Complex roles of inflammasomes in carcinogenesis.

The central role of chronic inflammation in the promotion of tumor growth is supported by a broad range of experimental and clinical evidence. However, the molecular mechanisms converting transient inflammatory tissue reactions into a tumor-promoting microenvironment remain largely elusive. Because inflammasomes have been shown to regulate the proinflammatory cytokines interleukin 1β (IL-1β) and IL-18, they have been implicated in the relationship between tumor genesis/progression and inflammation. For instance, many cancers have been directly linked to inflammasome-mediated sterile inflammation, where a blockade of IL-1β and IL-18 has been shown to inhibit tumor growth. On the other hand, inflammasome activation also has potent antitumorigenic effects, where malignant precursor cells are eliminated through pyroptotic cell death. Indeed, inflammasome activity can even increase the efficacy of certain chemotherapies. Here, we review the current understanding on the complex and sometimes contradictory role of inflammasomes in carcinogenesis.

Dual role of the antioxidant enzyme peroxiredoxin 6 in skin carcinogenesis.

The antioxidant enzyme peroxiredoxin 6 (Prdx6) is a key regulator of the cellular redox balance, particularly under stress conditions. We identified Prdx6 as an important player in different phases of skin carcinogenesis. Loss of Prdx6 in mice enhanced the susceptibility to skin tumorigenesis, whereas overexpression of Prdx6 in keratinocytes of transgenic mice had the opposite effect. The tumor-preventive effect of Prdx6, which was observed in a human papilloma virus 8-induced and a chemically induced tumor model, was not due to alterations in keratinocyte proliferation, apoptosis, or in the inflammatory response. Rather, endogenous and overexpressed Prdx6 reduced oxidative stress as reflected by the lower levels of oxidized phospholipids in the protumorigenic skin of Prdx6 transgenic mice and the higher levels in Prdx6-knockout mice than in control animals. In contrast to its beneficial effect in tumor prevention, overexpression of Prdx6 led to an acceleration of malignant progression of existing tumors, revealing a dual function of this enzyme in the pathogenesis of skin cancer. Finally, we found strong expression of PRDX6 in keratinocytes of normal human skin and in the tumor cells of squamous cell carcinomas, indicating a role of Prdx6 in human skin carcinogenesis. Taken together, our data point to the potential usefulness of Prdx6 activators or inhibitors for controlling different stages of skin carcinogenesis.

Effects of KRAS, BRAF, NRAS, and PIK3CA mutations on the efficacy of cetuximab plus chemotherapy in chemotherapy-refractory metastatic colorectal cancer: a retrospective consortium analysis.

Background Following the discovery that mutant KRAS is associated with resistance to anti-epidermal growth factor receptor (EGFR) antibodies, the tumours of patients with metastatic colorectal cancer are now profiled for seven KRAS mutations before receiving cetuximab or panitumumab. However, most patients with KRAS wild-type tumours still do not respond. We studied the effect of other downstream mutations on the efficacy of cetuximab in, to our knowledge, the largest cohort to date of patients with chemotherapy-refractory metastatic colorectal cancer treated with cetuximab plus chemotherapy in the pre-KRAS selection era. Methods 1022 tumour DNA samples (73 from fresh-frozen and 949 from formalin-fixed, paraffin-embedded tissue) from patients treated with cetuximab between 2001 and 2008 were gathered from 11 centres in seven European countries. 773 primary tumour samples had sufficient quality DNA and were included in mutation frequency analyses; mass spectrometry genotyping of tumour samples for KRAS, BRAF, NRAS, and PIK3CA was done centrally. We analysed objective response, progression-free survival (PFS), and overall survival in molecularly defined subgroups of the 649 chemotherapy-refractory patients treated with cetuximab plus chemotherapy. Findings 40.0% (299/747) of the tumours harboured a KRAS mutation, 14.5% (108/743) harboured a PIK3CA mutation (of which 68.5% [74/108] were located in exon 9 and 20.4% [22/108] in exon 20), 4.7% (36/761) harboured a BRAF mutation, and 2.6% (17/644) harboured an NRAS mutation. KRAS mutants did not derive benefit compared with wild types, with a response rate of 6.7% (17/253) versus 35.8% (126/352; odds ratio [OR] 0.13, 95% CI 0.07-0.22; p<0.0001), a median PFS of 12. weeks versus 24 weeks (hazard ratio [HR] 1 98, 1.66-2.36; p<0.0001), and a median overall survival of 32 weeks versus 50 weeks (1.75, 1.47-2.09; p<0.0001). In KRAS wild types, carriers of BRAF and NRAS mutations had a significantly lower response rate than did BRAF and NRAS wild types, with a response rate of 8.3% (2/24) in carriers of BRAF mutations versus 38.0% in BRAF wild types (124/326; OR 0.15, 95% CI 0.02-0.51; p=0.0012); and 7.7% (1/13) in carriers of NRAS mutations versus 38.1% in NRAS wild types (110/289; OR 0.14, 0.007-0.70; p=0.013). PIK3CA exon 9 mutations had no effect, whereas exon 20 mutations were associated with a worse outcome compared with wild types, with a response rate of 0.0% (0/9) versus 36.8% (121/329; OR 0.00,0.00-0.89; p=0.029), a median PFS of 11.5 weeks versus 24 weeks (HR 2.52, 1.33-4.78; p=0.013), and a median overall survival of 34 weeks versus 51 weeks (3.29, 1.60-6.74; p=0.0057). Multivariate analysis and conditional inference trees confirmed that, if KRAS is not mutated, assessing BRAF, NRAS, and PIK3CA exon 20 mutations (in that order) gives additional information about outcome. Objective response rates in our series were 24.4% in the unselected population, 36.3% in the KRAS wild-type selected population, and 41.2% in the KRAS, BRAF, NRAS, and PIK3CA exon 20 wild-type population. Interpretation While confirming the negative effect of KRAS mutations on outcome after cetuximab, we show that BRAF, NRAS, and PIK3CA,exon 20 mutations are significantly associated with a low response rate. Objective response rates could be improved by additional genotyping of BRAF, NRAS, and PIK3CA exon 20 mutations in a KRAS wild-type population.

Early investigational drugs that target epidermal growth factor receptors for the treatment of head and neck cancer.

INTRODUCTION: Squamous-cell carcinoma of the head and neck (SCCHN) remains a challenging clinical problem, due to the persistent high rate of local and distant failures and the occurrence of secondary primaries. For locally advanced SCCHN, a combination of chemotherapy (CT), radiation or surgery is often used, but there are limitations, which may reduce compliance. Molecular targeted therapies, namely anti-EGFR treatments, are in development with the aim of improving clinical outcomes and mitigating treatment-related toxicities. AREAS COVERED: This review provides an overview of early investigational drugs that target EGFR for the treatment of SCCHN and discusses the ongoing trials in this domain. EXPERT OPINION: Targeted therapies are increasingly used in oncology, especially in SCCHN. Cetuximab has demonstrated a significant improvement in the treatment outcome, both as a curative treatment in combination with radiation therapy and as a palliative treatment in combination with CT; however, it failed to show any benefit in combination with concomitant chemoradiotherapy. Presently, there are many new agents, including monoclonal antibodies and small-molecule tyrosine kinase inhibitors, which are either currently under investigation for or which warrant further investigation for treating SCCHN. The discovery of predictive factors that help to identify patients most likely to respond to EGFR inhibitors as well as patient-customized therapies would help to improve patient outcomes in the future.

Information provision and information needs in adult survivors of childhood cancer.

BACKGROUND: Knowledge about their past medical history is central for childhood cancer survivors to ensure informed decisions in their health management. Knowledge about information provision and information needs in this population is still scarce. We thus aimed to assess: (1) the information survivors reported to have received on disease, treatment, follow-up, and late effects; (2) their information needs in these four domains and the format in which they would like it provided; (3) the association with psychological distress and quality of life (QoL). PROCEDURE: As part of the Follow-up survey of the Swiss Childhood Cancer Survivor Study, we sent a questionnaire to all survivors (≥18 years) who previously participated to the baseline survey, were diagnosed with cancer after 1990 at an age of <16 years. RESULTS: Most survivors had received oral information only (on illness: oral: 82%, written: 38%, treatment: oral: 79%, written: 36%; follow-up: oral: 77%, written: 23%; late effects: oral: 68%, written: 14%). Most survivors who had not previously received any information rated it as important, especially information on late effects (71%). A large proportion of survivors reported current information needs and would like to receive personalized information especially on late effects (44%). Survivors with higher information needs reported higher psychological distress and lower QoL. CONCLUSIONS: Survivors want to be more informed especially on possible late effects, and want to receive personalized information. Improving information provision, both qualitatively and quantitatively, will allow survivors to have better control of their health and to become better decision makers.

New validated prognostic models and prognostic calculators in patients with low-grade gliomas diagnosed by central pathology review: a pooled analysis of EORTC/RTOG/NCCTG phase III clinical trials.

Background In a previous study, the European Organisation for Research and Treatment of Cancer (EORTC) reported a scoring system to predict survival of patients with low-grade gliomas (LGGs). A major issue in the diagnosis of brain tumors is the lack of agreement among pathologists. New models in patients with LGGs diagnosed by central pathology review are needed. Methods Data from 339 EORTC patients with LGGs diagnosed by central pathology review were used to develop new prognostic models for progression-free survival (PFS) and overall survival (OS). Data from 450 patients with centrally diagnosed LGGs recruited into 2 large studies conducted by North American cooperative groups were used to validate the models. Results Both PFS and OS were negatively influenced by the presence of baseline neurological deficits, a shorter time since first symptoms (<30 wk), an astrocytic tumor type, and tumors larger than 5 cm in diameter. Early irradiation improved PFS but not OS. Three risk groups have been identified (low, intermediate, and high) and validated. Conclusions We have developed new prognostic models in a more homogeneous LGG population diagnosed by central pathology review. This population better fits with modern practice, where patients are enrolled in clinical trials based on central or panel pathology review. We could validate the models in a large, external, and independent dataset. The models can divide LGG patients into 3 risk groups and provide reliable individual survival predictions. Inclusion of other clinical and molecular factors might still improve models' predictions.

Invasive lobular breast cancer and its variants: How special are they for systemic therapy decisions?

The WHO classification of breast tumors distinguishes, besides invasive breast cancer 'of no special type' (former invasive ductal carcinoma, representing 60-70% of all breast cancers), 30 special types, of which invasive lobular carcinoma (ILC) is the most common (5-15%). We review the literature on (i) the specificity and heterogeneity of ILC biology as documented by various analytical techniques, including the results of molecular testing for risk of recurrence; (ii) the impact of lobular histology on prediction of prognosis and effect of systemic therapies in patients. Though it is generally admitted that ILC has a better prognosis than IDC, is endocrine responsive, and responds poorly to chemotherapy, currently available data do not unanimously support these assumptions. This review demonstrates some lack of specific data and a need for improving clinical research design to allow oncologists to make informed systemic therapy decisions in patients with ILC. Importantly, future studies should compare various endpoints in ILC breast cancer patients among the group of hormonosensitive breast cancer.

Fourth European Conference on Infections in Leukaemia (ECIL-4): guidelines for diagnosis, prevention, and treatment of invasive fungal diseases in paediatric patients with cancer or allogeneic haemopoietic stem-cell transplantation.

Invasive opportunistic fungal diseases (IFDs) are important causes of morbidity and mortality in paediatric patients with cancer and those who have had an allogeneic haemopoietic stem-cell transplantation (HSCT). Apart from differences in underlying disorders and comorbidities relative to those of adults, IFDs in infants, children, and adolescents are unique with respect to their epidemiology, the usefulness of diagnostic methods, the pharmacology and dosing of antifungal agents, and the absence of interventional phase 3 clinical trials for guidance of evidence-based decisions. To better define the state of knowledge on IFDs in paediatric patients with cancer and allogeneic HSCT and to improve IFD diagnosis, prevention, and management, the Fourth European Conference on Infections in Leukaemia (ECIL-4) in 2011 convened a group that reviewed the scientific literature on IFDs and graded the available quality of evidence according to the Infectious Diseases Society of America grading system. The final considerations and recommendations of the group are summarised in this manuscript.

SV40-induced expression of calretinin protects mesothelial cells from asbestos cytotoxicity and may be a key factor contributing to mesothelioma pathogenesis.

The calcium-binding protein calretinin has emerged as a useful marker for the identification of mesotheliomas of the epithelioid and mixed types, but its putative role in tumor development has not been addressed previously. Although exposure to asbestos fibers is considered the main cause of mesothelioma, undoubtedly, not all mesothelioma patients have a history of asbestos exposure. The question as to whether the SV40 virus is involved as a possible co-factor is still highly debated. Here we show that increased expression of SV40 early gene products in the mesothelial cell line MeT-5A induces the expression of calretinin and that elevated calretinin levels strongly correlate with increased resistance to asbestos cytotoxicity. Calretinin alone mediates a significant part of this protective effect because cells stably transfected with calretinin cDNA were clearly more resistant to the toxic effects of crocidolite than mock-transfected control cells. Down-regulation of calretinin by antisense methods restored the sensitivity to asbestos toxicity to a large degree. The protective effect observed in clones with higher calretinin expression levels could be eliminated by phosphatidylinositol 3-kinase (PI3K) inhibitors, implying an important role for the PI3K/AKT signaling (survival) pathway in mediating the protective effect. Up-regulation of calretinin, resulting from either asbestos exposure or SV40 oncoproteins, may be a common denominator that leads to increased resistance to asbestos cytotoxicity and thereby contributes to mesothelioma carcinogenesis.

Decision making and management of gliomas: practical considerations.

Over the last decade, diagnostic options and introduction of novel treatments have expanded the armamentarium in the management of malignant glioma. Combined chemoradiotherapy has become the standard of care in glioblastoma up to the age of 70 years, while treatment in elderly patients or with lower grade glioma is less well defined. Molecular markers define different disease subtypes and allow for adapted treatment selection. This review focuses on simple questions arising in the daily management of patients.

Presence of an oligodendroglioma-like component in newly diagnosed glioblastoma identifies a pathogenetically heterogeneous subgroup and lacks prognostic value: central pathology review of the EORTC_26981/NCIC_CE.3 trial.

Glioblastoma (GBM) is a morphologically heterogeneous tumor type with a median survival of only 15 months in clinical trial populations. However, survival varies greatly among patients. As part of a central pathology review, we addressed the question if patients with GBM displaying distinct morphologic features respond differently to combined chemo-radiotherapy with temozolomide. Morphologic features were systematically recorded for 360 cases with particular focus on the presence of an oligodendroglioma-like component and respective correlations with outcome and relevant molecular markers. GBM with an oligodendroglioma-like component (GBM-O) represented 15% of all confirmed GBM (52/339) and was not associated with a more favorable outcome. GBM-O encompassed a pathogenetically heterogeneous group, significantly enriched for IDH1 mutations (19 vs. 3%, p = 0.003) and EGFR amplifications (71 vs. 48%, p = 0.04) compared with other GBM, while co-deletion of 1p/19q was found in only one case and the MGMT methylation frequency was alike (47 vs. 46%). Expression profiles classified most of the GBM-O into two subtypes, 36% (5/14 evaluable) as proneural and 43% as classical GBM. The detection of pseudo-palisading necrosis (PPN) was associated with benefit from chemotherapy (p = 0.0002), while no such effect was present in the absence of PPN (p = 0.86). In the adjusted interaction model including clinical prognostic factors and MGMT status, PPN was borderline nonsignificant (p = 0.063). Taken together, recognition of an oligodendroglioma-like component in an otherwise classic GBM identifies a pathogenetically mixed group without prognostic significance. However, the presence of PPN may indicate biological features of clinical relevance for further improvement of therapy.

Expression of Fas (APO-1/CD95) and Fas ligand (FasL) in human neuroblastoma.

BACKGROUND AND PROCEDURE: To determine the possible role of Fas/FasL system in the particularly heterogeneous behaviour of neuroblastoma (NB), we have measured the functional expression of Fas and its ligand, FasL, in primary neuroblastoma samples and cell lines by immunohistochemistry and flow cytometry. RESULTS: Our results reveal that while Fas expression is associated with low stage and more mature tumors, heterogeneous FasL expression was mostly detected in high stage tumors, with our apparent correlation to MYCN amplification. Flow cytometric analysis of cell lines demonstrated a high expression of Fas in epithelial-type, HLA class I positive cell lines, which was lost upon activation with phorbol esters. In contrast, Fas ligand was detected in only a small subset of cell lines. CONCLUSIONS: In some cell lines, cytotoxic assays revealed the ability of NB-associated Fas receptor to transduce an apoptotic signal upon triggering. The pattern of functional Fas/FasL expression in tumours and cell lines suggests that this system may be involved in the evasion of highly malignant neuroblastoma cells to host immune response.

Longer survival for patients with alternative lengthening of telomeres (ALT) glioblastoma multiforme is due to a less aggressive phenotype and not to improved response to adjuvant therapy

Introduction: The Alternative Lengthening of Telomeres (ALT) mechanism is a significant prognostic factor for longer survival in patients with GBM, irrespective of age. The reasons for this are unknown. We considered two possibilities; firstly that ALT identifies a subset of less aggressive GBMs, or alternatively, a group of tumours that respond more favourably to adjuvant therapy. Methods: ALT was determined by staining for ALT Associated PML Bodies (APBs) in archival tissue in a retrospective analysis of 573 GBM patients. IDH1 mutation was determined by immunohistochemistry in a subset of these. Results: We identified the presence of the telomerase-independent ALT in 15% of GBM patients and found that it correlated with survival (22% of ALT patients survive more than 2 years compared to 9% for non-ALT). This survival advantage was independent of surgery type (biopsy or full resection) and treatment (radiotherapy and chemotherapy). Interestingly ALT conferred a significant survival advantage for patients who only received surgery (13.3 months compared to 5.5 months) (19% vs 1% .2 year survival). This survival benefit was also observed in GBM patients who received surgery and radiotherapy (18.5% vs 2.4%. 2 year survival), but less so for chemotherapy (21% vs 17% . 2 year survival). For the ALT patients the fraction surviving more than 2 years did not improve significantly with adjuvant therapy. IDH1 mutation also associated with ALT. Conclusions: These data indicate ALT+ tumours are biologically distinct and associated with improved patient survival, probably due to less aggressive/invasive growth. However they respond poorly to current adjuvant treatment and therefore new therapies are urgently needed for this group.

Risk factors for survival after lung metastasectomy in colorectal cancer patients: systematic review and meta-analysis.

ABSTRACT  Despite the lack of randomized trials, lung metastasectomy is currently proposed for colorectal cancer patients under certain conditions. Many retrospective studies have reported different prognostic factors of poorer survival, but eligibility for pulmonary metastasectomy remains determined by the complete resection of all pulmonary metastases. The aim of this review is to clarify which pre-operative risk factors reported in systematic reviews or meta-analysis are determinant for survival in colorectal metastatic patients. Different criteria have been now identified to select which patient will really benefit from lung metastasectomy.