Hammersmith Hospital, formerly the Military Orthopaedic Hospital, and later the Special Surgical Hospital, is a major teaching hospital in White City, West London. It is part of Imperial College Healthcare NHS Trust in the London Borough of Hammersmith and Fulham, and is associated with the Imperial College Faculty of Medicine. Confusingly the hospital is not in Hammersmith but is located in White City adjacent to Wormwood Scrubs and East Acton.
Gefitinib is a specific inhibitor of the epidermal growth factor receptor (EGFR) that causes growth delay in cancer cell lines and human tumor xenografts expressing high levels of EGFR. An understanding of the downstream cellular targets of gefitinib will allow the discovery of biomarkers for predicting outcomes and monitoring antiEGFR therapies and provide information for key targets for therapeutic intervention. In this study, we investigated the role of FOXO3a in gefitinib action and resistance. Using two gefitinib-sensitive (i.e., BT474 and SKBR3) as well as three other resistant breast carcinoma cell lines (i.e., MCF-7, MDA-MB-231, and MDA-MB-453), we showed that gefitinib targets the transcription factor FOXO3a to mediate cell cycle arrest and cell death in sensitive breast cancer cells. In the sensitive cells, gefitinib treatment causes cell cycle arrest predominantly at the G0-G1 phase and apoptosis, which is associated with FOXO3a dephosphorylation at Akt sites and nuclear translocation, whereas in the resistant cells, FOXO3a stays phosphorylated and remains in the cytoplasm. The nuclear accumulation of FOXO3a in response to gefitinib was confirmed in tumor tissue sections from breast cancer patients presurgically treated with gefitinib as monotherapy. We also showed that knockdown of FOXO3a expression using small interfering RNA (siRNA) can rescue sensitive BT474 cells from gefitinib-induced cell-proliferative arrest, whereas reintroduction of active FOXO3a in resistant MDA-MB231 cells can at least partially restore cell-proliferative arrest and sensitivity to gefitinib. These results suggest that the FOXO3a dephosphorylation and nuclear localization have a direct role in mediating the gefitinib-induced proliferative arrest and in determining sensitivity to gefitinib. [Mol Cancer Ther 2007;6(12):3169–79]
Context: Cancer pain affects approximately 50% of patients with cancer, significantly reducing quality of life. Opioids remain first line for treatment however many patients report inadequate pain relief or intolerable side effects. Recently cannabis-based medicinal products (CBMPs) have become increasingly promising but are marred by low-quality evidence. Objectives: To evaluate the effectiveness and safety of CBMPs in treating cancer pain using data from the UK Medical Cannabis Registry.Methods116 patients were followed in a prospective observational study. Patient-reported outcome measures (PROMs), comprising of pain-specific and general measures of health-related quality of life, were collected at baseline, 1, 3, 6, 12, 18 and 24 month intervals. Adverse events were graded using the Common Terminology Criteria for Adverse Events. Longitudinal changes were evaluated using repeated-measures analysis of variance with Bonferroni-corrected post-hoc pairwise comparisons. Results: improvements were observed across all PROMs (p < 0.050). At 24 months, clinically meaningful improvements (MCID) were achieved by 50.00% (n = 58), 47.41% (n = 5), and 54.31% (n = 63) of patients for Pain VAS, BPI-Severity, and BPI-Interference, respectively. EQ-5D-5L index value improved from 0.38 +/- 0.36 at baseline to 0.62 +/- 0.26 at 24 months (p < 0.001). Fifty-five adverse events were reported by five patients (4.31%), of which 78.18% (n = 43) were mild-to-moderate in severity; no life-threatening or fatal events occurred. Conclusion: This study highlights the potential of CBMPs as an alternative to opioid treatment. Though this study builds on the limited body of evidence through strong external validity, future clinical trials is still required to conclusively determine the efficacy of CBMPs.
Background Volatile organic compounds (VOCs) originate from cellular metabolic activity and disease-related biochemical processes and are emerging as non-invasive biomarkers. Although immune cells undergo marked metabolic and functional reprogramming during activation and differentiation, their contribution to the cellular volatile metabolome remains poorly characterised. Aim of review This scoping review aims to systematically map experimental studies reporting untargeted VOCs emitted from mammalian immune cell cultures, with particular emphasis on volatilomics workflows and confidence in metabolite identification. Key scientific concepts of review A systematic literature search identified experimental studies analysing headspace VOCs from primary and immortalised immune cells. Data were extracted on cell models, stimulation conditions, headspace sampling strategies, analytical platforms and data processing workflows. Analytical quality and confidence in compound assignment were assessed using the Chemical Analysis Working Group-Metabolomics Standards Initiative (CAWG-MSI) criteria. Eleven studies met the inclusion criteria, employing a heterogeneous range of sampling and analytical approaches, including solid-phase microextraction, sorbent-based thermal desorption and secondary electrospray ionisation coupled to high-resolution mass spectrometry. Across studies, reported VOC profiles were able to distinguish immune cell type, activation state and external stimuli, supporting the biological plausibility of immune-derived volatilomic signatures. However, substantial methodological variability was evident. Only one study achieved CAWG-MSI level 1 identification, and most lacked key metadata, internal standards or validation procedures. Overall, immune cells appear to emit distinct VOC signatures linked to immunometabolic state, but current practices limit reproducibility, cross-study comparability and confident biological interpretation. This review identifies metabolomics-specific methodological priorities required to characterise immune-derived VOCs.
13 Background: Leucovorin/5-FU in combination with oxaliplatin (FOLFOX) or irinotecan (FOLFIRI) are common chemotherapies used in 1L mCRC. In patients (pts) with BRAF V600E-mutant mCRC, the Phase 3 portion of BREAKWATER (NCT04607421) demonstrated clinically meaningful and statistically significantly improved ORR by blinded independent central review (BICR), PFS by BICR, and OS with 1L EC + mFOLFOX6 vs chemotherapy ± bevacizumab (bev) (Kopetz Nat Med 2025; Elez N Engl J Med 2025). The safety lead-in portion of BREAKWATER previously showed that EC+FOLFIRI was tolerable with promising antitumor activity. The primary analysis results for EC+FOLFIRI vs FOLFIRI ± bev (control) from BREAKWATER Cohort 3 are reported here. Methods: Eligible pts in Cohort 3 had untreated BRAF V600E-mutant mCRC, measurable disease (RECIST 1.1), and ECOG PS 0-1. Pts were randomized 1:1 to receive EC+FOLFIRI or control. The primary endpoint (EP) is ORR by BICR; key secondary EP is PFS by BICR; and other secondary EPs include OS, DOR, time to response (TTR), and safety. Results: In Cohort 3, 147 pts were randomized (EC+FOLFIRI, n=73; control, n=74). Baseline demographics and disease characteristics were similar between arms (median age: 62 yrs; male: 46%; ECOG PS 0: 60%). At data cutoff (Mar 1, 2025), EC+FOLFIRI demonstrated a clinically meaningful and statistically significant improvement in confirmed ORR by BICR vs control (Table), meeting the primary EP. Responses observed with EC+FOLFIRI were rapid and durable. OS data were immature (median follow-up: 10.5 mo [EC+FOLFIRI] and 10.3 mo [control]) but suggested a potential survival benefit with EC+FOLFIRI vs control. Serious treatment-emergent adverse events (EC+FOLFIRI: n=71; control: n=68) occurred in 39.4% vs 36.8% of pts, respectively. The safety profile was consistent with that known for each agent. The addition of EC to FOLFIRI did not lead to substantial increases in FOLFIRI discontinuation (FOLFIRI [or bev] discontinuation: 9.9% vs 8.8%, respectively). Conclusions: BREAKWATER Cohort 3 demonstrated a clinically meaningful and statistically significant improved response rate that was rapid and durable with EC+FOLFIRI vs control in 1L BRAF V600E-mutant mCRC, with manageable toxicities and no new safety signals. These data support EC+FOLFIRI as a potential new standard of care in BRAF V600E-mutant mCRC. Clinical trial information: NCT04607421 . EC+FOLFIRI n=73 Controln=74 ORR, a % 64.4 39.2 Odds ratio (95% CI) P -value b 2.76 (1.42-5.35)0.001 Estimated medianresponse duration a,c (95% CI), mo NE (NE-NE) NE (7.0-NE) Pts with a response duration of ≥6 mo, a,c % 57.4 34.5 Median TTR a,c (range), weeks 6.9 (5.4-36.1) 7.1 (5.9-25.3) Median OS (95% CI), mo NE (NE-NE) NE (12.1-NE) OS hazard ratio (95% CI) 0.49 (0.24-1.03) a By BICR. b One-sided α=0.025. c In responders: n=47 and n=29, respectively. NE, not estimable.
The peritoneum, a membranous structure that lines the abdominal cavity, is one of the most common sites to which gastric, colorectal and ovarian cancer metastasise. The presence of peritoneal metastasis is associated with poor prognosis primarily due to the ineffectiveness of systemic therapies against this condition. Direct delivery of chemotherapy to the peritoneal cavity has been proposed as an alternative treatment, although its efficacy is limited by low drug retention. Hydrogel-based delivery solutions have the potential to augment the capabilities of intraperitoneal administration by facilitating sustained therapeutic drug concentrations via extended release. This systematic review provides a comprehensive overview of 39 preclinical studies that show improvements in therapeutic efficacy over carrier-free delivery. Synthetic hydrogels were generally favoured over hydrogels prepared from biomolecules and were largely used to administer small molecule anti-neoplastic agents over immunotherapies. An IDEAL framework analysis highlighted that whilst there is growing research interest, there has been limited clinical translation. Based on a critical analysis of the existing literature, this review offers recommendations and guidelines towards the translation of hydrogel-based drug delivery systems for the treatment of peritoneal metastasis.
