• Aberrant CDKN1A transcriptional response associates with abnormal sensitivity to radiation treatment.

      Badie, Christophe; Dziwura, S; Raffy, C; Tsigani, Theodora; Alsbeih, G; Moody, J; Finnon, Paul; Levine, Edward; Scott, David A; Bouffler, Simon; et al. (2008-06-03)
      Normal tissue reactions to radiation therapy vary in severity among patients and cannot be accurately predicted, limiting treatment doses. The existence of heritable radiosensitivity syndromes suggests that normal tissue reaction severity is determined, at least in part, by genetic factors and these may be revealed by differences in gene expression. To test this hypothesis, peripheral blood lymphocyte cultures from 22 breast cancer patients with either minimal (11) or very severe acute skin reactions (11) have been used to analyse gene expression. Basal and post-irradiation expression of four radiation-responsive genes (CDKN1A, GADD45A, CCNB1, and BBC3) was determined by quantitative real-time PCR in T-cell cultures established from the two patient groups before radiotherapy. Relative expression levels of BBC3, CCNB1, and GADD45A 2 h following 2 Gy X-rays did not discriminate between groups. However, post-irradiation expression response was significantly reduced for CDKN1A (P<0.002) in severe reactors compared to normal. Prediction of reaction severity of approximately 91% of individuals sampled was achieved using this end point. Analysis of TP53 Arg72Pro and CDKN1A Ser31Arg single nucleotide polymorphisms did not show any significant association with reaction sensitivity. Although these results require confirmation and extension, this study demonstrates the possibility of predicting the severity of acute skin radiation toxicity in simple tests.
    • Addition of novel degenerate electrical waveform stimulation with photodynamic therapy significantly enhances its cytotoxic effect in keloid fibroblasts: first report of a potential combination therapy.

      Sebastian, A; Allan, Ernest; Allan, Donald; Colthurst, J; Bayat, A; Plastic & Reconstructive Surgery Research, School of Translational Medicine, Manchester Interdisciplinary Biocentre (MIB), The University of Manchester, UK. (2011-12)
      We recently reported use of photodynamic therapy (PDT) for treating keloid disease (KD). However, in view of high recurrence rates post any treatment modality, adjuvant therapies should be considered. Additionally, we previously demonstrated the effect of a novel electrical waveform, the degenerate wave (DW) on differential gene expression in keloid fibroblasts.
    • Addressing the health technology assessment of biosimilar pharmaceuticals.

      Stewart, Alan L; Aubrey, Philip; Belsey, Jonathan (2010-09)
      Abstract The growing number of biosimilars presents challenges to regulatory and health technology assessment (HTA) systems. This paper illustrates these challenges by focusing on biosimilars used in the oncological setting. In particular, discordances between data required by regulatory and HTA authorities potentially deprive patients of effective treatments and hinder optimal resource allocation. Regulatory and HTA authorities need to harmonize requirements to foster the development and widespread use of biosimilars, which potentially release considerable resources. The authors believe that often-inappropriate methodology creates a very real chance that HTA authorities will reject some biosimilars. This would effectively extend patent protection and, in the absence of competitor pressure from biosimilars, result in prices remaining unnecessarily high. The authors propose that HTA organizations should accept pharmacokinetic and pharmacodynamic equivalence between the brand and the biosimilar as a proxy of biological comparability. HTA organizations should then adopt, in the absence of compelling reasons otherwise, cost-minimization analysis (CMA) as the basis of the cost-effectiveness deliberations. In the absence of adequate studies demonstrating equivalent efficacy, a prerequisite of CMA, HTA organizations should require threshold analysis. Once approved, biosimilar manufacturers and regulators should maintain rigorous pharmacovigilance to exclude immunoreactivity or other rare adverse events. Furthermore, cancer centres and trusts should regularly audit and publish the impact of biosimilars on clinical outcomes and resource use. When appropriate, regulatory and HTA authorities should demand revised cost-effectiveness analyses from biosimilar manufacturers. This approach would hone the accuracy of the cost-effectiveness analyses, protect patients and allow health services rapid access to low cost treatments.
    • Alternating irinotecan with oxaliplatin combined with UFT plus leucovorin (SCOUT) in metastatic colorectal cancer.

      Sheikh, Hamid Y; Valle, Juan W; Waddell, Thomas K; Palmer, Karen; Wilson, Gregory; Sjursen, Ann-Marie; Craven, Olive; Swindell, Ric; Saunders, Mark P; Department of Clinical Oncology, Christie Hospital, Manchester, UK. (2008-08-19)
      Tegafur-uracil (UFT) plus leucovorin (LV, folinic acid) with alternating irinotecan and oxaliplatin were effective and well tolerated in patients with metastatic colorectal cancer (mCRC) in a phase I study. This study expanded the maximum tolerated dose group. Patients aged >or=18 years had histologically confirmed, inoperable, previously untreated, measurable mCRC. Patients received irinotecan 180 mg m(-2) on day 1, oxaliplatin 100 mg m(-2) on day 15 and UFT 250 mg m(-2) plus LV 90 mg on days 1-21 every 28 days. The phase I/II study comprised 45 patients, 29 at the maximum tolerated dose (MTD). The response rate in 38 evaluable patients was 63% (95% confidence interval (CI): 49-80). Median time to progression and overall survival were 8.7 months (95% CI: 7.9-10.4) and 16.8 months (95% CI: 9.6-25.3), respectively. In the MTD group, one patient had grade 3 leucopenia; one had grade 3 neutropaenia; three had grade 3 diarrhoea; and one had grade 3 neurotoxicity. No hand-foot syndrome grade >1 was seen. In total, 67% of eligible patients received second-line therapy. UFT plus LV with alternating irinotecan and oxaliplatin is an efficacious first-line treatment for mCRC, with minimal neurotoxicity and hand-foot syndrome.
    • Anaesthesia for radiation therapy - Gliwice experience.

      Wojcieszek, E; Rembielak, Agata; Bialas, B; Wojcieszek, A; Department of Anaesthesia and Intensive Care, Centre of Oncology - MSC Institute, Gliwice, Poland. (2010)
      General anaesthesia is rarely applied during fractionated radiotherapy with the exception of unco-operative patients. We performed a retrospective study to inform our current practice in anaesthesia procedures for radiotherapy application in children, brachytherapy and intraoperative radiation. The records of anaesthetized radiotherapy patients between January 2000 and September 2005 were analyzed. We analysed demographic data, type and localisation of neoplasm , radiotherapy data, type of anaesthesia and anaesthesia - related complications. In order to provide safe and efficient anaesthesia outside the Department of Anaesthesiology, we designed a mobile anaesthesia workstation. In total we performed 739 anaesthesia procedures: 267 in 16 children, 321 in 284 brachytherapy patients, and 151 as a part of intraoperative radiotherapy. Children age ranged from 2 - 8 years (median 4.6). All were given midazolam and atropine, then thiopental or ketamine. Neither muscle relaxants, nor propofol were used. Brachytherapy patients underwent: spinal block in 190 cases, general anaesthesia in 115, and deep sedation in 16 cases. General anaesthesia was inducted by propofol, followed by etomidate, thiopental and fentanyl. For spinal block the patients were given hyperbaric bupivacaine and fentanyl. Deep sedation was performed with midazolam and fentanyl, and thiopental or propofol when needed. Intraoperative radiotherapy was applied immediately after breast conserving surgery. No serious complications in all 739 anaesthesia procedures occurred. In conclusion we demonstrated the feasibility and safety of anaesthesia applied in our radiotherapy patients. The custom designed mobile anaesthesia workstation allowed us to provide safe and efficient anaesthesia in any place outside the Department of Anaesthesiology.
    • Analysis of prostate-specific antigen bounce after I(125) permanent seed implant for localised prostate cancer.

      Mitchell, Darren M; Swindell, Ric; Elliott, Tony; Wylie, James P; Taylor, Cathy M; Logue, John P; Department of Clinical Oncology, Christie NHS Trust, Manchester, UK. dmmitchell@doctors.org.uk (2008-07)
      BACKGROUND AND PURPOSE: To report on the incidence of benign prostate-specific antigen bounce following permanent I(125) prostate brachytherapy, to describe the associations in our population and review the relationship of bounce to subsequent biochemical failure. MATERIALS AND METHODS: From February 2000 to May 2005, 374 patients with localised prostate cancer were treated with I(125) permanent prostate brachytherapy at a single institution. A prospectively collected database was used to identify cases of prostate-specific antigen (PSA) bounce, defined as a rise of 0.2 ng/ml above an initial PSA nadir with subsequent decline to or below that nadir without treatment. The patients who received neo-adjuvant or adjuvant hormone manipulation were excluded. Biochemical failure was determined using the both the ASTRO consensus definition and Phoenix (nadir +2 ng/mL) definition. RESULTS: Two hundred and five patients were identified with a median follow-up of 45 months (24-85). PSA bounce was noted in 79 (37%) men, occurring at a median of 14.8 months (1.7-40.6) following implant. The median peak PSA was 1.8 ng/ml (0.4-7.4) with a bounce magnitude of 0.91 ng/ml (0.2-5.8). When pre- and post-implant factors were assessed for association to bounce, only younger age was statistically significant (p=0.002). The threshold for biochemical failure as defined by the ASTRO consensus definition (1997) was met in 4 (5%) patients after experiencing bounce as opposed to 19 (15%) non-bounce patients (p=0.01). The threshold for Phoenix (nadir +2 ng/mL) was met in 6 (7.5%) patients following bounce versus 22 (17%) of non-bounce patients (p=0.003). Both definitions are prone to false positive calls during bounce. Median PSA velocity during the bounce was 0.08 ng/mL/month (0.02-0.98) and was statistically significantly lower than the median velocity prior to the Phoenix biochemical failure at 0.28 ng/mL/month (0.07-2.04) (p=0.0005). CONCLUSION: PSA bounce is a common finding in our population and is associated with a lower rate of subsequent biochemical failure. The noted differences in PSA velocity will require verification in a future analysis to reduce the influence of median follow-up on this finding. Patients should be advised of the potential of bounce in PSA follow-up after permanent I(125) prostate brachytherapy and physicians involved in follow-up of prostate brachytherapy patients should be aware of this phenomenon, allowing them to commit to appropriate PSA surveillance, avoiding the premature and inappropriate initiation of salvage therapy during PSA bounce.
    • Assessing the effect of a contouring protocol on postprostatectomy radiotherapy clinical target volumes and interphysician variation.

      Mitchell, Darren M; Perry, Lesley A; Smith, Steve; Elliott, Tony; Wylie, James P; Cowan, Richard A; Livsey, Jacqueline E; Logue, John P; Department of Clinical Oncology, Christie Hospital, Manchester, United Kingdom. dmmitchell@doctors.org.uk (2009-11-15)
      PURPOSE: To compare postprostatectomy clinical target volume (CTV) delineation before and after the introduction of a contouring protocol and to investigate its effect on interphysician variability METHODS AND MATERIALS: Six site-specialized radiation oncologists independently delineated a CTV on the computed tomography (CT) scans of 3 patients who had received postprostatectomy radiotherapy. At least 3 weeks later this was repeated, but with the physicians adhering to the contouring protocol from the Medical Research Council's Radiotherapy and Androgen Deprivation In Combination After Local Surgery (RADICALS) trial. The volumes obtained before and after the protocol were compared and the effect of the protocol on interphysician variability assessed. RESULTS: An increase in mean CTV for all patients of 40.7 to 53.9 cm(3) was noted as a result of observing the protocol, with individual increases in the mean CTV of 65%, 15%, and 24% for Patients 1, 2, and 3 respectively. A reduction in interphysician variability was noted when the protocol was used. CONCLUSIONS: Substantial interphysician variation in target volume delineation for postprostatectomy radiotherapy exists, which can be reduced by the use of a contouring protocol. The RADICALS contouring protocol increases the target volumes when compared with those volumes typically applied at our center. The effect of treating larger volumes on the therapeutic ratio and resultant toxicity should be carefully monitored, particularly if the same dose-response as documented in radical prostate radiotherapy applies to the adjuvant and salvage setting. Prostate cancer, Postprostatectomy, Radiotherapy, Target volume.
    • Assessment of bladder motion for clinical radiotherapy practice using cine-magnetic resonance imaging.

      McBain, Catherine A; Khoo, Vincent S; Buckley, David L; Sykes, Jonathan S; Green, Melanie M; Cowan, Richard A; Hutchinson, Charles E; Moore, Christopher J; Price, Patricia M; Academic Department of Radiation Oncology, The University of Manchester, Christie Hospital NHS Foundation Trust, Wilmslow Road, Manchester, United Kingdom. (2009-11-01)
      PURPOSE: Organ motion is recognized as the principal source of inaccuracy in bladder radiotherapy (RT), but there is currently little information on intrafraction bladder motion. METHODS AND MATERIALS: We used cine-magnetic resonance imaging (cine-MRI) to study bladder motion relevant to intrafraction RT delivery. On two occasions, a 28 minute cine-MRI sequence was acquired from 10 bladder cancer patients and 5 control participants immediately after bladder emptying, after abstinence from drinking for the preceding hour. From the resulting cine sequences, bladder motion was subjectively assessed. To quantify bladder motion, the bladder was contoured in imaging volume sets at 0, 14, and 28 min to measure changes to bladder volumes, wall displacements, and center of gravity (COG) over time. RESULTS: The dominant source of bladder motion during imaging was bladder filling (up to 101% volume increase); rectal and small bowel movements were transient, with minimal impact. Bladder volume changes were similar for all participants. However for bladder cancer patients, wall displacements were larger (up to 58 mm), less symmetrical, and more variable compared with nondiseased control bladders. CONCLUSIONS: Significant and individualized intrafraction bladder wall displacements may occur during bladder RT delivery. This important source of inaccuracy should be incorporated into treatment planning and verification.
    • Benign schwannoma in paranasal sinuses: a clinico-pathological study of five cases, emphasising diagnostic difficulties.

      Sheikh, Hamid Y; Chakravarthy, R P; Slevin, Nicholas J; Sykes, Andrew J; Banerjee, Saumitra S; Department of Clinical Oncology, Christie Hospital NHS Trust, Manchester, UK. hamid.sheikh@christie-tr.nwest.nhs.uk (2008-06)
      OBJECTIVES: To highlight the difficulty in making a correct diagnosis of benign schwannoma in the paranasal region, to raise awareness of this rare condition, and to suggest the most appropriate treatment. METHOD: Retrieval of cases retrospectively from archives of the histopathology department of a major UK cancer centre with central review of all cases. RESULTS: Five cases were identified since 1990 and clinical and pathological features are summarised. Median follow up of patients was 8.1 years. Radiological appearances of local bone invasion and histological features of tumour unencapsulation and hypercellularity could give the mistaken impression of malignant disease and lead to unnecessary over-treatment. CONCLUSION: Central pathological review and clinical awareness is required. Although local recurrence can occur, the prognosis is excellent. The treatment of choice is local excision. Radiotherapy can be considered, but in most cases it would incur unnecessary morbidity.
    • Bladder preservation multimodality therapy as an alternative to radical cystectomy for treatment of muscle invasive bladder cancer.

      Choudhury, Ananya; Cowan, Richard A; The Christie Hospital NHS Foundation Trust, Manchester (2011-11)
    • Capecitabine, bevacizumab, and mitomycin in first-line treatment of metastatic colorectal cancer: results of the Australasian Gastrointestinal Trials Group Randomized Phase III MAX Study.

      Tebbutt, Niall C; Wilson, Kate; Gebski, Val; Cummins, Michelle M; Zannino, Diana; Van Hazel, Guy A; Robinson, Bridget; Broad, Adam; Ganju, Vinod; Ackland, Stephen P; et al. (2010-07-01)
      PURPOSE: To determine whether adding bevacizumab, with or without mitomycin, to capecitabine monotherapy improves progression-free survival (PFS) in patients with metastatic colorectal cancer (mCRC) in an open-label, three-arm randomized trial. PATIENTS AND METHODS: Overall, 471 patients in Australia, New Zealand, and the United Kingdom with previously untreated, unresectable mCRC were randomly assigned to the following: capecitabine; capecitabine plus bevacizumab (CB); or capecitabine, bevacizumab, and mitomycin (CBM). We compared CB with capecitabine and CBM with capecitabine for progression-free survival (PFS). Secondary end points included overall survival (OS), toxicity, response rate (RR), and quality of life (QOL). RESULTS: Median PFS was 5.7 months for capecitabine, 8.5 months for CB, and 8.4 months for CBM (capecitabine v CB: hazard ratio [HR], 0.63; 95% CI, 0.50 to 0.79; P < .001; C v CBM: HR, 0.59; 95% CI, 0.47 to 0.75; P < .001). After a median follow-up of 31 months, median OS was 18.9 months for capecitabine and was 16.4 months for CBM; these data were not significantly different. Toxicity rates were acceptable, and all treatment regimens well tolerated. Bevacizumab toxicities were similar to those in previous studies. Measures of overall QOL were similar in all groups. CONCLUSION: Adding bevacizumab to capecitabine, with or without mitomycin, significantly improves PFS without major additional toxicity or impairment of QOL.
    • Case of rhabdomyosarcoma presenting with myasthenia gravis.

      Mehmood, Qurrat U; Shaktawat, S S; Parikh, O; The Christie NHS Foundation Trust, Wilmslow Rd, Manchester, M20 4BX, United Kingdom. (2011-08-01)
    • Clinical features of oral chemotherapy: results of a longitudinal prospective study of breast and colorectal cancer patients receiving capecitabine in the UK.

      Brearley, S G; Craven, Olive; Saunders, Mark P; Swindell, Ric; Molassiotis, A; University of Manchester, School of Nursing, Midwifery and Social Work, University Place, Manchester M13 9PL, UK. sarah.Brearley@manchester.ac.uk (2010-07)
      The aim was to describe the clinical sequelae of patients treated with capecitabine in terms of adverse events, treatment modifications and therapy cessation throughout the treatment trajectory. A total of 1232 toxicity assessments were undertaken on colorectal and breast cancer patients receiving palliative and adjuvant treatment prior to treatment and at days 7, 14 and 21 for six cycles of chemotherapy. Most common adverse events were diarrhoea, nausea, palmar-plantar erythrodysesthesia (PPE), fatigue and pain which were experienced by over 80% of subjects. Grades 2 and 3 adverse events were common (n= 916 and n= 113) but their development into grade 4 was uncommon (n= 2). There was a downward trend in the percentage incidence of toxicity; however, PPE increased. Almost 60% of subjects completed six cycles, or planned treatment. Some 40% of subjects commenced treatment on a dose reduction (<1250 mg/m(2)), and this increased to 70% at cycle 6. In total, 2.8-11.6% of subjects experienced toxicity-related treatment deferrals. While adverse events are common with capecitabine the lack of grade 4 adverse events support the efficacy of current clinical management strategies. The deferral and dose reduction data indicate that cycles 1 and 2 are important and require careful management and clinical interventions in order to prevent high-grade adverse events.
    • Clinical neurological outcome and quality of life among patients with limited small-cell cancer treated with two different doses of prophylactic cranial irradiation in the intergroup phase III trial (PCI99-01, EORTC 22003-08004, RTOG 0212 and IFCT 99-01).

      Le Péchoux, C; Laplanche, A; Faivre-Finn, Corinne; Ciuleanu, T; Wanders, R; Lerouge, D; Keus, R; Hatton, M; Videtic, G M; Senan, S; et al. (2011-05)
      We recently published the results of the PCI99 randomised trial comparing the effect of a prophylactic cranial irradiation (PCI) at 25 or 36 Gy on the incidence of brain metastases (BM) in 720 patients with limited small-cell lung cancer (SCLC). As concerns about neurotoxicity were a major issue surrounding PCI, we report here midterm and long-term repeated evaluation of neurocognitive functions and quality of life (QoL).
    • Clinical outcome for chemoradiotherapy in carcinoma of the cervix.

      Spensley, Saiqa; Hunter, Robin D; Livsey, Jacqueline E; Swindell, Ric; Davidson, Susan E; Department of Clinical Oncology, Christie Hospital, Manchester, UK. saiqa.spensley@slh.ie (2009-02)
      AIMS: Two recent meta-analyses have shown a survival advantage for the addition of concurrent chemotherapy to radiotherapy in the treatment of cervical cancer. However, there is insufficient information available on late toxicity and few data from UK practice. The aims of this study were to examine treatment outcomes (survival and toxicity) in patients with cervical cancer treated with chemoradiation and to compare these with outcomes in patients treated with radiation alone. MATERIALS AND METHODS: Between July 2000 and December 2003, 75 patients with cervical cancer were treated with chemoradiation. Case notes were reviewed retrospectively. Acute and late toxicity were recorded, with late toxicity graded using the Franco-Italian glossary. The median age was 47 years. All patients were staged with examination under anaesthesia and magnetic resonance imaging scans. Forty-two patients were treated with concurrent chemoradiation alone and 33 patients were treated with a combination of neoadjuvant and concurrent chemoradiation. This was due to waiting list problems. The chemotherapy used was cisplatin 40 mg/m(2) weekly with radiotherapy, (the neoadjuvant dose was 60 mg/m(2) 3 weekly). External beam radiotherapy was given to the pelvis (40-45 Gy/20 fractions/4 weeks) followed by low dose rate brachytherapy (22.5-32.5 Gy to point A). Patients who were unable to have brachytherapy were given an external beam boost (15-20 Gy/8-10 fractions). RESULTS: The 3-year overall survival rate was 70%, with an estimated 5-year overall survival rate of 60%. The 3-year disease-free survival was 63.6%, with an estimated 5-year disease-free survival rate of 55%. Compared with the cohort of 183 patients from the Christie Hospital in a 1993 audit, there was a trend towards improved overall survival from 49 to 60% (P=0.06), which may become significant with longer follow-up. There were seven patients (9.3%) with grade 3 toxicity and no cases of grade 4 toxicity. In comparison with patients treated in the 1993 audit, the late toxicity rate has increased from 3.4 to 9.3%, but this was not statistically significant (P=0.14). CONCLUSION: There was a trend towards improved survival with concurrent chemoradiation in this cohort of patients that may become significant with longer follow-up.
    • Collagen vascular diseases and enhanced radiotherapy-induced normal tissue effects--a case report and a review of published studies.

      Lee, C E; Prabhu, V; Slevin, Nicholas J; Department of Clinical Oncology, Christie Hospital, Manchester, UK. carolinelee@christie.nhs.co.uk (2011-03)
      Collagen vascular diseases (CVD) are a group of chronic, autoimmune conditions that can affect multiple organ systems. The mainstay of treatment involves the use of immunosuppressants. CVDs and immunosuppression increase the risk of these patients developing malignancy. The mechanisms through which these patients develop CVDs show similarities to those for radiotherapy late effects, especially fibrosis (via transforming growth factor β). Radiotherapy may in fact cause an active state to develop from a quiescent state of CVD, or exacerbate a pre-existing CVD. CVDs are said to be associated with increased normal tissue toxicity after radiotherapy. Here we present a case report of a patient with a long history of systemic lupus erythematosus and oropharyngeal carcinoma, treated with synchronous chemoradiotherapy. We also review published studies and formulate some guidance on the radiotherapy management of these patients.
    • Combined androgen deprivation therapy and radiation therapy for locally advanced prostate cancer: a randomised, phase 3 trial.

      Warde, P; Mason, M; Ding, K; Kirkbride, P; Brundage, M; Cowan, Richard A; Gospodarowicz, M; Sanders, K; Kostashuk, E; Swanson, G; et al. (2011-12-17)
      Whether the addition of radiation therapy (RT) improves overall survival in men with locally advanced prostate cancer managed with androgen deprivation therapy (ADT) is unclear. Our aim was to compare outcomes in such patients with locally advanced prostate cancer.
    • Comparison of patient-reported late treatment toxicity (LENT-SOMA) with quality of life (EORTC QLQ-C30 and QLQ-H&N35) assessment after head and neck radiotherapy.

      Ho, Kean F; Farnell, Damian J J; Routledge, Jacqueline A; Burns, Meriel P; Sykes, Andrew J; Slevin, Nicholas J; Davidson, Susan E; Academic Radiation Oncology, University of Manchester, The Christie NHS Foundation Trust, Manchester, UK. (2010-06-14)
      PURPOSE: The patient's role in toxicity reporting is increasingly acknowledged but requires the adaptation and validation of toxicity reporting instruments for patient use as most toxicity scales are designed for physician use. Recording of radiotherapy related late toxicity is important and needs to be improved. A patient-scored symptom questionnaire of late treatment effects using LENT-SOMA was compared with a recognised quality of life tool (EORTC QLQ-C30/H&N35). MATERIALS/METHODS: LENT-SOMA and EORTC QLQ-C30 patient questionnaires were prospectively completed by 220 head and neck cancer patients over 3years and 72 completed EORTC QLQ-H&N35 questionnaires at 2years post-radiotherapy. RESULTS: Endpoints common to both questionnaires (pain, swallowing, dental pain, dry mouth, opening mouth, analgesics) were matched. Spearman rank correlation coefficients with rho>0.6 (P<0.001) were obtained for all "matched" scales except for analgesics scale, rho=0.267 (P<0.05). There was good agreement between LENT-SOMA and EORTC QLQ-H&N35 except for analgesic endpoints. Global quality of life scores correlated negatively with average LENT-SOMA scores (P<0.001). Significant differences in average LENT-SOMA scores between treatment modalities were found. The LENT-SOMA questionnaire has demonstrated a high Cronbach's alpha value (0.786) indicating good reliability. CONCLUSIONS: LENT-SOMA patient questionnaire results agreed well with those from the EORTC QLQ-H&N35 questionnaire for toxicity items where they could be compared explicitly, particularly for subjective endpoints. Patient-reported late toxicity had a negative impact on quality of life. The LENT-SOMA patient questionnaire is both reliable and sensitive to differences between patients treated with different modalities. A patient-based questionnaire is an important contributor to capturing late radiotherapy effects.
    • Cost analysis of biomarker testing for mismatch repair deficiency in node-positive colorectal cancer.

      Barrow, E; McMahon, R; Evans, D Gareth R; Levine, Edward; Hill, J; Department of General Surgery, Manchester Royal Infirmary, St Mary's Hospital, Manchester, UK. emma.barrow@doctors.org.uk (2008-07)
      BACKGROUND: Microsatellite instability (MSI) in colorectal cancer is caused by defective DNA mismatch repair (MMR). It is present in 15 per cent of sporadic colorectal cancers owing to epigenetic mutL homologue 1 (MLH1) inactivation. The evidence suggests that patients with tumours caused by defective DNA MMR do not benefit from 5-fluorouracil (5-FU)-based chemotherapy. METHODS: The proportion of cancers with defective DNA MMR identified by MSI analysis or immunohistochemistry was calculated from published data. The cost of analysis was compared with the potential savings if 5-FU-based chemotherapy was not administered to these patients. RESULTS: Some 16.3 per cent of sporadic colorectal cancers had defective DNA MMR. Immunostaining for MLH1 and mutS homologue 2 (MSH2) had a sensitivity of 92.4 per cent and a specificity of 99.6 per cent for identifying MSI-high tumours. The strongest predictive variable was right-sidedness, with positive and negative predictive values of 0.329 and 0.948 respectively. If 5-FU-based chemotherapy were not administered, potential savings of up to pound 1.2 million per 1000 patients tested could be made. Costs would be higher if alternative chemotherapeutic regimens were substituted as a result of testing. CONCLUSION: Knowledge of MMR status may enable participation in trials of non-5-FU-based chemotherapy. The cost of MMR testing may be offset by more efficient use of chemotherapy.
    • CpG methylation profiling in VHL related and VHL unrelated renal cell carcinoma.

      McRonald, Fiona E; Morris, Mark R; Gentle, Dean; Winchester, Laura; Baban, Dilair; Ragoussis, Jiannis; Clarke, Noel W; Brown, Michael D; Kishida, Takeshi; Yao, Masahiro; et al. (2009)
      BACKGROUND: Renal cell carcinoma (RCC) is histopathologically heterogeneous with clear cell and papillary the most common subtypes. The most frequent molecular abnormality in clear cell RCC is VHL inactivation but promoter methylation of tumour suppressor genes is common in both subtypes of RCC. To investigate whether RCC CpG methylation status was influenced by histopathology and VHL status we performed high-throughput epigenetic profiling using the Illumina Goldengate Methylation Array in 62 RCC (29 RCC from von Hippel-Lindau (VHL) disease patients, 20 sporadic clear cell RCC with wild type VHL and 13 sporadic papillary RCC). RESULTS: 43 genes were methylated in >20% of primary RCC (range 20-45%) and most (37/43) of these had not been reported previously to be methylated in RCC. The distribution of the number of methylated CpGs in individual tumours differed from the expected Poisson distribution (p < 0.00001; log-likelihood G test) suggesting that a subset of RCC displayed a CpG Island Methylator Phenotype. Comparison of RCC subtypes revealed that, on average, tumour specific CpG methylation was most prevalent in papillary RCC and least in VHL RCC. Many of the genes preferentially methylated in pRCC were linked to TGFbeta or ERK/Akt signalling. CONCLUSION: These findings demonstrate differing patterns of tumour-specific CpG methylation in VHL and non VHL clear cell RCC and papillary RCC, and identify multiple novel potential CpG methylation biomarkers for RCC.