Antonio Pennella

p53 protein expression in central nervous system neoplasms.

AIMS: To demonstrate, immunohistochemically, p53 protein expression in a selection of central nervous system tumours; to investigate the relation between p53 expression and that of the proliferation related antigen, PCNA. METHODS: Surgical specimens from 86 central nervous system tumours were routinely fixed, paraffin wax embedded, and immunostained with a monoclonal (PAb 1801) and a policlonal antibody (CM1) p53 protein and a monoclonal antibody against PCNA (PC10). Normal brain samples obtained at necropsy and 10 surgically obtained samples of gliotic brain parenchyma were also immunostained. RESULTS: p53 protein expression was observed in 35 of 86 brain tumours, suggesting frequent p53 gene mutation. p53 protein alterations were associated with all grades of malignancy in tumours displaying solely astrocytic differentiation, with the exception of pilocytic astrocytomas. In those showing oligodendroglial or ependymal differentiation they appeared to be restricted almost to only high grade lesions. No p53 immunoreactivity was observed in normal or gliotic brain tissue; p53 altered expression was not related to the percentage of PCNA labelled cells. CONCLUSIONS: The use of sophisticated gene amplification techniques or highly sensitive immunohistochemical methods might be useful in distinguishing between reactive and neoplastic astrocytic lesions, and in the identification of malignant progression in other non-astrocytic glial tumours. Tumours with very similar histogenetic differentiation features might actually be a genetically heterogeneous group with possible different clinical courses.

NOTCH SIGNALLING MODULATES HYPOXIA-INDUCED NEUROENDOCRINE DIFFERENTIATION OF HUMAN PROSTATE CANCER CELLS

Prostate carcinoma is among the most common causes of cancer-related death in men, representing 15% of all male malignancies in developed countries. Neuroendocrine differentiation (NED) has been associated with tumor progression, poor prognosis, and with the androgen-independent status. Currently, no successful therapy exists for advanced, castration-resistant disease. Because hypoxia has been linked to prostate cancer progression and unfavorable outcome, we sought to determine whether hypoxia would impact the degree of neuroendocrine differentiation of prostate cancer cells in vitro. Results: Exposure of LNCaP cells to low oxygen tension induced a neuroendocrine phenotype, associated with an increased expression of the transcription factor neurogenin3 and neuroendocrine markers, such as neuron-specific enolase, chromogranin A, and β3-tubulin. Moreover, hypoxia triggered a significant decrease of Notch 1 and Notch 2 mRNA and protein expression, with subsequent downregulation of Notch-mediated signaling, as shown by reduced levels of the Notch target genes, Hes1 and Hey1. NED was promoted by attenuation of Hes1 transcription, as cells expressing a dominant-negative form of Hes1 displayed increased levels of neuroendocrine markers under normoxic conditions. Although hypoxia downregulated Notch 1 and Notch 2 mRNA transcription and receptor activation also in the androgen-independent cell lines, PC-3 and Du145, it did not change the extent of NED in these cultures, suggesting that androgen sensitivity may be required for transdifferentiation to occur. Conclusions: Hypoxia induces NED of LNCaP cells in vitro, which seems to be driven by the inhibition of Notch signaling with subsequent downregulation of Hes1 transcription. Mol Cancer Res; 10(2); 230–8. ©2011 AACR.

Malignant deciduoid mesothelioma of the pleura: report of two cases with long survival.

Malignant deciduoid mesothelioma of the pleura: report of two cases with long survival

Comparative genomic hybridisation in malignant deciduoid mesothelioma

Background: Malignant deciduoid mesothelioma is a rare variant of epithelioid mesothelioma. This tumour generally has poor prognosis, and can be asbestos related. Aim: To identify peculiar genetic changes responsible for critical phases in pathogenesis of malignant deciduoid mesothelioma and their prognostic relevance. Methods: Comparative genomic hybridisation was carried out in six cases of malignant pleural deciduoid mesothelioma, four sporadic and two familial. All cases were found to be asbestos related. Four patients died during follow-up and the mean survival was 29.5 (SD 14.2, range 12–43) months. Results: Genetic abnormalities were found in all the tumour tissues, the most frequent being chromosomal gains at 1p, 12q, 17, 8q, 19 and 20 and losses at 13q, 6q and 9p. Survival was found to be longer in those patients who presented a smaller number of losses (⩽2) in the tumorous chromosomes. Conclusions: Although numerous genetic changes are presented by deciduoid mesotheliomas, certain chromosomal regions are preferentially affected. The clinical outcome for this mesothelioma subtype is predicted by the number of losses.

Familial pleural mesothelioma with environmental asbestos exposure: losses of DNA sequences by comparative genomic hybridization (CGH)

1. Garber JE. Follow-up study of a family group exhibiting dominant inheritance for a syndrome including intestinal polyps, osteomas, fibromas and epidermal cysts. Am. J. Hum. Genet. 1962; 14; 1376– 1390. 2. Gurbuz AK, Giardiello FM, Petersen GM et al. Desmoid tumours in familial adenomatous polyposis. Gut 1994; 35; 377–381. 3. Lees CD, Hermann RE. Familial polyposis coli associated with bile duct cancer. Am. J. Surg. 1981; 141; 378–380. 4. Honore LH, Davey SJ. Endometrial carcinoma in young women. A report of four cases. J. Reprod. Med. 1989; 34; 845–849. 5. Beroud C, Soussi T. APC gene: database of germline and somatic mutations in human tumors and cell lines. Nucleic Acids Res. 1996; 24; 121–124. 6. Knudson AG Jr. Mutation and cancer: statistical study of retinoblastoma. Proc. Natl Acad. Sci. USA 1971; 68; 820–823.

High Wilms’ tumour gene (WT1) expression and low mitotic count are independent predictors of survival in diffuse peritoneal mesothelioma

Scattone A, Serio G, Marzullo A, Nazzaro P, Corsi F, Cocca M P, Mattoni M, Punzi A, Gentile M, Buonadonna A L & Pennella A 
(2012) Histopathology60, 472–481 
High Wilms’ tumour gene (WT1) expression and low mitotic count are independent predictors of survival in diffuse peritoneal mesothelioma

Characterization of a complex chromosome aberration in two cases of peritoneal mesothelioma arising primarily in the hernial sac

Malignant mesotheliomas of the hernial sac are uncommon and only a few cases have been diagnosed incidentally during herniorrhaphy procedures. The prognosis is poor and patient management is difficult because current treatment modalities do little to prolong survival. Molecular markers could be useful to identify potential therapeutic targets. Using microarray‐comparative genomic hybridization (aCGH), two cases of peritoneal mesothelioma that were found incidentally at the time of hernia repair, were investigated. A high number of genetic aberrations was detected in both cases. The gains were prevalent. The tumors showed identical lost regions at 2q13, 6q25.3, 6q26, 6q26→q27, 9q31.1→9q31.3, 10p15.3, 11q13.2, 13q14.2, 19q13.42→q43, and gains at 1p36.33, 3q29, 5p15.33, 7p22.3, 10p15.1→10p14, 11q13.2, 12q24.23, 12q24.33, 16p13.3, 17p13.3, 18p11.31, 19q13.43, 21q21.1→q21.2, 22q11.1→q11.22, Xp21.2, Xq28. Survival was longer in the patient with a lower total number of genetic defects. aCGH provides a high‐resolution map of copy number changes that may be critical to mesothelioma progression.

Genomic changes of chromosomes 8p23.1 and 1q21: novel mutations in malignant mesothelioma

INTRODUCTION Malignant mesothelioma is an aggressive malignancy of the thoracic cavity caused by prior asbestos exposure. In the peritoneum the mesothelioma is an extremely rare condition. In the present preliminary study, high-resolution array-comparative genomic hybridization (a-CGH) was performed to identify genetic imbalances in a series of malignant peritoneal mesothelioma cases. MATERIALS AND METHODS Between 1990 and 2008, among the cases recorded in the Apulia Mesothelioma Register, we found 22 peritoneal mesothelioma cases. CGH-array was performed on samples from all patients. RESULTS The CGH-array analysis revealed multiple chromosomal imbalances. Interestingly, deletion at 8p23.1 was observed in 12 cases. Furthermore, another novel deletion at 1q21 was present in 11. Often, 1q21 and 8p23.1 losses were present in the same patient (7 cases). Losses of BAP1 and CDKN2A loci were not detected. DISCUSSION The region at 8p23.1 contains the beta-defensin gene cluster (DEF) and 1q21 contains ubiquitin conjugating enzyme E2 (UBE2Q1). We hypotesized that the loss of function of ubiquitination, as well as of the defensins, could play an important role in the initial development and subsequent progression of mesothelioma.

Pathologic Grading of Malignant Pleural Mesothelioma: An Evidence-Based Proposal

Introduction: A pathologic grading system (PGS) for malignant pleural mesothelioma (MPM) is warranted to better identify different risk categories of patients, plan therapeutic options, and activate clinical trials. Methods: A series of 940 patients with MPM (328 in a training set and 612 in a validation set) that was diagnosed between October 1980 and June 2015 at the participant institutions was retrospectively assembled. A PGS was constructed by attributing to each histologic parameter, independent at multivariate analysis with excellent reproducibility (&kgr; > 0.75), different scores based on the increase in corresponding hazard ratios. The relevant PGS score thus ranged from 0 to 8 points for individual patients with MPM. Conclusions: The PGS was constructed by taking into consideration the histological subtyping of MPM (epithelioid/biphasic = 0 points; sarcomatoid = 2 points), necrosis (absent = 0 points versus present = 1 point), mitotic count per 1 mm2 (cutoffs as follows: 1–2 = 0 points, 3–5 = 1 point, 6–9 = 2 points, or ≥10 = 4 points), and Ki‐67 labeling index based on 2000 cells (<30% = 0 points versus ≥30 = 1 point), all of which are independent factors in both patient sets after adjustment for stage and age at diagnosis. No heterogeneity was seen across the validation centers (p = 0.19). Epithelioid/biphasic MPM patterning and biopsy versus resection did not affect survival, whereas the PGS outperformed mitotic count and Ki‐67 LI in both the training (area under the curve receiver operating characteristic = 0.76) and validation sets (area under the curve receiver operating characteristic = 0.73) (p < 0.01). Patient survival progressively deteriorated from a score of 0 (median times of 26.3 and 26.9 months) to a score 1 to 3 (median times of 12.8 and 14.4 months) and a score of 4 to 8 (median times of 3.7 and 7.7 months) in both sets of patients, with the hazard ratio for a 1‐point increase in score being 1.46 (95% confidence interval: 1.36–1.56) in the training set and 1.28 (95% confidence interval: 1.22–1.34) in the validation set (after adjustment for age and [when available] tumor stage). The PGS was effective even in subgroup analysis (epithelioid, biphasic, and sarcomatoid tumors). Discussion: A simple and reproducible multiparametric PGS effectively predicted survival in patients with MPM.