Clinical and Translational Oncology

Common misconceptions in the prognostic evaluation of clinically stable patients with febrile neutropenia and solid tumors

A comparative assessment of the effects of integrin inhibitor cilengitide on primary culture of head and neck squamous cell carcinoma (HNSCC) and HNSCC cell lines Abstract Background Integrins are highly attractive targets in oncology due to their involvement in angiogenesis in a wide spectrum of cancer entities. Among several integrin inhibitors, cilengitide is suggested to be one of the most promising inhibitors. However, little is known about the cellular processes induced during cilengitide chemotherapy in head and neck squamous cell carcinoma (HNSCC). Materials and methods For the current study, 3 HNSCC cell lines, SCC4, SCC15 and SCC25; and 3 primary culture cells, TU53, TU57, and TU63 were used. CD90, cytokeratin, and vimentin were stained immunohistochemically to identify the biological characteristics of these cell lines and primary culture cells and the cytostatic effect of cilengitide was evaluated. Quantitative polymerase chain reaction (qPCR) arrays were applied to evaluate target protein genes ITGAV, ITGB3, and ITGB5 of integrin αvβ3 and αvβ5 at respective concentrations of 50 and 100 μM cilengitide for 72 h. Results Cilengitide has significantly inhibited the proliferation of HNSCC cells in a dose-dependent way. At the same concentration, cilengitide suppressed the proliferation of primary culture cells even more strongly than it did that of cell lines, suggesting that primary culture cells retain more of their internal biological characteristics than do cell lines. qPCR assay detected downregulation of ITGAV, ITGB3, and ITGB5 gene expression after exposure to 50 μM of cilengitide. However, after exposure to 100-μM cilengitide, expression of these genes significantly increased both in cell lines and primary culture cells. Conclusions RGD-containing small-molecule synthetic peptides might be considered in tumor chemotherapy in the near future. The different reactions of primary culture cells and cell lines demonstrated that individualized chemotherapy plans may be a feasible option. However, research on the role of cilengitide in HNSCC therapy is still in its early stages, and further investigations are required.

Efficacy of nivolumab as checkpoint inhibitor drug on survival rate of patients with relapsed/refractory classical Hodgkin lymphoma: a meta-analysis of prospective clinical study Abstract Aims The primary standard treatment for classic Hodgkin's lymphoma (cHL) is chemotherapy and radiation therapy. However, some patients get relapsed, or their diseases become resistant. PD1 blocking antibodies have been used to increase the response of treatment in solid tumors, and led to potentially stable responses that are acceptable. Our purpose in this study is to investigate the effect of nivolumab as a PD1 blocking antibody on the survival rate of patients with Hodgkin's cancer. Methods Databases were found in International Medical Sciences, Web of Science, Medline, Scopus, Index Copernicus, PubMed, DOAJ, Google Scholar, EBSCO-CINAHL, and Persian databases containing SID and Magiran using keywords such as: "checkpoint inhibitor", "nivolumab", "Hodgkin lymphoma", and "PD1 Blockade". The risk of bias was determined by two external observers using the Cochrane checklists. After the search, the data provided in 51 documents was independently evaluated. Duplicate papers were excluded. Assessing the full texts of the remaining papers, 7 papers were approved. Results Pooled data of these seven studies revealed that the overall objective response rate was 68% (CI 64.1% to 72.1%; heterogeneity; I2 = 40.19%; p = 0.123) with partial remission (52%; CI 46.5% to 57.6%; heterogeneity; I2 = 28.36%; p = 0.212). In the pooled analysis, complete remission was 16.8 (CI 11.1% to 26.4%). Pooled data of six studies showed that stable disease was averaged to 19% (CI 16% to 23%; heterogeneity; I2 = 30%; p = 0.209; fixed-effect model). Conclusions The results of the study indicate that nivolumab as a PD1 pathway inhibitor can be effective in treating relapsed and refractory cHL patients compared to other therapies, and lead to more effective treatment over the long term. Furthermore, the adverse effects of nivolumab are controllable and have a good safety profile.

Efficacy of rechallenge with BRAF inhibition therapy in patients with advanced BRAFV600 mutant melanoma Abstract Background The treatment of patients with BRAFv600 mutant melanomas progressing to BRAF inhibitors (BRAFi) and immunotherapy remains challenging. Preclinical studies and a small phase 2 trials have recently suggested that rechallenging with BRAFi may have a roll in these patients. The aim of this systematic review was to summarise the current evidence on the efficacy of BRAF inhibition therapy rechallenge after progression to BRAFi in metastatic BRAFv600 melanoma patients. Materials and methods We performed a systematic literature search in MEDLINE, Embase and the Cochrane Library CENTRAL up to November 2018. The target was restricted to patients with unresectable and/or metastatic BRAF V600 mutant melanoma that had previously progressed on BRAFi, were off-treatment for a period of time and then retreated with a BRAF inhibition strategy. We included prospective trials, observational studies and case reports. The primary outcomes were overall response rate (ORR), disease control rate (DCR), median progression-free survival (PFS) and median overall survival since the start of the treatment. Results Up to November 2018, nine reports met our inclusion criteria: five case reports, three observational studies and a phase 2 trial. No comparative studies have been reported. In total, 188 patients met the inclusion criteria for this review. Efficacy results of the observational reports and the clinical trial are presented. ORR varied between 28 and 43% and DCR between 57 and 72%. Duration of response was reported in 1 retrospective study and was of 14 months. PFS varied between 4.9 and 5 months and OS was not reported in all studies. Conclusion Although no comparative studies have been conducted, rechallenging with BRAF inhibition therapy seems a plausible treatment option. Randomized trials are needed to confirm these results.

The RANK–RANKL axis: an opportunity for drug repurposing in cancer? Abstract Drug repurposing offers advantages over traditional drug development in terms of cost, speed and improved patient outcomes. The receptor activator of nuclear factor kappa B (RANK) ligand (RANKL) inhibitor denosumab is approved for the prevention of skeletal-related events in patients with advanced malignancies involving bone, including solid tumours and multiple myeloma. Following improved understanding of the role of RANK/RANKL in cancer biology, denosumab has already been repurposed as a treatment for giant cell tumour of bone. Here, we review the role of RANK/RANKL in tumourigenesis, including effects on tumour initiation, progression and metastasis and consider the impact of RANK/RANKL on tumour immunology and immune evasion. Finally, we look briefly at ongoing trials and future opportunities for therapeutic synergy when combining denosumab with anti-cancer agents such as immune checkpoint inhibitors.

The role of immunotherapy in small cell lung cancer Abstract Despite decades of research, prognosis for SCLC patients remains poor, and treatment options limited. SCLC is an immunogenic tumor with high somatic mutation rates due to tobacco exposure resulting in potential neo-antigens, the presence of suppressed immune responses, and occurrence of paraneoplastic disorders. The use of T cell immune-checkpoint inhibitors (anti-PD1: nivolumab, pembrolizumab; anti-PD-L1: atezolizumab, durvalumab; anti-CTLA-4: ipilimumab, tremelimumab) have shown promising antitumor activity with the potential to prolong survival in SCLC patients. In fact, atezolizumab when combined with chemotherapy has achieved the milestone of being the first drug to improve survival in patients with newly diagnosed extensive-stage SCLC. Other immunotherapeutic approaches evaluated in clinical trials for SCLC include the use of cytokines, cancer vaccines, antiganglioside therapies, TLR9 inhibition, anti-Notch signaling, and anti-CD47. This review discusses the rationale and clinical evidence of immunotherapy in SCLC, the conflictive clinical results of novel immunotherapeutic agents and combinatorial therapies under evaluation in SCLC patients.

Letrozole improves the sensitivity of breast cancer cells overexpressing aromatase to cisplatin via down-regulation of FEN1 Abstract Purpose Flap endonuclease 1 (FEN1) is up-regulated by estrogen (17β-estradiol, E2) and related to cisplatin resistance of human breast cancer cells. Letrozole, an aromatase inhibitor, suppresses the change of testosterone into estrogen and is frequently used to treat breast cancer. However, the effects of letrozole on FEN1 expression and cisplatin sensitivity in breast cancer cells overexpressing aromatase have not been revealed. Methods The expression of FEN1 and the proteins in ERK/Elk-1 signaling were evaluated by RT-PCR and Western blot. Cisplatin sensitivity was explored through CCK-8 and flow cytometry analysis, respectively. FEN1 siRNAs and FEN1 expression plasmid were transfected into cells to down-regulate or up-regulate FEN1 expression. The promotor activity of FEN1 was detected using luciferase reporter assay. Results FEN1 down-regulation improved cisplatin sensitivity of breast cancer cells overexpressing aromatase. Letrozole down-regulated FEN1 expression and increased cisplatin sensitivity. The sensitizing effect of letrozole to cisplatin was dependent on FEN1 down-regulation. FEN1 overexpression could block the sensitizing effect of letrozole to cisplatin. Testosterone up-regulated the promotor activity, protein expression of FEN1, and phosphorylation of ERK/Elk-1, which could be eliminated by both letrozole and MEK1/2 inhibitor U0126. Letrozole down-regulated FEN1 expression in an ERK/Elk-1-dependent manner. Conclusions Our findings clearly demonstrate that letrozole improves cisplatin sensitivity of breast cancer cells overexpressing aromatase via down-regulation of FEN1 and suggest that a combined use of letrozole and cisplatin may be a potential treatment protocol for relieving cisplatin resistance in human breast cancer.

Neurotrophic tropomyosin receptor kinase (NTRK) and nerve growth factor (NGF) are not expressed in Caucasian patients with biliary tract cancers: pooled data from three independent cohorts Abstract Background Neuronal signaling has been implicated in the pathophysiology of multiple malignancies. In biliary tract cancers (BTCs), tumor cell expression of nerve growth factor (NGF) and its receptor neurotrophic tropomyosin receptor kinase (NTRK) has been reported in Asian patients and linked to inferior clinical outcome. Furthermore, NTRK fusions have emerged as a promising target in various cancers. Expression patterns of these markers in Caucasian patients remain unknown. Methods In this study, 106 patients with BTCs were included. Immunohistochemistry for pan-NTRK and NGF-beta was performed on > 90 samples of this cohort. Additionally, samples from two independent cohorts, incorporating 254 cases, were used to confirm the findings of the original cohort. Results While expression of pan-NTRK and NGF-beta was readily detectable in peri-tumoral nerves, these markers were not detectable in malignant epithelial cells in our cohort. Conclusions In a large cohort of Caucasian patients with BTC, NTRK and NGF-beta were not detectable, underscoring potential differences between Caucasian and Asian patient populations.

Cost–utility analysis of germline BRCA1/2 testing in women with high-grade epithelial ovarian cancer in Spain Abstract Purpose Germline mutations in BRCA1 and/or BRCA2 genes (gBRCA1/2m) are associated with an increased risk of breast cancer (BC) and ovarian cancer (OC). The aim of this study was to estimate the efficiency of providing germline BRCA1/2 testing to high-grade epithelial ovarian cancer (HGEOC) patients without family history of OC or BC and the subsequent testing and management of their relatives with gBRCA1/2m in Spain. Methods/patients Incident HGEOC patients without family history of OC or BC who were gBRCA1/2m carriers and their relatives were simulated in a 50-year time horizon. The study compared two scenarios: BRCA1/2 testing vs no testing, using the perspective of the Spanish National Health Service. Cancer risk among gBRCA1/2m carriers was estimated based on their age and whether they had undergone risk-reducing surgeries. Direct healthcare costs and utilities of patients who developed EOC and BC were also included. A probabilistic sensitivity analysis (PSA) with 5 thousand simulations was developed considering ± 25% of the base-case value. Results The BRCA1/2-testing scenario amounted to €13,437,897.43 while the no-testing scenario amounted to €12,053,291.17. It was estimated that the screening test improved the quality of life among the patients' relatives by 43.8 quality-adjusted life years (QALYs). The incremental cost–utility ratio (ICUR) was €31,621.33/QALY in the base case. The PSA showed that 89.12% of the simulations were below the €50,000/QALY threshold. Conclusion Providing this screening test to HGEOC patients and their relatives is cost-effective and it allows one to identify a target population with high risk of cancer to provide effective prevention strategies.

Clinical significance of serum EGFR gene mutation and serum tumor markers in predicting tyrosine kinase inhibitor efficacy in lung adenocarcinoma Abstract Objective To study the clinical significance of serum epidermal growth factor receptor (EGFR) gene mutation and serum tumor markers in the prediction of tyrosine kinase inhibitor (TKI) efficacy in patients with lung adenocarcinoma. Methods Ninety patients with pathologically diagnosed lung adenocarcinoma were enrolled. Further, 51 out of 90 patients received the EGFR-TKI therapy, oral gefitinib. The correlations among serum EGFR gene mutations in exons 18–21, serum tumor markers such as carcinoembryonic antigen (CEA), carbohydrate antigen 24-2 (CA24-2), carbohydrate antigen 125, carbohydrate antigen 15-3 as well as carbohydrate antigen 19-9 (CA19-9) levels, and EGFR-TKI efficacy were determined. Results There was a high consistency of EGFR gene mutation rate between serum and tissue samples. The serum EGFR gene mutation rate in female patients or non-smokers was significantly higher than that in male patients or smokers, respectively. Serum CA19-9, CA24-2, and CEA levels were significantly correlated with serum EGFR mutation. After receiving gefitinib, the progression-free survivals (PFSs) of patients with high serum CEA level, high serum CA19-9 level, or serum EGFR gene mutation were significantly higher than those of normal patients, respectively. The PFSs were significantly prolonged in patients with EGFR gene mutation and high serum CEA level or patients with EGFR gene mutation and high serum CA19-9 level compared with those in patients with one abnormal biomarker and normal patients. Conclusion Combined detection of EGFR gene mutations as well as CA19-9 and CEA levels in peripheral blood can predict the efficacy of EGFR-TKI in the treatment of patients with lung adenocarcinoma.

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

European Radiology

Correction to: Diagnostic efficacy and safety of ultrasound-guided kidney transplant biopsy using cortex-only view: a retrospective single-center study The original version of this article, published on 17 December 2018, unfortunately contained a mistake. The following correction has therefore been made in the original: The name of Jaeseung Shin was presented incorrectly. The corrected author list is given above.

Correction to: Deep learning reconstruction improves image quality of abdominal ultra-high-resolution CT The original version of this article, published on 11 April 2019, unfortunately, contained a mistake. The following correction has therefore been made in the original: The image in Fig. 3c was wrong. The corrected figure is given below. The original article has been corrected.

Correction to: Is liver lesion characterisation by simplified IVIM DWI also feasible at 3.0 T? The original version of this article, published on 08 April 2019, unfortunately contained a mistake. The following correction has therefore been made in the original: The caption of Fig. 2 is wrong. The corrected version is given below.

Pericolic or paracolic? The right word in the right place for acute diverticulitis Key Point • The term "pericolic" is wrongly used to describe an abscess adjacent to the colon in patients with acute diverticulitis. We explain why the proper term is the word "paracolic."

Amide proton transfer–weighted MRI can detect tissue acidosis and monitor recovery in a transient middle cerebral artery occlusion model compared with a permanent occlusion model in rats Abstract Objectives To assess whether increases in amide proton transfer (APT)–weighted signal reflect the effects of tissue recovery from acidosis using transient rat middle cerebral artery occlusion (MCAO) models, compared to permanent occlusion models. Materials and methods Twenty-four rats with MCAO (17 transient and seven permanent occlusions) were prepared. APT-weighted signal (APTw), apparent diffusion coefficient (ADC), cerebral blood flow (CBF), and MR spectroscopy were evaluated at three stages in each group (occlusion, reperfusion/1 h post-occlusion, and 3 h post-reperfusion/4 h post-occlusion). Deficit areas showing 30% reduction to the contralateral side were measured. Temporal changes were compared with repeated measures of analysis of variance. Relationship between APTw and lactate concentration was calculated. Results Both APTw and CBF values increased and APTw deficit area reduced at reperfusion (largest p = .002) in transient occlusion models, but this was not demonstrated in permanent occlusion. No significant temporal change was demonstrated with ADC at reperfusion. APTw deficit area was between ADC and CBF deficit areas in transient occlusion model. APTw correlated with lactate concentration at occlusion (r = − 0.49, p = .04) and reperfusion (r = − 0.32, p = .02). Conclusions APTw values increased after reperfusion and correlated with lactate content, which suggests that APT-weighted MRI could become a useful imaging technique to reflect tissue acidosis and its reversal. Key Points • APT-weighted signal increases in the tissue reperfusion, while remains stable in the permanent occlusion. • APTw deficit area was between ADC and CBF deficit areas in transient occlusion model, possibly demonstrating metabolic penumbra. • APTw correlated with lactate concentration during ischemia and reperfusion, indicating tissue acidosis.

Non-measurable infiltrative HCC: is post-contrast attenuation on CT a sign of tumor response? Abstract Objectives To evaluate the value of CT attenuation to assess the response to sorafenib in infiltrative/endovascular non-measurable advanced hepatocellular carcinoma (HCC). Methods From 2007 to 2014, patients with infiltrative HCC ± tumor-in-vein (TIV) were retrospectively included. Attenuation of tumors and TIV were measured at baseline and follow-up on arterial and portal venous phase CT by two independent radiologists. Attenuation changes (overall and as per Choi criteria) and Child-Pugh score were correlated to overall survival. Results Forty patients were included (38 men, 95%). Attenuation of both the tumors and TIV was significantly lower in follow-up CT than on baseline CT (p = 0.002 (arterial), and p = 0.001 (portal) for tumor, and p = 0.004 (arterial) and p < 0.001 (porta) for TIV). Median attenuation of TIV was significantly lower than that of the tumor in follow-up images (p = 0.010). Median OS for the entire cohort was 4 ± 1 months (95% CI: 2.1–5.9), with estimated OS rates at 6, 12, and 24 months of 43%, 29 and 12%, respectively. Baseline and follow-up CT attenuation in tumors and TVI were not correlated with survival. Survival was not significantly increased in patients with Choi criteria >15% CT HU decrease in the tumor and/or TIV during follow-up. Only Child-Pugh A (HR 4.9 (95%CI 2.3–10.7), p < 0.001) was identified as an independent factor of improved survival on multivariate analysis. Conclusion Despite significant changes under sorafenib, tumor attenuation of infiltrative/endovascular non-measurable HCC may be of limited value to assess survival in this subgroup of patients with very poor prognosis. Key Points • Attenuation of both tumors and tumor-in-vein decreases after sorafenib. • Attenuation decrease is more marked in the tumor-in-vein than in the tumor. • Attenuation decrease is not associated with longer overall survival.

Differentiation between pilocytic astrocytoma and glioblastoma: a decision tree model using contrast-enhanced magnetic resonance imaging-derived quantitative radiomic features Abstract Objective To differentiate brain pilocytic astrocytoma (PA) from glioblastoma (GBM) using contrast-enhanced magnetic resonance imaging (MRI) quantitative radiomic features by a decision tree model. Methods Sixty-six patients from two centres (PA, n = 31; GBM, n = 35) were randomly divided into training and validation data sets (about 2:1). Quantitative radiomic features of the tumours were extracted from contrast-enhanced MR images. A subset of features was selected by feature stability and Boruta algorithm. The selected features were used to build a decision tree model. Predictive accuracy, sensitivity and specificity were used to assess model performance. The classification outcome of the model was combined with tumour location, age and gender features, and multivariable logistic regression analysis and permutation test using the entire data set were performed to further evaluate the decision tree model. Results A total of 271 radiomic features were successfully extracted for each tumour. Twelve features were selected as input variables to build the decision tree model. Two features S(1, -1) Entropy and S(2, -2) SumAverg were finally included in the model. The model showed an accuracy, sensitivity and specificity of 0.87, 0.90 and 0.83 for the training data set and 0.86, 0.80 and 0.91 for the validation data set. The classification outcome of the model related to the actual tumour types and did not rely on the other three features (p < 0.001). Conclusions A decision tree model with two features derived from the contrast-enhanced MR images performed well in differentiating PA from GBM. Key Points • MRI findings of PA and GBM are sometimes very similar. • Radiomics provides much more quantitative information about tumours. • Radiomic features can help to distinguish PA from GBM.

Radiomics model of contrast-enhanced computed tomography for predicting the recurrence of acute pancreatitis Abstract Objectives To predict the recurrence of acute pancreatitis (AP) by constructing a radiomics model of contrast-enhanced computed tomography (CECT) at AP first attack. Methods We retrospectively enrolled 389 first-attack AP patients (271 in the primary cohort and 118 in the validation cohort) from three tertiary referral centers; 126 and 55 patients endured recurrent attacks in each cohort. Four hundred twelve radiomics features were extracted from arterial and venous phase CECT images, and clinical characteristics were gathered to develop a clinical model. An optimal radiomics signature was chosen using a multivariable logistic regression or support vector machine. The radiomics model was developed and validated by incorporating the optimal radiomics signature and clinical characteristics. The performance of the radiomics model was assessed based on its calibration and classification metrics. Results The optimal radiomics signature was developed based on a multivariable logistic regression with 10 radiomics features. The classification accuracy of the radiomics model well predicted the recurrence of AP for both the primary and validation cohorts (87.1% and 89.0%, respectively). The area under the receiver operating characteristic curve (AUC) of the radiomics model was significantly better than that of the clinical model for both the primary (0.941 vs. 0.712, p = 0.000) and validation (0.929 vs. 0.671, p = 0.000) cohorts. Good calibration was observed for all the models (p > 0.05). Conclusions The radiomics model based on CECT performed well in predicting AP recurrence. As a quantitative method, radiomics exhibits promising performance in terms of alerting recurrent patients to potential precautions. Key Points • The incidence of recurrence after an initial episode of acute pancreatitis is high, and quantitative methods for predicting recurrence are lacking. • The radiomics model based on contrast-enhanced computed tomography performed well in predicting the recurrence of acute pancreatitis. • As a quantitative method, radiomics exhibits promising performance in terms of alerting recurrent patients to the potential need to take precautions.

Differentiation of clear cell and non-clear cell renal cell carcinomas by all-relevant radiomics features from multiphase CT: a VHL mutation perspective Abstract Objectives To develop a radiomics model with all-relevant imaging features from multiphasic computed tomography (CT) for differentiating clear cell renal cell carcinoma (ccRCC) from non-ccRCC and to investigate the possible radiogenomics link between the imaging features and a key ccRCC driver gene—the von Hippel-Lindau (VHL) gene mutation. Methods In this retrospective two-center study, two radiomics models were built using random forest from a training cohort (170 patients), where one model was built with all-relevant features and the other with minimum redundancy maximum relevance (mRMR) features. A model combining all-relevant features and clinical factors (sex, age) was also built. The radiogenomics association between selected features and VHL mutation was investigated by Wilcoxon rank-sum test. All models were tested on an independent validation cohort (85 patients) with ROC curves analysis. Results The model with eight all-relevant features from corticomedullary phase CT achieved an AUC of 0.949 and an accuracy of 92.9% in the validation cohort, which significantly outperformed the model with eight mRMR features (seven from nephrographic phase and one from corticomedullary phase) with an AUC of 0.851 and an accuracy of 81.2%. Combining age and sex did not benefit the performance. Five out of eight all-relevant features were significantly associated with VHL mutation, while all eight mRMR features were significantly associated with VHL mutation (false discovery rate-adjusted p < 0.05). Conclusions All-relevant features in corticomedullary phase CT can be used to differentiate ccRCC from non-ccRCC. Most subtype-discriminative imaging features were found to be significantly associated with VHL mutation, which may underlie the molecular basis of the radiomics features. Key Points • All-relevant features in corticomedullary phase CT can be used to differentiate ccRCC from non-ccRCC with high accuracy. • Most RCC-subtype-discriminative CT features were associated with the key RCC-driven gene—the VHL gene mutation. • Radiomics model can be more accurate and interpretable when the imaging features could reflect underlying molecular basis of RCC.

Initial exploration of coronary stent image subtraction using dual-layer spectral CT Abstract Objectives This study aimed to investigate the feasibility of coronary stent image subtraction using spectral tools derived from dual-layer spectral computed tomography (CT). Methods Forty-three patients (65 stents) who underwent coronary CT angiography using dual-layer spectral CT were included. Conventional, 50-keV (kilo electron-volt), 100-keV, and virtual non-contrast (VNC) images were reconstructed from the same cardiac phase. Stents were subtracted on VNC images from conventional (convsub), 100-keV (100-keVsub), and 50-keV (50-keVsub) images. The in-stent lumen diameters were measured on subtraction, conventional, and 100-keV images. Subjective evaluation of reader confidence and subtractive quality was evaluated. Friedman tests were performed to compare in-stent lumen diameters and subjective evaluation among different images. Correlation between stent diameter and subjective evaluation was expressed as Spearman's rank correlation coefficient (rs). The diagnostic accuracy was assessed according to invasive coronary angiography (ICA) performed in 11 patients (20 stents). Results In-stent lumen diameters were significantly larger on subtraction images than those on conventional and 100-keV images (p < 0.05). Higher reader confidence was found on 100-keV, convsub, 100-keVsub, and 50-keVsub images compared with conventional images (p < 0.05). Subtractive quality of 100-keVsub images was better than that of convsub images (p = 0.037). A moderate-to-strong correlation between stent diameter and subjective evaluation was found (rs = 0.527~0.790, p < 0.05). Higher specificity, positive predictive value, and negative predictive value of subtraction images were shown by ICA results. Conclusions Subtraction images derived from dual-layer spectral CT enhanced in-stent lumen visibility and could potentially improve diagnostic performance for evaluating coronary stents. Key Points • Dual-layer spectral CT enabled good subtractive quality of coronary stents without misregistration artifacts. • Subtraction images could improve in-stent lumen visibility. • Reader confidence and diagnostic performance were enhanced with subtraction images.

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

Amino Acids

Automated feature engineering improves prediction of protein–protein interactions Abstract Over the last decade, various machine learning (ML) and statistical approaches for protein–protein interaction (PPI) predictions have been developed to help annotating functional interactions among proteins, essential for our system-level understanding of life. Efficient ML approaches require informative and non-redundant features. In this paper, we introduce novel types of expert-crafted sequence, evolutionary and graph features and apply automatic feature engineering to further expand feature space to improve predictive modeling. The two-step automatic feature-engineering process encompasses the hybrid method for feature generation and unsupervised feature selection, followed by supervised feature selection through a genetic algorithm (GA). The optimization of both steps allows the feature-engineering procedure to operate on a large transformed feature space with no considerable computational cost and to efficiently provide newly engineered features. Based on GA and correlation filtering, we developed a stacking algorithm GA-STACK for automatic ensembling of different ML algorithms to improve prediction performance. We introduced a unified method, HP-GAS, for the prediction of human PPIs, which incorporates GA-STACK and rests on both expert-crafted and 40% of newly engineered features. The extensive cross validation and comparison with the state-of-the-art methods showed that HP-GAS represents currently the most efficient method for proteome-wide forecasting of protein interactions, with prediction efficacy of 0.93 AUC and 0.85 accuracy. We implemented the HP-GASmethod as a free standalone application which is a time-efficient and easy-to-use tool. HP-GAS software with supplementary data can be downloaded from: http://www.vinca.rs/180/tools/HP-GAS.php.

Regulation of arginine biosynthesis, catabolism and transport in Escherichia coli Abstract Already very early, the study of microbial arginine biosynthesis and its regulation contributed significantly to the development of new ideas and concepts. Hence, the term "repression" was proposed by Vogel (The chemical basis of heredity, The John Hopkins Press, Baltimore, 1957) (in opposition to induction) to describe the relative decrease in acetylornithinase production in Escherichia coli cells upon arginine supplementation, whereas the term "regulon" was coined by Maas and Clark (J Mol Biol 8:365–370, 1964) for the ensemble of arginine biosynthetic genes dispersed over the E. coli chromosome but all subjected to regulation by the trans-acting argR gene product. Since then, unraveling of the molecular mechanisms controlling arginine biosynthesis, catabolism, and transport in and out the cell, have revealed moonlighting activities of enzymes and transcriptional regulators that generate unexpected interconnections between at first sight totally unrelated cellular processes, and have continued to replenish scientific knowledge and stimulated creative thinking. Furthermore, arginine is much more than just a common amino acid for protein synthesis. It may also be used as sole source of nitrogen by E. coli and a source of nitrogen, carbon and energy by many other bacteria. It is a substrate for the synthesis of polyamines, and important for the extreme acid resistance of E. coli. Furthermore, the guanidino group of arginine is well suited to engage in multiple interactions involving hydrogen bonds and ionic interactions with proteins and nucleic acids. Here, we combine major historical discoveries with current state of the art knowledge on arginine biosynthesis, catabolism and transport, and especially the regulation of these processes in E. coli, with reference to other microorganisms.

The hypertrehalosaemic neuropeptide conformational twins of cicadas consist of only l -amino acids: are they cis – trans isomers? Abstract It is known for almost 25 years that the corpora cardiaca (neurosecretory glands) of cicadas synthesize two isobaric peptides with hypertrehalosaemic activity denominated Placa-HrTH-I and II. Both decapeptides have the same amino acid sequence (pGlu-Val-Asn-Phe-Ser-Pro-Ser-Trp-Gly-Asn amide) and mass, but differ in their chromatographic retention time. The slightly more hydrophobic peptide, Placa-HrTH-II, co-elutes with the synthetic peptide of the same sequence and is less active in biological assays than Placa-HrTH-I. Ion mobility separation in conjunction with high-resolution mass spectrometry detected the differing structural feature between both peptides in the region Pro6-Ser7-Trp8. Here, it was shown that Placa-HrTH-I co-eluted with a synthetic peptide containing d-Pro in position 6, while dextrorotatory amino acid residues in positions 7 and 8 could be excluded in this way. Amino acid hydrolysis followed by chiral analysis using a relative of Marfey's reagent was then used to validate the presence of d-Pro in Placa-HrTH-I. Interestingly, this experiment unambiguously proved both the absence of d-Pro and the presence of l-Pro in Placa-HrTH-I. Racemization as a reason for the structural differences of the twin adipokinetic hormones was hence ruled out and cis–trans isomerism as the likely alternative came into focus. It remains to be investigated if Pro6 in cis-conformation is indeed present and responsible for the increased bioactivity of Placa-HrTH-I.

Investigation of the impact of PTMs on the protein backbone conformation Abstract Post-translational modifications (PTMs) are known to play a critical role in the regulation of protein functions. Their impact on protein structures and their link to disorder regions have already been spotted in the past decade. Nonetheless, the high diversity of PTM types and the multiple schemes of protein modifications (multiple PTMs, of different types, at different time, etc.) make difficult the direct confrontation of PTM annotations and protein structure data. Therefore, we analyzed the impact of the residue modifications on the protein structures at the local level. Thanks to a dedicated structure database, namely PTM-SD, a large screen of PTMs have been done and analyzed at local protein conformation levels using the structural alphabet protein blocks (PBs). We investigated the relation between PTMs and the backbone conformation of modified residues, of their local environment, and at the level of the complete protein structure. The two main PTM types (N-glycosylation and phosphorylation) have been studied in non-redundant datasets, and then four different proteins were focused, covering three types of PTMs: N-glycosylation in renin endopeptidase and liver carboxylesterase, phosphorylation in cyclin-dependent kinase 2 (CDK2), and methylation in actin. We observed that PTMs could either stabilize or destabilize the backbone structure, at a local and global scale, and that these effects depend on the PTM types.

Isolation from Stevia rebaudiana of DMDP acetic acid, a novel iminosugar amino acid: synthesis and glycosidase inhibition profile of glycine and β-alanine pyrrolidine amino acids Abstract DMDP acetic acid [N-carboxymethyl-2,5-dideoxy-2,5-imino-d-mannitol] 5 from Stevia rebaudiana is the first isolated natural amino acid derived from iminosugars bearing an N-alkyl acid side chain; it is clear from GCMS studies that such derivatives with acetic and propionic acids are common in a broad range of plants including mulberry, Baphia, and English bluebells, but that they are very difficult to purify. Reaction of unprotected pyrrolidine iminosugars with aqueous glyoxal gives the corresponding N-acetic acids in very high yield; Michael addition of both pyrrolidine and piperidine iminosugars and that of polyhydroxylated prolines to tert-butyl acrylate give the corresponding N-propionic acids in which the amino group of β-alanine is incorporated into the heterocyclic ring. These easy syntheses allow the identification of this new class of amino acid in plant extracts and provide pure samples for biological evaluation. DMDP N-acetic and propionic acids are potent α-galactosidase inhibitors in contrast to potent β-galactosidase inhibition by DMDP.

Genetic regulation of dimethylarginines and endothelial dysfunction in rheumatoid arthritis Abstract Rheumatoid Arthritis (RA) confers an increased cardiovascular disease (CVD) risk which accounts for much of the premature morbidity and mortality observed in this population. Alterations in vascular function and morphology leading to increased atherosclerotic burden are considered the main drivers of CVD in RA individuals with systemic inflammation playing a key role in the dysregulation of endothelial homeostasis and initiation of vascular injury. Dimethylarginines are endogenous inhibitors of nitric oxide (NO) synthase and have emerged as novel, independent biomarkers of CVD in a wide range of conditions associated with vascular pathology. In RA several reports have demonstrated abnormal dimethylarginine metabolism attributable to various factors such as systemic inflammation, decreased degradation or upregulated synthesis. Although a causal relationship between dimethylarginines and vascular damage in RA has not been established, the tight interrelations between inflammation, dimethylarginines and endothelial dysfunction suggest that determination of dimethylarginine regulators may shed more light in the pathophysiology of the atherosclerotic process in RA and may also provide new therapeutic targets. The Alanine–Glyoxylate Aminotransferase 2 (AGTX2)-dependent pathway is a relatively recently discovered alternative pathway of dimethylarginine catabolism and its role on RA-related atherosclerotic disease is yet to be established. As factors affecting dimethylarginine concentrations linked to CVD risk and endothelial dysfunction are of prominent clinical relevance in RA, we present preliminary evidence that gene variants of AGTX-2 may influence dimethylarginine levels in RA patients and provide the rationale for larger studies in this field.

Discrimination power of knowledge-based potential dictated by the dominant energies in native protein structures Abstract Extracting a well-designed energy function is important for protein structure evaluation. Knowledge-based potential functions are one type of the energy functions which can be obtained from known protein structures. The pairwise potential between atom types is approximated using Boltzmann's law which relates the frequency of atom types to its potential. The total energy is approximated as a summation of pairwise potential between the atomic pairs. In the present study, the performance of knowledge-based potential function was assessed based on the strength of interaction between groups of amino acids. The dominant energies involved in the pairwise potentials were revealed by eigenvalue analysis of the matrix, the elements of which represent the energy between amino acids. For this purpose, the matrix including the mean of the energies of residue–residue interaction types was constructed using 500 native protein structures. The matrix has a dominant eigenvalue and amino acids, with LEU, VAL, ILE, PHE, TYR, ALA and TRP having high values along the dominant eigenvector. The results show that the ranking of amino acids is consistent with the power of amino acids in discriminating native structures using K-alphabet reduced model. In the reduced interactions, only amino acids from a subset of all 20 amino acids, along with their interactions are considered to assess the energy. In the K-alphabet reduced model, the reduced structures are constructed based on only the K-amino acid types. The dominant K-alphabet reduced model derived for the k-first amino acids in the list [LEU, VAL, PHE, ILE, TYR, ALA, TRP] of amino acids has the best discrimination of native structure among all possible K-alphabet reduced models. Knowledge-based potentials might be improved with a new strategy.

Dietary supplementation with arginine and glutamic acid alters the expression of amino acid transporters in skeletal muscle of growing pigs Abstract Sixty Duroc × Large White × Landrace pigs with an average initial body weight (BW) of 77.1 ± 1.3 kg were selected to investigate the effects of dietary supplementation with arginine (Arg) and/or glutamic acid (Glu) on free amino acid (FAA) profiles, expression of AA transporters, and growth-related genes in skeletal muscle. The animals were randomly assigned to one of five treatment groups (basic diet, iso-nitrogenous, Arg, Glu, and Arg + Glu groups). The results showed that plasma Glu concentration was lowest in the Arg + Glu group and highest in the Glu group (P < 0.05). In the longissimus dorsi (LD) muscle, the concentrations of histidine, Arg, and taurine in the Arg + Glu group were higher, and the concentrations of 3-methylhistidine was lower, than in the basic diet group (P < 0.05). The mRNA levels of ASC amino acid transporter-2 (ASCT2), L-type AA transporter 1, and sodium-coupled neutral amino acid transporter 2 in the LD muscle, as well as the mRNA levels of ASCT2 and proton-assisted amino acid transporter in the biceps femoris (BF) muscle, were higher in the Arg + Glu group compared to the basic diet group (P < 0.05). The mRNA levels of the muscle-specific RING finger-1 and muscle atrophy F-box genes in the LD muscle were downregulated in the Glu and Arg + Glu groups compared to the basic diet group (P < 0.05). Collectively, these findings suggest that dietary supplementation with both Arg and Glu increases intramuscular FAA concentrations and decreases the mRNA levels of genes involved in protein degradation in skeletal muscle.

The proton-coupled oligopeptide transporters PEPT2, PHT1 and PHT2 mediate the uptake of carnosine in glioblastoma cells Abstract The previous studies demonstrated that carnosine (β-alanyl-l-histidine) inhibits the growth of tumor cells in vitro and in vivo. Considering carnosine for the treatment of glioblastoma, we investigated which proton-coupled oligopeptide transporters (POTs) are present in glioblastoma cells and how they contribute to the uptake of carnosine. Therefore, mRNA expression of the four known POTs (PEPT1, PEPT2, PHT1, and PHT2) was examined in three glioblastoma cell lines, ten primary tumor cell cultures, in freshly isolated tumor tissue and in healthy brain. Using high-performance liquid chromatography coupled to mass spectrometry, the uptake of carnosine was investigated in the presence of competitive inhibitors and after siRNA-mediated knockdown of POTs. Whereas PEPT1 mRNA was not detected in any sample, expression of the three other transporters was significantly increased in tumor tissue compared to healthy brain. In cell culture, PHT1 expression was comparable to expression in tumor tissue, PHT2 exhibited a slightly reduced expression, and PEPT2 expression was reduced to normal brain tissue levels. In the cell line LN405, the competitive inhibitors β-alanyl-l-alanine (inhibits all transporters) and l-histidine (inhibitor of PHT1/2) both inhibited the uptake of carnosine. SiRNA-mediated knockdown of PHT1 and PHT2 revealed a significantly reduced uptake of carnosine. Interestingly, despite its low expression at the level of mRNA, knockdown of PEPT2 also resulted in decreased uptake. In conclusion, our results demonstrate that the transporters PEPT2, PHT1, and PHT2 are responsible for the uptake of carnosine into glioblastoma cells and full function of all three transporters is required for maximum uptake.

Novel stable analogues of the neurotensin C-terminal hexapeptide containing unnatural amino acids Abstract Neurotensin (NT) (pGlu–Leu–Tyr–Glu–Asn–Lys–Pro–Arg–Arg–Pro–Tyr–Ile–Leu) exerts a dual function as a neurotransmitter/neuromodulator in the central nervous system and as a hormone/cellular mediator in periphery. This dual function of NT establishes a connection between brain and peripheral tissues that renders this peptide a central player in energy homeostasis. Many biological actions of NT are mediated through its interaction with three types of NT receptors (NTS receptors). Despite its role in energy homeostasis, NT has a short half-life that hampers further determination of the biological actions of this peptide and its receptors in brain and periphery. The short half-life of NT is due to the proteolytic degradation of its C-terminal side by several endopeptidases. Therefore, it is important to synthesize NT analogues with resistant bonds against metabolic deactivation. Based on these findings, we herein report the synthesis of ten linear, two cyclic and two dimeric analogues of NT with modifications in its structure that improve their metabolic stability, while retaining the ability to bind to NTS receptors. Modifications at position 11 (introduction of d-Tyrosine (OEthyl) [d-Tyr(Et)] or d-1-naphtylalanine [d-1-Nal] were combined with introduction of a l-Lysine or a d-Arginine at positions 8 or 9, and 1-[2-(aminophenyl)-2-oxoethyl]-1H-pyrrole-2-carboxylic acid (AOPC) at positions 7 or 8, resulting in compounds NT4-NT21. AOPC is an unnatural amino acid with promise in applications as a building block for the synthesis of peptidomimetic compounds. To biologically evaluate these analogues, we determined their plasma stability and their binding affinities to type 1 NT receptor (NTS1), endogenously expressed in HT-29 cells, Among the fourteen NT analogues, compounds, NT5, NT6, and NT8, which have d-Tyr(Et) at position 11, bound to NTS1 in a dose–response manner and with relatively high affinity but still lower than that of the natural peptide. Despite their lower binding affinities compared to NT, the NT5, NT6, and NT8 exhibited a remarkably higher stability, as a result of their chemistry, which provides protection from enzymatic activity. These results will set the basis for the rational design of novel NT molecules with improved pharmacological properties and enhanced enzymatic stability.

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

International Urology and Nephrology

The effects of "unilateral midurethral sling cut down" in women with voiding dysfunctions after anti-incontinence surgery Abstract Purposes Midurethral synthetic sling (MUS) placement via either the retropubic or transobturator route is the standard surgical procedure for women with stress urinary incontinence. However, a small portion of patients experienced voiding dysfunction after the surgery, which was debilitating to their quality of life. Our study was aimed at demonstrating the effectiveness of the unilateral sling cut down for post-midurethral sling (MUS) voiding dysfunction and, secondarily, at evaluating the changes in urodynamic parameters. Methods We retrospectively reviewed the charts of patients who received unilateral midurethral sling cut down for voiding dysfunction after an MUS procedure. The cut-down procedures were performed at the urethral meatus, in the 9 or 3 o'clock direction. Preoperative and postoperative subjective and objective parameters were compared to evaluate the outcome of the cut-down procedures. Results We selected 15 patients who underwent unilateral MUS cut down for voiding dysfunction after anti-incontinence procedures with various MUSs. The cut-down procedures were performed at a median interval of 7.1 months after sling insertion. The subjective results of the Patient Global Impression of Improvement (PGI-I) after the cut-down procedure showed an overall satisfaction of 93.33%. After the cut-down procedure, the median flow rate increased from 14.8 to 22 ml/s (P > 0.05), and the post-void residual urine volume decreased from 193.5 to 35.0 ml (P < 0.05). All patients attained continence after the cut-down procedures. Conclusions Unilateral MUS cut down is effective in the management of voiding dysfunction after anti-incontinence surgery, with a low risk of recurrence of urinary incontinence.

Effects of intradialytic resistance exercise on systemic inflammation in maintenance hemodialysis patients with sarcopenia: a randomized controlled trial Abstract Purpose To investigate the effect of intradialytic resistance exercise on inflammation markers and sarcopenia indices in maintenance hemodialysis (MHD) patients with sarcopenia. Methods Forty-one MHD patients with sarcopenia were divided into an intervention group (group E, n = 21) and a control group (group C, n = 20). Group C patients only received routine hemodialysis care, whereas group E patients received progressive intradialytic resistance exercise with high or moderate intensity for 12 weeks at three times per week (using the weight of the lower limbs and elastic ball movement of the upper limb) on the basis of routine hemodialysis care. Results After 12 weeks, a significant difference in physical activity status (maximum grip strength, daily pace, and physical activity level), Kt/V, and C-reactive protein was found between groups E and C. Inflammatory factors (interleukin (IL)-6, IL-10, and tumor necrosis factor(TNF)-α) increased or decreased more significantly in group E than in group C. Conclusions This study showed that intradialytic resistance exercise can improve physical activity effectively and reduce microinflammatory reactions even if this simple exercise does not affect the muscle mass in MHD patients with sarcopenia.

Organ-sparing procedures in GU cancer: part 2-organ-sparing procedures in testicular and penile tumors Abstract Purpose Organ-sparing surgery (OSS) is recommended in selected patients with testicular tumors and penile cancer (PC). The functional and psychological impacts of organ excision for these genital tumors are profound. In this review, we summarize the indications, techniques and outcomes of OSS for these two tumors. Methods PubMed® was searched for relevant articles up to December 2018. For Testicular sparing surgery (TSS) search, keywords used were; testicular tumors alone and in combination with "testicular sparing surgery", "partial orchiectomy" and outcomes. For penile conserving surgery (PCS), keywords used were: penile cancer alone and in combination with "penile conserving surgery", "partial penectomy" and outcomes. Because of the low quality of available evidence, a narrative rather that systematic review has been performed. Results Indications of TSS are tumors ≤ 2 cm in solitary testis or bilateral tumors and no rete testis invasion. Prerequisites include normal testosterone and luteinizing hormone levels and patient compliance with follow-up. Indications for PCS are distal penile lesions with clinical stage ≤ T1. Adequate penile stump (3 cm) is required after surgery to maintain forward urine stream. Frozen section helps to reduce the risk of recurrence. Local recurrence after PCS is not associated with reduced survival and can be managed with another PCS in selected patients. The reported oncological and functional outcomes following TSS and PCS are adequate. Conclusions In properly selected patient OSS in testicular and penile tumors has a comparable oncological outcome to total organ excision with added advantages of preserving organ function and psychological well-being.

Correction to: The clinical utility of prostate cancer heterogeneity using texture analysis of multiparametric MRI Unfortunately, in the original article one co-author's name is missing. The co-author name and affiliation is given as follows.

Commentary to: "Morphologic changes after bladder neck intussusception in laparoscopic radical prostatectomy contribute to early postoperative continence"

Comments on the article entitled "Morphologic changes after bladder neck intussusception in laparoscopic radical prostatectomy contribute to early postoperative continence"

Lactic acidosis due to metformin in type 2 diabetes mellitus and chronic kidney disease stage 3–5: is it significant? Abstract Purpose To study the incidence of lactic acidosis due to metformin in patients with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD) stage 3–5. Methods We estimated plasma lactate in patients of CKD stage 3 and worse who were continuing metformin on their own prior to stopping the drug. Result Of 40 patients included, median duration of T2DM was 60 months (interquartile range IQR 24–120). The mean serum creatinine was 309.4 ± 159.1 µmol/L and mean eGFR was 27.82 ± 12.93 mL/min/1.73 m2 with 3 (7.5%), 16 (40%), 11 (27.5%) and 10 (25%) in CKD stages 3a, 3b, 4 and 5, respectively. They were receiving metformin for a median duration of 24 months (IQR 12.5–60), an average dose of 896 ± 350 mg per day. The median of plasma lactate was 1.36 mmol/L (IQR 1.11–1.75 mmol/L) with three (7.5%) having levels above normal, two (20%) in CKD stage 5 and one (9.1%) in stage 4. Conclusion Metformin can be safely used in CKD stage 3 and with regular measurement of plasma lactate in later stages.

Choosing an equation for glomerular filtration rate in decompensated cirrhosis: "Royal Free Hospital" formula is able to predict short-term mortality

A comprehensive review on apolipoproteins as nontraditional cardiovascular risk factors in end-stage renal disease: current evidence and perspectives Abstract Purpose Nontraditional cardiovascular risk factors such as lipoprotein(a) (Lp(a)), the genetic polymorphisms of apolipoprotein(a), apolipoprotein E (ApoE), and apolipoprotein B (ApoB) increase the prevalence of atherosclerosis in end-stage renal disease (ESRD) through quantitative and qualitative alterations. Given the high burden of cardiovascular fatal events in ESRD, this review aims to gather studies depicting apolipoproteins' changes in ESRD, to describe current evidence and to explore potential lipid-lowering therapies. Methods We searched the electronic database of PubMed, SCOPUS, EBSCO, and Cochrane CENTRAL for studies evaluating apolipoproteins in ESRD. Randomized controlled trials, observational studies (including case–control, prospective, or retrospective cohort), and reviews/meta-analysis were included if reference was made to apolipoproteins and cardiovascular consequences in ESRD. Results 21 studies met the inclusion criteria. We found a significant correlation between Lp(a) plasma concentrations and atherosclerosis. Lp(a) levels were independent risk factors for atherothrombosis and cardiovascular mortality. LMW apo(a) phenotype proved to be the best predictor for coronary events in ESRD. Single nucleotide polymorphisms in ApoE gene affected the expression and function of the protein, increasing the risk of cardiovascular events. ApoB had a significant correlation with the value of carotid intima–media thickness and vascular stiffness. Conclusions The picture of "lipid milieu" in ESRD has not been clearly described. Novel studies show that specific apolipoproteins suffer modifications in uremic patients, being correlated with cardiovascular events. Probably in the next years, the treatment of dyslipidemia in ESRD will not merely target LDL or total cholesterol, but specific isoforms of apolipoproteins which seem to become the central part of the problem.

Correlation of serum galectin-3 level with renal volume and function in adult polycystic kidney disease Abstract Purpose The decrease in kidney functions in autosomal dominant polycystic kidney disease (ADPKD) is strongly correlated with the severity and growth of kidney cysts. Total kidney volume (TKV) was shown to be an early marker of the severity of the disease and a predictor of reduction in kidney functions. New treatment approaches for ADPKD have led to a need for easily applicable strong biomarkers predicting progression of the disease. The profibrotic mediator of galectin-3 (Gal-3) is linked to development of renal fibrosis. Methods The study included 74 patients with ADPKD diagnosis and 40 healthy controls. The TKV of patients was calculated using the manual tracing method on MR images. The serum Gal-3 levels of patient and healthy control groups were measured with the ELISA method. The correlations between serum Gal-3 value with TKV and kidney function were assessed in patients. Results As the stage of chronic kidney disease (CKD) increased, serum Gal-3 and TKV values increased (p < 0.001, p = 0.049, respectively). Correlation analysis found a negative relationship between serum Gal-3 levels and eGFR (r: − 0.515, p < 0.001); however, there was no relationship between serum Gal-3 and TKV (r = 0.112, p = 0.344). Linear regression analysis showed the major parameter affecting Gal-3 was eGFR (p = 0.016). Conclusions In our study, we showed that renal impairment is an important determinant of Gal-3, and there is no correlation of Gal-3 and TKV in ADPKD. As a result, there is an urgent clinical need for new biomarkers to identify individuals with the chance of treatment in the early stage among ADPKD patients.

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

Acta Otorrinolaringológica Española

Complicaciones postoperatorias tras adenoamigdalectomía en 2 grupos de pacientes pediátricos: síndrome de apnea-hipopnea del sueño e infecciones de repetición Publication date: Available online 21 June 2019 Source: Acta Otorrinolaringológica Española Author(s): Jesús Rodríguez-Catalán, José Fernández-Cantalejo Padial, Paula Rodríguez Rodríguez, Fernando González Galán, Genoveva del-Río Camacho Resumen Introducción y objetivos La adenoamigdalectomía es una cirugía indicada por amigdalitis recurrentes e igualmente por síndrome de apnea-hipopnea del sueño (SAHS). Es considerada segura y con pocas complicaciones. Así, en pacientes mayores de 3 años y sin comorbilidades no hay más complicaciones respiratorias (fuera del postoperatorio inmediato), por lo que no precisan la hospitalización rutinaria en la unidad de cuidados intensivos pediátricos, independientemente de la gravedad del SAHS. El objetivo de este estudio es reanalizar la situación, para comprobar que esta tendencia se mantiene, poniendo especial énfasis en menores de 3 años, subgrupo donde hay menos datos disponibles. Métodos Estudio retrospectivo observacional, incluyendo los niños adenoamigdalectomizados en nuestro centro durante 5 años. Resultados Se operaron 418 niños (56,7% por amigdalitis y 43,3% por SAHS). Solo 24 (5,7%) tuvieron complicaciones: un 1,2% vómitos, un 3,1% sangrados y un 1,4% complicaciones respiratorias. Estas últimas ocurrieron siempre en quirófano o recuperación postanestésica y más frecuentemente en SAHS grave, mientras que las amigdalitis tuvieron más sangrados (p = 0,046). No hay diferencias por edad (p = 0,174), aunque el subgrupo de menores de 3 años sigue siendo más pequeño. Conclusiones No encontramos diferencias en el porcentaje de complicaciones entre SAHS y amigdalitis. Las amigdalitis tienen más sangrados, y el SAHS grave más complicaciones respiratorias, pero siempre en el postoperatorio inmediato en nuestra serie. Estos datos apoyan la hipótesis previa de no ingresar rutinariamente en la unidad de cuidados intensivos pediátricos salvo en los casos anteriormente mencionados. Abstract Introduction and objectives Adenotonsillectomy is a surgery to treat recurrent tonsillitis or obstructive sleep apnoea syndrome (OSAS). It is considered a safe procedure, with few complications. Moreover, patients over 3 years and without comorbidities do not present a higher rate of respiratory adverse events after the immediate postoperative period, and do not need systematic admission to a paediatric intensive care unit (PICU), regardless of their OSAS severity. The aim of this study is to reanalyse the situation, including patients under the age of 3 years, for whom there are fewer available data, to confirm that this trend has not changed. Methods A retrospective observational study was performed, including all adenotonsillectomised children in our hospital over 5 years. Results 418 adenotonsillectomised children were included, 56.7% due to recurrent tonsillitis, and 43.3% because of OSAS. Only 24 patients (5%7%) experienced adverse events, of whom 1.2% had vomiting, 3.1% bleeding, and 1.4% respiratory events. All the respiratory events occurred in the operating theatre or in the post-anaesthetic unit, most frequently in children with severe OSAS, while the tonsillitis group had more bleeding (P = .046). No differences in complications were observed according to age (P = 0.174), but the group of patients under three years was relatively small. Conclusions No differences were found in the percentage of complications between the two groups. Although the OSAS group exhibited more respiratory events, these occurred in the immediate postoperative period; otherwise, there was a higher risk of bleeding in the tonsillitis group. These results support the findings indicating that routine PICU admission is not required for these patients.

Nasal and lip polyps: Pai syndrome Publication date: Available online 10 June 2019 Source: Acta Otorrinolaringológica Española Author(s): Cinthia Giselle Pérez, Sandra Carrera Fernández, Agustin Rodríguez D'Aquila

La endoscopia del sueño inducido Publication date: Available online 4 June 2019 Source: Acta Otorrinolaringológica Española Author(s): Marina Carrasco Llatas, Paula Martínez Ruiz de Apodaca, Peter Baptista Jardín, Carlos O'Connor Reina, Guillermo Plaza Mayor, Iván Méndez-Benegassi Silva, Eugenio Vicente González, Isabel Vilaseca González, Ana Isabel Navazo Egía, Laura Samará Piñol, Irene Álvarez García, Javier Vila Martín, Eduard Esteller Moré Resumen Este documento pretende dar a conocer la endoscopia de sueño inducido entre los distintos especialistas que tratan a los pacientes con trastornos respiratorios del sueño y ser una guía para los especialistas que vayan a realizarla de modo que pueda ser reproducible. Abstract This document introduces drug-induced sleep endoscopy to the specialist treating sleep breathing disorders and is intended as a guide for those willing to perform the procedure so that it can be reproducible.

Consenso sobre el tratamiento de la disfunción tubárica obstructiva mediante dilatación con balón Publication date: Available online 24 May 2019 Source: Acta Otorrinolaringológica Española Author(s): Guillermo Plaza, Juan José Navarro, Jorge Alfaro, Marta Sandoval, Jaime Marco Resumen Objetivo Existe una gran variabilidad en el diagnóstico de la disfunción tubárica obstructiva y su tratamiento mediante la dilatación tubárica con balón (DTB). El objetivo de este trabajo es presentar unas recomendaciones de consenso sobre las indicaciones, contraindicaciones, metodología, complicaciones y resultados de la DTB. Materiales y métodos Presentamos un consenso sobre la DTB, mediante revisión sistemática de la literatura desde 1966 hasta noviembre de 2018, términos MESH Eustachian tube and (dilation or dysfunction), recogiendo un total de 1.943 artículos en español, inglés, alemán y francés. Del total de artículos revisados se seleccionaron 139 cuyo abstract era relevante, incluyendo 2 consensos internaciones sobre diagnóstico, 7 revisiones sistemáticas y 2 ensayos clínicos aleatorizados sobre la DTB. Resultados Las indicaciones de la DTB son el barotrauma, la otitis media secretora, la otitis media adhesiva, la atelectasia y el fracaso de una timpanoplastia, siempre que se haya podido demostrar una disfunción tubárica obstructiva crónica. La efectividad de la DTB es mayor en el barotrauma y la otitis media secretora. Hay estudios publicados de elevada evidencia sobre la DTB, cuyos buenos resultados se mantienen a largo plazo, frente a tratamiento médico conservador. Conclusiones La DTB es un procedimiento quirúrgico mínimamente invasivo que ha demostrado su efectividad y seguridad en el tratamiento de la disfunción tubárica crónica en adultos y en niños. Las indicaciones en las que es más efectiva son el barotrauma y la otitis media secretora. Abstract Objective There is a great variability in diagnosis of obstructive Eustachian tube dysfunction and its treatment by balloon Eustachian tuboplasty (BET). The aim of this paper was to present a consensus on indications, contraindications, methodology, complications and results after BET. Material and methods We obtained a consensus on BET, after a systematic review of the literature on BET from 1966 to November 2018, using MESH terms «Eustachian tube and (dilation or dysfunction)», including a total of 1.943 papers in Spanish, English, German and French. We selected 139 papers with a relevant abstract, including two international consensuses, seven systematic revisions, and two randomised control trials on BET. Results The indications for BET are barotrauma, serous otitis media, adhesive otitis, atelectatic middle ear and failure after tympanoplasty, once obstructive Eustachian tube dysfunction is confirmed. BET is more effective in barotrauma and serous otitis media. There are high- evidence reports on BET showing good results that persist long-term, as compared to conservative medical treatment. Conclusions BET is a surgical, minimally invasive treatment that has shown its effectiveness and safety in obstructive Eustachian tube dysfunction in adults and children. It is most effective in barotrauma and serous otitis media.

Incidencia de la hiperostosis esquelética difusa idiopática sobre un modelo clínico de disfagia Publication date: Available online 20 May 2019 Source: Acta Otorrinolaringológica Española Author(s): Francisco Javier García Callejo, Natsuki Oishi, Isabel López Sánchez, Beatriz Pallarés Martí, Andrea Rubio Fernández, María José Gómez Gómez Resumen Objetivo Relacionar la clínica de disfagia con la enfermedad de Forestier-Rotes-Querol o hiperostosis esquelética difusa idiopática (HEDI), desorden por osificación del ligamento cervical anterior común y calcificaciones en otras articulaciones. Pacientes y métodos Revisión del historial clínico-radiológico de 455 pacientes que en 5 años consultaron en nuestro centro por disfagia, remitidos desde Atención Primaria o diferentes especialidades. El diagnóstico de HEDI se estableció en función de los criterios descritos por Resnick. Resultados Sobre un volumen total de 32.544 pacientes atendidos, el 1,4% consultó por disfagia alta. En 51 casos con esta sintomatología —el 11,2% de los sujetos— pudieron verificarse datos congruentes con los hallazgos radiológicos diagnósticos de HEDI. La incidencia observada fue de 7:100.000 habitantes-año. Dos casos con disfagia severa mejoraron con la retirada del hueso cervical neoformado. Conclusiones La HEDI supone una osificación interarticular anquilosante habitualmente sistémica pero asintomática. Al manifestarse, distorsiona principalmente las funciones de cuello y vías altas, generando sobre todo disfagia. Unos pocos casos requieren cirugía liberadora de estas calcificaciones. Abstract Objective To relate symptoms of dysphagia to Forestier-Rotes Querol disease or diffuse idiopathic skeletal hyperostosis (DISH), a disorder due to ossification in the anterior longitudinal ligament and calcifications in other entheses. Patients and methods Review of clinical and radiological findings in 455 outpatients attended at our Centre with dysphagia, for 5 years, referred from dental, trauma, neurological or primary health care. A diagnosis of DISH was established using Resnick's criteria. Results We detected 51 cases with dysphagia consistent with DISH diagnostic criteria – 11.2% of subjects suffering this symptom- out of 32544 outpatients attended. An incidence of 7:100000 inhabitants per year was observed. Two cases showed significant improvement after removing the new bone in the spine. Conclusions DISH is an ankylosing ossification between the joints, frequently systemic but showing no clinical symptoms. When symptoms manifest, neck movements and upper airways are involved, mainly dysphagia. A few cases need surgery to relieve the calcification processes.

Schwannoma retrofaríngeo. Una infrecuente localización Publication date: Available online 18 May 2019 Source: Acta Otorrinolaringológica Española Author(s): Yolanda Escamilla Carpintero, Antón Francesc Aguilà Artal, Mario Prenafeta Moreno

Análisis de la producción científica en otorrinolaringología en España durante el periodo 2011-2015. Acta Otorrinolaringol Esp. 2018;69:275-282 Publication date: Available online 15 May 2019 Source: Acta Otorrinolaringológica Española Author(s): Francisco Santaolalla Montoya

Modified inspiratory muscle training (m-IMT) as promising treatment for gastro-oesophageal reflux disease (GERD) Publication date: Available online 15 May 2019 Source: Acta Otorrinolaringológica Española Author(s): Antonio Moffa, Giuseppe Oliveto, Francesco Di Matteo, Peter Baptista, Alicia Cárdenas, Michele Cassano, Manuele Casale Abstract Background Gastro-oesophageal reflux disease (GERD) is one of the most common diseases, but is still a challenge to cure. Different medical treatments are used, first of all Proton pump inhibitors (PPIs), however these are sometimes ineffective and long-term intake can lead to underestimated complications. Recently, some studies investigated the role of inspiratory muscle training (IMT) in the medical treatment of GERD. It seems that IMT is able to increase the pressure generated by the lower oesophageal sphincter (LES), reduce spontaneous releases of LES, acid exposure, use of PPIs, and improve symptoms and quality of life for GERD patients. Objective The aim of this study was to evaluate the effectiveness of IMT in association with myofunctional therapy exercises of swallowing set by Daniel Garliner (m-IMT) on the symptoms of patients with non-erosive gastro-oesophageal reflux disease (NERD). Methods Twenty-one adult patients with NERD were enrolled from May to December 2017 and performed m-IMT over a period of 4 weeks. Before and after treatment, all the patients completed the following questionnaires: GERD oesophageal symptomatology (GERDQ), extra-oesophageal GERD symptomatology (RSI), quality of life (GERD-Health Related Quality of Life Questionnaire (GERD-HRQL), and underwent laryngeal endoscopy. Results Nineteen patients completed m-IMT. GERDQ (from 8.36 ± 3.94 to 1.7 ± 3.41; p < .05), RSI (from to 21.68 ± 10.26 to 6.93 ± 8.37; p < .05) and GERDHRQL (from 25.68 ± 16.03 to 8.4 ± 11.06; p < .05) the questionnaire scores significantly reduced after treatment. In addition, the laryngeal endoscopy score greatly improved (from 14.24 ± 4.15 to 7.4 ± 1.77; p < .05). Conclusions m-IMT is a low cost therapy without side effects. It could be useful in association with PPI or alone for selected GERD cases and for mild NERD forms, in association with diet. Further studies are required to prove the effects of m-IMT on GERD symptoms and decide the best treatment schedule. Resumen Introducción La enfermedad por reflujo gastroesofágico (ERGE) es una de las enfermedades más comunes, pero sigue siendo un desafío para curar. Se utilizan diferentes tratamientos médicos, en primer lugar los inhibidores de la bomba de protones (IBP), sin embargo, en ocasiones son ineficaces y una ingesta a largo plazo puede llevar a complicaciones subestimadas. Recientemente, algunos estudios investigaron el papel del entrenamiento muscular inspiratorio (IMT) en el tratamiento médico de la ERGE. Parece que el IMT es capaz de aumentar la presión generada por el esfínter esofágico inferior (LES), reducir las liberaciones espontáneas del LES, la exposición al ácido, el uso de IBP, y mejorar los síntomas y la calidad de vida en pacientes con ERGE. Objetivo El objetivo de este estudio es evaluar la efectividad de la IMT en asociación con los ejercicios de terapia miofuncional de tragar de Daniel Garliner (m-IMT) en los síntomas de los pacientes con ERGE no erosivo (NERGE). Métodos Veintiún pacientes adultos con ERGE se inscribieron de mayo a diciembre de 2017 y realizaron un período de 4 semanas de m-IMT. Antes y después del tratamiento todos los pacientes completaron los siguientes cuestionarios: sintomatología esofágica de ERGE, sintomatología de ERGE extraesofágica (RSI), calidad de vida (cuestionario de calidad de vida relacionada con la salud [ERGE-HRQL]) y endoscopia laríngea. Resultados Diecinueve pacientes completaron m-IMT. GERDQ (desde 8,36 ± 3,94 a 1,7 ± 3,41; p < 0,05), RSI (desde hasta 21,68 ± 10,26 hasta 6,93 ± 8,37; p < 0,05) y ERGE-HRQL (desde 25,68 ± 16,03 hasta 8,4 ± 11,06; p < 0,05), las puntuaciones se redujeron significativamente después del tratamiento. Además, la puntuación de la endoscopia laríngea mejoró enormemente (de 14,24 ± 4,15 a 7,4 ± 1,77; p < 0,05). Conclusiones m-IMT es una terapia de bajo costo sin efectos secundarios. Podría ser útil en asociación con IBP o solo en casos seleccionados de ERGE y en formas NERGE leves, en asociación con la dieta. Se requieren estudios adicionales para probar los efectos de m-IMT en los síntomas de ERGE y establecer el mejor programa de tratamiento.

Parálisis facial: guía de práctica clínica de la Sociedad Española de ORL Publication date: Available online 13 May 2019 Source: Acta Otorrinolaringológica Española Author(s): Luis Lassaletta, José Manuel Morales-Puebla, Xabier Altuna, Álvaro Arbizu, Miguel Arístegui, Ángel Batuecas, Carlos Cenjor, Juan Manuel Espinosa-Sánchez, Leire García-Iza, Pilar García-Raya, Teresa González-Otero, Manuel Mañós, Carlos Martín, Susana Moraleda, Jose María Roda, Susana Santiago, Jesús Benítez, Laura Cavallé, Victor Correia, Jose Manuel Estévez Resumen La parálisis de Bell es la forma más común de paresia o parálisis facial. Sin embargo, no todos los pacientes con parálisis facial tienen una parálisis de Bell. Otras causas frecuentes incluyen las secuelas del tratamiento del neurinoma del viii par, el cáncer de cabeza y cuello, la iatrogenia, el zóster ótico y los traumatismos. El abordaje de cada una de estas situaciones es totalmente diferente. El objetivo de esta guía es servir de consejo para el tratamiento y el seguimiento de los pacientes con parálisis facial. Nuestra idea es que la guía sea práctica, haciendo hincapié en recomendaciones efectivas y útiles en el manejo diario de los pacientes. Esta guía ha sido promovida por la Sociedad Española de ORL y escrita por médicos con experiencia en la enfermedad del nervio facial, incluyendo al menos un especialista de cada comunidad autónoma. Redactada en un formato de preguntas y respuestas, incluye 56 cuestiones relevantes relacionadas con el nervio facial. Abstract Bell's palsy is the most common diagnosis associated with facial nerve weakness or paralysis. However, not all patients with facial paresis/paralysis have Bell's palsy. Other common causes include treatment of vestibular schwannoma, head and neck tumours, iatrogenic injuries, Herpes zoster, or trauma. The approach to each of these conditions varies widely. The purpose of this guideline is to provide clinicians with guidance on the treatment and monitoring of patients with different causes of facial paralysis. We intend to draft a practical guideline, focusing on operationalised recommendations deemed to be useful in the daily management of patients. This guideline was promoted by the Spanish Society of Otolaryngology and developed by a group of physicians with an interest in facial nerve disorders, including at least one physician from each Autonomous Community. In a question and answer format, it includes 56 relevant topics related to the facial nerve.

Experiencia de uso de fampridina en pacientes con nistagmo vertical inferior Publication date: Available online 8 May 2019 Source: Acta Otorrinolaringológica Española Author(s): Emilio Domínguez-Durán, Irene Mármol-Szombathy, Úrsula Baños-Roldán, Serafín Sánchez-Gómez Resumen Objetivo Presentar los resultados del tratamiento con fampridina de liberación prolongada (4-AP-SR) en pacientes con nistagmo vertical inferior. Material y método Serie de casos de nistagmo vertical inferior tratados con 10 mg de 4-AP-SR cada 12 h. Se valoraron la mejoría clínica y la variación del nistagmo antes y después del tratamiento, registrando la puntuación en el Dizziness Handicap Inventory, la velocidad de la fase lenta del nistagmo y su frecuencia. Resultados Se trataron 3 pacientes, ninguno de los cuales notó cambios durante el tratamiento en relación con los síntomas visuales, aunque 2 pacientes notaron mejoría subjetiva de la marcha. No se detectaron diferencias significativas en la puntuación del Dizziness Handicap Inventory ni en las variables videonistagmográficas estudiadas. Conclusión No se han detectado cambios en los síntomas visuales con el tratamiento con 4-AP-SR. La contradicción con estudios previos puede estar producida por un bajo tamaño muestral, la etiología de los casos o la forma de medir los resultados. Abstract Objective To present the results of treatment with sustained-release fampridine (4-AP-SR) in patients with downbeat nystagmus. Material and method Series of cases with downbeat nystagmus treated with 10 milligrams of 4-AP-SR every 12 hours. The clinical improvement and the variation of the nystagmus before and after the treatment were evaluated, recording the score in the Dizziness Handicap Inventory, the velocity of the slow phase of the nystagmus and its frequency. Results Three patients were treated, none of whom reported significant subjective changes during the treatment. No significant differences were detected in the Dizziness Handicap Inventory score or in the studied videonystagmographic variables. Conclusion This communication does not present positive results on the use of 4-AP-SR. The contradiction with previous studies may be caused by a small sample size, by the etiology of the cases or by the way in which the results were measured.

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
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6948891480

alsfakia@gmail.com