TRAIL induces apoptosis in cancer cells whilst sparing normal tissues. Despite promising pre-clinical results, few patients responded to treatment with recombinant TRAIL (Apo2L/Dulanermin) or TRAIL-R2-specific antibodies, such as conatumumab (AMG655). It is unknown whether this was due to intrinsic TRAIL resistance within primary human cancers or insufficient agonistic activity of the TRAIL-R-targeting drugs. FcγR-mediated crosslinking increases the cancer-cell-killing activity of TRAIL-R2-specific antibodies in vivo. We tested this phenomenon using FcγR-expressing immune cells from patients with ovarian cancer. However, even in the presence of high numbers of FcγR-expressing immune cells, as found in ovarian cancer ascites, AMG655-induced apoptosis was not enabled to any significant degree, indicating that this concept may not translate into clinical use. On the basis of these results we next set out to determine whether AMG655 possibly interferes with apoptosis induction by endogenous TRAIL which could be expressed by immune cells. To do so, we tested how AMG655 affected apoptosis induction by recombinant TRAIL. This, however, resulted in the surprising discovery of a striking synergy between AMG655 and non-tagged TRAIL (Apo2L/TRAIL) in killing cancer cells. This combination was as effective in killing cancer cells as highly active recombinant isoleucine-zipper-tagged TRAIL (iz-TRAIL). The increased killing efficiency was due to enhanced formation of the TRAIL death-inducing signalling complex (DISC), enabled by concomitant binding of Apo2L/TRAIL and AMG655 to TRAIL-R2. The synergy of AMG655 with Apo2L/TRAIL extended to primary ovarian cancer cells and was further enhanced by combination with the proteasome inhibitor bortezomib or a SMAC mimetic. Importantly, primary human hepatocytes were not killed by the AMG655-Apo2L/TRAIL combination, also not when further combined with bortezomib or a SMAC mimetic. We therefore propose that clinical-grade non-tagged recombinant forms of TRAIL, such as dulanermin, could be combined with antibodies such as AMG655 to introduce a highly active TRAIL-R2-agonistic therapy into the cancer clinic.
ImportanceAccurate identification of patient groups with the lowest level of protection following COVID-19 vaccination is important to better target resources and interventions for the most vulnerable populations. It is not known whether SARS-CoV-2 antibody testing has clinical utility for high-risk groups, such as people with cancer.ObjectiveTo evaluate whether spike protein antibody vaccine response (COV-S) following COVID-19 vaccination is associated with the risk of SARS-CoV-2 breakthrough infection or hospitalization among patients with cancer.Design, Setting, and ParticipantsThis was a population-based cross-sectional study of patients with cancer from the UK as part of the National COVID Cancer Antibody Survey. Adults with a known or reported cancer diagnosis who had completed their primary SARS-CoV-2 vaccination schedule were included. This analysis ran from September 1, 2021, to March 4, 2022, a period covering the expansion of the UK’s third-dose vaccination booster program.InterventionsAnti–SARS-CoV-2 COV-S antibody test (Elecsys; Roche).Main Outcomes and MeasuresOdds of SARS-CoV-2 breakthrough infection and COVID-19 hospitalization.ResultsThe evaluation comprised 4249 antibody test results from 3555 patients with cancer and 294 230 test results from 225 272 individuals in the noncancer population. The overall cohort of 228 827 individuals (patients with cancer and the noncancer population) comprised 298 479 antibody tests. The median age of the cohort was in the age band of 40 and 49 years and included 182 741 test results (61.22%) from women and 115 737 (38.78%) from men. There were 279 721 tests (93.72%) taken by individuals identifying as White or White British. Patients with cancer were more likely to have undetectable anti-S antibody responses than the general population (199 of 4249 test results [4.68%] vs 376 of 294 230 [0.13%]; P < .001). Patients with leukemia or lymphoma had the lowest antibody titers. In the cancer cohort, following multivariable correction, patients who had an undetectable antibody response were at much greater risk for SARS-CoV-2 breakthrough infection (odds ratio [OR], 3.05; 95% CI, 1.96-4.72; P < .001) and SARS-CoV-2–related hospitalization (OR, 6.48; 95% CI, 3.31-12.67; P < .001) than individuals who had a positive antibody response.Conclusions and RelevanceThe findings of this cross-sectional study suggest that COV-S antibody testing allows the identification of patients with cancer who have the lowest level of antibody-derived protection from COVID-19. This study supports larger evaluations of SARS-CoV-2 antibody testing. Prevention of SARS-CoV-2 transmission to patients with cancer should be prioritized to minimize impact on cancer treatments and maximize quality of life for individuals with cancer during the ongoing pandemic.
Background:Paracentesis for malignant ascites is usually performed as an in-patient procedure, with a median length of stay (LoS) of 3–5 days, with intermittent clamping of the drain due to a perceived risk of hypotension. In this study, we assessed the safety of free drainage and the feasibility and cost-effectiveness of daycase paracentesis.Method:Ovarian cancer admissions at Hammersmith Hospital between July and October 2009 were audited (Stage 1). A total of 21 patients (Stage 2) subsequently underwent paracentesis with free drainage of ascites without intermittent clamping (October 2010–January 2011). Finally, 13 patients (19 paracenteses, Stage 3), were drained as a daycase (May–December 2011).Results:Of 67 patients (Stage 1), 22% of admissions and 18% of bed-days were for paracentesis, with a median LoS of 4 days. In all, 81% of patients (Stage 2) drained completely without hypotension. Of four patients with hypotension, none was tachycardic or symptomatic. Daycase paracentesis achieved complete ascites drainage without complications, or the need for in-patient admission in 94.7% of cases (Stage 3), and cost £954 compared with £1473 for in-patient drainage.Conclusions:Free drainage of malignant ascites is safe. Daycase paracentesis is feasible, cost-effective and reduces hospital admissions, and potentially represents the standard of care for patients with malignant ascites.
Background:The mitogen-activated protein kinase (MAPK) phosphatases or dual specificity phosphatases (DUSPs) are a family of proteins that catalyse the inactivation of MAPK in eukaryotic cells. Little is known of the expression, regulation or function of the DUSPs in human neoplasia.Methods:We used RT–PCR and quantitative PCR (qPCR) to examine the expression of DUSP16 mRNA. The methylation in the DUSP16 CpG island was analysed using bisulphite sequencing and methylation-specific PCR. The activation of MAPK was determined using western blotting with phospho-specific antibodies for extra-cellular signal-related kinase (ERK), p38 and c-Jun N-terminal kinase (JNK). The proliferation of cell lines was assessed using the CellTiter 96 Aqueous One assay.Results:The expression of DUSP16, which inactivates MAPK, is subject to methylation-dependent transcriptional silencing in Burkitt's Lymphoma (BL) cell lines and in primary BL. The silencing is associated with aberrant methylation in the CpG island in the 5′ regulatory sequences of the gene blocking its constitutive expression. In contrast to BL, the CpG island of DUSP16 is unmethylated in other non-Hodgkin's lymphomas (NHLs) and epithelial malignancies. In BL cell lines, neither constitutive nor inducible ERK or p38 activity varied significantly with DUSP16 status. However, activation of JNK was increased in lines with DUSP16 methylation. Furthermore, methylation in the DUSP16 CpG island blocked transcriptional induction of DUSP16, thereby abrogating a normal physiological negative feedback loop that limits JNK activity, and conferred increased cellular sensitivity to agents, such as sorbitol and anthracycline chemotherapeutic agents that activate JNK.Conclusion:DUSP16 is a new epigenetically regulated determinant of JNK activation in BL.
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