bluuebunny/crossref_metadata_2025 huggingface dataset:
CUL4A, ERCC5, and ERCC1 as Predictive Factors for Trabectedin Efficacy in Advanced Soft Tissue Sarcomas (STS): A Spanish Group for Sarcoma Research (GEIS) Study
Authors: Moura David S. , Sanchez-Bustos Paloma , Fernandez-Serra Antonio , Lopez-Alvarez María , Mondaza-Hernandez José L. , Blanco-Alcaina Elena , Gavilan-Naranjo Angela , Martinez-Delgado Paula , Lacerenza Serena , Santos-Fernandez Paloma , Carrasco-Garcia Irene , Hidalgo-Rios Samuel , Gutierrez Antonio , Ramos Rafael , Hindi Nadia , Taron Miguel , Lopez-Guerrero Jose Antonio , Martin-Broto Javier
Published: May 2020

A translational study was designed to analyze the expression of nucleotide excision repair (NER) and homologous recombination (HR) genes as potential predictive biomarkers for trabectedin in soft-tissue sarcoma (STS). This study is part of a randomized phase II trial comparing trabectedin plus doxorubicin versus doxorubicin in advanced STS. Gene expression levels were evaluated by qRT-PCR, while CUL4A protein levels were quantified by immunohistochemistry. Expression levels were correlated with patients’ progression-free survival (PFS) and overall survival (OS). Gene expression was also evaluated in cell lines and correlated with trabectedin sensitivity. In doxorubicin arm and in the whole series, which includes samples from both arms, no significant differences in terms of PFS were observed amongst the analyzed genes. In the group treated with trabectedin plus doxorubicin, the median of PFS was significantly longer in cases with CUL4A, ERCC1, or ERCC5 overexpression, while BRCA1 expression did not correlated with PFS. Gene expression had no prognostic influence in OS. CUL4A protein levels correlated with worse PFS in doxorubicin arm and in the whole series. In cell lines, only overexpression of ERCC1 was significantly correlated with trabectedin sensitivity. In conclusion, CUL4A, ERCC5, and mainly ERCC1 acted as predictive factors for trabectedin efficacy in advanced STS.
Inflammation-Based Scores Increase the Prognostic Value of Circulating Tumor Cells in Primary Breast Cancer
Authors: Miklikova Svetlana , Minarik Gabriel , Sedlackova Tatiana , Plava Jana , Cihova Marina , Jurisova Silvia , Kalavska Katarina , Karaba Marian , Benca Juraj , Smolkova Bozena , Mego Michal
Published: May 2020

A correlation between circulating tumor cells (CTCs) and monocytes in metastatic breast cancer (BC), where CTCs and monocyte-to-lymphocyte ratio (MLR) were predictors of overall survival (OS), was recently shown. Herein, we aimed to assess the association between CTCs and the complete blood count (CBC)-derived inflammation-based scores in 284 primary BC patients. CTCs were determined in CD45-depleted peripheral blood mononuclear cells by real time-PCR. This method allowed us to detect a subset of CTCs with an epithelial-to-mesenchymal transition phenotype (CTC EMT), previously associated with inferior outcomes in primary BC. In the present study, CTC EMT positivity (hazard ratio (HR) = 2.4; 95% CI 1.20–4.66, p = 0.013) and elevated neutrophil-to-lymphocyte ratio (NLR) (HR = 2.20; 95% CI 1.07–4.55; p = 0.033) were associated with shorter progression-free survival (PFS) in primary BC patients. Multivariate analysis showed that CTC EMT-positive patients with NLR ≥ 3 had 8.6 times increased risk of disease recurrence (95% CI 2.35–31.48, p = 0.001) compared with CTC EMT-negative patients with NLR < 3. Similarly, disease recurrence was 13.14 times more likely in CTC EMT-positive patients with MLR ≥ 0.34 (95% CI 4.35–39.67, p < 0.001). Given its low methodological and financial demands, the CBC-derived inflammation-based score determination could, after broader validation, significantly improve the prognostication of BC patients.
Prospects for Comprehensive Analyses of Circulating Tumor Cells in Tumor Biology
Authors: Aoki Masahiko , Shoji Hirokazu , Kashiro Ayumi , Takeuchi Keiko , Shimizu Yoshihiro , Honda Kazufumi
Published: May 2020

The comprehensive analysis of biological and clinical aspects of circulating tumor cells (CTCs) has attracted interest as a means of enabling non-invasive, real-time monitoring of cancer patients and enhancing our fundamental understanding of tumor metastasis. However, CTC populations are extremely small when compared to other cell populations in the blood, limiting our comprehension of CTC biology and their clinical utility. Recently developed proteomic and genomic techniques that require only a small amount of sample have attracted much interest and expanded the potential utility of CTCs. Cancer heterogeneity, including specific mutations, greatly impacts disease diagnosis and the choice of available therapeutic strategies. The CTC population consists primarily of cancer stem cells, and CTC subpopulations are thought to undergo epithelial–mesenchymal transition during dissemination. To better characterize tumor cell populations, we demonstrated that changes in genomic profiles identified via next-generation sequencing of liquid biopsy samples could be expanded upon to increase sensitivity without decreasing specificity by using a combination of assays with CTCs and circulating tumor DNA. To enhance our understanding of CTC biology, we developed a metabolome analysis method applicable to single CTCs. Here, we review―omics studies related to CTC analysis and discuss various clinical and biological issues related to CTCs.
[18F]FDG-PET/CT Radiomics for Prediction of Bone Marrow Involvement in Mantle Cell Lymphoma: A Retrospective Study in 97 Patients
Authors: Mayerhoefer Marius E. , Riedl Christopher C. , Kumar Anita , Dogan Ahmet , Gibbs Peter , Weber Michael , Staber Philipp B. , Huicochea Castellanos Sandra , Schöder Heiko
Published: May 2020

Biopsy is the standard for assessment of bone marrow involvement in mantle cell lymphoma (MCL). We investigated whether [18F]FDG-PET radiomic texture features can improve prediction of bone marrow involvement in MCL, compared to standardized uptake values (SUV), and whether combination with laboratory data improves results. Ninety-seven MCL patients were retrospectively included. SUVmax, SUVmean, SUVpeak and 16 co-occurrence matrix texture features were extracted from pelvic bones on [18F]FDG-PET/CT. A multi-layer perceptron neural network was used to compare three combinations for prediction of bone marrow involvement—the SUVs, a radiomic signature based on SUVs and texture features, and the radiomic signature combined with laboratory parameters. This step was repeated using two cut-off values for relative bone marrow involvement: REL > 5% (>5% of red/cellular bone marrow); and REL > 10%. Biopsy demonstrated bone marrow involvement in 67/97 patients (69.1%). SUVs, the radiomic signature, and the radiomic signature with laboratory data showed AUCs of up to 0.66, 0.73, and 0.81 for involved vs. uninvolved bone marrow; 0.68, 0.84, and 0.84 for REL ≤ 5% vs. REL > 5%; and 0.69, 0.85, and 0.87 for REL ≤ 10% vs. REL > 10%. In conclusion, [18F]FDG-PET texture features improve SUV-based prediction of bone marrow involvement in MCL. The results may be further improved by combination with laboratory parameters.
A Novel 4-gene Score to Predict Survival, Distant Metastasis and Response to Neoadjuvant Therapy in Breast Cancer
Authors: Oshi Masanori , Katsuta Eriko , Yan Li , Ebos John M.L. , Rashid Omar M. , Matsuyama Ryusei , Endo Itaru , Takabe Kazuaki
Published: May 2020

We generated a 4-gene score with genes upregulated in LM2-4, a metastatic variant of MDA-MB-231 (DOK 4, HCCS, PGF, and SHCBP1) that was strongly associated with disease-free survival (DFS) in TCGA cohort (hazard ratio [HR]>1.2, p < 0.02). The 4-gene score correlated with overall survival of TCGA (HR = 1.44, p < 0.001), which was validated with DFS and disease-specific survival of METABRIC cohort. The 4-gene score was able to predict worse survival or clinically aggressive tumors, such as high Nottingham pathological grade and advanced cancer staging. High score was associated with worse survival in the hormonal receptor (HR)-positive/Her2-negative subtype. High score enriched cell proliferation-related gene sets in GSEA. The score was high in primary tumors that originated, in and metastasized to, brain and lung, and it predicted worse progression-free survival for metastatic tumors. Good tumor response to neoadjuvant chemotherapy or hormonal therapy was accompanied by score reduction. High scores were also predictive of response to neoadjuvant chemotherapy for HR-positive/Her2-negative subtype. High score tumors had increased expression of T cell exhaustion marker genes, suggesting that the score may also be a biomarker for immunotherapy response. Our novel 4-gene score with both prognostic and predictive values may, therefore, be clinically useful particularly in HR-positive breast cancer.
Alpha-Synuclein and LRRK2 in Synaptic Autophagy: Linking Early Dysfunction to Late-Stage Pathology in Parkinson’s Disease
Authors: Lamonaca Giulia , Volta Mattia
Published: May 2020

The lack of effective disease-modifying strategies is the major unmet clinical need in Parkinson’s disease. Several experimental approaches have attempted to validate cellular targets and processes. Of these, autophagy has received considerable attention in the last 20 years due to its involvement in the clearance of pathologic protein aggregates and maintenance of neuronal homeostasis. However, this strategy mainly addresses a very late stage of the disease, when neuropathology and neurodegeneration have likely “tipped over the edge” and disease modification is extremely difficult. Very recently, autophagy has been demonstrated to modulate synaptic activity, a process distinct from its catabolic function. Abnormalities in synaptic transmission are an early event in neurodegeneration with Leucine-Rich Repeat Kinase 2 (LRRK2) and alpha-synuclein strongly implicated. In this review, we analyzed these processes separately and then discussed the unification of these biomolecular fields with the aim of reconstructing a potential “molecular timeline” of disease onset and progression. We postulate that the elucidation of these pathogenic mechanisms will form a critical basis for the design of novel, effective disease-modifying therapies that could be applied early in the disease process.
Unmasking Intra-Tumoral Heterogeneity and Clonal Evolution in NF1-MPNST
Authors: Moon Chang-In , Tompkins William , Wang Yuxi , Godec Abigail , Zhang Xiaochun , Pipkorn Patrik , Miller Christopher A. , Dehner Carina , Dahiya Sonika , Hirbe Angela C.
Published: May 2020

Sarcomas are highly aggressive cancers that have a high propensity for metastasis, fail to respond to conventional therapies, and carry a poor 5-year survival rate. This is particularly true for patients with neurofibromatosis type 1 (NF1), in which 8%–13% of affected individuals will develop a malignant peripheral nerve sheath tumor (MPNST). Despite continued research, no effective therapies have emerged from recent clinical trials based on preclinical work. One explanation for these failures could be the lack of attention to intra-tumoral heterogeneity. Prior studies have relied on a single sample from these tumors, which may not be representative of all subclones present within the tumor. In the current study, samples were taken from three distinct areas within a single tumor from a patient with an NF1-MPNST. Whole exome sequencing, RNA sequencing, and copy number analysis were performed on each sample. A blood sample was obtained as a germline DNA control. Distinct mutational signatures were identified in different areas of the tumor as well as significant differences in gene expression among the spatially distinct areas, leading to an understanding of the clonal evolution within this patient. These data suggest that multi-regional sampling may be important for driver gene identification and biomarker development in the future.
Identification and Validation of Reference Genes for RT-qPCR Analysis in Switchgrass under Heavy Metal Stresses
Authors: Zhao Junming , Zhou Man , Meng Yu
Published: May 2020

Switchgrass (Panicum Virgatum L.) has been recognized as the new energy plant, which makes it ideal for the development of phytoremediation on heavy metal contamination in soils with great potential. This study aimed to screen the best internal reference genes for the real-time quantitative PCR (RT-qPCR) in leaves and roots of switchgrass for investigating its response to various heavy metals, such as cadmium (Cd), lead (Pb), mercury (Hg), chromium (Cr), and arsenic (As). The stability of fourteen candidate reference genes was evaluated by BestKeeper, GeNorm, NormFinder, and RefFinder software. Our results identified U2AF as the best reference gene in Cd, Hg, Cr, and As treated leaves as well as in Hg, Pb, As, and Cr stressed root tissues. In Pb treated leaf tissues, 18S rRNA was demonstrated to be the best reference gene. CYP5 was determined to be the optimal reference gene in Cd treated root tissues. The least stable reference gene was identified to be CYP2 in all tested samples except for root tissues stressed by Pb. To further validate the initial screening results, we used the different sets of combinatory internal reference genes to analyze the expression of two metal transport associated genes (PvZIP4 and PvPDB8) in young leaves and roots of switchgrass. Our results demonstrated that the relative expression of the target genes consistently changed during the treatment when CYP5/UBQ1, U2AF/ACT12, eEF1a/U2AF, or 18S rRNA/ACT12 were combined as the internal reference genes. However, the time-dependent change pattern of the target genes was significantly altered when CYP2 was used as the internal reference gene. Therefore, the selection of the internal reference genes appropriate for specific experimental conditions is critical to ensure the accuracy and reliability of RT-qPCR. Our findings established a solid foundation to further study the gene regulatory network of switchgrass in response to heavy metal stress.
Inhibition of Xanthine Oxidase-Catalyzed Xanthine and 6-Mercaptopurine Oxidation by Flavonoid Aglycones and Some of Their Conjugates
Authors: Mohos Violetta , Fliszár-Nyúl Eszter , Poór Miklós
Published: May 2020

Flavonoids are natural phenolic compounds, which are the active ingredients in several dietary supplements. It is well-known that some flavonoid aglycones are potent inhibitors of the xanthine oxidase (XO)-catalyzed uric acid formation in vitro. However, the effects of conjugated flavonoid metabolites are poorly characterized. Furthermore, the inhibition of XO-catalyzed 6-mercaptopurine oxidation is an important reaction in the pharmacokinetics of this antitumor drug. The inhibitory effects of some compounds on xanthine vs. 6-mercaptopurine oxidation showed large differences. Nevertheless, we have only limited information regarding the impact of flavonoids on 6-mercaptopurine oxidation. In this study, we examined the interactions of flavonoid aglycones and some of their conjugates with XO-catalyzed xanthine and 6-mercaptopurine oxidation in vitro. Diosmetin was the strongest inhibitor of uric acid formation, while apigenin showed the highest effect on 6-thiouric acid production. Kaempferol, fisetin, geraldol, luteolin, diosmetin, and chrysoeriol proved to be similarly strong inhibitors of xanthine and 6-mercaptopurine oxidation. While apigenin, chrysin, and chrysin-7-sulfate were more potent inhibitors of 6-mercaptopurine than xanthine oxidation. Many flavonoids showed similar or stronger (even 5- to 40-fold) inhibition of XO than the positive control allopurinol. Based on these observations, the extremely high intake of flavonoids may interfere with the elimination of 6-mercaptopurine.
Visual Feedback and Postural Control in Multiple Sclerosis
Authors: Inojosa Hernan , Schriefer Dirk , Trentzsch Katrin , Klöditz Antonia , Ziemssen Tjalf
Published: May 2020

As people with multiple sclerosis (pwMS) manifest heterogeneous demyelinating lesions that could affect somatosensory or vestibular ways, visual stimulus as feedback could be especially relevant to achieve postural control. This has clinical importance for the development of preventive measures and rehabilitation therapies in order to avoid falls and accidents in this group. In our study, we objectively evaluated the influence of visual feedback on the stabilization of balance in pwMS versus healthy controls (HC) and its potential utility in clinical evaluation. Static posturography tests were performed in 99 pwMS and 30 HC. Subjects stood on a force platform with open and closed eyes. During this procedure, three balance parameters were obtained for both vision conditions: average sway, average speed, and average speed of sway. Neurostatus-Expanded Disease Disability Score (EDSS) and Multiple Sclerosis Functional Composite (MSFC) were performed in parallel as well. A two-way mixed repeated measures ANCOVA, controlling for sex and age, was performed to evaluate the effect of vision, MS diagnosis, and the interaction of both in static posturography parameters. The difference between both closed and open eyes conditions was calculated for each parameter and further analyzed according to MS-relevant clinical variables. The magnitude of the vision effect differed between pwMS and HC as a significant interaction between the vision and the MS diagnosis in the delineated area (p < 0.001) and average speed of sway (p = 0.001) was seen. These parameters had a greater increase in pwMS than in HC after closing eyes. For the average sway, a significant main effect of vision was present (p = 0.047). Additionally, the differences obtained between open and closed eyes conditions assessed with the delineated area and average speed of sway were moderately correlated to the assessed clinical tests EDSS (r = 0.405 and r = 0.329, respectively) and the MSFC (r = −0.385 and r = −0.259, respectively). In our study, pwMS were more dependent of visual feedback than HC to maintain postural control. This easy and short evaluation by static posturography could support the development of targeted preventive measures and interventions in pwMS.
Insular Cell Integrity Markers Linked to Weight Concern in Anorexia Nervosa—An MR-Spectroscopy Study
Authors: Maier Simon , Nickel Kathrin , Perlov Evgeniy , Kukies Alina , Zeeck Almut , Tebartz van Elst Ludger , Endres Dominique , Spieler Derek , Holovics Lukas , Hartmann Armin , Dacko Michael , Lange Thomas , Joos Andreas
Published: May 2020

Objective: An insular involvement in the pathogenesis of anorexia nervosa (AN) has been suggested in many structural and functional neuroimaging studies. This magnetic resonance spectroscopy (MRS) study is the first to investigate metabolic signals in the anterior insular cortex in patients with AN and recovered individuals (REC). Method: The MR spectra of 32 adult women with AN, 21 REC subjects and 33 healthy controls (HC) were quantified for absolute N-acetylaspartate (NAA), glutamate + glutamine (Glx), total choline, myo-inositol, creatine concentrations (mM/L). After adjusting the metabolite concentrations for age and partial gray/white matter volume, group differences were tested using one-way multivariate analyses of variance (MANOVA). Post-hoc analyses of variance were applied to identify those metabolites that showed significant group effects. Correlations were tested for associations with psychometric measures (eating disorder examination), duration of illness, and body mass index. Results: The MANOVA exhibited a significant group effect. The NAA signal was reduced in the AN group compared to the HC group. The REC and the HC groups did not differ in metabolite concentrations. In the AN group, lower NAA and Glx signals were related to increased weight concern. Discussion: We interpret the decreased NAA availability in the anterior insula as a signal of impaired neuronal integrity or density. The association of weight concern, which is a core feature of AN, with decreased NAA and Glx indicates that disturbances of glutamatergic neurotransmission might be related to core psychopathology in AN. The absence of significant metabolic differences between the REC and HC subjects suggests that metabolic alterations in AN represent a state rather than a trait phenomenon.
Plasma Hyperosmolality Prolongs QTc Interval and Increases Risk for Atrial Fibrillation in Traumatic Brain Injury Patients
Authors: Dabrowski Wojciech , Siwicka-Gieroba Dorota , Robba Chiara , Badenes Rafael , Bialy Mateusz , Iwaniuk Paulina , Schlegel Todd T , Jaroszynski Andrzej
Published: May 2020

Introduction: Hyperosmotic therapy with mannitol is frequently used for treatment cerebral edema, and 320 mOsm/kg H2O has been recommended as a high limit for therapeutic plasma osmolality. However, plasma hyperosmolality may impair cardiac function, increasing the risk of cardiac events. The aim of this study was to analyze the relation between changes in plasma osmolality and electrocardiographic variables and cardiac arrhythmia in patients treated for isolated traumatic brain injury (iTBI). Methods: Adult iTBI patients requiring mannitol infusion following cerebral edema, and with a Glasgow Coma Score below 8, were included. Plasma osmolality was measured with Osmometr 800 CLG. Spatial QRS-T angle (spQRS-T), corrected QT interval (QTc) and STJ segment were calculated from digital resting 12-lead ECGs and analyzed in relation to four levels of plasma osmolality: (A) <280 mOsm/kg H2O; (B) 280–295 mOsm/kg H2O; (C) 295–310 mOsm/kg H2O; and (D) >310 mOsm/kg H2O. All parameters were measured during five consecutive days of treatment. Results: 94 patients aged 18-64 were studied. Increased plasma osmolality correlated with prolonged QTc (p < 0.001), intensified disorders in STJ and increased the risk for cardiac arrhythmia. Moreover, plasma osmolality >313 mOms/kg H2O significantly increased the risk of QTc prolongation >500 ms. Conclusion: In patients treated for iTBI, excessively increased plasma osmolality contributes to electrocardiographic disorders including prolonged QTc, while also correlating with increased risk for cardiac arrhythmias.
The Effect of an Abnormal BMI on Orthopaedic Trauma Patients: A Systematic Review and Meta-Analysis
Authors: Kinder Florence , Giannoudis Peter V. , Boddice Tim , Howard Anthony
Published: May 2020

Aims: The aim of this systemic review is to identify the complications that arise in operating on orthopaedic trauma patients with an abnormal body mass index (BMI). Materials and Methods: Systematic literature search using a combination of MESH subject headings and free text searching of Medline, Embase, SCOPUS and Cochrane databases in August 2019. Any orthopaedic injury requiring surgery was included. Papers were reviewed and quality assessed by two independent reviewers to select for inclusion. Where sufficiently homogenous, meta-analysis was performed. Results: A total of 26 articles (379,333 patients) were selected for inclusion. All complications were more common in those with a high BMI (>30). The odds ratio (OR) for high BMI patients sustaining post-operative complication of any type was 2.32 with a 23% overall complication rate in the BMI > 30 group, vs. 14% in the normal BMI group (p < 0.05). The OR for mortality was 3.5. The OR for infection was 2.28. The OR for non-union in tibial fractures was 2.57. Thrombotic events were also more likely in the obese group. Low BMI (<18.5) was associated with a higher risk of cardiac complications than either those with a normal or high BMI (OR 1.56). Conclusion: Almost all complications are more common in trauma patients with a raised BMI. This should be made clear during the consent process, and strategies developed to reduce these risks where possible. Unlike in elective surgery, BMI is a non-modifiable risk factor in the trauma context, but an awareness of the complications should inform clinicians and patients alike. Underweight patients have a higher risk of developing cardiac complications than either high or normal BMI patient groups, but as few studies exist, further research into this group is recommended.
Association of Salivary Human Papillomavirus Infection and Oral and Oropharyngeal Cancer: A Meta-Analysis
Authors: Rapado-González Óscar , Martínez-Reglero Cristina , Salgado-Barreira Ángel , Rodríguez-Fernández Almudena , Aguín-Losada Santiago , León-Mateos Luis , Muinelo-Romay Laura , López-López Rafael , Suarez-Cunqueiro María Mercedes
Published: May 2020

Background. Human papillomavirus (HPV) infection has been recognized as an important risk factor in cancer. The purpose of this systematic review and meta-analysis was to determine the prevalence and effect size of association between salivary HPV DNA and the risk of developing oral and oropharyngeal cancer. Methods. A systematic literature search of PubMed, EMBASE, Web of Science, LILACS, Scopus and the Cochrane Library was performed, without language restrictions or specified start date. Pooled data were analyzed by calculating odds ratios (ORs) and 95% confidence intervals (CIs). Quality assessment was performed using the Newcastle–Ottawa Scale (NOS). Results. A total of 1672 studies were screened and 14 met inclusion criteria for the meta-analysis. The overall prevalence of salivary HPV DNA for oral and oropharyngeal carcinoma was 43.2%, and the prevalence of salivary HPV16 genotype was 27.5%. Pooled results showed a significant association between salivary HPV and oral and oropharyngeal cancer (OR = 4.94; 2.82−8.67), oral cancer (OR = 2.58; 1.67−3.99) and oropharyngeal cancer (OR = 17.71; 6.42−48.84). Significant associations were also found between salivary HPV16 and oral and oropharyngeal cancer (OR = 10.07; 3.65−27.82), oral cancer (OR = 2.95; 1.23−7.08) and oropharyngeal cancer (OR = 38.50; 22.43−66.07). Conclusions. Our meta-analysis demonstrated the association between salivary HPV infection and the incidence of oral and oropharyngeal cancer indicating its value as a predictive indicator.
Genetic, Epigenetic, and Steroidogenic Modulation Mechanisms in Endometriosis
Authors: Zubrzycka Anna , Zubrzycki Marek , Perdas Ewelina , Zubrzycka Maria
Published: May 2020

Endometriosis is a chronic gynecological disease, affecting up to 10% of reproductive-age women. The exact cause of the disease is unknown; however, it is a heritable condition affected by multiple genetic, epigenetic, and environmental factors. Previous studies reported variations in the epigenetic patterns of numerous genes known to be involved in the aberrant modulation of cell cycle steroidogenesis, abnormal hormonal, immune and inflammatory status in endometriosis, apoptosis, adhesion, angiogenesis, proliferation, immune and inflammatory processes, response to hypoxia, steroidogenic pathway and hormone signaling are involved in the pathogenesis of endometriosis. Accumulating evidence suggest that various epigenetic aberrations may contribute to the pathogenesis of endometriosis. Among them, DNA methyltransferases, histone deacetylators, and non-coding microRNAs demonstrate differential expression within endometriotic lesions and in the endometrium of patients with endometriosis. It has been indicated that the identification of epigenetic differences within the DNA or histone proteins may contribute to the discovery of a useful prognostic biomarker, which could aid in the future earlier detection, timely diagnosis, and initiation of a new approach to the treatment of endometriosis, as well as inform us about the effectiveness of treatment and the stage of the disease. As the etiology of endometriosis is highly complex and still far from being fully elucidated, the presented review focuses on different approaches to identify the genetic and epigenetic links of endometriosis and its pathogenesis.
Effect of Dysmetabolisms and Comorbidities on the Efficacy and Safety of Biological Therapy in Chronic Inflammatory Joint Diseases
Authors: Cometi Laura , Bruni Cosimo , Chiti Nicolò , Tofani Lorenzo , Nacci Francesca , Bartoli Francesca , Bellando-Randone Silvia , Melchiorre Daniela , Fiori Ginevra , Guiducci Serena , Matucci-Cerinic Marco
Published: May 2020

In the present study we evaluated how systemic arterial hypertension (SAH), dyslipidemia and diabetes mellitus influence the efficacy, safety and retention rate of biological disease-modifying anti-rheumatic drug (bDMARD) treatment in rheumatic musculoskeletal disorders (RMDs). The charts of RMD patients treated with the first-line bDMARD were reviewed, collecting data on safety, efficacy and comorbidities at prescription (baseline, BL), after 6 months (6M) and at last observation on bDMARD (last observation time, LoT). In 383 RMD patients, a higher rate of adverse events at 6M (p = 0.0402) and at LoT (p = 0.0462) was present in dyslipidemic patients. Patients who developed dyslipidemia or SAH during bDMARD treatment had similar results (dyslipidemia p = 0.0007; SAH p = 0.0319) with a longer bDMARD retention as well (dyslipidemia p < 0.0001; SAH p < 0.0001). SAH patients on angiotensin converting enzyme inhibitors (ACEis) or angiotensin-II receptor blockers (ARBs) continued bDMARDs for longer than non-exposed patients (p = 0.001), with higher frequency of drug interruption for long-standing remission rather than inefficacy or adverse reactions (p = 0.0258). Similarly, dyslipidemic patients on statins had a better bDMARD retention than not-exposed patients (p = 0.0420). In conclusion, SAH and dyslipidemia may be associated with higher frequency of adverse events but a better drug retention of first-line bDMARD in RMDs, suggesting an additional effect of ACEis/ARBs or statins on the inflammatory process and supporting their use in RMD bDMARD patients with SAH/dyslipidemia.
Long-Term Treatment Outcome of Progressive Mycobacterium avium Complex Pulmonary Disease
Authors: Fukushima Kiyoharu , Kitada Seigo , Abe Yuko , Yamamoto Yuji , Matsuki Takanori , Kagawa Hiroyuki , Oshitani Yohei , Tsujino Kazuyuki , Yoshimura Kenji , Miki Mari , Miki Keisuke , Kida Hiroshi
Published: May 2020

Background: Multidrug therapy is essential for preventing respiratory failure in patients with highly progressive Mycobacterium avium complex pulmonary disease (MAC-PD). However, the prognosis and long-term outcome following combination therapy is poorly understood. Methods: We retrospectively evaluated the clinical characteristics and long-term outcomes in patients with chemo-naïve progressive MAC-PD, hospitalized for first-line multidrug therapy. Results: Among 125 patients, 86 (68.8%) received standardized treatment (rifampicin, ethambutol, clarithromycin), 25 (20.0%) received a fluoroquinolone (FQ)-containing regimen, and 53 (42.4%) received aminoglycoside injection. The sputum conversion rate was 80.0%, and was independently associated with standardized treatment. The incidence of refractory disease (45.6%) was independently and negatively associated with standardized regimen and aminoglycoside use. Choice of an FQ-containing regimen was not associated with positive outcome. Clarithromycin resistance occurred in 16.8% and was independently associated with refractory disease. MAC-PD-associated death occurred in 3.3% of patients with non-cavitary nodular bronchiectasis (NB) and 21.3% with cavitary MAC-PD over a median follow-up period of 56.4 months. The rates of MAC-PD-associated death were comparable between cavitary-NB and fibrocavitary disease. Concurrent chronic pulmonary aspergillosis (CPA) occurred in 13 (17.3%) patients with cavitary MAC-PD, and age, diabetes mellitus, and CPA were independent risk factors for mortality. Conclusions: Standardized intensive multidrug treatment reduces disease progression and persistence in progressive MAC-PD. Cavitary NB may differ from, rather than being just an advanced stage of, non-cavitary NB. The high incidence and significant mortality of CPA in cavitary MAC-PD highlight the need for early diagnosis and treatment.
Relationships Between Short-Term Exposure to an Indoor Environment and Dry Eye (DE) Symptoms
Authors: Idarraga Maria A. , Guerrero Juan S. , Mosle Samantha G. , Miralles Frank , Galor Anat , Kumar Naresh
Published: May 2020

Air composition influences Dry Eye (DE) symptoms as demonstrated by studies that have linked the outdoor environment to DE. However, there is insufficient data on the effect of short-term exposure to indoor environments on DE symptoms. We conducted a prospective experimental research, in which an older building served as an experimental site, and a newer building served as the control site. Indoor air quality was monitored in both buildings. One-hundred-and-ninety-four randomly selected individuals were interviewed in the afternoon exiting the buildings and de-identified responses were recorded. Self-reported DE symptoms were modeled with respect to experimental and control buildings, adjusting for potential confounders. The experimental site had 2-fold higher concentration of airborne particulate matter (24,436 vs. 12,213 ≥ 0.5 µm/ft3) and microbial colonies (1066 vs. 400/m3), as compared to the control building. DE symptoms were reported by 37.5% of individuals exiting the experimental and 28.4% exiting the control building. In the univariate analysis, subjects exiting the experimental building were 2.21× more likely to report worsening of DE symptoms since morning compared to the control building (p < 0.05). When adjusting for confounders, including a history of eye allergy, subjects from the experimental building were 13.3× more likely to report worsening of their DE symptoms (p < 0.05). Our findings suggest that short-term exposure to adverse indoor environmental conditions, specifically air pollution and bioaerosols, has an acutely negative impact on DE symptoms.
Gamma Knife Radiosurgery Followed by Flow-Reductive Embolization for Ruptured Arteriovenous Malformation
Authors: Kim Myung Ji , Park So Hee , Park Keun Young , Jung Hyun Ho , Chang Jong Hee , Chang Jin Woo , Lee Jae Whan , Chang Won Seok
Published: May 2020

Background: Aggressive treatment to achieve complete obliteration of brain arteriovenous malformation (AVM) is necessary in patients with a recent history of hemorrhage. The major drawback of Gamma knife radiosurgery (GKRS) alone for AVM is risk of bleeding during the latent period until the AVM occludes. At our center, patients who present with ruptured AVMs are frequently offered GKRS followed by embolization. The goal of this study was to compare outcomes of embolization for patients who have previously undergone GKRS for ruptured AVMs. Methods: A database including 150 GKRS for ruptured AVMs between November 2008 and October 2017 was reviewed. The embolized group was selected by including AVMs with post-GKRS embolization. The non-embolized group was defined as AVMs treated by GKRS alone. Outcomes including obliteration rate, incidence of repeat hemorrhage, and delayed cyst formation were compared between two groups. The predictive factors related to AVM obliteration and complications were analyzed. Results: The study consisted of 81 patients in the non-embolized group and 17 patients in the embolized group. Statistically significant differences were detected between the two groups with respect to age, Pollock-Flickinger score, Spetzler-Martin (SM) grade, eloquence of adjacent brain, and presence of aneurysms. The embolized group included more AVMs with larger median nidus volume. The predictive factors for the obliteration of ruptured AVMs were nidus volume, SM grade, Virginia Radiosurgery AVM Scale (VRAS), and Pollock-Flickinger score and for the subsequent hemorrhage were marginal dose, nidus volume, SM grade, VRAS, and Pollock-Flickinger score. The obliteration rates and complication rates after GKRS between groups were not significantly different. However, this study demonstrated statistically significant difference in the cumulative incidence of obliteration in AVMs with SM grade III and IV (p = 0.037). Conclusion: Although the current study demonstrated similar results in patients who underwent GKRS with and without embolization, the embolized group included more AVMs with larger nidus volume, higher SM grade, Pollock-Flickinger score, and aneurysm, which have a lower chance of obliteration and a higher probability of repeat hemorrhage. GKRS followed by embolization appears to be a beneficial approach for the treatment of ruptured AVMs that are at risk for obliteration failure and repeat hemorrhage during the latency period after single-session GKRS alone. Further studies involving a larger number of cases and continuous follow-up are necessary to confirm our conclusions.
Scoring System for Identification of “Survival Advantage” after Successful Percutaneous Coronary Intervention in Patients with Chronic Total Occlusion
Authors: Nakachi Tatsuya , Kohsaka Shun , Yamane Masahisa , Muramatsu Toshiya , Okamura Atsunori , Kashima Yoshifumi , Matsuno Shunsuke , Sakurada Masami , Seino Yoshitane , Habara Maoto
Published: May 2020

Background: Percutaneous coronary intervention (PCI) is widely used in patients with chronic total occlusion (CTO), but its benefit in improving long-term outcomes is controversial. We aimed to develop a prediction score for grading “survival advantage” conferred by successful results of CTO-PCI and a scoring system for prediction of the influence of CTO-PCI results on major adverse cardiac and cerebrovascular events (MACCEs). Methods: Follow-up data of 2625 patients who underwent CTO-PCI at 65 Japanese centers were analyzed. An integer scoring system was developed by including statistical effect modifiers on the association between successful CTO-PCI and one-year mortality. Results: Follow-up at 12 months was completed in 2034 patients. During follow-up, 76 deaths (3.7%) occurred. Patients with successful CTO-PCI had a better one-year survival than patients with failed CTO-PCI (log rank P = 0.016). Effect modifiers for the association between successful procedure and one-year mortality included diabetes (P interaction = 0.043), multivessel disease (P interaction = 0.175), Canadian Cardiovascular Society class ≥2 (P interaction = 0.088), and prior myocardial infarction (MI) (P interaction = 0.117). Each component was assigned a single point and summed to develop the scoring system. The patients were then categorized to specify the prediction of survival advantage by successful PCI: ≤2 (normal) and ≥3 (distinct). The differences in one-year mortality between patients with successful and failed treatment were −0.7% and 11.3% for normal and distinct score categories, respectively. In the scoring system for MACCE, score components were prior MI (P interaction = 0.19), left anterior descending artery (LAD)-CTO (P interaction = 0.079), and reattempt of CTO-PCI (P interaction = 0.18). The differences in one-year MACCEs between successful and failed patients for each score category (0, 1, and ≥2) were −1.7%, 7.5%, and 15.1%, respectively. Conclusions: The novel scoring system assessing the advantage of successful PCI can be easily applied in patients with CTO. It is a valid instrument for clinical decision-making while assessing the survival advantage of CTO-PCI and the influence of procedural results on MACCEs.
Outcome Comparison between Low-Dose Rabbit Anti-Thymocyte Globulin and Basiliximab in Low-Risk Living Donor Kidney Transplantation
Authors: Kim Sang Jin , Rhu Jinsoo , Yoo Heejin , Kim Kyunga , Lee Kyo Won , Park Jae Berm
Published: May 2020

The objective of this study was to compare outcomes between basiliximab and low-dose r-ATG in living donor kidney transplantation recipients with low immunological risk. Patients in the low-dose r-ATG group received 1.5 mg/kg of r-ATG for 3 days (total 4.5 mg/kg). Graft survival, patient survival, acute rejection, de novo donor specific antibody (DSA), estimated glomerular filtration rate (e-GFR) changes, and infection status were compared. Among 268 patients, 37 received r-ATG, and 231 received basiliximab. There was no noticeable difference in the graft failure rate (r-ATG vs. basiliximab: 2.7% vs. 4.8%) or rejection (51.4% vs. 45.9%). de novo DSA was more frequent in the r-ATG group (11.4% vs. 2.4%, p = 0.017). e-GFR changes did not differ noticeably between groups. Although most infections showed no noticeable differences between groups, more patients in the r-ATG group had cytomegalovirus (CMV) antigenemia and serum polyomavirus (BK virus) (73.0% vs. 51.9%, p = 0.032 in CMV; 37.8% vs. 15.6%, p = 0.002 in BK), which did not aggravate graft failure. Living donor kidney transplantation patients who received low-dose r-ATG and patients who received basiliximab showed comparable outcomes in terms of graft survival, function, and overall infections. Although CMV antigenemia, BK viremia were more frequent in the r-ATG group, those factors didn’t change the graft outcomes.
ROCK (RhoA/Rho Kinase) in Cardiovascular–Renal Pathophysiology: A Review of New Advancements
Authors: Seccia Teresa M. , Rigato Matteo , Ravarotto Verdiana , Calò Lorenzo A.
Published: May 2020

Rho-associated, coiled-coil containing kinases (ROCK) were originally identified as effectors of the RhoA small GTPase and found to belong to the AGC family of serine/threonine kinases. They were shown to be downstream effectors of RhoA and RhoC activation. They signal via phosphorylation of proteins such as MYPT-1, thereby regulating many key cellular functions including proliferation, motility and viability and the RhoA/ROCK signaling has been shown to be deeply involved in arterial hypertension, cardiovascular–renal remodeling, hypertensive nephropathy and posttransplant hypertension. Given the deep involvement of ROCK in cardiovascular–renal pathophysiology and the interaction of ROCK signaling with other signaling pathways, the reports of trials on the clinical beneficial effects of ROCK’s pharmacologic targeting are growing. In this current review, we provide a brief survey of the current understanding of ROCK-signaling pathways, also integrating with the more novel data that overall support a relevant role of ROCK for the cardiovascular–renal physiology and pathophysiology.
A History of Large for Gestational Age at Birth and Future Risk for Pediatric Neoplasms: A Population-Based Cohort Study
Authors: Kessous Roy , Sheiner Eyal , Landau Daniella , Wainstock Tamar
Published: May 2020

Objective: The aim of this study was to evaluate the association between large for gestational age (LGA) at birth and future risk of childhood neoplasm. Study design: a population-based cohort to compare the long-term risk (up to the age of 18 years) of childhood neoplasms (benign and malignant) in children that were born LGA vs. those that were appropriate for gestational age (AGA), between the years 1991–2014. Childhood neoplasms diagnosis were defined according to international classification of disease 9 (ICD-9) codes recorded medical files. Kaplan–Meier survival curves were used in order to compare cumulative incidence of oncological morbidity over the study period. The Cox proportional hazards model was used to control for confounders. Results: 231,344 infants met the inclusion criteria; out of those 10,369 were diagnosed LGA at birth. Children that were LGA at birth had a higher incidence of leukemia (OR 2.25, 95%CI 1.08–4.65, p = 0.025) as well as kidney tumors (OR = 4.7, 95%CI = 1.02–21.9, p = 0.028). In addition, cumulative incidence over time of childhood malignancies, leukemia, and kidney tumors were significantly higher in LGA children (Log Rank = 0.010, 0.021, and 0.028, respectively). In a Cox regression model controlling for other perinatal confounders, LGA at birth remained independently associated with an increased risk for childhood malignancy (adjusted HR 1.51, 95%CI 1.02–2.23, p = 0.039). Conclusion: LGA at birth is associated with increased long-term risk for childhood malignancy and specifically leukemia and kidney tumors. This possible link may help to improve current knowledge regarding potential exposures that are associated with childhood cancer development.
Breakthrough Pain in Patients with Lung Cancer. A Secondary Analysis of IOPS MS Study
Authors: Mercadante Sebastiano , Masedu Francesco , Valenti Marco , Aielli Federica
Published: May 2020

Aim: To characterize breakthrough cancer pain (BTcP) in patients with lung cancer. Methods: This was a secondary analysis of multicenter study of patients with BTcP. Background pain intensity and opioid dose were recorded. The number of BTcP episodes, their intensity, predictability, onset, duration and interference with daily activities were collected. Opioids used for BTcP, the mean time to meaningful pain relief after taking medication, satisfaction and adverse effects were assessed. Results: 1087 patients with lung cancer were examined. In comparison with other tumors, patients with lung cancer showed: higher background pain intensity (p = 0.006), lower opioid doses (p = 0.005), higher intensity of BTcP (p = 0.005), movement (79.5%) and cough (8.2%), as principal triggers for predictable BTcP (p < 0.009), larger BTcP interference with daily activity (p = 0.0001), higher use of adjuvants (p = 0.0001). No relevant differences in the other parameters examined were found. Conclusion: Patients with lung cancer have their own peculiarities, including higher basal and BTcP pain intensity and the use of more adjuvant drugs for background pain. The most frequent triggers for predictable BTcP are movement and cough. Future studies should be performed to analyze the prevalence of BTcP in patients with different lung cancers as well as the optimal management strategy for background pain and BTcP.
Ovarian Cancer in the Elderly: Time to Move towards a More Logical Approach to Improve Prognosis—A Study from the FRANCOGYN Group
Authors: Dion Ludivine , Mimoun Camille , Nyangoh Timoh Krystel , Bendifallah Sofiane , Bricou Alexandre , Collinet Pierre , Touboul Cyril , Ouldamer Lobna , Azaïs Henri , Dabi Yohann , Akladios Cherif , Canlorbe Geoffroy , Bolze Pierre-Adrien , Costaz Hélène , Mezzadri Mathieu , Gauthier Tristan , Kridelka Frederik , Chauvet Pauline , Bourdel Nicolas , Koskas Martin , Carcopino Xavier , Raimond Emilie , Graesslin Olivier , Lecointre Lise , Ballester Marcos , Levêque Jean , Huchon Cyrille , Lavoué Vincent
Published: May 2020

Background and objective: Elderly and/or frail women with ovarian cancer are often undertreated. The aim of the study is to compare the effects of age and frailty on surgical approaches, postoperative complications, and prognosis in elderly women with ovarian cancer. Methods: A retrospective multicenter study of women ≥70 years were treated for ovarian cancer at seven French university hospitals between 2007 and 2015. Results: Of the 1119 women treated for ovarian cancer during the study period, 147 were ≥70 years and had complete data. Of these women, 65 were aged 70–74 years, and 82 were aged ≥75 years. Overall, 77% of the younger women (49/65) received optimal treatment compared with 51% (40/82) of the older women (p = 0.018). Women ≥75 years underwent fewer bowel resections (32% vs. 67%, p < 0.001) and experienced fewer postoperative complications (22.6% vs. 38.9%, p < 0.001); 53.2% of the women in this age group were treated by primary surgery or surgery only. These women also received more chemotherapy with platinum only (15% [9/56] vs. 2% [1/57], p = 0.007) and less bevacizumab (9% [5/56] vs. 32% [18/57], p = 0.003). Patients with greater frailty (a modified Charlson Comorbidity Index [mCCI] score >3) had a five-year survival rate of 30% versus 62% for those with a score ≤3 (p < 0.001). Conclusions: Surgeons modify their approach to treating ovarian cancer in women ≥75 years probably to reduce immediate postoperative complications. The prognosis is significantly worse in patients with greater frailty. Improvements to the sequence of treatments administered, with priority given to neoadjuvant chemotherapy in patients with greater frailty, could help increase the number of women who receive optimal treatment and improve their prognosis.