Guy's and St Thomas' NHS Foundation Trust

About: Guy's and St Thomas' NHS Foundation Trust is a healthcare organization based out in London, United Kingdom. It is known for research contribution in the topics: Population & Medicine. The organization has 7686 authors who have published 9631 publications receiving 399353 citations. The organization is also known as: Guy's and St Thomas' National Health Service Foundation Trust & Guy's and St Thomas' National Health Service Trust.

Association of Genetic Variants in NUDT15 With Thiopurine-Induced Myelosuppression in Patients With Inflammatory Bowel Disease.

Abstract: Importance: Use of thiopurines may be limited by myelosuppression. TPMT pharmacogenetic testing identifies only 25% of at-risk patients of European ancestry. Among patients of East Asian ancestry, NUDT15 variants are associated with thiopurine-induced myelosuppression (TIM). Objective: To identify genetic variants associated with TIM among patients of European ancestry with inflammatory bowel disease (IBD). Design, Setting, and Participants: Case-control study of 491 patients affected by TIM and 679 thiopurine-tolerant unaffected patients who were recruited from 89 international sites between March 2012 and November 2015. Genome-wide association studies (GWAS) and exome-wide association studies (EWAS) were conducted in patients of European ancestry. The replication cohort comprised 73 patients affected by TIM and 840 thiopurine-tolerant unaffected patients. Exposures: Genetic variants associated with TIM. Main Outcomes and Measures: Thiopurine-induced myelosuppression, defined as a decline in absolute white blood cell count to 2.5 × 109/L or less or a decline in absolute neutrophil cell count to 1.0 × 109/L or less leading to a dose reduction or drug withdrawal. Results: Among 1077 patients (398 affected and 679 unaffected; median age at IBD diagnosis, 31.0 years [interquartile range, 21.2 to 44.1 years]; 540 [50%] women; 602 [56%] diagnosed as having Crohn disease), 919 (311 affected and 608 unaffected) were included in the GWAS analysis and 961 (328 affected and 633 unaffected) in the EWAS analysis. The GWAS analysis confirmed association of TPMT (chromosome 6, rs11969064) with TIM (30.5% [95/311] affected vs 16.4% [100/608] unaffected patients; odds ratio [OR], 2.3 [95% CI, 1.7 to 3.1], P = 5.2 × 10-9). The EWAS analysis demonstrated an association with an in-frame deletion in NUDT15 (chromosome 13, rs746071566) and TIM (5.8% [19/328] affected vs 0.2% [1/633] unaffected patients; OR, 38.2 [95% CI, 5.1 to 286.1], P = 1.3 × 10-8), which was replicated in a different cohort (2.7% [2/73] affected vs 0.2% [2/840] unaffected patients; OR, 11.8 [95% CI, 1.6 to 85.0], P = .03). Carriage of any of 3 coding NUDT15 variants was associated with an increased risk (OR, 27.3 [95% CI, 9.3 to 116.7], P = 1.1 × 10-7) of TIM, independent of TPMT genotype and thiopurine dose. Conclusions and Relevance: Among patients of European ancestry with IBD, variants in NUDT15 were associated with increased risk of TIM. These findings suggest that NUDT15 genotyping may be considered prior to initiation of thiopurine therapy; however, further study including additional validation in independent cohorts is required.

N-methyl-D-aspartate receptor antibody-mediated neurological disease: results of a UK-based surveillance study in children

Abstract: Objective N-methyl-D-aspartate receptor antibody (NMDAR-Ab) encephalitis is a well-recognised clinico-immunological syndrome that presents with neuropsychiatric symptoms cognitive decline, movement disorder and seizures. This study reports the clinical features, management and neurological outcomes of paediatric NMDAR-Ab-mediated neurological disease in the UK. Design A prospective surveillance study. Children with NMDAR-Ab-mediated neurological diseases were voluntarily reported to the British Neurological Surveillance Unit (BPNSU) from November 2010 to December 2011. Initial and follow-up questionnaires were sent out to physicians. Results Thirty-one children fulfilled the criteria for the study. Eight presented during the study period giving an incidence of 0.85 per million children per year (95% CI 0.64 to 1.06); 23 cases were historical. Behavioural change and neuropsychiatric features were present in 90% of patients, and seizures and movement disorders both in 67%. Typical NMDAR-Ab encephalitis was reported in 24 children and partial phenotype without encephalopathy in seven, including predominantly psychiatric (four) and movement disorder (three). All patients received steroids, 22 (71%) received intravenous immunoglobulin, 9 (29%) received plasma exchange,and 10 (32%) received second-line immunotherapy. Of the 23 patients who were diagnosed early, 18 (78%) made a full recovery compared with only 1 of 8 (13%) of the late diagnosed patients (p=0.002, Fisher9s exact test). Seven patients relapsed, with four needing additional second-line immunotherapy. Conclusions Paediatric NMDAR-Ab-mediated neurological disease appears to be similar to adult NMDAR-Ab encephalitis, but some presented with a partial phenotype. Early treatment was associated with a quick and often full recovery.

The estimated frequency of antiphospholipid antibodies in young adults with cerebrovascular events: a systematic review

Abstract: Background Around 10% of all thrombotic cerebrovascular events (CVE) occur in young population and in a large proportion of those the trigger remains undetermined. Antiphospholipid antibodies (aPL) are recognised risk factors for ischaemic stroke and recurrent thrombotic events; however, the frequency of aPL in young people with CVE is still an unresolved issue. Objectives To estimate the frequency of aPL in young adults with CVE and to determine whether aPL-positive young individuals are at greater risk of CVE when compared with individuals without aPL by systematically reviewing the literature. Methods Medline reports published between 1970 and 2013 investigating the presence of aPL in young patients ( Findings This systematic review is based on available data from 5217 patients and controls from 43 studies analysing the frequency of aPL in young patients with CVE. The overall aPL frequency was estimated as 17.4% (range 5%–56%) for any CVE, 17.2% (range 2%–56%) for stroke and 11.7% (range 2%–45%) for transient ischaemic attack (TIA). The presence of aPL increased the risk for CVE by 5.48-fold (95% CI 4.42 to 6.79). Based on available data, the frequency of aPL in young patients with CVE can be estimated at 17%, rising up to 22% for aCL in patients with stroke. The presence of aPL seems to confer a fivefold higher risk for stroke or TIA when compared with controls. However, variability in test reproducibility and cut-off definition still represent an important methodological limitation for the current diagnostic testing for aPL. These observations should be confirmed by appropriately designed population studies.

Nomenclature for alleles of the thiopurine methyltransferase gene.

Abstract: The drug-metabolizing enzyme thiopurine methyltransferase (TPMT) has become one of the best examples of pharmacogenomics to be translated into routine clinical practice. TPMT metabolizes the thiopurines 6-mercaptopurine, 6-thioguanine, and azathioprine, drugs that are widely used for treatment of acute leukemias, inflammatory bowel diseases, and other disorders of immune regulation. Since the discovery of genetic polymorphisms in the TPMT gene, many sequence variants that cause a decreased enzyme activity have been identified and characterized. Increasingly, to optimize dose, pretreatment determination of TPMT status before commencing thiopurine therapy is now routine in many countries. Novel TPMT sequence variants are currently numbered sequentially using PubMed as a source of information; however, this has caused some problems as exemplified by two instances in which authors' articles appeared on PubMed at the same time, resulting in the same allele numbers given to different polymorphisms. Hence, there is an urgent need to establish an order and consensus to the numbering of known and novel TPMT sequence variants. To address this problem, a TPMT nomenclature committee was formed in 2010, to define the nomenclature and numbering of novel variants for the TPMT gene. A website (http://www.imh.liu.se/tpmtalleles) serves as a platform for this work. Researchers are encouraged to submit novel TPMT alleles to the committee for designation and reservation of unique allele numbers. The committee has decided to renumber two alleles: nucleotide position 106 (G>A) from TPMT*24 to TPMT*30 and position 611 (T>C, rs79901429) from TPMT*28 to TPMT*31. Nomenclature for all other known alleles remains unchanged.

Anosmia and ageusia are emerging as symptoms in patients with COVID-19: What does the current evidence say?

Abstract: There have been several reports noting anosmia and ageusia as possible symptoms of COVID-19. This is of particular interest in oncology since patients receiving some cancer treatments such as chemotherapy or immune therapy often experience similar symptoms as side-effects. The purpose of this report was to summarise the evidence on the existence of anosmia and ageusia an emerging COVID-19 symptoms in order to better inform both oncology patients and clinicians. Currently, there is no published evidence or case reports noting anosmia or ageusia as symptoms of COVID-19. Nevertheless, experts in rhinology have suggested that the onset of such symptoms could either act as a trigger for testing for the disease where possible, or could be a new criterion to self-isolate. Whilst more data is currently needed to strengthen our knowledge of the symptoms of COVID-19, oncology patients who are concerned about anosmia or ageusia in the context of their systemic anti-cancer therapy should contact their acute oncology support line for advice.