Comparison of bulk milk antibody and youngstock serology screens for determining herd status for Bovine Viral Diarrhoea Virus

BACKGROUND: This paper examines the use of Bulk Milk antibody (BM Ab), Youngstock (YS) serology (Check Tests) and Bulk Milk PCR (BM PCR) for determining the presence or absence of animals persistently infected (PI) with Bovine Viral Diarrhoea Virus (BVDV) within a herd. Data is presented from 26 herds where average herd sizes were 343 and 98 animals for dairy and beef units respectively. Seventeen herds had sufficient data to analyse using Receiver Operating Characteristic (ROC) and probability curves enabling calculation of the sensitivity and specificity of BM Ab and YS Check tests for determining the presence of PI animals within herds in this dataset. RESULTS: Using BM Ab to screen a herd for the presence of PI animals, achieved a herd level sensitivity and specificity of 80.00 % (44.39–97.48 %) and 85.71 % (42.13–99.64 %) respectively (95 % confidence intervals quoted). Sensitivity and specificity of YS Check Tests at a cut off of 3/10 Ab positive YS were 81.82 % (48.22–97.72 %) and 66.67 % (22.28–95.67 %) respectively (95 % confidence interval). These results were achieved by comparing the screening tests to whole herd PI searches that took place 1–19 months after the initial screen with a mean interval of 8 months. Removal of this delay by taking BM samples on the day of a whole herd test and simulating a YS Check Test from the herd test data produced improvements in the reliability of the Check Tests. BM Ab sensitivity and specificity remained unchanged. However, the Check Test sensitivity and specificity improved to 90.9 % (58.72–99.77 %) and 100 % (54.07–100 %) respectively (95 % confidence interval) at a cut of off 2.5/10 Ab positive animals. Our limited BM PCR results identified 5/23 dairy farms with a positive BM PCR result; two contained milking PIs, two had non-milking PIs and another had no PIs identified. CONCLUSIONS: Delaying a PI search following an initial herd screen decreased the diagnostic accuracy and relevance of our results. With careful interpretation, longitudinal surveillance using a combination of the techniques discussed can successfully determine farm status and therefore allow changes in BVDV status to be detected early, thus enabling prompt action in the event of a BVDV incursion

Analogue peptides for the immunotherapy of human acute myeloid leukemia

Accepted manuscript. The final publication is available at: http://link.springer.com/article/10.1007%2Fs00262-015-1762-9The use of peptide vaccines, enhanced by adjuvants, has shown some efficacy in clinical trials. However, responses are often short-lived and rarely induce notable memory responses. The reason is that self-antigens have already been presented to the immune system as the tumor develops, leading to tolerance or some degree of host tumor cell destruction. To try to break tolerance against self-antigens, one of the methods employed has been to modify peptides at the anchor residues to enhance their ability to bind major histocompatibility complex molecules, extending their exposure to the T-cell receptor. These modified or analogue peptides have been investigated as stimulators of the immune system in patients with different cancers with variable but sometimes notable success. In this review we describe the background and recent developments in the use of analogue peptides for the immunotherapy of acute myeloid leukemia describing knowledge useful for the application of analogue peptide treatments for other malignancies

Wilms' Tumour 1 (WT1) peptide vaccination in patients with acute myeloid leukaemia induces short-lived WT1-specific immune responses.

Wilms' Tumour 1 (WT1) is a zinc finger transcription factor that is over-expressed in acute myeloid leukaemia (AML). Its restricted expression in normal tissues makes it a promising target for novel immunotherapies aiming to accentuate the cytotoxic T lymphocyte (CTL) response against AML. Here we report a phase I/II clinical trial of subcutaneous peptide vaccination with two separate HLA-A2-binding peptide epitopes derived from WT1, together with a pan-DR binding peptide epitope (PADRE), in Montanide adjuvant. Eight HLA-A2-positive patients with poor risk AML received five vaccination cycles at 3-weekly intervals. The three cohorts received 0·3, 0·6 and 1 mg of each peptide, respectively. In six patients, WT1-specific CTL responses were detected using enzyme-linked immunosorbent spot assays and pWT126/HLA-A*0201 tetramer staining, after ex vivo stimulation with the relevant WT1 peptides. However, re-stimulation of these WT1-specific T cells failed to elicit secondary expansion in all four patients tested, suggesting that the WT1-specific CD8(+) T cells generated following vaccination may be functionally impaired. No correlation was observed between peptide dose, cellular immune response, reduction in WT1 mRNA expression and clinical response. Larger studies are indicated to confirm these findings

CAR T in patients with large B-cell lymphoma not fit for autologous transplant

Large B-cell lymphoma (LBCL) patients with comorbidities and/or advanced age are increasingly considered for treatment with CD19 CAR T, but data on the clinical benefit of CAR T in the less fit patient population are still limited. We analysed outcomes of consecutive patients approved for treatment with axicabtagene ciloleucel (axi-cel) or tisagenlecleucel (tisa-cel) by the UK National CAR T Clinical Panel, according to fitness for autologous stem cell transplant (ASCT). 81/404 (20%) of approved patients were deemed unfit for ASCT. Unfit patients were more likely to receive tisa-cel versus axi-cel (52% vs. 48%) compared to 20% versus 80% in ASCT-fit patients; p < 0.0001. The drop-out rate from approval to infusion was significantly higher in the ASCT-unfit group (34.6% vs. 23.5%; p = 0.042). Among infused patients, response rate, progression-free and overall survival were similar in both cohorts. CAR T was well-tolerated in ASCT-unfit patients with an incidence of grade ≥3 cytokine release syndrome and neurotoxicity of 2% and 11%, respectively. Results from this multicentre real-world cohort demonstrate that CD19 CAR T can be safely delivered in carefully selected older patients and patients with comorbidities who are not deemed suitable for transplant

Brexucabtagene autoleucel for relapsed or refractory mantle cell lymphoma in the United Kingdom: A real-world intention-to-treat analysis

\ua9 2024 The Authors. HemaSphere published by John Wiley &amp; Sons Ltd on behalf of European Hematology Association. Brexucabtagene autoleucel (brexu-cel) is an autologous CD19 CAR T-cell product, approved for relapsed/refractory (r/r) mantle cell lymphoma (MCL). In ZUMA-2, brexu-cel demonstrated impressive responses in patients failing ≥2 lines, including a bruton\u27s tyrosine kinase inhibitor, with an overall and complete response rate of 93% and 67%, respectively. Here, we report our real-world intention-to-treat (ITT) outcomes for brexu-cel in consecutive, prospectively approved patients, from 12 institutions in the United Kingdom between February 2021 and June 2023, with a focus on feasibility, efficacy, and tolerability. Of 119 approved, 104 underwent leukapheresis and 83 received a brexu-cel infusion. Progressive disease (PD) and/or manufacturing (MF) were the most common reasons for failure to reach harvest and/or infusion. For infused patients, best overall and complete response rates were 87% and 81%, respectively. At a median follow-up of 13.3 months, median progression-free survival (PFS) for infused patients was 21 months (10.1–NA) with a 6- and 12-month PFS of 82% (95% confidence interval [CI], 71–89) and 62% (95% CI, 49–73), respectively. ≥Grade 3 cytokine release syndrome and neurotoxicity occurred in 12% and 22%, respectively. On multivariate analysis, inferior PFS was associated with male sex, bulky disease, ECOG PS &gt; 1 and previous MF. Cumulative incidence of non-relapse mortality (NRM) was 6%, 15%, and 25% at 6, 12, and 24 months, respectively, and mostly attributable to infection. Outcomes for infused patients in the UK are comparable to ZUMA-2 and other real-world reports. However, ITT analysis highlights a significant dropout due to PD and/or MF. NRM events warrant further attention

Autologous stem cell transplantation with low-dose cyclophosphamide to improve mucosal healing in adults with refractory Crohn's disease: the ASTIClite RCT

Some text in this abstract has been reproduced from Lindsay J, Din S, Hawkey C, Hind D, Irving P, Lobo A, et al. OFR-9 An RCT of autologous stem-cell transplantation in treatment refractory Crohn’s disease (low-intensity therapy evaluation): ASTIClite. Gut 2021;70(Suppl. 4):A4. Background Treatment-refractory Crohn’s disease is characterised by chronic symptoms, poor quality of life and high costs to the NHS, and through days of work lost by patients. A previous trial of autologous haematopoietic stem cell transplant (HSCT) failed its end point of medication-free clinical remission for 3 months with no evidence of disease activity, and reported high toxicity. Subsequent studies suggest that HSCT achieves complete mucosal healing in 50% of patients, and that toxicity likely relates to the cyclophosphamide dose. Objectives The primary objective was to assess the efficacy of HSCTlite (HSCT with low-dose cyclophosphamide) compared with standard care for inducing regression of intestinal ulceration in patients with refractory Crohn’s disease at week 48. Secondary objectives included the assessment of disease activity, quality of life and regimen safety. Mechanistic objectives included immune reconstitution after HSCTlite. Design Two-arm, parallel-group randomised controlled trial with a 2 : 1 (intervention : control) allocation ratio. Setting Nine NHS trusts (eight trusts were recruitment sites; one trust was a treatment-only site). Participants Adults with treatment-refractory Crohn’s disease, for whom surgery was inappropriate or who had declined surgery. Interventions The intervention treatment was HSCTlite using cyclophosphamide, and the control was any current available treatment for Crohn’s disease, apart from stem cell transplantation. Main outcomes The primary outcome was treatment success at week 48 [mucosal healing (Simple Endoscopic Score for Crohn’s Disease ulcer subscore of 0) without surgery or death], assessed by central readers blinded to allocation and timing of assessment. Key secondary outcomes were clinical remission, Simple Endoscopic Score for Crohn’s Disease scores at week 48, change in Crohn’s Disease Activity Index scores and safety. Results The trial was halted owing to Suspected unexpected serious adverse events that took place after randomising 23 patients (HSCTlite arm, n = 13; usual-care arm, n = 10). Ten out of the 13 patients randomised to the HSCTlite arm received the intervention and nine (one death) reached the 48-week follow-up. In the usual-care arm 9 out of the 10 patients randomised reached the 48-week follow-up (one ineligible). The primary outcome was available for 7 out of 10 HSCTlite patients (including the patient who died) and six out of nine usual-care patients. Absence of endoscopic ulceration without surgery or death was reported in three out of seven (43%) HSCTlite patients, compared with zero out of six (0%) usual-care patients. Centrally read Simple Endoscopic Score for Crohn’s Disease scores [mean (standard deviation)] were 10.8 (6.3) and 10.0 (6.1) at baseline, compared with 2.8 (2.9) and 18.7 (9.1) at week 48, in the HSCT and usual-care arms, respectively. Clinical remission (Crohn’s Disease Activity Index scores of < 150) occurred in 57% and 17% of patients in the HSCTlite and usual-care arms, respectively, at week 48. Serious adverse events were more frequent in the HSCTlite arm [38 in 13 (100%) patients] than in the usual-care arm [16 in 4 (40%) patients]. Nine suspected unexpected serious adverse reactions were reported in six HSCTlite patients, including three cases of delayed renal failure due to proven thrombotic microangiopathy. Two HSCTlite patients died. Conclusions Within the limitations of reduced patient recruitment and numbers of patients assessed, HSCTlite meaningfully reduced endoscopic disease activity, with three patients experiencing resolution of ulceration. Suspected unexpected serious adverse reactions, particularly relating to thrombotic microangiopathy, make this regimen unsuitable for future clinical use. Limitations The early trial closure prevented complete recruitment, and the impact of the coronavirus pandemic prevented completion of some study investigations. Small participant numbers meant analysis could only be descriptive. Future work Owing to undetermined aetiology of thrombotic microangiopathy, further trials of HSCTlite in this population are not considered appropriate. Priorities should be to determine optimal treatment strategies for patients with refractory Crohn’s disease, including those with a stoma or multiple previous resections

Glucagon-like peptide-1(7–36) amide is a new incretin/enterogastrone candidate

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/72032/1/j.1365-2362.1991.tb01802.x.pd

Autologous stem cell transplantation in refractory Crohn's disease - low intensity therapy evaluation (ASTIClite):study protocols for a multicentre, randomised controlled trial and observational follow up study

BACKGROUND: Intestinal inflammation in Crohn's disease (CD) is caused by mucosal immune system reactivity to luminal antigen and results in debilitating symptoms, reduced quality of life, impaired work productivity and significant health care costs. Not all patients respond to conventional and biologic therapies, with chronic inflammation ensuing. Although surgical resection may be required, disease frequently returns and surgery may not be an option, or may be declined. Case reports suggest potential benefit after haematopoietic stem cell transplant (HSCT) for patients with refractory CD. The ASTIC trial asked whether HSCT could cure CD. Few patients achieved the primary endpoint of clinical remission for 3 months, off all medication with no evidence of active disease, and there were a high number of adverse events (AEs) and serious adverse events (SAEs), including one patient death. However, beneficial effects were observed in some aspects of disease activity. The ASTIClite trial will investigate these potential benefits and safety using a lower intensity regimen than ASTIC.METHODS: Ninety-nine participants will be recruited from secondary care IBD centres in the UK into a multicentre, randomised controlled trial (RCT, ASTIClite) and an observational follow-up, and randomised to autologous HSCT versus standard care (ratio 2:1). The primary endpoint is treatment success at week 48, defined as mucosal healing without surgery or death. Secondary endpoints relating to efficacy, safety and mechanistic analyses will be evaluated at week 8, 14, 24, 32, 40 and 48. Long-term safety of the low intensity HSCT regimen forms the primary endpoint for the EBMT follow-up study and will be assessed annually for 4-7 years.DISCUSSION: ASTIClite will compare HSCTlite with standard care with respect to safety, efficacy and quality of life, and capture outcomes allowing findings to be generalised to current clinical practice in the UK. It will also provide significant mechanistic insights into the immunological consequences of HSCTlite and its impact on treatment outcomes. The observational follow-up will provide information, which is currently unavailable for this population.TRIAL REGISTRATION: The ASTIClite RCT was registered on 31st October 2017 ( ISRCTN17160440 ) and the EBMT follow-up study on 19th January 2018 ( ISRCTN31981313 ).</p