Cutaneous adverse reactions in B-RAF positive metastatic melanoma following sequential treatment with B-RAF/MEK inhibitors and immune checkpoint blockade or vice versa. A single-institutional case-series

Background With the advent of immune-checkpoint inhibitors and targeted treatments (TT), there have been unprecedented response rates and survival in advanced melanoma, but the optimal sequencing of these two treatments modalities is unknown. Combining or sequencing these agents could potentially result in unique toxicities. Cutaneous adverse events (CAE) after sequential exposure to these agents represents one toxicity that needs further description. Methods After retrospectively reviewing charts of patients from 2015 to 2018, we identified six patients who experienced CAEs after recent exposure to sequential immunotherapy and TT or vice versa for the treatment for metastatic melanoma at the University of North Carolina, Chapel Hill. Skin biopsies were available in five patients. Results Five patients received TT after immunotherapy, and one patient received immunotherapy after TT. TT consisted of vemurafenib/cobimetinib (V/C) in five patients with four patients starting V/C immediately before manifesting with a CAE. In patients receiving V/C after immunotherapy, the median time from beginning V/C to development of CAE was 14.5 days. The clinical presentation of diffuse morbilliform rash, fevers, hypotension, and end-organ damage raised concern for Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) syndrome. Histopathological features of lympho-eosinophilic infiltrate were supportive of a drug eruption. Immunotherapy or TT were re-initiated in five patients within 1–8 weeks after resolution of the index CAE. This resulted in two patients re-experiencing the CAE. Both of these patients were off prednisone at the time of therapy re-initiation, whereas none of the patients who were restarted on targeted therapy with a steroid overlap had a rash recurrence. Conclusions Sequential treatment using immunotherapy and TT, especially the sequence of V/C after immunotherapy appears to be the most common trigger for CAE with a median time to onset of approximately 2 weeks. Although the clinical presentation of these CAEs can be dramatic, they respond well to prednisone therapy. This unique presentation suggests that it may be reasonably safe to re-challenge certain patients with a steroid overlap after rash resolution

9G4 Autoreactivity Is Increased in HIV-Infected Patients and Correlates with HIV Broadly Neutralizing Serum Activity

The induction of a broadly neutralizing antibody (BNAb) response against HIV-1 would be a desirable feature of a protective vaccine. Vaccine strategies thus far have failed to elicit broadly neutralizing antibody responses; however a minority of HIV-infected patients do develop circulating BNAbs, from which several potent broadly neutralizing monoclonal antibodies (mAbs) have been isolated. The findings that several BNmAbs exhibit autoreactivity and that autoreactive serum antibodies are observed in some HIV patients have advanced the possibility that enforcement of self-tolerance may contribute to the rarity of BNAbs. To examine the possible breakdown of tolerance in HIV patients, we utilized the 9G4 anti-idiotype antibody system, enabling resolution of both autoreactive VH4-34 gene-expressing B cells and serum antibodies. Compared with healthy controls, HIV patients had significantly elevated 9G4+ serum IgG antibody concentrations and frequencies of 9G4+ B cells, a finding characteristic of systemic lupus erythematosus (SLE) patients, both of which positively correlated with HIV viral load. Compared to the global 9G4−IgD− memory B cell population, the 9G4+IgD− memory fraction in HIV patients was dominated by isotype switched IgG+ B cells, but had a more prominent bias toward “IgM only" memory. HIV envelope reactivity was observed both in the 9G4+ serum antibody and 9G4+ B cell population. 9G4+ IgG serum antibody levels positively correlated (r = 0.403, p = 0.0019) with the serum HIV BNAbs. Interestingly, other serum autoantibodies commonly found in SLE (anti-dsDNA, ANA, anti-CL) did not correlate with serum HIV BNAbs. 9G4-associated autoreactivity is preferentially expanded in chronic HIV infection as compared to other SLE autoreactivities. Therefore, the 9G4 system provides an effective tool to examine autoreactivity in HIV patients. Our results suggest that the development of HIV BNAbs is not merely a consequence of a general breakdown in tolerance, but rather a more intricate expansion of selective autoreactive B cells and antibodies

The LEAD study protocol: a mixed-method cohort study evaluating the lung cancer diagnostic and pre-treatment pathways of patients from Culturally and Linguistically Diverse (CALD) backgrounds compared to patients from Anglo-Australian backgrounds.

BACKGROUND: Lung cancer is the leading cause of cancer mortality worldwide. Early diagnosis and treatment is a key factor in reducing mortality and improving patient outcomes. To achieve this, it is important to understand the diagnostic pathways of cancer patients. Patients from Culturally and Linguistically Diverse (CALD) are a vulnerable group for lung cancer with higher mortality rates than Caucasian patients. The aim of this study is to explore differences in the lung cancer diagnostic pathways between CALD and Anglo-Australian patients and factors underlying these differences. METHODS: This is a prospective, observational cohort study using a mixed-method approach. Quantitative data regarding time intervals in the lung cancer diagnostic pathways will be gathered via patient surveys, General practitioner (GP) review of general practice records, and case-note analysis of hospital records. Qualitative data will be gathered via structured interviews with lung cancer patients, GPs, and hospital specialists. The study will be conducted in five study sites across three states in Australia. Anglo-Australian patients and patients from five CALD groups (i.e., Arabic, Chinese, Greek, Italian and Vietnamese communities) will mainly be identified through the list of new cases presented at lung multidisciplinary team meetings. For the quantitative component, it is anticipated that 724 patients (362 Anglo-Australian and 362 CALD patients) will be recruited to obtain a final sample of 290 (145 per group) assuming a 50% patient survey completion rate and a 80% GP record review completion rate. For the qualitative component, 60 interviews with lung cancer patients (10 Anglo-Australian and 10 patients per CALD group), 20 interviews with GPs, and 20 interviews with specialists will be conducted. DISCUSSION: This is the first Australian study to compare the time intervals along the lung cancer diagnostic pathway between CALD and Anglo-Australian patients. The study will also explore the underlying patient, healthcare provider, and health system factors that influence the time intervals in the two groups. This information will improve our understanding of the effect of ethnicity on health outcomes among lung cancer patients and will inform future interventions aimed at early diagnosis and treatment for lung cancer, particularly patients from CALD backgrounds. TRIAL REGISTRATION: The project was retrospectively registered with Australian New Zealand Clinical Trials Registry (registration number: ACTRN12617000957392 , date registered: 4th July 2017).The project is funded by Cancer Council Australia with the assistance of Cancer Australia through the 2015 round of the Priority-driven Collaborative Cancer Research Scheme

Telomeric expression sites are highly conserved in trypanosoma brucei

Subtelomeric regions are often under-represented in genome sequences of eukaryotes. One of the best known examples of the use of telomere proximity for adaptive purposes are the bloodstream expression sites (BESs) of the African trypanosome Trypanosoma brucei. To enhance our understanding of BES structure and function in host adaptation and immune evasion, the BES repertoire from the Lister 427 strain of T. brucei were independently tagged and sequenced. BESs are polymorphic in size and structure but reveal a surprisingly conserved architecture in the context of extensive recombination. Very small BESs do exist and many functioning BESs do not contain the full complement of expression site associated genes (ESAGs). The consequences of duplicated or missing ESAGs, including ESAG9, a newly named ESAG12, and additional variant surface glycoprotein genes (VSGs) were evaluated by functional assays after BESs were tagged with a drug-resistance gene. Phylogenetic analysis of constituent ESAG families suggests that BESs are sequence mosaics and that extensive recombination has shaped the evolution of the BES repertoire. This work opens important perspectives in understanding the molecular mechanisms of antigenic variation, a widely used strategy for immune evasion in pathogens, and telomere biology

School-based relationship and sexuality education intervention engaging adolescent boys for the reductions of teenage pregnancy: the JACK cluster RCT

BACKGROUND: The need to engage boys in gender-transformative relationships and sexuality education (RSE) to reduce adolescent pregnancy is endorsed by the World Health Organization and the United Nations Educational, Scientific and Cultural Organization. OBJECTIVES: To evaluate the effects of If I Were Jack on the avoidance of unprotected sex and other sexual health outcomes. DESIGN: A cluster randomised trial, incorporating health economics and process evaluations. SETTING: Sixty-six schools across the four nations of the UK. PARTICIPANTS: Students aged 13-14 years. INTERVENTION: A school-based, teacher-delivered, gender-transformative RSE intervention (If I Were Jack) versus standard RSE. MAIN OUTCOME MEASURES: Self-reported avoidance of unprotected sex (sexual abstinence or reliable contraceptive use at last sex) after 12-14 months. Secondary outcomes included knowledge, attitudes, skills, intentions and sexual behaviours. RESULTS: The analysis population comprised 6556 students: 86.6% of students in the intervention group avoided unprotected sex, compared with 86.4% in the control group {adjusted odds ratio 0.85 [95% confidence interval (CI) 0.58 to 1.26], p = 0.42}. An exploratory post hoc analysis showed no difference for sexual abstinence [78.30% intervention group vs. 78.25% control group; adjusted odds ratio 0.85 (95% CI 0.58 to 1.24), p = 0.39], but more intervention group students than control group students used reliable contraception at last sex [39.62% vs. 26.36%; adjusted odds ratio 0.52 (95% CI 0.29 to 0.920), p = 0.025]. Students in schools allocated to receive the intervention had significantly higher scores on knowledge [adjusted mean difference 0.18 (95% CI 0.024 to 0.34), p = 0.02], gender-equitable attitudes and intentions to avoid unintended pregnancy [adjusted mean difference 0.61 (95% CI 0.16 to 1.07), p = 0.01] than students in schools allocated to receive the control. There were positive but non-significant differences in sexual self-efficacy and communication skills. The total mean incremental cost of the intervention compared with standard RSE was £2.83 (95% CI -£2.64 to £8.29) per student. Over a 20-year time horizon, the intervention is likely to be cost-effective owing to its impact on unprotected sex because it would result in 379 (95% CI 231 to 477) fewer unintended pregnancies, 680 (95% CI 189 to 1467) fewer sexually transmitted infections and a gain of 10 (95% CI 5 to 16) quality-adjusted life-years per 100,000 students for a cost saving of £9.89 (95% CI -£15.60 to -£3.83). LIMITATIONS: The trial is underpowered to detect some effects because four schools withdrew and the intraclass correlation coefficient (0.12) was larger than that in sample size calculation (0.01). CONCLUSIONS: We present, to our knowledge, the first evidence from a randomised trial that a school-based, male engagement gender-transformative RSE intervention, although not effective in increasing avoidance of unprotected sex (defined as sexual abstinence or use of reliable contraception at last sex) among all students, did increase the use of reliable contraception at last sex among students who were, or became, sexually active by 12-14 months after the intervention. The trial demonstrated that engaging all adolescents early through RSE is important so that, as they become sexually active, rates of unprotected sex are reduced, and that doing so is likely to be cost-effective. FUTURE WORK: Future studies should consider the longer-term effects of gender-transformative RSE as students become sexually active. Gender-transformative RSE could be adapted to address broader sexual health and other settings. TRIAL REGISTRATION: This trial is registered as ISRCTN10751359. FUNDING: This project was funded by the National Institute for Health and Care Research (NIHR) Public Health Research programme (PHR 15/181/01) and will be published in full in Public Health Research; Vol. 11, No. 8. See the NIHR Journals Library website for further project information