High RRM1 Expression Is Associated with Adverse Outcome in Patients with Cisplatin/Vinorelbine-treated Malignant Pleural Mesothelioma.

BACKGROUND/AIM: A possible predictive impact of ribonucleotide-reductase subunit-1 (RRM1) on vinorelbine efficacy in non-small cell lung cancer (NSCLC) has been previously reported. The present study aimed to further explore this finding in malignant pleural mesothelioma (MPM). MATERIALS AND METHODS: Seventy-one patients with MPM receiving first-line chemotherapy with cisplatin-vinorelbine (CiV group, n=54) or carboplatin-pemetrexed (CaP group, n=17) were included. Formalin-fixed paraffin-embedded tumor specimens were analyzed by immunohistochemistry (IHC) for RRM1 expression using an H-score. RESULTS: In 66 patients eligible for IHC, the H-score was ≥upper quartile in 21 (RRM1-positive) and

A biomarker profile for predicting efficacy of cisplatin-vinorelbine therapy in malignant pleural mesothelioma.

PURPOSE: Malignant pleural mesothelioma (MPM) has a dismal prognosis. Treatment results may be improved by biomarker-directed therapy. We investigated the baseline expression and impact on outcome of predictive biomarkers ERCC1, BRCA1, and class III ß-tubulin in a cohort of MPM patients treated with cisplatin-vinorelbine. We further explored the possibility of combining markers into a treatment-response profile to increase the predictive power. METHODS: Formalin-fixed paraffin-embedded tumor specimens from 54 MPM patients included in a phase II trial were evaluated for ERCC1, BRCA1, and class III ß-tubulin by immunohistochemistry (IHC). Immunostaining was quantified by an H-score and dichotomized according to upper quartile values. The ERCC1- and class III ß-tubulin-status classified patients as treatment resistant (ERCC1 positive + class III ß-tubulin positive) or treatment responsive (ERCC1 negative + class III ß-tubulin negative). The remaining marker combinations were considered inconclusive. RESULTS: Fifty patients had tumor tissue available for IHC. Eleven had a responsive profile, and nine had a resistant profile. Thirty patients had an inconclusive profile. Median progression-free survival (PFS) was 6.7 months in the treatment-resistant group, 15.3 months in the treatment-responsive group, and 8.1 months in the inconclusive group (log-rank p = 0.03). Multivariate analysis revealed that treatment-resistant patients had a decreased PFS and overall survival (OS) compared with the treatment-responsive patients (HR 6.45, CI 95 % [2.02-20.64] p = 0.002 and HR 4.64, CI 95 % [1.56-13.79], p = 0.006, respectively). BRCA1 status was associated with neither PFS nor OS. CONCLUSION: Combined negative ERCC1 and class III ß-tubulin immunostaining is associated with significantly prolonged PFS and OS in MPM patients receiving cisplatin-vinorelbine therapy.

The diagnostic value of immunohistochemically detected methylthioadenosine phosphorylase deficiency in malignant pleural mesotheliomas.

AIMS: Malignant pleural mesothelioma (MPM) often causes diagnostic difficulties for pathologists. We assessed whether loss of methylthioadenosine phosphorylase (MTAP), a key enzyme in the intracellular recycling of adenosine triphosphate (ATP) often deleted in MPM, could be detected with immunohistochemistry (IHC) and used as a diagnostic marker for MPM. METHODS AND RESULTS: We used IHC to detect MTAP in a cohort of 99 MPMs and 39 reactive mesothelial proliferations (RP) (reactive mesothelial hyperplasia n = 33, reactive pleural fibrosis n = 6). MTAP staining was assessed by an H score. The median H score of the RP cohort was set as a reference point. Cases with H scores below this reference point were considered to have decreased MTAP expression. We found that 64 of 99 (65%) of the investigated MPMs had decreased MTAP expression, while this was only true for nine of 39 (23%) of the RPs (P = 0.001). We further evaluated MTAP expression in a cohort of coagulated pleural effusions from 14 patients with MPM and 20 patients with RP by using a double-staining technique with Wilms tumour 1 (WT1) as a mesothelial marker. In these samples, decreased MTAP expression diagnosed MPM with a sensitivity of 71% and a specificity of 90%. CONCLUSIONS: Decreased MTAP expression could potentially be useful in combination with other markers in the diagnosis of MPM.

Low ERCC1 expression in malignant pleural mesotheliomas treated with cisplatin and vinorelbine predicts prolonged progression-free survival.

INTRODUCTION: The relationship between excision repair cross-complementation group 1 (ERCC1) expression and outcome, in patients with malignant pleural mesothelioma (MPM), treated with cisplatin/vinorelbine combination-therapy, was retrospectively evaluated in a patient population from a previously published phase II clinical trial. METHODS: The study population consisted of 54 inoperable patients with MPM enrolled between 2003 and 2006. ERCC1 expression was evaluated by immunohistochemistry (IHC) on the formalin-fixed paraffin-embedded diagnostic biopsies. The immunoreaction was quantified using an H-score (staining intensity multiplied by a proportion score based on the percentage of stained tumor cells). The cutoff point was chosen as the median H-score in a cohort of non-neoplastic pleural samples from patients with benign thoracic diseases. The tumor samples were separated according to this cutoff point into ERCC1-negative (H-score ≤ median) and ERCC1-positive (H-score > median) cases. RESULTS: Fifty patients had tumor tissue available for IHC. There were 20 ERCC1-positive and 30 ERCC1-negative tumors. There was a significant correlation between negative ERCC1 status and long progression-free survival (PFS). Median PFS was 10.9 months in the ERCC1-negative group, opposed to 6.7 months in the ERCC1-positive group (p = 0.053). Multivariate Cox regression showed ERCC1 to be the only variable significantly associated with PFS, and ERCC1-positive patients had a significantly shorter time to progression compared with ERCC1-negative patients (hazard ratios, 2.24; 95% confidence interval, 1.16-4.34; p = 0.0163). We found no association between ERCC1 status and overall survival. CONCLUSION: Our retrospective study in MPM patients treated with cisplatin/vinorelbine suggests that low ERCC1 expression, evaluated by IHC, may predict longer PFS, a result that warrants further validation.

MMSET is highly expressed and associated with aggressiveness in neuroblastoma.

MMSET (WHSC1/NSD2) is a SET domain-containing histone lysine methyltransferase the expression of which is deregulated in a subgroup of multiple myelomas with the t(4;14)(p16;q32) translocation associated with poor prognosis. Recent studies have shown that MMSET mRNA levels are increased in other tumor types as well. We have carried out immunohistochemical staining of tissue microarrays and found that MMSET protein is frequently and highly expressed in neuroblastoma (MMSET positive in 75% of neuroblastomas, n = 164). The expression level of MMSET in neuroblastomas was significantly associated with poor survival, negative prognostic factors, and metastatic disease. Moreover, a subset of neuroblastomas for which pre- and postchemotherapy biopsies were available displayed a strong decrease in MMSET protein levels after chemotherapy. In agreement with neuroblastomas becoming more differentiated after treatment, we show that retinoic acid-induced differentiation of human neuroblastoma cells in vitro also leads to a strong decrease in MMSET levels. Furthermore, we show that the high levels of MMSET in normal neural progenitor cells are strongly downregulated during differentiation. Importantly, we show that MMSET is required for proliferation of neuroblastoma cells and brain-derived neural stem cells. Taken together, our results suggest that MMSET is implicated in neuroblastomagenesis possibly by supporting proliferation of progenitor cells and negatively regulating their differentiation. In this respect, MMSET might be a strong candidate therapeutic target in a subset of neuroblastomas with unfavorable prognosis.

Peripheral neuroblastic tumours in eastern Denmark 1972-2002.

The peripheral neuroblastic tumour group includes neuroblastoma, ganglioneuroblastoma and ganglioneuroma. Neuroblastoma is the most common extracranial solid tumour of childhood. We have evaluated the histological presentation, MYCN gene status, and clinical course of peripheral neuroblastic tumours diagnosed and treated in eastern Denmark from 1972-2002. 125 patients were diagnosed with peripheral neuroblastic tumour during this 30-year period. The histological material was reviewed and classified into three categories in accordance with the Shimada system: unfavourable histology, favourable histology, and benign tumours. MYCN status was determined by fluorescent in situ hybridization (FISH) on paraffin sections from the primary tumour. Clinical information was obtained from hospital records. Diagnostic likelihood ratios in the two groups were calculated to compare the ability of MYCN status and histological classification to predict 5-year outcome. 41 tumours showed unfavourable histology, 30 tumours showed favourable histology, 11 were benign, and 43 were unclassifiable due to limited amounts of primary tumour, bad preservation or inaccessibility of the primary tumour necessitating metastatic tumour biopsy for diagnosis. Unfavourable histology was associated with widespread disease (p<0.001). The overall 5-year survival rate was 45%, which correlates well with the European survival rate reported for this time period. The 5-year survival rate in the unfavourable group was 30% as compared to 100% in the favourable histology group (p<0.001). The survival rate in the unclassifiable group was 13%. 26% of the neuroblastomas were MYCN amplified. MYCN amplification was associated with undifferentiated histology, a histological subtype of the unfavourable histology group (p<0.001). For unfavourable histology the positive diagnostic likelihood ratio was 2.9 as compared to 4.7 for MYCN amplification. The study has confirmed the prognostic significance of the Shimada system in the peripheral neuroblastic tumour group in a retrospective material, and has also demonstrated the prognostic superiority of MYCN compared to histological classification, thus reducing the necessary amounts of tumour tissue.