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1.
BJU Int ; 125(4): 506-514, 2020 04.
Article in English | MEDLINE | ID: mdl-31900963

ABSTRACT

OBJECTIVE: To test the hypothesis that the baseline clinico-pathological features of the men with localized prostate cancer (PCa) included in the ProtecT (Prostate Testing for Cancer and Treatment) trial who progressed (n = 198) at a 10-year median follow-up were different from those of men with stable disease (n = 1409). PATIENTS AND METHODS: We stratified the study participants at baseline according to risk of progression using clinical disease stage, pathological grade and PSA level, using Cox proportional hazard models. RESULTS: The findings showed that 34% of participants (n = 505) had intermediate- or high-risk PCa, and 66% (n = 973) had low-risk PCa. Of 198 participants who progressed, 101 (51%) had baseline International Society of Urological Pathology Grade Group 1, 59 (30%) Grade Group 2, and 38 (19%) Grade Group 3 PCa, compared with 79%, 17% and 5%, respectively, for 1409 participants without progression (P < 0.001). In participants with progression, 38% and 62% had baseline low- and intermediate-/high-risk disease, compared with 69% and 31% of participants with stable disease (P < 0.001). Treatment received, age (65-69 vs 50-64 years), PSA level, Grade Group, clinical stage, risk group, number of positive cores, tumour length and perineural invasion were associated with time to progression (P ≤ 0.005). Men progressing after surgery (n = 19) were more likely to have a higher Grade Group and pathological stage at surgery, larger tumours, lymph node involvement and positive margins. CONCLUSIONS: We demonstrate that one-third of the ProtecT cohort consists of people with intermediate-/high-risk disease, and the outcomes data at an average of 10 years' follow-up are generalizable beyond men with low-risk PCa.


Subject(s)
Prostatic Neoplasms/pathology , Aged , Cohort Studies , Disease Progression , Follow-Up Studies , Humans , Kallikreins/blood , Male , Middle Aged , Neoplasm Staging , Prostate-Specific Antigen/blood , Prostatic Neoplasms/blood , Risk Assessment , Time Factors
2.
Histopathology ; 74(3): 377-390, 2019 Feb.
Article in English | MEDLINE | ID: mdl-30325065

ABSTRACT

AIMS: The International Collaboration on Cancer Reporting (ICCR) has provided detailed data sets based upon the published reporting protocols of the Royal College of Pathologists, the Royal College of Pathologists of Australasia and the College of American Pathologists. METHODS AND RESULTS: The data set for carcinomas of renal tubular origin treated by nephrectomy was developed to provide a minimum structured reporting template suitable for international use, and incorporated recommendations from the 2012 Vancouver Consensus Conference of the International Society of Urological Pathology (ISUP) and the fourth edition of the World Health Organisation Bluebook on tumours of the urinary and male genital systems published in 2016. Reporting elements were divided into those, which are required and recommended components of the report. Required elements are: specimen laterality, operative procedure, attached structures, tumour focality, tumour dimension, tumour type, WHO/ISUP grade, sarcomatoid/rhabdoid morphology, tumour necrosis, extent of invasion, lymph node status, surgical margin status, AJCC TNM staging and co-existing pathology. Recommended reporting elements are: pre-operative treatment, details of tissue removed for experimental purposes prior to submission, site of tumour(s) block identification key, extent of sarcomatoid and/or rhabdoid component, extent of necrosis, presence of tumour in renal vein wall, lymphovascular invasion and lymph node status (size of largest focus and extranodal extension). CONCLUSIONS: It is anticipated that the implementation of this data set in routine clinical practice will inform patient treatment as well as provide standardised information relating to outcome prediction. The harmonisation of data reporting should also facilitate international research collaborations.


Subject(s)
Carcinoma, Renal Cell , Datasets as Topic/standards , Kidney Neoplasms , Research Design/standards , Australasia , Humans , Pathology, Clinical/methods , Pathology, Clinical/standards
3.
Ann Diagn Pathol ; 18(6): 333-42, 2014 Dec.
Article in English | MEDLINE | ID: mdl-25263387

ABSTRACT

The diagnosis of intraductal carcinoma (IDC) of the prostate remains subjective because 3 sets of diagnostic criteria are in use. An internet survey was compiled from 38 photomicrographs showing duct proliferations: 14 signed out as high-grade prostatic intraepithelial neoplasia (HGPIN), 17 IDC, and 7 invasive cribriform/ductal carcinoma. Each image was assessed for the presence of 9 histologic criteria ascribed to IDC. Thirty-nine respondents were asked to rate images as (1) benign/reactive, (2) HGPIN, (3) borderline between HGPIN and IDC, (4) IDC, or (5) invasive cribriform/ductal carcinoma. Intraclass correlation coefficient was 0.68. There was 70% overall agreement with HGPIN, 43% with IDC, and 73% with invasive carcinoma (P < .001, χ(2)). Respondents considered 19 (50%) of 38 cases as IDC candidates, of which 5 (26%) had a two-thirds consensus for IDC; two-thirds consensus for either borderline or IDC was reached in 9 (47%). Two-thirds consensus other than IDC was reached in the remaining 19 of 38 cases, with 15 supporting HGPIN and 4 supporting invasive carcinoma. Findings that differed across diagnostic categories were lumen-spanning neoplastic cells (P < .001), 2× benign duct diameters (P < .001), duct space contours (round, irregular, and branched) (P < .001), papillary growth (P = .048), dense cribriform or solid growth (both P = .023), and comedonecrosis (P = .015). When the 19 of 38 images that attained consensus for HGPIN or invasive carcinoma were removed from consideration, lack of IDC consensus was most often attributable to only loose cribriform growth (5/19), central nuclear maturation (5/19), or comedonecrosis (3/19). Of the 9 histologic criteria, only 1 retained significant correlation with a consensus diagnosis of IDC: the presence of solid areas (P = .038). One case that attained IDC consensus had less than 2× duct enlargement yet still had severe nuclear atypia and nucleomegaly. Six fold nuclear enlargement was not significant (P = .083), although no image had both 6× nuclei and papillary or loose cribriform growth: a combination postulated as sufficient criteria for IDC. Finally, 20.5% of respondents agreed that an isolated diagnosis of IDC on needle biopsy warrants definitive therapy, 20.5% disagreed, and 59.0% considered the decision to depend upon clinicopathologic variables. Although IDC diagnosis remains challenging, we propose these criteria: a lumen-spanning proliferation of neoplastic cells in preexisting ducts with a dense cribriform or partial solid growth pattern. Solid growth, in any part of the duct space, emerges as the most reproducible finding to rule in a diagnosis of IDC. Comedonecrosis is a rarer finding, but in most cases, it should rule in IDC. Duct space enlargement to greater than 2× the diameter of the largest, adjacent benign spaces is usually present in IDC, although there may be rare exceptions.


Subject(s)
Carcinoma, Intraductal, Noninfiltrating/pathology , Prostatic Neoplasms/pathology , Diagnosis, Differential , Health Surveys , Humans , Male , Neoplasm Grading , Observer Variation , Physicians , Prognosis , Prostatic Intraepithelial Neoplasia/pathology , Reproducibility of Results
4.
J Transl Med ; 11: 255, 2013 Oct 11.
Article in English | MEDLINE | ID: mdl-24119769

ABSTRACT

BACKGROUND: Up to 40% of patients initially diagnosed with clinically-confined renal cell carcinoma (RCC) and who undergo curative surgery will nevertheless relapse with metastatic disease (mRCC) associated with poor long term survival. The discovery of novel prognostic/predictive biomarkers and drug targets is needed and in this context the aim of the current study was to investigate a putative caveolin-1/ERK signalling axis in clinically confined RCC, and to examine in a panel of RCC cell lines the effects of caveolin-1 (Cav-1) on pathological processes (invasion and growth) and select signalling pathways. METHODS: Using immunohistochemistry we assessed the expression of both Cav-1 and phosphorylated-ERK (pERK) in 176 patients with clinically confined RCC, their correlation with histological parameters and their impact upon disease-free survival. Using a panel of RCC cell lines we explored the functional effects of Cav-1 knockdown upon cell growth, cell invasion and VEGF-A secretion, as well Cav-1 regulation by cognate cell signalling pathways. RESULTS: We found a significant correlation (P = 0.03) between Cav-1 and pERK in a cohort of patients with clinically confined disease which represented a prognostic biomarker combination (HR = 4.2) that effectively stratified patients into low, intermediate and high risk groups with respect to relapse, even if the patients' tumours displayed low grade and/or low stage disease. In RCC cell lines Cav-1 knockdown unequivocally reduced cell invasive capacity while also displaying both pro-and anti-proliferative effects; targeted knockdown of Cav-1 also partially suppressed VEGF-A secretion in VHL-negative RCC cells. The actions of Cav-1 in the RCC cell lines appeared independent of both ERK and AKT/mTOR signalling pathways. CONCLUSION: The combined expression of Cav-1 and pERK serves as an independent biomarker signature with potential merit in RCC surveillance strategies able to predict those patients with clinically confined disease who will eventually relapse. In a panel of in-vitro RCC cells Cav-1 promotes cell invasion with variable effects on cell growth and VEGF-A secretion. Cav-1 has potential as a therapeutic target for the prevention and treatment of mRCC.


Subject(s)
Carcinoma, Renal Cell/metabolism , Carcinoma, Renal Cell/pathology , Caveolin 1/metabolism , Extracellular Signal-Regulated MAP Kinases/metabolism , Kidney Neoplasms/metabolism , Kidney Neoplasms/pathology , Carcinoma, Renal Cell/enzymology , Cell Line, Tumor , Cell Proliferation/drug effects , Down-Regulation/drug effects , Gene Knockdown Techniques , Humans , Kidney Neoplasms/enzymology , Multivariate Analysis , Neoplasm Invasiveness , Neoplasm Metastasis , Phosphorylation/drug effects , Prognosis , Proportional Hazards Models , Proto-Oncogene Proteins c-akt/metabolism , RANK Ligand/pharmacology , Signal Transduction/drug effects , TOR Serine-Threonine Kinases/metabolism , Vascular Endothelial Growth Factor A/metabolism , Von Hippel-Lindau Tumor Suppressor Protein/metabolism
5.
Histopathology ; 62(2): 203-18, 2013 Jan.
Article in English | MEDLINE | ID: mdl-23240714

ABSTRACT

This project was designed to harmonise the Royal College of Pathologists, College of American Pathologists and Royal College of Pathologists of Australasia datasets, checklists and structured reporting protocols for examination of radical prostatectomy specimens, with the aim of producing a common, internationally agreed, evidence-based dataset for prostate cancer reporting. The International Collaboration on Cancer Reporting prostate cancer expert review panel analysed the three existing datasets, identifying concordant items and classified these data elements as 'required' (mandatory) or 'recommended' (non-mandatory), on the basis of the published literature up to August 2011. Required elements were defined as those that have agreed evidentiary support at NHMRC level III-2 or above. Consensus response values were formulated for each item. Twelve concordant pathology data elements were identified, and, on review, all but one were included as required elements for tumour staging, grading, or prediction of prognosis. There was minor discordance between the three existing datasets for another eight items, with two of these being added to the required data set. Another 11 elements with a lesser level of evidentiary support were included in the recommended dataset. This process was found to be an efficient method for producing an evidence-based dataset for prostate cancer. Such internationally agreed datasets should facilitate meaningful comparison of benchmarking data, epidemiological studies, and clinical trials.


Subject(s)
Adenocarcinoma/pathology , Databases as Topic , Medical Records/standards , Pathology, Surgical/standards , Prostatectomy , Prostatic Neoplasms/pathology , Adenocarcinoma/surgery , Australasia , Consensus , Humans , International Cooperation , Male , Prognosis , Prostatic Neoplasms/surgery , United Kingdom , United States
6.
Cancer Res Commun ; 3(3): 444-458, 2023 03.
Article in English | MEDLINE | ID: mdl-36936664

ABSTRACT

Metastatic prostate cancer is essentially incurable and is a leading cause of cancer-related morbidity and mortality in men, yet the underlying molecular mechanisms are poorly understood. Plexins are transmembrane receptors for semaphorins with divergent roles in many forms of cancer. We show here that prostate epithelial cell-specific expression of a mutant form of Plexin-B1 (P1597L) which was identified in metastatic deposits in patients with prostate cancer, significantly increases metastasis, in particular metastasis to distant sites, in two transgenic mouse models of prostate cancer (PbCre+Ptenfl /flKrasG12V and PbCre+Ptenfl /flp53fl/ fl ). In contrast, prostate epithelial cell-specific expression of wild-type (WT) Plexin-B1 in PbCre+Ptenfl /flKrasG12V mice significantly decreases metastasis, showing that a single clinically relevant Pro1597Leu amino-acid change converts Plexin-B1 from a metastasis-suppressor to a metastasis-promoter. Furthermore, PLXNB1P1597L significantly increased invasion of tumor cells into the prostate stroma, while PLXNB1WT reduced invasion, suggesting that Plexin-B1 has a role in the initial stages of metastasis. Deletion of RhoA/C or PDZRhoGEF in Ptenfl /flKrasG12VPLXNB1P1597L mice suppressed metastasis, implicating the Rho/ROCK pathway in this phenotypic switch. Germline deletion of Plexin-B1, to model anti-Plexin-B1 therapy, significantly decreased invasion and metastasis in both models. Our results demonstrate that Plexin-B1 plays a complex yet significant role in metastasis in mouse models of prostate cancer and is a potential therapeutic target to block the lethal spread of the disease. Significance: Few therapeutic targets have been identified specifically for preventing locally invasive/oligometastatic prostate cancer from becoming more widely disseminated. Our findings suggest Plexin-B1 signaling, particularly from the clinically relevant P1597L mutant, is such a target.


Subject(s)
Antineoplastic Agents , Prostatic Neoplasms , Humans , Male , Mice , Animals , Proto-Oncogene Proteins p21(ras)/metabolism , Receptors, Cell Surface/genetics , Signal Transduction/genetics , Prostatic Neoplasms/genetics , Mice, Transgenic
7.
Mod Pathol ; 24(1): 39-47, 2011 Jan.
Article in English | MEDLINE | ID: mdl-20818343

ABSTRACT

The 2009 International Society of Urological Pathology Consensus Conference in Boston made recommendations regarding the standardization of pathology reporting of radical prostatectomy specimens. Issues relating to the infiltration of tumor into the seminal vesicles and regional lymph nodes were coordinated by working group 4. There was a consensus that complete blocking of the seminal vesicles was not necessary, although sampling of the junction of the seminal vesicles and prostate was mandatory. There was consensus that sampling of the vas deferens margins was not obligatory. There was also consensus that muscular wall invasion of the extraprostatic seminal vesicle only should be regarded as seminal vesicle invasion. Categorization into types of seminal vesicle spread was agreed by consensus to be not necessary. For examination of lymph nodes, there was consensus that special techniques such as frozen sectioning were of use only in high-risk cases. There was no consensus on the optimal sampling method for pelvic lymph node dissection specimens, although there was consensus that all lymph nodes should be completely blocked as a minimum. There was also a consensus that a count of the number of lymph nodes harvested should be attempted. In view of recent evidence, there was consensus that the diameter of the largest lymph node metastasis should be measured. These consensus decisions will hopefully clarify the difficult areas of pathological assessment in radical prostatectomy evaluation and improve the concordance of research series to allow more accurate assessment of patient prognosis.


Subject(s)
Adenocarcinoma/pathology , Lymph Nodes/pathology , Prostatectomy/methods , Prostatic Neoplasms/pathology , Seminal Vesicles/pathology , Specimen Handling/methods , Adenocarcinoma/surgery , Humans , Lymphatic Metastasis , Male , Neoplasm Invasiveness , Neoplasm Staging , Prostatic Neoplasms/surgery , Societies, Medical
8.
Mod Pathol ; 24(1): 6-15, 2011 Jan.
Article in English | MEDLINE | ID: mdl-20834234

ABSTRACT

The 2009 International Society of Urological Pathology Consensus Conference in Boston made recommendations regarding the standardization of pathology reporting of radical prostatectomy specimens. Issues relating to the handling and processing of radical prostatectomy specimens were coordinated by working group 1. Most uropathologists followed similar procedures for fixation of radical prostatectomy specimens, with 51% of respondents transporting tissue in formalin. There was also consensus that the prostate weight without the seminal vesicles should be recorded. There was consensus that the surface of the prostate should be painted. It was agreed that both the prostate apex and base should be examined by the cone method with sagittal sectioning of the tissue sample. There was consensus that the gland should be fully fixed before sectioning. Both partial and complete embedding of prostates was considered to be acceptable as long as the method of partial embedding is stated. No consensus was determined regarding the necessity of weighing and measuring the length of the seminal vesicles, the preparation of whole mounts rather than standardized blocks and the methodology for sampling of fresh tissue for research purposes, and it was agreed that these should be left to the discretion of the working pathologist.


Subject(s)
Adenocarcinoma/pathology , Histocytological Preparation Techniques/methods , Prostatectomy/methods , Prostatic Neoplasms/pathology , Specimen Handling/methods , Adenocarcinoma/surgery , Histocytological Preparation Techniques/standards , Humans , Male , Neoplasm Staging , Prostatic Neoplasms/surgery , Societies, Medical
9.
Mod Pathol ; 24(1): 26-38, 2011 Jan.
Article in English | MEDLINE | ID: mdl-20802467

ABSTRACT

The International Society of Urological Pathology Consensus Conference on Handling and Staging of Radical Prostatectomy Specimens in Boston made recommendations regarding the standardization of pathology reporting of radical prostatectomy specimens. Issues relating to extraprostatic extension (pT3a disease), bladder neck invasion, lymphovascular invasion and the definition of pT4 were coordinated by working group 3. It was agreed that prostate cancer can be categorized as pT3a in the absence of adipose tissue involvement when cancer bulges beyond the contour of the gland or beyond the condensed smooth muscle of the prostate at posterior and posterolateral sites. Extraprostatic extension can also be identified anteriorly. It was agreed that the location of extraprostatic extension should be reported. Although there was consensus that the amount of extraprostatic extension should be quantitated, there was no agreement as to which method of quantitation should be employed. There was overwhelming consensus that microscopic urinary bladder neck invasion by carcinoma should be reported as stage pT3a and that lymphovascular invasion by carcinoma should be reported. It is recommended that these elements are considered in the development of practice guidelines and in the daily practice of urological surgical pathology.


Subject(s)
Adenocarcinoma/pathology , Prostatectomy/methods , Prostatic Neoplasms/pathology , Specimen Handling/methods , Adenocarcinoma/classification , Adenocarcinoma/surgery , Boston , Humans , Internationality , Lymph Nodes/pathology , Lymphatic Metastasis , Male , Neoplasm Invasiveness , Neoplasm Staging , Prognosis , Prostatic Neoplasms/classification , Prostatic Neoplasms/surgery , Societies, Medical , Urinary Bladder/pathology
11.
Histopathology ; 58(2): 180-90, 2011 Jan.
Article in English | MEDLINE | ID: mdl-21255063

ABSTRACT

AIMS: Renal cell carcinoma (RCC) often recurs as distant metastasis; there is thus a need for new indicators to identify high-risk patients. Glutathione S-transferases (GST)-α and -π are involved in the renal bioactivation of toxic metabolites. The aim was to investigate whether their expression is of diagnostic and prognostic value. METHODS AND RESULTS: Western blotting of microdissected normal kidney and immunostaining of histological RCC microarrays shows expression of GST-α in proximal tubular cells, while GST-π was found in the distal nephron. Of the primary 174 RCC cases examined, GST-α immunoreactivity was restricted to conventional RCC (n=76, 68% positive) and was not seen in any other RCC subtypes. The cross-tabulation of the GST-α scores with other prognostic indices demonstrated that GST-α immunostaining was significantly more frequent in low-grade tumours (χ(2): P<0.004), and that conventional GST-α-positive RCC patients had a mean disease-free survival of 6.0 years (95% confidence interval 5.33-6.63), compared with 4.7 years (3.54-5.90) in GST-α-negative tumours (Kaplan-Meier survival analysis, P=0.011, log-rank test). CONCLUSIONS: GST-α is a highly specific diagnostic marker for primary conventional RCC, where it is a prognostic marker if grade is omitted from the multivariate analysis.


Subject(s)
Biomarkers, Tumor/analysis , Carcinoma, Renal Cell/enzymology , Glutathione Transferase/biosynthesis , Kidney Neoplasms/enzymology , Blotting, Western , Carcinoma, Renal Cell/mortality , Carcinoma, Renal Cell/pathology , Disease Progression , Disease-Free Survival , Humans , Immunohistochemistry , Kaplan-Meier Estimate , Kidney Neoplasms/mortality , Kidney Neoplasms/pathology , Neoplasm Staging , Prognosis , Tissue Array Analysis
12.
Nephrol Dial Transplant ; 26(5): 1559-63, 2011 May.
Article in English | MEDLINE | ID: mdl-20858764

ABSTRACT

BACKGROUND: Despite improvements in safety seen over the last 20 years, percutaneous renal biopsy is still associated with haemorrhagic complications. Due to concerns over delayed bleeding, most nephrologists would advocate overnight observation. Recent evidence in both adult and paediatric populations suggest that in some groups, this is unnecessary. Since 1991, we have provided a day-case renal biopsy service performing 70 such procedures per year. In this study, we present a retrospective analysis of this practice. METHODS: A total of 192 patients over a consecutive 3-year period were analysed retrospectively. Patients were selected according to standardized criteria, and biopsy was performed using a modern technique (automated biopsy needles under ultrasound guidance). Complications were identified by examination of case notes and local hospital admission databases, and by telephone interview. Our pathology database was examined for sample adequacy and diagnosis. RESULTS: There were no delayed complications in the study group with 187 patients (97.4%) being discharged home on the same day. Major complications occurred in five patients (2.6%), all related to bleeding. Of these, two needed radiological intervention to achieve haemostasis. Sufficient tissue for diagnosis was achieved in 97% of cases, with a mean of 47 ± 23 glomeruli obtained per patient. Most biopsies were obtained with ≤ 2 passes (84%). CONCLUSIONS: Our findings show that in selected adult patients, renal biopsy can be performed as a day-case procedure. Given the benefits of day-case strategies in terms of patient and healthcare costs, we advocate increased utilization of this technique.


Subject(s)
Biopsy/adverse effects , Biopsy/methods , Kidney/pathology , Postoperative Hemorrhage/prevention & control , Adult , Case-Control Studies , Female , Hospitalization , Humans , Male , Middle Aged , Postoperative Hemorrhage/etiology , Prognosis , Retrospective Studies
14.
Eur J Med Genet ; 63(9): 103972, 2020 Sep.
Article in English | MEDLINE | ID: mdl-32531461

ABSTRACT

Mutations in the TRIM8 gene have been described in patients with severe developmental delay, intellectual disability and epilepsy. Only six patients have been described to date. All the previous mutations were truncating variants clustered in the C-terminus of the protein. A previous patient with TRIM8-related epileptic encephalopathy was reported to have nephrotic syndrome. Here we describe the clinical, radiological and histological features of an 8-year-old male patient with a TRIM8 mutation who, in contrast to previous patients, had only mild intellectual disability and well-controlled epilepsy. The patient was found to have proteinuria at 2 years of age. Renal biopsy findings were suggestive of focal segmental glomerulosclerosis. His kidney function declined and peritoneal dialysis was started at 5 years of age. He underwent renal transplant at 7 years of age. Trio-based whole genome sequencing identified a novel de novo heterozygous frameshift mutation in TRIM8 (NM_030912.2) c.1198_1220del, p.(Tyr400ArgfsTer2). This patient is further evidence that TRIM8 mutations cause a syndrome with both neurological and renal features. Our findings suggest the spectrum of TRIM8-related disease may be wider than previously thought with the possibility of milder neurodevelopmental problems and/or a more severe, progressive renal phenotype. We highlight the need for proteinuria screening in patients with TRIM8 mutations.


Subject(s)
Carrier Proteins/genetics , Glomerulosclerosis, Focal Segmental/genetics , Intellectual Disability/genetics , Mutation , Nerve Tissue Proteins/genetics , Proteinuria/genetics , Child , Glomerulosclerosis, Focal Segmental/pathology , Humans , Intellectual Disability/pathology , Male , Proteinuria/pathology , Syndrome
15.
Arab J Urol ; 16(4): 378-385, 2018 Dec.
Article in English | MEDLINE | ID: mdl-30534435

ABSTRACT

OBJECTIVE: To report our long-term outcomes of surgical treatment of renal tumours with inferior vena cava (IVC) tumour thrombus above the hepatic veins, utilising cardiopulmonary bypass (CBP) and hypothermic circulatory arrest (HCA), as surgical resection remains the only effective treatment for renal cancers with extensive IVC tumour thrombus. PATIENTS AND METHODS: We retrospectively reviewed 48 consecutive patients (median age 58 years) who underwent surgical treatment for non-metastatic renal cancer with IVC tumour thrombus extending above the hepatic veins. Perioperative, histological, disease-free (DFS) and overall survival (OS) data were recorded. RESULTS: Tumour thrombus was level III in 23 patients and level IV in 25 patients. The median (range) CBP and HCA times were 162 (120-300) min and 35 (9-64) min, respectively. Three patients underwent synchronous cardiac surgical procedures. There were three (6.3%) perioperative deaths. American Society of Anesthesiologists grade and perioperative blood transfusion requirement were significant factors associated with perioperative death (P < 0.05). Despite extensive preoperative screening for metastases the median (range) DFS was only 10.2 (1.2-224.4) months. The median (range) OS was 23 (0-224.4) months. Cox regression analysis revealed that perinephric fat invasion conferred a significantly poorer DFS (P = 0.005). CONCLUSIONS: Radical surgery for patients with extensive IVC tumour thrombus has acceptable operative morbidity and mortality. It provides symptom palliation and the possibility of long-term survival. Improvements in preoperative detection of occult metastasis may improve case selection and newer adjuvant therapies may improve survival in this high-risk group.

16.
Oncogene ; 24(55): 8205-10, 2005 Dec 08.
Article in English | MEDLINE | ID: mdl-16116480

ABSTRACT

Deregulation of Wnt signalling has recently been implicated in human renal cancer. Here, we directly test this association by using a Cre-LoxP strategy to inactivate the Adenomatous Polyposis Coli (Apc) gene in the murine renal epithelium. Mice homozygous for a conditional Apc allele were intercrossed with mice transgenic for Cre recombinase under control of the Cyp1A promoter, which delivers constitutive recombination within a proportion of cells in the renal epithelium. Inactivation of Apc leads to the accumulation of nuclear beta-catenin and the rapid development of multiple dysplastic foci. Renal carcinoma was observed with an earliest onset of 4 months. This predisposition was accelerated by p53 deficiency, reducing the earliest onset to 2 months. Compared to other murine models of kidney neoplasia, this represents particularly rapid onset of disease, and so implicates an important role for Apc in suppressing renal carcinoma.


Subject(s)
Gene Deletion , Genes, APC , Kidney Neoplasms/genetics , Animals , Homozygote , Integrases/genetics , Integrases/metabolism , Mice , Mice, Knockout , Mice, Transgenic , Tumor Suppressor Protein p53/deficiency , Tumor Suppressor Protein p53/genetics , Urothelium/pathology , Urothelium/physiology
17.
Clin Cancer Res ; 11(7): 2510-7, 2005 Apr 01.
Article in English | MEDLINE | ID: mdl-15814627

ABSTRACT

PURPOSE: The origin licensing factors minichromosome maintenance 2 (Mcm2) and Geminin have recently been identified as critical regulators of growth and differentiation. Here we have investigated the regulation of these licensing factors together with Ki67 to further elucidate the cell cycle kinetics of renal cell carcinoma (RCC). Furthermore, we have examined the role of Ki67, Mcm2, and Geminin in disease-free survival after nephrectomy in patients with localized RCC. EXPERIMENTAL DESIGN: Tissue sections from 176 radical nephrectomy specimens were immunohistochemically stained with Mcm2, Geminin, and Ki67 antibodies. Labeling indices (LI) for these markers were compared with clinicopathologic parameters (median follow-up 44 months). RESULTS: In RCC, Mcm2 is expressed at much higher levels than Ki-67 and Geminin, respectively [medians 41.6%, 7.3%, and 3.5% (P < 0.001)] and was most closely linked to tumor grade (P < 0.001). For each marker, Kaplan-Meier survival curves provided strong evidence that increased expression is associated with reduced disease-free survival time (P < 0.001). Additionally, an Mcm2-Ki67 LI identified a unique licensed but nonproliferating population of tumor cells that increased significantly with tumor grade (P = 0.004) and was also of prognostic value (P = 0.01). On multivariate analysis, grade, vascular invasion, capsular invasion, Ki67 LI >12%, and age were found to be independent prognostic markers. CONCLUSIONS: Although Ki67 is identified as an independent prognostic marker, semiquantitative assessment is difficult due to the very low proliferative fraction identified by this marker. In contrast, Mcm2 identifies an increased growth fraction that is closely linked to grade, provides prognostic information, and is amenable to semiquantitative analysis in routine pathologic assessment.


Subject(s)
Biomarkers, Tumor/analysis , Carcinoma, Renal Cell/pathology , Cell Proliferation , Kidney Neoplasms/pathology , Carcinoma, Renal Cell/metabolism , Cell Cycle Proteins/analysis , Female , Geminin , Humans , Immunohistochemistry , Ki-67 Antigen/analysis , Kidney Neoplasms/metabolism , Male , Middle Aged , Minichromosome Maintenance Complex Component 2 , Multivariate Analysis , Nuclear Proteins/analysis , Prognosis , Regression Analysis , Survival Analysis
18.
Transplantation ; 75(3): 344-6, 2003 Feb 15.
Article in English | MEDLINE | ID: mdl-12589156

ABSTRACT

INTRODUCTION: The aim was to determine the impact of donor glomerulosclerosis on allograft outcome. METHODS: The percentage of glomerular sclerosis (%GS) was calculated in protocol biopsies taken at engraftment. Clinical variables were obtained from the Welsh Transplantation Research Group (WTRG) database. RESULTS: Of 210 allografts, 129 showed %GS=0, but 81 kidneys showed %GS between 1 and 60. Patients with %GS=0 had the highest glomerular filtration rate (GFR) at 1 year (62.0 mL/min) and the slowest deterioration of function (-3.8 mL/min per year). Patients with %GS greater than 20 had the lowest GFR at 1 year (36.0 mL/min) and the steepest rate of deterioration (-9.0 mL/min per year). The %GS of 10 alone can reduce GFR at 4 years by 8 mL/min, a similar reduction to a single rejection episode or an increase in donor age of 30 years. Actuarial 5-year graft survival for %GS=0 was 80%, and for %GS greater than 20 was 35% ( P=0.04). CONCLUSION: The findings indicate that a biopsy taken at procurement will provide information for the most appropriate allocation of a kidney.


Subject(s)
Glomerulosclerosis, Focal Segmental/pathology , Glomerulosclerosis, Focal Segmental/surgery , Graft Survival , Kidney Transplantation , Tissue and Organ Procurement/standards , Biopsy , Glomerulosclerosis, Focal Segmental/epidemiology , Humans , Middle Aged , Multivariate Analysis , Predictive Value of Tests , Proportional Hazards Models , Transplantation, Homologous
19.
J Clin Pathol ; 66(2): 120-3, 2013 Feb.
Article in English | MEDLINE | ID: mdl-23112115

ABSTRACT

AIM: To determine the degree of variation in the handling of prostate needle biopsies (PBNx) in laboratories across Europe. METHODS: A web based survey was emailed to members of the European Network of Uropathology and the British Association of Urological Pathologists. RESULTS: Responses were received from 241 laboratories in 15 countries. PNBx were generally taken by urologists (93.8%) or radiologists (23.7%) but in 8.7% were also taken by non-medical personnel such as radiographers, nurses or biomedical assistants. Of the responding laboratories, 40.8% received cores in separate containers, 42.3% processed one core/block, 54.2% examined three levels/block, 49.4% examined one H&E section/level and 56.1% retained spare sections for potential immunohistochemistry. Of the laboratories, 40.9% retained unstained spares for over a year while 36.2% discarded spares within 1 month of reporting. Only two (0.8%) respondents routinely performed immunohistochemistry on all PNBx. There were differences in laboratory practice between the UK and the rest of Europe (RE). Procurement of PNBx by non-medical personnel was more common in the UK. RE laboratories more commonly received each core in a separate container, processed one core/block, examined fewer levels/block and examined more H&E sections/level. RE laboratories also retained spares for potential immunohistochemistry less often and for shorter periods. Use of p63 as the sole basal cell marker was more common in RE. CONCLUSIONS: There are marked differences in procurement, handling and processing of PNBx in laboratories across Europe. This data can help the development of best practice guidelines.


Subject(s)
Biopsy, Needle/standards , Prostate/pathology , Prostatic Neoplasms/pathology , Benchmarking , Biomarkers, Tumor/analysis , Chi-Square Distribution , Europe , Health Care Surveys , Health Personnel/standards , Humans , Immunohistochemistry/standards , Internet , Male , Practice Guidelines as Topic , Predictive Value of Tests , Prostate/chemistry , Prostatic Neoplasms/chemistry , Staining and Labeling/standards , Surveys and Questionnaires , Time Factors , Transcription Factors/analysis , Tumor Suppressor Proteins/analysis
20.
Anal Quant Cytol Histol ; 31(2): 90-5, 2009 Apr.
Article in English | MEDLINE | ID: mdl-19402385

ABSTRACT

In pathology there is a need to rapidly disseminate professional information to the appropriate target groups. This is a surprisingly difficult task on an international level. Therefore, the European Network of Uropathology (ENUP) was recently organized by the Uropathology Working Group of the European Society of Pathology. The purposes were to establish a channel for distribution of information about uropathology, such as guidelines, consensus documents, meetings and courses; to organize research collaborations; and to set up mechanisms for survey studies. ENUP has recruited a total of 374 individual members from 338 pathology laboratories in 15 Western European countries. E-mail is used for all communication, and studies are carried out through interactive Web sites. Information e-mails are sent regularly, and 2 Web-based surveys on handling and reporting of urologic specimens have been conducted. Here we report on the methods used to organize this novel information network. We think that ENUP could serve as a model for other fields of pathology and other geographic regions.


Subject(s)
Information Dissemination , International Cooperation , Pathology, Surgical , Urology , Congresses as Topic , Consensus , Cooperative Behavior , Data Collection/methods , Electronic Mail , Europe , Humans , Personnel Selection , Practice Guidelines as Topic
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