The telovelar approach for fourth ventricular tumors in children: is removal of the posterior arch of C1 necessary?

PURPOSE: Various surgical nuances of the telovelar approach have been suggested. The necessity of removing the posterior arch of C1 to accomplish optimal tumor exposure is still debated. Therefore, we report on our experience and technical details of the fourth ventricular tumor resection in a modified prone position without systematic removal of the posterior arch of C1. METHODS: A retrospective analysis of all pediatric patients, who underwent a fourth ventricular tumor resection in the modified prone position between 2012 and 2021, was performed. RESULTS: We identified 40 patients with a median age of 6 years and a M:F ratio of 25:15. A telovelar approach was performed in all cases. In 39/40 patients, the posterior arch of C1 was not removed. In the remaining patient, the reason for removing C1 was tumor extension below the level of C2 with ventral extension. Gross or near total resection could be achieved in 34/39 patients, and subtotal resection in 5/39 patients. In none of the patients, a limited exposure, sight of view, or range of motion caused by the posterior arch of C1 was encountered, necessitating an unplanned removal of the posterior arch of C1. Importantly, in none of the cases, the surgeon had the impression of a limited sight of view to the most rostral parts of the fourth ventricle, which necessitated a vermian incision. CONCLUSION: A telovelar approach without the removal of the posterior arch of C1 allows for an optimal exposure of the fourth ventricle provided that critical nuances in patient positioning are considered.

Outcome of 107 conservatively managed unruptured brain arteriovenous malformations: a single center's 30-year experience.

OBJECTIVE: Since the publication of A Randomized Trial of Unruptured Brain AVMs (ARUBA), the management of unruptured brain arteriovenous malformations (bAVMs) has been controversially discussed. Long-term follow-up data on the exclusively conservative management of unruptured bAVMs are scarce. The authors evaluated the long-term outcomes of patients with unruptured untreated bAVMs in a real-life cohort. METHODS: A retrospective observational cohort of 107 patients (of 897 bAVM patients referred to the authors' institution) with a diagnosis of unruptured and conservatively managed bAVMs is presented. AVMs of all Spetzler-Martin grades were observed. The mean follow-up period was 84 months. In 44% of patients, a follow-up period of 5 years or longer was observed. A national death register comparison completed the outcome analysis. RESULTS: The median age at diagnosis, sex distribution, neurological presentation, and modified Rankin Scale score were comparable to the patients in the medical management arm of the ARUBA study. Patients were mainly young, predominantly male, and in good clinical condition. Similar to the ARUBA cohort, 77% of this study's cohort presented in an excellent clinical status at the time of last follow-up. However, 17% of patients had at least one hemorrhage, resulting in an overall annual hemorrhage risk of 2.7% in the observation period. Moreover, the cumulative 1-, 5-, and 10-year overall hemorrhage rates were 3.0%, 11.3%, and 15.3%, respectively. Consequently, the long-term follow-up AVM-related mortality rate amounted to 8%. The estimated median overall survival after AVM diagnosis was 19.3 years (95% CI 14.0-24.6 years). A multivariate Cox regression model revealed temporal and deep-seated localization as an independent risk factor for AVM hemorrhage, while the presence of seizures reached borderline significance as a risk factor. CONCLUSIONS: The authors' results represent the long-term course of unruptured untreated bAVMs. Their data support the conclusion that even in the post-ARUBA era, tailored active treatment options may be offered to patients with unruptured bAVMs. For patient counseling, individual risk factors should be weighed against the center's treatment-specific risks.

A novel MTX2 gene splice site variant resulting in exon skipping, causing the recently described mandibuloacral dysplasia progeroid syndrome.

Until recently, mandibuloacral dysplasia (MAD) with type A and type B lipodystrophy was the first to come to mind in the association of mandibular hypoplasia, lipodystrophy, and acro-osteolysis. However, it has recently been added to the differential diagnosis of MAD, a newly defined syndrome, called MDPS. MDPS is a skeletal dysplasia characterized by postnatal growth retardation, hypotonia, generalized lipodystrophy, skin changes, progeroid traits, and dysmorphic facial features, including prominent eyes, long pinched nose, mandibular hypoplasia, and a small mouth. Biallelic null variants of the MTX2 gene are responsible for this syndrome. We performed whole-exome sequencing (WES) in a 6-year-old patient with skeletal dysplasia. WES revealed a novel homozygous c.543+1G>T splice site variant in the MTX2 gene. We also extracted total RNA from peripheral blood and used reverse transcription-polymerase chain reaction to generate cDNA. Sanger sequencing from cDNA showed that exon 8 of MTX2 was skipped. This study adds to the genetics and phenotype of MDPS and underlines the importance of comprehensive clinical and molecular research.

EVs vs. EVs: MSCs and Tregs as a source of invisible possibilities.

Extracellular vesicles (EVs) are produced by various cells and exist in most biological fluids. They play an important role in cell-cell signaling, immune response, and tumor metastasis, and also have theranostic potential. They deliver many functional biomolecules, including DNA, microRNAs (miRNA), messenger RNA (mRNA), long non-coding RNA (lncRNA), lipids, and proteins, thus affecting different physiological processes in target cells. Decreased immunogenicity compared to liposomes or viral vectors and the ability to cross through physiological barriers such as the blood-brain barrier make them an attractive and innovative option as diagnostic biomarkers and therapeutic carriers. Here, we highlighted two types of cells that can produce functional EVs, namely, mesenchymal stem/stromal cells (MSCs) and regulatory T cells (Tregs), discussing MSC/Treg-derived EV-based therapies for some specific diseases including acute respiratory distress syndrome (ARDS), autoimmune diseases, and cancer.

Germline landscape of BRCAs by 7-site collaborations as a BRCA consortium in Turkey.

BRCA1/2 mutations play a significant role in cancer pathogenesis and predisposition particularly in breast, ovarian and prostate cancers. Thus, germline analysis of BRCA1 and BRCA2 is essential for clinical management strategies aiming at the identification of recurrent and novel mutations that could be used as a first screening approach. We analyzed germline variants of BRCA1/2 genes for 2168 individuals who had cancer diagnosis or high risk assessment due to BRCAs related cancers, referred to 10 health care centers distributed across 7 regions covering the Turkish landscape. Overall, 68 and 157 distinct mutations were identified in BRCA1 and BRCA2, respectively. Twenty-two novel variants were reported from both genes while BRCA2 showed higher mutational heterogeneity. We herein report the collective data as BRCA Turkish consortium that confirm the molecular heterogeneity in BRCAs among Turkish population, and also as the first study presenting the both geographical, demographical and gene based landscape of all recurrent and novel mutations which some might be a founder effect in comparison to global databases. This wider perspective leads to the most accurate variant interpretations which pave the way for the more precise and efficient management affecting the clinical and molecular aspects.

A teenager boy with a novel variant of Sitosterolemia presented with pancytopenia.

BACKGROUND: Sitosterolemia, also known as phytosterolemia, results from increased intestinal absorption of plant sterols and decreased intestinal and biliary excretion of sterols, resulting in increased levels of plant sterols in the plasma. The most common symptoms include xanthomas, premature atherosclerosis, hemolytic anemia and macrothrombocytopenia, however delayed diagnosis or misdiagnosis also occur. PATIENT AND METHODS: Clinical exome sequencing was performed on a 10-year-old boy whom we followed up with signs of pancytopenia accompanied by macrothrombocytopenia and stomatocytosis. In addition, the blood sterol levels of the patient and his family were studied. RESULTS: A novel homozygous c.904 + 5G > C intronic variant was detected in ABCG5 gene in index case. The mother and father were identified as carriers. The blood plant sterol levels of the patient and his family were studied, and the levels in the patient confirmed Sitosterolemia. Sitosterol levels decreased dramatically with restricted diet and ezetimibe treatment. CONCLUSION: In children, signs of Sitosterolemia may be subtle and the only symptom may be hematological. Therefore, Sitosterolemia should be kept in mind in children with stomatocytosis and macrothrombocytopenia.

The Effect of Gene Mutations on Metastasis and Overall Survival in Metastatic and Nonmetastatic Colon Cancers.

OBJECTIVE: It is known that many genes are associated with colon cancer. We aimed to investigate the effect of gene mutations on metastasis and overall survival in metastatic and non metastatic colon cancers. METHODS: A total of 50 patients with metastatic (n=25) and non metastatic (n=25) diagnosed with colon cancer between 2010 and 2018 were included in the study. APC, MUTYH, RAD50, MEN1, ATM, PALB2, NSH2, BRCA1, BRCA2, MLH1, BRIP1, TP53, PTEN, BARD1, MSH6, PMS2, NBN, and FAM175A gene mutations were evaluated using the next generation sequencing method. The effect of gene mutations on metastasis and overall survival were evaluated. RESULTS: The mean age of patients with colon cancer without distant metastasis was 48.64±14.72 years and for patients with distance metases was 56.68±11.65. The mean survival time of colon cancer patients with distant organ metastasis after the metastasis date was 104.36±58.59 weeks. The presence of APC, MUTYH, and TP53 genetic mutations was observed with a higher rate in metastatic colon cancer (p<0.05). CONCLUSION: We showed that APC, MUTYH, and TP53 mutations are associated with distant organ metastasis.

Refractory and Fatal Presentation of Severe Autoimmune Hemolytic Anemia in a Child With the DNASE1L3 Mutation Complicated With an Additional DOCK8 Variant.

Various autoimmune diseases may be associated with primary immune deficiencies. We reported a case with a loss-of-function mutation in DNASE1L3, a gene described previously in families with systemic lupus erythematosus. In addition, the patient showed a novel homozygous missense variant in DOCK8, a gene known to be responsible for the hyper-IgE recurrent infection syndrome (HIES). A 3-year-old girl born to consanguine parents presented with chronic urticarial rash, hemolytic anemia, pulmonary hemorrhage, and hypovolemic shock findings. She had a low hemoglobin level, a positive direct antiglobulin test, antinuclear antibody and anti-double stranded DNA, low C3 and C4, third-degree tricuspid regurgitation, and severe enlargement of the right ventricle on echocardiography, suggesting pulmonary embolism. Despite treatment with intravenous immunoglobulin, pulse metilprednisolone, rituximab, and supportive treatment for shock, the patient died on the seventh day. Whole-exome sequencing indicated a homozygous stop variant c.537G>A (p. Trp179Ter) in DNASE1L3. In addition, a possibly pathogenic homozygous missense variant in the HIES gene DOCK8 was detected. The occurrence of potentially clinically relevant, genetic variants in several genes posed various challenges with respect to diagnosis, treatment, and prognosis.

Effects of thymoquinone in prevention of experimental contrast-induced nephropathy in rats.

OBJECTIVES: This study aimed to show the effects of thymoquinone, which is known for its antioxidant, anti-inflammatory, and renal protective effects in contrast-induced nephropathy. MATERIALS AND METHODS: This is an experimental study in rats. 7 groups were included within the scope of our study: sham-vehicle (n=3), premedication-control (n=6), model (n=6), isolated thymoquinone (n=3+3), low-dose thymoquinone (n=6), and high-dose thymoquinone (n=7). In addition to 48 hr of water deprivation, we pre-medicated the rats with intra-peritoneal indomethacin and L-NAME administration. After premedication, 12.5 ml/kg dose of a high osmolar contrast agent-diatrizoat (Urografin %76) was administrated. Thymoquinone was administrated in two different doses of 1 mg/kg and 1.75 mg/kg for four days intraperitoneally. Renal functions, histopathological differences, oxidative stress parameters, and inflammatory indicators of rats were evaluated at the end of the study. RESULTS: Significant decreases were observed in levels of serum creatinine and serum BUN with low-dose thymoquinone (1 mg/kg) administration. In light microscopy, significantly less histopathological damage was observed in the low-dose thymoquinone group compared to the contrast agent group. While high-dose thymoquinone is accepted as ineffective biochemically, toxic evidence was identified histopathologically. There were no significant differences between M and TA groups for serum MDA and SOD levels, which were compared to evaluate oxidative stress (P:0.99, P:0.98; respectively). TNF-α, iNOS, and NF-кB gene expressions were not significantly different between all groups (P:0.748, P:0.531, P:0.910; respectively). CONCLUSION: This experimental study has demonstrated for the first time the protective effect of the TQ substance for CIN in 1 mg/kg dose, in the accompaniment of biochemical and histopathological data in rats.

Cadmium and lead bioaccumulation potentials of an aquatic macrophyte Ceratophyllum demersum L.: A laboratory study.

Cadmium (Cd) and lead (Pb) pollutions caused by industrial activities are one of the most serious threats to aquatic ecosystems. The aim of this study is to investigate the Cd and Pb bioaccumulations and diverse physiological and biochemical properties of Ceratophyllum demersum L. exposed to different concentrations of Cd (0.5-2.0mg/L) and Pb (25-100mg/L) in aqueous media for 1, 3 and 5 days. Cd and Pb accumulations increased with increase in the exposure times and concentrations, and the highest accumulation values of Cd and Pb were recorded at 2mg/L (2668.33mg/kg dw) and 100mg/L (22,504.10mg/kg dw), respectively, after 5 days. However, higher bioconcentration factors (BCF) were calculated as 645.43 at 25mg/L Pb and as 1357.92 at 1mg/L Cd after 5 days. The results showed that photosynthetic pigments (chlorophyll a, b and carotenoids) and protein contents of the plants exposed to Cd and Pb toxicities decreased with increasing metal concentration and exposure time, whereas their malondialdehyde (MDA) contents increased. Additionally, the single and synergistic effects of duration and metal concentration on the fresh and dry weights of the plant were determined. The results of this study reveal that C. demersum, propagated by tissue culture technique, can be used effectively in the phytoremediation of aquatic environments contaminated by Cd and Pb. This study will also make a positive contribution to the progression of new phytotechnologies on the purpose of the remediation of wastewater by plants in future.