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.

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.

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.

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.

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.

The Emerging Role of the Gut Microbiome in the Cancer Response to Immune Checkpoint Inhibitors: A Narrative Review.

The discovery of immune checkpoint inhibitors (ICIs) has revolutionized the care of cancer patients. However, the response to ICI therapy exhibits substantial interindividual variability. Efforts have been directed to identify biomarkers that predict the clinical response to ICIs. In recent years, the gut microbiome has emerged as a critical player that influences the efficacy of immunotherapy. An increasing number of studies have suggested that the baseline composition of a patient's gut microbiota and its dysbiosis are correlated with the outcome of cancer immunotherapy. This review tackles the rapidly growing body of evidence evaluating the relationship between the gut microbiome and the response to ICI therapy. Additionally, this review highlights the impact of antibiotic-induced dysbiosis on ICI efficacy and discusses the possible therapeutic interventions to optimize the gut microbiota composition to augment immunotherapy efficacy.

Characterization of older adults with cancer seeking acute emergency department care: A prospective observational study.

INTRODUCTION: Disparities in care of older adults in cancer treatment trials and emergency department (ED) use exist. This report provides a baseline description of older adults ≥65 years old who present to the ED with active cancer. MATERIALS AND METHODS: Planned secondary analysis of the Comprehensive Oncologic Emergencies Research Network observational ED cohort study sponsored by the National Cancer Institute. Of 1564 eligible adults with active cancer, 1075 patients were prospectively enrolled, of which 505 were ≥ 65 years old. We recruited this convenience sample from eighteen participating sites across the United States between February 1, 2016 and January 30, 2017. RESULTS: Compared to cancer patients younger than 65 years of age, older adults were more likely to be transported to the ED by emergency medical services, have a higher Charlson Comorbidity Index score, and be admitted despite no significant difference in acuity as measured by the Emergency Severity Index. Despite the higher admission rate, no significant difference was noted in hospitalization length of stay, 30-day mortality, ED revisit or hospital admission within 30 days after the index visit. Three of the top five ED diagnoses for older adults were symptom-related (fever of other and unknown origin, abdominal and pelvic pain, and pain in throat and chest). Despite this, older adults were less likely to report symptoms and less likely to receive symptomatic treatment for pain and nausea than the younger comparison group. Both younger and older adults reported a higher symptom burden on the patient reported Condensed Memorial Symptom Assessment Scale than to ED providers. When treating suspected infection, no differences were noted in regard to administration of antibiotics in the ED, admissions, or length of stay ≤2 days for those receiving ED antibiotics. DISCUSSION: We identified several differences between older (≥65 years old) and younger adults with active cancer seeking emergency care. Older adults frequently presented for symptom-related diagnoses but received fewer symptomatic interventions in the ED suggesting that important opportunities to improve the care of older adults with cancer in the ED exist.

The role of 18F-FDG PET/CT in predicting the pathological response to neoadjuvant PD-1 blockade in combination with chemotherapy for resectable esophageal squamous cell carcinoma.

PURPOSE: Accurate assessment of residual disease of tumor and lymph nodes after neoadjuvant immunochemotherapy is crucial in the active surveillance for patients with pathological complete response (pCR) and the optimal extent of lymphadenectomy for patients with non-pCR. This post hoc analysis aimed to evaluate the performance of 18F-FDG PET/CT to predict the pathological response to neoadjuvant immunochemotherapy for esophageal squamous cell carcinoma (ESCC). METHODS: Fifty-eight resectable ESCC patients received two cycles of camrelizumab in combination with chemotherapy and were enrolled in the final analysis. The 18F-FDG PET/CT scans were acquired at baseline (scan-1) and after immunochemotherapy but prior to surgery (scan-2). Maximum standardized uptake value (SUVmax), mean standardized uptake value (SUVmean), tumor-to-blood pool SUVmax ratio (SUVTBR), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) were evaluated for their association with the pathological response to immunochemotherapy. RESULTS: Nineteen patients (32.8%, 19/58) had pCR and thirty-nine patients (67.2%, 39/58) had non-pCR after two doses of camrelizumab and chemotherapy. At scan-2, the SUVmax, SUVmean, SUVTBR, TLG, and MTV were significantly lower in pCR than in non-pCR patients. Decrease in TLG and MTV between scan-2 and scan-1 of the same patient was significantly higher in the pCR than in the non-pCR group. In the receiver operating characteristic curve analysis, SUVmax, SUVmean, SUVTBR, TLG, and MTV in scan-2 showed excellent predictive value for the pCR of primary tumors. Furthermore, SUVmax in scan-2 were higher in positive lymph nodes than in negative ones, suggesting a high negative predictive ability (98.6%) with a cut-off value at 1.4. CONCLUSION: The parameters of 18F-FDG PET/CT have the excellent performance for predicting pCR after the combined neoadjuvant immunochemotherapy in resectable ESCC. TRIAL REGISTRATION: ChiCTR2000028900. Registered on January 6, 2020.

Palliative Care Needs and Clinical Outcomes of Patients with Advanced Cancer in the Emergency Department.

Background: Older adults with cancer use the emergency department (ED) for acute concerns. Objectives: Characterize the palliative care needs and clinical outcomes of advanced cancer patients in the ED. Design: A planned secondary data analysis of the Comprehensive Oncologic Emergencies Research Network (CONCERN) data. Settings/Subjects: Cancer patients who presented to the 18 CONCERN affiliated EDs in the United States. Measurements: Survey included demographics, cancer type, functional status, symptom burden, palliative and hospice care enrollment, and advance directive code status. Results: Of the total (674/1075, 62.3%) patients had advanced cancer and most were White (78.6%) and female (50.3%); median age was 64 (interquartile range 54-71) years. A small proportion of them were receiving palliative (6.5% [95% confidence interval; CI 3.0-7.6]; p = 0.005) and hospice (1.3% [95% CI 1.0-3.2]; p = 0.52) care and had a higher 30-day mortality rate (8.3%, [95% CI 6.2-10.4]). Conclusions: Patients with advanced cancer continue to present to the ED despite recommendations for early delivery of palliative care.

A signature of saliva-derived exosomal small RNAs as predicting biomarker for esophageal carcinoma: a multicenter prospective study.

BACKGROUND: The tRNA-derived small RNAs (tsRNAs) are produced in a nuclease-dependent manner in responses to variety of stresses that are common in cancers. We focus on a cancer-enriched tsRNA signature to develop a salivary exosome-based non-invasive biomarker for human esophageal squamous cell carcinoma (ESCC). METHODS: Cancer-enriched small RNAs were identified by RNA sequencing of salivary exosomes obtained from ESCC patients (n = 3) and healthy controls (n = 3) in a pilot study and further validated in discovery cohort (n = 66). A multicenter prospective observational study was conducted in two ESCC high-incidence regions (n = 320 and 200, respectively) using the newly developed biomarker signature. RESULTS: The tsRNA (tRNA-GlyGCC-5) and a previously undocumented small RNA were specifically enriched in salivary exosomes of ESCC patients, ESCC tissues and ESCC cells. The bi-signature composed of these small RNAs was able to discriminate ESCC patients from the controls with high sensitivity (90.50%) and specificity (94.20%). Based on the bi-signature Risk Score for Prognosis (RSP), patients with high-RSP have both shorter overall survival (OS) (HR 4.95, 95%CI 2.90-8.46) and progression-free survival (PFS) (HR 3.69, 95%CI 2.24-6.10) than those with low-RSP. In addition, adjuvant therapy improved OS (HR 0.47, 95%CI 0.29-0.77) and PFS (HR 0.36, 95%CI 0.21-0.62) only for patients with high but not low RSP. These findings are consistent in both training and validation cohort. CONCLUSIONS: The tsRNA-based signature not only has the potential for diagnosis and prognosis but also may serve as a pre-operative biomarker to select patients who would benefit from adjuvant therapy. TRIAL REGISTRATION: A prospective study of diagnosis biomarkers of esophageal squamous cell carcinoma, ChiCTR2000031507 . Registered 3 April 2016 - Retrospectively registered.

Neoadjuvant programmed cell death 1 blockade combined with chemotherapy for resectable esophageal squamous cell carcinoma.

BACKGROUND: Programmed cell death 1 (PD-1) blockade induces tumor regression in patients with advanced esophageal squamous cell carcinoma (ESCC); however, little is known about the efficacy of PD-1 blockade as neoadjuvant therapy in resectable ESCC. We aim to assess the safety and feasibility of using the combination of neoadjuvant PD-1 blockade with chemotherapy in patients with ESCC. METHODS: Patients with previously untreated, resectable (stage II or III) ESCC were enrolled. Each patient received two 21-day cycles of neoadjuvant treatment with camrelizumab, nab-paclitaxel, and carboplatin before undergoing surgical resection approximately 6-9 weeks after the first cycle. RESULTS: Between January 2020 and September 2020, 37 patients were screened, of whom 23 were enrolled. The neoadjuvant therapeutic regimen had an acceptable side effect profile, and no delays in surgery were observed. Severe (grade 3-4) treatment-related adverse events included neutropenia (9 of 23, 39.1%) and leukopenia (2 of 23, 8.7%). The objective response and disease control rates were 90.5% and 100%, respectively. Twenty patients received surgery, and R0 resection was achieved in all cases. Five (25%) patients had a pathological complete response (PCR) and 10 (50%) patients had a major pathological response. The proportion of patients with a high tumor mutation burden and a high expression of programmed death-ligand 1 (PD-L1) in primary tumor was significantly higher in the PCR group than in the non-PCR group (p=0.044). The number of infiltrating PD-L1+ CD163+ cells was significantly lower in the PCR group than in the non-PCR group after treatment (p=0.017). CONCLUSIONS: Neoadjuvant camrelizumab plus carboplatin and nab-paclitaxel had manageable treatment-related adverse effects and induced an objective response in 90.5% of patients, demonstrating its antitumor efficacy in resectable ESCC. TRIAL REGISTRATION NUMBER: ChiCTR2000028900.

Nine-Year Median Follow-up of Cardiotoxicity and Efficacy of Trastuzumab Concurrently With Anthracycline-Based and Anthracycline-Free Neoadjuvant Chemotherapy in HER2-Positive Breast Cancer Patients.

BACKGROUND: The combination of trastuzumab with anthracycline chemotherapy drugs is associated with synergistic cardiotoxicity. The aim of this study is to compare the efficacy and late-onset cardiac toxicity of neoadjuvant chemotherapy regimens, trastuzumab plus paclitaxel followed by 5-fluorouracil, epirubicin, and cyclophosphamide (PH-FECH) versus trastuzumab plus docetaxel and carboplatin (TCH), for human epidermal growth factor receptor 2-positive (HER2+) breast cancer (BC). METHODS: Patients with HER2+ BC who received neoadjuvant chemotherapy with PH-FECH or TCH between 2002 and 2009 at MD Anderson Cancer Center were included. The primary endpoint was progression-free survival (PFS). Secondary endpoints included pathological complete response (pCR), overall survival, cardiac events, breast cancer-specific survival, noncardiac toxicities, and chemotherapy interruption. RESULTS: We identified 249 consecutive patients (184 who received PH-FECH and 65 who received TCH). The 10-year PFS was higher in the PH-FECH group than in the TCH group (83.6% vs. 72.2%; P = .044). The pCR rate was significantly higher in the PH-FECH group (58.2% vs. 41.5%; P = .021). The rate of cardiac events was higher in the PH-FECH group, but the difference was not significant (13.0% vs. 7.7%; P = .352). More patients developed late-onset cardiotoxicity in the PH-FECH group (3.8%) than in the TCH group (1.5%). Hypertension (odds ratio, 4.402 [95% confidence interval, 1.020-18.998]; P = .047) was an independent predictor of late-onset cardiotoxicity. CONCLUSIONS: Both neoadjuvant regimens are effective and tolerable in patients with HER2+ BC. The PH-FECH regimen offers a higher pCR rate and higher PFS but no difference in overall survival or breast cancer-specific survival. Higher frequency of cardiac toxicity with PH-FECH was noted.

Prognostic Value of Procalcitonin, C-Reactive Protein, and Lactate Levels in Emergency Evaluation of Cancer Patients with Suspected Infection.

Cancer patients have increased risk of infections, and often present to emergency departments with infection-related problems where physicians must make decisions based on a snapshot of the patient's condition. Although C-reactive protein, procalcitonin, and lactate are popular biomarkers of sepsis, their use in guiding emergency care of cancer patients with infections is unclear. Using these biomarkers, we created a prediction model for short-term mortality in cancer patients with suspected infection. We retrospectively analyzed all consecutive patients who visited the emergency department of MD Anderson Cancer Center between 1 April 2018 and 30 April 2019. A clinical decision model was developed using multiple logistic regression for various clinical and laboratory biomarkers; coefficients were used to generate a prediction score stratifying patients into four groups according to their 14-day mortality risk. The prediction score had an area under the receiver operating characteristic curve value of 0.88 (95% confidence interval 0.85-0.91) in predicting 14-day mortality. The prediction score also accurately predicted intensive care unit admission and 30-day mortality. Our simple new scoring system for mortality prediction, based on readily available clinical and laboratory data, including procalcitonin, C-reactive protein, and lactate, can be used in emergency departments for cancer patients with suspected infection.

Cyst(e)ine in nutrition formulation promotes colon cancer growth and chemoresistance by activating mTORC1 and scavenging ROS.

Weight loss and cachexia are common problems in colorectal cancer patients; thus, parenteral and enteral nutrition support play important roles in cancer care. However, the impact of nonessential amino acid components of nutritional intake on cancer progression has not been fully studied. In this study, we discovered that gastrointestinal cancer patients who received cysteine as part of the parenteral nutrition had shorter overall survival (P < 0.001) than those who did not. Cystine indeed robustly promotes colon cancer cell growth in vitro and in immunodeficient mice, predominately by inhibiting SESN2 transcription via the GCN2-ATF4 axis, resulting in mTORC1 activation. mTORC1 inhibitors Rapamycin and Everolimus block cystine-induced cancer cell proliferation. In addition, cystine confers resistance to oxaliplatin and irinotecan chemotherapy by quenching chemotherapy-induced reactive oxygen species via synthesizing glutathione. We demonstrated that dietary deprivation of cystine suppressed colon cancer xenograft growth without weight loss in mice and boosted the antitumor effect of oxaliplatin. These findings indicate that cyst(e)ine, as part of supplemental nutrition, plays an important role in colorectal cancer and manipulation of cyst(e)ine content in nutritional formulations may optimize colorectal cancer patient survival.

Tumor-Associated Microbiota in Esophageal Squamous Cell Carcinoma.

Important evidence indicates the microbiota plays a key role in esophageal squamous cell carcinoma (ESCC). The esophageal microbiota was prospectively investigated in 18 patients with ESCC and 11 patients with physiological normal (PN) esophagus by 16S rRNA gene profiling, using next-generation sequencing. The microbiota composition in tumor tissues of ESCC patients were significantly different from that of patients with PN tissues. The ESCC microbiota was characterized by reduced microbial diversity, by decreased abundance of Bacteroidetes, Fusobacteria, and Spirochaetes. Employing these taxa into a microbial dysbiosis index demonstrated that dysbiosis microbiota had good capacity to discriminate between ESCC and PN esophagus. Functional analysis characterized that ESCC microbiota had altered nitrate reductase and nitrite reductase functions compared with PN group. These results suggest that specific microbes and the microbiota may drive or mitigate ESCC carcinogenesis, and this study will facilitate assigning causal roles in ESCC development to certain microbes and microbiota.

Impact of diabetes on promoting the growth of breast cancer.

BACKGROUND: Type II diabetes mellitus (DM2) is a significant risk factor for cancers, including breast cancer. However, a proper diabetic breast cancer mouse model is not well-established for treatment strategy design. Additionally, the precise diabetic signaling pathways that regulate cancer growth remain unresolved. In the present study, we established a suitable mouse model and demonstrated the pathogenic role of diabetes on breast cancer progression. METHODS: We successfully generated a transgenic mouse model of human epidermal growth factor receptor 2 positive (Her2+ or ERBB2) breast cancer with DM2 by crossing leptin receptor mutant (Leprdb/+ ) mice with MMTV-ErbB2/neu) mice. The mouse models were administrated with antidiabetic drugs to assess the impacts of controlling DM2 in affecting tumor growth. Magnetic resonance spectroscopic imaging was employed to analyze the tumor metabolism. RESULTS: Treatment with metformin/rosiglitazone in MMTV-ErbB2/Leprdb/db mouse model reduced serum insulin levels, prolonged overall survival, decreased cumulative tumor incidence, and inhibited tumor progression. Anti-insulin resistance medications also inhibited glycolytic metabolism in tumors in vivo as indicated by the reduced metabolic flux of hyperpolarized 13 C pyruvate-to-lactate reaction. The tumor cells from MMTV-ErbB2/Leprdb/db transgenic mice treated with metformin had reprogrammed metabolism by reducing levels of both oxygen consumption and lactate production. Metformin decreased the expression of Myc and pyruvate kinase isozyme 2 (PKM2), leading to metabolism reprogramming. Moreover, metformin attenuated the mTOR/AKT signaling pathway and altered adipokine profiles. CONCLUSIONS: MMTV-ErbB2/Leprdb/db mouse model was able to recapitulate diabetic HER2+ human breast cancer. Additionally, our results defined the signaling pathways deregulated in HER2+ breast cancer under diabetic condition, which can be intervened by anti-insulin resistance therapy.

Repurposing dextromethorphan and metformin for treating nicotine-induced cancer by directly targeting CHRNA7 to inhibit JAK2/STAT3/SOX2 signaling.

Smoking is one of the most impactful lifestyle-related risk factors in many cancer types including esophageal squamous cell carcinoma (ESCC). As the major component of tobacco and e-cigarettes, nicotine is not only responsible for addiction to smoking but also a carcinogen. Here we report that nicotine enhances ESCC cancer malignancy and tumor-initiating capacity by interacting with cholinergic receptor nicotinic alpha 7 subunit (CHRNA7) and subsequently activating the JAK2/STAT3 signaling pathway. We found that aberrant CHRNA7 expression can serve as an independent prognostic factor for ESCC patients. In multiple ESCC mouse models, dextromethorphan and metformin synergistically repressed nicotine-enhanced cancer-initiating cells (CIC) properties and inhibited ESCC progression. Mechanistically, dextromethorphan non-competitively inhibited nicotine binding to CHRNA7 while metformin downregulated CHRNA7 expression by antagonizing nicotine-induced promoter DNA hypomethylation of CHRNA7. Since dextromethorphan and metformin are two safe FDA-approved drugs with minimal undesirable side-effects, the combination of these drugs has a high potential as either a preventive and/or a therapeutic strategy against nicotine-promoted ESCC and perhaps other nicotine-sensitive cancer types as well.

Cancer pain management in the emergency department: a multicenter prospective observational trial of the Comprehensive Oncologic Emergencies Research Network (CONCERN).

PURPOSE: Many patients with cancer seek care for pain in the emergency department (ED). Prospective research on cancer pain in this setting has historically been insufficient. We conducted this study to describe the reported pain among cancer patients presenting to the ED, how pain is managed, and how pain may be associated with clinical outcomes. METHODS: We conducted a multicenter cohort study on adult patients with active cancer presenting to 18 EDs in the USA. We reported pain scores, response to medication, and analgesic utilization. We estimated the associations between pain severity, medication utilization, and the following outcomes: 30-day mortality, 30-day hospital readmission, and ED disposition. RESULTS: The study population included 1075 participants. Those who received an opioid in the ED were more likely to be admitted to the hospital and were more likely to be readmitted within 30 days (OR 1.4 (95% CI: 1.11, 1.88) and OR 1.56 (95% CI: 1.17, 2.07)), respectively. Severe pain at ED presentation was associated with increased 30-day mortality (OR 2.30, 95% CI: 1.05, 5.02), though this risk was attenuated when adjusting for clinical factors (most notably functional status). CONCLUSIONS: Patients with severe pain had a higher risk of mortality, which was attenuated when correcting for clinical characteristics. Those patients who required opioid analgesics in the ED were more likely to require admission and were more at risk of 30-day hospital readmission. Future efforts should focus on these at-risk groups, who may benefit from additional services including palliative care, hospice, or home-health services.