Rôle de la MGMT et implications cliniques dans les tumeurs cérébrales [Role of MGMT and clinical applications in brain tumours]

Glioblastoma multiforme is the most common and most malignant primary brain tumour with a dismal prognosis. The advent of new chemotherapies with alkylating agents crossing the blood-brain barrier, like temozolomide, have permitted to notably ameliorate the survival of a subgroup of patients. Improved outcome was associated with epigenetic silencing of the MGMT (O6-methylguanin methyltransferase) gene by promotor methylation, thereby blocking its repair capability, thus rendering the alkylating agents more effective. This particularity can be tested by methylation specific PCR on resected tumour tissue, best on fresh frozen biopsies, and allows identification of patients more susceptible to respond favourably to the treatment.

KIT mutations and dose selection for imatinib in patients with advanced gastrointestinal stromal tumours.

A recent randomized EORTC phase III trial, comparing two doses of imatinib in patients with advanced gastrointestinal stromal tumours (GISTs), reported dose dependency for progression-free survival. The current analysis of that study aimed to assess if tumour mutational status correlates with clinical response to imatinib. Pre-treatment samples of GISTs from 377 patients enrolled in phase III study were analyzed for mutations of KIT or PDGFRA by combination of D-HPLC and direct sequencing of tumour genomic DNA. Mutation types were correlated with patients' survival data. The presence of exon 9-activating mutations in KIT was the strongest adverse prognostic factor for response to imatinib, increasing the relative risk of progression by 171% (P<0.0001) and the relative risk of death by 190% (P<0.0001) when compared with KIT exon 11 mutants. Similarly, the relative risk of progression was increased by 108% (P<0.0001) and the relative risk of death by 76% (P=0.028) in patients without detectable KIT or PDGFRA mutations. In patients whose tumours expressed an exon 9 KIT oncoprotein, treatment with the high-dose regimen resulted in a significantly superior progression-free survival (P=0.0013), with a reduction of the relative risk of 61%. We conclude that tumour genotype is of major prognostic significance for progression-free survival and overall survival in patients treated with imatinib for advanced GISTs. Our findings suggest the need for differential treatment of patients with GISTs, with KIT exon 9 mutant patients benefiting the most from the 800 mg daily dose of the drug.

Epithelial to mesenchymal transition in the pathogenesis of uterine malignant mixed Müllerian tumours: the role of ubiquitin proteasome system and therapeutic opportunities.

Malignant mixed Müllerian tumours (malignant mixed mesodermal tumours, MMMT) of the uterus are metaplastic carcinomas with a sarcomatous component and thus they are also called carcinosarcomas. It has now been accepted that the sarcomatous component is derived from epithelial elements that have undergone metaplasia. The process that produces this metaplasia is epithelial to mesenchymal transition (EMT), which has recently been described as a neoplasia-associated programme shared with embryonic development and enabling neoplastic cells to move and metastasise. The ubiquitin proteasome system (UPS) regulates the turnover and functions of hundreds of cellular proteins. It plays important roles in EMT by being involved in the regulation of several pathways participating in the execution of this metastasis-associated programme. In this review the specifi c role of UPS in EMT of MMMT is discussed and therapeutic opportunities from UPS manipulations are proposed.

Invasive mould infections: a multi-disciplinary update.

Systemic fungal infections remain a significant cause of mortality in neutropenic and immunocompromised patients, despite advances in their diagnosis and treatment. The incidence of such infections is rising due to the use of intensive chemotherapy regimens in patients with solid tumours or haematological cancers, the increasing numbers of allogeneic haematopoietic stem cell and solid organ transplants, and the use of potent immunosuppressive therapy in patients with autoimmune disorders. In addition, the epidemiology of systemic fungal infections is changing, with atypical species such as Aspergillus terreus and zygomycetes becoming more common. Treatment has traditionally focused on empirical therapy, but targeted pre-emptive therapy in high-risk patients and prophylactic antifungal treatment are increasingly being adopted. New treatments, including lipid formulations of amphotericin B, second-generation broad-spectrum azoles, and echinocandins, offer effective antifungal activity with improved tolerability compared with older agents; the potential impact of these treatments is reflected in their inclusion in current treatment and prophylaxis guidelines. New treatment strategies, such as aerosolized lipid formulations of amphotericin B, may also reduce the burden of mortality associated with systemic fungal infections. The challenge is to identify ways of coupling potentially effective treatments with early and reliable identification of patients at highest risk of infection.

Influence of segmental chromosome abnormalities on survival in children over the age of 12 months with unresectable localised peripheral neuroblastic tumours without MYCN amplification.

BACKGROUND: The prognostic impact of segmental chromosome alterations (SCAs) in children older than 1 year, diagnosed with localised unresectable neuroblastoma (NB) without MYCN amplification enrolled in the European Unresectable Neuroblastoma (EUNB) protocol is still to be clarified, while, for other group of patients, the presence of SCAs is associated with poor prognosis. METHODS: To understand the role of SCAs we performed multilocus/pangenomic analysis of 98 tumour samples from patients enrolled in the EUNB protocol. RESULTS: Age at diagnosis was categorised into two groups using 18 months as the age cutoff. Significant difference in the presence of SCAs was seen in tumours of patients between 12 and 18 months and over 18 months of age at diagnosis, respectively (P=0.04). A significant correlation (P=0.03) was observed between number of SCAs per tumour and age. Event-free (EFS) and overall survival (OS) were calculated in both age groups, according to both the presence and number of SCAs. In older patients, a poorer survival was associated with the presence of SCAs (EFS=46% vs 75%, P=0.023; OS=66.8% vs 100%, P=0.003). Moreover, OS of older patients inversely correlated with number of SCAs (P=0.002). Finally, SCAs provided additional prognostic information beyond histoprognosis, as their presence was associated with poorer OS in patients over 18 months with unfavourable International Neuroblastoma Pathology Classification (INPC) histopathology (P=0.018). CONCLUSIONS: The presence of SCAs is a negative prognostic marker that impairs outcome of patients over the age of 18 months with localised unresectable NB without MYCN amplification, especially when more than one SCA is present. Moreover, in older patients with unfavourable INPC tumour histoprognosis, the presence of SCAs significantly affects OS.

Cobalamin deficiency resulting in a rare haematological disorder: a case report.

INTRODUCTION: We present the case of a patient with a cobalamin deficiency resulting in pancytopaenia, emphasizing the importance to define, diagnose and treat cobalamin deficiency. CASE PRESENTATION: A 52-year-old man from the Democratic Republic of Congo presented to the emergency department with shortness of breath and a sore tongue. Physical examination was unremarkable. His haemoglobin was low and the peripheral blood smear revealed pancytopaenia with a thrombotic microangiopathy. The findings were low cobalamin and folate levels, and high homocysteine and methylmalonate levels. Pernicious anaemia with chronic atrophic gastritis was confirmed by gastric biopsy and positive antiparietal cell and anti-intrinsic factor antibodies. Cobalamin with added folate was given. Six months later, the patient was asymptomatic. CONCLUSION: Cobalamin deficiency should always be ruled out in a patient with pancytopaenia. Our case report highlights a life-threatening cobalamin deficiency completely reversible after treatment.

A gene expression signature that distinguishes desmoid tumours from nodular fasciitis.

Nodular fasciitis (NF) is a rapidly growing cellular mass composed of fibroblasts/myofibroblasts, usually localized in subcutaneous tissues, that typically undergoes fibrosis and almost never recurs. Desmoid tumours (DTs) are rare forms of fibroblastic/myofibroblastic growth that arise in deep soft tissues, display a propensity for local infiltration and recurrence, but fail to metastasize. Given that both entities are primarily fibroblastic/myofibroblastic lesions with overlapping histological features, their gene expression profiles were compared to identify differentially expressed genes that may provide not only potential diagnostic markers, but also clues as to the pathogenesis of each disorder. Differentially expressed transcripts (89 clones displaying increased expression in DTs and 246 clones displaying increased expression in NF) included genes encoding several receptor and non-receptor tyrosine kinases (EPHB3, PTPRF, GNAZ, SYK, LYN, EPHA4, BIRC3), transcription factors (TWIST1, PITX2, EYA2, OAS1, MITF, TCF20), and members of the Wnt signalling pathway (AXIN2, WISP1, SFRP). Remarkably, almost one-quarter of the differentially expressed genes encode proteins associated with inflammation and tissue remodelling, including members of the interferon (IFN), tumour necrosis factor (TNF), and transforming growth factor beta (TGF-beta) signalling pathways as well as metalloproteinases (MMP1, 9, 13, 23), urokinase plasminogen activator (PLAU), and cathepsins. The observations provide the first comparative molecular characterization of desmoid tumours and nodular fasciitis and suggest that selected tyrosine kinases, transcription factors, and members of the Wnt, TGF-beta, IFN, and TNF signalling pathways may be implicated in influencing and distinguishing their fate.

Current state of knowledge on neuroendocrine small bowel tumours: non-systematic review of the literature based on one case.

More than 60% of neuroendocrine tumours, also called carcinoids, are localised within the gastrointestinal tract. Small bowel neuroendocrine tumours have been diagnosed with increasing frequency over the past 35 years, being the second most frequent tumours of the small intestine. Ileal neuroendocrine tumours diagnosis is late because patients have non-specific symptoms. We have proposed to illustrate as an example the case of a patient, and on its basis, to make a brief review of the literature on small bowel neuroendocrine tumours, resuming several recent changes in the field, concerning classification criteria of these tumours and new recommendations and current advances in diagnosis and treatment. This patient came to our emergency department with a complete bowel obstruction, along with a 2-year history of peristaltic abdominal pain, vomits and diarrhoea episodes. During emergency laparotomy, an ileal stricture was observed, that showed to be a neuroendocrine tumour of the small bowel.

Nilotinib in the treatment of advanced gastrointestinal stromal tumours resistant to both imatinib and sunitinib.

Patients diagnosed with advanced gastrointestinal stromal tumours (GISTs) who are resistant or intolerant to both imatinib and second-line sunitinib have a poor prognosis and few therapeutic options. We evaluated the efficacy of nilotinib, a novel tyrosine kinase inhibitor (TKI) in patients pretreated with imatinib and sunitinib. Fifty-two consecutive patients treated with oral nilotinib, 400mg twice daily, within the nilotinib compassionate use programme in 12 European cancer centres, were included in this retrospective analysis. Median age was 59 years (range 24-80), and all patients had WHO performance score better than 3. All patients had failed both imatinib and sunitinib pretreatment, either due to progressing GIST (96%) or intolerance (4%). Five patients (10%; 95% confidence interval (CI) 2-18) responded to nilotinib and 19 patients (37%; 95% CI 24-50) achieved a disease stabilisation. Nilotinib was generally well tolerated, but six patients (12%) discontinued treatment due to intolerance. Median progression-free survival of nilotinib treatment was 12 weeks (95% CI 9-15; range 0-104) and median overall survival was 34 weeks (95% CI 3-65; range 2-135). Nilotinib is active in GIST resistant to both imatinib and sunitinib. These results warrant further investigation of nilotinib in GIST.

Assessment of vascular invasion by bone and soft tissue tumours of the limbs: usefulness of MDCT angiography.

OBJECTIVE: To evaluate the accuracy of computed tomography angiography (CTA) in predicting arterial encasement by limb tumours, by comparing CTA with surgical findings (gold standard). METHODS: Preoperative CTA images of 55 arteries in 48 patients were assessed for arterial status: cross-sectional CTA images were scored as showing a fat plane between artery and tumour (score 0), slight contact between artery and tumour (score 1), partial arterial encasement (score 2) or total arterial encasement (score 3). Reformatted CTA images were assessed for arterial displacement, rigid wall, stenosis or occlusion. At surgery, arteries were classified as free or surgically encased; 45 arteries were free and 10 were surgically encased. RESULTS: Multivariate logistic regression identified the axial CTA score as a relevant predictor for arterial encasement and subsequent vascular intervention during surgery. All sites where CTA showed a fat plane between the tumour and the artery were classified as free at surgery (n = 28/28). The sensitivity of total arterial encasement on CTA (score 3) was 90%, specificity 93%, accuracy 93% and positive likelihood ratio 13.5. CONCLUSION: CTA evidence of total arterial encasement is a highly specific indication of arterial encasement. The presence of fat between the tumour and the artery on CTA rules out arterial involvement at surgery.

An EORTC Phase II study of caspofungin as first-line therapy of invasive aspergillosis in haematological patients.

OBJECTIVES: Caspofungin was evaluated as first-line monotherapy of invasive aspergillosis (IA) in patients with haematological malignancies and undergoing autologous transplants. METHODS: Adults with proven or probable IA, defined strictly according to EORTC-MSG criteria, were eligible. Those with possible IA were enrolled, but were not evaluable for efficacy unless upgraded to proven/probable disease within 7 days of registration based on investigations performed within 48 h after enrolment. Caspofungin dosage was 70 mg (day 1) followed by 50 mg/day. The primary endpoint was the proportion of patients with complete or partial response at the end of caspofungin therapy in the modified intention to treat (MITT) group; secondary endpoints were response and survival at day 84 and safety. RESULTS: In the MITT group (n = 61), 75% of patients had cancer not in remission (relapsing or refractory), 85% were neutropenic at enrolment and 49% had a Karnofsky score of < or =50. At end of treatment, 1 and 19 patients had complete and partial response, respectively [success rate 33% (20/61)], 9 (15%) achieved stabilization and 31 (51%) had disease progression. One patient was not evaluable. The 6 and 12 week survival rates were 66% (40/61) and 53% (32/60), respectively. Baseline characteristics associated with survival at day 84 were an underlying disease in remission (not relapsing or refractory) and Karnofsky score. Recovery from neutropenia at the end of treatment was also significantly associated with survival. No serious drug-related adverse events or discontinuations due to drug-related adverse events were observed. CONCLUSIONS: Caspofungin provided an observed response rate compatible with the null hypothesis of a true response rate of < or =35%. Underlying disease-related factors had a major impact on results.

Cardiovascular drug interactions with tyrosine kinase inhibitors

Imatinib mesylate, a selective inhibitor of tyrosine kinases, has excellent efficacy in the treatment of chronic myeloid leukaemia (CML) and gastrointestinal stromal tumour (GIST). Inducing durable responses and achieving prolonged survival, it has become the standard of care for the treatment of these diseases. It has opened the way to the development of additional tyrosine kinase inhibitors (TKIs), including sunitinib, nilotinib, dasatinib and sorafenib, all indicated for the treatment of various haematological malignancies and solid tumours. TKIs are prescribed for prolonged periods and are often taken by patients with - notably cardiovascular - comorbidities. Hence TKIs are regularly co-administered with cardiovascular drugs, with a considerable risk of potentially harmful drug-drug interactions due to the large number of agents used in combination. However, this aspect has received limited attention so far, and a comprehensive review of the published data on this important topic has been lacking. We review here the available data and pharmacological mechanisms of interactions between commonly prescribed cardiovascular drugs and the TKIs marketed at present. Regular updating of the literature on this topic will be mandatory, as will the prospective reporting of unexpected clinical observations, given the fact that these drugs have been only recently marketed.