Adverse event profile for immunotherapy agents compared with chemotherapy in solid organ tumors: a systematic review and meta-analysis of randomized clinical trials.

BACKGROUND: Immunotherapy agents are an innovative oncological treatment modality and as a result their use has expanded widely. Understanding the treatment-related adverse events (AEs) of these drugs compared with traditional chemotherapy is crucial for clinical practice. DESIGN: A systematic review of studies indexed in Medline (PubMed), Embase, Web of Science, and the Cochrane Databases from January 2000 to 14 February 2019 was conducted. Randomized clinical trials comparing immunotherapy [cytotoxic T-lymphocyte protein-4 (CTLA-4), programmed cell death protein 1 (PD-1), or programmed death-ligand 1 (PD-L1)] with standard-of-care chemotherapy in the treatment of advanced solid-organ neoplasms were included if AEs were reported as an outcome. Primary outcome was AEs ≥ grade 3 in severity. Secondary outcomes were proportion of overall AEs, treatment discontinuation due to AEs, deaths due to AEs, and specific AEs [fatigue, diarrhea, acute kidney injury (AKI), colitis, pneumonitis, and hypothyroidism]. Paule-Mandel pooling and a random effects model were used to produce odds ratios (ORs) for measures of effects. RESULTS: Among 10 598 abstracts screened, we included 22 studies involving 12 727 patients. In the immunotherapy group, 16.5% of patients developed an AE ≥ grade 3 in severity, compared with 41.09% in the chemotherapy arm [OR = 0.26, 95% confidence interval (CI) 0.19-0.35, I2 = 92%]. Patients receiving immunotherapy also had lower odds of developing an AE overall (OR = 0.35, 95% CI 0.28-0.44; I2 = 77%), terminating therapy due to an AE (OR = 0.55, 95% CI 0.39-0.78, I2 = 80%), or dying from a treatment-related AE (OR = 0.67, 95% CI 0.46-0.98, I2 = 0%). When treated with chemotherapy versus immunotherapy, patients more frequently experienced fatigue (25.10% versus 15.83%), diarrhea (14.97% versus 11.13%), and AKI (1.79% versus 1.31%). However, colitis (1.02% versus 0.26%), pneumonitis (3.36% versus 0.36%), and hypothyroidism (6.82% versus 0.37%) were more common in those treated with immunotherapy. CONCLUSIONS: Treatment of advanced solid-organ malignancies with immunotherapy compared with traditional chemotherapy is associated with a lower risk of AEs.

Complications following surgery with or without radiotherapy or radiotherapy alone for prostate cancer.

BACKGROUND: Men undergoing treatment of clinically localised prostate cancer may experience a number of treatment-related complications, which affect their quality of life. METHODS: On the basis of population-based retrospective cohort of men undergoing surgery, with or without subsequent radiotherapy, or radiotherapy alone for prostate cancer in Ontario, Canada, we measured the incidence of treatment-related complications using administrative and billing data. RESULTS: Of 36 984 patients, 15 870 (42.9%) underwent surgery alone, 4519 (12.2%) underwent surgery followed by radiotherapy, and 16 595 (44.9%) underwent radiotherapy alone. For all end points except urologic procedures, the 5-year cumulative incidence rates were lowest in the surgery only group and highest in the radiotherapy only group. Intermediary rates were seen in the surgery followed by radiotherapy group, except for urologic procedures where rates were the highest in this group. Although age and comorbidity were important predictors, radiotherapy as the primary treatment modality was associated with higher rates for all complications (adjusted hazard ratios 1.6-4.7, P=0.002 to <0.0001). CONCLUSIONS: In patients treated for prostate cancer, radiation after surgery increases the rate of complications compared with surgery alone, though these rates remain lower than patients treated with radiation alone. This information may inform patient and physician decision making in the treatment of prostate cancer.

The impact of a BRCA2 mutation on mortality from screen-detected prostate cancer.

BACKGROUND: Men with a BRCA2 mutation face an increased risk of prostate cancer. These cancers tend to have an aggressive nature and it has not yet been demonstrated that regular screening of BRCA2 carriers is associated with improved survival. METHODS: We identified 4187 men who underwent a prostate cancer biopsy for an elevated PSA or an abnormal digital rectal examination between 1998 and 2010. We screened the BRCA2 gene in its entirety for mutations and we followed the men for death from prostate cancer until December 2012. RESULTS: The 12-year prostate cancer-specific survival rate was 94.3% for men without a BRCA2 mutation and was 61.8% for men with a mutation (P<10(-4); log-rank test). CONCLUSIONS: The survival of men with screen-detected prostate cancer and a BRCA2 mutation is much poorer than expected.

Prostate cancer genes associated with TMPRSS2-ERG gene fusion and prognostic of biochemical recurrence in multiple cohorts.

BACKGROUND: Recent studies have indicated that prostate cancer patients with the TMPRSS2-ERG gene fusion have a higher risk of recurrence. To identify markers associated with TMPRSS2-ERG fusion and prognostic of biochemical recurrence, we analysed a cohort of 139 men with prostate cancer for 502 molecular markers. METHODS: RNA from radical prostatectomy tumour specimens was analysed using cDNA-mediated, annealing, selection, extension and ligation (DASL) to determine mRNAs associated with TMPRSS2-ERG T1/E4 fusion and prognostic of biochemical recurrence. Differentially expressed mRNAs in T1/E4-positive tumours were determined using significance analysis of microarrays (false discovery rate (FDR) <5%). Univariate and multivariate Cox regression determined genes, gene signatures and clinical factors prognostic of recurrence (P-value <0.05, log-rank test). Analysis of two prostate microarray studies (GSE1065 and GSE8402) validated the findings. RESULTS: In the 139 patients from this study and from a 455-patient Swedish cohort, 15 genes in common were differentially regulated in T1/E4 fusion-positive tumours (FDR <0.05). The most significant mRNAs in both cohorts coded ERG. Nine genes were found prognostic of recurrence in this study and in a 596-patient Minnesota cohort. A molecular recurrence score was significant in prognosticating recurrence (P-value 0.000167) and remained significant in multivariate analysis of a mixed clinical model considering Gleason score and TMPRSS2-ERG fusion status. CONCLUSIONS: TMPRSS2-ERG T1/E4 fusion-positive tumours had differentially regulated mRNAs observed in multiple studies, the most significant one coded for ERG. Several mRNAs were consistently associated with biochemical recurrence and have potential clinical utility but will require further validation for successful translation.

Rapid progression of prostate cancer in men with a BRCA2 mutation.

Men with BRCA2 mutations have been found to be at increased risk of developing prostate cancer. There is a recent report that BRCA2 carriers with prostate cancer have poorer survival than noncarrier prostate cancer patients. In this study, we compared survival of men with a BRCA2 mutation and prostate cancer with that of men with a BRCA1 mutation and prostate cancer. We obtained the age at diagnosis, age at death or current age from 182 men with prostate cancer from families with a BRCA2 mutation and from 119 men with prostate cancer from families with a BRCA1 mutation. The median survival from diagnosis was 4.0 years for men with a BRCA2 mutation vs 8.0 years for men with a BRCA1 mutation, and the difference was highly significant (P<0.01). It may be important to develop targeted chemotherapies to treat prostate cancer in men with a BRCA2 mutation.

Serum human glandular kallikrein-2 protease levels predict the presence of prostate cancer among men with elevated prostate-specific antigen.

PURPOSE: We hypothesize that serum human glandular kallikrein-2 (hK2) levels predict the presence of prostate cancer among men prescreened by prostate-specific antigen (PSA). PATIENTS AND METHODS: We conducted a cross-sectional study of 324 men who had no history of prostate cancer and who were referred for prostate biopsy. PSA and hK2 levels were measured using specific nonisotopic immunometric techniques. Cases were patients who were diagnosed with adenocarcinoma of the prostate from biopsy, and controls were patients who had no evidence of cancer from biopsy. The odds ratio for detection of prostate cancer was determined for hK2 measurements, controlling for age, total-PSA level, digital rectal examination, and symptoms of urinary obstruction. RESULTS: Of 324 men, 159 (49.1%) had cancer. Mean hK2 levels and hK2:free-PSA ratios were significantly higher in cases than in controls (1.18 v 0.53 ng/mL, respectively, for hK2, P =.0001; 1.17 v 0.62 for hK2:free-PSA ratio, P =.0001). The crude odds ratio for prostate cancer detection for patients in the highest quartile of hK2 level was 5.83 (95% confidence interval [CI], 2.8 to 12.1; P =.0001) compared with patients in the lowest quartile. The adjusted odds ratio was 6.72 (95% CI, 2.9 to 15.6; P =.0001). Similarly, the crude and adjusted odds ratios for prostate cancer detection using the hK2:free-PSA ratio were 7.36 (95% CI, 3.6 to 15.1; P =.0001) and 8.06 (95% CI, 3. 7 to 17.4; P =.0001), respectively. These odds ratios were higher than that observed for prostate cancer detection by total-PSA level (2.73; P =.03). CONCLUSION: Among men prescreened with PSA for prostate cancer, patients with high hK2 measurements have a five- to eight-fold increase in risk for prostate cancer, adjusting for PSA level and other established risk factors. hK2 measurements may be a useful adjunct to PSA in improving patient selection for prostate biopsy.

Relapse and cure rates of prostate cancer patients after radical prostatectomy and 5 years of follow-up.

OBJECTIVES: We have compared the ability of an ultrasensitive prostate specific antigen assay and a regular PSA assay to identify relapse and cure rates of prostate cancer patients after radical prostatectomy, during a 5-year follow-up period. DESIGN AND METHODS: We measured PSA by an ultrasensitive assay (detection limit 0.001 ng/mL) and a conventional PSA assay (detection limit 0.1 ng/mL) in serial serum samples obtained from 197 patients who have undergone radical prostatectomy. RESULTS: Based on ultrasensitive PSA analysis, we have identified three groups of patients: 62% of patients did not show any significant changes in serum PSA; 15% of patients demonstrated slow PSA increases over time but none of the measurements exceeded 0.1 ng/mL within 4 years; and 23% of the patients had relatively significant increases of serum PSA and were classified as having 'fast relapse'. The vast majority of these patients were subsequently identified to have relapse by the regular PSA assay. The ultrasensitive PSA assay detected relapse by an average of eighteen months earlier than the conventional PSA method. Fast relapsing patients were associated with other prognostic indicators of the disease including pre-operative PSA, tumor volume, Gleason score, clinical stage, surgical margin positivity, periprostatic tissue involvement, capsular invasion and seminal vesicle invasion. The group with slowly rising PSA had prognosis which was between the patients in remission and fast relapsing patients. CONCLUSIONS: The use of ultrasensitive PSA analysis for monitoring patients after radical prostatectomy provides earlier detection of relapse (by 18 months) and identifies three distinct groups of patients. Fast relapsing patients should be good candidates for early therapeutic interventions.

Influence of initial semen quality on the integrity of human sperm DNA following semen processing.

OBJECTIVE: To examine and compare the effects of density-gradient centrifugation on the integrity of sperm DNA from the semen of both fertile and infertile men. DESIGN: Prospective, observational study. SETTING: University infertility clinic. PATIENTS: Forty-four nonazoospermic, infertile men and nine fertile controls. INTERVENTIONS: Semen samples were processed by density-gradient centrifugation. Sperm motility and sperm chromatin structure (evaluated by flow cytometry analysis of acridine orange-treated spermatozoa) were monitored before and after semen was processed. MAIN OUTCOME MEASURES: Sperm motility and DNA integrity. RESULTS: Following density-gradient centrifugation, mean sperm motility (+/-SEM) improved significantly compared to whole semen in samples from fertile and infertile men, respectively (71 +/- 6 vs. 49 +/- 7% and 56 +/- 3 vs. 44 +/- 3%, P<0.05). However, the percentage of sperm with denatured DNA increased compared to whole semen after processing of samples from infertile (25 +/- 3 vs. 15 +/- 2%, P<0. 01) but not fertile men (9 +/- 3 vs. 8 +/- 2%, P>0.05). CONCLUSIONS: Our data indicate that the potential detrimental effect of density-gradient centrifugation on sperm DNA integrity is related to the initial semen quality. These data urge us to examine our current sperm-processing techniques to minimize sperm DNA damage.

Permanent flank bulge is a consequence of flank incision for radical nephrectomy in one half of patients.

The objective of the study was to determine the incidence and predictors of post operative pain and flank bulging in patients undergoing nephrectomy for a renal tumor through a flank or thoracoabdominal incision. Only one previous retrospective study (1974) has directly addressed this issue in urologic patients. This reported a 3% incidence of flank bulging. This was at variance with our own experience. To determine the incidence of pain and post-operative flank bulge after flank or thoraco-abdominal incision, a cross sectional survey among in 70 patients, who had a nephrectomy for a renal tumor between 1996 and 2000, was assessed by telephone interview. Four surgeons contributed patients to the study. Thirty-four of seventy (49%) patients complained of a flank bulge persisting more than 1 yr after surgery. Durable flank pain was experienced by 24%. This was severe in 3% of patients. Median pain magnitude was 5/10. There was no difference in bulge incidence between surgeons (P = 0.49). Flank bulging occurred more frequently in left sided nephrectomy (P = 0.054) than right. Other parameters including gender, age, and tumor size had no correlation with the rate of either complication. In all patients who described a flank bulge, the deformity was durable; there were no cases of spontaneous resolution. Patients described a significant impact on QOL, particularly in those under 60 yrs. The overall rate of postoperative flank bulging is considerably higher than has been previously reported. This deformity affects quality of life. The observation that almost 50% of patients experience a flank bulge following a flank incision supports the shift towards laparoscopic nephrectomy, and should be incorporated into decision making regarding the optimal surgical approach. This may be particularly relevant in the choice between open partial nephrectomy and laparoscopic radical nephrectomy in a patient with a normal contralateral kidney.

[Disorders of membrane mechanisms for regulating calcium homeostasis in cardiac arrhythmias in children]. / Narushennia membrannykh mekhanizmov reguliatsii kal'tsievogo gomeostaza pri aritmiiakh serdtsa u detei.

Importance of calmodulin and Ca2+ in membranes of erythrocytes and myocardium was studied in children with ectopic forms of cardiac arrhythmia--extrasystole, paroxysmal and nonparoxysmal tachycardia. Activation of lipid peroxidation and shifts in cytomembrane phospholipid spectrum were shown to be involved in impairments of calcium homeostasis regulation, which is responsible for control of electromechanical parameters and may be related to deterioration of myocardial electrophysiological properties.

MicroRNAs in prostate cancer: from biomarkers to molecularly-based therapeutics.

MicroRNAs (miRNAs) are effective regulators of gene expression that have a significant role in the pathogenesis of prostate and various other cancers. The high prevalence of aberrant miRNA expression in prostate cancer, and miRNAs' distinctive properties, give much hope that they can be used as biomarkers and next generation of molecular anticancer therapeutics. Herein, we review the literature on miRNA involvement in prostate cancer pathogenesis and the current understanding of their role as oncogenes, tumor suppressors and metastasis-regulators. We also review the latest research on miRNAs in prostate cancer preclinical studies and clinical trials, and highlight the advantages and challenges of possible miRNA-based therapies. The emerging information regarding the biology of miRNAs in prostate cancer is promising, and may lead to a role(s) for these molecules as diagnostic/prognostic markers and effective therapeutic tools for better molecularly targeted treatment of prostate cancer.

Fusion in the ETS gene family and prostate cancer.

It has recently been shown that the majority of prostate cancers harbour a chromosomal rearrangement that fuses the gene for an androgen-regulated prostate-specific serine protease, TMPRSS2, with a member of the ETS family of transcription factors, most commonly ERG. These are among the most common genetic alterations in any human solid tumour. This knowledge may provide us with clues to prostate carcinogenesis, and may lead to the development of important molecular-based biomarkers for patients with localised prostate cancer. The most common variant is fusion between the 5'-untranslated region of TMPRSS2 and the 3' region of ERG. However, over 20 other fusion variants have now been described (involving over 10 different genes) and the number of variants continues to grow. Fusion products can be identified by several techniques, including FISH, RT-PCR, and expression profiling using exon arrays. The protein products associated with the fusion transcripts have not been characterised, and the phenotypic expression of the various products of gene fusion on prostate cancer histology, or on the clinical course of cancer, are not yet understood. Several early cohort studies suggest that the presence of the TMPRSS2:ERG fusion product is associated with relatively poor cancer-specific survival. Studies that examine how individual variants and their associated phenotypes affect prostate cancer presentation and progression are required.

A genome-wide association screen identifies regions on chromosomes 1q25 and 7p21 as risk loci for sporadic prostate cancer.

We conducted a genome-wide association study of 3090 sporadic prostate cancer patients and controls using the Affymetrix 10 000 SNP GeneChip. Initial screening of 40 prostate cancer cases and 40 non-cancer controls revealed 237 SNPs to be associated with prostate cancer (P<0.05). Among these SNPs, 33 were selected for further association analysis of 2069 men who had undergone a cancer-screening prostate biopsy. Results identified five loci as being significantly associated with increased prostate cancer risk in this larger sample (rs 1930293, OR=1.7, P=0.03; rs 717809-2p12, OR=1.3, P=0.03; rs 494770-4q34, OR=1.3, P=0.01; rs 2348763-7p21, OR=1.5, P=0.01; rs 1552895-9p22, OR=1.5, P=0.002). To validate these association data, 61 additional HapMap tagSNPs spanning the latter five loci were genotyped in this subject cohort and an additional 1021 men (total subject number=3090). This analysis revealed tag SNP rs 4568789 (chromosome 1q25) and tag SNP rs 13225697 (chromosome 7p21) to be significantly associated with prostate cancer (P-values 0.009 and 0.008, respectively). Haplotype analysis revealed significant associations of prostate cancer with two allele risk haplotypes on both chromosome 1q25 (adjusted OR of 2.7 for prostate cancer, P=0.0003) and chromosome 7p21 (adjusted OR of 1.3, P=0.0004). As linkage data have identified a putative prostate cancer gene on chromosome 1q25 (HPC1), and microarray data have revealed the ETV1 oncogene to be overexpressed in prostate cancer tissue, it appears that chromosome 1q25 and 7p21 may be sites of gene variants conferring risk for sporadic and inherited forms of prostate cancer.

Expression of the TMPRSS2:ERG fusion gene predicts cancer recurrence after surgery for localised prostate cancer.

The prostate-specific gene, TMPRSS2 is fused with the gene for the transcription factor ERG in a large proportion of human prostate cancers. The prognostic significance of the presence of the TMPRSS2:ERG gene fusion product remains controversial. We examined prostate cancer specimens from 165 patients who underwent surgery for clinically localised prostate cancer between 1998 and 2006. We tested for the presence of TMPRSS2:ERG gene fusion product, using RT-PCR and direct sequencing. We conducted a survival analysis to determine the prognostic significance of the presence of the TMPRSS2:ERG fusion gene on the risk of prostate cancer recurrence, adjusting for the established prognostic factors. We discovered that the fusion gene was expressed within the prostate cancer cells in 81 of 165 (49.1%) patients. Of the 165 patients, 43 (26.1%) developed prostate-specific antigen (PSA) relapse after a mean follow-up of 28 months. The subgroup of patients with the fusion protein had a significantly higher risk of recurrence (58.4% at 5 years) than did patients who lacked the fusion protein (8.1%, P<0.0001). In a multivariable analysis, the presence of gene fusion was the single most important prognostic factor; the adjusted hazard ratio for disease recurrence for patients with the fusion protein was 8.6 (95% CI=3.6-20.6, P<0.0001) compared to patients without the fusion protein. Among prostate cancer patients treated with surgery, the expression of TMPRSS2:ERG fusion gene is a strong prognostic factor and is independent of grade, stage and PSA level.

Delayed rupture of the spleen and streptokinase therapy.

Delayed rupture of the spleen is a rare but serious complication of blunt abdominal trauma. A 47-year-old woman with a history of fractured pelvis from a motor vehicle accident 6 months earlier presented with evidence of a myocardial infarction. Subsequent streptokinase administration was complicated by splenic rupture, which was managed by evacuation of the clotted blood and splenectomy. The patient made a complete recovery. The risk of splenic rupture and bleeding complications resulting from thrombolytic therapy for myocardial infarction is discussed, as are the controversy over whether delayed splenic rupture is a true diagnosis, the mechanism of rupture and the clues to impending rupture.

Liver resection by ultrasonic dissection and intraoperative ultrasonography.

Ultrasonic dissection (USD) and intraoperative ultrasonography (IOUS) have shown encouraging results in a retrospective analysis of 109 patients with benign or malignant liver disease. Of 109 patients assessed between 1980 and 1993, 84 were resected: 27 by finger fracture technique (FFT) and 57 by USD. Hospital mortality was 4.8% (4/84) and 30-day mortality was 6.0% (5/84). Overall morbidity was 48.8% (41/84) and liver related morbidity (hepatic bleeding, sepsis, and bile leak) was 34.5% (29/84); of the 29 patients, 5 required re-operation. Liver complications occurred in 12/27 (44.4%) in the FFT group as opposed to 17/57 (29.8%) in the USD group. The incidence of postoperative hepatic bleeding was significantly less by USD than by FFT (p = 0.03). As well, intraoperative blood loss (p = 0.01) number of intraoperative blood units used (p = 0.002), and postoperative length of stay (p = 0.009) have been significantly reduced by USD. IOUS was used on 64 patients. Not only has it improved the sensitivity (99%) and specificity (98%) for detection of hepatic neoplasms, it has also helped increase the precision and accuracy of anatomical tumour localization. As a result, 11/64 patients (17.2%) had their preoperative plans changed: 8 were abandoned and 3 were revised. In summary, USD has significantly reduced intraoperative blood loss and hence reduced the number of intraoperative transfusions, incidence of postoperative complications and postoperative length of stay. IOUS should be routinely employed in patients undergoing liver resection since it provides critical information that could obviate oncologically useless resections.

Prostate specific antigen velocity as a measure of the natural history of prostate cancer: defining a 'rapid riser' subset.

OBJECTIVE: To study the rate of change in prostate specific antigen (PSA velocity) in patients with prostate cancer initially managed by 'watchful waiting'. PATIENTS AND METHODS: Serial PSA levels were determined in 141 patients with prostate cancer confirmed by biopsy, who were initially managed expectantly and enrolled between May 1990 and December 1995. Sixty-seven patients eventually underwent surgery (mean age 59 years) because they chose it (the decision for surgery was not based on PSA velocity). A cohort of 74 patients remained on 'watchful waiting' (mean age 69 years). Linear regression and logarithmic transformations were used to segregate those patients who showed a rapid rise, defined as a > 50% rise in PSA per year (or a doubling time of < 2 years) and designated 'rapid risers'. RESULTS: An initial analysis based on a minimum of two PSA values showed that 31% were rapid risers. Only 15% of patients with more than three serial PSA determinations over > or = 6 months showed a rapid rise in PSA level. There was no advantage of log-linear analysis over linear regression models. CONCLUSION: Three serial PSA determinations over > or = 6 months in patients with clinically localized prostate cancer identifies a subset (15%) of patients with a rapidly rising PSA level. Shorter PSA surveillance with fewer PSA values may falsely identify patients with rapid rises in PSA level. However, further follow-up is required to determine if a rapid rise in PSA level identifies a subset of patients with an aggressive biological phenotype who are either still curable or who have already progressed to incurability through metastatic disease.

Detection of prostate cancer relapse with prostate specific antigen monitoring at levels of 0.001 to 0.1 microG./L.

PURPOSE: The development of prostate specific antigen (PSA) assays with detection limits of approximately 0.001 microgram./l. is technically feasible. We examined if serum PSA changes of 0.001 to 0.1 microgram./l. for up to 3 years after radical prostatectomy have any clinical value. MATERIALS AND METHODS: We studied 148 patients with a postoperative PSA of less than 0.1 microgram./l. by a conventional PSA assay. At least 3 serial serum samples were collected per patient along with detailed clinicopathological features. Serial serum samples were analyzed for PSA with the ultrasensitive method. Associations between increase in serum PSA and clinicopathological features were analyzed with the unconditional logistic regression model. RESULTS: After establishing a set of interpretative criteria, we divided the patients into 51 with biochemical relapse, 93 who were free of relapse and 4 with equivocal status. Between the groups with and without relapse there was no difference in year of surgery, age at operation or length of followup. Compared to patients without relapse, those with biochemical relapse were likely to have positive surgical margins (p < 0.01), larger tumor volumes (p < 0.01), greater preoperative PSA (p = 0.03) and disease extending outside the prostate (p = 0.02). The relative risks for biochemical relapse estimated by a univariate logistic regression model were 3.1 (95% confidence interval 1.39 to 6.82, p < 0.01) for positive surgical margin, 3.4 (95% confidence interval 1.46 to 8.13, p < 0.01) for tumor volume, 2.3 (95% confidence interval 1.08 to 5.02, p = 0.03) for high preoperative PSA and 2.7 (95% confidence interval 1.12 to 6.26, p = 0.03) for extraprostatic tumor extension. At multivariate analysis with the same model the associations between positive surgical margins and biochemical relapse (relative risk 2.95, p = 0.04) and tumor volume (relative risk 3.36, p = 0.03) remained significant. These associations were still observed when we analyzed a subset of patients classified as having biochemical relapse based on PSA changes of 0.001 to 0.08 microgram./l. CONCLUSIONS: Increases in postoperative serum PSA at levels of 0.001 to 0.1 microgram./l. after radical prostatectomy are associated with clinicopathological features of poor prognosis. Monitoring postoperative cases with a highly sensitive PSA assay (detection limit 0.001 microgram./l.) could offer a simple and effective means of detecting clinically important biochemical relapse early after radical prostatectomy. These patients may be suitable for early intervention when effective treatments for relapse become available.