Rhian Gabe

Diagnostic accuracy of multi-parametric MRI and TRUS biopsy in prostate cancer (PROMIS): a paired validating confirmatory study.

BACKGROUND Men with high serum prostate specific antigen usually undergo transrectal ultrasound-guided prostate biopsy (TRUS-biopsy). TRUS-biopsy can cause side-effects including bleeding, pain, and infection. Multi-parametric magnetic resonance imaging (MP-MRI) used as a triage test might allow men to avoid unnecessary TRUS-biopsy and improve diagnostic accuracy. METHODS We did this multicentre, paired-cohort, confirmatory study to test diagnostic accuracy of MP-MRI and TRUS-biopsy against a reference test (template prostate mapping biopsy [TPM-biopsy]). Men with prostate-specific antigen concentrations up to 15 ng/mL, with no previous biopsy, underwent 1·5 Tesla MP-MRI followed by both TRUS-biopsy and TPM-biopsy. The conduct and reporting of each test was done blind to other test results. Clinically significant cancer was defined as Gleason score ≥4 + 3 or a maximum cancer core length 6 mm or longer. This study is registered on ClinicalTrials.gov, NCT01292291. FINDINGS Between May 17, 2012, and November 9, 2015, we enrolled 740 men, 576 of whom underwent 1·5 Tesla MP-MRI followed by both TRUS-biopsy and TPM-biopsy. On TPM-biopsy, 408 (71%) of 576 men had cancer with 230 (40%) of 576 patients clinically significant. For clinically significant cancer, MP-MRI was more sensitive (93%, 95% CI 88-96%) than TRUS-biopsy (48%, 42-55%; p<0·0001) and less specific (41%, 36-46% for MP-MRI vs 96%, 94-98% for TRUS-biopsy; p<0·0001). 44 (5·9%) of 740 patients reported serious adverse events, including 8 cases of sepsis. INTERPRETATION Using MP-MRI to triage men might allow 27% of patients avoid a primary biopsy and diagnosis of 5% fewer clinically insignificant cancers. If subsequent TRUS-biopsies were directed by MP-MRI findings, up to 18% more cases of clinically significant cancer might be detected compared with the standard pathway of TRUS-biopsy for all. MP-MRI, used as a triage test before first prostate biopsy, could reduce unnecessary biopsies by a quarter. MP-MRI can also reduce over-diagnosis of clinically insignificant prostate cancer and improve detection of clinically significant cancer. FUNDING PROMIS is funded by the UK Government Department of Health, National Institute of Health Research-Health Technology Assessment Programme, (Project number 09/22/67). This project is also supported and partly funded by UCLH/UCL Biomedical Research Centre and The Royal Marsden and Institute for Cancer Research Biomedical Research Centre and is coordinated by the Medical Research Council Clinical Trials Unit (MRC CTU) at UCL. It is sponsored by University College London (UCL).

Randomized Trial of Carboplatin Versus Radiotherapy for Stage I Seminoma: Mature Results on Relapse and Contralateral Testis Cancer Rates in MRC TE19/EORTC 30982 Study (ISRCTN27163214)

PURPOSE Initial results of a randomized trial comparing carboplatin with radiotherapy (RT) as adjuvant treatment for stage I seminoma found carboplatin had a noninferior relapse-free rate (RFR) and had reduced contralateral germ cell tumors (GCTs) in the short-term. Updated results with a median follow-up of 6.5 years are now reported. PATIENTS AND METHODS Random assignment was between RT and one infusion of carboplatin dosed at 7 × (glomerular filtration rate + 25) on the basis of EDTA (n = 357) and 90% of this dose if determined on the basis of creatinine clearance (n = 202). The trial was powered to exclude a doubling in RFRs assuming a 96-97% 2-year RFR after radiotherapy (hazard ratio [HR], approximately 2.0). RESULTS Overall, 1,447 patients were randomly assigned in a 3-to-5 ratio (carboplatin, n = 573; RT, n = 904). RFRs at 5 years were 94.7% for carboplatin and 96.0% for RT (RT-C 90% CI, 0.7% to 3.5%; HR, 1.25; 90% CI, 0.83 to 1.89). One death as a result of seminoma (in RT arm) occurred. Patients receiving at least 99% of the 7 × AUC dose had a 5-year RFR of 96.1% (95% CI, 93.4% to 97.7%) compared with 92.6% (95% CI, 88.0% to 95.5%) in those who received lower doses (HR, 0.51; 95% CI, 0.24 to 1.07; P = .08). There was a clear reduction in the rate of contralateral GCTs (carboplatin, n = 2; RT, n = 15; HR, 0.22; 95% CI, 0.05 to 0.95; P = .03), and elevated pretreatment follicle-stimulating hormone (FSH) levels (> 12 IU/L) was a strong predictor (HR, 8.57; 95% CI, 1.82 to 40.38). CONCLUSION These updated results confirm the noninferiority of single dose carboplatin (at 7 × AUC dose) versus RT in terms of RFR and establish a statistically significant reduction in the medium term of risk of second GCT produced by this treatment.

Temozolomide Versus Procarbazine, Lomustine, and Vincristine in Recurrent High-Grade Glioma

PURPOSE Temozolomide (TMZ) is an alkylating agent licensed for treatment of high-grade glioma (HGG). No prospective comparison with nitrosourea-based chemotherapy exists. We report, to our knowledge, the first randomized trial of procarbazine, lomustine, and vincristine (PCV) versus TMZ in chemotherapy-naive patients with recurrent HGG. PATIENTS AND METHODS Four hundred forty-seven patients were randomly assigned to PCV (224 patients) or TMZ (sub-random assignment: TMZ-5 [200 mg/m(2) for 5 days, 112 patients] or TMZ-21 [100 mg/m(2) for 21 days, 111 patients]) for up to 9 months or until progression. The primary outcomes were survival (PCV v TMZ) and 12-week progression-free survival (PFS; TMZ-5 v TMZ-21). This study is registered as ISRCTN83176944. RESULTS Percentages of patients completing 9 months of treatment in the PCV, TMZ-5, and TMZ-21 arms were 17%, 26%, and 13%, respectively. Major toxicity was similar across all three groups. With a median follow-up time of 12 months and 382 deaths, there was no clear survival benefit when comparing PCV with TMZ (hazard ratio [HR], 0.91; 95% CI, 0.74 to 1.11; P = .350). For TMZ-5 versus TMZ-21, 12-week PFS rates were similar (63.6% and 65.7%, respectively; P = .745), but TMZ-5 improved overall PFS (HR, 1.38; 95% CI, 1.05 to 1.82; P = .023), survival (HR, 1.32; 95% CI, 0.99 to 1.75; P = .056), and global quality of life (49% v 19% improved > 10 points at 6 months, respectively; P = .005). CONCLUSION Although TMZ (both arms combined) did not show a clear benefit compared with PCV, comparison of the TMZ schedules demonstrated that the 21-day schedule was inferior to the 5-day schedule in this setting. This challenges the current understanding of increasing TMZ dose-intensity by prolonged scheduling.

Clinical and cost-effectiveness of compression hosiery versus compression bandages in treatment of venous leg ulcers (Venous leg Ulcer Study IV, VenUS IV): a randomised controlled trial

BACKGROUND Drawbacks exist with the standard treatment (four-layer compression bandages) for venous leg ulcers. We have therefore compared the clinical effectiveness and cost-effectiveness of two-layer compression hosiery with the four-layer bandage for the treatment of such ulcers. METHODS We undertook this pragmatic, open, randomised controlled trial with two parallel groups in 34 centres in England and Northern Ireland. The centres were community nurse teams or services, family doctor practices, leg ulcer clinics, tissue viability clinics or services, and wound clinics. Participants were aged 18 years or older with a venous leg ulcer and an ankle brachial pressure index of at least 0·8, and were tolerant of high compression. We randomly allocated participants (1:1) to receive two-layer compression hosiery or a four-layer bandage, using a remote randomisation service and prevalidated computer randomisation program. Participants were stratified by ulcer duration and ulcer area with permuted blocks (block sizes four and six). The primary endpoint was time to ulcer healing, with a maximum follow-up of 12 months. Although participants and health-care providers were not masked to treatment allocation, the primary endpoint was measured by masked assessment of photographs. Primary analysis was intention to treat with Cox regression, with adjustment for ulcer area, ulcer duration, physical mobility, and centre. This trial is registered with the ISRCTN register, number ISRCTN49373072. FINDINGS We randomly allocated 457 participants to the two treatment groups: 230 to two-layer hosiery and 227 to the four-layer bandage, of whom 453 (230 hosiery and 223 bandage) contributed data for analysis. Median time to ulcer healing was 99 days (95% CI 84-126) in the hosiery group and 98 days (85-112) in the bandage group, and the proportion of ulcers healing was much the same in the two groups (70·9% hosiery and 70·4% bandage). More hosiery participants changed their allocated treatment (38·3% hosiery vs 27·0% bandage; p=0·02). 300 participants had 895 adverse events, of which 85 (9·5%) were classed as serious but unrelated to trial treatment. INTERPRETATION Two-layer compression hosiery is a viable alternative to the four-layer bandage-it is equally as effective at healing venous leg ulcers. However, a higher rate of treatment changes in participants in the hosiery group than in the bandage group suggests that hosiery might not be suitable for all patients. FUNDING NIHR Health Technology Assessment programme (07/60/26).

Randomized Trials in 2466 Patients With Stage I Seminoma: Patterns of Relapse and Follow-up

BACKGROUND From July 1, 1989, through March 31, 2001, 2466 patients with stage I seminoma were evaluated in three randomized noninferiority trials: the TE10, TE18, and TE19 trials. We analyzed mature results of these studies. METHODS The TE10 trial randomly assigned 478 patients to para-aortic and ipsilateral iliac lymph node (dogleg field) or para-aortic only radiation therapy (total dose = 30 Gy). The TE18 trial randomly assigned 1094 patients to a total dose of 30 or 20 Gy of radiation therapy, predominantly to a para-aortic field. The TE19 trial randomly assigned 1477 patients to radiation therapy or a single injection of carboplatin at a dose of seven times the area under the curve. Time to relapse was determined from Kaplan-Meier curves, and such data were compared by use of Cox regression models. Noninferiority in TE18 and TE19 required the upper limit of the 90% confidence intervals (CIs) (reflecting the one-sided test for noninferiority at a 5% statistical significance level) to exclude a hazard ratio (HR) of greater than 2.0 and a doubling of the 5-year relapse rates observed in the control arm. The TE10 trial was not powered to exclude clinically relevant differences in overall relapse rates but was assessed against the same criteria. RESULTS Median follow-up times were 6.4-12 years in the three trials. We identified the noninferiority of the following treatments: 20 Gy of radiation therapy in the TE18 trial (HR of relapse = 0.63, 90% CI = 0.38 to 1.04) and carboplatin in the TE19 trial (HR of relapse = 1.25, 90% CI = 0.83 to 1.89). Para-aortic radiation therapy in the TE10 trial was associated with a hazard ratio of relapse of 1.15 (90% CI = 0.54 to 2.44). Relapse occurred after 3 years in only four (0.2%) of all 2466 patients. Computed tomography scans had little impact on the detection of relapse after radiation therapy; seven of the 904 patients allocated radiation therapy in TE19 had a relapse detected by this method. CONCLUSION This large and mature dataset from three randomized trials has provided support for the use of either radiation therapy or carboplatin therapy as adjuvant treatment for stage I seminoma.

Clinical and biological significance of CXCL12 and CXCR4 expression in adult testes and germ cell tumours of adults and adolescents

Interaction between the chemokine CXCL12 (SDF1) and the G‐protein coupled receptor CXCR4 is responsible for the maintenance of adult stem cell niches and is known to play an important role in utero in the migration of primordial germ cells. We demonstrate expression of CXCL12 by Sertoli cells and confirm CXCR4 expression by the germ cell population of the adult human testes. CXCR4 is also known to mediate organ‐specific patterns of metastases in a range of common cancers. We identify consistent expression of CXCR4 mRNA and protein in testicular germ cell tumours (TGCT) that accounts for their patterns of relapse in sites of known CXCL12 expression. Extragonadal primary germ cell tumours express CXCR4 and their sites of occurrence are coincident with areas of known CXCL12 expression in utero. We show that CXCL12 stimulates the invasive migration of a TGCT cell line in vitro in a CXCR4‐dependent fashion and activates ERK. Furthermore, we demonstrate that expression of CXCL12 in stage I non‐seminomas is significantly associated with organ‐confined disease post‐orchidectomy and reduced risk of relapse (p = 0.003). This may be through the loss of CXCL12 gradients that might otherwise attract cells away from the primary tumour. We propose CXCL12 expression as a potential predictor of subsequent relapse that could lead to avoiding unnecessary treatment and associated late toxicities. Our observations support a role for CXCL12/CXCR4 in the adult germ cell population and demonstrate pathological function in germ cell tumour development and metastasis that may have clinical utility. Copyright

A case-control study to estimate the impact of the Icelandic population-based mammography screening program on breast cancer death.

Background: The Icelandic breast cancer screening program, initiated November 1987 in Reykjavik and covering the whole country from December 1989, comprises biennial invitation to mammography for women aged 40–69 years old. Purpose: To estimate the impact of mammography service screening in Iceland on deaths from breast cancer. Material and Methods: Cases were deaths from breast cancer from 1990 onwards in women aged 40 and over at diagnosis, during the period November 1987 to December 31, 2002. Age- and screening-area-matched, population-based controls were women who had also been invited to screening but were alive at the time their case died. Results: Using conditional logistic regression on the data from 226 cases and 902 controls, the odds ratio for the risk of death from breast cancer in those attending at least one screen compared to those never screened was 0.59 (95% CI 0.41–0.84). After adjustment for healthy-volunteer bias and screening-opportunity bias, the odds ratio was 0.65 (95% CI 0.39–1.09). Conclusion: These results indicate a 35–40% reduction in breast cancer deaths by attending the Icelandic breast cancer screening program. These results are consistent with the overall evidence from other observational evaluations of mammography-based programs.

Therapeutic Targeting of Integrin αvβ6 in Breast Cancer

Background Integrin αvβ6 promotes migration, invasion, and survival of cancer cells; however, the relevance and role of αvβ6 has yet to be elucidated in breast cancer. Methods Protein expression of integrin subunit beta6 (β6) was measured in breast cancers by immunohistochemistry (n > 2000) and ITGB6 mRNA expression measured in the Molecular Taxonomy of Breast Cancer International Consortium dataset. Overall survival was assessed using Kaplan Meier curves, and bioinformatics statistical analyses were performed (Cox proportional hazards model, Wald test, and Chi-square test of association). Using antibody (264RAD) blockade and siRNA knockdown of β6 in breast cell lines, the role of αvβ6 in Human Epidermal Growth Factor Receptor 2 (HER2) biology (expression, proliferation, invasion, growth in vivo) was assessed by flow cytometry, MTT, Transwell invasion, proximity ligation assay, and xenografts (n ≥ 3), respectively. A student’s t-test was used for two variables; three-plus variables used one-way analysis of variance with Bonferroni’s Multiple Comparison Test. Xenograft growth was analyzed using linear mixed model analysis, followed by Wald testing and survival, analyzed using the Log-Rank test. All statistical tests were two sided. Results High expression of either the mRNA or protein for the integrin subunit β6 was associated with very poor survival (HR = 1.60, 95% CI = 1.19 to 2.15, P = .002) and increased metastases to distant sites. Co-expression of β6 and HER2 was associated with worse prognosis (HR = 1.97, 95% CI = 1.16 to 3.35, P = .01). Monotherapy with 264RAD or trastuzumab slowed growth of MCF-7/HER2-18 and BT-474 xenografts similarly (P < .001), but combining 264RAD with trastuzumab effectively stopped tumor growth, even in trastuzumab-resistant MCF-7/HER2-18 xenografts. Conclusions Targeting αvβ6 with 264RAD alone or in combination with trastuzumab may provide a novel therapy for treating high-risk and trastuzumab-resistant breast cancer patients.

Dextrin Sulfate as a Vaginal Microbicide: Randomized, Double-Blind, Placebo-Controlled Trial Including Healthy Female Volunteers and Their Male Partners

Summary: This randomized, placebo‐controlled trial assessed the safety and acceptability of vaginally administered 0.125% dextrin sulfate (DS) gel in sexually active women and their male partners. A single 2‐mL dose of study gel was self‐administered every night over two 14‐day periods separated by a 7‐day interval, during which menses was expected to occur. Up to two supplementary doses per 24 hours were provided for use before sexual intercourse. Semistructured interview, colposcopy, and laboratory safety studies were used to assess adverse events. Male partners who agreed to participate in a substudy were exposed to gel through sexual intercourse during the second 14‐day exposure period. Seventy‐three women (36 DS recipients and 37 placebo recipients) used at least one application of gel, of whom 66 (33 DS recipients and 33 placebo recipients) completed follow‐up. Eleven women (5 DS recipients and 6 placebo recipients) reported intermenstrual bleeding during gel use, which in most cases was light and resolved within 24 hours. Ten male partners (4 with DS exposure and 6 with placebo exposure) were enrolled in the study and all completed follow‐up. There was no evidence of systemic toxicity or genital epithelial disruption attributable to DS gel.

PROMIS — Prostate MR imaging study: A paired validating cohort study evaluating the role of multi-parametric MRI in men with clinical suspicion of prostate cancer

Background Transrectal ultrasound-guided prostate biopsies are prone to detection errors. Multi-parametric MRI (MP-MRI) may improve the diagnostic pathway. Methods PROMIS is a prospective validating paired-cohort study that meets criteria for level 1 evidence in diagnostic test evaluation. PROMIS will investigate whether multi-parametric (MP)-MRI can discriminate between men with and without clinically-significant prostate cancer who are at risk prior to first biopsy. Up to 714 men will have MP-MRI (index), 10–12 core TRUS-biopsy (standard) and 5 mm transperineal template mapping (TPM) biopsies (reference). The conduct and reporting of each test will be blinded to the others. Results PROMIS will measure and compare sensitivity, specificity, and positive and negative predictive values of both MP-MRI and TRUS-biopsy against TPM biopsies. The MP-MRI results will be used to determine the proportion of men who could safely avoid biopsy without compromising detection of clinically-significant cancers. For the primary outcome, significant cancer on TPM is defined as Gleason grade >/= 4 + 3 and/or maximum cancer core length of ≥ 6 mm. PROMIS will also assess inter-observer variability among radiologists among other secondary outcomes. Cost-effectiveness of MP-MRI prior to biopsy will also be evaluated. Conclusions PROMIS will determine whether MP-MRI of the prostate prior to first biopsy improves the detection accuracy of clinically-significant cancer.