bluuebunny/crossref_metadata_2025 huggingface dataset:
Gender Differences in Demographic and Pharmacological Factors in Patients Diagnosed with Late-Onset of Alzheimer’s Disease
Authors: Bailey-Taylor Melissa J. , Poupore Nicolas , Theriot Roley Laurie , Goodwin Richard L. , Mcphail Brooks , Nathaniel Thomas I.
Published: January 2022

Background: Whether gender differences exist in late-onset of Alzheimer’s disease (LOAD) treated with cholinesterase inhibitors (ChEIs) is not fully understood. This study investigated demographic and pharmacological characteristics in LOAD patients to determine gender differences in LOAD patients treated with ChEIs alone and ChEIs with other medications. Methods: This 5-year retrospective data analysis included 9290 LOAD AD patients with 2949 men patients and 6341 women. Potential predictors of demographic and pharmacological characteristics associated gender differences in patients treated with and without ChEIs therapy were determined using univariate analysis, while multivariable models adjusted for demographic and pharmacological variables. Results: In the adjusted analysis, men patients with LOAD that presented with a history of alcohol use (ETOH) (OR = 1.339, 95% CI, 1.072–1.672, p = 0.010), treated with second generation antipsychotics (SGAs) (OR = 1.271, 95% CI, 1.003–1.610, p = 0.047), citalopram (OR = 5.103, 95% CI, 3.423–7.607, p < 0.001), memantine (OR = 4.409, 95% CI, 3.704–5.249, p < 0.001), and buspirone (OR = 2.166, 95% CI, 1.437–3.264, p < 0.001) were more likely to receive ChEIs therapy, whereas older men were less likely to be treated with ChEIs therapy. Women who were African Americans (OR = 1.387, 95% CI, 1.168–1.647, p < 0.001), that received memantine (OR = 3.412, 95% CI, 3.034–3.837, p < 0.001), selective serotonin reuptake inhibitor (SSRIs) (OR = 1.143, 95% CI, 1.016–1.287, p = 0.026), and a history of ETOH (OR = 2.109, 95% CI, 1.724–2.580, p < 0.001) were more likely to receive ChEIs therapy, whereas older women were less likely to receive ChEIs therapy. Conclusion: In both men and women patients, those with increasing age were less likely to be treated with ChEI therapy, while patients treated with memantine were also likely to receive ChEI therapy. Our findings highlight the importance for clinicians to optimize ChEI in LOAD to improve treatment effectiveness and eliminate gender differences in ChEI therapy.
Understanding the Burdens Associated with Huntington’s Disease in Manifest Patients and Care Partners–Comparing to Parkinson’s Disease and the General Population
Authors: Exuzides Alex , Matos Joana E. , Patel Anisha M. , Martin Ashley A. , Ricker Bryan , Bega Danny
Published: January 2022

Background: The study provides real-world data on the impact of Huntington’s disease (HD) from the perspective of individuals with HD (IHD) and care partners (HD-CP) and contextualizes these results relative to Parkinson’s disease (PD) and the general population (GP). Methods: Cross-sectional survey of IHD and HD-CP in the US (July 2019–August 2019) conducted using the Rare Patient Voice panel. Data for individuals with Parkinson’s Disease (IPD), the general population (GP), and respective care partners (PD-CP; GP-CP) came from the 2018 US National Health and Wellness Survey. Outcomes included demographics, mental health, clinical characteristics, and health-related quality of life (HRQoL). Results: IHD had greater comorbid anxiety (IHD = 51.2%, IPD = 28.8%, GP = 2.0%), and HD-CP had greater comorbid anxiety (HD-CP = 52.5%, PD-CP = 28.6%, GP-CP = 19.6%) and depression (HD-CP = 65.0%, PD-CP = 29.9%, GP-CP = 19.6%), relative to other cohorts (p < 0.05). Respective of their GP cohorts, IHD exhibited lower HRQoL (EQ-5D: 0.66 ± 0.21 vs. 0.81 ± 0.17) and greater depression (PHQ-9: 11.59 ± 7.20 vs. 5.85 ± 6.71), whereas HD-CP exhibited greater depression only (PHQ-9: 6.84 ± 6.38 vs. 4.15 ± 5.58) (p < 0.001). No differences were observed between HD/HD-CP and PD/PD-CP cohorts on PHQ-9 or HRQoL. Conclusions: HD has a significant burden on patients and care partners, which is higher than GP. Notably, anxiety and depression were greater among HD vs. PD, despite similar HRQoL.
Leader Humor and Followers’ Change-Oriented Organizational Citizenship Behavior: The Role of Leader Machiavellianism
Authors: Choi Yongjun , Ha Sun-Bok , Choi Dongwon
Published: January 2022

The purpose of this study is to explore the mechanisms by which leader humor affects followers’ change-oriented organizational citizenship behavior. Specifically, we examine the mediation effect of team commitment in the leader humor–change-oriented organizational citizenship behavior link and whether it varied by leader Machiavellianism. Using multi-sourced data from the four battalions of the Republic of Korean Army, our findings show that team commitment mediated the positive relationship between leaders’ affiliative humor and followers’ change-oriented organizational citizenship behavior. Furthermore, the mediated relationship was stronger when leader Machiavellianism was lower. On the other hand, we found no support for the negative relationship between leaders’ aggressive humor and followers’ change-oriented organizational citizenship behavior. Theoretical and practical implications are discussed.
Analyzing Critical Factors for the Smart Construction Site Development: A DEMATEL-ISM Based Approach
Authors: Xiahou Xiaer , Wu Yifan , Duan Tianle , Lin Peng , Li Funing , Qu Xiaojun , Liu Long , Li Qiming , Liu Jiaxin
Published: January 2022

The wide and in-depth adoption of advanced information technologies within the construction industry has led to its revolution of all aspects; the construction site is not an exception. Recently, the notion of a smart construction site (SCS) has drawn the attention of all stakeholders within the industry. While the practice of SCS could be witnessed in various regions and the notion is mentioned frequently, the concept of SCS is still emerging, a sound framework for SCS development is still absent. As a bottom-up phenomenon, a systematic analysis of critical factors would provide all stakeholders with a comprehensive view of SCS development. In this research, previous research and existing practices of SCS are referred to, which helps to identify 17 critical factors for SCS development from the perspective of management, technology, and organization. The DEMATEL-ISM approach is introduced to conduct the factor analysis, and a questionnaire survey is conducted among 10 experts to investigate their attitudes on these factors. Following the proposed method, the 17 factors are classified into seven hierarchies and further categorized into three layers, i.e., effect layer, operational layer, and input layer, which helps to demonstrate the interrelationship among the critical factors for SCS development. The effect layer consists of the first to the third hierarchy, which contains the factors of cost (F2), safety (F4), schedule (F5), environment (F9), and quality (F3) management; these factors belong to the management perspective and reflect the expectations during SCS development. The operational layer consists of the fourth to the sixth hierarchy, which contains seven factors, namely, processing (F8), information (F10), communication and coordination (F15), personnel (F5), material (F6), equipment (F7), and management regulation (F17); these factors are critical in processing the input resources into the final effect of SCS development. The input layer only consists of the seventh hierarchy, which contains hardware and software facility (F11), integrated platform (F12), data sharing center (F13), smart decision system (F14), and technical team (F16); these factors represent the investment of SCS development. The systematic analysis of critical factors provides new insights on SCS development, which could be adopted as references for future SCS development by all stakeholders like government and construction enterprises.
Digital Twins in Built Environments: An Investigation of the Characteristics, Applications, and Challenges
Authors: Shahzad Muhammad , Shafiq Muhammad Tariq , Douglas Dean , Kassem Mohamad
Published: January 2022

The concept of digital twins is proposed as a new technology-led advancement to support the processes of the design, construction, and operation of built assets. Commonalities between the emerging definitions of digital twins describe them as digital or cyber environments that are bidirectionally-linked to their physical or real-life replica to enable simulation and data-centric decision making. Studies have started to investigate their role in the digitalization of asset delivery, including the management of built assets at different levels within the building and infrastructure sectors. However, questions persist regarding their actual applications and implementation challenges, including their integration with other digital technologies (i.e., building information modeling, virtual and augmented reality, Internet of Things, artificial intelligence, and cloud computing). Within the built environment context, this study seeks to analyze the definitions and characteristics of a digital twin, its interactions with other digital technologies used in built asset delivery and operation, and its applications and challenges. To achieve this aim, the research utilizes a thorough literature review and semi-structured interviews with ten industry experts. The literature review explores the merits and the relevance of digital twins relative to existing digital technologies and highlights potential applications and challenges for their implementation. The data from the semi-structured interviews are classified into five themes: definitions and enablers of digital twins, applications and benefits, implementation challenges, existing practical applications, and future development. The findings provide a point of departure for future research aimed at clarifying the relationship between digital twins and other digital technologies and their key implementation challenges.
Forecasting the Collapse-Induced Ground Vibration Using a GWO-ELM Model
Authors: Yan Yu , Hou Xiaomeng , Cao Shaojun , Li Ruisen , Zhou Wei
Published: January 2022

Blasting demolition is a popular method in the area of building demolishing. Due to the complex process of the building components’ collapse, it is difficult to predict the collapse-induced ground vibrations. As the accuracy of the empirical equation in predicting the collapse-induced ground vibration is not high, there is a significant risk of damage to the surrounding structures. To mitigate this risk, it is necessary to control and predict the peak particle velocity (PPV) and dominant frequency of ground vibration with higher accuracy. In this study, the parameters on the PPV and frequency of collapse-induced ground vibration are analyzed based on the Hertz theory. Then, fall tests are performed to simulate the collapse process of structural components and to investigate the characteristics of influential parameters on PPV and frequency. Using kernel density estimation (KDE) and Pearson correlation, the PPV and frequency are correlated with the distance from the falling point to the monitored point (R) and the mass of the falling structural component (M). Using recorded ground vibration data, the PPV and frequency are predicted using an extreme learning machine in combination with gray wolf optimization. The efficiency of the proposed algorithm is compared with other predictive models. The results indicate that the accuracy pre-diction of the proposed algorithm is better than those of plain extreme learning machines and the empirical equations, which indicates that the approach can be applied for PPV and frequency prediction of collapse-induced ground vibrations during blasting demolition.
Assessment and Prediction Model of GFRP Bars’ Durability Performance in Seawater Environment
Authors: Li Wenchao , Wen Fusheng , Zhou Min , Liu Fusheng , Jiao Yuzhao , Wu Qingfeng , Liu Hengan
Published: January 2022

In this study, the performance degradation law and mechanism of glass fiber reinforced polymer (GFRP) bars were investigated by being immersed in natural seawater (denoted as SW), saline-alkali solution (SA), or wrapped with concrete, and then submerged in natural seawater (SWC). A series of short-beam shear tests were conducted to investigate the effects of aging temperature and time on the interlaminar shear strength (ILSS) of GFRP bars. Microstructure changes, glass transition temperature (Tg) difference, and hydrolysis degree of GFRP bars after aging in three environments for 183 days were analyzed using scanning electron microscopy (SEM), differential scanning calorimeter (DSC), and Fourier transform infrared spectroscopy (FTIR). Test results demonstrated that the temperature could accelerate the strength degradation of GFRP bars significantly. After 183-day aging treatment at 60 °C, the ILSS retention rates of GFRP bars in the three environments of SW, SWC, and SA were 66.41%, 53.10%, and 45.36%, respectively; and Tg was 1.7%, 7.0%, 7.8% lower than that of unconditioned sample, respectively. Meanwhile different degrees of damage, such as separation between fiber and resin and few holes in the resin, were observed on the GFRP bars in the SWC and SA environments. It was also found that irreversible hydrolysis took place in some resins. The durability prediction model of GFRP bars serving in the Yellow Sea of China was established by using Arrhenius equation, and the correlation coefficient with the test data was not less than 0.94.
Metformin as a Potential Treatment Option for Endometriosis
Authors: Kimber-Trojnar Żaneta , Dłuski Dominik Franciszek , Wierzchowska-Opoka Magdalena , Ruszała Monika , Leszczyńska-Gorzelak Bożena
Published: January 2022

Endometriosis is a common disease in women of reproductive age, and its pathogenesis seems to be largely affected by hormone imbalance, inflammation, oxidative stress, and autophagy dysregulation. These pathophysiological disturbances interact with one another through mechanisms that are still awaiting elucidation. The aim of this article is to present current knowledge regarding the possibilities of using metformin in the pharmacological treatment of endometriosis. Metformin is an insulin sensitizer widely used for the treatment of type 2 diabetes mellitus. The pleiotropic effects of metformin are mainly exerted through the activation of AMP-activated protein kinase, which is the key cellular energy homeostasis regulator that inhibits mTOR, a major autophagy suppressor. Metformin regresses endometriotic implants by increasing the activity of superoxide dismutase. It is also an inhibitor of metalloproteinase-2, decreasing the levels of the vascular endothelial growth factor and matrix metalloproteinase-9 in animal studies. In endometriosis, metformin might modify the stroma–epithelium communication via Wnt2/β-catenin. With its unique therapeutic mechanisms and no serious side effects, metformin seems to be a helpful anti-inflammatory and anti-proliferative agent in the treatment of endometriosis. It could be a missing link for the successful treatment of this chronic disease.
Predicting Glioblastoma Cellular Motility from In Vivo MRI with a Radiomics Based Regression Model
Authors: Mulford Kellen , McMahon Mariah , Gardeck Andrew M. , Hunt Matthew A. , Chen Clark C. , Odde David J. , Wilke Christopher
Published: January 2022

Characterizing the motile properties of glioblastoma tumor cells could provide a useful way to predict the spread of tumors and to tailor the therapeutic approach. Radiomics has emerged as a diagnostic tool in the classification of tumor grade, stage, and prognosis. The purpose of this work is to examine the potential of radiomics to predict the motility of glioblastoma cells. Tissue specimens were obtained from 31 patients undergoing surgical resection of glioblastoma. Mean tumor cell motility was calculated from time-lapse videos of specimen cells. Manual segmentation was used to define the border of the enhancing tumor T1-weighted MR images, and 107 radiomics features were extracted from the normalized image volumes. Model parameter coefficients were estimated using the adaptive lasso technique validated with leave-one-out cross validation (LOOCV) and permutation tests. The R-squared value for the predictive model was 0.60 with p-values for each individual parameter estimate less than 0.0001. Permutation test models trained with scrambled motility failed to produce a model that out-performed the model trained on the true data. The results of this work suggest that it is possible for a quantitative MRI feature-based regression model to non-invasively predict the cellular motility of glioblastomas.
Peptide Receptor Radionuclide Therapy with [177Lu]Lu-DOTA-TATE in Patients with Advanced GEP NENS: Present and Future Directions
Authors: del Olmo-García Maria I. , Prado-Wohlwend Stefan , Bello Pilar , Segura Angel , Merino-Torres Juan F.
Published: January 2022

This review article summarizes findings published in the last years on peptide receptor radionuclide therapy in GEP NENs, as well as potential future developments and directions. Unanswered questions remain, such as the following: Which is the correct dose and individual dosimetry? Which is the place for salvage PRRT-Lu? Whicht is the role of PRRT-Lu in the pediatric population? Which is the optimal sequencing of PRRT-Lu in advanced GEP NETs? Which is the place of PRRT-Lu in G3 NENs? These, and future developments such as inclusion new radiopharmaceuticals and combination therapy with different agents, such as radiosensitizers, will be discussed.
Expression of 3-Methylcrotonyl-CoA Carboxylase in Brain Tumors and Capability to Catabolize Leucine by Human Neural Cancer Cells
Authors: Gondáš Eduard , Kráľová Trančíková Alžbeta , Baranovičová Eva , Šofranko Jakub , Hatok Jozef , Kowtharapu Bhavani S. , Galanda Tomáš , Dobrota Dušan , Kubatka Peter , Busselberg Dietrich , Murín Radovan
Published: January 2022

Leucine is an essential, ketogenic amino acid with proteinogenic, metabolic, and signaling roles. It is readily imported from the bloodstream into the brain parenchyma. Therefore, it could serve as a putative substrate that is complementing glucose for sustaining the metabolic needs of brain tumor cells. Here, we investigated the ability of cultured human cancer cells to metabolize leucine. Indeed, cancer cells dispose of leucine from their environment and enrich their media with the metabolite 2-oxoisocaproate. The enrichment of the culture media with a high level of leucine stimulated the production of 3-hydroxybutyrate. When 13C6-leucine was offered, it led to an increased appearance of the heavier citrate isotope with a molar mass greater by two units in the culture media. The expression of 3-methylcrotonyl-CoA carboxylase (MCC), an enzyme characteristic for the irreversible part of the leucine catabolic pathway, was detected in cultured cancer cells and human tumor samples by immunoprobing methods. Our results demonstrate that these cancer cells can catabolize leucine and furnish its carbon atoms into the tricarboxylic acid (TCA) cycle. Furthermore, the release of 3-hydroxybutyrate and citrate by cancer cells suggests their capability to exchange these metabolites with their milieu and the capability to participate in their metabolism. This indicates that leucine could be an additional substrate for cancer cell metabolism in the brain parenchyma. In this way, leucine could potentially contribute to the synthesis of metabolites such as lipids, which require the withdrawal of citrate from the TCA cycle.
Optimising Multimodality Treatment of Resectable Oesophago-Gastric Adenocarcinoma
Authors: Suwaidan Ali , Gordon Anderley , Cartwright Elizabeth , Cunningham David
Published: January 2022

Oesophago–gastric adenocarcinoma remains a leading cause of cancer-related morbidity and mortality worldwide. Although there has been an enormous progress in the multimodality management of resectable oesophago–gastric adenocarcinoma, most patients still develop a recurrent disease that eventually becomes resistant to systemic therapy. Currently, there is no global consensus on the optimal multimodality approach and there are variations in accepted standards of care, ranging from preoperative chemoradiation to perioperative chemotherapy and, more recently, adjuvant immune checkpoint inhibitors. Ongoing clinical trials are aimed to directly compare multimodal treatment options as well as the additional benefit of targeted therapies and immunotherapies. Furthermore, our understanding of the molecular and genetic features of oesophago–gastric cancer has improved significantly over the last decade and these data may help inform the best approach for the individual patient, utilising biomarker selection and precision medicine.
IGF-I and Hyaluronic Acid Mitigate the Negative Effect of Irradiation on Human Skin Keratinocytes
Authors: Sörgel Celena A. , Schmid Rafael , Stadelmann Nina , Weisbach Volker , Distel Luitpold , Horch Raymund E. , Kengelbach-Weigand Annika
Published: January 2022

Ionizing radiation has become an integral part of modern cancer therapy regimens. Various side effects, such as radiation dermatitis, affect patients in acute and chronic forms and decrease therapy compliance significantly. In this study, primary keratinocytes were irradiated in a 2-dimensional (2D) culture as well as on a 3-dimensional (3D) collagen-elastin matrix with doses of 2 and 5 Gy. The effect of different concentrations of IGF-I, KGF, platelet lysate (PL), high and low molecular weight hyaluronic acid (H-HA, L-HA), and adipose-derived stem cell (ADSC) conditioned medium was analyzed in respect to cell viability (WST-8), wound closure (migration), and the gene expression (quantitative real-time PCR) of 2D cultures. The 3D culture was evaluated by WST-8. A mixture of H-HA and L-HA, as well as IGF-I, could significantly stimulate the keratinocyte viability and migration which were severely reduced by irradiation. The MKI67and IL6 gene expression of irradiated keratinocytes was significantly higher after H-HA/L-HA treatment. The stimulating effects of H-HA/L-HA and IGF-I were able to be confirmed in 3D culture. A positive influence on cell viability, migration, and gene expression was achieved after the treatment with H-L-HA and IGF-I. These results open the possibility of a novel therapeutic method for both the prevention and the treatment of radiation dermatitis.
Ex Vivo Fluorescence Confocal Microscopy in Specimens of the Liver: A Proof-of-Concept Study
Authors: Titze Ulf , Sievert Karl-Dietrich , Titze Barbara , Schulz Birte , Schlieker Heiko , Madarasz Zsolt , Weise Christian , Hansen Torsten
Published: January 2022

Ex vivo Fluorescence Confocal Microscopy (FCM) is a technique providing high-resolution images of native tissues. The method is increasingly used in surgical settings in areas of dermatology and urology. Only a few publications exist about examinations of tumors and non-neoplastic lesions of the liver. We report on the application of FCM in biopsies, surgical specimens and autopsy material (33 patients, 39 specimens) of the liver and compare the results to conventional histology. Our preliminary examinations indicated a perfect suitability for tumor diagnosis (ĸ = 1.00) and moderate/good suitability for the assessment of inflammation (ĸ = 0.4–0.6) with regard to their severity and localization. Macro-vesicular steatosis was reliably detected, micro-vesicular steatosis tended to be underestimated. Cholestasis and eosinophilic granules in granulocytes were not represented in the scans. The tissue was preserved as native material and maintained its quality for downstream histological, immunohistological and molecular examinations. In summary, FCM is a material sparing method that provides rapid feedback to the clinician about the presence of tumor, the degree of inflammation and structural changes. This can lead to faster therapeutic decisions in the management of liver tumors, treatment of hepatitis or in liver transplant medicine.
Predictive and Prognostic Role of Pre-Therapy and Interim 68Ga-DOTATOC PET/CT Parameters in Metastatic Advanced Neuroendocrine Tumor Patients Treated with PRRT
Authors: Durmo Rexhep , Filice Angelina , Fioroni Federica , Cervati Veronica , Finocchiaro Domenico , Coruzzi Chiara , Besutti Giulia , Fanello Silvia , Frasoldati Andrea , Versari Annibale
Published: January 2022

Peptide receptor radionuclide therapy (PRRT) is an effective therapeutic option in patients with metastatic neuroendocrine tumor (NET). However, PRRT fails in about 15–30% of cases. Identification of biomarkers predicting the response to PRRT is essential for treatment tailoring. We aimed to evaluate the predictive and prognostic role of semiquantitative and volumetric parameters obtained from the 68Ga-DOTATOC PET/CT before therapy (bPET) and after two cycles of PRRT (iPET). A total of 46 patients were included in this retrospective analysis. The primary tumor was 78% gastroenteropancreatic (GEP), 13% broncho-pulmonary and 9% of unknown origin. 35 patients (76.1%) with stable disease or partial response after PRRT were classified as responders and 11 (23.9%) as non-responders. Logistic regression analysis identified that baseline total volume (bTV) was associated with therapy outcome (OR 1.17; 95%CI 1.02–1.32; p = 0.02). No significant association with PRRT response was observed for other variables. High bTV was confirmed as the only variable independently associated with OS (HR 12.76, 95%CI 1.53–107, p = 0.01). In conclusion, high bTV is a negative predictor for PRRT response and is associated with worse OS rates. Early iPET during PRRT apparently does not provide information useful to change the management of NET patients.
Endocrine Toxicities of Antineoplastic Therapy: The Adrenal Topic
Authors: Barnabei Agnese , Senes Paola , Scoppola Alessandro , Chiefari Alfonsina , Iannantuono Giovanni Maria , Appetecchia Marialuisa , Torino Francesco
Published: January 2022

Immune checkpoint inhibitors (ICIs) have improved survival in patients affected by several solid tumours at the cost of new autoimmune adverse events. Endocrine toxicity is frequently reported in patients treated with these agents, mainly as thyroid dysfunction and hypophysitis. Primary adrenal insufficiency is reported in 1–2% of patients receiving a single ICI, but its rate is approximately 5% in patients treated with a combination of two ICIs. The clinical presentation of adrenal insufficiency may be insidious due to symptoms that are not specific. The same symptoms in cancer patients are frequently multifactorial, rendering the early diagnosis of adrenal insufficiency challenging in this group of patients. As adrenal insufficiency can be fatal if not rapidly diagnosed and treated, oncologists should be aware of its clinical presentations to timely involve endocrinologists to offer patients the appropriate management. In parallel, it is essential to educate patients, their caregivers, and relatives, providing them with detailed information about the risk of adrenal insufficiency and how to manage alarming symptoms at their onset. Finally, large collaborative trials are needed to develop appropriate tests to assess better the personal risk of drug-induced adrenal insufficiency and its early diagnosis and treatment, not only in cancer patients.
New Insights on the Genetics of Pheochromocytoma and Paraganglioma and Its Clinical Implications
Authors: Jhawar Sakshi , Arakawa Yasuhiro , Kumar Suresh , Varghese Diana , Kim Yoo Sun , Roper Nitin , Elloumi Fathi , Pommier Yves , Pacak Karel , Del Rivero Jaydira
Published: January 2022

Pheochromocytomas (PHEOs) and paragangliomas (PGLs) are rare neuroendocrine tumors that arise from chromaffin cells. PHEOs arise from the adrenal medulla, whereas PGLs arise from the neural crest localized outside the adrenal gland. Approximately 40% of all cases of PPGLs (pheochromocytomas/paragangliomas) are associated with germline mutations and 30–40% display somatic driver mutations. The mutations associated with PPGLs can be classified into three groups. The pseudohypoxic group or cluster I includes the following genes: SDHA, SDHB, SDHC, SDHD, SDHAF2, FH, VHL, IDH1/2, MHD2, EGLN1/2 and HIF2/EPAS; the kinase group or cluster II includes RET, NF1, TMEM127, MAX and HRAS; and the Wnt signaling group or cluster III includes CSDE1 and MAML3. Underlying mutations can help understand the clinical presentation, overall prognosis and surveillance follow-up. Here we are discussing the new genetic insights of PPGLs.
Recent Advances in the Diagnosis and Treatment of Natural Killer Cell Malignancies
Authors: Tse Eric , Kwong Yok-Lam
Published: January 2022

Natural killer (NK)/T-cell lymphomas are aggressive malignancies. Epstein–Barr virus (EBV) infection in lymphoma cells is invariable. NK/T-cell lymphomas are divided into nasal, non-nasal, and disseminated subtypes. Nasal NK/T-cell lymphomas involve the nasal cavity and the upper aerodigestive tract. Non-nasal NK/T-cell lymphomas involve the skin, gastrointestinal tract, testis and other extranodal sites. Disseminated NK/T-cell lymphoma involves multiple organs, rarely presenting with a leukaemic phase. Lymphoma cells are positive for CD3ε (not surface CD3), CD56, cytotoxic molecules and EBV-encoded small RNA. There is a predilection for Asian and Central/South American populations. Genome-wide association studies have identified lymphoma susceptibility loci in Asian patients. Positron emission tomography computed tomography and plasma EBV DNA quantification are crucial evaluations at diagnosis and follow-up. Stage I/II patients typically receive non-athracycline regimens containing asparaginse, together with sequential/concurrent radiotherapy. Anthracycline-containing regimens are ineffective. Stage III/IV patients are treated with asparaginase-containing regimens, followed by allogeneic haematopoietic stem cell transplantation (HSCT) in suitable cases. Autologous HSCT does not improve outcome. In relapsed/refractory patients, novel approaches are needed, involving PD1/PD-L1 targeting, EBV-specific cytotoxic T-cells, and monoclonal antibodies. Small molecules including histone deacetylase inhibitors may be beneficial in selected patients. Future strategies may include targeting of signalling pathways and driver mutations.
Diagnosing Vitreoretinal Lymphomas—An Analysis of the Sensitivity of Existing Tools
Authors: Sehgal Anahita , Pulido Jose S. , Mashayekhi Arman , Milman Tatyana , Deák Gabor Gy
Published: January 2022

Vitreoretinal lymphoma (VRL) is a rare ocular pathology that is notorious for mimicking chronic uveitis, which is a seemingly benign condition in comparison. The most common form of VRL is the diffuse large B-cell type, and there has been a high mortality rate. This dismal prognosis can be improved significantly if the disease is diagnosed early, but until now there is no consensus on an appropriate diagnostic algorithm. We conducted a retrospective search of PubMed Central® and analyzed results from thirty-three studies that were published between 2011–2021. The chosen studies incorporated some popular testing tools for VRL, and our analyses focused on comparing the average sensitivity of five diagnostic methods. The methods included cytology including ancillary immunohistochemistry, Myeloid Differentiation Factor 88 (MyD88) mutation analysis, polymerase chain reaction (PCR) for monoclonal rearrangements of immunoglobulin heavy chain (IgH) and T-cell Receptor (TCR) genes, flow cytometry, and IL10 and IL6 analysis. Across the varied diagnostic methods employed in thirty-three studies explored in this analysis, MyD88 mutation assay emerged as a strong contender given its sensitivity and low coefficient of variation. There is an imminent need for the introduction of newer assays that can further improve the sensitivity of identifying MyD88 mutation in cancer cells seen in the vitreous.
PARP Inhibitors: A Major Therapeutic Option in Endocrine-Receptor Positive Breast Cancers
Authors: Collet Laetitia , Péron Julien , Penault-Llorca Frédérique , Pujol Pascal , Lopez Jonathan , Freyer Gilles , You Benoît
Published: January 2022

Recently, OlympiAD and EMBRACA trials demonstrated the favorable efficacy/toxicity ratio of PARPi, compared to chemotherapy, in patients with HER2-negative metastatic breast cancers (mBC) carrying a germline BRCA mutation. PARPi have been largely adopted in triple-negative metastatic breast cancer, but their place has been less clearly defined in endocrine-receptor positive, HER2 negative (ER+/ HER2-) mBC. The present narrative review aims at addressing this question by identifying the patients that are more likely benefit from PARPi. Frequencies of BRCA pathogenic variant (PV) carriers among ER+/HER2- breast cancer patients have been underestimated, and many experts assume than 50% of all BRCA1/2 mutated breast cancers are of ER+/HER2- subtype. Patients with ER+/HER2- BRCA-mutated mBC seemed to have a higher risk of early disease progression while on CDK4/6 inhibitors and PARPi are effective especially when prescribed before exposure to chemotherapy. The OLYMPIA trial also highlighted the utility of PARPi in patients with early breast cancers at high risk of relapse and carrying PV of BRCA. PARPi might also be effective in patients with HRD diseases, representing up to 20% of ER+/HER2- breast cancers. Consequently, the future implementation of early genotyping strategies for identifying the patients with high-risk ER+/HER2- HRD breast cancers likely to benefit from PARPi is of high importance.
Senolysis-Based Elimination of Chemotherapy-Induced Senescent Breast Cancer Cells by Quercetin Derivative with Blocked Hydroxy Groups
Authors: Lewińska Anna , Przybylski Paweł , Adamczyk-Grochala Jagoda , Błoniarz Dominika , Litwinienko Grzegorz , Wnuk Maciej
Published: January 2022

Drug-induced senescence program may be activated both in normal and cancer cells as a consequence of chemotherapeutic treatment, leading to some adverse side effects such as senescence-associated secretory phenotype (SASP), secondary senescence, and cancer promotion. Targeted elimination of senescent cells can be achieved by drugs with senolytic activity (senolytics), for example, the plant-derived natural compound quercetin, especially when co-treated with kinase inhibitor dasatinib. In the present study, three quercetin derivatives were synthesized and tested for improved senolytic action against etoposide-induced senescent human normal mammary epithelial cells and triple-negative breast cancer cells in vitro. Transformation of catechol moiety into diphenylmethylene ketal and addition of three acetyl groups to the quercetin molecule (QD3 derivative) promoted the clearance of senescent cancer cells as judged by increased apoptosis compared to etoposide-treated cells. A QD3-mediated senolytic effect was accompanied by decreased SA-beta galactosidase activity and the levels of p27, IL-1β, IL-8, and HSP70 in cancer cells. Similar effects were not observed in senescent normal cells. In conclusion, a novel senolytic agent QD3 was described as acting against etoposide-induced senescent breast cancer cells in vitro. Thus, a new one-two punch anti-cancer strategy based on combined action of a pro-senescence anti-cancer drug and a senolytic agent is proposed.
Machine Learning and Deep Learning Applications in Multiple Myeloma Diagnosis, Prognosis, and Treatment Selection
Authors: Allegra Alessandro , Tonacci Alessandro , Sciaccotta Raffaele , Genovese Sara , Musolino Caterina , Pioggia Giovanni , Gangemi Sebastiano
Published: January 2022

Artificial intelligence has recently modified the panorama of oncology investigation thanks to the use of machine learning algorithms and deep learning strategies. Machine learning is a branch of artificial intelligence that involves algorithms that analyse information, learn from that information, and then employ their discoveries to make abreast choice, while deep learning is a field of machine learning basically represented by algorithms inspired by the organization and function of the brain, named artificial neural networks. In this review, we examine the possibility of the artificial intelligence applications in multiple myeloma evaluation, and we report the most significant experimentations with respect to the machine and deep learning procedures in the relevant field. Multiple myeloma is one of the most common haematological malignancies in the world, and among them, it is one of the most difficult ones to cure due to the high occurrence of relapse and chemoresistance. Machine learning- and deep learning-based studies are expected to be among the future strategies to challenge this negative-prognosis tumour via the detection of new markers for their prompt discovery and therapy selection and by a better evaluation of its relapse and survival.
Patient–Proxy Agreement Regarding Health-Related Quality of Life in Survivors with Lymphoma: A Propensity-Score Matching Analysis
Authors: Xu Richard Huan , Dong Dong
Published: January 2022

Objective: To assess the difference between lymphoma survivors’ self- and proxy-reported health-related quality of life (HRQoL) and its association with socioeconomic and health statuses. Methods: The data used in this study were obtained from a nationwide cross-sectional online survey in 2019. Information about participants’ demographics, health status and HRQoL were collected. The propensity-score matching (PSM) method was used to control the effect of potential confounders on selection bias. A chi-squared test, one-way analysis of variance, and multiple linear regression models were used to assess the relationship between HRQoL and response type adjusted to respondents’ background characteristics. Results: Out of the total 4400 participants, data of 2350 ones were elicited for analysis after PSM process. Patients’ self-reported outcomes indicated a slightly better physical, role and emotional functioning than proxy-reported outcomes. Regression analysis showed that patients, who were older, unemployed, and who received surgery, were more likely to report a lower HRQoL. Further analysis demonstrated that proxy-reported patients who had completed treatment were more likely to report a higher HRQoL than those who were being treated. Conclusions: Our study demonstrates that the agreement between self- and proxy-reported HRQoL is low in patients with lymphoma and the heterogeneities of HRQoL among patients with different types of aggressive NHL (Non-Hodgkin’s lymphoma) is large. Differences in self- and proxy-reported HRQoL should be considered by oncologists when selecting and deciding the optimal care plan for lymphoma survivors.
High Output Heart Failure in Multiple Myeloma: Pathogenetic Considerations
Authors: Carlisi Melania , Mancuso Salvatrice , Lo Presti Rosalia , Siragusa Sergio , Caimi Gregorio
Published: January 2022

The high output heart failure is a clinical condition in which the systemic congestion is associated to a high output state, and it can be observed in a non-negligible percentage of hematological diseases, particularly in multiple myeloma, a condition in which the risk of adverse cardiovascular events may increase, with a worse prognosis for patients. For this reason, though an accurate literature search, we provided in this review a complete overview of different pathogenetic mechanisms responsible for high output heart failure in multiple myeloma. Indeed, this clinical finding is present in the 8% of multiple myeloma patients, and it may be caused by artero-venous shunts, enhanced angiogenesis, glutamminolysis, hyperammonemia and hemorheological alterations with increase in plasma viscosity. The high output heart failure in multiple myeloma is associated with significant morbidity and mortality, emphasizing the need for a multidisciplinary approach.
Effect of 5-Aminolevulinic Acid and Sodium Fluorescein on the Extent of Resection in High-Grade Gliomas and Brain Metastasis
Authors: Ahrens Lasse Cramer , Krabbenhøft Mathias Green , Hansen Rasmus Würgler , Mikic Nikola , Pedersen Christian Bonde , Poulsen Frantz Rom , Korshoej Anders Rosendal
Published: January 2022

Surgery is essential in the treatment of high-grade gliomas (HGG) and gross total resection (GTR) is known to increase the overall survival and progression-free survival. Several studies have shown that fluorescence-guided surgery with 5-aminolevulinic acid (5-ALA) increases GTR considerably compared to white light surgery (65% vs. 36%). In recent years, sodium fluorescein (SF) has become an increasingly popular agent for fluorescence-guided surgery due to numerous utility benefits compared to 5-ALA, including lower cost, non-toxicity, easy administration during surgery and a wide indication range covering all contrast-enhancing lesions with disruption of the blood–brain barrier in the CNS. However, currently, SF is an off-label agent and the level of evidence for use in HGG surgery is inferior compared to 5-ALA. Here, we give an update and review the latest literature on fluorescence-guided surgery with 5-ALA and SF for brain tumors with emphasis on fluorescence-guided surgery in HGG and brain metastases. Further, we assess the advantages and disadvantages of both fluorophores and discuss their future perspectives.
The Role of New Technologies in the Diagnosis and Surveillance of Non-Muscle Invasive Bladder Carcinoma: A Prospective, Double-Blinded, Monocentric Study of the XPERT© Bladder Cancer Monitor and Narrow Band Imaging© Cystoscopy
Authors: Singer Gad , Ramakrishnan Venkat M. , Rogel Uwe , Schötzau Andreas , Disteldorf Daniel , Maletzki Philipp , Adank Jean-Pascal , Hofmann Marc , Niemann Tilo , Stadlmann Sylvia , Nocito Antonio , Lehmann Kurt , Hefermehl Lukas J.
Published: January 2022

Follow-up is essential for the early detection of recurrent non-muscle invasive bladder cancers (NMIBC). This study investigates the clinical relevance of new diagnostic tools such as an mRNA-based urine test (XPERT© Bladder Cancer Monitor, XBCM) and Narrow Band Imaging© (NBI) and compares them with the established follow-up diagnostics (white-light cystoscopy (WLC) and urine cytology). This was a prospective, double-blind, single-center study that involved patients undergoing NMIBC screening at a tertiary care center. Enrollment occurred between January 2018 and March 2020. In addition to standard care (WLC, cytology, and ultrasound), patients underwent XBCM urine testing and NBI cystoscopy. In total, 301 WLCs were performed; through this, 49 patients demonstrated NMIBC recurrence. NBI cystoscopy was congruent with WLC in all patients. Cytology showed a sensitivity (SE) and specificity (SP) of 27% and 97% (PPV: 65%; NPV 87%), respectively, whereas XBCM showed SE and SP of 58% and 89%, respectively (PPV: 51%; NPV: 92%; AUC: 0.79 (0.716–0.871)). Subgroup analysis showed improved SE and similar SP (PPV, NPV) for high grade (HG) recurrence, with a SE of 74% and SP of 89% (39%, 97%). NBI cystoscopy does not necessarily provide additional benefit over standard WLC. However, the XBCM may provide better SE and a diagnostic advantage in instances of HG disease recurrence.
Hepatocellular Carcinoma: Molecular Pathogenesis and Therapeutic Advances
Authors: Cucarull Blanca , Tutusaus Anna , Rider Patricia , Hernáez-Alsina Tania , Cuño Carlos , García de Frutos Pablo , Colell Anna , Marí Montserrat , Morales Albert
Published: January 2022

Hepatocellular carcinoma (HCC), the most common form of liver cancer, continues to be a serious medical problem with poor prognosis, without major therapeutic improvement for years and increasing incidence. Fortunately, advances in systemic treatment options are finally arriving for HCC patients. After a decade of sorafenib as a standard therapy for advanced HCC, several tyrosine kinase inhibitors (TKIs), antiangiogenic antibodies, and immune checkpoint inhibitors have reached the clinic. Although infections by hepatitis B virus and hepatitis C virus remain principal factors for HCC development, the rise of non- alcoholic steatohepatitis from diabetes mellitus or metabolic syndrome is impeding HCC decline. Knowledge of specific molecular mechanisms, based on the etiology and the HCC microenvironment that influence tumor growth and immune control, will be crucial for physician decision-making among a variety of drugs to prescribe. In addition, markers of treatment efficacy are needed to speed the movement of patients towards other potentially effective treatments. Consequently, research to provide scientific data for the evidence-based management of liver cancer is guaranteed in the coming years and discussed here.
Clinical Evidence for Thermometric Parameters to Guide Hyperthermia Treatment
Authors: Ademaj Adela , Veltsista Danai P. , Ghadjar Pirus , Marder Dietmar , Oberacker Eva , Ott Oliver J. , Wust Peter , Puric Emsad , Hälg Roger A. , Rogers Susanne , Bodis Stephan , Fietkau Rainer , Crezee Hans , Riesterer Oliver
Published: January 2022

Hyperthermia (HT) is a cancer treatment modality which targets malignant tissues by heating to 40–43 °C. In addition to its direct antitumor effects, HT potently sensitizes the tumor to radiotherapy (RT) and chemotherapy (CT), thereby enabling complete eradication of some tumor entities as shown in randomized clinical trials. Despite the proven efficacy of HT in combination with classic cancer treatments, there are limited international standards for the delivery of HT in the clinical setting. Consequently, there is a large variability in reported data on thermometric parameters, including the temperature obtained from multiple reference points, heating duration, thermal dose, time interval, and sequence between HT and other treatment modalities. Evidence from some clinical trials indicates that thermal dose, which correlates with heating time and temperature achieved, could be used as a predictive marker for treatment efficacy in future studies. Similarly, other thermometric parameters when chosen optimally are associated with increased antitumor efficacy. This review summarizes the existing clinical evidence for the prognostic and predictive role of the most important thermometric parameters to guide the combined treatment of RT and CT with HT. In conclusion, we call for the standardization of thermometric parameters and stress the importance for their validation in future prospective clinical studies.
Effects of Ammonia Solution and Pyrolysis Gas on NOx Emission from a 75 t/h Pulverized Coal Boiler
Authors: Wu Xiaojiang , Guo Xinwei , Li Zixiang , Zhang Zhongxiao , Bai Hao , Fan Junjie , Zhu Zhixiang
Published: January 2022

To explore methods of reducing NOx emission from pulverized coal boilers, the effects of injecting ammonia solution and pyrolysis gas into the furnace on NOx emission were experimentally investigated on a 75 t/h pulverized coal boiler. Results show that the deep air staging with 30% separated over fire air (SOFA) creates a high temperature and strong reducing atmosphere in the reducing zone, providing the prerequisites for NOx reduction by ammonia solution and pyrolysis gas. Compared with deep air staging itself, NOx emission can be reduced by 16.7% when ammonia solution is injected from the reducing zone with a normalized stoichiometric ratio of 2.0. However, NOx reduction efficiency is largely affected by its injection position. Similarly, NOx emission is decreased by 28.2% through injecting pyrolysis gas with its calorific value of 10% into the furnace, while a further increase of pyrolysis gas input will not increase NOx reduction efficiency. When ammonia solution and pyrolysis gas are simultaneously injected into the furnace under deep air staging conditions, the overall NOx reduction efficiency reaches 92.0% and NOx emission is decreased to 39.1 mg/m3. Considering the increasingly strict NOx emission standard, these findings can provide theoretical and practical guides to the future NOx reduction in pulverized coal boilers.