Fluctuation in prostate cancer gene 3 (PCA3) score in men undergoing first or repeat prostate biopsies.

OBJECTIVE: To evaluate the variability in prostate cancer gene 3 (PCA3) score over time in men with elevated serum prostate-specific antigen (PSA) levels who are undergoing first or repeat prostate biopsy. PATIENTS AND METHODS: A total of 360 men from two Italian institutions who had undergone at least two PCA3 assessments were selected. Of these, 97.5% were scheduled for first or repeat prostate biopsy because of elevated PSA level and/or positive digital rectal examination (DRE). We compared the PCA3 scores in men with a negative biopsy (normal parenchyma, benign prostatic hyperplasia [BPH], chronic prostatitis, high-grade prostate intraepithelial neoplasia [HG-PIN]) with those in men with a positive biopsy. We evaluated PCA3 repeated measures biological variability and its possible association with basic patient characteristics (age, family history of prostate cancer, DRE, prostate volume, BPH, prostatitis and HG-PIN). Three different thresholds were used to evaluate the possible changes in risk class: the standard threshold (a PCA3 score of 35), a US Food and Drug Administation-approved PCA3 threshold of 25 and a threshold selected based on our previous research which was a PCA3 score of 50. RESULTS: The PCA3 scores varied significantly (P < 0.001) when comparing men with a negative biopsy with those with a positive biopsy (median [range] PCA3 score: 25 [2-276] vs 43 [7-331]). There was no significant difference in PCA3 scores in men with chronic prostatitis and HG-PIN compared with other men with negative biopsies. The median (range) time between the two PCA3 assessments was 16.2 (3-53.7) months. No association was found between PCA3 repeated measures modifications and age, family history of prostate cancer, DRE, BPH, prostatitis, HG-PIN and use of 5-α-reductase inhibitors. The variability of PCA3 scores on repeated measures confirmed the risk class for about 80% of patients; of the remaining 20% of patients, the risk class was upgraded in two thirds and downgraded in one third. CONCLUSION: PCA3 score can be considered a stable marker over time in most cases but there is a group of men among whom there is clinically notable risk class change. Further investigation is required to determine the genesis of this phenomenon.

Differential expression of HER2, STAT3, SOX2, IFI16 and cell cycle markers during HPV-related head and neck carcinogenesis.

The aim of this study was to analyze protein and gene expression of HER2 in 224 head and neck precancerous and malignant lesions by immunohistochemistry and FISH analysis. In parallel, expression of pStat3, Sox2, IFI16 and p16, Ki67 was evaluated. Immunohistochemical analysis was assessed on formalin-fixed paraffin-embedded (FFPE) tissue specimens. A combined method for HPV detection consisting of p16 immunostaining and two PCR probes was applied. HER2 gene status was evaluated by FISH analysis. HPV DNA was detected in 24% of cases with predominant HPV16 genotype. HPV-positive lesions had higher HER2, pStat3 and within carcinoma group, and higher IFI16 expression compared to the HPV-negative group (Fig. 1A-B-C). A strong positive correlation between Sox2 and proliferative activity was observed, whereas IFI16 expression displayed a negative relationship with Sox2 and Ki67 activity. The most striking result was higher pStat3 expression in HPV-positive lesions and its strong positive correlation with IFI16 expression. The presence of HPV may induce upregulation of HER2/neu, pStat3 and IFI16. High levels and a strong positive correlation between pStat3 and IFI16 suggest their synergistic pro-apoptotic effects in HPV-positive lesions.

Detection and characterization of classical and "uncommon" exon 19 Epidermal Growth Factor Receptor mutations in lung cancer by pyrosequencing.

BACKGROUND: The management of advanced stage non-small cell lung cancer is increasingly based on diagnostic and predictive analyses performed mostly on limited amounts of tumor tissue. The evaluation of Epidermal Growth Factor Receptor (EGFR) mutations have emerged as the strongest predictor of response to EGFR-tyrosine kinase inhibitors mainly in patients with adenocarcinoma. Several EGFR mutation detection techniques are available, having both sensitivity and specificity issues, being the Sanger sequencing technique the reference standard, with the limitation of a relatively high amount of mutated cells needed for the analysis. METHODS: A novel nucleotide dispensation order for pyrosequencing was established allowing the identification and characterization of EGFR mutation not definable with commercially and clinically approved kits, and validated in a consecutive series of 321 lung cancer patients (246 biopsies or cytology samples and 75 surgical specimens). RESULTS: 61/321 (19%) mutated cases were detected, 17 (27.9%) in exon 21 and 44 (72.1%) in exon 19, these latter corresponding to 32/44 (72.7%) classical and 12/44 (27.3%) uncommon mutations. Furthermore, a novel, never reported, point mutation, was found, which determined a premature stop codon in the aminoacidic sequence that resulted in a truncated protein in the tyrosine kinase domain, thus impairing the inhibitory effect of specific therapy. CONCLUSIONS: The novel dispensation order allows to detect and characterize both classical and uncommon EGFR mutations. Although several phase III studies in genotypically defined groups of patients are already available, further prospective studies assessing the role of uncommon EGFR mutations are warranted.

Targeting TORC2 in multiple myeloma with a new mTOR kinase inhibitor.

Although preclinical work with rapalogs suggests potential in treatment of multiple myeloma (MM), they have been less successful clinically. These drugs allostearically inhibit the mammalian target of rapamycin kinase primarily curtailing activity of the target of rapamycin complex (TORC)1. To assess if the mammalian target of rapamycin within the TORC2 complex could be a better target in MM, we tested a new agent, pp242, which prevents activation of TORC2 as well as TORC1. Although comparable to rapamycin against phosphorylation of the TORC1 substrates p70S6kinase and 4E-BP-1, pp242 could also inhibit phosphorylation of AKT on serine 473, a TORC2 substrate, while rapamycin was ineffective. pp242 was also more effective than rapamycin in achieving cytoreduction and apoptosis in MM cells. In addition, pp242 was an effective agent against primary MM cells in vitro and growth of 8226 cells in mice. Knockdown of the TORC2 complex protein, rictor, was deleterious to MM cells further supporting TORC2 as the critical target for pp242. TORC2 activation was frequently identified in primary specimens by immunostaining for AKT phosphorylation on serine 473. Potential mechanisms of up-regulated TORC2 activity in MM were stimulation with interleukin-6 or insulin-like growth factor 1, and phosphatase and tensin homolog or RAS alterations. Combining pp242 with bortezomib led to synergistic anti-MM effects. These results support TORC2 as a therapeutic target in MM.

Pluripotent plasticity of stem cells and liver repopulation.

Different types of stem cells have a role in liver regeneration or fibrous repair during and after several liver diseases. Otherwise, the origin of hepatic and/or extra-hepatic stem cells in reactive liver repopulation is under controversy. The ability of the human body to self-repair and replace the cells and tissues of some organs is often evident. It has been estimated that complete renewal of liver tissue takes place in about a year. Replacement of lost liver tissues is accomplished by proliferation of mature hepatocytes, hepatic oval stem cells differentiation, and sinusoidal cells as support. Hepatic oval cells display a distinct phenotype and have been shown to be a bipotential progenitor of two types of epithelial cells found in the liver, hepatocytes, and bile ductular cells. In gastroenterology and hepatology, the first attempts to translate stem cell basic research into novel therapeutic strategies have been made for the treatment of several disorders, such as inflammatory bowel diseases, diabetes mellitus, celiachy, and acute or chronic hepatopaties. In the future, pluripotent plasticity of stem cells will open a variety of clinical application strategies for the treatment of tissue injuries, degenerated organs. The promise of liver stem cells lie in their potential to provide a continuous and readily available source of liver cells that can be used for gene therapy, cell transplant, bio-artificial liver-assisted devices, drug toxicology testing, and use as an in vitro model to understand the developmental biology of the liver.

Prognostic role of osteopontin expression in malignant pleural mesothelioma.

Malignant pleural mesothelioma (MPM) represents highly aggressive neoplasms with a mean survival of approximately 10 months. Osteopontin, a glycoprotein involved in cell-matrix interactions correlated with invasion and metastatic spread in several tumors, has recently been proposed as a serum marker of MPM in asbestos-exposed subjects. The aim of this study was to define the prognostic role of osteopontin in MPM. For the study, 32 long-term survivors (>24 months) and a random sample of 69 short-term survivors (

Co-expression of EGF receptor, TGFalpha and S6 kinase is significantly associated with colorectal carcinomas with distant metastases at diagnosis.

Autocrine tumour growth factor alpha (TGFalpha)/epidermal growth factor receptor (EGFR) stimulation in colorectal carcinoma (CRC) cells regulates cell adhesion and invasiveness via ribosomal protein S6 kinase (S6K) phosphorylation in pre-clinical studies. The aim of this study was to evaluate whether TGFalpha and EGFR expression might be correlated with a higher metastatic behaviour in human tumours. Paraffin-embedded material was retrospectively collected from 101 primitive CRCs including all stage IV patients at diagnosis treated at our Institution from 1999 to 2004 (50 cases, Group B) and 51 stage II-III control cases (Group A). EGFR and TGFalpha expression, together with signalling molecules (including signal transducer and activator of transcription [STAT3], serine-treonine kinase [Akt], mitogen-activated protein kinase [MAPK], mammalian target of rapamycin [mTOR] and S6K) in selected samples, was evaluated by immunohistochemistry using the EGFR Dako antibody. A total of 68/101 (67.3%) cases were EGFR positive and 79/101 (78.2%) cases were TGFalpha positive. EGFR/TGFalpha co-expression differed significantly (p = 0.02) between Group A and Group B tumours (23/51, 45.1% vs 34/50, 68.0%, respectively), whereas no differences in STAT, Akt, mTOR expression was evident between the two groups. Conversely, there was a significantly higher expression of phosphorylated S6K in stage IV cases (Group B) than in the controls (Group A; 70.4% vs 38.7%; p = 0.02). In agreement with in vitro data, EGFR, TGFalpha and S6K co-expression in human CRC was significantly higher in patients with advanced stage at diagnosis.

Basaloid adenocarcinoma. A new variant of pulmonary adenocarcinoma.

The 2004 WHO classification of lung tumours recognised basaloid carcinoma as a variant of squamous and large cell carcinoma. We report a unique case of primary pulmonary adenocarcinoma with a basaloid component. An 82-year-old man underwent pulmonary lobectomy for a 2.8 cm tumour. The patient is disease-free 13 months after diagnosis. Histologically, an invasive carcinoma having a glandular and a solid component was observed. The former was an adenocarcinoma with mucus containing spaces lined by columnar mucinous cells and basaloid cells. The solid component was an organoid proliferation of basaloid-type cells, as in cutaneous basal cell carcinoma. Basaloid cells, but not mucinous cells, were immunoreactive for high molecular weight cytokeratins (CK), CK 7 and, focally, for TTF-1. High Ki67 index, p53 and EGFR expression were also found. This tumour is unique in several respects: (1) The solid areas resemble a conventional basaloid carcinoma, except for the presence of small mucin-containing spaces. (2) The mucinous adenocarcinoma areas contain two layers of columnar and basaloid cells. (3) Both components are neoplastic based on cell morphology, invasive properties and phenotypic profile. These findings indicate that a basaloid variant of adenocarcinoma is also existing in the spectrum of basaloid carcinomas of the lung.

Frequency and distribution of trisomy 11 in multiple myeloma patients: relation with overexpression of CCND1 and t(11;14).

Multiple myelomas (MM) recently have been stratified into five groups (TC1-TC5) on the basis of the presence of the recurrent IgH chromosomal translocation and cyclin D expression. Cyclin D1 is detectable in up to one third of MM patients and plays crucial role in the regulation of G1-S transition in cell cycle. To evaluate the mechanisms of cyclin D1 overexpression, fluorescence in situ hybridization analysis with specific probes for the CCND1 gene and t(11;14)(q13;q32) were performed on highly purified plasma cells from bone marrow samples of 30 MM patients at diagnosis. CCND1 gene overexpression was detected in 14/30 cases (46.6%). Patients with evidence of the t(11;14) showed strong nuclear staining for cyclin D1 (TC1 group) and 7/8 demonstrated CCND1 overexpression. The remaining 7/15 cases with increased CCND1 gene copy numbers lacked the t(11;14) and showed low to negative levels of cyclin D1 protein (TC2 group). Trisomy 11 was demonstrated in 2/8 cases carrying the t(11;14) (TC1), 6/7 overexpressing cyclin D1 without the translocation (TC2), and 4/15 negative for both alterations (TC3-TC5). According to our data, trisomy 11 does not appear to directly cause CCND1 gene overexpression because it was present in 4/15 patients without the overexpression of the CCND1 gene and in 2/8 patients carrying the t(11;14). One patient belonging to the TC2 group overexpressed cyclin D1 and lacked both trisomy and translocation, suggesting that cyclin D1 can be dysregulated by additional mechanisms. In the TC2 group, trisomy 11 may probably be considered as a recurrent polisomy of the hyperdiploid status.

Cathepsin K is selectively expressed in the stroma of lung adenocarcinoma but not in bronchioloalveolar carcinoma. A useful marker of invasive growth.

Lung bronchioalveolar carcinomas (BACs) are noninvasive tumors showing lepidic growth and excellent prognosis, whereas all the other variants of adenocarcinoma are invasive tumors with a worse prognosis. The identification of minimal invasive foci in adenocarcinoma, therefore, is of prognostic relevance. A series of 68 pulmonary tumors, including 40 acinar/papillary adenocarcinomas, 18 adenocarcinomas of the mixed subtype, and 10 BACs was tested by immunohistochemical analysis for cathepsin K expression, a proteinase involved in bone and extracellular matrix remodeling. Cathepsin K was produced by epithelial tumor cells in most invasive adenocarcinomas and, interestingly, by macrophages and fibroblasts in the stroma of invasive adenocarcinomas but not of BACs (P < .001). Our findings suggest pathogenetic implications of cathepsin K in the mechanisms of tumor invasiveness in lung carcinoma; in addition, cathepsin K immunodetection may be a valuable adjunct in the correct classification of pulmonary adenocarcinomas, especially in small sclerosing BACs and mixed adenocarcinoma subtypes with minimal infiltrative growth.

Prognostic role of protease-activated receptors 1 and 4 in resected stage IB non-small-cell lung cancer.

BACKGROUND: Protease-activated receptor (PAR)-1 and PAR-4 are involved in extracellular matrix invasion and angiogenesis. PATIENTS AND METHODS: A series of 60 resected stage IB non-small-cell lung cancers (NSCLCs), including 30 adenocarcinomas (ADCs) and 30 squamous cell carcinomas (SCCs), were processed by immunohistochemistry with antibodies to PAR-1, PAR-4, vascular endothelial growth factor (VEGF), and CD34. RESULTS: Protease-activated receptor-1 was expressed in 37 cases (62%) and PAR-4 in 39 (65%). Adenocarcinomas were significantly more positive than SCC for PAR-1 (17 vs. 8 cases) and PAR-4 (10 vs. 5 cases). Vascular endothelial growth factor was expressed in 42 cases (70%): 22 ADC and 20 SCC. A significant correlation emerged between PAR-1 and/or PAR-4 expression and VEGF but not with microvessel density. Median follow-up was 38 months; actuarial 5-year survival was 43%. At univariate analysis, 3-year survival was shorter in patients expressing PAR-4 versus negative cases (29% vs. 60%; P = 0.002). In 46 patients expressing PAR-1 and/or PAR-4, 3-year survival was 30% versus 68% in 14 patients with no PAR expression (P = 0.002). A trend toward shorter 3-year survival was seen in PAR-1-positive versus PAR-1-negative cases (34% vs. 46%; P = 0.06). Multivariate analysis identified expression of PAR-1 and/or PAR-4 as an independent prognostic factor for reduced survival in resected stage IB NSCLC. CONCLUSION: Expression of PAR-1 and PAR-4 in early-stage NSCLC could be included in a molecular algorithm for the selection of patients eligible for adjuvant studies.

Retrospective study testing next generation sequencing of selected cancer-associated genes in resected prostate cancer.

PURPOSE: Prostate cancer (PCa) has a highly heterogeneous outcome. Beyond Gleason Score, Prostate Serum Antigen and tumor stage, nowadays there are no biological prognostic factors to discriminate between indolent and aggressive tumors.The most common known genomic alterations are the TMPRSS-ETS translocation and mutations in the PI3K, MAPK pathways and in p53, RB and c-MYC genes.The aim of this retrospective study was to identify by next generation sequencing the most frequent genetic variations (GVs) in localized and locally advanced PCa underwent prostatectomy and to investigate their correlation with clinical-pathological variables and disease progression. RESULTS: Identified non-synonymous GVs included TP53 p.P72R (78% of tumors), two CSFR1 SNPs, rs2066934 and rs2066933 (70%), KDR p.Q472H (67%), KIT p.M541L (28%), PIK3CA p.I391M (19%), MET p.V378I (10%) and FGFR3 p.F384L/p.F386L (8%). TP53 p.P72R, MET p.V378I and CSFR1 SNPs were significantly associated with the HI risk group, TP53 and MET variations with T≥T2c. FGFR3 p.F384L/p.F386L was correlated with T≤T2b. MET p.V378I mutation, detected in 20% of HI risk patients, was associated with early biochemical recurrence. EXPERIMENTAL DESIGN: Nucleic acids were obtained from tissue samples of 30 high (HI) and 30 low-intermediate (LM) risk patients, according to D'Amico criteria. Genomic DNA was explored with the Ion_AmpliSeq_Cancer_Hotspot_Panel_v.2 including 50 cancer-associated genes. GVs with allelic frequency (AF) ≥10%, affecting protein function or previously associated with cancer, were correlated with clinical-pathological variables. CONCLUSION: Our results confirm a complex mutational profile in PCa, supporting the involvement of TP53, MET, FGFR3, CSF1R GVs in tumor progression and aggressiveness.

Pathological patterns of prostate biopsy in men with fluctuations of prostate cancer gene 3 score: a preliminary report.

BACKGROUND: To evaluate pathological patterns of prostate biopsy in men with changes in risk class by prostate cancer gene 3 (PCA3) score and with elevated serum prostate-specific antigen (PSA) or positive digital rectal examination (DRE), undergoing a repeat biopsy. PATIENTS AND METHODS: A total of 108 males of two Italian Institutions who had undergone at least two PCA3 score assessments with changed PCA3 risk class were selected. Comparison of PCA3 score in patients with negative re-biopsy [normal parenchyma, benign prostatic hyperplasia (BPH), chronic prostatitis, high-grade prostate intraepithelial neoplasia (HG-PIN), atypical small acinar prostate (ASAP)] or positive re-biopsy was performed. RESULTS: The up- and down-grading rates for PCA3 score were 71.3% (n=77) and 28.7% (n=31), respectively. Among the 77 up-graded patients, the median change in PCA3 score was 24 (range=4-69), while among the 31 down-graded ones, the median change was 17 (2 to 55). The PCA3 score in 24 out of 29 (82.7%) patients with prostate cancer (PCa) was up-graded. No association was found for correlation of PCA3 score change with age >65 years (p=0.975), family history of prostate cancer (p=0.796), positive DRE (p=0.179), use of 5-alpha-reductase inhibitors (p=0.793) and BPH/prostatitis/HG-PIN/ASAP diagnosis (p=0.428). CONCLUSION: PCA3 score can be considered a marker that is stable over time in most cases; notably, up to 20% of patients have a clinically relevant change of risk class. The rate of PCa was higher in patients whose PCA3 score was up-graded, even if no robust cut-off for PCA3 score fluctuation was identified.

Prostate health index and prostate cancer gene 3 score but not percent-free Prostate Specific Antigen have a predictive role in differentiating histological prostatitis from PCa and other nonneoplastic lesions (BPH and HG-PIN) at repeat biopsy.

OBJECTIVE: To determine if prostate health index (PHI), prostate cancer antigen gene 3 (PCA3) score, and percentage of free prostate-specific antigen (%fPSA) may be used to differentiate asymptomatic acute and chronic prostatitis from prostate cancer (PCa), benign prostatic hyperplasia (BPH), and high-grade prostate intraepithelial neoplasia (HG-PIN) in patients with elevated PSA levels and negative findings on digital rectal examination at repeat biopsy (re-Bx). PATIENTS AND METHODS: In this prospective study, 252 patients were enrolled, undergoing PHI, PCA3 score, and %fPSA assessments before re-Bx. We used 3 multivariate logistic regression models to test the PHI, PCA3 score, and %fPSA as risk factors for prostatitis vs. PCa, vs. BPH, and vs. HG-PIN. All the analyses were performed for the whole patient cohort and for the "gray zone" of PSA (4-10ng/ml) cohort (171 individuals). RESULTS: Of the 252 patients, 43 (17.1%) had diagnosis of PCa. The median PHI was significantly different between men with a negative biopsy and those with a positive biopsy (34.9 vs. 48.1, P<0.001), as for the PCA3 score (24 vs. 54, P<0.001) and %fPSA (11.8% vs. 15.8%, P = 0.012). The net benefit of using PCA3 and PHI to differentiate prostatitis and PCa was moderate, although it extended to a good range of threshold probabilities (40%-100%), whereas that from using %fPSA was negligible: this pattern was reported for the whole population as for the "gray zone" PSA cohort. CONCLUSION: In front of a good diagnostic performance of all the 3 biomarkers in distinguishing negative biopsy vs. positive biopsy, the clinical benefit of using the PCA3 score and PHI to estimate prostatitis vs. PCa was comparable. PHI was the only determinant for prostatitis vs. BPH, whereas no biomarkers could differentiate prostate inflammation from HG-PIN.

mTOR pathway activation in multiple myeloma cell lines and primary tumour cells: pomalidomide enhances cytoplasmic-nuclear shuttling of mTOR protein.

mTOR is a protein kinase that plays a central role in regulating critical cellular processes. We evaluated the activation and cellular localization of the mTOR pathway in multiple myeloma (MM) and analyzed the role of pomalidomide in regulating mTOR. By immunohistochemistry cytoplasmic p-mTOR stained positive in 57 out 101 (57.6%) cases with a nuclear p-mTOR localization in 14 out 101 samples (13.8%). In the 70 MM samples analyzed for the entire pathway, p-mTOR expression significantly correlated with p-AKT, p-P70S6K, and p-4E-BP1 suggesting that the AKT/mTOR pathway is activated in a subset of MM patients. Immunofluorescence assays demonstrated that mTOR protein is distributed throughout the cytoplasm and the nucleus at baseline in MM cell lines and in plasma cells of 13 MM patients and that pomalidomide facilitated the shift of the mTOR protein in the nucleus. By western blotting, treatment with pomalidomide increased nuclear mTOR and p-mTOR expression levels in the nucleus with a concomitant decrease of the cytoplasmic fractions while does not seem to affect significantly AKT phosphorylation status. In MM cells the anti-myeloma activity of pomalidomide may be mediated by the regulation of the mTOR pathway.

Myxoid adrenocortical adenoma with a pseudoglandular pattern.

Myxoid changes rarely occur in adrenocortical adenomas and carcinomas. Only eight benign tumours with such features have been described thus far, five of which also had a prominent pseudoglandular component. We report an additional pseudoglandular myxoid adenoma of the adrenal gland detected in a 58-year-old male patient who developed mild hypertension. At surgery, a 4-cm mass was resected and found to contain cords and tubules of polygonal cells in a myxoid background. Limited areas of classical adrenocortical adenoma were detected in less than 20% of the tumour area. Lack of atypias and absence of mucin markers, together with an immunophenotype consistent with adrenal tumours (focal cytokeratin, vimentin, synaptophysin and alpha-inhibin immunoreactivities), led to a diagnosis of primary adrenocortical adenoma with an extensive pseudoglandular myxoid pattern. However, the differential diagnosis from metastatic well-differentiated adenocarcinomas, chordomas and retroperitoneal myxoid mesenchymal tumours (e.g. liposarcoma) may be difficult in the absence of a complete clinical history and a reliable immunoprofile. We strongly recommend staining of any myxoid or glandular tumour of the adrenal gland for alpha-inhibin and synaptophysin (probably the currently best characterised markers of adrenocortical origin) before considering alternative (probably more common) diagnoses of metastatic adenocarcinoma or retroperitoneal tumours localised to the adrenal gland.

Prostate cancer gene 3 urine assay cutoff in diagnosis of prostate cancer: a validation study on an Italian patient population undergoing first and repeat biopsy.

OBJECTIVE: To determine an optimal prostate cancer gene 3 (PCA3) cutoff in predicting prostate cancer in Italian patients undergoing first or repeat biopsy. STUDY DESIGN: In this observational multicenter study 1246 men with elevated prostate specific antigen (PSA) and negative digital rectal examination, with prostate biopsy after PCA3 assessment, were divided into two groups submitted to PCA3 testing before or after previous negative biopsies. Ideal PCA3 cutoff was identified using area under the curve of the receiver operating characteristic analysis. Various cutoff values were used to determine the best predictive score. Univariate and multivariate logistic regression models compared age, PSA, free-PSA, and PCA3 score to predict prostate cancer. RESULTS: PCA3 cutoff 39-50 had the highest accuracy in the repeat biopsy group in which cutoff of 39 could have avoided 51.9% negative repeat biopsies, eventually missing 7.8% of cancers (all low risk); cutoff of 50 would have prevented 56.5% of negative repeat biopsies, missing 29 tumors (10.3%), 5 potentially aggressive. The PCA3 test performed poorly in the first biopsy group. CONCLUSION: We confirm the usefulness of PCA3 in Italian men with a previous negative biopsy. We achieved the best performance at a cutoff of 39. PCA3 did not perform better than PSA in non-biopsy-selected men.

A DNA vaccine against ERBB2 impairs chemical carcinogenesis in random-bred hamsters.

Vaccines against oncoantigens halt early neoplastic lesions in several cancer-prone, genetically engineered mouse models, whereas their ability to prevent chemical carcinogenesis has not been explored. This is a significant issue, as exposure to chemical mutagens is responsible for a substantial percentage of cancers worldwide. Here, we show that the archetypal oncoantigen ERBB2 is transiently overexpressed in Syrian hamsters during the early stages of 7,12-dimethylbenz[α]anthracene (DMBA)-induced oral carcinogenesis. Repeated DNA vaccinations against ERBB2 significantly reduce the number, size, and severity of oral lesions in a manner directly proportional to the anti-ERBB2 antibody response. These results support the prospects of vaccines as a fresh strategy in the management of individuals at risk for exposure to defined carcinogenic agents.

Genetic markers of oral malignant melanoma analysed by fluorescence in situ hybridisation (FISH).

Oral malignant melanoma (OMM) is a rare condition, and our knowledge about morphological and genetic modifications is scanty and incomplete. The aim of this study is to report morphological and fluorescent in situ hybridisation (FISH) data obtained in four cases of OMM. FISH results were also compared with those of cutaneous malignant melanoma (CMM, three cases), desmoplastic cutaneous melanoma (DMM, four cases) and spindle cells cutaneous melanoma (SCCM, one case). All the OMM cases showed a combined radial and vertical growth pattern, with the invasive component characterised by malignant spindle cells intermingled among collagen bundles. Two cases of OMM resulted positively stained with p16, in contrast with frequent loss of immunoreactivity in CMM. Three OMM were suitable for FISH analysis: 9p21 locus was deleted in 1/3, 1p36 resulted deleted 3/3, while EGFR gene showed a relative deletion. Similar genetic alterations were found in DMM and SCMM, but not in CMM. Ultrastructural findings further enhanced differences between OMM and CMM; OMM displayed, mature-staged melanosomes only within in situ component. In conclusion, OMM presents a morphological and genetic profile similar to DMM; and SCCM, however, displays some differences from CMM.