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2.
Clin Oncol (R Coll Radiol) ; 31(2): 108-114, 2019 02.
Article in English | MEDLINE | ID: mdl-30471806

ABSTRACT

AIMS: Ductal adenocarcinoma is a rare variant of prostate cancer, and as such clinical outcomes and best management are not well defined. This series demonstrates the atypical presentation and unusual clinical behaviour of ductal adenocarcinoma and proposes management guidelines to assist clinicians. MATERIALS AND METHODS: A retrospective review of pure (nine patients) and mixed (18 patients) ductal adenocarcinoma of the prostate referred to the Departments of Radiation Oncology of the Sydney Cancer Centre, Royal Prince Alfred Hospital and Northern Sydney Cancer Centre, Royal North Shore Hospital, between 2000 and 2015. RESULTS: Twenty-seven patients were treated with definitive radiotherapy, nine patients (33%) with pure ductal and 18 (67%) with mixed ductal-acinar adenocarcinoma. The median follow-up was 38 months. Four patients (15%) failed locally, all of whom received less than 80 Gy, or no brachytherapy boost. Five patients (19%) failed distantly, four with biopsy-proven lung metastases. All distant failures occurred with a prostate-specific antigen (PSA) < 3 ng/ml. CONCLUSION: This series shows the atypical clinical presentation of this entity, as well as its propensity to metastasise to unusual sites. Relapse may occur at low absolute PSA values and is often asymptomatic. Ductal cancer should not simply be regarded as a high Gleason grade cancer. We propose management guidelines, including regular computed tomography examinations (rather than relying solely on PSA levels) as part of the follow-up for patients with any component of ductal adenocarcinoma.


Subject(s)
Carcinoma, Ductal , Prostatic Neoplasms , Aged , Aged, 80 and over , Humans , Male , Middle Aged , Neoplasm Recurrence, Local , Retrospective Studies
3.
Colorectal Dis ; 20(11): 1004-1013, 2018 11.
Article in English | MEDLINE | ID: mdl-29920909

ABSTRACT

AIM: Pelvic exenteration surgery remains the only curative option for recurrent rectal cancer. Microscopically involved surgical margins (R1) are associated with a higher risk of local recurrence and decreased survival. Our study aimed to develop a post hoc multidisciplinary case conference review and investigate its potential for identifying areas for improvement. METHOD: Patients who underwent pelvic exenteration surgery for recurrent rectal cancer with R1 resections at a tertiary referral centre between April 2014 and January 2016 were retrospectively reviewed from a prospectively maintained database. Patients with non-rectal cancers or who underwent palliative surgery were excluded. Cases, imaging and histopathology were evaluated by a dedicated panel including colorectal surgeons, an abdominal radiologist and a gastrointestinal pathologist. RESULTS: R1 resections were reported in 32 of 110 pelvic exenterations. Patients with other tumours were excluded and one patient had a palliative resection. Nine male patients with 11 exenterations were included with a median age of 56 years. All patients had positive soft tissue margins, and one patient also had an involved bony margin. Failures were due to (interdisciplinary) communication problems, specific management of tumour biology (multifocality, spiculated tumours), which can lead to radiological undercalling, and inadequate surgical technical planning. In hindsight, surgery would have been withheld from one patient. CONCLUSION: A retrospective multidisciplinary case evaluation of pelvic exenteration patients with involved surgical margins led to a list of recommendations which included the need to plan for wider surgical soft tissue resections and improvement in interdisciplinary communication. Lessons learned may increase clear margin rates in future resections.


Subject(s)
Neoplasm Recurrence, Local/prevention & control , Patient Care Team/standards , Pelvic Exenteration/standards , Postoperative Complications/prevention & control , Rectal Neoplasms/surgery , Adult , Aged , Female , Humans , Interdisciplinary Communication , Male , Margins of Excision , Middle Aged , Neoplasm Recurrence, Local/etiology , Pelvic Exenteration/adverse effects , Postoperative Complications/etiology , Qualitative Research , Quality Assurance, Health Care
4.
Ann Oncol ; 28(8): 1903-1909, 2017 Aug 01.
Article in English | MEDLINE | ID: mdl-28486686

ABSTRACT

BACKGROUND: Prostate cancers (PCs) with similar characteristics at the time of diagnosis can have very different disease outcomes. Conventional biomarkers of PC still lack precision in identifying individuals at high risk of PC recurrence. While many candidate biomarkers are proposed in the literature, few are in clinical practice as they lack rigorous validation. This study prospectively enrolled an independent phase III cohort to evaluate the clinical utility of zinc-alpha 2-glycoprotein (AZGP1) as a prognostic biomarker in localized PC. PATIENTS AND METHODS: In our multicentre, prospective phase III study, AZGP1 status in 347 radical prostatectomy specimens was assayed by immunohistochemistry in a NATA-accredited laboratory. The AZGP1 score was assessed in a multivariable model incorporating established prognostic factors. We also report extended outcomes from our previous phase II study. The primary endpoint was biochemical relapse-free survival (BRFS). Secondary endpoints were metastasis-free survival (MFS) and PC-specific survival (PCSS). RESULTS: In the phase II cohort, with a median follow-up of 15.8 years, low/absent AZGP1 expression was an independent predictor of poor BRFS (HR, 1.4; 95% CI, 1.1-1.9; P = 0.03), MFS (HR, 2.8; 95% CI, 1.2-6.6; P = 0.02) and PCSS (HR, 3.8; 95% CI, 1.5-9.5; P = 0.005). These results were validated in our prospective phase III cohort. Low/absent AZGP1 expression independently predicted for BRFS (HR, 1.9; 95% CI, 1.1-3.3; P = 0.02), with shorter MFS (HR, 2.0; 95% CI, 1.1-3.4; P = 0.02). AZGP1 improved the discriminatory value when incorporated into existing prognostic risk models. CONCLUSION: Our study provides prospective phase III validation that absent/low AZGP1 expression provides independent prognostic value in PC. This study provides robust evidence for the incorporation of this biomarker into clinical practice.


Subject(s)
Biomarkers, Tumor/metabolism , Carrier Proteins/metabolism , Glycoproteins/metabolism , Prostatic Neoplasms/metabolism , Adipokines , Adult , Aged , Biopsy , Cohort Studies , Humans , Male , Middle Aged , Prospective Studies , Prostatic Neoplasms/pathology
5.
Br J Surg ; 102(12): 1459-72, 2015 Nov.
Article in English | MEDLINE | ID: mdl-26350029

ABSTRACT

BACKGROUND: R0 resection rates (complete tumour removal with negative resection margins) in pancreatic cancer are 70-80 per cent when a 0-mm margin is used, declining to 15-24 per cent with a 1-mm margin. This review evaluated the R0 resection rates according to different margin definitions and techniques. METHODS: Three databases (MEDLINE from 1946, PubMed from 1946 and Embase from 1949) were searched to mid-October 2014. The search terms included 'pancreatectomy OR pancreaticoduodenectomy' and 'margin'. A meta-analysis was performed with studies in three groups: group 1, axial slicing technique (minimum 1-mm margin); group 2, other slicing techniques (minimum 1-mm margin); and group 3, studies with minimum 0-mm margin. RESULTS: The R0 rates were 29 (95 per cent c.i. 26 to 32) per cent in group 1 (8 studies; 882 patients) and 49 (47 to 52) per cent in group 2 (6 studies; 1568 patients). The combined R0 rate (groups 1 and 2) was 41 (40 to 43) per cent. The R0 rate in group 3 (7 studies; 1926 patients) with a 0-mm margin was 72 (70 to 74) per cent The survival hazard ratios (R1 resection/R0 resection) revealed a reduction in the risk of death of at least 22 per cent in group 1, 12 per cent in group 2 and 23 per cent in group 3 with an R0 compared with an R1 resection. Local recurrence occurred more frequently with an R1 resection in most studies. CONCLUSION: Margin clearance definitions affect R0 resection rates in pancreatic cancer surgery. This review collates individual studies providing an estimate of achievable R0 rates, creating a benchmark for future trials.


Subject(s)
Neoplasm Recurrence, Local/epidemiology , Pancreatectomy/methods , Pancreatic Neoplasms/surgery , Global Health , Humans , Incidence , Prognosis
6.
Ann Oncol ; 25(12): 2392-2397, 2014 Dec.
Article in English | MEDLINE | ID: mdl-25231954

ABSTRACT

BACKGROUND: The promyelocytic leukemia (PML) tumor suppressor plays an important role in the response to a variety of cellular stressors and its expression is downregulated or lost in a range of human tumors. We have previously shown that the E3 ligase E6-associated protein (E6AP) is an important regulator of PML protein stability but the relationship and clinical impact of PML and E6AP expression in prostatic carcinoma is unknown. METHODS: E6AP and PML expression was assessed in tissue microarrays from a phase I discovery cohort of 170 patients treated by radical prostatectomy for localized prostate cancer (PC). Correlation analysis was carried out between PML and E6AP expression and clinicopathological variates including PSA as a surrogate of disease recurrence. The results were confirmed in a phase II validation cohort of 318 patients with associated clinical recurrence and survival data. RESULTS: Survival analysis of the phase I cohort revealed that patients whose tumors showed reduced PML and high E6AP expression had reduced time to PSA relapse (P = 0.012). This was confirmed in the phase II validation cohort where the expression profile of high E6AP/low PML was significantly associated with reduced time to PSA relapse (P < 0.001), clinical relapse (P = 0.016) and PC-specific death (P = 0.014). In multivariate analysis, this expression profile was an independent prognostic indicator of PSA relapse and clinical relapse independent of clinicopathologic factors predicting recurrence. CONCLUSION: This study identifies E6AP and PML as potential prognostic markers in localized prostate carcinoma and supports a role for E6AP in driving the downregulation or loss of PML expression in prostate carcinomas.


Subject(s)
Nuclear Proteins/metabolism , Prostatic Neoplasms/metabolism , Transcription Factors/metabolism , Tumor Suppressor Proteins/metabolism , Ubiquitin-Protein Ligases/metabolism , Cohort Studies , Disease Progression , Humans , Male , Promyelocytic Leukemia Protein , Prostatic Neoplasms/mortality , Prostatic Neoplasms/pathology
7.
Br J Cancer ; 110(2): 313-9, 2014 Jan 21.
Article in English | MEDLINE | ID: mdl-24263063

ABSTRACT

BACKGROUND: Adjuvant chemotherapy improves survival for patients with resected pancreatic cancer. Elderly patients are under-represented in Phase III clinical trials, and as a consequence the efficacy of adjuvant therapy in older patients with pancreatic cancer is not clear. We aimed to assess the use and efficacy of adjuvant chemotherapy in older patients with pancreatic cancer. METHODS: We assessed a community cohort of 439 patients with a diagnosis of pancreatic ductal adenocarcinoma who underwent operative resection in centres associated with the Australian Pancreatic Cancer Genome Initiative. RESULTS: The median age of the cohort was 67 years. Overall only 47% of all patients received adjuvant therapy. Patients who received adjuvant chemotherapy were predominantly younger, had later stage disease, more lymph node involvement and more evidence of perineural invasion than the group that did not receive adjuvant treatment. Overall, adjuvant chemotherapy was associated with prolonged survival (median 22.1 vs 15.8 months; P<0.0001). Older patients (aged ≥70) were less likely to receive adjuvant chemotherapy (51.5% vs 29.8%; P<0.0001). Older patients had a particularly poor outcome when adjuvant therapy was not delivered (median survival=13.1 months; HR 1.89, 95% CI: 1.27-2.78, P=0.002). CONCLUSION: Patients aged ≥70 are less likely to receive adjuvant therapy although it is associated with improved outcome. Increased use of adjuvant therapy in older individuals is encouraged as they constitute a large proportion of patients with pancreatic cancer.


Subject(s)
Antineoplastic Agents/therapeutic use , Carcinoma, Pancreatic Ductal/drug therapy , Pancreatic Neoplasms/drug therapy , Age Factors , Aged , Carcinoma, Pancreatic Ductal/pathology , Carcinoma, Pancreatic Ductal/surgery , Chemotherapy, Adjuvant , Cohort Studies , Female , Humans , Lymph Nodes/drug effects , Lymph Nodes/pathology , Lymphatic Metastasis , Male , Pancreatic Neoplasms/pathology , Pancreatic Neoplasms/surgery , Prognosis
8.
J Clin Pathol ; 67(4): 333-40, 2014 Apr.
Article in English | MEDLINE | ID: mdl-24265323

ABSTRACT

AIMS: To determine the prognostic significance of pAkt expression in order to identify high-risk stage IB patients with non-small cell lung cancer (NSCLC) in an exploratory study. METHODS: We identified 471 consecutive patients with stage IB primary NSCLC according to the American Joint Commission on Cancer 6th edition tumour-node-metastasis (TNM) staging system, who underwent surgical resection between 1990 and 2008. Patients who received neoadjuvant or adjuvant treatments were excluded. Pathology reports were reviewed, and pathological characteristics were extracted. Expression of phosphorylated Akt (pAkt) in both cytoplasmic and nuclear locations was assessed by immunohistochemistry, and clinicopathological factors were analysed against 10-year overall survival using Kaplan-Meier and Cox proportional hazards model. RESULTS: 455 (96.6%) cancers were adequate for pAkt immunohistochemical analysis. The prevalence of pAkt expression in the cytoplasm and nucleus of the cancers was 60.7% and 43.7%, respectively. Patients whose cancers expressed higher levels of cytoplasmic pAkt had a trend towards longer overall survival than those with lower levels (p=0.06). Conversely, patients whose cancers expressed higher levels of nuclear pAkt had a poorer prognosis than those with lower levels of expression (p=0.02). Combined low cytoplasmic/high nuclear expression of pAkt was an independent predictor of overall survival (HR=2.86 (95% CI 1.35 to 6.04); p=0.006) when modelled with age (HR=1.05 (95% CI 1.03 to 1.07); p<0.001), extent of operation (HR=2.11 (95% CI 1.48 to 3.01); p<0.001), visceral pleural invasion (HR=1.63 (95% CI 1.24 to 2.15); p<0.001), gender, tumour size, histopathological type and grade (p>0.05). CONCLUSIONS: Level of expression of pAkt in the cytoplasm and nucleus is an independent prognostic factor that may help to select patients with high-risk disease.


Subject(s)
Biomarkers, Tumor/metabolism , Carcinoma, Non-Small-Cell Lung/pathology , Lung Neoplasms/pathology , Proto-Oncogene Proteins c-akt/metabolism , Adult , Aged , Aged, 80 and over , Carcinoma, Non-Small-Cell Lung/metabolism , Carcinoma, Non-Small-Cell Lung/mortality , Carcinoma, Non-Small-Cell Lung/surgery , Cell Nucleus/metabolism , Cytoplasm/metabolism , Female , Humans , Kaplan-Meier Estimate , Lung Neoplasms/metabolism , Lung Neoplasms/mortality , Lung Neoplasms/surgery , Male , Middle Aged , Neoplasm Staging , New South Wales/epidemiology , Phosphorylation , Prognosis , Proportional Hazards Models , Retrospective Studies , Tissue Array Analysis
9.
J Clin Pathol ; 66(9): 744-8, 2013 Sep.
Article in English | MEDLINE | ID: mdl-23757037

ABSTRACT

AIM: We assessed the diagnostic accuracy of epidermal growth factor receptor (EGFR) mutant-specific antibodies for detecting two common activating EGFR mutations. METHODS: Immunohistochemical expression of mutation-specific antibodies against EGFR exon 19 deletion E746-A750 ((c.2235_2249del15 or c.2236_2250del15, p. Glu746_Ala750del) and exon 21 L858R point mutation (c.2573T>G, p.Leu858Arg) were assessed in a cohort of 204 resected early stage node negative lung adenocarcinomas, and protein expression was compared with DNA analysis results from mass spectrometry analysis. RESULTS: Of seven cases with L858R point mutation, six were positive by immunohistochemistry (IHC). There were three false positive cases using L858R IHC (sensitivity 85.7%, specificity 98.5%, positive predictive value 66.7%, negative predictive value 99.5%). All seven E746-A750 exon 19 deletions identified by mutation analysis were positive by IHC. Four additional cases were positive for exon 19 IHC but negative by mutation analysis. The sensitivity of exon 19 IHC for E746-A750 was 100%, specificity 98.0%, positive predictive value 63.6% and negative predictive value 100%. CONCLUSIONS: Mutant-specific EGFR IHC has good specificity and sensitivity for identifying targeted activating EGFR mutations. Although inferior to molecular genetic analysis of the EGFR gene, IHC is highly specific and sensitive for the targeted EGFR mutations. The antibodies are likely to be of clinical value in cases where limited tumour material is available, or in situations where molecular genetic analysis is not readily available.


Subject(s)
Adenocarcinoma/metabolism , ErbB Receptors/metabolism , Lung Neoplasms/metabolism , Lung/metabolism , Adenocarcinoma/genetics , Adenocarcinoma/pathology , Adult , Aged , Aged, 80 and over , DNA Mutational Analysis , ErbB Receptors/genetics , Female , Humans , Immunohistochemistry , Lung/pathology , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Male , Mass Spectrometry , Middle Aged , Mutation , Sensitivity and Specificity , Tissue Array Analysis
10.
Int Urol Nephrol ; 45(3): 735-42, 2013 Jun.
Article in English | MEDLINE | ID: mdl-23666549

ABSTRACT

AIMS: Prostate cancer is very common and is the second most common cause of cancer death in males in Australia; however, brain metastases are exceedingly rare. MATERIALS AND METHODS: We review four cases of biopsy-proven brain metastases from prostate cancer and review the relevant literature. RESULTS: Three of four patients had acinar adenocarcinoma of prostate with one patient having ductal adenocarcinoma variant on histopathology. Three patients had the brain as the only site of metastatic disease. All patients underwent surgery, and three of four patients underwent adjuvant palliative radiotherapy to the brain. CONCLUSION: Brain metastases from prostate cancer are rare, but brain metastases without other sites of metastatic disease are exceedingly rare and may be more common with ductal adenocarcinoma variant.


Subject(s)
Adenocarcinoma/secondary , Biopsy , Brain Neoplasms/secondary , Prostatic Neoplasms/pathology , Adenocarcinoma/diagnosis , Aged , Aged, 80 and over , Brain Neoplasms/diagnosis , Diagnosis, Differential , Humans , Magnetic Resonance Imaging , Male , Neoplasm Staging , Tomography, X-Ray Computed
11.
Oncogene ; 32(23): 2891-9, 2013 Jun 06.
Article in English | MEDLINE | ID: mdl-22869146

ABSTRACT

Deregulation of microRNA (miRNA) expression can have a critical role in carcinogenesis. Here we show in prostate cancer that miRNA-205 (miR-205) transcription is commonly repressed and the MIR-205 locus is hypermethylated. LOC642587, the MIR-205 host gene of unknown function, is also concordantly inactivated. We show that miR-205 targets mediator 1 (MED1, also called TRAP220 and PPARBP) for transcriptional silencing in normal prostate cells, leading to reduction in MED1 mRNA levels, and in total and active phospho-MED1 protein. Overexpression of miR-205 in prostate cancer cells negatively affects cell viability, consistent with a tumor suppressor function. We found that hypermethylation of the MIR-205 locus was strongly related with a decrease in miR-205 expression and an increase in MED1 expression in primary tumor samples (n=14), when compared with matched normal prostate (n=7). An expanded patient cohort (tumor n=149, matched normal n=30) also showed significant MIR-205 DNA methylation in tumors compared with normal, and MIR-205 hypermethylation is significantly associated with biochemical recurrence (hazard ratio=2.005, 95% confidence interval (1.109, 3.625), P=0.02), in patients with low preoperative prostate specific antigen. In summary, these results suggest that miR-205 is an epigenetically regulated tumor suppressor that targets MED1 and may provide a potential biomarker in prostate cancer management.


Subject(s)
Adenocarcinoma/metabolism , Gene Silencing , Mediator Complex Subunit 1/metabolism , MicroRNAs/genetics , Prostatic Neoplasms/metabolism , Adenocarcinoma/genetics , Adenocarcinoma/mortality , Aged , Base Sequence , Cell Line, Tumor , Cell Survival , DNA Methylation , Epigenesis, Genetic , Gene Expression Regulation, Neoplastic , Humans , Kaplan-Meier Estimate , Male , MicroRNAs/metabolism , Middle Aged , Molecular Sequence Data , Phosphorylation , Prognosis , Promoter Regions, Genetic , Proportional Hazards Models , Prostatic Neoplasms/genetics , Prostatic Neoplasms/mortality , Protein Processing, Post-Translational
12.
Ann Oncol ; 23(7): 1713-22, 2012 Jul.
Article in English | MEDLINE | ID: mdl-22241899

ABSTRACT

BACKGROUND: Current staging methods for pancreatic cancer (PC) are inadequate, and biomarkers to aid clinical decision making are lacking. Despite the availability of the serum marker carbohydrate antigen 19.9 (CA19.9) for over two decades, its precise role in the management of PC is yet to be defined, and as a consequence, it is not widely used. METHODS: We assessed the relationship between perioperative serum CA19.9 levels, survival and adjuvant chemotherapeutic responsiveness in a cohort of 260 patients who underwent operative resection for PC. RESULTS: By specifically assessing the subgroup of patients with detectable CA19.9, we identified potential utility at key clinical decision points. Low postoperative CA19.9 at 3 months (median survival 25.6 vs 14.8 months, P=0.0052) and before adjuvant chemotherapy were independent prognostic factors. Patients with postoperative CA 19.9 levels>90 U/ml did not benefit from adjuvant chemotherapy (P=0.7194) compared with those with a CA19.9 of ≤90 U/ml (median 26.0 vs 16.7 months, P=0.0108). Normalization of CA19.9 within 6 months of resection was also an independent favorable prognostic factor (median 29.9 vs 14.8 months, P=0.0004) and normal perioperative CA19.9 levels identified a good prognostic group, which was associated with a 5-year survival of 42%. CONCLUSIONS: Perioperative serum CA19.9 measurements are informative in patients with detectable CA19.9 (defined by serum levels of >5 U/ml) and have potential clinical utility in predicting outcome and response to adjuvant chemotherapy. Future clinical trials should prioritize incorporation of CA19.9 measurement at key decision points to prospectively validate these findings and facilitate implementation.


Subject(s)
Biomarkers, Tumor/blood , CA-19-9 Antigen/blood , Carcinoma, Pancreatic Ductal/blood , Neoplasm Recurrence, Local , Pancreatic Neoplasms/blood , Adult , Aged , Aged, 80 and over , Carcinoma, Pancreatic Ductal/diagnosis , Carcinoma, Pancreatic Ductal/mortality , Carcinoma, Pancreatic Ductal/therapy , Chemotherapy, Adjuvant , Female , Humans , Kaplan-Meier Estimate , Male , Middle Aged , Pancreatectomy , Pancreatic Neoplasms/diagnosis , Pancreatic Neoplasms/mortality , Pancreatic Neoplasms/therapy , Perioperative Period , Prognosis , Proportional Hazards Models , Retrospective Studies
13.
Oncogene ; 28(43): 3847-56, 2009 Oct 29.
Article in English | MEDLINE | ID: mdl-19684615

ABSTRACT

GATA-2, a member of the GATA family of transcription factors, is involved in androgen receptor (AR) signaling, however, little is known regarding its role in prostate cancer. Here, we report that GATA-2 is expressed in a substantial proportion of prostate cancers and that high expression of GATA-2 is associated with biochemical recurrence and distant metastatic progression in a validation set of 203 cancers. In vitro data show that GATA-2 is directly recruited to the promoter region of the AR upon androgen stimulation of LNCaP prostate cancer cells with 5alpha-dihydroxytestosterone (DHT) for 24 h. Ectopic GATA-2 expression causes the induction of AR transcript levels under androgen-depleted conditions (P<0.05). The expression of the AR target gene, AZGP1, is induced upon androgen stimulation and this effect is repressed by GATA-2. In contrast, GATA-2 significantly increases transcript levels of KLK2, which increases further in a time-dependent manner on DHT treatment and in the presence of GATA-2. These results indicate that upregulation of GATA-2 may contribute to the progression to aggressive prostate cancer through modulation of expression of AR and key androgen-regulated genes, one of which, AZGP1, is associated with the progression to metastatic disease.


Subject(s)
GATA2 Transcription Factor/physiology , Gene Expression Regulation, Neoplastic , Prostatic Neoplasms/pathology , Adipokines , Carrier Proteins/genetics , GATA2 Transcription Factor/analysis , Glycoproteins/genetics , Humans , Male , Phenotype , Promoter Regions, Genetic , Prostatic Neoplasms/genetics , Receptors, Androgen/analysis , Receptors, Androgen/genetics , Tissue Kallikreins/genetics
14.
Br J Cancer ; 98(3): 537-41, 2008 Feb 12.
Article in English | MEDLINE | ID: mdl-18231110

ABSTRACT

Identification of a biomarker of prognosis and response to therapy that can be assessed preoperatively would significantly improve overall outcomes for patients with pancreatic cancer. In this study, patients whose tumours exhibited high LMO4 expression had a significant survival advantage following operative resection, whereas the survival of those patients whose tumours had low or no LMO4 expression was not significantly different when resection was compared with operative biopsy alone.


Subject(s)
Adenocarcinoma/metabolism , Carcinoma, Pancreatic Ductal/metabolism , Homeodomain Proteins/metabolism , Pancreatic Neoplasms/metabolism , Transcription Factors/metabolism , Adaptor Proteins, Signal Transducing , Adenocarcinoma/surgery , Adult , Aged , Aged, 80 and over , Biomarkers, Tumor/analysis , Carcinoma, Pancreatic Ductal/surgery , Cohort Studies , Female , Humans , LIM Domain Proteins , Male , Middle Aged , Pancreatectomy , Pancreatic Neoplasms/surgery , Prognosis , Survival Analysis , Treatment Outcome
15.
Diabetologia ; 50(4): 752-63, 2007 Apr.
Article in English | MEDLINE | ID: mdl-17268797

ABSTRACT

AIMS/HYPOTHESIS: Increased lipid supply causes beta cell death, which may contribute to reduced beta cell mass in type 2 diabetes. We investigated whether endoplasmic reticulum (ER) stress is necessary for lipid-induced apoptosis in beta cells and also whether ER stress is present in islets of an animal model of diabetes and of humans with type 2 diabetes. METHODS: Expression of genes involved in ER stress was evaluated in insulin-secreting MIN6 cells exposed to elevated lipids, in islets isolated from db/db mice and in pancreas sections of humans with type 2 diabetes. Overproduction of the ER chaperone heat shock 70 kDa protein 5 (HSPA5, previously known as immunoglobulin heavy chain binding protein [BIP]) was performed to assess whether attenuation of ER stress affected lipid-induced apoptosis. RESULTS: We demonstrated that the pro-apoptotic fatty acid palmitate triggers a comprehensive ER stress response in MIN6 cells, which was virtually absent using non-apoptotic fatty acid oleate. Time-dependent increases in mRNA levels for activating transcription factor 4 (Atf4), DNA-damage inducible transcript 3 (Ddit3, previously known as C/EBP homologous protein [Chop]) and DnaJ homologue (HSP40) C3 (Dnajc3, previously known as p58) correlated with increased apoptosis in palmitate- but not in oleate-treated MIN6 cells. Attenuation of ER stress by overproduction of HSPA5 in MIN6 cells significantly protected against lipid-induced apoptosis. In islets of db/db mice, a variety of marker genes of ER stress were also upregulated. Increased processing (activation) of X-box binding protein 1 (Xbp1) mRNA was also observed, confirming the existence of ER stress. Finally, we observed increased islet protein production of HSPA5, DDIT3, DNAJC3 and BCL2-associated X protein in human pancreas sections of type 2 diabetes subjects. CONCLUSIONS/INTERPRETATION: Our results provide evidence that ER stress occurs in type 2 diabetes and is required for aspects of the underlying beta cell failure.


Subject(s)
Apoptosis , Diabetes Mellitus, Type 2/metabolism , Diabetes Mellitus, Type 2/pathology , Endoplasmic Reticulum/metabolism , Gene Expression Regulation , Insulin-Secreting Cells/metabolism , Insulin-Secreting Cells/pathology , Animals , Blotting, Western , Cell Line , Endoplasmic Reticulum Chaperone BiP , Heat-Shock Proteins/genetics , Heat-Shock Proteins/physiology , Humans , Lipids/chemistry , Mice , Mice, Inbred C57BL , Molecular Chaperones/genetics , Molecular Chaperones/physiology , Oxidative Stress , RNA, Messenger/metabolism
16.
Oncogene ; 26(4): 543-53, 2007 Jan 25.
Article in English | MEDLINE | ID: mdl-16862169

ABSTRACT

Top quartile serum prolactin levels confer a twofold increase in the relative risk of developing breast cancer. Prolactin exerts this effect at an ill defined point in the carcinogenic process, via mechanisms involving direct action via prolactin receptors within mammary epithelium and/or indirect action through regulation of other hormones such as estrogen and progesterone. We have addressed these questions by examining mammary carcinogenesis in transplants of mouse mammary epithelium expressing the SV40T oncogene, with or without the prolactin receptor, using host animals with a normal endocrine system. In prolactin receptor knockout transplants the area of neoplasia was significantly smaller (7 versus 17%; P < 0.001 at 22 weeks and 7 versus 14%; P = 0.009 at 32 weeks). Low-grade neoplastic lesions displayed reduced BrdU incorporation rate (11.3 versus 17% P = 0.003) but no change in apoptosis rate. Tumor latency increased (289 days versus 236 days, P < 0.001). Tumor frequency, growth rate, morphology, cell proliferation and apoptosis were not altered. Thus, prolactin acts directly on the mammary epithelial cells to increase cell proliferation in preinvasive lesions, resulting in more neoplasia and acceleration of the transition to invasive carcinoma. Targeting of mammary prolactin signaling thus provides a strategy to prevent the early progression of neoplasia to invasive carcinoma.


Subject(s)
Cell Proliferation , Mammary Glands, Animal/metabolism , Mammary Neoplasms, Experimental/genetics , Receptors, Prolactin/genetics , Animals , Antigens, Polyomavirus Transforming/genetics , Apoptosis , Body Weight , Caspase 3/physiology , Disease Progression , Female , Male , Mammary Neoplasms, Experimental/pathology , Mice , Mice, Inbred C57BL , Mice, Transgenic , Neoplasm Invasiveness , Neoplasm Transplantation
17.
Gut ; 50(6): 861-8, 2002 Jun.
Article in English | MEDLINE | ID: mdl-12010891

ABSTRACT

BACKGROUND AND AIMS: Intraductal papillary mucinous tumours (IPMT) of the pancreas constitute a unique pathological entity with an overall incidence of associated invasive malignancy of 20%. The malignant potential of an individual IPMT cannot be accurately predicted. Preoperative estimation of the risk of associated invasive malignancy with IPMT would be of significant clinical benefit. As aberrations in cell cycle regulatory genes are associated with the progression of precursor pancreatic ductal lesions to invasive adenocarcinoma, we examined expression of key cell cycle regulatory genes in the cyclin D1/retinoblastoma pathway and the transforming growth factor beta/Smad4 signalling pathway in a cohort of patients with surgically resected IPMT. METHODS: Sections of formalin fixed paraffin embedded pancreatic tissue from a cohort of 18 patients with IPMT were examined using immunohistochemistry for protein expression of cell cycle regulatory genes p16(INK4A), p21(CIP1), p27(KIP1), cyclin D1, pRb, and p53, as well as the cell signalling molecule Smad4. A comparison of expression levels was made between adenoma/borderline IPMT (10 patients) and intraductal papillary mucinous carcinoma (IPMC) (eight patients, four of whom harboured invasive carcinoma). Statistical analysis was performed using the chi(2) and Fisher's exact tests. RESULTS: Aberrant expression of the proteins examined increased in frequency from adenoma/borderline IPMT to IPMC. Specifically, there was a significantly greater incidence of loss of p16(INK4A) expression in IPMC: 8/8 lesions (100%) compared with 1/10 (10%) adenoma/borderline IPMT (p<0.001). Similarly, loss of Smad4 expression was associated with IPMC: 3/8 (38%) versus adenoma/borderline IPMT 0/10 (p<0.03). Loss of Smad4 expression within the IPMT was the best marker for the presence of invasive carcinoma (p<0.001). CONCLUSIONS: These data indicate that loss of p16(INK4A) and Smad4 expression occur more frequently in IPMC alone, or with associated invasive carcinoma, compared with adenoma/borderline IPMT. Aberrant protein expression of these cell cycle regulatory genes in IPMT and pancreatic intraepithelial neoplasia in the current model of pancreatic cancer progression suggest similarities in their development and may also represent the subsequent risk of invasive carcinoma.


Subject(s)
Adenocarcinoma, Mucinous/metabolism , Carcinoma in Situ/metabolism , Carcinoma, Pancreatic Ductal/metabolism , Cyclin-Dependent Kinase Inhibitor p16/metabolism , DNA-Binding Proteins/metabolism , Pancreatic Neoplasms/metabolism , Trans-Activators/metabolism , Aged , Aged, 80 and over , Cell Cycle Proteins/metabolism , Cyclin D1/metabolism , Cyclin-Dependent Kinase Inhibitor p21 , Cyclin-Dependent Kinase Inhibitor p27 , Cyclins/metabolism , Female , Humans , Immunohistochemistry , Male , Middle Aged , Retinoblastoma Protein/metabolism , Smad4 Protein , Tumor Cells, Cultured , Tumor Suppressor Protein p53/metabolism , Tumor Suppressor Proteins/metabolism
18.
Cancer Res ; 61(24): 8830-7, 2001 Dec 15.
Article in English | MEDLINE | ID: mdl-11751405

ABSTRACT

Pancreatic cancer (PC) is thought to develop through a series of duct lesions termed pancreatic intraepithelial neoplasia (PanIN). Characterization of the molecular pathology of these lesions may lead to additional understanding of pancreatic ductal carcinogenesis. We examined the protein expression of four functionally related genes, p21(WAF1/CIP1) (CDKN1A), p53, cyclin D1 (CCND1), and DPC4/Smad4 (MADH4), aberrations of which are associated with PC, within 451 PanIN lesions present in the pancreata of 60 patients. p21(WAF1/CIP1) overexpression was present in the normal ducts of 9% of patients and increased progressively to 16% of patients with PanIN-1A lesions, to 32% of patients with PanIN-1B lesions, 56% of patients with PanIN-2 lesions, 80% of patients with PanIN-3 lesions, and 85% of patients with invasive carcinomas (P < 0.01). p53 and cyclin D1 overexpression occurred predominantly in PanIN-3 lesions (P < 0.01), and loss of DPC4/Smad4 expression occurred predominantly in PanIN-3 lesions and invasive carcinoma (P < 0.01). In addition, p21(WAF1/CIP1) overexpression occurred independently of p53 and DPC4/Smad4 expression within invasive carcinoma and PanIN-3 lesions. Cyclin D1 overexpression or loss of DPC4/Smad4 expression was apparent in 85% of invasive carcinomas but in only 14% of PanIN-2 lesions. These data demonstrate that overexpression of p21(WAF1/CIP1) occurs early in the development of PanIN, before aberrations in p53, cyclin D1, and DPC4/Smad4 expression. p21(WAF1/CIP1) overexpression, independent of p53 and/or DPC4/Smad4 expression, may reflect increased Ras activity, either directly through activating K-ras mutations or as a consequence of HER-2/neu (ERBB2) overexpression, both of which are common in PC and in early events in the development of PanIN. These data support further the current progression model for PC and demonstrate that aberrant expression of key cell cycle regulatory genes may be important in the early development and progression of PanIN.


Subject(s)
Carcinoma, Pancreatic Ductal/metabolism , Cyclins/biosynthesis , Pancreatic Neoplasms/metabolism , Precancerous Conditions/metabolism , Carcinoma, Pancreatic Ductal/genetics , Carcinoma, Pancreatic Ductal/pathology , Cyclin D1/biosynthesis , Cyclin D1/genetics , Cyclin-Dependent Kinase Inhibitor p21 , Cyclins/genetics , DNA-Binding Proteins/biosynthesis , DNA-Binding Proteins/genetics , Disease Progression , Gene Expression Regulation, Neoplastic , Humans , Pancreatic Neoplasms/genetics , Pancreatic Neoplasms/pathology , Precancerous Conditions/genetics , Precancerous Conditions/pathology , Smad4 Protein , Trans-Activators/biosynthesis , Trans-Activators/genetics , Tumor Suppressor Protein p53/biosynthesis , Tumor Suppressor Protein p53/genetics
19.
Pathology ; 30(4): 419-21, 1998 Nov.
Article in English | MEDLINE | ID: mdl-9839320

ABSTRACT

We describe a case of ductal carcinoma in situ (DCIS) occurring in a fibroadenoma diagnosed by fine needle aspiration (FNA) cytology. The cytological features comprised a small population of pleomorphic cells admixed with a dominant population of bland epithelial cells showing features consistent with those of a fibroadenoma. Excision biopsy confirmed the presence of DCIS within an otherwise typical fibroadenoma. Recent reviews have emphasised the potential for fibroadenoma to cytologically mimic carcinoma, leading to false positive findings, however the converse is also possible. We conclude that a false negative cytological diagnosis may be avoided by recommending histological confirmation by excision biopsy when significant atypia is present, even if the overall pattern is that of a fibroadenoma.


Subject(s)
Breast Neoplasms/pathology , Carcinoma in Situ/pathology , Carcinoma, Ductal, Breast/pathology , Fibroadenoma/pathology , Neoplasms, Multiple Primary/pathology , Adult , Biopsy, Needle , Female , Humans
20.
Pathology ; 29(1): 7-11, 1997 Feb.
Article in English | MEDLINE | ID: mdl-9094170

ABSTRACT

Five cases of intraductal papillary-mucinous neoplasm (IPMN) of the pancreas are here described. This group of tumors represents a distinct clinicopathological entity with characteristic endoscopic, radiological, gross and microscopic appearances. Our five cases all showed marked dilatation of the main pancreatic duct which contained mucin and papillary tumor, sometimes filling and sometimes lining the lumen. The papillae were lined by columnar epithelium showing varying degrees of dysplasia. In one case there was adjacent invasive adenocarcinoma. Immunohistochemical staining for p53 protein was strongly positive in a majority of cells in the three cases with severe epithelial dysplasia and in the invasive adenocarcinoma, while weaker staining in a minority of cells was seen in the remaining two cases. A small proportion of tumor cells expressed PCNA and Ki-67 immunohistochemically in four cases, while the case with severe dysplasia and invasive carcinoma showed positivity for these proliferation markers in most cells. The four cases of exclusively intraductal tumor showed no evidence of disease recurrence at follow-up (median 55 months). The patient with IPMN and associated invasive adenocarcinoma died 21 months post-operatively. In view of its relatively favourable prognosis, it is important that IPMN is recognised.


Subject(s)
Adenocarcinoma, Mucinous/chemistry , Carcinoma, Papillary/chemistry , Pancreatic Neoplasms/chemistry , Adenocarcinoma, Mucinous/pathology , Aged , Aged, 80 and over , Carcinoma, Papillary/pathology , Female , Humans , Immunohistochemistry , Ki-67 Antigen/analysis , Male , Middle Aged , Neoplasm Proteins/analysis , Pancreatic Neoplasms/pathology , Proliferating Cell Nuclear Antigen/analysis , Tumor Suppressor Protein p53/analysis
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