Gastric cancer (GC) pathogenesis is complex and heterogeneous, reflecting morphological, molecular and genetic diversity. Diffuse gastric cancer (DGC) and intestinal gastric cancer (IGC) are the major histological types. GC may be sporadic or hereditary; sporadic GC is related to environmental and genetic low-risk factors and hereditary GC is caused by inherited high-risk mutations, so far identified only for the diffuse histotype. DGC phenotypic heterogeneity challenges the current understanding of molecular mechanisms underlying carcinogenesis. The definition of a DGC-specific mutational profile remains controversial, possibly reflecting the heterogeneity of DGC-related histological subtypes [signet-ring cell carcinoma (SRCC) and poorly cohesive carcinoma not otherwise specified (PCC-NOS)]. Indeed, DGC and DGC-related subtypes may present specific mutational profiles underlying the particularly aggressive behaviour and dismal prognosis of DGC vs IGC and PCC-NOS vs SRCC. In this systematic review, we revised the histological presentations, molecular classifications and approved therapies for gastric cancer, with a focus on DGC. We then analysed results from the most relevant studies, reporting mutational analysis data specifying mutational frequencies, and their relationship with DGC and IGC histological types, and with specific DGC subtypes (SRCC and PCC-NOS). We aimed at identifying histology-associated mutational profiles with an emphasis in DGC and its subtypes (DGC vs IGC; sporadic vs hereditary DGC; and SRCC vs PCC-NOS). We further used these mutational profiles to identify the most commonly affected molecular pathways and biological functions, and explored the clinical trials directed specifically to patients with DGC. This systematic analysis is expected to expose a DGC-specific molecular profile and shed light into potential targets for therapeutic intervention, which are currently missing.

Flavonoids, a broad class of polyphenolic compounds, can potentially have several therapeutic properties in human diseases, including protective effects against oxidative stress, inflammation, cardiovascular disease, diabetes, neurodegenerative disorders, and cancers. Luteolin as a member of flavonoids has been found to exhibit several anticancer properties mainly through cell apoptosis induction, inhibition of invasion, cell proliferation, network formation, and migration. Recent studies have revealed that phytochemicals such as luteolin may exert therapeutic properties through microRNAs (miRNAs or miRs), which have been emerged as important molecules in cancer biology in recent years. miRNAs, as a class of noncoding RNAs, have several important roles in cancer progression or regression. In this review, we aimed to summarize and discuss the role of miRNAs in the luteolin effects on different cancers. This review can be in line with the studies, which have shown that miRNAs may be potential therapeutic targets in cancer treatment.

Tuberous sclerosis complex (TSC) is a multisystem genetic disorder associated with refractory early-onset epilepsy. Current evidence supports surgery as the intervention most likely to achieve long-term seizure freedom, but no specific guidelines are available on TSC pre-surgical workup. This critical review assesses which TSC patients are suitable for surgical treatment, when pre-surgical evaluation should start, and what degree of surgical resection is optimal for postsurgical outcome. We searched for publications from 2000 to 2020 in Pubmed and Embase using the terms "tuberous sclerosis," "epilepsy," and "epilepsy surgery". To evaluate postsurgical seizure outcome, we selected only studies with at least one year of follow-up. Overall, we collected data on 1,026 patients from 34 studies. Age at surgery ranged from one month to 54 years. Mean age at surgery was 8.41 years. Of the diagnostic non-invasive pre-surgical tools, MRI and video-EEG were considered most appropriate. Promising data for epileptogenic tuber detection is provided from invasive SEEG studies. Data on surgery and related outcome were available for 769 patients. Seizure freedom was seen in 64.4% of patients who underwent tuberectomy, 68.9% treated with lobectomy and 65.1% with multilobar resection. The most effective surgical approach was lobectomy, even though more recently tuberectomy associated with the resection of the perituberal area seems to be the best approach to reach seizure freedom. Published postsurgical seizure freedom rates in patients with TSC were between 65% and 75%, but reduced to 48%-57% over longer follow-up periods. Early surgery might positively affect neurodevelopmental trajectory in some patients, even though data on cognitive outcome are still to be confirmed with longitudinal studies. Considering the strong correlation between epilepsy duration and neurocognitive outcome, all patients with TSC ought to be referred early to a dedicated epilepsy centre for individually tailored pre-surgical evaluation by a multi-disciplinary epilepsy surgery team.

Aim: Long noncoding RNA (lncRNA) noncoding RNA activated by DNA damage (NORAD) is widely investigated in different tumors. Our meta-analysis intends to assess the prognostic and clinicopathological value of NORAD in cancers. Materials & methods: We searched PubMed, Web of Science, Embase and Chinese National Knowledge Infrastructure from inception to 1 August 2020. Results: The results showed that higher expression of NORAD had a significant association with worse overall survival. Additionally, correlations were detected between elevated level of NORAD and poor differentiation degree, positive lymph node metastasis and large tumor size in cancer patients. Conclusion: LncRNA NORAD can serve as a novel and promising biomarker for prognosis and clinicopathological characteristics in different cancers.

Mucosal melanoma is a rare subtype of melanoma. To date, there has been no comprehensive systematic collation and statistical analysis of the aberrations and aggregated frequency of driver events across multiple studies. Published studies using whole genome, whole exome, targeted gene panel, or individual gene sequencing were identified. Datasets from these studies were collated to summarize mutations, structural variants, and regions of copy-number alteration. Studies using next-generation sequencing were divided into the "main" cohort (n = 173; fresh-frozen samples), "validation" cohort (n = 48; formalin-fixed, paraffin-embedded samples) and a second "validation" cohort comprised 104 tumors sequenced using a targeted panel. Studies assessing mutations in BRAF, KIT, and NRAS were summarized to assess hotspot mutations. Statistical analysis of the main cohort variant data revealed KIT, NF1, BRAF, NRAS, SF3B1, and SPRED1 as significantly mutated genes. ATRX and SF3B1 mutations occurred more commonly in lower anatomy melanomas and CTNNB1 in the upper anatomy. NF1, PTEN, CDKN2A, SPRED1, ATM, CHEK2, and ARID1B were commonly affected by chromosomal copy loss, while TERT, KIT, BRAF, YAP1, CDK4, CCND1, GAB2, MDM2, SKP2, and MITF were commonly amplified. Further notable genomic alterations occurring at lower frequencies indicated commonality of signaling networks in tumorigenesis, including MAPK, PI3K, Notch, Wnt/β-catenin, cell cycle, DNA repair, and telomere maintenance pathways. This analysis identified genomic aberrations that provide some insight to the way in which specific pathways may be disrupted. IMPLICATIONS: Our analysis has shown that mucosal melanomas have a diverse range of genomic alterations in several biological pathways. VISUAL OVERVIEW: http://mcr.aacrjournals.org/content/molcanres/19/6/991/F1.large.jpg.

Understanding molecular pathogenesis of head and neck squamous cell carcinomas (HNSCC) has considerably improved in the last decades. As a result, novel therapeutic strategies have evolved, amongst which are epidermal growth factor receptor (EGFR)-targeted therapies. With the exception of cetuximab, targeted therapies for HNSCC have not yet been introduced into clinical practice. One important aspect of new treatment regimes in clinical practice is presence of robust biomarkers predictive for therapy response.

The burden of epidermal growth factor receptor (EGFR) exon 20 insertion mutation (Exon 20ins) in non-small cell lung cancer is not well understood. A systematic review was conducted to identify evidence on mutation frequency, prognostic impact, clinical, patient-reported, and economic outcomes associated with Exon 20ins.

The clinical relevance of telomerase subunits (human reverse transcriptase - hTERT, and human telomerase RNA - hTR) and TERT promotor mutations as biomarkers in genitourinary cancers was reviewed through the systematic analysis of the current literature. We performed a systematic literature search using 2 databases (Medline and Scopus) over the past 20 years. Primary outcomes were sensitivity and specificity of hTR, hTERT and TERT promoter mutations. Secondary outcomes were the biomarkers predictive values for tumor characteristics. Regarding bladder cancer, hTERT in urine showed high sensitivity (mean values: 55%-96%), and specificity (69%-100%): it correlated with bladder cancer grade and/or stage. hTR sensitivity ranged from 77% to 92%. With adapted cut-off, it demonstrated 72% to 89% specificity. TERT promoter mutation rate was up to 80% both in tissue and urine, resulting in 62%-92% sensitivity for primary tumors and 42% for relapse. Specificity ranged from 73% to 96%, no correlations with stage were observed. In prostate cancer, hTERT in tissue, prostate secretion and serum showed high sensitivity (97.9%, 36%, and 79.2%-97.5%, respectively) and specificity values (70%, 66%, 60%-100%). hTR showed very high sensitivity (88% in serum and 100% in tissue) although specificity values were highly variable depending on the series and techniques (0%-96.5%). In RCC, hTERT sensitivity on tissue ranged from 90 to 97%, specificity from 25 to 58%. There was an association of hTERT expression with tumor stage and grade. hTERT showed high accuracy in genitourinary cancers, while the value of hTR was more controversial. hTERT and TERT promotor mutations may have predictive value for bladder cancer and RCC staging and grading, while no such relationship was observed in CaP. Although telomerase subunits showed clinically relevant values in genitourinary cancers, developing fast and cost-effective methods is required before contemplating routine use.

A systematic review (SR) and meta-analysis were conducted to determine the prevalence of PI3K-AKT-mTOR signaling pathway mutations in patients with head and neck cancer (HNC). Overall, 105 studies comprising 8630 patients and 1306 mutations were selected. The estimated mutations prevalence was 13 % for PIK3CA (95 % confidence interval [CI] = 11-14; I2 = 82 %; p < 0.0001), 4% for PTEN (95 % CI = 3-5; I2 = 55 %; p < 0.0001), 3% for MTOR (95 % CI = 2-4; I2 = 5%; p = 0.40), and 2% for AKT (95 % CI = 1-2; I2 = 50 %; p = 0.0001). We further stratified the available data of the participants according to risk factors and tumor characteristics, including HPV infection, tobacco use, alcohol exposure, TNM stage, and histological tumor differentiation, and performed subgroup analysis. We identified significant associations between PI3K-AKT-mTOR pathway-associated mutations and advanced TNM stage (odds ratio [OR] = 0.20; 95 % CI = 0.09-0.44; I² = 71 %; p = 0.0001) and oropharyngeal HPV-positive tumors and PIK3CA mutations (OR = 17.48; 95 % CI = 4.20-72.76; I² = 69 %; p < 0.0002). No associations were found between alcohol and tobacco exposure, and tumor differentiation grade. This SR demonstrated that the PI3K-AKT-mTOR pathway emerges as a potential prognostic factor and could offer a molecular basis for future studies on therapeutic targeting in HNC patients.

We conducted a systematic review and meta-analysis of the association between somatic mutations of the TERT gene promoter and melanoma survival. Data from nineteen independent studies (>2,500 melanoma overall) were pooled using random effects meta-analysis models. TERT-mutated melanoma patients had a significantly worse overall survival (OS) (summary hazard ratio 1.43, 95 % confidence intervals (CI) 1.05-1.95) compared to wild-type ones. The association became stronger when combining risk estimates for overall and melanoma-specific survival (MSS) (1.52, 95 % CI 1.14-2.02), and when restricting the analysis to studies mostly based on invasive non-acral cutaneous melanomas (1.77, 95 % CI 1.00-3.15). Limited, yet suggestive evidence of a detrimental effect of TERT promoter mutations on melanoma prognosis emerged also for other survival measures (e.g. disease-free and distant metastasis-free survival). We found suggestive evidence of a detrimental effect of TERT mutations on melanoma patients' survival.

Different levels of miRNA expression have been described in salivary gland tumors as a potential diagnostic marker and predictor of survival. We systematically reviewed the literature to assess the diagnostic and prognostic value of miRNAs on salivary gland tumors.

Many studies have shown that IKAROS family zinc finger 1 (IKZF1) rs4132601 polymorphism is strongly linked to acute lymphoblastic leukemia (ALL) in children, but their conclusions have been inconsistent.

Osteosarcoma (OS) is the most common type of primary malignant bone tumor, The effect of tumor microenvironment components on OS oncogenesis remains unknown.

Composite phaeochromocytoma is a tumour containing a separate tumour of neuronal origin in addition to a chromaffin cell tumour. This study reports on two cases from a single centre's records and presents a systematic literature review of composite phaeochromocytomas.

A number of studies have linked positive Ki-67 expression with the prognosis of osteosarcoma (OS) patients. However, the results have been conflicting. To address this controversy, we conducted an analysis using a meta-analysis and a TCGA dataset to estimate the value of Ki-67 expression in the prognosis of OS.

MicroRNA (miRNA) is a form of short, single-stranded and non-coding RNA that is important in regulating the post-transcriptional modification of multiple downstream targets. Many miRNAs have been reported to involve in controlling the progression of human diseases, and one of them is miR-638, which play essential roles in regulating the development of human cancer. By targeting the 3'-ends of its targets, miR-638 can regulate cellular processes including proliferation, invasion, metastases, angiogenesis, apoptosis and inflammation. This review was aimed to summarize current findings on the roles of miR-638 in different human cancers based on the results from various in vitro, in vivo and clinical studies. The biogenesis process and tissue expression, followed by the roles of miR-638 in regulating the development of various human cancers by targeting different downstream targets were covered in this review. The potential applications and challenges of employing miR-638 as cancer biomarker and therapeutic agent were also discussed.

A recurrence score based on a 21-gene expression assay predicts the benefit of adjuvant chemotherapy in oestrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer. This systematic review aimed to determine whether the 21-gene expression assay performed on core biopsy at diagnosis predicted pathological complete response (pCR) to neoadjuvant chemotherapy.

Circular RNAs are a class of RNAs with a covalently closed configuration, and several members of them have been reported to be capable of regulating various biological processes and predicting the outcome of disease. Among them, circular RNA circ-ITCH has been identified to be aberrantly expressed and associated with disease progression in diverse cancers. However, the correlation of circ-ITCH expression with clinicopathological features, as well as the prognosis of cancers, remains inconclusive. Therefore, a meta-analysis was performed to investigate the clinical significance of circ-ITCH in cancers by systematically summarizing all eligible literatures. Up to August 31, 2020, relevant articles were searched in PubMed, Web of Science, Cochrane library, Embase, CNKI, and Wanfang databases. Pooled hazard ratios (HRs) and odds ratios (ORs) with corresponding 95% confidence intervals (CIs) were calculated. A total of 1604 patients from 14 studies were included in this meta-analysis. The results showed that cancer patients with low circ-ITCH expression were more susceptible to develop lymph node metastasis (OR = 2.25, 95% CI: 1.67-3.02, p ≤ 0.01), larger tumor size (OR = 3.01, 95% CI: 2.01-4.52, p ≤ 0.01), advanced TNM stage (OR = 2.82, 95% CI: 1.92-4.14, p ≤ 0.01), and poor overall survival (OS) (HR = 2.45, 95% CI: 2.07-2.90, p ≤ 0.01, univariate analysis; HR = 2.69, 95% CI: 1.82-3.96, p ≤ 0.01, multivariate analysis). Thus, low circ-ITCH expression was significantly associated with aggressive clinicopathological features and unfavorable outcome in various cancers. Therefore, circ-ITCH may serve as a molecular therapy target and a prognostic marker in human cancers.

The abnormal regulation of alternative splicing is usually accompanied by the occurrence and development of tumors, which would produce multiple different isoforms and diversify protein expression. The aim of the present study was to conduct a systematic review in order to describe the regulatory mechanisms of alternative splicing, as well as its functions in tumor cells, from proliferation and apoptosis to invasion and metastasis, and from angiogenesis to metabolism. The abnormal splicing events contributed to tumor progression as oncogenic drivers and/or bystander factors. The alterations in splicing factors detected in tumors and other mis-splicing events (i.e., long non-coding and circular RNAs) in tumorigenesis were also included. The findings of recent therapeutic approaches targeting splicing catalysis and splicing regulatory proteins to modulate pathogenically spliced events (including tumor-specific neo-antigens for cancer immunotherapy) were introduced. The emerging RNA-based strategies for the treatment of cancer with abnormally alternative splicing isoforms were also discussed. However, further studies are still required to address the association between alternative splicing and cancer in more detail.

In recent years, tremendous research efforts have been focused on investigating the effect of dysregulation of lncRNAs on cancer progression, most of which confirm a positive link. This inspired us to conduct the present meta-analysis to explore whether aberrant expression of multiple lncRNAs has a role in patients' outcome in ovarian cancer. This comprehensive meta-analysis pertains to the evaluation of association between dysregulated lncRNAs expression level with eventual outcome and clinicopathological characteristics of ovarian cancer patients. We systematically searched PubMed, Web of Science, and Scopus to find all eligible articles. Pooled hazard ratios (HRs) and 95% confidence intervals (95% CIs) for overall survival, disease-free survival and progression-free survival were measured with a fixed or random effects model. A total of 34 studies were included in the meta-analysis. Dysregulation of lncRNAs were contributed to shorter overall survival (34 studies, 1180 patients HR = 2.12, 95% CI: 1.73 ± 2.60, random-effects) in ovarian cancer. Furthermore, altered lncRNAs were also related to decreased progression-free survival (8 studies, 1180 patients HR: 1.88, 95% CI: (1.35-2.62) and disease-free survival (2 studies, 285 patients, HR: 6.07, 95% CI: 1.28-28.78) in this disease. Our analyses supported the robust prognostic significance of altered lncRNAs in ovarian cancer. However, more extended studies are encouraged to evaluate the clinical application potential of these lncRNAs in the prognosis evaluation of ovarian cancer.