bluuebunny/crossref_metadata_2025 huggingface dataset:
A Soft Label Deep Learning to Assist Breast Cancer Target Therapy and Thyroid Cancer Diagnosis
Authors: Wang Ching-Wei , Lin Kuan-Yu , Lin Yi-Jia , Khalil Muhammad-Adil , Chu Kai-Lin , Chao Tai-Kuang
Published: October 2022

According to the World Health Organization Report 2022, cancer is the most common cause of death contributing to nearly one out of six deaths worldwide. Early cancer diagnosis and prognosis have become essential in reducing the mortality rate. On the other hand, cancer detection is a challenging task in cancer pathology. Trained pathologists can detect cancer, but their decisions are subjective to high intra- and inter-observer variability, which can lead to poor patient care owing to false-positive and false-negative results. In this study, we present a soft label fully convolutional network (SL-FCN) to assist in breast cancer target therapy and thyroid cancer diagnosis, using four datasets. To aid in breast cancer target therapy, the proposed method automatically segments human epidermal growth factor receptor 2 (HER2) amplification in fluorescence in situ hybridization (FISH) and dual in situ hybridization (DISH) images. To help in thyroid cancer diagnosis, the proposed method automatically segments papillary thyroid carcinoma (PTC) on Papanicolaou-stained fine needle aspiration and thin prep whole slide images (WSIs). In the evaluation of segmentation of HER2 amplification in FISH and DISH images, we compare the proposed method with thirteen deep learning approaches, including U-Net, U-Net with InceptionV5, Ensemble of U-Net with Inception-v4, Inception-Resnet-v2 encoder, and ResNet-34 encoder, SegNet, FCN, modified FCN, YOLOv5, CPN, SOLOv2, BCNet, and DeepLabv3+ with three different backbones, including MobileNet, ResNet, and Xception, on three clinical datasets, including two DISH datasets on two different magnification levels and a FISH dataset. The result on DISH breast dataset 1 shows that the proposed method achieves high accuracy of 87.77 ± 14.97%, recall of 91.20 ± 7.72%, and F1-score of 81.67 ± 17.76%, while, on DISH breast dataset 2, the proposed method achieves high accuracy of 94.64 ± 2.23%, recall of 83.78 ± 6.42%, and F1-score of 85.14 ± 6.61% and, on the FISH breast dataset, the proposed method achieves high accuracy of 93.54 ± 5.24%, recall of 83.52 ± 13.15%, and F1-score of 86.98 ± 9.85%, respectively. Furthermore, the proposed method outperforms most of the benchmark approaches by a significant margin (p <0.001). In evaluation of segmentation of PTC on Papanicolaou-stained WSIs, the proposed method is compared with three deep learning methods, including Modified FCN, U-Net, and SegNet. The experimental result demonstrates that the proposed method achieves high accuracy of 99.99 ± 0.01%, precision of 92.02 ± 16.6%, recall of 90.90 ± 14.25%, and F1-score of 89.82 ± 14.92% and significantly outperforms the baseline methods, including U-Net and FCN (p <0.001). With the high degree of accuracy, precision, and recall, the results show that the proposed method could be used in assisting breast cancer target therapy and thyroid cancer diagnosis with faster evaluation and minimizing human judgment errors.
Systemic Therapy Development in Von Hippel–Lindau Disease: An Outsized Contribution from an Orphan Disease
Authors: Narayan Vivek , Jonasch Eric
Published: October 2022

Over the last several decades, an improved understanding of von Hippel–Lindau disease and its underlying biology has informed the successful development of numerous anti-cancer agents, particularly for the treatment of advanced renal cell carcinoma. Most recently, this has culminated in the first regulatory approval for a systemic therapy for VHL disease-associated neoplasms. This review will trace the clinical development of systemic therapies for VHL disease and additionally highlight anticipated challenges and opportunities for future VHL systemic therapy.
Prognostic Value of [18F]-FDG PET/CT Radiomics Combined with Sarcopenia Status among Patients with Advanced Gastroesophageal Cancer
Authors: Hinzpeter Ricarda , Mirshahvalad Seyed Ali , Kulanthaivelu Roshini , Ortega Claudia , Metser Ur , Liu Zhihui A. , Elimova Elena , Wong Rebecca K. S. , Yeung Jonathan , Jang Raymond Woo-Jun , Veit-Haibach Patrick
Published: October 2022

We investigated, whether 18[18F]-FDG PET/CT-derived radiomics combined with sarcopenia measurements improves survival prognostication among patients with advanced, metastatic gastroesophageal cancer. In our study, 128 consecutive patients with advanced, metastatic esophageal and gastroesophageal cancer (n = 128; 26 females; 102 males; mean age 63.5 ± 11.7 years; age range: 29–91 years) undergoing 18[18F]-FDG PET/CT for staging between November 2008 and December 2019 were included. Segmentation of the primary tumor and radiomics analysis derived from PET and CT images was performed semi-automatically with a commonly used open-source software platform (LIFEX, Version 6.30, lifexsoft.org). Patients’ nutritional status was determined by measuring the skeletal muscle index (SMI) at the level of L3 on the CT component. Univariable and multivariable analyses were performed to establish a survival prediction model including radiomics, clinical data, and SMI score. Univariable Cox proportional hazards model revealed ECOG (<0.001) and bone metastasis (p = 0.028) to be significant clinical parameters for overall survival (OS) and progression free survival (PFS). Age (p = 0.017) was an additional prognostic factor for OS. Multivariable analysis showed improved prognostication for overall and progression free survival when adding sarcopenic status, PET and CT radiomics to the model with clinical parameters only. PET and CT radiomics derived from hybrid 18[18F]-FDG PET/CT combined with sarcopenia measurements and clinical parameters may improve survival prediction among patients with advanced, metastatic gastroesophageal cancer.
Artificial Intelligence Predicted Overall Survival and Classified Mature B-Cell Neoplasms Based on Immuno-Oncology and Immune Checkpoint Panels
Authors: Carreras Joaquim , Roncador Giovanna , Hamoudi Rifat
Published: October 2022

Artificial intelligence (AI) can identify actionable oncology biomarkers. This research integrates our previous analyses of non-Hodgkin lymphoma. We used gene expression and immunohistochemical data, focusing on the immune checkpoint, and added a new analysis of macrophages, including 3D rendering. The AI comprised machine learning (C5, Bayesian network, C&R, CHAID, discriminant analysis, KNN, logistic regression, LSVM, Quest, random forest, random trees, SVM, tree-AS, and XGBoost linear and tree) and artificial neural networks (multilayer perceptron and radial basis function). The series included chronic lymphocytic leukemia, mantle cell lymphoma, follicular lymphoma, Burkitt, diffuse large B-cell lymphoma, marginal zone lymphoma, and multiple myeloma, as well as acute myeloid leukemia and pan-cancer series. AI classified lymphoma subtypes and predicted overall survival accurately. Oncogenes and tumor suppressor genes were highlighted (MYC, BCL2, and TP53), along with immune microenvironment markers of tumor-associated macrophages (M2-like TAMs), T-cells and regulatory T lymphocytes (Tregs) (CD68, CD163, MARCO, CSF1R, CSF1, PD-L1/CD274, SIRPA, CD85A/LILRB3, CD47, IL10, TNFRSF14/HVEM, TNFAIP8, IKAROS, STAT3, NFKB, MAPK, PD-1/PDCD1, BTLA, and FOXP3), apoptosis (BCL2, CASP3, CASP8, PARP, and pathway-related MDM2, E2F1, CDK6, MYB, and LMO2), and metabolism (ENO3, GGA3). In conclusion, AI with immuno-oncology markers is a powerful predictive tool. Additionally, a review of recent literature was made.
In Vivo Models for Prostate Cancer Research
Authors: Adamiecki Robert , Hryniewicz-Jankowska Anita , Ortiz Maria A. , Li Xiang , Porter-Hansen Baylee A. , Nsouli Imad , Bratslavsky Gennady , Kotula Leszek
Published: October 2022

In 2022, prostate cancer (PCa) is estimated to be the most commonly diagnosed cancer in men in the United States—almost 270,000 American men are estimated to be diagnosed with PCa in 2022. This review compares and contrasts in vivo models of PCa with regards to the altered genes, signaling pathways, and stages of tumor progression associated with each model. The main type of model included in this review are genetically engineered mouse models, which include conditional and constitutive knockout model. 2D cell lines, 3D organoids and spheroids, xenografts and allografts, and patient derived models are also included. The major applications, advantages and disadvantages, and ease of use and cost are unique to each type of model, but they all make it easier to translate the tumor progression that is seen in the mouse prostate to the human prostate. Although both human and mouse prostates are androgen-dependent, the fact that the native, genetically unaltered prostate in mice cannot give rise to carcinoma is an especially critical component of PCa models. Thanks to the similarities between the mouse and human genome, our knowledge of PCa has been expanded, and will continue to do so, through models of PCa.
K-RAS Associated Gene-Mutation-Based Algorithm for Prediction of Treatment Response of Patients with Subtypes of Breast Cancer and Especially Triple-Negative Cancer
Authors: Johnson Heather , Ali Amjad , Zhang Xuhui , Wang Tianyan , Simoulis Athanasios , Wingren Anette Gjörloff , Persson Jenny L.
Published: October 2022

Purpose: There is an urgent need for developing new biomarker tools to accurately predict treatment response of breast cancer, especially the deadly triple-negative breast cancer. We aimed to develop gene-mutation-based machine learning (ML) algorithms as biomarker classifiers to predict treatment response of first-line chemotherapy with high precision. Methods: Random Forest ML was applied to screen the algorithms of various combinations of gene mutation profiles of primary tumors at diagnosis using a TCGA Cohort (n = 399) with up to 150 months follow-up as a training set and validated in a MSK Cohort (n = 807) with up to 220 months follow-up. Subtypes of breast cancer including triple-negative and luminal A (ER+, PR+ and HER2−) were also assessed. The predictive performance of the candidate algorithms as classifiers was further assessed using logistic regression, Kaplan–Meier progression-free survival (PFS) plot, and univariate/multivariate Cox proportional hazard regression analyses. Results: A novel algorithm termed the 12-Gene Algorithm based on mutation profiles of KRAS, PIK3CA, MAP3K1, MAP2K4, PTEN, TP53, CDH1, GATA3, KMT2C, ARID1A, RunX1, and ESR1, was identified. The performance of this algorithm to distinguish non-progressed (responder) vs. progressed (non-responder) to treatment in the TCGA Cohort as determined using AUC was 0.96 (95% CI 0.94–0.98). It predicted progression-free survival (PFS) with hazard ratio (HR) of 21.6 (95% CI 11.3–41.5) (p < 0.0001) in all patients. The algorithm predicted PFS in the triple-negative subgroup with HR of 19.3 (95% CI 3.7–101.3) (n = 42, p = 0.000). The 12-Gene Algorithm was validated in the MSK Cohort with a similar AUC of 0.97 (95% CI 0.96–0.98) to distinguish responder vs. non-responder patients, and had a HR of 18.6 (95% CI 4.4–79.2) to predict PFS in the triple-negative subgroup (n = 75, p < 0.0001). Conclusions: The novel 12-Gene algorithm based on multitude gene-mutation profiles identified through ML has a potential to predict breast cancer treatment response to therapies, especially in triple-negative subgroups patients, which may assist personalized therapies and reduce mortality.
The Liver Maximum Capacity Test (LiMAx) Is Associated with Short-Term Survival in Patients with Early Stage HCC Undergoing Transarterial Treatment
Authors: Fischer Janett , Wellhöner Stella , Ebel Sebastian , Lincke Thomas , Böhlig Albrecht , Gerhardt Florian , Veelken Rhea , Goessmann Holger , Steinhoff Karen Geva , Denecke Timm , Sabri Osama , Berg Thomas , Bömmel Florian van
Published: October 2022

Transarterial chemoembolization (TACE) and transarterial radioembolization (TARE) are recommended to treat patients with early or intermediate hepatocellular carcinoma (HCC). The liver maximum capacity test (LiMAx) has been supposed to predict the risk of post-interventional liver failure. We investigated the correlation of LiMAx with short-term survival as primary endpoint and the occurrence of adverse events after therapy as secondary endpoint. Our study cohort prospectively included 69 patients receiving TACE (n = 57) or TARE (n = 12). LiMAx test and serological analyses were performed on the day before and 4 weeks after treatment. Hepatic and extrahepatic complications were monitored for 4 weeks. The LiMAx results were not associated with altered liver function and the occurrence of adverse events. The survival rates of patients with BCLC A with LiMAx ≤ 150 μg/kg/h were lower after 30 days (75.0 ± 15.3% vs. 100%, p = 0.011), 90 days (62.5 ± 17.7% vs. 95.8 ± 4.1%, p = 0.011) and 180 days (50.0 ± 17.7% vs. 95.8 ± 4.1%, p = 0.001) compared to those with higher LiMAx levels. The LiMAx test is not suitable to predict liver function abnormalities or the occurrence of complications 4 weeks after therapy but enables the identification of patients with early stage HCC and reduced short-term survival after treatment.
Transarterial Yttrium-90 Radioembolization in Intrahepatic Cholangiocarcinoma Patients: Outcome Assessment Applying a Prognostic Score
Authors: Schatka Imke , Jochens Hans V. , Rogasch Julian M. M. , Walter-Rittel Thula C. , Pelzer Uwe , Benckert Julia , Graef Josefine , Feldhaus Felix W. , Gebauer Bernhard , Amthauer Holger
Published: October 2022

Radioembolization (RE) is a viable therapy option in patients with intrahepatic cholangiocarcinoma (ICC). This study delineates a prognostic score regarding overall survival (OS) after RE using routine pre-therapeutic parameters. A retrospective analysis of 39 patients (median age, 61 [range, 32–82] years; 26 females, 13 males) with ICC and 42 RE procedures was conducted. Cox regression for OS included age, ECOG, hepatic and extrahepatic tumor burden, thrombosis of the portal vein, ascites, laboratory parameters and dose reduction due to hepatopulmonary shunt. Median OS after RE was 8.0 months. Using univariable Cox, ECOG ≥ 1 (hazard ratio [HR], 3.8), AST/ALT quotient (HR, 1.86), high GGT (HR, 1.002), high CA19-9 (HR, 1.00) and dose reduction of 40% (HR, 3.8) predicted shorter OS (each p < 0.05). High albumin predicted longer OS (HR, 0.927; p = 0.045). Multivariable Cox confirmed GGT ≥ 750 [U/L] (HR, 7.84; p < 0.001), ECOG > 1 (HR, 3.76; p = 0.021), albumin ≤ 41.1 [g/L] (HR, 3.02; p = 0.006) as a three-point pre-therapeutic prognostic score. More specifically, median OS decreased from 15.3 months (0 risk factors) to 7.6 months (1 factor) or 1.8 months (≥2 factors; p < 0.001). The proposed score may aid in improved pre-therapeutic patient identification with (un-)favorable OS after RE and facilitate the balance between potential life prolongation and overaggressive patient selection.
Recent Advances in Immunotherapy for Patients with Head and Neck Cutaneous Squamous Cell Carcinoma
Authors: Khorasanchi Adam , Wu Richard , Kendra Kari , Verschraegen Claire
Published: October 2022

Cutaneous squamous cell carcinoma (CSCC) is the second most common non-melanoma skin cancer. A majority of patients present with localized disease, but some can present with locally advanced or metastatic disease. Most of these advanced cases occur in the anatomical head and neck region and are associated with more aggressive disease, necessitating prompt and effective treatment. Prior to the emergence of immunotherapy, systemic treatment options were limited to platinum-based chemotherapy and salvaged with targeted epidermal growth factor therapy. These therapies were associated with poor efficacy and increased toxicity in an often frail, older population. Immunotherapy has dramatically improved outcomes in this patient population due to its favorable side effect profile, durable treatment response, and improved overall outcomes. In this review, an overview of the recent advances of immunotherapy in the management of CSCC in the anatomical head and neck region is provided, with a focus on advanced presentations.
Proteoglycans Determine the Dynamic Landscape of EMT and Cancer Cell Stemness
Authors: Karagiorgou Zoi , Fountas Panagiotis N. , Manou Dimitra , Knutsen Erik , Theocharis Achilleas D.
Published: October 2022

Proteoglycans (PGs) are pivotal components of extracellular matrices, involved in a variety of processes such as migration, invasion, morphogenesis, differentiation, drug resistance, and epithelial-to-mesenchymal transition (EMT). Cellular plasticity is a crucial intermediate phenotypic state acquired by cancer cells, which can modulate EMT and the generation of cancer stem cells (CSCs). PGs affect cell plasticity, stemness, and EMT, altering the cellular shape and functions. PGs control these functions, either by direct activation of signaling cascades, acting as co-receptors, or through regulation of the availability of biological compounds such as growth factors and cytokines. Differential expression of microRNAs is also associated with the expression of PGs and their interplay is implicated in the fine tuning of cancer cell phenotype and potential. This review summarizes the involvement of PGs in the regulation of EMT and stemness of cancer cells and highlights the molecular mechanisms.
Body Mass Index and Overall Survival of Patients with Newly Diagnosed Multiple Myeloma
Authors: Wang Bei , Derman Benjamin A. , Langerman Spencer S. , Johnson Julie , Zhang Wei , Jakubowiak Andrzej , Chiu Brian C.-H.
Published: October 2022

Obesity is associated with survival in several solid tumors and non-Hodgkin lymphoma, but its impact on multiple myeloma (MM) survival is unclear. We examined the associations between body mass index (BMI) at different periods of life up to the time of diagnosis and overall survival (OS) among 563 patients newly diagnosed with MM in 2010–2019. BMI at diagnosis was calculated using measured height and weight from electronic medical records (EMR). BMIs at age 20, maximum during adulthood, and 5 years before diagnosis were calculated using self-reported weights and measured height from EMR. Over a median follow-up of 49.3 months, 191 (33.93%) deaths were identified. We used multivariable Cox proportional-hazards models to examine the associations between BMIs and OS. Height as well as BMI before and at diagnosis was not associated with OS, but there is a U-shape association between weight and OS. Higher BMIs at diagnosis were associated with better OS among females (HR = 0.39 [0.22–0.71]), irrespective of race. In conclusion, our results suggest that BMI at different periods of life up to the time of diagnosis may not be associated with OS in MM, except that a higher BMI at diagnosis was associated with superior OS for females.
Tumor-Infiltrating Lymphocytes (TILs) in Epithelial Ovarian Cancer: Heterogeneity, Prognostic Impact, and Relationship with Immune Checkpoints
Authors: Hudry Delphine , Le Guellec Solenn , Meignan Samuel , Bécourt Stéphanie , Pasquesoone Camille , El Hajj Houssein , Martínez-Gómez Carlos , Leblanc Éric , Narducci Fabrice , Ladoire Sylvain
Published: October 2022

Epithelial ovarian cancers (EOC) are often diagnosed at an advanced stage with carcinomatosis and a poor prognosis. First-line treatment is based on a chemotherapy regimen combining a platinum-based drug and a taxane-based drug along with surgery. More than half of the patients will have concern about a recurrence. To improve the outcomes, new therapeutics are needed, and diverse strategies, such as immunotherapy, are currently being tested in EOC. To better understand the global immune contexture in EOC, several studies have been performed to decipher the landscape of tumor-infiltrating lymphocytes (TILs). CD8+ TILs are usually considered effective antitumor immune effectors that immune checkpoint inhibitors can potentially activate to reject tumor cells. To synthesize the knowledge of TILs in EOC, we conducted a review of studies published in MEDLINE or EMBASE in the last 10 years according to the PRISMA guidelines. The description and role of TILs in EOC prognosis are reviewed from the published data. The links between TILs, DNA repair deficiency, and ICs have been studied. Finally, this review describes the role of TILs in future immunotherapy for EOC.
Human Papillomavirus Oncoproteins Confer Sensitivity to Cisplatin by Interfering with Epidermal Growth Factor Receptor Nuclear Trafficking Related to More Favorable Clinical Survival Outcomes in Non-Small Cell Lung Cancer
Authors: Wang Jinn-Li , Lee Wei-Jiunn , Fang Chia-Lang , Hsu Han-Lin , Chen Bo-Jung , Liu Hsingjin-Eugene
Published: October 2022

High-risk human papillomavirus (HPV) infections and epidermal growth factor receptor (EGFR) expression have been reported to be associated with more favorable survival outcomes in lung adenocarcinoma patients. In this study, we utilized transfected HPV 16E5/16E6/16E7 H292 cells to investigate the mechanism of HPV oncoproteins interfering with EGFR nuclear trafficking related to a better response to cisplatin. Furthermore, we correlated HPV 16E6/18E6 expression and differentially localized EGFR expression with the clinical association and survival impact in lung adenocarcinoma patients. Our results found significantly higher phosphorylated nuclear EGFR expression upon epidermal growth factor stimulus and better responses to cisplatin in transfected HPV 16E5/16E6/16E7 NCI-H292 cells and xenograft animal models. Our data were compatible with clinical results of a high correlation of HPV 16E6/18E6 and EGFR expression in non-small cell lung cancer tissues and the synergistic effects of both with the best survival prognosis in a lung adenocarcinoma cohort, especially in patients with older age, no brain metastasis, smoking history, and wild-type EGFR status. Cumulatively, our study supports HPV 16E5/16E6/16E7 oncoproteins interfering with EGFR nuclear trafficking, resulting in increased sensitivity to cisplatin. HPV 16E6/18E6 and EGFR expression serve as good prognostic factors in lung adenocarcinoma patients.
The Role of Deep Learning in Advancing Breast Cancer Detection Using Different Imaging Modalities: A Systematic Review
Authors: Madani Mohammad , Behzadi Mohammad Mahdi , Nabavi Sheida
Published: October 2022

Breast cancer is among the most common and fatal diseases for women, and no permanent treatment has been discovered. Thus, early detection is a crucial step to control and cure breast cancer that can save the lives of millions of women. For example, in 2020, more than 65% of breast cancer patients were diagnosed in an early stage of cancer, from which all survived. Although early detection is the most effective approach for cancer treatment, breast cancer screening conducted by radiologists is very expensive and time-consuming. More importantly, conventional methods of analyzing breast cancer images suffer from high false-detection rates. Different breast cancer imaging modalities are used to extract and analyze the key features affecting the diagnosis and treatment of breast cancer. These imaging modalities can be divided into subgroups such as mammograms, ultrasound, magnetic resonance imaging, histopathological images, or any combination of them. Radiologists or pathologists analyze images produced by these methods manually, which leads to an increase in the risk of wrong decisions for cancer detection. Thus, the utilization of new automatic methods to analyze all kinds of breast screening images to assist radiologists to interpret images is required. Recently, artificial intelligence (AI) has been widely utilized to automatically improve the early detection and treatment of different types of cancer, specifically breast cancer, thereby enhancing the survival chance of patients. Advances in AI algorithms, such as deep learning, and the availability of datasets obtained from various imaging modalities have opened an opportunity to surpass the limitations of current breast cancer analysis methods. In this article, we first review breast cancer imaging modalities, and their strengths and limitations. Then, we explore and summarize the most recent studies that employed AI in breast cancer detection using various breast imaging modalities. In addition, we report available datasets on the breast-cancer imaging modalities which are important in developing AI-based algorithms and training deep learning models. In conclusion, this review paper tries to provide a comprehensive resource to help researchers working in breast cancer imaging analysis.
Oligometastatic Non-Small Cell Lung Cancer: A Practical Review of Prospective Trials
Authors: Baydoun Atallah , Lee VeAnn L. , Biswas Tithi
Published: October 2022

Oligometastatic non-small cell lung cancer (NSCLC) is an intermediate state between localized and widely metastatic NSCLC, where systemic therapy in combination with aggressive local therapy when feasible can yield a favorable outcome. While different societies have adopted different definitions for oligometastatic NSCLC, the feasibility of curative intent treatment remains a major determinant of the oligometastatic state. The management involves a multidisciplinary approach to identify such patients with oligometastatic stage, including the presence of symptomatic or potentially symptomatic brain metastasis, the presence of targetable mutations, and programmed death-ligand (PD-L1) expression. Treatment requires a personalized approach with the use of novel systemic agents such as tyrosine kinase inhibitors and immune checkpoint inhibitors with or without chemotherapy, and addition of local ablative therapy via surgery or stereotactic radiation therapy when appropriate.
Medical Device Advances in the Treatment of Glioblastoma
Authors: Foo Cher , Munir Nimrah , Kumaria Ashwin , Akhtar Qasim , Bullock Christopher , Narayanan Ashwin , Fu Richard
Published: October 2022

Despite decades of research and the growing emergence of new treatment modalities, Glioblastoma (GBM) frustratingly remains an incurable brain cancer with largely stagnant 5-year survival outcomes of around 5%. Historically, a significant challenge has been the effective delivery of anti-cancer treatment. This review aims to summarize key innovations in the field of medical devices, developed either to improve the delivery of existing treatments, for example that of chemo-radiotherapy, or provide novel treatments using devices, such as sonodynamic therapy, thermotherapy and electric field therapy. It will highlight current as well as emerging device technologies, non-invasive versus invasive approaches, and by doing so provide a detailed summary of evidence from clinical studies and trials undertaken to date. Potential limitations and current challenges are discussed whilst also highlighting the exciting potential of this developing field. It is hoped that this review will serve as a useful primer for clinicians, scientists, and engineers in the field, united by a shared goal to translate medical device innovations to help improve treatment outcomes for patients with this devastating disease.
Latent Microsporidia Infection Prevalence as a Risk Factor in Colon Cancer Patients
Authors: Redondo Fernando , Hurtado-Marcos Carolina , Izquierdo Fernando , Cuéllar Carmen , Fenoy Soledad , Sáez Yanira , Magnet Ángela , Galindo-Regal Lorena , Uribe Natalia , López-Bañeres Manuel , Jiménez Ana Isabel , Llombart-Cussac Antonio , Del Águila Carmen , Andreu-Ballester Juan Carlos
Published: October 2022

Microsporidia are opportunistic intracellular parasites, generating serious pathology in individuals with a compromised immune system. Infection by microsporidia inhibits p53 and Caspase 3, proteins involved in apoptosis and the cell cycle, which are vital in the malignant process of epithelial cells. The presence of microsporidia in the intestinal tissues of 87 colon cancer (CC) patients and 25 healthy controls was analyzed by real-time PCR and an immunofluorescence antibody test. Anti-Encephalitozoon antibodies were analyzed in serum samples by ELISA (enzyme linked immunosorbent assay). In 36 (41.3%) CC cases, microsporidia infections were identified in their tissues vs. no cases among control subjects (p < 0.0001). An increase in IgG and IgE anti-Encephalitozoon antibodies was found in patients with CC, which would demonstrate continuous and previous contact with the parasite. The high prevalence of microsporidia in tissues and the seroprevalence in patients with CC suggest a relationship between microsporidia and the etiopathogenesis of CC.
UM-164, a Dual Inhibitor of c-Src and p38 MAPK, Suppresses Proliferation of Glioma by Reducing YAP Activity
Authors: Xu Huizhe , Zhang Ye , Liu Jia , Cui Jing , Gan Yu , Wu Zhisheng , Chang Youwei , Sui Rui , Chen Yi , Shi Ji , Liang Haiyang , Liu Qiang , Sun Shulan , Piao Haozhe
Published: October 2022

UM-164 is a dual inhibitor of c-Src and p38 MAPK, and has been a lead compound for targeting triple-negative breast cancer. UM-164 shows stronger binding to the active sites of Src compared with the conventional Src inhibitor Dasatinib. While Dasatinib has displayed some inhibitory effects on glioma growth in clinical trials, whether UM-164 can suppress glioma growth has not been reported. Here we show that UM-164 suppressed the proliferation, migration and spheroid formation of glioma cells, and induced cell cycle arrest in the G1 phase. Moreover, UM-164 triggered YAP translocation to the cytoplasm and reduced the activity of YAP, as evidenced by a luciferase assay. Accordingly, UM-164 markedly decreased the expression levels of YAP target genes CYR61 and AXL. Importantly, ectopic expression of wild-type YAP or YAP-5SA (YAP constitutively active mutant) could rescue the anti-proliferative effect induced by UM-164. Intriguingly, p38 MAPK appears to play a greater role than Src in UM-164-mediated inhibition of YAP activity. Furthermore, the in vitro anti-glioma effect mediated by UM-164 was confirmed in a xenograft glioma model. Together, these findings reveal a mechanism by which UM-164 suppresses the malignant phenotypes of glioma cells and might provide a rationale for UM-164-based anti-glioma clinical trials.
Radiofrequency Electromagnetic Fields Cause Non-Temperature-Induced Physical and Biological Effects in Cancer Cells
Authors: Wust Peter , Veltsista Paraskevi D. , Oberacker Eva , Yavvari Prabhusrinivas , Walther Wolfgang , Bengtsson Olof , Sterner-Kock Anja , Weinhart Marie , Heyd Florian , Grabowski Patricia , Stintzing Sebastian , Heinrich Wolfgang , Stein Ulrike , Ghadjar Pirus
Published: October 2022

Non-temperature-induced effects of radiofrequency electromagnetic fields (RF) have been controversial for decades. Here, we established measurement techniques to prove their existence by investigating energy deposition in tumor cells under RF exposure and upon adding amplitude modulation (AM) (AMRF). Using a preclinical device LabEHY-200 with a novel in vitro applicator, we analyzed the power deposition and system parameters for five human colorectal cancer cell lines and measured the apoptosis rates in vitro and tumor growth inhibition in vivo in comparison to water bath heating. We showed enhanced anticancer effects of RF and AMRF in vitro and in vivo and verified the non-temperature-induced origin of the effects. Furthermore, apoptotic enhancement by AM was correlated with cell membrane stiffness. Our findings not only provide a strategy to significantly enhance non-temperature-induced anticancer cell effects in vitro and in vivo but also provide a perspective for a potentially more effective tumor therapy.
Chimeric Antigen Receptor Immunotherapy for Solid Tumors: Choosing the Right Ingredients for the Perfect Recipe
Authors: Castiello Luciano , Santodonato Laura , Napolitano Mariarosaria , Carlei Davide , Montefiore Enrica , Monque Domenica Maria , D’Agostino Giuseppina , Aricò Eleonora
Published: October 2022

Chimeric antigen receptor T cell therapies are revolutionizing the clinical practice of hematological tumors, whereas minimal progresses have been achieved in the solid tumor arena. Multiple reasons have been ascribed to this slower pace: The higher heterogeneity, the hurdles of defining reliable tumor antigens to target, and the broad repertoire of immune escape strategies developed by solid tumors are considered among the major ones. Currently, several CAR therapies are being investigated in preclinical and early clinical trials against solid tumors differing in the type of construct, the cells that are engineered, and the additional signals included with the CAR constructs to overcome solid tumor barriers. Additionally, novel approaches in development aim at overcoming some of the limitations that emerged with the approved therapies, such as large-scale manufacturing, duration of manufacturing, and logistical issues. In this review, we analyze the advantages and challenges of the different approaches under development, balancing the scientific evidences supporting specific choices with the manufacturing and regulatory issues that are essential for their further clinical development.
The E3 Ligases in Cervical Cancer and Endometrial Cancer
Authors: Zhai Fengguang , Wang Jie , Yang Weili , Ye Meng , Jin Xiaofeng
Published: October 2022

Endometrial (EC) and cervical (CC) cancers are the most prevalent malignancies of the female reproductive system. There is a global trend towards increasing incidence and mortality, with a decreasing age trend. E3 ligases label substrates with ubiquitin to regulate their activity and stability and are involved in various cellular functions. Studies have confirmed abnormal expression or mutations of E3 ligases in EC and CC, indicating their vital roles in the occurrence and progression of EC and CC. This paper provides an overview of the E3 ligases implicated in EC and CC and discusses their underlying mechanism. In addition, this review provides research advances in the target of ubiquitination processes in EC and CC.
Patients Regret Their Choice of Therapy Significantly Less Frequently after Robot-Assisted Radical Prostatectomy as Opposed to Open Radical Prostatectomy: Patient-Reported Results of the Multicenter Cross-Sectional IMPROVE Study
Authors: Wolff Ingmar , Burchardt Martin , Gilfrich Christian , Peter Julia , Baunacke Martin , Thomas Christian , Huber Johannes , Gillitzer Rolf , Sikic Danijel , Fiebig Christian , Steinestel Julie , Schifano Paola , Löbig Niklas , Bolenz Christian , Distler Florian A. , Huettenbrink Clemens , Janssen Maximilian , Schilling David , Barakat Bara , Harke Nina N. , Fuhrmann Christian , Manseck Andreas , Wagenhoffer Robert , Geist Ekkehard , Blair Lisa , Pfitzenmaier Jesco , Reinhardt Bettina , Hoschke Bernd , Burger Maximilian , Bründl Johannes , Schnabel Marco J. , May Matthias
Published: October 2022

Patient’s regret (PatR) concerning the choice of therapy represents a crucial endpoint for treatment evaluation after radical prostatectomy (RP) for prostate cancer (PCA). This study aims to compare PatR following robot-assisted (RARP) and open surgical approach (ORP). A survey comprising perioperative-functional criteria was sent to 1000 patients in 20 German centers at a median of 15 months after RP. Surgery-related items were collected from participating centers. To calculate PatR differences between approaches, a multivariate regressive base model (MVBM) was established incorporating surgical approach and demographic, center-specific, and tumor-specific criteria not primarily affected by surgical approach. An extended model (MVEM) was further adjusted by variables potentially affected by surgical approach. PatR was based on five validated questions ranging 0–100 (cutoff >15 defined as critical PatR). The response rate was 75.0%. After exclusion of patients with laparoscopic RP or stage M1b/c, the study cohort comprised 277/365 ORP/RARP patients. ORP/RARP patients had a median PatR of 15/10 (p < 0.001) and 46.2%/28.1% had a PatR >15, respectively (p < 0.001). Based on the MVBM, RARP patients showed PatR >15 relative 46.8% less frequently (p < 0.001). Consensual decision making regarding surgical approach independently reduced PatR. With the MVEM, the independent impact of both surgical approach and of consensual decision making was confirmed. This study involving centers of different care levels showed significantly lower PatR following RARP.
Proton Pump Inhibitors Use and the Risk of Pancreatic Cancer: Evidence from Eleven Epidemiological Studies, Comprising 1.5 Million Individuals
Authors: Poly Tahmina Nasrin , Islam Md. Mohaimenul , Walther Bruno Andreas , Lin Ming-Chin , Li Yu-Chuan (Jack)
Published: October 2022

Previous epidemiological studies have shown that proton pump inhibitor (PPI) may modify the risk of pancreatic cancer. We conducted an updated systematic review and meta-analysis of observational studies assessing the effect of PPI on pancreatic cancer. PubMed, Embase, Scopus, and Web of Science were searched for studies published between 1 January 2000, and 1 May 2022. We only included studies that assessed exposure to PPI, reported pancreatic cancer outcomes, and provided effect sizes (hazard ratio or odds ratio) with 95% confidence intervals (CIs). We calculated an adjusted pooled risk ratio (RR) with 95%CIs using the random-effects model. Eleven studies (eight case–control and three cohorts) that reported 51,629 cases of pancreatic cancer were included. PPI was significantly associated with a 63% increased risk of pancreatic cancer (RRadj. 1.63, 95%CI: 1.19–2.22, p = 0.002). Subgroup analysis showed that the pooled RR for rabeprazole and lansoprazole was 4.08 (95%CI: 0.61–26.92) and 2.25 (95%CI: 0.83–6.07), respectively. Moreover, the risk of pancreatic cancer was established for both the Asian (RRadj. 1.37, 95%CI: 0.98–1.81) and Western populations (RRadj.2.76, 95%CI: 0.79–9.56). The findings of this updated meta-analysis demonstrate that the use of PPI was associated with an increased risk of pancreatic cancer. Future studies are needed to improve the quality of evidence through better verification of PPI status (e.g., patient selection, duration, and dosages), adjusting for possible confounders, and ensuring long-term follow-up.
Pathologies of Precursor Lesions of Biliary Tract Carcinoma
Authors: Nakanuma Yasuni , Kakuda Yuko , Sugino Takashi , Sato Yasunori , Fukumura Yuki
Published: October 2022

Carcinomas and precursor lesions of the biliary tract belong to a spectrum of pancreatobiliary neoplasms that share common histology and cell lineages. Over the past two decades, preinvasive precursors to biliary tract carcinomas (BTCs) have been identified such as high-grade biliary intraepithelial neoplasm (high-grade BilIN), intraductal papillary neoplasm of bile duct (IPNB) and intracholecystic papillary neoplasm of the gallbladder (ICPN). While a majority of these precursors may arise from the biliary tract mucosa, some originate from the peribiliary glands and Rokitansky-Aschoff sinuses in the walls of the biliary tract. High-grade BilIN is a microscopically identifiable intraepithelial neoplasm of the biliary tract, whereas IPNB and ICPN are grossly visible intraductal or intraluminal preinvasive neoplasms in the bile duct and gallbladder, respectively. These neoplasms show characteristic histologic features according to four cell lineages and two-tiered grading, and show intraepithelial spreading to the surrounding mucosa and involve non-neoplastic glands in the walls of the biliary tract. These precursors are not infrequently associated with stromal invasion, and high-grade BilIN, in particular, are frequently identified in the surrounding mucosa of BTCs. Taken together, it seems likely that progression from these precursors to invasive carcinoma is a major process in biliary carcinogenesis.
Go with the Flow—Early Assessment of Measurable Residual Disease in Children with Acute Lymphoblastic Leukemia Treated According to ALL IC-BFM2009
Authors: Pawinska-Wasikowska Katarzyna , Bukowska-Strakova Karolina , Surman Marta , Rygielska Monika , Sadowska Beata , Ksiazek Teofila , Klekawka Tomasz , Wieczorek Aleksandra , Skoczen Szymon , Balwierz Walentyna
Published: October 2022

Measurable residual disease (MRD) is a well-known tool for the evaluation of the early response to treatment in patients with acute lymphoblastic leukemia (ALL). In respect to predicting the relapse the most informative cut-off and time point of MRD measurement during therapy were evaluated in our study. Between 1 January 2013 and 31 December 2019, multiparametric flow cytometry (MFC) MRD was measured in the bone marrow of 140 children with ALL treated according to the ALL IC-BFM2009 protocol. The MRD cut-off of 0.1% and day 33, end of induction, were the most discriminatory for all patients. Patients with negative MRD on day 15 and 33 had a higher 5-year overall survival—OS (100%) and a higher relapse-free survival—RFS rate (97.6%) than those with positive levels of MRD (≥0.01%) at both time points (77.8% and 55.6%, p = 0.002 and 0.001, respectively). Most patients with residual disease below 0.1% on day 15 exhibit hyperdiploidy or ETV6-RUNX1 in ALL cells. Measurement of MRD at early time points can be used with simplified genetic analysis to better identify low and high-risk patients, allowing personalized therapies and further improvement in outcomes in pediatric ALL.
Modified BaMnO3-Based Catalysts for Gasoline Particle Filters (GPF): A Preliminary Study
Authors: Torregrosa-Rivero Verónica , Sánchez-Adsuar María-Salvadora , Illán-Gómez María-José
Published: October 2022

Gasoline engines, mainly gasoline direct injection engines (GDI) require, in addition to three-way catalysts (TWC), a new catalytic system to remove the formed soot. Gasoline Particle Filters (GPF) are, among others, a possible solution. BaMnO3 and copper-doped BaMnO3 perovskites seem to be a feasible alternative to current catalysts for GPF. The physical and chemical properties of these two perovskites determining the catalytic performance have been modified using different synthesis routes: (i) sol-gel, (ii) modified sol-gel and iii) hydrothermal. The deep characterization allows concluding that: (i) all samples present a perovskite-like structure (hexagonal), except BMC3 which shows a polytype one (due to the distortion caused by copper insertion in the lattice), and ii) when a low calcination temperature is used during synthesis, the sintering effect decreases and the textural properties, the reducibility and the oxygen mobility are improved. The study of soot oxidation simulating the hardest GDI scenarios reveals that, as for diesel soot removal, the best catalytic performance involves the presence of oxygen vacancies to adsorb and activate oxygen and a labile Mn (IV)/Mn (III) redox pair to dissociate the adsorbed oxygen. The combination of both properties allows the transport of the dissociated oxygen towards the soot.
Anchoring Cu Species over SiO2 for Hydrogenation of Dimethyl Oxalate to Ethylene Glycol
Authors: San Xiaoguang , Gong Xiaohui , Lu Yiming , Xu Juhua , He Liming , Meng Dan , Wang Guosheng , Qi Jian , Jin Quan
Published: October 2022

Recently, the Cu-based catalyst has attracted wide attention for the hydrogenation of dimethyl oxalate (DMO) to ethylene glycol (EG) due to its high catalytic activity and it is low cost. However, its poor stability, ease of agglomeration, and the short life of the catalyst restrict its further development in industrial applications. Here, we constructed a novel MOF-derived Cu/SiO2 catalyst (MOF-CmS for short) with a controllable distribution of Cu active sites for the hydrogenation of the DMO to EG reaction. The catalyst was prepared by a hydrothermal method with the HKUST-1 uniformly coated on the surface of the silica microspheres. After the calcination, the highly dispersed and uniform Cu species were loaded on the surface of the silica. The resulted MOF-CmS catalyst showed a 100% conversion of DMO and over 98% selectivity of EG at 200 °C and 2 MPa while a traditional Cu/SiO2 catalyst exhibited serious agglomeration of Cu active sites and low catalytic activity (DMO conversion of 86.9% and EG selectivity of 46.6%). It is believed that the highly dispersed active metal center and the interaction between the active metal and carrier were the main reasons for higher catalytic activity of the MOF-CmS catalyst. Therefore, the developed method opened another avenue to synthesize highly dispersed and stable Cu-based catalysts.
Hydrogenolysis of Lignin and C–O Linkages Containing Lignin-Related Compounds over an Amorphous CoRuP/SiO2 Catalyst
Authors: Huang Liang-Qiu , Diao Zhi-Jun , Chen Bo , Du Qing-Pan , Duan Kai-Yang , Zhao Si-Jia
Published: October 2022

Efficient depolymerization of C–O linkages is essential for converting lignin into fuels and higher value-added chemicals. In this work, CoRuP/SiO2, an amorphous Ru-Co phosphide composite, was fabricated for the efficient hydrogenolysis of ether linkages. The 4–O–5 and α–O–4 linkages containing lignin-related compounds, such as diphenyl ether, benzyl phenyl ether, 3-methyl diphenyl ether, and dibenzyl ether, are selected as representatives of linkages in lignin. Under mild conditions, Ru-containing metallic phosphides have high-performance for the catalytic depolymerization of C–O linkages. Compared with other catalysts, CoRuP/SiO2 shows an outstanding selectivity for benzene and excellent efficiency in depolymerizing diphenyl ethers, yielding only a small amount of by-products. Furthermore, the total acidity shows a linear relationship with the hydrogenolysis reactivity in cleaving aromatic ether bonds. The mechanisms for the catalytic hydrogenolysis of 4–O–5 and α–O–4 bonds over CoRuP/SiO2 are proposed. Moreover, two-dimensional heteronuclear single quantum coherence nuclear magnetic resonance spectroscopic analysis demonstrates that CoRuP/SiO2 could effectively depolymerize C–O bonds of lignin. These dominant hydrogenolysis products from lignin have excellent potential in the production of high value-added drugs or pharmaceutical intermediates. The hydrogenolysis of lignin can be a highly efficient alternative to the existing method of lignin utilization.
Green Chemistry in Organic Synthesis: Recent Update on Green Catalytic Approaches in Synthesis of 1,2,4-Thiadiazoles
Authors: Rubab Laila , Anum Ayesha , Al-Hussain Sami A. , Irfan Ali , Ahmad Sajjad , Ullah Sami , Al-Mutairi Aamal A. , Zaki Magdi E. A.
Published: October 2022

Green (sustainable) chemistry provides a framework for chemists, pharmacists, medicinal chemists and chemical engineers to design processes, protocols and synthetic methodologies to make their contribution to the broad spectrum of global sustainability. Green synthetic conditions, especially catalysis, are the pillar of green chemistry. Green chemistry principles help synthetic chemists overcome the problems of conventional synthesis, such as slow reaction rates, unhealthy solvents and catalysts and the long duration of reaction completion time, and envision solutions by developing environmentally benign catalysts, green solvents, use of microwave and ultrasonic radiations, solvent-free, grinding and chemo-mechanical approaches. 1,2,4-thiadiazole is a privileged structural motif that belongs to the class of nitrogen–sulfur-containing heterocycles with diverse medicinal and pharmaceutical applications. This comprehensive review systemizes types of green solvents, green catalysts, ideal green organic synthesis characteristics and the green synthetic approaches, such as microwave irradiation, ultrasound, ionic liquids, solvent-free, metal-free conditions, green solvents and heterogeneous catalysis to construct different 1,2,4-thiadiazoles scaffolds.