• Waiting times for treatment of rectal cancer in North West England.

      Duff, Sarah E; Wood, C; McCredie, V; Levine, Edward; Saunders, Mark P; O'Dwyer, Sarah T; Department of Surgery, Christie Hospital NHS Trust, Manchester M20 4BX, UK. saraheduff@aol.com (2004-03)
      An interim goal of the NHS National Cancer Plan is that, by 2005, patients with cancer should be treated within one month of diagnosis and within two months from urgent general practitioner referral. Preoperative radiotherapy for rectal cancer reduces the risk of local recurrence and may translate into improved patient survival. We conducted a prospective audit of existing waiting times for preoperative radiotherapy experienced by 65 patients with rectal cancer referred to the Christie Cancer Centre, Manchester, UK, between May and November 2002. The median time between referral from the surgeon to the start of radiotherapy was 40 days (range 11-85). Only 4 patients (6%) received radiotherapy within 28 days of referral by the surgeon. 62 patients (95%) underwent surgery within 14 days of completing radiotherapy. Delays in the provision of preoperative radiotherapy were primarily due to shortages of radiography staff and equipment. Lack of such infrastructure will prove a major stumbling block to achieving the targets of the NHS Cancer Plan.
    • Warburg meets autophagy: cancer-associated fibroblasts accelerate tumor growth and metastasis via oxidative stress, mitophagy, and aerobic glycolysis.

      Pavlides, S; Vera, I; Gandara, Ricardo; Sneddon, Sharon; Pestell, R G; Mercier, I; Martinez-Outschoorn, U E; Whitaker-Menezes, D; Howell, Anthony; Sotgia, Federica; et al. (2012-06-01)
      Here, we review certain recent advances in oxidative stress and tumor metabolism, which are related to understanding the contributions of the microenvironment in promoting tumor growth and metastasis. In the early 1920s, Otto Warburg, a Nobel Laureate, formulated a hypothesis to explain the "fundamental basis" of cancer, based on his observations that tumors displayed a metabolic shift toward glycolysis. In 1963, Christian de Duve, another Nobel Laureate, first coined the phrase auto-phagy, derived from the Greek words "auto" and "phagy," meaning "self" and "eating." RECENT ADVANCES: Now, we see that these two ideas (autophagy and aerobic glycolysis) physically converge in the tumor stroma. First, cancer cells secrete hydrogen peroxide. Then, as a consequence, oxidative stress in cancer-associated fibroblasts drives autophagy, mitophagy, and aerobic glycolysis.
    • Watch and wait or surgery for clinical complete response in rectal cancer: a need to study both sides

      Parmar, Kat; Malcomson, Lee; Renehan, Andrew G; Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester (2019)
      In patients with rectal cancer who achieve clinical complete response (cCR) after neoadjuvant chemoradiotherapy (nCRT), watch and wait (W&W) is a novel management strategy with the potential to avoid major surgery.[1] W&W is not yet standard of care, nor is it offered routinely. The 2019 UK National Institute for Health and Care Excellence (NICE) guidelines [2] recommend that deferral of surgery in this setting should be in the context of a clinical trial or national registry.
    • Watch-and-wait approach for rectal cancer: concepts of a subject-specific method.

      Renehan, Andrew G; Malcomson, Lee; Emsley, R; Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK (2017-09)
    • Watch-and-wait approach versus surgical resection after chemoradiotherapy for patients with rectal cancer (the OnCoRe project): a propensity-score matched cohort analysis.

      Renehan, Andrew G; Malcomson, L; Emsley, R; Gollins, S; Maw, A; Myint, A; Rooney, P; Susnerwala, S; Blower, Anthony; Saunders, Mark P; et al. (2015-12-16)
      Induction of a clinical complete response with chemoradiotherapy, followed by observation via a watch-and-wait approach, has emerged as a management option for patients with rectal cancer. We aimed to address the shortage of evidence regarding the safety of the watch-and-wait approach by comparing oncological outcomes between patients managed by watch and wait who achieved a clinical complete response and those who had surgical resection (standard care).
    • Watch-and-wait strategy in rectal cancer - authors' reply.

      Chadi, S; Beets, G; Perez, R; Renehan, Andrew G; Division of Surgical Oncology and General Surgery, Princess Margaret Hospital and University Health Network, University of Toronto, Toronto, ON, Canada (2019)
      Background: Constitutional loss of function (LOF) single nucleotide polymorphisms (SNPs) in pattern recognition receptors FPR1, TLR3, and TLR4 have previously been reported to predict oxaliplatin benefit in colorectal cancer. Confirmation of this association could substantially improve patient stratification. Methods: We performed a retrospective biomarker analysis of the Short Course in Oncology Therapy (SCOT) and COIN/COIN-B trials. Participant status for LOF variants in FPR1 (rs867228), TLR3 (rs3775291), and TLR4 (rs4986790/rs4986791) was determined by genotyping array or genotype imputation. Associations between LOF variants and disease-free survival (DFS) and overall survival (OS) were analyzed by Cox regression, adjusted for confounders, using additive, dominant, and recessive genetic models. All statistical tests were two-sided. Results: Our validation study populations included 2929 and 1948 patients in the SCOT and COIN/COIN-B cohorts, respectively, of whom 2728 and 1672 patients had functional status of all three SNPs determined. We found no evidence of an association between any SNP and DFS in the SCOT cohort, or with OS in either cohort, irrespective of the type of model used. This included models for which an association was previously reported for rs867228 (recessive model, multivariable-adjusted hazard ratio [HR] for DFS in SCOT?=?1.19, 95% confidence interval [CI]?=?0.99 to 1.45, P?=?.07; HR for OS in COIN/COIN-B?=?0.92, 95% CI?=?0.63 to 1.34, P?=?.66), and rs4986790 (dominant model, multivariable-adjusted HR for DFS in SCOT?=?0.86, 95% CI?=?0.65 to 1.13, P?=?.27; HR for OS in COIN/COIN-B?=?1.08, 95% CI?=?0.90 to 1.31, P?=?.40). Conclusion: In this prespecified analysis of two large clinical trials, we found no evidence that constitutional LOF SNPs in FPR1, TLR3, or TLR4 are associated with differential benefit from oxaliplatin. Our results suggest these SNPs are unlikely to be clinically useful biomarkers.
    • Watch-and-wait versus surgical resection for patients with rectal cancer - Authors' reply.

      Renehan, Andrew G; Malcomson, Lee; Emsley, R; Scott, N; O'Dwyer, Sarah T; Institute of Cancer Sciences, Manchester Academic Health Science Centre, University of Manchester, Manchester M20 4BX, UK (2016-04)
    • Wearable technology is it the future?

      Cave, Louise; Digital Services, The Christie NHS Foundation Trust, Manchester, UK (2021)
      Background The aim of this research project is to review the current literature on wearable devices to monitor patient vital signs and understand the feasibility of introducing a similar device to a fast paced inpatient haematology ward. Neutropenic sepsis (NS) is recognised as one of the most fatal conditions that can be experienced by a patient undergoing an allogeneic stem cell transplant. NS is time critical with the ideal time to needle being under an hour. The inability to continuously monitor patients when they become septic led to nurses anecdotally reporting higher anxiety for their patients. The definition in acute care is that wearable vital sign monitoring devices may be defined as body- worn technologies that facilitate continuous, real-time vital sign monitoring without the need for nurse-to-patient contact or restrictive leads connecting the patient to wall-mounted or free-standing equipment. Results Four themes were identified from the literature: device clinically validated (33%),device not clinically validated (29%), devices ability to enable an early response to the deteriorating patient (24%) and devices ability to help reduce the length of hospital stay (5%). Conclusions From examining the literature the technology is still newly emerging and whilst increasingly more devices have been FDA approved and CE marked they haven't necessarily been clinically validated. It is evident that at this stage there is not a device that can replace all intermittent observations for all patients within the inpatient setting.There are some clear gaps in the literature around the acceptability to patients and the potential mental health effects of reducing the regular contact point with nursing staff. Within Haematology and Oncology the future use of wearable devices in the ambulatory care setting is likely to be introduced.
    • Weekly dose-dense chemotherapy in first-line epithelial ovarian, fallopian tube, or primary peritoneal carcinoma treatment (ICON8): primary progression free survival analysis results from a GCIG phase 3 randomised controlled trial

      Clamp, Andrew R; James, EC; McNeish, IA; Dean, A; Kim, JW; O'Donnell, DM; Hook, J; Coyle, C; Blagden, S; Brenton, JD; et al. (2019)
      BACKGROUND: Carboplatin and paclitaxel administered every 3 weeks is standard-of-care first-line chemotherapy for epithelial ovarian cancer. The Japanese JGOG3016 trial showed a significant improvement in progression-free and overall survival with dose-dense weekly paclitaxel and 3-weekly carboplatin. In this study, we aimed to compare efficacy and safety of two dose-dense weekly regimens to standard 3-weekly chemotherapy in a predominantly European population with epithelial ovarian cancer. METHODS: In this phase 3 trial, women with newly diagnosed International Federation of Gynecology and Obstetrics stage IC-IV epithelial ovarian cancer were randomly assigned to group 1 (carboplatin area under the curve [AUC]5 or AUC6 and 175 mg/m2 paclitaxel every 3 weeks), group 2 (carboplatin AUC5 or AUC6 every 3 weeks and 80 mg/m2 paclitaxel weekly), or group 3 (carboplatin AUC2 and 80 mg/m2 paclitaxel weekly). Written informed consent was provided by all women who entered the trial. The protocol had the appropriate national research ethics committee approval for the countries where the study was conducted. Patients entered the trial after immediate primary surgery, or before neoadjuvant chemotherapy with subsequent planned delayed primary surgery. The trial coprimary outcomes were progression-free survival and overall survival. Data analyses were done on an intention-to-treat basis, and were powered to detect a hazard ratio of 0á75 in progression-free survival. The main comparisons were between the control group (group 1) and each of the weekly research groups (groups 2 and 3). FINDINGS: Between June 6, 2011, and Nov 28, 2014, 1566 women were randomly assigned to treatment. 72% (365), completed six protocol-defined treatment cycles in group 1, 60% (305) in group 2, and 63% (322) in group 3, although 90% (454), 89% (454), and 85% (437) completed six platinum-based chemotherapy cycles, respectively. Paclitaxel dose intensification was achieved with weekly treatment (median total paclitaxel dose 1010 mg/m2 in group 1; 1233 mg/m2 in group 2; 1274 mg/m2 in group 3). By February, 2017, 1018 (65%) patients had experienced disease progression. No significant progression-free survival increase was observed with either weekly regimen (restricted mean survival time 24á4 months [97á5% CI 23á0-26á0] in group 1, 24á9 months [24á0-25á9] in group 2, 25á3 months [23á9-26á9] in group 3; median progression-free survival 17á7 months [IQR 10á6-not reached] in group 1, 20á8 months [11á9-59á0] in group 2, 21á0 months [12á0-54á0] in group 3; log-rank p=0á35 for group 2 vs group 1; group 3 vs 1 p=0á51). Although grade 3 or 4 toxic effects increased with weekly treatment, these effects were predominantly uncomplicated. Febrile neutropenia and sensory neuropathy incidences were similar across groups. INTERPRETATION: Weekly dose-dense chemotherapy can be delivered successfully as first-line treatment for epithelial ovarian cancer but does not significantly improve progression-free survival compared with standard 3-weekly chemotherapy in predominantly European populations.
    • Weekly integral dose and use of lipid lowering drugs are associated with worsening of functional outcomes in prostate cancer patients treated with IMRT.

      Cicchetti, A; Rancati, T; Joseph, N; Chang-Claude, J; Giandini, T; Fiorino, C; Cozzarini, C; Palorini, F; Morlino, S; Davidson, Susan E; et al. (2017-10)
    • Weekly paclitaxel in the treatment of recurrent ovarian carcinoma.

      Byrd, Louise M; Thistlethwaite, Fiona C; Clamp, Andrew R; Ton, Nhuan C; Hasan, Jurjees; Jayson, Gordon C; Cancer Research UK, Department of Medical Oncology, Christie Hospital NHS Trust, Manchester, UK. (2007)
      PURPOSE: To study the effect of weekly paclitaxel in the treatment of recurrent ovarian and peritoneal carcinoma. METHODS: A retrospective analysis of patients treated at Christie Cancer Centre between May 2003 and May 2005 was carried out. RESULTS: Fortynine patients with recurrent ovarian and peritoneal carcinoma were treated. The mean duration of treatment was 11 weeks, with 27 (54%) patients receiving 12 or more treatments. The most frequent non-haematological toxicities reported were mild nausea, constipation, lethargy and neuropathy. Moderate anaemia was noted in 50% of patients. Radiological assessment by CT scanning showed that complete or partial responses were achieved in 28% of patients. CA125 response was demonstrated in 63% of patients. Median time to recurrence was 149 days and median survival was 359 days. CONCLUSION: This study provides evidence for the role of weekly paclitaxel in the treatment of recurrent ovarian and peritoneal carcinoma even in a drug-resistant setting following multiple lines of prior therapy.
    • Weekly platinum-based chemotherapy versus 3-weekly platinum-based chemotherapy for newly diagnosed ovarian cancer (ICON8): quality-of-life results of a phase 3, randomised, controlled trial

      Blagden, S. P.; Cook, A. D.; Poole, C.; Howells, L.; McNeish, I. A.; Dean, A.; Kim, J. W.; O'Donnell, D. M.; Hook, J.; James, E. C.; et al. (2020)
      Background: The ICON8 study reported no significant improvement in progression-free survival (a primary endpoint) with weekly chemotherapy compared with standard 3-weekly treatment among patients with epithelial ovarian cancer. All ICON8 patients were eligible to take part in the accompanying health-related quality-of-life study, which measured the effect of treatment on self-reported wellbeing, reported here. Methods: In this open-label, randomised, controlled, phase 3, three-arm, Gynecologic Cancer Intergroup (GCIG) trial done at 117 hospital sites in the UK, Australia, New Zealand, Mexico, South Korea, and Republic of Ireland, women (aged at least 18 years) with newly diagnosed, histologically confirmed International Federation of Gynecology and Obstetrics stage IC-IV ovarian cancer and an Eastern Cooperative Oncology Group performance status of 0-2 were randomly assigned (1:1:1) centrally using minimisation to group 1 (intravenous carboplatin area under the curve [AUC]5 or AUC6 and 175 mg/m2 intravenous paclitaxel every 3 weeks), group 2 (carboplatin AUC5 or AUC6 every 3 weeks and 80 mg/m2 paclitaxel weekly), or group 3 (carboplatin AUC2 weekly and 80 mg/m2 paclitaxel weekly). Randomisation was stratified by GCIG group, disease stage, and outcome and timing of surgery. Patients and clinicians were not masked to treatment assignment. Patients underwent immediate or delayed primary surgery according to clinicians' choice. Patients were asked to complete European Organisation for Research and Treatment of Cancer QLQ-C30 and QLQ-OV28 questionnaires at enrolment, before each chemotherapy cycle, then 6-weekly up to 9 months, 3-monthly up to 2 years, and 6-monthly up to 5 years. Quality of life was a prespecified secondary outcome of the ICON8 study. Within the quality-of-life study, the co-primary endpoints were QLQ-C30 global health score at 9 months (cross-sectional analysis) and mean QLQ-C30 global health score from randomisation to 9 months (longitudinal analysis). Data analyses were done on an intention-to-treat basis. The trial is registered on ClinicalTrials.gov, NCT01654146 and ISRCTN Registry, ISRCTN10356387, and is currently in long-term follow up. Findings: Between June 6, 2011, and Nov 28, 2014, 1566 patients were recruited into ICON8 (522 were included in group 1, 523 in group 2, and 521 in group 3). Baseline quality-of-life questionnaires were completed by 1438 (92%) of 1566 patients and 9-month questionnaires by 882 (69%) of 1280 patients. We observed no significant difference in global health score at 9 months (cross-sectional analysis) between study groups (group 2 vs group 1, difference in mean score 2·3, 95% CI -0·4 to 4·9, p=0·095; group 3 vs group 1, -0·8, -3·8 to 2·2, p=0·61). Using longitudinal analysis, we found lower global health scores for those receiving weekly paclitaxel than for those receiving 3-weekly chemotherapy (group 2 vs group 1, mean difference -1·8, 95% CI -3·6 to -0·1, p=0·043; group 3 vs group 1, -2·9, -4·7 to -1·1, p=0·0018). Interpretation: We found no evidence of a difference in global quality of life between treatment groups at 9 months; however, patients receiving weekly treatment reported lower mean quality of life across the 9-month period after randomisation. Taken together with the lack of progression-free survival benefit, these findings do not support routine use of weekly paclitaxel-containing regimens in the management of newly diagnosed ovarian cancer.
    • Weekly VAPEC-B chemotherapy for high grade non-Hodgkin's lymphoma: results of treatment in 184 patients.

      Radford, John A; Whelan, J S; Rohatiner, A Z; Deakin, David P; Harris, Martin; Stansfeld, A G; Swindell, Ric; Wilkinson, Peter M; James, Roger D; Lister, T A; et al. (1994-02)
      BACKGROUND AND PATIENTS: A weekly schedule of chemotherapy (VAPEC-B) has been used to treat 184 consecutive patients with high grade non-Hodgkin's lymphoma (NHL). Median age for the group was 57 years (range 17-84) and 56% had stage IV disease. RESULTS: Following chemotherapy, 114 (62%) patients achieved CR or CR(u), 32 (17%) PR and 15 (8%) had not responded or progressed. Response to VAPEC-B was highly stage dependent with 70% or more of patients with stages I-III achieving CR or CR(u) but only 50% of those with stage IV. Twenty-four (15%) patients died during treatment with VAPEC-B and in 13 cases death was due to sepsis. This complication occurred mainly in patients with stage IV disease aged 60 years or older. After a median follow up period of 4.1 years, the actuarial 4 year survival for 184 patients is 45%, an overall result heavily influenced by the poor outcome for 103 patients with stage IV disease (4 year survival of 28%). Patients with earlier stage disease fared correspondingly better (44% for stage III, 68% for stage II and 80% for stage I). CONCLUSIONS: VAPEC-B gives similar results to other chemotherapy regimens currently used in the treatment of high grade NHL and has the advantage of brevity. Caution is advised in patients over the age of 60 especially in the presence of stage IV disease and dose reduction or haemopoietic growth factor support should be considered in these circumstances.
    • Weekly versus tri-weekly paclitaxel with carboplatin for first-line treatment in women with epithelial ovarian cancer

      Ngoi, N. Y.; Syn, N. L.; Goh, R. M.; Goh, B. C.; Huang, R. Y.; Soon, Y. Y.; James, E.; Cook, A.; Clamp, A.; Tan, D. S.; et al. (2022)
      Background Epithelial ovarian cancer is the sixth most common cancer worldwide: 295,414 new cases were diagnosed in 2018, with 184,799 deaths. The lack of an effective screening strategy has led to the majority of women being diagnosed at an advanced stage. For these women, intravenous carboplatin combined with paclitaxel for six cycles is widely accepted as the standard first‐line treatment for epithelial ovarian cancer, in combination with debulking surgery. However, there is conflicting evidence regarding the optimal dosing schedule of paclitaxel when combined with carboplatin in this setting. Objectives To compare the efficacy and tolerability of intravenous weekly paclitaxel with that of tri‐weekly paclitaxel, in combination with intravenous carboplatin, as first‐line treatment for epithelial ovarian cancer (defined as epithelial ovarian, primary peritoneal and fallopian tube cancer). Search methods We searched CENTRAL, MEDLINE, and Embase databases for relevant studies up to 15 November 2021, using keywords and MeSH terms. We additionally handsearched conference libraries, online clinical trial databases and screened through lists of retrieved references. Selection criteria We Included randomised controlled trials (RCTs) comparing weekly paclitaxel in combination with carboplatin versus tri‐weekly paclitaxel in combination with carboplatin, for treatment of newly‐diagnosed epithelial ovarian cancer. Data collection and analysis We used the hazard ratio (HR) to estimate the primary efficacy outcomes progression‐free (PFS) and overall survival (OS). We used the risk ratio (RR) to estimate the primary toxicity outcome of severe neutropenia and secondary outcomes of quality of life (QoL) and treatment‐related adverse events. Two review authors independently selected studies, extracted data, and assessed risk of bias, using standard Cochrane methodological procedures. We included individual participant data (IPD) from one of the included studies, ICON‐8, provided by the study team. We analysed data using a random‐effects model in Review Manager 5.4 software. Additionally, we reconstructed IPD for PFS and OS data from published Kaplan‐Meier curves from all studies and subsequently pooled these to analyse the two primary efficacy outcomes. Main results From 2469 records, we identified four eligible RCTs with data for 3699 participants. All eligible studies were included in the main meta‐analysis and reported on PFS and OS. There was likely a slight improvement in PFS when paclitaxel was dosed weekly compared to tri‐weekly (HR 0.89, 95% confidence interval (CI) 0.81 to 0.98; 4 studies, 3699 participants; moderate‐certainty evidence). We found little to no improvement in OS when paclitaxel was dosed weekly compared to tri‐weekly (HR 0.92, 95% CI 0.79 to 1.06; 4 studies, 3699 participants; high‐certainty evidence). There was likely little to no difference in high‐grade (grade 3 or 4) neutropenia when paclitaxel was dosed weekly compared to tri‐weekly (RR 1.11, 95% CI 0.86 to 1.43; 4 studies, 3639 participants; moderate‐certainty evidence). However, weekly paclitaxel increased high‐grade (grade 3 or 4) anaemia when compared to tri‐weekly dosing (RR 1.57, 95% CI 1.12 to 2.20; 4 studies, 3639 participants; high‐certainty evidence). There may be little to no difference in high‐grade neuropathy when paclitaxel was dosed weekly compared to tri‐weekly (RR 1.12, 95% CI 0.64 to 1.94; 4 studies, 3639 participants; low‐certainty evidence). The overall risk of detection bias and performance bias was low for OS, but was unclear for other outcomes, as treatments were not blinded. The risk of bias in other domains was low or unclear. We note that OS data were immature for three of the included studies (GOG‐0262, ICON‐8 and MITO‐7). Authors' conclusions Weekly paclitaxel combined with carboplatin for first‐line treatment of epithelial ovarian cancer likely improves PFS slightly (moderate‐certainty evidence) but not OS (high‐certainty evidence), compared to tri‐weekly paclitaxel combined with carboplatin. However, this was associated with increased risk for high‐grade anaemia, treatment discontinuation, dose delays and dose omissions (high‐ to low‐certainty evidence). Our findings may not apply to women receiving bevacizumab in first‐line therapy, those receiving treatment in the neo‐adjuvant setting, or those with rare subtypes of clear cell or mucinous ovarian cancer.
    • Weekly versus twice weekly bortezomib given in conjunction with rituximab, in patients with recurrent follicular lymphoma, mantle cell lymphoma and Waldenström macroglobulinaemia.

      Agathocleous, A; Rohatiner, A; Rule, S; Hunter, H; Kerr, J; Neeson, Susan M; Matthews, J; Strauss, S; Montoto, S; Johnson, P; et al. (2010-11)
      The combination of bortezomib and rituximab was evaluated in patients with mantle cell lymphoma (MCL), follicular lymphoma (FL) and Waldenström macroglobulinaemia (WM), in a Phase I and later, a randomized Phase II study. In the randomized study, 42 patients with recurrent/refractory disease received either: bortezomib 1·3 mg/m(2) on days 1, 4, 8 and 11 of a 3-week cycle with rituximab 375 mg/m(2) on day 1 (21 patients) or: bortezomib 1·6 mg/m(2) and rituximab on days 1, 8, 15 and 22 of a 5-week cycle (with rituximab being given only in cycles 1 and 4).Twenty-eight patients were withdrawn (toxicity 16, progression 7, and 'patient choice' 5). The main toxicities were neurological, gastro-intestinal and haematological. The overall response rate was 28/42(67%) and by histology: MCL 11/19, FL 8/15, and WM 9/10. Ten of 28 responding patients remained progression-free at 1-3·5 years. Toxicity and efficacy were equivalent between the two groups. The combination has significant toxicity but is effective, particularly in patients with WM.
    • Weibel-Palade bodies as a marker for neovascularization induced by tumor and rheumatoid angiogenesis factors.

      Kumar, Patricia; Erroi, A; Sattar, A; Kumar, Shant; Manchester Polytechnic, Chester Street, Manchester, M1 5GD (1985-09)
      An analysis was made of ultrastructural changes in capillary endothelial cells in experimentally induced angiogenesis and in a human pathological situation known to involve increased angiogenesis. Chick chorioalloantoic membrane (CAM) showing a positive angiogenic response to low-molecular weight angiogenesis factor isolated from rat Walker sarcoma or from human rheumatoid joint was compared with untreated CAM. Serotonin-treated CAM provided an additional control in that serotonin has the capacity to stimulate endothelial cell growth in vitro but did not induce angiogenesis on the CAM. Human rheumatoid joints were studied using normal healthy human joints as controls. The number of Weibel-Palade (W-P) bodies per unit of cytoplasmic area were higher in tumor angiogenesis factor-treated CAMs (not significant) and rheumatoid angiogenesis factor-treated CAMs (P less than 0.008) than in untreated controls. These differences were more pronounced if W-P body volumetric density was analyzed (P in both cases less than 0.008). Serotonin-treated control CAMs did not show higher numbers of W-P body or greater WPV than untreated controls. Numbers of W-P body and W-P body volumetric density were higher (P less than 0.008) in rheumatoid joints than normal joints. Median values for W-P body number were 16-fold higher and, for W-P body volumetric density, they were up to 30-fold higher in rheumatoid joints.
    • Weight change associated With telotristat ethyl in the treatment of carcinoid syndrome.

      Weickert, M; Kaltsas, G; Hoersch, D; Lapuerta, P; Pavel, M; Valle, Juan W; Caplin, M; Bergsland, E; Kunz, P; Anthony, L; et al. (2018)
    • Weight loss during intrauterine progestin treatment for obesity-associated atypical hyperplasia and early stage cancer of the endometrium

      Barr, C. E.; Ryan, N. A.; Derbyshire, A. E.; Wan, Y. L.; MacKintosh, M. L.; McVey, R. J.; Bolton, J.; Fitzgerald, C.; Awad, D.; Slade, Richard J; et al. (2021)
      Intrauterine progestin is a treatment option for women with atypical hyperplasia or low-risk endometrial cancer who wish to preserve their fertility, or whose poor surgical fitness precludes safe hysterectomy. We hypothesized that in such women with obesity, weight loss during progestin treatment may improve oncological outcomes. We conducted a prospective non-randomized study of women with obesity and atypical hyperplasia or low-grade stage 1a endometrial cancer undergoing progestin treatment. Women with a BMI{greater than or equal to}35kg/m2 were offered bariatric surgery; those who declined and those with BMI 30-34.9kg/m2 were encouraged to lose weight by low-calorie diet. We assessed uptake of bariatric surgery; weight lost during progestin treatment; and the impact of >10% total body weight loss on progestin treatment response at 12 months. 71 women [median age 58years-(IQR 35-65); mean BMI 48kg/m2-(SD 9.3)] completed the study. 23 women (32%) had bariatric surgery, on average 5 months (IQR 3-8) after progestin treatment commenced. Weight change during progestin treatment was -33.4kg (95%CI -42.1, -24.7) and -4.6kg (95%CI -7.8, -1.4) in women receiving bariatric surgery and low-calorie diet, respectively (p<0.001). 43 women (61%) responded to progestin, while 23(32%) showed stabilized and 5(7%) progressive disease. Response at 12 months was not predicted by age or baseline BMI, but women who lost >10% of their total body weight were more likely to respond to progestin than those who did not (adjusted odds ratio 3.95; 95%CI 1.3, 12.5; p=0.02). Thus weight loss may improve oncological outcomes in women with obesity-associated endometrial neoplastic abnormalities treated with progestin.
    • What are the benefits and harms of risk stratified screening as part of the NHS breast screening Programme? Study protocol for a multi-site non-randomised comparison of BC-predict versus usual screening (NCT04359420)

      French, DP; Astley, S; Brentnall, AR; Cuzick, J; Dobrashian, R; Duffy, SW; Gorman, LS; Harkness, EF; Harrison, F; Harvie, Michelle N; et al. (2020)
      Background: In principle, risk-stratification as a routine part of the NHS Breast Screening Programme (NHSBSP) should produce a better balance of benefits and harms. The main benefit is the offer of NICE-approved more frequent screening and/ or chemoprevention for women who are at increased risk, but are unaware of this. We have developed BC-Predict, to be offered to women when invited to NHSBSP which collects information on risk factors (self-reported information on family history and hormone-related factors via questionnaire; mammographic density; and in a sub-sample, Single Nucleotide Polymorphisms). BC-Predict produces risk feedback letters, inviting women at high risk (?8% 10-year) or moderate risk (?5 to < 8% 10-year) to have discussion of prevention and early detection options at Family History, Risk and Prevention Clinics. Despite the promise of systems such as BC-Predict, there are still too many uncertainties for a fully-powered definitive trial to be appropriate or ethical. The present research aims to identify these key uncertainties regarding the feasibility of integrating BC-Predict into the NHSBSP. Key objectives of the present research are to quantify important potential benefits and harms, and identify key drivers of the relative cost-effectiveness of embedding BC-Predict into NHSBSP. Methods: A non-randomised fully counterbalanced study design will be used, to include approximately equal numbers of women offered NHSBSP (n = 18,700) and BC-Predict (n = 18,700) from selected screening sites (n = 7). In the initial 8-month time period, women eligible for NHSBSP will be offered BC-Predict in four screening sites. Three screening sites will offer women usual NHSBSP. In the following 8-months the study sites offering usual NHSBSP switch to BC-Predict and vice versa. Key potential benefits including uptake of risk consultations, chemoprevention and additional screening will be obtained for both groups. Key potential harms such as increased anxiety will be obtained via self-report questionnaires, with embedded qualitative process analysis. A decision-analytic model-based cost-effectiveness analysis will identify the key uncertainties underpinning the relative cost-effectiveness of embedding BC-Predict into NHSBSP. Discussion: We will assess the feasibility of integrating BC-Predict into the NHSBSP, and identify the main uncertainties for a definitive evaluation of the clinical and cost-effectiveness of BC-Predict. Trial registration: Retrospectively registered with clinicaltrials.gov (NCT04359420). Keywords: Anxiety; Breast cancer; Chemoprevention; Early detection; High risk; Mammographic density; Psychological impact; Risk stratification; Screening; Tyrer-Cuzick.
    • What are the main causes of interfraction motion of the uterine fundus and cervix?

      Cree, Anthea; Vasquez Osorio, Eliana; Price, G.; Van Herk, Marcel; Hoskin, Peter J; Choudhury, Ananya; McWilliam, Alan; The Christie Hospital NHS Foundation Trust, Manchester, UK. (2020)
      Purpose or Objective Interfraction motion of uterus and cervix can be large and often exceeds applied CTV-PTV margins. There is variation between patients and different parts of the uterus move differently. Most strategies accounting for this are based on bladder filling. However, we hypothesise that there are other causes of uterine motion. Our study aims to provide a qualitative assessment of causes of motion of the uterine fundus and cervix in a large cohort of patients. Material and Methods Anonymised scans were retrospectively obtained for 83 patients who received radical radiotherapy for cervical cancer, with imaging at 3 time points (Fig. 1); diagnostic MRI scan (1), planning CT, ~2 weeks later (2) and final week MRI scan, ~6 weeks later (3). Scans were registered on bony anatomy to the diagnostic MRI for each patient. The uterus was contoured by a single observer for all 249 scans on a single sagittal slice identified as mid of the uterus on scan 1. Motion at the cervix and uterine fundus was evaluated between scans 1-2 (S1-2) and 1-3 (S1-3). The main cause of motion and direction of motion was recorded based on visual interpretation. Results In S1-2, large motion (>1cm) was seen in 44 cases (53%) at the cervix level and in 65 (78%) at the fundus level. In S1- 3, this was 57 (69%) at the cervix level and 64 (77%) at the fundus level. Large motion at the cervix rarely occurred without large motion at the fundus: in S1-2, 3 cases (4%) and S1-3, 9 cases (11%). The main causes and direction of motion are summarised in figure 2. For the cervix, the most common cause of motion in S1-2 was rectal change with 30 cases (36%) and in S1-3 it was tumour regression, also with 30 cases (36%). Bladder filling differences only accounted for cervix motion in 5 cases (6%) in S1-2 and 1 case (1%) in S1-3. Main drivers of motion at the fundus were bladder filling with 23 cases (28%) in S1-2 and 18 cases (22%) in S1-3. However, motion was also related to rectal changes in 13 cases (16%) in S1-2 and S1-3, to bowel changes in 21 cases (25 %) in S1-2 and 12 cases (15%) in S1- 3, and to tumour regression in 16 cases (19%) in S1-3. At the cervix, in S1-2, there was a superior/inferior component of motion in 20 cases (24%), mainly related to rectal changes. In S1-3, there was a superior/inferior component of motion in 38 cases (45%), mainly related to tumour regression. Conclusion The main causes of cervical motion in our cohort are changes in rectal filling and tumour regression, with bladder filling playing a limited role. Motion at the uterine fundus is affected by bladder filling but other factors also have an important role. Rectal motion can lead to changes in the superior/inferior position of the cervix, which should be considered if developing an ITV. Our study suggests that current radiotherapy motion management strategies based on bladder filling may not account for the most important causes of cervix motion. Alternative approaches such as online adaption may be beneficial.