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Journal articles on the topic 'Expressive arts therapies'
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Schwartz, Samuel, Amia Lieblich, Vivien Marcow Speiser, Elana Lakh, Tsiky Cohen, Pazit Dushi, Anat Gilad, and Sharon Vaisvaser. "Life story and the arts: A didactic crossroad." Journal of Applied Arts & Health 11, no. 3 (November 1, 2020): 315–28. http://dx.doi.org/10.1386/jaah_00043_7.
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The following notes from the field introduces an original approach to working with narrative, storytelling and artistic expression in the framework of the creative and expressive arts therapies. Using an interview methodology developed by Amia Lieblich, a team of creative and expressive arts therapists teaching at The Academic College of Society and the Arts in Netanya, Israel, shares their theoretical observations and practical perspectives about moving from verbal to non-verbal expression of personal and collective stories. These insights emerged during an introductory course that the authors taught to creative and expressive arts therapists. We posit that life story work, both in regard to oneself and to others, from single episode memory or the documentation of the entire life course, may be of tremendous worth in the training of creative and expressive art therapists.
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Sánchez García, Laura, and Angelica Pinna-Perez. "Expressive Flamenco ©: An Emerging Expressive Arts-Based Practice." American Journal of Dance Therapy 43, no. 1 (January 21, 2021): 3–35. http://dx.doi.org/10.1007/s10465-020-09339-2.
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AbstractExpressive Flamenco© theory and praxis is presented by Sánchez through this art-based personal reflection paper, which explores the applications of flamenco for its inherent psycho-somatic therapeutic capacities. She asserts the applied practice of flamenco (in its broadest definition), when combined with other expressive arts practices, can have therapeutic benefits; including (but not limited to) psycho-social, spiritual, and aesthetic connection to the individual's unconscious. During these experiences of arts based emotional expression, one can transcend the self into divine connection with their authentic self, what the author understands as the “duende”. By allowing one’s authentic truth to be expressed through Expressive Flamenco©, a spirit of evocation, born from within the self, appears when the self-connects with and is in creative conversation with its unconscious. The main hypothesis asserts the emergence of the “duende” facilitates an epistemological process of self-knowledge and an emotional process of catharsis, suggesting that when this art form is utilized as ‘Expressive Flamenco’ it helps facilitate holistic healing. This paper aims to stretch flamenco into new applied therapeutic practice territories, specifically in the arts therapies. Practical applications of Expressive Flamenco in the expressive therapies, including expressive arts therapy and dance/movement therapy, is presented along with the preliminary results of a virtual telehealth group facilitated during Covid-19. Professor Pinna-Perez′s critical reflections on Expressive Flamenco© and its importance to the field is presented in response to this emerging expressive arts practice.
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Lewis, Penny P. "The expressive arts therapies in the choreography of object relations." Arts in Psychotherapy 14, no. 4 (December 1987): 321–31. http://dx.doi.org/10.1016/0197-4556(87)90020-7.
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Damir, Miholic, and Martinec Renata. "Some aspects of using expressive arts-therapies in education and rehabilitation." Specijalna edukacija i rehabilitacija 12, no. 2 (2013): 221–40. http://dx.doi.org/10.5937/specedreh12-3506.
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Greene, Audra Holmes, Linda Goldenberg, and Madelyn Freundlich. "The Use of Expressive Therapies and Social Support with Youth in Foster Care: The Performing Arts Troupe." Journal of Youth Development 4, no. 1 (March 1, 2009): 60–77. http://dx.doi.org/10.5195/jyd.2009.275.
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The Performing Arts Troupe is a program that provides youth in foster care and youth from low income neighborhoods with expressive therapies and social support. The program is designed to assist youth in addressing the effects of trauma and developing competencies as they prepare to transition to adulthood. The article discusses the literature base for the program, the program activities and describes the impact of the program on youth through preliminary evaluations and case studies. The program offers an innovative combination of expressive therapies and social supports that has effectively met the needs of vulnerable youth.
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Bucharová, Monika, Andrea Malá, Jiří Kantor, and Zuzana Svobodová. "Arts Therapies Interventions and Their Outcomes in the Treatment of Eating Disorders: Scoping Review Protocol." Behavioral Sciences 10, no. 12 (December 9, 2020): 188. http://dx.doi.org/10.3390/bs10120188.
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Arts therapies (AsTs) are considered a valuable intervention for people with eating disorders, however the range of research studies and the comparison between the types of arts therapies are unknown. The goal of the future scoping review is to explore the therapeutic outcomes addressed by arts therapists in research studies on people with eating disorders and compare the different types of arts-based interventions. This scoping review will be conducted in accordance with the Joanna Briggs Institute methodology. Included will be research studies and sources oriented towards people with eating disorders of all ages and AsTs of any type (art therapy, drama therapy, music therapy, dance/movement therapy, and expressive therapies). There is no language/publication period limitation. The following databases will be searched: CINAHL Plus, EMBASE, MEDLINE (OvidSP), ProQuest Central, PsycINFO, PubMed, Scopus, and Web of Science. Sources of unpublished studies and grey literature will include Google Scholar, MedNar, clinical trials, and current controlled trials. Titles/abstracts and full texts of studies will be assessed against the inclusion criteria, and the data extracted by two independent reviewers. Based on the results, we will compare the types of AsTs according to the research designs, country/settings, intervention methods/materials, adverse effects reported, and therapeutic outcomes related to AsTs.
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Leyes, Sarah. "Expressive Therapies Now: Action Orientated Creative Arts Strategies for Healing and Growth in Children." Canadian Art Therapy Association Journal 20, no. 2 (September 2007): 55–56. http://dx.doi.org/10.1080/08322473.2007.11434774.
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Kothari, Saroj. "EFFECTS OF DANCE AND MUSIC THERAPY." International Journal of Research -GRANTHAALAYAH 3, no. 1SE (January 31, 2015): 1–8. http://dx.doi.org/10.29121/granthaalayah.v3.i1se.2015.3389.
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Arts have consistently been part of life as well as healing throughout the history of humankind. Today, expressive therapies have an increasingly recognized role in mental health, rehabilitation and medicine. The expressive therapies are defined as the use of art, music, dance/movement drama, poetry/creative writing, play and sand play within the context of psychotherapy, counseling, rehabilitation or health care.Through the centuries, the healing nature of these expressive therapies has been primarily reported in anecdotes that describe a way of restoring wholeness to a person struggling with either mind or body illness. The Egyptians are reported to have encouraged people with mental illness to engage in artistic activity (Fleshman & Fryrear, 1981); the Greeks used drama and music for its reparative properties (Gladding, 1992); and the story of King Saul in the Bible describes music’s calming attributes. Later, in Europe during the Renaissance, English physician and writer Robert Burton theorized that imagination played a role in health and well-being, while Italian philosopher de feltre proposed that dance and Play was central to children’s healthy growth and development (Coughlin, 1990).
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Toll, Haley Rebecca May. "Bridging memories and transformative narratives: A visual and written response to Art-making with refugees and survivors by Sally Adnams Jones / Rapprochements entre souvenirs et récits transformateurs : réponse visuelle et écrite à Art-making with refugees and survivors par Sally Adnams Jones." Canadian Review of Art Education / Revue canadienne d’éducation artistique 46, no. 2 (September 13, 2019): 76–81. http://dx.doi.org/10.26443/crae.v46i2.82.
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Book Response: Art-making with refugees and survivors: Creative and transformative responses to trauma after natural disasters, war, and other crises, edited by Sally Adnams Jones. London, England: Jessica Kingsley Publishers, 2018, 336 pp., ISBN: 1785922386Keywords: Community Arts; Refugees and Survivors; International Arts; Expressive and Creative Arts Therapies; Art Education; Transformative. Réaction livresque: Art-making with refugees and survivors: Creative and transformative responses to trauma after natural disasters, war, and other crises, edited by Sally Adnams Jones. London, England: Jessica Kingsley Publishers, 2018, 336 pp., ISBN: 1785922386Mots-clés : arts communautaires ; réfugiés et survivants ; arts internationaux ; thérapies par des activités créatives et d’expression ; éducation artistique ; transformateur.
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Southwell, Jenni. "Using ‘Expressive Therapies’ to Treat Developmental Trauma and Attachment Problems in Preschool-Aged Children." Children Australia 41, no. 2 (April 11, 2016): 114–25. http://dx.doi.org/10.1017/cha.2016.7.
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yourtown's Expressive Therapies Intervention (YETI) is a trauma and attachment informed creative arts and play therapy intervention developed for young children with emotional and behavioural problems stemming from traumatic exposure. YETI aims to improve participants’ emotional and social wellbeing; behavioural adjustment; quality of attachment relationships and self-concept. The intervention is integrated within holistic family support programmes, chiefly a domestic and family violence refuge and a young parents programme. This paper describes YETI's therapeutic model and presents findings of a two-year outcome evaluation. The findings suggest that the intervention can achieve significant positive outcomes for preschool-aged children associated with healing from developmental trauma and attachment difficulties. Analysis of pre/post assessments of participants’ social, emotional and behavioural functioning using the Child Behaviour Checklist revealed significant improvements from intake to exit in children's internalising, externalising and total problems. There were also marked decreases in the proportion of children with symptoms in the clinical or borderline clinical ranges. Thematic analyses of parent/carer surveys and therapists’ end-of-therapy reports similarly indicate widespread improvements in social, emotional and behavioural functioning as well as improvements in children's self-confidence and self-esteem, and in the quality of the parent–child attachment relationship.
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Demaine, Krystal, and Amy Morrison. "The Endicott College Expressive Therapies Symposium: Traditional Chinese Medicine, Arts, and Culture, Beverly, MA, 25 October 2019." Journal of Applied Arts & Health 11, no. 3 (November 1, 2020): 341–47. http://dx.doi.org/10.1386/jaah_00047_5.
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Demaine, Krystal. "Reflections on the First Bi-annual Endicott College Expressive Therapies Symposium: Traditional Chinese Medicine, Arts, and Culture." Creative Arts in Education and Therapy 6, no. 1 (August 1, 2020): 97–107. http://dx.doi.org/10.15212/caet/2020/6/18.
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Raybin, Jennifer L., Emily Barr, Marilyn Krajicek, and Jacqueline Jones. "How Does Creative Arts Therapy Reduce Distress for Children With Cancer? A Metasynthesis of Extant Qualitative Literature." Journal of Pediatric Oncology Nursing 37, no. 2 (November 26, 2019): 91–104. http://dx.doi.org/10.1177/1043454219888807.
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Introduction: As more children survive cancer, attention must be paid to their quality of life (QOL). Integrative therapies are an ideal modality for nurses to advocate for reducing distress and improving QOL for children with cancer. Creative arts therapy is a type of integrative health that may improve QOL in this population. Therefore, the research question was asked, “For children with cancer, what opportunities exist for creative arts therapy to reduce distress?” Method: A metasynthesis of the extant qualitative research was conducted to answer the research question. Seven qualitative studies were identified, which included 162 participants. New themes were identified through rigorous analyzation by the study team of each study as individual data. Results: Four derived analytic themes emerged through the analysis: (a) connection is established through creative expression, (b) coping is facilitated by creative arts, (c) communication is enabled by creative arts interventions, and (d) continuance (the concept of time) is experienced through creative arts. Examples of each theme with subthemes are delineated, including expressive quotes. Summary: Through this qualitative synthesis of studies with creative arts therapy, evocative opportunities to reduce the distress associated with the disease experience are revealed. Nurses are called now to promote creative arts therapy to improve the symptoms in children with cancer.
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Duhovska, Jana, and Inga Millere. "EXPRESSIVE THERAPIES CONTINUUM-INFORMED EVALUATION OF THREE RESOURCE-ORIENTED RECEPTIVE AND ACTIVE MUSIC THERAPY TECHNIQUES IN CANCER PATIENTS IN PSYCHOSOCIAL REHABILITATION PROGRAMME." SOCIETY. INTEGRATION. EDUCATION. Proceedings of the International Scientific Conference 7 (May 20, 2020): 34. http://dx.doi.org/10.17770/sie2020vol7.5115.
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Expressive Therapies Continuum (ETC), a model posed by Lusebrink and widely used in arts therapies, stipulates that human being is perceiving the world and processing the information in three modes – motion (kinesthetic-sensory perception), emotion (perceptual-emotional perception) and thought (cognitive-symbolic perception), and that optimally functioning person can freely function in all the modes, can slide between the poles of each of the mode and can integrate the elements from various modes and poles. And vice versa - difficulty or inability to function or being stuck in certain modes, can indicate to malfunction and even psychopathology. If that is the case - purposeful integration of various functions by offering expressive activity promoting utilisation of various functions of the ETC, can promote the optimal functioning. In order to find out the capacity of the three resource-based music therapy activities – 1) receptive music therapy activity, 2) semi-structured musical improvisation, 3) song-writing activity - to stimulate the utilisation of specific levels and polarities of the ETC, participants (n=24 cancer patients participating in the psychosocial rehabilitation programme) were asked to assess the elements of the ETC they applied while executing each of the activities. Results of the study show that during the receptive music therapy activity participants mostly used the affective, symbolic and sensory function, during the song-writing activity the mostly used all ETC functions except for sensory, but musical improvisation provoked application of all the ETC functions, and therefore turned out as ultimate activity, capable of integrating all the modes of perception and information processing.
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Best, Penelope A. "DANCE AND OTHER EXPRESSIVE ART THERAPIES: WHEN WORDS ARE NOT ENOUGH Edited by F. Levy with J. P. Fried and F. Leventhal Routledge, London, 1995." Dance Research 16, no. 1 (January 1998): 87–93. http://dx.doi.org/10.3366/drs.1998.16.1.87.
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Priebe, S., M. Savill, T. Wykes, R. P. Bentall, U. Reininghaus, C. Lauber, S. Bremner, S. Eldridge, and F. Röhricht. "Effectiveness of group body psychotherapy for negative symptoms of schizophrenia: Multicentre randomised controlled trial." British Journal of Psychiatry 209, no. 1 (July 2016): 54–61. http://dx.doi.org/10.1192/bjp.bp.115.171397.
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BackgroundNegative symptoms of schizophrenia have a severe impact on functional outcomes and treatment options are limited. Arts therapies are currently recommended but more evidence is required.AimsTo assess body psychotherapy as a treatment for negative symptoms compared with an active control (trial registration: ISRCTN84216587).MethodSchizophrenia out-patients were randomised into a 20-session body psychotherapy or Pilates group. The primary outcome was negative symptoms at end of treatment. Secondary outcomes included psychopathology, functional, social and treatment satisfaction outcomes at treatment end and 6-months later.ResultsIn total, 275 participants were randomised. The adjusted difference in negative symptoms was 0.03 (95% CI –1.11 to 1.17), indicating no benefit from body psychotherapy. Small improvements in expressive deficits and movement disorder symptoms were detected in favour of body psychotherapy. No other outcomes were significantly different.ConclusionsBody psychotherapy does not have a clinically relevant beneficial effect in the treatment of patients with negative symptoms of schizophrenia.
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Glidden, M. "Frostig, K., & Essex, M. (1998). Expressive arts therapies in schools: A supervision and program development guide, Springfield, IL: Charles C. Thomas Publisher. 108 pages. ISBN 0-398-06868-2. $20.95." Music Therapy Perspectives 18, no. 1 (January 1, 2000): 82. http://dx.doi.org/10.1093/mtp/18.1.82.
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Block, Azadeh Masalehdan, Leslie Aizenman, Adam Saad, Stephanie Harrison, Amanda Sloan, Simone Vecchio, and Vanessa Wilson. "Peer Support Groups: Evaluating a Culturally Grounded, Strengths-Based Approach for Work With Refugees." Advances in Social Work 18, no. 3 (September 18, 2018): 930–48. http://dx.doi.org/10.18060/21634.
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Many refugees will face unique socio-emotional stressors before, during, and after resettling in their new home country. The program presented herein focuses on the use of para-professionals, peer educators, from within refugee communities to build upon the Center for Torture and Trauma Survivors Clubhouse model. Group leaders seek to provide supports that will: 1) decrease feelings of isolation; 2) build community networks and; 3) increase feelings of empowerment within the community. To accurately represent the fluidity of the refugee population in this metropolitan region, background is presented on an established refugee population from Iraq and a more recent influx of refugees of Bhutan (ethnic Nepali). The juxtaposition of the two groups underscores the importance of presenting a dynamic program that is peer-led to provide the supports necessary to acclimate to their new environment. Program evaluation results from groups run in 2016-2017 indicate that the groups have been successful in helping participants make friends, get information, become more independent, and feel better about life in America. Additionally, participants report a significantly higher number of individuals who they can “talk to about problems or worries” and connect to with a sense of trust within their ethnic community. Finally, the utility of other therapeutic and support processes, such as horticultural and expressive arts therapies, are discussed apropos work with refugee populations.
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Morrison, Penny, Patricia W. Nishimoto, John B. Kim, Carolina Medina-Dupaix, and Erin O’Carroll Bantum. "Perceived Impact of Participation in a One-Time Expressive Arts Workshop." Military Medicine 184, no. 5-6 (September 25, 2018): e242-e247. http://dx.doi.org/10.1093/milmed/usy240.
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Abstract Introduction This 2015 study examined the use of art to express the experience of the cancer journey of military cancer patients/cancer survivors, family and friends, caregivers, volunteers, and staff members through a one-time art-making workshop, administered by non-art therapists. Using art to express a medical/cancer journey may give participants, who cannot express their feelings in words, the ability to articulate their experience through art that looks at the creative process rather than the end result – expressive art. Materials and Methods This mixed methods study examined the use of art to express the cancer journey of participants. Twenty-eight adults participated in a one-time expressive arts workshop conducted by non-professional art therapists at a military medical center. The five domains of the Emotion Thermometer were analyzed to determine if the pre-event and post-event assessment results would differ. The Silver Drawing Test and Draw-a-Story assessment tools were used to identify emotions and attitudinal stance on six separate five-point scales. A qualitative analysis was done using the phenomenological method of the post-interviews that facilitated open expression to identify themes. Results A significant difference was found between the pre-event and post-event analyses using the Emotion Thermometer, with post-assessment results revealing lower levels in the three domains of distress, anxiety, and depression. The Silver Drawing Test and Draw-a-Story were analyzed for six components using a five-point scale, with the highest scores being content/meaning, ability to combine, and creativity. A qualitative analysis was done using the phenomenological method; post-interviews provided information to categorize the experience into four key themes: environment, connection, emotions, and discoveries. Conclusions Using art to express one’s journey through cancer allows participants to articulate that journey “beyond language.” This mixed methods study was administered by five non-professional art therapists with three having no expressive arts background. This study established that an expressive arts workshop can effectively be conducted by non-professional art therapists. The team of non-professional art therapists, who facilitated this one-time art-making workshop, demonstrated that a military member’s stress can be decreased by giving them “a voice” through expressive art.
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Hinz, Lisa D. "The Healing Dance: The Life and Practice of an Expressive Arts Therapist." Art Therapy 31, no. 1 (January 2, 2014): 45–46. http://dx.doi.org/10.1080/07421656.2014.873968.
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Aldridge, David. "Music Therapy References Relating to Cancer and Palliative Care." British Journal of Music Therapy 17, no. 1 (June 2003): 17–25. http://dx.doi.org/10.1177/135945750301700104.
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Hospitals and clinics worldwide have incorporated music therapy in their work with cancer patients and in palliative care. As the music therapy profession has developed internationally, so has its role in palliative care. The arts and creative arts therapies are being seen as a form of spiritual care in healthcare settings, particularly where individuals are confronting life-threatening illnesses. By offering opportunities to engage in the arts and develop creative expression, people with cancer can be enabled to mourn, grieve, celebrate life, be empowered to endure their situation, and find healing and meaning. In many studies we find that music therapy is not simply used with the identified patients but also with their families and carers. As well as noting the importance of work with patients and their families, music therapists also emphasise the importance of music for their own healing. This is necessary to meet personal needs when working with the dying and in the context of a broader hospital milieu of colleagues and friends. The World Health Organisation's recommendations for cancer relief and palliative care are to affirm life and regard dying as a normal process, to provide relief from pain and distressing symptoms, to integrate the psychological and spiritual aspects of patient care, to offer a support system to help patients as actively as possible until death, and to offer a support system to help the family cope during the illness and in their own bereavement. Music therapy has the potential to meet all of these recommendations.
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Tran, Anh N., Nathaniel H. Boyd, Kiera Walker, and Anita B. Hjelmeland. "NOS Expression and NO Function in Glioma and Implications for Patient Therapies." Antioxidants & Redox Signaling 26, no. 17 (June 10, 2017): 986–99. http://dx.doi.org/10.1089/ars.2016.6820.
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Harris, David Alan. "The paradox of expressing speechless terror: Ritual liminality in the creative arts therapies’ treatment of posttraumatic distress." Arts in Psychotherapy 36, no. 2 (April 2009): 94–104. http://dx.doi.org/10.1016/j.aip.2009.01.006.
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D'Alessio, F. R., J. M. Craig, B. D. Singer, D. C. Files, J. R. Mock, B. T. Garibaldi, J. Fallica, et al. "Enhanced resolution of experimental ARDS through IL-4-mediated lung macrophage reprogramming." American Journal of Physiology-Lung Cellular and Molecular Physiology 310, no. 8 (April 15, 2016): L733—L746. http://dx.doi.org/10.1152/ajplung.00419.2015.
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Despite intense investigation, acute respiratory distress syndrome (ARDS) remains an enormous clinical problem for which no specific therapies currently exist. In this study, we used intratracheal lipopolysaccharide or Pseudomonas bacteria administration to model experimental acute lung injury (ALI) and to further understand mediators of the resolution phase of ARDS. Recent work demonstrates macrophages transition from a predominant proinflammatory M1 phenotype during acute inflammation to an anti-inflammatory M2 phenotype with ALI resolution. We tested the hypothesis that IL-4, a potent inducer of M2-specific protein expression, would accelerate ALI resolution and lung repair through reprogramming of endogenous inflammatory macrophages. In fact, IL-4 treatment was found to offer dramatic benefits following delayed administration to mice subjected to experimental ALI, including increased survival, accelerated resolution of lung injury, and improved lung function. Expression of the M2 proteins Arg1, FIZZ1, and Ym1 was increased in lung tissues following IL-4 treatment, and among macrophages, FIZZ1 was most prominently upregulated in the interstitial subpopulation. A similar trend was observed for the expression of macrophage mannose receptor (MMR) and Dectin-1 on the surface of alveolar macrophages following IL-4 administration. Macrophage depletion or STAT6 deficiency abrogated the therapeutic effect of IL-4. Collectively, these data demonstrate that IL-4-mediated therapeutic macrophage reprogramming can accelerate resolution and lung repair despite delayed use following experimental ALI. IL-4 or other therapies that target late-phase, proresolution pathways may hold promise for the treatment of human ARDS.
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Zhu, Ying-Gang, Jie-Ming Qu, Jing Zhang, Hong-Ni Jiang, and Jin-Fu Xu. "Novel Interventional Approaches for ALI/ARDS: Cell-Based Gene Therapy." Mediators of Inflammation 2011 (2011): 1–7. http://dx.doi.org/10.1155/2011/560194.
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Acute lung injury (ALI) and its more severe form, acute respiratory distress syndrome (ARDS), continue to be a major cause of morbidity and mortality in critically ill patients. The present therapeutic strategies for ALI/ARDS including supportive care, pharmacological treatments, and ventilator support are still controversial. More scientists are focusing on therapies involving stem cells, which have self-renewing capabilities and differentiate into multiple cell lineages, and, genomics therapy which has the potential to upregulate expression of anti-inflammatory mediators. Recently, the combination of cell and gene therapy which has been demonstrated to provide additive benefit has opened up a new chapter in therapeutic strategy and provides a basis for the development of an innovative approach for the prevention and treatment of ALI/ARDS.
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Mortola. "Play Becomes Real for Adults: Measuring Effectiveness of Expressive Arts Media for Therapists in Training Using the Oaklander Approach." Gestalt Review 23, no. 1 (2019): 67. http://dx.doi.org/10.5325/gestaltreview.23.1.0067.
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Liu, Chang, Wenling Wu, Meng Xu, Jinglin Mi, Longjiang Xu, and Rensheng Wang. "Development and Validation of an Autophagy-Related Signature for Head and Neck Squamous Cell Carcinoma." BioMed Research International 2021 (August 11, 2021): 1–12. http://dx.doi.org/10.1155/2021/1028158.
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Introduction. HNSCC is the sixth most frequent type of malignant carcinoma with a low prognosis rate. In addition, autophagy is important in cancer development and progression. The purpose of this study is to investigate the potential significance of ARGs in the diagnosis and treatment of HNSCC. Materials and Methods. Expression data and clinical information of HNSCC samples were collected from the TCGA database, and a list of ARGs was obtained from the MSigDB. Then, we used R software to perform differential expression analysis and functional enrichment analysis. Further analysis was also performed to find out the survival-related ARGs in HNSCC, and two prognosis-related ARGs, FADD and NKX2-3, were selected to construct a prognosis prediction model. Moreover, some methods were applied to validate the prognosis prediction model. Finally, we used cell lines and clinical tissue samples of HNSCC to analyze the importance of FADD and NKX2-3. Results. We screened a total of 38 differentially expressed ARGs, and enrichment analysis showed that these genes were mainly involved in autophagy. Then, we selected FADD and NKX2-3 to construct a prognosis model and the risk score calculated by the model was proved to be effective in predicting the survival of HNSCC patients. Additionally, significant differences of the clinicopathological parameters could also be observed in the risk scores and the expression of NKX2-3 and FADD. The expression of FADD and NKX2-3 in cell lines and HNSCC tissue samples also showed the same trends. Conclusions. ARGs may be a potential biomarker for HNSCC prognosis, and targeted therapies for FADD and NKX2-3 are possible to be a new strategy of HNSCC treatment.
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Liu, Dongdong, Pu Mao, Yongbo Huang, Yiting Liu, Xiaoqing Liu, Xiaoqing Pang, and Yimin Li. "Proteomic Analysis of Lung Tissue in a Rat Acute Lung Injury Model: Identification of PRDX1 as a Promoter of Inflammation." Mediators of Inflammation 2014 (2014): 1–14. http://dx.doi.org/10.1155/2014/469358.
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Acute respiratory distress syndrome (ARDS) remains a high morbidity and mortality disease entity in critically ill patients, despite decades of numerous investigations into its pathogenesis. To obtain global protein expression changes in acute lung injury (ALI) lung tissues, we employed a high-throughput proteomics method to identify key components which may be involved in the pathogenesis of ALI. In the present study, we analyzed lung tissue proteomes ofPseudomonas aeruginosa-induced ALI rats and identified eighteen proteins whose expression levels changed more than twofold as compared to normal controls. In particular, we found that PRDX1 expression in culture medium was elevated by a lipopolysaccharide (LPS) challenge in airway epithelial cellsin vitro. Furthermore, overexpression of PRDX1 increased the expression of proinflammatory cytokines interleukin-6 (IL-6), interleukin-8 (IL-8), and tumor necrosis factor-α(TNF-α), whereas knockdown of PRDX1 led to downregulated expression of cytokines induced by LPS. In conclusion, our findings provide a global alteration in the proteome of lung tissues in the ALI rat model and indicate that PRDX1 may play a critical role in the pathogenesis of ARDS by promoting inflammation and represent a novel strategy for the development of new therapies against ALI.
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Nan, J. K. M., Bobo Hi-Po Lau, M. M. L. Szeto, K. K. F. Lam, J. C. N. Man, and C. L. W. Chan. "Competence Enhancement Program of Expressive Arts in End-of-Life Care for Health and Social Care Professionals: A Mixed-Method Evaluation." American Journal of Hospice and Palliative Medicine® 35, no. 9 (April 5, 2018): 1207–14. http://dx.doi.org/10.1177/1049909118765410.
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In the recent decades, expressive arts (EXA) has been used in end-of-life care (EOLC) for facilitating the quality of life of the patients and the caregivers. However, it may not be practical for every EOLC service to dispense EXA activities solely by extensively trained art therapy specialists. There is currently a lack of brief training for nonart therapists, which may have stifled the application of the techniques in clinical settings. The current study therefore described and evaluated the effectiveness of a 2-day EXA training workshop in enhancing practice, knowledge, and self-competence among health and social care professionals working in EOLC using a mixed-method approach. The quantitative findings show significant improvement in perceived competence of providing services per holistic and person-centered EOLC objectives, nonpharmaceutical management of symptoms, and evidence-based psychosocial care as well as self-competence in death work (SCDW) after the workshop. The qualitative findings corroborated the quantitative results by suggesting that the improvement in competence could be associated with enhanced communication, meaning reconstruction, and therapeutic relationship with the clients as well as the improvement in mood, socialization, and self-esteem among the clients through the learned EXA activities. Our findings support the efficacy of a brief training of EXA activities for nonart therapists in enhancing multifaceted intervention competence. Further research on brief training will be needed to promote the use of EXA activities in the EOLC context.
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Zhu, Jianhua, Jiazeng Yang, Zihan Zeng, Wenjin Zhang, Liyan Song, Wei Wen, and Rongmin Yu. "Inducing Effect of Dihydroartemisinic Acid in the Biosynthesis of Artemisinins with Cultured Cells ofArtemisia annuaby Enhancing the Expression of Genes." Scientific World Journal 2014 (2014): 1–7. http://dx.doi.org/10.1155/2014/293190.
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Artemisinin has been used in the production of “artemisinin combination therapies” for the treatment of malaria. Feeding of precursors has been proven to be one of the most effective methods to enhance artemisinin production in plant cultured cells. At the current paper, the biosynthesis of artemisinin (ART) and its four analogs from dihydroartemisinic acid (DHAA) in suspension-cultured cells ofArtemisia annuawere investigated. ARTs were detected by HPLC/GC-MS and isolated by various chromatography methods. The structures of four DHAA metabolites, namely, dihydro-epi-deoxyarteannuin B, arteannuin I, arteannuin K, and 3-β-hydroxy-dihydro-epi-deoxyarteannuin B, were elucidated by physicochemical and spectroscopic analyses. The correlation between gene expression and ART content was investigated. The results of RT-PCR showed that DHAA could up-regulate expression of amorpha-4,11-diene synthase gene (ADS), amorpha-4,11-diene C-12 oxidase gene (CYP71AV1), and farnesyl diphosphate synthase gene (FPS) (3.19-, 7.21-, and 2.04-fold higher than those of control group, resp.), which indicated that biosynthesis processes from DHAA to ART were enzyme-mediated.
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Sonpavde, Guru, Andrea Necchi, Shilpa Gupta, Gary D. Steinberg, Juergen E. Gschwend, Michiel Simon Van Der Heijden, Nathalie Garzon, et al. "A phase 3 randomized study of neoadjuvant chemotherapy (NAC) alone or in combination with nivolumab (NIVO) ± BMS-986205 in cisplatin-eligible muscle invasive bladder cancer (MIBC)." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): TPS4587. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.tps4587.
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TPS4587 Background: Immuno-oncology (IO) therapies have revolutionized the treatment (tx) of pts with advanced bladder cancer (advBC). For pts with cisplatin-eligible MIBC, the recommended tx regimen is cisplatin-based NAC prior to radical cystectomy (RC). However, since only ≈ 30% of pts achieve a pathologic complete response (pCR) translating to improved long-term outcomes with approved regimens, new therapies are needed. PD-L1 expression is associated with aggressive BC and has been shown to increase in BC after NAC, suggesting that the PD-1/PD-L1 axis is a valid therapeutic target. Additionally, expression of indoleamine 2,3-dioxygenase (IDO) is higher in BC than in normal bladder tissue and is associated with advanced disease and poor clinical outcome. BMS-986205, a selective, potent, once-daily oral IDO1 inhibitor that works early in the IDO1 pathway to reduce kynurenine production, has demonstrated clinical activity in combination with NIVO (anti–PD-1) in pts with IO tx–naive advBC who had ≥ 1 prior line of therapy (ORR, 37%). Taken together, these data provide a rationale for investigating NAC + NIVO + BMS-986205 in MIBC. Here we describe a randomized, partially blinded, phase 3 study evaluating the efficacy and safety of NAC ± NIVO ± BMS-986205 followed by RC and continued IO tx in pts with MIBC (NCT03661320). Methods: Pts aged ≥ 18 years with previously untreated MIBC (clinical stage T2-T4a, N0, M0), creatinine clearance ≥ 50 mL/min, and predominant UC histology who are eligible for cisplatin-based NAC and RC will be enrolled. Pts with evidence of positive lymph node; metastatic BC; or prior systemic therapy, radiotherapy, or surgery for BC other than TURBT are not eligible. Pts will be randomized to receive NAC (gemcitabine/cisplatin; arm A), NAC + NIVO + oral placebo (arm B), or NAC + NIVO + BMS-986205 (arm C) followed by RC (all arms); arms B and C will receive continued IO tx. Primary endpoints include pCR after neoadjuvant tx and event-free survival (arms C vs A; arms B vs A). Secondary endpoints are overall survival and safety. This global study in 28 countries began accrual in Nov 2018 and has a target enrollment of 1200 pts. Clinical trial information: NCT03661320.
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Sonpavde, Guru, Andrea Necchi, Shilpa Gupta, Gary D. Steinberg, Juergen Gschwend, Michiel Simon Van Der Heijden, Audrey Richiero, et al. "A phase III randomized study of neoadjuvant chemotherapy (NAC) alone or in combination with nivolumab (NIVO) ± linrodostat mesylate, followed by adjuvant postsurgical NIVO ± linrodostat, in cisplatin-eligible muscle invasive bladder cancer (MIBC)." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): TPS5091. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.tps5091.
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TPS5091 Background: Immuno-oncology (IO) therapies have revolutionized the treatment (tx) of pts with advanced bladder cancer (advBC). For pts with cisplatin-eligible, muscle invasive BC (MIBC), the recommended tx is cisplatin-based neoadjuvant chemotherapy (NAC) prior to radical cystectomy (RC). However, since only ≈ 30% of pts achieve a pathologic complete response (pCR) translating to improved long-term outcomes with approved regimens, new therapies are needed. PD-L1 expression is associated with aggressive BC and has been shown to increase in BC after NAC, supporting the therapeutic pursuit of the PD-1/PD-L1 axis. Additionally, expression of indoleamine 2,3-dioxygenase (IDO) is higher in BC than in normal bladder tissue and is associated with advanced disease and poor clinical outcome. Linrodostat mesylate, a selective, potent, once-daily oral IDO1 inhibitor that works to reduce kynurenine production, has demonstrated clinical activity in combination with NIVO (anti–PD-1) in pts with IO tx–naive advBC who had ≥ 1 prior line of therapy (ORR, 37%). Taken together, these data provide a rationale for investigating NAC + NIVO + linrodostat in MIBC. Here we describe a randomized, partially blinded, phase 3 study evaluating the efficacy and safety of NAC ± NIVO ± linrodostat followed by RC and continued IO tx in pts with MIBC (NCT03661320). Methods: Pts aged ≥ 18 years with previously untreated MIBC (clinical stage T2-T4a, N0, M0), creatinine clearance ≥ 50 mL/min, and predominant UC histology who are eligible for cisplatin-based NAC and RC will be enrolled. Pts with evidence of positive lymph node; metastatic BC; or prior systemic therapy, radiotherapy, or surgery for BC other than TURBT are not eligible. Pts will be randomized to receive NAC (gemcitabine/cisplatin; arm A), NAC + NIVO + oral placebo (arm B), or NAC + NIVO + linrodostat (arm C) followed by RC (all arms); arms B and C will receive continued IO tx. Primary endpoints include pCR after neoadjuvant tx and event-free survival (arms C vs A; arms B vs A). Secondary endpoints are overall survival and safety. This global study in 28 countries began accrual in Nov 2018 and has a target enrollment of 1200 pts. Clinical trial information: NCT03661320 .
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Rosen, Alan. "Return from the vanishing point: a clinician's perspective on art and mental illness, and particularly schizophrenia." Epidemiologia e Psichiatria Sociale 16, no. 2 (June 2007): 126–32. http://dx.doi.org/10.1017/s1121189x00004747.
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SUMMARYAims - To examine earlier uses and abuses of artworks by individuals living with severe mental illnesses, and particularly schizophrenia by both the psychiatric and arts communities and prevailing stereotypes associated with such practices. Further, to explore alternative constructions of the artworks and roles of the artist with schizophrenia and other severe mental illnesses, which may be more consistent with amore contemporary recovery orientation, encompassing their potentials for empowerment, social inclusion as citizens and legitimacy of their cultural role in the community. Results - Earlier practices with regardto the artworks of captive patients of psychiatrists, psychotherapists, art therapists, occupational and diversional therapists, often emphasised diagnostic or interpretive purposes, or were used to gauge progress or exemplify particular syndromes. As artists and art historians began to take an interest in such artworks, they emphasised their expressive, communicative and aesthetic aspects, sometimes in relation to primitive art. These efforts to ascribe value to these works, while well-meaning, were sometimes patronising and vulnerable to perversion by totalitarian regimes, which portrayed them as degenerate art, often alongside the works of mainstream modernist artists. This has culminated in revelations that the most prominent European collection of psychiatric art still contains, and appears to have only started to acknowledge since these revelations, unattributed works by hospital patients who were exterminated in the so-called “euthanasia” program in the Nazi era. Conclusions - Terms like Psychiatric Art, Art Therapy, Art Brut and Outsider Art may be vulnerable to abuse and are a poor fit with the aspirations of artists living with severe mental illnesses, who are increasingly exercising their rights to live and work freely, without being captive, or having others controlling their lives, or mediating and interpreting their works. They sometimes do not mind living voluntarily marginal lives as artists, but they prefer to live as citizens, without being involuntarily marginalised by stigma. They also prefer to live with culturally valued roles which are recognised as legitimate in the community, where they are also more likely to heal and recover.Declaration of Interest: This paper was completed during a Visiting Fellowship, Department of Social Medicine, School of Public Health, & Department of Medical Anthropology, Faculty of Arts & Sciences, Harvard University, Cambridge, Mass, USA. A condensed version of this paper is published in “For Matthew & Others: Journeys with Schizophrenia”, Dysart, D, Fenner, F, Loxley, A, eds. Sydney, University of New South Wales Press in conjunction with Campbelltown Arts Centre & Joan Sutherland Performing Arts Centre, Penrith, 2006, to accompany with a large exhibition of the same name, with symposia & performances, atseveral public art galleries in Sydney & Melbourne, Australia. The author is also a printmaker, partly trained at Ruskin School, Oxford, Central St. Martin's School, London, and College of Fine Arts, University of New South Wales, Sydney.
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Dupuis, Jocelyn, Martin G. Sirois, Eric Rhéaume, Quang T. Nguyen, Marie-Élaine Clavet-Lanthier, Genevieve Brand, Teodora Mihalache-Avram, et al. "Colchicine reduces lung injury in experimental acute respiratory distress syndrome." PLOS ONE 15, no. 12 (December 2, 2020): e0242318. http://dx.doi.org/10.1371/journal.pone.0242318.
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The acute respiratory distress syndrome (ARDS) is characterized by intense dysregulated inflammation leading to acute lung injury (ALI) and respiratory failure. There are no effective pharmacologic therapies for ARDS. Colchicine is a low-cost, widely available drug, effective in the treatment of inflammatory conditions. We studied the effects of colchicine pre-treatment on oleic acid-induced ARDS in rats. Rats were treated with colchicine (1 mg/kg) or placebo for three days prior to intravenous oleic acid-induced ALI (150 mg/kg). Four hours later they were studied and compared to a sham group. Colchicine reduced the area of histological lung injury by 61%, reduced lung edema, and markedly improved oxygenation by increasing PaO2/FiO2 from 66 ± 13 mmHg (mean ± SEM) to 246 ± 45 mmHg compared to 380 ± 18 mmHg in sham animals. Colchicine also reduced PaCO2 and respiratory acidosis. Lung neutrophil recruitment, assessed by myeloperoxidase immunostaining, was greatly increased after injury from 1.16 ± 0.19% to 8.86 ± 0.66% and significantly reduced by colchicine to 5.95 ± 1.13%. Increased lung NETosis was also reduced by therapy. Circulating leukocytosis after ALI was not reduced by colchicine therapy, but neutrophils reactivity and CD4 and CD8 cell surface expression on lymphocyte populations were restored. Colchicine reduces ALI and respiratory failure in experimental ARDS in relation with reduced lung neutrophil recruitment and reduced circulating leukocyte activation. This study supports the clinical development of colchicine for the prevention of ARDS in conditions causing ALI.
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Innocenti, Federico, Akram Yazdani, Xueping Qu, Fang-Shu Ou, Scott Van Buren, Omar Kabbarah, Charles David Blanke, Alan P. Venook, Heinz-Josef Lenz, and Benjamin Garrett Vincent. "Immune signatures to affect overall survival (OS) and response to bevacizumab (Bev) or cetuximab (Cet) in patients (pts) with metastatic colorectal cancer (mCRC) of CALGB/SWOG 80405 (Alliance)." Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021): 3515. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.3515.
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3515 Background: CALGB/SWOG 80405 was a randomized phase III trial in first-line mCRC patients treated with Bev, Cet, or both, plus chemotherapy. No difference in OS was found between Bev and Cet. We tested the effect of immune signatures on OS in all the three arms of the study and analyzed differences in OS between the Cet and Bev arms. Methods: 578 primary tumors were profiled by RNAseq. Immune signatures of TGF-β, cytotoxic T cells, wound healing, macrophages, lymphocytes, and INF-γ, as well as relative frequencies of CD8+ T-cells, memory resting CD4+ T cells, memory activated CD4+ T cells, macrophages M1 and M2, and activated mast cells were measured. Multivariate Cox proportional hazard models were applied using elastic-net penalization with covariates (age, race, gender, all RAS and BRAF V600E mutations). For relevant signatures, optimal cut-offs for OS were calculated. Results: In all the three arms of the study, high expression of macrophages M2 (HR 6.81, 95% CI 3.56-30.16) and TGF-β (HR 1.37, 95% CI 1.03-2.10) conferred reduced OS compared to low expression; high expression of plasma cells (HR 0.52, 95% CI 0.27-0.83) and memory-activated CD4+ T cells (HR 0.34, 95% CI 0.10-0.65) conferred increased OS compared to low expression. Using optimal cut-offs from these 4 signatures, pts have been categorized as to whether they had either 4, 3, 2, 1, or 0 beneficial signatures associated with increased OS. In all arms of the study (N = 469, after accounting for covariates), the median (95% CI) OS decreased from 42.5 (35.8-47.8; N = 79), to 31.0 (28.8-34.4; N = 177), 25.2 (20.6-27.9; N = 144), and 17.0 (13.5-20.4; N = 69) months when the number of beneficial signatures decreased from 4, to 3, 2, and 0-1 (combined due to a low number of pts), respectively (p = 3.48e-11). In the Bev arm (N = 205), high expression of macrophages M2 conferred reduced OS compared to low expression (HR 6.6, 95% CI 2.7-67.1). In the Cet arm (N = 165), high expression of macrophages M2 conferred reduced OS compared to low expression (HR 4.3, 95% CI 2.1-79.8); high expression of plasma cells (HR 0.36, 95% CI 0.06-0.55) and memory activated CD4+ T cells (HR 0.37, 95% CI 0.03-0.98) conferred increased OS compared to low expression of either signatures. The plasma cell signature interacted with Bev and Cet on the OS of pts (interaction p = 0.009). Conclusions: Tumor immune signatures in mCRC pts are determinants of survival. In pts treated with Bev- and Cet-combination therapies that are standard of care, immune signatures affect response to therapy. These results, provide new markers for treatment selection and for the development of novel active combinations including immune checkpoint inhibitors. Support: U10CA180821, U10CA180882, U24CA196171; https://acknowledgments.alliancefound.org
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Panowski, Siler H., Tracy Kuo, Amy Chen, Tao Geng, Thomas J. Van Blarcom, Kevin Lindquist, Wei Chen, Javier Chaparro-Riggers, and Barbra Sasu. "Preclinical Evaluation of a Potent Anti-Bcma CD3 Bispecific Molecule for the Treatment of Multiple Myeloma." Blood 128, no. 22 (December 2, 2016): 383. http://dx.doi.org/10.1182/blood.v128.22.383.383.
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Abstract Multiple myeloma (MM) is a debilitating disease characterized by the abnormal accumulation of malignant plasma cells in the bone marrow. Despite recent advances in myeloma therapy, including proteasome inhibitors, immunomodulatory drugs, and targeted antibody therapies, patients relapse and the disease remains incurable and one of high unmet need. T cell redirecting therapies are a new and exciting class of therapeutics that harness the potent cytotoxic activity of T cells and redirect it to target tumor cells. T cell redirecting therapies are only as good as their targeted tumor associated antigen (TAA) and the potent nature of the therapy requires a lack of TAA expression in essential normal tissue. B-cell Maturation Antigen, BCMA, is a tumor necrosis factor superfamily member highly expressed on the surface of myeloma cells. Detectable normal BCMA tissue expression appears limited to plasmablasts and mature plasma cells, making it an ideal T cell redirecting target for the treatment of MM. Other groups have developed T cell redirecting therapies against BCMA, including CAR T and BiTE therapy (a short half-life CD3 bispecific). Here we present preclinical studies on a fully-human IgG CD3 bispecific molecule targeting BCMA (half-life in mice of ~3 days). This molecule utilizes anti-BCMA and anti-CD3 targeting arms paired through hinge mutation technology and placed in an IgG2A backbone. The molecule binds to BCMA-expressing myeloma cell lines and to T cells with affinities of 20pM and ~40nM, respectively. T cells co-cultured with MM cell lines were activated and de-granulated in the presence of BCMA bispecific. In vitro cytotoxicity assays revealed the high potency of the molecule, as it was able to drive lysis of MM target cells with an EC50 of 6± 8 pM (mean ± SD). We also observed strong in vitro potency with the BCMA bispecific in four different MM primary patient samples, EC50 =0.093±0.1 nM (mean ± SD). When the same four samples were targeted with a BCMA antibody drug conjugate (ADC), 3 of the samples gave EC50 values of 1.25±0.7 nM (mean ± SD) - i.e. a 43 fold decrease in potency compared to the CD3 bispecific. The fourth patient did not respond to the ADC. Together, these results illustrate the potential advantages of a CD3 bispecific over an ADC for targeting BCMA. In orthotopic, established, tumor mouse models utilizing three different MM cell lines, (OPM2, MM.1S and MOLP8), a single injection of BCMA bispecific effectively treated tumors in a dose-dependent manner. Re-dosing the bispecific was able to provide additional and prolonged efficacy. The extreme potency of T cell redirecting therapies results in outstanding efficacy, but can also lead to lysis of normal cells expressing even minute levels of target. The species cross-reactivity of the BCMA bispecific allowed for exploratory toxicity studies in cynomologus monkeys. The molecule was able to effectively deplete normal plasma B cells expressing low levels of BCMA, providing evidence of activity. Activity was accompanied by a cytokine spike following initial dosing. No cytokine release was observed following a second bispecific dose. Encouragingly, animals experienced no additional adverse events (AEs), confirming the favorable safety profile of BCMA as a target for MM. In summary, we report on a fully human IgG CD3 bispecific molecule targeting BCMA for the treatment of multiple myeloma. Our BCMA bispecific is expected to have an antibody-like half-life in humans and, taken together, our findings support that the molecule has the potential to be both a potent and safe therapeutic. Disclosures Panowski: Pfizer Inc.: Employment. Kuo:Alexo Therapeutics: Employment. Chen:Alexo Therapeutics: Employment. Geng:Kodiak Sciences: Employment. Van Blarcom:Pfizer Inc.: Employment. Lindquist:Pfizer Inc.: Employment. Chen:Pfizer Inc.: Employment. Chaparro-Riggers:Pfizer Inc.: Employment. Sasu:Pfizer Inc.: Employment.
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Shah, Dilip, Pragnya Das, Suchismita Acharya, Beamon Agarwal, Dale J. Christensen, Stella M. Robertson, and Vineet Bhandari. "Small Immunomodulatory Molecules as Potential Therapeutics in Experimental Murine Models of Acute Lung Injury (ALI)/Acute Respiratory Distress Syndrome (ARDS)." International Journal of Molecular Sciences 22, no. 5 (March 4, 2021): 2573. http://dx.doi.org/10.3390/ijms22052573.
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Background: Acute lung injury (ALI) or its most advanced form, acute respiratory distress syndrome (ARDS) is a severe inflammatory pulmonary process triggered by a variety of insults including sepsis, viral or bacterial pneumonia, and mechanical ventilator-induced trauma. Currently, there are no effective therapies available for ARDS. We have recently reported that a novel small molecule AVR-25 derived from chitin molecule (a long-chain polymer of N-acetylglucosamine) showed anti-inflammatory effects in the lungs. The goal of this study was to determine the efficacy of two chitin-derived compounds, AVR-25 and AVR-48, in multiple mouse models of ALI/ARDS. We further determined the safety and pharmacokinetic (PK) profile of the lead compound AVR-48 in rats. Methods: ALI in mice was induced by intratracheal instillation of a single dose of lipopolysaccharide (LPS; 100 µg) for 24 h or exposed to hyperoxia (100% oxygen) for 48 h or undergoing cecal ligation and puncture (CLP) procedure and observation for 10 days. Results: Both chitin derivatives, AVR-25 and AVR-48, showed decreased neutrophil recruitment and reduced inflammation in the lungs of ALI mice. Further, AVR-25 and AVR-48 mediated diminished lung inflammation was associated with reduced expression of lung adhesion molecules with improvement in pulmonary endothelial barrier function, pulmonary edema, and lung injury. Consistent with these results, CLP-induced sepsis mice treated with AVR-48 showed a significant increase in survival of the mice (80%) and improved lung histopathology in the treated CLP group. AVR-48, the lead chitin derivative compound, demonstrated a good safety profile. Conclusion: Both AVR-25 and AVR-48 demonstrate the potential to be developed as therapeutic agents to treat ALI/ARDS.
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Cohen, Adam D., Suzanne Trudel, Peter A. Forsberg, Rafael Fonseca, Amrita Y. Krishnan, Andrew Spencer, Jesus G. Berdeja, et al. "GO39775: A multicenter phase I trial evaluating the safety, pharmacokinetics, and activity of BFCR4350A, a FcRH5/CD3 T-cell dependent bispecific antibody, in patients with relapsed or refractory multiple myeloma." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): TPS8551. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.tps8551.
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TPS8551 Background: Multiple myeloma (MM) remains an incurable disease, with estimated median survival of 8–9 months in patients with relapsed or refractory (R/R) disease (Kumar et al. 2014; Usmani et al. 2016). There is no uniform standard of care for R/R MM, and combinations used in later lines have diminishing responses, especially after re-exposure to previously received classes of therapy (Gandhi et al. 2019). New targets and treatment modalities are needed. Fragment crystallizable receptor-like 5 (FcRH5) is expressed on myeloma cells across lines of therapy, and is overexpressed by myeloma cells with 1q21 gain; expression in healthy tissue is restricted to the B-cell lineage, and is retained in plasma cells (Li et al. 2017). BFCR4350A is an IgG-based T-cell-dependent bispecific antibody that was specifically engineered to target the most membrane-proximal domain of FcRH5 on myeloma cells and cluster of differentiation 3 (CD3) on T cells, with dual binding resulting in efficient immune synapse formation and T-cell killing of myeloma cells. BFCR4350A demonstrates potent killing of plasma cells and patient-derived myeloma cells (including those with low levels of FcRH5 expression) in vitro, and complete depletion of bone marrow plasma cells in primates, without severe or prolonged cytokine release (Li et al. 2017). GO39775 (NCT03275103) is an open-label, multicenter Phase I dose-escalation and dose-expansion trial evaluating the safety, pharmacokinetics (PK), and activity of BFCR4350A monotherapy in patients with R/R MM. Methods: Patients must be aged ≥18 years and must have R/R MM for which no established therapies are available or appropriate, or be intolerant to those therapies. Patients with prior CAR-T therapy and/or prior BCMA-directed therapy are not excluded. BFCR4350A is administered by intravenous infusion, and q3w dosing with Cycle 1 single-step or multi-step dosing is being investigated in dose-escalation (Arms A and B, respectively). Enrolment into both arms is ongoing, with patients receiving up to 17 cycles of treatment until disease progression or unacceptable toxicity. Primary objectives are to evaluate safety (including the maximum tolerated dose and dose-limiting toxicities) and to identify a recommended Phase II dose. Secondary objectives include assessment of PK, activity, immunogenicity, and pharmacodynamic biomarkers. Clinical trial information: NCT03275103 .
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Puig, Ana, Sang Min Lee, Linda Goodwin, and Peter A. D. Sherrard. "The efficacy of creative arts therapies to enhance emotional expression, spirituality, and psychological well-being of newly diagnosed Stage I and Stage II breast cancer patients: A preliminary study." Arts in Psychotherapy 33, no. 3 (January 2006): 218–28. http://dx.doi.org/10.1016/j.aip.2006.02.004.
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Papadimitrakopoulou, Vassiliki, J. Jack Lee, Ignacio I. Wistuba, Anne S. Tsao, Frank V. Fossella, Neda Kalhor, Sanjay Gupta, et al. "The BATTLE-2 Study: A Biomarker-Integrated Targeted Therapy Study in Previously Treated Patients With Advanced Non–Small-Cell Lung Cancer." Journal of Clinical Oncology 34, no. 30 (October 20, 2016): 3638–47. http://dx.doi.org/10.1200/jco.2015.66.0084.
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Purpose By applying the principles of real-time biopsy, biomarker-based, adaptively randomized studies in non–small-cell lung cancer (NSCLC) established by the Biomarker-Integrated Approaches of Targeted Therapy for Lung Cancer Elimination (BATTLE) trial, we conducted BATTLE-2 (BATTLE-2 Program: A Biomarker-Integrated Targeted Therapy Study in Previously Treated Patients With Advanced Non-Small Cell Lung Cancer), an umbrella study to evaluate the effects of targeted therapies focusing on KRAS-mutated cancers. Patients and Methods Patients with advanced NSCLC (excluding sensitizing EGFR mutations and ALK gene fusions) refractory to more than one prior therapy were randomly assigned, stratified by KRAS status, to four arms: (1) erlotinib, (2) erlotinib plus MK-2206, (3) MK-2206 plus AZD6244, or (4) sorafenib. Tumor gene expression profiling–targeted next-generation sequencing was performed to evaluate predictive and prognostic biomarkers. Results Two hundred patients, 27% with KRAS-mutated (KRAS mut+) tumors, were adaptively randomly assigned to erlotinib (n = 22), erlotinib plus MK-2206 (n = 42), MK-2206 plus AZD6244 (n = 75), or sorafenib (n = 61). In all, 186 patients were evaluable, and the primary end point of an 8-week disease control rate (DCR) was 48% (arm 1, 32%; arm 2, 50%; arm 3, 53%; and arm 4, 46%). For KRAS mut+ patients, DCR was 20%, 25%, 62%, and 44% whereas for KRAS wild-type patients, DCR was 36%, 57%, 49%, and 47% for arms 1, 2, 3, and 4, respectively. Median progression-free survival was 2.0 months, not different by KRAS status, 1.8 months for arm 1, and 2.5 months for arms 2 versus arms 3 and 4 in KRAS mut+ patients (P = .04). Median overall survival was 6.5 months, 9.0 and 5.1 months for arms 1 and 2 versus arms 3 and 4 in KRAS wild-type patients (P = .03). Median overall survival was 7.5 months in mesenchymal versus 5 months in epithelial tumors (P = .02). Conclusion Despite improved progression-free survival on therapy that did not contain erlotinib for KRAS mut+ patients and improved prognosis for mesenchymal tumors, better biomarker-driven treatment strategies are still needed.
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Bordeleau, Louise, John Paul Szalai, Marguerite Ennis, Molyn Leszcz, Michael Speca, Rami Sela, Richard Doll, et al. "Quality of Life in a Randomized Trial of Group Psychosocial Support in Metastatic Breast Cancer: Overall Effects of the Intervention and an Exploration of Missing Data." Journal of Clinical Oncology 21, no. 10 (May 15, 2003): 1944–51. http://dx.doi.org/10.1200/jco.2003.04.080.
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Purpose: To evaluate the effect of a standardized group psychosocial intervention on health-related quality of life (HrQOL) in women with metastatic breast cancer and to explore the effect of missing data in HrQOL analyses. Patients and Methods: Between 1993 and 1998, seven Canadian centers randomly assigned 235 eligible women to participate in a weekly, 90-minute, therapist-led support group that adhered to principles of supportive-expressive (SE) therapy or to a control arm (no SE). All women received educational material and any type of medical or psychosocial care deemed necessary. HrQOL data were prospectively collected using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30) at baseline, 4, 8, and 12 months. The primary HrQOL analyses compared scores in the two study arms. Analyses were limited to women with appropriate baseline HrQOL information (n = 215). Results: Baseline EORTC QLQ-C30 scores were not different between the two study arms (all P > .05). Primary analysis of all subscales failed to show a significant influence of the intervention on HrQOL (all P > .05). There was a significant deterioration over time in several functional scales of the EORTC QLQ-C30: global (P = .03), physical (P = .0002), role (P = .01), and cognitive functioning (P = .04); and in symptom scales: dyspnea (P = .007), appetite loss (P = .04), and fatigue (P = .003); these changes were independent of randomization allocation. Results were similar in additional analyses of overall HrQOL using a variety of approaches to handling missing data. Conclusion: Supportive-expressive group therapy in patients with metastatic breast cancer does not appear to influence HrQOL, as measured by the EORTC QLQ-C30.
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Hellmann, Matthew David, Patrick Alexander Ott, Jon Zugazagoitia, Neal E. Ready, Christine L. Hann, Filippo G. De Braud, Scott Joseph Antonia, et al. "Nivolumab (nivo) ± ipilimumab (ipi) in advanced small-cell lung cancer (SCLC): First report of a randomized expansion cohort from CheckMate 032." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): 8503. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.8503.
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8503 Background: Patients (pts) with advanced SCLC after first-line platinum-based chemotherapy (PLT-CT) have a poor prognosis and limited treatment options. CheckMate 032 is a phase I/II trial evaluating multiple regimens of nivo ± ipi in solid tumors, including advanced SCLC. Tolerability and efficacy of nivo ± ipi were demonstrated in early results from the initial treatment arms (Antonia, Lancet Oncol 2016), prompting long-term follow-up and the addition of a randomized expansion cohort to further evaluate nivo ± ipi in advanced SCLC. Methods: In the initial treatment arms, pts with advanced SCLC and disease progression after prior PLT-CT were assigned to nivo (3 mg/kg Q2W; n = 98) or nivo 1 + ipi 3 (1 mg/kg and 3 mg/kg Q3W x 4, then nivo 3 Q2W; n = 61); safety/efficacy was assessed with a follow-up of ~18 mo. In the subsequent SCLC expansion cohort, pts were randomized 3:2 to nivo vs nivo 1 + ipi 3 and stratified by number of prior therapies. The primary endpoint was objective response rate (ORR). Results: Updated efficacy/safety results from the initial (non-randomized) nivo and nivo 1 + ipi 3 arms are summarized in the table. Responses were durable and occurred regardless of PD-L1 expression or PLT-sensitivity; safety was consistent with prior nivo ± ipi studies. In the expansion cohort, 247 pts were randomized to nivo or nivo 1 + ipi 3. The presentation will contain the first report of efficacy/safety results and subgroup analyses from this randomized expansion cohort. Conclusions: Durable responses are observed with nivo and nivo + ipi in pts with previously treated SCLC. The expansion cohort represents the first randomized evaluation of combined immune checkpoint blockade in SCLC. Clinical trial information: NCT01928394. [Table: see text]
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Miekus, Kasia, Marcin Wysoczynski, Ryan Reca, Gozdzik Jolanta, Bertolone J. Salvatore, Anna Janowska-Wieczorek, and Mariusz Z. Ratajczak. "LIF-LIF-R and SDF-1-CXCR4 Axes Regulate Overlapping and Complementary Steps of Metastasis of Rhabdomyosarcoma - Implication for Developing Better Antimetastatic Therapies." Blood 106, no. 11 (November 16, 2005): 2296. http://dx.doi.org/10.1182/blood.v106.11.2296.2296.
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Abstract Rhabdomyosarcoma (RMS) and skeletal muscle-derived tumors frequently infiltrate bone marrow (BM). We have demonstrated that the stromal-derived factor (SDF)-1-CXCR4 receptor (Blood2002;100:2597) and Leukemia Inhibitory Factor (LIF)-LIF- receptor (LIF-R) axes play a pivotal role in RMS metastasis to BM. In this study performed on primary patient material (n=23) and human alveolar and embryonal RMS cell lines, we compared various prometastatic effects of both axes. First, we found that both motomorphogens (LIF and SDF-1) and their corresponding receptors (LIF-R and CXCR4) are upregulated in hypoxic conditions. Second, both functional receptors were expressed on RMS cells; however, the expression of LIF-R in contrast to CXCR4 was PAX3-FKHR-independent and did not correlate with the alveolar rhabdomyosarcoma (ARMS) phenotype. Both ligands stimulated similar signaling pathways (MAPKp42/44 and AKT) in RMS cells and similarly stimulated directional chemotaxis. However, SDF-1 affected the spontaneous motility of RMS cells to a higher degree than LIF and strongly upregulated the secretion of MMPs and VEGF. In contrast, LIF enhanced the resistance of RMS cells to cytostatics (e.g., etoposide). To compare the biological effects of both axes we focused on the ARMS cell line RH30 (highly responsive to SDF-1 and LIF) and selected cells that responded to SDF-1 but not LIF (RH30-S) and to LIF but not SDF-1 (RH30-L) by using repetitive chemotaxis to SDF-1 or LIF. We found that RH30-L cells, as compared to RH30-S cells, responded worse in chemotactic assay to BM-derived conditioned media; however, they adhered much better to BM stroma. When both cell populations (RH30-S and RH30-L), together with the parental RH30 cells, were tested in vivo for their seeding potential in various organs in RAG2 immunodeficient mice, we found that RH30-L cells seeded better to BM, liver and lymph nodes than RH30-S cells. More important, the metastatic potential of RH30 cells was significantly reduced only when the inhibitors of both receptors, (T140 for LIF-R and gp130 blocking antibody for CXCR4) were employed together. Hence, since RMS cells respond to more than one chemoattractant, strategies aimed at targeting a single factor-receptor axis would be ineffective. Targeting of the LIF-LIF-R axis, along with the SDF-1-CXCR4 axis, could thus become a new, more effective antimetastatic strategy to inhibit RMS metastasis.
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Di Bacco, Alessandra, Nizar J. Bahlis, Nikhil C. Munshi, Hervé Avet-Loiseau, Tamás Masszi, Luísa Viterbo, Ludek Pour, et al. "Higher c-MYC Expression Is Associated with Ixazomib-Lenalidomide-Dexamethasone (IRd) Progression-Free Survival (PFS) Benefit Versus Placebo-Rd: Biomarker Analysis of the Phase 3 Tourmaline-MM1 Study in Relapsed/Refractory Multiple Myeloma (RRMM)." Blood 128, no. 22 (December 2, 2016): 243. http://dx.doi.org/10.1182/blood.v128.22.243.243.
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Abstract Background Ixazomib, the first oral proteasome inhibitor, is approved by the US FDA, in combination with Rd, for the treatment of MM patients (pts) who have received at least 1 prior therapy. Approval was based on the double-blind, placebo-controlled phase 3 TOURMALINE-MM1 study (NCT01564537) in 722 pts with RRMM (Moreau et al, N Engl J Med 2016), in which IRd showed superior PFS versus placebo-Rd (HR 0.74) at the final prespecified analysis, with limited additional toxicity. Prespecified subgroup analyses showed a consistent PFS benefit with IRd, but with a differential treatment effect according to prior therapy exposure. An exploratory study objective was to evaluate potential relationships between treatment outcomes and tumor gene expression patterns. c-MYC is a proto-oncogene that encodes a transcription factor regulating cell proliferation, growth, protein translation, metabolism, and apoptosis, and increased c-MYC expression is involved in MM pathogenesis/progression. We analyzed the impact of c-MYC expression on PFS in RRMM pts treated with IRd or placebo-Rd. Methods Pts with RRMM after 1-3 prior lines of therapy were randomized 1:1 to receive oral ixazomib or placebo, plus lenalidomide and dexamethasone, until disease progression or unacceptable toxicity. Randomization was stratified by number of prior therapies (1 vs 2-3), proteasome inhibitor exposure, and ISS disease stage. The primary endpoint was PFS by independent review committee assessment. Data reported here are from the final prespecified statistical analysis of PFS (median follow-up ~15 months). Bone marrow aspirate samples were collected at screening for tumor gene expression analysis. Whole transcriptome sequencing (RNAseq) of bone marrow-sorted CD138+ cells was performed using the Illumina Truseq protocol on the Illumina HiSeq platform; this generated a median of 50 million paired-end reads (100 bp length) per sample. c-MYC expression was evaluated by treatment arm and according to number of prior therapies (1 vs 2-3). PFS was analyzed in subgroups dichotomized according to median c-MYC expression (c-MYC-high/c-MYC-low). Results RNAseq data were available for 59% (427/722) of enrolled pts; 213 (50%) had high and 219 (50%) had low c-MYC expression (dichotomized according to the median). Impact of c-MYC expression (high vs low) on PFS, irrespective of treatment arm, was not significant (p=0.98). However, a significant treatment effect of IRd vs placebo-Rd was only seen in pts with high c-MYC expression (interaction p=0.024); in these pts (IRd: n=109; placebo-Rd: n=104) a significant PFS benefit was seen with IRd (HR 0.41; 95% CI: 0.26-0.65, p=0.00011). Impact of c-MYC expression was then analyzed by number of prior therapies. In the overall TOURMALINE-MM1 population, per stratification, 212/213 pts in the IRd/placebo-Rd arms had 1 prior therapy, and 148/149 had 2-3 prior therapies. After median follow-up of ~15 months, median PFS in pts with 1 prior therapy was 20.6 vs 16.6 months with IRd vs placebo-Rd (HR 0.88; 95% CI: 0.65-1.20), and in pts with 2-3 prior therapies was not reached vs 12.9 months (HR 0.58; 95% CI: 0.40-0.84, p=0.0033). The level of c-MYC expression was shown to be significantly higher in pts with 2-3 prior therapies vs 1 prior therapy, with median expression of 6.94 (SD=1.71, n=177) vs 6.52 (SD=1.74, n=250) (log2 scale), t-test p-value 0.0153. In pts with 1 prior therapy, no differences in PFS were observed between pts with low c-MYC expression (HR 1; 95% CI: 0.59-1.8, p=0.934), while a prolonged PFS benefit was observed in pts with high c-MYC expression (HR 0.48; 95% CI: 0.26-0.88, p=0.0146) (Figure, A and B). In pts with 2-3 prior therapies, both the c-MYC-high and c-MYC-low pts showed improved PFS with IRd vs placebo-Rd; the difference in PFS was statistically significant only in c-MYC-high pts (HR 0.36; 95% CI: 0.18-0.72, p=0.00269) (Figure, C and D). Conclusions In TOURMALINE-MM1, c-MYC expression was higher in MM tumor samples from pts with 2-3 vs 1 prior therapies. The IRd regimen was active in c-MYC-high and c-MYC-low pts, but its impact on PFS vs placebo-Rd was greater in c-MYC-high pts, thus providing a potential explanation for the enhanced PFS benefit with IRd vs placebo-Rd in pts with 2-3 prior therapies. The PFS benefit with IRd in c-MYC-low pts with 2-3 prior lines suggests that, in advanced MM, further genomic alterations may also be contributing to ixazomib sensitivity. Disclosures Di Bacco: Millennium Pharmaceuticals Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Bahlis:BMS: Honoraria; Onyx: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Other: Travel Expenses, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Other: Travel Expenses, Research Funding, Speakers Bureau. Avet-Loiseau:Takeda: Speakers Bureau; Janssen: Speakers Bureau; Celgene: Speakers Bureau; Sanofi: Speakers Bureau. Masszi:Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Ganly:Medipics: Equity Ownership; Novartis: Honoraria; Roche: Honoraria. Cavo:Bristol-Myers Squibb: Consultancy, Honoraria; Millennium: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Langer:Celgene: Consultancy; Takeda: Consultancy; Janssen: Consultancy; Amgen: Consultancy; Novartis: Consultancy. Kumar:Array BioPharma: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding; AbbVie: Research Funding; Onyx: Consultancy, Research Funding; Noxxon Pharma: Consultancy, Research Funding; Glycomimetics: Consultancy; Kesios: Consultancy; BMS: Consultancy; Millennium: Consultancy, Research Funding; Skyline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Research Funding. Berg:Millennium Pharmaceuticals Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Lin:Millennium Pharmaceuticals Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Li:Millennium Pharmaceuticals Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Badola:Millennium Pharmaceuticals Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Shen:Millennium Pharmaceuticals Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Zhang:Millennium Pharmaceuticals Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Wang:Millennium Pharmaceuticals Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Esseltine:Takeda: Equity Ownership; Millennium Pharmaceuticals Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment; Johnson and Johnson: Equity Ownership. Luptakova:Takeda Oncology: Employment. van de Velde:Millennium Pharmaceuticals Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Richardson:Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees. Moreau:Bristol-Myers Squibb: Honoraria; Takeda: Honoraria; Celgene: Honoraria; Janssen: Honoraria, Speakers Bureau; Novartis: Honoraria; Amgen: Honoraria.
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Slaga, Dionysos, Diego Ellerman, T. Noelle Lombana, Rajesh Vij, Ji Li, Maria Hristopoulos, Robyn Clark, et al. "Avidity-based binding to HER2 results in selective killing of HER2-overexpressing cells by anti-HER2/CD3." Science Translational Medicine 10, no. 463 (October 17, 2018): eaat5775. http://dx.doi.org/10.1126/scitranslmed.aat5775.
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A primary barrier to the success of T cell–recruiting bispecific antibodies in the treatment of solid tumors is the lack of tumor-specific targets, resulting in on-target off-tumor adverse effects from T cell autoreactivity to target-expressing organs. To overcome this, we developed an anti-HER2/CD3 T cell–dependent bispecific (TDB) antibody that selectively targets HER2-overexpressing tumor cells with high potency, while sparing cells that express low amounts of HER2 found in normal human tissues. Selectivity is based on the avidity of two low-affinity anti-HER2 Fab arms to high target density on HER2-overexpressing cells. The increased selectivity to HER2-overexpressing cells is expected to mitigate the risk of adverse effects and increase the therapeutic index. Results included in this manuscript not only support the clinical development of anti-HER2/CD3 1Fab–immunoglobulin G TDB but also introduce a potentially widely applicable strategy for other T cell–directed therapies. The potential of this discovery has broad applications to further enable consideration of solid tumor targets that were previously limited by on-target, but off-tumor, autoimmunity.
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Serritella, Anthony, Daniel H. Shevrin, Elisabeth I. Heath, James Lloyd Wade, Elia Martinez, Theodore Karrison, Walter Michael Stadler, and Russell Zelig Szmulewitz. "Phase I/II trial of enzalutamide (Enz) plus mifepristone (Mif) for metastatic castration-resistant prostate cancer (mCRPC)." Journal of Clinical Oncology 38, no. 6_suppl (February 20, 2020): 91. http://dx.doi.org/10.1200/jco.2020.38.6_suppl.91.
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91 Background: Resistance to androgen receptor (AR) targeted therapies is common in mCRPC. Glucocorticoid receptor (GR) expression increases with AR inhibition in patients (pts) and blockade of GR signaling inhibits CRPC growth in preclinical models when combined with AR blockade. We thus conducted a phase I/II open label trial of Enz combined with Mif, a GR, AR, and progesterone receptor antagonist for pts with mCRPC to assess the feasibility and impact on disease progression with dual AR/GR antagonism. Methods: The phase I dose escalation portion assessed the safety of the two-drug combination and a recommended phase II dose (R2PD) was determined based on safety, pharmacokinetic and endocrine assessments. In the phase II portion, patients (pts) received 12 weeks of Enz (160mg/day) followed by randomization to Enz alone or Enz plus Mif with PSA-progression free survival (PFS) as the primary endpoint. 42 pts were to randomize to each arm to provide 80% power to detect a hazard ratio of 0.6, with a one-sided alpha of 0.1; there was a planned interim futility analysis after 50% of progression events. Results: 106 pts (18 phase I/88 phase II) were enrolled. Pts had a median age of 70 (range 53-89) and baseline PSA of 12.8 (range 0.1-755). 34% of pts received prior docetaxel. The RP2D was 120mg/day Enz and 300mg/day Mif. In phase II, 33 patients were randomized to each arm, with well-balanced baseline demographics. 22 pts were not randomized (15 due to disease progression, 2 due to toxicity, and 5 due to the interim study analysis). The interim analysis showed no difference between arms in PSA-PFS (hazard ratio = 1.34, p=0.395), 12-month PSA-PFS of 31% in both arms, and per-protocol, the trial was stopped. Toxicities were similar in the arms, e.g. fatigue (12% vs. 14%), hot flashes (6% vs. 5%), and pain (4% vs. 4%). Conclusions: The addition of Mif to Enz following a 12-week Enz lead-in did not delay time to PSA progression. Further analyses of secondary endpoints, including translational biomarkers such as hormone levels, GR/AR-v7 expression in circulating tumor cells and cell free DNA analyses are ongoing. Clinical trial information: NCT02012296.
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Laport, Ginna, John D. Powderly, Saurin Chokshi, Jason J. Luke, Johanna C. Bendell, Amanda Enstrom, Chan C. Whiting, and Thomas Walter Dubensky. "Phase 1/1b multicenter trial of TPST-1120, a peroxisome proliferator-activated receptor alpha (PPARα) antagonist as a single agent (SA) or in combination in patients with advanced solid tumors." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): TPS2665. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.tps2665.
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TPS2665 Background: Tumor cells initially favor glucose metabolism via aerobic glycolysis. As tumors rapidly proliferate and metastasize, glucose stores are depleted and facilitated by a hypoxic tumor microenvironment (TME) and metabolic reprogramming shifts intracellular metabolism(IcM) towards fatty acid oxidation (FAO). Fatty acids support metabolism of suppressive immune cells in the TME in addition to tumor growth. PPARα is a ligand-activated nuclear transcription factor which regulates lipid metabolism and FAO. TPST-1120 is a first in class, oral selective PPARα antagonist that blocks transcription of PPARα target genes leading to an intracellular metabolism shift from FAO to glycolysis. Reduction of fatty acids in the TME leads to direct killing of tumor cells dependent on FAO, skews macrophages from immune suppressive M2 phenotype to an effector M1 phenotype and facilitates the cytotoxicity of immune effector cells. TPST-1120 also restores thrombospondin-1, a known natural inhibitor of angiogenesis, to homeostatic levels within the TME. TPST-1120 has an IC50 of 0.04 nM with > 35 fold selectivity over other PPAR isoforms. Preclinical studies in multiple tumor models show efficacy of TPST-1120 as a SA and in combination(combo) with an anti-PD1 monoclonal antibody (mAb) and chemotherapy. Methods: We have initiated a phase 1/1b multicenter, open label Dose Escalation (DEs) and Dose Expansion (DEx) trial to evaluate TPST-1120 as a SA and in combo with nivolumab, an anti-PD1 mAb; docetaxel, a chemotherapeutic agent and cetuximab, an anti-EGFR mAb. Objectives: 1) evaluate safety and tolerability of continuous dosing of TPST-1120 2) identify a recommended phase 2 dose (RP2D) and 3) evaluate efficacy. Eligibility: 1) patients with select advanced solid tumors who have failed 1 and up to 5 prior therapies. This phase 1/1b adaptive design has 4 DEs arms, 1 SA arm and 3 combination arms in which TPST-1120 is combined with nivolumab, docetaxel or cetuximab. The RP2D of TPST-1120 to proceed to DEx will be determined by safety and biomarkers during DEs. The DEx arms have 8 histology-specific cohorts, 4 SA arms and 4 combo arms and will follow a 2-stage expansion design. Biomarker analyses include gene expression profiling of PPARα-associated genes, tumor markers of immune modulation and serum lipid profiling. The total sample size is up to 338 pts. This trial is accruing at U.S sites. Clinical trial information: NCT03829436.
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Grothey, Axel, Michael Howland, Lloryn Hubbard, Tania Szado, Anne McDonald, Walter C. Darbonne, Jonathan Levy, et al. "A study evaluating targeted therapies in participants who have advanced solid tumors with genomic alterations or protein expression patterns predictive of response (MyTACTIC)." Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021): TPS1588. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.tps1588.
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TPS1588 Background: Cancer treatment is evolving toward a more personalized approach in which the intersection of genomics, pathology and imaging methods leads to individualized care. Furthermore, identification of novel genomic alterations and other biomarkers has the potential to lead to customized, targeted treatments. Matching specific therapies to tumor biomarkers has the potential to yield valuable clinical information. Here we present a multiarm basket trial that matches patients with a broad array of metastatic solid cancers to investigational therapies alone or in combination based on specific, targetable genomic alterations or protein expression patterns that are potentially predictive of response (MyTACTIC). Historically, such trials have been conducted at large academic medical centers rather than community centers, where most US patients with cancer receive treatment. Prioritizing community centers for this study presents an exciting opportunity to generate data from a more representative patient population. Methods: This phase II, multicenter, nonrandomized, open-label study is enrolling approximately 200 participants with advanced solid tumors that harbor alterations including mutations, fusions, amplifications and protein loss in specific biomarkers that include human epidermal growth factor receptor 2 (HER2), phosphoinositide 3-kinase (PI3K), anaplastic lymphoma kinase (ALK), proto-oncogene tyrosine-protein kinase (ROS1), protein kinase B (AKT), phosphatase and tensin homolog (PTEN), high tumor mutational burden (TMB), high microsatellite instability (MSI) and deficient mismatch repair (dMMR). Patients aged ≥18 years with positive local biomarker results from tissue or blood samples will be enrolled from community oncology centers and practices. Eligibility criteria have been broadened to allow enrollment of a diverse population of patients, including those with nonmeasurable disease, HIV or viral hepatitis infections, and to allow for previous treatment with anticancer agents in the same class. Once general and arm-specific criteria are met, patients will be assigned to 1 of 10 treatment arms to receive mono- or combination therapy with targeted agents, immunotherapy and/or chemotherapy (≤25 patients per arm). The primary objective is to evaluate confirmed objective response rate, as assessed by the investigator according to RECIST version 1.1 or RANO criteria for primary central nervous system tumors. Progression-free survival, duration of response, overall survival and safety will also be assessed. Special attention has been paid to the study design and implementation to ensure equitable access, along with flexibility to add additional baskets. Enrollment is ongoing. Clinical trial information: NCT04632992.
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Philip, Philip A., Jacqueline Benedetti, Christopher L. Corless, Ralph Wong, Eileen M. O'Reilly, Patrick J. Flynn, Kendrith M. Rowland, et al. "Phase III Study Comparing Gemcitabine Plus Cetuximab Versus Gemcitabine in Patients With Advanced Pancreatic Adenocarcinoma: Southwest Oncology Group–Directed Intergroup Trial S0205." Journal of Clinical Oncology 28, no. 22 (August 1, 2010): 3605–10. http://dx.doi.org/10.1200/jco.2009.25.7550.
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Purpose Patients with advanced pancreas cancer present with disease that is poorly responsive to conventional therapies. Preclinical and early clinical evidence has supported targeting the epidermal growth factor receptor (EGFR) signaling pathway in patients with pancreas cancer. This trial was conducted to evaluate the contribution of an EGFR-targeted agent to standard gemcitabine therapy. Cetuximab is a monoclonal antibody against the ligand-binding domain of the receptor. Patients and Methods Patients with unresectable locally advanced or metastatic pancreatic adenocarcinoma were randomly assigned to receive gemcitabine alone or gemcitabine plus cetuximab. The primary end point was overall survival. Secondary end points included progression-free survival, time to treatment failure, objective response, and toxicity. Results A total of 745 eligible patients were accrued. No significant difference was seen between the two arms of the study with respect to the median survival time (6.3 months for the gemcitabine plus cetuximab arm v 5.9 months for the gemcitabine alone arm; hazard ratio = 1.06; 95% CI, 0.91 to 1.23; P = .23, one-sided). Objective responses and progression-free survival were similar in both arms of the study. Although time to treatment failure was longer in patients on gemcitabine plus cetuximab (P = .006), the difference in length of treatment was only 2 weeks longer in the combination arm. Among patients who were studied for tumoral EGFR expression, 90% were positive, with no treatment benefit detected in this patient subset. Conclusion In patients with advanced pancreas cancer, the anti-EGFR monoclonal antibody cetuximab did not improve the outcome compared with patients treated with gemcitabine alone. Alternate targets other than EGFR should be evaluated for new drug development.
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Alka Hande, Akhilesh Agrawal, Archana Sonone, Amol Gadbail, Madhuri Gawande, and Swati Patil. "Cucurbitacin: As a candidate against Cytokine Storm in Severe COVID-19 Infection." International Journal of Research in Pharmaceutical Sciences 11, SPL1 (September 25, 2020): 928–30. http://dx.doi.org/10.26452/ijrps.v11ispl1.3164.
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The severity of SARS-CoV-2 infection is marked by elevated cytokines and chemokines levels like interleukin 6 (IL-6), interferon-gamma (IFN-γ), tumour necrosis factor (TNF), IL-2 and monocyte chemotactic protein 1. This hyperactive pro-inflammatory response identified as the Cytokine Storm (CS) complicates the disease leading to extensive damage of the host tissue, Acute Respiratory Distress Syndrome (ARDS), which further result in multiple organ failures. CS is very critical for the disease progression and is responsible for high death rate in an infected patient. Accordingly, various therapeutic modalities are currently investigated for their effectiveness in subsiding the hyper-inflammatory syndrome either using immunomodulatory agents or anti-inflammatory therapies. Phytochemical (herbal) compounds are demonstrated to possess anti-inflammatory, antimicrobial or antioxidants properties. Various signalling pathways and molecules exacerbating the inflammation state complicate the pathophysiology of COVID-19. Cucurbitacins are tetracyclic bioactive phytochemical compounds found in cucurbitaceous plants. More than 100 species of cucurbitacins possess various pharmacological properties, including anti-inflammatory. Cucurbitacin E and R have shown to be down-regulated the expression of TNF alpha and IL-1beta. Cucurbitacin II B also alleviates the expression of TNF-α as well as IFN-γ and IL-6. Cucurbitacin1 has the potential to reduce the oxidative stress-induced with the reactive oxygen species, and thus prevents cardiovascular damage. Thus cucurbitacins may be pharmacologically manipulated to establish its clinical efficacy in minimizing the disease state and improvising the prognosis of the patients.