Data driven optimization of sexual assault case processing.

In recent years, several forensic laboratories have noted an increase in the number of sexual assault cases submitted for testing, often leading to longer turnaround times. In that context, forensic laboratories may be interested in reviewing their procedures to increase productivity. Here, we present two different strategies that were put in place in our laboratory. First, we changed the way sexual assault evidence kits (SAEK) are processed by implementing an optimized workflow that prioritizes the internal samples (vaginal, anal, and oral). This new procedure allowed for a drastic decrease in turnaround time, while maintaining a similar investigative power. Secondly, we used data from casework to target cases and samples that were likely to yield biological material from the perpetrator, in an attempt to avoid dedicating time and effort to cases for which there is a very low probability of obtaining foreign DNA evidence. Among other things, we looked at the likelihood of obtaining DNA from the perpetrator when the complainant reported the use of a condom, has showered after the assault or when the complainant has no memory of the assault. Results show that those circumstances do not dramatically decrease the probability of finding DNA from the perpetrator.

Alternative promoter usage and splicing of ZNF74 multifinger gene produce protein isoforms with a different repressor activity and nuclear partitioning.

We have previously shown that ZNF74, a candidate gene for DiGeorge syndrome, encodes a developmentally expressed zinc finger gene of the Kruppel-associated box (KRAB) multifinger subfamily. Using RACE, RT-PCR, and primer extension on human fetal brain and heart mRNAs, we here demonstrate the existence of six mRNA variants resulting from alternative promoter usage and splicing. These transcripts encode four protein isoforms differing at their N terminus by the composition of their KRAB motif. One isoform, ZNF74-I, which corresponds to the originally cloned cDNA, was found to be encoded by two additional mRNA variants. This isoform, which contains a KRAB motif lacking the N terminus of the KRAB A box, was devoid of transcriptional activity. In contrast, ZNF74-II, a newly identified form of the protein that is encoded by a single transcript and contains an intact KRAB domain with full A and B boxes, showed strong repressor activity. Deconvolution immunofluorescence microscopy using transfected human neuroblastoma cells and nonimmortalized HS68 fibroblasts revealed a distinct subcellular distribution for ZNF74-I and ZNF74-II. In contrast to ZNF74-I, which largely colocalizes with SC-35 in nuclear speckles enriched in splicing factors, the transcriptionally active ZNF74-II had a more diffuse nuclear distribution that is more characteristic of transcriptional regulators. Taken with the previously described RNA-binding activity of ZNF74-I and direct interaction with a hyperphosphorylated form of the RNA polymerase II participating in pre-mRNA processing, our results suggest that the two ZNF74 isoforms exert different or complementary roles in RNA maturation and in transcriptional regulation.

ZNF74, a gene deleted in DiGeorge syndrome, is expressed in human neural crest-derived tissues and foregut endoderm epithelia.

DiGeorge syndrome (DGS) is a developmental disorder associated with large hemizygous deletions on chromosome 22q11.2. ZNF74 zinc finger gene is a candidate from the commonly deleted region. To address the potential involvement of ZNF74 in DGS, its human developmental expression pattern has been assessed. In situ hybridization on Carnegie Stage 18 embryos revealed that ZNF74 expression is limited to specific neural crest-derived tissues and neuroepithelium of the spinal cord as well as to foregut endoderm epithelia (esophagus and respiratory tract). Interestingly, ZNF74 expression was detected in the wall of the pulmonary artery and aorta and in the aortic valve, which are populated by neural crest-derived cells. This finding is significant, considering that DGS is believed to result from defective neural crest contributions and that outflow tract and aorticopulmonary septation defects are typical features of the DGS phenotype. Thus, the restricted expression of ZNF74 in structures affected in DGS suggests a role for this putative regulator of gene expression in aspects of the DGS phenotype.

Thirty-day mortality rates and cumulative survival after radical retropubic prostatectomy.

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.

Three-dimensional computer-assisted analysis of sector biopsy of the prostate.

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.

Population-based patterns of radical retropubic prostatectomy use.

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.

Patient attitudes regarding treatment-related erectile dysfunction at time of early detection of prostate cancer.

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.

Direct interaction of the KRAB/Cys2-His2 zinc finger protein ZNF74 with a hyperphosphorylated form of the RNA polymerase II largest subunit.

We previously identified ZNF74 as a developmentally expressed gene commonly deleted in DiGeorge syndrome. ZNF74 encodes an RNA-binding protein tightly associated with the nuclear matrix and belongs to a large subfamily of Cys2-His2 zinc finger proteins containing a KRAB (Kruppel-associated box) repressor motif. We now report on the multifunctionality of the zinc finger domain of ZNF74. This nucleic acid binding domain is shown here to function as a nuclear matrix targeting sequence and to be involved in protein-protein interaction. By far-Western analysis and coimmunoprecipitation studies, we demonstrate that ZNF74 interacts, via its zinc finger domain, with the hyperphosphorylated largest subunit of RNA polymerase II (pol IIo) but not with the hypophosphorylated form. The importance of the phosphorylation in this interaction is supported by the observation that phosphatase treatment inhibits ZNF74 binding. Double immunofluorescence experiments indicate that ZNF74 colocalizes with the pol IIo and the SC35 splicing factor in irregularly shaped subnuclear domains. Thus, ZNF74 sublocalization in nuclear domains enriched in pre-mRNA maturating factors, its RNA binding activity, and its direct phosphodependent interaction with the pol IIo, a form of the RNA polymerase functionally associated with pre- mRNA processing, suggest a role for this member of the KRAB multifinger protein family in RNA processing.

Morphologic changes induced by neoadjuvant androgen ablation may result in underdetection of positive surgical margins and capsular involvement by prostatic adenocarcinoma.

OBJECTIVE: 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.

Characterization of intracellular calcium mobilization by bombesin-related neuropeptides in PC-3 human prostate cancer cells.

BACKGROUND: The objective of this study was to characterize the calcium mobilizing activity of bombesin-related neuropeptides in PC-3 cells. METHODS: Intracellular free Ca2+ concentration ([Ca2+]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 tyr4-bombesin 100 nM and 2% serum resulted in [Ca2+]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.

Outcome of sextant biopsy according to gland volume.

OBJECTIVES: To reassess positive rate of sextant biopsy according to gland size. METHODS: We evaluated 1974 consecutive men with systematic sextant biopsy, among whom we examined biopsy yield according to gland-volume intervals of 10 cc. RESULTS: Decreasing yield of sextant biopsy is strongly associated with increasing gland volume (P < 0.001). 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 (P > 0.05) throughout the range of gland-volume intervals. CONCLUSIONS: 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.

Computer-assisted comparative analysis of four-sector and six-sector biopsies of the prostate.

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.

Bombesin specifically induces intracellular calcium mobilization via gastrin-releasing peptide receptors in human prostate cancer cells.

Bombesin and gastrin-releasing peptide (GRP) are potent neuropeptides expressed by prostate cancer neuroendocrine cells and are related to the progression of this malignancy. This study characterizes bombesin receptors in human prostate cancer cell lines (PC-3, DU-145, LNCaP) and assesses the in vitro effect of bombesin on signal transduction and cell proliferation. [125I]Tyr4-bombesin binding assays (37 degrees C) and Scatchard analyses revealed the presence of a single class of high-affinity receptors with similar Kd values (1.5, 1.1 and 3.6 x 10(-10) M in PC-3, DU-145 and LNCaP cells respectively) but with significant differences in the number of binding sites per cell (47.6, 1.5 and 0.1 x 10(3) in PC-3, DU-145 and LNCaP cells respectively). Molecular characterization of the binding sites performed in PC-3 cells by cross-linking experiments and SDS/PAGE revealed a single radioactive band of 85 kDa. To determine which of the three known bombesin receptor subtypes (GRP receptor (GRP-R), neuromedin B receptor, bombesin receptor subtype-3) were expressed in the cell lines, reverse transcription/PCR analysis of cellular RNA followed by hybridization with receptor-specific cDNA was performed. This revealed the presence of GRP-R transcript in all cell lines, while neither of the other two receptor transcripts were expressed. When intracellular calcium mobilization was measured by Fura-2/AM cell labeling and spectrofluorometric monitoring, bombesin (100 nM) induced rapid calcium mobilization in both PC-3 (> 200% of baseline) and DU-145 (> 100% of baseline) cells, but not in LNCaP cells. However, as measured by 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide assay and [3H]thymidine incorporation, no growth modulation was observed with bombesin or bombesin receptor antagonist at various concentrations (0-500 nM). Our data indicate that bombesin is a potent inducer of signal transduction via GRP-R receptors in androgen-insensitive PC-3 and DU-145 prostate cancer cells. This suggests that the bombesin/GRP family of neuropeptides may play a regulatory role in the biology of androgen-independent prostate cancer.

Reassessment of nonplanimetric transrectal ultrasound prostate volume estimates.

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 prostate-specific 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.

The KRAB zinc finger gene ZNF74 encodes an RNA-binding protein tightly associated with the nuclear matrix.

We previously cloned ZNF74, a developmentally expressed zinc finger gene commonly deleted in DiGeorge syndrome. Here, the intron/exon organization of the human gene and the functional properties of the expressed protein are presented. This zinc finger gene from the transcription factor IIIA/Kruppel family contains three exons. A truncated Kruppel-associated box (KRAB) located at the N terminus of the predicted 64-kDa zinc finger protein is encoded by exon 2. The remainder of the protein including the zinc finger domain as well as the 3'-untranslated region (UTR) is encoded by exon 3. Both 5'-UTR (exon 1) and 3'-UTR contain repetitive Alu elements. In vitro translation of a cDNA encoding the entire ZNF74 coding region produced a 63-kDa protein as determined on sodium dodecyl sulfate-polyacrylamide gel. A bacterially expressed fusion protein shown to bind tightly to 65zinc was used to test the nucleic acid binding properties of ZNF74. By RNA binding assays, ZNF74 was found to bind specifically to poly(U) and poly(G) RNA homopolymers. The restricted binding to these homopolymers and not to poly(A) and poly(C) suggested that ZNF74 displays RNA sequence preferences. RNA binding was mediated by the zinc finger domain. Immunofluorescence studies on transfected cells revealed ZNF74 nuclear localization. The labeling pattern observed in the nuclei clearly excluded the nucleoli. The zinc finger region lacks a classical nuclear localization signal but was found to be responsible for nuclear targeting. Subcellular and in situ sequential fractionations further showed that ZNF74 is associated with the nuclear matrix. The RNA binding properties of this protein and its tight association with the nuclear matrix, a subnuclear compartment involved in DNA replication as well as RNA synthesis and processing, suggest a role for ZNF74 in RNA metabolism.

Value of systematic transition zone biopsies in the early detection of prostate cancer.

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%) contained malignancy, including only 8 (2.9%) with cancer found exclusively in the transition zone. The remaining 271 cases (97.1%) 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%) exclusively transition zone tumors among 145 cancers detected in this group. CONCLUSIONS: The low additional yield of transition zone biopsies (2.9 to 4.1%) does not warrant their systematic use for the early detection of prostate cancer.

Complications of ultrasound-guided prostate biopsy peripheral zone only versus combined peripheral and transition zone biopsy.

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.

Blunt cavernous nerve injury: A new animal model mimicking postradical prostatectomy neurogenic impotence.

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.

Multiple neuron-specific enhancers in the gene coding for the human neurofilament light chain.

To define DNA regions involved in the neuron-specific expression of the neurofilament light (NF-L) gene, we generated transgenic mice bearing different NF-L constructs. A 4.9-kilobase human NF-L fragment including -292 base pairs of 5'-flanking sequences contained sufficient elements for nervous system expression in transgenic mice. Deletion of introns 1 and 2 from this 4.9-kilobase DNA fragment resulted in reduced levels of transgene expression in the cortex, while deletion of intron 3 had little effect. Both introns 1 and 2 could act independently as enhancers to confer neuronal expression of the basal heat shock promoter (hsp68) fused to lacZ in transgenic mice. The hNF-L basal promoter (-292 base pairs) was found to contain elements for directing neuronal expression of either the lacZ reporter gene or an intronless hNF-L construct. Sequence comparison revealed that intron 1, intron 2, and the basal human NF-L promoter all contain an ETS-like motif, CAGGA, present in a variety of genes expressed in the nervous system.

Family history and the risk of prostatic carcinoma in a high risk group of urological patients.

PURPOSE: We examine the association of family history and prostatic carcinoma. MATERIALS AND METHODS: 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. RESULTS: 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 (p < 0.001, 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). CONCLUSIONS: 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.