Outpatient Training During Hospice and Palliative Medicine Fellowship: A National Survey.

CONTEXT: Outpatient palliative care (PC) has strong evidence demonstrating impact across serious illnesses, resulting in growing demand for skilled outpatient PC clinicians. However, there is limited literature examining the existing state and quality of outpatient PC education during post-graduate training. OBJECTIVES: Characterize the current state of outpatient training in United States (US) Hospice and Palliative Medicine (HPM) physician fellowships and elicit perceptions regarding quality of outpatient PC education. METHODS: A cross-sectional survey of US adult HPM fellowship program directors (PDs) or their designee conducted between March-July 2023. RESULTS: Of 161 programs, 85 participated (53% response rate) with representation across all US regions. HPM fellows spend a median of 4.8 weeks in outpatient PC compared to 24 weeks inpatient PC and 10.5 weeks in hospice settings. Over half (51%) of fellows saw outpatients from primarily one disease type with limited exposure to patients with other serious illnesses. Across programs, fellows' clinic structure, interdisciplinary team composition, and didactic experiences varied. On a 5-point rating scale, PDs reported significantly lower quality outpatient versus inpatient training (mean rating: 3.58 vs. 4.62, p< 0.001) and perceived fellows as less prepared for independent outpatient practice upon graduation (mean: 4.06 vs. 4.73, p< 0.001). CONCLUSION: Our survey of US HPM fellowships identified multiple gaps between outpatient and inpatient PC education and training during fellowship and raises concern about the adequacy of outpatient PC training. To prepare the HPM workforce to meet the diverse needs of seriously ill populations and ensure adequate access, outpatient PC training requires reform.

Palliative Medicine Fellows' Discussions, Perceptions, and Training Regarding Medical Cannabis.

CONTEXT: Medical cannabis is increasingly considered for palliation of pain, nausea/vomiting, anorexia, and other symptoms. OBJECTIVES: We aimed to determine whether training in hospice and palliative medicine (HPM) adequately prepares fellows to counsel patients about medical cannabis. METHODS: A previously validated questionnaire was adapted for HPM fellows. Domains included fellows' practices recommending cannabis and their knowledge of its effectiveness and risks compared with standard treatments. U.S. HPM fellowships were sent surveys in 2022 and 2023. RESULTS: Forty six programs participated, 123 fellows responded (response rate of 42%) including 69% female; 55% White, and 28% Asian. Of respondents, 65% reported receiving formal training regarding medical cannabis; 57% reported discussing medical cannabis with over five patients; 23% recommended medical cannabis to more than five patients in the preceding year. Only 19%, however, felt sufficiently informed to issue cannabis-related recommendations. HPM fellows with prior training were not more likely to feel sufficiently informed to discuss cannabis (RR: 1.17; 95% CI: 0.82-1.66) or to recommend cannabis to patients (RR: 2.05, 95% CI: 0.89-4.71). Fellows rate cannabis as equally or more effective than conventional treatments for the following symptoms: anorexia/cachexia (63%), nausea/vomiting (43%), pain (25%), and neuropathic pain (21%). CONCLUSION: Most HPM fellows report formal training in the use of medical cannabis. Over half of trainees reported discussing medical cannabis with patients, but few considered themselves sufficiently informed to make cannabis-related clinical recommendations. These results suggest both a need for expanded high-quality evidence for medical cannabis in palliative care and for improved formal education for HPM fellows.

Integrating palliative care into the evolving landscape of oncology.

Patients with cancer have many palliative care needs. Robust evidence supports the early integration of palliative care into the care of patients with advanced cancer. International organizations, such as the American Society of Clinical Oncology (ASCO) and the European Society for Medical Oncology (ESMO), have recommended early, longitudinal integration of palliative care into oncology care throughout the cancer trajectory. In this review, we pose a series of clinical questions related to the current state of early palliative care integration into oncology. We review the evidence to address each of these questions and highlight areas for further investigation. As cancer care continues to evolve, incorporating new treatment modalities and improving patient outcomes, we reflect on how to apply the existing evidence supporting early palliative care-oncology integration into this ever-changing therapeutic landscape and how specialty palliative care might adapt to meet the evolving needs of patients, caregivers, and the multidisciplinary oncology team.

Delivering Palliative Care to Hospitalized Oncology Patients: A Scoping Review.

CONTEXT: Early, longitudinal integration of palliative care (PC) is recommended for patients with advanced cancer, in both inpatient and outpatient settings. Despite the growth of specialty PC teams in the last decade, the majority of PC is still delivered in the inpatient setting using a traditional referral-based consult delivery model. However, traditional consultation can lead to significant variation or delay in inpatient PC utilization. New care delivery models and strategies are emerging to deliver PC to hospitalized oncology patients who would most benefit from their services and to better align with professional society recommendations. OBJECTIVES: To identify different care models to deliver PC to ho`spitalized oncology patients and summarize their impact on patient and health system-related outcomes. METHODS: We conducted a scoping review of peer-reviewed articles from 2006 to 2021 evaluating delivery of PC to oncology patients in acute inpatient care. We abstracted study characteristics, the study's intervention and comparison arms, and outcomes related to specialty PC intervention. RESULTS: We identified four delivery models that have been reported to deliver PC: 1) traditional referral-based consultation, 2) criterion-based or "triggered" consultation, 3) co-rounding with primary inpatient team, and 4) PC clinicians serving as the primary team. We summarize the known outcomes data from each model, and compare the benefits and limitations of each model. CONCLUSION: Our findings provide guidance to health systems about care delivery models to deploy and implement inpatient PC resources to best serve their unique populations.

Are Opioid Infusions Used Inappropriately at End of Life? Results From a Quality/Safety Project.

CONTEXT: Opioid continuous infusions are commonly used for end-of-life (EOL) symptoms in hospital settings. However, prescribing practices vary, and even the recent literature contains conflicting protocols and guidelines for best practice. OBJECTIVES: To determine the prevalence of potentially inappropriate opioid infusion use for EOL comfort care at an academic medical center, and determine if inappropriate use is associated with distress. METHODS: Through literature review and iterative interdisciplinary discussion, we defined three criteria for "potentially inappropriate" infusion use. We conducted a retrospective, observational study of inpatients who died over six months, abstracting demographics, opioid use patterns, survival time, palliative care (PC) involvement, and evidence of patient/caregiver/staff distress from the electronic medical record. RESULTS: We identified 193 decedents who received opioid infusions for EOL comfort care. Forty-four percent received opioid infusions that were classified as "potentially inappropriate." Insufficient use of as-needed intravenous opioid boluses and use of opioid infusions in opioid-naïve patients were the most common problems observed. Potentially inappropriate infusions were associated with more frequent patient (24% vs. 2%; P < 0.001) and staff distress (10% vs. 2%; P = 0.02) and were less common when PC provided medication recommendations (20% vs. 50%; P < 0.001). CONCLUSION: Potentially inappropriate opioid infusions are prevalent at our hospital, an academic medical center with an active PC team and existing contracts for in-hospital hospice care. Furthermore, potentially inappropriate opioid infusions are associated with increased patient and staff distress. We are developing an interdisciplinary intervention to address this safety issue.

An Elusive Seizure.

We present a case of a healthy 62-year-old woman who developed recurrent seizures preceded by subacute cognitive slowing, ataxia, night sweats, and weight loss. She was found to have cytopenias, multifocal T2/FLAIR hyperintensities on magnetic resonance imaging (MRI), and magnetic susceptibility artifact lesions on susceptibility weighted imaging (SWI). Her symptoms, imaging and laboratory abnormalities all improved with high-doses of steroids and intravenous immunoglobulin (IVIG). But recurred several weeks after completing treatment. Despite extensive work-up, she required multiple hospitalizations and repeat diagnostic studies to arrive at a diagnosis. With an expert discussant in hematology and oncology, we review the differential diagnosis and stepwise approach of unexplained neuro-inflammatory syndromes with cytopenias and systemic symptoms. Our case highlights how time, empiric treatment response, and repeated diagnostic studies refine differential diagnoses and subsequent evaluation. After revealing the diagnosis, we discuss the heterogenous clinical manifestations of this disease process.

Dramatic response to combination pembrolizumab and radiation in metastatic castration resistant prostate cancer.

Immune checkpoint inhibitors targeting PD-1 and PD-L1 have demonstrated anti-tumor activity in several advanced solid malignancies. In previously treated metastatic castration resistant prostate cancer (mCRPC), a small subset of patients have a therapeutic response to checkpoint inhibition. Those who do respond to anti-PD-1/PD-L1 therapy have a marked, durable response to treatment, suggesting some derive long-term benefit from immune checkpoint blockade. In other cancers, one strategy to increase the efficacy of immune checkpoint blockade is to combine it with a pro-immune stimulatory agent, such as radiation. Here we present a case of a patient with heavily treated mCRPC who had a significant tumor response to concurrent pembrolizumab and radiation therapy to the primary prostatic mass. We review the growing evidence supporting the use of this combination therapy in other cancers and its potential benefit and safety in mCRPC. Our report highlights a potential therapeutic approach that should be further investigated in previously treated mCRPC.

Shared ACVR1 mutations in FOP and DIPG: Opportunities and challenges in extending biological and clinical implications across rare diseases.

Gain-of-function mutations in the Type I Bone Morphogenic Protein (BMP) receptor ACVR1 have been identified in two diseases: Fibrodysplasia Ossificans Progressiva (FOP), a rare autosomal dominant disorder characterized by genetically driven heterotopic ossification, and in 20-25% of Diffuse Intrinsic Pontine Gliomas (DIPGs), a pediatric brain tumor with no effective therapies and dismal median survival. While the ACVR1 mutation is causal for FOP, its role in DIPG tumor biology remains under active investigation. Here, we discuss cross-fertilization between the FOP and DIPG fields, focusing on the biological mechanisms and principles gleaned from FOP that can be applied to DIPG biology. We highlight our current knowledge of ACVR1 in both diseases, and then describe the growing opportunities and barriers to effectively investigate ACVR1 in DIPG. Importantly, learning from other seemingly unrelated diseases harboring similar mutations may uncover novel mechanisms or processes for future investigation.

Overcoming resistance to single-agent therapy for oncogenic BRAF gene fusions via combinatorial targeting of MAPK and PI3K/mTOR signaling pathways.

Pediatric low-grade gliomas (PLGGs) are frequently associated with activating BRAF gene fusions, such as KIAA1549-BRAF, that aberrantly drive the mitogen activated protein kinase (MAPK) pathway. Although RAF inhibitors (RAFi) have been proven effective in BRAF-V600E mutant tumors, we have previously shown how the KIAA1549-BRAF fusion can be paradoxically activated by RAFi. While newer classes of RAFi, such as PLX8394, have now been shown to inhibit MAPK activation by KIAA1549-BRAF, we sought to identify alternative MAPK pathway targeting strategies using clinically relevant MEK inhibitors (MEKi), along with potential escape mechanisms of acquired resistance to single-agent MAPK pathway therapies. We demonstrate effectiveness of multiple MEKi against diverse BRAF-fusions with novel N-terminal partners, with trametinib being the most potent. However, resistance to MEKi or PLX8394 develops via increased RTK expression causing activation of PI3K/mTOR pathway in BRAF-fusion expressing resistant clones. To circumvent acquired resistance, we show potency of combinatorial targeting with trametinib and everolimus, an mTOR inhibitor (mTORi) against multiple BRAF-fusions. While single-agent mTORi and MEKi PLGG clinical trials are underway, our study provides preclinical rationales for using MEKi and mTORi combinatorial therapy to stave off or prevent emergent drug-resistance in BRAF-fusion driven PLGGs.

Integrated Molecular Meta-Analysis of 1,000 Pediatric High-Grade and Diffuse Intrinsic Pontine Glioma.

We collated data from 157 unpublished cases of pediatric high-grade glioma and diffuse intrinsic pontine glioma and 20 publicly available datasets in an integrated analysis of >1,000 cases. We identified co-segregating mutations in histone-mutant subgroups including loss of FBXW7 in H3.3G34R/V, TOP3A rearrangements in H3.3K27M, and BCOR mutations in H3.1K27M. Histone wild-type subgroups are refined by the presence of key oncogenic events or methylation profiles more closely resembling lower-grade tumors. Genomic aberrations increase with age, highlighting the infant population as biologically and clinically distinct. Uncommon pathway dysregulation is seen in small subsets of tumors, further defining the molecular diversity of the disease, opening up avenues for biological study and providing a basis for functionally defined future treatment stratification.

Ion channel blockers and glioblastoma risk and outcome: a nested case-control and retrospective cohort studies.

PURPOSE: Mutations in ion channels are common among patients with glioblastoma multiforme (GBM) and promote cell migration and invasion. We sought to evaluate the association between the use of specific ion channel blockers such as digoxin, amiodarone, diltiazem and verapamil and GBM risk and survival. METHODS: We conducted a nested case-control study in a large primary care database from the UK. Cases were defined as all individuals with incident diagnosis of GBM during follow-up. For each case, up to four controls were selected using incidence density sampling. The primary exposure of interest was active treatment with each of the four ion channel blockers. We used conditional logistic regression to estimate odds ratios and 95% confidence interval (CI) for the association between ion channel blocker use and GBM risk. We then performed a Cox regression analysis among those diagnosed with GBM in order to evaluate the association between use of ion channel blockers and overall survival. Both analyses were adjusted to common confounders. RESULTS: The study included 1076 cases and 4253 matched controls. There was no statistically significant difference between cases and controls in cardiac and metabolic risk factors. There was no change in GBM risk in active users of ion channel blockers compared with non-users. Among patients with GBM, active users of amiodarone had worse survival compared with never users with an HR of 4.41 (95%CI 1.95-9.96). There was no statistically significant change in survival among diltiazem, verapamil or digoxin users. CONCLUSION: Treatment with specific ion channel blockers was not associated with the risk of GBM but was associated with worse survival in patients with GBM. Copyright © 2016 John Wiley & Sons, Ltd.

MYB-QKI rearrangements in angiocentric glioma drive tumorigenicity through a tripartite mechanism.

Angiocentric gliomas are pediatric low-grade gliomas (PLGGs) without known recurrent genetic drivers. We performed genomic analysis of new and published data from 249 PLGGs, including 19 angiocentric gliomas. We identified MYB-QKI fusions as a specific and single candidate driver event in angiocentric gliomas. In vitro and in vivo functional studies show that MYB-QKI rearrangements promote tumorigenesis through three mechanisms: MYB activation by truncation, enhancer translocation driving aberrant MYB-QKI expression and hemizygous loss of the tumor suppressor QKI. To our knowledge, this represents the first example of a single driver rearrangement simultaneously transforming cells via three genetic and epigenetic mechanisms in a tumor.

Strain background influences neurotoxicity and behavioral abnormalities in mice expressing the tetracycline transactivator.

The tet-off system has been widely used to create transgenic models of neurological disorders including Alzheimer's, Parkinson's, Huntington's, and prion disease. The utility of this system lies in the assumption that the tetracycline transactivator (TTA) acts as an inert control element and does not contribute to phenotypes under study. Here we report that neuronal expression of TTA can affect hippocampal cytoarchitecture and behavior in a strain-dependent manner. While studying neurodegeneration in two tet-off Alzheimer's disease models, we unexpectedly discovered neuronal loss within the dentate gyrus of single transgenic TTA controls. Granule neurons appeared most sensitive to TTA exposure during postnatal development, and doxycycline treatment during this period was neuroprotective. TTA-induced degeneration could be rescued by moving the transgene onto a congenic C57BL/6J background and recurred on reintroduction of either CBA or C3H/He backgrounds. Quantitative trait analysis of B6C3 F2 TTA mice identified a region on Chromosome 14 that contains a major modifier of the neurodegenerative phenotype. Although B6 mice were resistant to degeneration, they were not ideal for cognitive testing. F1 offspring of TTA C57BL/6J and 129X1/SvJ, FVB/NJ, or DBA/1J showed improved spatial learning, but TTA expression caused subtle differences in contextual fear conditioning on two of these backgrounds, indicating that strain and genotype can interact independently under different behavioral settings. All model systems have limitations that should be recognized and mitigated where possible; our findings stress the importance of mapping the effects caused by TTA alone when working with tet-off models.