TP53INP1 as new therapeutic target in castration-resistant prostate cancer.

BACKGROUND: Prostate cancer (PC) is one of the most common malignancies in industrialized countries, and the second leading cause of cancer-related death in the United States. We recently showed that over-expression of tumor protein 53-induced nuclear protein 1 (TP53INP1), a cell stress response protein, is a worse prognostic factor in PC, particularly predictive of biological cancer relapse. Moreover, treatment of castration-sensitive (CS) LNCaP tumor cells with a TP53INP1 antisense oligonucleotide (TP53INP1 ASO) inhibits proliferation and induces apoptosis. The aim of this study was to investigate variations of TP53INP1 expression in PC during androgen withdrawal therapy and in castration-resistant prostate cancer (CRPC). METHODS: Quantitative measurements of immunohistochemical expression of TP53INP1 using high-throughput densitometry, assessed on digitized microscopic tissue micro-array images were correlated with hormone therapy (HT) status in human PC. Northern blot analysis of TP53INP1 after castration was performed in LNCaP xenograft. Treatment of CR C4-2 tumor cells in vitro with TP53INP1 ASO was analyzed. We also analyzed the effect of TP53INP1 ASO treatment in vivo on tumor xenograft growth. RESULTS: TP53INP1 protein expression decreases during HT and increases after HT in human CRPC. TP53INP1 mRNA increases significantly in CR tumors of LNCaP xenograft. Moreover, treatment of CR C4-2 cells with TP53INP1 ASO downregulates TP53INP1 protein level, inhibits proliferation, and induces apoptosis. Finally, in vivo, TP53INP1 ASO treatment significantly inhibits the tumoral progression of CR C4-2 xenograft and enhances docetaxel cytotoxicity. CONCLUSIONS: These results suggest that TP53INP1 could be considered as a relevant-specific target for molecular therapy of CRPC.

TP53INP1 overexpression in prostate cancer correlates with poor prognostic factors and is predictive of biological cancer relapse.

BACKGROUND: Tumor protein 53-induced nuclear protein 1 (TP53INP1) is a proapoptotic protein involved in cell stress response. Whereas there is an overexpression of TP53INP1 in numerous tissues submitted to stress agents, TP53INP1 is down-expressed in stomach, pancreatic, and inflammation-mediated colic carcinomas. In medullary thyroid carcinomas, TP53INP1 overexpression correlates with poor prognosis. TP53INP1 expression has never been reported in Prostate Cancer (PC). Our aim was to investigate variations of TP53INP1 expression and their correlation to clinicopathological parameters in PC. METHODS: Quantitative measurements of immunohistochemical expression of TP53INP1 using high-throughput densitometry, assessed on digitized microscopic tissue micro-array images, were correlated with clinicopathological parameters in 91 human PC. Treatment of LNCaP tumor cells in vitro with cytokines and with TP53INP1 antisense oligonucleotide (ASO) was also analyzed. RESULTS: In normal prostate tissues, TP53INP1 is only expressed in prostate basal cells. There is a de novo TP53INP1 expression in prostate luminal cells in inflammatory prostate tissues, high grade PIN lesions and in PC. Stimulation of LNCaP cells with inflammatory cytokines enhances the level of TP53INP1 mRNA. In PC, TP53INP1 overexpression correlates with high Gleason grade, unfavorable D'Amico score and lymph node invasion, and is an independent factor of biological cancer relapse. Moreover, treatment of LNCaP cells with a TP53INP1 ASO down-regulates TP53INP1 protein level, inhibits proliferation, and induces apoptosis. CONCLUSION: TP53INP1 overexpression in PC seems to be a worse prognostic factor, particularly predictive of biological cancer relapse. Results in vitro suggest that TP53INP1 could be considered as a relevant target for potential specific therapy.

Tumor protein p53-induced nuclear protein (TP53INP1) expression in medullary thyroid carcinoma: a molecular guide to the optimal extent of surgery?

BACKGROUND: Medullary thyroid cancer (MTC) is characterized by early regional lymph node metastasis, the presence of which represents a critical obstacle to cure. At present no molecular markers have been successfully integrated into the clinical care of sporadic MTC. The present study was designed to evaluate TP53INP1 expression in MTC and to assess its ability to guide the surgeon to the optimal extent of surgery performed with curative intent. METHODS: Thirty-eight patients with sporadic MTC were evaluated. TP53INP1 immunoexpression was studied on embedded paraffin material and on cytological smears. RESULTS: TP53INP1 was expressed in normal C cells, in C-cell hyperplasia, and in 57.9% of MTC. It was possible to identify two groups of MTC according to the proportion of TP53INP1 expressing tumor cells: group 1 from 0% to <50% and group 2 from 50% to 100% of positive cells. Patients with a decreased expression of TP53INP1 (group 1) had a lower rate of nodal metastasis (18.8% versus 63.4% in group 2; P = 0.009), with only minimal lymph node involvement per N1 patient (2.7% of positive lymph nodes versus 22.9%; P < 0.001) and better outcomes (100% of biochemical cure versus 55.5%; P < 0.001). Patients with distant metastases were only observed in group 2. Cytological samples exhibit similar results to their embedded counterparts. CONCLUSIONS: TP53INP1 immunoexpression appears to be a clinical predictor of lymph node metastasis in MTC. The evaluation of TP53INP1 expression may guide the extent of lymph node dissection in the clinically node-negative neck. These findings require prospective validation.

[Early breast carcinoma profiling based on quantitative immunocytochemistry can help predict the risk of early distant metastasis]. / Evaluation immunohistochimique du risque métastasique dans les cancers du sein débutants sur microbiopsies.

We examined a series of 667 patients with node-negative breast carcinomas in order to identify prognostic immunohistochemical molecular signatures for the prediction of early metastasis, and potential new therapeutic targets. We used a standardized quantitative immunocytochemical approach with 37 antibodies, based on high-throughput tissue microarrays and image analysis, and analyzed the results with respect to metastatic status after a mean follow-up of 86 months. Complete data were obtained for 586 patients. The predictive value of the markers was first analyzed individually by univariate analysis (log rank test) in 586 node-negative tumors, according to metastatic status during follow-up. Twenty-seven markers had significant prognostic value. ROC curve analysis (logistic regression) was then used to determine the marker combination that best classified the patients with and without metastases. A 15-marker signature (Bcl2, P16, P21, P27, P53, CD34, CA IX, c-kit, FGF-R1, P38, JAK, pSTAT3, CK9, STAT1 and ER) correctly classified 84.8% of the patients (sensitivity 85.5%, specificity 84.6%). When ER, PR and c-erb B2 were excluded from the analysis, a very similar signature, in which CK8-18 replaced ER, correctly classified 83.6% of the patients (sensitivity 84.5%, specificity 83.4%). These results show that quantitative immunoprofiling, independently of ER, PR and c-erb B2 status, can provide a basal-like signature, can properly predict the metastatic risk of node-negative breast carcinomas at diagnostic time. This may be helpful for selecting patients who do not need aggressive adjuvant chemotherapy, and for developing tailored therapies.

[High-throughput quantification of tissue microarrays: identification of candidate target proteins in inflammatory breast cancer]. / La lecture automatisée à haut débit des micro-biopsies en pathologie: mise en évidence de la surexpression de c-Met et PI3K dans les cancers du sein inflammatoire.

Inflammatory breast carcinoma (IBC) is a rare but very aggressive tumour phenotype. Increased c-Met protein expression correlates with reduced survival and a higher metastatic risk in many human malignancies, including breast cancer Several studies have shown that c-Met protein is targetable by specific drugs. Here we compared c-Met expression in IBC (n = 41) and non IBC (n = 480). Two microarrays of IBC and non IBC tissues were constructed and standardized. C-Met, P13K and E-cadherin were immunodetected (Ven-tana Benchmark Autostainer) on serial sections. The results were quantified with an automated image analysis device (SAMBA Technologies) by immunoprecipitate densitometry of each core section (0.6 microns thick). We found that (i) c-Met is significantly overexpressed in IBC compared to non IBC (p < 0. 001), (ii) P13K is also overexpressed (p < 0.001) in IBC, suggesting that overexpressed c-Met is functionally active, at least through the PI3K signal transduction pathway ; and (iii) E-cadherin is paradoxically overexpressed in IBC. We conclude that c-Met may constitute a target for specific therapy in patients with poor-prognosis malignancies like IBC Automated image analysis of TMA is a valuable tool for high-throughput quantification of the immunohistochemical expression of the tumor proteome.

Moesin expression is a marker of basal breast carcinomas.

Basal breast cancers (BBCs) have a high risk of metastasis, recurrence and death. Formal subtype definition relies on gene expression but can be approximated by protein expression. New markers are needed to help in the management of the basal subtype of breast cancer. In a previous transcriptional analysis of breast cell lines we found that Moesin expression was a potential basal marker. We show here that Moesin protein expression is a basal marker in breast tumors. In a tissue microarray (TMA) containing 547 sporadic breast cancers, of which 108 were profiled for gene expression, Moesin was expressed in 31% of all tumors and in 82% of the basal tumors. To confirm that Moesin expression remained associated with the basal phenotype in specific types of BBCs, we analyzed Moesin expression in 2 other TMAs containing 40 medullary breast cancers (MBCs) and 27 BRCA1-associated breast cancers (BRCA1-BCs), respectively. Moesin was strongly expressed in MBCs (87%; p = 2.4 x 10(-5)) and in BRCA1-BCs (58%; p = 1.3 x 10(-5)) as compared with non-MBCs and sporadic cases. Moesin-expressing tumors display features of BBCs, such as high proliferation rate, hormone receptors negativity, expression of putative basal/myoepithelial markers (CAV1, CD10, CK5/6, CK14, EGFR, P53, P-cadherin and SMA). Survival analysis showed a reduced specific survival and metastasis-free survival in Moesin-expressing tumors by log-rank test (p(SS) = 0.014 and p(MFS) = 0.014). In multivariate analysis, Moesin expression was nearly an independent prognostic marker of poor outcome as shown by Cox proportional hazard model in patients without lymph node metastasis (p = 0.052, HR = 2.38, CI 95[0.99-5.69]).

[An unusual perianal abscess]. / Un abcès périanal inhabituel.

Aggressive angiomyxoma (AA) is a mesenchymal tumour occurring in connective tissue of the perineum or lower pelvis with a marked tendency to local recurrence but which usually does not metastasize. Only 130 cases had been reported to date. We report the case of a 58-year-old woman, presenting with a pelvi-perineal mass, which was considered to be an anal abscess. After surgical excision, an AA was diagnosed, with classical histological features (myxoid and vascular components) and which was positive for vimentin and CD34. This case report shows that clinical diagnosis of AA is difficult and that delayed diagnosis can prevent optimal treatment of these tumors.

[A tumor-like lymphocytis mastitis]. / Mastite lymphocytaire pseudo-tumorale.

A 44-year-old woman presenting with an inflammatory and palpable firm breast lump underwent surgical excision. Intraoperative frozen section analysis showed an extensive lesion consisting of ducts with intraluminal "necrosis". In addition, a very dense stromal inflammation was observed around these ducts, suggesting an invasive ductal carcinoma with predominant intraductal proliferation. However, on paraffin sections, epithelial cells close to the lymphocytic infiltrate were rare, subatrophic, without any neoplastic feature. The density and architecture of the lymphocytic infiltrate mimicked a breast lymphoma. However, immunochemistry and molecular biology investigation favored the diagnosis of a tumor-like lymphocytic mastitis. Although extremely rare, this particular form of lymphocytic mastitis, a diagnostic pitfall particularly during peroperative examination, should be recognized by pathologists.

[Plasmablastic lymphoma in a patient with HIV infection: an unusual case located in the skin]. / Lymphome plasmoblastique du sujet infecté par le VIH: a propos d'un cas très inhabituel de localisation cutanée.

We report the case of a plasmablastic lymphoma involving the skin in a 45 year-old HIV-positive patient. Plasmablastic lymphoma was first described in 1997 and is considered to be a diffuse large B-cell lymphoma with a unique immunophenotype and a predilection for the oral cavity. In this case, the tumor was revealed by multiple purple cutaneous nodules predominantly localized on the trunk and proximal parts of the limbs. A skin biopsy led to the diagnosis of plasmablastic lymphoma in view of the presence of a dense nodular infiltrate invading the dermis and subcutaneous fat composed of large cells that expressed neither the leucocyte common antigen nor the B- and T-cell antigens CD20 and CD3, but which showed a strong immunostaining with plasma cell marker VS38c. Most of the cells expressed Kappa light chain of immunoglobulins, they did not express Lambda light chain. In situ hybridization with EBER probe revealed detection of Epstein Barr virus in about 15 % of tumor cells. The clinical course was aggressive and rapidly fatal. Despite one cycle chemotherapy the patient died four months after presentation. HIV-associated plasmablastic lymphoma is a poor prognosis malignancy that may resist typing due to the lack of expression of commonly used lymphoid markers.

Conservative treatment of cervical intraepithelial neoplasia using a cold-knife section technique.

OBJECTIVE: The purpose of this study was to evaluate a conservative cold-knife section technique for treatment of cervical intraepithelial neoplasia (CIN). This procedure can be adapted to patient age, preservation of childbearing potential and extent of dysplasia. DESIGN: Prospective study. SETTING: Gynecological Oncology Department in French Public Hospital. POPULATION: A total of 460 women treated for CIN between 1985 and 1999 were included. METHODS: A conservative cold-knife cervical section followed by blanket suture reconstruction was used in all cases. MAIN OUTCOME MEASURES: Immediate operative results, recurrence and reproductive function were assessed. RESULTS: The mean length of the cervical specimen was 11.4 mm (range, 4-22 mm). Mean specimen thickness was strongly correlated with age: 10.6 +/- 4.1 mm in women <40 years versus 12.1 in women >40 years; p < 0.001. Complete excision was achieved in 395 cases (85.8%). Post-operative bleeding was observed in 5 cases (1.1%). The mean duration of follow-up was 62 months (range, 12.3-156.5 months). Recurrences developed in 26 patients (6.6%) including CIN 1 in 9 cases, CIN 2 in 9 and CIN 3 in 8. No patient developed carcinoma. The actuarial risk of recurrence was 2.4% (+/- S.D., 0.9) at 24 months and 7.8% (+/-S.D., 1.9) at 60 months. A total of 52 pregnancies were observed in 39 patients. No case of de novo infertility was reported post-operatively. Amenorrhea was noted in 1 patient (0.1%) and dysmenorrhea in 1 patient (0.1%). CONCLUSIONS: This conservative cold-knife section technique is effective for treatment of CIN with low morbidity and little adverse effect on childbearing potential. Exposure of the squamocolumnar junction (SCJ) greatly facilitates follow-up.

[Immunohistochemical expression of PTEN antigen: a new tool for diagnosis of early endometrial neoplasia]. / L'expression immunohistochimique de l'antigène PTEN: un nouvel outil diagnostique dans les néoplasies débutantes de l'endomètre.

We examined immunohistochemical PTEN protein expression in endometrial samples obtained from perimenopausal women with uterine bleeding in order to diagnose early endometrial neoplasia. Paraffin sections of endometrial samples (biopsies, endometrium resection, hysterectomy) were reviewed and tested for immunocytochemical PTEN expression by epithelial cells. Immunohistochemical studies were performed with the Ventana Benchmark device and the immunoperoxidase technique with monoclonal anti-PTEN (6H2.1/Cascade Biosciences). We studied 45 samples of proliferative endometria, 42 samples of atypical hyperplasia (neoplasia), and 55 samples of endometrial carcinomas (30 endometrioid, 5 serous papillary, 10 clear cell, 5 adenosquamous, and 5 MMMT). A strong positive PTEN immunoreaction was observed in all 45 normal proliferative endometria, 2/30 endometrioid carcinomas, and 23/25 non endometrioid carcinomas. In contrast, PTEN immunoexpression was negative or weak in 40/42 atypical hyperplasia and 28/30 endometrioid carcinomas. Negative or weak PTEN expression correlated with endometrial neoplasia (atypical proliferation) (p < 0.001). Thus (i) PTEN immunoexpression in endometrial paraffin sections is a new diagnostic tool, distinguishing PTEN-positive cyclic abnormal monoclonal proliferative endometrium (anovulatory, non atypical, simple and complex hyperplasia) from PTEN-negative (or decreased) endometrial neoplasia, and especially early endometrial neoplasia (atypical simple and complex hyperplasia, in situ carcinoma, superficial carcinoma with focal invasion). (ii) Given the lack of reproducibility of histological identification of atypical (precancerous invasive) and non atypical (precancerous non invasive) endometrial hyperplasia, the new criteria (PTEN-negative crowded glands, gland/stroma ratio > 55%, nuclear pleomorphism, in areas > 1 mm) recently proposed to diagnose early endometrial neoplasia appear to be clinically relevant.