BRAF inhibitors and their immunological effects in malignant melanoma.

INTRODUCTION: The treatment of cutaneous melanoma has been revolutionized by the development of small-molecule inhibitors targeting the MAPK pathway, including inhibitors of BRAF (BRAFi) and MEK (MEKi), and immune checkpoint blockade antibodies, occurring in tandem. Despite these advances, the 5-year survival rate for patients with advanced melanoma remains only around 50%. Although not designed to alter immune responses within the tumor microenvironment (TME), MAPK pathway inhibitors (MAPKi) exert a range of effects on the host immune compartment that may offer opportunities for therapeutic interventions. AREAS COVERED: We review the effects of MAPKi, especially BRAFi, on the TME, focusing on alterations in inflammatory cytokine secretion, recruitment of immune cells and their functions, both during response to BRAFi treatment and as resistance develops. We outline potential combinations of MAPKi with established and experimental treatments. EXPERT OPINION: MAPKi in combination or in sequence with established treatments such as checkpoint inhibitors, anti-angiogenic agents, or new therapies such as adoptive cell therapies, may augment their immunological effects, reverse tumor-associated immune suppression, and offer the prospect of longer-lived clinical responses. Refining therapeutic tools at our disposal and embracing 'old friends' in the melanoma treatment arsenal, alongside new target identification, may improve the chances of therapeutic success.

Combined anti-PD-1 and anti-CTLA-4 checkpoint blockade: Treatment of melanoma and immune mechanisms of action.

Cytotoxic T-lymphocyte associated protein-4 (CTLA-4) and the Programmed Death Receptor 1 (PD-1) are immune checkpoint molecules that are well-established targets of antibody immunotherapies for the management of malignant melanoma. The monoclonal antibodies, Ipilimumab, Pembrolizumab, and Nivolumab, designed to interfere with T cell inhibitory signals to activate immune responses against tumors, were originally approved as monotherapy. Treatment with a combination of immune checkpoint inhibitors may improve outcomes compared to monotherapy in certain patient groups and these clinical benefits may be derived from unique immune mechanisms of action. However, treatment with checkpoint inhibitor combinations also present significant clinical challenges and increased rates of immune-related adverse events. In this review, we discuss the potential mechanisms attributed to single and combined checkpoint inhibitor immunotherapies and clinical experience with their use.

Effects of Glucagon-like Peptide-1 on the Reproductive Axis in Healthy Men.

CONTEXT: Glucagon-like peptide-1 (GLP-1) potently reduces food intake and augments glucose-stimulated insulin secretion. Recent animal data suggest that GLP-1 may also influence reproduction. As GLP-1 receptor agonists are currently widely used in clinical practice to treat obesity/type 2 diabetes, it is necessary to determine the effects of GLP-1 on the reproductive system in humans. OBJECTIVE: To investigate the effects of GLP-1 administration on the reproductive axis in humans. DESIGN: Single-blind, randomized, placebo-controlled crossover study. SETTING: Clinical Research Facility, Imperial College Healthcare NHS Trust. PARTICIPANTS: Eighteen healthy men (mean age 24.7 ± 0.1years, mean BMI 22.1 ± 0.4kg/m2). INTERVENTION: Eight-hour intravenous infusion of 0.8 pmol/kg/min GLP-1 or rate-matched vehicle infusion. MAIN OUTCOME MEASURES: Number of luteinizing hormone (LH) pulses, LH, follicle-stimulating hormone (FSH), and testosterone levels. RESULTS: The number of LH pulses (number of LH pulses/500 min: vehicle 4.2 ± 0.4, GLP-1 4.5 ± 0.3, P = 0.46), LH area under the curve (AUC) (vehicle 1518 ± 88min.IU/L, GLP-1 1524 ± 101min.IU/L, P = 0.95), follicle-stimulating hormone AUC (vehicle 1210 ± 112 min IU/L, GLP-1 1216 ± 112 min IU/L, P = 0.86), and testosterone AUC (vehicle 10893 ± 615 min nmol/L, GLP-1 11088 ± 792 min nmol/L, P = 0.77) did not significantly differ during vehicle and GLP-1 administration. Glucagon-like peptide-1 significantly reduced food intake (vehicle 15.7 ± 1.3 kcal/kg, GLP-1 13.4 ± 1.3 kcal/kg, P = 0.01). CONCLUSIONS: In contrast to the animal literature, our data demonstrate that acute GLP-1 administration does not affect reproductive hormone secretion in healthy men.

Effects of Peptide YY on the Hypothalamic-Pituitary-Gonadal Axis in Healthy Men.

CONTEXT: Central and peripheral administration of peptide YY (PYY) has potent anorectic effects, and PYY analogs are under development as antiobesity treatments. Recent animal data suggest PYY may also influence the reproductive axis; however the effects of PYY on the human reproductive system are unknown. OBJECTIVE: To investigate the effects of PYY administration on the reproductive axis in healthy young men. DESIGN: Single-blind, randomized, placebo-controlled crossover study. SETTING: Clinical Research Facility, Imperial College Healthcare NHS Trust. PARTICIPANTS: Eighteen healthy eugonadal men (mean age 24.1 ± 0.9 years, mean body mass index 22.2 ± 0.4 kg/m2). INTERVENTION: Eight-hour intravenous infusion of 0.4 pmol/kg/min PYY3-36 or rate-matched vehicle infusion. MAIN OUTCOME MEASURES: Number of luteinizing hormone (LH) pulses, LH, follicle stimulating hormone (FSH), and testosterone levels. RESULTS: The number of LH pulses (mean number of LH pulses/8 hours: PYY 4.4 ± 0.3 vs vehicle 4.4 ± 0.4, P > .99), LH area under the curve (AUC) (PYY 1503 ± 79 IU.min/L vs vehicle 1574 ± 86 IU.min/L, P = .36), FSH AUC (PYY 1158 ± 513 IU.min/L vs vehicle 1199 ± 476 IU.min/L, P = .49) and testosterone AUC (PYY 10 485 ± 684 IU.min/L vs vehicle 11 133 ± 803 IU.min/L, P = .24) were similar during PYY and vehicle infusions. CONCLUSIONS: Acute intravenous infusion of 0.4 pmol/kg/min PYY does not affect the reproductive axis in healthy men.

Cardiovascular Autonomic Dysfunction in Patients with Cancer.

PURPOSE OF REVIEW: Elucidating the mechanisms that contribute to adverse cardiovascular (CV) outcomes and reduce quality of life among patients with cancer is paramount. Cancer, certain cancer drugs, radiation therapy, cancer-associated lifestyle disturbances, and cancer-independent comorbidities combine to predispose oncology patients to autonomic dysfunction (AD). This review will explore the assessment, etiology, and clinical implications of AD in cancer patients and will speculate on therapeutic and research opportunities. RECENT FINDINGS: AD is particularly prevalent among patients with advanced cancer, but studies suggest increased prevalence across the entire continuum of cancer survivors compared to cancer-free controls. Data on cancer therapy-induced injury to the autonomic nervous system are limited to small studies. AD has been reported after cranial, neck, and mediastinal radiation therapy. Although AD has been shown to confer increased risk of adverse CV outcomes in cancer-free patients, the prognostic relevance of AD in oncology patients is less well investigated. Markers of AD including elevated resting heart rate (HR), reduced HR variability, and abnormal HR recovery have been associated with shorter survival times in various cancer cohorts. Furthermore, AD has been implicated in the etiology of cancer-related fatigue and exercise limitation. Multiple risk factors predispose oncology patients to AD, which is associated with adverse outcomes, including increased mortality, exercise limitation, and fatigue among this cohort. The contribution of AD to overall morbidity and mortality in cancer survivors has largely been overlooked to date. Further investigation is necessary to better understand cancer-treatment specific autonomic injury and to evaluate the role of various pharmacological and non-pharmacological interventions with potential to tackle the sympathovagal imbalance observed in cancer survivors.

Antibody structure and engineering considerations for the design and function of Antibody Drug Conjugates (ADCs).

Antibody-drug conjugates (ADCs) are emerging as effective tools in cancer therapy, combining the antibody's exquisite specificity for the target antigen-expressing cancer cell together with the cytotoxic potency of the payload. Much success stems from the rational design of "toxic warheads", chemically linked to antibodies, and from fine-tuning the intricate properties of chemical linkers. Here, we focus on the antibody moiety of ADCs, dissecting the impact of Fab, linkers, isotype and Fc structure on the anti-tumoral and immune-activating functions of ADCs. Novel design approaches informed by antibody structural attributes present opportunities that may contribute to the success of next generation ADCs.

Systematic Review of the Use of 3-Dimensional Printing in Surgical Teaching and Assessment.

OBJECTIVE: The use of 3-dimensional (3D) printing in medicine has rapidly expanded in recent years as the technology has developed. The potential uses of 3D printing are manifold. This article provides a systematic review of the uses of 3D printing within surgical training and assessment. METHODS: A structured literature search of the major literature databases was performed in adherence to PRISMA guidelines. Articles that met predefined inclusion and exclusion criteria were appraised with respect to the key objectives of the review and sources of bias were analysed. RESULTS: Overall, 49 studies were identified for inclusion in the qualitative analysis. Heterogeneity in study design and outcome measures used prohibited meaningful meta-analysis. 3D printing has been used in surgical training across a broad range of specialities but most commonly in neurosurgery and otorhinolaryngology. Both objective and subjective outcome measures have been studied, demonstrating the usage of 3D printed models in training and education. 3D printing has also been used in anatomical education and preoperative planning, demonstrating improved outcomes when compared to traditional educational methods and improved patient outcomes, respectively. CONCLUSIONS: 3D printing technology has a broad range of potential applications within surgical education and training. Although the field is still in its relative infancy, several studies have already demonstrated its usage both instead of and in addition to traditional educational methods.

Dispelling the nice or naughty myth: retrospective observational study of Santa Claus.

OBJECTIVE:  To determine which factors influence whether Santa Claus will visit children in hospital on Christmas Day. DESIGN:  Retrospective observational study. SETTING:  Paediatric wards in England, Northern Ireland, Scotland, and Wales. PARTICIPANTS:  186 members of staff who worked on the paediatric wards (n=186) during Christmas 2015. MAIN OUTCOME MEASURES:  Presence or absence of Santa Claus on the paediatric ward during Christmas 2015. This was correlated with rates of absenteeism from primary school, conviction rates in young people (aged 10-17 years), distance from hospital to North Pole (closest city or town to the hospital in kilometres, as the reindeer flies), and contextual socioeconomic deprivation (index of multiple deprivation). RESULTS:  Santa Claus visited most of the paediatric wards in all four countries: 89% in England, 100% in Northern Ireland, 93% in Scotland, and 92% in Wales. The odds of him not visiting, however, were significantly higher for paediatric wards in areas of higher socioeconomic deprivation in England (odds ratio 1.31 (95% confidence interval 1.04 to 1.71) in England, 1.23 (1.00 to 1.54) in the UK). In contrast, there was no correlation with school absenteeism, conviction rates, or distance to the North Pole. CONCLUSION:  The results of this study dispel the traditional belief that Santa Claus rewards children based on how nice or naughty they have been in the previous year. Santa Claus is less likely to visit children in hospitals in the most deprived areas. Potential solutions include a review of Santa's contract or employment of local Santas in poorly represented regions.