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Benchmarking of Machine Learning Models to Assist the Prognosis of Tuberculosis
Maicon Herverton Lino Ferreira da Silva Barros, Geovanne Oliveira Alves, Lubnnia Morais Florêncio Souza, Élisson da Silva Rocha, João Fausto Lorenzato de Oliveira, Theo Lynn, Vanderson Sampaio, Patricia Takako Endo
Subject: Mathematics & Computer Science, Algebra & Number Theory Keywords: machine learning; benchmarking; tuberculosis; prognosis
Tuberculosis (TB) is an airborne infectious disease caused by organisms in the Mycobacterium tuberculosis (Mtb) complex. In many low and middle-income countries, TB remains a major cause of morbidity and mortality. Once a patient has been diagnosed with TB, it is critical that healthcare workers make the most appropriate treatment decision given the individual conditions of the patient and the likely course of the disease based on medical experience. Depending on the prognosis, delayed or inappropriate treatment can result in unsatisfactory results including the exacerbation of clinical symptoms, poor quality of life, and increased risk of death. This work benchmarks machine learning models to aid TB prognosis using a Brazilian health database of confirmed cases and deaths related to TB in the State of Amazonas. The goal is to predict the probability of death by TB thus aiding the prognosis of TB and associated treatment decision making process. In its original form, the data set comprised 36,228 records and 130 fields but suffered from missing, incomplete, or incorrect data. Following data cleaning and preprocessing, a revised data set was generated comprising 24,015 records and 38 fields, including 22,876 reported cured TB patients and 1,139 deaths by TB. To explore how the data imbalance impacts model performance, two controlled experiments were designed using (1) imbalanced and (2) balanced data sets. The best result is achieved by the Gradient Boosting (GB) model using the balanced data set to predict TB-mortality, and the ensemble model composed by the Random Forest (RF), GB and Multi-layer Perceptron (MLP) models is the best model to predict the cure class.
Characteristics and Prognosis of COVID-19 in Patients with COPD
Desirée Graziani, Joan B Soriano, Carlos Del Rio-Bermudez, Diego Morena, Teresa Díaz, María Castillo, Miguel Alonso, Julio Ancochea, José Luis Izquierdo
Subject: Medicine & Pharmacology, General Medical Research Keywords: COPD; COVID-19; prevalence; prognosis
Patients with COPD have a higher prevalence of coronary ischemia and other factors that put them at risk for COVID-19-related complications. We aimed to explore the impact of COVID-19 in a large population-based sample of patients with COPD in Castilla-La Mancha, Spain. We analyzed clinical data in electronic health records from January 1st to May 10th, 2020 by using Natural Language Processing through the SAVANA Manager® clinical platform. Out of 31,633 COPD patients, 793 had a diagnosis of COVID-19. The proportion of patients with COVID-19 in the COPD population (2,51%; CI95% 2,33 – 2,68) was significantly higher than in the general population aged > 40 years (1,16%; 95%CI 1,14 – 1,18); P < .001. Compared with COPD-free individuals, COPD patients with COVID-19 showed significantly poorer disease prognosis, as evaluated by hospitalizations (31,1 % vs 39,8%: OR 1,57; 95%CI 1,14 – 1,18) and mortality (3,4% vs 9,3%: OR 2,93; 95%CI 2,27 – 3,79). Patients with COPD and COVID-19 were significantly older (75 vs. 66 years), predominantly male (83% vs 17%), smoked more frequently, and had more comorbidities than their non-COPD counterparts. Pneumonia was the most common diagnosis among COPD patients hospitalized due to COVID-19 (59%); 19% of patients showed pulmonary infiltrates suggestive of pneumonia and heart failure. Mortality in COPD patients with COVID-19 was associated with older age and prevalence of heart failure (P<0.05). COPD patients with COVID-19 showed higher rates of hospitalization and mortality, mainly associated with pneumonia. This clinical profile is different from exacerbations caused by other respiratory viruses in the winter season.
Should Tumor Infiltrating Lymphocyes, Androgen Receptor, and FOXA1 expression predict Clinical Outcome in Triple Negative Breast Cancer Patients?
Anita Mangia, Concetta Saponaro, Alessandro Vagheggini, Giuseppina Opinto, Matteo Centonze, Chiara Vicenti, Ondina Popescu, Maria Irene Pastena, Francesco Giotta, Nicola Silvestris
Subject: Medicine & Pharmacology, Oncology & Oncogenics Keywords: TILs; TNBC; AR; FOXA1; Prognosis
Online: 8 August 2019 (12:28:55 CEST)
Tumor-infiltrating lymphocytes (TILs) are a valuable indicator of the immune microenvironment that plays the central role in new anticancer drugs. TILs has a strong prognostic role in triple negative breast cancer (TNBC). Little is known about his interaction with Androgen receptor (AR) and Forkhead box A1 (FOXA1). We analyzed the relationships between TIL levels, AR and FOXA1 expression and their clinical significance in TNBC patients. Further, we investigated their interaction with other biomarkers like programmed cell death ligand-1 (PD-L1), Breast Cancer Type 1 susceptibility protein (BRCA1), Poly [ADP-Ribose] Polymerase 1 (PARP1) and Na+/H+ Exchanger Regulatory Factor 1 (NHERF1). The expression of the proteins was evaluated by immunohistochemistry in 124 TNBC samples. TILs were performed adhering to International TILs Working Group 2014 criteria. Cox proportional hazards models were also used to identify risk factors associated with poor prognosis. Multivariate analysis identified TILs as independent prognostic factor of disease free survival (DFS) (p=0.045). A Kaplan-Meyer analysis revealed that the patients with high TILs had a better DFS compared to patients with low TILs (p=0.037), and the phenotypes TILs-/AR+ and TILs-/FOXA1- had a worse DFS (p=0.032, p=0.001 respectively). AR was associated with FOXA1 expression (p=0.007), and the tumors FOXA1+ presented low levels of TILs (p=0.028). A poor DFS was observed for AR+/FOXA1+ tumors compared to other TNBCs (p=0.0117). Low TILs score was associated with poor patients' survival, and TILs level in combination with AR or FOXA1 expression affected patient's clinical outcome. In addition, AR+/FOXA1+ phenotype identified a specific subgroup of TNBC patients with poor prognosis. These data may suggest new ways of therapeutic intervention to support current treatments.
Propranolol Treatment is Associated with Better Survival in Cirrhotic Patients with Hepatic Encephalopathy
Pei-Chang Lee Lee, Yu-Ju Chen, Yueh-Ching Cho, Kuei-Chuan Lee, Ping-Hsien Chen, Wei-Yu Kao, Yi-Hsiang Huang, Teh-Ia Huo, Han-Chieh Lin, Ming-Chih Hou, Fa-Yauh Lee, Jaw-Ching Wu, Chien-Wei Su
Subject: Medicine & Pharmacology, Nursing & Health Studies Keywords: Cirrhosis; Hepatic encephalopathy; Propranolol; Prognosis
Hepatic encephalopathy (HE) reduces survival in cirrhotic patients and correlates with systemic inflammation and gut-liver disequilibrium. We investigated the association between propranolol treatment and outcomes for cirrhotic patients with HE. Using data from the Taiwan National Health Insurance Research Database, we identified 4,754 cirrhotic patients newly diagnosed with HE. Among them, 519 patients received propranolol treatment and the other 519 patients without exposure to propranolol were enrolled into our study, both of which were matched by sex, age, and propensity score. The median overall survival (OS) was longer in the propranolol-treated cohort than in the untreated cohort (3.46 versus 1.88 years, p<0.001). A dose-dependent increase in survival was observed (median OS: 4.49, 3.29, and 2.46 years in patients treated with propranolol >30mg/day, 20–30mg/day, and <20mg/day, respectively [p<0.001, p=0.001, and p=0.079 versus the untreated group]). In addition to reduce the risk of mortality (adjusted hazard ratio, 0.58; p<0.001), propranolol also diminished the risk of sepsis-related death (adjusted hazard ratio, 0.31; p=0.006) according to the multivariate analysis. However, the risk of circulatory or hepatic failure was non-significantly altered by propranolol treatment. In conclusion, propranolol treatment was associated with a better OS in cirrhotic patients with HE and its effects were dose-dependent.
Activation of ERBB4 in glioblastoma can contribute to increased tumorigenicity and influence therapeutic response
Jacqueline Donoghue, Lauren Kerr, Naomi Alexander, Sameer Greenall, Anthony Longano, Nicholas Gottardo, Rong Wang, Viviane Tabar, Timothy Adams, Paul Mischel, Terrance Johns
Subject: Life Sciences, Cell & Developmental Biology Keywords: GBM, EGFR, ERBB4, prognosis, therapy
Glioblastoma (GBM) is often resistant to conventional and targeted therapeutics. ERBB4 is expressed throughout normal brain and is an oncogene in several pediatric brain cancers; therefore, we investigated ERBB4 as a prognostic marker and therapeutic target in GBM. Using RT-qPCR, we quantified mRNA encoding total ERBB4 and known ERBB4 variants in GBM and non-neoplastic normal brain (NNB) samples. Using immunohistochemistry, we characterized the localization of total and phosphorylated ERBB4 (p-ERBB4) and EGFR protein in archived GBM samples and assessed their association with patient survival. Furthermore, we evaluated the effect of ERBB4 phosphorylation on angiogenesis and tumorigenicity in GBM xenograft models. Total ERBB4 mRNA was significantly lower in GBM than NNB samples, with the JM-a and CYT-2 variants predominating. ERBB4 protein was ubiquitously expressed in GBM but was not associated with patient survival. However, high p-ERBB4 in 11% of archived GBM samples, independent of p-EGFR, was associated with shorter patient survival (12.0±3.2 months) than was no p-ERBB4 (22.5±9.5 months). Increased ERBB4 activation was also associated with increased proliferation, angiogenesis, tumorigenicity and reduced sensitivity to anti-EGFR treatment in xenograft models. Despite low ERBB4 mRNA in GBM, the functional effects of increased ERBB4 activation identify ERBB4 as a potential prognostic and therapeutic target.
Preprint REVIEW | doi:10.20944/preprints202205.0328.v1
An Update on the General Features of Breast Cancer in Male Patients- a Literature Review
Sinziana Ionescu, Alin Nicolescu, Marian Marincas, Octavia Luciana Madge, Laurentiu Simion
Subject: Medicine & Pharmacology, Oncology & Oncogenics Keywords: male; breast; cancer; diagnosis; treatment; prognosis
Male breast cancers are uncommon, as men account for less than 1 percent of all breast carcinomas. Among the predisposing risk factors for male breast cancer, the following appear to be significant: a) breast/chest radiation exposure, b) estrogen use, diseases associated with hyper-estrogenism, such as cirrhosis or Klinefelter syndrome, and c) family health history. Furthermore, there are clear familial tendencies, with a higher incidence among men who have a large number of female relatives with breast cancer and d) major inheritance susceptibility. Moreover, in families with BRCA mutations, there is an increased risk of male breast cancer, although the risk appears to be greater with inherited BRCA2 mutations than with inherited BRCA1 mutations. Due to diagnostic delays, male breast cancer is more likely to present at an advanced stage. A core biopsy or a fine needle aspiration must be performed to confirm suspicious findings. Infiltrating ductal cancer is the most prevalent form of male breast cancer, while invasive lobular carcinoma is extremely uncommon. Male breast cancer is almost always positive for hormone receptors. A worse prognosis is associated with a more advanced stage at diagnosis for men with breast cancer. And randomized controlled trials which recruit both female and male patients should be developed in order to gain more consistent data on the optimal clinical approach.
Clinical Perspectives of Theranostics
Shozo Okamoto, Tohru Shiga, Nagara Tamaki
Subject: Medicine & Pharmacology, Allergology Keywords: PET; theranostics; radionuclide therapy; cancer; prognosis
Theranostics covers combination of diagnostic and therapeutic techniques for various cancers throughout body using suitable drug combination. This review covers well-known treatment of thyroid cancer and pheochromocytoma with I-131 compounds and also new radiopharmaceuticals for prostatic cancer and pancreatic cancer. Of particular, new trends toward patient outcome has been focused. A recent clinical study highlighted the ability of alpha-radiotherapy with high LET to overcome treatment resistance to beta--particle therapy. The theranostics will become an ever-increasing part of clinical nuclear medicine these days.
Distribution of Symptoms, Comorbidities, and Severity Among Patients with COVID-19 by Age Groups, Countries, and Stages of Outbreak: A Systematic Review and Meta-Analysis
Kuan-Fu Chen, Ismaeel Yunusa, Su-Hsun Liu, Chin‐Chieh Wu, Chun‐Fu Yeh, Shih-Tsung Han, Chih-Yang Mao, Dasari Harika, Richard Rothman, Andrew Pekosz
Subject: Keywords: COVID-19; sensitivity; specificity; diagnosis; prognosis
Study objective Since December 2019, the coronavirus disease (COVID-19) pandemic has caused over a million deaths and resulted in adverse socio-economic impacts worldwide. However, predictability and prognostication of clinical features vary among different populations. Methods We search PubMed, EMBASE, Cochrane Library, Google Scholar, and WHO Global Health Library from December 2019 to April 2020 for studies reporting the risk factors, clinical features, and outcomes. The random-effect models for transformed prevalence (single-arm) or bivariate random-effect models (sensitivity and specificity) for correlated performance indicators. Results Among the 189 included studies representing 53,659 patients, the most sensitive predictor for COVID-19 infection was fever in adults (83%, 95% confidence interval [CI]:73–90%), and the most specific predictor was fatigue (96%, 95% CI: 80–99%). Fever was the most sensitive symptom in predicting the severity (89%, 95% CI:83–92%), followed by cough (71%, 95% CI:63–78%). The most specific predictor of severe COVID-19 was a chronic obstructive pulmonary disease (99%, 95% CI:98–99%). The stage of the outbreak and age significantly affect the prevalence of fever, fatigue, cough, and dyspnea. Fever, cough, fatigue, hypertension, and diabetes mellitus combined have a 3.06 positive likelihood ratio (PLR) and a 0.59 negative likelihood ratio (NLR) in the diagnosis. Additionally, fever, cough, sputum production, myalgia, fatigue, and dyspnea combined have a 10.44 PLR and a 0.16 NLR in predicting severe COVID-19. Conclusions Understanding the different distribution of predictors essential for screening potential COVID-19 infection and severe outcomes and the combination of symptoms could improve the pre-test probability.
Heart in Patients Infected with 2019 Novel Coronavirus (COVID-19)
Abdallah Fayssoil, Benjamin Davido, Hazrije Mustafic, Aurélien Dinh, Nicolas Mansencal
Subject: Medicine & Pharmacology, Cardiology Keywords: coronavirus; heart; prognosis; COVID-19; ICU
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an emerging infectious disease with currently a pandemic state. Cardiac function can be involved, affecting prognosis, in addition with lung feature severity, particularly in patients with comorbidities. Since the renin angiotensin aldosterone (RAA) system may interact with SARS-Cov-2, researches are still ongoing to assess the prognostic value of RAA blockers in cardiology.
Review of Current Evidence in the etiopathogenesis, epidemiology, diagnosis and management of acute pancreatitis
Samantha Varley, Kirsten Rossi, Meghan Murray, Alissa Nichole
Subject: Medicine & Pharmacology, Gastroenterology Keywords: pancreatitis; epidemiology; diagnosis; complications; treatment; prognosis.
Acute pancreatitis (AP) is an inflammatory condition of the pancreas and is one of the most common ailments of the gastrointestinal system that results in significant morbidity and mortality. The main etiologic causes of AP are alcohol consumption, gallstones, hypertriglyceridemia, and biliary stones. The clinical signs and symptoms, and diagnostic criteria of AP are well established in the literature and multiple studies. Multiple scoring systems have been used to predict the severity, prognosis, and mortality associated with AP. The present review of the literature brings to light the significant and recent contributions in the etiology, risk factors, epidemiology, diagnosis, complications, prognosis and newest modalities in treatment that could be beneficial in the management of AP.
Preprint CASE REPORT | doi:10.20944/preprints201809.0203.v1
Primary Female Urethral Cancer:A Case Report and Review of Literature
Yupeng Guan, Gang Yu, Qianyun Tang, Huan Zhou, Zhiming Bai
Subject: Medicine & Pharmacology, Oncology & Oncogenics Keywords: Primary urethral cancer; Elderly female; Prognosis
Primary urethral malignancies are rare in clinical practice and elderly female are prone to suffer. The cause of PUC is unknown and may be related to long-term chronic inflammation, infection, sexual intercourse, pregnancy and irritation of the urethra. Incipient symptom of PUC is not distinctness and can easily lead to misdiagnosis. The final diagnosis relied on transvaginal ultrasound-guided mass biopsy and urethral biopsy. Early tumor treatment is mainly based on surgical resection. For advanced tumors, it is recommended to adopt a comprehensive treatment plan combining surgery, radiotherapy and chemotherapy We report this case with the aim of bringing attention to that primary urethral cancer progresses rapidly and has a poor prognosis, it is urged to call for a need of diagnostic and treatment specification.
Predicting Remission among Perinatal Women with Depression in Rural Pakistan: A Prognostic Model for Task-Shared Interventions in Primary Care Settings
Ahmed Waqas, Siham Sikander, Abid Malik, Najia Atif, Eirini Karyotaki, Atif Rahman
Subject: Medicine & Pharmacology, Psychiatry & Mental Health Studies Keywords: Perinatal depression; prognosis; prognostic modeling; nomogram; Pakistan
Task sharing approaches are challenged by the barriers fundamental to the use of non-specialists who lack specialist mental health training required to triage the candidates who could benefit from task-shared treatments. However, these challenges could be offset by using standardized and easy-to-implement algorithmic devices (e.g., nomograms) to help with the targeted dissemination of interventions. Therefore, the present investigation posits a prognostic model and a nomogram to predict the prognosis of perinatal depression among women in rural Pakistan. This secondary analysis utilizes data based on 903 pregnant women with depression who participated in a cluster randomized controlled trial that tested the effectiveness of the Thinking Healthy Program in rural Rawalpindi, Pakistan. The participants were recruited from 40 union councils in two sub-districts of Rawalpindi and randomly assigned to intervention and enhanced usual care. Sixteen sessions of the THP intervention were delivered by trained community health workers to women with depression over pregnancy and the postnatal period. A trained assessment team used the Structured Clinical Interview for the DSM-4 current major depressive episode module to diagnose depression at the baseline and post-intervention. The intervention received by the participants emerged as the most significant predictor in the model. Among clinical factors, baseline severity of core-emotional symptoms emerged as an essential predictor, followed by atypical symptoms and insomnia. Higher severity of these symptoms was associated with a poorer prognosis. Other important predictors of a favorable prognosis included living with paternal and maternal grandmothers, financial empowerment, higher socioeconomic class, and living in a joint family system. This prognostic model yielded acceptable discrimination (c-statistic =0.75) and calibration to aid in personalized delivery of psychological treatment.
Magnetic Resonance for Differential Diagnosis of Left Ventricular Hypertrophy: Diagnostic and Prognostic Implications
Giovanni Donato Aquaro, Elisabetta Corsi, Giancarlo Todiere, Chrysanthos Grigoratos, Andrea Barison, Valerio Barra, Gianluca di Bella, Michele Emdin, Fabrizio Ricci, Alessandro Pingitore
Subject: Medicine & Pharmacology, Cardiology Keywords: Left ventricular hypertrophy; Echocardiography; Magnetic Resonance; Prognosis
Online: 5 January 2022 (13:10:00 CET)
Background: Left ventricular hypertrophy (LVH) may be due to different causes, ranging from benign secondary forms to severe cardiomyopathies. Transthoracic Echocardiography (TTE) and ECG are the first level examination for LVH diagnosis. Cardiac magnetic resonance (CMR) defines accurately LVH type, extent and severity. Objectives: to evaluate the diagnostic and prognostic role of CMR in patients with TTE and/or ECG evidence of LVH. Methods: We performed CMR in 300 consecutive patients with echocardiographic and/or ECG signs of LVH. Results: Overall, 275 patients had TTE evidence of LVH with initial suspicion of hypertrophic cardiomyopathy (HCM) in 132 (44%), cardiac amyloidosis in 41 (14%), hypertensive LVH in 48 (16%), aortic stenosis in 4 (1%), undetermined LVH in 50(16%). The initial echocardiographic diagnostic suspicion of LVH was confirmed in 172 patients (57.3%) and changed in 128 patients (42.7%, p<0.0001): the diagnosis of HCM increased from 44% to 71% of patients; hypertensive and undetermined LVH decreased significantly (respectively to 4% and 5%). CMR allowed a diagnosis in 41 out of 50 (82%) with undetermined LVH at TTE. CMR also identified HCM in 17 out of 25 patients with apparently normal echo but with ECG criteria for LVH. Finally, the reclassification of the diagnosis by CMR was associated with a change of survival risk of patients: after CMR reclassification no events occurred in patients with undetermined or hypertensive LVH. Conclusions: CMR changed echocardiographic suspicion in almost half of patients with LVH. In the subgroup of patient with abnormal ECG, CMR identified LVH (particularly HCM) in 80% of patients. This study highlights the indication of CMR to better characterize the type, extent and severity of LVH detected at echocardiography and suspected with ECG.
The landscape of PDK1 in Breast Cancer
Na Wang, Jianjiang Fu, Zhihua Li, Ningni Jiang, Yanhong Chen, Juan Peng
Subject: Life Sciences, Molecular Biology Keywords: PDK1; breast cancer; survival; prognosis; targeted therapy
Given that 3-Phosphoinositide-dependent kinase 1 (PDK1) plays a crucial role in malignant biological behaviors of a wide-range of cancers, we further review the influence of PDK1 in breast cancer (BC). First, we describe the power of PDK1 in cellular behaviors and extensively demonstrate the interacting networks of PDK1 via PI3K-dependent/ PI3K-independent pathway. Then we enlighten the roles of PDK1 in carcinogenesis, growth and survival, metastasis, and chemoresistance in BC cells. More important, we sort the current preclinical or clinical trials of PDK1 targeted therapy in BC and find that even though at present no selective PDK1 inhibitor is available for BC therapy, but the combination trials of PDK1 targeted therapy and other agents have demonstrated some benefit. Thus, there is increasing anticipations that PDK1 targeted therapy will have its space in future therapeutic concepts of BC, and we hope to feature PDK1 in BC to the clinic and bring the new promising to patients for targeted therapies.
Hodgkin Lymphoma in People Living With HIV
Jose Tomas Navarro, Jose Moltó, Gustavo Tapia, Josep Maria Ribera
Subject: Medicine & Pharmacology, Oncology & Oncogenics Keywords: Hodgkin lymphoma, HIV,; antiretroviral therapy; prognosis; etiopathogenesis
Despite widespread use of combined antiretroviral therapy (cART) and increased life expectancy in people living with HIV (PLWH), HIV-related lymphomas (HRL) remain a leading cause of cancer morbidity and mortality for PLWH, even in patients optimally treated with cART. While incidence of aggressive forms of non-Hodgkin lymphoma decreased after cART advent, incidence of Hodgkin lymphoma (HL) has increased among PLWH in recent decades. The coinfection of Epstein Barr virus plays a crucial role in the pathogenesis of HL in the HIV setting. Currently, PLWH with HRL, including HL, are treated similarly to HIV-negative patients and, importantly, the prognosis of HL in PLWH is approaching to that of the general population. In this regard, effective chem-otherapy is strongly recommended since it has been shown to improve survival rates in all lymphoma subtypes, including HL. As a consequence, interdisciplinary collaboration between HIV specialists and hemato-oncologists for the management of potential drug-drug interactions and overlapping toxicities between antiretroviral and antineoplastic drugs is crucial for the op-timal treatment of PLWH with HL. In this article the authors review and update the epidemio-logical, clinical and biological aspects of HL presenting in PLWH with special emphasis in the improvement on prognosis and the factors that have contributed to it.
Working Paper REVIEW
Subject: Medicine & Pharmacology, Allergology Keywords: Hodgkin lymphoma, HIV; antiretroviral therapy; prognosis; etiopathogenesis
Online: 2 June 2021 (11:53:29 CEST)
Despite widespread use of combined antiretroviral therapy (ART) and increased life expectancy in people living with HIV (PLWH), HIV-related lymphomas (HRL) remain a leading cause of cancer morbidity and mortality for PLWH, even in patients optimally treated with ART. While incidence of aggressive forms of non-Hodgkin lymphoma decreased after ART advent, incidence of Hodgkin lymphoma (HL) has increased among PLWH in recent decades. The coinfection of Epstein Barr virus plays a crucial role in the pathogenesis of HL in the HIV setting. Currently, PLWH with HRL, including HL, are treated similarly to HIV-negative patients and, importantly, the prognosis of HL in PLWH is approaching to that of the general population. In this regard, effective chemotherapy is strongly recommended since it has been shown to improve survival rates in all lymphoma subtypes, including HL. As a consequence, interdisciplinary collaboration between HIV specialists and hemato-oncologists for the management of potential drug-drug interactions and overlapping toxicities between antiretroviral and antineoplastic drugs is crucial for the optimal treatment of PLWH with HL. In this article the authors review and update the epidemiological, clinical and biological aspects of HL presenting in PLWH with special emphasis in the improvement on prognosis and the factors that have contributed to it.
Discovery of Simple Blood-Based Test to Predict Early Onset of Alzheimer's Using Standard Clinical Mass Spectrometry Platforms
Simona Piccirella, Simone Cristoni, Christopher Fowler, James Doecke, Giulia Abate, Daniela Uberti
Subject: Medicine & Pharmacology, Clinical Neurology Keywords: Alzheimer's disease; biomarker; prognosis; P53; mass spectrometry
Despite the increasing number of individuals affected by Alzheimer's disease (AD) every year, no effective therapy has been developed to treat this neurodegenerative disease yet. The current methods for AD diagnosis are effective for clinical confirmation of the disease only when symptoms become apparent, years after molecular damage started within the patients' brains. As higher expression of a conformationally altered p53 has been correlated with AD, we developed a mass spectrometry-based method for highly sensitive, specific, and reproducible quantification of a p53 conformational variant in plasma samples of patients with known clinical outcome. In particular, we tested the prognostic performance of an AD-specific 2D3A8-immunoselected p53 peptide (AZ 284™) in different sets of individuals progressing from both cognitively unimpaired (CU) and mild cognitive impairment (MCI) patients progressing to AD dementia. Our data showed that quantitative analysis of AZ 284™ is a reliable tool for predicting AD progression up to 6 years prior to dementia onset with AUC >90%. Taken together, these results support the implementation of p53 conformational variant quantification as an affordable and powerful diagnostic tool for early, non-invasive AD diagnosis.
Prognostic Value of the Six-Minute Walk Test in Heart Failure
Vinicius Astolpho, Roberto Barbosa, Gabriela Devens, Leticia Louzada, Pietro Lima, Rodolfo Sylvestre, Renato Serpa, Osmar Calil, Luiz Fernando Barbosa
Subject: Medicine & Pharmacology, Allergology Keywords: heart failure; 6-minute walk test; prognosis
Online: 4 November 2020 (10:08:38 CET)
Background: The 6-minute walk test (6MWT) is a simple and low-cost method that allows assessment of functional capacity in patients with heart failure (HF). However, the prognostic role of 6MWT in HF remains uncertain. Objectives: We aimed to evaluate the 6MWT as a predictor of mid-term adverse outcomes in patients with HF with mid-range and reduced ejection fraction. Methods: Prospective single-center cohort study that included patients with HF with an ejection fraction under 50% at a specialized outpatient HF service. Patients underwent the 6MWT on admission and were compared according to the distance walked: Group I walked ≥350 meters and group II <350 meters. The primary outcome was a composite of death from any cause or hospitalization for HF decompensation in one-year follow-up. Secondary outcomes were the components of the primary outcome in an isolated analysis. Results: Sixty patients were included, 43.3% male, with a mean age of 61.1 ± 12.9 years and ejection fraction 34.3 ± 10.1%. 52 patients (86.7%) were on guideline-directed triple therapy for HF. The average distance walked in the 6MWT was 395.1 ± 98.8 meters, with 40 patients (66.7%) in group I and 20 (33.3%) in group II. The primary outcome in groups I and II were, respectively, 15,0% and 35,0% (p=0.05). One-year mortality was 5.0% vs 15.0% (p=0.18) and the hospitalization rate was 10.0% vs 20.0% (p=0.28). Conclusions: There was no association of distance <350 meters in the 6MWT with the primary outcome in patients with HF. Despite the higher occurrence of outcomes in group II, the difference was not statistically significant in this analysis. On a selective basis, the 6MWT may be a useful tool for prognostic stratification in HF, if combined with other methods.
Prognostic Impact of Acute Kidney Injury on Decompensated Heart Failure
Layane Batista, Roberto Barbosa, Caroline Carrera, Gabriella Curcio, Pietro Lima, Vinicius Astolpho, Rodolfo Sylvestre, Lucas De Barros, Renato Serpa, Osmar Calil, Luiz Fernando Barbosa
Subject: Medicine & Pharmacology, Allergology Keywords: Heart Failure; Acute Kidney Injury; Prognosis; Mortality.
Introduction: Decompensated heart failure (HF) is a complex and debilitating syndrome, which constitutes a severe emergency condition with high morbidity and mortality. The kidneys play fundamental roles in the pathophysiology of HF and, in the context of decompensations, acute kidney injury (AKI) has a bilateral cause-and-effect relationship, which can significantly worsen prognosis. However, the interaction between AKI and decompensated HF is poorly understood. Objective: This study aimed to assess the occurrence of AKI in patients hospitalized due to decompensated HF and to analyze its prognostic impact during hospitalization. Methods: Prospective single-center observational study that included patients hospitalized due to decompensated HF in a tertiary-level teaching hospital, conducted between July 2017 and January 2020. Patients who developed AKI during hospitalization were compared with those who did not develop it, until hospital discharge or death. AKI was defined as a serum creatinine increase greater than or equal to 0.3 mg/dl in 48 hours, a 1.5-fold increase in baseline creatinine in seven days or urinary volume <0.5 ml/kg/h during six hours, according to the Acute Kidney Injury Network (AKIN) criteria. The endpoints analyzed were death, need for invasive mechanical ventilation (IMV) and length of hospital stay. The Wilcoxon, Mann-Whitney and unpaired student t tests were used. Results: Ninety-nine patients were included, with a mean age of 65.4 ± 14 years, of which 47 (47.5%) were male and 52 (52.5%) were female. Reduced ejection fraction was observed in 77.8% of patients, whilst 22.2% had a diagnosis of HF with preserved EF. The decompensation clinical classifications were: dry and warm = 7 (7.1%), wet and warm = 72 (72.7%), wet and cold = 15 (15.1%) and dry and cold = 5 (5.1%). The average left ventricular ejection fraction was 38.3% ± 15. AKI ocurred in 22 patients (22.2%). Comparison between patients who evolved with and without AKI showed higher mortality (36.4% vs 10.4%, p = 0.004) and the need for IMV (54.5% vs 13%, p = 0.0001) in the first group. There was no significant difference regarding the length of in-hospital stay (22.9 ± 19 vs 18.8 ± 16 days, p = 0.26). Conclusions: The occurrence of AKI was frequent in patients with decompensated HF requiring hospitalization, affecting approximately one out of five patients. This complication was significantly associated with increased mortality and the need for IMV during hospitalization.
The Expression of RN7SL494P (7SL) Predicts Nodal Metastasis and Prognosis in Lung Adenocarcinoma
Xiao Zhu, Yongmei Huang, Hui Luo, Ying Xu
Subject: Life Sciences, Genetics Keywords: TCGA; lung adenocarcinoma; RN7SL494P; nodal metastasis; prognosis
The metastasis of lung cancer can spread to the lymph nodes around the lungs. Metastasis, rather than the primary cancer, judges patients survival. Wherefore, a more detailed study on transcriptome of metastatic lung adenocarcinoma including primary carcinoma was carried out. LUAD RNA-seq data and the corresponding clinical information were available from The Cancer Genome Atlas (TCGA), which included 522 cases but only 515 cases have transcriptome data. Differential expression analyses between cases and controls, between primary cancer and metastasis subgroup, or between TNM stages, were respectively carried out using edgeR package. Then, the Kruskal-Wallis tests were used to verify the gradient changes of cancer metastasis or staging with the differential expression genes. The survival analyses were calculated using the Kaplan-Meier algorithm and log-rank test. The functional predictions for the differentially expressed genes were porformed with the Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (GO/KEGG). Single gene set enrichment analysis (single GSEA) was run to explore the biological pathways associated with the expressions of RN7SL494P gene based on the Molecular Signatures Database (MSigDB). 406 and 439 differentially expressed genes were identified respectively in lymph node metastasis or TNM stages. 112/296 intersection genes were associated with nodal metastasis and/or staging, among them only 25 genes were associated with the nodal metastasis, 13 genes were associated with the staging with gradient changes. Only one gene (RN7SL494P) was found to be associated with prognosis. But RN7SL494P was not found joining any biological functions or processes or cellular components with GO/KEGG analyses. Finally, single GSEA enrichment and pathway analyses showed that RN7SL494P might be involving in cancer development process and poor outcome in lung adenocarcinoma. These findings highlight the potential applications of RN7SL494P as a promising molecular predictor not only in nodal metastasis but prognosis evalution in lung adenocarcinoma patients.
Prognostic Significance of EIF4G1 in Patients with Pancreatic Ductal Adenocarcinoma
Tae Sik Goh, Mihyang Ha, Jung Sub Lee, Dae Cheon Jeong, Eun Sang Jung, Myoung-Eun Han, Yun Hak Kim, Sae-Ock Oh
Subject: Medicine & Pharmacology, Oncology & Oncogenics Keywords: EIF4GI; pancreatic ductal adenocarcinoma; prognosis; GEO; TCGA
Background: The advances of genomics have greatly improved the survival rate cancer patients. However, due to genetic heterogeneity, pancreatic ductal adenocarcinoma (PDAC) is still difficult to diagnose early and the survival rate is extremely low. Therefore, we identified biomarkers that predict the prognosis of PDAC patients by using independent cohort data. Methods: To develop a novel prognostic biomarker, we used gene expression and clinical data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). In Kaplan-Meier survival curve using median values of genes as cut off, the only statistically significant gene in the three cohorts was EIF4G1. We analyzed prognostic significance of EIF4G1 using the time-dependent area under the curve (AUC) of the Uno's C-index, the AUC value of the receiver operating characteristics (ROC) at 3 years, and multivariate cox analysis. Also, we compare EIF4G1 levels between tumor and matched non-tumor. Results: EIF4G1 is the only prognostic gene patients with PDAC which was selected by Kaplan-Meier survival analysis. Kaplan-Meier survival analysis showed that high expression of EIF4G1 was associated with poor prognosis of PDAC with good discriminative ability in 3 independent cohorts. Risk stratifying ability of EIF4G1 was demonstrated by analyzing C-indices and AUC values. Multivariate cox regression analysis confirmed its prognostic significance. EIF4G1 expression was significantly higher in the PDAC tissues than in the matched normal tissues. Conclusions: Herein, the novel prognostic biomarker EIF4G1 could be used as prognostic maker for PDAC and determining suitable treatment options.
Impact of Sarcopenia as a Prognostic Biomarker of Bladder Cancer
Hiroshi Fukushima, Kosuke Takemura, Hiroaki Suzuki, Fumitaka Koga
Subject: Medicine & Pharmacology, Urology Keywords: sarcopenia; prognosis; biomarker; bladder cancer; urothelial carcinoma
Sarcopenia, the degenerative and systemic loss of skeletal muscle mass, indicates patient frailty and impaired physical function. Sarcopenia can be caused by multiple factors, including advanced age, lack of exercise, poor nutritional status, inflammatory diseases, endocrine diseases, and malignancies. Recently, growing evidence has indicated the importance of sarcopenia in the management of patients with various cancers. Sarcopenia is associated with not only higher rates of treatment-related complications but also worse prognosis in cancer-bearing patients. In this article, we conducted a systematic literature review regarding the significance of sarcopenia as a prognostic biomarker of bladder cancer. We also reviewed recent studies focusing on the prognostic role of changes in skeletal muscle mass during the course of treatment in bladder cancer patients.
A Novel Anoikis-Related Gene Signature Predicts Prognosis in Patients with Low-Grade Glioma and Reveals Immune Infiltration
Songyun Zhao, Hao Chi, Wei Ji, Qisheng He, Guichuan Lai, Gaoge Peng, Xiaoyu Zhao, Chao Cheng, Weiyi Huang
Subject: Medicine & Pharmacology, Oncology & Oncogenics Keywords: anoikis; Low-grade glioma; signature; prognosis; immune microenvironment
Low-grade glioma (LGG) is a highly aggressive disease in the skull. On the other hand, anoikis, a specific form of cell death induced by the loss of cell contact with the extracellular matrix, plays a key role in cancer metastasis. In this study,anoikis-related genes (ANRGs) were used to identify LGG subtypes and to construct a prognostic model for LGG patients. In addition, we explored the immune microenvironment and enrichment pathways between different subtypes. We constructed an anoikis-related gene signature using the TCGA cohort and investigated the differences in clinical features, mutational landscape, immune cell infiltration, etc. between different risk groups. Kaplan-Meier analysis showed that the characteristics of ANRGs in the high-risk group were associated with poor prognosis in LGG patients. The risk score was identified as an independent prognostic factor. The high-risk group had higher immune cell infiltration, tumor mutation load, immune checkpoint gene expression, and ICB treatment response. Functional analysis showed that these high- and low-risk groups had different immune statuses and drug sensitivity. Risk scores were used together with LGG clinicopathological features to construct a nomogram, and DCA analysis showed that the model could enable patients to benefit from clinical treatment strategies.
HLA-G 14bp ins/del Polymorphism, Plasma Level of Soluble HLA-G and Association with IL-6/IL-10 Ratio and Survival of Glioma Patients
Maria Bucova, Kristina Kluckova, Jan Kozak, Boris Rychly, Marian Svajdler, Viktor Matejcik, Juraj Steno, Eszter Zsemlye, Vladimíra Ďurmanová
Subject: Life Sciences, Immunology Keywords: glioma; HLA-G; IL-6; polymorphism; prognosis; survival
HLA-G is an immune checkpoint molecule with immunosuppressive and anti-inflammatory activities, and its expression and level of its soluble form (sHLA-G) may play an important role in tumor prognosis. The HLA-G 14 bp ins/del polymorphism and the plasma level of soluble HLA-G (sHLA-G) were investigated by a polymerase chain reaction and ELISA, respectively, in 59 glioma patients. A significantly higher proportion of glioma patients had the 14 nt insert in both homozygous and heterozygous states compared to the control group. Glioma patients had also higher plasma levels of sHLA-G. Patients with methylated MGMT promoter had lower levels of sHLA-G than those with unmethylated MGMT promoter. Level of sHLA-G negatively correlated with the overall survival of patients. Glioblastoma patients who survived more than one year after diagnosis had lower levels of sHLA-G than those surviving less than one year. Patients with sHLA-G levels below the cut off value 40 U/mL survived significantly longer than patients with sHLA-G above 40 U/mL. The levels of sHLA-G also negatively correlated with the level of IL-6 (P=0.0004) and positively with IL-10/IL-6 (P=0.046). Conclusion: The presence of 14 nt insert in both homozygous and heterozygous states of the HLA-G 14 bp ins/del polymorphism is more frequent in glioma patients and the elevated plasma levels of sHLA-G are negatively associated with their survival.
Challenging the Current Paradigm of Liquid Biopsy Through Dielectrophoresis (DEP) In Prostate Cancer
Giorgio I. Russo, Nicolò Musso, Alessandra Romano, Giuseppe Caruso, Salvatore Petralia, Luca Lanzanò, Giuseppe Broggi, Massimo Camarda
Subject: Life Sciences, Cell & Developmental Biology Keywords: circulating tumor cells; dielectrophoresis; prostate cancer; detection; prognosis
Liquid biopsy via isolation of circulating tumour cells (CTCs) represents a promising diagnostic tool capable of supplementing state-of-the-art for prostate cancer (PC) prognosis. Unfortunately, most of CTC technologies, such as AdnaTest or Cellsearch, critically rely on the Epithelial-Cell-Adhesion-Molecule (EpCAM) marker, limiting the possibility of detecting stem-like cells (CSCs) and mesenchymal-like cells (EMT-CTCs) that are present during PC progression. In this tontext, dielectrophoresis (DEP) is an epCAM independent, label-free, enrichment system, separating rare cells simply on the basis of their specific electrical properties. As compared to other technollgies, DEP represents a superior technique in terms of running costs, cells yield and specificity, but due to its higher complexity, requires still further technical as well as clinical development. Interestingly, DEP can be improved by the use of microfluid, nanostructured materials and fluoroimaging in order to increase its potential applications. In the context of PC, the utility of DEP can be translated in its capacity to detect CTC in the bloodstream in their epithelial, mesenchymal, or epithelial-mesenchymal phenotypes, which should be taken into account when choosing CTC enrichment and analysis methods for PC prognosis and early diagnosis.
Major Prosthetic Factors Influencing the Prognosis of Implant Prosthodontics. A Systematic Review.
Javier Montero
Subject: Medicine & Pharmacology, Allergology Keywords: Prognosis; prosthodontics; dental implant; clinical performance; risk factor.
Background: The treatment plan of prosthetic restorations supported by dental implants require comprehensive scientific knowledge to deliver prostheses with good prognosis, even before the implant insertion. This review aims to analyze the main prosthetic determinants of the prognosis of implant-supported prostheses. Methods: A systematic review of the literature was conducted with a PICO question: "For partially or complete edentulous subjects treated with implant-supported prostheses, which prosthetic factors could affect clinical outcomes?". A literature search was performed electronically in PubMed (MEDLINE), Scopus and Cochrane Library with the following equation [PROGNOS* OR RISK] FACTOR IMPLANT DENTAL, and by hand search in relevant journals and throughout the selected papers. Results: This revision was carried out based on 50 papers focused on several prosthodontics-related risk factors that were grouped as follows: implant-connection, loading protocol, transmucosal abutments, prosthetic fit, provisionalization, type of retention, impression technique, fabrication technique, and occlusion. More than a half of the studies were systematic reviews (30%), meta-analysis (16%) or prospective evaluations of prosthesis with various kinds of events (18%). But also narrative reviews of literature (14%) and in vitro/animal studies (16%) were found. Conclusions: The current literature provides insufficient evidence for most of the investigated topics. However, based on the accumulated data, it seems reasonable to defend that the best treatment approach is the use of morse taper implants with transmucosal abutments, recorded by means of rigidly splinted copings through the pick-up technique, and screwed by milled prosthesis occlusally adjusted to minimize functional overloading.
Unusual Faces of Bladder Cancer
Claudia Manini, José I. López
Subject: Medicine & Pharmacology, Allergology Keywords: Bladder cancer; diagnosis; differential diagnosis; prognosis; histopathology; immunohistochemistry
Online: 29 October 2020 (09:25:10 CET)
The overwhelming majority of bladder cancers are transitional cell carcinomas. Albeit mostly monotonous, carcinomas in the bladder may occasionally display a broad spectrum of histological features that should be recognized by pathologists because some of them represent a diagnostic problem and/or lead prognostic implications. Sometimes these features are focal in the context of conventional transitional cell carcinomas, but some others are generalized across the tumor making its recognition a challenge. For practical purposes, the review distributes the morphologic spectrum of changes in architectural and cytological. So, nested and large nested, micropapillary, myxoid stroma, small tubules and adenoma nephrogenic-like, microcystic, verrucous, and diffuse lymphoepithelioma-like, on one hand, and plasmacytoid, signet ring, basaloid-squamous, yolk-sac, trophoblastic, rhabdoid, lipid/lipoblastic, giant, clear, eosinophilic (oncocytoid), and sarcomatoid, on the other, are revisited. Key histological and immunohistochemical features useful in the differential diagnosis are mentioned. In selected cases, molecular data associated with the diagnosis, prognosis, and/or treatment are also included.
Effect of Lactate and Lactate Clearance Condition on the Prognosis of Sepsis in Children
D M Kamrul Hasan, Shafayat Hossain Evan, Md Rezaul Karim, Xin Yi Men, Zhang Huifeng, Chen Yuan
Subject: Medicine & Pharmacology, Pediatrics Keywords: Sepsis, Septic shock, Lactic acid, Dynamic monitoring, Prognosis
Online: 30 July 2020 (11:23:48 CEST)
Objectives: To investigate the value of early lactate dynamic monitoring index in predicting prognosis of patients with sepsis and septic shock. Methods: We performed our test on 50 patients. Out of 50 patients, 28 are male, and 22 are female. Prospectively studied pediatric patients with septic shock were performed. Vital signs, Lactate clearance, were obtained at presentation 6 h, 12 h, 24 h over the first 48 h of hospitalization. The therapy received, outcome parameters of mortality and duration of hospitalization were recorded. Results: The statistical data and comparative analysis showed that an average of 16.88 days after admission, 5 patients have died, 17 patients are poorly prognosis leaves the hospital, and the remaining 28 are recovered and discharged. The primary outcome variable of mean 16 days hospitalization mortality rate was 10%. Poor prognosis 34% and fully recovery 56 % were observed. In this retrospective cohort study, a lactate level of more than 2.5mmol/L was the best threshold to predict 28-day mortality among severe sepsis and septic shock patients. In our research, we found mean LC 6 h 3.08mmol/L, and after 48 h mean it is 1.79mmol/L. Significant LC 6 h found, which is 8.08mmol/L in the death group patient where 48 h mmol/L shows significant high. Poor prognosis also presents a clinical increase of lactate level high in the LC 6 h analysis, which is 3.32mmol/L. Recovered patients showed a significant improvement after administering treatment depending on the patient organ involvement and good decrease of lactate reports achieved, which is 1.20mmol/L, where admission reports show it was 1.91mmol/L in LC 6 h. Mean Heart rate 94/51mmhg, pulse 119, temperature 39℃, respiratory rate 32.26, and urine output 456 ml recorded during our study. Death patient shows a remarkable detonation of those reports but has a significant clinical report with the recovered patients. Conclusion: The early lactate dynamic monitoring index has a high value in predicting sepsis and septic shock patients' prognosis, thus worth popularizing.
Identification of Nine lncRNAs Signature for Predicting Survival Benefit of Melanoma Patients Treated with Immune Checkpoint Inhibitors
Jian-Guo Zhou, Bo Liang, Jian-Guo Liu, Su-Han Jin, Si-si He, Benjamin Frey, Ning Gu, Rainer Fietkau, Markus Hecht, Hu Ma, Udo Gaipl
Subject: Medicine & Pharmacology, Oncology & Oncogenics Keywords: lncRNA; melanoma; prognosis; immune checkpoint inhibit; WGCNA; NMF
Immune checkpoint inhibitors (ICI) have been widely used in melanoma, but to identify melanoma patients with survival benefit from ICI is still a big challenge. There is an urgent need for prognostic signatures improving the prediction of immunotherapy responses of cancer patients. We used data from EMBL-EBI database and analyzed RNA-seq information and clinical profiles in melanoma. Weighted gene co-expression network analysis (WGCNA) was used to identify the key module, then nonnegative matrix factorization (NMF) was conducted to cluster patients into two different cluster and compared them regarding overall survival (OS) and progression-free survival (PFS). Subsequently, the differentially expressed genes (DEGs) between different clusters were identified, and their function and pathway annotation were performed. 91 melanoma biopsies with complete survival information were included in our analyses and we first identified the key module (magenta) by WGCNA, then identified nine prognostic lncRNAs (ENSG00000258869, ENSG00000179840, ENSG00000206344, ENSG00000226777, ENSG00000205018, ENSG00000204261, ENSG00000163597, ENSG00000197536, and ENSG00000263069) signature that predicted for OS and PFS in patients treated with ICI by NMF. Finally, enrichment analysis showed that the functions of DEGs between two consensus clusters were mainly related to the immune process and treatment. In summary, the nine lncRNAs signature is a novel effective predictor for OS and PFS in melanoma patients treated with ICI.
Does Giant Cell Glioblastoma Have a Better Prognosis in Comparison to Glioblastoma Multiform? A Secondary Analysis of the SEER Database from 1985–2014
Amro K. Bin Abdulrahman, Yousef R. Bukhari, Abdulaziz M. Faqihi, Khalid A. Bin Abdulrahman, Juan Gabriel Ruiz
Subject: Medicine & Pharmacology, Oncology & Oncogenics Keywords: brain cancer; glioblastoma multiforme; giant cell glioblastoma; prognosis
Brain cancer is the tenth leading cause of death in the U.S. Glioblastoma multiforme (GBM) is the most lethal primary malignant central nervous system tumor in adults. The present study employed samples from 1985-2014 to discover the difference in prognosis among glioblastoma subtypes after the evolution of treatment modalities over the past few years. The current study aims to find the differences between Glioblastoma multiforme (GBM) and giant cell glioblastoma (GCG) in terms of prognosis among adults and elderly patients in the U.S. This study is a historical cohort type of study and is conducted on adults and elderly individuals with GBM or GCG from the years 1985-2014 in the U.S. Data were collected from the Surveillance, Epidemiology, and End Results Program (SEER) database. The study exposure was GBM or GCG and the outcome was mortality. The potential confounders were age, sex, race, ethnicity, year of diagnosis, primary site, and surgery. A chi-square test was used for categorical data. A univariate analysis was used for variables having a p-value < 0.05. Potential confounders were selected and evaluated using multivariate logistic regression models to calculate the odds ratio with stepwise selection. The study sample was 25,117. The incidences of GBM and GCG were not similar in relation to age group. Also, Spanish-Hispanic ethnicity was independently protective of GBM and GCG as compared to Non-Spanish-Hispanic ethnicity patients with GBM have a higher mortality rate than do GCG patients. The mortality rate was higher among patients diagnosed before 2010. In conclusion, GCG was not statistically significant in association to reduced mortality. Non-Spanish-Hispanics with GBM or GCG had a higher mortality rate than did Spanish-Hispanics. Factors such as being female, being age >59, and having a year of diagnosis before 2010 were independently associated with increased mortality.
Prognostic Impact of Visceral Fat Area Measured by Bioelectrical Impedance Analysis on Oncologic Outcomes of Colorectal Cancer
Kyeong Eui Kim, Sung Uk Bae, Woon Kyung Jeung, Seung Kyu Baek
Subject: Medicine & Pharmacology, Nutrition Keywords: colorectal neoplasm; nutrition assessment; body composition; electric impedance; prognosis
Online: 5 September 2022 (07:33:30 CEST)
Background: Some studies have shown that an increase in visceral fat is associated with postoperative clinical and oncologic outcomes. However, no studies have used bioelectrical impedance analysis (BIA) to determine the effects of visceral fat on the oncologic outcomes of colorectal cancer (CRC). This study aimed to investigate the relationship between visceral fat area (VFA) and clinical, and oncologic outcomes in CRC. Methods: This study included 203 patients who underwent anthropometric measurements by BIA before surgical treatment for CRC between January 2016 and June 2020. Results: According to the cutoff level of VFA by receiver operating characteristic curve analysis, 85 (40.5%) patients had a low VFA, and 119 (59.5%) had a high VFA. Multivariate analysis found that preoperative CRP (hazard ratio [HR], 3.882; 95% confidence interval [CI], 1.001–15.051; p=0.050) and nodal stage (HR, 7.996; 95% CI, 1.414–45.209; p=0.019) were independent prognostic factors for overall survival, while sex (HR, 0.110; 95% CI, 0.013–0.905; p=0.040), lymphovascular invasion (HR, 3.560; 95% CI, 1.098–11.544; p=0.034), and VFA (HR, 4.263; 95% CI, 1.280–14.196; p=0.040) were independent prognostic factors for disease-free survival (DFS). Conclusion: High VFA preoperatively measured by BIA was associated with inflammations and was an independent prognostic factor for DFS.
Coarsened Exact Matching of Excisional to Plasma-Ablative Ab Interno Trabeculectomy
Mohamad Dakroub, Raoul Verma-Fuehring, Alicja Strzalkowska, Jost Hillenkamp, Yousef Al Yousef, Nils A. Loewen
Subject: Medicine & Pharmacology, Ophthalmology Keywords: Glaucoma; TrabEx; Trabectome; ab-interno trabeculectomy; prognosis; intraocular pressure
Purpose: To compare ab interno trabeculectomy by trabecular meshwork excision to plasma-mediated ablation in primary open-angle glaucoma. Methods: Retrospectively collected data of TrabEx+ (TEx, n=56) and Trabectome (T, n=99) were compared by coarsened exact matching to reduce confounding and matched based on baseline IOP and age. Primary outcomes were IOP and number of glaucoma medications. Complications and need for additional glaucoma surgery were assessed. Patients were followed for up to one year. Results: 53 TEx could be matched to T. Baseline IOP was 16.5±4.6 mmHg in both; age was 73.7±8.8 and 71.5±9.9 years in TEx and T, respectively. TEx were taking more medications than T (p<0.001). IOP was reduced to 14.8±4.3 in TEx and to 13.4±3.4 in T at 6 months, and to 14.9±6.0 (p=0.13) in TEx and to 14.1±3.8 mmHg (all p<0.05) in T at 12 months. Medications were reduced at both 6 and 12 months (p< 0.05). No differences were seen between TEx and T at 6 and 12 months. In TEx, only one serious complication occurred, and two patients required further glaucoma surgery. Conclusion: Although both groups had a baseline IOP considered low for ab-interno trabeculectomy, IOP and medications were reduced further at 6 and 12 months. IOP reduction did not reach significance in TEx at 12 months. The inter-group comparison did not reveal any significant differences. Both had a low complication rate.
Fate of Surgical Patients with Small Nonfunctioning Pancreatic Neuroendocrine Tumors: An International Study Using Multi-Institutional Registries
In Woong Han, Jangho Park, Eun Young Park, So Jeong Yoon, Gang Jin, Dae Wook Hwang, Kuirong Jiang, Wooil Kwon, Xuefeng Xu, Jin Seok Heo, Delinag Fu, Woo-Jung Lee, Xueli Bai, Yoo-Seok Yoon, Yinmo Yang, Keun Soo Ahn, Chunhui Yuan, Hyeon Kook Lee, Bei Sun, Eun Kyu Park, Seung Eun Lee, Sunghwa Kang, Wen hui Lou, Sang-Jae Park
Subject: Medicine & Pharmacology, Allergology Keywords: Nonfunctioning neuroendocrine tumor of pancreas; Prognosis; Resection; Risk factors
Several treatment guidelines for sporadic, nonmetastatic nonfunctioning neuroendocrine tumors of the pancreas (NF-pNETs) have recommended resection, however, tumors ≤ 2 cm do not necessarily need surgery. This study aimed to establish a surgical treatment plan for NF-pNETs ≤ 2 cm. From 2000 to 2017, 483 patients who underwent resection for NF-pNETs ≤ 2cm in 18 institutions from Korea and China were enrolled and their medical records were reviewed. Median age was 56 (range 16- 80) years. The 10-year overall survival rate (10Y-OS) and recurrence-free survival rate (10Y-RFS) were 89.8 and 93.1%, respectively. In multivariable analysis, tumor size (> 1.5cm; p = 0.001) and nodal metastasis (p = 0.013) were independent adverse prognostic factors for OS. Perineural invasion (p = 0.008) and high Ki-67 index (≥3%; p < 0.001) were independent prognostic factors for poor RFS. NF-pNETs ≤ 2 cm showed unfavorable prognosis after resection when the tumor was larger than 1.5cm, Ki-67 index ≥ 3%, or nodal metastasis was present. NF-pNET patients with tumors ≤ 1.5cm can be observed if the preoperative Ki-67 index is under 3%, and if nodal metastasis is not suspected in preoperative radiologic studies. These findings support the clinical use to make decision about small NF-pNETs.
Clinical and Laboratory Characteristics of Kikuchi-Fujimoto Disease According to Age
Hye-Young Kim, Ha Young Jo, Seong Heon Kim
Subject: Medicine & Pharmacology, Pediatrics Keywords: Kikuchi-Fujimoto disease; histiocytic necrotizing lymphadenitis; prognosis; children; age
Background: Little information exists regarding the differences in the clinical and laboratory characteristics of Kikuchi-Fujimoto disease (KFD) according to age. Objective: To evaluate the clinical and laboratory characteristics of KFD according to age. Methods: We retrospectively evaluated patients diagnosed with KFD at Pusan National University Hospital between 2010 and 2020. Results: Eighty patients (46 children and 34 adults) with a mean age of 21.5 ± 11.8 years (range, 3–49 years) were included in the study. Among children, the male sex ratio was higher, in adults, the female sex ratio was higher. Fever, tenderness in the lymph node, and skin rashes were more common in children, while myalgia and weight loss were more common in adults. In children, the recurrence rate was significantly higher among boys than among girls (15.8% vs 0.0%, P=0.001). EBV and ANA positivity rates were higher in boys than in girls. In adults, the recurrence rate was significantly higher in women than in men (18.2% vs 0.0%, P=0.005). ANA positivity rates were higher in women than in men. Conclusion: The clinical features, laboratory findings, and recurrence of KFD may differ depending on age and sex. Clinicians should be aware of this.
Impact of Physical Activity on Recurrence Dynamics in Early Breast Cancer Patients
Elia Biganzoli, Christine Desmedt, Romano Demicheli
Subject: Medicine & Pharmacology, Allergology Keywords: early breast cancer; prognosis; physical activity; tumor dormancy; recurrence
Several studies have suggested that pre and/or postdiagnosis physical activity can reduce the risk of recurrence in breast cancer patients, however its effect according to follow-up time has not yet been investigated. We analyzed recurrence and mortality dynamics in randomized clinical trials (RCTs) from Australia and Canada. The combined Australian RCTs evaluated, at median follow-up of 8.3 years, an 8-month pragmatic exercise intervention in 337 women with newly diagnosed breast cancer, while the Canadian RCT evaluated, at median follow-up of 7.4 years, supervised aerobic or resistance exercise during chemotherapy in 242 patients. For each RCT, the control arm consisted of patients undergoing usual care. We estimated the event dynamics by the discrete hazard function, through flexible regression of yearly conditional event probabilities with generalized additive models. In the considered RCTs, the recurrence and mortality risk of patients enrolled in the physical activity arm was stably reduced at medium/long term after five year of follow-up. In the Australian RCTs where patients were recruited by urban versus rural area, the latter group did not display benefit from physical activity. Estimated Odds Ratios (95% Confidence Intervals) for Disease Free Survival (DFS) in urban women were 0.63 (0.22-1.85); 0.27 (0.079-0.90); 0.11 (0.013-0.96) at the 3rd, 5th and 7th year of follow-up, respectively. For rural women, DFS patterns were overlapping with ORs approximating 1 at the different years of follow-up. Although not reaching statistical evidence, the estimates in the Canadian trial were in line with the results from the Australian urban women with ORs (95% CI) forDFS of 0.70 (0.33-1.50); 0.47 (0.19-1.18); 0.32 (0.077-1.29) at 3rd, 5th, 7th follow-up year, respectively. While we acknowledge that the analyzed RCTs were not designed for investigating disease recurrence over time, these results support the evidence that physical activity reduces the risk of developing medium/long-term metastases. Additional translational research is needed to clarify the mechanisms underlying these observations.
Exhaustive Capture of Ovarian Cancer Transcriptional and Genomic Variant Integrating Canonical and Mapping-Free Protocols
Zhiqin Fu, Chao Lu, Chao Ding, Chengxi Zhou, Tingting Yu, Yue Yang, Liang Shi
Subject: Biology, Anatomy & Morphology Keywords: Ovarian cancer; mapping-based; mapping-free; SNVs; survival prognosis
Ovarian cancer is the most frequent cause of deaths in gynecologic malignancies. Many possible mechanisms have been proposed via RNAseq and DNAseq technique recently. However, the driving factors are still obscure. The possible reasons are attributed to the incomplete human reference. This study integrated the canonical mapping-based and mapping-free protocols to extract reliable variations and novel events. We eventually obtained 450 reliable SNVs from the WES data and novel events from the RNAseq data, including 154 SNVs, 462 intron events, two repeats and six splice events. We identified six differentially expressed genes and six contigs that are significantly related to survival prognosis. The recurrent SNVs in significantly differentially expressed genes can be validated in an independent cohort of 20 Chinese ovarian cancer patients.
Pulmonary Vesicle and Bullae Formation in Patients With COVID-19: Experiences from Wuhan
Hexiao Tang, Li Zhang, Yanhong Wei, Changsheng Li, Bo Hu, Jinping Zhao, Nahush A Mokadam, Hua Zhu, Jun Lin, Sufang Tian, Xuefeng Zhou
Subject: Keywords: Corona Virus Disease 2019; pulmonary vesicle; prognosis; surgical treatment
Background: The Corona Virus Disease 2019 (COVID-19) is spreading globally now. However, the clinical presentation that predict prognosis of the patients are still largely unknow. Methods: We enrolled 393 patients infected with COVID-19 and 30 patients with common pulmonary bulla and reviewed their clinical features to evaluate the potential prognostic value of pulmonary vesicles, especially in the patients with severe symptoms. One COVID-19 patient with vesicles was treated by bullectomy for last resort, and its characteristics of the patient's perioperative laboratory tests was analyzed. The pathological findings of bullectomy were described and compared with those of common bulla cases. Results: Patients infected with COVID-19 showed more dependence on ventilator, occurrence of super resistant bacteria, and prone to vesicle formation than common bulla (p<0.05). Disease severity is associated with age, sex, and usage of ventilator, ECMO and antibiotics, super resistance bacteria and vesicle formation (p<0.05). The average mortality rate of COVID-19 patients was 4.10% (25.4% in severe patients, 0.00% in mild patients). Interestingly, the mortality rate further increased in severe patients with pulmonary vesicles than those without pulmonary vesicles (35.7% vs 22.4%, p=0.0442). One COVID-19 patient with vesicles underwent bullectomy and had a poor prognosis, who showed diffuse alveolar damage and extensive necrosis in bullectomy specimen. Conclusions: Patients infected with COVID-19 are more prone to form pulmonary vesicles showed on chest CT scans, as an important poor prognosis factor, especially in the severe patients.
Insight into the Role and Regulation of Gap Junction Genes in Lung Cancer and Identification of Nuclear Cx43 as a Putative Biomarker of Poor Prognosis
Trond Aasen, Irene Sansano, Maria Ángeles Montero, Cleofé Romagosa, Jordi Temprana-Salvador, Alexandre Martínez-Marti, Teresa Moliné, Javier Hernández-Losa, Santiago Ramón y Cajal
Subject: Medicine & Pharmacology, Oncology & Oncogenics Keywords: connexins; Cx43; gap junctions; lung cancer; immunohistochemistry; prognosis; nuclear
Direct intercellular communication, mediated by gap junctions formed by the connexin transmembrane protein family, is frequently dysregulated in cancer. Connexins have been described as tumour suppressors, but emerging evidence suggests that they can also act as tumour promoters. This feature is connexin- and tissue-specific and may be mediated by complex signalling pathways through gap junctions or hemichannels or by completely junction-independent events. Lung cancer is the number one cancer in terms of mortality worldwide, and novel biomarkers and therapeutic targets are urgently needed. Our objective was to gain a better understanding of connexins in this setting. We used several in silico tools to analyse TCGA data in order to compare connexin mRNA expression between healthy lung tissue and lung tumours and correlated these results with gene methylation patterns. Using Kaplan-Meier plotter tools, we analysed a microarray dataset and an RNA-seq dataset of non-small cell lung tumours in order to correlate connexin expression with patient prognosis. We found that connexin mRNA expression is frequently either upregulated or downregulated in lung tumours. This correlated with both good and poor prognosis (overall survival) in a clear connexin isoform-dependent manner. These associations were strongly influenced by the histological subtype (adenocarcinoma versus squamous cell carcinoma). We present an overview of all connexins but particularly focus on four isoforms implicated in lung cancer: Cx26, Cx30.3, Cx32 and Cx43. We further analysed the protein expression and localization of Cx43 in a series of 72 human lung tumours. We identified a subset of tumours that exhibited a unique strong nuclear Cx43 expression pattern that predicted worse overall survival (p=0.014). Upon sub-stratification, the prognostic value remained highly significant in the adenocarcinoma subtype (p=0.002) but not in the squamous carcinoma subtype (p=0.578). This finding highlights the importance of analysis of connexin expression at the protein level, particularly the subcellular localization. Elucidation of the underlying pathways regulating Cx43 localization may provide for novel therapeutic opportunities.
Biomarkers for Predicting Clinical Outcomes of Chemoradiation-Based Bladder Preservation Therapy for Muscle-Invasive Bladder Cancer
Fumitaka Koga, Kosuke Takemura, Hiroshi Fukushima
Subject: Medicine & Pharmacology, Oncology & Oncogenics Keywords: biomarker; chemoradiation; prognosis; bladder preservation; bladder neoplasm; urothelial carcinoma
Chemoradiation-based bladder preservation therapy (BPT) is currently a curative option for non-metastatic muscle-invasive bladder cancer (MIBC) patients at favorable risk or an alternative to radical cystectomy (RC) for those who are unfit for RC. In BPT, only patients who achieve complete response (CR) after chemoradiation have favorable prognosis and quality of life with preserved functional bladder. Thus, predicting CR and favorable prognosis is important for optimal patient selection for BPT. We reviewed biomarkers for predicting clinical outcomes of chemoradiation-based BPT. Biomarkers studied were categorized into those related to apoptosis, cell proliferation, receptor tyrosine kinases, DNA damage response genes, hypoxia, molecular subtype, and others. Among these biomarkers, Ki-67 labeling index (Ki-67 LI) and meiotic recombination 11 may be used for selecting BPT or RC. Ki-67 LI and erythroblastic leukemia viral oncogene homolog 2 (erbB2) may be used for predicting both chemoradiation response and prognosis of patients on BPT. Concurrent use of trastuzumab and a combination of carbogen and nicotinamide can overcome chemoradiation resistance conferred by erbB2 overexpression and tumor hypoxia. Further studies are needed to confirm the practical utility of these biomarkers for progress on biomarker-directed personalized management of MIBC patients.
Estimation of ALU Repetitive Element in Plasma as a Cost-Effective Liquid Biopsy Tool for Disease Prognosis in Breast Cancer
Madhumathy G Nair, Rakesh S Ramesh, Chandrakala M, Apoorva D, Snijesh VP, Vishakha Ramamurthy, Vidya M Somashekaraiah, Anupama CE, Kiruthiga Raghunathan, Anuradha Panigrahi, Manjula Das, Sujan K. Dhar, Jyothi S Prabhu
Subject: Medicine & Pharmacology, Oncology & Oncogenics Keywords: Breast Cancer; Liquid biopsy; ctDNA; ALU 247; Disease progression; Prognosis
Background: Liquid biopsy is widely recognised as an efficient diagnostic method in oncology for disease detection and monitoring. Though examination of circulating tumor cell (CTC) is mostly implemented for assessment of genomic aberrations, need of complex methodologies for their detection has impeded its acceptance in low resource settings. We evaluated the cell free DNA (cfDNA) as a liquid biopsy tool and investigated its utility in breast cancer patients. Methods: Total cell free DNA was extracted from plasma of breast cancer patients (n=167) with median follow up of more than 5 years, at various stages of the disease. Quantitative PCR was performed to estimate the copy numbers of two fractions of ALU repetitive elements (ALU 115 and ALU 247) and DNA Integrity (DI) was calculated as the ratio of ALU 247/115. Mutations in TP53 and PIK3CA in the cfDNA was estimated by next-gen sequencing (NGS) in a subset of samples. Association of the levels of both the ALU fragments with various clinico-pathological factors and disease-free survival at various stages were examined. Nomogram models were constructed with clinical variables and ALU 247 levels to predict disease-free survival and best performing model was evaluated by decision curve analysis. Results: DI and ALU 247 levels were significantly lower (p<0.0001) in the post-operative plasma when compared to their pre-surgery levels. DI and ALU 247 were found to be significantly higher in patients with metastasis (p<0.05). Patients with higher levels of ALU 247 in their post-operative plasma had significantly poor disease-free survival (p=0.005). Higher level of ALU 247 in circulation also correlated with low tumor-infiltrating lymphocytes (TIL) within their primary tumors in the ER-negative breast cancer subtype (p=0.01). Cox proportional hazard analysis confirmed ALU 247 as an independent variable of disease-free survival both in univariate and multivariate analysis [HR 1.3 (95% CI 1.047 to 1.613, p= 0.017)]. Nomogram model showed addition of ALU 247 with other variables significantly improved (C-index-0.823) the predictive ability of the model. Conclusion: Our results confirm the utility of cfDNA as an evolving liquid biopsy tool for molecular analysis. Evaluation of larger fragment of cfDNA estimated through ALU 247 can provide vital information concurrent with the pathological process of disease evolution in breast cancer and warrants expansion to other cancer types.
Is there a Role of Warburg Effect in Prostate Cancer Aggressiveness? Analysis of Expression of Enzymes of Lipidic Metabolism by Immunohistochemistry in Prostate Cancer Patients (DIAMOND Study)
Giorgio Ivan Russo, Maria Giovanna Asmundo, Arturo Lo Giudice, Giuseppe Trefiletti, Sebastiano Cimino, Matteo Ferro, Riccardo Lombardo, Cosimo De Nunzio, Giuseppe Morgia, Eliana Piombino, Maria Failla, Rosario Caltabiano, Giuseppe Broggi
Subject: Life Sciences, Other Keywords: prostate cancer; Warburg effect; prognosis; radical prostatectomy; lipidic; metabolism; mortality
Prostate Cancer (PCa) is still ranked as the first cancer in male population and evidences have suggested an alteration of glycemic and lipidic metabolism that are related to its progression and prognosis. Aim of the study is to investigate associations between enzymes' expression, especially involved in the lipidic pathway, and PCa aggressiveness. We retrospectively analyzed data from 390 patients with PCa or benign prostatic hyperplasia (BPH) at the Department of Urology, University of Catania. Immunohistochemical slides were evaluated for the expression of proteins related to glucose and lipidic metabolism. A total of 286 were affected by PCa while 104 by BPH. We demonstrated that ATP-lyase (odds ratio [OR]: 1.71; p<0.01), fatty acide sinthase (OR: 4.82; p<0.01), carnitine palmitoyl transferase-1a (OR: 2.27; p<0.05) were associated with androgen receptor (AR) expression. We found that steaoryl Co-A desaturase expression in PCa patients with total cholesterol ≥ 200 mg/dl was independently associated with ISUP ≥4 (OR: 4.22; p=0.049). We found that CPT-1a+ was associated with biochemical recurrence (hazard ratio: 1.94; p=0.03]). Our results support the evidences that the manipulation of lipidic metabolism could serve in the future to contrast PCa progression.
Prognostic Value of Resistance Proteins in Plasma Cells From Multiple Myeloma Patients Treated With Bortezomib
Pawel Robak, J.; Szemraj, D.; Mikulski, I.; Drozdz, K; Juszczak, D. Jarych, W.; Robak, K; Kościelny, W.; Fendler, T.; Robak
Subject: Medicine & Pharmacology, Oncology & Oncogenics Keywords: bortezomib; cMAF; MAFb; multiple myeloma; POMP; prognosis; PFS; survival; OS
While multiple myeloma (MM) treatment with proteasome inhibitors and other agents yields encouraging results, primary and secondary resistance remains an emerging problem. An important factor in such treatment resistance is the overexpression of several proteins. The present study comprehensively evaluates the expression of POMP, PSMB5, NRF2, XBP1, cMAF and MAFb proteins in plasma cells isolated from the bone marrow of 39 MM patients treated with bortezomib-based regimens using enzyme-linked immunosorbent assay (ELISA). The proteins were selected on the basis of previous laboratory and clinical studies in bortezomib treated MM patients. It was found that the expression of the investigated proteins did not significantly differ between bortezomib-sensitive and bortezomib-refractory patients. However, the expression of some proteins correlated with overall survival (OS); this was significantly shorter in patients with higher POMP expression (HR 2.8, 95% CI: 1.1-7.0, p = 0.0277) and longer in those with higher MAFB expression (HR 0.32, 95% CI: 0.13-0.80, p = 0.0147). Our results indicate that high expression of POMP and MAFB in MM plasma cells may serve as predictors of OS in MM patients treated with bortezomib-based regimens. However, further studies are needed to determine the role of these factors in effective strategies for improving anti-myeloma therapy.
Prognostic Impact of Immunoglobulin Kappa C (IGKC) In Early Breast Cancer
Marcus Schmidt, Karolina Edlund, Jan G Hengstler, Anne-Sophie Heimes, Katrin Almstedt, Antje Lebrecht, Slavomir Krajnak, Marco J. Battista, Walburgis Brenner, Annette Hasenburg, Jörg Rahnenführer, Mathias Gehrmann, Pirkko-Liisa Kellokumpu-Lehtinen, Ralph M Wirtz, Heikki Joensuu
Subject: Medicine & Pharmacology, Allergology Keywords: triple-negative breast cancer; prognosis; immune system; immunoglobulin kappa C
We studied the prognostic impact of tumor immunoglobulin kappa C (IGKC) mRNA expression as a marker of the humoral immune system in the FinHer trial patient population, where 1,010 patients with early breast cancer were randomly allocated to either docetaxel-containing or vinorelbine-containing adjuvant chemotherapy. HER2-positive patients were additionally allocated to either trastuzumab or no trastuzumab. Hormone receptor-positive patients received tamoxifen. IGKC was evaluated in 909 tumors using quantitative real-time polymerase chain reaction, and the influence on distant disease-free survival (DDFS) was examined using univariable and multivariable Cox regression and Kaplan-Meier estimates. Interactions were analyzed using Cox regression. IGKC expression, included as continuous variable, was independently associated with DDFS in a multivariable analysis including also age, molecular subtype, grade, and pT and pN stage (HR 0.930, 95% CI 0.870 – 0.995, P = 0.034). An independent association with DDFS was also found in a subset analysis of triple-negative breast cancers (TNBC) (HR 0.843, 95% CI 0.724 – 0.983, P = 0.029), but not in luminal (HR 0.957, 95% CI 0.867 – 1.056, P = 0.383) or HER2-positive (HR 0.933, 95% CI 0.826 – 1.055, P = 0.271) cancers. No significant interaction between IGKC and chemotherapy or trastuzumab administration was detected (Pinteraction = 0.855 and 0.684, respectively). These results show that humoral immunity beneficially influences the DDFS of patients with early TNBC.
Quantitative Imaging and Radiomics in Multiple Myeloma: opportunity or hype?
Alberto Stefano Tagliafico, Alida Dominietto, Liliana Belgioia, Cristina Campi, Daniela Schenone, Michele Piana
Subject: Medicine & Pharmacology, Oncology & Oncogenics Keywords: multiple myeloma; computed tomography; artificial intelligence; radiomics; prognosis; imaging; diagnosis
Multiple Myeloma (MM) is the second most common type of hematological disease and, although it is rare among patients under 40 years of age, its incidence rises in elderly subject. MM manifestations are usually known with the abbreviation CRAB (hyperCalcemia, Renal failure, Anaemia, and lytic Bone lesions). In particular, the extent of the bone disease is negatively related to a decreased patients' quality of life and, in general, bone disease in MM increases both morbidity and mortality. The detection of lytic bone lesions on imaging, especially CT and MRI, is becoming crucial from the clinical viewpoint to separate asymptomatic from symptomatic MM patients and the detection of focal lytic lesion in these imaging data is becoming relevant even when no clinical symptoms are present. Therefore, radiology is pivotal in the staging and accurate management of patients with MM even in early phases of the disease. In this review we describe the opportunities offered by quantitative imaging and radiomics in multiple myeloma. At present time there is still high variability in the choice between various imaging methods to study MM patients and high variability in image interpretation with suboptimal agreement among readers even in tertiary centres. Therefore, the potential of medical imaging for patients affected by MM is still to be completely unveiled. In the next years, new insights to study MM with medical imaging will derive from artificial intelligence (AI) and radiomics usage in different bone lesions and from the wide implementations of quantitative methods to report CT and MRI. Eventually, medical imaging data can be integrated with the patient's outcomes with the purpose to find radiological biomarkers for predicting the disease prognostic flow and its therapeutic response.
Relationship between Dietary Fiber Intake and the Prognosis of Amyotrophic Lateral Sclerosis
Haelim Yu, Seung Hyun Kim, Min-Young Noh, Sang-Gon Lee, Yongsoon Park
Subject: Life Sciences, Biochemistry Keywords: Amyotrophic lateral sclerosis; dietary fiber; gut microbiota; prognosis; vegetable fiber
The gut microbiota has been suggested as an important factor in the pathogenic mechanisms of amyotrophic lateral sclerosis (ALS). This study aimed to investigate whether the intake of different kinds of dietary fiber was related to the disease progression rate (∆FS) and survival time. In total, 272 sporadic ALS patients diagnosed according to the revised EI Escorial criteria were recruited from March 2011 and were followed-up until the occurrence of events or the end of September 2020. The events included percutaneous endoscopic gastrostomy, tracheostomy, and death. Dietary fiber intake was calculated based on a 24-hour dietary recall and classified according to five major fiber-rich foods: vegetables, fruits, grains, legumes, and nuts/seeds. Among the total participants, the group with ∆FS values lower than the mean ∆FS (0.75) was noted in the highest tertiles of total and vegetable fiber intake. Participants with the highest tertile of vegetable fiber intake showed longer survival in the Kaplan–Meier analysis (p = 0.033). Notably, vegetable fiber intake was negatively correlated with pro-inflammatory cytokine (interleukin [IL]-1β, IL-6, and monocyte chemoattractant protein-1) levels in the cerebrospinal fluid. This study showed that vegetable fiber intake could influence the disease progression rate and survival time. Further clinical trials are needed to confirm whether dietary fiber supplementation improves the prognosis of ALS.
Non-Coding RNAs: Uncharted Mediators of Thyroid Cancer Pathogenesis
Hossein Tabatabaeian, Samantha Yang Peiling, Yvonne Tay
Subject: Medicine & Pharmacology, Oncology & Oncogenics Keywords: Thyroid carcinoma; non-coding RNA; radioactive iodine; drug resistance; prognosis
Thyroid cancer is the most prevalent malignancy of the endocrine system and the ninth most common cancer globally. Despite the advances in the management of thyroid cancer, there are critical issues with the diagnosis and treatment of thyroid cancer that result in the poor overall survival of undifferentiated and metastatic thyroid cancer patients. Recent studies have revealed the role of different non-coding RNAs (ncRNAs), such as microRNAs (miRNAs), long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs) that are dysregulated during thyroid cancer development or the acquisition of resistance to therapeutics, and may play key roles in treatment failure and poor prognosis of the thyroid cancer patients. Here, we systematically review the emerging roles and molecular mechanisms of ncRNAs that regulate thyroid tumorigenesis and drug response. We then propose the potential clinical implications of ncRNAs as novel diagnostic and prognostic biomarkers for thyroid cancer.
Altered Spatial Composition of the Immune Cell Repertoire in the Bone Marrow Stem Cell Niche in Myelodysplastic Syndromes and Secondary Acute Myeloid Leukemia
Marcus Bauer, Christoforos Vaxevanis, Haifa Kathrin Al-Ali, Nadja Jaekel, Christin Le Hoa Naumann, Judith Schaffrath, Achim Rau, Barbara Seliger, Claudia Wickenhauser
Subject: Medicine & Pharmacology, Pathology & Pathobiology Keywords: MDS; immune cell repertoire; prognosis; multiplex immunohistochemistry; stem cell niche
Purpose: Myelodysplastic syndromes (MDS) are caused by a stem cell failure, but the relationship between immune dysregulation and the course of disease has not yet been analyzed in detail. Experimental design: To get insights into the pathophysiologic and clinical relevance of the histotopography of immune cell subpopulations in this process, the immune cell infiltrate with focus on its spatial distribution was determined by multispectral imaging (MSI) in 147 bone marrow biopsies from MDS or secondary acute myeloid leukemia (sAML) patients and healthy controls (HC). In addition, the data were correlated to genetic alterations and clinical features of these patients including therapy response. Results: A high inter-tumoral heterogeneity in the frequency and spatial distribution of CD3+CD8+, CD3+CD8-, CD3+FOXP3+ T cell subsets, MUM1p+CD3- post-germinal B/plasma cells and CD34+ blasts was found in MDS and sAML samples. In HC only few B cells/plasma cells, but no T cell subpopulations were detected in the proximity to CD34+ blasts. In contrast, the frequency of these lymphocytes was increased in proximity to CD34+ blasts in both MDS and sAML independent of the karyotype, genetic alterations frequently detected in MDS, clinical risk stratification systems or treatment response to hypomethylating agents. Furthermore, an increased frequency of CD3+CD8+ T cells and MUM1p+ CD3- B cells was found in responders to epigenetic drugs. Conclusions: Thus, we conclude that (i) T cell subsets do not belong to the normal stem cell niche, (ii) the presence of T and B cell subpopulations not directly affect the course of MDS, (iii) lymphocytes in the proximity to CD34+ blasts might indicate defective stem cell properties and (iv) the number of lymphocytes is a predictor of therapy response to hypomethylating agents.
Impact of Gross Strap Muscle Invasion on Outcome of Differentiated Thyroid Cancer: Systematic Review and Meta-Analysis
Li Zhang, Jia Liu, Peisong Wang, Shuai Xue, Jie Li, Guang Chen
Subject: Life Sciences, Other Keywords: strap muscle invasion; prognosis; differentiated thyroid carcinoma; meta-analysis; review
Gross strap muscle invasion (gSMI) in patients with differentiated thyroid cancer (DTC) was defined as high-risk recurrent group in the 2015 American Thyroid Association guidelines. However, controversy persists because several studies suggested gSMI had little effect on disease outcome. Herein, a systematic review and meta-analysis was conducted to investigate impact of gSMI on outcome of DTC. Methods: A systematic search of electronic databases (PubMed, EMBASE, Cochrane Library, and MEDLINE) for studies published until February 2020 was performed. Case-control studies and randomized controlled trials that studied the impact of gSMI on outcome of DTC were included. Results: Six studies (all retrospective studies) involving 13639 patients met final inclusion criteria. Compared with no extrathyroidal extension (ETE), patients with gSMI were associated with increased risk of recurrence (P=0.0004,OR, 1.46; 95% CI: 1.18 to 1.80) and lymph node metastasis (LNM) (P<0.00001,OR 4.19;95% CI. 2.53 to 6.96). For mortality (P=0.34,OR 1.47;95% CI:0.67 to 3.25), ten-year disease-specific survival (P=0.80, OR 0.91;95% CI:0.44 to 1.88) and distant metastasis (DM) (P=0.21, OR 2.94;95% CI. 0.54 to 15.93), there was no significant difference between gSMI and no ETE group. In contrast with maximal ETE, patients with gSMI were associated with decreased risk of recurrence (P<0.0001,OR, 0.58; 95% CI: 0.44 to 0.76) , mortality (P=0.0003,OR 0.20;95% CI:0.08 to 0.48), LNM (P=0.0003,OR 0.64;95% CI. 0.50 to 0.81) and DM (P=0.0009,OR 0.28;95% CI. 0.13 to 0.59). Conclusions: DTC patients with gSMI had a higher risk of recurrence and LNM than those without ETE. However, in contrast with maximal ETE, a much better prognosis was observed in DTC patients with only gSMI. The findings of our meta-analysis provide supportive evidence for the validity of the T category changes in the 8th edition American Joint Committee on Cancer system. The actual impact of gSMI should be re-evaluated and revised in the recurrent risk stratification system in the future.
Forecasting the Bladder Tumor Size and Immune Response of a Patient Over the Time Using a Dynamic Mathematical Model
Clara Burgos, Noemí García-Medina, David Martínez-Rodríguez, José-Luis Pontones, David Ramos, Rafael-J. Villanueva
Subject: Medicine & Pharmacology, Oncology & Oncogenics Keywords: bladder cancer; dynamic model; uncertainty quantification; model calibration; cancer prognosis
Bladder cancer is one of the most common malignant diseases in the urinary system and a highly aggressive neoplasm. The prognosis is not favourable usually and its evolution for particular patients is very difficult to find out. In this paper we propose a dynamic mathematical model that describes the bladder tumor growth and the immune response evolution. This model is customized for a single patient, determining appropriate model parameter values via model calibration. Due to the uncertainty of the tumor evolution, using the calibrated model parameters, we predict the tumor size and the immune response evolution over the next few months assuming three different scenarios: favourable, neutral and unfavourable. In the former, the cancer disappears; in the second a 5mm tumor is expected around the middle of August 2018; in the worst scenario, a 5mm tumor is expected around the end of May 2018. The patient has been cited around June 15th, 2018, to check the tumor size, if it exists.
The Significance of mRNA in the Biology of Multiple Myeloma and Its Clinical Implications
Anna Puła, Paweł Robak, Damian Mikulski, Tadeusz Robak
Subject: Medicine & Pharmacology, Oncology & Oncogenics Keywords: biology; drug resistance; gene expression profiling; mRNA; multiple myeloma; prognosis; treatment
Multiple myeloma (MM) is a genetically complex disease that results from a multistep transformation of normal to malignant plasma cells in the bone marrow. However, the molecular mechanisms responsible for the initiation and heterogeneous evolution of MM remain largely unknown. A fundamental step needed to understand the oncogenesis of MM and its response to therapy is the identification of driver mutations. The introduction of gene expression profiling (GEP) in MM was an important step in elucidating the molecular heterogeneity of MM and its clinical relevance. Since some mutations in myeloma occur in non-coding regions, studies based on the analysis of mRNA provide more comprehensive information on the oncogenic pathways and mechanisms relevant to MM biology. In this review, we discuss the role of gene expression profiling in understanding the biology of multiple myeloma together with the clinical manifestation of the disease, as well as its impact on treatment decisions and future directions.
A Novel Approach for Early detection of Alzheimer's disease Based on Multi Level Fuzzy Neural Networks
Hamid Akramifard, MohammadAli Balafar, SeyedNaser Razavi, Abd Rahman Ramli
Subject: Behavioral Sciences, Applied Psychology Keywords: Alzheimer's disease; classification; early detection; Multi-Level Fuzzy Neural Networks; prognosis
Online: 29 March 2021 (17:09:46 CEST)
Timely diagnosis of Alzheimer's diseases(AD) is crucial to obtain more practical treatments. In this paper, a novel approach Based on Multi-Level Fuzzy Neural Networks (MLFNN) for early detection of AD is proposed. The focus of study was on the problem of diagnosing AD and MCI patients from healthy people using MLFNN and selecting the best feature(s) and most compatible classification algorithm. In this way, we achieve an excellent performance using only a single feature i.e. MMSE score, by fitting the optimum algorithm to the best area using optimum possible feature(s) namely one feature for a real life problem. It can be said, the proposed method is a discovery that help patients and healthy people get rid of painful and time consuming experiments. Experiments shows the effectiveness of proposed method in current research for diagnosis of AD with one of the highest performance (accuracy rates of 96.6%), ever reported in the literature.
Detection of Rare Germline Variants in the Genomes of B Cell Neoplasms
Adrian Mosquera Orgueira, Miguel Cid Lopez, Andres Peleteiro Raindo, Jose Angel Diaz Arias, Beatriz Antelo Rodriguez, Laura Bao Perez, Natalia Alonso Vence, Angeles Bendaña Lopez, Aitor Abuin Blanco, Paula Melero Valentin, Roi Ferreiro Ferro, Carlos Aliste Santos, Maximo Francisco Fraga Martinez, Marta Sonia Gonzalez Perez, Manuel Mateo Perez Encinas, Jose Luis Bello Lopez
Subject: Medicine & Pharmacology, Allergology Keywords: germline; rare variant; cancer; lymphoid; B-cell; lymphomal; CLL; driver; prognosis
Growing evidence has revealed the implication of germline variation in cancer predisposition and prognostication. Here, we describe an analysis of putatively disruptive rare variants across the genomes of 726 patients with B-cell lymphoid neoplasms. We discovered a significant enrichment of 26 genes in germline protein truncating variants (PTVs), affecting cell signaling (MET, JAK2, ANGPT2), energy metabolism (ACO1) and nucleic acid metabolism and repair pathways (NT5E, DCK). Interestingly, some of these variants were restricted to either chronic lymphocytic leukemia (CLL) (i.e., ANGPT2 and AKR1C3) or B-cell lymphoma cases (PNMT, TPT1 and IGHMBP2). Additionally, we detected 1,675 likely disrupting variants in genes associated with cancer, of which 44.75% were novel events and 7.88% were PTVs. Among these, the most frequently affected genes were ATM, BIRC6, CLTCL1A and TSC2. Homozygous or compound heterozygous variants were detected in 28 cases; and coexisting somatic events were observed in 17 patients, some of which affected key lymphoma drivers such as ATM, KMT2D and MYC. Finally, we observed that variants in the helicase gene WRN were independently associated with shorter survival in CLL. Our study results support an important role for rare germline variation in the pathogenesis, clinical presentation and disease outcome of B-cell lymphoid neoplasms.
Environmental Impact of Subsidy Concepts to Stimulate Car Sales in Germany
Malte Scharf, Ludger Heide, Alexander Grahle, Anne Syré, Dietmar Göhlich
Subject: Engineering, Automotive Engineering Keywords: subsidy; automotive industry; prognosis; COVID-19; environmental impact; life cycle analysis
This paper establishes a prognosis of the long term environmental impact of various car subsidy concepts. The CO2 emissions of the German car fleet impacted by the purchase subsidies are determined. A balance model of the CO2 emissions of the whole car life cycle is developed. Consideration of production-, use- and End-of-Life processes are taken into account. The implementation of different subsidy scenarios directly affects the forecasted composition of the vehicle population and therefore the resulting life cycle assessment. All scenarios compensate the additional emissions required by the production pull-in within the considered period and hence reduce the accumulated CO2 emissions until 2030. The exclusive funding of BEVs is most effective with a break-even in 2025.
Expression of Intestinal Stem Cell and Cancer Stem Cell Markers in Submucosal Invasion and Its Prognostic Significance in Gastric Cancers
Hye Sung Kim, Hyun Joo Song, In Ho Jeong, Bo Gun Jang
Subject: Medicine & Pharmacology, Pathology & Pathobiology Keywords: Gastric cancer; Submucosal invasion; Intestinal stem cell; Cancer stem cell; Prognosis
Submucosal invasion is a critical step in gastric cancer (GC) progression, which greatly enhances metastasis risk. Cancer stem cells are responsible for invasion, metastasis, and tumor growth. To identify stem cell-related markers associated with submucosal invasion in GCs, we investigated the expression of candidate cancer stem cell (CSC) markers (CD133, CD44, and ALDH1A) and intestinal stem cell (ISC) markers (EPHB2, OLFM4, and LGR5) in early GCs with submucosal invasion. Remarkably, expression of all ISC markers and CD133 was frequently confined to the basal area of the lamina propria (basal pattern) in mucosal cancer. The proportion of stem cell marker-positive cells substantially increased during submucosal invasion. Given that ISC markers are restricted to the crypt base of the normal intestinal mucosa, these findings suggest that many early GCs may retain hierarchical characteristics. CD44 expression showed a focal pattern, ALDH1A was predominantly expressed diffusely, and there was no expansion of CD44 or ALDH1A expression in the submucosal cancer cells. RSPO2 from muscularis mucosa seem to be partly responsible for the increased expression of ISC markers in GC cells at the basal areas. We also found that ISC markers were correlated with CDX2 expression in GCs, indicating that ISC markers are involved in the intestinal differentiation in GCs. Interestingly, ISC markers (EPHB2 and OLFM4) and CD133 showed a positive impact on clinical outcomes. In particular, the prognostic value of EPHB2 was significant for intestinal-type GCs in a multivariate analysis. In summary, ISC markers and CD133 showed a basal distribution pattern along with enhanced expression in submucosal invading cells in early GCs. EPHB2 was an independent prognostic marker in intestinal-type GCs.
The Hidden Story on Heterogeneous B-raf V600E Mutation Quantitative Protein Expression in Metastatic Melanoma – Association with Clinical Outcome and Tumor Phenotypes
Lazaro Hiram Betancourt, A. Marcell Szasz, Magdalena Kuras, Jimmy Rodriguez Murillo, Yutaka Sugihara, Indira Pla, Zsolt Horvath, Krzysztof Pawlowski, Melinda Rezeli, Kenichi Miharada, Jeovanis Gil, Jonatan Eriksson, Roger Appelqvist, Tasso Militois, Bo Baldetorp, Christian Ingvar, Håkan Olsson, Lotta Lundgren, Peter Horvatovich, Charlotte Welinder, Elisabet Wieslander, Ho Jeong Kwon, Johan Malm, Istvan Balazs Nemeth, Göran Jönsson, David Fenyo, Aniel Sanchez, György Marko-Varga
Subject: Medicine & Pharmacology, Oncology & Oncogenics Keywords: malignant melanoma; BRAF V600E mutation; proteomics; mass spectrometry genetics; heterogeneity; prognosis
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In comparison to other human cancer types, malignant melanoma exhibits the greatest amount of heterogeneity. After DNA-based detection of the BRAF V600E mutation in melanoma patients, targeted inhibitor treatment is the current recommendation. This approach, however, does not take the abundance of the therapeutic target, i.e., the B-raf V600E protein, into consideration. As shown by immunohistochemistry, the protein expression profiles of metastatic melanomas do clearly reveal the existence of inter- and intra-tumor variability. Nevertheless, the technique is only semi-quantitative. To quantitate the mutant protein there is a fundamental need for more precise techniques that are aimed at defining the currently non-existent link between the levels of the target protein and subsequent drug efficacy. Using cutting-edge mass spectrometry combined with DNA and mRNA sequencing, the mutated B-raf protein within metastatic tumors was quantitated for the first time. B-raf V600E protein analysis revealed a subjacent layer of heterogeneity for mutation-positive metastatic melanomas. These were characterized into two distinct groups with different tumor morphologies, protein profiles and patient clinical outcomes. This study provides evidence that a higher level of expression for the mutated protein is associated with a more aggressive tumor progression. Our study design that is comprised of surgical isolation of tumors, histopathological characterization, tissue biobanking, and protein analysis may enable the eventual delineation of patient responders/non-responders and the subsequent therapy of malignant melanoma.
Risk Stratification on Pheochromocytoma and Paraganglioma from Laboratory and Clinical Medicine
Noriko Kimura, Kazuhiro Takekoshi, Mitsuhide Naruse
Subject: Medicine & Pharmacology, Pathology & Pathobiology Keywords: pheochromocytoma; paraganglioma; GAPP; metastasis; prognosis; catecholamine; gene mutation; immunohistochemistry; pathology; diagnosis
Pheochromocytoma and sympathetic paraganglioma (PPGL) are rare neuroendocrine tumors characterized by catecholamine production in the adrenal medulla and extra-adrenal paraganglia. PPGL with metastasis was termed malignant PPGL. However, the distinction between "benign" and "malignant" PPGLs has been debated. Currently, all PPGLs are believed to have some metastatic potential and are assigned malignant tumors (ICD-O/3) by the WHO Classification of Endocrine Organs (2017, 4th edition). Therefore, the previous categories benign and malignant PPGL have been eliminated in favor of a risk stratification approach. The Grading of Adrenal Pheochromocytoma and Paraganglioma (GAPP) is a tool for risk stratification for predicting metastasis and the prognosis of patients. At least 30% of PPGLs are hereditary, with 20 genes identified and genotype-phenotype correlations clarified. Of these, VHL, RET, and NF1 have been well investigated and are the primary cause of bilateral PCC. In addition, succinate dehydrogenase gene subunits SDHB and SDHD are strongly correlated with extra-adrenal location, younger age, multiple tumors, metastasis, and poor prognosis. Disease stratification by catecholamine phenotype and molecular profiling correlates with histological grading by GAPP. PPGLs should be understood comprehensively based on clinical, biochemical, molecular, and pathological data for patient care. A flow chart for pathological diagnosis is included.
Evaluation of Baseline Characteristics and Prognostic Factors in Multisystemic Inflammatory Syndrome in Children: Is It Possible to Foresee the Prognosis in the First Step?
Benhur Sirvan Cetin, Ayşenur Paç Kısaarslan, Sedanur Tekin, Merve Basol Goksuluk, Ali Baykan, Başak Nur Akyıldız, Yılmaz Seçilmiş, Hakan Poyrazoglu
Subject: Medicine & Pharmacology, Pediatrics Keywords: COVID-19; multisystem inflammatory syndrome in children (MIS-C); risk classification; prognosis
Background: Two years after the first cases, critical gaps remain in identifying prognostic factors in multisystem inflammatory syndrome in children (MIS-C). Methods: This retrospective study included 99 patients with MIS-C hospitalized between August 2020 and March 2022 in a pediatric tertiary center. The patients were divided into two groups according to clinical severity (low and high-risk). Prognostic values of baseline clinical and laboratory characteristics were evaluated with advanced statistical analysis, including machine learning. Results: Sixty-three patients were male, and the median age was 83 (3–205) months. Fifty-nine patients (%59.6) were low-risk cases. Patients aged six years and over tended to be at higher risk. Involvement of aortic or tricuspid valve or >1 valve was more frequent in the high-risk group. Mortality in previously healthy children was 3.2%. Intensive care unit admission and mortality rate in the high-risk group were 37.5% and 7.5%, respectively. At admission, high-risk patients were more likely to have reduced lymphocyte count and total protein level and increased brain natriuretic peptide (BNP), ferritin, D-dimer, and troponin concentrations. The multiple logistic regression model showed that BNP, total protein, and troponin were associated with higher risk. When the laboratory parameters were used together, BNP, total protein, ferritin, and D-dimer provided the highest contribution to the discrimination of the risk groups (100%, 89.6%, 85.6%, and 55.8%, respectively). Conclusions: Our study widely evaluates and points to some clinical and laboratory parameters that, at admission, may indicate a more severe course. Modeling studies with larger sample groups are strongly needed.
ColoSTEM Dx Kit: Innovative Alliance of Cancer Stem Cells and Glycosylation for Earlier Prediction of Colon Cancer Aggressiveness and Prognosis
Sabrina Blondy, Stéphanie Durand, Aurélie Lacroix, Niki Christou, Charline Bouchaud, Maud Peyny, Serge Battu, Alain Chaunavel, Vincent Carre, Marie-Odile Jauberteau, Fabrice Lalloue, Muriel Mathonnet
Subject: Medicine & Pharmacology, Oncology & Oncogenics Keywords: Aggressiveness; biomarker; cancer stem cells; diagnosis; colon cancer; glycan; immunohistochemistry; lectin; prognosis
Nowadays, colon cancer prognosis still difficult to predict, especially in the early stages. Recurrences remain elevated, even in the early stages after curative surgery. Carcidiag Biotechnologies has developed an immunohistochemistry (IHC) kit called ColoSTEM Dx, based on a MIX of biotinylated plant lectins that specifically detects colon cancer stem cells (CSCs) through glycan patterns that they specifically (over)express. A retrospective clinical study was carried out on tumor tissues from 208 non-treated and 21 treated patients with colon cancer, that were stained by IHC with the MIX. Clinical performances of the kit were determined, and prognostic and predictive values were evaluated. With 78.3% and 70.6% of diagnostic sensitivity and specificity respectively, our kit shows great clinical performances. Moreover, patient prognosis is significantly poorer when the MIX staining is "High" compared to "Low", especially at 5-years of overall survival and for early stages. The ColoSTEM Dx kit allows an earlier and a more precise determination of patients' outcome. Thus, it affords an innovating clinical tool for predicting tumor aggressiveness earlier and determining prognosis value regarding therapeutic response in colon cancer patients.
Liquid Biopsies in Epilepsy: Biomarkers for Etiology, Diagnosis, Prognosis, and Therapeutics
Jordan H. Whitlock, Tabea M. Soelter, Avery S. Williams, Andrew A. Hardigan, Brittany N. Lasseigne
Subject: Keywords: liquid biopsy; epilepsy; circulating biomarkers; cfDNA; lncRNA; tRNA; miRNA; diagnosis; prognosis; therapeutics
Epilepsy is one of the most common disorders of the central nervous system, impacting nearly 50 million people around the world. Heterogeneous in nature, epilepsy presents in children and adults alike. Currently, surgery is the only treatment that can cure epilepsy. However, not all individuals are eligible or have successful outcomes. Difficulty in accessing samples of human brain tissue along with advances in sequencing technology have driven researchers to investigate sampling liquid biopsies in blood, serum, plasma, and cerebrospinal fluid within the context of epilepsy. Liquid biopsies provide minimal or non-invasive sample collection approaches and can be assayed relatively easily across multiple time points, unlike tissue-based sampling. Various efforts have investigated circulating nucleic acids from these samples including microRNAs, cell-free DNA, transfer RNAs, and long non-coding RNAs. Here, we review nucleic acid-based liquid biopsies in epilepsy to improve understanding of etiology, diagnosis, prediction, and therapeutic monitoring.
Prognostic Significance of CKS2 and CD47 Expression in Patients With Gastric Cancer Who Underwent Radical Gastrectomy
Yang zhou, Jing zeng, Haoran zhuang, wei zhou, keyan wu, weigan shen
Subject: Life Sciences, Biochemistry Keywords: Gastric cancer; Cyclin-dependent protein kinase; Cluster of differentiation (CD) 47; Prognosis
Objective: To investigate the protein expression levels of cyclin‑dependent kinase subunit 2 (CKS2) and cluster of differentiation (CD) 47 in gastric cancer (GC) and their clinical significances. Methods: A total of 126 GC patients who underwent radical resection were selected as study subjects. Additionally, 32 patients with benign gastric tumor, 42 patients with low-grade intraepithelial neoplasia (LGIEN), and 49 patients with high-grade intraepithelial neoplasia (HGIEN) who underwent surgery were selected as the control groups. Immunohistochemistry was used to detect the expression of CKS2 and CD47 in surgical specimens. We statistically analyzed the clinical significance of the expression of the two factors. Results: (1) The positivity rates for CKS2 in benign gastric tumor tissue, LGIEN tissue, HGIEN tissue, and GC tissue gradually increased, i.e., 6.3% (2/32), 30.9% (13/42), 38.8% (19/49), and 60.3% (76/126), respectively, and the positivity rates for CD47 were 18.8% (6/32), 38.1% (16/42), 46.9% (23/49), and 65.9% (83/126), respectively. (2) High expression of CKS2 and CD47 were associated with tumor diameter, Lauren classification, number of lymph node metastases, and TNM stage. In addition, the immunohistochemical scores for CKS2 and CD47 were positively correlated (r=0.625, P=0.000). (3) The median follow-up time of 126 patients was 46.5 months, and the overall survival rate was 40.5% (51/126). Survival analysis showed that compared with that in the CKS2 (-) group, the overall survival rate for patients in the CKS2 (+) group was significantly worse (25.0% vs 64.0%, 2=15.67, P=0.000) and that compared with the CD47 (-) group, the CD47 (+) group had significantly worse overall survival (30.1% vs 60.5%, 2=15.67, P=0.000). (4) The overall survival rates of CKS2(+)CD47(+) group, CKS2(+)CD47(-) group, CKS2(-)CD47(+) group, and CKS2 (-)CD47 (-) group were 20.0%(13/65), 58.3%(7/12), 57.1%(8/14), 65.7% (23/35), respectively, the prognosis of patients in CKS2(+)CD47(+) group was significantly poor. Conclusion: High expression levels of CKS2 and CD47 were closely related to the occurrence of GC and can be used as independent risk factors to assess the prognosis of patients.
Controlling Nutritional Status (CONUT) Score is a Prognostic Indicator for Patients with Hemorrhagic Stroke: Results from a 3-month Follow-up Study
Bei-lei Zhu, Yan-zhi Wu, Zhong-ming Cai, Cheng-wei Liao, Le-qiu Sun, Zhi-peng Liu, Hao-man Chen, Xue-rong Huang, Ren-qian Feng, Sheng-lie Ye, Qun-li Lin, Xu-dong Zhou, Man-man Zhang, Bo Yang
Subject: Medicine & Pharmacology, Allergology Keywords: Controlling Nutritional Status Score; Hemorrhagic stroke; Nutrition screening; Prognosis; Modified Rankin Scale
Controlling Nutritional Status (CONUT) Score is useful for the nutritional screening. We aimed to explore whether the CONUT score may predict a 3-month functional outcome in hemorrhagic stroke (AHS). Totally, 349 patients with incident AHS were consecutively recruited, and their malnutrition risks were determined using a high CONUT score of ≥ 2. Poor functional outcomes were defined as the modified Rankin Scale (mRS) score of ≥ 3 at 3 months. A total of 328 patients (mean age, 60.4 ± 12.83 years; 66.8% male) were included, 172 (52.40%) patients at malnutrition risk and 104 (31.7%) patients with a poor prognosis. High-CONUT patients had lower total lymphocyte counts and total cholesterol levels than low-CONUT patients (p < 0.001 and p = 0.012). At 3-month post discharge, patients with malnutrition risk had higher hospitalization costs (p = 0.021), lower Barthel Index (p = 0.001), and more infectious complications (p = 0.002) than those without, and there was a greater risk for poor functional outcomes in the high-CONUT compared with the low-CONUT patients at admission (adjusted odds ratio: 2.32, 95% confidence interval: 1.28-4.17). High-CONUT scores predict a 3-month poor prognosis in AHS, which may help identify the AHS patients who need additional nutritional managements.
Advances in Prognostic Methylation Biomarkers for Prostate Cancer
Dilys Lam, Susan Clark, Clare Stirzaker, Ruth Pidsley
Subject: Life Sciences, Biochemistry Keywords: DNA methylation; epigenetics; biomarkers; circulating DNA; cfDNA; prostate cancer; early detection; prognosis
There is a major clinical need for accurate biomarkers for prostate cancer prognosis, to better inform treatment strategies and disease monitoring. Current clinically recognised prognostic factors, including prostate-specific antigen (PSA) levels, lack sensitivity and specificity in distinguishing aggressive from indolent disease, particularly in patients with localised intermediate grade prostate cancer. There has therefore been a major focus on identifying molecular biomarkers that can add prognostic value to existing markers, including investigation of DNA methylation, which has a known role in tumorigenesis. In this review, we will provide a comprehensive overview of the current state of DNA methylation biomarker studies in prostate cancer prognosis, and highlight the advances that have been made in this field. We cover the numerous studies into well-established candidate genes, and explore the technological transition that has enabled hypothesis-free genome-wide studies and the subsequent discovery of novel prognostic genes.
An Integrated Pan-Cancer Analysis and Structure-Based Virtual Screening of GPR15
Yanjing Wang, Xiangeng Wang, Yi Xiong, Cheng‐Dong Li, Qin Xu, Lu Shen, Aman Chandra Kaushik, Dong-Qing Wei
Subject: Medicine & Pharmacology, Oncology & Oncogenics Keywords: GPR15, pan-cancer, TCGA, cancer immunity, differential gene expression, prognosis, virtual screening
G protein-coupled receptor 15 (GPR15, also known as BOB) is an extensively studied orphan GPCR involving HIV infection, colonic inflammation and smoking-related diseases. Recently, GPR15 was deorphanized and its corresponding natural ligand demonstrated an ability of inhibiting cancer cell growth. However, no study reported the potential role of GPR15 in a pan-cancer manner. Using large-scale publicly available data from the Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression (GTEx) databases, we found that GPR15 expression is significantly lower in colon adenocarcinoma (COAD) than in normal tissues. And among 33 cancer types, GPR15 expression is significantly correlated with the prognoses of COAD, neck squamous carcinoma (HNSC), lung adenocarcinoma (LUAD) positively and stomach adenocarcinoma (STAD) negatively. This study also revealed that commonly upregulated gene set in the high GPR15 expression group (stratified via median) of COAD, HNSC, LUAD and STAD are enriched in immune systems, indicating that GPR15 might be considered as a potential target for cancer immunotherapy. Furthermore, we modelled the 3D structure of GPR15 and conducted the structure-based virtual screening. The top 8 hits compounds were screened and then subjected to molecular dynamics (MD) simulation for stability analysis. Our study provided novel insights into the role of GPR15 in a pan-cancer manner and discovered a potential hit compound for GPR15 antagonists.
Effectiveness of Abdominal Ultrasonography for Improving the Prognosis of Pancreatic Cancer during Medical Checkup: A Single Center Retrospective Analysis
Atsushi Yamaguchi, Naohiro Kato, Syuhei Sugata, Takuro Hamada, Nao Furuya, Takeshi Mizumoto, Yuzuru Tamaru, Ryusaku Kusunoki, Toshio Kuwai, Hirotaka Kouno, Naoyuki Toyota, Takeshi Sudo, Kazuya Kuraoka, Hiroshi Kohno
Subject: Medicine & Pharmacology, Gastroenterology Keywords: pancreatic cancer (PC); abdominal ultrasonography (US); surveillance; prognosis; medical checkup; 5-year survival; cancer screening
Recent advancements in surgical and anti-cancer therapies have provided significant hope of long survival in patients with pancreatic cancer (PC). To realize this hope, routine medical checkups of asymptomatic people should be performed to identify operable PCs. In this study, we evaluated the efficacy of medical checkups using abdominal ultrasonography (US). We retrospectively analyzed 374 patients with PC at our institute between 2010 and 2021. We divided these patients into several groups according to the diagnostic approach and compared their background and prognosis. These groups comprised PCs diagnosed through (a) symptoms, 242 cases; (b) US during medical checkup for asymptomatic individuals, 17; and other means. Of the 375 patients, 192 were men (51.3%), and the median age was 74 years (34–105). Tumors were located in the pancreatic tail in 67 patients (17.9%). Excision ratio and 5-year survival rate were significantly better in group (b) than in (a) (58.8% vs. 23.1%, P<0.01 and 42.2% vs. 9.4%, P<0.001, respectively). The prognosis of patients diagnosed using US during medical checkup was better than that of patients identified through symptomatic presentation of PC. US for asymptomatic individuals with PC might be useful for promoting better prognosis of PCs.
Preprint DATA DESCRIPTOR | doi:10.20944/preprints202301.0473.v1
Prognosease: A Data Generator for Health Deterioration Prognosis
Tarek BERGHOUT, Mohamed Benbouzid
Subject: Mathematics & Computer Science, Applied Mathematics Keywords: Data generator; dataset; deep learning; health index; machine learning; prognosis and health management; remaining useful life
This paper presents PrognosEase; a software that provides an easier way to produce different types of run-to-failure data mimicking real-world conditions to simplify prognosis studies in terms of data collection and improvement in ML degradation modelling process. Different types of degradation types made available to meet different types of applications. Besides, some primary ML tests were performed to ensure that complexity patterns of real systems could be observed in the training/testing predictions attitude. This paper also presents the impacts, limitations and potential improvements of the data generator.
Tumor Microenvironment, HLA Class I and APM Expression in HPV-Negative Oral Squamous Cell Carcinoma
Claudia Wickenhauser, Daniel Bethmann, Matthias Kappler, Alexander Walter Eckert, André Steven, Juergen Bukur, Bernard A. Fox, Jana Beer, Barbara Seliger
Subject: Life Sciences, Biochemistry Keywords: oral squamous cell carcinoma; HLA class I; antigen processing machinery; immune cell infiltration; immune escape; prognosis
Progression of oral squamous cell carcinoma (OSCC) has been associated with an escape of tumor cells from the host immune surveillance due to an increased knowledge of its underlying molecular mechanisms and its modulation by the tumor microenvironment and immune cell repertoire. In this study the expression of HLA class I (HLA-I) antigens and of components of the antigen processing machinery (APM) was analyzed in 160 pathologically classified human papilloma virus (HPV)-negative OSCC lesions and correlated to the intra-tumoral immune cell response, IFN- signaling and to the patients outcome. A heterogeneous, but predominantly lower constitutive protein expression of HLA-I APM components was found in OSCC sections when compared to non-neoplastic cells. Tumoral HLA-I APM component expression was further categorized into the three major phenotypes HLA-Ihigh/APMhigh, HLA-Ilow/APMlow and HLA-Idiscordant high/low/APMhigh. In the HLA-Ihigh/APMhigh group, the highest frequency of intra-tumoral CD8+ T cells and lowest number of CD8+ T cells close to FoxP3+ cells was found. Patients within this group presented the most unfavorable survival, which was significantly evident in stage T2 tumors. Despite a correlation with the number of intra-tumoral CD8+ T cells, tumoral JAK1 expression as a surrogate marker for IFN- signaling was not associated with HLA-I/APM expression. Thus, the presented findings strongly indicate the presence of additional factors involved in the immunomodulatory process of HPV-negative OSCC with a possible tumor-burden-dependent complex network of immune escape mechanisms beyond HLA-I/APM components and T cell infiltration in this tumor entity.
Tumoral HLA Class I and APM Expression and Its Effect on Intratumoral T-cell Reaction and Outcome in HPV-Negative Oral Squamous Cell Carcinoma
Subject: Medicine & Pharmacology, Oncology & Oncogenics Keywords: oral squamous cell carcinoma; HLA class I; antigen processing machinery; immune cell infiltration; immune escape; prognosis
Progression of oral squamous cell carcinoma (OSCC) has been associated with an escape of tumor cells from the host immune surveillance with growing evidence of its underlying molecular mechanisms and its interaction with the immune cell control. In this study the expression of HLA class I (HLA-I) antigens and of components of the antigen processing machinery (APM) was analyzed in 160 consecutive human papilloma virus (HPV)-negative OSCC lesions and correlated to tumor specific parameters, the intratumoral immune cell response and to the patients outcome. A heterogeneous, but predominantly lower constitutive protein expression of HLA-I APM components was seen in OSCC sections when compared to non-neoplastic cells. Based on the expression levels of HLA-I APM components three main OSCC subgroups were detected and categorized into HLA-Ihigh/APMhigh, HLA-Ilow/APMlow and HLA-Idiscordant high/low/APMhigh phenotypes. In the HLA-Ihigh/APMhigh group, the highest frequency of intratumoral CD8+ T cells and lowest number of CD8+ T cells close to FoxP3 cells was found. Despite being associated with the highest T cell infiltration, patients within this group presented the most unfavorable survival, which was most evident in stage T2 tumors. Thus, the presented findings strongly indicate the presence of additional factors involved in the immunomodulatory process of HPV-negative OSCC with a possible tumor-burden-dependent complex network of immune escape mechanisms beyond HLA-I/APM components and T cell infiltration in this tumor entity.
Expression and Signaling Pathways of Nerve Growth Factor (NGF) And Pro-NGF in Breast Cancer: A Systematic Review
Francesco Bruno, Domenico Arcuri, Francesca Vozzo, Antonio Malvaso, Alberto Montesanto, Raffaele Maletta
Subject: Life Sciences, Molecular Biology Keywords: breast cancer; Nerve Growght Factor (NGF); TrkA; p75NTR; NGFR; pro-NGF; angiogenesis; invasion; metastasis; diagnosis; prognosis; treatment
Breast cancer represents the most frequent cancer and the leading cause of cancer death among women. Thus, the prevention and early diagnosis of breast cancer appears to be of primary urgency as well as the development of new treatments able to improve its prognosis. Nerve Growth Factor (NGF) is a neurotrophic factor that plays a key role in the regulation of neuronal functions thought the binding to the Tropomyosin receptor kinase A (TrkA) and the Nerve Growth Factor receptor or Pan-Neurotrophin Receptor 75 (NGFR/p75NTR). Also, its precursor (pro-NGF) can extert biological activity by forming a trimeric complex with NGFR/p75NTR and sortilin or by binding to TrkA receptors with low affinity. Both in vitro and in vivo studies showed that NGF is synthesized and released by breast cancer cells and has mitogen, antiapoptotic and angiogenic effects on these cells through the activation of different signaling cascades that involve TrkA and NGFR/p75NTR receptors. Conversely, pro-NGF signaling has been related to breast cancer invasion and metastasis. Other studies suggested that NGF and its receptors could represent a good diagnostic and prognostic tool, as well as promising therapeutic targets for breast cancer. Here, we comprehensively summarize and systematically review the current experimental evidence on this topic.
The Role of Diet in Prognosis among Cancer Survivors: A systematic Review and Meta-Analysis of Dietary Patterns and Diet Interventions
Carlota Castro-Espin, Antonio Agudo
Subject: Medicine & Pharmacology, Nutrition Keywords: systematic review; meta-analysis; dietary pattern; prospective cohort; randomized controlled trial; cancer prognosis; cancer survival; dietary intervention
Cancer survival continues to improve in high-income countries, partly explained by advances in screening and treatment. Previous studies have mainly examined the relationship between individual dietary components and cancer prognosis in tumours with good therapeutic response (breast, colon and prostate cancers). The aim of this review was to assess qualitatively (and quantitatively where appropriate) the associations of dietary patterns and cancer prognosis from published prospective cohort studies, as well as the effect of diet interventions by means of randomized controlled trials (RCT). A systematic search was conducted in PubMed, and a total of 35 prospective cohort studies and 14 RCT published between 2011 and 2021 were selected. Better overall diet quality was associated with improved survival among breast and colorectal cancer survivors; adherence to the Mediterranean diet was associated to lower risk of mortality in colorectal and prostate cancer survivors. A meta-analysis using a random-effects model showed that higher versus lower diet quality was associated with a 23% reduction in overall mortality in breast cancer survivors. There was evidence that dietary interventions, generally combined with physical activity, improved overall quality of life, though most studies were in breast cancer survivors. Further cohort and intervention studies in other cancers are needed to make more specific recommendations.
Desmoplastic Small Round Cell Tumor: A Review of Main Molecular Abnormalities and Emerging Therapy
Celso Abdon Mello, Fernando Augusto Batista Campos, Tiago Goss Santos, Maria Leticia Gobo Silva, Giovana Tardin Torrezan, Felipe D´Almeida Costa, Maria Nirvana Formiga, Ulisses Nicolau, Antonio Geraldo Nascimento, Cassia Silva, Suely Nakagawa, Maria Paula Curado, Ademar Lopes, Samuel Aguiar
Subject: Medicine & Pharmacology, Allergology Keywords: desmoplastic small round cell tumor; treatment; prognosis; surgery; radiotherapy; chemotherapy; tyrosine kinase receptor; target therapy; rare disease
Desmoplastic small round cell tumor (DSRCT) is an extremely rare, aggressive sarcoma affecting adolescents and young adults with male predominance. Generally, it originates from serosal surface of abdominal cavity. The hallmark characteristic of DSRCT is the EWSR1-WT1 gene fusion. This translocation up-regulates the expression of PDGFRα, VEGF and other proteins related to tumor and vascular cell proliferation. Current management of DSRCT includes a combination of chemotherapy, radiation and aggressive cytoreductive surgery plus intra-peritoneal hyperthermic chemotherapy (HIPEC). Despite advances in multimodal therapy, outcomes remain poor since the majority of patients present disease recurrence and die within 3 years. The dismal survival makes DSRCT an orphan disease with urgent need of new drugs. The treatment of advanced and recurrent disease with tyrosine kinase inhibitors, such as pazopanib, sunitinib, and mTOR inhibitors have been evaluated in small studies. Recent works using comprehensive molecular profiling of DSRCT identified potential therapeutic targets. In this review, we aim to describe the current studies conducted to better understand DSRCT biology and to explore the new therapeutic strategies under investigation in preclinical models and in early phase clinical trials.
An Atlas of the Genetic Variations Linking Dysregulation of Autophagy to Human Diseases: The Missing Environmental Link
Iris Grosjean, Barnabé Roméo, Marie-Angela Domdom, Nathalie Yazbeck, Grégoire D'Andréa, Amine Belaid, Olivier Camuzard, Olivia Vidal, Guillemette Crépeaux, Romain K. Gherardi, François Jerome Authier, Jean Daniel Masson, Eric Gilson, Charles Hugo Marquette, Sylvie Leroy, Jérémie Roux, Patrick Brest, Martin Von Bergen, Gérard Milano, Daniel J. Klionsky, Paul Hofman, Baharia Mograbi
Subject: Keywords: air pollutants/exposomics; autoimmunity; autophagy; cancers; COPD; environmental diseases; eQTL; infection; inflammatory; polymorphism; prognosis; risk; susceptibility; theragnosis
The rising incidence of complex illnesses and their costs have revolutionized basic research, patient management, and societal needs. Between 70 to 90% of the risk of developing a disease is due to the air we breathe, the water we drink, and the surroundings in which we work and live. Visibly polluted, infectious or not, the fact remains that we are more than ever exposed to environmental risks. Air pollution is the fourth most prevalent deadly risk factor worldwide and by far the leading risk factor for hundreds of diseases, including respiratory infections, inflammatory illness, and cancer. Thus, an unhealthy environment can be considered as a pandemic, affecting 280 million people and claiming 12 million deaths every year. Although critical for identifying of the people at risk, the causal environment components (pollutants and/or the microbiome), and the affected physiological mechanisms are not well understood. Herein, we consider the dysregulation of macroautophagy (hereafter referred to as 'autophagy'), as the mechanism at the heart of an immediate response to environmental stress. We discuss the missing link between the autophagy gene variations, and the exposome in the susceptibility, prognosis, and management of complex diseases when embracing personalized medicine.
A Novel Deep Clustering Method and Indicator for Time Series Soft Partitioning
Alexandre Eid, Guy Clerc, Badr Mansouri, Stella Roux
Subject: Mathematics & Computer Science, Artificial Intelligence & Robotics Keywords: semantic segmentation; time series; clustering; deep learning; kernel density estimation; electromechanical actuator; data labelling; prognosis and health management; aeronautics
The aerospace industry develops prognosis and health management algorithms to ensure better safety on board. Particularly for in-flight controls where jamming is dreaded. For that, vibration signals are monitored to predict future defect occurrences. However, time series are not labeled according to severity level, and the user can only assess the system health from the data mining procedure. To that extent, we developed a clustering algorithm using a deep neural network core. We encoded the time series into pictures to be feed into an artificially trained neural network: U-NET. From the segmented output, one-dimensional information on cluster frontiers is extracted and filtered without any parameter selection. Then, a kernel density estimation finally transforms the signal into an empirical density. Ultimately, a Gaussian mixture model extracts the latter independent components. The method empowered us to reveal different degrees of severity faults in the studied data, with their respective likelihood without prior knowledge. We compared it to state-of-the-art machine learning algorithms. However, internal clustering results evaluation for time series is an open question. As state-of-the-art indexes were not producing relevant results, we built a new indicator to fulfill this task. We applied the whole method to an actuator consisting of an induction machine linked to a ball screw. This study lays the groundwork for future training of diagnosis and prognosis structures in the health management framework.
Revisiting the Stress Concept in the Context of Solid Tumors Prognostic: A Role for the Stress Granules?
Anais Aulas, Pascal Finetti, Shawn Lyons, François Bertucci, Daniel Birnbaum, Claire Acquaviva, Emilie Mamessier
Subject: Biology, Other Keywords: stress granules; G3BP1; G3BP2; Caprin-1; USP10; TIA1; TIAR; cancer prognosis; biomarker; metastasis; resistance; cell death; pro-survival properties
Stress Granules formation is a pro-survival mechanism helping cells to cope with environmental challenges. Stress Granules have been studied for two decades in fundamental research, and are now being examined in the context of human pathogenesis. Here, we review studies highlighting stress granules' involvement in cancer development through translational pattern modification.
SCAND1 Reverts EMT and Suppresses Tumor Growth and Collective Migration
Takanori Eguchi, Eva Csizmadia, Thomas L. Prince, Barbara Wegiel, Stuart K. Calderwood
Subject: Medicine & Pharmacology, Oncology & Oncogenics Keywords: epithelial-to-mesenchymal transition (EMT); hybrid EMT; partial EMT; mesenchymal-to-epithelial transition (MET); SCAND1; SCAN zinc finger; MZF1; cancer prognosis
Epithelial-mesenchymal transition (EMT) is a reversible cellular program that transiently places epithelial (E) cells into pseudo-mesenchymal (M) cell states. The malignant progression and resistance of many types of carcinomas depends on EMT activation, partial EMT and hybrid E/M status in neoplastic cells. EMT is activated by tumor microenvironmental TGFβ signal and EMT-inducing transcription factors, such as ZEB1/2 in tumor cells. However, reverse EMT factors are less studied. We demonstrate that transcription factor SCAND1 can revert mesenchymal and hybrid E/M phenotype of cancer cells to a more epithelial, less invasive status and inhibit their proliferation and migration. SCAND1 is a SCAN domain-containing protein and hetero-oligomerizes with SCAN-zinc finger transcription factors, such as MZF1, for accessing DNA and transcriptional co-repression of target genes. We found that SCAND1-MZF1 co-expression and interaction correlated with maintaining epithelial features, whereas the simultaneous loss of SCAND1 and MZF1 correlated with mesenchymal features of tumor cells. Overexpression of SCAND1 over endogenous MZF1 in DU-145 prostate cancer cells reverted their hybrid E/M status into cobblestone morphology with increased epithelial adhesion by E-cadherin and β-catenin relocation. Consistently, co-expression analysis in TCGA PanCancer Atlas revealed that both SCAND1 and MZF1 co-express and are negatively correlated with EMT driver genes, including CTNNB1, ZEB1, ZEB2 and TGFBR, in prostate tumor specimens. In addition, SCAND1 overexpression suppressed tumor cell proliferation by reducing the MAP3K-MEK-ERK signaling pathway. Of note, SCAND1-overexpressing DU-145 cells migrated slower than control cells with decreased lymph node metastasis of prostate cancer in a mouse tumor xenograft model. Kaplan-Meyer analysis showed high expression of MZF1 and SCAND1 to correlate with better prognoses in pancreatic cancer and head and neck cancers, although with poorer prognosis in kidney cancer. Overall, these data suggest that the combination of SCAND1-MZF1 complexes may revert the EMT mechanism in cancer to establish an epithelial phenotype. These effects seem to include co-repression of EMT-driver genes and suppression of tumor cell proliferation via inhibition of the MAP3K-MEK-ERK signaling pathway.
Development and Validation of a Prediction Model for 28-Day in-Hospital Mortality in Critically Ill Patients with COVID-19
Paloma Ferrando-Vivas, Doug Gould, James Doidge, Karen Thomas, Paul Mouncey, Manu Shankar-Hari, Duncan Young, Kathryn Rowan, David Harrison
Subject: Medicine & Pharmacology, Allergology Keywords: COVID-19; Critical Illness; Hospital Mortality; Intensive Care Units; Outcome Assessment, Health Care; Prognosis; Risk Adjustment; Severe acute respiratory syndrome coronavirus 2
Objectives To develop and validate a prediction model for 28-day in-hospital mortality among adult patients critically ill with COVID-19 in the UK. Design Observational cohort study. Setting 287 adult critical care units in England, Wales and Northern Ireland, of which 260 admitted at least one eligible patient. Participants 10,933 patients with confirmed COVID-19 of whom 10,401 were eligible (excluding 532 patients with a duration of critical care less than 24 hours and 1 patient with unknown 28-day outcome): 8,666 development (March-April 2020) and 1,735 temporal validation (May-August 2020). Main outcome measures 28-day in-hospital mortality from start of critical care. Results Two models were developed using 14 patient level predictors selected from 30 candidate predictors, with and without adjustment for calendar time. In the temporal validation data, the model discrimination was maintained (c index 0.78) but calibration was poor, particularly for the model not adjusted for calendar time (ratio of observed to predicted mortality 0.74 versus 0.88 for the model adjusted for calendar time). Conclusions We developed and validated a prediction model for 28-day in-hospital mortality for patients critically ill with COVID-19. Although absolute predictions were inaccurate due to changing outcomes, the models will support risk-adjustment in analyses and monitoring changes in risk-adjusted outcome over time.
Recommendations for How to Respond When the Family Is Hoping for a Miracle
Subject: Medicine & Pharmacology, General Medical Research Keywords: Poor prognosis; medically non-beneficial care; futility; breaking bad news; withdrawal of care; miracle; hope; goals of care; communication; health disparities; racial discrimination; ethnocultural discrimination
Objective: To recommend how physicians can best respond to families whose hopes for a miracle via divine intervention influence their medical decisions, like, for example, making them not want to withdraw ventilatory support in cases of poor neurologic prognosis because they are still hoping for God to intervene. Methods: Auto-ethnographic analysis of chaplaincy experience in this clinical context yields a nuanced 90-second, point-of-care spiritual intervention physicians can use to address the religious aspect of families who base medical decisions on their hopes for a miracle via divine intervention. Explanation of how spiritual intervention dovetails with existing physician communication protocol for responding to families hoping for a miracle. Results: Spiritual intervention for religious aspect of miracle-hoping families is integrated into existing physician communication protocol for responding to families hoping for a miracle with recommendations for utilization of existing communication technology when necessary. Conclusion: Properly addressing the religious dimension of families hoping for a miracle may be helpful for physicians interested in decreasing their own stress levels, improving outcomes for this clinical context, and ensuring that unintentional discrimination does not perpetuate racial disparities in end-of-life care.
ANN Based Estimation of the Defects Severity at the Drilling of GFRP/Ti Multilayered Composite Structure
Igor Zhilyaev, Evgeny Chigrinets, Sergey Shevtsov, Samira Chotchaeva, Natalia Snezhina
Subject: Materials Science, Polymers & Plastics Keywords: polymeric composite drilling; GFRP reinforced with Ti interlayers; hole drilling quality; delaminations; defect severity prediction; ANN based prognosis of the quality; tool geometry and machining conditions.
The main purpose of this study was to develop a model for predicting the quality of holes drilled in the root part of a spar of helicopter main rotor blades made of the Glass Fiber Reinforced Plastic (GFRP)-Ti multilayer polymer composite. As the main quality criterion, delaminations at the entry and exit of the drill from the hole were taken. In the experimental study a conventional drill and two modified geometry drills: a double-point angle drill and a dagger drill were used. Preliminary experiments showed the best hole quality when using modified drills, which allowed further detailed study only with both modified drills at different drilling speeds and feed rates. Its results in the form of training sets were used to build the Artificial Neural Networks (ANNs) to predict delamination at the entry and exit of drilled holes. The analysis of the fitted response functions, presented as 3D surfaces plots and superimposed contour plots, made it possible to choose the better tool - a double-point angle drill and determine the optimal area for drilling speed and feed rates, confirming that the prediction of the quality and productivity of machining composites based on ANN is an effective tool to search and quantify the quality criteria of such technologies.
Stress-inducible SCAN Factors Suppress the Stress Response and Are Biomarkers for Enhanced Prognosis in Cancers
Takanori Eguchi, Mona Sheta, Stuart K Calderwood
Subject: Medicine & Pharmacology, Oncology & Oncogenics Keywords: cell stress response; heat shock protein 90 (HSP90); SCAN domain-containing proteins (SCAND); MZF1; heat shock factors (HSF); co-expression correlation; Kaplan-Meyer analysis; cancer patients prognosis
The cell stress response is an essential system present in every cell for responding and adapting to extracellular environmental stimulations. A major program for stress response is the heat shock factor (HSF)–heat shock protein (HSP) system that maintains proteostasis in cells and promotes cancer progression. However, less is known about how the cell stress response is regulated by alternative transcription factors. Here, we show that the SCAN domain-containing transcription factors (SCAN-TFs) are involved in repressing the stress response in cancer. SCAND1 and SCAND2 are SCAN-TFs that can hetero-oligomerize with SCAN-zinc finger transcription factors, such as MZF1(ZSCAN6), for accessing DNA and transcriptionally co-repressing target genes. We found that heat stress induced the expression of both SCAND1 and MZF1(ZSCAN6) bound to HSP90 gene promoter regions in prostate cancer cells. SCAND1 and MZF1 blocked the heat shock responsiveness of HSP90 in prostate cancer cells. Gene expression of SCAND2, SCAND1 and MZF1 was negatively correlated with HSP90 expression in patients-derived prostate adenocarcinoma. MZF1 and SCAND2 were more highly expressed in paired normal tissues than in tumor tissues in several cancer types. High expression of SCAND2, SCAND1 and MZF1 correlated with enhanced prognoses of pancreatic cancer and head and neck cancers. Additionally, high expression of SCAND2 was correlated with better prognoses of lung adenocarcinoma and sarcoma. In contrast, high expression of HSP90AA1 correlated with poorer prognoses in several cancer types. These data suggest that the stress-inducible SCAN-TFs can function as a feedback system, suppressing excessive stress response and inhibiting cancers.
T-cytotoxic Expression of Leukocyte-Associated Immunoglobulin-like Receptor-1 (LAIR-1) in post-HCV Hepatocellular Carcinoma
Reham Hammad, Reda Badr Aglan, Shaymaa A. Mohammed, Eman Abu-elnasr Awad, Marwa A. Elsaid, Hanan .M. Bedair, Seham K. Khirala, Mohamed A. Selim, Asmaa A. Abo Elqasem, Areej Rushdi, Mohamed Ali, Omaima I Abo-Elkheir, Eman F. Sanad, Nadia M. Hamdy
Subject: Life Sciences, Immunology Keywords: T cytotoxic cells; Leukocyte-associated Immunoglobulin-like Receptor-1; LAIR-1; Hepatitis C virus genotype 4; HCV G4; hepatocellular carcinoma; cirrhosis; immune inhibitory checkpoints; inflammation; prognosis; insulin resistance
Background and Aim. Since virus-related hepatocellular carcinoma (HCC) pathogenesis involves liver inflammation, therefore, post-hepatitis C virus (HCV) infection would be a cause for liver cirrhosis that would progress to HCC. Cytotoxic T cells (Tc) are known to be involved in post-HCV complications and HCC pathogenesis. The inhibitory checkpoint Leukocyte-Associated Immunoglobulin-like Receptor-1 (LAIR-1) is expressed on Tc. Therefore, we aimed to determine whether the Tc expression level of LAIR-1 is associated with HCC progression post-HCV and moreover, to evaluate LAIR-1 expression as a non-invasive biomarker for HCC progression in the context of liver cirrhosis post-HCV genotype 4 (G4) in Egyptian patients' peripheral venous blood liquid biopsy. We studied LAIR-1 expression on Tc related to the progression of liver cirrhosis in a case-controlled study enrolled 64 patients with post-HCV G4-HCC and 37 patients with post-HCV G4-liver cirrhosis. Methods: LAIR-1 expression was analyzed by flow cytometry. Results: LAIR-1 expression on Tc and the percentage of Tc positive for LAIR-1 (LAIR-1+Tc %) were significantly higher in the post-HCV G4-HCC group compared to the post-HCV G4-liver cirrhosis
Profiling of Matched Adipose and Skeletal Muscle in Human Pancreatic Cancer Cachexia Reveals Distinct Gene Profiles with Convergent Pathways
Ashok Narasimhan, Xiaoling Zhong, Ernie Au, Eugene P. Ceppa, Atilla Nakeeb, Michael G. House, Nicholas J. Zyromski, C. Max Schmidt, Katharyn N.H. Schloss, Daniel E.I. Schloss, Yunlong Liu, Guanglong Jiang, Bradley A. Hancock, Milan Radovich, Joshua K. Kays, Safi Shahda, Marion E. Couch, Leonidas G. Koniaris, Teresa A. Zimmers
Subject: Medicine & Pharmacology, Allergology Keywords: Pancreatic cancer; RNAseq; Humans; Weight loss; Prognosis; Rectus Abdominis; Carcinoma, Pancreatic Ductal; Adipose Tissue; Pancreatic Carcinoma; Pancreatic Neoplasms; Subcutaneous Fat; High-Throughput Nucleotide Sequencing; Body Composition; Muscles; Cachexia; Muscular Atrophy; Gene Expression
The vast majority of patients with pancreatic ductal adenocarcinoma (PDAC) suffer cachexia. Although cachexia results from concurrent loss of adipose and muscle tissue, most studies focus on muscle alone. Emerging data demonstrate the prognostic value of fat loss in cachexia. Here we sought to identify the muscle and adipose gene profiles and pathways regulated in cachexia. Matched rectus abdominis muscle and subcutaneous adipose tissue were obtained at surgery from patients with benign conditions (n=11) and patients with PDAC (n=24). Self-reported weight loss and body composition measurements defined cachexia status. Gene profiling was done using Ion proton sequencing. Results were queried against external datasets for validation. 961 DE genes were identified from muscle and 2000 from adipose tissue, demonstrating greater response of adipose than muscle. In addition to known cachexia genes such as FOXO1, novel genes from muscle, including PPP1R8 and AEN correlated with cancer weight loss. All the adipose correlated genes including SCGN and EDR17 are novel for PDAC cachexia. Pathway analysis demonstrated shared pathways but largely non-overlapping genes in both tissues. Age related muscle loss predominantly had a distinct gene profiles compared to cachexia. This analysis of matched, externally validate gene expression points to novel targets in cachexia.
GATA 3 Gene Overexpression Is A Biomarker of Adverse Prognosis for Peripheral T-Cell Lymphoma, Not Otherwise Specified and for ALK-Negative Anaplastic Large Cell Lymphoma: An Exploratory Analysis of 80 Latin American Cases of nodal PTCLs
Luís Alberto de Pádua Covas Lage, Cláudio Vinícius Brito, Débora Levy, Hebert Fabrício Culler, Samuel Campanelli Freitas Couto, Lucas Bassolli, Maria Claudia Nogueira Zerbini, Vanderson Rocha, Juliana Pereira
Subject: Medicine & Pharmacology, Oncology & Oncogenics Keywords: nodal peripheral T-cell lymphomas; peripheral T-cell lymphoma, not otherwise specified (PTCL/NOS); ALK-negative anaplastic large-cell lymphoma (ALCL/ALK-); Angioimmunoblastic T-cell lymphoma (AITL); diagnosis; prognosis; GATA3 gene expression
Background: Nodal peripheral T-cell lymphomas (nPTCLs) encompass a heterogeneous group of mature and aggressive lymphoid malignancies, including peripheral T-cell lymphoma, not otherwise specified (PTCL/NOS), angioimmunoblastic T-cell lymphoma (AITL) and anaplastic large cell lymphoma (ALCL) ALK-positive and ALK-negative. Their differential diagnosis and prognosis are an issue in the clinical practice. Accurate biomarkers to refine the different subtypes of nPTCLs and to stratify their prognosis are essential to improve their treatment approach. The aim of this study was to test the prognostic impact of GATA3 gene expression, and its capability to discriminate the different subtypes of nPTCLs. Patients and Methods: From 2000 to 2017, 80 patients with nPTCLs were eligible for GATA3 gene expression analysis that was assessed retrospectively by quantitative real time PCR (qRT-PCR) of neoplastic biopsies in Formalin-Fixed Paraffin-Embedded samples (FFPE). Results: Median age was 49 years old (IqR 34-59), 43/80 (53.7%) were male. Median follow-up was 1.72 years. Of them, 36.3% were classified as PTCL/NOS, 31.2% ALK-negative ALCL, 21.2% ALK-positive ALCL and 11.3% AITL. The majority of cases had advanced stage (III/IV). Two-year estimated overall survival (OS) and progression-free survival (PFS) were 52.2% and 39.5%, respectively. The median GATA3 gene expression level was 0.49% (range 0 – 7.07) in all cohort, it was 0.11% for ALK-positive ALCL, 0.46% for ALK-negative ALCL, 0.86% for PTCL/NOS and 0.67% for AITL. The difference of GATA3 gene expression among distinct variants of nPTCLs was statistically significant (p < 0.001). GATA3 gene expression levels ≥ 0.71% discriminate PTCL/NOS from ALK-negative ALCL and AITL with sensitivity of 62% and specificity of 80.3%. GATA3 gene expression levels ≥ median was associated with poor 2-year OS for PTCL/NOS (46.7% x 21.4%, p=0.04) and for ALK-negative ALCL (85.7% x 54.5%, p=0.04). Conclusion: Despite the relative small and heterogeneous group of patients with nPTCLs, GATA3 gene overexpression may be an important biomarker associated with poor prognosis in PTCL/NOS and ALK-negative ALCL. Moreover it may also discriminate different subtypes of nPTCLs. Further studies with larger series of patients should confirm our findings.