bluuebunny/crossref_metadata_2025 huggingface dataset:
Impact of Precision Medicine on Clinical Outcomes: A Single-Institution Retrospective Study
Authors: Quinn Ryann , Patel Rajvi , Sison Cristina , Singh Amandeep , Zhu Xin-Hua
Published: September 2021

Purpose

The strategy of precision medicine has been widely adopted in the practice of oncology, although the efficacy remains unclear. This study assesses clinical outcomes in patients with an actionable alteration found during FoundationOne CDx™ (F1CDx) testing and who received a targeted therapy based on the results.

Materials and Methods

This is a retrospective cohort study of patients with tumors that underwent F1CDx from September 2012 to July 2018. F1CDx provided actionable alterations for patients to select appropriate therapies. The primary objective was to estimate the objective response rate (ORR) at 3 months from the start of study treatment. The secondary objectives were to estimate progression-free survival (PFS) and overall survival (OS).

Results

One thousand patients underwent F1CDx testing. Six hundred fifty-two patients were identified as having actionable mutations. Thirty-eight patients (18 males and 20 females) received targeted therapy and were included in the study. The most common alterations were PD-1/PDL-1, high-TMB, P13K, and HER2/ERBB2. Patients received various treatments including nivolumab, pembrolizumab, trastuzumab, and everolimus. Eight (23.5%) and six (17.7%) patients achieved partial response (PR) and stable disease (SD), respectively; 20 (58.8%) had progression of disease (PD). The disease control rate was 41.2% (95% CI: 24.7% to 59.3%). The median PFS was 2.7 months (95% CI: 2.3 to 5.4 months), and median OS was 9.9 months (95% CI: 4.5 to 33.7 months).

Conclusion

Our results demonstrate promising data in precision medicine in real community oncology practice. It warrants further large and prospective studies in patients with actionable alterations.
Immune-Related Multiple-Organs Injuries Following ICI Treatment With Tislelizumab in an Advanced Non-Small Cell Lung Cancer Patient: A Case Report
Authors: Deng Chao , Yang Meng , Jiang Hong , Wang Renbin , Yang Zhaojun , Sun Hongliang , Cui Huijuan
Published: September 2021

Immune-related adverse events (irAEs) following treatment with immune checkpoint inhibitors (ICIs) can affect almost any organ systems. Multiple-organs irAEs are a rare occurrence which makes its management and treatment very challenging. This is a case report of a 71-year-old man with advanced non-small cell lung cancer (NSCLC) who developed multiple-organs irAEs (lung, muscle, myocardium, liver, and pituitary) after a single cycle (21 days) of the BGB-A317 (Tislelizumab). After more than two months of immunosuppression treatment with glucocorticoids, the tumor and inflammatory lesions in the lung were reduced. The levels of serum creatase, cardiac troponin T (TNT), and hepatic transaminase were also reduced. Four months after the termination of ICI therapy, the lung tumor reappeared in the previous site. This rare case report supplies several experiences in the management of multiple-organs irAEs, including full-scale monitoring of immunological indicators, early differential diagnosis, and prompt glucocorticoid therapy. This patient was not a candidate for the ICI re-challenge therapy due to the number and seriousness of irAEs. Multiple-organs irAEs add complexity to the management, and additional research is needed to develop optimal therapeutic guidelines.
“High-Risk Breast Cancer Screening in BRCA1/2 Carriers Leads to Early Detection and Improved Survival After a Breast Cancer Diagnosis”
Authors: Shraga Shay , Grinshpun Albert , Zick Aviad , Kadouri Luna , Cohen Yogev , Maimon Ofra , Adler-Levy Yael , Zeltzer Galina , Granit Avital , Maly Bella , Carmon Einat , Meiner Vardiella , Sella Tamar , Hamburger Tamar , Peretz Tamar
Published: September 2021

Background

Germline BRCA1/2 pathogenic variant (PV) carriers have high lifetime risk of developing breast cancer and therefore subjected to intense lifetime screening. However, solid data on the effectiveness of high-risk screening of the BRCA1/2 carrier population is limited.

Patients and Methods

Retrospectively, we analyzed 346 women diagnosed with breast tumors. Patients were divided according to the timing of BRCA1/2 PVrecognition, before (BRCA-preDx awareness, N = 62) or after (BRCA-postDx awareness group, N = 284) cancer diagnosis.

Results

Median follow-up times were 131.42 and 93.77 months in the BRCA-preDx awareness and BRCA-postDx awareness groups, respectively. In the BRCA-preDx awareness group, 78.7% of the patients had invasive tumors and 21.3% were diagnosed with pure ductal carcinoma in situ. In contrast, in the BRCA-postDx awareness group over 93% of women were diagnosed with invasive cancer and only 6.4% had in situ disease. The mode of tumor detection differed significantly between the groups: 71.9% in the BRCA-postDx awareness group and 26.2% in the BRCA-preDx awareness group were diagnosed after personally palpating a lump. Tumor size and nodal involvement were significantly more favorable in the BRCA-preDx awareness group. T stage was significantly lower in the BRCA-preDx awareness group: 54.84% at T1 and 20.96% at Tis. In the BRCA-postDx awareness group, only 37.54% were at T1 and 6.49% at Tis. The N stage was also significantly lower in the BRCA-preDx awareness group: 71% had no lymph node metastases, compared with 56.1% in the BRCA-postDx awareness group. Additionally, therapeutic procedures varied between the groups: BRCA-preDx awareness group patients underwent more breast conserving surgeries. Axillary lymph node dissection was done in 38% of women in the BRCA-postDx awareness group and in only 8.7% of the BRCA-preDx awareness group patients. Interestingly, improved survival was found among patients who underwent high-risk screening (hazard ratio=0.34).

Conclusions

High-risk screening might facilitate downstaging of detected breast tumor among BRCA1/2 carrier population.
Proteomics Analysis Identified ASNS as a Novel Biomarker for Predicting Recurrence of Skull Base Chordoma
Authors: Shen Yutao , Li Mingxuan , Xiong Yujia , Gui Songbai , Bai Jiwei , Zhang Yazhuo , Li Chuzhong
Published: September 2021

Background

The prognostic factors of skull base chordoma associated with outcomes of patients after surgery remain inadequately identified. This study was designed to identify a novel prognostic factor for patients with skull base chordoma.

Method

Using a proteomic technique, the tumor biomarkers that were upregulated in the rapid-recurrence group of chordoma were screened and then narrowed down by bioinformatic analysis. Finally one potential biomarker was chosen for validation by immunohistochemistry using tissue microarray (TMA). A total of 187 patients included in TMA were randomly divided into two cohorts, the training cohort included 93 patients and the validation cohort included 94 patients. Kaplan-Meier survival analysis was used to assess the patients’ survival. Univariable and multivariable Cox regression analysis were used to identify prognostic factors predicting recurrence-free survival (RFS). CCK-8 assay, clonal formation assay and transwell assay were used to test the effect of asparagine synthetase (ASNS) on the proliferation, migration and invasion in chordoma cell lines.

Results

Among 146 upregulated proteins, ASNS was chosen as a potential prognostic biomarker after bioinformatics analysis. The H-scores of ASNS ranged from 106.27 to 239.58 in TMA. High expression of ASNS was correlated with shorter RFS in both the training cohort (p = 0.0093) and validation cohort (p < 0.001). Knockdown of ASNS by small interfering RNA (siRNA) inhibited the growth, colony formation, migration and invasion of chordoma cells in vitro.

Conclusion

This study indicates that high expression of ASNS is correlated with poor prognosis of patients with skull base chordoma. ASNS may be a useful prognostic factor for patients with skull base chordoma.
Prognostic Factors for Overall Survival in Nasopharyngeal Cancer and Implication for TNM Staging by UICC: A Systematic Review of the Literature
Authors: Chiang Chi Leung , Guo Qiaojuan , Ng Wai Tong , Lin Shaojun , Ma Tiffany Sze Wai , Xu Zhiyuan , Xiao Youping , Li Jishi , Lu Tianzhu , Choi Horace Cheuk Wai , Chen Wenqi , Chau Eric Sze Chun , Luk Peter Ho Yin , Huang Shao Hui , O’Sullivan Brian , Pan Jianji , Lee Anne Wing Mui
Published: September 2021

This study aims to identify prognostic factors in nasopharyngeal carcinoma (NPC) to improve the current 8th edition TNM classification. A systematic review of the literature reported between 2013 and 2019 in PubMed, Embase, and Scopus was conducted. Studies were included if (1) original clinical studies, (2) ≥50 NPC patients, and (3) analyses on the association between prognostic factors and overall survival. The data elements of eligible studies were abstracted and analyzed. A level of evidence was synthesized for each suggested change to the TNM staging and prognostic factors. Of 5,595 studies screened, 108 studies (44 studies on anatomical criteria and 64 on non-anatomical factors) were selected. Proposed changes/factors with strong evidence included the upstaging paranasal sinus to T4, defining parotid lymph node as N3, upstaging N-category based on presence of lymph node necrosis, as well as the incorporation of non-TNM factors including EBV-DNA level, primary gross tumor volume (GTV), nodal GTV, neutrophil-lymphocyte ratio, lactate dehydrogenase, C-reactive protein/albumin ratio, platelet count, SUVmax of the primary tumor, and total lesion glycolysis. This systematic review provides a useful summary of suggestions and prognostic factors that potentially improve the current staging system. Further validation studies are warranted to confirm their significance.
Comparative Effectiveness of Adjuvant Treatment for Resected Hepatocellular Carcinoma: A Systematic Review and Network Meta-Analysis
Authors: Liu Ying , Wang Yuzhu , Guo Xinkun , He Yifeng , Zhou Jian , Lv Qianzhou , Huang Xiaowu , Li Xiaoyu
Published: September 2021

Background

It is controversial whether adjuvant treatment could be recommended for hepatocellular carcinoma (HCC) after curative hepatectomy. Thus, we performed a network meta-analysis (NMA) to assess adjuvant treatment’s benefit and determine the optimal adjuvant regimen.

Methods

We systematically searched PubMed, Embase, and Cochrane Library for randomized controlled trials comparing adjuvant therapy versus no active treatment after curative hepatectomy among patients with HCC. Pooled data on recurrence and overall survival (OS) were analyzed within pairwise meta-analysis and NMA.

Results

Twenty-three eligible trials (3,940 patients) reporting eight treatments were included. The direct meta-analysis showed that adjuvant therapy prevented the recurrence (OR = 0.65; 95% CI: 0.55, 0.77; P = 0.177; I2 = 21.7%) and contributed to OS (HR = 0.63; 95% CI: 0.54, 0.73; P = 0.087; I2 = 31.1%) in comparison to the observation. In the NMA, internal radiotherapy (IRT; OR = 0.55; 95% CI: 0.39, 0.77; SUCRA = 87.7%) followed by hepatic artery infusion chemotherapy (HAIC; OR = 0.6; 95% CI: 0.36, 0.97; SUCRA = 77.8%), and HAIC (HR = 0.44; 95% CI: 0.21, 0.87; SUCRA = 82.6%) followed by IRT (HR 0.54; 95% CI:0.36, 0.81; SUCRA = 69.7%) were ranked superior to other treatments in terms of preventing recurrence and providing survival benefit, respectively.

Conclusions

The addition of adjuvant therapy lowers the risk of recurrence and provide survival benefit after surgical resection for HCC. HAIC and IRT are likely to be the two most effective adjuvant regimens.

Systematic Review Registration

https://inplasy.com/inplasy-2020-11-0039/.
Is D2 Lymphadenectomy Alone Suitable for Gastric Cancer With Bulky N2 and/or Para-Aortic Lymph Node Metastases After Preoperative Chemotherapy?
Authors: Xu Wei , Liu Wentao , Wang Lingquan , He Changyu , Lu Sheng , Ni Zhentian , Hua Zichen , Zhu Zhenglun , Sah Birendra Kumar , Yang Zhongyin , Zheng Yanan , Feng Runhua , Li Chen , Yao Xuexin , Chen Mingmin , Yan Chao , Yan Min , Zhu Zhenggang
Published: September 2021

Background

For gastric cancer (GC) with extensive lymph node metastasis (bulky N2 and/or para-aortic lymph node metastases), there is no standard therapy worldwide. In Japan, preoperative chemotherapy (PCT) followed by D2 gastrectomy plus para-aortic lymph node dissection (PAND) is considered the standard treatment for these patients. However, in China, the standard operation for GC patients with only bulky N2 metastases was D2 gastrectomy. Besides, after PCT, whether doing PAND improves survival or not is debatable for GC patients with para-aortic lymph node (PAN) metastases. Therefore, we conducted this study to investigate whether D2 lymphadenectomy alone is suitable for these patients after PCT.

Methods

We retrospectively collected data on patients from our electronic medical record system. GC patients with bulky N2 and/or PAN metastases who underwent D2 lymphadenectomy alone after PCT were enrolled. The survival outcomes and chemotherapy responses were analyzed and compared with the results of the JCOG0405 study.

Results

From May 2009 to December 2017, a total of 83 patients met all eligibility criteria and were enrolled. The median survival duration for all patients was 40.0 months. The 3-year and 5-year OS rates for all patients were 50.3% and 45.6%, respectively. For patients with only bulky N2 metastasis, the 3-year and 5-year OS rates were 77.1% and 71.6%, respectively, which were similar to the results of the JCOG0405 study (82.7% and 73.4%). For patients with only PAN metastases, the 3-year and 5-year OS rates were 50.0% and 50.0%, respectively, which seemed to be lower than those of the JCOG0405 study (64.3% and 57.1%). For patients with bulky N2 and PAN metastases, the 3-year and 5-year OS rates were 7.4% and 0.0%, respectively, which were lower than those of the JCOG0405 study (20.0% and 20.0%).

Conclusion

The results of our study suggest that D2 lymphadenectomy alone is suitable for GC patients with only bulky N2 metastasis after PCT. However, D2 lymphadenectomy alone perhaps is not suitable for patients with bulky N2 and PAN metastases after PCT.
Prognostic Value of Inflammatory Biomarkers in Patients With Stage I Lung Adenocarcinoma Treated With Surgical Dissection
Authors: Shen Yu-Jia , Qian Li-Qiang , Ding Zheng-Ping , Luo Qing-Quan , Zhao Heng , Xia Wu-Yan , Fu Yuan-Yuan , Feng Wen , Zhang Qin , Yu Wen , Cai Xu-Wei , Fu Xiao-Long
Published: September 2021

Objective

Inflammation plays a crucial role in tumorigenesis and progression. Our purpose was to investigate the prognostic value of neutrophil-to-lymphocyte ratio (NLR), systemic inflammation response index (SIRI) and systemic immune-inflammation index (SII), and develop a nomogram to predict the cancer-specific survival (CSS) and disease-free survival (DFS) of stage I lung adenocarcinoma patients.

Methods

1431 patients undergoing surgical resection with pathologically confirmed stage I lung adenocarcinoma were reviewed. The optimal cut-off values for NLR, SII, and SIRI were defined by the receiver operating characteristic (ROC) curve. Cox proportional hazards regression analyses were performed to recognize factors significantly correlated with CSS and DFS to construct the nomogram. The value of adjuvant chemotherapy on model-defined high-risk and low-risk patients was further explored.

Results

The cohort had a median follow-up time of 63 months. Multivariate analysis revealed that higher NLR (≥2.606), higher SIRI (≥0.705), higher SII (≥580.671), later T stage, histological pattern with solid or micropapillary components and radiologic features with solid nodules were significantly associated with worse CSS and DFS. The concordance index (C-index) of the nomogram established by all these factors was higher than that of the TNM staging system both in CSS (validation set 0.778 vs 0.652) and DFS (validation set 0.758 vs 0.695). Furthermore, the value of the established nomogram on risk stratification in stage I lung adenocarcinoma patients was validated.

Conclusions

Higher NLR, SII and SIRI pretreatment were associated with worse survival outcomes. A practical nomogram based on these three inflammatory biomarkers may help clinicians to precisely stratify stage I lung adenocarcinoma patients into high- and low-risk and implement individualized treatment.
Regulatory Mechanism and Experimental Verification of Patchouli Alcohol on Gastric Cancer Cell Based on Network Pharmacology
Authors: Song Yanru , Chang Liang , Wang Xiaoyuan , Tan Bibo , Li Jianbo , Zhang Jie , Zhang Fengbin , Zhao Lianmei , Liu Guangjie , Huo Bingjie
Published: September 2021

Background

Pogostemon cablin is a traditional Chinese medicine (TCM) that is frequently used to treat various gastrointestinal diseases. Patchouli alcohol (PA), a compound extracted from the Pogostemon cablin, has been shown to have anti-tumor efficacy in human colorectal cancer. However, the mechanism of PA’s anticancer effect on gastric cancer (GC) remains unknown.

Methods

We used the public database to obtain the potential targets of PA and genes related to GC. Bioinformatic analyses, such as the Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene Ontology (GO), and protein-protein interactions (PPI), were used for analyzing the potential signal pathways and targets. Cell experiments were also conducted to further explain the impact and molecular mechanism of PA on GC, as well as to confirm the findings of network pharmacology.

Results

Using network pharmacological analysis, 161 possible targets were identified for the treatment of GC. Network analysis and functional enrichment analysis show that PA produced a marked effect in the treatment of GC through multi-targets and multi-pathways, especially the MAPK and PI3K/AKT signal pathways. In addition, PA showed the inhibition of GC cell proliferation, migration and invasion in cell experiments. According to our findings, PA could also cause G0/G1 phase arrest and apoptosis in GC cells.

Conclusion

Using network pharmacology, we aim to uncover the possible molecular mechanism of PA on GC treatment in this research. Cell experiments were also conducted to confirm the therapeutic effect of PA on GC.
Activated Pancreatic Stellate Cells Enhance the Warburg Effect to Cause the Malignant Development in Chronic Pancreatitis
Authors: Tao Ye , Shao Feng , Cai Ming , Liu Zhen , Peng Yao , Huang Qiang , Meng Futao
Published: September 2021

Chronic pancreatitis (CP) is a precancerous condition associated with pancreatic ductal adenocarcinoma (PDAC), but its evolutionary mechanism is unclear. Pancreatic stellate cells (PSCs) are closely related to the occurrence and development of CP and PDAC, but it is not clear whether PSCs play a key role in this “inflammation-cancer transition”. Our research found that co-culture with activated PSCs promoted the proliferation, migration and invasion of normal pancreatic duct epithelial cells and pancreatic cancer cells. At the same time, activated PSCs had a significant effect on the expression of the glycolysis markers (pyruvate kinase M2, lactate dehydrogenase A, glucose transporter 1, hexokinase-II and monocarboxylate transporter 4; PKM2, LDHA, GLUT1, HK2 and MCT4) in normal pancreatic duct epithelial cells and pancreatic cancer cells and increased lactic acid production and glucose consumption in these two cells. In vivo experiments showed that the expression of the glycolysis markers in pancreatic duct epithelial cells and the marker protein (α-SMA) of activated PSCs in the pancreatic duct peripancreatic interstitium were higher in pancreatic cancer tissues and chronic pancreatitis tissues than in normal pancreatic tissues in both animals and humans. In addition, analysis of human tissue specimens showed that there is a correlation between the expression of glycolysis markers and α-SMA. These findings indicate that activated PSCs play an important role in the development and progression of chronic pancreatitis into pancreatic cancer by regulating and promoting aerobic glycolysis. Our research provides a new theoretical basis for further understanding the mechanism of CP malignancy and the selection of targets for reversing CP malignancy.
The Mechanism and Clinical Significance of Circular RNAs in Hepatocellular Carcinoma
Authors: Huang Ziyue , Xia Haoming , Liu Shuqiang , Zhao Xudong , He Risheng , Wang Zhongrui , Shi Wenguang , Chen Wangming , Kang Pengcheng , Su Zhilei , Cui Yunfu , Yam Judy Wai Ping , Xu Yi
Published: September 2021

Hepatocellular carcinoma (HCC) is one of the most prevalent malignant tumors worldwide. In view of the lack of early obvious clinical symptoms and related early diagnostic biomarkers with high specificity and sensitivity, most HCC patients are already at the advanced stages at the time of diagnosis, and most of them are accompanied by distant metastasis. Furthermore, the unsatisfactory effect of the follow-up palliative care contributes to the poor overall survival of HCC patients. Therefore, it is urgent to identify effective early diagnosis and prognostic biomarkers and to explore novel therapeutic approaches to improve the prognosis of HCC patients. Circular RNA (CircRNA), a class of plentiful, stable, and highly conserved ncRNA subgroup with the covalent closed loop, is dysregulated in HCC. Increasingly, emerging evidence have confirmed that dysregulated circRNAs can regulate gene expression at the transcriptional or post-transcriptional level, mediating various malignant biological behaviors of HCC cells, including proliferation, invasion, metastasis, immune escape, stemness, and drug resistance, etc.; meanwhile, they are regarded as potential biomarkers for early diagnosis and prognostic evaluation of HCC. This article reviews the research progress of circRNAs in HCC, expounding the potential molecular mechanisms of dysregulated circRNAs in the carcinogenesis and development of HCC, and discusses those application prospects in the diagnosis and prognosis of HCC.
Virtual Surgical Planning of Deep Circumflex Iliac Artery Flap for Midface Reconstruction
Authors: Kang Yi-Fan , Lv Xiao-Ming , Qiu Shi-Yu , Ding Meng-Kun , Xie Shang , Zhang Lei , Cai Zhi-Gang , Shan Xiao-Feng
Published: September 2021

Objective

Midface reconstruction is challenging for functional and esthetic reasons. The present study analyzed the effect of virtual surgical planning (VSP) of the deep circumflex iliac artery (DCIA) flap for midface reconstruction.

Patients and Methods

Thirty-four patients who underwent midface reconstruction with the DCIA flap were included in this retrospective study. Of the 34 patients, 16 underwent preoperative VSP, which used a three-dimensionally printed surgical guide, computer-assisted navigation system, and pre-bent titanium implants to transfer VSP into real-world surgery. The other 18 patients underwent traditional midface reconstruction. The following were compared between the two groups: bony contact rate in the buttress region (BCR), dental arch reconstruction rate (DAR), surgical approach, position of vascular anastomosis, and dental implantation rate. The independent-samples t-test and Fisher’s exact test were used for analysis. P < 0.05 was considered statistically significant.

Results

In total, 12 males and 22 females were included in this study. All patients underwent midface reconstruction using the DCIA flap at the same institution. The median age of patients was 33 years (range: 16–68 years). The average BCR and DAR values in the VSP group were 59.4% ± 27.9% and 87.5% ± 18.9%, respectively, which were significantly higher compared with the non-VSP group (P = 0.049 and P = 0.004, respectively). The dental implantation rate in the VSP group (50.0%) was significantly higher compared with the non-VSP group (11.1%; P = 0.023). The intraoral approach for tumor ablation and vascular anastomosis was the most frequent choice in both groups. There was no significant difference between the two groups. All patients were satisfied with facial symmetry postoperatively.

Conclusions

VSP could effectively augment the effect of midface reconstruction with the DCIA flap. Stronger bone contact in the buttress region and higher DAR provide more opportunity for dental implantation, which might be the best solution to improve masticatory function in patients with midface defects.
Therapeutically Targeting Cancers That Overexpress FOXC1: A Transcriptional Driver of Cell Plasticity, Partial EMT, and Cancer Metastasis
Authors: Ray Tania , Ryusaki Terry , Ray Partha S.
Published: September 2021

Metastasis accounts for more than 90% of cancer related mortality, thus the most pressing need in the field of oncology today is the ability to accurately predict future onset of metastatic disease, ideally at the time of initial diagnosis. As opposed to current practice, what would be desirable is that prognostic, biomarker-based detection of metastatic propensity and heightened risk of cancer recurrence be performed long before overt metastasis has set in. Without such timely information it will be impossible to formulate a rational therapeutic treatment plan to favorably alter the trajectory of disease progression. In order to help inform rational selection of targeted therapeutics, any recurrence/metastasis risk prediction strategy must occur with the paired identification of novel prognostic biomarkers and their underlying molecular regulatory mechanisms that help drive cancer recurrence/metastasis (i.e. recurrence biomarkers). Traditional clinical factors alone (such as TNM staging criteria) are no longer adequately prognostic for this purpose in the current molecular era. FOXC1 is a pivotal transcription factor that has been functionally implicated to drive cancer metastasis and has been demonstrated to be an independent predictor of heightened metastatic risk, at the time of initial diagnosis. In this review, we present our viewpoints on the master regulatory role that FOXC1 plays in mediating cancer stem cell traits that include cellular plasticity, partial EMT, treatment resistance, cancer invasion and cancer migration during cancer progression and metastasis. We also highlight potential therapeutic strategies to target cancers that are, or have evolved to become, “transcriptionally addicted” to FOXC1. The potential role of FOXC1 expression status in predicting the efficacy of these identified therapeutic approaches merits evaluation in clinical trials.
Development and Validation of an Mesenchymal-Related Long Non-Coding RNA Prognostic Model in Glioma
Authors: Huang Kebing , Yue Xiaoyu , Zheng Yinfei , Zhang Zhengwei , Cheng Meng , Li Lianxin , Chen Zhigang , Yang Zhihao , Bian Erbao , Zhao Bing
Published: September 2021

Glioma is well known as the most aggressive and prevalent primary malignant tumor in the central nervous system. Molecular subtypes and prognosis biomarkers remain a promising research area of gliomas. Notably, the aberrant expression of mesenchymal (MES) subtype related long non-coding RNAs (lncRNAs) is significantly associated with the prognosis of glioma patients. In this study, MES-related genes were obtained from The Cancer Genome Atlas (TCGA) and the Ivy Glioblastoma Atlas Project (Ivy GAP) data sets of glioma, and MES-related lncRNAs were acquired by performing co-expression analysis of these genes. Next, Cox regression analysis was used to establish a prognostic model, that integrated ten MES-related lncRNAs. Glioma patients in TCGA were divided into high-risk and low-risk groups based on the median risk score; compared with the low-risk groups, patients in the high-risk group had shorter survival times. Additionally, we measured the specificity and sensitivity of our model with the ROC curve. Univariate and multivariate Cox analyses showed that the prognostic model was an independent prognostic factor for glioma. To verify the predictive power of these candidate lncRNAs, the corresponding RNA-seq data were downloaded from the Chinese Glioma Genome Atlas (CGGA), and similar results were obtained. Next, we performed the immune cell infiltration profile of patients between two risk groups, and gene set enrichment analysis (GSEA) was performed to detect functional annotation. Finally, the protective factors DGCR10 and HAR1B, and risk factor SNHG18 were selected for functional verification. Knockdown of DGCR10 and HAR1B promoted, whereas knockdown of SNHG18 inhibited the migration and invasion of gliomas. Collectively, we successfully constructed a prognostic model based on a ten MES-related lncRNAs signature, which provides a novel target for predicting the prognosis for glioma patients.
A Phase II Trial of the Double Epigenetic Priming Regimen Including Chidamide and Decitabine for Relapsed/Refractory Acute Myeloid Leukemia
Authors: Yin Jia , Wan Chao-Ling , Zhang Ling , Zhang Hao , Bai Lian , Zhou Hai-Xia , Xu Ming-Zhu , Chen Li-Yun , Qian Chong-Sheng , Qiu Hui-Ying , Chen Su-Ning , Tang Xiao-Wen , Wu De-Pei , Zhang Yan-Ming , Sun Ai-Ning , Xue Sheng-Li
Published: September 2021

Objective

To explore the role of chidamide, decitabine plus priming regimen in the salvage treatment of relapsed/refractory acute myeloid leukemia.

Methods

A clinical trial was conducted in relapsed/refractory acute myeloid leukemia patients using chidamide, decitabine, cytarabine, idarubicin, and granulocyte-colony stimulating factor, termed CDIAG, a double epigenetic priming regimen.

Results

Thirty-five patients were recruited. Three patients received 2 treatment cycles. In 32 evaluable patients and 35 treatment courses, the completed remission rate (CRR) was 42.9%. The median OS time was 11.7 months. The median OS times of responders were 18.4 months, while those of nonresponders were 7.4 months (P = 0.015). The presence of RUNX1 mutations was associated with a high CRR but a short 2-year OS (P = 0.023) and PFS (P = 0.018) due to relapse after treatment. The presence of IDH mutations had no effect on the remission rate (80.0% vs. 73.3%), but showed a better OS (2-year OS rate: 100.0% vs. 28.9%). Grade 3/4 nonhematological adverse events included pneumonia, hematosepsis, febrile neutropenia, skin and soft tissue infection and others.

Conclusion

The double epigenetic priming regimen (CDIAG regimen) showed considerably good antileukemia activity in these patients. Adverse events were acceptable according to previous experience. The study was registered as a clinical trial.

Clinical Trial Registration

https://clinicaltrials.gov/, identifier:NCT03985007
Design, Synthesis, and Biological Evaluation of Benzo[cd]indol-2(1H)-ones Derivatives as a Lysosome-Targeted Anti-metastatic Agent
Authors: Li Jinghua , Chen Shuai , Zhao Yancong , Gong Huiyuan , Wang Tong , Ge Xiaoling , Wang Yuxia , Zhu Chenguang , Chen Liang , Dai Fujun , Xie Songqiang , Wang Chaojie , Luo Wen
Published: September 2021

Lysosomes have become a hot topic in tumor therapy; targeting the lysosome is therefore a promising strategy in cancer therapy. Based on our previous lysosome-targeted bio-imaging agent, homospermine-benzo[cd]indol-2(1H)-one conjugate (HBC), we further developed three novel series of polyamine- benzo[cd]indol-2(1H)-one conjugates. Among them, compound 15f showed potent inhibitory activity in hepatocellular carcinoma migration both in vitro and in vivo. Our study results showed that compound 15f entered the cancer cells via the polyamine transporter localized in the lysosomes and caused autophagy and apoptosis. The mechanism of action revealed that the crosstalk between autophagy and apoptosis induced by 15f was mutually reinforcing patterns. Besides, 15f also targeted lysosomes and exhibited stronger green fluorescence than HBC, which indicated its potential as an imaging agent. To summarize, compound 15f could be used as a valuable dual-functional lead compound for future development against liver-cancer metastasis and lysosome imaging.
The Age, Sex, and Geographical Distribution of Self-Reported Asthma Triggers on Children With Asthma in China
Authors: Zhang Changhao , Kong Yan , Shen Kunling
Published: September 2021

Background: Asthma can be exacerbated by many triggers, and the heterogeneity of asthma triggers is clear among children with asthma. This study describes asthma triggers using a large-scale electronic dataset from the smartphone-based Chinese Children's Asthma Action Plan (CCAAP) app and aims to examine the difference in asthma triggers among different subgroups of children with asthma.

Methods: Data from the smartphone-based CCAAP app between February 22, 2017, and November 23, 2020, were reviewed, and children with asthma who reported their asthma triggers were enrolled. Eight common asthma triggers were listed in the software: upper respiratory infection (URI), allergen sensitization, exercise, emotional disturbances, pungent odors, air pollution/smog, weather change, and tobacco smoke. We compared the incidence of asthma triggers among different subgroups (<6 years vs. 6–17 years; boy vs. girl; eastern region vs. central region vs. western region).

Results: We enrolled 6,835 patients with self-reported asthma triggers. When compared by sex, boys had a higher proportion of exercise-triggered asthma than girls (boys vs. girls, 22.5 vs. 19.7%, p < 0.05). The proportion of patients <6 years of age with URI-triggered asthma was higher than that of patients 6–17 years of age (<6 vs. 6–17 years, 80.9 vs. 74.9%, p < 0.001). Patients 6–17 years of age were more likely than patients <6 years of age to report five of the asthma triggers: allergen sensitization (<6 vs. 6–17 years, 26.6 vs. 35.8%, p < 0.001), exercise (<6 vs. 6–17 years, 19.3 vs. 23.7%, p < 0.001), pungent odors (<6 vs. 6–17 years, 8.8 vs. 12.7%, p < 0.001), air pollution/smog (<6 vs. 6–17 years, 9.4 vs. 16.2%, p < 0.001), and tobacco smoke (<6 vs. 6–17 years, 3.5 vs. 5.3%, p < 0.001). In subgroups based on geographical distribution, asthma triggering of allergen sensitization was reported to be the most common in patients from the eastern region (eastern region vs. central region vs. western region, 35.0 vs. 24.6 vs. 28.0%, p < 0.001). Exercise-triggered asthma was found to be the most prevalent among patients from the central region (eastern region vs. central region vs. western region, 21.6 vs. 24.8 vs. 20.4%, p < 0.05). However, the proportion of patients with air pollution/smog as an asthma trigger was the lowest among those from the western region (eastern region vs. central region vs. western region, 14.1 vs. 14.1 vs. 10.8%, p < 0.05).

Conclusion: Children with asthma present different types of asthma triggers, both allergenic and nonallergenic. Age, sex, and geographical distribution affect specific asthma triggers. Preventive measures can be implemented based on a patient's specific asthma trigger.
Automated Quantitative Stress Perfusion Cardiac Magnetic Resonance in Pediatric Patients
Authors: Scannell Cian M. , Hasaneen Hadeer , Greil Gerald , Hussain Tarique , Razavi Reza , Lee Jack , Pushparajah Kuberan , Duong Phuoc , Chiribiri Amedeo
Published: September 2021

Background: Myocardial ischemia occurs in pediatrics, as a result of both congenital and acquired heart diseases, and can lead to further adverse cardiac events if untreated. The aim of this work is to assess the feasibility of fully automated, high resolution, quantitative stress myocardial perfusion cardiac magnetic resonance (CMR) in a cohort of pediatric patients and to evaluate its agreement with the coronary anatomical status of the patients.

Methods: Fourteen pediatric patients, with 16 scans, who underwent dual-bolus stress perfusion CMR were retrospectively analyzed. All patients also had anatomical coronary assessment with either CMR, CT, or X-ray angiography. The perfusion CMR images were automatically processed and quantified using an analysis pipeline previously developed in adults.

Results: Automated perfusion quantification was successful in 15/16 cases. The coronary perfusion territories supplied by vessels affected by a medium/large aneurysm or stenosis (according to the AHA guidelines), induced by Kawasaki disease, an anomalous origin, or interarterial course had significantly reduced myocardial blood flow (MBF) (median (interquartile range), 1.26 (1.05, 1.67) ml/min/g) as compared to territories supplied by unaffected coronaries [2.57 (2.02, 2.69) ml/min/g, p < 0.001] and territories supplied by vessels with a small aneurysm [2.52 (2.45, 2.83) ml/min/g, p = 0.002].

Conclusion: Automatic CMR-derived MBF quantification is feasible in pediatric patients, and the technology could be potentially used for objective non-invasive assessment of ischemia in children with congenital and acquired heart diseases.
Bowel Preparation for Pediatric Colonoscopy
Authors: Mamula Petar , Nema Noor
Published: September 2021

Colonoscopy is an important diagnostic and therapeutic tool in evaluating and treating gastrointestinal tract pathologies. Adequate visualization of the intestinal lumen is necessary for detection of lesions, and thus bowel preparation is a key component of the process. It is estimated that over 25% percent of pediatric patients have sub-optimal bowel preparations, which can lead to longer procedure times, missed pathology, unsuccessful ileal intubation, and possibly repeat procedure/anesthesia. There is no universal protocol for bowel preparation in pediatrics and there is a wide variability of practices around the world. The purpose of this paper is to review the recent published literature regarding bowel preparations for pediatric colonoscopy with focus on published work in the last decade exploring a number of factors involved in bowel preparation including the role of patient education, types of bowel preparation, and their efficacy and safety.
Congenital Disorders of Glycosylation: What Clinicians Need to Know?
Authors: Lipiński Patryk , Tylki-Szymańska Anna
Published: September 2021

Congenital disorders of glycosylation (CDG) are a group of clinically heterogeneous disorders characterized by defects in the synthesis of glycans and their attachment to proteins and lipids. This manuscript aims to provide a classification of the clinical presentation, diagnostic methods, and treatment of CDG based on the literature review and our own experience (referral center in Poland). A diagnostic algorithm for CDG was also proposed. Isoelectric focusing (IEF) of serum transferrin (Tf) is still the method of choice for diagnosing N-glycosylation disorders associated with sialic acid deficiency. Nowadays, high-performance liquid chromatography, capillary zone electrophoresis, and mass spectrometry techniques are used, although they are not routinely available. Since next-generation sequencing became more widely available, an improvement in diagnostics has been observed, with more patients and novel CDG subtypes being reported. Early and accurate diagnosis of CDG is crucial for timely implementation of appropriate therapies and improving clinical outcomes. However, causative treatment is available only for few CDG types.
Trauma Scores and Their Prognostic Value for the Outcome Following Pediatric Polytrauma
Authors: Wendling-Keim Danielle S. , Hefele Anja , Muensterer Oliver , Lehner Markus
Published: September 2021

Purpose: The management and prognostic assessment of pediatric polytrauma patients can pose substantial challenges. Trauma scores developed for adults are not universally applicable in children. An accurate prediction of the severity of trauma and correct assessment of the necessity of surgical procedures are important for optimal treatment. Several trauma scores are currently available, but the advantages and drawbacks for use in pediatric patients are unclear. This study examines the value of the trauma scores Injury Severity Score (ISS), Pediatric Trauma Score (PTS), National Advisory Committee for Aeronautics (NACA), and Glasgow Coma Score (GCS) for the assessment of the polytraumatized child.

Methods: In a retrospective study, 97 patients aged 0–17 years who presented with polytrauma and an ISS ≥16 in the trauma bay were included in the study. Patient records including radiological studies were analyzed. Pathological imaging findings and emergency surgery were assessed as outcome variables and the predictive value of the trauma scores were analyzed using receiver operator characteristic (ROC) curves. Statistical significance was set at an alpha level of P ≤ 0.05.

Results: In this study, 35 of the 97 studied children had pathological cranial computed findings. These either underwent craniectomy or trepanation or a parenchymal catheter was placed for intracranial pressure monitoring. Abdominal trauma was present in 45 patients, 16 of which were treated surgically. Forty-three patients arrived with thoracic injuries, 10 of which received a thoracic drainage. One child underwent an emergency thoracotomy. Predictive accuracy for emergency surgery calculated using receiver-operator characteristic (ROC) curves was highest for ISS and NACA scores (0,732 and 0.683, respectively), and lower for GCS (0.246) and PTS (0.261).

Conclusion: In our study cohort, initial ISS and NACA scores better predicted operative interventions and outcome than PTS or GCS for polytraumatized pediatric patients.
Reduced Systolic Function and Not Genetic Variants Determine Outcome in Pediatric and Adult Left Ventricular Noncompaction Cardiomyopathy
Authors: Schultze-Berndt Alina , Kühnisch Jirko , Herbst Christopher , Seidel Franziska , Al-Wakeel-Marquard Nadya , Dartsch Josephine , Theisen Simon , Knirsch Walter , Jenni Rolf , Greutmann Matthias , Oechslin Erwin , Berger Felix , Klaassen Sabine
Published: September 2021

Background: Left ventricular noncompaction cardiomyopathy (LVNC CMP) is a genetic cardiomyopathy. Genotype-phenotype correlation and clinical outcome of genetic variants in pediatric and adult LVNC CMP patients are still unclear.

Methods: The retrospective multicenter study was conducted in unrelated index patients with LVNC CMP, diagnosed between the years 1987 and 2017, and all available family members. All index patients underwent next-generation sequencing for genetic variants in 174 target genes using the Illumina TruSight Cardio Sequencing Panel. Major adverse cardiac events (MACE) included mechanical circulatory support, heart transplantation, survivor of cardiac death, and/or all-cause death as combined endpoint.

Results: Study population included 149 LVNC CMP patients with a median age of 27.8 (9.2–44.8) years at diagnosis; 58% of them were symptomatic, 18% suffered from non-sustained and sustained arrhythmias, and 17% had an implantable cardioverter defibrillator (ICD) implanted. 55/137 patients (40%) were ≤ 18 years at diagnosis.

A total of 134 variants were identified in 87/113 (77%) index patients. 93 variants were classified as variant of unknown significance (VUS), 24 as likely pathogenic and 15 as pathogenic. The genetic yield of (likely) pathogenic variants was 35/113 (31%) index patients. Variants occurred most frequently in MYH7 (n=19), TTN (n = 10) and MYBPC3 (n = 8). Altogether, sarcomere gene variants constituted 42.5% (n = 57) of all variants. The presence or absence of (likely) pathogenic variants or variants in specific genes did not allow risk stratification for MACE.

Reduced left ventricular (LV) systolic function and increased left ventricular end-diastolic diameter (LVEDD) were risk factors for event-free survival in the Kaplan-Meier analysis. Through multivariate analysis we identified reduced LV systolic function as the main risk factor for MACE. Patients with reduced LV systolic function were at a 4.6-fold higher risk for MACE.

Conclusions: Genetic variants did not predict the risk of developing a MACE, neither in the pediatric nor in the adult cohort. Multivariate analysis emphasized reduced LV systolic function as the main independent factor that is elevating the risk for MACE. Genetic screening is useful for cascade screening to identify family members at risk for developing LVNC CMP.
Time of Onset of Necrotizing Enterocolitis and Focal Perforation in Preterm Infants: Impact on Clinical, Surgical, and Histological Features
Authors: Berrington Janet Elizabeth , Embleton Nicholas David
Published: September 2021

Objective: There is no gold standard test for diagnosis of necrotizing enterocolitis (NEC). Timing of onset is used in some definitions and studies in an attempt to separate NEC from focal intestinal perforation (FIP) with 14 days used as a cutoff. In a large, detailed data set we aimed to compare NEC and FIP in preterm infants born <32 weeks gestation, presenting before 14 days of life in comparison to cases presenting later.

Design: Infants with NEC or FIP when parents had consented to enrollment in an observational and sample collection study were included from 2009 to 2019. Clinical, surgical, histological, and outcome data were extracted and reviewed by each author independently.

Patients/Episodes: In 785 infants, 174 episodes of NEC or FIP were identified of which 73 (42%) occurred before 14 days, including 54 laparotomies and 19 episodes of medically managed NEC (“early”). There were 56 laparotomies and 45 episodes of medically managed NEC presenting on or after 14 days age (“late”).

Results: In early cases, 41% of laparotomies were for NEC (22 cases) and 59% for FIP (32 cases), and in late cases, 91% of laparotomies (51 cases) were for NEC and 9% (five cases) were for FIP. NEC presenting early was more likely to present with an initial septic presentation rather than discrete abdominal pathology and less likely to have clear pneumatosis. Early cases did not otherwise differ clinically, surgically, or histologically or in outcomes compared with later cases. FIP features did not differ by age at presentation.

Conclusions: Although most FIP occurred early, 14% occurred later, whereas almost one third (29%) of NEC cases (surgical and medical) presented early. Infant demographics and surgical and histological findings of early- and late-presenting disease did not differ, suggesting that early and late cases are not necessarily different subtypes of the same disease although a common pathway of different pathogenesis cannot be excluded. Timing of onset does not accurately distinguish NEC from FIP, and caution should be exercised in including timing of onset in diagnostic criteria.
Clinical Research in Neonates: Redesigning the Informed Consent Process in the Digital Era
Authors: De Sutter Evelien , Coopmans Birte , Vanendert Femke , Dooms Marc , Allegaert Karel , Borry Pascal , Huys Isabelle
Published: September 2021

Background: Currently, many initiatives are devoted to optimizing informed consent for participation in clinical research. Due to the digital transformation in health care, a shift toward electronic informed consent (eIC) has been fostered. However, empirical evidence on how to implement eIC in clinical research involving neonates is lacking.

Methods: Semi-structured interviews were conducted with 31 health care professionals active in Belgium or the Netherlands. All health care professionals had experience in conducting clinical research involving neonates. Interviews were audio-recorded, transcribed and analyzed using the framework method.

Results: Interviewees generally supported the use of eIC in clinical research involving neonates. For example, eIC could enable parents to receive study feedback via the eIC system. Requirements were expressed for parental involvement to decide on which feedback would be appropriate to return. Moreover, experts specialized in presenting information and designing electronic systems should be involved. Broad consensus among health care professionals indicates that the face-to-face-interaction between parents and the research team is vital to establish a relationship of trust. Therefore, it is necessary that the use of eIC runs alongside personal interactions with the parents. Concerns were raised about the accessibility of eIC to parents. For this reason, it was suggested that parents should always be given the possibility to read and sign a paper-based informed consent form or to use eIC.

Conclusions: Health care professionals' views indicate that the use of eIC in clinical research with neonates may offer various opportunities. Further development and implementation will require a multi-stakeholder approach.