Exploring Patients' Trust from a New Perspective. A Text-Analysis Study.

The concept of trust has been extensively studied within the field of medicine. Yet, a list of factors that clearly influence patients' trust is still under debate. Moreover, the methodological approaches found in literature have been reported to be lacking in their assessments and measurements of trust relationships in the medical field although trust between a patient and medical provider has been proven to increase adherence and improve health outcomes. Hence, adding data to this debate and exploring a reliable method to explore the construct of trust is relevant. This study collects new evidence of the most salient indicators of patient trust by using a narrative approach and highlighting the potential of this method in collecting indicators that could be used to build training that aims to increase patients' trust. We used the Linguistic Inquiry and Word Count software for text analysis to examine the spontaneous narrations of episodes of trust and distrust within the doctor-patient relationship with a sample of 82 adult patients. Results demonstrate the role of the emotional aspects of the doctor-patient relationship. Data highlights the importance of doctors' benevolence toward patients, and positive emotions seem to be deeply connected with any experience of trust, which leads patients to feel more secure. Methods are presented to use these insights to construct mechanisms that establish medical trust and allow providers to implement effective interventions.

Asymptomatic Skeletal Cystic Angiomatosis May Be Managed Conservatively With Close Observation.

Cystic angiomatosis (CA) is a rare disease characterized by the proliferation of vascular and lymphatic channels lined by a single layer of endothelial cells. CA may present with isolated skeletal or visceral disease. There is no consensus for the standard of care in these patients, and diverse regimens for CA have been reported, including observation, surgery, radiation, and a variety of medical therapies. We present a case of multifocal, isolated skeletal CA, treated with close observation alone and review the literature. We suggest that these cases may be safely followed without intervention and may be stable for prolonged periods of time.

Time Course and Management of Protracted Anaphylaxis Due to PEG-Asparaginase.

Polyethylene glycosylated (PEG)-asparaginase is a cornerstone of treatment for acute lymphoblastic leukemia (ALL), and effective administration is associated with better outcomes. PEG-asparaginase is associated with a uniphasic hypersensitivity reaction in ∼10% to 20% of patients. We present a 17-year-old male individual diagnosed with very high-risk pre-B-ALL, who experienced protracted anaphylaxis 1 hour following administration of his second PEG-asparaginase dose. This type of allergic reaction has yet to be described in ALL patients treated with PEG-asparaginase. Here, we outline the time course and successful management of protracted anaphylaxis in an ALL patient.

The role of cell adhesion in hematopoiesis and leukemogenesis.

The cells of the bone marrow microenvironment are emerging as important contributors and regulators of normal hematopoiesis. This microenvironment is perturbed during leukemogenesis, and evidence points toward a bidirectional communication between leukemia cells and the normal cells of the bone marrow, mediated by direct cell-cell contact as well as soluble factors. These interactions are increasingly appreciated to play a role in leukemogenesis and possibly in resistance to chemotherapy. In fact, several compounds that specifically target the bone marrow microenvironment, including inhibitors of cell adhesion, are being tested as adjuncts to leukemia therapy.

Isolated Central Nervous System Chloroma as a Presenting Sign of Relapsed Pediatric Acute Lymphoblastic Leukemia.

Central nervous system (CNS) chloromas are an exceedingly rare presentation of CNS relapse in acute lymphoblastic leukemia (ALL). We report a relapsed ALL patient who presented with 2 separate chloromas and cerebrospinal fluid lymphoblastocytosis, and outline a treatment plan of systemic chemotherapy and CNS-directed radiation therapy. A review of the literature indicates that multiagent chemotherapy combined with CNS radiotherapy is effective, with hematopoietic stem cell transplantation used in half of reported cases. We conclude that intensive systemic multiagent chemotherapy with CNS-directed radiation therapy can be successfully used to treat relapsed pediatric ALL with CNS lymphoblastic chloroma.

Successful treatment of pediatric histiocytic sarcoma using abbreviated high-risk leukemia chemotherapy.

Histiocytic sarcoma (HS) is a malignant tumor composed of proliferating cells of histiocytic origin. True HS is exceedingly rare, particularly in pediatric patients. These tumors are frequently aggressive, and outcome for patients with HS has traditionally been poor. There is currently no consensus on the optimal management of these tumors, with the literature consisting largely of case reports and small case series utilizing a wide variety of therapies. We describe a case of HS in an 8-year-old female who was successfully treated with an abbreviated leukemia chemotherapy regimen.

Creation of a quality improvement collaborative to address adolescent and young adult cancer clinical trial enrollment: ATAQI (AYA trial access quality initiative).

Adolescent and young adult (AYA) participation in cancer clinical trials (CCTs) is suboptimal, hindering further improvements in survival, quality of life, and basic understanding of cancer pathophysiology in this population. Prior studies have identified barriers and facilitators to AYA CCT enrollment; however, few interventional studies have attempted to address these barriers and measure tangible changes. In September 2020, a task force was established to address CCT enrollment barriers at a multi-institutional level utilizing a quality improvement collaborative model for improvement. The AYA Trial Access Quality Initiative was developed with the goal of bring multidisciplinary teams together across multiple sites to learn, apply and share their methods of improvement. It uses a structured process of learning sessions lead by quality improvement and clinical experts who help facilitate learning and problem solving which are followed by action phases. During the pilot phase of the collaboration, one key driver of CCT enrollment in AYA's will be addressed: communication between adult and pediatric oncology by implementation of various interventions at sites. The number of AYAs screened for and enrolled on CCTs will be tracked over the course of the collaborative along with the process measures. It is expected that the interventions will promote engagement of stakeholders in the process of screening AYA oncology patients for eligibility on CCTs. This will hopefully create a favorable environment conducive for increasing enrollment on CCTs and lead to the development of a system-wide quality improvement framework to improve AYA CCT enrollment.

Successful treatment of disseminated cryptococcal infection in a pediatric acute lymphoblastic leukemia patient during induction.

Disseminated cryptococcal infection is rarely reported in the setting of pediatric acute leukemia, despite the immunocompromised state of these patients. However, when present, disseminated cryptococcal infection poses treatment challenges and is associated with significant morbidity and mortality. Treatment of invasive fungal disease in a child with acute leukemia requires a delicate balance between antifungal and antineoplastic therapy. This balance is particularly important early in the course of leukemia, as both the underlying disease and overwhelming infection can be life threatening. We describe the successful management of life-threatening disseminated cryptococcosis in a child with acute lymphoblastic leukemia during induction therapy.

Use of Communication Technology to Improve Clinical Trial Participation in Adolescents and Young Adults With Cancer: Consensus Statement From the Children's Oncology Group Adolescent and Young Adult Responsible Investigator Network.

Adolescents and young adults (AYAs; age 15-39 years) with cancer are under-represented in cancer clinical trials because of patient, provider, and institutional barriers. Health care technology is increasingly available to and highly used among AYAs and has the potential to improve cancer care delivery. The COVID-19 pandemic forced institutions to rapidly adopt novel approaches for enrollment and monitoring of patients on cancer clinical trials, many of which have the potential for improving AYA trial participation overall. This consensus statement from the Children's Oncology Group AYA Oncology Discipline Committee reviews opportunities to use technology to optimize AYA trial enrollment and study conduct, as well as considerations for widespread implementation of these practices. The use of remote patient eligibility screening, electronic informed consent, virtual tumor boards, remote study visits, and remote patient monitoring are recommended to increase AYA access to trials and decrease the burden of participation. Widespread adoption of these strategies will require new policies focusing on reimbursement for telehealth, license portability, facile communication between electronic health record systems and advanced safeguards to maintain patient privacy and security. Studies are needed to determine optimal approaches to further incorporate technology at every stage of the clinical trial process, from enrollment through study completion.

Epigenetic-Mediated Regulation of Gene Expression for Biological Control and Cancer: Fidelity of Mechanisms Governing the Cell Cycle.

The cell cycle is governed by stringent epigenetic mechanisms that, in response to intrinsic and extrinsic regulatory cues, support fidelity of DNA replication and cell division. We will focus on (1) the complex and interdependent processes that are obligatory for control of proliferation and compromised in cancer, (2) epigenetic and topological domains that are associated with distinct phases of the cell cycle that may be altered in cancer initiation and progression, and (3) the requirement for mitotic bookmarking to maintain intranuclear localization of transcriptional regulatory machinery to reinforce cell identity throughout the cell cycle to prevent malignant transformation.

Epigenetic-Mediated Regulation of Gene Expression for Biological Control and Cancer: Cell and Tissue Structure, Function, and Phenotype.

Epigenetic gene regulatory mechanisms play a central role in the biological control of cell and tissue structure, function, and phenotype. Identification of epigenetic dysregulation in cancer provides mechanistic into tumor initiation and progression and may prove valuable for a variety of clinical applications. We present an overview of epigenetically driven mechanisms that are obligatory for physiological regulation and parameters of epigenetic control that are modified in tumor cells. The interrelationship between nuclear structure and function is not mutually exclusive but synergistic. We explore concepts influencing the maintenance of chromatin structures, including phase separation, recognition signals, factors that mediate enhancer-promoter looping, and insulation and how these are altered during the cell cycle and in cancer. Understanding how these processes are altered in cancer provides a potential for advancing capabilities for the diagnosis and identification of novel therapeutic targets.

CXCR4 Mediates Enhanced Cell Migration in CALM-AF10 Leukemia.

Leukemia transformed by the CALM-AF10 chromosomal translocation is characterized by a high incidence of extramedullary disease, central nervous system (CNS) relapse, and a poor prognosis. Invasion of the extramedullary compartment and CNS requires leukemia cell migration out of the marrow and adherence to the cells of the local tissue. Cell adhesion and migration are increasingly recognized as contributors to leukemia development and therapeutic response. These processes are mediated by a variety of cytokines, chemokines, and their receptors, forming networks of both secreted and cell surface factors. The cytokines and cytokine receptors that play key roles in CALM-AF10 driven leukemia are unknown. We find high cell surface expression of the cytokine receptor CXCR4 on leukemia cells expressing the CALM-AF10 oncogenic protein, contributing to the migratory nature of this leukemia. Our discovery of altered cytokine receptor expression and function provides valuable insight into the propagation and persistence of CALM-AF10 driven leukemia.

MLLT10 in benign and malignant hematopoiesis.

Non-random chromosomal translocations involving the putative transcription factor Mixed Lineage Leukemia Translocated to 10 (MLLT10, also known as AF10) are commonly observed in both acute myeloid and lymphoid leukemias and are indicative of a poor prognosis. Despite the well-described actions of oncogenic MLLT10 fusion proteins, the role of wild-type MLLT10 in hematopoiesis is not well characterized. The protein structure and several interacting partners have been described and provide indications as to the potential functions of MLLT10. This review examines these aspects of MLLT10, contextualizing its function in benign and malignant hematopoiesis.

Genetic analysis of Ikaros target genes and tumor suppressor function in BCR-ABL1+ pre-B ALL.

Inactivation of the tumor suppressor gene encoding the transcriptional regulator Ikaros (IKZF1) is a hallmark of BCR-ABL1+ precursor B cell acute lymphoblastic leukemia (pre-B ALL). However, the mechanisms by which Ikaros functions as a tumor suppressor in pre-B ALL remain poorly understood. Here, we analyzed a mouse model of BCR-ABL1+ pre-B ALL together with a new model of inducible expression of wild-type Ikaros in IKZF1 mutant human BCR-ABL1+ pre-B ALL. We performed integrated genome-wide chromatin and expression analyses and identified Ikaros target genes in mouse and human BCR-ABL1+ pre-B ALL, revealing novel conserved gene pathways associated with Ikaros tumor suppressor function. Notably, genetic depletion of different Ikaros targets, including CTNND1 and the early hematopoietic cell surface marker CD34, resulted in reduced leukemic growth. Our results suggest that Ikaros mediates tumor suppressor function by enforcing proper developmental stage-specific expression of multiple genes through chromatin compaction at its target genes.

Bivalent Epigenetic Control of Oncofetal Gene Expression in Cancer.

Multiple mechanisms of epigenetic control that include DNA methylation, histone modification, noncoding RNAs, and mitotic gene bookmarking play pivotal roles in stringent gene regulation during lineage commitment and maintenance. Experimental evidence indicates that bivalent chromatin domains, i.e., genome regions that are marked by both H3K4me3 (activating) and H3K27me3 (repressive) histone modifications, are a key property of pluripotent stem cells. Bivalency of developmental genes during the G1 phase of the pluripotent stem cell cycle contributes to cell fate decisions. Recently, some cancer types have been shown to exhibit partial recapitulation of bivalent chromatin modifications that are lost along with pluripotency, suggesting a mechanism by which cancer cells reacquire properties that are characteristic of undifferentiated, multipotent cells. This bivalent epigenetic control of oncofetal gene expression in cancer cells may offer novel insights into the onset and progression of cancer and may provide specific and selective options for diagnosis as well as for therapeutic intervention.

Effects of iron depletion on CALM-AF10 leukemias.

Iron, an essential nutrient for cellular growth and proliferation, enters cells via clathrin-mediated endocytosis. The clathrin assembly lymphoid myeloid (CALM) protein plays an essential role in the cellular import of iron by clathrin-mediated endocytosis. CALM-AF10 leukemias harbor a single copy of the normal CALM gene and therefore may be more sensitive to the growth-inhibitory effect of iron restriction compared with normal hematopoietic cells. We found that CALM heterozygous (CALM(HET)) murine fibroblasts exhibit signs of iron deficiency, with increased surface transferrin receptor levels and reduced growth rates. CALM(HET) hematopoietic cells are more sensitive in vitro to iron chelators than their wild type counterparts. Iron chelation also displayed toxicity toward cultured CALM(HET)CALM-AF10 leukemia cells, and this effect was additive to that of chemotherapy. In mice transplanted with CALM(HET)CALM-AF10 leukemia, we found that dietary iron restriction reduced tumor burden in the spleen. However, dietary iron restriction, used alone or in conjunction with chemotherapy, did not increase survival of mice with CALM(HET)CALM-AF10 leukemia. In summary, although CALM heterozygosity results in iron deficiency and increased sensitivity to iron chelation in vitro, our data in mice do not suggest that iron depletion strategies would be beneficial for the therapy of CALM-AF10 leukemia patients.

Iron deprivation in cancer--potential therapeutic implications.

Iron is essential for normal cellular function. It participates in a wide variety of cellular processes, including cellular respiration, DNA synthesis, and macromolecule biosynthesis. Iron is required for cell growth and proliferation, and changes in intracellular iron availability can have significant effects on cell cycle regulation, cellular metabolism, and cell division. Perhaps not surprisingly then, neoplastic cells have been found to have higher iron requirements than normal, non-malignant cells. Iron depletion through chelation has been explored as a possible therapeutic intervention in a variety of cancers. Here, we will review iron homeostasis in non-malignant and malignant cells, the widespread effects of iron depletion on the cell, the various iron chelators that have been explored in the treatment of cancer, and the tumor types that have been most commonly studied in the context of iron chelation.

The PICALM protein plays a key role in iron homeostasis and cell proliferation.

The ubiquitously expressed phosphatidylinositol binding clathrin assembly (PICALM) protein associates with the plasma membrane, binds clathrin, and plays a role in clathrin-mediated endocytosis. Alterations of the human PICALM gene are present in aggressive hematopoietic malignancies, and genome-wide association studies have recently linked the PICALM locus to late-onset Alzheimer's disease. Inactivating and hypomorphic Picalm mutations in mice cause different degrees of severity of anemia, abnormal iron metabolism, growth retardation and shortened lifespan. To understand PICALM's function, we studied the consequences of PICALM overexpression and characterized PICALM-deficient cells derived from mutant fit1 mice. Our results identify a role for PICALM in transferrin receptor (TfR) internalization and demonstrate that the C-terminal PICALM residues are critical for its association with clathrin and for the inhibitory effect of PICALM overexpression on TfR internalization. Murine embryonic fibroblasts (MEFs) that are deficient in PICALM display several characteristics of iron deficiency (increased surface TfR expression, decreased intracellular iron levels, and reduced cellular proliferation), all of which are rescued by retroviral PICALM expression. The proliferation defect of cells that lack PICALM results, at least in part, from insufficient iron uptake, since it can be corrected by iron supplementation. Moreover, PICALM-deficient cells are particularly sensitive to iron chelation. Taken together, these data reveal that PICALM plays a critical role in iron homeostasis, and offer new perspectives into the pathogenesis of PICALM-associated diseases.