Showing papers in "Lancet Oncology in 2007"

Survival benefits from neoadjuvant chemoradiotherapy or chemotherapy in oesophageal carcinoma: a meta-analysis

Abstract: Summary Background Resectable oesophageal cancer is often treated with surgery alone or with preoperative (neoadjuvant) chemoradiotherapy or chemotherapy. We aimed to clarify the benefits of neoadjuvant chemoradiotherapy or chemotherapy versus surgery alone by a meta-analysis of randomised trial data. Methods Eligible trials were identified first from earlier published meta-analyses and systematic reviews. We also used MEDLINE, Cancerlit, and EMBASE databases to identify additional studies and published abstracts from major scientific meetings since 1980. Only randomised studies with an analysis by an intention-to-treat principle were included, and searches were restricted to those databases citing articles in English. We used published hazard ratios if available or estimates from other survival data or survival curves. Treatment effects by type of tumour and treatment sequencing were also investigated. Findings Ten randomised comparisons of neoadjuvant chemoradiotherapy versus surgery alone (n=1209) and eight of neoadjuvant chemotherapy versus surgery alone (n=1724) in patients with local operable oesophageal carcinoma were identified. The hazard ratio for all-cause mortality with neoadjuvant chemoradiotherapy versus surgery alone was 0·81 (95% CI 0·70–0·93; p=0·002), corresponding to a 13% absolute difference in survival at 2 years, with similar results for different histological tumour types: 0·84 (0·71–0·99; p=0·04) for squamous-cell carcinoma (SCC), and 0·75 (0·59–0·95; p=0·02) for adenocarcinoma. The hazard ratio for neoadjuvant chemotherapy was 0·90 (0·81–1·00; p=0·05), which indicates a 2-year absolute survival benefit of 7%. There was no significant effect on all-cause mortality of chemotherapy for patients with SCC (hazard ratio 0·88 [0·75–1·03]; p=0·12), although there was a significant benefit for those with adenocarcinoma (0·78 [0·64–0·95]; p=0·014). Interpretation A significant survival benefit was evident for preoperative chemoradiotherapy and, to a lesser extent, for chemotherapy in patients with adenocarcinoma of the oesophagus. The findings provide an evidence-based framework for the use of neoadjuvant treatment in management decisions.

Recent cancer survival in Europe: a 2000-02 period analysis of EUROCARE-4 data.

Abstract: BACKGROUND: Traditional cancer-survival analyses provide data on cancer management at the beginning of a study period, and are often not relevant to current practice because they refer to survival of patients treated with older regimens that might no longer be used. Therefore, shortening the delay in providing survival estimates is desirable. Period analysis can estimate cancer survival by the use of recent data. We aimed to apply the period-analysis method to data that were collected by European cancer registries to estimate recent survival by country and cancer site, and to assess survival changes in Europe. We also compared our findings with data on cancer survival in the USA from the US SEER (Surveillance, Epidemiology, and End Results) programme. METHODS: We analysed survival data for patients diagnosed with cancer in 2000-02, collected from 47 of the European cancer registries participating in the EUROCARE-4 study. 5-year period relative survival for patients diagnosed in 2000-02 was estimated as the product of interval-specific relative survival values of cohorts with different lengths of follow-up. 5-year survival profiles for patients diagnosed in 2000-02 were estimated for the European mean and for five European regions, and findings were compared with US SEER registry data for patients diagnosed in 2000-02. A 5-year survival profile for patients diagnosed in 1991-2002 and a 10-year survival profile for patients diagnosed in 1997-2002 were also estimated by the period method for all malignancies, by geographical area, and by cancer site. FINDINGS: For all cancers, age-adjusted 5-year period survival improved for patients diagnosed in 2000-02, especially for patients with colorectal, breast, prostate, and thyroid cancer, Hodgkin's disease, and non-Hodgkin lymphoma. The European mean age-adjusted 5-year survival calculated by the period method for 2000-02 was high for testicular cancer (97.3% [95% CI 96.4-98.2]), melanoma (86.1% [84.3-88.0]), thyroid cancer (83.2% [80.9-85.6]), Hodgkin's disease (81.4% [78.9-84.1]), female breast cancer (79.0% [78.1-80.0]), corpus uteri (78.0% [76.2-79.9]), and prostate cancer (77.5% [76.5-78.6]); and low for stomach cancer (24.9% [23.7-26.2]), chronic myeloid leukaemia (32.2% [29.0-35.7]), acute myeloid leukaemia (14.8% [13.4-16.4]), and lung cancer (10.9% [10.5-11.4]). Survival for patients diagnosed in 2000-02 was generally highest for those in northern European countries and lowest for those in eastern European countries, although, patients in eastern European had the highest improvement in survival for major cancer sites during 1991-2002 (colorectal cancer from 30.3% [28.3-32.5] to 44.7% [42.8-46.7]; breast cancer from 60% [57.2-63.0] to 73.9% [71.7-76.2]; for prostate cancer from 39.5% [35.0-44.6] to 68.0% [64.2-72.1]). For all solid tumours, with the exception of stomach, testicular, and soft-tissue cancers, survival for patients diagnosed in 2000-02 was higher in the US SEER registries than for the European mean. For haematological malignancies, data from US SEER registries and the European mean were comparable in 2000-02, except for non-Hodgkin lymphoma. INTERPRETATION: Cancer-service infrastructure, prevention and screening programmes, access to diagnostic and treatment facilities, tumour-site-specific protocols, multidisciplinary management, application of evidence-based clinical guidelines, and recruitment to clinical trials probably account for most of the differences that we noted in outcomes.

Technical outcomes of sentinel-lymph-node resection and conventional axillary-lymph-node dissection in patients with clinically node-negative breast cancer: results from the NSABP B-32 randomised phase III trial

Abstract: Summary Background The goals of axillary-lymph-node dissection (ALND) are to maximise survival, provide regional control, and stage the patient. However, this technique has substantial side-effects. The purpose of the B-32 trial is to establish whether sentinel-lymph-node (SLN) resection can achieve the same therapeutic goals as conventional ALND but with decreased side-effects. The aim of this paper is to report the technical success and accuracy of SLN resection plus ALND versus SLN resection alone. Methods 5611 women with invasive breast cancer were randomly assigned to receive either SLN resection followed by immediate conventional ALND (n=2807; group 1) or SLN resection without ALND if SLNs were negative on intraoperative cytology and histological examination (n=2804; group 2) in the B-32 trial. Patients in group 2 underwent ALND if no SLNs were identified or if one or more SLNs were positive on intraoperative cytology or subsequent histological examination. Primary endpoints, including survival, regional control, and morbidity, will be reported later. Secondary endpoints are accuracy and technical success and are reported here. This trial is registered with the Clinical Trial registry, number NCT00003830. Findings Data for technical success were available for 5536 of 5611 patients; 75 declined protocol treatment, had no SLNs removed, or had no SLN resection done. SLNs were successfully removed in 97·2% of patients (5379 of 5536) in both groups combined. Identification of a preincision hot spot was associated with greater SLN removal (98·9% [5072 of 5128]). Only 1·4% (189 of 13171) of SLN specimens were outside of axillary levels I and II. 65·1% (8571 of 13 171) of SLN specimens were both radioactive and blue; a small percentage was identified by palpation only (3·9% [515 of 13 171]). The overall accuracy of SLN resection in patients in group 1 was 97·1% (2544 of 2619; 95% CI 96·4–97·7), with a false-negative rate of 9·8% (75 of 766; 95% CI 7·8–12·2). Differences in tumour location, type of biopsy, and number of SLNs removed significantly affected the false-negative rate. Allergic reactions related to blue dye occurred in 0·7% (37 of 5588) of patients with data on toxic effects. Interpretation The findings reported here indicate excellent balance in clinical patient characteristics between the two randomised groups and that the success of SLN resection was high. These findings are important because the B-32 trial is the only trial of sufficient size to provide definitive information related to the primary outcome measures of survival and regional control. Removal of more than one SLN and avoidance of excisional biopsy are important variables in reducing the false-negative rate.

Carcinogenicity of shift-work, painting, and fire-fighting.

Abstract: In October, 2007, 24 scientists from ten countries met at the International Agency for Research on Cancer (IARC), Lyon, France, to assess the carcinogenicity of shift-work, painting, and fi re-fi ghting. These assessments will be published as volume 98 of the IARC Monographs. About 15–20% of the working population in Europe and the USA is engaged in shift-work that involves nightwork, which is most prevalent (above 30%) in the health-care, industrial manufactur ing, mining, transport, communication, leisure, and hospitality sectors. Among the many diff erent patterns of shiftwork, those including nightwork are the most disruptive for the circadian clock. Six of eight epidemiological studies from various geographical regions, most notably two independent cohort studies of nurses engaged in shiftwork at night, have noted a modestly increased risk of breast cancer in long-term employees compared with those who are not engaged in shiftwork at night. These studies are limited by potential confounding and inconsistent defi nitions of shiftwork, with several focused on a single profession. The incidence of breast cancer was also modestly increased in most cohorts of female fl ight attendants, who also experience circadian disruption by frequently crossing time zones. Limitations of studies in these fl ight attendants include the potential for detection bias, proxy measures of exposure, and potential uncontrolled confounding by reproductive factors and cosmic radiation. Several diff erent rodent models have been used to test the eff ect of disruption of the circadian system on tumour development. More than 20 studies investigated the eff ect of constant light, dim light at night, simulated chronic jet lag, or circadian timing of carcinogens, and most showed a major increase in tumour incidence. No clear eff ect was seen for light pulses at night or constant darkness. A similar number of studies investigated the eff ect of reduced nocturnal melatonin concentrations or removal of the pineal gland (where melatonin is produced) in tumour development and most showed increases in the incidence or growth of tumours. Exposure to light at night disturbs the circadian system with alterations of sleep-activity patterns, suppression of melatonin production, and de regul ation of circadian genes involved in cancer-related pathways. Inactivation of the circadian Period gene, Per2, promotes tumour develop ment in mice, and in human breast and endo metrial tumours, the expression of PERIOD genes is inhibited. In animals, melatonin suppression can lead to changes in the gonadotrophin axis. In humans, sleep deprivation and the ensuing melatonin suppression lead to immunodefi ciency. For example, sleep deprivation suppresses natural killer-cell activity and changes the T-helper 1/T-helper 2 cytokine balance, reducing cellular immune defence and surveillance. On the basis of “limited evidence in humans for the carcinogenicity of shift-work that involves nightwork”, and “suffi cient evidence in experimental animals for the carcinogenicity of light during the daily dark period (biological night)”, the Working Group concluded that “shift-work that involves circadian disruption is probably carcinogenic to humans” (Group 2A). Painters are potentially exposed to many chemicals used as pigments, extenders, binders, solvents, and additives. Painters can also be exposed to other workplace hazards, such as asbestos or crystalline silica. Cohort and linkage studies of painters have shown consistent and signifi cant increases in lung cancer compared with the general population. No information on tobacco smoking was available in the cohort studies; however, the increases are comparable to results from many case–control studies that controlled for smoking. A meta-analysis by the Working Group of all independent studies, including two recent large studies, showed a signifi cant excess risk of about 20% overall, and of 50% when the analysis was restricted to smoking-adjusted estimates from population-based case–control studies. Increased mortality from mesothelioma was consistently noted. Similarly, cohort and linkage studies showed consistent 20–25% increases in the occurrence of urinary bladder cancer in painters, and similar increases were noted in case– control studies that controlled for smoking. Although fi ndings for lymphatic and haemopoietic cancers in painters were inconsistent, four of fi ve case– control studies reported signifi cant increases in childhood leukaemia associated with maternal exposure to paint. The risks tended to be greater when mothers were exposed before or during, rather than after, pregnancy, and two studies showed some evidence of an increasing risk with increasing exposure. Upcoming meetings February 5–12, 2008 Industrial and cosmetic dyes and related exposures

Escalated-dose versus standard-dose conformal radiotherapy in prostate cancer: first results from the MRC RT01 randomised controlled trial

Abstract: Summary Background In men with localised prostate cancer, conformal radiotherapy (CFRT) could deliver higher doses of radiation than does standard-dose conventional radical external-beam radiotherapy, and could improve long-term efficacy, potentially at the cost of increased toxicity. We aimed to present the first analyses of effectiveness from the MRC RT01 randomised controlled trial. Methods The MRC RT01 trial included 843 men with localised prostate cancer who were randomly assigned to standard-dose CFRT or escalated-dose CFRT, both administered with neoadjuvant androgen suppression. Primary endpoints were biochemical-progression-free survival (bPFS), freedom from local progression, metastases-free survival, overall survival, and late toxicity scores. The toxicity scores were measured with questionnaires for physicians and patients that included the Radiation Therapy Oncology Group (RTOG), the Late Effects on Normal Tissue: Subjective/Objective/Management (LENT/SOM) scales, and the University of California, Los Angeles Prostate Cancer Index (UCLA PCI) scales. Analysis was done by intention to treat. This trial is registered at the Current Controlled Trials website http://www.controlled-trials.com/ISRCTN47772397. Findings Between January, 1998, and December, 2002, 843 men were randomly assigned to escalated-dose CFRT (n=422) or standard-dose CFRT (n=421). In the escalated group, the hazard ratio (HR) for bPFS was 0·67 (95% CI 0·53–0·85, p=0·0007). We noted 71% bPFS (108 cumulative events) and 60% bPFS (149 cumulative events) by 5 years in the escalated and standard groups, respectively. HR for clinical progression-free survival was 0·69 (0·47–1·02; p=0·064); local control was 0·65 (0·36–1·18; p=0·16); freedom from salvage androgen suppression was 0·78 (0·57–1·07; p=0·12); and metastases-free survival was 0·74 (0·47–1·18; p=0·21). HR for late bowel toxicity in the escalated group was 1·47 (1·12–1·92) according to the RTOG (grade ≥2) scale; 1·44 (1·16–1·80) according to the LENT/SOM (grade ≥2) scales; and 1·28 (1·03–1·60) according to the UCLA PCI (score ≥30) scale. 33% of the escalated and 24% of the standard group reported late bowel toxicity within 5 years of starting treatment. HR for late bladder toxicity according to the RTOG (grade ≥2) scale was 1·36 (0·90–2·06), but this finding was not supported by the LENT/SOM (grade ≥2) scales (HR 1·07 [0·90–1·29]), nor the UCLA PCI (score ≥30) scale (HR 1·05 [0·81–1·36]). Interpretation Escalated-dose CFRT with neoadjuvant androgen suppression seems clinically worthwhile in terms of bPFS, progression-free survival, and decreased use of salvage androgen suppression. This additional efficacy is offset by an increased incidence of longer term adverse events.

Triple-negative breast cancer: therapeutic options

Abstract: Triple-negative breast cancers are defined by a lack of expression of oestrogen, progesterone, and ERBB2 receptors. This subgroup accounts for 15% of all types of breast cancer and for a higher percentage of breast cancer arising in African and African-American women who are premenopausal. Because of the absence of specific treatment guidelines for this subgroup, triple-negative breast cancers are managed with standard treatment; however, such treatment leaves them associated with a high rate of local and systemic relapse. Histologically, such cancers are poorly differentiated, and most fall into the basal subgroup of breast cancers, characterised by staining for basal markers (ie, cytokeratin 5/6). Analyses of microarray gene-expression profiling data show that they form a homogeneous group (or so-called cluster) in transcriptional terms and, increasingly, research studies are identifying basal cancers on the basis of exhibiting this distinctive transcriptional profile. Histologically and transcriptionally, triple-negative breast cancers have many similarities to BRCA1-associated breast cancers, which suggests that dysfunction in BRCA1 or related pathways occurs in this subset of sporadic cancers. In this review, we discuss the molecular features of triple-negative breast cancers and consider how the use of existing cytotoxic agents can be optimised for this patient group. We discuss the implications of a possible underlying BRCA1-pathway dysfunction in this subgroup in terms of treatment and we also investigate the predominant proliferative signals and the on-going research addressing the suitability of these signals as therapeutic targets.

Survival for eight major cancers and all cancers combined for European adults diagnosed in 1995–99: results of the EUROCARE-4 study

Abstract: Summary Background EUROCARE is the largest population-based cooperative study on survival of patients with cancer. The EUROCARE project aims to regularly monitor, analyse, and explain survival trends and between-country differences in survival. This report (EUROCARE-4) presents survival data for eight selected cancer sites and for all cancers combined, diagnosed in adult (aged ≥15 years) Europeans in 1995–99 and followed up until the end of 2003. Methods We analysed data from 83 cancer registries in 23 European countries on 2 699 086 adult cancer cases that were diagnosed in 1995–99 and followed up to December, 2003. We calculated country-specific and mean-weighted age-adjusted 5-year relative survival for eight major cancers. Additionally, case-mix-adjusted 5-year survival for all cancers combined was calculated by countries ranked by total national expenditure on health (TNEH). Changes to survival were analysed relative to cases diagnosed in 1990–94. Findings Mean age-adjusted 5-year relative survival for colorectal (53·8% [95% CI 53·3–54·1]), lung (12·3% [12·1–12·5]), breast (78·9% [78·6–79·2]), prostate (75·7% [75·2–76·2]), and ovarian (36·3% [35·7–37·0]) cancer was highest in Nordic countries (except Denmark) and central Europe, intermediate in southern Europe, lower in the UK and Ireland, and worst in eastern Europe. Survival for melanoma (81·6% [81·0–82·3]), cancer of the testis (94·2% [93·4–95·0]), and Hodgkin's disease (80·0% [79·0–81·0]) varied little with geography. All-cancer survival correlated with TNEH for most countries. Denmark and UK had lower all-cancer survival than countries with similar TNEH; Finland had high all-cancer survival, but moderate TNEH. Survival increased and intercountry survival differences narrowed between the data for 1990–94 and 1995–99 for, notably, Hodgkin's disease (range 66·1–82·9 [IQR 72·2–78·6] vs 74·0–83·9 [78·6–81·9]), colorectal (29·4–56·7 [45·8–54·1] vs 38·8–59·7 [50·7–57·5]), and breast (61·7–82·7 [72·3–78·3] vs 69·3–87·6 [76·6–82·7]) sites. Interpretation Increases in survival and decreases in geographic differences over time, which are mainly due to improvements in health-care services in countries with poor survival, might indicate better cancer care. Wealthy countries with high TNEH generally had good cancer outcomes, but those with conspicuously worse outcomes than those with similar TNEH might not be allocating health resources efficiently.

Carcinogenicity of alcoholic beverages

Abstract: In February, 2007, 26 scientists from 15 countries met at the International Agency for Research on Cancer (IARC) in Lyon, France, to reassess the carcino-genicity of alcoholic beverages and of ethyl carbamate (urethane), a frequent contaminant of fermented foods and beverages. These assessments will be published as volume 96 of the IARC Monographs.

PET to assess early metabolic response and to guide treatment of adenocarcinoma of the oesophagogastric junction: the MUNICON phase II trial.

Abstract: Summary Background In patients with locally advanced adenocarcinoma of the oesophagogastric junction (AEG), early metabolic response defined by 18-fluorodeoxyglucose-PET ([ 18 F]FDG-PET) during neoadjuvant chemotherapy is predictive of histopathological response and survival. We aimed to assess the feasibility of a PET-response-guided treatment algorithm and its potential effect on prognosis. Methods Between May 27, 2002, and Aug 4, 2005, 119 patients with locally advanced adenocarcinoma of AEG type 1 (distal oesophageal adenocarcinoma) or type 2 (gastric cardia adenocarcinoma) were recruited into this prospective, single-centre study. All patients were assigned to 2 weeks of platinum and fluorouracil-based induction chemotherapy (evaluation period). Those with decreases in tumour glucose standard uptake values (SUVs), predefined as decreases of 35% or more at the end of the evaluation period and measured by PET, were defined as metabolic responders. Responders continued to receive neoadjuvant chemotherapy of folinic acid and fluorouracil plus cisplatin, or folinic acid and fluorouracil plus cisplatin and paclitaxel, or folinic acid and fluorouracil plus oxaliplatin for 12 weeks and then proceeded to surgery. Metabolic non-responders discontinued chemotherapy after the 2-week evaluation period and proceeded to surgery. The primary endpoint was median overall survival of metabolic responders and non-responders. Secondary endpoints were median event-free survival, postoperative complications and mortality, number of residual tumour-free (R0) resections, and histopathological responses. This study has been registered in the European Clinical Trials Database (EudraCT) as trial 2007-003356-11. Findings 110 patients were evaluable for metabolic responses. 54 of these patients had metabolic responses (ie, decrease of 35% or more in tumour glucose SUV) after 2 weeks of induction chemotherapy, corresponding to a response of 49% (95% CI 39–59). 104 patients had tumour resection (50 in the responder group and 54 in the non-responder group). After a median follow-up of 2·3 years (IQR 1·7–3·0), median overall survival was not reached in metabolic responders, whereas median overall survival was 25·8 months (19·4–32·2) in non-responders (HR 2·13 [1·14–3·99, p=0·015). Median event-free survival was 29·7 months (95% CI 23·6–35·7) in metabolic responders and 14·1 months (7·5–20·6) in non-responders (hazard ratio [HR] 2·18 [1·32–3·62], p=0·002). Major histological remissions ( Interpretation This study confirmed prospectively the usefulness of early metabolic response evaluation, and shows the feasibility of a PET-guided treatment algorithm. These findings might enable tailoring of multimodal treatment in accordance with individual tumour biology in future randomised trials.

Part I: Mechanisms of resistance to imatinib in chronic myeloid leukaemia

Abstract: Summary The introduction of selective tyrosine-kinase inhibitors (TKIs) for the treatment of chronic myeloid leukaemia has changed patient outcome and, consequently, management of this disease. Imatinib is now the treatment of choice for most newly diagnosed patients. Excellent responses, in terms of symptom control and haematological parameters, are usually obtained. However, failure to completely eradicate leukaemic cells and the escape of these cells from previous control has led to an intensive search for the mechanisms of resistance and subsequent treatments by which to overcome this resistance. Up to now, there has been considerable focus on the role of ABL-kinase-domain mutations as mediators of resistance to imatinib, thereby encouraging the development of a second generation of TKIs capable of inhibiting these mutant proteins. However, studies have increasingly shown that these mutations do not account for all cases of resistance and have a negligible role in the inability of TKIs to eradicate residual disease in patients who are good responders. More recently, attention has turned to the relative roles of drug bioavailability and drug efflux and drug influx proteins in the development of resistance to imatinib. This review is the first of two papers and discusses imatinib resistance and its potential causes. The second paper will focus on the assessment and subsequent management of patients with less than optimum responses to imatinib.

Bone-targeted radium-223 in symptomatic, hormone-refractory prostate cancer: a randomised, multicentre, placebo-controlled phase II study

Abstract: BACKGROUND: The alpha-emitter radium-223 ((223)Ra) is a bone-seeking radionuclide studied as a new treatment for patients with bone metastases from hormone-refractory prostate cancer. We aimed to s ...

Therapeutic strategies in oesophageal carcinoma: role of surgery and other modalities.

Abstract: Summary Traditionally, surgery is considered the best treatment for oesophageal cancer in terms of locoregional control and long-term survival. However, survival 5 years after surgery alone is about 25%, and, therefore, a multidisciplinary approach that includes surgery, radiotherapy, and chemotherapy, alone or in combination, could prove necessary. The role of each of these treatments in the management of oesophageal cancer is under intensive research to define optimum therapeutic strategies. In this report we provide an update on treatment strategies for resectable oesophageal cancers on the basis of recent published work. Results of the latest randomised trials allow us to propose the following guidelines: surgery is the standard treatment, to be used alone for stages I and IIa, or possibly with neoadjuvant chemotherapy or chemoradiotherapy for stage IIb disease. For locally advanced cancers (stage III), neoadjuvant chemotherapy or chemoradiotherapy followed by surgery is appropriate for adenocarcinomas. Chemoradiotherapy alone should only be considered in patients with squamous-cell carcinomas who show a morphological response to chemoradiotherapy, and produces a similar overall survival to chemoradiotherapy followed by surgery, but with less post-treatment morbidity. Although the addition of surgery to chemotherapy or chemoradiotherapy could result in improved local control and survival, surgery should be done in experienced hospitals where operative mortality and morbidity are low. Moreover, surgery should be kept in mind as salvage treatment in patients with no morphological response or persistent tumour after definitive chemoradiotherapy.

Axitinib treatment in patients with cytokine-refractory metastatic renal-cell cancer: a phase II study.

Abstract: Summary Background Axitinib (AG-013736) is an oral, potent, and selective inhibitor of vascular endothelial growth factor receptors 1, 2, and 3. We aimed to assess the activity and safety of axitinib in patients with metastatic renal-cell cancer who had failed on previous cytokine-based treatment. Methods Between Oct 3, 2003, and April 7, 2004, 52 patients were enrolled. All patients who had at least one measurable target lesion received axitinib orally (starting dose 5 mg twice daily). The primary endpoint was objective response (ie, percentage of patients with confirmed complete response or partial response by use of Response Evaluation Criteria In Solid Tumors [RECIST] criteria. Secondary endpoints were duration of response, time to progression, overall survival, safety, pharmacokinetics, and patient-reported health-related quality of life. This trial is registered on the clinical trials site of the US National Cancer Institute website http://www.clinicaltrials.gov/ct/show/NCT00076011. Findings In an intention-to-treat analysis, two complete and 21 partial responses were noted, for an objective response rate of 44·2% (95% CI 30·5–58·7). Median response duration was 23·0 months (20·9–not estimable; range 4·2–29·8). However, 12 of 23 initial responders progressed with response duration ranging from 4·2 months to 26·5 months. Additionally, 22 patients showed stable disease for longer than 8 weeks, including 13 patients with stable disease for 24 weeks or longer. Four patients had early disease progression. Three patients had missing response data. Median time to progression was 15·7 months (8·4–23·4, range 0·03–31·5) and median overall survival was 29·9 months (20·3–not estimable; range 2·4–35·8). Treatment-related adverse events included diarrhoea, hypertension, fatigue, nausea, and hoarseness. Treatment-related hypertension occurred in 30 patients and resolved with antihypertensive treatment in all but eight patients, of whom seven patients had a history of hypertension at baseline. Interpretation Axitinib shows clinical activity in patients with cytokine-refractory metastatic renal-cell cancer. Although 28 patients had grade 3 or grade 4 treatment-related adverse events, these adverse events were generally manageable and controlled by dose modification or supportive care, or both. Further studies are needed to confirm these findings.

Efficacy of trabectedin (ecteinascidin-743) in advanced pretreated myxoid liposarcomas: a retrospective study

Abstract: Summary Background Previous studies have suggested that trabectedin (ecteinascidin-743) could have antitumour activity in soft-tissue sarcoma. We aimed to study the usefulness of trabectedin in the treatment of patients with myxoid liposarcomas, a subtype of liposarcoma that is associated with specific chromosomal translocations t(12;16)(q13;p11) or t(12;22)(q13;q12) that result in the formation of DDIT3-FUS or DDIT3-EWSR1 fusion proteins. Methods 51 patients with advanced pretreated myxoid liposarcoma who started treatment with trabectedin between April 4, 2001, and Sept 18, 2006 at five institutions in a compassionate-use programme were analysed retrospectively. Centralised radiological and pathological reviews were done for most patients. Trabectedin was given either as a 24-h continuous infusion or as a 3-h infusion, every 21 days, at 1·1–1·5 mg 2 . 558 courses of trabectedin were given in total, with a median of ten courses for each patient (range 1–23). The primary endpoints were response rate and progression-free survival, and the secondary endpoint was overall survival. Findings According to Response Evaluation Criteria in Solid Tumors (RECIST), after a median follow-up of 14·0 months (IQR 8·7–20·0), two patients had complete responses (CR) and 24 patients had partial responses (PR); the overall response was 51% (95% CI 36–65). Five patients had early progressive disease. In 17 of the 23 patients who achieved PR or CR as defined by RECIST and who had centralised radiological review, tissue-density changes, consisting of a decrease in tumour density on CT scan or a decrease in contrast enhancement on MRI (or both), preceded tumour shrinkage. Median progression-free survival was 14·0 months (13·1–21·0), and progression-free survival at 6 months was 88% (79–95). Interpretation Trabectedin was associated with antitumour activity in this series of patients with myxoid liposarcoma. The noted patterns of tumour response were such that tissue density changes occurred before tumour shrinkage in several patients. In some patients, tissue-density changes only were seen. Long-lasting tumour control was noted in responsive patients. The compassionate-use programme is still ongoing. This analysis has resulted in the initiation of two prospective studies to assess the role of trabectedin in the treatment of patients with myxoid liposarcoma in preoperative and metastatic settings. Furthermore, the selective mechanism of action for trabectedin in this translocation-related sarcoma is being studied.

Skeletal effects of exemestane on bone-mineral density, bone biomarkers, and fracture incidence in postmenopausal women with early breast cancer participating in the Intergroup Exemestane Study (IES): a randomised controlled study

Abstract: Summary Background Tamoxifen preserves bone in postmenopausal women, but non-steroidal aromatase inhibitors accelerate bone loss and increase fracture risk. We aimed to study the effect on bone health in a subgroup of women included in the Intergroup Exemestane Study (IES), a large randomised trial that compared the switch to the steroidal aromatase inhibitor exemestane with continuation of tamoxifen in the adjuvant treatment of postmenopausal breast cancer. Methods Results were analysed from 206 evaluable patients from the IES, in which postmenopausal women with histologically confirmed and completely resected unilateral breast cancer (that was oestrogen-receptor positive or of unknown status), who were disease-free after 2–3 years of treatment with tamoxifen were randomised to continue oral tamoxifen 20 mg/day or switch to oral exemestane 25 mg/day to complete a total of 5 years of adjuvant endocrine therapy. The primary endpoint was change in bone-mineral density (BMD) assessed by dual energy X-ray absorptiometry. Changes in biochemical markers of bone turnover were also analysed in this substudy, and the incidence of fractures in the entire study reported. The IES is registered on the Current Controlled Trials website http://www.controlled-trials.com/ISRCTN11883920. Findings Within 6 months of switching to exemestane, BMD was lowered by 0·051 g/cm 3 (2·7%; 95% CI 2·0–3·4; p 3 (1·4%; 0·8–1·9; p Interpretation These results indicate that the increase in survival shown previously with the IES switch strategy is achieved at the expense of some detriment to skeletal health, so the risk-benefit ratio to women needs to be individually assessed.

Preoperative characterisation of clear-cell renal carcinoma using iodine-124-labelled antibody chimeric G250 (124I-cG250) and PET in patients with renal masses: a phase I trial

Abstract: Summary Background Preoperative identification of tumour type could have important implications for the choice of treatment for renal cancers. Antibody cG250 reacts against carbonic anhydrase-IX, which is over-expressed in clear-cell renal carcinomas. We aimed to assess whether iodine-124-labelled antibody chimeric G250 ( 124 I-cG250) PET predicts clear-cell renal carcinoma, the most common and aggressive renal tumour. Methods 26 patients with renal masses who were scheduled to undergo surgical resection by laparotomy received a single intravenous infusion of 185 MBq/10 mg of 124 I-cG250 over 20 min in this open-label pilot study. Surgery was scheduled 1 week after 124 I-cG250 infusion. PET and CT scanning of the abdomen, including the kidneys, within 3 h before surgery was planned for all patients. The obtained images were graded as positive (defined as a tumour-to-healthy-kidney ratio >3 to 1) or negative for antibody uptake, and the surgeon was informed of the scan results before surgery. After surgery, resected tumours were histopathologically classified as clear-cell renal carcinoma or otherwise. The trial is registered on the clinical trials site of the National Cancer Institute website http://clinicaltrials.gov/ct/show/NCT00199888. Findings One patient received inactive antibody and was excluded from analysis. 15 of 16 clear-cell carcinomas were identified accurately by antibody PET, and all nine non-clear-cell renal masses were negative for the tracer. The sensitivity of 124 I-cG250 PET for clear-cell kidney carcinoma in this trial was 94% (95% CI 70–100%); the negative predictive value was 90% (55–100%), and specificity and positive predictive accuracy were both 100% (66–100% and 78–100%, respectively). Interpretation PET with 124 I-cG250 can identify accurately clear-cell renal carcinoma; a negative scan is highly predictive of a less aggressive phenotype. Stratification of patients with renal masses by 124 I-cG250 PET can identify aggressive tumours and help decide treatment.

Management of breast cancer in elderly individuals: recommendations of the International Society of Geriatric Oncology

Abstract: Breast cancer is the most commonly diagnosed cancer and the leading cause of cancer mortality in women worldwide. Elderly individuals make up a large part of the breast cancer population, and there are important specific considerations for this population. The International Society of Geriatric Oncology created a task force to assess the available evidence on breast cancer in elderly individuals, and to provide evidence-based recommendations for the diagnosis and treatment of breast cancer in such individuals. A review of the published work was done with the results of a search on Medline for English-language articles published between 1990 and 2007 and of abstracts from key international conferences. Recommendations are given on the topics of screening, surgery, radiotherapy, (neo)adjuvant hormone treatment and chemotherapy, and metastatic disease. Since large randomised trials in elderly patients with breast cancer are scarce, there is little level I evidence for the treatment of such patients. The available evidence was reviewed and synthesised to provide consensus recommendations regarding the care of breast cancer in older adults.

From margins to centre: a review of the history of palliative care in cancer

Abstract: Palliative care and hospices have developed rapidly since the late 1960s. The pioneering work of Cicely Saunders was instrumental in drawing attention to the end-of-life care needs of patients with advanced malignant disease. Palliative care began to be defined as a subject of activity in the 1970s and came to be synonymous with the physical, social, psychological, and spiritual support of patients with life-limiting illness, delivered by a multidisciplinary team. Palliative care services have developed in many settings and have often been closely related to oncology. The worldwide need for this type of care remains much greater than the available provision, but there are encouraging signs of recognition by policymakers and influential bodies, and interest in palliative care has never been greater. This paper charts the modern history of such care around the world and concludes on some current issues and future challenges.

Presentation of childhood CNS tumours: a systematic review and meta-analysis.

Abstract: Findings 74 papers (n=4171) met the inclusion criteria. 56 symptoms and signs at diagnosis were identifi ed, ranked by frequency, and clustered according to age, anatomical criteria, and genetic criteria. The most frequent symptoms and signs at diagnosis were: headache (33%), nausea and vomiting (32%), abnormalities of gait and coordination (27%), and papilloedema (13%) for intracranial tumours; macrocephaly (41%), nausea and vomiting (30%), irritability (24%), and lethargy (21%) for children aged under 4 years with intracranial tumours; reduced visual acuity (41%), exophthalmia (16%), and optic atrophy (15%) for children with an intracranial tumour and neurofi bromatosis; nausea and vomiting (75%), headache (67%), abnormal gait and coordination (60%), and papilloedema (34%) for posterior fossa tumours; unspecifi ed symptoms and signs of raised intracranial pressure (47%), seizures (38%), and papilloedema (21%) for supratentorial tumours; headache (49%), abnormal eye movements (21%), squint (21%), and nausea and vomiting (19%) for central brain tumours; abnormal gait and coordination (78%), cranial nerve palsies (52%), pyramidal signs (33%), headache (23%), and squint (19%) for brainstem tumours; and back pain (67%), abnormalities of gait and coordination (42%), spinal deformity (39%), focal weakness (21%), and sphincter disturbance (20%) for spinal-cord tumours. Other features noted were weight loss, growth failure, and precocious puberty. Symptoms of raised intracranial pressure were absent in more than half of children with brain tumours. Other neurological features were heterogeneous and related to tumour location. Interpretation Apart from raised intracranial pressure, motor and visual system abnormalities, weight loss, macrocephaly, growth failure, and precocious puberty also suggest presence of an intracranial tumour. Children with signs and symptoms that could result from a CNS tumour need a thorough visual and motor system examination and an assessment of growth and pubertal status. Occurrence of multiple symptoms and signs should alert clinicians to possible CNS tumours.

Gastrointestinal symptoms after pelvic radiotherapy: a new understanding to improve management of symptomatic patients

Abstract: Gastrointestinal symptoms after pelvic radiotherapy, which affect quality of life, are substantially more common than generally recognised and are frequently poorly managed. These symptoms develop because radiation can induce change in one or more specific physiological functions in widely separated parts of the gastrointestinal tract that lie in the path of the radiotherapy beam. Radiation-induced changes are not confined by normal anatomical boundaries. Furthermore, pre-existing subclinical disease might be destabilised because of minor gastrointestinal changes induced by radiotherapy. New diseases might manifest after radiotherapy and be confused with symptoms induced by radiotherapy. Different functional deficits might cause the same symptoms. Many patients have more than one cause for their symptoms, which sometimes need very different treatments. Simple diagnostic tests that are used in other contexts, if applied appropriately to patients with new gastrointestinal symptoms after radiotherapy, can identify the underlying causes of new-onset symptoms. Starting treatment without knowing the cause of the symptom is commonly ineffective because prediction of the combination of treatments needed is difficult. Evidence suggests that many patients have unusual but highly treatable malfunctions of gastrointestinal physiology, which if correctly diagnosed may enable a patient with difficult symptoms to be helped.

Use of 70-gene signature to predict prognosis of patients with node-negative breast cancer: a prospective community-based feasibility study (RASTER)

Abstract: Summary Background A microarray-based 70-gene prognosis signature might improve the selection of patients with node-negative breast cancer for adjuvant systemic treatment. The main aims of this MicroarRAy PrognoSTics in Breast CancER (RASTER) study were to assess prospectively the feasibility of implementation of the 70-gene prognosis signature in community-based settings and its effect on adjuvant systemic treatment decisions when considered with treatment advice formulated from the Dutch Institute for Healthcare Improvement (CBO) and other guidelines. Methods Between January, 2004 and December, 2006, 812 women aged under 61 years with primary breast carcinoma (clinical T1–4N0M0) were enrolled. Fresh tumour samples were collected in 16 hospitals in the Netherlands within 1 h after surgery. Clinicopathological factors were collected and microarray analysis was done with a custom-designed array chip that assessed the mRNA expression index of the 70 genes previously identified for the prognostic signature. Patients with a "good" signature were deemed to have a good prognosis and, therefore, could be spared adjuvant systemic treatment with its associated adverse effects, whereas patients with a "poor" signature were judged to have a poor prognosis and should be considered for adjuvant systemic treatment. Concordance between risk predicted by the prognosis signature and risk predicted by commonly used clinicopathological guidelines (ie, St Gallen guidelines, Nottingham Prognostic Index, and Adjuvant! Online) was assessed. Findings Of 585 eligible patients, 158 patients were excluded because of sampling failure (n=128) and incorrect procedure (n=30). Prognosis signatures were assessed in 427 patients. The 70-gene prognosis signature identified 219 (51%) patients with good prognosis and 208 (49%) patients with poor prognosis. The Dutch CBO guidelines identified 184 patients (43%) with poor prognosis, which was discordant with those findings obtained with the prognosis signature in 128 (30%) patients. Oncologists recommended adjuvant treatment in 203 (48%) patients based on Dutch CBO guidelines, in 265 (62%) patients if the guidelines were used with the prognosis signature, and in 259 (61%) patients if Dutch CBO guidelines, prognosis signature, and patients' preferences for treatment were all taken into account. Adjuvant! Online guidelines identified more patients with poor prognosis than did the signature alone (294 [69%]), and discordance with the signature occurred in 160 (37%) patients. St Gallen guidelines identified 353 (83%) patients with poor prognosis with the signature and discordance in 168 (39%) patients. Nottingham Prognostic Index recorded 179 (42%) patients with poor prognosis with the signature and discordance in 117 (27%) patients. Interpretation Use of the prognosis signature is feasible in Dutch community hospitals. Adjuvant systemic treatment was advised less often when the more restrictive Dutch CBO guidelines were used compared with that finally given after use of the prognosis signature. For the other guidelines assessed, less adjuvant chemotherapy would be given when the data based on prognosis signature alone are used, which might spare patients from adverse effects and confirms previous findings. Future studies should assess whether use of the prognosis signature could improve survival or equal survival while avoiding unnecessary adjuvant systemic treatment without affecting patients' survival, and further assess the factors that physicians use to recommend adjuvant systemic treatment.

A multivariate analysis of limiting factors for stoma reversal in patients with rectal cancer entered into the total mesorectal excision (TME) trial: a retrospective study.

Abstract: Summary Background In many patients with rectal cancer, defunctioning stomas are created to limit the consequences of anastomotic leakage. Although intended to be temporary, a substantial proportion of these stomas might never be reversed for various reasons. We aimed to describe stoma policy by use of data from the total mesorectal excision (TME) trial in patients with rectal cancer and to identify factors that limit stoma reversal. Methods 924 Dutch patients with rectal cancer who underwent a low anterior resection were selected from the TME trial, a prospective, randomised multicentre trial studying the effects of short-term preoperative radiotherapy in 1861 patients who underwent TME. Creation of stomas and time to stoma reversal were analysed retrospectively by use of multivariate analysis. Findings In 523 of 924 (57%) patients, a primary stoma (defined as a stoma created at the time of TME) was constructed after a low anterior resection. Geographical differences in the number of primary stomas constructed were reported throughout the Netherlands. 19% of stomas that were created were never reversed. Postoperative complications and secondary constructed stomas (defined as a stoma created during a second or subsequent procedure after TME) were associated with a high likelihood of a permanent stoma. However, perioperative complications were not a limiting factor for stoma closure. Interpretation Postoperative complications are an important limiting factor for stoma reversal because, after occurrence of these complications, patients and surgeons might be reluctant to reverse the stoma, so a substantial proportion of these stomas are never closed. Future guidelines for stoma creation and closure should consider these factors.

Alternative splicing: an emerging topic in molecular and clinical oncology

Abstract: Alternative pre-mRNA splicing is a key molecular event that allows for protein diversity. Through this process, a single gene increases its coding capacity by expressing several related proteins with diverse and even antagonistic functions. Aberrant splicing has been found to be associated with various diseases, including cancer. Mutations in splicing regulatory elements within the nucleotide sequence and alterations in the cellular-splicing-regulatory machinery both result in changes in the splicing pattern of many cancer-related genes. The analysis of cancer-specific alternative splicing and its molecular consequences is promising. In this review we summarise the current knowledge on the mechanisms governing abnormal alternative splicing in cancer and the biological consequences associated with the alteration of splicing in some relevant cancer-related genes. The use of alternative splicing as a potential source for new diagnostic, prognostic, predictive, and therapeutic tools is also discussed.

Dynamic contrast-enhanced MRI as a predictor of tumour response to radiotherapy

Abstract: A predictive technique in the management of patients with cancer could improve the therapeutic index by allowing better individualisation of treatment. The standard risk factors that are currently used do not adequately account for the unpredictable and substantial variation seen in the treatment response of patients with a similar risk profile. Dynamic contrast-enhanced (DCE) MRI is a non-invasive technique that can provide anatomical and physiological information on the tumour. The DCE-MRI data reflects the tumour microenvironment variables that are known to influence radiation response. The aim of this review is to describe the potential clinical application of DCE-MRI as a predictor of radiation response. We have reviewed the literature and identified 29 studies (total of 1194 patients) that correlate DCE-MRI with histopathological or clinical outcome data relevant to radiotherapy.

Active versus passive mechanisms in metastasis: do cancer cells crawl into vessels, or are they pushed?

Abstract: Although millions of cells are shed from a tumour every day, haematogenous metastasis is believed to be very inefficient. This inefficiency is widely assumed to be a result of the destruction of cells in the bloodstream by shear stress and the immune system and a slow rate of extravasation and proliferation in the stroma at a secondary site. Here, we propose that, whereas active intravasation of cells into the circulation is important in some tumours, others might shed cells passively into the blood or lymphatic vessels without the involvement of active cell migration. We discuss the evidence for and against this passive-shedding hypothesis and the implications for future treatments.

Reproductive risk factors for ovarian cancer in carriers of BRCA1 or BRCA2 mutations: a case-control study

Abstract: Summary Background Several of the known risk factors for ovarian cancer are thought to act through their effects on ovulation and the menstrual cycle, such as parity, breastfeeding, and use of oral contraceptives. We aimed to assess the effect of these three risk factors, and of tubal ligation, on the risk of ovarian cancer in women who carry a mutation in the BRCA1 or BRCA2 genes. Methods We did a matched case-control study in women who were found to carry a pathogenetic mutation in BRCA1 or BRCA2 . Participants were derived from a population-based study of ovarian cancer in Ontario, Canada, and from an international registry of mutation carriers based in Toronto, ON, Canada. All participants completed a written questionnaire that detailed their reproductive history. Women with invasive ovarian cancer and controls were matched on year of birth, country of residence, mutation ( BRCA1 or BRCA2 ), and history of breast cancer. The odds ratios and 95% CI for ovarian cancer were estimated with respect to use of oral contraceptives, parity, breastfeeding, and tubal ligation. Findings Questionnaires were completed by 799 women with a history of invasive ovarian cancer (670 with BRCA1 mutations, 128 with BRCA2 mutations, and one with a mutation in both genes), and controls were 2424 women without ovarian cancer (2043 with BRCA1 mutations, 380 with BRCA2 mutations, and one with a mutation in both genes). Use of oral contraceptives reduced the risk of ovarian cancer in carriers of BRCA1 mutations (odds ratio 0·56 [95% CI 0·45–0·71]; p BRCA2 mutations (0·39 [0·23–0·66]; p=0·0004). Parity was associated with a reduced risk for carriers of BRCA1 mutations (0·67 [0·46–0·96]; p=0·03), but with an increased risk for those with BRCA2 mutations (2·74 [1·18–6·41]; p=0·02). Breastfeeding was associated with a reduced risk for carriers of BRCA1 mutations (0·74 [0·56–0·97]; p=0·03). An effect of similar magnitude was seen for carriers of BRCA2 mutations (0·72 [0·41–1·29]; p=0·27), but this was not statistically significant. The association with tubal ligation was not significant for carriers of BRCA1 mutations (0·80 [0·59–1·08]; p=0·15), or for carriers of BRCA2 mutations (0·63 [0·34–1·15]; p=0·13). Interpretation Oral contraceptives could be used as a means to prevent ovarian cancer in carriers of BRCA1 and BRCA2 mutations. The possible adverse effect of parity on ovarian-cancer risk in women with a BRCA2 mutation needs further study.

Retraction--Validation of gene signatures that predict the response of breast cancer to neoadjuvant chemotherapy: a substudy of the EORTC 10994/BIG 00-01 clinical trial.

Abstract: Summary Background We have previously described gene-expression signatures that predict growth inhibitory and cytotoxic effects of common chemotherapeutic drugs in vitro. The aim of this study was to confirm the validity of these gene-expression signatures in a large series of patients with oestrogen-receptor-negative breast tumours who were treated in a phase III neoadjuvant clinical trial. Methods This trial compares a non-taxane regimen (fluorouracil, epirubicin, and cyclophosphamide [FEC] for six cycles) with a taxane regimen (docetaxel for three cycles followed by epirubicin plus docetaxel [TET] for three cycles) in women with oestrogen-receptor-negative breast cancer. The primary endpoint of the study is the difference in progression-free survival based on TP53 status and will be reported later. Predicting response with gene signatures was a planned secondary endpoint of the trial and is reported here. Pathological complete response, defined as complete disappearance of the tumour with no more than a few scattered tumour cells detected by the pathologist in the resection specimen, was used to assess chemosensitivity. RNA was prepared from sections of frozen biopsies taken at diagnosis and hybridised to Affymetrix X3P microarrays. In-vitro single-agent drug sensitivity signatures were combined to obtain FEC and TET regimen-specific signatures. This study is registered on the clinical trials site of the US National Cancer Institute website http://www.clinicaltrials.gov/ct/show/NCT00017095. Findings Of 212 patients with oestrogen-receptor-negative tumours assessed, 87 patients were excluded. 125 oestrogen-receptor-negative tumours (55 that showed pathological complete responses) were tested: 66 in the FEC group (28 that showed pathological complete responses) and 59 in the TET group (27 that showed pathological complete responses). The regimen-specific signatures significantly predicted pathological complete response in patients treated with the appropriate regimen (p Interpretation We have validated the use of regimen-specific drug sensitivity signatures in the context of a multicentre randomised trial. The high NPV of both signatures may allow early selection of patients with breast cancer who should be considered for trials with new drugs.

Incomplete excision of cervical intraepithelial neoplasia and risk of treatment failure: a meta-analysis

Abstract: Summary Background Over 60 000 women are treated for cervical intraepithelial neoplasia (CIN) each year in England, most by excision. Management of women who have incomplete excision is controversial and the subject of much debate. Consequently, the completeness of excision is often ignored in the planning of subsequent treatment. We aimed to assess the effect of completeness of excision on the risk of post-treatment disease. Methods We undertook a meta-analysis of studies published between Jan 1, 1960, and Jan 31, 2007, that studied the risk of post-treatment disease (ie, CIN of any grade or invasive cancer) in relation to completeness of excision. Studies were included if they described treatment of CIN by excision; numbers of women with involved margins; prevalence of and numbers of women with post-treatment disease in relation to margin status. Criteria for post-treatment disease had to be stated as a defined abnormal cytology or histology. Studies were excluded if they described treatment of cervical glandular intraepithelial disease (CGIN); if all or nearly all women had reflex hysterectomy done soon after initial treatment; if women were immunosuppressed (eg, if they were HIV-positive); or if no control group with disease-free margins was used. The endpoint of our analysis was the relative risk (RR) of post-treatment disease in those whose treatment histology suggested that excision was complete compared with those in whom excision was incomplete or uncertain. RR meta-analysis was done by use of a random effects model. Findings The initial Medline search identified 1756 publications, from which 125 publications were short-listed. Of these, 65 and one unpublished study met our inclusion criteria; therefore, 66 studies were included in this meta-analysis. These studies described findings in 35 109 women of whom 8091 (23%) had at least one margin of the excision biopsy involved with disease. After incomplete excision, RR of post-treatment disease of any grade was 5·47 (95% CI 4·37–6·83) and RR of high-grade disease (ie, CIN 2 or 3, or high-grade squamous intraepithelial lesion) was 6·09 (3·87–9·60) compared with the reference group who had complete excision. High-grade post-treatment disease occurred in 597 of 3335 (18%) women who had incomplete excision versus 318 of 12 493 (3%) women who had complete excision. Interpretation Incomplete excision of CIN exposes women to a substantial risk of high-grade post-treatment disease. Some of these women would be safer with a second treatment, especially if deep margins are involved, but most will need close follow-up for at least 10 years. Every effort should be made to avoid incomplete excision. Adding extensive ablation in the treatment crater to compensate for inadequate excision should be avoided because this might delay detection of inadequately treated invasive disease and because the effectiveness of additional ablation to destroy any residual CIN cannot be assessed. Furthermore, extensive ablation does not decrease any risk of preterm delivery in subsequent pregnancies.

Magnesium wasting associated with epidermal-growth-factor receptor-targeting antibodies in colorectal cancer: a prospective study

Abstract: Summary Background Preliminary evidence suggests that magnesium wasting occurs in patients who are treated with epidermal-growth-factor receptor (EGFR)-targeting antibodies for colorectal cancer. The mechanism of this side-effect is unknown, and if all or a subset of patients are affected is also unclear. We aimed to assess the incidence, characteristics, and predictive factors of magnesium wasting during treatment with EGFR-targeting antibodies, and to study the pathophysiology of this phenomenon. Methods We measured prospectively magnesium concentrations in a cohort of 98 patients with colorectal cancer treated with EGFR-targeting antibodies with or without combined chemotherapy. The primary outcome measure was the slope of the serum magnesium concentrations over time. In 35 patients, 24-h urinary magnesium excretion was measured. In a subset of patients (n=5), an intravenous magnesium load test was done. 16 patients who had chemotherapy alone acted as controls. A clinical protocol was written before initiation of the study, but because this was a non-interventional study, the protocol was not formally registered. Findings 95 (97%) patients had decreasing serum magnesium concentrations during EGFR-targeting treatment compared with baseline measurements. The mean serum magnesium slope during EGFR-targeting treatment (with or without combined chemotherapy) was significantly lower compared with chemotherapy alone (−0·00157 mmol/L/day, SD 0·00162 [95% CI −0·00191 to −0·00123] vs 0·00014 mmol/L/day, SD −00076 [−0·00026 to 0·00055]; ( t test, p Interpretation EGFR-inhibiting antibodies compromised the renal magnesium retention capacity, leading to hypomagnesaemia in most patients. Future studies should address the effects of exposure and target affinity. Our study suggests a pivotal role of the EGFR-signalling pathway in regulating magnesium homoeostasis.

Use of combined apoptosis biomarkers for prediction of bladder cancer recurrence and mortality after radical cystectomy

Abstract: Summary Background Deregulation of apoptosis is a characteristic of human carcinogenesis. We aimed to investigate expression of the apoptosis markers Bcl-2, caspase-3, P53, and survivin and the association with oncological outcomes of patients treated by radical cystectomy and bilateral lymphadenectomy for urothelial-cell carcinoma of the bladder. Methods Bcl-2, caspase-3, P53, and survivin immunostaining was undertaken on serial tissue microarrays containing cores from 226 consecutive patients (median follow-up 36·9 months [IQR 13·3–79·0]). 200 bootstrap resamples with replacement were done to reduce overfit bias and for internal validation. Findings Expression of Bcl-2, caspase-3, P53, and survivin was altered in 73 (32%), 111 (49%), 120 (53%), and 141 (64%) patients, respectively. By univariate analysis, altered expression of Bcl-2, caspase-3, P53, and survivin were all associated with high probability of disease recurrence (hazard ratio 2·24 [95% CI 1·51–3·32], p Interpretation Bcl-2, caspase-3, P53, and survivin have a cooperative effect on progression of bladder cancer. Assessment of combined apoptosis marker status and number of altered markers in patients treated by radical cystectomy provides prognostic information that could help to identify those at high risk for disease recurrence and mortality, who could benefit from early adjuvant treatment.