Explore the vast range of titles available.

Soft tissue sarcoma (STS) is a rare malignancy of mesenchymal origin classified into more than 50 different subtypes with distinct clinical and pathologic features. Despite the poor prognosis in the majority of patients, only modest improvements in treatment strategies have been achieved, largely due to the rarity and heterogeneity of these tumors. Therefore, the discovery of new prognostic and predictive biomarkers, together with new therapeutic targets, is of enormous interest. Phosphatase and tensin homolog (PTEN) is a well-known tumor suppressor that commonly loses its function via mutation, deletion, transcriptional silencing, or protein instability, and is frequently downregulated in distinct sarcoma subtypes. The loss of PTEN function has consequent alterations in important pathways implicated in cell proliferation, survival, migration, and genomic stability. PTEN can also interact with other tumor suppressors and oncogenic signaling pathways that have important implications for the pathogenesis in certain STSs. The aim of the present review is to summarize the biological significance of PTEN in STS and its potential role in the development of new therapeutic strategies.

Background Expression levels of CD133, a cancer stem cell marker, and of the α-subunit of the dystroglycan (α-DG) complex, have been previously reported to be altered in colorectal cancers. Methods Expression levels of CD133 and α-DG were assessed by immunohistochemistry in a series of colon cancers and their prognostic significance was evaluated. Results Scattered cells positive for CD133 were rarely detected at the bases of the crypts in normal colonic mucosa while in cancer cells the median percentage of positive cells was 5% (range 0–80). A significant correlation was observed with pT parameter and tumor stage but not with tumor grade and N status. Recurrence and death from disease were significantly more frequent in CD133-high expressing tumors and Kaplan-Meier curves showed a significant separation between high vs low expressor groups for both disease-free (p = 0.002) and overall (p = 0.008) survival. Expression of α-DG was reduced in a significant fraction of tumors but low α-DG staining did not correlate with any of the classical clinical-pathological parameters. Recurrence and death from the disease were significantly more frequent in α-DG-low expressing tumors and Kaplan-Meier curves showed a significant separation between high vs low expressor tumors for both disease-free (p = 0.02) and overall (p = 0.02) survival. Increased expression of CD133, but not loss of α-DG, confirmed to be an independent prognostic parameters at a multivariate analysis associated with an increased risk of recurrence (RR = 2.4; p = 0.002) and death (RR = 2.3; p = 0.003). Conclusions Loss of α-DG and increased CD133 expression are frequent events in human colon cancer and evaluation of CD133 expression could help to identify high-risk colon cancer patients.

Background Much attention has been recently focused on the role of cancer stem cells (CSCs) in the initiation and progression of solid malignancies. Since CSCs are able to proliferate and self-renew extensively, thus sustaining tumor growth, the identification of CSCs through their antigenic profile might have relevant clinical implications. In this context, CD133 antigen has proved to be a marker of tumor cells with stemness features in several human malignancies. The aim of the study was to investigate the clinical role of the immunohistochemically assessed expression of CD133 in a large single Institution series of ovarian cancer patients. Methods The study included 160 cases admitted to the Gynecologic Oncology Unit, Catholic University of Campobasso and Rome. CD133 antigen was identified by the monoclonal mouse anti-CD133-1 antibody (clone CD133 Miltenyi biotec). Results In the overall series CD133 positive tumor cells were observed in 50/160 (31.2%) cases. A diffuse cytoplasmic pattern was identified in 30/50 (60.0%), while an apical cytoplasmic pattern was found in 20/50 (40.0%) of CD133 positive tumors. As of September 2008, the median follow up was 37 months (range: 2–112). During the follow up period, progression and death of disease were observed in 123 (76.9%), and 88 (55.0%) cases, respectively. There was no difference in TTP between cases with negative (median TTP = 23 months) versus positive CD133 expression (median TTP = 24 months) (p value = 0.3). Similar results were obtained for OS. When considering the TTP and OS curves according to the pattern of CD133 expression, a trend to a worse prognosis for cases with diffuse cytoplasmic versus the apical cytoplasmic pattern was documented, although the statistical significance was not reached. Conclusion The immunohistochemical assessment of CD133 expression seems not to provide additional prognostic information in ovarian cancer patients. The role of the different pattern of CD133 immunoreaction deserves further investigation in a larger series.

Well-differentiated liposarcoma (WDLPS), one of the most common human sarcomas, is poorly responsive to radiation and chemotherapy, and the lack of animal models suitable for experimental analysis has seriously impeded functional investigation of its pathobiology and development of effective targeted therapies. Here, we show that zebrafish expressing constitutively active Akt2 in mesenchymal progenitors develop WDLPS that closely resembles the human disease. Tumor incidence rates were 8% in p53 wild-type zebrafish, 6% in p53 heterozygotes, and 29% in p53-homozygous mutant zebrafish (P = 0.013), indicating that aberrant Akt activation collaborates with p53 mutation in WDLPS pathogenesis. Analysis of primary clinical specimens of WDLPS, and of the closely related dedifferentiated liposarcoma (DDLPS) subtype, revealed immunohistochemical evidence of AKT activation in 27% of cases. Western blot analysis of a panel of cell lines derived from patients with WDLPS or DDLPS revealed robust AKT phosphorylation in all cell lines examined, even when these cells were cultured in serum-free media. Moreover, BEZ235, a small molecule inhibitor of PI3K and mammalian target of rapamycin that effectively inhibits AKT activation in these cells, impaired viability at nanomolar concentrations. Our findings are unique in providing an animal model to decipher the molecular pathogenesis of WDLPS, and implicate AKT as a previously unexplored therapeutic target in this chemoresistant sarcoma.

Immunotherapy with monoclonal antibodies against programmed cell death (PD-1), such as nivolumab and pembrolizumab, has significantly improved the survival of patients with metastatic non-small cell lung cancer (NSCLC). In order to determine the subset of patients that can benefit most from these therapies, biomarkers such as programmed death ligand-1 (PD-L1) have been proposed. However, the predictive and prognostic role of the use of PD-L1 is controversial. Anti-PD-L1 immunohistochemistry may not represent the actual status of the tumour because of individual variability and tumour heterogeneity. Additionally, there may be analytical variability due to the use of different assays and antibodies to detect PD-L1. Moreover PD-L1 expression is also regulated by oncogenic drivers in NSCLC, such as epidermal growth factor receptor (EGFR), echinoderm microtubule-associated protein-like 4 (EML4) fusion with anaplastic lymphoma kinase (ALK), and Kirsten rat sarcoma viral oncogene homolog (KRAS). Preclinical studies have shown the potential role of targeted therapy in immune escape mechanisms in NSCLC cells. This review summarizes current literature data on the heterogeneity of PD-L1 expression and the relationship with such factors and with clinicopathological features of NSCLC.

Background:Despite high metastasis rates, adjuvant/neoadjuvant systemic therapy for localised soft tissue sarcoma (STS) is not used routinely. Progress requires tailoring therapy to features of tumour biology, which need exploration in well-documented cohorts. Hypoxia has been linked to metastasis in STS and is targetable. This study evaluated hypoxia prognostic markers in the phase III adjuvant radiotherapy VorteX trial.Methods:Formalin-fixed paraffin-embedded tumour biopsies, fresh tumour/normal tissue and blood were collected before radiotherapy. Immunohistochemistry for HIF-1α, CAIX and GLUT1 was performed on tissue microarrays and assessed by two scorers (one pathologist). Prognostic analysis of disease-free survival (DFS) used Kaplan-Meier and Cox regression.Results:Biobank and outcome data were available for 203 out of 216 randomised patients. High CAIX expression was associated with worse DFS (hazard ratio 2.28, 95% confidence interval: 1.44-3.59, P<0.001). Hypoxia-inducible factor-1α and GLUT1 were not prognostic. Carbonic anhydrase IX remained prognostic in multivariable analysis.Conclusions:The VorteX-Biobank contains tissue with linked outcome data and is an important resource for research. This study confirms hypoxia is linked to poor prognosis in STS and suggests that CAIX may be the best known marker. However, overlap between single marker positivity was poor and future work will develop an STS hypoxia gene signature to account for tumour heterogeneity.

Purpose Thymic epithelial tumors (TETs) are rare tumors of the mediastinum, with an estimated incidence of about 3 cases per 100,000 inhabitants. Although anthracycline- and platinum-based chemotherapy is an active treatment for TETs, novel systemic therapeutic options are especially needed for metastatic disease, which is virtually incurable. On the basis of the radiographic response obtained with imatinib (Novartis Pharma, Basel, Switzerland) in a patient with thymic carcinoma harboring the V560del c-KIT mutation, a phase II trial was initiated at the Department of Molecular and Clinical Oncology and Endocrinology of University “Federico II of Naples” with the purpose to test imatinib in TETs. Methods Imatinib was daily delivered at the dose of 400 mg to patients affected by TETs, who had progressed after at least one chemotherapy regimen. Positivity of c-KIT on immunohistochemistry was not mandatory for study entry. Radiographic responses were measured by CT scans performed every 3 months, according to the RECIST criteria. Toxicity was graded according to the Common Toxicity Criteria of the National Cancer Institute, version 3.0. Results Fifteen patients with advanced TETs were enrolled from March 2008 to May 2010. Three patients presented with thymic carcinomas. Two of these three patients presented c-kit expression on immunohistochemistry. No patient harbored a known c-kit activating mutation. Imatinib was very well tolerated, with no toxicity-related death. Diarrhea and migraine were the most frequent events, occurring both in 20% of patients, but were manageable and mild. No radiographic responses were recorded. Median progression-free survival was 3 months (interquartile range, 2.5–4). Median overall survival was not reached. The study was terminated before it reached its target accrual of 42 patients, because of the lack of responses and low accrual rate. Conclusions This trial indicates the lack of effectiveness of imatinib in unselected patients with thymic epithelial tumors. Nevertheless, imatinib may represent a valuable option in selected patients with TETs, such as those harboring the V560del c-KIT mutation.

Aim. The purpose of the present study was to characterize the morphological features of thymoma metastases in lymph nodes and to evaluate the possibility of their subtyping according to the 2004 WHO classification of thymus tumors. Materials and Methods. We reviewed 210 thymoma cases in our series of thymic epithelial tumors (TET), including their recurrences and lymphogenous metastases. Three cases of lymph node metastases, one case occurring synchronously with the primary tumor and one synchronously with the first relapse (both in intrathoracic location) and one case of metastasis observed in a laterocervical lymph node subsequently to two thymoma relapses were found. Results. The metastatic nodes were variably but extensively involved in all cases. The histological features were similar in both primary tumors and metastases. Thymoma metastases were subtyped according to the WHO classification as B3 (one case) and B2 (two cases), and distinctive features in comparison to metastatic epithelial neoplasias from other sites were observed. Conclusion. Thymoma lymph node metastases, although rare, can be subtyped according to the WHO classification on the basis of their morphological and immunohistochemical features. Clinically, the presence of nodal metastases may herald subsequent relapses and further metastases even in extrathoracic sites.

Introduction Ganglioneuroblastomas (GNBs) are embryonic neoplasms, whose behaviour are not well established; 80% of cases occur in the first decade, while only two cases in the adulthood had been reported. Clinical report This 60-year-old female presented with a 2-month history of headache, vertigo, amnesia. A right brachio-crural hemiparesis, right homonymous hemianopsia and sensorial dysphasia was evident. A CT scan revealed a left occipital lesion. MRI scan was not performed because the patient had an anal sphincter stimulator. Three years before thyroidectomy for a follicular carcinoma was performed. A total body CT scan was negative. A left occipital craniotomy was carried out and a solid mass was totally excised. A diagnosis of GNB was made from histopathological examination and immunohistochemistry. Post-operatively the patient recovered from the hemiparesis while the visual disturbances persisted. She underwent fractioned radiotherapy (60 Gy) and chemotherapy with Temozolomide. She remained disease free 18 months after diagnosis. A CT scan showed no evidence of recurrence. Discussion Recent observations suggest that in spite of an embryonal appearance, these tumours are circumscribed and have a better prognosis than malignant gliomas.