Innovative Topical Patches for Non-Melanoma Skin Cancer: Current Challenges and Key Formulation Considerations.

Non-melanoma skin cancer (NMSC) is the most prevalent malignancy worldwide, with approximately 6.3 million new cases worldwide in 2019. One of the key management strategies for NMSC is a topical treatment usually utilised for localised and early-stage disease owing to its non-invasive nature. However, the efficacy of topical agents is often hindered by poor drug penetration and patient adherence. Therefore, various research groups have employed advanced drug delivery systems, including topical patches to overcome the problem of conventional topical treatments. This review begins with an overview of NMSC as well as the current landscape of topical treatments for NMSC, specifically focusing on the emerging technology of topical patches. A detailed discussion of their potential to overcome the limitations of existing therapies will then follow. Most importantly, to the best of our knowledge, this work unprecedentedly combines and discusses all the current advancements in innovative topical patches for the treatment of NMSC. In addition to this, the authors present our insights into the key considerations and emerging trends in the construction of these advanced topical patches. This review is meant for researchers and clinicians to consider utilising advanced topical patch systems in research and clinical trials toward localised interventions of NMSC.

Development and Optimization of Imiquimod-Loaded Nanostructured Lipid Carriers Using a Hybrid Design of Experiments Approach.

Background: Imiquimod (IMQ) is an immunomodulating drug that is approved for the treatment of superficial basal cell carcinoma, actinic keratosis, external genital warts and perianal warts. However, IMQ cream (Aldara®) has several drawbacks including poor skin permeation, local toxicity, and compromised patient compliance as a topical pharmacological option. Methods: Our research aimed to develop and optimize nanostructured lipid carriers (NLCs) containing IMQ for the first time using a hybrid design of experiments approach. The optimized formulation was then incorporated into a matrix-type topical patch as an alternative dosage form for topical application and evaluated for IMQ deposition across different skin layers in comparison to the performance of the commercial product. Additionally, our work also attempted to highlight the possibility of implementing environment-friendly practices in our IMQ-NLCs formulation development by reviewing our analytical methods and experimental designs and reducing energy and solvent consumption where possible. Results: In this study, stearyl alcohol, oleic acid, Tween® 80 (polysorbate 80), and Gelucire® 50/13 (Stearoyl polyoxyl-32 glycerides) were selected for formulation development. The formulation was optimized using a 2k factorial design and a central composite design. The optimized formulation achieved the average particle size, polydispersity index, and zeta potential of 75.6 nm, 0.235, and - 30.9 mV, respectively. Subsequently, a matrix-type patch containing IMQ-NLCs was developed and achieved a statistically significant improvement in IMQ deposition in the deeper skin layers. The IMQ deposition from the patch into the dermis layer and receptor chamber was 3.3 ± 0.9 µg/cm2 and 12.3 ± 2.2 µg/cm2, while the commercial cream only deposited 1.0 ± 0.8 µg/cm2 and 1.5 ± 0.5 µg/cm2 of IMQ, respectively. Conclusion: In summary, IMQ-NLC-loaded patches represent great potential as a topical treatment option for skin cancer with improved patient compliance.

The effectiveness of various strategies to improve DNA analysis of formaldehyde-damaged tissues from embalmed cadavers for human identification purposes.

Formalin-fixed tissues provide the medical and forensic communities with alternative and often last resort sources of DNA for identification or diagnostic purposes. The DNA in these samples can be highly degraded and chemically damaged, making downstream genotyping using short tandem repeats (STRs) challenging. Therefore, the use of alternative genetic markers, methods that pre-amplify the low amount of good quality DNA present, or methods that repair the damaged DNA template may provide more probative genetic information. This study investigated whether whole genome amplification (WGA) and DNA repair could improve STR typing of formaldehyde-damaged (FD) tissues from embalmed cadavers. Additionally, comparative genotyping success using bi-allelic markers, including INDELs and SNPs, was explored. Calculated random match probabilities (RMPs) using traditional STRs, INDEL markers, and two next generation sequencing (NGS) panels were compared across all samples. Overall, results showed that neither WGA nor DNA repair substantially improved STR success rates from formalin-fixed tissue samples. However, when DNA from FD samples was genotyped using INDEL and SNP-based panels, the RMP of each sample was markedly lower than the RMPs calculated from partial STR profiles. Therefore, the results of this study suggest that rather than attempting to improve the quantity and quality of severely damaged and degraded DNA prior to STR typing, a more productive approach may be to target smaller amplicons to provide more discriminatory DNA identifications. Furthermore, an NGS panel with less loci may yield better results when examining FD samples, due to more optimized chemistries that result in greater allelic balance and amplicon coverage.

Comparison of neonatal outcomes with use of a soybean oil-based injectable lipid emulsion vs a 4-oil emulsion product.

PURPOSE: Results of a study comparing the safety and efficacy outcomes with use of a soybean oil-based injectable lipid emulsion (SO-ILE) vs a 4-oil alternative product in a neonatal population are presented. METHODS: In an institutional review board-approved, multicenter retrospective review, the medical records of 328 patients who were born at a gestational age of ≤34 weeks, had a birth weight of 500 to 2,000 g, were admitted to one of 2 neonatal intensive care units (NICUs) within a large health system, and received at least 7 days of a parenteral nutrition containing either lipid emulsion product were reviewed: 151 (46%) had received SO-ILE and 177 (54%) had received SMOFlipid (Fresenius Kabi). The primary outcome of the study was a composite of development of cholestasis and development of hypertriglyceridemia. Secondary outcomes included total duration of cholestasis treatment with ursodiol and change in body weight from initiation to completion of lipid emulsion treatment. RESULTS: The primary outcome of development of cholestasis or hypertriglyceridemia occurred in 14.6% of patients in the SO-ILE group and 18.1% of patients in the SMOFlipid group (P = 0.393). There were no statistically significant differences between the groups in total days of ursodiol treatment or average body weight change during the course of lipid emulsion treatment. CONCLUSION: In preterm neonates weighing 500 to 2,000 g, use of SMOFlipid did not significantly reduce the incidence of cholestasis or hypertriglyceridemia relative to the incidence with use of SO-ILE. Further research to validate these results is needed.

In situ spectroscopic identification of the six types of asbestos.

Exposure to asbestos fibres is related to a number of severe lung diseases, and therefore, rapid, accurate and reliable in situ or on-site asbestos detection in real-life samples is of considerable importance. This work presents a comprehensive investigation of all six types of asbestos by mid-infrared ATR-FTIR, NIR spectroscopy and Raman microspectroscopy. Our studies demonstrate that for practical applications, NIR spectroscopy is potentially the most powerful method for asbestos identification in materials utilised by the construction industry. By focusing on the narrow spectral region, 7300-7000 cm-1 (~1370-1430 nm, overtones of O‒H vibrations), which is highly specific to these materials, and optimising the sensitivity and resolution of the instrumentation, we have been able to discriminate and identify each of the six types of asbestos with the level of detection significantly better than 1 wt%. Furthermore, straightforward computational analysis has allowed for automated objective evaluation of the spectroscopic data.

Implementing a Clinic-Based Telehealth Support Service (FamilyStrong) for Family Caregivers of Individuals with Grade IV Brain Tumors.

Background: Nearly 3 million U.S. family caregivers support someone with cancer. However, oncology clinic-based service lines that proactively screen, assess, and support cancer caregivers are nearly nonexistent. Objective: To examine first-year experiences of a nurse-led clinic-based telehealth support service (FamilyStrong) for family caregivers of patients with recently diagnosed grade IV brain tumors. Methods: This is a retrospective evaluation of operational outcomes from initial implementation of the FamilyStrong Service, developed in partnership with Caregiver and Bereavement Support Services at the University of Alabama at Birmingham (UAB) and the UAB Center for Palliative and Supportive Care. From August 2018 to December 2019, 53 family caregivers were proactively identified and enrolled by a palliative care nurse, working approximately one day/week, who performed monthly caregiver distress thermometer screenings by phone and provided emotional, educational, problem-solving, and referral support. Results: Enrolled family caregivers were a mean age of 53.5 years and mostly female (62.3%), full- or part-time employed (67.9%), and the patient's spouse/partner (79.3%). Caregivers provided support 6.7 days/week for 11.2 hours/day. The palliative care nurse performed 235 distress screenings and provided support that included 68 documented instances of emotional, problem-solving, and educational support, 41 nurse-facilitated communications with the neuro-oncology team about patient issues, and 24 referrals to UAB and community services (e.g., counseling). The most common problems caregivers wanted assistance with included: managing their relative's health condition and symptoms (51%), coordinating care/services (21%), and planning for the future/advance care planning (17%). Discussion: The FamilyStrong Program is among the first "real world" oncology clinic-based formal support services for advance cancer family caregivers.

The natural history of vascular and other complications in patients treated with nilotinib for chronic myeloid leukemia.

Although second-generation tyrosine kinase inhibitors (TKIs) show superiority in achieving deep molecular responses in chronic myeloid leukemia in chronic phase (CML-CP) compared with imatinib, the differing adverse effect (AE) profiles need consideration when deciding the best drug for individual patients. Long-term data from randomized trials of nilotinib demonstrate an increased risk of vascular AEs (VAEs) compared with other TKIs, although the natural history of these events in response to dose modifications or cessation has not been fully characterized. We retrospectively reviewed the incidence of nilotinib-associated AEs in 220 patients with CML-CP at 17 Australian institutions. Overall, AEs of any grade were reported in 95 patients (43%) and prompted nilotinib cessation in 46 (21%). VAEs occurred in 26 patients (12%), with an incidence of 4.1 events per 100 patient-years. Multivariate analysis identified age (P = .022) and dyslipidemia (P = .007) as independent variables for their development. There was 1 fatal first VAE, whereas the remaining patients either continued nilotinib (14 patients) or stopped it immediately (11 patients). Recurrent VAEs were associated with ongoing therapy in 7 of 14 who continued (with 2 fatal VAEs) vs 1 of 11 who discontinued (P = .04). Nineteen of the 23 evaluable patients surviving a VAE ultimately stopped nilotinib, of whom 14 received an alternative TKI. Dose reduction or cessation because of VAEs did not adversely affect maintenance of major molecular response. These findings demonstrate that in contrast to other AEs, VAEs are ideally managed with nilotinib cessation because of the increased risk of additional events with its ongoing use.

Insight into imiquimod skin permeation and increased delivery using microneedle pre-treatment.

Basal cell carcinoma (BCC) is the most common skin cancer in humans. Topical treatment with imiquimod provides a non-invasive, self-administered treatment with relatively low treatment cost. Despite displaying excellent efficacy, imiquimod is only licensed by the FDA for superficial BCC. The current work employed HPLC and ToF-SIMS analysis to provide a novel assessment of imiquimod permeation from Aldara™ cream in skin depth and lateral distribution. Using Aldara™ cream and in vitro Franz cell studies with subsequent HPLC analysis, it is apparent that most of the topically applied imiquimod cream is left on the skin surface with more than 80% of the drug being recovered from skin wash. In addition, ToF-SIMS chemical imaging of recovered tape stripped skin samples illustrated significant detection of imiquimod signal over the entire skin area for the upper tape strips, whereas the deeper strips show large portions of the skin area without detected imiquimod. Given the limited permeation depth and non-uniform permeation observed at tape strips 6-18 when applied as a topical imiquimod cream, a permeation enhancement strategy utilising a skin pre-treatment with a microneedle device was investigated as a method to improve intradermal delivery. The recovered amount of imiquimod in tape strips and remaining skin determined by HPLC was approximately three times higher when Aldara™ was applied on microneedle pre-treated skin relative to intact skin. The ToF-SIMS ion images of the tape strips and cross-sections illustrated the existence of imiquimod in the microchannels which then laterally diffuses to peripheral epidermal strata. The current work demonstrates the first known attempt to enhance intradermal delivery of imiquimod using a microneedle device as well as underscoring the complementary role of ToF-SIMS analysis in chemically mapping imiquimod permeation into the skin with high sensitivity.

Multiparameter toxicity screening on a chip: Effects of UV radiation and titanium dioxide nanoparticles on HaCaT cells.

Microfluidic screening is gaining attention as an efficient method for evaluating nanomaterial toxicity. Here, we consider a multiparameter treatment where nanomaterials interact with cells in the presence of a secondary exposure (UV radiation). The microfluidic device contains channels that permit immobilization of HaCaT cells (human skin cell line), delivery of titanium dioxide nanoparticles (TNPs), and exposure to a known dose of UV radiation. The effect of single-parameter exposures (UV or TNP) was first studied as a benchmark, and then multiparameter toxicity (UV and TNP) at different concentrations was explored. The results demonstrate a concentration-dependent protective effect of TNP when exposed to UV irradiation.

Demonstration of the lack of cytotoxicity of unmodified and folic acid modified graphene oxide quantum dots, and their application to fluorescence lifetime imaging of HaCaT cells.

The authors describe the synthesis of water-soluble and fluorescent graphene oxide quantum dots via acid exfoliation of graphite nanoparticles. The resultant graphene oxide quantum dots (GoQDs) were then modified with folic acid. Folic acid receptors are overexpressed in cancer cells and hence can bind to functionalized graphene oxide quantum dots. On excitation at 305 nm, the GoQDs display green fluorescence with a peak wavelength at ~520 nm. The modified GoQDs are non-toxic to macrophage cells even after prolonged exposure and high concentrations. Fluorescence lifetime imaging and multiphoton microscopy was used (in combination) to image HeCaT cells exposed to GoQDs, resulting in a superior method for bioimaging. Graphical abstract Schematic representation of graphene oxide quantum dots, folic acid modified graphene oxide quantum dots (red), and the use of fluorescence lifetime to discriminate against green auto-fluorescence of HeCaT cells.

Novel Mutations Resulting in a Moderate to Severe Phenotypic Manifestation of Hemophilia A in a Female.

Hemophilia A is an X-linked, recessive disorder resulting from mutations in the f8 gene. Here we report the rare case of a female compound heterozygote with mild factor VIII deficiency (fVIII:C 9%) and moderate phenotype. On investigation she was confirmed to have normal Von Willebrand factor studies with a 46XY genotype. Further genetic testing revealed 3 mutations in the f8 gene: 1 novel missense mutation (c.6142T>G), 1 novel in-frame deletion (c.1281_1292del), and another missense mutation of unclear significance (c.3780C>G). Both parents had normal coagulation profiles; however, the 2 novel mutations were present in the patient's mother and the known missense mutation was present in her father. This unusual case demonstrates the utility in genetic analysis for f8 gene mutational analysis and suggests a compound effect of the 3 identified mutations as a cause for factor deficiency.

The incidence and natural history of dasatinib complications in the treatment of chronic myeloid leukemia.

Dasatinib has shown superiority over imatinib in achieving molecular responses (MRs) in chronic phase chronic myeloid leukemia but with a different toxicity profile, which may impact its overall benefit. Reported toxicities include pleural effusions and pulmonary hypertension, and although the incidence of these events is well described, response to therapy and impact of dose modifications on toxicity has not been comprehensively characterized in a real-world setting. We retrospectively reviewed the incidence of dasatinib adverse events in 212 chronic phase chronic myeloid leukemia patients at 17 Australian institutions. Adverse events were reported in 116 patients (55%), most commonly pleural effusions (53 patients, 25%), which was the predominant cause of permanent drug cessation. Age and dose were risk factors for pleural effusion (P < .01 and .047, respectively). Recurrence rates were higher in those who remained on 100 mg compared with those who dose reduced (P = .041); however, recurrence still occurred at 50 mg. Patients who developed pleural effusions were more likely to have achieved MR4.5 after 6 months of dasatinib than those without effusions (P = .008). Pulmonary hypertension occurred in 5% of patients, frequently in association with pleural effusion, and was reversible upon dasatinib cessation in 6 of 7 patients. Dose reductions and temporary cessations had minimal impact on MR rates. Our observations suggest that by using the lowest effective dose in older patients to minimize the effusion risk, dose modification for cytopenias, and care with concomitant antiplatelet therapy, the necessity for permanent dasatinib cessation due to toxicity is likely to be minimal in immunologically competent patients.