bluuebunny/crossref_metadata_2025 huggingface dataset:
The Development and Validation of the SWADOC: A Study Protocol for a Multicenter Prospective Cohort Study
Authors: Mélotte Evelyne , Belorgeot Marion , Herr Roxanne , Simon Jessica , Kaux Jean-François , Laureys Steven , Sanz Leandro R. D. , Lagier Aude , Morsomme Dominique , Pellas Frederic , Gosseries Olivia
Published: April 2021

Background: After a coma, patients with severe brain injury may present disorders of consciousness (DOC). A substantial proportion of these patients also suffer from severe dysphagia. Assessment of and therapy for swallowing disabilities of patients with DOC are essential because dysphagia has major functional consequences and comorbidities. Dysphagia evaluation in patients with DOC is impeded by the lack of adapted tools. The first aim of this study was to create a new tool, the SWallowing Assessment in Disorders Of Consciousness (SWADOC), and propose a validation protocol. The SWADOC was developed to help therapists assess factors related to swallowing in patients with DOC. The second aim was to investigate the relationship between patients' level of consciousness and SWADOC items and scores.

Method/Design: In this multicenter prospective cohort, 104 patients with DOC will be tested three times over five consecutive days with the SWADOC. Statistical analyses will focus on the reliability and validity of the SWADOC, especially the intrarater and interrater reliability, internal consistency, measures of dispersion, and concurrent validity with the Facial Oral Tract Therapy Swallowing Assessment of Saliva (FOTT-SAS). The level of consciousness will be assessed with the Simplified Evaluation of CONsciousness Disorders (SECONDs) and the Coma Recovery Scale-Revised (CRS-R).

Discussion: The assessment of swallowing abilities among patients with DOC is the first necessary step toward the development of a customized dysphagia care plan. A validated scoring tool will be essential for clinicians to better assess dysphagia in patients with DOC and document the evolution of their disorders.

Trial Registration: NCT04706689.
Clinical and Angiographic Outcomes After Stent-Assisted Coiling of Cerebral Aneurysms With Laser-Cut and Braided Stents: A Comparative Analysis of the Literatures
Authors: Zhang Longhui , Chen Xiheng , Dong Linggen , Liu Peng , Jia Luqiong , Zhang Yisen , Lv Ming
Published: April 2021

Introduction: Stent-assisted coiling (SAC) plays an important role in endovascular treatment of intracranial aneurysms (IAs). This comparative analysis examines the safety and efficacy of SAC in general and compares clinical and angiographic outcomes between laser-cut stents and braided stents.

Methods: Relevant English-language studies were identified via a PubMed search for published articles regarding outcomes of SAC using laser-cut stents and braided stents published from 2015 to 2020. Data from 56 studies that met our inclusion criteria were pooled and statistically compared.

Results: A total of 4,373 patients harboring with 4,540 IAs were included. Patients were divided into two groups on the basis of stent type: laser-cut stents (2,076 aneurysms in 1991 patients; mean follow-up, 12.99 months) and braided stents (2,464 aneurysms in 2382 patients; mean follow-up, 18.41 months). Overall, the rates of successful stent deployment, thromboembolic events, stent stenosis, periprocedural intracranial hemorrhage, permanent morbidity, mortality, and recanalization were 97.72, 4.72, 2.87, 1.51, 2.14, 1.16, and 6.06%, respectively. Laser-cut stents were associated with a significantly higher rate of successful deployment (p = 0.003) and significantly lower rate of periprocedural intracranial hemorrhage (p = 0.048). Braided stents were associated with a significantly lower rate of permanent morbidity (p = 0.015).

Conclusion: SAC of IAs using laser-cut stents or braided stents was effective and safe. Rates of thromboembolic events, stent stenosis, mortality, and recanalization were comparable between the stent types. Braided stents were associated with lower permanent morbidity while laser-cut stents were associated with more favorable rates of successful deployment and periprocedural intracranial hemorrhage.
Early Life Stress and the Fate of Kynurenine Pathway Metabolites
Authors: Coplan Jeremy D. , George Roza , Syed Shariful A. , Rozenboym Annalam V. , Tang Jean E. , Fulton Sasha L. , Perera Tarique D.
Published: April 2021

Early life stress (ELS) precedes alterations to neuro-immune activation, which may mediate an increased risk for stress-related psychiatric disorders, potentially through alterations of central kynurenine pathway (KP) metabolites, the latter being relatively unexplored. We hypothesized that ELS in a non-human primate model would lead to a reduction of neuroprotective and increases of neurotoxic KP metabolites. Twelve adult female bonnet macaques reared under conditions of maternal variable foraging demand (VFD) were compared to 27 age- and weight-matched non-VFD-exposed female controls. Baseline behavioral observations of social affiliation were taken over a 12-week period followed by the first cerebrospinal fluid (CSF) sample. Subjects were then either exposed to a 12-week repeated separation paradigm (RSP) or assigned to a “no-RSP” condition followed by a second CSF. We used high-performance liquid chromatography for kynurenine (KYN), tryptophan, 5-hydroxyindoleacetic acid, kynurenic acid (KYNA), and anthranilic acid (ANTH) as a proxy for quinolinic acid determination. At baseline, social affiliation scores were reduced in VFD-reared versus control subjects. CSF log KYNA and log KYNA/KYN ratio were lower in VFD-reared versus control subjects. CSF log KYNA/KYN was positively correlated with CSF log ANTH in VFD only (r = 0.82). Controlling for log KYNA/KYN, log ANTH was elevated in VFD-reared subjects versus controls. CSF log KYNA/KYN obtained post-RSP was positively correlated with mean social affiliation scores during RSP, specifically in VFD. ELS is associated with a reduced neuroprotective and increased neurotoxic pathway products. That the two contrasting processes are paradoxically correlated following ELS suggests a cross-talk between two opposing KP enzymatic systems.
Dietary Carbohydrate and Diverse Health Outcomes: Umbrella Review of 30 Systematic Reviews and Meta-Analyses of 281 Observational Studies
Authors: Liu Ya-Shu , Wu Qi-Jun , Lv Jia-Le , Jiang Yu-Ting , Sun Hui , Xia Yang , Chang Qing , Zhao Yu-Hong
Published: April 2021

Background and Aims: The associations between dietary carbohydrate and diverse health outcomes remain controversial and confusing. To summarize the existing evidence of the association between dietary carbohydrate intake and diverse health outcomes and to evaluate the credibility of these sources of evidence. We performed this umbrella review of evidence from meta-analyses of observational studies.

Methods: PubMed, Embase, Web of Science databases, and manual screening of references up to July 2020 were searched. Systematic reviews with meta-analyses of observational studies in humans investigating the association between dietary carbohydrate intake and multiple health outcomes were identified. We assessed the evidence levels by using summary effect sizes, 95% prediction intervals, between-study heterogeneity, evidence of small-study effects, and evidence of excess significance bias for each meta-analysis.

Results: We included 43 meta-analyses of observational research studies with 23 health outcomes, including cancer (n = 26), mortality (n = 4), metabolic diseases (n = 4), digestive system outcomes (n = 3), and other outcomes [coronary heart disease (n = 2), stroke (n = 1), Parkinson's disease (n = 1), and bone fracture (n = 2)]. This umbrella review summarized 281 individual studies with 13,164,365 participants. Highly suggestive evidence of an association between dietary carbohydrate intake and metabolic syndrome was observed with adjusted summary odds ratio of 1.25 [95% confidence interval (CI) 1.15–1.37]. The suggestive evidences were observed in associations of carbohydrate consumption with esophageal adenocarcinoma (0.57, 95% CI = 0.42–0.78) and all-cause mortality (adjusted summary hazard ratio 1.19, 95% CI = 1.09–1.30).

Conclusions: Despite the fact that numerous systematic reviews and meta-analyses have explored the relationship between carbohydrate intake and diverse health outcomes, there is no convincing evidence of a clear role of carbohydrate intake. However, there is highly suggestive evidence suggested carbohydrate intake is associated with high risk of metabolic syndrome, suggestive evidence found its association with increased risk of all-cause mortality and decreased risk of esophageal adenocarcinoma.

Systematic Review Registration: CRD42020197424.
Nomogram Predicts the Role of Contralateral Prophylactic Mastectomy in Male Patients With Unilateral Breast Cancer Based on SEER Database: A Competing Risk Analysis
Authors: Li Kunlong , Wang Bin , Yang Zejian , Yu Ren , Chen Heyan , Li Yijun , He Jianjun , Zhou Can
Published: April 2021

Background

Contralateral prophylactic mastectomy (CPM) in female breast cancer (FBC) is supported by multiple clinical studies and consensus guidelines, but knowledge of preventive contralateral mastectomy in male breast cancer (MaBC) is very limited and its benefits are still controversial.

Methods

A retrospective cohort study was enrolled with 4,405 MaBC patients who underwent unilateral mastectomy (UM) or CPM from the Surveillance, Epidemiology, and End Results (SEER) database from 1998 to 2015. A nomogram was built based on the corresponding parameters by competing risks regression to predict the 3-year, 5-year, and 8-year probabilities of BCSD (breast cancer-specific death). C-index and calibration curves were chosen for validation. Net reclassification index (NRI) and integrated discrimination improvement (IDI) were used to estimate the nomogram’s clinical utility.

Results

A total of 4,197 patients received UM and 208 patients received CPM, with 63-months median follow-up. In the competing risks regression, six variables (surgery, marital status, T-stage, N-stage, histology, tumor grade) were significantly associated with BCSD. Based on these independent prognosis factors, a nomogram model was constructed. The C-index 0.75 (95%CI: 0.73-0.77) in the training cohort and 0.73 (95%CI: 0.71-0.74) in the internal validation group suggested robustness of the model. In addition, the calibration curves exhibited favorably. The NRI values (training cohort: 0.54 for 3-year, 0.55 for 5-year, and 0.49 for 8-year BCSD prediction; validation cohort: 0.51 for 3-year, 0.45 for 5-year, and 0.33 for 8-year BCSD prediction) and IDI values (training cohort: 0.02 for 3-year, 0.03 for 5-year, and 0.04 for 8-year BCSD prediction; validation cohort: 0.02 for 3-year, 0.04 for 5-year, and 0.04 for 8-year BCSD prediction) indicated that the model performed better than the AJCC criteria-based tumor staging alone.

Conclusions

The administration of CPM was associated with the decrease in risk of BCSD in patients with MaBC. The nomogram could provide a precise and personalized prediction of the cumulative risk in patients with MaBC after CPM.
Adverse Prognostic Impact of Postoperative Complications After Gastrectomy for Patients With Stage II/III Gastric Cancer: Analysis of Prospectively Collected Real-World Data
Authors: Song Jeong Ho , Lee Sejin , Choi Seohee , Cho Minah , Kwon In Gyu , Kim Yoo Min , Son Taeil , Kim Hyoung-Il , Jung Minkyu , Hyung Woo Jin
Published: April 2021

Background

The impact of postoperative complications on the prognosis of gastric cancer remains controversial. This study aimed to evaluate the relationship between postoperative complications and long-term survival in patients undergoing gastrectomy for stage II/III gastric cancer.

Methods

Some 939 patients underwent curative gastrectomy for stage II/III gastric cancer were identified from real-world data prospectively collected between 2013 and 2015. We divided patients according to the presence of serious complications, specifically, Clavien-Dindo grade III or higher complications or those causing a hospital stay of 15 days or longer.

Results

Serious complications occurred in 125 (13.3%) patients. Patients without serious complications (64.3%) completed adjuvant chemotherapy significantly more than patients with serious complications (37.6%; p<0.001). The 5-year overall survival(OS) rate was 58.1% and recurrence-free survival(RFS) rate was 58.1% in patients with serious complications, which were significantly worse than those of patients without serious complications (73.4% and 74.7%, respectively; p<0.001 for both). In stage II, once patients completed adjuvant chemotherapy adequately, the OS and RFS of patients with serious complications did not differ from those without serious complications. However, in stage III, the patients with serious complications showed a worse OS even after completion of adequate adjuvant chemotherapy.

Conclusion

Serious complications after gastrectomy had a negative impact on the prognosis of stage II/III gastric cancer patients. Serious complications worsen the survival in association with inadequate adjuvant chemotherapy. Efforts to reduce serious complications, as well as support adequate chemotherapy through proper management of serious complications, would improve the prognosis of stage II/III gastric cancer patients.
Research Progress of circRNAs in Head and Neck Cancers
Authors: Li Panchun , Zhu Kunjie , Mo Yongzhen , Deng Xiangying , Jiang Xianjie , Shi Lei , Guo Can , Zhang Wenling , Zeng Zhaoyang , Li Guiyuan , Xiong Wei , Zhang Shanshan , Gong Zhaojian
Published: April 2021

Circular RNAs (circRNAs) are a novel type of non-coding RNAs. Because of their characteristics of a closed loop structure, disease- and tissue-specificity, and high conservation and stability, circRNAs have the potential to be biomarkers for disease diagnosis. Head and neck cancers are one of the most common malignant tumors with high incidence rates globally. Affected patients are often diagnosed at the advanced stage with poor prognosis, owing to the concealment of anatomic sites. The characteristics, functions, and specific mechanisms of circRNAs in head and neck cancers are increasingly being discovered, and they have important clinical significance for the early diagnosis, treatment, and prognosis evaluation of patients with cancer. In this study, the generation, characteristics, and functions of circRNAs, along with their regulatory mechanisms in head and neck cancers have been summarized. We report that circRNAs interact with molecules such as transcription and growth factors to influence specific pathways involved in tumorigenesis. We conclude that circRNAs have an important role to play in the proliferation, invasion, metastasis, energy and substance metabolism, and treatment resistance in cancers.
Enhanced Deep-Inspiration Breath Hold Superior to High-Frequency Percussive Ventilation for Respiratory Motion Mitigation: A Physiology-Driven, MRI-Guided Assessment Toward Optimized Lung Cancer Treatment With Proton Therapy
Authors: Emert Frank , Missimer John , Eichenberger Philipp A. , Walser Marc , Gmür Celina , Lomax Antony J. , Weber Damien C. , Spengler Christina M.
Published: April 2021

Background: To safely treat lung tumors using particle radiation therapy (PRT), motion-mitigation strategies are of critical importance to ensure precise irradiation. Therefore, we compared applicability, effectiveness, reproducibility, and subjects' acceptance of enhanced deep-inspiration breath hold (eDIBH) with high-frequency percussive ventilation (HFPV) by MRI assessment within 1 month.

Methods: Twenty-one healthy subjects (12 males/9 females; age: 49.5 ± 5.8 years; BMI: 24.7 ± 3.3 kg/m−2) performed two 1.5 T MRI scans in four visits at weekly intervals under eDIBH and HFPV conditions, accompanied by daily, home-based breath-hold training and spirometric assessments over a 3-week period. eDIBH consisted of 8-min 100% O2 breathing (3 min resting ventilation, 5 min controlled hyperventilation) prior to breath hold. HFPV was set at 200–250 pulses min−1 and 0.8–1.2 bar. Subjects' acceptance and preference were evaluated by questionnaire. To quantify inter- and intrafractional changes, a lung distance metric representing lung topography was computed for 10 reference points: a motion-invariant spinal cord and nine lung structure contours (LSCs: apex, carina, diaphragm, and six vessels as tumor surrogates distributed equally across the lung). To parameterize individual LSC localizability, measures of their spatial variabilities were introduced and lung volumes calculated by automated MRI analysis.

Results: eDIBH increased breath-hold duration by > 100% up to 173 ± 73 s at visit 1, and to 217 ± 67 s after 3 weeks of home-based training at visit 4 (p < 0.001). Measures of vital capacity and lung volume remained constant over the 3-week period. Two vessels in the lower lung segment and the diaphragm yielded a two- to threefold improved positional stability with eDIBH, whereby absolute distance variability was significantly smaller for five LSCs; ≥70% of subjects showed significantly better intrafractional lung motion mitigation under reproducible conditions with eDIBH compared with HFPV with smaller ranges most apparent in the anterior-posterior and cranial-caudal directions. Approximately 80% of subjects preferred eDIBH over HFPV, with “less discomfort” named as most frequent reason.

Conclusions: Both, eDIBH, and HFPV were well-tolerated. eDIBH duration was long enough to allow for potential PRT. Variability in lung volume was smaller and position of lung structures more precise with eDIBH. Subjects preferred eDIBH over HFPV. Thus, eDIBH is a very promising tool for lung tumor therapy with PRT, and further investigation of its applicability in patients is warranted.
Ultrasound-Based Radiomics Analysis for Predicting Disease-Free Survival of Invasive Breast Cancer
Authors: Xiong Lang , Chen Haolin , Tang Xiaofeng , Chen Biyun , Jiang Xinhua , Liu Lizhi , Feng Yanqiu , Liu Longzhong , Li Li
Published: April 2021

Background

Accurate prediction of recurrence is crucial for personalized treatment in breast cancer, and whether the radiomics features of ultrasound (US) could be used to predict recurrence of breast cancer is still uncertain. Here, we developed a radiomics signature based on preoperative US to predict disease-free survival (DFS) in patients with invasive breast cancer and assess its additional value to the clinicopathological predictors for individualized DFS prediction.

Methods

We identified 620 patients with invasive breast cancer and randomly divided them into the training (n = 372) and validation (n = 248) cohorts. A radiomics signature was constructed using least absolute shrinkage and selection operator (LASSO) Cox regression in the training cohort and validated in the validation cohort. Univariate and multivariate Cox proportional hazards model and Kaplan–Meier survival analysis were used to determine the association of the radiomics signature and clinicopathological variables with DFS. To evaluate the additional value of the radiomics signature for DFS prediction, a radiomics nomogram combining the radiomics signature and clinicopathological predictors was constructed and assessed in terms of discrimination, calibration, reclassification, and clinical usefulness.

Results

The radiomics signature was significantly associated with DFS, independent of the clinicopathological predictors. The radiomics nomogram performed better than the clinicopathological nomogram (C-index, 0.796 vs. 0.761) and provided better calibration and positive net reclassification improvement (0.147, P = 0.035) in the validation cohort. Decision curve analysis also demonstrated that the radiomics nomogram was clinically useful.

Conclusion

US radiomics signature is a potential imaging biomarker for risk stratification of DFS in invasive breast cancer, and US-based radiomics nomogram improved accuracy of DFS prediction.
The Potential of MET Immunoreactivity for Prediction of Lymph Node Metastasis in Early Oral Tongue Squamous Cell Carcinoma
Authors: De Herdt Maria J. , van der Steen Berdine , van der Toom Quincy M. , Aaboubout Yassine , Willems Stefan M. , Wieringa Marjan H. , Baatenburg de Jong Robert J. , Looijenga Leendert H. J. , Koljenović Senada , Hardillo Jose A.
Published: April 2021

Objective

MET positivity is independently associated with survival in oral squamous cell carcinoma (OSCC). Since MET is a known orchestrator of invasive tumor growth, we investigated its association with LNM in early oral tongue squamous cell carcinoma (OTSCC). As it is recommended by the NCCN to use tumor depth of invasion (DOI) in making decisions on elective neck dissection (END), the results obtained for MET positivity were aligned with those for DOI > 4 mm. The cutoff value used in our institution.

Methods

Tumor samples from patients who underwent primary tumor resection and neck dissection between 1995 and 2013, were collected from the archives of the Leiden and Erasmus University Medical Center. Immunohistochemistry with D1C2 was performed to identify MET negative (< 10% uniform positivity) and MET positive (≥ 10% uniform positivity) cancers. ROC curve analysis and the Chi-squared test were used to investigate the association of MET positivity with LNM (pN+ and occult). Binary logistic regression was used to investigate the association of MET positivity with LNM.

Results

Forty-five (44.1%) of the 102 cancers were MET positive. Ninety were cN0 of which 20 were pN+ (occult metastasis). The remaining 12 cancers were cN+, of which 10 were proven pN+ and 2 were pN0. MET positivity was associated with LNM with a positive predictive value (PPV) of 44.4% and a negative predictive value (NPV) of 82.5% for pN+. For the occult group, the PPV was 36.8% and the NPV was 88.5%. Regression analysis showed that MET positivity is associated with pN+ and occult LNM (p-value < 0.05).

Conclusion

MET positivity is significantly associated with LNM in early OTSCC, outperforming DOI. The added value of MET positivity could be in the preoperative setting when END is being considered during the initial surgery. For cases with DOI ≤ 4 mm, MET positivity could aid in the clinical decision whether regular follow-up, watchful waiting, or END is more appropriate. Realizing that these preliminary results need to be independently validated in a larger patient cohort, we believe that MET positivity could be of added value in the decision making on END in early OTSCC.
The Detection of Cancer Epigenetic Traces in Cell-Free DNA
Authors: Koval Anastasia P. , Blagodatskikh Konstantin A. , Kushlinskii Nikolay E. , Shcherbo Dmitry S.
Published: April 2021

Nucleic acid fragments found in blood circulation originate mostly from dying cells and carry signs pointing to specific features of the parental cell types. Deciphering these clues may be transformative for numerous research and clinical applications but strongly depends on the development and implementation of robust analytical methods. Remarkable progress has been achieved in the reliable detection of sequence alterations in cell-free DNA while decoding epigenetic information from methylation and fragmentation patterns requires more sophisticated approaches. This review discusses the currently available strategies for detecting and analyzing the epigenetic marks in the liquid biopsies.
Para-Aortic Nodal Radiation in the Definitive Management of Node-Positive Cervical Cancer
Authors: Sanders Jason C. , Muller Donald A. , Dutta Sunil W. , Corriher Taylor J. , Ring Kari L. , Showalter Timothy N. , Romano Kara D.
Published: April 2021

Objectives

To investigate the safety and outcomes of elective para-aortic (PA) nodal irradiation utilizing modern treatment techniques for patients with node positive cervical cancer.

Methods

Patients with pelvic lymph node positive cervical cancer who received radiation were included. All patients received radiation therapy (RT) to either a traditional pelvic field or an extended field to electively cover the PA nodes. Factors associated with survival were identified using a Cox proportional hazards model, and toxicities between groups were compared with a chi-square test.

Results

96 patients were identified with a mean follow up of 40 months. The incidence of acute grade ≥ 2 toxicity was 31% in the elective PA nodal RT group and 15% in the pelvic field group (Chi-square p = 0.067. There was no significant difference in rates of grade ≥ 3 acute or late toxicities between the two groups (p>0.05). The KM estimated 5-year OS was not statistically different for those receiving elective PA nodal irradiation compared to a pelvic only field, 54% vs. 73% respectively (log-rank p = 0.11).

Conclusions

Elective PA nodal RT can safely be delivered utilizing modern planning techniques without a significant increase in severe (grade ≥ 3) acute or late toxicities, at the cost of a possible small increase in non-severe (grade 2) acute toxicities. In this series there was no survival benefit observed with the receipt of elective PA nodal RT, however, this benefit may have been obscured by the higher risk features of this population. While prospective randomized trials utilizing a risk adapted approach to elective PA nodal coverage are the only way to fully evaluate the benefit of elective PA nodal coverage, these trials are unlikely to be performed and instead we must rely on interpretation of results of risk adapted approaches like those used in ongoing clinical trials and retrospective data.
Taming Cell-to-Cell Heterogeneity in Acute Myeloid Leukaemia With Machine Learning
Authors: Sánchez-Corrales Yara E. , Pohle Ruben V. C. , Castellano Sergi , Giustacchini Alice
Published: April 2021

Acute Myeloid Leukaemia (AML) is a phenotypically and genetically heterogenous blood cancer characterised by very poor prognosis, with disease relapse being the primary cause of treatment failure. AML heterogeneity arise from different genetic and non-genetic sources, including its proposed hierarchical structure, with leukemic stem cells (LSCs) and progenitors giving origin to a variety of more mature leukemic subsets. Recent advances in single-cell molecular and phenotypic profiling have highlighted the intra and inter-patient heterogeneous nature of AML, which has so far limited the success of cell-based immunotherapy approaches against single targets. Machine Learning (ML) can be uniquely used to find non-trivial patterns from high-dimensional datasets and identify rare sub-populations. Here we review some recent ML tools that applied to single-cell data could help disentangle cell heterogeneity in AML by identifying distinct core molecular signatures of leukemic cell subsets. We discuss the advantages and limitations of unsupervised and supervised ML approaches to cluster and classify cell populations in AML, for the identification of biomarkers and the design of personalised therapies.
Anti-PD-1 Immunotherapy and Bee Venom for Relapsed and Refractory Liposarcoma: A Case Report
Authors: Yang Wei , Zhang Yeke , Yang Gaoyi , Geng Yanhua , Chen Da , Wang Jun , Ye Yang , Wang Huaichong , Xia Dajing , Hu Fuliang , Jiang Jing , Xu Xiaofeng
Published: April 2021

Cancer immunotherapies, including immune checkpoint inhibitors, elicit long-term clinical responses but many cancer patients do not respond. Intensive efforts are therefore underway to identify additional immune pathways that may be modulated to enhance the efficacy of existing immunotherapies. Bee venom strongly stimulates the immune system, and is used as a complementary therapy to treat cancer pain in patients with advanced tumors in China. Bee venom contains several allergenic protease inhibitors and peptides. It triggers hypersensitivity reactions; that is, it is an immune system agonist. The generation of a spontaneous T cell response against tumor-associated antigens requires innate immune activation; this drives type I interferon production. We report a patient with a relapsed and refractory liposarcoma who had undergone several operations, chemotherapies, and radiotherapies. The tumor was large. The patient had attained the maximum radiation exposure dose. The tumor was resistant to chemotherapy and was infiltrating the pericardium, lungs, and diaphragm. The patient was a poor candidate for resection. He thus received apitherapy (a combination of bee venom and acupuncture) to control pain; then apatinib (an anti-angiogenic drug) was given to inhibit tumor growth but was terminated early because the patient could not tolerate the side effects. Subsequently, a programmed death 1 inhibitor was combined with apitherapy. Bee venom served as an innate immune system agonist promoting immune cell priming and recruitment in the tumor microenvironment. The patient was finally able to undergo radical liposarcoma resection, and no evidence of recurrence was found at re-examination 16 months after surgery.
MLH1/PMS2 Expression Could Tell Classical NTRK Fusion in Fluorescence In Situ Hybridization Positive Colorectal Carcinomas
Authors: Fu Yao , Li Zheng , Gao Fuping , Yang Jun , Wu Hongyan , Zhang Biao , Pu Xiaohong , Fan Xiangshan
Published: April 2021

To gain insight into the clinicopathologic profile of colorectal carcinomas harboring oncogenic NTRK fusions based on eastern populations as well as make the best testing algorithm for the screen, we use pan-Trk immunohistochemistry (IHC), fluorescence in situ hybridization (FISH) respectively to screen NTRK fusions in a large, unselected cohort of 819 colon cancers; either IHC or FISH positive cases were further detected by next-generation sequencing (NGS). IHC staining was observed in ten (1.22%) cases. FISH positive was observed in 13 (1.59%) cases, and finally, a total of 18 cases were under both a DNA-based and an RNA-based NGS assay. RNA-based NGS was positive in 13 of 18 cases, whereas DNA-based NGS was only positive in three of 18 cases. In total 13 RNA-based NGS NTRK fusion-positive cases, only six cases were pan-TRK IHC positive versus 12 were FISH positive. More important, in 13 RNA-based NGS cases only five cases contain the full length of NTRK tyrosine kinase (TK) domain and form the classical fusion chimeras, other six cases only maintain parts of the TK domain and form the sub-classical fusion chimeras, two cases totally miss the TK domain and form the non-classical fusions. For clinicopathologic characteristics, besides the MMR (mismatch repair) status (p = 0.001), there is no difference between the NTRK fusion-positive and negative cases. Nevertheless, classical fusion cases prefer low differentiation (p = 0.001) and different patterns of growth (p < 0.001). Besides, we found all five classical NTRK fusion cases, and only one sub-classical case was harboring MLH1/PMS2 deficiency. When combining FISH and MMR (Mismatch Repair) status, besides one sub-classical case, all five classical fusions were detected, which means MLH1/PMS2 expression could further narrow the classical fusions in FISH NTRK fusion positive cases. Given the low sensitivity and specificity of the pan-Trk antibody, it would be useless to use IHC to screen NTRK fusion-positive CRCs. Combining FISH and MLH1/PMS2 IHC would be a good testing algorithm for the screen effective NTRK fusions. Finally, if patients are going to undergo TRK-based targeted therapy, only RNA-based NGS for detection of the specific fusion could tell the precise rearrangement information.
Clinical and Molecular Properties of Human Immunodeficiency Virus-Related Diffuse Large B-Cell Lymphoma
Authors: de Carvalho Pedro S. , Leal Fabio E. , Soares Marcelo A.
Published: April 2021

Non-Hodgkin lymphoma is the most common malignancy affecting people living with HIV (PLWH). Among its several subtypes, diffuse large B-cell lymphoma (DLBCL) is an important manifestation within the HIV-infected compartment of the population. Since HIV is able to modulate B cells and promote lymphomagenesis through direct and indirect mechanisms, HIV-related DLBCL has specific characteristics. In this review, we address the clinical and molecular properties of DLBCL disease in the context of HIV infection, as well as the mechanisms by which HIV is able to modulate B lymphocytes and induce their transformation into lymphoma.
Driver Genes Associated With the Incidence of Venous Thromboembolism in Patients With Non-Small-Cell Lung Cancer: A Systematic Review and Meta-Analysis
Authors: Qian Xiaohan , Fu Mengjiao , Zheng Jing , Zhou Jianya , Zhou Jianying
Published: April 2021

Background

The association between driver genes and the incidence of thromboembolic events (TEs) in patients diagnosed with non-small-cell lung cancer (NSCLC) needs to be quantified to guide clinical management.

Methods

We interrogated PubMed, Embase, Web of Science and Cochrane library databases for terms related to venous thromboembolism (VTE) and arterial thromboembolism (ATE) in patients diagnosed with non-small-cell lung cancer harboring driver genes. This search was conducted for studies published between 1 January, 2000 and 31 December, 2020. A random-effects meta-analysis was performed to analyze the pooled incidence and odds ratios of VTE in patients with different driver genes.

Results

Of the 2,742 citations identified, a total of 25 studies that included 21,156 patients met eligibility criteria. The overall pooled incidence of VTE in patients with driver genes was 23% (95% CI 18-29). Patients with ROS1 rearrangements had the highest incidence of VTE (37%, 95%CI 23-52). ALK rearrangements were associated with increased VTE risks (OR=2.08,95% CI 1.69-2.55), with the second highest incidence of VTE (27%, 95%CI 20-35). Both groups of patients with EGFR and KRAS mutations did not show a significantly increased risk for VTE (OR=1.33, 95% CI 0.75-2.34; OR=1.31, 95% CI 0.40-4.28).

Conclusions

ALK rearrangements were shown to be associated with increased VTE risks in patients diagnosed with non-small lung cancer, while there was no significant relation observed between VTE risks and EGFR or KRAS mutations in lung cancer patients.
Clinical and Genetic Features in 31 Serial Chinese Children With Gitelman Syndrome
Authors: Zhang Lingxia , Huang Ke , Wang Shugang , Fu Haidong , Wang Jingjing , Shen Huijun , Lu Zhihong , Chen Junyi , Bao Yu , Feng Chunyue , Dong Guanping , Mao Jianhua
Published: April 2021

Gitelman syndrome (GS, OMIM 263800) is a genetic congenital tubulopathy associated with salt loss, which is characterized by hypokalemic metabolic toxicity, hypocalciuria, and hypomagnesemia. GS, which is typically detected in adolescence or adulthood, has long been considered a benign tubular lesion; however, the disease is associated with a significant decrease in the quality of life. In this study, we assessed the genotype–phenotype correlations based on the medical histories, clinical symptoms, laboratory test results, and whole-exome sequencing profiles from pediatric patients with GS. Between January 2014 and December 2020, all 31 consecutively enrolled patients complained of fatigue, salt craving, and muscle weakness. Sixteen patients demonstrated growth retardation, and five patients presented with nocturia and constipation. All patients presented with hypokalemic metabolic alkalosis, normal blood pressure, hyperaldosteronism, and a preserved glomerular filtration rate, and 24 of the 31 (77.4%) patients had hypomagnesemia. Homozygous, compound heterozygous, and heterozygous mutations in SLC12A3 were detected in 4, 24, and 3 patients, respectively. GS patients often present with muscle weakness and fatigue caused by hypokalemia and hypomagnesemia. Therefore, early diagnosis of GS is important in young children to reduce the possibility of growth retardation, tetany, and seizures. Next-generation sequencing such as whole-exome or whole-genome sequencing provides a practical tool for the early diagnosis and improvement of GS prognosis. Further whole-genome sequencing is expected to reveal more variants in SLC123A among GS patients with single heterozygous mutations.
Pre-eclampsia Complicated With Maternal Renal Dysfunction Is Associated With Poor Neurological Development at 3 Years Old in Children Born Before 34 Weeks of Gestation
Authors: Yoneda Noriko , Yoneda Satoshi , Tsuda Sayaka , Ito Mika , Shiozaki Arihiro , Niimi Hideki , Yoshida Taketoshi , Nakashima Akitoshi , Saito Shigeru
Published: April 2021

Objective: The purpose of this study was to investigate perinatal factors associated with a poor neurodevelopmental outcome in preterm infants.

Methods: A retrospective study was conducted by searching our clinical database between January 2006 and December 2016. A total of 165 singleton children who were born between 23 and 33 weeks of gestation were included. We defined poor neurological development outcomes as follows: cerebral palsy; intellectual disability; developmental disorder including autism and attention-deficit/hyperactivity disorder; low score (<85 points) on Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III); or low score of Kyoto Scale of Psychological Development corrected at 3 years old. We diagnosed maternal renal dysfunction according to the Clinical Practice Guideline for chronic kidney disease 2018 and the Best Practice Guide 2015 for Care and Treatment of Hypertension in Pregnancy.

Results: The rate of poor neurological development was 25/165 (15.2%): cerebral palsy (n = 1), intellectual disability (n = 1), developmental disorder (n = 2), low score of Bayley-III (n = 20), and low score of Kyoto Scale of Psychological Development (n = 1). Preeclampsia complicated with maternal renal dysfunction (P = 0.045) and delivery at <30 weeks of gestation (P = 0.007) were independent risk factors for poor neurological development.

Conclusions: In addition to previous risk factors such as delivery at <30 weeks of gestation, preeclampsia complicated with renal dysfunction was also associated with poor neurodevelopmental outcomes corrected at 3 years old.
COVID-19 in Immunosuppressed Children
Authors: Nicastro Emanuele , Verdoni Lucio , Bettini Laura Rachele , Zuin Giovanna , Balduzzi Adriana , Montini Giovanni , Biondi Andrea , D'Antiga Lorenzo
Published: April 2021

Following the spread of the SARS-CoV-2 infection and coronavirus disease 2019 (COVID-19) to a global pandemic, concerns have arisen for the disease impact in at-risk populations, especially in immunocompromised hosts. On the other hand, clinical studies have clarified that the COVID-19 clinical burden is mostly due to over-inflammation and immune-mediated multiorgan injury. This has led to downsizing the role of immunosuppression as a determinant of outcome, and early reports confirm the hypothesis that patients undergoing immunosuppressive treatments do not have an increased risk of severe COVID-19 with respect to the general population. Intriguingly, SARS-CoV-2 natural reservoirs, such as bats and mice, have evolved mechanisms of tolerance involving selection of genes optimizing viral clearance through interferon type I and III responses and also dampening inflammasome response and cytokine expression. Children exhibit resistance to COVID-19 severe manifestations, and age-related features in innate and adaptive response possibly explaining this difference are discussed. A competent recognition by the innate immune system and controlled pro-inflammatory signaling seem to be the pillars of an effective response and the premise for pathogen clearance in SARS-CoV-2 infection. Immunosuppression—if not associated with other elements of fragility—do not represent per se an obstacle to this competent/tolerant phenotype in children. Several reports confirm that children receiving immunosuppressive medications have similar clinical involvement and outcomes as the pediatric general population, indicating that maintenance treatments should not be interrupted in suspect or confirmed SARS-CoV-2 infection.
Case Report: Circulating Tumor Cells as a Response Biomarker in ALK-Positive Metastatic Inflammatory Myofibroblastic Tumor
Authors: Bonvini Paolo , Rossi Elisabetta , Zin Angelica , Manicone Mariangela , Vidotto Riccardo , Facchinetti Antonella , Tombolan Lucia , Affinita Maria Carmen , Santoro Luisa , Zamarchi Rita , Bisogno Gianni
Published: April 2021

Inflammatory myofibroblastic tumors (IMTs) are locally aggressive malignancies occurring at various sites. Surgery is the mainstay of treatment and prognosis is generally good. For children with unresectable or metastatic tumors, however, outcome is particularly severe, limited also by the lack of predictive biomarkers of therapy efficacy and disease progression. Blood represents a minimally invasive source of cancer biomarkers for real-time assessment of tumor growth, particularly when it involves the analysis of circulating tumor cells (CTC). As CTCs potentially represent disseminated disease, their detection in the blood correlates with the presence of metastatic lesions and may reflect tumor response to treatment. Herein, we present a case report of a 19-year-old boy with an ALK-positive IMT of the bladder, proximal osteolytic and multiple bilateral lung lesions, who received ALK inhibitor entrectinib postoperatively and underwent longitudinal CTC analysis during treatment. Antitumor activity of entrectinib was demonstrated and was accompanied by regression of lung lesions, elimination of CTCs from the blood and no development of relapses afterwards. Therapy continued without any clinical sign of progression and 24 months since the initiation of treatment the patient remains symptom-free and disease-free.
A Combined Phytochemistry and Network Pharmacology Approach to Reveal Potential Anti-NSCLC Effective Substances and Mechanisms in Marsdenia tenacissima (Roxb.) Moon (Stem)
Authors: Liu Pei , Xu Dong-Wei , Li Run-Tian , Wang Shao-Hui , Hu Yan-Lan , Shi Shao-Yu , Li Jia-Yao , Huang Yu-He , Kang Li-Wei , Liu Tong-Xiang
Published: April 2021

Marsdeniae tenacissimae Caulis is a traditional Chinese medicine, named Tongguanteng (TGT), that is often used for the adjuvant treatment of cancer. In our previous study, we reported that an ethyl acetate extract of TGT had inhibitory effects against adenocarcinoma A549 cells growth. To identify the components of TGT with anti-tumor activity and to elucidate their underlying mechanisms of action, we developed a technique for isolating compounds, which was then followed by cytotoxicity screening, network pharmacology analysis, and cellular and molecular experiments. We isolated a total of 19 compounds from a TGT ethyl acetate extract. Two novel steroidal saponins were assessed using an ultra-performance liquid chromatography-photodiode array coupled with quadrupole time-of-flight mass (UPLC-ESI-Q/TOF-MS). Then, we screened these constituents for anti-cancer activity against non-small cell lung cancer (NSCLC) in vitro and obtained six target compounds. Furthermore, a compound-target-pathway network of these six bioactive ingredients was constructed to elucidate the potential pathways that controlled anticancer effects. Approximately 205 putative targets that were associated with TGT, as well as 270 putative targets that were related to NSCLC, were obtained from online databases and target prediction software. Protein–protein interaction networks for drugs as well as disease putative targets were generated, and 18 candidate targets were detected based on topological features. In addition, pathway enrichment analysis was performed to identify related pathways, including PI3K/AKT, VEGF, and EGFR tyrosine kinase inhibitor resistance, which are all related to metabolic processes and intrinsic apoptotic pathways involving reactive oxygen species (ROS). Then, various cellular experiments were conducted to validate drug-target mechanisms that had been predicted using network pharmacology analysis. The experimental results showed the four C21 steroidal saponins could upregulate Bax and downregulate Bcl-2 expression, thereby changing the mitochondrial membrane potential, producing ROS, and releasing cytochrome C, which finally activated caspase-3, caspase-9, and caspase-8, all of which induced apoptosis in A549 cells. In addition, these components also downregulated the expression of MMP-2 and MMP-9 proteins, further weakening their degradation of extracellular matrix components and type IV collagen, and inhibiting the migration and invasion of A549 cells. Our study elucidated the chemical composition and underlying anti-tumor mechanism of TGT, which may be utilized in the treatment of lung cancer.
Polyphenols and Pharmacological Screening of a Monarda fistulosa L. dry Extract Based on a Hydrodistilled Residue By-Product
Authors: Shanaida Mariia , Hudz Nataliia , Jasicka-Misiak Izabela , Wieczorek Piotr P.
Published: April 2021

This study aimed to determine the composition and content of polyphenols in the dry extract obtained from the hydrodistilled residue by-product of the wild bergamot (Monarda fistulosa L., Lamiaceae Martinov family) herb (MFDE) and to evaluate its safety and pharmacological properties. The total phenolic content (TPC) in the MFDE was 120.64 mg GAE/g. The high-performance liquid chromatography (HPLC) analysis showed the presence of a plethora of phenolic compounds, including hydroxycinnamic acids and flavone derivatives in the MFDE, with rosmarinic acid and luteolin-7-O-glucoside being the main components. With an IC50 value of 0.285 mg/mL, it was found to be a strong DPPH radical scavenger. The acute toxicity study results indicate that the oral administration of MFDE to rats at the doses of 500–5,000 mg/kg did not produce any side effects or death in animals which indicates its safety. The results of the in vivo assay showed that the MFDE dose-dependently inhibited paw oedema and significantly reduced the number of writings in mice induced by the acetic acid injection suggesting its potent anti-inflammatory and analgesic activities, respectively. The conducted studies revealed that M. fistulosa hydrodistilled residue by-product could be regarded as a new natural source of polyphenols with valuable pharmacological properties.
Harmonizing Formula Prescription Patterns in Patients With Chronic Kidney Disease: A Population-Based Cross-Sectional Study
Authors: Lin Hung-Lung , Lin Ming-Yen , Tsai Cheng-Hsun , Wang Yi-Hsiu , Chen Chung-Jen , Hwang Shang-Jyh , Yen Ming-Hong , Chiu Yi-Wen
Published: April 2021

Objective: Harmonizing formulas are associated with beneficial renal outcomes in chronic kidney disease (CKD), but the therapeutic mechanisms are unclear. The study aims to explore the associations of intentions and independent factors with harmonizing formulas prescriptions for patients with CKD.

Methods: We conducted a population-based cross-sectional study to explore factors associated with harmonizing formulas prescription. Patients who had been prescribed harmonizing formulas after CKD diagnosis was defined as the using harmonizing formulas group. Disease diagnoses when having harmonizing formula prescriptions and patient characteristics related to these prescriptions were collected.

Results: In total, 24,971 patients were enrolled in this analysis, and 5,237 (21%) patients were prescribed harmonizing formulas after CKD diagnosis. The three most frequent systematic diseases and related health problems for which harmonizing formula prescriptions were issued in CKD were symptoms, signs, and ill-defined conditions (24.5%), diseases of the digestive system (20.67%), and diseases of the musculoskeletal system (12.9%). Higher likelihoods of harmonizing formula prescriptions were associated with young age (adjusted odds ratio: 0.98, 95% confidence interval: 0.97–0.98), female sex (1.79, 1.68–1.91), no diabetes (1.20, 1.06–1.36), no hypertension (1.38, 1.27–1.50), no cerebrovascular disease (1.34, 1.14–1.56), less disease severity (0.85, 0.83–0.88), using nonsteroidal anti-inflammatory drugs (NSAIDs) (1.65, 1.54–1.78), and using analgesic drugs other than NSAIDs (1.47, 1.35–1.59).

Conclusion: Harmonizing formulas are commonly used for treating symptoms of the digestive and musculoskeletal systems in CKD cases. Further research on harmonizing formula effectiveness with regard to particular characteristics of CKD patients is warranted.