Combination Therapy of Ipilimumab and Nivolumab-associated Toxic Epidermal Necrolysis (TEN) in a Patient With Metastatic Melanoma: A Case Report and Literature Review.

Ipilimumab and nivolumab are immune checkpoint inhibitors used in the treatment of metastatic melanoma. The authors report the case of a 62-year-old white male individual with metastatic choroidal melanoma who had commenced adjuvant systemic treatment with combination checkpoint inhibitor therapy of intravenous ipilimumab (anti-cytotoxic T-lymphocyte antigen-4) and nivolumab (anti-programmed cell death-1) at 3-week cycle intervals. On day 4 after the second cycle, he developed an acute widespread rash. On examination there was confluent erythema with bullae and epidermal loss over 60% of the body surface area, with severe oral mucosal ulceration. A clinical diagnosis of toxic epidermal necrolysis (TEN) was made and he was transferred to the intensive care unit. Despite active treatment, he deteriorated systemically and died from multiorgan failure. This is the first reported case of TEN associated with nivolumab and ipilimumab dual therapy for metastatic uveal melanoma. Monotherapy improves survival in metastatic melanoma, but dual therapy has shown a greater mortality benefit at 3 years. Although the literature demonstrates case reports of Stevens-Johnson syndrome and TEN in association with nivolumab, ipilimumab has generally been regarded as a "safe" treatment with regard to severe cutaneous adverse reactions. With the increased use of immunotherapies, it is important to plan the management and early recognition of drug-related skin toxicity. This is of greatest concern during treatment initiation and with the higher risk associated with combination therapy. Reporting of adverse events and infrequently encountered complications with systemic biologic treatments will augment pharmacovigilance and improve the stratification of patients to treatments.

The mortality risk of deferring optimal medical therapy in heart failure: a systematic comparison against norms for surgical consent and patient information leaflets.

AIMS: The prescription of optimal medical therapy for heart failure is often delayed despite compelling evidence of a reduction in mortality. We calculated the absolute risk resulting from delayed prescription of therapy. For comparison, we established the threshold applied by clinicians when discussing the risk for death associated with an intervention, and the threshold used in official patient information leaflets. METHODS AND RESULTS: We undertook a meta-analysis of randomized controlled trials to calculate the excess mortality caused by deferral of medical therapy for 1 year. Risk ratios for angiotensin-converting enzyme inhibitors, beta-blockers and aldosterone antagonists were 0.80, 0.73 and 0.77, respectively. In patients who might achieve a 1-year survival rate of 90% if treated, a 1-year deferral of treatment reduced survival to 78% (i.e. an annual absolute increase in mortality of 12 in 100 patients). This corresponds to an additional absolute mortality risk per month of 1%. A survey of clinicians carried out to establish the risk threshold at which they would obtain written consent showed the majority (85%) sought written consent for interventions associated with a 12-fold lower mortality risk: one in 100 patients. A systematic review of UK patient information leaflets to establish the magnitude of risk considered sufficient to be stated explicitly showed that leaflets begin to mention death at a ∼18 000-fold lower mortality risk of just 0.0007 in 100 patients. CONCLUSIONS: Deferring heart failure treatment for 1 year carries far greater risk than the level at which most doctors seek written consent, and 18 000 times more risk than the level at which patient information leaflets begin to mention death.

Distribution of lifespan gain from primary prevention intervention.

OBJECTIVE: When advising patients about possible initiation of primary prevention treatment, clinicians currently do not have information on expected impact on lifespan, nor how much this increment differs between individuals. METHODS: First, UK cardiovascular and non-cardiovascular mortality data were used to calculate the mean lifespan gain from an intervention (such as a statin) that reduces cardiovascular mortality by 30%. Second, a new method was developed to calculate the probability distribution of lifespan gain. Third, we performed a survey in three UK cities on 11 days between May-June 2014 involving 396 participants (mean age 40 years, 55% male) to assess how individuals evaluate potential benefit from primary prevention therapies. RESULTS: Among numerous identical patients, the lifespan gain, from an intervention that reduces cardiovascular mortality by 30%, is concentrated within an unpredictable minority. For example, men aged 50 years with national average cardiovascular risk have mean lifespan gain of 7 months. However, 93% of these identical individuals gain no lifespan, while the remaining 7% gain a mean of 99 months. Many survey respondents preferred a chance of large lifespan gain to the equivalent life expectancy gain given as certainty. Indeed, 33% preferred a 2% probability of 10 years to fivefold more gain, expressed as certainty of 1 year. CONCLUSIONS: People who gain lifespan from preventative therapy gain far more than the average for their risk stratum, even if perfectly defined. This may be important in patient decision-making. Looking beyond mortality reduction alone from preventative therapy, the benefits are likely to be even larger.

Identifying Quality Indicators Used by Patients to Choose Secondary Health Care Providers: A Mixed Methods Approach.

BACKGROUND: Patients in health systems across the world can now choose between different health care providers. Patients are increasingly using websites and apps to compare the quality of health care services available in order to make a choice of provider. In keeping with many patient-facing platforms, most services currently providing comparative information on different providers do not take account of end-user requirements or the available evidence base. OBJECTIVE: To investigate what factors were considered most important when choosing nonemergency secondary health care providers in the United Kingdom with the purpose of translating these insights into a ratings platform delivered through a consumer mHealth app. METHODS: A mixed methods approach was used to identify key indicators incorporating a literature review to identify and categorize existing quality indicators, a questionnaire survey to formulate a ranked list of performance indicators, and focus groups to explore rationales behind the rankings. Findings from qualitative and quantitative methodologies were mapped onto each other under the four categories identified by the literature review. RESULTS: Quality indicators were divided into four categories. Hospital access was the least important category. The mean differences between the other three categories hospital statistics, hospital staff, and hospital facilities, were not statistically significant. Staff competence was the most important indicator in the hospital staff category; cleanliness and up-to-date facilities were equally important in hospital facilities; ease of travel to the hospital was found to be most important in hospital access. All quality indicators within the hospital statistics category were equally important. Focus groups elaborated that users find it difficult to judge staff competence despite its importance. CONCLUSIONS: A mixed methods approach is presented, which supported a patient-centered development and evaluation of a hospital ratings mobile app. Where possible, mHealth developers should use systematic research methods in order to more closely meet the needs of the end user and add credibility to their platform.