% difference between the first and second gland volume estimates. Conclusions Although two consecutive nonplanimetric TRUS volume estimates show statistically good correlation, clinically up to a 25% volume difference should be expected between two such volume estimates. In consequence, nonplanimetric TRUS volume estimates should be interpreted with caution, especially when used for PSAD calculation, in the early detection of prostate cancer.

We examine the association of family history and prostatic carcinoma.A total of 2,968 consecutive patients referred for prostate cancer detection responded to a questionnaire and underwent transrectal ultrasound examination with or without biopsy.Of the men 329 (11.1%) had a family history of prostate cancer. No differences were observed between groups with and without a family history with respect to mean patient age, serum prostate specific antigen level or biopsy rate. Prostate cancer was detected in 133 of 329 patients (40.4%) with a family history and 769 of 2,639 (29.1) with no family history (p0.001, odds ratio 1.7). No significant differences were observed between cancer patients with or without a family history with respect to mean Gleason score (6.0 versus 6.2), patient age at diagnosis (65.8 versus 66.7) and prostate specific antigen level (16.8 versus 17.1).Patients with a family history of prostate cancer have a greater risk of the disease. In this select group of patients a positive family history was not associated with an earlier age at cancer diagnosis or a different histological grade of tumor.

Objectives To determine the potential role of prostate-specific antigen (PSA) density (PSAD) in the early detection of prostate carcinoma if we apply age-specific PSA reference ranges (2.5 ng/mL or less for ages 40 to 49 years, 3.5 or less for ages 50 to 59, 4.5 or less for ages 60 to 69, and 6.5 or less for ages 70 to 79. Methods We retrospectively reviewed 3234 cases referred to us by urologists for transrectal ultrasound (TRUS) between January 1, 1991, and September 28, 1993. We included 2429 patients in the study, ages 40 to 79 years, with Hybritech or Abbott IMx serum PSA determinations and without previously diagnosed prostate cancer. We performed digital rectal examination (DRE) and TRUS in all cases, and TRUS-guided biopsies when indicated. We used stringent criteria to define 736 cases without clinical evidence of malignancy that were designated as a “benign group.” Results In the benign group, we found serum PSA to increase with age in parallel with the increase in prostate volume with age (r = 0.25 and r = 0.26, respectively). The association between serum PSA and prostate volume was stronger (r = 0.46). Using multiple regression analysis, prostate volume accounted for 18% of the variation in serum PSA, whereas age accounted for only an additional 2%. PSAD, which directly relates serum PSA to prostate volume, showed a weak association with age (r = 0.1). In the entire study population of 2429 cases, 555 patients had negative DRE and TRUS results and a serum PSA level between the age-specific upper limit of normal and 10.0 ng/mL. According to the proposed age-specific algorithm, these patients would have required automatic biopsies. Of these, 315 cases (56.8%) still had a PSAD of less than 0.15. We performed biopsies in 108 of these 315 and detected only two cancers, for a positive biopsy rate (PBR) of 1.9%. The remaining 240 cases had a PSAD of 0.15 or higher, and we performed biopsies in 217 of these cases and detected 59 cancers, for a PBR of 27.2%. Conclusions The use of age-specific PSA reference ranges does not totally account for the effect of prostate volume on serum PSA. Therefore PSAD can still be used to reduce safely the number of biopsies performed in patients with negative DRE and TRUS results and a serum PSA level 10.0 ng/mL or less and above the age-specific upper limit of normal.

Neuroendocrine differentiation of prostatic adenocarcinoma has received considerable attention in recent years. The objectives of this study were to characterize the incidence, pattern of distribution and peptide hormone immunoreactivities of neuroendocrine differentiated tumor cells in prostatic carcinoma metastases; determine the correlation of neuroendocrine differentiation and deoxyribonucleic acid content in lymph node metastases, and determine the prognostic role of neuroendocrine differentiation of metastases in stage D1 cancer. We examined immunohistochemically 62 metastatic lesions (41 pelvic lymph nodes and 21 bone metastases) for the presence of chromogranin-A expressing tumor cells. Of 41 lymph nodes and 21 bone metastases 19 (46%) and 11 (52%), respectively, contained chromogranin-A immunoreactive cells. These cells were commonly found to comprise the minority of tumor cells in the metastases and typically were distributed in a dispersed pattern. Serotonin and peptide hormone immunocytochemistry in 19 cases (12 lymph nodes and 7 bone metastases) demonstrated neuroendocrine cells containing thyroid-stimulating hormone and serotonin in 17 (89%) and 10 (53%), respectively. All 7 bone metastases contained thyroid-stimulating hormone immunoreactive cells. The presence of chromogranin-A positive cells did not correlate statistically with deoxyribonucleic acid content of lymph node metastases nor with disease specific survival in patients with stage D1 prostate cancer. Our results indicate that a substantial proportion of prostate cancer metastases contain a subpopulation of cells expressing a neuroendocrine phenotype similar to primary tumors. These cells are capable of elaborating certain biogenic amines and peptide hormones. However, in stage D1 prostate cancer nodal lesions expressing neuroendocrine differentiation do not appear to have significant prognostic value.

Significant controversies persist in regard to the need for systematic biopsies in patients with serum prostate-specific antigen (PSA) levels above 4 ng/mL (Hybritech assay), especially if they show no signs of prostatic cancer on digital rectal examination (DRE) or transrectal ultrasonography (TRUS). We evaluated 565 consecutive patients referred to us for prostatism, suspicious lesions on DRE, or an elevated serum PSA level. These patients do not represent a purely screened population. A detection rate of 38.4 percent was achieved by performing directed biopsies of suspicious lesions on DRE and/or TRUS, and systematic biopsies of all patients with serum PSA levels above 4 ng/mL. Among 142 patients with serum PSA between 4.1 and 10 ng/mL, but without suspicion for cancer on DRE and TRUS (DRE- TRUS-), a large number of patients (6.2) were subjected to systematic biopsies to detect one cancer. A receiver-operating characteristics curve for PSA density (PSAD) applied to this population confirmed that the best cut-off point for biopsies was a PSAD of 0.15, below which only two of twenty-three cancers would have been missed, sparing biopsies in 77 of 142 patients. A similar approach was applied to DRE- TRUS- patients with serum PSA levels above 10 ng/mL. The number of cancers in those with serum PSA between 10.1 and 14 ng/mL was too low to establish a PSAD cut-off point. In patients with serum PSA above 14 ng/mL, the best PSAD cut-off point for biopsies was 0.3, below which two of thirteen cancers would have been missed, sparing biopsies in 19 of 39 patients. We conclude that PSAD can safely reduce the number of patients subjected to systematic biopsies without significantly compromising cancer detection.

Purpose: A prospective study was done to determine the value of performing 2 systematic transition zone biopsies in addition to systematic sextant peripheral zone biopsies for early detection of prostate cancer.Materials and Methods: From January 1 to August 31, 1994 we evaluated 847 consecutive patients referred to us for a suspicious lesion on digital rectal examination or an elevated serum prostate specific antigen level. All patients underwent 2 systematic transition zone biopsies in addition to systematic sextant biopsies of the peripheral zone.Results: Of the transition zone biopsies 68 (24.4 percent) contained malignancy, including only 8 (2.9 percent) with cancer found exclusively in the transition zone. The remaining 271 cases (97.1 percent) had 1 or more positive peripheral zone biopsies and would have been detected with or without additional systematic transition zone biopsies. The same analysis of 552 patients with a negative digital rectal examination yielded 6 (4.1 percent) exclusive...