ALBERT

Description: Langmuir DOI: 10.1021/acs.langmuir.5b02550

Description: The aims of this study were to compare the effectiveness of fluoride varnish and chlorhexidine gel in controlling white spot lesions (WSLs) adjacent to orthodontic brackets and to compare the ability of Quantitative Light-Induced Fluorescence (QLF) to measure mineral uptake with that of transverse microradiography (TMR). Thirty premolars with artificially induced WSLs were randomly assigned to three groups: (1) two applications of 5% NaF-varnish (F), with one-week interval, (2) two applications of 2% chlorhexidine gel (CHX), with one-week interval, and (3) control (CO), no treatment. QLF was used to measure changes in fluorescence before and after caries induction, 1 week after each application and 1, 2, and 3 months after the last application of F or CHX. TMR was performed to quantify lesion depth and mineral content after caries induction to evaluate the effects of F, CHX, and CO 3 months after the last application of agents. The data were analyzed by repeated measures ANOVA and Tukey’s test. All treatments increased the mineral content during the experimental period; however, F induced faster remineralization than CHX. The correlation between QLF and TMR was significantly moderate. Two applications of fluoride varnish or 2% chlorhexidine gel at one-week intervals were effective in controlling WSLs.

Description: Current strategies for the treatment of superficial non-melanoma skin cancer (NMSC) lesions include topical imoquimod, 5-fluorouracil, and photodynamic therapy. Although these treatments are effective, burning pain, blistering, and dermatitis have been reported as frequent side effects, making these therapies far from ideal. Plasmonic materials have been investigated for the induction of hyperthermia and use in cancer treatment. In this sense, the effectiveness of intratumorally and systemically injected gold nanorods (GnRs) in inducing cancer cell death upon near-infrared light irradiation has been confirmed. However, the in vivo long-term toxicity of these particles has not yet been fully documented. In the present manuscript, GnRs were included in a crosslinked polymeric film, evaluating their mechanical, swelling, and adhesion properties; moreover, their ability to heat up neonatal porcine skin (such as a skin model) upon irradiation was tested. Inclusion of GnRs into the films did not affect mechanical or swelling properties. GnRs were not released after film swelling, as they remained entrapped in the polymeric network; moreover, films did not adhere to porcine skin, altogether showing the enhanced biocompatibility of the material. GnR-loaded films were able to heat up the skin model over 40 °C, confirming the potential of this system for non-invasive local hyperthermia applications.

Description: The focus on novel systems for transdermal delivery of therapeutic agents has increased considerably over recent years, as this administration route comes with many advantages. Polymeric microarray patches (MAPs) are minimally invasive devices that enable systemic delivery of a wide range of drugs by overcoming the outer skin barrier. Conventionally, MAPs fabricated by micromoulding have a low needle density. In this study, the performance of hydrogel-forming MAPs cast using novel industrially manufactured micromoulds with a high needle density (600 needles/0.75 cm2) was compared to that of MAPs obtained using conventional moulds with a lower density (196 needles/0.89 cm2). Surrounding holders for micromoulds were designed for time-efficient fabrication of MAPs. The influence of needle densities on mechanical strength, insertion efficiency and in vitro permeation of ibuprofen sodium (IBU) was analysed. Insertion of both MAPs into an artificial skin model and neonatal porcine skin was comparable. No significant difference was observed in permeation studies of IBU (p 〉 0.05), with a delivery of 8.7 ± 1.7 mg for low-density and 9.5 ± 0.1 mg for high-density MAPs within 24 h. This highlights the potential of these novel micromoulds for manufacturing polymeric MAPs with a higher needle density for future applications.

Description: CD19-targeted chimeric antigen receptor (CAR)-T cell therapy is a novel treatment with promising results for patients with relapsed/refractory lymphoid malignancies. CAR-T cell therapy has known early toxicities of cytokine release syndrome (CRS) and neurotoxicity, but little is known about long-term neuropsychiatric adverse effects. We have utilized patient-reported outcomes (PROs), including PROMIS®measures, to assess outcomes of patients with relapse/refractory chronic lymphocytic leukemia (CLL), non-Hodgkin lymphoma (NHL), and acute lymphoblastic leukemia (ALL) who were treated with CD19-targeted CAR-T cells on a clinical trial in our institution (NCT01865617) and survived at least one year after treatment. Between October 2018 to February 2019, 52 patients (at their 1-5 year anniversary after CAR-T cell therapy) were sent a questionnaire. The questionnaire included the PROMIS Scale v1.2-Global Health and the PROMIS-29 Profile v2.1, as well as 30 additional questions, including questions pertaining to cognitive function. As of February 28, 2019, 40 questionnaires were returned (76.9% response rate) and were included in the analysis. Patients' characteristics are summarized in Table 1. Cognitive function was assessed by asking if patients had experienced difficulties with concentration, finding words, memory, or solving problems since their CAR-T cell therapy; answer "yes" to each of the questions received "1" point to determine the total cognitive difficulty score (0-4). PROMIS measures are standardized to a T-score metric, with a score of 50 representing the general US population mean. Clinically meaningful differences were defined as a 5-point difference in scores (1/2 standard deviation). The cohort's self-reported cognitive difficulties and PROMIS mean T scores are shown in Table 2. Mean T scores of PROMIS domains of Global Mental health, Global Physical Health, Social Function, anxiety, depression, fatigue, pain and sleep disturbance were not clinically meaningfully different from the mean in the general US population. However, 19 participants (47.5%) reported at least one cognitive difficulty and/or clinically meaningful depression and/or anxiety (Figure 1), and 7 participants (17.5%) scored ≤ 40 in Global Mental Health, indicating at least one standard deviation worse than the general population mean. On risk factor analysis, younger age was found to be associated with worse Global Mental Health (p=0.02), anxiety (p=0.01) and depression (p=0.01). Anxiety prior to CAR-T cell therapy was associated with increased likelihood of anxiety after CAR-T cell therapy (p=0.001). Multivariate analysis confirmed association between age and PROMIS Global Mental Health score (p=0.03). 15 participants (37.5%) reported cognitive difficulties post CAR-T cell therapy. On multivariate analysis, depression prior to CAR-T cell therapy was statistically significantly associated with higher likelihood of self-reported cognitive difficulties after CAR-T therapy (p=0.02) and there was a trend for association between acute neurotoxicity after CAR-T cell infusion and self-reported long-term cognitive difficulties (p=0.08). Having more cognitive difficulties was associated with worse Global Mental Health (p=0.0001) and worse Global Physical Health (p= 0.01). Similarly, worse scores for pain interference, sleep disturbance, fatigue, depression, anxiety, physical function, and social function were associated with more long-term self-reported cognitive difficulties (p=0.007,p=0.0003, p=0.00006, p=0.01, p=0.0007, p=0.003, p=0.0004 respectively). Our study demonstrates overall good neuropsychiatric outcomes in 40 long-term survivors after CAR-T cell therapy. However, despite good overall mean scores, nearly 50% of patients in the cohort reported at least one negative neuropsychiatric outcome (anxiety, depression or cognitive difficulty), and almost 20% scored at least one standard deviation lower than the general US population mean in Global Mental Health, indicating that there is a significant number of patients who would likely benefit from mental health services following CAR-T cell therapy. Younger age, anxiety and depression pre-CAR-T cell therapy, and acute neurotoxicity after CAR-T cell infusion may be risk factors for long-term neuropsychiatric problems in this patient population. Larger studies are needed to confirm these findings. Disclosures Shaw: Therakos: Other: Speaker Engagement. Lee:AstraZeneca: Research Funding; Incyte: Research Funding; Syndax: Research Funding; Amgen: Research Funding; Novartis: Research Funding; Takeda: Research Funding; Kadmon: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding. Turtle:T-CURX: Membership on an entity's Board of Directors or advisory committees; Kite/Gilead: Other: Ad hoc advisory board member; Caribou Biosciences: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Allogene: Other: Ad hoc advisory board member; Humanigen: Other: Ad hoc advisory board member; Juno Therapeutics: Patents & Royalties: Co-inventor with staff from Juno Therapeutics; pending, Research Funding; Nektar Therapeutics: Other: Ad hoc advisory board member, Research Funding; Precision Biosciences: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Eureka Therapeutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Novartis: Other: Ad hoc advisory board member. Maloney:Juno Therapeutics: Honoraria, Patents & Royalties: patients pending , Research Funding; A2 Biotherapeutics: Honoraria, Other: Stock options ; Celgene,Kite Pharma: Honoraria, Research Funding; BioLine RX, Gilead,Genentech,Novartis: Honoraria.

Description: Background: Adult T-cell leukemia/lymphoma (ATLL) is a rare disease described in Japan in 1977 and associated with human T-cell leukemia virus 1 (HTLV-1) infection. It is classified into four subgroups [1]: smoldering and chronic forms which are considered indolent and acute and lymphoma subtypes that present an aggressive behavior and short overall survival (OS) despite the treatment. Here, we describe an ATLL experience at a reference cancer treatment institution in Sao Paulo, Brazil. Methods: We retrospectively analyzed 29 ATLL patients who were attended from June/2006 to June/2015 at the Medicine School of Sao Paulo University, Brazil. ATLL was classified according to Shimoyama criteria [1] and Levine score [2] was used to estimate the probability of ATLL diagnosis. All patients were HTLV-1+. In the leukemic subtypes of ATLL, the neoplastic cells were CD3+/CD4+/CD8- or CD3+/CD4-/CD8- along with CD25+ and lack of CD7 expression. In the lymphoma type all patients showed a peripheral T cell lymphoma on their tissue biopsy. Statistical analysis was performed using GraphPad Prism Version 5.0 software. Results: Table 1 shows the clinical characteristics of patients on diagnosis. Acute ATLL was associated with higher Levine's score. The average age on diagnosis was 48.82 years old (18.69-74.26). Our data is in accordance with previous Brazilian studies that showed lower average age on diagnosis. This could be related to earlier infection, intrinsic characteristics of virus strains circulating in Americas or host immune particularities. There was confection with B hepatitis, C hepatitis and HIV in three, two and one case, respectively. Forty-five per cent of the patients had skin lesions and eight patients presented central nervous system disease (4 of acute ATLL). No patient had concomitant HTLV-I-Associated Myelopathy/Tropical Spastic Paraparesis. In our practice, smoldering ATLL was usually held in a watchfull-waiting approach. All six chronic ATLL patients were treated with interferon alpha and zidovudine (IFN+AZT) first-line. Progression-free survival (PFS) was 36.06 months and 12.4 months for smoldering and chronic subtypes, respectively. Acute and lymphoma subtypes had been treated with polichemotherapy, usually with CHOEP regimen (vincristine 1,4 mg/m2 i.v D1, doxorubicin 50mg/m2 i.v D1, cyclophosphamide 750mg/m2 i.v D1, etoposide 750 mg/m2 i.v D1, dexamethasone 20 mg i.v on day 1, prednisone 100 mg days 2 to 5) first-line. Overall average survival for lymphoma ATLL was 11.57 months, shorter than previous reports (average of 16 months, 86% treated with CHOP regimen [3]; survival of 19.7 months LSG15 protocol [4]). Eleven in 15 patients with acute ATLL had died after an average of 8.5 months (2.3 - 15.5) after the diagnosis. Overall survival for all subtypes was 15.17months (fig 1A), and 59.03; 44.47; 11.75 and 5.8 months (p= 0.0634) for smoldering, chronic, lymphoma and acute subtypes, respectively (fig 1B). Conclusion: We found an OS of 5.8 months for acute ATLL treated with chemotherapy as first-line, which is comparable to literature (average survival of 6 months [3]) but shorter than those patients treated with first-line IFN+AZT (average survival of 9 months [3]). In our setting it is still scarcely available trioxide arsenic and clinical trials for ATLL, and allogenic transplant related to mortality is still high. We are therefore changing our practice according to recent recommendations and aiming to treat leukemic ATLL first-line with higher tolerated doses of IFN+AZT to improve our survival curve. References 1. Shimoyama M. Diagnostic criteria and classification of clinical subtypes of adultT-cell leukaemia-lymphoma. A report from the Lymphoma Study Group (1984-87). Br J Haematol. 1991; 79(3):428-37. 2. Levine PH, et al. AdultT-cell leukemia/lymphoma: a working point-score classification for epidemiological studies. Int J Cancer. 1994; 59(4):491-3. 3. Bazarbachi A, et al. Meta-analysis on the use of zidovudine and interferon alfa in adult t cell leukemia/lymphoma showing improved survival in the leukemic subtypes. J Clin Oncol 2010; 28(27):4177-83. 4. Yamada Y, et al. A new gcsf supported combination chemotherapy LSG15, for adult T-Cell leukaemia -lymphoma: japan clinical oncology group study 9303. Br J Haematol 2001; 113(2):375-82. Table 1. Patient characteristics at diagnosis Table 1. Patient characteristics at diagnosis Figure 1. Overall survival for all casuistic (A) and for each subtype of ATLL patients (B). Figure 1. Overall survival for all casuistic (A) and for each subtype of ATLL patients (B). Disclosures No relevant conflicts of interest to declare.

Description: Recently two CD19-targeted CAR-T cell products were approved by the FDA for treatment of relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL) and non-Hodgkin lymphoma (NHL). Excellent anti-tumor activity has been observed in patients with B cell malignancies. However, data regarding long-term effects of this therapy are very limited. Here we report long-term effects in 59 patients (pts) with R/R NHL and chronic lymphocytic leukemia (CLL) who received a total of 85 CD19-targeted CAR-T cell infusions on a clinical trial in our institution (NCT01865617), survived more than a year, and had at least one year follow-up data after their first CAR-T cell infusion. One patient who survived more than a year was excluded from this report due to incomplete data. Median follow-up was 23 months (range, 13-57) after the first CAR-T cell infusion. We report adverse events that occurred or persisted beyond 90 days after the last CAR-T cell infusion, excluding events related to disease progression. Median age at CAR-T cell infusion was 60 years (range, 34-73). There were 42 (71%) pts with NHL and 17 (29%) with CLL. The median number of prior lines of treatment was 4 (range, 1-8). 23 (39%) pts had received prior autologous (auto) hematopoietic cell transplantation (HCT), and 9 (15%) pts had received prior allogeneic (allo) HCT. 35 (59%) pts received one CAR-T cell infusion, 22 (37%) pts received 2 infusions, and 2 (3%) pts received 3 infusions. 3 (5%) pts received a maximum cell dose of 2x10(5)/kg, 40 (68%) pts received a maximum cell dose of 2x10(6)/kg, and 16 (27%) pts received a maximum cell dose of 2x10(7)/kg. 65 (76%) infusions were preceded by cyclophosphamide and fludarabine. CRS grade I/II occurred in 38 (64%) pts, and grade III in 4 (7%) pts (graded per Lee et al. Blood, 2014). No grade IV CRS was reported in this cohort. Acute neurotoxicity occurred in 20 (34%) pts. At 2 months after CAR-T cell infusion complete response (CR) was documented in 34 (58%) pts, partial response (PR) in 12 (20%) pts, and disease progression (PD) in 13 (22%) pts. During the follow-up period, another 15 (25%) pts developed PD. 29 (49%) pts received salvage therapy after CAR-T cell infusion, 8 (14%) of them received allo HCT. 5 (8%) pts received allo HCT as consolidation after CAR-T cell. 5 of 25 (20%) pts who did not receive additional therapy after last CAR-T cell infusion experienced ongoing cytopenias requiring G-CSF support, or RBC or platelet transfusions, beyond 90 days after last CAR-T cells infusion. 8 (14%) pts were diagnosed with subsequent malignancies, including 3 (5%) myelodysplasia, 4 (7%) non-melanoma skin cancer, and 1 non-invasive bladder cancer. All, but 1 patient with skin cancer, had auto or allo HCT before CAR-T cell therapy. Neuropsychiatric disorders were documented in 5 (8%) pts; including major depression, suicidal attempt, myoclonic seizures, and TIA. 5 (8%) pts experienced cardiovascular events. 4 (7%) pts developed renal dysfunction. 3 (5%) pts developed respiratory disorders. One pt had gastrointestinal bleeding. Of the 9 pts who had undergone allo HCT before CAR-T cell therapy, 1 pt (11%) developed GVHD flare. Severe hypogammaglobulinemia (IgG 〈 400 mg/dL) or IgG replacement beyond day 90 after last CAR-T cell infusion (and before HCT if was done) were documented in 24 (41%) pts. 54 pts were included in the infection analysis. 178 suspected infection events beyond day 90 after last CAR-T cell infusion were documented in 40 (74%) pts. Antimicrobial treatments were documented for 124 infection events. 44 (25%) of the events were microbiologically proven. The most common infections were upper (92) and lower (29) respiratory tract infections. 25 (46%) pts required hospital admission due to infections, of them 8 (15%) were admitted to the ICU. When excluding infections that occurred after salvage therapy following CAR-T cell, we identified 117 infections in 28 (52%) pts. 3 pts died of non-relapse causes (2 due to infection after allo HCT, and 1 due to duodenal ulcer and gut perforation). In conclusion, our data suggest that long-term effects of CD19-targeted CAR-T cell therapy are acceptable. Most effects identified in our cohort were not severe, and many may have been related to prior or subsequent therapies (e.g. HCT before or after CAR-T cell therapy, or subsequent salvage treatments). Our data is consistent with recent published data demonstrating excellent long-term disease outcome for this heavily pre-treated population. Disclosures Turtle: Juno/Celgene: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Nektar Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Precision Biosciences: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Eureka Therapeutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Caribu Biosciences: Membership on an entity's Board of Directors or advisory committees. Maloney:Juno Therapeutics: Research Funding; GlaxoSmithKline: Research Funding; Janssen Scientific Affairs: Honoraria; Roche/Genentech: Honoraria; Seattle Genetics: Honoraria.