bluuebunny/crossref_metadata_2025 huggingface dataset:
Immersive and Non-Immersive Virtual Reality for Pain and Anxiety Management in Pediatric Patients with Hematological or Solid Cancer: A Systematic Review
Authors: Comparcini Dania , Simonetti Valentina , Galli Francesco , Saltarella Ilaria , Altamura Concetta , Tomietto Marco , Desaphy Jean-François , Cicolini Giancarlo
Published: February 2023

Invasive and painful procedures, which often induce feelings of anxiety, are necessary components of pediatric cancer treatment, and adequate pain and anxiety management during these treatments is of pivotal importance. In this context, it is widely recognized that a holistic approach, including pharmacological and non-pharmacological modalities, such as distraction techniques, should be the standard of care. Recent evidence suggested the use of virtual reality (VR) as an effective non-pharmacological intervention in pediatrics. Therefore, this systematic review aims to analyze previously published studies on the effectiveness of VR for the management of pain and/or anxiety in children and adolescents with hematological or solid cancer. Medline, SCOPUS, Web of Science, ProQuest, CINAHL, and The Cochrane Central Register of Controlled Trials were used to search for relevant studies in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses checklist. Randomized controlled trial, crossover trial, cluster randomized trial, and quasi-experimental studies were included. Thirteen studies, published between 1999 and 2022, that fulfilled the inclusion criteria were included. Regarding the primary outcomes measured, pain was considered in five studies, anxiety in three studies, and the remaining five studies analyzed the effectiveness of VR for both pain and anxiety reduction. Our findings suggested a beneficial effect of VR during painful vascular access procedures. Limited data are available on the reduction of anxiety in children with cancer.
Characterization of Inorganic Scintillator Detectors for Dosimetry in Image-Guided Small Animal Radiotherapy Platforms
Authors: Silvestre Patallo Ileana , Subiel Anna , Carter Rebecca , Flynn Samuel , Schettino Giuseppe , Nisbet Andrew
Published: February 2023

The purpose of the study was to characterize a detection system based on inorganic scintillators and determine its suitability for dosimetry in preclinical radiation research. Dose rate, linearity, and repeatability of the response (among others) were assessed for medium-energy X-ray beam qualities. The response’s variation with temperature and beam angle incidence was also evaluated. Absorbed dose quality-dependent calibration coefficients, based on a cross-calibration against air kerma secondary standard ionization chambers, were determined. Relative output factors (ROF) for small, collimated fields (≤10 mm × 10 mm) were measured and compared with Gafchromic film and to a CMOS imaging sensor. Independently of the beam quality, the scintillator signal repeatability was adequate and linear with dose. Compared with EBT3 films and CMOS, ROF was within 5% (except for smaller circular fields). We demonstrated that when the detector is cross-calibrated in the user’s beam, it is a useful tool for dosimetry in medium-energy X-rays with small fields delivered by Image-Guided Small Animal Radiotherapy Platforms. It supports the development of procedures for independent “live” dose verification of complex preclinical radiotherapy plans with the possibility to insert the detectors in phantoms.
Lower Expression of CFTR Is Associated with Higher Mortality in a Meta-Analysis of Individuals with Colorectal Cancer
Authors: Scott Patricia , Wang Shuo , Onyeaghala Guillaume , Pankratz Nathan , Starr Timothy , Prizment Anna E.
Published: February 2023

Individuals with cystic fibrosis (CF), caused by biallelic germline mutations in the cystic fibrosis transmembrane conductance regulator (CFTR), have higher risk and earlier onset of colorectal cancer (CRC). A subset of CRC patients in the non-CF population expresses low levels of tumoral CFTR mRNA which may also cause decreased CFTR activity. To determine the consequences of reduced CFTR expression in this population, we investigated association of tumoral CFTR expression with overall and disease-specific mortality in CRC patients. CFTR mRNA expression, clinical factors and survival data from 1177 CRC patients reported in the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus studies GSE39582 and GSE17538 were included. Log-transformed and z-normalized [mean = 0, standard deviation (SD) = 1] CFTR expression values were modeled as quartiles or dichotomized at the median. Univariate and multivariable Cox proportional hazards regression models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for overall and disease-specific mortality in individual studies and meta-analyses. Analyses of each of the three individual datasets showed a robust association of decreased CFTR expression with increased mortality. In meta-analyses adjusted for stage at diagnosis, age and sex, CFTR expression was inversely associated with risk of overall death [pooled HR (95% CI): 0.70 (0.57–0.86)] and disease-specific death [pooled HR (95% CI): 0.68 (0.47–0.99)]. Associations did not differ by stage at diagnosis, age, or sex. Meta-analysis of overall death stratified by microsatellite instable (MSI) versus microsatellite stable (MSS) status indicated potential interaction between MSI/MSS status and CFTR expression, (p-interaction: 0.06). The findings from these three datasets support the hypothesis that low CFTR expression is associated with increased CRC mortality.
Phenolic Phytochemicals for Prevention and Treatment of Colorectal Cancer: A Critical Evaluation of In Vivo Studies
Authors: De Samhita , Paul Sourav , Manna Anirban , Majumder Chirantan , Pal Koustav , Casarcia Nicolette , Mondal Arijit , Banerjee Sabyasachi , Nelson Vinod Kumar , Ghosh Suvranil , Hazra Joyita , Bhattacharjee Ashish , Mandal Subhash Chandra , Pal Mahadeb , Bishayee Anupam
Published: February 2023

Colorectal cancer (CRC) is the third most diagnosed and second leading cause of cancer-related death worldwide. Limitations with existing treatment regimens have demanded the search for better treatment options. Different phytochemicals with promising anti-CRC activities have been reported, with the molecular mechanism of actions still emerging. This review aims to summarize recent progress on the study of natural phenolic compounds in ameliorating CRC using in vivo models. This review followed the guidelines of the Preferred Reporting Items for Systematic Reporting and Meta-Analysis. Information on the relevant topic was gathered by searching the PubMed, Scopus, ScienceDirect, and Web of Science databases using keywords, such as “colorectal cancer” AND “phenolic compounds”, “colorectal cancer” AND “polyphenol”, “colorectal cancer” AND “phenolic acids”, “colorectal cancer” AND “flavonoids”, “colorectal cancer” AND “stilbene”, and “colorectal cancer” AND “lignan” from the reputed peer-reviewed journals published over the last 20 years. Publications that incorporated in vivo experimental designs and produced statistically significant results were considered for this review. Many of these polyphenols demonstrate anti-CRC activities by inhibiting key cellular factors. This inhibition has been demonstrated by antiapoptotic effects, antiproliferative effects, or by upregulating factors responsible for cell cycle arrest or cell death in various in vivo CRC models. Numerous studies from independent laboratories have highlighted different plant phenolic compounds for their anti-CRC activities. While promising anti-CRC activity in many of these agents has created interest in this area, in-depth mechanistic and well-designed clinical studies are needed to support the therapeutic use of these compounds for the prevention and treatment of CRC.
Repurposing the Bis-Biguanide Alexidine in Combination with Tyrosine Kinase Inhibitors to Eliminate Leukemic Stem/Progenitor Cells in Chronic Myeloid Leukemia
Authors: Muselli Fabien , Mourgues Lucas , Rochet Nathalie , Nebout Marielle , Guerci Agnès , Verhoeyen Els , Krug Adrien , Legros Laurence , Peyron Jean-François , Mary Didier
Published: February 2023

Background & aims: In CML, Leukemic Stem Cells (LSCs) that are insensitive to Tyrosine Kinase Inhibitors are responsible for leukemia maintenance and relapses upon TKI treatment arrest. We previously showed that downregulation of the BMI1 polycomb protein that is crucial for stem/progenitor cells self-renewal induced a CCNG2/dependent proliferation arrest leading to elimination of Chronic Myeloid Leukemia (CML) cells. Unfortunately, as of today, pharmacological inhibition of BMI1 has not made its way to the clinic. Methods: We used the Connectivity Map bioinformatic database to identify pharmacological molecules that could mimick BMI1 silencing, to induce CML cell death. We selected the bis-biguanide Alexidin (ALX) that produced a transcriptomic profile positively correlating with the one obtained after BMI silencing in K562 CML cells. We then evaluated the efficiency of ALX in combination with TKI on CML cells. Results: Here we report that cell growth and clonogenic activity of K562 and LAMA-84 CML cell lines were strongly inhibited by ALX. ALX didn’t modify BCR::ABL1 phosphorylation and didn’t affect BMI1 expression but was able to increase CCNG2 expression leading to autophagic processes that preceed cell death. Besides, ALX could enhance the apoptotic response induced by any Tyrosine Kinase Inhibitors (TKI) of the three generations. We also noted a strong synergism between ALX and TKIs to increase expression of caspase-9 and caspase-3 and induce PARP cleavage, Bad expression and significantly decreased Bcl-xL family member expression. We also observed that the blockage of the mitochondrial respiratory chain by ALX can be associated with inhibition of glycolysis by 2-DG to achieve an enhanced inhibition of K562 proliferation and clonogenicity. ALX specifically affected the differentiation of BCR::ABL1-transduced healthy CD34+ cells but not of mock-infected healthy CD34+ control cells. Importantly, ALX strongly synergized with TKIs to inhibit clonogenicity of primary CML CD34+ cells from diagnosed patients. Long Term Culture of Initiating Cell (LTC-IC) and dilution of the fluorescent marker CFSE allowed us to observe that ALX and Imatinib (IM) partially reduced the number of LSCs by themselves but that the ALX/IM combination drastically reduced this cell compartment. Using an in vivo model of NSG mice intravenously injected with K562-Luciferase transduced CML cells, we showed that ALX combined with IM improved mice survival. Conclusions: Collectively, our results validate the use of ALX bis-biguanide to potentiate the action of conventional TKI treatment as a potential new therapeutic solution to eradicate CML LSCs
Re-Irradiation by Stereotactic Radiotherapy of Brain Metastases in the Case of Local Recurrence
Authors: Touati Ruben , Bourbonne Vincent , Dissaux Gurvan , Goasduff Gaëlle , Pradier Olivier , Peltier Charles , Seizeur Romuald , Schick Ulrike , Lucia François
Published: February 2023

Purpose: To evaluate the efficacy and safety of a second course of stereotactic radiotherapy (SRT2) treatment for a local recurrence of brain metastases previously treated with SRT (SRT1), using the Hypofractionated Treatment Effects in the Clinic (HyTEC) reporting standards and the European Society for Radiotherapy and Oncology guidelines. Methods: From December 2014 to May 2021, 32 patients with 34 brain metastases received salvage SRT2 after failed SRT1. A total dose of 21 to 27 Gy in 3 fractions or 30 Gy in 5 fractions was prescribed to the periphery of the PTV (99% of the prescribed dose covering 99% of the PTV). After SRT2, multiparametric MRI, sometimes combined with 18F-DOPA PET-CT, was performed every 3 months to determine local control (LC) and radionecrosis (RN). Results: After a median follow-up of 12 months (range: 1–37 months), the crude LC and RN rates were 68% and 12%, respectively, and the median overall survival was 25 months. In a multivariate analysis, the performance of surgery was predictive of a significantly better LC (p = 0.002) and survival benefit (p = 0.04). The volume of a normal brain receiving 5 Gy during SRT2 (p = 0.04), a dose delivered to the PTV in SRT1 (p = 0.003), and concomitant systemic therapy (p = 0.04) were associated with an increased risk of RN. Conclusion: SRT2 is an effective approach for the local recurrence of BM after initial SRT treatment and is a potential salvage therapy option for well-selected people with a good performance status. Surgery was associated with a higher LC.
PARP Inhibitors and Proteins Interacting with SLX4
Authors: Jordheim Lars Petter
Published: February 2023

PARP inhibitors are small molecules currently used with success in the treatment of certain cancer patients. Their action was first shown to be specific to cells with DNA repair deficiencies, such as BRCA-mutant cancers. However, recent work has suggested clinical interest of these drugs beyond this group of patients. Preclinical data on relationships between the activity of PARP inhibitors and other proteins involved in DNA repair exist, and this review will only highlight findings on the SLX4 protein and its interacting protein partners. As suggested from these available data and depending on further validations, new treatment strategies could be developed in order to broaden the use for PARP inhibitors in cancer patients.
Qualitative and Semiquantitative Parameters of 18F-FDG-PET/CT as Predictors of Malignancy in Patients with Solitary Pulmonary Nodule
Authors: Corica Ferdinando , De Feo Maria Silvia , Stazza Maria Lina , Rondini Maria , Marongiu Andrea , Frantellizzi Viviana , Nuvoli Susanna , Farcomeni Alessio , De Vincentis Giuseppe , Spanu Angela
Published: February 2023

This study aims to evaluate the reliability of qualitative and semiquantitative parameters of 18F-FDG PET-CT, and eventually a correlation between them, in predicting the risk of malignancy in patients with solitary pulmonary nodules (SPNs) before the diagnosis of lung cancer. A total of 146 patients were retrospectively studied according to their pre-test probability of malignancy (all patients were intermediate risk), based on radiological features and risk factors, and qualitative and semiquantitative parameters, such as SUVmax, SUVmean, TLG, and MTV, which were obtained from the FDG PET-CT scan of such patients before diagnosis. It has been observed that visual analysis correlates well with the risk of malignancy in patients with SPN; indeed, only 20% of SPNs in which FDG uptake was low or absent were found to be malignant at the cytopathological examination, while 45.45% of SPNs in which FDG uptake was moderate and 90.24% in which FDG uptake was intense were found to be malignant. The same trend was observed evaluating semiquantitative parameters, since increasing values of SUVmax, SUVmean, TLG, and MTV were observed in patients whose cytopathological examination of SPN showed the presence of lung cancer. In particular, in patients whose SPN was neoplastic, we observed a median (MAD) SUVmax of 7.89 (±2.24), median (MAD) SUVmean of 3.76 (±2.59), median (MAD) TLG of 16.36 (±15.87), and a median (MAD) MTV of 3.39 (±2.86). In contrast, in patients whose SPN was non-neoplastic, the SUVmax was 2.24 (±1.73), SUVmean 1.67 (±1.15), TLG 1.63 (±2.33), and MTV 1.20 (±1.20). Optimal cut-offs were drawn for semiquantitative parameters considered predictors of malignancy. Nodule size correlated significantly with FDG uptake intensity and with SUVmax. Finally, age and nodule size proved significant predictors of malignancy. In conclusion, considering the pre-test probability of malignancy, qualitative and semiquantitative parameters can be considered reliable tools in patients with SPN, since cut-offs for SUVmax, SUVmean, TLG, and MTV showed good sensitivity and specificity in predicting malignancy.
CXCR3 Expression Is Associated with Advanced Tumor Stage and Grade Influencing Survival after Surgery of Localised Renal Cell Carcinoma
Authors: Lindner Andrea Katharina , Martowicz Agnieszka , Untergasser Gerold , Haybaeck Johannes , Compérat Eva , Kocher Florian , Seeber Andreas , Thurnher Martin , Pichler Renate
Published: February 2023

Background: Surgery is the standard treatment in localized renal cell carcinoma (RCC). Pembrolizumab is now approved for adjuvant therapy in high-risk patients. However, inhomogeneity of studies gives ambiguity which patient benefit most from adjuvant therapy. A high infiltration of CD8+ T cells is known to be linked with poor prognosis in RCC. CXCR3 is a key player of CD8+ T cell differentiation and infiltration. We aimed to evaluate CXCR3 as a potential marker for predicting recurrence. Methods: CXCR3 and immune cell subsets (CD4, CD8, CD68 and FoXP3) were measured on RCC samples by multiplex immunofluorescence (mIF) staining. Cellular localization of CXCR3 was evaluated using single-cell RNA analysis on a publicly available dataset. Results: Tumor samples of 42 RCC patients were analyzed, from which 59.5% were classified as clear-cell RCC and of which 20 had recurrence. Single-cell RNA analysis revealed that CXCR3 was predominantly expressed in intratumoral T cells and dendritic cells. CXCR3 expression was higher in advanced tumors stages (p = 0.0044) and grade (p = 0.0518), correlating significantly with a higher CD8+ T cell expression (p < 0.001). Patients with CXCR3high RCCs had also a significant shorter RFS compared to CXCR3low (median: 78 vs. 147 months, p = 0.0213). In addition, also tumor stage pT3/4 (p < 0.0001) as well as grade G3/4 (p = 0.0008) negatively influenced RFS. Conclusion: CXCR3high cell density was associated with high T cell infiltration and advanced tumor stage, worsening RFS in surgically resected RCC patients. Beside its prognostic value, CXCR3 might be a predictive biomarker to guide therapy decision for adjuvant therapy in localized RCC.
Combining the HCT-CI, G8, and AML-Score for Fitness Evaluation of Elderly Patients with Acute Myeloid Leukemia: A Single Center Analysis
Authors: Aydin Semra , Passera Roberto , Cerrano Marco , Giai Valentina , D’Ardia Stefano , Iovino Giorgia , Dellacasa Chiara Maria , Audisio Ernesta , Busca Alessandro
Published: February 2023

Background: Accurate assessment of elderly acute myeloid leukemia (AML) patients is essential before intensive induction chemotherapy and subsequent allogeneic hematopoietic stem cell transplantation. In this context, we investigated the capacity of three scores for frailty prediction. Methods: At diagnosis, 197 patients were clinically evaluated for appropriate treatment intensity. In parallel and independently, the G8-score, the Hematopoietic Stem Cell Index (HCT-CI) and the AML-score for CR were determined for each patient and analyzed with respect to overall survival (OS). Results: The G8-score and the HCT-CI were able to significantly separate “fit” from “unfit” patients, <0.001 and p = 0.008. In univariate Cox models, the predictive role for OS was confirmed: for the G8-score (HR: 2.35, 95% CI 1.53–3.60, p < 0.001), the HCT-CI (HR: 1.91, 95% CI 1.17–3.11, p = 0.009) and the AML-score (HR: 5.59, 95% CI 2.04–15.31, p = 0.001), the latter was subsequently used to verify the cohort. In the multivariate Cox model, the results were confirmed for the G8- (HR: 2.03, p < 0.001) and AML-score (HR: 3.27, p = 0.001). Of interest, when combining the scores, their prediction capacity was significantly enhanced, p < 0.001. Conclusions: The G8-, the HCTCI and the AML-score represent valid tools in the frailty assessment of elderly AML patients at diagnosis.
Systematic Review on CAR-T Cell Clinical Trials Up to 2022: Academic Center Input
Authors: Wang Valentine , Gauthier Mélanie , Decot Véronique , Reppel Loïc , Bensoussan Danièle
Published: February 2023

The development of Chimeric Antigen Receptor T cells therapy initiated by the United States and China is still currently led by these two countries with a high number of clinical trials, with Europe lagging in launching its first trials. In this systematic review, we wanted to establish an overview of the production of CAR-T cells in clinical trials around the world, and to understand the causes of this delay in Europe. We particularly focused on the academic centers that are at the heart of research and development of this therapy. We counted 1087 CAR-T cells clinical trials on ClinicalTrials.gov (Research registry ID: reviewregistry1542) on the date of 25 January 2023. We performed a global analysis, before analyzing the 58 European trials, 34 of which sponsored by academic centers. Collaboration between an academic and an industrial player seems to be necessary for the successful development and application for marketing authorization of a CAR-T cell, and this collaboration is still cruelly lacking in European trials, unlike in the leading countries. Europe, still far behind the two leading countries, is trying to establish measures to lighten the regulations surrounding ATMPs and to encourage, through the addition of fundings, clinical trials involving these treatments.
Prognostic Significance of Serum Albumin Level and Albumin-Based Mono- and Combination Biomarkers in Patients with Hepatocellular Carcinoma
Authors: Jeng Long-Bin , Chan Wen-Ling , Teng Chiao-Fang
Published: February 2023

Hepatocellular carcinoma (HCC) is the predominant form of primary liver cancer. Although many surgical and nonsurgical therapeutic options have been established for treating HCC, the overall prognosis for HCC patients receiving different treatment modalities remains inadequate, which causes HCC to remain among the most life-threatening human cancers worldwide. Therefore, it is vitally important and urgently needed to develop valuable and independent prognostic biomarkers for the early prediction of poor prognosis in HCC patients, allowing more time for more timely and appropriate treatment to improve the survival of patients. As the most abundant protein in plasma, human serum albumin (ALB) is predominantly expressed by the liver and exhibits a wide variety of essential biological functions. It has been well recognized that serum ALB level is a significant independent biomarker for a broad spectrum of human diseases including cancer. Moreover, ALB has been commonly used as a potent biomaterial and therapeutic agent in clinical settings for the treatment of various human diseases. This review provides a comprehensive summary of the evidence from the up-to-date published literature to underscore the prognostic significance of serum ALB level and various ALB-based mono- and combination biomarkers in the prediction of the prognosis of HCC patients after treatment with different surgical, locoregional, and systemic therapies.
Geographic Variation and Risk Factor Association of Early Versus Late Onset Colorectal Cancer
Authors: Dong Weichuan , Kim Uriel , Rose Johnie , Hoehn Richard S. , Kucmanic Matthew , Eom Kirsten , Li Shu , Berger Nathan A. , Koroukian Siran M.
Published: February 2023

The proportion of patients diagnosed with colorectal cancer (CRC) at age < 50 (early-onset CRC, or EOCRC) has steadily increased over the past three decades relative to the proportion of patients diagnosed at age ≥ 50 (late-onset CRC, or LOCRC), despite the reduction in CRC incidence overall. An important gap in the literature is whether EOCRC shares the same community-level risk factors as LOCRC. Thus, we sought to (1) identify disparities in the incidence rates of EOCRC and LOCRC using geospatial analysis and (2) compare the importance of community-level risk factors (racial/ethnic, health status, behavioral, clinical care, physical environmental, and socioeconomic status risk factors) in the prediction of EOCRC and LOCRC incidence rates using a random forest machine learning approach. The incidence data came from the Surveillance, Epidemiology, and End Results program (years 2000–2019). The geospatial analysis revealed large geographic variations in EOCRC and LOCRC incidence rates. For example, some regions had relatively low LOCRC and high EOCRC rates (e.g., Georgia and eastern Texas) while others had relatively high LOCRC and low EOCRC rates (e.g., Iowa and New Jersey). The random forest analysis revealed that the importance of community-level risk factors most predictive of EOCRC versus LOCRC incidence rates differed meaningfully. For example, diabetes prevalence was the most important risk factor in predicting EOCRC incidence rate, but it was a less important risk factor of LOCRC incidence rate; physical inactivity was the most important risk factor in predicting LOCRC incidence rate, but it was the fourth most important predictor for EOCRC incidence rate. Thus, our community-level analysis demonstrates the geographic variation in EOCRC burden and the distinctive set of risk factors most predictive of EOCRC.
The Diagnostic and Therapeutic Role of snoRNA and lincRNA in Bladder Cancer
Authors: Wang Hao , Feng Yanfei , Zheng Xiangyi , Xu Xin
Published: February 2023

Bladder cancer is one of the most common malignancies of the urinary tract and can be divided into non-muscle-invasive bladder cancer (NMIBC) and muscle-invasive bladder cancer (MIBC). Although the means of diagnosis and treatment have continually improved in recent years, the recurrence rate of bladder cancer remains high, and patients with MIBC typically have an unfavourable prognosis and a low quality of life. Emerging evidence demonstrates that long noncoding RNAs play a crucial role in the carcinogenesis and progression of bladder cancer. Long intergenic noncoding RNAs (lincRNAs) are a subgroup of long noncoding RNAs (lncRNAs) that do not overlap protein-coding genes. The potential role of lincRNAs in the regulation of gene expression has been explored in depth in recent years. Small nucleolar RNAs (snoRNAs) are a class of noncoding RNAs (ncRNAs) that mainly exist in the nucleolus, are approximately 60–300 nucleotides in length, and are hosted inside the introns of genes. Small nucleolar RNA host genes (SNHGs) have been associated with the origin and development of bladder cancer. In this review, we aim to comprehensively summarize the biological functions of these molecules in bladder cancer.
Antiapoptotic Gene Genotype and Allele Variations and the Risk of Lymphoma
Authors: Al-Amer Osama M. , Mir Rashid , Hamadi Abdullah , Alasseiri Mohammed I. , Altayar Malik A. , AlZamzami Waseem , Moawadh Mamdoh , Alatawi Sael , Niaz Hanan A. , Oyouni Atif Abdulwahab A. , Alzahrani Othman R. , Alatwi Hanan E. , Albalawi Aishah E. , Alsharif Khalaf F. , Albrakati Ashraf , Hawsawi Yousef M.
Published: February 2023

Background: The findings of earlier investigations of antiapoptotic gene genotypes and allele variants on lymphoma risk are ambiguous. This study aimed to examine the relationship between the mutation in the antiapoptotic genes and lymphoma risk among Saudi patients. Methods: This case–control study included 205 patients, 100 of whom had lymphoma (cases) and 105 who were healthy volunteers (controls). We used tetra amplification refractory mutation polymerase chain reaction (PCR) to identify antiapoptotic genes such as B-cell lymphoma-2 (BCL2-938 C > A), MCL1-rs9803935 T > G, and survivin (BIRC5-rs17882312 G > C and BIRC5-rs9904341 G > C). Allelic-specific PCR was used to identify alleles such as BIRC5-C, MCL1-G, and BIRC5-G. Results: The dominant inheritance model among cases showed that mutations in all four antiapoptotic genes were more likely to be associated with the risk of lymphoma by the odds of 2.0-, 1.98-, 3.90-, and 3.29-fold, respectively, compared to controls. Apart from the BCL-2-A allele, all three specified alleles were more likely to be associated with lymphoma by the odds of 2.04-, 1.65-, and 2.11-fold, respectively. Conclusion: Unlike healthy individuals, lymphoma patients are more likely to have antiapoptotic gene genotypes and allele variants, apart from BCL-2-A alterations. In the future, these findings could be used to classify and identify patients at risk of lymphoma.
Immunological Aspects of Richter Syndrome: From Immune Dysfunction to Immunotherapy
Authors: Mahmoud Abdurraouf Mokhtar , Gaidano Gianluca , Mouhssine Samir
Published: February 2023

Richter Syndrome (RS) is defined as the development of an aggressive lymphoma in patients with a previous or simultaneous diagnosis of chronic lymphocytic leukemia (CLL). Two pathological variants of RS are recognized: diffuse large B-cell lymphoma (DLBCL)-type and Hodgkin lymphoma (HL)-type RS. Different molecular mechanisms may explain the pathogenesis of DLBCL-type RS, including genetic lesions, modifications of immune regulators, and B cell receptor (BCR) pathway hyperactivation. Limited data are available for HL-type RS, and its development has been reported to be similar to de novo HL. In this review, we focus on the immune-related pathogenesis and immune system dysfunction of RS, which are linked to BCR over-reactivity, altered function of the immune system due to the underlying CLL, and specific features of the RS tumor microenvironment. The standard of care of this disease consists in chemoimmunotherapy, eventually followed by stem cell transplantation, but limited possibilities are offered to chemo-resistant patients, who represent the majority of RS cases. In order to address this unmet clinical need, several immunotherapeutic approaches have been developed, namely T cell engagement obtained with bispecific antibodies, PD-1/PD-L1 immune checkpoint blockade by the use of monoclonal antibodies, selective drug delivery with antibody-drug conjugates, and targeting malignant cells with anti-CD19 chimeric antigen receptor-T cells.
Does the Gain of Total Neoadjuvant Therapy Outweigh the Harm in Rectal Cancer? Importance of the ATRESS (neoAdjuvant Therapy-RElated Shortening of Survival) Phenomenon: A Systematic Review
Authors: Socha Joanna , Bujko Krzysztof
Published: February 2023

Background: We aimed to evaluate whether total neoadjuvant therapy (TNT) results in long-term overall survival (OS) or quality of life (QoL) benefit compared with chemoradiation if all patients are being considered for radical resection, and whether the ATRESS phenomenon (i.e., reduction in post-metastatic survival) impacts OS after TNT. Methods: Systematic review of randomised trials comparing TNT with neoadjuvant (chemo)radiation. Results: Six trials were identified. Follow-ups were too short to resolve whether TNT improves long-term OS. QoL analysis in one trial showed worse long-term neurotoxicity-related QoL (any neurotoxicity: 14% vs. 3%), higher rate of grade III+ acute toxicity (48% vs. 25%), longer duration of neoadjuvant treatment (19 vs. 6 weeks) and higher rate of locoregional failure (10% vs. 7%) in TNT vs. chemoradiation. This should be weighed against an absolute 8% reduction in the incidence of distant metastases (DM) after TNT. ATRESS could explain a discrepancy between reduction of DM and the absence of OS improvement after TNT in one trial. Conclusion: In the light of unproven OS benefit, the gain of TNT (reduction of DM) does not seem to outweigh the harm (excess of toxicity). ATRESS can be a reason for the absence of the OS benefit despite the reduction in DM.
A History of Targeted Therapy Development and Progress in Novel–Novel Combinations for Chronic Lymphocytic Leukemia (CLL)
Authors: Karr Matthew , Roeker Lindsey
Published: February 2023

Over the last 10 years, the traditional treatment paradigms for CLL have been upended as the use of traditional chemoimmunotherapy regimens has declined in favor of novel targeted therapies. Targeted therapies have become the new standard of care in CLL given their superior progression-free survival (and overall survival, in some cases) when compared with chemoimmunotherapy, as well as their improved toxicity profiles. Targeted agents are FDA approved for the treatment of CLL including ibrutinib, acalabrutinib, zanubrutinib, and venetoclax. Importantly, as opposed to traditional chemotherapy regimens, the benefits of these targeted therapies appear to be consistent regardless of high-risk mutational status. In this review, we discuss the pivotal CLL studies of the last decade and the data supporting doublet and triplet novel–novel combinations. We explore the use of new surrogate end points for PFS/OS in targeted therapies such as undetectable minimal residual disease (uMRD) and their potential role in minimizing toxicity by permitting earlier treatment discontinuation. We also highlight areas that warrant further exploration and future studies that may help address some of these key questions.
Advanced PSMA-PET/CT Imaging Parameters in Newly Diagnosed Prostate Cancer Patients for Predicting Metastatic Disease
Authors: Yechiel Yaniv , Orr Yaly , Gurevich Konstantin , Gill Ronit , Keidar Zohar
Published: February 2023

(1) Purpose: Recent studies indicate that advanced imaging parameters such as prostate PSMA tumor volume may have a value in predicting response to treatment of castration-resistant prostate cancer patients. In this study, we examine whether a relationship can be found between advanced imaging parameters such as prostate PSMA-TV and the presence of metastatic disease in newly diagnosed prostate cancer patients undergoing PSMA-PET/CT for staging purposes; (2) Methods: We retrospectively analyzed PET/CT studies of 91 patients with newly diagnosed prostate cancer. Prostate PSMA-TV was measured using the MIRADA-XD software. PET/CT results were recorded, as well as additional clinical parameters such as the Gleason score, etc.; (3) Results: Prostate PSMA-TV measurements were found to be able to significantly differentiate metastatic from the non-metastatic patient groups (13.7 vs. 5.5, p-value < 0.05). Overall, 54% percent of patients with levels of over 8.1 PSMA-TV had metastatic lesions found on their PSMA-PET/CT. A model based on this cutoff attained a sensitivity of 80%, a specificity of 68.3%, and a negative predictive value of 93.5% for identifying metastatic disease. Another bin model was found statistically capable of assessing the likelihood of the presence of metastatic disease with a p-value of 0.001; (4) Conclusions: Prostate PSMA-TV measurement has the potential to predict the presence of metastatic disease at staging and thus may impact further treatment decision and patient management.
Inhibition of CXCR4 Enhances the Efficacy of Radiotherapy in Metastatic Prostate Cancer Models
Authors: Gupta Nisha , Ochiai Hiroki , Hoshino Yoshinori , Klein Sebastian , Zustin Jozef , Ramjiawan Rakesh R. , Kitahara Shuji , Maimon Nir , Bazou Despina , Chiang Sarah , Li Sen , Schanne Daniel H. , Jain Rakesh. K. , Munn Lance L. , Huang Peigen , Kozin Sergey V. , Duda Dan G.
Published: February 2023

Radiotherapy (RT) is a standard treatment for patients with advanced prostate cancer (PCa). Previous preclinical studies showed that SDF1α/CXCR4 axis could mediate PCa metastasis (most often to the bones) and cancer resistance to RT. We found high levels of expression for both SDF1α and its receptor CXCR4 in primary and metastatic PCa tissue samples. In vitro analyses using PCa cells revealed an important role of CXCR4 in cell invasion but not radiotolerance. Pharmacologic inhibition of CXCR4 using AMD3100 showed no efficacy in orthotopic primary and bone metastatic PCa models. However, when combined with RT, AMD3100 potentiated the effect of local single-dose RT (12 Gy) in both models. Moreover, CXCR4 inhibition also reduced lymph node metastasis from primary PCa. Notably, CXCR4 inhibition promoted the normalization of bone metastatic PCa vasculature and reduced tissue hypoxia. In conclusion, the SDF1α/CXCR4 axis is a potential therapeutic target in metastatic PCa patients treated with RT.
Challenges and Therapeutic Opportunities in the dMMR/MSI-H Colorectal Cancer Landscape
Authors: Mulet-Margalef Núria , Linares Jenniffer , Badia-Ramentol Jordi , Jimeno Mireya , Sanz Monte Carolina , Manzano Mozo José Luis , Calon Alexandre
Published: February 2023

About 5 to 15% of all colorectal cancers harbor mismatch repair deficient/microsatellite instability–high status (dMMR/MSI-H) that associates with high tumor mutation burden and increased immunogenicity. As a result, and in contrast to other colorectal cancer phenotypes, a significant subset of dMMR/MSI-H cancer patients strongly benefit from immunotherapy. Yet, a large proportion of these tumors remain unresponsive to any immuno-modulating treatment. For this reason, current efforts are focused on the characterization of resistance mechanisms and the identification of predictive biomarkers to guide therapeutic decision-making. Here, we provide an overview on the new advances related to the diagnosis and definition of dMMR/MSI-H status and focus on the distinct clinical, functional, and molecular cues that associate with dMMR/MSI-H colorectal cancer. We review the development of novel predictive factors of response or resistance to immunotherapy and their potential application in the clinical setting. Finally, we discuss current and emerging strategies applied to the treatment of localized and metastatic dMMR/MSI-H colorectal tumors in the neoadjuvant and adjuvant setting.
Advanced Phytochemical-Based Nanocarrier Systems for the Treatment of Breast Cancer
Authors: Chavda Vivek P. , Nalla Lakshmi Vineela , Balar Pankti , Bezbaruah Rajashri , Apostolopoulos Vasso , Singla Rajeev K. , Khadela Avinash , Vora Lalitkumar , Uversky Vladimir N.
Published: February 2023

As the world’s most prevalent cancer, breast cancer imposes a significant societal health burden and is among the leading causes of cancer death in women worldwide. Despite the notable improvements in survival in countries with early detection programs, combined with different modes of treatment to eradicate invasive disease, the current chemotherapy regimen faces significant challenges associated with chemotherapy-induced side effects and the development of drug resistance. Therefore, serious concerns regarding current chemotherapeutics are pressuring researchers to develop alternative therapeutics with better efficacy and safety. Due to their extremely biocompatible nature and efficient destruction of cancer cells via numerous mechanisms, phytochemicals have emerged as one of the attractive alternative therapies for chemotherapeutics to treat breast cancer. Additionally, phytofabricated nanocarriers, whether used alone or in conjunction with other loaded phytotherapeutics or chemotherapeutics, showed promising results in treating breast cancer. In the current review, we emphasize the anticancer activity of phytochemical-instigated nanocarriers and phytochemical-loaded nanocarriers against breast cancer both in vitro and in vivo. Since diverse mechanisms are implicated in the anticancer activity of phytochemicals, a strong emphasis is placed on the anticancer pathways underlying their action. Furthermore, we discuss the selective targeted delivery of phytofabricated nanocarriers to cancer cells and consider research gaps, recent developments, and the druggability of phytoceuticals. Combining phytochemical and chemotherapeutic agents with nanotechnology might have far-reaching impacts in the future.
Assessment of Response to Neoadjuvant Systemic Treatment in Triple-Negative Breast Cancer Using Functional Tumor Volumes from Longitudinal Dynamic Contrast-Enhanced MRI
Authors: Panthi Bikash , Adrada Beatriz E. , Candelaria Rosalind P. , Guirguis Mary S. , Yam Clinton , Boge Medine , Chen Huiqin , Hunt Kelly K. , Huo Lei , Hwang Ken-Pin , Korkut Anil , Lane Deanna L. , Le-Petross Huong C. , Leung Jessica W. T. , Litton Jennifer K. , Mohamed Rania M. , Musall Benjamin C. , Pashapoor Sanaz , Patel Miral M. , Perez Frances , Son Jong Bum , Thompson Alastair , Valero Vicente , Wei Peng , White Jason , Xu Zhan , Pinsky Lawrence , Tripathy Debu , Yang Wei , Ma Jingfei , Rauch Gaiane M.
Published: February 2023

Early assessment of neoadjuvant systemic therapy (NAST) response for triple-negative breast cancer (TNBC) is critical for patient care in order to avoid the unnecessary toxicity of an ineffective treatment. We assessed functional tumor volumes (FTVs) from dynamic contrast-enhanced (DCE) MRI after 2 cycles (C2) and 4 cycles (C4) of NAST as predictors of response in TNBC. A group of 100 patients with stage I-III TNBC who underwent DCE MRI at baseline, C2, and C4 were included in this study. Tumors were segmented on DCE images of 1 min and 2.5 min post-injection. FTVs were measured using the optimized percentage enhancement (PE) and signal enhancement ratio (SER) thresholds. The Mann–Whitney test was used to compare the performance of the FTVs at C2 and C4. Of the 100 patients, 49 (49%) had a pathologic complete response (pCR) and 51 (51%) had a non-pCR. The maximum area under the receiving operating characteristic curve (AUC) for predicting the treatment response was 0.84 (p < 0.001) for FTV at C4 followed by FTV at C2 (AUC = 0.82, p < 0.001). The FTV measured at baseline was not able to discriminate pCR from non-pCR. FTVs measured on DCE MRI at C2, as well as at C4, of NAST can potentially predict pCR and non-pCR in TNBC patients.
Chloride Intracellular Channel Protein 1 Expression and Angiogenic Profile of Liver Metastasis of Digestive Origin
Authors: Ceausu Amalia Raluca , Ciolofan Alexandru , Blidisel Alexandru , Cosma Andrei Alexandru , Gaje Pusa Nela , Cretu Octavian
Published: February 2023

Chloride intracellular channel 1 (CLIC1) is involved in cell migration and metastasis. The histological growth patterns of liver metastasis are as follows: desmoplastic (d-HGP), replacement (r-HGP), pushing (p-HGP), and mixed. The aim of this study was to evaluate the relation between HGP, angiogenesis, and CLIC1 expression. Materials and Methods: A total of 40 cases of primary tumors and their LM: d-HGP (12 cases), r-HGP (13 cases), and p-HGP (15 cases), were evaluated through simple and double immunostaining. CLIC1 assessment was conducted as follows: scores of 0 (less than 10% of positive cells), 1 (10–30%), 2 (30–50%), or 3 (more than 50%) were assigned. Heterogeneous CLIC1 expression was found. CLIC1 in primary tumors correlated with grade G for all cases of LM with a p-HGP (p = 0.004). The CLIC1 score for LMs with an r-HGP correlated with grade G of the corresponding primary tumor (p = 0.027). CLIC1 and CD34+/Ki67+ vessels (p = 0.006) correlated in primary tumors. CLIC1 in primary tumors correlated with CD34+/Ki67+ vessels of LMs with a d HGP (p = 0.024). Conclusions: The CLIC1 score may have prognostic value, mainly for LMs with a p-HGP and r-HGP, and therapeutic value for LMs with a d-HGP.
A Review on Ceramic Matrix Composites and Environmental Barrier Coatings for Aero-Engine: Material Development and Failure Analysis
Authors: Fang Guangwu , Gao Xiguang , Song Yingdong
Published: February 2023

Ceramic matrix composites with environmental barrier coatings (CMC/EBCs) are the most promising material solution for hot section components of aero-engines. It is necessary to access relevant information and knowledge of the physical properties of various CMC and EBCs, the characteristics of defects and damages, and relevant failure mechanisms. Then, effective failure prediction models can be established. Individually assessing the failure of CMC and EBCs is not a simple task. Models considering the synergetic effect of coating properties and substrate fibrous architecture are more reasonable and more challenging. This paper offers a review and a detailed description of the materials features, failure mechanism, and failure modeling for both CMC substrate and EBC coatings. The various methods for failure analyses and their pros and cons are discussed. General remarks on technical development for failure modeling are summarized subsequently.
Antimicrobial Activity and Transparency of Polyvinyl Butyral Paint Containing Heated Scallop-Shell Powder
Authors: Akasaka Ryunosuke , Osawa Ayako , Wada Risei , Sawai Jun , Nakagawa Yoshitaka
Published: February 2023

The main component of seashells is calcium carbonate (CaCO3). When seashells are calcined at high temperatures, CaCO3 becomes calcium oxide (CaO), and this CaO exhibits antimicrobial activity. In this study, we attempted to develop a transparent coating that retains antimicrobial activity for a long time by mixing polyvinyl butyral (PVB), which has excellent adhesive and binding properties, with heated shell powder (HSP). The scallop HSPs used in this study were nanoparticles with a particle diameter of approximately several hundred nm, and the prepared paint showed high transparency. Elemental analysis showed that scallop HSP particles existed in the paint as Ca(OH)2. The antimicrobial activity of the surface applied with scallop HSP-containing PVB (HSSP-PVB) paint was then evaluated using JIS Z 2801 and ISO 21702: 2019. The HSSP-PVB paint-applied surfaces showed high antibacterial and antiviral activity. The antimicrobial activity of the scallop HSP-PVB paint-applied surface was attributed to the creation of a strongly alkaline environment due to surface hydration, and the strongly alkaline environment was maintained for a long period of time. It was suggested that the PVB covered the surface of the scalloped HSP particles, which significantly prevented the HSP from contacting CO2 and H2O molecules in the air.
Atmospheric-Pressure Plasma Jet-Induced Graft Polymerization of Composite Hydrogel on 3D-Printed Polymer Surfaces for Biomedical Application
Authors: Liao Shu-Chuan , Wu Yu-De , Siao Jhong-Kun
Published: February 2023

Poly(lactic acid) (PLA) is currently the most widely used material in 3D printing. PLA has good mechanical properties, chemical stability, and biodegradability, but its surface is hydrophobic and cannot be effectively used. The growth metabolism of attachments, how to increase the strength of PLA with high brittleness, and 3D printing of PLA materials for the biomedical field have always been a topic of research by scientists. This experiment used fused filament fabrication (FFF) to prepare structures. First, the 3D-printed polymer surfaces were treated with an atmospheric-pressure plasma jet (APPJ) to make the surface hydrophilic and increase the number of polar functional groups on the surface. Then, UV photo-grafting polymerization of 2-hydroxyethyl methacrylate (HEMA), poly(ethylene glycol) methacrylate (PEGMA), and hydroxyapatite (HAp) was applied onto the 3D-printed polymer surfaces. The experimental results of the water contact angle for the wettability test show that APPJ-treated and UV-grafted composite hydrogels become hydrophilic to activate the 3D-printed polymer surface successfully. For the in vitro study, the effect of APPJ treatment and composite hydrogel on the viability of osteoblast-like MG63 cells was examined using the Alamar Blue cell viability assay, indicating that biocompatibility has been improved in this study. This method is expected to have potential in the application of bone scaffolds in the future.