Checkpoint inhibitor-associated bullous cutaneous immune-related adverse events: a multicentre observational study.

BACKGROUND: Checkpoint inhibitor (CPI) therapy has significantly improved overall survival in several cancers including metastatic melanoma (MM) and in the adjuvant setting. Cutaneous immune-related adverse events (irAEs) secondary to CPIs are commonly observed; however, autoimmune blistering disorders such as bullous pemphigoid (BP) are rare. OBJECTIVES: To review the prevalence, incidence risk, clinicopathological features and management of toxicity in bullous cutaneous irAEs associated with CPI therapy. METHODS: A multicentre, retrospective, observational study of CPI-associated bullous irAEs in adults with all cancers across four UK specialist centres between 2006 and 2019. RESULTS: In total, 7391 patients were identified. CPI-associated bullous irAEs including BP (n = 16) occurred in 0·3% (n = 22). The median age of onset was 76 years, and there was a male predominance. Most patients had cutaneous melanoma (73%, n = 16), of which 81% (13 of 16) were BRAF wildtype. Grade 1, 2, 3 and 4 skin toxicity occurred in 9%, 45%, 41% and 5%, respectively. The mucosae were involved in 27%, and 25% of confirmed cases of BP did not present with bullae. The median time to onset of bullous irAEs was 12 months, with a median total symptom duration of 6 months. Single PD-1/PD-L1 agents had a longer time to onset of symptoms than combination therapy (median 12 vs. 7 months, respectively). Overall, 91%, 64% and 9% of patients required one, two or three lines of treatment, respectively. Two cases occurred after completion of CPIs (1 and 3 months). Of the 20 cases that presented while on CPIs this was permanently discontinued in 55% (11 of 20) and temporarily held in 20% (four of 20). In the four held cases of CPI, bullous eruption reflared in 50%. CONCLUSIONS: CPI-associated bullous skin toxicity is a rare cutaneous irAE occurring in approximately 0·3% of cases over 13 years of treated patients in this series. Not all cases are diagnostic of BP, but management remains the same. There is a prolonged latency of onset compared with other cutaneous irAEs, with a median time of 12 months, and they can occur after cessation of therapy. Discontinuation of CPIs may be required. Recognizing bullous irAEs promptly and referral to dermatology are essential to optimize management and improve patient outcomes and tumour responses. What is already known about this topic? Checkpoint inhibitor (CPI)-associated bullous pemphigoid is a rare dermatological immune-related adverse event (irAE) that has been reported in small case series and reports. What does this study add? This is the largest multicentre, observational study conducted in the UK over the longest period of 13 years, which demonstrates an overall incidence of bullous cutaneous irAEs secondary to CPIs of 0·3%. Clinical presentation is variable, with one-quarter of patients with bullous pemphigoid presenting without bullae, and mucosal involvement was noted in 27%. Prolonged pruritus is frequently a prodromal symptom. The median time to diagnosis is 12 months and irAEs rarely present after cessation of treatment. Time to onset of symptoms is longer with a single CPI, but with a shorter duration of symptoms compared with combination CPI therapy. Most patients had cutaneous melanoma, of which 81% were BRAF wildtype.

The clinical profile of tuberous sclerosis complex (TSC) in the United Kingdom: A retrospective cohort study in the Clinical Practice Research Datalink (CPRD).

BACKGROUND: Tuberous Sclerosis Complex (TSC) is a multi-system genetic disorder characterised by the development of benign growths and diverse clinical manifestations, varying in severity, age at onset and with high clinical burden. AIMS: This longitudinal study aims to describe the broad spectrum of clinical manifestation profiles in a large, representative cohort of TSC patients in the UK in order to better understand disease complexity. METHODS: TSC patients in the Clinical Practice Research Datalink (CPRD) and linked Hospital Episodes Statistics (CPRD-HES) were retrospectively identified between 1987 and 2013. Available history was extracted for each patient and clinical diagnosis, procedure and medication records reviewed. A random selection of patients from the CPRD-HES was used as a Comparator cohort. RESULTS: Three hundred and thirty-four TSC patients with a mean (SD) age of 30.3 (18.6) years were identified (53% female). TSC was diagnosed at mean age 3.2 (4.2) years. Epilepsy and psychiatric manifestations were reported frequently in paediatric (77% and 55%, respectively) and adult patients (66% and 68%, respectively). The prevalence of manifestations in the TSC cohort was markedly higher versus the Comparator cohort. The majority of paediatric (46%) and adult TSC patients (62%) developed clinical manifestations affecting at least three organ systems and forty-nine distinctive organ system manifestation profiles were identified. CONCLUSIONS: TSC patients present with multiple and complex clinical manifestations and profiles that necessitate the co-ordinated action of a multidisciplinary team in order to improve the quality and efficiency of care.

Pulsed dye laser and intralesional bleomycin for the treatment of recalcitrant cutaneous warts.

BACKGROUND: Viral warts are a common ailment. Clinicians often combine multiple treatments to boost efficacy. One such novel combination is pulsed dye laser with bleomycin intralesionally (PDL + BI), described for the successful treatment of single hand warts. OBJECTIVE: To evaluate PDL + BI for the treatment of poor prognosis hand and foot warts. STUDY DESIGN/PATIENTS AND METHODS: This 4-year retrospective case series examined the efficacy of PDL + BI used consecutively on patients whose warts were treated with this modality alone. PDL 595 nm was used in stacking mode to achieve hemorrhagic blistering prior to intralesional bleomycin (1 mg/ml normal saline). RESULTS: Twenty cases (65% male, age 13-62, mean age 42) were identified. Two (10%) were immunocompromised. Twenty five percent of warts affected hands, 55% feet, 20% both. Thirty five percent were solitary >1 cm(2) , 40% were multiple or mosaic verucae. The mean duration was 5.1 years (0.5-15). Seventy five percent received local anesthetic. Mean number of treatments was two. Post-operative pain varied from none to severe, sometimes causing difficulty in walking. Blistering and crusting disappeared after 17 days (range 7-42). Outcome had a mean follow-up of 24 months (3-53) with 60% complete response, 15% partial, 25% no response. Mean satisfaction level was 7 (range 0-10, 10 highest). Outcome was better with local anesthetic (complete response 75%) as it permitted more aggressive treatment. Patients that had both anesthetic and repeat treatment sessions experienced 92% complete response. CONCLUSION: PDL + BI offers a novel method for treatment of recalcitrant warts, but local anesthetic and repeat treatments are recommended.

Feasibility of skin surface elastography by tracking skin surface topography.

Recent advances have led to a multitude of image modalities being used for visualization of tissue stiffness. High-resolution images of tissue stiffness are desirable, as they have the potential to provide useful diagnostic information. A noncontact optical imaging method has the attractions of low cost, simplicity, and utility when skin contact is undesirable. However, previous optical techniques have required the application of paint or ink to the surface of the skin and so have required contact. Therefore, the present study assessed the feasibility of tracking skin surface topography to produce elastograms. The study showed, by analyzing a variety of silicone skin surface replicas from various body sites of subjects of different ages, that skin surface elastography by tracking surface topography would be feasible. The study further showed that the quality of the strain images can be optimized by measuring skin line pattern frequency. Skin samples with high skin line frequency will achieve best spatial resolution, in the order of 1 mm, comparable to contact techniques reported previously. A mechanically inhomogeneous silicone replica was then imaged, illustrating the technique's ability to detect strain contrast. Finally, the feasibility of implementing the technique in vivo was illustrated using a single pigmented skin lesion.

Phospholipid bilayers are viscoelastic.

Lipid bilayers provide the structural framework for cellular membranes, and their character as two-dimensional fluids enables the mobility of membrane macromolecules. Though the existence of membrane fluidity is well established, the nature of this fluidity remains poorly characterized. Three-dimensional fluids as diverse as chocolates and cytoskeletal networks show a rich variety of Newtonian and non-Newtonian dynamics that have been illuminated by contemporary rheological techniques. Applying particle-tracking microrheology to freestanding phospholipid bilayers, we find that the membranes are not simply viscous but rather exhibit viscoelasticity, with an elastic modulus that dominates the response above a characteristic frequency that diverges at the fluid-gel (L(α) - L(ß)) phase-transition temperature. These findings fundamentally alter our picture of the nature of lipid bilayers and the mechanics of membrane environments.

Synthetic trehalose glycolipids confer desiccation resistance to supported lipid monolayers.

Lipid-derived desiccation resistance in membranes is a rare, unique ability previously observed only with trehalose dimycolate (TDM), an abundant mycobacterial glycolipid. Here we present the first synthetic trehalose glycolipids capable of providing desiccation protection to membranes of which they are constituents. The synthetic glycolipids consist of a simple trehalose disaccharide headgroup, similar to TDM, with hydrophobic tail groups of two 15- or 18-carbon chains. The synthetic trehalose glycolipids protected supported monolayers of phospholipids against dehydration even as minority components of the overall membrane, down to as little as 20 mol % trehalose glycolipid as assessed by assays of membrane fluidity. The dependence of the desiccation protection on the synthetic trehalose glycolipid fraction is nearly identical to that of TDM. The striking similarity of the desiccation resistance observed with TDM and the synthetic trehalose glycolipids, despite the variety of hydrophobic tail structures employed, suggests that interactions between the trehalose headgroup and surrounding molecules are the determining factor in dehydration protection.

Reflectance of human skin using colour photometric stereo: with particular application to pigmented lesion analysis.

BACKGROUND/PURPOSE: The optical appearance of human skin is highly dependent on the interaction between the illumination (type and position), observer position and the skin surface structure. Different currently available photographic techniques record different aspects of this appearance, each providing its own incomplete description. This limits their usefulness, especially for pigmented skin lesion diagnosis. In this paper a new, easy to use, low-cost photographic method is described,which aims to generate an efficiently encoded yet reasonably complete representation of skin appearance. MATERIAL AND METHODS: A prototype hand-held camera was developed that rapidly acquires six colour images, each with the skin illuminated from a different direction. A novel photometric stereo processing was used to combine these into a colour image of the skin's diffuse reflectance, independent of the skin surface topography, as well as a separate representation of that topography in the form of a surface gradient image. Images of four clinical pigmented skin lesions were evaluated in comparison with conventional digital photographs by both visual judgement and automated lesion boundary detection. RESULTS: The new colour reflectance images were free from the effects of topographical shading, shadowing and specular reflections. Lesion boundaries obtained automatically from the reflectance images were always closer to the outline drawn by a dermatologist than those obtained from conventional photographs. Finally, recombining the colour reflectance and surface gradient data to form a virtual image of the skin surface that is highly realistic in appearance. CONCLUSIONS: The new colour photometric stereo camera produces images of skin and skin tumours in which the reflectance information that is related to subsurface pigment distribution is separated from the surface topographic information. The total information generated by the system, for use in visual or automated analysis, is potentially greater than that for either conventional photography or dermatoscopy alone. Its further development and broader clinical evaluation are warranted to determine its usefulness and role in a wide range of dermatological tasks, including tele-dermatology applications.

The Mycobacterium tuberculosis virulence factor trehalose dimycolate imparts desiccation resistance to model mycobacterial membranes.

Mycobacteria, including persistent pathogens like Mycobacterium tuberculosis, have an unusual membrane structure in which, outside the plasma membrane, a nonfluid hydrophobic fatty acid layer supports a fluid monolayer rich in glycolipids such as trehalose 6,6'-dimycolate (TDM; cord factor). Given the abilities of mycobacteria to survive desiccation and trehalose in solution to protect biomolecules and whole organisms during freezing, drying, and other stresses, we hypothesized that TDM alone may suffice to confer dehydration resistance to the membranes of which it is a constituent. We devised an experimental model that mimics the structure of mycobacterial envelopes in which an immobile hydrophobic layer supports a TDM-rich, two-dimensionally fluid leaflet. We have found that TDM monolayers, in stark contrast to phospholipid membranes, can be dehydrated and rehydrated without loss of integrity, as assessed by fluidity and protein binding. Strikingly, this protection from dehydration extends to TDM-phospholipid mixtures with as little as 25 mol % TDM. The dependence of the recovery of membrane mobility upon rehydration on TDM fraction shows a functional form indicative of spatial percolation, implying that the connectivity of TDM plays a crucial role in membrane preservation. Our observations are the first reported instance of dehydration resistance provided by a membrane glycolipid.