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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). [ABSTRACT FROM AUTHOR]

Background: Thromboembolism (TE) is a leading cause of death in cancer patients. Primary thromboprophylaxis (PTP) in ambulatory cancer patients receiving chemotherapy has been debated and considered to potentially improve survival by reducing TE occurrence. Objective: We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) in ambulatory lung cancer (LC) patients on chemotherapy to determine the benefit and risk of PTP with low-molecular-weight heparins (LMWHs). Method: A literature search using MEDLINE and EMBASE databases was performed through June 2016. RCTs with venous thromboembolism (VTE) reduction as primary or secondary endpoints were included. Mantel-Haenszel method was used to estimate the pooled event risk ratio as well as pooled absolute risk difference with 95% confidence interval (CI). Result: A total of 4315 LC patients from six studies were available for analysis. PTP lasted for 4 to 6 months. The venous thromboembolism (VTE) incidence was 4.0% and 7.9% in LMWH and control groups, respectively (risk ratio, 0.510 (95% CI, 0.397-0.654, P < 0.001). The absolute risk difference in VTE was -0.039 (95% CI, -0.053 to -0.025, P < 0.001), with an estimated number needed to treat (NNT) of 25 to prevent one VT Eevent. The pooled risk ratio for major bleeding was 1.468 (95% CI, 0.785-2.746, P = 0.229). The pooled risk ratio for overall survival was statistically nonsignificant at 1.020 (95% CI, 0.938-1.109, P = 0.648). Conclusion: Routine PTP for ambulatory LC patients receiving chemotherapy is not recommended and further studies are necessary to define a subset of ambulatory LC patients receiving chemotherapy who may benefit from PTP. [ABSTRACT FROM AUTHOR]

Intracranial hemorrhage (ICH) is a dreaded complication of both cancer and its treatment. To evaluate the characteristics and clinical outcomes of cancer patients with ICH, we identified all patients with ICH who visited The University of Texas MD Anderson Cancer Center emergency department between 1 September 2006 and 16 February 2016. Clinical and radiologic data were collected and compared. Logistic regression analyses were used to determine the association between clinical variables and various outcomes. During the period studied, 704 confirmed acute ICH cases were identified. In-hospital, 7-day, and 30-day mortality rates were 15.1, 11.4, and 25.6%, respectively. Hypertension was most predictive of intensive care unit admission (OR = 1.52, 95% CI = 1.09–2.12, p = 0.013). Low platelet count was associated with both in-hospital mortality (OR = 0.96, 95% CI = 0.94–0.99, p = 0.008) and 30-day mortality (OR = 0.98, 95% CI = 0.96–1.00, p = 0.016). Radiologic findings, especially herniation and hydrocephalus, were strong predictors of short-term mortality. Among known risk factors of ICH, those most helpful in predicting cancer patient outcomes were hypertension, low platelet count, and the presence of hydrocephalus or herniation. Understanding how the clinical presentation, risk factors, and imaging findings correlate with patient morbidity and mortality is helpful in guiding the diagnostic evaluation and aggressiveness of care for ICH in cancer patients. [ABSTRACT FROM AUTHOR]

The mammalian constitutive photomorphogenesis 9 (COP9) signalosome (CSN), a protein complex involved in embryonic development, is implicated in cell cycle regulation and the DNA damage response. Its role in tumor development, however, remains unclear. Here, we have shown that the COP9 subunit 6 (CSN6) gene is amplified in human breast cancer specimens, and the CSN6 protein is upregulated in human breast and thyroid tumors. CSN6 expression positively correlated with expression of murine double minute 2 (MDM2), a potent negative regulator of the p53 tumor suppressor. Expression of CSN6 appeared to prevent MDM2 autoubiquitination at lysine 364, resulting in stabilization of MDM2 and degradation of p53. Mice in which Csn6 was deleted died early in embryogenesis (E7.5). Embryos lacking both Csn6 and p53 survived to later in embryonic development (E10.5), which suggests that loss of p53 could partially rescue the effect of loss of Csn6. Mice heterozygous for Csn6 were sensitized to γ-irradiation-induced, p53-dependent apoptosis in both the thymus and the developing CNS. These mice were also less susceptible than wild-type mice to γ-irradiation-induced tumorigenesis. These results suggest that loss of CSN6 enhances p53-mediated tumor suppression in vivo and that CSN6 plays an important role in regulating DNA damage-associated apoptosis and tumorigenesis through control of the MDM2-p53 signaling pathway. [ABSTRACT FROM AUTHOR]

In recent years, a dramatic breakthrough in cancer treatment has arisen with the advent of immune-checkpoint inhibitor (ICI) therapy. However, these therapies are accompanied by multiple unique immune-related adverse effects that can present as an oncologic emergency to emergency department (ED). Here we describe the characteristics of cancer patients with no previous diagnosis of adrenal insufficiency who present to the emergency with low adrenocorticotropic hormone and cortisol levels following ICI therapy. Using data from a comprehensive cancer center, we conducted a retrospective cohort study of patients 18 years and older who received ICI between April 1 st, 2018, and December 31st, 2022, and presented to the ED with low ACTH and total cortisol levels. The billing database was used to exclude patients with prior diagnosis of adrenal insufficiency based on the ICD-10 codes. Demographics, clinical and cancerrelated data were collected from the institution's data warehouse. Descriptive statistics were used to analyze the data. A total of 101 cancer patients were identified based on the eligibility criteria, with a median age of 63 years (interquartile range= 58-72 years), who were mostly White race (83.2 %) and Not Hispanic or Latino ethnic group (86.1%). Melanoma, lung, renal and head and neck cancer were the most common cancer types for these patients. The median Charlson comorbidity index was 8 (interquartile range: 7–9). Most (98%) of the patients presented as level 2 or 3 on the emergency severity index. Almost all patients (94%) were admitted, of these, 26 patients (25.7%) were placed in the observation unit. Of the patients who got admitted, around 10% were placed in the intensive care unit during their hospital stay. The clinical use of ICI is continually broadening and certain ICI-induced toxicities including endocrinopathies requires immediate medical attention. We found that most patients presenting to the ED with low ACTH and cortisol levels with no previous diagnosis of adrenal insufficiency after ICI therapy require admission and close monitoring. Further studies are needed to better evaluate the incidence and outcomes of ICI-induced adrenal insufficiency among cancer patients after ICI therapy. [ABSTRACT FROM AUTHOR]

Simple Summary: This review explores hemoptysis in cancer patients. It delves into risk factors, epidemiology and clinical consequences. The need for a mortality prediction score for cancer patients with hemoptysis-related variables is needed, and this tool could aid in risk assessment, optimize the control of bleeding with critical care, implement tracheobronchial or vascular interventions, and guide treatment planning. Managing hemoptysis in cancer patients requires addressing the underlying cause and providing supportive care for improved quality of life. 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. [ABSTRACT FROM AUTHOR]

Purpose: Consultation to palliative care (PC) services in hospitalized patients is frequently late after admission to a hospital. The purpose of this study is to examine the association of in-hospital mortality and timing of palliative care consultation in cancer patients admitted through the emergency department (ED) of MD Anderson Cancer Center.Methods: Institutional databases were queried for unique medical admissions over a period of 1 year. Primary cancer type, ED versus direct admission, length of stay (LOS), presenting symptoms, and in-hospital mortality were reviewed; patient data were analyzed, and risk factors for in-hospital mortality were identified. The association of early palliative care consultation (within 3 days of admission) with these outcomes was studied. Descriptive statistics and multivariate logistic regression model were used.Results: Equal numbers of patients were admitted directly versus through the ED (7598 and 7538 respectively). However, of all patients who died in the hospital, 990 (88%) were admitted through the ED, compared with 137 admitted directly (P < 0.001). Patients who died in the hospital had longer median LOS compared with patients who were discharged alive (11 vs. 4 days, respectively, P < 0.001). Early palliative care consultation was associated with decreased mortality, compared with late consultation (P < 0.001). Chief complaints of respiratory problems, neurologic issues, or fatigue/weakness were significantly associated with in-hospital mortality.Conclusion: We found an association between ED admission and hospital mortality. Decedent cancer patients had a prolonged LOS, and early palliative care consultation for terminally ill symptomatic patients may prevent in-hospital mortality and improve quality of cancer care. [ABSTRACT FROM AUTHOR]

Background: The concurrence of ectopic adrenocorticotropic hormone (ACTH) syndrome (ectopic Cushing syndrome) and cancer is uncommon in the emergency department (ED) setting, but a constellation of nonspecific signs and symptoms can suggest the presence of Cushing syndrome.Case Report: A 65-year-old woman with diabetes visited the ED complaining of severe weight loss, generalized weakness, and hypokalemia. She was treated for hypokalemia and thrush. She was found to have a lung mass with a large pleural effusion. Upon discovery of the suspected malignancy, the patient was referred to the ED of a comprehensive cancer center, where she was diagnosed with ectopic Cushing syndrome and admitted to the hospital for further evaluation and treatment. WHY SHOULD THE EMERGENCY PHYSICIAN BE AWARE OF THIS?: The emergency physician should be able to recognize Cushing syndrome in cancer patients so that the paraneoplastic syndrome can be managed to avoid complications during cancer treatment. [ABSTRACT FROM AUTHOR]

Background: Cancer chemotherapy-associated febrile neutropenia (FN) is a common condition that is deadly when bacteremia is present. Detection of bacteremia depends on culture, which takes days, and no accurate predictive tools applicable to the initial evaluation are available. We utilized metabolomics and transcriptomics to develop multivariable predictors of bacteremia among FN patients. Methods: We classified emergency department patients with FN and no apparent infection at presentation as bacteremic (cases) or not (controls), according to blood culture results. We assessed relative metabolite abundance in plasma, and relative expression of 2,560 immunology and cancer-related genes in whole blood. We used logistic regression to identify multivariable predictors of bacteremia, and report test characteristics of the derived predictors. Results: For metabolomics, 14 bacteremic cases and 25 non-bacteremic controls were available for analysis; for transcriptomics we had 7 and 22 respectively. A 5-predictor metabolomic model had an area under the receiver operating characteristic curve of 0.991 (95%CI: 0.972,1.000), 100% sensitivity, and 96% specificity for identifying bacteremia. Pregnenolone steroids were more abundant in cases and carnitine metabolites were more abundant in controls. A 3-predictor gene expression model had corresponding results of 0.961 (95%CI: 0.896,1.000), 100%, and 86%. Genes involved in innate immunity were differentially expressed. Conclusions: Classifiers derived from metabolomic and gene expression data hold promise as objective and accurate predictors of bacteremia among FN patients without apparent infection at presentation, and can provide insights into the underlying biology. Our findings should be considered illustrative, but may lay the groundwork for future biomarker development. [ABSTRACT FROM AUTHOR]

Purpose: Patients with febrile neutropenia are a heterogeneous group with a minority developing serious medical complications. Outpatient management of low-risk febrile neutropenia has been shown to be safe and cost-effective. Scoring systems, such as the Multinational Association for Supportive Care in Cancer (MASCC) score and Clinical Index of Stable Febrile Neutropenia (CISNE), have been developed and validated to identify low-risk patients. We aimed to compare the performance of these two scores in identifying low-risk febrile neutropenic patients.Methods: We performed a pooled analysis of patients presenting with febrile neutropenia to three tertiary cancer emergency centers in the USA, UK, and South Korea in 2015. The primary outcome measures were the occurrence of serious complications. Admission to an intensive care unit (ICU) and 30-day mortality were secondary outcomes. The predictive performance of each score was analyzed.Results: Five hundred seventy-one patients presented with febrile neutropenia. With MASCC risk index, 508 (89.1%) were classified as low-risk febrile neutropenia, compared to 60 (10.5%) with CISNE classification. Overall, the MASCC score had a greater discriminatory power in the detection of low-risk patients than the CISNE score (AUC 0.772, 95% CI 0.726-0.819 vs. 0.681, 95% CI 0.626-0.737, p = 0.0024).Conclusion: Both MASCC and CISNE scores have reasonable discriminatory value in predicting patients with low-risk febrile neutropenia. Risk scores should be used in conjunction with clinical judgment for the identification of patients suitable for outpatient management of neutropenic fever. Developing more accurate scores, validated in prospective settings, will be useful in facilitating more patients being managed in an outpatient setting. [ABSTRACT FROM AUTHOR]

Background: The frequency of delirium among patients with cancer presenting to the emergency department (ED) is unknown. The purpose of this study was to determine delirium frequency and recognition by ED physicians among patients with advanced cancer presenting to the ED of The University of Texas MD Anderson Cancer Center.Methods: The study population was a random sample of English-speaking patients with advanced cancer who presented to the ED and met the study criteria. All patients were assessed with the Confusion Assessment Method (CAM) to screen for delirium and with the Memorial Delirium Assessment Scale (MDAS) to measure delirium severity (mild, ≤15; moderate, 16-22; and severe, ≥23). ED physicians were also asked whether their patients were delirious.Results: Twenty-two of the 243 enrolled patients (9%) had CAM-positive delirium, and their median MDAS score was 14 (range, 9-21 [30-point scale]). The median age of the enrolled patients was 62 years (range, 19-89 years). Patients with delirium had a poorer performance status than patients without delirium (P < .001); however, the 2 groups did not differ in other characteristics. Ten of the 99 patients who were 65 years old or older (10%) had CAM-positive delirium, whereas 12 of the 144 patients younger than 65 years (8%) did (P = .6). According to the MDAS scores, delirium was mild in 18 patients (82%) and moderate in 4 patients (18%). Physicians correctly identified delirium in 13 of the CAM-positive delirious patients (59%).Conclusions: Delirium is relatively frequent and is underdiagnosed by physicians in patients with advanced cancer who are visiting the ED. Further research is needed to identify the optimal screening tool for delirium in ED. Cancer 2016. © 2016 American Cancer Society. Cancer 2016;122:2918-2924. © 2016 American Cancer Society. [ABSTRACT FROM AUTHOR]

Cancer vaccines critically rely on the availability of targetable immunogenic cancer‐specific neoepitopes. However, mutation‐based immunogenic neoantigens are rare or even non‐existent in subgroups of cancer types. To address this issue, we exploited a cancer‐specific aberrant transcription‐induced chimeric RNA, designated A‐PaschiRNA, as a possible source of clinically relevant and targetable neoantigens. A‐PaschiRNA encodes a recently discovered cancer‐specific chimeric protein that comprises full‐length astrotactin‐2 (ASTN2) C‐terminally fused in‐frame to the antisense sequence of the 18th intron of pregnancy‐associated plasma protein‐A (PAPPA). We used extracellular vesicles (EVs) from A‐PaschiRNA‐transfected dendritic cells (DCs) to produce the cell‐free anticancer vaccine DEXA‐P. Treatment of immunocompetent cancer‐bearing mice with DEXA‐P inhibited tumour growth and prolonged animal survival. In summary, we demonstrate for the first time that cancer‐specific transcription‐induced chimeric RNAs can be exploited to produce a cell‐free cancer vaccine that induces potent CD8+ T cell‐mediated anticancer immunity. Our novel approach may be particularly useful for developing cancer vaccines to treat malignancies with low mutational burden or without mutation‐based antigens. Moreover, this cell‐free anticancer vaccine approach may offer several practical advantages over cell‐based vaccines, such as ease of scalability and genetic modifiability as well as enhanced shelf life. [ABSTRACT FROM AUTHOR]

Patients with a known cancer diagnosis are frequent visitors to general emergency departments (ED) Since MD Anderson Cancer Center is a dedicated oncologic hospital, new patients present with symptoms suspected to be attributable to a yet unconfirmed cancer diagnosis. The aim was to examine and characterize the oncologic ED presentation of new patients with a suspicion of cancer. Our institutional database was quired for all ED visits for subjects aged 18 and older with no prior cancer diagnosis (using tumor registry and billing database) between 11/1/2020 and 01/01/2022. Chart review was conducted to confirm the absence of previous cancer diagnosis in the identified subjects and to verify they received follow-up in our institution. Demographics, ED presentation and clinical data were collected. Descriptive statistics and Chi-Square test of independence were used to analyze, compare and report the presentation and the outcomes of final eligible patients. During the study period, of the 2727 subjects identified, 358 met the final eligibility criteria. The median age was 57 years (interquartile range: 45-66 years). The majority were male (51.1%), White or Caucasian race (57.0%) and not Hispanic or Latino ethnicity (74.0%). Almost all the patients (99.2%) were presented as emergent or urgent acuity level (i.e., Emergency Severity Index levels 2 or 3 respectively). The most frequent presenting complaint(s) were: Abnormal laboratory results (16.8%); Hypertension (9.8%); infection and/or suspected sepsis (7.5%); nausea/vomiting (7.3%); fatigue (7.0%); shortness of breath (6.7%) or headache (5.9%). Most of the patients were admitted either to the hospital (59.2%) or the observation unit (18.2%). Of the 212 admitted patients, 35 (16.5%) died within one year of the ED presentation, which was significantly (P=0.003) higher than the 5.5% one-year mortality rate for the patients who were discharged or placed in the observation unit. Most patients presenting to an oncologic emergency with unconfirmed suspicion of cancer require hospitalization. The admitted group have higher mortality for reasons that need further elucidation. Further research is also needed to understand why the fairly large segment that do not require hospitalization seek care in the ED setting. [ABSTRACT FROM AUTHOR]

Background: Studies suggest a high prevalence of pain in head and neck cancer (HNC) patients at diagnosis, during and after treatment; however, these studies had small sample sizes and did not comprehensively assess factors known to influence pain. We surveyed a large cohort of HNC survivors to determine variations in the prevalence of pain, its treatment and management by duration of survivorship, and assessed a comprehensive list of risk factors.Methods: A cross sectional survey of post-treatment survivors of HNC during routine follow-up clinic visits.Results: A total of 505 HNC survivors with a median follow up of 3 years from cancer diagnosis were included in the study. Overall, 45% (n = 224) reported pain and 14.5, 22 and 7% reported use of prescribed pain medication, over-the-counter pain medication and alternative pain therapies, respectively. Prevalence of severe pain was 7.3% and did not vary significantly by years of survivorship (< 1 year = 5.7%; 1 to < 3 years = 7.1%; 3 to < 8 years = 7.6%; 8 years or more =9.7%; P = 0.392). However, use of prescribed pain medication significantly varied by years of survivorship (< 1 year = 45.7%; 1 to < 3 years = 24.6%; 3 to < 8 years = 18.9; 8 years or more = 18.3%; p < 0.001). Of note, a significant proportion of survivors reported moderate to severe pain (moderate to severe = 55.7% versus none to mild = 44.3%) despite step 3 analgesic use (p < 0.001). Multivariable regression shows that recurrent disease (OR 6.77, 95% CI [1.44, 31.80]), history of chemotherapy (OR 6.00, 95% CI [2.10, 17.14]), and depression (Mild-moderate OR 5.30, 95% CI [2.20, 12.78]; Major OR 8.00, 95% CI [2.67, 23.96]) were significant risk factors for severe pain.Conclusions: We identified a high prevalence of pain among HNC survivors and determined that analgesic use varied by the duration of survivorship. Therefore, routine surveillance for pain must be consistent throughout the course of survivorship. [ABSTRACT FROM AUTHOR]

Background: The Multinational Association for Supportive Care in Cancer (MASCC) risk index has been utilized to determine the risk for poor clinical outcomes in patients with febrile neutropenia (FN) in an emergency center (EC). However, this index comprises subjective elements and elaborated metrics limiting its use in ECs. We sought to determine whether procalcitonin (PCT) level (biomarker of bacterial infection) with or without lactate level (marker of inadequate tissue perfusion) offers a potential alternative to MASSC score in predicting the outcomes of patients with FN presenting to an EC. Methods: We retrospectively identified 550 cancer patients with FN who presented to our EC between April 2018, and April 2019, and had serum PCT and lactate levels measured. Results: Compared with patients with PCT levels <0.25 ng/ml, those with levels ≥0.25 ng/ml had a significantly higher 14‐day mortality rate (5.2% vs. 0.7%; p = 0.002), a higher bloodstream infection (BSI) rate, and a longer hospital length of stay (LOS). Logistic regression analysis showed that patients with PCT levels ≥0.25 ng/ml and lactate levels >2.2 mmol/L were more likely to be admitted and have an LOS >7 days, BSI, and 14‐day mortality than patients with lower levels. PCT level was a significantly better predictor of BSI than MASSC score (p = 0.003) or lactate level (p < 0.0001). Conclusions: Procalcitonin level is superior to MASCC index in predicting BSI. The combination of PCT and lactate levels is a good predictor of BSI, hospital admission, and 14‐day mortality and could be useful in identifying high‐risk FN patients who require hospital admission. [ABSTRACT FROM AUTHOR]

Background: Prior research has confirmed that persistent hypomagnesemia was predictive of shorter survival among patients with ovarian cancer who received carboplatin‐based chemotherapy. In the current retrospective study, the authors examined the association between hypomagnesemia and survival in patients with head and neck cancer who received concurrent chemoradiation with weekly infusions of cisplatin and/or carboplatin. Methods: Patients with head and neck cancers who had undergone chemoradiation with cisplatin and/or carboplatin between January 1, 2010, and December 31, 2014, were included. Patients were aged ≥18 years with pathology of squamous cell carcinoma of the larynx, oral cavity, or oropharynx who had received at least 30 fractions of radiotherapy with concurrent weekly cisplatin and/or carboplatin. Pathology features, laboratory results, Eastern Cooperative Oncology Group performance status, social histories, and survival were recorded. The association between hypomagnesemia and survival was analyzed controlling for known prognostic factors. Results: The final cohort consisted of 439 patients with a median age of 59 years. A greater frequency of hypomagnesemia during the treatment course was found to be significantly associated with shorter survival (hazard ratio [HR], 1.13; P =.033) independent of age (HR, 1.65; P =.042), cancer site (nonoropharynx vs oropharynx: HR, 2.15 [P =.003]), Eastern Cooperative Oncology Group performance status (>1 vs ≤1: HR, 2.64 [P <.001]), and smoking history (smoker vs nonsmoker: HR, 1.88 [P =.012]). In addition, more severe hypomagnesemia was associated with shorter survival compared with the milder form. Conclusions: The frequency and severity of hypomagnesemia during treatment are prognostic of survival for patients with head and neck cancers who are receiving concurrent chemoradiation with cisplatin and/or carboplatin. A prospective study is needed to investigate the impact of the prevention of hypomagnesemia on survival in this patient population. Persistent hypomagnesemia appears to be predictive of shorter survival in patients with head and neck cancer who receive primary, concurrent, platinum‐based chemoradiation. The prevention of hypomagnesemia may be an indispensable component of a comprehensive anticancer strategy to improve the clinical outcomes for these patients. [ABSTRACT FROM AUTHOR]

Chimeric antigen receptor T cell infusion (CAR T) therapy revolutionized and led to a paradigm shift in the treatment of hematologic malignancies, but treatment- related toxicities including cytokine release syndrome and immune effector cell- associated neurotoxicity syndrome are of concern. In this study, we aimed to understand the timing and reasons for which patients present to the emergency department (ED) after CAR T therapy to better assist with early recognition and management of these toxicities. We conducted a retrospective observational study for patients who had undergone CAR T therapy in the past 6 months and visited the ED of our comprehensive cancer center between 04/01/2018 and 08/01/2022. We examined the timing of presentation after CAR T product infusion, patient characteristics, and outcomes of the ED visit. Survival analyses were conducted using Cox proportional hazards regression and Kaplan-Meier estimates. 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. Cancer patients who receive CAR T therapy frequently visit the ED and most are admitted and/or require urgent or emergent care. Early ED visits may indicate early systemic inflammatory response to CAR T therapy, with patients mainly presenting with constitutional symptoms such as fever and fatigue, and these early visits are associated with better overall survival. [ABSTRACT FROM AUTHOR]

Pain remains an undertreated complication of cancer and has been shown to affect patients' quality of life. Patients when presenting to an emergency department (ED) with pain have two routes to management: hospitalization or discharged for outpatient management. With the advent of observation units, there is now an opportunity to utilize hospital resources without an inpatient stay. In this study, we aimed to define the role of an EDOU in the management of cancer pain. We performed a retrospective observational study that included all patients aged 18 years and older who presented to our ED and were placed in the EDOU with uncontrolled cancer pain between 1 March 2019 and 29 February 2020. Patient characteristics were summarized using descriptive statistics and predictors of the disposition from the EDOU were identified with univariate and multivariate analyses. A total of 600 visits were eligible for analysis. The median age of the cohort was 59 years (interquartile range: IQR 48–68 years). Breast, lung, and colorectal cancer were the most common cancer types. The abdomen (29.0%), back (17.3%), and extremities (15.8%) were the most common locations of identified pain. Most patients were discharged home (61.8%), 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. Our data suggest that an EDOU appears to be an appropriate venue to care for a subsegment of patients presenting to an emergency department with cancer pain with low 72- hour ED revisits and 30-day mortality rates. Placing eligible cancer patients with pain in EDOU creates an optimal care environment than immediate admission or discharge for patients who require significant cancer pain management but may not require inpatient hospitalization for their therapy. [ABSTRACT FROM AUTHOR]

Background: Oral mucositis (OM) is a debilitating sequela for patients treated for squamous cell carcinoma of the head and neck (HNSCC). This study investigated whether oral microbial features before treatment or during treatment are associated with the time to onset of severe OM in patients with HNSCC. Methods: This was a cohort study of newly diagnosed patients with locoregional HNSCC who received chemotherapy with or without radiotherapy from April 2016 to September 2017. OM was based on the National Cancer Institute's Common Terminology Criteria for Adverse Events, version 4.0. The oral microbiome was characterized on the basis of the 16S ribosomal RNA V4 region with the Illumina platform. A mixture cure model was used to generate hazard ratios for the onset of severe OM. Results: Eighty‐six percent of the patients developed OM (n = 57 [33 nonsevere cases and 24 severe cases]) with a median time to onset of OM of 21 days. With adjustments for age, sex, and smoking status, genera abundance was associated with the hazard for the onset of severe OM as follows: 1) at the baseline (n = 66), Cardiobacterium (P =.03) and Granulicatella (P =.04); 2) immediately before the development of OM (n = 57), Prevotella (P =.03), Fusobacterium (P =.03), and Streptococcus (P =.01); and 3) immediately before the development of severe OM (n = 24), Megasphaera (P =.0001) and Cardiobacterium (P =.03). There were no differences in α‐diversity between the baseline samples and Human Microbiome Project data. Conclusions: Changes in the abundance of genera over the course of treatment were associated with the onset of severe OM. The mechanism and therapeutic implications of these findings need to be investigated in future studies. Oral mucositis is a debilitating sequela for patients treated for squamous cell carcinoma of the head and neck. Specific genera may be targeted for probiotic or antibiotic therapy for the prevention and treatment of oral mucositis. [ABSTRACT FROM AUTHOR]

Forkhead‐Box Class O 4 (FOXO4) is involved in critical biological functions, but its response to EGF‐PKB/Akt signal regulation is not well characterized. Here, it is reported that FOXO4 levels are downregulated in response to EGF treatment, with concurrent elevation of COP9 Signalosome subunit 6 (CSN6) and E3 ubiquitin ligase constitutive photomorphogenic 1 (COP1) levels. Mechanistic studies show that CSN6 binds and regulates FOXO4 stability through enhancing the E3 ligase activity of COP1, and that COP1 directly interacts with FOXO4 through a VP motif on FOXO4 and accelerates the ubiquitin‐mediated degradation of FOXO4. Metabolomic studies demonstrate that CSN6 expression leads to serine and glycine production. It is shown that FOXO4 directly binds and suppresses the promoters of serine‐glycine‐one‐carbon (SGOC) pathway genes, thereby diminishing SGOC metabolism. Evidence shows that CSN6 can regulate FOXO4‐mediated SGOC gene expression. Thus, these data suggest a link of CSN6‐FOXO4 axis and ser/gly metabolism. Further, it is shown that CSN6‐COP1‐FOXO4 axis is deregulated in cancer and that the protein expression levels of CSN6 and FOXO4 can serve as prognostic markers for cancers. The results illustrate a pathway regulation of FOXO4‐mediated serine/glycine metabolism through the function of CSN6‐COP1 axis. Insights into this pathway may be strategically designed for therapeutic intervention in cancers. [ABSTRACT FROM AUTHOR]

Mucositis is a complex, dose-limiting toxicity of chemotherapy or radiotherapy that leads to painful mouth ulcers, difficulty eating or swallowing, gastrointestinal distress, and reduced quality of life for patients with cancer. Mucositis is most common for those undergoing high-dose chemotherapy and hematopoietic stem cell transplantation and for those being treated for malignancies of the head and neck. Treatment and management of mucositis remain challenging. It is expected that multiple genes are involved in the formation, severity, and persistence of mucositis. We used Ingenuity Pathway Analysis (IPA), a novel network-based approach that integrates complex intracellular and intercellular interactions involved in diseases, to systematically explore the molecular complexity of mucositis. As a first step, we searched the literature to identify genes that harbor or are close to the genetic variants significantly associated with mucositis. Our literature review identified 27 candidate genes, of which ERCC1, XRCC1, and MTHFR were the most frequently studied for mucositis. On the basis of this 27-gene list, we used IPA to generate gene networks for mucositis. The most biologically significant novel molecules identified through IPA analyses included TP53, CTNNB1, MYC, RB1, P38 MAPK, and EP300. Additionally, uracil degradation II (reductive) and thymine degradation pathways (p = 1.06−08) were most significant. Finally, utilizing 66 SNPs within the 8 most connected IPA-derived candidate molecules, we conducted a genetic association study for oral mucositis in the head and neck cancer patients who were treated using chemotherapy and/or radiation therapy (186 head and neck cancer patients with oral mucositis vs. 699 head and neck cancer patients without oral mucositis). The top ranked gene identified through this association analysis was RB1 (rs2227311, p-value = 0.034, odds ratio = 0.67). In conclusion, gene network analysis identified novel molecules and biological processes, including pathways related to inflammation and oxidative stress, that are relevant to mucositis development, thus providing the basis for future studies to improve the management and treatment of mucositis in patients with cancer. [ABSTRACT FROM AUTHOR]

Background: Intratumoral heterogeneity presents a major obstacle to the widespread implementation of precision medicine. The authors assessed the origin of intratumoral heterogeneity in nonseminomatous germ cell tumor of the testis (NSGCT) and identified distinct tumor subtypes and a potentially lethal phenotype.Methods: In this retrospective study, all consecutive patients who had been diagnosed with an NSGCT between January 2000 and December 2010 were evaluated. The histologic makeup of primary tumors and the clinical course of disease were determined for each patient. A Fine and Gray proportional hazards regression analysis was used to determine the prognostic risk factors, and the Gray test was used to detect differences in the cumulative incidence of cancer death. In a separate prospective study, next-generation sequencing was performed on tumor samples from 9 patients to identify any actionable mutations.Results: Six hundred fifteen patients were included in this study. Multivariate analysis revealed that the presence of yolk sac tumor in the primary tumor (P = .0003) was associated with an unfavorable prognosis. NSGCT could be divided into 5 subgroups. Patients in the yolk sac-seminoma subgroup had the poorest clinical outcome (P = .0015). These tumors tended to undergo somatic transformation (P < .0001). Among the 9 NSGCTs that had a yolk sac tumor phenotype, no consistent gene mutation was detected.Conclusions: The current data suggest that intratumoral heterogeneity is caused in part by differentiation of pluripotent progenitor cells. Integrated or multimodal therapy may be effective at addressing intratumoral heterogeneity and treating distinct subtypes as well as a potentially lethal phenotype of NSGCT. Cancer 2016;122:1836-43. © 2016 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. [ABSTRACT FROM AUTHOR]

Background: Septic shock may be associated with myocardial damage; however, the prognostic value of cardiac enzymes in cancer patients with septic shock is unknown. In this study, we evaluated the prognostic significance of cardiac enzymes in combination with established prognostic factors in predicting the 7-day mortality rate of patients with septic shock, and we constructed a new scoring system, Septic Oncologic Patients in Emergency Department (SOPED), which includes cardiac enzymes, to predict 7-day mortality rates. Methods and Findings: We performed a retrospective cohort study of 375 adult cancer patients with septic shock who visited the emergency department of a comprehensive cancer center between 01/01/2004 and 12/31/2013. The 7-day and 28-day mortality rates were 19.7% and 37.6%, respectively. The creatine kinase myocardial band fraction and troponin-I were significantly higher in patients who died in ≤7 days and ≤28 days than in those who did not. In Cox regression models, troponin-I >0.05 ng/mL plus Predisposition, Infection, Response, and Organ Failure (PIRO2011) or Mortality in Emergency Department Sepsis (MEDS) score was a significant predictor of survival for ≤7 days. With our new SOPED scoring system, the receiver operating characteristic area under the curve was 0.836, higher than those for PIRO2011 and MEDS. Conclusions: Troponin-I >0.05 ng/mL was an important predictor of short-term mortality (≤7 days). The SOPED scoring system, which incorporated troponin-I, was more prognostically accurate than were other scores for 7-day mortality. Large multicenter studies are needed to verify our results and prospectively validate the prognostic performance of the SOPED score. [ABSTRACT FROM AUTHOR]

Background: Genetic susceptibility plays an important role in the risk of developing pain in individuals with cancer. As a complex trait, multiple genes underlie this susceptibility. We used gene network analyses to identify novel target genes associated with pain in patients newly diagnosed with squamous cell carcinoma of the head and neck (HNSCC). Results: We first identified 36 cancer pain-related genes (i.e., focus genes) from 36 publications based on a literature search. The Ingenuity Pathway Analysis (IPA) analysis identified additional genes that are functionally related to the 36 focus genes through pathway relationships yielding a total of 82 genes. Subsequently, 800 SNPs within the 82 IPA-selected genes on the Illumina HumanOmniExpress-12v1 platform were selected from a large-scale genotyping effort. Association analyses between the 800 candidate SNPs (covering 82 genes) and pain in a patient cohort of 1368 patients with HNSCC (206 patients with severe pain vs. 1162 with non-severe pain) showed the highest significance for MAPK1/ERK2, a gene belonging to the MAP kinase family (rs8136867, p value = 8.92 × 10-4; odds ratio [OR] = 1.33, 95 % confidence interval [CI]: 1.13-1.58). Other top genes were PIK3C2G (a member of PI3K [complex], rs10770367, p value = 1.10 × 10-3; OR = 1.46, 95 % CI: 1.16-1.82), TCRA (the alpha chain of T-cell receptor, rs6572493, p value = 2.84 × 10-3; OR = 0.70, 95 % CI: 0.55-0.88), PDGFC (platelet-derived growth factor C, rs6845322, p value = 4.88 × 10-3; OR = 1.32, 95 % CI: 1.09-1.60), and CD247 (a member of CD3, rs2995082, p value = 7.79 × 10-3; OR = 0.76, 95 % CI: 0.62-0.93). Conclusions: Our findings provide novel candidate genes and biological pathways underlying pain in cancer patients. Further study of the variations of these candidate genes could inform clinical decision making when treating cancer pain. [ABSTRACT FROM AUTHOR]

Hyperpolarized 1-13C-pyruvate has shown tremendous promise as an agent for imaging tumor metabolism with unprecedented sensitivity and specificity. Imaging hyperpolarized substrates by magnetic resonance is unlike traditional MRI because signals are highly transient and their spatial distribution varies continuously over their observable lifetime. Therefore, new imaging approaches are needed to ensure optimal measurement under these circumstances. Constrained reconstruction algorithms can integrate prior information, including biophysical models of the substrate/target interaction, to reduce the amount of data that is required for image analysis and reconstruction. In this study, we show that metabolic MRI with hyperpolarized pyruvate is biased by tumor perfusion, and present a new pharmacokinetic model for hyperpolarized substrates that accounts for these effects. The suitability of this model is confirmed by statistical comparison to alternates using data from 55 dynamic spectroscopic measurements in normal animals and murine models of anaplastic thyroid cancer, glioblastoma, and triple-negative breast cancer. The kinetic model was then integrated into a constrained reconstruction algorithm and feasibility was tested using significantly under-sampled imaging data from tumor-bearing animals. Compared to naïve image reconstruction, this approach requires far fewer signal-depleting excitations and focuses analysis and reconstruction on new information that is uniquely available from hyperpolarized pyruvate and its metabolites, thus improving the reproducibility and accuracy of metabolic imaging measurements. [ABSTRACT FROM AUTHOR]

Adrenocortical carcinoma is a rare malignancy with poor prognosis and limited response to chemotherapy. Hepatocyte growth factor (HGF) and its receptor cMET augment cancer growth and resistance to chemotherapy, but their role in adrenocortical carcinoma has not been examined. In this study, we investigated the association between HGF/cMET expression and cancer hallmarks of adrenocortical carcinoma. Transcriptomic and immunohistochemical analyses indicated that increased HGF/cMET expression in human adrenocortical carcinoma samples was positively associated with cancer-related biologic processes, including proliferation and angiogenesis, and negatively correlatedwith apoptosis. Accordingly, treatment of adrenocortical carcinoma cells with exogenous HGF resulted in increased cell proliferation in vitro and in vivo while short hairpin RNA-mediated knockdown or pharmacologic inhibition of cMET suppressed cell proliferation and tumor growth. Moreover, exposure of cells to mitotane, cisplatin, or radiation rapidly induced pro-cMET expression and was associated with an enrichment of genes (e.g., CYP450 family) related to therapy resistance, further implicating cMET in the anticancer drug response. Together, these data suggest an important role for HGF/cMET signaling in adrenocortical carcinoma growth and resistance to commonly used treatments. Targeting cMET, alone or in combination with other drugs, could provide a breakthrough in the management of this aggressive cancer [ABSTRACT FROM AUTHOR]

Summary Biomarkers for predicting prognosis are critical to treating colorectal cancer (CRC) patients. We found that CSN6, a subunit of COP9 signalosome, is overexpressed in CRC samples and that CSN6 overexpression is correlated with poor patient survival. Mechanistic studies revealed that CSN6 is deregulated by epidermal growth factor receptor (EGFR) signaling, in which ERK2 binds directly to CSN6 Leu163/Val165 and phosphorylates CSN6 at Ser148. Furthermore, CSN6 regulated β-Trcp and stabilized β-catenin expression by blocking the ubiquitin-proteasome pathway, thereby promoting CRC development. High CSN6 expression was positively correlated with ERK2 activation and β-catenin overexpression in CRC samples, and inhibiting CSN6 stability with cetuximab reduced colon cancer growth. Taken together, our study’s findings indicate that the deregulation of β-catenin by ERK2-activated CSN6 is important for CRC development. [ABSTRACT FROM AUTHOR]

Background: Addictions to alcohol and tobacco, known risk factors for cancer, are complex heritable disorders. Addictive behaviors have a bidirectional relationship with pain. We hypothesize that the associations between alcohol, smoking, and opioid addiction observed in cancer patients have a genetic basis. Therefore, using bioinformatics tools, we explored the underlying genetic basis and identified new candidate genes and common biological pathways for smoking, alcohol, and opioid addiction. Results: Literature search showed 56 genes associated with alcohol, smoking and opioid addiction. Using Core Analysis function in Ingenuity Pathway Analysis software, we found that ERK1/2 was strongly interconnected across all three addiction networks. Genes involved in immune signaling pathways were shown across all three networks. Connect function from IPA My Pathway toolbox showed that DRD2 is the gene common to both the list of genetic variations associated with all three addiction phenotypes and the components of the brain neuronal signaling network involved in substance addiction. The top canonical pathways associated with the 56 genes were: 1) calcium signaling, 2) GPCR signaling, 3) cAMP-mediated signaling, 4) GABA receptor signaling, and 5) G-alpha i signaling. Conlusions: Cancer patients are often prescribed opioids for cancer pain thus increasing their risk for opioid abuse and addiction. Our findings provide candidate genes and biological pathways underlying addiction phenotypes, which may be future targets for treatment of addiction. Further study of the variations of the candidate genes could allow physicians to make more informed decisions when treating cancer pain with opioid analgesics. [ABSTRACT FROM AUTHOR]

Metformin is derived from galegine, a natural ingredient, and recent studies have suggested that metformin could enhance the antitumor effects of hormone ablative therapy or chemotherapy and reduce prostate cancer-specific mortality. Zyflamend is a combination of herbal extracts that reduces inflammation and comprises turmeric, holy basil, green tea, oregano, ginger, rosemary, Chinese goldthread, hu zhang, barberry, and basil skullcap. We propose a maintenance regimen with metformin and/or Zyflamend that targets cancer stem cells and the tumor microenvironment to keep the cancer dormant and prevent it from activation from dormancy. Herein, we report the clinical course of four patients who experienced a clinical response after treatment with metformin and/or Zyflamend. [ABSTRACT FROM AUTHOR]

Background: Docetaxel, a lipophilic drug, is indicated for castration-resistant metastatic prostate cancer. Most men with such disease would have had androgen-deprivation therapy, which decreases muscle and increases body fat. Obesity and body composition changes may influence the outcomes of docetaxel therapy. Methods: We conducted a retrospective review of 333 patients with metastatic prostate cancer treated with docetaxel at a comprehensive cancer center between October 7, 2004 and December 31, 2012. Body composition parameters were measured based on the areas of muscle and adipose tissues in the visceral and subcutaneous compartments on CT images at L3-4 levels. Dose calculations, toxicity and adverse reaction profiles, and overall survival were analyzed. Results: Obese patients were younger at the diagnosis of prostate cancer and had a shorter duration from diagnosis to docetaxel therapy. Analysis of body composition found that a high visceral fat-to-subcutaneous fat area ratio (VSR) was associated with poor prognosis but a high visceral fat-to-muscle area ratio (VMR) and high body mass index were associated with increased duration from starting docetaxel to death, allowing such men to catch up with patients with normal body mass index in overall survival from cancer diagnosis to death. Cox proportional hazard regression showed that age ≥65 years, high VSR, abnormal serum alkaline phosphatase, and >10% reduction of initial dosage were significant predictors of shorter time between starting docetaxel and death, and that high VMR, obesity, and weekly regimens were significant predictors of longer survival after docetaxel. Conclusion: Obese and overweight patients may benefit more from weekly docetaxel regimens using the reference dosage of 35 mg/m2 without empirical dosage reduction. [ABSTRACT FROM AUTHOR]

Background: FGF21 is a promising intervention therapy for metabolic diseases as fatty liver, obesity and diabetes. Recent results suggest that FGF21 is highly expressed in hepatocytes under metabolic stress caused by starvation, hepatosteatosis, obesity and diabetes. Hepatic FGF21 elicits metabolic benefits by targeting adipocytes of the peripheral adipose tissue through the transmembrane FGFR1-KLB complex. Ablation of adipose FGFR1 resulted in increased hepatosteatosis under starvation conditions and abrogation of the anti-obesogenic action of FGF21. These results indicate that FGF21 may be a stress responsive hepatokine that targets adipocytes and adipose tissue for alleviating the damaging effects of stress on the liver. However, it is unclear whether hepatic induction of FGF21 is limited to only metabolic stress, or to a more general hepatic stress resulting from liver pathogenesis and injury. Methods: In this survey-based study, we examine the nature of hepatic FGF21 activation in liver tissues and tissue sections from several mouse liver disease models and human patients, by quantitative PCR, immunohistochemistry, protein chemistry, and reporter and CHIP assays. The liver diseases include genetic and chemical-induced HCC, liver injury and regeneration, cirrhosis, and other types of liver diseases. Results: We found that mouse FGF21 is induced in response to chemical (DEN treatment) and genetic-induced hepatocarcinogenesis (disruptions in LKB1, p53, MST1/2, SAV1 and PTEN). It is also induced in response to loss of liver mass due to partial hepatectomy followed by regeneration. The induction of FGF21 expression is potentially under the control of stress responsive transcription factors p53 and STAT3. Serum FGF21 levels correlate with FGF21 expression in hepatocytes. In patients with hepatitis, fatty degeneration, cirrhosis and liver tumors, FGF21 levels in hepatocytes or phenotypically normal hepatocytes are invariably elevated compared to normal health subjects. Conclusion: FGF21 is an inducible hepatokine and could be a biomarker for normal hepatocyte function. Activation of its expression is a response of functional hepatocytes to a broad spectrum of pathological changes that impose both cellular and metabolic stress on the liver. Taken together with our recent data, we suggest that hepatic FGF21 is a general stress responsive factor that targets adipose tissue for normalizing local and systemic metabolic parameters while alleviating the overload and damaging effects imposed by the pathogenic stress on the liver. This study therefore provides a rationale for clinical biomarker studies in humans. [ABSTRACT FROM AUTHOR]

Mammalian constitutive photomorphogenic 1 (COP1) is a p53 E3 ubiquitin ligase involved in regulating p53 protein level. In plants, the dynamic cytoplasm/nucleus distribution of COP1 is important for its function in terms of catalyzing the degradation of target proteins. In mammalian cells, the biological consequence of cytoplasmic distribution of COP1 is not well characterized. Here, we show that DNA damage leads to the redistribution of COP1 to the cytoplasm and that 14-3-3σ, a p53 target gene product, controls COP1 subcellular localization. Investigation of the underlying mechanism suggests that COP1 S387 phosphorylation is required for COP1 to bind 14-3-3σ. Significantly, upon DNA damage, 14-3-3σ binds to phosphorylated COP1 at S387, resulting in COP1's accumulation in the cytoplasm. Cytoplasmic COP1 localization leads to its enhanced ubiquitination. We also show that N-terminal 14-3- 3σ interacts with COP1 and promotes COP1 nuclear export through its NES sequence. Further, we show that COP1 is important in causing p53 nuclear exclusion. Finally, we demonstrate that 14-3-3σ targets COP1 for nuclear export, thereby preventing COP1-mediated p53 nuclear export. Together, these results define a novel, detailed mechanism for the subcellular localization and regulation of COP1 after DNA damage and provide a mechanistic explanation for the notion that 14-3-3σ's impact on the inhibition of p53 E3 ligases is an important step for p53 stabilization after DNA damage. [ABSTRACT FROM AUTHOR]

Background: Ovarian cancer is the leading cause of cancer-related death among women. Complete cytoreductive surgery followed by platinum-taxene chemotherapy has been the gold standard for a long time. Various compounds have been assessed in an attempt to combine them with conventional chemotherapy to improve survival rates or even overcome chemoresistance. Many studies have shown that an antidiabetic drug, metformin, has cytotoxic activity in different cancer models. However, the synergism of metformin as a neoadjuvant formula plus chemotherapy in clinical trials and basic studies remains unclear for ovarian cancer. Methods: We applied two clinical databases to survey metformin use and ovarian cancer survival rate. The Cancer Genome Atlas dataset, an L1000 microarray with Gene Set Enrichment Analysis (GSEA) analysis, Western blot analysis and an animal model were used to study the activity of the AKT/mTOR pathway in response to the synergistic effects of neoadjuvant metformin combined with chemotherapy. Results: We found that ovarian cancer patients treated with metformin had significantly longer overall survival than patients treated without metformin. The protein profile induced by low- concentration metformin in ovarian cancer predominantly involved the AKT/mTOR pathway. In combination with chemotherapy, the neoadjuvant metformin protocol showed beneficial synergistic effects in vitro and in vivo. Conclusions: This study shows that neoadjuvant metformin at clinically relevant dosages is efficacious in treating ovarian cancer, and the results can be used to guide clinical trials. [ABSTRACT FROM AUTHOR]

The article discusses role of Aurora B, a protein kinase involved in regulation of activity of p53 during the cell cycle. It describes Aurora B as a component of the chromosomal passenger protein complex (CPC) along with its high expression by cancerous cells, leading to dysregulated mitosis. It states that molecular mechanisms involved in inhibition of tumor growth by an Aurora B inhibitor through increasing the p53 up-regulated modulator of apoptosis (PUMA).

Background: FGF21 is a promising intervention therapy for metabolic diseases as fatty liver, obesity and diabetes. Recent results suggest that FGF21 is highly expressed in hepatocytes under metabolic stress caused by starvation, hepatosteatosis, obesity and diabetes. Hepatic FGF21 elicits metabolic benefits by targeting adipocytes of the peripheral adipose tissue through the transmembrane FGFR1-KLB complex. Ablation of adipose FGFR1 resulted in increased hepatosteatosis under starvation conditions and abrogation of the anti-obesogenic action of FGF21. These results indicate that FGF21 may be a stress responsive hepatokine that targets adipocytes and adipose tissue for alleviating the damaging effects of stress on the liver. However, it is unclear whether hepatic induction of FGF21 is limited to only metabolic stress, or to a more general hepatic stress resulting from liver pathogenesis and injury.Methods: In this survey-based study, we examine the nature of hepatic FGF21 activation in liver tissues and tissue sections from several mouse liver disease models and human patients, by quantitative PCR, immunohistochemistry, protein chemistry, and reporter and CHIP assays. The liver diseases include genetic and chemical-induced HCC, liver injury and regeneration, cirrhosis, and other types of liver diseases.Results: We found that mouse FGF21 is induced in response to chemical (DEN treatment) and genetic-induced hepatocarcinogenesis (disruptions in LKB1, p53, MST1/2, SAV1 and PTEN). It is also induced in response to loss of liver mass due to partial hepatectomy followed by regeneration. The induction of FGF21 expression is potentially under the control of stress responsive transcription factors p53 and STAT3. Serum FGF21 levels correlate with FGF21 expression in hepatocytes. In patients with hepatitis, fatty degeneration, cirrhosis and liver tumors, FGF21 levels in hepatocytes or phenotypically normal hepatocytes are invariably elevated compared to normal health subjects.Conclusion: FGF21 is an inducible hepatokine and could be a biomarker for normal hepatocyte function. Activation of its expression is a response of functional hepatocytes to a broad spectrum of pathological changes that impose both cellular and metabolic stress on the liver. Taken together with our recent data, we suggest that hepatic FGF21 is a general stress responsive factor that targets adipose tissue for normalizing local and systemic metabolic parameters while alleviating the overload and damaging effects imposed by the pathogenic stress on the liver. This study therefore provides a rationale for clinical biomarker studies in humans. [ABSTRACT FROM AUTHOR]