• Ipilimumab in the real world: the UK expanded access programme experience in previously treated advanced melanoma patients.

      Ahmad, S; Qian, W; Ellis, S; Mason, Elaine; Khattak, M; Gupta, A; Shaw, H; Quinton, A; Kovarikova, J; Thillai, K; et al. (2015-10)
      Before licensing, ipilimumab was first made available to previously treated advanced melanoma patients through an expanded access programme (EAP) across Europe. We interrogated data from UK EAP patients to inform future clinical practice. Clinicians registered in the UK EAP provided anonymized patient data using a prespecified variable fields datasheet. Data collected were baseline patient characteristics, treatment delivered, toxicity, response, progression-free survival and overall survival (OS). Data were received for 193 previously treated metastatic melanoma patients, whose primary sites were cutaneous (82%), uveal (8%), mucosal (2%), acral (3%) or unknown (5%). At baseline, 88% of patients had a performance status (PS) of 0-1 and 20% had brain metastases. Of the patients, 53% received all four planned cycles of ipilimumab; the most common reason for stopping early was disease progression, including death from melanoma. Toxicity was recorded for 171 patients, 30% of whom experienced an adverse event of grade 3 or higher, the most common being diarrhoea (13%) and fatigue (9%). At a median follow-up of 23 months, the median progression-free survival and OS were 2.8 and 6.1 months, respectively; the 1-year and 2-year OS rates were 31 and 14.8%, respectively. The 2-year OS was significantly lower for patients with poorer PS (P<0.0001), low albumin concentrations (P<0.0001), the presence of brain metastases (P=0.007) and lactate dehydrogenase levels more than two times the upper limit of normal (P<0.0001) at baseline. These baseline characteristics are negative predictors of benefit from ipilimumab and should be taken into consideration before prescription.
    • Ipilimumab versus ipilimumab plus anti-PD-1 for metastatic melanoma - Authors' reply

      da Silva, I. P.; Ahmed, T.; Reijers, I. L. M.; Warner, A. B.; Patrinely, J. R.; Serra-Bellver, Patricio; Allayous, C.; Mangana, J.; Zimmer, L.; Trojaniello, C.; et al. (2021)
    • The iR(2) regimen(ibrutinib, lenalidomide, and rituximab) is active with a manageable safety profile in patients with relapsed/refractory non-germinal center-like diffuse large B-cell lymphoma

      Ramchandren, R; Johnson, P; Ghosh, N; Ruan, J; Ardeshna, M; Johnson, R; Verhoef, G; Cunningham, D; de Vos, S; Kassam, S; et al. (2018)
    • Irinotecan with or without capecitabine as a beyond 2nd line regime for esophago-gastric adenocarcinomas

      Hapuarachi, Sonal B; Dawod, Mohammed; Weaver, Jamie M; Shaheen, Fadhel; Khan, Adeel; Hubner, Richard A; Waddell, Tom; Mansoor, Was; Christie NHS Foundation Trust, Manchester (2020)
      Background: Purpose: The aim of this retrospective study was to assess the efficacy and toxicity of irinotecan +/- capecitabine for patients with metastatic esophago-gastric (EG) adenocarcinomas previously treated with at least two chemotherapy regimens including platinum-based, fluoropyramidines and taxanes. Introduction: Treatment for metastatic EG cancer beyond 2nd line remains controversial. Recently, the TAGS phase III trial (Shitara et al., 2018) showed overall survival benefit with Trifluridine/tipiracil of 2.1 months compared to placebo as a third line. Apatinib is also approved for use as third line in China (Li et al., 2013). Based on minimal evidence (Kang et al., 2013), irinotecan in combination with capecitabine is used in the UK. We performed a retrospective study to assess the efficacy and toxicity of irinotecan as a beyond 2nd line regime in metastatic EG adenocarcinomas in one of Europe’s largest cancer centres, The Christie. Methods: Data was collected retrospectively from all metastatic EG adenocarcinoma patients who were treated with irinotecan +/- capecitabine as a beyond 2nd line palliative treatment at the Christie Hospital from January 2014 to December 2019. Irinotecan was either given 2 or 3 weekly at dose of 180 mg/m² with or without capecitabine 800 mg/m². Response rate (RR) was calculated according to RECIST version 1.1, overall survival measured and toxicity data collected. Results: Fifty-six patients received irinotecan as beyond 2nd line palliative chemotherapy. Out of the thirty-seven patients with measurable disease on their scans, the overall response rate was 8.1% and the disease control rate was 51.4% as per RECIST 1.1. Median overall survival was 5 months (95% CI 4.2-5.8). The presence of grade 3-4 toxicities was 16% (9 patients) and included neutropenia, fatigue, nausea and diarrhea. On average, 3.7 cycles were administered, 32% (18 patients) required dose reductions, mainly secondary to grade 2 diarrhea and fatigue. Conclusions: Irinotecan in combination with capecitabine is efficacious as a beyond 2nd line regime in metastatic EG with an acceptable toxicity profile with a limited role in patients with resistant disease to first line platinum-based chemotherapies with fluoropyramidines.
    • Irinotecan+5-fluorouracil with concomitant pre-operative radiotherapy in locally advanced non-resectable rectal cancer: a phase I/II study.

      Iles, S M; Gollins, Simon W; Susnerwala, Shabbir; Haylock, B; Myint, A Sun; Biswas, A; Swindell, Ric; Levine, Edward; Department of Clinical Oncology, The Christie Hospital NHS Trust, Manchester M20 4BX, UK. (2008-04-08)
      In the UK, 10% of patients diagnosed with rectal cancer have inoperable disease at presentation. This study ascertained whether the resectability rate of inoperable locally advanced rectal cancer was improved by administration of intravenous irinotecan, 5-fluorouracil (5-FU) and pelvic radiotherapy. During phase I of the trial (n=12), the dose of irinotecan was escalated in three-patient cohorts from 50 mg m(-2) to 60 mg m(-2) to 70 mg m(-2) to identify the maximum tolerated dose (60 mg m(-2)). In phase II, 31 patients with non-resectable disease received 45 Gy radiotherapy and 5-FU infusions (200 mg m(-2) per day) for 5 weeks. Irinotecan (60 mg m(-2)) was given on days 1, 8, 15 and 22. After treatment, patients were operated on if possible. Thirty patients completed the protocol, 28 underwent surgery. Before surgery, MRI restaging of 24 patients showed that 19 (79%) had a reduction in tumour stage after treatment (seven complete clinical response and 12 partial). Of 27 patients followed up after surgery, 22 (81%) had clear circumferential resection margins. Disease-free and overall survival estimates at 3 years were 65 and 90%, respectively. The regimen was well tolerated. Irinotecan, 5-FU and radiotherapy results in tumour downgrading, allowing resection of previously inoperable tumour with acceptable toxicity.
    • IRIS study: a phase II study of the steroid sulfatase inhibitor Irosustat when added to an aromatase inhibitor in ER-positive breast cancer patients.

      Palmieri, C; Stein, R; Liu, X; Hudson, E; Nicholas, H; Sasano, H; Guestini, F; Holcombe, C; Barrett, S; Kenny, L; et al. (2017-06-13)
      Irosustat is a first-generation, orally active, irreversible steroid sulfatase inhibitor. We performed a multicentre, open label phase II trial of the addition of Irosustat to a first-line aromatase inhibitor (AI) in patients with advanced BC to evaluate the safety of the combination and to test the hypothesis that the addition of Irosustat to AI may further suppress estradiol levels and result in clinical benefit.
    • Irradiation induced expression of CD31, ICAM-1 and VCAM-1 in human microvascular endothelial cells.

      Quarmby, Steven L; Hunter, Robin D; Kumar, Shant; Department of Pathological Sciences, Medical School, Manchester University M13 9PT, U.K. steven.l.quarmby@man.ac.uk (2000)
      The adherence and migration of leukocytes through the endothelium of blood vessels is an important early event which occurs in normal tissues following ionizing irradiation but the underlying mechanisms are not fully understood. ICAM-1, VCAM-1 and CD31 are membrane proteins of endothelial cells, mediate this process when the vasculature is exposed to other inflammatory stimuli. In this study, expression of ICAM-1, VCAM-1 and CD31 on human dermal microvascular endothelial cells (HDMECs) at 72 hours post-irradiation using flow cytometry and northern analysis was determined. Dose-dependent increases in the surface expression and mRNA of ICAM-1 and CD31 were observed. In contrast VCAM-1 was practically undetectable on both control and irradiated HDMECs but was strongly expressed in TNF-alpha activated positive control HDMECs. The upregulation in ICAM-1 and CD31 was independent of radiation-induced changes in cell size, number and cell cycle stage. We suggest that ICAM-1 is active over a prolonged period whereas VCAM-1 acts only transiently in leukocyte-endothelial interactions in the irradiated microvasculature. The late upregulation of CD31 is a novel finding and may have a function in radiation-induced leukocyte extravasation, platelet adherence to the vascular wall and abnormal endothelial cell proliferation. Both ICAM-1 and CD31 seem to be therapeutic targets for the amelioration of radiation-induced normal tissue damage.
    • Irradiation induces up-regulation of E9 protein (CD105) in human vascular endothelial cells.

      Wang, Ji Min; Kumar, Shant; Van Agthoven, A; Kumar, Patricia; Pye, David A; Hunter, Robin D; Christie Hospital, Manchester, UK. (1995-09-15)
      The use of MAb E-9 raised against tissue-cultured endothelial cells (EC) has shown marked heterogeneity in vascular EC lining the blood vessels of normal and tumour tissues. MAb E-9 is human EC-specific and the protein recognized by it is a homodimer with a molecular mass of 97 kDa. The E-9 protein is resistant to treatment by 3 mM sodium periodate, but is sensitive to 10% trichloroacetic acid and 70% ethanol. E-9 protein has been assigned to a new cluster, CD105, and mapped to human chromosome 9q3. It has approximately 70% homology with type-III cell-surface receptor for transforming growth factor beta (TGF-beta). Recently CD105 has been reported to be the gene in patients with hereditary haemorrhagic telangiectasia. We have examined the effects of radiation on its expression in normal human umbilical-vein endothelial cells (HUVEC) and brain-tumour-derived endothelial cells (BTEC). Irradiation induced dose- and time-dependent up-regulation in the expression of the E-9 protein on the plasma membranes of EC, and also resulted in greater increase in the expression of the E-9 protein in semi-confluent (proliferating) as compared with confluent (non-proliferating) EC. It may well be that, following radiotherapy in cancer patients, E-9 protein is also up-regulated. The presence of increased amounts of E-9 protein in EC makes it an attractive target in the control of angiogenesis, especially after radiotherapy in cancer patients. The time scale involved in the up-regulation of E-9 protein following irradiation has led us to suggest that it may be a secondary event, the primary being the production and release of mitogenic factors (such as basic fibroblast growth factor) from irradiated EC.
    • Irradiation induces upregulation of CD31 in human endothelial cells.

      Quarmby, Steven L; Kumar, Patricia; Wang, Ji Min; Macro, Janet A; Hutchinson, Jerry J; Hunter, Robin D; Kumar, Shant; Department of Pathological Sciences, University of Manchester, Christie Hospital, Metropolitan University of Manchester, Manchester, UK. (1999-03)
      Radiation-induced vascular injury is believed to be a major factor contributing to parenchymal atrophy, fibrosis and necrosis in normal tissue after radiotherapy. In this study irradiation of human umbilical vein endothelial cells (HUVECs) significantly increased adherence of U-937 cells in a time-dependent manner. Given the potential multifunctional role of CD31 in the vasculature we have examined the possible effects of irradiation on levels of CD31 expression in HUVECs. Irradiation upregulated CD31 expression on HUVECs, independently of initial plating density and radiation-induced changes such as cell number, cell cycle stage, or cell size. CD31 mRNA levels were raised in irradiated HUVECs relative to controls. Both CD31 mRNA and surface protein showed similar changes, suggesting that the increase in mRNA in irradiated HUVECs is responsible for the elevation in cell surface protein. A semi-quantitative study of tissue specimens from patients who had received radiotherapy indicated that CD31 staining in the blood vessels from irradiated tissues was increased compared with controls. Endothelial CD31 is important in the transmigration of leukocytes. We have demonstrated that the incorporation of monoclonal antibody to CD31 significantly inhibited the transmigration of human peripheral blood leukocytes through a monolayer of irradiated HUVECs. Taken together these data strongly suggest that irradiation induces a marked increase in CD31 expression on endothelial cells as part of a general response to irradiation. Its upregulation may play an important role in the development of radiation-induced normal tissue damage and thus is a possible target for therapeutic intervention.
    • Irradiation of bovine aortic endothelial cells enhances the synthesis and secretion of sulphated glycosaminoglycans.

      Pye, David A; Kumar, Shant; Wang, Ji Min; Hunter, Robin D; Department of Clinical Research, Christie Hospital, Manchester, UK. (1994-02-17)
      The effect of X-irradiation on the synthesis of heparan sulphate (HS) and chondroitin/dermatan sulphate (CS/DS) by bovine aortic endothelial cells (BAEC), was studied by measuring the incorporation of [35S]sulphate and [3H]glucosamine into newly synthesized glycosaminoglycan (GAG) chains. Medium extracts from irradiated cultures (5Gy) were found to contain approx. 130% more HS and 200% more CS/DS than unirradiated controls. Smaller increases were observed in cellular extracts, irradiated cultures (5Gy) containing approx. 60% more HS and 100% more CS/DS than unirradiated controls. Structural studies showed no significant changes occurred upon irradiation in either the amounts or distribution of N- and O-sulphate groups in the HS molecule. Values for N-sulphation of 41.1% control and 41.5% irradiated (5Gy) were obtained, the corresponding values for O-sulphation being 19.9% control and 20.2% irradiated. Isotope incorporation data indicated that sulphation of CS/DS may decrease after irradiation, however, analysis of chondroitin ABC lyase derived disaccharides showed no changes in the proportion of non-sulphated and O-sulphated disaccharides. The present study indicates that X-irradiation stimulates the synthesis and secretion of HS and CS/DS proteoglycans (PGs) by BAEC. This could be relevant to many features which are found to be indicative of radiation-induced damage.
    • Irradiation-induced growth failure.

      Shalet, Stephen M (1986-08)
      Short stature may complicate the treatment during childhood of brain tumours and, to a lesser extent, ALL. A number of factors may be responsible, including spinal irradiation, malnutrition, recurrent tumour, chemotherapy, precocious puberty and radiation-induced GH deficiency. GH is always the first pituitary hormone to be affected by radiation damage to the hypothalamic-pituitary axis but larger radiation doses may result in panhypopituitarism. Some children retain normal GH responses to certain provocative stimuli, although physiological GH secretion is reduced. Nonetheless, in children suspected of radiation-induced GH deficiency, pharmacological tests of GH secretion remain useful, the ITT being the test of choice because of the marked radiation sensitivity of the GH response to hypoglycaemia. The hypothalamus is more radiosensitive than the pituitary. In many patients with radiation-induced GH deficiency, the damage appears to be at the hypothalamic level resulting in a deficiency of endogenous GRF. Treatment with synthetic GRF may provide an alternative to GH therapy in such children. Finally, there is no evidence to suggest that GH therapy given to a child with radiation-induced GH deficiency might induce a brain tumour recurrence or a relapse of ALL.
    • Irreversible electroporation in pancreatic ductal adenocarcinoma: Is there a role in conjunction with conventional treatment?

      De Liguori Carino, N; O'Reilly, D; Siriwardena, A; Valle, Juan W; Radhakrishna, Ganesh; Pihlak, Rille; McNamara, Mairéad G; Regional Hepato-Pancreato-Biliary Unit, Manchester Royal Infirmary, Oxford Road, Manchester, M13 9WL, UK (2018-10)
      The incidence of pancreatic ductal adenocarcinoma (PDAC) is rapidly increasing. Up to 30% of patients present with locally advanced disease and therefore are not candidates for surgery. Locally advanced pancreatic cancer (LAPC) is an emerging entity lacking in level III evidence-based recommendations for its treatment. Currently, systemic chemotherapy is the main treatment for LAPC. However, due to lack of response or disease progression, downsizing of the tumour, making it resectable is successful in only a small proportion of patients. Radiotherapy is often advocated to improve local disease control if there is stability following chemotherapy. Recently, Irreversible Electroporation (IRE), a novel non-thermal ablation technique, has been proposed for the treatment of LAPC.
    • Is 'watch-and-wait' after chemoradiotherapy safe in patients with rectal cancer?

      Smith, FM; Cresswell, K; Myint, AS; Renehan, Andrew G; Department of Surgery, Royal Liverpool and Broadgreen University Hospitals NHS Trust, Liverpool, UK (2018)
    • Is a nurse-led telephone intervention a viable alternative to nurse-led home care and standard care for patients receiving oral capecitabine? Results from a large prospective audit in patients with colorectal cancer.

      Craven, Olive; Hughes, Carol A; Burton, A; Saunders, Mark P; Molassiotis, A; Christie Hospital NHS Foundation Trust, Manchester, UK. (2013-05)
      Home care nursing has been shown to be a valuable service for patients receiving oral chemotherapy; however, associated costs can be high and telephone-based services may be more cost-effective options. This prospective audit explored the usefulness of a nurse-led telephone intervention for supporting cancer patients treated with Capecitabine, comparing historical findings from a randomised trial evaluating a home-based intervention over standard care with a modified nurse-led telephone follow-up intervention. Self-reported toxicity and service use were assessed in 298 patients who received nurse-led telephone follow-up, compared with historical data from 164 patients (81 receiving standard care and 83 home care intervention). Findings suggested that nurse-led telephone follow-up can potentially lead to reduced toxicity (chest pain, vomiting, oral mucositis, nausea, insomnia) when compared with standard care, and that it has a similar impact on the management of some symptoms when compared with home care (i.e. vomiting, oral mucositis), although it was not as effective as the home care intervention for other toxicities (diarrhoea and insomnia). These encouraging findings need to be explored further using a randomised trial design before we reach any conclusions. Further research should also include a health economics study to assess the cost-effectiveness of the telephone-based services for patients receiving oral chemotherapy.
    • Is a policy of cervical screening for all women attending a genito-urinary medicine clinic justified?

      Stedman, Y; Woodman, Ciaran B J; Donnelly, Brad; Cytology Department, Christie Hospital NHS Trust, Withington, Manchester. (1995-03)
      BACKGROUND: The study took place at the Genito-Urinary Medicine Department at the University Hospital of South Manchester and the Cytology Department at Christie NHS Trust Hospital. There were two main objectives, as follows: (1) to determine if patients attending a Genito-Urinary Medicine (GUM) Clinic are less likely to have had a cervical smear in the preceding five years than a control group drawn from the general population; (2) to compare the prevalence of cytological abnormalitity in cases and controls. METHODS: Cases comprised all women attending the Withington GUM Clinic, between 1991 and 1993, who had had a cervical smear taken at this clinic. Controls were selected from residents of the North West Regional Health Authority who had a cervical smear taken either by a general practitioner (GP) or in an NHS Community Clinic during the same period. The design was a matched case-control study. The main outcome measures considered the proportion of women who had had a cervical smear taken by a GP or in an NHS Community Clinic during the five years preceding the index smear, and the prevalence of abnormal smears in cases and controls. RESULTS: There was no significant difference in the screening history of cases and controls; 363 (50.2 per cent) cases had had a cervical smear taken in the preceding five years as compared with 380 (52.6 per cent) controls [chi 2 (1df) = 0.95; p > 0.05; 95 per cent confidence interval (CI) on difference in proportions, -7.1 per cent to 2.4 per cent]. There was a small case-control difference of borderline significance in the prevalence of all grades of cytological abnormality: 22.7 per cent of cases had abnormal cytology as compared with 18.5 per cent of controls [chi 2 (1df) = 3.98; 0.01 < p < 0.05; 95 per cent CI on difference in proportions, 1 per cent to 8.2 per cent). This excess was largely attributable to differences in the prevalence of minor cytological abnormality. There was no significant difference in the prevalence of cytological abnormality in those case-control pairs who had had a smear in the preceding five years. CONCLUSION: A policy of cervical screening of all GUM patients can no longer be sustained. We would recommend cervical cytology only for those women who have not been screened in the previous three to five years.
    • Is age a barrier to receiving adjuvant chemotherapy for pancreatic ductal adenocarcinoma?

      Malik, A; Lamarca, Angela; Siriwardena, A; O'Reilly, Derek; Deshpande, R; Satyadas, T; Jamdar, S; Sheen, A; McNamara, Mairead G; Hubner, Richard A; et al. (2019)
    • Is cancer a metabolic rebellion against host aging? In the quest for immortality, tumor cells try to save themselves by boosting mitochondrial metabolism.

      Ertel, A; Tsirigos, A; Whitaker-Menezes, D; Birbe, R; Pavlides, S; Martinez-Outschoorn, U; Pestell, R; Howell, Anthony; Sotgia, F; Lisanti, M; et al. (2012-01-15)
      Aging drives large systemic reductions in oxidative mitochondrial function, shifting the entire body metabolically towards aerobic glycolysis, a.k.a, the Warburg effect. Aging is also one of the most significant risk factors for the development of human cancers, including breast tumors. How are these two findings connected? One simplistic idea is that cancer cells rebel against the aging process by increasing their capacity for oxidative mitochondrial metabolism (OXPHOS). Then, local and systemic aerobic glycolysis in the aging host would provide energy-rich mitochondrial fuels (such as L-lactate and ketones) to directly "fuel" tumor cell growth and metastasis. This would establish a type of parasite-host relationship or "two-compartment tumor metabolism", with glycolytic/oxidative metabolic-coupling. The cancer cells ("the seeds") would flourish in this nutrient-rich microenvironment ("the soil"), which has been fertilized by host aging. In this scenario, cancer cells are only trying to save themselves from the consequences of aging, by engineering a metabolic mutiny, through the amplification of mitochondrial metabolism. We discuss the recent findings of Drs. Ron DePinho (MD Anderson) and Craig Thomspson (Sloan-Kettering) that are also consistent with this new hypothesis, linking cancer progression with metabolic aging. Using data mining and bioinformatics approaches, we also provide key evidence of a role for PGC1a/NRF1 signaling in the pathogenesis of (1) two-compartment tumor metabolism, and (2) mitochondrial biogenesis in human breast cancer cells.
    • Is dual-phase abdominal CT necessary for the optimal detection of metastases from renal cell carcinoma?

      Jain, Yatin; Liew, S; Taylor, M B; Bonington, Suzanne C; The Christie NHS Foundation Trust, Manchester, UK. (2011-11)
      To determine whether dual-phase abdominal computed tomography (CT) detected more metastases than portal-phase CT alone in patients with renal cell carcinoma (RCC).