Nonsurgical treatment of skin cancer with local delivery of bioadhesive nanoparticles.

Keratinocyte-derived carcinomas, including squamous cell carcinoma (SCC), comprise the most common malignancies. Surgical excision is the therapeutic standard but is not always clinically feasible, and currently available alternatives are limited to superficial tumors. To address the need for a nonsurgical treatment for nodular skin cancers like SCC, we developed a bioadhesive nanoparticle (BNP) drug delivery system composed of biodegradable polymer, poly(lactic acid)-hyperbranched polyglycerol (PLA-HPG), encapsulating camptothecin (CPT). Nanoparticles (NPs) of PLA-HPG are nonadhesive NPs (NNPs), which are stealthy in their native state, but we have previously shown that conversion of the vicinal diols of HPG to aldehydes conferred NPs the ability to form strong covalent bonds with amine-rich surfaces. Herein, we show that these BNPs have significantly enhanced binding to SCC tumor cell surfaces and matrix proteins, thereby significantly enhancing the therapeutic efficacy of intratumoral drug delivery. Tumor injection of BNP-CPT resulted in tumor retention of CPT at ∼50% at 10 d postinjection, while CPT was undetectable in NNP-CPT or free (intralipid) CPT-injected tumors at that time. BNP-CPT also significantly reduced tumor burden, with a portion (∼20%) of BNP-CPT-treated established tumors showing histologic cure. Larger, more fully established PDV SCC tumors treated with a combination of BNP-CPT and immunostimulating CpG oligodeoxynucleotides exhibited enhanced survival relative to controls, revealing the potential for BNP delivery to be used along with local tumor immunotherapy. Taken together, these results indicate that percutaneous delivery of a chemotherapeutic agent via BNPs, with or without adjuvant immunostimulation, represents a viable, nonsurgical alternative for treating cutaneous malignancy.

Fusaric acid induces a notochord malformation in zebrafish via copper chelation.

Over a thousand extracts were tested for phenotypic effects in developing zebrafish embryos to identify bioactive molecules produced by endophytic fungi. One extract isolated from Fusarium sp., a widely distributed fungal genus found in soil and often associated with plants, induced an undulated notochord in developing zebrafish embryos. The active compound was isolated and identified as fusaric acid. Previous literature has shown this phenotype to be associated with copper chelation from the active site of lysyl oxidase, but the ability of fusaric acid to bind copper ions has not been well described. Isothermal titration calorimetry revealed that fusaric acid is a modest copper chelator with a binding constant of 4.4 × 10(5) M(-1). These results shed light on the toxicity of fusaric acid and the potential teratogenic effects of consuming plants infected with Fusarium sp.

Organizational culture in cardiovascular care in Chinese hospitals: a descriptive cross-sectional study.

BACKGROUND: Organizational learning, the process by which a group changes its behavior in response to newly acquired knowledge, is critical to outstanding organizational performance. In hospitals, strong organizational learning culture is linked with improved health outcomes for patients. This study characterizes the organizational learning culture of hospitals in China from the perspective of a cardiology service. METHODS: Using a modified Abbreviated Learning Organization Survey (27 questions), we characterized organizational learning culture in a nationally representative sample of 162 Chinese hospitals, selecting 2 individuals involved with cardiovascular care at each hospital. Responses were analyzed at the hospital level by calculating the average of the two responses to each question. Responses were categorized as positive if they were 5+ on a 7-point scale or 4+ on a 5-point scale. Univariate and multiple regression analyses were used to assess the relationship between selected hospital characteristics and perceptions of organizational learning culture. RESULTS: Of the 324 participants invited to take the survey, 316 responded (98 % response rate). Perceptions of organizational learning culture varied among items, among domains, and both among and within hospitals. Overall, the median proportion of positive responses was 82 % (interquartile range = 59 % to 93 %). "Training," "Performance Monitoring," and "Leadership that Reinforces Learning" were characterized as the most favorable domains, while "Time for Reflection" was the least favorable. Multiple regression analyses showed that region was the only factor significantly correlated with overall positive response rate. CONCLUSIONS: This nationally representative survey demonstrated variation in hospital organizational learning culture among hospitals in China. The variation was not substantially explained by hospital characteristics. Organizational learning culture domains with lower positive response rates reveal important areas for improvement.

Transparency and Dermatologic Device Approval by the US Food and Drug Administration.

Importance: The US Food and Drug Administration approves Class III medical devices via the premarket approval pathway, often requiring clinical data on safety and efficacy. Manufacturers can submit incremental device changes via supplemental applications, which are not subjected to such vetting measures and can cause understudied changes that lead to drift from a device's original design. Objectives: To characterize the postapproval changes to Class III dermatologic devices and to evaluate inconsistencies in the use of the premarket approval pathway. Design, Setting, and Participants: This study was a cross-sectional retrospective cohort analysis of a public US Food and Drug Administration database for premarket approval of devices. Included were dermatologic devices approved by the US Food and Drug Administration between January 1, 1980, and November 1, 2016, through the premarket pathway for device approval. Main Outcomes and Measures: Original devices were identified, and their supplements were characterized chronologically, by review track, and by modification category. Results: The 27 dermatologic devices studied consisted of 14 injectables, 11 photodynamic therapies, a dermal replacement matrix, and a diagnostic imaging instrument. Supplemental applications are increasingly used: the data-requiring panel-track pathway was the least common approach (2.8% [16 of 562 supplements]), while the 30-day track, which does not require clinical data, was most frequently used (42.5% [239 of 562 supplements]). Four devices (14.8%) underwent low-risk recalls (Class II or Class III), and 10 devices (37.0%) were voluntarily withdrawn. Conclusions and Relevance: As manufacturers make increasing use of supplemental applications, minor device changes may occur without supporting clinical data, which could pose a safety risk to patients.

Speed of Adoption of Immune Checkpoint Inhibitors of Programmed Cell Death 1 Protein and Comparison of Patient Ages in Clinical Practice vs Pivotal Clinical Trials.

Importance: The US Food and Drug Administration (FDA) is increasing its pace of approvals for novel cancer therapeutics, including for immune checkpoint inhibitors of programmed cell death 1 protein (anti-PD-1 agents). However, little is known about how quickly anti-PD-1 agents agents reach eligible patients in practice or whether such patients differ from those studied in clinical trials that lead to FDA approval (pivotal clinical trials). Objectives: To assess the speed with which anti-PD-1 agents agents reached eligible patients in practice and to compare the ages of patients treated in clinical practice with the ages of those treated in pivotal clinical trials. Design, Setting, and Participants: This retrospective cohort study, performed from January 1, 2011, through August 31, 2016, included patients from the Flatiron Health Network who were eligible for anti-PD-1 agents treatment of selected cancer types, which included melanoma, non-small cell lung cancer (NSCLC), and renal cell carcinoma (RCC). Main Outcomes and Measures: Cumulative proportions of eligible patients receiving anti-PD-1 agents treatment and their age distributions. Results: The study identified 3089 patients who were eligible for anti-PD-1 agents treatment (median age, 66 [interquartile range, 56-75] years for patients with melanoma, 66 [interquartile range, 58-72] years for patients with RCC, and 67 [interquartile range, 59-74] years for patients with NSCLC; 1742 male [56.4%] and 1347 [43.6%] female; 2066 [66.9%] white). Of these patients, 2123 (68.7%) received anti-PD-1 agents treatment, including 439 eligible patients with melanoma (79.1%), 1417 eligible patients with NSCLC (65.6%), and 267 eligible patients with RCC (71.2%). Within 4 months after FDA approval, greater than 60% of eligible patients in each cohort had received anti-PD-1 agents treatment. Overall, similar proportions of older and younger patients received anti-PD-1 agents treatment during the first 9 months after FDA approval. However, there were significant differences in age between clinical trial participants and patients receiving anti-PD-1 agents treatment in clinical practice, with more patients being older than 65 years in clinical practice (range, 327 of 1365 [60.6%] to 46 of 72 [63.9%]) than in pivotal clinical trials (range, 38 of 120 [31.7%] to 223 of 544 [41.0%]; all P < .001). Conclusions and Relevance: Anti-PD-1 agents rapidly reached patients in clinical practice, and patients treated in clinical practice differed significantly from patients treated in pivotal clinical trials. Future actions are needed to ensure that rapid adoption occurs on the basis of representative trial evidence.

Topical Corticosteroid Phobia in Atopic Dermatitis: A Systematic Review.

Importance: Topical corticosteroid (TCS) phobia refers to the negative feelings and beliefs related to TCSs experienced by patients and patients' caregivers. This phenomenon may be a major contributing factor in treatment failure in patients with atopic dermatitis, yet it has been sparsely described in the literature. Objective: To systematically assess the nomenclature, prevalence, origins, and effect on treatment adherence of TCS phobia in atopic dermatitis. Evidence Review: A literature search was conducted using specific eligibility criteria across electronic databases, including Ovid (MEDLINE, EMBASE), PubMed, and Web of Science, for articles published from January 1, 1946, to October 31, 2016. Included articles must have assessed TCS phobia in patients with atopic dermatitis or their caregivers. Quality ratings of studies were based on a modified version of the Oxford Centre for Evidence-Based Medicine quality rating scheme for individual studies. Findings: Of the 490 articles identified by literature search, 16 met the eligibility criteria. All studies were cross-sectional. Topical corticosteroid phobia prevalence ranged from 21.0% (95% CI, 15.8%-26.2%) to 83.7% (95% CI, 81.9%-85.5%). There was significant variation in how phobia was defined, ranging from concern to irrational fear. Questionnaires used to assess for TCS phobia included 1 to 69 questions. In the 2 studies that compared nonadherence between a phobia group and a nonphobia group, patients in both phobia groups were found to have a significantly higher rate of nonadherence (49.4% vs 14.1% and 29.3% vs 9.8%). The sources from which patients were receiving information about corticosteroids included physicians, friends and relatives, broadcast media, print media, and the internet. Conclusions and Relevance: Features of TCS phobia are commonly reported by patients across cultures and may be associated with a higher rate of nonadherence. Patients with TCS phobia and the sources from which patients are receiving information about corticosteroids may be targetable for intervention to increase adherence to treatment regimens. The nomenclature and assessment methods for TCS phobia used in studies, however, lack standardization, precluding quantitative comparison and extrapolation of data. Additional research, using standardized definitions and methods of assessment, is needed to better characterize this phenomenon and evaluate the efficacy of potential interventions.

Understanding the influence of patient demographics on disease severity, treatment strategy, and survival outcomes in merkel cell carcinoma: a surveillance, epidemiology, and end-results study.

OBJECTIVE: To identify trends in patient presentation and outcomes data that may guide the development of clinical algorithms on Merkel Cell Carcinoma (MCC). METHODS: We performed a retrospective cohort study searching in the National Cancer Institute's SEER registry for documented MCC cases from 1986-2013. No exclusion criteria were applied. We hereby identified 7,831 original MCC entries. Demographics, staging, and socioeconomic characteristics were identified and treatment modality likelihoods and survival data were calculated via logistic regression and Kaplan-Meier statistical modeling. RESULTS: Concerning tumor localization, 44.5% (n= 3,485) were located on the head and neck, and 47.8% were located on the trunk and extremities (n= 3,742). Male and younger patients are more likely to receive radiation than surgery with no differences seen among patient race. Caucasians and "Other" races both showed higher overall survival than African American patients. States with higher median household income levels demonstrated survival advantage. Income quartiles yielded no differences in surgical or radiotherapy interventions. Moreover, patients who forego radiotherapy had a poorer overall survival. LIMITATIONS: Generalizability of SEER data, potential intrinsic coding inconsistencies, and limited information on patient comorbidities, sentinel lymph node and surgical margin status are major limitations. There is no information regarding medical intervention such as systemic chemotherapy or immunotherapy. Recoding efforts are inconclusive regarding variables such as tumor infiltrating lymphocytes, mutations, or immunosuppression status, which are well-documented for other cancers within the database. CONCLUSION: MCC lesions of the head and neck region, lower income quartiles, and African American race are associated with higher mortality. MCC patients have a median household income that is significantly higher than national values with no significant difference in subsequent treatment modalities (surgery or radiotherapy) based on socioeconomic markers. A lack of radiotherapy is associated with higher mortality.

The skin as a window to the blood: Cutaneous manifestations of myeloid malignancies.

Cutaneous manifestations of myeloid malignancies are common and have a broad range of presentations. These skin findings are classified as specific, due to direct infiltration by malignant hematopoietic cells, or non-specific. Early recognition and diagnosis can have significant clinical implications, as skin manifestations may be the first indication of underlying hematologic malignancy, can reflect the immune status and stage of disease, and cutaneous reactions may occur from conventional and targeted agents used to treat myeloid disease. In addition, infections with cutaneous involvement are common in immunocompromised patients with myeloid disease. Given the varying presentations, dermatologic findings associated with myeloid malignancies can pose diagnostic challenges for hematologists and dermatologists. In this clinical review intended for the practicing hematologist/oncologist, we discuss the presentation, diagnosis, treatment, and prognostic value of the most common cutaneous manifestations associated with myeloid malignancies using illustrative macro- and microscopic figures and with a special emphasis on practical considerations.