MGMT promoter hypermethylation correlates with a survival benefit from temozolomide in patients with recurrent anaplastic astrocytoma but not glioblastoma

AimsTo investigate the correlation between O⁶-methylguanine-DNA-methyltransferase (MGMT) promoter methylation and benefit from temozolomide in patients with recurrent high-grade glioma.Patients and methodsA real-time, quantitative, methylation-specific PCR assay was performed on archival tissue blocks from patients treated with temozolomide at the first recurrence.ResultsA subgroup of 38 patients who were chemotherapy-naive at recurrence was analysed (22 glioblastoma, 12 anaplastic astrocytoma [AA] and 4 anaplastic oligoastrocytoma [AOA]); none had 1p/19q loss. Among 10 (26%) patients with a hypermethylated MGMT promoter, none experienced disease progression within the first two treatment cycles compared with 12 of 28 (43%) patients with an unmethylated promoter (p = 0.016). By Cox multivariate analysis, tumour grade and MGMT promoter methylation correlated with time to progression (p < 0.05); MGMT promoter methylation correlated with superior overall survival in AA/AOA but not in glioblastoma.ConclusionsMGMT promoter methylation predicted a survival benefit in patients with 1p/19q intact AA/AOA treated with temozolomide at recurrence.     

An international validation study of the EORTC brain cancer module (EORTC QLQ-BN20) for assessing health-related quality of life and symptoms in brain cancer patients

AimsThe psychometric properties of the EORTC QLQ-BN20, a brain cancer-specific HRQOL questionnaire, have been previously determined in an English-speaking sample of patients. This study examined the validity and reliability of the questionnaire in a multi-national, multi-lingual study.MethodsQLQ-BN20 data were selected from two completed phase III EORTC/NCIC clinical trials in brain cancer (N = 891), including 12 languages. Experimental treatments were surgery followed by radiotherapy (RT) and adjuvant PCV chemotherapy or surgery followed by concomitant RT plus temozolomide (TMZ) chemotherapy and adjuvant TMZ chemotherapy. Standard treatment consisted of surgery and postoperative RT alone. The psychometrics of the QLQ-BN20 were examined by means of multi-trait scaling analyses, reliability estimation, known groups validity testing, and responsiveness analysis.ResultsAll QLQ-BN20 items correlated more strongly with their own scale (r > 0.70) than with other QLQ-BN20 scales. Internal consistency reliability coefficients were high (all α ? 0.70). Known-groups comparisons yielded positive results, with the QLQ-BN20 distinguishing between patients with differing levels of performance status and mental functioning. Responsiveness of the questionnaire to changes over time was acceptable.ConclusionThe QLQ-BN20 demonstrates adequate psychometric properties and can be recommended for use in conjunction with the QLQ-C30 in assessing the HRQOL of brain cancer patients in international studies.     

Impact of age on choice of chemotherapy and outcome in advanced colorectal cancer

BackgroundAge is a major risk factor for development of sporadic colorectal cancer but elderly patients are underrepresented in clinical trials and are potentially offered chemotherapy less often.MethodsData were obtained from South Australian Clinical Registry for advanced colorectal cancer between 1st February 2006 and 9th September 2010. Patients who received chemotherapy were analysed to assess the impact of single versus combination chemotherapy and to assess the outcome in two age cohorts, age <70 years and ⩾70 years.ResultsOut of a total of 1745 patients in the database during this time period, 951 (54.5%) received systemic chemotherapy. 286 (30%) received first line therapy (median age 74 years) with single agent fluoropyrimidine and 643 patients (68%) received first line combination chemotherapy (median age 64 years). The median overall survival of patients receiving first line combination chemotherapy was 23.9 months compared to 17.2 months for those who received single agent fluoropyrimidine (p < 0.001). Combination chemotherapy was given to 81% of patients aged <70 years compared to 53% of those ⩾70 years. There was no significant difference in median overall survival of patients receiving chemotherapy by age cohort, 21.3 months for age <70 years and 21.1 months for age ⩾70 years (p = 0.4).ConclusionTreatment outcomes are comparable in both the elderly and younger patients. Patients who received initial combination chemotherapy were younger and had a longer median overall survival. In our study, age appeared to influence the treatment choices but not necessarily outcome.     

Temozolomide and irinotecan (TEMIRI regimen) as salvage treatment of irinotecan-sensitive advanced colorectal cancer patients bearing MGMT methylation

BackgroundNon-randomized studies showed that temozolomide (TMZ) achieves an average 10% response rate in heavily pretreated metastatic colorectal cancer (mCRC) patients with promoter methylation of the DNA repair gene O6-methylguanine-DNA methyltransferase (MGMT). In this phase II trial, irinotecan and temozolomide (TEMIRI) combination regimen was assessed in irinotecan-sensitive, MGMT methylated/microsatellite stable (MSS) pretreated mCRC patients.Patients and methodsKey inclusion criteria were centrally confirmed MGMT methylation by methylation-specific PCR, MSS mCRC, progression after at least two prior chemotherapy regimens for advanced disease and irinotecan-free interval >3 months. TEMIRI (TMZ 150 mg/m² on days 1–5 plus irinotecan 100 mg/m² on days 1, 15 q28 days) was administered for six cycles, followed by maintenance with TMZ. The primary end point was overall response rate (ORR). Exploratory translational analyses included MGMT immunohistochemistry (IHC) and methyl-BEAMing (MB).ResultsBetween December 2014 and June 2017, 25 patients were enrolled. The primary end point was met, since six patients achieved a partial response [ORR 24%, 95% confidence interval (CI) 11% to 43%]. At a median follow-up of 15.6 months, median progression-free survival (mPFS) and overall survival (mOS) were 4.4 and 13.8 months, respectively. Only four (16%) patients had ≥ grade 3 (CTCAE 4.0) adverse events. All patients whose cancer was MGMT-positive IHC were non-responders. Consistently, patients with MGMT-negative/low tumors had a significantly longer mPFS than others (6.9 versus 2.0 months; hazard ratio = 0.29, 95% CI 0.02–0.41; P = 0.003) and a non-significant trend for longer mOS. MB testing showed similar accuracy.ConclusionsTEMIRI regimen is a safe and active option in pre-treated, irinotecan-sensitive mCRC patients with MGMT methylation.     

The efficacy of adjuvant chemotherapy with 5-fluorouracil in colorectal cancer depends on the mismatch repair status

AimsThe aim of this study is to evaluate if mismatch repair (MMR) defective colorectal cancer has a different response to adjuvant 5-fluorouracil (5-FU) chemotherapy in a cohort of patients prospectively followed during 5 years.MethodsThe cohort included 754 surgically treated patients with colorectal cancer. MMR status was diagnosed by MLH1 and MSH2 immunohistochemistry and microsatellite instability analysis. Median follow-up was 49.2 months (range 1–73). At inclusion, 505 patients were diagnosed as TNM II or III stage, analysis of the efficacy of adjuvant chemotherapy was made on this population. Adjuvant chemotherapy was applied to 248 patients (98.2% 5-FU based).ResultsMMR deficiency was found in 76 patients (10.1%). No differences were found in overall survival (log-rank p = 0.3) or disease-free survival (log-rank p = 0.3) regarding MMR status. Adjuvant chemotherapy improves survival in patients in the II or III stage, but this improvement is only evident in patients with MMR-competent tumours (log-rank p = 0.00001). Survival of patients with MMR-defective tumours does not improve with adjuvant chemotherapy (log-rank p = 0.7). A multivariate analysis showed an independent effect of the interaction between MMR status and adjuvant chemotherapy (Hazard ratio 2.04; 95% confidence interval: 1.42–2.93).ConclusionIn a cohort of colorectal cancer patients, those with MMR-deficient tumours seem not to benefit from 5-FU-based chemotherapy.     

Combined temozolomide and sunitinib treatment leads to better tumour control but increased vascular resistance in O6-methylguanine methyltransferase-methylated gliomas

IntroductionCombined antiangiogenic and cytotoxic treatment represents an appealing treatment approach for malignant glioma. In this study we characterised the antitumoural and microvascular consequences of sunitinib (Su) and temozolomide (TMZ) therapy and verified the ideal treatment protocol, with special focus on a potential therapeutic window for combined scheduling.Materials and MethodsO⁶-Methylguanine methyltransferase (MGMT) status was analysed by pyrosequencing. Tumour growth of subcutaneous xenografts was assessed under different treatment protocols (TMZ, SU, SU followed by TMZ, TMZ followed by SU, combined TMZ/SU). Intravital microscopy (dorsal skinfold chamber model) assessed microvascular consequences. Immunohistochemistry included tumour and endothelial cell proliferation, apoptosis and vascular pericyte coverage. Real-time polymerase chain reaction (RT-PCR) analysed the expression of angiogenesis-related pathways in response to therapy.ResultsCombined TMZ/SU resulted in significantly reduced tumour growth compared to either monotreatment (TMZ: 106 ± 13mm³; SU: 114 ± 53mm³; TMZ/SU: 34 ± 7mm³) by additional antiangiogenic effects and synergistic induction of apoptosis versus TMZ monotreatment. Sequential treatment protocols did not show additive antitumour responses. TMZ/SU aggravated vascular resistance mechanisms characterised by significantly higher blood flow rate (TMZ: 74 ± 34 μl/s; SU: 164 ± 36 μl/s; TMZ/SU: 254 ± 95 μl/s), reduced permeability (TMZ: 1.05 ± 0.02; SU: 0.99 ± 0.07; TMZ/SU: 0.89 ± 0.05) and recovery of pericyte–endothelial interactions (TMZ: 89 ± 7%; SU: 67 ± 9%, TMZ/SU:80 ± 10%) versus either monotreatment. Vascular resistance was paralleled by an increase in Ang-1 and Tie-2 and by the downregulation of Dll4.ConclusionSequential application of TMZ and SU in the angiogenic window does not add antitumour efficacy to monotherapy. Simultaneous application yields beneficial tumour control due to additive antiangiogenic and proapoptotic effects. Combined treatment may aggravate pericyte-mediated vascular resistance mechanisms by altering Ang-1–Tie-2 and Dll4/Notch pathways.     

Characteristics and outcome of patients with ganglioneuroblastoma, nodular subtype: a report from the INRG project

AimDescribe characteristics and outcome of INRG patients with ganglioneuroblastoma, nodular subtype (GNBn).Patients and methodsAmongst 4071 patients in the INRG database with known INPC histological category, 232 patients with GNBn were identified. Patients were categorised by clinical, pathological and genetic characteristic. For event-free survival (EFS) and overall survival (OS), Kaplan–Meier curves and lifetables were generated, and the outcome of subgroups was compared using log rank test.ResultsPatients with GNBn were older (83% >18 months), a higher proportion had unfavourable INPC pathology (83%), and rarely had MYCN gene amplified tumours (2%). Otherwise, the distribution of clinical and biological risk factors including stage, ferritin, initial treatment, grade of NB differentiation, MKI, 11q, 1p, and 17q were similar between patients with GNBn and the overall INRG cohort. EFS and OS were 54% ± 5% and 68% ± 5%, respectively. A cohort with superior outcome was identified: OS for GNBn patients younger than 18 months was 95% ± 5% (n = 39) and for GNBn patients with stage 1, 2, 3, 4s was 95% ± 3% (n = 125). Conversely, a poor outcome sub-group could also be identified: OS for stage 4 was 35% ± 7% (n = 107).ConclusionsPatients with GNBn tumours are rare and have a very heterogeneous outcome. Except for LDH and MKI, the factors prognostic in the overall NB cohort are also prognostic in patients with GNBn. Similar to the overall NB cohort, patients with GNBn older than 18 months of age, with stage 4 disease represent a high-risk sub-group and should be considered for aggressive treatment upfront.     

Addition of cetuximab to chemotherapy as first-line treatment for KRAS wild-type metastatic colorectal cancer: pooled analysis of the CRYSTAL and OPUS randomised clinical trials

BackgroundThe CRYSTAL and OPUS randomised clinical trials demonstrated that adding cetuximab to first-line chemotherapy in patients with KRAS wild-type metastatic colorectal cancer (mCRC) significantly improved treatment outcome compared with chemotherapy alone. The objective of this pooled analysis was to further investigate these findings in patients with KRAS wild-type tumours using extended survival data and following an enhancement in the ascertainment rate of KRAS and BRAF tumour mutation status from these studies.MethodsPooled individual patient data from each study were analysed for overall survival (OS), progression-free survival (PFS) and best overall response rate (ORR) in patients evaluable for KRAS and BRAF mutation status. Treatment arms were compared according to mutation status using log–rank and Cochran–Mantel–Haenszel tests.ResultsIn 845 patients with KRAS wild-type tumours adding cetuximab to chemotherapy led to a significant improvement in OS (hazard ratio [HR] 0.81; p = 0.0062), PFS (HR 0.66; p < 0.001) and ORR (odds ratio 2.16; p < 0.0001). BRAF mutations were detected in 70/800 evaluable tumours. No significant differences were found in outcome between the treatment groups in these patients. Prognosis was worse in each treatment arm for patients with BRAF tumour mutations compared with those with BRAF wild-type tumours.ConclusionAnalysis of pooled data from the CRYSTAL and OPUS studies confirms the consistency of the benefit obtained across all efficacy end-points from adding cetuximab to first-line chemotherapy in patients with KRAS wild-type mCRC. BRAF mutation does not appear to be a predictive biomarker in this setting, but is a marker of poor prognosis.     

Pre-treatment haemoglobin levels and the prediction of response to neoadjuvant chemotherapy in breast cancer

AimsA low pre-treatment haemoglobin level has been shown to negatively influence outcome in the treatment of tumours of the cervix, bladder and head and neck by radiotherapy. The purpose of this study was to assess the influence of baseline haemoglobin levels on the response to neoadjuvant chemotherapy for breast cancer.Materials and methodsOne hundred and thirty-nine women receiving neoadjuvant chemotherapy for operable breast tumours (T2–4, N0–1, M0) were accessed from our prospective database. Women were treated between March 1999 and June 2004. The median age was 47 years (range 25–70). Most women were treated with 5-fluorouracil, epirubicin and cyclophosphamide chemotherapy (122/139 patients). Baseline haemoglobin levels were compared for clinical responders (partial or complete) and non-responders (stable or progressive disease) using Student's t test and logistic regression. The analysis was adjusted for nodal status, tumour size, tumour grade and menopausal status.ResultsThe overall response rate was 84.9% (118/139), with a complete clinical response in 24.5% (34/139). Mean haemoglobin levels were 13.3 g/dl in responders and 13.4 g/dl in non-responders (range 7.9–15.8). The distributions of haemoglobin levels were not significantly different when comparing either responders with non-responders or ‘good’ responders with ‘poor’ responders (P = 0.70 and P = 0.32, respectively). If haemoglobin is treated as a binary variable using 12.0 g/dl as the threshold, there is a non-significant trend towards a reduction in the probability of achieving a good response if baseline haemoglobin is below 12.0 g/dl (odds ratio = 0.26, confidence interval = 0.06–1.21; P = 0.086). The rate of complete pathological response was 4.3% (6/139). The mean haemoglobin level in these patients was 14.2 g/dl (range = 12.8–15.7), but the small numbers precluded further analysis.ConclusionsThere is no evidence for an influence of pre-treatment haemoglobin levels on the clinical response to neoadjuvant chemotherapy in breast cancer. It is unlikely that correction of anaemia above that which is warranted clinically will improve outcomes.     

The differential impact of microsatellite instability as a marker of prognosis and tumour response between colon cancer and rectal cancer

BackgroundMicrosatellite instability (MSI) is a distinct molecular phenotype of colorectal cancer related to prognosis and tumour response to 5-fluorouracil (5-FU)-based chemotherapy. We investigated the differential impact of MSI between colon and rectal cancers as a marker of prognosis and chemotherapeutic response.MethodsPCR-based MSI assay was performed on 1125 patients. Six hundred and sixty patients (58.7%) had colon cancer and 465 patients (41.3%) had rectal cancer.ResultsAmong 1125 patients, 106 (9.4%) had high-frequency MSI (MSI-H) tumours. MSI-H colon cancers (13%) had distinct phenotypes including young age at diagnosis, family history of colorectal cancer, early Tumor, Node, Metastasis (TNM) stage, proximal location, poor differentiation, and high level of baseline carcinoembryonic antigen (CEA), while MSI-H rectal cancers (4.3%) showed similar clinicopathological characteristics to MSS/MSI-L tumours except for family history of colorectal cancer. MSI-H tumours were strongly correlated with longer disease free survival (DFS) (P = 0.005) and overall survival (OS) (P = 0.009) than MSS/MSI-L tumours in colon cancer, while these positive correlations were not observed in rectal cancers. The patients with MSS/MSI-L tumours receiving 5-FU-based chemotherapy showed good prognosis (P = 0.013), but this positive association was not observed in MSI-H (P = 0.104).ConclusionThese results support the use of MSI status as a marker of prognosis and response to 5-FU-based chemotherapy in patients with colon cancers. Further study is mandatory to evaluate the precise role of MSI in patients with rectal cancers and the effect of 5-FU-based chemotherapy in MSI-H tumours.     

A comparison of Hickman line- and Port-a-Cath-associated complications in patients with solid tumours undergoing chemotherapy

AimsTo compare the complication rates of Hickman lines and Port-a-Caths in patients undergoing infusional chemotherapy for solid tumours.Materials and methodsA single institution retrospective analysis comparing complication rates for 30 Hickman lines and 33 Port-a-Caths inserted for chemotherapy in adults with solid tumours was carried out.ResultsPatients were well matched in terms of primary site and chemotherapy regimen. In both cases, over 85% were inserted radiologically under local anaesthetic. The total time in situ for Hickman lines and Port-a-Caths was 3539 days (median 83, range 6–585) and 5783 days (median 158, range 20–456), respectively. The complication rate for Hickman lines was 5.09/1000 catheter days, almost five times that for Port-a-Caths, with 1.04/1000 catheter days, a relative risk of 4.9 (confidence interval: 1.9–15.1, P = 0.0003). Most (73%) complications occurred within 4 weeks of insertion. However, some arose much later: the range of time to complication was 1–304 days for Hickman lines and 1–132 days for Port-a-Caths. Infection was the most common complication, accounting for nine of 18 Hickman line complications and five of six Port-a-Cath complications, giving an overall infection rate of 2.54/1000 catheter days and 0.86/1000 catheter days, respectively. Additionally, Hickman lines had a 26% leakage rate or displacement rate, which did not occur at all in the Port-a-Cath group. Complications required the removal of 16 Hickman lines and five Port-a-Caths. The rate of removal was five times higher for Hickman lines (Hickman lines = 4.52/1000 catheter days, Port-a-Caths = 0.86/1000 catheter days, P = 0.0027). Overall, the cost of Port-a-Caths was less than that of Hickman lines.ConclusionIn this study, Port-a-Caths were shown to be both safer and cheaper than Hickman lines for patients requiring infusional chemotherapy.     

Diagnosis and management of oligodendroglioma

The discovery of the sensitivity to chemotherapy of oligodendroglial tumors has greatly increased the interest in this tumor type. After the first studies showing the activity of chemotherapy with procarbazine, lomustine (CCNU), and vincristine (PCV), it is now clear that temozolomide is also effective in this tumor type. Fifty percent to 70% of patients with recurrent oligodendroglial tumors may respond to chemotherapy. The histological diagnosis of oligodendroglial tumors is still subject to a significant observer bias. This variation appears to be one of the causes of the recent relative increase in incidence of oligodendroglial tumors. Genetically, 60% to 70% of oligodendroglial tumors are characterized by the loss of the short arm of chromosome 1 (1p) and the loss of the long arm of chromosome 19 (19q). Virtually all tumors with the combined loss of 1p/19q respond to chemotherapy, which has been the first demonstration of the clinical usefulness of the genotyping of brain tumors. These tumors also more often have a classical oligodendroglial histology and have a much better prognosis than oligodendrogliomas without 1p/19q loss. Although the belief is widely held that in the near future the genotype of oligodendroglial tumors may help in selecting patients for treatment, this assumption has not been proven. Prospective trials on oligodendroglial tumors with analyses of the genotype are needed before such conclusions can be drawn. In the meantime it is clear that ultimately all patients with oligodendroglial tumors die of their disease, and that novel treatments are required to improve prognosis. For an improved prognosis, a better understanding of the aberrant pathways and the driving force behind these tumors is required.     

Outcome, quality of life and cognitive function of patients with brain metastases from non-small cell lung cancer treated with whole brain radiotherapy combined with gefitinib or temozolomide. A randomised phase II trial of the Swiss Group for Clinical Cancer Research (SAKK 70/03)

PurposePatients with brain metastases (BM) rarely survive longer than 6 months and are commonly excluded from clinical trials. We explored two combined modality regimens with novel agents with single agent activity and radiosensitizing properties.Patients and methodsIn this randomised phase II trial patients with BM from NSCLC were randomly assigned to 30 Gy WBRT with either concomitant gefitinib (GFT) 250 mg/day continuously or temozolomide (TMZ) 75 mg/m² for 21/28 days. The primary end-point was overall survival, with quality of life and cognitive function as secondary end-points.ResultsWe enrolled 59 patients (GFT 16, TMZ 43), and 56 patients have died, mainly (80%) from disease progression. Four patients succumbed complications of the disease or corticosteroids (intestinal perforation (2), CNS haemorrhage and pulmonary emboli). Median overall survival in the gefitinib arm was 6.3 months (95% CI 2.1–14.6), and 4.9 months (95% CI 2.3–5.6) in TMZ treated patients. Fatigue was the main complaint.ConclusionsNo relevant toxicity with those therapeutic regimens was observed. Fatal outcome in three patients may have been related to corticosteroids. Cognitive function improved during treatment. However, median overall survival for all patients was only 4.9 months (95% CI 2.3–5.7) and 1-year survival 25.4% (95% CI 15.4–37.0%).     

Treatment outcome after low intensity chemotherapy [CVP] in children and adolescents with early stage nodular lymphocyte predominant Hodgkin's lymphoma - an Anglo-French collaborative report

PurposeTo examine whether three cycles of a low-intensity chemotherapy consisting of cyclophosphamide [500 mg/m² – day 1], vinblastine [6 mg/m² – days 1 and 8] and prednisolone [40 mg/m² – days 1–7] (CVP) is safe and therapeutically effective in children and adolescents with early stage nodular lymphocyte predominant Hodgkin lymphoma [nLPHL].Patients and methodsFifty-five children and adolescents with early stage nLPHL [median age 13 years, range 4–17 years] diagnosed between June 2005 and October 2010 in the UK and France are the subjects of this report. Staging investigations included conventional cross sectional as well as 18 fluro-deoxyglucose [FDG] PET imaging. Histology was confirmed as nLPHL by an expert pathology panel.ResultsOf the 45 patients, who received CVP as first line treatment, 36 [80%, 95% Confidence Interval [CI]: (68; 92)] either achieved a complete remission [CR] or CR unconfirmed [CRu], the remaining nine patients achieved a partial response. All nine subsequently achieved CR with salvage chemotherapy [n = 7] or radiotherapy [n = 2]. Ten patients received CVP at relapse after primary treatment that consisted of surgery alone and all achieved CR. To date, only three patients have relapsed after CVP chemotherapy and all had received CVP as first line treatment at initial diagnosis. The 40-month freedom from treatment failure and overall survival for the entire cohort were 75.4% (SE ± 6%) and 100%, respectively. No significant early toxicity was observed.ConclusionsOur results show that CVP is an effective chemotherapy regimen in children and adolescents with early stage nLPHL that is well tolerated with minimal acute toxicity.     

Magnetic resonance spectroscopy in the assessment of pilocytic astrocytomas

BackgroundPilocytic astrocytomas (PA) are common childhood brain tumours whose management and prognosis vary widely depending on location. ¹H magnetic resonance spectroscopy (MRS) measures biochemistry in vivo and shows promise for characterising brain tumours and aiding management.MethodsSingle voxel MRS (1.5 Tesla, TE 30 ms, TR 1500 ms) was performed on 27 children with PAs. Cases were designated ‘progressors’ if tumour progression led to their clinical management plan being altered.ResultsPrior to treatment, supratentorial tumours had significantly higher myo-inositol (p < 0.01, t-test) and glutamate plus glutamine (p = 0.02, t-test) than cerebellar tumours. Optic pathway or thalamic tumours that progressed had a significantly (p = 0.04, t-test) lower myo-inositol at initial MRS than those with stable disease. Myo-inositol levels decreased significantly in progressors between the initial and subsequent MRS (p = 0.03, paired t-test). Changes in myo-inositol occurred before clinical and radiological progression.ConclusionsMRS identifies differences with anatomical location in PAs and yields potential non-invasive biomarkers of prognosis.     

Wnt1 overexpression promotes tumour progression in non-small cell lung cancer

BackgroundThe Wnt gene family is involved in embryogenesis and tumourigenesis. We investigated the clinical significance of Wnt1 expression in non-small cell lung cancer (NSCLC).MethodWe studied 216 NSCLC patients. Immunohistochemistry was performed to investigate the Wnt1 expression in relation to the expression of β-catenin and Wnt-targets, including c-Myc, Cyclin D1, VEGF-A and MMP-7. The Ki-67 proliferation index and the intratumoural microvessel density (IMD) were also evaluated.ResultsThe ratio of tumours with an aberrant β-catenin expression was significantly higher in Wnt1-positive tumours than in Wnt1-negative tumours (p < 0.0001). The Wnt1 expression significantly correlated with the expression of c-Myc (p < 0.0001), Cyclin D1 (p < 0.0001), VEGF-A (p = 0.0160), MMP-7 (p < 0.0001), the Ki-67 index (p = 0.0048) and the IMD (p = 0.0267). Furthermore, the Wnt1 status was a significant prognostic factor for NSCLC patients (p = 0.0127).ConclusionsThe Wnt1 overexpression is associated with the expression of tumour-associated Wnt-targets, tumour proliferation, angiogenesis and a poor prognosis in NSCLCs.     

Central nervous system atypical teratoid rhabdoid tumours: the Canadian Paediatric Brain Tumour Consortium experience

BackgroundAtypical teratoid rhabdoid tumours (ATRT) are aggressive brain tumours mostly occurring in early childhood. Largest published series arise from registries and institutional experiences (1–4). The aim of this report is to provide population-based data to further characterise this rare entity and to delineate prognostic factors.Patients and methodsA national retrospective study of children ⩽18 years diagnosed with a central nervous system (CNS) ATRT between 1995 and 2007 was undertaken. All cases underwent central pathology review.ResultsThere were 50 patients (31 males; median age at diagnosis of 16.7 months). Twelve patients were >36 months. Infratentorial location accounted for 52% of all cases. Nineteen patients (38%) had metastatic disease. Fifteen (30%) underwent gross total resection (GTR). Ten patients (20%) underwent palliation. Among the 40 remaining patients, 22 received conventional chemotherapy and 18 received high dose chemotherapy regimens (HDC); nine received intrathecal chemotherapy and 15 received adjuvant radiation.Thirty of the 40 treated patients relapsed/progressed at a median time of 5.5 months (0–32). The median survival time of the entire cohort was 13.5 months (1–117.5 months).Age, tumour location and metastatic status were not prognostic. Patients with GTR had a better survival (2 years overall survival (OS): 60% ± 12.6 versus 21.7% ± 8.5, p = 0.03). HDC conferred better outcome (2 years OS 47.9% ± 12.1 versus 27.3% ± 9.5, p = 0.036). Upfront radiation did not provide survival benefit. Six of the 12 survivors (50%) did not receive radiation.ConclusionThe outcome of CNS ATRT remains poor. However, the use of HDC provides encouraging results. GTR is a significant prognostic factor. The role of adjuvant radiation remains unclear.     

Phase I study of topotecan in combination with temozolomide (TOTEM) in relapsed or refractory paediatric solid tumours

PurposeTo evaluate maximum tolerated dose and recommended dose (RD) for phase II studies of topotecan (TPT) combined with temozolomide (TMZ) (TOTEM) in children and adolescents with relapsed or refractory solid malignancies.Patients and methodsMulticentre, phase I study with a standard ‘3 + 3’ design in five dose increments. Eligible patients: aged 6 months to 21 years, diagnosis of a solid malignancy failed at least 2 previous lines of therapy. TMZ was administered orally, starting at 100 mg/m²/d, and TPT intravenously over 30 min, starting at 0.75 mg/m²/d over 5 consecutive days every 28 d. A pharmacokinetics analysis was performed on Day 1 and Day 5 of cycle 1.ResultsBetween February and October 2007, 16 patients were treated. The median age was 8.5 years (range, 3–19 years). Dose-limiting toxicity (grade 4 neutropenia and/or thrombocytopenia lasting more than 7 d) during the first cycle occurred in 2 of 3 patients at level 3 (TMZ 150 mg/m²/d and TPT 1.0 mg/m²/d) and was always manageable. Confirmed complete and partial responses were observed in 4 patients (25%), three with metastatic neuroblastoma and one with high-grade glioma. Seven patients had a stable disease. Pharmacokinetic data show a wide inter-individual variability. No significant differences were observed between plasma TMZ and TPT concentrations on Day 1 and Day 5 indicating the absence of pharmacokinetic interaction between the drugs.ConclusionsThe RD for the combination is TMZ 150 mg/m²/d and TPT 0.75 mg/m²/d with dose-limiting haematological toxicity. The observed activity deserves further evaluation in paediatric malignancies.     

Lack of TIMP-1 tumour cell immunoreactivity predicts effect of adjuvant anthracycline-based chemotherapy in patients (n = 647) with primary breast cancer. A Danish Breast Cancer Cooperative Group Study

PurposeA number of prospective studies have shown that adjuvant CEF significantly improves disease-free and overall survival as compared to CMF in breast cancer patients. Our aim was to determine whether the benefit of epirubicin versus methotrexate differs according to TIMP-1 tumour cell immunoreactivity.Experimental designTissue micro arrays from 647 patients randomly assigned to CMF or CEF in DBCG trial 89D were included. The primary end-point was invasive disease-free survival (IDFS). A central assessment of tissue inhibitor of metalloproteinases 1 (TIMP-1) status was performed using immunohistochemistry (IHC). Tumours were regarded as TIMP-1 positive if epithelial breast cancer cells were stained using the anti-TIMP-1 monoclonal antibody VT7.ResultsBy central assessment 75% of tumours were classified as tumour cell TIMP-1 positive. Among CEF-treated patients, individuals with TIMP-1 negative tumours had a significant longer IDFS than patients with TIMP-1 positive tumours (p = 0.047). The multivariate Cox regression analysis of IDFS showed that CEF was superior to CMF among patients with TIMP-1 negative tumours (hazard ratio (HR) = 0.51; 95% confidence interval (CI): 0.31–0.84, p = 0.0085), while no significant difference could be demonstrated among patients with TIMP-1 positive tumours (HR = 0.88; 95% CI: 0.68–1.13, p = 0.32). A non-significant TIMP-1 status (positive or negative) versus treatment (CMF or CEF) interaction was detected for IDFS (p = 0.06) and OS (p = 0.21).ConclusionLack of TIMP-1 tumour cell immunoreactivity seems to predict a favourable effect of epirubicin-containing adjuvant therapy in primary breast cancer. However, an independent study is awaited to validate the potential predictive value of TIMP-1 immunoreactivity.     

The prognostic value of fast molecular response of marrow disease in patients aged over 1 year with stage 4 neuroblastoma

BackgroundQuantitative real-time (q)PCR for detection of minimal residual disease (MRD) in children with neuroblastoma (NB) can evaluate molecular bone marrow (BM) response to therapy, but the prognostic value of tumour kinetics in the BM during induction treatment remains to be established. The purpose of this study was to analyse at which time points MRD detection by sequential molecular assessment of BM was prognostic for overall survival (OS).MethodsIn this single centre study, qPCR was performed with five NB-specific markers: PHOX2B, TH, DDC, GAP43 and CHRNA3, on 106 retrospectively analysed BM samples of 53 patients >1 year with stage 4 neuroblastoma. The prognostic impact of MRD at diagnosis (n = 39), at 3 months after diagnosis (n = 38) and after completing induction chemotherapy (n = 29) was assessed using univariate and bivariate Cox regression analyses.ResultsThere was no correlation between tumour load at diagnosis and outcome (p = 0.93). Molecular BM remission was observed in 11/38 (29%) of patients at 3 months after diagnosis and associated with favourable outcome (5-y-OS 62 ± 15.0% versus 19 ± 8%; p = 0.009). After completion of induction chemotherapy, BM of 41% (12/29) of the patients was still MRD positive, which was associated with poor outcome (5-y-OS 0% versus 52 ± 12%; p < 0.001). For both time points, the prognostic value of molecular response remained significant in bivariate analysis.ConclusionsMRD detection measured by a panel of NB specific-PCR targets could identify fast responders, who clear their BM early during treatment. Fast molecular response was a prognostic factor, associated with better outcome. Our data indicate that MRD analysis during induction therapy should be included in prospective MRD studies.