Clear cell meningiomas-case presentation, review of radiographic identifiers, and treatment approaches.

Spinal clear cell meningiomas (CCMs) are a rare histological subtype of meningiomas that pose preoperative diagnostic challenges due to their radiographic similarities with other lesions. They are also more aggressive, exhibiting higher rates of recurrence, particularly in pediatric patients. Overcoming diagnostic challenges of these tumors can improve patient outcomes. In this report, we describe a case of a pediatric patient presenting with a lumbar CCM in whom we were able to obtain gross total resection. Our report reviews previously identified predictors of CCM recurrence, including the Ki-67 proliferation index, number of spinal segments involved, and hormonal influences related to age and sex. We describe the characteristic radiographic features that differentiate spinal CCMs from other tumors to improve pre-operative diagnosis. Furthermore, we provide our rationale for adjuvant therapy for pediatric patients to refine treatment protocols for these rare tumors.

DNA methylation landscapes in DIPG reveal methylome variability that can be modified pharmacologically.

Background: Diffuse intrinsic pontine glioma (DIPG) is a uniformly lethal brainstem tumor of childhood, driven by histone H3 K27M mutation and resultant epigenetic dysregulation. Epigenomic analyses of DIPG have shown global loss of repressive chromatin marks accompanied by DNA hypomethylation. However, studies providing a static view of the epigenome do not adequately capture the regulatory underpinnings of DIPG cellular heterogeneity and plasticity. Methods: To address this, we performed whole-genome bisulfite sequencing on a large panel of primary DIPG specimens and applied a novel framework for analysis of DNA methylation variability, permitting the derivation of comprehensive genome-wide DNA methylation potential energy landscapes that capture intrinsic epigenetic variation. Results: We show that DIPG has a markedly disordered epigenome with increasingly stochastic DNA methylation at genes regulating pluripotency and developmental identity, potentially enabling cells to sample diverse transcriptional programs and differentiation states. The DIPG epigenetic landscape was responsive to treatment with the hypomethylating agent decitabine, which produced genome-wide demethylation and reduced the stochasticity of DNA methylation at active enhancers and bivalent promoters. Decitabine treatment elicited changes in gene expression, including upregulation of immune signaling such as the interferon response, STING, and MHC class I expression, and sensitized cells to the effects of histone deacetylase inhibition. Conclusions: This study provides a resource for understanding the epigenetic instability that underlies DIPG heterogeneity. It suggests the application of epigenetic therapies to constrain the range of epigenetic states available to DIPG cells, as well as the use of decitabine in priming for immune-based therapies.

Effects of antineoplastic and immunomodulating agents on postvaccination SARS-CoV-2 breakthrough infections, antibody response, and serological cytokine profile.

BACKGROUND: Despite immunization, patients on antineoplastic and immunomodulating agents have a heightened risk of COVID-19 infection. However, accurately attributing this risk to specific medications remains challenging. METHODS: An observational cohort study from December 11, 2020 to September 22, 2022, within a large healthcare system in San Diego, California, USA was designed to identify medications associated with greatest risk of postimmunization SARS-CoV-2 infection. Adults prescribed WHO Anatomical Therapeutic Chemical (ATC) classified antineoplastic and immunomodulating medications were matched (by age, sex, race, and number of immunizations) with control patients not prescribed these medications yielding a population of 26 724 patients for analysis. From this population, 218 blood samples were collected from an enrolled subset to assess serological response and cytokine profile in relation to immunization. RESULTS: Prescription of WHO ATC classified antineoplastic and immunomodulatory agents was associated with elevated postimmunization SARS-CoV-2 infection risk (HR 1.50, 95% CI 1.38 to 1.63). While multiple immunization doses demonstrated a decreased association with postimmunization SARS-CoV-2 infection risk, antineoplastic and immunomodulatory treated patients with four doses remained at heightened risk (HR 1.23, 95% CI 1.06 to 1.43). Risk variation was identified among medication subclasses, with PD-1/PD-L1 inhibiting monoclonal antibodies, calcineurin inhibitors, and CD20 monoclonal antibody inhibitors identified to associate with increased risk of postimmunization SARS-CoV-2 infection. Antineoplastic and immunomodulatory treated patients also displayed a reduced IgG antibody response to SARS-CoV-2 epitopes alongside a unique serum cytokine profile. CONCLUSIONS: Antineoplastic and immunomodulating medications associate with an elevated risk of postimmunization SARS-CoV-2 infection in a drug-specific manner. This comprehensive, unbiased analysis of all WHO ATC classified antineoplastic and immunomodulating medications identifies medications associated with greatest risk. These findings are crucial in guiding and refining vaccination strategies for patients prescribed these treatments, ensuring optimized protection for this susceptible population in future COVID-19 variant surges and potentially for other RNA immunization targets.

Safety and Efficacy Outcomes in Immune Checkpoint Inhibitor-Treated Patients With Metastatic Urothelial Carcinoma Requiring Treatment Interruption or Discontinuation Due to Immune-Related Adverse Events.

INTRODUCTION: As most patients with metastatic urothelial carcinoma (mUC) will be treated with immune checkpoint inhibitors (ICI), familiarity with their associated immune-related adverse events (irAEs) is critical. We describe the characteristics and outcomes of ICI-treated mUC patients who experienced irAEs requiring treatment interruption (TI) or permanent discontinuation. MATERIALS AND METHODS: ICI-treated mUC patients who developed grade ≥2 irAEs were reviewed. Clinical-, treatment-, and toxicity-related data were evaluated. Toxicity was graded per common terminology for categorization of adverse events v5.0. Cohorts were divided into patients who underwent ICI rechallenge and those who required permanent ICI discontinuation. Time to treatment interruption (TTI), time to next treatment, and duration of clinical benefit were assessed descriptively. Progression-free survival and overall survival (OS) were estimated using Kaplan-Meier methodology. RESULTS: Of 200 ICI-treated mUC patients at Cleveland Clinic between October 2015 and October 2020, 16 (8%) experienced ≥ grade 2 irAEs necessitating TI. Median TTI among all patients was 6.5 months (range, 1-19). Eleven patients (69%) required corticosteroids. ICI were held and rechallenged in 10 patients (62%) and permanently discontinued in 6 patients (38%). Of the 10 ICI-rechallenged patients, 7 (70%) experienced another irAE upon rechallenge with median time to irAE recurrence of 2.9 months (range, 0.1-10.9); 3 (30%) eventually discontinued ICI due to recrudescent irAEs. Four (40%) of the 10 ICI-rechallenged patients received subsequent therapy. Five (83%) of the 6 patients who permanently discontinued ICI demonstrated durable clinical benefit off therapy with median duration of clinical benefit 17.7 months (range, 14.2-55.2). Two-year OS was 40% (95% CI: 19%-86%) in the ICI rechallenge cohort and 67% (95% CI: 38%-100%) in the permanent discontinuation cohort. CONCLUSION: ICI-treated mUC patients who developed irAEs requiring TI had a high rate of subsequent irAEs upon ICI rechallenge. Importantly, patients who permanently discontinued ICI due to irAE demonstrated durable clinical benefit off treatment.

Risk of Thromboembolism in Patients Receiving Immunotherapy-Based Combinations as Front-Line Therapy for Metastatic Renal Cell Carcinoma.

BACKGROUND: Most patients with treatment-naïve metastatic renal cell carcinoma (mRCC) receive combination-based immunotherapy with either 2 immune-oncology checkpoint inhibitors (IO/IO) or an IO agent in combination with a vascular endothelial growth factor receptor (VEGF-R) tyrosine kinase inhibitor (IO/TKI). The rates of thromboembolism (TE) in these cohorts are not clearly described and can potentially impact decision-making between IO/IO and IO/TKI. METHODS: We conducted a retrospective investigation of patients with treatment-naïve mRCC treated with IO-based combinations between January 2015 and April 2021 at the Cleveland Clinic. TE events, including venous and arterial, were identified in each group. Competing risk regression was done to identify factors associated with the development of TE following therapy, with all-cause mortality treated as a competing event. RESULTS: Of 180 patients identified, 77 (43%) received IO/TKI and 103 (57%) received IO/IO. Median age was 65 years, 75% were male, and 80% had clear cell histology. Baseline characteristics were similar between the 2 groups. At a median follow-up of 22.0 months, 10.0% of all patients had a TE. The one-year incidence of TE was 8.1% (95% CI: 3.3%-15.8%) with IO/TKI and 9.8% (95% CI: 5.0%-16.5%) with IO/IO and was not significantly different between the 2 groups (HR 0.89, 95% CI: 0.35%-2.28%). Occurrence of TE was associated with decreased overall survival regardless of IO/IO or IO/TKI therapy (HR 2.80, 95% CI: 1.57-5.02). There was no difference in incidence of TE based on patient age, gender, prior history of TE, International Metastatic Renal Cell Carcinoma (IMDC) risk group, or Khorana score. CONCLUSIONS: Incidence of TE is similar between IO/IO and IO/TKI regimens in treatment-naïve mRCC and is also associated with decreased overall survival. While risk of TE may not guide decision-making in choice of front-line mRCC therapy, careful attention should be given to the high risk of TE in this population.

A Case Report of Infant-Type Hemispheric Glioma with a Novel GAB1-ABL2 Kinase Fusion Treated with Dasatinib.

INTRODUCTION: Infant-type hemispheric glioma (IHG) is a rare form of cancer that affects newborns and infants. It is classified as a pediatric-type high-grade glioma and typically harbors receptor tyrosine kinase (RTK) gene fusions. Here, we present the finding of a novel gene fusion IHG treated with a targeted therapy that has yet to be implemented for any other IHG case to date. CASE PRESENTATION: We report the case of a 12-month-old boy with IHG who presented with obstructive hydrocephalus due to a large mass in the right frontal lobe. The patient initially underwent mass resection, but subsequent imaging showed rapid interval progression of the residual tumor. Comprehensive molecular analysis of the tumor tissue revealed a novel GAB1-ABL2 gene fusion, and the patient was started on dasatinib, an ABL kinase inhibitor. Shortly after initiation of dasatinib treatment, there was a significant reduction in tumor size and enhancement, followed by stabilization of disease. DISCUSSION: The patient's robust response to treatment suggests that dasatinib is an effective targeted therapy for IHG harboring a GAB1-ABL2 gene fusion. This finding may inform future investigations into the disease processes of IHG and help guide the diagnosis and treatment of IHG in the absence of previously identified gene fusions, improving clinical management of this vulnerable patient population.

Utilizing risk-stratified pathways to personalize post-hepatectomy discharge planning: A contemporary analysis of 1,354 patients.

BACKGROUND: While risk-stratified post-hepatectomy pathways (RSPHPs) reduce length-of-stay, can they stratify hepatectomy patients by risk of early postoperative events. METHODS: 90-day outcomes from consecutive hepatectomies were analyzed (1/1/2017-12/31/2021). Pre/post-pathway analysis was performed for pathways: minimally invasive surgery ("MIS"); non-anatomic resection/left hepatectomy ("low-intermediate risk"); right/extended hepatectomy ("high-risk"); "Combination" operations. Time-to-event (TTE) analyses for readmission and interventional radiology procedures (IRPs) was performed. RESULTS: 1354 patients were included: MIS/n= â€‹119 (9 â€‹%); low-intermediate risk/n= â€‹443 (33 â€‹%); high-risk/n= â€‹328 (24 â€‹%); Combination/n= â€‹464 (34 â€‹%). There was no difference in readmission (pre: 13 â€‹% vs. post:11.5 â€‹%, p â€‹= â€‹0.398). There were fewer readmissions in post-pathway patients amongst MIS, low-intermediate risk, and Combination patients (all p â€‹> â€‹0.1). 114 (8.4 â€‹%) patients required IRPs. Time-to-readmission and time-to-IR-procedure plots demonstrated lower plateaus and flatter slopes for MIS/low-intermediate-risk pathways post-pathway implementation (p â€‹< â€‹0.001). CONCLUSION: RSPHPs can reliably stratify patients by risks of readmission or need for an IR procedure by predicting the most frequent period for these events.

Racial disparities in pancreatic cancer clinical trials: Defining the problem and identifying solutions.

Underrepresented minority patients with pancreatic cancer have differential access to cancer treatments, including clinical trials. The successful conduct and completion of clinical trials is critical to improve outcomes for patients with pancreatic cancer. Therefore, it is essential to consider how to maximize eligibility of patients for both therapeutic and non-therapeutic clinical trials. It is important for clinicians and for the health system to understand individual-, clinician-, and system-level barriers to recruitment, enrollment, and completion of clinical trials to alleviate bias. Understanding strategies that lead to improved enrollment of underrepresented minorities, socioeconomically disadvantaged individuals, and underserved communities will improve generalizability of cancer clinical trials and advance health equity.

"It's like a forgotten issue sometimes ": Qualitative study of individuals living and caring for people with chronic breathlessness.

INTRODUCTION: This study aims to explore the perspectives of patients and carers with chronic breathlessness on current provision of care, care expectations, and self-management needs to develop relevant health services and resources to improve clinical outcomes. METHODS: In-depth semistructured interviews were conducted on patients living with chronic breathlessness and carers. RESULTS: Thirteen patients (cardiac, respiratory, and noncardiorespiratory) and two carers were interviewed (mean age 57 years, 47% female, median duration with breathlessness 5 years). Four main themes were identified: (1) living with breathlessness, (2) diagnosis delays, misdiagnosis, and knowledge gaps, (3) beyond curing disease: symptom relief and improving quality of life, and (4) self-management and limited support for it. CONCLUSION: Breathlessness has a high personal impact but remains a neglected condition in Australia. Patients suffer from lack of personal, community, and provider awareness, discontinuity of care, and too few clinical and self-management options.

Assessing What Matters to People Affected by Alzheimer's Disease: A Quantitative Analysis.

INTRODUCTION: In this phase of the ongoing What Matters Most study series, designed to evaluate concepts that are meaningful to people affected by Alzheimer's disease (AD), we quantified the importance of symptoms, impacts, and outcomes of AD to people at risk for or with AD and care partners of people with AD. METHODS: We administered a web-based survey to individuals at risk for or with AD (Group 1: unimpaired cognition with evidence of AD pathology; Group 2: AD risk factors and subjective cognitive complaints/mild cognitive impairment; Group 3: mild AD) and to care partners of individuals with moderate AD (Group 4) or severe AD (Group 5). Respondents rated the importance of 42 symptoms, impacts, and outcomes on a scale ranging from 1 ("not at all important") to 5 ("extremely important"). RESULTS: Among the 274 respondents (70.4% female; 63.1% white), over half of patient respondents rated all 42 items as "very important" or "extremely important," while care partners rated fewer items as "very important" or "extremely important." Among the three patient groups, the minimum (maximum) mean importance rating for any item was 3.4 (4.6), indicating that all items were at least moderately to very important. Among care partners of people with moderate or severe AD, the minimum (maximum) mean importance rating was 2.1 (4.4), indicating that most items were rated as at least moderately important. Overall, taking medications correctly, not feeling down or depressed, and staying safe had the highest importance ratings among both patients and care partners, regardless of AD phase. CONCLUSION: Concepts of importance to individuals affected by AD go beyond the common understanding of "cognition" or "function" alone, reflecting a desire to maintain independence, overall physical and mental health, emotional well-being, and safety. Preservation of these attributes may be key to understanding whether interventions deliver clinically meaningful outcomes.

Technical Review of Clinical Outcomes Assessments Across the Continuum of Alzheimer's Disease.

INTRODUCTION: Insight into the relationship between concepts that matter to the people affected by Alzheimer's disease (AD) and the clinical outcome assessments (COAs) commonly used in AD clinical studies is limited. Phases 1 and 2 of the What Matters Most (WMM) study series identified and quantitatively confirmed 42 treatment-related outcomes that are important to people affected by AD. METHODS: We compared WMM concepts rated as "very important" or higher to items included in COAs used commonly in AD studies. RESULTS: Twenty COAs designed to assess signs, symptoms, and impacts across the spectrum of AD were selected for review. Among these 20 COAs, only 5 reflected 12 or more WMM concepts [Integrated Alzheimer's Disease Rating Scale (iADRS), Alzheimer's Disease Cooperative Study-Activities of Daily Living Inventory (ADCS-ADL), Alzheimer's Disease Cooperative Study-Activities of Daily Living Inventory-Mild Cognitive Impairment (ADCS-ADL-MCI), Alzheimer's Disease Composite Scores (ADCOMS), and Clinical Dementia Rating; Clinical Dementia Rating-Sum of Boxes (CDR/CDR-SB)]. Multiple symptoms and impacts of AD identified as important and meaningful in the WMM studies map only indirectly at best to 7 of the 20 most widely used COAs. CONCLUSION: While many frequently used COAs in AD capture some concepts identified as important to AD populations and their care partners, overlap between any single measure and the concepts that matter to people affected by AD is limited. The highest singly matched COA reflects fewer than half (45%) of WMM concepts. Use of multiple COAs expands coverage of meaningful concepts. Future research should explore the content validity of AD COAs planned for AD trials based on further confirmation of the ecological validity of the WMM items. This research should inform development and use of core outcome sets that capture WMM items and selection or development of new companion tools to fully demonstrate clinically meaningful outcomes spanning WMM.

Management of chronic breathlessness in primary care: what do GPs, non-GP specialists, and allied health professionals think?

BACKGROUND: To explore the perspectives of GPs, non-GP specialists, and allied health professionals on the role of primary care in diagnosing and managing chronic breathlessness, the barriers faced, and the resources needed to optimise care of patients with chronic breathlessness. METHODS: This was a qualitative study involving focus group discussions that included 35GPs, non-GP specialists, and allied health professionals. Topics explored included: (1) views on the role of primary care in diagnosing and managing chronic breathlessness; (2) barriers to optimal assessment in primary care; and (3) facilitators to further optimise the care of patients with chronic breathlessness. RESULTS: All participants considered that primary care has a central role to play in the assessment and management of chronic breathlessness, but greater access to referral services, suitable funding structures, and upskilling on the use of diagnostic tests such as spirometry and electrocardiography are required for this to be realised. Both GPs and non-GP specialists described great potential for developing better linkages, including new ways of referral and online consultations, greater ease of referral to allied health services, even if conducted virtually, for patients with functional causes of breathlessness. Participants identified a need to develop integrated breathlessness clinics for patients referred by GPs, which would ensure patients receive optimal care in the shortest possible time frame. CONCLUSIONS: GPs are crucial to achieving optimal care for breathless patients, especially given the multifactorial and multimorbid nature of breathlessness; however, there are significant gaps in services and resources at present that limit their ability to perform this role.

Impact of cumulative operative time on postoperative complication risk in simultaneous resections of colorectal liver metastases and primary tumors.

BACKGROUND: Simultaneous resection of colorectal liver metastases (CLM) and primary colorectal cancers (CRC) is nuanced without firm rules for selection. This study aimed to identify factors associated with morbidity after simultaneous resection. METHODS: Using a prospective database, patients undergoing simultaneous CLM-CRC resection from 1/1/2017-7/1/2020 were analyzed. Regression modeling estimated impact of colorectal resection type, Kawaguchi-Gayet (KG) hepatectomy complexity, and perioperative factors on 90-day complications. RESULTS: Overall, 120 patients underwent simultaneous CLM-CRC resection. Grade≥2 complications occurred in 38.3% (n = 46); these patients experienced longer length of stay (median LOS 7.5 vs. 4, p < 0.001) and increased readmission (39% vs. 1.4%, p < 0.001) compared to patients with zero or Grade 1 complications. Median OR time was 298 min. Patients within highest operative time quartile (>506 min) had higher grade≥2 complications (57%vs. 23%, p = 0.04) and greater than 4-fold increased odds of grade≥2 morbidity (OR 4.3, 95% CI (Confidence Interval) 1.41-13.1, p = 0.01). After adjusting for Pringle time, KG complexity and colorectal resection type, increasing operative time was associated with grade≥2 complications, especially for resections in highest quartile of operative time (OR 7.28, 95% CI 1.73-30.6, p = 0.007). CONCLUSION: In patients undergoing simultaneous CLM-CRC resection, prolonged operative time is independently associated with grade≥2 complications. Awareness of cumulative operative time may inform intraoperative decision-making by surgical teams.

Applied behavior analysis and the zoo: Forthman and Ogden (1992) thirty years later.

The field of applied behavior analysis has been directly involved in both research and applications of behavioral principles to improve the lives of captive zoo animals. Thirty years ago, Forthman and Ogden (1992) wrote one of the first papers documenting some of these efforts. Since that time, considerable work has been done using behavioral principles and procedures to guide zoo welfare efforts. The current paper reexamines and updates Forthman and Ogden's original points, with attention to the 5 categories they detailed: (a) promotion of species-typical behavior, (b) reintroduction and repatriation of endangered species, (c) animal handling, (d) pest control, and (e) animal performances. In addition, we outline 3 current and future directions for behavior analytic endeavors: (a) experimental analyses of behavior and the zoo, (b) applied behavior analysis and the zoo, and (c) single-case designs and the zoo. The goal is to provide a framework that can guide future behavioral research in zoos, as well as create applications based on these empirical evaluations.

Impact of Visual Barrier Removal on the Behavior of Shelter-Housed Dogs.

With millions of dogs housed in shelters each year, it is important to consider how the shelter environment impacts welfare. Social isolation and a lack of control over the environment can negatively impact wellbeing. However, providing social opportunities requires costly resources and can raise concerns about increased barking. In this study, 17 dogs were observed before, during, and after a visual barrier was partially removed to increase the ability to see to other dogs and the surrounding room. Stress behaviors, crate position, and resting behaviors did not differ significantly across phases; however, vocalizations were lower in the visual access and post phases (Friedman's test, p = .02). In addition, in-room barking data (N = 66) revealed no change in barking duration when barriers were removed. This absence of an increase in vocalizations should alleviate some concerns with allowing visual social contact. However, the lack of impact on stress and resting behaviors may indicate that visual social contact alone is insufficient for providing significant welfare benefits and that shelters should prioritize increasing social contact through playgroups or group housing.

Re-excision After Unplanned Excision of Soft Tissue Sarcoma is Associated with High Morbidity and Limited Pathologic Identification of Residual Disease.

BACKGROUND: Patients with unplanned excision (UPE) of trunk and extremity soft tissue sarcoma (STS) present a significant management challenge for sarcoma specialists. Oncologic re-resection has been considered standard practice after UPE with positive or uncertain margins. A strategy of active surveillance or "watch and wait" has been suggested as a safe alternative to routine re-excision. In this context, the current study sought to evaluate short-term outcomes and morbidity after re-resection to better understand the risks and benefits of this treatment strategy. METHODS: A retrospective, single-institution study reviewed patients undergoing oncologic re-resection after UPE of an STS during a 5-year period (2015-2020), excluding those with evidence of gross residual disease. Short-term clinical outcomes were evaluated together with final pathologic findings. RESULTS: The review identified 67 patients undergoing re-resection after UPE of an STS. Of these 67 patients, 45 (67%) were treated with a combination of external beam radiation therapy (EBRT) and surgery. Plastic surgery was involved for reconstruction in 49 cases (73%). The rate of wound complications after re-resection was 45 % (n = 30), with 15 % (n = 10) of the patients experiencing a major wound complication. Radiation therapy and plastic surgery involvement were independently associated with wound complications. Notably, 45 patients (67%) had no evidence of residual disease in the re-resection specimen, whereas 13 patients (19 %) had microscopic disease, and 9 patients (13%) had indeterminate pathology. CONCLUSION: Given the morbidity of re-resection and limited identification of residual disease, treatment plans and discussions with patients should outline the expected pathologic findings and morbidity of surgery.

A nine-month-old boy with regression of milestones and severe constipation: an unusual case of a large spinal NTRK1 fusion pilocytic astrocytoma.

INTRODUCTION: Pilocytic astrocytoma, a World Health Organization grade 1 tumor, is the most common brain tumor in children between 5 and 14 years of age and the second most common in children younger than 5 and older than 14. Although classical to the cerebellum and hypothalamic regions, it can also arise in the spinal cord. Larotrectinib, a selective inhibitor of tropomyosin receptor kinase, has been effective in pediatric tumors with NTRK fusion mutations in children as young as 1-month-old. CASE: We share the case of a 9-month-old boy who presented with a 4-month history of regression of his milestones and severe constipation who was found to have a large spinal pilocytic astrocytoma with multiple intracranial periventricular lesions.