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.     

A long duration of the prediagnostic symptomatic interval is not associated with an unfavourable prognosis in childhood medulloblastoma

BackgroundDue to the lacking specificity of symptoms making a correct diagnosis can be a challenge in children with medulloblastoma. This can lead to prediagnostic symptomatic intervals (PSIs) of several weeks to months. It is unknown whether the length of the PSI is associated with an inferior survival outcome in this population.MethodsTo study the association of PSI with disease stage at diagnosis, tumour control and survival in children with medulloblastoma, prospectively collected data on PSI, clinical, and biological features were analysed in 224 patients diagnosed at the age of 3–18 years and treated within the prospective randomised multicentre trial HIT’91.ResultsPatients with lower-stage disease tended towards a longer median PSI than those with higher-stage disease (M0 stage, 2.0 months; M1 stage, 2.0 months; M2/M3 stage, 1 month; p = 0.094. M0/1 stage versus M2/3 stage; p = 0.025). The patient group with the longest PSI had the best survival outcome (PSI ⩾4.0 months: 10-year overall survival rate (OS), 71%; PSI <4.0 months, 10-year OS, 61%; p = 0.056). Age at diagnosis was positively correlated with PSI (p = 0.027). No associations were found between PSI and sex histological subtype, presence of postoperative residual tumour, or c-myc and TrkC mRNA expression.ConclusionContrary to a common belief that a longer PSI may adversely affect prognosis, a longer PSI was associated with a trend towards lower metastatic stage and better survival probabilities. Nevertheless these findings do not obviate the importance of a timely diagnosis in paediatric patients with medulloblastoma.     

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 impact of functional imaging with (123)I-mIBG in patients with stage 4 neuroblastoma >1 year of age on a high-risk treatment protocol: results of the German Neuroblastoma Trial NB97

Aim/Purpose¹²³I-meta-iodobenzylguanidine (¹²³I-mIBG) scintigraphy is well established for staging and evaluation of response in children with high-risk neuroblastoma but its prognostic value in highly intensive first-line treatment protocols is uncertain. The presence of any ¹²³I-mIBG positive tumour tissue was correlated with event-free survival (EFS) and overall survival (OS).Patients and methodsThe prognostic impact of residual ¹²³I-mIBG uptake into the primary tumour and metastases for predicting outcome in 113 stage 4 neuroblastoma patients >1 year of the German Neuroblastoma Trial NB97 was assessed using a univariate log-rank test and multivariate Cox regression analysis.ResultsAll patients had ¹²³I-mIBG positive disease at initial staging. After four courses of induction chemotherapy, 71% of patients were still ¹²³I-mIBG positive for the primary tumour and 61% for metastases. After six courses, 39% of patients had ¹²³I-mIBG uptake by the primary tumour and 45% residual ¹²³I-mIBG positive metastatic disease. The ¹²³I-mIBG status of the primary tumour site had no bearing on outcome. Residual ¹²³I-mIBG positive metastatic disease after four (3-y-EFS 25.7 ± 5.3% versus 55.9 ± 7.6%, p = 0.009; 3-y-OS 49.8 ± 6.1% versus 65.0 ± 7.3%; p = 0.021) and after six chemotherapy cycles (3-y-EFS 27.5 ± 6.2% versus 47.4 ± 6.4%, p = 0.011; 3-y-OS 50.5 ± 7.1% vs 60.0 ± 6.4%, p = 0.031) was associated with poor outcome.ConclusionFunctional imaging with ¹²³I-mIBG scintigraphy can identify poor responders with any persistent metastatic ¹²³I-mIBG uptake who are at a high risk of disease relapse. ¹²³I-mIBG response of the primary tumour site had no bearing on outcome.     

Quantification of angiogenesis by the Chalkley method and its prognostic significance in epithelial ovarian cancer

AimThe aim of the present study was to clarify prognostic role of angiogenesis in epithelial ovarian cancer.MethodsQuantification of angiogenesis was performed by the Chalkley method after immunostaining of 175 epithelial ovarian cancer specimens with an antibody against CD34.ResultsThe Chalkley count was categorised into two groups according to the median value: low <8 or high ⩾8. The low Chalkley count correlated significantly with serous and clear cell histological subtype of the tumour (p < 0.0005), whereas there existed no association with FIGO (International Federation of Gynecology and Obstetrics) stage, histological grade, presence of primary residual tumour, age at diagnosis, or chemotherapy response. In univariate analysis, the high Chalkley count predicted poor overall survival in the subgroup of patients with FIGO stages III–IV tumours (p = 0.007) but not in the entire study cohort. However, in multivariate analysis, the Chalkley count was found to be an independent predictor of death from ovarian cancer in the entire study cohort (p = 0.044, RR = 1.50, 95% CI 1.01–2.21) as well as in the subgroup of FIGO stages III–IV tumours (p = 0.046, RR = 1.58, 95% CI 1.01–2.46) together with the presence of primary residual tumour (p < 0.0005, RR = 5.10, 95% CI 3.02–8.62, and p = 0.002, RR = 4.28, 95% CI 1.34–13.73, respectively).ConclusionsThe Chalkley count seems to be suitable for evaluation of angiogenesis and to have prognostic significance in ovarian cancer.     

Association of galectin-3 expression with melanoma progression and prognosis

AimsGalectin-3 plays an important role in adhesion, proliferation, differentiation, angiogenesis and metastasis in multiple tumours. To investigate the role of galectin-3 in melanoma pathogenesis we examined the expression of galectin-3 in melanocytic lesions and analysed the correlation between galectin-3 expression and clinicopathologic factors including patient survival and BRAF mutation status.MethodsWe evaluated the expression of galectin-3 in 53 cases of benign naevi, 31 cases of dysplastic naevi, 59 in-situ melanomas, 314 cases of primary melanoma and 69 metastatic melanomas using tissue microarray and immunohistochemistry.ResultsMarked differences in expression of galectin-3 were seen between different categories of melanocytic lesions (ANOVA p < 0.0001). An increase in expression of galectin-3 between benign naevi and thin primary melanomas and a progressive decrease in expression between thin primary melanomas and thicker melanomas or metastatic melanomas was seen. Strong galectin-3 expression was associated with improved overall survival (p = 0.002 and p = 0.0002 for cytoplasmic and nuclear expression, respectively) and melanoma-specific survival (p = 0.017 and p = 0.003 for cytoplasmic and nuclear expression, respectively). A multifactorial Cox regression analysis suggested that galectin-3 expression was an independent prognostic marker for overall survival in melanoma (risk ratio 0.73, 95% CI 0.547–0.970, p = 0.031 for cytoplasmic expression and risk ratio 0.76, 95% CI 0.587–0.985, p = 0.036 for nuclear expression). No association between galectin-3 expression and BRAF mutation status was observed.ConclusionThis study suggests that galectin-3 is a marker of progression in melanocytic lesions and a novel prognostic marker in primary melanoma.     

Primary versus secondary cytoreduction for epithelial ovarian cancer: a paired analysis of tumour pattern and surgical outcome

ObjectiveRecurrence rates of Epithelial Ovarian Cancer (EOC) remain high. Aim of the present study was to compare tumour pattern and surgical outcome at primary and secondary tumourdebulking in a paired patients’ collective.MethodsSeventy-nine consecutive EOC-patients who underwent both primary and secondary cytoreduction in our institution between 09/2000 and 12/2010 were evaluated according to a validated documentation-tool (‘IMO’, Intraoperative Mapping Ovarian Cancer). Differences in tumour-pattern between paired samples were examined using McNemar-test or sign-test.ResultsA complete macroscopic tumour resection could be achieved significantly more often during primary versus secondary surgery (77% versus 50%; p < 0.001) in comparable operative times (242 min versus 199 min; p = 0.15) and by equivalent operative morbidity (25% versus 29%; p = 0.424). Tumour-residuals at primary correlated significantly with tumour-residuals at secondary cytoreduction (p = 0.003). Patients at relapse had significantly higher rates of tumour involvement of the gastric serosa (2.5% versus 16.9%; p = 0.001), serosa of small intestine (20.3% versus 44.9%; p < 0.001) and mesentery (30.4% versus 50%; p = 0.012). The relative-risk for peritoneal carcinosis, intestinal tumour involvement or positive lymph nodes at secondary tumourdebulking in the case of presence of these features at primary surgery was 1.53 (95% CI: 0.89–2.63); 0.92 (95% CI: 0.65–1.31) and 1.49 (95% CI: 0.83–2.68), respectively, and thus not reaching a statistical significance.ConclusionsSecondary cytoreduction due to EOC appears to be associated with significantly lower optimal tumourdebulking rates compared to primary setting, since the disease tends to recur in patterns less accessible to complete resection such as gastrointestinal serosa, mesentery and upper abdomen. By maximal surgical effort, tumour residuals significantly correlate between primary and secondary cytoreduction. No other predictors of surgical outcome or tumour-pattern could be identified.     

Incidence and long-term prognosis of papillary compared to clear cell renal cell carcinoma - A multicentre study

Aim of the studyPapillary renal cell carcinoma (pRCC) is the second most common subtype of RCC after the conventional clear cell type (cRCC). However, its characteristics and prognosis have been less intensively investigated. The aim of our study was to examine the tumour characteristics and long-term prognosis of pRCC compared to clear cell RCC (cRCC).MethodsIn total, 4941 evaluable patients were subjected to either radical nephrectomy or nephron-sparing surgery for pRCC or cRCC at five centres in Germany (University Hospitals of Hannover, Homburg/Saar, Mainz, Ulm and Marburg) between 1990 and 2010.ResultspRCC (n = 565) and cRCC (n = 4376) patients were comparable with regard to mean age, clinical symptoms, tumour differentiation and regional lymph node metastases. Patients with pRCC had a significantly higher rate of organ confined tumours (pT1-2, N/M0; 74.9% versus 62.9%), less synchronic visceral metastases (9.6% versus 15.2%), and a higher 5-year CSS rate than those with cRCC (85.1% versus 76.9%). Multivariate analysis identified the papillary subtype as a significant positive prognostic factor in localised (HR, 0.45) but as a negative prognostic factor in metastatic tumour stages (HR, 1.37).ConclusionpRCC can apparently be differentiated into two subgroups: an organ-confined/localised subgroup with a significantly better prognosis and an advanced/metastatic subgroup with a worse prognosis compared to cRCC.     

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.     

Cediranib monotherapy in patients with advanced renal cell carcinoma: results of a randomised phase II study

BackgroundCediranib is a highly potent vascular endothelial growth factor (VEGF) signalling inhibitor with activity against VEGF receptors 1, 2 and 3. This Phase II, randomised, double-blind, parallel-group study compared the efficacy of cediranib with placebo in patients with metastatic or recurrent clear cell renal cell carcinoma who had not previously received a VEGF signalling inhibitor.MethodsPatients were randomised (3:1) to cediranib 45 mg/day or placebo. The primary objective was comparison of change from baseline in tumour size after 12 weeks of therapy. Secondary objectives included response rate and duration, progression-free survival (PFS) and safety and tolerability. Patients in the placebo group could cross over to open-label cediranib at 12 weeks or earlier if their disease had progressed. This study has been completed and is registered with ClinicalTrials.gov, number NCT00423332.FindingsPatients (n = 71) were randomised to receive cediranib (n = 53) or placebo (n = 18). The primary study outcome revealed that, after 12 weeks of therapy, there was a significant difference in mean percentage change from baseline in tumour size between the cediranib (–20%) and placebo (+20%) arms (p < 0.0001). Eighteen patients (34%) on cediranib achieved a partial response and 25 (47%) experienced stable disease. Cediranib treatment prolonged PFS significantly compared with placebo (hazard ratio (HR) = 0.45, 90% confidence interval: 0.26–0.76, p = 0.017; median PFS 12.1 versus 2.8 months). The most common adverse events in patients receiving cediranib were diarrhoea (74%), hypertension (64%), fatigue (58%) and dysphonia (58%).InterpretationCediranib monotherapy demonstrated significant evidence of antitumour activity in patients with advanced renal cell carcinoma. The adverse event profile was consistent with previous studies of cediranib 45 mg.     

The clinical significance of lymphangiogenesis and angiogenesis in non-small cell lung cancer patients

BackgroundAngiogenesis and lymphangiogenesis have been reported to affect malignant phenotype.MethodWe investigated 147 patients with non-small cell lung cancer (NSCLC). Immunohistochemistry using D2-40 was performed to evaluate lymphatic vessel density (LVD), including Micro-LVD (without lumen), Tubal-LVD (with lumen) and lymphatic vessel invasion (LVI). The intratumoural microvessel density (MVD) was evaluated by CD-34 immunostaining. The expressions of vascular endothelial growth factor-A (VEGF-A) and VEGF-C were also studied.ResultsLymphangiogenesis was significantly associated with Micro-LVD (p = 0.0003). The VEGF-C expression was significantly associated with the Micro-LVD (p = 0.0057). In contrast, the VEGF-A expression was significantly associated with the MVD (p = 0.0092). The survival was significantly lower in patients with Micro-LVD-high tumours than in patients with Micro-LVD-low tumours (p = 0.0397). Survival was also significantly lower in patients with MVD-high tumours than in patients with MVD-low tumours (p = 0.0334). A multivariate analysis demonstrated that the Micro-LVD (p = 0.0363) and the MVD (p = 0.0232) were independent prognostic factors for NSCLC patients.ConclusionsLymphangiogenesis, specifically Micro-LVD and angiogenesis are independently associated with a poor prognosis in NSCLC patients.     

Magnetic resonance spectroscopy metabolite profiles predict survival in paediatric brain tumours

BackgroundBrain tumours cause the highest mortality and morbidity rate of all childhood tumour groups and new methods are required to improve clinical management. ¹H magnetic resonance spectroscopy (MRS) allows non-invasive concentration measurements of small molecules present in tumour tissue, providing clinically useful imaging biomarkers. The primary aim of this study was to investigate whether MRS detectable molecules can predict the survival of paediatric brain tumour patients.Patients and methodsShort echo time (30 ms) single voxel ¹H MRS was performed on children attending Birmingham Children’s Hospital with a suspected brain tumour and 115 patients were included in the survival analysis. Patients were followed-up for a median period of 35 months and Cox-Regression was used to establish the prognostic value of individual MRS detectable molecules. A multivariate model of survival was also investigated to improve prognostic power.ResultsLipids and scyllo-inositol predicted poor survival whilst glutamine and N-acetyl aspartate predicted improved survival (p < 0.05). A multivariate model of survival based on three MRS biomarkers predicted survival with a similar accuracy to histologic grading (p < 5e–5). A negative correlation between lipids and glutamine was found, suggesting a functional link between these molecules.ConclusionsMRS detectable biomolecules have been identified that predict survival of paediatric brain tumour patients across a range of tumour types. The evaluation of these biomarkers in large prospective studies of specific tumour types should be undertaken. The correlation between lipids and glutamine provides new insight into paediatric brain tumour metabolism that may present novel targets for therapy.     

HER3 expression in patients with primary colorectal cancer and corresponding lymph node metastases related to clinical outcome

AimTo evaluate the expression and prognostic value of the epidermal growth factor receptor HER3 in patients with primary colorectal cancer (CRC) and corresponding lymph node metastases.Patient and methodsHER3 expression was analysed immunohistochemically (IHC) in primary tumours and in corresponding lymph node metastases from 236 patients with stage II and III CRC. In 58 primary tumours, fluorescence in situ hybridisation (FISH) detection was performed.ResultsHER3 was detected at high frequency in the cell membrane. Seventy percent of the primary tumours had a high HER3 expression compared to 75% in the lymph node metastases. HER3 expression in the primary tumour was an independent prognostic factor for overall survival in the entire group of patients (p = 0.026) and in the subgroup of patients with colon cancer stage II (p = 0.030). A high HER3 expression in the primary tumour was associated with worse clinical outcome. The expression of HER3 was homogenous within the primary tumour (r = 0.9, p < 0.0001) and correlated with the HER3 expression in corresponding lymph node metastases (r = 0.6, p < 0.0001). No gene amplification with respect to HER3 was seen in primary tumours using FISH analysis.ConclusionA high HER3 expression was found in 70% of the primary CRC tumours and in 75% of the corresponding lymph node metastases. HER3 expression in the tumour was an independent prognostic factor, where a high HER3 expression was associated with worse clinical outcome. There was a correlation in HER3 expression between primary tumour and corresponding lymph node metastases.     

Long-term outcome and clinical prognostic factors in children with medulloblastoma treated in the prospective randomised multicentre trial HIT‘91

PurposeTo analyse long-term outcome and clinical prognostic factors in medulloblastoma.MethodsWe analysed 280 patients with medulloblastoma (3–18 years) included from 1991 to 1997 in the randomised multicentre trial HIT‘91 comparing pre-(‘sandwich’) and postradiation (‘maintenance’) chemotherapy (median follow-up of survivors for 10 years).ResultsIn 187 patients with complete staging, overall survival (OS) was higher after maintenance compared to sandwich treatment for M0 (10-year OS 91% and 62%, p = 0.001) and M1 patients (10-year OS 70% and 34%, p = 0.020). In M2/3 disease, 10-year OS was 42% and 45%. Incomplete staging, metastases, younger age and sandwich chemotherapy were independent adverse risk factors. Twelve percent of all relapses (13 of 107) occurred after more than five years, and 12 patients had secondary neoplasms.ConclusionsAfter maintenance therapy, long-term survival was excellent in fully assessable patients with localised medulloblastoma, and favourable for M1 patients. Patients should be followed longer for late relapses and secondary tumours.     

Treatment of adult nonmetastatic medulloblastoma patients according to the paediatric HIT 2000 protocol: A prospective observational multicentre study

BackgroundMedulloblastoma in adulthood is rare. Knowledge is limited, and the efficacy and toxicity of chemotherapy – especially in nonmetastatic disease – is still elusive.MethodsSeventy adults aged ?21 years (median age: 28.5 years) with nonmetastatic medulloblastoma were followed as observational patients within the prospective paediatric multicentre trial HIT 2000. Treatment consisted of radiotherapy (35.2 Gy to the craniospinal axis and a boost to 55.2 Gy to the posterior fossa) followed in most patients by maintenance chemotherapy (lomustine (CCNU), vincristine and cisplatin, n = 49).ResultsThe implementation of maintenance chemotherapy was feasible. Peripheral neuropathy (74%) and haematotoxicity (55%) during maintenance chemotherapy appear to be more common in adults than in children. At a median follow-up of 3.7 years, the 4-year event-free survival (EFS) and overall survival (OS) rates ± standard error (SE) were 68% ± 7% and 89% ± 5%. Patients with desmoplastic medulloblastoma and lateral tumour location (n = 19) had a lower EFS compared to patients with centrally located desmoplastic tumours (n = 10) (p = 0.011). Absence of residual postoperative tumour (n = 40) was associated to a lower rate of progression/relapse compared to present (n = 11) or unknown (n = 12) residual tumour status (p = 0.006). Lateral tumour location and unknown residual tumour status were independent negative prognostic factors.ConclusionsMaintenance chemotherapy is applicable in adults with nonmetastatic medulloblastoma. Histological subtype and tumour location were newly identified risk factors in this age-group, and should be further analysed in prospective trials.     

Epidermal growth factor receptor status predicts local response to radical radiotherapy in muscle-invasive bladder cancer

AimsEpidermal growth factor receptor (EGFR) is expressed by over 70% of muscle-invasive bladder tumours and is associated with diminished overall survival. In model tumour systems, ionising radiation has been shown to activate EGFR, leading to cellular proliferation and is therefore a possible mechanism of underlying radioresistance. We carried out an immunohistochemical study relating the clinical outcome of patients receiving radical radiotherapy for muscle-invasive bladder cancer to tumour EGFR status.Materials and methodsArchived paraffin-embedded tumours from 110 consecutive patients receiving radical radiotherapy for muscle-invasive bladder cancer between 1991 and 1997 were immunohistochemically stained for EGFR. Data were collected concerning the tumour stage and grade, the presence of ureteric obstruction, the response to radiotherapy at 3 months, local recurrence rates, metastatic spread and survival. Multivariate analysis of potential independent prognostic factors of impaired bladder cancer-specific survival was carried out using Cox's regression.ResultsOf 110 tumours, 79 (72%) stained positively for EGFR. Of 87 patients undergoing the 3-month check cystoscopy, 60 (69%) had a positive response to radiotherapy. A positive response to radiotherapy correlated significantly with a negative EGFR status (χ² test, P = 0.05). Kaplan–Meier survival analysis revealed a trend towards improved bladder cancer-specific survival in EGFR-negative patients (Log-rank, P = 0.10). A lack of response to radiotherapy at 3 months, local recurrence, metastatic spread and the presence of ureteric obstruction were all independent prognostic factors for diminished bladder cancer-specific survival (Cox's regression: P = 0.009, P = 0.001, P = 0.04 and P = 0.005, respectively).ConclusionsEGFR status predicts the local response to radiotherapy but does not provide prognostic utility in relation to overall or bladder cancer-specific survival. As EGFR status seems to be linked to the initial response to radiotherapy, its inhibition may be a means of enhancing the radio-responsiveness of these poor prognosis tumours.     

Tumour staging using magnetic resonance imaging in clinically localised prostate cancer: relationship to biochemical outcome after neo-adjuvant androgen deprivation and radical radiotherapy

AimsTo evaluate the prognostic significance of magnetic resonance imaging (MRI) tumour stage in clinically localised prostate cancer.Materials and methodsBetween 1988 and 1999, 199 men with clinically localised prostate cancer (T1–T4, N0/Nx, M0) were treated with neo-adjuvant androgen deprivation and radical radiotherapy, and were staged using MRI. Concordance between clinical tumour (cT) stage, as determined by digital rectal examination, and MRI tumour (mT) stage was assessed. Univariate and multivariate analyses using the Cox proportional hazards model were used to study the prognostic role of cT stage and mT stage in addition to established prognostic factors.ResultsOf these 199 patients, 103 (52%) were upstaged on MRI, seven (3%) were downstaged, and in 89 (45%) cT and mT stages were concordant. With median follow-up of 3.8 years, 5-year freedom from prostate-specific antigen (PSA) failure was 48% (95% confidence interval (CI) 39–56%). On univariate analysis, freedom from PSA failure was associated with mT stage (P = 0.009) as well as Gleason score (P < 0.001) and initial PSA (P < 0.001), but not cT stage (P = 0.449). On multivariate analysis, Gleason score (P = 0.001), initial PSA (P < 0.001), but not mT stage (P = 0.112) remained independent determinants of freedom from PSA failure. For the subgroup of 149 patients with cT1–2 disease, mT stage was a significant predictor of increased risk of PSA failure on univariate analysis (P = 0.005), but not multivariate analysis (P = 0.19).ConclusionFreedom from PSA failure was more closely associated with mT stage than cT stage. Future studies are warranted to determine whether mT stage is an independent determinant of treatment outcome.     

ERG protein expression reflects hormonal treatment response and is associated with Gleason score and prostate cancer specific mortality

BackgroundERG (ETS regulated gene) protein expression has been shown to reflect ERG genomic rearrangements in prostate cancer (PCA). However, ERG protein expression prognostic value has not been yet investigated.DesignERG protein expression was investigated in a cohort of 312 men with PCA diagnosed in transurethral resection of the prostate.ResultsERG expression was detected in 76/293 (25.9%) of patients. Overall ERG expression was associated with Gleason score (GS) (p < 0.0001), tumour volume (p = 0.04) and with cancer specific mortality (p = 0.15). Low ERG intensity was significantly associated with higher GS (p = 0.02) and marginally with cancer specific mortality (p = 0.11). The association with caner specific mortality was more significant in patients without any hormonal manipulation (p = 0.02). Multivariate Cox model using GS, tumour volume and ERG intensity to predict time to cancer specific death yielded a marginally significant effect for high versus low ERG protein expression (hazard ratio (HR) = 0.36; 95% confidence interval (CI): 0.10–1.38; p = 0.14) and a non-significant effect for GS >7 (HR = 4.85; 95% CI: 0.48, 48.65; p = 0.18). Men with ERG expression showed longer free progression time to castration resistant disease compared to men with no ERG expression (mean 11.39 versus 6.1 months, p = 0.08).ConclusionWe report significant association between ERG protein levels and each of GS, progression to castration resistant and cancer specific mortality. High ERG intensity was associated with lower GS, better overall survival and longer free progression times to castration resistant disease. ERG protein levels may have prognostic and therapeutic role in PCA and should be investigated in future studies.     

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.     

Adverse impact of regional lymph node involvement in osteosarcoma

BackgroundMetastatic dissemination in osteosarcoma occurs haematogenously, though regional lymph node involvement is rarely reported. We investigated incidence, patient characteristics and survival for patients with osteosarcoma and regional lymph node involvement at diagnosis.MethodsWe identified 2748 cases of high-grade osteosarcoma with available information regarding regional lymph node involvement in the Surveillance Epidemiology and End Results database from 1973 to 2009. Demographics were compared using chi-squared tests or t-tests. Overall survival was estimated using Kaplan–Meier method and compared with log-rank tests. Multivariate analysis of overall survival was performed using Cox proportional hazards methods.ResultsThere were 74 patients (2.7%) with regional lymph node involvement at diagnosis of whom 19 (0.7%) were pathologically confirmed. Patients with regional node involvement were more likely to have extraskeletal tumours, distant metastases, tumours arising outside the lower extremity (p < 0.0001 for all comparisons) and larger tumours (p = 0.033). Five-year overall survival in those with and without regional node involvement was 10.9% (95% confidence interval (CI) 4.6–20.4) and 54.3% (95% CI 52.2–56.4; p < 0.0001). In multivariate analysis, regional node involvement remained predictive of inferior survival after controlling for differences in metastatic status, age, tumour site and extraskeletal origin (hazard ratio 2.05, 95% CI 1.57–2.67; p < 0.0001). Similar survival results were found when the analysis was restricted to patients with pathologically confirmed positive or negative regional lymph nodes.ConclusionThis analysis confirms that regional node involvement is a significant adverse prognostic factor that is independent of metastatic status, extraskeletal origin, age and tumour site.