bluuebunny/crossref_metadata_2025 huggingface dataset:
Microglia in Alzheimer’s Disease: A Target for Therapeutic Intervention
Authors: Zhang Guimei , Wang Zicheng , Hu Huiling , Zhao Meng , Sun Li
Published: November 2021

Alzheimer’s disease (AD) is one of the most common types of age-related dementia worldwide. In addition to extracellular amyloid plaques and intracellular neurofibrillary tangles, dysregulated microglia also play deleterious roles in the AD pathogenesis. Numerous studies have demonstrated that unbridled microglial activity induces a chronic neuroinflammatory environment, promotes β-amyloid accumulation and tau pathology, and impairs microglia-associated mitophagy. Thus, targeting microglia may pave the way for new therapeutic interventions. This review provides a thorough overview of the pathophysiological role of the microglia in AD and illustrates the potential avenues for microglia-targeted therapies, including microglial modification, immunoreceptors, and anti-inflammatory drugs.
Epidemiologic Features, Survival, and Prognostic Factors Among Patients With Different Histologic Variants of Glioblastoma: Analysis of a Nationwide Database
Authors: Shieh Li-Tsun , Ho Chung-Han , Guo How-Ran , Huang Chien-Cheng , Ho Yi-Chia , Ho Sheng-Yow
Published: November 2021

Background: Glioblastoma (GBM) is the most common primary intracranial malignancy. Previous studies found incidence of GBM varies substantially by age, sex, race and ethnicity, and survival also varies by country, ethnicity, and treatment. Gliosarcoma (GSM) and giant cell glioblastoma (GC-GBM) are different histologic variants of GBM with distinct clinico-pathologic entities. We conducted a study to compare epidemiology, survival, and prognostic factors among the three.

Methods: We identified GBM patients diagnosed between 2000 and 2016 using the Taiwan Cancer Registry and followed them using the death registry. Survival was compared among conventional GBM and two histologic variants. The potential confounding factors evaluated in this study included registered year, age, sex, and treatment modality (resection, radiotherapy, and chemotherapy).

Results: We enrolled 3,895 patients, including 3,732 (95.8%) with conventional GBM, 102 (2.6%) with GSM, and 61 (1.6%) with GC-GBM. GC-GBM patients had younger mean age at diagnosis (49.5 years) than conventional GBM patients (58.7 years) and GSM patients (61.3 years) (p < 0.01). The three groups had similar sex distributions (p = 0.29). GC-GBM had a longer median survival [18.5, 95% confidence interval (CI): 15.8–25.3 months] than conventional GBM (12.5, 95%CI: 12.0–13.0 months) and GSM (12.8, 95%CI: 9.2–16.2 months), and the differences in overall survival did not attain statistical significance (p = 0.08, log-rank test). In univariate analysis, GC-GBM had better survival than conventional GBM, but the hazard ratio (0.91) did not reach statistical significance (95%CI: 0.69–1.20) in the multivariate analysis. Young ages (≤ 40 years), female sex, resection, radiotherapy, and chemotherapy were factors associated with better survival in overall GBMs. In subtype analyses, these factors remained statistically significant for conventional GBM, as well as radiotherapy for GSM.

Conclusion: Our analysis found conventional GBM and its variants shared similar poor survival. Factors with age ≤ 40 years, female sex, resection, radiotherapy, and chemotherapy were associated with better prognosis in conventional GBM patients.
Trauma Immediately Preceding REM-Behavior Disorder: A Valuable Prognostic Marker?
Authors: Williams Stevie R. , Henzler Nelly , Peřinová Pavla , Morrison Ian A. , Ellis Jason G. , Riha Renata L.
Published: November 2021

Background: The definition of rapid eye movement (REM) sleep behavior disorder (RBD) has varied over the years. Rapid eye movement sleep behavior disorder can be considered isolated or idiopathic or can occur in the context of other disorders, including trauma-associated sleep disorder (TSD) and overlap parasomnia. However, whether trauma in RBD carries any prognostic specificity is currently unknown.

Study Objectives: To test the hypothesis that RBD secondary to trauma is less likely to result in the development of neurodegeneration compared to idiopathic RBD (iRBD) without trauma in the general population.

Methods: A retrospective cohort study of 122 consecutive RBD patients (103 males) at two tertiary sleep clinics in Europe between 2005 and 2020 was studied. Patients were diagnosed as having iRBD by video polysomnography (vPSG) and had a semi-structured interview at presentation, including specifically eliciting any history of trauma. Patients with secondary RBD to recognized causes were excluded from the study. Patients with iRBD were categorized into three groups according to reported trauma history: (1) No history of trauma, (2) traumatic experience at least 12 months prior to RBD symptom onset, and (3) traumatic experience within 12 months of RBD symptom onset. Idiopathic RBD duration was defined as the interval between estimated onset of RBD symptoms and last hospital visit or death. Follow-up duration was defined as the interval between iRBD diagnosis and last hospital visit or death.

Results: In a follow-up period of up to 18 years, no patient who experienced trauma within 12 months preceding their iRBD diagnosis received a diagnosis of a neurodegenerative disorder (n = 35), whereas 38% of patients without trauma within the 12 months of symptom onset developed a neurodegenerative illness. These patients were also significantly more likely to have a family history of α-synucleinopathy or tauopathy.

Conclusions: The development of RBD within 12 months of experiencing a traumatic life event, indistinguishable clinically from iRBD, did not lead to phenoconversion to a neurodegenerative disorder even after 18 years (mean follow up 6 years). We suggest that a sub-type of RBD be established and classified as secondary RBD due to trauma. Additionally, we advocate that a thorough psychological and trauma history be undertaken in all patients presenting with dream enactment behaviors (DEB).
Autonomic Modulation in Duchenne Muscular Dystrophy During a Computer Task: A Prospective Transversal Controlled Trial Assessment by Non-linear Techniques
Authors: Alvarez Mayra Priscila Boscolo , Monteiro Carlos Bandeira de Mello , Silva Talita Dias da , Valenti Vitor E. , Ferreira-Filho Celso , Sterr Annette , Vanderlei Luiz Carlos Marques , Ferreira Celso , Garner David M.
Published: November 2021

Introduction: Due to functional and autonomic difficulties faced by individuals with Duchenne Muscular Dystrophy (DMD), the use of assistive technology is critical to provide or facilitate functional abilities. The key objective was to investigate acute cardiac autonomic responses, by application of Heart Rate Variability (HRV), during computer tasks in subjects with DMD via techniques based on non-linear dynamics.

Method: HRV was attained via a Polar RS800CX. Then, was evaluated by Chaotic Global Techniques (CGT). Forty-five male subjects were included in the DMD group and age-matched with 45 in the healthy Typical Development (TD) control group. They were assessed for 20 min at rest sitting, and then 5 min whilst performing the maze task on a computer.

Results: Both TD and DMD subjects exhibited a significantly reduced HRV measured by chaotic global combinations when undertaking the computer maze paradigm tests. DMD subjects presented decreased HRV during rest and computer task than TD subjects.

Conclusion: While there is an impaired HRV in subjects with DMD, there remains an adaptation of the ANS during the computer tasks. The identification of autonomic impairment is critical, considering that the computer tasks in the DMD community may elevate their level of social inclusion, participation and independence.
Translation, Cultural Adaptation, and Reliability and Validity Testing of a Chinese Version of the Freezing of Gait Questionnaire (FOGQ-CH)
Authors: Tao Ping , Shao Xuerong , Zhuang Jie , Wang Zhen , Dong Yuchen , Shen Xia , Guo Yunjie , Shu Xiaoyi , Wang Hong , Xu Yuanhong , Li Zhenlan , Adams Roger , Han Jia
Published: November 2021

Freezing of gait is a disabling symptom with a complex episodic nature that is frequently experienced by people with Parkinson's disease (PD). Although China has the largest population with PD in the world, no Chinese version of the freezing of gait questionnaire (FOGQ), the instrument that has been most widely used to assess FOG, has yet been developed. This study aimed to translate and adapt the original version of FOGQ to create a Chinese version, the FOGQ-CH, then assess its reliability, calculate the Minimal Detectable Change (MDC) and investigate its validity. The forward-backwards translation model was adopted, and cultural adaptation included expert review and pretesting. For the reliability study, 31 Chinese native speaking patients with PD were assessed two times in a 7–10 days interval. Internal consistency and test-retest reliability of the FOGQ-CH were measured by Cronbach's alpha (Cα) and the Intraclass Correlation Coefficient (ICC). For the validity study, 34 native speakers of Chinese with PD were included. To explore the convergent validity, relationships between the FOGQ-CH and the Unified Parkinson's Disease Rating Scale Part II (UPDRS II) and Part III (UPDRS III), Timed Up and Go Test (TUGT), Timed Up and Go Test in cognitive task (TUGT-Cog), walking speed (10 MWT speed), and step length (10 MWT step length) in a 10-m Walk Test were tested. To explore predictive validity, the number of falls followed up for 6 months were assessed. The area under the ROC curve (AUC) was employed to test the capacity of FOGQ-CH to discriminate those with falls. From the reliability study, Cα = 0.823, ICC = 0.786. The MDC0.90 = 4.538. From the validity study, the FOGQ-CH showed moderate correlations with UPDRS II (rho = 0.560, p = 0.001), UPDRS III (rho = 0.451, p = 0.007), TUGT (rho = 0.556, p = 0.007), TUGT-Cog (rho = 0.557, p = 0.001), 10MWT-speed (rho = −0.478, p = 0.004), 10MWT-step length (rho = −0.419, p = 0.014), and the number of falls followed up for 6 months (rho = 0.356, p = 0.045). The AUC = 0.777 (p = 0.036) for predicting whether the participants will have multiple falls (two or more) in the following 6 months. The FOGQ-CH showed good reliability and validity for assessing Chinese native speaking patients with PD. In addition, the FOGQ-CH showed good efficacy for predicting multiple falls in the following 6 months.
Best Practices in the Development, Translation, and Cultural Adaptation of Patient-Reported Outcome Measures for Adults With Hearing Impairment: Lessons From the Cochlear Implant Quality of Life Instruments
Authors: Laplante-Lévesque Ariane , Dubno Judy R. , Mosnier Isabelle , Ferrary Evelyne , McRackan Theodore R.
Published: November 2021

This manuscript summarizes available evidence-based best practices in the development, translation, and cultural adaptation of one type of outcome measure for adults with hearing impairment, patient-reported outcome measures (PROMs). It presents the development of the Cochlear Implant Quality of Life (CIQOL) instruments and the ongoing translation and cultural adaptation of the CIQOL-35 Profile from English to French as case studies and discusses useful lessons for selecting, developing, translating, culturally adapting, and using PROMs. Relevant best practice guides are introduced, described and their steps are illustrated with examples. Future trends in hearing-related PROMs, including computerized adaptive testing, patient-reported experience measures (PREMs), economic evaluation and allocation of scarce resources, and PROMs in low-resource settings, are discussed. The manuscript concludes on the lessons that can be learned from implementation science for the successful and sustainable integration of PROMs in clinical practice.
Risk Assessment by a Passenger of an Autonomous Vehicle Among Pedestrians: Relationship Between Subjective and Physiological Measures
Authors: Petit Jeffery , Charron Camilo , Mars Franck
Published: November 2021

Autonomous navigation becomes complex when it is performed in an environment that lacks road signs and includes a variety of users, including vulnerable pedestrians. This article deals with the perception of collision risk from the viewpoint of a passenger sitting in the driver's seat who has delegated the total control of their vehicle to an autonomous system. The proposed study is based on an experiment that used a fixed-base driving simulator. The study was conducted using a group of 20 volunteer participants. Scenarios were developed to simulate avoidance manoeuvres that involved pedestrians walking at 4.5 kph and an autonomous vehicle that was otherwise driving in a straight line at 30 kph. The main objective was to compare two systems of risk perception: These included subjective risk assessments obtained with an analogue handset provided to the participants and electrodermal activity (EDA) that was measured using skin conductance sensors. The relationship between these two types of measures, which possibly relates to the two systems of risk perception, is not unequivocally described in the literature. This experiment addresses this relationship by manipulating two factors: The time-to-collision (TTC) at the initiation of a pedestrian avoidance manoeuvre and the lateral offset left between a vehicle and a pedestrian. These manipulations of vehicle dynamics made it possible to simulate different safety margins regarding pedestrians during avoidance manoeuvres. The conditional dependencies between the two systems and the manipulated factors were studied using hybrid Bayesian networks. This relationship was inferred by selecting the best Bayesian network structure based on the Bayesian information criterion. The results demonstrate that the reduction of safety margins increases risk perception according to both types of indicators. However, the increase in subjective risk is more pronounced than the physiological response. While the indicators cannot be considered redundant, data modeling suggests that the two risk perception systems are not independent.
Assessment of Functional and Pasting Properties of Fresh Orange Maize Hybrids and Open-Pollinated Varieties as Influenced by Genotype, Harvesting Time, and Growing Location
Authors: Alamu Emmanuel Oladeji , Maziya-Dixon Busie , Menkir Abebe , Adesokan Michael , Olaofe Olorunfemi
Published: November 2021

The study evaluates the effects of genotype, maturity, and growing location on the functional and pasting properties of freshly harvested orange maize hybrids and open-pollinated varieties (OPVs). Eight fresh orange maize hybrid and eight fresh maize OPV, including the control, were harvested at three stages: 20, 27, and 34 days after planting (DAP). The freshly harvested maize samples were lyophilized and characterized for the pasting and functional properties using standard laboratory methods. The peak viscosity, final viscosity, and swelling power of the OPVs increased between 20 and 27 DAP. Additionally, the water absorption capacity increased between 20 and 27 DAP for the maize hybrids, with a decreasing trend between 27 and 34 DAP. However, genotypes 2, from the orange maize hybrid, and 5, amongst the OPV, were outstanding with the highest peak viscosities, indicating good final product quality. The combined ANOVA for the fresh orange maize hybrid and OPV showed a highly significant effect (p ≤ 0.01 and p ≤ 0.001) for the maturity and location on the pasting and functional properties except for the pasting temperature, final viscosity, and pasting time which showed no significant effect. In contrast, the location by genotypes by maturity interactions had no significant effects on the pasting and functional properties of the fresh maize hybrid and the orange OPV except only for the setback, which was highly significant at p ≤ 0.001. Nutritionists, food scientists, and maize breeders could use the information from this study to select the best maize genotypes at the appropriate harvesting period suitable for the production of the preferred maize-based products of consumers.
Formation of Shelf-Stable Pickering High Internal Phase Emulsion Stabilized by Sipunculus nudus Water-Soluble Proteins (WSPs)
Authors: Cao Yupo , Dai Yaping , Lu Xuli , Li Ruyi , Zhou Wei , Li Jihua , Zheng Baodong
Published: November 2021

To form a stable emulsion system, the water-soluble proteins (WSPs) of Sipunculus nudus were prepared as the sole effective stabilizer for the high internal phase emulsion (HIPEs), of which the influence of the WSPs concentration and environmental stability was investigated. The HIPEs were fabricated using a simple one-pot homogenization process (10,000 rpm/min, 3 min) that involved blending the WSPs (0.1, 1, 2, 3, 4, and 5 wt%) with soybean oil (60, 65, 70, 75, 80, 85, and 90%). The microstructure and properties of stable HIPEs were characterized by particle size, ζ-potential, visual observations, optical microscopy, and dynamic rheology property measurements. As the concentration of WSPs increases, the mean particle diameter of HIPEs decreases, on the contrary, the apparent viscosity and storage modulus gradually increase. At a given emulsifier concentration (3 wt%), the stable and gel-like HIPEs were formed at the oil internal phase (ϕ) values of 70–75%, all the pH range in values from 3 to 9, and the ionic strength from 100 to 500 mM. Furthermore, the HIPEs that were stabilized formed a gel-like state that was relatively stable to heat and storage (30 days). And there was a new phenomenon that the destabilized HIPE of the freeze-thaw treatments could still return to a gel-like state again after homogenizing. The study results suggest that the WSPs of S. nudus as a natural emulsifier could be widely used in the food industry.
Neuroprotection by the Ketogenic Diet: Evidence and Controversies
Authors: Gough Sarah M. , Casella Alicia , Ortega Kristen Jasmin , Hackam Abigail S.
Published: November 2021

The ketogenic diet (KD) is a high-fat low-carbohydrate diet that has been used for decades as a non-pharmacologic approach to treat metabolic disorders and refractory pediatric epilepsy. In recent years, enthusiasm for the KD has increased in the scientific community due to evidence that the diet reduces pathology and improves various outcome measures in animal models of neurodegenerative disorders, including multiple sclerosis, stroke, glaucoma, spinal cord injury, retinal degenerations, Parkinson's disease and Alzheimer's disease. Clinical trials also suggest that the KD improved quality of life in patients with multiple sclerosis and Alzheimer's disease. Furthermore, the major ketone bodies BHB and ACA have potential neuroprotective properties and are now known to have direct effects on specific inflammatory proteins, transcription factors, reactive oxygen species, mitochondria, epigenetic modifications and the composition of the gut microbiome. Neuroprotective benefits of the KD are likely due to a combination of these cellular processes and other potential mechanisms that are yet to be confirmed experimentally. This review provides a comprehensive summary of current evidence for the effectiveness of the KD in humans and preclinical models of various neurological disorders, describes molecular mechanisms that may contribute to its beneficial effects, and highlights key controversies and current gaps in knowledge.
Epiphycan Predicts Poor Outcomes and Promotes Metastasis in Ovarian Cancer
Authors: Deng Lu , Wang Dandan , Chen Shouzhen , Hu Weiguo , Zhang Ru
Published: November 2021

The small leucine-rich proteoglycan (SLRP) family is widely expressed in extracellular matrix and aggravates tumor progression. However, epiphycan (EPYC), as a member of the SLRPs family, its biological function in cancer has not been confirmed. Thus, we aimed to clarify the role of EPYC in progression of ovarian cancer (OC), and further analyze the molecular mechanisms implicated in tumorigenesis. Here, we analyzed the differential expression genes of GSE38734, including 4 matched primary OC and metastatic tissues. We obtained OC RNAseqs data from the Cancer Genome Atlas (TCGA) and analyzed the correlation between EPYC expression and OC staging, pathological grading, etc. The expression of EPYC in OC and normal ovarian tissues was compared in Oncomine website. We used siRNAs to interfere the expression of EPYC in ovarian cancer cell line SKOV3. Scratch test, transwell-matrigel chamber, CCK8 assay were used to detect the changes of SKOV3 migration, invasion and proliferation ability after EPYC was interfered. We used R software to make GO and KEGG analysis of related genes of EPYC. We used the Hitpredict website to predict interacting proteins. The results showed that the expression of EPYC in metastatic ovarian cancer was higher than primary ovarian cancer, and that in primary cancer was higher than normal ovaries. After siRNA interferes with EPYC expression, the migration, invasion and proliferation of SKOV3 cells were weakened. EPYC mainly played a role in ECM organization, and involved in PI3K/Akt, focal adhesion signaling pathways. EPYC might interact with PLCG2 and CRK, and be involved in signal transduction.
A Novel Lipid Prognostic Signature of ADCY2, LIPE, and OLR1 in Head and Neck Squamous Cell Carcinoma
Authors: Gao Xiaolei , Zhao Na , Dong Liying , Zheng Xuan , Zhang Yixin , Ding Chong , Zhao Shuyan , Ma Zeyun , Wang Yixiang
Published: November 2021

Simple Summary

Clinically, aberrant lipid metabolism is responsible for overweight and/or obesity. Overweight is considered as an independent factor of cancer risk in 2019. Therefore, lipid metabolic reprogramming is an emerging hallmark of malignancy. It is an urgent need to comprehensively understand the relationship among lipid metabolism and HNSCC and identify a valuable biomarker for predicting prognosis of HNSCC patients. Three new findings were found in this study. Firstly, we identified the lipid-related differentially expressed genes (DEGs) by using the GEO microarrays and TCGA dataset. A novel lipid-related mRNA prognostic signature (LRPS, consisting of ADCY2, LIPE and OLR1) was developed, which could predict the survival and prognosis of HNSCC patients as an independent effective prognostic factor. Secondly, we found that the LRPS could indicate the type of infiltrated immune cells in HNSCC tumor microenvironment. Thirdly, we verified that the LPPS score could interpret the TP53 status of HNSCC. Our new findings indicated that LRPS has a potential to be a promising indicator of overall survival, TP53 status, and immune characteristics in HNSCC, and perhaps can monitor and guide the treatment efficacy and prognosis of HNSCC in the future.

Background

Head and neck squamous cell carcinoma (HNSCC) is characterized by a high frequency of lymph node metastasis and a high mortality. Lipid metabolic reprogramming is an emerging carcinogen as its role in fulfilling cancer growth and spread. However, little is known about the correlation between lipid metabolism and HNSCC.

Materials and Methods

Expressions of lipid-related genes were obtained from the Cancer Genome Atlas (TCGA) and Gene expression Omnibus (GEO) databases for differential and functional analyses. A total number of 498 patients from TCGA with complete information were included to identify a lipid-related prognostic signature (LRPS), based on ADCY2, LIPE, and OLR1, by using univariate and multivariate Cox regression analyses. LRPS-high and LRPS-low groups were accordingly divided to pathway and cell enrichment analyses.

Results

LRS-low patients had a better overall survival and relapse - free survival than LRS-high ones in HNSCC. The LRPS-high group was significantly related to perineural invasion of cancer, cancer-related pathways, high TP53 mutation rate, high proportion of natural killer T cells (NKT), dendritic cells, monocytes, Treg, and M1 and M2 macrophage infiltration in HNSCC tumor tissues. Conversely, the LRPS-low group correlated with DNA damage-related and T-cell-regulated pathways, low frequency of mutated TP53, and high infiltration of B cells and CD4+ effector cells including Th1 and Th2.

Conclusion

LRPS has a potential to be a promising indicator of overall survival, prognosis, TP53 status, and immune characteristics in HNSCC.
Combination of Auranofin and ICG-001 Suppress the Proliferation and Metastasis of Colon Cancer
Authors: Lin Zhaoyan , Li Qingqing , Zhao Ying , Lin Zixiang , Cheng Nan , Zhang Di , Liu Gang , Lin Jiahao , Zhang Hong , Lin Degui
Published: November 2021

Colon cancer is one of the deadliest tumors in the world, and with high metastasis rate and mortality, effective drugs for its treatment are still in need. Auranofin (AF) is a gold complex that has been attested by FDA for treating human rheumatism, and researchers have found that AF acts as a great antitumor drug in recent years. ICG-001 is a small molecule inhibitor of Wnt/β-catenin pathway. In the present study, we aimed to explore the synergistic antitumor effects and the underlying mechanisms of AF and ICG-001 combination therapy on human colon cancer. The results showed that AF and ICG-001 synergistically depressed the growth and invasion of human colon cancer cells by inhibiting the phosphorylation of Signal Transducer and Activator of Transcription 3 (STAT3) and its downstream mediator B-cell lymphoma-2-like 1 (Bcl-xL) and inducing caspase-3-dependent apoptosis. Moreover, AF combined with ICG-001 synergistically inhibited the growth of colon cancer in subcutaneous xenograft mice models and restrained metastasis in lung metastasis mice models. In conclusion, our results demonstrated that combination of AF and ICG-001 suppressed the proliferation and metastasis of colon cancer by inhibiting STAT3 phosphorylation. Therefore, this combination therapy may possess potential therapeutic properties for human colon cancer.
Lenvatinib Plus PD-1 Inhibitors as First-Line Treatment in Patients With Unresectable Biliary Tract Cancer: A Single-Arm, Open-Label, Phase II Study
Authors: Zhang Qiyi , Liu Xingyu , Wei Shumei , Zhang Lufei , Tian Yang , Gao Zhenzhen , Jin Ming , Yan Sheng
Published: November 2021

Objective

We investigated lenvatinib plus programmed cell death-1 (PD-1) inhibitors as a first-line treatment for initially unresectable biliary tract cancer (BTC).

Methods

In this Phase II study, adults with initially unresectable BTC received lenvatinib (body weight ≥60 kg, 12 mg; <60 kg, 8 mg) daily and PD-1 inhibitors (pembrolizumab/tislelizumab/sintilimab/camrelizumab 200 mg or toripalimab 240 mg) every 3 weeks. Primary endpoints were objective response rate (ORR) and safety. Secondary endpoints included surgical conversion rate, disease control rate (DCR), event-free survival (EFS), overall survival (OS) and tumor biomarkers.

Results

Among 38 enrolled patients, the ORR was 42.1% and the DCR was 76.3%. Thirteen (34.2%) patients achieved downstaging and underwent surgery, six of whom (46.2%) achieved a major pathologic response (n=2) or partial pathologic response (n=4) in the primary tumor. In total, 84.2% of patients experienced ≥1 treatment-related adverse event (TRAE), 34.2% experienced a Grade ≥3 TRAE and no treatment-related deaths occurred. After a median follow-up of 13.7 months the median EFS was 8.0 months (95% CI: 4.6–11.4) and the median OS was 17.7 months (95% CI: not estimable).

Conclusions

Lenvatinib plus PD-1 inhibitors showed promising anti-tumor efficacy in patients with initially unresectable BTC and was generally well tolerated.

Clinical Trial Registration

www.chictr.org.cn, ChiCTR2100044476.
Variation in Plasma Levels of TRAF2 Protein During Development of Squamous Cell Carcinoma of the Oral Tongue
Authors: Gu Xiaolian , Coates Philip , Wang Lixiao , Erdogan Baris , Salehi Amir , Sgaramella Nicola , Zborayova Katarina , Nylander Karin
Published: November 2021

As early detection is crucial for improvement of cancer prognosis, we searched for biomarkers in plasma from individuals who later developed squamous cell carcinoma of the oral tongue (SCCOT) as well as in patients with an already established SCCOT. Levels of 261 proteins related to inflammation and/or tumor processes were measured using the proximity extension assay (PEA) in 179 plasma samples (42 collected before diagnosis of SCCOT with 81 matched controls; 28 collected at diagnosis of SCCOT with 28 matched controls). Statistical modeling tools principal component analysis (PCA) and orthogonal partial least square - discriminant analysis (OPLS-DA) were applied to provide insights into separations between groups. PCA models failed to achieve group separation of SCCOT patients from controls based on protein levels in samples taken prior to diagnosis or at the time of diagnosis. For pre-diagnostic samples and their controls, no significant OPLS-DA model was identified. Potentials for separating pre-diagnostic samples collected up to five years before diagnosis (n = 15) from matched controls (n = 28) were seen in four proteins. For diagnostic samples and controls, the OPLS-DA model indicated that 21 proteins were important for group separation. TNF receptor associated factor 2 (TRAF2), decreased in pre-diagnostic plasma (< 5 years) but increased at diagnosis, was the only protein showing altered levels before and at diagnosis of SCCOT (p-value < 0.05). Taken together, changes in plasma protein profiles at diagnosis were evident, but not reliably detectable in pre-diagnostic samples taken before clinical signs of tumor development. Variation in protein levels during cancer development poses a challenge for the identification of biomarkers that could predict SCCOT development.
Defining the Spectrum, Treatment and Outcome of Patients With Genetically Confirmed Gorlin Syndrome From the HIT-MED Cohort
Authors: Kloth Katja , Obrecht Denise , Sturm Dominik , Pietsch Torsten , Warmuth-Metz Monika , Bison Brigitte , Mynarek Martin , Rutkowski Stefan
Published: November 2021

Gorlin syndrome is a genetic condition associated with the occurrence of SHH activated medulloblastoma, basal cell carcinoma, macrocephaly and other congenital anomalies. It is caused by heterozygous pathogenic variants in PTCH1 or SUFU. In this study we included 16 patients from the HIT2000, HIT2000interim, I-HIT-MED, observation registry and older registries such as HIT-SKK87, HIT-SKK92 (1987 – 2020) with genetically confirmed Gorlin syndrome, harboring 10 PTCH1 and 6 SUFU mutations. Nine patients presented with desmoplastic medulloblastomas (DMB), 6 with medulloblastomas with extensive nodularity (MBEN) and one patient with classic medulloblastoma (CMB); all tumors affected the cerebellum, vermis or the fourth ventricle. SHH activation was present in all investigated tumors (14/16); DNA methylation analysis (when available) classified 3 tumors as iSHH-I and 4 tumors as iSHH-II. Age at diagnosis ranged from 0.65 to 3.41 years. All but one patient received chemotherapy according to the HIT-SKK protocol. Ten patients were in complete remission after completion of primary therapy; four subsequently presented with PD. No patient received radiotherapy during initial treatment. Five patients acquired additional neoplasms, namely basal cell carcinomas, odontogenic tumors, ovarian fibromas and meningioma. Developmental delay was documented in 5/16 patients. Overall survival (OS) and progression-free survival (PFS) between patients with PTCH1 or SUFU mutations did not differ statistically (10y-OS 90% vs. 100%, p=0.414; 5y-PFS 88.9% ± 10.5% vs. 41.7% ± 22.2%, p=0.139). Comparing the Gorlin patients to all young, SHH activated MBs in the registries (10y-OS 93.3% ± 6.4% vs. 92.5% ± 3.3%, p=0.738; 10y-PFS 64.9%+-16.7% vs. 83.8%+-4.5%, p=0.228) as well as comparing Gorlin M0 SKK-treated patients to all young, SHH activated, M0, SKK-treated MBs in the HIT-MED database did not reveal significantly different clinical outcomes (10y-OS 88.9% ± 10.5% vs. 88% ± 4%, p=0.812; 5y-PFS 87.5% ± 11.7% vs. 77.7% ± 5.1%, p=0.746). Gorlin syndrome should be considered in young children with SHH activated medulloblastoma, especially DMB and MBEN but cannot be ruled out for CMB. Survival did not differ to patients with SHH-activated medulloblastoma with unknown germline status or between PTCH1 and SUFU mutated patients. Additional neoplasms, especially basal cell carcinomas, need to be expected and screened for. Genetic counselling should be provided for families with young medulloblastoma patients with SHH activation.
Nonsteroidal Anti-Inflammatory Drugs Reduce Second Cancer Risk in Patients With Breast Cancer: A Nationwide Population-Based Propensity Score-Matched Cohort Study in Taiwan
Authors: Lu Yin-Che , Chen Pin-Tzu , Lin Mei-Chen , Lin Che-Chen , Wang Shi-Heng , Pan Yi-Jiun
Published: November 2021

Nonsteroidal anti-inflammatory drugs (NSAIDs) reduce mortality in patients with cancer, especially breast cancer, but their influence on second cancer risk is uncertain. This study aimed to examine whether NSAID use is associated with second cancer risk in patients with breast cancer. This population-based propensity score-matched cohort study using Taiwan’s National Health Insurance Research Database enrolled patients with newly diagnosed breast cancer (n = 7356) with and without (n = 1839) NSAID therapy from 2000 to 2009. They were followed up until the diagnosis of second cancer, death, or end of 2011. Cox proportional hazard models were used to estimate adjusted hazard ratios (aHR). The NSAID cohort had a lower incidence rate of second cancer than the non-NSAID cohort (5.57 vs. 9.19 per 1,000 person-years), with an aHR of 0.63 (95% confidence interval (CI) 0.46–0.87). When compared with the non-NSAID cohort, the second cancer incidence was lower in patients taking non-cyclooxygenase 2 inhibitors (aHR 0.67, 95% CI 0.47–0.94) and in those receiving multiple NSAIDs during follow-up (aHR 0.55, 95% CI 0.37–0.84). A dose–response relationship existed in NSAID cumulative days. The findings demonstrate that NSAID use reduces second cancer risk in a dose-dependent manner in patients with primary breast cancer.
Bothersome Hematospermia Following Stereotactic Body Radiation Therapy for Prostate Cancer
Authors: Shah Sarthak , Sholklapper Tamir , Creswell Michael , Pepin Abigail , Cantalino Jonathan , Hankins Ryan Andrew , Suy Simeng , Collins Sean P.
Published: November 2021

Background

Hematospermia following prostate radiation therapy is a benign and often self-limiting side effect. However, it may be bothersome to some men and their partners with a negative impact on sexual quality of life (QOL). This study sought to evaluate the incidence, duration, and resolution of hematospermia in patients following stereotactic body radiation therapy (SBRT) for prostate cancer.

Methods

227 patients treated with SBRT from 2013 to 2019 at Georgetown University Hospital for localized prostate carcinoma with a minimum follow up of two years were included in this retrospective review of data that was prospectively collected. Patients who were greater than 70 years old and/or received hormonal therapy were excluded. Hematospermia was defined as bright red blood in the ejaculate. Time points for data collection included initial consultation, pre-treatment, 1-, 3-, 6-, 9-, 12-, 18-, 24-month. All patients were treated with the CyberKnife Radiosurgical System (Accuray). Data on hematospermia including duration, resolution and recurrence was collected. Utilization of 5-alpha reductase inhibitors was documented at each visit.

Results

227 patients (45 low-, 177 intermediate-, and 5 high-risk according to the D’Amico classification) at a median age of 65 years (range 47-70) received SBRT for their localized prostate cancer. The 2-year cumulative incidence of hematospermia was 5.6%(14 patients). For these patients, all but one patient (93%) saw resolution of their hematospermia by two years post-SBRT. The median time for hematospermia was 9 months post-treatment. Of the 14 patients who reported hematospermia, 70% were managed with 5-alpha reductase inhibitors. Hematospermia was transient in most patients with 70% of the men reporting resolution by the next follow-up visit.

Conclusion

The incidence of bothersome hematospermia following SBRT was low. Hematospermia, as noted by other studies, often self-resolves. 5-alpha reductase inhibitors may lead to quicker resolution of bothersome hematospermia.
68Ga-P15-041, A Novel Bone Imaging Agent for Diagnosis of Bone Metastases
Authors: Guo Rui , Meng Xiangxi , Wang Fei , Yu Jiangyuan , Xie Qing , Zhao Wei , Zhu Lin , Kung Hank F. , Yang Zhi , Li Nan
Published: November 2021

Objectives

68Ga-P15-041 (68Ga-HBED-CC-BP) is a novel bone-seeking PET radiotracer, which can be readily prepared by using a simple kit formulation and an in-house 68Ga/68Ge generator. The aim of this study is to assess the potential human application of 68Ga-P15-041 for clinical PET/CT imaging and to compare its efficacy to detect bone metastases of different cancers with 99mTc-MDP whole-body bone scintigraphy (WBBS).

Methods

Initial kinetic study using Patlak analysis and parametric maps were performed in five histopathologically proven cancer patients (three males, two females) using 68Ga-P15-041 PET/CT scan only. Another group of 51 histopathologically proven cancer patients (22 males, 29 females) underwent both 99mTc-MDP WBBS and 68Ga-P15-041 PET/CT scans within a week, sequentially. Using either pathology examination or follow-up CT or MRI scans as the gold standard, the diagnostic efficacy and receiver operating characteristic curve (ROC) of the two methods in identifying bone metastases were compared (p <0.05, statistically significant).

Results

Fifty-one patients were imaged, and 174 bone metastatic sites were identified. 68Ga-P15-041 PET/CT and 99mTc-MDP WBBS detected 162 and 81 metastases, respectively. Sensitivity, specificity, positive predictive value, negative predictive value and accuracy of 68Ga-P15-041 PET/CT and 99mTc-MDP WBBS were 93.1% vs 81.8%, 89.8% vs 90.7%, 77.5% vs 69.2%, 97.2% vs 93.4% and 90.7% vs 88.4%, respectively. Our results showed that the mean of SUVmax was significantly higher in metastases than that in benign lesions, 15.1 ± 6.9 vs. 5.6 ± 1.3 (P <0.001). Using SUVmax = 7.6 as the cut-off value by PET/CT, it was possible to predict the occurrence of metastases (AUC = 0.976; P <0.001; 95% CI: 0.946–0.999). However, it was impossible to distinguish osteoblastic bone metastases from osteolytic bone lesions. Parametric maps based on Patlak analysis provided excellent images and highly valuable quantitative information.

Conclusions

68Ga-P15-041 PET/CT, offering a rapid bone scan and high contrast images in minutes, is superior to the current method of choice in detecting bone metastases. It is reasonable to suggest that 68Ga-P15-041 PET/CT could become a valuable routine nuclear medicine procedure in providing excellent images for detecting bone metastases in cancer patients. 68Ga-P15-041 could become a valuable addition expanding the collection of 68Ga-based routine nuclear medicine procedures where 18F fluoride is not currently available.
Bibliometric Insights in Advances of Anaplastic Thyroid Cancer: Research Landscapes, Turning Points, and Global Trends
Authors: Wang Hanyu , Yu Yuxin , Wang Kang , Sun Hui
Published: November 2021

Background

Thyroid cancers are the most common endocrine malignancies with a dramatic increase in incidences. Anaplastic thyroid cancer is a rare but deadly form among thyroid cancers. To better understand of this field, we assessed the global scientific outputs and tried to depict its overview via bibliometric methods.

Methods

Approximately 1,492 science publications published between 1997 and 2020 were included by systematic retrieval in the WoS database. The general information of them was characterized, and the developmental skeleton and research frontiers were explored.

Results

The article number in this field has been increasing in the past 24 years. North America, East Asia, and Western Europe have reached remarkable achievements. Mutations of BARF and TERT and their downstream pathways have attracted researchers’ attention, where genetic diagnosis provides new clinical insight and several targeted therapeutic approaches have been on the clinical trial.

Conclusions

Numerous efforts have been made to figure out gene expression reprogramming of anaplastic thyroid cancer and key mechanism in driving its dedifferentiation, invasion and migration process. Targeted therapy, immunotherapy, and systematic combination therapy are the recent current research hotspots. These results provide insightful clues for the funding direction and the potential breakthrough direction of the anaplastic thyroid cancer study.
Platelet Membranes Coated Gold Nanocages for Tumor Targeted Drug Delivery and Amplificated Low-Dose Radiotherapy
Authors: Chen Mingzhu , Wang Ping , Jiang Dazhen , Bao Zhirong , Quan Hong
Published: November 2021

Continuous high doses of radiation can cause irreversible side effects and radiation resistance; thus, advanced radiosensitizers are urgently needed. To overcome this problem, we developed a nano platelet radiosensitization system (PCA) by coating the chemotherapeutic drug cisplatin (CDDP) loaded gold nanocages (AuNs) within the platelet membrane. The developed PCA system may enable AuNs to have immune escape and targeting capabilities. After administration, PCA will actively target tumor cells and avoid being cleared by the immune system. Subsequently, CDDP, which destroys tumor cell DNA, can not only kill tumor cells directly but also combine with AuNs, which deposit radiation energy into tumor tissues, reducing RT resistance. In vivo and in vitro studies revealed that the combination of PCA with RT (2Gy) efficiently inhibits tumor proliferation without causing side effects such as inflammation. To conclude, this is the first attempt to use platelet membranes to correctly transport AuNs while also accomplishing low-dose RT, which could help AuNs-based tumor RT become more effective.
Stress and Pain Before, During and After the First Wave of the COVID-19 Pandemic: An Exploratory Longitudinal Mixed Methods Study
Authors: Pagé M. Gabrielle , Dassieu Lise , Develay Élise , Roy Mathieu , Vachon-Presseau Étienne , Lupien Sonia , Rainville Pierre
Published: November 2021

Aims: This study explores the association between subjective feeling of stress and pain experience in the context of the COVID-19 pandemic with a focus on characteristics known to trigger a physiological stress response [sense of low control, threat to ego, unpredictability and novelty (STUN)].

Methods: This exploratory longitudinal convergent mixed methods design consisted of online questionnaires over three time points (before, during and after the 1st wave of the COVID-19 pandemic) (N = 49) and qualitative interviews (N = 27) during the 1st wave of the pandemic on distinct samples of individuals living with chronic pain (CP). Both types of data sources were mixed upon integration using joint display.

Results: Mean pain intensity scores remained stable across time points, while pain unpleasantness and pain interference scores significantly improved. Global impression of change scores measured during the first wave of the pandemic do not entirely concord with pain scores evolution. Two thirds of participants reported a global deterioration of their pain condition at the beginning of the pandemic. Stress and pain catastrophizing before the pandemic were associated with pain scores throughout the pandemic; while most specific measures of stress due to the novel, uncontrollable, unpredictable and threatening nature of the pandemic were not. Qualitative data demonstrated that the deterioration reported in pain status reflected additional dimensions, including spatial expansion of the painful area, reduced access to treatments and challenges in adapting pain management strategies.

Conclusions: Helping individuals to negotiate stressful aspects of the pandemic might help offset the negative impacts of stress on pain status in this context or other important life events.
Effects of SARS-CoV-2 Infection During Late Pregnancy on Early Childhood Development: A Prospective Cohort Study
Authors: Wu Tianchen , Chen Lian , Wang Yuanyuan , Shi Huifeng , Niu Jieqiong , Yin Xiaohan , Li Mengshi , Tan Chang , Jiang Hai , Zheng Danni , Wei Yuan , Zhao Yangyu , Wang Xiaoli , Qiao Jie
Published: November 2021

Background: There is little direct or indirect evidence of the effects of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection during pregnancy on early childhood development.

Methods: We conducted a prospective, observational cohort study in China from May 1 to October 31, 2020, that enrolled 135 mother-infant dyads: 57 dyads in the infection cohort and 78 in the non-infection cohort. Among all infants, 14.0% were preterm birth in the infection cohort and 6.4% in the non-infection cohort. Participants were followed by telephone interviews to collect demographic characteristics, medical records of coronavirus disease 2019, breastfeeding data, and early childhood development was assessed by the Age and Stage Questionnaire (ASQ-3) and Age and Stage Questionnaire Social-Emotional (ASQ:SE-2) Chinese versions at 3 months after childbirth. We used multivariable Poisson regression models to estimate the relative risk (RR) of SARS-CoV-2 infection. Multivariable linear regression models and a mediation model were used to test the direct and indirect associations between SARS-CoV-2 infection and the ASQ-3 score. This study was approved by the Peking University Third Hospital Medical Science Research Ethics Committee (No. IRB00006761-M2020127).

Results: In the infection cohort, 13.6% of the children showed social–emotional developmental delay, and 13.5% showed overall developmental delay. The corresponding rates in the non-infection cohort were 23.4 and 8.1%. Compared with the non-infection cohort, SARS-CoV-2 infection during pregnancy did not increase the risk of social-emotional (RR = 0.87, 95% CI: 0.51–1.49) or overall (RR = 1.02, 95% CI: 0.60–1.73) developmental delay. The mediation model showed that SARS-CoV-2 infection indirectly affected the ASQ-3 score by increasing the length of mother–infant separation.

Conclusions: SARS-CoV-2 during late pregnancy did not increase the risk of developmental delay of the offspring 3 months after delivery. However, SARS-CoV-2 may have indirect effects on early childhood development by increasing mother-infant separation.