Co-enrolment of participants into multiple cancer trials: benefits and challenges

Opportunities to enter patients into more than one clinical trial are not routinely considered in cancer research and experiences with co-enrolment are rarely reported. Potential benefits of allowing appropriate co-enrolment have been identified in other settings but there is a lack of evidence base or guidance to inform these decisions in oncology. Here, we discuss the benefits and challenges associated with co-enrolment based on experiences in the Add-Aspirin trial – a large, multicentre trial recruiting across a number of tumour types, where opportunities to co-enrol patients have been proactively explored and managed. The potential benefits of co-enrolment include: improving recruitment feasibility; increased opportunities for patients to participate in trials; and collection of robust data on combinations of interventions, which will ensure the ongoing relevance of individual trials and provide more cohesive evidence to guide the management of future patients. There are a number of perceived barriers to co-enrolment in terms of scientific, safety and ethical issues, which warrant consideration on a trial-by-trial basis. In many cases, any potential effect on the results of the trials will be negligible – limited by a number of factors, including the overlap in trial cohorts. Participant representatives stress the importance of autonomy to decide about trial enrolment, providing a compelling argument for offering co-enrolment where there are multiple trials that are relevant to a patient and no concerns regarding safety or the integrity of the trials. A number of measures are proposed for managing and monitoring co-enrolment. Ensuring acceptability to (potential) participants is paramount. Opportunities to enter patients into more than one cancer trial should be considered more routinely. Where planned and managed appropriately, co-enrolment can offer a number of benefits in terms of both scientific value and efficiency of study conduct, and will increase the opportunities for patients to participate in, and benefit from, clinical research

Statins as Potential Chemoprevention or Therapeutic Agents in Cancer: a Model for Evaluating Repurposed Drugs

Purpose of Review: Repurposing established medicines for a new therapeutic indication potentially has important global and societal impact. The high costs and slow pace of new drug development have increased interest in more cost-effective repurposed drugs, particularly in the cancer arena. The conventional drug development pathway and evidence framework are not designed for drug repurposing and there is currently no consensus on establishing the evidence base before embarking on a large, resource intensive, potential practice changing phase III randomised controlled trial (RCT). Numerous observational studies have suggested a potential role for statins as a repurposed drug for cancer chemoprevention and therapy, and we review the strength of the cumulative evidence here. Recent Findings: In the setting of cancer, a potential repurposed drug, like statins, typically goes through a cyclical history, with initial use for several years in another disease setting, prior to epidemiological research identifying a possible chemo-protective effect. However, further information is required, including review of RCT data in the initial disease setting with exploration of cancer outcomes. Additionally, more contemporary methods should be considered, such as Mendelian randomization and pharmaco-epidemiological research with “target” trial design emulation using electronic health records. Pre-clinical and traditional observational data potentially support the role of statins in the treatment of cancer; however, randomised trial evidence is not supportive. Evaluation of contemporary methods provides little added support for the use of statin therapy in cancer. Summary: We provide complementary evidence of alternative study designs to enable a robust critical appraisal from a number of sources of the go/no-go decision for a prospective phase III RCT of statins in the treatment of cancer

An International Comparative Public Health Analysis of Sex Trafficking of Women and Girls in Eight Cities: Achieving a More Effective Health Sector Response

Sex trafficking, trafficking for the purpose of forced sexual exploitation, is a widespread form of human trafficking that occurs in all regions of the world, affects mostly women and girls, and has far-reaching health implications. Studies suggest that up to 50 % of sex trafficking victims in the USA seek medical attention while in their trafficking situation, yet it is unclear how the healthcare system responds to the needs of victims of sex trafficking. To understand the intersection of sex trafficking and public health, we performed in-depth qualitative interviews among 277 antitrafficking stakeholders across eight metropolitan areas in five countries to examine the local context of sex trafficking. We sought to gain a new perspective on this form of gender-based violence from those who have a unique vantage point and intimate knowledge of push-and-pull factors, victim health needs, current available resources and practices in the health system, and barriers to care. Through comparative analysis across these contexts, we found that multiple sociocultural and economic factors facilitate sex trafficking, including child sexual abuse, the objectification of women and girls, and lack of income. Although there are numerous physical and psychological health problems associated with sex trafficking, health services for victims are patchy and poorly coordinated, particularly in the realm of mental health. Various factors function as barriers to a greater health response, including low awareness of sex trafficking and attitudinal biases among health workers. A more comprehensive and coordinated health system response to sex trafficking may help alleviate its devastating effects on vulnerable women and girls. There are numerous opportunities for local health systems to engage in antitrafficking efforts while partnering across sectors with relevant stakeholders

Mineral-PET: Kimberlite sorting by nuclear-medical technology

A revolutionary new technology for diamond bearing rock sorting which has its roots in medical-nuclear physics has been taken through a substantial part of the R&D phase. This has led to the construction of the technology demonstrator. Experiments using the technology demonstrator and experiments at a hospital have established the scientific and technological viability of the project

A randomised comparison evaluating changes in bone mineral density in advanced prostate cancer: luteinising hormone-releasing hormone agonists versus transdermal oestradiol.

BACKGROUND: Luteinising hormone-releasing hormone agonists (LHRHa), used as androgen deprivation therapy (ADT) in prostate cancer (PCa) management, reduce serum oestradiol as well as testosterone, causing bone mineral density (BMD) loss. Transdermal oestradiol is a potential alternative to LHRHa. OBJECTIVE: To compare BMD change in men receiving either LHRHa or oestradiol patches (OP). DESIGN, SETTING, AND PARTICIPANTS: Men with locally advanced or metastatic PCa participating in the randomised UK Prostate Adenocarcinoma TransCutaneous Hormones (PATCH) trial (allocation ratio of 1:2 for LHRHa:OP, 2006-2011; 1:1, thereafter) were recruited into a BMD study (2006-2012). Dual-energy x-ray absorptiometry scans were performed at baseline, 1 yr, and 2 yr. INTERVENTIONS: LHRHa as per local practice, OP (FemSeven 100μg/24h patches). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary outcome was 1-yr change in lumbar spine (LS) BMD from baseline compared between randomised arms using analysis of covariance. RESULTS AND LIMITATIONS: A total of 74 eligible men (LHRHa 28, OP 46) participated from seven centres. Baseline clinical characteristics and 3-mo castration rates (testosterone ≤1.7 nmol/l, LHRHa 96% [26 of 27], OP 96% [43 of 45]) were similar between arms. Mean 1-yr change in LS BMD was -0.021g/cm(3) for patients randomised to the LHRHa arm (mean percentage change -1.4%) and +0.069g/cm(3) for the OP arm (+6.0%; p<0.001). Similar patterns were seen in hip and total body measurements. The largest difference between arms was at 2 yr for those remaining on allocated treatment only: LS BMD mean percentage change LHRHa -3.0% and OP +7.9% (p<0.001). CONCLUSIONS: Transdermal oestradiol as a single agent produces castration levels of testosterone while mitigating BMD loss. These early data provide further supporting evidence for the ongoing phase 3 trial. PATIENT SUMMARY: This study found that prostate cancer patients treated with transdermal oestradiol for hormonal therapy did not experience the loss in bone mineral density seen with luteinising hormone-releasing hormone agonists. Other clinical outcomes for this treatment approach are being evaluated in the ongoing PATCH trial. TRIAL REGISTRATION: ISRCTN70406718, PATCH trial (ClinicalTrials.gov NCT00303784)

High-density information storage in an absolutely defined aperiodic sequence of monodisperse copolyester

Synthesis of a polymer composed of a large discrete number of chemically distinct monomers in an absolutely defined aperiodic sequence remains a challenge in polymer chemistry. The synthesis has largely been limited to oligomers having a limited number of repeating units due to the difficulties associated with the step-by-step addition of individual monomers to achieve high molecular weights. Here we report the copolymers of ??-hydroxy acids, poly(phenyllactic-co-lactic acid) (PcL) built via the cross-convergent method from four dyads of monomers as constituent units. Our proposed method allows scalable synthesis of sequence-defined PcL in a minimal number of coupling steps from reagents in stoichiometric amounts. Digital information can be stored in an aperiodic sequence of PcL, which can be fully retrieved as binary code by mass spectrometry sequencing. The information storage density (bit/Da) of PcL is 50% higher than DNA, and the storage capacity of PcL can also be increased by adjusting the molecular weight (~38???kDa)

Second breast cancers in a Tuscan case series: characteristics, prognosis, and predictors of survival

Little is known about long-term outcomes following a second breast cancer diagnosis. We describe the epidemiology, characteristics and prognosis of second breast cancers in an Italian cohort. We identified women with two breast cancer diagnoses from 24 278 histology records at a Tuscan breast cancer service between 1980 and 2005, and determined their survival status. Disease-specific survival from second diagnosis was examined using Cox regression analyses. Second cancers were identified in 1044 women with a median age of 60 years. In all 455 were ipsilateral relapses and 589 were contralateral cancers. Median time between first and second diagnosis was 63.4 months. The majority of second cancers was small invasive or in situ tumours. Estimated 10-year survival from a second cancer diagnosis was 78%. Survival was poorest when the second cancer was large (HR=2.26) or node-positive (HR=3.43), when the time between the two diagnoses was <5 years (HR=1.45), or when the diagnosis was in an earlier epoch (HR=2.20). Second tumours were more likely to be large or node-positive if the first breast cancer had these features. Prognosis following a second breast cancer in this cohort was generally good. However, large or node-positive second tumours, and shorter intervals between diagnoses were indicators of poorer survival

Role of image-guided fine-needle aspiration biopsy in the management of patients with splenic metastasis

BACKGROUND: Splenic metastases are very rare and are mostly diagnosed at the terminal phase of the disease or at the time of autopsy. The cytohistological diagnosis, when done, is made prevalently by splenectomy. Reports on splenic percutaneous biopsies in the diagnosis of splenic metastasis are fragmentary and very poor. The aims of this study are to analyse retrospectively the accuracy, safety and the clinical impact of ultrasound (US)-guided fine-needle aspiration biopsy (UG-FNAB) in patients with suspected splenic metastasis. METHODS: A retrospective analysis of 1800 percutaneous abdominal biopsies performed at our institute during the period from 1993 to 2003 was done and 160 patients that underwent splenic biopsy were found. Among these 160 patients, 12 cases with the final diagnosis of solitary splenic metastases were encountered and they form the basis of this report. The biopsies were performed under US guidance using a 22-gauge Chiba needle. All the patients underwent laboratory tests, CT examination of the abdomen and chest, US examination of abdomen and pelvis. RESULTS: There were 5 women and 7 men, median age 65 years (range 48–80). Eight patients had a known primary cancer at the time of the diagnosis of splenic metastasis: 3 had breast adenocarcinoma, 2 colon adenocarcinoma, 2 melanoma and 1 lung adenocarcinoma. Four patients were undiagnosed at the time of the appearance of splenic metastasis and subsequent investigations showed adenocarcinoma of the lung in 2 patients and colon adenocarcinoma in the remaining 2. There was a complete correspondence between the US and Computed Tomography (CT) in detecting focal lesions of the spleen. The splenic biopsies allowed a cytological diagnosis of splenic metastasis in all the 12 patients and changed clinical management in all cases. Reviewing the 160 patients that underwent UG-FNAB of the spleen we found no complications related to the biopsies. CONCLUSION: These results indicate that UG-FNAB is a successful technique for diagnosis of splenic metastasis allowing an adequate treatment of the affected patients

Prognostic significance of circumferential resection margin involvement following oesophagectomy for cancer

The factors affecting long-term survival following oesophagectomy for oesophageal cancer are poorly understood. We examined the significance of microscopic tumour involvement at the circumferential resection margin (CRM) on postoperative survival following oesophagectomy. The case notes of 329 patients who underwent a potentially curative oesophagectomy for squamous or adenocarcinoma were reviewed retrospectively. As part of the procedure, all patients underwent an en-bloc resection of their periesophageal tissue. The presence of tumour either at, or within, 1 mm of the CRM was recorded and correlated with their TNM and survival data. A total of 67 patients (20%) were noted to have a positive CRM, of which 40 cases (12%) had tumour at the resection margin and the remainder had tumour within 1 mm of the margin. Univariate analysis showed no statistically significant association between survival and either category of CRM involvement. Multivariate analysis showed that only T-stage, nodal status and tumour grade were prognostic markers. In conclusion, the presence of microscopic tumour at the CRM following an en-bloc oesophagectomy is not a significant prognostic marker

Germline sequencing in men with metastatic castration-resistant prostate cancer from the BARCODE2 study reveals a wide range of pathogenic variants in DNA repair genes

Abstract Background The presence of germline mutations plays an increasingly important role in risk assessment and treatment of prostate cancer (PrCa). Screening for high-risk mutations in subsets of patients is becoming routine. We explore the prevalence of germline genetic mutations in men with metastatic castration-resistant prostate cancer (mCRPC) recruited to the BARCODE2 trial. Methods The BARCODE2 trial is a two-part study investigating the response to carboplatin chemotherapy in mCRPC patients carrying a germline variant in a DNA repair gene (DRG). We report interim data from Part 1, in which participants are recruited for germline genetic testing using a customised next-generation sequencing panel consisting of 115 genes. Results These interim results (N = 220) demonstrate a similar frequency of germline DRG variants in mCRPC patients compared with previously published data (15% detection rate). No significant clinical differences were identified between all carriers and non-carriers, though BRCA2/ATM carriers were found to have a shorter time to mCRPC diagnosis. Conclusions Germline pathogenic/likely pathogenic (P/LP) variants in BRCA2 and ATM genes are associated with a shorter time to progression and rarer P/LP variants in other DRG genes may play a role in mCRPC. This justifies the use of routine screening of men with advanced PrCa for germline variants and supports the need for an expanded panel test. </jats:sec