Institutional Transference in Serious Illness Care.

Institutional transference is a phenomenon describing patients' attitudes toward the institutions where they receive mental health or medical care. While transference toward individual clinicians in palliative care has been described, attitudes of patients with serious illness toward the institutions where they receive specialized care have not been described. Here, we present three cases which demonstrate the phenomenon of institutional transference in patients with serious illness and the resulting clinical implications, which include countertransferential responses of clinicians caring for them. We consider three conditions: (1) the idealized reputation of the academic cancer center, often a tertiary referral center; (2) loss of an institutional connection during care transitions; and (3) countertransferential reactions to institutional transference. We highlight characteristics and personality styles of individuals with cancer that may complicate and intensify institutional transference and identify potential interventions to address common challenges associated with institutional transference.

Dispensary personnel's views and experiences regarding oncologic cannabis and the counsel they offer adults with cancer.

BACKGROUND: A minority of oncologists feel qualified to advise adults with cancer on issues pertaining to medicinal cannabis. Adults with cancer frequently access medicinal cannabis information from non-medical sources such as cannabis dispensaries. We explored dispensary personnel's views and experiences regarding oncologic cannabis and the counsel they extend individuals with cancer. METHODS: Snowball sampling in this qualitative study facilitated recruitment across 13 states (N = 26). Semi-structured phone interviews ceased with thematic saturation. A multi-stage thematic analysis combined inductive and deductive codes. RESULTS: Of the 26 dispensary personnel interviewed, 54% identified as female and 19% as non-white. Median age was 40 years. A consensus emerged among participants concerning the botanical's efficacy for cancer-related symptoms; less so regarding its antineoplastic potential. Principles for serving those with cancer included provision of client-centered, symptom-based, and trial-and-error approaches. Non-inhalation modes of administration were generally recommended. No consensus was reached as to whether delta-9-tetrahydrocannabinal (THC)- or cannabidiol-predominant products were preferable in this population. Challenges in oncologic advising included successfully identifying individuals with cancer at the dispensary counter, financial toxicity, the special treatment required for the THC-naïve, and operating in the absence of standardized guidelines. CONCLUSIONS: These informed assertions suggest that members of the oncologic community should grapple with the extent to which they feel comfortable with both the nature and degree of counsel adults with cancer receive through dispensaries.

Harnessing the therapeutic potential of the stem cell secretome in neonatal diseases.

Preterm birth and intrapartum related complications account for a substantial amount of mortality and morbidity in the neonatal period despite significant advancements in neonatal-perinatal care. Currently, there is a noticeable lack of curative or preventative therapies available for any of the most common complications of prematurity including bronchopulmonary dysplasia, necrotizing enterocolitis, intraventricular hemorrhage, periventricular leukomalacia and retinopathy of prematurity or hypoxic-ischemic encephalopathy, the main cause of perinatal brain injury in term infants. Mesenchymal stem/stromal cell-derived therapy has been an active area of investigation for the past decade and has demonstrated encouraging results in multiple experimental models of neonatal disease. It is now widely acknowledged that mesenchymal stem/stromal cells exert their therapeutic effects via their secretome, with the principal vector identified as extracellular vesicles. This review will focus on summarizing the current literature and investigations on mesenchymal stem/stromal cell-derived extracellular vesicles as a treatment for neonatal diseases and examine the considerations to their application in the clinical setting.

Medical cannabis-related stigma: cancer survivors' perspectives.

BACKGROUND: Although the vast majority of medical cannabis laws in the USA includes cancer as a qualifying condition and medical cannabis-related stigma influences decision-making regarding the botanical, few studies have explored the phenomenon in oncology. Early findings indicated oncologic cannabis-related stigma to be quite widespread. METHODS: Semi-structured interviews with 24 adults with cancer histories using medical cannabis were analyzed using the Health Stigma and Discrimination Framework. RESULTS: Sixteen out of 24 participants discussed medical cannabis-related stigma in some depth. The phenomena emerged as more pervasive in medical than personal/professional domains and was internalized as well as experienced directly. It led some participants, but not others, to practice partial or complete secrecy. DISCUSSION: Taken together, our findings suggest that, while medical cannabis-related stigma remains widespread and led some study participants to alter behavior, an early shift in ethos towards greater medical cannabis acceptance could be underway. If so, this transition may be occurring more rapidly in non-medical than in clinical settings. CONCLUSION: Cancer survivors may experience heightened medical cannabis-related stigma in the clinic as compared to their personal/professional lives. Healthcare providers who depend on patient transparency when gathering medical histories and devising care plans may wish to neutralize perceptions of medical cannabis-related stigma.

Cancer Patients' Experiences with and Perspectives on the Medicinal Cannabis "High".

Background: Patients with cancer employ medicinal cannabis for poly-symptom management and as cancer-directed therapy. Little is known about their perspectives on the medicinal cannabis "high." Methods: Qualitative interviews across eight states with medicinal cannabis users with physician-verified cancer diagnoses (n = 24). Results: Every participant referenced and 15 spoke in depth about the medicinal cannabis "high." Antitheticals characterized it: sleepiness versus heightened attention; calm versus "agitation." The intensity of the "high" served as a proxy metric by which participant's judged medicinal cannabis' cancer-directed therapy and symptom management efficacies. Overall, however, study participants viewed the "high" as a barrier to medicinal cannabis use and worked to avoid experiencing for prolonged periods. Conclusions: The "high" is central to the manner with which patients with cancer experience medicinal cannabis. Clinicians should be aware that patients may struggle to fine-tune medicinal cannabis dosing in the setting of the "high," and this challenge should be included in clinical discussions regarding oncological medicinal cannabis use.

Symptom Burden of Nonresected Pancreatic Adenocarcinoma: An Analysis of 10,753 Patient-Reported Outcome Assessments.

OBJECTIVES: Pancreatic adenocarcinoma (PAC) is a debilitating disease. We sought to analyze symptom burden and trajectories after diagnosis of PAC and identify predictors of severe symptoms for nonresected patients. METHODS: This was a retrospective review of linked administrative health care databases examining patients with PAC not undergoing resection. Primary outcome was severe patient-reported symptoms (Edmonton Symptom Assessment System ≥7). Multivariable modified Poisson regression models were used to identify factors associated with reporting severe symptoms. RESULTS: A total of 10,753 symptom assessments from 2168 patients were analyzed. The median age was 67 years, and 47% were female; median survival was 7 months. Most common severe symptoms were tiredness (54.7%), anorexia (53.6%), overall impaired well-being (45.3%), and drowsiness (37.1%). Severity of symptoms decreased 1 month after diagnosis and plateaued 4 months after diagnosis. Female sex, comorbidities, and older age were associated with reporting severe symptoms; recent radiation treatment and residence in a rural community were associated with reporting less severe symptoms. CONCLUSIONS: The prevalence of severe symptoms in patients with nonresected PAC was high, but potentially modifiable. We identified vulnerable groups of patients that may benefit from focused interventions. This information is important for patient counseling and design of supportive care strategies.

Population-Level Symptom Assessment Following Pancreaticoduodenectomy for Adenocarcinoma.

Importance: Postoperative morbidity associated with pancreaticoduodenectomy (PD) for pancreatic adenocarcinoma (PA) remains as high as 70%. However, to our knowledge, few studies have examined quality of life in this patient population. Objective: To identify symptom burden and trajectories and factors associated with high symptom burden following PD for PA. Design, Setting, and Participants: This population-based cohort study of patients undergoing PD for PA diagnosed between 2009 and 2015 linked population-level administrative health care data to routinely prospectively collected Edmonton Symptom Assessment System (ESAS) scores from 2009 to 2015, with a data analysis undertaken in 2018. Exposures: Baseline characteristics, including age, sex, income quintile, rurality, immigration status, and comorbidity burden, as well as treatment characteristics, including year of surgery and receipt of chemotherapy. Main Outcome and Measures: The outcome of interest was moderate to severe symptoms (defined as ESAS ≥4) for anxiety, depression, drowsiness, lack of appetite, nausea, pain, shortness of breath, tiredness, and impaired well-being. The monthly prevalence of moderate to severe symptoms was presented graphically for each symptom. Multivariable regression models identified factors associated with the reporting of moderate to severe symptoms. Results: We analyzed 6058 individual symptom assessments among 615 patients with PA who underwent resection (285 women [46.3%]) with ESAS data. Tiredness (443 [72%]), impaired well-being (418 [68%]), and lack of appetite (400 [65%]) were most commonly reported as moderate to severe. The proportion of patients with moderate to severe symptoms was highest immediately after surgery (range, 14%-66% per symptom) and decreased over time, stabilizing around 3 months (range, 8%-42% per symptom). Female sex, higher comorbidity, and lower income were associated with a higher risk of reporting moderate to severe symptoms. Receipt of adjuvant chemotherapy was not associated with the risk of moderate to severe symptoms. Conclusions and Relevance: There is a high prevalence of symptoms following PD for PA, with improvement over the first 3 months following surgery. In what to our knowledge is the largest cohort reporting on symptom burden for this population, we have identified factors associated with symptom severity. These findings will aid in managing patients' perioperative expectations and designing strategies to improve targeted symptom management.

Magnetic Resonance-guided High-intensity Focused Ultrasound (MRgHIFU) Virtual Treatment Planning for Abdominal Neuroblastoma Utilizing Retrospective Diagnostic 3D CT Images.

Magnetic resonance-guided high-intensity focused ultrasound (MRgHIFU) is a novel treatment for neuroblastoma using ultrasound-induced thermal ablation with real-time MR thermometry. It is unclear which patients would be amenable to MRgHIFU given the retroperitoneal location of many neuroblastomas within the smaller pediatric abdomen. In addition, planning relies on MR scans, which are not routine in the standard pediatric neuroblastoma workup. This study sought to demonstrate that neuroblastomas are targetable with MRgHIFU and available computed tomographic imaging could be utilized for MRgHIFU virtual treatment. Cross-sectional images of 88 pediatric abdominal neuroblastoma patients were retrospectively processed with custom software to be made compatible with the Sonalleve MRgHIFU platform. Targetability measured percent treatment to lesion volume, within adequate safety margins from critical structures. All images were successfully converted into treatment planning files. Median lesion size was 191±195 cm and depth was 29±17 mm. Up to 78 (85%) patients had targetable lesions with a median targetable volume of 15% and ranging up to 79%. Targetability was highest in superficial, right upper quadrant lesions >200 cm, but limited by proximity to bowel and ribs. This study demonstrates the capacity for MRgHIFU to potentially treat the majority of abdominal neuroblastomas and the feasibility of using computed tomographic images for MRgHIFU virtual treatment planning.

Laparoscopic Revision of Ventriculoperitoneal Shunts in Pediatric Patients May Result in Fewer Subsequent Peritoneal Revisions.

INTRODUCTION: Ventriculoperitoneal shunts (VPSs) are the mainstay of treatment of hydrocephalus but frequently need revision. We sought to directly compare the impact of laparoscopic versus open peritoneal shunt revision on the need for subsequent VPS revisions in pediatric patients. MATERIALS AND METHODS: A prospectively maintained, externally validated database of pediatric patients who underwent a first peritoneal VPS revision at a single center between 2008 and 2016 was reviewed. Outcomes, including subsequent revisions, shunt infections, operative time, and hospital stay between open and laparoscopic groups, were compared. RESULTS: A total of 148 patients underwent a first peritoneal VPS revision during the time period-40 laparoscopically and 108 open-with no significant difference in age or gender between the groups. Operative time, length of stay after shunt revision, and shunt infection rates did not vary between laparoscopic versus open revisions. There was no significant difference between need for subsequent overall (peritoneal or ventricular) shunt revisions in the laparoscopic (20%) versus the open group (34%), P = .07. However, there were significantly fewer frequent peritoneal revisions in the laparoscopic group (3% versus 15%, P = .04). CONCLUSIONS: This first cohort analysis of laparoscopic versus open VPS revision in pediatric patients suggests that laparoscopic peritoneal VPS revision may reduce the rate of subsequent peritoneal revisions without increasing shunt infections or operative time in pediatric patients.

Laparoscopic insertion of ventriculoperitoneal shunts in pediatric patients - A retrospective cohort study.

INTRODUCTION: Ventriculoperitoneal shunts (VPSs) are the mainstay of treatment of hydrocephalus but have frequent complications including shunt failure and infection. There has been no comparison of laparoscopic versus open primary VPS insertion in children. We hypothesized that laparoscopic VP shunt insertion may improve patient outcomes. METHODS: A prospectively-maintained, externally-validated database of pediatric patients who underwent VPS insertion at a single center between 2012 and 2016 was reviewed. Outcomes including subsequent revisions, shunt infections, operative time, and hospital stay between open and laparoscopic groups were compared. RESULTS: 210 patients underwent VPS insertion - 41 laparoscopically and 169 open. Operative time was longer for laparoscopic insertions. There was no difference in shunt infections, complications or length of stay. There was no difference between overall revisions or in confirmed peritoneal obstructions in the laparoscopic (12%) versus open VPS insertions (5%), p = 0.13. CONCLUSIONS: This first cohort analysis of laparoscopic versus open VPS insertion in pediatric patients indicates no difference in confirmed peritoneal obstructions. With increasing use of laparoscopic placement in some centers, it remains important to elucidate if there is a subset of pediatric patients who might benefit from this technique; possible candidates may be those who are overweight/obese or have had previous intra-abdominal surgery. LEVEL OF EVIDENCE: III - Retrospective cohort study.

The impact of a clinical pathway on patient postoperative recovery following pancreaticoduodenectomy.

BACKGROUND: Pancreaticoduodenectomies (PD) are complex surgical procedures. Clinical pathways (CPW) are surgical process improvement tools that guide postoperative recovery and are associated with high quality care. Our objective was to report the quality of surgical care following implementation of a CPW. METHODS: We developed and implemented a CPW for patients undergoing PD at a single high volume hepato-pancreato-biliary (HPB) centre. Patient outcomes were collected prospectively during the implementation period. A comparator cohort was selected by identifying patients that underwent a PD prior to CPW development. RESULTS: 122 patients underwent a PD during the CPW implementation period; 83 patients were initiated on the CPW. 74 patients underwent PD during the 12-month period prior to the CPW. The median hospital stay decreased after the implementation of the CPW (11 vs 8 days, p < 0.01) with no significant changes to mortality, morbidity, reoperation, or readmission rates. In-hospital complications were significantly higher in patients that were not initiated on the CPW (54% vs 74%, p = 0.03). CONCLUSION: Results suggest the CPW reduced variability and allowed a greater proportion of patients to receive all elements of care, resulting in improved quality and efficiency of care based on current best evidence recommendations.

Janus and PI3-kinases mediate glucocorticoid resistance in activated chronic leukemia cells.

Glucorticoids (GCs) such as dexamethasone (DEX) remain important treatments for Chronic Lymphocytic Leukemia (CLL) but the mechanisms are poorly understood and resistance is inevitable. Proliferation centers (PC) in lymph nodes and bone marrow offer protection against many cytotoxic drugs and circulating CLL cells were found to acquire resistance to DEX-mediated killing in conditions encountered in PCs including stimulation by toll-like receptor agonists and interactions with stromal cells. The resistant state was associated with impaired glucocorticoid receptor-mediated gene expression, autocrine activation of STAT3 through Janus Kinases (JAKs), and increased glycolysis. The JAK1/2 inhibitor ruxolitinib blocked STAT3-phosphorylation and partially improved DEX-mediated killing of stimulated CLL cells in vitro but not in CLL patients in vivo. An automated microscopy-based screen of a kinase inhibitor library implicated an additional protective role for the PI3K/AKT/FOXO pathway. Blocking this pathway with the glycolysis inhibitor 2-deoxyglucose (2-DG) or the PI3K-inhibitors idelalisib and buparlisib increased DEX-mediated killing but did not block STAT3-phosphorylation. Combining idelalisib or buparlisib with ruxolitinib greatly increased killing by DEX. These observations suggest that glucocorticoid resistance in CLL cells may be overcome by combining JAK and PI3K inhibitors.

PPARα and fatty acid oxidation mediate glucocorticoid resistance in chronic lymphocytic leukemia.

High-dose glucocorticoids (GCs) can be a useful treatment for aggressive forms of chronic lymphocytic leukemia (CLL). However, their mechanism of action is not well understood, and resistance to GCs is inevitable. In a minimal, serum-free culture system, the synthetic GC dexamethasone (DEX) was found to decrease the metabolic activity of CLL cells, indicated by down-regulation of pyruvate kinase M2 (PKM2) expression and activity, decreased levels of pyruvate and its metabolites, and loss of mitochondrial membrane potential. This metabolic restriction was associated with decreased size and death of some of the tumor cells in the population. Concomitant plasma membrane damage increased killing of CLL cells by DEX. However, the nuclear receptor peroxisome proliferator activated receptor α (PPARα), which regulates fatty acid oxidation, was also increased by DEX, and adipocyte-derived lipids, lipoproteins, and propionic acid protected CLL cells from DEX. PPARα and fatty acid oxidation enzyme inhibitors increased DEX-mediated killing of CLL cells in vitro and clearance of CLL xenografts in vivo. These findings suggest that GCs prevent tumor cells from generating the energy needed to repair membrane damage, fatty acid oxidation is a mechanism of resistance to GC-mediated cytotoxicity, and PPARα inhibition is a strategy to improve the therapeutic efficacy of GCs.

Serotonin (5-HT) activation of immortalized hypothalamic neuronal cells through the 5-HT1B serotonin receptor.

Serotonin [or 5-hydroxytryptamine or (5-HT)] has been implicated as a key modulator in energy homeostasis and a primary focus in the treatment of obesity. There is growing evidence that 5-HT, acting through the 5-HT 1B receptor (5-HT(1B)R) in the paraventricular nucleus of the hypothalamus (PVN), is important to this regulation. However, there is some contention as to whether 5-HT(1B)R action occurs directly on PVN neurons or indirectly via inhibitory inputs into the PVN. To address these questions, we used a novel clonal, hypothalamic neuronal cell model, adult mouse hypothalamic-2/30 (mHypoA-2/30), expressing a PVN-specific marker, single-minded homolog 1, as well as a complement of PVN neuropeptides, including TRH, vasopressin, ghrelin, nucleobindin-2, and galanin. Adult mouse hypothalamic-2/30 neurons were also found to express the 5-HT(1B)R and 5-HT 6 receptor, but not 2C, all previously linked to feeding regulation. Direct serotonergic stimulation (100 nm to 10 µm) of these neurons resulted in dose-dependent cFos activation. 5-HT (10 µm) suppressed forskolin-induced cAMP levels and induced a rise in intracellular Ca(2+) through ER Ca(2+) release, effects that were mimicked by the 5-HT(1B)R agonists, CGS12066B and CP93129, and that were attenuated in the presence of the 5-HT(1B)R-specific inhibitors, GR55562 and isamoltane hemifumarate. Modest transcriptional changes in ghrelin and nucleobindin-2 were also observed in response to 100 nm and 10 µm 5-HT, respectively. These findings support the model wherein 5-HT action through the 1B receptor subtype occurs directly on PVN neurons, leading to potential modification of neuronal transcriptional and secretory machinery.

Immortalized neurons for the study of hypothalamic function.

The hypothalamus is a vital part of the central nervous system: it harbors control systems implicated in regulation of a wide range of homeostatic processes, including energy balance and reproduction. Structurally, the hypothalamus is a complex neuroendocrine tissue composed of a multitude of unique neuronal cell types that express a number of neuromodulators, including hormones, classical neurotransmitters, and specific neuropeptides that play a critical role in mediating hypothalamic function. However, neuropeptide and receptor gene expression, second messenger activation, and electrophysiological and secretory properties of these hypothalamic neurons are not yet fully defined, primarily because the heterogeneity and complex neuronal architecture of the neuroendocrine hypothalamus make such studies challenging to perform in vivo. To circumvent this problem, our research group recently generated embryonic- and adult-derived hypothalamic neuronal cell models by utilizing the novel molecular techniques of ciliary neurotrophic factor-induced neurogenesis and SV40 T antigen transfer to primary hypothalamic neuronal cell cultures. Significant research with these cell lines has demonstrated their value as a potential tool for use in molecular genetic analysis of hypothalamic neuronal function. Insights gained from hypothalamic immortalized cells used in conjunction with in vivo models will enhance our understanding of hypothalamic functions such as neurogenesis, neuronal plasticity, glucose sensing, energy homeostasis, circadian rhythms, and reproduction. This review discusses the generation and use of hypothalamic cell models to study mechanisms underlying the function of individual hypothalamic neurons and to gain a more complete understanding of the overall physiology of the hypothalamus.

Bone loss in anorexia nervosa: leptin, serotonin, and the sympathetic nervous system.

Anorexia nervosa (AN), a disorder characterized by the refusal to sustain a healthy weight, has the highest mortality of any psychiatric disorder. This review presents a model of AN that ties together advances in our understanding of how leptin, serotonin, and hypogonadism are brought about in AN and how they influence bone mass. Serotonin (5-hydroxytryptamine) is a key regulator of satiety and mood. The primary disturbance in AN results from alterations in serotonin signaling. AN patients suffer from serotonergic hyperactivity of Htr1a-dependent pathways that causes dysphoric mood and promotes restrictive behavior. By limiting carbohydrate ingestion, anorexics decrease their serotonin levels. Reduced serotonergic signaling in turn suppresses appetite through Htr1a/2b, decreases dysphoric mood through Htr1a/2a, and activates the sympathetic nervous system (SNS) through Htr2c receptors in the ventromedial hypothalamus. Activation of the SNS decreases bone mass through ß2-adrenergic signaling in osteoblasts. Additional topics reviewed here include osteoblastic feedback of metabolism in anorexia, mechanisms whereby dietary changes exacerbate bone loss, the role of caloric restriction and Sirt1 in bone metabolism, hypothalamic hypogonadism's effects on bone mass, and potential treatments.

Evolution, aging, and osteoporosis.

Aging is a process whereby organisms lose to the capacity to effectively handle life's stresses. Associated with aging are pathophysiological processes, such as decreases in bone mass, which in the extreme form lead to significant morbidity. Evolutionary theory suggests that these pathophysiological processes are permitted to occur because an organism need only preserve its body against stress only for the amount of time needed for effective reproduction. In this review, an understanding of osteoporosis and bone loss is discussed within the context of aging theory. Specific topics covered include: (1) bone loss as an antagonistically pleiotropic physiological process, (2) age-associated stress accumulation and its negative impact on bone turnover, and (3) the mechanisms whereby gonadal failure, increases in inflammatory cytokines, and cellular bone marrow changes lead to bone loss. This review concludes by examining purported hypotheses in the context of Werner's syndrome, a disease characterized by premature aging. We suggest that future osteoporosis therapy will likely focus on prevention of aging in general as a means to prevent the development of osteoporosis.