Proteins released by larvae of Schistosoma mansoni : their characterisation and cloning.

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Nitrous oxide myelopathy posing as spinal cord injury.

The authors describe a patient who presented with acute tetraparesis and a proposed acute traumatic spinal cord injury that was the result of nitrous oxide myelopathy. This 19-year-old man sustained a traumatic fall off a 6-ft high wall. His examination was consistent with a central cord syndrome with the addition of dorsal column impairment. Cervical MRI demonstrated an isolated dorsal column signal that was suggestive of a nontraumatic etiology. The patient\u27s symptoms resolved entirely over the course of 48 hours. Nitrous oxide abuse is increasing in prevalence. Its toxic side effects can mask vitamin B12 and folate deficiency and central cord syndrome. The patient\u27s history and radiographic presentation are key to establishing a diagnosis

Effect of modified vaccinia Ankara–5T4 and low-dose cyclophosphamide on antitumor immunity in metastatic colorectal cancer: A randomized clinical trial

Importance The success of immunotherapy with checkpoint inhibitors is not replicated in most cases of colorectal cancer; therefore, different strategies are urgently required. The oncofetal antigen 5T4 is expressed in more than 90% of cases of metastatic colorectal cancer (mCRC). Preliminary data using modified vaccinia Ankara–5T4 (MVA-5T4) in mCRC demonstrated that it safely induced serologic and T-cell responses. Objective To determine whether antitumor immunity in mCRC could be increased using MVA-5T4, metronomic low-dose cyclophosphamide, or a combination of both treatments. Design, Setting, and Participants In this randomized clinical trial, 55 patients with inoperable mCRC and prior stable disease after standard chemotherapy were enrolled at a single center and randomized to watch and wait (n = 9), cyclophosphamide treatment only (n = 9), MVA-5T4 only (n = 19), and a combination of MVA-5T4 and cyclophosphamide (n = 18). Patients were enrolled and treated from July 9, 2012, through February 8, 2016, and follow-up was completed on December 13, 2016. Data were analyzed based on intention to treat. Interventions Patients randomized to a cyclophosphamide group received 50 mg twice daily on treatment days 1 to 7 and 15 to 21. Patients randomized to a MVA-5T4 group received an intramuscular injection at a dose of 1 × 109 50% tissue culture infectious dose on treatment days 22, 36, 50, 64, 78, and 106. Main Outcomes and Measures The predefined primary end point was the magnitude of anti-5T4 immune responses (5T4-specific T-cell and antibody levels) generated at treatment week 7. Secondary end points included analysis of the kinetics of anti-5T4 responses, progression-free survival (PFS), and overall survival (OS). Results Fifty-two patients (38 men and 14 women; mean [SD] age, 64.2 [10.1] years) were included in the study analysis. The 5T4-specific antibody immune responses were significantly increased in the MVA-5T4 (83.41 [36.09] relative units [RU]; P = .02) and combination treatment (65.81 [16.68] RU; P = .002) groups compared with no treatment (20.09 [7.20] RU). Cyclophosphamide depleted regulatory T cells in 24 of 27 patients receiving MVA-5T4, independently prolonging PFS (5.0 vs 2.5 months; hazard ratio [HR], 0.48; 95% CI, 0.21-1.11; P = .09). MVA-5T4 doubled baseline anti-5T4 responses in 16 of 35 patients, resulting in significantly prolonged PFS (5.6 vs 2.4 months; HR, 0.21; 95% CI, 0.09-0.47; P < .001) and OS (20.0 vs 10.3 months; HR, 0.32; 95% CI, 0.14-0.74; P = .008). No grade 3 or 4 adverse events were observed. Conclusions and Relevance This initial randomized clinical immunotherapy study demonstrates a significant survival benefit in mCRC. Prior depletion of regulatory T cells by cyclophosphamide did not increase immune responses generated by MVA-5T4 vaccination; however, cyclophosphamide and MVA-5T4 each independently induced beneficial antitumor immune responses, resulting in prolonged survival without toxic effects. Larger clinical trials are planned to further validate these data

Definition and assessment of paediatric breakthrough pain: A qualitative interview study

Infants, children and young people with life-limiting or life-threatening conditions often experience acute, transient pain episodes known as breakthrough pain. There is currently no established way to assess breakthrough pain in paediatric palliative care. Anecdotal evidence suggests that it is frequently underdiagnosed and undertreated, resulting in reduced quality of life. The development of a standardised paediatric breakthrough pain assessment, based on healthcare professionals’ insights, could improve patient outcomes. This study aimed to explore how healthcare professionals define and assess breakthrough pain in paediatric palliative care and their attitudes towards a validated paediatric breakthrough pain assessment. This was a descriptive qualitative interview study. Semi-structured interviews were conducted with 29 healthcare professionals working in paediatric palliative care across the UK. An inductive thematic analysis was conducted on the data. Five themes were generated: ‘the elusive nature of breakthrough pain,’ ‘breakthrough pain assessment,’ ‘positive attitudes towards’, ‘reservations towards’ and ‘features to include in’ a paediatric breakthrough pain assessment. The definition and assessment of breakthrough pain is inconsistent in paediatric palliative care. There is a clear need for a validated assessment questionnaire to improve assessment, diagnosis and management of breakthrough pain followed by increased healthcare professional education on the concept

A rapid systematic review of breakthrough pain definitions and descriptions

Background Breakthrough pain is common in life-limiting conditions and at end-of-life. Despite over 30 years of study, there is little consensus regarding the definition and characteristics of breakthrough pain. Objective This study aims to update and expand a 2010 systematic review by Haugen and colleagues to identify (1) all definitions of breakthrough pain and (2) all descriptions and classifications of breakthrough pain reported by patients, caregivers, clinicians, and experts. Design This rapid systematic review followed the Cochrane Rapid Review Methods Group guidelines. A protocol is published on PROSPERO (CRD42019155583). Data sources CINAHL, MEDLINE, PsycINFO, and the Web of Science were searched for breakthrough pain terms from the inception dates of each database to 26th August 2022. Results We identified 65 studies that included data on breakthrough pain definitions, descriptions, or classifications from patients ( n = 30), clinicians ( n = 6), and experts ( n = 29), but none with data from caregivers. Most experts proposed that breakthrough pain was a sudden, severe, brief pain occurring in patients with adequately controlled mild-moderate background pain. However, definitions varied and there was no consensus. Pain characteristics were broadly similar across studies though temporal factors varied widely. Experts classified breakthrough pain into nociceptive, neuropathic, visceral, somatic, or mixed types. Patients with breakthrough pain commonly experienced depression, anxiety, and interference with daily life. Conclusions Despite ongoing efforts, there is still no consensus on the definition of breakthrough pain. A compromise is needed on breakthrough pain nomenclature to collect reliable incidence and prevalence data and to inform further refinement of the construct

Phase II trial of Modified Vaccinia Ankara (MVA) virus expressing 5T4 and high dose Interleukin-2 (IL-2) in patients with metastatic renal cell carcinoma

<p>Abstract</p> <p>Background</p> <p>Interleukin-2 (IL-2) induces durable objective responses in a small cohort of patients with metastatic renal cell carcinoma (RCC) but the antigen(s) responsible for tumor rejection are not known. 5T4 is a non-secreted membrane glycoprotein expressed on clear cell and papillary RCCs. A modified vaccinia virus Ankara (MVA) encoding 5T4 was tested in combination with high-dose IL-2 to determine the safety, objective response rate and effect on humoral and cell-mediated immunity.</p> <p>Methods</p> <p>25 patients with metastatic RCC who qualified for IL-2 were eligible and received three immunizations every three weeks followed by IL-2 (600,000 IU/kg) after the second and third vaccinations. Blood was collected for analysis of humoral, effector and regulatory T cell responses.</p> <p>Results</p> <p>There were no serious vaccine-related adverse events. While no objective responses were observed, three patients (12%) were rendered disease-free after nephrectomy or resection of residual metastatic disease. Twelve patients (48%) had stable disease which was associated with improved median overall survival compared to patients with progressive disease (not reached vs. 28 months, p = 0.0261). All patients developed 5T4-specific antibody responses and 13 patients had an increase in 5T4-specific T cell responses. Although the baseline frequency of Tregs was elevated in all patients, those with stable disease showed a trend toward increased effector CD8+ T cells and a decrease in Tregs.</p> <p>Conclusion</p> <p><b>V</b>accination with MVA-5T4 did not improve objective response rates of IL-2 therapy but did result in stable disease associated with an increase in the ratio of 5T4-specific effector to regulatory T cells in selected patients.</p> <p>Trial registration number</p> <p>ISRCTN83977250</p

Low-dose cyclophosphamide induces anti-tumor T-cell responses which associate with survival in metastatic colorectal cancer

Purpose: Anti-cancer T-cell responses can control tumors, but immune-suppressive mechanisms in vivo prevent their function. The role of regulatory T-cells (Tregs) in metastatic colorectal cancer (mCRC) is unclear. We have previously shown depletion of Tregs enhances CRC-specific effector T-cell responses. Low dose cyclophosphamide (CPM) targets Tregs in animal models and some human studies, however the effect of CPM in mCRC is unknown. Experimental Design: Fifty-five mCRC patients were enrolled onto a phase I/II trial and randomized to receive two week-long courses of low-dose (50mg twice-a-day) CPM or not. The absolute number, phenotype and anti-tumor function of peripheral blood-derived lymphocyte subsets were monitored throughout treatment, along with 18-month follow-up. Results: Initially CPM reduced proliferation in all lymphocyte subsets, however, a rapid mobilization of effector T-cells overcame this decrease, leading to increased absolute T-cell numbers. In contrast, a reduction in proportional and absolute Treg, B-cell and NK-cell numbers occurred. The expansion and subsequent activation of effector T-cells was focused on tumor-specific T-cells, producing both granzyme B and IFN-gamma. CPM-treated patients demonstrating the most enhanced IFN-gamma+ tumor-specific T-cell responses exhibited a significant delay in tumor progression (HR=0.29, 95% CI 0.12-0.69, P=0.0047), compared to non-responders and no-treatment controls. Conclusions: CPM-induced Treg-depletion is mirrored by a striking boost to anti-tumor immunity. This study provides the first direct evidence of the benefit of naturally primed T-cells in mCRC patients. Our results also support the concept that non-mutated self-antigens can act as useful targets for immunotherapies

A protocol for a systematic review and meta-analysis to identify measures of breakthrough pain and evaluate their psychometric properties.

INTRODUCTION: Breakthrough pain is common in children and adults with cancer and other conditions, including those approaching end-of-life, although it is often poorly managed, possibly partly due to a lack of validated assessment tools. This review aims to (1) identify all available instruments measuring breakthrough pain in infants, children, adolescents or adults and (2) critically appraise, compare and summarise the quality of the psychometric properties of the identified instruments using COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) criteria. METHODS AND ANALYSIS: Two searches will be carried out between October 2019 and January 2020, one for each aim of the review. The Cochrane Library, International Prospective Register of Systematic Reviews, Embase, Cumulative Index of Nursing and Allied Health Literature, Medical Literature Analysis and Retrieval System Online (MEDLINE), PsycINFO, Web of Science Core Collection, Google Scholar, the ProQuest Dissertations & Theses Database, Evidence Search and OpenGrey databases will be searched from database inception until the date the search is conducted. Reference lists of eligible articles will be screened and authors in the field contacted. For search 1, articles will be screened by two reviewers by abstract, and full-text where necessary, to identify if a breakthrough pain assessment was used. Search 2 will then be conducted to identify studies evaluating measurement properties of these assessments. Two reviewers will screen articles from search 2 by title and abstract. All potentially relevant studies will be screened by full text by both reviewers. For search 2, data will be extracted in parallel with the quality assessment process, as recommended by COSMIN. Two reviewers will assess methodological quality using the COSMIN Risk of Bias checklist and the COSMIN updated criteria for good measurement properties. Findings will be summarised and, if possible, data will be pooled using meta-analysis. The quality of the evidence will be graded and summarised using the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) guidelines. ETHICS AND DISSEMINATION: Results of this review will be submitted for publication in a peer review journal and presented at conferences. PROSPERO REGISTRATION NUMBER: CRD42019155583

Diamorphine pharmacokinetics and conversion factor estimates for intranasal diamorphine in paediatric breakthrough pain:systematic review

BACKGROUND: Intranasal diamorphine is a potential treatment for breakthrough pain but few paediatric data are available to assist dose estimation. AIM: To determine an intranasal diamorphine dose in children through an understanding of pharmacokinetics. DESIGN: A systematic review of the literature was undertaken to seek diamorphine pharmacokinetic parameters in neonates, children and adults. Parenteral and enteral diamorphine bioavailability were reviewed with respect to formation of the major metabolite, morphine. Clinical data quantifying equianalgesic effects of diamorphine and morphine were reviewed. REVIEW SOURCES: PubMed (1960-2020); EMBASE (1980-2020); IPA (1973-2020) and original human research studies that reported diacetylmorphine and metabolite after any dose or route of administration. RESULTS: The systematic review identified 19 studies: 16 in adults and 1 in children and 2 neonatal reports. Details of study participants were extracted. Age ranged from premature neonates to 67 years and weight 1.4-88 kg. Intranasal diamorphine bioavailability was predicted as 50%. The equianalgesic intravenous conversion ratio of morphine:diamorphine was 2:1. There was heterogeneity between pharmacokinetic parameter estimates attributed to routes of administration, lack of size standardisation, methodology and pharmacokinetic analysis. Estimates of the pharmacokinetic parameters clearance and volume of distribution were reduced in neonates. There were insufficient paediatric data to characterise clearance or volume maturation of either diamorphine or its metabolites. CONCLUSIONS: We estimate equianalgesic ratios of intravenous morphine:diamorphine 2:1, intravenous morphine:intranasal diamorphine 1:1 and oral morphine:intranasal diamorphine of 1:3. These ratios are based on adult literature, but are reasonable for deciding on an initial dose of 0.1 mg/kg in children 4-13 years

MVA-5T4 immunotherapy and low-dose cyclophosphamide for advanced colorectal cancer (TaCTiCC): An open-label, randomized phase I/II trial.

Background: Current immunotherapies including checkpoint inhibitors and vaccines for advanced colorectal cancer (CRC) have been largely ineffective. We hypothesized that combining an MVA-based vaccine targeting the tumor-associated antigen 5T4 (TroVax) with low-dose cyclophosphamide to deplete Foxp3+regulatory T-cells (Tregs), could improve immunological responses and patient outcomes. Methods: In this open-label phase I/II clinical trial, TaCTiCC (TroVax and Cyclophosphamide Treatment in Colorectal Cancer) 53 patients with inoperable metastatic CRC were randomized to receive either no treatment (group 1, n=8), metronomic low-dose CPM (50mg B.D. during treatment weeks 1&3; group 2, n=9), TroVax only (6 i.m. injections weeks 4 to 16, group 3, n=18), or low-dose CPM followed by TroVax (group 4, n=18). The primary endpoint was boosted anti-5T4 responses at week 7, as measured by increased T-cell and antibody responses; secondary endpoints included progression-free (PFS)/overall survival (OS), and anti-5T4 responses over the trial period. Results: CPM depleted Tregs in 21/27 patients during treatment week 3 (p=0.0045), resulting in significantly prolonged PFS amongst groups 2&4 over group 1 (5.0 vs. 2.5 months, HR=0.17 95% CI 0.048-0.62, p=0.0072). TroVax induced a >2-fold increase in anti-5T4 immune responses in 15/36 group 3&4 patients; these patients experienced significantly prolonged median PFS (6.5 vs. 2.4 months, HR 0.31 95% CI 0.14-0.65, p=0.0022) and OS (20 vs. 12 months, HR=0.37 95% CI 0.17-0.82, p=0.014). Combination of CPM & TroVax was not significantly superior. The primary endpoint at a single timepoint was not met since CPM-induced responses declined by week 7, and TroVax-induced responses were greatest at weeks 10-16. No serious adverse events were reported. Conclusions: Both CPM and TroVax induced highly beneficial anti-tumor immune responses resulting in significantly prolonged survival of end-stage CRC patients without toxicity. This is the first study to show a clear benefit of immunotherapy in advanced CRC, and suggests this approach may be superior (and less toxic) to continuous palliative chemotherapy in these patients