bluuebunny/crossref_metadata_2025 huggingface dataset:
Sex-specific Associations Between Type 2 Diabetes Incidence and Exposure to Dioxin and Dioxin-like Pollutants: A Meta-analysis
Authors: Gang Noa , Van Allen Kyle , Villeneuve Paul J. , MacDonald Heather , Bruin Jennifer E.
Published: February 2022

The potential for persistent organic pollutants (POPs), including dioxins and dioxin-like polychlorinated biphenyls (DL-PCBs), to increase the risk of incident diabetes in adults has been extensively studied. However, there is substantial variability in the reported associations both between and within studies. Emerging data from rodent studies suggest that dioxin disrupts glucose homeostasis in a sex-specific manner. Thus, we performed a review and meta-analysis of relevant epidemiological studies to investigate sex differences in associations between dioxin or DL-PCB exposure and type 2 diabetes incidence. Articles that met our selection criteria (n = 81) were organized into the following subcategories: data stratified by sex (n = 13), unstratified data (n = 45), and data from only 1 sex (n = 13 male, n = 10 female). We also considered whether exposure occurred either abruptly at high concentrations through a contamination event (“disaster exposure”) or chronically at low concentrations (“non-disaster exposure”). There were 8 studies that compared associations between dioxin/DL-PCB exposure and diabetes risk in males versus females within the same population. When all sex-stratified or single-sex studies were considered in the meta-analysis (n = 18), the summary relative risk (RR) for incident diabetes among those exposed relative to reference populations was 1.78 (95% CI = 1.37–2.31) and 1.95 (95% CI = 1.56–2.43) for female and males, respectively. However, when we restricted the meta-analysis to disaster-exposed populations, the RR was higher in females than males (2.86 versus 1.59, respectively). In contrast, in non-disaster exposed populations the RR for females was lower than males (1.40 and 2.02, respectively). Our meta-analysis suggests that there are sex differences in the associations between dioxin/DL-PCBs exposure and incident diabetes, and that the mode of exposure modifies these differences.
A Potential Nine-lncRNAs Signature Identification and Nomogram Diagnostic Model Establishment for Papillary Thyroid Cancer
Authors: Yao Jin-Ming , Zhao Jun-Yu , Lv Fang-Fang , Yang Xue-Bo , Wang Huan-Jun
Published: February 2022

The purpose of our current study was to establish a long non-coding RNA(lncRNA) signature and assess its prognostic and diagnostic power in papillary thyroid cancer (PTC). LncRNA expression profiles were obtained from the Cancer Genome Atlas (TCGA). The key module and hub lncRNAs related to PTC were determined by weighted gene co-expression network analysis (WGCNA) and LASSO Cox regression analyses, respectively. Functional enrichment analyses, including Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) and gene set enrichment analysis were implemented to analyze the possible biological processes and signaling pathways of hub lncRNAs. Associations between key lncRNA expressions and tumor-infiltrating immune cells were identified using the TIMER website, and proportions of immune cells in high/low risk score groups were compared. Kaplan-Meier Plotter was used to evaluate the prognostic significance of hub genes in PTC. A diagnostic model was conducted with logistic regression analysis, and its diagnostic performance was assessed by calibration/receiver operating characteristic curves and principal component analysis. A nine-lncRNAs signature (SLC12A5-AS1, LINC02028, KIZ-AS1, LINC02019, LINC01877, LINC01444, LINC01176, LINC01290, and LINC00581) was established in PTC, which has significant diagnostic and prognostic power. Functional enrichment analyses elucidated the regulatory mechanism of the nine-lncRNAs signature in the development of PTC. This signature and expressions of nine hub lncRNAs were correlated with the distributions of tumor infiltrating immune cells. A diagnostic nomogram was also established for PTC. By comparing with the published models with less than or equal to nine lncRNAs, our signature showed a preferable performace for prognosis prediction. In conclusion, our present research established an innovative nine-lncRNAs signature and a six-lncRNAs nomogram that might act as a potential indicator for PTC prognosis and diagnosis, which could be conducive to the PTC treatment.
Reinforcement Learning for Mean-Field Game
Authors: Agarwal Mridul , Aggarwal Vaneet , Ghosh Arnob , Tiwari Nilay
Published: February 2022

Stochastic games provide a framework for interactions among multiple agents and enable a myriad of applications. In these games, agents decide on actions simultaneously. After taking an action, the state of every agent updates to the next state, and each agent receives a reward. However, finding an equilibrium (if exists) in this game is often difficult when the number of agents becomes large. This paper focuses on finding a mean-field equilibrium (MFE) in an action-coupled stochastic game setting in an episodic framework. It is assumed that an agent can approximate the impact of the other agents’ by the empirical distribution of the mean of the actions. All agents know the action distribution and employ lower-myopic best response dynamics to choose the optimal oblivious strategy. This paper proposes a posterior sampling-based approach for reinforcement learning in the mean-field game, where each agent samples a transition probability from the previous transitions. We show that the policy and action distributions converge to the optimal oblivious strategy and the limiting distribution, respectively, which constitute an MFE.
Applying Deep Learning to Construct a Defect Detection System for Ceramic Substrates
Authors: Huang Chien-Yi , Lin I-Chen , Liu Yuan-Lien
Published: February 2022

Under the emerging topic of machine vision technology replacing manual examination, automatic optical inspection (AOI) technology has been adopted for the detection of defects in semi-finished/finished products and is widely used for the defect detection of printed circuit boards (PCB) in electronic industries where surface mount technology (SMT) is applied. In order to convert images from gray-scale to binary in the PCB process, a strict threshold value was set for AOI to prevent ‘escapes’, but this can lead to serious false alarm because of unwanted noises. Therefore, they tend to set up a Noise-Removal procedure after AOI, which increases the computational cost. By applying deep learning to circuit images of the ceramic substrates in AOI, this paper aimed to construct an automatic defect detection system that could also identify the categories as well as the locations of defects. This study proposed and evaluated three models with integrated structures: ResNeXt+YOLO v3, Inception v3+YOLO v3, and YOLO v3. The outcomes indicate that the defect detection system built on ResNeXt+YOLO v3 could most effectively detect standard images that had been misidentified as defects by AOI, categorize genuine defects, and find their location. The proposed method could not only increase the inspection accuracy to 99.2%, but also help decrease the cost of human resources generated by manual re-examination.
On the Free Vibration and the Buckling Analysis of Laminated Composite Beams Subjected to Axial Force and End Moment: A Dynamic Finite Element Analysis
Authors: Kashani MirTahmaseb , Hashemi Seyed M.
Published: February 2022

This work presents the bending–torsion coupled free vibration analysis of prestressed, layered composite beams subjected to axial force and end moment using the traditional finite element method (FEM) and dynamic finite element (DFE) techniques. Current trends in the literature, in terms of different types of modeling techniques and constraints, were briefly examined. The Galerkin-type weighted residual method was applied to convert the coupled differential equations of motion into a discrete problem using a polynomial interpolation function in the finite element method. In the dynamic finite element method, trigonometric shape functions were implemented to describe the equations in terms of nodal displacements. The eigenvalue problem resulting from the discretization along the length of the beam was solved in order to determine the system’s natural frequencies and modes. The results, showing the effects of axial load, end moment, and combined loading on natural frequencies, are discussed and are followed by some concluding remarks.
Evaluating the Impact of Planetary Boundary Layer, Land Surface Model, and Microphysics Parameterization Schemes on Simulated GOES-16 Water Vapor Brightness Temperatures
Authors: Griffin Sarah M. , Otkin Jason A.
Published: February 2022

The impact of several land surface models (LSMs) and microphysics (MP), planetary boundary layer (PBL), and surface layer schemes on the accuracy of simulated brightness temperatures (BTs) from water vapor (WV) sensitive bands was examined via comparison with observations from the GOES-16 Advanced Baseline Imager. Nine parameterization configurations were evaluated. Analysis revealed that, compared to the Thompson MP scheme, the National Severe Storms Laboratory MP scheme produced lower simulated WV BTs in the upper troposphere but higher WV BTs in the middle and lower troposphere. The configuration with the Geophysical Fluid Dynamics Laboratory MP and hybrid eddy-diffusivity mass-flux (EDMF) PBL instead of Mellor–Yamada–Nakanishi–Niino (MYNN) PBL produced higher BTs. Yet, changing the PBL from MYNN to Shin–Hong or EDMF reduced the simulated WV BTs. Changing the LSM from Noah to RUC also resulted in lower simulated WV BTs, which were further enhanced with the MYNN surface layer instead of the GFS. The location and orientation of upper-level jet streams and troughs was assessed using the location of WV gradient objects. Every configuration had an increased translation speed compared to the observations, as forecast WV gradient objects were west of the observation objects early in the forecast and then east later in the forecast.
A Heuristic Method for Modeling Odor Emissions from Open Roof Rectangular Tanks
Authors: Bellasio Roberto , Bianconi Roberto
Published: February 2022

This paper presents heuristic equations for estimating odor emissions from open-roof rectangular tanks as a function of the tank orientation, wind direction, wind speed and distance of the emitting surface from the tank top. These types of equations are important because they may help to improve emission calculations to avoid overestimations, which are damaging to the plant owner, and underestimations, which are negative for the population around the plant. Odor emissions were determined for four tanks with the same area, different shape factors and two different orientations and then used as inputs for a dispersion model in order to calculate separation distances and evaluate their differences. The results show that different separation distances were obtained depending on the tank orientation, shape factor and level of filling. Future field applications to verify and improve the proposed equations are desirable. If the effect of the tank orientation on odor emission is proven, the design of future industrial plants containing open-roof rectangular tanks should consider the results of detailed wind data analysis.
Effect of Polygonal Agglomerated Ice Crystals on Laser Scattering
Authors: Ren Shenhe , Gao Ming , Nan Ze , Wang Mingjun , Li Yan
Published: February 2022

Cirrus clouds contain a large number of irregular small ice crystals. These solid ice crystals cause energy loss and reduce the signal-to-noise ratio at the receiver, causing errors in reception. Considering the random motion and structural diversity of ice particles in cirrus clouds, the discrete dipole approximation method was used to establish sphere-sphere, sphere–ellipsoid, sphere-hexagonal prism, and sphere-hexagonal plate ice particle models. The effects of different agglomerated ice particles on the laser extinction, absorption, and scattering efficiency, as well as the laser intensity and Mueller matrix elements, were analyzed, and the scattering characteristics of agglomerated ice particles in different spatial orientations were preliminarily explored. The results show that the spatial orientation of the clustered particles has great influence on the scattering characteristics. The maximum relative error of the scattering efficiency was 200%, and the maximum relative error value of the elements of the Mueller matrix reaches 800-fold. The results of this study provide theoretical support for further analysis of the scattering characteristics of ice crystal particles with complex agglomeration structures and for further study of the scattering characteristics of randomly moving agglomeration particles in cirrus clouds.
Air Quality Analysis in Lima, Peru Using the NO2 Levels during the COVID-19 Pandemic Lockdown
Authors: Velayarce Diego , Bustos Qespisisa , García Maria Paz , Timaná Camila , Carbajal Ricardo , Salvatierra Noe , Horna Daniel , Murray Victor
Published: February 2022

The emergence of the new COVID-19 virus in Peru forced the Peruvian government to take swift measures to stop its proliferation. Consequently, a state of emergency was declared, which included mandatory social isolation and quarantine. This action meant that people would transit only in emergency cases. In this context, this study’s objective is to analyze the air quality changes in terms of the capital city’s NO2 levels due to these government decisions using satellite imagery data obtained from the Sentinel-5P satellite. One critical problem is the lack of spatially distributed air quality data. The Peruvian Meteorological Service only monitors air quality in Lima, the capital city. In addition, the air quality ground stations are not always functioning. Thus, there is a need to find new reliable methods to complement the official data obtained. One method of doing so is the use of remote sensing products, although the accuracy and applicability are yet to be determined; therefore, this is the article’s focus. A temporal and spatial analysis was developed quantitatively and qualitatively to measure the levels of NO2 in eighteen regions of Lima to contrast the quarantine’s effect on polluting gas emission levels. The measurements are also compared with the official Peruvian data from ground sensors using Pearson correlation coefficients, thus, showing that Sentinel-5P data can be used for changes in the mean daily concentration of NO2. We also developed the first version of an open platform that converts the satellite data into a friendly format for visualization. The results show NO2 ambient concentration reductions compared to 2019 of between 60% and 40% in the first two weeks and between 50% and 25% in the following two weeks of the COVID-19 lockdown. However, this effect could not be observed two months after the start of the lockdown.
Generalizations of the R-Matrix Method to the Treatment of the Interaction of Short-Pulse Electromagnetic Radiation with Atoms
Authors: Schneider Barry I. , Hamilton Kathryn R. , Bartschat Klaus
Published: February 2022

Since its initial development in the 1970s by Phil Burke and his collaborators, the R-matrix theory and associated computer codes have become the method of choice for the calculation of accurate data for general electron–atom/ion/molecule collision and photoionization processes. The use of a non-orthogonal set of orbitals based on B-splines, now called the B-spline R-matrix (BSR) approach, was pioneered by Zatsarinny. It has considerably extended the flexibility of the approach and improved particularly the treatment of complex many-electron atomic and ionic targets, for which accurate data are needed in many modelling applications for processes involving low-temperature plasmas. Both the original R-matrix approach and the BSR method have been extended to the interaction of short, intense electromagnetic (EM) radiation with atoms and molecules. Here, we provide an overview of the theoretical tools that were required to facilitate the extension of the theory to the time domain. As an example of a practical application, we show results for two-photon ionization of argon by intense short-pulse extreme ultraviolet radiation.
Overall Survival and Prognostic Factors among Older Patients with Metastatic Pancreatic Cancer: A Retrospective Analysis Using a Hospital Database
Authors: Conti Catherine , Pamoukdjian Frédéric , Aparicio Thomas , Mebarki Soraya , Poisson Johanne , Manceau Gilles , Taieb Julien , Rance Bastien , Katsahian Sandrine , Charles-Nelson Anaïs , Paillaud Elena
Published: February 2022

Pre-therapeutic factors associated with overall survival (OS) among older patients ≥70 years with metastatic pancreatic cancer (mPC) are not known. This was a retrospective single-centre cohort study in Paris including 159 consecutive older patients with mPC between 2000 and 2018. Alongside geriatric parameters, specific comorbidities, cancer-related data and chemotherapy regimens were retrieved. Cox multivariate models were run to assess predictors for OS. The median age was 80 years, 52% were women, 21.5% had diabetes, and 48% had pancreatic head cancer and 72% liver metastases. 62% of the patients (n = 99) received chemotherapy, among which the gemcitabine + nab-paclitaxel (GnP) regimen was the most frequent (72%). Median OS [95%CI] was 7.40 [5.60–10.0] and 1.40 [0.90–2.20] months respectively for patients with and without chemotherapy. The GnP regimen (aHR [95%CI] = 0.47 [0.25–0.89], p = 0.02) and diabetes (aHR = 0.44 [0.24–0.77], p = 0.004) (or anti-diabetic therapy) were multivariate protective factors for death, while ECOG-PS, liver metastases, and the neutrophil cell count were multivariate risk factors for death. In the chemotherapy group, ECOG-PS, number of metastatic sites and the GnP remained significantly associated with OS. Our study confirms the feasibility and efficacy of chemotherapy and the protective effects of diabetes among older patients with mPC.
Proton Radiation Therapy for Nasopharyngeal Cancer Patients: Dosimetric and NTCP Evaluation Supporting Clinical Decision
Authors: Vai Alessandro , Molinelli Silvia , Rossi Eleonora , Iacovelli Nicola Alessandro , Magro Giuseppe , Cavallo Anna , Pignoli Emanuele , Rancati Tiziana , Mirandola Alfredo , Russo Stefania , Ingargiola Rossana , Vischioni Barbara , Bonora Maria , Ronchi Sara , Ciocca Mario , Orlandi Ester
Published: February 2022

(1) Background: we proposed an integrated strategy to support clinical allocation of nasopharyngeal patients between proton and photon radiotherapy. (2) Methods: intensity-modulated proton therapy (IMPT) plans were optimized for 50 consecutive nasopharyngeal carcinoma (NPC) patients treated with volumetric modulated arc therapy (VMAT), and differences in dose and normal tissue complication probability (ΔNTCPx-p) for 16 models were calculated. Patient eligibility for IMPT was assessed using a model-based selection (MBS) strategy following the results for 7/16 models describing the most clinically relevant endpoints, applying a model-specific ΔNTCPx-p threshold (15% to 5% depending on the severity of the complication) and a composite threshold (35%). In addition, a comprehensive toxicity score (CTS) was defined as the weighted sum of all 16 ΔNTCPx-p, where weights follow a clinical rationale. (3) Results: Dose deviations were in favor of IMPT (ΔDmean ≥ 14% for cord, esophagus, brainstem, and glottic larynx). The risk of toxicity significantly decreased for xerostomia (−12.5%), brain necrosis (−2.3%), mucositis (−3.2%), tinnitus (−8.6%), hypothyroidism (−9.3%), and trismus (−5.4%). There were 40% of the patients that resulted as eligible for IMPT, with a greater advantage for T3–T4 staging. Significantly different CTS were observed in patients qualifying for IMPT. (4) Conclusions: The MBS strategy successfully drives the clinical identification of NPC patients, who are most likely to benefit from IMPT. CTS summarizes well the expected global gain.
An Orally Bioavailable and Highly Efficacious Inhibitor of CDK9/FLT3 for the Treatment of Acute Myeloid Leukemia
Authors: Anshabo Abel Tesfaye , Bantie Laychiluh , Diab Sarah , Lenjisa Jimma , Kebede Alemwork , Long Yi , Heinemann Gary , Karanjia Jasmine , Noll Benjamin , Basnet Sunita K. C. , Li Manjun , Milne Robert , Albrecht Hugo , Wang Shudong
Published: February 2022

Mutations in FMS-like tyrosine kinase 3 (FLT3) occur in approximately one-third of AML patients and are associated with a particularly poor prognosis. The most common mutation, FLT3-ITD, is a self-activating internal tandem duplication (ITD) in the FLT3 juxtamembrane domain. Many FLT3 inhibitors have shown encouraging results in clinical trials, but the rapid emergence of resistance has severely limited sustainable efficacy. Co-targeting of CDK9 and FLT3 is a promising two-pronged strategy to overcome resistance as the former plays a role in the transcription of cancer cell-survival genes. Most prominently, MCL-1 is known to be associated with AML tumorigenesis and drug resistance and can be down-regulated by CDK9 inhibition. We have developed CDDD11-8 as a potent CDK9 inhibitor co-targeting FLT3-ITD with Ki values of 8 and 13 nM, respectively. The kinome selectivity has been confirmed when the compound was tested in a panel of 369 human kinases. CDDD11-8 displayed antiproliferative activity against leukemia cell lines, and particularly potent effects were observed against MV4-11 and MOLM-13 cells, which are known to harbor the FLT3-ITD mutation and mixed lineage leukemia (MLL) fusion proteins. The mode of action was consistent with inhibition of CDK9 and FLT3-ITD. Most importantly, CDDD11-8 caused a robust tumor growth inhibition by oral administration in animal xenografts. At 125 mg/kg, CDDD11-8 induced tumor regression, and this was translated to an improved survival of animals. The study demonstrates the potential of CDDD11-8 towards the future development of a novel AML treatment.
Lynch-like Syndrome: Potential Mechanisms and Management
Authors: Martínez-Roca Alejandro , Giner-Calabuig Mar , Murcia Oscar , Castillejo Adela , Soto José Luis , García-Heredia Anabel , Jover Rodrigo
Published: February 2022

Lynch syndrome is an autosomal dominant disorder caused by germline mutations in DNA mismatch repair (MMR) system genes, such as MLH1, MSH2, MSH6, or PMS2. It is the most common hereditary colorectal cancer syndrome. Screening is regularly performed by using microsatellite instability (MSI) or immunohistochemistry for the MMR proteins in tumor samples. However, in a proportion of cases, MSI is found or MMR immunohistochemistry is impaired in the absence of a germline mutation in MMR genes, BRAF mutation, or MLH1 hypermethylation. These cases are defined as Lynch-like syndrome. Patients with Lynch-like syndrome represent a mixture of truly hereditary and sporadic cases, with a risk of colorectal cancer in first-degree relatives that is between the risk of Lynch syndrome in families and relatives of sporadic colon cancer cases. Although multiple approaches have been suggested to distinguish between hereditary and sporadic cases, a homogeneous testing protocol and consensus on the adequate classification of these patients is still lacking. For this reason, management of Lynch-like syndrome and prevention of cancer in these families is clinically challenging. This review explains the concept of Lynch-like syndrome, potential mechanisms for its development, and methods for adequately distinguishing between sporadic and hereditary cases of this entity.
Machine Learning Model to Stratify the Risk of Lymph Node Metastasis for Early Gastric Cancer: A Single-Center Cohort Study
Authors: Na Ji-Eun , Lee Yeong-Chan , Kim Tae-Jun , Lee Hyuk , Won Hong-Hee , Min Yang-Won , Min Byung-Hoon , Lee Jun-Haeng , Rhee Poong-Lyul , Kim Jae J.
Published: February 2022

Stratification of the risk of lymph node metastasis (LNM) in patients with non-curative resection after endoscopic resection (ER) for early gastric cancer (EGC) is crucial in determining additional treatment strategies and preventing unnecessary surgery. Hence, we developed a machine learning (ML) model and validated its performance for the stratification of LNM risk in patients with EGC. We enrolled patients who underwent primary surgery or additional surgery after ER for EGC between May 2005 and March 2021. Additionally, patients who underwent ER alone for EGC between May 2005 and March 2016 and were followed up for at least 5 years were included. The ML model was built based on a development set (70%) using logistic regression, random forest (RF), and support vector machine (SVM) analyses and assessed in a validation set (30%). In the validation set, LNM was found in 337 of 4428 patients (7.6%). Among the total patients, the area under the receiver operating characteristic (AUROC) for predicting LNM risk was 0.86 in the logistic regression, 0.85 in RF, and 0.86 in SVM analyses; in patients with initial ER, AUROC for predicting LNM risk was 0.90 in the logistic regression, 0.88 in RF, and 0.89 in SVM analyses. The ML model could stratify the LNM risk into very low (<1%), low (<3%), intermediate (<7%), and high (≥7%) risk categories, which was comparable with actual LNM rates. We demonstrate that the ML model can be used to identify LNM risk. However, this tool requires further validation in EGC patients with non-curative resection after ER for actual application.
Innovating Strategies and Tailored Approaches in Neuro-Oncology
Authors: Picca Alberto , Guyon David , Santonocito Orazio Santo , Baldini Capucine , Idbaih Ahmed , Carpentier Alexandre , Naccarato Antonio Giuseppe , Caccese Mario , Lombardi Giuseppe , Di Stefano Anna Luisa
Published: February 2022

Diffuse gliomas, the most frequent and aggressive primary central nervous system neoplasms, currently lack effective curative treatments, particularly for cases lacking the favorable prognostic marker IDH mutation. Nonetheless, advances in molecular biology allowed to identify several druggable alterations in a subset of IDH wild-type gliomas, such as NTRK and FGFR-TACC fusions, and BRAF hotspot mutations. Multi-tyrosine kinase inhibitors, such as regorafenib, also showed efficacy in the setting of recurrent glioblastoma. IDH inhibitors are currently in the advanced phase of clinical evaluation for patients with IDH-mutant gliomas. Several immunotherapeutic approaches, such as tumor vaccines or checkpoint inhibitors, failed to improve patients’ outcomes. Even so, they may be still beneficial in a subset of them. New methods, such as using pulsed ultrasound to disrupt the blood–brain barrier, gene therapy, and oncolytic virotherapy, are well tolerated and may be included in the therapeutic armamentarium soon.
A Prospective, Real-World, Multinational Study of Naloxegol for Patients with Cancer Pain Diagnosed with Opioid-Induced Constipation—The NACASY Study
Authors: Davies Andrew , Cinieri Saverio , Dupoiron Denis , España Fernandez Sofia , Leclerc Johan , Montesarchio Vincenzo , Mystakidou Kyriaki , Serna Judith , Tack Jan ,   on behalf of the NACASY Study Group
Published: February 2022

The Naloxegol Cancer Study (NACASY) was a multinational European study aimed to evaluate the 4-week safety and efficacy of naloxegol in a real-world setting in patients with cancer pain diagnosed with opioid-induced constipation. The primary safety endpoint was the incidence of adverse events leading to study discontinuation. We recruited 170 patients who received at least one dose of naloxegol (i.e., safety population). Out of 170 patients, 20 (11.8%, 95%CI 6.9–16.6) discontinued the study due to adverse events, and, of them, 12 (7.1%, 95%CI 3.2–10.9%) were study discontinuations due to naloxegol-related adverse events. From 76 patients subjects who had completed both 4 weeks of treatment and 28 days of the diary, 55 patients (72.4%, 95% CI 62.3–82.4%) were regarded as responders (i.e., showed ≥3 bowel-movements per week and an increase of ≥1 bowel-movement over baseline) to naloxegol treatment. The Patient Assessment of Constipation—Quality of Life Questionnaire total score and all its subscales improved from baseline to 4 weeks of follow up. Our findings support and provide new evidence about the beneficial effect of naloxegol in terms of improvement of constipation and quality-of-life in patients with cancer-related pain and opioid-induced constipation and show a safety profile consistent with previous pivotal and real-world studies.
Management of Patients with Metastatic Bladder Cancer in the Real-World Setting from the Multidisciplinary Team: Current Opinion of the SOGUG Multidisciplinary Working Group
Authors: González-del-Alba Aránzazu , Conde-Moreno Antonio José , García Vicente Ana M. , González-Peramato Pilar , Linares-Espinós Estefanía , Climent Miguel Ángel ,   the SOGUG Multidisciplinary Working Group
Published: February 2022

Based on the discussion of current state of research of relevant topics of metastatic bladder cancer (mBC) among a group of experts of a Spanish Oncology Genitourinary (SOGUG) Working Group, a set of recommendations were proposed to overcome the challenges posed by the management of mBC in clinical practice. First-line options in unfit patients for cisplatin are chemotherapy with carboplatin and immunotherapy in PD-L1 positive patients. FDG-PET/CT may be a useful imaging technique in the initial staging or re-staging. In patients with oligometastatic disease, it is important to consider not only the number of metastatic lesions, but also the tumor biology and the clinical course. The combination of stereotactic body radiotherapy and immunotherapy with anti-PD-L1 monoclonal antibodies is under investigation and could improve the results of systemic treatment in patient with oligometastatic disease. Rescue treatment with curative intent could be considered in patients with oligometastatic disease after complete response on FDG-PET/CT. Metastatic disease should be evaluated using the same imaging modality over the course of the disease from diagnosis until rescue treatment. For improving the outcome of patients with mBC, the involvement of a dedicated multidisciplinary team, including urologists, pathologists, oncologists, radiologists and other specialists is of outmost importance in the daily care of these patients.
Pharmacogenomics Testing in Phase I Oncology Clinical Trials: Constructive Criticism Is Warranted
Authors: Sissung Tristan M. , Figg William D.
Published: February 2022

While over ten-thousand phase I studies are published in oncology, fewer than 1% of these studies stratify patients based on genetic variants that influence pharmacology. Pharmacogenetics-based patient stratification can improve the success of clinical trials by identifying responsive patients who have less potential to develop toxicity; however, the scientific limits imposed by phase I study designs reduce the potential for these studies to make conclusions. We compiled all phase I studies in oncology with pharmacogenetics endpoints (n = 84), evaluating toxicity (n = 42), response or PFS (n = 32), and pharmacokinetics (n = 40). Most of these studies focus on a limited number of agent classes: Topoisomerase inhibitors, antimetabolites, and anti-angiogenesis agents. Eight genotype-directed phase I studies were identified. Phase I studies consist of homogeneous populations with a variety of comorbidities, prior therapies, racial backgrounds, and other factors that confound statistical analysis of pharmacogenetics. Taken together, phase I studies analyzed herein treated small numbers of patients (median, 95% CI = 28, 24–31), evaluated few variants that are known to change phenotype, and provided little justification of pharmacogenetics hypotheses. Future studies should account for these factors during study design to optimize the success of phase I studies and to answer important scientific questions.
Toward More Comprehensive Homologous Recombination Deficiency Assays in Ovarian Cancer, Part 1: Technical Considerations
Authors: Quesada Stanislas , Fabbro Michel , Solassol Jérôme
Published: February 2022

High-grade serous ovarian cancer (HGSOC), the most frequent and lethal form of ovarian cancer, exhibits homologous recombination deficiency (HRD) in 50% of cases. In addition to mutations in BRCA1 and BRCA2, which are the best known thus far, defects can also be caused by diverse alterations to homologous recombination-related genes or epigenetic patterns. HRD leads to genomic instability (genomic scars) and is associated with PARP inhibitor (PARPi) sensitivity. HRD is currently assessed through BRCA1/2 analysis, which produces a genomic instability score (GIS). However, despite substantial clinical achievements, FDA-approved companion diagnostics (CDx) based on GISs have important limitations. Indeed, despite the use of GIS in clinical practice, the relevance of such assays remains controversial. Although international guidelines include companion diagnostics as part of HGSOC frontline management, they also underscore the need for more powerful and alternative approaches for assessing patient eligibility to PARP inhibitors. In these companion reviews, we review and present evidence to date regarding HRD definitions, achievements and limitations in HGSOC. Part 1 is dedicated to technical considerations and proposed perspectives that could lead to a more comprehensive and dynamic assessment of HR, while Part 2 provides a more integrated approach for clinicians.
Evaluation of the Clinical Utility of Genomic Profiling to Inform Selection of Clinical Trial Therapy in Salivary Gland Cancer
Authors: Rack Samuel , Feeney Laura , Hapuarachi Brindley , Adderley Helen , Woodhouse Laura , Betts Guy , Burghel George J. , Harrington Kevin J. , Metcalf Robert
Published: February 2022

For most patients with salivary gland cancer, there are no effective standard systemic therapies. Although clinical trials of biomarker-led drug therapies have delivered significant recent advances, there remains a need to understand the clinical utility of genomic profiling of cancer as a means to match patients with recurrent or metastatic salivary gland cancer to clinical trial therapies. In total, 209 patients with salivary gland cancers were profiled with 24 gene (n = 209)) and >325 gene (n = 32) DNA-based next-generation sequencing panels. A retrospective systematic evaluation was performed to identify the frequency of available matched drug therapies within clinical trials based on the results. The matches were then stratified based upon the level of evidence supporting the drug–biomarker combination being investigated using the ESMO Scale for Clinical Actionability of Molecular Targets (ESCAT) to determine the strength of the clinical rationale for each gene–drug match identified. DNA-based next generation sequencing (NGS) analysis was successful in 175/209 (84%) patients with salivary gland cancer. Using the 24-gene NGS panel, actionable alterations were identified in 27% (48/175) patients. Alterations were most frequent in salivary duct carcinoma (88%) characterized by TP53 and/or PIK3CA mutations, with matched trials available for 63% (10/16). In ACC, biomarker-matched trials were available for 7% (8/115), and no genomic alterations were found in 96/115 (83%) of ACC patients. TP53 was the most frequently altered gene across all subtypes; however, there were no trials recruiting based on TP53 status. In 32 ACC patients with no genomic alterations using the 24-gene panel, a broader (>325 gene) panel identified alterations in 87% (27/32) of cases with biomarker-matched trials available in 40% (13/32) cases. This study identified that genomic profiling using focused (24-gene) NGS panels has potential utility in matching to trial therapies for most patients with non-ACC salivary gland cancer. For patients with ACC, broader genomic profiling has demonstrated added clinical utility. We describe the application of an approach to classification of levels of evidence which may be helpful to inform the clinician and patient decision making around the selection of clinical trial therapies.
Identification of Urine Biomarkers to Improve Eligibility for Prostate Biopsy and Detect High-Grade Prostate Cancer
Authors: Alijaj Nagjie , Pavlovic Blaz , Martel Paul , Rakauskas Arnas , Cesson Valérie , Saba Karim , Hermanns Thomas , Oechslin Pascal , Veit Markus , Provenzano Maurizio , Rüschoff Jan H. , Brada Muriel D. , Rupp Niels J. , Poyet Cédric , Derré Laurent , Valerio Massimo , Banzola Irina , Eberli Daniel
Published: February 2022

PCa screening is based on the measurements of the serum prostate specific antigen (PSA) to select men with higher risks for tumors and, thus, eligible for prostate biopsy. However, PSA testing has a low specificity, leading to unnecessary biopsies in 50–75% of cases. Therefore, more specific screening opportunities are needed to reduce the number of biopsies performed on healthy men and patients with indolent tumors. Urine samples from 45 patients with elevated PSA were collected prior to prostate biopsy, a mass spectrometry (MS) screening was performed to identify novel biomarkers and the best candidates were validated by ELISA. The urine quantification of PEDF, HPX, CD99, CANX, FCER2, HRNR, and KRT13 showed superior performance compared to PSA. Additionally, the combination of two biomarkers and patient age resulted in an AUC of 0.8196 (PSA = 0.6020) and 0.7801 (PSA = 0.5690) in detecting healthy men and high-grade PCa, respectively. In this study, we identified and validated novel urine biomarkers for the screening of PCa, showing that an upfront urine test, based on quantitative biomarkers and patient age, is a feasible method to reduce the number of unnecessary prostate biopsies and detect both healthy men and clinically significant PCa.
Patients Benefit from Liver Transplantation for Hepatocellular Carcinoma beyond Milan Criteria without Harming the Health Care System
Authors: Gundlach Jan-Paul , Linecker Michael , Dobbermann Henrike , Wadle Felix , Becker Thomas , Braun Felix
Published: February 2022

Liver transplantation (LT) is the only definitive treatment to cure hepatocellular carcinoma (HCC) in cirrhosis. Waiting-list candidates are selected by the model for end-stage liver disease (MELD). However, many indications are not sufficiently represented by labMELD. For HCC, patients are selected by Milan-criteria: Milan-in qualifies for standard exception (SE) and better organ access on the waiting list; while Milan-out patients are restricted to labMELD and might benefit from extended criteria donor (ECD)-grafts. We analyzed a cohort of 102 patients (2011–2020). Patients with labMELD (no SE, Milan-out, n = 56) and matchMELD (SE-HCC, Milan-in, n = 46) were compared. The median overall survival was not significantly different (p = 0.759). No difference was found in time on the waiting list (p = 0.881), donor risk index (p = 0.697) or median costs (p = 0.204, EUR 43,500 (EUR 17,800–185,000) for labMELD and EUR 30,300 (EUR 17,200–395,900) for matchMELD). Costs were triggered by a cut-off labMELD of 12 points. Overall, the deficit increased by EUR 580 per labMELD point. Cost drivers were re-operation (p < 0.001), infection with multiresistant germs (p = 0.020), dialysis (p = 0.017), operation time (p = 0.012) and transfusions (p < 0.001). In conclusion, this study demonstrates that LT for HCC is successful and cost-effective in low labMELD patients independent of Milan-criteria. Therefore, ECD-grafts are favorized in Milan-out HCC patients with low labMELD.
Quantifying the Epithelial-to-Mesenchymal Transition (EMT) from Bench to Bedside
Authors: Brown Meredith S. , Muller Kristen E. , Pattabiraman Diwakar R.
Published: February 2022

The epithelial-to-mesenchymal transition (EMT) and its reversal, the mesenchymal-to-epithelial transition (MET) are critical components of the metastatic cascade in breast cancer and many other solid tumor types. Recent work has uncovered the presence of a variety of states encompassed within the EMT spectrum, each of which may play unique roles or work collectively to impact tumor progression. However, defining EMT status is not routinely carried out to determine patient prognosis or dictate therapeutic decision-making in the clinic. Identifying and quantifying the presence of various EMT states within a tumor is a critical first step to scoring patient tumors to aid in determining prognosis. Here, we review the major strides taken towards translating our understanding of EMT biology from bench to bedside. We review previously used approaches including basic immunofluorescence staining, flow cytometry, single-cell sequencing, and multiplexed tumor mapping. Future studies will benefit from the consideration of multiple methods and combinations of markers in designing a diagnostic tool for detecting and measuring EMT in patient tumors.
The Practicality of the Use of Liquid Biopsy in Early Diagnosis and Treatment Monitoring of Oral Cancer in Resource-Limited Settings
Authors: Adeola Henry Ademola , Bello Ibrahim O. , Aruleba Raphael Taiwo , Francisco Ngiambudulu M. , Adekiya Tayo Alex , Adefuye Anthonio Oladele , Ikwegbue Paul Chukwudi , Musaigwa Fungai
Published: February 2022

An important driving force for precision and individualized medicine is the provision of tailor-made care for patients on an individual basis, in accordance with best evidence practice. Liquid biopsy(LB) has emerged as a critical tool for the early diagnosis of cancer and for treatment monitoring, but its clinical utility for oral squamous cell carcinoma (OSCC) requires more research and validation. Hence, in this review, we have discussed the current applications of LB and the practicality of its routine use in Africa; the potential advantages of LB over the conventional “gold-standard” of tissue biopsy; and finally, practical considerations were discussed in three parts: pre-analytic, analytic processing, and the statistical quality and postprocessing phases. Although it is imperative to establish clinically validated and standardized working guidelines for various aspects of LB sample collection, processing, and analysis for optimal and reliable use, manpower and technological infrastructures may also be an important factor to consider for the routine clinical application of LB for OSCC. LB is poised as a non-invasive precision tool for personalized oral cancer medicine, particularly for OSCC in Africa, when fully embraced. The promising application of different LB approaches using various downstream analyses such as released circulating tumor cells (CTCs), cell free DNA (cfDNA), microRNA (miRNA), messenger RNA (mRNA), and salivary exosomes were discussed. A better understanding of the diagnostic and therapeutic biomarkers of OSCC, using LB applications, would significantly reduce the cost, provide an opportunity for prompt detection and early treatment, and a method to adequately monitor the effectiveness of the therapy for OSCC, which typically presents with ominous prognosis.
The Role of Magnetic Resonance Imaging in the Management of Esophageal Cancer
Authors: Pellat Anna , Dohan Anthony , Soyer Philippe , Veziant Julie , Coriat Romain , Barret Maximilien
Published: February 2022

Esophageal cancer (EC) is the eighth more frequent cancer worldwide, with a poor prognosis. Initial staging is critical to decide on the best individual treatment approach. Current modalities for the assessment of EC are irradiating techniques, such as computed tomography (CT) and positron emission tomography/CT, or invasive techniques, such as digestive endoscopy and endoscopic ultrasound. Magnetic resonance imaging (MRI) is a non-invasive and non-irradiating imaging technique that provides high degrees of soft tissue contrast, with good depiction of the esophageal wall and the esophagogastric junction. Various sequences of MRI have shown good performance in initial tumor and lymph node staging in EC. Diffusion-weighted MRI has also demonstrated capabilities in the evaluation of tumor response to chemoradiotherapy. To date, there is not enough data to consider whole body MRI as a routine investigation for the detection of initial metastases or for prediction of distant recurrence. This narrative review summarizes the current knowledge on MRI for the management of EC.
Raman Spectroscopy: A Personalized Decision-Making Tool on Clinicians’ Hands for In Situ Cancer Diagnosis and Surgery Guidance
Authors: Kouri Maria Anthi , Spyratou Ellas , Karnachoriti Maria , Kalatzis Dimitris , Danias Nikolaos , Arkadopoulos Nikolaos , Seimenis Ioannis , Raptis Yannis S. , Kontos Athanassios G. , Efstathopoulos Efstathios P.
Published: February 2022

Accurate in situ diagnosis and optimal surgical removal of a malignancy constitute key elements in reducing cancer-related morbidity and mortality. In surgical oncology, the accurate discrimination between healthy and cancerous tissues is critical for the postoperative care of the patient. Conventional imaging techniques have attempted to serve as adjuvant tools for in situ biopsy and surgery guidance. However, no single imaging modality has been proven sufficient in terms of specificity, sensitivity, multiplexing capacity, spatial and temporal resolution. Moreover, most techniques are unable to provide information regarding the molecular tissue composition. In this review, we highlight the potential of Raman spectroscopy as a spectroscopic technique with high detection sensitivity and spatial resolution for distinguishing healthy from malignant margins in microscopic scale and in real time. A Raman spectrum constitutes an intrinsic “molecular finger-print” of the tissue and any biochemical alteration related to inflammatory or cancerous tissue state is reflected on its Raman spectral fingerprint. Nowadays, advanced Raman systems coupled with modern instrumentation devices and machine learning methods are entering the clinical arena as adjunct tools towards personalized and optimized efficacy in surgical oncology.
Immune Checkpoint Inhibitors—Associated Cardiotoxicity
Authors: Li Chenghui , Bhatti Sajjad A. , Ying Jun
Published: February 2022

Large population-based studies examining differences in ICI-associated cardiotoxicity across cancer types and agents are limited. Data of 5518 cancer patients who received at least one cycle of ICIs were extracted from a large network of health care organizations. ICI treatment groups were classified by the first ICI agent(s) (ipilimumab, nivolumab, pembrolizumab, cemiplimab, avelumab, atezolizumab, or durvalumab) or its class (PD-1 inhibitors, PD-L1 inhibitors, CTLA4-inhibitors, or their combination (ipilimumab + nivolumab)). Time to first cardiac adverse event (CAE) (arrhythmia, acute myocardial infarction, myocarditis, cardiomyopathy, or pericarditis) developed within one year after ICI initiation was analyzed using a competing-risks regression model adjusting for ICI treatment groups, patient demographic and clinical characteristics, and cancer sites. By month 12, 12.5% developed cardiotoxicity. The most common cardiotoxicity was arrhythmia (9.3%) and 2.1% developed myocarditis. After adjusting for patient characteristics and cancer sites, patients who initiated on monotherapy with ipilimumab (adjusted Hazard Ratio (aHR): 2.00; 95% CI: 1.49–2.70; p < 0.001) or pembrolizumab (aHR: 1.21; 95% CI: 1.01–1.46; p = 0.040) had a higher risk of developing CAEs within one year compared to nivolumab monotherapy. Ipilimumab and pembrolizumab use may increase the risk of cardiotoxicity compared to other agents. Avelumab also estimated a highly elevated risk (aHR: 1.92; 95% CI: 0.85–4.34; p = 0.117) compared to nivolumab and other PD-L1 agents, although the estimate did not reach statistical significance, warranting future studies.