Double-layered PLGA/HA microneedle systems as a long-acting formulation of polyphenols for effective and long-term management of atopic dermatitis.

Atopic dermatitis (AD) is a chronic, relapsing inflammatory disorder that requires long-term treatment to achieve optimal control. Topical corticosteroids or calcineurin inhibitors are the mainstay of treatment, but the safety and efficacy of their daily use remain a concern. Here, we report a double-layered poly(lactic-co-glycolic acid) (PLGA)/sodium hyaluronate (HA) microneedle (MN) patch as a long-acting formulation for sustained delivery of natural polyphenols, curcumin (CUR) and gallic acid (GA), into the inflamed skin. Upon insertion into the skin, the HA layer is rapidly dissolved within 5 min for triggering GA release; the PLGA tip is embedded into the dermis for sustained release of CUR for 2 months. Initially, CUR and GA are simultaneously released from the MNs to exert synergistic antioxidant and anti-inflammatory effects, thus promptly relieving AD symptoms. After the complete release of GA, the extended CUR release can maintain the improvement obtained for at least 56 days. Our results revealed that compared with the CUR-only MN and untreated AD groups, the administration of CUR/GA-loaded MNs not only rapidly reduced the dermatitis score from Day 2 but also significantly inhibited epidermal hyperplasia and mast cell accumulation, reduced serum IgE and histamine levels, and downregulated reactive oxygen species production in the skin lesions of Nc/Nga mice on Day 56. These findings demonstrated that the double-layered PLGA/HA MN patch can serve as an effective dual-polyphenol delivery system for rapid and long-term management of AD.

Polyphenol-assisted assembly of Au-deposited polylactic acid microneedles for SERS sensing and antibacterial photodynamic therapy.

3D SERS microneedles with self-assembled AuNPs were fabricated with tannic acid (chemical glue and reductant) on polylactic acid microneedles for in-depth chemical and biomolecular analysis, with LOD values below 200 ppb for small molecules and 102 CFU cm-2 for bacteria. The MB/Au-microneedles were used for photodynamic therapy with SERS-monitored photosensitizer degradation.

Peri-radiosurgical administration of bevacizumab improves radiographic response to single and fractionated stereotactic radiosurgery for large brain metastasis.

INTRODUCTION: Stereotactic radiosurgery (SRS) is a standard of care for brain metastases (BM) patients, yet large BM are at a greater risk for radionecrosis and local progression (LP). Concomitant bevacizumab and radiotherapy has been shown to improve outcomes in primary and metastatic brain tumors. This retrospective study investigated the efficacy and safety of concurrent bevacizumab and SRS for large BM. METHODS: From 2015 to 2019, patients with a BM diameter ≥ 2 cm who received either combination therapy (n = 49, SRS + BVZ group), or SRS alone (n = 73, SRS group) were enrolled. Bevacizumab was given peri-radiosurgically with a 2-week interval. Radiographic response was assessed using the RECIST version 1.1. Competing risk and logistic regression analysis were performed to evaluate prognostic factors. RESULTS: Radiographic response was achieved in 41 patients (84%) in the SRS + BVZ group and 37 patients (51%) in the SRS group (p = 0.001). In the multivariate regression analysis, concurrent bevacizumab was independently associated with a better radiographic response (p = 0.003). The cumulative incidences of LP and ≥ grade 2 radionecrosis at 12 months between the SRS + BVZ group and SRS group were 2% versus 6.8%, and 14.3% versus 14.6%, respectively. For patients with BM size ≥ 3 cm, the cumulative incidence of LP was significantly lower in the SRS + BVZ group (p = 0.03). No ≥ grade 4 toxicity was observed in either group. CONCLUSIONS: Concurrent bevacizumab and SRS for large BM is highly effective, with a better radiographic response and minimal excessive treatment-related toxicities. Peri-radiosurgical bevacizumab preferentially reduced the risk of LP, especially for BM size ≥ 3 cm.

Competing Risk Analysis of Outcomes of Unresectable Pancreatic Cancer Patients Undergoing Definitive Radiotherapy.

PURPOSE: We investigated potential factors, including clinicopathological features, treatment modalities, neutrophil-to-lymphocyte ratio (NLR), carbohydrate antigen (CA) 19-9 level, tumor responses correlating with overall survival (OS), local progression (LP), and distant metastases (DMs), in patients with locally advanced pancreatic cancer (LAPC) who received definitive radiotherapy (RT). METHODS: We retrospectively analyzed demographic characteristics; biologically effective doses (BED10, calculated with an α/ß of 10) of RT; and clinical outcomes of 57 unresectable LAPC (all pancreatic adenocarcinoma) patients receiving definitive RT using modern techniques with and without systemic therapy between January 2009 and March 2019 at our institution. We used Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 to evaluate the radiographic tumor response after RT. The association between prognostic factors and OS was assessed using the Kaplan-Meier analysis and a Cox regression model, whereas baseline characteristics and treatment details were collected for competing-risk regression of the association with LP and DM using the Fine-Gray model. RESULTS: A median BED10 of 67.1 Gy resulted in a disease control rate of 87.7%, and the median OS was 11.8 months after a median follow-up of 32.1 months. The 1-year OS rate, cumulative incidences of LP, and DM were 49.2%, 38.5%, and 62.9%, respectively. Multivariate analyses showed that pre-RT NLR ≥3.5 (adjusted hazard ratio [HR] = 8.245, p < 0.001), CA19-9 reduction rate ≥50% (adjusted HR = 0.261, p = 0.005), RT without concurrent chemoradiotherapy (adjusted HR = 5.903, p = 0.004), and administration of chemotherapy after RT (adjusted HR = 0.207, p = 0.03) were independent prognostic factors for OS. Positive lymph nodal metastases (adjusted subdistribution HR [sHR] = 3.712, p = 0.003) and higher tumor reduction after RT (adjusted sHR = 0.922, p < 0.001) were significant prognostic factors for LP, whereas BED10 ≥ 67.1 Gy (adjusted sHR = 0.297, p = 0.002), CA19-9 reduction rate ≥50% (adjusted sHR = 0.334, p = 0.023), and RT alone (adjusted sHR = 2.633, p = 0.047) were significant prognostic factors for DM. CONCLUSION: Our results indicate that pre-RT NLR and post-RT monitoring of CA19-9 and tumor size reduction can help identify whether patients belong to the good or poor prognostic group of LAPC. The incorporation of new systemic treatments during and after a higher BED10 RT dose for LAPC patients is warranted.

The importance of optimal ROIs delineation for FBPA-PET before BNCT.

One of the eligible criteria for patients to receive boron neutron capture therapy (BNCT) is based on the tumour-to-normal ratio (T/N) measured by FBPA-PET. However, there is no standard protocol for normal region-of-interested delineation. With comparison of contralateral cerebrum, our study revealed the consistency (p < 0.05) and high feasibility using the cerebellum as an alternative normal tissue baseline because of its homogeneous uptake. Following RECIST version 1.1, the standard-operating-procedure (SOP) for the BNCT fulfilled the expected tumour response and tumour shrinkage rate (p < 0.05). Our modified procedure can provide more precise information for BNCT within a reasonable time.

Role of BMI and age in predicting pathologic vertebral fractures in newly diagnosed multiple myeloma patients: A retrospective cohort study.

Vertebral fractures affect approximately 30% of myeloma patients and lead to a poor impact on survival and life quality. In general, age and body mass index (BMI) are reported to have an important role in vertebral fractures. However, the triangle relationship among age, BMI, and vertebral fractures is still unclear in newly diagnosed multiple myeloma (NDMM) patients. This study recruited consecutive 394 patients with NDMM at Taipei Veterans General Hospital between January 1, 2005 and December 31, 2015. Risk factors for vertebral fractures in NDMM patients were collected and analyzed. The survival curves were demonstrated using Kaplan-Meier estimate. In total, 301 (76.4%) NDMM patients were enrolled in the cohort. In the median follow-up period of 18.0 months, the median survival duration in those with vertebral fractures ≥ 2 was shorter than those with vertebral fracture < 2 (59.3 vs 28.6 months; P = 0.017). In multivariate Poisson regression, BMI < 18.5 kg/m2 declared increased vertebral fractures compared with BMI ≥ 24.0 kg/m2 (adjusted RR, 2.79; 95% CI, 1.44-5.43). In multivariable logistic regression, BMI < 18.5 kg/m2 was an independent risk factor for vertebral fractures ≥ 2 compared with BMI ≥ 24.0 kg/m2 (adjusted OR, 6.05; 95% CI, 2.43-15.08). Among age stratifications, patients with both old age and low BMI were at a greater risk suffering from increased vertebral fractures, especially in patients > 75 years and BMI < 18.5 kg/m2 (adjusted RR, 12.22; 95% CI, 3.02-49.40). This is the first study that demonstrated that age had a significant impact on vertebral fractures in NDMM patients with low BMI. Elder patients with low BMI should consider to routinely receive spinal radiographic examinations and regular follow-up.

Promoting self-assembly of collagen-related peptides into various higher-order structures by metal-histidine coordination.

Collagen is an important and widely used biomaterial and therapeutic. The construction of large-scale collagen structures via the self-assembly of small collagen-related peptides has been extensively studied in the past decade. Here, we report a highly effective and simple means to assemble small synthetic collagen-related peptides into various higher-order structures by utilizing metal-histidine coordination. In this work, two short collagen-related peptides in which histidine residues were incorporated as metal binding sites were designed and chemically synthesized: HG(PPG)(9)GH (X9) and HG(PPG)(4)(PHG)(PPG)(4)GH (PHG). Circular dichroism measurements indicated that these two peptides form only marginally stable collagen triple helices but that their stability can be increased upon the addition of metal ions. Dynamic light scattering analyses, turbidity measurements, TEM, and SEM results demonstrated the metal ion-dependent self-assembly of X9 and PHG into supramolecular structures ranging from various nanofibrils to microscale spherical, laminated, and granulated assemblies. The topology and size of these higher-order structures depends both on the metal ion identity and the location of the binding sites. Most intriguingly, the assembled fibrils show similar D-periodicity to that of natural collagen. Our results demonstrate that metal-histidine coordination can serve as an effective force to induce the self-assembly of unstable collagen-related peptides into higher-order structures.