Atypical tuberous sclerosis complex presenting as familial renal cell carcinoma with leiomyomatous stroma.

We report an atypical tuberous sclerosis complex (TSC) phenotype presenting as familial multiple renal cell carcinomas (RCCs) with (angio)leiomyomatous stroma (RCCLS) (5/7 familial RCCs) on a background of multiple angiomyolipomas, hypopigmented skin macules, and absence of neurological anomalies. In the index case and three relatives, germline genetic testing identified a heterozygous TSC2 missense pathogenic variant [c.2714 G > A, (p.Arg905Gln)], a rare TSC-associated alteration which has previously been associated with a milder TSC phenotype. Whole-exome sequencing of five RCCs from the index case and one RCC from his mother demonstrated either unique tumour-specific deleterious second hits in TSC2 or significant allelic imbalance at the TSC2 gene locus (5/6 RCCs). This study confirms the key tumourigenic role of tumour-specific TSC2 second hits in TSC-associated RCCs and supports the notion that RCCLS may be strongly related to abnormalities of the mTOR pathway.

Structural differences and architectural features of two different polypropylene slings (TVT-O and I-STOP) have no impact on biocompatibility and tissue reactions.

INTRODUCTION: To evaluate the impact of design features of the synthetic mid-urethral slings on tissue integrity and inflammatory responses. MATERIAL AND METHODS: In total 30 female Sprague-Dawley rats were implanted with type I monofilamentous, macroporous polypropylene meshes: Gynecare TVT-Obturator tape® (Ethicon Inc., Johnson & Johnson, Somerville, NJ, USA) and I-STOP® (CL Medical Inc., Lyon, France). All animal groups were sacrificed at set time intervals - 6 weeks, 3 months, 6 months, 9 months and 12 months - and the abdominal wall was harvested with mesh strips for histological evaluation. RESULTS: All mesh strips appeared to be well incorporated into the abdominal wall, and no signs of shrinkage was noticed. All specimens showed a thin/delicate, loose, fibrous interface between the synthetic graft plate and abdominal wall, along with mild inflammatory reactions from 6 weeks to 12 months. CONCLUSIONS: Both mesh brands induced comparable, minimal foreign body reactions and integrated well into the host tissues despite differences in architectural features. TVT-O® and I-STOP® evoked similar low-grade inflammatory responses up to 12 months in this animal model. Structural differences and architectural features of polypropylene slings used in this study have had no impact on tissue integrity and inflammatory responses.

ERRα mediates metabolic adaptations driving lapatinib resistance in breast cancer.

Despite the initial benefits of treating HER2-amplified breast cancer patients with the tyrosine kinase inhibitor lapatinib, resistance inevitably develops. Here we report that lapatinib induces the degradation of the nuclear receptor ERRα, a master regulator of cellular metabolism, and that the expression of ERRα is restored in lapatinib-resistant breast cancer cells through reactivation of mTOR signalling. Re-expression of ERRα in resistant cells triggers metabolic adaptations favouring mitochondrial energy metabolism through increased glutamine metabolism, as well as ROS detoxification required for cell survival under therapeutic stress conditions. An ERRα inverse agonist counteracts these metabolic adaptations and overcomes lapatinib resistance in a HER2-induced mammary tumour mouse model. This work reveals a molecular mechanism by which ERRα-induced metabolic reprogramming promotes survival of lapatinib-resistant cancer cells and demonstrates the potential of ERRα inhibition as an effective adjuvant therapy in poor outcome HER2-positive breast cancer.

PTP1B Deficiency Enables the Ability of a High-Fat Diet to Drive the Invasive Character of PTEN-Deficient Prostate Cancers.

Diet affects the risk and progression of prostate cancer, but the interplay between diet and genetic alterations in this disease is not understood. Here we present genetic evidence in the mouse showing that prostate cancer progression driven by loss of the tumor suppressor Pten is mainly unresponsive to a high-fat diet (HFD), but that coordinate loss of the protein tyrosine phosphatase Ptpn1 (encoding PTP1B) enables a highly invasive disease. Prostate cancer in Pten(-/-)Ptpn1(-/-) mice was characterized by increased cell proliferation and Akt activation, interpreted to reflect a heightened sensitivity to IGF-1 stimulation upon HFD feeding. Prostate-specific overexpression of PTP1B was not sufficient to initiate prostate cancer, arguing that it acted as a diet-dependent modifier of prostate cancer development in Pten(-/-) mice. Our findings offer a preclinical rationale to investigate the anticancer effects of PTP1B inhibitors currently being studied clinically for diabetes treatment as a new modality for management of prostate cancer. Cancer Res; 76(11); 3130-5. ©2016 AACR.

SPINK1 expression in relation to PTEN and ERG in matched primary and lymph node metastatic prostate cancer: Implications for biomarker development.

BACKGROUND: SPINK1, ERG, and PTEN are proposed prognostic biomarkers in prostate cancer (PCA). However, their relations and patterns of expression in primary and metastatic lymph node (LN) PCAs are not fully explored. METHODS: A tissue microarray of matched primary PCA and LN metastasis was constructed from 36 patients. SPINK1, ERG, and PTEN expression statuses were assessed by immunohistochemistry and correlated with each other. RESULTS: SPINK1 and ERG were expressed in 25% and 42.7% of primary PCA cases, respectively. PTEN loss of any degree was observed in 91.7% of primary PCA cases, with 54.2% showing complete loss. In primary PCA, 12.5% of the cases showed SPINK1+/ERG-phenotype, 16.7% showed SPINK1+/ERG+phenotype, 25.0% showed SPINK1-/ERG+phenotype, and 45.8% showed SPINK1-/ERG-phenotype. All PCAs with expression of either SPINK1 or ERG also exhibited PTEN loss, whereas PCA without PTEN loss (2 cases) expressed neither SPINK1 nor ERG. In primary PCA, evaluation of combined ERG and SPINK1 status, but not SPINK1 individually, was associated with a significant difference in proportion of Gleason patterns (P = 0.013), with the SPINK1+/ERG+and SPINK1-/ERG-phenotypes represented more in Gleason pattern>7 PCAs. In LN metastases, the overall SPINK1 protein expression frequency was significantly lower (6.5% of cases) compared with primary PCA (P = 0.03). Only 16.7% of cases with positive SPINK1 expression in primary PCA maintained expression in LN metastases. The down-regulated SPINK1 expression in LN was primarily because of a reduction in the SPINK1+/ERG+PCA subpopulation to 3.5% of cases (P = 0.16 compared with primary PCA). The frequencies of ERG expression and PTEN loss were relatively stable in primary PCA and LN metastases. CONCLUSION: SPINK1 expression is dynamically regulated with up-regulation in primary sites of nodal metastatic PCA and down-regulation in LN metastases. The increased SPINK1 expression in primary site of nodal metastatic PCA is secondary to an increased frequency of SPINK1+/ERG+tumors. In primary PCAs, the SPINK1+/ERG+phenotype is associated with higher Gleason grade, suggesting that this phenotype may mark a more aggressive PCA subpopulation with higher risk of LN metastases.

Inverted urothelial carcinoma: a series of 12 cases with a wide morphologic spectrum overlapping with the large nested variant.

The current series presents 12 cases of invasive urothelial carcinoma (UC) with inverted growth pattern that fulfill the architectural criteria of the recently described "large nested" variant of UC, but which display a wider spectrum of morphologic and cytologic changes. All cases had an associated component of usual invasive UC, and 10 had an associated surface papillary component. Although many areas within the tumors were indistinguishable from a noninvasive endophytic growth pattern, at least some had an irregular ragged contour, and all showed haphazard arrangement with variable amount of intervening stroma at least focally. Inflammatory stromal reaction was noted in 11 cases, and desmoplasia and retraction artifact were present in 8 cases each. Although major areas showed mild atypia, many tumors showed marked hyperchromasia, prominent nucleoli, marked irregular nuclear membranes, and brisk mitotic activity. Final pathological stage on cystectomy specimens was T2 in 4 cases, T3 in 2 cases, and T4 in 3 cases. In 3 cases, lymph node metastases were documented histologically. Review of the literature shows that the "large nested," "inverted," "endophytic," and "inverted papilloma-like" variants of invasive UC are interrelated entities and should probably be considered as one variant with a wide spectrum of cytoarchitectural features. They should also be separated from the "nested" variant with which they rarely coexist and which shows different characteristics at the morphologic level.

Outcome of repeated prostatic biopsy during active surveillance: implications for focal therapy.

INTRODUCTION: Active surveillance (AS) is commonly recommended for men with localized low-intermediate-risk prostate cancer (PCa). The aim of our study was to assess the probability that patients with PCa would develop unfavorable disease features (UDF) while under AS for the purpose of evaluating whether immediate hemiablation therapy (HAT) could bring clinical benefit to selected patients. METHODS: In our cohort of AS patients, 157 were diagnosed with unilateral PCa. Using five different definitions of UDF, patients' data were used to simulate the theoretical outcome whether these patients were managed by immediate unilateral HAT or remained on AS. RESULTS: The mean age at the time of diagnosis was 67 years (range 47-81). The median follow-up was 5.4 years [interquartile range (IQR) 3.4-8]. Baseline characteristics included a median PSA value of 5.5 ng/ml (IQR 4.5-7), median number of biopsy taken of 10 (IQR 6-10), and maximum cancer percentage on any core of 10 (IQR 5-20). Of the 157 patients, 144 (92 %) had a Gleason score (GS) of ≤6. Using the whole range of definition for UDF, 10-47 % of patients developed UDF while under AS. Using baseline GS, maximum percentage of cancer on any core, and PSA density, we found significant trends for higher development of UDF for patients under AS. CONCLUSION: The majority of our patients did not develop UDF while under AS. Our study, thus, suggests that careful patient selection for focal therapy should be performed to avoid subjecting patients to unnecessary treatment.

Biopsy characteristics in men with a preoperative diagnosis of prostatic adenocarcinoma with high Gleason score (8-10) predict pathologic outcome in radical prostatectomy.

Even if limited to one biopsy core, most urologists and radiation oncologists use the highest Gleason score (GS) to guide therapy. To evaluate the suitability of using biopsy characteristics to predict tumor characteristics at radical prostatectomy (RP) in men with high biopsy GS (BGS) cancer to better select men who will most benefit from various local therapies, we retrospectively reviewed the biopsy and RP findings of 144 men with a BGS 8-10. One hundred six and 38 patients with a BGS of 8 and 9-10, respectively, were included. Forty-eight percent of cases were downgraded to a final GS of 7 at RP, including 54% of BGS 8, and 32% of BGS 9-10 group. Overall, 31% had pT2 disease at RP. Multiple biopsy features, including the GS, the number of positive cores, the number of cores with high-GS cancer, and the maximum volume of high-grade cancer per core (MVPC) consistently predicted final GS and RP tumor stage. Multivariate analysis showed that biopsy GS and MVPC were independent predictors of final GS, while MVPC was also an independent predictor for final pT stage. Patients with high BGS are not a homogeneous group in terms of local tumor characteristics. In addition to BGS (9-10 being worse than 8), other biopsy findings, especially the number of involved cores, number of cores with high-BGS cancer, and MVPC are important predictors of findings at RP that should be incorporated in the decision treatment planning. Most patients with only one core BGS 8 cancer harbor GS 7 cancer.

Factors influencing disease progression of prostate cancer under active surveillance: a McGill University Health Center cohort.

OBJECTIVE: To evaluate the clinical and pathological factors influencing the risk of disease progression in a cohort of patients with low-intermediate risk prostate cancer under active surveillance (AS). PATIENTS AND METHODS: We studied 300 patients diagnosed between 1992 and 2012 with prostate adenocarcinoma with favourable parameters or who refused treatment and were managed with AS. Of those, 155 patients with at least one repeat biopsy and no progression criteria at the time of the diagnosis were included for statistical analyses. Patients were followed every 3-6 months for prostate-specific antigen (PSA) measurement and physical examination. Patients were offered repeat prostatic biopsy every year. Disease progression was defined as the presence of one or more of the following criteria: ≥ 3 positive cores, >50% of cancer in at least one core, and a predominant Gleason pattern of 4. RESULTS: For the 155 patients, the mean (sd) age at diagnosis was 67(7) years; the median (interquartile range) follow-up was 5.4(3.6-9.5) years. Of these, 67, 25, six, and two patients had two, three, four, and five repeat biopsies, respectively. At baseline, 11 (7%) patients had a Gleason score of 3+4, while the remaining 144 (93%) patients had a Gleason score of ≤ 6. In all, 50 (32.3%) patients had disease progression on repeat biopsies, with a median progression-free survival time of 7 years. The rate of disease progression decreased after the second repeat biopsy. The 5-year overall survival rate was 100%. Having a PSA density (PSAD) of >0.15 ng/mL/mL, >1 positive core, and Gleason score >6 at the time of the diagnosis was associated with a significantly higher rate of disease progression on univariate analysis (P < 0.05), while a maximum percentage of cancer in any core of >10% showed a trend toward significance for a higher progression rate (P = 0.054). On multivariate analysis, only the presence of a PSAD of >0.15 ng/mL/mL remained significant for a higher progression rate (P < 0.05). Of the 155 patients, five (3.2%) subsequently received radiotherapy, 13 (8.4%) received hormonal therapy, and 13 (8.4%) underwent radical prostatectomy. CONCLUSION: AS is a suitable management option for patients with clinically low-risk prostate cancer. A PSAD of >0.15 ng/mL/mL is an important predictor for disease progression.

ERG protein expression and gene rearrangements are present at lower rates in metastatic and locally advanced castration-resistant prostate cancer compared to localized disease.

OBJECTIVE: To compare ERG expression and gene rearrangements rates in metastatic and castration-resistant prostate cancer (CRPC) to localized disease as ERG is the most common genetic event in early prostate cancer (PCa) with potential prognostic and therapeutic implications. METHODS: We evaluated ERG protein expression in 344 patients with PCa in 3 cohorts including localized, metastatic, and castration-resistant disease using immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). RESULTS: ERG protein expression was detected exclusively in the neoplastic epithelium and was found in 6.8% and 46.3% of high-grade prostatic intraepithelial neoplasia (HGPIN) and localized PCa, respectively. In metastatic and locally advanced CRPC, ERG expression was significantly lower, occurring at 36.1% and 37.2%, respectively. In PCa with foamy gland morphology, ERG protein expression was detected in only 18.6% compared with reported rates of about 42%-48% in acinar PCa. Moreover, ERG protein expression and gene rearrangements showed an overall consistency rate of 90.6% (P <.0001). The consistency rate was 100% both in benign glands and HGPIN, and 96.1% in localized PCa. However, it was significantly lower at 76.9% and 85% in node metastatic and CRPC, respectively (P <.0001). CONCLUSION: ERG protein expression is restricted to neoplastic prostatic epithelium and is present at lower rates in metastatic and CRPC compared to localized PCa. IHC and FISH concordance rates were significantly lower in node metastatic and CRPC compared to localized PCa, which may suggest different biological and therapeutic implications. The lower rate of ERG protein expression in foamy gland PCa may suggest potential differences for this pattern of PCa at the molecular level.

Large-scale independent validation of the nuclear factor-kappa B p65 prognostic biomarker in prostate cancer.

PURPOSE: Over the last decade, we and others have uncovered a robust association between the nuclear localisation of nuclear factor-kappa B (NF-κB) p65, prostate cancer (PCa) aggressiveness and biochemical recurrence (BCR). Our goal was to validate these results in a large independent cohort of PCa patients who underwent radical prostatectomy. EXPERIMENTAL DESIGN: A set of 1826 fully annotated prostate cancers treated by radical prostatectomy were analysed in a tissue microarray (TMA) format for NF-κB p65 immunohistochemistry-based protein expression. We performed standard Cox proportional hazard regression models for follow-up data, bootstrap procedure for model internal validation, Harrell's concordance index for model discrimination and graphical assessment of predicted versus actual outcomes for model calibration. RESULTS: We observed a significant association between an increase in the nuclear frequency of NF-κB p65 and Gleason score (P<0.001), overall BCR (P<0.001) and development of metastases (P=0.001). NF-κB was found to be an independent predictor of BCR (P<0.001, Cox regression). However its contribution to the predictive accuracy of a multivariate model, which included preoperative PSA, Gleason score, extraprostatic extension, lymph node invasion, seminal vesicle involvement and surgical margin status, was modest. CONCLUSIONS: Our study offers validating results linking NF-κB p65 with disease progression using a large cohort of European men. However, the contribution of NF-κB to a post-surgical predictive model appears modest. Further validating work should focus on evaluating the contribution of NF-κB p65 in pre-treatment models.

Familial prostate cancer: the damage done and lessons learnt.

BACKGROUND: A 51-year-old French Canadian man presented to his family physician owing to an extensive family history of prostate cancer in five brothers, his father and two paternal uncles. His serum PSA level was 4.9 ng/ml and a six-core biopsy revealed the presence of a prostate adenocarcinoma with a Gleason score of 7 (3+4). He was treated with radical prostatectomy. Repeat PSA tests revealed a gradual rise in PSA levels despite androgen deprivation therapy with bicalutamide and goserelin over the course of 3 years. Genetic evaluation was undertaken in view of his personal and family history. The proband died at the age of 58 years of widespread metastasis. INVESTIGATIONS: PSA testing, six-core biopsy, genetic counselling and mutation analysis for French Canadian founder mutations in the BRCA1 and BRCA2 genes, histopathological review of tumour tissue from family members, examination of loss of heterozygosity at the BRCA2 gene locus, immunohistochemistry to determine the expression of the ERG nuclear oncoprotein in prostate tumours, genotyping with eight selected risk-associated single nucleotide polymorphisms, Doppler ultrasonography of the leg, CT of the abdomen and pelvis with intravenous and oral contrast, chest CT with intravenous contrast for the assessment of metastatic prostate cancer, genetic testing for the G84E variant in the HOXB13 gene. DIAGNOSIS: Early-onset and aggressive prostate cancer associated with a nonsense French Canadian BRCA2 founder mutation, c.5857G>T (p.Glu1953(*)). MANAGEMENT: Radical prostatectomy, hormone therapy with bicalutamide and goserelin, palliative chemotherapy initially with docetaxel plus prednisone then with mitoxantrone plus prednisone, as well as genetic counselling and testing for the proband and his family members.

PTP1B is an androgen receptor-regulated phosphatase that promotes the progression of prostate cancer.

The androgen receptor (AR) signaling axis plays a key role in the pathogenesis of prostate cancer. In this study, we found that the protein tyrosine phosphatase PTP1B, a well-established regulator of metabolic signaling, was induced after androgen stimulation of AR-expressing prostate cancer cells. PTP1B induction by androgen occurred at the mRNA and protein levels to increase PTP1B activity. High-resolution chromosome mapping revealed AR recruitment to two response elements within the first intron of the PTP1B encoding gene PTPN1, correlating with an AR-mediated increase in RNA polymerase II recruitment to the PTPN1 transcriptional start site. We found that PTPN1 and AR genes were coamplified in metastatic tumors and that PTPN1 amplification was associated with a subset of high-risk primary tumors. Functionally, PTP1B depletion delayed the growth of androgen-dependent human prostate tumors and impaired androgen-induced cell migration and invasion in vitro. However, PTP1B was also required for optimal cell migration of androgen-independent cells. Collectively, our results established the AR as a transcriptional regulator of PTPN1 transcription and implicated PTP1B in a tumor-promoting role in prostate cancer. Our findings support the preclinical testing of PTP1B inhibitors for prostate cancer treatment.

New insights into the pathogenesis of glucocorticoid-induced avascular necrosis: microarray analysis of gene expression in a rat model.

INTRODUCTION: Avascular necrosis of the femoral head (ANFH) occurs variably after exposure to corticosteroids. Microvascular thrombosis is a common pathological finding. Since systemic thrombophilia is only weakly linked with ANFH, we propose that microvascular vessel pathology may be more related to local endothelial dysfunction and femoral head apoptosis. Corticosteroid effects on the endothelium and resultant apoptosis have been reported. We hypothesize that corticosteroids contribute to a differential gene expression in the femoral head in rats with early ANFH. METHODS: Besides bone marrow necrosis, which is a common sign in ANFH and reported in the early stages, we include the presence of apoptosis in this study as a criterion for diagnosing early disease. Forty Wistar Kyoto (WKY) rats were randomized to either a corticosteroid-treated group or an age-matched control group for six months. After sacrifice, the femoral heads were examined for ANFH. Total mRNA was extracted from femoral heads. Affymetrix exon array (Santa Clara, CA, USA) was performed on 15 selected RNA samples. Validation methods included RT-PCR and immunohistochemistry (IHC). RESULTS: Although rat exon array demonstrated a significant upregulation of 51 genes (corticosteroid(+)/ANFH(+) VS control), alpha-2-macroglobulin (A2M) gene was particularly over-expressed. Results were validated by RT-PCR and IHC. Importantly, A2M is known to share vascular, osteogenic and cartilage functions relevant for ANFH. CONCLUSIONS: The findings suggest that corticosteroid-induced ANFH in rats might be mediated by A2M. Investigation of A2M as a potential marker, and a treatment target, for early ANFH should be carried out.

Subtyping of breast cancer by immunohistochemistry to investigate a relationship between subtype and short and long term survival: a collaborative analysis of data for 10,159 cases from 12 studies.

BACKGROUND: Immunohistochemical markers are often used to classify breast cancer into subtypes that are biologically distinct and behave differently. The aim of this study was to estimate mortality for patients with the major subtypes of breast cancer as classified using five immunohistochemical markers, to investigate patterns of mortality over time, and to test for heterogeneity by subtype. METHODS AND FINDINGS: We pooled data from more than 10,000 cases of invasive breast cancer from 12 studies that had collected information on hormone receptor status, human epidermal growth factor receptor-2 (HER2) status, and at least one basal marker (cytokeratin [CK]5/6 or epidermal growth factor receptor [EGFR]) together with survival time data. Tumours were classified as luminal and nonluminal tumours according to hormone receptor expression. These two groups were further subdivided according to expression of HER2, and finally, the luminal and nonluminal HER2-negative tumours were categorised according to expression of basal markers. Changes in mortality rates over time differed by subtype. In women with luminal HER2-negative subtypes, mortality rates were constant over time, whereas mortality rates associated with the luminal HER2-positive and nonluminal subtypes tended to peak within 5 y of diagnosis and then decline over time. In the first 5 y after diagnosis the nonluminal tumours were associated with a poorer prognosis, but over longer follow-up times the prognosis was poorer in the luminal subtypes, with the worst prognosis at 15 y being in the luminal HER2-positive tumours. Basal marker expression distinguished the HER2-negative luminal and nonluminal tumours into different subtypes. These patterns were independent of any systemic adjuvant therapy. CONCLUSIONS: The six subtypes of breast cancer defined by expression of five markers show distinct behaviours with important differences in short term and long term prognosis. Application of these markers in the clinical setting could have the potential to improve the targeting of adjuvant chemotherapy to those most likely to benefit. The different patterns of mortality over time also suggest important biological differences between the subtypes that may result in differences in response to specific therapies, and that stratification of breast cancers by clinically relevant subtypes in clinical trials is urgently required.

Interferon beta-induced panniculitis mimicking acute appendicitis.

BACKGROUND: As immunomodulatory therapies such as recombinant human interferon beta gain clinical applicability, patients are likely to experience some of their numerous cutaneous adverse effects at injection sites. We describe a case of interferon beta-induced septal panniculitis. OBSERVATIONS: A 43-year-old woman with multiple sclerosis treated with subcutaneous interferon beta presented with right lower abdominal quadrant pain, fever, and an indurated McBurney point. An abdominal computed tomographic scan showed an inflammatory subcutaneous fat infiltration reaching the surface of the right lateral rectus muscle. The patient was brought to the operating room, where a laparoscopic appendectomy was performed. She returned a week later unimproved. The infiltration near a site of subcutaneous injection progressed with areas of liquefaction. Histologic examination of a deep cutaneous biopsy specimen revealed a septal panniculitis without vasculitis. CONCLUSIONS: Panniculitides encompass various clinical syndromes characterized by inflammation of the fibrous septae, fatty lobules, or both components of the subcutaneous tissue. Interferon beta-1b should be considered among the list of putative agents.

Dietary habits and prostate cancer detection: a case-control study.

BACKGROUND: Many studies have suggested that nutritional factors may affect prostate cancer development. The aim of our study was to evaluate the relationship between dietary habits and prostate cancer detection. METHODS: We studied 917 patients who planned to have transrectal ultrasonography-guided prostatic biopsy based on an elevated serum prostate-specific antigen (PSA) level, a rising serum PSA level or an abnormal digital rectal examination. Before receiving the results of their biopsy, all patients answered a self-administered food frequency questionnaire. In combination with pathology data we performed univariable and multivariable logistic regression analyses for the predictors of cancer and its aggressiveness. RESULTS: Prostate cancer was found in 42% (386/917) of patients. The mean patient age was 64.5 (standard deviation [SD] 8.3) years and the mean serum PSA level for prostate cancer and benign cases, respectively, was 13.4 (SD 28.2) mug/L and 7.3 (SD 4.9) mug/L. Multivariable analysis revealed that a meat diet (e.g., red meat, ham, sausages) was associated with an increased risk of prostate cancer (odds ratio [OR] 2.91, 95% confidence interval [CI] 1.55-4.87, p = 0.027) and a fish diet was associated with less prostate cancer (OR 0.54, 95% CI 0.32-0.89, p = 0.017). Aggressive tumours were defined by Gleason score (>/= 7), serum PSA level (>/= 10 mug/L) and the number of positive cancer cores (>/= 3). None of the tested dietary components were found to be associated with prostate cancer aggressivity. CONCLUSION: Fish diets appear to be associated with less risk of prostate cancer detection, and meat diets appear to be associated with a 3-fold increased risk of prostate cancer. These observations add to the growing body of evidence suggesting a relationship between diet and prostate cancer risk.

Absence of prognostic value of nuclear shape factor analysis in colorectal carcinoma: relevance of interobserver and intraobserver variability.

PURPOSE: Several retrospective studies, including our previous investigation, have shown a prognostic value of nuclear shape factor in colorectal carcinomas. This prospective study was designed to assess the reliability of nuclear shape factor determined by nuclear morphometry and to confirm its prognostic value. METHODS: Ninety-eight patients who underwent colorectal carcinoma resection were prospectively enrolled. Measurement of nuclear shape factor was performed by using a computer-based image analysis system. Nuclear shape factor was defined as the degree of circularity of the nucleus (1.0 for a perfect circle and <1.0 for any other elliptical shape). The prognostic impact of nuclear shape factor on ten-year survival and the intraobserver and interobserver agreement were assessed. RESULTS: The nuclear shape factor mean values by American Joint Committee on Cancer stage were: 0.73 (0.07) in Stage I, 0.74 (0.06) in Stage II, and 0.75 (0.05) in Stage III carcinomas (P = 0.78, ANOVA). The intraobserver agreement was poor for observer A (r = 0.28) and practically nonexistent for observer B (r = -0.004, Pearson correlation). The intraclass coefficient for interobserver agreement was practically nonexistent. No significant association between nuclear shape factor and ten-year survival was found. CONCLUSIONS: Our prospective results, as opposed to our previous retrospective results, suggest that the reliability for nuclear shape factor morphometric analysis is very poor. We failed to confirm a prognostic value for nuclear shape factor in colorectal carcinoma.