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Supplementary Materials and Methods. Table S1: List of the different oligonucleotides used for mouse genotyping. Table S2: Phenotypic evaluation of prostate-specific PTP1B-overexpressing mice. Figure S1: Ptpn1 status does not alter the transition to mPIN in PtenPE-/- mice. Figure S2: Examples of mild and moderate desmoplasia. Figure S3: HFD drives invasive prostate cancer in the AP only in absence of Ptpn1. Figure S4: Ptpn1 status does not modulate mPIN formation in PtenPE+/- mice. Figure S5: Ptpn1 status influences PtenPE-/- phenotype in a dose-dependent manner.

Supplementary Materials and Methods, Supplementary Table, Supplementary References and Supplementary Figures S1 to S5

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.

Graphical abstract, Highlights • A case of amyloid light-chain amyloidosis with primarily severe MR is described. • Diagnosis was unrecognized preoperatively due to normal LV thickness and function. • Diagnosis was unrecognized preoperatively due to normal LV thickness and function. • Retrospective analysis of preoperative GLS was suggestive of amyloid cardiomyopathy.

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.

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.

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. 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. 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. 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.

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 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.

The three PRL (phosphatases of regenerating liver) protein tyrosine phosphatases (PRL-1, -2 and -3) have been identified as key contributors to metastasis in several human cancers, yet the molecular basis of their pro-oncogenic property is unclear. Among the subfamily of PRL phosphatases, overexpression of PRL-2 in breast cancer cells has been shown to promote tumor growth by a mechanism that remains to be uncovered. Here we show that PRL-2 regulates intracellular magnesium levels by forming a functional heterodimer with the magnesium transporter CNNM3. We further reveal that CNNM3 is not a phosphorylated substrate of PRL-2, and that the interaction occurs through a loop unique to the CBS pair domains of CNNM3 that exists only in organisms having PRL orthologs. Supporting the role of PRL-2 in cellular magnesium transport is the observation that PRL-2 knockdown results in a substantial decrease of cellular magnesium influx. Furthermore, in PRL-2 knockout mice, serum magnesium levels were significantly elevated as compared with control animals, indicating a pivotal role for PRL-2 in regulating cellular magnesium homeostasis. Although the expression levels of CNNM3 remained unchanged after magnesium depletion of various cancer cell lines, the interaction between endogenous PRL-2 and CNNM3 was markedly increased. Importantly, xenograft tumor assays with CNNM3 and a mutant form that does not associate with PRL-2 confirm that CNNM3 is itself pro-oncogenic, and that the PRL-2/CNNM3 association is important for conferring transforming activities. This finding is further confirmed from data in human breast cancer tissues showing that CNNM3 levels correlate positively with both PRL-2 expression and the tumor proliferative index. In summary, we demonstrate that oncogenic PRL-2 controls tumor growth by modulating intracellular magnesium levels through binding with the CNNM3 magnesium transporter.

The classification working group of the International Society of Urological Pathology consensus conference on renal neoplasia was in charge of making recommendations regarding additions and changes to the current World Health Organization Classification of Renal Tumors (2004). Members of the group performed an exhaustive literature review, assessed the results of the preconference survey and participated in the consensus conference discussion and polling activities. On the basis of the above inputs, there was consensus that 5 entities should be recognized as new distinct epithelial tumors within the classification system: tubulocystic renal cell carcinoma (RCC), acquired cystic disease-associated RCC, clear cell (tubulo) papillary RCC, the MiT family translocation RCCs (in particular t(6;11) RCC), and hereditary leiomyomatosis RCC syndrome-associated RCC. In addition, there are 3 rare carcinomas that were considered as emerging or provisional new entities: thyroid-like follicular RCC; succinate dehydrogenase B deficiency-associated RCC; and ALK translocation RCC. Further reports of these entities are required to better understand the nature and behavior of these highly unusual tumors. There were a number of new concepts and suggested modifications to the existing World Health Organization 2004 categories. Within the clear cell RCC group, it was agreed upon that multicystic clear cell RCC is best considered as a neoplasm of low malignant potential. There was agreement that subtyping of papillary RCC is of value and that the oncocytic variant of papillary RCC should not be considered as a distinct entity. The hybrid oncocytic chromophobe tumor, which is an indolent tumor that occurs in 3 settings, namely Birt-Hogg-Dubé Syndrome, renal oncocytosis, and as a sporadic neoplasm, was placed, for the time being, within the chromophobe RCC category. Recent advances related to collecting duct carcinoma, renal medullary carcinoma, and mucinous spindle cell and tubular RCC were elucidated. Outside of the epithelial category, advances in our understanding of angiomyolipoma, including the epithelioid and epithelial cystic variants, were considered. In addition, the apparent relationship between cystic nephroma and mixed epithelial and stromal tumor was discussed, with the consensus that these tumors form a spectrum of neoplasia. Finally, it was thought that the synovial sarcoma should be removed from the mixed epithelial and mesenchymal category and placed within the sarcoma group. The new classification is to be referred to as the International Society of Urological Pathology Vancouver Classification of Renal Neoplasia.

The International Society of Urologic Pathology 2012 Consensus Conference on renal cancer, through working group 3, focused on the issues of staging and specimen handling of renal tumors. The conference was preceded by an online survey of the International Society of Urologic Pathology members, and the results of this were used to inform the focus of conference discussion. On formal voting a Z65% majority was considered a consensus agreement. For specimen handling it was agreed that with radical nephrectomy specimens the initial cut should be made along the long axis and that both radical and partial nephrectomy specimens should be inked. It was recommended that sampling of renal tumors should follow a general guideline of sampling 1 block/cm with a minimum of 3 blocks (subject to modification as needed in individual cases). When measuring a renal tumor, the length of a renal vein/caval thrombus should not be part of the measurement of the main tumor mass. In cases with multiple tumors, sampling should include at a minimum the 5 largest tumors. There was a consensus that perinephric fat invasion should be determined by examining multiple perpendicular sections of the tumor/perinephric fat interface and by sampling areas suspicious for invasion. Perinephric fat invasion was defined as either the tumor touching the fat or extending as irregular tongues into the perinephric tissue, with or without desmoplasia. It was agreed upon that renal sinus invasion is present when the tumor is in direct contact with the sinus fat or the loose connective tissue of the sinus, clearly beyond the renal parenchyma, or if there is involvement of any endothelium-lined spaces within the renal sinus, regardless of the size. When invasion of the renal sinus is uncertain, it was recommended that at least 3 blocks of the tumor-renal sinus interface should be submitted. If invasion is grossly evident, or obviously not present (small peripheral tumor), it was agreed that only 1 block was needed to confirm the gross impression. Other recommendations were that the renal vein margin be considered positive only when there is adherent tumor visible microscopically at the actual margin. When a specimen is submitted separately as "caval thrombus, "the recommended sampling strategy is to take 2 or more sections to look for the adherent caval wall tissue. It was also recommended that uninvolved renal parenchyma be sampled by including normal parenchyma with tumor and normal parenchyma distant from the tumor. There was consensus that radical nephrectomy specimens should be examined for the purpose of identifying lymph nodes by dissection/palpation of the fat in the hilar area only; however, it was acknowledged that lymph nodes are found in

The International Society of Urological Pathology 2012 Consensus Conference made recommendations regarding classification, prognostic factors, staging, and immunohistochemical and molecular assessment of adult renal tumors. Issues relating to prognostic factors were coordinated by a workgroup who identified tumor morphotype, sarcomatoid/rhabdoid differentiation, tumor necrosis, grading, and microvascular invasion as potential prognostic parameters. There was consensus that the main morphotypes of renal cell carcinoma (RCC) were of prognostic significance, that subtyping of papillary RCC (types 1 and 2) provided additional prognostic information, and that clear cell tubulopapillary RCC was associated with a more favorable outcome. For tumors showing sarcomatoid or rhabdoid differentiation, there was consensus that a minimum proportion of tumor was not required for diagnostic purposes. It was also agreed upon that the underlying subtype of carcinoma should be reported. For sarcomatoid carcinoma, it was further agreed upon that if the underlying carcinoma subtype was absent the tumor should be classified as a grade 4 unclassified carcinoma with a sarcomatoid component. Tumor necrosis was considered to have prognostic significance, with assessment based on macroscopic and microscopic examination of the tumor. It was recommended that for clear cell RCC the amount of necrosis should be quantified. There was consensus that nucleolar prominence defined grades 1 to 3 of clear cell and papillary RCCs, whereas extreme nuclear pleomorphism or sarcomatoid and/or rhabdoid differentiation defined grade 4 tumors. It was agreed upon that chromophobe RCC should not be graded. There was consensus that microvascular invasion should not be included as a staging criterion for RCC.

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.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.Early-onset and aggressive prostate cancer associated with a nonsense French Canadian BRCA2 founder mutation, c.5857GT (p.Glu1953(*)).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.

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.

Background Microsatellite instability (MSI) is a form of genomic instability that has recently been implicated in the pathogenesis of thyroid cancer. The purpose of this study was to further define the distribution of MSI in both normal and neoplastic thyroid follicular epithelium. Design Using laser capture microdissection, cells from both normal and tumor tissue were individually collected. Polymerase chain reaction amplification of the DNA was then performed using six dinucleotide and two mononucleotide microsatellite markers. Results Forty benign and malignant thyroid tumors were compared with their adjacent normal thyroid follicular tissue and were analyzed for MSI. Nine of 14 papillary thyroid carcinomas and 10/16 of follicular thyroid carcinomas demonstrated MSI at ≥30–40% of loci tested. For benign follicular adenomas, 9/10 demonstrated microsatellite stability or low-frequency MSI. Conclusion MSI appears to play a role in thyroid pathogenesis as evidenced by the high frequency of MSI in malignant thyroid neoplasms. In addition our study showed a significant difference in MSI frequency between follicular adenomas and follicular carcinomas. More importantly, the technique of laser capture microdissection allows for more accurate selection of benign, malignant, and normal DNA.

BACKGROUND. Active surveillance (AS) with deferred treatment is an established management option for patients with prostate cancer and favorable clinical parameters. The impact of repeat biopsy after diagnosis was examined in a cohort of men with prostate cancer on AS. METHODS. In all, 186 men with prostate cancer with favorable parameters or who refused treatment were conservatively managed by AS. Of these, 92 patients had at least 1 biopsy after diagnosis. Patients were followed every 3 to 6 months with prostate-specific antigen (PSA) and physical examination and were offered rebiopsy annually or if there were any changes on physical examination or in the PSA value. Disease progression while on AS was defined as having ≥1 of the following: ≥cT2b disease, ≥3 positive cores, >50% of cancer in at least 1 core, or a predominant Gleason pattern of 4 in rebiopsies. RESULTS. The median age of the patients at the time of diagnosis was 67 years (range, 49–78 years). The median follow-up was 76 months (range, 20–169 months). Of the 92 patients who underwent repeat biopsies, 42 patients, 25 patients, 13 patients, 10 patients, and 2 patients had 1, 2, 3, 4, and 5 rebiopsies, respectively. A total of 34 patients (36%) demonstrated disease progression on rebiopsy. The first rebiopsy was positive for cancer in 48 patients (52.2%) and negative in 44 patients (47.8%). The 5-year actuarial progression-free probability was 82% for patients with a negative first repeat biopsy compared with 50% for patients with a positive first rebiopsy (P = .02). A PSA doubling time

To date, more than 200 cases of nephrogenic systemic fibrosis have been documented worldwide. All patients have had renal failure, most of them requiring dialysis. We herein describe the course of a hemodialyzed patient who developed nephrogenic systemic fibrosis in the months following magnetic resonance angiography of the lower extremities. The disease is characterized by skin thickening and tendon fibrosis leading to joint contractures that can quickly confine the patient to a wheelchair. Systemic involvement may occur, leading to cardiomyopathy, pulmonary fibrosis, pulmonary hypertension or even death. No consistently effective therapy has been reported. An association between gadolinium exposure and the development of the disease has been found, although no causal link has yet been proven. In a patient with renal failure, magnetic resonance imaging with gadolinium enhancement should be done only after having seriously considered the risk/benefit ratio. Implications concerning the choice of imaging methods when searching for ischemic nephropathy or aorto-iliac disease before renal transplantation are discussed.

Purpose: Cluster-of-differentiation antigen 9 (CD9) protein, a member of the tetraspanin family, has been implicated in carcinogenesis of various human tumors. Although decreased expression of the CD82 tetraspanin protein, a close CD9 relative, is associated with prostate cancer progression, CD9 expression has not been analyzed in this malignancy. Experimental Design: CD9 expression in human prostatic adenocarcinoma was analyzed by immunohistochemistry on 167 primary tumors and 88 lymph node or bone metastases. CD9 cDNA was sequenced from two human prostate cancer cell lines, prostatic adenocarcinoma, high-grade prostatic intraepithelial neoplasia (PIN), and normal prostatic tissues. Results: Although CD9 was detected in the epithelium of normal prostatic tissues, reduced or loss of CD9 expression within neoplastic cells was observed in 24% of 107 clinically localized primary adenocarcinomas, 85% of 60 clinically advanced primary adenocarcinomas, 85% of 65 lymph node metastases, and 65% of 23 bone metastases. Difference in CD9 expression between clinically localized and advanced diseases was highly significant (P < 1 × 10−7). Whereas there was no alteration of CD9 cDNA in normal tissues, all PC-3–derived cell lines, one PIN, and four prostatic adenocarcinomas harbored deletions in their CD9 cDNAs. Recurring CD9 point mutations were also found in PC-3M-LN4 cells, one PIN, and seven prostatic adenocarcinomas. Conclusions: CD9 expression is significantly reduced and even lost during prostate cancer progression. Moreover, deletions and mutations of the CD9 mRNA may be associated with loss of protein expression observed in tumor cells. Our data suggest that CD9 inactivation may play an important role in prostate cancer progression.

Papillary type 2 renal cell carcinoma (RCC) is part of the hereditary leiomyomatosis and renal cell carcinoma syndrome that is caused by a mutation in the fumarate hydratase (FH) gene. In this article, the authors present a tragic case of a young man who was diagnosed with papillary type 2 RCC and was managed with radical nephrectomy, immunotherapy, chemotherapy and surgical debulking. The article discusses the treatment and management of patients with renal manifestations of FH heterozygosity that are the most serious aspects of the syndrome, and underlines the need for genetic evaluation of patients and members of their families. Background A 17-year-old male presented with cervical adenopathy and a palpable left flank mass. After an initial biopsy of the neck mass, which revealed metastatic carcinoma, a left radical nephrectomy was performed as well as excision of a left supraclavicular lymph node. Subsequent inquiry revealed that the patient's father had died of metastatic renal cell carcinoma (RCC) at the age of 40 years, and that other family members had also developed skin and uterine leiomyomas. Investigations Physical examination, CT scans of the chest, abdomen, and pelvis, lymph-node biopsy and genetic counseling, followed by genetic testing. Diagnosis Papillary type 2 RCC described in the context of hereditary leiomyomatosis and renal cell cancer (HLRCC), an autosomal dominant syndrome attributable to a mutation in the fumarate hydratase (FH) gene on chromosome 1. Management Radical nephrectomy, immunotherapy, chemotherapy and repeat surgical debulking. Genetic counseling and testing for family members was also undertaken. Annual skin examination of the carriers and radiological evaluation of both kidneys with CT scan and/or MRI.

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., Despite initial benefits in treating HER2-positive breast cancer patients with lapatinib, resistance is prevalent. Here the authors show that lapatinib resistance can be ascribed to mTOR-mediated re-activation of ERRα and to the consequent induction of a metabolic adaptation.

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.

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.

Animal and laboratory studies suggest that regular use of non-steroidal anti-inflammatory drugs (NSAIDs) may reduce prostate cancer risk. The aim of this study was to investigate the association between NSAID use and prostate cancer in a high-risk population. We included 1299 men who were referred to our university's prostate cancer detection clinic for prostate biopsy between January 1999 and July 2003. Before transrectal ultrasonography and prostate biopsy, all men completed a self-administered questionnaire that included questions on drug use in the preceding 5 years. On average, NSAID users were older than non-users but there was no significant difference in mean baseline prostate-specific antigen (PSA). Four hundred and ninety-four (38%) had biopsy-confirmed prostate cancer. After adjustment for age, family history of prostate cancer and other potential confounders, use of aspirin was associated with a 42% reduction in the odds of prostate cancer detection [95% confidence interval (CI) 0.36-0.91]. Among cases, regular use of NSAIDs was inversely related to the risk of detection of more poorly differentiated cancers and cancers with higher percentage core involvement. These findings support other epidemiological and experimental evidence that suggests that aspirin may be useful in prostate cancer prevention. Further observational studies with adequate case definition and exposure measurements and careful adjustment for detection bias are warranted.

Purpose: BRCA1-related breast cancer frequently has a basal epithelial phenotype, and P-cadherin is a basal marker. We undertook a detailed evaluation of the relationship among P-cadherin, prognostic markers in breast cancer, and outcome. Experimental Design: This study was restricted to 292 cases of first primary invasive breast cancer diagnosed in Ashkenazi Jewish women between 1980 and 1995. All available blocks were stained for P-cadherin, and 261 were included in the final statistical analyses, including 27 germ line BRCA1 mutation carriers and 8 BRCA2 mutation carriers. Descriptive analyses were done followed by survival analyses and a Poisson regression analysis. Results: P-cadherin was present in 80 of the 261 breast cancers (31%) and was more frequently present in tumors that have a basal epithelial phenotype [i.e., high-grade, estrogen receptor– and KIP1 (p27Kip1)–negative tumors, with expression of cytokeratin 5/6, cyclin E, TP53, and presence of BRCA1 mutations and vascular nests (all P < 0.001)]. In a univariate survival model, expression of P-cadherin was associated with a relative risk (RR) of death from breast cancer at a 10-year follow-up of 2.9 (95% confidence interval, 1.8-4.7; P < 0.0001) and was a predictor of poor univariate survival in both lymph node–negative and –positive breast cancers. In a multivariate analysis, the effect of P-cadherin levels was not independent of other basal-related markers. Multivariable interaction modeling showed that P-cadherin positivity was highly predictive of a poor prognosis in small, node-negative breast cancers (RR, 7.1; P = 0.006). Conclusions: P-cadherin is a marker for basal-like breast cancers and is strongly associated with the presence of a BRCA1 mutation. It is an adverse prognostic factor, particularly in small, node-negative breast cancers.

OBJECTIVE To compare the performance of various ratios using total prostate specific antigen (PSA), complexed PSA (cPSA) and free PSA (fPSA) in the early detection of prostate cancer. PATIENTS AND METHODS The study included 535 consecutive patients evaluated at a prostate cancer detection clinic between January 1998 and October 1999. Patients had blood samples drawn before transrectal ultrasonography and prostate biopsy to measure PSA, cPSA and fPSA. Receiver operating characteristic (ROC) curves (sensitivity vs 1 − specificity) were used to evaluate the performance of PSA, cPSA, f/tPSA, cPSA/tPSA, fPSA/cPSA, tPSA/prostate volume (PV), fPSA/PV, and cPSA/PV. The areas under the curve (AUC) were calculated for each ratio. The performance of each ratio over all patients or in those with a tPSA of 4–6 or 4–10 ng/mL were evaluated. RESULTS Of the 535 patients, 204 (38%) had biopsy-confirmed prostate cancer. The AUC obtained with tPSA alone was 0.64; when measured for all patients the cPSA/PV (0.78), PSA/PV (0.77), f/tPSA (0.76) and fPSA/cPSA (0.75) performed better than tPSA alone. Furthermore, in patients with a tPSA of 4–10 ng/mL, tPSA/PV (0.72), cPSA/PV (0.71), f/tPSA (0.69), fPSA/cPSA (0.69) and cPSA/tPSA (0.62) performed better than tPSA alone (0.52). Finally, in patients with a tPSA of 4–6 ng/mL, PSA/PV and cPSA/PV performed better than the other ratios. CONCLUSIONS The use of PSA ratios gives a higher sensitivity and specificity for detecting prostate cancer than the use of tPSA alone.

Purpose: BRCA1-related breast cancers are more frequently estrogen receptor (ER) negative than are either BRCA2-related or nonhereditary breast cancers. The relationship between ER status and other clinical features of hereditary breast cancers has not been well studied. Experimental Design: ER status, grade, and histological tumor type were evaluated in 1131 women with invasive breast cancer, ascertained at 10 centers in North America. There were 208 BRCA1 mutation carriers, 88 BRCA2 carriers, and 804 women without a known mutation. We stratified the patients by mutation status, grade, age, and histological type and calculated the percentage of ER-positive tumors within each stratum. Results: BRCA1 mutation carriers were more likely to have ER-negative breast cancers than were women in other groups, after adjustment for age, grade, and histological subtype (P < 0.001). Only 3.9% of BRCA1-related breast cancers were ER-positive cancers occurring in women in their postmenopausal years. The direction and magnitude of the change in ER status with increasing age at diagnosis in BRCA1 carriers was significantly different from in BRCA2 carriers (Pintercept = 0.0002, Pslope = 0.04). Notably, changes in ER status with age at diagnosis for BRCA1 carriers and noncarriers were almost identical (Pslope = 0.98). Conclusions: The strong relationship between the presence of a BRCA1 mutation and the ER-negative status of the breast cancers is neither a consequence of the young age at onset nor the high grade but is an intrinsic property of BRCA1-related cancers. The ER-negative status of these cancers may reflect the cell of origin of BRCA1-related cancers.

Previous studies have shown that BRCA1-related breast cancers are often high-grade tumors that do not express estrogen receptors, HER2, p27Kip1, or cyclin D1, but do express p53 and cyclin E. In addition, the expression of cytokeratin 5/6 (CK5/6), indicating a basal epithelial phenotype, is frequent in BRCA1-related breast cancer. Here, in a series of 247 breast cancers, we demonstrate that CK5/6 expression was associated with nearly all of the features of BRCA1-related breast cancer and was also associated with a poor prognosis. In a parsimonious multivariable proportional hazards model, protein levels of cyclin E, p27Kip1, p53, and the presence of glomeruloid microvascular proliferation all independently predicted outcome after breast cancer. In this model, only cyclin E and p27Kip1 levels were independent predictors in lymph node-negative cancers, whereas glomeruloid microvascular proliferation and tumor size independently predicted outcome in node-positive disease. The molecular determinants of the basal epithelial phenotype encapsulate many of the key features of breast cancers occurring in germ-line BRCA1 mutation carriers and have independent prognostic value. Basal breast cancer deserves recognition as an important subtype of breast cancer.

OBJECTIVE To examine the relationship of serum insulin-like growth factor (IGF)-1 and IGF binding protein-3 (IGFBP-3) with histological cancer characteristics in men undergoing transrectal ultrasonography (TRUS)-guided biopsy. PATIENTS AND METHODS Patients (652), with either an elevated serum prostate-specific antigen level or an abnormal digital rectal examination, were initially evaluated by TRUS and sextant prostatic needle biopsy. Blood was drawn before biopsy, serum extracted and stored frozen until IGF-1 and IGFBP-3 were measured. In all, 241 patients had prostate cancer (37%) and were included in this study. The number of positive biopsies, the volume of tumour in each positive biopsy and the Gleason score were recorded. RESULTS Of the 241 patients, 37 had five or six positive biopsies (from six), 128 had two to four and 76 had one. Serum IGF-1 did not correlate with the number of positive biopsies, with means of 176.7, 178.3 and 164.4 ng/mL, respectively (P = 0.3), while the mean IGFBP-3 was 2695, 2795 and 2572 ng/mL, respectively (P = 0.09). The additive percentiles of tumour volume in positive biopsies were assessed for each patient but serum IGF-1 and IGFBP-3 did not correlate (P = 0.7 and 0.9, respectively). In all, 92 patients had a Gleason score of 7; the mean (sd) IGF-1 levels for the three groups were 181 (39), 174.6 (35) and 176 (26) ng/mL, and the mean IGFBP-3 2798 (240), 2735 (284) and 2647 (221) ng/mL, respectively, none of the differences being statistically significant. CONCLUSIONS Serum IGF-1 and IGFBP-3 do not correlate with quantity of cancer or Gleason score in biopsy samples from patients with prostate cancer.

BACKGROUND A positive correlation between breast tumor size and the number of axillary lymph nodes containing tumor is well established. It has been reported that patients with BRCA1-related breast carcinoma are more likely than patients with nonhereditary breast carcinoma to have negative lymph node status. Therefore, the authors questioned whether the known positive correlation between tumor size and lymph node status also was present in women with BRCA1-related breast carcinomas. METHODS The relation between the greatest dimension of the resected breast tumor (size) and the presence of positive axillary lymph nodes (expressed as a percentage of all lymph nodes examined) was evaluated in 1555 women with invasive breast carcinoma who were ascertained at 10 centers in North America between 1975 and 1997. There were 276 BRCA1 mutation carriers, 136 BRCA2 carriers, and 1143 women without a known mutation (208 BRCA1/BRCA2 noncarriers and 935 untested women). Patients were stratified according to tumor size, and odds ratios were estimated for the presence of positive lymph nodes with increasing tumor size. RESULTS A highly significant positive correlation between tumor size and the frequency of positive axillary lymph nodes was seen for BRCA1/BRCA2 noncarriers, for BRCA2 carriers, and for untested women (overall P < 0.0001 for each). In contrast, there was no clear correlation between tumor size and positive lymph node status in BRCA1 carriers (overall P = 0.20). CONCLUSIONS The relation between tumor size and lymph node status in patients with breast carcinoma appears to be different in BRCA1 carriers compared with BRCA2 carriers and noncarriers. These findings have important implications for estimating the route of metastatic spread and for evaluating the effectiveness of early diagnosis in patients with BRCA1-related breast carcinoma. Cancer 2003. ©2003 American Cancer Society. DOI 10.1002/cncr.11688

Objectives To compare the histological tissue reactions of urinary bladder in close contact with polypropylene mesh tension-free vaginal tape (TVT) or porcine small intestinal submucosal (SIS) grafts, as the commercial availability of various materials has considerably simplified sling procedures for treating urinary incontinence, but erosion and infection after using artificial sling materials remain an important concern. Materials and methods Thirty female New Zealand rabbits were randomized to three groups, i.e. group A (TVT, 12 animals), group B (SIS, 12) and group C (surgical control, six). Through a laparotomy under anaesthesia and an aseptic technique, the bladder was approached at its dome, where a 0.5 × 1 cm piece of TVT or SIS was fixed in direct contact with the bladder wall. The control group underwent only bladder manipulation with no material applied. Half the animals in each group were killed after 6 weeks and the other half after 12 weeks. The urinary bladder was harvested and examined histologically. Results The grafts in both groups were characterized by dense foreign-body type reactions and were mostly attached loosely to the bladder wall by a thin layer of fibrovascular tissue. More importantly, the bladder wall reactions showed no inflammation in all 12 animals in group A (TVT) but three of them had various grades of fibrosis. There was severe transmural inflammation in one animal in group B (SIS); one rabbit had grade I and two had grade II fibrosis. The controls, as expected, showed no bladder wall reactions. Conclusion In this descriptive analysis of reaction types elicited on the urinary bladder by these grafts, both materials appeared to be safe. Although TVT elicited fewer and less severe adverse reactions, no statistical conclusions can be drawn. The clinical significance of these findings should emerge from long-term clinical data when they become available.

Objectives. To compare the performance of prostate-specific antigen (PSA), the free/total PSA (F/T PSA) ratio, and complexed PSA (cPSA) in prostate cancer detection. Methods. Five hundred thirty-five patients evaluated at the UROMED prostate cancer detection clinic had total PSA, free PSA, and cPSA measured before undergoing transrectal ultrasonography and sextant prostate biopsies. A direct comparison was performed between the different PSA assays to evaluate their ability to detect prostate cancer. Results. Of the 535 patients evaluated, 38.1% had prostate cancer detected. The mean age of the entire population was 63.6 years (range 35 to 86). Abnormal digital rectal examination findings were present in 33.4% of the patients. The mean and median values of PSA and cPSA were significantly higher and the F/T PSA ratio was lower in patients with prostate cancer. The F/T PSA ratio performed better than either cPSA or total PSA. A higher specificity was observed with the F/T PSA ratio than with cPSA using either the entire patient population or subsets of patients with PSA levels between 4.0 and 10 ng/mL or 4.0 to 6.0 ng/mL. Conclusions. The use of the F/T PSA ratio offers improved prostate cancer detection compared with either cPSA or total PSA.

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.

The I1307K polymorphism in APC has been found to predispose to colorectal cancer in Ashkenazi Jews, and has recently been associated with an increased risk for breast cancer in the same population. In that study, we genotyped 205 paraffin-embedded breast cancers from Ashkenazi Jewish women diagnosed below the age of 65. We now present an extended analysis, with clinicopathological correlations between carriers of I1307K and non-carriers. Twenty-four of 209 cases (11.5%, 95% confidence interval 7.5–16.6) were found to carry the I1307K polymorphism. When stratifying the data by other relevant clinicopathological variables, we observed no association between the presence of this polymorphism and age at diagnosis (P = 0.52), grade (P = 0.074), tumour size (P = 0.99), lymph node status (P = 0.82), oestrogen receptor status (P = 0.23) or P53 immunoreactivity (P = 0.80). The breast-cancer specific 5-year survival for women with I1307 K polymorphism was 88.9% compared with 81.6% in women without I1307K (P = 0.34). Using microdissected samples and direct sequencing, no somatic mutations were observed in any of the 24 I1307K-positive cases. Single-strand conformation analysis of 158 of the I1307K-negative breast cancers that were available for study revealed no mobility shifts. We conclude that the presence of the I1307K polymorphism does not appear to be associated with any particular clinicopathological feature of breast cancer and importantly, does not affect the prognosis. © 1999 Cancer Research Campaign

Adenocarcinomas represent approximately 2% of primary bladder epithelial malignancies. Of these, the signet ring-cell variant is the rarest form. We report such a case, with the unusual presentation of oliguria, including radiologic and histopathologic findings. The current literature is reviewed.

We report the case of a primary renal carcinoid tumor associated with a horseshoe malformation in a 43-year-old man who presented with testicular pain. The tumor was centrally located and purely solid and had features ascribed to hindgut neuroendocrine neoplasia. The relative risk of developing a carcinoid tumor in a horseshoe kidney is estimated to be x82.

Malignancy metastasis to the penis is an uncommon clinicopathological entity. We present two cases of malignant priapism following penile metastasis, in which the diagnosis was established by core needle biopsy of the corpus cavernosum. Primary tumors were urothelial carcinoma of the urinary bladder in one case (the patient having concomitant high-grade prostatic adenocarcinoma) and prostatic adenocarcinoma in the other. The clinicopathological features of 51 previously reported cases of penile metastasis in the recent literature are reviewed.

Objectives Intracavernous needle injection is an effective delivery method for pharmacotherapy of erectile dysfunction. Needle phobia, pain, and concern about local tissue injury have stimulated the search for new, less invasive means of inducing penile erection. In this preliminary communication, we evaluate a jet injector as an alternative to needle injection for intracavernous delivery of vasoactive drugs. Methods Jet injection was evaluated in three groups of rats receiving either India ink, saline, or papaverine into the penis. The ability of the jet injection to penetrate through the tunica albuginea and deliver liquid to the corpora cavernosa smooth muscle was assessed by the degree of staining within the corpus cavernosum (ink group), histologic change (saline group), and rise in intracavernous pressure (papaverine group). Erectile capacity following cavernous nerve electric stimulation was compared before and 1 hour after injection of saline or papaverine. Results Ink traversed the skin and tunica albuginea with extensive deposition noted within the cavernous spaces. Varying degrees of subcutaneous hemorrhage were seen with saline jet injection; however, the corpus cavernous smooth muscles showed no evidence of injury. Jet injection of papaverine 3250 gmg significantly increased cavernous pressure (39.4 ± 4.6 cm H2O) compared with saline injection (2.8 ± 1.3 cm H2O). Conclusions We conclude that acute jet injection is an effective method for intracavernous delivery of drugs. Long-term effects should be evaluated prior to clinical use.

Benign thyroid disease is a risk factor for nonmedullary thyroid carcinoma [Houlston and Stratton: Q J Med 88:685-693, 1995]. We report on a family with 7 members with benign and/or malignant thyroid neoplasia; one affected female died of a paravertebral alveolar rhabdomyosarcoma at age 20. The occurrence of thyroid nodular hyperplasia, nonmedullary thyroid cancer, and rhabdomyosarcoma in the same family may be due to chance, common environmental factors, or, most likely, genetic predisposition.

While undergoing a repeat Caesarian section, a 21-year-old woman was found to have a subcutaneous, 3.5-cm tumor-like lesion in the abdominal wall. It had a lobulated contour and consisted of gelatinous tan nodules with intervening fibrous septa. It had a composite histology, including a solid pattern of large glassy cells with a predominant perivascular and pericystic/cisternal topography (35% surface area); a pattern of dyscohesive, vacuolated cells including physaliphorous-like forms (35% surface area); and a myxoid pattern of spindle to stellate cells showing frequent cell contact and lying within an optically clear or pale eosinophilic and bubbly extracellular matrix with a prominent capillary framework. A strong and diffuse cytoplasmic expression of vimentin (only) was present in all cytoarchitectural patterns. The extracellular matrix and intracytoplasmic vacuoles contained abundant acid mucosubstance, mostly hyaluronic acid. No distinct endometrial gland, stigma of hemorrhage, or nuclear estrogen/progesterone receptor protein expression was observed. There were variously sized and shaped cystic spaces lined by a flat to cuboidal cytokeratin-positive cell lining and focally containing neutral and acid mucosubstance. These spaces are interpreted as dilated endometrial glands rather than mechanically entrapped inclusions of mesothelial origin. In this setting, florid decidual reaction represents a potential diagnostic pitfall because it could be confused with more commonly encountered myxoid or epithelioid tumors of mesenchymal, epithelial, or melanocytic cell lineage.

International audience; The International Society of Urological Pathology convened a consensus conference on renal cancer, preceded by an online survey, to address issues relating to the diagnosis and reporting of renal neoplasia. In this report, the role of biomarkers in the diagnosis and assessment of prognosis of renal tumors is addressed. In particular we focused upon the use of immunohistochemical markers and the approach to specific differential diagnostic scenarios. We enquired whether cytogenetic and molecular tools were applied in practice and asked for views on the perceived prognostic role of biomarkers. Both the survey and conference voting results demonstrated a high degree of consensus in participants' responses regarding prognostic/predictive markers and molecular techniques, whereas it was apparent that biomarkers for these purposes remained outside the diagnostic realm pending clinical validation. Although no individual antibody or panel of antibodies reached consensus for classifying renal tumors, or for confirming renal metastatic disease, it was noted from the online survey that 87% of respondents used immunohistochemistry to subtype renal tumors sometimes or occasionally, and a majority (87%) used immunohistochemical markers (Pax 2 or Pax 8, renal cell carcinoma [RCC] marker, panel of pan-CK, CK7, vimentin, and CD10) in confirming the diagnosis of metastatic RCC. There was consensus that immunohistochemistry should be used for histologic subtyping and applied before reaching a diagnosis of unclassified RCC. At the conference, there was consensus that TFE3 and TFEB analysis ought to be requested when RCC was diagnosed in a young patient or when histologic appearances were suggestive of the translocation subtype; whereas Pax 2 and/or Pax 8 were considered to be the most useful markers in the diagnosis of a renal primary.

pp125FAK, a protein tyrosine kinase (PTK) co-localized with integrins in focal adhesion plaques, is known to transduce signals involved in the regulation of cell adhesion and motility as well as the anchorage-independent growth of transformed cells. We investigated whether pp125FAK could be part of a signalling pathway that contributes to the progression of human prostate carcinoma (PCa). Up-regulation of pp125FAK expression, its activation by phosphorylation on tyrosine and its association with paxillin and p50csk were preferentially observed in PCa tissues from patients with metastases, whereas normal and hyperplastic prostates and localized PCa tissues showed undetectable or low levels of both FAK mRNA and protein and an absence of pp125FAK signalling complexes. The increase in expression and activation of pp125FAK in metastatic PCa tissues was also corroborated by our findings in human PCa cell lines. Indeed, higher levels of pp125FAK and FAK mRNA were observed in highly tumorigenic PC-3 cells as was the presence of activated pp125FAK, as opposed to an inactive form in LNCaP cells, which have a lower tumorigenic ability. In addition, pp125FAK formed signalling complexes with both paxillin and p50csk in PC-3 cells as in metastatic PCa tissues. Together, our results show that an increase in FAK mRNA and protein, as well as pp125FAK activation and association with signalling proteins, correlates with progression and invasion in human PCa tissues and cells.

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.

Hepar lobatum is an acquired liver deformity mostly known as the end-stage of tertiary syphilis. The authors report two cases of hepar lobatum resulting from metastatic mammary ductal carcinoma in the liver and reassess the clinicopathologic features of seven previously reported cases (two in the German language). A liver of near-normal weight with an irregularly lobulated contour, capsular indentations/crevices from which intersecting (carcinoma-bearing) fibrous septa extended deep into the parenchyma, a predominant centrifugal distribution of lesional areas, and many septa abutting on the degenerated center of tumor nodules were the salient gross features. No significant tumor/fibrous occlusion of intrahepatic branches of portal or hepatic veins, nor cirrhotic type nodular hepatocellular regeneration was observed. Both of these patients experienced a drastic decrease in CEA serum levels during multiagent palliative chemotherapy. In one patient, abundant macrophages in conjunction with minimal residual tumor were present within intrahepatic septa. The pathogenesis of this condition appears largely related to an active phase of chemo-induced tumor regression with subsequent tissue collapse, followed by an organizing phase of healing and scar contraction.

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.