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1.  Enhanced clinical-scale manufacturing of TCR transduced T-cells using closed culture system modules 
Genetic engineering of T-cells to express specific T cell receptors (TCR) has emerged as a novel strategy to treat various malignancies. More widespread utilization of these types of therapies has been somewhat constrained by the lack of closed culture processes capable of expanding sufficient numbers of T-cells for clinical application. Here, we evaluate a process for robust clinical grade manufacturing of TCR gene engineered T-cells.
TCRs that target human papillomavirus E6 and E7 were independently tested. A 21 day process was divided into a transduction phase (7 days) and a rapid expansion phase (14 days). This process was evaluated using two healthy donor samples and four samples obtained from patients with epithelial cancers.
The process resulted in ~ 2000-fold increase in viable nucleated cells and high transduction efficiencies (64–92%). At the end of culture, functional assays demonstrated that these cells were potent and specific in their ability to kill tumor cells bearing target and secrete large quantities of interferon and tumor necrosis factor. Both phases of culture were contained within closed or semi-closed modules, which include automated density gradient separation and cell culture bags for the first phase and closed GREX culture devices and wash/concentrate systems for the second phase.
Large-scale manufacturing using modular systems and semi-automated devices resulted in highly functional clinical-grade TCR transduced T-cells. This process is now in use in actively accruing clinical trials and the NIH Clinical Center and can be utilized at other cell therapy manufacturing sites that wish to scale-up and optimize their processing using closed systems.
PMCID: PMC5784598  PMID: 29368612
E6 HPV; E7 HPV; HPV-16+; T-cell receptor; Cellular therapy; Cancer immunotherapy; Cervical cancer; Epithelial cancer; T-cell manufacturing
2.  Barriers to treatment: describing them from a different perspective 
Poor adherence is the result of many barriers. Most of the adherence research has focused on the patients’ hurdles to adherence, instead of the responsibility the physician has for assuring adherence to treatment.
The purpose of this review is to identify barriers to medication adherence and refocus how we describe those barriers in terms of physician behavior hurdles.
PubMed was systematically searched for systematic reviews published between January 01, 2010, and December 06, 2017, that provided barriers to medication adherence. The searches were limited to reviews having adherence to medication prescribed in the outpatient setting as the main topic.
Thirty-one reviews were included in this review, covering 13 different disease categories. Fifty-eight different barriers to adherence to medications for chronic conditions were identified. Nineteen barriers were cited 6 or more times, and these were further categorized based on the World Health Organization’s 5 dimensions of adherence and the number of times cited.
This review provides clear evidence that adherence to medication is affected by multiple barriers. To facilitate this, adherence barriers can be framed as physician/health system hurdles. With that focus in mind, we may put the responsibility where we have the most control.
PMCID: PMC5775743
medication adherence; patient compliance; medication non-compliance; patient acceptance of health care
3.  Inhibition of AKT signaling uncouples T cell differentiation from expansion for receptor-engineered adoptive immunotherapy 
JCI Insight  null;2(23):e95103.
Adoptive immunotherapies using T cells genetically redirected with a chimeric antigen receptor (CAR) or T cell receptor (TCR) are entering mainstream clinical practice. Despite encouraging results, some patients do not respond to current therapies. In part, this phenomenon has been associated with infusion of reduced numbers of early memory T cells. Herein, we report that AKT signaling inhibition is compatible with CAR and TCR retroviral transduction of human T cells while promoting a CD62L-expressing central memory phenotype. Critically, this intervention did not compromise cell yield. Mechanistically, disruption of AKT signaling preserved MAPK activation and promoted the intranuclear localization of FOXO1, a transcriptional regulator of T cell memory. Consequently, AKT signaling inhibition synchronized the transcriptional profile for FOXO1-dependent target genes across multiple donors. Expression of an AKT-resistant FOXO1 mutant phenocopied the influence of AKT signaling inhibition, while addition of AKT signaling inhibition to T cells expressing mutant FOXO1 failed to further augment the frequency of CD62L-expressing cells. Finally, treatment of established B cell acute lymphoblastic leukemia was superior using anti-CD19 CAR–modified T cells transduced and expanded in the presence of an AKT inhibitor compared with conventionally grown T cells. Thus, inhibition of signaling along the PI3K/AKT axis represents a generalizable strategy to generate large numbers of receptor-modified T cells with an early memory phenotype and superior antitumor efficacy.
T-cell expansion and differentiation can be pharmacologically uncoupled with an AKT inhibitor which promotes FOXO1-dependent memory formation and enhances in vivo antitumor efficacy.
PMCID: PMC5752304  PMID: 29212954
Immunology; Oncology; Cancer gene therapy; Cancer immunotherapy; Cellular immune response
4.  Calcipotriene/betamethasone dipropionate for the treatment of psoriasis vulgaris: an evidence-based review 
While topical medications remain the cornerstone of the psoriasis treatment paradigm, they also come with the risk of multiple side effects. An alternative topical treatment option, calcipotriene or calcipotriol, is a vitamin D derivative that is thought to work by inhibiting keratinocyte proliferation and enhancing keratinocyte differentiation. Multiple studies have demonstrated its efficacy and safety in improving psoriasis when used in combination with topical corticosteroids. Given the effectiveness and side effect profile seen with this combination of topical steroid and calcipotriene, the US Food and Drug Administration approved a calcipotriene/betamethasone dipropionate product for use in psoriasis patients over the age of 12 in 2006. Our paper seeks to review clinical trial evidence of this combination medication and its use in the treatment of psoriasis vulgaris. While assessment of available evidence indicates that the topical medication is both safe and effective for the treatment of psoriasis vulgaris, addressing limitations of what is known, such as tolerability, adherence, and patient preference, of this combination drug in future high-impact studies is needed.
PMCID: PMC5628677
calcipotriene; betamethasone diproprionate; psoriasis; topical treatment; steroids; vitamin D
5.  A Review of the Use of Secukinumab for Psoriatic Arthritis 
Rheumatology and Therapy  2017;4(2):233-246.
Psoriatic arthritis (PsA) is a chronic, seronegative spondyloarthropathy associated with psoriasis (PsO). Treatment options range from non-pharmacologic measures to NSAIDS, DMARDs, and biologics, depending on patient presentation. Secukinumab (Cosentyx©) is a new biologic treatment option that was approved for use in treating adult patients with PsA in October 2016. Our paper explores the clinical trial evidence available for secukinumab to examine its safety and efficacy as a therapeutic agent for the treatment of PsA. While indirect comparisons of indicate that secukinumab is as effective as other treatment options, further studies directly comparing available treatments will be necessary to establish its place in treatment guidelines. As these and other trials are conducted, the evidence produced will further elucidate the clinical potential of secukinumab as a treatment option for patients with rheumatologic disease.
PMCID: PMC5696288  PMID: 28849401
Biologics; IL-17; Psoriatic arthritis; Psoriasis; Rheumatology; Secukinumab
6.  Accountability: a missing construct in models of adherence behavior and in clinical practice 
Patient preference and adherence  2017;11:1285-1294.
Piano lessons, weekly laboratory meetings, and visits to health care providers have in common an accountability that encourages people to follow a specified course of action. The accountability inherent in the social interaction between a patient and a health care provider affects patients’ motivation to adhere to treatment. Nevertheless, accountability is a concept not found in adherence models, and is rarely employed in typical medical practice, where patients may be prescribed a treatment and not seen again until a return appointment 8–12 weeks later. The purpose of this paper is to describe the concept of accountability and to incorporate accountability into an existing adherence model framework. Based on the Self-Determination Theory, accountability can be considered in a spectrum from a paternalistic use of duress to comply with instructions (controlled accountability) to patients’ autonomous internal desire to please a respected health care provider (autonomous accountability), the latter expected to best enhance long-term adherence behavior. Existing adherence models were reviewed with a panel of experts, and an accountability construct was incorporated into a modified version of Bandura’s Social Cognitive Theory. Defining accountability and incorporating it into an adherence model will facilitate the development of measures of accountability as well as the testing and refinement of adherence interventions that make use of this critical determinant of human behavior.
PMCID: PMC5536091
autonomous accountability; controlled accountability; duress; health promotion; Self-Determination Theory; shame; Social Cognitive Theory; volition
7.  Spotlight on brimonidine topical gel 0.33% for facial erythema of rosacea: safety, efficacy, and patient acceptability 
Patient preference and adherence  2017;11:1143-1150.
Brimonidine tartrate is a highly selective alpha 2 agonist that induces direct vasoconstriction of small arteries and veins, thereby reducing vasodilation and edema.
To review the current literature regarding the safety, efficacy, and patient acceptability of brimonidine 0.33% gel.
A PubMed search was performed using the terms brimonidine 0.33% gel, rosacea, safety, efficacy, and acceptability. Peer-reviewed clinical trials and case reports from 2012 to 2016 were screened for inclusion of safety, efficacy, and/or patient acceptability data.
Brimonidine topical gel 0.33% is associated with mild, transient skin-related adverse reactions. Efficacy may be achieved within 30 minutes of administration with maximal reductions in erythema 3–6 hours after administration. Patient satisfaction with use of brimonidine topical gel is superior to vehicle gel for facial appearance, treatment effect, facial redness, and daily control of facial redness.
Studies were typically limited to 1-year follow-up. Only one study has examined the use of brimonidine topical gel in combination with other rosacea and acne medications.
Brimonidine topical gel 0.33% is a safe, effective, and patient-accepted treatment for facial erythema of rosacea.
PMCID: PMC5505675
patient satisfaction; adverse reactions; side effects
8.  Antitumor Activity of BRAF Inhibitor and IFNα Combination in BRAF-Mutant Melanoma 
BRAFV600E-mediated MAPK pathway activation is associated in melanoma cells with IFNAR1 downregulation. IFNAR1 regulates melanoma cell sensitivity to IFNα, a cytokine used for the adjuvant treatment of melanoma. These findings and the limited therapeutic efficacy of BRAF-I prompted us to examine whether the efficacy of IFNα therapy of BRAFV600E melanoma can be increased by its combination with BRAF-I.
BRAF/NRAS genotype, ERK activation, IFNAR1, and HLA class I expression were tested in 60 primary melanoma tumors from treatment-naive patients. The effect of BRAF-I on IFNAR1 expression was assessed in three melanoma cell lines and in four biopsies of BRAFV600E metastases. The antiproliferative, pro-apoptotic and immunomodulatory activity of BRAF-I and IFNα combination was tested in vitro and in vivo utilizing three melanoma cell lines, HLA class I-MA peptide complex-specific T-cells and immunodeficient mice (5 per group for survival and 10 per group for tumor growth inhibition). All statistical tests were two-sided. Differences were considered statistically significant when the P value was less than .05.
The IFNAR1 level was statistically significantly (P < .001) lower in BRAFV600E primary melanoma tumors than in BRAF wild-type tumors. IFNAR1 downregulation was reversed by BRAF-I treatment in the three melanoma cell lines (P ≤ .02) and in three out of four metastases. The IFNAR1 level in the melanoma tumors analyzed was increased as early as 10 to 14 days following the beginning of the treatment. These changes were associated with: 1) an increased susceptibility in vitro of melanoma cells to the antiproliferative (P ≤ .04), pro-apoptotic (P ≤ .009) and immunomodulatory activity, including upregulation of HLA class I antigen APM component (P ≤ .04) and MA expression as well as recognition by cognate T-cells (P < .001), of BRAF-I and IFNα combination and 2) an increased survival (P < .001) and inhibition of tumor growth of melanoma cells (P < .001) in vivo by BRAF-I and IFNα combination.
The described results provide a strong rationale for the clinical trials implemented in BRAFV600E melanoma patients with BRAF-I and IFNα combination.
PMCID: PMC4948304  PMID: 26851802
9.  Isolation and characterization of an HLA-DPB1*04:01-restricted MAGE-A3 T cell receptor for cancer immunotherapy 
Long-term tumor regressions have been observed in patients following the adoptive transfer of autologous tumor infiltrating lymphocytes (TILs) or genetically-modified T cells expressing MHC class I-restricted T cell receptors (TCRs), but clinical trials have not evaluated responses to genetically-modified T cells expressing anti-tumor MHC class II-restricted TCRs. Since studies carried out in a murine tumor model system have demonstrated that the adoptive transfer of CD4+ T cells could lead to the regression of established tumors, we plan to test the hypothesis that CD4+ T cells can also induce tumor regressions in cancer patients. In this study, two MAGE-A3-specific TCRs were isolated from a regulatory T cell clone (6F9) and an effector clone (R12C9), generated from the peripheral blood of two melanoma patients after MAGE-A3 vaccination. The results indicated that T cells transduced with 6F9 TCR mediated stronger effector functions than R12C9 TCR. The 6F9 TCR specifically recognized MAGE-A3 and the closely related MAGE-A6 gene product, but not other members of the MAGE-A family in the context of HLA-DPB1*04:01. To test the feasibility of a potential clinical trial using this TCR, a clinical-scale procedure was developed to obtain a large number of purified CD4+ T cells transduced with 6F9 TCR. Because HLA-DPB1*04:01 is present in ~60% of the Caucasian population and MAGE-A3 is frequently expressed in a variety of cancer types, this TCR immunotherapy could potentially be applicable for a significant portion of cancer patients.
PMCID: PMC4947411  PMID: 27163739
10.  Economic burden of comorbidities in psoriasis patients in the United States: results from a retrospective U.S. database 
Psoriasis is a multifactorial, inflammatory, skin disease associated with various comorbidities. The cost of those comorbidities is not well characterized. The present study assesses the incremental burden of comorbidities on healthcare resource utilization, direct costs and indirect costs associated with short-term disabilities among patients with psoriasis in the United States.
A retrospective, U.S. cohort analysis was conducted using a large claims database. Adult psoriasis patients with at least two diagnoses of psoriasis during the years 2010 and 2011 (one psoriasis diagnosis had to happen in the year 2010) and with continuous enrollment of medical and pharmacy benefits in the years 2010 and 2011 were included. Psoriasis patients were categorized and compared according to the presence or absence of pre-selected comorbidities in the year 2010. Adjusted annual direct (costs associated with outpatient, emergency room, and inpatient claims, and outpatient pharmacy claims) and indirect costs (short-term disabilities) was assessed in patients with and without comorbidities using a regression analysis, controlling for age, gender, and psoriasis severity in year 2010.
In total, 56,406 patients (mean [SD]) age, 51.6 [14.6] years) were included in the analysis. The most prevalent comorbidities were hypertension (34.3%), hyperlipidemia (33.5%), cardiovascular disease (17.7%), diabetes (14.2%), and psoriatic arthritis (9.9%). Psoriasis patients with comorbidities used more healthcare resources than those without comorbidities. The incidence rate ratio (IRR) (95% CI) for patients with cardiovascular disease was 1.5 (1.4 − 1.5) for outpatient visits, 2.6 (2.4 − 2.8) for hospitalizations, and 2.3 (2.2 − 2.5) for ER visits, showing higher IRRs across all three types of resource use. The mean annual adjusted direct cost differences (i.e., incremental adjusted costs) in psoriasis patients with and without comorbidities were $9914.3, $8386.5, and $8275.1 for psoriatic arthritis, peripheral vascular disease, and cardiovascular disease, respectively. The mean annual incremental adjusted indirect costs of short-term disabilities were $1333, $1195, $994.9, and $996.6 for cerebrovascular disease, obesity, peripheral vascular disease, and depression, respectively.
The presence of comorbidities was associated with higher healthcare resource utilization and costs among patients with psoriasis.
PMCID: PMC5422993  PMID: 28482887
Psoriasis; Costs; Comorbidities
11.  Allogeneic T Cells That Express an Anti-CD19 Chimeric Antigen Receptor Induce Remissions of B-Cell Malignancies That Progress After Allogeneic Hematopoietic Stem-Cell Transplantation Without Causing Graft-Versus-Host Disease 
Journal of Clinical Oncology  2016;34(10):1112-1121.
Progressive malignancy is the leading cause of death after allogeneic hematopoietic stem-cell transplantation (alloHSCT). After alloHSCT, B-cell malignancies often are treated with unmanipulated donor lymphocyte infusions (DLIs) from the transplant donor. DLIs frequently are not effective at eradicating malignancy and often cause graft-versus-host disease, a potentially lethal immune response against normal recipient tissues.
We conducted a clinical trial of allogeneic T cells genetically engineered to express a chimeric antigen receptor (CAR) targeting the B-cell antigen CD19. Patients with B-cell malignancies that had progressed after alloHSCT received a single infusion of CAR T cells. No chemotherapy or other therapies were administered. The T cells were obtained from each recipient’s alloHSCT donor.
Eight of 20 treated patients obtained remission, which included six complete remissions (CRs) and two partial remissions. The response rate was highest for acute lymphoblastic leukemia, with four of five patients obtaining minimal residual disease–negative CR. Responses also occurred in chronic lymphocytic leukemia and lymphoma. The longest ongoing CR was more than 30 months in a patient with chronic lymphocytic leukemia. New-onset acute graft-versus-host disease after CAR T-cell infusion developed in none of the patients. Toxicities included fever, tachycardia, and hypotension. Peak blood CAR T-cell levels were higher in patients who obtained remissions than in those who did not. Programmed cell death protein-1 expression was significantly elevated on CAR T cells after infusion. Presence of blood B cells before CAR T-cell infusion was associated with higher postinfusion CAR T-cell levels.
Allogeneic anti-CD19 CAR T cells can effectively treat B-cell malignancies that progress after alloHSCT. The findings point toward a future when antigen-specific T-cell therapies will play a central role in alloHSCT.
PMCID: PMC4872017  PMID: 26811520
12.  Ethical considerations in adherence research 
Patient preference and adherence  2016;10:2429-2435.
Poor adherence to treatment is a common cause of medical treatment failure. Studying adherence is complicated by the potential for the study environment to impact adherence behavior. Studies performed without informing patients about adherence monitoring must balance the risks of deception against the potential benefits of the knowledge to be gained. Ethically monitoring a patient’s adherence to a treatment plan without full disclosure of the monitoring plan requires protecting the patient’s rights and upholding the fiduciary obligations of the investigator. Adherence monitoring can utilize different levels of deception varying from stealth monitoring, debriefing after the study while informing the subject that some information had been withheld in regard to the use of adherence monitoring (withholding), informed consent that discloses some form of adherence monitoring is being used and will be disclosed at the end of the study (authorized deception), and full disclosure. Different approaches offer different benefits and potential pitfalls. The approach used must balance the risk of nondisclosure against the potential for confounding the adherence monitoring data and the potential benefits that adherence monitoring data will have for the research subjects and/or other populations. This commentary aims to define various methods of adherence monitoring and to provide a discussion of the ethical considerations that accompany the use of each method and adherence monitoring in general as it is used in clinical research.
Video abstract
PMCID: PMC5147396  PMID: 27980394
compliance; stealth monitoring; deception; adherence monitoring
13.  The Challenge of Managing Psoriasis: Unmet Medical Needs and Stakeholder Perspectives 
American Health & Drug Benefits  2016;9(9):504-513.
Psoriasis is a debilitating chronic inflammatory autoimmune disease affecting approximately 7.4 million adults in the United States. Plaque psoriasis is the most common form, affecting 80% to 90% of patients.
To describe the impact and challenges that psoriasis presents for various stakeholders, and to provide nondermatologist healthcare decision makers with information to enhance their contributions to drug and pharmacy benefit design discussions.
Psoriasis carries an increased risk for early mortality and an increased prevalence of comorbidities, including psoriatic arthritis, cardiovascular disease, and diabetes. It is also associated with anxiety, depression, and social isolation, and can negatively impact patients' relationships, productivity, and careers. The physical, psychologic, social, and economic impact of psoriasis, plus the associated stigma, result in cumulative impairment over a patient's lifetime. The current treatments for moderate-to-severe psoriasis include topical therapy, phototherapy, and systemic drugs (nonbiologic and biologic); however, patient satisfaction remains low, combination therapy and treatment switching are common, and many patients remain untreated or undertreated. Clinicians should consider the patient holistically, and should select treatment based on a range of factors, including disease severity (with physical and psychosocial manifestations), susceptibility to cumulative life-course impairment (considering personality, behavior, and cognition), comorbidities, concomitant medication, and patient preference. It is estimated that the total annual direct cost of treating psoriasis in the United States in 2015 exceeded $12.2 billion.
Psoriasis is a complex disease, and appropriate management is correspondingly complex. Newer psoriasis treatments provide improved efficacy and safety versus traditional treatments, but challenges remain in ensuring patients access to these medications. An improved understanding of the barriers to appropriate treatment is needed, as well as clear and accessible information for payers and clinicians on current treatment options, to ensure that decision makers can control costs while providing patients with optimal care.
PMCID: PMC5394561
chronic disease; cost; disease burden; disease management; healthcare decision makers; plaque psoriasis; psoriasis; treatment; unmet medical needs
14.  31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016): part one 
Lundqvist, Andreas | van Hoef, Vincent | Zhang, Xiaonan | Wennerberg, Erik | Lorent, Julie | Witt, Kristina | Sanz, Laia Masvidal | Liang, Shuo | Murray, Shannon | Larsson, Ola | Kiessling, Rolf | Mao, Yumeng | Sidhom, John-William | Bessell, Catherine A. | Havel, Jonathan | Schneck, Jonathan | Chan, Timothy A. | Sachsenmeier, Eliot | Woods, David | Berglund, Anders | Ramakrishnan, Rupal | Sodre, Andressa | Weber, Jeffrey | Zappasodi, Roberta | Li, Yanyun | Qi, Jingjing | Wong, Philip | Sirard, Cynthia | Postow, Michael | Newman, Walter | Koon, Henry | Velcheti, Vamsidhar | Callahan, Margaret K. | Wolchok, Jedd D. | Merghoub, Taha | Lum, Lawrence G. | Choi, Minsig | Thakur, Archana | Deol, Abhinav | Dyson, Gregory | Shields, Anthony | Haymaker, Cara | Uemura, Marc | Murthy, Ravi | James, Marihella | Wang, Daqing | Brevard, Julie | Monaghan, Catherine | Swann, Suzanne | Geib, James | Cornfeld, Mark | Chunduru, Srinivas | Agrawal, Sudhir | Yee, Cassian | Wargo, Jennifer | Patel, Sapna P. | Amaria, Rodabe | Tawbi, Hussein | Glitza, Isabella | Woodman, Scott | Hwu, Wen-Jen | Davies, Michael A. | Hwu, Patrick | Overwijk, Willem W. | Bernatchez, Chantale | Diab, Adi | Massarelli, Erminia | Segal, Neil H. | Ribrag, Vincent | Melero, Ignacio | Gangadhar, Tara C. | Urba, Walter | Schadendorf, Dirk | Ferris, Robert L. | Houot, Roch | Morschhauser, Franck | Logan, Theodore | Luke, Jason J. | Sharfman, William | Barlesi, Fabrice | Ott, Patrick A. | Mansi, Laura | Kummar, Shivaani | Salles, Gilles | Carpio, Cecilia | Meier, Roland | Krishnan, Suba | McDonald, Dan | Maurer, Matthew | Gu, Xuemin | Neely, Jaclyn | Suryawanshi, Satyendra | Levy, Ronald | Khushalani, Nikhil | Wu, Jennifer | Zhang, Jinyu | Basher, Fahmin | Rubinstein, Mark | Bucsek, Mark | Qiao, Guanxi | MacDonald, Cameron | Hylander, Bonnie | Repasky, Elizabeth | Chatterjee, Shilpak | Daenthanasanmak, Anusara | Chakraborty, Paramita | Toth, Kyle | Meek, Megan | Garrett-Mayer, Elizabeth | Nishimura, Michael | Paulos, Chrystal | Beeson, Craig | Yu, Xuezhong | Mehrotra, Shikhar | Zhao, Fei | Evans, Kathy | Xiao, Christine | Holtzhausen, Alisha | Hanks, Brent A. | Scharping, Nicole | Menk, Ashley V. | Moreci, Rebecca | Whetstone, Ryan | Dadey, Rebekah | Watkins, Simon | Ferris, Robert | Delgoffe, Greg M. | Peled, Jonathan | Devlin, Sean | Staffas, Anna | Lumish, Melissa | Rodriguez, Kori Porosnicu | Ahr, Katya | Perales, Miguel | Giralt, Sergio | Taur, Ying | Pamer, Eric | van den Brink, Marcel R. M. | Jenq, Robert | Annels, Nicola | Pandha, Hardev | Simpson, Guy | Mostafid, Hugh | Harrington, Kevin | Melcher, Alan | Grose, Mark | Davies, Bronwyn | Au, Gough | Karpathy, Roberta | Shafren, Darren | Ricca, Jacob | Merghoub, Taha | Wolchok, Jedd D. | Zamarin, Dmitriy | Batista, Luciana | Marliot, Florence | Vasaturo, Angela | Carpentier, Sabrina | Poggionovo, Cécile | Frayssinet, Véronique | Fieschi, Jacques | Van den Eynde, Marc | Pagès, Franck | Galon, Jérôme | Hermitte, Fabienne | Smith, Sean G. | Nguyen, Khue | Ravindranathan, Sruthi | Koppolu, Bhanu | Zaharoff, David | Schvartsman, Gustavo | Bassett, Roland | McQuade, Jennifer L. | Haydu, Lauren E. | Davies, Michael A. | Tawbi, Hussein | Glitza, Isabella | Kline, Douglas | Chen, Xiufen | Fosco, Dominick | Kline, Justin | Overacre, Abigail | Chikina, Maria | Brunazzi, Erin | Shayan, Gulidanna | Horne, William | Kolls, Jay | Ferris, Robert L. | Delgoffe, Greg M. | Bruno, Tullia C. | Workman, Creg | Vignali, Dario | Adusumilli, Prasad S. | Ansa-Addo, Ephraim A | Li, Zihai | Gerry, Andrew | Sanderson, Joseph P. | Howe, Karen | Docta, Roslin | Gao, Qian | Bagg, Eleanor A. L. | Tribble, Nicholas | Maroto, Miguel | Betts, Gareth | Bath, Natalie | Melchiori, Luca | Lowther, Daniel E. | Ramachandran, Indu | Kari, Gabor | Basu, Samik | Binder-Scholl, Gwendolyn | Chagin, Karen | Pandite, Lini | Holdich, Tom | Amado, Rafael | Zhang, Hua | Glod, John | Bernstein, Donna | Jakobsen, Bent | Mackall, Crystal | Wong, Ryan | Silk, Jonathan D. | Adams, Katherine | Hamilton, Garth | Bennett, Alan D. | Brett, Sara | Jing, Junping | Quattrini, Adriano | Saini, Manoj | Wiedermann, Guy | Gerry, Andrew | Jakobsen, Bent | Binder-Scholl, Gwendolyn | Brewer, Joanna | Duong, MyLinh | Lu, An | Chang, Peter | Mahendravada, Aruna | Shinners, Nicholas | Slawin, Kevin | Spencer, David M. | Foster, Aaron E. | Bayle, J. Henri | Bergamaschi, Cristina | Ng, Sinnie Sin Man | Nagy, Bethany | Jensen, Shawn | Hu, Xintao | Alicea, Candido | Fox, Bernard | Felber, Barbara | Pavlakis, George | Chacon, Jessica | Yamamoto, Tori | Garrabrant, Thomas | Cortina, Luis | Powell, Daniel J. | Donia, Marco | Kjeldsen, Julie Westerlin | Andersen, Rikke | Westergaard, Marie Christine Wulff | Bianchi, Valentina | Legut, Mateusz | Attaf, Meriem | Dolton, Garry | Szomolay, Barbara | Ott, Sascha | Lyngaa, Rikke | Hadrup, Sine Reker | Sewell, Andrew Kelvin | Svane, Inge Marie | Fan, Aaron | Kumai, Takumi | Celis, Esteban | Frank, Ian | Stramer, Amanda | Blaskovich, Michelle A. | Wardell, Seth | Fardis, Maria | Bender, James | Lotze, Michael T. | Goff, Stephanie L. | Zacharakis, Nikolaos | Assadipour, Yasmine | Prickett, Todd D. | Gartner, Jared J. | Somerville, Robert | Black, Mary | Xu, Hui | Chinnasamy, Harshini | Kriley, Isaac | Lu, Lily | Wunderlich, John | Robbins, Paul F. | Rosenberg, Steven | Feldman, Steven A. | Trebska-McGowan, Kasia | Kriley, Isaac | Malekzadeh, Parisa | Payabyab, Eden | Sherry, Richard | Rosenberg, Steven | Goff, Stephanie L. | Gokuldass, Aishwarya | Blaskovich, Michelle A. | Kopits, Charlene | Rabinovich, Brian | Lotze, Michael T. | Green, Daniel S. | Kamenyeva, Olena | Zoon, Kathryn C. | Annunziata, Christina M. | Hammill, Joanne | Helsen, Christopher | Aarts, Craig | Bramson, Jonathan | Harada, Yui | Yonemitsu, Yoshikazu | Helsen, Christopher | Hammill, Joanne | Mwawasi, Kenneth | Denisova, Galina | Bramson, Jonathan | Giri, Rajanish | Jin, Benjamin | Campbell, Tracy | Draper, Lindsey M. | Stevanovic, Sanja | Yu, Zhiya | Weissbrich, Bianca | Restifo, Nicholas P. | Trimble, Cornelia L. | Rosenberg, Steven | Hinrichs, Christian S. | Tsang, Kwong | Fantini, Massimo | Hodge, James W. | Fujii, Rika | Fernando, Ingrid | Jochems, Caroline | Heery, Christopher | Gulley, James | Soon-Shiong, Patrick | Schlom, Jeffrey | Jing, Weiqing | Gershan, Jill | Blitzer, Grace | Weber, James | McOlash, Laura | Johnson, Bryon D. | Kiany, Simin | Gangxiong, Huang | Kleinerman, Eugenie S. | Klichinsky, Michael | Ruella, Marco | Shestova, Olga | Kenderian, Saad | Kim, Miriam | Scholler, John | June, Carl H. | Gill, Saar | Moogk, Duane | Zhong, Shi | Yu, Zhiya | Liadi, Ivan | Rittase, William | Fang, Victoria | Dougherty, Janna | Perez-Garcia, Arianne | Osman, Iman | Zhu, Cheng | Varadarajan, Navin | Restifo, Nicholas P. | Frey, Alan | Krogsgaard, Michelle | Landi, Daniel | Fousek, Kristen | Mukherjee, Malini | Shree, Ankita | Joseph, Sujith | Bielamowicz, Kevin | Byrd, Tiara | Ahmed, Nabil | Hegde, Meenakshi | Lee, Sylvia | Byrd, David | Thompson, John | Bhatia, Shailender | Tykodi, Scott | Delismon, Judy | Chu, Liz | Abdul-Alim, Siddiq | Ohanian, Arpy | DeVito, Anna Marie | Riddell, Stanley | Margolin, Kim | Magalhaes, Isabelle | Mattsson, Jonas | Uhlin, Michael | Nemoto, Satoshi | Villarroel, Patricio Pérez | Nakagawa, Ryosuke | Mule, James J. | Mailloux, Adam W. | Mata, Melinda | Nguyen, Phuong | Gerken, Claudia | DeRenzo, Christopher | Spencer, David M. | Gottschalk, Stephen | Mathieu, Mélissa | Pelletier, Sandy | Stagg, John | Turcotte, Simon | Minutolo, Nicholas | Sharma, Prannda | Tsourkas, Andrew | Powell, Daniel J. | Mockel-Tenbrinck, Nadine | Mauer, Daniela | Drechsel, Katharina | Barth, Carola | Freese, Katharina | Kolrep, Ulrike | Schult, Silke | Assenmacher, Mario | Kaiser, Andrew | Mullinax, John | Hall, MacLean | Le, Julie | Kodumudi, Krithika | Royster, Erica | Richards, Allison | Gonzalez, Ricardo | Sarnaik, Amod | Pilon-Thomas, Shari | Nielsen, Morten | Krarup-Hansen, Anders | Hovgaard, Dorrit | Petersen, Michael Mørk | Loya, Anand Chainsukh | Junker, Niels | Svane, Inge Marie | Rivas, Charlotte | Parihar, Robin | Gottschalk, Stephen | Rooney, Cliona M. | Qin, Haiying | Nguyen, Sang | Su, Paul | Burk, Chad | Duncan, Brynn | Kim, Bong-Hyun | Kohler, M. Eric | Fry, Terry | Rao, Arjun A. | Teyssier, Noam | Pfeil, Jacob | Sgourakis, Nikolaos | Salama, Sofie | Haussler, David | Richman, Sarah A. | Nunez-Cruz, Selene | Gershenson, Zack | Mourelatos, Zissimos | Barrett, David | Grupp, Stephan | Milone, Michael | Rodriguez-Garcia, Alba | Robinson, Matthew K. | Adams, Gregory P. | Powell, Daniel J. | Santos, João | Havunen, Riikka | Siurala, Mikko | Cervera-Carrascón, Víctor | Parviainen, Suvi | Antilla, Marjukka | Hemminki, Akseli | Sethuraman, Jyothi | Santiago, Laurelis | Chen, Jie Qing | Dai, Zhimin | Wardell, Seth | Bender, James | Lotze, Michael T. | Sha, Huizi | Su, Shu | Ding, Naiqing | Liu, Baorui | Stevanovic, Sanja | Pasetto, Anna | Helman, Sarah R. | Gartner, Jared J. | Prickett, Todd D. | Robbins, Paul F. | Rosenberg, Steven A. | Hinrichs, Christian S. | Bhatia, Shailender | Burgess, Melissa | Zhang, Hui | Lee, Tien | Klingemann, Hans | Soon-Shiong, Patrick | Nghiem, Paul | Kirkwood, John M. | Rossi, John M. | Sherman, Marika | Xue, Allen | Shen, Yueh-wei | Navale, Lynn | Rosenberg, Steven A. | Kochenderfer, James N. | Bot, Adrian | Veerapathran, Anandaraman | Gokuldass, Aishwarya | Stramer, Amanda | Sethuraman, Jyothi | Blaskovich, Michelle A. | Wiener, Doris | Frank, Ian | Santiago, Laurelis | Rabinovich, Brian | Fardis, Maria | Bender, James | Lotze, Michael T. | Waller, Edmund K. | Li, Jian-Ming | Petersen, Christopher | Blazar, Bruce R. | Li, Jingxia | Giver, Cynthia R. | Wang, Ziming | Grossenbacher, Steven K. | Sturgill, Ian | Canter, Robert J. | Murphy, William J. | Zhang, Congcong | Burger, Michael C. | Jennewein, Lukas | Waldmann, Anja | Mittelbronn, Michel | Tonn, Torsten | Steinbach, Joachim P. | Wels, Winfried S. | Williams, Jason B. | Zha, Yuanyuan | Gajewski, Thomas F. | Williams, LaTerrica C. | Krenciute, Giedre | Kalra, Mamta | Louis, Chrystal | Gottschalk, Stephen | Xin, Gang | Schauder, David | Jiang, Aimin | Joshi, Nikhil | Cui, Weiguo | Zeng, Xue | Menk, Ashley V. | Scharping, Nicole | Delgoffe, Greg M. | Zhao, Zeguo | Hamieh, Mohamad | Eyquem, Justin | Gunset, Gertrude | Bander, Neil | Sadelain, Michel | Askmyr, David | Abolhalaj, Milad | Lundberg, Kristina | Greiff, Lennart | Lindstedt, Malin | Angell, Helen K. | Kim, Kyoung-Mee | Kim, Seung-Tae | Kim, Sung | Sharpe, Alan D. | Ogden, Julia | Davenport, Anna | Hodgson, Darren R. | Barrett, Carl | Lee, Jeeyun | Kilgour, Elaine | Hanson, Jodi | Caspell, Richard | Karulin, Alexey | Lehmann, Paul | Ansari, Tameem | Schiller, Annemarie | Sundararaman, Srividya | Lehmann, Paul | Hanson, Jodi | Roen, Diana | Karulin, Alexey | Lehmann, Paul | Ayers, Mark | Levitan, Diane | Arreaza, Gladys | Liu, Fang | Mogg, Robin | Bang, Yung-Jue | O’Neil, Bert | Cristescu, Razvan | Friedlander, Philip | Wassman, Karl | Kyi, Chrisann | Oh, William | Bhardwaj, Nina | Bornschlegl, Svetlana | Gustafson, Michael P. | Gastineau, Dennis A. | Parney, Ian F. | Dietz, Allan B. | Carvajal-Hausdorf, Daniel | Mani, Nikita | Velcheti, Vamsidhar | Schalper, Kurt | Rimm, David | Chang, Serena | Levy, Ronald | Kurland, John | Krishnan, Suba | Ahlers, Christoph Matthias | Jure-Kunkel, Maria | Cohen, Lewis | Maecker, Holden | Kohrt, Holbrook | Chen, Shuming | Crabill, George | Pritchard, Theresa | McMiller, Tracee | Pardoll, Drew | Pan, Fan | Topalian, Suzanne | Danaher, Patrick | Warren, Sarah | Dennis, Lucas | White, Andrew M. | D’Amico, Leonard | Geller, Melissa | Disis, Mary L. | Beechem, Joseph | Odunsi, Kunle | Fling, Steven | Derakhshandeh, Roshanak | Webb, Tonya J. | Dubois, Sigrid | Conlon, Kevin | Bryant, Bonita | Hsu, Jennifer | Beltran, Nancy | Müller, Jürgen | Waldmann, Thomas | Duhen, Rebekka | Duhen, Thomas | Thompson, Lucas | Montler, Ryan | Weinberg, Andrew | Kates, Max | Early, Brandon | Yusko, Erik | Schreiber, Taylor H. | Bivalacqua, Trinity J. | Ayers, Mark | Lunceford, Jared | Nebozhyn, Michael | Murphy, Erin | Loboda, Andrey | Kaufman, David R. | Albright, Andrew | Cheng, Jonathan | Kang, S. Peter | Shankaran, Veena | Piha-Paul, Sarina A. | Yearley, Jennifer | Seiwert, Tanguy | Ribas, Antoni | McClanahan, Terrill K. | Cristescu, Razvan | Mogg, Robin | Ayers, Mark | Albright, Andrew | Murphy, Erin | Yearley, Jennifer | Sher, Xinwei | Liu, Xiao Qiao | Nebozhyn, Michael | Lunceford, Jared | Joe, Andrew | Cheng, Jonathan | Plimack, Elizabeth | Ott, Patrick A. | McClanahan, Terrill K. | Loboda, Andrey | Kaufman, David R. | Forrest-Hay, Alex | Guyre, Cheryl A. | Narumiya, Kohei | Delcommenne, Marc | Hirsch, Heather A. | Deshpande, Amit | Reeves, Jason | Shu, Jenny | Zi, Tong | Michaelson, Jennifer | Law, Debbie | Trehu, Elizabeth | Sathyanaryanan, Sriram | Hodkinson, Brendan P. | Hutnick, Natalie A. | Schaffer, Michael E. | Gormley, Michael | Hulett, Tyler | Jensen, Shawn | Ballesteros-Merino, Carmen | Dubay, Christopher | Afentoulis, Michael | Reddy, Ashok | David, Larry | Fox, Bernard | Jayant, Kumar | Agrawal, Swati | Agrawal, Rajendra | Jeyakumar, Ghayathri | Kim, Seongho | Kim, Heejin | Silski, Cynthia | Suisham, Stacey | Heath, Elisabeth | Vaishampayan, Ulka | Vandeven, Natalie | Viller, Natasja Nielsen | O’Connor, Alison | Chen, Hui | Bossen, Bolette | Sievers, Eric | Uger, Robert | Nghiem, Paul | Johnson, Lisa | Kao, Hsiang-Fong | Hsiao, Chin-Fu | Lai, Shu-Chuan | Wang, Chun-Wei | Ko, Jenq-Yuh | Lou, Pei-Jen | Lee, Tsai-Jan | Liu, Tsang-Wu | Hong, Ruey-Long | Kearney, Staci J. | Black, Joshua C. | Landis, Benjamin J. | Koegler, Sally | Hirsch, Brooke | Gianani, Roberto | Kim, Jeffrey | He, Ming-Xiao | Zhang, Bingqing | Su, Nan | Luo, Yuling | Ma, Xiao-Jun | Park, Emily | Kim, Dae Won | Copploa, Domenico | Kothari, Nishi | doo Chang, Young | Kim, Richard | Kim, Namyong | Lye, Melvin | Wan, Ee | Kim, Namyong | Lye, Melvin | Wan, Ee | Kim, Namyong | Lye, Melvin | Wan, Ee | Knaus, Hanna A. | Berglund, Sofia | Hackl, Hubert | Karp, Judith E. | Gojo, Ivana | Luznik, Leo | Hong, Henoch S. | Koch, Sven D. | Scheel, Birgit | Gnad-Vogt, Ulrike | Kallen, Karl-Josef | Wiegand, Volker | Backert, Linus | Kohlbacher, Oliver | Hoerr, Ingmar | Fotin-Mleczek, Mariola | Billingsley, James M. | Koguchi, Yoshinobu | Conrad, Valerie | Miller, William | Gonzalez, Iliana | Poplonski, Tomasz | Meeuwsen, Tanisha | Howells-Ferreira, Ana | Rattray, Rogan | Campbell, Mary | Bifulco, Carlo | Dubay, Christopher | Bahjat, Keith | Curti, Brendan | Urba, Walter | Vetsika, E-K | Kallergi, G. | Aggouraki, Despoina | Lyristi, Z. | Katsarlinos, P. | Koinis, Filippos | Georgoulias, V. | Kotsakis, Athanasios | Martin, Nathan T. | Aeffner, Famke | Kearney, Staci J. | Black, Joshua C. | Cerkovnik, Logan | Pratte, Luke | Kim, Rebecca | Hirsch, Brooke | Krueger, Joseph | Gianani, Roberto | Martínez-Usatorre, Amaia | Jandus, Camilla | Donda, Alena | Carretero-Iglesia, Laura | Speiser, Daniel E. | Zehn, Dietmar | Rufer, Nathalie | Romero, Pedro | Panda, Anshuman | Mehnert, Janice | Hirshfield, Kim M. | Riedlinger, Greg | Damare, Sherri | Saunders, Tracie | Sokol, Levi | Stein, Mark | Poplin, Elizabeth | Rodriguez-Rodriguez, Lorna | Silk, Ann | Chan, Nancy | Frankel, Melissa | Kane, Michael | Malhotra, Jyoti | Aisner, Joseph | Kaufman, Howard L. | Ali, Siraj | Ross, Jeffrey | White, Eileen | Bhanot, Gyan | Ganesan, Shridar | Monette, Anne | Bergeron, Derek | Amor, Amira Ben | Meunier, Liliane | Caron, Christine | Morou, Antigoni | Kaufmann, Daniel | Liberman, Moishe | Jurisica, Igor | Mes-Masson, Anne-Marie | Hamzaoui, Kamel | Lapointe, Rejean | Mongan, Ann | Ku, Yuan-Chieh | Tom, Warren | Sun, Yongming | Pankov, Alex | Looney, Tim | Au-Young, Janice | Hyland, Fiona | Conroy, Jeff | Morrison, Carl | Glenn, Sean | Burgher, Blake | Ji, He | Gardner, Mark | Mongan, Ann | Omilian, Angela R. | Conroy, Jeff | Bshara, Wiam | Angela, Omilian | Burgher, Blake | Ji, He | Glenn, Sean | Morrison, Carl | Mongan, Ann | Obeid, Joseph M. | Erdag, Gulsun | Smolkin, Mark E. | Deacon, Donna H. | Patterson, James W. | Chen, Lieping | Bullock, Timothy N. | Slingluff, Craig L. | Obeid, Joseph M. | Erdag, Gulsun | Deacon, Donna H. | Slingluff, Craig L. | Bullock, Timothy N. | Loffredo, John T. | Vuyyuru, Raja | Beyer, Sophie | Spires, Vanessa M. | Fox, Maxine | Ehrmann, Jon M. | Taylor, Katrina A. | Korman, Alan J. | Graziano, Robert F. | Page, David | Sanchez, Katherine | Ballesteros-Merino, Carmen | Martel, Maritza | Bifulco, Carlo | Urba, Walter | Fox, Bernard | Patel, Sapna P. | De Macedo, Mariana Petaccia | Qin, Yong | Reuben, Alex | Spencer, Christine | Guindani, Michele | Bassett, Roland | Wargo, Jennifer | Racolta, Adriana | Kelly, Brian | Jones, Tobin | Polaske, Nathan | Theiss, Noah | Robida, Mark | Meridew, Jeffrey | Habensus, Iva | Zhang, Liping | Pestic-Dragovich, Lidija | Tang, Lei | Sullivan, Ryan J. | Logan, Theodore | Khushalani, Nikhil | Margolin, Kim | Koon, Henry | Olencki, Thomas | Hutson, Thomas | Curti, Brendan | Roder, Joanna | Blackmon, Shauna | Roder, Heinrich | Stewart, John | Amin, Asim | Ernstoff, Marc S. | Clark, Joseph I. | Atkins, Michael B. | Kaufman, Howard L. | Sosman, Jeffrey | Weber, Jeffrey | McDermott, David F. | Weber, Jeffrey | Kluger, Harriet | Halaban, Ruth | Snzol, Mario | Roder, Heinrich | Roder, Joanna | Asmellash, Senait | Steingrimsson, Arni | Blackmon, Shauna | Sullivan, Ryan J. | Wang, Chichung | Roman, Kristin | Clement, Amanda | Downing, Sean | Hoyt, Clifford | Harder, Nathalie | Schmidt, Guenter | Schoenmeyer, Ralf | Brieu, Nicolas | Yigitsoy, Mehmet | Madonna, Gabriele | Botti, Gerardo | Grimaldi, Antonio | Ascierto, Paolo A. | Huss, Ralf | Athelogou, Maria | Hessel, Harald | Harder, Nathalie | Buchner, Alexander | Schmidt, Guenter | Stief, Christian | Huss, Ralf | Binnig, Gerd | Kirchner, Thomas | Sellappan, Shankar | Thyparambil, Sheeno | Schwartz, Sarit | Cecchi, Fabiola | Nguyen, Andrew | Vaske, Charles | Hembrough, Todd
Journal for Immunotherapy of Cancer  2016;4(Suppl 1):1-106.
PMCID: PMC5123387
15.  Interventions to increase adherence to acne treatment 
Patient preference and adherence  2016;10:2091-2096.
Adherence to acne medication is poor and is a major reason why treatment plans are ineffective. Recognizing solutions to nonadherence is critical.
The purpose of this study is to describe the hurdles associated with acne nonadherence and to provide mechanisms on how to ameliorate them.
PubMed database was searched. Of the 419 search results, 29 articles were reviewed to identify hurdles to adherence and corresponding solutions.
Hurdles to primary nonadherence where the medication is not even started, include lack of knowledge, confusion about usage, weak physician–patient relationship, fear of adverse reactions, and cost. Secondary nonadherence hurdles where the medication is started but is not taken as directed include lack of results, complex regimens, side effects, busy lifestyle, forgetfulness, inconvenience, and psychiatric comorbidity. Solutions to these hurdles include treatment simplification, technology, and dynamic education.
Adherence is affected by numerous factors, but available literature analyzing acne adherence and interventions to improve adherence to treatment is limited.
There are several hurdles in adhering to acne treatment. Recognition of these hurdles and finding appropriate solutions may be as important to treatment outcomes as choosing the right medication to prescribe.
PMCID: PMC5067002  PMID: 27784999
acne vulgaris; adherence; pathogenesis; treatment; quality of life; prevalence; physician–patient relationship; lifestyle; clinic visit; disease severity
16.  Treatment of plaque psoriasis with an ointment formulation of the Janus kinase inhibitor, tofacitinib: a Phase 2b randomized clinical trial 
BMC Dermatology  2016;16:15.
Most psoriasis patients have mild to moderate disease, commonly treated topically. Current topical agents have limited efficacy and undesirable side effects associated with long-term use. Tofacitinib is a small molecule Janus kinase inhibitor investigated for the topical treatment of psoriasis.
This was a 12-week, randomized, double-blind, parallel-group, vehicle-controlled Phase 2b study of tofacitinib ointment (2 % and 1 %) applied once (QD) or twice (BID) daily in adults with mild to moderate plaque psoriasis. Primary endpoint: proportion of patients with Calculated Physician’s Global Assessment (PGA-C) clear or almost clear and ≥2 grade improvement from baseline at Weeks 8 and 12. Secondary endpoints: proportion of patients with PGA-C clear or almost clear; proportion achieving Psoriasis Area and Severity Index 75 (PASI75) response; percent change from baseline in PASI and body surface area; change from baseline in Itch Severity Item (ISI). Adverse events (AEs) were monitored and clinical laboratory parameters measured.
Overall, 435 patients were randomized and 430 patients received treatment. The proportion of patients with PGA-C clear or almost clear and ≥2 grade improvement from baseline at Week 8 was 18.6 % for 2 % tofacitinib QD (80 % confidence interval [CI] for difference from vehicle: 3.8, 18.2 %) and 22.5 % for 2 % tofacitinib BID (80 % CI: 3.1, 18.5 %); this was significantly higher vs vehicle for both dosage regimens. No significant difference vs vehicle was seen at Week 12. Significantly more patients achieved PGA-C clear or almost clear with 2 % tofacitinib QD and BID and 1 % tofacitinib QD (not BID) at Week 8, and with 2 % tofacitinib BID at Week 12. Pruritus was significantly reduced vs vehicle with 2 % and 1 % tofacitinib BID (starting Day 2), and 2 % tofacitinib QD (starting Day 3). Overall, 44.2 % of patients experienced AEs, 8.1 % experienced application site AEs, and 2.3 % experienced serious AEs. The highest incidence of AEs (including application site AEs) was in the vehicle QD group.
In adults with mild to moderate plaque psoriasis, 2 % tofacitinib ointment QD and BID showed greater efficacy than vehicle at Week 8, but not Week 12, with an acceptable safety and local tolerability profile.
Trial registration
NCT01831466 registered March 28, 2013.
Electronic supplementary material
The online version of this article (doi:10.1186/s12895-016-0051-4) contains supplementary material, which is available to authorized users.
PMCID: PMC5048458  PMID: 27716172
Psoriasis; Topical; Tofacitinib; CP-690,550; Physician’s Global Assessment; Psoriasis Area and Severity Index; PASI; Dermatology Life Quality Index; Pruritus; Itch
17.  Cardiovascular Disease Outcomes Associated with Three Major Inflammatory Dermatologic Diseases: A Propensity-Matched Case Control Study 
Dermatology and Therapy  2016;6(4):649-658.
Inflammation is an established component of cardiovascular disease (CVD) and an underlying factor of several dermatologic conditions including rosacea, atopic dermatitis, and psoriasis. Identifying potential associations between these dermatologic and cardiovascular diseases can better inform holistic healthcare approaches. The objective of this study was to determine whether rosacea, psoriasis or atopic dermatitis are independent risk factors for CVD 1 year following diagnosis.
Using a large commercial claims database of 21,801,147 lives, we employed a propensity-matched logistic regression to evaluate the association between diagnoses of rosacea, psoriasis, or atopic dermatitis and a 1-year risk of being diagnosed with cardiovascular disease. Control patients were matched based on health-care utilization, age and overall health status as defined by a modified Deyo–Charlson comorbidity index.
The analysis included 2105 rosacea, 622 atopic dermatitis, 1536 psoriasis, and 4263 control patients. Compared to propensity-matched controls, the adjusted odds of cardiovascular disease were not higher in patients with rosacea (odds ratio: 0.894, p = 0.2713), atopic dermatitis (OR 1.032, p = 0.8489), or psoriasis (OR 1.087, p = 0.4210). In univariate analysis, the unadjusted odds of cardiovascular disease was higher in patients with psoriasis (OR 1.223, p = 0.0347).
Limitations of this study include the short follow-up period and inclusion of only commercially insured patients limit the generalizability of these findings. In this large study of patients with rosacea, atopic dermatitis, and psoriasis, we did not detect an increased 1-year risk of cardiovascular disease after adjusting for confounders.
Electronic supplementary material
The online version of this article (doi:10.1007/s13555-016-0144-3) contains supplementary material, which is available to authorized users.
PMCID: PMC5120633  PMID: 27659680
Atopic dermatitis; Cardiac health; Eczema; Heart failure; Ischemic stroke; Myocardial infarction; Psoriasis; Rosacea
18.  Economic and Comorbidity Burden Among Moderate‐to‐Severe Psoriasis Patients with Comorbid Psoriatic Arthritis 
Arthritis Care & Research  2015;67(5):708-717.
To compare the prevalence of comorbidities, health care utilization, and costs between moderate‐to‐severe psoriasis (PsO) patients with comorbid psoriatic arthritis (PsA) and matched controls.
Adults ages 18–64 years with concomitant diagnoses of PsO and PsA (PsO+PsA) were identified in the OptumHealth Reporting and Insights claims database between January 2007 and March 2012. Moderate‐to‐severe PsO was defined based on the use of at least one systemic or phototherapy during the 12‐month study period after the index date (randomly selected date after the first PsO diagnosis). Control patients without PsO and PsA were demographically matched 1:1 with PsO+PsA patients. Multivariate regressions were employed to examine PsO/PsA‐related comorbidities, medications, health care utilization, and costs between PsO+PsA patients and controls, adjusting for demographics, index year, insurance type, and non–PsO/PsA‐related comorbidities.
Among 1,230 matched pairs of PsO+PsA patients and controls, PsO+PsA patients had significantly more PsO/PsA‐related comorbidities, with the top 3 most common in both groups being hypertension (35.8% versus 23.5%), hyperlipidemia (34.6% versus 28.5%), and diabetes mellitus (15.9% versus 10.0%). Compared with controls, PsO+PsA patients had a higher number of distinct prescriptions filled (incidence rate ratio 2.3, P < 0.05); were more likely to have inpatient admissions (odds ratio [OR] 1.6), emergency room visits (OR 1.3), and outpatient visits (OR 62.7) (all P < 0.05); and incurred significantly higher total, pharmacy, and medical costs (adjusted annual cost differences per patient $23,160, $17,696, and $5,077, respectively; all P < 0.01).
Compared with matched PsO‐ and PsA‐free controls, moderate‐to‐severe PsO patients with comorbid PsA had higher comorbidity and health care utilization and costs.
PMCID: PMC5029589  PMID: 25303478
19.  Phototherapy in Scleroderma 
Dermatology and Therapy  2016;6(4):519-553.
Systemic and localized scleroderma are difficult to manage diseases with no accepted gold standard of therapy to date. Phototherapeutic modalities for scleroderma show promise. A PubMed search of information on phototherapy for scleroderma was conducted. The information was classified into effects on pathogenesis and clinical outcomes. Studies on photopheresis were excluded. There were no randomized, double-blind, placebo-controlled studies, and only three controlled studies. The vast majority of identified studies evaluated ultraviolet A1 (UVA1) phototherapy. More rigorous studies are needed to evaluate phototherapy in the treatment of scleroderma. Based on the limited studies available, 20–50 J/cm2 of UVA1 therapy 3–4 times a week for 30 treatments is recommended.
PMCID: PMC5120625  PMID: 27519050
Morphea; Phototherapy; PUVA; Scleroderma; UVA; UVB
20.  Pregnancy Outcomes in the Tofacitinib Safety Databases for Rheumatoid Arthritis and Psoriasis 
Drug Safety  2016;39:755-762.
Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA), and is being investigated for the treatment of psoriasis. Both conditions can present in women of child-bearing potential, but pregnancy was an exclusion and discontinuation criterion in tofacitinib randomized controlled trials (RCTs) because of the unknown effects of tofacitinib on mother and child. Tofacitinib is a small molecule that has the potential to cross the placenta.
The objective was to report outcomes of pregnancy cases identified through April 2014 from tofacitinib RA/psoriasis RCTs, RA post-approval non-interventional studies, and spontaneous adverse-event reporting.
Pregnancy outcomes were categorized as follows: healthy newborn, medical termination, fetal death, congenital malformation, spontaneous abortion, or pending/lost to follow-up.
Out of 9815 patients, 1821 female patients of child-bearing age were enrolled in the RA/psoriasis RCTs; 47 women became pregnant, including 33 who received tofacitinib monotherapy, 13 who received combination therapy with methotrexate (RA patients only), and one patient whose therapy was still blinded. No fetal deaths were reported. One congenital pulmonary valve stenosis (monotherapy, n = 1), seven spontaneous abortions (monotherapy, n = 4; combination therapy, n = 3), and eight medical terminations (monotherapy, n = 4; combination therapy, n = 3; blinded therapy, n = 1) were identified. Remaining cases reported healthy newborns (n = 25) or were pending/lost to follow-up (n = 6). Forty-four cases of paternal exposure to tofacitinib were reported (monotherapy, n = 43; combination therapy, n = 1), including five spontaneous abortions (monotherapy, n = 4; combination therapy, n = 1), 23 healthy newborns, and 16 pending/lost to follow-up.
The pregnancy outcomes reported in this small number of RA/psoriasis patients appear similar to those observed in the general population and in patients treated with biologic therapies for inflammatory diseases. However, definitive conclusions cannot be drawn, and pregnancy outcomes in patients receiving tofacitinib will continue to be monitored.
Electronic supplementary material
The online version of this article (doi:10.1007/s40264-016-0431-z) contains supplementary material, which is available to authorized users.
PMCID: PMC4933738  PMID: 27282428
21.  Rosacea Management 
Skin Appendage Disorders  2016;2(1-2):26-34.
Rosacea is a chronic inflammatory skin condition associated with four distinct subtypes: erythematotelangiectatic, papulopustular, phymatous, and ocular.
To review the different kinds of management for all subtypes.
We divided rosacea management into three main categories: patient education, skin care, and pharmacological/procedural interventions.
Flushing is better prevented rather than treated, by avoiding specific triggers, decreasing transepidermal water loss by moisturizers, and blocking ultraviolet light. Nonselective β-blockers and α2-adrenergic agonists decrease erythema and flushing. The topical α-adrenergic receptor agonist brimonidine tartrate 0.5% reduces persistent facial erythema. Intradermal botulinum toxin injection is almost safe and effective for the erythema and flushing. Flashlamp-pumped dye, potassium-titanyl-phosphate and pulsed-dye laser, and intense pulsed light are used for telangiectasias. Metronidazole 1% and azelaic acid 15% cream reduce the severity of erythema. Both systemic and topical remedies treat papulopustules. Systemic remedies include metronidazole, doxycycline, minocycline, clarithromycin and isotretinoin, while topical remedies are based on metronidazole 0.75%, azelaic acid 15 or 20%, sodium sulfacetamide, ivermectin 1%, permethrin 5%, and retinoid. Ocular involvement can be treated with oral or topical antibacterial. Rhinophyma can be corrected by dermatosurgical procedures, decortication, and various types of lasers.
There are many options for rosacea management. Patients may have multiple subtypes, and each phase has its own treatment.
PMCID: PMC5096126  PMID: 27843919
Inflammatory lesion; Ocular rosacea; Laser; Ivermectin; Azelaic acid; Demodex; Rosacea; Isotretinoin
22.  Tumor Infiltrating Lymphocytes Genetically Engineered with an Inducible Gene Encoding Interleukin-12 for the Immunotherapy of Metastatic Melanoma 
Infusion of interleukin-12 (IL-12) can mediate anti-tumor immunity in animal models, yet its systemic administration to patients with cancer results in minimal efficacy and severe toxicity. Here, we evaluated the anti-tumor activity of adoptively transferred human tumor infiltrating lymphocytes (TIL) genetically engineered to secrete single-chain IL-12 selectively at the tumor site.
Experimental design
Thirty-three patients with metastatic melanoma were treated in a cell-dose escalation trial of autologous TIL transduced with a gene encoding a single chain IL-12 driven by a nuclear factor of activated T cells promoter (NFAT.IL12). No IL-2 was administered.
The administration of 0.001-0.1 X 109 NFAT.IL12 transduced TIL to 17 patients resulted in a single objective response (5.9%). However, at doses between 0.3-3 X 109 cells, 10 of 16 patients (63%) exhibited objective clinical responses. The responses tended to be short and the administered IL-12 producing cells rarely persisted at one month. Increasing cell doses were associated with high serum levels of IL-12 and gamma-interferon as well as clinical toxicities including liver dysfunction, high fevers and sporadic life threatening hemodynamic instability.
In this first-in-man trial, administration of TIL transduced with an inducible IL-12 gene mediated tumor responses in the absence of IL-2 administration using cell doses 10-100 fold lower than conventional TIL. However, due to toxicities, likely attributable to the secreted IL-12, further refinement will be necessary before this approach can be safely utilized in the treatment of cancer patients.
PMCID: PMC4433819  PMID: 25695689
23.  New developments in the treatment of rosacea – role of once-daily ivermectin cream 
Rosacea is a chronic dermatological disorder with a variety of clinical manifestations localized largely to the central face. The unclear etiology of rosacea fosters therapeutic difficulty; however, subtle clinical improvement with pharmacologic treatments of various drug categories suggests a multifactorial etiology of the disease. Factors that may contribute to disease pathogenesis include immune abnormality, vascular abnormality, neurogenic dysregulation, presence of cutaneous microorganisms, UV damage, and skin barrier dysfunction. The role of ivermectin in the treatment of rosacea may be as an anti-inflammatory and anti-parasitic agent targeting Demodex mites. In comparing topical ivermectin and metronidazole, ivermectin was more effective; this treatment modality boasted more improved quality of life, reduced lesion counts, and more favorable participant and physician assessment of disease severity. Patients who received ivermectin 1% cream had an acceptable safety profile. Ivermectin is efficacious in decreasing inflammatory lesion counts and erythema.
PMCID: PMC4807898  PMID: 27051311
papulopustular rosacea; topical ivermectin; metronidazole; azelaic acid; topical
24.  A pilot trial using lymphocytes genetically engineered with an NY-ESO-1-reactive T cell receptor: Long term follow up and correlates with response 
Although adoptive cell therapy can be highly effective for the treatment of patients with melanoma, the application of this approach to the treatment of other solid tumors has been limited. The observation that the cancer germline (CG) antigen NY-ESO-1 is expressed in 70–80% and in approximately 25% of patients with synovial cell sarcoma and melanoma, respectively, prompted us to perform this first-in-man clinical trial employing the adoptive transfer of autologous PBMC that were retrovirally transduced with an NY-ESO-1 reactive TCR to heavily pretreated patients bearing these metastatic cancers.
Experimental Design
HLA-*0201 patients with metastatic synovial cell sarcoma or melanoma refractory to standard treatments and whose cancers expressed NY-ESO-1 received autologous TCR-transduced T cells following a lymphodepleting preparative chemotherapy. Response rates using Response Evaluation Criteria in Solid Tumors (RECIST), as well as immunologic correlates of response, are presented in this report.
Eleven of 18 patients with NY-ESO-1+ synovial cell sarcomas (61%) and 11 of 20 patients with NY-ESO-1 positive melanomas (55%) who received autologous T cells transduced with an NY-ESO-1-reactive TCR demonstrated objective clinical responses. The estimated overall three and five year survival rates for patients with synovial cell sarcoma were 38 and 14%, respectively, while the corresponding estimated survival rates for patients with melanoma were both 33%.
The adoptive transfer of autologous T cells transduced with a retrovirus encoding a TCR against an HLA-A*0201 restricted NY-ESO-1 epitope can be an effective therapy for some patients bearing synovial cell sarcomas and melanomas that are refractory to other treatments.
PMCID: PMC4361810  PMID: 25538264
25.  Chemotherapy-Refractory Diffuse Large B-Cell Lymphoma and Indolent B-Cell Malignancies Can Be Effectively Treated With Autologous T Cells Expressing an Anti-CD19 Chimeric Antigen Receptor 
Journal of Clinical Oncology  2014;33(6):540-549.
T cells can be genetically modified to express an anti-CD19 chimeric antigen receptor (CAR). We assessed the safety and efficacy of administering autologous anti-CD19 CAR T cells to patients with advanced CD19+ B-cell malignancies.
Patients and Methods
We treated 15 patients with advanced B-cell malignancies. Nine patients had diffuse large B-cell lymphoma (DLBCL), two had indolent lymphomas, and four had chronic lymphocytic leukemia. Patients received a conditioning chemotherapy regimen of cyclophosphamide and fludarabine followed by a single infusion of anti-CD19 CAR T cells.
Of 15 patients, eight achieved complete remissions (CRs), four achieved partial remissions, one had stable lymphoma, and two were not evaluable for response. CRs were obtained by four of seven evaluable patients with chemotherapy-refractory DLBCL; three of these four CRs are ongoing, with durations ranging from 9 to 22 months. Acute toxicities including fever, hypotension, delirium, and other neurologic toxicities occurred in some patients after infusion of anti-CD19 CAR T cells; these toxicities resolved within 3 weeks after cell infusion. One patient died suddenly as a result of an unknown cause 16 days after cell infusion. CAR T cells were detected in the blood of patients at peak levels, ranging from nine to 777 CAR-positive T cells/μL.
This is the first report to our knowledge of successful treatment of DLBCL with anti-CD19 CAR T cells. These results demonstrate the feasibility and effectiveness of treating chemotherapy-refractory B-cell malignancies with anti-CD19 CAR T cells. The numerous remissions obtained provide strong support for further development of this approach.
PMCID: PMC4322257  PMID: 25154820

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