Challenges in the treatment of gastric cancer in the older patient

Gastric cancer is considered an age-related disease, with the majority of new cases in the UK diagnosed in individuals over the age of 75. At present most guidance related to the management of gastric cancer is based on trials undertaken in the fit, younger patient. Historically the elderly have been underrepresented in clinical trials, which frequently have a restricted inclusion to an upper age limit of 75. The European Society for Medical Oncology (ESMO) recommends use of a geriatric assessment to determine functional age when initiating treatment in elderly patients with gastric cancer, which has been shown to be a better predictor of treatment response than chronological age. The physiological changes that occur with age, including reduced organ function and pharmacokinetic and pharmacodynamic variability, together with impaired functional status, necessitate a more individualised approach to treatment decisions in the older patient to provide them with the same advantages from radical treatment and palliative chemotherapy as younger patients. This review summarises the current evidence extrapolated from trial data on how best to optimise treatment for elderly patients with gastric cancer

Insulin signalling in granulosa cells

Polycystic ovary syndrome (PCOS) is characterised by hyperandrogenism and insulin resistance. Granulosa cells in PCOS demonstrate impaired insulin-induced glucose uptake and lactate accumulation, suggesting a post receptor, signalling pathway-specific impairment of insulin action. Gonadotrophins are also important in the regulation of glucose metabolism by of granulosa cells. The first objective of this project was to use KK1 cells an immortalised mouse granulosa cell line, to characterise insulin, androgen and FSH signalling as well as glucose metabolism. Cell lysates were subjected to western immunoblotting for key proteins in the insulin signalling pathways. Glucose metabolism of KK1 cells was also measured. Surprisingly, androgen alone stimulated glucose uptake and lactate production and augmented insulin-induced glucose metabolism. This suggests that the insulin resistance observed in granulosa cells from women with PCOS is not a direct effect of exposure to androgen. The main part of the thesis was examination of insulin action on human primary ovarian granulosa-lutein (GL) cells to investigate the mechanism of insulin resistance in PCOS. Insulin and FSH signalling in GL cells from women with anovulatory PCOS (anovPCO, n=11) was compared to that in GL cells from ovulatory women with (ovPCO, n=8) and without polycystic ovaries (controls n=12). Primary GL cells were incubated with insulin or FSH and analysed for glucose metabolism and progesterone production. Cell lysates were prepared for identification of signalling pathways, using western immunoblotting. The results confirmed selective impairment of glucose metabolism in cells from anovulatory PCOS. No significant impairment of insulin stimulated PI3K signalling was observed. However there was a reduction of p42/44ERK phosphorylation in the ovulatory PCOS group compared to controls. The significance of this finding with respect to impaired glucose metabolism in granulosa cells remains to be determined. We also showed FSH induced glucose metabolism, but without clear evidence of activation of the PI3-kinase pathway

The role of aspirin in the prevention of ovarian, endometrial and cervical cancers

Drug repurposing is the application of an existing licenced drug for a new indication and potentially provides a faster and cheaper approach to developing new anti-cancer agents. Gynaecological cancers contribute significantly to the global cancer burden, highlighting the need for low cost, widely accessible therapies. A large body of evidence supports the role of aspirin as an anti-cancer agent, and a number of randomized trials are currently underway aiming to assess the potential benefit of aspirin in the treatment of cancer. This review summarizes the evidence underpinning aspirin use for the prevention of the development and recurrence of gynaecological cancers (ovarian, endometrial and cervical) and potential mechanisms of action

A cross-sectional study of pain sensitivity, disease-activity assessment, mental health, and fibromyalgia status in rheumatoid arthritis

INTRODUCTION: Pain remains the most important problem for people with rheumatoid arthritis (RA). Active inflammatory disease contributes to pain, but pain due to non-inflammatory mechanisms can confound the assessment of disease activity. We hypothesize that augmented pain processing, fibromyalgic features, poorer mental health, and patient-reported 28-joint disease activity score (DAS28) components are associated in RA. METHODS: In total, 50 people with stable, long-standing RA recruited from a rheumatology outpatient clinic were assessed for pain-pressure thresholds (PPTs) at three separate sites (knee, tibia, and sternum), DAS28, fibromyalgia, and mental health status. Multivariable analysis was performed to assess the association between PPT and DAS28 components, DAS28-P (the proportion of DAS28 derived from the patient-reported components of visual analogue score and tender joint count), or fibromyalgia status. RESULTS: More-sensitive PPTs at sites over or distant from joints were each associated with greater reported pain, higher patient-reported DAS28 components, and poorer mental health. A high proportion of participants (48%) satisfied classification criteria for fibromyalgia, and fibromyalgia classification or characteristics were each associated with more sensitive PPTs, higher patient-reported DAS28 components, and poorer mental health. CONCLUSIONS: Widespread sensitivity to pressure-induced pain, a high prevalence of fibromyalgic features, higher patient-reported DAS28 components, and poorer mental health are all linked in established RA. The increased sensitivity at nonjoint sites (sternum and anterior tibia), as well as over joints, indicates that central mechanisms may contribute to pain sensitivity in RA. The contribution of patient-reported components to high DAS28 should inform decisions on disease-modifying or pain-management approaches in the treatment of RA when inflammation may be well controlled

Multimodal Treatment in Metastatic Colorectal Cancer (mCRC) Improves Outcomes—The University College London Hospital (UCLH) Experience

Background: Despite notable advances in the management of metastatic colorectal cancer (mCRC) over the last two decades, treatment intent in the vast majority of patients remains palliative due to technically unresectable disease, extensive disease, or co-morbidities precluding major surgery. Up to 30% of individuals with mCRC are considered potentially suitable for primary or metastasis-directed multimodal therapy, including surgical resection, ablative techniques, or stereotactic radiotherapy (RT), with the aim of improving survival outcomes. We reviewed the potential benefits of multimodal therapy on the survival of patients with mCRC treated at the UCLH. Methods: Clinical data on baseline characteristics, multimodal treatments, and survival outcomes were retrospectively collected from all patients with mCRC receiving systemic chemotherapy between January 2013 and April 2017. Primary outcome was the impact of multimodal therapy on overall survival, compared to systemic therapy alone, and the effect of different types of multimodal therapy on survival outcome, and was assessed using the Kaplan–Meier approach. All analyses were adjusted for age, gender, and side of primary tumour. Results: One-hundred and twenty-five patients with mCRC were treated during the study period (median age: 62 years (range 19–89). The liver was the most frequent metastatic site (78%; 97/125). A total of 52% (65/125) had ≥2 lines of systemic chemotherapy. Of the 125 patients having systemic chemotherapy, 74 (59%) underwent multimodal treatment to the primary tumour or metastasis. Median overall survival (OS) was 25.7 months [95% Confidence Interval (CI) 21.5–29.0], and 3-year survival, 26%. Univariate analysis demonstrated that patients who had additional procedures (surgery/ablation/RT) were significantly less likely to die (Hazard Ratio (HR) 0.18, 95% CI 0.12–0.29, p < 0.0001) compared to those receiving systemic chemotherapy alone. Increasing number of multimodal procedures was associated with an incremental increase in survival—with median OS 28.4 m, 35.7 m, and 64.8 m, respectively, for 1, 2, or ≥3 procedures (log-rank p < 0.0001). After exclusion of those who received systemic chemotherapy only (n = 51), metastatic resections were associated with improved survival (adjusted HR 0.36, 95% CI 0.20–0.63, p < 0.0001), confirmed in multivariate analysis. Multiple single-organ procedures did not improve survival. Conclusion: Multimodal therapy for metastatic bowel cancer is associated with significant survival benefit. Resection/radical RT of the primary and resection of metastatic disease should be considered to improve survival outcomes following multidisciplinary team (MDT) discussion and individual assessment of fitness

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

Site staff perspectives on communicating trial results to participants: Cost and feasibility results from the Show RESPECT cluster randomised, factorial, mixed-methods trial

BACKGROUND/AIMS: Sharing trial results with participants is an ethical imperative but often does not happen. Show RESPECT (ISRCTN96189403) tested ways of sharing results with participants in an ovarian cancer trial (ISRCTN10356387). Sharing results via a printed summary improved patient satisfaction. Little is known about staff experience and the costs of communicating results with participants. We report the costs of communication approaches used in Show RESPECT and the views of site staff on these approaches. METHODS: We allocated 43 hospitals (sites) to share results with trial participants through one of eight intervention combinations (2 × 2 × 2 factorial; enhanced versus basic webpage, printed summary versus no printed summary, email list invitation versus no invitation). Questionnaires elicited data from staff involved in sharing results. Open- and closed-ended questions covered resources used to share results and site staff perspectives on the approaches used. Semi-structured interviews were conducted. Interview and free-text data were analysed thematically. The mean additional site costs per participant from each intervention were estimated jointly as main effects by linear regression. RESULTS: We received questionnaires from 68 staff from 41 sites and interviewed 11 site staff. Sites allocated to the printed summary had mean total site costs of sharing results £13.71/patient higher (95% confidence interval (CI): -3.19, 30.60; p = 0.108) than sites allocated no printed summary. Sites allocated to the enhanced webpage had mean total site costs £1.91/patient higher (95% CI: -14, 18.74; p = 0.819) than sites allocated to the basic webpage. Sites allocated to the email list had costs £2.87/patient lower (95% CI: -19.70, 13.95; p = 0.731) than sites allocated to no email list. Most of these costs were staff time for mailing information and handling patients' queries. Most site staff reported no concerns about how they had shared results (88%) and no challenges (76%). Most (83%) found it easy to answer queries from patients about the results and thought the way they were allocated to share results with participants would be an acceptable standard approach (76%), with 79% saying they would follow the same approach for future trials. There were no significant effects of the randomised interventions on these outcomes. Site staff emphasised the importance of preparing patients to receive the results, including giving opt-in/opt-out options, and the need to offer further support, particularly if the results could confuse or distress some patients. CONCLUSIONS: Adding a printed summary to a webpage (which significantly improved participant satisfaction) may increase costs to sites by ~£14/patient, which is modest in relation to the cost of trials. The Show RESPECT communication interventions were feasible to implement. This information could help future trials ensure they have sufficient resources to share results with participants

Site staff perspectives on communicating trial results to participants : Cost and feasibility results from the Show RESPECT cluster randomised, factorial, mixed-methods trial

We are grateful to the patients and site staff who participated in this study. We dedicate this article to the memory of Amanda Hunn, who was part of the steering group for this study until she passed away in 2022. We thank other members of the steering group for their input into the study, especially Conor Tweed and Liz James. We acknowledge the hard work and diligence of Cara Purvis, the trial manager, and the data managers for Show RESPECT. We also thank the ICON8 trial team for their support, particularly Babasola Popoola, Francesca Schiavone, Jonathan Badrock, Andrew Clamp and Rick Kaplan.Peer reviewe