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Background Tumor-Treating Fields (TTFields) is an emerging treatment modality for glioblastoma (GBM). Studies have shown a good safety profile alongside improved efficacy in newly diagnosed GBM (ndGBM), while a less clear effect was shown for recurrent GBM (rGBM). Despite regulatory support, sectors of the neuro-oncology community have been reluctant to accept it as part of the standard treatment protocol. To establish an objective understanding of TTFields' mechanism of action, safety, efficacy, and economical implications, we conducted a systematic literature review and meta-analysis. Methods A systematic search was conducted in PubMed, Scopus, and Cochrane databases. Twenty studies met the pre-defined inclusion criteria, incorporating 1,636 patients (542 ndGBM and 1,094 rGBM), and 11,558 patients (6,403 ndGBM and 5,155 rGBM) analyzed for the clinical outcomes and safety endpoints, respectively. Results This study demonstrated improved clinical efficacy and a good safety profile of TTFields. For ndGBM, pooled median OS and PFS were 21.7 (95%CI=19.6-23.8) and 7.2 (95%CI=6.1-8.2) months, respectively. For rGBM, pooled median OS and PFS were 10.3 (95%CI=8.3-12.8) and 5.7 (95%CI=2.8-10) months, respectively. Compliance of ≥75% was associated with an improved OS and the predominant adverse events were dermatologic, with a pooled prevalence of 38.4% (95%CI=32.3-44.9). Preclinical studies demonstrated TTFields' diverse molecular mechanism of action, its potential synergistic efficacy, and suggest possible benefits for certain populations. Conclusions This study supports the use of TTFields for GBM, alongside the standard-of-care treatment protocol and provides a practical summary, discussing the current clinical and pre-clinical aspects of the treatment and their implication on the disease course.

Multiple evidence support the prenatal predisposition of autism spectrum disorder (ASD). Nevertheless, robust data about abnormalities in fetuses later developing into children diagnosed with ASD are lacking. Prenatal ultrasound is an excellent tool to study abnormal fetal development as it frequently used to monitor fetal growth and identify fetal anomalies throughout pregnancy. We conducted a retrospective case-sibling-control study of children diagnosed with ASD (cases); their own typically developing, closest-in-age siblings (TDS); and typically developing children from the general population (TDP), matched by year of birth, sex and ethnicity to investigate the association between ultrasonography fetal anomalies (UFAs) and ASD. The case group was drawn from all children diagnosed with ASD enrolled at the Azrieli National Center of Autism and Neurodevelopment Research. Fetal ultrasound data from the fetal anatomy survey were obtained from prenatal ultrasound clinics of Clalit Health Services (CHS) in southern Israel. The study comprised 659 children: 229 ASD, 201 TDS, and 229 TDP. UFAs were found in 29.3% of ASD cases vs. only 15.9% and 9.6% in the TDS and TDP groups (aOR = 2.23, 95%CI = 1.32-3.78, and aOR = 3.50, 95%CI = 2.07-5.91, respectively). Multiple co-occurring UFAs were significantly more prevalent among ASD cases. UFAs in the urinary system, heart, and head&brain were the most significantly associated with ASD diagnosis (aORUrinary =2.08, 95%CI = 0.96-4.50 and aORUrinary = 2.90, 95%CI = 1.41-5.95; aORHeart = 3.72, 95%CI = 1.50-9.24 and aORHeart = 8.67, 95%CI = 2.62-28.63; and aORHead&Brain = 1.96, 95%CI = 0.72-5.30 and aORHead&Brain = 4.67, 95%CI = 1.34-16.24; vs. TDS and TDP, respectively). ASD females had significantly more UFAs than ASD males (43.1% vs. 25.3%, p = 0.013) and a higher prevalence of multiple co-occurring UFAs (15.7% vs. 4.5%, p = 0.011). No sex differences were seen among TDS and TDP controls. ASD fetuses were characterized by a narrower head and a relatively wider ocular-distance vs. TDP fetuses (ORBPD = 0.81, 95%CI = 0.70-0.94, and aOROcular-Distance = 1.29, 95%CI = 1.06-1.57). UFAs were associated with more severe ASD symptoms. Our findings shed important light on the abnormal multiorgan embryonic development of ASD and suggest fetal ultrasonography biomarkers for ASD.

In light of the development of RAS inhibitors, a reliable assessment of the prevalence of RAS mutations and their correlation with the clinical features of patients with HNC is crucially needed. This meta-analysis compiles the findings of 149 studies with over 8500 HNC patients and assesses the global prevalence of mutations in the HRAS, KRAS and NRAS genes. The available data were stratified according to geographical region, clinical features, and tumor characteristics, including human papillomavirus (HPV) infection status and tumor stage. In addition, the distribution of codon substitutions in each RAS gene was assessed. The estimated mutation rate is highest for HRAS (7%), followed by KRAS (2.89%) and NRAS (2.20%). HRAS prevalence in South Asia (15.28%) is twice as high as the global estimate. HRAS mutations are more prevalent in oral cavity and salivary gland tumors. In contrast, KRAS mutations are found more frequently in sinonasal tumors, and NRAS mutations are found chiefly in tumors of the nasopharynx. OR analyses show a significant association between HRAS mutations and a high tumor stage (OR=3.63). In addition, there is a significant association between HPV-positive status and KRAS mutations (OR=2.09). This study highlights RAS as a potential therapeutic target in certain subsets of HNC patients.

ImportanceThere is considerable variation among different studies for the prevalence of RAS mutations in head and neck cancer (HNC) patients. In light of the development of RAS inhibitors, a reliable assessment of the prevalence of RAS mutations and their correlation with the clinical features of patients with HNC is crucially needed.ObjectiveTo assess the worldwide prevalence of HRAS, KRAS, and NRAS mutations in HNC in the relation to geographical region, anatomical site(s) of the tumor(s) and clinical features.Data SourcesA systematic search of the PubMed, Embase, Web of Science, and Cochrane Central Register of Controlled Trials databases was performed to identify studies published since January 2000. Data were analyzed between June and September 2021.Study SelectionStudies that included mutational analyses of at least one of the target genes and reported the prevalence and frequency of mutations as an outcome measure were included. Studies including less than ten patients or were conducted before year 2000 were excluded.Data Extraction and SynthesisTwo researchers independently reviewed the literature according to Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guidelines. Random-effects models were applied to results with high heterogeneity. Otherwise, fixed-effects models were used for the analyses. Dichotomous variables were pooled as odds ratios (OR).Main Outcome(s) and Measure(s)The primary outcome was mutation prevalence. Secondary outcomes included the location of the mutated codon and amino acid substitution.ResultsThe estimated mutation rate is highest for HRAS (7%), followed by KRAS (2.89%) and NRAS (2.20%). HRAS prevalence in South Asia (15.28%) is twice as high as the global estimate. HRAS mutations are more prevalent in oral cavity and salivary gland tumors. In contrast, KRAS mutations are found more frequently in sinonasal tumors, and NRAS mutations are found chiefly in tumors of the nasopharynx. OR analyses show a significant association between HRAS mutations and a high tumor stage (OR=3.63). In addition, there is a significant association between HPV-positive status and KRAS mutations (OR=2.09).Conclusions and RelevanceRAS mutations occur in a subset of HNC patients and their prevalence varies according to geography, tumor’s anatomical site, stage, and HPV status. This meta-analysis provides support for their potential as viable therapeutic targets in HNC patients.Key PointsQuestionWhat is the prevalence of mutations in RAS genes in head and neck cancer (HNC) with respect to anatomical site, geographical region, and clinical features?FindingsThis meta-analysis compiles the findings of 149 studies with over 8500 HNC patients and assesses the global prevalence of mutations in the HRAS, KRAS and NRAS genes. The prevalence of RAS mutations varies between the seven major anatomical sites of HNC. The HRAS mutation rate in South Asia is double that in other geographical regions. Mutations in HRAS are associated with advanced disease, and mutations in KRAS are positively associated with HPV status.MeaningThis study presents the most comprehensive assessment of the prevalence of RAS mutations in HNC and their correlation with geographical regions and with clinical features.