Immune-related adverse event in the emergency department: methodology of the immune-related emergency disposition index (IrEDi).

For many cancer patients, immune checkpoint inhibitors (ICIs) can be life-saving. However, the immune-related adverse events (irAEs) from ICIs can be debilitating and can quickly become severe or even be fatal. Often, irAEs will precipitate visits to the emergency department (ED). Therefore, early recognition and the decision to admit, observe, or discharge these patients from the ED can be key to a cancer patient's morbidity and mortality. ED clinicians typically make their decision for disposition (admit, observe, or discharge) within 2-6 h from their patient's ED presentation. However, irAEs are particularly challenging in the ED because of atypical presentations, the absence of classic symptoms, the delayed availability of diagnostic tests during the ED encounter, and the fast pace in the ED setting. At present, there is no single sufficiently large ED data source with clinical, biological, laboratory, and imaging data that will allow for the development of a tool that will guide early recognition and appropriate ED disposition of patients with potential irAEs. We describe an ongoing federally funded project that aims to develop an immune-related emergency disposition index (IrEDi). The project capitalizes on a multi-site collaboration among 4 members of the Comprehensive Oncologic Emergency Research Network (CONCERN): MD Anderson Cancer Center, Ohio State University, Northwestern University, and University of California San Diego. If the aims are achieved, the IrEDi will be the first risk stratification tool derived from a large racial/ethnically and geographically diverse population of cancer patients. The future goal is to validate irEDi in general EDs to improve emergency care of cancer patients on ICIs.

A case series of adrenal insufficiency (likely due to hypophysitis) in cancer patients treated with immune checkpoint inhibitors.

The number of approved immune checkpoint inhibitors (ICIs) and their indications have significantly increased over the past decade. Immune-related adverse effects (irAEs) of ICIs vary widely in presentation and symptoms and can present diagnostic challenges to emergency department (ED) physicians. Moreover, when ICIs are combined with radiotherapy, cytotoxic chemotherapy, or targeted therapy, the attribution of signs and symptoms to an immune-related cause is even more difficult. Here, we report a series of 5 ED cases of adrenal insufficiency in ICI-treated cancer patients. All 5 patients presented with severe fatigue and nausea. Four patients definitely had and one patient possibly had central adrenal insufficiency, and 4 patients had undetectable serum cortisol levels. The majority of the patients had nonspecific symptoms that were not recognized at their first ED presentation. These cases illustrate the need for a heightened level of suspicion for adrenal insufficiency in ICI-treated cancer patients with hypotension, nausea and/or vomiting, abdominal pain, fatigue, or hypoglycemia. As ICI use increases, irAE-associated oncologic emergencies will become more prevalent. Thus, ED physicians must update their knowledge regarding the diagnosis and management of irAEs and routinely inquire about the specific antineoplastic therapies that their ED patients with cancer are receiving. A random cortisol level (results readily available in most EDs) with interpretation taking the circadian rhythm and the current level of physiological stress into consideration can inform the differential diagnosis and whether further investigation of this potential irAE is warranted.

Long-term overall survival of patients who undergo breast-conserving therapy or mastectomy for early operable HER2-Positive breast cancer after preoperative systemic therapy: an observational cohort study.

Background: Understanding the survival outcomes associated with breast-conserving therapy (BCT) and mastectomy after preoperative systemic therapy (PST) enables clinicians to provide more personalized treatment recommendations. However, lack of firm survival benefit data limits the breast surgery choices of human epidermal growth factor receptor 2 (HER2)-positive breast cancer patients who receive PST. We sought to determine whether BCT or mastectomy after PST for early operable HER2-positive breast cancer is associated with better long-term survival outcomes and determine the degree to which PST response affects this association. Methods: In this observational cohort study, we compared the long-term survival outcomes of BCT and mastectomy after PST for HER2-positive breast cancer and evaluated the impact of PST response on the relationship between breast surgery performed and survival outcomes. Our cohort included 625 patients with early operable HER2-positive breast cancer who received PST followed by BCT or mastectomy between January 1998 and October 2009. These patients also received standard postoperative radiation, trastuzumab, and endocrine therapy as indicated clinically. We used propensity score matching to assemble mastectomy and BCT cohorts with similar baseline characteristics and used Kaplan-Meier plots and Cox proportional hazards regression to detect associations between surgery types and outcomes. Furthermore, in this study, we analyzed the original data of 625 patients using the inverse probability of treatment weighting (IPTW) method to enhance the reliability of the comparison between the mastectomy and BCT cohorts by addressing potential confounding variables. Findings: Propensity score matching yielded cohorts of 221 patients who received BCT and 221 patients who underwent mastectomy. At the median follow-up time of 9.9 years, compared with BCT, mastectomy was associated with worse overall survival (hazard ratio, 1.66; 95% confidence interval [CI]: 1.08-2.57; P = 0.02). In patients who had axillary lymph node pathological complete response, mastectomy was associated with worse overall survival before matching (hazard ratio, 2.17; 95% CI: 1.22-3.86; P < 0.01) and after matching (hazard ratio, 2.12; 95% CI: 1.15-3.89; P = 0.02). Among patients with pathological complete response in the breast, the survival results did not differ significantly between BCT and mastectomy patients. IPTW method validated that BCT offers better overall survival in patients who had axillary lymph node pathological complete response. Interpretation: People with HER2-positive breast cancer who have already had PST are more likely to survive after BCT, especially if they get a pathological complete response in the axillary lymph nodes. These findings underscore the necessity for further investigation into how responses to PST can inform the choice of surgical intervention and the potential impact on overall survival. Such insights could lead to the development of innovative tools that support personalized surgical strategies in the management of breast cancer. Funding: This work was supported by grants from the Nantong Science and Technology Project (JCZ2022079), Nantong Health Commission Project (QA2021031, MSZ2023040) and National Natural Science Foundation of China (No. 82394430).

Cardiovascular events after cancer immunotherapy as oncologic emergencies: Analyses of 610 head and neck cancer patients treated with immune checkpoint inhibitors.

BACKGROUND: Cardio-oncology and emergency medicine are closely collaborative, as many cardiac events in cancer patients require evaluation and treatment in the emergency department (ED). Immune checkpoint inhibitors (ICIs) have become a common treatment for patients with head and neck cancer (HNC). However, the immune-related adverse events (irAEs) from ICIs can be clinically significant. METHODS: We reviewed and analyzed cardiovascular diagnoses among HNC patients who received ICI during the period April 1, 2016-December 31, 2020 in a large tertiary cancer center. Demographics, clinical and cancer-related data were abstracted, and billing databases were queried for cardiovascular disease (CVD)-related diagnosis using International Classification of Disease-version10 (ICD-10) codes. We recorded receipt of care at the ED as one of the outcome variables. RESULTS: A total of 610 HNC patients with a median follow-up time of 12.3 months (median, interquartile range = 5-30 months) comprised our study cohort. Overall, 25.7% of patients had pre-existing CVD prior to ICI treatment. Of the remaining 453 patients without pre-existing CVD, 31.5% (n = 143) had at least one CVD-related diagnosis after ICI initiation. Tachyarrhythmias (91 new events) was the most frequent CVD-related diagnosis after ICI. The time to diagnosis of myocarditis from initiation of ICI occurred the earliest (median 2.5 months, 1.5-6.8 months), followed by myocardial infarction (3.7, 0.5-9), cardiomyopathy (4.5, 1.6-7.3), and tachyarrhythmias (4.9, 1.2-11.4). Patients with myocarditis and tachyarrhythmias mainly presented to the ED for care. CONCLUSION: The use of ICI in HNC is still expanding and the spectrum of delayed manifestation of ICI-induced cardiovascular toxicities is yet to be fully defined in HNC survivors.

Attempts to Understand Oral Mucositis in Head and Neck Cancer Patients through Omics Studies: A Narrative Review.

Oral mucositis (OM) is a common and clinically impactful side effect of cytotoxic cancer treatment, particularly in patients with head and neck squamous cell carcinoma (HNSCC) who undergo radiotherapy with or without concomitant chemotherapy. The etiology and pathogenic mechanisms of OM are complex, multifaceted and elicit both direct and indirect damage to the mucosa. In this narrative review, we describe studies that use various omics methodologies (genomics, transcriptomics, microbiomics and metabolomics) in attempts to elucidate the biological pathways associated with the development or severity of OM. Integrating different omics into multi-omics approaches carries the potential to discover links among host factors (genomics), host responses (transcriptomics, metabolomics), and the local environment (microbiomics).

Premature senescence and cardiovascular disease following cancer treatments: mechanistic insights.

Cardiovascular disease (CVD) is a leading cause of morbidity and mortality, especially among the aging population. The "response-to-injury" model proposed by Dr. Russell Ross in 1999 emphasizes inflammation as a critical factor in atherosclerosis development, with atherosclerotic plaques forming due to endothelial cell (EC) injury, followed by myeloid cell adhesion and invasion into the blood vessel walls. Recent evidence indicates that cancer and its treatments can lead to long-term complications, including CVD. Cellular senescence, a hallmark of aging, is implicated in CVD pathogenesis, particularly in cancer survivors. However, the precise mechanisms linking premature senescence to CVD in cancer survivors remain poorly understood. This article aims to provide mechanistic insights into this association and propose future directions to better comprehend this complex interplay.

Hemoptysis in Cancer Patients.

Hemoptysis in cancer patients can occur for various reasons, including infections, tumors, blood vessel abnormalities and inflammatory conditions. The degree of hemoptysis is commonly classified according to the quantity of blood expelled. However, volume-based definitions may not accurately reflect the clinical impact of bleeding. This review explores a more comprehensive approach to evaluating hemoptysis by considering its risk factors, epidemiology and clinical consequences. In particular, this review provides insight into the risk factors, identifies mortality rates associated with hemoptysis in cancer patients and highlights the need for developing a mortality prediction score specific for cancer patients. The use of hemoptysis-related variables may help stratify patients into risk categories; optimize the control of bleeding with critical care; implement the use of tracheobronchial or vascular interventions; and aid in treatment planning. Effective management of hemoptysis in cancer patients must address the underlying cause while also providing supportive care to improve patients' quality of life.

Salivary Extracellular MicroRNAs for Early Detection and Prognostication of Esophageal Cancer: A Clinical Study.

BACKGROUND & AIMS: Early detection of esophageal squamous cell carcinoma (ESCC) will facilitate curative treatment. We aimed to establish a microRNA (miRNA) signature derived from salivary extracellular vesicles and particles (EVPs) for early ESCC detection and prognostication. METHODS: Salivary EVP miRNA expression was profiled in a pilot cohort (n = 54) using microarray. Area under the receiver operator characteristic curve (AUROC) and least absolute shrinkage and selector operation regression analyses were used to prioritize miRNAs that discriminated patients with ESCC from controls. Using quantitative reverse transcription polymerase chain reaction, the candidates were measured in a discovery cohort (n = 72) and cell lines. The prediction models for the biomarkers were derived from a training cohort (n = 342) and validated in an internal cohort (n = 207) and an external cohort (n = 226). RESULTS: The microarray analysis identified 7 miRNAs for distinguishing patients with ESCC from control subjects. Because 1 was not always detectable in the discovery cohort and cell lines, the other 6 miRNAs formed a panel. A signature of this panel accurately identified patients with all-stage ESCC in the training cohort (AUROC = 0.968) and was successfully validated in 2 independent cohorts. Importantly, this signature could distinguish patients with early-stage (stage Ⅰ/Ⅱ) ESCC from control subjects in the training cohort (AUROC = 0.969, sensitivity = 92.00%, specificity = 89.17%) and internal (sensitivity = 90.32%, specificity = 91.04%) and external (sensitivity = 91.07%, specificity = 88.06%) validation cohorts. Moreover, a prognostic signature based on the panel was established and efficiently predicted the high-risk cases with poor progression-free survival and overall survival. CONCLUSIONS: The salivary EVP-based 6-miRNA signature can serve as noninvasive biomarkers for early detection and risk stratification of ESCC. Chinese Clinical Trial Registry, ChiCTR2000031507.

14-3-3σ-NEDD4L axis promotes ubiquitination and degradation of HIF-1α in colorectal cancer.

A hypoxic microenvironment contributes to tumor progression, with hypoxia-inducible factor-1α (HIF-1α) being a critical regulator. We have reported that 14-3-3σ is negatively associated with HIF-1α expression; however, its role in hypoxia-induced tumor progression remains poorly characterized. Here we show that 14-3-3σ suppresses cancer hypoxia-induced metastasis and angiogenesis in colorectal cancer (CRC). 14-3-3σ opposes HIF-1α expression by regulating the protein stability of HIF-1α, thereby decreasing HIF-1α transcriptional activity and suppressing tumor progression. Mechanistic studies show that the 14-3-3σ-interacting protein neural precursor cell-expressed developmentally down-regulated 4-like (NEDD4L) is an E3 ligase that targets HIF-1α. 14-3-3σ promotes the binding of S448-phosphorylated NEDD4L to HIF-1α, thereby enhancing HIF-1α poly-ubiquitination and subsequent proteasome-mediated degradation. Consistent with this anti-tumorigenic function for 14-3-3σ, low 14-3-3σ expression levels correlate with poor CRC patient survival, and 14-3-3σ enhances the response of CRC to bevacizumab. These results reveal an important mechanism for 14-3-3σ in tumor suppression through HIF-1α regulation.

Age-related decline in hippocampal tyrosine phosphatase PTPRO is a mechanistic factor in chemotherapy-related cognitive impairment.

Chemotherapy-related cognitive impairment (CRCI) or "chemo brain" is a devastating neurotoxic sequela of cancer-related treatments, especially for the elderly individuals. Here we show that PTPRO, a tyrosine phosphatase, is highly enriched in the hippocampus, and its level is tightly associated with neurocognitive function but declined significantly during aging. To understand the protective role of PTPRO in CRCI, a mouse model was generated by treating Ptpro-/- female mice with doxorubicin (DOX) because Ptpro-/- female mice are more vulnerable to DOX, showing cognitive impairments and neurodegeneration. By analyzing PTPRO substrates that are neurocognition-associated tyrosine kinases, we found that SRC and EPHA4 are highly phosphorylated/activated in the hippocampi of Ptpro-/- female mice, with increased sensitivity to DOX-induced CRCI. On the other hand, restoration of PTPRO in the hippocampal CA3 region significantly ameliorate CRCI in Ptpro-/- female mice. In addition, we found that the plant alkaloid berberine (BBR) is capable of ameliorating CRCI in aged female mice by upregulating hippocampal PTPRO. Mechanistically, BBR upregulates PTPRO by downregulating miR-25-3p, which directly targeted PTPRO. These findings collectively demonstrate the protective role of hippocampal PTPRO against CRCI.

An ERK5-NRF2 Axis Mediates Senescence-Associated Stemness and Atherosclerosis.

BACKGROUND: ERK5 (extracellular signal-regulated kinase 5) is a dual kinase transcription factor containing an N-terminal kinase domain and a C-terminal transcriptional activation domain. Many ERK5 kinase inhibitors have been developed and tested to treat cancer and inflammatory diseases. However, recent data have raised questions about the role of the catalytic activity of ERK5 in proliferation and inflammation. We aimed to investigate how ERK5 reprograms myeloid cells to the proinflammatory senescent phenotype, subsequently leading to atherosclerosis. METHODS: A ERK5 S496A (dephosphorylation mimic) knock in (KI) mouse model was generated using CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/clustered regularly interspaced short palindromic repeat-associated 9), and atherosclerosis was characterized by hypercholesterolemia induction. The plaque phenotyping in homozygous ERK5 S496A KI and wild type (WT) mice was studied using imaging mass cytometry. Bone marrow-derived macrophages were isolated from hypercholesterolemic mice and characterized using RNA sequencing and functional in vitro approaches, including senescence, mitochondria reactive oxygen species, and inflammation assays, as well as by metabolic extracellular flux analysis. RESULTS: We show that atherosclerosis was inhibited in ERK5 S496A KI mice. Furthermore, ERK5 S496 phosphorylation mediates both senescence-associated secretory phenotype and senescence-associated stemness by upregulating AHR (aryl hydrocarbon receptor) in plaque and bone marrow-derived macrophages isolated from hypercholesterolemic mice. We also discovered that ERK5 S496 phosphorylation could induce NRF2 (NFE2-related factor 2) SUMOylation at a novel K518 site to inhibit NRF2 transcriptional activity without altering ERK5 catalytic activity and mediates oxidized LDL (low-density lipoprotein)-induced senescence-associated secretory phenotype. Specific ERK5 kinase inhibitors (AX15836 and XMD8-92) also inhibited ERK5 S496 phosphorylation, suggesting the involvement of ERK5 S496 phosphorylation in the anti-inflammatory effects of these ERK5 kinase inhibitors. CONCLUSIONS: We discovered a novel mechanism by which the macrophage ERK5-NRF2 axis develops a unique senescence-associated secretory phenotype/stemness phenotype by upregulating AHR to engender atherogenesis. The finding of senescence-associated stemness phenotype provides a molecular explanation to resolve the paradox of senescence in proliferative plaque by permitting myeloid cells to escape the senescence-induced cell cycle arrest during atherosclerosis formation.

PTPRO suppresses lymph node metastasis of esophageal carcinoma by dephosphorylating MET.

Protein tyrosine phosphatase receptor-type O (PTPRO) is a membrane-bound tyrosine phosphatase. Notably, epigenetically silenced PTPRO due to promoter hypermethylation is frequently linked to malignancies. In this study, we used cellular and animal models, and patient samples to demonstrate that PTPRO can suppress the metastasis of esophageal squamous cell carcinoma (ESCC). Mechanistically, PTPRO can inhibit MET-mediated metastasis by dephosphorylating Y1234/1235 in the kinase activation loop of MET. Patients with PTPROlow/p-METhigh had significantly poor prognosis, suggesting that PTPROlow/p-METhigh can serve as an independent prognostic factor for patients with ESCC.

Anti-miR-93-5p therapy prolongs sepsis survival by restoring the peripheral immune response.

Sepsis remains a leading cause of death for humans and currently has no pathogenesis-specific therapy. Hampered progress is partly due to a lack of insight into deep mechanistic processes. In the past decade, deciphering the functions of small noncoding miRNAs in sepsis pathogenesis became a dynamic research topic. To screen for new miRNA targets for sepsis therapeutics, we used samples for miRNA array analysis of PBMCs from patients with sepsis and control individuals, blood samples from 2 cohorts of patients with sepsis, and multiple animal models: mouse cecum ligation puncture-induced (CLP-induced) sepsis, mouse viral miRNA challenge, and baboon Gram+ and Gram- sepsis models. miR-93-5p met the criteria for a therapeutic target, as it was overexpressed in baboons that died early after induction of sepsis, was downregulated in patients who survived after sepsis, and correlated with negative clinical prognosticators for sepsis. Therapeutically, inhibition of miR-93-5p prolonged the overall survival of mice with CLP-induced sepsis, with a stronger effect in older mice. Mechanistically, anti-miR-93-5p therapy reduced inflammatory monocytes and increased circulating effector memory T cells, especially the CD4+ subset. AGO2 IP in miR-93-KO T cells identified important regulatory receptors, such as CD28, as direct miR-93-5p target genes. In conclusion, miR-93-5p is a potential therapeutic target in sepsis through the regulation of both innate and adaptive immunity, with possibly a greater benefit for elderly patients than for young patients.

A new paradigm for classifying and treating HER2-positive breast cancer.

BACKGROUND: Because of the phenomenal success of treatment with monoclonal antibodies and antibody-drug conjugates targeting human epidermal growth factor receptor 2 (HER2), most patients with early-stage HER2-positive breast cancer (HER2+ BC) and some with limited metastatic diseases have been cured, and those who have not been cured have achieved significant improvements in overall survival, which has weakened the role of the TNM staging system in the prognosis of HER2+ BC today. Given that the disease is now highly curable, treatment conception, classification, and modalities should differ from those of cancer types with a poor prognosis. It is warranted to build a new paradigm for classifying and treating HER2+ BC. RECENT FINDINGS: In our personal view, we suggest that the classification system should be based not only on traditional anatomy and cancer biology but also on available treatment regimens, their exceptional outcomes, and their toxicities. In this regard, we developed a new concise classification of HER2+ BC based on the TNM staging system, a review of the literature, research results, and our clinical experience, dividing the patients into four distinct groups: curable (lymph-node negative and small (≤3 cm) early breast cancer), do our best to cure (locally advanced or tumors >3 cm early breast cancer), hope for cure (local-regional recurrent, limited metastases, and exceptional responders), and incurable (metastatic breast cancer with poor performance status or non-exceptional responders). CONCLUSION: It will assist clinicians in developing an optimal treatment regimen at the outset, curing more HER2+ BC patients and improving their quality of life.

Emergency department use by patients who received chimeric antigen receptor T cell infusion therapy.

Background: Chimeric antigen receptor T cell infusion (CAR T) therapy has revolutionized the treatment of hematologic malignancies, but treatment-related toxicities are of concern. Understanding the timing and reasons for which patients present to the emergency department (ED) after CAR T therapy can assist with the early recognition and management of toxicities. Methods: A retrospective observational cohort study was conducted for patients who had undergone CAR T therapy in the past 6 months and visited the ED of The University of Texas MD Anderson Cancer Center between 04/01/2018 and 08/01/2022. The timing of presentation after CAR T product infusion, patient characteristics, and outcomes of the ED visit were examined. Survival analyses were conducted using Cox proportional hazards regression and Kaplan-Meier estimates. Results: During the period studied, there were 276 ED visits by 168 unique patients. Most patients had diffuse large B-cell lymphoma (103/168; 61.3%), multiple myeloma (21/168; 12.5%), or mantle cell lymphoma (16/168; 9.5%). Almost all 276 visits required urgent (60.5%) or emergent (37.7%) care, and 73.5% of visits led to admission to the hospital or observation unit. Fever was the most frequent presenting complaint, reported in 19.6% of the visits. The 30-day and 90-day mortality rates after the index ED visits were 17.0% and 32.2%, respectively. Patients who had their first ED visit >14 days after CAR T product infusion had significantly worse overall survival (multivariable hazard ratio 3.27; 95% confidence interval 1.29-8.27; P=0.012) than patients who first visited the ED within 14 days of CAR T product infusion. Conclusion: Cancer patients who receive CAR T therapy commonly visit the ED, and most are admitted and/or require urgent or emergent care. During early ED visits patients mainly present with constitutional symptoms such as fever and fatigue, and these early visits are associated with better overall survival.

Advances in immune checkpoint inhibitors induced-cardiotoxicity.

Immune checkpoint inhibitors (ICIs) are approved as the first-line drug for treating many cancers and has shown significant survival benefits; however, it also causes immune-related adverse events (irAEs) while activating the immune system, involving multiple organs. Among them, cardiovascular immune-related adverse events (CV-irAE) are rare, but common causes of death in ICIs treated cancer patients, which manifest as myocardial, pericardial, vascular and other cardiovascular toxicities. Therefore, it is important that irAEs, especially CV-irAE should be carefully recognized and monitored during the whole ICIs treatment because early detection and treatment of CV-irAE can significantly reduce the mortality of such patients. Consequently, it is urgent to fully understand the mechanism and management strategies of CV-irAE. The effects of ICIs are multifaceted and the exact mechanism of CV-irAE is still elusive. Generally, T cells identify tumor cell antigens as well as antigen in cardiomyocytes that are the same as or homologous to those on tumor cells, thus causing myocardial damage. In addition, ICIs promote formation of cardiac troponin I (cTnI) that induces cardiac dysfunction and myocardial dilatation; moreover, ICIs also increase the production of cytokines, which promote infiltration of inflammation-linked molecules into off-target tissues. Currently, the management and treatment of cardiovascular toxicity are largely dependent on glucocorticoids, more strategies for prevention and treatment of CV-irAE, such as predictive markers are being explored. This review discusses risk factors, potential pathophysiological mechanisms, clinical manifestations, and management and treatment of CV-irAE, guiding the development of more effective prevention, treatment and management strategies in the future.

Evaluation and management of acute high-grade immunotherapy-related neurotoxicity.

Immune checkpoint inhibitor monoclonal antibodies allow the host's immune system to attack tumors, which has revolutionized cancer care over the last decade. As the use of immune checkpoint inhibitors has expanded, so have autoimmune-like complications known as immune-related adverse events. These include the infrequent but increasingly more common, potentially deadly neurological immune related adverse events. When feeling acutely ill, patients will often seek care not from their oncologist but from their family physician, clinics, emergency, and urgent care sites, or other available providers. Thus, while assessing acutely ill cancer patients who are experiencing neurological symptoms, non-oncologists should be prepared to recognize, diagnose, and treat neurological immune related adverse events in addition to more familiar conditions. This narrative review is designed to update acute care clinicians on current knowledge and to present a symptom-based framework for evaluating and treating neurological immune related adverse events based on the leading immunotoxicity organizations' latest recommendations.

The prevalence and spectrum of reported incidental adrenal abnormalities in abdominal computed tomography of cancer patients: The experience of a comprehensive cancer center.

Background: The increasing use of computed tomography (CT) has identified many patients with incidental adrenal lesions. Further evaluation of these lesions is often dependent on the language used in the radiology report. Compared to the general population, patients with cancer have a higher risk for adrenal abnormalities, yet data on the prevalence and type of incidental adrenal lesions reported on radiologic reports in cancer patients is limited. In this study, we aimed to determine the prevalence and nature of adrenal abnormalities as an incidental finding reported on radiology reports of cancer patients evaluated for reasons other than suspected adrenal pathology. Methods: Radiology reports of patients who underwent abdominal CT within 30 days of presentation to a tertiary cancer center were reviewed and analyzed. We used natural language processing to perform a multi-class text classification of the adrenal reports. Patients who had CT for suspected adrenal mass including adrenal protocol CT were excluded. Three independent abstractors manually reviewed abnormal and questionable results, and we measured the interobserver agreement. Results: From June 1, 2006, to October 1, 2017, a total of 600,399 abdominal CT scans were performed including 66,478 scans obtained within 30 days of the patient's first presentation. Of these, 58,512 were eligible after applying the exclusion criteria. Adrenal abnormalities were identified in 7,817 (13.4%) reports, with adrenal nodularity (3,401 [43.5%]), adenomas (1,733 [22.2%]), and metastases (1,337 [17.1%]) being the most reported categories. Only 10 cases (0.1%) were reported as primary adrenal carcinomas and 2 as pheochromocytoma. Interobserver agreement using 300 reports yielded a Fleiss kappa of 0.893, implying almost perfect agreement between the abstractors. Conclusions: Incidental adrenal abnormalities are commonly reported in abdominal CT reports of cancer patients. As the terminology used by radiologists to describe these findings greatly determine the subsequent management plans, further studies are needed to correlate some of these findings to the actual confirmed diagnosis based on hormonal, histological and follow-up data and ascertain the impact of such reported findings on patients' outcomes.

Characteristics and Outcomes of Patients with Cancer Pain Placed in an Emergency Department Observation Unit.

Pain remains an undertreated complication of cancer, with poor pain control decreasing patients' quality of life. Traditionally, patients presenting to an emergency department with pain have only had two dispositions available to them: hospitalization or discharge. A third emerging healthcare environment, the emergency department observation unit (EDOU), affords patients access to a hospital's resources without hospitalization. To define the role of an EDOU in the management of cancer pain, we conducted a retrospective study analyzing patients placed in an EDOU with uncontrolled cancer pain for one year. Patient characteristics were summarized using descriptive statistics and predictors of disposition from the EDOU and were identified with univariate and multivariate analyses. Most patients were discharged home, and discharged patients had low 72-hour revisit and 30-day mortality rates. Significant predictors of hospitalization were initial EDOU pain score (odds ratio (OR) = 1.12; 95% CI 1.06−1.19; p < 0.001) and supportive care (OR = 2.04; 95% CI 1.37−3.04; p < 0.001) or pain service (OR = 2.67; 95% CI 1.63−4.40; p < 0.001) consultations. We concluded that an EDOU appears to be the appropriate venue to care for a subsegment of patients presenting to an emergency department with cancer pain, with patients receiving safe care as well as appropriate consultation and admission when indicated.

Radiation therapy induces immunosenescence mediated by p90RSK.

Radiation therapy (RT) to the chest increases the patients' risk of cardiovascular disease (CVD). A complete understanding of the mechanisms by which RT induces CVD could lead to specific preventive, therapeutic approaches. It is becoming evident that both genotoxic chemotherapy agents and radiation induce mitochondrial dysfunction and cellular senescence. Notably, one of the common phenotypes observed in cancer survivors is accelerated senescence, and immunosenescence is closely related to both cancer risk and CVD development. Therefore, suppression of immunosenescence can be an ideal target to prevent cancer treatment-induced CVD. However, the mechanism(s) by which cancer treatments induce immunosenescence are incompletely characterized. We isolated peripheral blood mononuclear cells (PBMCs) before and 3 months after RT from 16 thoracic cancer patients. We characterized human immune cell lineages and markers of senescence, DNA damage response (DDR), efferocytosis, and determinants of clonal hematopoiesis of indeterminant potential (CHIP), using mass cytometry (CyTOF). We found that the frequency of the B cell subtype was decreased after RT. Unsupervised clustering of the CyTOF data identified 138 functional subsets of PBMCs. Compared with baseline, RT increased TBX21 (T-bet) expression in the largest B cell subset of Ki67-/DNMT3a+naïve B cells, and T-bet expression was correlated with phosphorylation of p90RSK expression. CD38 expression was also increased in naïve B cells (CD27-) and CD8+ effector memory CD45RA T cells (TEMRA). In vitro, we found the critical role of p90RSK activation in upregulating (1) CD38+/T-bet+ memory and naïve B, and myeloid cells, (2) senescence-associated ß-gal staining, and (3) mitochondrial reactive oxygen species (ROS) after ionizing radiation (IR). These data suggest the crucial role of p90RSK activation in immunosenescence. The critical role of p90RSK activation in immune cells and T-bet induction in upregulating atherosclerosis formation has been reported. Furthermore, T-bet directly binds to the CD38 promoter region and upregulates CD38 expression. Since both T-bet and CD38 play a significant role in the process of immunosenescence, our data provide a cellular and molecular mechanism that links RT-induced p90RSK activation and the immunosenescence with T-bet and CD38 induction observed in thoracic cancer patients treated by RT and suggests that targeting the p90RSK/T-bet/CD38 pathway could play a role in preventing the radiation-associated CVD and improving cancer prognosis by inhibiting immunosenescence.