• VAC (vincristine, adriamycin, cyclophosphamide) chemotherapy for metastatic carcinoma from an unknown primary site.

      Anderson, Heather; Thatcher, Nick; Rankin, Elaine M; Wagstaff, John; Scarffe, J Howard; Crowther, Derek; Cancer Research Campaign, Dept. of Medical Oncology, Manchester University and Christie Hospital & Holt Radium Institute, Wilmslow Road, Manchester M20 9BX, U.K. (1983-01)
      Twenty patients presenting with metastatic carcinoma from an unknown primary site were studied. All patients were treated with a triple chemotherapy regimen of vincristine, adriamycin and cyclophosphamide repeated at three-week intervals. The response rate was 50%, and the four patients achieving complete response are alive and disease-free at 13, 16, 36 and 39 months. Toxicity was minimal and the majority of patients' performance status improved with the chemotherapy. VAC chemotherapy is indicated for patients with metastases, particularly of soft tissues originating from a carcinoma from an unknown primary site.
    • Vaccination of colorectal cancer patients with modified vaccinia Ankara delivering the tumor antigen 5T4 (TroVax) induces immune responses which correlate with disease control: a phase I/II trial.

      Harrop, Richard; Connolly, Noel B; Redchenko, Irina; Valle, Juan W; Saunders, Mark P; Ryan, Matthew G; Myers, Kevin A; Drury, Noel L; Kingsman, Susan M; Hawkins, Robert E; et al. (2006-06-01)
      PURPOSE: The highly attenuated strain of vaccinia virus, modified vaccinia Ankara (MVA), encoding the tumor antigen 5T4 (termed TroVax), has been evaluated in an open-label phase I/II study in colorectal cancer patients. The primary objectives were to assess the safety and immunogenicity of ascending doses of TroVax and to determine the biodistribution of the vector. EXPERIMENTAL DESIGN: TroVax was given to 22 patients with metastatic colorectal cancer. Seventeen patients received doses of TroVax ranging from 5 x 10(7) up to 5 x 10(8) plaque-forming units at 0, 4, and 8 weeks and were considered to be evaluable for assessment of immunologic responses. Both antibody and cellular responses specific for the tumor antigen 5T4 and the viral vector were monitored throughout the study. RESULTS: TroVax was well tolerated in all patients with no serious adverse events attributed to vaccination. Of 17 evaluable patients, 16 showed 5T4-specific cellular responses whereas 14 had detectable antibody levels following vaccination. TroVax was able to boost 5T4-specific immune responses in the presence of MVA neutralizing antibodies. Periods of disease stabilization ranging from 3 to 18 months were observed in five patients, all of whom mounted 5T4-specific immune responses. Furthermore, statistical analysis showed a positive association between the development of a 5T4 (but not MVA) antibody response and patient survival or time to disease progression. CONCLUSION: These data indicate that vaccination with TroVax is safe and well tolerated and that immune responses to 5T4 can be induced without any evidence of autoimmune toxicity. Furthermore, 5T4-specific antibody responses correlate with evidence of disease control.
    • Vaccines for the treatment of non-small cell lung cancer: investigational approaches and clinical experience.

      Mellstedt, H; Vansteenkiste, J; Thatcher, Nick; Cancer Centre Karolinska, Department of Oncology, Karolinska University Hospital, Solna, SE-171 76 Stockholm, Sweden. (2011-07)
      Globally, lung cancer remains the most common malignancy and the leading cause of cancer-related death. Whilst resection is a therapeutic option for patients with early stage non-small cell lung cancer (NSCLC), most patients have locally advanced or metastatic disease at diagnosis, the treatment of which still presents a considerable challenge for medical oncologists. Therapeutic cancer vaccines offer a novel approach for the treatment of patients with NSCLC in both the adjuvant and advanced disease settings. Although early attempts to use such technologies were of limited success, increased knowledge of the molecular pathology of tumors, of the immune system in general, and of tumor immunity in particular, has facilitated the production of more sophisticated anticancer vaccines. A number of promising vaccine candidates based on different types of antigenic stimulus have now been evaluated in clinical studies. These include belagenpumatucel-L, a vaccine derived from four genetically modified, irradiated NSCLC cell lines and target protein-specific vaccines designed to induce responses against epidermal growth factor (EGF), melanoma-associated antigen A3 (MAGE-A3) and mucin 1 (MUC1). The purpose of this review is to describe the mode of action of the vaccine candidates that are most advanced in their clinical development for the treatment of NSCLC, and to summarize the most recent data from clinical studies of these vaccines.
    • VAD chemotherapy as remission induction for multiple myeloma.

      Anderson, Heather; Scarffe, J Howard; Ranson, Malcolm R; Young, R; Wieringa, Gilbert E; Morgenstern, Godfrey R; Fitzsimmons, Lesley; Ryder, W David J; Department of Medical Oncology, Christie Hospital, Manchester, UK. (1995-02)
      A total of 142 patients with multiple myeloma received VAD as remission induction therapy. Seventy-five were previously untreated and 67 had relapsed (31) or refractory disease (36). Vincristine (total dose 1.6 mg) was infused with doxorubicin 36 mg m-2 by continuous ambulatory pump over 4 days. In addition, oral dexamethasone 40 mg day-1 was given for 4 days. Intermittent dexamethasone was only given to 19 patients. Courses were repeated every 21 days. The overall response rate was 84% [27% complete response (CR)] in previously untreated patients and 61% (3% CR) in patients with relapsed and refractory disease. The median survival was 36 months for untreated patients and 10 months for those who had received prior therapy. VAD was well tolerated; however, despite prophylaxis, 54% patients received antibiotics at some time during therapy and 37% had dyspepsia. Twenty-three patients subsequently received a transplant (eight allografts, eight marrow autografts and seven peripheral blood stem cell transplants). Eight have died-four in the allogeneic group and four in the autologous group. The overall median survival of transplanted patients has not yet been reached. VAD is an effective, out-patient therapy for inducing remission in multiple myeloma. Post-remission therapy needs to be optimised, but it is likely that the needs of previously untreated patients may be different from those with relapsed and refractory disease.
    • VAD chemotherapy--toxicity and efficacy--in patients with multiple myeloma and other lymphoid malignancies.

      Anderson, Heather; Scarffe, J Howard; Lambert, M; Smith, David B; Chan, C C; Chadwick, G; McMahon, A; Chang, James; Crowther, Derek; Swindell, Ric; et al. (1987)
      Thirty-three patients with multiple myeloma (11 untreated, 15 refractory and seven relapsed patients) have received vincristine and adriamycin infusion therapy with oral dexamethasone (VAD). The median number of course received was five. In addition 16 patients with lymphoid malignancy have received a median of four courses of VAD. Three patients who relapsed after VAD have received further VAD therapy making 52 patient treatments assessable for toxicity. Ten per cent had nausea, 4 per cent vomiting, 4 per cent total alopecia, 25 per cent constipation, 33 per cent paraesthesiae, 8 per cent proximal myopathy, 33 per cent dyspepsia, 23 per cent proven bacteraemia, and 19 per cent chest infections. Infections were not usually associated with neutropenia. Shingles was seen in four patients with myeloma, but none of the patients with lymphoid malignancy. The response rate in myeloma was 9/11, for previously untreated patients, 3/7 for relapsed, and 8/15 for refractory patients. Responses have been seen in other lymphoid malignancies-1/2 patients with relapsed acute lymphoblastic leukaemia had a complete remission. Two out of seven patients with chronic lymphocytic leukaemia achieved a partial remission, and a further three had a clinical improvement. Three out of six patients with non-Hodgkin lymphoma and one patient with macroglobulinaemia achieved a partial remission.
    • Vaginal dose de-escalation in cervix brachytherapy

      Aldred, Gillian; Hallett, Lisa; The Christie NHS Foundation Trust, Brachytherapy, Manchester, (2021)
      Purpose or Objective Vaginal toxicity post cervix brachytherapy is well documented [1]. The EMBRACE 2 protocol specifies dose points which can be used to measure dose to the vagina. The vaginal TRAK gives the percentage of dwell time being delivered via the ring/ovoids and can also be used to measure vaginal dose. This study aims to reduce the dose to the vaginal dose points and TRAK through changes to our plan optimisation process, whilst keeping changes to target and OAR doses minimal, as reported by S. Mohamed et al [2]. Since Feb 2018, we have had the option of using the Venezia applicator with interstitial needles. This may help to reduce the vaginal dose in patients with larger tumours, as dose can be delivered laterally via the needles rather than the ovoids. However, significantly larger CTV volumes are now being referred for brachytherapy rather than external beam boosts. Prior to Feb 2018, 6.2% of brachytherapy patients had a HR-CTV >30cm3. Since then, 41.8% of patients have had an HR-CTV > 30cm3. This is likely to have an effect on the outcome of this study as larger volumes may require higher vaginal TRAK to achieve coverage. Materials and Methods Twenty plans using either Rotterdam or Venezia applicators (with or without interstitial needles) were retrospectively replanned with the aim of reducing the vaginal TRAK whilst maintaining original EQD2 doses to targets and OAR. The vaginal TRAK and vaginal dose points were compared between the original plans and the new plans. Results The vaginal TRAK was reduced by an average of 18%. This resulted in a reduction to the PIBS point doses of between 22% and 31% and a reduction in the RV point dose of 24%. Target doses remained within 5% of the original plans and OAR doses were reduced apart from bowel which increased by an average of 1.4%. Conclusion Reduction of vaginal TRAK during plan optimisation results in a reduction to vaginal point doses. This has been shown to reduce vaginal side effects [3], therefore vaginal TRAK should be minimised in the optimisation process whilst meeting target and OAR dose limits. The current planning protocol limits vaginal TRAK to the EMBRACE recommendations of 30-40%, however much lower values can be easily achieved in most cases.
    • Vaginal leiomyosarcoma.

      Umeadi, Uchenna P; Ahmed, Ahmed S; Slade, Richard J; Menasce, Lia P; Department of Surgery, Christie Hospital NHS Foundation Trust, Manchester, UK. uchenna.umeadi@christie.nhs.uk (2008-07)
    • Valid informed consent and participative decision-making in children with cancer and their parents: a report of the SIOP Working Committee on psychosocial issues in pediatric oncology.

      Spinetta, John J; Masera, Giuseppe; Jankovic, Momcilo; Oppenheim, Daniel; Martins, Antonio Gentil; Ben Arush, Myriam Weyl; Van Dongen-Melman, Jeanette; Epelman, Claudia; Medin, Gabriela; Pekkanen, Kirsti; et al. (2003-04)
      This is the tenth official document of the SIOP Working Committee on psychosocial issues in pediatric oncology, instituted in 1991. It is addressed to the pediatric oncology community. Children clearly have a right to participate in medical decisions regarding their own treatment, based on the developmental level of the child. The objective of these guidelines is to encourage physicians to share with the child developmentally relevant medical information specific to that particular child's health status, in the context of the child's own culture, so that he or she can actively participate in the decision-making process regarding his or her own health. These guidelines, geared toward this objective, discuss the child's right to medical information, the parents' legal responsibility for but not exclusive right over the child's health, and ways of encouraging the younger child's active participation in his or her own health care at an age-appropriate level of understanding. For adolescents, there should be a full and legally mandated power to make their own decisions regarding medical treatment.
    • Validating a Monte Carlo approach to absolute dose quality assurance for proton pencil beam scanning.

      Winterhalter, C; Fura, E; Tian, Y; Aitkenhead, Adam H; Bolsi, A; Dieterle, M; Fredh, A; Meier, G; Oxley, D; Siewert, D; et al. (2018-08-23)
      For radiotherapy, it is crucial to guarantee that the delivered dose matches the planned dose. Therefore, patient specific quality assurance (QA) of absolute dose distributions is necessary. Here, we investigate the potential of replacing patient specific QA for pencil beam scanned proton therapy with Monte Carlo simulations. First, the set-up of the automated Monte Carlo model is presented with an emphasis on the absolute dose validation. Second, the absolute dose results obtained from the Monte Carlo simulation for a comprehensive set of patient fields are compared to patient specific QA measurements. Absolute doses measured with the Farmer chamber are shown to be 1.4% higher than the doses measured with the Semiflex chamber. For single energy layers, Monte Carlo simulated doses are 2.1%  ±  0.4% lower than the ones measured with the ionization chamber and 1.1%  ±  1.0% lower than measurements compared to patient field verification measurements. After rescaling to account for this 1.1% discrepancy, 98 fields (94.2%) agree within 2% to measurements, the maximum difference being 2.3%. In conclusion, an automated, easy-to-use Monte Carlo calculation system has been set up. This system reproduced patient specific QA results over a wide range of cases, showing that the time consuming measurements could be reduced or even replaced using Monte Carlo simulations without jeopardizing treatment quality.
    • Validation and commissioning of AI contouring tools

      Green, Andrew; The University of Manchester c/o The Christie NHS Foundation Trust, Department 58- Radiotherapy Related Research, Manchester, (2020)
      Abstract text Artificial Intelligence (AI) has become ubiquitous in modern life, and has inevitably found uses in the clinic. The recent approval of several commercial tools for OAR segmentation has accelerated the uptake of AI contouring tools, and their validation, commissioning and ongoing QA is now of great interest and importance. In this lecture, we will explore the fundamental process by which an AI contouring tool produces contours, and investigate the implications on validation and commissioning. We will compare the commissioning of an AI tool to that of a standard registration-based tool with which the community is already familiar and highlight particular pitfalls specific to AI tools that may not have been encountered when commissioning other tools. As a concrete example, we will look at work done by colleagues at The Christie Hospital, UK during their commissioning an AI contouring workflow.
    • Validation and physiological association of changes in magnetic resonance imaging radiomic features in response to androgen deprivation therapy in patients with high-risk prostate cancer

      Tharmalingam, Hannah; Beasley, William J; Alonzi, R; McWilliam, Alan; Hoskin, Peter J; Choudhury, Ananya; Mount Vernon Cancer Centre, London (2019)
    • Validation and reproducibility of changes in magnetic resonance imaging radiomic features in response to androgen deprivation therapy in patients with high-risk prostate cancer.

      Tharmalingam, Hannah; Beasley, William J; Alonzi, R; McWilliam, Alan; Hoskin, Peter J; Choudhury, Ananya; Mount Vernon Cancer Centre, Middlesex (2019)
    • Validation of a companion diagnostic biomarker for prospective use in prostate radiotherapy trials

      Thiruthaneeswaran, Niluja; Bibby, Becky A; Pereira, R.; More, E.; Bristow, Robert G; Choudhury, Ananya; West, Catharine M L; University of Manchester, Translational Radiobiology, Manchester, (2020)
      Purpose or Objective A 28-gene hypoxia-associated signature (HS) was derived for prostate cancer. The signature was validated for prognostic significance in eight prostatectomy, a definitive radiotherapy cohort and a salvage radiotherapy cohort. Biomarker validation using scant or minimal formalin-fixed paraffin-embedded (FFPE) tissue from diagnostic biopsies is a challenge due to nucleic acid degradation and low tissue volume. The aim of this study was to technically validate the robustness of the signature for reproducibility, reliability and intratumour heterogeneity. Material and Methods Diagnostic FFPE needle core (NC) biopsies from high-risk prostate cancer patients treated with different radiotherapy regimens were collected (n=663). Intratumour heterogeneity was assessed in 40 patient samples with multiple tumour FFPE NC blocks. Correlation was assessed in matched needle core to macrodissected prostatectomy samples in 12 patients. To assess downstream usability of extracted retrospective RNA three gene expression technologies were assessed (Taqman array cards, RNA-seq, Affymetrix Clariom S). Results The 24 prospective samples (age <12 months) yielded higher quality RNA than the retrospective samples (p = 0.008). Success rate of gene expression using Clariom S was achieved in 560 samples (84%). All samples passed QC metric and all 28 genes of the prostate HS were detected and measurable. RNA quality (r=0.03) and yield (r=-0.05) did not correlate with HS. HS did not increase with Gleason grade group (G3 2.40±0.16, G4 2.31±0.30, G5 2.69±0.22). Clariom S consistently outperformed the other platforms studied. There was an inverse correlation between probe amplicon length and gene expression (n=33, r=-0.67) with the Taqman array card. Intratumour heterogeneity based on HS group was demonstrated in 18 samples (45%). No correlation was seen between histopathological adverse features and HS. Conclusion This is the largest prostate radiotherapy cohort with full gene expression data available and hence a valuable resource for research. The Clariom S gene expression platform was superior to Taqman array cards and RNA-seq for validation of a prostate hypoxia gene signature in definitive radiotherapy cohorts using archival FFPE NC.
    • Validation of a hypoxia related gene signature in multiple soft tissue sarcoma cohorts.

      Yang, Lingjian; Forker, Laura-Jane; Iram, Joely J; Pillay, N; Choudhury, Ananya; West, Catharine M L; Translational Radiobiology Group, Division of Cancer Sciences, University of Manchester, Manchester Academic Health Science Centre, Christie Hospital, Manchester, UK (2018-02-15)
    • Validation of a model to predict survival in elderly patients with acute myeloid leukaemia.

      Johnson, Peter R; Ryder, W David J; Yin, J A; Department of Haematology, Christie Hospital, Manchester. (1995-08)
      Intensive chemotherapy is the treatment of choice for selected elderly patients with acute myeloid leukaemia (AML). We recently developed a model to predict survival, thereby providing objective information upon which to select appropriate therapy for such patients. Such models, however, must be validated on a cohort of patients not used during the development of the model. We have tested the model using a series of 61 elderly patients consecutively treated with intensive chemotherapy. Using several statistical techniques, we have shown that the model is of value in predicting prognosis, though two patients did markedly better than the model prediction. This model may be useful for predicting survival in elderly patients with AML and warrants more extensive validation.
    • Validation of clinical/dosimetric/genetic risk factor models for late RT-induced rectal bleeding

      Rancati, T; Seibold, P; Webb, A; Chang-Claude, J; Cicchetti, A; Azria, D; De Ruysscher, D; Elliott, Rebecca M; Gutierrez-Enriquez, S; Rosenstein, BS; et al. (2019)
    • Validation of lysyl oxidase-like 2 (LOXL2) as prognostic marker for gastro-entero-pancreatic neuroendocrine tumours (GEP-NET) Using an independent cohort

      Barriuso, Jorge; Benavent, M; Lamarca, Angela; Bernal, E; Guerra-Pastrian, L; Heredia, V; Miguel, V; Garcia-Calderon, C; Alvarez-Escola, C; Castell, J; et al. (2016)
    • Validation of nomogram for disease free survival for colon cancer in UK population: A prospective cohort study.

      Kazem, M; Khan, A; Selvasekar, Chelliah; Surgery and Cancer Division, Leighton Hospital, Middlewich Road, Crewe CW1 4QJ, UK (2016-01-18)
      To externally validate the MSKCC nomogram in a UK population, and determine if it could be used in our practice here in the UK.
    • Validation of pharmacodynamic assays to evaluate the clinical efficacy of an antisense compound (AEG 35156) targeted to the X-linked inhibitor of apoptosis protein XIAP.

      Cummings, Jeffrey; Ward, Timothy H; Lacasse, Eric; Lefebvre, C; St-Jean, M; Durkin, J; Ranson, Malcolm R; Dive, Caroline; Clinical and Experimental Pharmacology, Paterson Institute for Cancer Research, Christie Hospital NHS Trust, Wilmslow Road, Manchester M20 4BX, UK. jcummings@picr.man.ac.uk (2005-02-14)
      The inhibitor of apoptosis protein, XIAP, is frequently overexpressed in chemoresistant human tumours. An antisense oligonucleotide (AEG 35156/GEM 640) that targets XIAP has recently entered phase I trials in the UK. Method validation data are presented on three pharmacodynamic assays that will be utilised during this trial. Quantitative RT-PCR was based on a Taqman assay and was confirmed to be specific for XIAP. Assay linearity extended over four orders of magnitude. MDA-MB-231/U6-E1 cells and clone X-G4 stably expressing an RNAi vector against XIAP were chosen as high and low XIAP expression quality controls (QCs). Within-day and between-day coefficients of variation (CVs) in precision for cycle threshold (CT) and delta CT values (employing GAPDH and beta 2 microglobulin as housekeepers) were always less than 10%. A Western blotting technique was validated using a GST-XIAP fusion protein as a standard and HeLa cells and SF268 (human glioblastoma) cells as high and low XIAP expression QCs. Specificity of the final choice of antibody for XIAP was evaluated by analysing a panel of cell lines including clone X-G4. The assay was linear over a 29-fold range of protein concentration and between-day precision was 29% for the low QC and 23% for the high QC when normalised to GAPDH. XIAP protein was also shown to be stable at -80 degrees C for at least 60 days. M30-Apoptosense plasma Elisa detects a caspase-cleaved fragment of cytokeratin 18 (CK18), believed to be a surrogate marker for tumour cell apoptosis. Generation of an independent QC was achieved through the treatment of X-G4 cells with staurosporine and collection of media. Measurements on assay precision and kit-to-kit QC were always less than 10%. The M30 antigen (CK18-Asp396) was stable for 3 months at -80 degrees C, while at 37 degrees C it had a half-life of 80-100 h in healthy volunteer plasma. Results from the phase I trial are eagerly awaited.
    • Validation of ROS1 by immunohistochemistry against fluorescent in situ hybridisation on cytology and small biopsy samples in a large teaching hospital

      Narine, N.; Wallace, A. J.; Dore, J.; O'Leary-Jackson, S.; Al-Najjar, H.; Bailey, S.; Khan, K. A.; Teng, B.; Qasim, M.; Shelton, D.; et al. (2021)
      Objective: This is a prospective evaluation of ROS1 analysis by IHC against FISH on cytology and small biopsy samples in a routine diagnostic setting and demonstrates both technical and clinical validation. Methods: From 1st March to 31st December 2019, cytology cell blocks and small biopsy samples from a selected cohort of NSCLC patients were concurrently tested for ROS1 gene rearrangement by Vysis 6q22 Break Apart FISH probe and IHC using Cell Signalling D4D6 antibody. Mismatch cases were tested by an RNA fusion NGS panel. Results: In a prospective population of 95 cases, 91 were negative and 2 were positive by both FISH and IHC. Both dual positive cases were female never smokers and benefited from TKI treatment. Another 2 cases were positive by FISH but negative by IHC and repeat by NGS showed one to be negative but one failed. Turnaround time for IHC was 0 to 8 days from request to authorisation whilst that of FISH was 9 to 42 days at a cost of £51 and £159 respectively. Conclusion: IHC to assess for the protein product of ROS1 gene rearrangement on cytology cell blocks and small biopsy samples in a routine setting is a promising screening method to assess eligibility for TKI treatment with positive and indeterminate cases confirmed by FISH or NGS as it has good NPV, faster turnaround time and is cost effective with proven technical and clinical validation