Retrospective case note review of chronic spontaneous urticaria outcomes and adverse effects in patients treated with omalizumab or ciclosporin in UK secondary care.

BACKGROUND: Omalizumab is approved in the UK as add-on treatment for chronic spontaneous urticaria (CSU) in patients with inadequate response to H1-antihistamines. Ciclosporin is an established but unlicensed 3rd line option for CSU. Two parallel retrospective observational studies were conducted to describe outcomes of treatment and adverse events with omalizumab or ciclosporin for CSU treatment. METHODS: Data from UK specialist centres prescribing omalizumab (five centres) or ciclosporin (three centres) in CSU patients were collected from hospital records by clinical staff and pooled for analysis. RESULTS: Forty-six patients prescribed omalizumab and 72 patients prescribed ciclosporin were included. Twenty-two (48%) omalizumab-treated patients had paired Urticaria Activity Scores (UAS7), showing a 25.4 point improvement during treatment (P < 0.0001). Paired Dermatology Life Quality Index (DLQI) was available in 28 (61%) omalizumab-treated and 17 (24%) ciclosporin-treated patients. At least a 75% improvement in DLQI score was observed in 79% of omalizumab-treated and 41% of ciclosporin-treated patients, and 65% of omalizumab-treated patients had complete resolution of their quality-of-life impairment (DLQI 0-1) versus 21% of ciclosporin-treated patients. Clinician comments reported symptom clearance in 15/36 (42%) omalizumab-treated and 10/60 (17%) ciclosporin-treated patients. Proportions of patients with adverse events were similar but those for omalizumab resembled CSU symptoms, making causality assignment difficult, whereas those for ciclosporin were consistent with its known adverse effect profile. CONCLUSIONS: Validated patient-reported measures of disease severity and quality of life should be used routinely in CSU management. Based on clinician comments and DLQI scores, symptoms and quality of life showed a greater improvement in the omalizumab-treated cohort than in the ciclosporin-treated cohort

A risk prediction algorithm based on family history and common genetic variants: application to prostate cancer with potential clinical impact.

Genome wide association studies have identified several single nucleotide polymorphisms (SNPs) that are independently associated with small increments in risk of prostate cancer, opening up the possibility for using such variants in risk prediction. Using segregation analysis of population-based samples of 4,390 families of prostate cancer patients from the UK and Australia, and assuming all familial aggregation has genetic causes, we previously found that the best model for the genetic susceptibility to prostate cancer was a mixed model of inheritance that included both a recessive major gene component and a polygenic component (P) that represents the effect of a large number of genetic variants each of small effect, where . Based on published studies of 26 SNPs that are currently known to be associated with prostate cancer, we have extended our model to incorporate these SNPs by decomposing the polygenic component into two parts: a polygenic component due to the known susceptibility SNPs, , and the residual polygenic component due to the postulated but as yet unknown genetic variants, . The resulting algorithm can be used for predicting the probability of developing prostate cancer in the future based on both SNP profiles and explicit family history information. This approach can be applied to other diseases for which population-based family data and established risk variants exist

Tracking Antigen-Specific T-Cells during Clinical Tolerance Induction in Humans

Allergen immunotherapy presents an opportunity to define mechanisms of induction of clinical tolerance in humans. Significant progress has been made in our understanding of changes in T cell responses during immunotherapy, but existing work has largely been based on functional T cell assays. HLA-peptide-tetrameric complexes allow the tracking of antigen-specific T-cell populations based on the presence of specific T-cell receptors and when combined with functional assays allow a closer assessment of the potential roles of T-cell anergy and clonotype evolution. We sought to develop tools to facilitate tracking of antigen-specific T-cell populations during wasp-venom immunotherapy in people with wasp-venom allergy. We first defined dominant immunogenic regions within Ves v 5, a constituent of wasp venom that is known to represent a target antigen for T-cells. We next identified HLA-DRB1*1501 restricted epitopes and used HLA class II tetrameric complexes alongside cytokine responses to Ves v 5 to track T-cell responses during immunotherapy. In contrast to previous reports, we show that there was a significant initial induction of IL-4 producing antigen-specific T-cells within the first 3–5 weeks of immunotherapy which was followed by reduction of circulating effector antigen-specific T-cells despite escalation of wasp-venom dosage. However, there was sustained induction of IL-10-producing and FOXP3 positive antigen-specific T cells. We observed that these IL-10 producing cells could share a common precursor with IL-4-producing T cells specific for the same epitope. Clinical tolerance induction in humans is associated with dynamic changes in frequencies of antigen-specific T-cells, with a marked loss of IL-4-producing T-cells and the acquisition of IL-10-producing and FOXP3-positive antigen-specific CD4+ T-cells that can derive from a common shared precursor to pre-treatment effector T-cells. The development of new approaches to track antigen specific T-cell responses during immunotherapy can provide novel insights into mechanisms of tolerance induction in humans and identify new potential treatment targets

Communication about genetic testing with breast and ovarian cancer patients: a scoping review

© 2018, The Author(s). Genetic testing of patients with cancer is increasingly offered to guide management, resulting in a growing need for oncology health professionals to communicate genetics information and facilitate informed decision-making in a short time frame. This scoping review aimed to map and synthesise what is known about health professionals’ communication about genetic testing for hereditary breast and ovarian cancer with cancer patients. Four databases were systematically searched using a recognised scoping review method. Areas and types of research were mapped and a narrative synthesis of the findings was undertaken. Twenty-nine papers from 25 studies were included. Studies were identified about (i) information needs, (ii) process and content of genetic counselling, (iii) cognitive and emotional impact, including risk perception and recall, understanding and interpretation of genetic test results, and anxiety and distress, (iv) patients’ experiences, (v) communication shortly after diagnosis and (vi) alternatives to face-to-face genetic counselling. Patients’ need for cancer-focused, personalised information is not always met by genetic counselling. Genetic counselling tends to focus on biomedical information at the expense of psychological support. For most patients, knowledge is increased and anxiety is not raised by pre-test communication. However, some patients experience anxiety and distress when results are disclosed, particularly those tested shortly after diagnosis who are unprepared or unsupported. For many patients, pre-test communication by methods other than face-to-face genetic counselling is acceptable. Research is needed to identify patients who may benefit from genetic counselling and support and to investigate communication about hereditary breast and ovarian cancer by oncology health professionals

Universal BRCA1/BRCA2 Testing for Ovarian Cancer Patients is Welcomed, but with Care: How Women and Staff Contextualize Experiences of Expanded Access

Decreasing costs of genetic testing and advances in treatment for women with cancer with germline $\textit{BRCA1/BRCA2}$ mutations have heralded more inclusive genetic testing programs. The Genetic Testing in Epithelial Ovarian Cancer (GTEOC) Study, investigates the feasibility and acceptability of offering genetic testing to all women recently diagnosed with epithelial ovarian cancer (universal genetic testing or UGT). Study participants and staff were interviewed to: (i) assess the impact of UGT (ii) integrate patients' and staff perspectives in the development of new UGT programs. Semi-structured interviews were conducted with twelve GTEOC Study participants and five members of staff involved in recruiting them. The transcripts were transcribed $\textit{verbatim}$ and analyzed using Interpretative Phenomenological Analysis. There are two super-ordinate themes: $\textit{motivations and influences around offers of genetic testing}$ and $\textit{impacts of genetic testing in ovarian cancer patients}$. A major finding is that genetic testing is contextualized within the broader experiences of the women; the impact of UGT was minimized in comparison with the ovarian cancer diagnosis. Women who consent to UGT are motivated by altruism and by their relatives' influence, whilst those who decline are often considered overwhelmed or fearful. Those without a genetic mutation are usually reassured by this result, whilst those with a genetic mutation must negotiate new uncertainties and responsibilities towards their families. Our findings suggest that UGT in this context is generally acceptable to women. However, the period shortly after diagnosis is a sensitive time and some women are emotionally overburdened. UGT is considered a 'family affair' and staff must acknowledge this.This work was supported by Target Ovarian Cancer grant number T005MT. Marc Tischkowitz was supported by funding from the European Union Seventh Framework Program (2007Y2013)/ European Research Council (Grant No. 310018)

Targeted prostate cancer screening in BRCA1 and BRCA2 mutation carriers: Results from the initial screening round of the IMPACT study

Background Men with germline breast cancer 1, early onset (BRCA1) or breast cancer 2, early onset (BRCA2) gene mutations have a higher risk of developing prostate cancer (PCa) than noncarriers. IMPACT (Identification of Men with a genetic predisposition to ProstAte Cancer: Targeted screening in BRCA1/2 mutation carriers and controls) is an international consortium of 62 centres in 20 countries evaluating the use of targeted PCa screening in men with BRCA1/2 mutations. Objective To report the first year\u27s screening results for all men at enrolment in the study. Design, setting and participants We recruited men aged 40-69 yr with germline BRCA1/2 mutations and a control group of men who have tested negative for a pathogenic BRCA1 or BRCA2 mutation known to be present in their families. All men underwent prostate-specific antigen (PSA) testing at enrolment, and those men with PSA &gt;3 ng/ml were offered prostate biopsy. Outcome measurements and statistical analysis PSA levels, PCa incidence, and tumour characteristics were evaluated. The Fisher exact test was used to compare the number of PCa cases among groups and the differences among disease types. Results and limitations We recruited 2481 men (791 BRCA1 carriers, 531 BRCA1 controls; 731 BRCA2 carriers, 428 BRCA2 controls). A total of 199 men (8%) presented with PSA &gt;3.0 ng/ml, 162 biopsies were performed, and 59 PCas were diagnosed (18 BRCA1 carriers, 10 BRCA1 controls; 24 BRCA2 carriers, 7 BRCA2 controls); 66% of the tumours were classified as intermediate- or high-risk disease. The positive predictive value (PPV) for biopsy using a PSA threshold of 3.0 ng/ml in BRCA2 mutation carriers was 48% - double the PPV reported in population screening studies. A significant difference in detecting intermediate- or high-risk disease was observed in BRCA2 carriers. Ninety-five percent of the men were white, thus the results cannot be generalised to all ethnic groups. Conclusions The IMPACT screening network will be useful for targeted PCa screening studies in men with germline genetic risk variants as they are discovered. These preliminary results support the use of targeted PSA screening based on BRCA genotype and show that this screening yields a high proportion of aggressive disease. Patient summary In this report, we demonstrate that germline genetic markers can be used to identify men at higher risk of prostate cancer. Targeting screening at these men resulted in the identification of tumours that were more likely to require treatment. \ua9 2014 European Association of Urology

Global patient outcomes after elective surgery: prospective cohort study in 27 low-, middle- and high-income countries.

BACKGROUND: As global initiatives increase patient access to surgical treatments, there remains a need to understand the adverse effects of surgery and define appropriate levels of perioperative care. METHODS: We designed a prospective international 7-day cohort study of outcomes following elective adult inpatient surgery in 27 countries. The primary outcome was in-hospital complications. Secondary outcomes were death following a complication (failure to rescue) and death in hospital. Process measures were admission to critical care immediately after surgery or to treat a complication and duration of hospital stay. A single definition of critical care was used for all countries. RESULTS: A total of 474 hospitals in 19 high-, 7 middle- and 1 low-income country were included in the primary analysis. Data included 44 814 patients with a median hospital stay of 4 (range 2-7) days. A total of 7508 patients (16.8%) developed one or more postoperative complication and 207 died (0.5%). The overall mortality among patients who developed complications was 2.8%. Mortality following complications ranged from 2.4% for pulmonary embolism to 43.9% for cardiac arrest. A total of 4360 (9.7%) patients were admitted to a critical care unit as routine immediately after surgery, of whom 2198 (50.4%) developed a complication, with 105 (2.4%) deaths. A total of 1233 patients (16.4%) were admitted to a critical care unit to treat complications, with 119 (9.7%) deaths. Despite lower baseline risk, outcomes were similar in low- and middle-income compared with high-income countries. CONCLUSIONS: Poor patient outcomes are common after inpatient surgery. Global initiatives to increase access to surgical treatments should also address the need for safe perioperative care. STUDY REGISTRATION: ISRCTN5181700

Prostate-specific antigen velocity in a prospective prostate cancer screening study of men with genetic predisposition.

This corrects the article DOI: 10.1038/bjc.2017.429

Anti-lymphocyte function associated antigen-1 inhibits T-helper 2 function of human allergen-specific CD4+ T cells

Background Blockade of lymphocyte function associated antigen‐1 (LFA‐1) is proving successful in the management of psoriasis and other inflammatory skin conditions including atopic dermatitis (AD), but the dependence of allergen‐specific CD4+ T‐cell function on LFA‐1 has not been studied extensively. Objectives We sought to investigate the potential ability of LFA‐1 inhibition to influence keratinocyte presentation of allergen to specific T‐helper (Th) 2 cell clones. Methods Using human leucocyte antigen class II tetrameric complexes, we generated Der p 1‐specific DRB1*1501‐restricted CD4+ T‐cell lines (n =5) and clones (n =4) from the peripheral blood of five adults with AD. Results Using doses of anti‐LFA‐1 present in vivo, we observed significant inhibition (P <0·05) of allergen‐specific CD4+ T‐cell production of interleukin‐4 with such inhibition occurring during presentation of allergen by keratinocytes. Conclusions These data show that at doses present in vivo, LFA‐1 blockade inhibits keratinocyte presentation to allergen‐specific Th2 cells, suggesting one mechanism through which anti‐LFA‐1 may be beneficial therapeutically