Siriwardena A.K.,Royal Infirmary |
Mason J.M.,Durham University |
Mullamitha S.,Christie Hospital |
Hancock H.C.,Durham University |
Jegatheeswaran S.,Royal Infirmary
Nature Reviews Clinical Oncology | Year: 2014
Up to a fifth of patients with colorectal cancer (CRC) present with synchronous hepatic metastases. In patients with CRC who present without intestinal obstruction or perforation and in whom comprehensive whole-body imaging confirms the absence of extrahepatic disease, evidence indicates a state of equipoise between several different management pathways, none of which has demonstrated superiority. Neoadjuvant systemic chemotherapy is advocated by current guidelines, but must be integrated with surgical management in order to remove the primary tumour and liver metastatic burden. Surgery for CRC with synchronous liver metastases can take a number of forms: the 'classic' approach, involving initial colorectal resection, interval chemotherapy and liver resection as the final step; simultaneous removal of the liver and bowel tumours with neoadjuvant or adjuvant chemotherapy; or a 'liver-first' approach (before or after systemic chemotherapy) with removal of the colorectal tumour as the final procedure. In patients with rectal primary tumours, the liver-first approach can potentially avoid rectal surgery in patients with a complete response to chemoradiotherapy. We overview the importance of precise nomenclature, the influence of clinical presentation on treatment options, and the need for accurate, up-to-date surgical terminology, staging tests and contemporary management options in CRC and synchronous hepatic metastatic disease, with an emphasis on multidisciplinary care. © 2014 Macmillan Publishers Limited. All rights reserved.
Cunningham D.,Royal Marsden Hospital |
Lang I.,National Institute of Oncology |
Marcuello E.,Hospital Of Sant Pau Of Barcelona |
Lorusso V.,Italian National Cancer Institute |
And 7 more authors.
The Lancet Oncology | Year: 2013
Background: Elderly patients are often under-represented in clinical trials of metastatic colorectal cancer. We aimed to assess the efficacy and safety of bevacizumab plus capecitabine compared with capecitabine alone in elderly patients with metastatic colorectal cancer. Methods: For this open-label, randomised phase 3 trial, patients aged 70 years and older with previously untreated, unresectable, metastatic colorectal cancer, who were not deemed to be candidates for oxaliplatin-based or irinotecan-based chemotherapy regimens, were randomly assigned in a 1:1 ratio via an interactive voice-response system, stratified by performance status and geographical region. Treatment consisted of capecitabine (1000 mg/m2 orally twice a day on days 1-14) alone or with bevacizumab (7·5 mg/kg intravenously on day 1), given every 3 weeks until disease progression, unacceptable toxic effects, or withdrawal of consent. Efficacy analyses were based on the intention-to-treat population. The primary endpoint was progression-free survival. The trial is registered with ClinicalTrials.gov, number NCT00484939. Findings: From July 9, 2007, to Dec 14, 2010, 280 patients with a median age of 76 years (range 70-87) were recruited from 40 sites across ten countries. Patients were randomly assigned to receive either bevacizumab plus capecitabine (n=140) or capecitabine only (n=140). Progression-free survival was significantly longer with bevacizumab and capecitabine than with capecitabine alone (median 9·1 months [95% CI 7·3-11·4] vs 5·1 months [4·2-6·3]; hazard ratio 0·53 [0·41-0·69]; p<0·0001). Treatment-related adverse events of grade 3 or worse occurred in 53 (40%) patients in the combination group and 30 (22%) in the capecitabine group, and treatment-related serious adverse events in 19 (14%) and 11 (8%) patients. The most common grade 3 or worse adverse events of special interest for bevacizumab or chemotherapy were hand-foot syndrome (21 [16%] vs nine [7%]), diarrhoea (nine [7%] vs nine [7%]), and venous thromboembolic events (11 [8%] vs six [4%]). Treatment-related deaths occurred in five patients in the combination group and four in the capecitabine group. The most common any-grade adverse event of special interest for bevacizumab was haemorrhage (34 [25%] vs nine [7%]). Interpretation: The combination of bevacizumab and capecitabine is an effective and well-tolerated regimen for elderly patients with metastatic colorectal cancer. Funding: F Hoffmann-La Roche. © 2013 Elsevier Ltd.
Mitchell C.,John Radcliffe Hospital |
Richards S.,University of Oxford |
Harrison C.J.,Northumbria University |
Eden T.,Christie Hospital
Leukemia | Year: 2010
Between 1980 and 2001, the United Kingdom Medical Research Council Childhood Leukemia Working Party conducted four clinical trials in acute lymphoblastic leukaemia (ALL), which recruited a total of 6516 patients. UKALL VIII examined the role of daunorubicin in induction chemotherapy, and UKALL X examined the role of post-induction intensification. Both resulted in major improvement in the outcomes. UKALL XI examined the efficacy of different methods of central nervous system-directed therapy and the effects of an additional intensification. ALL97, which was initially based on the UKALL XD template (two intensification phases), examined the role of different steroids in induction and of different thiopurines through continuing chemotherapy. A reappraisal of results from UKALL XI compared with other cooperative group results led to a redesign in 1999, which subsequently resulted in a major improvement in outcomes. In addition, ALL97 and ALL97/99 showed a significant advantage for the use of dexamethasone rather than prednisolone; although the use of 6-thioguanine resulted in fewer relapses, this advantage was offset by an increased incidence of deaths in remission. Over the era encompassed by these four trials, there has been a major improvement in both event-free and overall survival for children in the United Kingdom with ALL. © 2010 Macmillan Publishers Limited All rights reserved.
Nonaka D.,Christie Hospital |
Nonaka D.,University of Manchester
American Journal of Surgical Pathology | Year: 2012
Distinguishing between lung adenocarcinoma and squamous cell carcinoma is becoming increasingly important, given the different treatment regimens available. Although histologic subdivision between the two is generally not difficult in differentiated tumors, it can be challenging in poorly differentiated tumors and may require a panel of immunohistochemistry stains. The p63 gene encodes two different N-termini (TA and ΔN). ΔNp63 is selectively expressed in squamous cell carcinoma, whereas TAp63 is not restricted only to it. 4A4, a widely used anti-p63 antibody, identifies both isoforms and is expressed in about 15% of adenocarcinomas, and, although generally focal, its expression can be diffuse. In this study, a total of 150 lung adenocarcinomas and 50 squamous cell carcinomas were immunostained by antibodies for p63 (4A4), ΔNp63 (p40), and TTF-1 (8G7G3/1). Twenty-seven adenocarcinomas (18%) were positive for p63 to a variable extent, with diffuse reaction being seen in 13 tumors (8.7%). p63 expression was seen in all subtypes of adenocarcinomas, except for the mucinous type. p40 was negative in all adenocarcinomas. All squamous cell carcinomas were diffusely positive for both p63 and p40. Four of 27 p63-positive adenocarcinomas were negative for TTF-1. p63 expression is not uncommonly seen in adenocarcinomas, whereas ΔNp63 (p40) expression is specific for squamous cell carcinoma, with sensitivity comparable to that of p63 expression. Presence of p63-positive cells in poorly differentiated lung adenocarcinoma may be erroneously interpreted as evidence of squamous cell differentiation. p40 appears to be a more reliable marker for squamous cell carcinoma. © 2012 by Lippincott Williams & Wilkins.
O'Connor J.P.B.,University of Manchester |
O'Connor J.P.B.,Christie Hospital |
Jayson G.C.,Paterson Institute for Cancer Research |
Jayson G.C.,Christie Hospital
Clinical Cancer Research | Year: 2012
The management of solid tumors has been transformed by the advent of VEGF pathway inhibitors. Early clinical evaluation of these drugs has used pharmacodynamic biomarkers derived from advanced imaging such as dynamic MRI, computed tomography (CT), and ultrasound to establish proof of principle. We have reviewed published studies that used these imaging techniques to determine whether the same biomarkers relate to survival in renal, hepatocellular, and brain tumors in patients treated with VEGF inhibitors. Data show that in renal cancer, pretreatment measurements of Ktrans and early pharmacodynamic reduction in tumor enhancement and density have prognostic significance in patients treated with VEGF inhibitors. A weaker, but significant, relationship is seen with subtle early size change (10% in one dimension) and survival. Data from high-grade glioma suggest that pretreatment fractional blood volume and Ktrans were prognostic of overall survival. However, lack of control data with other therapies prevents assessment of the predictive nature of these biomarkers, and such studies are urgently required. ©2012 AACR.
Nonaka D.,Christie Hospital |
Nonaka D.,University of Manchester |
Bishop P.W.,Wythenshawe Hospital
American Journal of Surgical Pathology | Year: 2014
A group of tumors referred to as atypical fibroxanthoma (AFX) and pleomorphic dermal sarcoma (PDS) predominantly occur in sun-damaged skin of the elderly, particularly in the head and neck region. Although this group of tumors is often regarded as of mesenchymal phenotype, the matter of histogenesis has not been entirely resolved. Evans H and Smith JL reported in 1980 that prognosis was not significantly different irrespective of whether there was a definite squamous cell carcinoma component or not, supporting a view that these are all carcinomata in nature (sarcomatoid carcinoma [SC]). There are a number of clinicopathologic studies of AFX in the literature but information on morphologically similar sarcoma-like tumors with immunohistochemical evidence of epithelial differentiation is sparse. One hundred sarcoma-like tumors (SLTs) of head and neck skin of the elderly, treated by surgical excision, were studied. Clinical information was obtained, and pathology reports and hematoxylin and eosin sections were reviewed to document size (maximum dimension), extent of invasion, mitotic count, vascular and perineural invasion, margin status, ulceration, necrosis, and the presence of actinic keratosis in adjacent/overlying skin. Immunostains examined included: pan-cytokeratins (CKs) (AE1/AE3, MNF116), high-molecular weight CKs (34βE12, CK5/6, CK14), p63, and melanocytic (S100, Melan A, HMB-45, MITF), vascular (CD31, CD34), and muscle markers (SMA, desmin, h-caldesmon) to exclude melanoma and definite sarcoma entities. The tumors were divided into AFX/PDS (G1), the SC group, which was subdivided into SLT with only p63 positivity (G2a) and SLT with CK positivity regardless of p63 status (G2b), and SLT with a minor morphologic squamous cell carcinoma component (G3). Clinicopathologic findings of each group were compared, in relation to outcomes. Age at diagnosis ranged from 51 to 96 years (median, 79 y), with M:F=11.5:1. There were 53 tumors in G1 (19AFX, 34PDS), 37 in G2 (25 in G2a, 12 in G2b), and 10 in G3. There was no statistically significant difference in clinical and pathologic parameters or survival among all 3 groups. CKs and p63 expression, size, extent of invasion, vascular invasion, perineural invasion, mitotic count, and ulcer did not affect outcome, whereas margin status and necrosis did by both univariate and multivariate analysis and by only univariate analysis, respectively. Sixty patients had multiple nonmelanomatous skin cancers. Actinic keratosis was observed in overlying/adjacent epidermis in 51 cases. Eight patients had prior radiotherapy to head skin cancers; 1 patient developed 2 separate tumors (G1 and G3) after radiotherapy. Four patients died of tumor (1 G1, 2 G2b, and 1 G3); of these, 3 cases had positive margin, and 1 had narrow margin. Our results have shown similarities of various clinicopathologic parameters between AFX/PDS and SC, raising the possibility that both entities are related, and some of the former entities may represent complete dedifferentiation (complete loss of epithelial phenotype) with a gain of mesenchymal phenotype. In addition, the difference between AFX and PDS appears to be the extent of invasiveness (stage) rather than a different histogenesis. Further investigations are needed. However, from a practical point of view, efforts should be made to excise this group of tumors with clear margins, as margin status appears to be the most important prognostic factor regardless of the presence or absence of epithelial differentiation. Copyright © 2014 by Lippincott Williams & Wilkins.
O'Connor J.P.B.,University of Manchester |
Jackson A.,University of Manchester |
Parker G.J.M.,University of Manchester |
Roberts C.,University of Manchester |
Jayson G.C.,Christie Hospital
Nature Reviews Clinical Oncology | Year: 2012
About 100 early-phase clinical trials and investigator-led studies of targeted antivascular therapies-both anti-angiogenic and vascular-targeting agents-have reported data derived from T1-weighted dynamic contrast-enhanced (DCE)-MRI. However, the role of DCE-MRI for decision making during the drug-development process remains controversial. Despite well-documented guidelines on image acquisition and analysis, several key questions concerning the role of this technique in early-phase trial design remain unanswered. This Review describes studies of single-agent antivascular therapies, in which DCE-MRI parameters are incorporated as pharmacodynamic biomarkers. We discuss whether these parameters, such as volume transfer constant (K trans), are reproducible and reliable biomarkers of both drug efficacy and proof of concept, and whether they assist in dose selection and drug scheduling for subsequent phase II trials. Emerging evidence indicates that multiparametric analysis of DCE-MRI data offers greater insight into the mechanism of drug action than studies measuring a single parameter, such as K trans. We also provide an overview of current data and appraise the future directions of this technique in oncology trials. Finally, major hurdles in imaging biomarker development, validation and qualification that hinder a wide application of DCE-MRI techniques in clinical trials are addressed. © 2012 Macmillan Publishers Limited. All rights reserved.
Iavazzo C.,Christie Hospital |
Gkegkes I.D.,General Hospital of Attica KAT
Archives of Gynecology and Obstetrics | Year: 2016
Objective: Robotic hysterectomy is an alternative approach to the management of female genital tract pathology. Methods: A systematic literature review was performed to evaluate the till now available literature evidence on robotic assisted hysterectomy in obese and morbidly obese patients. Results: In total, robotic assisted hysterectomy was performed on 2769 patients. The most frequent indication for robotic hysterectomy was endometrial carcinoma (1832 out of 2769 patients, 66.2 %). Hypertension, diabetes mellitus, obstructive sleep apnea, chronic obstructive pulmonary disease and venous thromboembolism were the most common comorbidities reported. The conversion rate to laparotomy was 92 out of 2226 patients (4.1 %). The most frequent intraoperative complications for robotic hysterectomy were gastrointestinal injury (17 out of 2769 patients, 0.6 %), haemorrhage (five out of 2769 patients, 0.2 %) and bladder injury (five out of 2769 patients, 0.2 %). Wound infections/dehiscence (66 out of 2769 patients, 2.4 %), fever (56 out of 2769 patients, 2 %), pulmonary complications (55 out of 2769 patients, 1.9 %), urogenital complications (36 out of 2769 patients, 1.3 %) and postoperative ileus (28 out of 2769 patients, 1 %) were the most common postoperative complications. Death was reported in three out of 2769 patients (0.1 %). The ICU admitted patients were eight of 2226 patients (0.4 %). Conclusion: The robotic technique, especially in obese, can optimize the surgical approach and recovery of such patients with equally if not better outcomes compared to open and/or laparoscopic techniques. © 2016, Springer-Verlag Berlin Heidelberg.
Iavazzo C.,Christie Hospital |
Gkegkes I.D.,General Hospital of Attica KAT
Archives of Gynecology and Obstetrics | Year: 2015
Introduction: Port-site metastasis is an extremely rare event in patients with cancer treated with robotic-assisted surgery. However, as robotic procedures are increasing, the incidence of port-site metastases might also increase. The purpose of our review is to evaluate the up-to-now existing literature data on robotic port-site metastasis in the field of gynecological oncology. Materials and methods: The authors retrieved the included results of the study after performing a systematic search in PubMed, Scopus, and Cochrane Library. Results: In total, 20 patients were included in the study. The mean age of them was 56.3 (range 27–82) years. In the majority of the cases, endometrial cancer was responsible for port-site recurrences. The port-site metastasis occurred after 1–36 months postoperatively with the tumor measuring from 0.8 to 10.5 cm. As far as the management of this type of local recurrence, the most common therapeutic strategy adopted was the local excision followed by combined radiotherapy/chemotherapy. Conclusions: Robotic surgery is a rather new technique and port-site metastasis is a rare complication of it. Due to this fact, we could not reach safe conclusions. The purpose of this study was to raise doctor’s clinical suspicion level to such a rare complication. Additional studies should be performed with the intention to clarify both port-site metastasis rates in gynecological oncology patients, as well as to elucidate the possible mechanisms of this type of local recurrence. © 2015, Springer-Verlag Berlin Heidelberg.
Hendry J.H.,Christie Hospital
Annals of the ICRP | Year: 2015
Tissue reactions (deterministic effects) become manifest either early or late after doses above a threshold dose, which is the basis for recommended dose limits for avoiding such effects. Threshold doses have been defined for comparative purposes at 1% incidence of an effect, although the choice of incidence level may be scenario-dependent in practice. Latency time before manifestation is related to cell turnover rates and tissue complexity. In general, threshold doses become lower for longer follow-up times because of the slow progression of injury before manifestation, particularly after lower doses. Radiosensitive individuals may contribute to low threshold doses, which would provide a safety margin for the majority of a population. A threshold dose of 0.5 Gy was proposed for radiation-induced circulatory disease, after acute or chronic exposures, in the International Commission on Radiological Protection Publication 118. However, more recent meta-analyses of low-dose population studies suggest that, if a linear dose-incidence is assumed, the risk of some types of circulatory disease after doses <0.5 Gy or <10 mGy day−1 may be positive and similar to that for induced cancer. Animal studies show that doses >2 Gy induce the expression of inflammatory and thrombotic molecules in endothelial cells. This causes progressive loss of capillaries in the heart and leads to reduced perfusion, myocardial cell death, and fibrosis. However, doses <1 Gy inhibit both inflammatory cell adhesion to endothelial cells and the development of atherosclerosis in mice. Different mechanisms of injury at low and high doses preclude the simple extrapolation of risk on a linear-quadratic basis from acute to chronic exposures. © The International Society for Prosthetics and Orthotics Reprints and permissions: sagepub.co.uk/journalsPermissions.nav